WO2005087700A2 - Bisphenyl compounds useful as vitamin d3 receptor agonists - Google Patents

Bisphenyl compounds useful as vitamin d3 receptor agonists Download PDF

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Publication number
WO2005087700A2
WO2005087700A2 PCT/US2005/007747 US2005007747W WO2005087700A2 WO 2005087700 A2 WO2005087700 A2 WO 2005087700A2 US 2005007747 W US2005007747 W US 2005007747W WO 2005087700 A2 WO2005087700 A2 WO 2005087700A2
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WIPO (PCT)
Prior art keywords
methyl
ethyl
phenyl
hydroxy
propyl
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PCT/US2005/007747
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French (fr)
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WO2005087700A3 (en
Inventor
David Wallace
Thomas Arrhenius
Anna Russell
Dingguo Liu
Amy Xing
Sovouthy Tith
Zheng Hou
Tadakatsu Takahashi
Yoshiyuki Ono
Hirotaka Kashiwagi
Kazuki Shimizu
Hitoshi Ikura
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Chugai Seiyaku Kabushiki Kaisha
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Application filed by Chugai Seiyaku Kabushiki Kaisha filed Critical Chugai Seiyaku Kabushiki Kaisha
Priority to EP05727224A priority Critical patent/EP1740522A2/en
Publication of WO2005087700A2 publication Critical patent/WO2005087700A2/en
Publication of WO2005087700A3 publication Critical patent/WO2005087700A3/en

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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/20—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hydrogen atoms and substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D309/22—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
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    • C07C2601/14—The ring being saturated

Definitions

  • 1 ⁇ ,25-Dihydroxyvitamin D3 has various physiological activities and is widely used as various pharmaceuticals.
  • the pharmaceutical agent containing 1 ⁇ ,25-Dihydroxyvitamin D3 as active ingredient marketed as ROCALTROL (TM) and used for the treatment of psoriasis and secondary hyperparathyroidism.
  • ROCALTROL TM
  • 1 ⁇ ,25-Dihydroxyvitamin D3 has a serious side effect elevating serum calcium level and sometimes it leads to hypercalcemia.
  • the present invention relates to bisphenyl compounds useful as modulators of the vitamin D receptor activity or their synthetic intermediates, represented by formula I:
  • X is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene, an ethynylene, -S(0)n-, -NH-, or -0-; n is an integer of 0 to 2; Y is COOR8, CON(R9)R10, S(0)mR11 or a substituent represented by following formula: R8 and R11 are each independently selected from an optionally substituted C1-10 alkyl group or an optionally substituted C3-10 cycloalkyl group; R9 and R10 are each independently selected from a hydrogen atom, an optionally substituted C1-10 alkyl group or an optionally substituted C3-10 cycloalkyl group; m is an integer of 0 to 2; a is an integer of 0 to 3; R is a hydrogen atom or a protecting group for a hydroxyl group; R12 and R13 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-10 alkyl group
  • R15 and R16 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C6-
  • R17 is selected from an optionally substituted C1-6 alkyl group or an optionally substituted C3-C6 cycloalkyl group;
  • R18 and R19 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C6 cycloalkyl group, or R18 and R19 may together form an optionally substituted C3-C12 cycloalkyl group or an optionally substituted 3-12 membered heterocyclic group; or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and
  • R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered cyclic ring which is selected from the group consisting of an amidine ring, an amine ring, an ether ring, a lactam ring, a lactone ring, an acetal ring, a hemiacetal ring, a carbonate ring, a carbamate ring, an urea ring, combinations thereof;
  • R1 and R2 are each independently selected from the group consisting of a C1-6 alkyl group optionally substituted with a halogen atom(s), a C3-6 cycloalkyl group optionally substituted with a halogen atom(s), a C2-6 alkenyl group optionally substituted with a halogen atom(s), a C2-6 alkynyl group optionally substituted with a halogen atom(s), or R1 and R2 may together form a C3-8 cycloalkyl
  • Optionally substituted or "which may be substituted” means that the compounds of the present invention can optionally have one or more substituent(s) in that position. In the case having two or more substituents, each substituents can be same or different.
  • a "halogen atom” according to the invention is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • a "C1-10 alkyl group” is a linear or branched alkyl group of 1 to 10 carbons, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, an isohexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group or the like.
  • a “C1-6 alkyl group” is a linear or branched alkyl group of 1 to 6 carbons, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec- butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, an isohexyl group or the like.
  • a “C1-4 alkyl group” according to the invention is a linear or branched alkyl group of 1 to 3 carbons, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec- butyl group, a tert-butyl group or the like.
  • a “C1-3 alkyl group” according to the invention is a linear or branched alkyl group of 1 to 3 carbons, such as a methyl group, an ethyl group, a propyl group, an isopropyl group or the like.
  • a "C3-12 cycloalkyl group” is a cyclic saturated hydrocarbon group of 3 to 12 carbons, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, a cycloundecyl group, a cyclododecyl group or the like.
  • a "C3-10 cycloalkyl group” is a cyclic saturated hydrocarbon group of 3 to 10 carbons, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group or the like.
  • a “C3-8 cycloalkyl group” according to the invention is a cyclic saturated hydrocarbon group of 3 to 8 carbons, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group or the like.
  • a “C3-6 cycloalkyl group” according to the invention is a cyclic saturated hydrocarbon group of 3 to 6 carbons, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or the like.
  • a "C2-10 alkenyl group” is a linear, branched or cyclic alkenyl group of 2 to 10 carbons, such as a vinyl group, an allyl group, an isopropenyl group, a 2-butenyl group, a 3-butenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, a 1-cyclopentenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, a 5-hexenyl group, a 1 -cyclohexenyl group or the like.
  • a "C2-6 alkenyl group” is a linear, branched or cyclic alkenyl group of 2 to 6 carbons, such as a vinyl group, an allyl group, an isopropenyl group, a 2-butenyl group, a 3-butenyl group, a 2- pentenyl group, a 3-pentenyl group, a 4-pentenyl group, a 1-cyclopentenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, a 5-hexenyl group, a 1 -cyclohexenyl group or the like.
  • a "C3-8 cycloalkenyl group” according to the invention is a cyclic alkenyl group of 3 to 8 carbons, such as a 1-cyclopentenyl group, a 1- cyclohexenyl group, 2-cyclohexenyl group or the like.
  • a “C2-10 alkynyl group” is a linear or branched alkynyl group of 2 to 10 carbons, such as an ethynyl group, a 2- propynyl group, a 2-butynyl group, a 3-butynyl group, a 2-pentynyl group, a 3-pentynyl group, a 4-pentynyl group, a 2-hexynyl group, a 3-hexynyl group, a 4-hexynyl group, a 5-hexynyl group or the like.
  • a “C2-6 alkynyl group” is a linear or branched alkynyl group of 2 to 6 carbons, such as an ethynyl group, a 2- propynyl group, a 2-butynyl group, a 3-butynyl group, a 2-pentynyl group, a 3-pentynyl group, a 4-pentynyl group, a 2-hexynyl group, a 3-hexynyl group, a 4-hexynyl group, a 5-hexynyl group or the like.
  • a “C6-12 aryl group” according to the invention is an aryl group of 6 to 12 carbons, such as a phenyl group, a naphthyl group or the like.
  • a “(C6-12)aryl-(C1-4)alkyl group” according to the invention is an alkyl group of 1 to 4 carbons with an aryl group of 6 to 12 carbons, such as a benzyl group, a phenethyl group, a 3-phenyl-propyl group, a 4-phenyl-butyl group, a naphthalen-1-yl-methyl group, a naphthalen-2-yl-methyl group or the like.
  • a "3-12 membered heterocyclic group" is a mono- and polycyclic group having 3 to 12 membered ring(s) wherein the ring(s) contains at least one heteroatom. Suitable heteroatoms include oxygen, nitrogen, sulfur, phosphorus and boron. Heterocyclic group may be attached at a carbon atom or heteroatom.
  • Heterocyclic groups include an aziridine group, an azetidine group, an oxetane group, a pyrrolidine group, a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an imidazole group, an oxazole group, a thiazolegroup, a 1 ,2,5-oxadiazole group, a 1 ,3,4- oxadiazole group, a 1 ,3,4-thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a tetrazole group, a piperidine group, a pyridine group, a pyridazine group, a pyrimidine group, a pyrazine group, a tetrahydr
  • a "C1-8 alkoxy group” is an oxygen group which is substituted with a linear or branched alkyl group, alkenyl group, alkynyl group, aralkyl group or aryl group of 1 to 8 carbons, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a hexyloxy group, an allyloxy, group, a 2-propynyloxy group, a benzyloxy group, a phenoxy group or the like.
  • a "C3-8 cycloalkylidene group” according to the invention is a divalent group formed from cycloalkanes of 3 to 8 carbons by removal of two hydrogen atoms from the same carbon atom, the free valencies of which are part of a double bond.
  • Examples of C3-8 cycloalkylidene groups are such as a cyclopentylidene group, a cyclohexyl idene group, a cycloheptylidene group or the like.
  • A"protecting group for a hydroxyl group" is a substituent which is useful for protecting a hydroxyl group, such as a methoxymethyl group, a methylthiomethyl group, a (phenyldimethylsilyl)methoxymethyl group, a benzyloxymethyl group, a p- methoxybenzyloxymethyl group, a p-nitrobenzyloxymethyl group, an o- nitrobenzyloxymethyl group, a (4-methoxyphenoxy)methyl group, a guaiacol methyl group, a t-butoxymethyl group, a 4-pentenyloxymethyl group, a siloxymethyl group, a 2-methoxyethoxymethyl group, 2,2,2- trichloroethoxymethyl group, a bis(2-chloroethoxy)methyl group, a 2- (trimethylsilyl)ethoxymethyl group, a menthoxymethyl group, a tetrahydropyranyl group,
  • prodrug or "prodrug,” as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • Prodrugs of the present invention may be rapidly transformed in vivo to a parent compound of formula (I), for example, by hydrolysis in blood.
  • a through discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in drug Design, American Pharmaceutical Association and Pergamon Press (1987), hereby incorporated by reference.
  • the present invention offers bisphenyl compounds of formula I.
  • X is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene, an ethynylene, -S(0)n-, -NH-, or -0-.
  • Preferable X is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene or an ethynylene. More preferable X is a methylene, an ethylene, a vinylene or an ethynylene a methylene. Furthermore preferable X is an ethylene, a vinylene or an ethynylene a methylene.
  • An optionally substituted methylene is, in particular, a methylene which may be substituted with a halogen atom(s) and/or a C1-4 alkyl group(s), and is preferablely a methylene.
  • An optionally substituted vinylene is, in particular, a vinylene which may be substituted with a halogen atom(s) and/or a C1-4 alkyl group(s), and is preferablely a vinylene.
  • An optionally substituted ethylene is, in particular, an ethylene which may be substituted with a halogen atom(s) and/or a C1-4 alkyl group(s), and is preferablely an ethylene.
  • n is an integer of 0 to 2, therefore, "-S(0)n-” means -S-, - SO- or -S0 2 -.
  • Y is COOR8, CON(R9)R10, S(0)mR11 or a substituent represented by following formula:
  • Y is a substituent represented by following formula:
  • R8 is selected an optionally substituted C1-10 alkyl group or an optionally substituted C3-10 cycloalkyl group.
  • an optionally substituted C1-10 alkyl group is, in particular, a C1-10 alkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C1-10 alkyl group.
  • An optionally substituted C3-10 cycloalkyl group is, in particular, a C3-10 cycloalkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C3-10 cycloalkyl group.
  • R9 and R10 are each independently selected from a hydrogen atom, an optionally substituted C1-10 alkyl group or an optionally substituted C3-10 cycloalkyl group.
  • an optionally substituted C1-10 alkyl group is, in particular, a C1-10 alkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C1- 10 alkyl group.
  • An optionally substituted C3-10 cycloalkyl group is, in particular, a C3-10 cycloalkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C3-10 cycloalkyl group.
  • S(0)mR11 m is an integer of 0 to 2, therefore, "S(0)mR11” means -S-R11 , -SO-R11 or -S0 2 -R11 , and R11 is selected an optionally substituted C1-10 alkyl group or an optionally substituted C3-10 cycloalkyl group.
  • an optionally substituted C1-10 alkyl group is, in particular, a C1-10 alkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C1-10 alkyl group.
  • An optionally substituted C3-10 cycloalkyl group is, in particular, a C3-10 cycloalkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C3-10 cycloalkyl group.
  • Y is a substituent represented by following formula: a is an integer of 0 to 3, and is preferablely 0.
  • R is a hydrogen atom or a protecting group for a hydroxyl group.
  • R is preferablely a hydrogen atom.
  • the compound wherein R is a protecting group for a hydroxyl group is useful as a synthetic intermediate of a modulator of the vitamin D receptor activity.
  • some of these compounds exhibit the vitamin D receptor modulating activity, and such compounds are also useful as a modulator of the vitamin D receptor activity.
  • a protecting group for a hydroxyl group is, in particular, a methoxymethyl group, a methylthiomethyl group, a (phenyldimethylsilyl)methoxymethyl group, a benzyloxymethyl group, a p- methoxybenzyloxymethyl group, a p-nitrobenzyloxymethyl group, an o- nitrobenzyloxymethyl group, a (4-methoxyphenoxy)methyl group, a guaiacolmethyl group, a t-butoxymethyl group, a 4-pentenyloxymethyl group, a siloxymethyl group, a 2-methoxyethoxymethyl group, 2,2,2- trichloroethoxymethyl group, a bis(2-chloroethoxy)methyl group, a 2- (trimethylsilyl)ethoxymethyl group, a menthoxymethyl group, a tetrahydropyranyl group, a 3-bromotetrahydropyranyl group, a terta
  • a protecting group for a hydroxyl group is preferablely selected from a methoxymethyl group, a 2- (trimethylsilyl)ethoxymethyl group, a tetrahydropyranyl group, a benzyl group, a p-methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t-buthyldiphenylsilyl group, an acetyl group, a pivaloyl group, a benzoyl group, a methanesulfonyl group, a tosyl group or a trifluoromethanesulfonyl group.
  • R12 and R13 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-10 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted C2-10 alkenyl group, an optionally substituted C2-10 alkynyl group, or R12 and R13 may together form an optionally substituted C3-C12 cycloalkyl group or an optionally substituted 3-12 membered heterocyclic group.
  • R12 and R13 are preferablely each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-10 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted C2-10 alkenyl group, an optionally substituted C2-10 alkynyl group, or R12 and R13 may together form an optionally substituted C3-C12 cycloalkyl group.
  • R12 and R13 are more preferablely each independently selected from the group consisting of a hydrogen atom, a C1-8 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3- 8 cycloalkyl group which may be substituted with a C1-4 alkyl group.
  • R12 and R13 are furthermore preferablely each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3- 8 cycloalkyl group.
  • R12 and R13 are preferablely selected from the group consisting of i) one of R12 and R13 is a hydrogen atom and the other is a C1-6 alkyl group, ii) one of R12 and R13 is a hydrogen atom and the other is a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, iii) both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group.
  • R12 and R13 are, in particular, a hydrogen atom and a tert-butyl group, or both a trifluoromethyl group.
  • an optionally substituted C1-10 alkyl group is, in particular, a C1-10 alkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1 -8 alkoxy group(s), and is preferablely a C1 -10 alkyl group.
  • An optionally substituted C1-10 alkenyl group is, in particular, a C1-10 alkenyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C1-10 alkenyl group.
  • An optionally substituted C1-10 alkynyl group is, in particular, a C1-10 alkynyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C1-10 alkynyl group.
  • An optionally substituted C3-10 cycloalkyl group is, in particular, a C3-10 cycloalkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s), a C1-4 alkyl group and/or a C1-8 alkoxy group(s), and is preferablely a C3-10 cycloalkyl group which may be substituted with a C1-4 alkyl group.
  • “An optionally substituted 3-12 membered heterocyclic group” is, in particular, a 3-12 membered heterocyclic group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s).
  • W is a hydroxyl group, a carboxyl group, a trifluoromethanesulfonyloxy group or a substituent represented by following formula:
  • W is preferablely a substituent represented by following formula:
  • the compound having a carboxyl group at its terminal end is preffered.
  • the compound wherein W is a hydroxyl group, a carboxyl group or a trifluoromethanesulfonyloxy group is useful as a synthetic intermediate of a modulator of the vitamin D receptor activity.
  • some of these compounds exhibit the vitamin D receptor modulating activity, and such compounds are also useful as a modulator of the vitamin D receptor activity.
  • Y is a substituent represented by following formula:
  • b is an integer of 0 to 10
  • k is an integer of 0 to 2, and is preferablely 1.
  • An optionally substituted methylene is, in particular, a methylene which may be substituted with a halogen atom(s) and/or a C1-4 alkyl group(s), and is preferablely a methylene.
  • An optionally substituted vinylene is, in particular, a vinylene which may be substituted with a halogen atom(s) and/or a C1-4 alkyl group(s), and is preferablely a vinylene.
  • An optionally substituted ethylene is, in particular, an ethylene which may be substituted with a halogen atom(s) and/or a C1-4 alkyl group(s), and is preferablely an ethylene.
  • R14 is a hydrogen atom, a hydroxyl group, an optionally substituted carboxyl group, an optionally substituted carbamoyl group, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C1-6 alkenyl group, an optionally substituted C1-6 alkynyl group, an optionally substituted C6-C12 aryl group, an optionally substituted (C6-C12)aryl-(C1 -4)alkyl group, -OR17 or -N(R18)R19.
  • R14 is preferablely a hydrogen atom, a hydroxyl group, a carboxyl group which may be substituted with a C1-4 alkyl group, a carbamoyl group which may be substituted with a C1-4 alkyl group, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group which may be substituted with a C1- 4 alkyl group, a phenyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a benzyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, - OR17 or -N(R18)R19.
  • R14 is more preferablely a hydrogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group, a phenyl group which may be substituted with a hydroxyl group or a carboxyl group, a benzyl group which may be substituted with a hydroxyl group or a carboxyl group, -OR17 or -N(R18)R19.
  • R17 is an optionally substituted C1-6 alkyl group or an optionally substituted C3-C6 cycloalkyl group.
  • R17 is preferablely a C1-4 alkyl group.
  • an optionally substituted C1-6 alkyl group is, in particular, a C1-6 alkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C1-6 alkyl group.
  • An optionally substituted C3-6 cycloalkyl group is, in particular, a C3-6 cycloalkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C3-6 cycloalkyl group.
  • R18 and R19 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C6 cycloalkyl group, or R18 and R19 may together form an optionally substituted C3-C12 cycloalkyl group or an optionally substituted 3-12 membered heterocyclic group.
  • R18 and R19 are preferablely each independently selected from a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C6 cycloalkyl group.
  • R18 and R19 are more preferablely each independently selected from a hydrogen atom or a C1-4 alkyl group.
  • R18 is a hydrogen atom and R19 is a hydrogen atom, i.e. "- N(R18)R19" represents an amino group.
  • an optionally substituted C1-6 alkyl group is, in particular, a C1-6 alkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C1-6 alkyl group.
  • An optionally substituted C3-6 cycloalkyl group is, in particular, a C3-6 cycloalkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C3-6 cycloalkyl group.
  • An optionally substituted C3-12 cycloalkyl group is, in particular, a C3-12 cycloalkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C3-12 cycloalkyl group.
  • R15 and R16 are preferablely each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C6-C12 aryl group, an optionally substituted (C6-C12)aryl-(C1-4)alkyl group, an optionally substituted 3-12 membered heterocyclic group selected from the group consisting of an aziridine group, an azetidine group, an oxetane group, a pyrrolidine group, a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an imidazole group, an oxazole group, a thiazolegroup, a 1 ,2,5-oxadiazole group, a 1 ,3,4-oxadia
  • R15 and R16 are more preferablely each independently selected from the group consisting of a hydrogen atom, a C1- 6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group which may be substituted with a C1-4 alkyl group, a phenyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a benzyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a 3-8 membered heterocyclic group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, wherein said heterocyclic
  • R15 and R16 are furthermore preferablely each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group, a phenyl group which may be substituted with a hydroxyl group or a carboxyl group, a benzyl group which may be substituted with a hydroxyl group or a carboxyl group, a 3-8 membered heterocyclic group selected from the group consisting of a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an oxazole group, a thiazole group, a 1 ,2,5- oxadiazole group, a 1 ,3,4-o
  • R14, R15 and R16 it is preferred that at least one of R14, R15 or R16 is a hydrogen atom, and/or at least one of R14, R15 or R16 is a substituent which have a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group. Also, it is preferred that R14 is a hydroxyl group, and/or one of R15 and R16 is a hydrogen atom and the other is a C1-6 alkyl group substituted with a carboxyl group.
  • R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered cyclic ring which is selected from the group consisting of an amidine ring, an amine ring, an ether ring, a lactam ring, a lactone ring, an acetal ring, a hemiacetal ring, a carbonate ring, a carbamate ring, an urea ring, combinations thereof.
  • said cyclic ring is preferablely a lactam ring or a lactone ring, and is more preferablely a lactone ring.
  • R1 and R2 are each independently selected from the group consisting of a C1-6 alkyl group optionally substituted with a halogen atom(s), a C3-6 cycloalkyl group optionally substituted with a halogen atom(s), a C2-6 alkenyl group optionally substituted with a halogen atom(s), a C2-6 alkynyl group optionally substituted with a halogen atom(s), or R1 and R2 may together form a C3-8 cycloalkyl group optionally substituted with a halogen atom(s), a C3-8 cycloalkenyl group optionally substituted with a halogen atom(s) or a C3-8 cycloalkylidene group optionally substituted with a halogen atom(s).
  • R1 is a C1-6 alkyl group, more preferable R1 is a C1-4 alkyl group, and the most preferable R1 is an ethyl group.
  • Preferable R2 is a C1-6 alkyl group, more preferable R2 is a C1-4 alkyl group, and the most preferable R2 is an ethyl group.
  • R3, R4, R5 and R6 are each independently selected from a hydrogen atom, a halogen atom, a C1-6 alkyl group optionally substituted with a halogen atom(s) or a C3-6 cycloalkyl group optionally substituted with a halogen atom(s).
  • Preferable R3 is a hydrogen atom or a C1-6 alkyl group, more preferable R3 is a hydrogen atom or a C1-4 alkyl group, and the most preferable R3 is a hydrogen atom or a methyl group.
  • Preferable R4 is a halogen atom or a C1-6 alkyl group, more preferable R4 is a halogen atom or a C1-4 alkyl group, and the most preferable R4 is a chlorine atom or a methyl group.
  • Preferable R5 is a hydrogen atom.
  • R6 is a halogen atom or a C1-6 alkyl group, more preferable R6 is a halogen atom or a C1-4 alkyl group, and the most preferable R6 is a chlorine atom, a methyl group, an ethyl group, a propyl group or an isopropyl group.
  • X is selected from an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene or an ethynylene.
  • Examples of the preferred compounds of the present invention are represented as follows.
  • X is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene or an ethynylene;
  • Y is COOR8, CON(R9)R10, S(0)mR11 or a substituent represented by following formula:
  • R is a hydrogen atom;
  • R12 and R13 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-10 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted C1-10 alkenyl group, an optionally substituted C1-10 alkynyl group, or R12 and R13 may together form an optionally substituted C3-10 cycloalkyl group;
  • W is a substituent represented by following formula:
  • R 15 and R16 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C6- C12 aryl group, an optionally substituted (C6-C12)aryl-(C1-4)alkyl group, an optionally substituted 3-12 membered heterocyclic group selected from the group consisting of an aziridine group, an azetidine group, an oxetane group, a pyrrolidine group, a tetrahydrofuran group, a pyrrole group, a furan group,
  • R 16 Q is -0-, a methylene, an ethylene, a vinylene, an ethynylene, -
  • R14 is a hydrogen atom, a hydroxyl group, a carboxyl group which may be substituted with a C1-4 alkyl group, a carbamoyl group which may be substituted with a C1-4 alkyl group, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group which may be substituted with a C1-
  • R15 and R16 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group which may be substituted with a C1-4 alkyl group, a phenyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a benzyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a 3-8 membered heterocyclic group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a 3-8 membered heterocyclic group which
  • R12 and R13 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3-8 cycloalkyl group;
  • R14 is a hydrogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl
  • R12 and R13 are selected from the group consisting of one of R12 and R13 is a hydrogen atom and the other is a C1- 6 alkyl group, one of R12 and R13 is a hydrogen atom and the other is a C3- 8 cycloalkyl group which may be substituted with a C1-4 alkyl group, both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group;
  • R1 is an ethyl group;
  • R2 is an ethyl group;
  • R3 is a hydrogen atom or a methyl group;
  • R4 is a chlorine atom or a methyl group;
  • R6 is a chlorine atom, a methyl group, an ethyl group,
  • (22) The compound according to (21) selected from the group consisting of (S)-5-(4- ⁇ 1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3- methyl-phenyl]-propyl ⁇ -2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-3- (4- ⁇ 1 -Ethyl-1 -[4-(3-hyd roxy-4, 4-di methyl-pent- 1 -ynyl)-3-methyl-phenyl]- propyl ⁇ -2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4- ⁇ 1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl- phenoxymethyl)-propane-1 ,3-diol, 5-(4
  • R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group;
  • R1 is an ethyl group;
  • R2 is an ethyl group;
  • R3 is a hydrogen atom;
  • R4 is a chlorine atom or a methyl group;
  • R6 is a chlorine atom or a methyl group.
  • (64) The compound according to (63) selected from the group consisting of 3-(4- ⁇ 1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl ⁇ -2-methyl-phenyl)-propionic acid, 3- (4- ⁇ 1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-phenyl]-propyl ⁇ -2-methyl-phenyl)-propionic acid, 6-(4- ⁇ 1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl ⁇ -2-methyl-phenyl)-hex-5-ynoic acid, 6-(4- ⁇ 1 -Ethyl-1
  • X is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene or an ethynylene;
  • R is a protecting group for a hydroxyl group selected from the group consisting of a methoxymethyl group, a methylthiomethyl group, a (phenyldimethylsilyl)methoxymethyl group, a benzyloxymethyl group, a p- methoxybenzyloxymethyl group, a p-nitrobenzyloxymethyl group, an o- nitrobenzyloxymethyl group, a (4-methoxyphenoxy)methyl group, a guaiacolmethyl group, a t-butoxymethyl group, a 4-pentenyloxymethyl group, a siloxymethyl group, a 2-methoxyethoxymethyl group, 2,2,2- trichloroethoxymethyl group, a bis(2-chloroethoxy)methyl group, a 2- (trimethyl
  • R14 is a hydrogen atom, a hydroxyl group, an optionally substituted carboxyl group, an optionally substituted carbamoyl group, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted G6-C12 aryl group, an optionally substituted (C6-C12)aryl-(C1 -4)alkyl group, -OR17 or -N(R18)R19;
  • R15 and R16 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cyclo
  • X is an ethylene, a vinylene, or an ethynylene
  • b is an integer of 0 to 5;
  • R14 is a hydrogen atom, a hydroxyl group, a carboxyl group which may be substituted with a C1-4 alkyl group, a carbamoyl group which may be substituted with a C1-4 alkyl group, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group which may be substituted with a C1- 4 alkyl group, a phenyl group which may be substituted with a C1-4 alkyl group, a hydroxy
  • R12 and R13 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3-8 cycloalkyl group;
  • W is a substituent represented by following formula: ⁇ R-
  • R15 and R16 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group, a phenyl group which may be substituted with a hydroxyl group or a carboxyl group, a benzyl group which may be substituted with a hydroxyl group or a carboxyl group, a 3-8 membered heterocyclic group selected from the group consisting of a tetrahydrofuran group, a pyrrole group, a furan
  • R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group;
  • R1 is an ethyl group;
  • R2 is an ethyl group;
  • R3 is a hydrogen atom or a methyl group;
  • R4 is a chlorine atom or a methyl group;
  • R6 is a chlorine atom, a methyl group, an ethyl group, a propyl group or an isopropyl group.
  • R12 and R13 are a hydrogen atom and the other is a C3- 8 cycloalkyl group which may be substituted with a C1-4 alkyl group, both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group;
  • R1 is an ethyl group;
  • R2 is an ethyl group;
  • R3 is a hydrogen atom;
  • R4 is a chlorine atom or a methyl group;
  • R6 is a chlorine atom or a methyl group.
  • R14, R15 or R16 is a substituent which have a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group.
  • R12 and R13 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1 -4 alkyl group, or R12 and R13 are together form a C3-8 cycloalkyl group;
  • R1 is a C1-4 alkyl group;
  • R2 is a C1-4 alkyl group;
  • R3 is a hydrogen atom or a C1-4 alkyl group;
  • R4 is a halogen atom or a C1-4 alkyl group;
  • R5 is a hydrogen atom;
  • R6 is a halogen atom or a C1-4 alkyl group.
  • R12 and R13 are a hydrogen atom and the other is a C3- 8 cycloalkyl group which may be substituted with a C1-4 alkyl group, both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group;
  • R1 is an ethyl group;
  • R2 is an ethyl group;
  • R3 is a hydrogen atom or a methyl group;
  • R4 is a chlorine atom or a methyl group;
  • R6 is a chlorine atom, a methyl group, an ethyl group, a propyl group or an isopropyl group.
  • the compounds of the present invention exhibit VDR modulating activity. Therefore, the compounds and compositions of the present invention are useful as pharmaceuticals, such as, for the treatment of abscess, acne, adhesion, alopecia, Alzheimer's disease, benign prostatic hyperplasia, bone fracture healing, cancer, autoimmune induced diabetes, host-graft rejection, insufficient sebum secretion, insufficient dermal firmness, humoral hypercalcemia, insufficient dermal hydration, leukemia, lupus, multiple sclerosis, osteomalacia, osteoporosis, psoriaticarthritis, psoriasis, renal failure, renal osteodystrophy, rheumatoid arthritis, scleroderma, secondary hyperparathyroidism, systemic lupus erythematosus, and wrinkles, cornea wound, cornea healing, retinopathy, sway, muscle weakness, fall, chronic glomerulonephritis, lupus nephritis, diabetic
  • the compounds and compositions of the present invention are useful as pharmaceuticals for the treatment of benign prostatic hyperplasia, cancer, osteoporosis, psoriasis, secondary hyperparathyroidism, chronic glomerulonephritis, lupus nephritis, diabetic nephropathy, sway, muscle weakness, fall, rheumatoid arthritis and/or osteoarthritis.
  • typical disease subjected to the treatment by the compounds and compositions of the present invention are benign prostatic hyperplasia, cancer, osteoporosis, psoriasis, secondary hyperparathyroidism, chronic glomerulonephritis, lupus nephritis and/or diabetic nephropathy.
  • Certain compounds of the present invention are useful as a synthetic intermediate thereof.
  • compositions of the present invention comprise:
  • a "safe and therapeutically effective amount" of a compound useful in the present invention is an amount that exhibits VDR modulating activity, in a subject, a tissue, or a cell, and preferably in an animal, more preferably in a mammal, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio, when used in the manner of this invention.
  • compositions of the present invention contain a pharmaceutically- acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents or encapsulating substances, which are suitable for administration to a mammal.
  • compatible means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction, which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations.
  • Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration preferably to an animal, preferably mammal being treated.
  • substances which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water
  • a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered. If the subject compound is to be injected, the preferred pharmaceutically-acceptable carrier is sterile, physiological saline, with blood-compatible suspending agent, the pH of which has been adjusted to about 7.4.
  • pharmaceutically-acceptable carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen- free water.
  • Preferred carriers for parental administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil.
  • the compositions of this invention are preferably provided in unit dosage form.
  • a "unit dosage form" is a composition of this invention containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. (The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day, and are expected to be given more than once during a course of therapy, though a single administration is not specifically excluded.
  • compositions useful for this invention may be in any of a variety of forms, suitable (for example) for oral, nasal, rectal, topical (including transdermal), ocular, intracereberally, intravenous, intramuscular, or parental administration.
  • oral and nasal compositions comprise compositions that are administered by inhalation, and made using available methodologies.
  • a variety of pharmaceutically-acceptable carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances.
  • Optional pharmaceutically-active materials may be included, which do not substantially interfere with the activity of the compound.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981 ); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).
  • Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount.
  • Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non- effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • the pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration is well-known in the art.
  • Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrates such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance.
  • inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose
  • binders such as starch, gelatin and sucrose
  • disintegrates such as starch, alginic acid and croscarmelose
  • lubricants such as magnesium stearate
  • Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • Capsules typically comprise one or more solid diluents disclosed above.
  • the selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be readily made by a person skilled in the art.
  • Peroral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • the pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591 , tragacanth and sodium alginate;
  • typical wetting agents include lecithin and polysorbate 80;
  • typical preservatives include methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
  • compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action.
  • dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
  • Compositions of the subject invention may optionally include other drug actives.
  • Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms.
  • compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • the compositions of this invention can also be administered topically to a subject in a treatment of dermatological conditions such as psoriasis, e.g., by the direct application or spreading of the composition on the epidermal or epithelial tissue of the subject, or transdermally via a "patch".
  • Such compositions include, for example, lotions, creams, solutions, gels and solids.
  • Topical compositions preferably comprise a safe and effective amount.
  • Suitable carriers for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water.
  • the carrier is organic in nature and capable of having dispersed or dissolved therein the compound.
  • the carrier may include pharmaceutically-acceptable emollient, emulsifiers, thickening agents, solvents and the like.
  • the compounds and compositions useful in this invention can be administered topically or systemically.
  • Systemic application includes any method of introducing compound into the tissues of the body, e.g., intra- articular, intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual administration, inhalation, rectal, or oral administration.
  • the compounds useful in the present invention are preferably administered orally.
  • the specific dosage of the compound to be administered, as well as the duration of treatment is to be individualized by the treating clinicians.
  • ng/kg to 50 mg/kg preferably from about 1 ng /kg to about 1 mg/kg, more preferably from about 10 ng/kg to about 100 ⁇ g/kg, of selected compound is administered per day.
  • these dosage ranges are by way of example only, and that daily administration can be adjusted depending on the factors i.e. type of disease, level of disease, ages of patients, sex of patients, route to be administered, etc.
  • the compounds useful in the present invention can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.
  • the compound of general formula (1 ) obtained by the same procedure as described in WOOO/10958 and the corresponding U.S. Patent 6,218,430 B1 may be reacted with trifluoromethanesulfonic acid anhydride in the presence of a base to give a compound of general formula (2) (step 1).
  • Suitable bases for use in the above step 1 include pyridine, 2,6- lutidine, 2,4,6-collidine,N,N-dimethylaminopyridine, imidazole, triethylamine, more preferably pyridine.
  • Suitable solvents for use in the above step 1 include diethyl ether, tetrahydrofuran, dichloromethane, 1 ,2-dichloroethane, chloroform, benzene, toluene, more preferably dichloromethane.
  • the reaction temperature of the above step 1 is in the range from -50 °C to 50 °C, preferably from -20 °C to 30 °C, though it is not specifically limited so far as the reaction proceeds.
  • the compound of general formula (2) may be reacted with trimethylsilyl acetylene in the presence of a palladium catalyst, copper (I) iodide, and triethyamine to give a compound of general formula (3) (step 2).
  • Suitable palladium catalysts for use in the above step 2 include tetrakis(triphenylphosphine)palladium, Pd(dba)2, Pd2(dba)3-CHCI3, palladium acetate, palladium chloride, [1 ,1'-bis(diphenylphosphino)- ferrocenejpalladium dichloride dichloromethane complex, (dba; dibenzylideneacetone)
  • a ligand such as triphenylphosphine, tributhylphosphine, tricyclohexylphosphine, 1 ,3-bis(diphenylphosphinopropane) or tri-t-buthyl phosphine, may be used in the above step 2 to increase the catalytic activity and/or the reaction selectivity.
  • Suitable solvents for use in the above step 2 include N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl- 2-imidazolidinone, tetrahydrofuran, toluene, acetonitrile, more preferably N,N-dimethylformamide or acetonitrile.
  • the reaction temperature of the above step 2 is in the range from 0 °C to 200 °C, preferably from 20 °C to 150 °C, though it is not specifically limited so far as the reaction proceeds.
  • the compound of general formula (3) may be reacted with tetra-n-butyl ammonium fluoride to give a compound of general formula (4) (step 3).
  • Suitable solvents for use in the above step 3 include N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl- 2-imidazolidinone, tetrahydrofuran, toluene, acetonitrile, more preferably tetrahydrofuran.
  • the reaction temperature of the above step 3 is in the range from 0 °C to 100 °C, preferably from 0 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
  • Suitable bases for use in the above step 4 include n-butyl lithium, sec- butyl lithium, tert-butyl lithium, methyl lithium, phenyl lithium, methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, isopropyl magnesium bromide, diisopropyl magnesium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, lithium 2,2,6,6- tetramethylpiperidide, lithium amide, sodium hydride, sodium bis(trimethylsilyl)amide, potassium hydride, potassium bis(trimethylsilyl) more preferably n-butyl lithium.
  • Suitable solvents for use in the above step 4 include hydrocarbon- ether-based solvents or the likes, such as pentane, hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, anisole, more preferably tetrahydrofuran.
  • the reaction temperature of the above step 1 is in the range from - 100 °C to 50 °C, preferably from -80 °C to 30 °C, though it is not specifically limited so far as the reaction proceeds.
  • Step 5 includes the reduction by LiAIH4, Red-AI (sodium bis(2- methoxyethoxy)aluminium hydride) or hydrogenation using Lindlar catalyst.
  • Suitable solvents for use in the reduction by lithium aluminum hydride or Red-AI include hydrocarbon- ether-based solvents or the like, such as pentane, hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 1,4-dioxane, anisole, more preferably tetrahydrofuran.
  • Suitable solvents for use in the hydrogenation by Lindlar catalyst include methanol, ethanol, ethyl acetate, more preferably methanol.
  • the reaction temperature of the above step 5 is in the range from -50 °C to 200 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
  • the compound of general formula (5, 6) may be subjected to hydrogenation to give a compound of general formula (7) (step 6)
  • Suitable catalysts for use in the above step 6 include palladium-, rhodium-, ruthenium-, nickel-, platinum-based catalysts or the like, such as palladium on carbon, palladium hydroxide, platinum oxide, rhodium on alumina, Wilkinson's catalyst, more preferably palladium on carbon.
  • Suitable solvents for use in the above step 6 include methanol, ethanol, ethyl acetate, acetic acid, more preferably methanol.
  • the reaction temperature of the above step 6 is in the range from -50 °C to 200 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
  • the compound of general formula (5-7) may be subjected to protection of hydroxyl group with a compound of general formula (9)
  • R' a methoxymethyl group, a 2-(trimethylsilyl)ethoxymethyl group, a benzyl group, a p-methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t-buthyldiphenylsilyl group or an acetyl group
  • X a halogen atom, a methanesulfonyloxy group, a toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group or an acethyloxy group) in the presence of a base to give a compound of general formula (8) (step 7).
  • Suitable bases for use in the above step 7 include sodium tert- butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, pyridine, triethylamine, diisopropylethylamine, 2,6-lutidine, 2,4,6-collidine, N,N- dimethylaminopyridine, more preferably sodium hydride, potassium carbonate, or pyridine.
  • Suitable solvents for use in the above step 7 include dichloromethane, 1 ,2-dichloroethane, chloroform, hexane, benzene, toluene, diethyl ether, t- butyl methyl ether, tetrahydr Aran, 1 ,2-dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide,1 ,3-dimethyl-2-imidazolidinone,1 ,3-dimethyl-3,4,5,6- tetrahydro-2(1 H)-pyrimidinone, acetonitrile, more preferably N,N- dimethylformamide.
  • the reaction temperature of the above step 7 is in the range from -50 °C to 200 °C, preferably from -20 °C to 100 °C, though it is not specifically limited so far as the
  • Suitable bases for use in the above step 8 include sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably sodium hydride or potassium carbonate.
  • Suitable solvents for use in the above step 8 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, methanol, ethanol, isopropanol, acetonitrile, more preferably N,N-dimethylformamide.
  • the reaction temperature of the above step 8 is in the range from -50 °C to 200 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
  • suitable solvents for use in the above step 8 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, more preferably toluene, tetrahydrofuran.
  • reaction temperature of the above step 8 is in the range from -50 °C to 200 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
  • Compound 11 can also be synthesized from compound 4 in order of step 8, step 4, step 5, step 6 and step 7.
  • the compound of general formula (11) may be subjected to deprotection in the presence of an acid to give a compound of general formula (12) (step 9).
  • Suitable acids for use in the above step 9 include hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, trifluoroacetic acid, 10- camphorsulfonic acid, p-toluenesulfonic acid, pyridinium p-toluenesuifonic acid, trifluoroborane-diethyl ether complex, carbon tetrabromide, trimethylsilyl bromide, methanesulfonic acid, acidic ion exchange resin.
  • Suitable solvents for use in the above step 9 include dichloromethane, 1 ,2-dichloroethane, chloroform, acetone, methanol, ethanol, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,4-dioxane, diethyl ether, water, the mixtures.
  • the reaction temperature of the above step 9 is in the range from -10 °C to 150 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
  • Suitable bases for use in the above step 10 include sodium tert- butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably potassium carbonate.
  • Suitable solvents for use in the above step 10 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, methanol, ethanol, isopropanol, acetonitrile, more preferably N,N-dimethylformamide.
  • the reaction temperature of the above step 10 is in the range from - 50 °C to 200 °C, preferably from 0 °C to 150 °C, though it is not specifically limited so far as the reaction proceeds.
  • suitable solvents for use in the above step 10 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, more preferably toluene, tetrahydrofuran.
  • the reaction temperature of the above step 10 is in the range from - 50 °C to 200 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
  • the compound of general formula (14) may be hydrolyzed in the presence of a base to give a compound of general formula (15) (step 11).
  • Suitable bases for use in the above step 11 include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably sodium hydroxide or potassium hydroxide.
  • Suitable solvents for use in the above step 11 include acetone, methanol, ethanol, tetrahydrofuran, 1 ,4-dioxane, 1 ,2-dimethoxyethane, water, the mixtures more preferably methanol-water mixture.
  • the reaction temperature of the above step 11 is in the range from - 10 °C to 120 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
  • Suitable bases for use in the above step 12 include sodium tert- butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably potassium carbonate.
  • Suitable solvents for use in the above step 12 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, methanol, ethanol, isopropanol, acetonitrile, more preferably N,N-dimethylformamide.
  • the reaction temperature of the above step 12 is in the range from - 50 °C to 200 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
  • suitable solvents for use in the above step 12 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, more preferably toluene, tetrahydrofuran.
  • the reaction temperature of the above step 12 is in the range from - 50 °C to 200 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
  • the compound of general formula (17) may be hydrolyzed in the presence of a base to give a compound of general formula (18) (step 13).
  • Suitable bases for use in the above step 13 include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably sodium hydroxide or potassium hydroxide.
  • Suitable solvents for use in the above step 13 include acetone, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, 1 ,4-dioxane, 1,2- dimethoxyethane, water, the mixtures more preferably methanol-water mixture.
  • the reaction temperature of the above step 13 is in the range from -
  • Suitable bases for use in the above step 14 include sodium tert- butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably potassium carbonate.
  • Suitable solvents for use in the above step 14 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, methanol, ethanol, isopropanol, acetonitrile, more preferably acetonitrile.
  • the reaction temperature of the above step 14 is in the range from -
  • suitable solvents for use in the above step 14 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, more preferably toluene, tetrahydrofuran.
  • the reaction temperature of the above step 14 is in the range from - 50 °C to 200 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
  • the step for obtaining a compound of general formula (21) from the compound of general formula (20) may be performed with hydrazine or methylamine (step 15).
  • Suitable solvents for use in the above step 15 include methanol, ethanol, n-propanol, isopropanol, more preferably methanol.
  • the reaction temperature of the above step 15 is in the range from 0
  • °C to 200 °C preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
  • Suitable palladium catalysts for use in the above step 16 include tetrakis(triphenylphosphine)palladium, Pd(dba)2, Pd2(dba)3-CHCI3, palladium acetate, palladium chloride, [1 ,1'-bis(diphenylphosphino)- ferrocenejpalladium dichloride dichloromethane complex, (dba; dibenzylideneacetone)
  • a ligand such as triphenylphosphine, tributhylphosphine, tricyclohexylphosphine, 1 ,3-bis(diphenylphosphinopropane) or tri-t-buthyl phosphine, may be used in the above step 16 to increase the activity of catalyst or the reaction selectivity.
  • Suitable solvents for use in the above step 16 include N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,-dimethyl- 2-imidazolidinone, tetrahydrofuran, toluene, acetonitrile, more preferably N,N-dimethylformamide.
  • the reaction temperature of the above step 16 is in the range from 0 °C to 200 °C, preferably from 20 °C to 150 °C, though it is not specifically limited so far as the reaction proceeds.
  • Suitable hydroboration reagents for use in the above step 17 include borane-tetrahydrofuran complex, borane-methyl sulfide complex, borane- pyridine complex, borane-trimethylamine complex, or 9-BBN.
  • Suitable oxidizing agents for use in the above step 17 include hydrogen peroxide-sodium hydroxide, or sodium perborate.
  • Suitable solvent for use in the above step 17 includes tetrahydrofuran.
  • the reaction temperature of the above step 17 is in the range from - 78 °C to 100 °C, preferably from -50 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
  • Suitable oxidizing agents for use in the above step 18 include pyridinium chlorochromate, pyridinium dichromate, manganese dioxide, osmium tetraoxide, ruthenium trichloride, tetrapropylammonium perruthenate, oxaryl chloride/dimethyl sulfoxide/triethylamine, triphosgene/dimethyl sulfoxide, sulfur trioxide pyridine complex/dimethyl sulfoxide, acetone/aluminium triisopropoxide, cyclohexanone/aluminium triisopropoxide, Dess-Martin reagent, more preferably Dess-Martin reagent
  • Suitable solvents for use in the above step 18 include benzene, toluene, hexane, heptane, dichloromethane, 1 ,2-dichloroethane, chloroform, tetrahydrofuran, acetone
  • Suitable Wittig reagents for use in the above step 19 include methyl triphenylphosphonium bromide, ethyl triphenylphosphonium bromide, n- propyl triphenylphosphonium iodide, isopropyl triphenylphosphonium iodide etc.
  • Suitable bases for use in the above step 19 include sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, more preferably n-butyl lithium.
  • Suitable solvents for use in the above step 19 include diethyl ether, tetrahydrofuran, benzene, toluene, dimethylsulfoxide, more preferably tetrahydrofuran.
  • the reaction temperature of the above step 19 is in the range from - 78 °C to 120 °C, preferably from -78 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
  • Suitable solvents for use in the above step 20 include acetone, acetonitrile, t-butanol, water or mixtures, more preferably acetone/t- butanol/water mixture.
  • the reaction temperature of the above step 20 is in the range from - 78 °C to 120 °C, preferably from -40 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
  • Suitable bases for use in the above step 21 include sodium tert-butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably potassium carbonate.
  • Suitable solvents for use in the above step 21 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, methanol, ethanol, isopropanol, acetonitrile, more preferably acetonitrile.
  • the reaction temperature of the above step 21 is in the range from - 50 °C to 200 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
  • the step for obtaining a compound of general formula (29) from the compound of general formula (28) may be performed with sodium azide, combination of sodium azide and triethyamine hydrochloride salt, azidotributyltin or combination of trimethylsilylazide and di-n-butyltinoxide (step 22).
  • Suitable solvents for use in the above step 22 include benzene, toluene, xylene, dyglyme.
  • the reaction temperature of the above step 22 is in the range from 0 °C to 200 °C, preferably from 10 °C to 150 °C, though it is not specifically limited so far as the reaction proceeds.
  • the compound of general formula (5-8) may be reacted with trifluoromethanesulfonic acid anhydride in the presence of a base to give a compound of general formula (30) (step 23).
  • Suitable bases for use in the above step 23 include pyridine, 2,6- lutidine, 2,4,6-collidine,N,N-dimethylaminopyridine, imidazole, triethylamine, more preferably pyridine.
  • Suitable solvents for use in the above step 23 include diethyl ether, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, more preferably dichloromethane.
  • the reaction temperature of the above step 23 is in the range from - 50 °C to 50 °C, preferably from -20 °C to 30 °C, though it is not specifically limited so far as the reaction proceeds.
  • Suitable palladium catalysts for use in the above step 24 include tetrakis(triphenylphosphine)palladium, Pd(dba)2, Pd2(dba)3-CHCI3, palladium acetate, palladium chloride, [1,1'-bis(diphenylphosphino)- ferrocenejpalladium dichloride dichloromethane complex, (dba; dibenzylideneacetone)
  • a ligand such as triphenylphosphine, tributhylphosphine, tricyclohexylphosphine, 1 ,3-bis(diphenylphosphinopropane) or tri-t-buthyl phosphine, may be used in the above step 24 to increase the catalytic activity and/or the reaction selectivity.
  • Suitable solvents for use in the above step 24 include N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl- 2-imidazolidinone, tetrahydrofuran, toluene, acetonitrile, more preferably N,N-dimethylformamide or acetonitrile.
  • the reaction temperature of the above step 24 is in the range from 0 °C to 200 °C, preferably from 20 °C to 150 °C, though it is not specifically limited so far as the reaction proceeds.
  • Suitable solvents for use in the above step 25 include methanol, ethanol, isopropanol, dichloromethane, 1 ,2-dichloroethane or mixtures, more preferably methanol/dichloromethane mixture.
  • the reaction temperature of the above step 25 is in the range from - 40 °C to 100 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
  • Suitable bases for use in the above step 26 include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, tetrabutylammonium fluoride, more preferably sodium hydroxide, potassium hydroxide or tetrabutylammonium fluoride.
  • Suitable solvents for use in the above step 26 include acetone, methanol, ethanol, tetrahydrofuran, 1 ,4-dioxane, 1 ,2-dimethoxyethane, water, the mixtures more preferably methanol-water mixture or tetrahydrofuran.
  • the reaction temperature of the above step 26 is in the range from -
  • the compound of general formula (30) may be reacted with acetylene derivative in the presence of a palladium catalyst, copper (I) iodide, and triethyamine to give a compound of general formula
  • step 27 Suitable palladium catalysts for use in the above step 27 include
  • PdCI2(dppf)2-CH2CI2 complex tetrakis(triphenylphosphine)palladium, Pd(dba)2, Pd2(dba)3-CHCI3, palladium acetate, palladium chloride, (dba; dibenzylideneacetone, dppf; diphenylphosphino)ferrocene)
  • a ligand such as triphenylphosphine, tributhylphosphine, tricyclohexylphosphine, 1 ,3-bis(diphenylphosphinopropane) or tri-t-buthyl phosphine, may be used in the above step 27 to increase the catalytic activity and/or the reaction selectivity.
  • Suitable solvents for use in the above step 27 include N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-
  • reaction temperature of the above step 27 is in the range from 0
  • °C to 200 °C preferably from 20 °C to 150 °C, though it is not specifically limited so far as the reaction proceeds.
  • Suitable bases for use in the above step 28 include sodium tert- butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably potassium carbonate.
  • Suitable solvents for use in the above step 28 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, methanol, ethanol, isopropanol, acetonitrile, more preferably N,N-dimethylformamide, acetonitrile.
  • the reaction temperature of the above step 28 is in the range from -
  • suitable solvents for use in the above step 28 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, more preferably toluene, tetrahydrofuran.
  • the reaction temperature of the above step 28 is in the range from - 50 °C to 200 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
  • the compound of general formula (36) may be hydrolyzed in the presence of an acid to give a compound of general formula (37) (step 29).
  • Suitable acids for use in the above step 29 include hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, phosphoric acid, trifluoroacetic acid, 10-camphorsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, more preferably hydrochloric acid.
  • Suitable solvents for use in the above step 29 include acetone, methanol, ethanol, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,4-dioxane, diethyl ether, water, the mixtures.
  • the reaction temperature of the above step 29 is in the range from 0 °C to 200 °C, preferably from 20 °C to 120 °C, though it is not specifically limited so far as the reaction proceeds.
  • the compound of general formula (12) may be subjected to cyclization in the presence of triphenylphosphine and dialkyl azocarboxylate to give a compound of general formula (38) (step 30).
  • Suitable solvents for use in the above step 30 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, more preferably toluene, tetrahydrofuran.
  • the reaction temperature of the above step 30 is in the range from -
  • Ra and Rb are each independently selected from the group consisiting of a hydrogen atom, an optionally substituted C1 -10 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted phenyl group, an optionally substituted benzyl group, an optionally substituted phenethyl group, or Ra and Rb may together form an optionally substituted C3-10 cycloalkyl group.
  • substitution group is a hydroxyl group, an amino group, a carboxyl group or a carboxylic amide group with an appropriate protecting group described in Protecting Groups in Organic Synthesis, third edition, John Wiley & Sons, Inc., for example, tert-butyl group, tert-butoxycarbonyl group, trityl group.
  • Rc is a protecting group selected from a C1-5 alkyl group or polystylene-bound 4-benzyloxy-benzyl group.
  • the cleavage of a protecting group such as tert-butyl group, tert-butoxycarbonyl group, trityl group or polystylene-bound 4-benzyloxy-benzyl group may be carried by trifluoroacetic acid in dichloromethane.
  • Suitable coupling reagents for use in the above step 31 include 1 ,3- dicylcohexylcarbodiimide, 1 ,3-diisopropylcarbodiimide, N-ethyl-N'-(3- dimethylaminopropyl)carbodiimide, benzotriazol-1-yloxy- tris(dimethylamino)phosphoniunr) hexafluorophosphate, diphenylphosphoryl azide.
  • a reagent such as N-hydroxysuccinimide, 1- hydroxybenzotriazole or hydroxy-3,4-dihydro-4-oxo-1 ,2,3-benzotriazine may be used in the above step 31 to increase the yields.
  • Suitable solvents for use in the coupling process in step 31 include benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6- tetrahydro-2(1 H)-pyrimidinone, acetonitrile.
  • the reaction temperature of the above step 31 is in the range from - 50 °C to 200 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
  • the compound of general formula (2) may be reacted with tert-butyl-(1-tert-butyl-prop-2-ynyloxy)-dimethyl-silane in the presence of a palladium catalyst, copper (I) iodide, and triethyamine to give a compound of general formula (40) (step 32).
  • Suitable palladium catalysts for use in the above step 32 include tetrakis(triphenylphosphine)palladium, Pd(dba)2, Pd2(dba)3-CHCI3, palladium acetate, palladium chloride, [1 ,1'-bis(diphenylphosphino)- ferrocenejpalladium dichloride dichloromethane complex, (dba; dibenzylideneacetone)
  • a ligand such as triphenylphosphine, tributhylphosphine, tricyclohexylphosphine, 1 ,3-bis(diphenylphosphinopropane) or tri-t-buthyl phosphine, may be used in the above step 32 to increase the catalytic activity and/or the reaction selectivity.
  • Suitable solvents for use in the above step 32 include N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl- 2-imidazolidinone, tetrahydrofuran, toluene, acetonitrile, more preferably N,N-dimethylformamide or acetonitrile.
  • the reaction temperature of the above step 32 is in the range from 0 °C to 200 °C, preferably from 20 °C to 150 °C, though it is not specifically limited so far as the reaction proceeds.
  • Suitable bases for use in the above step 33 include sodium tert- butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably potassium carbonate.
  • Suitable solvents for use in the above step 33 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, methanol, ethanol, isopropanol, acetonitrile,, acetone more preferably N,N-dimethylformamide, acetone.
  • the reaction temperature of the above step 33 is in the range from - 50 °C to 200 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
  • suitable solvents for use in the above step 33 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, more preferably toluene, tetrahydrofuran.
  • the reaction temperature of the above step 33 is in the range from - 50 °C to 200 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
  • Suitable acids for use in the deprotection step of the compounds of general formula (8, 11, 12, 14, 15, 17, 18, 20, 21 , 28, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 40, 42)
  • R a methoxymethyl group, a 2- (trimethylsilyl)ethoxymethyl group, a benzyl group, a p-methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t- buthyldiphenylsilyl group
  • hydrochloric acid hydrobromic acid, sulfuric acid, acetic acid, phosphoric acid, trifluoroacetic acid, formic acid, 10-camphorsulfonic acid, p-toluenesulfonic acid, pyridinium p-toluenesuifonic acid, trifluoroborane-diethyl ether complex, methanesul
  • (trimethylsilyl)ethoxymethyl group, a benzyl group, a p-methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t- buthyldiphenylsilyl group or an acetyl group) is in the range from -50 °C to 200 °C, preferably from -20 °C to 120 °C, though it is not specifically limited so far as the reaction proceeds.
  • Nuclear magnetic resonanse (NMR) analyses were performed on AXR 300 (Bruker), a EX-270 sectrometer (JEOL), or Gemini2000/300 (Varian) in CDCI 3 using tetramethylsilane as a internal standard, otherwise indicated.
  • Mass spectrum (MS) analyses were performed on ZQ2000 (Waters), LOQ Classic (Thermo), or Q-micro, Triple Quadrupole Mass Spectrometer (MICROMASS) in APCI/ESI (atmospheric chemical pressure ionization/ electron spray ionization) negative or positive mode.
  • APCI/ESI atmospheric pressure ionization/ electron spray ionization
  • Example 3 Using the same procedure as described for the preparation of Example 3, the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)).
  • Example 3 Using the same procedure as described for the preparation of Example 3, the title compound was prepared from 4-[1 -ethyl- 1-(4-ethy nyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)).
  • Example 3 Using the same procedure as described for the preparation of Example 3, the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)).
  • Example 3 Using the same procedure as described for the preparation of Example 3, the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)).
  • Example 3 Using the same procedure as described for the preparation of Example 3, the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)).
  • Example 9 Using the same procedure as described for the preparation of Example 9, the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(1-hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 7).
  • Example 9 Using the same procedure as described for the preparation of Example 9, the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(1-hydroxy- cyclohexylethynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 8).
  • Example 9 Using the same procedure as described for the preparation of Example 9, the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy-3-methyl- but-1-ynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 5).
  • Example 9 Using the same procedure as described for the preparation of Example 9, the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy-3-propyl- hex-1 -ynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 4).
  • Example 9 Using the same procedure as described for the preparation of Example 9, the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 3).
  • Example 9 Using the same procedure as described for the preparation of Example 9, the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(1-hydroxy- cyclobutylethynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 6).
  • Enantiomer A Racemic mixture of 2-chloro-4- ⁇ 1-[3-chloro-4-(3-hydroxy-4,4-dimethyl- pent-1-ynyl)-phenyl]-1-ethyl-propyl ⁇ -phenol (compound prepared in Example
  • Enantiomer A Racemic mixture of 4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3- methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 3)
  • Example 5 Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy-3- methyl-but-1-ynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 5). The yield was 58%.
  • Example 1- (7) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy-
  • Example 12 Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-((E)-3-hyd roxy-3- methyl-but-1-enyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 12). The yield was 44%.
  • Example 1- (7) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4- ⁇ 1 -ethyl-1 -[4-((E)-3- hydroxy-3-methyl-but-1 -enyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 22- (1 )). The yield was 90%.
  • Example 1-(4) Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(3-ethyl-3-hydroxy- pent-1 -ynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 1-(4)). The yield was 56%.
  • Example 23-(1) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4- ⁇ 1 -ethyl-1 -[4-(3-ethyl-3- hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 23-(1)). The yield was 76%.
  • Example 4 Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy-3- propyl-hex-1-ynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 4). The yield was 78%.
  • Example 1- (7) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy- 3-propyl-hex-1-ynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 25-(1 )). The yield was 95%.
  • Example 13 Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-((E)-3-hydroxy-3- propyl-hex-1-enyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 13). The yield was 70%.
  • Example 26- (1) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4- ⁇ 1 -ethyl-1 -[4-((E)-3- hydroxy-3-propyl-hex-1-enyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 26- (1)). The yield was 93%.
  • Example 3 Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pent-1 -ynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 3). The yield was 38%.
  • Example 14 Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-((E)-3-hydroxy-4,4- dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 14). The yield was 78%.
  • Example 1- (7) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4- ⁇ 1 -ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 28- (1 )). The yield was 41%.
  • Example 18 Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 18). The yield was 88%.
  • Example 29-(1) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 29-(1)). The yield was 76%.
  • Example 1- (6) Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl ⁇ -2-methyl-phenol (compound prepared in Example 30-(1)). The yield was 62%.
  • Example 35-(3) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4- ⁇ 1 -ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl ⁇ -2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 35-(3)). The yield was 49%.
  • Example 1- (7) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4- ⁇ 1 -ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl ⁇ -2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 31- (1 )). The yield was 54%.
  • Example 6-(1-hydroxy- cyclobutylethynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol compound prepared in Example 6
  • the yield was 51 %.
  • Example 32-(1) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4- ⁇ 1 -ethyl-1 -[4-(1-hydroxy- cyclobutylethynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 32-(1)). The yield was 95%.
  • Example 15 Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-(1 -ethyl-1 - ⁇ 4-[(E)-2-(1-hydroxy- cyclobutyl)-vinyl]-3-methyl-phenyl ⁇ -propyl)-2-methyl-phenol (compound prepared in Example 15). The yield was 74%.
  • Example 33- (1) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-[4-(1 -ethyl-1 - ⁇ 4-[(E)-2-(1 - hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl ⁇ -propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one (compound prepared in Example 33- (1)). The yield was 98%.
  • Example 34-(1 ) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4- ⁇ 1 -ethyl-1 -[4-(1-hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 34-(1 )). The yield was 83%.
  • Example 10 Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-(1 -ethyl-1 - ⁇ 4-[(E)-2-(1-hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl ⁇ -propyl)-2-methyl-phenol (compound prepared in Example 10). The yield was 54%.
  • Example 35- (1) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-[4-(1 -ethyl-1 - ⁇ 4-[(E)-2-(1- hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl ⁇ -propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one (compound prepared in Example 35- (1)). The yield was 97%.
  • Example 8 Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(1-hydroxy- cyclohexylethynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 8). The yield was 72%.
  • Example 11 Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-(1 -ethyl-1 - ⁇ 4-[(E)-2-(1-hydroxy- cyclohexyl)-vinyl]-3-methyl-phenyl ⁇ -propyl)-2-methyl-phenol (compound prepared in Example 11). The yield was 71%.
  • Example 37- (1) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-[4-(1 -ethyl-1 - ⁇ 4-[(E)-2-(1- hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl ⁇ -propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one (compound prepared in Example 37- (1)). The yield was 98%.
  • Example 38-(3) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-heptyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 38-(3)). The yield was 90%.
  • Example 38- (1) Using the same procedure as described for the preparation of Example 38- (1), the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)) and 2,2-dimethyl hexanal. The yield was 24%.
  • Example 38- (2) Using the same procedure as described for the preparation of Example 38- (2), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-oct-1-ynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 39-(1 )). The yield was 86%.
  • Example 39-(2) Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-octyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 39-(2)). The yield was 58%.
  • Example 38- (1) Using the same procedure as described for the preparation of Example 38- (1), the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)) and
  • Example 38- (2) Using the same procedure as described for the preparation of Example 38- (2), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-dec-1-ynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 40-(4)). The yield was 81%.
  • Example 40-(5) Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-decyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 40-(5)). The yield was 67%.
  • Example 40-(6) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-decyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 40-(6)). The yield was
  • Example 40- (1 ) Using the same procedure as described for the preparation of Example 40- (1 ), the title compound was prepared from Isobutyric acid ethyl ester and iodopentane. The yield was 86%.
  • Example 40- (2) Using the same procedure as described for the preparation of Example 40- (2), the title compound was prepared from 2,2-dimethyl-heptanoic acid ethyl ester (compound prepared in Example 41 -(1 )). The yield was 89%.
  • 1 H-NMR 300MHz, CDCI 3 ): 0.86 (s, 6H), 0.89 (t, 3H), 1.23-1.35 (m, 9H), 3.31 (s, 2H).
  • Example 41 -(2) Using the same procedure as described for the preparation of Example 40- (3), the title compound was prepared from 2,2-dimethyl-heptan-1-ol (compound prepared in Example 41 -(2)). The yield was 83%.
  • 1 H-NMR 300MHz, CDCI 3 ): 0.88 (t, 3H), 1.05 (s, 6H), 1.20-1.31 (m, 6H), 1.42-1.48 (m, 2H), 9.45 (s, 1 H).
  • Example 38- (1) Using the same procedure as described for the preparation of Example 38- (1), the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)) and 2,2-dimethyl-heptanal (compound prepared in Example 41 -(3)). The yield was 80%.
  • Example 38- (2) Using the same procedure as described for the preparation of Example 38- (2), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-non-1-ynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 41 -(4)). The yield was 81%.
  • Example 41 -(5) Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-nonyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 41 -(5)). The yield was 65%.
  • Example 41 -(6) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4- ⁇ 1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-nonyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 41 -(6)). The yield was 92%.
  • Example 1-(6) Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-(3-ethyl-3-hyd roxy- pent-1 -ynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 1-(4)) and Toluene-4-sulfonic acid (R)-5-oxo-tetrahydro-furan-2- yl methyl ester. The yield was 51%.
  • Example 42 Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (R)-5-(4- ⁇ 1 -ethyl- 1-[4-(3-ethyl-3- hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 42). The yield was 98%.
  • Example 1-(6) Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 1-(5)) and toluene-4-sulfonic acid (R)-5-oxo-tetrahydro- furan-2-ylmethyl ester. The yield was 82%.
  • Example 1- (6) Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl ⁇ -2- methyl-phenol (compound prepared in Example 2-(2)) and toluene-4-sulfonic acid (R)-5-oxo-tetrahydro-furan-2-ylmethyl ester. The yield was 42%.
  • Example 2- (4) Using the same procedure as described for the preparation of Example 2- (4), the title compound was prepared from (R)-5-(4- ⁇ 1 -ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl ⁇ -2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 46-(1)). The yield was 54%.
  • Example 46-(2) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (R)-5-(4- ⁇ 1 -ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl ⁇ -2- methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 46-(2)). The yield was 96%.
  • Example 1- (6) Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl ⁇ -2-methyl-phenol (compound prepared in Example 30-(1)) and toluene-4-sulfonic acid (R)-5-oxo-tetrahydro-furan-2-ylmethyl ester. The yield was 89%.
  • Example 2- (4) Using the same procedure as described for the preparation of Example 2- (4), the title compound was prepared from (R)-5-(4- ⁇ 1 -ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl ⁇ -2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 48-(1)). The yield was 84%.
  • Example 48-(2) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (R)-5-(4- ⁇ 1 -ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl ⁇ -2- methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 48-(2)). The yield was 93%.
  • the reaction mixture was neutralized by careful addition of sat. NaHCO ⁇ solution and the products were extracted with ethyl acetate. The extracts were washed with brine, dried over MgS0 4 , filtered and concentrated in vacuo. The obtained residue was dissolved in MeOH (5 ml). To the mixture, 1N KOH aq. (0.55 ml, 0.55 mmol) was added at room temperature and the mixture was stirred for 5 h. The reaction mixture was concentrated in vacuo and poured into saturated NH 4 CI aq. The products were extracted with ethyl acetate. The extracts were washed with brine, dried over MgS0 4 , filtered and concentrated in vacuo.
  • Example 51- (2) Using the same procedure as described for the preparation of Example 51- (2), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl ⁇ -2-methyl-phenol (compound prepared in Example 30-(1 )).
  • Example 51- (3) Using the same procedure as described for the preparation of Example 51- (3), the title compound was prepared from (S)-3-(tert-Butyl-dimethyl- silanyloxy)-4-(4- ⁇ 1 -ethyl-1 -[3-methyl-4-((E)-4 ,4,4-trifluoro-3-methoxymethoxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl ⁇ -2-methyl-phenoxy)-butyric acid ethyl ester (compound prepared in Example 52-(1 )).
  • Example 51- (3) Using the same procedure as described for the preparation of Example 51- (3), the title compound was prepared from (R)-3-(tert-Butyl-dimethyl- silanyloxy)-4-(4- ⁇ 1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl ⁇ -2-methyl-phenoxy)-butyric acid ethyl ester (compound prepared in Example 53-(2)).
  • Example 51- (2) Using the same procedure as described for the preparation of Example 51- (2), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl ⁇ -2-methyl-phenol (compound prepared in Example 30-(1)) and 3R- (tert-Butyl-dimethyl-silanyloxy)-4-hydroxy-butyric acid ethyl ester (compound prepared in Example 53-(1)).
  • Example 51- (3) Using the same procedure as described for the preparation of Example 51- (3), the title compound was prepared from (R)-3-(tert-Butyl-dimethyl- silanyloxy)-4-(4- ⁇ 1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifiuoro-3-methoxymethoxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl ⁇ -2-methyl-phenoxy)-butyric acid ethyl ester (compound prepared in Example 54-(1 )).
  • Example 55 Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-6-(4- ⁇ 1 -ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl ⁇ -2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one (compound prepared in Example 55). The yield was 91%.
  • Example 1- (7) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-6-(4- ⁇ 1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl ⁇ -2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one (compound prepared in Example 57-(2)). The yield was 99%.
  • Example 55 Using the same procedure as described for the preparation of Example 55, the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl ⁇ -2- methyl-phenol (compound prepared in Example 2-(2)) and (R)-6- hydroxymethyl-tetrahydro-pyran-2-one (J. Chem. Soc, Perkin Trans. 1, 2000, 20, 3519). The yield was 46%.
  • Example 1- (7) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (R)-6-(4- ⁇ 1 -ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl ⁇ -2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one (compound prepared in Example 59-(2)). The yield was 99%.
  • Example 55 Using the same procedure as described for the preparation of Example 55, the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[3-methyl-4-((E)-4 ,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl ⁇ -2- methyl-phenol (compound prepared in Example 30-(1)) and (R)-6- hydroxymethyl-tetrahydro-pyran-2-one (J. Chem. Soc, Perkin Trans. 1, 2000, 20, 3519). The yield was 35%.
  • Example 59- (2) Using the same procedure as described for the preparation of Example 59- (2), the title compound was prepared from (R)-6-(4- ⁇ 1 -ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl ⁇ -2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one (compound prepared in Example 61 -(1)). The yield was 92%.
  • Example 1- (7) Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (R)-6-(4- ⁇ 1 -ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl ⁇ -2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one (compound prepared in Example 61 -(2)). The yield was quant.
  • Example 63- (2) Using the same procedure as described for the preparation of Example 63- (2), the title compound was prepared from (E)-1-(4- ⁇ 1-[4-((R)-2,2-dimethyl- [1 ,3]dioxolan-4-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl ⁇ -2-methyl- phenyl)-3-ethyl-pent-1-en-3-ol (compound prepared in Example 64-(1)). The yield was 38%.
  • Example 64- (1) Using the same procedure as described for the preparation of Example 64- (1), the title compound was prepared from 4- ⁇ 1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 3). The yield was 74%.
  • Example 64- (1) Using the same procedure as described for the preparation of Example 64- (1), the title compound was prepared from 4- ⁇ 1 -ethyl-1 -[4-((E)-3-hyd roxy-4 ,4- dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl ⁇ -2-methyl-phenol (compound prepared in Example 14). The yield was 74%.
  • Example 64- (1 ) Using the same procedure as described for the preparation of Example 64- (1 ), the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)). The yield was 43%.
  • Example 68- (3) Using the same procedure as described for the preparation of Example 68- (3), the title compound was prepared from (E)-4-(4- ⁇ 1-[4-((R)-2,2-dimethyl- [1 ,3]dioxolan-4-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl ⁇ -2-methyl- phenyl)-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2-ol (compound prepared in Example 69-(1 )). The yield was 74%.

Abstract

The present invention discloses bisphenyl compounds of the formula (1): wherein R1, R2, R3, R4, R5, R6, X, Y, W are defined herein after. These compounds are useful as pharmaceuticals.

Description

BISPHENYL COMPOUNDS USEFUL AS VITAMIN D? RECEPTOR AGONISTS RELATED APPLICATIONS Priority is claimed herein to U.S. provisional patent application no. 60/551 ,193, filed March 08, 2004, entitled BISPHENYL COMPOUNDS USEFUL AS VITAMIN D3 RECEPTOR AGONISTS. The disclosure of the above-referenced application is incorporated by reference herein in its entirety. FIELD OF THE INVENTION This invention relates to novel bisphenyl compounds and their pharmaceutically acceptable salts, pharmaceutical compositions containing said such bisphenyl compounds and the use thereof.
BACKGROUND OF THE INVENTION It is well-known that 1α,25-Dihydroxyvitamin D3 has various physiological activities and is widely used as various pharmaceuticals. For example, the pharmaceutical agent containing 1α,25-Dihydroxyvitamin D3 as active ingredient marketed as ROCALTROL (™) and used for the treatment of psoriasis and secondary hyperparathyroidism. However, it is also well-known that 1α,25-Dihydroxyvitamin D3 has a serious side effect elevating serum calcium level and sometimes it leads to hypercalcemia. Because of this side effect, there are some limitations in administering 1 ,25-Dihydroxyvitamin D3, such as, for example, limitation of maximum administration dosages or limitation of patients to be treated, and therefore, the benefit of the various physiological activities of the compound for treating diseases cannot be fully redlined. To overcome this problem, various derivatives of vitamin D3 have been synthesized, and recently, mimic compounds of the vitamin D3 not having a secosteroidal structure (VD3 mimics) were suggested. For example, International Publication No. WOOO/10958 and corresponding U.S. Patent 6,218,430 B1 disclose bisphenyl compounds useful as VD3 mimics, however, no compound has been launched or tested in clinical trials. Accordingly, there is a demand for a vitamin D3 derivative with stronger physiological activities and weaker calcemic effect than VD3 mimics and compounds previously described.
SUMMARY OF THE INVENTION The present invention relates to bisphenyl compounds useful as modulators of the vitamin D receptor activity or their synthetic intermediates, represented by formula I:
Figure imgf000003_0001
wherein X is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene, an ethynylene, -S(0)n-, -NH-, or -0-; n is an integer of 0 to 2; Y is COOR8, CON(R9)R10, S(0)mR11 or a substituent represented by following formula:
Figure imgf000003_0002
R8 and R11 are each independently selected from an optionally substituted C1-10 alkyl group or an optionally substituted C3-10 cycloalkyl group; R9 and R10 are each independently selected from a hydrogen atom, an optionally substituted C1-10 alkyl group or an optionally substituted C3-10 cycloalkyl group; m is an integer of 0 to 2; a is an integer of 0 to 3; R is a hydrogen atom or a protecting group for a hydroxyl group; R12 and R13 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-10 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted C2-10 alkenyl group, an optionally substituted C2-10 alkynyl group, or R12 and R13 may together form an optionally substituted C3-C12 cycloalkyl group or an optionally substituted 3-12 membered heterocyclic group; W is a hydroxyl group, a carboxyl group, a trifluoromethanesulfonyloxy group or a substituent represented by following formula:
-Q-(CH2)b— ^R15 R-i 6 Q is -0-, -S-, -NH-, an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene, an ethynylen, - (CH2)k-NHC(=0)-, -(CH2)k-C(=0)NH-, -(CH2)k-NHC(=0)NH-, -0-(CH2)k-
NHC(=0)-, -0-(CH2)k-C(=0)NH-, -0-(CH2)k-NHC(=0)NH- or -(CH2)k-S02-; b is an integer of 0 to 10; k is an integer of 0 to 2; R14 is a hydrogen atom, a hydroxyl group, an optionally substituted carboxyl group, an optionally substituted carbamoyl group, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C1-6 alkenyl group, an optionally substituted
C1-6 alkynyl group, an optionally substituted C6-C12 aryl group, an optionally substituted (C6-C12)aryl-(C1-4)alkyl group, -OR17 or -N(R18)R19; R15 and R16 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C6-
C12 aryl group, an optionally substituted (C6-C12)aryl-(C1-4)alkyl group, an optionally substituted 3-12 membered heterocyclic group, or R15 and R16 may together form =0; R17 is selected from an optionally substituted C1-6 alkyl group or an optionally substituted C3-C6 cycloalkyl group; R18 and R19 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C6 cycloalkyl group, or R18 and R19 may together form an optionally substituted C3-C12 cycloalkyl group or an optionally substituted 3-12 membered heterocyclic group; or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and
R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered cyclic ring which is selected from the group consisting of an amidine ring, an amine ring, an ether ring, a lactam ring, a lactone ring, an acetal ring, a hemiacetal ring, a carbonate ring, a carbamate ring, an urea ring, combinations thereof; R1 and R2 are each independently selected from the group consisting of a C1-6 alkyl group optionally substituted with a halogen atom(s), a C3-6 cycloalkyl group optionally substituted with a halogen atom(s), a C2-6 alkenyl group optionally substituted with a halogen atom(s), a C2-6 alkynyl group optionally substituted with a halogen atom(s), or R1 and R2 may together form a C3-8 cycloalkyl group optionally substituted with a halogen atom(s), a C3-8 cycloalkenyl group optionally substituted with a halogen atom(s) or a C3-8 cycloalkylidene group optionally substituted with a halogen atom(s); R3, R4, R5 and R6 are each independently selected from the group consisting of a hydrogen atom, a halogen atom, a C1-6 alkyl group optionally substituted with a halogen atom(s), a C3-6 cycloalkyl group optionally substituted with a halogen atom(s); When X is -S(0)n-, -NH- or -0-, Q is selected from the group consisting of a methylene which may be substituted an C1-4 alkyl group, an ethylene, a vinylene, an ethynylene, -(CH2)k-NHC(=0)-, -(CH2)k-C(=0)NH-, - (CH2)k-NHC(=0)NH-, -(CH2)k-S02-; When Q is -0-, -S-, -NH-, -0-(CH2)k-NHC(=0)-, -0-(CH2)k-C(=0)NH- or -0-(CH2)k-NHC(=0)NH-, X is selected from the group consisting of an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene, an ethynylene; and pharmaceutically acceptable salts and prodrugs thereof. DETAILED DESCRIPTION OF THE INVENTION
Definitions
"Optionally substituted" or "which may be substituted" means that the compounds of the present invention can optionally have one or more substituent(s) in that position. In the case having two or more substituents, each substituents can be same or different. A "halogen atom" according to the invention is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. A "C1-10 alkyl group" according to the invention is a linear or branched alkyl group of 1 to 10 carbons, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, an isohexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group or the like. A "C1-6 alkyl group" according to the invention is a linear or branched alkyl group of 1 to 6 carbons, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec- butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, an isohexyl group or the like. A "C1-4 alkyl group" according to the invention is a linear or branched alkyl group of 1 to 3 carbons, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec- butyl group, a tert-butyl group or the like. A "C1-3 alkyl group" according to the invention is a linear or branched alkyl group of 1 to 3 carbons, such as a methyl group, an ethyl group, a propyl group, an isopropyl group or the like. A "C3-12 cycloalkyl group" according to the invention is a cyclic saturated hydrocarbon group of 3 to 12 carbons, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, a cycloundecyl group, a cyclododecyl group or the like. A "C3-10 cycloalkyl group" according to the invention is a cyclic saturated hydrocarbon group of 3 to 10 carbons, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group or the like. A "C3-8 cycloalkyl group" according to the invention is a cyclic saturated hydrocarbon group of 3 to 8 carbons, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group or the like. A "C3-6 cycloalkyl group" according to the invention is a cyclic saturated hydrocarbon group of 3 to 6 carbons, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or the like. A "C2-10 alkenyl group" according to the invention is a linear, branched or cyclic alkenyl group of 2 to 10 carbons, such as a vinyl group, an allyl group, an isopropenyl group, a 2-butenyl group, a 3-butenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, a 1-cyclopentenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, a 5-hexenyl group, a 1 -cyclohexenyl group or the like. A "C2-6 alkenyl group" according to the invention is a linear, branched or cyclic alkenyl group of 2 to 6 carbons, such as a vinyl group, an allyl group, an isopropenyl group, a 2-butenyl group, a 3-butenyl group, a 2- pentenyl group, a 3-pentenyl group, a 4-pentenyl group, a 1-cyclopentenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, a 5-hexenyl group, a 1 -cyclohexenyl group or the like. A "C3-8 cycloalkenyl group" according to the invention is a cyclic alkenyl group of 3 to 8 carbons, such as a 1-cyclopentenyl group, a 1- cyclohexenyl group, 2-cyclohexenyl group or the like. A "C2-10 alkynyl group" according to the invention is a linear or branched alkynyl group of 2 to 10 carbons, such as an ethynyl group, a 2- propynyl group, a 2-butynyl group, a 3-butynyl group, a 2-pentynyl group, a 3-pentynyl group, a 4-pentynyl group, a 2-hexynyl group, a 3-hexynyl group, a 4-hexynyl group, a 5-hexynyl group or the like. A "C2-6 alkynyl group" according to the invention is a linear or branched alkynyl group of 2 to 6 carbons, such as an ethynyl group, a 2- propynyl group, a 2-butynyl group, a 3-butynyl group, a 2-pentynyl group, a 3-pentynyl group, a 4-pentynyl group, a 2-hexynyl group, a 3-hexynyl group, a 4-hexynyl group, a 5-hexynyl group or the like. A "C6-12 aryl group" according to the invention is an aryl group of 6 to 12 carbons, such as a phenyl group, a naphthyl group or the like. A "(C6-12)aryl-(C1-4)alkyl group" according to the invention is an alkyl group of 1 to 4 carbons with an aryl group of 6 to 12 carbons, such as a benzyl group, a phenethyl group, a 3-phenyl-propyl group, a 4-phenyl-butyl group, a naphthalen-1-yl-methyl group, a naphthalen-2-yl-methyl group or the like. A "3-12 membered heterocyclic group" according to the invention is a mono- and polycyclic group having 3 to 12 membered ring(s) wherein the ring(s) contains at least one heteroatom. Suitable heteroatoms include oxygen, nitrogen, sulfur, phosphorus and boron. Heterocyclic group may be attached at a carbon atom or heteroatom. Heterocyclic groups include an aziridine group, an azetidine group, an oxetane group, a pyrrolidine group, a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an imidazole group, an oxazole group, a thiazolegroup, a 1 ,2,5-oxadiazole group, a 1 ,3,4- oxadiazole group, a 1 ,3,4-thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a tetrazole group, a piperidine group, a pyridine group, a pyridazine group, a pyrimidine group, a pyrazine group, a tetrahydropyran group, a pyran group, a thiopyran group, an indole group, a benzofuran group, a benzothiophene group, an indazole group, a benzisoxazole group, a benzisothiazole group, a benzimidazole group, a benzoxazole group, a benzothiazole gorup, a quinoline group, an isoquinoline group, a cinnoline group, a phthalazine group, a quinazoline group, a quinoxaline group or the like. A "C1-8 alkoxy group" according to the invention is an oxygen group which is substituted with a linear or branched alkyl group, alkenyl group, alkynyl group, aralkyl group or aryl group of 1 to 8 carbons, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a hexyloxy group, an allyloxy, group, a 2-propynyloxy group, a benzyloxy group, a phenoxy group or the like. A "C3-8 cycloalkylidene group" according to the invention is a divalent group formed from cycloalkanes of 3 to 8 carbons by removal of two hydrogen atoms from the same carbon atom, the free valencies of which are part of a double bond. Examples of C3-8 cycloalkylidene groups are such as a cyclopentylidene group, a cyclohexyl idene group, a cycloheptylidene group or the like. A"protecting group for a hydroxyl group" according to the invention is a substituent which is useful for protecting a hydroxyl group, such as a methoxymethyl group, a methylthiomethyl group, a (phenyldimethylsilyl)methoxymethyl group, a benzyloxymethyl group, a p- methoxybenzyloxymethyl group, a p-nitrobenzyloxymethyl group, an o- nitrobenzyloxymethyl group, a (4-methoxyphenoxy)methyl group, a guaiacol methyl group, a t-butoxymethyl group, a 4-pentenyloxymethyl group, a siloxymethyl group, a 2-methoxyethoxymethyl group, 2,2,2- trichloroethoxymethyl group, a bis(2-chloroethoxy)methyl group, a 2- (trimethylsilyl)ethoxymethyl group, a menthoxymethyl group, a tetrahydropyranyl group, a 3-bromotetrahydropyranyl group, a tertahydrothiopyranyl group, a 1 -methoxycyclohexyl group, 4- methoxytetrahydrothiopyranyl, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group, a 1 -ethoxyethyl group, a 1 -(2-chloroethoxy)ethyl group, a 1-[2-(trimethylsilyl)ethoxy]ethyl group, a 1-methyl-1-methoxyethyl group, a 1-methyl-1-benzyloxyethyl group, a 1-methyl-1-benzyloxy-2- fluoroethyl group, a 1 -methyl- 1 -phenoxyethyl group, a 2,2,2-trichloroethyl group, a 1 ,1-dianisyl-2,2,2-trichloroethyl group, a 2-trimethylsilylethyl group, a 2-(benzylthio)ethyl group, a 2-(phenylselenyl)ethyl group, a t-butyl group, an allyl group, a propargyl group, a p-chlorophenyl group, a p- methoxyphenyl group, a p-nitrophenyl group, a 2,4-dinitrophenyl group, a benzyl group, a p-methoxybenzyl group, a 3, 4-di methoxy benzyl group, an o- nitrophenyl group, a p-nitrophenyl group, a p-halobenzyl group, a 2,6- dichlorobenzyl group, a p-cyanobenzyl group, a p-phenylbenzyl group, a 2,6- difluorobenzyl group, a p-acylaminobenzyl group, a 2-triflluoromethyl benzyl group, a 2-picolyl group, a 4-picolyl group, a 2-quinolinylmethyl group, a triphenylmethyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a dimethylisopropylsilyl group, a diethylisopropylsilyl group, a t-butyldimethylsilyl group, a t-buthyldiphenylsilyl group, a tribenzylsilyl group, a triphenylsilyl group, a diphenylmethylsilyl group, a di-t- buthylmethylsilyl group, tris(trimethylsilyl)silyl group, a formyl group, a benzoylformyl group, an acetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a methoxyacetyl group, a pivaloyl group, a benzoyl group, a 2,4,6-trimethylbenzoyl group, a methylcarbonyloxy group, a methoxymethylcarbonyloxy group, an ethylcarbonyloxy group, an isobutylcarbonyloxy group, a vinylcarbonyloxy group, an allylcarbonyloxy group, a benzylcarbonyloxy group, a p-methoxybenzylcarbonyloxy group, an allylsulfonyl group, a methanesulfonyl group, a benzylsulfonyl group, a tosyl group, a trifluoromethanesulfonyl group or the like. The term "pharmaceutically acceptable prodrug" or "prodrug," as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. Prodrugs of the present invention may be rapidly transformed in vivo to a parent compound of formula (I), for example, by hydrolysis in blood. A through discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in drug Design, American Pharmaceutical Association and Pergamon Press (1987), hereby incorporated by reference.
The present invention offers bisphenyl compounds of formula I.
In the above fomula I, X is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene, an ethynylene, -S(0)n-, -NH-, or -0-. Preferable X is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene or an ethynylene. More preferable X is a methylene, an ethylene, a vinylene or an ethynylene a methylene. Furthermore preferable X is an ethylene, a vinylene or an ethynylene a methylene. "An optionally substituted methylene" is, in particular, a methylene which may be substituted with a halogen atom(s) and/or a C1-4 alkyl group(s), and is preferablely a methylene. "An optionally substituted vinylene" is, in particular, a vinylene which may be substituted with a halogen atom(s) and/or a C1-4 alkyl group(s), and is preferablely a vinylene. "An optionally substituted ethylene" is, in particular, an ethylene which may be substituted with a halogen atom(s) and/or a C1-4 alkyl group(s), and is preferablely an ethylene. In "-S(0)n-", n is an integer of 0 to 2, therefore, "-S(0)n-" means -S-, - SO- or -S02-. In the above fomula I, Y is COOR8, CON(R9)R10, S(0)mR11 or a substituent represented by following formula:
Figure imgf000011_0002
Preferable Y is a substituent represented by following formula:
Figure imgf000012_0001
In "COOR8", R8 is selected an optionally substituted C1-10 alkyl group or an optionally substituted C3-10 cycloalkyl group. In this case, "an optionally substituted C1-10 alkyl group" is, in particular, a C1-10 alkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C1-10 alkyl group. "An optionally substituted C3-10 cycloalkyl group" is, in particular, a C3-10 cycloalkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C3-10 cycloalkyl group. In "CON(R9)R10", R9 and R10 are each independently selected from a hydrogen atom, an optionally substituted C1-10 alkyl group or an optionally substituted C3-10 cycloalkyl group. In this case, "an optionally substituted C1-10 alkyl group" is, in particular, a C1-10 alkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C1- 10 alkyl group. "An optionally substituted C3-10 cycloalkyl group" is, in particular, a C3-10 cycloalkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C3-10 cycloalkyl group. In "S(0)mR11", m is an integer of 0 to 2, therefore, "S(0)mR11" means -S-R11 , -SO-R11 or -S02-R11 , and R11 is selected an optionally substituted C1-10 alkyl group or an optionally substituted C3-10 cycloalkyl group. In this case, "an optionally substituted C1-10 alkyl group" is, in particular, a C1-10 alkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C1-10 alkyl group. "An optionally substituted C3-10 cycloalkyl group" is, in particular, a C3-10 cycloalkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C3-10 cycloalkyl group. When Y is a substituent represented by following formula:
Figure imgf000013_0001
a is an integer of 0 to 3, and is preferablely 0. R is a hydrogen atom or a protecting group for a hydroxyl group. As a modulator of the vitamin D receptor activity, R is preferablely a hydrogen atom. The compound wherein R is a protecting group for a hydroxyl group is useful as a synthetic intermediate of a modulator of the vitamin D receptor activity. However, some of these compounds exhibit the vitamin D receptor modulating activity, and such compounds are also useful as a modulator of the vitamin D receptor activity. "A protecting group for a hydroxyl group" is, in particular, a methoxymethyl group, a methylthiomethyl group, a (phenyldimethylsilyl)methoxymethyl group, a benzyloxymethyl group, a p- methoxybenzyloxymethyl group, a p-nitrobenzyloxymethyl group, an o- nitrobenzyloxymethyl group, a (4-methoxyphenoxy)methyl group, a guaiacolmethyl group, a t-butoxymethyl group, a 4-pentenyloxymethyl group, a siloxymethyl group, a 2-methoxyethoxymethyl group, 2,2,2- trichloroethoxymethyl group, a bis(2-chloroethoxy)methyl group, a 2- (trimethylsilyl)ethoxymethyl group, a menthoxymethyl group, a tetrahydropyranyl group, a 3-bromotetrahydropyranyl group, a tertahydrothiopyranyl group, a 1 -methoxycyclohexyl group, 4- methoxytetrahydrothiopyranyl, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group, a 1 -ethoxyethyl group, a 1 -(2-chloroethoxy)ethyl group, a 1-[2-(trimethylsilyl)ethoxy]ethyl group, a 1-methyl-1-methoxyethyl group, a 1 -methyl- 1 -benzyloxyethy I group, a 1-methyl-1-benzyloxy-2- fluoroethyl group, a 1-methyl-1-phenoxyethyl group, a 2,2,2-trichloroethyl group, a 1 ,1-dianisyl-2,2,2-trichloroethyl group, a 2-tri methylsi lyl ethyl group, a 2-(benzylthio)ethyl group, a 2-(phenylselenyl)ethyl group, a t-butyl group, an allyl group, a propargyl group, a p-chlorophenyl group, a p- methoxyphenyl group, a p-nitrophenyi group, a 2,4-dinitrophenyl group, a benzyl group, a p-methoxybenzyl group, a 3,4-dimethoxybenzyl group, an o- nitrophenyl group, a p-nitrophenyl group, a p-halobenzyl group, a 2,6- dichlorobenzyl group, a p-cyanobenzyl group, a p-phenylbenzyl group, a 2,6- difluorobenzyl group, a p-acylaminobenzyl group, a 2-triflluoromethyl benzyl group, a 2-picolyl group, a 4-picolyl group, a 2-quinolinylmethyl group, a triphenylmethyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a dimethylisopropylsilyl group, a diethylisopropylsilyl group, a t-butyldimethylsilyl group, a t-buthyldiphenylsilyl group, a tribenzylsilyl group, a triphenylsilyl group, a diphenylmethylsilyl group, a di-t- buthylmethylsilyl group, tris(trimethylsilyl)silyl group, a formyl group, a benzoylformyl group, an acetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a methoxyacetyl group, a pivaloyl group, a benzoyl group, a 2,4,6-trimethylbenzoyl group, a methylcarbonyloxy group, a methoxymethylcarbonyloxy group, an ethylcarbonyloxy group, an isobutylcarbonyloxy group, a vinylcarbonyloxy group, an allylcarbonyloxy group, a benzylcarbonyloxy group, a p-methoxybenzylcarbonyloxy group, an allylsulfonyl group, a methanesulfonyl group, a benzylsulfonyl group, a tosyl group, a trifluoromethanesulfonyl group or the like. "A protecting group for a hydroxyl group" is preferablely selected from a methoxymethyl group, a 2- (trimethylsilyl)ethoxymethyl group, a tetrahydropyranyl group, a benzyl group, a p-methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t-buthyldiphenylsilyl group, an acetyl group, a pivaloyl group, a benzoyl group, a methanesulfonyl group, a tosyl group or a trifluoromethanesulfonyl group. R12 and R13 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-10 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted C2-10 alkenyl group, an optionally substituted C2-10 alkynyl group, or R12 and R13 may together form an optionally substituted C3-C12 cycloalkyl group or an optionally substituted 3-12 membered heterocyclic group. R12 and R13 are preferablely each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-10 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted C2-10 alkenyl group, an optionally substituted C2-10 alkynyl group, or R12 and R13 may together form an optionally substituted C3-C12 cycloalkyl group. R12 and R13 are more preferablely each independently selected from the group consisting of a hydrogen atom, a C1-8 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3- 8 cycloalkyl group which may be substituted with a C1-4 alkyl group. R12 and R13 are furthermore preferablely each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3- 8 cycloalkyl group. Especially, R12 and R13 are preferablely selected from the group consisting of i) one of R12 and R13 is a hydrogen atom and the other is a C1-6 alkyl group, ii) one of R12 and R13 is a hydrogen atom and the other is a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, iii) both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group. One of the preferred combinations of R12 and R13 are, in particular, a hydrogen atom and a tert-butyl group, or both a trifluoromethyl group. In this case, "an optionally substituted C1-10 alkyl group" is, in particular, a C1-10 alkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1 -8 alkoxy group(s), and is preferablely a C1 -10 alkyl group. "An optionally substituted C1-10 alkenyl group" is, in particular, a C1-10 alkenyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C1-10 alkenyl group. "An optionally substituted C1-10 alkynyl group" is, in particular, a C1-10 alkynyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C1-10 alkynyl group. "An optionally substituted C3-10 cycloalkyl group" is, in particular, a C3-10 cycloalkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s), a C1-4 alkyl group and/or a C1-8 alkoxy group(s), and is preferablely a C3-10 cycloalkyl group which may be substituted with a C1-4 alkyl group. "An optionally substituted 3-12 membered heterocyclic group" is, in particular, a 3-12 membered heterocyclic group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s). In the above fomula I, W is a hydroxyl group, a carboxyl group, a trifluoromethanesulfonyloxy group or a substituent represented by following formula:
Figure imgf000016_0001
As a modulator of the vitamin D receptor activity, W is preferablely a substituent represented by following formula:
Figure imgf000016_0002
Among them, especially as pharmaceuticals for the treatment of osteoporosis, the compound having a carboxyl group at its terminal end is preffered. On the other hand, the compound wherein W is a hydroxyl group, a carboxyl group or a trifluoromethanesulfonyloxy group is useful as a synthetic intermediate of a modulator of the vitamin D receptor activity. However, some of these compounds exhibit the vitamin D receptor modulating activity, and such compounds are also useful as a modulator of the vitamin D receptor activity. When Y is a substituent represented by following formula:
Figure imgf000016_0003
, b is an integer of 0 to 10, is preferablely an integer of 0 to 5, and is more preferablely 0, 1 or 2. Q is -0-, -S-, -NH-, an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene, an ethynylene, - (CH2)k-NHC(=0)-, -(CH2)k-C(=0)NH-, -(CH2)k-NHC(=0)NH-, -0-(CH2)k- NHC(=0)-, -0-(CH2)k-C(=0)NH-, -0-(CH2)k-NHC(=0)NH- or -(CH2)k-S02-. Preferable Q is selected from -0-, a methylene, an ethylene, a vinylene, an ethynylene, -(CH2)k-C(=0)NH- or -0-(CH2)k-C(=0)NH-. In this case, k is an integer of 0 to 2, and is preferablely 1. "An optionally substituted methylene" is, in particular, a methylene which may be substituted with a halogen atom(s) and/or a C1-4 alkyl group(s), and is preferablely a methylene. "An optionally substituted vinylene" is, in particular, a vinylene which may be substituted with a halogen atom(s) and/or a C1-4 alkyl group(s), and is preferablely a vinylene. "An optionally substituted ethylene" is, in particular, an ethylene which may be substituted with a halogen atom(s) and/or a C1-4 alkyl group(s), and is preferablely an ethylene. R14 is a hydrogen atom, a hydroxyl group, an optionally substituted carboxyl group, an optionally substituted carbamoyl group, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C1-6 alkenyl group, an optionally substituted C1-6 alkynyl group, an optionally substituted C6-C12 aryl group, an optionally substituted (C6-C12)aryl-(C1 -4)alkyl group, -OR17 or -N(R18)R19. R14 is preferablely a hydrogen atom, a hydroxyl group, a carboxyl group which may be substituted with a C1-4 alkyl group, a carbamoyl group which may be substituted with a C1-4 alkyl group, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group which may be substituted with a C1- 4 alkyl group, a phenyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a benzyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, - OR17 or -N(R18)R19. R14 is more preferablely a hydrogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group, a phenyl group which may be substituted with a hydroxyl group or a carboxyl group, a benzyl group which may be substituted with a hydroxyl group or a carboxyl group, -OR17 or -N(R18)R19. In "-OR17", R17 is an optionally substituted C1-6 alkyl group or an optionally substituted C3-C6 cycloalkyl group. R17 is preferablely a C1-4 alkyl group. In this case, "an optionally substituted C1-6 alkyl group" is, in particular, a C1-6 alkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C1-6 alkyl group. "An optionally substituted C3-6 cycloalkyl group" is, in particular, a C3-6 cycloalkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C3-6 cycloalkyl group. In "-N(R18)R19", R18 and R19 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C6 cycloalkyl group, or R18 and R19 may together form an optionally substituted C3-C12 cycloalkyl group or an optionally substituted 3-12 membered heterocyclic group. R18 and R19 are preferablely each independently selected from a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C6 cycloalkyl group. R18 and R19 are more preferablely each independently selected from a hydrogen atom or a C1-4 alkyl group. Especially, it is preferred that R18 is a hydrogen atom and R19 is a hydrogen atom, i.e. "- N(R18)R19" represents an amino group. In this case, "an optionally substituted C1-6 alkyl group" is, in particular, a C1-6 alkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C1-6 alkyl group. "An optionally substituted C3-6 cycloalkyl group" is, in particular, a C3-6 cycloalkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C3-6 cycloalkyl group. "An optionally substituted C3-12 cycloalkyl group" is, in particular, a C3-12 cycloalkyl group which may be substituted with a halogen atom(s), a hydroxyl group(s), an amino group(s), a carboxyl group(s) and/or a C1-8 alkoxy group(s), and is preferablely a C3-12 cycloalkyl group. R15 and R16 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C6- C12 aryl group, an optionally substituted (C6-C12)aryl-(C1-4)alkyl group, an optionally substituted 3-12 membered heterocyclic group, or R15 and R16 may together form =0. R15 and R16 are preferablely each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C6-C12 aryl group, an optionally substituted (C6-C12)aryl-(C1-4)alkyl group, an optionally substituted 3-12 membered heterocyclic group selected from the group consisting of an aziridine group, an azetidine group, an oxetane group, a pyrrolidine group, a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an imidazole group, an oxazole group, a thiazolegroup, a 1 ,2,5-oxadiazole group, a 1 ,3,4-oxadiazole group, a 1 ,3,4-thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a tetrazole group, a piperidine group, a pyridine group, a pyridazine group, a pyrimidine group, a pyrazine group, a tetrahydropyran group, a pyran group, a thiopyran group, an indole group, a benzofuran group, a benzothiophene group, an indazole group, a benzisoxazole group, a benzisothiazole group, a benzimidazole group, a benzoxazole group, a benzothiazole gorup, a quinoline group, an isoquinoline group, a cinnoline group, a phthalazine group, a quinazoline group, a quinoxaline group, or R15 and R16 may together form =0. R15 and R16 are more preferablely each independently selected from the group consisting of a hydrogen atom, a C1- 6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group which may be substituted with a C1-4 alkyl group, a phenyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a benzyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a 3-8 membered heterocyclic group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, wherein said heterocyclic group selected from the group consisting of an oxetane group, a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an oxazole group, a thiazole group, a 1 ,2,5-oxadiazole group, a 1 ,3,4-oxadiazole group, a
1 ,3,4-thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a tetrazole group, a pyridine group, a pyridazine group, a pyrimidine group, a pyrazine group, a tetrahyd ropy ran group, a pyran group, a thiopyran group, or R15 and R16 may together form =0. R15 and R16 are furthermore preferablely each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group, a phenyl group which may be substituted with a hydroxyl group or a carboxyl group, a benzyl group which may be substituted with a hydroxyl group or a carboxyl group, a 3-8 membered heterocyclic group selected from the group consisting of a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an oxazole group, a thiazole group, a 1 ,2,5- oxadiazole group, a 1 ,3,4-oxadiazole group, a 1 ,3,4-thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a pyridine group, a tetrahyd ropyran group. Regarding R14, R15 and R16, it is preferred that at least one of R14, R15 or R16 is a hydrogen atom, and/or at least one of R14, R15 or R16 is a substituent which have a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group. Also, it is preferred that R14 is a hydroxyl group, and/or one of R15 and R16 is a hydrogen atom and the other is a C1-6 alkyl group substituted with a carboxyl group. Or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered cyclic ring which is selected from the group consisting of an amidine ring, an amine ring, an ether ring, a lactam ring, a lactone ring, an acetal ring, a hemiacetal ring, a carbonate ring, a carbamate ring, an urea ring, combinations thereof. In this case, said cyclic ring is preferablely a lactam ring or a lactone ring, and is more preferablely a lactone ring. In the above fomula I, R1 and R2 are each independently selected from the group consisting of a C1-6 alkyl group optionally substituted with a halogen atom(s), a C3-6 cycloalkyl group optionally substituted with a halogen atom(s), a C2-6 alkenyl group optionally substituted with a halogen atom(s), a C2-6 alkynyl group optionally substituted with a halogen atom(s), or R1 and R2 may together form a C3-8 cycloalkyl group optionally substituted with a halogen atom(s), a C3-8 cycloalkenyl group optionally substituted with a halogen atom(s) or a C3-8 cycloalkylidene group optionally substituted with a halogen atom(s). Preferable R1 is a C1-6 alkyl group, more preferable R1 is a C1-4 alkyl group, and the most preferable R1 is an ethyl group. Preferable R2 is a C1-6 alkyl group, more preferable R2 is a C1-4 alkyl group, and the most preferable R2 is an ethyl group. In the above fomula I, R3, R4, R5 and R6 are each independently selected from a hydrogen atom, a halogen atom, a C1-6 alkyl group optionally substituted with a halogen atom(s) or a C3-6 cycloalkyl group optionally substituted with a halogen atom(s). Preferable R3 is a hydrogen atom or a C1-6 alkyl group, more preferable R3 is a hydrogen atom or a C1-4 alkyl group, and the most preferable R3 is a hydrogen atom or a methyl group. Preferable R4 is a halogen atom or a C1-6 alkyl group, more preferable R4 is a halogen atom or a C1-4 alkyl group, and the most preferable R4 is a chlorine atom or a methyl group. Preferable R5 is a hydrogen atom. Preferable R6 is a halogen atom or a C1-6 alkyl group, more preferable R6 is a halogen atom or a C1-4 alkyl group, and the most preferable R6 is a chlorine atom, a methyl group, an ethyl group, a propyl group or an isopropyl group. When X is -S(0)n-, -NH- or -0-, Q is selected from a methylene which may be substituted an C1-4 alkyl group, an ethylene, a vinylene, an ethynylene, -(CH2)k-NHC(=0)-, -(CH2)k-C(=0)NH-, -(CH2)k-NHC(=0)NH- or -(CH2)k-S02-; When Q is -0-, -S-, -NH-, -0-(CH2)k-NHC(=0)-, -0-(CH2)k-C(=0)NH- or -0-(CH2)k-NHC(=0)NH-, X is selected from an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene or an ethynylene.
Examples of the preferred compounds of the present invention are represented as follows. (1) The compound of the above fomula I wherein X is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene or an ethynylene; Y is COOR8, CON(R9)R10, S(0)mR11 or a substituent represented by following formula:
Figure imgf000022_0001
R is a hydrogen atom; R12 and R13 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-10 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted C1-10 alkenyl group, an optionally substituted C1-10 alkynyl group, or R12 and R13 may together form an optionally substituted C3-10 cycloalkyl group; W is a substituent represented by following formula:
— Q-(CH2)b— ^R15 R16 Q is -0-, a methylene, an ethylene, a vinylene, an ethynylene, - (CH2)k-C(=0)NH- or -0-(CH2)k-C(=0)NH-; R15 and R16 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C6- C12 aryl group, an optionally substituted (C6-C12)aryl-(C1-4)alkyl group, an optionally substituted 3-12 membered heterocyclic group selected from the group consisting of an aziridine group, an azetidine group, an oxetane group, a pyrrolidine group, a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an imidazole group, an oxazole group, a thiazolegroup, a 1 ,2,5- oxadiazole group, a 1 ,3,4-oxadiazole group, a 1 ,3,4-thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a tetrazole group, a piperidine group, a pyridine group, a pyridazine group, a pyrimidine group, a pyrazine group, a tetrahyd ropyran group, a pyran group, a thiopyran group, an indole group, a benzofuran group, a benzothiophene group, an indazole group, a benzisoxazole group, a benzisothiazole group, a benzimidazole group, a benzoxazole group, a benzothiazole gorup, a quinoline group, an isoquinoline group, a cinnoline group, a phthalazine group, a quinazoline group, a quinoxaline group, or R15 and R16 may together form =0; R17 is an optionally substituted C1-6 alkyl group or an optionally substituted C3-C6 cycloalkyl group; R18 and R19 are each independently selected from a hydrogen atom, an optionally substituted C1-6 alkyl group or an optionally substituted C3-C6 cycloalkyl group; or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered cyclic ring which is selected from a lactam ring or a lactone ring; R1 is a C1-6 alkyl group; R2 is a C1-6 alkyl group; R3 is a hydrogen atom or a C1-6 alkyl group; R4 is a halogen atom or a C1-6 alkyl group; R5 is a hydrogen atom; R6 is a halogen atom or a C1-6 alkyl group.
(2) The compound according to (1 ) wherein X is an ethylene, a vinylene, or an ethynylene; Y is a substituent represented by following formula:
Figure imgf000024_0001
R is a hydrogen atom; R12 and R13 are each independently selected from the group consisting of a hydrogen atom, a C1-8 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group; W is a substituent represented by following formula:
-Q-(CH2)b— ^R15 R16 Q is -0-, a methylene, an ethylene, a vinylene, an ethynylene, -
(CH2)k-C(=0)NH- or -0-(CH2)k-C(=0)NH-; b is an integer of 0 to 5; R14 is a hydrogen atom, a hydroxyl group, a carboxyl group which may be substituted with a C1-4 alkyl group, a carbamoyl group which may be substituted with a C1-4 alkyl group, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group which may be substituted with a C1-
4 alkyl group, a phenyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a benzyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, -
OR17 or -N(R18)R19; R15 and R16 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group which may be substituted with a C1-4 alkyl group, a phenyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a benzyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a 3-8 membered heterocyclic group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, wherein said heterocyclic group selected from the group consisting of an oxetane group, a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an oxazole group, a thiazole group, a 1 ,2,5-oxadiazole group, a 1 ,3,4- oxadiazole group, a 1 ,3,4-thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a tetrazole group, a pyridine group, a pyridazine group, a pyrimidine group, a pyrazine group, a tetrahyd ropyran group, a pyran group, a thiopyran group, or R15 and R16 may together form =0; and at least one of R14, R15 or R16 is a hydrogen atom; R17 is a C1-4 alkyl group; R18 and R19 are each independently selected from a hydrogen atom or a C1-4 alkyl group; or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered lactone ring. (3) The compound according to (2) wherein R12 and R13 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3-8 cycloalkyl group; W is a substituent represented by following formula:
Figure imgf000026_0001
Q is -0-, -(CH2)k-C(=0)NH- or -0-(CH2)k-C(=0)NH-; b is O, 1 or 2; k is 1 ; R14 is a hydrogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group, a phenyl group which may be substituted with a hydroxyl group or a carboxyl group, a benzyl group which may be substituted with a hydroxyl group or a carboxyl group, -OR17 or -N(R18)R19; R15 and R16 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group, a phenyl group which may be substituted with a hydroxyl group or a carboxyl group, a benzyl group which may be substituted with a hydroxyl group or a carboxyl group, a 3-8 membered heterocyclic group selected from the group consisting of a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an oxazole group, a thiazole group, a 1 ,2,5-oxadiazole group, a 1 ,3,4-oxadiazole group, a 1 ,3,4- thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a pyridine group, a tetrahydropyran group; and at least one of R14, R15 or R16 is a hydrogen atom; R18 is a hydrogen atom; R19 is a hydrogen atom; or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered lactone ring; R1 is a C1-4 alkyl group; R2 is a C1-4 alkyl group; R3 is a hydrogen atom or a C1-4 alkyl group; R4 is a halogen atom or a C1-4 alkyl group; R5 is a hydrogen atom; R6 is a halogen atom or a C1-4 alkyl group. > (4) The compound according to (3) wherein R12 and R13 are selected from the group consisting of one of R12 and R13 is a hydrogen atom and the other is a C1- 6 alkyl group, one of R12 and R13 is a hydrogen atom and the other is a C3- 8 cycloalkyl group which may be substituted with a C1-4 alkyl group, both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group; Q is -O- or -0-(CH2)k-C(=0)NH-; R1 is an ethyl group; R2 is an ethyl group; R3 is a hydrogen atom or a methyl group; R4 is a chlorine atom or a methyl group; R6 is a chlorine atom, a methyl group, an ethyl group, a propyl group or an isopropyl group.
(5) The compound according to (4) selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 - Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 - Ethyl-1 -[4-(3-hydroxy-4,4-di methyl-pent- 1 -ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy )-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 - Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4- [(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxy]-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- hexanoic acid, 1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol, (E)-4-[4-(1 -Ethyl-1 -{3- methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1- trifluoro-2-trifluoromethyl-but-3-en-2-ol, (E)-1 -(4-{1 -[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1 -en-3-ol, 1 - [(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2- methyl-phenyl)-vinyl]-cyclopentanol, (E)-4-(4-{1-[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2- trifluoromethyl-but-3-en-2-ol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy- 4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4- (3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- benzoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1,4- diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(R)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 -trif luoro-2-trif luoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(S)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 -trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-propyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-propyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 5(S)-hydroxy-hexanoic acid, 6(R)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro- pyran-2-one, (E)-N-(2-Amino-ethyl)-2-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hyd roxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetamide, (E)-5- (4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-oxo-pentanoic acid, 2- (R)- [2-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- acetylaminoj-propionic acid, 2- (S)-[2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-3- phenyl-propionic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo-pentanoic acid, 5-(4-{1 - Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-pentane-1 ,4-diol, (R)-5-(2-Chloro-4-{1 -[3-chloro-4-((R)-3- hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxymethyl)- dihydro-furan-2-one, (R)-5-(2-Chloro-4-{1 -[3-chloro-4-((S)-3-hydroxy-4,4- dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro- furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro- furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5- (4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 - methyl-cyclohexyl)-prop-1-ynyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 - methyl-cyclohexyl)-propyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 - methyl-cyclopentyl)-prop-1-ynyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1- methyl-cyclopentyl)-propyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 - methyl-cyclopropyl)-prop-1-ynyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 - methyl-cyclopropyl)-propyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl-1 -[4-((S)-3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (S)-5-(4-{1 -[4-((E)-1 ,3-Diethyl-3- hydroxy-pent-1 -enyl)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,5,5,5-pentafluoro-3-hydroxy-3-pentafluoroethyl-pent-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3- methyl-4-(2-methyl-propane-2-sulfinylmethyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(2- methyl-propane-2-sulfonylmethyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4, 4,4- trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2τone, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- ethyl-3-hydroxy-1-methyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-dec-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hept-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hex-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-non-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-oct-1-en-4-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1- enyl)-3-methyl-phenyl]-propyl}-phenoxymethyl)-dihydro-furan-2-one, (S)-5- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-propyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- ethyl-3-hydroxy-undec-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-undec-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-propyl-hex-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(1-hydroxy- cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5- (4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl- 3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 -ynyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)- 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-propyl-hex-1 -ynyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-decyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-heptyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro- furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-nonyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1- Ethyl- 1 -[4-(3-hyd roxy-4 ,4-d i methyl-octyl )-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4- dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5- [4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)- 2-methyl-phenoxymethyl]-dihydro-furan-2-one, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2- (1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (S)-5-{4-[1-(4-tert-Butylsulfanylmethyl- 3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxymethyl}-dihydro-furan-2- one, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl- 1-[4-((R)-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[4-((S)-3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one.
(6) The compound according to (4) wherein R3 is a hydrogen atom.
(7) The compound according to (6) selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1- Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2- methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1-
Ethyl-1-[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S )-3-(4-{1 -Ethyl- 1 -[4-((E)-3-ethyl-3-hyd roxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-l-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4- [(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxy]-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- hexanoic acid , 1 -(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol, (E)-4-[4-(1 -Ethyl-1 -{3- methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1- trifluoro-2-trifluoromethyl-but-3-en-2-ol, (E)-1 -(4-{1 -[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1-en-3-ol, 1- [(E)-2-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2- methyl-phenyl)-vinyl]-cyclopentanol, (E)-4-(4-{1-[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1 -trifluoro-2- trifluoromethyl-but-3-en-2-ol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy- 4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4- (3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- benzoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(R)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(S )-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-propyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-propyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5(S)-hydroxy-hexanoic acid, 6(R)-(4-{1 - Ethyl-1-[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (E)-N-(2-Amino-ethyl)-2-(4- {1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-acetamide, (E)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent- 1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo-pentanoic acid, 2- (R)- [2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-acetylamino]-propionic acid, 2- (S)-[2-(4-{1 -Ethyl- 1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl )-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-acetylamino]-3-phenyl-propionic acid, 5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4- oxo-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol.
(8) The compound according to (4) wherein R4 is a chlorine atom.
(9) The compound according to (8) selected from 5-(2-Chloro-4-{1 -[3- chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-
4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4- dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl- pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2- Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1 -ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt.
(10) The compound according to (4) wherein R6 is a chlorine atom. (11) The compound according to (10) selected from the group consisting of 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro- 4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}- phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1 -[3- chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)- 4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4- dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt.
(12) The compound according to (4) wherein R6 is a methyl group. (13) The compound according to (12) selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5- (4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4- {1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pent-1 -ynyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1-Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 - Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl )-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy- pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro- 3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4- [(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxy]-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- hexanoic acid, 1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol, (E)-4-[4-(1 -Ethyl-1 -{3- methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1- trifluoro-2-trifluoromethyl-but-3-en-2-ol, (E)-1 -(4-{1 -[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1-en-3-ol, 1- [(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2- methyl-phenyl)-vinyl]-cyclopentanol, (E)-4-(4-{1-[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1-trifluoro-2- trifluoromethyl-but-3-en-2-ol, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- benzoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(R)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 -trif luoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(S)-1-(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 -trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-propyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-propyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 5(S)-hydroxy-hexanoic acid, 6(R)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro- pyran-2-one, (E)-N-(2-Amino-ethyl)-2-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetamide, (E)-5- (4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-oxo-pentanoic acid, 2- (R)- [2-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- acetylamino]-propionic acid, 2- (S)-[2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-3- phenyl-propionic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo-pentanoic acid, 5-(4-{1 - Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-pentane-1 ,4-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3- hyd roxy-4 ,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4- (3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 6-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5(S)-hydroxy- hexanoic acid.
(14) The compound according to (4) wherein X is an ethylene.
(15) The compound according to (14) selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2- (4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)- phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 - [4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol, 2- (R)- [2-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-acetylamino]-propionic acid, 2- (S)-[2-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- acetylamino]-3-phenyl-propionic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo- pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol. (16) The compound according to (4) wherein X is a vinylene.
(17) The compound according to (16) selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5- (4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4- [(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxy]-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy- cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5- (4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5- (4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4- (4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4- {1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 - Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1- enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)- 6-(4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl- but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)- 6-(4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl- but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 - Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane- 1 ,3-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1- Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1- enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 5-(4-{1 - Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclopentyl)- vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 5-[4-(1 - Ethyl-1 -{4-[(E)-2-( 1 -hyd roxy-cyclohexyl )-vi nyl]-3-methyl-phenyl}-pro pyl )-2- methyl-phenoxy]-pentanoic acid, 3-(4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-propionic acid, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)- butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but- 3-en-2-ol, (E)-1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-3-ethyl-pent-1-en-3-ol, 1-[(E)-2-(4-{1-[4-(5-Amino- pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-vinyl]- cyclopentanol, (E)-4-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2-ol, 4-(4- {1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxymethyl)-benzoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-pentane-1 ,4-diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(R)-1 - (tetrahyd ro-furan-2-yl)methoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1,1- trifluoro-2-trifluoromethyl-but-3-en-2-ol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-pentane-1 ,4-diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(S)-1- (tetrahydro-furan-2-yl)methoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1- trifluoro-2-trifluoromethyl-but-3-en-2-ol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-phenoxy)-4-hydroxy- pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2,6-dimethyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]- propyl}-2,6-dimethyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 - [4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-propyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-propyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, 6(R)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (E)-N-(2-Amino-ethyl)-2-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetamide, (E)-5-(4-{1 -Ethyl-1 -[4- (3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 4-oxo-pentanoic acid.
(18) The compound according to (4) wherein X is an ethynylene.
(19) The compound according to (18) selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trif luoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-6- (4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)- 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - ynyI)-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)- 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4- {1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane- 1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2- diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl- but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol.
(20) The compound according to (4) wherein one of R12 and R13 is a hydrogen atom and the other is a C1-6 alkyl group.
(21 ) The compound according to (20) wherein one of R12 and R13 is a hydrogen atom and the other is a tert-butyl group.
(22) The compound according to (21) selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-3- (4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4-di methyl-pent- 1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 1-(4-{1- [4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)- 4,4-dimethyl-pentan-3-ol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5- (4-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1 -Ethyl-1 - [4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methylτphenoxy)-4(R)-hydroxy- pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4- dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1- ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2- Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1 -ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4- (3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 6-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5(S)-hydroxy- hexanoic acid, 2- (R)- [2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-propionic acid, 2- (S)-[2-(4-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-acetylamino]-3-phenyl-propionic acid. (23) The compound according to (4) wherein both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s).
(24) The compound according to (23) wherein R12 is a trifluoromethyl group and R13 are is a trifluoromethyl group.
(25) The compound according to (24) selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5- (4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4- {1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4- hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)- vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -enyl)-phenyl]- propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl- 1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-6-(4-{1- Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)- phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4- {1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)- phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4- {1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 - Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1- enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)- 6-(4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl- but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)- 3-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane- 1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1- Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2- (4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 - Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 - Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-((E)-3- ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}- propyl)-2-methyl-phenoxy]-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]- pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)- 2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2-ol, (E)-1-(4-{1-[4- (5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3- ethyl-pent- 1-en-3-ol, 1-[(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]- 1 -ethyl-propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol, (E)-4-(4-{1 -[4-(5- Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1- trifluoro-2-trifluoromethyl-but-3-en-2-ol, 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- benzoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(R)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(S)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1- enyl)-3-propyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-propyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, 6(R)-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (E)-N-(2-Amino-ethyl)-2-(4-{1 -ethyl- 1-[4-(3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-acetamide, (E)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo-pentanoic acid, 2- (R)- [2- (4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-acetylamino]-propionic acid, 2- (S)-[2-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- acetylamino]-3-phenyl-propionic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo- pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol. (26) The compound according to (4) wherein Q is -0-.
(27) The compound according to (26) selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5- (4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4- {1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1-Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 - Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyi]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4- [(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxy]-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- hexanoic acid, 1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol, (E)-4-[4-(1 -Ethyl-1 -{3- methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1- trifluoro-2-trifluoromethyl-but-3-en-2-ol, (E)-1 -(4-{1 -[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1 -en-3-ol, 1 - [(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2- methyl-phenyl)-vinyl]-cyclopentanol, (E)-4-(4-{1 -[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1 -trifluoro-2- trifluoromethyl-but-3-en-2-ol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy- 4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4- (3-hyd roxy-4 ,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- benzoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(R)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(S )-1 -(tetrahyd ro-fu ran-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-propyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-propyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 5(S)-hydroxy-hexanoic acid, 6(R)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro- pyran-2-one, (E)-N-(2-Amino-ethyl)-2-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetamide, (E)-5- (4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-oxo-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo- pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol.
(28) The compound according to (4) wherein at least one of R14, R15 or R16 is a substituent which have a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group. (29) The compound according to (28) selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5- (4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4- {1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5- (4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4- (4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4- {1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 - Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1- enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4- {1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1- Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1- enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4- {1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane- 1,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1-ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1-
Ethyl-1-[4-((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane- 1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 - [4-((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4- [(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxy]-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- hexanoic acid, 1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol, (E)-4-[4-(1 -Ethyl-1 -{3- methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1- trifluoro-2-trifluoromethyl-but-3-en-2-ol, (E)-1 -(4-{1 -[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1-en-3-ol, 1- [(E)-2-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2- methyl-phenyl)-vinyl]-cyclopentanol, (E)-4-(4-{1-[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1-trifluoro-2- trifluoromethyl-but-3-en-2-ol, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy- 4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4- (3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- benzoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1,4- diol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-propyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5(S)-hydroxy-hexanoic acid, (E)-N-(2- Amino-ethyl)-2-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetamide, (E)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl- 3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo- pentanoic acid, 2- (R)- [2-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-propionic acid, 2- (S)-[2-(4-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-acetylamino]-3-phenyl-propionic acid, 5-(4-{1 - Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-oxo-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol.
(30) The compound according to (4) wherein R14 is a hydroxyl group.
(31) The compound according to (30) selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5- (4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4- {1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5- (4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4- (4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4- {1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1- Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1- enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4- {1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 - Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4- {1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane- 1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 - Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane- 1 ,2-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4- (3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4- (3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy- 4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl- but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol, (S)-5-(4-{1- Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol, (R)-5-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-pentane-1 ,4-diol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-phenoxy)-4-hydroxy- pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2,6-dimethyl-phenoxy)-4-hydroxy-pentanoic acid, (S)- 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-propyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 5(S)-hydroxy-hexanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol. (32) The compound according to (4) wherein one of R15 and R16 is a hydrogen atom and the other is a C1-6 alkyl group substituted with a carboxyl group. (33) The compound according to (32) selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5- (4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4- {1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5- (4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4- (4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4- {1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 - Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4- {1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1- Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1- enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, 2-(4-{1- Ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]- pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-hexanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3- hyd roxy-4 ,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3- hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4- (3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-phenoxy)-4-hydroxy- pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2,6-dimethyl-phenoxy)-4-hydroxy-pentanoic acid, (S)- 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-propyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 5(S)-hydroxy-hexanoic acid.
(34) The compound according to (4) wherein one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and
R19) together form a 3-12 membered lactone ring.
(35) The compound according to (34) selected from the group consisting of (R)-5-(2-Chloro-4-{1 -[3-chloro-4-((R)-3-hydroxy-4,4-dimethyl- pentyl)-phenyl]-1 -ethyl-propyl}-phenoxymethyl)-dihydro-furan-2-one, (R)-5- (2-Chloro-4-{1-[3-chloro-4-((S)-3-hydroxy-4 ,4-dimethyl-pentyl )-phenyl]-1- ethyl-propyl}-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3- hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-di methyl-pentyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)- 5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cycIohexyl)-prop-1 -ynyl]-3-methyl- phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1- Ethyl-1-{4-[3-hydroxy-3-(1-methyl-cyclohexyl)-propyl]-3-methyl-phenyl}- propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4- [3-hydroxy-3-(1-methyl-cyclopentyl)-prop-1-ynyl]-3-methyl-phenyl}-propyl)-2- methyl-phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3- hydroxy-3-(1-methyl-cyclopentyl)-propyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 - methyl-cyclopropyl)-prop-1-ynyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 - methyl-cyclopropyl)-propyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl-1 -[4-((S)-3- hyd roxy-4 ,4-dimethyl-pentyl )-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (S)-5-(4-{1 -[4-((E)-1 ,3-Diethyl-3- hydroxy-pent-1 -enyl)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,5,5,5-pentafluoro-3-hydroxy-3-pentafluoroethyl-pent-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3- methyl-4-(2-methyl-propane-2-sulfinylmethyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(2- methyl-propane-2-sulfonylmethyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- ethyl-3-hydroxy-1-methyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-dec-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hept-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hex-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-non-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-oct-1-en-4-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1- enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-methyl-phenyl]-propyl}-phenoxymethyl)-dihydro-furan-2-one, (S)-5- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-propyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- ethyl-3-hydroxy-undec-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-undec-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1- enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-propyl-hex-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(1 -hydroxy- cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5- (4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl- 3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 -ynyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)- 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-propyl-hex-1 -ynyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-decyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-heptyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro- furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-nonyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-octyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5- [4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)- 2-methyl-phenoxymethyl]-dihydro-furan-2-one, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2- (1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 - hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (S)-5-{4-[1-(4-tert-Butylsulfanylmethyl- 3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxymethyl}-dihydro-furan-2- one, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl- 1-[4-((R)-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[4-((S)-3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one. (36) The compound according to (3) wherein R12 and R13 are selected from the group consisting of one of R12 and R13 is a hydrogen atom and the other is a C1- 6 alkyl group, one of R12 and R13 is a hydrogen atom and the other is a C3-
8 cycloalkyl group which may be substituted with a C1-4 alkyl group, both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group; Q is a methylene, an ethylene, an ethynylene or -(CH2)k-C(=0)NH-; R1 is an ethyl group; R2 is an ethyl group; R3 is a hydrogen atom; R4 is a chlorine atom or a methyl group; R6 is a chlorine atom or a methyl group.
(37) The compound according to (36) selected from the group consisting of 3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 3- (4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)- but-1 -enyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 5-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)- phenyl]-propyl}-2-methyl-phenyl)-pent-4-ynoic acid, 7-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]- propyl}-2-methyl-phenyl)-hept-6-ynoic acid.
(38) The compound according to (36) wherein R3 is a hydrogen atom. (39) The compound according to (38) selected from the group consisting of 3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 3- (4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)- but-1 -enyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 5-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)- phenyl]-propyl}-2-methyl-phenyl)-pent-4-ynoic acid, 7-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]- propyl}-2-methyl-phenyl)-hept-6-ynoic acid.
(40) The compound according to (36) wherein R4 is a chlorine atom.
(41) The compound according to (36) wherein R6 is a chlorine atom.
(42) The compound according to (36) wherein R6 is a methyl group.
(43) The compound according to (42) selected from the group consisting of 3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 3- (4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 6-(4-{1-Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)- but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 5-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)- phenyl]-propyl}-2-methyl-phenyl)-pent-4-ynoic acid , 7-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]- propyl}-2-methyl-phenyl)-hept-6-ynoic acid.
(44) The compound according to (36) wherein X is an ethylene.
(45) The compound according to (44) which is 6-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-hex- 5-ynoic acid.
(46) The compound according to (36) wherein X is a vinylene.
(47) The compound according to (46) selected from the group consisting of 3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 6-(4-{1-Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)- but-1 -enyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 5-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)- phenyl]-propyl}-2-methyl-phenyl)-pent-4-ynoic acid, 7-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]- propyl}-2-methyl-phenyl)-hept-6-ynoic acid.
(48) The compound according to (36) wherein X is an ethynylene.
(49) The compound according to (48) selected from 3-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenyl)-propionic acid or 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenyl)-hex-5-ynoic acid. (50) The compound according to (36) wherein one of R12 and R13 is a hydrogen atom and the other is a C1-6 alkyl group.
(51 ) The compound according to (50) wherein one of R12 and R13 is a hydrogen atom and the other is a tert-butyl group.
(52) The compound according to (51 ) which is 6-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-hex- 5-ynoic acid.
(53) The compound according to (36) wherein both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s). (54) The compound according to (53) wherein R12 is a trifluoromethyl group and R13 are is a trifluoromethyl group.
(55) The compound according to (54) selected from the group consisting of 3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 3- (4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-hex-5-ynoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)- pent-4-ynoic acid, 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid.
(56) The compound according to (36) wherein Q is an ethylene. (57) The compound according to (56) selected from 3-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenyl)-propionic acid or 3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenyl)-propionic acid.
(58) The compound according to (36) wherein Q is an ethynylene. (59) The compound according to (58) selected from the group consisting of 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 6-(4-{1-Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)- but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 5-(4-{1-Ethyl- 1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1 -enyl)- phenyl]-propyl}-2-methyl-phenyl)-pent-4-ynoic acid, 7-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]- propyl}-2-methyl-phenyl)-hept-6-ynoic acid, 7-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenyl)-hept-6-ynoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid.
(60) The compound according to (36) wherein at least one of R14, R15 or R16 is a substituent which have a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group.
(61) The compound according to (60) selected from the group consisting of 3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 3- (4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-hex-5-ynoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4 ,4-trifluoro-3- hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)- pent-4-ynoic acid, 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid, 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl- but-1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid, 6-(4-{1 -Ethyl- 1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenyl)-hex-5-ynoic acid.
(62) The compound according to (36) wherein R14 is a hydroxyl group. (63) The compound according to (36) wherein one of R15 and R16 is a hydrogen atom and the other is a C1-6 alkyl group substituted with a carboxyl group.
(64) The compound according to (63) selected from the group consisting of 3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 3- (4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-hex-5-ynoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3- hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)- pent-4-ynoic acid, 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenyl)-hex-5-ynoic acid. (65) The compound according to (36) wherein one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) together form a 3-12 membered lactone ring.
Another examples of the preferred compounds of the present invention are represented as follows. (66) The compound of the above fomula I wherein X is an optionally substituted vinylene, or an ethynylene.
(67) The compound of the above fomula I wherein W is a substituent represented by following formula:
Figure imgf000075_0001
Q is selected from the group consisting of -0-, a methylene, an ethylene, a vinylene, and an ethynylene; and wherein b is 1 ; R14 is a hydroxyl group; R15 is a hydrogen atom; R16 is a C1-6 alkyl group substituted with a carboxyl group.
(68) The compound of the above fomula I selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5- (4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4- {1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3- hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6- (4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(3-ethyl-3- hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane- 1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(3-ethyl- 3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 - Ethyl-1-[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-ynyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 - [4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenyl)-propionic acid, 1 -(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 - ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1 -yn-3-ol, 3-Ethyl-1 -[4-(1 -ethyl-1 - {3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]- pent-1-yn-3-ol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-((E)-3- ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5- hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, (E)-1 -(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2- methyl-phenyl)-3-ethyl-pent-1-en-3-ol, (E)-3-Ethyl-1 -[4-(1 -ethyl-1 -{3-methyl- 4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-pent-1-en-3- ol, (S)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl- 3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 - Ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4- {1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pentyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3- hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 6-(4-{1-Ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 1 -(4-{1 -[4- (5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-3- ethyl-pentan-3-ol, 3-Ethyl-1-[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)- butoxy]-phenyl}-propyl)-2-methyl-phenyl]-pentan-3-ol, (R)-5-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenol, 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenyl)-propionic acid, 4-(4-{1 -[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1-trifluoro-2- trifluoromethyl-but-3-yn-2-ol, 4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)- butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 -trifluoro-2-trifluoromethyl-but- 3-yn-2-ol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2- diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 - [3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)- phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-propionic acid, (E)-4-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]- 1-ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}- propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2-ol, (S)-5- (4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1- Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2- methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4 ,4-trifluoro-3- hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2- methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro- 3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)- hexanoic acid, 3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 4-(4- {1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)- 1 ,1 ,1-trifluoro-2-trifluoromethyl-butan-2-ol, 4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H- tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 -trifluoro-2- trifluoromethyl-butan-2-ol, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 - ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4- (3-hydroxy-3-methyl-but-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 - ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3- methyl-but-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but-1-ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but- 1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 6-(4-{1 - Ethyl-1-[4-(3-hydroxy-3-methyl-but-1-ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but- 1 -ynyl)-3-methyl-phenyl]-propy|}-2-methyl-phenyl)-propionic acid, 4-(4-{1 -[4- (5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-2- methyl-but-3-yn-2-ol, 4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)- butoxy]-phenyl}-propyl)-2-methyl-phenyl]-2-methyl-but-3-yn-2-ol, (S)-5-(4-{1- Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 -enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-3-methyl-but-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4- ((E)-3-hydroxy-3-methyl-but-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 4- {1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 -enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4- ((E)-3-hydroxy-3-methyl-but-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1- enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, (E)-4-(4-{1- [4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-2- methyl-but-3-en-2-ol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)- butoxy]-phenyl}-propyl)-2-methyl-phenyl]-2-methyl-but-3-en-2-ol, (S)-5-(4-{1- Ethyl-1-[4-(3-hydroxy-3-methyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3- methyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-butyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 - Ethyl-1 -[4-(3-hydroxy-3-methyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3- methyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1-Ethyl-1-[4-(3-hydroxy-3-methyl-butyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(3-hydroxy-3- methyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4- (3-hydroxy-3-methyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-butyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-(3- hydroxy-3-methyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 4-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2- methyl-phenyl)-2-methyl-butan-2-ol, 4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H- tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-2-methyl-butan-2-ol, (S)-5-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclobutylethynyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(1- hydroxy-cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclobutylethynyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6- (4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(1-hydroxy- cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2- diol, 2-(4-{1 -Ethyl-1 -[4-(1-hydroxy-cyclobutylethynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(1 - hydroxy-cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4- {1 -Ethyl-1 -[4-(1 -hydroxy-cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(1-hydroxy- cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-(1-hydroxy-cyclobutylethynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenyl)-propionic acid, 1 -(4-{1 -[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenylethynyl)-cyclobutanol, 1 -[4-(1 - Ethyl-1-{3-methyl-4-[4-(1H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl- phenylethynyl]-cyclobutanol, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (R)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclobutyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (S)-6- [4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)- 2-methyl-phenoxy]-5-hydroxy-hexanoic acid, (R)-6-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 - hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-5- hydroxy-hexanoic acid, (S)-3-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclobutyl)- vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-propane-1 ,2-diol, 2-[4-(1 - Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)-2- methyl-phenoxymethyl]-propane-1 ,3-diol, 4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol, 5-[4-(1 -Ethyl-1 - {4-[(E)-2-(1-hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxyj-pentanoic acid, 6-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclobutyl)- vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid, 3-[4-(1- Ethyl-1-{4-[(E)-2-(1-hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)-2- methyl-phenyl]-propionic acid, 1-[(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-vinyl]-cyclobutanol, 1 -{(E)-2- [4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2- methyl-phenyl]-vinyl}-cyclobutanol, (S)-5-[4-(1 -Ethyl-1 -{4-[2-(1-hydroxy- cyclobutyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (R)-5-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclobutyl)-ethyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (S)-6- [4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclobutyl)-ethyl]-3-methyl-phenyl}-propyl)-2- methyl-phenoxy]-5-hydroxy-hexanoic acid, (R)-6-[4-(1 -Ethyl-1 -{4-[2-(1 - hydroxy-cyclobutyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-5- hydroxy-hexanoic acid, (S)-3-[4-(1 -Ethyl- 1-{4-[2-(1-hyd roxy-cyclobutyl )- ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-propane-1 ,2-diol, 2-[4-(1- Ethyl-1-{4-[2-(1-hydroxy-cyclobutyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-propane-1 ,3-diol, 4-(1 -Ethyl-1 -{4-[2-(1-hydroxy-cyclobutyl)- ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol, 5-[4-(1 -Ethyl-1 -{4-[2-(1- hydroxy-cyclobutyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]- pentanoic acid, 6-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclobutyl)-ethyl]-3-methyl- phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid, 3-[4-(1 -Ethyl-1 -{4-[2-(1- hydroxy-cyclobutyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]- propionic acid, 1 -[2-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-ethyl]-cyclobutanol, 1-{2-[4-(1 -Ethyl-1 -{3-methyl-4- [4-(1H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-ethyl}- cyclobutanol, (S)-5-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 - Ethyl-1 -[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-(1-hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4- {1 -Ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-(1 -hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-(1 -hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-(1 -hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 1 -(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2- methyl-phenylethynyl)-cyclopentanol, 1-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H- tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenylethynyl]-cyclopentanol, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}- propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5-[4-(1 -Ethyl-1 -{4- [(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxy]-4-hydroxy-pentanoic acid, (S)-6-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-5-hydroxy- hexanoic acid, (R)-6-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-5-hydroxy-hexanoic acid, (S)-3-[4- (1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)- 2-methyl-phenoxy]-propane-1 ,2-diol, 2-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]- propane-1 ,3-diol, 4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenol, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 6-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3-methyl- phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid, 3-[4-(1 -Ethyl-1 -{4-[(E)-2- (1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]- propionic acid, 1-[(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol, 1 -{(E)-2-[4-(1 -Ethyl-1 -{3- methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]- vinyl}-cyclopentanol, (S)-5-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclopentyl)-ethyl]- 3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)- 5-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-propyl)- 2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (S)-6-[4-(1 -Ethyl-1 -{4-[2-(1 - hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-5- hydroxy-hexanoic acid, (R)-6-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclopentyl)- ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-5-hydroxy-hexanoic acid, (S)-3-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}- propyl)-2-methyl-phenoxy]-propane-1 ,2-diol, 2-[4-(1 -Ethyl-1 -{4-[2-(1-hydroxy- cyclopentyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]- propane-1 ,3-diol, 4-(1 -Ethyl-1 -{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl- phenyl}-propyl)-2-methyl-phenol, 5-[4-(1 -Ethyl-1 -{4-[2-(1-hydroxy- cyclopentyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 6-[4-(1 -Ethyl-1 -{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}- propyl)-2-methyl-phenoxy]-hexanoic acid, 3-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy- cyclopentyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-propionic acid, 1 -[2-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl- phenyl)-ethyl]-cyclopentanol, 1 -{2-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5- yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-cyclopentanol, (S)-5-(4- {1 -Ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(1- hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid, (S )-6-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6- (4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(1 -hydroxy- cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2- diol, 2-(4-{1 -Ethyl-1 -[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(1 - hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4- {1 -Ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(1-hyd roxy- cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenyl)-propionic acid, 1-(4-{1-[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenylethynyl)-cyclohexanol, 1 -[4- (1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl- phenylethynylj-cyclohexanol, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (R)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (S)-6- [4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)- 2-methyl-phenoxy]-5-hydroxy-hexanoic acid, (R)-6-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 - hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-5- hydroxy-hexanoic acid, (S)-3-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)- vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-propane-1 ,2-diol, 2-[4-(1- Ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2- methyl-phenoxymethyl]-propane-1 ,3-diol, 4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy- cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol, 5-[4-(1 -Ethyl-1 - {4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxy]-pentanoic acid, 6-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclohexyl)- vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid, 3-[4-(1 - Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2- methyl-phenyl]-propionic acid, 1 -[(E)-2-(4-{1 -[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-vinyl]-cyclohexanol, 1 -{(E)- 2-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2- methyl-phenyl]-vinyl}-cyclohexanol, (S)-5-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy- cyclohexyl )-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (R)-5-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclohexyl)-ethyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (S)-6- [4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl)-2- methyl-phenoxy]-5-hydroxy-hexanoic acid, (R)-6-[4-(1 -Ethyl-1 -{4-[2-(1- hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-5- hydroxy-hexanoic acid, (S)-3-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclohexyl)- ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-propane-1 ,2-diol, 2-[4-(1 - Ethyl-1 -{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl)-2- methyl-phenoxymethyl]-propane-1 ,3-diol, 4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy- cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol, 5-[4-(1 -Ethyl-1 -
{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxy]-pentanoic acid,
6-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl)- 2-methyl-phenoxy]-hexanoic acid, 3-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy- cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-propionic acid, 1 -[2-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl- phenyl)-ethyl]-cyclohexanol, 1 -{2-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5- yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-cyclohexanol, (S)-5-(4-{1- Ethyl-1 -[4-(3-hyd roxy-4, 4-di methyl-pent- 1 -ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5- hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pent- 1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 - ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 - Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenyl)-propionic acid , 1 -(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pent-1-yn-3-ol, 1-[4-(1- Ethyl-1-{3-methyl-4-[4-(1H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl- phenyl]-4,4-dimethyl-pent-1 -yn-3-ol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy- 4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl- pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, (S )-6-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4 ,4-dimethyl-pent-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1- Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4 ,4- dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy- 4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid , 3-(4-{1 -Ethyl-1 -[4- ((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenyl)-propionic acid, (E)-1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]- 1-ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pent-1-en-3-ol, (E)-1-[4-(1- Ethyl-1-{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl- phenyl]-4,4-dimethyl-pent-1-en-3-ol, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-6- (4-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-ρropane-1 ,2-diol, 2-(4-{1 -Ethyl-1 - [4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4-di methyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyi)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)- propionic acid, 1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol, 1 -[4-(1 -Ethyl-1 -{3-methyl- 4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-4,4-dimethyl- pentan-3-ol, 4-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenyl)-butane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((R)- 3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (R)-3-(4-{1 -Ethyl-1 -[4-((R)-3-hydroxy-4,4-dimethyl-pentyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 - Ethyl-1 -[4-((S)-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol, (R)-3-(4-{1 -Ethyl-1 -[4-((S)-3-hydroxy-4,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2- diol, 2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 3-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol, 1-(4-{1 -Ethyl-1 - [4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenyl)-4,4-dimethyl-pentan-3-ol, 1-(4-{1 -Ethyl-1 -[4-(3-hydroxy-propyl)-3- methyl-phenyl]-propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol, (S)-3-(4- {1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol, (R)-3-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2- diol, 4-(4-{1 -Ethyl-1 -[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]- propyl}-2-methyl-phenyl)-butane-1 ,2-diol, 1-(4-{1 -Ethyl-1 -[4-(3-hydroxy- propyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol, 3-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}- 2-methyl-phenyl)-propane-1 ,2-diol, 3-(4-{1 -Ethyl-1 -[4-(2-hydroxy-3, 3- dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-butane-1 ,2-diol, 1 -(4-{1 -Ethyl-1 -[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}- 2-methyl-phenyl)-propane-1 ,2-diol, 1-(4-{1 -Ethyl-1 -[4-(3-hydroxy-butyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol, (E)-4-(4- {1 -Ethyl-1 -[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2- methyl-phenyl)-but-3-en-2-ol, 3-(4-{1 -Ethyl-1 -[4-(2-hydroxy-3,3-dimethyl- butoxy)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-butan-1-ol, 1-(4-{1-[4- (2,3-Dihydroxy-propyl)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenoxy)- 3,3-dimethyl-butan-2-one, 1-(4-{1-[4-(2,3-Dihydroxy-1-methyl-propyl)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one, 1 -(4-{1 -Ethyl-1 -[4-(3-hydroxy-butyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-3,3-dimethyl-butan-2-one, 3-(4-{1 -Ethyl-1 -[4-(2-hydroxy-3,3- dimethyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2- diol, (E)-1-(4-{1-[4-((S)-2,3-Dihydroxy-propoxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pent-1 -en-3-one, (E)-1 -(4-{1 -[4-((R)- 2,3-Dihydroxy-propoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)- 4,4-dimethyl-pent-1 -en-3-one, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4- dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane- 1 ,2-diol, (R)-3-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 1-(4-{1-[4-((R)- 2,3-Dihydroxy-propoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)- 4,4-dimethyl-pentan-3-one.
(69) The compound of the above fomula I which is (S)-5-(4-{1 -Ethyl-1 - [4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid. (70) The compound of the above fomula I which is (S )-5-(4-{1 -Ethyl- 1 - [3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid. Another examples of the preferred compounds of the present invention are represented as follows. (71) The compound of the above fomula I wherein Y is a substituent represented by following formula:
Figure imgf000090_0001
and R is a protecting group for a hydroxyl group.
(72) The compound according to (71) wherein X is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene or an ethynylene; R is a protecting group for a hydroxyl group selected from the group consisting of a methoxymethyl group, a methylthiomethyl group, a (phenyldimethylsilyl)methoxymethyl group, a benzyloxymethyl group, a p- methoxybenzyloxymethyl group, a p-nitrobenzyloxymethyl group, an o- nitrobenzyloxymethyl group, a (4-methoxyphenoxy)methyl group, a guaiacolmethyl group, a t-butoxymethyl group, a 4-pentenyloxymethyl group, a siloxymethyl group, a 2-methoxyethoxymethyl group, 2,2,2- trichloroethoxymethyl group, a bis(2-chloroethoxy)methyl group, a 2- (trimethylsilyl)ethoxymethyl group, a menthoxymethyl group, a tetrahydropyranyl group, a 3-bromotetrahydropyranyl group, a tertahydrothiopyranyl group, a 1 -methoxycyclohexyl group, 4- methoxytetrahydrothiopyranyl, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group, a 1-ethoxyethyl group, a 1-(2-chloroethoxy)ethyl group, a 1-[2-(trimethylsilyl)ethoxy]ethyl group, a 1-methyl-1-methoxyethyl group, a 1 -methyl- 1 -benzyloxyethyl group, a 1 -methyl- 1 -benzyloxy-2- fluoroethyl group, a 1-methyl-1-phenoxyethyl group, a 2,2,2-trichloroethyl group, a 1,1-dianisyl-2,2,2-trichloroethyl group, a 2-trimethylsilylethyl group, a 2-(benzylthio)ethyl group, a 2-(phenylselenyl)ethyl group, a t-butyl group, an allyl group, a propargyl group, a p-chlorophenyl group, a p- methoxyphenyl group, a p-nitrophenyl group, a 2,4-dinitrophenyl group, a benzyl group, a p-methoxybenzyl group, a 3,4-dimethoxybenzyl group, an o- nitrophenyl group, a p-nitrophenyl group, a p-halobenzyl group, a 2,6- dichlorobenzyl group, a p-cyanobenzyl group, a p-phenylbenzyl group, a 2,6- difluorobenzyl group, a p-acylaminobenzyl group, a 2-triflluoromethyl benzyl group, a 2-picolyl group, a 4-picolyl group, a 2-quinolinylmethyl group, a triphenylmethyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a dimethylisopropylsilyl group, a diethylisopropylsilyl group, a t-butyldimethylsilyl group, a t-buthyldiphenylsilyl group, a tribenzylsilyl group, a triphenylsilyl group, a diphenylmethylsilyl group, a di-t- buthylmethylsilyl group, tris(trimethylsilyl)silyl group, a formyl group, a benzoylformyl group, an acetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a methoxyacetyl group, a pivaloyl group, a benzoyl group, a 2,4,6-trimethylbenzoyl group, a methylcarbonyloxy group, a methoxymethylcarbonyloxy group, an ethylcarbonyloxy group, an isobutylcarbonyloxy group, a vinylcarbonyloxy group, an allylcarbonyloxy group, a benzylcarbonyloxy group, a p-methoxybenzylcarbonyloxy group, an allylsulfonyl group, a methanesulfonyl group, a benzylsulfonyl group, a tosyl group, a trifluoromethanesulfonyl group; R12 and R13 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-10 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted C1-10 alkenyl group, an optionally substituted C1-10 alkynyl group, or R12 and R13 may together form an optionally substituted C3-10 cycloalkyl group; W is a substituent represented by following formula: ✓ R14
-Q-(CH2)b— ^R15 R16 Q is -0-, a methylene, an ethylene, a vinylene, an ethynylene, - (CH2)k-C(=0)NH- or -0-(CH2)k-C(=0)NH-; R14 is a hydrogen atom, a hydroxyl group, an optionally substituted carboxyl group, an optionally substituted carbamoyl group, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted G6-C12 aryl group, an optionally substituted (C6-C12)aryl-(C1 -4)alkyl group, -OR17 or -N(R18)R19; R15 and R16 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C6- C12 aryl group, an optionally substituted (C6-C12)aryl-(C1-4)alkyl group, an optionally substituted 3-12 membered heterocyclic group selected from the group consisting of an aziridine group, an azetidine group, an oxetane group, a pyrrolidine group, a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an imidazole group, an oxazole group, a thiazolegroup, a 1 ,2,5- oxadiazole group, a 1 ,3,4-oxadiazole group, a 1 ,3,4-thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a tetrazole group, a piperidine group, a pyridine group, a pyridazine group, a pyrimidine group, a pyrazine group, a tetrahyd ropyran group, a pyran group, a thiopyran group, an indole group, a benzofuran group, a benzothiophene group, an indazole group, a benzisoxazole group, a benzisothiazole group, a benzimidazole group, a benzoxazole group, a benzothiazole gorup, a quinoline group, an isoquinoline group, a cinnoline group, a phthalazine group, a quinazoline group, a quinoxaline group, or R15 and R16 may together form =0; R17 is an optionally substituted C1 -6 alkyl group or an optionally substituted C3-C6 cycloalkyl group; R18 and R19 are each independently selected from a hydrogen atom, an optionally substituted C1-6 alkyl group or an optionally substituted C3-C6 cycloalkyl group; or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered cyclic ring which is selected from a lactam ring or a lactone ring; R1 is a C1-6 alkyl group; R2 is a C1-6 alkyl group; R3 is a hydrogen atom or a C1-6 alkyl group; R4 is a halogen atom or a C1-6 alkyl group; R5 is a hydrogen atom; R6 is a halogen atom or a C1-6 alkyl group.
(73) The compound according to (72) wherein X is an ethylene, a vinylene, or an ethynylene; R is a protecting group for a hydroxyl group selected from the group consisting of a methoxymethyl group, a 2-(trimethylsilyl)ethoxymethyl group, a tetrahydropyranyl group, a benzyl group, a p-methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t- buthyldiphenylsilyl group, an acetyl group, a pivaloyl group, a benzoyl group, a methanesulfonyl group, a tosyl group, a trifluoromethanesulfonyl group; R12 and R13 are each independently selected from the group consisting of a hydrogen atom, a C1-8 alkyl group which may be substituted with a halogen atom(s) a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group; W is a substituent represented by following formula: κ R14
-Q-(CH2)b-^R15 R-I 6 Q is -0-, a methylene, an ethylene, a vinylene, an ethynylene, - (CH2)k-C(=0)NH- or -0-(CH2)k-C(=0)NH-; b is an integer of 0 to 5; R14 is a hydrogen atom, a hydroxyl group, a carboxyl group which may be substituted with a C1-4 alkyl group, a carbamoyl group which may be substituted with a C1-4 alkyl group, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group which may be substituted with a C1- 4 alkyl group, a phenyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a benzyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, OR17 or -N(R18)R19; R15 and R16 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group which may be substituted with a C1-4 alkyl group, a phenyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a benzyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a 3-8 membered heterocyclic group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, wherein said heterocyclic group selected from the group consisting of an oxetane group, a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an oxazole group, a thiazole group, a 1 ,2,5-oxadiazole group, a 1 ,3,4- oxadiazole group, a 1 ,3,4-thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a tetrazole group, a pyridine group, a pyridazine group, a pyrimidine group, a pyrazine group, a tetrahydropyran group, a pyran group, a thiopyran group, or R15 and R16 may together form =0; and at least one of R14, R15 or R16 is a hydrogen atom; R17 is a C1 -4 alkyl group; R18 and R19 are each independently selected from a hydrogen atom or a C1-4 alkyl group; or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered lactone ring. (74) The compound according to (73) wherein R12 and R13 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3-8 cycloalkyl group; W is a substituent represented by following formula: κR-|4
-Q-(CH2)b-^Ri5 R16 Q is -0-, -(CH2)k-C(=0)NH- or -0-(CH2)k-C(=0)NH-; b is O, 1 or 2; k is 1 ; R14 is a hydrogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amide group, a
C3-C8 cycloalkyl group, a phenyl group which may be substituted with a hydroxyl group or a carboxyl group, a benzyl group which may be substituted with a hydroxyl group or a carboxyl group, -OR17 or -N(R18)R19; R15 and R16 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group, a phenyl group which may be substituted with a hydroxyl group or a carboxyl group, a benzyl group which may be substituted with a hydroxyl group or a carboxyl group, a 3-8 membered heterocyclic group selected from the group consisting of a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an oxazole group, a thiazole group, a 1 ,2,5-oxadiazole group, a 1 ,3,4-oxadiazole group, a 1 ,3,4- thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a pyridine group, a tetrahydropyran group; and at least one of R14, R15 or R16 is a hydrogen atom; R18 is a hydrogen atom; R19 is a hydrogen atom; or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered lactone ring; R1 is a C1-4 alkyl group; R2 is a C1 -4 alkyl group; R3 is a hydrogen atom or a C1-4 alkyl group; R4 is a halogen atom or a C1-4 alkyl group; R5 is a hydrogen atom; R6 is a halogen atom or a C1 -4 alkyl group.
(75) The compound according to (74) wherein R12 and R13 are selected from the group consisting of one of R12 and R13 is a hydrogen atom and the other is a C1- 6 alkyl group, one of R12 and R13 is a hydrogen atom and the other is a C3-
8 cycloalkyl group which may be substituted with a C1-4 alkyl group, both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group; Q is -O- or -0-(CH2)k-C(=0)NH-; R1 is an ethyl group; R2 is an ethyl group; R3 is a hydrogen atom or a methyl group; R4 is a chlorine atom or a methyl group; R6 is a chlorine atom, a methyl group, an ethyl group, a propyl group or an isopropyl group.
(76) The compound according to (74) wherein R12 and R13 are selected from the group consisting of one of R12 and R13 is a hydrogen atom and the other is a C1-
6 alkyl group, one of R12 and R13 is a hydrogen atom and the other is a C3- 8 cycloalkyl group which may be substituted with a C1-4 alkyl group, both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group; Q is a methylene, an ethylene, an ethynylene or -(CH2)k-C(=0)NH-; R1 is an ethyl group; R2 is an ethyl group; R3 is a hydrogen atom; R4 is a chlorine atom or a methyl group; R6 is a chlorine atom or a methyl group.
(77) The compound according to (75) or (76) wherein R3 is a hydrogen atom.
(78) The compound according to (75) or (76) wherein R4 is a chlorine atom.
(79) The compound according to (75) or (76) wherein R6 is a chlorine atom.
(80) The compound according to (75) or (76) wherein R6 is a methyl group. (81) The compound according to (75) or (76) wherein X is an ethylene.
(82) The compound according to (75) or (76) wherein X is a vinylene.
(83) The compound according to (75) or (76) wherein X is an ethynylene. (84) The compound according to (75) or (76) wherein one of R12 and R13 is a hydrogen atom and the other is a C1-6 alkyl group.
(85) The compound according to (84) wherein one of R12 and R13 is a hydrogen atom and the other is a tert-butyl group.
(86) The compound according to (75) or (76) wherein both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s).
(87) The compound according to (86) wherein R12 is a trifluoromethyl group and R13 is a trifluoromethyl group.
(88) The compound according to (75) wherein Q is -0-.
(89) The compound according to (76) wherein Q is an ethylene.
(90) The compound according to (76) wherein Q is an ethynylene. (91 ) The compound according to (75) or (76) wherein at least one of
R14, R15 or R16 is a substituent which have a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group.
(92) The compound according to (75) or (76) wherein R14 is a hydroxyl group.
(93) The compound according to (75) or (76) wherein one of R15 and R16 is a hydrogen atom and the other is a C1-6 alkyl group substituted with a carboxyl group. (94) The compound according to (75) or (76) wherein one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) together form a 3-12 membered lactone ring. Another examples of the preferred compounds of the present invention are represented as follows. (95) The compound of the above fomula I wherein W is a hydroxyl group, a carboxyl group or a trifluoromethanesulfonyloxy group. (96) The compound according to (95) wherein X is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene or an ethynylene; Y is COOR8, CON(R9)R10, S(0)mR11 or a substituent represented by following formula: /OR (CH2)a \ R12 R13 R is a hydrogen atom or a protecting group for a hydroxyl group selected from the group consisting of a methoxymethyl group, a methylthiomethyl group, a (phenyldimethylsilyl)methoxymethyl group, a benzyloxymethyl group, a p-methoxybenzyloxymethyl group, a p- nitrobenzyloxymethyl group, an o-nitrobenzyloxymethyl group, a (4- methoxyphenoxy)methyl group, a guaiacolmethyl group, a t-butoxymethyl group, a 4-pentenyloxymethyl group, a siloxymethyl group, a 2- methoxyethoxymethyl group, 2,2,2-trichloroethoxymethyl group, a bis(2- chloroethoxy)methyl group, a 2-(trimethylsilyl)ethoxymethyl group, a menthoxymethyl group, a tetrahydropyranyl group, a 3- bromotetrahydropyranyl group, a tertahydrothiopyranyl group, a 1- methoxycyclohexyl group, 4-methoxytetrahydrothiopyranyl, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group, a 1-ethoxyethyl group, a 1 -(2-chloroethoxy)ethyl group, a 1-[2-(trimethylsilyl)ethoxy]ethyl group, a 1-methyl-1-methoxyethyl group, a 1-methyl-1-benzyloxyethyl group, a 1-methyl-1-benzyloxy-2-fluoroethyl group, a 1 -methyl- 1 -phenoxyethyl group, a 2,2,2-trichloroethyl group, a 1 ,1-dianisyl-2,2,2-trichloroethyl group, a 2-trimethylsilylethyl group, a 2-(benzylthio)ethyl group, a 2- (phenylselenyl)ethyl group, a t-butyl group, an allyl group, a propargyl group, a p-chlorophenyl group, a p-methoxyphenyl group, a p-nitrophenyl group, a 2,4-dinitrophenyl group, a benzyl group, a p-methoxybenzyl group, a 3,4- dimethoxybenzyl group, an o-nitrophenyl group, a p-nitrophenyl group, a p- halobenzyl group, a 2,6-dichlorobenzyl group, a p-cyanobenzyl group, a p- phenylbenzyl group, a 2,6-difluorobenzyl group, a p-acylaminobenzyl group, a 2-triflluoromethyl benzyl group, a 2-picolyl group, a 4-picolyl group, a 2- quinolinylmethyl group, a triphenylmethyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a dimethylisopropylsilyl group, a diethylisopropylsilyl group, a t-butyldimethylsilyl group, a t-buthyldiphenylsilyl group, a tribenzylsilyl group, a triphenylsilyl group, a diphenylmethylsilyl group, a di-t-buthylmethylsilyl group, tris(trimethylsilyl)silyl group, a formyl group, a benzoylformyl group, an acetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a methoxyacetyl group, a pivaloyl group, a benzoyl group, a 2,4,6-trimethylbenzoyl group, a methylcarbonyloxy group, a methoxymethylcarbonyloxy group, an ethylcarbonyloxy group, an isobutylcarbonyloxy group, a vinylcarbonyloxy group, an allylcarbonyloxy group, a benzylcarbonyloxy group, a p- methoxybenzylcarbonyloxy group, an allylsulfonyl group, a methanesulfonyl group, a benzylsulfonyl group, a tosyl group, a trifluoromethanesulfonyl group; R12 and R13 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-10 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted C1-10 alkenyl group, an optionally substituted C1-10 alkynyl group, or R12 and R13 may together form an optionally substituted C3-10 cycloalkyl group; R1 is a C1-6 alkyl group; R2 is a C1 -6 alkyl group; R3 is a hydrogen atom or a C1-6 alkyl group; R4 is a halogen atom or a C1-6 alkyl group; R5 is a hydrogen atom; R6 is a halogen atom or a C1-6 alkyl group.
(97) The compound according to (96) wherein X is an ethylene, a vinylene, or an ethynylene; Y is a substituent represented by following formula:
Figure imgf000101_0001
R is a hydrogen atom or a protecting group for a hydroxyl group selected from the group consisting of a methoxymethyl group, a 2- (trimethylsilyl)ethoxymethyl group, a tetrahydropyranyl group, a benzyl group, a p-methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t-buthyldiphenylsilyl group, an acetyl group, a pivaloyl group, a benzoyl group, a methanesulfonyl group, a tosyl group, a trifluoromethanesulfonyl group; R12 and R13 are each independently selected from the group consisting of a hydrogen atom, a C1-8 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group.
(98) The compound according to (97) wherein R12 and R13 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1 -4 alkyl group, or R12 and R13 are together form a C3-8 cycloalkyl group; R1 is a C1-4 alkyl group; R2 is a C1-4 alkyl group; R3 is a hydrogen atom or a C1-4 alkyl group; R4 is a halogen atom or a C1-4 alkyl group; R5 is a hydrogen atom; R6 is a halogen atom or a C1-4 alkyl group.
(99) The compound according to (98) wherein R12 and R13 are selected from the group consisting of one of R12 and R13 is a hydrogen atom and the other is a C1-
6 alkyl group, one of R12 and R13 is a hydrogen atom and the other is a C3- 8 cycloalkyl group which may be substituted with a C1-4 alkyl group, both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group; R1 is an ethyl group; R2 is an ethyl group; R3 is a hydrogen atom or a methyl group; R4 is a chlorine atom or a methyl group; R6 is a chlorine atom, a methyl group, an ethyl group, a propyl group or an isopropyl group.
(100) The compound according to (99) wherein W is a carboxyl group.
(101) The compound according to (100) which is 4-{1 -Ethyl-1 -[4-((E)- 3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid. (102) The compound according to (99) or (100) wherein wherein R3 is a hydrogen atom.
(103) The compound according to (99) or (100) wherein R4 is a chlorine atom.
(104) The compound according to (99) or (100) wherein R6 is a chlorine atom. (105) The compound according to (99) or (100) wherein R6 is a methyl group. (106) The compound according to (99) or (100) wherein X is an ethylene.
(107) The compound according to (99) or (100) wherein X is a vinylene.
(108) The compound according to (99) or (100) wherein X is an ethynylene.
(109) The compound according to (99) or (100) wherein one of R12 and R13 is a hydrogen atom and the other is a C1-6 alkyl group.
(110) The compound according to (109) wherein one of R12 and R13 is a hydrogen atom and the other is a tert-butyl group. (111 ) The compound according to (99) or (100) wherein both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s).
(112) The compound according to (111 ) wherein R12 is a trifluoromethyl group and R13 is a trifluoromethyl group.
Pharmaceutical Use
The compounds of the present invention exhibit VDR modulating activity. Therefore, the compounds and compositions of the present invention are useful as pharmaceuticals, such as, for the treatment of abscess, acne, adhesion, alopecia, Alzheimer's disease, benign prostatic hyperplasia, bone fracture healing, cancer, autoimmune induced diabetes, host-graft rejection, insufficient sebum secretion, insufficient dermal firmness, humoral hypercalcemia, insufficient dermal hydration, leukemia, lupus, multiple sclerosis, osteomalacia, osteoporosis, psoriaticarthritis, psoriasis, renal failure, renal osteodystrophy, rheumatoid arthritis, scleroderma, secondary hyperparathyroidism, systemic lupus erythematosus, and wrinkles, cornea wound, cornea healing, retinopathy, sway, muscle weakness, fall, chronic glomerulonephritis, lupus nephritis, diabetic nephropathy, hypocalcemia, hypoparathyroidism, rickets, osteoarthritis, and the like conditions and diseases. Especially, the compounds and compositions of the present invention are useful as pharmaceuticals for the treatment of benign prostatic hyperplasia, cancer, osteoporosis, psoriasis, secondary hyperparathyroidism, chronic glomerulonephritis, lupus nephritis, diabetic nephropathy, sway, muscle weakness, fall, rheumatoid arthritis and/or osteoarthritis. Among the above mentioned diseases, typical disease subjected to the treatment by the compounds and compositions of the present invention are benign prostatic hyperplasia, cancer, osteoporosis, psoriasis, secondary hyperparathyroidism, chronic glomerulonephritis, lupus nephritis and/or diabetic nephropathy. Certain compounds of the present invention are useful as a synthetic intermediate thereof.
Pharmaceutical Compositions The compositions of the present invention comprise:
(a) a safe and therapeutically effective amount of a compound of the present invention, or its corresponding enantiomer, diastereoisomer or tautomer, or pharmaceutically acceptable salt, or a prodrug thereof; and
(b) a pharmaceutically acceptable carrier. The compounds useful in this invention can be formulated into pharmaceutical compositions for use in the treatment of numerous diseases as mentioned above, i.e. prophylaxis, management and treatment of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. A "safe and therapeutically effective amount" of a compound useful in the present invention is an amount that exhibits VDR modulating activity, in a subject, a tissue, or a cell, and preferably in an animal, more preferably in a mammal, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio, when used in the manner of this invention. The specific "safe and therapeutically effective amount" will vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of treatment, the nature of concurrent therapy (if any), the specific dosage form to be used, the carrier employed, the solubility of the compound therein, and the dosage regimen desired for the composition. In addition to the selected compound useful for the present invention, the compositions of the present invention contain a pharmaceutically- acceptable carrier. The term "pharmaceutically-acceptable carrier", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances, which are suitable for administration to a mammal. The term "compatible", as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction, which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration preferably to an animal, preferably mammal being treated. Some examples of substances, which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions. The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered. If the subject compound is to be injected, the preferred pharmaceutically-acceptable carrier is sterile, physiological saline, with blood-compatible suspending agent, the pH of which has been adjusted to about 7.4. In particular, pharmaceutically-acceptable carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen- free water. Preferred carriers for parental administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. The compositions of this invention are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition of this invention containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. (The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day, and are expected to be given more than once during a course of therapy, though a single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.) The compositions useful for this invention may be in any of a variety of forms, suitable (for example) for oral, nasal, rectal, topical (including transdermal), ocular, intracereberally, intravenous, intramuscular, or parental administration. (The skilled artisan will appreciate that oral and nasal compositions comprise compositions that are administered by inhalation, and made using available methodologies.) Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the activity of the compound. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981 ); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976). Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non- effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents. The pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration is well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrates such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be readily made by a person skilled in the art. Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591 , tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above. Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac. Compositions of the subject invention may optionally include other drug actives. Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included. The compositions of this invention can also be administered topically to a subject in a treatment of dermatological conditions such as psoriasis, e.g., by the direct application or spreading of the composition on the epidermal or epithelial tissue of the subject, or transdermally via a "patch". Such compositions include, for example, lotions, creams, solutions, gels and solids. These topical compositions preferably comprise a safe and effective amount. Suitable carriers for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water. Generally, the carrier is organic in nature and capable of having dispersed or dissolved therein the compound. The carrier may include pharmaceutically-acceptable emollient, emulsifiers, thickening agents, solvents and the like.
Methods of Administration
The compounds and compositions useful in this invention can be administered topically or systemically. Systemic application includes any method of introducing compound into the tissues of the body, e.g., intra- articular, intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual administration, inhalation, rectal, or oral administration. The compounds useful in the present invention are preferably administered orally. The specific dosage of the compound to be administered, as well as the duration of treatment is to be individualized by the treating clinicians. Typically, for a human adult, from about 1 ng/kg to 50 mg/kg, preferably from about 1 ng /kg to about 1 mg/kg, more preferably from about 10 ng/kg to about 100 μg/kg, of selected compound is administered per day. It is understood that these dosage ranges are by way of example only, and that daily administration can be adjusted depending on the factors i.e. type of disease, level of disease, ages of patients, sex of patients, route to be administered, etc. In all of the foregoing, of course, the compounds useful in the present invention can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.
General Synthetic Method
Figure imgf000110_0001
In the above scheme, the compound of general formula (1 ) obtained by the same procedure as described in WOOO/10958 and the corresponding U.S. Patent 6,218,430 B1 may be reacted with trifluoromethanesulfonic acid anhydride in the presence of a base to give a compound of general formula (2) (step 1). Suitable bases for use in the above step 1 include pyridine, 2,6- lutidine, 2,4,6-collidine,N,N-dimethylaminopyridine, imidazole, triethylamine, more preferably pyridine. Suitable solvents for use in the above step 1 include diethyl ether, tetrahydrofuran, dichloromethane, 1 ,2-dichloroethane, chloroform, benzene, toluene, more preferably dichloromethane. The reaction temperature of the above step 1 is in the range from -50 °C to 50 °C, preferably from -20 °C to 30 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000111_0001
In the above scheme, the compound of general formula (2) may be reacted with trimethylsilyl acetylene in the presence of a palladium catalyst, copper (I) iodide, and triethyamine to give a compound of general formula (3) (step 2). Suitable palladium catalysts for use in the above step 2 include tetrakis(triphenylphosphine)palladium, Pd(dba)2, Pd2(dba)3-CHCI3, palladium acetate, palladium chloride, [1 ,1'-bis(diphenylphosphino)- ferrocenejpalladium dichloride dichloromethane complex, (dba; dibenzylideneacetone) A ligand, such as triphenylphosphine, tributhylphosphine, tricyclohexylphosphine, 1 ,3-bis(diphenylphosphinopropane) or tri-t-buthyl phosphine, may be used in the above step 2 to increase the catalytic activity and/or the reaction selectivity. Suitable solvents for use in the above step 2 include N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl- 2-imidazolidinone, tetrahydrofuran, toluene, acetonitrile, more preferably N,N-dimethylformamide or acetonitrile. The reaction temperature of the above step 2 is in the range from 0 °C to 200 °C, preferably from 20 °C to 150 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000112_0001
In the above scheme, the compound of general formula (3) may be reacted with tetra-n-butyl ammonium fluoride to give a compound of general formula (4) (step 3). Suitable solvents for use in the above step 3 include N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl- 2-imidazolidinone, tetrahydrofuran, toluene, acetonitrile, more preferably tetrahydrofuran. The reaction temperature of the above step 3 is in the range from 0 °C to 100 °C, preferably from 0 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000112_0002
In the above scheme, the compound of general formula (4) may be reacted with a ketone or an aldehyde, described as R12(C=0)R13, in the presence of a base to give a compound of general formula (5) (step 4). Suitable bases for use in the above step 4 include n-butyl lithium, sec- butyl lithium, tert-butyl lithium, methyl lithium, phenyl lithium, methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, isopropyl magnesium bromide, diisopropyl magnesium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, lithium 2,2,6,6- tetramethylpiperidide, lithium amide, sodium hydride, sodium bis(trimethylsilyl)amide, potassium hydride, potassium bis(trimethylsilyl) more preferably n-butyl lithium. Suitable solvents for use in the above step 4 include hydrocarbon- ether-based solvents or the likes, such as pentane, hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, anisole, more preferably tetrahydrofuran. The reaction temperature of the above step 1 is in the range from - 100 °C to 50 °C, preferably from -80 °C to 30 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000113_0001
In the above scheme, the compound of general formula (5) may be reduced to give a compound of general formula (6) (step 5). Step 5 includes the reduction by LiAIH4, Red-AI (sodium bis(2- methoxyethoxy)aluminium hydride) or hydrogenation using Lindlar catalyst. Suitable solvents for use in the reduction by lithium aluminum hydride or Red-AI include hydrocarbon- ether-based solvents or the like, such as pentane, hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 1,4-dioxane, anisole, more preferably tetrahydrofuran. Suitable solvents for use in the hydrogenation by Lindlar catalyst include methanol, ethanol, ethyl acetate, more preferably methanol. The reaction temperature of the above step 5 is in the range from -50 °C to 200 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000114_0001
In the above scheme, the compound of general formula (5, 6) may be subjected to hydrogenation to give a compound of general formula (7) (step
6). Suitable catalysts for use in the above step 6 include palladium-, rhodium-, ruthenium-, nickel-, platinum-based catalysts or the like, such as palladium on carbon, palladium hydroxide, platinum oxide, rhodium on alumina, Wilkinson's catalyst, more preferably palladium on carbon. Suitable solvents for use in the above step 6 include methanol, ethanol, ethyl acetate, acetic acid, more preferably methanol. The reaction temperature of the above step 6 is in the range from -50 °C to 200 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000115_0001
In the above scheme, the compound of general formula (5-7) may be subjected to protection of hydroxyl group with a compound of general formula (9) (R' = a methoxymethyl group, a 2-(trimethylsilyl)ethoxymethyl group, a benzyl group, a p-methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t-buthyldiphenylsilyl group or an acetyl group; X = a halogen atom, a methanesulfonyloxy group, a toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group or an acethyloxy group) in the presence of a base to give a compound of general formula (8) (step 7). Suitable bases for use in the above step 7 include sodium tert- butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, pyridine, triethylamine, diisopropylethylamine, 2,6-lutidine, 2,4,6-collidine, N,N- dimethylaminopyridine, more preferably sodium hydride, potassium carbonate, or pyridine. Suitable solvents for use in the above step 7 include dichloromethane, 1 ,2-dichloroethane, chloroform, hexane, benzene, toluene, diethyl ether, t- butyl methyl ether, tetrahydr Aran, 1 ,2-dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide,1 ,3-dimethyl-2-imidazolidinone,1 ,3-dimethyl-3,4,5,6- tetrahydro-2(1 H)-pyrimidinone, acetonitrile, more preferably N,N- dimethylformamide. The reaction temperature of the above step 7 is in the range from -50 °C to 200 °C, preferably from -20 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000116_0001
10 In the above scheme, the compound of general formula (5-8) (R = a hydrogen atom, a methoxymethyl group, a 2-(trimethylsilyl)ethoxymethyl group, a benzyl group, a p-methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t-buthyldiphenylsilyl group or an acetyl group) may be subjected to alkylation with a compound of general formula (10) (m = an integer of 1 to 5, n = an integer of 1 to 5, X = a halogen atom, a methanesulfonyloxy group, a toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group) in the presence of a base to give a compound of general formula (11 ) (step 8). Suitable bases for use in the above step 8 include sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably sodium hydride or potassium carbonate. Suitable solvents for use in the above step 8 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, methanol, ethanol, isopropanol, acetonitrile, more preferably N,N-dimethylformamide. The reaction temperature of the above step 8 is in the range from -50 °C to 200 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds. In addition, the compound of general formula (5-8) may be subjected to alkylation with a compound of general formula (10) (X = a hydroxyl group) in the presence of triphenylphosphine and dialkyl azocarboxylate to give a compound of general formula (11) in the above scheme (step 8). In the case using a compound of general formula (10) (X = a hydroxyl group), suitable solvents for use in the above step 8 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, more preferably toluene, tetrahydrofuran. In the case using a compound of general formula (10) (X = a hydroxyl group), the reaction temperature of the above step 8 is in the range from -50 °C to 200 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds. Compound 11 can also be synthesized from compound 4 in order of step 8, step 4, step 5, step 6 and step 7.
Figure imgf000117_0001
In the above scheme, the compound of general formula (11) may be subjected to deprotection in the presence of an acid to give a compound of general formula (12) (step 9). Suitable acids for use in the above step 9 include hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, trifluoroacetic acid, 10- camphorsulfonic acid, p-toluenesulfonic acid, pyridinium p-toluenesuifonic acid, trifluoroborane-diethyl ether complex, carbon tetrabromide, trimethylsilyl bromide, methanesulfonic acid, acidic ion exchange resin. Suitable solvents for use in the above step 9 include dichloromethane, 1 ,2-dichloroethane, chloroform, acetone, methanol, ethanol, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,4-dioxane, diethyl ether, water, the mixtures. The reaction temperature of the above step 9 is in the range from -10 °C to 150 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000118_0001
13 In the above scheme, the compound of general formula (5-8) may be subjected to alkylation with a compound of general formula (13) (m = an integer of 1 to 5, X = a halogen atom, a methanesulfonyloxy group, a toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group) in the presence of a base to give a compound of general formula (14) (step 10). Suitable bases for use in the above step 10 include sodium tert- butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably potassium carbonate. Suitable solvents for use in the above step 10 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, methanol, ethanol, isopropanol, acetonitrile, more preferably N,N-dimethylformamide. The reaction temperature of the above step 10 is in the range from - 50 °C to 200 °C, preferably from 0 °C to 150 °C, though it is not specifically limited so far as the reaction proceeds. In addition, the compound of general formula (5-8) may be subjected to alkylation with a compound of general formula (13) (X = a hydroxyl group) in the presence of triphenylphosphine and dialkyl azocarboxylate to give a compound of general formula (14) in the above scheme (step 10). In the case using a compound of general formula (13) (X = a hydroxyl group), suitable solvents for use in the above step 10 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, more preferably toluene, tetrahydrofuran. In the case using a compound of general formula (13) (X = a hydroxyl group), the reaction temperature of the above step 10 is in the range from - 50 °C to 200 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000119_0001
In the above scheme, the compound of general formula (14) may be hydrolyzed in the presence of a base to give a compound of general formula (15) (step 11). Suitable bases for use in the above step 11 include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably sodium hydroxide or potassium hydroxide. Suitable solvents for use in the above step 11 include acetone, methanol, ethanol, tetrahydrofuran, 1 ,4-dioxane, 1 ,2-dimethoxyethane, water, the mixtures more preferably methanol-water mixture. The reaction temperature of the above step 11 is in the range from - 10 °C to 120 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000120_0001
In the above scheme, the compound of general formula (5-8) may be subjected to alkylation with a compound of general formula (16) (p = an integer of 1 to 10, X = a halogen atom, a methanesulfonyloxy group, a toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group) in the presence of a base to give a compound of general formula (17) (step 12). Suitable bases for use in the above step 12 include sodium tert- butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably potassium carbonate. Suitable solvents for use in the above step 12 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, methanol, ethanol, isopropanol, acetonitrile, more preferably N,N-dimethylformamide. The reaction temperature of the above step 12 is in the range from - 50 °C to 200 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds. In addition, the compound of general formula (5-8) may be subjected to alkylation with a compound of general formula (16) (X = a hydroxyl group) in the presence of triphenylphosphine and dialkyl azocarboxylate to give a compound of general formula (17) in the above scheme (step 12). In the case using a compound of general formula (16) (X = a hydroxyl group), suitable solvents for use in the above step 12 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, more preferably toluene, tetrahydrofuran. In the case using a compound of general formula (16) (X = a hydroxyl group), the reaction temperature of the above step 12 is in the range from - 50 °C to 200 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000121_0001
In the above scheme, the compound of general formula (17) may be hydrolyzed in the presence of a base to give a compound of general formula (18) (step 13). Suitable bases for use in the above step 13 include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably sodium hydroxide or potassium hydroxide. Suitable solvents for use in the above step 13 include acetone, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, 1 ,4-dioxane, 1,2- dimethoxyethane, water, the mixtures more preferably methanol-water mixture. The reaction temperature of the above step 13 is in the range from -
10 °C to 120 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000122_0001
19 In the above scheme, the compound of general formula (5-8) may be subjected to alkylation with a compound of general formula (19) (q = an integer of 2 to 10, X = a halogen atom, a methanesulfonyloxy group, a toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group) in the presence of a base to give a compound of general formula (20) (step 14). Suitable bases for use in the above step 14 include sodium tert- butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably potassium carbonate. Suitable solvents for use in the above step 14 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, methanol, ethanol, isopropanol, acetonitrile, more preferably acetonitrile. The reaction temperature of the above step 14 is in the range from -
50 °C to 200 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds. In addition, the compound of general formula (5-8) may be subjected to alkylation with a compound of general formula (19) (X = a hydroxyl group) in the presence of triphenylphosphine and dialkyl azocarboxylate to give a compound of general formula (20) in the above scheme (step 14). In the case using a compound of general formula (19) (X = a hydroxyl group), suitable solvents for use in the above step 14 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, more preferably toluene, tetrahydrofuran. In the case using a compound of general formula (19) (X = a hydroxyl group), the reaction temperature of the above step 14 is in the range from - 50 °C to 200 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000123_0001
In the above scheme, the step for obtaining a compound of general formula (21) from the compound of general formula (20) may be performed with hydrazine or methylamine (step 15). Suitable solvents for use in the above step 15 include methanol, ethanol, n-propanol, isopropanol, more preferably methanol. The reaction temperature of the above step 15 is in the range from 0
°C to 200 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000123_0002
In the above scheme, the compound of general formula (21 ) (R20 = an optionally protected hydroxyl group, an optionally substituted C1-15 alkyl group or an optionally substituted C1-8 alkoxyl group) may be reacted with allyltributyltin in the presence of a palladium catalyst and lithium chloride to give a compound of general formula (22) (step 16). Suitable palladium catalysts for use in the above step 16 include tetrakis(triphenylphosphine)palladium, Pd(dba)2, Pd2(dba)3-CHCI3, palladium acetate, palladium chloride, [1 ,1'-bis(diphenylphosphino)- ferrocenejpalladium dichloride dichloromethane complex, (dba; dibenzylideneacetone) A ligand, such as triphenylphosphine, tributhylphosphine, tricyclohexylphosphine, 1 ,3-bis(diphenylphosphinopropane) or tri-t-buthyl phosphine, may be used in the above step 16 to increase the activity of catalyst or the reaction selectivity. Suitable solvents for use in the above step 16 include N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,-dimethyl- 2-imidazolidinone, tetrahydrofuran, toluene, acetonitrile, more preferably N,N-dimethylformamide. The reaction temperature of the above step 16 is in the range from 0 °C to 200 °C, preferably from 20 °C to 150 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000124_0001
In the above scheme, the compound of general formula (22) (R20 = an optionally protected hydroxyl group, an optionally substituted C1-15 alkyl group or an optionally substituted C1-8 alkoxyl group) may be subjected to hydroboration and oxidation to give a compound of general formula (23) (step 17). Suitable hydroboration reagents for use in the above step 17 include borane-tetrahydrofuran complex, borane-methyl sulfide complex, borane- pyridine complex, borane-trimethylamine complex, or 9-BBN. Suitable oxidizing agents for use in the above step 17 include hydrogen peroxide-sodium hydroxide, or sodium perborate. Suitable solvent for use in the above step 17 includes tetrahydrofuran. The reaction temperature of the above step 17 is in the range from - 78 °C to 100 °C, preferably from -50 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000125_0001
In the above scheme, the compound of general formula (23) (R20 = an optionally protected hydroxyl group, an optionally substituted C1-15 alkyl group or an optionally substituted C1-8 alkoxyl group) may be oxidized to give a compound of general formula (24) (step 18). Suitable oxidizing agents for use in the above step 18 include pyridinium chlorochromate, pyridinium dichromate, manganese dioxide, osmium tetraoxide, ruthenium trichloride, tetrapropylammonium perruthenate, oxaryl chloride/dimethyl sulfoxide/triethylamine, triphosgene/dimethyl sulfoxide, sulfur trioxide pyridine complex/dimethyl sulfoxide, acetone/aluminium triisopropoxide, cyclohexanone/aluminium triisopropoxide, Dess-Martin reagent, more preferably Dess-Martin reagent Suitable solvents for use in the above step 18 include benzene, toluene, hexane, heptane, dichloromethane, 1 ,2-dichloroethane, chloroform, tetrahydrofuran, acetone, water, more preferably dichloromethane. The reaction temperature of the above step 18 is in the range from - 78 °C to 50 °C, preferably from 0 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000125_0002
In the above scheme, the compound of general formula (24) (R20 = an optionally protected hydroxyl group, an optionally substituted C1-15 alkyl group or an optionally substituted C1-8 alkoxyl group) may be subjected to alkylation with Wittig reagent, such as R21CH2-PPh3G (R21 = a hydrogen atom or an optionally substituted 01-15 alkyl group; G = a halogen atom) in the presence of a base to give a compound of general formula (25) (step 19). Suitable Wittig reagents for use in the above step 19 include methyl triphenylphosphonium bromide, ethyl triphenylphosphonium bromide, n- propyl triphenylphosphonium iodide, isopropyl triphenylphosphonium iodide etc. Suitable bases for use in the above step 19 include sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, more preferably n-butyl lithium. Suitable solvents for use in the above step 19 include diethyl ether, tetrahydrofuran, benzene, toluene, dimethylsulfoxide, more preferably tetrahydrofuran. The reaction temperature of the above step 19 is in the range from - 78 °C to 120 °C, preferably from -78 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000126_0001
In the above scheme, the compound of general formula (25) (R20 = an optionally protected hydroxyl group, an optionally substituted C1-15 alkyl group or an optionally substituted C1-8 alkoxyl group; R21 = a hydrogen atom or an optionally substituted C1-15 alkyl group) may be reacted with osmium tetraoxide/4-methylmorpholine N-oxide to give a compound of general formula (26) (step 20). Suitable solvents for use in the above step 20 include acetone, acetonitrile, t-butanol, water or mixtures, more preferably acetone/t- butanol/water mixture. The reaction temperature of the above step 20 is in the range from - 78 °C to 120 °C, preferably from -40 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000127_0001
In the above scheme, the compound of general formula (5-8) may be subjected to alkylation with a compound of general formula (27) (s = an integer of 1 to 10, X = a halogen atom, a methanesulfonyloxy group, a toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group) in the presence of a base to give a compound of general formula (28) (step 21 ). Suitable bases for use in the above step 21 include sodium tert-butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably potassium carbonate. Suitable solvents for use in the above step 21 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, methanol, ethanol, isopropanol, acetonitrile, more preferably acetonitrile. The reaction temperature of the above step 21 is in the range from - 50 °C to 200 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000128_0001
In the above scheme, the step for obtaining a compound of general formula (29) from the compound of general formula (28) may be performed with sodium azide, combination of sodium azide and triethyamine hydrochloride salt, azidotributyltin or combination of trimethylsilylazide and di-n-butyltinoxide (step 22). Suitable solvents for use in the above step 22 include benzene, toluene, xylene, dyglyme. The reaction temperature of the above step 22 is in the range from 0 °C to 200 °C, preferably from 10 °C to 150 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000128_0002
In the above scheme, the compound of general formula (5-8) may be reacted with trifluoromethanesulfonic acid anhydride in the presence of a base to give a compound of general formula (30) (step 23). Suitable bases for use in the above step 23 include pyridine, 2,6- lutidine, 2,4,6-collidine,N,N-dimethylaminopyridine, imidazole, triethylamine, more preferably pyridine. Suitable solvents for use in the above step 23 include diethyl ether, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, more preferably dichloromethane. The reaction temperature of the above step 23 is in the range from - 50 °C to 50 °C, preferably from -20 °C to 30 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000129_0001
In the above scheme, the compound of general formula (30) may be reacted with acrylic acid ester in the presence of a palladium catalyst, and triethyamine to give a compound of general formula (31) (R22 = a C1-3 alkyl group)(step 24). Suitable palladium catalysts for use in the above step 24 include tetrakis(triphenylphosphine)palladium, Pd(dba)2, Pd2(dba)3-CHCI3, palladium acetate, palladium chloride, [1,1'-bis(diphenylphosphino)- ferrocenejpalladium dichloride dichloromethane complex, (dba; dibenzylideneacetone) A ligand, such as triphenylphosphine, tributhylphosphine, tricyclohexylphosphine, 1 ,3-bis(diphenylphosphinopropane) or tri-t-buthyl phosphine, may be used in the above step 24 to increase the catalytic activity and/or the reaction selectivity. Suitable solvents for use in the above step 24 include N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl- 2-imidazolidinone, tetrahydrofuran, toluene, acetonitrile, more preferably N,N-dimethylformamide or acetonitrile. The reaction temperature of the above step 24 is in the range from 0 °C to 200 °C, preferably from 20 °C to 150 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000129_0002
In the above scheme, the compound of general formula (31 ) (R22 = a C1-3 alkyl group) may be reacted with NaBH4 in the presence of NiCI2- 6H20 to give a compound of general formula (32) (R22 = a C1 -3 alkyl group) (step 25). Suitable solvents for use in the above step 25 include methanol, ethanol, isopropanol, dichloromethane, 1 ,2-dichloroethane or mixtures, more preferably methanol/dichloromethane mixture. The reaction temperature of the above step 25 is in the range from - 40 °C to 100 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000130_0001
In the above scheme, the compound of general formula (32) (R22 = a C1-3 alkyl group) may be hydrolyzed in the presence of a base to give a compound of general formula (33) (step 26). Suitable bases for use in the above step 26 include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, tetrabutylammonium fluoride, more preferably sodium hydroxide, potassium hydroxide or tetrabutylammonium fluoride. Suitable solvents for use in the above step 26 include acetone, methanol, ethanol, tetrahydrofuran, 1 ,4-dioxane, 1 ,2-dimethoxyethane, water, the mixtures more preferably methanol-water mixture or tetrahydrofuran. The reaction temperature of the above step 26 is in the range from -
10 °C to 120 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000130_0002
In the above scheme, the compound of general formula (30) may be reacted with acetylene derivative in the presence of a palladium catalyst, copper (I) iodide, and triethyamine to give a compound of general formula
(34) (R22 = a C1-3 alkyl group)(step 27). Suitable palladium catalysts for use in the above step 27 include
PdCI2(dppf)2-CH2CI2 complex, tetrakis(triphenylphosphine)palladium, Pd(dba)2, Pd2(dba)3-CHCI3, palladium acetate, palladium chloride, (dba; dibenzylideneacetone, dppf; diphenylphosphino)ferrocene) A ligand, such as triphenylphosphine, tributhylphosphine, tricyclohexylphosphine, 1 ,3-bis(diphenylphosphinopropane) or tri-t-buthyl phosphine, may be used in the above step 27 to increase the catalytic activity and/or the reaction selectivity. Suitable solvents for use in the above step 27 include N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-
2-imidazolidinone, tetrahydrofuran, toluene, acetonitrile, more preferably
N,N-dimethylformamide or acetonitrile. The reaction temperature of the above step 27 is in the range from 0
°C to 200 °C, preferably from 20 °C to 150 °C, though it is not specifically limited so far as the reaction proceeds.
The compound of general formula (34) (R22 = a C1-3 alkyl group) may be hydrolyzed by the same procedure as described in step 26 to give the corresponding carboxylic acid.
Figure imgf000131_0001
35 In the above scheme, the compound of general formula (5-8) may be subjected to alkylation with a compound of general formula (35) (m = an integer of 1 to 5, X = a halogen atom, a methanesulfonyloxy group, a toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group) in the presence of a base to give a compound of general formula (36) (step 28). Suitable bases for use in the above step 28 include sodium tert- butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably potassium carbonate. Suitable solvents for use in the above step 28 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, methanol, ethanol, isopropanol, acetonitrile, more preferably N,N-dimethylformamide, acetonitrile. The reaction temperature of the above step 28 is in the range from -
50 °C to 200 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds. In addition, the compound of general formula (5-8) may be subjected to alkylation with a compound of general formula (35) (X = a hydroxyl group) in the presence of triphenylphosphine and dialkyl azocarboxylate to give a compound of general formula (36) in the above scheme (step 28). In the case using a compound of general formula (35) (X = a hydroxyl group), suitable solvents for use in the above step 28 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, more preferably toluene, tetrahydrofuran. In the case using a compound of general formula (35) (X = a hydroxyl group), the reaction temperature of the above step 28 is in the range from - 50 °C to 200 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000133_0001
In the above scheme, the compound of general formula (36) may be hydrolyzed in the presence of an acid to give a compound of general formula (37) (step 29). Suitable acids for use in the above step 29 include hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, phosphoric acid, trifluoroacetic acid, 10-camphorsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, more preferably hydrochloric acid. Suitable solvents for use in the above step 29 include acetone, methanol, ethanol, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,4-dioxane, diethyl ether, water, the mixtures. The reaction temperature of the above step 29 is in the range from 0 °C to 200 °C, preferably from 20 °C to 120 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000133_0002
In the above scheme, the compound of general formula (12) may be subjected to cyclization in the presence of triphenylphosphine and dialkyl azocarboxylate to give a compound of general formula (38) (step 30). Suitable solvents for use in the above step 30 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, more preferably toluene, tetrahydrofuran. The reaction temperature of the above step 30 is in the range from -
50 °C to 200 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000134_0001
In the above scheme, the compound of general formula (18) may be reacted with amine derivative NHR23(R24) (R23 = a hydrogen atom or a C1-3 alkyl group, R24 is represented by following formula) in the presence of coupling reagent used to form amide bonds, after that, may be subjected to deprotection to give a compound of general formula (39) (step 31). R24: Ra
Rb COORc Ra and Rb are each independently selected from the group consisiting of a hydrogen atom, an optionally substituted C1 -10 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted phenyl group, an optionally substituted benzyl group, an optionally substituted phenethyl group, or Ra and Rb may together form an optionally substituted C3-10 cycloalkyl group. The substitution group is a hydroxyl group, an amino group, a carboxyl group or a carboxylic amide group with an appropriate protecting group described in Protecting Groups in Organic Synthesis, third edition, John Wiley & Sons, Inc., for example, tert-butyl group, tert-butoxycarbonyl group, trityl group. Rc is a protecting group selected from a C1-5 alkyl group or polystylene-bound 4-benzyloxy-benzyl group. In the deprotection step, the cleavage of a protecting group such as tert-butyl group, tert-butoxycarbonyl group, trityl group or polystylene-bound 4-benzyloxy-benzyl group may be carried by trifluoroacetic acid in dichloromethane. Suitable coupling reagents for use in the above step 31 include 1 ,3- dicylcohexylcarbodiimide, 1 ,3-diisopropylcarbodiimide, N-ethyl-N'-(3- dimethylaminopropyl)carbodiimide, benzotriazol-1-yloxy- tris(dimethylamino)phosphoniunr) hexafluorophosphate, diphenylphosphoryl azide. In the coupling step, a reagent, such as N-hydroxysuccinimide, 1- hydroxybenzotriazole or hydroxy-3,4-dihydro-4-oxo-1 ,2,3-benzotriazine may be used in the above step 31 to increase the yields. Suitable solvents for use in the coupling process in step 31 include benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6- tetrahydro-2(1 H)-pyrimidinone, acetonitrile. The reaction temperature of the above step 31 is in the range from - 50 °C to 200 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000135_0001
In the above scheme, the compound of general formula (2) may be reacted with tert-butyl-(1-tert-butyl-prop-2-ynyloxy)-dimethyl-silane in the presence of a palladium catalyst, copper (I) iodide, and triethyamine to give a compound of general formula (40) (step 32). Suitable palladium catalysts for use in the above step 32 include tetrakis(triphenylphosphine)palladium, Pd(dba)2, Pd2(dba)3-CHCI3, palladium acetate, palladium chloride, [1 ,1'-bis(diphenylphosphino)- ferrocenejpalladium dichloride dichloromethane complex, (dba; dibenzylideneacetone) A ligand, such as triphenylphosphine, tributhylphosphine, tricyclohexylphosphine, 1 ,3-bis(diphenylphosphinopropane) or tri-t-buthyl phosphine, may be used in the above step 32 to increase the catalytic activity and/or the reaction selectivity. Suitable solvents for use in the above step 32 include N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl- 2-imidazolidinone, tetrahydrofuran, toluene, acetonitrile, more preferably N,N-dimethylformamide or acetonitrile. The reaction temperature of the above step 32 is in the range from 0 °C to 200 °C, preferably from 20 °C to 150 °C, though it is not specifically limited so far as the reaction proceeds.
Figure imgf000136_0001
41 In the above scheme, the compound of general formula (5-8) may be subjected to alkylation with a compound of general formula (41) (m' = 0 or 1 , n' = 0, 1 or 2, A = an oxygen atom, a sulfur atom, a nitrogen atom or a carbon atom, X = a halogen atom, a methanesulfonyloxy group, a toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, R25 = a C1-4 alkyl group) in the presence of a base to give a compound of general formula (42) (step 33). Suitable bases for use in the above step 33 include sodium tert- butoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, more preferably potassium carbonate. Suitable solvents for use in the above step 33 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, methanol, ethanol, isopropanol, acetonitrile,, acetone more preferably N,N-dimethylformamide, acetone. The reaction temperature of the above step 33 is in the range from - 50 °C to 200 °C, preferably from 0 °C to 100 °C, though it is not specifically limited so far as the reaction proceeds. In addition, the compound of general formula (5-8) may be subjected to alkylation with a compound of general formula (41 ) (X = a hydroxyl group) in the presence of triphenylphosphine and dialkyl azocarboxylate to give a compound of general formula (42) in the above scheme (step 33). In the case using a compound of general formula (41) (X = a hydroxyl group), suitable solvents for use in the above step 33 include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, dichloromethane, 1 ,2- dichloroethane, chloroform, more preferably toluene, tetrahydrofuran. In the case using a compound of general formula (41 ) (X = a hydroxyl group), the reaction temperature of the above step 33 is in the range from - 50 °C to 200 °C, preferably from -20 °C to 50 °C, though it is not specifically limited so far as the reaction proceeds. The compound of general formula (42) (R25 = a C1 -3 alkyl group) may be hydrolyzed by the same procedure as described in step 26 to give the corresponding carboxylic acid.
The compounds of general formula (8, 11 , 12, 14, 15, 17, 18, 20, 21 , 28, 29, 30, 31 , 32, 33, 34, 36, 37, 38, 39, 40, 42) (R = a methoxymethyl group, a 2-(trimethylsilyl)ethoxymethyl group, a benzyl group, a p- methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a t- butyldimethylsilyl group, a t-buthyldiphenylsilyl group or an acetyl group) may be subjected to deprotection in the presence of an acid, a base or a fluorine compound to give the compounds of general formula (8, 11 , 12, 14, 15, 17, 18, 20, 21 , 28, 29, 30, 31 , 32, 33, 34, 36, 37, 38, 39, 40, 42) (R = a hydrogen atom). Suitable acids for use in the deprotection step of the compounds of general formula (8, 11, 12, 14, 15, 17, 18, 20, 21 , 28, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 40, 42) (R = a methoxymethyl group, a 2- (trimethylsilyl)ethoxymethyl group, a benzyl group, a p-methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t- buthyldiphenylsilyl group) include hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, phosphoric acid, trifluoroacetic acid, formic acid, 10-camphorsulfonic acid, p-toluenesulfonic acid, pyridinium p-toluenesuifonic acid, trifluoroborane-diethyl ether complex, methanesulfonic acid, acidic ion exchange resin. Suitable bases for use in the deprotection step of the compounds of general formula (8, 11 , 12, 14, 15, 17, 18, 20, 21 , 28, 29, 30, 31 , 32, 33, 34, 36, 37, 38, 39, 40, 42) (R = an acetyl group) include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate. Suitable fluorine compounds for use in the deprotection step of the compounds of general formula (8, 11 , 12, 14, 15, 17, 18, 20, 21 , 28, 29, 30, 31 , 32, 33, 34, 36, 37, 38, 39, 40, 42) (R = a 2-(trimethylsilyl)ethoxymethyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t-buthyldiphenylsilyl group or an acetyl group) include tetrabutylammonium fluoride, aqueous hydrogen fluoride, hydrogen fluoride-pyridine, hydrogen fluoride-triethylamine, potassium fluoride, sodium fluoride, calcium fluoride, cesium fluoride. Suitable solvents for use in the deprotection step of the compounds of general formula (8, 11 , 12, 14, 15, 17, 18, 20, 21 , 28, 29, 30, 31 , 32, 33, 34, 36, 37, 38, 39, 40, 42) (R = a methoxymethyl group, a 2- (trimethylsilyl)ethoxymethyl grou@, a benzyl group, a p-methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t-buthyldiphenylsilyl group or an acetyl group) include hexane, benzene, toluene, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, diisopropyl ether, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1 ,3-dimethyl-2-imidazolidinone, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, methanol, ethanol, isopropanol, acetonitrile, acetone, water, the mixtures. The reaction temperature in the deprotection step of the compounds of general formula (8, 11 , 12, 14, 15, 17, 18, 20, 21 , 28, 29, 30, 31 , 32, 33, 34, 36, 37, 38, 39, 40, 42) (R = a methoxymethyl group, a 2-
(trimethylsilyl)ethoxymethyl group, a benzyl group, a p-methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t- buthyldiphenylsilyl group or an acetyl group) is in the range from -50 °C to 200 °C, preferably from -20 °C to 120 °C, though it is not specifically limited so far as the reaction proceeds.
EXAMPLES To further illustrate this invention, the following examples are included. The examples should not, of course, be construed as specifically limiting the invention. Variations of these examples are within the purview of one skilled in the art and considered to fall within the scope of the invention as described and claimed herein. The reader will recognize that the skilled artisan, in possession of the present disclosure and skilled in the art, is able to prepare and use the invention without exhaustive examples. Materials used herein identified with trademarks are examples only and reflect illustrative materials used at the time of the invention. The skilled artisan will recognize that variations in lot, manufacturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the invention. Reactions were performed under nitrogen or argon atmosphere at room temperature in stirring condition, otherwise indicated. Chromatographs were performed with nitrogen pressure using silica gel from Kanto Chemicals (silica gel 60N (Spherical neutral) 40-50 micro m) or Merck (silica gel 60 (230-400 mesh ASTM) 40-50 micro m). Nuclear magnetic resonanse (NMR) analyses were performed on AXR 300 (Bruker), a EX-270 sectrometer (JEOL), or Gemini2000/300 (Varian) in CDCI3 using tetramethylsilane as a internal standard, otherwise indicated. Mass spectrum (MS) analyses were performed on ZQ2000 (Waters), LOQ Classic (Thermo), or Q-micro, Triple Quadrupole Mass Spectrometer (MICROMASS) in APCI/ESI (atmospheric chemical pressure ionization/ electron spray ionization) negative or positive mode. The following abbreviations have the indicated meanings:
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Example 1
Preparation of (S)-5-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000143_0001
(1) Preparation of trifluoro-methanesulfonic acid 4-[1 -ethyl-1 -(4-hydroxy-3- methyl-phenyl)-propyl]-2-methyl-phenyl ester
Figure imgf000143_0002
To a solution of 3,3-bis[4-hydroxy-3-methylphenyl]pentane (9.0 g, 31.6 mmol) in dichloromethane (300 ml), pyridine (3 ml, 37.2 mmol) and trifluoromethanesulufonic anhydride (5.7 ml, 34.7 mmol) were added at 0 °C and stirred at 0 °C for 1 h. To the mixture, ethylacetate was added and the organic layer was washed with saturated NaHC03 solution and brine, dried over MgS0 , concentrated in vacuo, and chromatographed (ethylacetate/hexane = 1/10 to ethyl acetate only) to give the title compound (4.9 g, 37 %).
1H-NMR: 0.62 (t, 6H), 2.03 (q, 4H), 2.20 (s, 3H), 2.38 (s, 3H), 4.67 (s, 1H), 6.68 (d, 1 H), 6.80-6.88 (m, 2H), 7.02-7.11 (m, 3H); MS (ESI+) : 417 ([M+H]+).
(2) Preparation of 4-[1 -ethyl-1 -(3-methyl-4-trimethylsilanylethynyl-phenyl)- propyl]-2-methyl-phenol
Figure imgf000143_0003
To a solution of trifluoromethanesulfonic acid 4-[1 -ethyl-1 -(4-hydroxy-3- methyl-phenyl)-propyl]-2-methyl-phenyl ester (compound prepared in Example 1-(1)) (25 g, 60.03 mmol) in acetonitrile (300 ml), triethylamine (25.1 ml, 180.09mmol), ethynyltrimethylsilane (25.5 ml, 180.09 mmol), Cul (1.143 g, 6.00 mmol), and Pd(PPh3)4 (6.93 g, 6.00 mmol) were added. The mixture was stirred at 110 °C for 18 h and concentrated in vacuo. To the residue, ethylacetate and H2O added and the pH was adjusted at 7 by addition of 1 N HCl. The organic layer was dried over MgS04, concentrated in vacuo, and chromatographed (ethylacetate/hexane = 1/15) to give the title compound (16 g, 74 %).
1H-NMR: 0.25 (s, 9H), 0.60 (t, 6H), 2.04 (q, 4H), 2.18 (s, 3H), 2.38 (s, 3H), 4.58 (s, 1H), 6.63 (d, 1H), 6.83-6.88 (m, 2H), 6.92 (d, 1H), 7.00 (s, 1H), 7.30 (d, 1 H).
(3) Preparation of 4-[1 -ethyl-1 -(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl- phenol
Figure imgf000144_0001
To a solution of 4-[1 -ethyl-1 -(3-methyl-4-trimethylsilanylethynyl-phenyl)- propyl]-2-methyl-phenol (compound prepared in Example 1-(2)) (19.03 g, 52.19 mmol) in THF (520 ml), 1 M terabutylanmonium fluoride in THF (78.3 ml, 78.3 mmol) was added. The mixture was stirred for 0.5 h, concentrated in vacuo, extracted with ethylacetate, washed with brine, dried over MgS04, concentrated in vacuo, and chromatographed (ethylacetate/hexane = 1/10) to give the title compound (15.6 g, 94 %). 1H-NMR: 0.60 (t, 6H), 2.04 (q, 4H), 2.20 (s, 3H), 2.41 (s, 3H), 3.23 (s, 1 H), 4.51 (s, 1 H), 6.64 (d, 1H), 6.82-6.86 (m, 2H), 6.90-6.95 (m, 1 H), 7.00 (s, 1 H), 7.29 (d, 1 H); MS (ESI-) : 291 ([M-H]'). (4) Preparation of 4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000145_0001
To a solution of 4-[1 -ethyl-1 -(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl- phenol (compound prepared in Example 1-(3)) (4.28 g, 14.69 mmol) in THF (92 ml), 2.5 M n-butyl lithium in hexane (14.7 ml, 36.73 mmol) was added at -78 °C. To the mixture, pentan-3-one (4.85 ml, 44.07 mmol) was added at - 78 °C, stirred at -78 °C for 3 h, and concentrated in vacuo. To the residue, ethylacetate and H20 were added and the pH was adjusted at 6 by addition of 1 N HCl. Extracted with ethylacetate, dried over Na2S04, concentrated in vacuo, and chromatographed (ethylacetate/hexane = 1/6) to give the title compound (3.66 g, 62 %).
1H-NMR: 0.61 (t, 6H), 1.11 (t, 6H), 1.72-1.78 (m, 4H), 2.02 (q, 4H), 2.19 (s, 3H), 2.38 (s, 3H), 4.50 (s, 1H), 6.65 (d, 1H), 6.82-6.86 (m, 2H), 6.90-6.95 (m, 1 H), 7.00 (s, 1 H), 7.29 (d, 1 H); MS (ESI-): 377 ([M-H]").
(5) Preparation of 4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-(1 E)-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol
Figure imgf000145_0002
To a solution of 4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(4)) (800 mg, 2.11 mmol) in THF (8 ml), 1 M LiAIH4 in THF (5.28 ml, 5.28 mmol) was added. The mixture was refluxed for 18 h and H2O was added after cooling. Filtrated, extracted with ethylacetate, washed with brine, dried over MgS04, concentrated in vacuo, and chromatographed (ethylacetate/hexane = 1/7) to give the title compound (500mg, 62%).
1H-NMR: 0.60 (t, 6H), 0.93 (t, 6H), 1.64 (q, 4H), 2.04 (q, 4H), 2.20 (s, 3H),
2.31 (s, 3H), 4.59 (s, 1H), 6.02 (d, 1H), 6.66 (d, 1H), 6.75 (d, 1H), 6.83-6.92
(m, 4H), 7.28 (d, 1 H)
MS (ESI-) : 379 ([M-H]").
(6) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000146_0001
To a solution of 4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-(1 E)-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1- (5)) (150 mg, 0.394 mmol) in dimethylformamide (4 ml), K2C03 (136 mg, 0.985 mmol) was added and stirred for 0.5 h. To the mixture, toluene-4- sulfonic acid (S)-5-oxo-tetrahydro-furan-2-ylmethyl ester (160 mg, 0.591 mmol) was added and stirred at 100 °C for 15 h. After cooling to room temperature, saturated NH4CI solution was added. Extracted with ethylacetate, washed with brine, dried over MgS04, concentrated in vacuo, and chromatographed (ethylacetate/hexane = 1/5 to 1/3) to give the title compound (170 mg, 90 %).
1H-NMR: 0.62 (t, 6H), 0.92 (t, 6H), 1.65 (q, 4H), 2.04 (q, 4H), 2.17 (s, 3H), 2.32 (s, 3H), 2.34-2.84 (m, 4H), 4.05-4.20 (m, 2H), 4.85-4.92 (m, 1 H), 6.02 (d, 1 H), 6.67 (d, 1 H), 6.75 (d, 1 H), 6.90-6.97 (m, 4H), 7.29 (d, 1 H); MS (ESI+) : 501 ([M+Na]+).
(7) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000147_0001
To a solution of (S)-5-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 1-(6)) (170 mg, 0.355 mmol) in methanol (7 ml), 1 N KOH solution (0.7 ml) was added. The mixture was stirred for 2 h, concentrated in vacuo, extracted with ethylacetate, washed with brine, dried over MgS04, concentrated in vacuo, and chromatographed (dichloromethane/methanol = 20/1) to give the title compound (150 mg, 85 %).
1H-NMR (measured in CD3OD as potassium salt): 0.63 (t, 6H), 0.97 (t, 6H), 1.68 (q, 4H), 1.84-1.94 (m, 1H), 1.97-2.04 (m, 1 H), 2.10 (q, 4H), 2.21 (s, 3H), 2.32 (s, 3H), 2.42 (t, 2H), 3.93-4.03 (m, 3H), 6.04 (d, 1 H), 6.78 (d, 1 H), 6.81 (s, 1 H), 6.91 (s, 1 H), 6.95-7.00 (m, 3H), 7.31 (d, 1H); MS (ESI-) : 495 ([M-H]"
Example 2
Preparation of (S)-5-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid
Figure imgf000147_0002
(1 ) Preparation of 4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenol
Figure imgf000148_0001
To a solution of 4-[1 -ethyl-1 -(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl- phenol (compound prepared in Example 1-(3)) (4.4 g, 15.1 mmol) in THF (108 ml), 2.5 M n-butyl lithium in hexane (12 ml, 30.2 mmol) was added at - 78 °C and stirred at -78 °C for 1h. To the mixture, hexafluoroacetone was passed by bubbling at -78 °C and stirred at -78 °C for 2 h. To the reaction mixture, diethylether and H2O were added, and the pH was adjusted at 7 by addition of 1 N HCl. Extracted with diethyl ether, dried over MgS04, concentrated in vacuo, chromatographed two times (ethyl acetate/hexane = 1/10 and 1/5), and purified by HPLC (column:Merck Lobar column 40-63 micrometer 400x40 mm (ODS) , MeOH/H20 = 2/1 , 3/1 , and 4/1 , isocratic) to give the title compound (2.0 g, 29 %).
1H-NMR: 0.61 (t, 6H), 2.05 (q, 4H), 2.20 (s, 3H), 2.39 (s, 3H), 3.50 (s, 1H), 4.58 (s, 1 H), 6.66 (d, 1 H), 6.80-6.83 (m, 2H), 6.99 (d, 1 H), 7.07 (s, 1H), 7.34 ( , 1H).
(2) Preparation of 4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenol
Figure imgf000148_0002
To a solution of 4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 2-(1)) (356 mg, 0.777 mmol) in dimethylformamide (5 ml), K2CO3 (268 mg, 1.94 mmol) was added and stirred for 20min. To the mixture, chloromethoxymethane (71 μl, 0.935 mmol) was added and stirred for 1 h. To the reaction mixture, saturated NH4CI (20 ml) was added. Extracted with ethylacetate and dried over MgS04, concentrated in vacuo, and chromatographed (ethylacetate/hexane = 1/6) to give the title compound (349 mg, 89 %).
1H-NMR: 0.60 (t, 6H), 2.05 (q, 4H), 2.20 (s, 3H), 2.40 (s, 3H), 3.49 (s, 3H), 4.59 (s, 1 H), 5.17 (s, 2H), 6.65 (d, 1 H), 6.80-6.83 (m, 2H), 6.99 (d, 1 H), 7.07 (s, 1 H), 7.38 (d, 1H).
(3) Preparation of (S)-5-(4-{1 -ethyl-1 -[3-methyl-4-(4, 4, 4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one
Figure imgf000149_0001
To a solution of 4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy- 3-trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 2-(2)) (300 mg, 0.597 mmol) in dimethylformamide (3 ml), 60 % NaH (29 mg, 0.725 mmol) was added and stirred for 0.5 h. To the mixture, toluene-4-sulfonic acid (S)-5-oxo-tetrahydro-furan-2-ylmethyl ester (194 mg, 0.719 mmol) was added and stirred at 110-120 °C for 16 h. To the reaction mixture, saturated NH4CI solution was added. Extracted with ethylacetate, washed with brine, dried over MgSθ4, concentrated in vacuo, and chromatographed (ethylacetate/hexane = 1/3) to give the title compound (158 mg, 44 %). 1H-NMR: 0.60 (t, 6H), 2.05 (q, 4H), 2.17 (s, 3H), 2.42 (s, 3H), 2.25-2.80 (m, 4H), 3.49 (s, 3H), 4.04-4.17 (m, 2H), 4.86-4.92 (m, 1 H), 5.17 (s, 2H), 6.67 (d, 1H), 6.83 (s, 1 H), 6.92 (d, 1H), 6.98 (d, 1H), 7.02 (s, 1H), 7.38 (d, 1H). (4) Preparation of (S)-5-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro- furan-2-one
Figure imgf000150_0001
To a solution of (S)-5-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 2-(3)) (338 mg, 0.562 mmol) in dichloromethane (10 ml), trifluoroacetic acid (1 ml) was added and stirred for 16 h. Concentrated in vacuo, and chromatographed (ethylacetate/hexane = 1/3) to give the title compound (153 mg, 49 %).
1H-NMR: 0.60 (t, 6H), 2.05 (q, 4H), 2.14 (s, 3H), 2.39 (s, 3H), 2.25-2.81 (m, 4H), 4.04-4.17 (m, 2H), 4.86-4.91 (m, 1H), 6.63 (d, 1H), 6.83 (s, 1H), 6.90 (dd, 1H), 6.96 (dd, 1 H), 7.02 (s, 1 H), 7.38 (d, 1H); MS (ESI-) : 555 ([M-H]").
(5) Preparation of (S)-5-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid
Figure imgf000150_0002
To a solution of (S)-5-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro- furan-2-one (compound prepared in Example 2-(4)) (70.2 mg, 0.126 mmol) in ethanol (3 ml), 1 N KOH solution (0.378 ml) was added and stirred for 3 h. Concentrated in vacuo and extracted with diethylether. The pH was adjusted at 9 by addition of saturated KHS04. The organic layer was filtrated through celite and concentrated in vacuo to give the title compound (36.7 mg, 52 %).
1H-NMR (measured in CD3OD as potassium salt): 0.60 (t, 6H), 1.77-1.88 (m, 1 H), 1.93-2.03 (m, 1H), 2.09 (q, 4H), 2.15 (s, 3H), 2.38 (s, 3H), 2.38-2.44 (m, 2H), 3.88-3.92 (m, 2H), 3.93-4.00 (m, 1H), 6.78 (d, 1H), 6.84 (s, 1H), 6.94 (dd, 1 H), 7.03 (d, 1 H), 7.09 (s, 1 H), 7.34 (d, 1 H); MS (ESI-) : 573 ([M-H]").
Example 3
Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000151_0001
Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000151_0002
To a solution of 4-[1 -ethyl-1 -(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl- phenol (compound prepared in Example 1-(3)) (12.22 g, 41.8 mmol) in THF (300 ml) was added 2.44 M n-butyl lithium in hexane (42.8 ml, 104.5 mmol) at 0 degrees C. The reaction mixture was stirred for 30min at 0 degrees C. Trimethylacetaldehyde (13.79 ml, 125.4 mmol) was added, stirred at 0 degrees C for 30min. To the reaction mixture, saturated aqueous NH4CI was added and extracted with ethyl acetate, washed with brine, dried over MgS04, concentrated in vacuo, and chromatographed on silica gel (ethyl acetate/hexane= 10/90 to 25/75) to give the title compound (13.08 g, 83%). 1H-NMR(CDCI3): 0.59 (t, 6H), 1.07 (s, 9H), 1.86 (d, 1 H), 2.03 (q, 4H), 2.19 (s, 3H), 2.38 (s, 3H), 4.26 (d, 1H), 4.59 (s, 1 H), 6.65 (d, 1 H), 6.82-6.85 (m, 2H), 6.92-6.95 (m, 1 H), 7.00 (s, 1 H), 7.28 (d, 1H).
Example 4
Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-3-propyl-hex-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000152_0001
Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-3-propyl-hex-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000152_0002
Using the same procedure as described for the preparation of Example 3, the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)). 1H-NMR(CDCI3): 0.60 (t, 6H), 0.92(t, 3H), 1.30-1.61 (m, 8H),2.05(q, 4H), 2.19(s,3H), 2.30(s,3H), 4.70(s, 1H), 6.65(d, 1H), 6.83(m, 2H), 7.00(d,1H), 7.18(d, 1 H), 7.28(d, 1 H); MS (ESI-) : 405 ([M-H]-).
Example 5 Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000153_0001
Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000153_0002
Using the same procedure as described for the preparation of Example 3, the title compound was prepared from 4-[1 -ethyl- 1-(4-ethy nyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)). 1H-NMR(CDCI3): 0.59 (t, 6H), 1.62(s,6H), 2.02(q,4H), 2.05(s, 1H), 2.18(s,3H), 2.36(s,3H), 4.60(bs, 1 H), 6.63-7.00(m, 5H), 7.26(d, 1 H).
Example 6
Preparation of 4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclobutylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000153_0003
Preparation of 4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclobutylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000153_0004
Using the same procedure as described for the preparation of Example 3, the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)). 1H-NMR(CDCI3): 0.61 (t, 6H), 1.81-2.05(m, 6H), 2.01(q, 4H), 2.18(s, 3H), 2.36(s, 3H), 4.86(s, 1H), 6.65(d, 1 H), 6.82(dd, 1H), 6.84(s, 1H),6.93(dd, 1 H), 7.00(d,1 H), 7.26(d, 1 H); MS (ESI-) : 361 ([M-H]-).
Example 7
Preparation of 4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000154_0001
Preparation of 4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000154_0002
Using the same procedure as described for the preparation of Example 3, the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)). 1H-NMR(CDCI3): 0.59 (t, 6H), 1.68-1.91 (m,4H), 1.99-2.10(m, 4H), 2.01 (q, 4H), 2.18(s,3H), 2.36(s,3H), 4.86(s, 1 H), 6.65(d, 1 H), 6.82(dd, 1 H), 6.84(s, 1 H), 6.93(dd, 1 H), 7.00(d,1 H), 7.26(d, 1 H); MS (ESI-) : 375 ([M-H]').
Example 8
Preparation of 4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000155_0001
Preparation of 4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000155_0002
Using the same procedure as described for the preparation of Example 3, the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)). 1H-NMR(CDCI3): 0.59 (t, 6H), 1.52-1.79(m, 7H), 1.92-2.08(m, 4H), 2.02(q, 4H), 2.18(s,3H), 2.38(s,3H), 4.58(s, 1 H), 6.64(d, 1 H), 6.84(dd, 1 H), 6.86(s, 1 H) ,6.94(dd, 1 H), 7.00(s, 1 H), 7.28(d, 1H); MS (ESI-) : 389 ([M-H]").
Example 9
Preparation of 4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenol
Figure imgf000155_0003
Preparation of 4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenol
Figure imgf000155_0004
To a solution of 4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 2-(1)) (0.5 g, 1.09 mmol) in THF (10 ml) was slowly added LiAIH4 (1 M in THF) (4.22 ml, 4.226 mmol) at 25 degrees C. The reaction mixture was refluxed for 2 h. The reaction mixture was cooled to 0 degrees C. To the mixture, saturated aqueous NH4CI was added and extracted with diethyl ether. The mixture was filtered through celite, washed with brine, dried over Na2S0 , concentrated in vacuo, and chromatographed on silica gel (hexane/dichloromethane/ethyl acetate=1/10/1) to give the title compound (0.4 g, 80%).
1H NMR (CDCI3): 7.39(s, 1H), 7.34(t, 1 H), 7.00(d, 1 H), 6.99(s, 1 H), 6.91- 6.84(m, 2H), 6.65(d, 1 H), 6.10(d, 1H), 4.52(s, 1 H), 3.11 (s, 1H), 2.33(s, 3H), 2.25(s, 3H), 2.04(q, 4H), 0.59(t, 6H).
Example 10
Preparation of 4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3-methyl- phenyl}-propyl)-2-methyl-phenol
Figure imgf000156_0001
Preparation of 4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3-methyl- phenyl}-propyl)-2-methyl-phenol
Figure imgf000156_0002
Using the same procedure as described for the preparation of Example 9, the title compound was prepared from 4-{1 -ethyl-1 -[4-(1-hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 7). 1H-NMR(CDCI3): 0.60(t, 6H), 0.92(t,3H), 1.68-1.91 (m,4H), 1.99-2.10(m, 4H), 2.04(q, 4H), 2.19(s,3H), 2.31 (s,3H), 4.58(s, 1H), 6.26(d, 1H), 6.64(d, 1H), 6.81-6.96(m, 5H), 7.32(d, 1H); MS (ESI-) : 377 ([M-H]").
Example 11
Preparation of 4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3-methyl- phenyl}-propyl)-2-methyl-phenol
Figure imgf000157_0001
Preparation of 4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3-methyl- phenyl}-propyl)-2-methyl-phenol
Figure imgf000157_0002
Using the same procedure as described for the preparation of Example 9, the title compound was prepared from 4-{1 -ethyl-1 -[4-(1-hydroxy- cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 8).
1H-NMR(CDCI3): 0.60 (t, 6H), 1.33-1.74(m, 10H), 2.04(q, 4H), 2.23(s,3H), 2.31 (s,3H), 4.68(s, 1H), 6.23(d, 1H), 6.65(d, 1H), 6.79-7.00(m, 5H) ,7.31 (d, 1H); MS (ESI-) : 391 ([M-H]").
Example 12
Preparation of 4-{1 -ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000157_0003
Preparation of 4-{1 -ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000158_0001
Using the same procedure as described for the preparation of Example 9, the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hydroxy-3-methyl- but-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 5). H-NMR(CDCI3): 0.60 (t, 6H), 1.42(s, 6H), 2.05(q, 4H), 2.18(s, 3H), 2.30(s, 3H), 4.97(s, 1 H), 6.22(d, 1H), 6.64(d, 1H), 6.76(d, 1H), 6.84-6.90(m, 2H), 6.94-6.97(m, 2H), 7.31 (d, 1H); MS (ESI-) : 351 ([M-H]")-
Example 13
Preparation of 4-{1 -ethyl-1 -[4-((E)-3-hydroxy-3-propyl-hex-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000158_0002
Preparation of 4-{1 -ethyl-1 -[4-((E)-3-hydroxy-3-propyl-hex-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000158_0003
Using the same procedure as described for the preparation of Example 9, the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hydroxy-3-propyl- hex-1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 4).
1H-NMR(CDCI3): 0.61 (t, 6H), 0.92(t, 3H), 1.32-1.50(m, 3H), 1.54~1.64(m, 5H), 2.03(q, 4H), 2.19(s,3H), 2.30(s,3H), 4.71(s, 1 H), 6.06(d, 1H), 6.69(d, 1 H), 6.75(d, 1 H), 6.85~6.96(m, 4H), 7.32(d, 1 H); MS (ESI-) : 407 ([M-H]").
Example 14
Preparation of 4-{1 -ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol
Figure imgf000159_0001
Preparation of 4-{1 -ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol
Figure imgf000159_0002
Using the same procedure as described for the preparation of Example 9, the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 3).
1H-NMR(CDCI3): 0.60 (t, 6H), 0.96 (s, 9H), 2.03(q, 4H), 2.19(s, 3H), 2.29(s, 3H), 3.92(d, 1 H), 6.12(dd, 1 H), 6.65(d, 1 H), 6.73(d, 1 H), 6.84-6.97(m, 4H), 7.31 (d, 1H); MS (ESI-) : 379 ([M-H]").
Example 15
Preparation of 4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclobutyl)-vinyl]-3-methyl- phenyl}-propyl)-2-methyl-phenol
Figure imgf000160_0001
Preparation of 4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclobutyl)-vinyl]-3-methyl- phenyl}-propyl)-2-methyl-phenol
Figure imgf000160_0002
Using the same procedure as described for the preparation of Example 9, the title compound was prepared from 4-{1 -ethyl-1 -[4-(1-hydroxy- cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 6).
1H-NMR(CDCI3): 0.61 (t, 6H), 1.54-1.91 (m, 3H), 2.05(q, 4H), 2.18(s,3H), 2.30(m, 3H), 2.32(s, 3H), 4.75(s, 1H), 6.47(d, 1H), 6.68(d, 1H), 6.81-7.00(m, 5H), 7.39(d, 1H).
Example 16
Preparation of 2-chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenol (Enantiomer 1)
Figure imgf000160_0003
(1) Preparation of trifluoro-methanesulfonic acid 2-chloro-4-[1 -(3-chloro-4- hydroxy-phenyl)-1 -ethyl-propylj-phenyl ester
Figure imgf000160_0004
To a mixture of 2-chloro-phenol (12.86 g, 100 mmol) and 3-pentanone (5.30 ml, 50 mmol), trifluoromethane sulfonic acid (3.1 ml, 35 mmol) was added and stirred for 17hr at 90 degrees C. The reaction mixture was chromatographed on silica gel (ethyl acetate/hexane = 0/100 to 17/83) to give the brown foam (324 mg). The foam was dissolved with CH2CI2 (5 ml) and pyridine (0.097 ml, 1.2 mmol), trifluoromethane sulfonic anhydride (0.185ml, 1.1 mmol) was added and stirred for 1.5h at 0 degrees C. To the reaction mixture, aqueous KHSO4 was added and extracted with ethyl acetate, washed with brine, dried over MgS04, concentrated in vacuo, and chromatographed on silica gel (ethyl acetate/hexane = 0/100 to 18/82) to give the title compound (117mg, 0.5%).
1H-NMR: 0.63 (t, 6H), 2.04 (q, 4H), 5.46 (s, 1H), 6.90-7.34 (m, 6H); MS(ESI-) : 455([M-HT).
(2) Preparation of 2-chloro-4-[1 -(3-chloro-4-trimethylsilanylethynyl-phenyl)-1 - ethyl-propylj-phenol
Figure imgf000161_0001
To a solution of trifluoro-methanesulfonic acid 2-chloro-4-[1-(3-chloro-4- hydroxy-phenyl)-1-ethyl-propyl]-phenyl ester (compound prepared in Example 16-(1 )) (117mg, 0.256 mmol) in MeCN (1 ml) was added trimethylsilylacethylene (0.109 ml, 0.768 mmol), Pd(PPh3)4 (30mg, 0.026 mmol), Cul (5mg, 0.026 mmol) and triethylamine (0.107mL, 0.768 mmol) were added and stirred for 1 h at 100 degrees C under nitrogen atmosphere. To the reaction mixture, saturated aqueous NH4CI was added and extracted with ethyl acetate, washed with H20 twice, dried over MgSθ4, concentrated in vacuo, and chromatographed on silica gel (ethyl acetate/hexane = 0/100 to 15/85) to give the title compound (27mg, 26%).
1H-NMR: 0.26 (s, 9H), 0.61 (t, 6H), 2.01 (q, 4H), 5.35-5.45 (brs, 1H), 6.88- 7.39 (m, 6H). (3) Preparation of 2-chloro-4-[1-(3-chloro-4-ethynyl-phenyl)-1-ethyl-propylj- phenol
Figure imgf000162_0001
To a solution of 2-chloro-4-[1-(3-chloro-4-trimethylsilanylethynyl-phenyl)-1- ethyl-propylj-phenol (compound prepared in Example 16-(2)) (27 mg, 0.067 mmol) in THF (0.5 ml) was added 1 M TBAF in THF (0.33 ml, 0.33 mmol) at room temperature. The reaction mixture was allowed for 3min. To the reaction mixture, aqueous KHSO4 was added and extracted with ethyl acetate/hexane=1/1 , washed with aqueous NaHC03, aqueous KHSO4, aqueous NaHC03, aqueous KHSO4, aqueous NaHC03, successively, dried over MgS04, concentrated in vacuo to give the title compound (20mg, 90%). 1H-NMR: 0.62 (t, 6H), 2.03 (q, 4H), 3.33 (s, 1H), 6.90-7.41 (m, 6H).
(4) Preparation of 2-chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pent-1- ynyl)-phenyl]-1-ethyl-propyl}-phenol
Figure imgf000162_0002
To a solution of 2-chloro-4-[1 -(3-chloro-4-ethynyl-phenyl)-1 -ethyl-propyl]- phenol (compound prepared in Example 16-(3)) (20 mg, 0.06 mmol) in THF (0.6 ml) was added 1.59 M n-butyl lithium in hexane (0.094 ml, 0.15 mmol) at 0 degrees C. The reaction mixture was stirred for 30min at 0 degrees C. trimethylacetaldehyde (0.020 ml, 0.18 mmol) was added, stirred at 0 degrees C for 30min. To the reaction mixture, saturated aqueous NH4CI was added and extracted with ethyl acetate, washed with brine, dried over MgS04, concentrated in vacuo, and chromatographed on silica gel (ethyl acetate/hexane=1/5) to give the title compound (15 mg, 60%). 1H-NMR: 0.62 (t, 6H), 1.08 (s, 9H), 2.02 (q, 4H), 4.26 (s, 1 H), 6.90-6.98 (m, 3H), 7.09-7.21 (m, 2H), 7.35 (d, 1H).
(5) Chiral separation of 2-chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl- pent-1 -ynyl)-phenyl]-1 -ethyl-propyl}-phenol
Figure imgf000163_0001
Enantiomer A Enantiomer B Racemic mixture of 2-chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl- pent-1-ynyl)-phenyl]-1-ethyl-propyl}-phenol (compound prepared in Example
16-(4)) (15 mg, 0.036 mmol) was separated with HPLC (CHIRALPAK OJ
[DAICEL, 20 mm I.D., 250 mm], Ethanol/hexane = 15/85), to give each enantiomer (Enantiomer A : 6 mg / Enantiomer B : 6 mg).
Enantiomer A Column: CHIRALPAK OJ-RH 4.6*150 mm (DAICEL)
Eluent: Hexane/EtOH=85/15
Temperature: 35 degrees C.
Flow rate: 1.0 ml/min.
Retention time: 4.1 min. Enantiomer B
Retention time: 6.1 min.
(6) Preparation of 2-chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenol (Enantiomer 1)
Figure imgf000163_0002
To a solution of 2-chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pent-1- ynyl)-phenyl]-1-ethyl-propyl}-phenol (Enantiomer A prepared in Example 16- (5)) (6 mg, 0.014 mmol) in ethyl acetate (1 ml), 10% Pd-C (1 mg) was added and the mixture was stirred under hydrogen atmosphere for 90min. The reaction mixture was filtered and concentrated in vacuo to give the title compound (6 mg, 99 %).
1H-NMR: 0.62 (t, 6H), 0.89 (s, 9H), 1.43-1.59 (m, 1 H), 1.81-1.92 (m, 1 H), 2.02 (q, 4H), 2.66-2.76 (m, 1 H), 2.92-3.02 (m, 1 H), 3.21-3.25 (m, 1 H), 5.40 (s, 1 H), 6.88-6.95 (m, 3H), 7.10-7.15 (m, 3H).
Example 17
Preparation of 2-chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenol (Enantiomer 2)
Figure imgf000164_0001
Preparation of 2-chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenol (Enantiomer 2)
Figure imgf000164_0002
To a solution of 2-chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pent-1- ynyl)-phenyl]-1-ethyl-propyl}-phenol (Enantiomer B prepared in Example 16- (5)) (6 mg, 0.014 mmol) in ethyl acetate (1 ml), 10% Pd-C (1 mg) was added and the mixture was stirred under hydrogen atmosphere for 90min. The reaction mixture was filtered and concentrated in vacuo to give the title compound (6 mg, 99 %).
1H-NMR: 0.62 (t, 6H), 0.89 (s, 9H), 1.43-1.59 (m, 1 H), 1.81-1.92 (m, 1 H), 2.02 (q, 4H), 2.66-2.76 (m, 1 H), 2.92-3.02 (m, 1 H), 3.21-3.25 (m, 1 H), 5.40 (s, 1 H), 6.88-6.95 (m, 3H), 7.10-7.15 (m, 3H). Example 17
Preparation of 2-chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenol (Enantiomer 2)
Figure imgf000165_0001
Preparation of 2-chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenol (Enantiomer 2)
Figure imgf000165_0002
To a solution of 2-chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pent-1- ynyl)-phenyl]-1-ethyl-propyl}-phenol (Enantiomer B prepared in Example 16-
(5)) (6 mg, 0.014 mmol) in ethyl acetate (1 ml), 10% Pd-C (1mg) was added and stirred under hydrogen atmosphere for 90min. The reaction mixture was filtered and concentrated under vacuum to give the title compound (6 mg, 99 %). 1H-NMR: 0.62 (t, 6H), 0.89 (s, 9H), 1.43-1.59 (m, 1 H), 1.81-1.92 (m, 1 H),
2.02 (q, 4H), 2.66-2.76 (m, 1H), 2.92-3.02 (m, 1H), 3.21-3.25 (m, 1H), 5.40
(s, 1H), 6.88-6.95 (m, 3H), 7.10-7.15 (m, 3H).
Example 18 Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000165_0003
(1) Preparation of (E)-3-{4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- methyl-phenyl}-acrylic acid methyl ester Trifluoromethanesulfonic acid 4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)- propyl]-2-methyl-phenyl ester (compound prepared in Example 1-(1)) (10 g, 24.0 mmol) was dissolved in anhydrous DMF (70 ml) under nitrogen atmosphere. To this solution were added triethylamine (4.0 ml, 28.8 mmol), methylacrylate (2.6 ml, 28.8 mmol), 1 ,3-bis(diphenylphosphine)propane (544 mg, 1.32 mmol) and palladium acetate (269 mg, 1.2 mmol) at room temperature. After stirring 1.5 h at 100 degrees C, the resulting solution was diluted with CH2CI2, and washed with 5% HCl solution and water until neutrality was achieved, and dried over Na2S04. The solution was evaporated under reduced pressure and purified by silica-gel column (hexane/ethyl acetate=7:1) to yield the title compound (7.6 g, 21.5 mmol, 90%).
1H NMR (CDCI3): 7.94 (d, 1 H), 7.42 (d, 1 H), 7.00 (m, 2H), 6.85 (m, 2H), 6.65 (d, 1 H), 6.32 (d, 1 H), 4.70 (s, phenol), 3.79 (s, 3H), 2.38 (s, 3H), 2.19 (s, 3H), 2.04 (q, 4H), 0.60 (t, 6H).
(2) Preparation of 3-{4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- methyl-phenyl}-propionic acid methyl ester
Figure imgf000166_0001
(E)-3-{4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}- acrylic acid methyl ester (compound prepared in Example 18-(1)) (270 mg, 0.76 mmol) was dissolved in methanol (7 ml). To this solution was added palladium carbon (10 mg), and stirred at room temperature under hydrogen gas overnight. The resulting solution was filtered through celite, and the filtrate was evaporated under reduced pressure and purified by silica-gel chromatography (hexane/ethyl acetate=10:1) to give the title compound (266 mg, 0.75 mmol, 98%). 1H NMR (CDCI3): 6.99-6.83 (m, 5H), 6.64 (d, 1 H), 4.54 (s, phenol), 3.67 (s, 3H), 2.89 (dt, 2H), 2.57 (dt, 2H), 2.24 (s, 3H), 2.19 (s, 3H), 2.02 (q, 4H), 0.59 (t, 6H).
(3) Preparation of 1 -{4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- methyl-phenyl}-4,4-dimethyl-pentan-3-one
Figure imgf000167_0001
3-{4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}- propionic acid methyl ester (compound prepared in Example 18-(2)) (3.0 g, 8.46 mmol) was dissolved in anhydrous THF (80 ml) under nitrogen atmosphere. The solution was cooled to -78 degrees C. To this solution was added t-BuLi (4.97 ml, 8.46 mmol, 1.7M in pentane) at -78 degrees C. After stirring 30min at -78 degrees C, the solution was diluted with dichloromethane, and washed with saturated NH4CI aq., water and brine, and dried over Na2S04. The solution was evaporated under reduced pressure and purified by silica-gel chromatography (hexane/ethyl acetate=7:1) to give the title compound (2.5 g, 6.56 mmol, 77%). 1H NMR (CDCI3): 7.03-6.83 (m, 5H), 6.64 (d, 1 H), 4.60 (s, phenol), 2.82 (dt, 2H), 2.71 (dt, 2H), 2.24 (s, 3H), 2.18 (s, 3H), 2.04 (q, 4H), 1.09 (s, 9H), 0.58 (t, 6H).
(4) Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000167_0002
1 -{4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}-4,4- dimethyl-pentan-3-one (compound prepared in Example 18-(3)) (200 mg, 0.52 mmol) was dissolved in methanol (5 ml) under nitrogen atmosphere. To this solution was added sodium borohydride (29.8 mg, 0.78 mmol) at 0 degrees C. After stirring 1.0 h at room temperature, the solution was evaporated under reduced pressure and the obtained residue was purified by silica-gel chromatography (hexane/ethyl acetate=7:1) to give the title compound (190 mg, 0.50 mmol, 95%).
1H NMR (CDCI3): 7.03-6.83 (m, 5H), 6.63 (d, 1 H), 4.99 (s, phenol), 3.25 (dt, 1 H), 2.86 (m, 1H), 2.55 (m, 1 H), 2.24 (s, 3H), 2.18 (s, 3H), 2.03 (q, 4H), 1.79 (m, 1 H), 1.50 (m, 1 H), 0.89 (s, 9H), 0.59 (t, 6H).
Example 19
Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (Enantiomer 1 )
Figure imgf000168_0001
(1) Chiral separation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1-ynyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenol
Figure imgf000168_0002
Enantiomer A Enantiomer B Racemic mixture of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 3)
(13.08 g, 34.6 mmol) was separated with HPLC (CHIRALPAK AD [DAICEL, 20 mm I.D., 250 mm], 2-propanol/hexane = 15/85), to give each enantiomer
(Enantiomer A : 99.9% ee, 5.58g / Enantiomer B : 5.00g, 99.4%ee).
Enantiomer A
Column: CHIRALPAK AD-H 4.6x150 mm (DAICEL)
Eluent: Hexane/2-propanol=85/15 Flow rate: 1.0 ml/min.
Retention time: 5.1 min.
Enantiomer B Retention time: 7.2 min.
(2) Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (Enantiomer 1 )
Figure imgf000169_0001
To a solution of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol (Enantiomer A prepared in Example 19-(1)) (796 mg, 2.1 mmol) in ethyl acetate (10 ml), 10% Pd-C (0.1 g) was added and stirred under hydrogen atmosphere for 40min. The reaction mixture was filtered and concentrated in vacuo to give the title compound (732 mg, 91%).
1H-NMR: 0.60 (t, 6H), 0.89 (s, 9H), 1.40 (d, 1H), 1.44-1.55 (m, 1 H), 1.74- 1.85 (m, 1 H), 2.03 (q, 4H), 2.19 (s, 3H), 2.25 (s, 3H), 2.51-2.61 (m, 1 H), 2.81-2.91 (m, 1 H), 3.25 (dd, 1 H), 4.59 (s, 1 H), 6.64 (d, 1 H), 6.85-7.00 (m, 4H), 7.03 (d, 1 H).
Example 20
Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (Enantiomer 2)
Figure imgf000169_0002
Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (Enantiomer 2)
Figure imgf000170_0001
To a solution of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1-ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol (Enantiomer B prepared in Example 19-(1 )) (725 mg, 1.92 mmol) in ethyl acetate (10 ml), 10% Pd-C (0.1 g) was added and stirred under hydrogen atmosphere for 40 min. The reaction mixture was filtered and concentrated in vacuo to give the title compound (720 mg, 98%).
1H-NMR: 0.60 (t, 6H), 0.89 (s, 9H), 1.40 (d, 1 H), 1.44-1.55 (m, 1 H), 1.74- 1.85 (m, 1 H), 2.03 (q, 4H), 2.19 (s, 3H), 2.25 (s, 3H), 2.51-2.61 (m, 1 H), 2.81-2.91 (m, 1H), 3.25 (dd, 1H), 4.59 (s, 1H), 6.64 (d, 1 H), 6.85-7.00 (m, 4H), 7.03 (d, 1 H).
Example 21
Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000170_0002
(1) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-3-methyl-but-1-ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000170_0003
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hydroxy-3- methyl-but-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 5). The yield was 58%. 1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.57 (s, 6H), 2.09 (q, 4H), 2.16 (s, 3H), 2.26 (m, 1 H), 2.34 (s, 3H), 2.39-2.62 (m, 3H), 2.71-2.82 (m, 1H), 4.06 (dd, 1H), 4.14 (dd, 1 H), 4.84-4.91 (m, 1H)„ 6.69 (d, 1H), 6.89 (m, 2H), 6.95 (d, 1 H), 7.00 (s, 1 H), 7.27 (d, 1 H).
(2) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000171_0001
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-
3-methyl-but-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 21 -(1 )). The yield was
71 %.
1H-NMR (300MHz, CD3OD as potassium salt): 0.60 (t, 6H), 1.57 (s, 6H), 1.79-2.02 (m, 2H), 2.04 (q, 4H), 2.16 (s, 3H), 2.34 (s, 3H), 2.35 (td, 2H),
3.90-3.93 (m, 3H), 6.77 (d, 1 H), 6.84 (s, 1 H), 6.94 (dd, 2H), 7.00 (s, 1 H),
7.21 (d, 1 H); MS(ESI-) : m/z: 465 ([M-H]").
Example 22
Preparation of (S)-5-(4-{1 -ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000171_0002
(1) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1-enyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000171_0003
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-((E)-3-hyd roxy-3- methyl-but-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 12). The yield was 44%. 1H-NMR (300MHz, CDCI3): 0.57 (t, 6H), 1.42 (s, 6H), 2.05 (q, 4H), 2.20 (s, 3H), 2.29 (m, 1 H), 2.34 (s, 3H), 2.39-2.62 (m, 3H), 2.71-2.82 (m, 1 H), 4.06 (dd, 1 H), 4.14 (dd, 1 H), 4.84-4.91 (m, 1 H), 6.16 (d, 1 H), 6.72 (s, 1 H), 6.76 (d, 1 H), 6.83 (s, 1 H), 6.91-6.95 (m, 3H), 7.32 (d, 1 H). (2) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 -enyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000172_0001
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[4-((E)-3- hydroxy-3-methyl-but-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 22- (1 )). The yield was 90%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.60 (t, 6H), 1.57 (s, 6H), 1.82-2.01 (m, 2H), 2.05 (q, 4H), 2.13 (s, 3H), 2.25 (s, 3H), 2.37 (td, 2H), 3.90- 3.93 (m, 3H), 6.16 (d, 1 H), 6.72 (s, 1 H), 6.76 (d, 1 H), 6.83 (s, 1 H), 6.90-6.95 (m, 3H), 7.27 (d, 1 H); MS(ESI-) : 467 ([M-H]").
Example 23
Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000172_0002
(1) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000173_0001
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy- pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(4)). The yield was 56%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.11 (t, 6H), 1.72-1.81 (q, 4H), 2.03 (q, 4H), 2.14 (s, 3H), 2.37 (s, 3H), 2.28-2.62 (m, 3H), 2.72-2.85 (m, 1 H), 4.04-4.19 (m, 2H), 4.89 (m, 1 H), 6.65 (d, 1 H), 6.87 (d, 2H), 6.91 (s, 1 H), 6.98 (s, 1 H), 7.27 (d, 1 H).
(2) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000173_0002
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[4-(3-ethyl-3- hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 23-(1)). The yield was 76%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.11 (t, 6H), 1.72-1.81 (m, 4H), 1.87-1.98 (m, 2H), 2.03 (q, 4H), 2.16 (s,3H), 2.37 (s,3H), 2.62 (t, 2H), 3.82- 3.87 (dd, 1 H), 3.95-3.99 (dd, 1 H), 4.05-4.11 (m, 1 H), 6.67 (d, 1 H), 6.86 (s, 1 H), 6.90 (s, 1 H), 6.94 (d,1 H), 6.99 (d, 1 H), 7.27 (d, 1 H); MS(ESI-) : 493 ([M-H]"). Example 24
Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000174_0001
Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000174_0002
To a solution of (S)-5-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid (compound prepared in Example 23-(2)) (50 mg, 0.101 mmol) in EtOH (10 ml) was added Pd(OH)2 (10 mg) and the mixture was stirred under hydrogen gas at room temperature for 12 h. The reaction mixture was filtered through celite. and concentrated in vacuo. The crude mixture (40 mg) was dissolved in MeOH (7 ml). 1 N-KOH (0.3 ml, 0.30 mmol) was added at room temperature and the mixture was stirred for 4 h. The reaction mixture was concentration in vacuo, diluted with EtOAc, washed with brine, dried over MgS04, filtered, and concentration in vacuo. The obtained residue was purified by silica gel chromatography eluting with CH2CI2/ EtOAc (20:1) to give the title compound (26 mg, 52%) as a white solid. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.91 (t, 6H), 1.51-1.59 (m, 4H), 1.63-1.69 (m, 2H), 1.88-1.96 (m, 2H), 2.00-2.07 (q, 4H), 2.17 (s,3H), 2.25 (s,3H), 2.54-2.65 (m, 4H), 3.82-3.87 (dd, 1 H), 3.95-3.99 (dd, 1 H), 4.05-4.11 (m, 1 H), 6.67 (d, 1 H), 6.86 (d, 1 H), 6.89-7.01 (m, 5H); MS (ESI-) : 497 ([M- H]-).
Example 25 Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-3-propyl-hex-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000175_0001
(1) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-3-propyl-hex-1-ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000175_0002
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hydroxy-3- propyl-hex-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 4). The yield was 78%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.98 (t, 6H), 1.54-1.74 (m, 8H), 2.02 (q, 4H), 2.14 (s, 3H), 2.26 (m, 1 H), 2.36 (s, 3H), 2.39-2.62 (m, 3H), 2.71-2.82 (m, 1 H), 4.06 (dd, 1 H), 4.14 (dd, 1 H), 4.87 (m, 1 H), 6.65 (d, 1 H), 6.87 (s, 1 H), 6.95 (dd, 2H), 6.98 (s, 1 H), 7.27 (d, 1 H).
(2) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-3-propyl-hex-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000175_0003
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy- 3-propyl-hex-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 25-(1 )). The yield was 95%. 1H-NMR (300MHz, CD3OD as potassium salt): 0.59 (t, 6H), 1.00 (t, 6H), 1.52-1.92 (m, 10H), 2.06 (q, 4H), 2.16 (s, 3H), 2.35 (s,3H), 2.38 (td, 2H), 3.91-3.98 (m, 3H), 6.78 (d, 1H), 6.85 (s, 1 H), 6.96 (d, 2H), 7.01 (s, 1 H), 7.23 (d, 1H); MS (ESI-) : 521 ([M-H]-).
Example 26
Preparation of (S)-5-(4-{1 -ethyl-1 -[4-((E)-3-hydroxy-3-propyl-hex-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000176_0001
(1) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-((E)-3-hydroxy-3-propyl-hex-1 -enyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000176_0002
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-((E)-3-hydroxy-3- propyl-hex-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 13). The yield was 70%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.98 (t, 6H), 1.54-1.74 (m, 8H), 2.02 (q, 4H), 2.14 (s, 3H), 2.26 (m, 1 H), 2.36 (s, 3H), 2.39-2.62 (m, 3H), 2.71-2.82 (m, 1 H), 4.06 (dd, 1 H), 4.14 (dd, 1 H), 4.87 (m, 1 H), 6.07 (d, 1 H), 6.75 (dd, 1H), 6.87 (d, 2H), 6.94 (s, 2H), 6.99 (td, 1H), 7.29 (d, 1H).
(2) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-((E)-3-hydroxy-3-propyl-hex-1 -enyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000177_0001
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[4-((E)-3- hydroxy-3-propyl-hex-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 26- (1)). The yield was 93%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.62 (t, 6H), 0.95 (t, 6H), 1.39-1.51 (m, 4H), 1.56-1.62 (m, 4H), 1.87-2.02 (m,2H), 2.07 (q, 4H), 2.17 (s, 3H), 2.29 (s,3H), 2.39 (td, 2H), 3.93 (d, 2H), 3.98 (m, 1 H), 6.07 (d, 1 H), 6.75 (dd, 1 H), 6.87 (d, 2H), 6.94 (s, 2H), 6.99 (td, 1 H), 7.29 (d, 1 H); MS (ESI- ) : 523 ([M-H]").
Example 27
Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000177_0002
(1 ) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000177_0003
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 3). The yield was 38%.
1H-NMR (300MHz, CDCI3): 0.58 (t, 6H), 1.06 (s, 9H), 1.76 (d, 1 H), 2.04 (q, 4H), 2.14 (s, 3H), 2.38 (s, 3H), 2.25-2.62 (m, 3H), 2.71-2.83 (m, 1H), 4.06 (dd, 1 H), 4.16 (dd, 1 H), 4.25 (d, 1 H), 4.84-4.91 (m, 1 H), 6.66 (d, 1 H), 6.87- 6.98 (m, 4H), 7.28 (d, 1 H); MS (ESI+) : 499 ([M+Na]+).
(2) Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000178_0001
Using the same procedure as described for the preparation of Example 1-
(7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[4-(3-hyd roxy- 4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 27- (1)). The yield was 43%. H-NMR (300MHz, CD3OD as potassium salt): 0.62 (t, 6H), 1.08 (s, 9H), 1.80-2.03 (m, 2H), 2.10 (q, 4H), 2.18 (s, 3H), 2.38-2.42 (m, 5H), 3.92-4.03 (m, 3H), 4.22 (s, 1 H), 6.80 (d, 1 H), 6.87 (1 H, m), 6.95-7.03 (m, 3H), 7.28 (d, 1 H); MS (ESI+) : 517 ([M+Na]+).
Example 28
Preparation of 5-(4-{1 -ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000178_0002
(1 ) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000179_0001
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-((E)-3-hydroxy-4,4- dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 14). The yield was 78%.
1H-NMR (CDCI3): 0.60 (t, 6H), 0.96 (s, 9H), 2.04 (q, 4H), 2.15 (s, 3H), 2.29 (s, 3H), 2.30-2.61 (m, 3H), 2.70-2.82 (m, 1 H), 2.92 (d, 1 H), 4.03-4.18 (m, 2H), 4.83-4.90 (m, 1 H), 6.12 (dd, 1 H), 6.66 (d, 1 H), 6.91-6.97 (m, 5H), 7.30 (d, 1 H); MS (ESI+) : 496 ([M+NH4]+).
(2) Preparation of 5-(4-{1 -ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 - enyl)-3-methyl-phenyl]-propyl}-2-methy|-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000179_0002
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 28- (1 )). The yield was 41%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.60 (t, 6H), 0.96 (s, 9H), 1.88-1.97 (m, 2H), 2.05 (q, 4H), 2.17 (s, 3H), 2.29 (s, 3H), 2.62 (t, 2H), 3.82- 3.99 (m, 2H), 4.03-4.11 (m, 1 H), 4.13-4.18 (m, 1 H), 4.42-4.49 (m, 1 H), 6.12 (dd, 1 H), 6.66 (d,1 H), 6.73 (d, 1 H), 6.90-6.96 (m, 4H), 7.30 (d, 1 H); MS (ESI- ) : 495 ([M-H]").
Example 29 Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000180_0001
(1 ) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000180_0002
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18). The yield was 88%.
1H-NMR (300MHz, CD3OD): 0.59 (t, 6H), 0.88 (s, 9H), 1.38-1.52 (m, 1H), 1.72-2.02 (m, 3H), 2.09 (q, 4H), 2.15 (s, 3H), 2.25 (s,3H), 2.42 (td, 2H), 2.48- 2.59 (m, 1 H), 2.87 (m, 1 H), 3.18 (dd, 1 H), 3.90-3.99 (m, 3H), 4.02-4.19 (m, 2H), 4.90 (m, 1 H), 6.75 (d, 1 H), 6.86-6.98(m, 4H), 7.02 (d, 1 H).
(2) Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000180_0003
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 29-(1)). The yield was 76%. 1H-NMR (300MHz, CD3OD as potassium salt): 0.59 (t, 6H), 0.88 (s, 9H), 1.56 (m, 1 H), 1.72-2.05 (m, 3H), 2.09 (q, 4H), 2.15 (s, 3H), 2.25 (s,3H), 2.37- 2.43 (td, 2H), 2.54-2.57 (m, 1H), 2.83-2.89 (m, 1H), 3.20 (dd, 1H), 3.90-3.97 (m, 3H), 6.75 (d, 1 H), 6.86-6.97 (m, 4H), 7.02 (d, 1 H); MS (ESI-) : 497 ([M- H]-).
Example30
(S)-5-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid
Figure imgf000181_0001
(1 ) Preparation of 4-{1 -ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenol
Figure imgf000181_0002
To a solution of 4-{1 -ethyl-1 -[3-methyl-4-((E)-4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 9) (400 mg, 0.87 mmol) in DMF (5 ml) was added NaH (34.8 mg, 0.87 mmol) and the mixture was stirred at 25 degrees C for 0.5 h. To the reaction mixture, methoxymethyl chloride (0.132 ml, 1.74 mmol) was added and stirred at 50 degrees C for overnight. The mixture was cooled to 0 degrees C, saturated NH4CI was added and extracted with diethyl ether. The organic layer was washed with brine, dried over Na2Sθ4, concentrated in vacuo, and chromatographed on silica gel
(AcOEt/hexane/dichloromethane =1/1/10) to give the title compound (180 mg, 41 %). 1H NMR (CDCI3): 7.36 (s, 1 H), 7.33 (d, 1 H), 7.00 (d, 1 H), 6.99 (s, 1 H), 6.91- 6.84 (m, 2H), 6.65 (d, 1 H), 6.07 (d, 1 H), 4.96 (s, 2H), 4.61 (s, 1 H), 3.50 (s, 3H), 2.82-2.24 (m, 4H), 2.32 (s, 3H), 2.19 (s, 3H), 2.09 (q, 4H), 0.60 (t, 6H).
(2) Preparation of (S)-5-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one
Figure imgf000182_0001
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenol (compound prepared in Example 30-(1)). The yield was 62%. 1H-NMR (CDCI3): 7.36 (s,1 H), 7.33 (d, 1 H), 7.01-6.90 (m, 4H), 6.67 (d, 1 H), 6.05 (d, 1 H), 4.96 (s, 2H), 4.90-4.84 (m, 1 H), 4.19-4.04 (m, 2H), 3.50 (s, 3H), 2.82-2.24 (m, 4H), 2.32 (s, 3H), 2.19 (s, 3H), 2.04 (q, 4H), 0.60 (t, 6H).
(3) Preparation of (S)-5-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid
Figure imgf000182_0002
To a solution of (S)-5-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 30- (2)) (134 mg, 0.22 mmol) in 1 ,4-dioxane(5 ml) was added conc-HCI (0.5 ml) and the mixture was stirred at room temperature for 13 h. The reaction mixture was poured into H2O and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2Sθ4., concentrated in vacuo, and the obtained residue was chromatographed on silica gel (AcOEt/hexane/ dichloromethane =1/1/10) to give the title compound (85 mg, 69%) . 1H-NMR (CDCI3): 7.39-7.26 (m, 2H), 7.01-6.90 (m, 4H), 6.67 (d, 1 H), 6.07 (d, 1H), 4.90-4.84 (m, 1 H), 4.19-4.04 (m, 2H), 3.22 (s, 1H), 2.82-2.24 (m, 4H), 2.32 (s, 3H), 2.19 (s, 3H), 2.04 (q, 4H), 0.60 (t, 6H).
(4) Preparation of (S)-5-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4 ,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid
Figure imgf000183_0001
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 35-(3)). The yield was 49%.
1H-NMR (CD3OD as potassium salt): 7.43 (d, 1 H), 7.34 (d, 1H), 6.99-6.87 (m, 4H), 6.69 (d, 1H), 6.23 (d, 1H), 4.00-3.91 (m, 3H), 2.41-1.81 (m, 14H), 0.60 (t, 6H).; MS (ESI-):575 ([M-H]").
Example 31 Preparation of (S)-5-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000184_0001
(1 ) Preparation of (S)-5-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro- furan-2-one
Figure imgf000184_0002
To a solution of (S)-5-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 30- (3)) (45 mg, 0.08 mmol) in MeOH (5 ml) was added palladium hydroxide (4.5 mg 10%w/w)) at room temperature under H2 gas and the mixture was stirred for 3 h. The reaction mixture was filtered through celite and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (Hexane/CH CI2/ EtOAc=1 :1 :1 )to give the title compound (45 mg, quant).
1H-NMR (CDCI3); 7.01-6.80 (m, 5H), 6.70 (d, 1 H), 4.90-4.84 (m, 1 H), 4.19- 4.04 (m, 2H), 2.88-1.90 (m, 18H), 0.60 (t, 6H).
(2) Preparation of (S)-5-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000184_0003
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 31- (1 )). The yield was 54%.
1H-NMR (300MHz, CD3OD as potassium salt): 7.05-6.88 (m, 5H), 6.80 (d, 1 H), 4.01-3.92 (m, 3H), 2.87-2.77 (m, 4H), 2.44-1.81 (m, 14H), 0.60 (t, 6H); MS (ESI-) : 577 ([M-H]").
Example 32
Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclobutylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000185_0001
(1 ) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(1-hydroxy-cyclobutylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000185_0002
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-(1-hydroxy- cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 6). The yield was 51 %.
1H-NMR (300MHz, CDCI3): 0.58 (t, 6H), 1.64-1.90 (m, 4H), 2.02 (q, 4H), 2.14 (s, 3H), 2.26 (m, 2H), 2.34 (s, 3H), 2.39-2.62 (m, 3H), 2.71-2.82 (m, 1 H), 4.06 (dd, 1 H), 4.14 (dd, 1 H), 4.87 (m, 1 H), 6.68 (d, 1 H), 6.84 (m, 2H), 6.91 (d, 1 H), 7.00 (s, 1 H), 7.27 (d, 1 H). (2) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(1-hydroxy-cyclobutylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000186_0001
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[4-(1-hydroxy- cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 32-(1)). The yield was 95%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.62 (t, 6H), 1.79-2.01 (m,4H), 2.06 (q, 4H), 2.20 (s,3H), 2.25 (m, 4H), 2.32 (s, 3H), 2.39 (td, 2H), 3.89-3.98 (m, 3H), 6.73 (d, 1 H), 6.80 (m, 2H), 6.91 (d, 2H), 6.96 (s, 1 H), 7.20 (d, 1 H); MS (ESI-) : 477 ([M-H]").
Example 33
Preparation of (S)-5-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclobutyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000186_0002
(1 ) Preparation of (S)-5-[4-(1 -ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclobutyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
Figure imgf000186_0003
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-(1 -ethyl-1 -{4-[(E)-2-(1-hydroxy- cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol (compound prepared in Example 15). The yield was 74%. 1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.64-1.90 (m, 4H), 2.04 (q, 4H), 2.15 (s, 3H), 2.26 (m, 2H), 2.34 (s, 3H), 2.39-2.62 (m, 3H), 2.71-2.82 (m, 1 H), 4.06 (dd, 1 H), 4.14 (dd, 1 H), 4.84-4.91 (m, 1 H), 6.34 (d, 1 H), 6.66 (d, 1 H), 6.81 (d, 1 H), 6.91-6.97 (m, 4H), 7.40 (d, 1 H).
(2) Preparation of (S )-5-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclobutyl)-vinyl]- 3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000187_0001
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-[4-(1 -ethyl-1 -{4-[(E)-2-(1 - hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one (compound prepared in Example 33- (1)). The yield was 98%. H-NMR (300MHz, CD3OD as potassium salt): 0.59 (t, 6H), 1.52-1.82 (m, 4H), 1.83-1.92 (m, 1 H), 1.87-2.10 (m,2H), 1.97 (q, 4H), 2.06 (s, 3H), 2.19 (s, 3H), 2.15 (m, 4 H), 2.31 (td, 2H), 3.81-3.89 (m, 3H), 6.25 (d, 1 H), 6.67-6.77 (m, 3H), ), 6.84-6.88 (m, 3H), 7.25 (d, 1 H) ; MS (ESI-) : 479 ([M-H]").
Example 34 Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000187_0002
(1 ) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000188_0001
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-(1-hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 7). The yield was 58%. 1H-NMR (300MHz, CDCI3): 0.58 (t, 6H), 1.75-1.95 (m, 5H), 1.97-2.10 (m, 8H), 2.14 (s, 3H), 2.27-2.35 (m, 1 H), 2.36 (s, 3H), 2.39-2.62 (m, 2H), 2.71- 2.82 (m, 1 H), 4.06 (dd, 1 H), 4.14 (dd, 1 H), 4.84-4.91 (m, 1 H), 6.66 (d, 1 H), 6.85 (s, 1H), 6.94 (d, 2H), 6.90 (s, 1 H), 7.26 (d, 1H) ; MS(ESI+) : 497 ([M+Na]+).
(2) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000188_0002
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[4-(1-hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 34-(1 )). The yield was 83%. 1H-NMR (300MHz, CD3OD as potassium salt): 0.60 (t, 6H), 1.81-1.85 (m, 5H), 1.91-2.01 (m, 5H), 2.02 (q, 4H), 2.16 (s, 3H), 2.34 (s,3H), 2.39 (td, 2H), 3.90-3.99 (m, 3H), 6.78 (d, 1 H), 6.84 (s, 1H), 6.94 (dd, 2H), 7.00 (s, 1H), 7.22 (d, 1 H); MS (ESI-) : 491 ([M-H]"). Example 35 Preparation of (S)-5-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000189_0001
(1 ) Preparation of (S)-5-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]- 3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
Figure imgf000189_0002
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-(1 -ethyl-1 -{4-[(E)-2-(1-hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol (compound prepared in Example 10). The yield was 54%.
1H-NMR (300MHz, CDCI3): 0.58 (t, 6H), 1.75-1.95 (m, 5H), 1.97-2.10 (m, 8H), 2.14 (s, 3H), 2.34 (s,3H), 2.38 (m, 1 H), 2.39-2.62 (m, 2H), 2.71-2.82 (m, 1 H), 4.06 (dd, 1 H), 4.14 (dd, 1 H), 4.84-4.91 (m, 1 H), 6.23 (d, 1 H), 6.68 (d, 1H), 6.81 (d, 1H), 6.90-6.99 (m, 4H), 7.32 (d, 1H); MS (ESI+) : 499 ([M+Naf).
(2) Preparation of (S)-5-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]- 3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000189_0003
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-[4-(1 -ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one (compound prepared in Example 35- (1)). The yield was 97%. 1H-NMR (300MHz, CD3OD as potassium salt): 0.60 (t, 6H), 1.76-2.00 (m, 12H), 2.06 (q, 4H), 2.16 (s, 3H), 2.29 (s,3H), 2.41 (td, 2H), 3.90-3.99 (m, 3H), 6.23 (d, 1 H), 6.77 (d,1 H), 6.84 (d, 1 H), 6.93-6.99 (m, 4H), 7.32 (d, 1 H); MS (ESI-) : 493 ([M-H]").
Example 36
Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000190_0001
(1) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(1-hydroxy-cyclohexylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000190_0002
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-(1-hydroxy- cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 8). The yield was 72%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.61-1.79 (m, 6H), 1.99-2.09 (m, 8H), 2.14 (s, 3H), 2.26 (m, 1 H), 2.38 (s, 3H), 2.39-2.62 (m, 3H), 2.71-2.82 (m, 1 H), 4.08 (dd, 1 H), 4.14 (dd, 1 H), 4.84-4.91 (m, 1 H), 6.65 (d, 1 H), 6.87 (s, 1 H), 6.92 (d, 2H), 7.00 (s, 1 H), 7.27 (d, 1 H).
(2) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000191_0001
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[4-(1-hydroxy- cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 36-(1)). The yield was 92%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.59 (t, 6H), 1.59-1.89 (m, 9H), 1.95-2.03 (m, 3H), 2.08 (q, 4H), 2.15 (s, 3H), 2.35 (s,3H), 2.36 (td, 2H), 3.89-3.98 (m, 3H), 6.77 (d, 1 H), 6.84 (s, 1 H), 6.95 (d, 1 H), 7.00 (s, 1H), 7.23 (d, 1 H); MS (ESI-) : 505 ([M-H]").
Example 37
Preparation of (S)-5-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000191_0002
(1 ) Preparation of (S)-5-[4-(1 -ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]- 3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
Figure imgf000191_0003
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-(1 -ethyl-1 -{4-[(E)-2-(1-hydroxy- cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol (compound prepared in Example 11). The yield was 71%.
1H-NMR(300MHz, CDCI3): 0.60 (t, 6H), 1.61-1.79 (m, 6H), 1.99-2.09 (m, 8H), 2.14 (s, 3H), 2.26 (m, 1 H), 2.30 (s, 3H), 2.39-2.62 (m, 3H), 2.71-2.82 (m, 1 H), 4.08 (dd, 1 H), 4.14 (dd, 1 H), 4.84-4.91 (m, 1 H), 6.20 (d, 1 H), 6.66 (d, 1 H), 6.81 (d, 1 H), 6.89-6.97 (m, 5H), 7.32 (d, 1 H).
(2) Preparation of (S)-5-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]- 3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000192_0001
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-[4-(1 -ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one (compound prepared in Example 37- (1)). The yield was 98%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.60 (t, 6H), 1.30-1.37 (m, 1H), 1.56-2.02 (m, 11 H), 2.06 (q, 4H), 2.15 (s, 3H), 2.28 (s,3H), 2.37 (td, 2H), 3.89-3.98 (m, 1 H), 6.16 (d, 1 H), 6.76-6.98 (m, 2H), 6.84 (d, 1 H), 6.93- 6.98 (m, 3H), 7.30 (d, 1 H); MS (ESI-) : 507 ([M-H]").
Example 38
Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-heptyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000192_0002
(1 ) Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-hept-6-en-1 -ynyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenol
Figure imgf000192_0003
To a solution of 4-[1 -ethyl-1 -(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl- phenol (compound prepared in Example 1-(3)) (1 g, 3.42 mmol) in THF (20 ml) was added 1.6N n-BuLi in Hex (5.34 ml, 8.55 mmol) at -78 degrees C under nitrogen atmosphere. The mixture was stirred at -78 degrees C for 1 h and 2,2-dimethyl-4-pentenal (1.39 ml, 10.26 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 12 h. The mixture was poured into saturated NH4CI aq. and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was purified by Silica gel chromatography (EtOAc: n-Hexane=1 :12) to give the title compound (829 mg, 60%).
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.04 (d, 6H), 2.03 (q, 4H), 2.18 (s, 3H), 2.20 (m, 2H), 2.38 (s, 3H), 4.34 (s, 1 H), 5.10 (m, 2H), 5.87 (m, 1 H), 6.65 (d, 1 H), 6.80-7.00 (m, 4H), 7.28 (d, 1 H); MS (ESI-) : 403 ([M-H]").
(2) Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-heptyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000193_0001
To a solution of4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-hept-6-en-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 38- (1 )) (830 mg, 2.05 mmol) in MeOH (20 ml) was added 10% palladium on activated carbon (100 mg) and the mixture was stirred at room temperature under H2 gas for 3 h. The mixture was filtered through celite and concentrated under reduced pressure. The obtained residue was purified by flash chromatography on silica gel (n-Hexane:EtOAc=10:1 ) to give the title compound (670 mg, 80%).
1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 0.85 (m, 9H), 1.21 (m, 4H), 1.52 (m, 1 H), 1.77 (m, 1 H), 2.03 (q, 4H), 2.19 (s, 3H), 2.24 (s, 3H), 2.55 (m, 1 H), 2.85 (m, 1 H), 3.32 (d, 1 H), 6.64 (d, 1 H), 6.84-7.03 (m, 5H). (3) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-heptyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000194_0001
Using the same procedure as described for the preparation of Example 1-
(6), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-heptyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 38-(2)). The yield was 52%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.86 (m, 9H), 1.24 (m, 4H), 1.50 (m,
1 H), 1.77 (m, 1 H), 2.03 (q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.29-2.62 (m, 4H),
2.71-2.89 (m, 2H), 3.30 (d, 1 H), 4.12 (m, 2H), 4.88 (m, 1 H), 6.66 (d, 1 H),
6.91 (m, 4H), 7.02 (d, 1 H).
(4) Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-heptyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000194_0002
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-heptyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 38-(3)). The yield was 90%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.59 (t, 6H), 0.82 (m, 9H), 1.21 (m, 4H), 1.50 (m, 1 H), 1.70 (m, 1 H), 1.89 (m, 2H), 2.05 (q, 4H), 2.14 (s, 3H), 2.24 (s, 3H), 2.37 (t, 2H), 2.54 (m, 1 H), 2.86 (m, 1 H), 3.22 (d, 1H), 3.94 (m, 3H), 6.76 (d, 1 H), 6.92 (m, 4H), 7.01 (d, 1 H); MS (ESI-) : 525 ([M-H]").
Example 39
Figure imgf000195_0001
of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-octyl)-3-methyl- pheriyi]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000195_0002
(1 ) Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-oct-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol
Figure imgf000195_0003
Using the same procedure as described for the preparation of Example 38- (1), the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)) and 2,2-dimethyl hexanal. The yield was 24%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.91 (t, 3H), 1.01 (s,3H), 1.03 (s, 3H), 1.30 (m, 6H), 2.03 (q, 4H), 2.19 (s, 3H), 2.38 (s, 3H), 4.33 (m, 1H), 6.65 (d, 1 H), 6.83-7.00 (m, 4H), 7.29 (d, 1H).
(2) Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-octyl)-3-methyl- phenyl]-propyl}-2-methyl- phenol
Figure imgf000195_0004
Using the same procedure as described for the preparation of Example 38- (2), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-oct-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 39-(1 )). The yield was 86%. 1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 0.86 (m, 9H), 1.26 (m, 6H), 1.52 (m, 1H), 1.78 (m, 1 H), 2.03 (q, 4H), 2.20 (s, 3H), 2.25 (s, 3H), 2.55 (m, 1 H), 2.85 (m, 1 H), 3.32 (m, 1H), 6.64 (d, 1H), 6.84-6.92 (m, 4H), 7.02 (d, 1 H).
(3) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-octyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000196_0001
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-octyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 39-(2)). The yield was 58%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.85 (m, 9H), 1.23 (m, 6H), 1.52 (m, 1 H), 1.76 (m, 1 H), 2.03 (q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.29-2.62 (m, 4H), 2.71-2.88 (m, 2H), 3.31 (d, 1H), 4.11 (m, 2H), 4.87 (m, 1H), 6.66 (d, 1H), 6.92 (m, 4H), 7.02 (d, 1 H).
(4) Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-octyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000196_0002
Using the same procedure as described for the preparation of Example 1-
(7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-
4,4-dimethyl-octyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 39-(3)). The yield was
92%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.59 (t, 6H), 0.84 (m, 9H),
1.25 (m, 6H), 1.51 (m, 1H), 1.73 (m, 1 H), 1.89 (m, 2H), 2.05 (q, 4H), 2.15 (s, 3H), 2.24 (s, 3H), 2.37 (t, 2H), 2.55 (m, 1H), 2.86 (m, 1H), 3.23 (d, 1H), 3.94 (m, 3H), 6.76 (d, 1H), 6.92 (m, 4H), 7.02 (d, 1H); MS (ESI-) : 539 ([M-H]').
Example 40
Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-decyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000197_0001
(1) Preparation of 2,2-dimethyl-octanoic acid ethyl ester
Figure imgf000197_0002
To a solution of Isobutyric acid ethyl ester (4.3 g, 37.02 mmol) in anhydrous THF (37 ml) under nitrogen atmosphere at -78 degrees C was added LDA (6.7 ml, 10.65 mmol) and the mixture was stirred for 30 min. To the mixture, iodohexane (6 ml, 40.72 mmol.) was added and the mixture was stirred at - 78 degrees C for 5 h. Then the mixture was warmed to room temperature and poured into 1 N-HCI and the products were extracted with diethyl ether. The extracts were washed with brine, dried over MgS04, filtered, and concentration in vacuo. The obtained residue was purified by distillation (78-82 degrees C, 12 torr) to give the title compound (6.5 g, 87%). 1H-NMR (300MHz, CDCI3): 0.87 (t, 3H), 1.15 (s, 6H), 1.21-1.40 (m, 10H), 1.50 (m, 2H), 4.10 (q, 2H).
(2) Preparation of 2,2-dimethyl-octan-1-ol
Figure imgf000197_0003
To a solution of 2,2-dimethyl-octanoic acid ethyl ester (compound prepared in Example 40-(1 )) (5.79 g, 28.90 mmol) in anhydrous THF (29 ml) at 0 degrees C under nitrogen atmosphere was added 1 N-LiAIH4/THF (14.5 ml, 14.50 mmol) and the mixture was stirred at 0 degrees C for 4 h. Then the mixture was warmed to room temperature and quenched with H20, 10% NaOH solution and H20. The reaction mixture was filtered through celite and the filtrate was washed with brine, dried over MgS04, filtered, and concentrated in vacuo. The obtained residue was purified by silica gel chromatography eluting with dichloromethane to give the title compound (3.12 g, 69.0 %) .
1H-NMR(300MHz, CDCI3): 0.86(s, 6H), 0.88(t, 3HJ, 1.25 (m, 1 H), 3.31 (s, 2H).
(3) Preparation of 2,2-dimethyl-octanal
Figure imgf000198_0001
To a solution of 2,2-dimethyl-octan-1-ol (compound prepared in Example 40-(2)) (3.12 g, 19.71 mmol) in anhydrous dichloromethane (27.5 ml) under nitrogen atmosphere was added PCC (6.54 g, 30.35 mmol) and the mixture was stirred at room temperature for 3 h. The mixture was diluted with diethyl ether and filtered through a celite and silicagel and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (hexane/ EtOAc= 10:1)to give the title compound (2.55 g, 82%) . 1H-NMR (300MHz, CDCI3): 0.88 (t, 3H), 1.04 (s, 6H), 1.15-1.29 (m, 9H), 1.43-1.48 (m, 2H), 9.21 (s, 1 H).
(4) Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-dec-1-ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol
Figure imgf000198_0002
Using the same procedure as described for the preparation of Example 38- (1), the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)) and
2,2-dimethyl-octanal (compound prepared in Example 40-(3)). The yield was
58%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.88 (t, 3H), 1.01 (s,3H), 1.02 (s,
3H), 1.25-1.49 (m, 10H), 1.75 (d, 1 H), 2.02 (q, 4H), 2.19 (s, 3H), 2.38 (s,
3H), 4.32 (d, 1 H), 4.52 (s, 1 H). 6.65 (d, 1 H), 6.82-6.86 (m, 2H), 6.93 (dd,
1 H), 7.00 (s, 1 H), 7.28 (d, 1 H).
(5) Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-decyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000199_0001
Using the same procedure as described for the preparation of Example 38- (2), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-dec-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 40-(4)). The yield was 81%. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.86 (t, 9H), 1.17-1.29 (m, 9H), 1.42-1.60 (m, 2H), 1.72-1.83 (m, 1 H), 2.03 (q, 4H), 2.19 (s, 3H), 2.24 (s, 3H), 2.50-2.60 (m, 1 H), 2.82-2.91 (m, 1 H), 3.34 (d, 1 H), 5.01 (s, 1 H), 6.64 (d, 1 H), 6.84 (dd, 1 H), 6.90-6.92 (m, 2H), 7.02 (s, 1 H), 7.26 (d, 1 H).
(6) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-decyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000199_0002
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-decyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 40-(5)). The yield was 67%. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.83 (s, 3H), 0.85 (s, 3H), 0.88 (t, 3H), 1.25-1.49 (m, 11 H), 1.40-1.52 (m, 1 H), 1.78 (m, 1 H), 2.03 (q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.29-2.62 (m, 4H), 2.71-2.88 (m, 2H), 3.30 (d, 1 H), 4.04-4.19 (m, 2H), 4.87 (m, 1 H), 6.66 (d, 1 H), 6.92 (m, 4H), 7.02 (d, 1 H); MS (ESI+) : 573 ([M+Na]+).
(7) Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-decyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000201_0001
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-decyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 40-(6)). The yield was
95%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.58 (t, 6H), 0.80 (s, 3H),
0.84 (s, 3H), 0.89 (t, 3H), 1.16-1.33 (m, 10H), 1.46-1.52 (m, 1 H), 1.68-2.00 (m, 4H), 2.05 (q, 4H), 2.14 (s, 3H), 2.24 (s,3H), 2.37-2.40 (td, 2H), 2.55-2.57 (m, 1 H), 2.84-2.85 (m, 1 H), 3.23 (d, 1 H), 3.88-4.01 (m, 3H), 6.75 (d, 1 H), 6.84 (s, 1 H), 6.84-6.95 (m, 3H), 7.01 (d, 1 H); MS (ESI+) : 591 ([M+Na]+).
Example 41
Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-nonyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000201_0002
(1 ) Preparation of 2,2-dimethyl-heptanoic acid ethyl ester
Figure imgf000201_0003
Using the same procedure as described for the preparation of Example 40- (1 ), the title compound was prepared from Isobutyric acid ethyl ester and iodopentane. The yield was 86%.
1H-NMR (300MHz, CDCI3): 0.87 (t, 3H), 1.16 (s, 6H), 1.21-1.40 (m, 8H), 1.54 (m, 2H), 4.14 (q, 2H). (2) Preparation of 2,2-dimethyl-heptan-1-ol
Figure imgf000202_0001
Using the same procedure as described for the preparation of Example 40- (2), the title compound was prepared from 2,2-dimethyl-heptanoic acid ethyl ester (compound prepared in Example 41 -(1 )). The yield was 89%. 1H-NMR (300MHz, CDCI3): 0.86 (s, 6H), 0.89 (t, 3H), 1.23-1.35 (m, 9H), 3.31 (s, 2H).
(3) Preparation of 2,2-dimethyl-heptanal
Figure imgf000202_0002
Using the same procedure as described for the preparation of Example 40- (3), the title compound was prepared from 2,2-dimethyl-heptan-1-ol (compound prepared in Example 41 -(2)). The yield was 83%. 1H-NMR (300MHz, CDCI3): 0.88 (t, 3H), 1.05 (s, 6H), 1.20-1.31 (m, 6H), 1.42-1.48 (m, 2H), 9.45 (s, 1 H).
(4) Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-non-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol
Figure imgf000202_0003
Using the same procedure as described for the preparation of Example 38- (1), the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)) and 2,2-dimethyl-heptanal (compound prepared in Example 41 -(3)). The yield was 80%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.86 (t, 3H), 1.01 (s,3H), 1.03 (s, 3H), 1.25-1.49 (m, 8H), 1.75 (m, 1 H), 2.02 (q, 4H), 2.19 (s, 3H), 2.38 (s, 3H), 4.33 (d, 1 H), 4.60 (s, 1 H). 6.65 (d, 1 H), 6.86 (dd, 2H), 6.94 (dd, 1 H), 7.01 (s, 1 H), 7.27 (d, 1 H).
(5) Preparation of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-nonyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000203_0001
Using the same procedure as described for the preparation of Example 38- (2), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-non-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 41 -(4)). The yield was 81%. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.86 (t, 9H), 1.17-1.29 (m, 9H), 1.42-1.60 (m, 2H), 1.72-1.83 (m, 1 H), 2.03 (q, 4H), 2.19 (s, 3H), 2.24 (s, 3H), 2.50-2.55 (m, 1 H), 2.82-2.91 (m, 1 H), 3.34 (dd, 1 H), 5.01 (s, 1 H), 6.64 (d, 1 H), 6.84 (dd, 2H), 6.90-6.92 (m, 3H), 7.01 (s, 1 H), 7.27 (d, 1 H).
(6) Preparation of (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-nonyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000203_0002
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-nonyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 41 -(5)). The yield was 65%. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.83 (s, 3H), 0.85 (s, 3H), 0.87 (t, 3H), 1.15-1.33 (m, 10H), 1.42-1.54 (m, 1H), 1.71-1.83 (m, 1H), 2.03 (q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.29-2.61 (m, 4H), 2.71-2.88 (m, 2H), 3.30 (d, 1 H), 4.11 (m, 2H), 4.87 (m, 1 H), 6.65 (d, 1 H), 6.89-6.97 (m, 4H), 7.02 (d, 1 H). (7) Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-nonyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000204_0001
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-5-(4-{1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-nonyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 41 -(6)). The yield was 92%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.58 (t, 6H), 0.80 (s, 3H), 0.84 (s, 3H), 0.89 (t, 3H), 1.16-1.33 (m, 8H), 1.46-1.52 (m, 1 H), 1.65-2.00 (m, 3H), 2.05 (q, 4H), 2.14 (s, 3H), 2.24 (s,3H), 2.37-2.40 (td, 2H), 2.55-2.57 (m, 1 H), 2.84-2.85 (m, 1 H), 3.23 (d, 1 H), 3.90-3.91 (m, 3H), 6.75 (d, 1 H), 6.84 (s, 1 H), 6.84-6.97 (m, 3H), 7.01 (d, 1 H); MS (ESI-) : 553 ([M-H]").
Example 42
Preparation of (R)-5-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000204_0002
Preparation of (R)-5-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000204_0003
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-ethyl-3-hyd roxy- pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(4)) and Toluene-4-sulfonic acid (R)-5-oxo-tetrahydro-furan-2- yl methyl ester. The yield was 51%.
1H-NMR (300MHz, CDCI3): 0.58 (t, 6H), 1.11 (t, 6H), 1.76 (q, 4H), 2.02 (q, 4H), 2.14 (s, 3H), 2.36 (s, 3H), 2.22-2.61 (m, 3H), 2.71-2.83 (m, 1H), 4.06 (dd, 1 H), 4.14 (dd, 1 H), 4.87 (m, 1 H), 6.65 (d, 1 H), 6.87 (s, 1 H), 6.92 (d, 2H), 6.98 (s, 1 H), 7.27 (d, 1H); MS (ESI+) : 499 ([M+Na]+).
Example 43
Preparation of 5-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid
Figure imgf000205_0001
Preparation of 5-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid
Figure imgf000205_0002
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (R)-5-(4-{1 -ethyl- 1-[4-(3-ethyl-3- hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 42). The yield was 98%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.61 (t, 6H), 1.11 (t, 6H), 1.70-1.77 (m, 5H), 1.90-2.01 (m, 1H), 2.07 (q, 4H), 2.17 (s, 3H), 2.36 (s, 3H), 2.37 (td, 2H), 3.91-4.00 (m, 3H), 6.79 (d, 1H), 6.85 (s, 1H), 6.95 (d, 2H), 7.01 (s, 1 H), 7.24 (d, 1H); MS (ESI-) : 493 ([M-H]"). Example 44
Preparation of (R)-5-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000206_0001
Preparation of (R)-5-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000206_0002
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(5)) and toluene-4-sulfonic acid (R)-5-oxo-tetrahydro- furan-2-ylmethyl ester. The yield was 82%. 1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 0.92 (t, 6H), 1.64 (q, 4H), 2.06 (q, 4H), 2.16 (s, 3H), 2.31 (s, 3H), 2.34-2.62 (m, 3H), 2.72-2.83 (m, 1 H), 4.06 (dd, 1 H), 4.15 (dd, 1 H), 4.87 (m, 1 H), 6.01 (d, 1 H), 6.66 (d, 1 H), 6.74 (d, 1 H), 6.91-6.98 (m, 4H), 7.29 (d, 1 H); MS (ESI+) : 501 ([M+Na]+).
Example 45 Preparation of 5-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid
Figure imgf000206_0003
Preparation of 5-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid
Figure imgf000207_0001
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (R)-5-(4-{1 -ethyl-1 -[4-((E)-3-ethyl- 3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one (compound prepared in Example 44). The yield was 91%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.60 (t, 6H), 0.92 (t, 6H), 1.63 (q, 4H), 1.81-2.01 (m, 3H), 2.06 (q, 4H), 2.16 (s, 3H), 2.28 (s, 3H), 2.38 (td, 2H), 3.89-3.99 (m, 3H), 6.01 (d, 1H), 6.74 (d, 1 H), 6.79 (s, 1 H), 6.86 (s, 1H), 6.93-6.95 (m, 3H), 7.29 (d, 1 H); MS (ESI-) : 495 ([M-H]").
Example 46
Preparation of (R)-5-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro- furan-2-one
Figure imgf000207_0002
(1) Preparation of (R)-5-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one
Figure imgf000207_0003
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenol (compound prepared in Example 2-(2)) and toluene-4-sulfonic acid (R)-5-oxo-tetrahydro-furan-2-ylmethyl ester. The yield was 42%. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 2.04 (q, 4H), 2.15 (s, 3H), 2.27-2.50 (m, 2H), 2.39 (s, 3H), 2.56 (m, 1 H), 2.77 (m, 1 H), 3.48 (s, 3H), 4.12 (m, 2H), 4.88 (m, 1 H), 5.15 (s, 2H), 6.67 (d, 1 H), 6.85-7.03 (m, 4H), 7.37 (d, 1 H).
(2) Preparation of (R)-5-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one
Figure imgf000208_0001
Using the same procedure as described for the preparation of Example 2- (4), the title compound was prepared from (R)-5-(4-{1 -ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 46-(1)). The yield was 54%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 2.04 (q, 4H), 2.14 (s, 3H), 2.27-2.50 (m, 2H), 2.38 (s, 3H), 2.55 (m, 1 H), 2.76 (m, 1 H), 4.02 (s, 1 H), 4.12 (m, 2H), 4.88 (m, 1 H), 6.66 (d, 1 H), 6.85-7.03 (m, 4H), 7.35 (d, 1 H); MS (ESI-) : 555 ([M-H]").
Example 47
Preparation of (R)-5-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid
Figure imgf000208_0002
Preparation of (R)-5-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid
Figure imgf000209_0001
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (R)-5-(4-{1 -ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 46-(2)). The yield was 96%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.59 (t, 6H), 1.80-2.00 (m, 2H), 2.07 (q, 4H), 2.15 (s, 3H), 2.35 (s, 3H), 2.38 (m, 2H), 3.94 (m, 3H), 6.78 (d, 1 H), 6.84 (m, 1 H), 6.93-6.98 (m, 3H), 7.28 (d, 1H); MS (ESI-) : 573 ([M- H]-).
Example 48
Preparation of (R)-5-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-
3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one
Figure imgf000209_0002
(1) Preparation of (R)-5-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one
Figure imgf000209_0003
Using the same procedure as described for the preparation of Example 1- (6), the title compound was prepared from 4-{1 -ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenol (compound prepared in Example 30-(1)) and toluene-4-sulfonic acid (R)-5-oxo-tetrahydro-furan-2-ylmethyl ester. The yield was 89%.
1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 2.05 (q, 4H), 2.15 (s, 3H), 2.32 (s, 3H), 2.25-2.85 (m, 4H), 3.50 (s, 3H), 4.12 (m, 2H), 4.88 (m, 1H), 4.96 (s, 2H), 6.06 (d, 1 H), 6.67 (d, 1 H), 6.96 (m, 4H), 7.34 (m, 2H).
(2) Preparation of (R)-5-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one
Figure imgf000210_0001
Using the same procedure as described for the preparation of Example 2- (4), the title compound was prepared from (R)-5-(4-{1 -ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 48-(1)). The yield was 84%.
1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 2.05 (q, 4H), 2.15 (s, 3H), 2.34 (s, 3H), 2.25-2.83 (m, 4H), 3.24 (s, 1H), 4.11 (m, 2H), 4.88 (m, 1H), 6.08 (d, 1H), 6.67 (d, 1H), 6.95 (m, 4H), 7.35 (m, 2H); MS (ESI-) : 557 ([M-H]").
Example 49
Preparation of 5-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy- pentanoic acid
Figure imgf000211_0001
Preparation of 5-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy- pentanoic acid
Figure imgf000211_0002
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (R)-5-(4-{1 -ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 48-(2)). The yield was 93%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.60 (t, 6H), 1.80-2.20 (m, 2H), 2.07 (q, 4H), 2.15 (s, 3H), 2.32 (s, 3H), 2.37 (m, 2H), 3.94 (m, 3H), 6.18 (d, 1H), 6.77 (d, 1H), 6.86 (m, 1H), 6.97 (m, 3H), 7.37 (m, 2H); MS (ESI-) : 575 ([M-H]").
Example 50
Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid
Figure imgf000211_0003
Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid
Figure imgf000211_0004
To a solution of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-phenyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) (190 mg, 0.50 mmol) in anhydrous DMF (5 ml) under nitrogen atmosphere were added K2C03 (138.2 mg, 1.0 mmol) and (R)-toluene-4-sulfonic acid 5-oxo- tetrahydrofuran-2-ylmethyl ester (162.2 mg, 0.6 mmol) and the mixture was stirred overnight at 100 degrees C. The mixture was diluted with ethyl acetate, washed with sat. NH4CI, water and brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was dissolved in methanol- H2O (10:1 , 5.5 ml). To the solution was added KOH as 1 tablet. After stirring for 30min at room temperature, the mixture was concentrated under reduced pressure and the obtained residue was purified by silica-gel chromatography (hexane/EtOAc=4:1) to give the title compound (125 mg, 50%) as a solid. 1H NMR (CDCI3); 7.03-6.89 (m, 5H), 6.67 (d, 1 H), 4.06 (m, 1 H), 3.97 (ddd, 1 H), 3.85 (ddd, 1 H), 3.24 (dt, 1 H), 2.86 (m, 1 H), 2.64-2.50 (m, 3H), 2.25 (s, 3H), 2.17 (s, 3H), 2.04 (q, 4H), 1.93 (m, 2H), 1.79 (m, 1H), 1.50 (m, 1H), 0.88 (s, 9H), 0.59 (t, 6H); MS (ESI-) : 497 ([M-H]").
Example 51 Preparation of (S)-4-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy- butyric acid
Figure imgf000212_0001
(1) Preparation of 3(S)-(tert-Butyl-dimethyl-silanyloxy)-4-hydroxy-butyric acid ethyl ester
Figure imgf000212_0002
To a stirred solution of 3(S),4-Dihydroxy-butyric acid ethyl ester (TefraΛec/ron.l 992, 48(20), 4067.) (569 mg, 3.8 mmol) in DMF (12 ml) were added TBSCI (1.7 g, 11.2 mmol) and imidazole (1.55 g, 22.8 mmol) at room temperature and the mixture was stirred at room temperature for 12 h. The reaction mixture was poured into water and the products were extracted with ethyl acetate. The extracts were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (ethyl acetate/hexane = 1/40) to give disilylated compound (1.4g, 96%). To a stirred solution of the disilylated compound (1.33 g, 3.5 mmol) in MeOH (35 ml) was added PPTs (133 mg, 0.5 mmol) at room temperature and the mixture was stirred at room temperature for 17 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (ethyl acetate/hexane=1/5) to give the titled compound (393 mg, 43%).
1H-NMR (CDCI3): 0.09 (3H, s), 0.11 (3H, s), 0.90 (9H, s), 1.25(3H, t), 1.92 (1 H, dd), 2.55 (2H, d), 3.45-3.70 (2H, m), 4.12 (2H, q), 4.15-4.30 (1H, s).
(2) Preparation of 3(S)-(tert-Butyl-dimethyl-silanyloxy)-4-(4-{1 -ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-butyric acid ethyl ester
Figure imgf000213_0001
To a solution of 4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenol (compound prepared in Example 2-(2)) (255 mg, 0.502 mmol) and triphenylphosphine (145 mg, 0.552 mmol) in anhydrous Toluene (4 ml) was added dropwise DEAD (0.086 ml, 0.552 mmol) at 0 degrees C under nitrogen atmosphere, and the mixture was stirred at room temperature. To the reaction mixture, a solution of 3-(tert-Butyl-dimethyl-silanyloxy)-4- hydroxy-butyric acid ethyl ester (compound prepared in Example 51 -(1)) (158 mg, 0.602 mmol) in anhydrous Toluene (1 ml) was added. The resulting mixture was stirred at 60 degrees C for 5 h. After removal of solvent, diethyl ether was added and the resulting mixture was stirred for 1 h. The insoluble solid was filtered off. The filtrate was concentrated in vacuo and the obtained residue was purified by silica gel chromatography (ethyl acetate/hexane = 1/14) to give the titled compound (168 mg, 45%). 1H-NMR (CDCI3): 0.09 (s, 6H), 0.61 (t, 3H), 0.87 (s, 9H), 1.26 (t, 3H), 2.05 (q, 4H), 2.15 (s, 3H), 2.32 (s, 3H), 2.55 (dd, 1 H), 2.70 (dd, 1 H), 3.50 (s, 3H), 3.80 (dd, 1 H), 3.96 (dd, 1 H), 4.10-4.19 (m, 2H), 4.48-4.52 (m, 1 H), 5.15 (s, 2H), 6.67 (d, 1 H), 6.83 (s, 1 H), 6.89 (dd, 1 H), 7.00 (dd, 1 H), 7.06 (s, 1 H), 7.36 (d, 1 H); MS (ESI+) : 747([M+H]+).
(3) Preparation of (S)-4-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy- butyric acid
Figure imgf000214_0001
A stirred solution of 3(S)-(tert-Butyl-dimethyl-silanyloxy)-4-(4-{1 -ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-butyric acid ethyl ester (compound prepared in Example 51 -(2)) (143 mg, 0.19 mmol) in 1 ,4-dioxane (4 ml), cone. HCl (0.2 ml) was slowly added at 0 degrees C and the mixture was stirred at 50 degrees C for 10 h. The reaction mixture was neutralized by careful addition of sat. NaHCOβ solution and the products were extracted with ethyl acetate. The extracts were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was dissolved in MeOH (5 ml). To the mixture, 1N KOH aq. (0.55 ml, 0.55 mmol) was added at room temperature and the mixture was stirred for 5 h. The reaction mixture was concentrated in vacuo and poured into saturated NH4CI aq. The products were extracted with ethyl acetate. The extracts were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (ethyl acetate/hexane = 1/15) to give the titled compound (50 mg, 65%) as a white solid. 1H-NMR (CDCI3): 0.60 (t, 6H), 2.05 (q, 4H), 2.17 (s, 3H), 2.34 (s, 3H), 2.76 (t, 2H), 3.99 (d, 2H), 4.45 (m, 1 H), 6.68 (d, 1 H), 6.84 (s, 1 H), 6.92 (dd, 1 H), 6.97 (d, 1 H), 7.04 (s, 1 H), 7.34 (d, 1 H); MS(ESI-) : 559 ([M-H]").
Example 52 Preparation of (S)-4-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy- butyric acid
Figure imgf000215_0001
(1) Preparation of (S)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(4-{1 -ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1 -enyl)- phenyl]-propyl}-2-methyl-phenoxy)-butyric acid ethyl ester
Figure imgf000215_0002
Using the same procedure as described for the preparation of Example 51- (2), the title compound was prepared from 4-{1 -ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenol (compound prepared in Example 30-(1 )). 1H-NMR (CDCI3): 0.09 (s, 6H), 0.61 (t, 3H), 0.87 (s, 9H), 1.26 (t, 3H), 2.05 (q, 4H), 2.15 (s, 3H), 2.32 (s, 3H), 2.55 (dd, 1 H), 2.70 (dd, 1 H), 3.50 (s, 3H), 3.80 (dd, 1 H), 3.96 (dd, 1 H), 4.10-4.19 (m, 2H), 4.48-4.52 (m, 1 H), 4.96 (s, 2H), 6.05 (d, 1 H), 6.68 (d, 1 H), 6.87-7.03 (m, 4H), 7.32 (d, 1 H), 7.36 (s, 1 H). (2) Preparation of (S)-4-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4 ,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3- hydroxy-butyric acid
Figure imgf000216_0001
Using the same procedure as described for the preparation of Example 51- (3), the title compound was prepared from (S)-3-(tert-Butyl-dimethyl- silanyloxy)-4-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4 ,4,4-trifluoro-3-methoxymethoxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-butyric acid ethyl ester (compound prepared in Example 52-(1 )). 1H-NMR (CDCI3): 0.61 (t, 6H), 2.05 (q, 4H), 2.17 (s, 3H), 2.34 (s, 3H), 2.76 (t, 2H), 3.99 (d, 2H), 4.45 (m, 1 H), 6.09 (d, 1 H), 6.69 (d, 1 H), 6.90-7.00 (m, 4H), 7.34 (t, 1 H), 7.35 (d, 1 H); MS (ESI-) : 561 ([M-H]").
Example 53 Preparation of (R)-4-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy- butyric acid
Figure imgf000216_0002
(1 ) Preparation of 3(R)-(tert-butyl-dimethyl-silanyloxy)-4-hydroxy-butyric acid ethyl ester EtOOC^ ^OH ► EtOOC^' ^OH OH OTBS Using the same procedure as described for the preparation of Example 51-
(1 ), the title compound was prepared from 3(S),4-dihydroxy-butyric acid ethyl ester (compound prepared using the same procedure in Tetrahedron, 1992, 48(20), 4067.) from diethyl (R)-malate). 1H-NMR (CDCI3): 0.09 (3H, s), 0.11 (3H, s), 0.89 (9H, s), 1.25(3H, t), 1.92 (1 H, brt), 2.55 (2H, d), 3.45-3.70 (2H, m), 4.12 (2H, q), 4.15-4.30 (1H, s).
(2) Preparation of (R)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(4-{1 -ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-butyric acid ethyl ester
Figure imgf000217_0001
Using the same procedure as described for the preparation of Example 51-
(2), the title compound was prepared from 4-{1 -ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1 -ynyl) -phenyl]-propyl}-2- methyl-phenol (compound prepared in Example 2-(2)) and 3(R)-(tert-Butyl- dimethyl-silanyloxy)-4-hydroxy-butyric acid ethyl ester (compound prepared in Example 53-(1)). 1H-NMR (CDCI3): 0.09 (s, 6H), 0.61 (t, 3H), 0.87 (s, 9H), 1.26 (t, 3H), 2.05 (q, 4H), 2.15 (s, 3H), 2.32 (s, 3H), 2.55 (dd, 1 H), 2.70 (dd, 1 H), 3.50 (s, 3H), 3.80 (dd, 1 H), 3.96 (dd, 1 H), 4.10-4.19 (m, 2H), 4.48-4.52 (m, 1 H), 5.15 (s, 2H), 6.67 (d, 1 H), 6.83 (s, 1 H), 6.89 (dd, 1 H), 7.00 (dd, 1 H), 7.06 (s, 1 H), 7.36 (d, 1 H).
(2) Preparation of (R)-4-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy- butyric acid
Figure imgf000217_0002
Using the same procedure as described for the preparation of Example 51- (3), the title compound was prepared from (R)-3-(tert-Butyl-dimethyl- silanyloxy)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-butyric acid ethyl ester (compound prepared in Example 53-(2)). 1H-NMR (CDCI3): 0.59 (t, 6H), 2.03 (q, 4H), 2.15 (s, 3H), 2.38 (s, 3H), 2.76 (t, 2H), 3.99 (d, 2H), 4.45 (m, 1 H), 6.68 (d, 1 H), 6.84 (d, 1H), 6.92 (dd, 1 H), 6.97 (d, 1 H), 7.04 (s, 1 H), 7.34 (d, 1 H); MS (ESI-) : 559 ([M-H]").
Example 54
Preparation of (R)-4-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy- butyric acid
Figure imgf000218_0001
(1 ) Preparation of (R)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(4-{1 -ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)- phenyl]-propyl}-2-methyl-phenoxy)-butyric acid ethyl ester
Figure imgf000218_0002
Using the same procedure as described for the preparation of Example 51- (2), the title compound was prepared from 4-{1 -ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenol (compound prepared in Example 30-(1)) and 3R- (tert-Butyl-dimethyl-silanyloxy)-4-hydroxy-butyric acid ethyl ester (compound prepared in Example 53-(1)).
1H-NMR (CDCI3): 0.09 (s, 6H), 0.61 (t, 3H), 0.87 (s, 9H), 1.26 (t, 3H), 2.05 (q, 4H), 2.15 (s, 3H), 2.32 (s, 3H), 2.55 (dd, 1H), 2.70 (dd, 1H), 3.50 (s, 3H), 3.80 (dd, 1 H), 3.96 (dd, 1H), 4.10-4.19 (m, 2H), 4.48-4.52 (m, 1H), 4.96 (s, 2H), 6.05 (d, 1 H), 6.68 (d, 1 H), 6.87-7.03 (m, 4H), 7.32 (d, 1 H), 7.36 (s, 1 H). (2) Preparation of (R)-4-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3- hydroxy-butyric acid
Figure imgf000219_0001
Using the same procedure as described for the preparation of Example 51- (3), the title compound was prepared from (R)-3-(tert-Butyl-dimethyl- silanyloxy)-4-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifiuoro-3-methoxymethoxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-butyric acid ethyl ester (compound prepared in Example 54-(1 )). 1H-NMR (CDCI3): 0.60 (t, 6H), 2.04 (q, 4H), 2.17 (s, 3H), 2.34 (s, 3H), 2.76 (t, 2H), 3.99 (d, 2H), 4.46 (m, 1 H), 6.08 (d, 1 H), 6.69 (d, 1 H), 6.90-7.00 (m, 4H), 7.26-7.39 (m, 2H); MS(ESI-) : 561 ([M-H]").
Example 55
Preparation of (S)-6-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-
3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- tetrahydro-pyran-2-one
Figure imgf000219_0002
Preparation of (S)-6-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-
3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- tetrahydro-pyran-2-one
Figure imgf000219_0003
To a solution of 4-{1 -ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenol (compound prepared in Example 30-(1 )) (50 mg, 0.384 mmol) in toluene (3 ml) were added triphenylphosphine (151 mg, 0.576 mmol), DEAD (0.09 ml, 0.576 mmol) and (S)-6-Hydroxymethyl-tetrahydro-pyran-2-one (J. Chem. Soc, Perkin Trans. 1, 2000, 20, 3519) (194 mg, 0.384 mmol) and the mixture was stirred at room temperature overnight and at 40 degrees C for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EtOAc:Hex=1 :5) to give (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one (78mg, 33%). To a solution of (S)-6- (4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-methoxymethoxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- tetrahydro-pyran-2-one (65 mg, 0.105 mmol) in CH2CI2 (3 ml) at -30 degrees C was added TMSBr (0.017 ml, 0.126 mmol) and the mixture was stirred at - 30 degrees C for 1 h and at 0 degrees C for 30 min. The reaction mixture was poured into sat. NaHC03 aq. and the products were extracted with CH2CI2. The extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EtOAc:Hex=1 :4) to give the title compound (65 mg, 79%).
1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.80-2.12 (m, 8H), 2.15 (s, 3H), 2.33 (s, 3H), 2.45-2.70 (m, 2H), 2.90 (t, 2H), 3.35 (s, 1 H), 4.01-4.14 (m ,2H), 4.66 (m, 1H), 6.07 (d, 1H), 6.67 (d, 1H), 6.87-7.01 (m, 4H), 7.32-7.39 (m, 2H); MS (ESI-) : 571 ([M-H]').
Example 56
Preparation of (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-
3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid
Figure imgf000220_0001
Preparation of (S)-6-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid
Figure imgf000221_0001
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-6-(4-{1 -ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one (compound prepared in Example 55). The yield was 91%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.63 (t, 6H), 1.61-1.84 (m, 4H), 2.10 (q, 4H), 2.18 (s, 3H), 2.24 (t, 2H), 2.35 (s, 3H), 2.45-2.70 (m, 2H), 2.90 (t, 2H), 3.35 (s, 1H), 3.90-4.03 (m, 3H), 6.21 (d, 1H), 6.79 (d, 1H), 6.89- 7.03 (m, 4H), 7.37 (d, 1H), 7.44 (d, 1H); MS (ESI-) : 589 ([M-H]").
Example 57
Preparation of (S)-6-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- tetrahydro-pyran-2-one
Figure imgf000221_0002
(1) Preparation of (S)-6-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one
Figure imgf000222_0001
Using the same procedure as described for the preparation of Example 55, the title compound was prepared from 4-{1 -ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenol (compound prepared in Example 2-(2)) and (S)-6- hydroxymethyl-tetrahydro-pyran-2-one (J. Chem. Soc, Perkin Trans. 1, 2000, 20, 3519). The yield was 46%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.80-2.09 (m, 8H), 2.15 (s, 3H), 2.39 (s, 3H), 2.45-2.69 (m, 2H), 3.47 (s, 3H), 4.01-4.14 (m ,2H), 4.69 (m, 1 H), 5.15 (s, 2h), 6.67 (d, 1H), 6.84-7.04 (m, 4H), 7.36 (d, 1H).
(2) Preparation of (S)-6-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- tetrahydro-pyran-2-one
Figure imgf000222_0002
To a solution of (S)-6-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one (compound prepared in Example 57-(1)) (78 mg, 0.127 mmol) in CH2CI2(2 ml) at 0 degrees C were added thiophenol (0.020 ml, 0.190 mmol) and BF3-OEt2 (0.048 ml, 0.381 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into phosphate buffer and the products were extracted with EtOAc. The extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EtOAc:Hex=1:5) to give the title compound (45 mg, 62%).
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.80-2.09 (m, 8H), 2.14 (s, 3H), 2.38 (s, 3H), 2.45-2.71 (m, 2H), 3.34 (s, 1H), 4.01-4.14 (m ,2H), 4.67 (m, 1H), 6.66 (d, 1H), 6.84-7.04 (m, 4H), 7.34 (d, 1H); MS (ESI+) : 571 ([M+H]+).
Example 58
Preparation of (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid
Figure imgf000223_0001
Preparation of (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trif luoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid
Figure imgf000223_0002
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one (compound prepared in Example 57-(2)). The yield was 99%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.62 (t, 6H), 1.58-1.88 (m, 4H), 2.10 (q, 4H), 2.18 (s, 3H), 2.24 (t, 2H), 2.38 (s, 3H), 3.89-4.02 (m ,3H), 6.80 (d, 1H), 6.87-7.08 (m, 4H), 7.34 (d, 1H); MS (ESI-) : 587 ([M-H]").
Example 59 Preparation of (R)-6-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- tetrahydro-pyran-2-one
Figure imgf000224_0001
(1 ) Preparation of (R)-6-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one
Figure imgf000224_0002
Using the same procedure as described for the preparation of Example 55, the title compound was prepared from 4-{1 -ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenol (compound prepared in Example 2-(2)) and (R)-6- hydroxymethyl-tetrahydro-pyran-2-one (J. Chem. Soc, Perkin Trans. 1, 2000, 20, 3519). The yield was 46%. 1H-NMR(CDCI3): 7.37(d, 1H), 7.04-6.84 (m, 4H), 6.67 (d, 1H), 5.15 (s, 2H), 4.69 (m, 1 H), 4.12 (m, 2H), 3.84 (s, 3H), 2.60 (m, 2H), 2.39 (s, 3H), 2.15 (s, 3H), 2.04 (m, 6H), 1.88 (m, 2H), 0.59 (t, 6H).
(2) Preparation of (R)-6-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- tetrahydro-pyran-2-one
Figure imgf000224_0003
To a solution of (R)-6-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one (compound prepared in Example 59-(1)) (43 mg, 0.07 mmol) in CH2CI2 (3 ml) at -30 degrees C was added TMSBr (0.014 ml, 0.105 mmol) and the mixture was stirred at -30 degrees C for 1 h and at 0 degrees C for 30 min. The reaction mixture was poured into sat. NaHC03 aq. and the products were extracted with CH2CI2. The extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (CH2CI2: MeOH=30:1) to give the title compound (21 mg, 53%). 1H-NMR(CDCI3): 7.36 (d, 1H), 7.04 (s, 1H), 6.99 (s, 1 H), 6.91 (dd, 1H), 6.84 (d, 1 H), 6.66 (d, 1 H), 4.69 (m, 1 H), 4.09 (m, 2H), 2.58 (m, 2H), 2.38 (s, 3H), 2.15 (s, 3H), 2.04 (m, 6H), 1.88 (m, 2H), 0.59 (t, 6H); MS(ESI-) : 569 ([M-H]"
Example 60
Preparation of (R)-6-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid
Figure imgf000225_0001
Preparation of (R)-6-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid
Figure imgf000225_0002
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (R)-6-(4-{1 -ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one (compound prepared in Example 59-(2)). The yield was 99%.
1H-NMR (300MHz, CD3OD as potassium salt): 0.62 (t, 6H), 1.58-1.84 (m, 4H), 2.10 (q, 4H), 2.18 (s, 3H), 2.24 (t, 2H), 2.38 (s, 3H), 3.89-3.99 (m ,3H), 6.80 (d, 1H), 6.95-7.07 (m, 4H), 7.34 (d, 1H); MS (ESI-) : 587 ([M-H]").
Example 61
Preparation of (R)-6-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-
3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- tetrahydro-pyran-2-one
Figure imgf000226_0001
(1) Preparation of (R)-6-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one
Figure imgf000226_0002
Using the same procedure as described for the preparation of Example 55, the title compound was prepared from 4-{1 -ethyl-1 -[3-methyl-4-((E)-4 ,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenol (compound prepared in Example 30-(1)) and (R)-6- hydroxymethyl-tetrahydro-pyran-2-one (J. Chem. Soc, Perkin Trans. 1, 2000, 20, 3519). The yield was 35%.
1H-NMR (CDCI3): 7.36 (d, 1H), 7.02-6.89 (m, 4H), 6.67 (d, 1H), 6.05 (d,1H), 4.96 (s, 2H), 4.68 (m, 1 H), 4.09 (m, 2H), 3.50 (s, 3H), 2.57 (m, 2H), 2.32 (s,3H), 2.16 (s, 3H), 2.05 (m, 6H), 1.89 (m, 2H), 0.61 (t, 6H). (2) Preparation of (R)-6-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one
Figure imgf000227_0001
Using the same procedure as described for the preparation of Example 59- (2), the title compound was prepared from (R)-6-(4-{1 -ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one (compound prepared in Example 61 -(1)). The yield was 92%.
1H-NMR(CDCI3): 7.33 (d, 1H), 7.01-6.88 (m, 4H), 6.66 (d, 1H), 6.07 (d,1H), 4.67 (m, 1 H), 4.08 (m, 2H), 2.58 (m, 2H), 2.33 (s,3H), 2.15 (s, 3H), 2.04 (t, 6H), 1.88 (m, 2H), 0.61 (t, 6H); MS(ESI-) : 571.49 ([M-H]').
Example 62
Preparation of (R)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3-hydroxy-
3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid
Figure imgf000227_0002
Preparation of (R)-6-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid
Figure imgf000227_0003
Using the same procedure as described for the preparation of Example 1- (7), the title compound was prepared from (R)-6-(4-{1 -ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one (compound prepared in Example 61 -(2)). The yield was quant.
1H-NMR (300MHz, CD3OD as potassium salt): 8.44 (d, 1H), 8.35 (d, 1H), 7.99 (d, 1 H), 7.88 (d, 1 H), 7.78 (d, 1 H),7.21 (d, 1 H), 4.92 (m, 3H), 3.35 (s, 3H), 3.24 (t, 2H), 3.17 (s, 3H), 3.10 (q, 4H), 2.91 (s, 3H), 2.73 (m, 2H), 2.61 (m, 1H), 1.6 (t, 6H); MS (ESI-) : 589 ([M-H]").
Example 63 Preparation of (S)-3-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000228_0001
(1) Preparation of 1-(4-{1-[4-((R)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1-yn-3-ol
Figure imgf000228_0002
To a solution of 4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(4)) (250 mg, 0.660 mmol) in anhydrous DMF (6.6 ml) were added NaOH (40 mg, 0.99 mmol) and toluene-4-sulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4- ylmethyl ester (214 mg, 0.792 mmol) and the mixture was stirred at 60 degrees C for 11 h. The mixture was poured into saturated NH4CI aq. and the products were extracted with EtOAc. The extacts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was purified by Silica gel chromatography (EtOAc:n- Hexane=1 :10) to give the title compound (177 mg, 56%) as a white solid. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.11 (t, 6H), 1.40 (s, 3H), 1.46 (s, 3H), 1.70-1.83 (m, 4H), 2.04 (q, 4H), 2.14 (s, 3H), 2.37 (s, 3H), 3.89-3.99 (m, 2H), 4.04-4.19 (m, 3H), 4.42-4.50 (m, 1H), 6.68 (d, 1 H), 6.84 (s, 1 H), 6.90 (d, 2H), 6.99 (s, 1H), 7.27 (d, 1H).
(2) Preparation of (S)-3-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000229_0001
To a solution of 1-(4-{1-[4-((R)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyrj-1 -ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1 -yn-3-ol
(compound prepared in Example 63-(1)) (104 mg, 0.211 mmol) in THF:H20 (4:1, 2.5 ml) was added TFA (1 ml, 12.98 mmol) and the mixture was stirred at 0 degrees C for 3 h. The mixture was poured into saturated NaHC03 aq. and the products were extracted with EtOAc. The extacts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EtOAc:n- Hexane=1 :1 ) to give the title compound (63mg, 66%). 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.11 (t, 6H), 1.70-1.81 (m, 4H), 2.00 (m, 1H), 2.04 (q, 4H), 2.07 (s, 3H), 2.37 (s, 3H), 2.52 (d, 1H), 3.82-3.90 (m, 2H), 4.03 (d, 2H), 4.11-4.17 (m, 1H), 6.69 (d, 1 H), 6.86 (d, 1 H), 6.90 (s, 1H), 6.94 (s ,1H), 6.99 (d, 1H), 7.27 (d, 1H); MS (ESI+) : 470 ([M+H]+).
Example 64
Preparation of (S)-3-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000229_0002
(1) Preparation of (E)-1-(4-{1-[4-((R)-2,2-dimethyl-[1 ,3]dioxolan-4- ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1- en-3-ol
Figure imgf000230_0001
To a solution of 4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1- (5)) (150 mg, 0.394 mmol) in anhydrous DMF (6.6 ml) were added K2C03 (136 mg, 0.985 mmol) and toluene-4-sulfonic acid (S)-2,2-dimethyl- [1 ,3]dioxolan-4-ylmethyl ester (169 mg, 0.591 mmol) and the mixture was stirred at 100 degrees C for 14 h. The mixture was poured into saturated NH4CI aq. and the products were extracted with EtOAc. The extacts were washed with brine, dried over MgS0 , filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EtOAc:n-Hexane=1 :7) to give the title compound (170 mg, 88%).
1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 0.92 (t, 6H), 1.40 (s, 3H),1.46 (s, 3H), 1.63 (q, 4H), 2.04 (q, 4H), 2.16 (s, 3H), 2.31 (s, 3H), 3.89-4.16 (m, 4H), 4.48 (m, 1 H), 6.00 (d, 1 H), 6.68 (d, 1 H), 6.74 (s, 1 H), 6.91-6.97 (m, 4H), 7.29 (d, 1 H).
(2) Preparation of (S)-3-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000230_0002
Using the same procedure as described for the preparation of Example 63- (2), the title compound was prepared from (E)-1-(4-{1-[4-((R)-2,2-dimethyl- [1 ,3]dioxolan-4-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl- phenyl)-3-ethyl-pent-1-en-3-ol (compound prepared in Example 64-(1)). The yield was 38%.
1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 0.92 (t, 6H), 1.65 (q, 4H), 2.00 (m, 1 H), 2.04 (q, 1 H), 2.17 (s,3H), 2.31 (s,3H), 2.52 (d, 1 H), 3.76-3.86 (m 2H), 4.03-4.04 (m, 2H), 4.08-4.14 (m, 1 H), 6.01 (d, 1 H), 6.72 (s, 1 H), 6.73 (d, 1 H), 6.91-6.98 (m, 4H), 7.29 (d, 1H).
Example 65
Preparation of (S)-3-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000231_0001
(1) Preparation of 3-(4-{1-[4-((S)-2,3-dihydroxy-propoxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-propionic acid methyl ester
Figure imgf000231_0002
To a solution of 3-{4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- methyl-phenyl}-propionic acid methyl ester (compound prepared in Example 18-(2)) (320 mg, 0.90 mmol) in anhydrous DMF (9 ml) at room temperature under nitrogen atmosphere were added K2CO3 (248 mg, 1.80 mmol) and (S)-toluene-4-sulfonic acid 2,2-dimethyl-[1 ,3]dioxolan-4-ylmethyl ester (309 mg, 1.08 mmol). After stirring overnight at 100 degrees C, the reaction mixture was diluted with ethyl acetate, washed with sat. NH4CI, water and brine, and dried over MgS04. The solution was concentrated under reduced pressure and the obtained residue was dissolved in methanol (9 ml). To the solution was added concentrated HCl with 4drops and the mixture was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica-gel chromatography (hexane/EtOAc=7:1) to give the title compound (187 mg, 0.43 mmol, 48%). 1H NMR (CDCI3): 6.99-6.83 (m, 5H), 6.69 (d, 1 H), 4.10 (m, 1 H), 4.03 (dd, 2H), 3.82 (m, 2H), 3.67 (s, 3H), 2.89 (dt, 2H), 2.57 (dt, 2H), 2.25 (s, 3H), 2.16 i (s, 3H), 2.04 (q, 4H), 0.59 (t, 6H).
(2) Preparation of (S)-3-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000232_0001
To a solution of 3-(4-{1-[4-((S)-2,3-dihydroxy-propoxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-propionic acid methyl ester (compound prepared in Example 65-(1)) (187 mg, 0.43 mmol) in anhydrous THF (4 mL) under nitrogen atmosphere at 0 degrees C was added ethyl magnesium bromide (1.3 ml, 1.3 mmol, 1.0M in THF) and the mixture was stirred at 0 degrees C for 2 h. The mixture was poured into saturated NH4CI aq. and the products were extracted with EtOAc. The extacts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EtOAc:n- Hexane=1 :7) to give the title compound (110 mg, 56%). 1H NMR (CDCI3); 7.01-6.89 (m, 5H), 6.69 (d, 1 H), 4.10 (m, 1 H), 4.02 (dd, 2H), 3.84 (dd, 1 H), 3.76 (dd, 1 H), 2.56 (m, 2H), 2.25 (s, 3H), 2.16 (s, 3H), 2.04 (q, 4H), 1.65 (m, 2H), 1.55 (q, 4H), 0.90 (t, 6H), 0.59 (t, 6H); MS (ESI-) : 455 ([M-H]"). Example 66 Preparation of 3-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2(S)-diol
Figure imgf000233_0001
(1) Preparation of 1-(4-{1-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pent-1-yn-3-ol
Figure imgf000233_0002
Using the same procedure as described for the preparation of Example 64- (1), the title compound was prepared from 4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 3). The yield was 74%.
1H-NMR (300MHz, CDCI3): 0.58 (t, 6H), 1.06 (s, 9H), 1.40 (s, 3H), 1.45 (s, 3H), 1.76 (d, 1H), 2.03 (q, 4H), 2.14 (s, 3H), 2.37 (s, 3H), 3.89-3.98 (m, 2H), 4.03-4.16 (m, 2H), 4.25 (d, 1H), 4.42-4.50 (m, 1H), 6.68 (d, 1H), 6.85-6.99 (m, 4H), 7.28 (d, 1H).
(2) Preparation of 3-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1,2(S)-diol
Figure imgf000233_0003
To a solution of 1-(4-{1-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pent-1-yn-3-ol (compound prepared in Example 66-(1)) (134 mg, 0.272 mmol) in MeOH (6 ml) was added conc.HCI (0.23 ml, 2.72 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized by sat. NaHC03 solution, extracted with CH2CI2, dried over MgS04, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EtOAc:hexane=1:1) to give the title compound (40 mg, 33 %).
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.06 (s, 9H), 1.78 (d, 1 H), 1.98-2.07 (m, 5H), 2.15 (s, 3H), 2.37 (s, 3H), 2.54 (d, 1H), 3.73-3.89 (m, 2H), 4.03 (m, 2H), 4.11 (m, 1 H), 4.25 (d, 1 H), 6.69 (d, 1 H), 6.86-6.99 (m, 4H), 7.28 (d, 1 H); MS (ESI+) : 475 (M+Na)+.
Example 67
Preparation of 3-(4-{1 -ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2(S)-diol
Figure imgf000234_0001
(1) Preparation of (E)-1-(4-{1-[4-((R)-2,2-dimethyl-[1 ,3]dioxolan-4- ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl- pent-1-en-3-ol
Figure imgf000234_0002
Using the same procedure as described for the preparation of Example 64- (1), the title compound was prepared from 4-{1 -ethyl-1 -[4-((E)-3-hyd roxy-4 ,4- dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 14). The yield was 74%.
1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 0.96 (s, 9H), 1.40 (s, 3H), 1.45 (s, 3H), 2.04 (q, 4H), 2.15 (s, 3H), 2.29 (s, 3H), 3.89-3.98 (m, 3H), 4.04-4.08 (m, 1 H), 4.13-4.18 (m, 1 H), 4.42-4.49 (m, 1 H), 6.12 (dd, 1 H), 6.67-6.76 (m, 2H), 6.68-6.96 (m, 4H), 7.31 (d, 1H).
(2) Preparation of 3-(4-{1 -ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 ■ enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2(S)-diol
Figure imgf000235_0001
To a solution of (E)-1-(4-{1-[4-((R)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethoxy)- 3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pent-1-en-3- ol (compound prepared in Example 67-(1)) (201 mg, 0.406 mmol) in THF/H20 (10/1 , 8 ml) was added 10-camphorsulfonic acid (289 mg, 1.21 mmol) and the mixture was stirred at 50 degrees C for 1 h. The reaction mixture was poured into sat. NaHC03 solution, extracted with CH2CI2, dried over MgS0 , filtered, and concentrated under reduced pressure. The obtained residue was purified by ODS chromatography (MeOH/ H2O) to give the title compound (24.8 mg, 13%).
1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 0.96 (s, 9H), 1.50 (m, 1H), 1.96-2.08 (m, 5H), 2.16 (s, 3H), 2.29 (s, 3H), 2.53 (d, 1H), 3.74-3.93 (m, 3H), 4.02-4.04 (m, 2H), 4.07-4.15 (m, 1H), 4.42-4.49 (m, 1 H), 6.12 (dd, 1 H), 6.68-6.76 (m, 2H), 6.90-6.98 (m, 4H), 7.30 (d, 1 H); MS (ESI+) : 477 ([M+Na]+).
Example 68
Preparation of 3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-
1 ,2(S)-diol
Figure imgf000235_0002
(1 ) Preparation of (R)-4-{4-[1 -Ethyl-1 -(4-ethynyl-3-methyl-phenyl)-propyl]-2- methyl-phenoxymethyl}-2,2-dimethyl-[1 ,3]dioxolane
Figure imgf000235_0003
Using the same procedure as described for the preparation of Example 64- (1 ), the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)). The yield was 43%.
1H-NMR (300MHz, CDCI3): 7.33 (1 H, d), 7.01 (1 H, d), 6.95 (1 H, d), 6.91 (1 H, m), 6.86 (1 H, d), 6.69 (1 H, d), 4.46 (1 H, m), 4.11 (2H, m), 3.94 (2H, m), 2.39 (3H, s), 2.15 (3H, s), 2.04 (4H, q), 1.46 (3H, s), 1.40 (3H, s), 0.59 (6H, t).
(2) Preparation of 4-(4-{1-[4-((R)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1-trifluoro-2- trifluoromethyl-but-3-yn-2-ol
Figure imgf000236_0001
To a solution of (R)-4-{4-[1 -ethyl-1 -(4-ethynyl-3-methyl-phenyl)-propyl]-2- methyl-phenoxymethyl}-2,2-dimethyl-[1 ,3]dioxolane (compound prepared in Example 68-(1 )) (540 mg, 1.328 mmol) in anhydrous THF (15 ml) at -78 degrees C under nitrogen atmosphere was added n-BuLi (2.5N, 0.585 ml, 1.462 mmol) dropwise and the mixture was stirred for 20 min. Then to the mixture, hexafluoroacetone was added until the solution was made colorless. The reaction mixture was poured into saturated NH4CI aq. and the products were extracted with diethyl ether. The extacts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EtOAc:n- Hexane=1 :8) to give the title compound (686 mg, 90%). 1H-NMR (300MHz, CDCI3): 7.32 (1H, d), 7.04 (1H, d), 6.96 (1H, dd), 6.90 (1 H, dd), 6.82 (1 H, d), 6.67 (1 H, d), 4.46 (1 H, m), 4.42 (1 H, s), 4.10 (2H, m), 3.94 (2H, m), 2.37 (3H, s), 2.13 (3H, s), 2.04 (4H, q), 1.46 (3H, s), 1.40 (3H, s), 0.59 (6H, t). (3) Preparation of (S)-3-(4-{1 -ethyl-1 -[3-methyl-4-(4,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2- diol
Figure imgf000237_0001
To a solution of 4-(4-{1-[4-((R)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyrj-1 -ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1 -trifluoro-2- trifluoromethyl-but-3-yn-2-ol (compound prepared in Example 68-(2)) (98 mg, 0.171 mmol) in THF (6 ml) was added 2N-HCI (2 ml) and the mixture was stirred at room temperature for 10 h. The reaction mixture was poured into water and the products were extracted with diethyl ether. The extracts were washed with brine and dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-Hexane:EtOAc=1 :1) to give the title compound (83.5 mg, 92%).
1H-NMR (300MHz, CDCI3): 7.34 (1H, d), 7.04 (1H, s), 6.96 (1H, dd), 6.92 (1 H, dd), 6.83 (1 H, d), 6.68 (1 H, d), 4.11 (1 H, m), 4.03 (1 H, s), 4.02 (2H, d), 3.82 (2H, m), 2.61 (1 H, d), 2.37 (3H, s), 2.14(3H, s), 2.04 (4H, q), 1.64 (1 H, s), 0.60 (6H, t); MS (ES-) : 531.08 ([M-H]").
Example 69
Preparation of (S)-3-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2- diol
Figure imgf000237_0002
(1 ) Preparation of (E)-4-(4-{1-[4-((R)-2,2-dimethyl-[1 ,3]dioxolan-4- ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-
2-trifluoromethyl-but-3-en-2-ol
Figure imgf000238_0001
To a solution of 4-(4-{1 -[4-((R)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1-trifluoro-2- trifluoromethyl-but-3-yn-2-ol (compound prepared in Example 68-(2)) (168 mg, 0.293 mmol) in anhydrous THF (5 ml) was added LiAIH4 (0.350 ml, 0.350 mmol) at room temperature under N2 atmosphere and the mixture was stirred for 1 h and refluxed for 1 h. The reaction mixture was poured into saturated NH4CI aq. and the products were extracted with diethyl ether. The extacts were washed with brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EtOAc:n-Hexane=1 :8) to give the title compound (154 mg, 91 %).
1H-NMR (300MHz, CDCI3): 7.37 (1H, d), 7.33 (1 H, d), 7.01 (1 H, d), 6.94 (1 H, s), 6.91 (1 H, m), 6.88 (1H, d), 6.68 (1 H, d), 6.10 (1H, d), 4.46 (1H, m), 4.11 (2H, m), 3.94 (2H, m), 3.33 (1H, s), 2.33 (3H, s), 2.16 (3H, s), 2.05 (4H, q), 1.45 (3H, s), 1.40 (3H, s), 0.60 (6H, t).
(2) Preparation of (S)-3-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol
Figure imgf000238_0002
Using the same procedure as described for the preparation of Example 68- (3), the title compound was prepared from (E)-4-(4-{1-[4-((R)-2,2-dimethyl- [1 ,3]dioxolan-4-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl- phenyl)-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2-ol (compound prepared in Example 69-(1 )). The yield was 74%.
1H-NMR (300MHz, CDCI3): 7.37 (1 H, d), 7.33 (1 H, d), 7.00 (1 H, d), 6.98 (1 H, s), 6.94 (1 H, dd), 6.89 (1 H, d), 6.70 (1 H, d), 6.08 (1 H, d), 4.11 (1 H, m), 4.04 (1 H, s), 4.02 (1 H, d), 3.81 (2H, m), 3.36 (1 H, s), 2.57 (1 H, d), 2.33 (3H, s), 2.16 (3H, s), 2.05(4H, q), 2.04(1 H, s), 0.60 (6H, t); MS (ES-) : 533 ([M-H]").
Example 70
Preparation of (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000239_0001
(1 ) Preparation of 4-(4-{1-[4-((R)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1 -trifluoro-2- trifluoromethyl-butan-2-ol
Figure imgf000239_0002
To a solution of 4-(4-{1-[4-((R)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1-trifluoro-2- trifluoromethyl-but-3-yn-2-ol (compound prepared in Example 68-(2)) (110 mg, 0.192 mmol) in MeOH (5 ml) was added Pd-C (20 mg, 10 wt%). The mixture was stirred at room temperature for 20 h under H2 atmosphere. The mixture was filtered through celite 545, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EtOAc:n-Hex=1 :7) to give the title compound (106 mg, 96%).
1H-NMR (300MHz, CDCI3): 7.02-6.88 (5H, m), 6.68 (1H, d), 4.46 (1H, m), 4.16 (1 H, dd), 4.06 (1 H, dd), 3.94 (2H, m), 3.12 (1 H, s), 2.80 (2H, dd), 2.25 (3H, s), 2.16 (3H, s), 2.15 (2H, m), 2.03 (4H, q), 1.46 (3H, s), 1.40 (3H, s), 0.59 (6H, t).
(2) Preparation of (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy- 3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000240_0001
Using the same procedure as described for the preparation of Example 68- (3), the title compound was prepared from 4-(4-{1-[4-((R)-2,2-dimethyl- [1 ,3]dioxolan-4-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl- phenyl)-1 ,1 ,1 -trifluoro-2-trifluoromethyl-butan-2-ol (compound prepared in Example 70-(1)). The yield was 73%.
1H-NMR (300MHz, CDCI3): 7.02-6.88 (5H, m), 6.70 (1 H, d), 4.11 (1 H, m), 4.04 (1 H, s), 4.03 (1 H, s), 3.82 (2H, m), 3.43 (1 H, brd), 2.80 (2H, dd), 2.65 (1 H, brd), 2.25 (3H, s), 2.16 (3H, s), 2.15 (2H, m), 2.03 (4H, q), 0.59 (6H, t); MS (ES-) : 535 ([M-H]").
Example 71
Preparation of 2-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol
Figure imgf000240_0002
(1) Preparation of 1-(4-{1-[4-(2,2-dimethyl-[1 ,3]dioxan-5-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1-yn-3-ol
Figure imgf000240_0003
To a solution of 4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(4)) (205 mg, 0.542 mmol) in anhydrous DMF (5.4 ml) were added K2C03 (187 mg, 1.36 mmol) and toluene-4-sulfonic acid 2,2-dimethyl-[1 ,3]dioxan-5-ylmethyl ester (prepared from following procedure as described in Tetrahedron, 1991, 47, 1001.) (244 mg, 1.355 mmol) and the mixture was stirred at 110 degrees C for 15 h. The reaction mixture was poured into saturated NH4CI aq. and the products were extracted with EtOAc. The extacts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EtOAc:n- Hexane=1 :6) to give the title compound (184 mg, 67%) . 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.11 (t, 6H), 1.43 (s, 3H), 1.46 (s, 3H), 1.72-1.85 (m, 4H), 2.04 (q, 4H), 2.14 (s, 3H), 2.13-2.20 (m, 1 H), 2.37 (s, 3H), 3.89-4.20 (m, 5H), 6.68 (d, 1 H), 6.84 (s, 1H), 6.91-6.94 (m, 2H), 6.99 (s, 1 H), 7.27 (d, 1 H).
(2) Preparation of 2-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol
Figure imgf000241_0001
Using the same procedure as described for the preparation of Example 63- (2), the title compound was prepared from 1-(4-{1-[4-(2,2-Dimethyl- [1 ,3]dioxan-5-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)- 3-ethyl-pent-1-yn-3-ol (compound prepared in Example 71 -(1)). The yield was 38%. 1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 0.92 (t, 6H), 1.57-1.70 (m, 4H), 2.04 (q, 4H), 2.15 (s,3H), 2.26 (t, 3H), 2.31 (s,3H), 3.95 (d, 4H), 4.09 (d, 2H), 6.70 (d, 1 H), 6.82 (s, 1H), 6.88 (d, 2H), 6.98 (s, 1H), 7.27 (d, 1H); MS (ESI-) : 465 ([M-H]'). Example 72
Preparation of 2-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol
Figure imgf000242_0001
(1) Preparation of (E)-1-(4-{1-[4-(2,2-dimethyl-[1 ,3]dioxan-5-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1-en-3-ol
Figure imgf000242_0002
Using the same procedure as described for the preparation of Example 71- (1), the title compound was prepared from 4-{1 -ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(5)). The yield was 85%.
1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 0.92 (t, 6H), 1.43 s, 3H), 1.46 (s, 3H), 1.64 (q, 4H), 2.04 (q, 4H), 2.15 (s, 3H), 2.18 (m, 1 H), 2.31 (s, 3H), 3.89- 4.20 (m, 6H), 6.01 (d, 1 H), 6.68 (d, 1 H), 6.74 (d, 1 H), 6.90-7.02 (m, 4H), 7.29 (d, 1 H).
(2) Preparation of 2-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol
Figure imgf000242_0003
Using the same procedure as described for the preparation of Example 63- (2), the title compound was prepared from (E)-1-(4-{1-[4-(2,2-dimethyl- [1 ,3]dioxan-5-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)- 3-ethyl-pent-1-en-3-ol (compound prepared in Example 72-(1)). The yield was 44%. H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 0.92 (t, 6H), 1.57-1.70 (m, 6H), 2.04 (q, 4H), 2.15 (s,3H), 2.26 (m, 3H), 2.31 (s,3H), 3.95 (d, 4H), 4.09 (d, 2H), 6.01 (d, 1H), 6.71 (d, 1H), 6.74 (s, 1H), 6.89 (d, 1H), 6.96-7.02 (m, 3H), 7.32 (d, 1H); MS (ESI-) : 467 ([M-H]").
Example 73
Preparation of 2-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol
Figure imgf000243_0001
(1) Preparation of 1-(4-{1-[4-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pentan-3-ol
Figure imgf000243_0002
Using the same procedure as described for the preparation of Example 71- (1), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared by hydrogenation of 4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (Example 1-(4)). The yield was 73%. 1H-NMR(300MHz, CDCI3): 0.60 (t, 6H), 0.91 (t, 6H), 1.43 (s, 3H), 1.46 (s, 3H), 1.55 (m, 6H), 1.63-1.69 (m, 1H), 2.02 (q, 4H), 2.14 (s, 3H), 2.18 (m, 1H), 2.26 (s, 3H), 2.55 (m, 2H), 3.89-4.16 (m, 6H), 6.68 (d, 1H), 6.90-6.97 (m, 4H), 7.00 (d, 1H); MS (ESI+) : 528 ([M+NH4]+)
(2) Preparation of 2-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol
Figure imgf000244_0001
Using the same procedure as described for the preparation of Example 63- (2), the title compound was prepared from 1-(4-{1-[4-(2,2-Dimethyl- [1 ,3]dioxan-5-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)- 3-ethyl-pentan-3-ol (compound prepared in Example 73-(1)). The yield was 73%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (t, 6H), 1.54 (q, 4H), 1.65 (m, 2H), 2.00 (q, 4H), 2.15 (s,3H), 2.25 (m, 1H), 2.31 (s,3H), 2.53-2.59 (m, 2H), 3.93 (d, 4H), 4.07 (d, 2H), 6.70 (d, 1 H), 6.91-7.00 (m, 5H); MS (ESI-) : 469 ([M-H]").
Example 74
Preparation of 2-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol
Figure imgf000244_0002
(1 ) Preparation of 1-(4-{1-[4-(2,2-dimethyl-[1 ,3]dioxan-5-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pent-1-yn-3-ol
Figure imgf000244_0003
Using the same procedure as described for the preparation of Example 71- (1 ), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 3). The yield was 68%. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.06 (s, 9H), 1.43 (s, 3H), 1.46 (s, 3H), 1.76 (d, 1H), 2.10 (q, 4H), 2.13 (s, 3H), 2.16-2.23 (m, 1H), 2.38 (s, 3H), 3.92 (dd, 2H), 4.00 (d, 2H), 4.06 (dd, 2H), 4.25 (d, 2H), 6.68 (d, 1H), 6.84- 7.00 (m, 4H), 7.27 (d, 1H); MS (ESI+) : 524 ([M+NH4]+).
(2) Preparation of 2-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol
Figure imgf000245_0001
Using the same procedure as described for the preparation of Example 68- (2), the title compound was prepared from 1-(4-{1-[4-(2,2-dimethyl-
[1,3]dioxan-5-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-
4,4-dimethyl-pent-1-yn-3-ol (compound prepared in Example 74-(1)). The yield was 57%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.06 (s, 9H), 1.79 (d, 1H), 2.10 (q, 4H), 2.14 (s, 3H), 2.25 (m, 1H), 2.38 (s, 3H), 3.93-3.96 (m, 4H), 4.09 (d, 2H),
4.25 (d, 1H), 6.71 (d, 1H), 6.85-6.99 (m, 4H), 6.97-7.05 (m, 4H), 7.27 (d, 1H);
MS (ESI-) : 465 ([M-H]").
Example 75 Preparation of 2-(4-{1 -ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol
Figure imgf000245_0002
(1 ) Preparation of (E)-1-(4-{1-[4-(2,2-dimethyl-[1 ,3]dioxan-5-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pent-1-en-3-ol
Figure imgf000246_0001
Using the same procedure as described for the preparation of Example 71- (1), the title compound was prepared from 4-{1 -ethyl-1 -[4-((E)-3-hyd roxy-4 ,4- dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 14). The yield was 53%.
1 H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 0.96 (s, 9H), 1.43 (s, 3H), 1.46 (s, 3H), 1.51 (d, 1H), 2.04 (q, 4H), 2.14 (s, 3H), 2.20 (m, 1H), 2.29 (s, 3H), 3.89- 4.09 (m, 7H), 6.12 (dd, 1 H), 6.68 (d, 1 H), 6.73 (d, 1 H), 6.90-6.96 (m, 4H), 7.31 (d, 1H); MS (ESI+) : 526 ([M+NH4]+).
(2) Preparation of 2-(4-{1 -ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol
Figure imgf000246_0002
Using the same procedure as described for the preparation of Example 63- (2), the title compound was prepared from (E)-1-(4-{1-[4-(2,2-dimethyl- [1 ,3]dioxan-5-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)- 4,4-dimethyl-pent-1-en-3-ol (compound prepared in Example 75-(1)). The yield was 30%. 1H-NMR (300MHz, CDCI3): 0.68 (t, 6H), 1.04 (s, 9H), 1.59 (m, 1 H), 2.13 (q, 4H), 2.22 (s, 3H), 2.29-2.37 (m, 1 H), 2.37 (s, 3H), 3.98-4.04 (m, 5H), 4.17 (d, 2H), 6.19 (dd, 1H), 6.78-6.84 (m, 2H), 6.97-7.05 (m, 4H), 7.38 (d, 1H); MS (ESI-) : 467 ([M-H]").
Example 76
Preparation of 2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol
Figure imgf000247_0001
Preparation of 2-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol
Figure imgf000247_0002
Using the same procedure as described for the preparation of Example 65, the title compound was prepared from 4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4 ,4- dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) and toluene-4-sulfonic acid 2,2-dimethyl- [1 ,3]dioxan-5-ylmethyl ester (prepared from following procedure as described in Tetrahedron, 1991, 47, 1001.). The yield was 36%. 1H NMR (CDCI3): 7.03-6.89 (m, 5H), 6.71 (d, 1H), 4.09 (d, 2H), 3.95 (d, 4H), 3.24 (dt, 1 H), 2.85 (m, 1 H), 2.55 (m, 1 H), 2.25 (s, 3H), 2.15 (s, 3H), 2.04 (q, 4H), 1.79 (m, 1 H), 1.50 (m, 1 H), 0.89 (s, 9H), 0.59 (t, 6H); MS (ESI-) : 469 ([M-H]").
Example 77
Preparation of 2-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol
Figure imgf000247_0003
(1) Preparation of 5-{4-[1 -ethyl-1 -(4-ethynyl-3-methyl-phenyl)-propyl]-2- methyl-phenoxymethyl}-2,2-dimethyl-[1 ,3]dioxane
Figure imgf000248_0001
Using the same procedure as described for the preparation of Example 71- (1 ), the title compound was prepared from 4-[1 -ethyl-1 -(4-ethynyl-3-methyl- phenyl)-propyl]-2-methyl-phenol (compound prepared in Example 1-(3)). The yield was 73%.
1H NMR (CDCI3): 7.33 (d, 1 H), 7.00-6.84 (m, 4H), 6.68 (d, 1 H), 4.10-3.89 (m, 6H), 3.21 (s, 1H), 2.39 (s, 3H), 2.18-2.02 (m, 1 H), 2.00 (s, 3H), 2.03 (q, 4H), 1.15 (s, 6H), 0.59 (t, 3H).
(2) Preparation of 4-(4-{1-[4-(2,2-Dimethyl-[1 ,3]dioxan-5-ylmethoxy)-3- methyl-phenyrj-1 -ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1 -trifluoro-2- trifluoromethyl-but-3-yn-2-ol
Figure imgf000248_0002
Using the same procedure as described for the preparation of Example 68- (2), the title compound was prepared from 5-{4-[1 -Ethyl-1 -(4-ethynyl-3- methyl-phenyl)-propyl]-2-methyl-phenoxymethyl}-2,2-dimethyl-[1 ,3]dioxane (compound prepared in Example 77-(1 )). The yield was 69%. 1H NMR (CDCI3): 7.33 (d, 1 H), 7.00-6.84 (m, 4H), 6.68 (d, 1 H), 4.13-3.89 (m, 6H), 3.45 (s, 1 H), 2.38 (s, 3H), 2.20-2.16 (m, 1 H), 2.08 (s, 3H), 2.03 (q, 4H), 1.46 (s, 3H), 1.43 (s, 3H), 0.59 (t, 3H).
(3) Preparation of 2-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol
Figure imgf000249_0001
Using the same procedure as described for the preparation of Example 66- (2), the title compound was prepared from 4-(4-{1-[4-(2,2-dimethyl- [1 ,3]dioxan-5-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)- 1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-yn-2-ol (compound prepared in Example 77-(2)). The yield was 69%.
1H NMR (CDCI3): 7.34 (d, 1 H), 7.00-6.82 (m, 4H), 6.70 (d, 1 H), 4.08 (d, 2H), 3.95 (m, 4H), 3.83 (s, 1 H), 2.38 (s, 3H), 2.27-2.24 (m, 1 H), 2.13 (s, 3H), 2.03 (q, 4H), 0.59 (t, 3H); MS (ESI-) : 545 ([M-H]").
Example 78
Preparation of 2-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol
Figure imgf000249_0002
(1 ) Preparation of (E)-4-(4-{1-[4-(2,2-dimethyl-[1 ,3]dioxan-5-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1-trifluoro-2- trifluoromethyl-but-3-en-2-ol
Figure imgf000249_0003
Using the same procedure as described for the preparation of Example 69- (1 ), the title compound was prepared from 4-(4-{1-[4-(2,2-dimethyl- [1 ,3]dioxan-5-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)- 1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-yn-2-ol (compound prepared in Example 77-(2)). The yield was 39%. 1H NMR (CDCI3); 7.39-7.32 (m, 2H), 7.01-6.86 (m, 4H), 6.69 (d, 1 H), 6.10 (d, 1 H), 4.15-3.89 (m, 6H), 3.11 (s, 1 H), 2.33 (s, 3H), 2.20-2.16 (m, 1 H), 2.08 (s, 3H), 2.03 (q, 4H), 1.46 (s, 3H), 1.43 (s, 3H), 0.59 (t, 3H).
(2) Preparation of 2-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol
Figure imgf000250_0001
using the same procedure as described for the preparation of Example 66- (2), the title compound was prepared from (E)-4-(4-{1-[4-(2,2-dimethyl-
[1 ,3]dioxan-5-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)- 1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2-ol (compound prepared in Example 78-(1 )). The yield was 83%.
1H NMR (CDCI3): 7.39-7.32 (m, 2H), 7.02-6.88 (m, 4H), 6.67 (d, 1H), 6.10 (d, 1 H), 4.12 (d, 2H), 3.96 (d, 4H), 3.18 (s, 1 H), 2.33 (s, 3H), 2.27-2.16 (m, 1 H), 2.08 (s, 3H), 2.04 (q, 4H), 0.59 (t, 3H); MS (ESI-) : 547 ([M-H]").
Example 79
Preparation of 2-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3- diol
Figure imgf000250_0002
Preparation of 2-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3- diol
Figure imgf000251_0001
To a solution of 2-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol (compound prepared in Example 78-(2)) (50 mg, 0.091 mmol) in MeOH (5 ml) was added Pd(OH)2/C (5 mg, 10 wt%). The mixture was stirred at room temperature for 3 h under H2 atmosphere. The mixture was filtered through celite 545, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-Hexane: CH2CI2: EtOAc=1 :1 :1) to give the title compound (28.5 mg, 57%).
1H NMR (CDCI3): 7.01-6.90 (m, 5H), 6.72 (d, 1 H), 6.67 (d, 1 H), 6.10 (d, 1 H), 4.09 (d, 2H), 3.96 (d, 2H), 3.95 (d, 2H), 3.13 (s, 1 H), 2.79 (dd, 2H), 2.25 (s, 3H), 2.18-2.00 (m, 6H), 2.15 (s, 3H), 0.59 (t, 3H); MS (ESI-) : 549 ([M-H]").
Example 80
Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000251_0002
(1) Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid ethyl ester
Figure imgf000251_0003
To a solution of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) (200 mg, 0.52 mmol) in DMF (5 ml) were added K2C03 (144 mg, 1.04 mmol) and ethyl-5-bromovalerate (0.169 ml, 1.04 mmol) and the mixture was stirred at 70 degrees 0 for 13 h. The reaction mixture was cooled to room temperature, poured into water and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1:10) to give the title compound (170 mg, 64%).
1H-NMR (300MHz, CDCI3): 0.6 (t, 6H), 0.89 (s, 9H), 1.25 (t, 3H), 1.52 (m, 1 H), 1.81 (m, 5H), 2.05 (q, 4H), 2.16 (s,3H), 2.26 (s,3H), 2.39 (m, 2H), 2.56 (m, 1H), 2.85 (m, 1 H), 3.26 (m, 1H), 3.94 (t, 2H), 4.12 (q, 2H), 6.66 (d, 1H), 6.90 (m, 4H), 7.02 (d, 1 H).
(2) Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
To a stirred solution of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid ethyl ester (compound prepared in Example 80-(1)) (170 mg, 0.333 mmol) in MeOH (3 ml) was added 1 N-KOH (1.0ml, 1.0 mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was poured into 1 N-HCI and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS0 , filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n- Hexane (1 :3) to give the title compound (108 mg, 67%). 1H-NMR (300MHz, CDCI3): 0.6 (t, 6H), 0.89 (s, 9H), 1.52 (m, 1 H), 1.81 (m, 1 H), 1.86 (m, 4H), 2.05 (q, 4H), 2.16 (s,3H), 2.26 (s,3H), 2.46 (m, 2H), 2.56 (m, 1 H), 2.85 (m, 1 H), 3.26 (m, 1 H), 3.94 (t, 2H), 6.66 (d, 1 H), 6.90 (m, 4H), 7.02 (d, 1 H); MS (ESI-) : 481 ([M-H]").
Example 81 Preparation of 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000253_0001
(1 ) Preparation of 5-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid ethyl ester
Figure imgf000253_0002
Using the same procedure as described for the preparation of Example 80- (1 ), the title compound was prepared from 4-{1 -ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(5)). The yield was 87%.
1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 0.92 (t, 6H), 1.25 (t,3H), 1.64 (q, 4H), 1.84 (m, 4H), 2.04 (q, 4H), 2.16 (s, 3H), 2.31 (s, 3H), 2.39 (t, 2H), 3.95 (t, 2H), 4.14 (q, 2H), 5.99 (d, 1 H), 6.66 (d, 1 H), 6.74 (d, 1 H), 6.91-6.96 (m, 4H), 7.29 (d, 1 H) ; MS (ESI+) : 531 ([M+Na]+).
(2) Preparation of 5-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000253_0003
Using the same procedure as described for the preparation of Example 80- (2), the title compound was prepared from 5-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid ethyl ester (compound prepared in Example 81 -(1)). The yield was 82%. 1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 0.92 (t, 6H), 1.64 (q, 4H), 1.85 (m, 1 H), 2.04 (q, 4H), 2.15 (s, 3H), 2.31 (s, 3H), 2.46 (t, 2H), 3.95 (t, 2H), 5.99 (d, 1 H), 6.66 (d, 1 H), 6.74 (d, 1 H), 6.91-6.96 (m, 4H), 7.29 (d, 1 H) ; MS (ESI- ) : 479 ([M-H]").
Example 82
Preparation of 5-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000254_0001
Preparation of 5-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000254_0002
Using the same procedure as described for the preparation of Example 80- (1 ), 5-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-pentanoic acid ethyl ester was prepared from 4- {1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenol (compound prepared in Example 1-(4)). The yield was 53%. Using the same procedure as described for the preparation of Example 80- (2), the title compound was prepared from 5-(4-{1 -ethyl-1 -[4-(3-ethyl-3- hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid ethyl ester. The yield was 88%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.11 (t, 6H), 1.75-1.87 (m, 8H), 2.05 (q, 4H), 2.37 (s, 3H), 2.39 (s, 3H), 2.46 (td, 2H), 3.95 (t, 2H), 6.65 (d, 1 H), 6.84 (s, 1 H), 6.91 (td, 2H), 7.00 (s, 1 H), 7.27 (d, 1 H); MS (ESI-) : 477 ([M-H]" ).
Example 83 Preparation of 5-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000255_0001
(1) Preparation of 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid ethyl ester
Figure imgf000255_0002
Using the same procedure as described for the preparation of Example 80- (1), the title compound was prepared from 4-{1 -ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2- methyl-phenol (compound prepared in Example 2-(2)). The yield was 67%. 1H-NMR (300MHz, CDCI3): 7.40 (d, 1H), 7.08 (bs, 1H), 7.00 (dd, 1H), 6.90 (dd, 1H), 6.85 (bd, 1H), 6.70 (d, 1H), 5.15 (s, 2H), 4.15 (q, 2H), 3.95 (m, 2H), 3.48 (s, 3H), 2.45-2.30 (m, 5H), 2.15 (s, 3H), 2.05 (q, 4H), 1.90-1.75 (m, 4H), 1.25 (t, 3H), 0.60 (t, 6H).
(2) Preparation of 5-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid ethyl ester
Figure imgf000255_0003
To a stirred solution of 5-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid ethyl ester (compound prepared in Example 83-(1 )) (147 mg, 0.23 mmol) in i-PrOH (1.2 ml) was added CBr4(7.60 mg, 10 mol%) under N2 atmosphere at room temperature and the reaction mixture was refluxed for 6.0 h. The reaction mixture was poured into water and the products were extracted with EtOAc. The extracts were washed with water and brine, dried over anhydrous Na2S04 , filtered and evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-Hexane:EtOAc=6:1 ) to give the title compound (140 mg, 86%) as colorless sticky oil.
1H-NMR (300MHz, CDCI3): 7.40 (d, 1 H), 7.08 (bs, 1 H), 7.00 (dd, 1 H), 6.90 (dd, 1 H), 6.85 (bd, 1 H), 6.70 (d, 1 H), 4.15 (q, 2H), 3.95 (m, 3H), 2.45-2.30 (m, 5H), 2.15 (s, 3H), 2.05 (q, 4H), 1.90-1.75 (m, 4H), 1.25 (t, 3H), 0.60 (t, 6H); MS (ESI-) : 585 ([M-H]").
(3) Preparation of 5-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000256_0001
Using the same procedure as described for the preparation of Example 80- (2), the title compound was prepared from 5-(4-{1 -ethyl-1 -[3-methyl-4-(4,4 ,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid ethyl ester (compound prepared in Example 83- (2)). The yield was 80%.
1H-NMR(300MHz, CDCI3): 7.40 (d, 1 H), 7.08 (bs, 1 H), 7.00 (dd, 1 H), 6.90 (dd, 1 H), 6.85 (bd, 1 H), 6.70 (d, 1 H), 3.95 (m, 2H), 3.80 (m, 1 H), 2.50-2.35 (m, 5H), 2.15 (s, 3H), 2.05 (q, 4H), 1.90-1.75 (m, 4H), 0.60 (t, 6H); MS (ESI-) : 557 ([M-H]").
Example 84
Preparation of 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000257_0001
(1) Preparation of 5-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid ethyl ester
Figure imgf000257_0002
Using the same procedure as described for the preparation of Example 80- (1 ), the title compound was prepared from 4-{1 -ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenol (compound prepared in Example 30-(1)). The yield was 84%.
1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 1.25 (t, 3H), 1.83 (m, 4H), 2.05 (q, 4H), 2.16 (s, 3H), 2.31 (s, 3H), 2.39 (m, 2H), 3.50 (s, 3H), 3.94 (m, 2H), 4.12 (q, 2H), 4.96 (s, 2H), 6.06 (d, 1 H), 6.67 (d, 1 H), 6.88-7.03 (m, 4H), 7.35 (m, 2H).
(2) Preparation of 5-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid ethyl ester
Figure imgf000257_0003
Using the same procedure as described for the preparation of Example 83- (2), the title compound was prepared from 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-pentanoic acid ethyl ester (compound prepared in Example 84-(1)). The yield was 84%. 1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 1.25 (t, 3H), 1.83 (m, 4H), 2.05 (q, 4H), 2.15 (s, 3H), 2.34 (s, 3H), 2.39 (m, 2H), 3.18 (s, 1 H), 3.94 (m, 2H), 4.12 (q, 2H), 6.08 (d, 1H), 6.67 (d, 1 H), 6.87-7.03 (m, 4H), 7.35 (m, 2H).
(3) Preparation of 5-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000258_0001
Using the same procedure as described for the preparation of Example 80- (2), the title compound was prepared from 5-(4-{1 -ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-pentanoic acid ethyl ester (compound prepared in Example 84-(2)). The yield was 81%.
1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 1.26 (t, 3H), 1.85 (m, 4H), 2.05 (q, 4H), 2.15 (s, 3H), 2.33 (s, 3H), 2.46 (m, 2H), 3.95 (m, 2H), 6.08 (d, 1 H), 6.67 (d, 1H), 6.88-7.02 (m, 3H), 7.26-7.39 (m, 3H); MS (ESI-) : 559 ([M-H]").
Example 85
Preparation of 5-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000258_0002
(1) Preparation of 5-(4-{1 -ethyl-1 -[4-(1-hydroxy-cyclopentylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid ethyl ester
Figure imgf000258_0003
Using the same procedure as described for the preparation of Example 80- (1 ), the title compound was prepared from 4-{1 -ethyl-1 -[4-(1 -hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 7). The yield was 84%.
1H-NMR (CDCI3): 7.27 (d, 1H), 7.0 (s, 1H), 6.92 (m, 2H), 6.84 (dd, 1H), 6.65 (d, 1 H), 4.12 (q, 2H), 3.94 (m, 2H), 2.39 (m, 2H), 2.36 (s, 3H), 2.14 (s, 3H), 2.03 (m, 6H), 1.84 (m, 8H), 1.25 (m, 6H), 0.59 (t, 6H).
(2) Preparation of 5-(4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000259_0001
Using the same procedure as described for the preparation of Example 80- (2), the title compound was prepared from 5-(4-{1 -ethyl-1 -[4-(1-hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid ethyl ester (compound prepared in Example 85-(1 )). The yield was 31%.
1H-NMR (CDCI3): 7.26 (d, 1 H), 7.0 (s, 1 H), 6.92 (m, 2H), 6.84 (dd, 1 H), 6.65 (d, 1 H), 3.94 (m, 2H), 2.45 (m, 2H), 2.36 (s, 3H), 2.14 (s, 3H), 2.03 (m, 8H), 1.85 (m, 8H), 0.58 (t,6H); MS (ESI-) : 475 ([M-H]").
Example 86 Preparation of 5-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid
Figure imgf000259_0002
(1) Preparation of 5-[4-(1 -ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid ethyl ester
Figure imgf000260_0001
Using the same procedure as described for the preparation of Example 80- (1), the title compound was prepared from 4-(1 -ethyl-1 -{4-[(E)-2-(1-hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol (compound prepared in Example 10). The yield was 51 %.
1H-NMR (300MHz, CDCI3): 0.58 (t, 6H), 1.25 (t, 3H), 1.48-1.91 (m, 12H), 2.04 (q, 4H), 2.13 (s, 3H), 2.36 (s, 3H), 2.32 (t, 2H), 3.92 (t, 2H), 4.12 (q, 2H), 6.21 (d, 1H), 6.69 (d, 1H), 6.84 (d, 1H), 6.87-7.00 (m, 4H), 7.35 (d, 1H).
(2) Preparation of 5-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid
Figure imgf000260_0002
Using the same procedure as described for the preparation of Example 80- (2), the title compound was prepared from 5-[4-(1 -ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]- pentanoic acid ethyl ester (compound prepared in Example 86-(1)). The yield was 79%.
1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.32-1.79 (m, 12H), 2.05 (q, 4H), 2.15 (s, 3H), 2.31 (s, 3H), 2.46 (t, 2H), 3.95 (t, 2H), 6.25 (d, 1H), 6.65 (d, 1 H), 6.81-6.95 (m, 5H), 7.32 (d, 1H); MS (ESI-) : 477 ([M-H]").
Example 87
Preparation of 5-(4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000261_0001
(1 ) Preparation of 5-(4-{1 -ethyl-1 -[4-(1-hydroxy-cyclohexylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid ethyl ester
Figure imgf000261_0002
Using the same procedure as described for the preparation of Example 80- (1 ), the title compound was prepared from 4-{1 -ethyl-1 -[4-(1-hydroxy- cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 8). The yield was 51 %.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.25 (t, 3H), 1.52-1.79 (m, 8H), 1.85 (q, 4H), 2.03 (m, 6H), 2.15 (s, 3H), 2.38 (s, 3H), 2.38 (t, 2H), 3.95 (t, 2H), 6.66 (d, 1 H), 6.84 (s, 1H), 6.92 (td, 2H), 7.00 (s, 1 H), 7.27 (d, 1 H).
(2) Preparation of 5-(4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000261_0003
Using the same procedure as described for the preparation of Example 80- (2), the title compound was prepared from 5-(4-{1 -Ethyl-1 -[4-(1-hydroxy- cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid ethyl ester (compound prepared in Example 87-(1)). The yield was 80%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.25 (m, 1 H), 1.52-1.79 (m, 7H), 1.85 (m, 4H), 2.03 (q, 6H), 2.14 (s, 3H), 2.38 (s, 3H), 2.46 (t, 2H), 3.95 (t, 2H), 6.66 (d, 1 H), 6.84 (s, 1 H), 6.92 (td, 2H), 7.00 (s, 1 H), 7.27 (d, 1 H) ; MS (ESI-) : 489 ([M-H]'). Example 88
Preparation of 5-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid
Figure imgf000262_0001
(1) Preparation of 5-[4-(1 -ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid ethyl ester
Figure imgf000262_0002
Using the same procedure as described for the preparation of Example 80- (1 ), the title compound was prepared from 4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol (compound prepared in Example 11). The yield was 64%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.25 (t, 3H), 1.31-1.79 (m, 10H),
1.85 (m, 4H), 2.03 (q, 4H), 2.14 (s, 3H), 2.38 (s, 3H), 2.38 (t, 2H), 3.99 (t, 2H), 4.18 (q, 2H), 6.21 (d, 1 H), 6.69 (d, 1 H), 6.84 (d, 1 H), 6.87-7.00 (m, 4H),
7.35 (d, 1 H).
(2) Preparation of 5-[4-(1 -ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid
Figure imgf000262_0003
Using the same procedure as described for the preparation of Example 80- (2), the title compound was prepared from 5-[4-(1 -ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]- pentanoic acid ethyl ester (compound prepared in Example 88-(1)). The yield was 83%. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.32 (m, 1 H), 1.52-1.79 (m, 9H), 1.85 (m, 4H), 2.03 (q, 4H), 2.14 (s, 3H), 2.38 (s, 3H), 2.46 (t, 2H), 3.95 (t, 2H), 6.20 (d, 1H), 6.69 (d, 1H), 6.81 (d, 1H), 6.87-7.00 (m, 4H), 7.31 (d, 1H) ; MS (ESI-) : 491 ([M-H]').
Example 89
Preparation of 6-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl )-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid
Figure imgf000263_0001
(1) Preparation of 6-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid ethyl ester
Figure imgf000263_0002
Using the same procedure as described for the preparation of Example 80- (1), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy- pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(4)) and ethyl-6-bromohexanoate. The yield was 64%. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.11 (t, 6H), 1.25 (t, 3H), 1.44-1.57 (m, 2H), 1.64-1.85 (m, 8H), 1.98-2.07 (m, 4H), 2.14 (s, 3H), 2.33 (t, 2H), 2.37 (s,3H), 3.92 (t, 2H), 4.13 (q, 2H), 6.60 (d, 1 H, J=8.4 Hz), 6.83-6.95 (m, 3H), 7.00 (s, 1 H), 7.27 (d, 1 H, J=8.0 Hz).
(2) Preparation of 6-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid
Figure imgf000263_0003
Using the same procedure as described for the preparation of Example 80- (2), the title compound was prepared from 6-(4-{1 -ethyl-1 -[4-(3-ethyl-3- hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid ethyl ester (compound prepared in Example 89-(1 )). The yield was 85%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.11 (t, 6H), 1.49-1.59 (m, 2H), 1.67-1.85 (m, 8H), 2.03 (q, 4H), 2.14 (s, 3H), 2.36-2.42 (m, 5H), 3.92 (t, 2H), 6.66 (d, 1H, J=8.4 Hz), 6.84-6.95 (m, 3H), 7.00 (s, 1H), 7.26 (d, 1H, J=8.0 Hz); MS (ESI-) : 491 ([M-H]").
Example 90
Preparation of 6-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid
Figure imgf000264_0001
(1) Preparation of 6-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid ethyl ester
Figure imgf000264_0002
Using the same procedure as described for the preparation of Example 80- (1), the title compound was prepared from 4-{1 -ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(5)) and ethyl-6-bromohexanoate. The yield was 75%.
1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 0.91 (t, 6H),1.25 (t, 3H), 1.47-1.85 (m, 10H), 2.05 (q, 4H), 2.15 (s,3H), 2.30 (s,3H), 2.39 (t, 2H), 3.95 (t 2H), 4.13 (q, 2H), 6.00 (d, 1 H, J= 16.0 Hz), 6.66 (d, 1 H, J= 8.4 Hz), 6.74 (d, 1 H, J= 16.0 Hz), 6.90-6.96 (m, 4H), 7.29 (d, 1H, J= 8.7 Hz). (2) Preparation of 6-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid
Figure imgf000265_0001
Using the same procedure as described for the preparation of Example 80- (2), the title compound was prepared from 6-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid ethyl ester (compound prepared in Example 90-(1)). The yield was 75%.
1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 0.91 (t, 6H), 1.49-1.85 (m, 10H), 2.04 (q, 4H), 2.15 (s,3H), 2.30 (s,3H), 2.39 (t, 2H), 3.93 (t 2H), 6.00 (d, 1 H, J = 16.0 Hz), 6.66 (d, 1 H, J = 8.4 Hz), 6.74 (d, 1 H, J = 16.0 Hz), 6.90-6.96 (m, 4H), 7.29 (d, 1H, J=8.7 Hz); MS (ESI-) : 493 ([M-H]").
Example 91
Preparation of 6-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}
-2-methyl-phenoxy)-hexanoic acid
Figure imgf000265_0002
(1) Preparation of 6-(4-{1 -ethyl-1 -[3-methyl-4-(4,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxy)-hexanoic acid ethyl ester
Figure imgf000265_0003
Using the same procedure as described for the preparation of Example 80- (1), the title compound was prepared from 4-{1 -ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenol (compound prepared in Example 2-(2))and ethyl-6- bromohexanoate. The yield was 80%.
1H-NMR (300MHz, CDCI3): 7.40 (d, 1 H), 7.08 (bs, 1 H), 7.00 (dd, 1H), 6.90 (dd, 1 H), 6.85 (bd, 1 H), 6.70 (d, 1 H), 5.15 (s, 2H), 4.15 (q, 2H), 3.95 (m, 2H), 3.48 (s, 3H), 2.45-2.30 (m, 5H), 2.15 (s, 3H), 2.05 (q, 4H), 1.90-1.65 (m, 4H), 1.60-1.45 (m, 2H), 1.25 (t, 3H), 0.60 (t, 6H).
(2) Preparation of 6-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid ethyl ester
Figure imgf000266_0001
Using the same procedure as described for the preparation of Example 83- (2), the title compound was prepared from 6-(4-{1 -ethyl-1 -[3-methyl-4-(4, 4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2- methyl-phenoxy)-hexanoic acid ethyl ester (compound prepared in Example 91 -(1)). The yield was 90%.
1H-NMR (300MHz, CDCI3): 7.40 (d, 1 H), 7.08 (bs, 1 H), 7.00 (dd, 1 H), 6.90 (dd, 1H), 6.85 (bd, 1H), 6.70 (d, 1H), 4.15 (q, 2H), 3.95 (m, 3H), 2.45-2.30 (m, 5H), 2.15 (s, 3H), 2.05 (q, 4H), 1.90-1.75 (m, 4H), 1.30-1.20 (m, 5H), 0.60 (t, 6H).
(3) Preparation of 6-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl} -2-methyl-phenoxy)-hexanoic acid
Figure imgf000266_0002
Using the same procedure as described for the preparation of Example 80- (2), the title compound was prepared from 6-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxy)-hexanoic acid ethyl ester (compound prepared in Example 91 -(2)). The yield was 72%.
1H-NMR (300MHz, CDCI3): 7.40 (d, 1H), 7.08 (bs, 1H), 7.00 (dd, 1H), 6.90 (dd, 1H), 6.85 (bd, 1H), 6.70 (d, 1H), 3.95 (m, 2H), 3.80 (m, 1H), 2.50-2.35 (m, 5H), 2.15 (s, 3H), 2.05 (q, 4H), 1.90-1.70 (m, 4H), 1.65-1.50 (m, 2H), 0.60 (t, 6H); MS (ESI-) : 571 ([M-H]").
Example 92
Preparation of 6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid
Figure imgf000267_0001
(1 ) Preparation of 6-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-hexanoic acid ethyl ester
Figure imgf000267_0002
To a stirred solution of 4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenol (compound prepared in Example 30-(1)) (143 mg, 0.28 mmol) and ethyl-6-bromohexanoate (0.15 ml, 0.85 mmol) in anhydrous DMF (1.4 ml) was added K2C03 (116 mg, 0.84 mmol) under N2 atmosphere at room temperature and the mixture was stirred at 110 degrees C for 5 h. The reaction mixture was poured into water and the products were extracted with AcOEt. The extracts were washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane:EtOAc (5:1 ) to give the title compound (160 mg, 88%) as colorless sticky oil. 1H-NMR (300MHz, CDCI3): 7.50 (m, 2H), 7.15 (m, 2H), 7.00-6.85 (m, 2H), 6.70 (d, 1 H), 6.08 (d, 1H), 4.98 (s, 2H), 4.15 (q, 2H), 3.95 (t, 2H), 3.50 (s, > 3H), 2.40-2.35 (m, 6H), 2.15-2.00 (m, 4H), 1.90-1.50 (m, 8H), 1.25 (t, 3H), 0.60 (t, 6H).
(2) Preparation of 6-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid ethyl ester
Figure imgf000268_0001
To a stirred solution of 6-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-hexanoic acid ethyl ester (compound prepared in Example 92-(1 )) (160 mg, 0.25 mmol) in of EtOH (2.0 ml) was added CBr4 (13.6 mg, 10 mol%) under N2 atmosphere at room temperature and the mixture was stirred at reflux temperature for 2.5 h. The reaction mixture was cooled to room temperature, poured into water and the products were extracted with EtOAc. The extracts were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :10) to give the title compound (122 mg, 73%) as colorless sticky oil. 1H-NMR (300MHz, CDCI3): 7.35 (m, 2H), 7.05 (m, 2H), 6.95-6.85 (m, 2H), 6.68 (d, 1 H), 6.10 (d, 1H), 4.15 (q, 2H), 3.95 (t, 2H), 3.20 (bs, 1 H), 2.40-2.30 (m, 5H), 2.15 (s, 3H), 2.05 (q, 4H), 1.85-1.65 (m, 4H), 1.60-1.45 (m, 2H), 1.25 (t, 3H), 0.60 (t, 6H).
(3) Preparation of 6-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid
Figure imgf000269_0001
To a stirred solution of 6-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4 ,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- hexanoic acid ethyl ester (compound prepared in Example 92-(2)) (122 mg, 0.20 mmol) in EtOH/Water (4/1 v/v, 2.5 ml) was added KOH (23.0 mg, 0.41 mmol) and the mixture was stirred at room temperature for 4 h. The reaction mixture was poured into 0.1 N HCl and the products were extracted with EtOAc. The extracts were washed with brine, dried over Na2Sθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :2) to give the title compound (90 mg, 78%) as colorless sticky oil.
1H-NMR (300MHz, CDCI3): 7.35 (m, 2H), 7.05 (m, 2H), 6.95-6.85 (m, 2H), 6.68 (d, 1 H), 6.10 (d, 1H), 3.95 (t, 2H), 2.40-2.30 (m, 5H), 2.15 (s, 3H), 2.05 (q, 4H), 1.85-1.65 (m, 4H), 1.60-1.45 (m, 2H), 0.60 (t, 6H); MS (ESI") : 573 ([M-H]').
Example 93
Preparation of 6-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid
Figure imgf000269_0002
(1 ) Preparation of 6-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid ethyl ester
Figure imgf000269_0003
To a solution of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) (200 mg, 0.52 mmol) in DMF (5 ml) were added K2CO3 (144 mg, 1.04 mmol) and 6-bromohexanoic acid ethyl ester (0.184 ml, 1.04 mmol) and the mixture was stirred at 50 degrees 0 for 13 h. The reaction mixture was cooled to room temperature, poured into water and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :10) to give the title compound (214 mg, 78%).
1H-NMR (300MHz, CDCI3): 0.6 (t, 6H), 0.89 (s, 9H), 1.29 (m, 3H), 1.52 (m, 3H), 1.81 (m, 5H), 2.05 (q, 4H), 2.16 (s,3H), 2.26 (s,3H), 2.35 (t, 2H), 2.56 (m, 1 H), 2.85 (m, 1 H), 3.26 (m, 1H), 3.92 (t, 2H), 4.12 (q, 2H), 6.66 (d, 1 H), 6.90 (m, 4H), 7.02 (d, 1 H).
(2) Preparation of 6-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid
Figure imgf000270_0001
To a stirred solution of 6-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid ethyl ester (compound prepared in Example 93-(1)) (214 mg, 0.408 mmol) in MeOH (3 ml) was added 1 N-KOH (1.22 ml, 1.22 mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was poured into 1 N-HCI and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n- Hexane (1 :3) to give the title compound (144 mg, 71%). 1H-NMR (300MHz, CDCI3): 0.6 (t, 6H), 0.89 (s, 9H), 1.52 (m, 3H), 1.81 (m, 5H), 2.05 (q, 4H), 2.16 (s,3H), 2.26 (s,3H), 2.39 (t, 2H), 2.56 (m, 1 H), 2.85 (m, 1 H), 3.26 (m, 1H), 3.92 (t, 2H), 6.66 (d, 1H), 6.90 (m, 4H), 7.02 (d, 1 H); MS (ESP) : 495 ([M-H]").
Example 94 Preparation of 6-(4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid
Figure imgf000271_0001
(1) Preparation of 6-(4-{1 -ethyl-1 -[4-(1-hydroxy-cyclopentylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid ethyl ester
Figure imgf000271_0002
To a solution of 4-{1 -ethyl-1 -[4-(1-hydroxy-cyclopentylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 7) (114 mg, 0.303 mmol) in DMF (5 ml) were added K2C03 (126 mg, 0.908 mmol) and 6-bromo-hexanoic acid ethyl ester (135 mg, 0.606 mmol) and the mixture was stirred at 90 degrees C for 6 h. The reaction mixture was cooled to room temperature, poured into water and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :6) to give the title compound (71 mg, 45%).
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.25 (t, 3H), 1.31-1.79 (m, 10H), 1.85 (m, 4H), 2.03 (q, 4H), 2.14 (s, 3H), 2.30 (t, 2H), 2.36 (s, 3H), 3.99 (t, 2H), 4.18 (q, 2H), 6.68 (d, 1H), 6.84 (m, 2H), 6.91 (d, 1H), 7.00 (s, 1H), 7.27 (d, 1H).
(2) Preparation of 6-(4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid
Figure imgf000271_0003
To a stirred solution of 6-(4-{1 -ethyl-1 -[4-(1-hydroxy-cyclopentylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid ethyl ester (compound prepared in Example 94-(1)) (71 mg, 0.137 mmol) in MeOH (1.4 ml) was added 1 N-KOH (0.41 ml, 0.411 mmol) and the mixture was stirred at room temperature for 18 h. The reaction mixture was poured into 1 N-HCI and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :2) to give the title compound (56.6 mg, 84%). 1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.32-1.79 (m, 14H), 2.03 (q, 4H), 2.14 (s, 3H), 2.37 (s, 3H), 2.40 (t, 2H), 3.91 (t, 2H), 6.68 (d, 1 H), 6.84 (m, 2H), 6.91 (d, 1 H), 7.00 (s, 1H), 7.27 (d, 1H); MS (ESI-) : 489 ([M-H]").
Example 95
Preparation of 6-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid
Figure imgf000272_0001
(1) Preparation of 6-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hyd roxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid ethyl ester
Figure imgf000272_0002
To a solution of 4-(1 -ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenol (compound prepared in Example 10) (110 mg, 0.291 mmol) in DMF (5 ml) were added K2C03 (120 mg, 0.872 mmol) and 6-bromo-hexanoic acid ethyl ester (130 mg, 0.582 mmol) and the mixture was stirred at 90 degrees C for 6 h. The reaction mixture was cooled to room temperature, poured into water and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :7) to give the title compound (73 mg, 48%).
1H-NMR (300MHz, CDCI3): 0.58 (t, 6H), 1.25 (t, 3H), 1.39-1.88 (m, 14H), 2.03 (q, 4H), 2.13 (s, 3H), 2.30 (t, 2H), 2.38 (s, 3H), 3.92 (t, 2H), 4.12 (q, 2H), 6.21 (d, 1H), 6.69 (d, 1 H), 6.84 (d, 1H), 6.87-7.00 (m, 4H), 7.35 (d, 1H).
(2) Preparation of 6-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid
Figure imgf000273_0001
To a stirred solution of 6-[4-(1 -ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclopentyl)- vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid ethyl ester (compound prepared in Example 95-(1)) (73 mg, 0.140 mmol) in MeOH (1.4 ml) was added 1 N-KOH (0.42 ml, 0.420 mmol) and the mixture was stirred at room temperature for 18 h. The reaction mixture was poured into 1 N-HCI and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :2) to give the title compound (60 mg, 87%). 1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.32-1.79 (m, 14H), 2.03 (q, 4H), 2.14 (s, 3H), 2.31 (s, 3H), 2.40 (t, 2H), 3.93 (t, 2H), 6.25 (d, 1 H), 6.65 (d, 1 H), 6.81-6.96 (m, 5H), 7.31 (d, 1 H); MS(ESI-) : 491 ([M-H]').
Example 96 Preparation of 6-(4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid
Figure imgf000273_0002
(1) Preparation of 6-(4-{1 -ethyl-1 -[4-(1-hydroxy-cyclohexylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid ethyl ester
Figure imgf000274_0001
To a solution of 4-{1 -ethyl-1 -[4-(1-hydroxy-cyclohexylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 8) (110 mg, 0.28 mmol) in DMF (3 ml) were added K2C03 (116 mg, 0.84 mmol) and 6-bromo-hexanoic acid ethyl ester (0.1 ml, 0.56 mmol) and the mixture was stirred at 90 degrees C for 13 h. The reaction mixture was cooled to room temperature, poured into saturated NH4CI aq. and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :6) to give the title compound (133 mg, 89%). 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.25 (t, 3H), 1.49-1.82 (m, 16H), 2.03 (q, 4H), 2.14 (s, 3H), 2.33 (t, 2H), 2.38 (s, 3H), 3.92 (t, 2H), 4.12 (q, 2H), 6.66 (d, 1 H), 6.84-7.01 (m, 4H), 7.27 (d, 1 H).
(2) Preparation of 6-(4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid
Figure imgf000274_0002
To a stirred solution of 6-(4-{1 -ethyl-1 -[4-(1-hydroxy-cyclohexylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid ethyl ester (compound prepared in Example 96-(1)) (133 mg, 0.25 mmol) in MeOH (2 ml) was added 1 N-KOH (0.75 ml, 0.75 mmol) and the mixture was stirred at room temperature for 13 h. The reaction mixture was poured into saturated NH4CI aq. and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS0 , filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :2) to give the title compound (95 mg, 75%). 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.43-1.82 (m, 16H), 2.03 (q, 4H), 2.14 (s, 3H), 2.38 (s, 3H), 2.40 (t, 2H), 3.93 (t, 2H), 6.66 (d, 1 H), 6.84-7.01 (m, 4H), 7.27 (d, 1 H); MS (ESI-) : 503 ([M-H]").
Example 97
Preparation of 6-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid
Figure imgf000275_0001
(1 ) Preparation of 6-[4-(1 -ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid ethyl ester
Figure imgf000275_0002
To a solution of 4-(1 -ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenol (compound prepared in Example 11 ) (96.6 mg, 0.246 mmol) in DMF (3 ml) were added K2C03 (102 mg, 0.738 mmol) and 6-bromo-hexanoic acid ethyl ester (110 mg, 0.492 mmol) and the mixture was stirred at 90 degrees C for 12 h. The reaction mixture was cooled to room temperature, poured into water and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :6) to give the title compound (112 mg, 85%).
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.25 (t, 3H), 1.31-1.79 (m, 12H), 1.85 (m, 4H), 2.03 (q, 4H), 2.14 (s, 3H), 2.30 (s, 3H), 2.38 (t, 2H), 3.92 (t, 2H), 4.3 (q, 2H), 6.19 (d, 1 H), 6.65 (d, 1 H), 6.82 (d, 1 H), 6.89-7.00 (m, 4H), 7.32 (d, 1 H) ; MS (ESI+) : 557 ([M+Na]+). (2) Preparation of 6-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid
Figure imgf000276_0001
To a stirred solution of 6-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)- vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid ethyl ester (compound prepared in Example 97-(1)) (112 mg, 0.209 mmol) in MeOH (2.1 ml) was added 1 N-KOH (0.63 ml, 0.63 mmol) and the mixture was stirred at room temperature for 12 h. The reaction mixture was poured into saturated NH4CI aq. and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :2) to give the title compound (76 mg, 71%). 1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.32-1.79 (m, 16H), 2.03 (q, 4H), 2.14 (s, 3H), 2.30 (s, 3H), 2.40 (t, 2H), 3.93 (t, 2H), 6.19 (d, 1 H), 6.65 (d, 1 H), 6.80 (d, 1 H), 6.9-6.95 (m, 4H), 7.30 (d, 1 H); MS (ESI-) : 505 ([M-H]").
Example 98
Preparation of 7-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-heptanoic acid
Figure imgf000276_0002
(1 ) Preparation of 7-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-heptanoic acid ethyl ester
Figure imgf000276_0003
To a solution of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) (200 mg, 0.52 mmol) in DMF (5 ml) were added K2CO3 (144 mg, 1.04 mmol) and 7-bromoheptanoic acid ethyl ester (0.202 ml, 1.04 mmol) and the mixture was stirred at 50 degrees C for 13 h. The reaction mixture was cooled to room temperature, poured into water and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :10) to give the title compound (231 mg, 83%).
1H-NMR (300MHz, CDCI3): 0.6 (t, 6H), 0.89 (s, 9H), 1.29 (m, 3H), 1.45 (m, 5H), 1.69 (m, 2H), 1.81 (m, 3H), 2.05 (q, 4H), 2.16 (s,3H), 2.26 (s,3H), 2.31 (t, 2H), 2.56 (m, 1H), 2.85 (m, 1H), 3.26 (m, 1H), 3.92 (t, 2H), 4.12 (q, 2H), 6.66 (d, 1H), 6.90 (m, 4H), 7.02 (d, 1H).
(2) Preparation of 7-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-heptanoic acid
Figure imgf000277_0001
To a stirred solution of 7-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-heptanoic acid ethyl ester
(compound prepared in Example 98-(1)) (231 mg, 0.429 mmol) in MeOH (3 ml) was added 1 N-KOH (1.29 ml, 1.29 mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was poured into 1 N-HCI and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n- Hexane (1 :3) to give the title compound (153 mg, 70%). 1H-NMR (300MHz, CDCI3): 0.6 (t, 6H), 0.89 (s, 9H), 1.45 (m, 5H), 1.69 (m, 2H), 1.81 (m, 3H), 2.05 (q, 4H), 2.16 (s,3H), 2.26 (s,3H), 2.38 (t, 2H), 2.56 (m, 1H), 2.85 (m, 1H), 3.26 (m, 1H), 3.91 (t, 2H), 6.66 (d, 1H), 6.90 (m, 4H), 7.02 (d, 1H); MS (ESI-) : 509 ([M-H]").
Example 99 Preparation of 1 -(4-{1 -[4-(2-amino-ethoxy)-3-methyl-phenyl]-1 -ethyl-propyl}- 2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000278_0001
Preparation of 1 -(4-{1 -[4-(2-amino-ethoxy)-3-methyl-phenyl]-1 -ethyl-propyl}- 2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000278_0002
To a solution of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) (100 mg, 0.261 mmol) in THF-DMF(5:1 , 0.45 ml) was added NaH (46 mg, 1.17 mmol) at 0 degrees C and the mixture was stirred at room temperature for 15 min. Then bromoethylamine HBr salt (79 mg, 0.391 mmol) was added and the mixture was stirred at 55 degrees C for 1.5 h. The reaction mixture was cooled to 0 degrees C, neutralized to pH7 with sat. NH4CI aq. The reaction mixture was poured into water and the products were extracted with EtOAc. The extracts were washed with brine, dried over Na2Sθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on amino functionalized silica gel with EtOAc-n-Hexane (3:1) to give the title compound (55 mg, 50%).
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.43-1.57 (m, 1H), 1.74-1.84 (m, 1H), 2.03 (q, 4H), 2.17(s, 3H), 2.25 (s, 3H), 2.50-2.60 (m, 1H), 2.81-2.91 (m, 1 H), 3.07 (t, 2H), 3.24 (d, 1 H), 3.96 (t, 2H), 6.68 (d, 1 H), 6.90- 6.96 (m, 4H), 7.01 (d, 1H); MS (ESI+) : 426 ([M+H]+). Example 100
Preparation of 1 -(4-{1 -[4-(3-amino-propoxy)-3-methyl-phenyl]-1 -ethyl-propyl}-
2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000279_0001
(1 ) Preparation of 2-[3-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propyl]-isoindole-1 ,3-dione
Figure imgf000279_0002
To a solution of 4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) (340 mg, 0.915 mmol) in acetonitrile (9 ml) were added K2C03 (253 mg, 1.83 mmol) and N-(3-bromopropyl)phthalimide (491 mg, 1.83 mmol) and the mixture was stirred at reflux temperature for 5 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water and brine, dried over Na2S0 , filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :6) to give the title compound (460 mg, 88%).
1H-NMR (300MHz, CDCI3): 0.58 (t, 6H), 0.89 (s, 9H), 1.37 (d, 1H), 1.42-1.53 (m, 1H), 1.78-1.84 (m,1H), 2.04 (q, 4H), 2.11(s, 3H), 2.14-2.21 (m, 2H), 2.25 (s, 3H), 2.50-2.60 (m, 1H), 2.77-2.92 (m, 1H), 3.21-3.27 (dd, 1H), 3.91 (t,
2H), 4.00 (t, 2H), 6.66 (d, 1H), 6.88-6.92 (m, 4H), 7.00 (d, 1H), 7.68-7.71 (m, 2H), 7.82-7.85 (m, 2H); MS (ESI+) : 587 ([M+NH4]+).
(2) Preparation of 1-(4-{1-[4-(3-amino-propoxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000280_0001
To a solution of 2-[3-(4-{1 -ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propyl]-isoindole-1 ,3-dione (compound prepared in Example 100-(1)) (460 mg, 0.807 mmol) in EtOH (6 ml) was added hydrazine hydrate(0.4 ml, 8.07 mmol) and the mixture was stirred at reflux temperature for 1 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure. The obtained residue was diluted with EtOAc, and filtered. The filtrate was concentrated, and purified by amino fu notional ized silica gel chromatography (EtOAc-n- Hexane=1 :1 to EtOAc) to give the title compound (264 mg, 74%).
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.43-1.57 (m, 1 H), 1.74-1.84 (m, 1 H), 1.92 (q, 2H), 2.03 (q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.49- 2.62 (m, 1H), 2.81-2.89 (m, 1H), 2.92 (t, 2H), 3.23 (dd, 1H), 4.01 (t, 2H), 6.68 (d, 1 H), 6.90-6.96 (m, 4H), 7.01 (d, 1 H); MS (ESI+) : 440 ([M+H]+).
Example 101
Preparation of 1 -(4-{1 -[4-(4-amino-butoxy)-3-methyl-phenyl]-1 -ethyl-propyl}-
2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000280_0002
(1 ) Preparation of 2-[4-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-butyl]-isoindole-1 ,3-dione
Figure imgf000280_0003
Using the same procedure as described for the preparation of Example 100-(1), the title compound was prepared from 4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) and N-(4-bromobutyl)phthalimide. The yield was
97%.
1H-NMR (300MHz, CDCI3): 0.58 (t, 6H), 0.88 (s, 9H), 1.39 (d, 1 H), 1.44-1.55
(m, 1 H), 1.74-1.96 (m, 5H), 2.03 (q, 4H), 2.14 (s, 3H), 2.25 (s, 3H), 2.49-2.62
(m, 1 H), 2.79-2.92 (m, 1 H), 3.23 (dd, 1 H), 3.77 (t, 2H), 3.96 (t, 2H), 6.64 (d,
1 H), 6.87-6.95 (m, 4H), 7.00 (d, 1 H), 7.65-7.75 (m, 2H), 7.78-7.87 (m, 2H);
MS (ESI+) : 601 ([M+NH4]+).
(2) Preparation of 1-(4-{1-[4-(4-amino-butoxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000281_0001
Using the same procedure as described for the preparation of Example 100-(2), the title compound was prepared from 2-[4-(4-{1 -ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- butyl]-isoindole-1 ,3-dione (compound prepared in Example 101-(1)). The yield was 87%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.44-1.59 (m, 1 H), 1.59-1.70 (m, 2H), 1.72-1.88 (m, 3H), 2.03 (q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.48-2.62 (m, 1 H), 2.75 (t, 2H), 2.80-2.92 (m, 1 H), 3.24 (dd, 1 H), 3.94 (t, 2H), 6.64 (d, 1H), 6.88-6.96 (m, 4H), 7.01 (d, 1 H); MS (ESI+) : 454 ([M+H]+).
Example 102
Preparation of 1 -(4-{1 -[4-(5-amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000281_0002
(1 preparation of 2-[5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentyl]-isoindole-1 ,3-dione
Figure imgf000282_0001
Using the same procedure as described for the preparation of Example 100-(1), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) and N-(5-bromopentyl)phthalimide. The yield was 99%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.38 (d, 1H), 1.45-1.58 (m, 3H), 1.71-1.87 (m, 5H), 2.06 (q, 4H), 2.11 (s, 3H), 2.25 (s, 3H), 2.50-2.61 (m, 1 H), 2.80-2.90 (m, 1 H), 3.24 (dd, 1H), 3.72 (t, 2H), 3.91 (t, 2H), 6.64 (d, 1 H), 6.85-6.95 (m, 4H), 7.01 (d, 1H), 7.66-7.72 (m, 2H), 7.78-7.88 (m, 2H); MS (ESI+) : 615 ([M+NH4]+).
(2) Preparation of 1-(4-{1-[4-(5-amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000282_0002
Using the same procedure as described for the preparation of Example 100-(2), the title compound was prepared from 2-[5-(4-{1 -ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- pentyl]-isoindole-1 ,3-dione (compound prepared in Example 102-(1)). The yield was 87%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.45-1.56 (m, 5H), 1.74-1.84 (m, 3H), 2.03 (q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.50-2.60 (m, 1 H), 2.72 (t, 2H), 2.80-2.90 (m, 1 H), 3.24 (dd, 1 H), 3.92 (t, 2H), 6.67 (d, 1 H), 6.85-6.96 (m, 4H), 7.02 (d, 1 H); MS (ESI+) : 468 ([M+H]+).
Example 103 Preparation of 1 -(4-{1 -[4-(6-amino-hexyloxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000283_0001
(1 ) Preparation of 2-[6-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexyl]-isoindole-1 ,3-dione
Figure imgf000283_0002
Using the same procedure as described for the preparation of Example 100-(1), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) and N-(6-bromohexyl)phthalimide. The yield was 99%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.36-1.56 (m, 5H), 1.65-1.85 (m, 5H), 2.03 (q, 4H), 2.13 (s, 3H), 2.25 (s, 3H), 2.50-2.60 (m, 1H), 2.81-2.90 (m, 1H), 3.24 (dd, 1 H), 3.69 (t, 2H), 3.90 (t, 2H), 6.65 (d, 1 H), 6.89- 6.93 (m, 4H), 7.01 (d, 1H), 7.65-7.74 (m, 2H), 7.78-7.87 (m, 2H); MS (ESI+) : 629 ([M+NH4]+).
(2) Preparation of 1-(4-{1-[4-(6-Amino-hexyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000283_0003
Using the same procedure as described for the preparation of Example 100-(2), the title compound was prepared from 2-[6-(4-{1 -ethyl-1 -[4-(3- hyd roxy-4, 4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- hexyl]-isoindole-1 ,3-dione (compound prepared in Example 103-(1)). The yield was 60%. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.35-1.56 (m, 7H), 1.74-1.84 (m, 3H), 2.03 (q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.50-2.60 (m, 1 H), 2.70 (t, 2H), 2.81-2.91 (m, 1 H), 3.24 (dd, 1 H), 3.92 (t, 2H), 6.67 (d, 1 H), 6.90- 6.95 (m, 4H), 7.01 (d, 1H); MS (ESI+) : 482 ([M+H]+).
Example 104
Preparation of 3-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenyl)-propionic acid
Figure imgf000284_0001
(1 ) Preparation of 3-ethyl-1 -trimethylsilanyl-pent-1 -yn-3-ol ^ — TMS *- TMS =-: ^-OH To a solution of TMS-acetylene (1.55g, 15.78mmol) in THF (20 ml) under nitrogen atmosphere at -40 degrees C were added n-BuLi (7.5 mL, 18.93mmol, 2.5M in hexane) and 3-pentanone (2.0 mL, 18.93 mmol) and the mixture was stirred for 3 h. The reaction mixture was diluted with diethyl ether, washed with sat. NH4CI aq., water and brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :15) to give the title compound (2.8 g, 96%). 1H NMR (CDCI3): 1.86 (br, OH), 1.65 (m, 4H), 1.02 (t, 6H), 0.16 (s, 9H).
(2) Preparation of 3-ethyl-pent-1-yn-3-ol TMS-^≡ — < OH *■ ≡= — ^OH To a solution of 3-ethyl-1 -trimethylsilanyl-pent-1 -yn-3-ol (compound prepared in Example 104-(1)) (920 mg, 4.99 mmol) in diethyl ether (10 ml) under nitrogen atmosphere at 0 degrees C was added TBAF (7.48mL, 7.48mmol, 1.0M in THF) and the mixture was stirred for 2 h. The reaction mixture was diluted with diethyl ether, and washed with sat. NH4CI aq., H20 and brine, and dried over MgS0 , filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :10) to give the title compound (200 mg, 35%). 1H NMR (CDCI3): 2.43 (s, 1H), 1.88 (br, OH), 1.69 (m, 4H), 1.04 (t, 6H).
(3) Preparation of 3-{4-[1 -ethyl-1 -(3-methyl-4-trifluoromethanesulfonyloxy- phenyl)-propyl]-2-methyl-phenyl}-propionic acid methyl ester
Figure imgf000285_0001
To a solution of 3-{4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- methyl-phenyl}-propionic acid methyl ester (compound prepared in Example 18-(2)) (1.81 g, 5.1 mmol) in anhydrous CH2CI2 (30 ml) under nitrogen atmosphere at room temperature were added trifluoromethanesulfonic anhydride (1.3 ml, 7.65 mmol) and pyridine (1.3 ml, 15.3 mmol). After stirring 1.5 h at room temperature, the mixture was poured into sat. NH4CI aq. and the products were extracted with CH2CI2. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on amino functionalized silica gel with EtOAc-n-Hexane (1 :10) to give the title compound (2.0 g, 80%).
1H NMR (CDCI3): 7.11-6.99 (m, 4H), 6.88 (m, 2H), 3.67 (s, 3H), 2.90 (dt, 2H), 2.58 (dt, 2H), 2.31 (s, 3H), 2.26 (s, 3H), 2.04 (q, 4H), 0.59 (t, 6H).
(4) Preparation of 3-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid methyl ester
Figure imgf000285_0002
To a solution of 3-{4-[1 -ethyl-1 -(3-methyl-4-trifluoromethanesulfonyloxy- phenyl)-propyl]-2-methyl-phenyl}-propionic acid methyl ester (compound prepared in Example 104-(3)) (100mg, 0.2mmol) in anhydrous CH3CN (2m) under nitrogen atmosphere were added Pd(PPh3)4 (46 mg, 0.04 mmol), Cul (7.6 mg, 0.04 mmol), triethylamine (0.083 ml, 0.6 mmol) and 3-ethyl-pent-1- yn-3-ol (compound prepared in Example 104-(2)) (200 mg, 1.78 mmol). After stirring overnight at 100 degrees C, the mixture was poured into sat. NH4CI aq. and the products were extracted with diethyl ether. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on amino functionalized silica gel with EtOAc-n-Hexane (1 :15) to give the title compound (40 mg, 44%).
1H NMR (CDCI3): 7.01-6.88 (m, 6H), 3.67 (s, 3H), 2.89 (dt, 2H), 2.57 (dt, 2H), 2.37 (s, 3H), 2.24 (s, 3H), 2.04 (q, 4H), 1.69 (q, 4H), 1.10 (t, 6H), 0.58 (t, 6H).
(5) Preparation of 3-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid
Figure imgf000286_0001
To a solution of 3-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenyl)-propionic acid methyl ester (compound prepared in Example 104-(4)) (40 mg, 0.089 mmol) in MeOH- H20 (10:1 , 1.1 ml) was added KOH as 0.5 tablets and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into sat. NH4CI aq. and the products were extracted with diethyl ether. The extracts were washed with water and brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on amino functionalized silica gel with C^C /MeOH (20:1) to give the title compound (19 mg, 49%). 1H NMR (CDCI3): 7.37 (d, 1H), 6.98 (m, 2H), 6.90 (m, 3H), 2.89 (dt, 2H), 2.60 (dt, 2H), 2.36 (s, 3H), 2.22 (s, 3H), 2.04 (q, 4H), 1.75 (m, 4H), 1.10 (t, 6H), 0.58 (t, 6H); MS (ESI-) : 433 ([M-H]").
Example 105
Preparation of 3-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid
Figure imgf000287_0001
(1 ) Preparation of 3-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid methyl ester
Figure imgf000287_0002
To a solution of 3-{4-[1 -ethyl-1 -(3-methyl-4-trifluoromethanesulfonyloxy- phenyl)-propyl]-2-methyl-phenyl}-propionic acid methyl ester (compound prepared in Example 104-(3)) (170mg, 0.35mmol) in anhydrous DMF (4 ml) under nitrogen atmosphere were added triethylamine (0.058 ml, 0.42 mmol), 3-ethyl-pent-1-en-3-ol (1.0 g, 8.75 mmol), 1 ,3- bis(diphenylphosphine)propane (36 mg, 0.08 mmol) and palladium acetate (15.6 mg, 0.07 mmol). After stirring overnight at 100 degrees C, the reaction mixture was poured into water and the products were extracted with diethyl ether. The extracts were washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on amino functionalized silica gel with EtOAc-n- Hexane (1 :10) to give the title compound (10 mg, 5%). 1H NMR (CDCI3); 6.95 (m, 6H), 6.74 (d, 1 H), 6.00 (d, 1 H), 3.67 (s, 3H), 2.89 (dt, 2H), 2.57 (dt, 2H), 2.30 (s, 3H), 2.25 (s, 3H), 2.04 (q, 4H), 1.649 (q, 4H), 0.91 (t, 6H), 0.60 (t, 6H). (2) Preparation of 3-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid
Figure imgf000288_0001
To a solution of 3-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid methyl ester (compound prepared in Example 105-(1)) (10 mg, 0.022 mmol) in MeOH- H20 (10:1 , 1.1 ml) was added KOH as 0.5 tablets and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into sat. NH4CI aq. and the products were extracted with diethyl ether. The extracts were washed with water and brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on amino functionalized silica gel with CH2Cl2/MeOH (20:1) to give the title compound (7.6 mg, 79%).
1H NMR (CDCI3): 6.95 (m, 6H), 6.74 (d, 1 H), 6.00 (d, 1 H), 2.90 (t, 2H), 2.62 (t, 2H), 2.30 (s, 3H), 2.25 (s, 3H), 2.04 (q, 4H), 1.63 (q, 4H), 0.91 (t, 6H), 0.60 (t, 6H); MS (ESI-) : 435([M-H]").
Example 106
Preparation of 3-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid
Figure imgf000288_0002
(1) Preparation of Trifluoro-methanesulfonic acid 4-{1 -ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenyl ester
Figure imgf000288_0003
To a solution of 4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy- 3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 2-(2)) (400 mg, 0.8 mmol) in dichloromethane (4 ml), Tf20 (0.15 ml, 0.89 mmol) and pyridine (0.13 ml, 1.6 mmol) were added at 0 degrees C and the mixture was stirred at 0 degrees C for 2 h. The reaction mixture was poured into water and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :20) to give the title compound (410 mg, 81 %)
1H-NMR (CDCI3): 0.60 (t, 6H, J= 7.3 Hz), 2.07 (q, 4H, J= 7.3 Hz), 2.32 (s, 3H), 2.41 (s, 3H), 3.48 (s, 3H), 5.15 (s, 2H), 6.90-7.05 (m, 4H), 7.11 (d, 1 H, J= 9.2 Hz), 7.40 (d, 1H, J= 8.1 Hz).
(2) Preparation of (E)-3-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenyl)-acrylic acid methyl ester
Figure imgf000289_0001
To a solution of Trifluoro-methanesulfonic acid 4-{1 -ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenyl ester (compound prepared in Example 106-(1 )) (136 mg, 0.214 mmol) in DMF (2 ml) were added Pd(OAc)2 (10 mg, 0.0429 mmol), dppp (22 mg, 0.0535 mmol), Et3N (0.036 ml, 0.214 mmol) and ethylacrylae (0.029 ml, 0.321 mmol) and the mixture was stirred at 110 degrees C for 5 h. The reaction mixture was cooled to room temperature, poured into water and the products were extracted with EtOAc The extracts were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :15) to give the title compound (53 mg, 43%) H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 2.07 (q, 4H), 2.37 (s, 3H), 2.38 (s, 3H), 3.46 (s, 3H), 3.79 (s, 3H), 5.13 (s, 2H), 6.31 (d, 1 H), 6.94-7.03 (m, 4H), 7.36-7.44 (m, 2H), 7.92 (d, 1 H).
(3) Preparation of 3-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenyl)-propionic acid methyl ester
Figure imgf000290_0001
To a solution of (E)-3-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenyl)-acrylic acid methyl ester (compound prepared in Example 106-(2)) (36 mg, 0.0631 mmol) in CH2CI (2 ml) and MeOH (4 ml) at 0 degrees C were added NiCI2-6H20 (30 mg, 0.126 mmol), and NaBH4 (51 mg, 1.33 mmol) and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into sat. NH4CI aq. and the products were extracted with EtOAc. The extracts were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :25) to give the title compound (30 mg, 84%).
1H-NMR (300MHz, CDCI3): 0.52 (t, 6H), 1.99 (q, 4H), 2.17 (s, 3H), 2.32 (s, 3H), 2.50 (t, 2H), 2.82 (t, 2H), 3.40 (s, 3H), 3.60 (s, 3H), 5.13 (s, 2H), 6.79- 6.98 (m, 5H), 7.29 (d, 1H); MS (ESI+) : 573 ([M+H]+).
(4) Preparation of 3-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid methyl ester
Figure imgf000290_0002
To a solution of 3-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenyl)-propionic acid methyl ester (compound prepared in Example 106- (3)) (35 mg, 0.0611 mmol) in i-PrOH (0.8 ml) were added CBr4 (2 mg, 0.0061 mmol) and the mixture was refluxed overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1:8) to give the title compound (28 mg, 86%).
1H-NMR (300MHz, CDCI3): 0.58 (t, 6H), 2.05 (q, 4H), 2.24 (s, 3H), 2.38 (s, 3H), 2.52 (t, 2H), 2.89 (m, 2H), 3.67 (s, 3H), 6.85-7.05 (m, 5H), 7.34 (d, 1 H).
(5) Preparation of 3-(4-{1 -ethyl-1 -[3-methyl-4-(4,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid
Figure imgf000291_0001
To a solution of 3-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid methyl ester (compound prepared in Example 106-(4)) (30 mg, 0.0539 mmol) in MeOH (1 ml) was added 1 N- KOH(0.2 ml, 0.2 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was poured into sat. NH4CI aq. and the products were extracted with EtOAc. The extracts were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with C^C -MeOH (20:1 ) to give the title compound (22 mg, 75%). 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 2.05 (q, 4H), 2.24 (s, 3H), 2.38 (s, 3H), 2.61 (t, 2H), 2.90 (t, 2H), 3.67 (s, 3H), 6.87-7.05 (m, 5H), 7.34 (d, 1 H); MS (ESI-) : 513 ([M-H]").
Example 107 Preparation of 3-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid
Figure imgf000292_0001
(1) Preparation of trifluoro-methanesulfonic acid 4-{1 -ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenyl ester
Figure imgf000292_0002
To a stirred solution of 4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenol (compound prepared in Example 30-(1)) (394 mg, 0.78 mmol) in 7.80 ml of CH2CI2 were added Tf20 (0.197 ml, 1.17 mmol) and Et3N at -30 degrees C under N2 atmosphere. After stirred for 1 h, the reaction mixture was quenched with 30 ml of sat. NaHCθ3 aq. and the products were extracted with CH2CI2. The extracts were washed with brine, dried over anhydrous Na2S04, filtered and evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (n- Hexane:EtOAc=5:1) to give the title compound (440 mg, 88.7%) as colorless oil. 1H-NMR (300MHz, CDCI3): 7.40-7.30 (m, 2H), 7.15-6.95 (m, 5H), 6.10 (d, 1 H), 5.00 (s, 2H), 3.50 (s, 3H), 2.35 (s, 6H), 2.10 (q, 4H), 0.60 (t, 6H).
(2) Preparation of (E)-3-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-acrylic acid ethyl ester
Figure imgf000292_0003
To a stirred solution of trifluoro-methanesulfonic acid 4-{1 -ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)- phenyl]-propyl}-2-methyl-phenyl ester (compound prepared in Example 107- (1 )) (234 mg, 0.37 mmol) in DMF (3.7 ml) were added Pd(OAc)2 (16.6 mg, 20 mol%), dppp (38.2 mg, 25 mol%), ethylacrylate (0.40 ml, 3.70 mmol) and Et3N (0.103 ml, 0.74 mmol) at room temperature under N2 atmosphere. Then the reaction mixture was stirred at 110 degrees C for 16 h. The reaction mixture was cooled to room temperature, poured into water and the products were extracted with EtOAc. The extracts were dried over anhydrous Na2S04, filtered and evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-Hexane:EtOAc=10:1) to give the title compound (138 mg, 63.6%) as colorless sticky oil. 1H-NMR(300MHz, CDCI3): 7.95 (d, 1 H), 7.50-7.35 (m, 3H), 7.05-6.95 (m, 4H), 6.35 (d, 1 H), 6.08 (d, 1H), 5.00 (s, 2H), 4.25 (q, 2H), 3.50 (s, 3H), 2.40 (s, 3H), 2.35 (s, 3H), 2.10 (q, 4H), 1.35 (t, 3H), 0.60 (t, 6H).
(3) Preparation of 3-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-propionic acid ethyl ester
Figure imgf000293_0001
To a stirred solution of (E)-3-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4 ,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-acrylic acid ethyl ester (compound prepared in Example 107-(2)) (138 mg, 0.24 mmol) in MeOH/CH2Cl2 (2/1 v/v, 30 ml) was added NiCI2 6H20(114 mg, 0.48 mmol) and NaBH4 at 0 degrees C under N2 atmosphere and the mixture was stirred for 1 h. The reaction mixture was poured into sat. NH4CI aq. and the products were extracted with EtOAc. The extracts were dried over anhydrous Na2Sθ4, filtered and evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-Hexane:EtOAc=10:1) to give the title compound (116 mg, 82.3%) as colorless sticky oil.
1H-NMR (300MHz, CDCI3): 7.40-7.30 (m, 2H), 7.05-6.85 (m, 5H), 6.08 (d, 1 H), 5.00 (s, 2H), 4.15 (q, 2H), 3.50 (s, 3H), 2.90 (t, 2H), 2.55 (t, 2H), 2.35 (s, 3H), 2.30 (s, 3H), 2.10 (q, 4H), 1.35 (t, 3H), 0.60 (t, 6H).
(4) Preparation of Preparation of 3-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4 ,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-propionic acid
Figure imgf000294_0001
To a stirred solution of 3-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-propionic acid ethyl ester (compound prepared in Example 107-(3)) (116 mg, 0.20 mmol) in EtOH (2 ml) was added CBr (6.60 mg, 10 mol%) under N2 atmosphere at room temperature. The reaction mixture was refluxed for 4.5 h. The reaction mixture was poured into water and the products were extracted with EtOAc. The extracts were washed with water and brine, dried over Na2Sθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :10) to give 3-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4 ,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenyl)-propionic acid ethyl ester (84.0 mg, 78.5%) as colorless sticky oil. To a stirred solution of 3-(4-{1 -ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-propionic acid ethyl ester (84.0 mg, 0.15 mmol) in EtOH/Water (4/1 v/v, 1.9 ml) was added KOH (16.8 mg, 0.30 mmol) at room temperature and the reaction mixture was stirred for 4 h. The reaction mixture was poured into 0.1 N-HCI and the products were extracted with EtOAc. The extracts were washed with water and brine, dried over anhydrous Na2S04, filtered and evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-Hexane:EtOAc=1 :1 ) to give the title compound (69.0 mg, 89.0%) as colorless sticky oil. 1H-NMR (300MHz, CDCI3): 7.40-7.30 (m, 2H), 7.05-6.85 (m, 5H), 6.10 (d, 1 H), 2.90 (t, 2H), 2.65 (t, 2H), 2.35 (s, 3H), 2.25 (s, 3H), 2.15-2.00 (m, 5H), 0.60 (t, 6H); MS (ESI-) : 515 ([M-H]").
Example 108
Preparation of 3-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenyl)-propionic acid
Figure imgf000295_0001
(1 ) Preparation of trifluoro-methanesulfonic acid 4-{1-[4-(4,4-dimethyl-3-oxo- pentyl)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl ester
Figure imgf000295_0002
To a solution of 1-{4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- methyl-phenyl}-4,4-dimethyl-pentan-3-one (compound prepared in Example 18-(3)) (410 mg, 1.07 mmol) in anhydrous CH2CI2 (10 ml) under nitrogen atmosphere were added trifluoromethanesulfonic anhydride (0.26 ml, 1.6 mmol) and pyridine (0.26 ml, 3.21 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into sat. NH4CI aq. and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :7) to give the title compound (470 mg, 85%). 1H NMR (CDCI3): 7.10-6.97 (m, 4H), 6.88 (m, 2H), 2.82 (m, 2H), 2.72 (m, 2H), 2.31 (s, 3H), 2.25 (s, 3H), 2.04 (q, 4H), 1.10 (s, 9H), 0.59 (t, 6H). (2) Preparation of (E)-3-(4-{1-[4-(4,4-dimethyl-3-oxo-pentyl)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-acrylic acid methyl ester
Figure imgf000296_0001
To a solution of trifluoro-methanesulfonic acid 4-{1-[4-(4,4-dimethyl-3-oxo- pentyl)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl ester (compound prepared in Example 108-(1 )) (470 mg, 0.91 mmol) in anhydrous DMF (10 ml) under nitrogen atmosphere were added triethylamine (0.15 ml, 1.08 mmol), methylacrylate (0.12 ml, 1.3 mmol), 1 ,3- bis(diphenylphosphine)propane (93 mg, 0.22 mmol) and palladium acetate (40 mg, 0.18 mmol). The reaction mixture was stirred at 100 degrees C for 1.5 h and poured into sat. NH4CI aq. and the products were extracted with ethyl acetate. The extracts were washed with brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :7) to give the title compound (230 mg, 56%).
1H NMR (CDCI3): 7.95 (d, 1 H), 7.42 (d, 1 H), 7.04-6.96 (m, 3H), 6.90 (m, 2H), 6.32 (d, 1 H), 3.79 (s, 3H), 2.82 (m, 2H), 2.71 (m, 2H), 2.38 (s, 3H), 2.24 (s, 3H), 2.06 (q, 4H), 1.09 (s, 9H), 0.60 (t, 6H).
(3) Preparation of (E)-3-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenyl)-acrylic acid methyl ester
Figure imgf000296_0002
To a solution of (E)-3-(4-{1-[4-(4,4-dimethyl-3-oxo-pentyl)-3-methyl-phenyl]- 1-ethyl-propyl}-2-methyl-phenyl)-acrylic acid methyl ester (compound prepared in Example 108-(2)) (220 mg, 0.49 mmol) in methanol (5 ml) under nitrogen atmosphere was added sodium borohydride (37 mg, 0.98 mmol) and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was poured into water and the products were extracted with ethyl acetate. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :7) to give the title compound (160 mg, 72%). 1H NMR (CDCI3): 7.95 (d, 1 H), 7.43 (d, 1 H), 7.04-6.98 (m, 3H), 6.91 (m, 2H), 6.31 (d, 1 H), 3.79 (s, 3H), 3.24 (m, 1 H), 2.86 (m, 1 H), 2.56 (m, 1 H), 2.39 (s, 3H), 2.25 (s, 3H), 2.08 (q, 4H), 1.79 (m, 1 H), 1.48 (m, 1 H), 0.89 (s, 9H), 0.61 (t, 6H).
(4) Preparation of 3-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid
Figure imgf000297_0001
To a solution of (E)-3-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenyl)-acrylic acid methyl ester (compound prepared in Example 108-(3)) (160 mg, 0.35 mmol) in methanol (3 ml) was added 10% palladium carbon (10 mg) and the mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (3 ml)/H2θ (0.1 ml). To the mixture was added KOH as 1 tablet and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into 0.1 N- HCI and the products were extracted with ethyl acetate. The extracts were washed with brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :3) to give the title compound (110 mg, 71 % for two steps) as a solid.
1H NMR (CDCI3): 7.03-6.89 (m, 6H), 3.25 (dt, 1 H), 2.86 (m, 3H), 2.58 (m, 3H), 2.25 (s, 6H), 2.04 (q, 4H), 1.79 (m, 1 H), 1.50 (m, 1 H), 0.88 (s, 9H), 0.59 (t, 6H); MS (ESI-) : 437 ([M-H]"). Example 109
Preparation of (E)-3-ethyl-1-[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)- butoxy]-phenyl}-propyl)-2-methyl-phenyl]-pent-1-en-3-ol
Figure imgf000298_0001
(1) Preparation of 5-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanenitrile
Figure imgf000298_0002
To a stirred solution of 4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1- (5)) (274 mg, 0.72 mmol) and 5-Bromovaleronitrile (350 mg, 2.16 mmol) in 7.20ml of anhydrous DMF was added K2C03 (299 mg, 2.16 mmol) under N2 atmosphere at room temperature. The reaction mixture was stirred at 100 degrees C for 12 h. The reaction mixture was cooled to room temperature, poured into water and the products were extracted with EtOAc. The extracts were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :6) to give the title compound (184 mg, 55%) as colorless oil.
1H-NMR (300MHz, CDCI3): 7.30 (d, 1 H), 7.00-6.85 (m, 4H), 6.75 (d, 1 H), 6.65 (d, 1 H), 6.00 (d, 1H), 4.00 (t, 2H), 2.50 (t, 2H), 2.35 (s, 3H), 2.25 (s, 3H), 2.15 (s, 3H), 2.10-1.85 (m, 8H), 1.70-1.55 (m, 4H), 0.90 (t, 6H), 0.60 (t, 6H).
(2) Preparation of (E)-3-ethyl-1-[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5- yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-pent-1 -en-3-ol
Figure imgf000299_0001
To a solution of 5-(4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanenitrile (compound prepared in Example 109-(1)) (46.5 mg, 0.10 mmol) in anhydrous toluene (1.2 ml) was added Me3SnN3 (61.7 mg, 0.30 mmol) and the mixture was stirred at 110 degrees C for 12 h. The reaction mixture was cooled to room temperature, poured into water and the products were extracted with EtOAc. The extracts were washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with CH2CI2: MeOH (50:1) to give the title compound (13 mg, 26%) as amorphous.
1H-NMR(300MHz, CDCI3): 7.30 (d, 1H), 7.00-6.85 (m, 4H), 6.75 (d, 1H), 6.65 (d, 1H), 6.00 (d, 1H), 3.98 (t, 2H), 3.10 (t, 2H), 2.35 (s, 3H), 2.25 (s, 3H), 2.15 (s, 3H), 2.10-1.95 (m, 8H), 1.90-1.80 (m, 2H), 1.70-1.55 (m, 4H), 0.90 (t, 6H), 0.60 (t, 6H); MS (ESI-) : 503 ([M-H]+).
Example 110
Preparation of 1-[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]- phenyl}-propyl)-2-methyl-phenylethynyl]- cyclopentanol
Figure imgf000299_0002
(1 preparation of 5-(4-{1 -ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentanenitrile
Figure imgf000299_0003
Using the same procedure as described for the preparation of Example 109-(1), the title compound was prepared from 4-{1 -Ethyl-1 -[4-(1-hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 7). The yield was 55%.
1H-NMR (300MHz, CDCI3): 7.30 (d, 1 H), 7.00 (bs, 1 H), 6.95-6.85 (m, 2H), 6.85 (bs, 1 H), 6.65 (d, 1 H), 3.98 (t, 2H), 2.50 (t, 2H), 2.38 (s, 3H), 2.15 (s, 3H), 2.10-1.70 (m, 17H), 0.60 (t, 6H).
(2) Preparation of 1-[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]- phenyl}-propyl)-2-methyl-phenylethynyl]- cyclopentanol
Figure imgf000300_0001
Using the same procedure as described for the preparation of Example 109-(2), the title compound was prepared from 5-(4-{1 -Ethyl-1 -[4-(1-hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- pentanenitrile (compound prepared in Example 110-(1 )). The yield was 44%.
1H-NMR (300MHz, CDCI3): 7.25 (d, 1 H), 7.00 (bs, 1 H), 6.95-6.85 (m, 2H), 6.85 (bs, 1 H), 6.65 (d, 1 H), 3.98 (t, 2H), 3.15 (t, 2H), 2.35 (s, 3H), 2.15 (s, 3H), 2.10-1.70 (m, 17H), 0.60 (t, 6H); MS (ESI-) : 499 ([M-H]").
Example 111
Preparation of 1-{(E)-2-[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]- phenyl}-propyl)-2-methyl-phenyl]-vinyl}-cyclopentanol
Figure imgf000300_0002
(1) Preparation of 5-[4-(1 -ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanenitrile
Figure imgf000301_0001
Using the same procedure as described for the preparation of Example 109-(1 ), the title compound was prepared from 4-(1 -Ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol (compound prepared in Example 10). The yield was 96%. 1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.69-1.97 (m, 8H), 2.00-2.07 (m, 6H), 2.14 (s, 3H), 2.30 (s, 3H), 2.46 (t, 2H), 3.97 (t, 2H), 6.25 (d, 1 H), 6.66 (d, 1 H), 6.83 (d, 1 H), 6.90-6.95 (m, 4H), 7.32 (d, 1 H).
(2) Preparation of 1-{(E)-2-[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)- butoxy]-phenyl}-propyl)-2-methyl-phenyl]-vinyl}-cyclopentanol
Figure imgf000301_0002
Using the same procedure as described for the preparation of Example 109-(2), the title compound was prepared from 5-[4-(1 -ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]- pentanenitrile (compound prepared in Example 111-(1 )). The yield was 4%. 1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.69-1.95 (m, 8H), 2.00-2.09 (m, 6H), 2.15 (s, 3H), 2.30 (s, 3H), 3.10 (t, 2H), 4.00 (t, 2H), 6.25 (d, 1 H), 6.68 (d, 1 H), 6.83 (d, 1H), 6.90-6.95 (m, 4H), 7.32 (d, 1H); MS (ESI-) : 501 ([M-HT ).
Example 112
Preparation of
1 -[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2- methyl-phenylethynyl]-cyclohexanol
Figure imgf000302_0001
(1) Preparation of 5-(4-{1 -Ethyl-1 -[4-(1-hydroxy-cyclohexylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentanenitrile
Figure imgf000302_0002
Using the same procedure as described for the preparation of Example 109-(1 ), the title compound was prepared from 4-{1 -ethyl-1 -[4-(1-hydroxy- cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 8). The yield was 70%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.57-2.00 (m, 14H), 2.03 (q, 4H), 2.14 (s, 3H), 2.38 (s, 3H), 2.50 (t, 2H), 3.98 (t, 2H), 6.66 (d, 1H), 6.85-7.00 (m, 4H), 7.27 (d, 1 H).
(2) Preparation of 1-[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]- phenyl}-propyl)-2-methyl-phenylethynyl]-cyclohexanol
Figure imgf000302_0003
Using the same procedure as described for the preparation of Example 109-(2), the title compound was prepared from 5-(4-{1 -Ethyl-1 -[4-(1-hyd roxy- cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- pentanenitrile (compound prepared in Example 112-(1 )). The yield was 26%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.57-2.00 (m, 14H), 2.03 (q, 4H), 2.14 (s, 3H), 2.37 (s, 3H), 3.10 (t, 2H), 3.99 (t, 2H), 6.67 (d, 1 H), 6.86-7.00 (m, 4H), 7.26 (d, 1 H); MS (ESI+) : 537 ([M+Na]+). Example 113
Preparation of 1-{(E)-2-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)- butoxy]-phenyl}-propyl)-2-methyl-phenyl]-vinyl}-cyclohexanol
Figure imgf000303_0001
(1 ) Preparation of 5-[4-(1 -ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanenitrile
Figure imgf000303_0002
Using the same procedure as described for the preparation of Example 109-(1), the title compound was prepared from 4-(1 -ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol (compound prepared in Example 11). The yield was 73%. 1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.57-2.00 (m, 14H), 2.04 (q, 4H), 2.14 (s, 3H), 2.30 (s, 3H), 2.44 (m, 2H), 3.98 (t, 2H), 6.20 (d, 1H), 6.66 (d, 1H), 6.81 (d, 1 H), 6.90-6.96 (m, 4H), 7.32 (d, 1H).
(2) Preparation of 1 -{(E)-2-[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)- butoxy]-phenyl}-propyl)-2-methyl-phenyl]-vinyl}-cyclohexanol
Figure imgf000303_0003
Using the same procedure as described for the preparation of Example 109-(2), the title compound was prepared from 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]- pentanenitrile (compound prepared in Example 113-(1)). The yield was 24%. 1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.57-2.00 (m, 14H), 2.04 (q, 4H), 2.14 (s, 3H), 2.29 (s, 3H), 3.10 (t, 2H), 3.98 (t, 2H), 6.20 (d, 1 H), 6.67 (d, 1 H), 6.81 (d, 1 H), 6.90-6.96 (m, 4H), 7.31 (d, 1 H); MS (ESI-) : 515 ([M-H]")-
Example 114
Preparation of 4-[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-yn-2- ol
Figure imgf000304_0001
(1 ) Preparation of 5-[4-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxy)-butyl]-1 H-tetrazole
Figure imgf000304_0002
Using the same procedure as described for the preparation of Example 109- (1 ), 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentanenitrile was prepared from 4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenol (compound prepared in Example 2-(2)). The yield was 99%. Using the same procedure as described for the preparation of Example 109- (2), the title compound was prepared from 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenoxy)-pentanenitrile. The yield was 66%. 1H-NMR (300MHz, CDCI3): 7.40 (d, 1H), 7.05 (bs, 1H), 7.00-6.85 (m, 2H), 6.82 (bs, 1 H), 6.65 (d, 1 H), 5.15 (s, 2H), 4.00 (t, 2H), 3.50 (s, 3H), 3.15 (t, 2H), 2.40 (s, 3H), 2.15 (s, 3H), 2.15-2.00 (m, 6H), 2.00-1.80 (m, 2H), 0.60 (t, 6H). (2) Preparation of 4-[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-yn-2- ol
Figure imgf000305_0001
To a solution of 5-[4-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxy)-butyl]-1 H-tetrazole (compound prepared in Example 114-(1 )) (21.0 mg, 0.03 mmol) in MeOH (0.34 ml) was added pTsOH (9.70 mg, 0.05 mmol) and the mixture was stirred at 60 degrees C for 12 h. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (CH2θl2:MeOH=30:1) to give the title compound (16.0 mg, 80.8%) as colorless sticky oil 1H-NMR (300MHz, CDCI3): 7.30 (d, 1 H), 7.05 (bs, 1H), 7.00-6.80 (m, 3H), 6.65 (d, 1 H), 3.98 (t, 2H), 3.10 (t, 2H), 2.35 (s, 3H), 2.15 (s, 3H), 2.15-2.00 (m, 6H), 2.00-1.80 (m, 2H), 0.60 (t, 6H); MS (ESI-) : 581 ([M-H]").
Example 115
Preparation of (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol
Figure imgf000305_0002
(1) Preparation of 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-pentanenitrile
Figure imgf000306_0001
Using the same procedure as described for the preparation of Example 109-(1 ), the title compound was prepared from 4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenol (compound prepared in Example 30-(1 )). The yield was 90%.
1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 1.83-2.04 (m, 4H), 2.05 (q, 4H), 2.15 (s, 3H), 2.31 (s, 3H), 2.41 (t, 2H), 3.50 (s, 3H), 3.98 (t, 2H), 4.97 (s, 2H), 6.06 (d, 1 H), 6.66 (d, 1 H), 6.89-7.02 (m, 4H), 7.30-7.39 (m, 2H).
(2) Preparation of 5-[4-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-butyl]-1 H-tetrazole
Figure imgf000306_0002
Using the same procedure as described for the preparation of Example 109-(2), the title compound was prepared from 5-(4-{1 -ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-pentanenitrile (compound prepared in Example 115-(1 )). The yield was 60%.
1H-NMR (300MHz, CDCI3): 0.61 (t, 6H), 1.83-2.04 (m, 4H), 2.05 (q, 4H), 2.15 (s, 3H), 2.32 (s, 3H), 3.11 (m, 2H), 3.50 (s, 3H), 4.00 (t, 2H), 4.96 (s, 2H), 6.06 (d, 1 H), 6.69 (d, 1H), 6.89-7.02 (m, 4H), 7.30-7.39 (m, 2H).
(3) Preparation of (E)-4-[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)- butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but- 3-en-2-ol
Figure imgf000307_0001
Using the same procedure as described for the preparation of Example 114-(2), the title compound was prepared from 5-[4-(4-{1 -ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-butyl]-1 H-tetrazole (compound prepared in Example 115-(2)). The yield was 61 %.
1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.83-2.04 (m, 4H), 2.05 (q, 4H), 2.14 (s, 3H), 2.32 (s, 3H), 3.12 (t, 2H), 4.00 (t, 2H), 6.08 (d, 1H), 6.68 (d, 1H), 6.89-7.00 (m, 4H), 7.30-7.39 (m, 2H); MS (ESI-) : 583 ([M-H]").
Example 116
Preparation of 1-[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]- phenyl}-propyl)-2-methyl-phenyl]-4,4-dimethyl-pentan-3-ol
Figure imgf000307_0002
(1 ) Preparation of 5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanenitrile
Figure imgf000307_0003
Using the same procedure as described for the preparation of Example 109-(1), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18). The yield was 98%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.38 (m, 1 H), 1.43-1.53 (m, 1H), 1.74-1.97 (m, 5H), 2.04 (q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.46 (d, 2H), 2.52-2.60 (m, 1 H), 2.81-2.91 (m, 1 H), 3.24 (d, 1 H), 3.97 (t, 2H), 6.65 (d, 1 H), 6.90-6.96 (m, 4H), 7.01 (d, 1 H). (2) Preparation of 1-[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]- phenyl}-propyl)-2-methyl-phenyl]-4,4-dimethyl-pentan-3-ol
Figure imgf000308_0001
Using the same procedure as described for the preparation of Example 109-(2), the title compound was prepared from 5-(4-{1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- pentanenitrile (compound prepared in Example 116-(1 )). The yield was 65%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.38 (m, 1 H), 1.44-1.58 (m, 1H), 1.76-1.91 (m, 3H), 1.99-2.08 (m, 6H), 2.13 (s, 3H), 2.25 (s, 3H), 2.52-2.62 (m, 1 H), 2.80-2.89 (m, 1 H), 3.08 (t, 2H), 3.26 (dd, 1 H), 3.98 (t, 2H), 6.65 (d, 1 H), 6.89-6.95 (m, 4H), 7.01 (d, 1 H); MS (ESI-) : 505 ([M-H]").
Example 117
Preparation of 1-[4-(1 -ethyl-1 -{3-methyl-4-[5-(1 H-tetrazol-5-yl)-pentyloxy]- phenyl}-propyl)-2-methyl-phenyl]-4,4-dimethyl-pentan-3-ol
Figure imgf000308_0002
(1 ) Preparation of 6-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanenitrile
Figure imgf000308_0003
Using the same procedure as described for the preparation of Example 109-(1 ), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) and 6-bromohexanenitrile. The yield was 89%. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.41-1.87(m, 8H), 2.04 (q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.38 (t, 2H), 2.50-2.60 (m, 1 H), 2.81-2.91 (m, 1 H), 3.24 (dd, 1 H), 3.94 (t, 2H), 6.65 (d, 1 H), 6.89-6.95 (m, 4H), 7.01 (d, 1 H).
(2) Preparation of 1-[4-(1 -Ethyl-1 -{3-methyl-4-[5-(1 H-tetrazol-5-yl)-pentyloxy]- phenyl}-propyl)-2-methyl-phenyl]-4,4-dimethyl-pentan-3-ol
Figure imgf000309_0001
Using the same procedure as described for the preparation of Example 109-(2), the title compound was prepared from 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- hexanenitrile (compound prepared in Example 117-(1)). The yield was 52%. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.44-1.62 (m, 3H), 1.76-1.94 (m, 5H), 2.03 (q, 4H), 2.11 (s, 3H), 2.24 (s, 3H), 2.52-2.62 (m, 1 H), 2.79-2.89 (m, 1H), 2.99 (t, 2H), 3.26 (dd, 1H), 3.92 (t, 2H), 6.63 (d, 1 H), 6.90- 6.93 (m, 4H), 7.01 (d, 1 H); MS (ESI-) : 519 ([M-H]").
Example 118
Preparation of 1 -(4-{1 -[4-(5-amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-3-ethyl-pent-1-yn-3-ol
Figure imgf000310_0001
(1) Preparation of 2-[5-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentyl]-isoindole-1 ,3-dione
Figure imgf000310_0002
Using the same procedure as described for the preparation of Example 102-(1), the title compound was prepared from 4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 - ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(4)). The yield was 57%.
1H NMR (CDCI3): 7.84 (m, 2H), 7.70 (m, 2H), 7.26 (m, 1 H), 7.00 (m, 1 H), 6.91 (m, 2H), 6.82 (m, 1 H), 6.64 (d, 1H), 3.91 (t, 2H), 3.70 (t, 2H), 2.36 (s, 3H), 2.09 (s, 3H), 2.04 (q, 4H), 1.91 (m, 4H), 1.75 (m, 4H), 1.25 (t, 2H), 1.10 (t, 6H), 0.58 (t, 6H).
(2) Preparation of 1 -(4-{1 -[4-(5-amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-3-ethyl-pent-1-yn-3-ol
Figure imgf000310_0003
To a solution of 2-[5-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentyl]-isoindole-1 ,3-dione (compound prepared in Example 118-(1)) (90 mg, 0.15 mmol) in EtOH (1 ml) under nitrogen atmosphere was added methylamine (0.3 ml, 40 wt% in water) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with CH2CI2:MeOH (5:1 ) to give the title compound (14 mg, 20%). 1H NMR (CDCI3): 7.27 (m, 1 H), 7.00 (m, 1 H), 6.90 (m, 2H), 6.84 (m, 1 H), 6.65 (d, 1 H), 3.92 (t, 2H), 2.74 (m, 2H), 2.56 (br, NH2), 2.37 (s, 3H), 2.13 (s, 3H), 2.04 (q, 4H), 1.75 (m, 6H), 1.10 (t, 6H), 0.58 (t, 6H); MS (ESI+) : 464 ([M+H]+).
Example 119
Preparation of (E)-1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-3-ethyl-pent-1-en-3-ol
Figure imgf000311_0001
(1 preparation of 2-[5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentyl]-isoindole-1 ,3-dione
Figure imgf000311_0002
Using the same procedure as described for the preparation of Example 102-(1), the title compound was prepared from 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(5)). The yield was 34%.
1H NMR (CDCI3): 7.84 (m, 2H), 7.70 (m, 2H), 6.93 (m, 5H), 6.74 (d, 1 H), 6.64 (d, 1 H), 6.00 (d, 1 H), 3.91 (t, 2H), 3.72 (t, 2H), 2.30 (s, 3H), 2.10 (s, 3H), 2.04 (q, 4H), 1.79 (m, 4H), 1.64 (q, 4H), 1.25 (t, 2H), 0.91 (t, 6H), 0.60 (t, 6H).
(2) Preparation of (E)-1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-3-ethyl-pent-1-en-3-ol
Figure imgf000311_0003
Using the same procedure as described for the preparation of Example 118-(2), the title compound was prepared from 2-[5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentyl]- isoindole-1 ,3-dione (compound prepared in Example 119-(1)). The yield was
24%.
1H NMR (CDCI3): 7.29 (m, 1H), 6.91 (m, 4H), 6.74 (d, 1H), 6.63 (d, 1H), 6.00 (d,
1 H), 3.87 (t, 2H), 3.75 (br, NH2), 2.74 (m, 2H), 2.29 (s, 3H), 2.13 (s, 3H), 2.04 (q,
4H), 1.74 (m, 2H), 1.66-1.46 (m, 8H), 0.91 (t, 6H), 0.60 (t, 6H); MS (ESI+) : 466
([M+H]+).
Example 120
Preparation of 1 -(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2- methyl-phenylethynyl)-cyclopentanol
Figure imgf000312_0001
(1 ) Preparation of 2-[5-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentyl]-isoindole-1 ,3-dione
Figure imgf000312_0002
Using the same procedure as described for the preparation of Example 102-(1 ), the title compound was prepared from 4-{1 -Ethyl-1 -[4-(1-hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 7). The yield was 68%.
1H-NMR (300MHz, CDCI3): 0.58 (t, 6H), 1.47-1.58 (m, 4H), 1.72-1.88 (m, 6H), 1.98-2.05 (q, 8H), 2.09 (s, 3H), 2.35 (s, 3H), 3.72 (t, 2H), 3.91 (t, 2H), 6.64 (d, 1H), 6.81-7.00 (m, 5H), 7.68-7.71 (m, 2H), 7.82-7.85 (m, 2H).
(2) Preparation of 1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenylethynyl)-cyclopentanol
Figure imgf000313_0001
Using the same procedure as described for the preparation of Example 100-(2), the title compound was prepared from 2-[5-(4-{1 -Ethyl-1 -[4-(1-hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentyl]- isoindole-1 ,3-dione (compound prepared in Example 120-(1)). The yield was 74%.
1H-NMR (300MHz, CDCI3): 0.58 (t, 6H), 1.47-1.58 (m, 4H), 1.72-1.92 (m, 6H), 1.98-2.07 (q, 8H), 2.14 (s, 3H), 2.36 (s, 3H), 2.72 (t, 2H), 2.92 (t, 2H), 6.66 (d, 1 H), 6.83-7.00 (m, 5H); MS (ESI+) : 462 ([M+H]+).
Example 121
Preparation of 1 -[(E)-2-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol
Figure imgf000313_0002
(1) Preparation of 2-{5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentyl}-isoindole-1 ,3-dione
Figure imgf000313_0003
Using the same procedure as described for the preparation of Example 102-(1), the title compound was prepared from 4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol (compound prepared in Example 10). The yield was 63%. H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.47-1.88 (m, 14H), 2.02 (q, 4H), 2.10 (s, 3H), 2.38 (s, 3H), 3.72 (t, 2H), 3.92 (t, 2H), 6.66 (d, 1 H), 6.82-7.00 (m, 4H), 7.27 (d, 1H). (2) Preparation of 1-[(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol
Figure imgf000314_0001
Using the same procedure as described for the preparation of Example 118-(2), the title compound was prepared from 2-{5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hyd roxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentyl}-isoindole- 1 ,3-dione (compound prepared in Example 121-(1 )). The yield was 49%. 1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.52 (m 4H), 1.70-1.99 (m, 10H), 2.04 (q, 4H), 2.15 (s, 3H), 2.31 (s, 3H), 2.72 (t, 2H), 3.93 (d, 2H), 6.25 (d, 1 H), 6.67 (d, 1 H), 6.68-6.96 (m, 5H), 7.31-7.34 (m, 1 H); MS (ESI+) : 464 ([M+H]+).
Example 122
Preparation of 1 -(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2- methyl-phenylethynyl)-cyclohexanol
Figure imgf000314_0002
(1 ) Preparation of 2-[5-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentyl]-isoindole-1 ,3-dione
Figure imgf000314_0003
Using the same procedure as described for the preparation of Example 102-(1 ), the title compound was prepared from 4-{1 -Ethyl-1 -[4-(1-hydroxy- cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 8). The yield was 83%. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.47-1.88 (m, 16H), 2.02 (q, 4H), 2.10 (s, 3H), 2.38 (s, 3H), 3.72 (t, 2H), 3.92 (t, 2H), 6.65 (d, 1 H), 6.82-7.00 (m, 4H), 7.27 (d, 1 H), 7.71 (m, 2H), 7.84 (m, 2H).
(2) Preparation of 1 -(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenylethynyl)-cyclohexanol
Figure imgf000315_0001
Using the same procedure as described for the preparation of Example 118-(2), the title compound was prepared from 2-[5-(4-{1 -Ethyl-1 -[4-(1-hyd roxy- cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentyl]-isoindole- 1 ,3-dione (compound prepared in Example 122-(1)). The yield was 34%. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.47-1.88 (m, 16H), 2.03 (q, 4H), 2.14 (s, 3H), 2.38 (s, 3H), 3.73 (m, 2H), 3.92 (t, 2H), 6.66 (d, 1H), 6.82-7.00 (m, 4H), 7.27 (d, 1 H); MS (ESI+) : 476 ([M+H]+).
Example 123
Preparation of 1 -[(E)-2-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-vinyl]-cyclohexanol
Figure imgf000315_0002
(1) Preparation of 2-{5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentyl}-isoindole-1 ,3-dione
Figure imgf000315_0003
Using the same procedure as described for the preparation of Example 102-(1), the title compound was prepared from 4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclohexyl)-vinyl]-3-methyl-pheny|}-propyl)-2-methyl-phenol (compound prepared in Example 11). The yield was 89%.
1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.32-1.85 (m, 16H), 2.03 (q, 4H), 2.10 (s, 3H), 2.30 (s, 3H), 3.72 (t, 2H), 3.91 (t, 2H), 6.20 (d, 1 H), 6.65 (d, 1 H), 6.78- 6.95 (m, 5H), 7.31 (d, 1 H), 7.71 (m, 2H), 7.84 (m, 2H).
(2) Preparation of 1-[(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-vinyl]-cyclohexanol
Figure imgf000316_0001
Using the same procedure as described for the preparation of Example 118-(2), the title compound was prepared from 2-{5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy- cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentyl}-isoindole- 1 ,3-dione (compound prepared in Example 123-(1)). The yield was 34%. 1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.32-1.85 (m, 16H), 2.04 (q, 4H), 2.15 (s, 3H), 2.30 (s, 3H), 3.73 (m, 2H), 3.93 (t, 2H), 6.20 (d, 1 H), 6.66 (d, 1H), 6.81 (d, 1 H), 6.89-6.95 (m, 4H), 7.32 (d, 1 H); MS (ESI+) : 478 ([M+H]+).
Example 124
Preparation of 4-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2- methyl-phenyl)-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-yn-2-ol
Figure imgf000316_0002
(1 ) Preparation of 2-[5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxy)-pentyl]-isoindole-1 ,3-dione
Figure imgf000317_0001
Using the same procedure as described for the preparation of Example 102-(1 ), the title compound was prepared from 4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 2-(2)). The yield was 86%. 1H-NMR (300MHz, CDCI3): 7.85 (m, 2H), 7.70 (m, 2H), 7.40 (d, 1 H), 7.10-6.95 (m, 2H), 6.90-6.80 (m, 2H), 6.65 (d, 1 H), 5.15 (s, 2H), 3.95 (t, 2H), 3.75 (t, 2H), 3.50 (s, 3H), 2.40 (s, 3H), 2.10 (s, 3H), 2.05 (q, 4H), 1.90-1.70 (m, 4H), 1.60-1.50 (m, 2H), 0.60 (t, 6H).
(2) Preparation of 2-[5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentyl]-isoindole- 1 ,3-dione
Figure imgf000317_0002
To a solution of 2-[5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxy)-pentyl]-isoindole-1 ,3-dione (compound prepared in Example 124-(1 )) (72.0 mg, 0.01 mmol) in MeOH/CH2CI2(4/1 v/v, 2 ml) was added pTsOH(30.0 mg, 0.015 mmol) and the mixture was stirred at 60 degrees C for 12 h. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (n-Hexane: EtOAc = 6:1 ) to give the title compound (61.5 mg, 91%) as colorless sticky oil. 1H-NMR (300MHz, CDCI3): 7.85 (m, 2H), 7.70 (m, 2H), 7.40 (d, 1 H), 7.10-6.95 (m, 2H), 6.90-6.80 (m, 2H), 6.65 (d, 1 H), 4.10 (bs, 1 H), 3.95 (t, 2H), 3.75 (t, 2H), 2.35 (s, 3H), 2.10 (s, 3H), 2.05 (q, 4H), 1.90-1.70 (m, 4H), 1.60-1.50 (m, 2H), 0.60 (t, 6H). (3) Preparation of 4-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-yn-2-ol
Figure imgf000318_0001
Using the same procedure as described for the preparation of Example 118-(2), the title compound was prepared from 2-[5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxy)-pentyl]-isoindole-1 ,3-dione (compound prepared in Example 124-(2)). The yield was 22%.
1H-NMR (300MHz, CDCI3): 7.30 (d, 1 H), 7.05 (bs, 1 H), 7.00-6.80 (m, 3H), 6.65 (d, 1 H), 4.70-4.50 (bs, 2H), 3.75 (t, 2H), 2.70 (t, 2H), 2.35 (s, 3H), 2.10 (s, 3H), 2.05 (q, 4H), 1.75-1.40 (m, 6H), 0.60 (t, 6H); MS (ESI-) : 542 ([M-H]").
Example 125
Preparation of (E)-4-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-1 ,1 ,1 -trifluoro-2-trifluoromethyl-but-3-en-2-ol
Figure imgf000318_0002
(1 ) Preparation of 2-[5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-pentyl]-isoindole-1 ,3-dione
Figure imgf000318_0003
Using the same procedure as described for the preparation of Example 100-(1), the title compound was prepared from 4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4 ,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenol (compound prepared in Example 30-(1 )). The yield was 80%. 1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.47-1.58 (m, 2H), 1.72-1.88 (m, 4H), 2.04 (q, 4H), 2.11 (s, 3H), 2.31 (s, 3H), 3.49 (s, 3H), 3.72 (t, 2H), 3.91 (t, 2H), 4.96 (s, 2H), 6.05 (d, 1 H), 6.65 (d, 1 H), 6.85-7.02 (m, 4H), 7.31-7.36 (m, 2H), 7.69-7.71 (m, 2H), 7.82-7.85 (m, 2H).
(2) Preparation of 2-[5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentyl]-isoindole- 1 ,3-dione
Figure imgf000319_0001
Using the same procedure as described for the preparation of Example 55 (deprotection procedure of MOM group with TMSBr), the title compound was prepared from 2-[5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-pentyl]-isoindole-1 ,3-dione (compound prepared in Example 125-(1)). The yield was 95%.
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 1.47-1.58 (m, 2H), 1.70-1.88 (m, 4H), 2.03 (q, 4H), 2.10 (s, 3H), 2.32 (s, 3H), 3.71 (t, 2H), 3.90 (t, 2H), 6.07 (d, 1 H), 6.64 (d, 1 H), 6.85-7.00 (m, 4H), 7.31-7.39 (m, 2H), 7.67-7.70 (m, 2H), 7.81-7.84 (m, 2H).
(3) Preparation of (E)-4-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-1 ,1 ,1 -trifluoro-2-trifluoromethyl-but-3-en-2-ol
Figure imgf000319_0002
Using the same procedure as described for the preparation of Example 118-(2), the title compound was prepared from 2-[5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-pentyl]-isoindole-1 ,3-dione (compound prepared in Example 125-(2)). The yield was 32%. 1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 1.47-1.58 (m, 4H), 1.73-1.81 (m, 2H), 2.04 (q, 4H), 2.13 (s, 3H), 2.31 (s, 3H), 3.71 (t, 2H), 3.90 (t, 2H), 6.08 (d, 1 H), 6.64 (d, 1 H), 6.86-7.02 (m, 4H), 7.31-7.38 (m, 2H); MS (ESI+) : 546 ([M+H]+).
Example 126
Preparation of 5(R)-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-pyrrolidin-2-one
Figure imgf000320_0001
To a solution of 4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-phenyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) (300 mg, 0.78 mmol) in anhydrous CH3CN (7 ml) under nitrogen atmosphere were added K2CO3 (161 mg, 1.17 mmol) and (R)-toluene-4-sulfonic acid 5-oxo-pyrrolidin-2- ylmethyl ester (315 mg, 1.17 mmol) and the mixture was stirred at 100 degrees C overnight. The reaction mixture was cooled to room temperature, poured into sat. NH4CI aq. and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc- n-Hexane (1 :1 ) to give the title compound (200 mg, 53%). 1H NMR (CDCI3): 7.02 (d, 1 H), 6.93 (m, 4H), 6.63 (d, 1 H), 5.94 (s, NH), 4.08 (m, 1 H), 3.96 (dd, 1 H), 3.80 (dd, 1 H), 3.23 (dt, 1 H), 2.86 (m, 1 H), 2.55 (m, 1 H), 2.38 (m, 2H), 2.25 (s, 3H), 2.14 (s, 3H), 2.04 (q, 4H), 1.93 (m, 1 H), 1.79 (m, 1 H), 1.48 (m, 2H), 0.88 (s, 9H), 0.59 (t, 6H); MS (ESI+) : 502 ([M+Na]+).
Example 127 Preparation of 5(S)-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-pyrrolidin-2-one
Figure imgf000320_0002
Preparation of 5(S)-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-pyrrolidin-2-one
Figure imgf000321_0001
Using the same procedure as described for the preparation of Example 126, the title compound was prepared from 4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- phenyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) and (S)-toluene-4-sulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester. The yield was 53%.
1H NMR (CDCI3): 7.02 (d, 1 H), 6.93 (m, 4H), 6.63 (d, 1 H), 5.94 (s, NH), 4.08 (m, 1 H), 3.96 (dd, 1 H), 3.80 (dd, 1 H), 3.23 (dt, 1 H), 2.86 (m, 1 H), 2.55 (m, 1 H), 2.38 (m, 2H), 2.25 (s, 3H), 2.14 (s, 3H), 2.04 (q, 4H), 1.93 (m, 1 H), 1.79 (m, 1 H), 1.48 (m, 2H), 0.88 (s, 9H), 0.59 (t, 6H); MS (ESI+) : 502 ([M+Na]+).
Example 128
Preparation of 4(R)-Amino-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000321_0002
Preparation of 4(R)-Amino-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000321_0003
5(S)-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxymethyl)-pyrrolidin-2-one (compound prepared in Example 126) (100 mg, 0.21 mmol) was dissolved in concentrated HCl (0.5 ml, 36wt% in water) and the mixture was stirred at reflux temperature overnight. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by ODS chromatography (CH3OH / H20 (0.1 %TFA) = 80 / 20) to give the title compound (25 mg, 24%).
1H NMR (CD3OD): 7.10-6.95 (m, 5H), 6.90 (d, 1 H), 4.28 (dd, 1 H), 4.14 (dd, 1 H), 3.76 (m, 1 H), 3.22 (dt, 1 H), 2.93 (m, 1 H), 2.60 (m, 3H), 2.30 (s, 3H), 2.27 (s, 3H), 2.14 (m, 6H), 1.82 (m, 1 H), 1.55 (m, 1 H), 0.94 (s, 9H), 0.65 (t, 6H); MS (ESI+) : 498 ([M+H]+).
Example 129
Preparation of 4(S)-Amino-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000322_0001
Preparation of 4(S)-Amino-5-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid
Figure imgf000322_0002
Using the same procedure as described for the preparation of Example 128, the title compound was prepared from 5(S)-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-pyrrolidin-2-one (compound prepared in Example 127). The yield was 17%. 1H NMR (CD3OD): 7.10-6.95 (m, 5H), 6.90 (d, 1 H), 4.28 (dd, 1 H), 4.14 (dd, 1 H), 3.76 (m, 1 H), 3.22 (dt, 1 H), 2.93 (m, 1 H), 2.60 (m, 3H), 2.30 (s, 3H), 2.27 (s, 3H), 2.14 (m, 6H), 1.82 (m, 1 H), 1.55 (m, 1 H), 0.94 (s, 9H), 0.65 (t, 6H); MS (ESI+) : 498 ([M+H]+).
Example 130
Preparation of 1-(4-{1-[4-((S )-2-Amino-3-hydroxy-propoxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000323_0001
(1) Preparation of (S)-2,2-Dimethyl-4-(toluene-4-sulfonyloxymethyl)-oxazolidine- 3-carboxylic acid tert-butyl ester
Figure imgf000323_0002
To a solution of (S)-2,2-Dimethyl-oxazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 4-methyl ester (435 mg, 1.678 mmol) in THF (5 ml) under nitrogen atmosphere was added 1 N-LiAIH (5 ml, 5.033 mmol) at degrees C and the mixture was stirred at room temperature for 1 h. The mixture was quenched with water and 10% NaOH solution, filtered through celite. The filtrate was diluted with EtOAc and washed with brine, dried over MgS04, filtered, and concentration in vacuo. The obtained residue was purified by flash chromatography eluting with 5:1 Hexane/Ethyl acetate to give the (R)-4-Hydroxymethyl-2,2-dimethyl- oxazolidine-3-carboxylic acid tert-butyl ester (383 mg, 99%) as a white solid. To a solution of (R)-4-Hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (383 mg, 1.656 mmol) in anhydrous pyridine (4 ml) under nitrogen atmosphere was added tosyl chloride (631 mg, 3.312 mmol) at 0 degrees C and the mixture was stirred for 24 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc, washed with brine, dried over MgS04, filtered, and concentrated. Recrystallization from EtOAc-n-hexane to give the title compound (554 mg, 87%).
1H-NMR (300MHz, CDCI3): 1.40 (s, 9H), 1.54 (s, 3H), 2.45 (s, 3H), 3.78-4.20 (m, 5H), 7.40 (d, 2H), 7.81 (d, 2H); MS (ESI+) : 408 ([M+Na]+).
(2) Preparation of 4(R)-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
Figure imgf000324_0001
To a solution of 4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) (110 mg, 0.288 mmol) in anhydrous DMF (3 ml) under nitrogen atmosphere were added Cs2C03 (281 mg, 0.864 mmol) and (S)-2,2-Dimethyl-4-(toluene-4- sulfonyloxymethyl)-oxazolidine-3-carboxylic acid tert-butyl ester (compound prepared in Example 130-(1)) (167 mg, 0.432 mmol) and the mixture was stirred at 110 degrees C for 3 h. The reaction mixture was cooled to room temperature, poured into sat. NH4CI aq. and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :9) to give the title compound (169 mg, 77%) as a white solid. 1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 0.89 (s, 9H), 1.43-1.84 (m, 5H), 2.04 (q, 4H), 2.16 (s, 3H), 2.25 (s,3H), 2.50-2.61 (m, 1 H), 2.81-2.91 (m, 1 H), 3.27 (dd, 1 H), 3.78-3.93 (m, 1 H), 3.93-4.02 (m, 1 H), 6.82 (d, 1 H), 6.90-6.97 (m, 4H), 7.01 (d, 1 H).
(3) Preparation of 1-(4-{1-[4-((S)-2-Amino-3-hydroxy-propoxy)-3-methyl-phenyl]- 1 -ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000324_0002
To a solution of 4(R)-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (compound prepared in Example 130-(2)) (148 mg, 0.248 mmol) in 1 ,4-dioxane (10 ml) was added cone. HCl (2 ml) at 0 degrees C and the mixture was stirred at room temperature for 4 h. The mixture was neutralized by sat. NaHC03 solution, diluted with EtOAc, washed with brine, dried over MgS04, filtered, and concentration in vacuo. The obtained residue was chromatographed on amino functionalized silica gel with EtOAc to give the title compound (30 mg, 26.5%).
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.55 (m, 1 H), 1.75-1.84 (m, 1 H), 2.04 (q, 4H), 2.16 (s, 3H), 2.25 (s,3H), 2.55-2.57 (m, 1 H), 2.84-2.85 (m, 1 H), 3.23 (d, 1 H), 3.25-3.40 (m, 1 H), 3.60 (dd, 1 H), 3.75 (dd, 1 H), 3.91-3.98 (m, 2H), 6.70 (d, 1 H), 6.90-6.97 (m, 4H), 7.02 (d, 1 H) ; MS (ESI+) : 456 ([M+H]+).
Example 131 Preparation of 1 -(4-{1 -[4-((R)-2-Amino-3-hydroxy-propoxy)-3-methyl-phenyl]-1 - ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000325_0001
(1) Preparation of (R)-2,2-Dimethyl-4-(toluene-4-sulfonyloxymethyl)-oxazolidine- 3-carboxylic acid tert-butyl ester
Figure imgf000325_0002
Using the same procedure as described for the preparation of Example 130-(1 ), the title compound was prepared from (R)-2,2-Dimethyl-oxazolidine-3,4- dicarboxylic acid 3-tert-butyl ester 4-methyl ester. The yield was 49%. 1H-NMR (300MHz, CDCI3): 1.40 (m, 9H), 1.51 (s, 3H), 2.49 (s, 3H), 3.71-4.20 (m, 5H), 7.40 (d, 2H), 7.81 (d, 2H); MS (ESI+) : 408 ([M+H]+).
(2) Preparation of 4(S)-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
Figure imgf000325_0003
Using the same procedure as described for the preparation of Example 130-(2), the title compound was prepared from 4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4-di methyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18). The yield was 78%.
1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 0.89 (s, 9H), 1.43-1.84 (m, 5H), 2.04 (q, 4H), 2.16 (s, 3H), 2.25 (s,3H), 2.50-2.61 (m, 1 H), 2.81-2.91 (m, 1 H), 3.27 (dd, 1H), 3.78-3.93 (m, 1H), 3.93-4.02 (m, 1H), 6.82 (d, 1 H), 6.90-6.97 (m, 4H), 7.01 (d, 1 H).
(3) Preparation of 1-(4-{1-[4-((R)-2-Amino-3-hydroxy-propoxy)-3-methyl-phenyl]- 1-ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000326_0001
Using the same procedure as described for the preparation of Example 130-(3), the title compound was prepared from 4(S)-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-2,2- dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (compound prepared in Example 131 -(2)). The yield was 59%.
1H-NMR (300MHz, CDCI3): 0.60 (t, 6H), 0.89 (s, 9H), 1.43-1.57 (m, 1H), 1.68- 1.84 (m, 4H), 2.04 (q, 4H), 2.16 (s, 3H), 2.25 (s,3H), 2.51-2.61 (m, 1H), 2.81- 2.91 (m, 1 H), 3.22 (dd, 1 H), 3.25-3.40 (m, 1 H), 3.61 (dd, 1 H), 3.75 (dd, 1 H), 3.91-3.98 (m, 2H), 6.68 (d, 1 H), 6.90-6.97 (m, 4H), 7.01 (d, 1 H); MS (ESI+) : 456 ([M+H]+).
Example 132 Preparation of 1 (R)-(4-{1 -[4-((R)-2-Amino-4-hydroxy-butoxy)-3-methyl-phenyl]-1 ■ ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000326_0002
(1) Preparation of (R)-1-(tert-Butyl-dimethyl-silanyl)-4-hydroxymethyl-azetidin-2- one o .^OH ^ AOH
O TBDMS <f XTBDMS To a solution of (R)-1-(tert-Butyl-dimethyl-silanyl)-4-oxo-azetidine-2-carboxylic acid (800 mg, 3.49 mmol) in CH2CI2 (30 ml) were added BnOH (0.4 ml, 3.84 mmol), EDO (803 mg, 4.19 mmol), and DMAP (catalytic amount) and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc- n-Hexane (1 :40) to give (R)-1-(tert-Butyl-dimethyl-silanyl)-4-oxo-azetidine-2- carboxylic acid benzyl ester (954 mg, 86%).
To a solution of CaCI2 (994 mg, 8.96 mmol) in EtOH (6 ml) and THF (12 ml) was added NaBH4 (567 mg, 14.9 mmol) at room temperature. To the mixture, (R)-1- (tert-Butyl-dimethyl-silanyl)-4-oxo-azetidine-2-carboxylic acid benzyl ester (954 mg, 2.97 mmol) was added and the mixture was stirred at 0 degrees C for 3 h. The reaction mixture was poured into water and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :5) to give the title compound (150 mg, 23%).
1H-NMR (300MHz, CDCI3): 0.23 (s, 3H), 0.26 (s, 3H), 0.94 (s, 9H), 1.74-1.84 (m, 1 H), 2.84 (dd, 1 H), 3.08 (dd, 1 H), 3.63-3.84 (m, 3H).
(2) Preparation of 1 -(tert-Butyl-dimethyl-silanyl)-4(R)-(4-{1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-azetidin- 2-one
Figure imgf000328_0001
To a solution of 4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) (140 mg, 0.65 mmol) were added triphenylphosphine (256 mg, 0.975 mmol), DEAD (0.15 ml, 0.975 mmol), and (R)-1-(tert-Butyl-dimethyl-silanyl)-4-hydroxymethyl- azetidin-2-one (compound prepared in Example 132-(1 )) (274mg, 0.715mmol) and the mixture was stirred at room temperature for 2days. The mixture was filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :7) to give the title compound (186 mg, 49%).
1H-NMR (300MHz, CDCI3): 0.23 (s, 3H), 0.26 (s, 3H), 0.59 (t, 6H), 0.89 (s, 9H), 0.94 (s, 9H), 1.39 (d, 1 H), 1.48-1.57 (m, 1 H), 1.74-1.84 (m, 1 H), 2.03 (q, 4H), 2.12 (s, 3H), 2.25 (s, 3H), 2.49-2.69 (m, 1 H), 2.98 (m, 1 H), 3.31-3.27 (m, 2H), 3.89-3.95 (m, 1H), 4.08-4.22 (m, 2H), 6.63 (d, 1H), 6.89-6.97 (m, 4H), 7.01 (d, 1 H); MS (ESI+) : 602 ([M+Na]+).
(3) Preparation of 2(R)-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-4-oxo-azetidine-1 -carboxylic acid tert- butyl ester
Figure imgf000328_0002
To a solution of 1-(tert-Butyl-dimethyl-silanyl)-4(R)-(4-{1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-azetidin- 2-one (compound prepared in Example 132-(2)) (184 mg, 0.317 mmol) in THF (3 ml) was added 1M TBAF in THF (0.48 ml, 0.48 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and the products were extracted with EtOAc. The extracts were washed with brine, dried over Na2S0 , filtered and concentrated under reduced pressure. The obtained residue was dissolved in CH2CI2 (3 ml). To the mixture, DMAP (catalytic amount), triethylamine (0.13 ml, 0.96 mmol), and (Boc)20 (95 mg, 0.42 mmol) were added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the products were extracted with EtOAc. The extracts were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :4) to give the title compound (127 mg, 71 %).
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.47 (s, 9H), 1.48-1.57 (m, 1H), 1.74-1.84 (m, 1H), 2.03 (q, 4H), 2.14 (s, 3H), 2.25 (s, 3H), 2.50-2.60 (m, 1 H), 2.81-2.91 (m, 1 H), 3.12 (t, 2H), 3.24 (d, 1 H), 4.19-4.29 (m, 2H), 4.38 (dd, 1H), 6.68 (d, 1H), 6.89-6.97 (m, 4H), 7.01 (d, 1 H).
(4) Preparation of [1(R)-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-3-hydroxy-propyl]-carbamic acid tert-butyl ester
Figure imgf000329_0001
To a solution of 2(R)-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-4-oxo-azetidine-1 -carboxylic acid tert- butyl ester (compound prepared in Example 132-(3)) (127 mg, 0.224 mmol) in THF (2 ml) was added 1 M LAH in THF (0.33 ml, 0.33 mmol) and the mixture was stirred at 0 degrees C for 30min. The reaction mixture was quenched with water and 10% NaOH, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc- n-Hexane (1 :3) to give the title compound (114 mg, 87%). 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.45 (s, 9H), 1.48-1.57 (m, 1H), 1.73-1.89 (m, 3H), 2.03 (q, 4H), 2.16 (s, 3H), 2.25 (s, 3H), 2.50-2.60 (m, 1 H), 2.81-2.91 (m, 1 H), 3.21-3.26 (m, 1 H), 3.36 (m, 1 H), 3.71 (m, 2H), 3.91-3.95 (dd,1 H), 4.08-4.20 (m, 2H), 4.38 (dd, 1 H), 6.66 (d, 1 H), 6.88-6.98 (m, 4H), 7.01 (d, 1 H).
(5) Preparation of 1(R)-(4-{1-[4-((R)-2-Amino-4-hydroxy-butoxy)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000330_0001
To a solution of [1 (R)-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-3-hydroxy-propyl]-carbamic acid tert- butyl ester (compound prepared in Example 132-(4)) (111 mg, 0.195 mmol) in dioxane (2.5 ml) was added cone. HCl (1.1 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into sat. NaHC03 aq. and the products were extracted with EtOAc. The extracts were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with CH2Cl2-MeOH (10:1 ) to give the title compound (50 mg, 54%).
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.43-1.57 (m, 1 H), 1.70- 1.89 (m, 3H), 2.03 (q, 4H), 2.17 (s, 3H), 2.25 (s, 3H), 2.50-2.60 (m, 1 H), 2.81- 2.91 (m, 1 H), 3.24 (d, 1 H), 3.31-3.40 (m, 1 H), 3.74 (m, 1 H), 3.85-3.91 (m,2H), 6.66 (d, 1H), 6.88-6.98 (m, 4H), 7.01 (d, 1H); MS (ESI+) : 470 ([M+H]+).
Example 133
Preparation of 1 (S)-(4-{1-[4-((S)-2-Amino-4-hydroxy-butoxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000330_0002
(1) Preparation of (S)-1-(tert-Butyl-dimethyl-silanyl)-4-hydroxymethyl-azetidin-2- one
Figure imgf000331_0001
Using the same procedure as described for the preparation of Example 132-(1), the title compound was prepared from (S)-1-(tert-Butyl-dimethyl-silanyl)-4-oxo- azetidine-2-carboxylic acid. The yield was 88%. 1 H-NMR (300MHz, CDCI3): 0.23 (s, 3H), 0.26 (s, 3H), 0.94 (s, 9H), 1.74-1.84 (m, 1 H), 2.84 (dd, 1H), 3.08 (dd, 1H), 3.63-3.84 (m, 3H).
(2) Preparation of 1-(tert-Butyl-dimethyl-silanyl)-4(S)-(4-{1 -ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-azetidin- 2-one
Figure imgf000331_0002
Using the same procedure as described for the preparation of Example 132-(2), the title compound was prepared from 4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 18) and (S)-1-(tert-Butyl-dimethyl-silanyl)-4-hydroxymethyl-azetidin-2- one (compound prepared in Example 133-(1 )). The yield was 19%. 1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.39 (d, 1 H), 1.48-1.57 (m, 1 H), 1.57 (s, 15H), 1.74-1.84 (m, 1 H), 2.04 (q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.50-2.60 (m, 1 H), 2.81-2.91 (m, 2H), 3.11-3.18 (dd, 1 H), 3.21-3.27 (dd, 1 H), 3.93-3.98 (dd, 1 H), 4.02-4.07 (m, 1 H), 4.11-4.16 (m, 1 H), 6.66 (d, 1 H), 6.89-6.97 (m, 4H), 7.01 (d, 1 H); MS (ESI+) : 602 ([M+Na]+).
(3) Preparation of 2(S)-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4-di methyl-pentyl )-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-4-oxo-azetidine-1 -carboxylic acid tert- butyl ester
Figure imgf000332_0001
Using the same procedure as described for the preparation of Example 132-(3), the title compound was prepared from 1-(tert-Butyl-dimethyl-silanyl)-4(S)-(4-{1- ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-azetidin-2-one (compound prepared in Example 133-(2)). The yield was 67%
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.47 (s, 9H), 1.48-1.57 (m, 1H), 1.72-1.84 (m, 1 H), 2.02 (q, 4H), 2.14 (s, 3H), 2.25 (s, 3H), 2.50-2.60 (m, 1 H), 2.81-2.91 (m, 1 H), 3.12 (t, 2H), 3.22 (d, 1 H), 4.19-4.29 (m, 2H), 4.38 (dd, 1 H), 6.68 (d, 1 H), 6.89-6.94 (m, 4H), 7.01 (d, 1 H).
(4) Preparation of [1 (S)-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-3-hydroxy-propyl]-carbamic acid tert-butyl ester
Figure imgf000332_0002
Using the same procedure as described for the preparation of Example 132-(4), the title compound was prepared from 2(S)-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-4-oxo- azetidine-1 -carboxylic acid tert-butyl ester (compound prepared in Example 133- (3)). The yield was 84%
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.45 (s, 9H), 1.48-1.57 (m, 1 H), 1.73-1.89 (m, 3H), 2.03 (q, 4H), 2.16 (s, 3H), 2.25 (s, 3H), 2.50-2.60 (m, 1H), 2.81-2.91 (m, 1 H), 3.22 (d, 1H), 3.39 (m, 1H), 3.71 (m, 2H), 3.91-3.95 (dd,1 H), 4.08-4.20 (m, 2H), 4.38 (dd, 1 H), 6.66 (d, 1 H), 6.88-6.98 (m, 4H), 7.01 (d, 1 H). (5) Preparation of 1(S)-(4-{1-[4-((S)-2-Amino-4-hydroxy-butoxy)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000333_0001
Using the same procedure as described for the preparation of Example 132-(5), the title compound was prepared from [1(S)-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-3-hydroxy- propyl]-carbamic acid tert-butyl ester (compound prepared in Example 133-(4)). The yield was 42%
1H-NMR (300MHz, CDCI3): 0.59 (t, 6H), 0.89 (s, 9H), 1.45-1.54 (m, 1H), 1.73- 1.83 (m, 3H), 2.03 (q, 4H), 2.18 (s, 3H), 2.24 (s, 3H), 2.28-2.37 (m, 2H), 2.50- 2.60 (m, 1 H), 2.81-2.91 (m, 1H), 3.24 (m, 1H), 3.84-4.03 (m, 2H), 4.24-4.29 (m, 1H), 4.45-4.51 (m,1H), 6.69 (d, 1H), 6.88-6.95 (m, 4H), 7.01 (d, 1H); MS (ESI+) : 470 ([M+H]+).
Example 134
Preparation of 4-[2-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4-di methyl-pentyl )-3-methyl- phenyl]-propyl}-2-methyl-phenyl)-ethanesulfonyl]-butyric acid
Figure imgf000333_0002
(1) Preparation of Trifluoro-methanesulfonic acid 4-{1-[4-(4,4-dimethyl-3-oxo- pentyl)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl ester
Figure imgf000333_0003
To a solution of 1-{4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl- phenyl}-4,4-dimethyl-pentan-3-one (compound prepared in Example 18-(3)) (6.4 g, 16.8 mmol) in CH2CI2 (100 ml) were added Tf20 (4.2 ml, 25.2 mmol) and pyridine (4.1 ml, 50.4 mmol) at 0 degrees C under N2 atmosphere and the mixture was stirred at room temperature for 5 h. The reaction mixture was poured into sat. NaHC03 and the products were extracted with CH2CI2. The extracts were washed with brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane: EtOAc (50:1) to give the title compound (7.25 g, 84%). 1H-NMR (300MHz, CDCI3): 0.60 (6H, t), 1.08 (9H, s), 2.05 (4H, q), 2.27 (3H, s), 2.31 (3H, s), 2.69-2.76 (2H, m), 2.80-2.88 (2H, m), 6.84-6.89 (2H, m), 6.96-7.10 (4H, m).
(2) Preparation of 1 -{4-[1 -(4-Allyl-3-methyl-phenyl)-1 -ethyl-propyl]-2-methyl- phenyl}-4,4-dimethyl-pentan-3-one
Figure imgf000334_0001
To a solution of Trifluoro-methanesulfonic acid 4-{1-[4-(4,4-dimethyl-3-oxo- pentyl)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl ester (compound prepared in Example 134-(1)) (7.25 g, 14.15 mmol) in DMF (70 ml) under argon atmosphere were added allyltributyltin (17.55 ml, 56.59 mmol), PdCl2(PPh3)2 (993 mg, 1.415 mmol), PPh3 (742 mg, 2.830 mmol) and LiCI (5.04 g, 119 mmol) and the mixture was stirred at 140 degrees C for 3 h. The mixture was quenched with sat. NH4CI aq. and filtered through celite. The filtrate was poured into water and the products were extracted with diethyleter. The extracts were washed with brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n- Hexane:EtOAc (50:1 ) to give the title compound (4.79 g, 84%). 1H-NMR (300MHz, CDCI3): 0.59 (6H, t), 1.10 (9H, s), 2.06 (4H, q), 2.22 (3H, s), 2.26 (3H, s), 2.69-2.78 (2H, m), 2.80-2.87 (2H, m), 3.33 (2H, d), 4.95-5.05 (2H, m), 5.88-6.02 (1 H, m), 6.88-7.00 (6H, m).
(3) Preparation of 1-{4-[1-(4-Allyl-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl- phenyl}-4,4-dimethyl-pentan-3-ol
Figure imgf000335_0001
To a solution of 1-{4-[1-(4-Allyl-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl- phenyl}-4,4-dimethyl-pentan-3-one (compound prepared in Example 134-(2)) (4.79 g, 11.84 mmol) in EtOH (100 ml) was added NaBH4 (537 mg, 14.21 mmol) at 0 degrees C and the mixture was stirred at room tempareture for 3 h. The reaction mixture was quenched with water and poured into sat. NH4CI aq and the products were extracted with EtOAc. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane:EtOAc (20:1 ) to give the title compound (2.7 g, 56%).
1H-NMR (300MHz, CDCI3): 0.60 (6H, t), 0.90 (9H, s), 1.45-1.59 (1 H, m), 1.74- 1.85 (1H, m), 2.07 (4H, q), 2.23 (3H, s), 2.28 (3H, s), 2.51-2.60 (1H, m), 2.80- 2.90 (1 H, m), 3.22-3.29 (1 H, m), 3.32 (2H, d), 4.85-5.08 (2H, m), 5.90-6.02 (1 H, m), 6.89-7.03 (6H, m).
(4) Preparation of [1-(2-{4-[1-(4-Allyl-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl- phenyl}-ethyl)-2,2-dimethyl-propoxy]-triethyl-silane
Figure imgf000335_0002
To a stirred solution of 1-{4-[1-(4-Allyl-3-methyl-phenyl)-1-ethyl-propyl]-2- methyl-phenyl}-4,4-dimethyl-pentan-3-ol (compound prepared in Example 134- (3)) (1.40 g, 3.44 mmol) in anhydrous DMF (11.5 ml) were added Et3SiCI (0.69 ml, 4.12mmol) and imidazole (585 mg, 8.59 mmol) at 0 degrees C under N2 atmosphere and the mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water and the products were extracted with EtOAc. The extracts were washed with 1 N HCl, sat. NaHC03 and brine, dried over Na2Sθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane:EtOAc (30:1) to give the title compound (1.79 g, 100%) as colorless sticky oil. 1H-NMR (300MHz, CDCI3): 7.05-6.85 (m, 6H), 6.00-5.90 (m, 1 H), 5.10-4.90 (m, 2H), 3.40-3.30 (m, 3H), 2.85-2.70 (m, 1H), 2.50-2.40 (m, 1H), 2.25 (s, 3H), 2.20 (s, 3H), 2.05 (q, 4H), 1.85-1.70 (m, 1 H), 1.55-1.40 (m, 1 H), 1.05-0.90 (m, 15H), 0.70-0.50 (m, 15H).
(5) Preparation of 2-(4-{1-[4-(4,4-Dimethyl-3-triethylsilanyloxy-pentyl)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-ethanol
Figure imgf000336_0001
To a stirred solution of [1-(2-{4-[1-(4-Allyl-3-methyl-phenyl)-1-ethyl-propyl]-2- methyl-phenyl}-ethyl)-2,2-dimethyl-propoxy]-triethyl-silane (compound prepared in Example 134-(4)) (1.79 g, 3.44 mmol) in Acetone/tBuOH/Water (4/1/1 v/v, 96 ml) were added NMO (1.01 g, 8.62 mmol) and Os04(2.5%w/w in tBuOH, 4.30 ml, 10 mol%) at room temp, under N2 atmosphere. After stirring for 12.0 h, the reaction mixture was quenched with sat. NaHC03 aq. and stirred for additionally 20 min. The reaction mixture was extracted with EtOAc. Resulted organic layer was washed with brine and dried over anhydrous Na2S04, filtered, and evaporated under reduced pressure. The obtained residue was dissolved in EtOH/Water (1/1 v/v, 82 ml). To the solution, Nal04 (866 mg, 4.05 mmol) and NaBH4 (460 mg, 12.2 mmol) was added and the mixture was stirred at 0 degrees C for 30 min. The reaction mixture was poured into sat. NH4CI aq. and the products were extracted with EtOAc. The extracts were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane: EtOAc (10:1) to give the title compound (1.33 g, 74%) as colorless sticky oil. 1H-NMR (300MHz, CDCI3): 7.05-6.85 (m, 6H), 3.90-3.80 (m, 2H), 3.40 (dd, 1 H), 2.90-2.70 (m, 3H), 2.50-2.40 (m, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 2.05 (q, 4H), 1.85-1.70 (m, 1 H), 1.55-1.40 (m, 1 H), 1.00 (t, 9H), 0.90 (t, 9H), 0.60 (t, 6H).
(6) Preparation of {1-[2-(4-{1-[4-(2-Bromo-ethyl)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-ethyl]-2,2-dimethyl-propoxy}-triethyl-silane
Figure imgf000337_0001
To a stirred solution of 2-(4-{1-[4-(4,4-Dimethyl-3-triethylsilanyloxy-pentyl)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-ethanol (compound prepared in Example 134-(5)) (1.33 g, 2.54 mmol) in CH2CI2 (8.5 ml) were added CBr4 (1.05 g, 3.18 mmol) and PPh3 (999 mg, 3.80 mmol) at 0 degrees C under N2 atmosphere. After stirring for 30min., the reaction mixture was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-Hexane:Acetone=20:1) to give the title compound (829 mg, 54%) as colorless sticky oil.
1H-NMR (300MHz, CDCI3): 7.05-6.85 (m, 6H), 3.50 (t, 3H), 3.40 (dd, 1 H), 3.15 (t, 2H), 2.85-2.70 (m, 1H), 2.50-2.35 (m, 1H), 2.25 (s, 3H), 2.20 (s, 3H), 2.05 (q, 4H), 1.85-1.70 (m, 1 H), 1.55-1.40 (m, 1 H), 1.00 (t, 9H), 0.90 (t, 9H), 0.60 (t, 6H).
(7) Preparation of 1-(4-{1-[4-(2-Bromo-ethyl)-3-methyl-phenyl]-1-ethyl-propyl}-2- methyl-phenyl)-4,4-dimethyl-pentan-3-oi
Figure imgf000337_0002
To a stirred solution of {1-[2-(4-{1-[4-(2-Bromo-ethyl)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-ethyl]-2,2-dimethyl-propoxy}-triethyl-silane (compound prepared in Example 134-(6)) (1.00 g, 1.70 mmol) in CH3CN (17 ml) was added 1 N HCl (1.7 ml) at room temperature. After stirring for 3.0 h, the reaction mixture was poured into water and the products were extracted with EtOAc. The extracts were washed with sat. NaHC03 aq., dried over Na2Sθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane: EtOAc (7:1) to give the title compound (735 mg, 91%) as colorless sticky oil.
1H-NMR (300MHz, CDCI3): 7.05-6.85 (m, 6H), 3.50 (t, 3H), 3.25 (m, 1H), 3.15 (t, 2H), 2.90-2.80 (m, 1 H), 2.60-2.50 (m, 1 H), 2.25 (s, 6H), 2.05 (q, 4H), 1.85-1.70 (m, 1 H), 1.55-1.40 (m, 1 H), 0.90 (t, 9H), 0.60 (t, 6H). (8) Preparation of 4-Mercapto-butyric acid methyl ester
Figure imgf000338_0001
To a stirred solution of Dihydro-thiophen-2-one (2.06 g, 20.2 mmol) in 70.0 mL of MeOH was added Et3N (4.67 ml, 33.5 mmol) and refluxed for 24 h. The reaction mixture was evaporated under reduced pressure to give the title compound (2.50 g, 92.3%). 1H-NMR (300MHz, CDCI3): 3.70 (s, 3H), 2.60 (m, 2H), 2.48 (t, 2H), 1.95 (m, 2H). (9) Preparation of 4-[2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenyl)-ethylsulfanyl]-butyric acid ethyl ester
Figure imgf000338_0002
To a stirred solution of 1-(4-{1-[4-(2-Bromo-ethyl)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol (compound prepared in Example 134-(7)) (360 mg, 0.76 mmol) and 4-Mercapto-butyric acid methyl ester (compound prepared in Example 134-(8)) (204 mg, 1.52 mmol) in 3.80 ml of anhydrous DMF was added i-Pr2EtN (0.20 ml, 1.15 mmol) under N2 atmosphere at room temperature. The reaction mixture was stirred for 18 h at room temperature. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (n-
Hexane:EtOAc = 10:1) to give the title compound (48.5 mg, 12%) as colorless sticky oil.
1H-NMR (300MHz, CDCI3): 7.05-6.85 (m, 6H), 3.70 (s, 3H), 3.25 (d, 1 H), 2.90- 2.50 (m, 10H), 2.25 (s, 6H), 2.05 (q, 4H), 1.85-1.75 (m, 1H), 1.55-1.40 (m, 1H), 0.90 (s, 9H), 0.60 (t, 6H).
(10) Preparation of 4-[2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenyl)-ethanesulfonyl]-butyric acid ethyl ester
Figure imgf000339_0001
To a stirred solution of 4-[2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenyl)-ethylsulfanyl]-butyric acid ethyl ester (compound prepared in Example 134-(9)) (100 mg, 0.19 mmol) in 2.00ml of CH2CI2 was added mCPBA (144 mg, 0.48 mmol) at 0 degrees C and gradually warmed up to room temperature. The reaction mixture was stirred for 3.0 h at room temperature. The reaction mixture was poured into Na2S203 aq. and the products were extracted with CH2CI2. The extracts were washed with brine, dried over Na2Sθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane: EtOAc (4:1) to give the title compound (103 mg, 99%) as colorless sticky oil. 1H-NMR (300MHz, CDCI3): 7.05-6.85 (m, 6H), 3.70 (s, 3H), 3.30-3.00 (m, 7H), 2.95-2.80 (m, 1 H), 2.65-2.50 (m, 3H), 2.30 (s, 3H), 2.25 (s, 3H), 2.20-2.05 (m, 6H), 1.85-1.75 (m, 1 H), 1.60-1.45 (m, 1 H), 0.90 (s, 9H), 0.60 (t, 6H).
(11 ) Preparation of 4-[2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenyl)-ethanesulfonyl]-butyric acid
Figure imgf000339_0002
To a stirred solution of 4-[2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenyl)-ethanesulfonyl]-butyric acid ethyl ester (compound prepared in Example 134-(10)) (103 mg, 0.18 mmol) in 2.50 ml of Dioxane/Water (4/1 v/v) was added NaOH (14.4 mg, 0.36 mmol) at room temperature. The reaction mixture was stirred for 2.5 h at room temperature. The reaction mixture was poured into 1 N HCl and extracted with EtOAc. The extracts were washed with brine, dried over Na2Sθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane: EtOAc (1 :1) to give the title compound (44.1 mg, 45%) as colorless sticky oil. 1H-NMR (300MHz, CDCI3): 7.05-6.85 (m, 6H), 3.30-3.00 (m, 7H), 2.90-2.75 (m, 1 H), 2.60-2.40 (m, 3H), 2.20 (s, 6H), 2.20-2.05 (m, 6H), 1.85-1.70 (m, 1 H), 1.55- 1.40 (m, 1 H), 0.90 (s, 9H), 0.60 (t, 6H); MS (ESI-) : 543 ([M-H]").
Example 135
Preparation of 3-[2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenyl)-ethanesulfonyl]-propionic acid
Figure imgf000340_0001
(1 ) Preparation of 3-[2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenyl)-ethylsulfanyl]-propionic acid methyl ester
Figure imgf000340_0002
Using the same procedure as described for the preparation of Example 134-(9), the title compound was prepared from 1-(4-{1-[4-(2-Bromo-ethyl)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol (compound prepared in Example 134-(7)) and Methyl 3-mercaptopropionate. The yield was 36%.
1H-NMR (300MHz, CDCI3): 7.05-6.85 (m, 6H), 3.70 (s, 3H), 3.25 (d, 1 H), 2.90- 2.50 (m, 10H), 2.25 (s, 6H), 2.05 (q, 4H), 1.85-1.70 (m, 1 H), 1.55-1.40 (m, 1 H), 0.90 (t, 9H), 0.60 (t, 6H); MS (ESI+) : 535 ([M+Na]+).
(2) Preparation of 3-[2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenyl)-ethanesulfonyl]-propionic acid methyl ester
Figure imgf000340_0003
Using the same procedure as described for the preparation of Example 134- (10), the title compound was prepared from 3-[2-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-ethylsulfanyl]- propionic acid methyl ester (compound prepared in Example 135-(1)). The yield was 91 %.
1H-NMR (300MHz, CDCI3): 7.05-6.85 (m, 6H), 3.70 (s, 3H), 3.30-3.10 (m, 7H),
2.90-2.75 (m, ,3H), 2.65-2.50 (m, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 2.05 (q, 4H),
1.85-1.70 (m, 1 H), 1.55-1.40 (m, 1 H), 0.90 (t, 9H), 0.60 (t, 6H); MS (ESI+) : 567
([M+Na]+).
(3) Preparation of 3-[2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenyl)-ethanesulfonyl]-propionic acid
Figure imgf000341_0001
Using the same procedure as described for the preparation of Example 134- (11), the title compound was prepared from 3-[2-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-ethanesulfonyl]- propionic acid methyl ester (compound prepared in Example 135-(2)). The yield was 19%.
1H-NMR (300MHz, CDCI3); 7.05-6.85 (m, 6H), 3.30-3.15 (m, 6H), 3.10-3.00 (m, 2H), 2.90-2.75 (m, 3H), 2.65-2.50 (m, 1 H), 2.25 (s, 6H), 2.05 (m, 4H), 1.85-1.70 (m, 1 H), 1.55-1.40 (m, 1 H), 0.90 (t, 9H), 0.60 (t, 6H); MS (ESI-) : 529 ([M-H]").
Example 136
Preparation of N-tert-Butyl-2-(4-{1 -[4-((S)-2,3-dihydroxy-propoxy)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-acetamide
Figure imgf000341_0002
(1 ) Preparation of 4-{1-[4-((R)-2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3-methyl- phenyl]-1 -ethyl-propyl}-2-methyl-phenol
Figure imgf000341_0003
To a solution of 3,3-bis[4-hydroxy-3-methylphenyl]pentane (1 g, 3.52 mmol) in DMSO (9 ml) was added t-BuOK (379 mg, 3.38 mmol) at room temperature under N2 atmosphere. After 5min., (S)-(+)-2,2-dimethyl 1 ,3-dioxolan-4-yl-methyl- p-toluenesulfonate (796 mg, 2.78 mmol) was added and the reaction mixture was stirred at 60 degrees C for 12 h. Then the reaction mixture was poured into sat. NH4CI and the products were extracted with EtOAc. The extracts were washed with brine, dried over Na2Sθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n- Hexane:Acetone (20:1) to give the title compound (472 mg, 42.6%) as a white amorphous.
1H-NMR (300MHz, CDCI3): 7.00-6.80 (m, 4H), 6.80-6.60 (m, 2H), 4.90 (s, 1H), 4.55-4.45 (m, 1H), 4.20-3.90 (m, 4H), 2.10, 2.20(S, 6H), 2.10-1.90 (m, 4H), 1.49 (s, 3H), 1.48 (s, 3H), 0.60 (t, 6H). (2) Preparation of Trifluoro-methanesulfonic acid 4-{1 -[4-((R)-2,2-dimethyl- [1 ,3]dioxolan-4-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl ester
Figure imgf000342_0001
To a stirred solution of 4-{1-[4-((R)-2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenol (compound prepared in Example 136-(1)) (18.6 g, 46.7 mmol) in CH2CI2 (460 ml) were added Tf20 (11.8 ml, 70.1 mmol) and pyridine (7.6 ml, 93.4 mmol) and the mixture was stirred at 0 degrees C under N2 atmosphere for 1 h. Then the reaction mixture was poured into sat. NaHC03 and the products were extracted with CH2CI2. The extracts were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n- Hexane:Acetone (10:1) to give the title compound (14.5 g, 85%) as yellow oil. 1H-NMR (300MHz, CDCI3): 7.00-7.15 (m, 3H), 6.80-7.00 (m, 2H), 6.70 (d, 1 H), 4.45-4.55 (m, 1 H), 4.15 (m, 1 H), 4.05 (m, 1 H), 3.90-4.00 (m, 1 H), 2.35 (s, 3H), 2.15 (s, 3H), 2.05 (q, 4H), 1.50 (s, 3H), 1.40 (s, 3H), 0.60 (t, 6H). (3) Preparation of (R)-4-{4-[1-(4-Allyl-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl- phenoxymethyl}-2,2-dimethyl-[1 ,3]dioxolane
Figure imgf000343_0001
To a stirred solution of Trifluoro-methanesulfonic acid 4-{1 -[4-((R)-2,2-dimethyl- [1 ,3]dioxolan-4-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl ester (compound prepared in Example 136-(2)) (8.52 g, 16.1 mmol) in DMF (80 ml) were added Pd2CI2(PPh3)2 (1.13 g, 10 mol%), PPh3 (842 mg, 20 mol%) and LiCI (5.72 g, 135 mmol) at room temperature under N2 atmosphere. After stirred for 10min., allyltributyltin (19.9 ml, 64.2 mmol) was added to the reaction mixture and stirred at 130 degrees C for 6 h. The reaction mixture was cooled to room temperature, poured into 1 N HCl and the products were extracted with diethylether. The extracts were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane:EtOAc (20:1) to give the title compound (6.08 g, 90%) as colorless oil.
1H-NMR (300MHz, CDCI3): 7.05-6.90 (m, 5H), 6.70 (d, 1 H), 6.05-5.85 (m, 1 H), 5.05-4.90 (m, 2H), 4.50 (m, 1 H), 4.15 (m, 1 H), 4.05 (m, 1 H), 4.00-3.85 (m, 2H), 3.35 (d, 2H), 2.20 (s, 3H), 2.15 (s, 3H), 2.05 (q, 4H), 1.50 (s, 3H), 1.40 (s, 3H), 0.60 (t, 6H).
(4) Preparation of 2-(4-{1-[4-((R)-2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-ethanol
Figure imgf000343_0002
To a stirred solution of (R)-4-{4-[1 -(4-Allyl-3-methyl-phenyl)-1 -ethyl-propyl]-2- methyl-phenoxymethyl}-2,2-dimethyl-[1 ,3]dioxolane (compound prepared in Example 136-(3)) (5.14 g, 12.2 mmol) in 336ml of Acetone/t-BuOH/Water (4/1/1 v/v) were added NMO (3.57 g, 30.5 mmol) and Os04 (2.5% w/w in t-BuOH, 15.2 ml, 10 mol%) at room temperature under N2 atmosphere and the mixture was stirred for 12 h. The mixture was poured into sat. NaHC03 and the products were extracted with EtOAc. The extracts were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to give 6.18 g of crude diol compound. The obtained crude diol compound (6.18 g) was dissolved in 274 ml of EtOH/Water (1/1 v/v). Then Nal04 (2.89 g, 13.5 mmol) was added to the reaction mixture at 0 degrees C and followed the addition of NaBH (1.54 g, 13.5 mmol) portion wise. The reaction mixture was stirred for 30min and poured into sat. NH4CI and the products were extracted with EtOAc. The extracts were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n- Hexane:EtOAc (5:1) to give the title compound (3.46 g, 67%) as yellowish oil. 1H-NMR (300MHz, CDCI3): 7.05-6.90 (m, 5H), 6.70 (d, 1H), 4.45 (m, 1H), 4.15 (m, 1 H), 4.05 (m, 1 H), 4.00-3.85 (m, 2H), 3.70 (t, 2H), 2.85 (t, 2H), 2.30 (s, 3H), 2.15 (s, 3H), 2.05 (q, 4H), 1.50 (s, 3H), 1.40 (s, 3H), 0.60 (t, 6H).
(5) Preparation of (4-{1-[4-((R)-2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-acetic acid
Figure imgf000344_0001
To a stirred solution of 2-(4-{1-[4-((R)-2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)- 3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-ethanol (compound prepared in Example 136-(4)) (1.34 g, 3.14 mmol) in CH3CN (15 ml) and NaH2P04 buffer solution (0.67M, 11.4 ml) were added TEMPO (34.3 mg, 0.22 mmol), NaOCI2 (710 mg, 6.28 mmol) in water (3 ml) and NaOCI (0.00387 ml, 2 mol%). The reaction mixture was stirred for 4.0 h at 35 degrees C. The mixture was poured into sat. NaHC03 and the products were extracted with EtOAc The extracts were washed with brine, dried over Na2S0 , filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane: EtOAc (5:1 ) to give the title compound (1.21 g, 95%) as colorless sticky oil.
1H-NMR (300MHz, CDCI3): 7.05 (m, 1 H), 7.00-6.90 (m, 4H), 6.70 (d, 1 H), 4.45 (m, 1H), 4.15 (m, 1H), 4.05 (m, 1H), 4.00-3.90 (m, 2H), 3.60 (s, 2H), 2.25 (s, 3H), 2.15 (s, 3H), 2.05 (q, 4H), 1.45 (s, 3H), 1.40 (s, 3H), 0.60 (t, 6H).
(6) Preparation of N-tert-Butyl-2-(4-{1-[4-((R)-2,2-dimethyl-[1 ,3]dioxolan-4- ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-acetamide
Figure imgf000345_0001
To a stirred solution of (4-{1-[4-((R)-2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-acetic acid (compound prepared in Example 136-(5)) (530 mg, 1.20 mmol) in anhydrous DMF (9.3 ml) were added t-BuNH2 (263 mg, 3.60 mmol), EDC (345 mg, 1.80 mmol), HOBT (243 mg, 1.80 mmol) and i-Pr2EtN (0.31 ml, 3.60 mmol) at 0 degrees C and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the products were extracted with EtOAc. The extracts were washed with 1 N HCl, sat. NaHCOs aq. and brine, dried over Na2Sθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane:Acetone (4:1) to give the title compound (525 mg, 88%) as a white amorphous.
1H-NMR (300MHz, CDCI3): 7.05-6.90 (m, 4H), 6.85 (m, 1 H), 6.70 (d, 1 H), 5.05 (bs, 1 H), 4.50 (m, 1 H), 4.15 (m, 1 H), 4.05 (m, 1 H), 4.00-3.90 (m, 2H), 3.50 (s, 2H), 2.25 (s, 3H), 2.15 (s, 3H), 2.05 (q, 4H), 1.45 (s, 3H), 1.40 (s, 3H), 1.25 (s, 9H), 0.60 (t, 6H); MS (ESI+) : 496 ([M+H]+).
(7) Preparation of N-tert-Butyl-2-(4-{1-[4-((S)-2,3-dihydroxy-propoxy)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-acetamide
Figure imgf000346_0001
To a stirred solution of N-tert-Butyl-2-(4-{1-[4-((R)-2,2-dimethyl-[1 ,3]dioxolan-4- ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-acetamide (compound prepared in Example 136-(6)) (525 mg, 1.06 mmol) in THF/H20 (5/1 v/v, 4.9 ml) was added TFA (0.82 ml, 10.6 mmmol) at 0 degrees C under N2 atmosphere and the mixture was stirred at room temperature for 5 h. The mixture was poured into sat. NaHCθ3 aq. and the products were extracted with CH2CI2. The extracts were washed with brine, dried over Na2S0 , filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane:EtOAc (1 :1) to give the title compound (233 mg, 48%) as colorless sticky oil.
1H-NMR (300MHz, CDCI3): 7.05-6.90 (m, 4H), 6.85 (m, 1 H), 6.70 (d, 1 H), 5.05 (bs, 1 H), 4.15 (m, 1 H), 4.05 (m, 2H), 4.00-3.90 (m, 2H), 3.50 (s, 2H), 2.60 (d, 1 H), 2.25 (s, 3H), 2.15 (s, 3H), 2.05 (m, 5H), 1.25 (s, 9H), 0.60 (t, 6H); MS (ESI+) : 456 ([M+H]+).
Example 137
Preparation of (4-{1 -[4-((S)-2,3-Dihydroxy-propoxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-acetic acid tert-butyl ester
Figure imgf000346_0002
(1 ) Preparation of (4-{1-[4-((R)-2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-acetic acid tert-butyl ester
Figure imgf000346_0003
To a stirred solution of (4-{1-[4-((R)-2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-acetic acid (compound prepared in Example 136-(5)) (408 mg, 0.93 mmol) in CH2CI2 (9,3 ml) were added t-BuOH (207 mg, 2.79 mmol), DOC (230 mg, 1.11 mmol) and DMAP (11.4 mg, 10 mol%) at 0 degrees C and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the products were extracted with EtOAc. The extracts were washed with 1N HCl, sat. NaHCOsaq. and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane:Acetone (5:1) to give the title compound (217 mg, 47%) as a white amorphous. 1H-NMR(300MHz, CDCI3): 7.05-6.85 (m, 6H), 6.65 (d, 1H), 4.50 (m, 1H), 4.20 (m, 1H), 4.05 (m, 1H), 4.00-3.90 (m, 2H), 3.50 (s, 2H), 2.25 (s, 3H), 2.15 (s, 3H), 2.05 (q, 4H), 1.45 (s, 3H), 1.40 (s, 12H), 0.60 (t, 6H); MS (ESI+) : 514 ([M+NH4]+).
(2) Preparation of (4-{1-[4-((S)-2,3-Dihydroxy-propoxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-acetic acid tert-butyl ester
Figure imgf000347_0001
Using the same procedure as described for the preparation of Example 136-(7), the title compound was prepared from (4-{1-[4-((R)-2,2-Dimethyl-[1 ,3]dioxolan-4- ylmethoxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-acetic acid tert- butyl ester (compound prepared in Example 137-(1)). The yield was 75%.
1H-NMR (300MHz, CDCI3): 7.05 (m, 1H), 7.00-6.90 (m, 4H), 6.65 (d, 1H), 4.50 (m, 1H), 4.15 (m, 1H), 4.05 (m, 1H), 3.90-3.70 (m, 2H), 3.50 (s, 2H), 2.75 (d, 1H), 2.25 (s, 3H), 2.15 (s, 3H), 2.05 (m, 5H), 1.40 (s, 9H), 0.60 (t, 6H); MS (ESI+) : 474 ([M+NH4]+).
Example 138
Preparation of 3-[4-(1 -Ethyl-1 -{3-methyl-4-[2-(2-methyl-propane-2-sulfinyl)-ethyl]- phenyl}-propyl)-2-methyl-phenoxy]-propane-1,2(S)-diol
Figure imgf000348_0001
(1) Preparation of (R)-4-(4-{1-[4-(2-Bromo-ethyl)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenoxymethyl)-2,2-dimethyl-[1 ,3]dioxolane
Figure imgf000348_0002
To a stirred solution of 2-(4-{1 -[4-((R)-2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)- 3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-ethanol (compound prepared in Example 136-(4)) (2.51 g, 5.88 mmol) in 20 ml of CH2CI2 were added CBr4 (2.44 g, 7.36 mmol) and PPh3 (2.31 g, 8.81 mmol) at 0 degrees C under N2 atmosphere. After stirred for 30min., the reaction mixture was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (n-Hexane:Acetone=10:1 ) to give the title compound (2.76 g, 96%) as yellowish oil.
1H-NMR (300MHz, CDCI3): 7.05-6.90 (m, 5H), 6.70 (d, 1 H), 4.45 (m, 1 H), 4.15 (m, 1 H), 4.05 (m, 1 H), 4.00-3.85 (m, 2H), 3.50 (t, 2H), 3.10 (t, 2H), 2.25 (s, 3H), 2.15 (s, 3H), 2.05 (q, 4H), 1.48 (s, 3H), 1.40 (s, 3H), 0.60 (t, 6H).
(2) Preparation of (R)-4-(4-{1-[4-(2-tert-Butylsulfanyl-ethyl)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenoxymethyl)-2,2-dimethyl-[1 ,3]dioxolane
Figure imgf000348_0003
To a stirred solution of (R)-4-(4-{1 -[4-(2-Bromo-ethyl)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenoxymethyl)-2,2-dimethyl-[1 ,3]dioxolane (compound prepared in Example 138-(1 )) (1.33 g, 2.72 mmol) in 27.0 ml of acetone were added t-BuSH (0.46 ml, 4.08 mmol) and KOH (275 mg, 4.90 mmol) in 27.0ml of EtOH. The reaction mixture was refluxed for 5.0 h. The mixture was poured into water and the products were extracted with EtOAc. The extracts were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane:EtOAc (10:1 ) to give the title compound (962 mg, 71%) as yellowish sticky oil. 1H-NMR (300MHz, CDCI3): 7.05 (m, 1 H), 7.00-6.85 (m, 4H), 6.70 (d, 1 H), 4.50 (m, 1 H), 4.15 (m, 1 H), 4.05 (m, 1 H), 4.00-3.90 (m, 2H), 2.90-2.65 (m, 4H), 2.25 (s, 3H), 2.15 (s, 3H), 2.05 (q, 4H), 1.45 (s, 3H), 1.40 (s, 3H), 1.35 (s, 9H), 0.60 (t, 6H).
(3) Preparation of 4(R)-[4-(1 -Ethyl-1 -{3-methyl-4-[2-(2-methyl-propane-2- sulfinyl)-ethyl]-phenyl}-propyl)-2-methyl-phenoxymethyl]-2,2-dimethyl- [1 ,3]dioxolane
Figure imgf000349_0001
To a solution of (R)-4-(4-{1-[4-(2-tert-Butylsulfanyl-ethyl)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenoxymethyl)-2,2-dimethyl-[1 ,3]dioxolane (compound prepared in Example 138-(2)) (379 mg, 0.76 mmol) in EtOH/H20 (1/2 v/v, 0.76 ml) at 0 degrees C was added Nal0 (163 mg, 0.76 mmol) and the mixture was stirred for 5 h. The mixture was poured into water and the products were extracted with CH2CI2. The extracts were washed with brine, dried over Na2Sθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with CH2Cl2:MeOH (30:1 ) to give the title compound (366 mg, 94%) as a white amorphous.
1H-NMR (300MHz, CDCI3): 7.05 (m, 1 H), 7.00-6.85 (m, 4H), 6.70 (d, 1 H), 4.45 (m, 1 H), 4.15 (m, 1 H), 4.05 (m, 1 H), 4.00-3.90 (m, 2H), 3.20 (m, 1 H), 3.00 (m, 1 H), 2.70 (m, 2H), 2.30 (s, 3H), 2.15 (s, 3H), 2.05 (q, 4H), 1.45 (s, 3H), 1.40 (s, 3H), 1.25 (s, 9H), 0.60 (t, 6H) M.S.(ESI+): [M+H]+= 515
(4) Preparation of 3-[4-(1 -Ethyl-1 -{3-methyl-4-[2-(2-methyl-propane-2-sulfinyl)- ethyl]-phenyl}-propyl)-2-methyl-phenoxy]-propane-1 ,2(S)-diol
Figure imgf000350_0001
To a stirred solution of 4(R)-[4-(1 -Ethyl-1 -{3-methyl-4-[2-(2-methyl-propane-2- sulfinyl)-ethyl]-phenyl}-propyl)-2-methyl-phenoxymethyl]-2,2-dimethyl- [1 ,3]dioxolane (compound prepared in Example 138-(3)) (366 mg, 0.71 mmol) in THF/H20 (5/1 v/v, 3.2 ml) was added TFA (0.55 mL, 7.10 mmmol) at 0 degrees C under N2 atmosphere and the reaction mixture was stirred at room temperature for 5.0 h. The mixture was poured into sat. NaHCOs aq. and the products were extracted with CH2CI2. The extracts were washed with brine, dried over Na2Sθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane:EtOAc (1 :1) to give the title compound (109 mg, 32%) as colorless sticky oil. 1H-NMR (300MHz, CDCI3): 7.05(m, 1 H), 7.00-6.85 (m, 4H), 6.70 (d, 1 H), 4.15 (m, 1H), 4.05 (m, 2H), 3.90-3.70 (m, 2H), 3.20 (m, 1 H), 3.00 (m, 1 H), 2.65 (m, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 2.05 (q, 4H), 1.25 (s, 9H), 0.60 (t, 6H); MS (ESI+) : 475 ([M+H]+).
Example 139
Preparation of 3-[4-(1 -Ethyl-1 -{3-methyl-4-[2-(2-methyl-propane-2-sulfonyl)- ethyl]-phenyl}-propyl)-2-methyl-phenoxy]-propane-1 ,2(S)-diol
Figure imgf000350_0002
(1) Preparation of (R)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[2-(2-methyl-propane-2- sulfonyl)-ethyl]-phenyl}-propyl)-2-methyl-phenoxymethyl]-2,2-dimethyl- [1 ,3]dioxolane
Figure imgf000350_0003
To a stirred solution of (R)-4-(4-{1-[4-(2-tert-Butylsulfanyl-ethyl)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenoxymethyl)-2,2-dimethyl-[1 ,3]dioxolane (compound prepared in Example 138-(2)) (503 mg, 1.00 mmol) in CH2CI2 (5 ml) was added mCPBA (757 mg, 2.5 mmol) at 0 degrees C and the reaction mixture was stirred for 12 h at room temperature. The mixture was poured into Na2S2θ3 aq. and the products were extracted with CH2CI2. The extracts were washed with brine, dried over Na2Sθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane: EtOAc (3:1) to give the title compound (320 mg, 60%) as a white amorphous. 1 H-NMR (300MHz, CDCI3): 7.05 (m, 1 H), 7.00-6.85 (m, 4H), 6.70 (d, 1 H), 4.45 (m, 1 H), 4.15 (m, 1 H), 4.05 (m, 1 H), 4.00-3.90 (m, 2H), 3.20- 3.00 (m, 4H), 2.30 (s, 3H), 2.15 (s, 3H), 2.05 (q, 4H), 1.50 (s, 3H), 1.48 (s, 9H), 1.40 (s, 3H), 0.60 (t, 6H); MS (ESI+) : 548 ([M+NH4]+).
(2) Preparation of (S)-3-[4-(1 -Ethyl-1 -{3-methyl-4-[2-(2-methyl-propane-2- sulfonyl)-ethyl]-phenyl}-propyl)-2-methyl-phenoxy]-propane-1 ,2-diol
Figure imgf000351_0001
Using the same procedure as described for the preparation of Example 138-(4), the title compound was prepared from (R)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[2-(2- methyl-propane-2-sulfonyl)-ethyl]-phenyl}-propyl)-2-methyl-phenoxymethyl]-2,2- dimethyl-[1 ,3]dioxolane (compound prepared in Example 139-(1)). The yield was 56%.
1H-NMR (300MHz, CDCI3): 7.05 (m, 1 H), 7.00-6.85 (m, 4H), 6.70 (d, 1 H), 4.15 (m, 1 H), 4.05 (m, 2H), 3.90-3.70 (m, 2H), 3.20-3.00 (m, 4H), 2.55 (d, 1 H), 2.30 (s, 3H), 2.20 (s, 3H), 2.05 (m, 5H), 1.50 (s, 9H), 0.60 (t, 6H); MS (ESI+) : 508 ([M+NH4]+). Example 140
Preparation of 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt
Figure imgf000352_0001
(1) Preparation of 5(R)-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000352_0002
To a stirred solution of 4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 19-(2)) (702 mg, 1.83 mmol) in N,N-dimethylacetamide (18 ml) were added K2CO3 (633 mg, 4.58 mmol) and toluene-4-sulfonic acid (R)-5-oxo-tetrahydro-furan-2-ylmethyl ester (743 mg, 2.75 mmol) and the mixture was stirred at 130 degrees C for 3 h. The reaction mixture was cooled to room temperature and poured into aqueous NH4CI. The products were extracted with ethyl acetate and hexane. The extracts were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (ethyl acetate/hexane = 20/80 to 35/65) to give the title compound (755 mg, 86 %). 1H-NMR: 0.59 (t, 6H), 0.89 (s, 9H), 1.38 (d, 1 H), 1.44-1.55 (m, 1 H), 1.74-1.84 (m, 1 H), 2.03 (q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.27-2.62 (m, 4H), 2.72-2.91 (m, 2H), 3.21-3.27 (m, 1 H), 4.04-4.19 (m, 2H), 4.84-4.91 (m, 1 H), 6.66 (d, 1 H), 6.89- 6.97 (m, 4H), 7.02 (d, 1 H).
(2) 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt
Figure imgf000353_0001
To a solution of 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 140-(1 )) (547 mg, 1.14mmol) in methanol (4.5 ml) and tetrahydrofuran (4.5 ml) was added 1 N KOH solution (4.55 ml) and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo and poured into aqueous KHSθ4and the products were extracted with AcOEt. The extracts were washed with H2O, dried over MgSθ4, filtered and concentrated in vacuo. The obtained residue (524 mg) was dissolved with
MeOH (2 ml) and 1.0M solution of NaOMe in MeOH (1.027 ml, 1.051 mmol) was added. The mixture was stirred for 2 min. and concentrated in vacuo to give the title compound (545 mg, 92%). 1H-NMR (CD3OD): 0.58 (t, 6H), 0.86 (s, 9H), 1.43-1.54 (m, 1 H), 1.73-1.99 (m, 3H), 2.04 (q, 4H), 2.14 (s, 3H), 2.23 (s, 3H), 2.36 (dt, 2H), 2.48-2.58 (m, 1 H), 2.81-2.91 (m, 1H), 3.15 (dd, 1 H), 3.88-3.97 (m, 3H), 6.75 (d, 1 H), 6.83-7.02 (m, 5H); MS (ESI-) : 497 ([M-H]").
Example 141 Preparation of 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt
Figure imgf000353_0002
(1 ) Preparation of 5(R)-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000354_0001
To a stirred solution of 4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 20) (670 mg, 1.75 mmol) in N,N-dimethylacetamide (17 ml) were added K2C03 (605 mg, 4.38 mmol) and toluene-4-sulfonic acid (R)-5-oxo-tetrahydro-furan-2-ylmethyl ester (710 mg, 2.63 mmol) and the mixture was stirred at 130 degrees C for 3 h. The reaction mixture was cooled to room temperature and poured into aqueous NH4CI. The products were extracted with ethyl acetate and hexane. The extracts were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (ethyl acetate/hexane = 20/80 to 35/65) to give the title compound (330 mg, 39%). 1H-NMR: 0.59 (t, 6H), 0.89 (s, 9H), 1.38 (d, 1H), 1.44-1.55 (m, 1H), 1.74-1.84 (m, 1 H), 2.03 (q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.27-2.62 (m, 4H), 2.72-2.91 (m, 2H), 3.21-3.27 (m, 1 H), 4.04-4.19 (m, 2H), 4.84-4.91 (m, 1 H), 6.66 (d, 1H), 6.89- 6.97 (m, 4H), 7.01 (d, 1 H).
(2) 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt
Figure imgf000354_0002
To a solution of 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 141 (1)) (306 mg, 0.636 mmol) in methanol (2.5 ml) and tetrahydrofuran (2.5ml) was added 1 N KOH solution (2.55 ml) and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo and poured into aqueous KHS04and the products were extracted with AcOEt. The extracts were washed with H2O, dried over MgSθ4, filtered and concentrated in vacuo. The obtained residue (316 mg) was dissolved with MeOH (2 ml) and 1.0M solution of NaOMe in MeOH (0.621 ml, 0.635 mmol) was added. The mixture was stirred for 2 min. and concentrated in vacuo to give the title compound (330 mg, 100%).
1H-NMR (CD3OD): 0.58 (t, 6H), 0.86 (s, 9H), 1.43-1.54 (m, 1 H), 1.73-1.99 (m, 3H), 2.04 (q, 4H), 2.14 (s, 3H), 2.23 (s, 3H), 2.36 (dt, 2H), 2.48-2.58 (m, 1 H), 2.81-2.91 (m, 1 H), 3.15 (dd, 1 H), 3.88-3.97 (m, 3H), 6.74 (d, 1 H), 6.83-7.02 (m, 5H); MS (ESI-): 497 ([M-H]").
Example 142
Preparation of 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt
Figure imgf000355_0001
(1 ) Preparation of 5(R)-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl- pentyl)-phenyl]-1-ethyl-propyl}-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000355_0002
To a stirred solution of 2-Ohloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pent- 1-ynyl)-phenyl]-1-ethyl-propyl}-phenol (compound prepared in Example 16-(6)) (6 mg, 0.014 mmol) in N,N-dimethylacetamide (0.14 ml) were added K2CO3 (4.9 mg, 0.035 mmol) and toluene-4-sulfonic acid (R)-5-oxo-tetrahydro-furan-2- ylmethyl ester (7.6 mg, 0.028 mmol) and the mixture was stirred at 130 degrees C for 1.5 h. The reaction mixture was cooled to room temperature and poured into aqueous NH4CI. The products were extracted with ethyl acetate and hexane. The extracts were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was purified by preparative TLC (ethyl acetate/hexane = 2/3) to give the title compound (6.0 mg, 81%). 1H-NMR: 0.61 (t, 6H), 0.89 (s, 9H), 1.42-1.59 (m, 2H), 1.81-1.92 (m, 1 H), 2.02 (q, 4H), 2.35-2.75 (m, 4H), 2.90-3.02 (m, 2H), 3.21-3.31 (m, 1 H), 4.07-4.27 (m, 2H), 4.86-4.91 (m, 1 H), 6.79 (d, 1 H), 6.91 (dd, 1 H), 6.98 (dd, 1 H), 7.11-7.19 (m, 3H).
(2) Preparation of 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt
Figure imgf000356_0001
To a solution of (5R)-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 142-(1 )) (6.0 mg, 0.012 mmol) in methanol (0.5 ml) and tetrahydrofuran (0.5ml) was added 1 N KOH solution (0.5 ml) and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo and poured into aqueous KHS04and the products were extracted with AcOEt. The extracts were washed with H2O, dried over MgS04, filtered and concentrated in vacuo. The obtained residue (6.1 mg) was dissolved with MeOH (0.5 ml) and 1.0M solution of NaOMe in MeOH (0.0111 ml, 0.0114 mmol) was added. The mixture was stirred for 2 min. and concentrated in vacuo to give the title compound (6.2 mg, 96%).
1H-NMR (CD3OD): 0.62 (t, 6H), 0.86 (s, 9H), 1.28-1.98 (m, 4H), 2.06 (q, 4H), 2.37 (t, 2H), 2.64-2.74 (m, 1 H), 2.92-3.01 (m, 1 H), 3.12-3.15 (m, 1 H), 3.97 (s, 3H), 6.96-7.20 (m, 6H); MS (ESI-): 537 ([M-H]").
Example 143
Preparation of 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt
Figure imgf000357_0001
(1) Preparation of 5(R)-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl- pentyl)-phenyl]-1-ethyl-propyl}-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000357_0002
To a stirred solution of 2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pent- 1-ynyl)-phenyl]-1-ethyl-propyl}-phenol (compound prepared in Example 17) (6 mg, 0.014 mmol) in N,N-dimethylacetamide (0.14 ml) were added K2CO3 (4.9 mg, 0.035 mmol) and toluene-4-sulfonic acid (R)-5-oxo-tetrahydro-furan-2- ylmethyl ester (7.6 mg, 0.028 mmol) and the mixture was stirred at 130 degrees C for 1.5 h. The reaction mixture was cooled to room temperature and poured into H2O. The products were extracted with ethyl acetate and hexane. The extracts were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was purified by preparative TLC (ethyl acetate/hexane = 2/3) to give the title compound (6.0 mg, 81 %). 1H-NMR: 0.61 (t, 6H), 0.89 (s, 9H), 1.42-1.59 (m, 2H), 1.82-1.91 (m, 1 H), 2.02 (q, 4H), 2.35-2.76 (m, 4H), 2.90-3.02 (m, 2H), 3.21-3.30 (m, 1 H), 4.07-4.27 (m, 2H), 4.86-4.91 (m, 1 H), 6.80 (d, 1 H), 6.91 (dd, 1 H), 6.98 (dd, 1 H), 7.11-7.17 (m, 3H).
(2) 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1 -ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt
Figure imgf000357_0003
To a solution of (5R)-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxymethyl)-dihydro-furan-2-one(compound prepared in Example 143-(1 )) (6.0 mg, 0.012 mmol) in methanol (0.5 ml) and tetrahydrofuran (0.5ml) was added 1 N KOH solution (0.5 ml) and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo and poured into aqueous KHS04 and the products were extracted with AcOEt. The extracts were washed with H20, dried over MgS0 , filtered and concentrated in vacuo. The obtained residue (6.3 mg) was dissolved with MeOH (0.5 ml) and 1.0M solution of NaOMe in MeOH (0.0114 ml, 0.0117mmol) was added. The mixture was stirred for 2 min. and concentrated in vacuo to give the title compound (6.6 mg, 96%).
1H-NMR (CD3OD): 0.62 (t, 6H), 0.86 (s, 9H), 1.28-2.01 (m, 4H), 2.06 (q, 4H), 2.37 (t, 2H), 2.63-2.74 (m, 1H), 2.92-3.01 (m, 1H), 3.13 (dd, 1H), 3.97 (s, 3H), 6.96-7.20 (m, 6H); MS (ESI-) : 537 ([M-H]").
Example 144
Preparation of (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-pyrrolidin-2-one
Figure imgf000358_0001
Preparation of (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-pyrrolidin-2-one
Figure imgf000358_0002
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(5)) (300 mg, 0.788 mmol) in MeCN (5 ml), toluene-4-sulfonic acid (R)-5-oxo-pyrrolidin-2- ylmethyl ester (425 mg, 1.577 mmol) and K2C0 (545 mg, 3.942 mmol) were added at room temperature and the mixture was stirred at 108 degrees C for 24 h. To the mixture, ethyl acetate was added and the mixture was washed with brine, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:EtOAc= 100:0 to 0:100) to give the title compound (159.2 mg, 42.3%).
1H-NMR (CDCI3): 0.61 (t, 6H, J=7.2Hz), 0.92 (t, 6H, J=7.5Hz), 1.64-1.60 (q, 4H, J=7.5Hz), 1.86-2.00 (m, 1 H), 2.05 (q, 4H, J=7.2Hz), 2.15 (s, 3H), 2.31 (s, 3H), 4.07-4.13 (m, 3H), 3.31 (dd, 2H, J=7.5, 9.3Hz), 3.97 (dd, 1 H, J=3.8, 9.3Hz), 4.07-4.13 (m, 1 H), 6.01 (d, 1 H, J=15.9Hz), 6.64 (d, 1 H, J=8.4Hz), 6.74 (d, 1 H, j=15.9Hz), 6.90-6.96 (m, 4H), 7.29 (d, 1 H, J=8.7Hz); MS (ESI+) : 478 ([M+H]+).
Example 145
Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-pyrrolidin-2-one
Figure imgf000359_0001
Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-pyrrolidin-2-one
Figure imgf000359_0002
To a solution of 4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(5)) (300 mg, 0.788 mmol) in MeCN (5 ml), toluene-4-sulfonic acid (S)-5-oxo-pyrrolidin-2- ylmethyl ester (425 mg, 1.577 mmol) and K2C03 (545 mg, 3.942 mmol) were added at room temperature and the mixture was stirred at 108 degrees C for 24 h. To the mixture, ethyl acetate was added and the mixture was washed with brine, dried over magnesium sulfate, concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane: EtOAc= 100:0 to 0:100) to give the title compound (152.6 mg, 40.5%).
1H-NMR (chloroform-d): 0.61 (t, 6H, J=7.2Hz), 0.92 (t, 6H, J=7.5Hz), 1.64 (q, 4H,
J=7.5Hz), 1.67 (s, 1 H), 1.88-1.99 (m, 1 H), 2.05 (q, 4H, J=7.2Hz), 2.15 (s, 3H),
2.31 (s, 3H), 2.27-2.52 (m, 2H), 3.81 (dd, 1H, J=7.5, 9.3Hz), 3.97 (dd, 1 H, J=3.8,
9.3Hz), 4.06-4.13 (m, 1 H), 5.99 (brs, 1 H), 6.01 (d, 1 H, J=15.9Hz), 6.64 (d, 1 H,
J=8.1 Hz), 6.74 (d, 1 H), 6.89-6.98 (m, 4H), 7.29 (d, 1 H); MS (ESI+) : 478
«M+H]+).
Example 146
Preparation of 3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-benzoic acid
Figure imgf000360_0001
Preparation of 3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-benzoic acid
Figure imgf000360_0002
To a solution of compound prepared in Example 1-(5) (4-{1 -Ethyl-1 -[4-(3-ethyl- 3-hydroxy-(1 E)-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol ) (20 mg, 0.0526 mmol) in DMF (0.4 ml), K2C03 (21.8 mg, 0.158 mmol ) and 3- bromomethyl-benzoic acid methyl ester (14.5 mg, 0.0632 mmol) were added at room temperature and the mixture was stirred at 120 degrees C for 16 h. To the mixture, ethyl acetate was added and the mixture was washed with H20 and brine, dried over MgS04, concentrated in vacuo. The obtained residue was dissolved in MeOH (0.5 ml), and 1N NaOH (0.2 ml) was added at room temperature and the mixture was stirred at 45 degrees C for 11 h. The mixture was evaporated in vacuo and the obtained residue was chromatographed on silica gel (n-hexane: EtOAc= 100:0 to 0:100) and re-purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (4.7 mg, 17%). 1H-NMR: 0.62 (t, 6H), 0.92 (t, 6H), 1.62 (q, 4H), 2.03 (q, 4H), 2.20 (s, 3H), 2.34 (s, 3H), 5.06 (s, 2H), 6.01 (d, 1 H), 6.68 (d, 1 H), 6.78 (s, 1 H), 7.50 (t, 1 H), 7.68 (d, 1 H), 8.02 (d, 1 H), 8.12 (s, 1 H); MS (ESI+) : 532 ([M+NH4]+).
Example 147
Preparation of 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-benzoic acid
Figure imgf000361_0001
(1 ) Preparation of 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-benzoic acid methyl ester
Figure imgf000361_0002
To a solution of compound prepared in Example 1-(5) (20 mg, 0.0526 mmol) (4- {1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-(1 E)-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenol ) in DMF (0.5 ml), K2C03 (29 mg, 0.21 mmol ) and 4- bromomethyl-benzoic acid methyl ester (14.4 mg, 0.0631 mmol) were added at room temperature and the mixture was stirred for 16 h. To the mixture, ethyl acetate was added and the mixture was washed with H2O, dried over MgSθ4, filtered and concentrated in vacuo. The obtained residue was purified by prerparative TLC (ethyl acetate/hexane = 1/1) to give the title compound (25.3 mg, 91 %).
1H-NMR: 0.61 (t, 6H), 0.92 (t, 6H), 1.64 (q, 4H), 2.03 (q, 4H), 2.24 (s, 3H), 2.31 (s, 3H), 3.93 (s, 3H), 5.09 (s, 2H), 6.00 (d, 1 H), 6.71-6.77 (m, 2H), 6.92-6.95 (m, 4H), 7.50 (d, 2H), 8.04 (d, 2H); MS (ESI+) : 511 ([M-OH]+). (2) Preparation of 3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-benzoic acid
Figure imgf000362_0001
To a solution of 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-benzoic acid methyl ester (compound prepared in Example 147-(1 )) (25.3 mg, 0.0479 mmol) in EtOH (2 ml), 1 N NaOH (0.1 ml) was added at room temperature, and the mixture was stirred at 40 degrees C for 16h and concentrated in vacuo. The obtained residue was purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H2O) to give the title compound (19.0 mg, 77%).
1H-NMR: 0.61 (t, 6H), 0.92 (t, 6H), 1.66 (q, 4H), 2.05 (q, 4H), 2.05 (s, 3H), 2.31 (s, 3H), 5.12 (s, 2H), 6.00 (d, 1 H), 6.70-6.80 (m, 2H), 7.54 (d, 2H), 8.11 (d, 2H); MS (ESI+) : 497([M-OH]+).
Example 148
Preparation of (E)-3-Ethyl-1 -(4-{1 -ethyl-1 -[3-methyl-4-(pyridin-3-ylmethoxy)- phenyl]-propyl}-2-methyl-phenyl)-pent-1-en-3-ol
Preparation of (E)-3-Ethyl-1 -(4-{1 -ethyl-1 -[3-methyl-4-(pyridin-3-ylmethoxy)- phenyl]-propyl}-2-methyl-phenyl)-pent-1-en-3-ol
Figure imgf000362_0003
To a solution of compound prepared in Example 1-(5) (4-{1 -Ethyl-1 -[4-(3-ethyl- 3-hydroxy-(1 E)-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol) (20 mg, 0.0526 mmol) in DMF (0.5 ml), K2C03 (60 mg, 0.435 mmol) and 3-bromomethyl- pyridine hydrochloride (25.0 mg, 0.099 mmol) were added and the mixture was stirred at 110 degrees C for 80 h. To the mixture, ethyl acetate was added and the mixture was washed with H20 and brine, dried over MgS04, concentrated in vacuo. The obtained residue was purified by prerparative TLC (ethyl acetate:hexane = 1 :3) to give the title compound (11.7 mg, 47%). 1H-NMR: 0.61 (t, 6H), 0.92 (t, 6H), 1.63 (q, 4H), 2.04 (q, 4H), 2.22 (s, 3H), 2.32 (s, 3H), 5.06 (s, 2H), 6.01 (d, 1H), 6.72-6.88 (m, 2H), 7.24-7.37 (m, 3H), 7.80 (d, 1 H), 8.57 (d, 1 H), 8.60 (s, 1 H); MS (ESI+) : 454 ([M-OH]+).
Example 149
Preparation of (E)-3-Ethyl-1 -(4-{1 -ethyl-1 -[3-methyl-4-(pyridin-4-ylmethoxy)- phenyl]-propyl}-2-methyl-phenyl)-pent-1-en-3-ol
Figure imgf000363_0001
Preparation of (E)-3-Ethyl-1-(4-{1 -ethyl-1 -[3-methyl-4-(pyridin-4-ylmethoxy)- phenyl]-propyl}-2-methyl-phenyl)-pent-1-en-3-ol
Figure imgf000363_0002
To a solution of compound prepared in Example 1-(5) (4-{1 -Ethyl-1 -[4-(3-ethyl- 3-hydroxy-(1 E)-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol ) (20 mg, 0.0526 mmol) in DMF (0.5 ml), K2C03 (29 mg, 0.210 mmol) and 4-chloromethyl- pyridine hydrochloride (10.3 mg, 0.063 mmol) were added and the mixture was stirred at room temperature for 16 h. To the mixture, ethyl acetate was added and the mixture was washed with H20 and brine, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was purified by prerparative TLC (ethyl acetate: hexane = 1 :3) to give the title compound (17.8 mg, 72%). 1H-NMR: 0.61 (t, 6H), 0.92 (t, 6H), 1.64 (q, 4H), 2.05 (q, 4H), 2.26 (s, 3H), 2.31 (s, 3H), 5.06 (s, 2H), 6.01 (d, 1 H), 6.70-6.80 (m, 2H), 6.92-6.97 (m, 4H) , 7.25 (d, 1 H), 7.38 (d, 2H), 8.62 (d, 2H); MS (ESI+) : 454 ([M-OH]+).
Example 150
Preparation of 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-benzoic acid methyl ester
Figure imgf000364_0001
(1) Preparation of
4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-benzoic acid methyl ester
Figure imgf000364_0002
To a solution of compound prepared in Example 1-(5) (4-{1 -Ethyl-1 -[4-(3-ethyl- 3-hydroxy-(1 E)-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol) (20 mg, 0.0526 mmol) in DMF (0.5 ml), K2C03 (21.8 mg, 0.158 mmol ) and 4-fluoro- benzoic acid methyl ester (13.3 mg, 0.0789 mmol) were added and the mixture was stirred at 110 degrees C for 16 h. To the mixture, ethyl acetate was added and the mixture was washed with H2O and brine, dried over MgSθ4, filtered and concentrated in vacuo. The obtained residue was purified by prerparative TLC (ethyl acetate:hexane = 1 :3) to give the title compound (19.0 mg, 70%). 1H-NMR: 0.64 (t, 6H), 0.92 (t, 6H), 1.62 (q, 4H), 2.05-2.11 (m, 7H), 2.33 (s, 3H), 3.88 (s, 3H), 6.02 (d, 1H), 6.73-7.34 (m, 9H), 7.96 (d, 2H); MS (ESI+) : 515 ([M+H]+). (2) Preparation of 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-benzoic acid
Figure imgf000365_0001
To a solution of 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-benzoic acid methyl ester (compound prepared in Example 150-(1)) (17 mg, 0.0331 mmol) in EtOH (2 ml), 1N NaOH (0.1 ml) was added, and the mixture was stirred at 50 degrees C for 16h and concentrated in vacuo. The obtained residue was purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H2O and ethyl acetate:hexane = 1:1 saturated with H20) to give the title compound (3.2 mg, 19 %).
1H-NMR: 0.65 (t, 6H), 0.93 (t, 6H), 1.66 (q, 4H), 2.05-2.34 (m, 7H), 2.34 (s, 3H), 6.03 (d, 1 H), 6.73-7.35 (m, 9H), 8.02 (d, 2H); MS (ESI+) : 518 ([M+NH4]+).
Example 151
Preparation of (E)-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetic acid
Figure imgf000365_0002
(1) Preparation of (E)-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetic acid methyl ester
Figure imgf000365_0003
To a stirred solution of 4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(5)) (700 mg, 1.84 mmol) in acetone (18 ml) were added K C03 (763 mg, 5.52 mmol) and bromoaceticacid methyl ester (563 mg, 3.68 mmol) at room temperature and the mixture was refluxed for 4 h. The reaction mixture was concentrated and poured into H2O and the products were extracted with ethyl acetate. The extracts were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (ethyl acetate/hexane = 0/100 to 5/95) to give the title compound (892 mg, quant). 1H-NMR: 0.61 (t, 6H), 0.92 (t, 6H), 1.64 (q, 4H), 2.05 (q, 4H), 2.23 (s, 3H), 2.31 (s, 3H), 3.80 (s, 3H), 4.62 (s, 2H), 6.02 (d, 1 H), 6.57 (d, 1 H), 6.75 (d, 1 H), 6.92-6.94 (m, 4H) 7.30 (d, 1H).
(2) Preparation of (E)-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetic acid
Figure imgf000366_0001
To a solution of (4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetic acid methyl ester (compound prepared in Example 151-(1)) (892 mg, 1.97 mmol) in methanol (3 ml) and tetrahydrofuran (2 ml) was added 1 N KOH solution (3 ml) and the mixture was stirred for 2 h at room temperature. The reaction mixture was poured into aqueous KHSO4, and the products were extracted with AcOEt. The extracts were washed with brine, dried over MgS04, filtered and concentrated in vacuo to give the title compound (807 mg, 100 %).
1H-NMR: 0.60 (t, 6H), 0.92 (t, 6H), 1.64 (q, 4H), 2.05 (q, 4H), 2.23 (s, 3H), 2.31 (s, 3H), 4.65 (s, 2H), 6.01 (d, 1H), 6.62 (d, 1 H), 6.75 (d, 1 H), 6.92-6.97 (m, 4H) 7.29 (d, 1 H).
Example 152
Preparation of (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol
Figure imgf000367_0001
Preparation of (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy- 3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol
Figure imgf000367_0002
To a solution of (R)-5-(4-{1 -ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 46-(1 )) (39 mg, 0.065 mmol) in Et20 (1 ml), LAH (7 mg, 0.195 mmol) was added and the mixture was stirred at room temperature for 18 h. To the mixture, ethyl acetate and brine were added and the organic layer was filtered through celite, and the filtrate was concentrated in vacuo. To the solution of the residue (7.3 mg) in i- PrOH (0.1 ml), CBr4 (0.33 mg 0.001 mmol) was added and the mixture was stirred at 85 degrees C for 3.5 h. The mixture was purified by silica gel chromatography (n-hexane/ethyl acetate =1/1 ) to give the title compound (7.2 mg, 91.7%).
1H-NMR (chloroform-d): 0.59 (t, 6H, J=7.2Hz), 1.67-1.83 (m, 4H), 2.04 (q, 4H, J=7.2Hz), 2.14 (s, 3H), 2.37 (s, 3H), 2.83 (brs, 1 H), 3.66-3.77 (m, 2H), 3.81 (dd, 1 H, J=7.4, 9.2Hz), 3.92 (dd, 1 H, J=3.5, 9.2Hz), 3.86-4.09 (m, 1 H), 4.72 (brs, 1 H), 6.65 (d, 1 H, J=8.6Hz), 6.83-7.04 (m, 5H), 7.33 (d, 1 H, J=-8.0Hz); MS(ESI+) : 583([M+Na]+).
Example 153
Preparation of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol
Figure imgf000368_0001
Preparation of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol
Figure imgf000368_0002
To a solution of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 2-(3)) (38 mg, 0.063 mmol) in Et20 (1 ml), LAH (7.2mg 0.19mmol) was added and the mixture was stirred at room temperature for 18 h. To the mixture, ethyl acetate and brine were added and the organic layer was filtered through celite, and the filtrate was concentrated in vacuo. To the solution of the residue (7.3 mg) in i- PrOH (0.1 ml), CBr (0.33 mg 0.001 mmol) was added and the mixture was stirred at 85 degrees C for 3.5 h. The mixture was purified by silica gel chromatography (n-hexane/ethyl acetate =1/1) to give the title compound (5 mg, 74.4%).
1H-NMR (chloroform-d): 0.59 (t, 6H, J=7.3Hz), 1.53-1.80 (m, 4H), 2.05 (q, 4H, J=7.3Hz), 2.15 (s, 3H), 2.37 (s, 3H), 2.80 (brs, 1H), 3.73 (dd, 2H, J=5.0, 10.7Hz), 3.82 (dd, 1H, J=7.4, 9.3Hz), 3.93 (dd, 1H, J=3.6, 9.3Hz), 4.01-4.10 (m, 1H), 4.31 (brs, 1H), 6.66 (d, 1H, J=8.5Hz), 6.83-7.04 (m, 4H), 7.34 (d, 1H, J=8.1Hz); MS (ESI+): 583 ([M+Na]+).
Example 154
Preparation of (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol
Figure imgf000369_0001
Example 155
Preparation of (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(R)-1 -(tetrahydro-furan-2- yl)methoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 -trifluoro-2-trifluoromethyl-but-
3-en-2-ol
Figure imgf000369_0002
Preparation of (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol and (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(R)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 -trifluoro-2-trifluoromethyl-but-3-en-2-ol
Figure imgf000369_0003
Example 155 To a solution of (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 48-(1 )) (39.9 mg, 0.066 mmol) in Et20 (1 ml), LAH (7.5 mg, 0.199 mmol) was added and the mixture was stirred at room temperature for 18 h. To the mixture, ethyl acetate and brine were added and the organic layer was filtered through celite, and the filtrate was concentrated in vacuo. To the residue (25.6 mg), conc.HCI in MeOH (1 ml) was added and the mixture was stirred at 85 degrees C for 3.5 h. The mixture was chromatographed on silica gel (n-hexane/ethyl acetate =1/1 ) to give the title compounds (example 154 (15 mg, 63.2%) and example 155 (3.5 mg, 15.2%)). Example 154
1H-NMR (chloroform-d): 0.61 (t, 6H, J=7.2Hz), 1.58-1.83 (m, 4H), 2.06 (q, 4H, J=7.2Hz), 2.17 (s, 3H), 2.33 (s, 3H), 2.61 (brs, 1 H), 3.72 (dd, 2H, J=5.1 , 10.5Hz), 3.84 (dd, 1H, J=7.2, 9.3Hz), 3.95 (dd, 1 H, J=3.5, 9.3Hz), 3.93 (brs, 1H), 4.01- 4.11 (m, 1 H), 6.08 (d, 1 H, J=15.9Hz), 6.68 (d, 1 H, J=8.4Hz), 6.87-7.06 (m, 4H), 7.33 (d, 1H, J=5.7Hz), 7.37 (d, 1H, J=13.2Hz); MS (ESI+) : 585 ([M+Na]+). Example 155
1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.2Hz), 1.80-2.12 (m, 4H), 2.05 (q, 4H, J=7.2Hz), 2.17 (s, 3H), 2.33 (s, 3H), 3.19 (brs, 1 H), 3.79-4.00 (m, 4H), 4.24-4.33 (m, 1 H), 6.08 (d, 1 H, J=16.2Hz), 6.68 (d, 1 H, J=8.7Hz), 6.87-7.02 (m, 4H), 7.33 (d, 1 H, J=5.1Hz), 7.37 (d, 1 H, J=12.9Hz); MS (ESI+) : 562 ([M+NH4]+).
Example 156
Preparation of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol
Figure imgf000370_0001
Example 157
Preparation of (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(S)-1-(tetrahydro-furan-2- yl)methoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 -trifluoro-2-trifluoromethyl-but- 3-en-2-ol
Figure imgf000370_0002
Preparation of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol and (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(S)-1 -(tetrahyd ro-fu ran-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 -trifluoro-2-trifluoromethyl-but-3-en-2-ol
Figure imgf000371_0001
Example 157 To a solution of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 30-(2)) (40.1 mg, 0.067 mmol) in Et20 (1 ml), LAH (7.6 mg, 0.200 mmol) was added and stirred at room temperature for 18 h. To the mixture, ethyl acetate and brine were added and the organic layer was filtered through celite, and the filtrate was concentrated in vacuo. To the residue (20.7 mg), conc.HCI in MeOH (1 ml) was added and the mixture was stirred at 85 degrees C for 3.5 h. To the same residue (13.4 mg) in iPrOH (0.2 ml), CBr4 (0.7 mg, 0.002 mmol) was added and the mixture was stirred at 85 degrees C for 3.5 h. The mixture was chromatographed on silica gel (n-hexane/ethyl acetate =1/1) to give the title compounds (example 156 (21.8 mg, 68.9%) and example 157 (1 mg, 5.4%)). Example 156 1H-NMR (chloroform-d): 0.61 (t, 6H, J=7.3Hz), 1.61-1.83 (m, 4H), 2.06 (q, 4H, J=7.3Hz), 2.17 (s, 3H), 2.33 (s, 3H), 2.54 (brs, 1H), 2.89 (brs, 1H), 3.77-3.67 (m, 2H), 3.84 (dd, 1 H, J=7.4, 9.3Hz), 0.00 (dd, 1H, J=3.6, 9.3Hz), 4.01-4.09 (m, 1H), 4.25 (brs, 1H), 6.08 (d, 1H, J=15.8Hz), 6.68 (d, 1H, J=8.5Hz), 6.89-7.01 (m, 4H), 7.37 (d, 1H, J=15.8Hz), 7.34 (d, 1H, J=7.9Hz); MS (ESI+) : 585([M+Na]+). Example 157 1H-NMR (chloroform-d): 0.61 (t, 6H), 1.83-2.16 (m, 4H), 2.05 (q, 4H, J=7.3Hz), 2.17 (s, 3H), 2.33 (s, 3H), 3.20 (brs, 1H), 3.79-4.01 (m, 4H), 4.25-4.33 (m, 1H), 6.08 (d, 1 H, J=15.3Hz), 6.68 (d, 1 H, J=8.7Hz), 6.87-6.97 (m, 2H), 6.99-7.03 (m, 2H), 7.33 (d, 1H, J=7.8Hz), 7.36 (d, 1H, J=15.3Hz); MS (ESI+): 567([M+Na]+).
Example 158
Preparation of (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol
Figure imgf000372_0001
Preparation of (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol
Figure imgf000372_0002
To a solution of (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
(compound prepared in Example 44) (55.7 mg, 0.116 mmol) in Et2θ (3 ml), LAH (13 mg, 0.349 mmol) was added and the mixture was stirred at room temperature for 18 h. To the mixture, ethyl acetate and brine were added and the organic layer was filtered through celite, and the filtrate was concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane/ethyl acetate =1/3 to ethyl acetate) to give the title compound (18.7 mg, 33.3%). 1H-NMR (chloroform-d): 0.61 (t, 6H, J=7.4Hz), 0.92 (t, 6H, J=7.8Hz), 0.00 (q, 4H, J=7.8Hz), 1.70-1.81 (m, 4H), 2.05 (q, 4H, J=7.4Hz), 2.18 (s, 3H), 2.31 (s, 3H), 2.81 (brs, 1 H), 3.65 (brs, 1 H), 3.68-3.78 (m, 2H), 3.83 (dd, 1 H, J=7.4, 9.3Hz), 3.95 (dd, 1 H, J=3.6, 9.3Hz), 4.02-4.11 (m, 1 H), 6.01 (d, 1 H, J=15.9Hz), 6.68 (d, 1 H, J=8.4Hz), 6.74 (d, 1 H, J=15.9Hz), 6.91-6.97 (m, 4H), 7.30 (d, 1 H, J=8.7Hz); MS (ESI+) : 500 ([M+NH4]+).
Example 159
Preparation of (E)-3-Ethyl-1 -[4-(1 -ethyl-1 -{3-methyl-4-[(R)-1 -(tetrahydro-furan-2- yl)methoxy]-phenyl}-propyl)-2-methyl-phenyl]-pent-1-en-3-ol
Figure imgf000373_0001
Preparation of (E)-3-Ethyl-1 -[4-(1 -ethyl-1 -{3-methyl-4-[(R)-1 -(tetrahydro-furan-2- yl)methoxy]-phenyl}-propyl)-2-methyl-phenyl]-pent-1-en-3-ol
Figure imgf000373_0002
To a solution of (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol (compound prepared in Example 158) (30 mg, 0.062 mmol) in THF (0.5 ml), PPh3 (48.91 mg, 0.186 mmol), phthalimide (27.43 mg, 0.186 mmol), DEAD (32.47 mg, 0.186 mmol) were added and the mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo, and the obtained residue was purified by preparative TLC (n-hexane/ethyl acetate =3/1 and 1/1) to give the title compound (22.1 mg, 76.5%).
1H-NMR (chloroform-d): 0.58 (t, 6H, J=7.5Hz), 0.92 (t, 6H, J=7.2Hz), 1.64 (q, 4H, J=7.2Hz), 1.80-2.15 (m, 4H), 2.05 (q, 4H, J=7.5Hz), 2.18 (s, 3H), 2.31 (s, 3H), 3.79-4.02 (m, 4H), 4.24-4.34 (m, 1 H), 6.01 (d, 1 H, J=15.9Hz), 6.68 (d, 1 H, J=8.7Hz), 6.75 (d, 1 H, J=16.2Hz), 6.87-6.98 (m, 4H), 7.29 (d, 1 H, J=8.7Hz); MS (ESI+) : 482 ([M+NH4]+). Example 160
Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol
Figure imgf000374_0001
Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol
Figure imgf000374_0002
To a solution of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 1-(6)) (59.2 mg, 0.124 mmol) in Et2θ (3 ml), LAH (14 mg, 0.371 mmol) was added and the mixture was stirred at room temperature for 18 h. To the mixture, ethyl acetate and brine were added and the organic layer was filtered through celite, and the filtrate was concentrated in vacuo The obtained residue was purified by preparative TLC (n-hexane/ethyl acetate =1/1 and 1/3) to give the title compound (28.8 mg, 48.2%).
1H-NMR (chloroform-d): 0.61 (t, 6H, J=7.3Hz), 0.92 (t, 6H, J=7.6Hz), 1.47 (brs, 1H), 1.64 (q, 4H, J=7.6Hz), 1.72-1.82 (m, 4H), 2.05 (q, 4H, J=7.3Hz), 2.18 (s, 3H), 2.31 (s, 3H), 2.81 (brs, 1H), 3.70-3.75 (m, 2H), 3.85 (dd, 1H, J=7.5, 9.2Hz), 3.95 (dd, 1H, J=3.5, 9.2Hz), 4.02-4.09 (m, 1H), 6.01 (d, 1H, J=16.0Hz), 6.68 (d, 1 H, J=8.3Hz), 6.74 (d, 1 H, J=16.0Hz), 6.90-6.97 (m, 4H), 7.30 (d, 1 H, J=8.8Hz); MS (ESI+) : 500 ([M+NH4f).
Example 161
Preparation of 4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,5,5,5-pentafluoro-3-hydroxy-3- pentafluoroethyl-pent-1-enyl)-phenyl]-propyl}-2-methyl-phenol
Figure imgf000375_0001
(1 ) Preparation of (E)-3-{4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- methyl-phenylj-acrylic acid methyl ester
Figure imgf000375_0002
To a solution of compound prepared in Example 1-(1 ) (trifluoro-methanesulfonic acid 4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl ester), (200 mg, 0.481 mmol) in DMF (2 ml), NaHC03 (162 mg, 1.926 mmol), LiBr (29.3 mg, 0.337 mmol), dppp (20 mg, 0.048 mmol), PdCI2(PPh3)2 (33.7 mg, 0.048 mmol) and acrylic acid methyl ester (0.347 ml, 3.85 mmol) were added at room temperature and the mixture was stirred at 140 degrees C for 16h. To the mixture, ethyl acetate was added and the mixture was washed with H20, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethyl acetate=100:0 to 50:50) to give the title compound (15 mg, 9%). 1H-NMR: 0.61 (t, 6H), 2.03 (q, 4H), 2.20 (s, 3H), 2.39 (s, 3H), 3.80 (s, 3H), 4.67 (s, 1 H), 6.32 (d, 1 H), 6.66 (d, 1 H), 7.42 (d ,1 H), 7.96 (d, 1 H).
(2) Preparation of 4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4, 5,5, 5-pentafluoro-3-hydroxy- 3-pentafluoroethyl-pent-1-enyl)-phenyl]-propyl}-2-methyl-phenol
Figure imgf000375_0003
To a solution of C2F5I (0.426 mmol) in diethyl ether (0.5 ml) at -78 degrees C, 1.5M MeLi in diethyl ether (0.284 ml, 0.426 mmol) was added, and then (E)-3-{4- [1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}-acrylic acid methyl ester (compound prepared in Example 161-(1)) (15 mg, 0.0426 mmol) in diethyl ether (0.5 ml) were added. The mixture was stirred at -78 degrees C for 10min. To the mixture, ethyl acetate was added and the mixture was washed with H20, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethyl acetate=100:0 to 50:50) to give the title compound (5 mg, 21 %).
1H-NMR: 0.61 (t, 6H), 2.03 (q, 4H), 2.20 (s, 3H), 2.30 (s, 3H), 3.35 (s, 1 H), 5.98 (d, 1H), 6.66 (d, 1H), 6.82-6.90 (m, 2H), 6.95-7.00 (m, 2H), 7.35 (d, 1H); MS (ESI+) : 561 ([M+H]+).
Example 162
Preparation of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,5,5,5-pentafluoro-3- hydroxy-3-pentafluoroethyl-pent-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one
Figure imgf000376_0001
Preparation of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,5,5,5-pentafluoro-3- hydroxy-3-pentafluoroethyl-pent-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one
Figure imgf000376_0002
To a solution of compound prepared in Example 161-(2) (4-{1 -ethyl-1 -[3-methyl- 4-((E)-4,4,5,5,5-pentafluoro-3-hydroxy-3-pentafluoroethyl-pent-1-enyl)-phenyl]- propyl}-2-methyl-phenol) (34 mg, 0.0607 mmol) in DMF (0.5 ml), K2C03 (25.3 mg, 0.183 mmol) and (S)-(+)-dihydro-5-(p-tolenesulfonylmethyl)-2(3H)-furanone (18 mg, 0.0668 mmol) were added at room temperature and stirred at 100 degrees C for 16h. To the mixture, ethyl acetate was added and the mixture was washed with H2O, dried over MgSθ4, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (13.7 mg, 34%).
1H-NMR: 0.61 (t, 6H), 2.05 (q, 4H), 2.20 (s, 3H), 2.34 (s, 3H), 2.55-2.63 (m, 2H),
3.90-3.98 (m, 1 H), 4.17-4.22 (m, 1 H), 4.63-4.73 (m ,1 H), 5.89 (d, 1 H), 6.65 (d,
1 H), 6.82-6.90 (m, 2H), 6.97-7.02 (m, 2H), 7.35 (d, 1 H); MS (ESI+): 676
([M+NH4]+).
Example 163
Preparation of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,5,5,5-pentafluoro-3- hydroxy-3-pentafluoroethyl-pent-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid
Figure imgf000377_0001
Preparation of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,5,5,5-pentafluoro-3- hydroxy-3-pentafluoroethyl-pent-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid
Figure imgf000377_0002
To a solution of compound prepared in Example 162 ((S)-5-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,5,5,5-pentafluoro-3-hydroxy-3-pentafluoroethyl-pent-1-enyl)- phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one) (8.1 mg, 0.0123 mmol) in MeOH (1 ml), 1 N NaOH (0.1 ml) were added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (4.4 mg, 54%). 1H-NMR: 0.61 (t, 6H), 2.04 (q, 4H), 2.20 (s, 3H), 2.30 (s, 3H), 2.59 (t, 2H), 3.83- 3.98 (m, 3H), 5.92 (d,1H), 6.66 (d, 1H), 6.83-6.89 (m, 2H), 6.97-7.02 (m, 2H); MS (ESI+): 694 ([M+NH4]+).
Example 164
Preparation of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-phenol
Figure imgf000378_0001
(1 ) Preparation of 3-(4-Bromo-3-methyl-phenyl)-pentan-3-ol
Figure imgf000378_0002
To a solution of 4-bromo-3-methyl-benzoic acid methyl ester (3.0 g, 13.1 mmol) in THF (300 ml), 0.89M EtMgBr in THF (39.2 ml, 34.9 mmol) were added at 0 degrees C for 5min and stirred at room temperature for 16h. To the mixture, saturated NH4CI solution and ethyl acetate was added and the organic layer was washed with saturated NH4CI solution, dried over MgS04, concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane only to ethyl acetate/n-hexane = 1/4) to give the title compound (2.71 g, 81 %). 1H-NMR: 0.75 (t, 6H), 1.74-1.82 (m, 4H), 2.40 (s, 3H), 7.00 (dd, 1 H), 7.45 (d, 1 H); MS (ESI+) : 239 ([M-OH]+).
(2) Preparation of 4-[1-(4-Bromo-3-methyl-phenyl)-1-ethyl-propyl]-phenol
Figure imgf000378_0003
To a mixture of 3-(4-bromo-3-methyl-phenyl)-pentan-3-ol (150 mg, 0.586 mmol) and phenol (82 mg, 0.88 mmol), trifluoromethanesulfonic acid (0.1 ml) were added at room temperature and the mixture was stirred at room temperature for 16h. The mixture applied onto silica and chromatographed (n-hexane to ethyl acetate/n- hexane = 1/1 ) to give the title compound as mixture of phenol. 1H-NMR: 0.60 (t, 6H), 2.03 (q, 4H), 2.32 (s, 3H), 6.72 (s, 1H), 6.83-7.38 (m, 6H); MS (ESI+) : 333 ([M+H]+).
(3) Preparation of (E)-1-{4-[1 -Ethyl-1 -(4-hydroxy-phenyl)-propyl]-2-methyl- phenyl}-pent-1 -en-3-
Figure imgf000379_0001
To a solution of 4-[1-(4-Bromo-3-methyl-phenyl)-1-ethyl-propyl]-phenol prepared in Example 164-(2) in DMF (3 ml), NaHC03 (454 mg, 5.4 mmol), LiBr (40 mg, 0.46 mmol), dppp (58 mg, 0.14 mmol), PdCI2(PPh3)2 (98 mg, 0.14 mmol) and pent-1-en-3-one (1.08 ml, 1.08 mmol) were added at room temperature and the mixture was stirred at 130 degrees C for 16h. To the mixture, ethyl acetate was added and the organic layer was washed with H2O, dried over MgS04, concentrated in vacuo. The obtained residue was purified by preparative TLC (n- hexane:ethyl acetate=1 :3) to give the title compound (353 mg). 1H-NMR: 0.61 (t, 6H), 1.17 (t, 3H), 2.04 (q, 4H), 2.37 (s, 3H), 2.69 (q, 2H), 6.63 (d, 1 H), 6.75 (d, 1 H), 6.98-7.05 (m, 2H), 7.45 (d, 1 H), 7.82 (d, 1 H); MS (ESI+) : 337 ([M+H]+).
(4) Preparation of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-phenol
Figure imgf000379_0002
To a solution of (E)-1-{4-[1 -ethyl-1 -(4-hydroxy-phenyl)-propyl]-2-methyl-phenyl}- pent-1-en-3-one (350 mg, 1.04 mmol) in THF (2 ml), 0.5 M EtLi in THF (10.4 ml, 5.21 mmol) was added at 0 degree and the mixture was stirred at room temperature for 1 h. To the mixture, saturated NH4CI was added, flirted through celite and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate/n-hexane = 1/2) to give the title compound (145 mg, 38%). 1H-NMR: 0.60 (t, 6H), 0.92 (t, 6H), 1.61 (q, 4H), 2.03 (q, 4H), 2.30 (s, 3H), 5.99 (d, 1 H), 6.70-7.28 (m, 8H); MS (ESI+): 349 ([M-OH]+).
Example 165
Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000380_0001
(1 ) Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000380_0002
To a solution of 4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-phenol (compound prepared in Example 164-(4)) (135 mg, 0.369 mmol) in DMF (2 ml), K2C03 (153 mg, 1.11 mmol) and (S)-(+)-dihydro-5-(p- tolenesulfonylmethyl)-2(3H)-furanone (150 mg, 0.554 mmol) were added at room temperature and the mixture was stirred at 100 degrees C for 16h. To the mixture, ethyl acetate was added and the mixture was washed with H20, dried over MgS04, concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane to n-hexane:ethyl acetate=1 :1) to give the title compound (117 mg, 68%). 1H-NMR: 0.62 (t, 6H), 0.91 (t, 6H), 1.62-1.65 (q, 4H), 2.30 (s, 3H), 4.05-4.17 (m, 2H), 4.82-4.89 (m, 1H), 6.01 (d, 1H), 6.70-6.82 (m, 3H), 7.08 (d, 1H), 7.29(d, 1H); MS (ESI+) : 465 ([M+H]+).
(2) Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000381_0001
To a solution of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 165-(1)) (117 mg, 0.252 mmol) in MeOH (3 ml), 1N NaOH (0.6 ml) were added at room temperature and the mixture was stirred at room temperature for 1h. The mixture was concentrated in vacuo, and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (59 mg, 49%).
1H-NMR: 0.61 (t, 6H), 0.91 (t, 6H), 1.63 (q, 4H), 2.02 (q, 4H), 2.17 (s, 3H), 2.66 (t, 2H), 3.79-3.89 (m, 1H), 3.93-4.08 (m, 2H), 6.00 (d, 1H), 6.72-7.31 (m, 8H); MS (ESI+) : 500 ([M+NH4]+).
Example 166 Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2,6-dimethyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000381_0002
(1) Preparation of 4-[1-(4-Bromo-3-methyl-phenyl)-1-ethyl-propyl]-2,6-dimethyl- phenol
Figure imgf000382_0001
To a solution of 3-(4-Bromo-3-methyl-phenyl)-pentan-3-ol (compound prepared in Example 164-(1)) (200 mg, 0.780 mmol) and 2,6-dimethyl-phenol (285 mg, 2.34 mmol) in toluene (0.2 ml), AICI3 (52 mg, 0.390 mmol) was added and the mixture was stirred at room temperature for 60 h. The mixture applied onto silica and chromatographed (n-hexane:CH2Cl2=30:70 to 0:100) to give the title compound as mixture of 2,6-dimethyl-phenol (356 mg). 1H-NMR: 0.59 (t, 6H, -CHz-C±y, 2.03 (q, 4H, -CHZ-CH3); MS (ESI+) : 361 ([M+H]+).
(2) Preparation of (E)-1-{4-[1 -Ethyl-1 -(4-hydroxy-3,5-dimethyl-phenyl)-propyl]-2- methyl-phenyl}-pent-1 -en-3-
Figure imgf000382_0002
To a solution of 4-[1-(4-bromo-3-methyl-phenyl)-1-ethyl-propyl]-2,6-dimethyl- phenol prepared in Example 166-(1) (110 mg) in DMF (1 ml), NaHC03 (81 mg, 0.96 mmol), LiBr (14.7 mg, 0.17 mmol), dppp (10 mg, 0.024 mmol), PdCI2(PPh3)2 (16.9 mg, 0.024 mmol) and pent-1-en-3-one (0.20 ml, 0.20 mmol) were added at room temperature and the mixture was stirred at 140 degrees C for 16h. To the mixture, ethyl acetate was added and the mixture was washed with H2O, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (CH2CI2:MeOH=100:0 to 10:1 ) to give the title compound (85 mg). H-NMR: 0.60 (t, 6H), 1.17 (t, 3H), 2.04 (q, 4H), 2.19 (s, 6H), 2.67 (q, 2H), 4.56 (s, 1H), 6.65 (d, 1 H), 6.73 (s, 1H), 6.98-7.03 (m, 2H), 7.46 (d, 1H), 7.80 (d, 1 H); MS (ESI+) : 365 ([M+H]+). (3) Preparation of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2,6-dimethyl-phenol
Figure imgf000383_0001
To a solution of (E)-1-{4-[1 -Ethyl-1 -(4-hydroxy-3, 5-dimethyl-phenyl)-propyl]-2- methyl-phenyl}-pent-1-en-3-one (compound prepared in Example 166-(2)) (85 mg, 0.233 mmol) in THF (2 ml), 0.89 M EtMgBr in THF (1.63 ml, 1.35 mmol) was added at 0 degrees C and the mixture was stirred at room temperature for 1h. To the mixture, saturated NH4CI was added, the mixture was flirted through celite and concentrated in vacuo. The obtained residue was purified by preparative TLC (ethyl acetate/n-hexane = 1/4) to give the title compound (17 mg, 19%).
1H-NMR: 0.60 (t, 6H), 0.92 (t, 6H), 1.61 (q, 4H), 2.02 (q, 4H), 2.19 (s, 6H), 2.38 (s, 3H), 4.47 (s, 1H), 6.00 (d, 1H), 6.73-7.30 (m, 6H); MS (ESI+) : 395 ([M+H]+).
(4) Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2,6-dimethyl-phenoxymethyl)-dihydro-furan-2-
Figure imgf000383_0002
one To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2,6-dimethyl-phenol (compound prepared in Example 166-(3)) (16 mg, 0.0406 mmol) in DMF (0.3 ml), K2C03 (16.9 mg, 0.122 mmol) and (S)- (+)-dihydro-5-(p-tolenesulfonylmethyl)-2(3H)-furanone (21.9 mg, 0.0812 mmol) were added at room temperature and the mixture was stirred at 100 degrees C for 16h. To the mixture, ethyl acetate was added and the mixture was washed with H20, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (16 mg, 80%).
1H-NMR: 0.60 (t, 6H), 0.92 (t, 6H), 1.65 (q, 4H), 2.05 (q, 4H), 2.21 (s, 6H), 3.90-
4.01 (m, 2H), 4.78-4.82 (m, 1H), 6.02 (d, 1H), 6.75-7.30 (m, 5H); MS (ESI+): 510
([M+NH4]+).
Example 167
Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2,6-dimethyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000384_0001
Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2,6-dimethyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000384_0002
To a solution of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2,6-dimethyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 166-(4)) (11 mg, 0.022 mmol) in MeOH (0.3 ml), 1 N NaOH (0.1 ml) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (4.7 mg, 41%).
1H-NMR: 0.60 (t, 6H), 0.92 (t, 6H), 1.64 (q, 4H), 2.02 (q, 4H), 2.21 (s, 6H), 2.34 (s, 3H), 2.61 (t, 2H), 3.66-3.79 (m, 2H), 4.01-4.10 (m, 1 H), 6.02 (d, 1 H), 6.72- 7.34(m, 6H); MS (ESI+): 528 ([M+NH4]+).
Example 168 Preparation of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-propyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000385_0001
(1) Preparation of 1-(4-Hydroxy-3-propyl-phenyl)-propan-1-one
Figure imgf000385_0002
To a mixture of 2-propyl-phenol (2.0 g, 14.7 mmol) and propionyl chloride (1.36 g, 14.7 mmol), AICI3 (2.15 g, 16.2 mmol) was added and the mixture was stirred at room temperature for 1h. The mixture was applied onto silica and chromatographed (ethyl acetate:n-hexane = 0:100 to 50:50) to give the title compound (0.30 g, 11%).
1H-NMR: 0.97 (t, 3H), 1.22 (t, 3H), 1.64 (q, 2H), 2.63 (t, 2H), 2.96 (q, 2H), 6.85 (d, 1H), 7.72-7.79 (m, 2H); MS (ESI+): 193 ([M+H]+).
(2) Preparation of 4-(1 -Ethyl-1 -hydroxy-propyl)-2-propyl-phenol
Figure imgf000385_0003
To a solution of 4-(1 -ethyl-1 -hydroxy-propyl)-2-propyl-phenol (compound prepared in Example 168-(1)) (0.30 g, 1.56 mmol) in THF (5 ml), 3M EtMgBr in diethyl ether (2.6 ml, 7.80 mmol) was added at 0 degrees C and the mixture was stirred at room temperature for 16h. To the mixture, H2O and ethyl acetate were added and the organic layer was washed with H2O, dried over MgSθ4, concentrated in vacuo. The obtained residue was chromatographed on silica gel (ethyl acetate: n-hexane = 0:100 to 50:50) to give the title compound (0.32 g, 94%). 1H-NMR: 0.76 (t, 6H), 0.96 (t, 3H), 1.77-1.83 (m, 4H), 2.58 (t, 2H), 4.68-4.71 (m, 1 H), 6.70 (d, 1 H), 7.02-7.07 (m, 2H).
(3) Preparation of Trifluoro-methanesulfonic acid 4-(1 -ethyl-1 -hydroxy-propyl)-2- propyl-phenyl ester
Figure imgf000386_0001
To a solution of 4-(1 -ethyl-1 -hydroxy-propyl)-2-propyl-phenol (compound prepared in Example 168-(2)) (315 mg, 1.42 mmol) in CH2CI2 (5 ml), pyridine (0.172 ml, 2.13 mmol) and trifluoromethanesulfonic anhydride (0.239 ml, 1.42 mmol) were added at 0 degrees C and the mixture was stirred at 0 degrees C for 2h. The mixture was applied onto silica and chromatographed (ethyl acetate:n- hexane = 0:100 to 50:50) to give the title compound (0.21 g, 42%). 1H-NMR: 0.67 (t, 6H), 0.97 (t, 3H), 1.78-1.83 (m, 4H), 2.65 (t, 2H), 7.16-7.32 (m, 3H).
(4) Preparation of Trifluoro-methanesulfonic acid 4-[1 -ethyl-1 -(4-hydroxy-3- methyl-phenyl)-propyl]-2-propyl-phenyl ester
Figure imgf000386_0002
To a mixture of 2-methyl-phenol (84 mg, 0.78 mmol) and trifluoromethanesulfonic acid 4-(1 -ethyl-1 -hydroxy-propyl)-2-propyl-phenyl ester (compound prepared in Example 168-(3)) (138 mg, 0.39 mmol) in tolunene (0.3 ml), trifluoromethanesulfonic acid (0.040 ml) was added and the mixture was stirred at room temperature for 16h. To the mixture, ethyl acetate was added and the mixture was washed with H20, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethyl acetate=100:0 to 50:50) to give the mixture of the title compound containing 2-methyl-phenol (192 mg). 1H-NMR: 0.60 (t, 6H, -CH2CH3), 0.90 (t, 3H, -CH2CH2CH3), 1.65 (q, 2H, - CHzChbCHs), 2.02 (q, 4H, -CH2CH^). 2.12 (s, 3H, Ph-CHs), 2.61 (t, 2H, - CH2CH2CH3); MS (ESI+) : 445 ([M+H]+).
(5) Preparation of (E)-1-{4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- propyl-phenyl}-pent-1 -en-3-one
Figure imgf000387_0001
To a solution of compound prepared in Example 168-(4) (trifluoromethanesulfonic acid 4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2-propyl- phenyl ester) (compound prepared in Example 168-(4)) (192 mg) in DMF (3 ml), NaHC03 (131 mg, 1.56 mmol), LiBr (23.4 mg, 0.273 mmol), dppp (16.1 mg, 0.039 mmol), PdCI2(PPh3)2 (27.4 mg, 0.039 mmol) and pent-1-en-3-one (0.381 ml, 3.12 mmol) were added at room temperature and the mixture was stirred at 130 degrees C for 64 h. To the mixture, ethyl acetate was added and the mixture was washed with H20, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was purified by preparative TLC (n-hexane:ethyl acetate=3:1 ) to give the title compound (74 mg).
1H-NMR: 0.64 (t, 6H), 0.90 (t, 3H), 1.17 (t, 3H), 1.52 (q, 2H), 2.04 (q, 4H), 2.18 (s, 3H), 2.69 (q, 2H), 4.93 (s, 1 H), 6.62-6.66 (m, 2H), 6.82-6.86 (m, 1 H), 7.45 (d, 1 H), 7.85 (s, 1 H) MS (ESI+): 379 ([M+H]+).
(6) Preparation of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-propyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000388_0001
To a solution of (E)-1-{4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- propyl-phenyl}-pent-1-en-3-one (compound prepared in Example 168-(5)) (70 mg, 0.185 mmol) in THF (2 ml), 0.5 M EtLi in THF (1.85 ml, 0.93 mmol) was added at 0 degree and the mixture was stirred at room temperature for 16h. To the mixture, saturated NH CI was added, the products were extracted with ethyl acetate and the extracts were washed with H2O, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was purified by preparative TLC (n-hexane:ethyl acetate=5:1) to give the title compound (34 mg, 45%). 1H-NMR: 0.61 (t, 6H), 0.92 (t, 6H), 1.62 (q, 4H), 2.04 (q, 4H), 2.20 (s, 3H), 2.61 (t, 2H), 4.78 (s, 1 H), 6.00 (d, 1 H), 6.62 (d, 1 H), 6.73-6.95 (m, 1 H), 7.28 (d, 1 H); MS (ESI+) : 391 ([M-OH]+).
Example 169
Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- propyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000388_0002
Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- propyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000388_0003
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-propyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 168-(5)) (27 mg, 0.066 mmol) in DMF (0.5 ml), K2C03 (27.3 mg, 0.198 mmol) and (S)-(+)- dihydro-5-(p-toluenesulfonylmethyl)-2(3H)-furanone (26.8 mg, 0.0991 mmol) were added at room temperature and the mixture was stirred at 100 degrees C for 16 h. To the mixture, ethyl acetate was added and the mixture was washed with H2O, dried over MgS0 , filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethyl acetate=2:1 ) to give the title compound (20 mg, 60%).
1H-NMR: 0.61 (t, 6H), 0.91 (t, 6H), 1.59 (q, 4H), 2.05 (q, 4H), 2.15 (s, 3H), 2.55- 2.63 (m, 2H), 4.02-4.20 (m, 2H), 4.83-4.93 (m ,1H), 6.00 (d, 1H), 6.63 (d, 1H), 6.78 (d, 1 H), 7.25 (d, 1H); MS (ESI+): 524 ([M+NH4]+).
Example 170
Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- propyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000389_0001
Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- propyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000389_0002
To a solution of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- propyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example169) (16.8 mg, 0.033 mmol) in THF (1 ml) and MeOH (0.1 ml), 1 N NaOH (0.1 ml) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (12.4 mg, 72%).
1H-NMR: 0.61 (t, 6H), 0.91 (t, 6H), 1.60 (q, 4H), 2.02 (q, 4H), 2.15 (s, 3H), 3.80- 4.15 (m, 3H), 5.98 (d,1H), 6.66 (d, 1 H), 6.78 (d, 1 H), 6.87-6.93 (m, 2H); MS (ESI+) : 507 ([M-OH]+).
Example 171
Preparation of (S)-5-{4-[1 -(4-tert-Butylsulfanylmethyl-3-methyl-phenyl)-1 -ethyl- propyl]-2-methyl-phenoxymethyl}-dihydro-furan-2-one
Figure imgf000390_0001
(1 ) Preparation of 4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl- benzoic acid methyl ester
Figure imgf000390_0002
To a solution of trifluoro-methanesulfonic acid 4-[1 -ethyl-1 -(4-hydroxy-3-methyl- phenyl)-propyl]-2-methyl-phenyl ester (compound prepared in Example 1-(1)) (1480 mg, 3.554 mmol) in DMF (25 ml) and MeOH (25 ml), Pd(OAc)2 (240 mg, 1.069 mmol), dppp (440 mg, 1.067 mmol), and Et3N (1.3 ml, 9.321 mmol) were added at room temperature and the mixture was stirred at 100 degrees C for 16 h under CO gas. To the mixture, ethyl acetate was added and the mixture was washed with saturated ammonium chloride solution and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane/ethyl acetate =10/1 to 3/1 ) to give the title compound (363 mg, 31.3%). 1H-NMR (chloroform-d): 0.61 (t, 6H, J=7.2Hz), 2.07 (q, 4H, J=7.2Hz), 2.19 (s, 3H), 2.56 (s, 3H), 3.87 (s, 3H), 4.88 (brs, 1 H), 6.66 (d, 1 H, J=8.1 Hz), 6.82-6.86 (m, 2H), 7.03-7.06 (m, 2H), 7.80 (d, 1 H, J=9.0Hz); MS (ESI+) : 349 ([M+Na]+). (2) Preparation of 4-{1 -Ethyl-1 -[3-methyl-4-(tetrahydro-pyran-2-yloxy)-phenyl]- propyl}-2-methyl-benzoic acid methyl ester
Figure imgf000391_0001
To a solution of 4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl- benzoic acid methyl ester (compound prepared in Example 171-(1)) (220 mg, 0.674 mmol) in dichloromethane (1 ml), DHP (0.075 ml, 0.809 mmol) and PPTs (17 mg, 0.068 mmol) were added and the mixture was stirred at room temperature for 25.3 h. To the mixture, ethyl acetate was added and themixture was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n- hexane/ethyl acetate =10/1 to 3/1 ) to give the title compound (243 mg, 87.8%) 1H-NMR (chloroform-d): 0.63 (t, 6H, J=7.3Hz), 1.55-1.76 (m, 3H), 1.85-1.88 (m, 2H), 1.95-2.13 (m, 1 H), 2.09 (q, 4H, J=7.3Hz), 2.21 (s, 3H), 2.58 (s, 3H), 3.59- 3.63 (m, 1 H), 3.87 (s, 3H), 3.91-3.98 (m, 1 H), 5.39 (t, 1 H, J=3.2Hz), 6.88-7.13 (m, 5H), 7.82 (d, 1 H, J=8.8Hz); MS (ESI+) : 433 ([M+Na]+).
(3) Preparation of (4-{1 -Ethyl-1 -[3-methyl-4-(tetrahydro-pyran-2-yloxy)-phenyl]- propyl}-2-methyl-phenyl)-methanol
Figure imgf000391_0002
To a solution of 4-{1 -Ethyl-1 -[3-methyl-4-(tetrahydro-pyran-2-yloxy)-phenyl]- propyl}-2-methyl-benzoic acid methyl ester (compound prepared in Example 171 -(2)) (177 mg, 0.431 mmol) in THF (2 ml), LAH (20 mg, 0.527 mmol) was added and the mixture was stirred at room temperature for 18 h. To the mixture, ethyl acetate and brine were added and the organic layer was filtered through celite, concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane/ethyl acetate =1/1) to give the title compound (165 mg, quant).
1 H-NMR (chloroform-d): 0.61 (t, 6H, J=7.3Hz), 1.58-1.74 (m, 4H), 1.84-1.89 (m,
2H), 2.06 (q, 4H, J=7.3Hz), 2.20 (s, 3H), 2.30 (s, 3H), 3.58-3.64 (m, 1 H), 3.90-
3.98 (m, 1 H), 4.66 (s, 2H), 5.37 (t, 1 H, J=3.3Hz), 6.89-7.03 (m, 5H), 7.20 (d, 1 H,
J=7.9Hz).
(4) Preparation of 2-{4-[1-(4-Chloromethyl-3-methyl-phenyl)-1-ethyl-propyl]-2- methyl-phenoxy}-tetrahydro-pyran
Figure imgf000392_0001
To a solution of (4-{1 -Ethyl-1 -[3-methyl-4-(tetrahydro-pyran-2-yloxy)-phenyl]- propyl}-2-methyl-phenyl)-methanol (compound prepared in Example 171 -(3)) (178.3 mg, 0.466 mmol) in CH2CI2 (3 ml), MsCI (0.1 ml, 1.292 mmol), Et3N (325 ml, 2.33 mmol) and DMAP (6 mg, 0.049 mmol) were added at 0 degrees C and the mixture was stirred at 0 degrees C for 17 h. To the mixture, ethyl acetate was added and the mixture was washed with saturated sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. To the solution of the residue in DMF (1 ml), LiCI (20 mg, 0.472 mmol) was added and the mixture was stirred at room temperature for 2.5 h. To the mixture, ethyl acetate was added and the mixturer was washed with saturated ammonium chloride solution and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane/ethyl acetate =5/1 ) to give the title compound (137.9 mg, 73.8%). 1 H-NMR (chloroform-d): 0.61 (t, 6H, J=7.3Hz), 1.57-1.75 (m, 4H), 1.85-1.90 (m, 2H), 0.00 (q, 4H, J=7.3Hz), 2.21 (s, 3H), 2.37 (s, 3H), 3.58-3.65 (m, 1 H), 3.90- 3.98 (m, 1 H), 4.60 (s, 2H), 5.38 (t, 1 H, J=3.3Hz), 6.89-7.00 (m, 5H), 7.18 (d, 1 H, J=8.8Hz); MS (ESI+) : 418 ([M+NH4]+). (5) Preparation of 2-{4-[1-(4-tert-Butylsulfanylmethyl-3-methyl-phenyl)-1-ethyl- propyl]-2-methyl-phenoxy}-tetrahydro-pyran
Figure imgf000393_0001
To a solution of 2-{4-[1-(4-Chloromethyl-3-methyl-phenyl)-1-ethyl-propyl]-2- methyl-phenoxyj-tetrahydro-pyran (compound prepared in Example 171 -(4)) (96.2 mg, 0.24 mmol) in Acetone (3 ml), t-BuSH (334 mg, 3.71 mmol), KOH (212 mg, 3.79 mmol) in EtOH (6 ml) was added at room temperature and the mixture was stirred at 71 degrees C for 1 h. To the mixture, ethyl acetate was added and the mixture was washed with saturated sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, filtered and concentrated in vacuo.
The obtained residue was chromatographed on silica gel (n-hexane/ethyl acetate =7/1 to 3/1) to give the title compound (106.2 mg, 97.4%). 1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.3Hz), 1.40 (s, 9H), 1.55-1.75 (m, 4H), 1.84-1.90 (m, 2H), 2.03 (q, 4H, J=7.3Hz), 2.20 (s, 3H), 2.36 (s, 3H), 3.55-3.65 (m, 1 H), 3.73 (s, 2H), 3.91-3.98 (m, 1 H), 5.37 (t, 1 H, J=3.2Hz), 6.89-6.99 (m, 5H), 7.13 (d, 2H, J=8.5Hz); MS (ESI+) : 472([M+NH4]+).
(6) Preparation of (S)-5-{4-[1-(4-tert-Butylsulfanylmethyl-3-methyl-phenyl)-1- ethyl-propyl]-2-methyl-phenoxymethyl}-dihydro-furan-2-one
Figure imgf000393_0002
To a solution of 2-{4-[1-(4-tert-Butylsulfanylmethyl-3-methyl-phenyl)-1-ethyl- propyl]-2-methyl-phenoxy}-tetrahydro-pyran (compound prepared in Example 171 -(5)) (106.2 mg, 0.234 mmol) in MeOH (3ml), Montmorillinite K-10 (60mg) was added and the mixture was stirred at room temperature for 17.5 h. To the mixture, ethyl acetate and brine were added and the organic layer was filtered through celite, concentrated in vacuo. To the solution of the residue in DMF (3 ml), toluene-4-sulfonic acid (S)-5-oxo-tetrahydro-furan-2-ylmethyl ester (140 mg, 0.515 mmol), K2C03 (75 mg, 0.538 mmol) were added at room temperature and the mixture was stirred at 83 degrees C for 8 h. To the mixture, ethyl acetate was added and the mixture was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane/ethyl acetate =3/1 ) to give the title compound (71.2 mg, 64.9%) as colorless oil.
1H-NMR (chloroform-d): 0.58 (t, 6H, J=7.3Hz), 1.39 (s, 9H), 2.02 (q, 4H, J=7.3Hz), 2.15 (s, 3H), 2.35 (s, 3H), 2.27-2.62 (m, 3H), 2.77 (ddd, 1 H, J=7.3, 10.2, 17.6Hz), 3.72 (s, 2H), 4.06 (dd, 1 H, J=3.5, 10.4Hz), 4.16 (dd, 1H, J=3.5, 10.4Hz), 4.84-4.91 (m, 1 H), 6.65 (d, 1 H, J=8.2Hz), 6.90-6.95 (m, 4H), 7.12 (d, 1 H, J=8.5Hz); MS (ESI+) : 486 ([M+NH4f).
Example 172 Preparation of (S)-5-{4-[1 -(4-tert-Butylsulfanylmethyl-3-methyl-phenyl)-1 -ethyl- propyl]-2-methyl-phenoxy}-4-hydroxy-pentanoic acid
Figure imgf000394_0001
Preparation of (S)-5-{4-[1 -(4-tert-Butylsulfanylmethyl-3-methyl-phenyl)-1 -ethyl- propyl]-2-methyl-phenoxy}-4-hydroxy-pentanoic acid
Figure imgf000394_0002
To a solution of (S)-5-{4-[1-(4-tert-Butylsulfanylmethyl-3-methyl-phenyl)-1-ethyl- propyl]-2-methyl-phenoxymethyl}-dihydro-furan-2-one (compound prepared in Example 171) (10 mg, 0.021 mmol) in MeOH (1 ml), 1 N KOH aqueous solution (0.12 ml, 0.12 mmol) was added and stirred at room temperature for 12 h. The mixture was concentrated in vacuo and purified by preparative TLC
(chroloform/methanol =8/3, saturated by water) to give the title compound (5.5 mg, 53%).
1 H-NMR (chloroform-d): 0.60 (t, 3H, J=7.5Hz), 1.39 (s, 9H), 1.88-2.12 (m, 2H),
2.04 (q, 4H, J=7.5Hz), 2.18 (s, 3H), 2.36 (s, 3H), 2.63 (bit, 2H, J=7.2Hz), 3.73 (s,
2H), 3.86 (dd, 1 H, J=6.8, 9.2Hz), 3.99 (dd, 1 H, J=3.5, 9.2Hz), 4.05-4.13 (m, 1 H),
6.68 (d, 1H, J=8.3Hz), 6.92-6.96 (m, 4H), 7.14 (d, 1 H, J=8.5Hz); MS (ESI+) : 504
([M+NH4]+).
Example 173
Preparation of 5(S)-(4-{1 -Ethyl-1 -[3-methyl-4-(2-methyl-propane-2- sulfinylmethyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000395_0001
Preparation of 5(S)-(4-{1 -Ethyl-1 -[3-methyl-4-(2-methyl-propane-2- sulfinylmethyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000395_0002
To a solution of (S)-5-{4-[1-(4-tert-Butylsulfanylmethyl-3-methyl-phenyl)-1-ethyl- propyl]-2-methyl-phenoxymethyl}-dihydro-furan-2-one (compound prepared in Example 171) (20 mg, 0.043 mmol) in CH2CI2 (6 ml), mCPBA (>65%) (10.75 mg, 0.041 mmol) in CH2CI2 (2 ml) was added slowly at -78 degrees C and the mixture was stirred at -78 degrees C for 7 min. The mixture was concentrated in vacuo and purified by preparative TLC (n-hexane/ethyl acetate =1/99) to give the title compound (18.7 mg, 90.4%).
1 H-NMR (chloroform-d): 0.59 (t, 6H, J=7.3Hz), 1.34 (s, 9H), 2.04 (q, 4H, J=7.3Hz), 2.16 (s, 3H), 2.30 (s, 3H), 2.26-2.62 (m, 3H), 2.77 (ddd, 1 H, J=7.1 , 10.3, 17.2Hz), 3.59 (d, 1 H, J=12.9Hz), 3.88 (d, 1 H, J=12.7Hz), 4.04-4.19 (m, 2H), 4.85-4.91 (m, 1 H), 6.66 (d, 1 H, J=8.3Hz), 6.91-7.00 (m, 4H), 7.15 (d, 1 H, J=7.9Hz); MS (ESI+) : 485 ([M+H]+).
Example 174
Preparation of 5-(4-{1 -Ethyl-1 -[3-methyl-4-(2-methyl-propane-2-sulfinylmethyl)- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000396_0001
Preparation of 5-(4-{1 -Ethyl-1 -[3-methyl-4-(2-methyl-propane-2-sulfinylmethyl)- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000396_0002
To a solution of 5(S)-(4-{1 -Ethyl-1 -[3-methyl-4-(2-methyl-propane-2- sulfinylmethyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 173) (10 mg, 0.021 mmol) in MeOH (1 ml), 1 N KOH aqueous solution (0.12 ml, 0.124 mmol) was added and the mixture was stirred at room temperature for 12 h. The mixture was concentrated in vacuo and purified by preparative TLC (chroloform/methanol =8/3, saturated by water) to give the title compound (2.3 mg, 22.2%).
1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.3Hz), 1.34 (s, 9H), 1.85-1.98 (m, 2H), 2.05 (q, 4H, J=7.3Hz), 2.18 (s, 3H), 2.31 (s, 3H), 2.59 (t, 2H, J=7.2Hz), 3.60 (d, 1 H, J=13.0Hz), 3.89 (d, 1 H, J=13.2Hz), 3.83-4.00 (m, 2H), 4.03-4.09 (m, 1 H), 6.68 (d, 1 H, J=8.8Hz), 6.91-6.98 (m, 4H), 7.15 (d, 1 H, J=8.3Hz); MS (ESI+) : 503 «M+H]+). Example 175
Preparation of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(2-methyl-propane-2- sulfonylmethyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000397_0001
Preparation of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(2-methyl-propane-2- sulfonylmethyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000397_0002
To a solution of (S)-5-{4-[1-(4-tert-Butylsulfanylmethyl-3-methyl-phenyl)-1-ethyl- propyl]-2-methyl-phenoxymethyl}-dihydro-furan-2-one (compound prepared in Example 171) (20 mg, 0.043 mmol) in CH2CI2 (6 ml), mCPBA (>65%) (20 mg, 0.085 mmol) in CH2CI2 (2 ml) was added slowly at 0 degrees C and the mixture was stirred at 0 degrees C for 0.5 h. The mixture was concentrated in vacuo and purified by preparative TLC (n-hexane/ethyl acetate =3/1 ) to give the title compound (20.3 mg, 95%). 1 H-NMR (chloroform-d): 0.59 (t, 6H, J=7.4Hz), 1.49 (s, 9H), 2.04 (q, 4H,
J=7.4Hz), 2.16 (s, 3H), 2.37 (s, 3H), 2.26-2.62 (m, 3H), 2.77 (ddd, 1H, J=7.0, 10.2, 17.2Hz), 4.04-4.20 (m, 2H), 4.20 (s, 2H), 4.85-4.91 (m, 1H), 6.66 (d, 1H, J=8.2Hz), 6.92-7.01 (m, 4H), 7.23 (d, 1H, J=8.5Hz); MS (ESI+) : 518 ([M+NH4f).
Example 176
Preparation of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(2-methyl-propane-2- sulfonylmethyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000398_0001
Preparation of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(2-methyl-propane-2- sulfonylmethyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000398_0002
To a solution of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(2-methyl-propane-2- sulfonylmethyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 175) (10 mg, 0.02 mmol) in MeOH (1 ml), 1 N KOH aqueous solution (0.12 ml, 0.12 mmol was added and the mixture was stirred at room temperature for 12 h. The mixture was concentrated in vacuo and purified by preparative TLC (chroloform/methanol=8/3, saturated by water) to give the title compound (4.3 mg, 41.5%).
1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.3Hz), 1.49 (s, 9H), 1.83-2.14 (m, 2H), 0.00 (q, 4H, J=7.3Hz), 2.17 (s, 3H), 2.37 (s, 3H), 2.62 (t, 2H, J=7.5Hz), 3.85 (dd, 1 H, J=6.8, 9.3Hz), 3.97 (dd, 1 H, J=3.6, 9.3Hz), 4.04-4.11 (m, 1 H), 4.20 (s, 2H), 6.68 (d, 1 H, J=8.3Hz), 6.91-7.02 (m, 4H), 7.23 (d, 1 H, J=8.5Hz); MS (ESI+) : 536 ([M+NH4]+).
Example 177
Preparation of 5(S)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-dec-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000398_0003
(1) Preparation of (E)-1-{4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- methyl-phenyl}-pent-1 -en-3-one
Figure imgf000399_0001
To a solution of compound prepared in Example 1-(1) (trifluoro-methanesulfonic acid 4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl ester) (100 mg, 0.24 mmol) in DMF (1 ml), NaHC03 (80.6 mg, 0.96 mmol), LiBr (14.6 mg, 0.17 mmol), dppp (9.9 mg, 0.024 mmol), PdCI2(PPh3)2 (16.8 mg, 0.024 mmol) and acrylic acid methyl ester (0.20 ml, 2.0 mmol) were added at room temperature and the mixture was stirred at 150 degrees C for 5h. To the mixture, ethyl acetate was added and the mixture was washed with H2O, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethyl acetate=100:0 to 70:30) to give the title compound (33 mg, 39%). 1H-NMR: 0.61 (t, 6H), 1.13 (t, 3H), 2.02 (q, 4H), 2.15 (s, 3H), 2.37 (s, 3H), 3.75 (s, 1 H), 6.58 (m ,2H), 6.78-6.83 (m, 2H), 6.97-7.02 (m, 2H), 7.45 (d, 1 H), 7.81 (d, 1H); MS (ESI+) : 351 ([M+H]+).
(2) Preparation of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-dec-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000399_0002
To a solution of (E)-1-{4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl- phenyl}-pent-1-en-3-one (compound prepared in Example 177-( )) (70 mg, 0.200 mmol) in THF (2 ml), 1 M heptyl magnesium bromide in THF (0.80 ml, 0.80 mmol) was added at 0 degrees C and the mixture was stirred at 0 degrees C for 30min and at room temperature for 2h. To the mixture, saturated NH4CI solutionwas added and the mixture was filtrated through celite, concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethyl acetate=100:0 to 50:50) to give the title compound (17 mg, 19%). 1H-NMR: 0.61 (t, 6H), 0.83-0.94 (m, 6H), 2.02 (q, 4H), 2.19 (s, 3H), 2.29 (s, 3H), 4.73 (s, 1H), 6.02 (d, 1H), 6.62-7.31 (m, 7H); MS (ESI+) : 433 ([M-OH]+).
(3) Preparation of 5(S)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-dec-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000400_0001
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-dec-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 177-(2)) (17 mg, 0.0378 mmol) in DMF (0.3 ml), K2C03 (15.7 mg, 0.113 mmol) and (S)-(+)- dihydro-5-(p-toluenesulfonylmethyl)-2(3H)-furanone (20.4 mg, 0.0756 mmol) were added at room temperature and the mixture was stirred at 110 degrees C for 16h. To the mixture, ethyl acetate was added and the mixture was washed with H2O, dried over MgSθ4, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethyl acetate=100:0 to 5:1 ) to give the title compound (10.5 mg, 51%). 1H-NMR: 0.60 (t, 6H), 0.82-0.92 (m, 6H), 2.02 (q, 4H), 2.17 (s, 3H), 2.32 (s, 3H), 4.02-4.18 (m, 2H), 4.84-4.91 (m, 1 H), 6.01 (d, 1 H), 6.63-6.75 (m ,2H), 6.91-6.98 (m, 4H), 7.29 (d, 1 H); MS (ESI+) : 566 ([M+NH4]+).
Example 178 Preparation of 5(S)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-undec-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000400_0002
(1) Preparation of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-undec-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol
Figure imgf000401_0001
To a solution of (E)-1-{4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- methyl-phenyl}-pent-1-en-3-one (compound prepared in Example 177-(1)) (70 mg, 0.200 mmol) in THF (2 ml), 2M octyl magnesium bromide in THF (0.40 ml, 0.80 mmol) were added at 0 degrees C and the mixture was stirred at 0 degrees C for 30min and at room temperature for 2h. To the mixture, saturated NH4CI solutionwas added and the mixture was filtrated through celite and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n- hexane:ethyl acetate=100:0 to 50:50) to give the title compound (22 mg, 24%). 1H-NMR: 0.60 (t, 6H), 0.80-0.90 (m, 6H), 2.02 (q, 4H), 2.19 (s, 3H), 2.29 (s, 3H), 6.02 (d, 1H), 6.61-7.30 (m, 7H); MS (ESI+) : 447 ([M-OH]+).
(2) Preparation of 5(S)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-undec-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000401_0002
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-undec-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 178-(1)) (22 mg, 0.0474 mmol) in DMF (0.3 ml), K2C03 (19.7 mg, 0.144 mmol) and (S)-(+)- dihydro-5-(p-toluenesulfonylmethyl)-2(3H)-furanone (25.6 mg, 0.0948 mmol) were added at room temperature and the mixture was stirred at 110 degrees C for 16h. To the mixture, ethyl acetate was added and the mixture was washed with H20, dried over MgSθ4, concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethyl acetate=100:0 to 5:1) to give the title compound (9.9 mg, 37%).
1H-NMR: 0.61 (t, 6H), 0.84-0.93 (m, 6H), 2.04 (q, 4H), 2.15 (s, 3H), 2.32 (s, 3H), 4.02-4.18 (m, 2H), 4.84-4.91 (m, 1 H), 6.01 (d, 1 H), 6.63-6.75 (m ,2H), 6.91-6.98 (m, 4H), 7.29 (d, 1H); MS (ESI+) : 580 ([M+NH4]+).
Example 179
Preparation of 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hex-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000402_0001
(1 ) Preparation of 4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-hex-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000402_0002
To a solution of (E)-1-{4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- methyl-phenyl}-pent-1-en-3-one (compound prepared in Example 177-(1)) (70 mg, 0.200 mmol) in THF (2 ml), 0.93M n-propyl magnesium bromide in THF (1.08 ml, 1.00 mmol) were added at 0 degrees C and the mixture was stirred at 0 degrees C for 30min and at room temperature for 2h. To the mixture, saturated NH4CI solution was added and the mixture was filtrated through celite, concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethyl acetate=100:0 to 50:50) to give the title compound (37 mg, 47%).
1H-NMR: 0.57 (t, 6H), 0.83-0.92 (m, 6H), 2.00 (q, 4H), 4.98 (s, 1 H), 6.01 (d, 1 H), 6.61-7.30 (m, 7H). (2) Preparation of 5(S)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hex-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000403_0001
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-undec-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol compound prepared in Example 179-(1)) (18 mg, 0.0457 mmol) in DMF (0.4 ml), K2C03 (16.6 mg, 0.120 mmol) and (S)-(+)- dihydro-5-(p-toluenesulfonylmethyl)-2(3H)-furanone (24.3 mg, 0.090 mmol) were added at room temperature and the mixture was stirred at 100 degrees C for 60 h. To the mixture, ethyl acetate was added and the mixture was washed with H2O, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethylacetate=100:0 to 5:1) to give the title compound (13 mg, 58%).
1H-NMR: 0.60 (t, 6H), 0.89-0.95 (m, 6H), 2.04 (q, 4H), 2.16 (s, 3H), 2.30 (s, 3H), 4.01-4.18 (m, 2H), 4.83-4.90 (m, 1H), 6.00 (d, 1H), 6.63-6.75 (m ,2H), 6.89-6.97 (m, 4H), 7.29 (d, 1H); MS (ESI+) : 475 ([M-OH]+).
(3) Preparation of 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hex-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000403_0002
To a solution of 5(S)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hex-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 179-(2)) (13 mg, 0.026 mmol) in MeOH (1 ml), 1N NaOH (0.1 ml) was added at room temperature and the mixture was stirred at room temperature for 1h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (2.0 mg, 15%).
1H-NMR: 0.60 (t, 6H), 0.87-0.92 (m, 6H), 2.01 (q, 4H), 2.18 (s, 3H), 2.30 (s, 3H), 2.59 (t, 2H), 3.80-4.07 (m, 3H), 6.01 (d,1H), 6.64-6.75 (m, 2H), 6.88-6.97 (m, 4H), 7.25 (d, 1H); MS (ESI+) : 528 ([M+NH4]+).
Example 180 Preparation of 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hept-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000404_0001
(1) Preparation of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hept-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000404_0002
To a solution of (E)-1-{4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- methyl-phenyl}-pent-1-en-3-one (compound prepared in Example 177-(1)) (70 mg, 0.200 mmol) in THF (2 ml), 1.58M n-butyl lithium in n-hexane (0.632 ml, 1.00 mmol) were added at 0 degrees C and the mixture was stirred at 0 degrees C for 30min and at room temperature for 2h. To the mixture, saturated NH4CI solution was added and the mixture was filtrated through celite, concentrated in vacuo. The obtained residue was chromatographed on silica gel
(n-hexane:ethyl acetate=100:0 to 50:50) to give the title compound (51 mg,
62%).
1H-NMR: 0.61 (t, 6H), 0.82-0.92 (m, 6H), 2.01 (q, 4H), 2.18 (s, 3H), 2.30 (s, 3H), 4.95 (s, 1 H), 6.00 (d, 1 H), 6.62-7.30 (m, 7H); MS (ESI+) : 409 ([M+H]+). (2) Preparation of 5(S)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hept-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2- one
Figure imgf000405_0001
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hept-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 180-(1 )) (18 mg, 0.0441 mmol) in DMF (0.4 ml), K2C03 (16.6 mg, 0.120 mmol) and (S)-(+)- dihydro-5-(p-toluenesulfonylmethyl)-2(3H)-furanone (24.3 mg, 0.090 mmol) were added at room temperature and the mixture was stirred at 100 degrees C for 60 h. To the mixture, ethyl acetate was added and the mixture was washed with H20, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethylacetate=100:0 to 5:1 ) to give the title compound (20 mg, 90%). 1H-NMR: 0.60 (t, 6H), 0.89-0.92 (m, 6H), 2.02 (q, 4H), 2.17 (s, 3H), 2.28 (s, 3H), 4.02-4.18 (m, 2H), 4.82-4.90 (m, 1 H), 6.01 (d, 1 H), 6.64-6.75 (m ,2H), 6.89-6.95 (m, 4H), 7.25 (d, 1 H); MS (ESI+) : 489 ([M-OH]+).
(3) Preparation of 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hept-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000405_0002
To a solution of 5(S)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hept-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 180-(2)) (20 mg, 0.040 mmol) in MeOH (1 ml), 1 N NaOH (0.1 ml) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCI :MeOH=8:3 saturated with H20) to give the title compound (7.1 mg, 34%).
1H-NMR: 0.61 (t, 6H), 0.87-0.92 (m, 6H), 2.01 (q, 4H), 2.17 (s, 3H), 2.30 (s, 3H), 2.61 (t, 2H), 3.80-4.10 (m, 3H), 6.01 (d,1H), 6.63-6.75 (m, 2H), 6.83-6.96 (m, 4H), 7.26 (d, 1 H); MS (ESI+) : 542 ([M+NH4]+).
Example 181
Preparation of 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000406_0001
(1) Preparation of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000406_0002
To a solution of (E)-1-{4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- methyl-phenyl}-pent-1-en-3-one (compound prepared in Example 177-(1)) (70 mg, 0.200 mmol) in THF (2 ml), 2M pentyl magnesium bromide in THF (0.500ml, 1.OOmmol) was added at 0 degrees C and the mixture was stirred at 0 degrees C for 30min and at room temperature for 2h. To the mixture, saturated NH4CI solution was added and the mixture was filtrated through celite, concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethyl acetate=100:0 to 50:50) to give the title compound (23 mg, 27%). 1H-NMR: 0.60 (t, 6H), 0.80-0.90 (m, 6H), 2.00 (q, 4H), 2.17 (s, 3H), 2.28 (s, 3H), 4.88 (s, 1 H), 6.00 (d, 1 H), 6.60-7.28 (m, 7H); MS (ESI+) : 423 ([M+H]+).
(2) Preparation of 5(S)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2- one
Figure imgf000407_0001
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound preprared in Example 181-(1 )) (18 mg, 0.0427 mmol) in DMF (0.4 ml), K2C03 (16.6 mg, 0.120 mmol) and (S)-(+)- dihydro-5-(p-toluenesulfonylmethyl)-2(3H)-furanone (24.3 mg, 0.090 mmol) were added at room temperature and the mixture was stirred at 100 degrees C for 60 h. To the mixture, ethyl acetate was added and the mixture was washed with H20, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethylacetate=100:0 to 5:1 ) to give the title compound (22 mg, 99%).
1H-NMR: 0.61 (t, 6H), 0.83-0.92 (m, 6H), 2.03 (q, 4H), 2.12 (s, 3H), 2.30 (s, 3H), 4.01-4.18 (m, 2H), 4.83-4.90 (m, 1 H), 5.98 (d, 1 H), 6.60-6.72 (m ,2H), 6.82-6.95 (m, 4H), 7.25 (d, 1 H); MS (ESI+) : 503 ([M-OH]+).
(3) Preparation of 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000407_0002
To a solution of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
(compound prepared in Example 181 -(2)) (22 mg, 0.042 mmol) in MeOH (1 ml), 1 N NaOH (0.1 ml) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (1.8 mg, 8%). 1H-NMR: 0.60 (t, 6H), 0.82-0.90 (m, 6H), 2.03 (q, 4H), 2.18 (s, 3H), 2.30 (s, 3H), 2.59 (t, 2H), 3.80-4.13 (m, 3H), 6.00 (d,1H), 6.65-6.75 (m, 2H), 6.90-7.00 (m, 4H), 7.26 (d, 1H); MS (ESI+) : 556 ([M+NH4]+).
Example 182
Preparation of 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-non-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000408_0001
(1) Preparation of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-non-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl- phenol
Figure imgf000408_0002
To a solution of (E)-1-{4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- methyl-phenyl}-pent-1-en-3-one (compound prepared in Example 177-(1)) (70 mg, 0.200 mmol) in THF (2 ml), 2M hexyl magnesium bromide in THF (0.500 ml, 1.00 mmol) were added at 0 degrees C and the mixture was stirred at 0 degrees C for 30 min and at room temperature for 2 h. To the mixture, saturated NH4CI solution was added and the mixture was filtrated through celite, concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethyl acetate=100:0 to 50:50) to give the title compound (15 mg, 17%). 1H-NMR: 0.62 (t, 6H), 0.82-0.90 (m, 6H), 2.00 (q, 4H), 2.17 (s, 3H), 2.28 (s, 3H), 4.70 (s, 1 H), 6.00 (d, 1H), 6.60-7.28 (m, 7H); MS (ESI+) : 437 ([M+H]+).
(2) Preparation of 5(S)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-non-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2- one
Figure imgf000409_0001
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-non-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 182-(1)) (18 mg, 0.0413 mmol) in DMF (0.4 ml), K2C03 (16.6 mg, 0.120 mmol) and (S)-(+)- dihydro-5-(p-toluenesulfonylmethyl)-2(3H)-furanone (24.3 mg, 0.090 mmol) were added at room temperature and the mixture was stirred at 100 degrees C for 60 h. To the mixture, ethyl acetate was added and the mixture was washed with H2O, dried over MgSθ4, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethylacetate=100:0 to 5:1 ) to give the title compound (17 mg, 77%).
1H-NMR: 0.62 (t, 6H), 0.82-0.92 (m, 6H), 2.05 (q, 4H), 2.15 (s, 3H), 2.30 (s, 3H), 4.01-4.18 (m, 2H), 4.82-4.90 (m, 1 H), 6.00 (d, 1 H), 6.61-6.72 (m ,2H), 6.88-6.95 (m, 4H), 7.26 (d, 1 H); MS (ESI+) : 517 ([M-OH]+).
(3) Preparation of 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-non-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000409_0002
To a solution of 5(S)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-non-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 182-(2)) (17 mg, 0.032 mmol) in MeOH (1 ml), 1 N NaOH (0.1 ml) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (6.1 mg, 35%). 1H-NMR: 0.62 (t, 6H), 0.84-0.94 (m, 6H), 2.03 (q, 4H), 2.18 (s, 3H), 2.30 (s, 3H), 2.61 (t, 2H), 3.80-4.10 (m, 3H), 6.01 (d,1 H), 6.65-6.77 (m, 2H), 6.90-6.97 (m, 4H), 7.26 (d, 1 H); MS (ESI+) : 570 ([M+NH4]+).
Example 183
Preparation of 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-dec-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000410_0001
Preparation of 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-dec-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000410_0002
To a solution of compound prepared in Example 177-(3) ((S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-dec-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one) (6.3 mg, 0.011 mmol) in MeOH (1 ml), 1 N NaOH (0.1 ml) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (4.9 mg, 79%). 1H-NMR: 0.60 (t, 6H), 0.86-0.92 (m, 6H), 2.01 (q, 4H), 2.12 (s, 3H), 2.30 (s, 3H), 2.57 (t, 2H), 3.80-4.08 (m, 3H), 6.00 (d,1 H), 6.63-6.78 (m, 2H), 6.88-6.93 (m, 4H); MS (ESI+): 584 ([M+NH4]+).
Example 184
Preparation of 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-undec-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000411_0001
Preparation of 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-undec-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000411_0002
To a solution of 5(S)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-undec-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid (compound prepared in Example 178-(2)) (7.0 mg, 0.012 mmol) in MeOH (1 ml), 1 N NaOH (0.1 ml) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (3.7 mg, 55%). 1H-NMR: 0.60 (t, 6H), 0.84-0.92 (m, 6H), 2.01 (q, 4H), 2.15 (s, 3H), 2.30 (s, 3H), 2.58 (t, 2H), 3.80-4.07 (m, 3H), 6.00 (d,1 H), 6.62-6.72 (m, 2H), 6.85-6.93 (m, 4H); MS (ESI+) : 598 ([M+NH4]+).
Example 185
Preparation of 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1 -en-4-ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000411_0003
(1) Preparation of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1-en-4-ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol
Figure imgf000412_0001
To a solution of 1-pentyne (0.0986 ml, 1.00 mmol) in THF (1 ml), 1.56M n-butyl lithium in n-hexane (0.646 ml, 1.02 mmol) was added at 0 degrees C and the mixture was stirred at room temperature for 30min. To the mixture, a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1 -en-4-ynyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenol (compound prepared in Example 177-(1)) (70 mg, 0.20 mmol) in THF (1 ml) was added at room temperature and the mixture was stirred at room temperature for 1 h. To the mixture, saturated NH4CI solution was added and the mixture was filtrated through celite, concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethyl acetate=100:0 to 50:50) to give the title compound (70 mg, 84%).
1H-NMR: 0.59 (t, 6H), 2.00 (q, 4H), 2.19 (s, 3H), 2.24 (t, 2H), 2.30 (s, 3H), 4.67 (s, 1 H), 6.05 (d, 1 H), 6.63 (d, 1 H), 6.82-6.95 (m, 4H), 7.08 (d, 1 H), 7.36 (d, 1 H); MS (ESI+) : 419 ([M+H]+).
(2) Preparation of 5(S)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1-en-4- ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2- one
Figure imgf000412_0002
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1 -en-4-ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 185-(1)) (15 mg, 0.0359 mmol) in DMF (0.4 ml), K2C03 (16.6 mg, 0.120 mmol) and (S)-(+)- dihydro-5-(p-toluenesulfonylmethyl)-2(3H)-furanone (24.3 mg, 0.090 mmol) were added at room temperature and the mixture was stirred at 100 degrees C for 60 h. To the mixture, ethyl acetate was added and the mixture was washed with H20, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (n-hexane:ethyl acetate=100:0 to
5:1) to give the title compound (18 mg, 97%).
1H-NMR: 0.59 (t, 6H), 0.97-1.04 (m, 6H), 2.03 (q, 4H), 2.16 (s, 3H), 2.27 (t, 2H),
2.32 (s, 3H), 4.01-4.18 (m, 2H), 4.82-4.90 (m, 1H), 6.03 (d, 1H), 6.62 (d, 1H),
6.90-6.97 (m, 4H), 7.03 (d, 1H), 7.37 (d, 1H)
MS (ESI+): 499 ([M-OH]+)
(3) Preparation of 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1 -en-4-ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(S)-hydroxy-pentanoic acid
Figure imgf000413_0001
To a solution of 5(S)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1-en-4-ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 185-(2)) (18 mg, 0.035 mmol) in MeOH (1 ml), 1N NaOH (0.1 ml) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (5.2 mg, 29%). 1H-NMR: 0.60 (t, 6H), 0.97-1.03 (m, 6H), 1.52-1.60 (m, 4H), 2.02 (q, 4H), 2.17 (s, 3H), 2.28 (t, 2H), 2.30 (s, 3H), 2.62 (t, 2H), 3.82-4.08 (m, 3H), 6.08 (d, 1 H), 6.68 (d, 1 H), 6.88-6.92 (m, 4H), 7.08 (d, 1 H), 7.32 (d, 1 H); MS (ESI+) : 552 ([M+NH4]+).
Example 186
Preparation of 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5(S)-hydroxy-hexanoic acid
Figure imgf000413_0002
(1 ) Preparation of 4-(1 -{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]- 3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenol
Figure imgf000414_0001
To a solution of 4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 20) (5.04 g, 13.2 mmol) in CH2CI2 (40 ml) and lutidine (4.76 ml, 40.9 mmol), Trifluoromethanesulfonic acid tert-butyldimethylsilyl ester (0.51 ml, 3.09 mmol) was added at 0 degrees C and the mixture was stirred for 0.5 h at 0 degrees C. The reaction mixture was poured into H2O and the products were extracted with ethyl acetate and hexane. The extracts were washed with saturated aqueous NH4CI, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (ethyl acetate/hexane=0/100 to 10/90) to give the disilylated compound (7.32 g). This disilylated compound was dissolved with THF (113 ml) and 1 M TBAF in THF solution (12.6 ml, 12.6 mmol) was added at 0 degrees C and the mixture was stirred for 5 min at 0 degrees C. The reaction mixture was poured into brine and the products were extracted with ethyl acetate and hexane. The extracts were washed with brine twice, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (ethyl acetate/hexane=10/90 to 20/80) to give the title compound (5.66 g, 86%).
1H-NMR: 0.07 (s, 3H), 0.10 (s, 3H), 0.60 (t, 6H), 0.88 (s, 9H), 0.93 (s, 9H), 1.51- 1.63 (m, 1 H), 1.73-1.84 (m, 1 H), 2.03 (q, 4H), 2.20 (s, 3H), 2.23 (s, 3H), 2.36- 2.46 (m, 1H), 2.71-2.81 (m, 1H), 3.34 (dd, 1 H), 4.50 (s, 1H), 6.64 (d, 1 H), 6.85- 6.99 (m, 5H).
(2) Preparation of 6(S)-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxymethyl]-tetrahydro- pyran-2-one
To a solution of 4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3- methyl-phenyl}-1-ethyl-propy|)-2-methyl-phenol (compound prepared in Example 186-(1)) (55.7 mg, 0.112 mmol), PPh3 (88.2 mg, 0.336 mmol), (S)-6- Hydroxymethyl-tetrahydro-pyran-2-one (J. Chem. Soc, Perkin Trans. 1, 2000, 20, 3519.) (43.7 mg, 0.336 mmol) in THF (0.2 ml), DEAD (58.6 mg, 0.336 mmol) was added slowly and the mixture was stirred at room temperature for 15 h. The mixture was concentrated in vacuo and purified by preparative TLC (n- hexane/ethyl acetate =1/1 and 3/1) to give the title compound (5.9 mg, 8.6%). 1H-NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.60 (t, 6H, J=7.3Hz), 0.88 (s, 9H), 0.94 (s, 9H), 1.72-2.13 (m, 6H), 2.04 (q, 4H, J=7.3Hz), 2.16 (s, 3H), 2.24 (s, 3H), 2.36-2.81 (m, 4H), 3.34 (dd, 1 H, J=3.2Hz), 4.04 (dd, 1 H, J=5.6, 9.8Hz), 4.13 (dd, 1 H, J=4.3, 9.8Hz), 4.64-4.71 (m, 1 H), 6.67 (d, 1 H, J=8.3Hz), 6.89-7.00 (m, 5H).
(3) Preparation of 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5(S)-hydroxy-hexanoic acid
Figure imgf000415_0001
To a solution of 6(S)-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxymethyl]-tetrahydro- pyran-2-one (compound prepared in Example 186-(2)) (5.9 mg, 0.01 mmol) in THF (0.1 ml), 1.0M TBAF (0.24 ml, 0.24 mmol) was added and the mixture was stirred at 70 degrees C for 7 h. To the mixture, ethyl acetate was added and the mixture was washed with diluted potassium hydrogen sulfate aq., saturated sodium hydrogen carbonate solution, and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (dichrolomethane/methanol =15/1 ) to give the title compound (2.6 mg, 52.3%).
1H-NMR (methanol-d4): 0.58 (t, 6H, J=7.3Hz), 0.82 (s, 9H), 1.45-1.84 (m, 6H), 0.00 (q, 4H, J=7.3Hz), 2.14 (s, 3H), 2.23 (s, 3H), 2.34 (t, 2H, J=7.2Hz), 2.48-2.58 (m, 1 H), 2.81-2.91 (m, 1 H), 3.15 (dd, 1H, J=1.5, 10.5Hz), 3.87-3.92 (m, 3H), 6.74 (d, 1 H, J=8.5Hz), 6.84-6.96 (m, 4H), 7.00 (d, 1 H, J=7.9Hz); MS (ESI+) : 535 ([M+Na]+).
Example 187 Preparation of 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5(S)-hydroxy-hexanoic acid
Figure imgf000416_0001
(1 ) Preparation of 4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]- 3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenol
Figure imgf000416_0002
Using the same procedure as described for the preparation of Example 186- (1 ), the title compound was prepared from 4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 19).
1H-NMR: 0.07 (s, 3H), 0.10 (s, 3H), 0.60 (t, 6H), 0.88 (s, 9H), 0.93 (s, 9H), 1.51- 1.63 (m, 1 H), 1.73-1.84 (m, 1 H), 2.03 (q, 4H), 2.20 (s, 3H), 2.23 (s, 3H), 2.36- 2.46 (m, 1H), 2.71-2.81 (m, 1 H), 3.34 (dd, 1H), 4.50 (s, 1H), 6.64 (d, 1H), 6.85- 6.99 (m, 5H).
(2) Preparation of 6(S)-[4-(1 -{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxymethyl]-tetrahydro- pyran-2-one
Figure imgf000416_0003
To a solution of 4-(1-{4-[(S)-3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenol (compound prepared in Example 187-(1)) (45.1 mg, 0.091 mmol), PPh3 (71.4 mg, 0.272 mmol) and (S)- 6-Hydroxymethyl-tetrahydro-pyran-2-one (J. Chem. Soc, Perkin Trans. 1, 2000, 20, 3519.) (35.4 mg, 0.272 mmol) in THF (0.15 ml), DEAD (47.4 mg, 0.272 mmol) was added slowly and the mixture was stirred at room temperature for 15 h. The mixture was concentrated in vacuo and purified by preparative TLC (n- hexane/ethyl acetate =3/1 ) to give the title compound (10 mg, 18.1%). 1H-NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.60 (t, 6H, J=7.3Hz), 0.88 (s, 9H), 0.94 (s, 9H), 1.73-2.13 (m, 6H), 0.00 (q, 4H, J=7.3Hz), 2.36-2.81 (m, 4H), 3.35 (dd, 1 H, J=3.3, 7.1Hz), 4.04 (dd, 1H, J=5.6, 9.8Hz), 4.13 (dd, 1H, J=4.3, 9.8Hz), 4.66-4.71 (m, 1 H), 6.67 (d, 1 H, J=8.2Hz), 6.89-6.93 (m, 4H), 6.98 (d, 1 H, J=8.5Hz).
(3) Preparation of 6-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4-di methyl-pentyl )-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5(S)-hydroxy-hexanoic acid
Figure imgf000417_0001
To a solution of 6(S)-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxymethyl]-tetrahydro- pyran-2-one (compound prepared in Example 187-(2)) (10 mg, 0.016 mmol) in THF (0.2 ml), 1.0M TBAF in THF (0.4 ml, 0.4 mmol) was added and the mixture was stirred at 70 degrees C for 4 h. To the mixture, ethyl acetate was added and the mixture was washed with diluted potassium hydrogen sulfate aq., saturated sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by preparative TLC (dichrolomethane/methanol =15/1) to give the title compound (3.3 mg, 39.2%).
1H-NMR (methanol-d4): 0.58 (t, 6H, J=7.3Hz), 0.86 (s, 9H), 1.41-1.84 (m, 6H), 2.05 (q, 4H, J=7.3Hz), 2.14 (s, 3H), 2.28 (s, 3H), 2.35 (t, 2H, J=7.0Hz), 2.48-2.58 (m, 1 H), 2.81-2.91 (m, 1 H), 3.15 (dd, 1 H, J=1.6, 10.6Hz), 3.87-3.93 (m, 3H), 6.74 (d, 1 H, J=8.5Hz), 6.84-6.96 (m, 4H), 7.00 (d, 1 H, J=8.0Hz); MS (ESI+) : 535 ([M+Na]+).
Example 188
Preparation of 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5(R)-hydroxy-hexanoic acid
Figure imgf000418_0001
(1) Preparation of 6(R)-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxymethyl]-tetrahydro- pyran-2-one
Figure imgf000418_0002
To a solution of 4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3- methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenol (compound prepared in Example 187-(1 )) (40 mg, 0.081 mmol), PPh3 (63.3 mg, 0.242 mmol) and (R)-6- Hydroxymethyl-tetrahydro-pyran-2-one (J. Chem. Soc, Perkin Trans. 1, 2000, 20, 3519.) (31.4 mg, 0.242 mmol) in THF (0.1 ml), DEAD (42.1 mg, 0.242 mmol) was added and the mixture was stirred at room temperature for 37 h. The mixture was concentrated in vacuo and purified by preparative TLC (n- hexane/ethyl acetate =3/1 and 2/1) to give the title compound (13.5 mg, 27.4%). 1H-NMR (chloroform-d): 0.07 (s, 3H), 0.11 (s, 3H), 0.60 (t, 6H), 0.89 (s, 9H), 0.94 (s, 9H), 1.73-2.21 (m, 6H), 2.04 (q, 4H, J=7.5Hz), 2.16 (s, 3H), 2.24 (s, 3H), 2.36-2.81 (m, 4H), 3.35 (dd, 1 H, J=3.2, 7.1 Hz), 4.04 (dd, 1 H, J=5.4, 9.9Hz), 4.13 (dd, 1 H, J=4.4, 9.8Hz), 4.64-4.72 (m, 1 H), 6.67 (d, 1 H, J=8.1 Hz), 6.89-6.94 (m, 4H), 6.98 (d, 1 H, J=8.7Hz). (2) Preparation of 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5(R)-hydroxy-hexanoic acid
Figure imgf000419_0001
To a solution of 6(R)-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxymethyl]-tetrahydro- pyran-2-one (compound prepared in Example 188-(1)) (16.5 mg, 0.033 mmol) in THF (0.2 ml) and MeOH (0.2 ml), 1 N KOH aq (0.2 ml, 0.2 mmol) was added and the mixture was stirred at 65 degrees C for 1.5 h. To the mixture, ethyl acetate was added and the mixture was washed with diluted potassium hydrogen sulfate aq., water, saturated sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by preparative TLC (dichrolomethane/methanol =10/1) to give the title compound (8.4 mg, 49.1 %). 1H-NMR (methanol-d4): 0.57 (t, 6H, J=7.3Hz), 0.86 (s, 9H), 1.40-1.90 (m, 6H), 2.04 (q, 4H, J=7.3Hz), 2.13 (s, 3H), 2.23 (s, 3H), 2.36 (brt, 2H), 2.47-2.58 (m, 1H), 2.81-2.91 (m, 1H), 3.15 (dd, 1H, J=1.5, 10.4Hz), 3.86-3.98 (m, 3H), 6.73 (d, 1 H, J=8.4Hz), 6.84-6.96 (m, 4H), 7.00 (d, 1 H, J=8.1 Hz); MS (ESI+) : 530 ([M+NH4]+).
Example 189
Preparation of 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5(R)-hydroxy-hexanoic acid
Figure imgf000419_0002
(1) Preparation of 6(R)-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxymethyl]-tetrahydro- pyran-2-one
Figure imgf000420_0001
To a solution of 4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3- methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenol (compound prepared in Example 186-(1)) (40 mg, 0.081 mmol) PPh3 (63 mg, 0.242 mmol), (R)-6-Hydroxymethyl- tetrahydro-pyran-2-one (J. Chem. Soc, Perkin Trans. 1, 2000, 20, 3519.) (31 mg, 0.242 mmol) in THF (0.1 ml), DEAD (42 mg, 0.242 mmol) was added and the mixture was stirred at room temperature for 37 h. The mixture was concentrated in vacuo and purified by preparative TLC (n-hexane/ethyl acetate =3/1 and 2/1 ) to give the title compound (13.5 mg, 27.5%). 1 H-NMR (chloroform-d): 0.07 (s, 3H), 0.10 (s, 3H), 0.60 (t, 6H), 0.88 (s, 9H), 0.94 (s, 9H), 1.73-2.16 (m, 6H), 2.04 (q, 4H, J=7.5Hz), 2.16 (s, 3H), 2.24 (s, 3H), 2.36-2.81 (m, 4H), 3.35 (dd, 1 H, J=3.3, 7.1 Hz), 4.04 (dd, 1 H, J=5.6, 9.8Hz), 4.13 (dd, 1 H, J=4.3, 9.9Hz), 4.64-4.72 (m, 1H), 6.67 (d, 1H, J=8.2Hz), 6.89-6.94 (m, 4H), 6.98 (d, 1 H, J=8.5Hz).
(2) Preparation of 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5(R)-hydroxy-hexanoic acid
Figure imgf000420_0002
To a solution of 6(R)-[4-(1-{4-[(R)-3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxymethyl]-tetrahydro- pyran-2-one (compound prepared in Example 189-(1 )) (16.5 mg, 0.027 mmol) in THF (0.2 ml) and MeOH (0.2 ml), 1 N KOH aq (0.2 ml, 0.2 mmol) was added at room temperature and the mixture was stirred at 65 degrees C for 1.5 h. To the mixture, ethyl acetate was added and the mixture was washed with diluted potassium hydrogen sulfate aq., water, saturated sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by preparative TLC (dichrolomethane/methanol =10/1 , twice) to give the title compound (6.9 mg, 49.7%).
1H-NMR (methanol-d4): 0.58 (t, 6H, J=7.3Hz), 0.86 (s, 9H), 1.38-1.84 (m, 6H), 2.05 (q, 4H, J=7.3Hz), 2.14 (s, 3H), 2.23 (s, 3H), 2.34 (t, 2H, J=7.0Hz), 2.47-2.58 (m, 1 H), 2.81-2.91 (m, 1 H), 3.15 (dd, 1 H, J=1.5, 10.5Hz), 3.87-3.98 (m, 3H), 6.73 (d, 1 H, J=8.6Hz), 6.84-6.96 (m, 4H), 7.00 (d, 1 H, J=7.9Hz); MS (ESI+) : 513 ([M+H]+).
Example 190
Preparation of 6(R)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one
Figure imgf000421_0001
Preparation of 6(R)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one
Figure imgf000421_0002
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(5)) (30 mg, 0.079 mmol), PPh3 (62.0 mg, 0.236 mmol), (R)-6-Hydroxymethyl-tetrahydro- pyran-2-one (J. Chem. Soc, Perkin Trans. 1, 2000, 20, 3519.) (30.8 mg, 0.236 mmol) in THF (0.1 ml), DEAD (41.2 mg, 0.236 mmol) was added slowly and the mixture was stirred at room temperature for 37 h. The mixture was concentrated in vacuo and purified by preparative TLC (n-hexane/ethyl acetate =1/3, 3/1 , 3 times, 1/1 , dichloromethane/methanol=15/1) to give the title compound (8.5 mg, 21.9%).
1H-NMR (chloroform-d): 0.61 (t, 6H, J=7.3Hz), 0.92 (t, 6H, J=7.5Hz), 1.64 (q, 4H, J=7.6Hz), 1.82-1.95 (m, 4H), 2.05 (q, 4H, J=7.3Hz), 2.16 (s, 3H), 2.31 (s, 3H), 2.46-2.71 (m, 2H), 4.04 (dd, 1 H, J=5.5, 9.9Hz), 4.13 (dd, 1 H, J=4.3, 9.9Hz), 4.65-4.72 (m, 1 H), 6.01 (d, 1 H, J=16.1 Hz), 6.67 (d, 1 H, J=8.5Hz), 6.74 (d, 1 H, J=16.0Hz), 6.92-6.97 (m, 4H), 7.29 (d, 1 H, J=8.6Hz); MS (ESI+) : 510 ([M+NH4]+).
Example 191
Preparation of 6-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5(R)-hydroxy-hexanoic acid
Figure imgf000422_0001
Preparation of 6-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5(R)-hydroxy-hexanoic acid
Figure imgf000422_0002
To a solution of 6(R)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one (compound prepared in Example 190) (5.9 mg, 0.012 mmol) in THF (0.1 ml) and , MeOH (0.1 ml), 1 N KOH aq (0.1 ml, 0.1 mmol) was added at room temperature and the mixture was stirred at 70 degrees C for 4 h. To the mixture, ethyl acetate was added and the mixture was washed with diluted potassium hydrogen sulfate aq. and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by preparative TLC (dichrolomethane /methanol =15/1 , twice) to give the title compound (4.9mg, 80.1%). 1H-NMR (methanol-d4): 0.59 (t, 6H, J=8.1 Hz), 0.91 (t, 6H, J=8.3Hz), 1.62 (q, 4H, J=8.3Hz), 1.52-1.82 (m, 4H), 2.06 (q, 4H, J=8.1Hz), 2.14 (s, 3H), 2.21 (t, 2H, J=8.0Hz), 2.27 (s, 3H), 3.82-3.98 (m, 3H), 5.98 (d, 1 H, J=17.8Hz), 6.75 (d, 1 H, J=17.9Hz), 6.75 (d, 1 H, J=9.3Hz), 6.91-6.96 (m, 3H), 7.27 (d, 1 H, J=9.2Hz); MS (ESI+) : 493 ([M-OH]+).
Example 192
Preparation of 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl )-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid
Figure imgf000423_0001
(1 ) Preparation of Trifluoro-methanesulfonic acid 4-{1 -ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenyl ester
Figure imgf000423_0002
To a solution of 4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 2-(2)) (200 mg, 0.398 mmol) in CH2CI2 (2 ml), pyridine (63.8 mg, 0.796 mmol) and trifluoromethanesulfonic anhydride (0.0737 ml, 0.438 mmol) were added and the mixture was stirred at room temperature for 16h. The mixture was chromatographed on silica gel (ethyl acetate/n- hexane = 0/100 to 1/5) to give the title compound (197 mg, 78%).
1H-NMR: 0.60 (t, 6H), 2.06 (q, 4H), 2.32 (s, 3H), 2.41 (s, 3H), 3.48 (s, 3H), 5.15 (s, 2H), 6.94-7.05 (m, 4H), 7.12 (d, 1 H), 7.30 (d, 1 H).
(2) Preparation of Hex-5-ynoic acid methyl ester ^^^^COOH ^^^-\^COOMe To a solution of hex-5-ynoic acid (2.0 g, 17.9 mmol) in MeOH (4 ml), cone. H2SO4 (4 drops) was added at room temperature and the mixture was stirred at 60 degrees C for 60 h. To the mixture, ethyl acetate was added and the mixture was washed with saturated NaHC03, dried over MgS04 filtered and concentrated in vacuo to give the title compound (2.0 g, 89%). 1H-NMR: 1.80-1.90 (m ,2H), 1.97-1.99 (m, 1 H), 2.23-2.30 (m, 2H), 2.48 (t, 2H), 3.68 (s, 3H)
(3) Preparation of 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-methoxymethoxy- 3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid methyl ester
Figure imgf000424_0001
To a solution of trifluoro-methanesulfonic acid 4-{1 -ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenyl ester (compound prepared in Example 192-(1 )) (23 mg, 0.0363 mmol) in DMF (0.5 ml), Et3N (0.0253 ml, 0.182 mmol), Cul (3.4 mg, 0.0181 mmol), PdCI (PPh3)2 (12.7 mg, 0.0181 mmol) and hex-5-ynoic acid methyl ester (compound prepared in Example 192-(2)) (13.7 mg, 0.109 mmol) were added at room temperature and the mixture was stirred at 160 degrees C for 30min. To the mixture, ethyl acetate was added and the mixture was washed with H2O, dried over MgSθ4, filtered and concentrated in vacuo. The obtained residue was purified by preparative TLC (n-hexane:ethyl acetate=5:1 ) to give the title compound (8.5 mg, 38%).
1H-NMR: 0.59 (t, 6H), 1.91 (t, 2H), 2.08 (q, 4H), 2.34 (s, 3H), 2.39 (s, 3H), 2.53 (t, 2H), 3.48 (s, 2H), 3.68 (s, 3H), 5.15 (s, 2H), 6.87-7.38 (m, 6H). (4) Preparation of 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid methyl ester
Figure imgf000425_0001
6-(4-{1 -ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl- but-1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid methyl ester (compound prepared in Example 192-(3)) (8.5 mg, 0.0139 mmol) was dissolved in 4N HCI/dioxane (0.5 ml) at room temperature, and the mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and purified by preparative TLC (n-hexane:ethyl acetate=5:1) to give the title compound (6.3 mg, 80%). H-NMR: 0.60 (t, 6H), 1.92 (t, 2H), 2.04 (q, 4H), 2.35 (s, 3H), 2.37 (s, 3H), 2.52 (t, 2H), 3.70 (s, 3H), 6.83-7.39 (m, 6H); MS (ESI+) : 584 ([M+NH4]+).
(5) Preparation of 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid
Figure imgf000425_0002
To a solution of 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid methyl ester (compound prepared in Example 192-(4)) (6.3 mg, 0.0111 mmol) in MeOH (0.5 ml), 1N NaOH (0.1 ml) was added and the mixture was stirred at room temperature for 1h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (2.4mg, 39%). 1H-NMR: 0.61 (t, 6H), 1.90-1.99 (m, 2H), 2.06 (q, 4H), 2.35 (s, 3H), 2.37 (s, 3H), 2.52-2.60 (m, 2H), 6.85-7.02 (m, 4H), 7.35 (d, 1 H); MS (ESI+) : 570 ([M+NH4]+).
Example 193 Preparation of 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl )-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid
Figure imgf000426_0001
(1) Preparation of Hept-6-ynoic acid methyl ester "COOH "COOMe To a solution of hept-6-ynoic acid (2.0 g, 15.9 mmol) in MeOH (4 ml), cone. H2SO4 (4 drops) was added at room temperature and stirred at 60 degrees C for 60 h. To the mixture, ethyl acetate was added and the mixture was washed with saturated NaHC03, dried over MgS04 and concentrated in vacuo to give the title compound (2.0 g, 90%).
1H-NMR: 1.52-1.61 (m, 2H), 1.68-1.80 (m, 2H), 1.95-1.97 (m, 1 H), 2.18-2.23 (m, 2H), 2.35 (t, 2H), 3.68 (s, 3H).
(2) Preparation of 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-methoxymethoxy- 3-trifluoromethyl-but-1 -ynyl)-phenyl]- propyl}-2-methyl-phenyl)-hept-6-ynoic acid methyl ester
Figure imgf000426_0002
To a solution of trifluoro-methanesulfonic acid 4-{1 -ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenyl ester (compound prepared in Example 192-(1)) (23 mg, 0.0363 mmol) in DMF (0.5 ml), Et3N (0.0253 ml, 0.182 mmol), Cul (3.4 mg, 0.0181 mmol), PdCI2(PPh3)2 (12.7 mg, 0.0181 mmol) and hept-6-ynoic acid methyl ester (15.3 mg, 0.109 mmol) were added at room temperature and the mixture was stirred at 160 degrees C for 30min. To the mixture, ethyl acetate was added and the mixture was washed with H20, dried over MgS04, concentrated in vacuo and purified by preparative TLC (n-hexane:ethyl acetate=5:1 ) to give the title compound (4.0 mg, 18%).
1H-NMR: 0.59 (t, 6H), 2.08 (q, 4H), 2.35 (s, 3H), 2.38 (s, 3H), 2.47 (t, 2H), 3.47 (s, 2H), 3.67 (s, 3H), 5.15 (s, 2H), 6.87-7.38 (m, 6H).
(3) Preparation of 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid methyl ester
Figure imgf000427_0001
7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - ynyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid methyl ester (compound prepared in Example 193-(2)) (4.0 mg, 0.0064 mmol) was dissolved in 4N HCI/dioxane (0.5 ml) at room temperature, the mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and purified by preparative TLC (n-hexane:ethyl acetate=5:1) to give the title compound (2.6 mg, 70%).
1H-NMR: 0.60 (t, 6H), 1.85-1.91 (m, 2H), 2.05 (q, 4H), 2.35 (s, 3H), 2.37 (s, 3H), 2.47 (t, 2H), 3.67 (s, 3H), 6.83-7.37 (m, 6H); MS (ESI+) : 598 ([M+NH4]+).
(4) Preparation of 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid
Figure imgf000428_0001
To a solution of 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid methyl ester (2.6 mg, 0.0045 mmol) in MeOH (0.5 ml), 1 N NaOH (0.1 ml) was added and the mixture was stirred at room temperature for 1h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCl3:MeOH=8:3 saturated with H2O) to give the title compound (1.0 mg, 40%). 1H-NMR: 0.59 (t, 6H), 1.79-1.89 (m, 2H), 2.06 (q, 4H), 2.35 (s, 3H), 2.37 (s, 3H), 2.42-2.50 (m, 2H), 6.85-7.35 (m, 6H); MS (ESI+) : 584 ([M+NH4]+).
Example 194
Preparation of
5-(4-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxymethyl)- furan-2-carboxylic acid
Figure imgf000428_0002
(1) Preparation of 5-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl} -1-ethyl-propyl)-2-methyl-phenoxymethyl]-furan-2- carboxylic acid ethyl ester
Figure imgf000428_0003
To a solution of 4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3- methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenol (compound prepared in Example 187-(1 )) (60 mg, 0.12 mmol) in DMF (0.6 ml), ethyl 5-(chloromethyl)-2-furan carboxylate (27 mg, 0.14 mmol), and K2CO3 (20 mg, 0.14 mmol) were added at room temperature and stirred at 80 degrees C for 8 h. To the mixture, ethyl acetate was added and the mixture was washed with saturated NH4CI solution and water, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (ethyl acetate/hexane =1/4) to give the title compound (60 mg, 93%) as colorless oil.
1 H-NMR (CDCI3): 0.06 (s, 3H),0.1 (s, 3H),0.6 (t, 6H , J=7.3Hz),0.88 (s, 9H),0.93 (s, 9H),1.38 (t, 3H , J=7.2Hz),1.52-1.64 (m, 1H),1.71-1.82 (m, 1H),2.04 (q, 4H , J=7.3Hz),2.17 (s, 3H),2.23 (s, 3H),2.41 (dt, 1H , J=4.7, 13.2Hz),2.76 (dt, 1 H , J=5.4, 12.8Hz),3.34 (dd, 1 H , J=3.3, 7.3Hz),4.37 (q, 2H , J=7.2Hz),6.49 (d, 1 H , J=3.5Hz),6.73 (d, 1H , J=9.1Hz),6.9-7.0 (m, 5H),7.15 (d, 1H , J=3.5Hz).
(2) Preparation of 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl -phenoxymethyl)-furan-2-carboxylic acid
Figure imgf000429_0001
To a solution of 5-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]- 3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxymethyl]-furan-2-carboxylic acid ethyl ester (compound prepared in Example 194-(1)) (60 mg, 0.11 mmol) in THF (1 ml), TBAF (1.0 M in THF) (1 ml, 1 mmol) was added at room temperature and refluxed for 5 h. To the mixture, ethyl acetate was added and the mixture was washed with 30% NaH2P04 aq. and brine, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (MeOH/CH CI2 =1/10) to give the title compound (25 mg, 45%) as colorless oil. 1H-NMR (CDCI3): 0.59 (t, 6H , J=7.3Hz),0.89 (s, 9H),1.43-1.58 (m, 1H),1.74-1.82 (m, 1H),2.03 (q, 4H, J=7.3Hz),2.16 (s, 3H),2.25 (s, 3H),2.5-2.61 (m, 1H),2.81- 2.92 (m, 1H),3.25 (dd, 1H, J=1.6, 10.4Hz),4.06 (brs, 1H),5.04 (s, 2H),6.5-6.49 (d, 1H, J=3.5Hz),6.73-6.70 (d, 1 H, J=5.5Hz),6.89-6.95 (m, 4H),7.02 (d, 1 H, J=8.6Hz),7.25 (d, 1 H, J=4.3Hz); MS (ESI+) : 529 ([M+Naf). Example 195
Preparation of Preparation of (E)-N-(2-Amino-ethyl)-2-(4-{1 -ethyl-1 -[4-(3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetamide
Figure imgf000430_0001
(1) Preparation of (E)-{2-[2-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-ethyl}-carbamic acid 9H- fluoren-9-ylmethyl ester
Figure imgf000430_0002
To a solution of (4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetic acid (compound prepared in Example 151 -(2)) (74.4 mg, 0.17 mmol) in CH2CI2 (1.7 ml) and diisopropylethylamine (0.118ml, 0.68 mmol) was added (2-Amino-ethyl)-carbamic acid 9H-fluoren-9- ylmethyl ester (108 mg, 0.34 mmol), WSCI hydrochloride (65 mg, 0.34 mmol) and HOBt monohydrate (26 mg, 0.17 mmol), and the mixture was stirred for 18 h at room temperature. The reaction mixture was poured into H2O and extracted with CH2CI2. The organic phase was concentrated in vacuo. The resulting residue was chromatographed on silica gel (ethyl acetate/hexane = 60/40 to 100/0) to give the title compound (92.2 mg, 77%).
1H-NMR: 0.59 (t, 6H), 0.91 (t, 6H), 1.63 (dq, 4H), 2.03 (q, 4H), 2.21 (s, 3H), 2.30 (s, 3H), 3.30-3.55 (m, 4H), 4.19 (t, 1 H), 4.38 (d, 2H), 4.47 (s, 2H), 5.16 (br, 1 H), 6.00 (d, 1 H), 6.62 (d, 1 H), 6.73 (d, 1 H), 6.90-7.75 (m, 14H).
(2) Preparation of (E)-N-(2-Amino-ethyl)-2-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetamide
Figure imgf000431_0001
To a solution of {2-[2-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-ethyl}-carbamic acid 9H-fluoren- 9-ylmethyl ester (92 mg, 0.13 mmol) in DMF (1.3 ml), diethylamine (0.134 ml, 1.3 mmol) was added and the mixture was stirred for 3 h at room temperature. The reaction mixture was poured into water and the products were extracted with AcOEt. The extracts were washed with H2O twice, dried over MgS04, filtered and concentrated in vacuo. The obtained residue was chromatographed on silica gel (ethyl acetate/EtOH = 10/1) to give the title compound (41.1 mg, 65%). 1H-NMR: 0.61 (t, 6H), 0.92 (t, 6H), 1.64 (dq, 4H), 2.05 (q, 4H), 2.23 (s, 3H), 2.31 (s, 3H), 2.87 (t, 2H), 3.40 (q, 2H), 4.49 (s, 2H), 6.01 (d, 1 H), 6.66 (d, 1 H), 6.74 (d, 1 H), 6.90-7.75 (m, 6H).
Example 196
Preparation of Preparation of (E)-2-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-N-(2-hydroxy-ethyl)-acetamide
Figure imgf000431_0002
Preparation of (E)-2-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-N-(2-hydroxy-ethyl)-acetamide
Figure imgf000431_0003
To a solution of (4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetic acid (compound prepared in Example 151 -(2)) (78 mg, 0.178 mmol) in CH2CI2 (1.8 ml) and triethylamine (0.074 ml, 0.534 mmol) was added ethanolamine (0.032 ml, 0.534 mmol), WSCI hydrochloride (102 mg, 0.534 mmol) and HOBt monohydrate (27 mg, 0.178 mmol), and the mixture was stirred for 2 h at room temperature. To the reaction mixture, H2O was added and separated. The organic phase was concentrated in vacuo. The resulting residue was chromatographed on silica gel (ethyl acetate/hexane = 60/40 to 100/0) to give the title compound (21.5 mg, 25%). 1H-NMR: 0.61 (t, 6H), 0.92 (t, 6H), 1.64 (dq, 4H), 2.05 (q, 4H), 2.22 (s, 3H), 2.31 (s, 3H), 3.54 (q, 2H) , 3.76-3.79 (m, 2H), 4.50 (s, 2H), 6.01 (d, 1 H), 6.65-7.31 (m, 8H); MS (ESI+) : 464 ([M-OH]+).
Example 197 Preparation of
[2-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-acetylamino]-acetic acid
Figure imgf000432_0001
Preparation of [2-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-acetic acid
Figure imgf000432_0002
To a solution of (4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetic acid (compound prepared in Example 151 -(2)) ( (172 mg, 0.39 mmol) in CH2CI2 (3.9 ml) and triethylamine (0.231 ml, 1.66 mmol) was added H-Gly-OMe hydrochloride (98 mg, 0.78 mmol), WSCI hydrochloride (150 mg, 0.78 mmol) and HOBt monohydrate (60 mg, 0.39 mmol), stirred for 18 h at room temperature. The reaction mixture was concentrated in vacuo, separated with ethyl acetate and aqueous KHSO4, the organic phase was washed with aqueous NaHC03 and brine, dried over MgS0 , concentrated in vacuo to obtain the residue (174 mg). Then, 96.8 mg of the residue was dissolved with THF (1 ml) and MeOH (1 ml), 1 N aqueous KOH (1 ml) was added and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo, separated with ethyl acetate and aqueous KHS04, the organic phase was washed with brine, dried over MgS0 , concentrated in vacuo, and chromatographed on silica gel (MeOH/CHCI3 = 0/100 to 27/73) to give the title compound (87 mg, 81 %).
1H-NMR (CD3OD): 0.59 (t, 6H), 0.91 (t, 6H), 1.62 (q, 4H), 2.06 (q, 4H), 2.22 (s, 3H), 2.26 (s, 3H), 3.84 (s, 2H), 4.49 (s, 2H), 5.98 (d, 1 H), 6.71-6.99 (m, 6H) 7.27 (d, 1 H).; MS (El): 477 ([M-H20]+).
Example 198
Preparation of (E)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-oxo-pentanoic acid
Figure imgf000433_0001
(1 ) Preparation of (E)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo-pentanoic acid methyl ester
Figure imgf000433_0002
To a solution of 5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 44) (194 mg, 0.41 mmol) was dissolved with THF (1.5 ml) and MeOH (1.5 ml). 1 N aqueous KOH (1.5 ml) was added and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo, separated with ethyl acetate and aqueous KHSO4, the organic phase was washed with brine, dried over MgS0 , concentrated in vacuo. The resulting residue was dissolved with CH2CI2 (0.8 ml), tetrapropylammmonium perruthenate (14.4 mg, 0.041 mmol), MS4A (200 mg), and N-methylmorphorine- N-oxide (96 mg, 0.82 mmol) was added and stirred for 2 h at room temperature. The reaction mixture was concentrated in vacuo and treated with short pad of silica gel (ethyl acetate/EtOH = 10/1). The resulting black residue was dissolved with Et20 (2 ml) and MeOH (1 ml). Trimethylsilyldiazomethane (2M in hexane, ca.0.2 ml), was added and stirred for 2 min. at room temperature. The reaction mixture was concentrated in vacuo and chromatographed (ethyl acetate / hexane = 15/85 to 30/70) to give the title compound (65 mg, 32%). 1H-NMR : 0.61 (t, 6H), 0.91 (t, 6H), 1.64 (q, 4H), 2.05 (q, 4H), 2.24 (s, 3H), 2.31 (s, 3H), 2.66 (t, 2H), 2.99 (t, 2H), 3.68 (s, 3H), 4.55 (s, 2H), 6.01 (d, 1 H), 6.56 (d, 1 H), 6.74 (d, 1H), 6.92-6.96 (m, 4H), 7.30 (d, 1H).
(2) Preparation of (E)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo-pentanoic acid
Figure imgf000434_0001
To a solution of 5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-oxo-pentanoic acid methyl ester (compound prepared in Example 198-(1 )) (65 mg, 0.41 mmol) was dissolved with THF (1 ml) and MeOH (1 ml). 1 N aqueous KOH (1 ml) was added and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo, separated with ethyl acetate and aqueous KHSO4, the organic phase was washed with brine, dried over MgS04, concentrated in vacuo to give the title compound (63 mg, 100%). 1H-NMR(CD3OD): 0.61 (t, 6H), 0.91 (t, 6H), 1.62 (q, 4H), 2.06 (q, 4H), 2.19 (s, 3H), 2.26 (s, 3H), 2.59-2.63 (m, 2H), 2.84-2.88 (m, 2H), 5.98 (dd, 1 H), 6.64 (d, 1 H), 6.74 (d, 1 H), 6.89-6.95 (m, 4H), 7.27 (d, 1 H),.; MS (El): 476 ([M-H20] +).
Example 199
Preparation of (E)-3-[2-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-propionic acid
Figure imgf000435_0001
Preparation of (E)-3-[2-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-propionic acid
Figure imgf000435_0002
To a solution of (4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetic acid (compound prepared in Example 151 -(2)) ( (166 mg, 0.38 mmol) in CH2CI2 (3.8 ml) and triethylamine (0.212 ml, 1.52 mmol) was added H-beta-Ala-OMe hydrochloride (106 mg, 0.76 mmol), WSCI hydrochloride (146 mg, 0.76 mmol) and HOBt monohydrate (58 mg, 0.38 mmol), and the mixture was stirred for 18 h at room temperature. The reaction mixture was concentrated in vacuo, separated with ethyl acetate and aqueous KHS04, the organic phase was washed with aqueous NaHC03 and brine, dried over MgS04, concentrated in vacuo to obtain the residue (162mg). Then, 103.6 mg of the residue was dissolved with THF (1 mL) and MeOH (1 ml). 1N aqueous KOH (1 ml) was added and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo, separated with ethyl acetate and aqueous KHSO4, the organic phase was washed with brine, dried over MgS04, concentrated in vacuo, and chromatographed on silica gel (MeOH/CHCI3= 0/100 to 27/73) to give the title compound (78 mg, 63%).
1H-NMR: 0.60 (t, 6H), 0.91 (t, 6H), 1.63 (dq, 4H), 2.04 (q, 4H), 2.20 (s, 3H), 2.30 (s, 3H), 2.64 (t, 2H), 3.64 (q, 2H), 4.45 (s, 2H), 6.00 (d, 1 H), 6.63 (d, 1H), 6.73 (d, 1 H), 6.91-7.30 (m, 5H).; MS (El) : 491 ([M-H20]+).
Example 200
Preparation of (2S,3S)-2-[2-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-3-methyl-pentanoic acid
Figure imgf000436_0001
(1) Preparation of [4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-
3-methyl-phenyl}-1-ethyl-propyl)
-2-methyl-phenoxy]-acetic acid methyl ester
Figure imgf000436_0002
To a solution of compound prepared in Example 186-(1) (4-(1-{4-[3-(tert-Butyl- dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2- methyl-phenol) (450 mg, 0.91 mmol) in acetone (10 ml), K2C03 (377 mg, 2.73 mmol) and bromoacetic acid methyl ester (278 mg, 1.82 mg) were added at room temperature and the mixture was stirred at 45 degrees C for 68 h. The mixture was applied onto silica and chromatographed (n-hexane only to n- hexane:ethyl acetate=5:1) to give the title compound (436 mg, 84%). 1H-NMR: 0.07 (s, 3H), 0.11 (s, 3H), 0.60 (t, 6H), 0.89 (s, 9H), 0.94 (s, 9H), 2.03 (s, 4H), 2.24 (s, 6H), 2.35-2.46 (m, 1 H), 2.70-2.82 (m, 1 H), 3.33-3.38 (m, 1 H), 3.80 (s, 3H), 4.62 (s, 2H), 6.59 (d, 1H), 6.88-7.00 (m, 5H).
(2) Preparation of [4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]- 3-methyl-phenyl}-1 -ethyl-propyl)-2-methyl-phenoxy]-acetic acid
Figure imgf000436_0003
To a solution of [4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]- 3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxy]-acetic acid methyl ester (436 mg, 0.767 mmol) in EtOH (3 ml), 1N NaOH (1 ml) was added at room temperature and the mixture was stirred at room temperature for 16 h. To the mixture, 1 % HCl was added to adjust pH at 6 and extracted with ethyl acetate, washed with brine, dried over MgSθ4 and concentrated in vacuo to give the title compound (424 mg, 100%).
1H-NMR: 0.07 (s, 3H), 0.10 (s, 3H), 0.60 (t, 6H), 0.88 (s, 9H), 0.94 (s, 9H), 2.03 (s, 4H), 2.23 (s, 6H), 2.35-2.47 (m, 1 H), 2.70-2.82 (m, 1 H), 3.33-3.38 (m, 1 H), 4.61 (s, 2H), 6.62 (d, 1 H), 6.88-7.02 (m, 5H).
(3) Preparation of (2S,3S)-2-[2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-3-methyl-pentanoic acid
Fmoc-L-lle-Wang resin
Figure imgf000437_0001
Fmoc-L-lle-Wang resin (0.57 mmol/g as amino acid loading, 35 mg, 0.020 mmol amino acid loading) was treated with 20% (v/v) piperidine in DMF (0.5 ml) two times to deprotect Fmoc group and washed with DMF (1 ml, 5 times). To the resin, solutions of [4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxy]-acetic acid (16.0 mg, 0.029 mmol) in DMF (0.2 ml), benzotriazole-1-yl-oxy- tris(dimethylamino)phosphonium hexafluorophosphate (17.7 mg, 0.040 mmol) in DMF (0.2 ml) and N,N-diisopropyl ethyl amine (0.0105 ml, 0.060 mmol) in DMF (0.1 ml) were added at room temperature, agitated at room temperature for 16h, filtrated, washed with DMF (2 ml, 3 times), i-PrOH (2 ml, 3 times), THF (2 ml, 3 times), MeOH (2 ml, 3 times) and CH2CI2 (2 ml, 3 times) and dried in vacuo. To the resin, 20% TFA in CH2CI2 (v/v) (1 ml) was added at room temperature, agitated at room temperature for 16h, filtrated, washed with CH2CI2 (1 ml, 2 times) and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (CAPCELLPAK C18 MG2 20mm(ID)-50mm column, gradient elution 50 to 90% B/A over 10min, and 100% B over 2.5min (solvent A = 10mM ammonium acetate H20, solvent B = MeOH, UV detection at 220 and 277nm) to give the titled compound (3.4 mg, 31%).
1H-NMR: 0.59 (t, 6H), 0.89 (s, 9H), 0.89-0.97 (m, 6H), 2.04 (q, 4H), 2.23 (s, 3H), 2,25 (s, 3H), 3.25 (d, 1 H), 4.51 (s, 2H), 4.60-4.68 (m, 1 H), 5.30 (s, 2H), 6.65 (d, 1 H), 6.88-7.05 (m, 4H), 7.12 (d, 1 H); MS (ESI+) : 571 ([M+NH4f).
Example 201-202 Examples 201 to 202 were prepared according to same procedure as Example 200-(3) from corresponding Fmoc-amino acid-Wang resin listed in below table.
Figure imgf000438_0001
Starting Fmoc-amino acid-Wang resin
Figure imgf000438_0002
Example 203 Preparation of [2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-acetic acid
Figure imgf000439_0001
Preparation of [4-(1 -{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3- methyl-phenyl}-1 -ethyl-propyl) -2-methyl-phenoxy]-acetic acid methyl ester
Figure imgf000439_0002
To a solution of compound prepared in Example 187-(1 ) (4-(1-{4-[3-(tert-Butyl- dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2- methyl-phenol) (1.00 g, 2.02 mmol) in acetone (20 ml), K2C03 (836 mg, 6.06 mmol) and bromoacetic acid methyl ester (618 mg, 4.04 mmol) was added at room temperature and stirred at 45 degrees C for 68 h. The mixture was applied onto silica and chromatographed (n-hexane only to n-hexane:ethyl acetate=5:1) to give the title compound (720 mg, 63%). 1H-NMR: 0.06 (s, 3H), 0.11 (s, 3H), 0.59 (t, 6H), 0.88 (s, 9H), 0.93 (s, 9H), 2.03 (s, 4H), 2.23 (s, 6H), 2.35-2.46 (m, 1 H), 2.70-2.82 (m, 1H), 3.34 (dd, 1 H), 3.80 (s, 3H), 4.61 (s, 2H), 6.57 (d, 1 H), 6.90-6.99 (m, 5H).
(2) Preparation of [4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]- 3-methyl-phenyl}-1 -ethyl-propyl)-2-methyl-phenoxy]-acetic acid
Figure imgf000439_0003
To a solution of [4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]- 3-methyl-phenyl}-1 -ethyl-propyl) -2-methyl-phenoxy]-acetic acid methyl ester prepared in Example 203-(1 ) (720 mg, 1.27 mmol) in MeOH (5 ml) and THF (5 ml), 1 N NaOH (1 ml) was added at room temperature and the mixture was stirred at room temperature for 16h. To the mixture, 1% HCl was added to adjust pH at 6 and extracted with ethyl acetate, washed with brine, dried over MgS04 and concentrated in vacuo to give the title compound (690 mg, 100%). 1H-NMR: 0.07 (s, 3H), 0.10 (s, 3H), 0.60 (t, 6H), 0.88 (s, 9H), 0.93 (s, 9H), 2.05 (s, 4H), 2.23 (s, 6H), 2.35-2.46 (m, 1 H), 2.70-2.82 (m, 1 H), 3.34 (dd, 1 H), 4.65 (s, 2H), 6.61 (d, 1 H), 6.88-7.02 (m, 5H).
(3) Preparation of [2-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-acetic acid
Fmoc-Gly-Wang resin
Figure imgf000440_0001
Fmoc-Gly-Wang resin (0.73 mmol/g as amino acid loading, 27.4 mg, 0.020 mmol amino acid loading) was treated with 20% (v/v) piperidine in DMF (0.5 ml) two times to deprotect Fmoc group and washed with DMF (1 ml, 5 times). To the resin, solutions of [4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]- 3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxy]-acetic acid (16.0 mg, 0.029 mmol) in DMF (0.2 ml), benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (17.7 mg, 0.040 mmol) in DMF (0.2 ml) and N,N- diisopropyl ethyl amine (0.0105 ml, 0.060 mmol) in DMF (0.1 ml) were added at room temperature, agitated at room temperature for 16h, filtrated, washed with DMF (2 ml, 3 times), i-PrOH (2 ml, 3 times), THF (2 ml, 3 times), MeOH (2 ml, 3 times) and CH2CI2 (2 ml, 3 times) and dried in vacuo. To the resin, 20% TFA in CH2CI2 (v/v) (1 ml) was added at room temperature, agitated at room temperature for 16 h, filtrated, washed with CH2CI2 (1 ml, 2 times) and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (CAPCELLPAK C18 MG2 20mm(ID)-50mm column, gradient elution 50 to 90% B/A over 10min, and 100% B over 2.5min (solvent A = 10mM ammonium acetate H20, solvent B = MeOH, UV detection at 220 and 277nm) to give the titled compound (2.6 mg, 26%).
1H-NMR: 0.59 (s, 6H), 0.87 (s, 9H), 2.07 (q, 4H), 2.24 (S, 6H), 3.15 (d, 1 H), 3.91 (d, 2H), 4.52 (s, 2H), 6.77 (d, 1H), 6.87-7.04 (m, 5H); MS (ESI+): 515 ([M+NH4]+).
Example 204-243 Examples 204 to 243 were prepared according to same procedure as Example 203-(3) from corresponding Fmoc-amino acid-Wang resin listed in below table.
Figure imgf000442_0001
Figure imgf000443_0001
Figure imgf000444_0001
H
444
Figure imgf000445_0001
Figure imgf000446_0001
(
446
Figure imgf000447_0001
Figure imgf000448_0001
Figure imgf000449_0001
Starting Fmoc-amino acid-Wang resin
Figure imgf000450_0001
Example 244 Preparation of 3-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000451_0001
(1 ) Preparation of 4-{1 -[4-(2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenol
Figure imgf000451_0002
To a solution of 3,3-bis-(4-hydroxy-3-methyl-phenyl)-pentane (2.91 g, 10.2 mmol) in DMSO (26 ml) were added t-BuOK (1.1 g, 9.80 mmol) and 2,2- dimethyl-1 ,3-dioxolan-4-yl-methyl p-toluensulfonate (2.3 g, 8.03 mmol) and the mixture was stirred at 60 degrees C for 8 h. The reaction mixture was poured into sat. NH4CI aq. and the products were extracted with AcOEt. The extracts were washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with CH2CI2:AcOEt (50/1 to 2/1) to give the title compound (1.37 g, 43%) as colorless oil.
1H NMR (CDCI3, 400 MHz): 0.61 (6H, t, J= 7.2 Hz), 1.40 (3H, s), 1.46 (3H, s), 2.00 (4H, q, J=7.5 Hz), 2.15 (3H, s), 2.19 (3H, s), 3.89-4.18 (4H, m), 4.60 (1 H, s), 6.67 (2H, m), 6.83-6.96 (4H, m).
(2) Preparation of Trifluoro-methanesulfonic acid 4-{1-[4-(2,2-dimethyl-
[1 ,3]dioxolan-4-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl ester
Figure imgf000451_0003
To a solution of 4-{1-[4-(2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenol (compound prepared in Example 244- (1)) (1.57 g, 3.939 mmol) in CH2CI2 (40 ml) under N2 atmosphere were added Tf20 (0.969 ml, 5.909 mmol) and pyridine (0.954 ml, 11.82 mmol) and the mixture was stirred for 30 min. The reaction mixture was poured into sat. NaHC03 aq. and the products were extracted with CH2CI2. The extracts were dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :20) to give the title compound (1.5 g, 50%) as colorless oil. 1H-NMR (CDCI3): 0.59 (6H, t, J = 7.25 Hz), 1.40 (3H, s), 1.46 (3H, s), 1.97-2.11 (4H, m), 2.16 (3H, s), 2.31 (3H, s), 3.90-4.20 (4H, m), 4.40-4.52 (1 H, m), 6.70 (1 H, d, J = 8.57 Hz), 6.81-6.95 (2H, m), 7.00-7.15 (3H, m).
(3) Preparation of 3-(4-{1-[4-(2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-propionic acid ethyl ester
Figure imgf000452_0001
To a solution of Trifluoro-methanesulfonic acid 4-{1 -[4-(2,2-dimethyl-
[1 ,3]dioxolan-4-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl ester (compound prepared in Example 244-(2)) (310 mg, 0.584 mmol) in DMF (1.0 ml) was added Pd(PPh3)4 (67 mg) and the mixture was stirred for 5 min. To the reaction mixture, 3-Ethoxy-3-oxopropylzinc bromide 0.5 M THF solution (2.9 ml, 1.45 mmol) and HMPA (1.45 ml, 8.30 mmol) were added and the mixture was stirred at 60 degrees C for 3.5 h. The reaction mixture was poured into water and the products were extracted with AcOEt. The extracts were dried over Na2Sθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :5) to give the title compound (175 mg, 62%) as colorless oil.
1H NMR (CDCI3); 0.58 (6H, t, J= 7.4 Hz), 1.24 (3H, t, J= 7.1 Hz), 1.40 (3H, s), 1.46 (3H, s), 2.01 (4H, q, J=7.4 Hz), 2.15 (3H, s), 2.25 (3H, s), 2.56 (2H, t, J=7.4 Hz), 2.89 (2H, t, J=8.5 Hz), 3.93-4.11 (m, 6H), 4.46 (m, 1H), 6.68 (1H, d, J= 8.5 Hz), 6.94 (5H, m). (4) Preparation of 1-(4-{1-[4-(2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3-methyl- phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pentan-3-ol
Figure imgf000453_0001
To a solution of 3-(4-{1-[4-(2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-propionic acid ethyl ester (compound prepared in Example 244-(3)) (37.5 mg, 0.078 mmol) in THF (2 ml) at -78 degrees C under N2 atmosphere was added EtLi (ca.0.4 mol/l, 0.585 ml, 0.234 mmol) and the mixture was stirred for 1 h. The reaction mixture was poured into sat. NH4CI aq. and the products were extracted with AcOEt. The extracts were washed with water and brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was purified by preparative TLC (Hex:AcOEt 2:1) to give the title compound (30.4 mg, 79%) as colorless oil. 1H-NMR (CDCI3): 0.59 (6H, t, J = 7.08 Hz), 0.91 (6H, t, J = 7.42 Hz), 1.40 (3H, s), 1.46 (3H, s), 1.48-1.70 (6H, m), 1.95-2.05 (4H, m), 2.16 (3H, s), 2.25 (3H, s), 2.50-2.61 (2H, m), 3.89-4.20 (4H, m), 4.40-4.50 (1 H, m), 6.68 (1 H, d, J = 8.24 Hz), 6.85-7.03 (5H, m).
(5) Preparation of 3-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hyd roxy-pentyl )-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000453_0002
To a solution of 1-(4-{1-[4-(2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pentan-3-ol (compound prepared in Example 244-(4)) (30.4 mg, 0.061 mmol) in THF-H2O(10:1 , 3.3 ml) was added CSA (42.7 mg, 0.184 mmol) and the mixture was stirred at 50 δδdegrees C for 5 h. The reaction mixture was poured into sat. NaHC03 aq. and the products were extracted with CH2CI2. The extracts were dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was purified by preparative TLC (AcOEt) to give the title compound (19.4 mg, 70%) as colorless oil.
1H-NMR (CDCI3): 0.59 (6H, t, J = 7.09 Hz), 0.91 (6H, t, J = 7.42 Hz), 1.46-1.70 (6H, m), 1.95-2.10 (4H, m), 2.17 (3H, s), 2.25 (3H, s), 2.50-2.62 (2H, m), 3.72- 3.90 (2H, m), 3.96-4.15 (3H, m), 6.69 (1 H, d, J = 8.25 Hz), 6.85-7.03 (5H, m); MS (ESI+) : 474 ([M+NH4]+).
Example 246
Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-1 -methyl-pent- 1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000454_0001
(1) Preparation of (E)-3-{4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- methyl-phenyl}-but-2-enoic acid ethyl ester
Figure imgf000454_0002
To a solution of Trifluoro-methanesulfonic acid4-[1 -ethyl-1 -(4-hydroxy-3-methyl- phenyl)-propyl]-2- methyl-phenyl ester (compound prepared in Example 1-(1)) (52.5 mg, 0.105 mmol) in DMF(0.35 ml) were added Crotonic acid ethyl ester (0.052 ml, 0.419 mmol), NaHC03 (37 mg, 0.440 mmol), dppp(4.3 mg, 0.0104 mmol), LiBr(6.3 mg, 0.0725 mmol) and PdCI2 (PPh3) 2 (7.4 mg, 0.0105 mmol) and the mixture was stirred at 140 degrees C for 12h. The reaction mixture was cooled to room temperature, poured into sat. NH4CI aq. and the products were extracted with CH2CI2. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :4) to give the title compound (13.7 mg, 28%) as colorless oil. 1H-NMR (CDCU): 0.58 (6H, t, J = 7.09 Hz), 1.28 (3H, t, J = 7.25 Hz), 2.05 (4H, q, J = 7.26 Hz), 2.20 (3H, s), 2.22 (3H, s), 2.43 (3H, s), 4.19 (2H, q, J = 7.25 Hz), 4.65 (1H, s), 5.76 (1H, s), 6.66 (1H, d, J = 8.24 Hz), 6.95 (5H, m).
(2) Preparation of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-1 -methyl-pent- 1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol
Figure imgf000455_0001
To a solution of (E)-3-{4-[1 -Ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]-2- methyl-phenyl}-but-2-enoic acid ethyl ester (compound prepared in Example 246-(1 ))(64 mg, 0.168 mmol) in THF(2 ml) was added EtMgBr(3M in Et20, 0.28 ml, 0.840 mmol) at 0 degrees C under nitrogen atmosphere and the reaction mixture was stirred for 2.5 h at room temperature. The reaction mixture was poured into sat. NH4CI aq. and the products were extracted with CH2CI2. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :2) to give the title compound (30 mg, 45%) as colorless oil.
1H-NMR (CDCI3): 0.61 (6H, t, J = 7.25 Hz), 0.97 (6H, t, J = 7.41 Hz), 1.66 (4H, q, J = 7.42 Hz), 2.03 (4H, q, J = 7.42 Hz), 2.11 (3H, d, J = 0.99 Hz), 2.21 (3H, s), 2.23 (3H, s), 4.65 (1 H, brs), 5.18 (1H, d, J = 1.16 Hz), 6.65 (1 H, d, J = 8.41 Hz), 6.85-6.92 (5H, m).
(3) Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-1-methyl-pent-1- enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000455_0002
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-1-methyl-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 246- (2)) (15 mg, 0.038 mmol) in DMF(1 ml) were added K2CO3(10.5 mg, 0.076 mmol) and (S)-Dihydro-5-(toluenesulfonylmethyl)-2-(3H)furanone (20.5 mg, 0.076 mmol) and the mixture was stirred at 100 degrees C for 7 h. The reaction mixture was poured into sat. NaHC03 aq. and the products were extracted with AcOEt. The extracts were washed with water and brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :2) to give the title compound (15.2 mg, 81%) as colorless oil.
1H-NMR (CDCI3): 0.60 (6H, t, J = 7.25 Hz), 0.97 (6H, t, J = 7.26 Hz), 1.66 (4H, q, J = 7.26 Hz), 1.98-2.08 (4H, m), 2.11 (3H, d, J = 0.82 Hz), 2.16 (3H, s), 2.23 (3H, s), 2.25-2.85 (4H, m), 4.05-4.20 (2H, m), 4.82-4.92 (1 H, m), 5.18 (1H, s), 6.67 (1H, d, J = 8.24 Hz), 6.85-7.00 (5H, m).
(4) Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-1-methyl-pent-1- enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000456_0001
To a solution of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-1-methyl-pent-1- enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 246-(3)) (15.8 mg, 0.038 mmol) in MeOH (0.360 ml) was added 1 N KOH(0.180 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by preparative TLC (CHCI3:MeOH=8:3, saturated with H20) to give the title compound (15.2 mg, 81%) as colorless oil. 1H-NMR (CDCI3): 0.61 (6H, t, J = 7.09 Hz), 0.97 (6H, t, J = 7.42 Hz), 1.66 (4H, q, J = 7.25 Hz), 1.98-2.08 (6H, m), 2.11 (3H, s), 2.19 (3H, s), 2.23 (3H, s), 2.62 (2H, t, J = 6.92 Hz), 3.85 (1 H, t, J = 9.07 Hz), 3.98 (1 H, d, J = 9.07 Hz), 4.10 (1 H, m), 5.18 (1 H, s), 6.68 (1H, d, J = 8.07Hz), 6.94 (5H, m); MS (ESI+) : 528 ([M+NH4]+). Example 247
Preparation of (S)-5-(4-{1-[4-((E)-1 ,3-Diethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000457_0001
(1) Preparation of 2,2-Dimethyl-propionic acid 4-[1 -ethyl-1 -(3-methyl-4- trifluoromethanesulfonyloxy-phenyl)-propyl]-2-methyl-phenyl ester
Figure imgf000457_0002
To a solution of Trifluoro-methanesulfonic acid 4-[1 -ethyl-1 -(4-hydroxy-3-methyl- phenyl)-propyl]-2-methyl-phenyl ester(compound prepared in Example 1-(1 )) (1.75 g, 4.20 mmol) in CH2CI2 (22 ml) were added Et3N (0.643 ml, 4.64 mmol) and Pivaloyl chloride(0.566 ml, 4.60 mmol) and the mixture was stirred at 0 degrees C for 1 h and at room temperature for 1 h. The reaction mixture was poured into water and the products were extracted with CH2CI2. The extracts were dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :4) to give the title compound (1.66 g, 79%).
1H-NMR (CDCI3): 0.60 (6H, t, J = 7.14 Hz), 1.37 (9H, s), 2.05 (4H, q, J = 7.41 Hz ), 2.12 (3H, s), 2.31 (3H, s), 6.87 -7.13 (6H, m).
(2) Preparation of (E)-3-(4-{1-[4-(2,2-Dimethyl-propionyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-pent-2-enoic acid methyl ester
Figure imgf000457_0003
2,2-Dimethyl-propionic acid 4-[1 -ethyl-1 -(3-methyl-4-trifluoromethanesulfonyloxy- phenyl)-propyl]-2-methyl-phenyl ester(compound prepared in Example 247-(1 )) (945 mg, 1.89 mmol) in DMF(6.3 ml) were added Methyl trans-2-pentanoate (0.929 ml, 7.33 mmol), NaHC03 (662 mg, 7.88 mmol), dppp(78 mg, 0.188 mmol), LiBr(117 mg, 1.35 mmol) and PdCI2 (PPh3)2 (139 mg, 0.198 mmol) and the mixture was stirred at 150 degrees C for 12h. The reaction mixture was cooled to room temperature, poured into sat. NH4CI aq. and the products were extracted with CH2CI2. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :4) to give the title compound (253 mg, 29%) as colorless oil. 1H-NMR (CDCI3): 0.61 (6H, t, J = 7.25 Hz), 1.301 (6H, t, J = 7.09 Hz), 1.37 (9H, s), 2.06 (4H, q, J = 7.25 Hz ), 2.13 (3H, s), 2.23 (3H, s), 2.43 (3H, s), 4.20 (4H, q, J = 7.25 Hz), 5.76 (1 H, s), 6.87 (1 H, d, J = 8.41 Hz), 6.94-7.00 (5H, m).
(3) Preparation of 2,2-Dimethyl-propionic acid 4-{1-[4-((E)-1 ,3-diethyl-3-hydroxy- pent-1 -enyl)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl ester
Figure imgf000458_0001
To a solution of (E)-3-(4-{1-[4-(2,2-Dimethyl-propionyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-pent-2-enoic acid methyl ester (compound prepared in Example 247-(2))(128.1 mg, 0.276 mmol) in THF(3 ml) was added EtMgBr (3M in Et20, 0.552 ml, 1.656 mmol) at 0 degrees C and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into sat. NH4CI aq. and the products were extracted with CH2CI2. The extracts were dried over MgS04, filtered and concentrated under reduced pressure to give the title compound (124 mg, 91%) as colorless oil. 1H-NMR (CDCI3): 0.61 (6H, t, J = 7.26 Hz), 0.85 (3H, t, J = 7.42 Hz), 0.97 (6H, t, J = 7.42 Hz), 1.36 (9H, s), 1.65 (4H, q, J = 7.42 Hz), 2.06 (4H, q, J = 7.25 Hz), 2.12 (3H, s), 2.22 (3H, s), 2.64 (2H, q, J = 7.42 Hz), 5.11 (1 H, s), 6.84-7.03 (6H, m). (4) Preparation of 4-{1 -[4-((E)-1 ,3-Diethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenol
Figure imgf000459_0001
To a solution of 2,2-Dimethyl-propionic acid 4-{1 -[4-((E)-1 ,3-diethyl-3-hydroxy- pent-1 -enyl)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl ester (compound prepared in Example 247-(3))(124 mg, 0.252 mmol) in MeOH (3 ml) was added 1 N-KOH(0.503 ml, 0.503 mmol) and the mixture was stirred at room temperature for 1.5 h and at 60 degrees C for 0.5 h. The reaction mixture was poured into sat. NH4CI aq. and the products were extracted with CH2CI . The extracts were dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was purified by preparative TLC (Hex:AcOEt 2:1) to give the title compound (99.5 mg, 97%) as colorless oil.
1H-NMR (CDCI3): 0.60 (6H, t, J = 7.25 Hz), 0.85 (3H, t, J = 7.42 Hz), 0.97 (6H, t, J = 7.26 Hz), 1.66 (4H, q, J = 7.25 Hz), 2.03 (4H, q, J = 7.26 Hz), 2.20 (3H, s), 2.22 (3H, s), 2.64 (2H, q, J = 7.42 Hz), 4.85 (1H, brs), 5.11 (1H, s), 6.65 (1H, d, J = 8.24 Hz), 6.85-6.98 (5H, m).
(5) Preparation of (S)-5-(4-{1-[4-((E)-1 ,3-Diethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000459_0002
To a solution of 4-{1-[4-((E)-1 ,3-Diethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]- 1 -ethyl-propyl}-2-methyl-phenol (compound prepared in Example 247-(4)) (49 mg, 0.120 mmol) in DMF(1 ml) were added K2C03(33.2 mg, 0.240 mmol) and (S)-Dihydro-5-(toluenesulfonylmethyl)-2-(3H)furanone (64.9 mg, 0.240 mmol) and the mixture was stirred at 100 degrees C overnight. The reaction mixture was poured into sat. NaHC03 aq. and the products were extracted with AcOEt. The extracts were washed with water and brine, dried over MgS0 , filtered and concentrated under reduced pressure. The obtained residue was purified by preparative TLC (Hex:AcOEt 2:1) to give the title compound (39.9 mg, 66%) as colorless oil.
1H-NMR (CDCI3): 0.60 (6H, t, J = 7.26 Hz), 0.85 (3H, t, J = 7.41 Hz), 0.97 (6H, t, J = 7.25 Hz), 1.65 (4H, q, J = 7.26 Hz), 1.97-2.10 (4H, m), 2.16 (3H, s), 2.22 (3H, s), 2.25-2.85 (6H, m), 4.03-4.20 (2H, m), 4.83-4.92 (1H, m), 5.11 (1H, s), 6.67 (1H, d, J = 8.08 Hz), 6.85-7.00 (5H, m).
(6) Preparation of (S)-5-(4-{1-[4-((E)-1 ,3-Diethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000460_0001
To a solution of (S)-5-(4-{1-[4-((E)-1 ,3-Diethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 247-(5)) (39.9 mg, 0.0787 mmol) in MeOH (0.854 ml) was added 1N KOH solution (0.427 ml) and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and obtained residure was purified by preparative TLC (CHCI3:MeOH=8:3, saturated with H 0) to give the title compound (41.8 mg, quant) as colorless oil. 1H-NMR (CDCI3): 0.60 (6H, t, J = 7.09 Hz), 0.85 (3H, t, J = 7.42 Hz), 0.97 (6H, t, J = 7.26 Hz), 1.65 (4H, q, J = 7.08 Hz), 1.90-2.05 (6H, m), 2.18 (3H, s), 2.22 (3H, s), 2.62 (4H, m), 3.85 (1H, t, J = 9.23 Hz), 3.97 (1H, d, J = 9.23 Hz), 4.10 (1H, m), 5.11 (1H, s), 6.68 (1H, d, J = 8.24Hz), 6.94 (5H, m); MS (ESI+) : 542 ([M+NH4]+).
Example 248
Preparation of (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-1 -methyl-pent-1 ■ enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000461_0001
(1) Preparation of (E)-5-(4-{1-[4-((R)-2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-hex-4-en-3-ol
Figure imgf000461_0002
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-1-methyl-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 246- (2)) (15 mg, 0.038 mmol) in DMF(1 ml) were added K2CO3(10.5 mg, 0.076 mmol) and (S)-2,2-Dimethyl-1 ,3-dioxolane-4-ylmethyl p-toluenesulfonate(21.8 mg, 0.076 mmol) and the mixture was stirred at 100 degrees C for 7 h. The reaction mixture was poured into sat. NaHCθ3 aq. and the products were extracted with AcOEt. The extracts were washed with water and brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :2) to give the title compound (13.1 mg, 68%) as colorless oil.
1H-NMR (CDCI3): 0.60 (6H, t, J = 7.26 Hz), 0.97 (6H, t, J = 7.26 Hz), 1.40 (3H, s), 1.46 (3H, s), 1.66 (4H, q, J = 7.25 Hz), 1.97-2.08 (4H, m), 2.11 (3H, s), 2.17 (3H, s), 2.23 (3H, s), 3.88-4.20 (4H, m), 4.40-4.50 (1 H, m), 5.18 (1 H, s), 6.69 (1 H, d, J = 8.25 Hz), 6.85-7.00 (5H, m).
(2) Preparation of (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-1 -methyl-pent-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000461_0003
To a solution of (E)-5-(4-{1-[4-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-hex-4-en-3-ol (compound prepared in Example 248-(1))(7.0 mg, 0.0138 mmol) in THF/H2O=10/1 (0.2 ml) was added CSA(6.8 mg, 0.0292 mmol) and the mixture was stirred at room temperature for 12 h. The reaction mixture was poured into sat. NaHC03 aq. and the products were extracted with CH2CI2. The extracts were dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :2) to give the title compound (2.0 mg, 31%) as colorless oil. 1H-NMR (CDCI3): 0.61 (6H, t, J = 7.09 Hz), 0.97 (6H, t, J = 7.41 Hz), 1.62 (4H, q, J = 7.59 Hz), 2.03 (4H, q, J = 7.42 Hz), 2.11 (3H, s), 2.18 (3H, s), 2.23 (3H, s), 2.54 (1H, d, J = 4.78 Hz), 3.74-3.86 (2H, m), 4.03-4.12 (3H, m), 5.18 (1H, s), 6.70 (1H, d, J = 8.41 Hz), 6.90-6.94 (5H, m).
Example 249
Preparation of (S)-3-(4-{1-[4-((E)-1 ,3-Diethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-1 -ethyl-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000462_0001
(1 ) Preparation of (E)-5-(4-{1-[4-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-hept-4-en-3-ol
Figure imgf000462_0002
To a solution of 4-{1-[4-((E)-1 ,3-Diethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]- 1-ethyl-propyl}-2-methyl-phenol (compound prepared in Example 247-(4)) (50 mg, 0.122 mmol) in DMF (1 ml) were added K2C03(33.9 mg, 0.245 mmol) and (S)-2,2-Dimethyl-1 ,3-dioxolane-4-ylmethyl p-toluenesulfonate (70.2 mg, 0.245 mmol) and the mixture was stirred at 100 degrees C overnight. The reaction mixture was poured into sat. NaHC03 aq. and the products were extracted with AcOEt. The extracts were washed with water and brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was purified by preparative TLC (Hex:AcOEt 2:1) to give the title compound (35.8 mg, 56%) as colorless oil. 1H-NMR (CDCI3): 0.60 (6H, t, J = 7.25 Hz), 0.85 (3H, t, J = 7.41 Hz), 0.97 (6H, t, J = 7.25 Hz), 1.40 (3H, s), 1.46 (3H, s), 1.65 (4H, q, J = 7.26 Hz) 1.97-2.02 (4H, m), 2.17 (3H, s), 2.22 (3H, s), 2.64 (2H, q, J = 7.42 Hz), 3.90-4.20 (4H, m), 4.40- 4.50 (1H, m), 5.11 (1H, s), 6.69 (1H, d, J = 8.41 Hz), 6.88-6.96 (5H, m).
(2) Preparation of (S)-3-(4-{1 -[4-((E)-1 ,3-Diethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000463_0001
To a solution of (E)-5-(4-{1-[4-((R)-2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-hept-4-en-3-ol (compound prepared in Example 249-(1)) (32.7 mg, 0.063 mmol) in
THF/H20=10/1 (0.94 ml) was added CSA(31 mg, 0.133 mmol) and the mixture was stirred at room temperature for 12 h. The reaction mixture was poured into sat. NaHC03 aq. and the products were extracted with CH2CI2. The extracts were dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :2) to give the title compound (16.0 mg, 53%) as colorless oil. 1H-NMR (CDCI3): 0.60 (6H, t, J = 7.14 Hz), 0.85 (3H, t, J = 7.41 Hz), 0.97 (6H, t, J = 7.41 Hz), 1.64 (4H, q, J = 7.41 Hz) 2.04 (4H, q, J = 7.41 Hz), 2.18 (3H, s), 2.22 (3H, s), 2.57 (1H, d, J = 4.94 Hz), 2.64 (4H, q, J = 7.41 Hz), 3.74-3.87 (2H, m), 4.03-4.14 (3H, m), 5.11 (1 H, s), 6.71 (1 H, d, J = 8.23 Hz), 6.88-6.99 (5H, m).
Example 250
Preparation of (S)-3-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-1 -methyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000464_0001
(1) Preparation of (E)-3-(4-{1-[4-(2,2-Dimethyl-propionyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-but-2-enoic acid ethyl ester
Figure imgf000464_0002
To a solution of 2,2-Dimethyl-propionic acid 4-[1 -ethyl-1 -(3-methyl-4- trifluoromethanesulfonyloxy- phenyl)-propyl]-2-methyl-phenyl ester(compound prepared in Example 247-(1)) (562.3 mg, 1.12 mmol) in DMF(3.7 ml) were added Crotonic acid ethyl ester (0.557 ml, 4.50 mmol), NaHC03 (396 mg, 4.71 mmol), dppp(46 mg, 0.110 mmol), LiBr(67 mg, 0.771 mmol) and PdCI2 (PPh3) (79 mg, 0.113 mmol) and the mixture was stirred at 140 degrees C for 9 h. The reaction mixture was cooled to room temperature, poured into sat. NH4CI aq. and the products were extracted with CH2CI2. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :4) to give the title compound (176.8 mg, 34%) as colorless oil.
1H-NMR (CDCI3): 0.61 (6H, t, J = 7.08 Hz), 0.97 (3H, t, J = 7.41 Hz), 1.37 (9H, s), 2.06 (4H, q, J = 7.41 Hz ), 2.13 (3H, s), 2.21 (3H, s), 2.95 (4H, q, J = 7.09 Hz ), 3.73 (3H, s), 5.69 (1H, s), 6.85-7.01 (6H, m).
(2) Preparation of 2,2-Dimethyl-propionic acid 4-{1 -ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-1 -methyl-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl ester
Figure imgf000464_0003
To a solution of (E)-3-(4-{1-[4-(2,2-Dimethyl-propionyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-but-2-enoic acid ethyl ester (compound prepared in Example 250-(1 )) (177 mg, 0.381 mmol) in THF(5 ml) was added EtMgBr (3M in Et20, 0.381 ml, 1.143 mmol) at 0 degrees C and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into sat. NH CI aq. and the products were extracted with CH2CI2. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :2) to give the title compound (123 mg, 68%) as colorless oil. 1H-NMR (CDCI3): 0.61 (6H, t, J = 7.26 Hz), 0.97 (6H, t, J = 7.41 Hz), 1.36 (9H, s), 1.66 (4H, q, J = 7.41 Hz), 2.00-216 (10H, m), 2.23 (3H, s), 5.17 (1H, s), 6.82- 7.05 (6H, m).
(3) Preparation of 2,2-Dimethyl-propionic acid 4-{1 -ethyl-1 -[4-(3-ethyl-3-hyd roxy- 1-methyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl ester
Figure imgf000465_0001
To a solution of 2,2-Dimethyl-propionic acid 4-{1 -ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-1 -methyl-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl ester (compound prepared in Example 250-(2))(123 mg, 0.257 mmol) in EtOH(5 ml) was added Pd(OH)2(20 mg) and the mixture was stirred at room temperature under H2 atmosphere overnight. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give the title compound (115 mg, 93%) as colorless oil.
1H-NMR (CDCI3): 0.58 (6H, t, J = 7.25 Hz), 1.72-1.85 (6H, m), 1.15-1.45 (16H, m), 1.65-1.75 (1H, m), 1.89-2.13 (8H, m), 2.30 (3H, s), 3.10-3.20 (1H, m), 6.80- 7.12 (6H, m).
(4) Preparation of 4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-1 -methyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol
Figure imgf000465_0002
To a solution of 2,2-Dimethyl-propionic acid 4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-1- methyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl ester (compound prepared in Example 250-(3)) (115 mg, 0.238 mmol) in MeOH(3 ml) was added 1 N-KOH (0.476 ml, 0.476 mmol) and the mixture was stirred at 60 degrees C for 1 h. The reaction mixture was poured into sat. NH4CI aq. and the products were extracted with CH2CI2. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :2) to give the title compound (75.6 mg, 80%) as colorless oil. 1H-NMR (CDCI3): 0.57 (6H, t, J = 7.25 Hz), 0.73-0.83 (6H, m), 1.19 (3H, d, J = 6.93 Hz), 1.34-1.45 (4H, m), 1.66-1.73 (1 H, m), 1.91-2.05 (5H, m), 2.17 (3H, s), 2.30 (3H, s), 3.08-3.20 (1H, m), 5.05 (1H, brs), 6.61 (1H, d, J = 8.25 Hz), 6.82- 6.96 (4H, m), 7.11 (1 H, d, J = 8.07 Hz).
(5) Preparation of 5-(4-{1 -[4-((R)-2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-hexan-3-ol
Figure imgf000466_0001
To a solution of 4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-1-methyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 250-(4)) (31.1 mg, 0.078 mmol) in DMF(0.8 ml) were added K2C03(21.7 mg, 0.156 mmol) and (S)-2,2-Dimethyl-1 ,3-dioxolane-4-ylmethyl p-toluenesulfonate (44.7 mg, 0.156 mmol) and the mixture was stirred at 100 degrees C overnight. The reaction mixture was poured into sat. NaHC03 aq. and the products were extracted with AcOEt. The extracts were washed with water and brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was purified by preparative TLC (Hex:AcOEt 2:1) to give the title compound (22.6 mg, 57%) as colorless oil.
1H-NMR (CDCI3): 0.57 (6H, t, J = 7.26 Hz), 0.73-0.82 (6H, m), 1.19 (3H, d, J = 6.93 Hz), 1.30-1.40 (4H, m), 1.40 (3H, s), 1.46 (3H, s), 1.65-1.72 (1H, m), 1.88- 2.08 (5H, m), 2.15 (3H, s), 2.31 (3H, s), 3.10-3.21 (1H, s), 3.88-4.18 (4H, m), 4.41-4.50 (1 H, m), 6.68 (1H, d, J = 8.40 Hz), 6.89-6.95 (4H, m), 7.11 (1H, d, J = 8.08 Hz).
(6) Preparation of (S)-3-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-1 -methyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000467_0001
To a solution of 5-(4-{1-[4-((R)-2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-hexan-3-ol (compound prepared in Example 250-(5))(22.6 mg, 0.044 mmol) in THF-H2O(10:1 , 1.1 ml) was added CSA(3.1 mg, 0.013 mmol) and the mixture was stirred at 60 degrees C for 5 h. The reaction mixture was poured into sat. NaHC03 aq. and the products were extracted with CH2CI2. The extracts were dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with EtOAc-n-Hexane (1 :1) to give the title compound (13.8 mg, 67%) as colorless oil.
1H-NMR (CDCI3): 0.58 (6H, t, J = 7.26 Hz), 0.73-0.82 (6H, m), 1.19 (3H, d, J = 6.93 Hz), 1.30-1.44 (4H, m), 1.65-1.73 (1H, m), 1.90-2.08 (5H, m), 2.16 (3H, s), 2.31 (3H, s), 3.08-3.22 (1H, m), 3.72-3.90 (2H, m), 4.00-4.18 (3H, m), 6.69 (1H, d, J = 8.41 Hz), 6.89-6.95 (4H, m), 7.11 (1H, d, J = 8.07 Hz); MS (ESI+) : 488 ([M+NH4]+).
Example 251
Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-1 -methyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000467_0002
(1) Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-1-methyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one
Figure imgf000468_0001
To a solution of 4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-1-methyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 250-(4)) (44.5 mg, 0.112 mmol) in DMF(1 ml) were added K2C03(31 mg, 0.224 mmol) and (S)- Dihydro-5-(toluenesulfonylmethyl)-2-(3H)furanone (60.5 mg, 0.224 mmol) and the mixture was stirred at 100 degrees C overnight. The reaction mixture was poured into sat. NaHCθ3 aq. and the products were extracted with AcOEt. The extracts were washed with water and brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was purified by preparative TLC (Hex:AcOEt 2:1) to give the title compound (39.9 mg, 51%) as colorless oil. 1H-NMR (CDCI3): 0.57 (6H, t, J = 7.26 Hz), 0.73-0.82 (6H, m), 1.19 (3H, d, J = 6.93 Hz), 1.32-1.45 (4H, m), 1.65-1.73 (1 H, m), 1.90-2.10 (5H, m), 2.15 (3H, s), 2.31 (3H, s), 2.30-2.82 (4H, m), 3.10-3.23 (1 H, m), 4.03-4.19 (2H, m), 4.85-4.92 (1 H, m), 6.65 (1 H, d, J = 8.41 Hz), 6.88-6.95 (4H, m), 7.11 (1 H, d, J = 8.07 Hz).
(2) Preparation of (S)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-1 -methyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid
Figure imgf000468_0002
To a solution of (S)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-1-methyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (compound prepared in Example 251 -(1)) (28.4 mg, 0.057 mmol) in MeOH (1 ml) was added 1 N-KOH(0.3 ml) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and obtained residure was purified by preparative TLC (CHCl3:MeOH=8:3, saturated with H20) to give the title compound (13.3 mg, 46%) as colorless oil. 1H-NMR (CDCI3): 0.58 (6H, t, J = 7.26 Hz), 0.73-0.82 (6H, m), 1.19 (3H, d, J = 6.76 Hz), 1.32-1.47 (4H, m), 1.65-1.72 (1 H, m), 1.80-2.10 (7H, m), 2.17 (3H, s), 2.31 (3H, s), 2.61 (2H, t, J = 6.59 Hz), 3.08-3.21 (1 H, m), 3.80-3.90 (1 H, m), 3.95-4.15 (2H, m), 6.66 (1 H, d, J = 8.57 Hz), 6.91-6.94 (4H, m), 7.11 (1 H, d, J = 8.08 Hz); MS (ESI-) : 511 ([M-H]-).
Example 252
Preparation of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-benzoic acid
Figure imgf000469_0001
(1) Preparation of Trifluoromethanesulfonic acid 4-{1 -ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl ester
Figure imgf000469_0002
A stirred solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(5)) (490 mg, 1.29 mmol) in CH2CI2 (13 ml), pyridine (0.208 ml, 2.58 mmol) and trifluoromethanesulfonic anhydride (0.212 ml, 1.29 mmol) were added and the mixture was stirred at room temperature for 1 h. To the reaction mixture, H2O was added. The organic layer was separated and concentrated in vacuo. The obtained residue was chromatographed on silica gel (ethyl acetate/hexane = 0/100 to 15/85) to give the title compound (491 mg, 74%). 1H-NMR: 0.61 (t, 6H), 0.92 (t, 6H), 1.65 (q, 4H), 2.07 (q, 4H), 2.32 (s, 3H), 2.32 (s, 3H), 6.02 (d, 1H), 6.75 (d, 1H), 6.90-6.92 (m, 2H), 7.03-7.12 (m, 3H), 7.31 (d, 1H). (2) Preparation of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-benzoic acid methyl ester
Figure imgf000470_0001
To a solution of Trifluoromethanesulfonic acid 4-{1 -ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl ester (compound prepared in Example 252-(1)) (461 mg, 0.90 mmol) in methanol (5 ml) and DMF (9 ml) was added triethylamine (0.376 ml, 2.70 mmol) and Pd(PPh3)4 (1 -04 g, 0.90 mmol) and the mixture was stirred for 2 days at 60 degrees C under CO atmosphere. The reaction mixture was separated with ethyl acetate and H2O, the organic phase was washed with brine three times, dried over MgS04, concentrated in vacuo. The obtained residue was chromatographed on silica gel (ethyl acetate / hexane = 0/100 to 15/85) to give the title compound (299 mg, 79%). 1H-NMR: 0.62 (t, 6H), 0.92 (t, 6H), 1.64 (dq, 4H), 2.10 (q, 4H), 2.30 (s, 3H), 2.55 (s, 3H), 3.86 (s, 3H), 6.03 (d, 1H), 6.74 (d, 1H), 6.91-7.06 (m, 4H), 7.30 (d, 1H), 7.79 (d, 1H).
(3) Preparation of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-benzoic acid
Figure imgf000470_0002
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-benzoic acid methyl ester (compound prepared in Example 252-(2)) (209 mg, 0.49 mmol) in MeOH (2 ml) and THF (2 ml) was added 1 N KOH solution (3 ml) and stirred for 4 h at 60 degrees C. The reaction mixture was separated with ethyl acetate and aqueous KHSO4, the organic phase was washed with brine, dried over MgSθ4, concentrated in vacuo to give the title compound (199.2 mg, 99 %).
1H-NMR: 0.63 (t, 6H), 0.92 (t, 6H), 1.64 (d, 4H), 2.11 (q, 4H), 2.31 (s, 3H), 2.60 (s, 3H), 6.02 (d, 1H), 6.75 (d, 1H), 6.91-7.09 (m, 4H), 7.31 (d, 1H), 7.93 (d, 1H). MS (ESI+) : 390 ([M-H20] +)
Example 253
Preparation of 3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid
Figure imgf000471_0001
Preparation of 3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid
Figure imgf000471_0002
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-benzoic acid (compound prepared in Example 252-(3)) (27 mg, 0.066 mmol) in CH2CI2 (0.7 ml) and triethylamine (0.028ml, 0.198 mmol) was added beta-Ala methyl ester hydrochloride (28 mg, 0.198 mmol), WSCI hydrochloride (38 mg, 0.198 mmol) and HOBt monohydrate (10 mg, 0.066 mmol), and the mixture was stirred for 16 h at room temperature. To the reaction mixture, H20 and CH2CI2 were added. The organic layer was separated, concentrated in vacuo. The resulting residue was dissolved in THF (1 ml) and MeOH (1 ml). To the mixture, 1 N aqueous KOH (1 ml) was added and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo, separated with ethyl acetate and aqueous KHSO4, the organic phase was washed with brine, dried over MgS0 , concentrated in vacuo. The obtained residue was chromatographed on silica gel (C^C /EtOH
= 10/1) to give the title compound (25.9 mg, 82%).
1H-NMR: 0.61 (t, 6H), 0.91 (t, 6H), 1.64 (dq, 4H), 2.07 (q, 4H), 2.30 (s, 3H),
2.38 (s, 3H), 2.70 (t, 2H), 3.66-3.76 (m, 2H), 6.01 (d, 1H), 6.37 (t, 1H), 6.73 (d,
1H), 6.90-7.02 (m, 4H), 7.22 (d, 1H) , 7.29 (d, 1H).
MS (ESI+) : 480 ([M+H] +)
Example 254 Preparation of 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-benzoylamino)-butyric acid
Figure imgf000472_0001
Preparation of 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-benzoylamino)-butyric acid
Figure imgf000472_0002
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-benzoic acid(compound prepared in Example 252-(3)) (34 mg, 0.08 mmol) in CH2CI2 (0.8 ml) and triethylamine (0.067ml, 0.48 mmol) was added gamma-aminobuthylic acid methyl ester hydrochloride (37 mg, 0.24 mmol), WSCI hydrochloride (46 mg, 0.24 mmol) and HOBt monohydrate (12 mg, 0.08 mmol), and the mixture was stirred for 18 h at room temperature. To the reaction mixture, H2O and CH2CI2 were added. The organic layer was separated, concentrated in vacuo. The resulting residue was dissolved in THF (1 mL) and MeOH (1 ml). 1 N aqueous KOH (1 ml) was added and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo, separated with ethyl acetate and aqueous KHSO4, the organic phase was washed with brine, dried over MgS04, concentrated in vacuo. The obtained residue was chromatographed on silica gel (CH2d2/Et0H = 10/1) to give the title compound (30.8 mg, 75%).
1H-NMR: 0.61 (t, 6H), 0.92 (t, 6H), 1.64 (q, 4H), 1.89-1.99 (m, 1H), 2.07 (q, 4H), 2.30 (s, 3H), 2.40 (s, 3H), 2.47 (t, 2H), 2.50 (q, 2H), 5.98-6.04 (m, 2H), 6.74 (d, 1 H), 6.93-7.03 (m, 4H), 7.23 (d, 1H) , 7.29 (d, 1H). MS (ESI+) : 494 ([M+H] +)
Example 255 Preparation of N-(4-Amino-butyl)-4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-benzamide
Figure imgf000473_0001
Preparation of N-(4-Amino-butyl)-4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 ■ enyl)-3-methyl-phenyl]-propyl}-2-methyl-benzamide
Figure imgf000473_0002
To a solution of 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-benzoic acid (compound prepared in Example 252-(3)) (31.5 mg, 0.077 mmol) in CH2CI2 (0.8 ml) and triethylamine (0.064ml, 0.46 mmol) was added (4-Amino-butyl)-carbamic acid 9H-fluoren-9-ylmethyl ester hydrochloride (80 mg, 0.23 mmol), WSCI hydrochloride (44 mg, 0.23 mmol) and HOBt monohydrate (12 mg, 0.077 mmol), and the mixture was stirred for 16 h at room temperature. To the reaction mixture, H20 and CH2CI2 were added. The organic layer was separated, concentrated in vacuo. The resulting residue was dissolved in DMF (0.8 ml), diethylamine (0.08 ml, 0.77 mmol) was added and the mixture was stirred for 3 h at room temperature. The reaction mixture was separated with ethyl acetate and H20, the organic phase was washed with H20 twice, dried over MgS04, concentrated in vacuo. The obtained residue was chromatographed on silica gel (ethyl acetate/EtOH = 10/1) to give the title compound (18.3 mg, 50%).
1H-NMR: 0.61 (t, 6H), 0.92 (t, 6H), 1.49-1.58 (m, 4H), 1.64 (dq, 4H), 2.07 (q, 4H), 2.30 (s, 3H), 2.40 (s, 3H), 2.75 (t, 2H), 3.44 (q, 2H), 6.01 (d, 1 H), 6.05-6.07 (m, 1 H), 6.74 (d, 1H), 6.90-7.02 (m, 4H), 7.22 (d, 1H) , 7.29 (d, 1H); MS (ESI+): 479 ([M+H]+).
Example 256
Preparation of 1 -(4-{1 -Ethyl-1 -[3-methyl-(S)-4-(tetrahydro-furan-2-ylmethoxy)- phenyl]-propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000474_0001
Preparation of 5(S)-[4-(1 -{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl- phenyl}-1-ethyl-propyl)-2-methyl-phenoxymethyl]-dihydro-furan- 2-one
Figure imgf000474_0002
To a solution of 4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3- methyl-phenyl}-1 -ethyl- propyl)-2-methyl-phenol (compound prepared in
Example 187-(1)) (140 mg, 0.28 mmol) in DMF (1.4 ml), (S)-(+)-dihydro-5-(p- tolylsulfonyloxymethyl)-2(3H)-furanone (228 mg, 0.84 mmol), and K2C03 (195 mg, 1.41 mmol) were added at room temperature and the mixture was stirred at room temperature for 8 h. To the mixture, ethyl acetate was added and the mixture was washed with 30% NaH2P04 aq. and brine, dried over MgS04, concentrated in vacuo. The obtained residue was chromatographed on silica gel (AcOEt/hexane =1/2 to 2/1) to give the title compound (140 mg, 36%) as colorless oil.
1H-NMR (CDCI3): 0.07 (s, 3H),0.10 (s, 3H),0.59 (t, 6H, J=7.3Hz),0.84 (s, 9H),0.93 (s, 9H),1.5-1.9 (m, 2H),2.04 (q, 4H, J=7.3Hz),2.16 (s, 3H),2.24 (s, 3H),2.32-2.48 (m, 4H),2.50-2.82 (m, 2H),3.34 (dd, 1H, J=3.2, 7.2Hz),4.12 (ddd, 2H, J=3.5, 10.3, 13.7Hz),4.85-4.95 (m, 1H),6.66 (d, 1H, J=8.2Hz),6.85-7.00 (m, 5H);
(2) Preparation of tert-Butyl-{1-[2-(4-{1 -ethyl-1 -[3-methyl-(S)-4-(tetrahydro-furan- 2-ylmethoxy)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-2,2-dimethyl-propoxy}- dimethyl-silane
Figure imgf000475_0001
To a solution of 5(S)-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}- 1 -ethyl-propyl )-2-methyl-phenoxymethyl]-d i hyd ro-f u ran- 2-one (compound prepared in Example 256-(1))(62 mg, 0.1 mmol) in Et2θ (1 ml), UAIH4 (6 mg, 0.16 mmol) was added at 0 degrees C and the mixture was stirred at room temperature for 2 h. To the mixture, ethyl acetate and brine were added and the mixture was stirred at room temperature for 0.5 h, dried over MgS04, concentrated in vacuo to give 5-[4-(1-{4-[3-(tert-Butyl-dimethyl- silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl- phenoxy]-(4S)-pentane-1 ,4-diol (60mg) as colorless oil.
To a solution of 5-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]- 3-methyl-phenyl} -1-ethyl-propyl)-2-methyl-phenoxy]-(4S)-pentane-1 ,4-diol (45 mg, 0.075mmol) in THF (0.5ml), PPh3 (20 mg, 0.076 mmol) and DEAD (0.014 ml, 0.077 mmol) were added at 0 degrees C and the mixture was stirred at room temperature for 2 h. To the mixture, Et20 was added and the mixture was washed with water and brine, dried over MgS04, concentrated in vacuo. The obtained residue was chromatographed on silica gel (AcOEt/hexane =1/10) to give the title compound (22 mg, 50%) as colorless oil. 1H-NMR (CDCI3): 0.07 (s, 3H), 0.10 (s, 3H), 0.60 (t, 6H, J=7.3Hz), 0.88 (s, 9H), 0.93 (s, 9H), 1.50-1.60 (m, 1 H), 1.80-2.08 (m, 10H), 2.18 (s, 3H), 2.23 (s, 3H), 2.41 (dt, 1 H, J=4.5, 12.9Hz), 2.76 (dt, 1 H, J=5.6, 12.6Hz), 3.34 (dd, 1 H, J=3.2, 7.2Hz), 3.80-4.10 (m, 4H), 4.20-4.40 (m, 1H), 6.68 (d, 1H, J=8.1Hz), 6.91-6.99 (m, 5H).
(3) Preparation of 1-(4-{1 -Ethyl-1 -[3-methyl-(S)-4-(tetrahydro-furan-2-ylmethoxy)- phenyl]-propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000476_0001
To a solution of tert-Butyl-{1 -[2-(4-{1 -ethyl-1 -[3-methyl-(S)-4-(tetrahydro-furan-2- ylmethoxy)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-2,2-dimethyl-propoxy}- dimethyl-silane (compound prepared in Example 256-(2)) (20 mg, 0.034 mmol) in THF (1 ml), TBAF (1M in THF, 0.5 ml, 0.5 mmol) was added at room temperature and the mixture was refluxed for 3 h. To the mixture, Et20 was added and the mixture was washed with water, dried over MgS04, concentrated in vacuo. The obtained residue was chromatographed on silica gel (AcOEt/hexane =1/2) to give the title compound (8 mg, 51%) as colorless oil. 1H-NMR (CDCI3): 0.59 (t, 6H, J=7.3Hz), 0.89 (s, 9H), 1.26 (t, 3H, J=7.2Hz), 1.30-1.60 (m, 1 H), 1.70-2.15 (m, 10H), 2.18 (s, 3H), 2.25 (s, 3H), 2.50-2.65 (m, 1 H), 2.80-2.90 (m, 1 H), 3.20-4.00 (m, 4H), 4.20-4.40 (m, 1 H), 6.68 (d, 1 H,
J=8.2Hz), 6.90-6.95 (m, 4H), 7.02 (d, H, J=8.6Hz) ; MS (ESI+) : 484 ([M+NH4]+).
Example 257
5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-oxo-pentanoic acid
Figure imgf000476_0002
(1 ) Preparation of 5-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl} -1-ethyl-propyl)-2-methyl-phenoxy]-4(S)-hydroxy- pentanoic acid methyl ester
Figure imgf000477_0001
To a solution of (S)-5-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxymethyl]-dihydro-furan- 2-one (compound prepared in Example 256-(1)) (60 mg, 0.1 mmol) in THF (0.5 ml) and MeOH (1 ml), 1N KOH aq. (0.2 ml, 0.2 mmol) was added at room temperature and the mixture was stirred at room temperature for 2 h. To the mixture, ethyl acetate was added and the mixture was washed with 30% NaH2Pθ4 aq. and brine, dried over MgS04, concentrated in vacuo, and chromatographed on silica gel (AcOEt/hexane =1/2) to give carboxylic acid. To a solution of the carboxylic acid in toluene (0.5 ml) and MeOH (0.5 ml), TMSCHN2 (1M in Et20) was added at room temperature and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the obtained residue was chromatographed on silica gel (AcOEt/hexane =1/2) to give the title compound (60 mg, 95%) as colorless oil. 1H-NMR (CDCI3): 0.07 (s, 3H), 0.11 (s, 3H), 0.61 (t, 6H, J=7.2Hz), 0.89 (s, 9H), 0.94 (s, 9H), 1.50-1.65 (m, 1H), 1.70-1.96 (m, 3H), 2.02 (q, 4H, J=7.1Hz), 2.18 (s, 3H), 2.24 (s, 3H), 2.30-2.60 (m, 3H), 2.70-2.85 (m, 1H), 3.30-3.40 (m, 1H), 3.70 (s, 3H), 3.80-4.10 (m, 2H), 4.10 (brs, 1H), 6.68 (d, 1H, J=8.1Hz), 6.90-7.10 (m, 5H);
(2) Preparation of 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-oxo-pentanoic acid
Figure imgf000478_0001
To a solution of 5-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxy]-4(S)-hydroxy- pentanoic acid methyl ester (compound prepared in Example 257-(1))(60 mg, 0.1 mmol) in dichloromethane (1 ml), Dess-Martin reagent (50 mg, 0.12 mmol) was added at 0 degrees C and the mixture was stirred at room temperature for 1 h. To the mixture, ethyl acetate was added and the mixture was washed with saturated NaHCθ3 aq., water, and brine, dried over MgS04, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (AcOEt/hexane =1/2) to give 5-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4- dimethyl-pentyl]-3-methyl-phenyl}-1 -ethyl-propyl )-2-methyl-phenoxy]-4-oxo- pentanoic acid methyl ester (58mg, 97%) as colorless oil. To a solution of 5-[4-(1 -{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]- 3-methyl-phenyl} -1 -ethyl-propyl)-2-methyl-phenoxy]-4-oxo-pentanoic acid methyl ester (58 mg, 0.1 mmol) in THF (1ml), TBAF (1 M in THF, 1 ml, 1 mmol) was added at 0 degrees C and the mixture was refluxed for 4 h. To the mixture, ethyl acetate was added and the mixture was washed with 30% NaH2P04 aq., dried over MgSθ4, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (AcOEt/hexane =5/1) to give the title compound (11 mg, 23%) as colorless oil.
1H-NMR (CDCI3): 0.59 (t, 6H, J=7.3Hz), 0.89 (s, 9H), 1.40-1.60 (m, 1H), 1.70- 1.90 (m, 1H), 2.04 (q, 4H, J=7.1Hz), 2.24 (s, 3H), 2.25 (s, 3H), 2.50-2.61 (m, 1 H), 2.71 (t, 2H, J=6.4Hz), 2.80-3.30 (m, 3H), 4.12 (dd, 1 H, J=7.2, 14.3Hz), 4.52 (brs, 2H), 6.56 (d, 1H, J=9.1Hz), 6.80-7.10 (m, 5H); MS (ESI+) : 519 ([M+Na]+).
Example 258
Preparation of 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol
Figure imgf000479_0001
Preparation of 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-(4S)-pentane-1 ,4-diol
Figure imgf000479_0002
To a solution of 5(S)-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxymethyl]-dihydro-furan- 2-one (compound prepared in Example 256-(1)) (62 mg, 0.1 mmol) in Et 0 (1 ml), LiAIH4 (6 mg, 0.16 mmol) was added at 0 degrees C and the mixture was stirred at room temperature for 2 h. To the mixture, ethyl acetate and brine were added and the mixture was stirred at room temperature for 0.5 h, dried over MgS04, concentrated in vacuo to give 5-[4-(1-{4-[3-(tert-Butyl-dimethyl- silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl- phenoxy]-(4S)-pentane-1 ,4-diol (60 mg) as colorless oil.
To a solution of 5-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]- 3-methyl-phenyl} -1-ethyl-propyl)-2-methyl-phenoxy]-(4S)-pentane-1 ,4-diol (15 mg, 0.075mmol) in THF (1 ml), TBAF (1M in THF, 1 mmol) was added at room temperature and the mixture was refluxed for 4 h. To the mixture, ethyl acetate was added and the mixture was washed with 30% NaH2P04 aq., dried over
MgS0 , concentrated in vacuo, and the obtained residue was chromatographed on silica gel (AcOEt/hexane =5/1) to give the title compound (11 mg, 90%) as colorless oil. 1H-NMR (CDCI3): 0.60 (t, 6H, J=7.3Hz), 0.93 (s, 9H), 1.40-1.90 (m, 6H), 2.04 (q, 4H, J=7.4Hz), 2.18 (s, 3H), 2.26 (s, 3H), 2.50-2.65 (m, 1H), 2.80-2.95 (m, 1H), 3.25 (dd, 1H, J=1.6, 10.4Hz), 3.65-3.80 (m, 2H), 3.84 (dd, 1H, J=7.4, 9.2Hz), 3.96 (dd, 1 H, J=3.6, 9.1Hz), 4.00-4.15 (m, 1 H), 6.68 (d, 1 H, J=8.2Hz), 6.85-7.00 (m, 4H), 7.02 (d, 1H, J=8.7Hz); MS (ESI+) : 485 ([M+H]+).
Example 259
Preparation of 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid
Figure imgf000480_0001
(1) Preparation of Trifluoro-methanesulfonic acid 4-(1-{4-[3-(tert-butyl-dimethyl- silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl ester
Figure imgf000480_0002
To a solution of 4-(1 -{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3- methyl-phenyl}-1-ethyl-propyl)-2-methyl- phenol (compound prepared in Example 187-(1)) (1.8 g, 3.6 mmol) in dichloromethane (18 ml), pyridine (0.44 ml, 5.4 mmol), and Tf20 (0.73 ml, 4.3 mmol) were added at 0 degrees C and the mixture was stirred at room temperature for 0.5 h. To the mixture, ethyl acetate was added and the mixture was washed with water, dried over MgSθ4, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (ethyl acetate/hexane =1/10) to give the title compound (1.55 g, 68%) as colorless oil. 1H-NMR (CDCI3): 0.06 (s, 3H), 0.09 (s, 3H), 0.59 (t, 6H, J=7.3Hz), 0.87 (s, 9H), 0.93 (s, 9H), 1.50-1.65 (m, 1 H), 1.70-1.85 (m, 1 H), 2.04 (q, 4H, J=7.3Hz), 2.23 (s, 3H), 2.31 (s, 3H), 2.41 (dt, 1H, J=4.5, 13.0Hz), 2.76 (dt, 1H, J=5.5, 13.0Hz), 3.34 (dd, 1 H, J=3.3, 7.0Hz), 6.80-6.90 (m, 2H), 6.95-7.15 (m, 4H).
(2) Preparation of Trifluoro-methanesulfonic acid 4-{1 -ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl ester
Figure imgf000481_0001
To a solution of trifluoro-methanesulfonic acid 4-(1-{4-[3-(tert-butyl-dimethyl- silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1 -ethyl-propyl )-2-methyl-phenyl ester (compound prepared in Example 259-(1 )) (95 mg, 0.15 mmol) in dichloromethane (0.75 ml), trifluoroacetic acid (0.25 ml) was added at room temperature and the mixture was stirred at room temperature for 1.5 h. The mixture was concentrated in vacuo, and chromatographed on silica gel (ethyl acetate/hexane =1/2) to give the title compound (70 mg, 90%) as colorless oil. 1H-NMR (CDCI3): 0.60 (t, 6H, J=7.3Hz), 0.90 (s, 9H), 1.35-1.60 (m, 2H), 1.70- 1.90 (m, 1 H), 2.06 (q, 4H, J=7.3Hz), 2.27 (s, 3H), 2.32 (s, 3H), 2.50-2.65 (m, 1H), 2.80-3.00 (m, 1H), 3.26 (brd, 1 H, J=10.2Hz), 6.80-6.95 (m, 2H), 7.00-7.20 (m, 4H);
(3) Preparation of 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid
Figure imgf000481_0002
To a solution of trifluoro-methanesulfonic acid 4-(1-{4-[3-(tert-butyl-dimethyl- silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl ester (compound prepared in Example 259-(2)) (50 mg, 0.1 mmol) in DMF (1 ml), PdCI2(dppf)2-CH2Cl2 (8 mg, 0.01 mmol), Et3N (0.05 ml, 0.3 mmol), Cul (20 mg, 0.1 mmol), and hex-5-ynoic acid methyl ester (20 mg, 0.16 mmol) were added at room temperature under nitrogen and stirred at 120 degrees C for 8 h. To the mixture, ethyl acetate was added and the mixture was washed with water and brine, dried over MgS04, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (ethyl acetate/hexane =1/4) to give 6-(4-{1- ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenyl)-hex-5-ynoic acid methyl ester (16mg) as colorless oil including impurities.
To a solution of 6-(4-{1 -ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid methyl ester(16 mg) in MeOH (1 ml), 1N NaOH aq. (0.2 ml, 0.2 mmol) was added at room temperature and stirred at room temperature for 4 h. To the mixture, ethyl acetate was added and the mixture was washed with 30% NaH2Pθ4 aq., dried over MgSθ4, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (ethyl acetate/hexane =1/1) to give the title compound (6 mg, 13%, 2steps) as colorless oil.
1H-NMR (CDCI3): 0.59 (t, 6H, J=7.3Hz), 0.89 (s, 9H), 1.40-1.60 (m, 1H), 1.70- 2.00 (m, 3H), 2.05 (q, 4H, J=7.3Hz), 2.24 (s, 3H), 2.35 (s, 3H), 2.45-2.65 (m, 5H), 2.80-2.95 (m, 1 H), 3.24 (dd, 1 H, J=1.5, 10.4Hz), 6.80-7.05 (m, 5H), 7.23 (d, 1 H, J=8.1Hz); MS (ESI+) : 494 ([M+NH4]+).
Example 260
Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclohexyl)-prop-1 ■ ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
Figure imgf000482_0001
(1) Preparation of 1 -Methyl-cyclohexanecarboxylic acid N-methoxy-N-methyl- amide
Figure imgf000483_0001
To a solution of 1-Methyl-1 -cyclohexanecarboxylic acid (500 mg, 3.516 mmol) in CH2CI2 (5 ml), methoxymethyl amine hydrochloride (411.6 mg, 4.219 mmol), DMAP (214.8 mg, 1.758 mmol), Et3N (996.2 mg, 9.845 mmol) and HCl salt of WSCI (943.7 mg, 4.923 mmol) were added under nitrogen gas at 0 degrees C and the mixture was stirred at room temperature for 17 h. To the mixture, ethyl acetate was added and the organic layer was washed with brine, dried over magnesium sulfate, concentrated in vacuo and the obtained residue was chromatographed on silica gel (dichrolomethane/methanol =90/10) to give the title compound (373.5 mg, 57.3%).
1H-NMR (chloroform-d): 1.17 (s, 3H), 1.24-1.56 (m, 8H), 2.05-2.11 (m, 2H), 3.15 (s, 3H), 3.64 (s, 3H); MS (ESI+) : 186([M+H]+).
(2) Preparation of tert-Butyl-{4-[1 -ethyl-1 -(4-ethynyl-3-methyl-phenyl)-propyl]-2- methyl-phenoxyj-dimethyl-silane
Figure imgf000483_0002
To a solution of 4-[1 -Ethyl-1 -(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl- phenol (compound prepared in Example 1-(3)) (639 mg, 2.185 mmol) in DMF (2.7 ml), TBSCI (658.8 mg, 4.371 mmol) and imidazole (743.9 mg, 10.926 mmol) were added at room temperature and the mixture was stirred at room temperature for 17 h. To the mixture, ethyl acetate was added and the mixture was washed with water and brine, dried over magnesium sulfate, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (n- hexane/ethyl acetate =97/3 to ethyl acetate=only) to give the title compound (555.2 mg, 62.5%) as colorless oil.
1H-NMR (chloroform-d): 0.23 (s, 6H), 0.62 (t, 6H, J=7.3Hz), 1.03 (s, 9H), 2.06 (q, 4H, J=7.3Hz), 2.18 (s, 3H), 2.42 (s, 3H), 3.23 (s, 1H), 6.67 (d, 1H, J=8.4Hz), 6.84 (dd, 1H, J=2.6, 8.4Hz), 6.90 (d, 1H, J=2.4Hz), 6.97 (dd, 1H, J=2.0, 8.1Hz), 7.04 (brs, 1H), 7.36 (d, 1H, J=8.2Hz); MS (ESI+) : 407([M+H]+).
(3) Preparation of 3-(4-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-1 -(1 -methyl-cyclohexyl)-prop-2-yn-1 -one
Figure imgf000484_0001
To a solution of tert-Butyl-{4-[1 -ethyl-1 -(4-ethynyl-3-methyl-phenyl)-propyl]-2- methyl-phenoxy}-dimethyl-silane (compound prepared in Example 260-(2)) (50 mg, 0.123 mmol) in THF (0.2 ml), n-BuLi in n-hexane (0.07 ml, 0.172 mmol) was added at -78 degrees C under nitrogen gas and the mixture was stirred at room temperature for 20 min. And then, to this solution, 1-methyl- cyclohexanecarboxylic acid methoxy-methyl-amide (compound prepared in Example 260-(1)) (34.2 mg, 0.185 mmol) was added at -78 degrees C under nitrogen gas and the mixture was stirred for 15 h raising the reaction temperature from -78 degrees C to room temperature. To the mixture, ethyl acetate was added and the mixture was washed with saturated ammonium chloride solution and brine, dried over magnesium sulfate, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (n- hexane/ethyl acetate =10/1) to give the title compound (41.1 mg, 62.9%). MS (ESI+) : 531([M+H]+).
(4) Preparation of 3-(4-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-1 -(1 -methyl-cyclohexyl)-prop-2-yn-1 -ol
Figure imgf000484_0002
To a solution of 3-(4-{1 -[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1 ■ ethyl-propyl}-2-methyl-phenyl)-1 -(1 -methyl-cyclohexyl)-prop-2-yn-1 -one (compound prepared in Example 260-(3)) (41.1 mg, 0.077 mmol) in THF (0.8 ml) and MeOH (0.3 ml), NaBH4 (8.8 mg, 0.232 mmol) was added at room temperature and stirred at room temperature for 13 h. To the mixture, ethyl acetate was added and the mixture was washed with brine, dried over magnesium sulfate, concentrated in vacuo, and chromatographed on silica gel (n-hexane/ethyl acetate =30/1) to give the title compound (36.5 mg, 88.5%). 1H-NMR (chloroform-d): 0.21 (s, 6H), 0.60 (t, 6H, J=7.4Hz), 1.02 (s, 9H), 1.08 (s, 3H), 1.40-1.63 (m, 10H), 1.77 (brs, 1H), 2.04 (q, 4H, J=7.4Hz), 2.15 (s, 3H), 2.39 (s, 3H), 4.35 (s, 1H), 6.63 (d, 1H, J=8.2Hz), 6.81 (dd, 1H, J=2.5, 8.3Hz), 6.86 (d, 1 H, J=2.3Hz), 6.94 (dd, 1 H, J=1.6, 8.1 Hz), 7.00 (brs, 1 H), 7.29 (d, 1H, J=8.2Hz).
(5) Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclohexyl)-prop- 1-ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
Figure imgf000485_0001
To a solution of 3-(4-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-1 -(1 -methyl-cyclohexyl)-prop-2-yn-1 -ol (compound prepared in Example 260-(4)) (36 mg, 0.068 mmol) in THF (0.7 ml), 1.0M TBAF in THF (0.1 ml, 0.1 mmol) was added at room temperature and stirred at room temperature for 15 h. To the mixture, ethyl acetate was added and the mixture was washed with diluted potassium hydrogen sulfate aq. and brine, dried over magnesium sulfate, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (n-hexane/ethyl acetate =10/1 and 7/1) to give the mixture including the title compound (28.8 mg). To a solution of this mixture (10 mg) in DMF (0.2 ml), (R)-(-)-Dihydro-5-(p-tolyl- sulfonyloxymethyl)-2(3H)-furanone (16.1 mg, 0.06 mmol) and K2C03 (13.2 mg, 0.096 mmol) were added at room temperature and stirred at 105 degrees C for 11 h. To the reaction mixture, ethyl acetate was added and the mixture was washed with brine, dried over magnesium sulfate, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (n-hexane/ethyl acetate =3/1) to give the title compound (4.6 mg, 37.3% for 2 steps). 1H-NMR (chloroform-d): 0.59 (t, 6H, J=7.3Hz), 1.07 (s, 3H), 1.40-1.64 (m, 10H), 1.74 (d, 1H, J=6.2Hz), 2.04 (q, 4H, J=7.3Hz), 2.15 (s, 3H), 2.26-2.63 (m, 3H), 2.39 (s, 3H), 2.78 (ddd, 1H, J=6.8, 9.7, 17.0Hz), 4.06 (dd, 1H, J=3.5, 10.3Hz), 4.17 (dd, 1H, J=3.3, 10.3Hz), 4.35 (d, 1H, J=6.3Hz), 4.86-4.92 (m, 1H), 6.66 (d, 1H, J=8.5Hz), 6.87 (brd, 1H, J=1.8Hz), 6.90-6.95 (m, 2H), 6.98 (brs, 1H), 7.29 (d, 1H, J=8.1 Hz); MS (ESI+) : 534([M+NH4]+).
Example 261
Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclohexyl)-propyl]-
3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
Figure imgf000486_0001
(1) Preparation of 4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclohexyl)-propyl]-3- methyl-phenyl}-propyl)-2-methyl-phenol
Figure imgf000486_0002
To a solution of 4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclohexyl)-prop-1-ynyl]- 3-methyl-phenyl}-propyl)-2-methyl-phenol (compound prepared in Example 260- (5)) (18 mg, 0.043 mmol) in AcOEt (1 ml), 10% Pd-C (2 mg) was added and the mixture was stirred at room temperature under hydrogen gas for 15 h. To the mixture, ethyl acetate was added and the mixture was filtered through celite, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (n-hexane/ethyl acetate =3/1 and 1/1) to give the title compound (15.5 mg, 85.3%). 1 H-NMR (chloroform-d): 0.60 (t, 6H, J=7.5Hz), 0.85 (s, 3H), 1.23-1.59 (m, 12H), 1.75-1.84 (m, 1 H), 2.04 (q, 4H, J=7.5Hz), 2.20 (s, 3H), 2.26 (s, 3H), 2.56 (ddd, 1H, J=6.3, 10.0, 13.9Hz), 2.88 (ddd, 1 H, J=5.0, 10.1 , 15.1 Hz), 3.32 (brd, 1 H, J=10.0Hz), 4.71 (brs, 1H), 6.65 (d, 1H, J=8.2Hz), 6.84-6.92 (m, 4H), 7.02 (d, 1H, J=8.6Hz); MS(positive): 440([M+NH4]+).
(2) Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclohexyl)- propyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
Figure imgf000487_0001
To a solution of 4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclohexyl)-propyl]-3- methyl-phenyl}-propyl)-2-methyl-phenol (compound prepared in Example 261- (1)) (15 mg, 0.035 mmol) in DMF (0.4 ml), toluene-4-sulfonic acid (R)-5-oxo- tetrahydro-furan-2-ylmethyl ester (24 mg, 0.089 mmol) and K2CO3 (19.6 mg, 0.142 mmol) was added at room temperature and the mixture was stirred at 60 degrees C for 4 h and at 85 degrees C for 4 h. To the mixture, ethyl acetate was added and the mixture was washed with water and brine, dried over magnesium sulfate, concentrated in vacuo and the obtained residue was chromatographed on silica gel (n-hexane/ethyl acetate =3/1 and 1/1) to give the title compound (9.3 mg, 50.4%). 1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.3Hz), 0.85 (s, 3H), 1.16-1.65 (m, 11 H), 1.73-1.87 (m, 1 H), 2.04 (q, 4H, J=7.3Hz), 2.16 (s, 3H), 2.18 (s, 3H), 2.26-2.63 (m, 4H), 2.73-2.92 (m, 2H), 3.28-3.33 (m, 1 H), 4.07 (dd, 1 H, J=3.5, 10.3Hz), 4.17 (dd, 1H, J=3.4, 10.3Hz), 4.86-4.92 (m, 1H), 6.66 (d, 1H, J=8.3Hz), 6.89-7.03 (m, 5H); MS (ESI+) : 538 ([M+NH4]+).
Example 262
Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclohexyl)-prop-1 - ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000488_0001
Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclohexyl)-prop-1 - ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000488_0002
To a solution of 5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclohexyl)-prop-1- ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one (compound prepared in Example 260-(5)) (4 mg, 0.008 mmol) in THF (0.15 ml) and MeOH (0.05 ml), 1N KOH aq (0.05 ml, 0.05 mmol) was added at room temperature and the mixture was stirred at 65-70 degrees C for 2 h. The mixture was concentrated in vacuo and chromatographed on silica gel (dichloromethane/methanol =10/1) to give the title compound (2.1 mg, 50.7%). 1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.3Hz), 1.07 (s, 3H), 1.40-1.68 (m, 10H), 1.89-2.02 (m, 2H), 2.04 (q, 4H, J=7.3Hz), 2.16 (s, 3H), 2.39 (s, 3H), 2.63 (t, 2H, J=7.2Hz), 3.85 (dd, 1H, J=6.9, 9.2Hz), 3.97 (dd, 1H, J=3.5, 9.2Hz), 4.02-4.16 (m, 1H), 4.35 (s, 1H), 6.67 (d, 1H, J=8.4Hz), 6.87-6.99 (m, 4H), 7.29 (d, 1H, J=8.1Hz); MS (ESI-) : 533([M-H]").
Example 263 Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclohexyl)-propyl]- 3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000488_0003
Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclohexyl)-propyl]- 3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000489_0001
To a solution of 5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclohexyl)-propyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
(compound prepared in Example 261) (8.7 mg, 0.017 mmol) in THF (0.3 ml) and MeOH (0.1 ml), 1 N KOH aq (0.1 ml, 0.1 mmol) was added at room temperature and the mixture was stirred at 65-70 degrees C for 2 h. The mixture was concentrated in vacuo and chromatographed on silica gel (dichloromethane/methanol =10/1) to give the title compound (3.7 mg, 41.1%). 1H-NMR (chloroform-d): 0.60 (t, 6H, J=7.2Hz), 0.85 (s, 3H), 1.15-1.59 (m, 11 H), 1.74-1.84 (m, 1 H), 1.89-1.99 (m, 2H), 2.04 (q, 4H, J=7.3Hz), 2.17 (s, 3H), 2.26 (s, 3H), 2.51-2.60 (m, 1 H), 2.62 (dt, 2H, J=1.6, 7.1 Hz), 2.87 (ddd, 1H, J=4.8, 10.1, 13.9Hz), 3.31 (brd, 1H, J=9.1Hz), 3.85 (dd, 1H, J=6.7, 9.2Hz), 3.98 (dd, 1 H, J=3.5, 9.2Hz), 4.04-4.11 (m, 1 H), 6.67 (d, 1 H, J=8.2Hz), 6.89-6.97 (m, 4H), 7.02 (d, 1 H, J=8.6Hz); MS (ESI-) : 537([M-HT).
Example 264
Preparation of 4-(4-{1 -Ethyl-1 -[4-((S)-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-benzoic acid
Figure imgf000489_0002
(1) Preparation of 4-[4-(1-{4-[(S)-3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxymethyl]-benzoic acid methyl ester
Figure imgf000490_0001
To a solution of 4-(1-{4-[(S)-3-(tert!Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenol (compound prepared in
Example 187-(1)) (45 mg, 0.091 mmol) in DMF (0.9 ml), methyl 4- (bromomethyl)benzoate (52 mg, 0.226 mmol) and K2C03 (50 mg, 0.362 mmol) were added at room temperature and the mixture was stirred at 110 degrees C for 13 h. To the mixture, ethyl acetate was added and the mixture was washed with brine, dried over magnesium sulfate, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (n-hexane/ethyl acetate =10/1 ) to give the title compound (33.6 mg, 57.5%).
1 H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.62 (t, 6H, J=7.3Hz), 0.89 (s, 9H), 0.95 (s, 9H), 1.52-1.65 (m, 1 H), 1.74-1.85 (m, 1 H), 2.06 (q, 4H, J=7.3Hz), 2.25 (s, 6H), 2.43 (dt, 1 H, J=4.7, 12.3Hz), 2.77 (dt, 1H, J=5.3, 13.6Hz), 3.35 (dd, 1H, J=3.2, 7.2Hz), 3.93 (s, 3H), 5.10 (s, 2H), 6.74 (d, 1H, J=8.8Hz), 6.91-7.01 (m, 5H), 7.52 (d, 2H, J=8.6Hz), 8.06 (d, 2H, J=8.4Hz).
(2) Preparation of 4-(4-{1 -Ethyl-1 -[4-((S)-3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-benzoic acid
Figure imgf000490_0002
To a solution of 4-[4-(1-{4-[(S)-3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenoxymethyl]-benzoic acid methyl ester (compound prepared in Example 264-(1)) (33.6 mg, 0.052 mmol) in THF (0.5 ml), 1.0M TBAF in THF (0.26 ml, 0.26 mmol) was added at room temperature and the mixture was stirred at 70 degrees C for 4 h. To the mixture, ethyl acetate was added and the mixture was washed with diluted potassium hydrogen sulfate aq. and brine, dried over magnesium sulfate, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (dichloromethane/methanol =10/1 and dichloromethane/methanol =15/1) to give the title compound (16.5 mg, 61.3%).
1H-NMR (chloroform-d): 0.61 (t, 6H, J=7.3Hz), 0.90 (s, 9H), 1.45-1.58 (m, 1H), 1.76-1.85 (m, 1 H), 2.05 (q, 4H, J=7.3Hz), 2.25 (s, 3H), 2.26 (s, 3H), 2.56 (ddd, 1H, J=6.0, 10.1, 14.1Hz), 2.88 (ddd, 1H, J=5.1, 10.7, 14.1 Hz), 3.26 (dd, 1H, J=1.5Hz), 5.12 (s, 2H), 6.74 (d, 1H, J=9.1Hz), 6.91-6.97 (m, 4H), 7.03 (d, 1H, J=7.9Hz), 7.56 (d, 2H, J=8.2Hz), 8.13 (d, 2H, J=8.2Hz); MS (ESI-) : 515([M-HT).
Example 265
Preparation of 4-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenylcarbamoyl)-butyric acid
Figure imgf000491_0001
(1 ) Preparation of 3-m-Tolyl-pentan-3-ol
Figure imgf000491_0002
To a solution of 3-Methyl-benzoic acid methyl ester (5 g, 33.29 mmol) in THF (50 ml) at 0 degrees C was added EtMgBr (3M in Et 0, 33 ml) and the mixture was stirred at 0 degrees C for 1 h. The reaction mixture was poured into sat. NH4CI aq. and the products were extacted with AcOEt. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure to give the title compound (5.67 g, 96%). 1H NMR (CDCI3): 0.76 (6H, t, J = 7.59 Hz), 1.75-1.90 (4H, m), 2.36 (3H, s), 7.03 (1 H, d, J = 7.42 Hz), 7.12-7.26 (3H, m)
(2) Preparation of 4-(1 -Ethyl-1 -m-tolyl-propyl)-2-methyl-phenol
Figure imgf000492_0001
To a solution of 3-m-Tolyl-pentan-3-ol (5.57 g, 31 24 mmol) (compound prepared in Example 265-(1))in toluene (50 ml) were added cresol (12.5 ml, 93.73 mmol) and AICI3 (4.58 g, 34.36 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 N-HCI and the products were extacted with CH2CI2. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with CH2CI2 to give the title compound (8 g, 95%) as colorless oil.
1H NMR (CDCI3): 0.60 (6H, t, J = 7.26 Hz), 2.00-2.09 (4H, q, J = 7.25 Hz), 2.19 (3H, s), 2.29 (3H, s), 4.57 (1H, s), 6.63-7.13 (7H, m)
(3) Preparation of Trifluoro-methanesulfonic acid 4-(1 -ethyl-1 -m-tolyl-propyl)-2- methyl-phenyl ester
Figure imgf000492_0002
To a solution of 4-(1 -Ethyl-1 -m-tolyl-propyl)-2-methyl-phenol (compound prepared in Example 265-(2)) (400mg, 1.490 mmol) were added Tf20 (0.276 ml, 1.639 mmol) and Et3N (0.310 ml, 2.235 mmol) and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into sat. NaHCθ3 aq. and the products were extacted with CH2CI2. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n- Hexane-AcOEt (1:1) to give the title compound (412 mg, 69%) as colorless oil. 1H NMR (CDCI3): 0.60 (6H, t, J = 7.25 Hz), 2.07 (4H, q, J = 7.42 Hz), 2.30 (3H, s), 2.32 (3H, s), 6.92-7.18 (7H, m) (4) Preparation of Trifluoro-methanesulfonic acid 4-[1 -ethyl-1 -(3-methyl-4-nitro- phenyl)-propyl]-2-methyl-phenyl ester
Figure imgf000493_0001
To a solution of Trifluoro-methanesulfonic acid 4-(1 -ethyl-1 -m-tolyl-propyl)-2- methyl-phenyl ester (compound prepared in Example 265-(3)) (100 mg, 0.250 mmol) in MeCN (3 ml) at 0 degrees C was added N02BF4 (40 mg, 0.300 mmol) and the mixture was stirred at 0 degrees C for 15 min. The reaction mixture was poured into sat. NaHC03 aq. and the products were extacted with CH2CI2. The extracts were washed with brine, dried over MgS0 , filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane-AcOEt (10:1) to give the title compound (42.2 mg, 38%) as colorless oil. 1H NMR (CDCI3): 0.62 (6H, t, J = 7.42 Hz), 2.11 (4H, q, J = 7.42 Hz), 2.33 (3H, s), 2.58 (3H, s), 6.98-7.18 (5H, m), 7.91 (1H, d, J = 9.06 Hz)
(5) Preparation of Trifluoro-methanesulfonic acid 4-[1 -(4-amino-3-methyl- phenyl)-1 -ethyl-propyl]-2-methyl-phenyl ester
Figure imgf000493_0002
To a solution of Trifluoro-methanesulfonic acid 4-[1 -ethyl-1 -(3-methyl-4-nitro- phenyl)-propyl]-2-methyl-phenyl ester (compound prepared in Example 265-(4)) (130 mg, 0.292 mmol) in MeOH (3 ml) was added Pd/C (10%, 20 mg) and the mixture was stirred at room temperature under H2 atmosphere for 1.5 h. The mixture was filtered through celite and concentrated under reduced pressure to give the title compound (113.2 mg, 93%).
1H NMR (CDCI3): 0.59 (6H, t, J = 7.25 Hz), 2.02 (4H, q, J = 7.42 Hz), 2.12 (3H, s), 2.31 (3H, s), 6.58 (1H, d, J = 8.91 Hz), 6.77-6.83 (2H, m), 7.04-7.12 (3H, m) (6) Preparation of 4-{4-[1 -Ethyl-1 -(3-methyl-4-trifluoromethanesulfonyloxy- phenyl)-propyl]-2-methyl-phenylcarbamoyl}-butyric acid methyl ester
Figure imgf000494_0001
To a solution of Trifluoro-methanesulfonic acid 4-[1-(4-amino-3-methyl-phenyl)-1- ethyl-propyl]-2-methyl-phenyl ester (compound prepared in Example 265-(5)) (113 mg, 0.272 mmol) in CH2CI2 (3 ml) were added glutaric acid mono methyl ester (60 mg, 0.409 mmol), EDC (104 mg, 0.544 mmol) and Et3N (0.113 ml, 0.816 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was poured into sat. NaHCθ3 aq. and the products were extacted with CH2CI2. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane-AcOEt (1 :1) to give the title compound (111.5 mg, 75%) as colorless oil.
1H NMR (CDCI3): 0.60 (6H, t, J = 7.25 Hz), 2.00-2.15 (6H, m), 2.21 (3H, s), 2.31 (3H, s), 2.41-2.50 (4H, m), 3.69 (3H, s), 6.91 (1 H, s), 6.97-7.15 (5H, m), 7.74 (1 H, d, J = 8.41 Hz)
(7) Preparation of tert-Butyl-(1 -tert-butyl-prop-2-ynyloxy)-dimethyl-silane
Figure imgf000494_0002
To a solution of 4,4-Dimethyl-pent-1-yn-3-ol (J. Org. Chem. 53; 20; 1988; 4736- 4745) (360 mg, 3.209 mmol) in CH2CI2 (10 ml) were added TBSOTf (0.884 ml, 3.851 mmol) and imidazole (437 mg, 6.418 mmol) and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into sat. NaHC03 aq. and the products were extacted with CH2CI2. The extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n- Hexane-AcOEt (7:3) to give the title compound (314 mg, 43%) as colorless oil. 1H NMR (CDCI3): 0.02 (3H, s), 0.09 (3H, s), 0.91 (9H, s), 0.95 (9H, s), 2.34 (1H, s), 3.95 (1 H, s)
(8) Preparation of 4-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pent- 1 -ynyl]-3-methyl-phenyl}-1 -ethyl-propyl)-2-methyl-phenylcarbamoyl]-butyric acid methyl ester
Figure imgf000495_0001
To a solution of 4-{4-[1 -Ethyl-1 -(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)- propyl]-2-methyl-phenylcarbamoyl}-butyric acid methyl ester (compound prepared in Example 265-(6)) (111 mg, 0.204 mmol) in DMF (3 ml) were added tert-Butyl-(1-tert-butyl-prop-2-ynyloxy)-dimethyl-silane (compound prepared in Example 265-(7)) (92 mg, 0.408 mmol), PdCI2(dppf)-CH2CI2 (18 mg, 0.022 mmol), Cul (7.8 mg, 0.041 mmol) and Et3N (0.085 ml, 0.612 mmol) and the mixture was stirred under nitrogen atmosphere at 100 degrees C overnight. The reaction mixture was poured into sat. NH4CI aq. and the products were extacted with AcOEt. The extracts were washed with brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with n-Hexane-AcOEt (1:1) to give the title compound (50 mg, 40%) as colorless oil.
1H NMR (CDCI3): 0.10 (3H, s), 0.12 (3H, s), 0.60 (6H, t, J = 7.26 Hz), 0.93 (9H, s), 1.01 (9H, s), 2.00-2.13 (6H, m), 2.20 (3H, s), 2.36 (3H, s), 2.42-2.50 (4H, m), 3.69 (3H, s), 6.90-7.07 (5H, m), 7.25 (1 H, d, J = 7.92 Hz), 7.71 (1 H, d, J = 8.24 Hz)
(9) Preparation of 4-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pent- 1 -ynyl]-3-methyl-phenyl}-1 -ethyl-propyl)-2-methyl-phenylcarbamoyl]-butyric acid and 4-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenylcarbamoyl)-butyric acid
Figure imgf000496_0001
To a solution of 4-[4-(1 -{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pent-1 - ynyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenylcarbamoyl]-butyric acid methyl ester (compound prepared in Example 265-(8)) (50 mg, 0.081 mmol) in THF-H20 (10:1, 3.3 ml) was added CSA (56 mg, 0.243 mmol) and the mixture was stirred at 70 degrees C for 6 h. The reaction mixture was poured into sat. NaHC03 aq. and the products were extacted with CH2CI2. The extracts were washed with brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with CHCI3- MeOH (10:1) to give 4-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl- pent-1-ynyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenylcarbamoyl]-butyric acid (21.4 mg, 44%) and 4-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenylcarbamoyl)-butyric acid (6.4 mg, 16%). 4-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pent-1-ynyl]-3-methyl- phenyl}-1-ethyl-propyl)-2-methyl-phenylcarbamoyl]-butyric acid ; 1H NMR (CDCI3): 0.12 (3H, s), 0.18 (3H, s), 0.59 (6H, t, J = 7.26 Hz), 0.92 (9H, s), 1.01 (9H, s), 2.00-2.15 (6H, m), 2.19 (3H, s), 2.36 (3H, s), 2.43-2.57 (4H, m), 6.95- 7.05 (5H, m), 7.25 (1H, d), 7.68 (1 H, d, J = 8.41 Hz)
4-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenylcarbamoyl)-butyric acid ; 1H NMR (CDCI3): 0.59 (6H, t, J = 7,42 Hz), 1.06 (9H, s), 2.00-2.13 (6H, m), 2.18 (3H, s), 2.37 (3H, s), 2.43-2.57 (4H, m), 6.90-7.04 (5H, m), 7.28 (1 H, d), 7.68 (1 H, d, J = 8.24 Hz) ; MS (ESI+) : 474 ([M+H-H20]+). Example 266
Preparation of 4-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenylcarbamoyl)-butyric acid
Figure imgf000497_0001
Preparation of 4-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenylcarbamoyl)-butyric acid methyl ester
Figure imgf000497_0002
To a solution of 4-[4-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pent-1- ynyl]-3-methyl-phenyl}-1 -ethyl-propyl)-2-methyl-phenylcarbamoyl]-butyric acid (compound prepared in Example 265-(9)) (21.4 mg, 0.035 mmol) in MeOH (3 ml) was added Pd(OH)2 (10%, 30 mg) and the mixture was stirred at room temperature under H2 atmosphere overnight. The mixture was filtered through celite and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with CHCl3-MeOH (10:1) to give the title compound (13.5 mg, 76%).
1H NMR (CDCI3): 0.60 (6H, t, J = 7.26 Hz), 0.89 (9H, s), 1.45-1.55 (1 H, m), 1.72- 1.88 (1 H, m), 2.00-2.10 (6H, m), 2.20 (3H, s), 2.25 (3H, s), 2.41-2.50 (4H, m), 2.52-2.62 (1H, m), 2.80-2.92 (1H, m), 3.20-3.30 (1H, m), 3.69 (3H, s), 6.88-7.05 (5H, m), 7.69 (1 H, d, J = 8.74 Hz); MS (ESI+) : 510 [(M+H)+].
(2) Preparation of 4-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenylcarbamoyl)-butyric acid
Figure imgf000497_0003
To a solution of 4-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenylcarbamoyl)-butyric acid methyl ester (compound prepared in Example 266-(1)) (11.4 mg, 0.022 mmol) in MeOH (1 ml) was added 1N-NaOH (0.22 ml, 0.220 mmol) and the mixture was stirred at room temperature overnight. The mixture was poured into 1 N-HCI and the products were extacted with CH2CI2. The extracts were washed with brine, dried over MgSθ4, filtered and concentrated under reduced pressure. The obtained residue was chromatographed on silica gel with CHCI3-MeOH (10:1) to give the title compound (7.3 mg, 67%).
1H NMR (CDCI3): 0.60 (6H, t, J = 7.25 Hz), 0.89 (9H, s), 1.40-1.62 (1H, m), 1.70- 1.90 (1H, m), 2.00-2.13 (6H, m), 2.19 (3H, s), 2.25 (3H, s), 2.44-2.62 (5H, m), 2.79-2.95 (1 H, m), 3.22-3.27 (1H, m), 6.86-7.05 (5H, m), 7.65 (1H, d, J = 8.24 Hz); MS (ESI+) : 496 [(M+H)+].
Example 267
Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopropyl)-prop-1 ■ ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000498_0001
(1) Preparation of 3-(4-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-1 -(1 -methyl-cyclopropyl)-prop-2-yn-1 -ol
Figure imgf000498_0002
To a solution of compound prepared in Example 260-(2) (tert-Butyl-{4-[1 -ethyl-1 - (4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenoxy}-dimethyl-silane) (188 mg, 0.46 mmol) in THF (3 ml), 1.58M n-BuLi in hexane (0.35 ml, 0.55 mmol) was added at -78 degrees C and the mixture was stirred at -78 degrees C for 10min. To the mixture, 1-Methyl-cyclopropanecarbaldehyde (J. Org. Chem. 64, 26, 1999, 9587 - 9595) (0.2 ml) was added at -78 degrees C and the mixture was stirred at room temperature for 16h. To the mixture, H2O and ethyl acetate were added and the mixture was washed with H20, dried over MgS04, concentrated in vacuo and the obtained residue was chromatographed ethyl acetate/n-hexane =0/100 to 3/7) to give the title compound (126 mg, 56%).
1H-NMR: 0.19 (s, 6H), 0.40 (q, 2H), 0.58 (t, 6H), 0.67-0.72 (m, 2H), 1.00 (s, 9H), 1.27 (s, 3H), 2.01 (q, 4H), 2.14 (s, 3H), 2.37 (s, 3H), 4.26 (d, 1H), 6.61 (d, 1H), 6.77-7.00 (m, 4H), 7.26 (s, 1H)
(2) Preparation of 4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopropyl)-prop-1 - ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol (Enantiomer A, Enantiomer B)
Figure imgf000499_0001
To a solution of tert-butyl-{4-[1 -ethyl-1 -(4-ethynyl-3-methyl-phenyl)-propyl]-2- methyl-phenoxyj-dimethyl-silane (90 mg, 0.184 mmol) in THF (2 ml), 1M TBAF in THF (0.1 ml) was added at room temperature, and the mixture was stirred at room temperature for 1h and concentrated in vacuo. The obtained residue was chromatographed (ethyl acetate/n-hexane = 0/100 to 1/1) to give the mixture of title compounds (47 mg). The racemic mixture was separated with chiral HPLC (CHIRALPAK OJ-H [DAICEL, 20mml.D., 250mm], ethanol/n-hexane = 10/90) to obtain each enantiomer (Enantiomer A : 20 mg, 100% ee, / Enantiomer B : 15 mg, 100%ee).
Enantiomer A: Retention time: 11.874min., Enantiomer B: Retention time: 13.291min. Column: CHIRALPAK OJ-H 4.6x150mm (DAICEL) Eluent: A: n-hexnane, B: EtOH, %B 1 (0min) - 70 (15min) Flow rate: 0.5ml/min.
1H-NMR for mixture Enantiomer A and Enantiomer B: 0.41 (q, 2H), 0.59 (t, 6H), 0.67-0.72 (m, 2H), 1.27 (s, 3H), 2.02 (q, 4H), 2.18 (s, 3H), 2.37 (s, 3H), 4.26 (d, 1 H), 4.67 (s, 1 H), 6.64 (d, 1 H), 6.80-7.00 (m, 4H), 7.26 (d, 1 H) ; MS for mixture Enantiomer A and Enantiomer B (negative mode): 375([M-H]")
(3) Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclopropyl)- prop-1 -ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2- one
Figure imgf000500_0001
To a solution of 4-(1 -ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopropyl)-prop-1 -ynyl]- 3-methyl-phenyl}-propyl)-2-methyl-phenol (Enantiomer A) (10 mg, 0.0266 mmol) in DMF (0.5 ml), K2C03 (10 mg, 0.0725 mmol) and toluene-4-sulfonic acid (R)-5- oxo-tetrahydro-furan-2-ylmethyl ester (10 mg, 0.0756 mmol) were added at room temperature and the mixture was stirred at 90 degrees C for 64 h. To the mixture, ethyl acetate was added and the mixture was washed with H20, dried over MgS04, concentrated in vacuo and the obtained residue was purified by preparative TLC (n-hexane:ethyl acetate=1:1 and CH2CI :MeOH=20:1) to give the title compound (6.7 mg, 53%).
1H-NMR: 0.41 (q, 2H), 0.59 (t, 6H), 0.61-0.69 (m ,2H), 1.25 (s, 3H), 1.83 (d, 1 H), 2.02 (q, 4H), 2.14 (s, 3H), 2.37 (s, 3H), 2.38-2.83 (m ,4H), 4.04-4.28 (m, 3H), 4.84-4.92 (m, 1 H), 6.66 (d, 1 h), 6.82-6.98 (m, 4H), 7.25 (d, 1 H); MS (ESI+) : 457 ([M-OH]+). (4) Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclopropyl)- prop-1-ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000501_0001
To a solution of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopropyl)-prop- 1-ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one (prepared in Example 267-(3)) (6.7 mg, 0.014 mmol) in MeOH (0.5 ml) and THF (0.5 ml), INNaOH (0.1 ml) was added at room temperature and the mixture was stirred at room temperature for 1h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (3.3 mg, 47%).
1H-NMR: 0.41 (q, 4H), 0.60 (t, 6H), 0.64-0.69 (m, 2H), 1.26 (s, 3H), 1.90-2.05 (m, 7H), 2.16 (s, 3H), 2.37 (s, 3H), 2.62 (t, 2H), 3.83-4.10 (m, 3H), 4.25 (s, 1H), 6.66 (s, 1H), 6.83-7.02 (m, 3H), 7.29 (s, 1H); MS (ESI-) : 491 ([M-H]-).
Example 268
Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopropyl)-prop-1 - ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000501_0002
Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopropyl)-prop-1 ■ ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
Figure imgf000502_0001
To a solution of compound prepared in Example 267-(2) (4-(1 -ethyl-1 -{4-[3- hydroxy-3-(1-methyl-cyclopropyl)-prop-1-ynyl]-3-methyl-phenyl}-propyl)-2- methyl-phenol (Enantiomer B) ) (8 mg, 0.0213 mmol) in DMF (0.5 ml), K2C03 (10 mg, 0.0725 mmol) and toluene-4-sulfonic acid (R)-5-oxo-tetrahydro-furan-2- ylmethyl ester (10 mg, 0.0756 mmol) were added at room temperature and the mixture was stirred at 90 degrees C for 64 h. To the mixture, ethyl acetate was added and the mixture was washed with H20, dried over MgS04, concentrated in vacuo and the obtained residue was purified by preparative TLC (n-hexane:ethyl acetate=1 :1 and CH2CI2:MeOH=20:1) to give the title compound (4.9 mg, 49%). 1H-NMR: 0.41 (q, 2H), 0.59 (t, 6H), 0.61-0.69 (m ,2H), 1.26 (s, 3H), 1.82 (d, 1 H), 2.02 (q, 4H), 2.14 (s, 3H), 2.37 (s, 3H), 2.38-2.83 (m ,4H), 4.04-4.30 (m, 3H), 4.84-4.92 (m, 1 H), 6.65 (d, 1h), 6.84-6.72 (m, 4H), 7.25 (d, 1H); MS (ESI+) : 457 «M-OH]+).
(2) Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclopropyl)- prop-1-ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000502_0002
To a solution of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclopropyl)-prop- 1-ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one (prepared in Example 268-(1)) (4.9 mg, 0.010 mmol) in MeOH (0.5 ml) and THF (0.5 ml), I NNaOH (0.1 ml) was added at room temperature and the mixture was stirred at room temperature for 1 h. The mixture concentrated in vacuo, and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (1.3 mg, 25%).
1H-NMR: 0.41 (q, 4H), 0.59 (t, 6H), 0.64-0.69 (m, 2H), 1.27 (s, 3H), 1.90-2.05 (m, 7H), 2.16 (s, 3H), 2.37 (s, 3H), 2.62 (t, 2H), 3.81-4.10 (m, 3H), 4.26 (s, 1H), 6.66 (s, 1H), 6.85-7.00 (m, 3H), 7.27 (s, 1H); MS (ESI-) : 491 ([M-H]-).
Example 269
Preparation of (R)- 5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopropyl)- propyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000503_0001
(1 ) Preparation of 4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopropyl)-propyl]-3- methyl-phenyl}-propyl)-2-methyl-phenol
Figure imgf000503_0002
Enantiomer A Enantiomer 1
To a solution of compound prepared in Example 267-(2) (4-(1 -ethyl-1 -{4-[3- hydroxy-3-(1-methyl-cyclopropyl)-prop-1-ynyl]-3-methyl-phenyl}-propyl)-2- methyl-phenol (Enantiomer A) ) (15 mg, 0.0399 mmol) in ethyl acetate (2 ml), palladium carbon (5 mg) was added at room temperature and the mixture was stirred at room temperature for 3h under hydrogen gas. The mixture was filtrated through silica and concentrated in vacuo to give the title compound (15 mg, 100%).
1H-NMR: 0.30-0.40 (m, 4H), 0.59 (t, 3H), 1.05 (s, 3H), 1.76-1.84 (m, 2H), 2.03 (q, 4H), 2.19 (s, 3H), 2.25 (s, 3H), 2.53-2.80 (m, 2H), 2.89 (t, 1H), 4.68 (s, 1H), 6.64 (d, 1H), 6.82-7.04 (m, 5H); MS (ESI-) : 379 ([M-H]-). (2) Preparation of (R)- 5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclopropyl)- propyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
Figure imgf000504_0001
Enantiomer 1 To a solution of 4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopropyl)-propyl]-3- methyl-phenyl}-propyl)-2-methyl-phenol (Enantiomer 1 prepared in Example 269- (1)) (15 mg, 0.0395 mmol) in DMF (0.5 ml), K2C03 (10 mg, 0.0725 mmol) and toluene-4-sulfonic acid (R)-5-oxo-tetrahydro-furan-2-ylmethyl ester (10 mg, 0.0756 mmol) were added at room temperature and the mixture was stirred at 90 degrees C for 64 h. To the mixture, ethyl acetate was added and the mixture was washed with H20, dried over MgS04, concentrated in vacuo and the obtained residue was purified by preparative TLC (n-hexane:ethyl acetate=1:1 and CH2CI2:MeOH=20:1) to give the title compound (5.2 mg, 28%). 1H-NMR: 0.28-0.42 (m, 4H), 0.59 (t, 6H), 1.05 (s, 3H), 1.26 (t, 1 H), 1.78-1.84 (m, 2H), 2.02 (q, 4H), 2.17 (s, 3H), 2.25 (s, 3H), 2.29-2.92 (m, 6H), 4.01-4.20 (m, 2H), 4.82-4.92 (m, 1H), 6.66 (d, 1H), 6.89-7.04 (m, 5H); MS (ESI+) : 496 ([M+NH4]+).
(3) Preparation of (R)- 5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopropyl)- propyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000504_0002
To a solution of ((R)- 5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopropyl)- propyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one) (prepared in Example 269-(2))(5.2 mg, 0.011 mmol) in MeOH (0.5 ml) and THF (0.5 ml), 1 NNaOH (0.1 ml) was added at room temperature and the mixture was stirred at room temperature for 1h. The mixture was concentrated in vacuo, and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (3.9 mg, 73%).
1H-NMR: 0.32-0.42 (m, 4H), 0.59 (t, 6H), 1.05 (s, 3H), 1.78-1.85 (m ,2H), 1.90- 2.00 (m, 2H), 2.05 (q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.56-2.91 (m, 5H), 3.82- 4.15 (m, 3H), 6.67 (d, 1H), 6.89-7.01 (m, 5H); MS (ESI-) : 495 ([M-H]").
Example 270
Preparation of (R)- 5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopropyl)- propyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000505_0001
Preparation of 4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopropyl)-propyl]-3- methyl-phenyl}-propyl)-2-methyl-phenol
Figure imgf000505_0002
Enantiomer B Enantiomer 2
To a solution of compound prepared in Example 267-(2) (4-(1 -ethyl-1 -{4-[3- hydroxy-3-(1-methyl-cyclopropyl)-prop-1-ynyl]-3-methyl-phenyl}-propyl)-2- methyl-phenol (Enantiomer B) ) (10 mg, 0.0266 mmol) in ethyl acetate (2 ml), palladium carbon (5 mg) was added at room temperature and the mixture was stirred at room temperature for 3h under hydrogen gas. The mixture was filtrated through silica and concentrated in vacuo to give the title compound (10 mg, 100%).
1H-NMR: 0.30-0.40 (m, 4H), 0.59 (t, 3H), 1.05 (s, 3H), 1.76-1.84 (m, 2H), 2.04 (q, 4H), 2.19 (s, 3H), 2.23 (s, 3H), 2.53-2.80 (m, 2H), 2.88 (t, 1H), 4.80 (s, 1H), 6.64 (d, 1H), 6.82-7.03 (m, 5H); MS (ES!-) : 379 ([M-H]"). (2) Preparation of (R)- 5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclopropyl)- propyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
Figure imgf000506_0001
Enantiomer 2 To a solution of 4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclopropyl)-propyl]-3- methyl-phenyl}-propyl)-2-methyl-phenol4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl- cyclopropyl)-propyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol (Enantiomer 2 prepared in Example 270-(1)) (10 mg, 0.0263 mmol) in DMF (0.5 ml), K2C03 (10 mg, 0.0725 mmol) and toluene-4-sulfonic acid (R)-5-oxo-tetrahydro-furan-2- ylmethyl ester (10 mg, 0.0756 mmol) were added at room temperature and stirred at 90 degrees C for 64 h. To the mixture, ethyl acetate was added and the organic layer was washed with H2O, dried over MgS04, concentrated in vacuo and the obtained residue was purified by preparative TLC (n-hexane:ethyl acetate=1 :1 and CH2Cl2:MeOH=20:1) to give the title compound (6.7 mg, 53%). 1H-NMR: 0.28-0.42 (m, 4H), 0.59 (t, 6H), 1.05 (s, 3H), 1.26 (t, 1 H), 1.78-1.84 (m, 2H), 2.04 (q, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.25-2.95 (m, 6H), 4.01-4.22 (m, 2H), 4.83-4.94 (m, 1H), 6.66 (d, 1H), 6.89-7.04 (m, 5H); MS (ESI+) : 496 ([M+NH4]+).
(3) Preparation of (R)- 5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopropyl)- propyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000506_0002
To a solution of (R)- 5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclopropyl)- propyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one (prepared in Example 270-(2))(6.7 mg, 0.014 mmol) in MeOH (0.5 ml) and THF (0.5 ml), 1 NNaOH (0.1 ml) was added at room temperature and the mixture was stirred at room temperature for 1h. The mixture was concentrated in vacuo, and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (3.6 mg, 52%).
1H-NMR: 0.32-0.41 (m, 4H), 0.59 (t, 6H), 1.05 (s, 3H), 1.26 (s, 1 H), 1.77-1.85 (m ,2H), 1.89-2.00 (m, 2H), 2.02 (q, 4H), 2.17 (s, 3H), 2.25 (s, 3H), 2.58-2.92 (m, 5H), 3.82-4.15 (m, 3H), 6.67 (d, 1H), 6.89-7.01 (m, 5H); MS (ESI-) : 495 ([M-H]').
Example 271
Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-(1 -ethyl-cyclopropyl)-3-hydroxy-propyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000507_0001
(1 ) Preparation of Cyclopropanecarboxylic acid 2, 6-di-tert-butyl-4-methyl-phenyl ester
Figure imgf000507_0002
n-BuLi (2.44 mol/l in hexane) (2 Y2.7 mTmol) w"as added to an ice-cooled solution of 2, 6-Di-t-butyl-p-cresol (5.0 g, 22.7 mmol) in 25 ml of THF. After a period of 15 min, Cyclopropanecarbonyl Chloride (2.5 g, 23.8 mmol) was added and the mixture stirred at room temperature for 24h and poured onto 10 ml of saturated aqueous NH4CI. After separation of the layers, the aqueous layer was extracted with 25 ml of ether, and the organic phase were combined and washed with saturated aqueous NaHC03 and brine, dried over MgS04, and concentrated in vacuo. The residue was chromatographed on silica gel (ethyl acetate/hexane = 0/100 to 10/90) to give the title compound (5.6 g, 85%). 1H-NMR: 1.00-1.07 (m, 2H), 1.13-1.18 (m, 2H), 1.34 (s, 18H), 1.89-1.97 (m, 1H), 2.31 (s, 3H), 7.10 (s, 2H); MS (ESI+) : 306 ([M+NH4]+).
(2) Preparation of 1-Ethyl-cyclopropanecarboxylic acid 2,6-di-tert-butyl-4-methyl- phenyl ester
Figure imgf000508_0001
To a solution of Cyclopropanecarboxylic acid 2, 6-di-tert-butyl-4-methyl-phenyl ester (compound prepared in Example 271 -(1)) (3.0 g, 10.4 mmol) in THF (20 ml) was added t-BuLi (1.47 mol/l in n-pentane) (11.4 mmol) at -78 degrees C. The solution was stirred under N2for 30 min, and Ethyl Iodide (1.9 g, 12.5 mmol, dissolved in 3 ml of THF) was added. The solution was allowed to warm to room temperature within 4h. The reaction was quenched with saturated aqueous NH4CI. The mixture was diluted with Et.20, washed with saturated aqueous NH4CI and brine, dried over MgS04, and concentrated in vacuo to give the title compound (320 mg, 37%).
1 H-NMR: 0.89-0.93 (m, 2H), 1.05 (t, J=7.3 Hz, 3H), 1.32 (s, 18H), 1.45-1.52 (m, 2H), 1.82 (q, J=7.3 Hz, 2H), 2.30 (s, 3H), 7.09 (s, 2H)
(3) Preparation of 1-Ethyl-cyclopropanecarboxylic acid
Figure imgf000508_0002
A suspension of 1-Ethyl-cyclopropanecarboxylic acid 2,6-di-tert-butyl-4-methyl- phenyl ester (compound prepared in Example 271 -(2)) (2.41 g, 7.6 mmol), t- BuOK (5.13 g, 45.7 mmol), and H20 (274 mg, 15.2 mmol) in 38 ml of THF was heated under reflux for 36h. After extraction with 2N KOH, the H20 phase was acidified with concentrated HCl, extracted with Et20. The extracts were dried over MgSθ4 and concentrated in vacuo and the obtained residue was chromatographed on silica gel (Et20/n-pentane = 3/97) to give the title compound (2.41 g, 73%).
1H-NMR: 0.73-0.81 (m, 2H), 1.01 (t, J=7.3 Hz, 3H), 1.22-1.30 (m, 2H), 1.56 (q, J=7.3 Hz, 2H); MS (ESI+) : 251 ([2xM+Na]+).
(4) Preparation of 1-Ethyl-cyclopropanecarboxylic acid N-methoxy-N-methyl- amide
Figure imgf000509_0001
To a solution of 1-Ethyl-cyclopropanecarboxylic acid (compound prepared in Example 271 -(3)) (320 mg, 2.8 mmol) in dichloromethane (10 ml) was added methoxymethylamine hydrochloride (328 mg, 3.4 mmol), 4- dimethylaminopyridine (171 mg, 1.4 mmol), triethyamine (793 mg, 7.8 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (751 mg, 3.9 mmol) at 0 degrees C. The solution was stirred under N2 for 20h, and diluted with ethyl acetate, washed with 1 N HCl, saturated aqueous NaHC03 and brine, dried over MgS04, and concentrated in vacuo. The residue was chromatographed on silica gel (ethyl acetate/hexane = 0/100 to 40/60) to give the title compound (200 mg, 45%).
1H-NMR: 0.55-0.57 (m, 2H), 0.93-1.02 (m, 5H), 1.59 (q, J=7.7 Hz, 2H), 3.25 (s, 3H), 3.72 (s, 3H); MS (ESI+) : 158([M+H]+).
(5) Preparation of 3-(4-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-1-(1-ethyl-cyclopropyl)-prop-2-yn-1-one
Figure imgf000509_0002
To a solution of tert-Butyl-{4-[1 -ethyl-1 -(4-ethynyl-3-methyl-phenyl)-propyl]-2- methyl-phenoxyj-dimethyl-silane (compound prepared in Example 260-(1)) (345 mg, 0.85 mmol) in THF (2 ml) was added n-BuLi (2.44 mol/l in hexane) (1.19 mmol) at -78 degrees C. The solution was stirred at room temperature under N2 for 20 min. The solution was cooled to -78 degrees C, and added THF solution (0.5 ml) of 1-Ethyl-cyclopropanecarboxylic acid N-methoxy-N-methyl-amide (compound prepared in Example 271-(4)) (200 mg, 1.27 mmol). The solution was allowed to warm to room temperature overnight. The reaction was quenched with saturated aqueous NH4CI, extracted with ethyl acetate, washed with brine, dried over MgS04, and concentrated in vacuo. The residue was chromatographed on silica gel (ethyl acetate/hexane = 0/100 to 5/95) to give the title compound (380 mg, 89%).
1H-NMR: 0.20 (s, 6H), 0.59 (t, J=7.0 Hz, 6H), 0.95-1.06 (m, 14H), 1.51-1.56 (m, 2H), 1.73 (q, J= 7.3 Hz, 2H), 2.03 (q, J=7.0 Hz, 4H), 2.14 (s, 3H), 2.41 (s, 3H), 6.63 (d, J=8.4 Hz, 1 H), 6.79 (d, J=8.1 Hz, 1 H), 6.84 (s, 1H), 6.99 (d, J=8.1 Hz, 1 H), 7.04 (s, 1 H), 7.38 (d, J=8.1 Hz, 1 H); MS (ESI+) : 503([M+H] +).
(6) Preparation of 3-(4-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-1 -(1 -ethyl-cyclopropyl)-prop-2-yn-1 -ol
Figure imgf000510_0001
To a solution of 3-(4-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-1 -(1 -ethyl-cyclopropyl)-prop-2-yn-1 -one (compound prepared in Example 271 -(5)) (380 mg, 0.76 mmol) in THF/MeOH (4 ml/4 ml) was added NaBH4 (86 mg, 2.28 mmol) at room temperature. The solution was stirred at room temperature under N2 for 1 h, quenched with H2O, and extracted with ethyl acetate, washed with brine, dried over MgSθ4, and concentrated in vacuo. The residue was chrornatographed on silica gel (ethyl acetate/hexane = 0/100 to 10/90) to give the title compound (350 mg, 91%). 1H-NMR: 0.19 (s, 6H), 0.35-0.46 (m, 2H), 0.58 (t, J=7.3 Hz, 6H), 0.68-0.78 (m, 2H), 0.95-1.03 (m, 12H), 1.30-1.40 (m, 1H), 1.74 (d, J=7.0 Hz, 1 H), 1.87-1.96 (m, 1H), 2.03 (q, J=7.0 Hz, 4H), 2.14 (s, 3H), 2.36 (s, 3H), 4.63 (d, J=7.0 Hz, 1 H), 6.62 (d, J=8.4 Hz, 1 H), 6.79 (d, J=8.8 Hz, 1 H), 6.85 (s, 1 H), 6.92 (d, J=8.1 Hz, 1 H), 6.99 (s, 1H), 7.25 (m, 1 H); MS (ESI-) : 503([M-H]-).
(7) Preparation of 4-(1 -Ethyl-1 -{4-[3-(1-ethyl-cyclopropyl)-3-hydroxy-prop-1-ynyl]- 3-methyl-phenyl}-propyl)-2-methyl-phenol
Figure imgf000511_0001
To a solution of 3-(4-{1 -[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1 - ethyl-propyl}-2-methyl-phenyl)-1 -(1-ethyl-cyclopropyl)-prop-2-yn-1 -ol (compound prepared in Example 271 -(6)) (350 mg, 0.69 mmol) in THF (7 ml) was added tetrabutylammonium fluoride (1 M in THF) (1.0 mmol) at room temperature. The solution was stirred at room temperature under N2 for 30 min, and diluted with ethyl acetate, washed with diluted KHSO4 and brine, dried over MgSθ4, and concentrated in vacuo. The residue was chromatographed on silica gel (ethyl acetate/hexane = 0/100 to 40/60) to give the title compound (240 mg, 89%). 1 H-NMR: 0.35-0.46 (m, 2H), 0.59 (t, J=7.3 Hz, 6H), 0.68-0.78 (m, 2H), 0.97 (t, j=7.7 Hz, 3H), 1.29-1.41 (m, 1 H), 1.74 (d, J=7.0 Hz, 1 H), 1.87-1.97 (m, 1H), 2.02 (q, J=7.3 Hz, 4H), 2.19 (s, 3H), 2.36 (s, 3H), 4.57 (d, J=4.4 Hz, 1 H), 4.63 (d,
J=6.6 Hz, 1 H), 6.65 (d, J=8.1 Hz, 1H), 6.83-6.88 (m, 2H), 6.92 (d, J=8.1 Hz, 1H), 6.99 (s, 1H), 7.28-7.30 (m, 1H); MS (ESI-) : 389([M-HT).
(8) Preparation of 4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1-ethyl-cyclopropyl)-propyl]-3- methyl-phenyl}-propyl)-2-methyl-phenol
Figure imgf000511_0002
A solution of 4-(1 -Ethyl-1 -{4-[3-(1 -ethyl-cyclopropyl)-3-hydroχy-prop-1 -ynyl]-3- methyl-phenyl}-propyl)-2-methyl-phenol (compound prepared in Example 271- (7)) (38 mg, 0.097 mmol) in AcOEt/MeOH (1 ml/1 ml) was hydrogenated on 10% palladium on carbon (5 mg) as catalyst. After 4h the reaction mixture was filtered through a Celite, the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate/hexane = 1/3) to give the title compound (33 mg, 87%).
1 H-NMR: 0.30-0.42 (m, 4H), 0.59 (t, J=7.3 Hz, 6H), 0.87 (t, J=7.3 Hz, 3H), 1.20- 1.38 (m, 2H), 1.60-1.72 (m, 1 H), 1.73-1.86 (m, 2H), 2.02 (q, J=7.7 Hz, 4H), 2.20 (s, 3H), 2.25 (s, 3H), 2.53-2.62 (m, 1H), 2.72-2.82 (m, 1 H), 3.08-3.15 (m, 1 H), 4.55 (s, 1 H), 6.64 (d, J=8.1 Hz, 1 H), 6.85-6.95 (m, 4H), 7.01 (d, J=8.4 Hz, 1H); MS (ESI-) : 393([M-H]-).
(9) Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-(1-ethyl-cyclopropyl)-3-hydroxy- propyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
Figure imgf000512_0001
To a solution of 4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1-ethyl-cyclopropyl)-propyl]-3- methyl-phenyl}-propyl)-2-methyl-phenol (compound prepared in Example 271- (8)) (33 mg, 0.084 mmol) in dimethylacetamide (0.8 ml), K2C03 (35 mg, 0.252 mmol) was added and stirred at room temperature. To the mixture, (R)-(-)- dihydro-5-(p-tolylsulfonyloxymethyl)-2-(3H)-furanone (34 mg, 0.126 mmol) was added and stirred at 100 degrees C for 15 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with H2O and brine, dried over MgS04, and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate/hexane = 2/3) to give the title compound (24 mg, 58%).
1H-NMR: 0.31-0.42 (m, 4H), 0.59 (t, J=7.3 Hz, 6H), 0.86 (t, J=7.3 Hz, 3H), 1.20- 1.40 (m, 2H), 1.60-1.72 (m, 1H), 1.73-1.82 (m, 2H), 2.03 (q, J=7.3 Hz, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 2.28-2.50 (m, 2H), 2.52-2.62 (m, 2H), 2.72-2.82 (m, 2H), 3.08-3.15 (m, 1H), 4.02-4.20 (m, 2H), 4.85-4.92 (m, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.85-6.97 (m, 4H), 7.01 (d, J=8.4 Hz, 1H); MS (ESI-) : 491 ([M-H]').
(10) Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-(1 -ethyl-cyclopropyl)-3-hydroxy- propyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid
Figure imgf000513_0001
To a solution of (R)-5-[4-(1 -Ethyl-1 -{4-[3-(1 -ethyl-cyclopropyl)-3-hydroxy-propyl]- 3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one (compound prepared in Example 271 -(9)) (21 mg, 0.084 mmol) in THF/MeOH (2.5 ml/2.5 ml ), 1 N NaOH (0.5 ml) was added at room temperature and stirred at room temperature for 1h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCI3:MeOH=8:3 saturated with H20) to give the title compound (21 mg, 96%).
1H-NMR: 0.30-0.42 (m, 4H), 0.59 (t, J=7.0 Hz, 6H), 0.86 (t, J=7.3 Hz, 3H), 1.23- 1.37 (m, 1 H), 1.60-1.72 (m, 1H), 1.73-2.20 (m, 9H), 2.16 (s, 3H), 2.25 (s, 3H), 2.53-2.65 (m, 3H), 2.72-2.80 (m, 1H), 3.08-3.15 (m, 1H), 3.80-3.98 (m, 2H), 4.00-4.09 (m, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.85-6.97 (m, 4H), 7.01 (d, J=8.1 Hz, 1H); MS (ESI-): 509([M-HD.
Example 272
Preparation of (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(5,5,5-trifluoro-3-hydroxy-4- methyl-4-trifluoromethyl-pentyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid
Figure imgf000513_0002
(1) Preparation of 1-(4-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-5,5,5-trifluoro-4-methyl-4-trifluoromethyl-pent-1- yn-3-one
Figure imgf000514_0001
To a solution of tert-Butyl-{4-[1 -ethyl-1 -(4-ethynyl-3-methyl-phenyl)-propyl]-2- methyl-phenoxyj-dimethyl-silane (compound prepared in Example 260-(1)) (296.3 mg, 0.729 mmol) in THF (1.2 ml), 2.44 M n-butyl lithium in hexane (0.420 ml, 1.02 mmol) was added at -78 degrees C. To the mixture, 3,3,3-Trifluoro-2- methyl-2-trifluoromethyl-propionyl fluoride (0.160 ml, 1.11 mmol) in THF (0.5 ml) was added at -78 degrees C, the mixture was stirred at -78 degrees C to room temperature overnight. To the mixture, brine was added. The products were extracted with ethyl acetate and the extracts were dried over MgS04, concentrated in vacuo. The obtained residue was chromatographed on silica gel (ethyl acetate/hexane = 0/100 to 3/97) to give the title compound (289.8 mg, 66 %).
1 H-NMR (chloroform-d): 0.20 (s, 6H), 0.59 (t, 6H, J=7.1 Hz), 1.00 (s, 9H), 1.77 (s, 3H), 2.04 (q, 4H, J=7.2Hz), 2.14 (s, 3H), 2.45 (s, 3H), 6.64 (d, 1 H, J=8.4Hz), 6.79 (d, 1 H, J=8.8Hz), 6.84 (s, 1 H), 7.04 (d, 1H, J=7.7Hz), 7.09 (s, 1 H), 7.47 (d, 1 H, J=8.4Hz); MS (ESI+): 599 ([M+H]+).
(2) Preparation of 1-(4-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-5,5,5-trifluoro-4-methyl-4-trifluoromethyl-pent-1- yn-3-ol
Figure imgf000514_0002
To a solution of 1-(4-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-5,5,5-trifluoro-4-methyl-4-trifluoromethyl-pent-1- yn-3-one (compound prepared in Example 272-(1)) (289 mg, 0.483 mmol) in MeOH (1 ml) and THF (4 ml), NaBH4 was added at room temperature, and the mixture was stirred at room temperature for 30 min. To the mixture, ethyl acetate was added and the solution was washed with brine, dried over MgS0 , concentrated in vacuo. The obtained residue was chromatographed on silica gel (ethyl acetate/hexane = 0/100 to 5/95) to give the title compound (209.9 mg, 72 %).
1H-NMR (chloroform-d): 0.19 (s, 6H), 0.58 (t, 6H, J=7.1Hz), 1.00 (s, 9H), 1.54 (s, 3H), 2.02 (q, 4H, J=7.1Hz), 2.14 (s, 3H), 2.28 (d, 1H, J=8.1Hz), 2.36 (s, 3H), 0.00 (d, 1H, J=7.7Hz), 6.63 (d, 1 H, J=8.4Hz), 6.80 (d, 1 H, J=8.4Hz), 6.85 (s, 1H), 6.96 (d, 1H, J=8.0Hz), 7.02 (s, 1H), 7.28 (d, 1H, J=8.4Hz); MS(ESI+): 601 ([M+H]+).
(3) Preparation of Acetic acid 3-(4-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl- phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-1 -(2,2,2-trifluoro-1 -methyl- 1 - trifluoromethyl-ethyl)-prop-2-ynyl ester
Figure imgf000515_0001
To a solution of 1-(4-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-5,5,5-trifluoro-4-methyl-4-trifluoromethyl-pent-1- yn-3-ol (compound prepared in Example 272-(2)) (23.8 mg, 0.0396 mmol) in CH2CI2 (1 ml), pyridine (0.0096 ml) and Ac20 (0.0056 ml) were added at room temperature, and the mixture was stirred at room temperature for 12 h. CH2CI2 was removed in vacuo and pyridine (0.3 ml) and Ac20 (0.0112 ml) were added to the mixture again and the mixture was stirred at room temperature for 1.5 h. To the mixture ethyl acetate was added and the solution was washed with dil.HCI and brine, dried over MgS04, concentrated in vacuo. The obtained residue was purified by preparative TLC (ethyl acetate/hexane = 1/20) to give the title compound (21.3 mg, 84 %).
1 H-NMR (chloroform-d): 0.19 (s, 6H), 0.58 (t, 6H, J=7.1 Hz), 1.00 (s, 9H), 1.59 (s, 3H), 2.02 (q, 4H, J=7.2Hz), 2.14 (s, 3H), 2.14 (s, 3H), 2.34 (s, 3H), 6.11 (s, 1 H), 6.62 (d, 1H, J=8.8Hz), 6.78 (d, 1H, J=8.1Hz), 6.84 (s, 1H), 6.94 (d, 1H, J=8.8Hz), 7.00 (s, 1 H), 7.28 (d, 1H, J=8.1 Hz); MS(ESI+): 665 ([M+Na]+).
(4) Preparation of Acetic acid 3-{4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)- propyl]-2-methyl-phenyl}-1 -(2,2,2-trifluoro-1 -methyl-1 -trifluoromethyl-ethyl)-prop- 2-ynyl ester
Figure imgf000516_0001
To a solution of Acetic acid 3-(4-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl- phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-1 -(2,2,2-trifluoro-1 -methyl-1 - trifluoromethyl-ethyl)-prop-2-ynyl ester (compound prepared in Example 272-(3)) (19.9 mg, 0.0310 mmol) in THF (2 ml), 1 M terabutylammonium fluoride in THF (0.040 ml, 0.040 mmol) was added. The mixture was stirred for 5 min. To the mixture, ethyl acetate was added and the solution was washed with brine, dried over MgS0 , concentrated in vacuo, The obtained residue was purified by preparative TLC (ethyl acetate/hexane = 1/10) to give the title compound (14.1 mg, 86 %).
1H-NMR (chloroform-d): 0.58 (t, 6H, J=7.3Hz), 1.59 (s, 3H), 2.02 (q, 4H, J=7.0Hz), 2.14 (s, 3H), 2.18 (s, 3H), 2.34 (s, 3H), 4.85 (brs, 1H), 6.11 (s, 1H), 6.65 (d, 1 H, J=8.0Hz), 6.82 (d, 1 H, J=8.1 Hz), 6.83 (s, 1 H), 6.95 (d, 1 H, J=8.4Hz), 7.00 (s, 1 H, J=8.4Hz); MS(ESI-): 527 ([M-H]-).
(5) Preparation of Acetic acid 1-(2-{4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)- propyl]-2-methyl-phenyl}-ethyl)-2,2-dimethyl-propyl ester
Figure imgf000517_0001
To a solution of Acetic acid 3-{4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)-propyl]~ 2-methyl-phenyl}-1 -(2,2,2-trifluoro-1 -methyl-1 -trifluoromethyl-ethyl)-prop-2-ynyl ester (compound prepared in Example 272-(4)) (14.1mg, 0.0267 mmol) in MeOH (2 ml), 10%Pd/C (4.7 mg) was added. The mixture was stirred at room temperature for 13 h under hydrogen. The mixture was filtered, concentrated in vacuo and purified by preparative TLC (ethyl acetate/hexane = 1/5) to give the title compound (12.9 mg, 91 %).
1H-NMR (chloroform-d): 0.59 (t, 6H, J=7.3Hz), 1.37 (s, 3H), 1.90-2.05 (m, 6H), 2.12 (s, 3H), 2.19 (s, 3H), 2.20 (s, 3H), 2.45-2.58 (m, 2H), 4.69 (brs, 1H), 5.47 (d, 1H), 6.65 (d, 1H), 6.84-6.99 (m, 5H); MS(ESI-): 531 ([M-H]-).
(6) Preparation of Acetic acid 1-[2-(4-{1 -ethyl-1 -[3-methyl-4-((R)-5-oxo- tetrahydro-furan-2-ylmethoxy)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-3,3,3- trifluoro-2-methyl-2-trifluoromethyl-propyl ester
Figure imgf000517_0002
To a solution of Acetic acid 1-(2-{4-[1 -ethyl-1 -(4-hydroxy-3-methyl-phenyl)- propyl]-2-methyl-phenyl}-ethyl)-2,2-dimethyl-propyl ester (compound prepared in Example 272-(5)) (12.9 mg, 0.0242 mmol) in N,N-dimethylacetamide (0.5 ml), K2C03 (11.1 mg, 0.0803 mmol) and (R)-(-)-dihydro-5-(p-tolylsulfonyloxymethyl)- 2(3H)-furanone (10.2 mg, 0.0377 mmol) were added. The mixture was stirred at 90 degrees C for 27 h. After cooled to room temperature, (R)-(-)-dihydro-5-(p- tolylsulfonyloxymethyl)-2(3H)-furanone (10.2 mg, 0.0377 mmol) was added. The mixture was stirred at 90 degrees C for 14 h. After cooled to room temperature, the mixture was poured into brine and the products were extracted with ethyl acetate. The organic layer was washed with brine, dried over MgS04, concentrated in vacuo. The obtained residue was purified by preparative TLC (ethyl acetate/hexane = 1/1) to give the title compound (11.2 mg, 73 %). 1H-NMR (chloroform-d): 0.58 (t, 6H, J=7.1Hz), 1.37 (s, 3H), 1.92-2.06 (m, 6H), 2.12 (s, 3H), 2.15 (s, 3H), 2.20 (s, 3H), 2.24-2.36 (m, 1H), 2.39-2.61 (m, 4H), 2.73-2.82 (m, 1 H), 4.06 (dd, 1H, J=3.4, 10.2Hz), 4.16 (dd, 1H, J=3.2, 10.4Hz), 4.87-4.90 (m, 1H), 5.46 (d, 1H), 6.66 (d, 1H), 6.90-7.00 (m, 5H); MS(ESI+): 631 ([M+H]+).
(7) Preparation of (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(5,5,5-trifluoro-3-hydroxy-4- methyl-4-trifluoromethyl-pentyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid
Figure imgf000518_0001
To a solution of Acetic acid 1-[2-(4-{1 -ethyl-1 -[3-methyl-4-((R)-5-oxo-tetrahydro- furan-2-ylmethoxy)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-3,3,3-trifluoro-2- methyl-2-trifluoromethyl-propyl ester (compound prepared in Example 272-(6)) (6.8 mg, 0.0108 mmol) in MeOH (0.5 ml) and THF (0.5 ml), 1N NaOH solution was added. The mixture was stirred at room temperature for 5.5 h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCI3/MeOH = 8/3 saturated with H2O) to give the title compound (4.7 mg, 72 %). 1H-NMR (chloroform-d): 0.59 (t, 6H, J=7.3Hz), 1.35 (s, 3H), 1.74-2.06 (m, 8H), 2.16 (s, 3H), 2.25 (s, 3H), 2.57-2.63 (m, 3H), 2.91-2.98 (m, 1H), 3.83-3.90 (m, 2H), 3.97 (d, 1H, J=9.2Hz), 4.04-4.11 (m, 1 H), 6.67 (d, 1H, J=8.5Hz), 6.91-6.96 (m, 4H), 7.00 (d, 1H, J=8.0Hz); MS(ESI+): 607([M+H]+).
Example 273
Preparation of 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-pent-4-ynoic acid
Figure imgf000519_0001
(1 ) Preparation of Trifluoro-methanesulfonic acid 4-{1 -ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2- methyl-phenyl ester
Figure imgf000519_0002
To a solution of 4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 30-(1 )) (0.2 g, 0.4 mmol) in dichloromethane (4 ml), pyridine (0.07 ml, 0.87 mmol), and Tf20 (0.08 ml, 0.48 mmol) were added at 0 degrees C and the mixture was stirred at room temperature for 15 minutes. To the mixture, ethyl acetate was added and the mixture was washed with water, dried over MgS04, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (ethyl acetate/hexane =1/20) to give the title compound (0.22 g, 87%) as colorless oil.
1H-NMR (CDCI3): 0.61 (t, 6H, J=7.3Hz), 2.08 (q, 4H, J=7.3Hz), 2.32 (s, 3H), 2.33 (s, 3H), 2.50 (s, 3H), 4.97 (s, 2H), 6.08 (d, 1H, J=16.6Hz), 6.95-7.15 (m, 5H), 7.30-7.40 (m, 2H).
(2) Preparation of Trifluoro-methanesulfonic acid 4-{1 -ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl ester
Figure imgf000519_0003
To a solution of Trifluoro-methanesulfonic acid 4-{1 -ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3'methoxymethoxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2- methyl-phenyl ester (compound prepared in Example 273-(1) (220 mg, 0.35 mmol) in dichloromethane (0.75 ml), trifluoroacetic acid (0.25 ml) was added at room temperature and the mixture was stirred at room temperature for 14 h. The mixture was concentrated in vacuo, and chromatographed on silica gel (ethyl acetate/hexane =1/10) to give the title compound (180 mg, 88%) as colorless oil. 1H-NMR (CDCI3): 0.61 (t, 6H, J=7.3Hz), 2.08 (q, 4H, J=7.3Hz), 2.32 (s, 3H), 2.35 (s, 3H), 3.43 (s, 1H), 6.09 (d, 1 H, J=15.8Hz), 6.90-7.15 (m, 5H), 7.30-7.45 (m, 2H).
(3) Preparation of 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-pent-4-ynoic acid methyl ester
Figure imgf000520_0001
To a solution of trifluoro-methanesulfonic acid 4-{1 -ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl ester (compound prepared in Example 273-(2)) (30 mg, 0.05 mmol) in DMF (1 ml), PdCI2(dppf)2-CH2Cl2 (4 mg, 0.005 mmol), Et3N (0.024 ml, 0.17 mmol), Cul (10 mg, 0.05 mmol), and pent-4-ynoic acid methyl ester (11 mg, 0.1 mmol) were added at room temperature under nitrogen and stirred at 120 degrees C for 14 h. To the mixture, ethyl acetate was added and the mixture was washed with water and brine, dried over MgS04, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (ethyl acetate/hexane =1/5) to give the title compound (20 mg, 71%) as colorless oil. 1 H-NMR (CDCI3): 0.60 (t, 6H, J=7.3Hz), 2.06 (q, 4H, J=7.3Hz), 2.32 (s, 3H), 2.33 (s, 3H), 2.55-2.80 (m, 4H), 3.12 (s, 1 H), 3.71 (s, 3H), 6.08 (d, 1 H, J=15.8Hz), 6.80-7.00 (m, 4H), 7.23 (d, 1 H, J=8.1Hz), 7.30-7.40 (m, 2H). (4) Preparation of 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-pent-4-ynoic acid
Figure imgf000521_0001
To a solution of 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-pent-4-ynoic acid methyl ester (compound prepared in Example 273-(3)) (20 mg, 0.036mmol) in MeOH (1 ml), 1 N NaOH aq. (0.2 ml, 0.2 mmol) was added at room temperature and stirred at room temperature for 4 h. To the mixture, ethyl acetate was added and the mixture was washed with 30% NaH P04 aq., dried over MgS04, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (ethyl acetate/hexane =3/1) to give the title compound (12 mg, 62%) as colorless oil. 1 H-NMR (CDCI3): 0.60 (t, 6H, J=7.3Hz), 2.06 (q, 4H, J=7.3Hz), 2.32 (s, 3H), 2.34 (s, 3H), 2.60-2.85 (m, 4H), 6.08 (d, 1 H, J=15.7Hz), 6.80-7.00 (m, 4H), 7.23 (d, 1H, J=7.9Hz), 7.30-7.40 (m, 2H); MS(ESI+): 541([M+H]+)
Example 274
Preparation of 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid
Figure imgf000521_0002
(1) Preparation of 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid methyl ester
Figure imgf000522_0001
To a solution of trifluoro-methanesulfonic acid 4-{1 -ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl ester (compound prepared in Example 273-(2)) (30 mg, 0.05 mmol) in DMF (1 ml), PdC.2(dppf)2-CH2Cl2 (4 mg, 0.005 mmol), Et3N (0.024 ml, 0.17 mmol), Cul (10 mg, 0.05 mmol), and hex-5-ynoic acid methyl ester (13 mg, 0.1 mmol) were added at room temperature under nitrogen and stirred at 120 degrees C for 14 h. To the mixture, ethyl acetate was added and the mixture was washed with water and brine, dried over MgS04, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (ethyl acetate/hexane =1/5) to give the title compound (20 mg, 69%) as colorless oil. 1H-NMR (CDCI3): 0.60 (t, 6H, J=7.3Hz), 1.80-2.00 (m, 2H), 2.08 (q, 4H, J=7.2Hz), 2.33 (s, 3H), 2.35 (s, 3H), 2.45-2.60 (m, 4H), 3.68 (s, 3H), 6.08 (d, 1H, J=15.7Hz), 6.84-7.02 (m, 4H), 7.20-7.28 (m, 1 H), 7.30-7.40 (m, 2H).
(2) Preparation of 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid
Figure imgf000522_0002
To a solution of 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid methyl ester (compound prepared in Example 274-(1)) (20 mg, 0.035mmol) in MeOH (1 ml), 1 N NaOH aq. (0.2 ml, 0.2 mmol) was added at room temperature and stirred at room temperature for 4 h. To the mixture, ethyl acetate was added and the mixture was washed with 30% NaH2P04 aq., dried over MgSθ4, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (ethyl acetate/hexane =3/1 ) to give the title compound (14 mg, 72%) as colorless oil.
1H-NMR (CDCI3): 0.60 (t, 6H, J=7.3Hz), 1.85-2.00 (m, 2H), 2.06 (q, 4H, J=7.2Hz), 2.33 (s, 3H), 2.35 (s, 3H), 2.54 (t, 2H, J=6.8Hz), 2.58 (t, 2H, J=7.4Hz), 6.11-6.05 (d, 1 H, J=15.8Hz), 6.85-7.05 (m, 4H), 7.20-7.27 (m, 1 H), 7.30-7.40 (m, 2H); MS(ESI+): 555([M+H]+)
Example 275
Preparation of 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid
Figure imgf000523_0001
(1 ) Preparation of 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid methyl ester
Figure imgf000523_0002
To a solution of trifluoro-methanesulfonic acid 4-{1 -ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl ester (compound prepared in Example 273-(2)) (30 mg, 0.05 mmol) in DMF (1 ml), PdCI2(dppf)2-CH2Cl2 (4 mg, 0.005 mmol), Et3N (0.024 ml, 0.17 mmol), Cul (10 mg, 0.05 mmol), and hex-5-ynoic acid methyl ester (14 mg, 0.1 mmol) were added at room temperature under nitrogen and stirred at 120 degrees C for 14 h. To the mixture, ethyl acetate was added and the mixture was washed with water and brine, dried over MgSθ4, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (ethyl acetate/hexane =1/5) to give the title compound (18 mg, 61%) as colorless oil. 1H-NMR (CDCI3): 0.60 (t, 6H, J=7.3Hz), 1.55-1.70 (m, 2H), 1.72-1.90 (m, 2H), 2.06 (q, 4H, J=7.3Hz), 2.33 (s, 3H), 2.35 (s, 3H), 2.37 (t, 2H, J=7.1 Hz), 2.46 (t, 2H, J=6.9Hz), 3.16 (s, 1H), 3.67 (s, 3H), 6.08 (d, 1 H, J=16.1 Hz), 6.85-7.05 (m, 4H), 7.20-7.26 (m, 1H), 7.30-7.40 (m, 2H).
(2) Preparation of 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid
Figure imgf000524_0001
To a solution of 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid methyl ester (compound prepared in Example 275-(1)) (18 mg, 0.031 mmol) in MeOH (1 ml), 1 N NaOH aq. (0.2 ml, 0.2 mmol) was added at room temperature and stirred at room temperature for 4 h. To the mixture, ethyl acetate was added and the mixture was washed with 30% NaH2P04 aq., dried over MgS04, concentrated in vacuo, and the obtained residue was chromatographed on silica gel (ethyl acetate/hexane =3/1) to give the title compound (13 mg, 74%) as colorless oil. 1H-NMR (CDCI3): 0.60 (t, 6H, J=7.2Hz), 1.60-1.75 (m, 2H), 1.76-1.90 (m, 2H), 2.06 (q, 4H, J=7.2Hz), 2.32 (s, 3H), 2.35 (s, 3H), 2.39 (t, 2H, J=7.4Hz), 2.47 (t, 2H, J=6.9Hz), 6.08 (d, 1 H, J=16.0Hz), 6.85-7.02 (m, 4H), 7.20-7.27 (m, 1 H), 7.30-7.40 (m, 2H);MS(ESI+): 569([M+H]+)
Example 276
Preparation of (R)-2-[2-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]- propionic acid
Figure imgf000525_0001
(1) Preparation of (4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-acetic acid methyl ester
Figure imgf000525_0002
Using the same procedure as described for the preparation of Example 203-(1 ), the title compound was prepared from 4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenol (compound prepared in 30-(1)). H-NMR(CDCI3): 0.60 (t, 6H), 2.04 (q, 4H), 2.23 (s, 3H), 2.32 (s, 3H), 3.50 (s, 3H), 3.80 (s, 3H), 4.62 (s, 2H), 4.96 (s, 2H), 6.06 (d, 1 H), 6.57 (d, 1H), 6.88-7.05 (m, 4H), 7.30-7.38 (m ,2H)
(2) Preparation of (4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-acetic acid
Figure imgf000525_0003
Using the same procedure as described for the preparation of Example 203-(2), the title compound was prepared from (4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-acetic acid methyl ester (compound prepared in 276-(1)). 1H-NMR(CDCI3): 0.56 (t, 6H), 2.01 (q, 4H), 2.15 (s, 3H), 2.28 (s, 3H), 3.48 (s, 3H), 4.46 (s, 2H), 4.94 (s, 2H), 6.04 (d, 1H), 6.57 (d, 1H), 6.85-7.01 (m, 4H), 7.28-7.37 (m, 2H)
(3) preparaton of (R)-2-[2-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]- propionic acid
Fmoc-D-Ala-Wang resin
Figure imgf000526_0001
Fmoc-D-Ala-Wang resin (0.54mmol/g as amino acid loading, 37.0 mg, 0.020mmol amino acid loading) was treated with 20% (v/v) piperidine in DMF (0.5ml) two times to deprotect Fmoc group and washed with DMF (1ml, 5 times). To the resin, solutions of (4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-acetic acid (prepared in Example 276-(2)) (16.3mg, 0.029mmol) in DMF (0.2ml), benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (17.7mg, 0.040mmol) in DMF (0.2ml) and N,N-diisopropyl ethyl amine (0.0105ml, 0.060mmol) in DMF (0.1ml) were added at room temperature, agitated at room temperature for 16h, filtrated, washed with DMF (2ml, 3 times), iPrOH (2ml, 3 times), THF (2ml, 3 times), MeOH (2ml, 3 times) and CH2CI2 (2ml, 3 times) and dried in vacuo. To the resin, 20% TFA in CH2CI2 (v/v) (1ml) was added at room temperature, agitated at room temperature for 16h, filtrated, washed with CH2CI2 (1ml, 2 times) and concentrated under vacuum to give the crude titled compound. MS (positive mode): 590 ([M+H]+) Example 277
Preparation of (R)-2-[2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]- propionic acid
Figure imgf000527_0001
(1) Preparation of (4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-pr opyl}-2-methyl-phenoxy)-acetic acid methyl ester
Figure imgf000527_0002
Using the same procedure as described for the preparation of Example 203-(1), the title compound was prepared from 4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-pro pyl}-2-methyl-phenol (compound prepared in 2-(2)).
1H-NMR(CDCI3): 0.59 (t, 6H), 2.04 (q, 4H), 2.21 (s, 3H), 2.39 (s, 3H), 3.47 (s, 3H), 3.80 (s, 3H), 4.62 (s, 2H), 5.15 (s, 2H), 6.57 (s, 1H), 6.83-7.05 (m, 4H), 7.36 (d, 1 H) (2) Preparation of (4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-pr opyl}-2-methyl-phenoxy)-acetic acid
Figure imgf000528_0001
Using the same procedure as described for the preparation of Example 200-(2), the title compound was prepared from (4-{1 -Ethyl-1 -[3-methyl- 4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-pr opyl}-2-methyl-phenoxy)-acetic acid methyl ester (compound prepared in 277-(1)).
1H-NMR(CDCI3): 0.59 (t, 6H), 2.04 (q, 4H), 2.16 (s, 3H), 2. 39 (s, 3H), 3.48 (s, 3H), 4.65 (s, 2H), 5.15 (s, 2H), 6.61 (d, 1 H), 6.85-7.05 (m, 4H), 7.37 (d, 1 H)
(3) preparaton of (R)-2-[2-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]- propionic acid
Fmoc-D-Ala-Wang resin
Figure imgf000528_0002
Using the same procedure as described for the preparation of Example 276-(3), the crude title compound was prepared from Fmoc-D-Ala-Wang resin and (4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-pr opyl}-2-methyl-phenoxy)-acetic acid (compound prepared in 277-(2)) MS (positive mode): 588 ([M+H]+) Example 278
Preparation of (S)-2-[2-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-3- phenyl-propionic acid
Figure imgf000529_0001
Using the same procedure as described for the preparation of Example 276- (3), the crude title compound was prepared from Fmoc-L-Phe-Wang resin and (4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl- but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-acetic acid (compound prepared in 276-(2)) MS (positive mode): 666 ([M+Hf)
Example 279
Preparation of (S)-2-[2-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-3- phenyl-propionic acid
Figure imgf000529_0002
Using the same procedure as described for the preparation of Example 276-(3), the crude title compound was prepared from Fmoc-L-Phe-Wang resin and (4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-pr opyl}-2-methyl-phenoxy)-acetic acid (compound prepared in 277-(2)) MS (positive mode): 664 ([M+H]+) Example 280
3-(4-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000530_0001
Example 281
3-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000530_0002
Example 282
(R)-3-(4-{1-Ethyl-1-[4-((R)-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000530_0003
Example 283
(S)-3-(4-{1-Ethyl-1-[4-((S)-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000530_0004
Example 284
(R)-3-(4-{1-Ethyl-1-[4-((S)-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000531_0001
Example 285
(S)-3-(4-{1-Ethyl-1-[4-((R)-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000531_0002
Example 286 (R)-3-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000531_0003
Example 287
(S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol
Figure imgf000531_0004
Example 288
(R)-3-(4-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol
Figure imgf000532_0001
Example 289
(S)-3-(4-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol
Figure imgf000532_0002
Example 290
(S)-5-(4-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-pentane-1 ,4-diol
Figure imgf000532_0003
Example 291
4-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenyl)-butane-1 ,2-diol
Figure imgf000532_0004
Example 292
4-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2- methyl-phenyl)-butane-1 ,2-diol
Figure imgf000532_0005
Example 293
1 -(4-{1 -Ethyl-1 -[4-(3-hydroxy-propyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-3,3-dimethyl-butan-2-ol
Figure imgf000533_0001
Example 294
1 -(4-{1 -Ethyl-1 -[4-(3-hydroxy-propyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-
4,4-dimethyl-pentan-3-ol
Figure imgf000533_0002
Example 295
3-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2- methyl-phenyl)-butan-1 -ol
Figure imgf000533_0003
Example 296
(E)-4-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-
2-methyl-phenyl)-but-3-en-2-ol
Figure imgf000533_0004
Example 297
1 -(4-{1 -Ethyl-1 -[4-(3-hydroxy-butyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-
3,3-dimethyl-butan-2-ol
Figure imgf000533_0005
Example 298 3-(4-{1 -Ethyl-1 -[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2- methyl-phenyl)-propane-1 ,2-diol
Figure imgf000534_0001
Example 299
3-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2- methyl-phenyl)-butane-1 ,2-diol
Figure imgf000534_0002
Example 300
1-(4-{1-[4-(2,3-Dihydroxy-propyl)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl- phenoxy)-3,3-dimethyl-butan-2-one
Figure imgf000534_0003
Example 301
1 -(4-{1 -[4-(2,3-Dihydroxy-1 -methyl-propyl)-3-methyl-phenyl]-1 -ethyl-propyl}-2- methyl-phenoxy)-3,3-dimethyl-butan-2-one
Figure imgf000534_0004
Example 302
1 -(4-{1 -[4-(1 ,2-Dihydroxy-propyl)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl- phenoxy)-3,3-dimethyl-butan-2-one
Figure imgf000534_0005
Example 303
1 -(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenyl)-4,4-dimethyl-pentan-3-ol
Figure imgf000535_0001
The following compounds are prepared in accordance with the procedure described as in the above Examples.
Example 304
Preparation of (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopentyl)-prop-1 ■ ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
Figure imgf000535_0002
Example 305
Preparation of 5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopentyl)-prop-1 - ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4(R)-hydroxy-pentanoic acid
Figure imgf000535_0003
Example 306
Preparation of (R)-5-[4-(1 -ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopentyl)-propyl]-
3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
Figure imgf000535_0004
(1) Preparation of 1-methyl-cyclopentanecarboxylic acid N-methoxy-N-methyl- amide
Figure imgf000536_0001
To a solution of N,0-dimethylhydroxylamine hydrochloride (594.5 mg, 6.09 mmol) in THF (4 ml) was added 2.67M n-butyl lithium in hexane (4.10 ml, 10.95 mmol) dropwise at -78 degrees C, and the mixture was stirred at room temperature for 10 min. The mixture was cooled to -78 degrees C, and 1-methyl- cyclopentanecarboxylic acid methyl ester (430.5 mg, 3.03 mmol) in THF (2 ml) was added dropwise to the mixture. After stirring at -78 degrees C for 1h 45min, diethyl ether was added, and the solution was washed with sat.N^CI aq. and brine, dried over MgSθ4, filtered, concentrated in vacuo, and chromatographed (ethyl acetate/hexane = 0/100 to 15/85) to give the title compound (154.2 mg, 30 %). 1 H-NMR (CDCI3): 1.23 (s, 3H), 1.55-1.66 (m, 6H), 2.03-2.08 (m, 2H), 3.18 (s, 3H), 3.66 (s, 3H); MS(ESI+): 172([M+H]+).
(2) Preparation of 3-(4-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-1 -(1 -methy!-cyclopentyl)-prop-2-yn-1 -one
Figure imgf000536_0002
To a solution of tert-butyl-{4-[1 -ethyl-1 -(4-ethynyl-3-methyl-phenyl)-propyl]-2- methyl-phenoxyj-dimethyl-silane (compound prepared in Example 260-(2)) (434.1 mg, 1.07 mmol) in THF (3 ml), 2.67 M n-butyl lithium in hexane (0.420 ml, 1.12 mmol) was added at -78 degrees C. To the mixture, 1-methyl- cyclopentanecarboxylic acid N-methoxy-N-methyl-amide (compound prepared in Example 306-(1)) (151.9 mg, 0.887 mmol) in THF (2 ml) was added at -78 degrees C, stirred at -78 degrees C to room temperature for 2.5 h. The mixture was poured into brine and extracted with ethyl acetate. Organic layer was washed with brine, dried over MgS04, filtered, concentrated in vacuo, and chromatographed (ethyl acetate/hexane = 0/100 to 2/98) to give the title compound (434.9 mg, 95 %).
1 H-NMR (CDCI3): 0.19 (s, 6H), 0.58 (t, 6H, J=7.3Hz), 0.99 (s, 9H), 1.32 (s, 3H), 1.42-1.51 (m, 2H), 1.69-1.74 (m, 4H), 2.03 (q, 4H, J=7.2Hz), 2.14 (s, 3H), 2.24- 2.32 (m, 2H), 2.44 (s, 3H), 6.63 (d, 1 H, J=8.4Hz), 6.79 (dd, 1 H, J=8.4, 2.0Hz), 6.84 (s, 1H), 7.00 (d, 1H, J=8.9Hz), 7.05 (s, 1H), 7.41 (d, 1H, J=8.1Hz); MS(ESI+): 517([M+H]+).
(3) Preparation of 4-(1 -ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopentyl)-prop-1 - ynyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol
Figure imgf000537_0001
To a solution of 3-(4-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-1 -(1 -methyl-cyclopentyl)-prop-2-yn-1 -one (compound prepared in Example 306-(2)) (432 mg, 0.835 mmol) in MeOH (3 ml) and THF (8 ml), NaBH4 (155.5 mg, 4.11 mmol) was added at room temperature, stirred at room temperature for 30 min. Ethyl acetate was added. The solution was washed with brine, dried over MgS04, concentrated in vacuo. The residue was dissolved to THF (16 ml), and 1M terabutylammonium fluoride in THF (0.880 ml, 0.880 mmol) was added at -10 degrees C. The mixture was stirred for 5 min. Ethyl acetate was added. The solution was washed with brine, dried over MgS04, concentrated in vacuo, and purified by preparative TLC (ethyl acetate/hexane = 0/100 to 25/75) to give the title compound (352 mg, quant.). 1 H-NMR (CDCI3): 0.58 (t, 6H, J=7.3Hz), 1.14 (s, 3H), 1.37-1.44 (m, 2H), 1.57- 1.80 (m, 6H), 1.82 (d, 1H, J=5.9Hz), 2.02 (q, 4H, J=7.3Hz), 2.18 (s, 3H), 2.36 (s, 3H), 4.38 (d, 1H, J=5.9Hz), 4.51 (s, 1H), 6.63 (dd, 1H, J=8.8, 1.5Hz), 6.81-6.85 (m, 2H), 6.92 (dd, 1H, J=8.1 , 1.6Hz), 6.98 (s, 1H), 7.27 (d, 1H, J=8.3Hz); MS(ESI+): 405([M+H]+). (4) Preparation of (R)-5-[4-(1 -ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclopentyl)- propyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one
Figure imgf000538_0001
To a solution of 4-(1 -ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclopentyl)-prop-1-ynyl]- 3-methyl-phenyl}-propyl)-2-methyl-phenol (compound prepared in Example 306- (3)) (140 mg, 0.346 mmol) in MeOH (15 ml), 10%Pd/C (31.1 mg) was added. The mixture was stirred at room temperature for 16 h under hydrogen. The mixture was filtered, concentrated in vacuo. To the residue in N,N- dimethylacetamide (5 ml), K2CO3 (194 mg, 1.40 mmol) and (R)-(-)-dihydro-5-(p- tolylsulfonyloxymethyl)-2(3H)-furanone (152 mg, 0.562 mmol) were added. The mixture was stirred at 90 degrees C for 27 h. After cooled to room temperature, (R)-(-)-dihydro-5-(p-tolylsulfonyloxymethyl)-2(3H)-furanone (10.2 mg, 0.0377 mmol) was added. The mixture was stirred at 90 degrees C for 6.5 h. After cooled to room temperature, brine was added, extracted with ethyl acetate. The organic layer was washed with brine, dried over MgS04, concentrated in vacuo, and chromatographed (ethyl acetate/hexane = 0/100 to 40/60) to give the title compound (109.1 mg, 62 %).
1 H-NMR (CDCI3): 0.58 (t, 6H, J=7.3Hz), 0.90 (s, 3H), 1.23-1.40 (m, 4H), 1.49- 1.73 (m, 6H), 2.03 (q, 4H, J=7.2Hz), 2.14 (s, 3H), 2.25 (s, 3H), 2.28-2.62 (m, 4H), 2.71-2.87 (m, 2H), 3.30-3.34 (m, 1H), 4.11 (ddd, 2H, J=28.2, 8.4, 3.29Hz), 4.85-4.90 (m, 1H), 6.65 (d, 1H, J=8.4Hz), 6.88-7.03 (m, 5H); MS(ESI-): 505([M- H]-).
Example 307 Preparation of 5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclopentyl)-propyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4(R)-hydroxy-pentanoic acid
Figure imgf000539_0001
To a solution of (R)-5-[4-(1 -ethyl-1 -{4-[3-hydroxy-3-(1-methyl-cyclopentyl)- propyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one (compound prepared in Example 306-(4)) (105.7 mg, 0.209 mmol) in MeOH (10 ml) and THF (10 ml), 1 NaOH solution (2 ml) was added. The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and purified by preparative TLC (CHCI3/MeOH = 8/3 saturated with H20) to give the title compound (86.1 mg, 79 %).
1 H-NMR (CDCI3): 0.58 (t, 6H, J=7.2Hz), 0.89 (s, 3H), 1.20-1.80 (m, 10H), 1.87- 1.93 (m, 2H), 2.03 (q, 4H, J=7.2Hz), 2.16 (s, 3H), 2.25 (s, 3H), 2.50-2.63 (m, 3H), 2.79-2.90 (m, 1 H), 3.33 (dd, 1 H, J=10.0, 1.6Hz), 3.83 (dd, 1 H, J=9.6, 6.8Hz), 3.95 (dd, 1 H, J=9.6, 3.5Hz), 4.00-4.10 (m, 1 H), 6.66 (d, 1 H, J=8.3Hz), 6.88-6.95 (m, 4H), 7.01 (d, 1 H, J=8.4Hz); MS(ESI-): 523([M-H]").
Example 308
Preparation of (S)-6-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one
Figure imgf000539_0002
Preparation of (S)-6-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one
Figure imgf000539_0003
To a solution of 4-{1 -ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol (compound prepared in Example 1-(5)) (50mg, 0.131 mmol), PPh3 (103mg, 0.394mmol), (S)-6-hydroxymethyl-tetrahydro-pyran- 2-one (J. Chem. Soc, Perkin Trans. 1, 2000, 20, 3519.) (51 mg, 0.394mmol) in THF (0.2ml), DEAD (69mg, 0.394mmol) was added slowly at room temperature and stirred at room temperature for 37 h. The mixture was concentrated in vacuo and chromatographed (n-hexane/ethyl acetate =1/3 developed once, n- hexane/ethyl acetate =3/1 developed once, n-hexane/ethyl acetate =1/1 developed once) to give the title compound (5.3mg, 8.2%). MS(positive): 510([M+NH4]+).
Example 309
Preparation of (S)-6-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid
Figure imgf000540_0001
Preparation of (S)-6-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-ρent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid
Figure imgf000540_0002
To a solution of (S)-6-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one (compound prepared in Example 308) (0.53mg, 0.001 mmol) in THF (0.05ml) and , MeOH (0.05ml), 1 N KOH aq (0.05ml, O.Oδmmol) was added at rt and stirred at 60 degrees C for 12 h. The mixture was extracted with ethyl acetate, dried over MgSθ4, filtered, concentrated in vacuo to give the title compound. MS(positive): 493([M-OH]+), MS(negative): 509([M-H]_). Test Example
Biological activities
Preparation of tested compounds 1 ,25(OH)2D3 was purchased from Solvay Pharmaceuticals (Weesp,
The Netherlands). LG190178 (the compound disclosed in WOOO/10958 and the corresponding U.S. Patent 6,218,430 B1) was prepared in accordance with the procedure described as the said patent specification (Example 10). Compound A, B, C, and D (the compounds disclosed in WO03/101978A1 ) were prepared in accordance with the procedure described as the said patent specification (Example 110 and its diastereomers). The compounds of the present invention were prepared as exemplified above. The chemical structure of LG190178 is as follows:
Figure imgf000541_0001
The chemical structure of compound A is as follows:
Figure imgf000541_0002
The chemical structure of compound B (epimer of compound A) is as follows:
Figure imgf000541_0003
The chemical structure of compound C is as follows:
Figure imgf000541_0004
The chemical structure of compound D (epimer of compound C) is as follows:
Figure imgf000542_0001
Test Example 1 PTH Production From Bovine Parathyroid Cells
Preparation of parathyroid cells Fresh bovine parathyroid glands obtained from a slaughterhouse were transported to the laboratory in ice-cold DMEM/F-12 (GIBCO BAL, NY, USA) containing antibiotic-antimycotic (GIBCO BAL). The parathyroid glands were trimmed of excess fat and connective tissue with scissors and sliced with the slicer. They were minced finely (not more than 1 mm fragments) and suspended in digestion medium consisting of DMEM/F-12 (10 ml digestion medium/1 g parathyroid tissue) containing 2 mg/ml collagenase (Wako Pure Chemical Industries, Ltd., Osaka, Japan), 40 mg/ml deoxyribonuclease II (SIGMA-ALDRICH Co., St. Louis MO, USA), and antibiotics (penicillin, streptomycin). The mixture was incubated at 37 °C with shaking (120 strokes/min.) for 120-180 min. to disperse the cells. The turbid solution was then filtered through nylon mesh (70 μm cell strainer) and centrifuged at 1100 rpm. (240 x g) for 10 min. at 4 °C. The pellet was resuspended and washed twice in DMEM/F-12. The pellet was finally resuspended in DMEM/F-12 containing 10 % fetal bovine serum (FBS) and aliquots were taken for cell counting.
Parathyroid cell cultures The dispersed cells were plated in 96-well plate at a concentration of
2 x 104 cells/well and incubated for 2 days at 37 °C. The culture medium was then replaced with the same medium containing various concentrations of 1 ,25(OH)2D3 (as a positive control), LG190178 (the compound disclosed in WOOO/10958 and the corresponding U.S. Patent 6,218,430 B1) or the compounds of the present invention, and cells were cultured for 3 days at 37 °C. To determine the rate of PTH secretion, the cells were washed once with DMEM/F-12 (FBS free), and then incubate for 4 hr. in fresh FBS free medium at 37 °C. The medium were collected and frozen at -30 °C until assay for the concentration of PTH.
Radio immuno assay of PTH in the medium PTH concentration in the culture media was determined using the PTH assay kit YAMASA RIA kit available from YAMASA Co., (Chiba, Japan).
Comparison of inhibitory activity on PTH release in parathyroid cells The 50 % inhibitory concentration (IC50) values were determined from the PTH concentrations. The inhibitory activity was calculated as the ratio of the IC50 value of the compounds to that of 1 ,25(OH)2D3. The results are shown in the following Table 2. The relationship between the diseases and the inhibitory activity on PTH release in parathyroid cells is described in Am J Kidney Dis. 1995 Nov:26(5):852-60 for example.
Test Example 2 The mRNA expression assay of ECAC2 in Caco-2 cells
Caco-2 cell cultures The dispersed cells were plated in 48-well plate at a concentration of 6.3 x 104 cells/well and incubated for 4 days at 37 °C. The culture medium (Dulbecco's Modified Eagle Medium (D-MEM) without NaHC03 with 44 mM NaHC03, 1 mM non-essential amino acids, and 2 mM L-glutamine, 90%; fetal bovine serum, 10%) was then replaced with the same medium containing various concentrations of LG190178 (the compound disclosed in WOOO/10958 and the corresponding U.S. Patent 6,218,430 B1) or the compounds of the present invention, and cells were cultured for 1 day at 37 °C. The culture medium containing the compounds was changed twice per day. Total RNA isolation from Caco-2 cell Total RNA was isolated from Caco-2 cell following ABI PRISM™ 6100 Nucleic Acid PrepStation protocol from Applied Biosystems.
Real time RT-PCR assay of ECAC2 ECAC2 mRNA expression was determined using TaqMan One-step RT-PCR Master Mix Reagents Kit and PRISM7000 systems from Applied Biosystems. Primer information and cycle conditions are 1)ECAC2, forward 5'- CCTTCACCATCATGATTCAGAAG-3', reverse 5'- GTCCTCTGTCTGGAAGATGA-3', Taqman probe 5'- TTCTGCTGGCTGATGGCTGTGGTC-3', 55 cycles, annealing temperature (Ta) = 60 °C; 2)GAPDH, forward 5'-GAAGGTGAAGGTCGGAGTC-3\ reverse S'-GAAGATGGTGATGGGATTTC-S', Taqman probe 5- CAAGCTTCCCGTTCTCAGCC-3', 55 cycles, Ta = 60 °C. ECAC2 mRNA values were normalized for the expression of GAPDH mRNA within each sample.
Comparison of ECAC2 mRNA value The EC50 values of ECAC2 mRNA values were analyzed by Emax models. The ECAC2 mRNA ratio was calculated as the ratio of the EC50 value of the compounds to that of LG190178. The results are shown in the following Table 4. ECAC2 is a channel-like transporter mediating intestinal calcium absoφtion. It is described in J Biol Chem. 1999 Aua 6:274(32):22739-46 for example.
Test Example 3
MG-63 Osteocalcin Induction Assay
Preparation of MG-63 Cells
RECTIFIED SHEET (RULE 91) ISA/EP MG-63 cells were cultured in MEM (minimum essential medium) medium (pH 7.0) (Invitrogen Corp., Carlsbad, CA, USA) containing 5% fetal bovine serum (FBS) (Hyclone, Logan, UT, USA) before assay. MG-63 cells were detached by Trypsin-EDTA solution and resuspended in MEM medium. Cell density was adjusted to 4.0 x 104 cells/mL with the MEM medium and 0.2 mL of the cells was seeded onto each well of 96-well plate. The cells were incubated at 37 °C in 5% C02 for 24 hours.
MG-63 Cells Culture The cells were washed once with 200 micro L of MEM medium containing 5% of DCC-FBS. Then, the 180 micro L of MEM medium containing 5% dextran/charcoal-treated FBS (DCC-FBS) were added onto each well of 96-well plate. 1 ,25(OH) D3 was purchased from Solvay Pharmaceuticals (Weesp, The Netherlands) and was used for standard. Test compounds were diluted to 1.0 x 10'3 mol/L, 1.0 x 10"4 mol/L, 1.0 x 10"5 mol/L, 1.0 x 10'6 mol/L, 1.0 x 10"7 mol/L and 1.0 x 10"8 mol/L with DMSO. These compounds solutions were stored at -20 °C until use. MG-63 cells were treated with these compounds (20 micro L) at final concentration of 1.0 x 10"6 mol/L, 1.0 x 10"7 mol/L, 1.0 x 10"8 mol/L, 1.0 x 10"9 mol/L, 1.0 x 10"10 mol/L and 1.0 x 10"11 mol/L in MEM medium containing 5% DCC-FBS. The plate was mixed gently and incubated at 37 °C and 5% C02 for 8 hours. The final concentration of DMSO was less than 0.1 %. After the incubation, cultured medium were removed and 200 micro L of MEM containing 5% DCC-FBS were added onto each well of 96-well plate. The cells were incubated at 37 °C and 5% C02 for 4 days. After 4 days culture, 150 micro L of supernatant was collected into new 96-well plate and stored at -80 °C.
Enzyme Immunoassay of Osteocalcin Osteocalcin concentration of supernatant was determined by Gla-type osteocalcin EIA kit (Takara Bio. Inc., Tokyo, Japan). Frozen supernatant was thawed slowly with shaking gently at room temperature prior to use. The absorbance was measured at 450 nm with a microplate reader (Model 3550, Bio-Rad Laboratories, Hercules, CA, USA). Each concentration was calculated by comparison with standards using Microplate Manager III software (Bio-Rad Laboratories).
Comparison of induction activity on osteocalcin in MG-63 cells The 50 % effect concentration (ECso) values were determined from the osteocalcin concentrations. The inductive activity was calculated as the. ratio of the EC5o value of the compounds to that of 1 ,25(OH)2D3. The results are shown in the following Table 3. The relationship between the diseases and the induction activity on osteocalcin is suggested in Lancet (1984 May 19). 1(8386). 1091-3. Steroids 66. 159-170 (2001) or Journal of Steroid Biochemistry & Molecular Biology 89-90. 269-271 (2004) for example.
Test Example 4 Bone mineral density in the ovariectomized (QVX) rats (1 )
Reagents The compounds of the present invention were prepared as exemplified above, dissolved in a vehicle (medium chain triglyceride, MCT) and diluted to a given concentration. The stock solutions were protected from light and stored at 4 °C.
Animals Eight-moπth-old female Sprague-Dawley (Crl:CD(SD)) rats were purchased from Charles River Japan Inc. (Kanagawa, Japan) and acclimated under standard laboratory conditions at 24 ± 2 °C and 50-60% humidity. The rats were allowed free access to tap water and commercial standard rodent chow CE-2 (Clea Japan Inc., Japan).
Experimental design
RECTIFIED SHEET (RULE 91) ISA EP Sham-operated (n = 8) and the ovariectomized (OVX) rats were used.
The OVX rats were divided into each group (n = 8) one day after the surgery.
In the sham and OVX control groups, rats received the vehicle (MOT) p.o. at a dose of 1 ml/kg body weight (BW) five times a week. Each compound was given orally five times a week for 4 weeks. These animal studies were carried out in accordance with Chugai Pharmaceutical's ethical guidelines for animal care, and the experimental protocols were approved by the animal care committee of the institution. During the 24 hours from the last administration, urine was collected with metabolic cage, and blood was drawn from the abdominal aorta under ether anesthesia. Blood and urine samples were centrifuged to obtain the supernatant, which were stored at -20 °C until assay. The lumbar vertebrae and femur were removed. The lumbar vertebra and the right femur were stored in 70% ethanol at 4 °C for the measurement of bone mineral density (BMD).
Serum and urine biochemistry Serum calcium (Ca) and inorganic phosphorus (Pi) concentrations were measured with an autoanalyzer (Hitachi 7170, Tokyo, Japan). The serum osteocalcin concentration was measured with Osteocalcin rat ELISA system (Amersham Pharmacia Biotech, Tokyo, Japan). Urinary Ca, Pi, and creatinine (Cre) were measured with an autoanalyzer. Urinary deoxypyridinoline (D-Pyr) was measured using a Metra DPD EIA kit (Quidel Co., USA), and the data were corrected for urinary Cre concentrations.
Measurement of bone mineral density The second through fourth lumbar vertebaral (L2-L4) BMD (mg/cm2) and femoral BMD were measured by dual-energy X-ray absorptiometry (DCS-600-EX, Aloka, Japan). The results are shown in the following Table 5. Test Example 5 Bone mineral density in the ovariectomized (OVX) rats (2) Reagents Alfacalcidol was synthesized in Chugai Pharmaceutical Co., Ltd., Japan, dissolved in a vehicle (medium chain triglyceride, MOT) and diluted to a given concentration. The stock solutions were protected from light and stored at 4 °C.
Animals Eight-month-old female Sprague-Dawley (Crl:CD(SD)) rats were purchased from Charles River Japan Inc. (Kanagawa, Japan) and acclimated under standard laboratory conditions at 23 ± 2 °C and 40-70% humidity. The rats were allowed free access to tap water and commercial standard rodent chow CRF-1 (Oriental Yeast Co. Ltd., Japan).
Experimental design Sham-operated (n = 8) and the ovariectomized (OVX) rats were used. The OVX rats were divided into each group (n = 8) one day after the surgery. In the sham and OVX control groups, rats received the vehicle (MCT) p.o. at a dose of 1 ml/kg body weight (BW) every day. Each compound was given orally seven times a week for 4 weeks. During the 24 hours from the last administration, urine was collected with metabolic cage, and blood was drawn from the jugular vein under ether anesthesia. Blood and urine samples were centrifuged to obtain the supernatant, which were stored at -20 °C until assay. The lumbar vertebrae and femora were removed. The lumbar vertebra and the right femur were stored in 70% ethanol at 4 °C for the measurement of bone mineral density (BMD).
Serum and urine biochemistry Serum calcium (Ca) and inorganic phosphorus (Pi) concentrations were measured with an autoanalyzer (Hitachi 7170, Tokyo, Japan). The serum osteocalcin concentration was measured with Osteocalcin rat ELISA system (Amersham Pharmacia Biotech, Tokyo, Japan). Urinary Ca, Pi, and creatinine (Cre) were measured with an autoanalyzer. Urinary deoxypyridinoline (D-Pyr) was measured using a Metra DPD EIA kit (Quidel Co., USA), and the data were corrected for urinary Cre concentrations.
Measurement of bone mineral density The second through fifth lumbar vertebaral (L2-L5) BMD (mg/cm2) and femoral BMD were measured by dual-energy X-ray absorptiometry (DCS-600-EX, Aloka, Japan). The results are shown in the following Table 6.
Table 2
Figure imgf000549_0001
Figure imgf000550_0001
Table 3
Figure imgf000550_0002
Figure imgf000551_0001
Figure imgf000552_0001
Table 4
Figure imgf000553_0001
Figure imgf000554_0001
Figure imgf000555_0001
Table 5
Figure imgf000555_0002
Table 6
Figure imgf000555_0003
Figure imgf000556_0001
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

We Claim:
1. A compound of the formula:
Figure imgf000557_0001
wherein X is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene, an ethynylene, -S(0)n-, -NH-, or -0-; n is an integer of 0 to 2; Y is COOR8, CON(R9)R10, S(0)mR11 or a substituent represented by following formula:
Figure imgf000557_0002
R8 and R11 are each independently selected from an optionally substituted C1 -10 alkyl group or an optionally substituted C3-10 cycloalkyl group; R9 and R10 are each independently selected from a hydrogen atom, an optionally substituted C1-10 alkyl group or an optionally substituted C3-10 cycloalkyl group; m is an integer of 0 to 2; a is an integer of 0 to 3; R is a hydrogen atom or a protecting group for a hydroxyl group; R12 and R13 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted 01 -10 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted C2-10 alkenyl group, an optionally substituted C2-10 alkynyl group, or R12 and R13 may together form an optionally substituted 03-012 cycloalkyl group or an optionally substituted 3-12 membered heterocyclic group; W is a hydroxyl group, a carboxyl group, a trifluoromethanesulfonyloxy group or a substituent represented by following formula:
Figure imgf000558_0001
Q is -0-, -S-, -NH-, an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene, an ethynylen, - (CH2)k-NHC(=0)-, -(CH2)k-C(=0)NH-, -(CH2)k-NHC(=0)NH-, -0-(CH2)k- NHC(=0)-, -0-(CH2)k-C(=0)NH-, -0-(CH2)k-NHC(=0)NH- or -(CH2)k-S02-; b is an integer of 0 to 10; k is an integer of 0 to 2; R14 is a hydrogen atom, a hydroxyl group, an optionally substituted carboxyl group, an optionally substituted carbamoyl group, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C1-6 alkenyl group, an optionally substituted C1-6 alkynyl group, an optionally substituted C6-C12 aryl group, an optionally substituted (C6-C12)aryl-(C1-4)alkyl group, -OR17 or -N(R18)R19; R15 and R16 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C6- C12 aryl group, an optionally substituted (C6-C12)aryl-(C1-4)alkyl group, an optionally substituted 3-12 membered heterocyclic group, or R15 and R16 may together form =0; R17 is selected from an optionally substituted C1-6 alkyl group or an optionally substituted C3-C6 cycloalkyl group; R18 and R19 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C6 cycloalkyl group, or R18 and R19 may together form an optionally substituted C3-C12 cycloalkyl group or an optionally substituted 3-12 membered heterocyclic group; or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and
R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered cyclic ring which is selected from the group consisting of an amidine ring, an amine ring, an ether ring, a lactam ring, a lactone ring, an acetal ring, a hemiacetal ring, a carbonate ring, a carbamate ring, an urea ring, combinations thereof; R1 and R2 are each independently selected from the group consisting of a C1-6 alkyl group optionally substituted with a halogen atom(s), a C3-6 cycloalkyl group optionally substituted with a halogen atom(s), a C2-6 alkenyl group optionally substituted with a halogen atom(s), a C2-6 alkynyl group optionally substituted with a halogen atom(s), or R1 and R2 may together form a C3-8 cycloalkyl group optionally substituted with a halogen atom(s), a C3-8 cycloalkenyl group optionally substituted with a halogen atom(s) or a C3-8 cycloalkylidene group optionally substituted with a halogen atom(s); R3, R4, R5 and R6 are each independently selected from the group consisting of a hydrogen atom, a halogen atom, a C1 -6 alkyl group optionally substituted with a halogen atom(s), a C3-6 cycloalkyl group optionally substituted with a halogen atom(s); When X is -S(0)n-, -NH- or -0-, Q is selected from the group consisting of a methylene which may be substituted an C1-4 alkyl group, an ethylene, a vinylene, an ethynylene, -(CH2)k-NHC(=0)-, -(CH2)k-C(=0)NH-, - (CH2)k-NHC(=0)NH-, -(CH2)k-S02-; When Q is -0-, -S-, -NH-, -0-(CH2)k-NHC(=0)-, -0-(CH2)k-C(=0)NH- or -0-(CH2)k-NHC(=0)NH-, X is selected from the group consisting of an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene, an ethynylene; and pharmaceutically acceptable salts and prodrugs thereof.
2. The compound according to claim 1 wherein X is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene or an ethynylene; Y is COOR8, CON(R9)R10, S(0)mR11 or a substituent represented by following formula:
Figure imgf000560_0001
R is a hydrogen atom; R12 and R13 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-10 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted C1-10 alkenyl group, an optionally substituted C1-10 alkynyl group, or R12 and R13 may together form an optionally substituted 03-10 cycloalkyl group; W is a substituent represented by following formula:
-Q-(CH2)b— ^R15 R16 Q is -0-, a methylene, an ethylene, a vinylene, an ethynylene, -
(CH2)k-C(=0)NH- or -0-(CH2)k-C(=0)NH-; R15 and R16 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C6- C12 aryl group, an optionally substituted (C6-C12)aryl-(C1-4)alkyl group, an optionally substituted 3-12 membered heterocyclic group selected from the group consisting of an aziridine group, an azetidine group, an oxetane group, a pyrrolidine group, a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an imidazole group, an oxazole group, a thiazolegroup, a 1 ,2,5- oxadiazole group, a 1 ,3,4-oxadiazole group, a 1 ,3,4-thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a tetrazole group, a piperidine group, a pyridine group, a pyridazine group, a pyrimidine group, a pyrazine group, a tetrahydropyran group, a pyran group, a thiopyran group, an indole group, a benzofuran group, a benzothiophene group, an indazole group, a benzisoxazole group, a benzisothiazole group, a benzimidazole group, a benzoxazole group, a benzothiazole gorup, a quinoline group, an isoquinoline group, a cinnoline group, a phthalazine group, a quinazoline group, a quinoxaline group, or R15 and R16 may together form =0; R17 is an optionally substituted C1-6 alkyl group or an optionally substituted C3-C6 cycloalkyl group; R18 and R19 are each independently selected from a hydrogen atom, an optionally substituted C1-6 alkyl group or an optionally substituted C3-C6 cycloalkyl group; or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered cyclic ring which is selected from a lactam ring or a lactone ring; R1 is a C1-6 alkyl group; R2 is a C1 -6 alkyl group; R3 is a hydrogen atom or a C1-6 alkyl group; R4 is a halogen atom or a C1 -6 alkyl group; R5 is a hydrogen atom; R6 is a halogen atom or a C1-6 alkyl group.
3. The compound according to claim 2 wherein X is an ethylene, a vinylene, or an ethynylene; Y is a substituent represented by following formula: OR (CH2)a R12 R13 R is a hydrogen atom; R12 and R13 are each independently selected from the group consisting of a hydrogen atom, a C1-8 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group; W is a substituent represented by following formula:
Figure imgf000561_0001
Q is -0-, a methylene, an ethylene, a vinylene, an ethynylene, - (CH2)k-C(=0)NH- or -0-(CH2)k-C(=0)NH-; b is an integer of 0 to 5; R14 is a hydrogen atom, a hydroxyl group, a carboxyl group which may be substituted with a C1-4 alkyl group, a carbamoyl group which may be substituted with a C1-4 alkyl group, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group which may be substituted with a C1- 4 alkyl group, a phenyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a benzyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, - OR17 or -N(R18)R19; R15 and R16 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group which may be substituted with a C1-4 alkyl group, a phenyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a benzyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a 3-8 membered heterocyclic group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, wherein said heterocyclic group selected from the group consisting of an oxetane group, a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an oxazole group, a thiazole group, a 1 ,2,5-oxadiazole group, a 1 ,3,4- oxadiazole group, a 1 ,3,4-thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a tetrazole group, a pyridine group, a pyridazine group, a pyrimidine group, a pyrazine group, a tetrahydropyran group, a pyran group, a thiopyran group, or R15 and R16 may together form =0; and at least one of R14, R15 or R16 is a hydrogen atom; R17 is a C1 -4 alkyl group; R18 and R19 are each independently selected from a hydrogen atom or a C1 -4 alkyl group; or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered lactone ring.
4. The compound according to claim 3 wherein R12 and R13 are each independently selected from the group consisting of a hydrogen atom, a C1 -6 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3-8 cycloalkyl group; W is a substituent represented by following formula:
Figure imgf000563_0001
Q is -0-, -(CH2)k-C(=0)NH- or -0-(CH2)k-C(=0)NH-; b is O, 1 or 2; k is l ; R14 is a hydrogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group, a phenyl group which may be substituted with a hydroxyl group or a carboxyl group, a benzyl group which may be substituted with a hydroxyl group or a carboxyl group, -OR17 or -N(R18)R19; R15 and R16 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group, a phenyl group which may be substituted with a hydroxyl group or a carboxyl group, a benzyl group which may be substituted with a hydroxyl group or a carboxyl group, a 3-8 membered heterocyclic group selected from the group consisting of a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an oxazole group, a thiazole group, a 1 ,2,5-oxadiazole group, a 1 ,3,4-oxadiazole group, a 1 ,3,4- thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a pyridine group, a tetrahydropyran group; and at least one of R14, R15 or R16 is a hydrogen atom; R18 is a hydrogen atom; R19 is a hydrogen atom; or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered lactone ring; R1 is a C1-4 alkyl group; R2 is a C1 -4 alkyl group; R3 is a hydrogen atom or a C1-4 alkyl group; R4 is a halogen atom or a C1-4 alkyl group; R5 is a hydrogen atom; R6 is a halogen atom or a C1-4 alkyl group.
5. The compound according to claim 4 wherein R12 and R13 are selected from the group consisting of one of R12 and R13 is a hydrogen atom and the other is a 01- 6 alkyl group, one of R12 and R13 is a hydrogen atom and the other is a C3-
8 cycloalkyl group which may be substituted with a C1-4 alkyl group, both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group; Q is -O- or -0-(CH2)k-C(=0)NH-; R1 is an ethyl group; R2 is an ethyl group; R3 is a hydrogen atom or a methyl group; R4 is a chlorine atom or a methyl group; R6 is a chlorine atom, a methyl group, an ethyl group, a propyl group or an isopropyl group.
6. The compound according to claim 5 selected from the group consisting of (S)-5-(4-{1-Ethyl-1-[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4- (3-hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy- 4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)- vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}- propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1- Ethyl-1-[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hyd roxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4- [(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxyj-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- hexanoic acid, 1 -(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol, (E)-4-[4-(1 -Ethyl-1 -{3- methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1- trifluoro-2-trifluoromethyl-but-3-en-2-ol, (E)-1 -(4-{1 -[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1-en-3-ol, 1- [(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2- methyl-phenyl)-vinyl]-cyclopentanol, (E)-4-(4-{1-[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1 -trifluoro-2- trifluoromethyl-but-3-en-2-ol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1- Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy- 4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4- (3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- benzoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(R)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(S)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-propyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-propyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3- hyd roxy-4 ,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 5(S)-hydroxy-hexanoic acid, 6(R)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro- pyran-2-one, (E)-N-(2-Amino-ethyl)-2-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy- pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetamide, (E)-5- (4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-oxo-pentanoic acid, 2- (R)- [2-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- acetylaminoj-propionic acid, 2- (S)-[2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-3- phenyl-propionic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo-pentanoic acid, 5-(4-{1 - Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-pentane-1 ,4-diol, (R)-5-(2-Chloro-4-{1 -[3-chloro-4-((R)-3- hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxymethyl)- dihydro-furan-2-one, (R)-5-(2-Chloro-4-{1-[3-chloro-4-((S)-3-hydroxy-4,4- dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyI)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro- furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro- furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5- (4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[4-(3- hyd roxy-4 ,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 - methyl-cyclohexyl)-prop-1-ynyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1- methyl-cyclohexyl)-propyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 - methyl-cyclopentyl)-prop-1-ynyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1- methyl-cyclopentyl)-propyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 - methyl-cyclopropyl)-prop-1-ynyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1- methyl-cyclopropyl)-propyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyI}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1-Ethyl- 1-[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl-1 -[4-((S)-3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (S)-5-(4-{1 -[4-((E)-1 ,3-Diethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,5,5,5-pentafluoro-3-hydroxy-3-pentafluoroethyl-pent-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3- methyl-4-(2-methyl-propane-2-sulfinylmethyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(2- methyl-propane-2-sulfonylmethyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- ethyl-3-hydroxy-1 -methyl-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-dec-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hept-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hex-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-non-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-oct-1-en-4-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1- enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-methyl-phenyl]-propyl}-phenoxymethyl)-dihydro-furan-2-one, (S)-5- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-propyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- ethyl-3-hydroxy-undec-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-undec-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-propyl-hex-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(1 -hydroxy- cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5- (4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl- 3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 -ynyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)- 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-propyl-hex-1 -ynyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-decyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-heptyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro- furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-nonyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1- Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-octyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4-di methyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5- [4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)- 2-methyl-phenoxymethyl]-dihydro-furan-2-one, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2- (1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 - hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (S)-5-{4-[1-(4-tert-Butylsulfanylmethyl- 3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxymethyl}-dihydro-furan-2- one, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1-Ethyl- 1-[4-((R)-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[4-((S)-3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one.
7. The compound according to claim 5 wherein R3 is a hydrogen atom.
8. The compound according to claim 7 selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4- (3-hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy- 4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclopentyl)- vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (S )-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}- propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1-Ethyl- 1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1- Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4-di methyl-pent-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4- [(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxy]-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- hexanoic acid, 1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol, (E)-4-[4-(1 -Ethyl-1 -{3- methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1- trifluoro-2-trifluoromethyl-but-3-en-2-ol, (E)-1 -(4-{1 -[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1-en-3-ol, 1- [(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2- methyl-phenyl)-vinyl]-cyclopentanol, (E)-4-(4-{1 -[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1 -trifluoro-2- trifluoromethyl-but-3-en-2-ol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1- Ethyl-1-[4-(3-hyd roxy-4 ,4-dimethyl-pentyl )-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy- 4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4- (3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- benzoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(R)-1-(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 -trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(S)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-propyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-propyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5(S)-hydroxy-hexanoic acid, 6(R)-(4-{1- Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (E)-N-(2-Amino-ethyl)-2-(4- {1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-acetamide, (E)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent- 1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo-pentanoic acid, 2- (R)- [2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-acetylamino]-propionic acid, 2- (S)-[2-(4-{1 -Ethyl- 1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-acetylamino]-3-phenyl-propionic acid, 5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4- oxo-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol.
9. The compound according to claim 5 wherein R4 is a chlorine atom.
10. The compound according to claim 9 selected from 5-(2-Chloro-4-{1 -[3- chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)- 4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4- dimethyl-ρentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl- pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2- Ohloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt.
11. The compound according to claim 5 wherein R6 is a chlorine atom.
12. The compound according to claim 11 selected from the group consisting of 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1 - ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1 -[3- chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)- 4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3- hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt.
13. The compound according to claim 5 wherein R6 is a methyl group.
14. The compound according to claim 13 selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 - Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1- Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclopentyl )-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (S )-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1- Ethyl-1-[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy- pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro- 3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4- [(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxy]-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- hexanoic acid, 1 -(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol, (E)-4-[4-(1 -Ethyl-1 -{3- methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1- trifluoro-2-trifluoromethyl-but-3-en-2-ol, (E)-1 -(4-{1 -[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1-en-3-ol, 1- [(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2- methyl-phenyl)-vinyl]-cyclopentanol, (E)-4-(4-{1-[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1 -trifluoro-2- trifluoromethyl-but-3-en-2-ol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- benzoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(R)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(S)-1-(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 -trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-propyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-propyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 5(S)-hydroxy-hexanoic acid, 6(R)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro- pyran-2-one, (E)-N-(2-Amino-ethyl)-2-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy- pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetamide, (E)-5- (4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-oxo-pentanoic acid, 2- (R)- [2-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- acetylamino]-propionic acid, 2- (S)-[2-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-3- phenyl-propionic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo-pentanoic acid, 5-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-pentane-1 ,4-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Ohloro-4-{1-[3-chloro-4-(3- hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4- (3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5(S)-hydroxy- hexanoic acid.
15. The compound according to claim 5 wherein X is an ethylene.
16. The compound according to claim 15 selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl- butyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-3-(4- {1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)- phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 1 -(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl- phenyl)-4,4-dimethyl-pentan-3-ol, 2- (R)- [2-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]- propionic acid, 2- (S)-[2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-3-phenyl-propionic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4-oxo-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- pentane-1 ,4-diol.
17. The compound according to claim 5 wherein X is a vinylene.
18. The compound according to claim 17 selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1- Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4- hydroxy-pentanoic acid, (S )-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)- vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl- 1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 - Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)- 6-(4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl- but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)- 3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2- (4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxymethyl)-propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}- propyl)-2-methyl-phenoxy]-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]- pentanoic acid, 3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)- 2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2-ol, (E)-1-(4-{1-[4- (5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3- ethyl-pent-1 -en-3-ol, 1 -[(E)-2-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]- 1 -ethyl-propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol, (E)-4-(4-{1 -[4-(5- Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1- trifluoro-2-trifluoromethyl-but-3-en-2-ol, 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- benzoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(R)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 -trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(S)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-propyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-propyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, 6(R)-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (E)-N-(2-Amino-ethyl)-2-(4-{1-ethyl- 1-[4-(3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-acetamide, (E)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo-pentanoic acid.
19. The compound according to claim 5 wherein X is an ethynylene.
20. The compound according to claim 19 selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl- but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)- 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1-Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1-Ethyl- 1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4- (3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1-ynyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 - Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol.
21. The compound according to claim 5 wherein one of R12 and R13 is a hydrogen atom and the other is a C1-6 alkyl group.
22. The compound according to claim 21 wherein one of R12 and R13 is a hydrogen atom and the other is a tert-butyl group.
23. The compound according to claim 22 selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-3-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4- dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 1-(4-{1-[4-(5- Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-4,4- dimethyl-pentan-3-ol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5- (4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1 -Ethyl-1 - [4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy- pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4- dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1- ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2- Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4- (3-hyd roxy-4 ,4-dimethyl-pentyl )-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 6-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5(S)-hydroxy- hexanoic acid, 2- (R)- [2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-propionic acid, 2- (S)-[2-(4-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-acetylamino]-3-phenyl-propionic acid.
24. The compound according to claim 5 wherein both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s).
25. The compound according to claim 24 wherein R12 is a trifluoromethyl group and R13 are is a trifluoromethyl group.
26. The compound according to claim 25 selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 - Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 - Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1- Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2- (4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - ynyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 - Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1- enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1-
Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-((E)-3- ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}- propyl)-2-methyl-phenoxy]-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 - hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]- pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)- 2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2-ol, (E)-1-(4-{1-[4- (5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3- ethyl-pent-1-en-3-ol, 1-[(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]- 1 -ethyl-propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol, (E)-4-(4-{1 -[4-(5- Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1- trifluoro-2-trifluoromethyl-but-3-en-2-ol, 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- benzoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl )-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(R)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(S)-1-(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-propyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-propyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, 6(R)-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (E)-N-(2-Amino-ethyl)-2-(4-{1-ethyl- 1-[4-(3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-acetamide, (E)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo-pentanoic acid, 2- (R)- [2- (4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl )-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-acetylamino]-propionic acid, 2- (S)-[2-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- acetylamino]-3-phenyl-propionic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo- pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol.
27. The compound according to claim 5 wherein Q is -O-
28. The compound according to claim 27 selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 - Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1- Ethyl-1-[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4- [(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxyj-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- hexanoic acid, 1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol, (E)-4-[4-(1 -Ethyl-1 -{3- methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 - trifluoro-2-trifluoromethyl-but-3-en-2-ol, (E)-1-(4-{1-[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1-en-3-ol, 1- [(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2- methyl-phenyl)-vinyl]-cyclopentanol, (E)-4-(4-{1-[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1-trifluoro-2- trifluoromethyl-but-3-en-2-ol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy- 4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1 -ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4- (3-hyd roxy-4 ,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- benzoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(R)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[(S)-1 -(tetrahydro-furan-2-yl)methoxy]- phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 -trifluoro-2-trifluoromethyl-but-3-en-2- ol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-propyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-propyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 5(S)-hydroxy-hexanoic acid, 6(R)-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-tetrahydro- pyran-2-one, (E)-N-(2-Amino-ethyl)-2-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetamide, (E)-5- (4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-oxo-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo- pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol.
29. The compound according to claim 5 wherein at least one of R14, R15 or R16 is a substituent which have a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group.
30. The compound according to claim 29 selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 - Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 - Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)~ 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5- (4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4- (4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4- {1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 - Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4- {1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 - Ethyl-1 -[3-methyl-4-((E)-4 ,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4- {1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane- 1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1- Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane- 1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 - [4-((E)-3-hyd roxy-4 ,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4- [(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxy]-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)- hexanoic acid, 1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol, (E)-4-[4-(1 -Ethyl-1 -{3- methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1- trifluoro-2-trifluoromethyl-but-3-en-2-ol, (E)-1 -(4-{1 -[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1 -en-3-ol, 1 - [(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2- methyl-phenyl)-vinyl]-cyclopentanol, (E)-4-(4-{1 -[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1-trifluoro-2- trifluoromethyl-but-3-en-2-ol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1- Ethyl-1-[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy- 4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4- (3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 4-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- benzoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-propyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5(S)-hydroxy-hexanoic acid, (E)-N-(2- Amino-ethyl)-2-(4-{1 -ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-acetamide, (E)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl- 3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-oxo- pentanoic acid, 2- (R)- [2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-acetylamino]-propionic acid, 2- (S)-[2-(4-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-acetylamino]-3-phenyl-propionic acid, 5-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-oxo-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4- diol.
31. The compound according to claim 5 wherein R14 is a hydroxyl group.
32. The compound according to claim 31 selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1- Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 - Ethyl-1 -[4-(3-hyd roxy-4 ,4-d i methyl-pent- 1 -ynyl )-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (S )-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5- (4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4- (4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4- {1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 - Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1- enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4- {1 -Ethyl-1 -[3-methyl-4-(4 ,4 ,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1- Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1- enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4- {1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane- 1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1-ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 - Ethyl-1-[4-((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane- 1 ,2-diol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4- (3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Ohloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1-[3-chloro-4- (3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy- 4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl- but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol, (S)-5-(4-{1 - Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol, (R)-5-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-pentane-1 ,4-diol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-phenoxy)-4-hydroxy- pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2,6-dimethyl-phenoxy)-4-hydroxy-pentanoic acid, (S)- 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-propyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4 ,4-dimethyl-pentyl )-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 5(S)-hydroxy-hexanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol.
33. The compound according to claim 5 wherein one of R15 and R16 is a hydrogen atom and the other is a C1-6 alkyl group substituted with a carboxyl group.
34. The compound according to claim 33 selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 - Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 - Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl )-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5- (4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-4- (4-{1-Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -enyl)-ρhenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (R)-4-(4- {1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - enyl)-phenyl]-propyl}-2-methyl-phenoxy)-3-hydroxy-butyric acid, (S)-6-(4-{1 - Ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1- enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4- {1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 - Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1- enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, 2-(4-{1 - Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 5-(4-{1 -Ethyl-1 -[4-(3- hyd roxy-4 ,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 5-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -enyl)-phenyl]- propyl}-2-methyl-phenoxy)-pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]- pentanoic acid, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenoxy)-hexanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3- hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy- pentanoic acid, 5-(2-Ohloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid sodium salt, 5-(2-Chloro-4-{1-[3-chloro-4-(3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1 -ethyl- propyl}-phenoxy)-4(R)-hydroxy-pentanoic acid, 5-(2-Chloro-4-{1 -[3-chloro-4- (3-hydroxy-4 ,4-dimethyl-pentyl )-phenyl]-1-ethyl-propyl}-phenoxy)-4(R)- hydroxy-pentanoic acid sodium salt, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-phenoxy)-4-hydroxy- pentanoic acid, (S )-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2,6-dimethyl-phenoxy)-4-hydroxy-pentanoic acid, (S)- 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-propyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3- hyd roxy-4 ,4-dimethyl-pentyl )-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 5(S)-hydroxy-hexanoic acid.
35. The compound according to claim 5 wherein one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) together form a 3-12 membered lactone ring.
36. The compound according to claim 35 selected from the group consisting of (R)-5-(2-Chloro-4-{1-[3-chloro-4-((R)-3-hydroxy-4,4-dimethyl-pentyl)- phenyl]-1-ethyl-propyl}-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(2- Chloro-4-{1-[3-chloro-4-((S)-3-hydroxy-4,4-dimethyl-pentyl)-phenyl]-1-ethyl- propyl}-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3- ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3- hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (R)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (R)- 5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 -methyl-cyclohexyl)-prop-1 -ynyl]-3-methyl- phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1- Ethyl-1-{4-[3-hydroxy-3-(1-methyl-cyclohexyl)-propyl]-3-methyl-phenyl}- propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4- [3-hydroxy-3-(1-methyl-cyclopentyl)-prop-1-ynyl]-3-methyl-phenyl}-propyl)-2- methyl-phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3- hydroxy-3-(1-methyl-cyclopentyl)-propyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 - methyl-cyclopropyl)-prop-1-ynyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-5-[4-(1 -Ethyl-1 -{4-[3-hydroxy-3-(1 - methyl-cyclopropyl)-propyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (R)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl- 1-[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (R)-6-(4-{1 -Ethyl-1 -[4-((S)-3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (S)-5-(4-{1 -[4-((E)-1 ,3-Diethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4- ((E)-4,4,5,5,5-pentafluoro-3-hydroxy-3-pentafluoroethyl-pent-1-enyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3- methyl-4-(2-methyl-propane-2-sulfinylmethyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(2- methyl-propane-2-sulfonylmethyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-methoxymethoxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- ethyl-3-hydroxy-1-methyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-dec-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hept-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-hex-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-non-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-oct-1-en-4-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-oct-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-methyl-phenyl]-propyl}-phenoxymethyl)-dihydro-furan-2-one, (S)-5- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-propyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3- ethyl-3-hydroxy-undec-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-undec-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-propyl-hex-1-enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4- ((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(1 -hydroxy- cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5- (4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl- 3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 -ynyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)- 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-propyl-hex-1 -ynyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-decyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-heptyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro- furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-nonyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1- Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-octyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- dihydro-furan-2-one, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one, (S)-5- [4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)- 2-methyl-phenoxymethyl]-dihydro-furan-2-one, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2- (1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1- hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-dihydro-furan-2-one, (S)-5-{4-[1-(4-tert-Butylsulfanylmethyl- 3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxymethyl}-dihydro-furan-2- one, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl- 1-[4-((R)-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one, (S)-6-(4-{1 -Ethyl-1 -[4-((S)-3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-tetrahydro-pyran-2-one.
37. The compound according to claim 4 wherein R12 and R13 are selected from the group consisting of one of R12 and R13 is a hydrogen atom and the other is a C1- 6 alkyl group, one of R12 and R13 is a hydrogen atom and the other is a C3- 8 cycloalkyl group which may be substituted with a C1-4 alkyl group, both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group; Q is a methylene, an ethylene, an ethynylene or -(CH2)k-C(=0)NH-; R1 is an ethyl group; R2 is an ethyl group; R3 is a hydrogen atom; R4 is a chlorine atom or a methyl group; R6 is a chlorine atom or a methyl group.
38. The compound according to claim 37 selected from the group consisting of 3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 3-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenyl)-propionic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-dimethyl-pentyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1- [3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)- phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl- 4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenyl)-pent-4-ynoic acid, 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-hept-6-ynoic acid.
39. The compound according to claim 37 wherein R3 is a hydrogen atom.
40. The compound according to claim 39 selected from the group consisting of 3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 3-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenyl)-propionic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl- phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 - [3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)- phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl- 4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenyl)-pent-4-ynoic acid, 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-hept-6-ynoic acid.
41. The compound according to claim 37 wherein R4 is a chlorine atom.
42. The compound according to claim 37 wherein R6 is a chlorine atom.
43. The compound according to claim 37 wherein R6 is a methyl group.
44. The compound according to claim 43 selected from the group consisting of 3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 3-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenyl)-propionic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid , 6-(4-{1 -Ethyl-1 - [3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)- phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl- 4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenyl)-pent-4-ynoic acid, 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-hept-6-ynoic acid.
45. The compound according to claim 37 wherein X is an ethylene.
46. The compound according to claim 45 which is 6-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-hex- 5-ynoic acid.
47. The compound according to claim 37 wherein X is a vinylene.
48. The compound according to claim 47 selected from the group consisting of 3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl- but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 6-(4-{1 -Ethyl-1 - [3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)- phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl- 4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenyl)-pent-4-ynoic acid, 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-hept-6-ynoic acid.
49. The compound according to claim 37 wherein X is an ethynylene.
50. The compound according to claim 49 selected from 3-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenyl)-propionic acid or 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenyl)-hex-5-ynoic acid.
51. The compound according to claim 37 wherein one of R12 and R13 is a hydrogen atom and the other is a C1-6 alkyl group.
52. The compound according to claim 51 wherein one of R12 and R13 is a hydrogen atom and the other is a tert-butyl group.
53. The compound according to claim 52 which is 6-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-hex- 5-ynoic acid.
54. The compound according to claim 37 wherein both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s).
55. The compound according to claim 54 wherein R12 is a trifluoromethyl group and R13 are is a trifluoromethyl group.
56. The compound according to claim 55 selected from the group consisting of 3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 3-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenyl)-propionic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)- hex-5-ynoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-pent-4-ynoic acid, 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl- (E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid.
57. The compound according to claim 37 wherein Q is an ethylene.
58. The compound according to claim 57 selected from 3-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenyl)-propionic acid or 3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)- 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2- methyl-phenyl)-propionic acid.
59. The compound according to claim 37 wherein Q is an ethynylene.
60. The compound according to claim 59 selected from the group consisting of 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]- propyl}-2-methyl-phenyl)-hex-5-ynoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-pent-4-ynoic acid, 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)- hept-6-ynoic acid, 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenyl)-hex-5-ynoic acid.
61. The compound according to claim 37 wherein at least one of R14, R15 or R16 is a substituent which have a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group.
62. The compound according to claim 61 selected from the group consisting of 3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1-ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 3-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenyl)-propionic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)- hex-5-ynoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenyl)-pent-4-ynoic acid, 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4-trifluoro-3-hydroxy-3-trifluoromethyl- (E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid, 7-(4-{1- Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)- phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid, 6-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-hex- 5-ynoic acid.
63. The compound according to claim 37 wherein R14 is a hydroxyl group.
64. The compound according to claim 37 wherein one of R15 and R16 is a hydrogen atom and the other is a C1-6 alkyl group substituted with a carboxyl group.
65. The compound according to claim 64 selected from the group consisting of 3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but- 1 -ynyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 3-(4-{1 -Ethyl-1 -[3- methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]- propyl}-2-methyl-phenyl)-propionic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenyl)-hex-5-ynoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-(E)-but-1-enyl)-phenyl]-propyl}-2-methyl-phenyl)- hex-5-ynoic acid, 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-(E)-but-1-eny|)-phenyl]-propyl}-2-methyl-phenyl)-pent-4-ynoic acid, 7-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl- (E)-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenyl)-hept-6-ynoic acid, 6-(4-{1 - Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- i methyl-phenyl)-hex-5-ynoic acid.
66. The compound according to claim 37 wherein one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) together form a 3-12 membered lactone ring.
67. The compound according to claim 1 wherein X is an optionally substituted vinylene, or an ethynylene.
68. The compound according to claim 1 wherein W is a substituent represented by following formula:
Figure imgf000612_0001
Q is selected from the group consisting of -0-, a methylene, an ethylene, a vinylene, and an ethynylene; and wherein b is 1 ; R14 is a hydroxyl group; R15 is a hydrogen atom; R16 is a C1-6 alkyl group substituted with a carboxyl group.
69. The compound according to claim 1 selected from the group consisting of (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1- Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-5-(4-{1- Ethyl-1-[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3- hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6- (4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(3-ethyl-3- hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane- 1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(3-ethyl- 3-hydroxy-pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 - Ethyl-1-[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pent-1 -ynyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 - [4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenyl)-propionic acid, 1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1- ethyl-propyl}-2-methyl-phenyl)-3-ethyl-pent-1-yn-3-ol, 3-Ethyl-1-[4-(1 -ethyl-1 - {3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]- pent-1-yn-3-ol, (S )-5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5- (4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-((E)-3- ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5- hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-((E)-3-ethyl-3- hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, (E)-1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2- methyl-phenyl)-3-ethyl-pent-1 -en-3-ol, (E)-3-Ethyl-1 -[4-(1 -ethyl-1 -{3-methyl- 4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-pent-1-en-3- ol, (S)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(3-ethyl- 3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1- Ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4- {1-Ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pentyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-(3-ethyl-3- hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-(3-ethyl-3-hydroxy- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 1-(4-{1-[4- (5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3- ethyl-pentan-3-ol, 3-Ethyl-1 -[4-(1 -ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)- butoxy]-phenyl}-propyl)-2-methyl-phenyl]-pentan-3-ol, (R)-5-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S )-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2- methyl-phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]-propyl}-2-methyl- phenol, 5-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1 - ynyl)-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenyl)-propionic acid, 4-(4-{1-[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1-trifluoro-2- trifluoromethyl-but-3-yn-2-ol, 4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)- butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but- 3-yn-2-ol, (S)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy- 3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2- diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 4-{1 -Ethyl-1 -[3-methyl-4-((E)-4 ,4 ,4-trifluoro-3-hydroxy-3- trifluoromethyl-but-1 -enyl)-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 - [3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)- phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl- 4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}- 2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[3-methyl-4-((E)-4,4 ,4- trifluoro-3-hydroxy-3-trifluoromethyl-but-1-enyl)-phenyl]-propyl}-2-methyl- phenyl)-propionic acid, (E)-4-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]- 1-ethyl-propyl}-2-methyl-phenyl)-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2- ol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}- propyl)-2-methyl-phenyl]-1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-en-2-ol, (S)-5- (4-{1-Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1- Ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2- methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[3-methyl-4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[3-methyl-4-(4 ,4,4- trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3- hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2- methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro- 3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenoxy)- hexanoic acid, 3-(4-{1 -Ethyl-1 -[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 4-(4- {1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)- 1 ,1 ,1-trifluoro-2-trifluoromethyl-butan-2-ol, 4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H- tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-1 ,1 ,1 -trifluoro-2- trifluoromethyl-butan-2-ol, (S )-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 - ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4- (3-hydroxy-3-methyl-but-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 - ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 -ynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3- methyl-but-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but- 1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 6-(4-{1 - Ethyl-1 -[4-(3-hydroxy-3-methyl-but-1-ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-but- 1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 4-(4-{1-[4- (5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-2- methyl-but-3-yn-2-ol, 4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)- butoxy]-phenyl}-propyl)-2-methyl-phenyl]-2-methyl-but-3-yn-2-ol, (S)-5-(4-{1- Ethyl-1-[4-((E)-3-hydroxy-3-methyl-but-1-enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3- hydroxy-3-methyl-but-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 -enyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4- ((E)-3-hydroxy-3-methyl-but-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 4- {1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 -enyl)-3-methyl-phenyl]-propyl}-2- methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4- ((E)-3-hydroxy-3-methyl-but-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-3-methyl-but-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, (E)-4-(4-{1 - [4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-2- methyl-but-3-en-2-ol, (E)-4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)- butoxy]-phenyl}-propyl)-2-methyl-phenyl]-2-methyl-but-3-en-2-ol, (S)-5-(4-{1- Ethyl-1-[4-(3-hydroxy-3-methyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3- methyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-butyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1- Ethyl-1-[4-(3-hydroxy-3-methyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3- methyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1-Ethyl-1-[4-(3-hydroxy-3-methyl-butyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(3-hydroxy-3- methyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4- (3-hydroxy-3-methyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-3-methyl-butyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-(3- hydroxy-3-methyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 4-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2- methyl-phenyl)-2-methyl-butan-2-ol, 4-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H- tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-2-methyl-butan-2-ol, (S)-5-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclobutylethynyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(1- hydroxy-cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclobutylethynyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6- (4-{1 -Ethyl-1 -[4-(1-hyd roxy-cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(1-hydroxy- cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2- diol, 2-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclobutylethynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(1- hydroxy-cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4- {1 -Ethyl-1 -[4-(1 -hydroxy-cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(1 -hydroxy- cyclobutylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclobutylethynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenyl)-propionic acid, 1-(4-{1-[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenylethynyl)-cyclobutanol, 1 -[4-(1 - Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl- phenylethynyl]-cyclobutanol, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (R)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclobutyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (S)-6- [4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)- 2-methyl-phenoxy]-5-hydroxy-hexanoic acid, (R)-6-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 - hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-5- hydroxy-hexanoic acid, (S)-3-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclobutyl)- vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-propane-1 ,2-diol, 2-[4-(1 - Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)-2- methyl-phenoxymethyl]-propane-1 ,3-diol, 4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy- cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol, 5-[4-(1 -Ethyl-1 - {4-[(E)-2-(1-hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxy]-pentanoic acid, 6-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclobutyl)- vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid, 3-[4-(1- Ethyl-1-{4-[(E)-2-(1-hydroxy-cyclobutyl)-vinyl]-3-methyl-phenyl}-propyl)-2- methyl-phenylj-propionic acid, 1-[(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-vinyl]-cyclobutanol, 1 -{(E)-2- [4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2- methyl-phenyl]-vinyl}-cyclobutanol, (S)-5-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy- cyclobutyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (R)-5-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclobutyl)-ethyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (S)-6- [4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclobutyl)-ethyl]-3-methyl-phenyl}-propyl)-2- methyl-phenoxy]-5-hydroxy-hexanoic acid, (R)-6-[4-(1 -Ethyl-1 -{4-[2-(1 - hydroxy-cyclobutyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-5- hydroxy-hexanoic acid, (S)-3-[4-(1 -Ethyl-1 -{4-[2-(1-hydroxy-cyclobutyl)- ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-propane-1 ,2-diol, 2-[4-(1 - Ethyl-1 -{4-[2-(1 -hydroxy-cyclobutyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxymethyl]-propane-1 ,3-diol, 4-(1 -Ethyl-1 -{4-[2-(1-hydroxy-cyclobutyl)- ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol, 5-[4-(1 -Ethyl-1 -{4-[2-(1 - hydroxy-cyclobutyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]- pentanoic acid, 6-[4-(1 -Ethyl-1 -{4-[2-(1-hydroxy-cyclobutyl)-ethyl]-3-methyl- phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid, 3-[4-(1 -Ethyl-1 -{4-[2-(1 - hydroxy-cyclobutyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]- propionic acid, 1-[2-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-ethyl]-cyclobutanol, 1-{2-[4-(1 -Ethyl-1 -{3-methyl-4- [4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-ethyl}- cyclobutanol, (S)-5-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 - Ethyl-1 -[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-(1 -hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4- {1 -Ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-(1 -hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(1-hydroxy-cyclopentylethynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-(1-hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclopentylethynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-(1-hydroxy- cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-propionic acid, 1 -(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2- methyl-phenylethynyl)-cyclopentanol, 1 -[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H- tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenylethynyl]-cyclopentanol, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}- propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)-5-[4-( 1 -Ethyl-1 -{4- [(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxy]-4-hydroxy-pentanoic acid, (S)-6-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-5-hydroxy- hexanoic acid, (R)-6-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-5-hydroxy-hexanoic acid, (S)-3-[4- (1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)- 2-methyl-phenoxy]-propane-1 ,2-diol, 2-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]- propane-1 ,3-diol, 4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenol, 5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy- cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 6-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclopentyl)-vinyl]-3-methyl- phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid, 3-[4-(1 -Ethyl-1 -{4-[(E)-2- (1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]- propionic acid, 1 -[(E)-2-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 - ethyl-propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol, 1-{(E)-2-[4-(1 -Ethyl-1 -{3- methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]- vinylj-cyclopentanol, (S)-5-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclopentyl)-ethyl]- 3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (R)- 5-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-propyl)- 2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (S)-6-[4-(1 -Ethyl-1 -{4-[2-(1 - hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-5- hydroxy-hexanoic acid, (R)-6-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclopentyl)- ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-5-hydroxy-hexanoic acid, (S)-3-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}- propyl)-2-methyl-phenoxy]-propane-1 ,2-diol, 2-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy- cyclopentyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]- propane-1 ,3-diol, 4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclopentyl)-ethyl]-3-methyl- phenyl}-propyl)-2-methyl-phenol, 5-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy- cyclopentyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-pentanoic acid, 6-[4-(1 -Ethyl-1 -{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}- propyl)-2-methyl-phenoxy]-hexanoic acid, 3-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy- cyclopentyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-propionic acid, 1 -[2-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl- phenyl)-ethyl]-cyclopentanol, 1 -{2-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5- yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-cyclopentanol, (S)-5-(4- {1 -Ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(1- hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6- (4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(1 -hydroxy- cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2- diol, 2-(4-{1 -Ethyl-1 -[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(1 - hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4- {1 -Ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(1 -hydroxy- cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4-(1 -hydroxy-cyclohexylethynyl)-3-methyl-phenyl]- propyl}-2-methyl-phenyl)-propionic acid, 1-(4-{1-[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenylethynyl)-cyclohexanol, 1 -[4- (1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl- phenylethynyl]-cyclohexanol, (S)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy- cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (R)-5-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (S)-6- [4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)- 2-methyl-phenoxy]-5-hydroxy-hexanoic acid, (R)-6-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 - hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-5- hydroxy-hexanoic acid, (S)-3-[4-(1 -Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)- vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-propane-1 ,2-diol, 2-[4-(1 - Ethyl-1 -{4-[(E)-2-(1 -hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2- methyl-phenoxymethyl]-propane-1 ,3-diol, 4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy- cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol, 5-[4-(1 -Ethyl-1 - {4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxy]-pentanoic acid, 6-[4-(1 -Ethyl-1 -{4-[(E)-2-(1-hydroxy-cyclohexyl)~ vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-hexanoic acid, 3-[4-(1- Ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2- methyl-phenyl]-propionic acid, 1-[(E)-2-(4-{1-[4-(5-Amino-pentyloxy)-3- methyl-phenyl]-1 -ethyl-propyl}-2-methyl-phenyl)-vinyl]-cyclohexanol, 1 -{(E)- 2-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2- methyl-phenyl]-vinyl}-cyclohexanol, (S)-5-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy- cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy- pentanoic acid, (R)-5-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclohexyl)-ethyl]-3- methyl-phenyl}-propyl)-2-methyl-phenoxy]-4-hydroxy-pentanoic acid, (S)-6- [4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl)-2- methyl-phenoxy]-5-hydroxy-hexanoic acid, (R)-6-[4-(1 -Ethyl-1 -{4-[2-(1- hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-5- hydroxy-hexanoic acid, (S)-3-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclohexyl)- ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-propane-1 ,2-diol, 2-[4-(1 - Ethyl-1 -{4-[2-(1 -hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl )-2- methyl-phenoxymethyl]-propane-1 ,3-diol, 4-(1 -Ethyl-1 -{4-[2-(1-hydroxy- cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol, 5-[4-(1 -Ethyl-1 - {4-[2-(1 -hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl)-2-methyl- phenoxyj-pentanoic acid,
6-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy-cyclohexyl )-ethyl]-3-methyl-phenyl}-propyl)- 2-methyl-phenoxy]-hexanoic acid, 3-[4-(1 -Ethyl-1 -{4-[2-(1 -hydroxy- cyclohexyl )-ethyl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-propionic acid, 1 -[2-(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1 -ethyl-propyl}-2-methyl- phenyl)-ethyl]-cyclohexanol, 1 -{2-[4-(1 -Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5- yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-cyclohexanol, (S)-5-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-4-hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-4-hydroxy-pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4- dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5- hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent- 1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 -ynyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- pent-1 -ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pent-1 - ynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1- Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2- methyl-phenyl)-propionic acid, 1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl- phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pent-1-yn-3-ol, 1-[4-(1- Ethyl-1-{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl- phenyl]-4,4-dimethyl-pent-1 -yn-3-ol, (S)-5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy- 4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4- hydroxy-pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl- pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, (S)-6-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 - enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1 -enyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy-hexanoic acid, (S)-3-(4-{1- Ethyl-1-[4-((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}- 2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4- dimethyl-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxymethyl)- propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy- 4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 -[4- ((E)-3-hydroxy-4,4-dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl- phenyl)-propionic acid, (E)-1 -(4-{1 -[4-(5-Amino-pentyloxy)-3-methyl-phenyl]- 1 -ethyl-propyl}-2-methyl-phenyl)-4,4-dimethyl-pent-1 -en-3-ol, (E)-1 -[4-(1 - Ethyl-1 -{3-methyl-4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl- phenyl]-4,4-dimethyl-pent-1-en-3-ol, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy- pentanoic acid, (R)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid, (S)-6- (4-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-5-hydroxy-hexanoic acid, (R)-6-(4-{1 -Ethyl-1 -[4-(3-hydroxy- 4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-5-hydroxy- hexanoic acid, (S)-3-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 2-(4-{1 -Ethyl-1 - [4-(3-hyd roxy-4 ,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxymethyl)-propane-1 ,3-diol, 4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl- pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol, 5-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- pentanoic acid, 6-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl- phenyl]-propyl}-2-methyl-phenoxy)-hexanoic acid, 3-(4-{1 -Ethyl-1 ~[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)- propionic acid, 1-(4-{1-[4-(5-Amino-pentyloxy)-3-methyl-phenyl]-1-ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol, 1 -[4-(1 -Ethyl-1 -{3-methyl- 4-[4-(1 H-tetrazol-5-yl)-butoxy]-phenyl}-propyl)-2-methyl-phenyl]-4,4-dimethyl- penta n-3-ol , 4-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4 ,4-d i methyl-pentyl )-3-methyl- phenyl]-propyl}-2-methyl-phenyl)-butane-1 ,2-diol, (S)-3-(4-{1 -Ethyl-1 -[4-((R)- 3-hyd roxy-4 ,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (R)-3-(4-{1 -Ethyl-1 -[4-((R)-3-hydroxy-4,4-dimethyl-pentyl)- 3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, (S)-3-(4-{1 - Ethyl-1 -[4-((S)-3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol, (R)-3-(4-{1 -Ethyl-1 -[4-((S )-3-hyd roxy-4 ,4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2- diol, 2-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]- propyl}-2-methyl-phenoxymethyl)-propane-1 ,3-diol, 3-(4-{1 -Ethyl-1 -[4-(3- hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- propane-1 ,2-diol, (S)-5-(4-{1 -Ethyl-1 -[4-(3-hydroxy-4,4-dimethyl-pentyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-pentane-1 ,4-diol, 1 -(4-{1 -Ethyl-1 - [4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl- phenyl)-4,4-dimethyl-pentan-3-ol, 1-(4-{1 -Ethyl-1 -[4-(3-hydroxy-propyl)-3- methyl-phenyl]-propyl}-2-methyl-phenyl)-4,4-dimethyl-pentan-3-ol, (S)-3-(4- {1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2- methyl-phenoxy)-propane-1 ,2-diol, (R)-3-(4-{1 -Ethyl-1 -[4-(3-hyd roxy-4, 4- dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2- diol, 4-(4-{1 -Ethyl-1 -[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]- propyl}-2-methyl-phenyl)-butane-1 ,2-diol, 1-(4-{1 -Ethyl-1 -[4-(3-hydroxy- propyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol, 3-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}- 2-methyl-phenyl)-propane-1 ,2-diol, 3-(4-{1 -Ethyl-1 -[4-(2-hydroxy-3,3- dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-butane-1 ,2-diol, 1 -(4-{1 -Ethyl-1 -[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}- 2-methyl-phenyl)-propane-1 ,2-diol, 1-(4-{1 -Ethyl-1 -[4-(3-hydroxy-butyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol, (E)-4-(4- {1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2- methyl-phenyl)-but-3-en-2-ol, 3-(4-{1 -Ethyl-1 -[4-(2-hydroxy-3,3-dimethyl- butoxy)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-butan-1-ol, 1-(4-{1-[4- (2,3-Dihydroxy-propyl)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenoxy)- 3,3-dimethyl-butan-2-one, 1 -(4-{1 -[4-(2,3-Dihydroxy-1 -methyl-propyl)-3- methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one, 1 -(4-{1 -Ethyl-1 -[4-(3-hydroxy-butyl)-3-methyl-phenyl]-propyl}-2-methyl- phenoxy)-3,3-dimethyl-butan-2-one, 3-(4-{1 -Ethyl-1 -[4-(2-hydroxy-3,3- dimethyl-butyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2- diol, (E)-1 -(4-{1 -[4-((S)-2,3-Dihydroxy-propoxy)-3-methyl-phenyl]-1 -ethyl- propyl}-2-methyl-phenyl)-4,4-dimethyl-pent-1 -en-3-one, (E)-1 -(4-{1 -[4-((R)- 2,3-Dihydroxy-propoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)- 4,4-dimethyl-pent-1 -en-3-one, (S)-3-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4,4- dimethyl-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane- 1 ,2-diol, (R)-3-(4-{1 -Ethyl-1 -[4-((E)-3-hydroxy-4 ,4-dimethyl-pent-1 -enyl)-3- methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1 ,2-diol, 1-(4-{1-[4-((R)- 2,3-Dihydroxy-propoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)- 4,4-dimethyl-pentan-3-one.
70. The compound according to claim 1 which is (S)-5-(4-{1 -Ethyl-1 -[4-((E)- 3-ethyl-3-hydroxy-pent-1-enyl)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)- 4-hydroxy-pentanoic acid.
71. The compound according to claim 1 which is (S)-5-(4-{1 -Ethyl-1 -[3- methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-but-1-ynyl)-phenyl]- propyl}-2-methyl-phenoxy)-4-hydroxy-pentanoic acid.
72. A pharmaceutical composition comprising the compound according to any one of claims 1 to 71.
73. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 71 in combination with a pharmaceutically acceptable carrier.
74. A method for modulating the activity of the vitamin D receptor in a mammal comprising administering an effective amount of the compound according to any one of claims 1 to 71.
75. A method of treating a condition associated with the vitamin D receptor in a mammal comprising administering an affective amount of the compound according to any one of claims 1 to 71.
76. A method of treating a condition comprising administering an affective amount of the compound according to any one of claims 1 to 71 , wherein the condition is selected from the group consisting of abscess, acne, adhesion, alopecia, Alzheimer's disease, benign prostatic hyperplasia, bone fracture healing, cancer, autoimmune induced diabetes, host-graft rejection, insufficient sebum secretion, insufficient dermal firmness, humoral hypercalcemia, insufficient dermal hydration, leukemia, lupus, multiple sclerosis, osteomalacia, osteoporosis, psoriatic arthritis, psoriasis, renal failure, renal osteodystrophy, rheumatoid arthritis, scleroderma, secondary hyperparathyroidism, systemic lupus erythematosus, and wrinkles, cornea wound, cornea healing, retinopathy, sway, muscle weakness, fall, chronic glomerulonephritis, lupus nephritis, diabetic nephropathy, hypocalcemia, hypoparathyroidism, rickets, osteoarthritis.
77. The method according to claim 76 wherein said condition is selected from the group consisting of benign prostatic hyperplasia, cancer, osteoporosis, psoriasis, secondary hyperparathyroidism, chronic glomerulonephritis, lupus nephritis, diabetic nephropathy, sway, muscle weakness, fall, rheumatoid arthritis, osteoarthritis.
78. The method according to claim 76 wherein said condition is benign prostatic hyperplasia.
79. The method according to claim 76 wherein said condition is cancer.
80. The method according to claim 76 wherein said condition is osteoporosis.
81. The method according to claim 76 wherein said condition is psoriasis.
82. The method according to claim 76 wherein said condition is secondary hyperparathyroidism.
83. The method according to claim 76 wherein said condition is chronic glomerulonephritis.
84. The method according to claim 76 wherein said condition is lupus nephritis.
85. The method according to claim 73 wherein said condition is diabetic nephropathy.
86. An agent for modulating the activity of the vitamin D receptor in a mammal, which comprises the compound according to any one of claims 1 to 71 as an active ingredient.
87. An agent for treating a condition associated with the vitamin D receptor in a mammal, which comprises the compound according to any one of claims 1 to 71 as an active ingredient.
88. An agent for treating a condition, which comprises the compound according to any one of claims 1 to 71 as an active ingredient, wherein the condition is selected from the group consisting of abscess, acne, adhesion, alopecia, Alzheimer's disease, benign prostatic hyperplasia, bone fracture healing, cancer, autoimmune induced diabetes, host-graft rejection, insufficient sebum secretion, insufficient dermal firmness, humoral hypercalcemia, insufficient dermal hydration, leukemia, lupus, multiple sclerosis, osteomalacia, osteoporosis, psoriatic arthritis, psoriasis, renal failure, renal osteodystrophy, rheumatoid arthritis, scleroderma, secondary hyperparathyroidism, systemic lupus erythematosus, and wrinkles, cornea wound, cornea healing, retinopathy, sway, muscle weakness, fall, chronic glomerulonephritis, lupus nephritis, diabetic nephropathy, hypocalcemia, hypoparathyroidism, rickets, osteoarthritis.
89. The agent for treating a condition according to claim 88, wherein said condition is selected from the group consisting of benign prostatic hyperplasia, cancer, osteoporosis, psoriasis, secondary hyperparathyroidism, chronic glomerulonephritis, lupus nephritis, diabetic nephropathy, sway, muscle weakness, fall, rheumatoid arthritis, osteoarthritis.
90. The agent for treating a condition according to claim 88, wherein said condition is benign prostatic hyperplasia.
91. The agent for treating a condition according to claim 88, wherein said condition is cancer.
92. The agent for treating a condition according to claim 88, wherein said condition is osteoporosis.
93. The agent for treating a condition according to claim 88, wherein said condition is psoriasis.
94. The agent for treating a condition according to claim 88, wherein said condition is secondary hyperparathyroidism.
95. The agent for treating a condition according to claim 88, wherein said condition is chronic glomerulonephritis.
96. The agent for treating a condition according to claim 88, wherein said condition is lupus nephritis.
97. The agent for treating a condition according to claim 88, wherein said condition is diabetic nephropathy.
98. Use of the compound according to any one of claims 1 to 71 for the preparation of an agent for modulating the activity of the vitamin D receptor in a mammal.
99. Use of the compound according to any one of claims 1 to 71 for the preparation of an agent for treating a condition associated with the vitamin D receptor in a mammal.
100. Use of the compound according to any one of claims 1 to 71 for the preparation of an agent for treating a condition selected from the group consisting of abscess, acne, adhesion, alopecia, Alzheimer's disease, benign prostatic hyperplasia, bone fracture healing, cancer, autoimmune induced diabetes, host-graft rejection, insufficient sebum secretion, insufficient dermal firmness, humoral hypercalcemia, insufficient dermal hydration, leukemia, lupus, multiple sclerosis, osteomalacia, osteoporosis, psoriatic arthritis, psoriasis, renal failure, renal osteodystrophy, rheumatoid arthritis, scleroderma, secondary hyperparathyroidism, systemic lupus erythematosus, and wrinkles, cornea wound, cornea healing, retinopathy, sway, muscle weakness, fall, chronic glomerulonephritis, lupus nephritis, diabetic nephropathy, hypocalcemia, hypoparathyroidism, rickets, osteoarthritis.
101. The use according to according to claim 100, wherein said condition is selected from the group consisting of benign prostatic hyperplasia, cancer, osteoporosis, psoriasis, secondary hyperparathyroidism, chronic glomerulonephritis, lupus nephritis, diabetic nephropathy, sway, muscle weakness, fall, rheumatoid arthritis, osteoarthritis.
102. The use according to according to claim 100, wherein said condition is benign prostatic hyperplasia.
103. The use according to according to claim 100, wherein said condition is cancer.
104. The use according to according to claim 100, wherein said condition is osteoporosis.
105. The use according to according to claim 100, wherein said condition is psoriasis.
106. The use according to according to claim 100, wherein said condition is secondary hyperparathyroidism.
107. The use according to according to claim 100, wherein said condition is chronic glomerulonephritis.
108. The use according to according to claim 100, wherein said condition is lupus nephritis.
109. The use according to according to claim 100, wherein said condition is diabetic nephropathy.
110. The compound according to claim 1 wherein Y is a substituent represented by following formula:
Figure imgf000632_0001
and R is a protecting group for a hydroxyl group.
111. The compound according to claim 110 wherein X is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene or an ethynylene; R is a protecting group for a hydroxyl group selected from the group consisting of a methoxymethyl group, a methylthiomethyl group, a
(phenyldimethylsilyl)methoxymethyl group, a benzyloxymethyl group, a p- methoxybenzyloxymethyl group, a p-nitrobenzyloxymethyl group, an o- nitrobenzyloxymethyl group, a (4-methoxyphenoxy)methyl group, a guaiacolmethyl group, a t-butoxymethyl group, a 4-pentenyloxymethyl group, a siloxymethyl group, a 2-methoxyethoxymethyl group, 2,2,2- trichloroethoxymethyl group, a bis(2-chloroethoxy)methyl group, a 2- (trimethylsilyl)ethoxymethyl group, a menthoxymethyl group, a tetrahydropyranyl group, a 3-bromotetrahydropyranyl group, a tertahydrothiopyranyl group, a 1 -methoxycyclohexyl group, 4- methoxytetrahydrothiopyranyl, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group, a 1-ethoxyethyl group, a 1 -(2-chloroethoxy)ethyl group, a 1-[2-(trimethylsilyl)ethoxy]ethyl group, a 1 -methyl-1 -methoxyethyl group, a 1 -methyl-1 -benzyloxyethyl group, a 1 -methyl-1 -benzyloxy-2- fluoroethyl group, a 1 -methyl-1 -phenoxyethyl group, a 2,2,2-trichloroethyl group, a 1,1-dianisyl-2,2,2-trichloroethyl group, a 2-trimethylsilylethyl group, a 2-(benzylthio)ethyl group, a 2-(phenylselenyl)ethyl group, a t-butyl group, an allyl group, a propargyl group, a p-chlorophenyl group, a p- methoxyphenyl group, a p-nitrophenyl group, a 2,4-dinitrophenyl group, a benzyl group, a p-methoxybenzyl group, a 3,4-dimethoxybenzyl group, an o- nitrophenyl group, a p-nitrophenyl group, a p-halobenzyl group, a 2,6- dichlorobenzyl group, a p-cyanobenzyl group, a p-phenylbenzyl group, a 2,6- difluorobenzyl group, a p-acylaminobenzyl group, a 2-triflluoromethyl benzyl group, a 2-picolyl group, a 4-picolyl group, a 2-quinolinylmethyl group, a triphenylmethyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a dimethylisopropylsilyl group, a diethylisopropylsilyl group, a t-butyldimethylsilyl group, a t-buthyldiphenylsilyl group, a tribenzylsilyl group, a triphenylsilyl group, a diphenylmethylsilyl group, a di-t- buthylmethylsilyl group, tris(trimethylsilyl)silyl group, a formyl group, a benzoylformyl group, an acetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a methoxyacetyl group, a pivaloyl group, a benzoyl group, a 2,4,6-trimethylbenzoyl group, a methylcarbonyloxy group, a methoxymethylcarbonyloxy group, an ethylcarbonyloxy group, an isobutylcarbonyloxy group, a vinylcarbonyloxy group, an allylcarbonyloxy group, a benzylcarbonyloxy group, a p-methoxybenzylcarbonyloxy group, an allylsulfonyl group, a methanesulfonyl group, a benzylsulfonyl group, a tosyl group, a trifluoromethanesulfonyl group; R12 and R13 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-10 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted C1-10 alkenyl group, an optionally substituted C1-10 alkynyl group, or R12 and R13 may together form an optionally substituted C3-10 cycloalkyl group; W is a substituent represented by following formula:
Figure imgf000634_0001
Q is -0-, a methylene, an ethylene, a vinylene, an ethynylene, - (CH2)k-C(=0)NH- or -0-(CH2)k-C(=0)NH-; R14 is a hydrogen atom, a hydroxyl group, an optionally substituted carboxyl group, an optionally substituted carbamoyl group, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C6-C12 aryl group, an optionally substituted (C6-C12)aryl-(C1-4)alkyl group, -OR17 or -N(R18)R19; R15 and R16 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-C12 cycloalkyl group, an optionally substituted C6- C12 aryl group, an optionally substituted (C6-C12)aryl-(C1-4)alkyl group, an optionally substituted 3-12 membered heterocyclic group selected from the group consisting of an aziridine group, an azetidine group, an oxetane group, a pyrrolidine group, a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an imidazole group, an oxazole group, a thiazolegroup, a 1 ,2,5- oxadiazole group, a 1 ,3,4-oxadiazole group, a 1 ,3,4-thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a tetrazole group, a piperidine group, a pyridine group, a pyridazine group, a pyrimidine group, a pyrazine group, a tetrahydropyran group, a pyran group, a thiopyran group, an indole group, a benzofuran group, a benzothiophene group, an indazole group, a benzisoxazole group, a benzisothiazole group, a benzimidazole group, a benzoxazole group, a benzothiazole gorup, a quinoline group, an isoquinoline group, a cinnoline group, a phthalazine group, a quinazoline group, a quinoxaline group, or R15 and R16 may together form =0; R17 is an optionally substituted C1-6 alkyl group or an optionally substituted C3-C6 cycloalkyl group; R18 and R19 are each independently selected from a hydrogen atom, an optionally substituted C1-6 alkyl group or an optionally substituted C3-C6 cycloalkyl group; or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered cyclic ring which is selected from a lactam ring or a lactone ring; R1 is a C1-6 alkyl group; R2 is a C1 -6 alkyl group; R3 is a hydrogen atom or a C1-6 alkyl group; R4 is a halogen atom or a C1-6 alkyl group; R5 is a hydrogen atom; R6 is a halogen atom or a C1-6 alkyl group.
112. The compound according to claim 111 wherein X is an ethylene, a vinylene, or an ethynylene; R is a protecting group for a hydroxyl group selected from the group consisting of a methoxymethyl group, a 2-(trimethylsilyl)ethoxymethyl group, a tetrahydropyranyl group, a benzyl group, a p-methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t- buthyldiphenylsilyl group, an acetyl group, a pivaloyl group, a benzoyl group, a methanesulfonyl group, a tosyl group, a trifluoromethanesulfonyl group; R12 and R13 are each independently selected from the group consisting of a hydrogen atom, a C1-8 alkyl group which may be substituted with a halogen atom(s) a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group; W is a substituent represented by following formula:
Figure imgf000635_0001
Q is -0-, a methylene, an ethylene, a vinylene, an ethynylene, -
(CH2)k-C(=0)NH- or -0-(CH2)k-C(=0)NH-; b is an integer of 0 to 5; R14 is a hydrogen atom, a hydroxyl group, a carboxyl group which may be substituted with a C1 -4 alkyl group, a carbamoyl group which may be substituted with a C1-4 alkyl group, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group which may be substituted with a C1- 4 alkyl group, a phenyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a benzyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, OR17 or -N(R18)R19; R15 and R16 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group which may be substituted with a C1-4 alkyl group, a phenyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a benzyl group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a 3-8 membered heterocyclic group which may be substituted with a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, wherein said heterocyclic group selected from the group consisting of an oxetane group, a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an oxazole group, a thiazole group, a 1 ,2,5-oxadiazole group, a 1,3,4- oxadiazole group, a 1 ,3,4-thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a tetrazole group, a pyridine group, a pyridazine group, a pyrimidine group, a pyrazine group, a tetrahydropyran group, a pyran group, a thiopyran group, or R15 and R16 may together form =0; and at least one of R14, R15 or R16 is a hydrogen atom; R17 is a C1-4 alkyl group; R18 and R19 are each independently selected from a hydrogen atom or a C1 -4 alkyl group; or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and
R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered lactone ring.
113. The compound according to claim 112 wherein R12 and R13 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3-8 cycloalkyl group; W is a substituent represented by following formula: y R14
-Q-(CH2)b— ^R15 R16 Q is -0-, -(CH2)k-C(=0)NH- or -0-(CH2)k-C(=0)NH-; b is O, 1 or 2; k is 1; R14 is a hydrogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amide group, a C3-C8 cycloalkyl group, a phenyl group which may be substituted with a hydroxyl group or a carboxyl group, a benzyl group which may be substituted with a hydroxyl group or a carboxyl group, -OR17 or -N(R18)R19; R15 and R16 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group, a C3-C8 cycloalkyl group, a phenyl group which may be substituted with a hydroxyl group or a carboxyl group, a benzyl group which may be substituted with a hydroxyl group or a carboxyl group, a 3-8 membered heterocyclic group selected from the group consisting of a tetrahydrofuran group, a pyrrole group, a furan group, a thiophene group, a pyrazole group, an isoxazole group, an isothiazole group, an oxazole group, a thiazole group, a 1 ,2,5-oxadiazole group, a 1 ,3,4-oxadiazole group, a 1 ,3,4- thiadiazole group, a 1 ,2,4-oxadiazole group, a 1 ,2,4-thiadiazole group, a pyridine group, a tetrahydropyran group; and at least one of R14, R15 or R16 is a hydrogen atom; R18 is a hydrogen atom; R19 is a hydrogen atom; or one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) may together form a 3-12 membered lactone ring; R1 is a C1-4 alkyl group; R2 is a C1-4 alkyl group; R3 is a hydrogen atom or a C1-4 alkyl group; R4 is a halogen atom or a C1-4 alkyl group; R5 is a hydrogen atom; R6 is a halogen atom or a C1-4 alkyl group.
114. The compound according to claim 113 wherein R12 and R13 are selected from the group consisting of one of R12 and R13 is a hydrogen atom and the other is a C1-
6 alkyl group, one of R12 and R13 is a hydrogen atom and the other is a C3- 8 cycloalkyl group which may be substituted with a C1-4 alkyl group, both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group; Q is -O- or -0-(CH2)k-C(=0)NH-; R1 is an ethyl group; R2 is an ethyl group; R3 is a hydrogen atom or a methyl group; R4 is a chlorine atom or a methyl group; R6 is a chlorine atom, a methyl group, an ethyl group, a propyl group or an isopropyl group.
115. The compound according to claim 113 wherein R12 and R13 are selected from the group consisting of one of R12 and R13 is a hydrogen atom and the other is a C1- 6 alkyl group, one of R12 and R13 is a hydrogen atom and the other is a C3- 8 cycloalkyl group which may be substituted with a C1-4 alkyl group, both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group; Q is a methylene, an ethylene, an ethynylene or -(CH2)k-C(=0)NH-; R1 is an ethyl group; R2 is an ethyl group; R3 is a hydrogen atom; R4 is a chlorine atom or a methyl group; R6 is a chlorine atom or a methyl group.
116. The compound according to claim 114 or 115 wherein R3 is a hydrogen atom.
117. The compound according to claim 114 or 115 wherein R4 is a chlorine atom.
118. The compound according to claim 114 or 115 wherein R6 is a chlorine atom.
119. The compound according to claim 114 or 115 wherein R6 is a methyl group.
120. The compound according to claim 114 or 115 wherein X is an ethylene.
121. The compound according to claim 114 or 115 wherein X is a vinylene.
122. The compound according to claim 114 or 115 wherein X is an ethynylene.
123. The compound according to claim 114 or 115 wherein one of R12 and R13 is a hydrogen atom and the other is a C1-6 alkyl group.
124. The compound according to claim 123 wherein one of R12 and R13 is a hydrogen atom and the other is a tert-butyl group.
125. The compound according to claim 114 or 115 wherein both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s).
126. The compound according to claim 125 wherein R12 is a trifluoromethyl group and R13 is a trifluoromethyl group.
127. The compound according to claim 114 wherein Q is -0-.
128. The compound according to claim 115 wherein Q is an ethylene.
129. The compound according to claim 115 wherein Q is an ethynylene.
130. The compound according to claim 114 or 115 wherein at least one of R14, R15 or R16 is a substituent which have a hydroxyl group, a carboxyl group, a carbamoyl group or an amino group.
131. The compound according to claim 114 or 115 wherein R14 is a hydroxyl group.
132. The compound according to claim 114 or 115 wherein one of R15 and R16 is a hydrogen atom and the other is a C1-6 alkyl group substituted with a carboxyl group.
133. The compound according to claim 114 or 115 wherein one of (R15 and R17), (R16 and R17), (R15 and R18), (R16 and R18), (R15 and R19) or (R16 and R19) together form a 3-12 membered lactone ring.
134. The compound according to claim 1 wherein W is a hydroxyl group, a carboxyl group or a trifluoromethanesulfonyloxy group.
135. The compound according to claim 134 wherein X is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted vinylene or an ethynylene; Y is COOR8, CON(R9)R10, S(0)mR11 or a substituent represented by following formula:
Figure imgf000641_0001
R is a hydrogen atom or a protecting group for a hydroxyl group selected from the group consisting of a methoxymethyl group, a methylthiomethyl group, a (phenyldimethylsilyl)methoxymethyl group, a benzyloxymethyl group, a p-methoxybenzyloxymethyl group, a p- nitrobenzyloxymethyl group, an o-nitrobenzyloxymethyl group, a (4- methoxyphenoxy)methyl group, a guaiacolmethyl group, a t-butoxymethyl group, a 4-pentenyloxymethyl group, a siloxymethyl group, a 2- methoxyethoxymethyl group, 2,2,2-trichloroethoxymethyl group, a bis(2- chloroethoxy)methyl group, a 2-(trimethylsilyl)ethoxymethyl group, a menthoxymethyl group, a tetrahydropyranyl group, a 3- bromotetrahydropyranyl group, a tertahydrothiopyranyl group, a 1- methoxycyclohexyl group, 4-methoxytetrahydrothiopyranyl, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group, a 1-ethoxyethyl group, a 1 -(2-chloroethoxy)ethyl group, a 1-[2-(trimethylsilyl)ethoxy]ethyl group, a 1 -methyl-1 -methoxyethyl group, a 1 -methyl-1 -benzyloxyethyl group, a 1 -methyl-1 -benzyloxy-2-fluoroethyl group, a 1 -methyl-1 -phenoxyethyl group, a 2,2,2-trichloroethyl group, a 1 ,1-dianisyl-2,2,2-trichloroethyl group, a 2-trimethylsilylethyl group, a 2-(benzylthio)ethyl group, a 2- (phenylselenyl)ethyl group, a t-butyl group, an allyl group, a propargyl group, a p-chlorophenyl group, a p-methoxyphenyl group, a p-nitrophenyl group, a 2,4-dinitrophenyl group, a benzyl group, a p-methoxybenzyl group, a 3,4- dimethoxybenzyl group, an o-nitrophenyl group, a p-nitrophenyl group, a p- halobenzyl group, a 2,6-dichlorobenzyl group, a p-cyanobenzyl group, a p- phenylbenzyl group, a 2,6-difluorobenzyl group, a p-acylaminobenzyl group, a 2-triflluoromethyl benzyl group, a 2-picolyl group, a 4-picolyl group, a 2- quinolinylmethyl group, a triphenylmethyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a dimethylisopropylsilyl group, a diethylisopropylsilyl group, a t-butyldimethylsilyl group, a t-buthyldiphenylsilyl group, a tribenzylsilyl group, a triphenylsilyl group, a diphenylmethylsilyl group, a di-t-buthylmethylsilyl group, tris(trimethylsilyl)silyl group, a formyl group, a benzoylformyl group, an acetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a methoxyacetyl group, a pivaloyl group, a benzoyl group, a 2,4,6-trimethylbenzoyl group, a methylcarbonyloxy group, a methoxymethylcarbonyloxy group, an ethylcarbonyloxy group, an isobutylcarbonyloxy group, a vinylcarbonyloxy group, an allylcarbonyloxy group, a benzylcarbonyloxy group, a p- methoxybenzylcarbonyloxy group, an allylsulfonyl group, a methanesulfonyl group, a benzylsulfonyl group, a tosyl group, a trifluoromethanesulfonyl group; R12 and R13 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted 01 -10 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted C1-10 alkenyl group, an optionally substituted C1-10 alkynyl group, or R12 and R13 may together form an optionally substituted C3-10 cycloalkyl group; R1 is a C1-6 alkyl group; R2 is a C1-6 alkyl group; R3 is a hydrogen atom or a C1-6 alkyl group; R4 is a halogen atom or a C1-6 alkyl group; R5 is a hydrogen atom; R6 is a halogen atom or a C1-6 alkyl group.
136. The compound according to claim 135 wherein X is an ethylene, a vinylene, or an ethynylene; Y is a substituent represented by following formula:
Figure imgf000643_0001
R is a hydrogen atom or a protecting group for a hydroxyl group selected from the group consisting of a methoxymethyl group, a 2- (trimethylsilyl)ethoxymethyl group, a tetrahydropyranyl group, a benzyl group, a p-methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t-buthyldiphenylsilyl group, an acetyl group, a pivaloyl group, a benzoyl group, a methanesulfonyl group, a tosyl group, a trifluoromethanesulfonyl group; R12 and R13 are each independently selected from the group consisting of a hydrogen atom, a C1-8 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group.
137. The compound according to claim 136 wherein R12 and R13 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl group which may be substituted with a halogen atom(s), a C3-8 cycloalkyl group which may be substituted with a C1-4 alkyl group, or R12 and R13 are together form a C3-8 cycloalkyl group; R1 is a C1-4 alkyl group; R2 is a C1-4 alkyl group; R3 is a hydrogen atom or a C1-4 alkyl group; R4 is a halogen atom or a C1-4 alkyl group; R5 is a hydrogen atom; R6 is a halogen atom or a C1-4 alkyl group.
138. The compound according to claim 137 wherein R12 and R13 are selected from the group consisting of one of R12 and R13 is a hydrogen atom and the other is a C1- 6 alkyl group, one of R12 and R13 is a hydrogen atom and the other is a C3-
8 cycloalkyl group which may be substituted with a C1-4 alkyl group, both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s), or R12 and R13 are together form a C3-10 cycloalkyl group; R1 is an ethyl group; R2 is an ethyl group; R3 is a hydrogen atom or a methyl group; R4 is a chlorine atom or a methyl group; R6 is a chlorine atom, a methyl group, an ethyl group, a propyl group or an isopropyl group.
139. The compound according to claim 138 wherein W is a carboxyl group.
140. The compound according to claim 139 which is 4-{1 -Ethyl-1 -[4-((E)-3- ethyl-3-hydroxy-pent-1 -enyl)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid.
141. The compound according to claim 138 or 139 wherein R3 is a hydrogen atom.
142. The compound according to claim 138 or 139 wherein R4 is a chlorine atom.
143. The compound according to claim 138 or 139 wherein R6 is a chlorine atom.
144. The compound according to claim 138 or 139 wherein R6 is a methyl group.
145. The compound according to claim 138 or 139 wherein X is an ethylene.
146. The compound according to claim 138 or 139 wherein X is a vinylene.
147. The compound according to claim 138 or 139 wherein X is an ethynylene.
148. The compound according to claim 138 or 139 wherein one of R12 and R13 is a hydrogen atom and the other is a C1-6 alkyl group.
149. The compound according to claim 148 wherein one of R12 and R13 is a hydrogen atom and the other is a tert-butyl group.
150. The compound according to claim 138 or 139 wherein both of R12 and R13 are same and a C1-6 alkyl group which may be substituted with a halogen atom(s).
151. The compound according to claim 150 wherein R12 is a trifluoromethyl group and R13 is a trifluoromethyl group.
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