WO2008154023A1 - Novel uses of ppar delta agonists - Google Patents

Novel uses of ppar delta agonists Download PDF

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Publication number
WO2008154023A1
WO2008154023A1 PCT/US2008/007284 US2008007284W WO2008154023A1 WO 2008154023 A1 WO2008154023 A1 WO 2008154023A1 US 2008007284 W US2008007284 W US 2008007284W WO 2008154023 A1 WO2008154023 A1 WO 2008154023A1
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alkyl
group
carbon atoms
isopropyl
halogen
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PCT/US2008/007284
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French (fr)
Inventor
Ronald Barbaras
Daniela Carmen Oniciu
Jean-Louis Henri Dasseux
Constance H. Keyserling
John R. Wetterau
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Cerenis Therapeutics S.A.
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Publication of WO2008154023A1 publication Critical patent/WO2008154023A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the compounds provided which are PPAR ⁇ agonists, are useful for one or more of the following: inducing reverse cholesterol transport, inducing reverse lipid transport, increasing HDL, HDL-cholesterol, ApoA-I, HDL- phospholipids, pre- ⁇ HDL, pre- ⁇ HDL-cholesterol levels in mammals, or the number of HDL and/or pre- ⁇ HDL particles in mammals.
  • PPAR ⁇ receptor nomenclature has been recently revised and a recommendation is made to change the denomination from ⁇ to ⁇ . Most recent articles reference the receptors as PPAR ⁇ / ⁇ . We shall however nominate them below as PPAR ⁇ .
  • the peroxisome is a small organ present in cells of animals and plants, and its matrix contains various enzymes such as catalases.
  • Various compounds such as fibrates, herbicides, and phthalic acid plasticizers are known as peroxisome proliferators, which induce proliferation of peroxisomes.
  • Isseman, et al. have identified a nuclear receptor which is activated by peroxisome proliferator and called it peroxisome proliferator activated receptor (PPAR) ⁇ Nature, 347:645-650, 1990). Since then three subtypes of PPAR such as PP ARa, PPARy and PPAR ⁇ have been identified (Proc. Natl. Acad. Sci.
  • PPAR ⁇ agonists increase the levels of ApoA-I and/or of pre- ⁇ HDL particles and can be used for preventing, reversing, or treating atherosclerosis-related cardiovascular diseases, thereby augmenting the process of plaque elimination from the cardiovascular system of patients in need of such treatment.
  • PPAR ⁇ agonists that increase the levels of
  • ApoA-I and/or pre- ⁇ HDL, and/or pre- ⁇ HDL-cholesterol, and/or phospholipids, and/or the number of pre- ⁇ HDL particles in mammals are provided.
  • Diseases or conditions related to plaque build-up include, but are not limited to, a cardiovascular disease including atherosclerosis and hypertriglyceridemia, heart failure, acute coronary syndrome, angina, type II diabetes mellitus, type I diabetes, insulin resistance, epithelial hyperproliferative disease including eczema and psoriasis, and hypertension, as well as related to the accumulation or deposit of lipids such as Alzheimer's, Parkinson's, degenerative disease, inflammation..
  • a cardiovascular disease including atherosclerosis and hypertriglyceridemia, heart failure, acute coronary syndrome, angina, type II diabetes mellitus, type I diabetes, insulin resistance, epithelial hyperproliferative disease including eczema and psoriasis, and hypertension, as well as related to the accumulation or deposit of lipids such as Alzheimer's, Parkinson's, degenerative disease, inflammation.
  • the compounds described herein induce reverse cholesterol transport in mammals, hi other embodiments, the mammal is a primate or a human. In certain embodiments, the mammal is a human.
  • the compounds described herein increase HDL and/or HDL-cholesterol levels in mammals.
  • the compounds described herein increase the ApoA-I levels leading to the formation of the pre- ⁇ HDL particles.
  • the methods use compounds that increase HDL levels and/or ApoA-I levels in mammals.
  • the compounds described herein increase the pre- ⁇ HDL and/or pre- ⁇ HDL cholesterol levels in mammals. In yet another embodiment, the compounds described herein increase the level of HDL- phospholipids in connection with the lipid cholesterol transport.
  • the compounds described herein increase HDL levels and/or ApoA-I levels, and/or pre- ⁇ HDL levels in mammals. In yet another embodiment, the increase in the ApoA-I levels and/or pre- ⁇ HDL levels occurs without significantly raising in HDL-cholesterol levels. [0018] In another embodiment, in the methods provided, the use of a low dose of a
  • PPAR ⁇ agonist provided such as 0.1 mg/day to about 2500 mg/day for humans results in increase in pre- ⁇ -HDL levels while avoiding the side effects associated with the use of PP ARa and PPAR ⁇ agonists, or classical PPAR agonist class side effects. [0019] In another embodiment, in the methods provided, the use of a low dose of a
  • PPAR ⁇ agonist provided such as 0.001 mg/kg/day to 25 mg/kg/day for humans results in increase in pre- ⁇ -HDL levels while avoiding the side effects associated with the use of PP ARa and PPAR ⁇ agonists, or classical PPAR agonist class side effects.
  • PPAR ⁇ agonist provided such as 0.1 mg/kg/day to 30 mg/kg/day in non-human primates results in increase in pre- ⁇ -HDL levels while avoiding the side effects associated with the use of PP ARa and PPAR ⁇ agonists, or classical PPAR agonist class side effects.
  • the use of a low dose of any selective PPAR ⁇ agonist with a selectivity of >500 over PP ARa and PPAR ⁇ results in increase in pre- ⁇ HDL levels while avoiding the side effects associated with the use of PP ARa and PPAR ⁇ agonists, or classical PPAR agonist side effects.
  • Exemplary compounds include but thy are not limited to GW-501516 (Ligand/GSK), RWJ-800025 (JNJ/Metabolex), KD-3010 (Kalypsys, Inc.), BAY 68-5042 (Bayer), or compounds described in Bratton, L. D. et ah, Bioorg. Med. Chem. Lett. 2007 (web edition) and Kasuga, J. I. et ah, Bioorg. Med. Chem. 2007 (web edition).
  • the compounds described herein decrease LDL-cholesterol levels in mammals.
  • the compounds described herein decrease VLDL-cholesterol levels in mammals.
  • the compounds described herein decrease triglyceride levels in mammals.
  • the compounds described herein increase the levels of HDL and/or ApoA-I, and/or pre- ⁇ HDL, HDL and ApoA-I, and/or HDL, ApoA-I and pre- ⁇ HDL, and/or ApoA-I rich HDL, and decrease the levels of LDL, or VLDL, or triglycerides, or LDL and VLDL, or LDL, VLDL and triglycerides levels in mammals.
  • the compounds have the following general formula (I) or a salt thereof: wherein R 1 is phenyl, naphthyl, pyridyl, thienyl, furyl, quinolyl or benzothienyl, any of which can have substituents selected from the group consisting of Ci -8 alkyl, Cj -8 alkyl having halogen, Ci -8 alkoxy, Ci -8 alkoxy having halogen, C 2-8 alkenyl, C 2-8 alkynyl, halogen, C 2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl and pyridyl;
  • R 2 is Ci -8 alkyl, Ci -8 alkyl having halogen, C 2 . 8 alkenyl, C 2-8 alkynyl, 3-7 membered cycloalkyl, Ci -8 alkyl having 3-7 membered cycloalkyl, or Ci -6 alkyl substituted with phenyl, naphthyl or pyridyl, any of which can have substituents selected from the group consisting Of Ci -8 alkyl, Ci -8 alkyl having halogen, Ci -8 alkoxy, Ci -8 alkoxy having halogen, C 2-8 alkenyl, C 2-8 alkynyl, halogen, C 2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl and pyridyl;
  • A is oxygen, sulfur or NR 9 in which R 9 is hydrogen or Ci -8 alkyl
  • X is a Ci -8 alkylene chain which can have substituents selected from the group consisting Of Ci -8 alkyl, Ci -8 alkoxy and hydroxyl and which can contain a double bond;
  • each of R 3 , R 4 and R 5 is hydrogen, Ci -8 alkyl, Ci -8 alkyl having halogen, Ci -8 alkoxy, Ci -8 alkoxy having halogen, C 2-8 alkenyl, C 2-8 alkynyl, halogen, C 2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl, or pyridyl;
  • B is CH or nitrogen;
  • Z is oxygen or sulfur
  • each of R 6 and R 7 is hydrogen, Ci -8 alkyl, Ci -8 alkyl having halogen;
  • R 8 is hydrogen or Ci -8 alkyl
  • the invention also provides an activator of peroxisome proliferator activated receptor ⁇ , which contains as an effective component a compound of the formula (I) or a salt thereof.
  • a compound has the following general formula (II) or a salt thereof:
  • each of R 1 and R 2 independently is a hydrogen atom, a halogen atom, nitro, an alkyl group having 1-8 carbon atoms, an alkoxy group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkoxy group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, a 3-7 membered cycloalkyl group, an alkyl group having 1-8 carbon atom which has a 3-7 membered cycloalkyl substituent, an aryl group having 6-10 carbon atoms which optionally has a substituent, an arylalkyl group which has a C 6-I0 aryl portion and C 1-8 alkyl portion, a heterocyclic group which optionally has a substituent or a heterocyclic-alkyl group having an alkyl
  • A is an oxygen atom, a sulfur atom, or NR 3 in which R 3 is a hydrogen atom or an alkyl group having 1-8 carbon atoms;
  • the compound has the following formula (III) or a salt thereof:
  • each of R 11 and R 12 independently is a hydrogen atom, a halogen atom, nitro, hydroxyl, amino, an alkyl group having 1-8 carbon atoms, an alkoxy group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkoxy group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, a 3-7 membered cycloalkyl group, an alkyl group having 1-8 carbon atoms which has a 3-7 membered cycloalkyl substituent, or a phenyl, naphthyl, benzyl, phenethyl, pyridyl, thienyl, furyl, quinolyl, or benzothienyl group which optionally has a substituent selected from the group consisting of a substituent
  • the invention resides in an activator of peroxisome proliferator activated receptor which contains as an effective component a phenylacetic acid derivative of the formula (II) or a phenylacetic acid derivative of the formula (III) or their salts.
  • the compound has the following general formula (IV) or a salt thereof:
  • A is O, S or NR 7 in which R 7 is hydrogen or Cj -8 alkyl
  • B 1 is CW or N in which W is hydrogen or a bond
  • B 2 is O, S or NR 8 in which
  • Y is a C J -8 alkylene chain, which can be substituted with Ci -8 alkyl or Ci -8 alkyl substituted with 1 -3 halogens;
  • Z is NH, O or S;
  • R 1 is aryl, which can be substituted with a group or atom selected from the group consisting of Ci -8 alkyl, Ci -8 alkoxy, Ci -8 alkyl substituted with 1-3 halogens, hydroxyl, nitro, amino, phenyl, pyridyl and halogen, or a heterocyclic group having five to eight membered ring comprising one to three hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur and the other atoms consisting of carbon (benzene ring can be condensed with the heterocyclic ring);
  • R 2 is C 2-8 alkyl, Ci -8 alkyl substituted with 1-3 halogens, C 3-7 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, alkyl (comprising Ci -4 alkyl moiety) substituted with aryl, which can be substituted with a group or
  • each of R 4 and R 5 is hydrogen, Ci -8 alkyl or C ]-8 alkyl substituted with 1-3 halogens; and R 6 is hydrogen, Ci -8 alkyl substituted with amino, Ci -8 alkyl or alkali metal; [0056] provided that each of Z and R 3 is attached to the benzene ring, and X 2 is not attached to the benzene ring.
  • the invention also provides an activator of peroxisome proliferator activated receptor ⁇ , which contains as an effective component a compound of the formula (IV) or a salt thereof.
  • subject is an animal, such as a mammal, including human, such as a patient.
  • biological activity refers to the in vivo activities of a compound or physiological responses that result upon in vivo administration of a compound, composition or other mixture.
  • Biological activity thus, encompasses therapeutic effects and pharmacokinetic behaviour of such compounds, compositions and mixtures. Biological activities can be observed in in vitro systems designed to test for such activities.
  • pharmaceutically acceptable derivatives of a compound include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof.
  • Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization.
  • the compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs.
  • salts include, but are not limited to, amine salts, such as but not limited to N 5 N'- dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, 1 -para-chlorobenzyl-2-pyrrolidin- 1 '-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and inorganic salts, such as but not limited to, sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited
  • esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids.
  • Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
  • treatment means any manner in which one or more of the symptoms of a disease or disorder are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein, such as use for treating inflammation.
  • amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
  • the IC 50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.
  • the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.
  • substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • MS mass spectrometry
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as reverse phase HPLC.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
  • alkyl, alkenyl and alkynyl carbon chains if not specified, contain from 1 to 20 carbons, or 1 to 16 carbons, and are straight or branched.
  • Exemplary alkyl, alkenyl and alkynyl groups herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec- butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, ethenyl, propenyl, butenyl, pentenyl, acetylenyl and hexynyl.
  • lower alkyl, lower alkenyl, and lower alkynyl refer to carbon chains having from about 1 or about 2 carbons up to about 6 carbons.
  • alk(en)(yn)yl refers to an alkyl group containing at least one double bond and at least one triple bond.
  • cycloalkyl refers to a saturated mono- or multicyclic ring system, in certain embodiments of 3 to 10 carbon atoms, in other embodiments of 3 to 6 carbon atoms; cycloalkenyl and cycloalkynyl refer to mono- or multicyclic ring systems that respectively include at least one double bond and at least one triple bond. Cycloalkenyl and cycloalkynyl groups may, in certain embodiments, contain 3 to 10 carbon atoms, with cycloalkenyl groups, in further embodiments, containing 4 to 7 carbon atoms and cycloalkynyl groups, in further embodiments, containing 8 to 10 carbon atoms.
  • ring systems of the cycloalkyl, cycloalkenyl and cycloalkynyl groups may be composed of one ring or two or more rings which may be joined together in a fused, bridged or spiro- connected fashion.
  • Cycloalk(en)(yn)yl refers to a cycloalkyl group containing at least one double bond and at least one triple bond.
  • substituted alkyl refers to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl groups, respectively, that are substituted with one or more substituents, in certain embodiments one to three or four substituents, where the substituents are as defined herein, generally selected from Ql.
  • aryl refers to aromatic monocyclic or multicyclic groups containing from 6 to 19 carbon atoms.
  • Aryl groups include, but are not limited to groups such as fluorenyl, substituted fluorenyl, phenyl, substituted phenyl, naphthyl and substituted naphthyl.
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system, in certain embodiments, of about 5 to about 15 members where one or more, in one embodiment 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including, but not limited to,, nitrogen, oxygen or sulfur.
  • heteroaryl group may be optionally fused to a benzene ring.
  • Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl and isoquinolinyl.
  • heteroarylium is a heteroaryl group that is positively charged on one or more of the heteroatoms.
  • heterocyclyl refers to a monocyclic or multicyclic non- aromatic ring system, in one embodiment of 3 to 10 members, in another embodiment of 4 to 7 members, in a further embodiment of 5 to 6 members, where one or more, in certain embodiments, 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including, but not limited to,, nitrogen, oxygen or sulfur.
  • the nitrogen is optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acyl, guanidino, amidino or the nitrogen may be quaternized to form an ammonium group where the substituents are selected as above.
  • substituted aryl refers to aryl, heteroaryl and heterocyclyl groups, respectively, that are substituted with one or more substituents, in certain embodiments one to three or four substituents, where the substituents are as defined herein, generally selected from Ql.
  • aralkyl refers to an alkyl group in which one of the hydrogen atoms of the alkyl is replaced by an aryl group.
  • heterooaralkyl refers to an alkyl group in which one of the hydrogen atoms of the alkyl is replaced by a heteroaryl group.
  • alkylene refers to a straight, branched or cyclic, in certain embodiments straight or branched, divalent aliphatic hydrocarbon group, in one embodiment having from 1 to about 20 carbon atoms, in another embodiment having from 1 to 12 carbons. In a further embodiment alkylene includes lower alkylene.
  • Alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-(CH 2 ) 3 -), methylenedioxy (-0-CH 2 -O-) and ethylenedioxy (-O-(CH 2 ) 2 -O-).
  • the term "lower alkylene” refers to alkylene groups having 1 to 6 carbons. In certain embodiments, alkylene groups are lower alkylene, including alkylene of 1 to 3 carbon atoms.
  • alkenylene refers to a straight, branched or cyclic, in one embodiment straight or branched, divalent aliphatic hydrocarbon group, in certain embodiments having from 2 to about 20 carbon atoms and at least one double bond, in other embodiments 1 to 12 carbons.
  • alkenylene groups include lower alkenylene. There may be optionally inserted along the alkenylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, where the nitrogen substituent is alkyl.
  • alkenylene refers to alkenylene groups having 2 to 6 carbons. In certain embodiments, alkenylene groups are lower alkenylene, including alkenylene of 3 to 4 carbon atoms.
  • alkynylene refers to a straight, branched or cyclic, in certain embodiments straight or branched, divalent aliphatic hydrocarbon group, in one embodiment having from 2 to about 20 carbon atoms and at least one triple bond, in another embodiment 1 to 12 carbons. In a further embodiment, alkynylene includes lower alkynylene.
  • the term "lower alkynylene” refers to alkynylene groups having 2 to 6 carbons. In certain embodiments, alkynylene groups are lower alkynylene, including alkynylene of 3 to 4 carbon atoms.
  • alk(en)(yn)ylene refers to a straight, branched or cyclic, in certain embodiments straight or branched, divalent aliphatic hydrocarbon group, in one embodiment having from 2 to about 20 carbon atoms and at least one triple bond, and at least one double bond; in another embodiment 1 to 12 carbons.
  • alk(en)(yn)ylene includes lower alk(en)(yn)ylene. There may be optionally inserted along the alkynylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, where the nitrogen substituent is alkyl.
  • the term "lower alk(en)(yn)ylene” refers to alk(en)(yn)ylene groups having up to 6 carbons. In certain embodiments, alk(en)(yn)ylene groups have about 4 carbon atoms.
  • cycloalkylene refers to a divalent saturated mono- or multicyclic ring system, in certain embodiments of 3 to 10 carbon atoms, in other embodiments 3 to 6 carbon atoms; cycloalkenylene and cycloalkynylene refer to divalent mono- or multicyclic ring systems that respectively include at least one double bond and at least one triple bond. Cycloalkenylene and cycloalkynylene groups may, in certain embodiments, contain 3 to 10 carbon atoms, with cycloalkenylene groups in certain embodiments containing 4 to 7 carbon atoms and cycloalkynylene groups in certain embodiments containing 8 to 10 carbon atoms.
  • the ring systems of the cycloalkylene, cycloalkenylene and cycloalkynylene groups may be composed of one ring or two or more rings which may be joined together in a fused, bridged or spiro-connected fashion.
  • Cycloalk(en)(yn)ylene refers to a cycloalkylene group containing at least one double bond and at least one triple bond.
  • substituted alkylene refers to alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene and cycloalkynylene groups, respectively, that are substituted with one or more substituents, in certain embodiments one to three or four substituents, where the substituents are as defined herein, generally selected from Q 1 .
  • arylene refers to a monocyclic or polycyclic, in certain embodiments monocyclic, divalent aromatic group, in one embodiment having from 5 to about 20 carbon atoms and at least one aromatic ring, in another embodiment 5 to 12 carbons. In further embodiments, arylene includes lower arylene. Arylene groups include, but are not limited to, 1,2-, 1,3- and 1 ,4-phenylene. The term “lower arylene” refers to arylene groups having 5 or 6 carbons.
  • heteroarylene refers to a divalent monocyclic or multicyclic aromatic ring system, in one embodiment of about 5 to about 15 members where one or more, in certain embodiments 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including, but not limited to,, nitrogen, oxygen or sulfur.
  • heterocyclylene refers to a divalent monocyclic or multicyclic non-aromatic ring system, in certain embodiments of 3 to 10 members, in one embodiment 4 to 7 members, in another embodiment 5 to 6 members, where one or more, including 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including, but not limited to,, nitrogen, oxygen or sulfur.
  • substituted arylene substituted heteroarylene
  • substituted heterocyclylene refer to arylene, heteroarylene and heterocyclylene groups, respectively, that are substituted with one or more substituents, in certain embodiments one to three or four substituents, where the substituents are as defined herein, generally selected from Q 1 .
  • halo refers to F, Cl, Br or I.
  • pseudohalides or pseudohalo groups are groups that behave substantially similar to halides. Such compounds can be used in the same manner and treated in the same manner as halides. Pseudohalides include, but are not limited to, cyano, thiocyanate, selenocyanate, trifluoromethoxy, and azide.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl and 1 chloro 2 fluoroethyl.
  • haloalkoxy refers to RO in which R is a haloalkyl group.
  • carboxy refers to a divalent radical, -C(O)O-.
  • aminocarbonyl refers to C(O)NH 2 .
  • alkylaminocarbonyl refers to C(O)NHR in which R is alkyl, including lower alkyl.
  • dialkylaminocarbonyl refers to C(O)NR 1 R in which R 1 and R are independently alkyl, including lower alkyl;
  • carboxamide refers to groups of formula -NR'COR in which R' and R are independently alkyl, including lower alkyl.
  • arylalkylaminocarbonyl refers to -C(O)NRR' in which one of R and R' is aryl, including lower aryl, such as phenyl, and the other of R and R' is alkyl, including lower alkyl.
  • arylaminocarbonyl refers to -C(O)NHR in which R is aryl, including lower aryl, such as phenyl.
  • hydroxycarbonyl refers to -COOH.
  • alkoxycarbonyl refers to -C(O)OR in which R is alkyl, including lower alkyl.
  • aryloxycarbonyl refers to -C(O)OR in which R is aryl, including lower aryl, such as phenyl.
  • alkoxy and arylthio refer to RO- and RS- , in which R is alkyl, including lower alkyl.
  • aryloxy and arylthio refer to RO- and RS-, in which R is aryl, including lower aryl, such as phenyl.
  • haloalkyl may include one or more of the same or different halogens.
  • haloalkyl may include one or more of the same or different halogens.
  • Ci. 3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three carbons.
  • selective PPAR ⁇ agonist refers to a compound that is more active against PPAR ⁇ as compared to the compound's activity against PP ARa and/or PPAR ⁇ .
  • a selective PPAR ⁇ agonist is >100 times, >250 times, >500 times, >750 times, >1000 times or more active against PPAR ⁇ as compared to activity against
  • examples of the alkyl groups having 1-8 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and pentyl.
  • examples of the alkyl groups having 1-8 carbon atoms and a halogen substituent include methyl, ethyl, propyl, isopropyl, butyl, and t-butyl which are substituted with 1-3 halogens such as fluorine, chlorine, and bromine. Examples include trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl and 2-fluoroethyl.
  • alkoxy groups having 1-8 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy and pentyloxy.
  • alkoxy groups having 1-8 carbon atoms and a halogen substituent include methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy groups substituted with 1-3 halogen atoms such as fluorine atom, chlorine atom or bromine atom. Trifluoromethoxy, chloromethoxy, 2-chloroethoxy, 2-bromoethoxy and 2-fluoroethoxy are included.
  • Examples of the alkenyl groups having 2-8 carbon atoms include vinyl and allyl.
  • Examples of the alkynyl groups having 2-8 carbon atoms include propargyl.
  • Examples of 3-7 membered cycloalkyl groups include cyclohexyl and cyclopentyl.
  • Examples of the alkyl groups having 1-8 carbon atoms and a 3-7 membered cycloalkyl substituent include cyclohexylmethyl and cyclopentylmethyl.
  • a compound provided is a compound of the formula
  • R 1 is phenyl which can have substituents selected from the group consisting of Ci -8 alkyl, Ci -8 alkyl having 1-3 halogen atoms, Ci -8 alkoxy, C 1-8 alkoxy having 1-3 halogen atoms, C 2-8 alkenyl, C 2-8 alkynyl, halogen, C 2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl and pyridyl.
  • a compound provided is a compound of the formula (I), a salt thereof or (1), in which R 2 is C 2-8 alkyl.
  • a compound provided is a compound of the formula (I), a salt thereof, (1) or (2), in which R 1 is attached to the 2nd position.
  • R 1 is attached to the 2nd position
  • R 4 is attached to the 4th position and --X-- Y-- is attached to the 5th position, or R 4 is attached to the 5th position and --X-- Y-- is attached to the 4th position.
  • a compound provided is a compound of the formula (I), a salt thereof, (1), (2) or (3), in which A is oxygen or sulfur.
  • a compound provided is a compound of the formula (I), a salt thereof, (1), (2), (3) or (4), in which X is a Ci -8 alkylene chain.
  • compound provided is a compound of the formula (I), a salt thereof, (1), (2), (3), (4), (5) or (6), in which each of R 3 , R 4 and R 5 is hydrogen, Ci -8 alkyl or Ci -8 alkyl having halogen.
  • a compound provided is a compound of the formula (I), a salt thereof, (1), (2), (3), (4), (5), (6) or (7), in which B is CH.
  • a compound provided is a compound of the formula (I), a salt thereof, (1), (2), (3), (4), (5), (6), (7) or (8), in which Z is oxygen.
  • a compound provided is a compound of the formula (I), a salt thereof, (1), (2), (3), (4), (5), (6), (7), (8) or (9), in which each of R 6 and R 7 is hydrogen or Ci -4 alkyl.
  • a compound provided is a compound of the formula (I), a salt thereof, (1), (2), (3), (4), (5), (6), (7), (8) or (9), in which R 8 is hydrogen.
  • a compound provided is a compound of the formula (I) or a salt thereof, in which R 1 is phenyl or naphthyl, each of which can have substituents selected from the group consisting of C 1-8 alkyl, C 1-8 alkyl having halogen, C 1-8 alkoxy, Ci -8 alkoxy having halogen, C 2-8 alkenyl, C 2-8 alkynyl, halogen, C 2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl and pyridyl;
  • R 2 is C 2-8 alkyl
  • A is oxygen or sulfur
  • X is a C 1-8 alkylene chain which can have a Ci -8 alkyl substituent and which can contain a double bond;
  • each of R 3 , R 4 and R 5 is hydrogen, C 1-8 alkyl, Ci -8 alkyl having halogen, Ci -8 alkoxy, Ci -8 alkoxy having halogen, C 2-8 alkenyl, C 2-8 alkynyl, halogen, C 2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl, or pyridyl;
  • B is CH;
  • Z is oxygen or sulfur;
  • each of R 6 and R 7 is hydrogen or Ci -8 alkyl
  • R 8 is hydrogen or Cu 8 alkyl.
  • a compound provided is a compound of (12), in which X is a Ci -8 alkylene chain.
  • a compound provided is a compound of (12) or
  • a compound provided is a compound of (12), (13), (14) or (15), in which the substituents of R 3 , R 4 and R 5 other than hydrogens are placed at ortho-positions with respect to -Z-CR 6 R 7 CO 2 R 8 .
  • the compound of the formula (I) can be present in the form of geometrical isomers such as cis and trans and optical isomers. These isomers are included in the compounds provided. Further, the compounds provided can be in the form of pharmaceutically acceptable salts, such as alkali metal salts, e.g., sodiun or potassium salt. [00142] The processes for preparing the compound of the formula (I) provided herein is described below.
  • Q is a releasing group such as tosyloxy or halogen (e.g., bromine), and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, X, Y, B and Z are those described hereinbefore.
  • the compound of the formula (I) according to the invention can be prepared by reacting a phenol or thiophenol compound of the general formula (a) with an acetic acid derivative of the general formula (b). The reaction can be carried out in a solvent such as methyl ethyl ketone in the presence of a base such as potassium carbonate.
  • the starting compound of the formula (a) can be prepared by a process similar to the below-mentioned synthetic scheme.
  • n is an integer of 1 to 7
  • Bn is benzyl
  • a and B are those described herein before.
  • R 1 , R 2 , R 3 , R 4 , R 5 , A, B, X and Y are those described herein before.
  • the phenol compound is treated with dimethylthiocarbamoyl chloride in the presence of a base such as triethylamine to obtain a dimethylthiocarbamoyloxy compound.
  • the dimethylthiocarbamoyloxy compound is heated in n-tetradecane or no solvent to obtain a dimethylcarbamoylsulfanyl compound as a rearranged compound.
  • the dimethylcarbamoyl group is treated with NaOH or MeONa to be converted to a thiophenol compound.
  • m is an integer of O to 6
  • R 1 , R 2 , R 3 , R 4 , R 5 , A, B and Bn are those described herein before.
  • the acetophenone compound and the aldehyde compound synthesized according to a conventional method are condensed with hydration using a base such as NaOH, KOH, MeONa, EtONa, piperidine in a solvent such as methanol, ethanol, anhydrous benzene to obtain a ⁇ , ⁇ -unsaturat- ed ketone compound.
  • the ⁇ , ⁇ -unsaturated ketone compound is treated, for example subjected to a hydride contact reduction to conduct reduction of the olefin and the debenzylation to obtain the subject compound.
  • R 1 , R 2 , R 3 , R 4 , R 5 , A, B, n and Bn are those described herein before.
  • the benzaldehyde compound is treated with a Grignard reagent obtained according to a conventional method in the presence of a solvent such as a ether or THF under the condition of a low temperature to obtain an alcohol compound.
  • the alcohol compound can be converted into a ketone compound by using a Jones reagent (chromium(VI)oxide- sulfuric acid-acetone) or chromium(VI)-pyridine complex (e.g., pyridinium chlorochromate, pyridinium dichromate).
  • the alcohol compound can also be converted into the ketone body in the same manner by using DMSO oxidation.
  • the ketone body is subjected to debenzylation to be converted into the subject phenol compound.
  • R a is hydrogen atom or an alkyl group having 1 to 5 carbon atoms
  • R 1 , R 2 , A, X, Y and B are those described hereinbefore.
  • the phenol compound is subjected to an allylation according to a conventional method, and heated (at 150° C. or higher) with no solvent or in a solvent such as quinoline to obtain a compound having the rearranged allyl group at the ortho-position.
  • R is an alkyl group having 1 to 6 carbon atoms
  • A, X, Y and B are those described herein before.
  • the phenol compound is subjected to an acylation according to a conventional method, and heated in the presence of a Lewis acid catalyst to obtain a compound having the rearranged acyl group at the ortho-position.
  • R 1 , R 2 , R 3 , R 4 , R 5 , A, B, n and Bn are those described herein before.
  • the phenol compound obtained in the Synthesis example 1 for starting compound is treated with a reducing agent such as lithium aluminum hydride, sodium boron hydride to obtain an alcohol compound.
  • a reducing agent such as lithium aluminum hydride, sodium boron hydride to obtain an alcohol compound.
  • the alcohol compound is subjected to dehydration using a halogenation agent, a sulfonation agent or a dehydration agent to obtain an olefin compound.
  • R° is an alkyl group having 1 to 8 carbon atoms
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A, X, B and Z are those described herein before.
  • OH)) according to the invention can be obtained by reacting the ketone compound of the formula (d) with hydroxylamine.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A, B, Z and n are those described herein before.
  • a base such as t-BuOK, n-BuLi, sec-BuLi, EtONa in a solvent such as a dry ether or THE (according to Wittig reaction) to introduce a methylene chain into the compound.
  • R 10 is an alkyl group having 1 to 10 carbon atoms
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, B, Z and n are those described herein before.
  • alkyl halide such as iodomethane
  • the S-stereoisomer is prepared as represented in the following scheme:
  • the R-stereoisomer is prepared as represented in the following scheme:
  • Numeral in ( ) means a position of the group.
  • Numeral in ( ) means a position of the group.
  • Numeral in ( ) means a position of the group.
  • Numeral in ( ) means a position of the group.
  • Numeral in ( ) means a position of the group.
  • the halogen atom for R 1 and R 2 can be fluorine, chlorine, or bromine.
  • the alkyl groups having 1-8 carbon atoms for R 1 , R 2 , R 3 , R 4 and R 5 can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, or pentyl.
  • the alkoxy group having 1-8 carbon atoms for R 1 and R 2 can be methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, t-butyloxy, or pentyloxy.
  • the alkyl group having 1-8 carbon atoms which has 1-3 halogen substituents for R 1 and R 2 can be chloromethyl, fluoromethyl, bromomethyl, 2-chloroethyl, 2-fluoroethyl, or trifluoromethyl.
  • the alkoxy group having 1-8 carbon atoms which has 1-3 halogen substituents for R 1 and R 2 can be chloromethoxy, fluoromethoxy, bromomethoxy, 2-chloroethoxy, 2- fluoroethoxy, or trifluoroethoxy.
  • the alkenyl group having 2-8 carbon atoms for R 1 and R 2 can be vinyl or allyl.
  • the alkynyl group having 2-8 carbon atoms can be propargyl.
  • 3-7 carbon atoms can be cyclohexyl or cyclopentyl.
  • the alkyl group having a 3-7 membered cycloalkyl substituent can be cyclohexylmethyl or cyclopentylmethyl.
  • the aryl group for the aryl group optionally having a substituent for R 1 and R 2 can be phenyl or naphthyl.
  • the arylalkyl group for the arylalkyl group (which has an aryl moiety of 6-10 carbon atoms and an alkyl moiety of 1-8 carbon atoms) optionally having a substituent can be benzyl or phenethyl.
  • the heterocyclic group for the heterocyclic group optionally having a substituent can be a 5-7 membered cyclic group having ring-forming 1-4 hetero atoms such as nitrogen, oxygen and sulfur.
  • a benzene ring condensed with the heterocyclic group such as quinolyl or benzothienyl can be mentioned.
  • the heterocyclic group for the heterocyclic ring-alkyl group (the alkyl moiety has 1-8 carbon atoms) optionally having a substituent can be the same as that described hereinbefore for the heterocyclic group optionally having a substituent.
  • the alkyl group preferably has 1-3 carbon atoms.
  • the substituent for the substituents of the aryl group optionally having a substituent, the arylalkyl group (the aryl moiety has 6-10 carbon atoms, and the alkyl moiety has 1 -8 carbon atoms) optionally having a substituent, the heterocyclic group optionally having a substituent, and a heterocyclic ring-alkyl group (the alkyl moiety has 1-8 carbon atoms) optionally having a substituent can be a halogen atom such as chlorine, bromine, or fluorine, nitro, hydroxyl, amino, an alkyl amino group having 1-8 carbon atoms such as methylamino, or ethylamino, a dialkylamino group having 2-10 carbon atoms such as dimethylamino, an alkyl group having 1 -8 carbon atoms such as methyl, ethyl, propyl, isopropyl, or butyl, an alkoxy group having 1-8 carbon atoms
  • the halogen atom, alkoxy groups having 1-8 carbon atoms, alkyl group having 1-8 carbon atoms which has 1-3 halogen substituents, alkoxy group having 1-8 carbon atoms which has 1-3 halogen substituents, alkenyl group having 2-8 carbon atoms, alkynyl group having 2-8 carbon atoms, cycloalkyl group having 3-7 carbon atoms, alkyl group having 1-8 carbon atoms which has a cycloalkyl group of 3-7 carbon atoms for R 11 and R 12 can be those described for the halogen atom, alkoxy group, alkyl group having 1-8 carbon atoms which has a halogen substituent, alkoxy group having 1 -8 carbon atoms which has a halogen substituent, alkenyl, alkynyl, cycloalkyl group, and alkyl group having 1-8 carbon atoms which has a cycloalkyl group of 3-7 carbon atoms for R
  • R 11 or R 12 is phenyl, naphthyl, benzyl, phenethyl, pyridyl, thienyl, furyl, quinolyl, or benzothienyl
  • these rings may have such substituents as a halogen atom such as chlorine, bromine, or fluorine, nitro, hydroxyl, amino, an alkyl amino group having 1-8 carbon atoms such as methylamino, or ethylamino, a dialkylamino group having 2 10 carbon atoms such as dimethylamino, an alkyl group having 1-8 carbon atoms such as methyl, ethyl, propyl, isopropyl, or butyl, an alkoxy group having 1-8 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, or butoxy, an alkyl group having 1 -8 carbon atoms which has 1-3 halogen substituents such as chlor
  • the compound provided is a phenylacetic acid derivative of the formula (III) in which -X'-Y'-Z 1 - is bonded to the 3- or 4-position of the phenylacetic acid or a salt thereof.
  • the compound provided is a phenylacetic acid derivative of the formula (III) or a phenylacetic acid derivative of (1) or (2) above in which - X'-Y'-Z 1 - is bonded to the 4-position of the oxazole ring, or a salt thereof.
  • the compound provided is a phenylacetic acid derivative of the formula (III) or a phenylacetic acid derivative of one of (1) to (3) above in which R 11 is a phenyl or naphthyl group which optionally has a substituent selected from the group consisting chlorine, fluorine, hydroxyl, an alkyl group having 1-5 carbon atoms, and an alkyl group having 1-5 carbon atoms, and it is bonded to the 2-position of the oxazole ring, or a salt thereof.
  • the compound provided is a phenylacetic acid derivative of the formula (III) or a phenylacetic acid derivative of one of (1) to (4) above in which R 12 is an alkyl group having 3-6 carbon atoms, and it is bonded to the 5-position of the oxazole ring, or a salt thereof.
  • the compound provided that is a phenylacetic acid of the formula (III), or a salt thereof, can be a stereoisomer such as cis or trans, or an optical isomer. These isomers are included in the invention.
  • the compound provided includes a pharmaceutically acceptable salt such as an alkali metal salt, e.g., sodium salt or potassium salt.Further, the compounds provided can be in the form of pharmaceutically acceptable salts such as alkali metal salts, e.g., sodium salt and potassium salt.
  • a pharmaceutically acceptable salt such as an alkali metal salt, e.g., sodium salt or potassium salt.
  • the compounds provided can be in the form of pharmaceutically acceptable salts such as alkali metal salts, e.g., sodium salt and potassium salt.
  • the variables in formula (IV) are described in further detail below.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , the substituent of the alkylene chain of Y, the substituent of the aryl and the heterocyclic group of R 3 , the substituent of the alkyl group substituted with aryl of R 2 , and the substituent of the alkyl group substituted with a heterocyclic group of R can be an alkyl group having 1-8 carbon atoms.
  • the alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
  • R 2 can be an alkyl group having 2-8 carbon atoms.
  • alkyl groups include ethyl, propyl, iso-propyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
  • R 2 , R 4 , R 5 , the substituent of the alkylene chain of Y, the substituent of the aryl or heterocyclic group of R 1 , the substituent of the alkyl group substituted with aryl of R 2 , and the substituent of the alkyl group substituted with a heterocyclic group of R 2 can be an alkyl groups having 1-8 carbon atoms substituted with 1-3 halogens.
  • haloalkyl groups examples include methyl, ethyl, propyl, isopropyl, butyl, and t-butyl which are substituted with 1-3 halogens such as fluorine, chlorine, and bromine. Trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl and 2-fiuoroethyl are preferred.
  • R 2 and R 3 can be an alkenyl group having 2-8 carbon atoms. Examples of the alkenyl groups include vinyl and allyl. R 2 and R 3 can be an alkynyl group having 2-8 carbon atoms. Examples of the alkynyl groups include propargyl. [00199] R 3 can be a halogen atom. Examples of the halogen atoms include fluorine, chlorine and bromine.
  • R 2 can be a cycloalkyl group having 3-7 carbon atoms.
  • the cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl.
  • the substituent of the aryl or heterocyclic group of R 1 , the substituent of the alkyl group substituted with aryl of R 2 , and the substituent of the alkyl group substituted with a heterocyclic group of R 2 can be an alkoxy groups having 1-8 carbon atoms. Examples of the alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t- butoxy, pentyloxy and hexyloxy.
  • R 1 and the aryl moiety of the aryl substituted with alkyl of R 2 can be an aryl group.
  • the aryl groups include phenyl and naphthyl.
  • R 1 and the substituent of the alkyl group of R 2 can be a heterocyclic group having five to eight membered ring.
  • heterocyclic groups examples include pyridyl, thienyl, fiiryl, thiazolyl and quinolyl.
  • R 1 can be a heterocyclic group having five to eight membered ring comprising one to three hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur and the other atoms consisting of carbon.
  • a benzene ring can be condensed with the heterocyclic ring.
  • condensed rings examples include quinoline ring and benzothiophene ring.
  • Y can be an alkylene chain having 1 to 8 carbon atoms.
  • alkylene chains include methylene and ethylene.
  • R 3 can be one to three groups. Two or three groups of R 3 can be different from each other.
  • R 6 can be an alkyl group having 1-8 carbon atoms substituted with amino.
  • aminoalkyl groups examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl which are substituted with an amino group such as piperidino, pyrrolidino, dimethylamino, and diethylamino.
  • a compound provided is a compound of the formula
  • a compound provided is a compound of the formula (IV), a salt thereof or (1), in which B 1 is N, and B 2 is O.
  • a compound provided is a compound of the formula (IV), a salt thereof, (1) or (2), in which R 6 is hydrogen.
  • a compound provided is a compound of the formula (IV), a salt thereof, (1), (2) or (3), in which X 2 is a bond.
  • a compound provided is a compound of the formula (IV), a salt thereof, (1), (2), (3) or (4), in which X 1 is a bond.
  • a compound provided is a compound of the formula (IV), a salt thereof, (1), (2), (3), (4) or (5), in which R 1 is aryl substituted with a group or atom selected from the group consisting Of Ci -8 alkyl, Cj -8 alkoxy, C 1-8 alkyl substituted with 1-3 halogens, hydroxyl, nitro, amino, phenyl, pyridyl and halogen.
  • a compound provided is a compound of the formula (IV), a salt thereof, (1), (2), (3), (4), (5) or (6), in which R 2 is C 2-8 alkyl.
  • a compound provided is a compound of the formula (IV), a salt thereof, (1), (2), (3), (4), (5), (6) or (7), in which R 3 is Ci -8 alkyl or C 2-8 alkenyl.
  • the compound of the formula (IV) can be in the form of pharmaceutically acceptable salts such as alkali metal salts, e.g., sodium salt and potassium salt.
  • Methods of Use are methods for treating, preventing, or ameliorating one or more symptoms of a disease or condition related to plaque built-in in a vessel. These conditions include but are not limited to a cardiovascular disease including atherosclerosis and hypertriglyceridemia, heart failure, acute coronary syndrome, angina, type II diabetes mellitus, type I diabetes, insulin resistance, epithelial hyperproliferative disease including eczema and psoriasis, and hypertension.
  • a cardiovascular disease including atherosclerosis and hypertriglyceridemia, heart failure, acute coronary syndrome, angina, type II diabetes mellitus, type I diabetes, insulin resistance, epithelial hyperproliferative disease including eczema and psoriasis, and hypertension.
  • the methods provided comprise administering to a subject having or being suspected to have such a condition, a PPAR ⁇ agonist including those described herein.
  • the methods provided comprise administering to a subject having or being suspected to have such a condition, a selective PPAR ⁇ agonist including those described herein.
  • the present invention provides methods for treating plaque build-up by administering to a subject in need thereof one or more compounds of Formulae I to IV.
  • Such compound unclude but are not limited to a single enantiomer, a mixture of the (+)-enantiomer and the (-)-enantiomer, a mixture of about 90% or more by weight of the (-)- enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (-)- enantiomer, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or produg thereof.
  • the compounds described herein induce reverse cholesterol transport in mammals.
  • the mammal is a primate or a human.
  • the mammal is a human.
  • the compounds described herein are useful in treatment of atherosclerosis.
  • the compounds described herein are useful in reducing atherosclerotic plaque.
  • the compounds described herein increase HDL levels in mammals by daily oral administration.
  • the compounds described herein increase ApoA-I levels in mammals by daily oral administration.
  • the compounds described herein increase ApoA-I levels that lead to the formation of pre- ⁇ -HDL particles.
  • the compounds described herein increase pre- ⁇ -HDL levels in mammals by daily oral administration.
  • the compounds described herein increase HDL levels and/or ApoA-I levels in mammals.
  • the compounds described herein increase HDL levels and/or ApoA-I levels, and/or pre- ⁇ -HDL levels in mammals.
  • the increase in ApoA-I levels and/or pre- ⁇ -HDL levels occurs without significantly raising HDL-cholesterol levels.
  • the compounds described herein decrease LDL levels in mammals.
  • the compounds described herein decrease VLDL levels in mammals.
  • the compounds described herein decrease triglyceride levels in mammals.
  • the compounds described herein decrease LDL and/or VLDL levels in mammals.
  • the compounds described herein decrease LDL, and/or VLDL and/or triglyceride levels in mammals.
  • the compounds described herein increase the levels of HDL, and/or ApoA-I, and/or pre- ⁇ HDL, HDL and ApoA-I, and/or HDL, ApoA-I, pre- ⁇ HDL and ApoA-I rich HDL and decrease the levels of LDL, or VLDL, or triglycerides, or LDL and VLDL, or LDL, VLDL and triglycerides levels in mammals.
  • GSK-501516 Ligand/GSK
  • RWJ-800025 JNJ/Metabolex
  • KD-3010 Kalypsys, Inc.
  • BAY 68-5042 Boyer
  • Bratton L. D. et al., Bioorg. Med. Chem. Lett. 2007 (web edition) and Kasuga, J. I. et al., Bioorg. Med. Chem.
  • 2007 may be administered by oral or parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant) routes of administration, and may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the compounds provided are administered orally.
  • an appropriate dosage level of a PPAR ⁇ agonist for humans is about 0.1 mg/day to about 2500 mg/day and results in increase in pre- ⁇ -HDL levels while avoiding the side effects associated with the use of PP ARa and PPAR ⁇ agonists, or classical PPAR agonist class side effects.
  • the dose is about 0.25 mg/day to about 500 mg/day.
  • the dose is about 0.5 mg/day to about 250 mg/day.
  • the dose is about 0.75 mg/day to about 50 mg/day.
  • the dose is about 1.0 mg/day to about 25 mg/day.
  • a dose of a PPAR ⁇ agonist for humans is about 0.001 mg/kg/day to about 25 mg/kg/day results in increase in pre- ⁇ -HDL levels while avoiding the side effects associated with the use of PP ARa and PPAR ⁇ agonists, or classical PPAR agonist class side effects.
  • dose is about 0.005 mg/kg/day to about 15 mg/kg/day.
  • the dose is about 0.01 mg/kg/day to about 10 mg/kg/day.
  • the dose is about 0.5 mg/kg/day to about 5 mg/kg/day.
  • the dose is about 1.0 mg/kg/day to about 2.5 mg/kg/day, which may be administered in a single or divided doses.
  • the dosage may be about 0.1 mg, about 0,25 mg, about 0.5 mg, about 0.75 mg, about 1.0 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg per day.
  • the low doses of the PPAR ⁇ agonists such as 0.05 to 30 mg/kg/day in monkeys and 0.5 mg/day to 300 mg/day in humans do not cause significant side effects usually reported to be associated with the PPAR ⁇ agonists.
  • compounds provided may be used in combination with any other active agents or pharmaceutical compositions where such combined therapy is useful to reduce plaque build-up and therefore treat the conditions related thereto.
  • compositions comprising one or more compounds of Formulae I to IV, as well as any PPAR ⁇ agonist, including, but not limited to, GW-501516 (Ligand/GSK), RWJ-800025 (JNJ/Metabolex), KD-3010 (Kalypsys, Inc.), BAY 68-5042 (Bayer), or compounds described in Bratton, L. D. et al., Bioorg. Med. Chem. Lett. 2007 (web edition) and Kasuga, J. I. et al., Bioorg. Med. Chem.
  • compositions in modified release dosage forms which comprise one or more compounds of Formulae I to IV, as well as any PPAR ⁇ agonist, including, but not limited to, GW-501516 (Ligand/GSK), RWJ-800025 (JNJ/Metabolex), KD-3010 (Kalypsys, Inc.), BAY 68-5042 (Bayer), or compounds described in Bratton, L. D. et al., Bioorg. Med. Chem. Lett.
  • modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof.
  • the pharmaceutical compositions may also comprise non-release controlling excipients.
  • compositions in enteric coated dosage forms which comprise one or more compounds of Formulae I to IV or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release controlling excipients for use in an enteric coated dosage form.
  • the pharmaceutical compositions may also comprise non-release controlling excipients.
  • compositions in a dosage form that has an instant releasing component and at least one delayed releasing component, and is capable of giving a discontinuous release of the compound in the form of at least two consecutive pulses separated in time from 0.1 up to 24 hours.
  • the pharmaceutical compositions comprise one or more compounds of Formulae I to IV, as well as any PPAR ⁇ agonist including, but not limited to, GW-501516 (Ligand/GSK), RWJ-800025 (JNJ/Metabolex), KD-3010 (Kalypsys, Inc.), BAY 68-5042 (Bayer), or compounds described in Bratton, L. D. et al., Bioorg. Med. Chem. Lett. 2007 (web edition) and Kasuga, J. I. et al., Bioorg. Med. Chem.
  • compositions in a dosage form for oral administration to a subject which comprise one or more compounds of Formulae I to IV or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more pharmaceutically acceptable excipients or carriers, enclosed in an intermediate reactive layer comprising a gastric juice-resistant polymeric layered material partially neutralized with alkali and having cation exchange capacity and a gastric juice-resistant outer layer.
  • pharmaceutical compositions that comprise about 0.1 mg/day to about 2500 mg/day of a PPAR ⁇ agonist.
  • pharmaceutical compositions comprise about 0.25 mg/day to about 500 mg/day of a PPAR ⁇ agonist.
  • compositions comprise about 0.5 mg/day to about 250 mg/day of a PPAR ⁇ agonist. In yet another embodiment, pharmaceutical compositions comprise about 0.75 mg/day to about 50 mg/day of a PPAR ⁇ agonist. In yet another embodiment, pharmaceutical compositions comprise about 1.0 mg/day to about 25 mg/day of a PPAR ⁇ agonist. [00246] In another embodiment, pharmaceutical compositions provided herein comprise about 0.001 mg/kg/day to about 25 mg/kg/day of a PPAR ⁇ agonist. In yet another embodiment, pharmaceutical compositions provided herein comprise about 0.005 mg/kg/day to about 15 mg/kg/day of a PPAR ⁇ agonist.
  • compositions provided herein comprise about 0.01 mg/kg/day to about 10 mg/kg/day of a PPAR ⁇ agonist. In yet another embodiment, pharmaceutical compositions provided herein comprise about 0.5 mg/kg/day to about 5 mg/kg/day of a PPAR ⁇ agonist. In yet another embodiment, pharmaceutical compositions provided herein comprise about 1.0 mg/kg/day to about 2.5 mg/kg/day of a PPAR ⁇ agonist, which may be administered in a single or divided doses.
  • the pharmaceutical compositions further comprise about 0.1% to about 2% sodium chloride, about 0.1% to about 2% ammonium acetate, about 0.001% to about 0.1% edetate disodium, about 0.1% to about 2% benzyl alcohol, with a pH of about 6 to about 8.
  • the pharmaceutical compositions provided herein may be provided in unit- dosage forms or multiple-dosage forms.
  • Unit-dosage forms refer to physically discrete units suitable for administration to human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients.
  • unit-dosage forms include ampouls, syringes, and individually packaged tablets and capsules. Unit- dosage forms may be administered in fractions or multiples thereof.
  • a multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of multiple-dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.
  • the compounds of Formulae I to IV, as well as any PP AR ⁇ agonist including, but not limited to, GW-501516 (Ligand/GSK), RWJ-800025 (JNJ/Metabolex), KD-3010 (Kalypsys, Inc.), BAY 68-5042 (Bayer), or compounds described in Bratton, L. D. et al., Bioorg. Med. Chem. Lett. 2007 (web edition) and Kasuga, J. I. et al., Bioorg. Med. Chem. 2007 (web edition) provided herein may be administered alone, or in combination with one or more other compounds provided herein, or one or more other active ingredients.
  • compositions that comprise compounds provided herein may be formulated in various dosage forms for oral administration.
  • the pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art ⁇ see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126).
  • compositions provided herein may be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
  • oral administration also include buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.
  • binders fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.
  • Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression.
  • Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose
  • Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre- gelatinized starch, and mixtures thereof.
  • the binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.
  • Certain diluents such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
  • Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof.
  • the amount of disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
  • Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL ® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL ® (Cabot Co. of Boston, MA); and mixtures thereof.
  • the pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
  • Suitable glidants include colloidal silicon dioxide, CAB-O-SIL ® (Cabot Co. of
  • Coloring agents include any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof.
  • a color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye.
  • Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.
  • Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.
  • Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN ® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN ® 80), and triethanolamine oleate.
  • Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrolidone.
  • Preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
  • Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil.
  • Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.
  • compositions provided herein may be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets.
  • Enteric- coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach.
  • Enteric-coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.
  • Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation.
  • Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material.
  • Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating.
  • Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
  • the tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • the pharmaceutical compositions provided herein may be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
  • the hard gelatin capsule also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient.
  • DFC dry-filled capsule
  • the soft elastic capsule is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propylparabens, and sorbic acid.
  • the liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos.
  • the capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • the pharmaceutical compositions provided herein may be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.
  • An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil.
  • Emulsions may include a pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent, and preservative.
  • Suspensions may include a pharmaceutically acceptable suspending agent and preservative.
  • Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl)acetal of a lower alkyl aldehyde (the term "lower” means an alkyl having between 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol.
  • Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative.
  • a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
  • a pharmaceutically acceptable liquid carrier e.g., water
  • Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly- alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
  • formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • compositions provided herein may be provided as non- effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
  • Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents can be used in all of the above dosage forms.
  • compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • compositions provided herein may be co-formulated with other active ingredients which do not impair the desired therapeutic action, or with substances that supplement the desired action, such as antacids, proton pump inhibitors, and F ⁇ -receptor antagonists.
  • compositions in an osmotic controlled-release dosage form may further comprise additional conventional excipients as described herein to promote performance or processing of the formulation.
  • the osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art ⁇ see, Remington: The
  • the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients.
  • AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
  • compositions provided herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), hydroxylethyl cellulose, and other pharmaceutically acceptable excipients.
  • compounds provided are administered once daily in a single or divided dose in the amount of about 0.001 to about 25 mg/kg, where kg refers to a subject's body weight.
  • compounds provided are administered once daily in a single or divided dose in the amount of about 0.005 to about 15 mg/kg.
  • compounds provided are administered once daily in a single or divided dose in the amount of about 0.01 to about 10 mg/kg.
  • compounds provided are administered once daily in a single or divided dose in the amount of about 0.5 to about 5 mg/kg.
  • compounds provided are administered once daily in a single or divided dose in the amount of about 1.0 to about 2.5 mg/kg.
  • compounds provided are administered once daily in a single or divided dose in the amount of about 0.1 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1.0 mg, about 2.5 mg, about 5.0 mg, about 7.5 mg, about 10 mg, about 15 mg, or about 25 mg.
  • any compound possessing PPAR ⁇ agonist activity may be used.
  • compounds that are selective PPAR ⁇ agonists are used.
  • Exemplary compounds include, but are not limited to, GW-501516 (Ligand/GSK), RWJ-
  • Example 1 2-[4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4- oxazolyI]propionyl]-2-methyl-phenoxy]-2-methylpropionic acid.
  • Example 3 4-[3-[4-Isopropyl -2-[4-(trifluoromethyl)phenyl]-5- thiazolyl]propionyl]-2-methyIphenoxyacetic acid.
  • Example 1 using the synthetic intermediate (1) of Example 3, namely l-(4-Hydroxy-3- methylphenyl)-3-[4-isopropyl -2-[4-(trifluoromethyl)phenyl]-5-thiazolyl] propan-1-one (yield
  • Example 8 2-[4-[3-[2-(2-Hydroxy-4-chlorophenyl)-5-isopropyI-4- oxazolyl]propionyl]-2-methylphenoxy]-2-methylpropionic acid.
  • Example 9 [4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-l- propenyl] -2-methy lphenoxy ] acetic acid.
  • Example 10 [4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]- l-propenyl]-2-methyIphenoxy]acetic acid.
  • Example 11 [4-[3-[4-Hexyl-2-(4-trifluoromethyl)phenyl-5- thiazoly 1] propionyl] -2-methy Iphenoxy] acetic acid.
  • IR (KBr) Cm- 1 2970, 2929, 2872, 1716, 1616, 1500, 1325, 1167, 1126, 1066,
  • IR (KBr) cm “1 2962, 1741, 1672, 1603, 1574, 1450, 1325, 1260, 1236, 1211, 1168, 1126, 1066, 976, 849, 698, 611.
  • Example 15 [4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4- oxazolyl] propiony 1] -3-methy lphenoxy ] acetic acid.
  • IR (KBr) cm '1 3454, 2976, 1730, 1682, 1637, 1605, 1564, 1460, 1383, 1363,
  • Example 16 [4-[3-[4-IsopropyI-2-(4-trifluoromethyl)phenyl-5- thiazoly 1] propiony 1] -3-methy lphenoxy] -2-methy (propionic acid.
  • Example 17 2-[4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4- oxazolyl] propiony I] -3-methy lphenoxy] -2-methy Ip ropionic acid.
  • IR (KBr) Cm "1 2980, 2940, 1720, 1680, 1600, 1560, 1460, 1250, 1145, 1125.
  • Example 18 [4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5- thiazolyl]propionyl]-2-propylphenoxy]acetic acid.
  • Methyl triphenyl phosphonium bromide (175 mg, 0.49 mmol), a dry ether (5 mL) and potassium t-butoxide (60 mg, 0.53 mmol) were added to the reaction mixture. The resulting mixture was stirred for 30 minutes at room temperature. The mixture was refluxed for 4 hours, and allowed to room temperature. Ethyl acetate (10 mL) was added to the reaction mixture. The mixture was washed with water (10 mL), and a saturated saline (10 mL), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate/hexane (1/9) to give the desired compound (131 g) as colorless oil (yield 29%).
  • IR (KBr) cm '1 3088, 2968, 2927, 2872, 1736, 1605, 1564, 1504, 1460, 1225,
  • Example 21 2-[4-[4-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-l- buten-2-yl]-2-methylphenoxy]-2-methylpropionic acid.
  • Example 22 [4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-2- methylpropionyI]-2-methylphenoxy]acetic acid.
  • IR (KBr) cm “1 3427, 2970, 2931, 2873, 1740, 1672, 1599, 1564, 1502, 1456,
  • Example 23 2-[4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-2- methylpropionyl]-2-methylphenoxy]-2-methylpropionic acid.
  • Example 25 2-[4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5- thiazolyl] propenoy 1] -2-methylphenoxy] -2-methy lpropionic acid.
  • Example 1 Yellow crystal (mp: 187- 189° C.)
  • Example 26 [4-[3-[4-Isopropyl-2-(4-methoxyphenyl)-5- thiazolyl]propionyl]-2-methylphenoxy]propionic acid.
  • Example 27 [4-[3-[2-(3,5-Difluorophenyl)-4-isopropylthiazol-5- yl]propionyl]-2-methylphenoxy]acetic acid.
  • Example 28 2-[4-[3-[2-(3,5-Difluorophenyl)-4-isopropyl-5- thiazolyl] propiony 1] -2-methy Iphenoxy] -2-methy lpropionic acid.
  • IR (KBr) crn 1 2974, 2927, 1741, 1652, 1620, 1605, 1535, 1506, 1502, 1458,
  • IR (KBr) cm “1 3845, 3745, 3429, 2962, 2929, 2368, 2345, 1749, 1676, 1601,
  • IR (KBr) cm '1 3435, 2960, 2929, 2870, 2860, 2368, 1741, 1676, 1601, 1502,
  • Example 32 2-[4-[3-[2-(4-Butylphenyl)-4-isopropyI-5- thiazolyl] propiony 1] -2-methylphenoxy] -2-methy lpropionic acid.
  • Example 33 [4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyI-5- thiazoly 1] propiony 1] -2-chlorophenoxy ] acetic acid.

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Abstract

The compounds provided, which are PPARδ agonists, induce reverse cholesterol transport, reverse lipid transport, or increase the HDL and/or ApoA-I, and/or HDL-phospholipids, and/or pre-β HDL levels, and/or ApoA-I rich HDL levels in mammals, as well as the number of pre-β HDL particles when using low doses in humans. Specifically, compounds selective for PPARδ can be used in methods for treatment of a condition related to an atherosclerotic plaque build-up in a vessel, hypertriglyceridemia or dyslipidemia.

Description

NOVEL USES OF PPAR DELTA AGONISTS
RELATED APPLICATIONS
[0001] This application claims the benefit of US provisional application
No. 60/934,335, filed on June 11, 2007, the content of which is hereby incorporated by reference in its entirety.
FIELD
[0002] Provided herein are methods for treatment of a disease or condition related to atherosclerotic plaque build-up in a vessel by administering the compounds provided, or pharmaceutical compositions comprising them. The compounds provided, which are PPARδ agonists, are useful for one or more of the following: inducing reverse cholesterol transport, inducing reverse lipid transport, increasing HDL, HDL-cholesterol, ApoA-I, HDL- phospholipids, pre-β HDL, pre-β HDL-cholesterol levels in mammals, or the number of HDL and/or pre-β HDL particles in mammals. Specifically, compounds selective for PPARδ are used in methods for increasing the number of pre-β HDL particles and pre-β HDL- cholesterol, or Apo A-I or HDL-phospholipids in connection with the treatment of cardiovascular diseases. PPARδ receptor nomenclature has been recently revised and a recommendation is made to change the denomination from δ to β. Most recent articles reference the receptors as PPAR δ/β. We shall however nominate them below as PPARδ.
BACKGROUND
[0003] The peroxisome is a small organ present in cells of animals and plants, and its matrix contains various enzymes such as catalases. Various compounds such as fibrates, herbicides, and phthalic acid plasticizers are known as peroxisome proliferators, which induce proliferation of peroxisomes. [0004] Isseman, et al. have identified a nuclear receptor which is activated by peroxisome proliferator and called it peroxisome proliferator activated receptor (PPAR) {Nature, 347:645-650, 1990). Since then three subtypes of PPAR such as PP ARa, PPARy and PPARδ have been identified (Proc. Natl. Acad. Sci. USA, 91 : 7335-7359, 1994). [0005] Different compounds have been shown to modulate PPAR activity. The fibrates used as serum triglyceride (TG) lowering drugs modulate PP ARa activity, and thiazolidine compounds (Troglitazone, Rosiglitazone, Pioglitazone) useful in the treatment of diabetes are known as ligands of PPARγ.
[0006] Pre-β HDL particles were first described by C. Fielding (Biochemistry
27(l):25-29 (1988)) and are small HDL discoidal particles with very few molecules of lipids, mainly phospholipids, and apoA-I. They were described as the first acceptors of cholesterol from peripheral cells. The mechanism of interaction between pre-β particles and cells is still largely unknown. Nevertheless, ABCAl transporters seem to be involved in the cholesterol efflux from cells to pre-β HDL. Following the efflux, the pre-β HDL particles are further transformed into more mature and larger particles such as HDL3 and HDL2. The latter interact with liver cells for cholesterol elimination through the bile duct. It is noteworthy that this pathway, which is the reverse cholesterol transport, is the main, if not the only, cholesterol eliminaton pathway from the body. This pathway is also called reverse lipid transport since other lipids, such as oxidized lipids, are transported and cleared by the same mechanism. [0007] The two different studies in humans using apoA-I milano and human plasma apoA-I associated with small artificial HDL particles (JAMA 290(17):2292-2300 (2003); and JAMA 297(15):1675-1678 (2007)) have demonstrated the important role of pre-β HDL particles in plaque regression. Additionally, a recent post-hoc analysis of two large clinical trials by Steeg et al. (JACC 51:634-643 (2008)) found that when controlling for apoAI, HDL- C and apoB, elevated apoAI is a better predictor of decreased cardiovascular risk than HDL- C. The study further suggested that at very high HDL-C levels, HDL-C may actually increase risk. These results in combination suggest that the apoA-I and HDL profile induced by a selective PPAR δ agonist will be particularly effective at preventing, reversing, or treating atherosclerosis related cardiovascular diseases. [0008] Provided PPARδ agonists increase the levels of ApoA-I and/or of pre-β HDL particles and can be used for preventing, reversing, or treating atherosclerosis-related cardiovascular diseases, thereby augmenting the process of plaque elimination from the cardiovascular system of patients in need of such treatment.
SUMMARY
[0009] In one embodiment, provided are PPARδ agonists that increase the levels of
ApoA-I and/or pre-β HDL, and/or pre-β HDL-cholesterol, and/or phospholipids, and/or the number of pre-β HDL particles in mammals. [0010] In another embodiment, provided are methods for treatment a disease or condition related to plaque build-in in a vessel by administration of a PPARδ agonist provided herein.
[0011] In another embodiment, provided are methods for treatment a disease or condition related to plaque build-in in a vessel by administration of a selective PPARδ agonist provided herein.
[0012] Diseases or conditions related to plaque build-up include, but are not limited to, a cardiovascular disease including atherosclerosis and hypertriglyceridemia, heart failure, acute coronary syndrome, angina, type II diabetes mellitus, type I diabetes, insulin resistance, epithelial hyperproliferative disease including eczema and psoriasis, and hypertension, as well as related to the accumulation or deposit of lipids such as Alzheimer's, Parkinson's, degenerative disease, inflammation..
[0013] In another embodiment, in the methods provided, the compounds described herein induce reverse cholesterol transport in mammals, hi other embodiments, the mammal is a primate or a human. In certain embodiments, the mammal is a human.
[0014] In another embodiment, in the methods provided, the compounds described herein increase HDL and/or HDL-cholesterol levels in mammals.
[0015] In another embodiment, in the methods provided, the compounds described herein increase the ApoA-I levels leading to the formation of the pre-β HDL particles. In another embodiment, the methods use compounds that increase HDL levels and/or ApoA-I levels in mammals.
[0016] In another embodiment, in the methods provided, the compounds described herein increase the pre-β HDL and/or pre-β HDL cholesterol levels in mammals. In yet another embodiment, the compounds described herein increase the level of HDL- phospholipids in connection with the lipid cholesterol transport.
[0017] In another embodiment, in the methods provided, the compounds described herein increase HDL levels and/or ApoA-I levels, and/or pre-β HDL levels in mammals. In yet another embodiment, the increase in the ApoA-I levels and/or pre-β HDL levels occurs without significantly raising in HDL-cholesterol levels. [0018] In another embodiment, in the methods provided, the use of a low dose of a
PPARδ agonist provided such as 0.1 mg/day to about 2500 mg/day for humans results in increase in pre-β-HDL levels while avoiding the side effects associated with the use of PP ARa and PPARγ agonists, or classical PPAR agonist class side effects. [0019] In another embodiment, in the methods provided, the use of a low dose of a
PPARδ agonist provided such as 0.001 mg/kg/day to 25 mg/kg/day for humans results in increase in pre-β-HDL levels while avoiding the side effects associated with the use of PP ARa and PPARγ agonists, or classical PPAR agonist class side effects. [0020] In another embodiment, in the methods provided, the use of a low dose of a
PPARδ agonist provided such as 0.1 mg/kg/day to 30 mg/kg/day in non-human primates results in increase in pre-β-HDL levels while avoiding the side effects associated with the use of PP ARa and PPARγ agonists, or classical PPAR agonist class side effects. [0021] In another embodiment, in the methods provided, the use of a low dose of any selective PPARδ agonist with a selectivity of >500 over PP ARa and PPARγ results in increase in pre-β HDL levels while avoiding the side effects associated with the use of PP ARa and PPARγ agonists, or classical PPAR agonist side effects. Exemplary compounds include but thy are not limited to GW-501516 (Ligand/GSK), RWJ-800025 (JNJ/Metabolex), KD-3010 (Kalypsys, Inc.), BAY 68-5042 (Bayer), or compounds described in Bratton, L. D. et ah, Bioorg. Med. Chem. Lett. 2007 (web edition) and Kasuga, J. I. et ah, Bioorg. Med. Chem. 2007 (web edition).
[0022] In another embodiment, in the methods provided, the compounds described herein decrease LDL-cholesterol levels in mammals. [0023] In another embodiment, in the methods provided, the compounds described herein decrease VLDL-cholesterol levels in mammals.
[0024] In another embodiment, in the methods provided, the compounds described herein decrease triglyceride levels in mammals.
[0025] In another embodiment, in the methods provided, the compounds described herein increase the levels of HDL and/or ApoA-I, and/or pre-β HDL, HDL and ApoA-I, and/or HDL, ApoA-I and pre-β HDL, and/or ApoA-I rich HDL, and decrease the levels of LDL, or VLDL, or triglycerides, or LDL and VLDL, or LDL, VLDL and triglycerides levels in mammals.
[0026] Examples of PPARδ compounds for use in the compositions and methods provided are described below. [0027] In one embodiment, the compounds have the following general formula (I) or a salt thereof:
Figure imgf000006_0001
wherein R1 is phenyl, naphthyl, pyridyl, thienyl, furyl, quinolyl or benzothienyl, any of which can have substituents selected from the group consisting of Ci-8 alkyl, Cj-8 alkyl having halogen, Ci-8 alkoxy, Ci-8 alkoxy having halogen, C2-8 alkenyl, C2-8 alkynyl, halogen, C2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl and pyridyl;
[0028] R2 is Ci-8 alkyl, Ci-8 alkyl having halogen, C2.8 alkenyl, C2-8 alkynyl, 3-7 membered cycloalkyl, Ci-8 alkyl having 3-7 membered cycloalkyl, or Ci-6 alkyl substituted with phenyl, naphthyl or pyridyl, any of which can have substituents selected from the group consisting Of Ci-8 alkyl, Ci-8 alkyl having halogen, Ci-8 alkoxy, Ci-8 alkoxy having halogen, C2-8 alkenyl, C2-8 alkynyl, halogen, C2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl and pyridyl;
[0029] A is oxygen, sulfur or NR9 in which R9 is hydrogen or Ci-8 alkyl;
[0030] X is a Ci-8 alkylene chain which can have substituents selected from the group consisting Of Ci-8 alkyl, Ci-8 alkoxy and hydroxyl and which can contain a double bond; [0031] Y is C(=O), C(==N--OR10), CH(OR1 '), CH==CH, C-C, or C(==CH2) in which each of R10 and R11 is hydrogen or Ci-8 alkyl;
[0032] each of R3, R4 and R5 is hydrogen, Ci-8 alkyl, Ci-8 alkyl having halogen, Ci-8 alkoxy, Ci-8 alkoxy having halogen, C2-8 alkenyl, C2-8 alkynyl, halogen, C2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl, or pyridyl; [0033] B is CH or nitrogen;
[0034] Z is oxygen or sulfur;
[0035] each of R6 and R7 is hydrogen, Ci-8 alkyl, Ci-8 alkyl having halogen; and
[0036] R8 is hydrogen or Ci-8 alkyl;
[0037] provided that at least one of R3, R4 and R5 is not hydrogen. [0038] The invention also provides an activator of peroxisome proliferator activated receptor δ, which contains as an effective component a compound of the formula (I) or a salt thereof.
[0039] In another aspect, a compound has the following general formula (II) or a salt thereof:
Figure imgf000007_0001
wherein each of R1 and R2 independently is a hydrogen atom, a halogen atom, nitro, an alkyl group having 1-8 carbon atoms, an alkoxy group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkoxy group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, a 3-7 membered cycloalkyl group, an alkyl group having 1-8 carbon atom which has a 3-7 membered cycloalkyl substituent, an aryl group having 6-10 carbon atoms which optionally has a substituent, an arylalkyl group which has a C6-I0 aryl portion and C1-8 alkyl portion, a heterocyclic group which optionally has a substituent or a heterocyclic-alkyl group having an alkyl group of 1-8 carbon atoms;
[0040] A is an oxygen atom, a sulfur atom, or NR3 in which R3 is a hydrogen atom or an alkyl group having 1-8 carbon atoms;
[0041] each of X and Z independently is -C(=O)-, -C(O)NH-, -C(=N-OR4)-, -
CH(OR5)-, -NH(C=O)-, -NHSO2-, -SO2NH-, -CH=CH-, -C≡C-, or a bond in which each of R4 and R5 is a hydrogen atom or an alkyl group having 1-8 carbon atoms; and [0042] Y is an alkylene chain having 1-8 carbon atoms.
[0043] In another aspect, the compound has the following formula (III) or a salt thereof:
Figure imgf000007_0002
wherein each of R11 and R12 independently is a hydrogen atom, a halogen atom, nitro, hydroxyl, amino, an alkyl group having 1-8 carbon atoms, an alkoxy group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkoxy group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, a 3-7 membered cycloalkyl group, an alkyl group having 1-8 carbon atoms which has a 3-7 membered cycloalkyl substituent, or a phenyl, naphthyl, benzyl, phenethyl, pyridyl, thienyl, furyl, quinolyl, or benzothienyl group which optionally has a substituent selected from the group consisting of a halogen atom, nitro, hydroxyl, amino, an alkyl group having 1-8 carbon atoms, an alkoxy group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkoxy group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, a 3-7 membered cycloalkyl group, an alkyl group having 1-8 carbon atoms which has a 3-7 membered cycloalkyl substituent, phenyl and pyridyl; [0044] each of X1 and Z1 independently is -C(=O)-, -C(O)NH-, -C(=N-0R14)-, -
CH(OR15)-, -NH(C=O)-, -NHSO2 -, -SO2NH-, -CH=CH-, -C≡C-, or a bond in which each of R14 and R15 is a hydrogen atom or an alkyl group having 1-8 carbon atoms; and [0045] Y1 is an alkylene chain having 1-8 carbon atoms.
[0046] Further, the invention resides in an activator of peroxisome proliferator activated receptor which contains as an effective component a phenylacetic acid derivative of the formula (II) or a phenylacetic acid derivative of the formula (III) or their salts. [0047] In another aspect, the compound has the following general formula (IV) or a salt thereof:
Figure imgf000008_0001
wherein A is O, S or NR7 in which R7 is hydrogen or Cj-8 alkyl;
[0048] B1 is CW or N in which W is hydrogen or a bond; B2 is O, S or NR8 in which
R8 is hydrogen or Ci-8 alkyl; [0049] each of X1 and X2 is O, S, NH, NHC(O), C(O), C(=N-0R9, CH(OR10),
C=C, C≡C or a bond in which each of R9 and R10 is hydrogen or C1-8 alkyl;
[0050] Y is a CJ -8 alkylene chain, which can be substituted with Ci-8 alkyl or Ci-8 alkyl substituted with 1 -3 halogens;
[0051] Z is NH, O or S; [0052] R1 is aryl, which can be substituted with a group or atom selected from the group consisting of Ci-8 alkyl, Ci-8 alkoxy, Ci-8 alkyl substituted with 1-3 halogens, hydroxyl, nitro, amino, phenyl, pyridyl and halogen, or a heterocyclic group having five to eight membered ring comprising one to three hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur and the other atoms consisting of carbon (benzene ring can be condensed with the heterocyclic ring); [0053] R2 is C2-8 alkyl, Ci-8 alkyl substituted with 1-3 halogens, C3-7 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, alkyl (comprising Ci-4 alkyl moiety) substituted with aryl, which can be substituted with a group or atom selected from the group consisting of Ci-8 alkyl, Ci-8 alkoxy, Ci-8 alkyl substituted with 1-3 halogens, hydroxyl, nitro, amino, phenyl, pyridyl and halogen, or alkyl (comprising Ci-4 alkyl moiety) substituted with a heterocyclic group having five to eight membered ring (comprising one to three hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur and the other atoms consisting of carbon); [0054] R3 is halogen, trifluoromethyl, Ci-8 alkyl, C2-8 alkenyl or C2-8 alkynyl;
[0055] each of R4 and R5 is hydrogen, Ci-8 alkyl or C]-8 alkyl substituted with 1-3 halogens; and R6 is hydrogen, Ci-8 alkyl substituted with amino, Ci-8 alkyl or alkali metal; [0056] provided that each of Z and R3 is attached to the benzene ring, and X2 is not attached to the benzene ring.
[0057] The invention also provides an activator of peroxisome proliferator activated receptor δ, which contains as an effective component a compound of the formula (IV) or a salt thereof.
DETAILED DESCRIPTION
Definitions
[0058] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
[0059] The singular forms "a," "an," and "the" include plural references, unless the context clearly dictates otherwise. [0060] As used herein "subject" is an animal, such as a mammal, including human, such as a patient.
[0061] As used herein, biological activity refers to the in vivo activities of a compound or physiological responses that result upon in vivo administration of a compound, composition or other mixture. Biological activity, thus, encompasses therapeutic effects and pharmacokinetic behaviour of such compounds, compositions and mixtures. Biological activities can be observed in in vitro systems designed to test for such activities.
[0062] As used herein, pharmaceutically acceptable derivatives of a compound include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof. Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization. The compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N5N'- dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, 1 -para-chlorobenzyl-2-pyrrolidin- 1 '-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and inorganic salts, such as but not limited to, sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, mesylates, and fumarates. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of formula C=C(OR) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of formula C=C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules. [0063] As used herein, treatment means any manner in which one or more of the symptoms of a disease or disorder are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein, such as use for treating inflammation. [0064] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition. [0065] As used herein, the IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.
[0066] It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form. [0067] As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound. The instant disclosure is meant to include all such possible isomers, as well as, their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as reverse phase HPLC. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
[0068] As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. is used as is generally understood by those of skill in this art. [0069] As used herein, alkyl, alkenyl and alkynyl carbon chains, if not specified, contain from 1 to 20 carbons, or 1 to 16 carbons, and are straight or branched. Alkenyl carbon chains of from 2 to 20 carbons, in certain embodiments, contain 1 to 8 double bonds, and the alkenyl carbon chains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 double bonds. Alkynyl carbon chains of from 2 to 20 carbons, in certain embodiments, contain 1 to 8 triple bonds, and the alkynyl carbon chains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 triple bonds. Exemplary alkyl, alkenyl and alkynyl groups herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec- butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, ethenyl, propenyl, butenyl, pentenyl, acetylenyl and hexynyl. As used herein, lower alkyl, lower alkenyl, and lower alkynyl refer to carbon chains having from about 1 or about 2 carbons up to about 6 carbons. As used herein, "alk(en)(yn)yl" refers to an alkyl group containing at least one double bond and at least one triple bond.
[0070] As used herein, "heteroalkyl" refers to a straight, branched or cyclic, in certain embodiments straight or branched, aliphatic hydrocarbon group having, inserted in the hydrocarbon chain one or more oxygen, sulfur, including S(=O) and S(=O)2 groups, or substituted or unsubstituted nitrogen atoms, including -NR- and -N+RR- groups, where the nitrogen substituent(s) is(are) alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, S(=O)2R' or COR, where R1 is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, OY or -NYY', where Y and Y' are each independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, in one embodiment having from 1 to about 20 atoms, in another embodiment having from 1 to 12 atoms in the chain.
[0071] As used herein, "cycloalkyl" refers to a saturated mono- or multicyclic ring system, in certain embodiments of 3 to 10 carbon atoms, in other embodiments of 3 to 6 carbon atoms; cycloalkenyl and cycloalkynyl refer to mono- or multicyclic ring systems that respectively include at least one double bond and at least one triple bond. Cycloalkenyl and cycloalkynyl groups may, in certain embodiments, contain 3 to 10 carbon atoms, with cycloalkenyl groups, in further embodiments, containing 4 to 7 carbon atoms and cycloalkynyl groups, in further embodiments, containing 8 to 10 carbon atoms. The ring systems of the cycloalkyl, cycloalkenyl and cycloalkynyl groups may be composed of one ring or two or more rings which may be joined together in a fused, bridged or spiro- connected fashion. "Cycloalk(en)(yn)yl" refers to a cycloalkyl group containing at least one double bond and at least one triple bond.
[0072] As used herein, "substituted alkyl," "substituted alkenyl," "substituted alkynyl," "substituted cycloalkyl," "substituted cycloalkenyl," and "substituted cycloalkynyl" refer to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl groups, respectively, that are substituted with one or more substituents, in certain embodiments one to three or four substituents, where the substituents are as defined herein, generally selected from Ql. [0073] As used herein, "aryl" refers to aromatic monocyclic or multicyclic groups containing from 6 to 19 carbon atoms. Aryl groups include, but are not limited to groups such as fluorenyl, substituted fluorenyl, phenyl, substituted phenyl, naphthyl and substituted naphthyl. [0074] As used herein, "heteroaryl" refers to a monocyclic or multicyclic aromatic ring system, in certain embodiments, of about 5 to about 15 members where one or more, in one embodiment 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including, but not limited to,, nitrogen, oxygen or sulfur. The heteroaryl group may be optionally fused to a benzene ring. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl and isoquinolinyl.
[0075] As used herein, a "heteroarylium" group is a heteroaryl group that is positively charged on one or more of the heteroatoms. [0076] As used herein, "heterocyclyl" refers to a monocyclic or multicyclic non- aromatic ring system, in one embodiment of 3 to 10 members, in another embodiment of 4 to 7 members, in a further embodiment of 5 to 6 members, where one or more, in certain embodiments, 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including, but not limited to,, nitrogen, oxygen or sulfur. In embodiments where the heteroatom(s) is(are) nitrogen, the nitrogen is optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acyl, guanidino, amidino or the nitrogen may be quaternized to form an ammonium group where the substituents are selected as above.
[0077] As used herein, "substituted aryl," "substituted heteroaryl" and "substituted heterocyclyl" refer to aryl, heteroaryl and heterocyclyl groups, respectively, that are substituted with one or more substituents, in certain embodiments one to three or four substituents, where the substituents are as defined herein, generally selected from Ql. [0078] As used herein, "aralkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl is replaced by an aryl group. [0079] As used herein, "heteroaralkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl is replaced by a heteroaryl group.
[0080] As used herein, "alkylene" refers to a straight, branched or cyclic, in certain embodiments straight or branched, divalent aliphatic hydrocarbon group, in one embodiment having from 1 to about 20 carbon atoms, in another embodiment having from 1 to 12 carbons. In a further embodiment alkylene includes lower alkylene. There may be optionally inserted along the alkylene group one or more oxygen, sulfur, including S(=O) and S(=O)2 groups, or substituted or unsubstituted nitrogen atoms, including -NR- and -N+RR- groups, where the nitrogen substituent(s) is(are) alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, S(=O)2R' or COR1, where R' is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OY or -NYY', where Y and Y' are each independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl. Alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-(CH2)3-), methylenedioxy (-0-CH2-O-) and ethylenedioxy (-O-(CH2)2-O-). The term "lower alkylene" refers to alkylene groups having 1 to 6 carbons. In certain embodiments, alkylene groups are lower alkylene, including alkylene of 1 to 3 carbon atoms. [0081] As used herein, "alkenylene" refers to a straight, branched or cyclic, in one embodiment straight or branched, divalent aliphatic hydrocarbon group, in certain embodiments having from 2 to about 20 carbon atoms and at least one double bond, in other embodiments 1 to 12 carbons. In further embodiments, alkenylene groups include lower alkenylene. There may be optionally inserted along the alkenylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, where the nitrogen substituent is alkyl. Alkenylene groups include, but are not limited to, — CH=CH — CH=CH — and — CH=CH — CH2 — . The term "lower alkenylene" refers to alkenylene groups having 2 to 6 carbons. In certain embodiments, alkenylene groups are lower alkenylene, including alkenylene of 3 to 4 carbon atoms. [0082] As used herein, "alkynylene" refers to a straight, branched or cyclic, in certain embodiments straight or branched, divalent aliphatic hydrocarbon group, in one embodiment having from 2 to about 20 carbon atoms and at least one triple bond, in another embodiment 1 to 12 carbons. In a further embodiment, alkynylene includes lower alkynylene. There may be optionally inserted along the alkynylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, where the nitrogen substituent is alkyl. Alkynylene groups include, but are not limited to, —C≡C— C≡C— , -C=C- and -C=C-CH2-. The term "lower alkynylene" refers to alkynylene groups having 2 to 6 carbons. In certain embodiments, alkynylene groups are lower alkynylene, including alkynylene of 3 to 4 carbon atoms. [0083] As used herein, "alk(en)(yn)ylene" refers to a straight, branched or cyclic, in certain embodiments straight or branched, divalent aliphatic hydrocarbon group, in one embodiment having from 2 to about 20 carbon atoms and at least one triple bond, and at least one double bond; in another embodiment 1 to 12 carbons. In further embodiments, alk(en)(yn)ylene includes lower alk(en)(yn)ylene. There may be optionally inserted along the alkynylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, where the nitrogen substituent is alkyl. Alk(en)(yn)ylene groups include, but are not limited to, — C=C- (CH2)n-C≡C— , where n is 1 or 2. The term "lower alk(en)(yn)ylene" refers to alk(en)(yn)ylene groups having up to 6 carbons. In certain embodiments, alk(en)(yn)ylene groups have about 4 carbon atoms.
[0084] As used herein, "cycloalkylene" refers to a divalent saturated mono- or multicyclic ring system, in certain embodiments of 3 to 10 carbon atoms, in other embodiments 3 to 6 carbon atoms; cycloalkenylene and cycloalkynylene refer to divalent mono- or multicyclic ring systems that respectively include at least one double bond and at least one triple bond. Cycloalkenylene and cycloalkynylene groups may, in certain embodiments, contain 3 to 10 carbon atoms, with cycloalkenylene groups in certain embodiments containing 4 to 7 carbon atoms and cycloalkynylene groups in certain embodiments containing 8 to 10 carbon atoms. The ring systems of the cycloalkylene, cycloalkenylene and cycloalkynylene groups may be composed of one ring or two or more rings which may be joined together in a fused, bridged or spiro-connected fashion.
"Cycloalk(en)(yn)ylene" refers to a cycloalkylene group containing at least one double bond and at least one triple bond.
[0085] As used herein, "substituted alkylene," "substituted alkenylene," "substituted alkynylene," "substituted cycloalkylene," "substituted cycloalkenylene," and "substituted cycloalkynylene" refer to alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene and cycloalkynylene groups, respectively, that are substituted with one or more substituents, in certain embodiments one to three or four substituents, where the substituents are as defined herein, generally selected from Q1. [0086] As used herein, "arylene" refers to a monocyclic or polycyclic, in certain embodiments monocyclic, divalent aromatic group, in one embodiment having from 5 to about 20 carbon atoms and at least one aromatic ring, in another embodiment 5 to 12 carbons. In further embodiments, arylene includes lower arylene. Arylene groups include, but are not limited to, 1,2-, 1,3- and 1 ,4-phenylene. The term "lower arylene" refers to arylene groups having 5 or 6 carbons. [0087] As used herein, "heteroarylene" refers to a divalent monocyclic or multicyclic aromatic ring system, in one embodiment of about 5 to about 15 members where one or more, in certain embodiments 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including, but not limited to,, nitrogen, oxygen or sulfur. [0088] As used herein, "heterocyclylene" refers to a divalent monocyclic or multicyclic non-aromatic ring system, in certain embodiments of 3 to 10 members, in one embodiment 4 to 7 members, in another embodiment 5 to 6 members, where one or more, including 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including, but not limited to,, nitrogen, oxygen or sulfur.
[0089] As used herein, "substituted arylene," "substituted heteroarylene" and
"substituted heterocyclylene" refer to arylene, heteroarylene and heterocyclylene groups, respectively, that are substituted with one or more substituents, in certain embodiments one to three or four substituents, where the substituents are as defined herein, generally selected from Q1.
[0090] As used herein, "halo", "halogen" or "halide" refers to F, Cl, Br or I.
[0091] As used herein, pseudohalides or pseudohalo groups are groups that behave substantially similar to halides. Such compounds can be used in the same manner and treated in the same manner as halides. Pseudohalides include, but are not limited to, cyano, thiocyanate, selenocyanate, trifluoromethoxy, and azide.
[0092] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl and 1 chloro 2 fluoroethyl. [0093] As used herein, "haloalkoxy" refers to RO in which R is a haloalkyl group. [0094] As used herein, "carboxy" refers to a divalent radical, -C(O)O-.
[0095] As used herein, "aminocarbonyl" refers to C(O)NH2.
[0096] As used herein, "alkylaminocarbonyl" refers to C(O)NHR in which R is alkyl, including lower alkyl. As used herein, "dialkylaminocarbonyl" refers to C(O)NR1R in which R1 and R are independently alkyl, including lower alkyl; "carboxamide" refers to groups of formula -NR'COR in which R' and R are independently alkyl, including lower alkyl.
[0097] As used herein, "arylalkylaminocarbonyl" refers to -C(O)NRR' in which one of R and R' is aryl, including lower aryl, such as phenyl, and the other of R and R' is alkyl, including lower alkyl. [0098] As used herein, "arylaminocarbonyl" refers to -C(O)NHR in which R is aryl, including lower aryl, such as phenyl.
[0099] As used herein, "hydroxycarbonyl" refers to -COOH.
[00100] As used herein, "alkoxycarbonyl" refers to -C(O)OR in which R is alkyl, including lower alkyl. [00101] As used herein, "aryloxycarbonyl" refers to -C(O)OR in which R is aryl, including lower aryl, such as phenyl.
[00102] As used herein, "alkoxy" and "alkylthio" refer to RO- and RS- , in which R is alkyl, including lower alkyl. [00103] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, in which R is aryl, including lower aryl, such as phenyl.
[00104] Where the number of any given substituent is not specified (e.g., "haloalkyl"), there may be one or more substituents present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, [00105] "Ci.3alkoxyphenyl" may include one or more of the same or different alkoxy groups containing one, two or three carbons.
[00106] As used herein, "selective PPARδ agonist" refers to a compound that is more active against PPARδ as compared to the compound's activity against PP ARa and/or PPARγ.
In certain embodiments, a selective PPARδ agonist is >100 times, >250 times, >500 times, >750 times, >1000 times or more active against PPARδ as compared to activity against
PP ARa and/or PPARγ.
[00107] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, (1972) Biochem. 11 :942-944). Compounds
[00108] In the formula (I), examples of the alkyl groups having 1-8 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and pentyl. [00109] Examples of the alkyl groups having 1-8 carbon atoms and a halogen substituent include methyl, ethyl, propyl, isopropyl, butyl, and t-butyl which are substituted with 1-3 halogens such as fluorine, chlorine, and bromine. Examples include trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl and 2-fluoroethyl.
[00110] Examples of the alkoxy groups having 1-8 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy and pentyloxy. [00111] Examples of the alkoxy groups having 1-8 carbon atoms and a halogen substituent include methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy groups substituted with 1-3 halogen atoms such as fluorine atom, chlorine atom or bromine atom. Trifluoromethoxy, chloromethoxy, 2-chloroethoxy, 2-bromoethoxy and 2-fluoroethoxy are included.
[00112] Examples of the alkenyl groups having 2-8 carbon atoms include vinyl and allyl. [00113] Examples of the alkynyl groups having 2-8 carbon atoms include propargyl.
[00114] Examples of 3-7 membered cycloalkyl groups include cyclohexyl and cyclopentyl.
[00115] Examples of the alkyl groups having 1-8 carbon atoms and a 3-7 membered cycloalkyl substituent include cyclohexylmethyl and cyclopentylmethyl. [00116] (1) In one embodiment, a compound provided is a compound of the formula
(I) or salt thereof, in which R1 is phenyl which can have substituents selected from the group consisting of Ci-8 alkyl, Ci-8 alkyl having 1-3 halogen atoms, Ci-8 alkoxy, C1-8 alkoxy having 1-3 halogen atoms, C2-8 alkenyl, C2-8 alkynyl, halogen, C2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl and pyridyl. [00117] (2) In another embodiment, a compound provided is a compound of the formula (I), a salt thereof or (1), in which R2 is C2-8 alkyl.
[00118] (3) In another embodiment, a compound provided is a compound of the formula (I), a salt thereof, (1) or (2), in which R1 is attached to the 2nd position. In the case that R1 is attached to the 2nd position, R4 is attached to the 4th position and --X-- Y-- is attached to the 5th position, or R4 is attached to the 5th position and --X-- Y-- is attached to the 4th position.
[00119] (4) In another embodiment, a compound provided is a compound of the formula (I), a salt thereof, (1), (2) or (3), in which A is oxygen or sulfur. [00120] (5) In another embodiment, a compound provided is a compound of the formula (I), a salt thereof, (1), (2), (3) or (4), in which X is a Ci-8 alkylene chain.
[00121] (6) In another embodiment, a compound provided is a compound of the formula (I), a salt thereof, (1), (2), (3), (4) or (5), in which Y is C(=O). [00122] (7) In another embodiments compound provided is a compound of the formula (I), a salt thereof, (1), (2), (3), (4), (5) or (6), in which each of R3, R4 and R5 is hydrogen, Ci-8 alkyl or Ci-8 alkyl having halogen.
[00123] (8) In another embodiment, a compound provided is a compound of the formula (I), a salt thereof, (1), (2), (3), (4), (5), (6) or (7), in which B is CH. [00124] (9) In another embodiment, a compound provided is a compound of the formula (I), a salt thereof, (1), (2), (3), (4), (5), (6), (7) or (8), in which Z is oxygen. [00125] (10) In another embodiment, a compound provided is a compound of the formula (I), a salt thereof, (1), (2), (3), (4), (5), (6), (7), (8) or (9), in which each of R6 and R7 is hydrogen or Ci-4 alkyl.
[00126] (11) In another embodiment, a compound provided is a compound of the formula (I), a salt thereof, (1), (2), (3), (4), (5), (6), (7), (8) or (9), in which R8 is hydrogen.
[00127] (12) In another embodiment, a compound provided is a compound of the formula (I) or a salt thereof, in which R1 is phenyl or naphthyl, each of which can have substituents selected from the group consisting of C1-8 alkyl, C1-8 alkyl having halogen, C1-8 alkoxy, Ci-8 alkoxy having halogen, C2-8 alkenyl, C2-8 alkynyl, halogen, C2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl and pyridyl;
[00128] R2 is C2-8 alkyl;
[00129] A is oxygen or sulfur;
[00130] X is a C1-8 alkylene chain which can have a Ci-8 alkyl substituent and which can contain a double bond; [00131] Y is C(=O), CH=CH, or C(==CH2);
[00132] each of R3, R4 and R5 is hydrogen, C1-8 alkyl, Ci-8 alkyl having halogen, Ci-8 alkoxy, Ci-8 alkoxy having halogen, C2-8 alkenyl, C2-8 alkynyl, halogen, C2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl, or pyridyl;
[00133] B is CH; [00134] Z is oxygen or sulfur;
[00135] each of R6 and R7 is hydrogen or Ci-8 alkyl; and
[00136] R8 is hydrogen or Cu8 alkyl.
[00137] (13) In another embodiment, a compound provided is a compound of (12), in which X is a Ci-8 alkylene chain. [00138] (14) In another embodiment, a compound provided is a compound of (12) or
(13), in which R1 is attached to the 2nd position.
[00139] (15) In another embodiment, a compound provided is a compound of (12),
(13) or (14), in which R8 is hydrogen.
[00140] (16) In another embodiment, a compound provided is a compound of (12), (13), (14) or (15), in which the substituents of R3, R4 and R5 other than hydrogens are placed at ortho-positions with respect to -Z-CR6R7CO2R8.
[00141] The compound of the formula (I) can be present in the form of geometrical isomers such as cis and trans and optical isomers. These isomers are included in the compounds provided. Further, the compounds provided can be in the form of pharmaceutically acceptable salts, such as alkali metal salts, e.g., sodiun or potassium salt. [00142] The processes for preparing the compound of the formula (I) provided herein is described below.
[Synthetic: prorpss 1]
Figure imgf000020_0001
(a) (b)
[00143] In the formulas, Q is a releasing group such as tosyloxy or halogen (e.g., bromine), and R1, R2, R3, R4, R5, R6, R7, R8, A, X, Y, B and Z are those described hereinbefore. [00144] In the above-described process, the compound of the formula (I) according to the invention can be prepared by reacting a phenol or thiophenol compound of the general formula (a) with an acetic acid derivative of the general formula (b). The reaction can be carried out in a solvent such as methyl ethyl ketone in the presence of a base such as potassium carbonate. [00145] The starting compound of the formula (a), can be prepared by a process similar to the below-mentioned synthetic scheme.
[Synthesis example 1 for starting compound in which Y is CO, 7. is O]
Figure imgf000020_0002
Figure imgf000021_0001
[00146] In the formulas, n is an integer of 1 to 7, Bn is benzyl, and R1, R2, R3, R4, R5
A and B are those described herein before.
[Synthesis example 2 for starting compound in which 7, is S]
Figure imgf000021_0002
250° C./n-tetradecane
Figure imgf000021_0003
MeONa
Figure imgf000021_0004
[00147] In the formulas, R1, R2, R3, R4, R5, A, B, X and Y are those described herein before.
[00148] The phenol compound is treated with dimethylthiocarbamoyl chloride in the presence of a base such as triethylamine to obtain a dimethylthiocarbamoyloxy compound.
The dimethylthiocarbamoyloxy compound is heated in n-tetradecane or no solvent to obtain a dimethylcarbamoylsulfanyl compound as a rearranged compound. The dimethylcarbamoyl group is treated with NaOH or MeONa to be converted to a thiophenol compound. rSjyntVip.sis p.yampip. "λ fπr starting pnmpnnnH in whinn V is ("Y-)^ 7. is O]
BnBr, K2Cθ3/Acetone
Figure imgf000022_0001
Figure imgf000022_0002
Reduction of olefin
Figure imgf000022_0003
Debenzylation
Figure imgf000022_0004
[00149] In the formulas, m is an integer of O to 6, and R1, R2, R3, R4, R5, A, B and Bn are those described herein before.
[00150] The acetophenone compound and the aldehyde compound synthesized according to a conventional method are condensed with hydration using a base such as NaOH, KOH, MeONa, EtONa, piperidine in a solvent such as methanol, ethanol, anhydrous benzene to obtain a α,β-unsaturat- ed ketone compound. The α,β-unsaturated ketone compound is treated, for example subjected to a hydride contact reduction to conduct reduction of the olefin and the debenzylation to obtain the subject compound. [Synthesis P.yflmplfi 4-ff)r størtjnp rnmnoiinri in which Y is (^Qj 7f.i.s_Q]
Figure imgf000023_0001
Oxidation Debenzylation
Figure imgf000023_0002
Figure imgf000023_0003
[00151] In the formulas, R1, R2, R3, R4, R5, A, B, n and Bn are those described herein before.
[00152] The benzaldehyde compound is treated with a Grignard reagent obtained according to a conventional method in the presence of a solvent such as a ether or THF under the condition of a low temperature to obtain an alcohol compound. The alcohol compound can be converted into a ketone compound by using a Jones reagent (chromium(VI)oxide- sulfuric acid-acetone) or chromium(VI)-pyridine complex (e.g., pyridinium chlorochromate, pyridinium dichromate). The alcohol compound can also be converted into the ketone body in the same manner by using DMSO oxidation. Finally, the ketone body is subjected to debenzylation to be converted into the subject phenol compound.
[Synthesis example 5 for starting compound in which 7. is O]
Figure imgf000024_0001
Δ Claisen rearrangement reaction
Figure imgf000024_0002
Figure imgf000024_0003
[00153] In the formulas, Ra is hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R1, R2, A, X, Y and B are those described hereinbefore.
[00154] The phenol compound is subjected to an allylation according to a conventional method, and heated (at 150° C. or higher) with no solvent or in a solvent such as quinoline to obtain a compound having the rearranged allyl group at the ortho-position.
[Synthesis PYamplp. f> for starring rnmpniinrl in which 7. is O]
RbCOCl Base
Fries rearrangement reaction
Figure imgf000024_0004
Figure imgf000024_0005
[00155] In the formulas, R is an alkyl group having 1 to 6 carbon atoms, and R1, R2,
A, X, Y and B are those described herein before. [00156] The phenol compound is subjected to an acylation according to a conventional method, and heated in the presence of a Lewis acid catalyst to obtain a compound having the rearranged acyl group at the ortho-position.
[Synthesis p.yample 7 for staring compound in which Y is CH-CH]
Figure imgf000025_0001
Dehydration
Figure imgf000025_0002
Figure imgf000025_0003
[00157] In the formulas, R1 , R2, R3, R4, R5, A, B, n and Bn are those described herein before.
[00158] The phenol compound obtained in the Synthesis example 1 for starting compound is treated with a reducing agent such as lithium aluminum hydride, sodium boron hydride to obtain an alcohol compound. The alcohol compound is subjected to dehydration using a halogenation agent, a sulfonation agent or a dehydration agent to obtain an olefin compound.
[Synthp.sis prnrp.ss 7. (whe.re.in B° is H)
Figure imgf000025_0004
[00159] In the formulas, R° is an alkyl group having 1 to 8 carbon atoms, and R1, R2,
R3, R4, R5, R6, R7, A, X, Y, B and Z are those described herein before. [00160] In the above-illustrated process for preparation, a compound of the formula (I)
(R8==H) according to the invention can be obtained by the ester compound of the formula (c) is hydrolyzed in a solvent such as aqueous ethanol in the presence of a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide.
[Synthesis process 3 (wherein Y is C ( = N — OH)]
Figure imgf000026_0001
[00161] In the formulas, R1, R2, R3, R4, R5, R6, R7, A, X, B and Z are those described herein before. [00162] In the above-illustrated process, a compound of the formula (I) (Y is C(=N~
OH)) according to the invention can be obtained by reacting the ketone compound of the formula (d) with hydroxylamine.
[Synthetic process 4 (wherein Y is C( =QΑi$)
Figure imgf000026_0002
Figure imgf000027_0001
[00163] In the formulas, R1, R2, R3, R4, R5, R6, R7, A, B, Z and n are those described herein before.
[00164] The ketone compound (Y is C(=O)) can be treated with methyl triphenyl phosphonium bromide in the presence of a base such as t-BuOK, n-BuLi, sec-BuLi, EtONa in a solvent such as a dry ether or THE (according to Wittig reaction) to introduce a methylene chain into the compound.
Figure imgf000027_0002
Rl0-Ha'°' Base .
Figure imgf000027_0003
Figure imgf000027_0004
[00165] In the formulas, R10 is an alkyl group having 1 to 10 carbon atoms, R1, R2, R3, R4, R5, R6, R7, R8, A, B, Z and n are those described herein before.
[00166] The ketone compound (Y is C(=O)) can be treated with alkyl halide such as iodomethane in the presence of a base such as t-BuOK, BuLi, EtONa, NaH in a solvent such as a dry ether or THF to introduce an alkyl chain into the compound at the α-position of the carbonyl group. [00167] Synthesis of an exemplary compound represented by formula (I):
Figure imgf000028_0001
The S-stereoisomer is prepared as represented in the following scheme:
Figure imgf000028_0002
The R-stereoisomer is prepared as represented in the following scheme:
Figure imgf000028_0003
[00168] (1) In one embodiment, compounds for use in the methods provided herein have the following formula:
Figure imgf000029_0001
in which R > 1', τ R>22, τ
Figure imgf000029_0002
R)44, τ R> 6b, n R'', A, X, Y and Z are shown in Tables 1 to 4.
TABLE 1
R1 R2 Rj R4 R6 R7 X Y
S (4-CF3)Ph Isopropyl Me(2) H H H CH2CH2 C=O(4) O
S (4-CF3)Ph Isopropyl Me(2) H H H CH2CH2 C-0H(4) O
S (4-CF3)Ph Isopropyl Me(2) H H H CH2CH2 C-0H(4) O
(R-isomer)
S (4-CF3)Ph Isopropyl Me(2) H H H CH2CH2 C-0H(4) O
(S-isomer)
S (4-CF3)Ph Isopropyl Me(2) H Me Me CH2CH2 C=O(4) 0
S (4-CF3)Ph Isopropyl Me(2) H H H CH2 CH=CH(4) 0
S (4-CF3)Ph Hexyl Me(2) H H H CH2CH2 C=0(4) O
S (4-CF3)Ph Hexyl Me(2) H Me Me CH2CH2 C=O(4) O
S (4-CF3)Ph Isopropyl Me(2) H Me Me CH2 CH=CH(4) O
S (4-CF3)Ph Isopropyl Me(3) H H H CH2CH2 C=O(4) O
S (4-CF3)Ph Isopropyl Me(3) H Me Me CH2CH2 C=O(4) O
S (4-CF3)Ph Isopropyl Pr(2) H H H CH2CH2 C=O(4) O
S (4-CF3)Ph Isopropyl Allyl(2) H H H CH2CH2 C=O(4) O
S (4-CF3)Ph Isopropyl Me(2) H H H CH=CH C=O(4) 0
S (4-CF3)Ph Isopropyl Me(2) H Me Me CH=CH C=O(4) 0
S (4-OMe)Ph Isopropyl Me(2) H H H CH2CH2 C=O(4) 0
S (3,5,-F)Ph Isopropyl Me(2) H H H CH2CH2 C=O(4) 0
S (3,5,-F)Ph Isopropyl Me(2) H Me Me CH2CH2 C=O(4) 0
S 2-Naphthyl Isopropyl Me(2) H H H CH2CH2 C=O(4) O
S 2-Naphthyl Isopropyl Me(2) H Me Me CH2CH2 C=O(4) 0
S (4-Bu)Ph Isopropyl Me(2) H H H CH2CH2 C=O(4) 0
S (4-Bu)Ph Isopropyl Me(2) H Me Me CH2CH2 C=O(4) O
S (4-CF3)Ph Isopropyl Cl(2) H H H CH2CH2 C=O(4) 0
S (4-CF3)Ph Isopropyl Cl(2) H Me Me CH2CH2 C=O(4) 0
S (4-CF3)Ph Isopropyl Me(2) H H H CH2CH2 C=O(5) O
S (4-CF3)Ph Isopropyl Me(2) H Me Me CH2CH2 C=O(5) O
S (4-CF3)Ph Isopropyl Me(2) H Me H CH2CH2 C=O(4) 0
Remark:
Numeral in ( ) means a position of the group. TABLE 2
A R1 R2 R3 R4 R6 R7 X Y Z
S (4-CF3)Ph Hexyl Me(2) H Me Me CH2 CH=CH(4) 0
S (4-CF3)Ph Hexyl Me(2) H Me Me CH2 CH2=CH2(4) O
S (4-CF3)Ph Hexyl Me(2) H Me Me CH2CH2 C=0(5) 0
S (4-CF3)Ph Ethyl Me(2) H H H CH2CH2 C=0(4) O
S (4-CF3)Ph Ethyl Me(2) H Me Me CH2CH2 C=0(4) 0
S (4-Me)Ph Isopropyl Me(2) H H H CH2CH2 C=0(4) 0
S (4-Me)Ph Isopropyl Me(2) H Me Me CH2CH2 C=O(4) O
S (4-CF3)Ph Isopropyl Me(2) H H H CH2CH2 C=O(4) S
S (4-Et)Ph Isopropyl Me(2) H H H CH2CH2 C=0(4) 0
S (4-iPr)Ph Isopropyl Me(2) H H H CH2CH2 C=O(4) 0
S (4-t-Bu)Ph Isopropyl Me(2) H H H CH2CH2 C=0(4) O
S (4-Cl)Ph Isopropyl Me(2) H H H CH2CH2 C=0(4) 0
S (4-F)Ph Isopropyl Me(2) H H H CH2CH2 C=0(4) 0
S (4-NO2)Ph Isopropyl Me(2) H H H CH2CH2 C=0(4) O
S (4-NMe2)Ph Isopropyl Me(2) H H H CH2CH2 C=0(4) 0
S (4-CF3)Ph Isopropyl Me(2) H Me Me CH2CH2 C=0(4) O
S (4-Et)Ph Isopropyl Me(2) H Me Me CH2CH2 C=O(4) 0
S (4-iPr)Ph Isopropyl Me(2) H Me Me CH2CH2 C=0(4) 0
S (4-t-Bu)Ph Isopropyl Me(2) H Me Me CH2CH2 C=0(4) O
S (4-Cl)Ph Isopropyl Me(2) H Me Me CH2CH2 C=0(4) 0
S (4-F)Ph Isopropyl Me(2) H Me Me CH2CH2 C=0(4) O
S (4-NO2)Ph Isopropyl Me(2) H Me Me CH2CH2 C=0(4) O
S (4-NMe2)Ph Isopropyl Me(2) H Me Me CH2CH2 C=0(4) O
S (4-Cl)Ph Isopropyl Allyl(2) H H H CH2CH2 C=0(4) 0
Remark:
Numeral in ( ) means a position of the group.
TABLE 3
A R1 R2 R3 R4 R6 R7 X Y Z
O (2-OH,4-Cl)Ph Isopropyl Allyl(2) H H H CH2CH2 C=O(4) O
O (2-OH,4-Cl)Ph Isopropyl Me(2) H Me M CH2CH2 CH=CH(3) O
6
O (4-Me)Ph Isopropyl Me(2) H H H CH2CH2 00(4) S
O (2,4-Me)Ph Isopropyl Pr(2) H Me M CH(Me)CH2 00(4) O
C
S (2-OH,4-Me)Ph Bu Benzyl(2; ) H H H CH2CH2 00(3) O
NH (2-OH,4-CF3)Ph Pr Acetyl(2) H H H CH2CH2 00(4) O
N— (2-OH,4-Cl)Ph Hexyl Cl(2) H H H CH2CH2 00(4) O
Me
S (2,4-Me)Ph Et Br(2) H H H CH2CH2 00(4) S
S (3,4-Cl)Ph Bu CF3(2) H Me Et CH2CH2 00(4) O
S (2,4-Me)Ph Hexyl Me(2) Me( Me M CH(Me)CH2 00(4) O
6) e
S (2,4-Cl)Ph Bu Me(2) Me( H H CH2CH2 00(4) O
Figure imgf000031_0001
S (2-OH.3.4- Pr Cl(2) Cl(6 H H CH2CH2 CH=CH(4) O
Me)Ph )
S (2,4-F)Ph Hexyl Me(2) H Me M CH2CH2 CH=CH(4) O
6
O (3,4,5-Me)Ph Et Me(2) H H H CH2CH2 00(4) S
O (2-OH,3,4- Bu Me(3) H Me M CH2CH2 00(4) O
Me)Ph e
O (2-OH,4-CF3)Ph Phenylethyl Me(2,6) H H H CH2CH2 00(3) O
O (4-OMe)Ph Isopropyl Me(2) Me( H H CH2CH2 00(4) O v)
S (2-Cl,4-OPh)Ph Isopropyl Acetyl(2) H H H CH2CH2 00(4) O
NH 1-Naphthyl Isopropyl Cl(3) H H H CH2 CH=CH(4) S
N— 2-Naphthyl Isopropyl Br(3) H Me Et CH(Me)CH2 00(4) O
Me
S 2-Quinolyl Isopropyl CF3(2) H Me M CH2CH2 00(4) O
C
NH 8-Quinolyl Isopropyl Me(2) H Me M CH2CH2 00(4) O
6
N— 3-Quinolyl Isopropyl Me(2) H H H CH2CH2 C=O(4) O
Me
S 2-Pryimidyl Isopropyl Allyl(3) H H H CH2CH2 00(4) O
Remark:
Numeral in ( ) means a position of the group.
TABLE 4
A R1 R2 R3 R4 R6 R7 X Y Z
S 2-Thyenyl Isopropyl Me(2) H H H CH2 CH=CH(4) S
S 2-Pyridyl Isopropyl Me(2) H H H CH2CH2 00(4) O
S 4-Pyridyl Isopropyl Me(2) H H H CH2CH2 00(4) O
S 5-Bt-2-Pyridyl Isopropyl Me(2) H H H CH2CH2 00(4) O
S 5-Me-2-Pyridyl Isopropyl Me(2) H H H CH2CH2 00(4) O
S 5-Et-2-Pyridyl Isopropyl Me(2) H Me Me CH2CH2 00(4) O
S 2-Furanyl Isopropyl Me(2) H H H CH2CH2 00(4) O
S 2-Imidazolyl Isopropyl Me(2) H Me Et CH2CH2 00(4) O
O 2-Indolyl Isopropyl Pr(2) H Me Me CH2CH2 00(4) O A R1 R2 R3 R4 R6 R7 X Y Z
O 2-Benzofuranyl Isopropyl Benzyl(2) H Me Me CH2CH2 C=O(4) O
O 2-Benzothienyl Isopropyl Acetyl(2) H Me Me CH2CH2 C=O(4) S
O 2-Benzoimidazolyl Isopropyl Cl(2) Cl(6) Me Me CH2CH2 C=O(4) S
S (4-CF3)Ph sec-Bu Me(2) H H H CH2CH2 C=O(4) O
S (4-CF3)Ph sec-Bu Me(2) H Me Me CH2CH2 C=O(4) O
S (4-CF3)Ph Isobutyl Me(2) H H H CH2CH2 C=O(4) O
S (4-CF3)Ph Phenylethyl Me(2) H H H CH2CH2 C=O(4) O
S (4-CF3)Ph Isopropyl CF3(2) H H H CH2CH2 C=O(4) O
S (4-CF3)Ph Isopropyl CHF2(2) H H H CH2CH2 C=O(4) O
S (4-CF3)Ph Isopropyl Me(2) H H H CH2CH2 C=CH2(4) O
Remark:
Numeral in ( ) means a position of the group
[00169] ( 2) In another embodiment, compounds for use in the methods provided herein have the following formula:
Figure imgf000032_0001
in which R1, R2, R3, R6, R7, A, X, Y and Z are shown in Tables 5 and 6.TABLE 5
R1 R2 R' R4 R" R7 X
O (2,4-Cl)Ph Isopropyl Me(2) H Me Me CH2CH2 C=O(4) O
O (2,4-Cl)Ph Isopropyl Me(2) H H H CH2CH2 C=O(4) O
O (2,4-Cl)Ph Isopropyl Allyl(2) H H H CH2CH2 C=O(4) O
O (2-OH,4-Cl)Ph Isopropyl Me(2) H H H CH2CH2 C=O(4) O
O (2-OH,4-Cl)Ph Isopropyl Me(2) H Me Me CH2CH2 C=O(4) O
O (2,4-Cl)Ph Isopropyl Me(2) H H H CH2CH2 C=O(4) S
O (2,4-Cl)Ph Isopropyl Me(2) H H H CH2CH2 CH=CH(4) O
O (2,4-Cl)Ph Isopropyl Me(3) H H H CH2CH2 C=O(4) O
O (2,4-Cl)Ph Isopropyl Me(3) H Me Me CH2CH2 0=0(4) O
O (2,4-Cl)Ph Isopropyl Me(2) H H H CH2CH2 C=CH2(4) O
O (2,4-Cl)Ph Isopropyl Me(2) H Me Me CH2CH2 C=CH2(4) O
O (2,4-Cl)Ph Isopropyl Me(2) H H H CH2CH(Me) C=O(4) O
O (2,4-Cl)Ph Isopropyl Me(2) H Me Me CH2CH(Me) C=O(4) O
O (2,4-Cl)Ph Isopropyl Cl(2) H H H CH2CH2 C=O(4) O
O (2,4-Cl)Ph Isopropyl Cl(2) H Me Me CH2CH2 C=0(4) O
S 4-CF3)Ph Isopropyl Me(2) H H H CH2CH2 C=O(4) O
S 4-CF3)Ph Isopropyl Me(2) H Me Me CH2CH2 C=O(4) O
S (2,4-Cl)Ph Isopropyl Me(2) H H H CH2CH2 C=O(4) O
S (2,4-Cl)Ph Isopropyl Me(2) H Me Me CH2CH2 C=O(4) O
O (2,4-Me)Ph Isopropyl Pr(3) H Me Me CH(Me)CH2 C=O(4) O
S (2-OH,4-Me)Ph Bu Benzyl(2) H H H CH2CH2 C=O(3) O
NH (2-OH,4-CF3)Ph Pr Acetyl(2) H H H CH2CH2 C=O(4) O A R1 R2 R3 R4 R6 R7 X Y Z
N-Me (2-OH,4-Cl)Ph Hexyl Cl(2) H H CH2CH2 C=O(4) O S (2,4-Me)Ph Et Br(2) H H CH2CH2 C=O(4) S O (3,4-Cl)Ph Bu CF3(3) Me Et CH2CH2 C=O(4) O
Remark:
Numeral in ( ) means a position of the group.
TABLE 6
R1 R2 R3 R4 R" R7
O (2,4-Me)Ph Hexyl Me(2) Me(6) Me Me CH(Me)CH2 C=O(4) O
O (2,4-Cl)Ph Bu Me(2) Me(3) H H CH2CH2 C=O(4) O
O (2-OH.3, 4-Me)Ph Pr Allyl(2) H H H CH2CH2 CH=CH(4) O
S (2,4-F)Ph Hexyl Ph(2) H Me Me CH2CH2 CH=CH(4) O
NH (3,4,5-Me)Ph Et Me(2) H H H CH2CH2 C=O(4) S
N-Me (2-OH,3, 4-Me)Ph Bu Me(3) H Me Me CH2CH2 C=O(4) O
S (2-OH,4-CF3)Ph Isopropyl Me(2) Me(6) H H CH2CH2 C=O(3) O
O (2-Cl,4-OMe)Ph Isopropyl Me(2) Me(6) H H CH2CH2 C=O(4) O
O (2-Cl,4-OPh)Ph Isopropyl Acetyl(2) H H H CH2CH2 C=O(4) O
O 1-Naphthyl Isopropyl Cl(2) H H H CH2 CH=CH(4) S
O 2-Naphthyl Isopropyl Br(2) H Me Et CH(Me)CH2 C=O(4) O
S 2-Quinolyl Isopropyl CF3(2) H Me Me CH2CH2 C=O(4) O
NH 8-Quinolyl Isopropyl Me(2) H Me Me CH2CH2 C=O(4) O
N-Me 3-Quinolyl Isopropyl Me(2) H H H CH2CH2 C=O(4) O
S 2-Pyrimidyl Isopropyl Allyl(2) H H H CH2CH2 C=0(4) O
O 2-Thienyl Isopropyl Me(2) H H H CH2 CH=CH(4) S
O 2-Furanyl Isopropyl Me(2) H H H CH2CH2 C=O(4) O
O 2-Imidazolyl Isopropyl Me(2) H Me Et CH2CH2 C=O(4) O
O 2-Indolyl Isopropyl Pr(2) H Me Me CH2CH2 C=O(4) O
O 2-Benzofuranyl Isopropyl Benzyl(2) H Me Me CH2CH2 C=O(4) O
S 2-Benzothienyl Isopropyl Acetyl(2) H Me Me CH2CH2 C=O(4) S
S 2-Benzimidazolyl Isopropyl Cl(2) Cl(6) Me Me CH2CH2 C=O(4) S
Remark:
Numeral in ( ) means a position of the group.
[00170] 3) In another embodiment, compounds for use in the methods provided herein have the following formula:
Figure imgf000033_0001
wherein R1, R2, R3, R4, R6, R7, A, X, Y and Z are shown in Table 7. TABLE 7
A R1 R2 R3 R4 R6 R7 X Y Z
O (2,4-Me)Ph Hexyl Me(2) Me(6) Me Me C==0(4) CH(Me)CH O
2
O (2,4-Cl)Ph Bu Me(2) Me(3) H H C==O(4) CH2CH2 O S (2-OH,4-CF3)Ph Isopr Me(2) Me(6) H H C=O(3) CH2CH2 O O (2-Cl,4-OMe)Ph Isopr Me(2) Me(6) H H C==O(4) CH2CH2 O
S 2-Benzimidazolyl Isopr Cl(2) Cl(6) Me Me C==O(4) CH2CH2 S
Remark:
Numeral in ( ) means a position of the group.
[00171] The variables in formula (II) are described in further detail below.
[00172] The halogen atom for R1 and R2 can be fluorine, chlorine, or bromine.
[00173] The alkyl groups having 1-8 carbon atoms for R1, R2, R3, R4 and R5 can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, or pentyl.
[00174] The alkoxy group having 1-8 carbon atoms for R1 and R2 can be methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, t-butyloxy, or pentyloxy.
[00175] The alkyl group having 1-8 carbon atoms which has 1-3 halogen substituents for R1 and R2 can be chloromethyl, fluoromethyl, bromomethyl, 2-chloroethyl, 2-fluoroethyl, or trifluoromethyl.
[00176] The alkoxy group having 1-8 carbon atoms which has 1-3 halogen substituents for R1 and R2 can be chloromethoxy, fluoromethoxy, bromomethoxy, 2-chloroethoxy, 2- fluoroethoxy, or trifluoroethoxy.
[00177] The alkenyl group having 2-8 carbon atoms for R1 and R2 can be vinyl or allyl.
The alkynyl group having 2-8 carbon atoms can be propargyl. The cycloalkyl group having
3-7 carbon atoms can be cyclohexyl or cyclopentyl. The alkyl group having a 3-7 membered cycloalkyl substituent can be cyclohexylmethyl or cyclopentylmethyl.
[00178] The aryl group for the aryl group optionally having a substituent for R1 and R2 can be phenyl or naphthyl.
[00179] The arylalkyl group for the arylalkyl group (which has an aryl moiety of 6-10 carbon atoms and an alkyl moiety of 1-8 carbon atoms) optionally having a substituent can be benzyl or phenethyl.
[00180] The heterocyclic group for the heterocyclic group optionally having a substituent can be a 5-7 membered cyclic group having ring-forming 1-4 hetero atoms such as nitrogen, oxygen and sulfur. For instance, pyridyl, thienyl and furyl can be mentioned. Further, a benzene ring condensed with the heterocyclic group such as quinolyl or benzothienyl can be mentioned.
[00181] The heterocyclic group for the heterocyclic ring-alkyl group (the alkyl moiety has 1-8 carbon atoms) optionally having a substituent can be the same as that described hereinbefore for the heterocyclic group optionally having a substituent. The alkyl group preferably has 1-3 carbon atoms.
[00182] The substituent for the substituents of the aryl group optionally having a substituent, the arylalkyl group (the aryl moiety has 6-10 carbon atoms, and the alkyl moiety has 1 -8 carbon atoms) optionally having a substituent, the heterocyclic group optionally having a substituent, and a heterocyclic ring-alkyl group (the alkyl moiety has 1-8 carbon atoms) optionally having a substituent can be a halogen atom such as chlorine, bromine, or fluorine, nitro, hydroxyl, amino, an alkyl amino group having 1-8 carbon atoms such as methylamino, or ethylamino, a dialkylamino group having 2-10 carbon atoms such as dimethylamino, an alkyl group having 1 -8 carbon atoms such as methyl, ethyl, propyl, isopropyl, or butyl, an alkoxy group having 1-8 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, or butoxy, an alkyl group having 1-8 carbon atoms which has 1-3 halogen substituents such as chloromethyl, fluoromethyl, bromomethyl, 2-chloroethyl, 2- fluoroethyl, or trifluoromethyl, an alkoxy group having 1-8 carbon atoms which has 1-3 halogen substituents such as chloromethoxy, fluoromethoxy, bromomethoxy, 2-chloroethoxy, 2-fluoroethoxy, or trifluoromethoxy, an alkyenyl group having 2-8 carbon atoms such as vinyl or allyl, an alkynyl group having 2-8 carbon atoms such as propargyl, a cycloalkyl group having 3-7 carbon atoms such as cyclohexyl or cyclopentyl, an alkyl group having a cycloalkyl group of 3-7 carbon atoms such as cyclohexylmethyl or cyclopentylmethyl, phenyl, or pyridyl. [00183] The variables in formula (III) are described in further detail below.
[00184] The halogen atom, alkoxy groups having 1-8 carbon atoms, alkyl group having 1-8 carbon atoms which has 1-3 halogen substituents, alkoxy group having 1-8 carbon atoms which has 1-3 halogen substituents, alkenyl group having 2-8 carbon atoms, alkynyl group having 2-8 carbon atoms, cycloalkyl group having 3-7 carbon atoms, alkyl group having 1-8 carbon atoms which has a cycloalkyl group of 3-7 carbon atoms for R11 and R12 can be those described for the halogen atom, alkoxy group, alkyl group having 1-8 carbon atoms which has a halogen substituent, alkoxy group having 1 -8 carbon atoms which has a halogen substituent, alkenyl, alkynyl, cycloalkyl group, and alkyl group having 1-8 carbon atoms which has a cycloalkyl group of 3-7 carbon atoms for R1 and R2. [00185] The alkyl group having 1-8 carbon atoms for R11, R12, R14, and R15 can be an alkyl group described for R1, R2, R3, R4 and R5.
[00186] In the case that R11 or R12 is phenyl, naphthyl, benzyl, phenethyl, pyridyl, thienyl, furyl, quinolyl, or benzothienyl, these rings may have such substituents as a halogen atom such as chlorine, bromine, or fluorine, nitro, hydroxyl, amino, an alkyl amino group having 1-8 carbon atoms such as methylamino, or ethylamino, a dialkylamino group having 2 10 carbon atoms such as dimethylamino, an alkyl group having 1-8 carbon atoms such as methyl, ethyl, propyl, isopropyl, or butyl, an alkoxy group having 1-8 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, or butoxy, an alkyl group having 1 -8 carbon atoms which has 1-3 halogen substituents such as chloromethyl, fiuoromethyl, bromomethyl, 2- chloroethyl, 2-fluoroethyl, or trifluoromethyl, an alkoxy group having 1-8 carbon atoms which has 1-3 halogen substituents such as chloromethoxy, fluoromethoxy, bromomethoxy, 2-chloroethoxy, 2-fluoroethoxy, or trifluoromethoxy, an alkyenyl group having 2-8 carbon atoms such as vinyl or allyl, an alkynyl group having 2-8 carbon atoms such as propargyl, a cycloalkyl group having 3-7 carbon atoms such as cyclohexyl or cyclopentyl, an alkyl group having a cycloalkyl group of 3-7 carbon atoms such as cyclohexylmethyl or cyclopentylmethyl, phenyl, or pyridyl.
[00187] (1) In one embodiment, the compound provided is a phenylacetic acid derivative of the formula (III) in which -X'-Y'-Z1- is bonded to the 3- or 4-position of the phenylacetic acid or a salt thereof.
[00188] (2) In another embodiment, the compound provided is a phenylacetic acid derivative of the formula (III) or a phenylacetic acid derivative of (1) above in which X1 is a bond, and Z1 is -C(=O)-, or a salt thereof. [00189] (3) In another embodiment, the compound provided is a phenylacetic acid derivative of the formula (III) or a phenylacetic acid derivative of (1) or (2) above in which - X'-Y'-Z1- is bonded to the 4-position of the oxazole ring, or a salt thereof. [00190] (4) In another embodiment, the compound provided is a phenylacetic acid derivative of the formula (III) or a phenylacetic acid derivative of one of (1) to (3) above in which R11 is a phenyl or naphthyl group which optionally has a substituent selected from the group consisting chlorine, fluorine, hydroxyl, an alkyl group having 1-5 carbon atoms, and an alkyl group having 1-5 carbon atoms, and it is bonded to the 2-position of the oxazole ring, or a salt thereof.
[00191] (5) In another embodiment, the compound provided is a phenylacetic acid derivative of the formula (III) or a phenylacetic acid derivative of one of (1) to (4) above in which R12 is an alkyl group having 3-6 carbon atoms, and it is bonded to the 5-position of the oxazole ring, or a salt thereof.
[00192] The compound provided, that is a phenylacetic acid of the formula (III), or a salt thereof, can be a stereoisomer such as cis or trans, or an optical isomer. These isomers are included in the invention.
[00193] The compound provided includes a pharmaceutically acceptable salt such as an alkali metal salt, e.g., sodium salt or potassium salt.Further, the compounds provided can be in the form of pharmaceutically acceptable salts such as alkali metal salts, e.g., sodium salt and potassium salt. [00194] The variables in formula (IV) are described in further detail below.
[00195] In the formula (IV), R3, R4, R5, R6, R7, R8, R9, R10, the substituent of the alkylene chain of Y, the substituent of the aryl and the heterocyclic group of R3, the substituent of the alkyl group substituted with aryl of R2, and the substituent of the alkyl group substituted with a heterocyclic group of R can be an alkyl group having 1-8 carbon atoms. Examples of the alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
[00196] R2 can be an alkyl group having 2-8 carbon atoms. Examples of the alkyl groups include ethyl, propyl, iso-propyl, butyl, isobutyl, t-butyl, pentyl and hexyl. [00197] R2, R4, R5, the substituent of the alkylene chain of Y, the substituent of the aryl or heterocyclic group of R1, the substituent of the alkyl group substituted with aryl of R2, and the substituent of the alkyl group substituted with a heterocyclic group of R2 can be an alkyl groups having 1-8 carbon atoms substituted with 1-3 halogens. Examples of the haloalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, and t-butyl which are substituted with 1-3 halogens such as fluorine, chlorine, and bromine. Trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl and 2-fiuoroethyl are preferred.
[00198] R2 and R3 can be an alkenyl group having 2-8 carbon atoms. Examples of the alkenyl groups include vinyl and allyl. R2 and R3 can be an alkynyl group having 2-8 carbon atoms. Examples of the alkynyl groups include propargyl. [00199] R3 can be a halogen atom. Examples of the halogen atoms include fluorine, chlorine and bromine.
[00200] R2 can be a cycloalkyl group having 3-7 carbon atoms. Examples of the cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl. [00201] The substituent of the aryl or heterocyclic group of R1, the substituent of the alkyl group substituted with aryl of R2, and the substituent of the alkyl group substituted with a heterocyclic group of R2 can be an alkoxy groups having 1-8 carbon atoms. Examples of the alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t- butoxy, pentyloxy and hexyloxy.
[00202] R1 and the aryl moiety of the aryl substituted with alkyl of R2 can be an aryl group. Examples of the aryl groups include phenyl and naphthyl. R1 and the substituent of the alkyl group of R2 can be a heterocyclic group having five to eight membered ring.
Examples of the heterocyclic groups include pyridyl, thienyl, fiiryl, thiazolyl and quinolyl. R1 can be a heterocyclic group having five to eight membered ring comprising one to three hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur and the other atoms consisting of carbon. A benzene ring can be condensed with the heterocyclic ring.
Examples of the condensed rings include quinoline ring and benzothiophene ring.
[00203] Y can be an alkylene chain having 1 to 8 carbon atoms. Examples of the alkylene chains include methylene and ethylene.
[00204] R3 can be one to three groups. Two or three groups of R3 can be different from each other.
[00205] R6 can be an alkyl group having 1-8 carbon atoms substituted with amino.
Examples of the aminoalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl which are substituted with an amino group such as piperidino, pyrrolidino, dimethylamino, and diethylamino. [00206] (1) In one embodiment, a compound provided is a compound of the formula
(IV) or salt thereof, in which R1 is attached to the 2nd position of the oxazole, thiazole or imidazole ring.
[00207] (2) In another embodiment, a compound provided is a compound of the formula (IV), a salt thereof or (1), in which B1 is N, and B2 is O. [00208] (3) In another embodiment, a compound provided is a compound of the formula (IV), a salt thereof, (1) or (2), in which R6 is hydrogen.
[00209] (4) In another embodiment, a compound provided is a compound of the formula (IV), a salt thereof, (1), (2) or (3), in which X2 is a bond.
[00210] (5) In another embodiment, a compound provided is a compound of the formula (IV), a salt thereof, (1), (2), (3) or (4), in which X1 is a bond.
[00211] (6) In another embodiment, a compound provided is a compound of the formula (IV), a salt thereof, (1), (2), (3), (4) or (5), in which R1 is aryl substituted with a group or atom selected from the group consisting Of Ci-8 alkyl, Cj-8 alkoxy, C1-8 alkyl substituted with 1-3 halogens, hydroxyl, nitro, amino, phenyl, pyridyl and halogen. [00212] (7) In another embodiment, a compound provided is a compound of the formula (IV), a salt thereof, (1), (2), (3), (4), (5) or (6), in which R2 is C2-8 alkyl. [00213] (8) In another embodiment, a compound provided is a compound of the formula (IV), a salt thereof, (1), (2), (3), (4), (5), (6) or (7), in which R3 is Ci-8 alkyl or C2-8 alkenyl.
[00214] The compound of the formula (IV) can be in the form of pharmaceutically acceptable salts such as alkali metal salts, e.g., sodium salt and potassium salt.
Methods of Use [00215] Provided are methods for treating, preventing, or ameliorating one or more symptoms of a disease or condition related to plaque built-in in a vessel. These conditions include but are not limited to a cardiovascular disease including atherosclerosis and hypertriglyceridemia, heart failure, acute coronary syndrome, angina, type II diabetes mellitus, type I diabetes, insulin resistance, epithelial hyperproliferative disease including eczema and psoriasis, and hypertension.
[00216] In one embodiment, the methods provided comprise administering to a subject having or being suspected to have such a condition, a PPARδ agonist including those described herein. [00217] In another embodiment, the methods provided comprise administering to a subject having or being suspected to have such a condition, a selective PPARδ agonist including those described herein.
[00218] In one aspect, the present invention provides methods for treating plaque build-up by administering to a subject in need thereof one or more compounds of Formulae I to IV. Such compound unclude but are not limited to a single enantiomer, a mixture of the (+)-enantiomer and the (-)-enantiomer, a mixture of about 90% or more by weight of the (-)- enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (-)- enantiomer, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or produg thereof. [00219] In another embodiment, in the methods provided, the compounds described herein induce reverse cholesterol transport in mammals. In other embodiments, the mammal is a primate or a human. In certain embodiments, the mammal is a human. [00220] In another embodiment, in the methods provided, the compounds described herein are useful in treatment of atherosclerosis. [00221] In another embodiment, in the methods provided, the compounds described herein are useful in reducing atherosclerotic plaque.
[00222] In another embodiment, in the methods provided, the compounds described herein increase HDL levels in mammals by daily oral administration. [00223] In another embodiment, in the methods provided, the compounds described herein increase ApoA-I levels in mammals by daily oral administration.
[00224] In another embodiment, in the methods provided, the compounds described herein increase ApoA-I levels that lead to the formation of pre-β-HDL particles.
[00225] In another embodiment, in the methods provided, the compounds described herein increase pre-β-HDL levels in mammals by daily oral administration.
[00226] In another embodiment, in the methods provided, the compounds described herein increase HDL levels and/or ApoA-I levels in mammals.
[00227] In another embodiment, in the methods provided, the compounds described herein increase HDL levels and/or ApoA-I levels, and/or pre-β-HDL levels in mammals. In certain enbodiments, the increase in ApoA-I levels and/or pre-β-HDL levels occurs without significantly raising HDL-cholesterol levels.
[00228] In another embodiment, in the methods provided, the compounds described herein decrease LDL levels in mammals.
[00229] In another embodiment, in the methods provided, the compounds described herein decrease VLDL levels in mammals.
[00230] In another embodiment, in the methods provided, the compounds described herein decrease triglyceride levels in mammals.
[00231] In another embodiment, in the methods provided, the compounds described herein decrease LDL and/or VLDL levels in mammals. [00232] In another embodiment, in the methods provided, the compounds described herein decrease LDL, and/or VLDL and/or triglyceride levels in mammals.
[00233] In another embodiment, in the methods provided, the compounds described herein increase the levels of HDL, and/or ApoA-I, and/or pre-β HDL, HDL and ApoA-I, and/or HDL, ApoA-I, pre-β HDL and ApoA-I rich HDL and decrease the levels of LDL, or VLDL, or triglycerides, or LDL and VLDL, or LDL, VLDL and triglycerides levels in mammals.
[00234] Depending on the disease to be treated and the subject's condition, the compounds of Formulas I to IV, as well as any PPARδ agonist, including, but not limited to,
GSK-501516 (Ligand/GSK), RWJ-800025 (JNJ/Metabolex), KD-3010 (Kalypsys, Inc.), BAY 68-5042 (Bayer), or compounds described in Bratton, L. D. et al., Bioorg. Med. Chem. Lett. 2007 (web edition) and Kasuga, J. I. et al., Bioorg. Med. Chem. 2007 (web edition) provided herein may be administered by oral or parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant) routes of administration, and may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In one embodiment, the compounds provided are administered orally. [00235] In certain embodiments, in the methods provided herein, an appropriate dosage level of a PPARδ agonist for humans is about 0.1 mg/day to about 2500 mg/day and results in increase in pre-β-HDL levels while avoiding the side effects associated with the use of PP ARa and PPARγ agonists, or classical PPAR agonist class side effects. In yet another embodiment, the dose is about 0.25 mg/day to about 500 mg/day. In yet another embodiment, the dose is about 0.5 mg/day to about 250 mg/day. In yet another embodiment, the dose is about 0.75 mg/day to about 50 mg/day. In yet another embodiment, the dose is about 1.0 mg/day to about 25 mg/day.
[00236] In another embodiment, in the methods provided, a dose of a PPARδ agonist for humans is about 0.001 mg/kg/day to about 25 mg/kg/day results in increase in pre-β-HDL levels while avoiding the side effects associated with the use of PP ARa and PPARγ agonists, or classical PPAR agonist class side effects. In yet another embodiment, dose is about 0.005 mg/kg/day to about 15 mg/kg/day. In yet another embodiment, the dose is about 0.01 mg/kg/day to about 10 mg/kg/day. In yet another embodiment, the dose is about 0.5 mg/kg/day to about 5 mg/kg/day. In yet another embodiment, the dose is about 1.0 mg/kg/day to about 2.5 mg/kg/day, which may be administered in a single or divided doses. Within this range the dosage may be about 0.1 mg, about 0,25 mg, about 0.5 mg, about 0.75 mg, about 1.0 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg per day. [00237] In another embodiment, in the methods provided, the low doses of the PPARδ agonists, such as 0.05 to 30 mg/kg/day in monkeys and 0.5 mg/day to 300 mg/day in humans do not cause significant side effects usually reported to be associated with the PPARδ agonists. [00238] In another embodiment, compounds provided may be used in combination with any other active agents or pharmaceutical compositions where such combined therapy is useful to reduce plaque build-up and therefore treat the conditions related thereto.
Pharmaceutical Compositions [00239] Provided herein are pharmaceutical compositions comprising one or more compounds of Formulae I to IV, as well as any PPARδ agonist, including, but not limited to, GW-501516 (Ligand/GSK), RWJ-800025 (JNJ/Metabolex), KD-3010 (Kalypsys, Inc.), BAY 68-5042 (Bayer), or compounds described in Bratton, L. D. et al., Bioorg. Med. Chem. Lett. 2007 (web edition) and Kasuga, J. I. et al., Bioorg. Med. Chem. 2007 (web edition) as active ingredients or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof. [00240] Provided herein are pharmaceutical compositions in modified release dosage forms, which comprise one or more compounds of Formulae I to IV, as well as any PPARδ agonist, including, but not limited to, GW-501516 (Ligand/GSK), RWJ-800025 (JNJ/Metabolex), KD-3010 (Kalypsys, Inc.), BAY 68-5042 (Bayer), or compounds described in Bratton, L. D. et al., Bioorg. Med. Chem. Lett. 2007 (web edition) and Kasuga, J. I. et al., Bioorg. Med. Chem. 2007 (web edition) or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release controlling excipients as described herein. Suitable modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof. The pharmaceutical compositions may also comprise non-release controlling excipients.
[00241] Further provided herein are pharmaceutical compositions in enteric coated dosage forms, which comprise one or more compounds of Formulae I to IV or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release controlling excipients for use in an enteric coated dosage form. The pharmaceutical compositions may also comprise non-release controlling excipients.
[00242] Additionally provided are pharmaceutical compositions in a dosage form that has an instant releasing component and at least one delayed releasing component, and is capable of giving a discontinuous release of the compound in the form of at least two consecutive pulses separated in time from 0.1 up to 24 hours.
[00243] In one embodiment, the pharmaceutical compositions comprise one or more compounds of Formulae I to IV, as well as any PPARδ agonist including, but not limited to, GW-501516 (Ligand/GSK), RWJ-800025 (JNJ/Metabolex), KD-3010 (Kalypsys, Inc.), BAY 68-5042 (Bayer), or compounds described in Bratton, L. D. et al., Bioorg. Med. Chem. Lett. 2007 (web edition) and Kasuga, J. I. et al., Bioorg. Med. Chem. 2007 (web edition) or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release controlling and non-release controlling excipients, such as those excipients suitable for a disruptable semi-permeable membrane and as swellable substances.
[00244] Provided herein also are pharmaceutical compositions in a dosage form for oral administration to a subject, which comprise one or more compounds of Formulae I to IV or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more pharmaceutically acceptable excipients or carriers, enclosed in an intermediate reactive layer comprising a gastric juice-resistant polymeric layered material partially neutralized with alkali and having cation exchange capacity and a gastric juice-resistant outer layer. [00245] Provided herein are pharmaceutical compositions that comprise about 0.1 mg/day to about 2500 mg/day of a PPARδ agonist. In yet another embodiment, pharmaceutical compositions comprise about 0.25 mg/day to about 500 mg/day of a PPARδ agonist. In yet another embodiment, pharmaceutical compositions comprise about 0.5 mg/day to about 250 mg/day of a PPARδ agonist. In yet another embodiment, pharmaceutical compositions comprise about 0.75 mg/day to about 50 mg/day of a PPARδ agonist. In yet another embodiment, pharmaceutical compositions comprise about 1.0 mg/day to about 25 mg/day of a PPARδ agonist. [00246] In another embodiment, pharmaceutical compositions provided herein comprise about 0.001 mg/kg/day to about 25 mg/kg/day of a PPARδ agonist. In yet another embodiment, pharmaceutical compositions provided herein comprise about 0.005 mg/kg/day to about 15 mg/kg/day of a PPARδ agonist. In yet another embodiment, pharmaceutical compositions provided herein comprise about 0.01 mg/kg/day to about 10 mg/kg/day of a PPARδ agonist. In yet another embodiment, pharmaceutical compositions provided herein comprise about 0.5 mg/kg/day to about 5 mg/kg/day of a PPARδ agonist. In yet another embodiment, pharmaceutical compositions provided herein comprise about 1.0 mg/kg/day to about 2.5 mg/kg/day of a PPARδ agonist, which may be administered in a single or divided doses. The pharmaceutical compositions further comprise about 0.1% to about 2% sodium chloride, about 0.1% to about 2% ammonium acetate, about 0.001% to about 0.1% edetate disodium, about 0.1% to about 2% benzyl alcohol, with a pH of about 6 to about 8. [00247] The pharmaceutical compositions provided herein may be provided in unit- dosage forms or multiple-dosage forms. Unit-dosage forms, as used herein, refer to physically discrete units suitable for administration to human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include ampouls, syringes, and individually packaged tablets and capsules. Unit- dosage forms may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of multiple-dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. [00248] The compounds of Formulae I to IV, as well as any PP ARδ agonist, including, but not limited to, GW-501516 (Ligand/GSK), RWJ-800025 (JNJ/Metabolex), KD-3010 (Kalypsys, Inc.), BAY 68-5042 (Bayer), or compounds described in Bratton, L. D. et al., Bioorg. Med. Chem. Lett. 2007 (web edition) and Kasuga, J. I. et al., Bioorg. Med. Chem. 2007 (web edition) provided herein may be administered alone, or in combination with one or more other compounds provided herein, or one or more other active ingredients. The pharmaceutical compositions that comprise compounds provided herein may be formulated in various dosage forms for oral administration. The pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art {see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126). [00249] The pharmaceutical compositions provided herein may be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
Oral Administration
[00250] The pharmaceutical compositions provided herein may be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also include buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents. [00251] Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH- 101, AVICEL-PH- 103, AVICEL RC-581 , AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre- gelatinized starch, and mixtures thereof. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein. [00252] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
[00253] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
[00254] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
[00255] Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of
Boston, MA), and asbestos-free talc. Coloring agents include any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.
[00256] It should be understand that many carriers and excipients may serve several functions, even within the same formulation. [00257] The pharmaceutical compositions provided herein may be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric- coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets. [00258] The tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges. [00259] The pharmaceutical compositions provided herein may be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propylparabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. [00260] The pharmaceutical compositions provided herein may be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl)acetal of a lower alkyl aldehyde (the term "lower" means an alkyl having between 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration. [00261] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly- alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates. [00262] The pharmaceutical compositions provided herein for oral administration may be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Miccellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458. [00263] The pharmaceutical compositions provided herein may be provided as non- effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide. [00264] Coloring and flavoring agents can be used in all of the above dosage forms.
[00265] The pharmaceutical compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
[00266] The pharmaceutical compositions provided herein may be co-formulated with other active ingredients which do not impair the desired therapeutic action, or with substances that supplement the desired action, such as antacids, proton pump inhibitors, and F^-receptor antagonists.
Controlled-Release Dosage Forms
[00267] The pharmaceutical compositions in an osmotic controlled-release dosage form may further comprise additional conventional excipients as described herein to promote performance or processing of the formulation.
[00268] The osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art {see, Remington: The
Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J Controlled Release 2002, 79, 7-27).
[00269] In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
[00270] In certain embodiment, the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), hydroxylethyl cellulose, and other pharmaceutically acceptable excipients. Dosing
[00271] In certain embodiments, compounds provided are administered once daily in a single or divided dose in the amount of about 0.001 to about 25 mg/kg, where kg refers to a subject's body weight. [00272] In certain embodiments, compounds provided are administered once daily in a single or divided dose in the amount of about 0.005 to about 15 mg/kg.
[00273] In certain embodiments, compounds provided are administered once daily in a single or divided dose in the amount of about 0.01 to about 10 mg/kg.
[00274] In certain embodiments, compounds provided are administered once daily in a single or divided dose in the amount of about 0.5 to about 5 mg/kg.
[00275] In certain embodiments, compounds provided are administered once daily in a single or divided dose in the amount of about 1.0 to about 2.5 mg/kg.
[00276] In certain embodiments, compounds provided are administered once daily in a single or divided dose in the amount of about 0.1 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1.0 mg, about 2.5 mg, about 5.0 mg, about 7.5 mg, about 10 mg, about 15 mg, or about 25 mg.
Additional Compounds
[00277] In one embodiment, any compound possessing PPARδ agonist activity may be used. In another embodiment, compounds that are selective PPARδ agonists are used. Exemplary compounds include, but are not limited to, GW-501516 (Ligand/GSK), RWJ-
800025 (JNJ/Metabolex), KD-3010 (Kalypsys, Inc.) and BAY 68-5042 (Bayer).
[00278] Incorporated herein by reference in their entirety are the US Patents
6,787,552; 7,078,422 and 7,119,104 assigned to Nippon Chemiphar Co. Ltd., disclosing
PPARδ agonists. [00279] The invention is further described by the following non-limiting examples.
EXAMPLES
[00280] Example 1. 2-[4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4- oxazolyI]propionyl]-2-methyl-phenoxy]-2-methylpropionic acid.
Figure imgf000050_0001
[00281] (l) 3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-l-(4-hydroxy-3- methylphenyl)propan- 1 -one.
[00282] To an ice-cold THF (5 mL) was added 60% sodium hydride (97 mg, 2.42 mmol). Subsequently, a solution of ethyl 2-[(3-methyl-4-benzyloxy)benzoyl- ]acetate (757 mg, 2.42 mmol) in THF (4 mL) was dropwise added for 30 minutes. The mixture was allowed to room temperature, and then stirred for 30 minutes. To the mixture was added 4- iodomethyl-5-isopropyl-2-(2,4— dichlorophenyl)oxazole (960 mg, 2.42 mmol). The resulting mixture was refluxed for 20 hours under nitrogen atmosphere, and allowed to room temperature. THF was removed under reduced pressure. To the residue was added acetic acid (6.4 mL)-conc. hydrochloric acid (1.6 mL), and the mixture was refluxed for 10 hours, and allowed to room temperature. The reaction mixture was poured into ice water. Ethyl acetate was added to the mixture. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and a saline, dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure, and the residue was purified by column chromatography on silica gel with hexane/ethyl acetate (3/1) to give the desired compound (706 mg) as pale yellowish white crystalline (yield 70%).
[00283] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(d, 6H, J=7 Hz), 2.26(s, 3H), 2.95(t, 2H,
J=7 Hz), 3.19(dq, IH, J=7 Hz, J=7 Hz), 3,30(t, 2H, J=7 Hz), 5.75(s, IH), 6.75(d, IH, J=8 Hz), 7.30(dd, IH, J=2, 8 Hz), 7.49(d, IH, J=2 Hz), 7.70(dd, IH, J=2, 8 Hz), 7.76(d, IH, J=2 Hz), 7.88(d, IH, J=8 Hz).
[00284] ( 2) Ethyl 2-[4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl-
] -2-methylphenoxy] -2-methylpropionate.
[00285] In methyl ethyl ketone (10 mL) were suspended the obtained 3-[2-(2,4- dichlorophenyl)-5-isopropyl-4-oxazolyl]-l-(4-hydroxy-3-methylphenyl)propan-l-one (209 mg, 0.50 mmol), ethyl 2-bromo-2-methylpropionate (489 mg, 2.50 mmol), and potassium carbonate (346 mg, 2.50 mmol). The suspension was refluxed for 40 hours. The suspension was then allowed to room temperature, filtered to remove insolubles, and washed with methyl ethyl ketone. The solvent was distilled off. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (7/1) to give the desired compound (272 mg) as colorless oil (quantitative yield).
[00286] 1H-NMR (CDCl3, 400 MHz) δ: 1.26(t, 3H, J=7 Hz), 1.29(d, 6H, J=7 Hz),
1.64(s, 6H), 2.25(s, 3H), 2.95(t, 2H, J=7 Hz), 3.18(dq, IH, J=7 Hz, J=7 Hz), 3.32(t, 2H, J=7 Hz), 4.2 l(q, 2H, J=7 Hz), 6.60(d, IH, J=8 Hz), 7.30(dd, IH, J=2, 8 Hz), 7.49(d, IH, J=2 Hz), 7.71(dd, IH, J=2, 8 Hz), 7.80(d, IH, J=2 Hz), 7.89(d, IH, J=8 Hz). [00287] (3) 2-[4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]-2-me- thylphenoxy]-2-methylpropionic acid.
[00288] In a mixture of ethanol (6 mL) and water (3 mL) was dissolved the obtained ester compound (270 mg, 0.51 mmol), and then lithium hydroxide monohydrate (65 mg) was added. The mixture was refluxed for 48 hours, and allowed to room temperature. Ice water was added to the reaction mixture. The mixture was neutralized by addition of 3N hydrochloric acid. Precipitated crystals were filtered, washed with water, dried in air over night, and further dried under reduced pressure (60° C.) to give 170 mg of the desired compound (yield 68%). [00289] White powder (mp: 100-105° C.)
[00290] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(d, 6H, J=7 Hz), 1.66(s, 6H), 2.24(s, 3H),
2.94(t, 2H, J=7 Hz), 3.21(dq, IH, J=7 Hz, J=7 Hz), 3.26(t, 2H, J=7 Hz), 6.7 l(d, IH, J=8 Hz), 7.29(dd, IH, J=2, 8 Hz), 7.49(d, IH5 J=2 Hz), 7.56(dd, IH, J=2, 8 Hz), 7.79(d, IH, J=2 Hz), 7.84(d, IH, J=8 Hz). [00291] Example 2. [4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4- oxazolyl]propionyl]-2-methylphenoxy]acetic acid.
Figure imgf000052_0001
[00292] (1) Ethyl [4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]-2- methylphenoxy] acetate . [00293] The synthetic intermediate of Example 1, namely 3-[2-(2,4-dichlorophenyl)-5- isopropyl-4-oxazolyl]-l-(4-hydroxy3-methylphenyl)propan-l-one (105 mg, 0.25 mmol) and potassium carbonate (103 mg, 0.75 mmol) were suspended in acetone (3 mL). Ethyl bromoacetate (0.08 mL, 0.75 mmol) was added to the suspension while cooling with ice. The suspension was allowed to room temperature, and refluxed while heating for 6 hours. Insolubles were filtered, and washed with acetone. Subsequently, the solvent was distilled off. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (7/1-4/1) to give the subject compound (117 mg) as colorless oil (yield 92%) [00294] 1H-NMR (CDCl3, 400 MHz) δ: 1.26(t, 3H, J=7 Hz), 1.30(d, 6H, J=7 Hz),
2.31(s, 3H), 2.75(t, 2H, J=7 Hz), 3.18(dq, IH, J=7 Hz, J=7 Hz), 3.33(t, 2H, J=7 Hz), 4.26(q, 2H, J=7 Hz), 4.69(s, 2H), 6.69(d, IH, J=8 Hz), 7.30(dd, IH, J=2, 8 Hz), 7.49(d, IH, J=2 Hz), 7.8-7.85(m, 2H), 7.89(d, IH, J=8 Hz). [00295] (2) [4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]-2- methylphenoxy] acetic acid.
[00296] In a mixture of ethanol (27 mL) and water (13 mL) was dissolved the obtained ester compound (1.2Og, 2.38mmol), and then lithium hydroxide monohydrate (200mg,4.76mmol) was added. The mixture was refluxed for 6 hours, and allowed to room temperature. Ice water was added to the reaction mixture. The mixture was neutralized by addition of 3N hydrochloric acid. Precipitated crystals were filtered, washed with water, dried in air over night, and further dried under reduced pressure (60° C.) to give 1.03g of the desired compound (yield 91%). [00297] White powder (mp: 157-1590 C)
[00298] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(d, 6H, J=7 Hz), 2.27(s, 3H), 2.96(t, 2H,
J=7 Hz), 3.20(dq, IH, J=7 Hz, J=7 Hz), 3.29(t, 2H, 3=7 Hz), 4.70(s, 2H), 6.68(d, IH, J=8 Hz), 7.30(dd, IH, J=2, 8 Hz), 7.49(d, IH, J=2 Hz), 7.8-7.8(m, 2H), 7.85(d, IH, J=8 Hz). [00299] Example 3. 4-[3-[4-Isopropyl -2-[4-(trifluoromethyl)phenyl]-5- thiazolyl]propionyl]-2-methyIphenoxyacetic acid.
Figure imgf000053_0001
[00300] (1) l-(4-Hydroxy-3-methylphenyl)-3-[4-isopropyl -2-[4-
(trifluoromethyl)phenyl]-5-thiazolyl] propan-1-one. [00301] 4-Isopropyl-2-[4-(trifluoromethyl)phenyl]thiazole-5-methanol (70 g) was dissolved in EtOAc (0.7 L), and to the mixture SOCl2 (32.3 g) was added dropwise. After 1 h of stirring at room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with aqueous NaHCO3 and brine, and then dried over Na2SO4. The solvent was evaporated and the residue was dried in vacuo to give 5- chloromethyl-4-isopropyl-2-[4-(trifluoromethyl)phenyl]thiazole (73.5 g, yield 98.9%) as a white solid. Under nitrogen atmosphere, NaNH2 (9.74 g) was suspended in THF (270 mL), and to the mixture was added the solution of ethyl 3-(4-benzyloxy-3-methylphenyl)-3- oxopropionate (0.65 g) in THF (270 mL). After stirring at room temperature for 0.5 h, the solution of 5-chloromethyl-4-isopropyl-2-[4-(trifluoromethyl)phenyl]thiazole (73.2 g) in THF (270 mL) was added dropwise and the mixture was refluxed for 14 h. The solvent was evaporated, and to the residue was added AcOH (270 mL) and CHCl3 (134 mL) and the mixture was refluxed for 8 h. After cooling to room temperature, the resultant suspension was stirred in ice bath for 3 h. The filtrated crystal was dried in vacuo to give l-(4-hydroxy-3- methylphenyl)-3-[4-isopropyl-2-[4-(trifluoromethyl)phenyl]-5-thiazolyl]propan- 1 -one (80 g, yield 88.7% from ethyl 3-(4-benzyloxy-3-methylphenyl)-3-oxopropionate) as a pale yellow solid.
[00302] 1H-NMR (CDCl3, 400 MHz): 1.33(d, 6H, J=7 Hz), 2.29(s, 3H), 3.14(dq, IH, J=7 Hz, J=7 Hz), 3.2-3.3(m, 4H), 5.35(s, IH), 6.80(d, IH, J=8 Hz), 7.63(d, 2H, J=8 Hz), 7.74(dd, IH, J=2, 8 Hz), 7.79(d, IH, J=2 Hz), 7.89(d, 2H, J=8 Hz). [00303] (2) Ethyl 4-[3-[4-isopropyl -2-[4-(trifluoromethyl)phenyl]-5- thiazolyl]propionyl]-2-methylphenoxyacetate. [00304] l-(4-Hydroxy-3-methylphenyl)-3-[4-isopropyl-2-[4-(trifluoromethyl)phenyl]- 5-thiazolyl]propan-l-one (79.5 g) and Cs2CO3 (65.7 g) were suspended in acetone (0.8 L), and to the mixture was added ethyl bromoacetate (31.7 g). After refluxing for 2 h, the solvent was evaporated and to the residue was added water to extract with EtOAc. The organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated to give crude product, which was recrystallized from n-hexane to give ethyl 4-[3-[4-isopropyl-2-[4- (trifluoromethyl)phenyl]-5-thiaz-olyl]propionyl]-2-methylphenoxyacetate(81.2 g, yield 85.2%) as a white crystal.
[00305] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(t, 3H, J=7 Hz), 1.33(d, 6H, J=7 Hz),
2.33(s, 3H), 3.15(dq, IH, J=7 Hz, J=7 Hz), 3.2-3.3(m, 4H), 4.27(q, 2H, J=7 Hz), 4.71(s, 2H), 6.71(d, IH, J=8 Hz), 7.64(d, 2H, J=8 Hz), 7.75(dd, IH, J=2, 8 Hz), 7.81(d, IH, J=2 Hz), 8.00(d, 2H, J=8 Hz).
[00306] (3) [4-[3-[2-(4-Trifluoromethyl)phenyl-4-iso-propyl-5-thiazolyl]propionyl]~
2-methylphenoxy]acetic acid.
[00307] Ethyl 4-[3-[4-isopropyl-2-[4-(trifluoromethyl)phenyl]-5-thiazolyl]propionyl]-
2-methylphenoxy- acetate (80 g) was suspended in EtOH (400 mL), and to the mixture was added the solution of NaOH (12.33 g) in water (400 mL). After stirring at room temperature for 2 h, to the mixture was added HCl (2 mol/L) to extract with EtOAc. The organic layer was washed with water and brine, then dried over Na2SO4TlIe solvent was evaporated to give the crude product, which was recrystallized from THF/n-hexane to give 4-[3-[4-isopropyl]-2- [4-((trifluoromethyl)phenyl]-5-thiazolyl]propionyl]-2-methylphenoxy-acetic acid (63 g, yield 83.1%) as a white crystal..
[00308] White powder (mp: 145-155° C.)
[00309] 1H-NMR (CDCl3, 400 MHz) δ: 1.33(d, 6H, J=7 Hz), 2.32(s, 3H), 3.15(dq, IH,
J=7 Hz, J=7 Hz), 3.2-3.3(m, 4H), 4.76(s, 2H), 6.75(d, IH, J=8 Hz), 7.64(d, 2H, J=8 Hz), 7.81(dd, IH, J=2, 8 Hz), 7.82(d, IH, J=2 Hz), 8.00(d, 2H, J=8 Hz). [00310] Example 4. 2-[4-[3-[2-(4-Trifluoromethyl)phenyl-4-isopropyl-5- thiazolyl] propionyl] -2-methy lphenoxy] -2-methyIpropionic acid .
Figure imgf000055_0001
[00311] (1) Ethyl 2-[4-[3-[2-(4-Trifluoromethyl)phenyl-4-isopropyl-5-thiazolyl]pro- pionyl]-2-methylphenoxy]-2-methylpropionate.
[00312] The desired compound was obtained in an analogous manner as in (2) of
Example 1 using the synthetic intermediate (1) of Example 3, namely l-(4-Hydroxy-3- methylphenyl)-3-[4-isopropyl -2-[4-(trifluoromethyl)phenyl]-5-thiazolyl] propan-1-one (yield
74%). [00313] Colorless Oil
[00314] 1H-NMR (CDCl3, 400 MHz) δ: 1.21(t, 3H, J=7 Hz), 1.33(d, 6H, J=7 Hz),
1.65(s, 6H), 2.27(s, 3H), 3.15(dq, IH, J=7 Hz, J=7 Hz), 3.2-3.3(m, 4H), 4.22(q, 2H, J=7 Hz),
6.62(d, IH, J=8 Hz), 7.64(d, 2H, J=8 Hz), 7.70(dd, IH, J=2, 8 Hz), 7.80(d, IH, J=2 Hz),
8.00(d, 2H, J=8 Hz). [00315] (2) 2-[4-[3-[2-(4-Trifluoromethyl)phenyl-4-isopropyl-5-thiazolyl]propionyl- ]-
2-methylphenoxy] -2-methy lpropionic acid.
[00316] The desired compound was obtained in an analogous manner as in (3) of
Example 1 using the obtained ester compound (yield 90%).
[00317] Pale Yellow Amorphous [00318] 1H-NMR (CDCl3, 400 MHz) δ: 1.33(d, 6H, J=7 Hz), 1.67(s, 6H), 2.27(s, 3H),
3.14(dq, IH, J=7 Hz, J=7 Hz), 3.2-3.3(m, 4H)., 6.75(d, IH, J=8 Hz), 7.63(d, 2H, J=8 Hz),
7.72(dd, IH, 5=2, 8 Hz), 7.80(d, IH, J=2 Hz), 7.99(d, 2H, J=8 Hz).
[00319] Example 5. [2-Allyl-4-[3-[2-(2,4-dichIorophenyl)-5-isopropyl-4- oxazolyl] propionyl] phenoxy] acetic acid.
Figure imgf000055_0002
[00320] (l) 3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-ox-azolyl]-l-(4- hydroxyphenyl)p- ropan-1-one.
[00321] To an ice-cold THF (15 mL) was added 60% sodium hydride (120 mg, 3.00 mmol). Subsequently, a solution of ethyl 2-[(4-benzyloxy)benzoyl]ace- tate (900 mg, 3.02 mmol) in THF (15 mL) was dropwise added for 30 minutes. The mixture was allowed to room temperature, and then stirred for 30 minutes. To the mixture was added 4-iodomethyl- 5-isopropyl-2-(2,4-dichlor- ophenyl)oxazole (1.20 g, 3.00 mmol). The resulting mixture was refluxed for 20 hours under nitrogen atmosphere, and allowed to room temperature. THF was removed under reduced pressure. To the residue was added acetic acid (7.5 mL)-conc. hydrochloric acid (2.0 mL), and the mixture was refluxed for 5 hours, and allowed to room temperature. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and a saline, dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure, and the residue was purified by column chromatography on silica gel with hexane/ethyl acetate (3/1) to give the desired compound (650 mg) as pale yellowish white crystal (yield 53%).
[00322] 1H-NMR (CDCl3, 400 MHz) δ: 1.32(d, 6H, J=7 Hz), 2.96(t.2H, J=7 Hz),
3.22(dq, IH, J=7 Hz, J=7 Hz), 3.25(t, 2H, J=7 Hz), 6.77(d, 2H, J=8 Hz), 7.29(dd, 1H.J=2, 8 Hz), 7.49(d, IH, J=2 Hz), 7.60(s, IH), 7.76(d, 2H, J=8 Hz), 7.84(d, IH, J=8 Hz). [00323] (2) 3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-ox-azolyl]-l-(4-allyloxyphenyl)- propan-1-one.
[00324] In acetone (5 mL), 3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl- ]-l-(4- hydroxyphenyl)propan-l-one (202 mg, 0.50 mmol) and potassium carbonate (103 mg, 0.75 mmol) were suspended. Allyl bromide (91 mg, 0.75 mmol) was added to the suspension while cooling with ice. The suspension was stirred at room temperature for 20 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with water, and a saline, dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure to give the subject compound (205 mg) as pale yellow solid residue (yield 92%). [00325] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(d, 6H, J=7 Hz), 2.96(t, 2H.J=7 Hz),
3.18(dq, 1H.J=7 Hz, J=7 Hz), 3.34(t, 2H, J=7 Hz), 4.59(dt, 2H, J=2, 5 Hz), 5.25-5.35(m, IH), 5.40-5.45(m, IH), 5.95-6.10(m, IH), 6.93(d, 2H, J=9 Hz), 7.29(dd, IH, J=2, 8 Hz), 7.49(d, IH, J=2 Hz), 7.89(d, IH, J=8 Hz), 7.96(d, 2H, J=9 Hz). [00326] (3) 3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-ox-azolyl]-l-(3-allyl-4-hydroxy- phenyl)propan- 1 -on.
[00327] At 180° C, 3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl- ]-l-(4- allyloxyphenyl)propan-l-one (200 mg, 0.45 mmol) was heated for 5 hours. The compound was allowed to room temperature, the resulting compound was purified by column chromatography on silica gel with hexane/ethyl acetate (3/1) to give the desired compound
(36 mg) as pale yellow oil (yield 18%).
[00328] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(d, 6H, J=7 Hz), 2.96(t, 2H, J=7 Hz),
3.18(dq, IH, J=7 Hz, J=7 Hz), 3.33(t, 2H, J=7 Hz), 3.43(d, 2H, J=6 Hz), 5.1-5.2(m, 2H), 5.51(s, IH), 5.85-6.1(m, IH), 6.82(d, IH, J=8 Hz), 7.29(dd, IH, J=2, 8 Hz), 7.49(d, IH, J=2
Hz), 7.79(d, IH, d, J=2 Hz), 7.80(dd, IH, J=2, 8 Hz), 7.88(d, IH, J=8 Hz).
[00329] (4) [2-Allyl-4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl-
Jphenoxy] ethyl acetate.
[00330] The desired compound was obtained in an analogous manner as in (1) of Example 2 (yield 84%).
[00331] Colorless Oil.
[00332] 1H-NMR (CDCl3, 400 MHz) δ: 1.29(t, 3H, J=7 Hz), 1.30(d, 6H, J=7 Hz),
2.96(t, 2H, J=7 Hz), 3.18(dq, IH, J=7 Hz, J=7 Hz), 3.33(t, 2H, J=7 Hz), 3.47(d, 2H, J=6 Hz),
4.26(q, 2H, J=7 Hz), 4.69(s, 2H), 5.05-5.15(m, 2H), 5.95-6.10(m, IH), 6.73(d, IH, J=8 Hz), 7.30(dd, IH, J=2, 8 Hz), 7.49(d, IH, J=2 Hz), 7.83(d, IH, J=2 Hz), 7.84(dd, IH, J=2, 8 Hz),
7.88(d, IH, J=8 Hz).
[00333] (5) [2-Allyl-4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl-
]phenoxy]acetic acid
[00334] The desired compound was obtained in an analogous manner as in (2) of Example 2 (yield 81 %).
[00335] White powder (mp: 145-150° C.)
[00336] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(d, 6H, J=7 Hz), 2.96(t, 2H, J=7 Hz),
3.19(dq, IH, J=7 Hz, J=7 Hz), 3.32(t, 2H, J=7 Hz), 3.46(d, 2H, J=6 Hz), 4.71(s, 2H), 5.05-
5.15(m, 2H), 5.95-6.10(m, IH), 6.95(d, IH, J=8 Hz), 7.30(dd, IH, J=2, 8 Hz), 7.49(d, IH, J=2 Hz), 7.81(dd, IH, J=2, 8 Hz), 7.83(d, IH, J=2 Hz), 7.86(d, IH, J=8 Hz).
[00337] Example 6. [4-[3-[2-(2-Hydroxy-4-chlorophenyl)-5-isopropyl-4- oxazolyl] propionyl] -2-methy lphenoxy] acetic acid.
Figure imgf000057_0001
[00338] (l) 3-[2-(2-Methoxy-4-chlorophenyl)-5-isopropyl-4-oxazolyl]-l-(3-methyl-4- hydroxyphenyl)propan- 1 -on.
Figure imgf000058_0001
[00339] To an ice-cold THF (50 mL) was added 60% sodium hydride (204 mg, 5.10 mmol). Subsequently, a solution of ethyl 2-[(3-methyl-4-benzyloxy)be- nzoyljacetate (1.6 g, 5.12 mmol) in THF (25 mL) was drop wise added for 30 minutes. The mixture was allowed to room temperature, and then stirred for 30 minutes. To the mixture was added 4-iodomethyl- 5-isopropyl-2-(2-me- thoxy-4-chlorophenyl)oxazole (2.00 g, 5.11 mmol). The resulting mixture was refluxed for 20 hours under nitrogen atmosphere, and allowed to room temperature. THF was removed under reduced pressure. To the residue was added acetic acid (16 mL)-conc. hydrochloric acid (4 mL), and the mixture was refluxed for 10 hours under heating. The mixture was allowed to room temperature, and poured into ice water. Ethyl acetate was added to the mixture. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and a saline, dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure, and the obtained residue was filtered, washed with an ether, and hexane to give the desired compound as white powder. Subsequently, the washings was concentrated, and the residue was filtered, washed with an ether, and hexane in the same manner as is mentioned above. The obtained powder was mixed with the previously obtained powder, and the mixed powder was dried under reduced pressure to give the desired compound (1.8 g) as pale yellowish white crystal (yield 70%). [00340] 1H-NMR (CDCl3, 400 MHz) δ: 1.32(d, 6H, J=7 Hz), 2.18(s, 3H), 2.91(t, 2H,
J=7 Hz), 3.06(t, 2H, J=7 Hz), 3.18(dq, IH, J=7 Hz, J=7 Hz), 3.87(s, 3H), 6.70(d, IH, J=8 Hz), 6.99(d, IH, J=2 Hz), 7.03(dd, IH, J=2, 8 Hz), 7.41(dd, IH, J=2, 8 Hz), 7.49(d, IH, J=2 Hz), 7.83(d, IH, J=8 Hz), 8.94(s, IH). [00341] (2) 3-[2-(2-Hydroxy-4-chlorophenyl)-5-isopropyl-4-oxazolyl]-l-(3-methyl-4- hydroxyphenyl)propan- 1 -one.
Figure imgf000058_0002
[00342] The obtained 3-[2-(2-methoxy4-chlorophenyl)-5-isopropyl-4-oxazolyl]-l-(3- methyl-4-hydroxyphenyl)propan-l-one (621 mg, 1.50 mmol) was suspended in methylene chloride (30 mL) and cooled with ice. To the suspension, a IM methylene chloride solution of boron trichloride (BCl3) (3.0 mL, 3.00 mmol) was dropwise added for 1 minute. The mixture was allowed to room temperature, stirred for 72 hours, and poured into ice water. Chloroform and saturated sodium hydrogen carbonate were added to the mixture. The organic layer was washed with water, and a saline, dried over anhydrous sodium sulfate. The chloroform was removed under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (3/1) to give the desired compound (385 mg) as colorless oil (yield 64%).
[00343] 1H-NMR (CDCl3, 400 MHz) δ: 1.3 l(d, 6H, 3=1 Hz), 2.27(s, 3H), 2.94(t,
2H.J=7 Hz), 3.19(dq, IH, J=7 Hz, J=7 Hz), 3.29(t, 2H, 3=1 Hz), 5.22(s, IH), 6.79(d, IH, J=8 Hz), 6.90(dd, IH, 3=2, 8 Hz), 7.04(d, IH, J=2 Hz), 7.68(d, IH, J=8 Hz), 7.74(dd, IH, 3=2, 8 Hz), 7.78(d, IH, J=2 Hz), 11.50(s, IH).
[00344] (3) [4-[3-[2-(2-Hydroxy-4-chlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]-
2-methylphenoxy] ethyl acetate. [00345] The obtained 3-[2-(2-hydroxy-4-chlorophenyl)-5-isopropyl-4-oxazolyl- ]-l-(3- methyl-4-hydroxyphenyl)propan-l-one (378 mg, 0.95 mmol) was dissolved in acetone (20 mL). To the solution, potassium carbonate (158 mg, 0.95 mmol) and ethyl bromoacetate (158 mg, 0.95 mmol) were added while cooling with ice. The mixture was allowed to room temperature, and stirred for 20 hours. After insoluble was filtered off, the mixture was washed with acetone to remove the solvent. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (4/1) to give the desired compound (315 mg) as white solid (yield 69%).
[00346] 1H-NMR (CDCl3, 400 MHz) δ: 1.29(t, 3H, J=7 Hz), 1.3 l(d, 6H, 3=1 Hz),
2.3 l(s, 3H), 2.94(t, 2H, J=7 Hz), 3.20(dq, IH, 3=1 Hz, 3=1 Hz), 3.30(t, 2H, 3=1 Hz), 4.26(q, 2H, J=7 Hz), 4.69(s, 2H), 6.70(d, IH, J=8 Hz), 6.90(dd, IH, 3=2, 8 Hz), 7.04(d, IH, J=2 Hz), 7.68(d, IH, J=8 Hz), 7.75-7.85(m, 2H), 11.48(s, IH).
[00347] (4) [4-[3-[2-(2-Hydroxy-4-chlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]-
2-methylphenoxy]acetic acid.
[00348] The desired compound was obtained in an analogous manner as in (2) of
Example 2 (yield 87%). [00349] White powder (mp: 159-161° C.)
[00350] 1H-NMR (CDCl3, 400 MHz) δ: 1.31(d, 6H, 3=1 Hz), 2.3 l(s, 3H), 2.94(t, 2H,
3=1 Hz), 3.19(dq, IH, 3=1 Hz, 3=1 Hz), 3.30(t, 2H, 3=1 Hz), 4.76(s, 2H), 6.74(d, IH, J=8 Hz), 6.90(dd, IH, J=2, 8 Hz), 7.04(d, IH, 3=2 Hz), 7.68(d, IH, J=8 Hz), 7.80-7.85(m, 2H). [00351] Example 7. [4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4- oxazolyl] propionyl] -2-methy Ipheny lsulfanyl] acetic acid.
Figure imgf000060_0001
[00352] (l) 3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-l-[3-methyl-4-
(dimethylthiocarbamoyloxy)phenyl]propan- 1 -one.
Figure imgf000060_0002
[00353] In dry dioxane (5 mL), 3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxaz- olyl]-l-
(3-methyl-4-hydroxyphenyl)propan-l-one (417 mg, 1.00 mmol) obtained in (1) of Example 1, 4-dimethylaminopyridine (12 mg, 0.10 mmol) and triethylamine (0.28 mL, 2.00 mmol). To the solution, dimethylthiocarbamoyl chloride (148 mg, 1.20 mmol) was added while cooling with ice. The reaction temperature was increased, and refluxed over night. The mixture was allowed to room temperature. To the mixture, 4-dimethylaminopyridine (12 mg, 0.10 mmol) and dimethylthiocarbamoyl chloride (148 mg, 1.20 mmol) were again added. The mixture was refluxed for 20 hours. The reaction mixture was allowed to room temperature, and poured into ice water. Ethyl acetate was added to the mixture. The organic layer was washed with water, and a saline, dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (3/1), and chloroform/methanol (100/1) to give the desired compound (170 mg) as a mixture with the starting materials. [00354] (2) 3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-l-[3-methyl-4-
(dimethylcarbamoylsulfanyl)phenyl]propan- 1 -one.
Figure imgf000060_0003
[00355] The obtained crude thiocarbamoyl compound (160 mg) was dissolved in n- tetradecane (10 mL). The solution was refluxed at the internal temperature of 250° C. for 8 hours. The mixture was allowed to room temperature. The reaction mixture was directly purified by column chromatography on silica gel with hexane/ethyl acetate (3/1) to give the desired compound (120 mg) as a pale yellow oil (two steps yield 24%). [00356] 1H-NMR (CDCl3, 400 MHz) δ: 1.31 (d, 6H, J=7 Hz), 2.45(s, 3H), 2.97(t, 2H,
J=7 Hz), 3.0-3.2(br, 6H), 3.19(dq, IH, J=7 Hz, J=7 Hz), 3.38(t, 2H, J=7 Hz), 7.30(dd, IH, J=2, 8 Hz), 7.48(d, IH, J=2 Hz), 7.57(d, IH, J=8 Hz), 7.78(dd, IH, J=2, 8 Hz), 7.88(d, IH, J=2 Hz), 7.89(d, IH, J=8 Hz). [00357] (3) 3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-l-(3-methyl-4-mercap- tophenyl)propan- 1 -one.
Figure imgf000061_0001
[00358] The obtained carbamoyl compound (110 mg, 0.22 mmol) was dissolved in dry methanol (5 mL). To the solution, 0.5N MeONa (0.66 mL, 0.33 mmol) was added. The mixture was refluxed for 20 hours, and allowed to room temperature. The mixture was poured into ice water. The mixture was neutralized with 3N hydrochloric acid. Ethyl acetate was added to the mixture. The organic layer was washed with water, and a saline, dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure to obtain the desired compound (80 mg) as pale yellow oil (yield 84%). [00359] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(d, 6H, J=7 Hz), 2.34(s, 3H), 2.96(t, 2H,
J=7 Hz), 3.18(dq, IH, J=7 Hz, J=7 Hz), 3.34(t, 2H, J=7 Hz), 3.51(s, IH), 7.2-7.3(m, 2H), 7.49(d, IH, J=2 Hz), 7.66(dd, IH, J=2, 8 Hz), 7.75(d, IH, J=2 Hz), 7.88(d, IH, J=8 Hz). [00360] (4) Ethyl [4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]-2- methylphenylsulfany 1] acetate .
Figure imgf000061_0002
[00361] The desired compound was obtained in an analogous manner as in (1) of
Example 2 (yield 89%). [00362] Colorless Oil
[00363] 1H-NMR (CDCl3, 400 MHz) δ: 1.25(t, 3H, J=7 Hz), 1.30(d, 6H, J=7 Hz), 2.39(s, 3H), 2.96(t, 2H, J=7 Hz), 3.18(dq, IH, J=7 Hz, J=7 Hz), 3.35(t, 2H, J=7 Hz), 3.73(s, 2H), 4.20(q, 2H, J=7 Hz), 7.2-7.35(m, 2H), 7.49(d, IH, J=2 Hz), 7.7-7.8(m, 2H), 7.88(d, IH, J=8 Hz).
[00364] (5) [4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]-2-meth- ylphenylsulfanyl] acetic acid. [00365] The desired compound was obtained in an analogous manner as in (2) of
Example 2 using the obtained ester compound (yield 71%).
[00366] White powder (mp: 140-145° C.)
[00367] 1H-NMR (CDCl3, 400 MHz) δ: 1 ,30(d, 6H, J=7 Hz), 2.39(s, 3H), 2.96(t,
2H.J=7 Hz), 3.19(dq, IH, J=7 Hz, J=7 Hz), 3.32(t, 2H, J=7 Hz), 3.77(s, 2H), 7.2-7.35(m, 2H),
7.49(d, IH, J=2 Hz), 7.7-7.8(m, 2H), 7.87(d, IH, J=8 Hz).
[00368] Example 8. 2-[4-[3-[2-(2-Hydroxy-4-chlorophenyl)-5-isopropyI-4- oxazolyl]propionyl]-2-methylphenoxy]-2-methylpropionic acid.
Figure imgf000062_0001
[00369] (1) Ethyl 2-[4-[3-[2-(2-hydroxy-4-chlorophenyl)-5-isopropyl-4-oxazolyl]pro- pionyl]-2-methylphenoxy]-2-methylpropionate.
Figure imgf000062_0002
[00370] In methyl ethyl ketone (10 mL), 3-[2-(2-hydroxy-4-chlorophenyl)-5-i- sopropyl-4-oxazolyl]-l-(3-methyl-4-hydroxyphenyl)propan-l-one (150 mg, 0.38 mmol), obtained in (2) of Examole 6, ethyl 2-bromo-2-methylpropionate (146 mg, 0.75 mmol) and potassium carbonate (103 mg, 0.75 mmol) were suspended. The suspension was refluxed for 20 hours, and allowed to room temperature. After insoluble was filtered off, the mixture was washed with methyl ethyl ketone to removed the solvent. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (8/1) to give the desired compound (83 mg) as colorless oil (yield 43%).
[00371] 1H-NMR (CDCl3, 400 MHz) δ: 1.21(t, 3H, J=7 Hz), 1.31(d, 6H, J=7 Hz),
1.64(s, 6H), 2.25(s, 3H), 2.93(t, 2H, J=7 Hz), 3.19(dq, IH, J=7 Hz, J=7 Hz), 3.28(t, 2H, J=7 Hz), 4.22(q, 2H, J=7 Hz), 6.60(d, IH, J=9 Hz), 6.90(dd, IH, J=2, 9 Hz), 7.04(d, IH, J=2 Hz), 7.68(d, IH, J=9 Hz), 7.70(dd, IH, J=2, 9 Hz), 7.78(d, IH, J=2 Hz), 11.48(s, IH). [00372] (2) 2-[4-[3-[2-(2-Hydroxy-4-chlorophenyl)-5-isopropyl-4-oxazolyl]propionyl-
] -2-methylphenoxy] -2-methylpropionic acid.
[00373] The desired compound was obtained in an analogous manner as in (3) of
Example 1 using the obtained ester compound (yield 33%). [00374] Pale White Amorphous [00375] 1H-NMR (CDCl3, 400 MHz) δ: 1.31 (d, 6H, J=7 Hz), 1.68(s, 6H), 2.27(s, 3H),
2.94(t, 2H, J=7 Hz), 3.20(dq, IH, J=7 Hz, J=7 Hz), 3.29(t, 2H, J=7 Hz), 6.77(d, IH, J=9 Hz), 6.90(dd, IH, J=2, 9 Hz), 7.04(d, IH, J=2 Hz), 7.68(d, IH, J=9 Hz), 7.74(dd, IH, J=2, 9 Hz), 7.80(d, IH, J=2 Hz).
[00376] Example 9. [4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-l- propenyl] -2-methy lphenoxy ] acetic acid.
Figure imgf000063_0001
[00377] (l) 4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyloxazol-4-yl]-l-hydroxypropyl]-
2-methylphenol.
Figure imgf000063_0002
[00378] To a solution of lithium aluminum hydride (92 mg, 2.42 mmol) in dry THF
(20 mL), 3-[2-(2,4-dichlorophenyl)-5-isopropyloxazol-4-yl]-l-(4-hydro- xy-3- methylphenyl)propan-l-one (1.01 g, 2.41 mmol), obtained in (1) of Example 1, was gradually added while cooling with ice. The mixture was stirred for 1 hour, and further stirred at room temperature. The reaction mixture was again cooled with ice. To the mixture, a saturated aqueous sodium sulfate solution was dropwise added. After insoluble materials were filtered out, the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate, washed with water (15 mL) containing a small amount of a IM aqueous solution of hydrochloric acid, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the desired compound (997 mg) as ocher yellow crystal (yield 98%).
[00379] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(d, 3H, 3=7 Hz), 1.31 (d, 3H, J=7 Hz),
2.07(dt, 2H, J=7 Hz, 7 Hz), 2.24(s, 3H), 2.67(dt, 2H, J=2 Hz, 7 Hz), 3.07(m, IH), 3.65(brs, IH), 4.72(t, 2H, J=7 Hz), 5.06(s, IH), 6.7 l(d, IH, J=8 Hz), 7.06(dd, 1 IH, J=2 Hz, 8 Hz), 7.15(d, IH, J=2 Hz), 7.30(dd, IH, J=2 Hz, 8 Hz), 7.50(d, IH, J=2 Hz), 7.91(d, IH, J=8 Hz). [00380] (2) 4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyloxazol-4-yl]-l-propenyl]-2- methylphenol.
Figure imgf000063_0003
[00381] To the obtained phenol compound (840 mg, 2.00 mmol), DMSO (8 mL) was added. The mixture was stirred at 150° C. for 2 hours, and allowed to room temperature.
Ethyl acetate (20 mL) was added to the mixture. The mixture was washed with water (20 mL), and then a saturated saline (20 mL). After the mixture was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was recrystallized with ethyl acetate/hexane=l/10 (6.6 mL) to give the desired compound (58 mg) as pale yellow crystal (total yield 81%).
[00382] 1H-NMR (CDCl3, 400 MHz) δ: 1.31(d, 6H, J=7 Hz), 2.22(s, 3H), 3.13(m, IH),
3.45(dd, 2H, J=I Hz, 6 Hz), 4.72(brs, IH), 6.19(dt, IH, J=6 Hz, 16 Hz), 6.37(d, IH, J=16 Hz), 6.69(d, IH, J=8 Hz), 7.06(d, IH, J=8 Hz), 7.12(s, IH), 7.30(dd, IH, J=2 Hz, 8 Hz),
7.50(d, IH, J=2 Hz), 7.93(d, IH, J=8 Hz).
[00383] (3) Ethyl [4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]-l-propenyl- ]-
2-methylphenoxy]acetate.
[00384] The desired compound was obtained in an analogous manner as in (1) of Example 2.
[00385] 1H-NMR (CDCl3, 400 MHz) δ: 1.29(t, 3H, J=7 Hz), 1.3 l(d, 6H, J=7 Hz),
2.27(s, 3H), 3.12(m, IH), 3.46(dd, 2H, J=I Hz, 6 Hz), 4.25(q, 2H, J=7 Hz), 4.6 l(s, 2H),
6.22(dt, IH, J=6 Hz, 16 Hz), 6.39(d, IH, J=16 Hz), 6.63(d, IH, J=8 Hz), 7.10(dd, IH, J=2
Hz, 8 Hz), 7.18(d, IH, J=2 Hz), 7.30(dd, IH, J=2 Hz, 8 Hz), 7.50(d, IH, J=2 Hz), 7.94(d, IH, J=8 Hz).
[00386] (4) [4- [3 - [2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl] - 1 -propenyl] -2-me- thylphenoxy] acetic acid.
[00387] The desired compound was obtained in an analogous manner as in (2) of
Example 2. [00388] Pale yellow crystal (mp: 143-144° C.)
[00389] 1H-NMR (DMSO-d6, 400 MHz) δ: 1.27(d, 6H, J=7 Hz), 2.17(s, 3H), 3.22(m,
IH), 3.43(d, 2H, J=6 Hz), 4.66(s, 2H), 6.21(dt, IH, J=6 Hz, 16 Hz), 6.39(d, IH, J=16 Hz),
6.74(d, IH, J=8 Hz), 7.14(dd, IH, J=2 Hz, 8 Hz), 7.22(d, IH, J=2 Hz), 7.56(dd, IH, J=2 Hz, 8
Hz), 7.78(d, IH, J=2 Hz), 7.98(d, IH, J=8 Hz). [00390] IR(KBr) CnV1: 2968, 2931, 1734, 1564, 1502, 1458, 1387, 1242, 1203, 1138,
1119,966,804. [00391] Example 10. [4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]- l-propenyl]-2-methyIphenoxy]acetic acid.
Figure imgf000065_0001
[00392] (1) Ethyl [4-[3-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]-l-ρr- openyl]-2-methylphenoxy]acetate.
[00393] The desired compound was obtained in an analogous manner as in Example 9.
[00394] 1H-NMR (CDCl3, 400 MHZ) δ: 1.29(t, 3H, J=7 Hz), 1.34(d, 6H, J=7 Hz),
2.28(s, 3H), 3.12(m, IH), 3.67(dd, 2H, J=I Hz, 6 Hz), 4.26(q, 2H, J=7 Hz), 4.62(s, 2H),
6.17(dt, IH, J=6 Hz, 16 Hz), 6.40(d, IH, J=16 Hz), 6.65(d, IH, J=8 Hz), 7.11(dd, IH, J=2 Hz, 8 Hz), 7.19(d, IH, J=2 Hz), 7.64(d, 2H, J=8 Hz), 8.01(d, 2H, J=8 Hz).
[00395] (2) [4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]-l-propenyl- ]-
2-methylphenoxy]acetic acid.
[00396] The desired compound was obtained in an analogous manner as in (2) of
Example 2. [00397] Pale yellow powder (mp: 125-128° C.)
[00398] 1H-NMR (CDCl3, 400 MHz) δ: 1.34(d, 6H, J=7 Hz), 2.28(s, 3H), 3.13(m, IH),
3.68(dd, 2H, J=I Hz, 6 Hz), 4.68(s, 2H), 6.19(dt, IH, J=6 Hz, 16 Hz), 6.40(d, IH, J=I 6 Hz),
6.69(d, IH5 J=8 Hz), 7.13(dd, IH, J=2 Hz, 8 Hz), 7.20(d, IH, J=2 Hz), 7.64(d, 2H, J=8 Hz),
8.01(d,2H,J=8Hz). [00399] IR (KBr) cm'1: 2974, 1751, 1506, 1325, 1252, 1225, 1169, 1136, 1122, 1119,
1066,843.
[00400] Example 11. [4-[3-[4-Hexyl-2-(4-trifluoromethyl)phenyl-5- thiazoly 1] propionyl] -2-methy Iphenoxy] acetic acid.
Figure imgf000065_0002
[00401] (1) Ethyl [4-[3-[4-hexyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propionyl- ]-
2-methy Iphenoxy] acetate .
[00402] The desired compound was obtained in an analogous manner as in (1) of
Example 2.
[00403] 1H-NMR (CDCl3, 400 MHz) δ: 0.89(t, 3H, J=7 Hz), 1.29(t, 3H, J=7 Hz), 1.3- 1.5(m, 6H), 1.7-1.8(m, 2H), 2.33(s, 3H), 2.75(t, 2H, J=8 Hz), 3.2-3.3(m, 4H), 4.27(q, 2H, J=7 Hz), 4.71(s, 2H), 6.72(d, IH, J=8 Hz), 7.64(d, 2H, J=8 Hz), 7.8-7.9(m, 2H), 7.97(dd, 2H, J=I Hz, 8 Hz).
[00404] (2) [4-[3-[4-Hexyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propionyl]-2-me- thylphenoxy] acetic acid. [00405] The desired compound was obtained in an analogous manner as in (2) of
Example 2.
[00406] Yellow Amorphous.
[00407] 1H-NMR (CDCl3, 400 MHz) δ: 0.88(t, 3H, J=7 Hz), 1.3-1.5(m, 6H), 1.7-
1.8(m, 2H), 2.32(s, 3H), 2.75(t, 2H, J=8 Hz), 3.2-3.3(m, 4H), 4.76(s, 2H), 6.75(d, IH, J=8 Hz), 7.64(d, 2H, J=8 Hz), 7.7-7.9(m, 2H), 7.97(dd, 2H, J-I Hz, 8 Hz).
[00408] IR (KBr) cm"1: 2954, 2929, 2858, 1724, 1676, 1603, 1500, 1441, 1327, 1284,
1219, 1169, 1142, 1111, 1068.
[00409] Example 12. 2-[4-[3-[4-Hexyl-2-(4-trifluoromethyl)phenyl-5- thiazolyl]propionyl]-2-methylphenoxy]-2-methyIpropionic acid.
Figure imgf000066_0001
[00410] (1) Ethyl 2-[4-[3-[4-hexyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl] propionyl]-2-methylphenoxy]-2-methylpropionate.
[00411] The desired compound was obtained in an analogous manner as in (2) of
Example 1. [00412] 1H-NMR (CDCl3, 400 MHz) δ: 0.89(t, 3H, J=7 Hz), 1.21(t, 3H, J=7 Hz), 1.2-
1.5(m, 6H), 1.65(s, 6H), 1.7-1.8(m, 2H), 2.27(s, 3H), 2.74(t, 2H, J=8 Hz), 3.2-3.3(m, 4H),
4.22(q, 2H, J=7 Hz), 6.62(d, IH, J=8 Hz), 7.64(d, 2H, J=8 Hz), 7.70(dd, IH, J=2 Hz, 8 Hz),
7.80(d, IH, J=2 Hz), 7.98(d, 2H, J=8 Hz).
[00413] (2) 2-[4-[3-[4-Hexyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propionyl]-2- methylphenoxy]-2-methylpropionic acid.
[00414] The desired compound was obtained in an analogous manner as in (3) of
Example 1.
[00415] Yellow Oil.
[00416] 1H-NMR (CDCl3, 400 MHz) δ: 0.88(t, 3H, J=7 Hz), 1.3-1.5(m, 6H), 1.6- 1.8(m, 2H), 1.69(s, 6H), 2.27(s, 3H), 2.74(t, 2H, J=8 Hz), 3.2-3.3(m, 4H), 6.75(d, IH, J=8
Hz), 7.63(d, 2H, J=8 Hz), 7.72(dd, IH, J=2 Hz, 8 Hz), 7.80(d, IH, J=2 Hz), 7.97(d, 2H, J=8
Hz). [00417] IR (KBr) Cm-1: 2956, 2927, 2858, 1741, 1678, 1601, 1500, 1325, 1261, 1169,
1124, 1066, 845.
[00418] Example 13. 2-[4-[3-[4-Isopropyl-2-(4-trifluoromethyI)phenyl-5- thiazolyl]-l-propenyl]-2-methylphenoxy]-2-methylpropionic acid.
Figure imgf000067_0001
[00419] (1) Ethyl 2-[4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]-l- propenyl]-2-methylphenoxy]-2-methylpropionate.
[00420] The desired compound was obtained in an analogous manner as in (1), (2) of
Example 9 and (2) of Example 1. [00421] 1H-NMR (CDCl3, 400 MHz) δ: 1.25(t, 3H, J=7 Hz), 1.34(d, 6H, J=7 Hz),
1.55(s, 6H), 2.21(s, 3H), 3.12(m, IH), 3.67(dd, 2H, J=I Hz, 6 Hz), 4.24(q, 2H, J=7 Hz),
6.17(dt, IH, J=6 Hz, 16 Hz), 6.38(d, IH, J=16 Hz), 6.60(d, IH, J=8 Hz), 7.03(dd, IH, J=2
Hz, 8 Hz), 7.16(d, IH, J=2 Hz), 7.64(d, 2H, J=8 Hz), 8.01(d, 2H, J=8 Hz).
[00422] (2) 2-[4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]- 1 -propen- yl]-2-methylphenoxy]-2-methylpropionic acid.
[00423] The desired compound was obtained in an analogous manner as in (3) of
Example 1.
[00424] Yellow Oil.
[00425] 1H-NMR (CDCl3, 400 MHz) δ: 1.34(d, 6H, J=7 Hz), 1.61(s, 6H), 2.23(s, 3H), 3.13(m, IH), 3.68(dd, 2H, J=I Hz, 6 Hz), 6.20(dt, IH, J=6 Hz, 16 Hz), 6.40(d, IH, J=16 Hz),
6.77(d, IH, J=8 Hz), 7.09(dd, IH, J=2 Hz, 8 Hz), 7.19(d, IH, J=2 Hz), 7.64(d, 2H, J=8 Hz),
8.01(d, 2H, J=8 Hz).
[00426] IR (KBr) Cm-1: 2970, 2929, 2872, 1716, 1616, 1500, 1325, 1167, 1126, 1066,
964, 845. [00427] Example 14. [4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5- thiazolyl]propionyl]-3-methylphenoxy]acetic acid.
Figure imgf000067_0002
[00428] (1) Ethyl [4-[3-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propi- ony 1] -3 -methy lphenoxy] acetate . [00429] The desired compound was obtained in an analogous manner as in (1) of
Example 2.
[00430] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(t, 3H, J=7 Hz), 1.33(d, 6H, J=7 Hz),
2.56(s, 3H), 3.15(m, IH), 3.23(s, 4H), 4.28(q, 2H, J=7 Hz), 4.65(s, 2H), 6.75(dd, IH, J=2 Hz, 9 Hz), 6.78(d, IH, J=2 Hz), 7.64(d, 2H, J=9 Hz), 7.70(d, IH, J=9 Hz), 8.00(d, 2H, J=9 Hz).
[00431] (2) [4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propionyl]- 3- methylphenoxyjacetic acid.
[00432] The desired compound was obtained in an analogous manner as in (2) of
Example 2. [00433] White crystal (mp: 136-142° C.)
[00434] 1H-NMR (CDCl3, 400 MHz) δ: 1.33(d, 6H, J=7 Hz), 2.56(s, 3H), 3.15(m, IH),
3.23(s, 4H), 4.72(s, 2H), 6.7-6.8(m, 2H), 7.64(d, 2H, J=8 Hz), 7.71(d, IH, J=9 Hz), 8.00(d,
2H, J=8 Hz).
[00435] IR (KBr) cm"1: 2962, 1741, 1672, 1603, 1574, 1450, 1325, 1260, 1236, 1211, 1168, 1126, 1066, 976, 849, 698, 611.
[00436] Example 15. [4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4- oxazolyl] propiony 1] -3-methy lphenoxy ] acetic acid.
Figure imgf000068_0001
[00437] (1) Ethyl [4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]-3- methy lphenoxy] acetate.
[00438] The desired compound was obtained in an analogous manner as in (1) of
Example 2.
[00439] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(t, 3H, J=7 Hz), 1.30(d, 6H, J=7 Hz),
2.53(s, 3H), 2.94(t, 2H, J=7 Hz), 3.19(m, IH), 3.29(t, 2H, J=7 Hz), 4.27(q, 2H, J=7 Hz), 4.64(s, 2H), 6.72(dd, IH, J=2 Hz, 8 Hz), 6.76(d, IH, J=2 Hz), 7.30(dd, IH, J=2, 9 Hz),
7.49(d, IH, J=2 Hz), 7.76(d, IH, J=9 Hz), 7.88(d, IH, J=8 Hz).
[00440] (2) [4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]-3-meth- ylphenoxy] acetic acid.
[00441] The desired compound was obtained in an analogous manner as in (2) of Example 2.
[00442] White crystal (mp: 97-102° C.) [00443] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(d, 6H, J=7 Hz), 2.51(s, 3H), 2.93(t, 2H,
J=7 Hz), 3.19(m, IH), 3.26(t, 2H, J=7 Hz), 4.65(s, 2H), 6.71(dd, IH, J=2 Hz, 8 Hz), 6.75(d,
IH, J=2 Hz), 7.29(dd, IH, J=2 Hz, 8 Hz), 7.48(d, IH, J=2 Hz), 7.72(d, IH, J=8 Hz), 7.85(d, lH, J=8 Hz).
[00444] IR (KBr) cm'1: 3454, 2976, 1730, 1682, 1637, 1605, 1564, 1460, 1383, 1363,
1317, 1242, 1201, 1178, 1120, 1072, 1051, 978, 868, 818, 741.
[00445] Example 16. [4-[3-[4-IsopropyI-2-(4-trifluoromethyl)phenyl-5- thiazoly 1] propiony 1] -3-methy lphenoxy] -2-methy (propionic acid.
Figure imgf000069_0001
[00446] (1) Ethyl 2-[4-[3-[2-[(4-trifluoromethyl)phenyl]-4-isopropyl-5-thiazolyl]- propionyl] -3 -methy lphenoxy] -2-methy lpropionate .
[00447] The desired compound was obtained in an analogous manner as in (2) of
Example 1.
[00448] 1H-NMR (CDCl3, 400 MHz) δ: 1.22(t, 3H, J=7 Hz), 1.33(d, 6H, J=7 Hz), 1.63(s, 6H), 2.52(s, 3H), 3.14(m, IH), 3.22(s, 4H), 4.22(q, 2H, J=7 Hz), 6.63(dd, IH, J=2 Hz,
9 Hz), 6.90(d, IH, J=2 Hz), 7.64(d, IH, J=9 Hz), 7.64(d, 2H, J=9 Hz), 8.00(d, 2H, J=9 Hz).
[00449] (2) [4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propionyl]-3- methylphenoxy]-2-methylpropionic acid.
[00450] The desired compound was obtained in an analogous manner as in (3) of Example 1.
[00451] Yellow Amorphous.
[00452] 1H-NMR (CDCl3, 400 MHz) δ: 1.33(d, 6H, J=7 Hz), 1.66(s, 6H), 2.53(s, 3H),
3.14(m, IH), 3.23(s, 4H), 6.74(dd, IH, J=2 Hz, 8 Hz), 6.78(d, IH, J=2 Hz), 7.64(d, 2H, J=8
Hz), 7.66(d, IH, J=8 Hz), 8.00(d, 2H, J=8 Hz). [00453] IR (KBr) cm"1: 3456, 2968, 2929, 2873, 1740, 1736, 1678, 1603, 1325, 1248,
1167,1126,1066.
[00454] Example 17. 2-[4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4- oxazolyl] propiony I] -3-methy lphenoxy] -2-methy Ip ropionic acid.
Figure imgf000069_0002
[00455] (1) Ethyl 2-[4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]ρropionyl- ]-
3-methylphenoxy]-2-methylpropionate.
[00456] The desired compound was obtained in an analogous manner as in (2) of
Example 1. [00457] 1H-NMR (CDCl3, 400 MHz) δ: 1.22(t, 3H, 3=7 Hz), 1.30(d, 6H, 3=7 Hz),
1.63(s, 6H), 2.49(s, 3H), 2.93(t, 2H, J=7 Hz), 3.18(m, IH), 3.28(t, 2H, J=7 Hz), 4.23(q, 2H,
J=7 Hz), 6.61(dd, IH, 3=2 Hz, 9 Hz), 6.67(d, IH, 3=2 Hz), 7.30(dd, IH, 3=2 Hz, 9 Hz),
7.49(d, IH, 3=2 Hz), 7.70(d, IH, J=9 Hz), 7.88(d, IH, 3=9 Hz)
[00458] (2) 2-[4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]-3-me- thylphenoxy]-2-methylpropionic acid.
[00459] The desired compound was obtained in an analogous manner as in (3) of
Example 1.
[00460] White crystal (mp: 98-100° C.)
[00461] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(d, 6H, J=7 Hz), 1.63(s, 6H), 2.47(s, 3H), 2.92(t, 2H, J=7 Hz), 3.1-3.3(m, 3H), 6.66(dd, IH, J=2 Hz, 9 Hz), 6.73(d, IH, J=2 Hz),
7.27(dd, IH, J=2 Hz, 8 Hz), 7.48(d, IH, 3=2 Hz), 7.55(d, IH, 3=9 Hz), 7.83(d, IH, J=8 Hz).
[00462] IR (KBr) Cm"1: 2980, 2940, 1720, 1680, 1600, 1560, 1460, 1250, 1145, 1125.
[00463] Example 18. [4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5- thiazolyl]propionyl]-2-propylphenoxy]acetic acid.
Figure imgf000070_0001
[00464] (1) Ethyl 2-allyl-4-[3-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl] propionyl]phenoxyacetate.
Figure imgf000070_0002
[00465] The desired compound was obtained in an analogous manner as in (2), (3) and (4) of Example 5.
[00466] 1H-NMR (CDCl3, 400 MHz) δ: 1.29(t, 3H, 3=7 Hz), 1.33(d, 6H, 3=7 Hz),
3.15(m, IH), 3.2-3.3(m, 4H), 3.48(d, 2H, 3=7 Hz), 4.26(q, 2H, 3=7 Hz), 4.71(s, 2H), 5.1- 5.2(m, 2H), 5.9-6.1(m, IH), 6.75(d, IH, 3=9 Hz), 7.64(d, 2H, J=8 Hz), 7.8-7.9(m, 2H), 8.00(d, 2H, J=8 Hz). [00467] (2) Ethyl [4-[3-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl] propionyl]-2-propylphenoxy]acetate.
Figure imgf000071_0001
[00468] Ethyl 2-allyl-4-[3-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5- thiazolyl]propionyl]phenoxyacetate(1.21g, 2.34 mmol) was dissolved in ethanol (4OmL). To the solution, 10% Pd-C (60 mg) was added. The mixture was stirred for 3 hours under hydrogen atmosphere. After insoluble was filtered off, the filtrate was condensed to give the desired compound (1.12g) as pale yellow crystal in the residue (yield 92%).
[00469] 1H-NMR (CDCl3, 400 MHz) δ: 0.95(t, 3H, J=7 Hz), 1.28(t, 3H, J=7 Hz), 1.33(d, 6H, J=7 Hz), 1.6-1.8(m, 2H), 2.68(t, 2H, J=7 Hz), 3.15(dq, IH, J=7 Hz, 7 Hz), 3.2-
3.3(m, 4H), 4.26(q, 2H, J=7 Hz), 4.70(s, 2H), 6.72(d, IH, J=9 Hz), 7.64(d, 2H, J=8 Hz), 7.7-
7.9(m, 2H), 8.00(d, 2H, J=8 Hz).
[00470] (3) [4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propionyl]- 2- propylphenoxy] acetic acid. [00471] The desired compound was obtained in an analogous manner as in (2) of
Example 2.
[00472] Pale white crystal (mp: 145-150° C.)
[00473] 1H-NMR (CDCl3, 400 MHz) δ: 0.96(t, 3H, J=7 Hz), 1.33(d, 6H, J=7 Hz), 1.6-
1.8(111, 2H), 2.68(t, 2H, J=7 Hz), 3.15(dq, IH, J=7 Hz, 7 Hz), 3.2-3.3(m, 4H), 4.77(s, 2H), 6.76(d, IH, J=9 Hz), 7.64(d, 2H, J=8 Hz), 7.7-7.9(m, 2H), 8.00(d, 2H, J=8 Hz).
[00474] Example 19. 2-Allyl-4-[3-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5- thiazolyl]propionyl]phenoxy acetic acid.
Figure imgf000071_0002
[00475] The desired compound was obtained in an analogous manner as in (1) of Example 18 and in (2) of Example 2.
[00476] Pale yellow crystal (mp: 165-175° C.)
[00477] 1H-NMR (CDCl3, 400 MHz) δ: 1.33(d, 6H, J=7 Hz), 3.15(dq, IH, J=7 Hz, 7
Hz), 3.2-3.4(m, 4H), 3.48(d, 2H, J=7 Hz), 4.76(s, 2H), 5.0-5. l(m, 2H), 5.9-6.1(m, IH), 6.79(d, IH, J=9 Hz), 7.64(d, 2H, J=8 Hz), 7.8-7.9(m, 2H), 8.00(d, 2H, J=8 Hz). [00478] Example 20. [4-[4-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-l- buten-2-yl]-2-methylphenoxy]acetic acid.
Figure imgf000072_0001
[00479] (1) Ethyl [4-[4-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]-l-buten-2- yl]-2-methylphenoxy]acetate.
Figure imgf000072_0002
[00480] In a dry ether (2 mL), potassium t-butoxide (120 mg, 1.07 mmol) was suspended. Methyl triphenyl phosphonium bromide (350 mg, 0.98 mmol) was added to the suspension. The mixture was stirred for 2 hours at room temperature. Ethyl [4-[3-[2-(2,4- dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]-2-methylphenoxy] acetate (450 mg, 0.89 mmol) and a dry ether (1.5 mL) were added to the mixture. The resulting mixture was stirred for 16 hours at room temperature. Methyl triphenyl phosphonium bromide (175 mg, 0.49 mmol), a dry ether (5 mL) and potassium t-butoxide (60 mg, 0.53 mmol) were added to the reaction mixture. The resulting mixture was stirred for 30 minutes at room temperature. The mixture was refluxed for 4 hours, and allowed to room temperature. Ethyl acetate (10 mL) was added to the reaction mixture. The mixture was washed with water (10 mL), and a saturated saline (10 mL), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate/hexane (1/9) to give the desired compound (131 g) as colorless oil (yield 29%).
[00481] 1H-NMR (CDCl3, 400 MHz) δ: 1.24(d, 6H, J=7 Hz), 1.30(t, 3H, J=7 Hz),
2.29(s, 3H), 2.6-2.7(m, 2H), 2.8-3.0(m, 3H), 3.27(q, 2H, J=7 Hz), 4.63(s, 2H), 5.00(d, IH, J=I Hz), 5.23(d, IH, J=I Hz), 7.66(d, IH, J=8 Hz), 8.21(dd, IH, J=2 Hz, 8 Hz), 7.26(d, IH, J=2 Hz), 7.31(dd, IH, J=2 Hz, 8 Hz), 7.50(d, IH, J=2 Hz), 7.92(d, IH, J=8 Hz). [00482] (2) [4-[4-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-l-buten-2-yl]-2~ methylphenoxy] acetic acid.
[00483] The desired compound was obtained in an analogous manner as in (2) of
Example 2. [00484] Pale Yellow Oil. [00485] 1H-NMR (CDCl3, 400 MHz) δ: 1.25(d, 6H, J=7 Hz), 2.29(s, 3H), 2.6-2.7(m,
2H), 2.8-2.9(m, 2H), 2.93(m, IH), 4.65(s, 2H), 5.01(d, IH, J=I Hz), 5.23(d, IH, J=I Hz),
6.69(d, IH, J=8 Hz), 7.22(dd, IH, J=2 Hz, 8 Hz), 7.26(d, IH, J=2 Hz), 7.32(dd, IH, J=2 Hz, 8
Hz), 7.50(d, IH, J=2 Hz), 7.91(d, IH, J=8 Hz).
[00486] IR (KBr) cm'1: 3088, 2968, 2927, 2872, 1736, 1605, 1564, 1504, 1460, 1225,
1142,1107.
[00487] Example 21. 2-[4-[4-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-l- buten-2-yl]-2-methylphenoxy]-2-methylpropionic acid.
Figure imgf000073_0001
[00488] (1) Ethyl 2-[4-[4-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]-l-buten-2- yl]-2-methylphenoxy]-2-methylpropionate.
Figure imgf000073_0002
[00489] The desired compound was obtained in an analogues manner as in (1) of example 20 and in (2) of Example 1. [00490] 1H-NMR (CDCl3, 400 MHz) δ: 1.23(d, 6H, J=7 Hz), 1.26(t, 3H, J=7 Hz),
1.59(s, 6H), 2.30(s, 3H), 2.6-2.7(m, 2H), 2.8-3.0(m, 3H), 3.25(q, 2H, J=7 Hz), 4.99(d, IH,
J=I Hz), 5.23(d, IH, J=I Hz), 6.62(d, IH, J=8 Hz), 7.13(dd, 2H, J=I Hz, 8 Hz), 7.24(d, IH,
J=2 Hz), 7.31(dd, IH, J=2 Hz, 8 Hz), 7.50(d, IH, J=2 Hz), 7.92(d, IH, J=8 Hz).
[00491] (2) 2-[4-[4-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-l-buten-2-yl]~ 2- methylphenoxy]-2-methylpropionic acid.
[00492] The desired compound was obtained in an analogous manner as in (3) of
Example 1.
[00493] Brown Oil.
[00494] 1H-NMR (CDCl3, 400 MHz) δ: 1.24(d, 6H, J=7 Hz), 1.61(s, 6H), 2.24(s, 3H), 2.6-2.7(m, 2H), 2.8-2.9(m, 2H), 2.91(m, IH), 5.03(d, IH, J=I Hz), 5.25(d, IH, J=I Hz),
6.79(d, IH, J=8 Hz), 7.18(dd, IH, J=2 Hz, 8 Hz), 7.26(m, IH), 7.31(dd, IH, J=2 Hz, 8 Hz),
7.50(d, IH, J=2 Hz), 7.91(d, IH, J=8 Hz).
[00495] IR (KBr) cm"1: 2972, 2935, 2873, 1716, 1603, 1564, 1500, 1464, 1385, 1250,
1151,1107. [00496] Example 22. [4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-2- methylpropionyI]-2-methylphenoxy]acetic acid.
Figure imgf000074_0001
[00497] (1) Ethyl [4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]-2-methyl propionyl]-2-methylphenoxy]acetate.
Figure imgf000074_0002
[00498] Ethyl [4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]propiony- 1]-2- methylphenoxy] acetate (450 mg, 0.89 mmol) was dissolved in dry THF (4 mL). Sodium hydride (40 mg, 1.00 mmol) was gradually added to the solution. The mixture was stirred for 30 minutes at room temperature. Methyl iodide (0.07 mL, 1.12 mmol) was dropwise added to the mixture. The resulting mixture was stirred for 27 hours at room temperature. Sodium hydride (10 mg, 0.25 mmol) and methyl iodide (0.02 mL, 0.32 mmol) were further added to the mixture. The resulting mixture was stirred for 19 hours 30 minutes at room temperature. The solvent was removed under reduced pressure. Ethyl acetate (5 mL) was added to the residue. The residue was washed with a saturated saline (2 mL), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate/hexane (1/9) to give the desired compound (218 mg) as colorless oil (purity 97%, yield 29%).
[00499] 1H-NMR (CDCl3, 400 MHz) δ: 1.18(d, 3H, J=7 Hz), 1.22(d, 3H, J=7 Hz),
1.28(d, 3H, J=7 Hz), 1.29(t, 3H, J=7 Hz), 2.29(s, 3H), 2.63(dd, IH, J=7 Hz, 14 Hz), 3.00(dd,
IH, J=7 Hz, 14 Hz), 3.10(m, IH), 4.00(m, IH), 4.26(q, 2H, J=7 Hz), 4.68(s, 2H), 6.67(d, IH,
J=8 Hz), 7.30(dd, IH, J=2 Hz, 8 Hz), 7.48(d, IH, J=2 Hz), 7.8-7.9(m, 2H), 7.85(d, IH, J=8
Hz).
[00500] (2) [4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-2-methylpropiony- l]-2-methylphenoxy]acetic acid.
[00501] The desired compound was obtained in an analogous manner as in (2) of
Example 2. [00502] White Amorphous.
[00503] 1H-NMR (CDCl3, 400 MHz) δ: 1.18(d, 3H, J=7 Hz), 1.22(d, 3H, J=7 Hz),
1.28(d, 3H, J=7 Hz), 2.28(s, 3H), 2.64(dd, IH, J=7, 14 Hz), 2.98(dd, IH, J=7 Hz, 14 Hz),
3.13(m, IH), 3.95(m, IH), 4.64(s, 2H), 6.66(d, IH, J=8 Hz), 7.30(dd, IH, J=2 Hz, 8 Hz),
7.48(d, IH, J=2 Hz), 7.76(dd, IH, J=2 Hz, 8 Hz), 7.81(m, IH), 7.82(d, IH, J=8 Hz).
[00504] IR (KBr) cm"1: 3427, 2970, 2931, 2873, 1740, 1672, 1599, 1564, 1502, 1456,
1383,1271,1230,1120.
[00505] Example 23. 2-[4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-2- methylpropionyl]-2-methylphenoxy]-2-methylpropionic acid.
Figure imgf000075_0001
[00506] (1) Ethyl 2-[4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]-2-methyl- propionyl] -2-methylphenoxy] -2-methylpropionate .
[00507] The desired compound was obtained in an analogous manner as in (1) of
Example 22 and (2) of Example 1. [00508] 1H-NMR (CDCl3, 400 MHz) δ: 1.20(d, 3H, J=7 Hz), 1.22(d, 3H, J=7 Hz),
1.27(d, 3H, J=7 Hz), 1.63(s, 3H), 1.63(s, 3H), 2.23(s, 3H), 2.62(dd, IH, J=7 Hz, 14 Hz),
2.99(dd, IH, J=7 Hz, 14 Hz), 3.10(m, IH), 3.99(m, IH), 4.20(q, 2H, J=7 Hz), 6.58(d, IH, J=8
Hz), 7.30(dd, IH, J=2 Hz, 8 Hz), 7.48(d, IH, J=2 Hz), 7.73(dd, IH, J=2 Hz, 8 Hz), 7.80(d,
IH, J=2 Hz), 7.85(d, IH, J=8 Hz). [00509] (2) 2-[4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]-2-methylpropio- nyl] -2-methylphenoxy] -2-methylpropionic acid.
[00510] The desired compound was obtained in an analogous manner as in (3) of
Example 1.
[00511] White Amorphous. [00512] 1H-NMR (CDCl3, 400 MHz) δ: 1.16(d, 3H, J=7 Hz), 1.21(d, 3H, J=7 Hz),
1.27(d, 3H, J=7 Hz), 1.65(s, 3H), 1.66(s, 3H), 2.23(s, 3H), 2.63(dd, IH, J=7 Hz, 14 Hz),
2.97(dd, IH, J=7 Hz, 14 Hz), 3.13(m, IH), 3.94(m, IH), 6.71(d, IH, J=8 Hz), 7.26(m, IH),
7.46(d, IH, J=2 Hz), 7.61(dd, IH, J=2 Hz, 8 Hz), 7.7-7.9(m, 2H).
[00513] IR (KBr) cm'1: 3456, 3431, 2972, 2933, 2873, 1740, 1674, 1599, 1564, 1498, 1462,1385,1257,1142,1119. [00514] Example 24. [4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5- thiazolyl]propenoyl]-2-methylphenoxy]acetic acid.
Figure imgf000076_0001
[00515] (1) 3-[4-Isopropyl-2-(4-trifluoromethylphenyl)thiazol-5-yl]-l -(4-methoxyme- thoxy-3-methylphenyl)propenone
[00516] To a mixture of dry MeOH (3 mL) and dry THF (3 mL), 4-isopropyl-2-(4- trifluoromethylphenyl)thiazol-5-carboxyl aldehyde (803 mg, 2.68 mmol), l-(4- methoxymethoxy3-methylphenyl)ethanone (521 mg, 2.68 mmol) and sodium methoxide (9 mg, 0.13 mmol) were added. The resulting mixture was stirred for 14 hours at room temperature. Sodium methoxide (36 mg, 0.53 mmol) and dry MeOH (3 mL) were added again to the mixture. The resulting mixture was stirred for 26 hours at room temperature. The solvent was removed under reduced pressure. Ethyl acetate (30 mL) was added to the residue. The residue was washed with water (40 mL). The aqueous layer was extracted with ethyl acetate (30 mL, 20 mL). The organic layer was added to the aqueous layer. The mixture was washed with a saturated saline (20 mL), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate/hexane (1/9) to give the desired compound (1.04 g) as a yellow crystal (yield 81%). [00517] 1H-NMR (CDCl3, 400 MHz) δ: 1.39(d, 6H, J=7 Hz), 2.33(s, 3H), 3.43(m, IH), 3.51(s, 3H), 5.30(s, 2H), 7.14(d, IH, J=8 Hz), 7.30(d, IH, J=15 Hz), 7.71(d, 2H, J=8 Hz), 7.8-7.9 (m, 2H), 8.04 (d, IH, J=15 Hz), 8.11 (d, 2H, J=8 Hz)
[00518] (2) 1 -(4-Hydroxy-3-methylphenyl)-3-[4-isopropyl-2-(4-trifluoromethylphenyl-
)thiazol-5-yl]propenone. [00519] In a mixture of isopropanol (4 mL) and THF (16 mL), 3-[4-isopropyl-2-(4- trifluoromethylphenyl)thiazol-5-yl]- 1 -(4-methoxymetho- xy3-methylphenyl)propenone (1.04 g, purity 99.6%, 2.18 mmol) was dissolved. To the mixture, a IM aqueous solution of hydrochloric acid (2.6 mL) was added. The resulting mixture was stirred for 4 hours at room temperature, and for 19 hours and 30 minutes at 65° C. The solvent was removed under reduced pressure. The residue was suspended in a mixture of ethanol (6 mL) and hexane (2 mL). The crystals were filtered, washed with a mixture of ethanol (2 mL) and hexane (2 mL), and with hexane (2 mL), and dried for 30 minutes at room temperature under reduced pressure to give the desired compound (908 mg) as a yellow crystal (yield 97%). [00520] 1H-NMR (CDCl3, 400 MHz) δ: 1.39(d, 6H, J=7 Hz), 2.32(s, 3H), 3.44(m, IH),
6.85(d, IH, J=8 Hz), 7.3 l(d, IH, J=15 Hz), 7.71(d, 2H, J=8 Hz), 7.81(dd, IH, J=2 Hz, 8 Hz),
7.81(bs, IH), 8.03(d, IH, J=15 Hz), 8.1 l(d, 2H, J=8 Hz).
[00521] (3) Ethyl [4-[3-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]prope- noyl]-2-methylphenoxy]acetate.
[00522] The desired compound was obtained in an analogous manner as in (1) of
Example 2.
[00523] 1H-NMR (CDCl3, 400 MHz) δ: 1.31(t, 3H, J=7 Hz), 1.39(d, 6H, J=7 Hz),
2.38(s, 3H), 3.44(m, IH), 4.29(q, 2H, J=7 Hz), 4.74(s, 2H), 6.77(d, IH, J=8 Hz), 7.29(d, IH, J=15 Hz), 7.71(d, 2H, J=8 Hz), 7.86(dd, IH, J=2 Hz, 8 Hz), 7.88(bs, IH), 8.03(d, IH, J=15
Hz), 8.11(d, 2H, J=8 Hz).
[00524] (4) [4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propenoyl]~ 2- methylphenoxy] acetic acid.
[00525] The desired compound was obtained in an analogous manner as in (2) of Example 2.
[00526] Yellow crystal (mp: 203-205° C. (dec.))
[00527] 1H-NMR (CD3OD/CDC13=1/20, 400 MHz) δ: 1.39(d, 6H, J=7 Hz), 2.37(s,
3H), 3.44(m, IH), 4.71(s, 2H), 6.82(d, IH, J=8 Hz), 7.30(d, IH, J=15 Hz), 7.72(d, 2H, J=8
Hz), 7.8-7.9(m, 2H), 8.03(d, IH, J=15 Hz), 8.1l(d, 2H, J=8 Hz). [00528] IR(KBr)Cm"1: 2964,2870, 1761, 1741, 1601, 1581, 1329, 1269, 1230, 1188,
1171,1132,1109,1168,823.
[00529] Example 25. 2-[4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5- thiazolyl] propenoy 1] -2-methylphenoxy] -2-methy lpropionic acid.
Figure imgf000077_0001
[00530] (1) Ethyl 2-[4-[3-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazole]prop- enoyl]-2-methylphenoxy]-2-methylpropionate.
[00531] The desired compound was obtained in an analogous manner as in (1) and (2) of Example 24 and (2) of Example (1)..
[00532] 1H-NMR (CDCl3, 400 MHz) δ: 1.23(t, 3H, J=7 Hz), 1.38(d, 6H, J=7 Hz), 1.68(s, 6H), 2.32(s, 3H), 3.44(m, IH), 4.24(q, 2H, J=7 Hz), 6.68(d, IH, J=8 Hz), 7.29(d, IH,
J=15 Hz), 7.71(d, 2H, J=8 Hz), 7.78(dd, IH, 3=2 Hz, 8 Hz), 7.87(d, IH, J=2 Hz), 8.02(d, IH,
J=I 5 Hz), 8.1 l(d, 2H, J=8 Hz). [00533] (2) 2-[4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazole]propenoyl]- -
2-methylphenoxy]-2-methylpropionic acid.
[00534] The desired compound was obtained in an analogous manner as in (3) of
Example 1. [00535] Yellow crystal (mp: 187- 189° C.)
[00536] 1H-NMR (CDCl3, 400 MHz) δ: 1.38(d, 6H, J=7 Hz), 1.72(s, 6H), 2.33(s, 3H),
3.46(m, IH), 6.82(d, IH, J=8 Hz), 7.28(d, IH, J=15 Hz), 7.71(d, 2H, J=8 Hz), 7.82(dd, IH, J=2 Hz, 8 Hz), 7.88(d, IH, J=2 Hz), 8.04(d, IH, J=15 Hz), 8.10(d, 2H, J=8 Hz). [00537] IR (KBr) cm'1: 3466, 2972, 1740, 1657, 1655, 1639, 1603, 1500, 1327, 1325, 1273, 1169, 1128, 1068.
[00538] Example 26. [4-[3-[4-Isopropyl-2-(4-methoxyphenyl)-5- thiazolyl]propionyl]-2-methylphenoxy]propionic acid.
Figure imgf000078_0001
[00539] (1) Ethyl [4-[3-[4-isopropyl-2-(4-methoxyphenyl)-5-thiazolyl]propionyl]-2~ methylphenoxy] propionate .
Figure imgf000078_0002
[00540] The desired compound was obtained in an analogous manner as in (2) of
Example 1.
[00541] 1H-NMR (CDCl3, 400 MHz) δ: 1.29(t, 3H, J=7 Hz), 1.32(d, 6H, J=7 Hz), 2.32(s, 3H), 3.1 l(dq, IH, J=7 Hz, 7 Hz), 3.1-3.3(m, 4H), 3.84(s, 3H), 4.27(q, 2H, J=7 Hz),
4.70(s, 2H), 6.7 l(d, IH, J=8 Hz), 6.8-7.0(m, 2H), 7.7-7.9(m, 4H).
[00542] (2) [4-[3-[4-Isopropyl-2-(4-methoxyphenyl)-5-thiazolyl]propionyl]-2-methyl- phenoxy] propionic acid.
[00543] The desired compound was obtained in an analogous manner as in (3) of Example 1.
[00544] Pale yellow crystal (mp: 170- 172° C.)
[00545] 1H-NMR (CDCl3, 400 MHz) δ: 1.31(d, 6H, J=7 Hz), 2.32(3H, s), 3.1 l(dq, IH,
J=7 Hz, 7 Hz), 3.1-3.3(m, 4H), 3.84(s, 3H), 4.76(s, 2H), 6.74(d, IH, J=8 Hz), 6.9 l(d, 2H, J=9
Hz), 7.7-7.9(m, 4H). [00546] IR (KBr) cm-1: 2970, 1726, 1672, 1605, 1517, 1456, 1367, 1304, 1302, 1300,
1282, 1261, 1209, 1 176, 1130, 1065, 1034, 1018, 995, 843, 824. [00547] Example 27. [4-[3-[2-(3,5-Difluorophenyl)-4-isopropylthiazol-5- yl]propionyl]-2-methylphenoxy]acetic acid.
Figure imgf000079_0001
[00548] (1) Ethyl [4-[3-[2-(3,5-difluorophenyl)-4-isopropylthiazol-5-yl]propionyl]-2- methylphenoxy] acetate.
[00549] The desired compound was obtained in an analogous manner as in (1) of
Example 2. [00550] 1H-NMR (CDCl3, 400 MHz) δ: 1.28(t, 3H, J=7 Hz), 1.32(d, 6H, J=7 Hz),
2.33(s, 3H), 3.14(m, IH), 3.2-3.3(m, 4H), 4.27(q, 2H, J=7 Hz), 4.71(s, 2H), 6.71(d, IH, J=8
Hz), 6.7-6.9(m, IH), 7.4-7.5(m, 2H), 7.7-7.8(m, 2H).
[00551] (2) [4-[3-[2-(3,5-Difluorophenyl)-4-isopropylthiazol-5-yl]propionyl]-2-met- hylphenoxy] acetic acid. [00552] The desired compound was obtained in an analogous manner as in (2) of
Example 2.
[00553] Pale yellow crystal (mp: 125-128° C.)
[00554] 1H-NMR (CDCl3, 400 MHz) δ: 1.31(d, 6H, J=7 Hz), 2.32(s, 3H), 3.13(m, IH),
3.2-3.3(m, 4H), 4.75(s, 2H), 6.7-6.8(m, 2H), 7.4-7.5(m, 2H), 7.7-7.9(m, 2H). [00555] IR (KBr) cm"1: 3446, 2970, 2929, 2376, 1749, 1743, 1676, 1620, 1599, 1533,
1504, 1502, 1458, 1439, 1363, 1321, 1271, 1230, 1176, 1136, 1134, 1132, 1072, 1053, 987,
879, 847, 808, 677.
[00556] Example 28. 2-[4-[3-[2-(3,5-Difluorophenyl)-4-isopropyl-5- thiazolyl] propiony 1] -2-methy Iphenoxy] -2-methy lpropionic acid.
Figure imgf000079_0002
[00557] (1) Ethyl 2-[4-[3-[2-(3,5-difluorophenyl)-4-isopropyl-5-thiazolyl]propiony- I]-
2-methylphenoxy]-2-methylpropionate.
[00558] The desired compound was obtained in an analogous manner as in (2) of
Example 1. [00559] 1H-NMR (CDCl3, 400 MHz) δ: 1.21(t, 3H, J=7 Hz), 1.31(d, 6H, J=7 Hz),
1.65(s, 6H), 2.27(3H, s), 3.13(dq, IH, J=7 Hz, 7 Hz), 3.2-3.3(m, 4H), 4.22(q, 2H, J=7 Hz),
6.62(d, IH, J=9 Hz), 6.79(dt, IH, J=2 Hz, 9 Hz), 7.4-7.5(m, 2H), 7.69(dd, IH, J=2 Hz, 9 Hz),
7.79(d, lH, J=2 Hz). [00560] (2) 2-[4-[3-[2-(3,5-Difluorophenyl)-4-isopropylthiazol-5-yl]propionyl]-2-m- ethylphenoxy] -2-methylpropionic acid.
[00561] The desired compound was obtained in an analogous manner as in (3) of
Example 1.
[00562] White crystal (mp: 132-133° C.) [00563] 1H-NMR (CDCl3, 400 MHz) δ: 1.31(d, 6H, J=7 Hz), 1.69(s, 6H), 2.28(s, 3H),
3.13(dq, IH, J=7 Hz, 7 Hz), 3.2-3.3(m, 4H), 6.77(d, IH, J=9 Hz), 6.7-6.8(m, IH), 7.4-7.5(m,
2H), 7.73(dd, IH, J=2 Hz, 9 Hz), 7.81(d, IH, J=2 Hz).
[00564] IR (KBr) crn 1: 2974, 2927, 1741, 1652, 1620, 1605, 1535, 1506, 1502, 1458,
1363, 1327, 1321, 1284, 1263, 1147, 1122, 1068, 987, 876, 850, 675. [00565] Example 29. [4-[3-[4-Isopropyl-2-(2-naphthyl)-5-thiazolyl]propionyl]-2- methylphenoxy] acetic acid.
Figure imgf000080_0001
[00566] (1) Ethyl [4-[3-[4-isopropyl-2-(2-naphthyl)-5-thiazolyl]propionyl]-2-methy- lphenoxy] acetate. [00567] The desired compound was obtained in an analogous manner as in (1) of
Example 2.
[00568] 1H-NMR (CDCl3, 400 MHz) δ: 1.28(3H, t, J=7 Hz), 1.37(6H, d, J=7 Hz),
2.33(3H, s), 3.18(1H, m), 3.2-3.3(4H, m), 4.25(2H, q, J=7 Hz), 4.69(2H, s), 6.71(1H, d, J=8
Hz), 6.4-6.5(2H, m), 7.7-7.9(5H, m), 8.04(1H, dd, J=2 Hz, 8 Hz), 8.34(1H, s) [00569] (2) [4-[3-[4-Isopropyl-2-(2-naphthyl)-5-thiazolyl]propionyl]-2-methylpheno- xyjacetic acid.
[00570] The desired compound was obtained in an analogous manner as in (2) of
Example 2.
[00571] Pale yellow crystal (mp: 97-100° C.) [00572] 1H-NMR (CDCl3, 400 MHz) δ: 1.37(6H, d, J=7 Hz), 2.32(3H, s), 3.18(1H, m),
3.2-3.3(4H, m), 4.76(2H, s), 6.74(1H, d, J=8 Hz), 7.4-7.5(2H, m), 7.7-7.9(5H, m), 8.03(1H, dd, J=2 Hz, 8 Hz), 8.33(lH, s).
[00573] IR (KBr) cm"1: 3845, 3745, 3429, 2962, 2929, 2368, 2345, 1749, 1676, 1601,
1506, 1502, 1362, 1255, 1228, 1132, 1068, 858, 813, 748, 476, 420
[00574] Example 30. 2-[4-[3-[4-Isopropyl-2-(2-naphthyl)-5-thiazolyl]propionyl]-
2-methylphenoxy]-2-methylpropionic acid.
Figure imgf000081_0001
[00575] The desired compound was obtained in an analogous manner as in (3) of Example 1.
[00576] White crystal (mp: 164-166° C.)
[00577] 1H-NMR (CDCl3, 400 MHz) δ: 1.36(d, 6H, J=7 Hz), 1.68(s, 6H), 2.28(s, 3H),
3.16(dq, IH, J=7 Hz, 7 Hz), 3.2-3.4(m, 4H), 6.76(d, IH, J=8 Hz), 7.4-7.5(m, 2H), 7.73(dd,
IH, J=2 Hz, 8 Hz), 7.8-7.9(m, 3H), 7.82(d, IH, J=2 Hz), 8.03(dd, IH, J=2 Hz, 9 Hz), 8.34(s, IH).
[00578] IR(KBr)Cm"1: 2966, 1741, 1655, 1620, 1605, 1365, 1284, 1263, 1180, 1147,
1146,808,750.
[00579] Example 31. [4-[3-[2-(4-ButylphenyI)-4-isopropyl-5-thiazolyl]propionyl]-
2-methylphenoxy] acetic acid.
Figure imgf000081_0002
[00580] (1) Ethyl [4-[3-[2-(4-butylphenyl)-4-isopropyl-5-thiazolyl]propionyl]-2-me- thy lphenoxy] acetate .
[00581] The desired compound was obtained in an analogous manner as in (1) of
Example 2. [00582] 1H-NMR (CDCl3, 400 MHz) δ: 0.92(3H, t, J=7 Hz), 1.29(3H, t, J=7 Hz),
1.32(6H, d, J=7 Hz), 1.3-1.4(2H, m), 1.5-1.6(2H, m), 2.32(3H, s), 2.62(2H, t, J=8 Hz), 3.15(1H, m), 3.2-3.3(4H, m), 4.26(2H, q, J=7 Hz), 4.70(2H, s), 6.71(1H, d, J=8 Hz), 7.19(2H, d, J=8 Hz), 7.7-7.8(4H, m).
[00583] (2) [4- [3 - [2-(4-Butylphenyl)-4-isopropyl-5-thiazolyl]propionyl] -2-methylph- enoxyjacetic acid. [00584] The desired compound was obtained in an analogous manner as in (2) of
Example 2.
[00585] Pale Yellow Amorphous.
[00586] 1H-NMR (CDCl3, 400 MHz) δ: 0.92(3H, t, J=7 Hz), 1.31(6H, d, J=7 Hz), 1.3-
1.4(2H, m), 1.5-1.7(2H, m), 2.31(3H, s), 2.62(2H, t, J=8 Hz), 3.12(1H, m), 3.1-3.3(4H, m), 4.74(2H, s), 6.72(1H, d, J=8 Hz), 7.19(2H, d, J=8 Hz), 7.7-7.8(4H, m).
[00587] IR (KBr) cm'1: 3435, 2960, 2929, 2870, 2860, 2368, 1741, 1676, 1601, 1502,
1456, 1414, 1360, 1319, 1275, 1230, 1176, 1138, 1065, 985, 885, 837, 812, 627. [00588] Example 32. 2-[4-[3-[2-(4-Butylphenyl)-4-isopropyI-5- thiazolyl] propiony 1] -2-methylphenoxy] -2-methy lpropionic acid.
Figure imgf000082_0001
[00589] (1) Ethyl 2-[4-[3-[2-(4-butylphenyl)-4-isopropyl-5-thiazolyl]propionyl]-2~ methylphenoxy] -2-methy lpropionate .
[00590] The desired compound was obtained in an analogous manner as in (2) of
Example 1. [00591] 1H-NMR (CDCl3, 400 MHz) δ: 0.92(t, 3H, J=7 Hz), 1.21(t, 3H, J=7 Hz),
1.32(d, 6H, J=7 Hz), 1.3-1.4(m, 2H), 1.5-1.7(m, 2H), 1.65(s, 6H), 2.26(s, 3H), 2.62(t, 2H, J=8
Hz), 3.1 l(dq, IH, J=7 Hz, 7 Hz) 3.2-3.3(m, 4H), 4.22(q, 2H, J=7 Hz), 6.61(d, IH, J=9 Hz),
7.19(d, 2H, J=8 Hz), 7.70(dd, IH, J=2 Hz, 9 Hz), 7.79(d, 2H, J=8 Hz), 7.79(d, IH, J=2 Hz).
[00592] (2) 2-[4-[3-[2-(4-Butylphenyl)-4-isopropyl-5-thiazolyl]propionyl]-2-methyl- phenoxy]-2-methylpropionic acid.
[00593] The desired compound was obtained in an analogous manner as in (3) of
Example 1.
[00594] White crystal (mp: 121-122° C.)
[00595] 1H-NMR (CDCl3, 400 MHz) d: 0.92(t, 3H, J=7 Hz), 1.3 l(d, 6H, J=7 Hz), 1.3- 1.4(m, 2H), 1.5-1.7(m, 2H), 1.68(s, 6H), 2.27(s, 3H), 2.62(t, 2H, J=8 Hz), 3.11(dq, IH, J=7
Hz, 7 Hz), 3.2-3.3(m, 4H), 6.76(ld, IH, J=9 Hz), 7.19(d, 2H, J=8 Hz), 7.72(dd, IH, J=2 Hz, 9
Hz), 7.78(d, 2H, J=8 Hz), 7.80(d, IH, J=2 Hz). [00596] Example 33. [4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyI-5- thiazoly 1] propiony 1] -2-chlorophenoxy ] acetic acid.
Figure imgf000083_0001
[00597] (1) Ethyl [4-[3-[4-isopropyl-2-(4-trifluoromethyl)ρhenyl-5-thiazolyl]propi- onyl]-2-chlorophenoxy]acetate.
[00598] The desired compound was obtained in an analogous manner as in (1) of
Example 2.
[00599] 1H NMR (CDCl3, 400 MHz) δ: 1.29(t, 3H, J=7 Hz), 1.34(d, 6H, J=7 Hz),
3.15(m, IH), 3.26(s, 4H), 4.27(q, 2H, J=7 Hz), 4.77(s, 2H), 6.85(d, IH, J=9 Hz), 7.64(d, 2H, J=8 Hz), 7.84(dd, IH, J=2 Hz, 9 Hz), 8.00(d, 2H, J=8 Hz), 8.03(d, IH, J=2 Hz).
[00600] (2) [4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propionyl]- 2- chlorophenoxy] acetic acid.
[00601] The desired compound was obtained in an analogous manner as in (2) of
Example 2. [00602] White crystal (mp: 149-1510 C.)
[00603] 1H-NMR (CDCl3, 400 MHz) δ: 1.34(d, 6H, J=7 Hz), 3.15(m, IH), 3.26(s, 4H),
4.82(s, 2H), 6.90(d, IH, J=8 Hz), 7.64(d, 2H, J=8 Hz), 7.87(dd, IH, J=2 Hz, 8 Hz), 8.00(d,
2H, J=8 Hz), 8.04(d, IH, J=2 Hz).
[00604] IR (KBr) cm"1: 1724, 1684, 1616, 1595, 1496, 1406, 1360, 1329, 1281, 1232, 1203, 1157, 1117, 1016, 839, 773.
[00605] Example 34. [4-[3-[2-(4-Trifluoromethyl)phenyl-4-isopropyl-5- thiazolyl]propionyl]-2-chlorophenoxy]-2-methylpropionic acid.
Figure imgf000083_0002
[00606] (1) Ethyl [4-[3-[2-(4-trifluoromethyl)phenyl-4-isopropyl-5-thiazolyl]propi- onyl]-2-chlorophenoxy]-2-methylpropionate.
[00607] The desired compound was obtained in an analogous manner as in (2) of
Example 1.
[00608] 1H-NMR (CDCl3, 400 MHz) δ: 1.23(t, 3H, J=7 Hz), 1.33(d, 6H, J=7 Hz),
1.68(s, 6H), 3.14(m, IH), 3.25(s, 4H), 4.23(q, 2H, J=7 Hz), 6.82(d, IH, J=8 Hz), 7.64(d, 2H, J=8 Hz), 7.75(dd, IH, J=2 Hz, 8 Hz), 8.00(d, 2H, J=8 Hz), 8.01(d, IH, J=2 Hz). [00609] (2) [4-[3-[2-(4-Trifluoromethyl)phenyl-4-isopropyl-5-thiazolyl]propionyl]~ 2- chlorophenoxy] -2-methylpropionic acid.
[00610] The desired compound was obtained in an analogous manner as in (3) of
Example 1. [00611] Pale Yellow Amorphous.
[00612] 1H-NMR (CDCl3, 400 MHz) δ: 1.33(d, 6H, J=7 Hz), 1.71(s, 6H), 3.14(m, IH),
3.26(s, 4H), 7.02(d, IH, J=8 Hz), 7.64(d, 2H, J=8 Hz), 7.80(dd, IH, J=2 Hz, 8 Hz), 8.00(d, 2H, J=8 Hz), 8.03(d, IH, J=2 Hz)
[00613] Example 35. [4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyI-4- oxazoly 1] propionyl] -2-chlorophenoxy ] acetic acid.
Figure imgf000084_0001
[00614] (1) Ethyl [4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]- 2- chlorophenoxy] acetate.
[00615] The desired compound was obtained in an analogous manner as in (1) of Example 2.
[00616] 1H-NMR (CDCl3, 400 MHz) δ: 1.28(t, 3H, J=7 Hz), 1.30(d, 6H, J=7 Hz),
2.96(t, 2H, J=7 Hz), 3.17(m, IH), 3.33(t, 2H, J=7 Hz), 4.27(q, 2H, J=7 Hz), 4.76(s, 2H),
6.83(d, IH, J=8 Hz), 7.30(dd, IH, J=2 Hz, 8 Hz), 7.49(d, IH, J=2 Hz), 7.8-7.9(m, 2H),
8.05(d, IH, J=8 Hz). [00617] (2) [4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]-2-chlo- rophenoxy] acetic acid
[00618] The desired compound was obtained in an analogous manner as in (2) of
Example 2.
[00619] White crystal (mp: 134-137° C.) [00620] 1H-NMR (CDCl3, 400 MHz) δ: 1.3 l(d, 6H, J=7 Hz), 2.96(t, 2H, J=7 Hz),
3.19(m, IH), 3.30(t, 2H, J=7 Hz), 4.78(s, 2H), 6.84(d, IH, J=8 Hz), 7.31(dd, IH, J=2 Hz, 8
Hz), 7.49(d, IH, J=2 Hz), 7.81(dd, IH, 3=2 Hz, 8 Hz), 7.84(d, IH, J=8 Hz), 8.03(d, IH, J=2
Hz).
[00621] IR (KBr) cm'1: 3437, 1720, 1687, 1593, 1562, 1497, 1458, 1406, 1221, 1203, 1088, 1038, 833, 808, 744, 692. [00622] Example 36. 2-[4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4- oxazolyl]propionyl]-2-chlorophenoxy]-2-methylpropionic acid.
Figure imgf000085_0001
[00623] (1) Ethyl 2-[4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl- ]- 2-chlorophenoxy]-2-methylpropionate.
[00624] The desired compound was obtained in an analogous manner as in (2) of
Example 1.
[00625] 1H-NMR (CDCl3, 400 MHz) δ: 1.23(t, 3H, J=7 Hz), 1.30(d, 6H, J=7 Hz),
1.67(s, 6H), 2.95(t, 2H, J=7 Hz), 3.17(m, IH), 3.31(t, 2H, J=7 Hz)5 4.23(q, 2H, J=7 Hz), 6.80(d, IH, J=9 Hz), 7.30(dd, IH, J=2 Hz, 9 Hz), 7.49(d, IH, J=2 Hz), 7.77(dd, IH, J=2 Hz, 9
Hz), 7.88(d, IH, J=9 Hz), 8.03(d, IH, J=2 Hz).
[00626] (2) 2- [4- [3 - [2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl] -2-ch- lorophenoxy] -2-methylpropionic acid.
[00627] The desired compound was obtained in an analogous manner as in (3) of Example 1.
[00628] White crystal (mp: 76-79° C.)
[00629] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(d, 6H, J=7 Hz), 1.68(s, 6H), 2.95(t, 2H,
J=7 Hz), 319(m, IH), 3.29(t, 2H, J=7 Hz), 6.97(d, IH, J=9 Hz), 7.29(dd, IH, J=2 Hz, 9 Hz),
7.48(d, IH, J=2 Hz), 7.72(dd, IH, J=2 Hz, 8 Hz), 7.84(d, IH, J=8 Hz), 8.02(d, IH, J=2 Hz). [00630] IR (KBr) cm"1: 2968, 1720, 1686, 1593, 1562, 1493, 1460, 1402, 1385, 1306,
1259, 1200, 1180, 1146, 1059, 968, 902, 879, 822, 777, 739, 700, 571.
[00631] Example 37. [4-[3-[5-Isopropyl-2-(4-trifluoromethyl)phenyl-4- thiazolyl]propionyl]-2-methylphenoxy]acetic acid.
Figure imgf000085_0002
[00632] (1) [4-[3-[5-Isopropyl-2-(4-trifluoromethyl)phenyl-4-thiazolyl]propionyl]~ 2- methylphenoxy] ethyl acetate.
[00633] The desired compound was obtained in an analogous manner as in (1) of
Example 2. [00634] 1H-NMR (CDCl3, 400 MHz) δ: 1.29(t, 3H, J=7 Hz), 1.33(d, 6H, J=7 Hz),
2.3 l(s, 3H), 3.14(t, 2H, J=7 Hz), 3.37(m, IH), 3.43(t, 2H, J=7 Hz), 4.26(q, 2H, J=7 Hz),
4.70(s, 2H), 6.70(d, IH, J=9 Hz), 7.63(d, 2H, J=8 Hz), 7.8-7.9(m, 2H), 7.95(d, 2H, J=8 Hz).
[00635] (2) [4-[3-[2-(4-Trifluoromethyl)phenyl-5-isopropyl-4-thiazolyl]propionyl]~ 2- methylphenoxy] acetic acid.
[00636] The desired compound was obtained in an analogous manner as in (2) of
Example 2.
[00637] White crystal (mp: 125-132° C.)
[00638] 1H-NMR (CDCl3, 400 MHz) δ: 1.33(d, 6H, J=7 Hz), 2.30(s, 3H), 3.14(t, 2H5 J=7 Hz), 3.37(m, IH), 3.42(t, 2H, J=7 Hz), 4.74(s, 2H), 6.73(d, IH, J=9 Hz), 7.63(d, 2H, J=8
Hz), 7.8-7.9(m, 2H), 7.94(d, 2H, J=8 Hz).
[00639] IR (KBr) cm'1: 3425, 2964, 1751, 1686, 1603, 1581, 1504, 1433, 1410, 1365,
1329,1252, 1173,1132,1111, 1068,1018,989,841,815,675,611.
[00640] Example 38. 2-[4-[3-[5-IsopropyI-2-(4-trifluoromethyl)phenyl-4- thiazolyl]propionyl]-2-methylphenoxy]-2-methylpropionic acid.
Figure imgf000086_0001
[00641] (1) Ethyl [4-[3-[5-isopropyl-2-(4-trifluoromethyl)phenyl-4-thiazolyl]propi- onyl]-2-methylphenoxy]-2-methylpropionat.
[00642] The desired compound was obtained in an analogous manner as in (2) of Example 1.
[00643] 1H-NMR (CDCl3, 400 MHz) δ: 1.21(t, 3H, J=7 Hz), 1.33(d, 6H, J=7 Hz),
1.64(s, 6H), 2.25(s, 3H), 3.14(t, 2H, J=7 Hz), 3.36(m, IH), 3.41(t, 2H, J=7 Hz), 4.21(q, 2H,
J=7 Hz), 6.61(d, IH, J=8 Hz), 7.63(d, 2H, J=8 Hz), 7.74(dd, IH, J=2, 8 Hz), 7.81(bs, IH),
7.95(d, 2H, J=8 Hz). [00644] (2) 2-[4-[3-[5-Isopropyl-2-(4-trifluoromethyl)phenyl-4-thiazolyl]propionyl- ]-
2-methylphenoxy]-2-methylpropionic acid.
[00645] The desired compound was obtained in an analogous manner as in (3) of
Example 1.
[00646] White crystal (mp: 89-93° C.) [00647] 1H-NMR (CDCl3, 400 MHz) δ: 1.34(d, 6H, J=7 Hz), 1.67(s, 6H), 2.25(s, 3H),
3.14(t, 2H, J=7 Hz), 3.38(m, IH), 3.40(t, 2H, J=7 Hz), 6.75(d, IH, J=8 Hz), 7.63(d, 2H, J=8
Hz), 7.72(dd, IH, J=2 Hz, 8 Hz), 7.82(d, IH, J=2 Hz), 7.93(d, 2H, J=8 Hz). [00648] IR (KBr) cm-1: 2964, 1720, 1678, 1601, 1498, 1458, 1410, 1365, 1325, 1257,
1169, 1135, 1068, 1016, 972, 847, 771, 606.
[00649] Example 39. [4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4- thiazolyl]propionyl]-2-methylphenoxy]acetic acid.
Figure imgf000087_0001
[00650] (1) [4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-thiazolyl]propionyl]-2-met- hylphenoxy] acetic acid.
[00651] The desired compound was obtained in an analogous manner as in (2) of
Example 2. [00652] White crystal (mp: 158-161° C.)
[00653] 1H-NMR (CDCl3, 400 MHz) δ: 1.34(d, 6H, J=7 Hz), 2.29(s, 3H), 3.15(t, 2H,
J=7 Hz), 3.37(m, IH), 3.40(t, 2H, J=7 Hz), 4.73(s, 2H), 6.71 (d, IH, J=8 Hz), 7.2-7.3(m, IH),
7.47(d, IH, J=2 Hz), 7.7-7.9(m, 2H), 8.03(d, IH, J=8 Hz).
[00654] IR (KBr) cm'1: 2953, 1740, 1664, 1602, 1583, 1551, 1504, 1475, 1429, 1363, 1317, 1277, 1254, 1244, 1176.1132, 1103, 1063, 989, 887, 862, 821, 777, 683.
[00655] Example 40. 2-[4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyI-4- thiazoIyl]propionyl]-2-methylphenoxy]-2-methylpropionic acid.
Figure imgf000087_0002
[00656] (1) Ethyl 2-[4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-thiazolyl]propiony- 1]- 2-methylphenoxy] -2-methylpropionat.
[00657] The desired compound was obtained in an analogous manner as in (2) of
Example 1.
[00658] 1H-NMR (CDCl3, 400 MHz) δ: 1.21(t, 3H, J=7 Hz), 1.34(d, 6H, J=7 Hz),
1.62(s, 6H), 2.25(s, 3H), 3.14(t, 2H, J=7 Hz), 3.36(m, IH), 3.40(t, 2H, J=7 Hz), 4.22(q, 2H, J=7 Hz), 6.60(d, IH, J=9 Hz), 7.27(dd, IH, J=2, 9 Hz), 7.47(d, IH, J=2 Hz), 7.73(dd, IH, J=2
Hz, 8 Hz), 7.81(bs, IH), 8.07(d, IH, J=8 Hz).
[00659] (2) 2-[4-[3-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-thiazolyl]propionyl]-2-m- ethylphenoxy]-2-methylpropionic acid.
[00660] The desired compound was obtained in an analogous manner as in (3) of Example 1. [00661] White amorphous.
[00662] 1H-NMR (CDCl3, 400 MHz) δ: 1.34(d, 6H, J=7 Hz), 1.66(s, 6H), 2.25(s, 3H),
3.14(t, 2H5 3=7 Hz), 3.38(m, IH), 3.39(t, 2H, 3=7 Hz), 6.73(d, IH, J=8 Hz), 7.26(dd, IH, J=2
Hz, 9 Hz), 7.46(d, IH, 3=2 Hz), 7.70(dd, IH, J=2 Hz, 8 Hz), 7.8 l(d, IH, J=2 Hz), 8.02(d, IH,
J=8 Hz).
[00663] Example 41. [5-[3-[4-IsopropyI-2-(4-trifluoromethyl)phenyl-5- thiazolyl]propionyl]-2-methyIphenoxy] acetic acid.
Figure imgf000088_0001
[00664] (1) Ethyl [5-[3-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]ρropi- onyl]-2-methylphenoxy]acetate.
[00665] The desired compound was obtained in an analogous manner as in (1) of
Example 2.
[00666] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(t, 3H, 3=7 Hz), 1.33(d, 6H, J=7 Hz),
2.35(s, 3H), 3.14(m, IH), 3.2-3.3(m, 4H), 4.26(q, 2H, 3=7 Hz), 4.71(s, 2H), 7.24(d, IH, 3=7 Hz), 7.35(d, IH, 3=2 Hz), 7.49(dd, IH, 3=2 Hz, 7 Hz), 7.64(d, 2H, J=8 Hz), 8.00(d, 2H, J=8
Hz).
[00667] (2) [5-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propionyl]- 2- methylphenoxy] acetic acid.
[00668] The desired compound was obtained in an analogous manner as in (2) of Example 2.
[00669] Pale yellow crystal (mp: 130-133° C.)
[00670] 1H-NMR (DMSOd6, 400 MHz) δ: 1.28(d, 6H, 3=7 Hz), 2.26(s, 3H), 3.1-
3.3(m, 3H), 3.38(t, 2H, 3=7 Hz), 4.77(s, 2H), 7.30(d, IH, J=8 Hz), 7.35(s, IH), 7.55(d, IH,
J=8 Hz), 7.8l(d, 2H, J=8 Hz), 8.05(d, 2H, J=8 Hz). [00671] IR (KBr) cm"1: 2968, 2931, 2872, 1767, 1741, 1678, 1618, 1616, 1579, 1533,
1506, 1450, 1412, 1362, 1327, 1294, 1242, 1167, 1126, 1124, 1122, 1068, 1016, 978, 874,
847, 777, 609.
[00672] Example 42. 2-[5-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5- thiazolyl]propionyl]-2-methylphenoxy]-2-methylpropionic acid.
Figure imgf000088_0002
[00673] (1) Ethyl 2-[5-[3-[4-isopropyl-2-(4-trifluoromethylphenyl)-5-thiazolyl]pro- pionyl]-2-methylphenoxy]-2-methylpropionate.
[00674] The desired compound was obtained in an analogous manner as in (2) of
Example 1. [00675] 1H-NMR (CDCl3, 400 MHz) δ: 1.26(t, 3H, J=7 Hz), 1.33(d, 6H, J=7 Hz),
1.63(s, 6H), 2.29(s, 3H), 3.14(m, IH), 3.2-3.4(m, 4H), 4.26(q, 2H, J=7 Hz), 7.22(d, IH, J=8
Hz), 7.3 l(d, IH, J=2 Hz), 7.47(dd, IH, J=2 Hz, 8 Hz), 7.64(d, 2H, J=8 Hz), 8.00(d, 2H, J=8
Hz)
[00676] (2) 2-[5-[3-[4-Isopropyl-2-(4-trifluoromethylphenyl)-5-thiazolyl]propionyl- ]- 2-methylphenoxy]-2-methylpropionic acid.
[00677] The desired compound was obtained in an analogous manner as in (3) of
Example 1.
[00678] White crystal (mp: 124-126° C.)
[00679] 1H-NMR (DMSOd6, 400 MHz) δ: 1.27(d, 6H, J=7 Hz), 1.54(s, 6H), 2.22(s, 3H), 3.1-3.4(m, 5H), 7.30(s, LH), 7.31(d, IH, J=8 Hz), 7.56(d, IH, J=8 Hz), 7.81(d, 2H, J=8
Hz), 8.05(d, 2H, J=8 Hz), 13.12(bs, IH)
[00680] IR(KBr) cm-1: 2972, 1736, 1684, 1618, 1616, 1498, 1452, 1412, 1327, 1259,
1167, 1130, 1068, 1016, 972, 845, 777.
[00681] Example 43. 2-[4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5- thiazolyl]propionyl]-2-methylphenoxy] propionic acid.
Figure imgf000089_0001
[00682] (1) Ethyl 2-[4-[3-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]pro- pionyl]-2-methylphenoxy]propionate.
[00683] Intermediate of Example 3, namely 3-[2-(4-trifluoromethyl)phenyl-4~ isopropyl-5-thiazolyl]-l-(3-methyl-4-hydroxyphenyl)propan-l-one (433 mg, 1.00 mmol) and potassium carbonate (166 mg, 1.20 mmol) was suspended in acetone (10 mL). To the suspension, ethyl 2-bromopropionate (216 mg, 1.20 mmol) was added while cooling with ice.
The mixture was stirred for 20 hours at room temperature. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water (20 mL) and a saturated saline (20 mL), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (5/1) to give the desired compound (534 mg) as a colorless oil (quantitative yield).
[00684] 1H NMR (CDCl3, 400 MHz) δ: 1.24(t, 3H, J=7 Hz), 1.33(d, 6H, J=7 Hz),
1.66(d, 3H, J=7 Hz), 2.31(s, 3H), 3.15(dq, IH, J=7 Hz, 7 Hz), 3.2-3.3(m, 4H), 4.20(q, 2H, J=7 Hz), 4.82(q, IH, J=7 Hz), 6.68(d, IH, J=8 Hz), 7.64(d, 2H, J=8 Hz), 7.76(dd, IH, J=2
Hz, 8 Hz), 7.80(d, IH, J=2 Hz), 8.00(d, 2H, J=8 Hz).
[00685] (2) 2-[4-[3-[4-Isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propionyl- ]-
2-methylphenoxy]propionic acid.
[00686] The desired compound was obtained in an analogous manner as in (2) of Example 2.
[00687] White crystal (mp: 120-123° C.)
[00688] 1H-NMR (CDCl3, 400 MHz) δ: 1.33(d, 6H, J=7 Hz), 1.70(d, 3H, J=7 Hz),
2.3 l(s, 3H), 3.15(dq, IH, J=7 Hz, 7 Hz), 3.2-3.3(m, 4H), 4.88(q, IH, J=7 Hz), 6.73(d, IH,
J=9 Hz), 7.63(d, 2H, J=8 Hz), 7.77(dd, IH, J=2, 9 Hz), 7.80(d, IH, J=2 Hz), 7.99(d, 2H, J=8 Hz).
[00689] [0386] IR (KBr) cm'1: 2950, 1740, 1670, 1600, 1500, 1450, 1320, 1300, 1275,
1250, 1190, 1160, 1130, 1060, 845.
[00690] Example 44. 4-[3-[4-Methyl-2-(4-trifluoromethyl)phenyl-5- thiazoIyl]propionyl]-2-methyl- phenoxy] acetic acid.
Figure imgf000090_0001
[00691] (1) Ethyl [4-[3-[4-methyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propiony-
1] -2-methylphenoxy] acetate .
[00692] The desired compound was obtained in an analogous manner as in (1) of
Example 2. [00693] 1H-NMR (CDCl3, 400 MHz) δ: 1.29(t, 3H, J=7 Hz), 2.3 l(s, 3H), 2.46(s, 3H),
3.2-3.3(m, 4H), 4.26(q, 2H, J=7 Hz), 4.70(s, 2H), 6.71(d, IH, J=8 Hz), 7.64(d, 2H, J=8 Hz),
7.76(dd, IH, J=2 Hz, 8 Hz), 7.80(d, IH, J=2 Hz), 7.97(d, 2H, J=8 Hz).
[00694] (2) [4-[3-[4-Methyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propionyl]-2-m- ethylphenoxy] acetic acid. [00695] The desired compound was obtained in an analogous manner as in (1) of
Example 2.
[00696] White crystal (mp: 194-195° C.) [00697] 1H-NMR (CDCl3, 400 MHz) δ: 2.32(s, 3H), 2.45(s, 3H), 3.2-3.3(m, 4H),
4.75(s, 2H), 6.74(d, IH, J=8 Hz), 7.64(d, 2H, J=8 Hz), 7.7-7.9(m, 2H), 7.96(d, 2H, J=8 Hz).
[00698] [0392] IR (KBr) cm"1: 3500, 2900, 1780, 1730, 1680, 1610, 1500, 1410, 1370,
1330,1240,1180,1080,850.
[00699] Example 45. 2-[4-[3-[4-Hexyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]-l- propenyI]-2-methylphenoxy]-2-methylpropionic acid.
Figure imgf000091_0001
[00700] (1) Ethyl 2-[4-[3-[4-hexyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]-l-prop- enyl] -2-methylphenoxy] -2-methylpropionate . [00701] The desired compound was obtained in an analogous manner as in (1) of
Example 9 and (2) of Example 1.
[00702] 1H-NMR (CDCl3, 400 MHz) δ: 0.88(t, 3H, J=7 Hz), 1.25(t, 3H, J=7 Hz), 1.3-
1.5(m, 6H), 1.58(s, 6H), 1.7-1.8(m, 2H), 2.22(s, 3H), 2.74(t, 2H, J=7 Hz), 3.65(d, 2H, J=6
Hz), 4.24(q, 2H, J=7 Hz), 6.16(dt, IH, J=6 Hz, 16 Hz), 6.40(d, IH, J= 16 Hz), 6.60(d, IH, J=8 Hz), 7.04(dd, IH, J=2, 8 Hz), 7.16(d, IH, J=2 Hz), 7.64(d, 2H, J=8 Hz), 7.99(d, 2H, J=8 Hz)
[00703] (2) 2-[4-[3-[4-Hexyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]- 1 -propenyl]- 2- methylphenoxy] -2-methylpropionic acid.
[00704] The desired compound was obtained in an analogous manner as in (3) of
Example 1. [00705] Pale brown powder (mp: 152-155° C.)
[00706] 1H-NMR (CDCl3, 400 MHz) δ: 0.88(t, 3H, J=7 Hz), 1.2-1.5(m, 6H), 1.61(s,
6H), 1.7-1.8(m, 2H), 2.23(s, 3H), 2.74(t, 2H, J=7 Hz), 3.66(d, 2H, J=6 Hz), 6.20(dt, IH, J=6
Hz, 16 Hz), 6.41(d, IH, J=16 Hz), 6.78(d, IH, J=8 Hz), 7.09(dd, IH, J=2 Hz, 8 Hz), 7.19(d,
IH, J=2 Hz), 7.64(d, 2H, J=8 Hz), 7.99(d, 2H, J=8 Hz). [00707] IR (KBr) cm"1: 2920, 1700, 1610, 1500, 1445, 1320, 1250, 1160, 1120, 1060,
900, 840.
[00708] Example 46. 2-[5-[3-[4-Hexyl-2-(4-trifluoromethyl)phenyl-5- thiazolyl]propionyl]-2-methylphenoxy]-2-methylpropionic acid.
Figure imgf000091_0002
[00709] (1) Ethyl 2-[5-[3-[4-hexyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propion- yl]-2-methylphenoxy]-2-methylpropionate.
[00710] The desired compound was obtained in an analogous manner as in (2) of
Example 1. [00711] 1H-NMR (CDCl3, 400 MHz) δ: 0.89(t, 3H, J=7 Hz), 1.26(t, 3H, J=7 Hz), 1.3-
1.4(m, 6H), 1.54(s, 6H), 1.7-1.8(m, 2H), 2.29(s, 3H), 2.74(t, 2H, J=8 Hz), 3.2-3.3(m, 4H),
4.26(q, 2H, J=7 Hz), 7.22(d, IH, J=8 Hz), 7.3 l(d, 2H, J=8 Hz), 7.47(dd, IH, J=2 Hz, 8 Hz),
7.64(d, IH, J=2 Hz), 7.98(d, 2H, J=8 Hz).
[00712] (2) 2-[5-[3-[4-Hexyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propionyl]-2- methylphenoxy] -2-methylpropionic acid.
[00713] The desired compound was obtained in an analogous manner as in (3) of
Example 1.
[00714] Yellow Oil.
[00715] 1H-NMR (CDCl3, 400 MHz) δ: 0.88(t, 3H, J=7 Hz), 1.2-1.4(m, 6H), 1.64(s, 6H), 1.7-1.8(m, 2H), 2.29(s, 3H), 2.73(t, 2H, J=7 Hz), 3.2-3.3(m, 4H), 7.25(d, IH, J=8 Hz),
7.43(s, IH)5 7.50(d, IH, J=8 Hz), 7.62(d, 2H, J=8 Hz), 7.96(d, 2H, J=8 Hz)
[00716] Example 47. [4-[3-[4-Ethyl-2-(4-trifluoromethyl)phenyl-5- thiazolyl]propionyl]-2-methyl-phenoxy]acetic acid.
Figure imgf000092_0001
[00717] (1) Ethyl [4-[3-[4-ethyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propionyl-]-2- methylphenoxy] acetate .
[00718] The desired compound was obtained in an analogous manner as in (1) of
Example 2.
[00719] 1H-NMR (CDCl3, 400 MHz) δ: 1.30(t, 3H, J=7 Hz), 1.32(t, 3H, J=7 Hz), 2.33(s, 3H), 2.79(q, 2H, J=7 Hz), 3.2-3.3(m, 4H), 4.27(q, 2H, J=7 Hz), 4.71(s, 2H), 6.71(d,
IH, J=8 Hz), 7.64(d, 2H, J=8 Hz), 7.8-7.9(m, 2H), 7.99(d, 2H, J=8 Hz).
[00720] (2) [4-[3-[4-Ethyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propionyl]-2-me- thylphenoxy] acetic acid.
[00721] The desired compound was obtained in an analogous manner as in (2) of Example 2.
[00722] White crystal (mp: 165-167° C.) [00723] 1H-NMR (CDCl3, 400 MHz) δ: 1.31(t, 3H, 5=7 Hz), 2.32(s, 3H), 2.79(q, 2H,
5=7 Hz), 3.2-3.3(m, 4H), 4.76(s, 2H), 6.74(d, IH, J=8 Hz), 7.64(d, 2H, J=8 Hz), 7.80(dd, IH,
5=2, 8 Hz), 7.8 l(d, IH, 5=2 Hz), 7.97(d, 2H, J=8 Hz).
[00724] IR (KBr) cm"1: 2975, 1760, 1740, 1670, 1610, 1600, 1580, 1500, 1440, 1360,
1320, 1260, 1220, 1160, 1130, 1110, 1960, 840, 820.
[00725] Example 48. 2-[4-[3-[4-Ethyl-2-(4-trifluoromethyl)phenyl-5- thiazolyl]propionyl]-2-methyIphenoxy]-2-methylpropionic acid.
Figure imgf000093_0001
[00726] (1) Ethyl 2-[4-[3-[4-ethyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]propion- yl]-2-methylphenoxy]-2-methylpropionate.
[00727] The desired compound was obtained in an analogous manner as in (2) of
Example 1.
[00728] 1H-NMR (CDCl3, 400 MHz) δ: 1.21(t, 3H, J=7 Hz), 1.32(t, 3H, J=7 Hz),
1.55(s, 6H), 2.27(s, 3H), 2.79(q, 2H, J=7 Hz), 3.2-3.3(m, 4H), 4.22(q, 2H, J=7 Hz), 6.62(d, IH, J=8 Hz), 7.64(d, 2H, J=8 Hz), 7.69(dd, IH, J=2, 8 Hz), 7.79(d, IH, 5=2 Hz), 7.99(d, 2H,
J=8 Hz).
[00729] (2) 2- [4-[3 - [4-Ethyl-2-(4-trifluoromethyl)phenyl-5 -thiazolyljpropionyl] -2- methylphenoxy] -2-methylpropionic acid.
[00730] The desired compound was obtained in an analogous manner as in (3) of Example 1.
[00731] White crystal (mp: 168-170° C.)
[00732] 1H-NMR (CDCl3, 400 MHz) δ: 1.3 l(t, 3H, 5=7 Hz), 1.69(s, 6H), 2.27(s, 3H),
2.78(q, 2H, 5=7 Hz), 3.2-3.3(m, 4H), 6.75(d, IH, J=8 Hz), 7.63(d, 2H, J=8 Hz), 7.72(dd, IH,
5=2, 8 Hz), 7.80(d, IH, 5=2 Hz), 7.97(d, 2H, J=8 Hz). [00733] IR (KBr) cm"1: 2950, 1720, 1680, 1660, 1580, 1540, 1440, 1400, 1360, 1320,
1260, 1160, 1120, 1060, 960, 840, 820.
[00734] Example 49. [4-[3-[4-Isopropyl-2-(4-methylphenyl)-5- thiazolyl]propionyl]-2-methylphenoxy]acetic acid.
Figure imgf000093_0002
[00735] (1) Ethyl [4-[3-[4-isopropyl-2-(4-methylphenyl)-5-thiazolyl]propionyl]-2-m- ethylphenoxy] acetate.
[00736] The desired compound was obtained in an analogous manner as in (1) of
Example 2. [00737] 1H-NMR (CDCl3, 400 MHz) δ: 1.29(t, 3H, J=7 Hz), 1.3 l(d, 6H, J=7 Hz),
2.32(s, 3H), 2.37(s, 3H), 3.12(dq, IH, J=7 Hz, 7 Hz), 3.2-3.3(m, 4H), 4.27(q, 2H, J=7 Hz),
4.70(s, 2H), 6.7 l(d, IH, J=8 Hz), 7.19(d, 2H, J=8 Hz), 7.7-7.8(m, 4H).
[00738] (2) [4-[3-[4-Isopropyl-2-(4-methylphenyl)-5-thiazolyl]propionyl]-2-methylp- henoxy] acetic acid. [00739] The desired compound was obtained in an analogous manner as in (2) of
Example 2.
[00740] White crystal (mp: 188-190° C.)
[00741] 1H-NMR (CDCl3, 400 MHz) δ: 1.32(d, 6H, J=7 Hz), 2.32(s, 3H), 2.37(s, 3H),
3.12(dq, IH, J=7 Hz, 7 Hz), 3.2-3.3(m, 4H), 4.75(s, 2H), 6.73(d, IH, J=8 Hz), 7.18(d, 2H, J=8 Hz), 7.7-7.8(m, 4H).
[00742] IR (KBr) cnT1: 2950, 1720, 1670, 1600, 1580, 1500, 1440, 1360, 1310, 1280,
1210,1180,1120,1060,820.
[00743] Example 50. 2-[4-[3-[4-Isopropyl-2-(4-methylphenyl)-5- thiazoly 1] propiony 1] -2-methy Iphenoxy ] -2-methylpropionic acid .
Figure imgf000094_0001
[00744] (1) Ethyl 2-[4-[3-[4-isopropyl-2-(4-methylphenyl)-5-thiazolyl]propionyl]-2- - methylphenoxy]-2-methylpropionate.
[00745] The desired compound was obtained in an analogous manner as in (2) of
Example 1. [00746] 1H-NMR (CDCl3, 400 MHz) δ: 1.21(t, 3H, J=7 Hz), 1.32(d, 6H, J=7 Hz),
1.65(s, 6H), 2.26(s, 3H), 2.37(s, 3H), 3.1 l(dq, IH, J=7 Hz, 7 Hz), 3.2-3.3(m, 4H), 4.22(q, 2H,
J=7 Hz), 6.6 l(d, IH, J=8 Hz), 7.19(d, 2H, J=8 Hz), 7.69(dd, IH, J=2, 8 Hz), 7.7-7.8(m, 3H).
[00747] (2) 2-[4-[3-[4-Isopropyl-2-(4-methylphenyl)-5-thiazolyl]propionyl]-2-methy- lphenoxy] -2-methylpropionic acid. [00748] The desired compound was obtained in an analogous manner as in (3) of
Example 1.
[00749] Yellow Amorphous. [00750] 1H-NMR (CDCl3, 400 MHz) δ: 1.31(d, 6H, J=7 Hz), 1.67(s, 6H), 2.27(s, 3H),
2.36(s, 3H), 3.1 l(dq, IH, J=7 Hz, 7 Hz), 3.2-3.3(m, 4H), 6.72(d, IH, J=8 Hz), 7.18(d, 2H, J=8 Hz), 7.70(d, IH, J=8 Hz), 7.72(d, 2H, J=8 Hz), 7.79(s, IH).
[00751] Example 51. 3-[2-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazoIyl]ethyl]- 5-methyl-l,2-benzisoxazol-6-yl]oxyacetic acid.
[00752] (l) 6-Acetamido-3-[2-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]ethyl]-
1,2-benzisoxazole.
[00753] 6-Acetamido-3,5-methyl-l,2-benzisoxazole (5.10g, 25.0mmol) was dissolved in dry THF (150 mL). 2M of LDA (27mL, 54 mmol) was dropwise added to the solution for 30 minutes under nitrogen atmosphere at -80- -75°C. A solution of 4-iodomethyl-5- isopropyl-2-(2,4-dichlorophenyl)oxazole (9.9Og, 25.0 mmol) in THF 25 mL was dropwise added to the resulting mixture for 15 minutes at -80 — 70°C. The mixture was stirred for 1 hour under the same conditions. The mixture was allowed to at 10°C . A saturated aqueous ammonium chloride solution and ethyl acetate were added to the mixture. The organic layer was washed with water and saline, and dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform/methanol (200/1) to give the desired compound (5.34g) as pale yellow crystal(yield 45%). [00754] 1H-NMR (CDCl3, 400MHz) δ :1.10 (d, 6H, J=7Hz), 2.24 (bs, 3H), 2.26 (s, 3H), 2.92 (m, IH), 3.05 (t, 2H, J=7Hz), 3.33 (t, 2H, J=7Hz), 7.16 (bs, IH), 7.28 (s, IH), 7.32 (dd, IH, J=2,9Hz), 7.51 (d, IH, J=2Hz), 7.91 (d, IH, J=9Hz), 8.34 (bs, IH). [00755] ( 2) 6-Amino-3-[2-[2- (2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]ethyl]-5- methyl-1 ,2-benzisoxazole. [00756] The obtained 6-acetamido-3-[2-[2-(2,4-dichlorophenyl)-5-isopropyl-4- oxazolyl]ethyl]-l,2-benzisoxazole (13.7g, 29.0mmol) was reacted in 3N hydrochloric acid (40OmL) and acetic acid(200mL) at 100°C for 16 hours. The reaction mixture was allowed to room temperature, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saline, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (2/1) to give the desired compound (10.4g) as colorless oil(yield 83%).
[00757] 1H-NMR (CDCl3, 400MHz) δ :1.10 (d, 6H, J=7Hz), 2.14 (s, 3H), 2.92 (m,
IH), 3.03 (t, 2H, J=7Hz), 3.27 (t, 2H, J=7Hz),3.97 (bs, 2H), 6.72 (s, IH), 7.13 (s, IH), 7.32 (dd, IH, J=2,8Hz), 7.51 (d, IH, J=2Hz), 7.92 (d, IH, J=8Hz). [00758] ( 3) 3-[2-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]ethyl]- 6-hydroxy-5- methyl- 1 ,2-benzisoxazole
[00759] The product (12.2g, 27.4 mmol) was suspended in 25% sulfuric acid (134 mL), and cooled with ice. Sodium nitrite (2.46g, 35.6 mmol) was portionwise added to the suspension for 15 minutes. The resulting creamy suspension was stirred for 30 minutes under the same conditions. The reaction mixture was dropwise added to a 75% sulfuric acid (67 mL) while refluxing for 10 minutes, and the mixture was refluxed for 90 minutes. The reaction mixture was left to get cool, extracted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and saline, and dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform/methanol (50/1) to give the desired compound (7.9g) as pale brown crystal (yield 65%).
[00760] 1H-NMR (CDCl3, 400MHz) δ : 1.11 (d, 6H, J=7Hz), 2.22 (s, 3H), 2.92 (m,
IH), 3.05 (t, 2H, J=7Hz), 3.29 (t, 2H, J=7Hz), 6.15 (bs, IH), 6.88 (s, IH), 7.19 (s, IH), 7.32 (dd, IH, J=2,9Hz), 7.51 (d, IH, J=2Hz),7.90 (d, IH, J=9Hz).
[00761] ( 4) Ethyl [[3-[2-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]ethyl]-5- methyl- 1 ,2-benzisoxazol-6-yl]oxyacetate
[00762] The desired compound was obtained in an analogous manner as in (1) of
Example 2 (yield 93%). [00763] 1H-NMR (CDCl3, 400MHz) δ :
1.11 (d, 6H, J=7Hz), 1.30 (t, 3H, J=7Hz), 2.27 (s, 3H), 2.91 (m, IH), 3.04 (t, 2H, J=7Hz),
3.31 (t, 2H, J=7Hz), 4.28 (q, 2H, J=7Hz), 4.69 (s, 2H), 6.80 (s, IH), 7.24 (s, IH), 7.33 (dd,
IH, J=2,8Hz), 7.51 (d, IH, J=2Hz), 7.91 (d, IH, J=8Hz).
[00764] ( 5) [3-[2-[2-(2,4-Dichlorophenyl)-5-isopropyl-4-oxazolyl]ethyl]-5-methyl- 1 ,2-benzisoxazol-6-yl]oxyacetic acid
[00765] The desired compound was obtained in an analogous manner as in (3) of
Example 3 (yield 86%).
[00766] White crystal (mp (dec) 182- 184 ° C).
[00767] 1H-NMR (CDCl3, 400MHz) δ: 1.11 (d, 6H, J=7Hz), 2.26 (s, 3H), 2.93 (m, IH), 3.04 (t, 2H, J=7Hz), 3.30 (t, 2H, J=7Hz), 4.76 (s, 2H), 6.84 (s, IH), 7.23 (s, IH), 7.33
(dd, IH, J=2,8Hz), 7.52 (d, IH, J=2Hz),7.99 (d, IH, J=8Hz).
[00768] IR(KBr)Cm"1:1749, 1718, 1626, 1562, 1522, 1458, 1446, 1429, 1389, 1362,
1317, 1284, 1251, 1163, 1103, 1088, 1041, 899, 864, 831, 818, 775, 733, 674, 667, 611. [00769] Example 52. 4-[3-[4-Isopropyl-2-[(4-trifluoromethyl)phenyl]-5- thiazolyl] propionyl]-2-methylphenylthioacetic acid
[00770] ( 1 ) 1 -(4- Dimethylthiocarbamoyloxy -3 -methylphenyl)-3 - [4-isopropyl-2- [(4- trifluoromethyl)-phenyl]thiazol-5-yl]propan- 1 -one [00771] In dry dioxane (50 mL), l-(4-Hydroxy-3-methylphenyl)-3-[4-isopropyl-2-
[(4-trifluoromethyl)phenyl]thiazol-5-yl]propan-l-one (3.0g, 6.92mmol) obtained in (1) of Example 3, 4-dimethylaminopyridine (85mg, 0.69mmol) and triethylamine (1.93mL,13.8mmol). To the solution, dimethylthiocarbamoyl chloride (1.1 Ig, 9.00 mmol) was added while cooling with ice. The reaction temperature was increased, and refluxed over night.The reaction mixture was allowed to room temperature, and poured into ice water. Ethyl acetate was added to the mixture. The organic layer was washed with water, and a saline, dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (4/1), to give the desired compound (3.10g) as a colorless oil(yield 86%). [00772] l H-NMR (CDCl 3 , 400 MHz) δ: 1.34 (d, 6H, J=7 Hz), 2.26 (s, 3H), 3.16 (dq,
IH, J=7 Hz, J=7 Hz), 3.2-3.4(m,4H),3.37(s,3H),3.47(s,3H), 7.09 (d, IH, J=8 Hz), 7.64 (d, 2H, J=8Hz), 7.55(dd, IH, J=I, 8 Hz), 7.87 (d, IH, J=IHz), 8.00(d, 2H5 J=8 Hz). [00773] (2) l-(4- Dimethylcarbamoylsulfanyl -3-methylphenyl)-3-[4-isopropyl-2-[(4- trifluoromethyl)-phenyl] -thiazol-5 -yl]propan- 1 -one [00774] l-(4- Dimethylthiocarbamoyloxy -3-methylphenyl)-3-[4-isopropyl-2-[(4- trifluoromethyl)-phenyl]-thiazol-5-yl]propan-l-one (3.05g , 5.86mmol) was dissolved in n-tetradecane (60 mL). The solution was refluxed at the internal temperature of 250° C for 10 hours. The mixture was allowed to room temperature. The reaction mixture was directly purified by column chromatography on silica gel with hexane/ethyl acetate (3/1) to give the desired compound (2.9Og) as a pale yellow solid (yield 95%).
[00775] ' H-NMR (CDCl 3 , 400 MHz) δ: 1.33(d, 6H, J=7 Hz), 2.47 (s, 3H), 3.0-3.2
(br, 6H), 3.16 (dq, IH, J=7 Hz, J=7 Hz), 3.2-3.4 (m, 4H), 7.59 (d, IH, J=8 Hz), 7.64(d, 2H, J=8 Hz), 7.76 (dd, IH, J=2, 8 Hz), 7.86 (d, IH, J=2 Hz), 8.00(d, 2H, J=8 Hz). [00776] (3) 3-[4-Isopropyl-2-[(4-trifluoromethyl)phenyl]thiazol-5-yl]- l-(3- methyl-4- mercaptophenyl)propan- 1 -one
[00777] l-(4- Dimethylcarbamoylsulfanyl -3-methylphenyl)-3-[4-isopropyl-2-[(4- trifluoromethyl)-phenyl]thiazol-5-yl]propan-l-one (2.85g, 5.47mmol) was dissolved in dry methanol (40 mL). To the solution, 0.5N MeONa (14.OmL, 7.1 lmmol) was added. The mixture was refluxed for 20hours, and allowed to room temperature. The mixture was poured into ice water. The mixture was neutralized with 3N hydrochloric acid. Ethyl acetate was added to the mixture. The organic layer was washed with water, and a saline, dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure to obtain the desired compound (2.50 g) as pale yellow solid(quantive yield). [00778] ' H-NMR (CDCl 3 , 400 MHz) δ: 1.33 (d, 6H, J=7 Hz), 2.36 (s, 3H), 3.14 (dq,
IH, J=7 Hz, J=7 Hz), 3.2-3.3 (m, 4H), 3.53 (s, IH), 7.38 (d, IH, J=8Hz), 7.6-7.7 (m, 3H),
7.74 (d, IH, J=2 Hz), 8.00 (d, IH, J=8 Hz).
[00779] (4) Ethyl 4-[3-[4-Isopropyl-2-[(4-trifluoromethyl)phenyl]-5- thiazolyl]propionyl]-2-methylphenylthioacetate [00780] The desired compound was obtained in an analogous manner as in (1) of
Example 2 (yield 85%).
[00781] Colorless oil.
[00782] ' H-NMR (CDCl 3 , 400 MHz) δ: 1.26(t,3H,J=7Hz),l .33(d, 6H, J=7 Hz), 2.40
(s, 3H), 3.15 (dq, IH. J=7 Hz, J=7 Hz), 3.2-3.4(m, 4H), 3.74 (s, 2H), 4.20(q, 2H, J=7Hz),7.31(1H, d, J=8Hz), 7.63 (d, 2H, J=8 Hz), 7.75 (d, IH, J=8 Hz), 7.75 (d, IH, J=2 Hz),
7.99 (d, IH, J=8 Hz).
[00783] (5) 4- [3 - [4-Isopropyl-2- [(4-trifluoromethyl)phenyl] -5 -thiazolyl]propionyl]-2- methylphenylthioacetic acid
[00784] The desired compound was obtained in an analogous manner as in (3) of Example 3 using the obtained ester compound (yield 78%).
[00785] White powder (mp: 152-153° C).
[00786] ' H-NMR (CDCl 3 , 400 MHz) δ: 1.33(d, 6H, J=7 Hz), 2.40 (s, 3H), 3.15 (dq,
IH. J=7 Hz, J=I Hz), 3.2-3.4(m, 4H), 3.98 (s, 2H), 7.3O(1H, d, J=8Hz), 7.64 (d, 2H, J=8 Hz),
7.76 (d, IH, J=8 Hz), 7.77 (d, IH, J=2 Hz), 7.99 (d, IH, J=8 Hz). [00787] IR(KBr)Cm-1:3095, 2967, 2910, 2869, 1706, 1675, 1616, 1592, 1511, 1442,
1407, 1382, 1359, 1326, 1297, 1272, 1232, 1222, 1218, 1170, 1120, 1118, 1116, 1070, 1066,
1064, 1010, 993, 890, 844, 819, 781, 779.
[00788] Example 53. (4-{l-(R,S)-Hydroxy-3-[4-isopropyl-2-(4- trifluoromethyIphenyl)-thiazol-5-yl]-propyl}-2-methyl-phenoxy)-acetic acid [00789] 4-{3-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propionyl}-2- methyl-phenoxy)-acetic acid (3.5 g, 7.13 mmol) was dissolved in a mixture of sodium hydroxide (0.284 g, 7.13 mmol), water (3.5 mL), and isopropanol (11 mL). Sodium borohydride (0.27 g, 7.13 mmol) was added in portion to the solution. After addition of the sodium borohydride, the reaction mixture was heated to 50-70 °C (oil bath temperature) for 2 hours, then room temperature overnight. Ice-water (35 mL) was added to the reaction mixture. Any non-polar material was extracted with methyl tert-butyl ether (2 x 35 mL), which was discarded. The aqueous solution was adjusted with acetic acid to pH = 6 and was extracted with methyl tert-butyl ether (3 x 40 mL). The combined methyl tert-butyl ether extracts were washed with water (2 x 30 mL) and brine (30 mL). The ether solution was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The experiment provided (4- { 1 -(R,S)-Hydroxy-3-[4-isopropyl-2-(4-trifIuoromethylphenyl)-thiazol-5-yl]- propyl}-2-methyl-phenoxy)-acetic acid (2.8 g, 79.3% yield, Mp 136-137 °C, 99.4% purity by HPLC) as a white powder. [00790] 1H NMR (Field: 300 MHz, Solvent: DMSO-de/TMS) δ (ppm): 12.95 (br, IH),
8.08 (d, 2H, J= 8.1 Hz), 7.84 (d, 2H, J= 8.1 Hz), 7.15 (s, IH), 7.12 (d, IH, J= 8.1 Hz), 6.79 (d, IH, J= 8.1 Hz), 5.27 (br, IH), 4.68 (s, 2H), 4.52 (m, IH), 3.08 (m, IH), 2.89 (t, 2H, J= 7.5 Hz), 2.21 (s, 3H), 1.93 (q, 2H, J =7.5 Hz), 1.27 (d, 6H, J =6.6 Hz). 13C NMR (Field: 75 MHz, Solvent: DMSO-d6/TMS) δ (ppm): 170.16, 160.58, 158.60, 154.63, 137.71, 137.00, 132.92, 128.71 (q, J= 31 Hz), 128.01, 126.09, 125.96, 125.31, 123.97, 110.69, 70.80, 64.74, 41.56, 27.55, 22.71, 22.09, 16.23.
[00791] Example 54. (4-{l-(R)-Hydroxy-3-[4-isopropyl-2-(4-trifluoromethyl- phenyl)-thiazol-5-yl]-propyl}-2-methylphenoxy)-acetic acid [00792] ( 1 ) (4- { 3 - [4-Isopropyl-2-(4-trifiuoromethylphenyl)-thiazol-5-yl] -propionyl } - 2-methylphenoxy)-acetic acid methyl ester.
[00793] 4-{3-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propionyl}-2- methyl-phenoxy)-acetic acid (18.01 g, 0.0409 mol) dissolved in DMF (120 mL) with iodomethane (60 mL) and potassium carbonate (10 g). The mixture stirred for 24 hours under an argon atmosphere at room temperature. The mixture was added to cold water (1 L) and the product was extracted with ethyl acetate (2x250 mL). The ethyl acetate fractions were combined, dried over sodium sulfate, filtered, and concentrated. The remaining oil was purified by column chromatography on silica gel (200 g), eluting with 1 : 1 heptane/ethyl acetate. The experiment provided (4-{3-[4-Isopropyl-2-(4-trifluoromethylphenyl)-thiazol-5- yl]-propionyl}-2-methylphenoxy)-acetic acid methyl ester (18.1 g, 96.2% yield) as a white solid (m.p. 93-94 0C).
[00794] 1H NMR (300 MHz, CDC13/TMS): δ = 7.99 (d, 2H, J= 6.6 Hz), 7.812 (m,
2H), 7.62 (d, 2H, J=6.6 Hz), 6.70 (d, IH, J= 7.2 Hz), 4.71 (br s, 2H), 3.78 (s, 3H), 3.35-3.10 (m, 5H), 2.31 (s, 3H), 1.34 (d, 6H, J= 5.1 Hz). 13C NMR (75 MHz, CDCl3ATMS): δ = 196.69, 168.73, 162.07, 160.00, 159.69, 137.37, 131.29, 130.11, 127.88, 127.59, 126.34, 125.70, 110.25, 65.27, 52.43, 40.27, 28.53, 22.95, 20.75, 16.49.
[00795] (2) 4-{ 1 -(R)-Hydroxy-3-[4-isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5- yl] -propyl }-2-methylphenoxy)-acetic acid methyl ester. [00796] (4-{3-[4-Isopropyl-2-(4-trifluoromethylphenyl)-thiazol-5-yl]-propionyl}-2- methylphenoxy)-acetic acid methyl ester (8.7 g, 19.26 mmol) and (S)-(-)-2-methyl-CBS- oxazaborilidine (0.55 g, 1.98 mmol) were dissolved in THF (200 mL) under an argon atmosphere. The flask was cooled in an acetone-dry ice bath and IM borane-THF (25 mL) was added drop-wise. The mixture stirred at -78 to -65 0C for 1 week under an argon atmosphere. Portions of IM borane-THF (5 mL) and the catalyst (S)-(-)-2-methyl-CBS- oxazaborilidine (50 mg) were added every 24 hours. After 1 week, the flask was slowly warmed to -50 °C and quenched with water (50 mL), added in small portions. Once the temperature reached 0 °C the pH was adjusted to 2 with concentrated hydrochloric acid and the product was extracted with dichloromethane (2x50 mL). The dichloromethane extracts were dried over sodium sulfate, filtered, and concentrated. The remaining oil (9.2 g) was purified by crystallization twice from methanol (35 mL). The experiment generated the desired compound 4-{ l-(R)-Hydroxy-3-[4-isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5- yl] -propyl }-2-methylphenoxy)-acetic acid methyl ester (6.66 g, 76.5% yield) as a white solid (m.p. 106-107 0C). [00797] 1H NMR (300 MHz, CDC13/TMS): δ = 8.00 (d, 2H, J= 7.8 Hz), 7.63 (d, 2H,
J= 7.8 Hz), 7.14 (s, IH), 7.10 (d, IH, J= 8.1 Hz), 6.66 (d, IH, J= 8.1 Hz), 4.64 (m, 3H), 3.79 (s, 3H), 3.05 (m, IH), 2.89 (m, 2H), 2.29 (s, 3H), 2.11 (m, IH), 1.98 (m, 2H), 1.30 (d, 6H, J= 5.4 Hz). 13C NMR (75 MHz, CDC13/TMS): δ = 169.55, 161.9, 159.57, 155.78, 137.50, 137.18, 132.00, 130.85 (q, J= 32 Hz), 128.79, 127.73, 126.40, 125.84, 125.80, 124.32, 111.25, 73.13, 65.80, 52.42, 41.13, 28.52, 22.98, 22.86, 16.59.
[00798] (3) (4-{ 1 -(R)-Hydroxy-3-[4-isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5- yl] -propyl }-2-methylphenoxy)-acetic acid.
[00799] 4- { 1 -(R)-Hydroxy-3-[4-isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]- propyl}-2-methylphenoxy)-acetic acid methyl ester (6.0 g, 13.22 mmol) and lithium hydroxide (1.0 g, 41.75 mmol) were dissolved in 1 :1 THF/water (200 mL) and stirred for 2 hours at room temperature. After 2 hours, the solution was acidified with concentrated hydrochloric acid (5 mL) and extracted with dichloromethane (2><250 mL). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated. The remaining oil was combined with fresh dichloromethane (100 mL) and heated to 40-50 0C on a water bath with stirring. Heptane (50 mL) was added to the mixture and the mixture was allowed to stand for 1 hour at room temperature. The solids were filtered and the filtrate was stored in a freezer (-10 °C) for 2 hours. A second crop of crystals was obtained by filtration. The solids were combined and dried to a constant weight under high vacuum at room temperature, then 4 hours at 70 °C under high vacuum. The experiment generated (4-{l-(R)-Hydroxy-3-[4- isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propyl}-2-methylphenoxy)-acetic acid (5.27 g, 90.7% yield, 99.61% purity by HPLC, [α]D 25= -5.7 ° (c= 0.0134, 25 °C, ethanol), mp = 130-1310C) as a white solid. [00800] 1H NMR (300 MHz, DMSO-d6): δ = 12.95 (br s, IH), 8.04 (d, 2H, J- 8.1 Hz),
7.79 (d, 2H, J= 8.1 Hz), 7.13 (s, IH), 7.09 (d, IH, J= 8.4 Hz), 6.77 (d, IH, J= 8.4 Hz), 5.25 (br s, IH), 4.67 (s, 2H), 4.51 (br t, IH), 3.06 (m, IH), 2.86 (m, 2H), 2.19 (s, 3H), 1.88 (m, 2H), 1.24 (d, 6H, J= 6.3 Hz). 13C NMR (75 MHz, DMSOd6): δ = 170.16, 160.58, 158.60, 154.65, 137.72, 136.82, 132.90, 128.71 (q, J= 31 Hz), 128.01, 126.06, 125.94, 125.32, 123.98, 110.69, 70.82, 64.75, 41.56, 27.55, 22.69, 22.10, 16.21.
[00801] Example 55. Pre-β HDL elevating effect of a selective PPARδ agonist.
The effects of a selective PPARδ agonist provided herein (Example 3) on lipid regulation in normal Macaca fascicularis monkeys of about 2 years old were studied. Different doses of the PPARδ agonist were administered orally once a day for 2 weeks. Blood samples were collected at one week intervals and analyzed for lipoprotein profiles using online HPLC chromatography. The results demonstrated an increase in HDL and ApoA-I levels (27% and 30%, respectively) in normal monkeys. An increase in pre-β HDL levels (> 70%) was observed (Figure 1). A decrease in LDL, VLDL and tryglyceride levels in these animals was also observed. These results demonstrate that a PPARδ agonist provided is a potent pre-β HDL particle enhancer.
[00802] The HPLC Chromatography Profile of Plasma from Normal Monkeys
{Macaca fascicularis) is shown below. Animals were orally treated at 10 mg/kg of NP-730 PP (straight line) for 2 weeks as compare to pre-dose (dashed line). The profile represents a typical post-column online measurement of phospholipids to allow detection of pre-β HDL particles as shown by the arrows. An important increase in the pre-β HDL fraction (increase in number of pre-β HDL particles) was detected.
Figure imgf000102_0001
time (mln)
[00803] Example 56. PPAR selectivity of the compounds provided.
Assays with GAL4-PPAR chimera receptors [00804] Receptor expression plasmids: An established chimeric receptor system (1) was utilized to allow comparison of the relative transcriptional activity of the receptor subtypes. The mammalian expression vectors pSG5-GAL4-hPPARα, pSG5-GAL4-hPPARγ and pSG5-GAL4-hPPARδ, which express the ligand binding domains (LBDs) of human PP ARa (amino acids 167-468), PPARγl (amino acids 176-477) and PPARδ (amino acids 139-441 ) each fused to the yeast transcription factor GAL4 DNA binding domain (amino acid 1-147), were used. MH100x4-tk-luc (2) was used as the reporter plasmid.
Assays with full-length receptors
[00805] Receptor expression plasmids: Full-length coding sequences for human
PP ARa, PPARγ and PPARδ were inserted into the mammalian expression vector pcDNA3.1+ or pCMX. The full-length coding sequence for human RXRα was inserted into pcDNA3.1+.
Reporter plasmid: PPREx3-tk-luc (3) was used as the reporter plasmid. It contains three copies of rat Acyl-CoA oxidase peroxisome proliferator response element (PPRE) sequence (AGGACA-A-AGGTCA). Transient transfection assays
[00806] The African green monkey kidney cell line, CV-I was used for the transfection assays. CV-I cells were seeded in 24-well plates at 0.5 x 105 cells per well and were cultured for 24 hours. Transfection mixtures for chimera receptors contained 30 ng of receptor expression plasmid, 120 ng of the reporter plasmid, 350 ng of pCMX-β- galactosidase (βGAL) expression plasmid as a control for transfection efficiency, 250 ng of pGEM4 carrier plasmid and 2 μL of a lipofection reagent (Lipofectamine 2000, Invitrogen). Transfection mixtures for full-length receptors contained 15 ng of receptor expression plasmid, 15 ng of hRXRα expression plasmid, 120 ng of the reporter plasmid, 350 ng of pCMX-βGAL, 250 ng of pGEM4 and 2 μL of Lipofectamine 2000. These mixtures were added to cells and incubated for 5 hours according to the manufacturer's instructions. After the transfection, cells were incubated for an additional 40 hours in the presence of NP-0730- PP or each reference compound. Cell lysates were prepared with a lysis buffer (Passive Lysis Buffer, Promega) and used in the luciferase and βGAL assays. The luciferase and βGAL activity were measured according to the methods of Umesono, K. et al. (4) with slight modifications. A substrate reagent kit (Picagene, Toyo Ink) was used for the luciferase assay. Assays were performed in duplicate and triplicate for GAL4-chimeras and full-length receptors, respectively. Experiments were repeated at least four times.
Calculation of relative PPAR transactivation activities [00807] Each point of a relative PPAR transcriptional activity to maximal activity was calculated based on the values bellow:
[00808] Luciferase activity of cells treated with a positive control (10"6 M GW-590735 for hPPARα, 3 x 10'6 M rosiglitazone maleate for hPPARγ assays and 10"7 M GW-501516 for hPPARδ) as the maximal activity, and luciferase activity of cells treated with 0.1 % of DMSO as the minimum activity. Calculation of EC50 values
[00809] EC50 values defined as the concentration of NP-0730-PP and GW-501516 to produce 50 % of maximal reporter activity were calculated with Prism software (Graphpad Software).
Table 8. PPAR Selectivity Data for Selected Compounds provided in Cell-Based Transactivation Assays
Transactivation activity GAL Transactivation activity FULL-
Molecular 4 DBD-hPPAR LBD (EC50- hPPAR +mRXRalpha (EC50-
Type Weight Um) Um) Structure
alpha gamma delta alpha gamma delta
491.52 >10 >8 0.018 3.2 5.8 0.0022
Figure imgf000104_0001
457.91 >10 >10 0.032 3.8 9.8 0.058
489.35 >10 >10 0.025 7.8 >10 0.007
489.52 >10 >10 0.045 >10 >10 0.019
Figure imgf000104_0002
O
Figure imgf000105_0001
[00810] Example 57. Experiments in vivo
[00811] The effect of a selective PPARδ agonist on lipoprotein metabolism in hAPOA-I transgenic mice was investigated. This model, which is used to investigate the effects of drugs on apo A-I and HDL-C metabolism, contains the entire human apolipoprotein A-I (apoA-I) gene, including its promoter. Nine- week old animals were fed a pelleted rodent chow throughout the two-week study. Lipid, lipoprotein, and apoA-I levels were measured in serum collected following a six hour fast using commercially available kits in conjunction with high performance gel filtration chromatography to measure the distribution of lipids between lipoprotein fractions. [00812] It was shown that human apoA-I increased 25% versus baseline levels following two weeks dosing with a selective PPAR δ agonist at 10 mg/kg BID, while vehicle- treated animals had a nonsignificant 7.6% increase in apoA-I. As expected, there was no drug related effect of the selective PPAR δ agonist on HDL-C. [00813] The effect of a selective PPARδ agonist on apoA-I levels in six male cynomolgus monkeys was investigated in a study in which animals fed a standard diet were treated for two weeks with a selective PPAR δ agonist at 0.1 mg/kg and 3.0 mg/kg. Following a 6 hour fast, blood was collected into EDTA, and plasma was obtained by centrifugation. ApoA-I was measured using a commercially available kit. The selective PPAR δ agonist at a dose of 3 mg/kg/day produced a significant 20% increase in plasma apoA-I levels (as shown in Table 9 below).
Table 9: Mean CER-002 Drug Level, Weight, and ApoA-I Levels in Cynomolgus Monkeys following a 1- and 2-week Treatment
ApoA-I
Dose Weight (mg/dL;±
(mg/kg) (kg;± SD) SD)
Baseline 3 37 ± 021 146 ± 29
0.1 Week 1 3 41 1026 138 ± 25
0.1 Week 2 3 43 ± 0 32 142 ± 23
3 Week 1 333 ± 031 175 ± 31*
3 Week 2 3 36 ± 033 175 + 34"
5 wk post-dose 3 34 ± 0 11 161 ± 31"
'Significantly different from baseline at p<0.05 by a paired two tailed T test with a Bonferroni adjustment for multiple comparisons
[00814] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

We claim:
1. A method for increasing pre-β HDL levels in a mammal, comprising administering to the mammal a selective PPARδ agonist.
2. The method of claim 1, wherein said PPARδ agonist is a molecule having a molecular weight less than 1000 g/mol.
3. The method of claim 1 , wherein said PPARδ agonist is >500 selective for PPARδ over PP ARa or PPARγ.
4. The method of claim 1, wherein said PPARδ agonist is >1000 selective for PPARδ over PP ARa or PPARγ.
5. A method for increasing pre-β HDL levels and/or ApoA-I levels while reducing or avoiding a significant increase in an HDL-cholesterol level in a mammal, comprising administering a selective PPARδ agonist.
6. A method for increasing pre-β HDL levels and/or ApoA-I levels and/or HDL levels while reducing or avoiding a significant increase in an HDL-cholesterol level in a mammal, comprising administering a selective PPARδ agonist.
7. A method for increasing pre-β HDL levels and/or ApoA-I levels and/or ApoA-I rich HDL levels while reducing or avoiding a significant increase in an HDL- cholesterol level in a mammal, comprising administering a selective PPARδ agonist.
8. A method for increasing pre-β HDL levels and/or ApoA-I levels and/or ApoA-I rich HDL levels and/or HDL-phospholipids levels while reducing or avoiding a significant increase in an HDL-cholesterol level in a mammal, comprising administering a selective PPARδ agonist.
9. A method of reducing atherosclerotic plaque in a patient, comprising administering selective PPARδ agonist.
10. The method of claim 9, wherein said patient has not been previously treated with a lipid lowering agent or cholesterol lowering agent.
11. The method of claim 9, wherein said patient has been previously treated with a lipid lowering agent or cholesterol lowering agent.
12. The method of claim 9, wherein a dose of said agonist is below the conventional therapy for a thiazolidinedione compound (PP ARγ agonist) or a fibrate (PP ARa agonist).
13. The method of claim 9, wherein the dose is administered daily.
14. The method of claim 13, wherein the human dose is about 0.001 to about 0.25 mg/kg/day.
15. The method of claim 14, wherein the human dose is about 0.005 to about 0.15 mg/kg/day.
16. The method of claim 15, wherein the human dose is about 0.01 to about 0.1 mg/kg/day.
17. The method of claim 13, wherein the human dose is about 0.1 to about 250 mg/day.
18. The method of claim 17, wherein the human dose is about 0.5 to about 200 mg/day.
19. The method of claim 18, wherein the human dose is about 1.0 to about 100 mg/day.
20. The method of claim 19, wherein the human dose is about 2.5 to about 50 mg/day.
21. The method of claim 20, wherein the human dose is about 5.0 to about 25 mg/day.
22. A method of inducing reverse cholesterol transport, comprising administering to a mammal a selective PPARδ agonist.
23. A method of inducing reverse lipid transport, comprising administering to a mammal a selective PPARδ agonist.
24. A method of increasing pre-β HDL-cholesterol levels, comprising administering to a mammal a selective PPARδ agonist.
25. A method of increasing the number of pre-β HDL particles, comprising administering to a mammal a selective PPARδ agonist.
26. A method of increasing ApoA-I levels, comprising administering to a mammal a selective PPARδ agonist.
27. A method of increasing HDL-phospholipid levels, comprising administering to a mammal a selective PPARδ agonist.
28. A method of using the increase in pre-β HDL or ApoA-I or HDL-phospholipid levels as a biomarker when administering to a mammal a selective PPARδ agonist for the treatment of a cardiovascular disease including atherosclerosis, dyslipidemia, and hypertriglyceridemia.
29. A method of any one of claims 1-28, wherein a PPARδ agonist has formula (I) or a salt thereof:
Figure imgf000110_0001
wherein:
R1 is phenyl, naphthyl, pyridyl, thienyl, furyl, quinolyl or benzothienyl, any of which can have substituents selected from the group consisting of Cj-8 alkyl, C1-8 alkyl having halogen, Cj-8 alkoxy, Cj-8 alkoxy having halogen, C2-8 alkenyl, C2-8 alkynyl, halogen, C2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl and pyridyl;
R2 is Ci-8 alkyl, Ci-8 alkyl having halogen, C2-8 alkenyl, C2-8 alkynyl, 3-7 membered cycloalkyl, Ci-8 alkyl having 3-7 membered cycloalkyl, or Ci-6 alkyl substituted with phenyl, naphthyl or pyridyl, any of which can have substituents selected from the group consisting of Ci-8 alkyl, Ci-8 alkyl having halogen, Ci-8 alkoxy, Ci-8 alkoxy having halogen, C2-8 alkenyl, C2-8 alkynyl, halogen, C2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl and pyridyl;
A is oxygen, sulfur or NR9 in which R9 is hydrogen or Cj.8 alkyl; X is a Ci-8 alkylene chain which can have substituents selected from the group consisting Of Ci-8 alkyl, Ci-8 alkoxy and hydroxyl and which can contain a double bond;
Y is C(=O), C(==N-OR10), CH(OR11), CH==CH, C-C, or C(==CH2) in which each of R10 and R11 is hydrogen or Ci-8 alkyl; each of R3, R4 and R5 is hydrogen, Ci-8 alkyl, Ci-8 alkyl having halogen, Ci-8 alkoxy, Ci-8 alkoxy having halogen, C2-8 alkenyl, C2-8 alkynyl, halogen, Qi.η acyl, benzoyl, hydroxyl, nitro, amino, phenyl, or pyridyl;
B is CH or nitrogen;
Z is oxygen or sulfur; each of R6 and R7 is hydrogen, Ci-8 alkyl, Ci-8 alkyl having halogen; R8 is hydrogen or Ci-8 alkyl; provided that at least one of R3, R4 and R5 is not hydrogen; or formula (II) or a salt thereof:
Figure imgf000111_0001
wherein: each of R1 and R2 independently is a hydrogen atom, a halogen atom, nitro, an alkyl group having 1-8 carbon atoms, an alkoxy group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkoxy group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, a 3-7 membered cycloalkyl group, an alkyl group having 1-8 carbon atom which has a 3-7 membered cycloalkyl substituent, an aryl group having 6-10 carbon atoms which optionally has a substituent, an arylalkyl group which has a C6-Io aryl portion and Ci-8 alkyl portion, a heterocyclic group which optionally has a substituent or a heterocyclic-alkyl group having an alkyl group of 1 -8 carbon atoms;
A is an oxygen atom, a sulfur atom, or NR3 in which R3 is a hydrogen atom or an alkyl group having 1-8 carbon atoms; each of X and Z independently is -C(=O)-, -C(O)NH-, -C(=N-0R4)-, -CH(OR5)-, - NH(C=O)-, -NHSO2-, -SO2NH-, -CH=CH-, -C≡C-, or a bond in which each of R4 and R5 is a hydrogen atom or an alkyl group having 1 -8 carbon atoms; Y is an alkylene chain having 1-8 carbon atoms; or formula (III) or a salt thereof:
Figure imgf000112_0001
wherein: each of R11 and R12 independently is a hydrogen atom, a halogen atom, nitro, hydroxyl, amino, an alkyl group having 1 -8 carbon atoms, an alkoxy group having 1 -8 carbon atoms, an alkyl group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkoxy group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, a 3-7 membered cycloalkyl group, an alkyl group having 1-8 carbon atoms which has a 3-7 membered cycloalkyl substituent, or a phenyl, naphthyl, benzyl, phenethyl, pyridyl, thienyl, furyl, quinolyl, or benzothienyl group which optionally has a substituent selected from the group consisting of a halogen atom, nitro, hydroxyl, amino, an alkyl group having 1-8 carbon atoms, an alkoxy group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkoxy group having 1-8 carbon atoms which has 1 to 3 halogen substituents, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, a 3-7 membered cycloalkyl group, an alkyl group having 1-8 carbon atoms which has a 3-7 membered cycloalkyl substituent, phenyl and pyridyl; each of X1 and Z1 independently is -C(=0)-, -C(O)NH-, -C(=N-0R14)-, -CH(OR15)-, -NH(C=O)-, -NHSO2 -, -SO2NH-, -CH=CH-, -C≡C-, or a bond in which each of R14 and R15 is a hydrogen atom or an alkyl group having 1-8 carbon atoms; Y1 is an alkylene chain having 1-8 carbon atoms; or formula (IV) or a salt thereof:
Figure imgf000113_0001
wherein:
A is O, S or NR7 in which R7 is hydrogen or C1-8 alkyl;
B1 is CW or N in which W is hydrogen or a bond; B2 is O, S or NR8 in which R8 is hydrogen or C1-8 alkyl; each of X1 and X2 is O, S, NH, NHC(=0), C(=O), C(=N-0R9, CH(OR10), C=C, C≡C or a bond in which each of R9 and R10 is hydrogen or C1-8 alkyl;
Y is a C1-8 alkylene chain, which can be substituted with Ci-8 alkyl or Cj-8 alkyl substituted with 1-3 halogens; Z is NH, O or S;
R1 is aryl, which can be substituted with a group or atom selected from the group consisting Of Ci-8 alkyl, Ci-8 alkoxy, Ci-8 alkyl substituted with 1-3 halogens, hydroxyl, nitro, amino, phenyl, pyridyl and halogen, or a heterocyclic group having five to eight membered ring comprising one to three hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur and the other atoms consisting of carbon (benzene ring can be condensed with the heterocyclic ring);
R2 is C2-8 alkyl, Ci-8 alkyl substituted with 1-3 halogens, C3-7 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, alkyl (comprising Ci-4 alkyl moiety) substituted with aryl, which can be substituted with a group or atom selected from the group consisting of Ci-8 alkyl, Ci-8 alkoxy, Ci-8 alkyl substituted with 1-3 halogens, hydroxyl, nitro, amino, phenyl, pyridyl and halogen, or alkyl (comprising Ci-4 alkyl moiety) substituted with a heterocyclic group having five to eight membered ring (comprising one to three hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur and the other atoms consisting of carbon);
R3 is halogen, trifluoromethyl, Ci-8 alkyl, C2-8 alkenyl or C2-8 alkynyl; each of R4 and R5 is hydrogen, Ci-8 alkyl or Ci-8 alkyl substituted with 1-3 halogens; and R6 is hydrogen, Ci-8 alkyl substituted with amino, Ci-8 alkyl or alkali metal; provided that each of Z and R3 is attached to the benzene ring, and X2 is not attached to the benzene ring.
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