WO2006059210A2 - Fused bicyclic pyrrols as hmg-coa reductase inhibitors - Google Patents

Fused bicyclic pyrrols as hmg-coa reductase inhibitors Download PDF

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WO2006059210A2
WO2006059210A2 PCT/IB2005/003608 IB2005003608W WO2006059210A2 WO 2006059210 A2 WO2006059210 A2 WO 2006059210A2 IB 2005003608 W IB2005003608 W IB 2005003608W WO 2006059210 A2 WO2006059210 A2 WO 2006059210A2
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phenyl
pharmaceutically acceptable
fluoro
acceptable salt
prodrug
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PCT/IB2005/003608
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WO2006059210A3 (en
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Jeffrey Allen Pfefferkorn
Yuntao Song
Bharat K. Trivedi
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Warner-Lambert Company Llc
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Publication of WO2006059210A2 publication Critical patent/WO2006059210A2/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

Abstract

HMGCo-A reductase inhibitor compounds useful as hypocholesterolemic and hypolipidenuc compounds are provided. Also provided are pharmaceutical compositions of the compounds. Methods of making and methods of using the compounds are also provided.

Description

FUSED BICYCLIC PYRROLES AS HMG - CoA REDUCTASE INHIBITORS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional Patent Application No. 60/632,855 filed December 3, 2004, and U.S. Provisional Patent Application No. 60/635,649 filed December 13, 2004.

FIELD OF THE INVENTION

The present invention relates to compounds and pharmaceutical compositions useful as hypocholesterolemic and hypolipidemic agents. More specifically, the present invention concerns certain potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase ("HMG CoA reductase"). The invention further relates to methods of using such compounds and compositions to treat subjects, including humans, suffering from hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, Alzheimer's Disease, BPH, diabetes and osteoporosis.

BACKGROUND OF THE INVENTION

High levels of blood cholesterol and blood lipids are conditions involved in the onset of atherosclerosis. The conversion of HMG-CoA to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from catalyzing this conversion. As such, statins are collectively potent lipid lowering agents. Thus, statins are the drugs of first choice for management of many lipid disorders. Representaative statins include atorvastatin, lovastatin, pravastatin and simvastatin.

It is known that inhibitors of HMG-CoA reductase are effective in lowering the blood plasma level of low density lipoprotein cholesterol (LDL-C), in man. (cf. M.S. Brown and J. L. Goldstein, New England Journal of Medicine, 305, No. 9, 515-517 (1981). It has been established that lowering LDL-C levels affords protection from coronary heart disease (cf. Journal of the American Medical Association, 251 , No. 3, 351-374 (1984). Further, it is known that certain derivatives of mevalonic acid (3,5-dihydroxy-3- methylpentanoic acid) and the corresponding ring-closed lactone form mevalonolactone, inhibit the biosynthesis of cholesterol (cf. F. M. Singer et al., Proc. Soc. Exper. Biol. Med., 102: 370 (1959) and F.H. Hulcher, Arch. Biochem. Biophys., 146: 422 (1971 )). U.S. Pat. Nos. 3,983,140; 4,049,495 and 4,137,322 disclose the fermentative production of a natural product, now called compactin, having an inhibitory effect on cholesterol biosynthesis. Compactin has veen shown to have a complex structure which includes a mevalonolactone moiety (Brown et al., J. Chem. Soc. Perkin I (1976) 1165. U.S. Pat. No. 4,255,444 to Oka et al. discloses several synthetic derivatives of mevalonolactone having antilipidemic activity. U.S. Pat. Nos. 4,198,425 and 4,262,013 to Mitsue et al. disclose aralkyl derivatives of mevalonolactone which are useful in the treatment of hyperlipidemia. Atorvastatin and pharmaceutically acceptable salts thereof are selective, competitive inhibitors of HMG-CoA reductase. As such, atorvastatin calcium is a potent lipid lowering compound and is thus useful as a hypolipidemic and/or hypocholesterolemic agent, as well as in the treatment of osteoporosis and Alzheimer's disease. A number of patents have issued disclosing atorvastatin. These include: United States Patent Numbers 4,681 ,893; 5,273,995 and 5,969,156, which are incorporated herein by reference

All statins interfere, to varying degrees, with the conversion of HMG-CoA to the cholesterol precursor mevalonate by HMG-CoA reductase. These drugs share many features, but also exhibit differences in pharmacologic attributes that may contribute to differences in clinical utility and effectiveness in modifying lipid risk factors for coronary heart disease. (Clin. Cardiol. BoI. 26 (Suppl. Ill), II1-32-III-38 (2003). Some of the desirable pharmocologic features with statin therapy include potent reversible inhibition of HMGCoA reductase, the ability to produce large reductions in LDL-C and non-high- density lipoprotein cholesterol (non-HDL-C), the ability to increase HDL cholesterol (HDL-C), tissue selectivity optimal pharmacokinetics, availability of once a day dosing and a low potential for drug-drug interactions. Also desirable is the ability to lower circulating very-low-density-lipoprotein(VLDL) as well as the ability to lower triglyeride levels.

At the present time, the most potent statins display invitro IC50 values, using purified human HMG- CoA reductase catalytic domain preparations, of between about 5.4 and about 8.0 nM. Am J. Cardiol 2001 ;87(suppl):28B-32B; Atheroscer Suppl. 2002;2:33-37. Generally, the most potent LDL-C-lowering statins are also the most potent non-HDL-C-lowering statins. Thus, maximum inhibitory activity is desirable. With respect to HDL-C, the known statins generally produce only modest increases in HDL-C. Therefor, the ability to effect greater increases in HDL-C would be advantageous as well.

With respect to tissue selectivity, differences among statins in relative lipophilicity or hydrophilicity may influence drug kinetics and tissue selectivity. Relatively hydrophilic drugs may exhibit reduced access to nonhepatic cells as a result of low passive diffusion and increased relative hepatic cell uptake through selective organic ion transport. In addition, the relative water solubility of a drug may reduce the need for extensive cytochrome P450 (CYP) enzyme metabolism. Many drugs, including the known statins, are metabolized by the CYP3A4 enzyme system. Arch Intern Med 2000; 160:2273-2280; JAm Pharm Assoc 2000; 40:637-644. Thus, relative hydrophilicity is desirable with statin therapy.

Two important pharmacokinetic variables for statins are bioavailability and elimination half-life. It would be advantageous to have a statin with limited systemic availability so as to minimize any potential risk of systemic adverse effects, while at the same time having enough systemic availability so that any pleiotropic effects can be observed in the vasculature with statin treatment. Theses pleiotropic effects include improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, reduction in blood plasma levels of certain markers of inflammation such as C-reactive protein, decreasing oxidative stress and reducing vascular inflammation. Arterioscler Thromb Vase Biol 2001 ; 21:1712-1719; Heart Dis 5(1):2-7, 2003. Further, it would be advantageous to have a statin with a long enough elimination half-life to maximize effectiveness for lowering LDL-C. Finally, it would be advantageous to have a statin that is either not metabolized or minimally metabolized by the CYP 3A4 systems so as to minimize any potential risk of drug-drug interactions when statins are given in combination with other drugs.

Accordingly, it would be most beneficial to provide a statin having a combination of desirable properties including high potency in inhibiting HMG-CoA reductase, the ability to produce large reductions in LDL-C and non-high density lipoprotein cholesterol, the ability to increase HDL cholesterol, selectivity of effect or uptake in hepatic cells, optimal systemic bioavailability, prolonged elimination half-life, and absence or minimal metabolism via the CYP3A4 system.

SUMMARY OF THE INVENTION

This invention provides a novel series of fused bicyclic pyrroles as HMG-CoA reductase inhibitors. Compounds of the invention are potent inhibitors of cholesterol biosynthesis. Accordingly, the compounds find utility as therapeutic agents to treat hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, Alzheimer's Disease, BPH, diabetes and osteoporosis. More specifically, the present invention provides a compound having a Formula I,

Figure imgf000004_0001

Formula I or a pharmaceutically acceptable salt, ester, amide, stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug, wherein R1 is C1 - C6 alkyl or C3 - C8 cycloalkyl; R2 and R5 are each independently H; C1-C7 alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; said alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted with a halogen, C1-C6 alkyl, -(CH2)mOH-, C1-C6 alkoxy, C(O)OR' or C(O)NR1R"; R' and R" are each independently C1-C6 alkyl or C1-C6 alkenyl, optionally substituted; or H; R3 and R4 taken together with the carbons to which they are attached, form a 5 to 8 member saturated or unsaturated ring, optionally containing one or more heteroatom; wherein is a bond or is absent; m is 0-6 and n is 0-3. Further provided is compound having a Formula II,

Figure imgf000004_0002

Formula Il -A- or a pharmaceutically acceptable salt, ester, amide, stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug, wherein R1 is C1-C6 alkyl or C3 - C8 cycloalkyl; R2 and R5 are each independently H; C1- C7 alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; said alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted with a halogen, C1-C6 alkyl, (CH2)mOH~, CrC6 alkoxy, C(O)OR' or C(O)NR1R"; R' and R" are each independently C1-C6 alkyl or C1-C6 alkenyl, optionally substituted; or H; wherein is a bond or is absent; m is 0-6 and n is 0-3.

Further provided is a compound having a Formula III,

Figure imgf000005_0001

Formula III

Wherein R1 is C1 - C6 alkyl or C3 - C8 cycloalkyl; R2 and R5 are each independently selected from H; C1- C7 alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; said alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted with a halogen, C1-C6 alkyl, -(CH2)mOH- or C1 - C6 alkoxy; R' is C1-C7 alkyl or alkenyl optionally substituted with one or more groups selected from: -OH, -OR, - COR", P+Ph3Br-, or P(O)(OR")2; R" is C1 - C6 alkyl or H; m is 0-6 and n is 0-3.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound having a Formula I,

Figure imgf000005_0002

Formula I or a pharmaceutically acceptable salt, ester, amide, stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug, wherein R1 is C1 - C6 alkyl or C3 - C8 cycloalkyl; R2 and R5 are each independently H; C1-C7 alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; said alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted with a halogen, C1-C6 alkyl, -(CH2)mOH- , C1 - C6 alkoxy, C(O)OR' or C(O)NR1R"; R' and R" are each independently C1-C6 alkyl or C1-C6 alkenyl, optionally substituted; or H; R3 and R4 taken together with the carbons to which they are attached, form a 5 to 8 member saturated or unsaturated ring, optionally containing one or more heteroatom; wherein is a bond or is absent m is 0-6; and n is 0-3. Further provided is the compound or the pharmaceutically acceptable salt, ester amide, stereoisomer or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug, wherein R1 is isopropyl.

Further provided is the above-referenced compound or the pharmaceutically acceptable salt, ester amide, stereoisomer or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug, wherein R2 is H. Further provided is the compound wherein R2 is phenyl or phenyl substituted with a halogen. Further provided is the compound wherein R2 is benzyl or benzyl substituted with a halogen.

Further provided is the above referenced compound or the pharmaceutically acceptable salt, ester amide, stereoisomer or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug wherein R3 and R4 taken together with the carbon atoms to which they are attached form a phenyl.

Further provided is the above compound or the pharmaceutically acceptable salt, ester amide, stereoisomer or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug wherein R2 and R5 are each independently benzyl, benzyl substituted with a halogen, phenyl, or phenyl substituted with a halogen. Further provided is the compound wherein R2 and R5 are each independently phenyl or phenyl substituted with fluorine.

Further provided is compound having a Formula II,

Figure imgf000006_0001

Formula Il or a pharmaceutically acceptable salt, ester, amide, stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug, wherein R1 is C1-C6 alkyl or C3 - C8 cycloalkyl; R2 and R5 are each independently H; C1- C7 alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; said alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted with a halogen, C1-C6 alkyl, -(CH2)mOH-, C1-C6 alkoxy, C(O)OR' or C(O)NR1R"; R' and R" are each independently C1-C6 alkyl or C1-C6 alkenyl, optionally substituted; or H; wherein is a bond or is absent; m is 0-6 and n is 0-3.

Further provided is the compound wherein R1 is isopropyl. Further provided is the compound wherein R2 is H. Further provided is the compound wherein n is 0 or 1.

The present invention provides inter alia the following compounds:

7-[1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid;

7-[1 -(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6-tetrahydro-3,5-diaza-benzo[e]azulen-2- y!]-3,5-dihydroxy-heptanoic acid;

7-[1-(4-fluoro-phenyl)-5-(3-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-

2-yl]-3,5-dihydroxy-heptanoic acid;

7-[1 ,5-bis-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid; y-ti .δ-bis-CΦfluoro-phenyO-S-isopropyl-Φoxo^.S-dihydro-SH-pyrrolo^.S-clquinolin^-y^-S.S- dihydroxy-hept-6-enoic acid;

7-[5-(3-chloro-phenyl)-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-

2-yl]-3,5-dihydroxy-heptanoic acid;

7-[5-biphenyl-4-yl-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2- yl]-3,5-dihydroxy-heptanoic acid ;

7-[5-benzyl-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid ;

7-[5-(2-fluoro-benzyl)-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-

2-yl]-3,5-dihydroxy-heptanoic acid ;

7-[5-(3-fluoro-benzyl)-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-

2-yl]-3,5-dihydroxy-hept-6-enoic acid ;

7-[5-(3-fiuoro-benzyl)-3-isopropyl-4-oxo-1-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid ;

7-[5-(4-fluoro-benzyl)-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolot2,3-c]quinolin-

2-yl]-3,5-dihydroxy-hept-6-enoic acid;

7-[5-(4-fluoro-benzyl)-3-isopropyl-4-oxo-1-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid;

7-[1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5-dihydroxy- heptanoic acid; and pharmaceutically acceptable salts, esters and amides thereof.

Further provided is a compound having a Formula III,

Figure imgf000007_0001

Formula III

Wherein R1 is C1 - C6 alkyl or C3 - C8 cycloalkyl; R2 and R5 are each independently H; C1-C7 alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; said alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted with a halogen, C1 -C6 alkyl, -(CH2)mOH- or C1 - C6 alkoxy;

R' is C1-C7 alkyl or C1-C7 alkenyl optionally substituted with one or more groups selected from: -OH, -OR, -COR", P+Ph3Br-, or P(O)(OFT)2; R" is C1 - C6 alkyl or H; m is 0-6 and n is 0-3.

Further provided is a stereoisomer of the above compound comprising a (3R, 5R)-isomer. Further provided is a stereoisomer of the compound comprising a (3R, 5S)-isomer. Further provided is a stereoisomer of the compound comprising a (3S, 5S)-isomer. Further provided is a stereoisomer of the compound comprising a (3S, 5R)-isomer. Further provided is a pharmaceutical composition comprising the above compound or the pharmaceutically acceptable salt, ester, amide or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug; or a mixture thereof; and a pharmaceutically acceptable carrier, diluent or vehicle. Further provided is a method of inhibiting cholesterol biosynthesis in a mammal requiring inhibition comprising administering to the mammal a therapeutically effective amount of the above compound or the pharmaceutically acceptable salt, ester, amide or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug.

Further provided is a method of lowering LDL cholesterol in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of the above compound or the pharmaceutically acceptable salt, ester, amide or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug.

Further provided is a method of raising HDL cholesterol in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of the above compound or the pharmaceutically acceptable salt, ester, amide or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug.

Further provided is a method of treating, preventing or controlling hyperlipidemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of the above compound. Further provided is a method of treating, preventing or controlling hypercholesterolemia in a mammal. Further provided is a method of treating, preventing or controlling atherosclerosis in a mammal. Further provided is a method of treating, preventing or controlling Alzheimer's disease, BPH, diabetes or osteoporosis in a mammal.

Further provided is a lactone form of the above compound, said lactone having a Formula IV,

Figure imgf000008_0001

Formula IV or a pharmaceutically acceptable salt, ester, amide, stereoisomer, racemic mixture or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug, wherein R1, R2, R3, R4, R5, and n are as defined above.

Further provided is a combination of the above-referenced compound or the pharmaceutically acceptable salt, ester amide, stereoisomer or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug, and another pharmaceutically active agent. Further provided is the combination wherein the other pharmaceutically active agent is a CETP inhibitor, a PPAR- activator, an MTP/Apo B secretion inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, an ion- exchange resin, an antioxidant, an ACAT inhibitor, or bile sequestrant; an anti-hypertensive agent; or an acetylcholine esterase inhibitor. Further provided is a pharmaceutical compostion comprising the above referenced combination and a pharmaceutically acceptable carrier, diluent or vehicle.

The following definitions are used, unless otherwise described. Halo is fluoro, chloro, bromo or iodo. Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups.

The term "alkyl" as used herein refers to a straight or branched hydrocarbon of from 1 to 11 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. The alkyl group can also be substituted with one or more of the substituents selected from lower alkoxy, lower thioalkoxy, -0(CH2)o-2CF3, halogen, nitro, cyano, =0, =S, -OH, -SH, -CF3, -CO2H, -CO2C1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -CONR'R", or -N(CrC6alkyl)2 where R' and R" are independently alkyl, akenyl, alkynyl, aryl, or joined together to form a 4 to 7 member ring. Useful alkyl groups have from 1 to 6 carbon atoms (C1-C6 alkyl).

The term "lower alkyl" as used herein refers to a subset of alkyl which means a straight or branched hydrocarbon radical having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, fe/f-butyl, n-pentyl, n-hexyl, and the like. Optionally, lower alkyl is referred to as "C1-C6 alkyl."

The term "haloalkyl" as used herein refers to a lower alkyl radical, as defined above, bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl, or 1 ,1 ,1- trifluoroethyl and the like. Haloalkyl can also include perfluoroalkyl wherein all hydrogens of a loweralkyl group are replaced with fluorine atoms.

The term "alkenyl" means a straight or branched unsaturated hydrocarbon radical from 2 to 12 carbon atoms and includes, for example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 3-heptenyl, l-octenyl, 1-nonenyl, 1 - decenyl, 1 -undecenyl, 1 -dodecenyl, and the like.

The term "alkynyl" means a straight or branched hydrocarbon radical of 2 to 12 carbon atoms having at least one triple bond and includes, for example, 3-propynyl, 1-butynyl, 3-butynyl, 1-pentynyl, 3- pentynyl, 3-methyl-3-butynyl, 1-hexynyl, 3-hexynyl, 3-hexynyl, 3-heptynyl, l-octynyl, 1-nonynyl, 1 -decynyl, 1-undecynyl, 1-dodecynyl, and the like.

The term "alkylene" as used herein refers to a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 10 carbon atoms by the removal of two hydrogen atoms, for example methylene, 1 ,2-ethylene, 1 ,1 -ethylene, 1 ,3-propylene, 2,2- dimethylpropylene, and the like. The alkylene groups of this invention can be optionally substituted with one or more of the substituents selected from lower alkyl, lower alkoxy, lower thioalkoxy, -O(CH2)0.2CF3, halogen, nitro, cyano, =0, =S, -OH, -SH, -CF3, -CO2H, -CO2C1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -CONR1R", or -N(CrC6alkyl)2 where R' and R" are independently alkyl, akenyl, alkynyl, aryl, or joined together to form a 4 to 7 member ring. Useful alkylene groups have from 1 to 6 carbon atoms (C1-C6 alkylene).

The term "heteroatom" as used herein represents oxygen, nitrogen, or sulfur (O, N, or S) as well as sulfoxyl or sulfonyl (SO or SO2) unless otherwise indicated.

The term "hydrocarbon chain" as used herein refers to a straight hydrocarbon of from 2 to 6 carbon atoms. The hydrocarbon chain is optionally substituted with one or more substituents selected from lower alkyl, lower alkoxy, lower thioalkoxy, -O(CH2)0-2CF3, halogen, nitro, cyano, =0, =S, -OH, -SH, -CF3, -CO2H, -CO2C1-C6 alkyl, -NH2, -NHC1-C8 alkyl, -CONR'R", or -N(CrC6alkyl)2 where R' and R" are independently alkyl, alkenyl, alkynyl, aryl, or joined together to form a 4 to 7 member ring.

The term "hydrocarbon-heteroatom chain" as used herein refers to a hydrocarbon chain wherein one or more carbon atoms are replaced with a heteroatom. The hydrocarbon-heteroatom chain is optionally substituted' with one or more substituents selected from lower alkyl, lower alkoxy, lower thioalkoxy, -0(CH2)O-2CF3, halogen, nitro, cyano, =0, =S, -OH, -SH, -CF3, -CO2H, -CO2C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -CONR'R", or -N(CrC6alkyl)2 where R' and R" are independently alkyl, alkenyl, alkynyl, aryl, or joined together to form a 4 to 7 member ring.

The term "heteroalkylene" as used herein, refers to an alkylene radical as defined above that includes one or more heteroatoms such as oxygen, sulfur, or nitrogen (with valence completed by hydrogen or oxygen) in the carbon chain or terminating the carbon chain.

The terms "lower alkoxy" and "lower thioalkoxy" as used herein refers to O-alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for "lower alky!."

The term "aryl" as used herein refers to an aromatic ring which is unsubstituted or optionally substituted by 1 to 4 substituents selected from lower alkyl, lower alkoxy, lower thioalkoxy, -O(CH2)pCF3, halogen, nitro, cyano -OH, -SH, -CF3, -CO2H, -CO2C1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -S02alkyl, -SO2NH2, -CONR'R", or -N(CrC6alkyl)2 where R' and R" are independently alkyl, alkenyl, alkynyl, aryl, or joined together to form a 4 to 7 member ring. Examples include, but are not limited to phenyl, biphenyl, naphthyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, A- methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyI, 2-chloro-3-methylphenyl, 2-chloro- 4-methylphenyl, 2-chloro-5-methylphenyl, 3-chloro-2-methylphenyl, 3-chloro-4-methylphenyl, 4-chloro-2- methylphenyl, 4-chloro-3-methylphenyl, 5-chloro-2-methylphenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, or the like. Further, the term "aryl" means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms, and being unsubstituted or substituted with up to 4 of the substituent groups recited above for alkyl, alkenyl, and alkynyl.

The term aralkyl as used herein means aryl, as defined above, attached to an alkyl group.

The term "heteroaryl" means an aromatic ring containing one or more heteroatom. The heteroaryl is optionally substituted with one or more groups enumerated for aryl. Examples of heteroaryl include, but are not limited to thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, and quinazolinyl, and the like. Further, the term "heteroaryl" means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (i.e. 1-4) heteroatoms selected from N, O, and S, which mono-, bi-, or polycyclic ring is optionally substituted with - OH, -O(alkyl), SH, S(alkyl), amine, halogen, acid, ester, amide, amidine, alkyl ketone, aldehyde, nitrile, fluoroalkyl, nitro, sulphone, sulfoxide or C|.6 alkyl. Examples further include I-, 2-, A-, or 5-imidazolyl, I-, 3-, A-, or 5-pyrazolyl, 2-, A-, or 5-thiazolyl, 3-, A-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, A-, or 5-isoxazolyl, 1 , 3-, or 5-triazolyl, I-, 2-, or 3-tetrazolyl, 2-pyrazinyl, 2-, A-, or 5-pyrimidinyl. Examples of suitable bicyclic heteroaryl compounds include, but are not limited to indolizinyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, I-, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, I-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, I-, 2-, 3-, A-, 5-, Q-, or 7-isoindolyl, 2-, 3-, A-, 5-, 6-, or 7-benzothienyl, 2-, A-, 5-, 6-, or 7-benzoxazolyl, 1-, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, and I-, 3- , 4-, 5-, 6-, 7-, or 8-isoquinolinyl.

The term heteroaralkyl, as used herein, means heteroaryl, as defined above, attached to an alkyl group.

The term "heterocycle" means a saturated mono- or poiycyclic (i.e. bicyclic) ring incorporating one or more (i.e. 1-4) heteroatoms selected from N, O, and S. It is understood that a heterocycle is optionally substituted with -OH, -O(alkyl), SH, S(alkyl), amine, halogen, acid, ester, amide, amidine, alkyl ketone, aldehyde, nitrile, fluoroalkyl, nitro, sulphone, sulfoxide or CI-6 alkyl. Examples of suitable monocyclic heterocycles include, but are not limited to piperidinyl, pyrrolidinyl, piperazinyl, azetidinyl, aziridinyl, morpholinyl, thietanyl, oxetaryl.

The term "cycloalkyl" means a saturated hydrocarbon ring. Further, the term "cycloalkyl" means a hydrocarbon ring containing from 3 to 12 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, decalinyl, norpinanyl, and adamantyl. The cycloalkyl ring may be unsubstituted or substituted by 1 to 3 substituents selected from alkyl, alkoxy, thioalkoxy, hydroxy, thiol, nitro, halogen, amino, alkyl and dialkylamino, formyl, carboxyl, CN, -NH-CO-R-CO-NHR-, -CO2R-, -COR-

, aryl, or heteroaryl, wherein alkyl, aryl, and heteroaryl are as defined herein. Examples of substituted cycloalkyl groups include fluorocyclopropyl, 2-iodocyclobutyl, 2,3-dimethylcyclopentyl, 2,2- dimethoxycyclohexyl, and 3-phenylcyclopentyl.

The term "cycloalkenyl" means a cycloalkyl group having one or more carbon-carbon double bond. Example includes cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclobutadiene, cyclopentadiene, and the like.

The term "isomer" means "stereoisomer" and "geometric isomer" as defined below.

The term "stereoisomer" means compounds that possess one or more chiral centers and each center may exist in the R or S configuration. Stereoisomers includes all diastereomeric, enantiomeric and epimeric forms as well as racemates and mixtures thereof.

The term "geometric isomer" means compounds that may exist in cis, trans syn, anti, entgegen (E), and zusammen (Z) forms as well as mixtures thereof.

The symbol "=" means a double bond.

The symbol "n" means a bond to a group wherein a 4 to 8 membered ring is formed. Typically this symbol will appear in pairs.

When a bond to a substituent is shown to cross the bond connecting 2 atoms in a ring, then such substituent may be bonded to any atom in the ring, provided the atom will accept the substituent without violating its valency. When there appears to be several atoms of the substituent that may bond to the ring atom, then it is the first atom of the listed substituent that is attached to the ring.

When a bond from a substituent is shown to cross the bond connecting 2 atoms in a ring of the substituent, then such substituent may be bonded from any atom in the ring which is available.

When a bond is represented by a line such as "---" this is meant to represent that the bond may be absent or present provided that the resultant compound is stable and of satisfactory valency. If an asymetric carbon is created by such a bond, a particular stereochemistry is not to be implied. As used herein, the following terms have the meanings given: RT means room temperature. MP means melting point. MS means mass spectroscopy. TLC means thin layer chromatography. [S]at. means saturated. [C]onc. means concentrated. TBIA means tert- Butylisopropylidene amine. DCM means dichloromethane, which is used interchangeably with methylene chloride. NBS means N- Bromosuccinimide. "h" means hour, "v/v" means volume ratio or "volume per volume". R{ means retention factor. Tf2O means "triflic anhydride" or C(F)3S(O)2OS(O)2C(F)3Or (CF3SO2)2O. Ac2O means acetic anhydride. "|T]rifluorotol." means trifluorotoluene. "DMF" means dimethylformamide. "DCE" means dichloroethane. "Bu" means butyl. "Me" means methyl. "Et" means ethyl. "DBU" means 1 ,8- Diazabicyclo-[5.4.0]undec-7-ene. 'TBDMS" means tert-Butyldimethylsilyl. "DMSO" means dimethyl sulfoxide.

The term "patient" means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits.

A "therapeutically effective amount" is an amount of a compound of the present invention that when administered to a patient ameliorates a symptom of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or atheroscelerois.

The term "a pharmaceutically acceptable salt, ester, amide, or prodrug" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "a pharmaceutically acceptable salt" refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free form with a suitable organic or inorganic acid or base and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. Pharmaceutically acceptable salts also include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, Berge S. M., et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, which is incorporated herein by reference.) The free base form may be regenerated by contacting the salt form with a base. While the free base may differ from the salt form in terms of physical properties, such as solubility, the salts are equivalent to their respective free bases for the purposes of the present invention.

Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C1-C6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. CrC4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.

Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6 alky! amines and secondary Ci-C6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.

"Prodrugs" are intended to include any covalently bonded carrier which releases the active parent drug according to Formula I in vivo. Further, the term "prodrug" refers to compounds that are transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference. Examples of prodrugs include acetates, formates, benzoate derivatives of alcohols, and amines present in compounds of Formula I.

In some situations, compounds may exist as tautomers. All tautomers are included within Formula I and are provided by this invention.

Certain compounds of the present invention can exist in unsolvated form as well as solvated form including hydrated form. In general, the solvated form including hydrated form is equivalent to the unsolvated form and is intended to be encompassed within the scope of the present invention.

Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration. The present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers may be obtained, if desired, by methods known in the art as, for example, the separation of stereoisomers by chiral chromatographic columns and by chiral synthesis. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

The compounds of the present invention are suitable to be administered to a patient for the treatment, control, or prevention of, hypercholesteremia, hyperlipidemia, atherosclerosis and hypertriglyceridemia. The terms "treatment", "treating", "controlling", "preventing" and the like, refers to reversing, alleviating, or inhibiting the progress of the disease or condition to which such term applies, or one or more symptoms of such disease or condition. As used herein, these terms also encompass, depending on the condition of the patient, preventing the onset of a disease or condition or of symptoms associated with a disease or condition, including reducing the severity of a disease or condition or symptoms associated therewith prior to affliction with said disease or condition. Such prevention or reduction prior to affliction refers to administration of the compound of the invention to a subject that is not at the time of administration afflicted with the disease or condition. "Preventing" also encompasses preventing the recurrence of a disease or condition or of symptoms associated therewith. Accordingly, the compounds of the present invention can be administered to a patient alone or as part of a composition that contains other components such as excipients, diluents, and carriers, all of which are well-known in the art. The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneal^, intravesical^, locally (powders, ointments, or drops), or as a buccal or nasal spray.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzόate, propyleneglycol, 1 ,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 2,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art.

Combination Aspect of the Invention

The compounds of this invention may be used, either alone or in combination with the other pharmaceutical agents described herein, in the treatment of the following diseases/conditions: dyslipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, peripheral vascular disease, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, diabetes and vascular complications of diabetes, obesity, unstable angina pectoris, Alzheimer's Disease, BPH, osteoporosis, cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhythmia, pulmonary vascular disease, renal-vascular disease, renal disease, vascular hemostatic disease, autoimmune disorders, pulmonary disease, sexual dysfunction, cognitive dysfunction, cancer, organ transplant rejection, psoriasis, endometriosis, and macular degeneration.

The compounds of this invention may also be used in conjunction with other pharmaceutical agents (e.g., HDL-cholesterol raising agents, triglyceride lowering agents) for the treatment of the disease/conditions described herein. A combination aspect of this invention includes a pharmaceutical composition comprising a compound of this invention or its pharmaceutically acceptable salt and at least one other compound. For example, the compounds of this invention may be used in combination with cholesterol absorption inhibitors, MTP/Apo B secretion inhibitors, or other cholesterol modulating agents such as fibrates, niacin, ion-exchange resins, antioxidants, ACAT inhibitors, PPAR-activators, CETP inhibitors or bile acid sequestrants. In combination therapy treatment, both the compounds of this invention and the other drug therapies are administered to mammals by conventional methods. The following discussion more specifically describes the various combination aspects of this invention.

Any cholesterol absorption inhibitor can be used in a combination aspect of this invention. The term cholesterol absorption inhibition refers to the ability of a compound to prevent cholesterol contained within the lumen of the intestine from entering into the intestinal cells and/or passing from within the intestinal cells into the blood stream. Such cholesterol absorption inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., J. Lipid Res. (1993) 34: 377-395). Cholesterol absorption inhibitors are known to those skilled in the art and are described, for example, in PCT WO 94/00480. An example of a recently approved cholesterol absorption inhibitor is ZETIA™.

Any cholesterol ester transfer protein ("CETP") inhibitor may be used in a combination aspect of this invention. The term CETP inhibitor refers to compounds that inhibit the transfer of cholesteryl ester and triglyceride between lipoprotein particles, including high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL), and chylomicrons. The net result of CETP activity is a lowering of HDL cholesterol and an increase in LDL cholesterol, such net effect therefore being pro-atherogenic. Thus, the effect of a CETP inhibitor on lipoprotein profile is believed to be antiatherogenic. Such inhibition is readily determined by those skilled in the art by determining the amount of agent required to alter plasma lipid levels, for example HDL cholesterol levels, LDL cholesterol levels, VLDL cholesterol levels or triglycerides, in the plasma of certain mammals, (e.g., Crook et al. Arteriosclerosis 10, 625, 1990; U.S. Pat. No. 6,140,343). A variety of these compounds are described and referenced below, however other CETP inhibitors will be known to those skilled in the art. For example, U.S. Patent Nos. 6,197,786, 6,723,752 and 6,723,753 (the disclosures of each of which is incorporated herein by reference) disclose cholesteryl ester transfer protein inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascualar diseases in some mammals, including humans. Examples of useful CETP inhibitors include the following compounds: [2R, 4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2- ethyl-δ-trifluoromethyl-S^-dihydroxycarbonyl-aminoj^-ethyl-δ-trifluoromethyl-S^-dihydro^H-quinoline-i- carboxylic acid ethyl ester, which is also known as Torcetrapib™ , and 3-{[3-(4-Chloro-3-ethyl-phenoxy)- phenyl]-[3-(1 ,1 ,2,2-tetraf luoro-ethoxy)-benzyl]-amino}-1 ,1 ,1 -trifluoro-propan-2-ol. Many of the CETP inhibitors of this invention are poorly soluble and a dosage form that increases solubility facilitates the administration of such compounds. One such dosage form is a dosage form comprising (1) a solid amorphous dispersion comprising a cholesteryl ester transfer protein (CETP) inhibitor and an acidic concentration-enhancing polymer; and (2) an acid-sensitive HMG-CoA reductase inhibitor. This dosage form is more fully described in USSN 10/739,567 and entitled "Dosage Forms Comprising a CETP Inhibitor and an HMG-CoA Reductase Inhibitor", the specification of which is incorporated herein by reference.

Any compound that activates or otherwise interacts with a human peroxisome proliferator activated receptor ("PPAR") may be used in a combination aspect of this invention. Three mammalian peroxisome proliferator-activated receptors have been isolated and termed PPAR-alpha, PPAR-gamma, and PPAR-beta (also known as NUC1 or PPAR-delta). These PPARs regulate expression of target genes by binding to DNA sequence elements, termed PPAR response elements. These elements have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism suggesting that PPARs play a pivotal role in the adipogenic signaling cascade and lipid homeostasis. PPAR-gamma receptors are associated with regulation of insulin sensitivity and blood glucose levels. PPAR-α activators are associated with lowering plasma triglycerides and LDL cholesterol. PPAR-β activators have been reported to both increase HDL-C levels and to decrease LDL-C levels. Thus, activation of PPAR-β alone, or in combination with the simultaneous activation of PPAR-α and/or PPAR- gamma may be desirable in formulating a treatment for dyslipidemia in which HDL is increased and LDL lowered. PPAR-activation is readily determined by those skilled in the art by the standard assays (e.g. US 2003/0225158 and US 2004/0157885). A variety of these compounds are described and referenced below, however other PPAR-activator compounds will be known to those skilled in the art. The following patents and published patent applications, the disclosure of each of which is incorporated herein by reference, provides a sampling. US 2003/0225158 discloses compounds that alter PPAR activity and methods of using them as therapeutic agents for treating or preventing dyslipidemia, hypercholesterolemia, obesity, hyperglycemia, atherosclerosis and hypertriglyceridemia. U.S. Pat. No. 6,710,063 discloses selective activators of PPAR delta. US 2003/0171377 discloses certain PPAR- activator compounds that are useful as anti-diabetic agents. US 2004/0157885 relates to PPAR agonists, in particular, certain PPARα agonists, pharmaceutical compositions containing such agonists and the use of such agonists to treat atherosclerosis, hypercholesterolemia, hypertriglyceridemia, diabetes, obesity, osteoporosis and Syndrome X or metabolic syndrome.

Examples of useful PPAR-activator compounds include the following compounds: [5-Methoxy-2- methly-4-(4'-trifluoromethly-biphenyl-4ylmethylsulfanyl)-phenoxy]-acetic acid; [5-Methoxy-2-methyl-4-(3'- trifloromethly-biphenyl^-ylmethylsulfanyO-phenoxyJ-acetic acid;

[4-(4'Fluoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2methy!-phenoxy]-acetic acid; {5-Methoxy-2methyl- 4-[4-(4-trifluoromethy!-benzyloxy)-benzylsulfanyl]-phenoxy}-acetic acid; {{5-Methoxy-2-methyl-4-[4-(5- trifluoromethyl-pryidin^-yO-benzylsulfanylJ-phenoxyJ-acetic acid; (4-{4-[2-(3-Fluoro-phenyl)-vinyl]-benzylsulfanyl}-5-methoxy-2-methyl-phenoxy)-acetic acid; [5-Methoxy-2- methyl-4-(3-methyl-4'-trifluoromθthyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acθtic acid; [5-Methoxy-2- methyl-4-(4'-trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-phenoxy]- acetic acid;

{5-Methoxy-2-methyl-4-[2-(4-trifluoromethyi-benzyloxy)-benzylsulfanyl]-phenoxy}acetic acid; 3-{5-t2-(-5-

Methyl-2 phenyl-oxazol-4-yl-ethoxy] -indol- 1-yl} -propionic acid; 3-{4[2-(5-methyl-2- phenyl-1 ,3-oxazol-4- yl)ethoxy- 1 H-indazol-1 yljpropanoic acid; 2-Methyl-2-{3-[({2-(5-methyl-2-phenyl-1 ,3-oxazol-4- yi)ethoxy]carbonyl}amino)methyl]phenoxy}propionic acid; 1 -{3'-[2-5-Methyl-2-phenyl-1 ,3-oxazol-4-y]-1 ,1 ' - biphenyl-3-yl}oxy)cyclobutanecarboxylic acid;

3-[3-(1 -Carboxy-1 -methyl-ethoxy)-phenyl]-piperidine-1 -carboxylic acid 3-trif luoromethyl-benzyl ester;

2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}me thyl)sulfanyl]phenoxy}acetic acid;

2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl )phenyl]-1 ,3-oxazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid; methyl 2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sul fanyl]phenoxy}acetate;

2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yi}methyl)sulf anyl]phenoxy}acetic acid;

(E)-3-[2-methyl-4-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl }methoxy)phenyl]-2-propenoic acid;

2-{3-chloro-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}me thyl)sulfanyl]phenyl}acetic acid;

2-{2-methyl-4-[({4-methyl-2-t3-fluoro-4-(trifluoromethyl)phenyl]-1 ,3-thiazo l-5- yl}methyl)sulfanyl]phenoxy}acetic acid; and pharmaceutically acceptable salts thereof.

Any MTP/Apo B secretion (microsomal triglyceride transfer protein and/or apolipoprotein B secretion) inhibitor can be used in the combination aspect of the present invention. The term MTP/Apo B secretion inhibitor refers to compounds, which inhibit the secretion of triglycerides, cholesteryl ester and phospholipids. Such inhibition is readily determined by those skilled in the art according to standard assays (e.g., Wetterau, J. R. 1992; Science 258:999). A variety of these compounds are known to those skilled in the art, including imputapride (Bayer) and additional compounds such as those disclosed in WO 96/40640 and WO 98/23593.

Any ACAT inhibitor can serve in the combination therapy aspect of the present invention. The term ACAT inhibitor refers to compounds that inhibit the intracellular esterification of dietary cholesterol by the enzyme acyl CoA: cholesterol acyltransferase. Such inhibition may be determined readily by one of skill in the art according to standard assays, such as the method of Heider et al. described in Journal of Lipid Research. 24:1127 (1983). A variety of these compounds are known to those skilled in the art, for example, U.S. Pat. No. 5,510,379 discloses certain carboxysulfonates, while WO 96/26948 and WO 96/10559 both disclose urea derivatives having ACAT inhibitory activity. Examples of ACAT inhibitors include compounds such as Avasimibe (Pfizer), CS-505 (Sankyo) and Eflucimibe (EIi Lilly and Pierre Fabre).

A lipase inhibitor can serve in the combination therapy aspect of the present invention. A lipase inhibitor is a compound that inhibits the metabolic cleavage of dietary triglycerides into free fatty acids and monoglycerides. Under normal physiological conditions, lipolysis occurs via a two-step process that involves acylation of an activated serine moiety of the lipase enzyme. This leads to the production of a fatty acid-lipase hemiacetal intermediate, which is then cleaved to release a diglyceride. Following further deacylation, the lipase-fatty acid intermediate is cleaved, resulting in free lipase, a monoglyceride and a fatty acid. The resultant free fatty acids and monoglycerides are incorporated into bile acid-phospholipid micelles, which are subsequently absorbed at the level of the brush border of the small intestine. The micelles eventually enter the peripheral circulation as chylomicrons. Such lipase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. 286: 190-231).

Pancreatic lipase mediates the metabolic cleavage of fatty acids from triglycerides at the 1- and 3- carbon positions. The primary site of the metabolism of ingested fats is in the duodenum and proximal jejunum by pancreatic lipase, which is usually secreted in vast excess of the amounts necessary for the breakdown of fats in the upper small intestine. Because pancreatic lipase is the primary enzyme required for the absorption of dietary triglycerides, inhibitors have utility in the treatment of obesity and the other related conditions. Such pancreatic lipase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. 286: 190-231).

Gastric lipase is an immunologically distinct lipase that is responsible for approximately 10 to 40% of the digestion of dietary fats. Gastric lipase is secreted in response to mechanical stimulation, ingestion of food, the presence of a fatty meal or by sympathetic agents. Gastric lipolysis of ingested fats is of physiological importance in the provision of fatty acids needed to trigger pancreatic lipase activity in the intestine and is also of importance for fat absorption in a variety of physiological and pathological conditions associated with pancreatic insufficiency. See, for example, C. K. Abrams, et al., Gastroenterology, 92,125 (1987). Such gastric lipase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. 286: 190-231).

A variety of gastric and/or pancreatic lipase inhibitors are known to one of ordinary skill in the art. Preferred lipase inhibitors are those inhibitors that are selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), valilactone, esterastin, ebelactone A, and ebelactone B. The compound tetrahydrolipstatin is especially preferred. The lipase inhibitor, N-3-trifluoromethylphenyl-N1- 3-chloro-4'- trifluoromethylphenylurea, and the various urea derivatives related thereto, are disclosed in U.S. Pat. No. 4,405,644. The lipase inhibitor, esteracin, is disclosed in U.S. Pat. Nos. 4,189,438 and 4,242,453. The lipase inhibitor, cyclo-0,0'-[(1,6-hexanediyl)-bis-(iminoc- arbonyl)]dioxime, and the various bis(iminocarbonyl)dioximes related thereto may be prepared as described in Petersen et al., Liebig's Annalen, 562, 205-229 (1949).

A variety of pancreatic lipase inhibitors are described herein below. The pancreatic lipase inhibitors lipstatin, (2S,3S,5S,7Z,10Z)-5-[(S)-2-formamido-4-methy!-valeryloxy]-2-hexyl-3-hydro- xy-7,10- hexadecanoic acid lactone, and tetrahydrolipstatin (orlistat), (2S,3S,5S)-5-[(S)-2-formamido-4-methyl- valeryloxy]-2-hexyl-3-hydroxy-hexa- decanoic 1 ,3 acid lactone, and the variously substituted N- formylleucine derivatives and stereoisomers thereof, are disclosed in U.S. Pat. No. 4,598,089. For example, tetrahydrolipstatin is prepared as described in, e.g., U.S. Pat. Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874. The pancreatic lipase inhibitor, FL-386, 1-[4-(2-methylpropyl)cyclohexyl]-2-[- (phenylsulfonyl)oxy]-ethanone, and the variously substituted sulfonate derivatives related thereto, are disclosed in U.S. Pat. No. 4,452,813. The pancreatic lipase inhibitor, WAY-121898, 4-phenoxyphenyl-4- methylpipe- ridin-1-yl-carboxylate, and the various carbamate esters and pharmaceutically acceptable salts related thereto, are disclosed in U.S. Pat. Nos. 5,512,565; 5,391 ,571 and 5,602,151. The pancreatic lipase inhibitor, valilactone, and a process for the preparation thereof by the microbial cultivation of Actinomycetes strain MG147-CF2, are disclosed in Kitahara, et al., J. Antibiotics, 40 (11), 1647-1650 (1987). The pancreatic lipase inhibitors, ebeiactone A and ebelactone B, and a process for the preparation thereof by the microbial cultivation of Actinomycetes strain MG7-G1 , are disclosed in Umezawa, et al., J. Antibiotics, 33, 1594-1596 (1980). The use of ebelactones A and B in the suppression of monoglyceride formation is disclosed in Japanese Kokai 08-143457, published Jun. 4, 1996.

Other compounds that are marketed for hyperlipidemia, including hypercholesterolemia and which are intended to help prevent or treat atherosclerosis include bile acid sequestrants, such as Welchol®, Colestid®, LoCholest® , Questran® and fibric acid derivatives, such as Atromid®, Lopid® and Tricor®"

Compunds of the present invention can be used with anti-diabetic compounds. Diabetes can be treated by administering to a patient having diabetes (especially Type II), insulin resistance, impaired glucose tolerance, or the like, or any of the diabetic complications such as neuropathy, nephropathy, retinopathy or cataracts, a therapeutically effective amount of a Formula I compound in combination with other agents (e.g., insulin) that can be used to treat diabetes. This includes the classes of anti-diabetic agents (and specific agents) described herein.

Any glycogen phosphorylase inhibitor can be used in combination with a Formula I compound of the present invention. The term glycogen phosphorylase inhibitor refers to compounds that inhibit the bioconversion of glycogen to glucose-1 -phosphate which is catalyzed by the enzyme glycogen phosphorylase. Such glycogen phosphorylase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., J. Med. Chem. 41 (1998) 2934-2938). A variety of glycogen phosphorylase inhibitors are known to those skilled in the art including those described in WO 96/39384 and WO 96/39385.

Any aldose reductase inhibitor can be used in combination with a Formula I compound of the present invention. The term aldose reductase inhibitor refers to compounds that inhibit the bioconversion of glucose to sorbitol, which is catalyzed by the enzyme aldose reductase. Aldose reductase inhibition is readily determined by those skilled in the art according to standard assays (e.g., J. Malone, Diabetes, 29:861-864 (1980). "Red Cell Sorbitol, an Indicator of Diabetic Control"). A variety of aldose reductase inhibitors are known to those skilled in the art.

Any sorbitol dehydrogenase inhibitor can be used in combination with a Formula I compound of the present invention. The term sorbitol dehydrogenase inhibitor refers to compounds that inhibit the bioconversion of sorbitol to fructose which is catalyzed by the enzyme sorbitol dehydrogenase. Such sorbitol dehydrogenase inhibitor activity is readily determined by those skilled in the art according to standard assays (e.g., Analyt. Biochem (2000) 280: 329-331). A variety of sorbitol dehydrogenase inhibitors are known, for example, U.S. Pat. Nos. 5,728,704 and 5,866,578 disclose compounds and a method for treating or preventing diabetic complications by inhibiting the enzyme sorbitol dehydrogenase.

Any glucosidase inhibitor can be used in combination with a Formula I compound of the present invention. A glucosidase inhibitor inhibits the enzymatic hydrolysis of complex carbohydrates by glycoside hydrolases, for example amylase or maltase, into bioavailable simple sugars, for example, glucose. The rapid metabolic action of glucosidases, particularly following the intake of high levels of carbohydrates, results in a state of alimentary hyperglycemia which, in adipose or diabetic subjects, leads to enhanced secretion of insulin, increased fat synthesis and a reduction in fat degradation. Following such hyperglycemias, hypoglycemia frequently occurs, due to the augmented levels of insulin present.

Additionally, it is known chyme remaining in the stomach promotes the production of gastric juice, which initiates or favors the development of gastritis or duodenal ulcers. Accordingly, glucosidase inhibitors are known to have utility in accelerating the passage of carbohydrates through the stomach and inhibiting the absorption of glucose from the intestine. Furthermore, the conversion of carbohydrates into lipids of the fatty tissue and the subsequent incorporation of alimentary fat into fatty tissue deposits is accordingly reduced or delayed, with the concomitant benefit of reducing or preventing the deleterious abnormalities resulting therefrom. Such glucosidase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Biochemistry (1969) 8: 4214).

A generally preferred glucosidase inhibitor includes an amylase inhibitor. An amylase inhibitor is a glucosidase inhibitor that inhibits the enzymatic degradation of starch or glycogen into maltose. Such amylase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. (1955) 1 : 149). The inhibition of such enzymatic degradation is beneficial in reducing amounts of bioavailable sugars, including glucose and maltose, and the concomitant deleterious conditions resulting therefrom.

A variety of glucosidase inhibitors are known to one of ordinary skill in the art and examples are provided below. Preferred glucosidase inhibitors are those inhibitors that are selected from the group consisting of acarbose, adiposine, voglibose, miglitol, emiglitate, camiglibose, tendamistate, trestatin, pradimicin-Q and salbostatin. The glucosidase inhibitor, acarbose, and the various amino sugar derivatives related thereto are disclosed in U.S. Pat. Nos. 4,062,950 and 4,174,439 respectively. The glucosidase inhibitor, adiposine, is disclosed in U.S. Pat. No. 4,254,256. The glucosidase inhibitor, voglibose, 3,4-dideoxy-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-2-C-(hydroxymethy- l)-D-epi-inositol, and the various N-substituted pseudo-aminosugars related thereto, are disclosed in U.S. Pat. No. 4,701 ,559. The glucosidase inhibitor, miglitol, (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydr- oxymethyl)- 3,4,5-piperidinetriol, and the various 3,4,5-trihydroxypiperidines related thereto, are disclosed in U.S. Pat. No. 4,639,436. The glucosidase inhibitor, emiglitate, ethyl p-β-f^R.SR^R.δShSAδ-trihyd- roxy-2- (hydroxymethyl)piperidino]ethoxy]-benzoate, the various derivatives related thereto and pharmaceutically acceptable acid addition salts thereof, are disclosed in U.S. Pat. No. 5,192,772. The glucosidase inhibitor, MDL-25637, 2,6-dideoxy-7-O-.beta.-D-glucopyrano-syl-2,6-imino-- D-glycero-L-gluco-heptitol, the various homodisaccharides related thereto and the pharmaceutically acceptable acid addition salts thereof, are disclosed in U.S. Pat. No. 4,634,765. The glucosidase inhibitor, camiglibose, methyl 6-deoxy-6- [(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxym- ethyl)piperidino]-.alpha.-D-glucopyranoside sesquihydrate, the deoxy-nojirimycin derivatives related thereto, the various pharmaceutically acceptable salts thereof and synthetic methods for the preparation thereof, are disclosed in U.S. Pat. Nos. 5,157,116 and 5,504,078. The glycosidase inhibitor, salbostatin and the various pseudosaccharides related thereto, are disclosed in U.S. Pat. No. 5,091 ,524. A variety of amylase inhibitors are known to one of ordinary skill in the art. The amylase inhibitor, tendamistat and the various cyclic peptides related thereto, are disclosed in U.S. Pat. No. 4,451 ,455. The amylase inhibitor Al-3688 and the various cyclic polypeptides related thereto are disclosed in U.S. Pat. No. 4,623,714. The amylase inhibitor, trestatin, consisting of a mixture of trestatin A, trestatin B and trestatin C and the various trehalose-containing aminosugars related thereto are disclosed in U.S. Pat. No. 4,273,765.

Additional anti-diabetic compounds, which can be used in combination with a Formula I compound of the present invention, includes, for example, the following: biguanides (e.g., metformin), insulin secretagogues (e.g., sulfonylureas and glinides), glitazones, non-glitazone PPAR.gamma. agonists, PPAR.beta. agonists, inhibitors of DPP-IV, inhibitors of PDE5, inhibitors of GSK-3, glucagon antagonists, inhibitors of f-1 ,6-BPase (Metabasis/Sankyo), GLP-1/analogs (AC 2993, also known as exendin-4), insulin and insulin mimetics (Merck natural products). Other examples would include PKC- .beta. inhibitors and AGE breakers.

Compounds of the present invention can be used in combination with anti-obesity agents. Any anti-obesity agent can be used in such combinations and examples are provided herein. Such anti-obesity activity is readily determined by those skilled in the art according to standard assays known in the art. Suitable anti-obesity agents include phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, .beta..sub.3 adrenergic receptor agonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (e.g., sibutramine), sympathomimetic agents, serotoninergic agents, cannabinoid receptor antagonists (e.g., rimonabant (SR-141.716A)), dopamine agonists (e.g., bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (e.g., tetrahydrolipstatin, i.e. orlistat), bombesin agonists, anorectic agents (e.g., a bombesin agonist), Neuropeptide-Y antagonists, thyroxine, thyromimetic agents, dehydroepiandrosterones or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (e.g., Axokine.TM.), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists, and the like.

Any thyromimetic can be used in combination with compounds of the present invention. Such thyromimetic activity is readily determined by those skilled in the art according to standard assays (e.g., Atherosclerosis (1996) 126: 53-63). A variety of thyromimetic agents are known to those skilled in the art, for example those disclosed in U.S. Pat. Nos. 4,766,121 ; 4,826,876: 4,910,305; 5,061 ,798; 5,284,971 ; 5,401 ,772; 5,654,468; and 5,569,674. Other antiobesity agents include sibutramine which can be prepared as described in U.S. Pat. No. 4,929,629. and bromocriptine which can be prepared as described in U.S. Pat. Nos. 3,752,814 and 3,752,888.

Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated. The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. Worldwide fracture incidence is forecasted to increase three-fold over the next 60 years, and one study has estimated that there will be 4.5 million hip fractures worldwide in 2050. Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.

Those skilled in the art will recognize that anti-resorptive agents (for example progestins, polyphosphonates, bisphosphonate(s), estrogen agonists/antagonists, estrogen, estrogen/progestin combinations, Premarin.RTM., estrone, estriol or 17.alpha.- or 17.beta.-ethynyl estradiol) may be used in conjunction with the compounds of Formula I of the present invention. Exemplary progestins are available from commercial sources and include: algestone acetophenide, altrenogest, amadinone acetate, anagestone acetate, chlormadinone acetate, cingestol, clogestone acetate, clomegestone acetate, delmadinone acetate, desogestrel, dimethisterone, dydrogesterone, ethynerone, ethynodiol diacetate, etonogestrel, flurogestone acetate, gestaclone, gestodene, gestonorone caproate, gestrinone, haloprogesterone, hydroxyprogesterone caproate, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, melengestrol acetate, methynodiol diacetate, norethindrone, norethindrone acetate, norethynodrel, norgestimate, norgestomet, norgestrel, oxogestone phenpropionate, progesterone, quingestanol acetate, quingestrone, and tigestol. Preferred progestins are medroxyprogestrone, norethindrone and norethynodrel. Exemplary bone resorption inhibiting polyphosphonates include polyphosphonates of the type disclosed in U.S. Pat. No. 3,683,080, the disclosure of which is incorporated herein by reference. Preferred polyphosphonates are geminal diphosphonates (also referred to as bis-phosphonates). Tiludronate disodium is an especially preferred polyphosphonate. lbandronic acid is an especially preferred polyphosphonate. Alendronate and resindronate are especially preferred polyphosphonates. Zoledronic acid is an especially preferred polyphosphonate. Other preferred polyphosphonates are 6-amino-1-hydroxy-hexylidene-bisphosphonic acid and 1 -hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid. The polyphosphonates may be administered in the form of the acid, or of a soluble alkali metal salt or alkaline earth metal salt. Hydrolyzable esters of the polyphosphonates are likewise included. Specific examples include ethane-1- hydroxy 1 ,1 -diphosphonic acid, methane diphosphonic acid, pentane-1-hydroxy-1 ,1-diphosphonic acid, methane dichloro diphosphonic acid, methane hydroxy diphosphonic acid, ethane-1-amino-1 ,1- diphosphonic acid, ethane-2-amino-1 ,1 -diphosphonic acid, propane-3-amino-1-hydroxy-1 ,1 -diphosphonic acid, propane-N,N-dimethyl-3-amino-1-hydroxy-1 ,1 -diphosphonic acid, propane-3,3-dimethyl-3-amino-1- hydroxy-1 ,1 -diphosphonic acid, phenyl amino methane diphosphonic acid, N,N-dimethylamino methane diphosphonic acid, N(2-hydroxyethyl) amino methane diphosphonic acid, butane-4-amino-1-hydroxy-1 ,1- diphosphonic acid, pentane-5-amino-1 -hydroxy- -1 ,1 -diphosphonic acid, hexane-6-amino-1-hydroxy-1 ,1- diphosphonic acid and pharmaceutically acceptable esters and salts thereof.

In particular, the compounds of this invention may be combined with a mammalian estrogen agonist/antagonist. Any estrogen agonist/antagonist may be used as the second compound of this invention. The term estrogen agonist/antagonist refers to compounds which bind with the estrogen receptor, inhibit bone turnover and/or prevent bone loss. In particular, estrogen agonists are herein defined as chemical compounds capable of binding to the estrogen receptor sites in mammalian tissue, and mimicking the actions of estrogen in one or more tissue. Estrogen antagonists are herein defined as chemical compounds capable of binding to the estrogen receptor sites in mammalian tissue, and blocking the actions of estrogen in one or more tissues. Such activities are readily determined by those skilled in the art of standard assays including estrogen receptor binding assays, standard bone histomorphometric and densitometer methods, and Eriksen E. F. et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S. J. et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv. Radiol., 1996, 31 (1):50-62; Wahner H. W. and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296). A variety of these compounds are described and referenced below.

Another preferred estrogen agonist/antagonist is 3-(4-(1 ,2-diphenyl-but-1-enyl)-phenyl)-acrylic acid, which is disclosed in Willson et al., Endocrinology, 1997, 138, 3901 -3911. Another preferred estrogen agonist/antagonist is tamoxifen: (ethanamine,2-(-4-(1 ,2-diphenyl-1-butenyl)phenoxy)-N,N- dimethyl, (Z)-2-, 2-hydroxy-1 ,2,3-propanetricarboxylate (1 :1)) and related compounds which are disclosed in U.S. Pat. No. 4,536,516, the disclosure of which is incorporated herein by reference. Another related compound is 4-hydroxy tamoxifen, which is disclosed in U.S. Pat. No. 4,623,660, the disclosure of which is incorporated herein by reference.

A preferred estrogen agonist/antagonist is raloxifene: (methanone, (6-hydroxy-2-(4- hydroxyphenyl)benzo[b]thien-3-yl)(4-(2-(1-piperidinyl)eth- oxy)phenyl)-hydrochloride) which is disclosed in U.S. Pat. No. 4,418,068, the disclosure of which is incorporated herein by reference. Another preferred estrogen agonist/antagonist is toremifene: (ethanamine, 2-(4-(4-chloro-1 ,2-diphenyl-1 - butenyl)phenoxy)-N,N-dimethyl~ , (Z)-, 2-hydroxy-1 ,2,3-propanetricarboxylate (1 :1) which is disclosed in U.S. Pat. No. 4,996,225, the disclosure of which is incorporated herein by reference. Another preferred estrogen agonist/antagonist is centchroman: 1 -(2-((4-(-methoxy-2,2, dimethyl-3-phenyl-chroman-4-yl)- phenoxy)-ethyl)-p- yrrolidine, which is disclosed in U.S. Pat. No. 3,822,287, the disclosure of which is incorporated herein by reference. Also preferred is levormeloxifene.

Another preferred estrogen agonist/antagonist is idoxifene: (E)-1-(2-(4-(1-(4-iodo-phenyl)-2- phenyl-but-1-enyl)-phenoxy)-ethyl)-pyrro- lidinone, which is disclosed in U.S. Pat. No. 4,839,155, the disclosure of which is incorporated herein by reference.

Another preferred estrogen agonist/antagonist is 2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl- ethoxy)-phenoxy]-benzo[b]thio- phen-6-ol which is disclosed in U.S. Pat. No. 5,488,058, the disclosure of which is incorporated herein by reference.

Another preferred estrogen agonist/antagonist is 6-(4-hydroxy-phenyl)-5-(4-(2-piperidin-1-yl- ethoxy)-benzyl)-naphthalen-2~ ol, which is disclosed in U.S. Pat. No. 5,484,795, the disclosure of which is incorporated herein by reference.

Another preferred estrogen agonist/antagonist is (4-(2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy)-phenyl)-(6- hydroxy-2-(4-hyd- roxy-phenyl)-benzo[b]thiophen-3-yl)-methanone which is disclosed, along with methods of preparation, in PCT publication no. WO 95/10513 assigned to Pfizer Inc. , the disclosure of which is incorporated herein by reference. Other preferred estrogen agonist/antagonists include the compounds, TSE-424 (Wyeth-Ayerst Laboratories) and arazoxifene.

Other preferred estrogen agonist/antagonists include compounds as described in commonly assigned U.S. Pat. No. 5,552,412, the disclosure of which is incorporated herein by reference. Especially preferred compounds described therein are: cis-6-(4-fluoro-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,- 7,8-tetrahydro-naphthalene-2-ol; (-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1 -yl-ethoxy)-phenyl)-5,6,7,8-te- trahydro-naphthalene-2-ol (also known as lasofoxifene); cis-6-phenyl-5-(4-(2-pyrrolidin-1 -yl-ethoxy)-phenyl)-5,6,7.8-tetrah- ydro-naphthalene-2-ol; cis-1 -(6'-pyrrolodinoethoxy-3'-pyridyl)-2-phenyl-6-hydroxy-1 ,2,3,4-- tetrahydronaphthalene; 1 -(4'-pyrrolidinoethoxyphenyl)-2-(4"-f luorophenyl)-6-hydroxy-1 ,2,3,- 4-tetrahydroisoquinoline; is-6-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,- 7,8-tetrahydro-naphthalene-2-ol; and 1 -(4'-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1 ,2,3,4-tetrahyd- roisoquinoline.

Other estrogen agonist/antagonists are described in U.S. Pat. No. 4,133,814 (the disclosure of which is incorporated herein by reference). U.S. Pat. No. 4,133,814 discloses derivatives of 2-phenyl-3- aroyl-benzoth- iophene and 2-phenyl-3-aroylbenzothiophene-1 -oxide.

Other anti-osteoporosis agents, which can be used in combination with a Formula I compound of the present invention, include, for example, the following: parathyroid hormone (PTH) (a bone anabolic agent); parathyroid hormone (PTH) secretagogues (see, e.g., U.S. Pat. No. 6,132,774), particularly calcium receptor antagonists; calcitonin; and vitamin D and vitamin D analogs.

Any compound that is an antihypertensive agent may be used in a combination aspect of this invention. Such compounds include amlodipine and related dihydropyridine compounds, calcium channel blockers, angiotensin converting enzyme inhibitors ("ACE-lnhibitors"), angiotensin-ll receptor antagonists, beta-adrenergic receptor blockers and alpha-adrenergic receptor blockers. Such antihypertensive activity is determined by thoseskilled in the art according to standard tests (e.g. blood pressure measurements).

Amlodipine and related dihydropyridine compounds are disclosed in U.S. Pat. No. 4,572,909, which is incorporated herein by reference, as potent anti-ischemic and antihypertensive agents. U.S. Pat. No. 4,879,303, which is incorporated herein by reference, discloses amlodipine benzenesulfonate salt (also termed amlodipine besylate). Amlodipine and amlodipine besylate are potent and long lasting calcium channel blockers. As such, amlodipine, amlodipine besylate and other pharmaceutically acceptable acid addition salts of amlodipine have utility as antihypertensive agents and as antiischemic agents. Amlodipine and its pharmaceutically acceptable acid addition salts are also disclosed in U.S. Pat. No. 5,155,120 as having utility in the treatment of congestive heart failure. Amlodipine besylate is currently sold as Norvasc®.

Calcium channel blockers which are within the scope of this invention include, but are not limited to: bepridil, which may be prepared as disclosed in U.S. Pat. No. 3,962, 238 or U.S. Reissue No. 30,577; clentiazem, which may be prepared as disclosed in U.S. Pat. No. 4,567,175; diltiazem, which may be prepared as disclosed in U.S. Pat. No. 3,562, fendiline, which may be prepared as disclosed in U.S. Pat. No. 3,262,977; gallopamil, which may be prepared as disclosed in U.S. Pat. No. 3,261 ,859; mibefradil, prenylamine, semotiadil, terodiline, verapamil, aranipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, and perhexiline The disclosures of all such U.S. Patents are incorporated herein by reference.

Angiotensin Converting Enzyme Inhibitors (ACE-lnhibitors) which are within the scope of this invention include, but are not limited to: alacepril, which may be prepared as disclosed in U.S. Pat. No. 4,248,883; benazepril, which may be prepared as disclosed in U.S. Pat. No. 4,410,520; accupril, captopril, ceronapril, delapril, enalapril, fosinopril, imadapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril, and trandolapril. The disclosures of all such U.S. patents are incorporated herein by reference.

Angiotensin-ll receptor antagonists (A-Il antagonists) which are within the scope of this invention include, but are not limited to: candesartan, which may be prepared as disclosed in U.S. Pat. No. 5,196,444; eprosartan, which may be prepared as disclosed in U.S. Pat. No. 5,185,351 ; irbesartan, losartan, and valsartan. The disclosures of all such U.S. patents are incorporated herein by reference.

Beta-adrenergic receptor blockers (beta- or .beta.-blockers) which are within the scope of this invention include, but are not limited to: acebutolol, which may be prepared as disclosed in U.S. Pat. No. 3,857,952; alprenoloi, amosulalol, which may be prepared as disclosed in U.S. Pat. No. 4,217,305; arotinolol, atenolol, befunolol, betaxolol; The disclosures of all such U.S. patents are incorporated herein by reference.

Alpha-adrenergic receptor blockers (alpha- or .alpha.-blockers) which are within the scope of this invention include, but are not limited to: amosulalol, which may be prepared as disclosed in U.S. Pat. No. 4,217,307; arotinolol, which may be prepared as disclosed in U.S. Pat. No. 3,932,400; dapiprazole, doxazosin, fenspiride, indoramin, labetolol, naftopidil, nicergoline, prazosin, tamsulosin, tolazoline, trimazosin, and yohimbine, which may be isolated from natural sources according to methods well known to those skilled in the art. The disclosures of all such U.S. patents are incorporated herein by reference.

Any compound that is known to be useful in the treatment of Alzheimer's Disease may be used in a combination aspect of this invention. Such compounds include acetylcholine esterase inhibitors. Examples of known acetylcholine esterase inhibitors include donepezil (Aricept®), tacrine (Cognex®), rivastigmine (Exelon®) and galantamine (Reminyl). Aricept® is disclosed in the following U.S. patents, all of which are fully incorporated herein by reference: 4,895,841 , 5,985,864, 6,140,321 , 6,245,911 and 6,372,760. Exelon® is disclosed in U.S. Patent Nos. 4,948,807 and 5,602,176 which are fully incorporated herein by reference. Cognex® is disclosed in U.S. Patent Nos. 4,631 ,286 and 4,816,456 (fully incorporated herein by reference). Remynil® is disclosed in U.S. Patent Nos. 4,663,318 and 6,099,863 which are fully incorporated herein by reference.

PREPARATION OF COMPOUNDS OF THE INVENTION

The present invention contains compounds that can be synthesized in a number of ways familiar to one skilled in organic synthesis. The compounds outlined herein can be synthesized according to the methods described below, along with methods typically utilized by a synthetic chemist, and combinations or variations of those methods, which are generally known to one skilled in the art of synthetic chemistry. The synthetic route of compounds in the present invention is not limited to the methods outlined below. It is assumed that one skilled in the art will be able to use the schemes outlined below to synthesize compounds claimed in this invention. Individual compounds may require manipulation of the conditions in order to accommodate various functional groups. A variety of protecting groups generally known to one skilled in the art may be required. Purification, if necessary, can be accomplished on a silica gel column eluted with the appropriate organic solvent system. Also, reverse phase HPLC or recrystallization may be employed.

Scheme 1 shows the preparation of compounds of the invention wherein R3 and R4 taken together with the carbons to which they are attached, form a 6 member unsaturated ring and n is 0. Scheme 1a shows a further example.

Scheme 1

Figure imgf000027_0001
Scheme Ia

Figure imgf000028_0001

Scheme 1a

Scheme 1a illustrates the synthesis of a compound containing an aryl-fused six-membered lactam ring. As shown, 4-fluorobenzyl bromide (17) was reacted with silver nitrite to give 1-fluoro-4-nitromethyl- benzene (18). In parallel, 2-bromobenzaldehyde (19) was condensed with n-BuNH2 to afford imine (20) which was reacted with 1-fluoro-4-nitromethyl-benzene (18) in the presence of AcOH to afford 1-bromo-2- (2-nitro-2-(4-fluorophenyl)-vinyl)-benzene (21). Intermediate (21) was converted to pyrrole (22) via cycloaddition with ethyl isocyanoacetate followed by alkylation with 2-iodopropane to provide compound (23). Vilsmeier-Hack formylation of pyrrole (23) gave aldehyde (24) and subsequent base hydrolysis provided carboxylic acid (25). Carboxylic acid (25) was then converted to amide (26) via the intermediacy of an acid chloride. An intramolecular N-arylation reaction was then undertaken by treatment of intermediate (26) with Pd(OAc)2, BINAP and Cs2CO3 to provide lactam (27). The aldehyde functionality of intermediate (27) was then reduced to the corresponding to alcohol (28) which was subsequently converted to phosphonium salt (29) upon treatment with triphenylphosphine hydrobromide. Alternatively, a phosphonate ester intermediate may be prepared and utilized in a similar fashion. Wittig olefination of phosphonium salt (29) afforded olefin (30) which was subjected to hydrogenation to give intermediate (31). Finally, the ester of compound (31) was hydrolyzed by treatment with NaOH to give compound (32) which was isolated as a carboxylate salt.

Scheme 2 shows the preparation of compounds of the invention wherein R3 and R4 taken together with the carbons to which they are attached, form 6 member unsaturated ring and n is 1. Scheme 2a shows a further example.

Scheme 2

DMF

Figure imgf000030_0001
Scheme 2a

Scheme 2a illustrates the synthesis of a compound containing an aryl-fused seven-membered lactam ring. As shown, 4-fluorobenzyl bromide (17) was reacted with silver nitrite to give 1-fluoro-4- nitromethyl-benzene (18). In parallel, 2-methylbenzaldehyde (33) was condensed with n-BuNH2 to afford imine (34) which was" reacted with 1-fluoro-4-nitromethyl-benzene (18) in the presence of AcOH to provide 1 -methyl-2-(2-nitro-2-(4-fluorophenyl)-vinyl)-benzene (47). Intermediate (47) was converted to pyrrole (48) via cycloaddition with ethyl isocyanoacetate followed by alkylation with 2-iodopropane to provide compound (49). Vilsmeier-Hack formylation of pyrrole (49) gave aldehyde (50) and subsequent base hydrolysis provided carboxylic acid (51). Carboxylic acid (51) was then converted to amide (52) via the intermediacy of an acid chloride. Benzylic bromination of compound (52) with NBS and AIBN provided bromide (53). The aldehyde functionality of compound (52) was lost during this transformation. Subsequently, an intramolecular alkylation reaction was conducted by treatment of intermediate (53) with NaH to provide lactam (54). A subsequent Vilsmeier-Hack formylation of pyrrole (54) re-installed the aldehyde functionality that was lost during the bromination reaction. This aldehyde functionality was reduced to the corresponding to alcohol which was converted to phosphonium salt (55) by treatment with triphenylphosphine hydrobromide. Wittig olefination of phosphonium salt (55) afforded, after acid catalyzed removal of the acetonide protecting group, olefin (56). This olefin was subjected to hydrogenation to give intermediate (57). Finally, the ester of compound (57) was hydrolyzed by treatment with NaOH to give compound (58) as a carboxylate salt.

Scheme 2a

Figure imgf000032_0001
EXAMPLES

The following non-limiting Examples show how to carry out the present invention. The synthetic route of compounds of the present invention is not limited to the methods outlined below. It is assumed that one skilled in the art will be able to use the schemes outlined below to synthesize compounds claimed in this invention.

EXAMPLE 1

(3R,5R)-7-[1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid sodium salt

Figure imgf000033_0001

Step A

1 -Fluoro-4-nitromethyl-benzene

Figure imgf000033_0002

To a suspension of AgNO2 (17.9 g, 116 mmol) in ether (400 mL) at 0 0C was slowly added 4-flourobenzyl bromide (20.0 g, 106 mmol). The reaction mixture was warmed to 25 °C and stirred at that temperature for 12 hr. Subsequently, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated to afford a yellow oil that was purified by silica gel chromatography (0 to 5% EtOAc/Hex) to provide 1 -fluoro-4-nitromethyl-benzene (10.6 g, 65%): MS(APCI'): m/z 154.0 (M-H).

Step B

(2-Bromo-benzylidene)-butyl-amine

Figure imgf000033_0003

To a solution of 2-bromobenzaldehyde (12.7 g, 68.3 mmol) in toluene (250 mL) at 250C was added n- butyl amine (5.00 g, 68.3 mmol). The reaction mixture was then heated to reflux for 2 hrs with a Dean- Stark apparatus in place to collect an equivalent of water. Subsequently, the reaction was then cooled to 25 0C and solvent was removed by evaporation to afford (2-bromo-benzylidene)-butyl-amine (16.3 g, 99%) as a yellow oil that was used without further purification. Step C

1-Bromo-2-(2-nitro-2-(4-fluorophenyl)-vinyl)-benzene

Figure imgf000034_0001
To a mixture of 1 -fluoro-4-nitromethyl-benzene (10.6 g, 68.3 mmol) and (2-bromo-benzylidene)-butyl- amine (16.3 g, 67.9 mmol) was added glacial AcOH (20 ml_). The resulting reaction mixture was stirred at 25 0C for 1 hr, and it was then allowed to stand undisturbed for 5 hr during which time a crystalline product formed. The solid was isolated by filtration and dried under vacuum for 12 hr to provide 1 -bromo-2-(2- nitro-2-(4-fluorophenyl)-vinyl)-benzene (20.1 g, 92%): H-NMR (CDCI3) pδ.35 (s, 1 H), 7.58 (d, 1 H), 7.24- 6.98 (m, 6 H), 6.73 (d, 1 H).

Step D

3-(2-Bromo-phenyl)-4-(4-fluoro-phenyl)-1 H-pyrrole-2-carboxylic acid ethyl ester

Figure imgf000034_0002

To a solution of 1-bromo-2-(2-nitro-2-(4-fluorophenyl)-vinyl)-benzene (47.0 g, 146 mmol) and ethyl isocyanoacetate (16.7 g, 146 mmol) in THF (500 mL) at 0 0C was slowly added DBU (22.7 g, 149 mmol). After the addition was complete, the reaction was warmed to 25 0C and stirred at that temperature for 2 hr. Once starting material was consumed, the solvent was removed under reduced pressure and EtOAc (500 m L) was added. The organic layer was then separated and washed with 10% HCI, saturated

NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated to a brown oil that was purified by silica gel chromatography (10% to 20% EtOAc/Hex) to afford 3-(2-Bromo-phenyl)-4-(4-fluoro- phenyl)-1 H-pyrrole-2-carboxylic acid ethyl ester (18.7 g, 33%): MS(APCI+): m/z 389.9 (M+H).

Step E

3-(2-Bromo-phenyl)-4-(4-fluoro-phenyl)-1 -isopropyl-1 H-pyrrole-2-carboxylic acid ethyl ester

Figure imgf000034_0003
To a solution of 3-(2-bromo-phenyl)-4-(4-f!uoro-phenyl)-1 H-pyrrole-2-carboxylic acid ethyl ester (18.7 g, 48.2 mmol) in DMSO (100 mL) at 25 °C was added powdered KOH (10.2 g, 181 mmol). The reaction mixture was then stirred at 25 0C for 45 min. Subsequently 2-iodopropane (18.5g, 109 mmol) was slowly added to the reaction and stirring was continued for an additional 45 min at 25 °C. Ether (150 mL) and water (150 mL) were then added and the organic layer was separated, dried (Na2SO4) and concentrated to an oil that was purified by silica gel chromatography (1 - 8% EtOAc/Hex) to afford 3-(2- bromo-phenyl)-4-(4-fluoro-phenyl)-1-isopropyl-1 H-pyrrole-2-carboxylic acid ethyl ester (8.0 g, 51 %) as a solid: H-NMR (CDCI3) D7.55 (d, 1 H), 7.18-6.98 (m, 6 H), 6.84-6.78 (m, 2 H), 5.48 (sept, 1 H), 4.03-3.90 (m, 2 H), 1.53-1.48 (m, 6 H), 0.79 (t, 3 H).

Step F

3-(2-Bromo-phenyl)-4-(4-f luoro-phenyl)-5-formyl-1 -isopropyl-1 H-pyrrole-2-carboxylic acid ethyl ester

Figure imgf000035_0001

To DMF (28.6 mL) at 0 0C was slowly added POCI3 (14.2 g, 92.4 mmol). The reaction was stirred warmed to 25 0C and stirred for 1 hr. Subsequently, a solution of 3-(2-bromo-pheny!)-4-(4-fluoro-phenyl)- 1 -isopropyl-1 H-pyrrole-2-carboxylic acid ethyl ester (7.95 g, 18.5 mmol) 1 ,2dichloroethane (100 mL) was added and the reaction was heated to 80 0C for 8 hrs. After cooling to 25 0C, saturated NaHCO3 (100 mL) was slowly added and the resulting mixture was stirred at 25 °C for 8 hrs. The organic layer was then separated, dried (Na2SO4 ) and concentrated to a brown oil that was purified by silica gel chromatography (5% EtOAc/Hex) to afford 3-(2-bromo-phenyl)-4-(4-fluoro-phenyl)-5-formyl-1 -isopropyl-1 H-pyrrole-2- carboxylic acid ethyl ester (5.Og, 59%): H-NMR (CDCI3) D9.51 (s, 1 H), 7.49 (d, 1 H), 7.14-6.85 (m, 7 H), 5.65 (sept, 1 H), 4.08-3.95 (m, 2 H), 1.62 (d, 6 H), 0.92-0.81 (m, 3 H).

Step G

3-(2-Bromo-phenyl)-4-(4-f luoro-phenyl)-5-formyl-1 -isopropyl-1 H-pyrrole-2-carboxylic acid

Figure imgf000035_0002

To a solution of 3-(2-bromo-phenyl)-4-(4-fluoro-phenyl)-5-formyl-1 -isopropyl-1 H-pyrrole-2- carboxylic acid ethyl ester (5.0 g, 10.9 mmol) in MeOH (80 mL) was added NaOH (1.75 g in 20 ml water, 43.6 mmol). The reaction was heated to 60 °C for 8 hrs. The organic solvent was removed under reduced pressure and water (50 mL) was then added. The aqueous layer (basic) was washed once with ether (50 ml_) and then acidified by addition of 10% HCi to pH 2 as a white precipitate developed. Subsequently, EtOAc (150 mL) was added and the organic layer was separated, dried (Na2SO4) and concentrated to afford 3-(2-Bromo-phenyl)-4-(4-fluoro-phenyl)-5-formyl-1-isopropyl-1 H-pyrrole-2-carboxylic acid (3.88 g, 83%) as a light yellow solid of sufficient purity for use in subsequent steps: H-NMR (DMSO-d6) D9.39 (s, 1 H), 7.48 (d, 1 H), 7.21-7.00 (m, 7 H), 5.54 (sept, 1 H), 1.52 (d, 6 H).

Step H

3-(2-Bromo-phenyl)-4-(4-fluoro-phenyl)-5-formyl-1 -isopropyl-1 H-pyrrole-2-carboxylic acid phenylamide

Figure imgf000036_0001

To 3-(2-bromo-phenyl)-4-(4-f luoro-phenyl)-5-formyl-1 -isopropyl-1 H-pyrrole-2-carboxylic acid (2.50 g, 5.81 mmol) was added thionyl chloride (15 mL) and the reaction mixture was heated to 75 0C for 2 hr after which time it was cooled to 25 0C and the excess thionyl chloride was removed under reduced pressure. Subsequently, dichloromethane (25 mL) was added to the crude acid chloride and the solution was cooled to 00C. Aniline (0.595 g, 6.39 mmol) and triethylamine (1.38 g, 12.8 mmol) were then added and the reaction mixture was stirred at 0 °C for an additional 12 hrs. Saturated NaHCO3 was added and organic layer separated, dried (Na2SO4) and concentrated. The product was purified by silica gel chromatography (10% EtOAC/hex) to afford 3-(2-bromo-phenyl)-4-(4-fluoro-phenyl)-5-formyl-1-isopropyl- 1 H-pyrrole-2-carboxylic acid phenylamide (0.53 g, 18%): MS(APCI+): m/z 506.9 (M+2).

Step I

1-(4-Fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-2-carbaldehyde

Figure imgf000036_0002

To 3-(2-bromo-phenyl)-4-(4-fluoro-phenyl)-5-formyl-1 -isopropyl-1 H-pyrrole-2-carboxylic acid phenylamide (0.53 g, 1.06 mmol) was added Cs2CO3 (0.481 g, 1.47 mmol), palladium acetate (0.012 g, 0.053 mmol) and 4,5-bis(diphenylphosphino)-9,9 dimethylxanthene (0.043 g, 0.074 mmol). Anhydrous toluene (10 mL) was then added and the reaction vessel was purged with nitrogen prior to being capped and heated to 100 0C for 16 hrs. TLC analysis indicated that reaction was 80% complete, and an additional amount of palladium acetate (0.012 g, 0.053 mmol) was added and the reaction was heated to 100 0C for an additional 4 hr. After cooling to 25 °C, the reaction was filtered through celite, and the filtrate was concentrated to a crude oil that was purified by silica gel chromatography (10% EtOAc/Hex) to give ^(Φfluoro-phenyO-S-isopropyl^-oxo-δ-phenyl^.δ-dihydro-SH-pyrrolo^.S-cJquinoline^-carbaldehyde (0.360 g, 80%): MS(APCI+): m/z 425.1 (M+H).

Step J

1-(4-Fluoro-phenyl)-2-hydroxymethyl-3-isopropyl-5-phenyl-3,5-dihydro-pyrrolo[2,3-c]quinolin-4-one

Figure imgf000037_0001

To a solution of 1 -(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[2,3- c]quinoline-2-carbaldehyde (0.360 g, 0.85 mmol) in THF (20 ml_) at 00C was added 1.0 M lithium tri-tert- butoxyaluminohydride (1.48 mL, 1.48 mmol). The reaction was stirred for 30 min at 0 0C at which point TLC analysis indicated the reaction was complete and the solvent was removed under reduced pressure. To the reaction residue was added ethyl acetate (50 mL) and saturated NaHCO3 (15 mL), and the organic layer was separated, dried (Na2SO4) and concentrated. The resulting oil was purified by silica gel chromatography (30% EtOAc/Hex) to afford 1-(4-fluoro-phenyl)-2-hydroxymethyl-3-isopropyl-5-phenyl- S.δ-dihydro-pyrroloβ.S-clquinolirM-one (0.275 g, 76%): MS(APCI+): m/z 427.1 (M+H).

Step K

[1-(4-Fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-ylmethyl]- triphenyl-phosphonium bromide

Figure imgf000037_0002

To a solution of 1-(4-fluoro-phenyl)-2-hydroxymethyl-3-isopropyl-5-phenyl-3,5-dihydro-pyrrolo[2,3- c]quinolin-4-one (0.275 g, 0.645 mmol) in DCM (20 mL) was added triphenylphosphine hydrobromide (0.22 g, 0.645 mmol). The reaction was heated to 50 0C for 2.5 hr after which time all starting material was consumed as determined by TLC. The reaction solvent was removed under reduced pressure and the resulting yellow solid was dried under high vacuum for 12 hr to provide [1-(4-fluoro-phenyl)-3- isopropyM-oxo-S-phenyl^.δ-dihydro-SH-pyrrolop.a-cjquinolin^-ylmethylJ-triphenyl-phosphonium bromide (0.484 g, 99%) in sufficient purity for use in the next step.

Step L

(6-{2-[1-(4-Fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-vinyl}- 2,2-dimethyl-[1 ,3]dioxan-4-yl)-acetic acid tert-butyl ester

Figure imgf000038_0001
To a solution of [1 -(4-f luoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[2,3- c]quinolin-2-ylmethyl]-triphenyl-phosphonium bromide (0.433 g, 0.645 mmol) in THF (50 ml_) at -78 0C was added 1.0 M NaHMDS (0.967 mL, 0.967 mmol). An orange color was noted as the base was added. The reaction mixture was stirred at -78 °C for 5 min after which time a solution of (6-formyl-2,2-dimethyl- [1 ,3]dioxan-4-yl)-acetic acid tert-butyl ester (0.249 g, 0.9672 mmol) in THF (10 mL) was slowly added. After the addition, the reaction mixture was stirred at -78 C for 30 min then allowed to warm to 25 0C over 1.5 hr. The reaction was quenched by drop-wise addition of saturated NH4CI. Ethyl acetate (25 mL) was then added and organic layer was separated, washed with water, dried (Na2SO4), concentrated. The crude product was purified by silica gel chromatography (15-20% EtOAc/Hex) to afford (6-{2-[1 -(4-Fluoro- phenyO-S-isopropyi^-oxo-δ-phenyl^.δ-dihydro-SH-pyrroloβ.S-clquinolin^-yll-vinylJ^^-dimethyl- [1 ,3]dioxan-4-yl)-acetic acid tert-butyl ester (0.230 g, 55%) as an in separable mixture of cis/trans olefin isomers: MS(APCI+): m/z 651.3 (M+H).

Step M

7-[1-(4-Fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid tert-butyl ester

Figure imgf000038_0002

To a solution of (6-{2-[1 -(4-Fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[2,3- c]quinolin-2-yl]-vinyl}-2,2-dimethyl-[1 ,3]dioxan-4-yl)-acetic acid tert-butyl ester (0.220 g, 0.338 mmol) in MeOH (20 mL) was added 10% Pd-C (500 mg). The reaction vessel was evacuated and filled with hydrogen gas (50 psi) for 3 hours. The reaction mixture was then filtered through a pad of celite and to the filtrate was added 1 N HCI (10 mL) and the solution was stirred for 3 hrs at 25 0C. Subsequently, the reaction solvent was removed under reduced pressure and ethyl acetate (50 ml_) and saturated NaHCO3 (10 mL) were added. The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by silica gel chromatography (30-50% EtOAc/Hex) to provide 7-[1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid tert-butyl ester (190 mg, 86%): MS(APCI+): /n/z613.2 (M+H).

Step N

7-[1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid sodium salt

Figure imgf000039_0001

To a solution of 7-[1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[2,3- c]quinolin-2-yl]-3,5-dihydroxy-heptanoic acid tert-butyl ester (0.122g, 0.199 mmol) in MeOH (5 mL) was added 1.0 N NaOH (0.209 mL, 0.209 mmol) and the reaction was stirred at 25 0C for 48 hr after which time the reaction was solvent was removed under reduced pressure. The resulting solid was then azeotroped toluene (3 x 100 mL) and triturated with diethyl ether to provide a light yellow solid that was dried under vacuum at 60 0C to afford 7-[1 -(4-f luoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-4,5-dihydro-3H- pyrrolo[2,3-c]quinolin-2-yl]-3,5-dihydroxy-heptanoic acid sodium salt (0.085 g, 74%): MS(APCI+): m/z 557.2 (M+H).

EXAMPLE 2

(3R,5R)-7-[1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6-tetrahydro-3,5-diaza-benzo[e]azulen-2- yl]-3,5-dihydroxy-heptanoic acid sodium salt

Figure imgf000039_0002

Step A

Butyl-(2-methyl-benzylidene)-amine

Figure imgf000039_0003
To a solution of 2-methylbenzaldehyde (10.8g, 90.3 mmol) in toluene (250 mL) at 25 0C was added n-butyl amine (6.60 g, 73.2 mmol). The reaction mixture was then heated to reflux for 2 hrs with a Dean-Stark apparatus in place to collect an equivalent of water. Subsequently, the reaction was then cooled to 25 0C and solvent was removed by evaporation to afford butyl-(2-methyl-benzylidene)-amine (15.7 g, 99%) as a yellow oil that was used without further purification.

Step B

1-Methyl-2-(2-nitro-2-(4-fluorophenyl)-vinyl)-benzene

Figure imgf000040_0001

To a mixture of 1-fluoro-4-nitromethyl-benzene (14.0 g, 90.3 mmol) [from Example 1 , Step A] and (2-methyl-benzylidene)-butyl-amine (15.7 g, 90.3 mmol) was added glacial AcOH (30 mL). The resulting reaction mixture was stirred at 25 °C for 1 hr, and it was then allowed to stand undisturbed for 5 hrs during which time a crystalline product formed. The solid was isolated by filtration and dried under vacuum for 12 hr to provide 1-methyl-2-(2-nitro-2-(4-fluorophenyl)-vinyl)-benzene (18.2 g, 78%).

Step C

4-(4-Fluoro-phenyl)-3-o-tolyl-1 H-pyrrole-2-carboxylic acid ethyl ester

Figure imgf000040_0002

To a solution of 1-methyl-2-(2-nitro-2-(4-fluorophenyl)-vinyl)-benzene (18.2 g, 70.8 mmol) and ethyl isocyanoacetate (8.07 g, 114 mmol) in THF (500 mL) at 0 0C was slowly added DBU (11.3 g, 74.3 mmol). After the addition was complete, the reaction was warmed to 25 0C and stirred at that temperature for 2 hr. Once starting material was consumed, the solvent was removed under reduced pressure and EtOAc (500 mL) was added. The organic layer was then separated and washed with 10% HCI, saturated NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated to a brown oil that was purified by silica gel chromatography (10% to 20% EtOAc/Hex) to afford 4-(4-fluoro-phenyl)-3-o-tolyl-1 H- pyrrole-2-carboxylic acid ethyl ester (7.74 g, 33%): MS(APCl+): m/z 324.1 (M+H).

Step D

4-(4-Fluoro-phenyl)-1-isopropyl-3-o-tolyl-1 H-pyrrole-2-carboxylic acid ethyl ester

Figure imgf000041_0001

To a solution of 4-(4-fluoro-phenyl)-3-o-to!yl-1 H-pyrrole-2-carboxylic acid ethyl ester (7.74 g, 23.9 mmol) in DMSO (100 mL) at 25 0C was added powdered KOH (6.72 g, 120 mmol). The reaction mixture was then stirred at 25 0C for 45 min. Subsequently 2-iodopropane (12.2g, 71.8 mmol) was slowly added to the reaction and stirring was continued for an additional 45 min at 25 0C. Ether (150 mL) and water (150 mL) were then added and the organic layer was separated, dried (Na2SO4) and concentrated to an oil that was purified by silica gel chromatography (1 - 8% EtOAc/Hex) to afford 4-(4fFluoro-phenyl)-1 - isopropyl-3-o-tolyl-1 H-pyrrole-2-carboxylic acid ethyl ester (5.35 g, 61 %) as a solid: MS(APCI+): m/z 366.1 (M+H).

Step E

4-(4-Fluoro-phenyl)-5-formyl-1-isopropyl-3-o-tolyl-1 H-pyrrole-2-carboxylic acid ethyl ester

Figure imgf000041_0002

To DMF (22.6 mL) at 0 0C was slowly added POCI3 (11.2 g, 73.2 mmol). The reaction was stirred warmed to 25 0C and stirred for 1 hr. Subsequently, a solution of 4-(4-f luoro-phenyl)-1 -isopropyl-3-o- tolyl-1 H-pyrrole-2-carboxylic acid ethyl ester (5.35 g, 14.6 mmol) in 1 ,2dichloroethane (100 mL) was added and the reaction was heated to 80 °C for 8 hrs. After cooling to 25 0C, saturated NaHCO3 (100 mL) was slowly added and the resulting mixture was stirred at 25 0C for 8 hrs. The organic layer was then separated, dried (Na2SO4 ) and concentrated to a brown oil that was purified by silica gel chromatography (5% EtOAc/Hex) to afford 4-(4-f luoro-phenyl)-5-formyl-1 -isopropyl-3-o-tolyl-1 H-pyrrole-2-carboxylic acid ethyl ester (4.81 g, 84%): MS(APCI+): m/z 394.1 (M+H).

Step F

4-(4-Fluoro-phenyl)-5-formyl-1 -isopropyl-3-o-tolyl-1 H-pyrrole-2-carboxylic acid

Figure imgf000041_0003

To a solution of 4-(4-fluoro-phenyl)-5-formyl-1-isopropyl-3-o-tolyl-1 H-pyrrole-2-carboxylic acid ethyl ester (4.81 g, 12.2 mmol) in MeOH (80 mL) was added NaOH (1.96 g in 20 ml water, 48.9 mmol). The reaction was heated to 60 0C for 8 hrs. The organic solvent was removed under reduced pressure and water (50 mL) was then added. The aqueous layer (basic) was washed once with ether (50 ml_) and then acidified by addition of 10% HCI to pH 2 as a white precipitate developed. Subsequently, EtOAc (150 mL) was added and the organic layer was separated, dried (Na2SO4) and concentrated to afford 4- (4-fluoro-phenyl)-5-formyl-1-isopropyl-3-o-tolyl-1 H-pyrrole-2-carboxylic acid (3.80 g, 85%) as a light yellow solid of sufficient purity for use in subsequent steps: MS(APCI+): m/z 366.0 (M+H).

Step G

4-(4-Fluoro-phenyl)-5-formyl-1 -isopropyl-3-o-tolyl-1 H-pyrrole-2-carboxylic acid phenylamide

Figure imgf000042_0001

To 4-(4-fluoro-phenyl)-5-formyl-1-isopropyl-3-o-tolyl-1 H-pyrrole-2-carboxylic acid (1.0 g, 2.74 mmol) was added thionyl chloride (10 mL) and the reaction mixture was heated to 750C for 2 hr after which time it was cooled to 25 0C and the excess thionyl chloride was removed under reduced pressure. Subsequently, dichloromethane (25 mL) was added to the crude acid chloride and the solution was cooled to 0 0C. Aniline (0.280 g, 3.01 mmol) and triethylamine (0.42 g, 4.11 mmol) were then added and the reaction mixture was stirred at 0 0C for an additional 12 hrs. Saturated NaHCO3 was added and organic layer separated, dried (Na2SO4) and concentrated. The product was purified by silica gel chromatography (10% EtOAC/hex) to afford 4-(4-f luoro-phenyl)-5-formyl-1 -isopropyl-3-o-tolyl-1 H-pyrrole-2-carboxylic acid phenylamide (0.610 g, 51%): MS(APCI+): m/z 441.2 (M+H).

Step H

3-(2-Bromomethyl-phenyl)-4-(4-f luoro-phenyl)-1 -isopropyl-1 H-pyrrole-2-carboxylic acid phenylamide

Figure imgf000042_0002

To a solution of 4-(4-fluoro-phenyl)-5-formyl-1-isopropyl-3-o-tolyl-1 H-pyrrole-2-carboxylic acid phenylamide (1.44 g, 3.27 mmol) in CCI4 (50 mL) was added N-bromosuccinimide (1.28 g, 7.19 mmol) and AIBN (0.032 g, 0.163 mmol). The reaction was heated to 80 0C for 2 hrs then cooled to 25 0C. The reaction mixture was then filtered and the filtrate was concentrated to a yellow oil that was subjected to silica gel chromatography (1-5 % Et2O/Hex) to give 3-(2-bromomethyl-phenyl)-4-(4-fluoro-phenyl)-1- isopropyl-1H-pyrrole-2-carboxylic acid phenylamide (0.213 g, 13 %): MS(APCI+): m/z 493.0 (M+2). Note that decarbonylation of pyrrole heterocycle occurred under these reaction conditions.

Step I

1-(4-Fluoro-phenyl)-3-isopropyl-5-phenyl-5,6-dihydro-3H-3,5-diaza-benzo[e]azulen-4-one

Figure imgf000043_0001
To a solution of 3-(2-bromomethyl-phenyl)-4-(4-fluoro-phenyl)-1-isopropyl-1H-pyrrole-2-carboxylic acid phenylamide (0.119 g, 0.242 mmol) in THF (10 mL) at 0 0C was added NaH (0.048 g of 60%, 1.21 mmol). The reaction was stirred at 0 °C for 30 min and 25 0C for 24 hrs after which time sat. NH4CI was ) added and the reaction mixture was extracted with EtOAc (50 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated to an oil. The crude product was purified by silica gel chromatography (15% EtOAc/Hex) to provide 1-(4-fluoro-phenyl)-3-isopropyl-5-phenyl-5,6-dihydro-3H- 3,5-diaza-benzo[e]azulen-4-one (0.091 g, 92%): MS(APCI+): m/z 411.0 (M+H).

5 Step J

1-(4-Fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6-tetrahydro-3,5-diaza-benzo[e]azulene-2- carbaldehyde

Figure imgf000043_0002

To DMF (0.58 mL) at 0 0C was slowly added POCI3 (0.290 g, 1.89 mmol). The reaction was stirred warmed to 25 0C and stirred for 1 hr. Subsequently, a solution of 1-(4-fluoro-phenyl)-3-isopropyl-

5-phenyl-5,6-dihydro-3H-3,5-diaza-benzo[e]azulen-4-one (0.155 g, 0.377 mmol) in 1 ,2dichloroethane (10 mL) was added and the reaction was heated to 80 0C for 8 hrs. After cooling to 25 0C, saturated NaHCO3

(10 mL) was slowly added and the resulting mixture was stirred at 25 0C for 8 hrs. The organic layer was then separated, dried (Na2SO4 ) and concentrated to a brown oil that was . purified by . silica gel chromatography (5% EtOAc/Hex) to afford 1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6- tetrahydro-3,5-diaza-benzo[e]azulene-2-carbaldehyde (0.133 g, 80%): MS(APCI+): m/z 439.1 (M+H).

Step K

1-(4-Fluoro-phenyl)-2-hydroxymethyl-3-isopropyl-5-phenyl-5,6-dihydro-3H-3,5-diaza-benzo[e]azulen-4- one

Figure imgf000044_0001

To a solution of 1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6-tetrahydro-3,5-diaza- benzo[e]azulene-2-carbaldehyde (0.133 g, 0.303 mmol) in THF (10 ml_) at 0 0C was added 1.0 M lithium tri-tert-butoxyaluminohydride (0.455 mL, 0.455 mmol). The reaction was stirred for 30 min at 0 0C at which point TLC analysis indicated the reaction was complete and the solvent was removed under reduced pressure. To the reaction residue was added ethyl acetate (50 mL) and saturated NaHCO3 (15 mL), and the organic layer was separated, dried (Na2SO4) and concentrated. The resulting oil was purified by silica gel chromatography (35% EtOAc/Hex) to afford 1-(4-fluoro-phenyl)-2-hydroxymethyl-3- isopropyI-5-phenyl-5,6-dihydro-3H-3,5-diaza-benzo[e]azulen-4-one (0.090 g, 67%): MS(APCI+): m/z 441.1 (M+H).

Step L

[1-(4-Fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6-tetrahydro-3,5-diaza-benzofe]azulen-2-ylmethyl]- triphenyl-phosphonium bromide

Figure imgf000044_0002

To a solution of 1-(4-fluoro-phenyl)-2-hydroxymethyl-3-isopropyl-5-phenyl-5,6-dihydro-3H-3,5- diaza-benzo[e]azulen-4-one (0.090 g, 0.204 mmol) in DCM (10 mL) was added triphenylphosphine hydrobromide (0.070 g, 0.204 mmol). The reaction was heated to 50 0C for 2.5 hr after which time all starting material was consumed as determined by TLC. The reaction solvent was removed under reduced pressure and the resulting yellow solid was dried under high vacuum for 12 hr to provide [1 -(4- fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6-tetrahydro-3,5-diaza-benzo[e]azulen-2-ylmethyl]- triphenyl-phosphonium bromide (0.156 g, 99%) in sufficient purity for use in the next step.

Step M

(6-{2-[1-(4-Fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6-tetrahydro-3,5-diaza-benzo[e]azulen-2-yl]- vinyl}-2,2-dimethyl-[1 ,3Jdioxan-4-yl)-acetic acid tert-butyl ester

Figure imgf000045_0001

To a solution of [1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6-tetrahydro-3,5-diaza- benzo[e]azulen-2-ylmethyi]-triphenyl-phosphonium bromide (0.156 g, 0.204 mmol) in THF (20 ml.) at -78 0C was added 1.0 M NaHMDS (0.306 mL, 0.306 mmol). An orange color was noted as the base was added. The reaction mixture was stirred at -78 0C for 5 min after which time a solution of (6-formyl-2,2- dimethyl-[1 ,3]dioxan-4-yl)-acetic acid tert-butyl ester (0.105 g, 0.407 mmol) in THF (10 mL) was slowly added. After the addition, the reaction mixture was stirred at -78 C for 30 min then allowed to warm to 25 0C over 1.5 hr. The reaction was quenched by drop-wise addition of saturated NH4CI. Ethyl acetate (25 mL) was then added and organic layer was separated, washed with water, dried (Na2SO4), concentrated. The crude product was purified by silica gel chromatography (15-20% EtOAc/Hex) to afford (6-{2-[1-(4- fiuoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6-tetrahydro-3,5-diaza-benzo[e]azulen-2-yl]-vinyl}-2,2- dimethyl-[1 ,3]dioxan-4-yl)-acetic acid tert-butyl ester (0.088 g, 65%) as an in separable mixture of cis/trans olefin isomers: MS(APCI+): m/z 665.2 (M+H).

Step N

7-[1-(4-Fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyI-3,4,5,6-tetrahydro-3,5-diaza-benzo[e]azulen-2-yl]-3,5- dihydroxy-heptanoic acid tert-butyl ester

Figure imgf000045_0002

To a solution of (6-{2-[1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6-tetrahydro-3,5-diaza- benzo[e]azulen-2-yl]-vinyl}-2,2-dimethyl-[1 ,3]dioxan-4-yl)-acetic acid tert-butyl ester (0.088 g, 0.132 mmol) in MeOH (10 mL) was added 10% Pd-C (15 mg). The reaction vessel was evacuated and filled with hydrogen gas (50 psi) for 3 hours. The reaction mixture was then filtered through a pad of celite and to the filtrate was added 1 N HCI (0.5 mL) and the solution was stirred for 3 hrs at 25 0C. Subsequently, the reaction solvent was removed under reduced pressure and ethyl acetate (30 mL) and saturated NaHCO3 (15 mL) were added. The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by silica gel chromatography (30-50% EtOAc/Hex) to provide 7-[1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6-tetrahydro-3,5-diaza-benzo[e]azulen-2- yl]-3,5-dihydroxy-heptanoic acid tert-butyl ester (61 mg, 69%): MS(APCI+): m/z 627.3 (M+H). Step O

7-[1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6-tetrahydro-3,5-diaza-ben2o[e]azuIen-2-yl]-3,5- dihydroxy-heptanoic acid sodium salt

Figure imgf000046_0001

To a solution of 7-[1 -(4-f luoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6-tetrahydro-3,5-diaza- benzo[e]azulen-2-yl]-3,5-dihydroxy-heptanoic acid tert-butyl ester (0.041 g, 0.065 mmol) in MeOH (5 ml_) was added 1.0 N NaOH (0.065 ml_, 0.065 mmol) and the reaction was stirred at 25 0C for 48 hr after which time the reaction was solvent was removed under reduced pressure. The resulting solid was then azeotroped toluene (3 x 100 mL) and triturated with diethyl ether to provide a light yellow solid that was dried under vacuum at 60 0C to afford 7-[1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6- tetrahydro-3,5-diaza-benzo[e]azulen-2-yl]-3,5-dihydroxy-heptanoic acid sodium salt (0.021 g, 54%): MS(APCI+): m/z 571.1 (M+H); H-NMR (DMSO-d6) D7.69-7.64 (m, 1 H)1 7.34-6.97 (m, 11 H), 6.72 (d, 1 H), 4.78-4.75 (m, 2 H), 4.48 (d, 1 H), 3.63-3.56 (m, 1 H), 3.50-3.44 (m, 1 H), 2.79-2.61 (m, 2 H), 1.94-1.89 (m, 1 H), 1.69-1.13 (m, 11 H).

EXAMPLE 3

(3R,5R)-7-[1-(4-fluoro-phenyl)-5-(3-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin- 2-yl]-3,5-dihydroxy-heptanoic acid sodium salt

Figure imgf000046_0002

Prepared using the method of Example 1 : MS(APCI+): m/z 575.2 (M+H); H-NMR (DMSO-d6) P7.77 (s, 1 H), 7.69-7.58 (m, 1 H), 7.40-7.04 (m, 8 H), 6.84 (t, 1 H), 6.40 (d, 1 H)1 4.84-4.80 (m, 1 H), 4.78-4.72 (m, 1 H), 3.71-3.61 (m, 1 ), 3.49-3.41 (m, 1 H), 2.66-2.61 (m, 1 H), 2.48-2.45 (m, 1 H), 1.95-1.91 (m, 1 H), 1.71-1.66 (m, 1 H), 1.58-1.28 (10 H).

EXAMPLE 4

(3R,5R)-7-[1 ,5-bis-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolot2,3-c]quinolin-2-yI]-3,5- dihydroxy-heptanoic acid sodium salt

Figure imgf000047_0001

Prepared using the method of Example 1: MS(APCl+): m/z 575.0 (M+H); H-NMR (DMSOd6) Q7.41-7.04 (m, 9 H), 6.82 (t, 1 H), 6.40 (d, 1 H), 5.69-5.68 (m, 1 H), 4.70 (bs, 1 H), 3.66-3.62 (m, 1 H), 3.52-3.48 (m, 1 H), 2.65-2.61 (m, 1 H), 2.44-2.39 (m, 1 H), 1.93-1.89 (m, 1 H), 1.74-1.68 (m, 1 HO, 1.57- 1.17 (m, 10 H).

EXAMPLE 5

(3R,5R)-7-[1 ,5-bis-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-hept-6-enoic acid sodium salt

Figure imgf000047_0002

Prepared using the method of Example 1 : MS(APCI+): m/z 573.0 (M+H); H-NMR (DMSOd6) P7.42-7.05 (m, 10 H)1 6.83 (t, 1 H), 6.52-6.48 (m, 1 H), 6.42 (d, 1 H), 5.49-5.44 (m, 1 H), 5.08 (bs, 1 H), 4.09-4.05 (m, 1 H), 3.43-3.40 (m, 1 H), 1.94-1.89 (m, 1 H), 1.73-1.67 (m, 1 H), 1.51 (d, 6 H), 1.35-1.28 (m, 1 H)1 0.99-0.94 (m, 1 H).

EXAMPLE 6

(3R,5R)-7-[5-(3-chloro-phenyl)-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3- c]quinolin-2-yl]-3,5-dihydroxy-heptanoic acid sodium salt

Figure imgf000047_0003

Prepared using the method of Example 1 : MS(APCI+): m/z 593.0 (M+H); H-NMR (DMSO-d6) D7.61-7.57 (m, 2 H), 7.47-7.28 (m, 6 H), 7.11-7.06 (m, 2 H), 6.85 (t, 1 H), 6.40 (d, 1 H), 4.76 (bs, 1 H), 3.66-3.62 (m, 1 H), 3.50-3.55 (m, 1 H), 2.68-2.62 (m, 1 H), 2.53-2.47 (m, 1 H), 1.95-1.91 (m, 1 H), 1.76- 1.71 (m, 1 H), 1.58-1.18 (m, 10 H).

EXAMPLE 7

(3R,5R)-7-[5-biphenyl-4-yl-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2- yl]-3,5-dihydroxy-heptanoic acid sodium salt

Figure imgf000048_0001

Prepared using the method of Example 1 : MS(APCI+): m/z 633.0 (M+H); H-NMR (DMSO-d6) P7.84 (d, 2 H), 7.73 (d, 2 H), 7.48 (t, 1 H), 7.39-7.29 (m, 8 H), 7.14-7.05 (m, 2 H), 6.85 (t, 1 H), 6.50 (d, 1 H), 4.67-4.62 (m, 1 H), 4.43 (sept, 1 H), 3.65-3.62 (m, 1 H), 3.35-3.49 (m, 1 H), 2.62-2.52 (m, 1 H), 1.97- 1.91 (m, 1 H), 1.89-1.75 (m, 1 H), 1.63-1.19 (m, 10 H).

EXAMPLE 8

(3R,5R)-7-[5-benzyl-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid sodium salt

Figure imgf000048_0002

Prepared using the method of Example 1 : MS(APCI+): m/z 571.3 (M+H); H-NMR (DMSOd6) D7.37-6.89 (m, 11 H), 6.82-6.75 (m, 2 H), 5.49-5.45 (m, 2 H), 4.71-4.61 (m, 1 H), 4.03-3.95 (m, 1 H), 3.62- 3.57 (m, 1 H), 2.62-2.58 (m, 1 H), 2.43-2.39 (m, 1 H), 1.98-1.91 (m, 1 H), 1.89-1.15 (m, 11 H).

EXAMPLE 9

(3R,5R)-7-[5-(2-fluoro-ben2yl)-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolot2,3-c]quinolin- 2-yl]-3,5-dihydroxy-heptanoic acid sodium salt

Figure imgf000049_0001

Prepared using the method of Example 1 : MS(APCI+): m/z 589.0 (M+H); H-NMR (DMSOd6) D7.44-7.13 (m, 9 H), 6.99-6.97 (m, 1 H), 6.87-6.83 (m, 1 H), 6.72 (t, 1 H)1 5.59 (s, 2 H), 4.76 (bs, 2 H), 3.66-3.61 (m, 1 H), 3.51-3.47 (m, 1 H), 2.69-2.63 (m, 1 H), 2.49-2.41 (m, 1 H), 1.96-1.92 (m, 1 H), 1.86- 1.74 (m, 1 H), 1.72-1.17 (m, 10 H).

EXAMPLE 10

(3R,5R)-7-[5-(3-fluoro-benzyl)-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin- 2-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt

Figure imgf000049_0002

Prepared using the method of Example 1 : MS(APCI+): m/z 587.0 (M+H); H-NMR (DMS0-d6) D7.57-6.71 (m, 12 H), 6.47-6.42 (m, 1 H), 5.67-5.39 (m, 3 H), 4.13-4.09 (m, 1 H), 3.51-3.42 (m, 2 H), 1.97- 1.91 (m, 1 H), 1.72-1.65 (m, 6 H), 1.61 -1.52 (m, 8 H).

EXAMPLE 11

(3R,5R)-7-[5-(3-fluoro-benzyl)-3-isopropyl-4-oxo-1-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid sodium salt

Figure imgf000049_0003

Prepared using the method of Example 1 : MS(APCI+): m/z 588.9 (M+H); H-NMR (DMSO-d6) D7.36-6.81 (m, 12 H), 5.61-5.57 (m, 2 H), 4.78-4.71 (m, 1 H), 3.83-3.75 (m, 1 H), 3.51-3.48 (m, 1 H), 2.69- 2.61 (m, 1 H), 2.44-2.39 (m, 1 H), 1.97-1.94 (m, 1 H), 1.81-1.15 (m, 11 H).

EXAMPLE 12

(3R,5R)-7-[5-(4-f!uoro-benzyl)-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin- 2-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt

Figure imgf000050_0001

Prepared using the method of Example 1 : H-NMR (DMSOd6) 07.32-7.01 (m, 11 H)1 6.84 (t, 1 H), 6.50 (d, 1 H)1 5.55-5.44 (m, 3 H), 4.09-4.07 (m, 1 H), 3.51 -3.19 (m, 2 H), 1.93-1.89 (m, 1 H), 1.75-1.71 (m, 1 H), 1.61-1.12 (m, 8 H).

EXAMPLE 13

(3R,5R)-7-[5-(4-fluoro-benzyl)-3-isopropyl-4-oxo-1-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid sodium salt

Figure imgf000050_0002

Prepared using the method of Example 1 : H-NMR (DMSO-d6) D7.37-7.05 (m, 11 H), 6.83 (t, 1 H), 5.58-5.51 (m, 2 H), 4.78-4.72 (m, 1 H), 3.67-3.62 (m, 1 H), 3.53-3.49 (m, 1 H), 2.67-2.61 (m, 1 H), 2.47- 2.41 (m, 1 H), 1.96-1.92 (m, 1 H), 1.76-1.18 (m, 11 H).

EXAMPLE 14

(3R,5R)-7-[1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5-dihydroxy- heptanoic acid sodium salt

Figure imgf000050_0003

Prepared using the method of Example 1: MS(APCI+): m/z 481.3 (M+H); H-NMR (DMSO-d6) G7.46 (s, 1 H)1 7.35-7.24 (m, 4 H), 7.15-7.11 (m, 1 H), 6.97 (d, 1 H), 6.75 (t, 1 H), 4.75-4.67 (m, 2 H),

0 3.67-3.63 (m, 1 H), 3.52-3.48 (m, 1 H), 2.65-2.59 (m, 1 H), 2.45-2.43 (m, 1 H), 1.95-1.90 (m, 1 H), 1.78- 1.17 (m, 11 H).

FORMULATIONS

The compounds of the present invention including those exemplified herein and all compounds of ,5 Formula I, hereafter referred to as "compound(s)" can be administered alone or in combination with one or more therapeutic agents. These include, for example, other agents for treating, preventing or controlling dyslipidemia, non-insulin dependent diabetes meilitus, obesity, hyperglycemia, hypercholesteremia, hyperlipidemia, atherosclerosis, hypertriglyceridemia, or hyperinsulinemia.

The compounds are thus well suited to formulation for convenient administration to mammals for the prevention and treatment of such disorders.

The following examples further illustrate typical formulations of the compounds provided by the invention.

Formulation 1

Figure imgf000051_0001

The above ingredients are mixed and dissolved in the saline for IV administration to a patient.

Formulation 2

Figure imgf000051_0002

The ingredients are blended to uniformity and pressed into a tablet that is well suited for oral administration to a patient.

Formulation 3

Figure imgf000051_0003

The ingredients are combined and milled to afford material suitable for filling hard gelatin capsules administered to a patient.

Formulation 4

Figure imgf000051_0004
Figure imgf000052_0001

The ingredients are combined via melting and then poured into molds containing 2.5 g total weight.

While embodiments of the invention have been illustrated and described, it is not intended that i these embodiments illustrate and describe all possible forms of the invention. Rather, the words used in the specification are words of description rather than limitation, and it is understood that various changes may be made without departing from the spirit and scope of the invention.

BIOLOGICAL ASSAYS

) The compounds of the invention have demonstrated HMG Co-A reductase inhibition in standard assays commonly employed by those skilled in the art. (See, e.g., J. of Lipid Research 1998;39:75-84; Analytical Biochemistry, 1991 ;196:211-214; RR 740-01077 Pharmacology 8-Nov-82). Accordingly, such compounds and formulations comprising such compounds are useful for treating, controlling or preventing inter alia hypercholesterolemia, hyperlipidemia, hypertriglyceridemia or atherosclerosis.

5

A.) In Vitro Assay

Rat Liver Microsomal Isolation Procedure:

Male Charles River Sprague-Dawley rats were fed with 2.5% cholestyramine in rat chow diets for 5 days before sacrificing. Livers were minced and homogenized in a sucrose homogenizing solution in an ice bath 10 times. Homogenates were diluted into a final volume of 200 mL, and centrifuged 15 min. with a Sorvall Centrifuge at 50C, 10,000 rpm (12,000 x G). The upper fat layer was removed and the supernatant decanted into fresh tubes. This step was repeated one more time before transferring the supernatant into ultracentrifuge tubes and centrifuged at 36,000 rpm (105,000 x G) for an hour at 50C. The resulting supernatant was discarded and the pellet was added to total of 15 mL 0.2 M KH2PO4. Pellets were homogenized gently by hand about 10 times. Samples were pooled and diluted into total of

60 mL buffer. The protein concentration of the homogenate was determined by the Lowry Method using a BCA kit from Pierce Chemical Company. 1 mL aliquots of microsomes were kept frozen in liquid nitrogen.

HMGCoA (3-Hydroxy-3-methylglutaryl CoA) Reductase Assay: Materials and Methods:

[3-14C]-HMGCoA (57.0 mCi/mmol) was purchased from Amersham Biosciences, UK. HMGCoA, mevalonolactone, NADPH were purchased from Sigma Chemical Co. AG 1-8X resin was purchased from Bio-Rad Laboratory.

One μL of dimethyl sulfoxide (DMSO) or 1 μL of DMSO containing a test compound at a 5 concentration sufficient to give a final assay concentration of between 0.1 nM to 1 mM was placed into each well of a Corning 96 well plate. A Volume of 34 μL of buffer (100 mM NaH2PO4, 10 mM Imidazole and 10 mM EDTA) containing with 50 Mg/mL rat liver microsomes was added into each well. After incubation for 30 min. on ice, 15 μL of 14C-HMGCoA (0.024 μCi) with 15 mM NADPH , 25 mM DTT was added and incubated at 370C for an additional 45 min. The reaction was terminated by the addition of 10 μL of HCI followed by 5 μL of mevalonolactone. Plates were incubated at room temperature overnight to allow lactonization of mevaionate to mevalonolactone. The incubated samples were applied to columns

5 containing 300 μL of AG1 -X8 anion exchange resin in a Corning filter plate. The eluates were collected into Corning 96 well capture plates. Scintillation cocktail (Uitima-Flo-M) was added into each well and plates counted on a Trilux Microbeta Counter. The IC50 values were calculated with GraphPad software (Prism). Procedure:

) 1. Add 1 μL DMSO or compounds into the wells according to the protocol

2. Add 35 μL incubation buffer with the rat microsomes into each well. Incubate 30 min. at 40C

3. Add 15 μL 14C-HMGCoA. Incubate 45 min. at 370C

4. Add 10 μL HCI stop reagent

5. Add 5 μL mevelonolactone. Incubate overnight at room temperature

5 6. Apply the containing into the AG 1 -X8 anion exchange resin in Corning filter plate

7. Collect the eluate into Corning capture plate

8. Add scintillation cocktail Ultima-Flo-M

9. Count on a Trilux Microbeta Counter

10. Calculate IC50 values

0 Compounds of the invention exhibit a range of IC50 values of less than about 50OnM, in the aforementioned in vitro assay. Preferred compounds of the invention exhibit a range of IC50 values of less than about 10OnM. More preferred compounds of the invention exhibit a range of IC50 values of less than about 20 nM.

5 B.) Cell Assay

Protocol for Sterol Biosynthesis in Rat Hepatocytes:

Cell culture, compounds treatment and cell labeling:

Frozen rat hepatocytes purchased from XenoTech(cat# N400572) were seeded on 6-well collagen I coated plates at a density of 105 cells/per well. The cells were grown in DMEM medium (Gibco, 0 #11054-020) containing 10% FBS and 10 mM HEPES(Gibco # 15630-080) for 24 hrs. The cells were pre-incubated with compounds for 4 hrs and then labeled by incubating in medium containing 1 uCi/per ml of 14C acetic acid for an additional 4 hrs. After labeling, the cells were washed twice with 5 mM MOPS solution containing 150 mM NaCI and 1 mM EDTA and collected in the lysis buffer containing 10% KOH and 80%(vol.) ethanol.

■5

Cholesterol extraction and data analysis:

In order to separate labeled cholesterol from labeled non-cholesterof lipids, the cells lysates were subject to saponification at 6O0C for 2 hrs. The lysates were then combined with 0.5 volume of H2O and 2 volumes of hexane, followed by 30 minutes of vigorous shaking. After the separation of two phases, the upper-phase solution was collected and combined with 5 volumes of scintillation cocktail. The amount of 14C cholesterol was quantified by liquid scintillation counting. The IC50 values were calculated with GraphPad software (Prism 3.03).

Compounds of the invention exhibit a range of IC50 values of less than about 1 ,00OnM in the aforementioned cell assay. Preferred compounds of the invention exhibit a range of IC50 values of less than about 10OnM.

C.) Protocol for Sterol Biosynthesis in L6 Rat Myoblast: Cell culture, compounds treatment and cell labeling: L6 rat myoblast purchased from ATCC (CRL-1458) were grown in T-150 vented culture flasks and seeded on 12-well culture plates at a density of 60,000 cells per well. The cells were grown in DMEM, (Dulbecco's Modified Eagle Medium) (Gibco, #10567-014) containing 10% heat inactivated FBS (Fetal Bovine Serum) (Gibco # 10082-139) for 72 hours until reaching confluence. The cells were pre-incubated in media with compound and 0.2% DMSO (dimethyl sulfoxide) for 3 hours and then labeled by incubating in medium containing compound, 0.2% DMSO and 1 DCi/per mL of 14C acetic acid for an additional 3 hours. After labeling, the cells were washed once with 1x PBS (Gibco #14190-144) then lysed overnight at 40C in buffer containing 10% KOH and 78%(vol.) ethanol.

Cholesterol extraction and data analysis: Lipid ester bonds were hydrolyzed by saponification of the lysates at 6O0C for 2 hours. Sterols

(including cholesterol) were extracted from saponified lysates by combining with 3 volumes of hexane and mixing by pipette 6 times. The upper organic phase solution was collected and combined with an equal volume of 1 N KOH in 50% methanol and mixed by pipette 6 times. The upper organic phase was collected in a scintilant-coated plate (Wallac #1450-501) and hexanes removed by evaporation at room temperature for 3 hours. The amount of 14C cholesterol was quantified by scintillation counting in a Trilux

1450 plate reader (Wallac). The IC50 values were calculated from % inhibitions relative to negative controls vs. compound concentration on Microsoft excel 2000 data analysis wizard using a sigmoid inhibition curve model with formula: y = Bmax (1-(x7Kn+xn)) + y2 Where K is the IC50 for the inhibition curve, X is inhibitor concentration, Y is the response being inhibited and Bmax+Y2 is the limiting response as X approaches zero. Compounds of the invention have a L6 IC50 value greater than about 10OnM in the aforementioned L6 Ray Myoblast assay. Preferred compounds of the invention exhibit a hepatocyte selectivity greater than about 1000 ((L6 IC50 / Rat hepatocyte IC50) > 1000).

Claims

CLAIMSWhat is claimed is:
1. A compound having a Formula I,
Figure imgf000055_0001
Formula I or a pharmaceutically acceptable salt, ester, amide, stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug, wherein R1 is C1 - C6 alkyl or C3 - C8 cycloalkyl; R2 and R5 are each independently H; C1-C7 alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; said alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted with a halogen, C1-C6 alkyl, - (CH2)mOH-, C1 - C6 alkoxy, C(O)OR' or C(O)NR1R"; R' and R" are each independently C1-C6 alkyl or C1-C6 alkenyl, optionally substituted, or H; R3 and R4 taken together with the carbons to which they are attached, form a 5 to 8 member saturated or unsaturated ring, optionally containing one or more heteroatom; wherein is a bond or is absent; m is 0-6 and n is 0-3.
2. A compound of claim 1 or the pharmaceutically acceptable salt, ester amide, stereoisomer or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug, wherein R1 is isopropyl.
3. A compound of claim 1 or the pharmaceutically acceptable salt, ester amide, stereoisomer or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug, wherein R2 is H.
4. A compound of claim 1 or the pharmaceutically acceptable salt, ester amide, stereoisomer or p prrooddrruugg t thheerreeooff,, o orr t thhee p phhaarrmmaacceeuuitically acceptable salt of the prodrug, wherein R2 is phenyl phenyl substituted with a halogen.
5. A compound of claim 1 or the pharmaceutically acceptable salt, ester amide, stereoisomer or p prrooddrruugg t thheerreeooff,, o orr t thhee p phhaarrmmaacceeiutically acceptable salt of the prodrug, wherein R2 is benzyl or benzyl substituted with a halogen.
6. A compound of claim 1 or the pharmaceutically acceptable salt, ester amide, stereoisomer or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug, wherein R2 and R5 are each independently benzyl, benzyl substituted with a halogen, phenyl, or phenyl substituted with a halogen.
7. A compound of claim 6 or the pharmaceutically acceptable salt, ester amide, stereoisomer or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug, wherein R2 and R5 are each independently phenyl or phenyl substituted with fluorine.
8. A compound having a Formula II,
Figure imgf000056_0001
Formula Il or a pharmaceutically acceptable salt, ester, amide, stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.wherein R1 is C1-C6 alkyl or
D C3- C8 cycloalkyl;
R2 and R5 are each independently H; C1- C7 alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; said alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted with a halogen, C1-C6 alkyl, -(CH2)m OH-, C1-C6 alkoxy, C(O)OR' or C(O)NR1R"; R' and R" are each independently C1-C6 alkyl or C1-C6 alkenyl, optionally substituted, or H; wherein is a bond or is absent; and m is 0-6
5 n is 0-3.
9. A compound of claim 8 or the pharmaceutically acceptable salt, ester amide, stereoisomer or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug, wherein R2 is H.
10. A compound selected from the group consisting of 7-[1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5-
0 dihydroxy-heptanoic acid;
7-[1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-5-phenyl-3,4,5,6-tetrahydro-3,5-diaza-benzo[e]azulen-2- yl]-3,5-dihydroxy-heptanoic acid;
7-[1-(4-fluoro-phenyl)-5-(3-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-
2-yl]-3,5-dihydroxy-heptanoic acid; 5 7-[1 ,5-bis-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid;
7-[1 ,5-bis-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-hept-6-enoic acid;
7-[5-(3-chloro-phenyl)-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin- 0 2-yl]-3,5-dihydroxy-heptanoic acid;
7-[5-biphenyl-4-yl-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2- yl]-3,5-dihydroxy-heptanoic acid ; 7-[5-benzyl-1-(4-fluoro-phenyl)-3-isopropyi-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid ;
7-[5-(2-fluoro-benzyl)-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-
2-yl]-3,5-dihydroxy-heptanoic acid ;
7-[5-(3-fluoro-benzyl)-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-
2-yl]-3,5-dihydroxy-hept-6-enoic acid ;
7-[5-(3-fluoro-benzyl)-3-isopropyl-4-oxo-1-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid ;
7-[5-(4-fluoro-benzyl)-1-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-
2-yl]-3,5-dihydroxy-hept-6-enoic acid;
7-[5-(4-fluoro-benzyl)-3-isopropyl-4-oxo-1-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5- dihydroxy-heptanoic acid;
7-[t-(4-fluoro-phenyl)-3-isopropyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-2-yl]-3,5-dihydroxy- heptanoic acid; and pharmaceutically acceptable salts, esters and amides thereof.
11. A compound having a Formula III,
Figure imgf000057_0001
Formula III
Wherein R1 is C1 - C6 alkyl or C3 - C8 cycloalkyl; R2 and R5 are each independently H; C1-C7 alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; said alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted with a halogen, C1-C6 alkyl, -(CH2)mOH- or C1 - C6 alkoxy; R' is C1-C7 alkyl or C1-C7 alkenyl optionally substituted with one or more groups selected from: - OH, -OR, -COR", P+Ph3Br, or P(O)(OR")2; R" is C1 - C6 alkyl or H; m is 0-6 and n is 0-3.
12. A pharmaceutical composition comprising a compound of claim 1 or the pharmaceutically acceptable salt, ester, amide or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug; or a mixture thereof; and a pharmaceutically acceptable carrier, diluent or vehicle.
13. A method of treating, preventing or controlling atherosclerosis in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim 1 or the pharmaceutically acceptable salt, ester, amide or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug.
14. A lactone form of the compound of claim 1 , said lactone having a Formula IV,
Figure imgf000058_0001
or a pharmaceutically acceptable salt, ester, amide, stereoisomer, racemic mixture or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug, wherein R1, R2, R3, R4, R5, and n are as defined in claim 1.
15. A combination of claim 1 or the pharmaceutically acceptable salt, ester, amide, stereoisomer or prodrug thereof, or the pharmaceutically acceptable salt of the prodrug, and another pharmaceutically active agent.
PCT/IB2005/003608 2004-12-03 2005-11-25 Fused bicyclic pyrrols as hmg-coa reductase inhibitors WO2006059210A2 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2190850A1 (en) * 2007-07-03 2010-06-02 The University Of British Columbia Small molecule correctors of deltaf508 cftr trafficking
EP2190850A4 (en) * 2007-07-03 2011-03-09 Univ British Columbia Small molecule correctors of deltaf508 cftr trafficking

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