WO2010056788A1 - Composés anti-hypercholestérolémiques - Google Patents

Composés anti-hypercholestérolémiques Download PDF

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Publication number
WO2010056788A1
WO2010056788A1 PCT/US2009/064092 US2009064092W WO2010056788A1 WO 2010056788 A1 WO2010056788 A1 WO 2010056788A1 US 2009064092 W US2009064092 W US 2009064092W WO 2010056788 A1 WO2010056788 A1 WO 2010056788A1
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substituted
unsubstituted
phenyl
alkyl
mmol
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PCT/US2009/064092
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Gregori J. Morriello
Robert J. Devita
Sander G. Mills
Christopher R. Moyes
Peter Lin
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Merck Sharp & Dohme Corp.
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Publication of WO2010056788A1 publication Critical patent/WO2010056788A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the instant invention relates to substituted 2-azetidinones and the pharmaceutically acceptable salts there of, and to their use alone or in combination with other active agents to treat hypercholesterolemia and for preventing, halting or slowing the progression of atherosclerosis and related conditions and disease events. It has been clear for several decades that elevated blood cholesterol is a major risk factor for coronary heart disease, and many studies have shown that the risk of CHD events can be reduced by lipid-lowering therapy. Prior to 1987, the lipid-lowering armamentarium was limited essentially to a low saturated fat and cholesterol diet, the bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), the fibrates and probucol.
  • Probucol produces only a small reduction in LDL cholesterol and also reduces HDL cholesterol, which, because of the strong inverse relationship between HDL cholesterol level and CHD risk, is generally considered undesirable.
  • lovastatin the first inhibitor of HMG-CoA reductase to become available for prescription in 1987, for the first time physicians were able to obtain large reductions in plasma cholesterol with very few adverse effects.
  • Ezetimibe the first compound to receive regulatory approval in this class, is currently marketed in the U.S. under the tradename ZETIA®. Ezetimibe has the following chemical structure and is described in U.S. Patent No.'s Re. 37721 and
  • the instant invention provides novel cholesterol absorption inhibitors, described below.
  • One object of the instant invention is to provide novel cholesterol absorption inhibitors of Formula I
  • a second object of the instant invention is to provide a method for inhibiting cholesterol absorption comprising administering a therapeutically effective amount of a compound of Formula I to a patient in need of such treatment.
  • Another object is to provide a method for reducing plasma cholesterol levels, especially LDL-cholesterol, and treating hypercholesterolemia comprising administering a therapeutically effective amount of a compound of Formula I to a patient in need of such treatment.
  • methods for preventing or reducing the risk of developing atherosclerosis, as well as for halting or slowing the progression of atherosclerotic disease once it has become clinically evident, comprising the administration of a prophylactically or therapeutically effective amount, as appropriate, of a compound of Formula I to a patient who is at risk of developing atherosclerosis or who already has atherosclerotic disease.
  • Another object of the present invention is the use of the compounds of the present invention for the manufacture of a medicament useful in treating, preventing or reducing the risk of developing these conditions.
  • Other objects of this invention are to provide processes for making the compounds of Formula I and to provide novel pharmaceutical compositions comprising these compounds. Additional objects will be evident from the following detailed description.
  • novel cholesterol absorption inhibitors of the instant invention are compounds of structural Formula ⁇
  • Ar is aryl, optionally substituted with one to three substituents selected from halo or Cj-C ⁇ alkyl;
  • R is independently selected from H or unsubstituted or substituted C ⁇ -Cg alkyl
  • Ra is independently selected from H, unsubstituted or substituted Cj-C ⁇ alkyl, oxo, -(CR2)tOR 12 , -C(O)ORl 2, -OC(O)Rl 2, -0C(0)0Rl2, -OC(O)NR7 2 , unsubstituted or substituted aryl;
  • Rb is independently selected from H, unsubstituted or substituted C]-Cg alkyl, -(CR2)tORl2 ⁇ -C(O)ORl 2, O r unsubstituted or substituted aryl;
  • Rl and R2 are independently selected from H or -OR;
  • R4 is -S(O)2R 6 , Cj-Cg alkyl, -OR, aryl, heteroaryl, -NR7 2 , -C(O)OR, where Cj-C 6 alkyl, aryl or heteroaryl is optionally substituted with -CONR ⁇ , -(CRa2)pS(O)2R 6 ;
  • R ⁇ is independently unsubstituted or substituted Cj-Cg alkyl or unsubstituted or substituted aryl;
  • R? is independently H, unsubstituted or substituted Cj-Cg alkyl or unsubstituted or substituted aryl;
  • R8 is independently (CRb 2 ) m , C 2 -Cg alkenyl, or C2-Cg alkynyl;
  • R9 is independently (CRa 2 ) H , C 2 -Cg alkenyl, or C2-Cg alkynyl;
  • Rl 2 is independently selected from H or unsubstituted or substituted Cj-Cg alkyl
  • X is a bond, O, NR?, or C(O);
  • n O, 1, 2, 3, 4, 5 or 6
  • p is O or 1
  • q is O 9 1, 2, 3 or 4
  • t is O, 1, 2, 3 or 4;
  • R is independently selected from H or unsubstituted or substituted C]-Cg alkyl
  • R a is independently selected from H, unsubstituted or substituted C]-Cg alkyl, oxo, -(CR.2)tORl2, -C(O)ORl2 5 -OC(O)Rl 2, -0C(0)0Rl2, -OC(O)NRV 2 , unsubstituted or substituted aryl;
  • Rb is independently selected from H, unsubstituted or substituted C]-Cg alkyl, -(CR2XOR ⁇ 2, -C(O)ORl 2, or unsubstituted or substituted aryl;
  • Rl and R2 are independently selected from H or OR;
  • R4 is -S(O)2R 6 , C 1 -Cg alkyl, -OR, aryl, heteroaryl, -NR?2, -C(O)OR, where C j -Cg alkyl, aryl or heteroaryl is optionally substituted with -CONR72, -(CR a 2)pS(O)2R 6 ;
  • R6 is independently unsubstituted or substituted C]-Cg alkyl or unsubstituted or substituted aryl;
  • R 7 is independently H, unsubstituted or substituted C]-Cg alkyl or unsubstituted or substituted aryl;
  • R8 is independently (CRb2) m , C2 ⁇ Cg alkenyl, or C2-Cg alkynyl;
  • R9 is independently (CR ⁇ ) n , C2-Cg alkenyl, or C 2 -Cg alkynyl;
  • Rl 2 is independently selected from H or unsubstituted or substituted C]-Cg alkyl
  • X is a bond, O, NR7, or C(O); m is O, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4, 5 or 6; p is 0 or 1 ; q is O, I 5 2, 3 or 4; t is 0 or 1 ;
  • R is independently selected from H or unsubstituted or substituted C j-Cg alkyl
  • Ra is independently selected from H, unsubstituted or substituted C]-Cg alkyl, oxo, -(CR2)tORl2 ; -C(O)OR 12 , unsubstituted or substituted aryl;
  • Rb is independently selected from H 5 unsubstituted or substituted Ci-Cg alkyl, -(CR2)tORl2, -C(O)OR 12 , or unsubstituted or substituted aryl;
  • R 1 and R 2 are independently selected from H or OR;
  • R4 is -S(O)2R 6 , C i -Cg alkyl, -OR, aryl, heteroaryl, -NR?2, -C(O)OR 5 where C i -C 6 alkyl, aryl or heteroaryl is optionally substituted with -CONR ⁇ , ⁇ (CRa2) p S(O)2R 6 ;
  • R6 is independently unsubstituted or substituted C]-Cg alkyl or unsubstituted or substituted aryl
  • R7 is independently H, unsubstituted or substituted Ci-Cg alkyl or unsubstituted or substituted aryl
  • Rl2 is independently selected from H or unsubstituted or substituted C]-Cg alkyl
  • X is a bond, O 5 NR7, or C(O);
  • n O 5 1, 2, 3, 4, 5 or 6;
  • p is 0 or 1 ;
  • t is 0 or 1 ;
  • An embodiment of the instant invention is a compound selected from: (3- ⁇ 4-[(2S,3i?)-3- ⁇ (3S)-3-(4-fluorophenyl)-3-hydroxypropyI]-l-(4- ⁇ 3 ""
  • each embodiment, class or sub-class described above for each variable (i.e., R, Ra, R7, etc.) in Formulae I, Ia and II may be combined with one or more of the embodiments, classes or sub-classes described above for one or more other variables, and all such sub-generic combinations are included within the scope of this invention.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C ⁇ -CiO, as in “Ci-Cio alkyl” is defined to include groups having 1, 2 S 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear or branched arrangement.
  • C 1 -C I o alkyl specifically includes methyl, ethyl, ⁇ -propyl, /-propyl, n-butyl, /-butyl, /-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.
  • cycloalkyl means a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • the cycloalkyl is optionally bridged (i.e., forming a bicyclic moiety), for example with a methylene, ethylene or propylene bridge.
  • the bridge may be optionally substituted or branched.
  • the cycloalkyl may be fused with an aryl group such as phenyl, and it is understood that the cycloalkyl substituent is attached via the cycloalkyl group.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2- dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on.
  • cycloalkyl includes the groups described immediately above and further includes monocyclic unsaturated aliphatic hydrocarbon groups.
  • cycloalkyl as defined in this embodiment includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl and so on.
  • alkyl refers to Cl -C 12 alkyl and in a further embodiment, “alkyl” refers to C1-C6 alkyl.
  • cycloalkyl refers to C3-C10 cycloalkyl and in a further embodiment, “cycloalkyl” refers to C3-C7 cycloalkyl.
  • examples of “alkyl” include methyl, ethyl, ⁇ -propyl, /-propyl, n-butyl, f-butyl and i-butyl.
  • alkyl groups defined herein may be "mono- or poly- substituted with -OH,” meaning that one or more hydroxyl substituents is present on the alkyl group, and that each carbon atom available for substitution in the alkyl group may independently be unsubstituted or mono-substituted with hydroxyl provided that at least one carbon atom is substituted with hydroxyl.
  • alkylene means a hydrocarbon diradical group having the specified number of carbon atoms.
  • alkylene includes -CH2-, -CH2CH2- and the like.
  • alkylene refers to C1-C12 alkylene and in a further embodiment, “alkylene” refers to C1-C6 alkylene.
  • alkenyl refers to a non- aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present.
  • C2-C6 alkenyl means an alkenyl radical having from 2 to 6 carbon atoms.
  • Alkenyl groups include ethenyl, propenyl, butenyi, 2-methylbutenyl and cyclohexenyl.
  • alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present.
  • C2-C6 alkynyl means an alkynyl radical having from 2 to 6 carbon atoms.
  • Alkynyl groups include ethynyl, propynyl, butynyl, 3- methylbutynyl and so on.
  • the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl.
  • the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • aryl is an aromatic ring of 5 to 14 carbons atoms, and includes a carbocyclic aromatic group fused with a 5-or 6-membered cycloalkyl group such as indan.
  • carbocyclic aromatic groups include, but are not limited to, phenyl, naphthyl, e.g., 1-naphthyl and 2-naphthyl; anthracenyl, e.g., 1-anthracenyl, 2-anthracenyl; phenanthrenyl; fiuorenonyl, e.g., 9-fluorenonyl, indanyl and the like.
  • heteroaryl represents a stable monocyclic, bicyclic or tricyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic ring of 5- to 14-ring atoms of carbon and from one to four heteroatoms selected from O, N, or S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline.
  • heteroaryl is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.
  • heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment can be via the aromatic ring, the non-aromatic ring, or via the heteroatom containing ring,
  • heteroaryl is a monocyclic, bicyclic or tricyclic aromatic ring of 5- to 14-ring atoms of carbon and from one to four heteroatoms selected from O, N, or S.
  • heteroaryl include, but are not limited to pyridyl, e.g., 2-pyridyl (also referred to as ⁇ -pyridyl), 3 -pyridyl (also referred to as ⁇ -pyridyl) and 4-pyridyl (also referred to as ( ⁇ -pyridyl); thienyl, e.g., 2-thienyl and 3-thienyl; furanyl, e.g., 2-furanyl and 3-furanyl; pyrimidyl, e.g., 2-pyrimidyl and 4-pyrimidyl; imidazolyl, e.g., 2-imidazolyl; pyranyl, e.g., 2- pyranyl and 3
  • heteroaryl may also include a "fused polycyclic aromatic", which is a heteroaryl fused with one or more other heteroaryl or nonaromatic heterocyclic ring.
  • Examples include, quinolinyl and isoquinolinyl, e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5- quinolinyl, 6-quinolinyl, 7-quinolinyl and 8-quinolinyl, 1 -isoquinolinyl, 3-quinolinyl, 4- isoquinolinyl, 5 "isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl and 8-isoquinolinyl; benzofuranyl, e.g., 2-benzofuranyl and 3 -benzofuranyl; dibenzofuranyl, e.g., 2,3- dihydrobenzofuranyl; dibenzothiophenyl; be
  • heterocycle (also referred to herein as “heterocyclyl”), is a monocyclic, bicyclic or tricyclic saturated or unsaturated ring of 5- to 14-ring atoms of carbon and from one to four heteroaloms selected from O, N, S or P.
  • Heterocyclyl therefore includes the above mentioned heteroaryls, as well as dihydro and tetrathydro analogs thereof. Further examples of “heterocyclyl” include, but are not limited to the following: azetidinyl, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl
  • substitutable group can be a hydrogen atom that is replaced with a group other than hydrogen (i.e., a substituent group).
  • substituent groups can be present. When multiple substituents are present, the substituents can be the same or different and substitution can be at any of the substitutable sites.
  • alkyl groups which can also be substituted, with one or more substituents
  • alkoxy groups which can be substituted
  • a halogen or halo group F, Cl, Br, I
  • amino, azido, N- alkylamino or N.,N-dialkylamino in which the alkyl groups can also be substituted
  • N-arylamino or N,N-diarylamino in which the aryl groups can also be substituted
  • esters (-C(O)-OR, where R can be a group such as alkyl, aryl, etc., which can be substituted), ureas (-NHC(O)-NHR, where R can be a group such as
  • alkylaryl group is an alkyl group substituted with an aromatic group, preferably a phenyl group.
  • a preferred alkylaryl group is a benzyl group.
  • Suitable aromatic groups are described herein and suitable alkyl groups are described herein. Suitable substituents for an alkylaryl group are described herein.
  • alkylheterocyclyl is an alkyl group substituted with a heterocyclyl group. Suitable heterocyclyl groups are described herein and suitable alkyl groups are described herein. Suitable substituents for an alkyheterocyclyl group are described herein, An “alkylcycloalkyl group” is an alkyl group substituted with a cycloalkyl group.
  • Suitable cycloalkyl groups are described herein and suitable alkyl groups are described herein. Suitable substituents for an alkycycloalkyl group are described herein.
  • aryloxy group is an aryl group that is attached to a compound via an oxygen (e.g., phenoxy).
  • alkoxy group alkyloxy
  • alkyloxy is a straight chain or branched C 1 -
  • alkoxy groups include but are not limited to methoxy, ethoxy and propoxy.
  • arylalkoxy group is an arylalkyl group that is attached to a compound via an oxygen on the alkyl portion of the arylalkyl (e.g., phenylmethoxy).
  • arylamino group as used herein, is an aryl group that is attached to a compound via a nitrogen.
  • an "arylalkylamino group” is an arylalkyl group that is attached to a compound via a nitrogen on the alkyl portion of the arylalkyl.
  • alkylsulfonyl group is an alkyl group that is attached to a compound via the sulfur of a sulfonyl group
  • Hydroxyl protecting groups may be used on intermediates during the synthetic procedures for making final products within the scope of this invention.
  • Suitable protecting groups (designated as "PG" herein) for the hydroxyl groups include but are not limited to those that are known to be useful as hydroxyl protecting groups, such as for example benzyl, acetyl, benzoyl, f ⁇ ft-butyldiphenylsilyl, trimethylsilyl, /? ⁇ ra-methoxybenzyl, benzylidine, dimethylacetal and methoxy methyl. Conditions required to selectively add and remove such protecting groups are found in standard textbooks such as Greene, T, and Wuts, P. G. M., Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, NY, 1999.
  • Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, enantiomeric mixtures, diastereomeric mixtures and individual diastereomers. All such isomeric forms of the compounds of Formula I are included within the scope of this invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water or organic solvents. Such hydrates and solvates are also encompassed within the scope of this invention.
  • Ar is phenyl, which may be optionally substituted with one to three substituents selected from halo or C ⁇ -Cg alkyl.
  • R is H or unsubstituted Cj-Cg alkyl.
  • R is H
  • Ra is independently selected from H or -(CR2)tOR* 2.
  • Rb is H.
  • Rl is H.
  • R4 is S(O)2R 6 , Cj-Cg alkyl, OR, aryl, heteroaryl, where C ⁇
  • C ⁇ alkyl, aryl or heteroaryl is optionally substituted with CONR ⁇ , (CR a 2)pS(O)2R 6 ;
  • R*> is -(CRb2)m-
  • R9 is
  • X is a bond, O or NR?.
  • the compounds of the present invention can be used in screening assays, where the assay is designed to identify new cholesterol absorption inhibitors.
  • Radioactive isotopes of the compounds of Formula I are particularly useful in such assays, for example compounds of Formula I wherein sulfur is replaced with "hot" -35s- s and particularly wherein the radioactive sulfur isotope is incorporated within the R9 moiety. All such radioactive isotopes of the compounds of Formula I are included within the scope of this invention.
  • the term "pharmaceutically acceptable salts” means non-toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammoniurn, as well as those salts formed from amines such as ammonia, ethylenedi amine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, 1- p-chlorobenzyl-2-pyrrolidine-r-yl-methylbenzimidazole, diethylamine, piperazine, morphoHne, 2,4,4-trimethyl-2 ⁇ entamine and tris(hydroxymethyl)armnomethane.
  • a suitable organic or inorganic base particularly those formed from c
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
  • esters of available hydroxy or carboxylic acid groups can optionally be formed as well.
  • examples of pharmaceutically acceptable esters include, but are not limited to, -C 1-4 alkyl and -C 1-4 alkyl substituted with phenyl, dimethylamino and acetylamino.
  • the term "patient” includes mammals, especially humans, who use the instant active agents for the prevention or treatment of a medical condition. Administering of the drug to the patient includes both self-administration and administration to the patient by another person.
  • the patient may be in need of treatment for an existing disease or medical condition, or may desire prophylactic treatment to prevent or reduce the risk for diseases and medical conditions affected by inhibition of cholesterol absorption.
  • therapeutically effective amount is intended to mean that amount of a pharmaceutical drug that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • prophylactically effective amount is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
  • the dosage a patient receives can be selected so as to achieve the amount of LDL cholesterol lowering desired; the dosage a patient receives may also be titrated over time in order to reach a target LDL level.
  • the dosage regimen utilizing a compound of the instant invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound chosen to be administered; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition.
  • the compounds of the instant invention are cholesterol absorption inhibitors and are useful for reducing plasma cholesterol levels, particularly reducing plasma LDL cholesterol levels, when used either alone or in combination with another active agent, such as an anti- atherosclerotic agent, and more particularly a cholesterol biosynthesis inhibitor, for example an HMG-CoA reductase inhibitor.
  • another active agent such as an anti- atherosclerotic agent
  • a cholesterol biosynthesis inhibitor for example an HMG-CoA reductase inhibitor.
  • the instant invention provides methods for inhibiting cholesterol absorption and for treating lipid disorders including hypercholesterolemia, comprising administering a therapeutically effective amount of a compound of Formula I to a person in need of such treatment.
  • methods for preventing or reducing the risk of developing atherosclerosis, as well as for halting or slowing the progression of atherosclerotic disease once it has become clinically evident comprising the administration of a prophylactically or therapeutically effective amount, as appropriate, of a compound of Formula I to a mammal who is at risk of developing atherosclerosis or who already has atherosclerotic disease.
  • Atherosclerosis encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine.
  • Atherosclerotic cardiovascular disease including restenosis following revascularization procedures, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease including multi-infarct dementia, and peripheral vessel disease including erectile dysfunction are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms "atherosclerosis” and "atherosclerotic disease.”
  • a compound of Formula ⁇ may be administered to prevent or reduce the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication.
  • Coronary heart disease events are intended to include CHD death, myocardial infarction (i.e., a heart attack), and coronary revascularization procedures.
  • Cerebrovascular events are intended to include ischemic or hemorrhagic stroke (also known as cerebrovascular accidents) and transient ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vessel disease.
  • an atherosclerotic disease event as used herein is intended to encompass coronary heart disease events, cerebrovascular events, and intermittent claudication. It is intended that persons who have previously experienced one or more non-fatal atherosclerotic disease events are those for whom the potential for recurrence of such an event exists.
  • the instant invention also provides a method for preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic disease event comprising the administration of a prophylactically effective amount of a compound of Formula I to a patient at risk for such an event.
  • the patient may or may not have atherosclerotic disease at the time of administration, or may be at risk for developing it.
  • Persons to be treated with the instant therapy include those at risk of developing atherosclerotic disease and of having an atherosclerotic disease event.
  • Standard atherosclerotic disease risk factors are known to the average physician practicing in the relevant fields of medicine. Such known risk factors include but are not limited to hypertension, smoking, diabetes, low levels of high density lipoprotein (HDL) cholesterol, and a family history of atherosclerotic cardiovascular disease.
  • HDL high density lipoprotein
  • the oral dosage amount of the compound of Formula I is from about 0.1 to about 30 mg/kg of body weight per day, preferably about 0.1 to about 15 mg/kg of body weight per day. For an average body weight of 70 kg, the dosage level is therefore from about 5 mg to about 1000 mg of drug per day. However, dosage amounts will vary depending on factors as noted above, including the potency of the particular compound.
  • the active drug of the present invention may be administered in divided doses, for example from two to four times daily, a single daily dose of the active drug is preferred. As examples, the daily dosage amount may be selected from, but not limited to, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 40 mg, 50 mg, 75 mg, 80 mg, 100 mg and 200 mg.
  • the active drug employed in the instant therapy can be administered in such oral forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • Oral formulations are preferred, and particularly solid oral formulations such as tablets.
  • administration of the active drug can be via any pharmaceutically acceptable route and in any pharmaceutically acceptable dosage form. This includes the use of oral conventional rapid-release, time controlled-release and delayed-release (such enteric coated) pharmaceutical dosage forms. Additional suitable pharmaceutical compositions for use with the present invention are known to those of ordinary skill in the pharmaceutical arts; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.
  • the active drug is typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active drug component can be combined with a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannilol, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
  • a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannilol, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
  • suitable binders, lubricants, disintegrating agents and coloring and flavoring agents can also be incorporated into the mixture.
  • Stabilizing agents such as antioxidants, for example butylated hydroxyanisole (BHA), 2,6-di-tert-butyl-4-methylphenol (BHT), propyl gallate, sodium ascorbate, citric acid, calcium metabisulphite, hydroquinone, and 7-hydroxycoumarin, particularly BHA, propyl gallate and combinations thereof, can also be added to stabilize the dosage forms.
  • BHA butylated hydroxyanisole
  • BHT 2,6-di-tert-butyl-4-methylphenol
  • propyl gallate sodium ascorbate
  • citric acid calcium metabisulphite
  • hydroquinone hydroquinone
  • 7-hydroxycoumarin particularly BHA, propyl gallate and combinations thereof
  • a compound of Formula I is formulated together with an HMG-CoA reductase inhibitor such as simvastatin
  • the instant invention also encompasses a process for preparing a pharmaceutical composition comprising combining a compound of Formula I with a pharmaceutically acceptable carrier. Also encompassed is the pharmaceutical composition which is made by combining a compound of Formula I with a pharmaceutically acceptable carrier.
  • One or more additional active agents may be administered in combination with a compound of Formula I, and therefore an embodiment of the instant invention encompasses a drug combination.
  • the drug combination encompasses a single dosage formulation comprised of the compound of Formula I and additional active agent or agents, as well as administration of each of the compound of Formula I and the additional active agent or agents in separate dosage formulations, which allows for concurrent or sequential administration of the active agents.
  • the additional active agent or agents can be lipid modifying agents, particularly a cholesterol biosynthesis inhibitor such as an HMG-CoA reductase inhibitor, or agents having other pharmaceutical activities, or agents that have both lipid-modifying effects and other pharmaceutical activities.
  • HMG-CoA reductase inhibitors useful for this purpose include statins in their lactonized or dihydroxy open acid forms and pharmaceutically acceptable salts and esters thereof, including but not limited to lovastatin (MEVACOR®; see US Patent No. 4,342,767); simvastatin (ZOCOR®; see US Patent No. 4,444,784); dihydroxy open-acid simvastatin, particularly the ammonium or calcium salts thereof; pravastatin, particularly the sodium salt thereof (PRA VACOL®; see US Patent No. 4,346,227); fluvastatin particularly the sodium salt thereof (LES COL®; see US Patent No.
  • statins in their lactonized or dihydroxy open acid forms and pharmaceutically acceptable salts and esters thereof including but not limited to lovastatin (MEVACOR®; see US Patent No. 4,342,767); simvastatin (ZOCOR®; see US Patent No. 4,444,784); dihydroxy open-acid simvastatin,
  • atorvastatin particularly the calcium salt thereof
  • CRESTOR® see US Patent No. 5,260,440
  • pitavastatin also referred to as NK-104 (see PCT international publication number WO 97/23200).
  • additional active agents include but are not limited to one or more of FLAP inhibitors; 5 -lipoxygenase inhibitors; additional cholesterol absorption inhibitors such as ezetimibe (ZETI A®), described in U.S. Patent No.'s Re.
  • cholesterol ester transfer protein (CETP) inhibitors for example JTT-705 and torcetrapib, also known as CP529,414
  • HMG-CoA synthase inhibitors for example JTT-705 and torcetrapib
  • HMG-CoA synthase inhibitors for example JTT-705 and torcetrapib
  • squalene epoxidase inhibitors for example squalene synthetase inhibitors
  • acyl-coenzyme A cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors of ACAT-I or ACAT-2 as well as dual inhibitors of ACATl and -2
  • microsomal triglyceride transfer protein (MTP) inhibitors niacin; niacin receptor agonists such as acipimox and acifran, as well as niacin receptor partial agonists
  • platelet aggregation inhibitors
  • a therapeutically or prophylactically effective amount, as appropriate, of a compound of Formula I can be used for the preparation of a medicament useful for inhibiting cholesterol absorption, as well as for treating and/or reducing the risk for diseases and conditions affected by inhibition of cholesterol absorption, such as treating lipid disorders, preventing or reducing the risk of developing atherosclerotic disease, halting or slowing the progression of atherosclerotic disease once it has become clinically manifest, and preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic disease event.
  • the medicament may be comprised of about 5 mg to about 1000 mg of a compound of Formula L
  • the medicament comprised of a compound of Formula I may also be prepared with one or more additional active agents, such as those described supra.
  • the compounds of structural Formula I of the present invention can be prepared according to the procedures of the following Scheme and Examples, using appropriate materials, and are further exemplified by specific examples which follow. Moreover, by utilizing the procedures described herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein.
  • the compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention.
  • HPLC High Performance Liquid Chromatography
  • HPLC Medium Pressure Liquid
  • intermediate 1-1 is treated with a terminal alkyne of type 1-2 containing the R 12a group in the presence of a suitable palladium catalyst such as tetrakistriphenylphosphine ⁇ alladium(O) or [1,1'- bis(diphenyl ⁇ hosphino)ferrocene]dichloropalladium(II) or the like, and copper(I) iodide and an initiator such as tetra-n-butylammonium iodide.
  • a suitable palladium catalyst such as tetrakistriphenylphosphine ⁇ alladium(O) or [1,1'- bis(diphenyl ⁇ hosphino)ferrocene]dichloropalladium(II) or the like
  • copper(I) iodide and an initiator such as tetra-n-butylammonium iodide.
  • the reaction is usually performed in an inert organic solvent such as DMF
  • R 12a group within intermediate 1-2 may possess either carboxylic acid-protected or unprotected alkynyl-R 12a derivative 1-2.
  • carboxylic acid protecting groups include, for example, benzyl, ethyl, methyl or any other suitable oxygen protecting group, or combinations thereof, compatible with earlier or subsequent chemical reactions.
  • R !2a includes but is not limited to -Ci-ealkyl-
  • Conversion of 1-3 to 1-4 can be achieved by treatment with guanidine and triethylamine in methanol to selectively remove the phenolic acetate; then converting the intermediate phenol to the triflate 1-4 via treatment with bis(trifluoromethylsulfonyl)amino pyridine in the presence of either triethylamine or N,N diiso ⁇ ropyl-N- ethyl amine in dichloromethane medium.
  • the resulting triflate 1-4 is treated with an alkynyl-(CH 2 )y-heteroaryl group of type 1-5 in the presence of a suitable palladium catalyst such as tetrakistriphenylphosphine palladium(O) and copper(I) iodide with an initiator such as tetrabutylammonium iodide.
  • a suitable palladium catalyst such as tetrakistriphenylphosphine palladium(O) and copper(I) iodide
  • an initiator such as tetrabutylammonium iodide.
  • the reaction is usually performed in an inert organic solvent such as DMF, at RT to 50 0 C, for a period of 1 to 5 hrs, and the product possesses an alkynyl-(CH2) y - heteroaryl group of structure 1-6.
  • Hydrogenation of this bisalkyne intermediate 1-6 by treatment with 10% palladium on carbon catalyst under hydrogen atmosphere in a solvent such as ethyl acetate over 15-24 hours may achieve hydrogenation of the triple bonds along with the removal of any benzyl protecting groups in 1-6.
  • An additional deprotection step may be included if there are useful protecting groups on the heteroaryl group know to those skilled in the art necessary to allow the chemistry to proceed in a facile fashion.
  • These protecting groups may include trityl groups, t-butylcarbamate groups or other groups suitable for the protection of heterocyclic compounds or the functional groups attached to the heterocyclic group known to those skilled in the art.
  • intermediate 1-4 from the above Scheme I may be utilized in reaction using trimethylsilyl acetylene 1-8 in the presence of a suitable palladium catalyst such as tetrakistriphenylphosphine palladium(O) and copper(I) iodide with an initiator such as tetrabutylammonium iodide.
  • a suitable palladium catalyst such as tetrakistriphenylphosphine palladium(O) and copper(I) iodide with an initiator such as tetrabutylammonium iodide.
  • the reaction is usually performed in an inert organic solvent such as DMF, at RT to 50 0 C, for a period of 1 to 5 hrs.
  • the intermediate possessing a trimethylsilylalkynyl group may subsequently be treated with tetra-n- butylammonium fluoride in THF at O 0 C to remove the TM S -group and afford the terminal alkyne of structure 1-9.
  • the reaction is usually performed in an inert organic solvent such as DMF, at RT to 50 0 C, for a period of 1 to 5 hrs, and the product possesses an alkynyl- heteroaryl group of structure I- 10.
  • an inert organic solvent such as DMF
  • Similar reaction steps as described in Scheme I may be utilized as outlined in Scheme II to afford compounds of the present invention 1-7.
  • an additional deprotection step may be included if there are useful protecting groups on the heteroaryl group know to those skilled in the art necessary to allow the chemistry to proceed in a facile fashion.
  • Hydrolysis or cleavage of any remaining hydroxyl protecting groups may be achieved with potassium cyanide or potassium trimethylsilanoate in an alcohol solvent such as ethanol at ambient temperature or heated to 5O 0 C for 1-2 hours affords the free hydroxyl groups of compounds 1-7.
  • Scheme III describes the synthesis of compounds of present invention that contain heteroatom linked heteroaryl groups at R 9 of the present invention.
  • the intermediate 1-4 may be reacted in a Pd-catalyzed cross-coupling reaction using the general conditions described earlier with an alkynylalcohol of general structure 1-11. Alternatively the hydroxyl group of 1-11 may be protected.
  • the resulting alcohol intermediate 1-12 may be hydrogenated using the general conditions described above and the resulting alcohol oxidized to an aldehyde using conditions known to those skilled in the art such as the "Dess-Martin" reagent to provide intermediate 1-13.
  • the aldehyde group of 1-13 may reacted in a reductive amination reaction with heteroaryl amine compounds using conditions known to those skilled in the art such as sodiumtriacetoxyboro hydride in the presence of a buffer such as KOAc and molecular sieves.
  • the reaction product so obtained may be deprotected using the general procedures described earlier to produce compounds of the present invention I- 14 in which a nitrogen atom is in the link form the aryl group to the heteroaryl group.
  • Conversion of 1-21 to -1-22 can be achieved by hydrogenation of the triple bond in the R? position, followed by treatment with guanidine and triethylamine in methanol to selectively remove the phenolic acetate; then converting the phenol to the triflate 1-22 via treatment with bis(trifluoromethylsulfonyl)amino pyridine in the presence of either triethylamine or N 9 N diisopropyl-N- ethyl amine in dichloromethane medium, Incorporation of the alkynyl-R 12a group is achieved by palladium assisted coupling of the triflate 1-22 with either carboxylic acid protected or unprotected alkynyl- R !2a derivative 1-23.
  • carboxylic acid protecting groups include, for example, benzyl, ethyl, methyl or any other suitable oxygen protecting group, or combinations thereof, compatible with earlier or subsequent chemical reactions.
  • R 12a includes but is
  • 1-22 is treated with an alkynyl-R 12a of type 1-23 in the presence of a suitable palladium catalyst such as tetrakistriphenylphosphine palladium(O) and copper(I) iodide with an initiator such as tetrabutylammonium iodide.
  • a suitable palladium catalyst such as tetrakistriphenylphosphine palladium(O) and copper(I) iodide with an initiator such as tetrabutylammonium iodide.
  • the reaction is usually performed in an inert organic solvent such as DMF, at 50 0 C, for a period of 1 to 5 hrs, and the product possesses an alkynyl-R 12a of structure 1-24.
  • Hydrogenation of the triple bond occurs along with the removal of any benzyl protecting groups contained in R 12a by treatment with 10% palladium on carbon catalyst under hydrogen atmosphere in a solvent such as ethyl acetate reacting over 15- 24 hours to form 1-25. Hydrolysis or cleavage of any remaining hydroxyl protecting groups may be performed at this time, or non-benzylic protecting groups can be removed prior to the hydrogenation step.
  • alkyl carbonates that are contained in R 12a may be removed by treatment with mild aqueous base.
  • the acetoxy group may be converted to the triflate using procedures described previously to produce 1-28 which may undergo alkyne cross coupling with with heteroaryl, sulfonamide and/or sulfone substituted alkynes as described in earlier Schemes to arrive at intermediate 1-29.
  • the intermediate 1-29 may be converted to compounds of the present invention 1-7, 1-18, and/or 1-25 by the previously described hydrogenation and subsequent deprotection steps necessary to complete the synthesis.
  • R 14 -(CH 2 ) y -heteroaryl, - ⁇ CH 2 ) y -S0 2 aikyl, or - ⁇ CH 2 ) y NR 10 R 11
  • the preparation of compounds possessing a 2-hydroxyphenyl group in the final product 1-34 is outlined in Scheme VII.
  • the bis(benzyloxy)intermediate 1-30 may be treated with a terminal alkyne of type 1-24 in the presence of a suitable palladium catalyst such as tetrakistriphenylphosphine palladium(O) or [l,l '-bis(diphenylphosphino)ferrocene] dichloropalladium(II) or the like, and copper(I) iodide.
  • a suitable palladium catalyst such as tetrakistriphenylphosphine palladium(O) or [l,l '-bis(diphenylphosphino)ferrocene] dichloropalladium(II) or the like, and copper(I) iodide.
  • the reaction is usually performed in an inert organic solvent such as DMF, between room temperature and 100 0 C, for a period of 6-48
  • Alkyne 1-24 may contain a radioactive atom such as 35s to provide the corresponding radiolabeled adduct upon reaction with 1-30.
  • Conversion of 1-31 to 1-32 can be achieved by hydrogenation of the triple bond, with concomitant selective hydrogenolysis of the benzyl ether which is not at the 2-position, followed by converting the resulting phenol to the trifiate 1-32 via treatment with triflic anhydride 0 (trifiuoromethanesulfonic acid anhydride) in the presence of pyridine in dichloromethane medium.
  • triflic anhydride 0 trifiuoromethanesulfonic acid anhydride
  • Methansulfonylchloride (1.40 mL, 18.1 mmol) was added dropwise to a stirred solution of propargylamine (1.00 g, 18.1 mmol) and dimethyl aminopyridine (44.0 mg, 0.36 mmol) in pyridine (10 mL) at 0 0 C. After aging for approximately 15 h, the reaction mixture was poured into IN HCl and extracted twice with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, brine, dried (MgS ⁇ 4), filtered and concentrated in vacuo, to afford the title compound i-1. Crude i-1 crystallized on standing and was used without further purification.
  • Methanesulfonylchloride (1.12 mL, 14,5 mmol) was added to a stirred solution of iV-methylpropargylamine (1.22 mL, 14.5 mmol) and dimethylaminopyridine (35 mg, 0.30 mmol) in pyridine (10 mL) at room temperature. After aging for approximately 15 h, the reaction mixture was poured into ethyl acetate and washed successively with IN HCl and brine. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated in vacuo, to afford the title compound (i-2), which was used without further purification.
  • Step C Preparation of (lS)-l-(4-fluorophenyl)-3-[(3 ⁇ , 45)-l-(4- ⁇ 3- [(methylsulfonyl)amino]propyl ⁇ phenyl)-2-oxo-4-(4- ⁇ [(trifluoromethyl)- sulfonyl]oxy ⁇ phenyl)azetidin-3-yl]propyl acetate (i-10a wherein RlO is -H)
  • Guanidine hydrochloride (1.34 g, 13.93 mmol) was added to a mixture of the intermediate from Step B, (8.5g, 13,93 mmol) and triethylamine (1.95 mL, 13.93 mmol) in methanol (150 mL). After 3 h, the solvent was removed under vacuum and the residue was dissolved in EtOAc (20OmL) / water (10OmL) and 2N aq. HCl. The mixture was transferred to a separatory funnel and the layers separated. The organic layer was washed with brine (10OmL), dried (MgSO 4 ), filtered and concentrated in vacuo to afford a clear oil.
  • the crude intermediate was dissolved in methylene chloride (100 mL) and to the solution was added (bis(trifiuoromethylsulfonyl)amino pyridine (8.14g, 13.93 mmol), triethylamine (1.95 mL, 13.93mmol), DMAP ( ⁇ 100 rag, catalytic).
  • the resulting solution was stirred for 2 h at room temperature.
  • the reaction was quenched with IN aq. HCl and the organic layer was separated.
  • the organic extract was washed with brine, dried (MgSO 4 ) and concentrated in vacuo.
  • Step D Preparation of dibenzyl (3- ⁇ 4-[(25,3 ⁇ )-3-[(3S)-3-(acetyloxy)-3-(4- fluorophenyl)propyl]-l-(4- ⁇ 3 -[(methylsulfonyl)amino]propyl ⁇ phenyl)-4- oxoazetindin-2-yl)phenyl ⁇ prop-2-yn- 1 -yl)malonate
  • EtOAc (-ImL) was added to cover the solid catalyst mixture. To this mixture was added a solution of the intermediate from above in ethanol (4mL) and ethyl acetate (2 mL). The resulting suspension set under hydrogen atmosphere and stirred vigorously for 2 hours. The catalyst was filtered through filter aid and MgSO 4 and washed with EtOH/EtOAc.
  • Step A Preparation of (1 S)- 1 -(4-fluorophenyl)-3-[(2S,3R)-l -(4-hydroxyphenyl)-2-(4- iodophenyl) ⁇ 4-oxoazetidin-3-yl] propyl acetate.
  • Step D Preparation of dibenzyl ⁇ 3-[4-((2S r ,3 ⁇ )-3-[(35)-3-(acetyloxy)-3-(4- fluorophenyl)propyl] - 1 - ⁇ 4- [6-(methylsulfonyl)hex- 1 -yn- 1 -yljphenyl ⁇ -4- oxoazetidin-2-yl)phenyl]prop-2-yn-l-yl ⁇ malonate.
  • Step E Preparation of ⁇ 3-[4-((2S r s 3 J R)-3-[(35)-3-(Acetyloxy)-3-(4-fluorophenyl)pro ⁇ yl]- 1 ⁇
  • Step F Preparation of ⁇ 3-[4-((25,3 ⁇ )-3-[(35)-3-(4-Fluorophenyl)-3-hydroxypropyl]-l - ⁇ 4-
  • Step A Preparation of dibenzyl ⁇ 3-[4-((25 5 3/?)-3-[(35)-3-(acetyloxy)-3-(4- fluorophenyl)pro ⁇ yl]-4-oxo-l- ⁇ 4-[(trimethylsilyl)ethynyl]phenyt ⁇ azetidin-2- yl)phenyl]prop-2-yn- 1 -yl ⁇ malonate.
  • Step C Preparation of dibenzyl (3- ⁇ 4-[(2S,3i ⁇ )-3-[(3S)-3-(acetyloxy)-3-(4- fiuorophenyl)propyl] - 1 -(4- ⁇ [2-(aminocarbony I)- 1 ,3 -thiazol-4-yl ] ethynyl ⁇ phenyl)- 4-oxoazetidin-2 -yl] phenyl ⁇ prop-2-yn- 1 -yl)mal onate.
  • the bis ⁇ acetylene compound (6.5 mg) from Example 30, Step C was dissolved in ethanol (3 ml) and 10% palladium on carbon (5 mg) was added to the ethanol solution. After three vacuum then flush with hydrogen cycles, the ethanol solution was hydrogenated at atmospheric pressure and at room temperature with hydrogen gas contained in a balloon reservoir for 2 hours when the reaction was judged to be essentially over by analytical lc-ms.
  • Step A Preparation of dibenzyl ⁇ 3-[4-((25,3 ⁇ )-3-[(35)-3-(acetyloxy)-3-(4- fluorophenyl)propyl] - 1 - ⁇ 4- [3 -(benzy loxy)prop- 1 -yn- 1 -yl]phenyl ⁇ -4-oxoazeti di n- 2-yl)phenyl]prop-2-yn-l-yl ⁇ malonate.
  • Step F the acetate from Example 41, Step B above (12 mg; 0.0194mmol) was dissolved in ethanol (ImI) and potassium trimethylsilanoate (9.9 mg; 0.0775 mmol) added and stirred at room temperature for about 6.5 hours.
  • the aqueous acetonitrile product fractions containing the desired product were concentrated down under reduced pressure to give the desired compound.
  • Step A Preparation of dibenzyl (3- ⁇ 4-[(2 1 ?,3/?)-3-[(35)-3-(acetyloxy)-3-(4- fluorophenyl) ⁇ ropyl]-l-(4-allyiphenyi)-4-oxoazetidin-2-yl]phenyl ⁇ prop-2-yn-l- yl)malonate.
  • the acetylene compound (10 mg) from Example 42, Step A was dissolved in ethanol (2ml) and ethyl acetate (2 ml) and 10% palladium on carbon (5 mg) was added to the solution. After three vacuum then flush with hydrogen cycles, the ethanol solution was hydrogenated at atmospheric pressure and at room temperature with hydrogen gas contained in a balloon reservoir. After 2.5 hours of hydrogenation, the reaction was judged to be essentially complete by lc-ms. The spent hydrogenation catalyst was removed by filtering through a 0,45- micron Acrodisk syringe filter and the filtrates obtained concentrated down to leave a colorless gum. m/z (ES) 544 (M- OAc) + .
  • Step A Preparation of (3- ⁇ 4-[(2S,3 ⁇ )-3-[(35)-3-(acetyloxy)-3-(4-fluorophenyl)propyl]-l-
  • step B above The acetate from step B above (11.5 mg) was dissolved in ethanol (2.5ml) and potassium trimethylsilanoate (7.5 mg) added stirred at room temperature for approximately 3.5 hours.
  • the aqueous acetonitrile product fractions containing the desired product were concentrated down under reduced pressure to give the desired compound.
  • Step A Preparation of dibenzyl [3-(4- ⁇ (25,3 J R)-3-[(35)-3-(acetyloxy)-3-(4- fluorophenyl) ⁇ ropyl]-4-oxo-l-[4-(pyrimidin-2-ylethynyl)phenyl]azetidin-2- yl ⁇ phenyl)prop-2 ⁇ yn- 1 -y 1] malonate
  • the bis-acetylene compound (30 mg) from Example 44, Step A was dissolved in ethanol (5 ml) and ethyl acetate (2.5 ml) and 10% palladium on carbon (10 mg) was added to the solution. After three vacuum then flush with hydrogen cycles, the ethanol / EtOAc solution was hydrogenated at atmospheric pressure and at room temperature with hydrogen gas contained in a balloon reservoir. After 3 hours of hydrogenation, the reaction was judged to be essentially over by lc-ms. The spent hydrogenation catalyst was removed by filtering through a 0.45-micron Acrodisk syringe filter and the filtrates obtained concentrated down to leave a colorless gum.
  • Step D Preparation of dibenzyl (3-[4-((2S r ,3i?)-3-[(35)-3-(acetyloxy)-3-(4-fluorophenyl) propyl] - 1 - ⁇ 4 ⁇ [3 -(methylthio)prop- 1 -yn- 1 -yl] ⁇ henyl ⁇ -4-oxoazetidin-2- yl) ⁇ henyl]prop-2-yn ⁇ l-yl ⁇ malonate.
  • Step E Preparation of dibenzyl ⁇ 3-[4-((25 t ,3i?)-3-[(35)-3-(acetyloxy)-3-(4- fluoro ⁇ henyl)propyl]- 1 - ⁇ 4- [3-(methylsulfonyl)prop- 1 -yn- 1 -yl]phenyl ⁇ -4- oxoazetidin-2-yl)phenyl]prop-2-yn- 1 -yl ⁇ malonate
  • Step F Preparation of ⁇ 3-[4-((2S,3R)-3-[(3S)-3-(acetyloxy) ⁇ 3-(4-fluorophenyl)propyl]-l-
  • Step G Preparation of ⁇ 3-[4-((2S,3i?)-3-[(35)-3-(4-fluorophenyl)-3-hydroxypropyl]-l- ⁇ 4-
  • Step A Preparation of 5 -(methyl thio)pent- 1 -yn-3-ol.
  • Step D Preparation of dibenzyl ⁇ 3-[4"((25,3i?)-3-[(35)-3-(Acetyloxy)-3-(4- fluoro ⁇ henyl) ⁇ ropyl]-l- ⁇ 4-[3-(benzyloxy)-5-(methylsulfonyl)pent-l-yn-l- y 1] phenyl ⁇ -4-oxoazetidin-2-yl)pheny 1 ] prop-2 ⁇ yn- 1 -yl ⁇ malonate.
  • the yellow oil was dissolved in anhydrous THF (10 ml) and stirred at O 0 C under a nitrogen atmosphere to which a 50% sodium hydride dispersion in oil (240mg mg; 5.000 mmol) was added in small batches. A cloudy yellow colored solution was formed after the evolution of hydrogen had ceased.
  • Benzyl bromide (275 ⁇ l; 2.304 mmol) was injected in a single portion to the reaction mixture and the mixture stirred 24h at room temperature under the nitrogen atmosphere.
  • the reaction was quenched with brine (10ml) along with 2N hydrochloric acid (5 ml), stirred for 5 minutes then the aqueous reaction mixture was extracted with diethyl ether (2 x 25 ml).
  • Step C Preparation of [3-(4- ⁇ (2,S',3 J ff>3-[(35)-3-(acetyloxy)-3-(4-fiuorophenyl)propyl]- 1 -
  • Step D Preparation of [3-(4- ⁇ (25,3 J R)-l-[4-(3,4-dihydroxybutyl)phenyl]-3-t(35)-3-(4- fluoro ⁇ henyl)-3 -hydroxypropyl] -4-oxoazetidin-2-yl ⁇ phenyl)propyl]malonic acid
  • Step A Preparation of dibenzyl [3-(4- ⁇ (2S,3i?)-3-[(3S) ⁇ 3-(acetyloxy>3-(4- fluorophenyl)propyl] - 1 - [4-(acety loxy)phenyl] ⁇ 4-oxoazetidin-2 ⁇ yl ⁇ phenyl)prop-2- yn-l-yljmalonate.
  • Step D Preparation of (3- ⁇ 4-[(2 ) S,3i?)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-l -(4- hydroxy ⁇ henyl)-4-oxoazetidin-2-yl] ⁇ henyl ⁇ propyl)malonic acid.
  • Step A Preparation of dibenzyl ⁇ 3-[4-((2S',3 ⁇ )-3-[(3S)-3-(acetyloxy)-3-(4- fluoro ⁇ henyl) ⁇ ro ⁇ yl] - 1 - ⁇ 4- [6-(methylsulfonyl)hex- 1 -yn- 1 -yl]phenyl ⁇ -4- oxoazetidin-2-yl)phenyl]prop-2-yn-l -yl ⁇ (hydroxy)malonate.
  • Step C Preparation of ⁇ 3-[4-((2S,3 J R)-3-[(35)-3-(4-fluorophenyl)-3-hydroxy ⁇ ropyl]-l- ⁇ 4-
  • the sulfone (18mg; 0.0243 mmol) from Example 50, Step B was dissolved in ethanol (1.5 ml) and potassium trimethylsilanoate (10.9 mg; 0.052 mmol).
  • the reaction solution was stirred at room temperature.
  • the deprotection reaction was judged to be essentially complete by analytical lc-ms after 2h.
  • the crude reaction solution was diluted to 2 ml with more ethanol, the solution was filtered through a0.45-micron Acrodisk syringe filter.
  • the fractions containing the product were concentrated down under reduced pressure to give the hydroxymalonate.
  • Step A Preparation of l- ⁇ [/er/-Butyl(dimethyi)silyl]oxy ⁇ but-3-yn-2-ol
  • the light yellow colored filtrate was concentrated down under reduced pressure and the yellow oil residue obtained after evaporation was purified by column chromatography on a Biotage SPl on a 4OM Flash cartridge using a ethyl acetate and hexanes gradient 5% rising to 25%.
  • the alcohol product was isolated as a clear oil.
  • Step B Preparation of ⁇ [2-(benzyloxy)but ⁇ 3-yn4-yl]oxy ⁇ (f ⁇ r ⁇ butyl)dimethylsilane.
  • the black oil thus obtained was purified by preparative lie on silica gel plates eluted with EtOAc and hexanes (2:3 v/v) to obtain the title compound, mlz (ES) 1048 (M+Na) + , 966 (M- OAc) + .
  • Step D Preparation of dibenzyl ⁇ 3-[4-((2S,3 ⁇ )-3-[(35)-3-(acetyloxy)-3-(4- fluorophenyl) ⁇ ropyl] - 1 - ⁇ 4- [3-(benzyloxy)-4-hydroxybut- 1 -yn- 1 -y ⁇ ]phenyl ⁇ -4- oxoazetidin-2-yl)phenyl]prop-2-yn- 1 -yl ⁇ malonate.
  • Step G Preparation of ⁇ 3-[4-((25,3i?)-3-[(35)-3-(acetyloxy)-3-(4-fluorophenyl)pro ⁇ yl]-l- ⁇ 4-[3 -hydroxy-4 ⁇ (methylthio)butyl]phenyl ⁇ -4-oxoazetidin-2- yl)phenyl]propyl ⁇ malonic acid.
  • Step H Preparation of ⁇ 3-[4-((2S,3 ⁇ -3-[(3S)-3-(acetyloxy)-3-(4-fluorophenyl)propyl]-l -
  • Step I Preparation of ⁇ 3-[4 ⁇ ((25' s 3 J R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-l- ⁇ 4-
  • Step A Preparation of 2-hydroxy-4-iodobenzaldehyde.
  • reaction vessel with the reflux condenser in place was removed from the cooling bath and warmed quickly to 80 0 C (bath temperature). After 0.25 h of heating the solids started to dissolve and around 1 h of heating the reaction solution was almost a homogeneous golden yellow color which slowly started to turn to an orange color. The reaction was kept at 80 0 C for 18.5 hours; the reaction had become a deep orange in color.
  • the reaction mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride solution (350 ml). The aqueous acetonitrile mixture was shaken with EtOAc (150 ml) and transferred into a separatory funnel.
  • the solid was purified in 3 batches on a Biotage SPl system on 4OM Flash silica cartridge using a gradient of EtOAc and hexanes 0->2% (350 ml), 2->15% (1250 ml) 15->20% (350 ml).
  • the aldehyde fractions were concentrated down to leave an off-white feathery solid. This solid was crystallized from hexanes to give 6g of the pure aldehyde.
  • the mother liqours were purified on silica gel preparative tic plates eluted with EtOAc and hexanes (7:93 v/v) from which a further 300 of the desired aldehyde was recovered (Total 6.3g).
  • AUyI iodide (2.32 ml; 25.4 mmol) was added over 5 minutes drop by drop to a solution of 2-hydroxy-4-iodobenzaldehyde (6g; 24.2 mmol) from Example 16 Step A above and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.83 ml; 25.4 mmol) in dry acetonitrile (30 ml).
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • Step C Preparation of iV ⁇ (lir)-[2-(allyloxy)-4-iodophenyl]methylene ⁇ -4-bromoaniline.
  • Step D Preparation of (4i?)-3-[(5.y)-5- ⁇ [/er/-butyI(dimethyl)silyl]oxy ⁇ -5-(4 ⁇ fluorophenyl)- -l,3-oxazolidin-2-one.
  • Step E Preparation of (4 ⁇ )-3-[(2/?,55)-2- ⁇ (5)-[2-(allyloxy)-4-iodophenyl][(4- bromophenyl)amino]methyl ⁇ -5- ⁇ [f ⁇ r ⁇ -butyl(dimethyl)silyl]oxy ⁇ -5-(4- fluorophenyl)pentanoyl]-4-phenyl- 1 ,3-oxazolidin-2-one.
  • Step F Preparation of (3i?,4S)-4-[2-(al ⁇ yloxy)-4-iodophenyl]-l ⁇ (4-bromo ⁇ henyl) ⁇ 3-[(3S>
  • N,O-Bis(t ⁇ methylsilyl)acetamide (1.6 ml) was added to a solution of the oxazolidinone product (1685 mg; 1.8461 mmol) from Step E above in anhydrous methyl t-butyl ether MTBE) (3.5 ml). This solution stirred for 0.25 hour at room temperature under a nitrogen atmosphere then tetrabutylammonium fluoride trihydrate (29.1 mg; 0.0923 mmol) was quickly weighed and added to the MTBE solution. The reaction mixture was allowed to stir at room temperature under a nitrogen atmosphere overnight. The reaction was checked by lc-ms for product formation.
  • Step G Preparation of dibenzyl [3-(3-(allyloxy)-4- ⁇ (2S,3 ⁇ )-l-(4-)-3-[(35)-3- ⁇ [fert- butyl(dimethyI)silyl]oxy ⁇ -3-(4-fluorophenyl)propyl]-4-oxoazetidin-2- yl ⁇ henyl)prop-2-yn-l-ylJmalonate.
  • Step H Preparation of dibenzyl ⁇ 3-[4-((25,3i?)-3-[(35)-3- ⁇ [fert-butyl(dimethyl)silyl]oxy ⁇ - 3 -(4-fiuorophenyl)propyl] - 1 - ⁇ 4- [6-(methylsulfonyl)hex- 1 -yn- 1 -yljphenyl ⁇ -4- oxoazetidin-2-yl)-3-hydroxyphenyl]prop-2-yn- 1 -yljmalonate
  • Step I Preparation of dibenzyl ⁇ 3-[4 ⁇ ((2S,3i?)-3 ⁇ [(35)-3-(4-fiuorophenyl)-3- hydroxypropyl] - 1 - ⁇ 4- [6-(methylsulfonyl)hex- 1 -yn- 1 -yl]phenyl ⁇ -4-oxoazetidin-2- yl)-3-hydroxyphenyl]prop-2-yn- 1 -yl ⁇ malonate.
  • Step J Preparation of ⁇ 3-[4-((25 ; 3i?)-3-[(35)-3-(4-fluorophenyl)-3-hydroxypropyl]-l - ⁇ 4-
  • Step A Preparation of dibenzyl [3-(4- ⁇ (2S,3RyH ⁇ - ⁇ omo ⁇ ny ⁇ )-3-[(3S)'3 ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ -3-(4-fluorophenyl)propyl]-4-oxoazetidin-2-yl ⁇ -3- hydroxyphenyl)prop-2-yn- 1 -yljmalonate.
  • Example 53, Step F dibenzyl prop- 2-yn-l-ylmalonate (515 mg; 1.5988 mmol)
  • Example 53, Step A were dissolved in anhydrous CH 2 Cl 2 (2.5 ml). Tetrakis(triphenylphosphine)-palladium(0) (92.4 mg; 0.0799 mmol), tetrabutylammonium iodide (29.5 mg; 0.0799 mmol) and copper(I) iodide (15.2 mg; 0.0799 mmol) were added then triethylamine (3 ml).
  • the band at the top of the preparative tic plate that fluoresced under ultra-violet and had a R f ⁇ 0.75 was dibenzyl [3-(3-(allyloxy)-4- ⁇ (2S,3R)- 1 -(4- ⁇ 5-(benzyloxy)-4-[(benzyloxy)carbonyl]-5-oxopent- 1 -yn- 1 -yl ⁇ phenyl)-3-[(3S)-3- ⁇ [terf-butyl(dimethyl)silyl]oxy ⁇ -3-(4-fluorophenyl)propyl]-4-oxoazetidin-2-yl ⁇ phenyl)prop-2- yn-l-yl]malonate (150 mg), the second band (R f ⁇ 0.55) was the desired dibenzyl [3-(4-((25,3 ⁇ )- l-(4-bromophenyl)-3-[(3S)-3- ⁇
  • Step C Preparation of dibenzyl ⁇ 3-[4-((2 ( S,3i?)-3-[(3S)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-oxo-l - ⁇ 4-[4-( IH- 1 ,2,4-triazol- 1 -yl)but- 1 -yn-1 - y l]phenyl ⁇ azetidin-2-yl)-3 -hydroxyphenyl] prop-2-yn ⁇ 1 -y 1 ⁇ malonate .
  • Step D Preparation of ⁇ 3-[4-((25,3i?)-3-[(35)-3-(4-fluorophenyl)-3-]-4-oxo-l- ⁇ 4-[4-(lH- l,2,4-triazol-l-yl)butyl]phenyl ⁇ azetidin-2-yl)-3-hydroxyphenyl]propyl ⁇ malonic acid.
  • Compounds of this invention were determined to inhibit cholesterol absorption employing the Cholesterol Absorption Assay in Rat, below.
  • the assay involves comparing a test compound to ezetimibe with respect to their ability to inhibit cholesterol absorption in rat or mice. Both ezetimibe and the tested compounds of this invention inhibited cholesterol absorption by >90% at the highest dose tested. Compounds of this inventions that were tested had an ID 50 ⁇ lmg/kg.

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Abstract

La présente invention concerne de nouveaux inhibiteurs de l'absorption du cholestérol représentés par la Formule I ou des sels pharmaceutiquement acceptables de ceux-ci.
PCT/US2009/064092 2008-11-17 2009-11-12 Composés anti-hypercholestérolémiques WO2010056788A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011140219A1 (fr) 2010-05-04 2011-11-10 Codexis, Inc. Biocatalyseurs pour la synthèse d'ézétimibe
CN105814068A (zh) * 2014-02-27 2016-07-27 四川海思科制药有限公司 一种取代的氨基磷酸酯类衍生物、其制备方法及其应用
US11919879B2 (en) 2021-06-16 2024-03-05 Celgene Corporation Carboxylic acid containing azetidinyl compounds for the treatment of neurodegenerative diseases

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7176193B2 (en) * 2002-06-19 2007-02-13 Sanofi-Aventis Deutschland Gmbh Acid-group-substituted diphenylazetidinones, process for their preparation, medicaments comprising these compounds, and their use
US20070078098A1 (en) * 2005-10-05 2007-04-05 Devita Robert J Anti-hypercholesterolemic compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7176193B2 (en) * 2002-06-19 2007-02-13 Sanofi-Aventis Deutschland Gmbh Acid-group-substituted diphenylazetidinones, process for their preparation, medicaments comprising these compounds, and their use
US20070078098A1 (en) * 2005-10-05 2007-04-05 Devita Robert J Anti-hypercholesterolemic compounds

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011140219A1 (fr) 2010-05-04 2011-11-10 Codexis, Inc. Biocatalyseurs pour la synthèse d'ézétimibe
CN105814068A (zh) * 2014-02-27 2016-07-27 四川海思科制药有限公司 一种取代的氨基磷酸酯类衍生物、其制备方法及其应用
US11919879B2 (en) 2021-06-16 2024-03-05 Celgene Corporation Carboxylic acid containing azetidinyl compounds for the treatment of neurodegenerative diseases

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