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US 2003OO69221A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0069221A1 KOSOglou et al. (43) Pub. Date: Apr. 10, 2003

(54) COMBINATIONS OF STEROL ABSORPTION Related U.S. Application Data INHIBITOR(S) WITH CARDIOVASCULAR AGENT(S) FOR THE TREATMENT OF (60) Provisional application No. 60/323,842, filed on Sep. WASCULAR CONDITIONS 21, 2001. Provisional application No. 60/264,396, filed on Jan. 26, 2001. Provisional application No. (75) Inventors: Teddy Kosoglou, Jamison, PA (US); 60/264,600, filed on Jan. 26, 2001. Provisional appli Rudyard J. Ress, Flemington, NJ (US); cation No. 60/264,275, filed on Jan. 26, 2001. John T. Strony, Lebanon, NJ (US); Enrico P. Veltri, Princeton, NJ (US); Publication Classification William Hauer, Warren, NJ (US) (51) Int. Cl...... A61K 31/397 Correspondence Address: (52) U.S. Cl...... 514/210.02 SCHERING-PLOUGH CORPORATION PATENT DEPARTMENT (K-6-1, 1990) (57) ABSTRACT 2000 GALLOPING HILL ROAD KENILWORTH, NJ 07033-0530 (US) The present invention provides compositions, therapeutic (73) Assignee: Schering Corporation combinations and methods including: (a) at least one Sterol absorption inhibitor and (b) at least one cardiovascular agent (21) Appl. No.: 10/057,339 different from the sterol absorption inhibitor, which can be useful for treating vascular conditions, obesity, diabetes and (22) Filed: Jan. 25, 2002 lowering plasma levels of Sterols. US 2003/0069221A1 Apr. 10, 2003

COMBINATIONS OF STEROL ABSORPTION ever means, less cholesterol is delivered to the liver. The INHIBITOR(S) WITH CARDIOVASCULAR consequence of this action is decreased hepatic lipoprotein AGENT(S) FOR THE TREATMENT OF WASCULAR (VLDL) production and an increase in the hepatic clearance CONDITIONS of plasma cholesterol, mostly as LDL. Thus, the net effect of inhibiting intestinal cholesterol absorption is a decrease in CROSS-REFERENCE TO RELATED plasma cholesterol levels. APPLICATIONS 0007 U.S. Pat. Nos. 5,767,115, 5,624,920, 5,668,990, 0001. This application claims the benefit of priority from 5,656,624 and 5,688,787, respectively, disclose hydroxy U.S. Provisional Patent Application Serial No. 60/323,842 Substituted azetidinone compounds and Substituted B-lactam filed Sep. 21, 2001, U.S. Provisional Patent Application compounds useful for lowering cholesterol and/or in inhib Serial No. 60/264,396 filed Jan. 26, 2001, U.S. Provisional iting the formation of cholesterol-containing lesions in Patent Application Serial No. 60/264,600 filed Jan. 26, 2001, mammalian arterial walls. U.S. Pat. Nos. 5,846,966 and and U.S. Provisional Patent Application Serial No. 60/264, 5,661,145, respectively, disclose hydroxy-Substituted azeti 275 filed Jan. 26, 2001, each incorporated herein by refer dinone compounds or Substituted B-lactam compounds in CCC. combination with HMG CoA reductase inhibitors for pre venting or treating atherosclerosis and reducing plasma FIELD OF THE INVENTION cholesterol levels. 0002 The present invention relates to methods, compo 0008 PCT Patent Application No. WO 00/38725 dis Sitions and therapeutic combinations comprising certain closes cardiovascular therapeutic combinations including an cardiovascular agents and Sterol absorption inhibitors for ileal bile acid transport inhibitor or cholesteryl ester trans treating atherOSclerosis, coronary artery disease and other port protein inhibitor in combination with a fibric acid derivative, nicotinic acid derivative, microSomal triglyceride vascular conditions in mammals. transfer protein inhibitor, cholesterol absorption antagonist, phytosterol, Stanol, antihypertensive agent or bile acid BACKGROUND OF THE INVENTION Sequestrant. 0.003 Vascular disease is a term that broadly encom 0009 U.S. Pat. No. 5,698,527 discloses ergostanone passes all disorders of blood vessels including Small and derivatives Substituted with disaccharides as cholesterol large arteries and veins and blood flow. The most prevalent absorption inhibitors, employed alone or in combination form of vascular disease is arterioSclerosis, a condition with certain other cholesterol lowering agents, which are associated with the thickening and hardening of the arterial useful in the treatment of hypercholesterolemia and related wall. Arteriosclerosis of the large vessels is referred to as disorders. atherosclerosis. Atherosclerosis is the predominant underly ing factor in vascular disorderS Such as coronary artery 0010. Other vascular conditions frequently coexist with disease, aortic aneurysm, arterial disease of the lower cholesterol levels associated with atherosclerosis. These extremities and cerebrovascular disease. may include hypertension, angina and/or arrhythmia. The relevance of, for example, elevated blood pressure as a risk 0004 One major risk factor for arteriosclerosis is high factor for atherosclerosis, cardiovascular and cerebrovascu Serum cholesterol. A total cholesterol level in excess of lar disease in both men and women has been clarified in a 225-250 mg/dl is associated with significant elevation of risk large number of epidemiological Studies. of vascular disease, particularly coronary heart disease. 0011 Clinical trials of blood pressure lowering using 0005 Cholesteryl esters are a major component of ath cardiovascular agents including, for example, calcium chan erosclerotic lesions and the major Storage form of choles nel blockers, have shown beneficial effects in the treatment terol in arterial wall cells. Formation of cholesteryl esters is of early atheroscleroticlesions (see, e.g., Lichtien, P. R. et al. also a step in the intestinal absorption of dietary cholesterol. :Lancet, 335: 1109-1113 (1990) and Waters, D. et al. Cir Thus, inhibition of cholesteryl ester formation and reduction culation 82: 1940-1953 (1990)). Scott (PCT patent Appli of Serum cholesterol can inhibit the progression of athero cation No. WO 99/11260) describes combinations of an Sclerotic lesion formation, decrease the accumulation of HMG CoA reductase inhibitor with an antihypertensive cholesteryl esters in the arterial wall, and block the intestinal agent for the treatment of atherosclerosis and other Symp absorption of dietary cholesterol. toms of vascular disease risk. Additionally, Egon et al. (PCT 0006 The regulation of whole-body cholesterol homeo Patent Application No. WO 96/40255) describe a combina Stasis in mammals and animals involves the regulation of tion therapy of antihypertensive agents including eplerenone dietary cholesterol and modulation of cholesterol biosynthe and angiotensin II antagonist for treating cardiovascular sis, bile acid biosynthesis and the catabolism of the choles disease. terol-containing plasma lipoproteins. The liver is the major 0012 Despite recent improvements in the treatment of organ responsible for cholesterol biosynthesis and catabo vascular disease, there remains a need in the art for lism and, for this reason, it is a prime determinant of plasma improved compositions and treatments for atherosclerosis, cholesterol levels. The liver is the site of synthesis and other vascular diseases and conditions associated with vas secretion of very low density lipoproteins (VLDL) which are cular diseases Such as hypertension, atherosclerosis, and Subsequently metabolized to low density lipoproteins (LDL) hyperlipidaemia. in the circulation. LDL are the predominant cholesterol carrying lipoproteins in the plasma and an increase in their SUMMARY OF THE INVENTION concentration is correlated with increased atherosclerosis. 0013 In one embodiment the present invention provides When intestinal cholesterol absorption is reduced, by what a composition comprising (a) at least one Sterol absorption US 2003/0069221A1 Apr. 10, 2003 inhibitor or pharmaceutically acceptable Salt or Solvate 0020 “Cardiovascular agents” which may used to treat thereof or prodrug of the at least one Sterol absorption the vascular conditions of the present invention, obesity or inhibitor or of the salt or solvate thereof; and (b) at least one diabetes and/or to reduce the level of Sterol(s) in the plasma, cardiovascular agent for treating a vascular condition, dia as used herein, are members of different classes, including betes, obesity and/or lowering a concentration of a Sterol in calcium channel blockers, angiotensin-converting enzyme plasma of a mammal which is different from the at least one (ACE) inhibitors, angiotensin-II receptor antagonists, sterol absorption inhibitor. diuretics, adrenergic blockers including beta-adrenergic 0.014. Therapeutic combinations also are provided com receptor blockers and alpha-adrenergic receptor blockers, prising: (a) a first amount of at least one sterol absorption adrenergic Stimulants, coronary vasodilators, antihyperten inhibitor or pharmaceutically acceptable Salt or Solvate Sive agents, diuretics, anti-anginal agents and combinations thereof or prodrug of the at least one Sterol absorption thereof. The phrase “cardiovascular agents' as used herein inhibitor or of the salt or solvate thereof; and (b) a second does not include HMGCoA reductase inhibitors. The car amount of at least one cardiovascular agent for treating a diovascular agents as defined above are chemically or Struc vascular condition in a mammal which is different from the turally different from the sterol absorption inhibitor(s) dis at least one sterol absorption inhibitor, wherein the first cussed below, for example, they contain one or more amount and the Second amount together comprise a thera different atoms, have a different arrangement of atoms or a peutically effective amount for the treatment or prevention different number of one or more atoms than the sterol of a vascular condition, diabetes, obesity and/or lowering a absorption inhibitor(s) discussed below. concentration of a Sterol in plasma of a mammal. 0021. Useful “adrenergic blockers' include those com 0.015 Pharmaceutical compositions for the treatment or pounds which are B-receptor inhibitors and/or C-receptor prevention of Vascular conditions, obesity, diabetes and/or inhibitors. Adrenergic blockers which are B receptor inhibi lowering a concentration of a Sterol in plasma of a mammal, tors receptor inhibitors include a class of drugs that antago comprising a therapeutically effective amount of the above nize the cardiovascular effects of catecholamines in hyper compositions or therapeutic combinations and a pharmaceu tension, angina pectoris, and cardiac arrhythmias. tically acceptable carrier also are provided. B-adrenergic receptor blockers include, but are not limited to, bunolol hydrochloride (1(2H)-Naphthalenone, 5-3-(1,1- 0016 Methods of treating or preventing vascular condi dimethylethyl)amino-2-hydroxypropoxy-3,4-dihydro-, tions, obesity, diabetes or lowering a concentration of a hydrochloride, CAS RN31969-05-8 which can be obtained Sterol in plasma of a mammal, comprising the Step of from Parke-Davis); (+N-3-Acetyl-4-2-hy administering to a mammal in need of Such treatment an droxy-3-(1 methylethyl)aminopropoxyphenyl-butana effective amount of the above compositions or therapeutic mide, or (t)-3'-Acetyl-4-2-hydroxy -3-(isopropylamino) combinations also are provided. propoxybutyranilide); acebutolol hydrochloride (Such as 0.017. Other than in the operating examples, or where N-3-acetyl-4-2-hydroxy-3-1-methyl-ethyle)aminopro otherwise indicated, all numbers expressing quantities of poxyphenyl-, monohydrocochloride, (-t-,-3'-Acetyl-4-2- ingredients, reaction conditions, and So forth used in the hydroxy-3-(isopropylamino)propoxybutyranilide monohy Specification and claims are to be understood as being drochloride, for example, SECTRAL(R) Capsules available modified in all instances by the term “about.” from Wyeth-Ayerst); hydrochloride (2-Propanol, DETAILED DESCRIPTION 1-(1-methylethyl)amino-3-2-(2-propenyl)phenoxyl-, hydrochloride, CAS RN 13707-88-5 see Netherlands Patent 0.018. In one embodiment, the present invention is Application No. 6,605,692); (such as benzeneac directed to compositions, pharmaceutical compositions, etamide 4-2'-hydroxy-3'-(1-methylethyl)amino therapeutic combinations, kits and methods of treatment propoxy-, for example, TENORMIN(E) I.V. Injection avail using the same comprising (a) at least one (one or more) able from AstraZeneca); hydrochloride (Such as Sterol absorption inhibitor(s), Such as but not limited to, 5-3-(1,1-dimethylethyl)amino-2-hydroxypropoxy-3,4- substituted azetidinone sterol absorption inhibitors or Sub dihydro-2(1H)-quinolinone monohydrochloride, for Stituted B-lactam Sterol absorption inhibitors discussed in example, Cartrol(R) Filmtab(R) Tablets available from detail below, or pharmaceutically acceptable Salts or Sol Abbott); hydrochloride (3-3-Acetyl-4-3-(tert Vates thereof or prodrugs of the at least one Sterol absorption butylamino)-2-hydroxypropoxylphenyl-1,1-diethylurea inhibitor or of the salts or solvates thereof; and (b) at least monohydrochloride, CAS RN57470-78-7, also see in U.S. one (one or more) cardiovascular agent(s) different from the Pat. No. 4,034,009); hydrochloride (Acetamide, Sterol absorption inhibitor(s) (component (a)). 2-2-3-(1,1-dimethylethyl)amino-2-hydroxypropoxy 0019. The compositions and therapeutic combinations of phenoxy-N-methyl-, monohydrochloride, CAS RN 77590 the present invention can be administered to a mammal in 95-5, see also U.S. Pat. No. 4,059,622); hydro need of Such treatment in a therapeutically effective amount chloride (Such S 5-1-hydroxy-2-(1-methyl-3- to treat vascular conditions Such as atherosclerosis, hyper phenylpropyl) amino ethylsalicylamide lipidaemia (including but not limited to hypercholestero monohydrochloride, for example, NORMODYNE(R) Tablets laemia, hypertriglyceridaemia, Sitosterolemia), hyperten available from Schering; esmolol hydrochloride ((+)-Methyl Sion, vascular inflammation, angina, cardiac arrhythmias, p-2-hydroxy-3-(isopropylamino) propoxyhydrocinnamate Stroke, as well as diabetes, obesity, and/or to reduce the level hydrochloride, for example, BREVIBLOC(R) Injection avail of Sterol(s) in the plasma. The compositions and treatments able from Baxter); levobetaxolol hydrochloride (such as can be administered by any Suitable means which produce (S)-1-p-2-(cyclopropylmethoxy)ethylphenoxy-3-(iso contact of these compounds with the Site of action in the propylamino)-2-propanol hydrochloride, for example, body, for example in the plasma, liver or Small intestine of BETAXONTM Ophthalmic Suspension available from a mammal or human. Alcon); hydrochloride (such as (-)-5-3-(tert US 2003/0069221A1 Apr. 10, 2003

Butylamino)-2-hydroxypropoxy-3,4-dihydro-1 (2H)-naph 0022 Adrenergic receptors which are O.-receptor inhibi thalenone hydrochloride, for example, BETAGANOR Liqui tors act to block vasoconstriction induced by endogenous film(R) with C CAP(R) Compliance Cap available from catecholamines. The resulting fall in peripheral resistance Allergan); (Such as 1-(tert-butylamino)-3-(5,6,7,8- leads to a fall in mean blood pressure. The magnitude of this tetrahydro-cis-6,7-dihydroxy-1-naphthyl)oxy-2-propanol, effect is dependent upon the degree of Sympathetic tone at for example, Nadolol Tablets available from Mylan); prac the time the antagonist is administered. tolol (Acetamide, N-4-2-hydroxy-3-1-methylethy 0023 Suitable adrenergic receptors which are C-receptor l)amino-propoxyphenyl-, CAS RN 6673-35-4, see also inhibitors include, but are not limited to, hydro U.S. Pat. No. 3,408,387); hydrochloride (1-(lso chloride (which may be prepared as disclosed in U.S. Pat. propylamino)-3-(1-naphthyloxy)-2-propanol hydrochloride No. 3,399,192 herein incorporated by reference); proroxan CAS RN 318-98-9); Sotalol hydrochloride (such as d.I-N- (CAS RN33743-96-3); hydrochloride (CAS RN: 4-1-hydroxy-2-(1-methylethyl)aminoethyl-phenyl 81403-68-1); and labetalol hydrochloride as described methane-Sulfonamide monohydrochloride, for example, above or combinations thereof. BETAPACE AFTM Tablets available from Berlex);timolol 0024. Adrenergic blockers with C. and 3 receptor inhibi (2-Propanol,1-(1,1-dimethylethyl)aminol-3-4-4-(4-mor tor activity which may be used with the present invention pholinyl)-1,2,5-thiadiazol-3-yl)oxy-, hemihydrate, (S)-, include, but are not limited to, bretylium tosylate (CAS RN: CAS RN 91524-16-2); timolol maleate (S)-1-(1,1-dimeth 61-75-6); dihydroergtamine meSylate (Such as ergotaman-3', ylethyl)aminol-3-4-(4-morpholinyl)-1,2,5-thiadiazol-3- 6', 18-trione.9,-10-dihydro-12'-hydroxy-2-methyl-5'-(phe yl)oxy-2-propanol (Z)-2-butenedioate (1:1) salt, CAS RN nylmethyl)-(5'(alpha))-, monomethaneSulfonate, for 26921-17-5); bisoprolol (2-Propanol, 1-4-2-(1-methyl example, DHE 450R. Injection available from Novartis); ethoxy)ethoxy-methylphenoxyl-3-(1-methylethy (such as (+)-1-(Carbazol-4-yloxy)-3-2-(o-meth l)amino-, (+), CAS RN 66722-44-9); bisoprolol fumarate oxyphenoxy)ethylamino-2-propanol, for example, (such as (+)-1-4-2-(1-Methylethoxy) ethoxymethylphe COREGOR Tablets available from SmithKline Beecham); noxy-3-(1-methylethyl)amino-2-propanol (E) -2-butene labetalol (such as 5-1-hydroxy-2-(1-methyl-3-phenylpro dioate (2:1) (salt), for example, ZEBETATM Tablets avail pyl) amino ethylsalicylamide monohydrochloride, for able from Lederle Consumer); nebivalol (2H-1-Benzopyran example, NORMODYNE(R) Tablets available from Scher 2-methanol, C.C.'-iminobis(methylene)bis 6-fluoro-3,4- ing); bretylium tosylate (Benzenemethanaminium, 2-bromo dihydro-, CAS RN 992.00-09-6 see also U.S. Pat. No. N-ethyl-N,N-dimethyl-, salt with 4-methylbenzenesulfonic 4,654,362); hydrochloride, such 2-Propanol, acid (1:1) CAS RN 61-75-6); mesylate (Phe 1-4-2-(cyclopropylmethoxy)ethoxyphenoxy-3-1-meth nol, 3-(4,5-dihydro-1H-imidazol-2-yl)methyl(4-meth ylethyl)amino-, hydrochloride, A.A.S. RN 63686-79-3); ylphenyl)amino-, monomethanesulfonate (salt) CAS RN and dexpropranolol hydrochloride (2-Propanol, 1-1-methyl 65-28-1); Solypertine tartrate (5H-1,3-Dioxolo4.5-findole, ethyl)-aminol-3-(1-naphthalenyloxy)-hydrochloride (CAS 7-2-4-(2-methoxyphenyl)-1-piperazinyl)ethyl-, (2R,3R)- RN 13071-11-9); hydrochloride (Acetamide, 2,3-dihydroxybutanedioate (1:1) CAS RN 5591-43-5); Zol N-3-acetyl-4-2-hydroxy-3-(1-methyl-ethyl)aminopro ertine hydrochloride (, 1-phenyl4-2-(1H-tetra poxyphenyl-, monohydrochloride CAS RN 69796-04 zol-5-yl)ethyl-, monohydrochloride (8Cl, 9C) CAS RN 9);dilevalol hydrochloride (Benzamide, 2-hydroxy-5-1-hy 7241-94-3) droxy-2-1-methyl-3-phenylpropyl)aminoethyl-, 0025 Vascular conditions may be caused or aggravated monohydrochloride, CAS RN 75659-08-4); by hypertension. Hypertension is defined as persistently hydrochloride (2-Propanol, 1-(2-cyclohexylphenoxy)-3-(1- high blood pressure. Generally, adults are classified as being methylethyl)amino-, hydrochloride CAS RN 59333-90-3); hypertensive when Systolic blood pressure is persistently sulfate (Benzoic acid, 2-fluro-3-2-aminocarbo above 140 mmHg or when diastolic blood pressure is above nyl)amino- -dimethylethylamino-2-hydroxypropyl ester, 90 mmHG. Long-term risks for cardiovascular mortality (+)-sulfate (1:1) (salt), CAS RN88844-73-9; metalol hydro increase in a direct relationship with persistent blood pres chloride (Methanesulfonamide, N-4-1-hydroxy-2-(methy Sure. Suitable examples of antihypertensive agents which lamino)propylphenyl-, monohydrochloride CAS RN may be used in the present invention include althiazide 7701-65-7);metoprolol 2-Propanol, 1-4-(2-methoxyeth (2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4- yl)phenoxy-3-1-methylethyl)amino-; CAS RN37350-58 dihydro-3-(2-propenylthio)methyl-, 1,1-dioxide CAS RN 6);metoprolol tartrate (Such as 2-Propanol, 1-4-(2-meth 5588-16-9); benzthiazide (2H-1,2,4-Benzothiadiazine-7- oxyethyl)phenoxy-3-(1-methylethyl)amino-, for example, Sulfonamide, 6-chloro-3-(phenylmethyl)thiomethyl-, LOPRESSOR(R) available from Novartis); sulfate 1,1-dioxide CAS RN 91-33-8); captopril (L-Proline, (Carbamic acid, 2-4-2-hydroxy-3-(1-methylethyl)amino 1-(2S)-3-mercapto-2-methyl-1-oxopropyl- CAS RN propoxylphenyl-ethyl-, methyl ester, (t) Sulfate (salt) 62571-86-2); carvedilol (2-Propanol, 1-(9H-carbazol-4- (2:1), CAS RN 59954-01-7); sulfate (2-Propanol, yloxy)-3-2-(2-methoxyphenoxy)ethylamino- CAS RN 1-(2-cyclopentylphenoxy)-3-1,1-dimethylethyl)amino1, 72956-09-3), chlorothiazide (sodium 2-Propanol, 1-(9H (S)-, sulfate (2:1) (salt), CAS RN 38.363-32-5); carbazol-4-yloxy)-3-2-(2-methoxyphenoxy)ethylamino (Acetamide, N-4-2-hydroxy-3-(1-methylethyl)amino CAS RN 72956-09-3); hydrochloride (1H-Imida propoxyphenyl-, CAS RN 6673-35-4) hydro zol-2-amine, N-(2,6-dichlorophenyl)4,5-dihydro-, monohy chloride (Propanol, 1-(1-methylethyl)aminol-3-2-(meth drochloride CAS RN 4205-91-8); cyclothiazide (2H-1,2,4- ylthio)-phenoxy-, hydrochloride, (+), CAS RN39832-43 Benzothiadiazine-7-sulfonamide, 3-bicyclo2.2.1]hept-5- 4); (Benzamide, 4-2-2-hydroxy-3-(2- en-2-yl-6-chloro-3,4-dihydro-, 1,1-dioxide CAS RN 2259 methylphenoxy)-propylaminolethoxyl-, CAS RN 38.103 96-3); delapril hydrochloride (2H-1,2,4-Benzothiadiazine 61-6). 7-sulfonamide, 3-bicyclo2.2.1]hept-5-en-2-yl-6-chloro-3, US 2003/0069221A1 Apr. 10, 2003

4-dihydro-, 1,1-dioxide CAS RN 2259-96-3); dilevalol 0026. An angiotensin system inhibitor is an agent that hydrochloride (2H-1,2,4-Benzothiadiazine-7-sulfonamide, interferes with the function, synthesis or catabolism of 3-bicyclo2.2.1]hept-5-en-2-yl-6-chloro-3,4-dihydro-, 1,1- angiotensin II. These agents which may be used in the dioxide CAS RN 2259-96-3); delapril hydrochloride (Gly present invention include but are not limited to angiotensin cine, N-(1S)-1-(ethoxycarbonyl)-3-phenylpropyl)-L-ala converting enzyme (ACE) inhibitors, angiotensin II antago nyl-N-(2,3-dihydro-1H-inden-2-yl)-, monohydrochloride nists, angiotensin II receptor antagonists, agents that activate CAS RN 83435-67-0), mesylate (Piperazine, the catabolism of angiotensin II and agents that prevent the 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2,3-dihy Synthesis of angiotensin I from which angiotensin II is dro-1,4-benzodioxin-2-yl)carbonyl-, monomethane ultimately derived. The renin-angiotensin System is involved sulfonate CAS RN 77883-43-3); fosinopril sodium (L-Pro in the regulation of hemodynamics and water and electrolyte line, 4-cyclohexyl-1-((R)-(1S)-2-methyl-1-(1- balance. Factors that lower blood Volume, renal profusion, Oxopropoxy)propox); moexipril hydrochloride or the concentration of Na+ in plasma tend to activate the (3-Isoquinolinecarboxylic acid, 2-(2S)-2-(1S)-1-(ethoxy System, while factors that increase these parameters tend to carbonyl)-3-phenylpropylamino-1-oxopropyl-1,2,3,4-tet SuppreSS its function. Angiotensin I and angiotensin II are rahydro-6,7-dimethoxy-, monohydrochloride, (3S)- CAS Synthesized by the enzymatic renin-angiotensin pathway. RN 82586-52-5); maleate (1-Piperazinebutana The Synthetic process is initiated when the enzyme renin mide, N-(6,11-dihydrodibenzo(b.e)thiepin-11-yl)-(4-fluo acts on angiotensinogen, a pseudoglobulin in blood plasma, rophenyl)-, (+)-, (Z)-2-butenedioate (1:1) (+)-N-(6,11-Dihy to produce the cecapeptide angiotensin I. Angiotensin I is drodibenzo(b.e)thiepin-11-yl)-4-(p-fluorophenyl)-1- converted by angiotensin-converting enzyme (ACE) to piperazinebutyramide maleate (1:1) CAS RN 132046-06-1), angiotensin II. The latter is an active pressor Substance Metoprolol Succinate (Butanedioic acid, compd. with 1-4- which has been implicated as a causative agent in Several (2-methoxyethyl)phenoxy-3-(1-methylethyl)amino-2- forms of hypertension in various mammalian Species. propanol (1:2) CAS RN 98418-47-4); hydro 0027 “Angiotensin II receptor antagonists' are com chloride (Benzeneacetamide, N-(aminoiminomethyl)-2,6- pounds which interfere with the activity of angiotensin II by dichloro-, monohydrochloride CAS RN 29110-48-3; binding to angiotensin II receptors and interfering with its (L-, 3-hydroxy-alpha.-methyl- CAS activity. Well known angiotensin II receptor antagonists RN 555-30-6); quinaprilat (3-Isoquinolinecarboxylic acid, which may be used in the present invention include peptide 2-(2S)-2-(1S)-1-carboxy-3-phenylpropylamino-1-oxo compounds and non-peptide compounds. Non-limiting propyl-1,2,3,4-tetrahydro-, (3S)- CAS RN 82768-85-2); examples of angiotensin II receptor antagonists include: quinapril hydrochloride (3-Isoquinolinecarboxylic acid, candesartan cilexetil (1H-Benzimidazole-7-carboxylic acid, 2-(2S)-2-(1S)-1-(ethoxycarbonyl)-3-phenylpropyl 2-ethoxy-1-2'-(1H-tetrazol-5-yl)1,1'-biphenyl-4-yl)me amino-1-oxopropyl-1,2,3,4-tetrahydro-, monohydrochlo thyl-, 1-(cyclohexyloxy)carbonyloxyethyl ester) CAS ride, (3S)- CAS RN 82586-55-8); Primidolol (2.4(1H,3H)- RN 145040-37-5); telmisartan(1,1'-Biphenyl)-2-carboxylic Pyrimidinedione, 1-2-2-hydroxy-3-(2- acid, 4'-(1,4'-dimethyl-2'-propyl2,6'-bi-1H-benzimidazol methylphenoxy)propylaminoethyl-5-methyl- CAS RN 1'-yl)methyl- CAS RN 144701-48-4); candesartan (1H 67227-55-8); hydrochloride (Piperazine, 1-(4- Benzimidazole-7-carboxylic acid, 2-ethoxy-1-2'-(1H-tet amino-6,7-dimethoxy-2-quinazolinyl)-(2-furanylcarbo razol-5-yl)1,1'-biphenyl-4-yl)methyl- CAS RN 139481 nyl)-, monohydrochloride CAS RN 19237-84-4); hydrochloride 2,4(1H,3H)-Quinazolinedione, 3-3-(4-phe 59-7); losartan potassium (1H-Imidazole-5-methanol, nyl-1-piperazinyl)propyl-, monohydrochioride CAS RN 2-butyl-4-chloro-1-2'-(1H-tetrazol-5-yl)1,1'-biphenyl)-4- 42877-18-9); hydrochloride (Benzen yl)methyl-, monopotassium Irbesartan1,3-Diazaspiro4.4 emethanamine, N-(2-chloroethyl)-N-(1-methyl-2-phe non-1-en-4-one, 2-butyl-3-2'-(1H-tetrazol-5-yl)1,1'-bi noxyethyl)-, hydrochloride CAS RN 63-92-3); candesartan phenyl-4-yl)methyl- CAS RN 138402-11-6). cilexetil (1H-Benzimidazole-7-carboxylic acid, 2-ethoxy-1- 0028) “Angiotensin-converting enzyme (ACE), is an 2'-(1H-tetrazol-5-yl)1,1'-biphenyl-4-yl)methyl-,1-(cy enzyme which catalyzes the conversion of angiotensin I to clohexyloxy)carbonyloxyethyl ester CAS RN 145040-37 angiotensin II. ACE inhibitors which may be used in the 5); telmisartan (1,1'-Biphenyl-2-carboxylic acid, 4'-(1,4'- present invention include amino acids and derivatives dimethyl-2'-propyl2,6'-bi-1H-benzimidazol-1'-yl)methyl thereof, peptides, including di and tripeptides and antibod CAS RN 144701-48-4); candesartanl H-Benzimidazole-7- ies to ACE which intervene renin-angiotensin System by carboxylic acid, 2-ethoxy-1-2'-(1H-tetrazol-5-yl)1,1'-bi inhibiting the activity of ACE thereby reducing or eliminat phenyl 4-yl)methyl- CAS RN 139481-59-7); amlodipine ing the formation of pressor Substance angiotensin II. ACE besylate3,5-Pyridinedicarboxylic acid, 2-(2-aminoet inhibitors have been used medically to treat hypertension, hoxy)methyl4-(2-chlorophenyl)-1,4-dihydro-6-methyl-, congestive heart failure, myocardial infarction and renal 3-ethyl 5-methyl ester, monobenzenesulfonate CAS RN 111470-99-6 Amlodipine maleate 3.5-Pyridinedicarboxylic disease. Suitable ACE inhibitors include, but are not limited acid, 2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-1,4- to, hydrochloride (such as 3-1-(ethoxycarbo dihydro-6-methyl-, 3-ethyl 5-methyl ester, (2Z)-2-butene nyl)-3-phenyl-(1S)-propylamino-2,3,4,5-tetrahydro-2- dioate (1:1) CAS RN 88150-474); hydrochloride OXO-1H-1-(3S)-benzazepine-1- monohydrochlo (Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)- ride, for example, LOTREL(R) Capsules available from (tetrahydro-2-furanyl)carbonyl-, monohydrochloride CAS Novartis); captopril (Such as 1-(2S)-3-mercapto-2-methyl RN 63074-08-8); bevantolol hydrochloride (2-Propanol, propionyl-L-proline, for example, CAPTOPRIL Tablets 1-2-(3,4-dimethoxyphenyl)ethylaminol-3-(3-methylphe available from Mylan); fosinopril (Such as L-proline, 4-cy noxy)-, hydrochloride CAS RN 42864-78-8); ramipril clohexyl-1-(2-methyl-1-(1-oxopropoxy) propoxy (4-phe (Cyclopentablpyrrole-2-carboxylic acid, 1-(2S)-2-(1S)- nylbutyl) phosphinyl)acetyl-, Sodium salt, trans-, for 1-(ethoxycarbonyl)-3-phenylpropylamino-1-oxopropyl example, MONOPRIL(R) Tablets available from Bristol octahydro-, (2S,3aS,6aS)- CAS RN 87333-19-5). Myers Squibb); moexipril hydrochloride (such as 3S-2 US 2003/0069221A1 Apr. 10, 2003

R*(R*)),3R)-2-2-1- (Ethoxycarbonyl)-3-phenylpro Therapeutic Prospects, John Wiley, New York (1983); pylamino-1-oxopropyl-1,2,3,4-tetrahydro-6,7- McCall, D., Curr. Pract Cardiol., v. 10, p.1-11 (1985), each dimethoxy-3-isoquinolinecarboxylic acid, of which are incorporated herein by reference). Calcium monohydrochloride, for example, UNIRETIC(R) Tablets channel blockers are a heterogeneous group of drugs that available from Schwarz); perindopril erbumine (Such as prevent or slow the entry of calcium into cells by regulating 2S,3aS,7aS)-1-(S)-N-(S)-1-Carboxybutylalanylhexahy cellular calcium channels (Remington, The Science and dro-2-indolinecarboxylic acid, 1-ethyl ester, compound with Practice of Pharmacy, Nineteenth Edition, Mack Publishing tert-butylamine (1:1), for example, ACEONOR Tablets avail Company, Eaton, Pa., p. 963 (1995) incorporated herein by able from Solvay); quinapril (such as 3S-2R*(R*)),3R)- reference). Calcium channel blockers useful in the present 2-2-1-(ethoxycarbonyl)-3-phenylpropylamino-1-oxo invention include but are not limited to, the besylate salt of propyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, amlodipine (Such as 3-ethyl-5-methyl-2-(2-aminoethoxym monohydrochloride, for example, ACCURETICOR Tablets ethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-py available from Parke-Davis); ramipril (such as 2-aza-bicyclo ridinedicarboxylate benzenesulphonate, for example, NOR 3.3.0-octane-3-carboxylic acid derivative, for example, VASCOR available from Pfizer); clentiazem maleate (1.5- ALTACE(R) Capsules available from Monarch); enalapril Benzothiazepin-4(5H)-one, 3-(acetyloxy)-8-chloro-5-2- maleate (such as (S)-1-N-1-(ethoxycarbonyl)-3-phenyl (dimethylamino)ethyl-2,3-dihydro-2-(4-methoxyphenyl)- propyl-L-alanyl-L-proline, (Z)-2-butenedioate Salt (1:1)., (2S-cis)-, (Z)-2-butenedioate (1:1), see also U.S. Pat. No. for example, VASOTEC(R) Tablets available from Merck); 4,567,195); isradipine (3.5-Pyridinedicarboxylic acid, 4-(4- lisinopril (such as (S)-1-N 2-(1-carboxy-3-phenylpropyl)- benzofurazanyl)-1,4-dihydro-2,6-dimethyl-, methyl 1-meth L-lysyl-L-proline dihydrate, for example, PRINZIDE(R) ylethyl ester, (E)-4-(4-benzofurazanyl)-1,4-dihydro-2,6-dim Tablets available from Merck); delapril (which may be ethyl-3,5-pyridinedicarboxylate, see also U.S. Pat. No. prepared as disclosed in U.S. Pat. No. 4,385,051); and 4,466.972), nimodipine (Such as is isopropyl (2-methoxy spirapril (which may be prepared as disclosed in U.S. Pat. ethyl) 1,4-dihydro -2,6-dimethyl-4- (3-nitrophenyl)-3,5- No. 4,470,972); benazeprilat (1H-1-Benzazepine-1-acetic pyridine - dicarboxylate, for example, NIMOTOP(R) avail acid, 3-(1S)-1-carboxy-3-phenylpropylamino-2,3,4,5- able from Bayer); felodipine (such as ethyl methyl 4-(2,3- tetrahydro-2-oxo-, (3S)- CAS RN 86541-78-8); delapril dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedi hydrochloride (Glycine, N-(1S)-1-(ethoxycarbonyl)-3-phe carboxylate, for example, PLENDIL(R) Extended-Release nylpropyl)-L-alanyl-N-(2,3-dihydro-1H-inden-2-yl)-, Tablets available from AstraZeneca LP); nilvadipine (3,5- monohydrochloride CAS RN 83.435-67-0); fosinopril Pyridinedicarboxylic acid, 2-cyano-1,4-dihydro-6-methyl sodium (L-Proline, 4-cyclohexyl-1-((R)-(1S)-2-methyl-1- 4-(3-nitrophenyl)-3-methyl 5-(1-methylethyl) ester, also (1-oxopropoxy)propoxy(4-phenylbutyl)phosphinylactyl-, see U.S. Pat. No. 3,799,934); nifedipine (such as 3.5- sodium salt, (4S)- CAS RN 88889-14-9); libenzapril (1H pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2- 1-Benzazepine-1-acetic acid, 3-(1S)-5-amino-1-carboxy nitrophenyl)-, dimethyl ester, for example, PROCARDIA pentyl)amino-2,3,4,5-tetrahydro-2-oxo-, (3S)- CAS RN XL(R) Extended Release Tablets available from Pfizer); dil 109214-55-3); pentopril (1H-Indole-1-pentanoic acid, 2-car tiazem hydrochloride (such as 1.5-Benzothiazepin-4(5H)- boxy-2,3-dihydro-alpha., gamma.-dimethyl-..delta.-OXO-, one,3-(acetyloxy)-52-(dimethylamino)ethyl-2,3-dihydro alpha.-ethyl ester, (alpha.R. gamma.R,2S)- CAS RN 2(4-methoxyphenyl)-, monohydrochloride, (+)-cis., for 82924-03-6); perindopril 1H-Indole-2-carboxylic acid, example, TIAZAC(R) Capsules available from Forest); vera 1-(2S)-2-(1S)-1-(ethoxycarbonyl)butylamino-1-oxo pamil hydrochloride (Such as benzeneacetronitrile, (alpha)- propyloctahydro-, (2S,3aS,7aS)- CAS RN 82834-16-0); 3-2-(3,4-dimethoxyphenyl) ethylmethylaminopropyl quinapril hydrochloride (3-Isoquinolinecarboxylic acid, 3,4-dimethoxy-(alpha)-(1-methylethyl) hydrochloride, for 2-(2S)-2-(1S)-1-(ethoxycarbonyl)-3-phenylpropyl example, ISOPTINGR SR Tablets available from Knoll amino-1-oxopropyl-1,2,3,4-tetrahydro-, monohydrochlo Labs); teludipine hydrochloride (3,5-Pyridinedicarboxylic ride, (3S)- CAS RN 82586-55-); quinaprilat (3-Isoquinoli acid, 2-(dimethylamino)methyl4-2-(1E)-3-(1,1-dimeth necarboxylic acid, 2-(2S)-2-(1S)-1-carboxy-3- ylethoxy)-3-oxo-1-propenylphenyl-1,4-dihydro-6-me phenylpropylamino-1-oxopropyl-1,2,3,4-tetrahydro-, thyl-, diethyl ester, monohydrochloride) CAS RN 108700 (3S)- CAS RN 82768-85-2); spirapril hydrochloride (1,4- 03-4); belfosdil (Phosphonic acid, 2-(2-phenoxyethyl)-1,3- Dithia-7-azaspiro4.4nonane-8-carboxylic acid, 7-(2S)-2- propanediyl)bis-, tetrabutyl ester CAS RN 103486-79-9); (1S)-1-(ethoxycarbonyl)-3-phenylpropylamino-1-oxo fostedil (Phosphonic acid, 4-(2-benzothiazolyl)phenyl propyl-, monohydrochloride, (8S)- CAS RN 94841-17-5); methyl-, diethyl ester CAS RN 75889-62-2). spiraprilat 1 (4-Dithia-7-azaspiro4.4nonane-8-carboxylic acid, 7-(2S)-2-(1S)-1-carboxy-3-phenylpropylamino)-1- 0030 Cardiovascular agents of the present invention which also act as “anti-angina agents' are useful in the oxopropyl-, (8S)- CAS RN 83602-05-5); teprotide (Brady present invention. Angina includes those Symptoms that kinin potentiator BPP9a CAS RN 35115-60-7); lisinopril occur when myocardial oxygen availability is insufficient to (L-Proline, N-(1S)-1-carboxy-3-phenylpropyl-L-lysyl meet myocardial oxygen demand. Non-limiting examples of CAS RN 76547-98-3); Zofenopril (L-Proline, 1-(2S)-3- these agents include: ranolazine (hydrochloride 1-Pipera (benzoylthio) -2-methyl-1-oxopropyl-4-(phenylthio)-, cal zineacetamide, N-(2,6-dimethylphenyl)-4-2-hydroxy-3-(2- cium salt (2:1), (4S)- CAS RN 81938-43-4). methoxyphenoxy)propyl-, dihydrochloride CAS RN 0029. “Calcium channel blockers' are a chemically 95635-56-6); betaxolol hydrochloride (2-Propanol, 1-4-2 diverse class of compounds having important therapeutic (cyclopropylmethoxy)ethylphenoxy-3-(1-methylethy value in the control of a variety of diseases including Several l)amino-, hydrochloride CAS RN 63659-19-8); buto cardiovascular disorderS Such as hypertension, angina, and prozine hydrochloride (Methanone, 4-3(dibutylamino)pro cardiac arrhythmias (Fleckenstein, Cir. Res. V. 52 (suppl. 1), poxyphenyl(2-ethyl-3-indolizinyl)-, monohydrochloride p. 13-16 (1983); Fleckenstein, Experimental Facts and CAS RN 62134-34-3); cinepazet maleate1-Piperazineacetic US 2003/0069221A1 Apr. 10, 2003 acid, 4-1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl-, perhexiline maleate (Piperidine, 2-(2,2-dicyclohexylethyl)-, ethyl ester, (2Z)-2-butenedioate (1:1) CAS RN50679-07-7); (2Z)-2-butenedioate (1:1) CAS RN 6724-53-4); tosifen (Benzenesulfonamide, 4-methyl-N-(1S)-1-me hydrochloride2-Propanol, 1-(1-methylethyl)aminol-3-2- thyl-2-phenylethylaminocarbonyl- CAS RN32295-184); (2-propenyloxy)phenoxy-, hydrochloride CAS RN 6452 Verapamilhydrochloride (Benzeneacetonitrile, alpha.-3- 73-9); pentrinitrol (1,3-Propanediol, 2,2-bis(nitrooxy)m- 2-(3,4-dimethoxyphenyl)ethylmethylaminopropyl-3,4- ethyl-, mononitrate (ester) CAS RN 1607-17-6); Verapamil dimethoxy-alpha.-(1-methylethyl)-, monohydrochloride (Benzeneacetonitrile, alpha-3-2-(3,4-dimethoxyphenyl) CAS RN 152-114); molsidomine (1,2,3-Oxadiazolium, ethylmethylaminopropyl-3,4-dimethoxy-alpha.-(1-meth 5-(ethoxycarbonyl)aminol-3-(4-morpholinyl)-, inner Salt CAS RN 25717-80-0); ranolazine hydrochloride (1-Pipera ylethyl)- CAS RN 52-53-9). Zineacetamide, N-(2,6-dimethylphenyl)-2-hydroxy-3-(2- 0032. The term “diuretic' includes compounds that methoxyphenoxy)propyl-, dihydrochloride CAS RN increase the excretion of Solutes (mainly NaCl) and water. In 95635-56-6); tosifen (Benzenesulfonamide, 4-methyl-N- general, the primary goal of diuretic therapy is to reduce (1S)-1-methyl-2-phenylethylaminocarbonyl- CAS RN extracellular fluid volume in order to lower blood pressure 32295-184). or rid the body of excess interstitial fluid (edema). Non 0.031 “Coronary vasodilators' may act to reduce angina limiting examples of diuretics which may be used within the Systems by increasing the oxygen Supply to the heart. Scope of this invention include althiazide (which may be Coronary vasodilators useful in the present invention prepared as disclosed in British Patent No. 902,658); ben include, but are not limited to, diltiazem hydrochloride (Such Zthiazide (which may be prepared as disclosed in U.S. Pat. as 1.5-Benzothiazepin-4(5H)-one,3-(acetyloxy)-52-(dim No. 3,108,097); buthiazide (which may be prepared as ethylamino)ethyl-2,-3-dihydro-2(4-methoxyphenyl)-, disclosed in British Patent Nos. 861,367); chlorothiazide monohydrochloride, (+)-cis, for example, TIAZAC(R) Cap (which may be prepared as disclosed in U.S. 2,809,194); Sules available from Forest); isosorbide dinitrate (such as spironolactone (CAS Number 52-01-7); and triamterene 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate, for example, (CAS Number 396-01-0). ISORDIL(R) TITRADOSE(R) Tablets available from Wyeth Ayerst); SOSorbide mononitrate (Such as 1,4:3,6-dianhydro 0033 “Adrenergic stimulants' useful as cardiovascular D-glucitol,5-nitrate, an organic nitrate, for example, Ismo (F) agents in the present invention include, but are not limited Tablets available from Wyeth-Ayerst); nitroglycerin (such as to, guanfacine hydrochloride (Such as N-amidino-2-(2,6- 2.3 propanetriol trinitrate, for example, NITROSTATR Tab dichlorophenyl) acetamide hydrochloride, for example, lets available from Parke-Davis); Verapamil hydrochloride TENEX(R) Tablets available from Robins); methyldopa-hy (Such as benzeneacetonitrile, (-)-(alpha)3-2-(3,4 drochlorothiazide (such as levo-3-(3,4-dihydroxyphenyl)-2- dimethoxyphenyl)ethylmethylaminopropyl-3,4- methylalanine) combined with Hydrochlorothiazide (such as dimethoxy-(alpha)- (1-methylethyl) hydrochloride, for 6-chloro-3,4-dihydro-2H -1,2,4-benzothiadiazine-7- Sul example, COVERA HS(R) Extended-Release Tablets avail able from Searle); chromonar (which may be prepared as fonamide 1,1-dioxide, for example, the combination as, for disclosed in U.S. Pat. No. 3,282,938); clonitate (Annalen example, ALDORIL(R) Tablets available from Merck); meth 1870 155); droprenilamine (which may be prepared as yldopa-chlorothiazide (such as 6-chloro-2H-1, 2,4-ben disclosed in German Patent No. 2,521,113); lidoflazine Zothiadiazine-7-Sulfonamide 1,1-dioxide and methyldopa as (which may be prepared as disclosed in U.S. Pat. No. described above, for example, ALDOCLORr(R) Tablets 3,267,104); (which may be prepared as dis available from Merck); clonidine hydrochloride (such as closed in U.S. Pat. No. 3,152.173); propatyl nitrate (which 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride may be prepared as disclosed in French Patent No. 1,103, and chlorthalidone (such as 2-chloro-5-(1-hydroxy-3-oxo 113); mioflazine hydrochloride (1-Piperazineacetamide, 1-isoindolinyl) benzenesulfonamide), for example, COM 3-(aminocarbonyl)-4,4-bis(4-fluorophenyl)butyl-N-(2,6- BIPRES(R) Tablets available from Boehringer Ingelheim); dichlorophenyl)-, dihydrochloride CAS RN 83898-67-3); clonidine hydrochloride (Such as 2-(2,6-dichloropheny mixidine (Benzeneethanamine, 3,4-dimethoxy-N-(1-me lamino)-2-imidazoline hydrochloride, for example, CATAP thyl-2-pyrrolidinylidene)- Pyrrolidine, 2-(3,4-dimethox RES(R) Tablets available from Boehringer Ingelheim); cloni yphenethyl)imino-1-methyl-1-Methyl-2-(3,4-dimethox dine (1H-Imidazol-2-amine, N-(2,6-dichlorophenyl)4.5- yphenethyl)iminolpyrrolidine CAS RN 27737-38-8); dihydro- CAS RN 4205-90-7). molsidomine (1,2,3-Oxadiazolium, 5-(ethoxycarbony l)aminol-3-(4-morpholinyl)-, inner salt CAS RN25717-80 0034 Generally, a total dosage of the above-described 0); isosorbide mononitrate (D-Glucitol, 14:3,6-dianhydro-, agents or medications can range from 1 to 3,000 mg/day, 5-nitrate CAS RN 16051-77-7); erythrityl tetranitrate (1.2, preferably from about 1 to 1,000 mg/day and more prefer 3,4-Butanetetrol, tetranitrate, (2R,3S)-rel-CAS RN 7297 ably from about 1 to 200 mg/day in single or 24 divided 25-8); clonitrate(1.2-Propanediol, 3-chloro-, dinitrate (7CI, doses. 8CI, 9CI) CAS RN 2612-33-1); dipyridamole , 2,2', 2",2"-(4,8-di-1-piperidinylpyrimido5,4-dpyrimidine-2,6- 0035. The cardiovascular agents useful for treating vas diyl)dinitrilotetrakis- CAS RN 58-32-2); nicorandil (CAS cular conditions are administered in a therapeutically effec RN 65141-46-03-); pyridinecarboxamide (N-2-(nitrooxy) tive amount to treat the Specified condition, for example, in ethyl-Nisoldipine3,5-Pyridinedicarboxylic acid, 1,4-dihy a daily dose preferably ranging from about 1 to about 3000 dro-2,6-dimethyl-4-(2-nitrophenyl)-, methyl 2-methylpro mg per day, and more preferably about 5 to about 200 mg per pyl ester CAS RN 63675-72-9); nifedipine3.5-Pyridinedi day, given in a single dose or 24 divided doses. The exact carboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2- dose, however, is determined by the attending clinician and nitrophenyl)-, dimethyl ester CAS RN 21829-25-4); is dependent on Such factors as the potency of the compound US 2003/0069221A1 Apr. 10, 2003 administered, the age, weight, condition and response of the patient. (I) 0.036 The term “therapeutically effective amount’ means R R2 that amount of a therapeutic agent of the composition, Such Arl-X th-y- d Zp Ari as the cardiovascular agents, Sterol absorption inhibitor(s) and other pharmacological or therapeutic agents described below, that will elicit a biological or medical response of a N tissue, System, animal or mammal that is being Sought by the O YA2 administrator (Such as a researcher, doctor or veterinarian) which includes alleviation of the symptoms of the condition or disease being treated and the prevention, Slowing or 0040 or isomers of the compounds of Formula (I), or halting of progression of the condition (for example a pharmaceutically acceptable Salts or Solvates of the com vascular condition as discussed above). pounds of Formula (I) or of the isomers of the compounds 0037 AS used herein, “combination therapy” or “thera of Formula (I), or prodrugs of the compounds of Formula (I) peutic combination” means the administration of two or or of the isomers, Salts or Solvates of the compounds of more different therapeutic agents, Such as cardiovascular Formula (I), wherein, in Formula (I) above: agent(s) and sterol absorption inhibitor(s), to prevent or treat a vascular condition, Such as hyperlipidaemia (for example 0041) Ar" and Arfare independently selected from atherosclerosis, hypercholesterolemia or Sitosterolemia), the group consisting of aryland R-Substituted aryl; Stroke, diabetes, obesity and/or reduce the level of Sterol(s) 0042 Ar is aryl or R-substituted aryl; in the plasma. AS used herein, "vascular comprises cardio vascular, cerebrovascular and combinations thereof. Such 0043 X, Y and Z are independently selected from administration includes coadministration of these therapeu the group consisting of -CH2-, -CH(lower tic agents in a Substantially simultaneous manner, Such as in alkyl)- and -C(dillower alkyl)-; a Single tablet or capsule having a fixed ratio of active ingredients or in multiple, Separate capsules for each thera 0044) R' and Rare independently selected from the peutic agent. Also, Such administration includes use of each group consisting of -OR. -O(CO)R, type of therapeutic agent in a Sequential manner. In either —O(CO)OR and—O(CO)NR'R'; case, the treatment using the combination therapy will provide beneficial effects in treating the vascular condition 004:5) R' and Rare independently selected from the and other conditions as discussed above. A potential advan group consisting of hydrogen, lower alkyl and aryl; tage of the combination therapy disclosed herein may be a 0046) q is 0 or 1; r is 0 or 1; m, n and p are reduction in the required amount of an individual therapeutic independently selected from 0, 1, 2, 3 or 4; provided compound or the overall total amount of therapeutic com that at least one of q and r is 1, and the Sum of m, n, pounds that are effective in treating the vascular condition. p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when By using a combination of therapeutic agents, the side p is 0 and r is 1, the Sum of m, q and n is 1, 2, 3, 4 effects of the individual compounds can be reduced as or 5; compared to a monotherapy, which can improve patient compliance. Also, therapeutic agents can be Selected to 0047) R' is 1-5 substituents independently selected provide a broader range of complimentary effects or com from the group consisting of lower alkyl, -OR, plimentary modes of action. –O(CO)R’, –O(CO)OR, O(CH), OR, -O(CO)NR'R7, -NRR7, -NR(CO)R’, 0.038. As discussed above, the compositions, pharmaceu -NR(CO)OR,-NR(CO)NR7R,-NRSOR, tical compositions and therapeutic combinations of the -COOR, -CONR'R'', -COR, -SONR'R'', present invention comprise one or more Sterol absorption S(O)o R', -O(CH)-o-COOR, -O(CH)-o inhibitors, Such as the Substituted azetidinone Sterol absorp CONR'R',-(lower alkylene)COOR, -CH=CH tion inhibitors or substituted B-lactam sterol absorption COOR, -CF, -CN, -NO and halogen; inhibitors discussed in detail below. AS used herein, “sterol absorption inhibitor” means a compound capable of inhib 0048) R is 1-5 substituents independently selected iting the absorption of one or more Sterols, including but not from the group consisting of -OR. --O(CO)R, limited to cholesterol, phytosterols (Such as Sitosterol, –O(CO)OR, –O(CH), OR, –O(CO)NR'R'', campesterol, Stigmasterol and avenosterol), 5C.-Stanols -NRR7 NR(CO)R7, -NR(CO)OR, (Such as cholestanol, 5C-campestanol, 5C-sitostanol), and -NR(CO)NR7R, -NR SOR, -COOR, mixtures thereof, when administered in a therapeutically –CONR'R'', -COR. -SONR'R', S(O).R. effective (sterol absorption inhibiting) amount to a mammal -O(CH)-o-COOR. --O(CH-)-oCONR'R'', or human. -(lower alkylene)COOR and -CH=CH COOR; 0039. In a preferred embodiment, sterol absorption inhibitors useful in the compositions, therapeutic combina 0049) R, R7 and Rare independently selected from tions and methods of the present invention are represented the group consisting of hydrogen, lower alkyl, aryl by Formula (I) below: and aryl-Substituted lower alkyl, and US 2003/0069221A1 Apr. 10, 2003

0050 R is lower alkyl, aryl or aryl-substituted maleic, methaneSulfonic and other mineral and carboxylic lower alkyl. acids well known to those in the art. The salt is prepared by contacting the free base form with a Sufficient amount of the 0051) Preferably, R is 1-3 independently selected sub desired acid to produce a Salt. The free base form may be stituents, and R is preferably 1-3 independently selected regenerated by treating the Salt with a Suitable dilute aque Substituents. ous base Solution Such as dilute aqueous Sodium bicarbon 0052. As used herein, the term “alkyl” or “lower alkyl” ate. The free base form differs from its respective salt form means Straight or branched alkyl chains having from 1 to 6 Somewhat in certain physical properties, Such as in carbon atoms and “alkoxy' means alkoxy groups having 1 polar Solvents, but the Salt is otherwise equivalent to its to 6 carbon atoms. Non-limiting examples of lower alkyl respective free base forms for purposes of the invention. groups include, for example, methyl, ethyl, propyl, and butyl 0062 Certain compounds of the invention are acidic groupS. (e.g., those compounds which possess a carboxyl group). 0.053 “Alkenyl' means straight or branched carbon These compounds form pharmaceutically acceptable Salts chains having one or more double bonds in the chain, with inorganic and organic bases. Examples of Such Salts are conjugated or unconjugated. Similarly, “alkynyl' means the Sodium, potassium, calcium, aluminum, gold and Silver Straight or branched carbon chains having one or more triple Salts. Also included are Salts formed with pharmaceutically bonds in the chain. Where an alkyl, alkenyl or alkynyl chain acceptable amines Such as ammonia, alkyl amines, hydroxy joins two other variables and is therefore bivalent, the terms alkylamines, N-methylglucamine and the like. alkylene, alkenylene and alkynylene are used. 0063 AS used herein, “solvate” means a molecular or 0.054 “Cycloalkyl” means a saturated carbon ring of 3 to ionic complex of molecules or ions of Solvent with those of 6 carbon atoms, while “cycloalkylene' refers to a corre Solute (for example, one or more compounds of Formulae sponding bivalent ring, wherein the points of attachment to I-XI, isomers of the compounds of Formulae I-XI, or other groups include all positional isomers. prodrugs of the compounds of Formulae I-XI). Non-limiting 0.055 “Halogeno” refers to fluorine, chlorine, bromine or examples of useful Solvents include polar, protic Solvents iodine radicals. Such as water and/or alcohols (for example methanol). 0056 "Aryl” means phenyl, naphthyl, indenyl, tetrahy 0064. As used herein, “prodrug” means compounds that dronaphthyl or indanyl. are drug precursors which, following administration to a patient, release the drug in Vivo Via Some chemical or 0057 “Phenylene” means a bivalent phenyl group, physiological process (e.g., a prodrug on being brought to including ortho, meta and para-Substitution. the physiological pH or through enzyme action is converted 0058. The statements wherein, for example,R,R,R and to the desired drug form). R are said to be independently selected from a group of 0065 Preferred compounds of Formula (I) are those in substituents, mean that R, R, R and Rare independently which Ar' is phenyl or R-substituted phenyl, more prefer selected, but also that where an R, R', R and R variable ably (4-R")-substituted phenyl. Ar is preferably phenyl or occurs more than once in a molecule, each occurrence is R"-substituted phenyl, more preferably (4-R")-substituted independently selected (e.g., if R is -OR, wherein R is phenyl. Ar is preferably R-substituted phenyl, more pref hydrogen, R can be -OR wherein R is lower alkyl). erably (4-R)-substituted phenyl. When Ar' is (4-R")-sub Those skilled in the art will recognize that the size and stituted phenyl, R' is preferably a halogen. When Ari and nature of the substituent(s) will affect the number of Sub Ar are R'- and R-substituted phenyl, respectively, R" is Stituents that can be present. preferably halogen or -OR and R is preferably -OR, 0059 Compounds of the invention have at least one wherein R is lower alkyl or hydrogen. Especially preferred asymmetrical carbon atom and therefore all isomers, includ are compounds wherein each of Ar' and Art is 4-fluorophe ing enantiomers, Stereoisomers, rotamers, tautomers and nyl and Ar is 4-hydroxyphenyl or 4-methoxyphenyl. racemates of the compounds of Formulae (I-XI) (where they exist) are contemplated as being part of this invention. The (0.066) X, Y and Z are each preferably -CH-. R" and invention includes d and I isomers in both pure form and in R are each preferably hydrogen. R" and R are preferably admixture, including racemic mixtures. Isomers can be -OR wherein R is hydrogen, or a group readily metabo prepared using conventional techniques, either by reacting lizable to a hydroxyl (such as -O(CO)R, -O(CO)OR optically pure or optically enriched Starting materials or by and —O(CO)NR'R', defined above). Separating isomers of a compound of the Formulae I-XI. IsomerS may also include geometric isomers, e.g., when a 0067. The sum of m, n, p, q and r is preferably 2, 3 or 4, double bond is present. more preferably 3. Preferred are compounds wherein m, in and r are each Zero, q is 1 and p is 2. 0060 Those skilled in the art will appreciate that for Some of the compounds of the Formulas I-XI, one isomer 0068 Also preferred are compounds of Formula (I) in will show greater pharmacological activity than other iso which p, q and n are each Zero, r is 1 and m is 2 or 3. More CS. preferred are compounds wherein m, n and r are each Zero, q is 1, p is 2, Z is -CH- and R is -OR, especially when 0061 Compounds of the invention with an amino group R is hydrogen. can form pharmaceutically acceptable Salts with organic and inorganic acids. Examples of Suitable acids for Salt forma 0069. Also more preferred are compounds of Formula (I) tion are hydrochloric, Sulfuric, phosphoric, acetic, citric, wherein p, q and n are each Zero, r is 1, m is 2, X is -CH2 Oxalic, malonic, Salicylic, malic, fumaric, Succinic, ascorbic, and R is -OR, especially when R is hydrogen. US 2003/0069221A1 Apr. 10, 2003

0070 Another group of preferred compounds of Formula (I) is that in which Ar" is phenyl or R-substituted phenyl, -continued Ar is phenyl or R'-substituted phenyl and Aris R-substi R2 R3 tuted phenyl. Also preferred are compounds in which Ar' is V M phenyl or R-substituted phenyl, Ar is phenyl or R'-sub stituted phenyl, Aris R-substituted phenyl, and the sum of m, n, p, q and r is 2, 3 or 4, more preferably 3. More preferred are compounds wherein Ar is phenyl or R s O X -substituted phenyl, Art is phenyl or R'substituted phenyl, A.101 i. O Aris R-substituted phenyl, and wherein m, n and rare each Zero, q is 1 and p is 2, or wherein p, q and n are each Zero, 0075 wherein R' and Rare RandR, respectively, or are r is 1 and m is 2 or 3. Suitably protected hydroxy groups; Ar" is Ar", a Suitably 0071. In a preferred embodiment, a sterol inhibitor of protected hydroxy-Substituted aryl or a Suitably protected Formula (I) useful in the compositions, therapeutic combi amino-Substituted aryl; and the remaining variables are as nations and methods of the present invention is represented defined above for Formula I, provided that in lactone of by Formula (II) (ezetimibe) below: formula B, when n and r are each Zero, p is 1-4, 0076 (b) reacting the product of step (a) with an imine of the formula

(II) Ar30

NA20

0.077 wherein Ar' is Art, a suitably protected hydroxy Substituted aryl or a Suitably protected amino-Substituted aryl; and Ari is Ar., a suitably protected hydroxy-substi tuted aryl or a Suitably protected amino-Substituted aryl; 0078 c) quenching the reaction with an acid; 0079 d) optionally removing the protecting groups 0.072 or pharmaceutically acceptable salts or Solvates of from R', R, Ar'', Ar’’ and Ar, when present; and the compounds of Formula (II), or prodrugs of the com 0080 e) optionally functionalizing hydroxy or pound of Formula (II) or of the salts or solvates of the amino substituents at R, R, Ar", Art and Ar. compound of Formula (II). 0081. Using the lactones shown above, compounds of 0.073 Compounds of Formula I can be prepared by a Formula IA and IB are obtained as follows: variety of methods well known to those skilled in the art, for example such as are disclosed in U.S. Pat. Nos. 5,631,365, 5,767,115, 5,846,966, 6,207,822, U.S. Provisional Patent Application No. 60/279,288 filed Mar. 28, 2001 and PCT He Patent Application WO 93/02048, each of which is incor O N YA20 porated herein by reference, and in the Example below. For example, Suitable compounds of Formula I can be prepared (RR), by a method comprising the Steps of 101"X A. 0074 (a) treating with a strong base a lactone of the Formula A or B: pi Arl-X. sy--, Art R1 R3

O NAr2

IA US 2003/0069221A1 Apr. 10, 2003 10

0082 wherein the variables are as defined above; and –O(CO)OR. --O(CH), OR. --O(CO)NR'R'', -NRR7, -NR(CO)R7, -NR(CO)OR, -NR(CO)NR'R'', -NRSO-lower alkyl, R2 R3 -NRSO-aryl, -CONRR7, - COR, N / –SONRR", S(O)-2-alkyl, S(O)-2-aryl, Orsz, Ar30 Yn -O(CH)-o-COOR, -O(CH2)CONRR7, R -- He o-halogeno, m-halogeno, O-lower alkyl, m-lower N alkyl, -(lower alkylene)-COOR, and O YA20 -CH=CH-COOR; X A101" O 0.095 R and R' are independently 1-3 substituents B independently Selected from the group consisting of R., hydrogen, p-lower alkyl, aryl, -NO,-CFs and it p-halogeno; Arl-X, C-Yi (C) -Z, Ari 0096) R, R7 and Rare independently selected from k . the group consisting of hydrogen, lower alkyl, aryl N and aryl-substituted lower alkyl; and R is lower IB O N,Air alkyl, aryl or aryl-Substituted lower alkyl. 0097. Preferred compounds of Formula I include those in which Ar" is R-substituted phenyl, especially (4-R)-sub 0.083 wherein the variables are as defined above. stituted phenyl. Ar is preferably R-substituted phenyl, 0084. Alternative sterol absorption inhibitors useful in especially (4-R")-substituted phenyl. Ar is preferably the compositions, therapeutic combinations and methods of R-substituted phenyl, especially (4-R)-substituted phenyl. the present invention are represented by Formula (III) Mono-substitution of each of Ar", Ar and Ar is preferred. below: 0.098 Y and Z are each preferably -CH-. R is pref erably hydrogen. R' is preferably -OR wherein R is (III) hydrogen, or a group readily metabolizable to a hydroxyl R1 (such as —O(CO)R, -O(CO)OR and –O(CO)NR'R'', defined above). Also preferred are compounds wherein R' Ar-A-Y-|---- Zip Ar3 and R together are =O. k 0099. The sum of q and p is preferably 1 or 2, more preferably 1. Preferred are compounds wherein p is Zero and O NAr2 q is 1. More preferred are compounds wherein p is Zero, q is 1, Y is -CH2- and R' is -OR, especially when R is hydrogen. 0085 or isomers of the compounds of Formula (III), or pharmaceutically acceptable Salts or Solvates of the com 0100 Another group of preferred compounds is that in pounds of Formula (III) or of the isomers of the compounds which Ar' is R-substituted phenyl, Ar is R-substituted of Formula (III), or prodrugs of the compounds of Formula phenyl and Aris R-substituted phenyl. (III) or of the isomers, salts or solvates of the compounds of 0101) Also preferred are compounds wherein Ar' is Formula (III), wherein, in Formula (III) above: R-substituted phenyl, Ar is R'-substituted phenyl, Ar is R-Substituted phenyl, and the Sum of p and q is 1 or 2, 0086) Ar' is R-substituted aryl; especially 1. More preferred are compounds wherein Ar' is 0087 Art is R-substituted aryl; R-substituted phenyl, Ar is R'-substituted phenyl, Ar is R-Substituted phenyl, p is Zero and q is 1. 0088) Aris R-substituted aryl; 0102) A is preferably -O-. 0089 Y and Z are independently selected from the 01.03 R is preferably -COOR, -CONRR7 , group consisting of -CH2-, -CH(lower alkyl)- —COR, -SONR'R', S(O)-alkyl, S(O)''-aryl, NO or and -C(dillower alkyl)-; halogeno. A more preferred definition for R is halogeno, 0090 A is selected from -O-, -S-, -S(O)- especially fluoro or chloro. or -S(O)-; 0104) R' is preferably hydrogen, lower alkyl, -OR, 0091) R' is selected from the group consisting of —O(CO)R’, –O(CO)OR. --O(CO)NR'R'', -NRR7, –OR, —O(CO)R, -O(CO)OR and COR or halogeno, wherein R and R7 are preferably inde -O(CO)NR'R'; R is selected from the group con pendently hydrogen or lower alkyl, and R is preferably sisting of hydrogen, lower alkyl and aryl; or R' and lower alkyl. A more preferred definition for R' is hydrogen R° together are =O; or halogeno, especially fluoro or chloro. 0092 q is 1, 2 or 3; 01.05 R is preferably -OR, –O(CO)R, -O(CO)OR", –O(CO)NR'R' -NR'R' -(lower alky 0093 p is 0, 1,2,3 or 4; lene)-COOR or -CH=CH-COOR, wherein R and 0094) R is 1-3 substituents independently selected R are preferably independently hydrogen or lower alkyl, and from the group consisting of -OR. --O(CO)R, R’ is preferably lower alkyl. A more preferred definition for US 2003/0069221A1 Apr. 10, 2003 11

R is -OR, -(lower alkylene)-COOR or -CH=CH 0119), R is selected from: COOR, wherein R is preferably hydrogen or lower alkyl. 0106 Methods for making compounds of Formula III are well known to those skilled in the art. Non-limiting examples of Suitable methods are disclosed in U.S. Pat. No. -CH-, -C(C-C alkyl)-, -CF-, 5,688,990, which is incorporated herein by reference. 0107. In another embodiment, sterol absorption inhibi -C(OH)-, -C(CH-R') , -N-, or -'NO; tors useful in the compositions, therapeutic combinations and methods of the present invention are represented by Formula (IV): 0120 R and R7 are independently selected from the group consisting of -CH2-, -CH(C-C alkyl)-, (IV) -C(di-(C-C)C. alkyl)=CH-, alkyl), or R -CH=CH-together with and an adjacent-C(C- R°, or R together with an adjacent R, form a -CH=CH- or a -CH=C(C-C alkyl)- group; Arl-R1-O S. 0121 a and b are independently 0, 1, 2 or 3, pro vided both are not zero; provided that when R is -CH=CH- or -C(C-C alkyl)=CH-, a is 1; provided that when R7 is -CH=CH- or -C(C- C alkyl)=CH-, b is 1; provided that when a is 2 or 3, the R's can be the same or different; and 0108 or isomers of the compounds of Formula (IV), or provided that when b is 2 or 3, the R7's can be the pharmaceutically acceptable Salts or Solvates of the com Same or different; pounds of Formula (IV) or of the isomers of the compounds of Formula (IV), or prodrugs of the compounds of Formula 0122) and when Q is a bond, R also can be selected (IV) or of the isomers, salts or solvates of the compounds of from: Formula (IV), wherein, in Formula (IV) above: 0109) A is selected from the group consisting of R-sub R10 R12 R10 stituted heterocycloalkyl, R-substituted heteroaryl, R-sub stituted benzofused heterocycloalkyl, and R-substituted -----. --d--d-- O benzofused heteroaryl; k le l 0110 Ar' is aryl or R-substituted aryl; R10 0111 Art is aryl or R-substituted aryl; -X-((), Y-S(O) - ; 0112 Q is a bond or, with the 3-position ring carbon ki of the azetidinone, forms the Spiro group 0123 where M is -O-, -S-, -S(O)- or -S(O)-; R5- (R): 0.124 X, Y and Z are independently selected from the group consisting of -CH2-, -CH(C-C, cks alkyl)- and -C(di-(C-C) alkyl); 0125) R' and R'' are independently selected from 0113 and the group consisting of –OR'', -O(CO)R', –O(CO)OR and –O(CO)NR'R'': 0114) R' is selected from the group consisting of: 0126) R' and R' are independently selected from 0115) -(CH2), , wherein q is 2-6, provided that the group consisting of hydrogen, (C-C)alkyl and when Q forms a Spiro ring, q can also be Zero or aryl; or R'' and R' together are=O, or R'' and R' 1, together are =O; 0116 -(CH)-G-(CH) , wherein G is O127 d is 1, 2 or 3; -O-, -C(O)-, phenylene, -NR - or -S(O)o, e is 0-5 and r is 0-5, provided that the 0128 h is 0,1,2,3 or 4; Sum of e and r is 1-6, 0.129 s is 0 or 1; t is 0 or 1; m, n and p are 0117 -(C-C alkenylene)-; and independently 0-4, provided that at least one of S and t is 1, and the Sum of m, n, p, S and t is 1-6, provided 0118) -(CH2)-V-(CH) , wherein V is that when p is 0 and t is 1, the Sum of m, S and n is C-C cycloalkylene, fis 1-5 and g is 0-5, provided 1-5; and provided that when p is 0 and s is 1, the sum that the Sum of f and g is 1-6, of m, t and n is 1-5, US 2003/0069221A1 Apr. 10, 2003 12

0130 v is 0 or 1; 0140) R' is hydrogen or (C-C)alkyl; and 0131 j and k are independently 1-5, provided that 0141) R' is hydrogen, hydroxy or (C-C)alkoxy. the Sum of j, k and V is 1-5, 0142. As used in Formula (IV) above, “A” is preferably 0132) R is 1-3 substituents on the ring carbon atoms an R-substituted, 6-membered heterocycloalkyl ring con Selected from the group consisting of hydrogen, taining 1 or 2 nitrogen atoms. Preferred heterocycloalkyl (C-Clio)alkyl, (C-Clio)alkenyl, (C-Clio)alkynyl, rings are piperidinyl, piperazinyl and morpholinyl groups. (C-C)cycloalkyl, (C-C)cycloalkenyl, R''-Substi The ring “A” is preferably joined to the phenyl ring through tuted aryl, R'7-substituted benzyl, R'7 substituted a ring nitrogen. Preferred R Substituents are hydrogen and benzyloxy, R-Substituted aryloxy, halogeno, lower alkyl. R' is preferably hydrogen. -NRR17 s NR'R' (C-C, alkylene)-, NR14RC(O)(C-C alkylene)-, -NHC(O)R', OH, 0143 Ari is preferably phenyl or R'-phenyl, especially C-C alkoxy, -OC(O)R',-COR'', hydroxy(C- (4-R)-substituted phenyl. Preferred definitions of R" are C.)alkyl, (C-C)alkoxy(C-C)alkyl, NO, lower alkoxy, especially methoxy, and halogeno, especially -S(O)o R', -SO2NR'R'' and -(C-C alky fluoro. lene)COOR'; when R is a substituent on a hetero 0144) Ar' is preferably phenyl or R-substituted phenyl, cycloalkyl ring, R is as defined, or is =O or especially (4-R)-substituted phenyl. 0145 There are several preferred definitions for the -R-Q- combination of variables: N CH.) : 0146) Q is a bond and R' is lower alkylene, prefer O ably propylene; 0147 Q is a spiro group as defined above, wherein 0133) and, where R is a substituent on a substitutable preferably R and Rare each ethylene and R is ring nitrogen, it is hydrogen, (C-C)alkyl, aryl, (C- C.)alkoxy, aryloxy, (C-C)alkylcarbonyl, arylcarbonyl, hydroxy, -(CH) CONR'R'', -CH- or -C(OH)-; O R18 n N 0148 Q is a bond and R is J O M (CH2)04 O

0134) wherein J is -O-, -NH-, -NR'- or -CH-; 0135 Rand Rare independently selected from the group consisting of 1-3 Substituents independently 0149 wherein the variables are chosen such that R is Selected from the group consisting of (C-C)alkyl, -O-CH-CH(OH)-; 0150. Q is a bond and R is

14

R16 s -O(CH)-o-COOR", -O(CH)-o CONR'R'', -(C-C alkylene) -COOR'', -CH=CH-COOR'', -CF, -CN, -NO and halogen; 0136 R is hydrogen, (C-C)alkyl, aryl (C- C.)alkyl, -C(O)R' or -COOR'"; 0151 wherein the variables are chosen such that R is 0137) R' and R'' are independently 1-3 groups inde -CH(OH)-(CH-)-; and pendently Selected from the group consisting of 0152 Q is a bond and R is hydrogen, (C-C)alkyl, (C-C)alkoxy, -COOH, NO, -NR'R'', OH and halogeno; 0138) R'' and R' are independently selected from R10 the group consisting of hydrogen, (C-C)alkyl, aryl and aryl-Substituted (C-C)alkyl, -X-(C) Y-S(O) - R11 0139) R' is (C-C)alkyl, aryl or R'7-substituted aryl; US 2003/0069221A1 Apr. 10, 2003

0153 wherein the variables are chosen such that R' is 0167) -(lower alkylene)COOR and -CH=CH -CH(OH)-CH-S(O)-. COOR; 0154 Methods for making compounds of Formula IV are 0168 R, R7 and Rare independently selected from well known to those skilled in the art. Non-limiting the group consisting of hydrogen, lower alkyl, aryl examples of Suitable methods are disclosed in U.S. Pat. No. and aryl-substituted lower alkyl; 5,656,624, which is incorporated herein by reference. O155 In another embodiment, sterol absorption inhibi 0169) R' is lower alkyl, aryl or aryl-substituted tors useful in the compositions, therapeutic combinations lower alkyl, and and methods of the present invention are represented by 0170) R' is 1-5 substituents independently selected Formula (V): from the group consisting of lower alkyl, —OR, –O(CO)R , —O(CO)OR. -O(CH), OR, -O(CO)NR'R7, -N RR7, -N R(CO)R7, (V) -NR(CO)OR,-NR(CO)NR7R,-NRSOR, -COOR,-CONRR7, -COR, -SONRR7, Arl N 1. (C '' 1. SO( ), Ar2 -S(O)2R , —O(CH-)-COOR , Xm R1 Y –O(CH) CONR'R'', N 0171 -CF, -CN, -NO and halogen. O Ar3 0172. Within the scope of Formula V, there are included two preferred Structures. In Formula VA, q is Zero and the 0156 or isomers of the compounds of Formula (V), or remaining variables are as defined above, and in Formula pharmaceutically acceptable Salts or Solvates of the com VB, q is 1 and the remaining variables are as defined above: pounds of Formula (V) or of the isomers of the compounds of Formula (V), or prodrugs of the compounds of Formula (V) or of the isomers, salts or solvates of the compounds of VA Formula (V), wherein, in Formula (V) above: A11 Xm n1 S(O), Ar O157 Ar' is aryl, R'-substituted aryl or heteroaryl; N 0158 Ar is aryl or R'-substituted aryl; O Ar3 VB O159 AriIS aryl1 or R. Substituted arylaryl; Arl C S(O) Ar2 0160 X and Y are independently selected from the N 1N 1S group consisting of -CH2-, -CH(lower alkyl)- Xm R1 Y. and -C(dillower alkyl)-; N (0161), R is -OR. --O(CO)R', -O(CO)OR' or O Ar3 -O(CO)NR'R7; R is hydrogen, lower alkyl or aryl; or R and R' together are =O; 0173 R', R and R' are each preferably 1-3 inde 0162 q is 0 or 1; pendently Selected Substituents as Set forth above. Preferred are compounds of Formula (V) wherein 0163) r is 0, 1 or 2; Ar is phenyl, R'-substituted phenyl or thienyl, 0.164 m and n are independently 0, 1, 2, 3, 4 or 5; especially (4-R")-substituted phenyl or thienyl. Arf provided that the Sum of m, n and q is 1,2,3,4 or 5, is preferably R-substituted phenyl, especially (4- R")-substituted phenyl. Ar is preferably phenyl or 0165) R' is 1-5 substituents independently selected R-substituted phenyl, especially (4-R)-substituted from the group consisting of lower alkyl, -OR, phenyl. When Ar' is R'-substituted phenyl, R' is preferably halogeno, especially fluoro. When Art is R"-substituted phenyl, R' is preferably -OR espe cially wherein R is hydrogen or lower alkyl. When Ar is R-substituted phenyl, R is preferably halo -SONR'R''., S(O).R,-O(CH-)-COOR, geno, especially fluoro. Especially preferred are –O(CH) CONRR7 -(lower alkylene)COOR compounds of Formula (V) wherein Ar' is phenyl, and -CH=CH-COOR; 4-fluorophenyl or thienyl, Art is 4-(alkoxy or 0166 R is 1-5 substituents independently selected hydroxy)phenyl, and Ar is phenyl or 4-fluorophe from the group consisting of -OR. --O(CO)R, nyl. –O(CO)OR,-O(CH)1-5OR,-O(CO)NR'R7, 0174 X and Y are each preferably -CH-. The sum of -NR'R' , – NR(CO)R’, -NR(CO)OR, m, n and q is preferably 2, 3 or 4, more preferably 2. When -NR(CO)NR'R' ,-NR SOR, -COOR, q is 1, n is preferably 1 to 5. –CONRR7 –COR, -SONR'R' , S(O).R. -O(CH)-o-COOR. --O(CH)-oCONR'R'', 0175 Preferences for X, Y, Ar", Art and Arare the same -CF, -CN, -NO, halogen, in each of Formulae (VA) and (VB). US 2003/0069221A1 Apr. 10, 2003

0176). In compounds of Formula (VA), the sum of m and -CH=CH- or -C(lower alkyl)=CH-, v is 1; n is preferably 2, 3 or 4, more preferably 2. Also preferred provided that when R, is-CH=CH-or-C(lower are compounds wherein the Sum of m and n is 2, and r is 0 alkyl)=CH-, u is 1; provided that when v is 2 or 3, or 1. the R's can be the same or different; and provided 0177. In compounds of Formula (VB), the sum of m and that when u is 2 or 3, the R's can be the same or n is preferably 1, 2 or 3, more preferably 1. Especially different; preferred are compounds wherein m is Zero and n is 1. R' is 0185 R. is selected from B-(CH),C(O), preferably hydrogen and R is preferably -OR wherein R wherein m is 0,1,2,3,4 or 5: B-(CH) , wherein is hydrogen, or a group readily metabolizable to a hydroxyl q is 0, 1, 2, 3, 4, 5 or 6; B-(CH)-Z-(CH), , (such as —O(CO)R, -O(CO)OR and —O(CO)NR'R''. wherein Z is -O-, -C(O)-, phenylene, defined above), or R and R together form a =O group. -N(Rs.)- or-S(O), e is 0,1,2,3,4 or 5 and r is 0, 1, 2, 3, 4 or 5, provided that the sum of e and 0.178 Methods for making compounds of Formula V are r is 0, 1, 2, 3, 4.5 or 6; B-(C-C alkenylene)-; well known to those skilled in the art. Non-limiting B-(C-C alkadienylene)-; B-(CH-)-Z-(C-C, examples of Suitable methods are disclosed in U.S. Pat. No. alkenylene)-, wherein Z is as defined above, and 5,624,920, which is incorporated herein by reference. wherein t is 0, 1, 2 or 3, provided that the sum of t 0179. In another embodiment, sterol absorption inhibi and the number of carbon atoms in the alkenylene tors useful in the compositions, therapeutic combinations chain is 2, 3, 4, 5 or 6; B-(CH-)-V-(CH) , and methods of the present invention are represented by wherein V is C-C cycloalkylene, f is 1, 2, 3, 4 or 5 Formula (VI): and g is 0, 1, 2, 3, 4 or 5, provided that the Sum of fand g is 1, 2, 3, 4, 5 or 6; B-(CH2)-V-(C-C, alkenylene)- or B-(C-C alkenylene)-V- (VI) (CH), wherein V and t are as defined above, R provided that the sum of t and the number of carbon 4 R-R(2)” -Ra atoms in the alkenylene chain is 2, 3, 4, 5 or 6, (R3)u B-(CH), Z-(CH2)-V-(CH) , wherein Z and V are as defined above and a, b and d are N independently 0, 1, 2, 3, 4, 5 or 6, provided that the N Sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; or T-(CH) , wherein T is cycloalkyl of 3-6 carbon atoms and S is 0, 1, 2, 3, 4, 5 or 6; or 0180 or isomers of the compounds of Formula (VI), or pharmaceutically acceptable Salts or Solvates of the com 0186 R and R together form the group pounds of Formula (VI) or of the isomers of the compounds of Formula (VI), or prodrugs of the compounds of Formula (VI) or of the isomers, salts or solvates of the compounds of Formula (VI), wherein: B-CHFC 0181 R is 0187 B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl or W-substituted heteroaryl, wherein heteroaryl is Selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imida -CH-, -C(lower alkyl)- -CF-, Zolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the N-oxides thereof, or C(OH)-, -C(CHS)-, -C(CH-Rs)-

B-CHEC -N-, or -NO; 0188 W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycar 0182 R and R are independently selected from the bonylalkoxy, (lower alkoxyimino)-lower alkyl, lower group consisting of alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, -CF, 0183 -CH-, -CH(lower alkyl)-, -C(di-lower -OCF, benzyl, R7-benzyl, benzyloxy, R7-benzyloxy, phe alkyl)-, -CH=CH- and -C(lower noxy, R7-phenoxy, dioxolanyl, NO, -N(Rs)(R), alkyl)=CH-, or R together with an adjacent R, or N(Rs)(R)-lower alkylene-, N(Rs)(R)-lower alkylenyloxy-, R together with an adjacent R, form a OH, halogeno, -CN, -N, -NHC(O)OR, -NH C(O)Rio, ROSNH-, (ROS)-N-, -S(O)NH2, -CH=CH- or a -CH=C(lower alkyl)- group; -S(O)2R, tert-butylidimethyl-silyloxymethyl, 0.184 u and v are independently 0, 1, 2 or 3, pro -C(O)R, -COOR, -CONCRs)(R), vided both are not zero; provided that when R is -CH=CHC(O)R, -lower alkylene-C(O)R, US 2003/0069221A1 Apr. 10, 2003

RoC(O)(lower alkylenyloxy)-, N(Rs)(R)C(O)(lower alky (lower alkyl), -COOR, -CONCRs)(R), lenyloxy)- and —COR2, phenoxy, benzyloxy, -OCF, -CH=C(O)R or tert-butylidimethylsilyloxy, wherein Rs, Ro, Rio, R. and Rio are as defined for Formula IV. When W is 2 or 3 substituents, the -CH-N R13 Substituents can be the Same or different. 0202) Another group of preferred compounds of Formula VI is that in which Rao is phenyl or W-substituted phenyl, 0189 for Substitution on ring carbon atoms, and the wherein preferred meanings of W are as defined above for Substituents on the Substituted heteroaryl ring nitrogen preferred definitions of R. atoms, when present, are Selected from the group consisting 0203 More preferred are compounds of Formula VI of lower alkyl, lower alkoxy, -C(O)OR. -C(O)Rio, OH, wherein Rao is phenyl or W-Substituted phenyl and R is N(Rs)(R)-lower alkylene-, N(Rs)(R)-lower alkylenyloxy-, phenyl, W-substituted phenyl, indanyl, benzofuranyl, ben -S(O)NH and 2-(trimethylsilyl)-ethoxymethyl; Zodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrim 0190. R is 1-3 groups independently selected from idinyl, quinolyl or cyclopropyl; W is lower alkyl, lower the group consisting of lower alkyl, lower alkoxy, alkoxy, OH, halogeno, -N(R)(R), -NHC(O)OR, -NHC(O)Rio, NO,-CN, -N, -SH, -S(O)-(lower -COOH, NO, -N(Rs)(R), OH, and halogeno; alkyl), -COOR, -CONCRs)(R), -COR, phenoxy, 0191 Rs and Ro are independently selected from H benzyloxy, -CH=CHC(O)R,-OCF or tert-butyl-dim or lower alkyl; ethyl-silyloxy, wherein when W is 2 or 3 substituents, the 0.192 Rio is selected from lower alkyl, phenyl, Substituents can be the same or different, and wherein Rs, R7-phenyl, benzyl or R7-benzyl, Ro, Rio, R and Rio are as defined in Formula VI. 0193 R is selected from OH, lower alkyl, phenyl, 0204 Also preferred are compounds of Formula VI benzyl, R7-phenyl or R7-benzyl, wherein R is 0194 R is selected from H, OH, alkoxy, phenoxy, benzyloxy, R15 =7R, -N R 13s 0205 Another group of preferred compounds of Formula VI is in which R and R are each -CH- and the sum of 0195 -N(Rs)(R), lower alkyl, phenyl or R7-phenyl; u and v is 2, 3 or 4, with u=v-2 being more preferred. 0.196 R is selected from -O-, -CH-, 0206 R is preferably B-(CH), or B-(CH2)-Z- -NH-, -N(lower alkyl)- or -NC(O)Rio. (CH),-, wherein B, Z, q, e and r are as defined above. B 0197) R, R and R, are independently selected is preferably from the group consisting of H and the groups defined for W.; or Rs is hydrogen and R and R7, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring; -CH or -C(OH)-. 0198 Rio is H, lower alkyl, phenyl or phenyl lower alkyl, and 0207 wherein R and R, are each hydrogen and 0199 Rao and R are independently selected from wherein Rs is preferably H, OH, lower alkoxy, especially the group consisting of phenyl, W-Substituted phe methoxy, or halogeno, especially chloro. nyl, naphthyl, W-Substituted naphthyl, indanyl, inde nyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, 0208 Preferably Z is -O-, e is 0, and r is 0. W-substituted heteroaryl, benzofused heteroaryl, 0209 Preferably q is 0-2. W-substituted benzofused heteroaryl and cyclopro pyl, wherein heteroaryl is as defined above. 0210 Rao is preferably phenyl or W-substituted phenyl. 0200. One group of preferred compounds of Formula VI 0211 Preferred W substituents for Rao are lower alkoxy, is that in which R is selected from phenyl, W-substituted especially methoxy and ethoxy, OH, and -C(O)R2, phenyl, indanyl, benzofuranyl, benzodioxolyl, tetrahy wherein R is preferably lower alkoxy. dronaphthyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl or cyclopropyl, 0212 Preferably R is selected from phenyl, lower alkoxy-Substituted phenyl and F-phenyl. 0201 wherein W is lower alkyl, lower alkoxy, OH, halogeno, -N(Rs)(R), -NHC(O)OR, -NH 0213 Especially preferred are compounds of Formula VI C(O)Ro, NO, -CN, -N, -SH, -S(O)o- wherein R is US 2003/0069221A1 Apr. 10, 2003 16

-continued

VR2' -CH-, or -C(OH)-. B is / X —f R, 0214) R- and R are each -CH2-, u=v-2, R is B-(CH), , wherein B is phenyl or phenyl substituted by lower alkoxy or chloro, q is 0-2, Rao is phenyl, OH-phenyl, 0219) D is -(CH2),C(O)- or -(CH2), lower alkoxy-Substituted phenyl or lower alkoxycarbonyl wherein m is 1, 2, 3 or 4 and q is 2, 3 or 4, Substituted phenyl, and R2 is phenyl, lower alkoxy-Substi 0220 E is Co to Co alkyl or -C(O)-(Co. to tuted phenyl or F-phenyl. Co)-alkyl, wherein the alkyl is straight or branched, Saturated or containing one or more double bonds, 0215 Methods for making compounds of Formula VI are 0221 R is hydrogen, C-Cs alkyl, Straight or well known to those skilled in the art. Non-limiting branched, Saturated or containing one or more examples of Suitable methods are disclosed in U.S. Pat. No. double bonds, or B-(CH) , wherein r is 0, 1, 2, 5,698,548, which is incorporated herein by reference. or 3; 0216) In another embodiment, sterol inhibitors useful in 0222 R, R2, R, R, R2", and R', are independently the compositions, therapeutic combinations and methods of Selected from the group consisting of hydrogen, the present invention are represented by Formulae is (VIIA) lower alkyl, lower alkoxy, carboxy, NO, NH, OH, and (VIIB): halogeno, lower alkylamino, dilower alkylamino, —NHC(O)ORs, R.O.SNH- and -S(O)NH2. 0223 R is (VIIA)

(ORs) B-D - 5"

R4 and 0224 wherein n is 0, 1, 2 or 3; (VIIB) 0225 R is lower alkyl; and 0226 R is OH, lower alkyl, phenyl, benzyl or substituted phenyl wherein the substituents are 1-3 groups independently Selected from the group con Sisting of lower alkyl, lower alkoxy, carboxy, NO, NH, OH, halogeno, lower alkylamino and dilower alkylamino. 0227 Preferred are compounds of Formula (VIIA) wherein R is hydrogen, Saturated or mono-unsaturated 0217 or isomers of the compounds of Formulae (VIIA) C-Clio alkyl or phenyl. Another group of preferred com or (VIIB), or pharmaceutically acceptable salts or solvates of pounds of Formula (VIIA) is that in which D is propyl (i.e., the compounds of Formulae (VIIA) or (VIIB) or of the -(CH2), and q is 3). A third group of preferred com isomers of the compounds of Formulae (VIIA) or (VIIB), or pounds of Formula (VIIA) is that wherein R is p-methox prodrugs of the compounds of Formulae (VIIA) or (VIIB) or yphenyl or 2,4,6-trimethoxyphenyl. Still another group of of the isomers, Salts or Solvates of the compounds of preferred compounds of Formula (VIIA) is that wherein A is ethylene or a bond (i.e., -(CH2) - wherein p is zero). R', Formulae (VIIA) or (VIIB), wherein in Formulae (VIIA) R', and Rare preferably each hydrogen, and preferably R and (VIIB) above: is hydrogen, hydroxy, nitro, lower alkoxy, amino or t-bu 0218) A is -CH=CH-, or -(CH2) toxycarbonyl-amino and R and R are each hydrogen. wherein p is 0, 1 or 2; 0228 More preferred are compounds of Formula (VIIA) wherein R, R2, and Rare each hydrogen; R is hydrogen, hydroxy, nitro, lower alkoxy, amino or t-butoxycarbonyl amino and R and R are each hydrogen; R is hydrogen, V ethyl or phenyl; D is propyl; R is p-methoxyphenyl or 2,4,6-trimethoxyphenyl; and A is ethylene or a bond. SC EM R3 0229. Preferred compounds of Formula (VIIA), wherein B' is phenyl, are shown in the following table: US 2003/0069221A1 Apr. 10, 2003 17

(VII) or of the isomers, salts or solvates of the compounds of Formula (VII), wherein, in Formula (VII) above, D R A. B R 0236 R is H or OG'; -(CH2)- H -MeO- p-MeO-pheny 0237) G and G' are independently selected from the pheny group consisting of -CHC(O)- phenyl pheny p-MeO-pheny -(CH2)- H pheny p-MeO-pheny

-(CH2)- H D-OH- p-MeO-pheny pheny -(CH2)- H ethylene p-MeO- p-MeO-pheny pheny -(CH2)- H 3-MeO- p-MeO-pheny ... iiiiIOR3, pheny -(CH2)- ethyl pheny p-MeO-pheny -(CH2)- phenyl pheny p-MeO-pheny -(CH2)- ethyl pheny 2,4,6-tri-MeO CHOR phenyl -(CH2)- methyl pheny p-MeO-pheny -(CH2)- H p-NH- p-MeO-pheny pheny

0230. The first-listed compound in the above table having the (3R,4S) absolute stereochemistry is more preferred. 0231 Preferred compounds of Formula (VIIB) are those wherein R is hydrogen, methyl, ethyl, phenyl or phenylpro pyl. Another group of preferred compounds of Formula (VIIB) is that wherein R is p-methoxyphenyl or 2,4,6- trimethoxyphenyl. Still another group of preferred com pounds of Formula (VIB) is that wherein A is ethylene or a bond. Yet another group of preferred compounds of Formula O CHR (VIIB) is that wherein E is decyl, oleoyl or 7-Z-hexadecenyl. Preferably R, R2 and R are each hydrogen. provided that when R’ is Hor OH, G is not H: 0232 More preferred compounds of Formula (VIIB) are those wherein R is hydrogen, methyl, ethyl, phenyl or 0238 provided that when R is H or OH, G is not H; phenylpropyl; R" is p-methoxyphenyl or 2,4,6-trimethox 0239) R, R and Rare independently selected from yphenyl; A is ethylene or a bond; E is decyl, oleoyl or the group consisting of H, -OH, halogeno, -NH2, 7-Z-hexadecenyl; and azido, (C-C)alkoxy(C-C)-alkoxy or -W-R'; 0233 R', R and Rare each hydrogen. 5A preferred 0240 W is independently selected from the group con compound of Formula (VIIB) is that wherein E is sisting of -NH-C(O)-, -O-C(O)-, -O-C(O) decyl, R is hydrogen, B-A is phenyl and R is p-meth N(R)-, NH-C(O)-N(R) and O-C(S) Oxyphenyl. N(R)-; 0241) R' and Rare independently selected from the 0234. In another embodiment, sterol inhibitors useful in group consisting of H., (C-C)alkyl, aryl and the compositions, therapeutic combinations and methods of aryl(C-C)alkyl, the present invention are represented by Formula (VIII): 0242) R, R", R, R", R* and R" are independently Selected from the group consisting of H., (C- (VIII) C.)alkyl, aryl(C-C)alkyl, -C(O)(C-C)alkyl and R°-Z Y-O-G -C(O)aryl; W 0243) R' is selected from the group consisting of Arl-R-O S. R-substituted T, R-substituted-T (C-C)alkyl, R*-substituted-(C-C)alkenyl, R-substituted (C-C)alkyl, R-substituted-(C-C)cycloalkyl and R*-substituted-(C-C)cycloalkyl(C-C)alkyl; 0244) R' is selected from the group consisting of H and (C-C)alkyl, 0235 or isomers of the compounds of Formula (VIII), or 0245 T is selected from the group consisting of pharmaceutically acceptable Salts or Solvates of the com phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, pounds of Formula (VII) or of the isomers of the compounds thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, of Formula (VII), or prodrugs of the compounds of Formula pyrazolyl, imidazolyl and pyridyl; US 2003/0069221A1 Apr. 10, 2003

0246) R' is independently selected from 1-3 sub 0259 provided that when R' is -CH=CH- or Stituents independently Selected from the group con -C(C-C alkyl)=CH-, a is 1; sisting of halogeno, (C-C)alkyl, -OH, phenoxy, -CF, -NO, (C.C)alkoxy, methylenedioxy, Oxo, 0260 provided that when R'' is -CH=CH- or (C-C)alkylsulfanyl, (C-C)alkylsulfinyl, (C- -C(C-C alkyl)=CH-, b is 1; C.)alkylsulfonyl, -N(CH), -C(O)-NH(C- C.)alkyl, -C(O)-N((C-C)alkyl), -C(O)- 0261) provided that when a is 2 or 3, the R's can (C-C)alkyl, -C(O)-(C-C)alkoxy and be the same or different; and pyrrolidinylcarbonyl; or R° is a covalent bond and R", the nitrogen to which it is attached and R form 0262 provided that when b is 2 or 3, the R's can a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, be the same or different; indolinyl or morpholinyl group, or a (C- C.)alkoxycarbonyl-Substituted pyrrolidinyl, pip 0263) and when Q is a bond, R' also can be: eridinyl, N-methylpiperazinyl, indolinyl or mor pholinyl group; R15 R17 R15 0247 Ar' is aryl or R'-substituted aryl; 0248 Ar’ is aryl or R' -substituted aryl; -M-Y-C-Z,k -, -Xin (C)le Yi ()-Zl - or 0249 Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the Spiro group

R12- (R), ; and cell R16

0250) and 0264 Mis-O-, -S-, -S(O)- or -S(O)-; 0251) R' is selected from the group consisting of 0265 X, Y and Z are independently selected from 0252) -(CH) , wherein q is 2-6, provided that the group consisting of -CH2-, -CH(C- when Q forms a Spiro ring, q can also be Zero or C.)alkyl- and -C(di-(C-C)alkyl); 1, 0253 -(CH2)-E-(CH), wherein E is 0266) R' and R'' are independently selected from -O-, -C(O)-, phenylene, -NR’- or the group consisting of 1-3 Substituents indepen -S(O)o, e is 0-5 and r is 0-5, provided that the dently selected from the group consisting of (C- Sum of e and r is 1-6, C.)alkyl, -OR', -O(CO)R', -O(CO)OR, -O(CH), OR. --O(CO)NR'R'', -NR'R'', 0254 -(C-C)alkenylene-; and -NR(CO)R°, -NR(CO)OR°, -NR 0255) -(CH2)-V-(CH2) , wherein V is C-C, (CO)NR'R'', -NR'SOR, -COOR , cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of CONR''R.20 R,-COR'', 19 -SONR'R'',192O S(O), f and g is 1-6, R21, -O(CH-)-o-COOR', -O(CH)-o CONR1°R2O, -(C-C1 - 6 alkylene)-COOR',y 0256 R2 is -CH=CH-COOR', -CF, -CN, -NO and halogen; 0267) R' and R7 are independently selected from -CH-, -C(C-C alkyl)-, -CF-, the group consisting of –OR', –O(CO)R', –O(CO)OR" and –O(CO)NR'R'': -C(OH)-, -C(CH-R23)-, -N-, or - NO; 0268) R' and R' are independently selected from the group consisting of H, (C-C)alkyl and aryl; or R" and R together are =O, or R7 and R' 0257) R' and R'' are independently selected from together are =O; the group consisting of -CH2-, -CH(C-C, 0269 d is 1, 2 or 3; alkyl)-, -C(di-(C-C) alkyl), -CH=CH- and -C(C-C alkyl)=CH-; or R together with an 0270 h is 0, 1,2,3 or 4; adjacent R', or R' together with an adjacent R', form a -CH=CH- or a -CH=C(C-C alkyl)- 0271 s is 0 or 1; t is 0 or 1; m, n and p are grOup, independently 0-4; 0258 a and b are independently 0, 1, 2 or 3, pro 0272 provided that at least one of S and t is 1, and vided both are not zero; the Sum of m, n, p, S and t is 1-6, US 2003/0069221A1 Apr. 10, 2003

0273 provided that when p is 0 and t is 1, the sum 0289 Q is a bond and R is of m, s and n is 1-5; and provided that when p is O and S is 1, the Sum of m, t and n is 1-5, 0274) v is 0 or 1; 0275 j and k are independently 1-5, provided that the Sum of j, k and V is 1-5, 0276 and when Q is a bond and R' is 0290 wherein the variables are chosen such that R' is -O-CH-CH(OH)-; R15 0291 Q is a bond and R' -X-(C), Y-S(O) -, R17 R15 R16 -Xin (C) Yi ()-Z - R18 R16 0277 Ar' can also be pyridyl, isoxazolyl, furanyl, pyr rolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl; 0292 wherein the is variables are chosen such that R' is 0278) R' and R' are independently selected from -CH(OH)-(CH)-; and the group consisting of H., (C-C)alkyl, aryl and 0293 Q is a bond and R is aryl-Substituted (C-C)alkyl, 0279) R' is (C-C)alkyl, aryl or R-substituted R15 aryl; 0280 R is H., (C-C)alkyl, aryl (C-C)alkyl, R16 –C(O)R’ or -COOR'; 0281) R' and R' are independently 1-3 groups independently Selected from the group consisting of 0294 wherein the variables are chosen such that R' is H., (C-C)alkyl, (C-C)alkoxy, -COOH, NO, -CH(OH)-CH-S(O)--. -NR'R'', -OH and halogeno; and 0295) A preferred compound of Formula (VIII) therefore, is one wherein G and G' are as defined above and in which 0282 R is H, -OH or (C-C)alkoxy. the remaining variables have the following definitions: 0283 Ari is preferably phenyl or R'-phenyl, especially 0296 Ar' is phenyl or R' '-substituted phenyl, (4-R')-substituted phenyl. Preferred definitions of R'' are wherein R' is halogeno; lower alkoxy, especially methoxy, and halogeno, especially 0297 Art is phenyl or R''-phenyl, wherein R' is 1 fluoro. to 3 substituents independently selected from the group consisting of C-C alkoxy and halogeno; 0284 Ar' is preferably phenyl or R'-substituted phenyl, 0298 Q is a bond and R is lower alkylene; Q, with especially (4-R')-substituted phenyl. Preferably R'' is the 3-position ring carbon of the azetidinone, forms halogeno, and more preferably fluoro. the group 0285) There are several preferred definitions for the -R'-Q- combination of variables: N 0286 Q is a bond and R' is lower alkylene, prefer R12- (R), ably propylene; al 0287 Q is a spiro group as defined above, wherein preferably R' and R'' are each ethylene and 0299 wherein preferably R' and R'' are each ethylene and a and b are each 1, and wherein R' is

R12 is -CH- or -C(OH)- -CH- or -C(OH)-; 0288 and R is -(CH2), wherein q is 0-6; US 2003/0069221A1 Apr. 10, 2003 20

0300 Q is a bond and R is -O-CH-CH(OH)-; Q 0310 Preferred combinations of R, R and R are as is a bond and R is -CH(OH)-(CH-)-; or Q is a bond follows: and R' is -CH(OH)-CH-S(O)--. 0311 1) R, R and R are independently -OH or 0301 Preferred variables for G and G' groups of the -O-C(O)-NH-R', especially wherein R is formulae –OH and R and Rare -O-C(O)-NH-R and R" is selected from the preferred substituents iden tified above, or wherein R and R are each -OH and Ris-O-C(O)-NH-R wherein R is 2-fluo rophenyl, 2,4-difluoro-phenyl, 2,6-dichlorophenyl, 0312 2) R' is -OH, halogeno, azido or (C-C)- alkoxy(C-C)alkoxy, R is H, halogeno, azido or (C-C)alkoxy(C-C)-alkoxy, and R is -O-C(O)-NH-R', especially compounds wherein R is -OH, R is H and R is 2-fluorophe nyl;

OR7 (0313) 3) R, R* and R are independently -OH or -O-C(O)-R and R is (C-C)alkyl, T, or T Substituted by one or two halogeno or (C-C)alkyl IIIORS groups, especially compounds wherein R is -OH and R and R are -O-C(O)-R wherein R is 2-furyl; and OR4 0314. 4) R, R and R are independently -OH or halogeno. Three additional classes of preferred com 0302) are as follows: pounds are those wherein the C'' anomeric oxy is beta, wherein the C anomeric oxy is beta, and 0303 R,R,R,R, R and R7 are independently wherein the R group is alpha. Selected from the group consisting of H., (C- C.)alkyl, benzyl and acetyl. 0315 G and G' are preferably selected from: 0304 Preferred variables for group G or G' of the for mula: OH OH OH OH 12 2.

OR3a III IOH, III IOH, R"O, R CO2H CH2OH OR3 OH OAc

RO//, O O CHRP2 III IOH, ... III IOAc,

O CHR OH COCH OCH2Ph 0305) are as follows: 0306 R, R, R and R* are selected from the IIIOCH2Ph, IIIOCH2Ph, group consisting of H., (C-C)alkyl, benzyl and acetyl, CO2CH2Ph COOCHPh

0307) R, R and R are independently selected from OCH OAc OAc the group consisting of H, -OH, halogeno, -NH2, azido, (C-C)alkoxy(C-C)alkoxy and -W-R', III IOCH2Ph, 0308 wherein Wis-O-C(O)- or -O-C(O)- NR-, R is Hand R is (C-C)alkyl, -C(O)– S (C-C)alkoxy-(C-C)alkyl, T, T-(C-C)alkyl, or OCH2Ph OCH2Ph Tor T (C-C)alkyl wherein T is substituted by one OH OH or two halogeno or (C-C)alkyl groups. 0309 Preferred R substituents are selected from the (iiiIOH, group consisting of 2-fluorophenyl, 2,4-difluoro-phenyl, 2,6-dichlorophenyl, 2-methylphenyl, 2-thienylmethyl, 2-methoxy-carbonylethyl, thiazol-2-yl-methyl, 2-furyl, COCH 2-methoxycarbonylbutyl and phenyl. US 2003/0069221A1 Apr. 10, 2003 21

0323) c) fluorine and -continued 0324 d) chlorine. 0325) R' is selected from the group consisting of

O CHR -SO3H; natural and unnatural amino acids.

0316 wherein Ac is acetyl and Ph is phenyl. 0326 -SoH, natural and unnatural amino acids. 0327) R, R and Rare independently selected from 0317 Preferably, R is H or OH, more preferably H. The the group consisting of H, -OH, halogeno, -NH2, -O-G substituent is preferably in the 4-position of the azido, (C-C)alkoxy(C-C)-alkoxy and phenyl ring to which it is attached. - W. R. 0318. In another embodiment, sterol inhibitors useful in 0328 W is independently selected from the group the compositions, therapeutic combinations and methods of consisting of NH-C(O), O-C(O), the present invention are represented by Formula (IX) O-C(O)-N(R)-, -NH-C(O)-N(R) below: and -O-C(S)-N(R)-; 0329 Rand Rare independently selected from the group consisting of H., (C-C)alkyl, aryl and (IX) aryl(C-C)alkyl, 0330) R,R,R,R,R and R* are independently Selected from the group consisting of H., (C- C.)alkyl, aryl(C-C)alkyl, -C(O)(C-C)alkyl and -C(O)aryl; 0331) R' is independently selected form the group consisting of R-substituted T, R-substituted-T (C-C)alkyl, R-substituted-(C-C)alkenyl, R 0319 or isomers of the compounds of Formula (IX), or Substituted-(C-C)alkyl, R*-substituted-(C- pharmaceutically acceptable Salts or Solvates of the com C7)cycloalkyl and R-substituted-(C- pounds of Formula (IX) or of the isomers of the compounds C7)cycloalkyl(C-C)alkyl, of Formula (IX), or prodrugs of the compounds of Formula (IX) or of the isomers, salts or solvates of the compounds of 0332 R is independently selected from the group Formula (IX), wherein consisting of H and (C-C)alkyl, 0333 T is independently selected from the group 0320 R is selected from the group consisting of: consisting of phenyl, furyl, thienyl, pyrrolyl, Oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, ben 0321) a) OH: Zothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and 0322 b) OCH; pyridyl, US 2003/0069221A1 Apr. 10, 2003 22

0334) R' is independently selected from 1-3 sub -CONR'R'',-COR', -SONR'R'', S(O), Stituents independently Selected from the group con R°, -O(CH)-o-COOR', —O(CH)1- sisting of H, halogeno, (C-C)alkyl, -OH, phe 10CONR 'R'', -(C-C alkylene)-COOR', noXy, -CF, -NO, (C-C)alkoxy, -CH=CH-COOR', -CF, -CN, methylenedioxy, OXO, (C-C)alkylsulfanyl, (C- C.)alkylsulfinyl, (C-C)alkylsulfonyl, -N(CH), 0343 -NO and halogen; -C(O)-NH(C-C)alkyl, -C(O)-N((C- 0344) Ar' can also be pyridyl, isoxazolyl, furanyl, C.)alkyl), -C(O)-(C-C)alkyl, -C(O)-(C- pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, C.)alkoxy and pyrrolidinylcarbonyl; or Rf is a pyrazinyl, pyrimidinyl or pyridaZinyl, covalent bond and R', the nitrogen to which it is attached and R' form a pyrrolidinyl, piperidinyl, 0345) R' and R' are independently selected from N-methyl-piperazinyl, indolinyl or morpholinyl the group consisting of H., (C-C)alkyl, aryl and group, or a (C-C)alkoxycarbonyl-Substituted pyr aryl-Substituted (C-C)alkyl, rolidinyl, piperidinyl, N-methylpiperazinyl, indoli 0346) R' is (C-C)alkyl, aryl or R-substituted nyl or morpholinyl group; aryl; 0335) Ar' is aryl or R'-substituted aryl; 0347) R is H., (C-C)alkyl, aryl (C-C)alkyl, 0336 Art is aryl or R' -substituted aryl; –C(O)R or -COOR'; 0348 RandR'' are independently 1-3 groups indepen 0337) Qis-(CH2). , wherein q is 2-6, or, with the dently Selected from the group consisting of H., (C- 3-position ring carbon of the azetidinone, C.)alkyl, (C-C)alkoxy, -COOH, NO, -NR'R'', 0338 forms the spiro group -OH and halogeno; and 0349 R is H, -OH or (C-C)alkoxy. N 0350 Ar is preferably phenyl or R'-phenyl, espe R12-(R13): cially (4-R')-substituted phenyl. Preferred defini tions of R'' are lower alkoxy, especially methoxy, al and halogeno, especially fluoro. 0351) Ar' is preferably phenyl or R'-substituted phenyl, especially (4-R")— substituted phenyl. A 0339) R' is preferred definition of R' is halogeno, especially fluoro. 0352 Preferably Q is a lower alkyl or a spiro group as defined above, wherein preferably R' and R'' are each -CH-, -C(C-C alkyl)-, -CF-, ethylene and R' is -C(OH)-, -C(CH-R2)-, -N-, or –

-CH- or -C(OH)-. 0340) R' and R'' are independently selected from the group consisting of -CH2-, -CH(C-C, 0353 A preferred compound of formula IX, therefore, is alkyl)-, -C(di-(C-C) alkyl), -CH=CH- and one wherein R' is as defined above and in which the —C(C-C alkyl)=CH-; or R2 together with an remaining variables have the following definitions: adjacent R', or R' together with an adjacent R', form a -CH=CH- or a -CH=C(C-C alkyl)- 0354) Ar' is phenyl or R'-substituted phenyl, grOup, wherein R' is halogeno; 0341) a and b are independently 0, 1, 2 or 3, pro 0355 Art is phenyl or R' -phenyl, wherein R' is 1 vided both are not zero; provided that when R' is to 3 substituents independently selected from the -CH=CH- or -C(C-C alkyl)=CH-, a is 1; group consisting Of C-C alkoxy and halogeno; provided that when R' is -CH=CH- or -C(C- 0356) Q is a lower alkyl (i.e. C-1 to C-2) with Q=C-2 C alkyl)=CH-, b is 1; provided that when a is 2 being preferred, or Q, with the or 3, the R's can be the same or different; and provided that when b is 2 or 3, the R's can be the 0357 3-position ring carbon of the azetidinone, Same or different; forms the group 0342) R' and R'' are independently selected from the group consisting of 1-3 Substituents indepen N dently selected from the group consisting of (C- R12- (R), C.)alkyl, -OR', -O(CO)R', -O(CO)OR, -O(CH), OR,-O(CO)NR'R'',-NR'R'', -NR (CO)R’, -NR (CO)OR°, -NR al (CO)NROR25, -NR SOR2, -COOR 19, US 2003/0069221A1 Apr. 10, 2003

0358 wherein preferably R' and R'' are each ethylene 2-thienylmethyl, 2-methoxy-carbonylethyl, thiazol-2-yl-me and a and b are each 1, and wherein R' is thyl, 2-furyl, 2-methoxycarbonylbutyl and phenyl. Preferred combinations of R, R and R are as follows: (1) R, R and R are independently -OH or -O-C(O)-NH-R, especially wherein R is -OH and R and R are -CH- or -C(OH)-; -O-C(O)-NH-R' and R is selected from the pre ferred Substituents identified above, or wherein R and R are 0359 Preferred variables for R' groups of the formula –OH and R is -O-C(O)-NH-R wherein R is 2-fluorophenyl, 2,4-difluoro-phenyl, 2,6-dichlorophenyl; (2) R" is -OH, halogeno, azido or (C-C)-alkoxy(C- C.)alkoxy, R is H, halogeno, azido or (C-C)alkoxy(C- C)-alkoxy, and R is -O-C(O)-NH-R', especially compounds wherein R is -OH, R is H and R is 2-fluo rophenyl; (3) R, R and R are independently -OH or -O-C(O)-R' and R is (C-C)alkyl, T , or Tsubsti tuted by one or two halogeno or (C-C)alkyl groups,

especially compounds wherein Ris-OH and R and Rare -O-C(O)-R wherein R is 2-furyl; and (4) R, R and R are independently -OH or halogeno. Three additional classes of preferred are compounds are those wherein the C" anomeric oxy is beta, wherein the Canomeric oxy is beta, and wherein the R group is alpha. R' is preferably selected from:

OH OH 0360 are as follows: 0361 R,R,R,R, R and R7 are independently Selected from the group consisting of H., (C- iiiiOH, iiiiOH, C.)alkyl, benzyl and acetyl. 0362 Preferred variables for group R' of the formula CO2H CH2OH

OR3a OH OAc RaOW, R OR3 -CH III OH, ... IIIOAc,

RO't, O O CHRP2 OH COCH

O CHR

OCH2Ph OCH2Ph

are as follows: 0363) iii.IOCHPh, iiiIOCHPh, 0364) R, R, R and R* are selected from the group consisting of H., (C-C)alkyl, benzyl and acetyl, CO2CH2Ph COOCHPh 0365) R, R and Rare independently selected from the group consisting of H, -OH, halogeno, -NH2,

azido, (C-C)alkoxy(C-C)alkoxy and -W-R', wherein W is -O-C(O)- or -O-C(O) OCH OAc NR-, R is Hand R is (C-C)alkyl, -C(O)– (C-C)alkoxy-(C-C)alkyl, T, T-(C-C)alkyl, or Tor T (C-C)alkyl wherein T is substituted by one iiiIOCHPh, III IOAc, or two halogeno or (C-C)alkyl groups. 0366 Preferred R substituents are 2-fluorophenyl, 2,4- of H.P. OCH2Ph CHOAc difluoro-phenyl, 2,6-dichlorophenyl, 2-methylphenyl, US 2003/0069221A1 Apr. 10, 2003 24

0370. A more preferred compound is one represented by -continued formula XI: OCH

(XI)

iiiiOH,

OH

0371 or pharmaceutically acceptable salts or Solvates of OAc the compound of Formula (XI), or prodrugs of the com OAC pound of Formula (XI) or of the salts or solvates of the compound of Formula (XI). 0372. In another embodiment, compositions, pharmaceu CHOAc, and tical compositions, therapeutic combinations, kits and meth ods of treatment as described above are provided which comprise: (a) a first amount of at least one cardiovascular agent; and (b) a second amount of at least one sterol F absorption inhibitor, or pharmaceutically acceptable Salt or O Solvate thereof, or prodrug of the sterol absorption inhibitor or of the salt or solvate of the sterol absorption inhibitor, O-C-N wherein the first amount and the Second amount together in their totality (whether administered concurrently or con secutively) comprise a therapeutically effective amount for CH2OH the treatment or prevention of a vascular condition, diabetes, obesity or lowering of a concentration or level of a Sterol in plasma of a mammal. Suitable Sterol absorption inhibitors include Substituted azetidinone compounds or Substituted B-lactam compounds Such as any of the compounds dis cussed above in Formulae I-XI, isomers of the Substituted aZetidinone compounds or Substituted B-lactam compounds, 0367 wherein Ac is acetyl and Ph is phenyl. Salts or Solvates of the Substituted azetidinone compounds or 0368. An example of a useful compound of this invention Substituted B-lactam compounds or of the isomers of the is one represented by the formula X: Substituted azetidinone compounds or Substituted B-lactam compounds or prodrugs of the Substituted aZetidinone com pounds or Substituted B-lactam compounds or of the iso mers, Salts or Solvates of the Substituted azetidinone com OH pounds or Substituted B-lactam compounds. Other useful OR Substituted azetidinone compounds include N-Sulfonyl-2- azetidinones Such as are disclosed in U.S. Pat. No. 4,983,597 and ethyl 4-(2-oxoaZetidin4-yl)phenoxy-alkanoates Such as are disclosed in Ram et at., Indian J. Chem. Sect. B. 29B, 12 (1990), p. 1134-7, which are incorporated by reference herein. 0373 The compounds of Formulae I-XI can be prepared by known methods, including the methods discussed above and, for example, WO 93/02048 describes the preparation of compounds wherein -R-Q- is alkylene, alkenylene or 0369 or pharmaceutically acceptable salts or Solvates of alkylene interrupted by a hetero atom, phenylene or the compound of Formula (X), or prodrugs of the compound cycloalkylene; WO 94/17038 describes the preparation of of Formula (X) or of the salts or solvates of the compound compounds wherein Q is a spirocyclic group; WO95/08532 of Formula (X), wherein R is defined as above. describes the preparation of compounds wherein -R- US 2003/0069221A1 Apr. 10, 2003

Q- is a hydroxy-substituted alkylene group; PCT/US95/ cholesterol biosynthesis inhibitor comprises one or more 03.196 describes compounds wherein -R-Q- is a HMG CoA reductase inhibitors, such as, for example, lov hydroxy-substituted alkylene attached to the Ar' moiety astatin, pravastatin and/or Simvastatin. through an -O- or S(O)- group; and U.S. Ser. No. 0380. In another alternative embodiment, the composi 08/463,619, filed Jun. 5, 1995, describes the preparation of tions or treatments of the present invention can further compounds wherein -R-Q- is a hydroxy-substituted comprise nicotinic acid (niacin) and/or derivatives thereof alkylene group attached the azetidinone ring by a -S(O)o- coadministered with or in combination with the cardiovas 2- group. cular agent(s) and Sterol absorption inhibitor(s) discussed 0374. The daily dose of the sterol absorption inhibitor(s) above. can range from about 0.1 to about 1000 mg per day, 0381 AS used herein, “nicotinic acid derivative” means a preferably about 0.25 to about 50 mg/day, and more pref compound comprising a pyridine-3-carboxylate Structure or erably is about 10 mg, given in a Single dose or 2-4 divided a pyrazine-2-carboxylate Structure, including acid forms, doses. The exact dose, however, is determined by the Salts, esters, Zwitterions and tautomers, where available. attending clinician and is dependent on the potency of the Examples of nicotinic acid derivatives include niceritrol, compound administered, the age, weight, condition and nicofuranose and acipimox (5-methyl pyrazine-2-carboxylic response of the patient. acid 4-oxide). Nicotinic acid and its derivatives inhibit 0375 For administration of pharmaceutically acceptable hepatic production of VLDL and its metabolite LDL and Salts of the above compounds, the weights indicated above increases HDL and apo A-1 levels. An example of a Suitable refer to the weight of the acid equivalent or the base nicotinic acid product is NIASPAN(R) (niacin extended equivalent of the therapeutic compound derived from the release tablets) which are available from Kos. Salt. 0382 Generally, a total daily dosage of nicotinic acid or 0376. In one embodiment of the present invention, the a derivative thereof can range from about 500 to about compositions or therapeutic combinations can further com 10,000 mg/day, preferably about 1000 to about 8000 prise one or more pharmacological or therapeutic agents or mg/day, and more preferably about 3000 to about 6000 drugs. Such as cholesterol biosynthesis inhibitors and/or mg/day in Single or divided doses. lipid-lowering agents discussed below. 0383. In another alternative embodiment, the composi 0377 Non-limiting examples of cholesterol biosynthesis tions or treatments of the present invention can further inhibitors for use in the compositions, therapeutic combina comprise one or more AcylCoA:Cholesterol O-acyltrans tions and methods of the present invention include competi ferase (“ACAT.") Inhibitors, which can reduce LDL and tive inhibitors of HMG CoA reductase, the rate-limiting step VLDL levels, coadministered with or in combination with in cholesterol biosynthesis, Squalene Synthase inhibitors, the cardiovascular agent(s) and Sterol absorption inhibitor(s) Squalene epoxidase inhibitors and mixtures thereof. Non discussed above. ACAT is an enzyme responsible for esteri limiting examples of suitable HMG CoA reductase inhibi fying exceSS intracellular cholesterol and may reduce the tors include statins such as lovastatin (for example MEVA synthesis of VLDL, which is a product of cholesterol COR(R) which is available from Merck & Co.), pravastatin esterification, and overproduction of apo B-100-containing (for example PRAVACHOL(R) which is available from Bris lipoproteins. tol Meyers Squibb), fluvastatin, simvastatin (for example 0384. Non-limiting examples of useful ACAT inhibitors ZOCOR(R) which is available from Merck & Co.), atorvas include avasimibe (2,4,6-tris(1-methylethyl)phenyl tatin, cerivastatin, rosuvastatin, rivastatin (Sodium 7-(4-fluo acetylsulfamic acid, 2,6-bis(1-methylethyl)phenyl ester, rophenyl)-2,6-diisopropyl-5-methoxymethylpyridin-3-yl)- formerly known as CI-1011), HL-004, lecimibide (DuP-1 3,5-dihydroxy-6-heptanoate, CI-981 and pitavastatin (such 28) and CL-277082 (N-(2,4-difluorophenyl)-N-4-(2,2- as NK-1 04 of Negma Kowa of Japan); HMG CoA syn dimethylpropyl)phenyl)methyl-N-heptylurea). See P. thetase inhibitors, for example L-659,699 ((E,E)-11-3'R- (hydroxy-methyl)-oxo-2R-oxetanyl-3,5,7R-trimethyl-2, Chang et al., “Current, New and Future Treatments in 4-undecadienoic acid), Squalene Synthesis inhibitors, for Dyslipidaemia and Atherosclerosis', Drugs 2000 example Squalestatin 1; and Squalene epoxidase inhibitors, July;60(1); 55-93, which is incorporated by reference herein. for example, NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2- 0385) In another alternative embodiment, the composi hepten-4-ynyl)-3-(3,3'-bithiophen-5-yl)methoxybenzene tions or treatments of the present invention can further methanamine hydrochloride) and other sterol biosynthesis comprise probucol or derivatives thereof (such as AGI-1067 inhibitors. Such as DMP-565. Preferred HMG CoA reductase and other derivatives disclosed in U.S. Pat. Nos. 6,121,319 inhibitors include lovastatin, pravastatin and Simvastatin. and 6,147.250), which can reduce LDL levels, coadminis The most preferred HMG CoA reductase inhibitor is simv tered with or in combination with the cardiovascular astatin. agent(s) and Sterol absorption inhibitor(s) discussed above. 0378 Generally, a total daily dosage of cholesterol bio 0386 Generally, a total daily dosage of probucol or synthesis inhibitor(s) can range from about 0.1 to about 160 derivatives thereof can range from about 10 to about 2000 mg per day, and preferably about 0.2 to about 80 mg/day in mg/day, and preferably about 500 to about 1500 mg/day in Single or 2-3 divided doses. Single or 24 divided doses. 0379. In another preferred embodiment, the composition 0387. In another alternative embodiment, the composi or treatment comprises the compound of Formula (II) in tions or treatments of the present invention can further combination with one or more cardiovascular agents and one comprise low-density lipoprotein (LDL) receptor activators, or more cholesterol biosynthesis inhibitors. Preferably the coadministered with or in combination with the cardiovas US 2003/0069221A1 Apr. 10, 2003 26 cular agent(s) and Sterol absorption inhibitor(s) discussed apo B/E (LDL) receptors which bind LDL from plasma to above. Non-limiting examples of Suitable LDL-receptor further reduce cholesterol levels in the blood. activators include HOE-402, an imidazolidinyl-pyrimidine 0395. Non-limiting examples of suitable bile acid seques derivative that directly stimulates LDL receptor activity. See trants include cholestyramine (a styrene-divinylbenzene M. Huettinger et al., “Hypolipidemic activity of HOE-402 is copolymer containing quaternary ammonium cationic Mediated by Stimulation of the LDL Receptor Pathway', groups capable of binding bile acids, Such as QUES Arterioscler. Thromb. 1993; 13:1005-12. TRANTM or QUESTRAN LIGHTS(R) cholestyramine which 0388 Generally, a total daily dosage of LDL receptor are available from Bristol-Myers Squibb), colestipol (a activator(s) can range from about 1 to about 1000 mg/day in copolymer of diethylenetriamine and 1-chloro-2,3-ep Single or 24 divided doses. oxypropane, such as COLESTID(R) tablets which are avail able from Pharmacia), colesevelam hydrochloride (such as 0389. In another alternative embodiment, the composi WelChol(R) Tablets (poly(allylamine hydrochloride) cross tions or treatments of the present invention can further linked with epichlorohydrin and alkylated with 1-bromode comprise fish oil, which contains Omega 3 fatty acids cane and (6-bromohexyl)-trimethylammonium bromide) (3-PUFA), which can reduce VLDL and triglyceride levels, which are available from Sankyo), water soluble derivatives coadministered with or in combination with the cardiovas Such as 3.3-ioene, N-(cycloalkyl) alkylamines and poli cular agent(s) and Sterol absorption inhibitor(s) discussed glusam, insoluble quaternized polystyrenes, Saponins and above. Generally, a total daily dosage of fish oil or Omega mixtures thereof. Other useful bile acid Sequestrants are 3 fatty acids can range from about 1 to about 30 grams per disclosed in PCT Patent Applications Nos. WO 97/11345 day in Single or 24 divided doses. and WO 98157652, and U.S. Pat. Nos. 3,692,895 and 0390. In another alternative embodiment, the composi 5,703,188 which are incorporated herein by reference. Suit tions or treatments of the present invention can further able inorganic cholesterol Sequestrants include bismuth Sali comprise natural water Soluble fibers, Such as psyllium, cylate plus montmorillonite clay, aluminum hydroxide and guar, oat and pectin, which can reduce cholesterol levels, calcium carbonate antacids. coadministered with or in combination with the cardiovas 0396 Generally, a total daily dosage of bile acid seques cular agent(s) and Sterol absorption inhibitor(s) discussed trant(s) can range from about 1 to about 50 grams per day, above. Generally, a total daily dosage of natural water and preferably about 2 to about 16 grams per day in Single soluble fibers can range from about 0.1 to about 10 grams or 2-4 divided doses. per day in Single or 24 divided doses. 0397 Also useful with the present invention are compo 0391) In another alternative embodiment, the composi Sitions or therapeutic combinations that can further comprise tions or treatments of the present invention can further at least one (one or more) activators for peroxisome prolif comprise plant Sterols, plant Stanols and/or fatty acid esters erator-activated receptors (PPAR). These activators act as of plant Stanols, Such as Sitostanol ester used in agonists for the peroxisome proliferator-activated receptorS. BENECOLOR margarine, which can reduce cholesterol lev Three subtypes of PPAR have been identified, and these are els, coadministered with or in combination with the cardio designated as peroxisome proliferator-activated receptor vascular agent(s) and sterol absorption inhibitor(s) discussed alpha (PPARC), peroxisome proliferator-activated receptor above. Generally, a total daily dosage of plant Sterols, plant gamma (PPARY) and peroxisome proliferator-activated Stanols and/or fatty acid esters of plant Stanols can range receptor delta (PPAR8). It should be noted that PPARö is from about 0.5 to about 20 grams per day in single or 24 also referred to in the literature as PPARB and as NUC1, and divided doses. each of these names refers to the same receptor. 0392. In another alternative embodiment, the composi 0398 PPARC. regulates the metabolism of lipids. PPARC. tions or treatments of the present invention can further is activated by fibrates and a number of medium and comprise antioxidants, Such as probucol, tocopherol, ascor long-chain fatty acids, and it is involved in Stimulating bic acid, B-caroteine and Selenium, or Vitamins Such as B-oxidation of fatty acids. The PPARY receptor subtypes are Vitamin B or vitamin B, coadministered with or in com involved in activating the program of adipocyte differentia bination with the cardiovascular agent(s) and Sterol absorp tion and are not involved in Stimulating peroxisome prolif tion inhibitor(s) discussed above. Generally, a total daily eration in the liver. PPARö has been identified as being dosage of antioxidants or Vitamins can range from about useful in increasing high density lipoprotein (HDL) levels in 0.05 to about 10 grams per day in single or 24 divided doses. humans. See, e.g., WO 97/28149. 0393. In another alternative embodiment, the composi 0399 PPARC. activator compounds are useful for, among tions, therapeutic combinations or methods of the present other things, lowering triglycerides, moderately lowering invention can further comprise one or more bile acid Seques LDL levels and increasing HDL levels. Useful examples of trants (insoluble anion exchange resins), coadministered PPARC. activators include the fibrates discussed above. with or in combination with the cardiovascular agents and sterol absorption inhibitor(s) discussed above. 0400 Other examples of PPARC. activators useful with the practice of the present invention include Suitable fluo 0394 Bile acid sequestrants bind bile acids in the intes rophenyl compounds as disclosed in U.S. No. 6,028,109 tine, interrupting the enterohepatic circulation of bile acids which is incorporated herein by reference; certain Substi and causing an increase in the faecal excretion of Steroids. tuted phenylpropionic compounds as disclosed in WO Use of bile acid Sequestrants is desirable because of their 00/75103 which is incorporated herein by reference; and non-Systemic mode of action. Bile acid Sequestrants can PPARC. activator compounds as disclosed in WO 98/43081 lower intrahepatic cholesterol and promote the Synthesis of which is incorporated herein by reference. US 2003/0069221A1 Apr. 10, 2003 27

0401 Non-limiting examples of PPARY activator include herein by reference; compounds as disclosed in WO Suitable derivatives of glitaZones or thiazolidinediones, Such 00/63196 and WO 00/63209 which are incorporated herein as, troglitazone (such as REZULINGR) troglitazone (-5-4- by reference; Substituted 5-aryl-2,4-thiazolidinediones com 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopy pounds as disclosed in U.S. Pat. No. 6,008,237 which is ran-2-yl)methoxyphenyl methyl-2,4-thiazolidinedione) incorporated herein by reference, arylthiazolidinedione and commercially available from Parke-Davis); rosiglitaZone aryloxazolidinedione compounds as disclosed in WO (such as AVANDIACR rosiglitazone maleate (-5-4-2-(me 00178312 and WO 00/78313G which are incorporated thyl-2-pyridinylamino)ethoxyphenyl)methyl-2,4-thiazo herein by reference; GW2331 or (2-(4-difluorophenyl-1 lidinedione, (Z)-2-butenedioate) (1:1) commercially avail heptylureido)ethylphenoxy)-2-methylbutyric compounds able from SmithKline Beecham) and pioglitazone (such as as disclosed in WO 98/05331 which is incorporated herein ACTOSTM pioglitazone hydrochloride (5-4-2-(5-ethyl-2- by reference; aryl compounds as disclosed in U.S. Pat. No. pyridinyl)ethoxyphenylmethyl-2,4- thiazolidinedione 6,166,049 which is incorporated herein by reference; monohydrochloride) commercially available from Takeda oxazole compounds as disclosed in WO 01/17994 which is Pharmaceuticals). Other useful thiazolidinediones include incorporated herein by reference, and dithiolane compounds ciglitaZone, englitaZone, dargilitaZone and BRL 49653 as as disclosed in WO 01/25225 and WO 01/2.5226 which are disclosed in WO 98/05331 which is incorporated herein by incorporated herein by reference. reference; PPARY activator compounds disclosed in WO 04.05) Other useful PPAR activator compounds include 00/76488 which is incorporated herein by reference; and Substituted benzylthiazolidine-2,4-dione compounds as dis PPARY activator compounds disclosed in U.S. Pat. No. closed in WO 01/14349, WO 01/14350 and WO/01/04351 5,994,554 which is incorporated herein by reference. which are incorporated herein by reference, mercaptocar 0402. Other useful classes of PPARY activator com boxylic compounds as disclosed in WO 00/50392 which is pounds include certain acetylphenols as disclosed in U.S. incorporated herein by reference; ascofuranone compounds Pat. No. 5,859,051 which is incorporated herein by refer as disclosed in WO 00/53563 which is incorporated herein ence; certain quinoline phenyl compounds as disclosed in by reference; carboxylic compounds as disclosed in WO WO 99/20275 which is incorporated herein by reference; 99/46232 which is incorporated herein by reference; com aryl compounds as disclosed by WO 99138845 which is pounds as disclosed in WO99/12534 which is incorporated incorporated herein by reference; certain 1,4-disubstituted herein by reference; compounds as disclosed in WO phenyl compounds as disclosed in WO 00/63161; certain 99/15520 which is incorporated herein by reference; aryl compounds as disclosed in WO 01/00579 which is o-anisamide compounds as disclosed in WO 01/21578 incorporated herein by reference; benzoic acid compounds which is incorporated herein by reference; and PPAR acti as disclosed in WO 01/12612 & WO 01/12.187 which are vator compounds as disclosed in WO 01/40192 which is incorporated herein by reference; and Substituted 4-hy incorporated herein by reference. droxy-phenylalconic acid compounds as disclosed in WO 0406 The peroxisome proliferator-activated receptor(s) 97131907 which is incorporated herein by reference. activator(s) are administered in a therapeutically effective 0403 PPARö compounds are useful for, among other amount to treat the Specified condition, for example in a things, lowering triglyceride levels or raising HDL levels. daily dose preferably ranging from about 50 to about 3000 Non-limiting examples of PPARö activators include suitable mg per day, and more preferably about 50 to about 2000 mg thiazole and oxazole derivates, Such as C.A.S. Registry No. per day, given in a Single dose or 24 divided doses. The exact 317318-324, as disclosed in WO 01/00603 which is incor dose, however, is determined by the attending clinician and porated herein by reference); certain fluoro, chloro or thio is dependent on Such factors as the potency of the compound phenoxy phenylacetic acids as disclosed in WO 97/28149 administered, the age, weight, condition and response of the which is incorporated herein by reference, Suitable non-B- patient. oxidizable fatty acid analogues as disclosed in U.S. Pat. No. 0407. The compositions or treatments of the present 5,093,365 which is incorporated herein by reference; and invention can further comprise one or more ileal bile acid PPARö compounds as disclosed in WO991.04815 which is transport (“IBAT”) inhibitors (or apical sodium co-depen incorporated herein by reference. dent bile acid transport ("ASBT) inhibitors) coadminis 0404 Moreover, compounds that have multiple function tered with or in combination with the cardiovascular ality for activating various combinations of PPARC, PPARY agent(s) and Sterol absorption inhibitor(s) discussed above. and PPARö are also useful with the practice of the present The IBAT inhibitors can inhibit bile acid transport to reduce invention. Non-limiting examples include certain Substi LDL cholesterol levels. Non-limiting examples of suitable tuted aryl compounds as disclosed in U.S. Pat. No. 6,248, IBAT inhibitors include benzothiepines such as therapeutic 781; WO 00/23416; WO 00123415; WO 00/23425; WO compounds comprising a 2,3,4,5-tetrahydro-1-benzothi 00/23445; WO 00/23451; and WOOO/63153, all of which epine 1,1-dioxide structure such as are disclosed in PCT are incorporated herein by reference, are described as being Patent Application WO 00/38727 which is incorporated useful PPARC. and/or PPARY activator compounds. Other herein by reference. non-limiting examples of useful PPARC. and/or PPARY activator compounds include activator compounds as dis 0408 Generally, a total daily dosage of IBAT inhibitor(s) closed in WO 97/25042 which is incorporated herein by can range from about 0.01 to about 1000 mg/day, and reference, activator compounds as disclosed in WO preferably about 0.1 to about 50 mg/day in single or 24 00/63190 which is incorporated herein by reference; acti divided doses. vator compounds as disclosed in WO 01/21181 which is 04.09 The compositions or treatments of the present incorporated herein by reference; biaryl-Oxa(thia)Zole com invention can further comprise one or more Cholesteryl pounds as disclosed in WO 01/16120 which is incorporated Ester Transfer Protein (“CETP) Inhibitors coadministered US 2003/0069221A1 Apr. 10, 2003 28 with or in combination with the cardiovascular agent(s) and Sulfate; available from Duramed Pharmaceuticals, sterol absorption inhibitor(s) discussed above. CETP is Inc., Cincinnati, Ohio, under the tradename Cenes responsible for the exchange or transfer of cholesteryl ester tin, carrying HDL and triglycerides in VLDL. 0418 (b) ethinyl estradiol (19-nor-17 a -pregna-1,3, 0410. Non-limiting examples of suitable CETP inhibitors 5(10)-trien-20-yne-3,17-diol; available by Schering are disclosed in PCT Patent Application No. WO 00/38721 Plough Corporation, Kenilworth, N.J., under the and U.S. Pat. No. 6,147,090, which are incorporated herein tradename Estinyl, by reference. Pancreatic cholesteryl ester hydrolase (PCEH) inhibitors Such as WAY-121898 also can be coadministered 0419 (c) esterified estrogen combinations such as Sodium estrone Sulfate and Sodium equilin Sulfate; with or in combination with the peroxisome proliferator available from Solvay under the tradename Estratab activated receptor(s) activator and sterol absorption inhibi and from Monarch Pharmaceuticals, Bristol, Tenn., tor(s) discussed above. under the tradename Menest; 0411 Generally, a total daily dosage of CETP inhibitor(s) 0420 (d) estropipate (piperazine estra-1,3,5(10)- can range from about 0.01 to about 1000 mg/day, and trien-17-one, 3-(sulfooxy)-estrone sulfate); available preferably about 0.5 to about 20 mg/kg body weight/day in from Pharmacia & Upjohn, Peapack, N.J., under the Single or divided doses. tradename Ogen and from Women First Health Care, 0412. The compositions or treatments of the present Inc., San Diego, Calif., under the tradename Ortho invention can further comprise probucol or derivatives Est; and thereof (such as AGI-1067 and other derivatives disclosed in U.S. Pat. Nos. 6,121,319 and 6,147.250), which can reduce 0421 (e) conjugated estrogens (17 C-dihydroegui LDL and HDL levels, coadministered with or in combina lin, 17 C-estradiol, and 17 B-dihydroequilin); avail tion with the cardiovascular agent(s) and Sterol absorption able from Wyeth-Ayerst Pharmaceuticals, Philadel inhibitor(s) discussed above. phia, Pa., under the tradename Premarin. 0413. The compositions or treatments of the present 0422 Progestins and estrogens may also be administered invention can further comprise monocyte and macrophage with a variety of dosages, generally from about 0.05 to about inhibitors such as polyunsaturated fafty acids (PUFA), thy 2.0 mg progestin and about 0.001 mg to about 2 mg roid hormones including throXine analogues Such as CGS estrogen, desirably from about 0.1 mg to about 1 mg 26214 (a thyroxine compound with a fluorinated ring), gene progestin and about 0.01 mg to about 0.5 mg estrogen. therapy and use of recombinant proteins Such as recombi Examples of progestin and estrogen combinations that may nant apo E. Generally, a total daily dosage of these agents vary in dosage and regimen include: can range from about 0.01 to about 1000 mg/day in single 0423 (a) the combination of estradiol (estra-1, 3, 5 or 2-4 divided doses. (10)-triene-3, 17 B-diol hemihydrate) and norethin 0414. Also useful with the present invention are compo drone (17 B-acetoxy-19-nor-17 C-pregn-4-en-20-yn Sitions or therapeutic combinations which further comprise 3-one); which is available from Pharmacia & hormone replacement agents and compositions. Useful hor Upjohn, Peapack, N.J., under the tradename mone agents and compositions for hormone replacement Activella; therapy of the present invention include androgens, estro 0424 (b) the combination of levonorgestrel (d(-)-13 gens, progestins, their pharmaceutically acceptable Salts and f3-ethyl-17 C-ethinyl-17 f-hydroxygon-4-en-3-one) derivatives. Combinations of these agents and compositions and ethinyl estradial; available from Wyeth-Ayerst are also useful. under the tradename Alesse, from Watson Laborato 0415 The dosage of androgen and estrogen combinations ries, Inc., Corona, Calif., under the tradenames vary, desirably from about 1 mg to about 4 mg androgen and Levora and Trivora, Monarch Pharmaceuticals, from about 1 mg to about 3 mg estrogen. Examples include, under the tradename Nordette, and from Wyeth but are not limited to, androgen and estrogen combinations Ayerst under the tradename Triphasil; Such as the combination of esterified estrogens (Sodium 0425 (c) the combination of ethynodiol diacetate estrone Sulfate and Sodium equilin Sulfate) and methyltest (19-nor-17 C-pregn-4-en-20-yne-3 ?, 17-diol diac osterone (17-hydroxy-17-methyl-, (17B)- androst-4-en-3- etate) and ethinyl estradiol; available from G.D. one) available from Solvay Pharmaceuticals, Inc., Marietta, Searle & Co., Chicago, Ill., under the tradename Ga., under the tradename Estratest. Demulen and from Watson under the tradename 0416 Estrogens and estrogen combinations may vary in Zovia, dosage from about 0.01 mg up to 8 mg, desirably from about 0426 (d) the combination of desogestrel (13-ethyl 0.3 mg to about 3.0 mg. Examples of useful estrogens and 11- methylene-18,19-dinor-17 C-pregn-4-en-20-yn estrogen combinations include: 17-ol) and ethinyl estradiol; available from Organon 0417 (a) the blend of nine (9) synthetic estrogenic under the tradenames DeSogen and Mircette, and Substances including Sodium estrone Sulfate, Sodium from Ortho-McNeil Pharmaceutical, Raritan, N.J., equilin Sulfate, Sodium 17 C-dihydroeguilinu Sulfate, under the tradename Ortho-Cept; Sodium 17 C-estradiol sulfate, sodium 17 B-dihy 0427 (e) the combination of norethindrone and ethi droeguilin Sulfate, Sodium 17 O-dihydroeguilenin nyl estradiol; available from Parke-Davis, Morris Sulfate, Sodium 17 B-dihydroeguilenin Sulfate, Plains, N.J., under the tradenames Estrostep and Sodium equilenin Sulfate and Sodium 17 B-estradiol femhrt, from Watson under the tradenames Micro US 2003/0069221A1 Apr. 10, 2003 29

gestin, Necon, and Tri-Norinyl, from Ortho-McNeil 10 polypeptide; a monoamine oxidase inhibitor (Such as under the tradenames Modicon and Ortho-Novum, befloxatone, moclobemide, brofaromine, phenoxathine, eSu and from Warner Chilcott Laboratories, Rockaway, prone, befol, toloxatone, pirlindol, amiflamine, Serclorem N.J., under the tradename Ovcon, ine, bazinaprine, lazabemide, millacemide and caroxazone); 0428 (f) the combination of norgestrel ((+)-13 a compound for increasing lipid metabolism (Such as evo ethyl-17-hydroxy-18, 19-dinor-17 C.-preg-4-en-20 diamine compounds); and a lipase inhibitor (Such as Orl yn-3-one) and ethinyl estradiol; available from istat). Generally, a total dosage of the above-described Wyeth-Ayerst under the tradenames Ovral and obesity control medications can range from 1 to 3,000 Lo/Ovral, and from Watson under the tradenames mg/day, desirably from about 1 to 1,000 mg/day and more OgeStrel and Low-Ogestrel; desirably from about 1 to 200 mg/day in single or 2-4 0429 (g) the combination of norethindrone, ethinyl divided doses. estradiol, and mestranol (3-methoxy-19-nor-1 7 0435 The compositions, therapeutic combinations or C-pregna-1,3,5(10)-trien-20-yn-1 7-ol); available methods of the present invention can further comprise one or from Watson under the tradenames Brevicon and more blood modifiers which are chemically or structurally Norinyl; different from the sterol absorption inhibitors (such as 0430 (h) the combination of 17 P-estradiol (estra compounds (I-XI) above) and the cardiovascular agents 1,3,5(10)-triene-3,17 B-diol) and micronized norges discussed above, for example, they contain one or more timate (17 C-1 7-(Acetyloxyl)-13-ethyl-18,19-di different atoms, have a different arrangement of atoms or a norpregn-4-en-20-yn-3-one3-oxime); available from different number of one or more atoms than the sterol Ortho-McNeil under the tradename Ortho-Prefest; absorption inhibitor(s) and the cardiovascular agents dis 0431 (i) the combination of norgestimate (18,19 cussed above. Different blood modifiers include but are not dinor-17-pregn-4-en-20-yn-3-one, 17-(acetyloxy)- limited to anti-coagulants (argatroban, bivalirudin, dalte parin Sodium, desirudin, dicumarol, lyapolate Sodium, nafa 13-ethyl-, oxime, (17(C)-(+)-) and ethinyl estradiol; mostat meSylate, phenprocoumon, tinzaparin Sodium, war available from Ortho-McNeil under the tradenames farin Sodium); antithrombotic (anagrelide hydrochloride, Ortho Cyclen and Ortho Tri-Cyclen; and bivalirudin, ciloStaZol, dalteparin Sodium, danaparoid 0432 j) the combination of conjugated estrogens Sodium, daZOXiben hydrochloride, efegatran Sulfate, enox (Sodium estrone Sulfate and Sodium equilin Sulfate) aparin Sodium, fluretofen, ifetroban, ifetroban Sodium, lami and medroxyprogesterone acetate (20-dione, fiban, lotrafiban hydrochloride, napsagatran, orbofiban 17-(acetyloxy)-6-methyl-, (6(C))- pregn-4-ene-3); acetate, roXifiban acetate, Sibrafiban, tinzaparin Sodium, available from Wyeth-Ayerst under the tradenames trifenagrel, abciximab, Zolimomab aritox); fibrinogen recep Premphase and Prempro. tor antagonists (roxifiban acetate, fradafiban, orbofiban, lotrafiban hydrochloride, tirofiban, xemilofiban, monoclonal 0433. In general, a dosage of progestins may vary from antibody 7E3, sibrafiban); platelet inhibitors (cilostazol, about 0.05 mg to about 10 mg or up to about 200 mg if clopidogrel bisulfate, epoprostenol, epoprostenol Sodium, microSized progesterone is administered. Examples of ticlopidine hydrochloride, aspirin, ibuprofen, naproxen, progestins include norethindrone; available from ESI Led Sulindae, idomethacin, mefenamate, droxicam, diclofenac, erle, Inc., Philadelphia, Pa., under the tradename Aygestin, Sulfinpyrazone, piroxicam, dipyridamole); platelet aggrega from Ortho-McNeil under the tradename Micronor, and tion inhibitors (acadesine, beraprost, beraprost Sodium, from Watson under the tradename Nor-QD; norgestrel; ciprostene calcium, itaZigrel, lifarizine, lotrafiban hydro available from Wyeth-Ayerst under the tradename Ovrette; chloride, orbofiban acetate, OXagrelate, fradafiban, orbo micronized progesterone (pregn-4-ene-3,20-dione); avail fiban, tirofiban, xemilofiban); hemorrheologic agents (pen able from Solvay under the tradename Prometrium; and toxifylline); lipoprotein associated coagulation inhibitor; medroxyprogesterone acetate; available from Pharmacia & Factor VIIa inhibitors (4H-31-benzoxazin-4-ones, 4H-3,1- Upjohn under the tradename Provera. benzoxazin-4-thiones, quinazolin-4-ones, quinazolin-4- 0434. The compositions, therapeutic combinations or thiones, benzothiazin-4-ones, imidazolyl-boronic acid-de methods of the present invention can further comprise one or rived peptide analogues TFPI-derived peptides, more obesity control medications. Different obesity control naphthalene-2-sulfonic acid {1-3-(aminoiminomethyl)- medications include, but are not limited to, drugs that reduce benzyl)-2-oxo-pyrrolidin-3-(S)-yl amide trifluoroacetate, energy intake or SuppreSS appetite, drugs that increase dibenzofuran-2-sulfonic acid 1-3-(aminomethyl)-benzyl energy expenditure and nutrient-partitioning agents. Suit 5-oxo-pyrrolidin-3-yl)-amide, tolulene-4-Sulfonic acid {1- able obesity control medications include, but are not limited 3-(aminoiminomethyl)-benzyl)-2-oxo-pyrrolidin-3-(S)- to, noradrenergic agents (such as diethylpropion, , yl)-amide trifluoroacetate, 3,4-dihydro-1H-isoquinoline-2- phenylpropanolamine, phentermine, , Sulfonic acid {1-3-(aminoiminomethyl)-benzyl)-2-oxo phendamine tartrate, , phendimetrazine pyrrolin-3-(S)-yl)-amide trifluoroacetate); Factor Xa and tartrate); Serotonergic agents (such as Sibutramine, fen inhibitors (disubstituted pyrazolines, disubstituted triazo fluramine, dexfenfluramine, fluoxetine, fluvoxamine and lines, Substituted n-(aminoiminomethyl)phenyl propyla paroxtine); thermogenic agents (Such as ephedrine, , mides, Substituted n-(aminomethyl)phenyl propylamides, , and Selective f33-adrenergic agonists); an tissue factor pathway inhibitor (TFPI), low molecular alpha-blocking agent; a kainite or AMPA receptor antago weight heparins, heparinoids, benzimidazolines, benzox nist; a leptin-lipolysis Stimulated receptor, a phosphodi azolinones, benzopiperazinones, indanones, dibasic (amidi esterase enzyme inhibitor, a compound having nucleotide noaryl) propanoic acid derivatives, amidinophenyl-pyrro Sequences of the mahogany gene; a fibroblast growth factor lidines, amidinophenyl-pyrrolines, amidinophenyl US 2003/0069221A1 Apr. 10, 2003 30 isoxazolidines, amidinoindoles, amidinoazoles, bis erS and the like. The amount of excipient or additive can arly Sulfonylaminobenzamide derivatives, peptidic Factor range from about 0.1 to about 90 weight percent of the total Xa inhibitors). weight of the treatment composition or therapeutic combi 0436 The compositions, therapeutic combinations or nation. One skilled in the art would understand that the methods of the present invention can further comprise one or amount of carrier(s), excipients and additives (if present) can more antidiabetic medications for reducing blood glucose vary. levels in a human. Different antidiabetic medications 0441 The treatment compositions of the present inven include, but are not limited to, drugs that reduce energy tion can be administered in any conventional dosage form, intake or SuppreSS appetite, drugs that increase energy preferably an oral dosage form Such as a capsule, tablet, expenditure and nutrient-partitioning agents. Suitable powder, cachet, Suspension or Solution. The formulations antidiabetic medications include, but are not limited to, and pharmaceutical compositions can be prepared using Sulfonylurea (Such as acetohexamide, chlorpropamide, glia conventional pharmaceutically acceptable and conventional milide, gliclazide, glimepiride, glipizide, glyburide, glib techniques. Several examples of preparation of dosage for enclamide, tolazamide, and tolbutamide), meglitinide (Such mulations are provided below. as repaglinide and nateglinide), biguamide (such as met formin and buformin), thiazolidinedione (such as troglita 0442. The following formulations exemplify some of the Zone, rosiglitaZone, pioglitaZone, ciglitaZone, englitaZone, dosage forms of this invention. In each formulation, the term and dargilitaZone), alpha-glucosidase inhibitor (Such as acar “Active Compound I' designates a sterol absorption inhibi bose, miglitol, camiglibose, and Voglibose), certain peptides tor and the term "Active Compound II designates a car (Such as amlintide, pramlintide, exendin, and GLP-1 ago diovascular agent described herein above. nistic peptides), and orally administrable insulin or insulin composition for intestinal delivery thereof. Generally, a total EXAMPLE dosage of the above-described antidiabetic medications can range from 0.1 to 1,000 mg/day in single or 2-4 divided 0443) doses. 0437. Mixtures of any of the pharmacological or thera peutic agents described above can be used in the composi Tablets tions and therapeutic combinations of these other embodi ments of the present invention. No. Ingredient mg/tablet 1. Active Compound I 1O 0438. The compositions and therapeutic combinations of 2 Lactose monohydrate NF 55 the present invention can be administered to a mammal in 3 Microcrystalline cellulose 2O need of Such treatment in a therapeutically effective amount 4 Povidone (K29-32) USP 4 5 Croscarmellose sodium NF 8 to treat vascular conditions Such as hypertension. The com 6 Sodium lauryl sulfate 2 positions and treatments can be administered by any Suitable 7 Magnesium stearate NF 1. means that produce contact of these compounds with the Site of action in the body, for example in the plasma, liver or Total 1OO Small intestine of a mammal. 0439. The daily dosage for the various compositions and 0444. In the present invention, the above-described tablet therapeutic combinations described above can be adminis can be coadministered with a tablet, capsule, etc. comprising tered to a patient in a single dose or in multiple Subdoses, as a dosage of Active Compound II, for example a cardiovas desired. Subdoses can be administered 2 to 6 times per day, for example. Sustained release dosages can be used. Where cular agent as described above. the cardiovascular agents and Sterol absorption inhibitor(s) 04:45 Method of Manufacture are administered in Separate dosages, the number of doses of each component given per day may not necessarily be the 0446 Mix Item No. 4 with purified water in Suitable Same, e.g., one component may have a greater duration of mixer to form binder solution. Spray the binder Solution and activity and will therefore need to be administered less then water over Items 1, 2, 6 and a portion of Item 5 in a frequently. fluidized bed processor to granulate the ingredients. Con tinue fluidization to dry the damp granules. Screen the dried 0440 The pharmaceutical treatment compositions and granules and blend with Item No. 3 and the remainder of therapeutic combinations of the present invention can fur Item 5. Add Item No. 7 and mix. Compress the mixture to ther comprise one or more pharmaceutically acceptable appropriate Size and weight on a Suitable tablet machine. carriers, one or more excipients and/or one or more addi tives. Non-limiting examples of pharmaceutically accept 0447 For coadministration in separate tablets or cap able carriers include Solids and/or liquids Such as ethanol, Sules, representative formulations comprising a cholesterol glycerol, water and the like. The amount of carrier in the absorption inhibitor Such as are discussed above are well treatment composition can range from about 5 to about 99 known in the art and representative formulations comprising weight percent of the total weight of the treatment compo a cardiovascular agent Such as are discussed above are well Sition or therapeutic combination. Non-limiting examples of known in the art. It is contemplated that where the two active Suitable pharmaceutically acceptable excipients and addi ingredients are administered as a Single composition, the tives include non-toxic compatible fillers, binderS Such as dosage forms disclosed above for Sterol absorption inhibitor Starch, disintegrants, buffers, preservatives, anti-oxidants, may readily be modified using the knowledge of one skilled lubricants, flavorings, thickeners, coloring agents, emulsifi in the art. US 2003/0069221A1 Apr. 10, 2003

0448. Since the present invention relates to reducing the 0.61 mol) and the reaction mixture was cooled to 0° C. plasma Sterol (especially cholesterol) concentrations or lev Methyl-4-(chloroformyl)butyrate (50 g., 0.3 mol) was added els by treatment with a combination of active ingredients or as a solution in CHCl (375 ml) dropwise over 1 h, and the treating vascular conditions, Stroke or obesity wherein the reaction was allowed to warm to 22 C. After 17 h, water and active ingredients may be administered Separately, the HSO(2N, 100 ml), was added, the layers were separated, invention also relates to combining Separate pharmaceutical and the organic layer was washed sequentially with NaOH compositions in kit form. That is, a kit is contemplated (10%), NaCl (sat'd) and water. The organic layer was dried wherein two separate units are combined: a pharmaceutical over MgSO and concentrated to obtain a Semicrystalline composition comprising at least one cardiovascular agent product. and a Separate pharmaceutical composition comprising at least one sterol absorption inhibitor as described above. The 0454) Step 2): kit will preferably include directions for the administration 0455) To a solution of TiCl (18.2 ml, 0.165 mol) in of the Separate components. The kit form is particularly CHCl (600 ml) at 0°C., was added isopropoxide advantageous when the Separate components must be (16.5 ml, 0.055 mol). After 15 min., the product of Step 1 administered in different dosage forms (e.g., oral and (49.0 g, 0.17 mol) was added as a solution in CHCl (100 parenteral) or are administered at different dosage intervals. ml). After 5 min., diisopropylethylamine (DIPEA) (65.2 ml, 0449 The treatment compositions and therapeutic com 0.37 mol) was added and the reaction mixture was stirred at binations of the present invention can inhibit the intestinal 0° C. for 1 h, the reaction mixture was cooled to -20°C., and absorption of cholesterol in mammals, as shown in the 4-benzyloxybenzylidine(4-fluoro)aniline (114.3 g, 0.37 Example below, and can be useful in the treatment and/or mol) was added as a Solid. The reaction mixture was stirred prevention of vascular conditions, Such as vascular inflam vigorously for 4 hat -20°C., then acetic acid was added as mation, atherOSclerosis, hypercholesterolemia and Sitoster a Solution in CH2Cl dropwise over 15 min., the reaction olemia, Stroke, obesity and lowering of plasma levels of mixture was allowed to warm to 0°C., and HSO(2N) was added. The reaction mixture was stirred an additional 1 h, cholesterol in mammals, in particular in humans. the layers were Separated, washed with water, Separated and 0450. In another embodiment of the present invention, the organic layer was dried. The crude product was crystal the compositions and therapeutic combinations of the lized from ethanol/water to obtain the pure intermediate. present invention can inhibit Sterol absorption or reduce plasma concentration of at least one Sterol Selected from the 0456 Step 3): group consisting of phytosterols (Such as Sitosterol, campes 0457 To a solution of the product of Step 2 (8.9 g, 14.9 terol, Stigmasterol and avenosterol), 5C-stanols (Such as mmol) in toluene (100 ml) at 50° C., was added N.O- cholestanol, 5C-campestanol, 5C.-sitostanol), cholesterol bis(trimethylsilyl)acetamide (BSA) (7.50 ml, 30.3 mmol). and mixtures thereof. The plasma concentration can be After 0.5 h, solid TBAF (0.39 g, 1.5 mmol) was added and reduced by administering to a mammal in need of Such the reaction mixture stirred at 50 C. for an additional 3 h. treatment an effective amount of at least one treatment The reaction mixture was cooled to 22 C., CHH (10 ml), composition or therapeutic combination comprising at least was added. The reaction mixture was washed with HCl (1 one cardiovascular agent and at least one Sterol absorption N), NaHCO (1 N) and NaCl (satd.), and the organic layer inhibitor described above. The reduction in plasma concen was dried over MgSO. tration of Sterols can range from about 1 to about 70 percent, and preferably about 10 to about 50 percent. Methods of 0458 Step 4): measuring Serum total blood cholesterol and total LDL 0459. To a solution of the product of Step 3 (0.94g, 2.2 cholesterol are well known to those skilled in the art and for mmol) in CHH (3 ml), was added water (1 ml) and example include those disclosed in PCT WO 99/38498 at LiOH.HO (102 mg, 2.4 mmole). The reaction mixture was page 11, incorporated by reference herein. Methods of stirred at 22° C. for 1 h and then additional LiOH.HO (54 determining levels of other Sterols in Serum are disclosed in mg, 1.3 mmole) was added. After a total of 2 h, HCl (1 N) H. Gylling et al., “Serum Sterols During Stanol Ester and EtOAc was added, the layers were Separated, the organic Feeding in a Mildly Hypercholesterolemic Population”, J. layer was dried and concentrated in vacuo. To a Solution of Lipid Res. 40: 593-600 (1999), incorporated by reference the resultant product (0.91 g, 2.2 mmol) in CHCl at 22°C., herein. was added CICOCOCI (0.29 ml, 3.3 mmol) and the mixture 0451 Illustrating the invention is the following example stirred for 16 h. The solvent was removed in vacuo. which, however, are not to be considered as limiting the invention to their details. Unless otherwise indicated, all 0460 Step 5): parts and percentages in the following examples, as well as 0461) To an efficiently stirred suspension of 4-fluorophe throughout the Specification, are by weight. nylzinc chloride (4.4 mmol) prepared from 4-fluorophenyl magnesium bromide (1 M in THF, 4.4 ml, 4.4 mmol) and EXAMPLE ZnCl, (0.6 g. 4.4 mmol) at 4°C., was added tetrakis(triph enylphosphine)palladium (0.25 g, 0.21 mmol) followed by PREPARATION OF COMPOUND OF FORMULA the product of Step 4 (0.94g, 2.2 mmol) as a solution in THF (II) (2 ml). The reaction was stirred for 1 h at 0°C. and then for 0.5 h at 22° C. HCl (1 N, 5 ml) was added and the mixture 0452 Step 1): was extracted with EtOAc. The organic layer was concen 0453 To a solution of (S)-4-phenyl-2-oxazolidinone (41 trated to an oil and purified by Silica gel chromatography to g, 0.25 mol) in CHCl (200 ml), was added 4-dimethylami obtain 1-(4-fluorophenyl)-4-(S)-(4-hydroxyphenyl)-3(R)-(3- nopyridine (2.5 g., 0.02 mol) and triethylamine (84.7 ml, OXO-3-phenylpropyl)-2-azetidinone: US 2003/0069221A1 Apr. 10, 2003 32

0462 HRMS calc'd for CHFNO=408.1429, found 408.1411. (I) 0463) Step 6): R R2 0464) To the product of Step 5 (0.95 g, 1.91 mmol) in Arl-X dry- d Zp Ari THF (3 ml), was added (R)-tetrahydro-1-methyl-3,3-diphe nyl-1H .3H-pyrrolo-1,2-c.1.3.2 oxazaborole (120 mg, 0.43 mmol) and the mixture was cooled to -20° C. After 5 min, borohydride-dimethylsulfide complex (2M in THF, O NAr2 0.85 ml, 1.7 mmol) was added dropwise over 0.5 h. After a total of 1.5 h, CHH was added followed by HCl (1 N) and the reaction mixture was extracted with EtOAc to obtain or isomers thereof, or pharmaceutically acceptable Salts or 1-(4-fluorophenyl)-3(R)-3(S)-(4-fluorophenyl)-3-hydrox Solvates of the compounds of Formula (I) or of the isomers ypropyl)4(S)-4-(phenylmethoxy)phenyl-2-azetidinone thereof, or prodrugs of the compounds of Formula (I) or of (compound 6A-1) as an oil. H in CDCld H3-4.68. J=2.3 the isomers, Salts or Solvates thereof, wherein: Hz. Cl (MH) 500. Ar' and Art are independently selected from the group 0465. Use of (S)-tetra-hydro-1-methyl-3,3-diphenyl-1H, consisting of aryl and R-Substituted aryl; 3H-pyrrolo-1,2-c.1.3.2 oxazaborole gives the correspond ing 3(R)-hydroxypropyl azetidinone (compound 6B-1). "H Ar is aryl or R-substituted aryl; in CDC1 d H3–4.69. J-2.3 Hz. Cl (MH) 500. X, Y and Z are independently Selected from the group 0466 To a solution of compound 6A-1 (0.4g, 0.8 mmol) consisting of -CH-, -CH(lower alkyl)- and in ethanol (2 ml), was added 10% Pd/C (0.03 g) and the -C(dillower alkyl)-; reaction mixture was stirred under a pressure (60 psi) of H R and R are independently selected from the group gas for 16 h. The reaction mixture was filtered and the consisting of -OR, -O(CO)R, —O(CO)OR and Solvent was concentrated to obtain compound 6A. Mp -O(CO)NR'R'; 164-166° C.; Cl (MH) 410. C-28.1° (c 3, CHOH) Elemental analysis calcd for CHFNO: Co.; H 5.17; R" and R are independently selected from the group N 3.42; found Cos; H 5.19; N 3.54. consisting of hydrogen, lower alkyl and aryl; 0467 Similarly treat compound 6B-1 to obtain com q is 0 or 1; pound 6B. r is 0 or 1; 0468 Mp 129.5-132.5° C.; C1 (MH) 410. Elemental analysis catc'd for CHFNO: C70.41; H 5.17; N 3.42; m, n and p are independently Selected from 0, 1, 2, 3 or found C 70.30; H 5.14; N 3.52. 4, provided that at least one of q and r is 1, and the Sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6, and provided that 0469 Step 640 (Alternative): when p is 0 and r is 1, the Sum of m, q and n is 1, 2, 0470 To a solution of the product of Step 5 (0.14g, 0.3 3, 4 or 5; mmol) in ethanol (2 ml), was added 10% Pd/C (0.03 g) and R" is 1-5 substituents independently selected from the the reaction was stirred under a pressure (60 psi) of H2 gas group consisting of lower alkyl, -OR. --O(CO)R, for 16 h. The reaction mixture was filtered and the solvent –O(CO)OR. --O(CH), OR, –O(CO)NR'R'', was concentrated to afford a 1:1 mixture of compounds 6A -NRR7, -NR(CO)R7, -NR(CO)OR, and 6B. -NR(CO)NR7R, -NR SOR, -COOR , 0471. It will be appreciated by those skilled in the art that –CONR'R''. COR, -SONR'', S(O).R. changes could be made to the embodiments described above -O(CH-)-o-COOR, -O(CH)-oCONR'R' , without departing from the broad inventive concept thereof. -(lower alkylene)COOR , -CH=CH-COOR , It is understood, therefore, that this invention is not limited -CF, -CN, -NO and halogen; to the particular embodiments disclosed, but it is intended to R is 1-5 substituents independently selected from the cover modifications which are within the Spirit and Scope of group consisting of -OR. --O(CO)R, the invention, as defined by the appended claims. —O(CO)OR', —O(CH), OR, —O(CO)NR'R''. Therefore, we claim: -NR'R' , -NR(CO)R7, -NR(CO)OR, 1. A composition comprising: -NR(CO)NR7R, -NRSOR , -COOR, –CONR'R'', -COR , -SONR'R', S(O).R. (a) at least one Sterol absorption inhibitor or pharmaceu –O(CH-)-COOR. -O(CH) CONR'R'', tically acceptable Salt or Solvate thereof or prodrug of -(lower alkylene)COOR and -CH=CH-COOR; the at least one sterol absorption inhibitor or of the salt or Solvate thereof, and R, R and Rare independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl (b) at least one cardiovascular agent for treating vascular Substituted lower alkyl; and conditions which is different from the at least one sterol absorption inhibitor. R’ is lower alkyl, aryl or aryl-substituted lower alkyl. 2. The composition according to claim 1, wherein the at 3. The composition according to claim 2, wherein the least one sterol absorption inhibitor is represented by For sterol absorption inhibitor is represented by Formula (II) mula (I): below: US 2003/0069221A1 Apr. 10, 2003

R and R" are independently 1-3 substituents indepen dently selected from the group consisting of R hydro (IV) gen, p-lower alkyl, aryl, -NO, -CF and p-halo R19X)-A genO, W R, R and Rare independently selected from the group Arl-R-O S. consisting of hydrogen, lower alkyl, aryl and aryl Substituted lower alkyl; and R’ is lower alkyl, aryl or aryl-substituted lower alkyl. N 5. The composition according to claim 1, wherein the at O Ar2 least one sterol absorption inhibitor is represented by For mula (IV): or pharmaceutically acceptable Salts or Solvates thereof, or prodrugs of the compound of Formula (II) or of the salts or Solvates thereof. N 4. The composition according to claim 1, wherein the at R5-(R), least one sterol absorption inhibitor is represented by For mula (III): ck- an or isomers thereof, or pharmaceutically acceptable Salts or (III) Solvates of the compounds of Formula (IV) or of the isomers R1 thereof, or prodrugs of the compounds of Formula (IV) or of al-a-y--, Art the isomers, Salts or Solvates thereof, wherein, in Formula (IV) above: R2 A is selected from the group consisting of R-substituted N heterocycloalkyl, R-substituted heteroaryl, R-substi O Ar2 tuted benzofused heterocycloalkyl, and R-substituted benzofused heteroaryl; or isomers thereof, or pharmaceutically acceptable Salts or Solvates of the compounds of Formula (III) or of the isomers Ar" is aryl or R-substituted aryl; thereof, or prodrugs of the compounds of Formula (III) or of Ar is aryl or R'-substituted aryl; the isomers, Salts or Solvates thereof, wherein, in Formula Q is a bond or, with the 3-position ring carbon of the (III) above: aZetidinone, forms the Spiro group Ar' is R-substituted aryl; Ar is R-substituted aryl; Ar is R-substituted aryl; Y and Z are independently Selected from the group R11 consisting of -CH-, -CH(lower alkyl)- and 12 10 -C(dillower alkyl)-; A is selected from -O-, -S-, -S(O)- or -X- s Y- g-z- O R13 R11 -S(O)-; R10 R" is selected from the group consisting of -OR, –O(CO)R,-O(CO)OR and –O(CO)NR'R7; R is -X-(C) Y-S(O) - ; Selected from the group consisting of hydrogen, lower alkyl and aryl; or R' and R together are =O; R11

q is 1, 2 or 3; and p is 0, 1,2, 3 or 4, R" is selected from the group consisting of: R is 1-3 substituents independently selected from the group consisting of -OR. --O(CO)R , -(CH), , wherein q is 2-6, provided that when Q —O(CO)OR”, —O(CH), OR, —O(CO)NR'R', forms a Spiro ring, q can also be Zero or 1, -NRR7 , -NR(CO)R’, -NR(CO)OR, -(CH-)-G-(CH), , wherein G is -O-, -NR(CO)NR'R', -NR SO-lower alkyl, -C(O)-, phenylene, -NR-or-S(O)o, e is -NRSO-aryl, -CONR'R''. COR , -SO2NR 0-5 and r is 0-5, provided that the sum of e and r is R" , S(O)-2-alkyl, S(O)o 2-aryl, -O(CH)-o- 1-6; COOR,-O(CH) CONRR7, o-halogeno, m-ha -(C-C alkenylene)-; and logeno, O-lower alkyl, m-lower alkyl, -(lower alky -(CH-)-V-(CH) , wherein V is C-C, lene)-COOR, and cycloalkylene, f is 1-5 and g is 0-5, provided that the -CH=CH-COOR; Sum of f and g is 1-6, US 2003/0069221A1 Apr. 10, 2003 34

R is selected from: tuted benzyl, R''-substituted benzyloxy, R'-substi tuted aryloxy, halogeno, -NR'R'', NR'R' (C-C, alkylene)-, NR'R''C(O)(C-C alkylene)-, -NH C(O)R', OH, C-C alkoxy, —OC(O)R',-COR'', -CH-, -C(C-C alkyl)-, -CF-, hydroxy(C-C)alkyl, (C-C)alkoxy(C-C)alkyl, NO, -S(O) R', -SO2NR'R'' and —(C-C, alkylene)COOR'" ; when R is a substituent on a -C(OH)-, -C(CH-R') , -N-, or -'NO; heterocycloalkyl ring, R is as defined, or is =O or

R and R are independently selected from the group Ar2 consisting of -CH-, -CH(C-C alkyl)-, -C(di Arl n 1 (C) qn 1. S(O) (C-C) alkyl), -CH=CH- and -C(C-C, X1 Y. alkyl)=CH-; or R together with an adjacent R, or R1 R together with an adjacent R", form a -CH=CH N or a -CH=C(C-C alkyl)- group; O Ar3 a and b are independently 0, 1, 2 or 3, provided both are not zero; provided that when R is -CH=CH- or and, where R is a substituent on a substitutable ring -C(C-C alkyl)=CH-, a is 1; provided that when R7 nitrogen, it is hydrogen, (C-C)alkyl, aryl, (C- is -CH=CH- or -C(C-C alkyl)=CH-, b is 1; C.)alkoxy, aryloxy, (C-C)alkylcarbonyl, arylcarbo provided that when a is 2 or 3, the R's can be the same nyl, hydroxy, -(CH2)CONR'R'', or different; and provided that when b is 2 or 3, the R7's can be the same or different; and when Q is a bond, R' also can be selected from: O R18 N O J O y R18 (CH2)04 O a A. " - N J O M (CH2)04 O wherein J is -O-, -NH-, -NR'- or -CH2-, R and R are independently selected from the group where M is -O-, -S-, -S(O)- or S(O) consisting of 1-3 Substituents independently Selected from the group consisting of (C-C)alkyl, -OR'', X, Y and Z are independently Selected from the group –O(CO)R'', -O(CO)OR, –O(CH), OR'', consisting of -CH2-, -CH(C-C alkyl)- and -O(CO)NR'R'', -NR'R'', -NR'(CO)R, -C(di-(C-C) alkyl); -NR'(CO)OR, -NR'(CO)NR'R' , NR' R" and R'' are independently selected from the group SOR , -COOR'', -CONR'R' , -COR'', consisting of -OR'', -O(CO)R'', -O(CO)OR -SONR'R'', S(O) R' , -O(CH)-o- and –O(CO)NR'R'; COOR'', -O(CH) CONR'R'', -(C-C alky R'' and R' are independently selected from the group lene)-COOR', -CH=CH-COOR'', -CF, consisting of hydrogen, (C-C)alkyl and aryl; or R' -CN, -NO and halogen; and R'' together are =O, or R'' and R together are R is hydrogen, (C-C)alkyl, aryl (C-C)alkyl, –C(O)R or -COOR'; d is 1, 2 or 3; R” and R'' are independently 1-3 groups independently h is 0, 1, 2, 3 or 4, Selected from the group consisting of hydrogen, (C- S is 0 or 1; t is 0 or 1; m, n and p are independently 0-4, C.)alkyl, (C-C)alkoxy, -COOH, NO, -NR'R'', provided that at least one of S and t is 1, and the Sum OH and halogeno; of m, n, p, S and t is 1-6, provided that when p is 0 and R'' and R' are independently selected from the group t is 1, the Sum of m, S and n is 1-5, and provided that consisting of hydrogen, (C-C)alkyl, aryl and aryl when p is O and S is 1, the Sum of m, t and n is 1-5, Substituted (C-C)alkyl, v is 0 or 1; R' is (C-C)alkyl, aryl or R-substituted aryl; j and k are independently 1-5, provided that the Sum of j, k and v is 1-5; R" is hydrogen or (C-C)alkyl; and R’ is 1-3 substituents on the ring carbon atoms selected R' is hydrogen, hydroxy or (C-C)alkoxy. from the group consisting of hydrogen, (C-Co.)alkyl, 6. The composition according to claim 1, wherein the at (C-Clio)alkenyl, (C-Clio)alkynyl, (C-C)cycloalkyl, least one sterol absorption inhibitor is represented by For (C-C)cycloalkenyl, R'7-substituted aryl, R'7-substi mula (V): US 2003/0069221A1 Apr. 10, 2003 35

-O(CH)-oCONR'R'', -CF, -CN, -NO and halo gen. V 7. The composition according to claim 1, where the at least one sterol absorption inhibitor is represented by For 1. mula (VI): Ar 1 's Y S(O), Ar2 R1 N O Ya. B-CH=C- ; or isomers thereof, or pharmaceutically acceptable Salts or or isomers thereof, or pharmaceutically acceptable Salts or Solvates of the compounds of Formula (V) or of the isomers Solvates of the compounds of Formula (VI) or of the isomers thereof, or prodrugs of the compounds of Formula (V) or of thereof, or prodrugs of the compounds of Formula (VI) or of the isomers, Salts or Solvates thereof, wherein, in Formula the isomers, Salts or Solvates thereof, wherein: (V) above: R is Ar' is aryl, R'-substituted aryl or heteroaryl; Art is aryl or R-substituted aryl; Ar is aryl or R-substituted aryl; -CH-, -C(lower alkyl)- -CF-, X and Y are independently Selected from the group consisting of -CH-, -CH(lower alkyl)- and C(OH)-, -C(CHS)-, -C(CH-Rs)- -C(dillower alkyl)-; R is -OR, –O(CO)R, –O(CO)OR or -O(CO)NR'R'; R is hydrogen, lower alkyl or aryl; or R and R together are =O; -N-, or -NO; q is 0 or 1; r is 0, 1 or 2, m and n are independently 0, 1, 2, 3, 4 or 5; provided that R° and R are independently selected from the group the Sum of m, n and q is 1,2,3,4 or 5, consisting of: -CH-, -CH(lower alkyl)-, -C(di lower alkyl)-, -CH=CH- and -C(lower R" is 1-5 substituents independently selected from the alkyl)=CH-, or R together with an adjacent R, or group consisting of lower alkyl, -OR. --O(CO)R, R, together with an adjacent R, form a -CH=CH –O(CO)OR, –O(CH), OR , –O(CO)NR'R'', or a -CH=C(lower alkyl)- group; -NRR7, -NR(CO)R’, -NR(CO)OR, -NR(CO)NR7R, -NRSOR, -COOR , u and v are independently 0, 1, 2 or 3, provided both are –CONR'R'', -COR, -SONR'R', S(O).R. not zero; provided that when R is -CH=CH- or -O(CH-)-o-COOR, –O(CH) CONRR", -C(lower alkyl)=CH-, v is 1; provided that when -(lower alkylene)COOR and -CH=CH-COOR; Ris-CH=CH-or-C(lower alkyl)=CH-, u is 1; provided that when v is 2 or 3, the R's can be the same R is 1-5 substituents independently selected from the or different; and provided that when u is 2 or 3, the R's group consisting of -OR. --O(CO)R , can be the same or different; –O(CO)OR. --O(CH), OR , –O(CO)NR'R' , -NRR7, -NR(CO)R7, -NR(CO)OR, R is selected from B-(CH),C(O), wherein m is 0, 1, -NR(CO)NR7R, -NRSOR, -COOR , 2, 3, 4 or 5; –CONR'R'', -COR, -SONR'R', S(O).R. B-(CH2). , wherein q is 0, 1, 2, 3, 4, 5 or 6; –O(CH)-o-COOR , —O(CH2)CONR'R' , -CF, -CN, -NO, halogen, B-(CH), Z-(CH), wherein Z is -O-, -C(O)-, phenylene, -N(R)- or -S(O)o-, e -(lower alkylene)COOR and -CH=CH-COOR; is 0,1,2,3,4 or 5 and r is 0, 1, 2, 3, 4 or 5, provided R, R and Rare independently selected from the group that the Sum of e and r is 0, 1, 2, 3, 4, 5 or 6; consisting of hydrogen, lower alkyl, aryl and aryl B-(C-C alkenylene)-; Substituted lower alkyl; B-(C-C alkadienylene)-; R’ is lower alkyl, aryl or aryl-substituted lower alkyl; and B-(CH-)-Z-(C-C alkenylene)-, wherein Z is as R" is 1-5 substituents independently selected from the defined above, and whereint is 0, 1, 2 or 3, provided group consisting of lower alkyl, -O(CO)R, that the Sum of t and the number of carbon atoms in –O(CO)OR. --O(CH), OR, –O(CO)NR'R'', the alkenylene chain is 2, 3, 4, 5 or 6; -NRR7, -NR(CO)R’, -NR(CO)OR, B-(CH2)-V-(CH2), wherein V is C-C, -NR(CO)NR7R, -NRSOR, -COOR, cycloalkylene, f is 1, 2, 3, 4 or 5 and g is 0,1,2,3, 4 –CONR'R'', -COR, -SONR'R'', -S(O).R. or 5, provided that the sum of f and g is 1,2,3,4, 5 or -O(CH-)-COOR, 6; US 2003/0069221A1 Apr. 10, 2003 36

B-(CH)-V-(C-C alkenylene)- or B-(C-C alkenylene)-V-(CH), wherein V and t -CH-N R13 are as defined above, provided that the Sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6; for Substitution on ring carbon atoms, and the Substituents on the Substituted heteroaryl ring nitrogen atoms, when B-(CH), Z-(CH-)-V-(CH) , wherein Z present, are Selected from the group consisting of lower and V are as defined above and a, b and d are alkyl, lower alkoxy, -C(O)ORio, -C(O)Rio, OH, independently 0, 1, 2, 3, 4, 5 or 6, provided that the N(Rs)(R)-lower alkylene-, N(Rs)(R)-lower alkyleny Sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; or loxy-, -S(O)NH and 2-(trimethylsilyl)-ethoxym T-(CH), , wherein T is cycloalkyl of 3-6 carbon ethyl; atoms and S is 0, 1, 2, 3, 4, 5 or 6; or R7 is 1-3 groups independently Selected from the group R and R together form the group consisting of lower alkyl, lower alkoxy, -COOH, NO, -N(Rs)(R), OH, and halogeno; R15 Rs and Ro are independently Selected from H or lower / / x R16 alkyl, Ro is Selected from lower alkyl, phenyl, R7-phenyl, 7 benzyl or R-benzyl; B is Selected from indanyl, indenyl, naphthyl, tetrahy R is Selected from OH, lower alkyl, phenyl, benzyl, dronaphthyl, heteroaryl or W-substituted heteroaryl, R7-phenyl or R,-benzyl, wherein heteroaryl is Selected from the group consist R is Selected from H, OH, alkoxy, phenoxy, benzyloxy, ing of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, tri azinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, Oxazolyl and furanyl, and for nitrogen-containing het -N R13, eroaryls, the N-oxides thereof, or (VIIA) -N(Rs)(R), lower alkyl, phenyl or R'-phenyl; R" is selected from -O-, -CH-, -NH-, R A -N(lower alkyl)- or -NC(O)Ro: B-D Rs, R and R7 are independently Selected from the N group consisting of H and the groups defined for W.; or N O R4 Rs is hydrogen and R and R 7, together with adja cent carbon atoms to which they are attached, form a and dioxolanyl ring; (VIIB) B Ro is H., lower alkyl, phenyl or phenyl lower alkyl, and R A Rao and R are independently Selected from the group consisting of phenyl, W-Substituted phenyl, naphthyl, E W-substituted naphthyl, indanyl, indenyl, tetrahy N dronaphthyl, benzodioxolyl, heteroaryl, W-substituted N heteroaryl, benzofused heteroaryl, W-substituted ben O R4 Zofused heteroaryland cyclopropyl, wherein heteroaryl is as defined above. W is 1 to 3 substituents independently selected from the 8. The composition according to claim 1, wherein the at group consisting of lower alkyl, hydroxy lower alkyl, least one sterol absorption inhibitor is represented by For lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbo nylalkoxy, (lower alkoxyimino)-lower alkyl, lower mula (VIIA) or (VIIB): alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, -CF, -OCF, benzyl, R-benzyl, benzyloxy, R7-benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, NO, -N(Rs)(R), N(Rs)(R)-lower alkylene-, N(Rs)(R)- B is lower alkylenyloxy-, OH, halogeno, -CN, -Ns, -NHC(O)OR, -NHC(O)R, ROSNH-, (ROS)-N-, -S(O)NH, -S(O)-Rs, tert-bu tyldimethyl-silyloxymethyl, -C(O)R, -COOR, —CON(Rs)(R), -CH=CHC(O)R, -lower alky lene-C(O)R, RC(O)(lower alkylenyloxy)-, N(R)(R)C(O)(lower alkylenyloxy)- and US 2003/0069221A1 Apr. 10, 2003 37 or isomers thereof, or pharmaceutically acceptable Salts or R is Solvates of the compounds of Formula (VIIA) or Formula (VIIB) or of the isomers thereof, or prodrugs of the com pounds of Formula (VIIA) or Formula (VIIB) or of the isomers, Salts or Solvates thereof, wherein in Formula (VIIA) and Formula (VIIB): A is -CH=CH-, -C=C- or -(CH2)- wherein p is 0, 1 or 2; B is B is

(VIII) R-Na. A-O-G Arl-R1-O S.

N wherein n is 0, 1, 2 or 3; O YA2 Rs is lower alkyl, and R is OH, lower alkyl, phenyl, benzyl or substituted B' is phenyl wherein the Substituents are 1-3 groups inde pendently Selected from the group consisting of lower

alkyl, lower alkoxy, carboxy, NO, NH, OH, halo geno, lower alkylamino and dilower alkylamino. 9. The composition according to claim 1, wherein the at least one sterol absorption inhibitor represented by Formula (VIII):

R12-(R13):

d s or isomers thereof, or pharmaceutically acceptable Salts or Solvates of the compounds of Formula (VII) or of the isomers thereof, or prodrugs of the compounds of Formula (VIII) or of the isomers, salts or solvates thereof, wherein, in Formula (VIII) above, R’ is H or OG; O CHR G and G' are independently selected from the group consisting of

D is -(CH2),C(O)- or -(CH2), wherein m is 1, 2, 3 or 4 and q is 2, 3 or 4; E is Co to Coalkylor-C(O)-(Co to Co)-alkyl, wherein the alkyl is Straight or branched, Saturated or containing one or more double bonds; R is hydrogen, C-C alkyl, Straight or branched, Satu rated or containing one or more double bonds, or B-(CH), , wherein r is 0, 1, 2, or 3; R, R2, R, R, R2, and R are independently Selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, carboxy, NO, NH, OH, halogeno, lower alkylamino, dilower alkylamino, -NH C(O)ORs, R.O.SNH- and -S(O)NH2. US 2003/0069221A1 Apr. 10, 2003 38

Q is a bond or, with the 3-position ring carbon of the -continued aZetidinone, forms the Spiro group

RaO, a.

-CH- -C(C-Calkyl)- - -CF R"O, O O CHR -?(OH)- - -Ö(CH-R23)- - -N-- or

O CHR -*NO;

provided that when R26 is H or OH, G is not H; R, R and R are independently selected from the group consisting of H, -OH, halogeno, -NH2, azido, (C- and C.)alkoxy(C-C)-alkoxy or -W-R'; R" is selected from the group consisting of W is independently Selected from the group consisting of NH-C(O), O-C(O), O-C(O) -(CH), , wherein q is 2-6, provided that when Q N(R)-, NH-C(O)-N(R) and forms a Spiro ring, q can also be Zero or 1, -O-C(S)-N(R)-; -(CH-)-E-(CH) , wherein E is -O-, R° and R are independently selected from the group -C(O)-, phenylene, -NR’- or -S(O)--, e consisting of H., (C-C)alkyl, aryl and aryl(C- is 0-5 and r is 0-5, provided that the sum of e and r C.)alkyl, is 1-6, R. R", R, R", R* and R" are independently selected from the group consisting of H., (C-C)alkyl, aryl(C- -(C-C)alkenylene-, and C.)alkyl, -C(O)(C-C)alkyl and -C(O)aryl; -(CH2)-V-(CH2), wherein V is C-C, R" is selected from the group consisting of R-substi cycloalkylene, f is 1-5 and g is 0-5, provided that the tuted T. Sum of f and g is 1-6, R°-substituted-T (C-C)alkyl, R-substituted-(C- R’ is Cl)alkenyl, R°-substituted-(C-C)alkyl, R*-substituted-(C- C7)cycloalkyl and R15 R-substituted-(C-C)cycloalkyl(C-C)alkyl; -X-(C) Y-S(O) - R is selected from the group consisting of H and R16 (C-C)alkyl, T is Selected from the group consisting of phenyl, furyl, R" and R'' are independently selected from the group thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, consisting of -CH2-, -CH(C-C alkyl)-, -C(di iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, (C-C) alkyl), -CH=CH- and -C(C-C, imidazolyl and pyridyl; alkyl)=CH-, or R' together with an adjacent R', or R’ is independently selected from 1-3 substituents inde R° together with an adjacent R", form a pendently Selected from the group consisting of halo -CH=CH- or a -CH=C(C-C alkyl)- group; geno, (C-C)alkyl, -OH, phenoxy, -CF, -NO, (C-C)alkoxy, methylenedioxy, OXO, (C- a and b are independently 0, 1, 2 or 3, provided both are Cl)alkylsulfanyl, (C-C)alkylsulfinyl, (C- not Zero, C.)alkylsulfonyl, -N(CH), -C(O)-NH(C- C.)alkyl, -C(O)-N((C-C)alkyl), -C(O)-(C- provided that when R' is -CH=CH- or -C(C-C, C.)alkyl, -C(O)-(C-C)alkoxy and alkyl)=CH-, a is 1; pyrrolidinylcarbonyl; or R is a covalent bond and R", the nitrogen to which it is attached and R form provided that when R'' is -CH=CH- or -C(C-C, a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, alkyl)=CH-, b is 1; indolinyl or morpholinyl group, or a (C- C.)alkoxycarbonyl-Substituted pyrrolidinyl, piperidi provided that when a is 2 or 3, the R's can be the same nyl, N-methylpiperazinyl, indolinyl or morpholinyl or different; and grOup, provided that when b is 2 or 3, the R's can be the same Ar' is aryl or R'-substituted aryl; or different; Art is aryl or R' '-substituted aryl; and when Q is a bond, R also can be: US 2003/0069221A1 Apr. 10, 2003 39

R'' and Rao are independently selected from the group consisting of H., (C-C)alkyl, aryl and aryl-substituted R15 R17 R15 (C-C)alkyl, -M-Y-C-Zl -, -Xin (C)le Yi (Q)-Zl - or R’ is (C-C)alkyl, aryl or R-substituted aryl; R15 R’ is H., (C-C)alkyl, aryl (C-C)alkyl, -C(O)R' or -COOR'; -X-(C) Y-S(O) -: R° and R' are independently 1-3 groups independently l Selected from the group consisting of H., (C-C)alkyl, (C-C)alkoxy, -COOH, NO,-NR'R'', -OH and M is -O-, -S-, -S(O)- or -S(O) ; halogeno; and X, Y and Z are independently Selected from the group R’ is H, -OH or (C-C)alkoxy. consisting of -CH2-, -CH(C-C)alkyl- and 10. The composition according to claim 1, wherein the at least one sterol absorption inhibitor represented by Formula R'' and R'' are independently selected from the group (IX): consisting of 1-3 Substituents independently Selected from the group consisting of (C-C)alkyl, -OR, (IX) -O(CO)R’ , --O(CO)OR. --O(CH)1-50R . –O(CO)NR'R'', -NR'R'', -NR (CO)R’, -NR (CO)OR2, -NRI (CO)NR20R25, -NR 9 SOR', -COOR', -CONR 'R'', -COR', -SO2NR 'R', S(O) R', -O(CH)– COOR',-O(CH)1-10CONR'R'',-(C-C alky lene)-COOR', -CH=CH-COOR', -CF, -CN, -NO and halogen; R" and R7 are independently selected from the group consisting of -OR', -O(CO)R', -O(CO)OR or isomers thereof, or pharmaceutically acceptable Salts or and-O(CO)NR'R''; Solvates of the compounds of Formula (IX) or of the isomers R'' and R' are independently selected from the group thereof, or prodrugs of the compounds of Formula (IX) or of consisting of H., (C-C)alkyl and aryl; or R' and R' the isomers, Salts or Solvates thereof, wherein, in Formula together are =O, or R'' and R' together are =O; (IX) above, d is 1, 2 or 3; R is selected from the group consisting of: h is 0, 1, 2, 3 or 4, a) OH: S is 0 or 1; t is 0 or 1; m, n and p are independently 0-4, b) OCH: provided that at least one of S and t is 1, and the Sum of m, n, p, S and t is 1-6, c) fluorine and provided that when p is 0 and t is 1, the Sum of m, S and d) chlorine. n is 1-5; and provided that when p is 0 and t is 1, the Sum of m, t and n is 1-5, R" is selected from the group consisting of

v is 0 or 1; j and k are independently 1-5, provided that the Sum of j, k and v is 1-5; and when Q is a bond and R' is iiil IOR3, ... iiiiIOR, (IX) COR2 CHOR

OR7

iiiiOR, Ar' can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, OR4 pyrimidinyl or pyridazinyl; US 2003/0069221A1 Apr. 10, 2003 40

Q is -(CH2), , wherein q is 2-6, or, with the 3-position -continued ring carbon of the azetidinone, forms the Spiro group

R'O (a.

OR3 R12- (R), R"O, O O CHR

O CHR R1 is

-SOH, natural and unnatural amino acids. R, R and R are independently selected from the group -CH-, -C(C-C alkyl)-, -CF-, -C(OH)-, consisting of H, -OH, halogeno, -NH2, azido, (C- C.)alkoxy(C-C)-alkoxy and -W-R'; -C(CH-R2)-, -N-, O -*NO; W is independently Selected from the group consisting of R" and R'' are independently selected from the group consisting of -CH-, -CH(C-C alkyl)-, -C(di R and R are independently selected from the group (C-C) alkyl), -CH=CH- and -C(C-C, consisting of H., (C-C)alkyl, aryl and aryl(C- alkyl)=CH-, or R' together with an adjacent R', or C.)alkyl, R° together with an adjacent R", form a -CH=CH- or a -CH=C(C-C alkyl)- group; R. R. R. R. R* and R“ are independently selected a and b are independently 0, 1, 2 or 3, provided both are from the group consisting of H., (C-C)alkyl, aryl(C- not zero; provided that when R' is -CH=CH- or C.)alkyl, -C(O)(C-C)alkyl and -C(O)aryl; - C(C-C alkyl)=CH-, a is 1; provided that when R" is independently selected form the group consisting of R is --CH=CH- or -C(C-C alkyl)=CH-, b is R-substituted T, R-substituted-T (C-C)alkyl, 1; provided that when a is 2 or 3, the R's can be the R*-substituted-(C-C)alkenyl, R-substituted-(C- same or different; and provided that when b is 2 or 3, C.)alkyl, R-substituted-(C-C)cycloalkyl and R the R's can be the same or different; Substituted-(C-C7)cycloalkyl (C-C)alkyl, R'' and R' are independently selected from the group R is independently selected from the group consisting of consisting of 1-3 Substituents independently Selected H and (C-C)alkyl; from the group consisting of (C-C)alkyl, R', –O(CO)R', 9 –O(CO)OR°, -O(CH)1-50R', T is independently Selected from the group consisting of -O(CO)NR' R20, -NR, R20, -NRI (CO)R2, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, -NR(CO)OR°, -NR (CO)NR'R'', -NR thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, SOR2, -COOR, -CONR'R'', -COR', pyrazolyl, imidazolyl and pyridyl; - SONR'R'', -S(O)2R, -O(CH)-o- R is independently selected from 1-3 substituents inde COOR',-O(CH)1-10CONR'R'',-(C-C alky pendently Selected from the group consisting of H, lene)-COOR', -CH=CH-COOR', -CF, halogeno, (C-C)alkyl, -OH, phenoxy, -CF, -CN, -NO and halogen; -NO, (C-C)alkoxy, methylenedioxy, OXO, (C- R'' and R'' are independently selected from the group C.)alkylsulfanyl, (C-C)alkylsulfinyl, (C- consisting of H., (C-C)alkyl, aryl and aryl-substituted C.)alkylsulfonyl, -N(CH), -C(O)-NH(C- (C-C)alkyl, C.)alkyl, -C(O)-N((C-C)alkyl), -C(O)-(C- Cl)alkyl, -C(O)-(C-C)alkoxy and R’ is (C-C)alkyl, aryl or R-substituted aryl; pyrrolidinylcarbonyl; or R’ is a covalent bond and R’ is H., (C-C)alkyl, aryl (C-C)alkyl, -C(O)R' or R", the nitrogen to which it is attached and R form -COOR'; a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C- R° and R' are independently 1-3 groups independently Cl)alkoxycarbonyl-Substituted pyrrolidinyl, piperidi Selected from the group consisting of H., (C-C)alkyl, nyl, N-methylpiperazinyl, indolinyl or morpholinyl (C-C)alkoxy, -COOH, NO,-NR'R'', -OH and grOup, halogeno; and Ar' is aryl, R' '-substituted aryl; pyridyl, isoxazolyl, R’ is H, -OH or (C-C)alkoxy. furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiaz 11. The composition according to claim 1, wherein the at olyl, pyrazinyl, pyrimidinyl or pyridazinyl; least one cardiovascular agent for treating vascular condi tions is Selected from the group consisting of channel Art is aryl or R' '-substituted aryl; blockers, adrenergic blockers, adrenergic Stimulants, angio US 2003/0069221A1 Apr. 10, 2003 tensin-converting enzyme (ACE) inhibitors, antihyperten 23. The composition according to claim 22, wherein the Sive agents, angiotensin II receptor antagonists, anti-anginal antihypertensive agent is Selected from the group consisting agents, coronary vasodilators, diuretics and combinations of althiazide, benzthiazide, captopril, carvedilol, chlorothi thereof. azide Sodium, clonidine hydrochloride, cyclothiazide, dela 12. The composition according to claim 11, wherein the at pril hydrochloride, dilevalol hydrochloride, doxazosin least one cardiovascular agent is an adrenergic blocker. meSylate, foSinopril Sodium, guanfacine hydrochloride, 13. The composition according to claim 12, wherein the methyldopa, metoprolol Succinate, moexipril hydrochloride, adrenergic blocker is an O-receptor inhibitor Selected from monatepil maleate, pelanSerin hydrochloride, phenoxyben the group consisting of fenspiride hydrochloride, labetalol Zamine hydrochloride, prazosin hydrochloride, primidolol, hydrochloride, proroXan, alfuZoSin hydrochloride and com quinapril hydrochloride, quinaprilat, ramipril, teraZosin binations thereof. hydrochloride, candesartan, candesartan cileXetil, telmisar 14. The composition according to claim 12, wherein the tan, amlodipine besylate, amlodipine maleate, bevantolol adrenergic blocker is a p-receptor inhibitor Selected from the hydrochloride and combinations thereof. group consisting of acebutolol, acebutolol hydrochloride, 24. The composition according to claim 11, wherein the at alprenolol hydrochloride, atenolol, bunolol hydrochloride, least one cardiovascular agent is an angiotensin II receptor carteolol hydrochloride, celiprolol hydrochloride, cetamolol antagonist. hydrochloride, cicloprolol hydrochloride, deXpropranolol 25. The composition according to claim 24, wherein the hydrochloride, diacetolol hydrochloride, dilevalol hydro angiotensin 11 receptor antagonist is Selected from the group chloride, eSmolol hydrochloride, exaprolol hydrochloride, consisting of candesartan, irbesartan, losartan potassium, flestolol sulfate, labetalol hydrochloride, levobetaxolol candesartan cileXetil, telmisartan and combinations thereof. hydrochloride, levobunolol hydrochloride, metalol hydro 26. The composition according to claim 11, wherein the at chloride, metoprolol, metoprolol tartrate, nadolol, pamatolol least one cardiovascular agent is an anti-anginal agent. Sulfate, penbutolol Sulfate, practolol, propranolol hydrochlo 27. The composition according to claim 26, wherein the ride, Sotalol hydrochloride, timolol, timolol maleate, tipre anti-anginal agent is Selected from the group consisting of nolol hydrochloride, tolamolol, bisoprolol, bisoprolol fuma amlodipine besylate, amlodipine maleate, betaxolol hydro rate, nebivolol and combinations thereof. chloride, bevantolol hydrochloride, butoprozine hydrochlo 15. The composition according to claim 12, wherein the ride, carvedilol, cinepaZet maleate, metoprolol Succinate, adrenergic blocker is Selected from the group consisting of molsidomine, monatepil maleate, primidolol, ranolazine bretylium tosylate, meSylate, phentola hydrochoride, toSifen, Verapamil hydrochloride and combi mine meSylate, Solypertine tartrate, hydrochloride, nations thereof. carvedilol, labetalol hydrochloride and combinations 28. The composition according to claim 11, wherein the at thereof. least one cardiovascular agent is a coronary vasodilator. 16. The composition according to claim 11, wherein the at 29. The composition according to claim 28, wherein the least one cardiovascular agent is a calcium channel blocker. coronary vasodilator is Selected from the group consisting of 17. The composition according to claim 16, wherein the fostedil, azaclorZine hydrochloride, chromonar hydrochlo calcium channel blocker is Selected from the group consist ride, clonitrate, diltiazem hydrochloride, dipyridamole, dro ing of clentiazem maleate, amlodipine beSylate, isradipine, premilamine, erythrityl tetranitrate, isosorbide dinitrate, isoS nimodipine, felodipine, nilvadipine, nifedipine, teludipine orbide mononitrate, lidoflazine, mioflazine hydrochloride, hydrochloride, diltiazem hydrochloride, belfosdil, Verapamil mixidine, molsidomine, nicorandil, nifedipine, nisoldipine, hydrochloride, fostedil and combinations thereof. nitroglycerine, Oxprenolol hydrochloride, pentrinitrol, per 18. The composition according to claim 11, wherein the at heXiline maleate, prenylamine, propatyl nitrate, terodiline least one cardiovascular agent is an angiotensin-converting hydrochloride, tolamolol, Verapamil and combinations enzyme (ACE) inhibitor. thereof. 19. The composition according to claim 18, wherein the angiotensin-converting enzyme inhibitor is Selected from 30. The composition according to claim 11, wherein the at the group consisting of benazepril hydrochloride, benazep least one cardiovascular agent is a diuretic. rilat, captopril, delapril hydrochloride, fosinopril Sodium, 31. The composition according to claim 30, wherein the libenzapril, moexipril hydrochloride, pentopril, perindopril, diuretic is Selected from the group consisting of the combi quinapril hydrochloride, quinaprilat, ramipril, spirapril nation product of hydrochlorothiazide and Spironolactone hydrochloride, Spiraprilat, teprotide, enalapril maleate, lisi and the combination product of hydrochlorothiazide and nopril, Zofenopril calcium, perindopril erbumine and com triamterene. binations thereof. 32. The composition according to claim 1, wherein the at 20. The composition according to claim 11, wherein the at least one cardiovascular agent is labetalol hydrochloride. least one cardiovascular agent is an adrenergic Stimulant. 33. The composition according to claim 1, wherein the at 21. The composition according to claim 20, wherein the least one cardiovascular agent for treating vascular condi adrenergic Stimulant is Selected from the group consisting of tions is administered to a mammal in an amount ranging the combination product of chlorothiazide and methyldopa, from about 50 to about 3000 milligrams of cardiovascular the combination product of methyldopa hydrochlorothiazide agent per day. and methyldopa, clonidine hydrochloride, clonidine, the 34. The composition according to claim 1, wherein the at combination product of chlorthalidone and clonidine hydro least one Sterol absorption inhibitor is administered to a chloride, guanfacine hydrochloride, and combinations mammal in an amount ranging from about 0.1 to about 1000 thereof. milligrams of Sterol absorption inhibitor per day. 22. The composition according to claim 11, wherein the at 35. The composition according to claim 1, further com least one cardiovascular agent is an antihypertensive agent. prising at least one cholesterol biosynthesis inhibitor. US 2003/0069221A1 Apr. 10, 2003 42

36. The composition according to claim 35, wherein the 47. A method of treating or preventing vascular condi at least one cholesterol biosynthesis inhibitor comprises at tions, diabetes, obesity or lowering a concentration of a least one HMG CoA reductase inhibitor. Sterol in plasma of a mammal, comprising the Step of 37. The composition according to claim 36 wherein the at administering to a mammal in need of Such treatment: least one HMG CoA reductase inhibitor comprises lovasta tin, pravastatin, fluvastatin, Simvastatin, atorvastatin, roSu (a) an effective amount of at least one sterol absorption vastatin, rivastatin, cerivastatin and mixtures thereof. inhibitor or pharmaceutically acceptable Salt or Solvate 38. The composition according to claim 37, wherein the thereof or prodrug of the at least one Sterol absorption at least one HMG CoA reductase inhibitor comprises sim inhibitor or of the Salt or Solvate thereof, and vastatin. (b) an effective amount of at least one cardiovascular 39. The composition according to claim 1, further com agent which is different from the sterol absorption prising at least one bile acid Sequestrant. inhibitor. 40. The composition according to claim 1, further com prising at least one AcylCoA:Cholesterol O-acyltransferase 48. The method according to claim 47, wherein the Inhibitor. vascular condition is hyperlipidemia. 41. The composition according to claim 1, further com 49. A therapeutic combination comprising: prising probucol or a derivative thereof. (a) a first amount of at least one sterol absorption inhibitor 42. The composition according to claim 1, further com or pharmaceutically acceptable Salt or Solvate thereof prising at least one low-density lipoprotein receptor activa or prodrug of the at least one Sterol absorption inhibitor tor. 43. The composition according to claim 1, further com or of the Salt or Solvate thereof, and prising at least one Omega 3 fatty acid. (b) a second amount of at least one cardiovascular agent 44. The composition according to claim 1, further com different from the at least one sterol absorption inhibi prising at least one natural water Soluble fiber. tor. 45. The composition according to claim 1, further com prising at least one antioxidant or Vitamin. wherein the first amount and the Second amount together 46. A pharmaceutical composition for the treatment or comprise a therapeutically effective amount for the prevention of vascular conditions, obesity, diabetes or low treatment or prevention of a vascular condition, obesity, ering a concentration of a Sterol in plasma of a mammal, diabetes or lowering a concentration of a Sterol in comprising a therapeutically effective amount of the com plasma of a mammal. position of claim 1 and a pharmaceutically acceptable car C.