Combinations of sterol absorption inhibitor(s) with cardiovascular agent(s) for the treatment of vas

专利摘要:
The present invention provides a pharmaceutical composition comprising (a) one or more sterol absorption inhibitors, which may be useful for treating vascular disease, obesity, diabetes and lowering plasma concentrations of sterols; And (b) at least one cardiovascular agent that is different from the sterol absorption inhibitor.
公开号:KR20040025889A
申请号:KR10-2003-7009793
申请日:2002-01-25
公开日:2004-03-26
发明作者:코소글로우테디；레스루드야드죠셉；스트로니죤；벨트리엔리코피.；하우어윌리엄
申请人:쉐링 코포레이션；
IPC主号:

专利说明:

Combinations of sterol absorption inhibitor (s) with cardiovascular agent (s) for the treatment of vascular conditions}
[1] See related applications
[2] This application is filed on Sep. 21, 2001, US Provisional Patent Application No. 60 / 323,842, filed on Jan. 26, 2001, US Provisional Patent Application No. 60 / 264,396, filed Jan. 26, 2001 Priority is claimed from U.S. Provisional Patent Application No. 60 / 264,600 and U.S. Provisional Patent Application No. 60 / 264,275, filed January 26, 2001, each of which is incorporated herein by reference.
[4] Vascular disease is a term that broadly encompasses all disorders of the arteries and blood vessels, including the vena cava and aorta and the vena cava, and blood flow. The most frequent form of vascular disease is atherosclerosis, a disease associated with thickening and hardening of the arterial walls. Atherosclerosis of the large vessel is called atherosclerosis. Atherosclerosis is an underlying factor that predominates in vascular disorders such as coronary artery disease, aortic aneurysm, arterial disease of the lower limbs and cerebrovascular disease.
[5] One of the major risk factors for atherosclerosis is high serum cholesterol levels. Cholesterol total concentrations above 225-250 mg / dl are associated with a real (significant) rise in the incidence of vascular diseases, particularly coronary heart disease.
[6] Cholesteryl esters are a major component of atherosclerosis lesions, which are the main storage form of cholesterol in arterial wall cells. Formation of cholesteryl esters is also a step in the intestinal absorption of dietary cholesterol. Thus, inhibiting cholesteryl ester formation and lowering serum cholesterol concentrations can inhibit the progression of atherosclerotic lesion formation, reduce the accumulation of cholesteryl esters in the arterial walls and intestinal absorption of dietary cholesterol. Can be blocked.
[7] Regulation of systemic cholesterol homeostasis in mammals and animals is associated with regulation of dietary cholesterol and modulation of cholesterol biosynthesis, adjustment of bile acid biosynthesis and catabolism of cholesterol-containing plasma lipoproteins. Since the main organ involved in cholesterol biosynthesis and catabolism is the liver, for this reason, the liver is the most important determinant of cholesterol concentration in plasma. The liver is the site of synthesis and secretion of extremely low density lipoprotein (VLDL), which is metabolized to low density lipoprotein (LDL) during subsequent circulation. LDL is a lipoprotein that transports cholesterol preferentially in plasma, and its concentration is correlated with worsening of atherosclerosis. By any means, reducing intestinal cholesterol absorption results in less cholesterol being delivered to the liver. This leads to a decrease in hepatic lipoprotein (VLDL) production and usually an increase in hepatic clearance of plasma cholesterol as LDL. Thus, the overall effect of inhibiting intestinal cholesterol absorption is a decrease in plasma cholesterol concentrations.
[8] U.S. Pat.Nos. 5,767,115, 5,624,920, 5,668,990, 5,656,624 and 5,688,787, respectively, are hydroxy-substituted useful for inhibiting the formation of cholesterol-containing lesions in mammalian arterial walls and / or lowering cholesterol concentrations. Azetidinone compounds and substituted β-lactam compounds are described. U.S. Patents 5,846,966 and 5,661,145, respectively, disclose hydroxy-substituted azetidinone compounds or substituted β-lactam compounds in combination with HMG CoA reductase inhibitors to prevent or treat atherosclerosis and lower plasma cholesterol levels. This is described.
[9] PCT International Publication WO 00/38725 discloses ileal bile acid transport inhibitors in combination with fibric acid derivatives, nicotinic acid derivatives, microsomal triglyceride transfer protein inhibitors, cholesterol absorption antagonists, phytosterols, stanols, blood pressure lowering agents or bile acid sequestrants. Or cardiovascular therapeutic combinations including cholesteryl ester transport protein inhibitors are described.
[10] US Pat. No. 5,698,527 describes ergostanone derivatives substituted by disaccharides as cholesterol absorption inhibitors, used alone or in combination with certain other cholesterol lowering agents, useful in the treatment of hypercholesterolemia and related disorders. have.
[11] Other vascular diseases often coexist with cholesterol levels associated with atherosclerosis. These may include hypertension, angina and / or arrhythmia. For example, a number of epidemiologic studies have clearly revealed a rise in blood pressure as a risk factor for atherosclerosis, cardiovascular and cerebrovascular diseases in both men and women.
[12] For example, clinical attempts to lower blood pressure using cardiovascular agents, including calcium channel blockers, have been found to be useful in treating early atherosclerotic lesions. See, eg, Lichtien, R.R. et al .: Lancet, 335: 1109-1113 (1990) and Waters, D. et al. Circulatio 82: 1940-1953 (1990). PCT International Publication WO 99/11260 (Scott) describes a combination of an HMG CoA reductase inhibitor and a blood pressure lowering agent for treating atherosclerosis and other vascular disease risk symptoms. In addition, PCT International Publication WO 96/40255 (Egon et al) describes a combination therapy of blood pressure lowering agents, including eplelenone and angiotensin II antagonists, for the treatment of cardiovascular diseases.
[13] Despite recent improvements in the treatment of vascular diseases, in the art, improved compositions and therapies for atherosclerosis, other vascular diseases, and other diseases associated with vascular diseases such as hypertension, atherosclerosis, and hyperlipidemia This is constantly desired.
[14] Summary of the Invention
[15] In one aspect, the present invention provides a pharmaceutical composition comprising (a) at least one sterol absorption inhibitor, a pharmaceutically acceptable salt or solvate thereof, or a prodrug of the at least one sterol absorption inhibitor or a salt or solvate thereof; And (b) at least one cardiovascular agent different from the at least one sterol absorption inhibitor, for treating vascular disease, diabetes, obesity and / or lowering the concentration of sterol in the plasma of a mammal.
[16] (A) a first amount of at least one sterol absorption inhibitor, a pharmaceutically acceptable salt or solvate thereof, or a prodrug of the at least one sterol absorption inhibitor or a salt or solvate thereof; And (b) a second amount of at least one cardiovascular agent for treating a vascular disease in a mammal, different from said at least one sterol absorption inhibitor, wherein said first and second amounts are together A therapeutically effective amount is provided for treating or preventing a disease, diabetes, obesity, and / or lowering the concentration of sterols in the plasma of a mammal).
[17] A pharmaceutical for treating or preventing vascular disease, diabetes, obesity and / or lowering the concentration of sterols in mammalian plasma, comprising a therapeutically effective amount of the composition or therapeutic combination and a pharmaceutically acceptable carrier. Compositions are also provided.
[18] Also provided is a method for treating or preventing vascular disease, diabetes, obesity, or lowering the concentration of sterols in a mammal's plasma, comprising administering to a mammal in need thereof an effective amount of said composition or therapeutic combination. do.
[19] All numbers used in this specification and in the claims to express amounts of such components, reaction conditions, etc., except as indicated in the operating examples or otherwise indicated, are in all instances modified by the term "about". It should be recognized.
[3] The present invention relates to methods, compositions and therapeutic combinations comprising certain cardiovascular agents and inhibitors of sterol absorption for the treatment of atherosclerosis, coronary artery disease and other vascular diseases in mammals.
[20] In one aspect, the present invention provides a pharmaceutical composition comprising (a) at least one sterol absorption inhibitor, including, but not limited to, substituted azetidinone sterol absorption inhibitors or substituted β-lactam sterol absorption inhibitors, discussed in detail below. Acceptable salts or solvates, or prodrugs of the one or more sterol absorption inhibitors or salts or solvates thereof; And (b) at least one cardiovascular agent different from the sterol absorption inhibitor (component (a)), a pharmaceutical composition, a therapeutic combination, a kit, and a method of treatment using the same.
[21] Compositions and therapeutic combinations of the present invention include, but are not limited to, vascular diseases such as atherosclerosis, hyperlipidemia (hypercholesterolemia, hypertriglyceridemia, cytosterolemia) in mammals in need of treatment. It can be administered in a therapeutically effective amount to treat hypertension, vasculitis, angina pectoris, heart failure, stroke as well as diabetes, obesity and / or lower the level of sterol (s) in plasma. The compositions and therapeutics may be administered by any suitable means for bringing these compounds into contact with sites of action in the mammalian or human body, such as plasma, liver or small intestine.
[22] As used herein, “cardiovascular agents” that can be used to treat the vascular disease, obesity or diabetes of the invention and / or lower the level of sterols in the plasma are calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors. , Angiotensin-II receptor antagonists, diuretics, adrenergic blockers (including beta-adrenergic receptor blockers and alpha-adrenergic receptor blockers), adrenergic stimulants, coronary vasodilators, blood pressure lowering agents, diuretics, antianginal agents and Members of different classes, including combinations thereof. As used herein, “cardiovascular agent” does not include HMG CoA reductase inhibitors. Cardiovascular agents as defined above are chemically or structurally different from the sterol absorption inhibitors discussed below, for example, these agents contain one or more different atoms and are different from the sterol absorption inhibitors discussed below. Have one or more atoms in an atomic arrangement or in a different number.
[23] Useful “adrenergic blockers” include compounds that are β-receptor inhibitors and / or α-receptor inhibitors. Adrenergic agonists, β-receptor inhibitors, include a class of drugs that antagonize the cardiovascular effects of catecholamines in hypertension, angina, and heart failure. β-adrenergic receptor blockers include butolol hydrochloride (1 (2H) -naphthalenone, 5- [3- (1,1-dimethylethyl) amino] -2-hydroxypropoxy] -3,4- Dihydro-hydrochloride, CAS RN 31969-05-8, obtainable from Parke-Davis); Acebutolol (± N- [3-acetyl-4- [2-hydroxy-3-[(1-methylethyl) amino] propoxy] phenyl] -butanamide, or (±) -3'-acetyl- 4 '-[2-hydroxy-3- (isopropylamino) propoxy] butyranilide); Acebutolol hydrochloride such as N- [3-acetyl-4- [2-hydroxy-3- [1-methyl-ethyl) amino] propoxy] phenyl]-, monohydrochloride, (±-; 3 '-Acetyl-4'-[2-hydroxy-3- (isopropylamino) propoxy] butyranilide monohydrochloride such as SECTRAL® capsules available from Wyeth-Ayerst); Alprenolol hydrochloride (2-propanol, 1-[(1-methylethyl) amino] -3- [2- (2-propenyl) phenoxy]-, hydrochloride, CAS RN 13707-88-5 (see: Dutch Patent Application No. 6,605,692)); Atenolol (eg, benzeneacetamide 4- [2'-hydroxy-3 '-[(1-methylethyl) amino] propoxy]-, for example TENORMIN® intravenous injection available from AstraZeneca); Carteolol hydrochloride, such as 5- [3-[(1,1-dimethylethyl) amino] -2-hydroxypropoxy] -3,4-dihydro-2 (1H) -quinolinone monohydrochloride (Eg, Cartrol® Filmtab® tablets available from Abbott); Celiprolol hydrochloride (3- [3-acetyl-4- [3- (tert-butylamino) -2-hydroxypropoxy] phenyl] -1,1-diethylurea monohydrochloride, CAS RN 57470 -78-7, see US Pat. No. 4,034,009); Cetamolol hydrochloride (acetamide, 2- [2- [3-[(1,1-dimethylethyl) amino] -2-hydroxypropoxy] -phenoxy] -N-methyl-, monohydrochloride, CAS RN 77590-95-5, see US Pat. No. 4,059,622); Labetalol hydrochloride (eg 5- [1-hydroxy-2-[(1-methyl-3-phenylpropyl) amino] ethyl] salicylamide monohydrochloride, for example NORMODYNE® tablets available from Schering ); Esmolol hydrochloride ((±) -methyl p- [2-hydroxy-3- (isopropylamino) propoxy] hydrocinnamate hydrochloride such as BREVIBLOC® injection available from Baxter); Levobetaxolol hydrochloride such as (S) -1- [- [2- (cyclopropylmethoxy) ethyl] phenoxy] -3- (isopropylamino) -2-propanol hydrochloride, for example , BETAXON ™ ophthalmic suspensions available from Alcon; Levobunolol hydrochloride, such as (-)-5- [3- (tert-butylamino) -2-hydroxypropoxy] -3,4-dihydro-1 (2H) -naphthalenone hydrochloride For example BETAGAN® Liquifilm® with a C CAP® compliance cap available from Allergan; Nadolol, such as 1- (tert-butylamino) -3-[(5,6,7,8-tetrahydro-cis-6,7-dihydro-1-naphthyl) oxy] -2-propanol (Eg, Nadolol tablets available from Mylan); Fructolol (acetamide, N- [4- [2-hydroxy-3- [1-methylethyl) -amino] propoxy] phenyl]-, CAS RN 6673-35-4, see US Pat. No. 3,408,387 ); Propranolol hydrochloride (1- (isopropylamino) -3- (1-naphthyloxy) -2-propanol hydrochloride, CAS RN 318-98-9); Sotalol hydrochloride such as d, lN- [4- [1-hydroxy-2-[(1-methylethyl) amino] ethyl] -phenyl] methane-sulfonamide monohydrochloride, for example from Berlex Available BETAPACE AF® tablets); Timolol (2-propanol, 1-[(1,1-dimethylethyl) amino] -3-[[4-4 (4-morpholinyl) -1,2,5-thiadiazol-3-yl] Oxy-, hemihydrate, (S)-, CAS RN 91524-16-2); Timolol maleate ((S) -1-[(1,1-dimethylethyl) amino] -3-[[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl ] Oxy] -2-propanol (Z) -2-butenedioate (1: 1) salt, CAS RN 26921-17-5); Bisoprolol (2-propanol, 1- [4-[[2- (1-methylethoxy) ethoxy] -methyl] phenoxyl] -3-[(1-methylethyl) amino]-, (±) , CAS RN 66722-44-9); Bisoprolol fumarate, such as (±) -1- [4-[[2- (1-methylethoxy) ethoxy] methyl] phenoxy] -3-[(1-methylethyl) amino] -2 Propanol (E) -2-butenedioate (2: 1) (salts), for example ZEBETA ™ tablets available from Lederle Consumer; Nebivalol (2H-1-benzopyran-2-methanol, αα '-[iminobis (methylene)] bis [6-fluoro-3,4-dihydro-, CAS RN 99200-09-6, see US Patent 4,654,362); Cycloprolol hydrochloride such as 2-propanol, 1- [4- [2- (cyclopropylmethoxy) ethoxy] phenoxy] -3- [1-methylethyl) amino]-, hydrochloride, A.A.S. RN 63686-79-3); And dexpropranolol hydrochloride (2-propanol, 1- [1-methylethyl) -amino] -3- (1-naphthalenyloxy) -hydrochloride CAS RN 13071-11-9); Diacetolol hydrochloride (acetamide, N- [3-acetyl-4- [2-hydroxy-3-[(1-methyl-ethyl) amino] propoxy] [henyl]-, monohydrochloride CAS RN 69796 -04-9); Direvalol hydrochloride (benzamide, 2-hydroxy-5- [1-hydroxy-2- [1-methyl-3-phenylpropyl) amino] ethyl]-, monohydrochloride, CAS RN 75659-08-4 ); Exaprolol hydrochloride (2-propanol, 1- (2-cyclohexylphenoxy) -3-[(1-methylethyl) amino]-, hydrochloride CAS RN 59333-90-3); Plestolol sulfate (benzoic acid, 2-fluoro-, 3-[[2- [aminocarbonyl) amino] -1-dimethylethyl] amino] -2-hydroxypropyl ester, (±) -sulfate (1: 1) (salt), CAS RN 88844-73-9); Metalroll hydrochloride (methanesulfonamide, N- [4- [1-hydroxy-2- (methylamino) propyl] phenyl]-, monohydrochloride CAS RN 7701-65-7); Metoprolol (2-propanol, 1- [4- (2-methoxyethyl) phenoxy] -3- [1-methylethyl) amino]-, CAS RN 37350-58-6); Metoprolol tartrate (eg 2-propanol, 1- [4- (2-methoxyethyl) phenoxy] -3-[(1-methylethyl) amino]-, eg LOPRESSOR® available from Novartis) ; Parmatolol sulfate (carbamic acid, [2- [4- [2-hydroxy-3-[(1-methylethyl) amino] propoxy] phenyl] -ethyl]-, methyl ester, (±) sulfate (salt) (2: 1), CAS RN 59954-01-7); Penbutolol Sulfate (2-propanol, 1- (2-cyclopentylphenoxy) -3- [1,1-dimethylethyl) amino] 1, (S)-, sulfate (2: 1) (salt), CAS RN 38363-32-5); Fructolol (acetamide, N- [4- [2-hydroxy-3-[(1-methylethyl) amino] -propoxy] phenyl]-, CAS RN 6673-35-4); Thiprenolol hydrochloride (propanol, 1-[(1-methylethyl) amino] -3- [2- (methylthio) -phenoxy]-, hydrochloride, (±), CAS RN 39832-43-4) ; Tolamolol (benzamide, 4- [2-[[2-hydroxy-3- (2-methylphenoxy) -propyl] amino] ethoxy]-, CAS RN 38103-61-6) It is not limited.
[24] The adrenergic receptor, an α-receptor inhibitor, acts to block vasoconstriction induced by endogenous catecholamines. This lowers the peripheral resistance and lowers the average blood pressure. The extent of this effect depends on the degree of sympathetic tone at the time the antagonist is administered. Adrenergic agonists that are suitable as α-receptor inhibitors include penpyred hydrochloride (which may be prepared as described in US Pat. No. 3,399,192, incorporated herein by reference); Prooxane (CAS RN 33743-96-3); Alfuzosin hydrochloride (CAS RN 81403-68-1); And labetalol hydrochloride as mentioned above, or combinations thereof.
[25] Adrenergic agonists that exhibit α and β-receptor inhibitor activity that may be used in the present invention include brethlium tosylate (CAS RN 61-75-6); Dihydroergamine mesylate (e.g. ergotaman-3 ', 6', 18-trione, 9 ',-10-dihydro-12'-hydroxy-2'-methyl-5'-(phenylmethyl )-, (5 '(alpha))-, monomethanesulfonate such as DHE 45® injections available from Novartis); Carvedilol, such as (±) -1- (carbazol-4-yloxy) -3-[[2- (o-methoxyphenoxy) ethyl] amino] -2-propanol, for example SmithKline COREG® tablets available from Beecham); Labetalol (eg 5- [1-hydroxy-2-[(1-methyl-3-phenylpropyl) amino] ethyl] salicyamide monohydrochloride, for example NORMODYNE® tablets available from Schering); Brethlium tosylate (salt with benzenemethanealuminum, 2-bromo-N-ethyl-N, N-dimethyl-, 4-methylbenzenesulfonic acid (1: 1) CAS RN 61-75-6); Pentolamine mesylate (phenol, 3-[[(4,5-dihydro-1H-imidazol-2-yl) methyl] (4-methylphenyl) amino]-, monomethanesulfonate (salt) CAS RN 65- 28-1); Solifertin tartrate (5H-1,3-dioxolol [4,5-f] indole, 7- [2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl]-, ( 2R, 3R) -2,3-dihydroxybutanedioate (1: 1) CAS RN 5591-43-5); Zolertin Hydrochloride (Piperazine, 1-phenyl-4- [2- (1H-tetrazol-5-yl) ethyl]-, Monohydrochloride (8Cl, 9Cl) CAS RN 7241-94-3) However, it is not limited thereto.
[26] Vascular disease may be caused or exacerbated by hypertension. Hypertension is defined as a condition where the blood pressure is constantly high. In general, adults are classified as hypertension if their systolic blood pressure is consistently greater than 140 mm Hg or if their diastolic blood pressure is greater than 90 mm Hg. Long-term risk factors for cardiovascular mortality are directly correlated with sustained increases in blood pressure. Suitable examples of blood pressure lowering agents that can be used in the present invention include althiazide (2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[(2). -Propenylthio) methyl]-, 1,1-dioxide CAS RN 5588-16-9); Benzthiazide (2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3-[[(phenylmethyl) thio] methyl]-, 1,1-dioxide CAS RN 91-33 -8); Captopril (L-proline, 1-[(2S) -3-mercapto-2-methyl-1-oxopropyl] -CAS RN 62571-86-2); Carvedilol (2-propanol, 1- (9H-carbazol-4-yloxy) -3-[[2- (2-methoxyphenoxy) ethyl] amino] -CAS RN 72956-09-3), Chlorothiazide (sodium 2-propanol, 1- (9H-carbazol-4-yloxy) -3-[[2- (2-methoxyphenoxy) ethyl] amino] -CAS RN 72956-09-3) ; Clonidine hydrochloride (1H-imidazol-2-amine, N- (2,6-dichlorophenyl) -4,5-dihydro-, monohydrochloride CAS RN 4205-91-8); Cyclothiazide (2H-1,2,4-benzothiadiazine-7-sulfonamide-, 3-bicyclo [2.2.1] hept-5-en-2-yl-6-chloro-3,4- Dihydro-, 1,1-dioxide, CAS RN 2259-96-3); Delapril hydrochloride (2H-1,2,4-benzothiadiazine-7-sulfonamide, 3-bicyclo [2.2.1] hept-5-en-2-yl-6-chloro-3,4- Dihydro-, 1,1-dioxide, CAS RN 2259-96-3); Dilevalol hydrochloride (2H-1,2,4-benzothiadiazine-7-sulfonamide, 3-bicyclo [2.2.1] hept-5-en-2-yl-6-chloro-3,4- Dihydro-, 1,1-dioxide, CAS RN 2259-96-3); Delapril hydrochloride (glycine, N-[(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl-N- (2,3-dihydro-1H-indene-2- Il)-, monohydrochloride CAS RN 83435-67-0); Doxazosin mesylate (piperazine, 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4-[(2,3-dihydro-1,4-benzodioxin-2-yl ) Carbonyl]-, monomethanesulfonate CAS RN 77883-43-3); Posinopril sodium (L-proline, 4-cyclohexyl-1-[[(R)-[(1S) -2-methyl-1- (1-oxopropoxy) propoxy); Moexipril hydrochloride (3-isoquinolinecarboxylic acid, 1-[(2S) -2 [[(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] amino] -1-oxopropyl] -1 , 2,3,4-tetrahydro-6,7-dimethoxy-, monohydrochloride, (3S) -CAS RN 82586-52-5); Monatefil Maleate (1-piperazinbutanamide, N- (6,11-dihydrodibenzo (b, e) thipin-11-yl) -4- (4-fluorophenyl)-, (±) -, (Z) -2-butenedioate (1: 1) (±) -N- (6,11-dihydrodibenzo (b, e) thipin-11-yl) -4- (p-fluoro Rophenyl) -1-piperazinbutyramide maleate (1: 1) CAS RN 132046-06-1); Compound with metoprolol succinate (butanedioic acid, 1- [4- (2-methoxyethyl) phenoxy] -3-[(1-methylethyl) amino] -2-propanol (1: 2) CAS RN 98418 -47-4); Guanfacin hydrochloride (benzeneacetamide, N- (aminoiminomethyl) -2,6-dihydro-, monohydrochloride CAS RN 29110-48-3); Methyldopa (L-tyrosine, 3-hydroxy-alpha-methyl-CAS RN 555-30-6); Quinaprylat (3-isoquinolinecarboxylic acid, 2-[(2S) -2-[[(1S) -1-carboxy-3-phenylpropyl] amino] -1-oxopropyl] -1,2,3,4 -Tetrahydro-, (3S) -CAS RN 82768-85-2); Quinapryl hydrochloride (3-isoquinolinecarboxylic acid, 2-[(2S) -2-[[(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] amino] -1-oxopropyl] -1 , 2,3,4-tetrahydro-, monohydrochloride, (3S) -CAS RN 82586-55-8); Primidolol (2,4 (1H, 3H) -pyrimidinedione, 1- [2-[[2-hydroxy-3- (2-methylphenoxy) propyl] amino] ethyl] -5-methyl-CAS RN 67227-55-8); Prazosin hydrochloride (piperazin, 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furanylcarbonyl)-, monohydrochloride CAS RN 19237-84- 4); Pelanserine hydrochloride (2,4 (1H, 3H) -quinazolindione, 3- [3- (4-phenyl-1-piperazinyl) propyl]-, monohydrochloride CAS RN 42877-18-9); Phenoxybenzamine hydrochloride (benzenemethanamine, N- (2-chloroethyl) -N- (1-methyl-2-phenoxyethyl)-, hydrochloride CAS RN 63-92-3); Candesartan cilexetil (1H-benzimidazole-7-carboxylic acid, 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) [1,1'-biphenyl] -4- Il] methyl]-, 1-[[(cyclohexyloxy) carbonyl] oxy] ethyl ester CAS RN 145040-37-5); Telmisartan (1,1'-biphenyl] -2-carboxylic acid, 4 '-[(1,4'-dimethyl-2'-propyl [2,6'-bi-1H-benzimidazole] -1' -Yl) methyl]-CAS RN 144701-48-4); Candesartan (1H-benzimidazole-7-carboxylic acid, 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) [1,1'-biphenyl] -4-yl] Methyl] -CAS RN 139481-59-7); Amlodipine besylate (3,5-pyridinedicarboxylic acid, 2-[(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-, 3-ethyl 5 Methyl ester, monobenzenesulfonate CAS RN 111470-99-6); Amlodipine maleate (3,5-pyridinedicarboxylic acid, 2-[(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-, 3-ethyl 5 Methyl ester, (2Z) -2-butenedioate (1: 1) CAS RN 88150-47-4); Terrazosin Hydrochloride (Piperazine, 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4-[(tetrahydro-2-furanyl) carbonyl]-, monohydrochloride CAS RN 63074-08-8); Bevantolol hydrochloride (2-propanol, 1-[[2- (3,4-dimethoxyphenyl) ethyl] amino] -3- (3-methylphenoxy)-, hydrochloride CAS RN 42864-78-8) ; Ramipril (cyclopenta [b] pyrrole-2-carboxylic acid, 1-[(2S) -2-[[(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] amino] -1-oxopropyl] Octahydro-, (2S, 3aS, 6aS) -CAS RN 87333-19-5).
[27] Angiotensin system inhibitors are agents that interfere with the function, synthesis or catabolism of angiotensin II. These agents that can be used in the present invention include the synthesis of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists, angiotensin II receptor antagonists, agents that activate catabolic activity of angiotensin II, and ultimately angiotensin I from which angiotensin II is induced. Agents to prevent are included, but are not limited thereto. The Lenin-Angiotensin system is involved in hemodynamics and regulation of water and electrolyte balance. Factors that lower blood dose, renal profusion, or Na ⁺ concentration in plasma tend to activate the system, while factors that increase these parameters tend to inhibit their function. Angiotensin I and Angiotensin II are synthesized by the enzymatic renin-angiotensin pathway. This synthetic process is initiated when the enzyme renin acts on angiotensinogen, a pseudoglobulin (pseudoglobulin) in plasma, to produce secapeptide angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE). The latter is an active booster substance that has a close effect as a causative agent of several forms of hypertension in various mammalian species.
[28] Angiotensin II receptor antagonists are compounds that interfere with the activity of angiotensin II by binding to and interfering with its activity. Well known angiotensin II receptor antagonists that can be used in the present invention include peptide compounds and non-peptide compounds. Non-limiting examples of angiotensin II receptor antagonists include: candesartan cilexetil (1H-benzimidazole-7-carboxylic acid, 2-ethoxy-1-[[2 '-(1H-tetrazol-5) -Yl) [1,1'-biphenyl] -4-yl] methyl-, 1-[[(cyclohexyloxy) carbonyl] oxy] ethyl ester) CAS RN 145040-37-5); Telmisartan ([1,1'-biphenyl] -2-carboxylic acid, 4 '-[(1,4'-dimethyl-2'-propyl [2,6'-bi-1H-benzimidazole] -1 '-Yl) methyl]-CAS RN 144701-48-4); Candesartan (1H-benzimidazole-7-carboxylic acid, 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) [1,1'-biphenyl] -4-yl] Methyl-CAS RN 139481-59-7); Losartan potassium (1H-imidazol-5-methanol, 2-butyl-4-chloro-1-[[2 '-(1H-tetrazol-5-yl) [1,1'-biphenyl] -4- Il] methyl]-, monopotassium irbesartan 1,3-diazaspiro [4.4] non-1-en-4-one, 2-butyl-3-[[2 '-(1H-tetrazol-5- Yl) [1,1'-biphenyl] -4-yl] methyl] -CAS RN 138402-11-6).
[29] "Angiotensin-converting enzyme (ACE)" is an enzyme that catalyzes the conversion of angiotensin I to angiotensin II. ACE inhibitors that can be used in the present invention include antibodies, amino acids and derivatives thereof, and peptides (D and Tripeptides). ACE inhibitors have been used medically to treat hypertension, congestive heart failure, myocardial infarction and kidney disease. Suitable ACE inhibitors include benazepril hydrochloride, such as 3-[[1- (ethoxycarbonyl) -3-phenyl- (1S) -propyl] amino] -2,3,4,5-tetrahydro-2 Oxo-1H-1- (3S) -benzazepine-1-acetic acid monohydrochloride, for example LOTREL® capsules available from Novartis); Captopril (eg 1-[(2S) -3-mercapto-2-methylpropionyl] -L-proline, eg CAPTOPRIL tablet available from Mylan); Posinopril (e.g., L-proline, 4-cyclohexyl-1-[[[2-methyl-1- (1-oxopropoxy) propoxy] (4-phenylbutyl) phosphinyl] acetyl]-, sodium Salts, trans-, eg, MONOPRIL® tablets available from Bristol-Myers Squibb); Moexipril hydrochloride, such as [3S- [2 [R * (R *)], 3R *]]-2- [2-[[1- (ethoxycarbonyl) -3-phenylpropyl] amino] -1-oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid, monohydrochloride such as UNIRETIC® tablets available from Schwarz); Perindopril erbumin, such as (2S, 3aS, 7aS) -1-[(S) -N-[(S) -1-carboxybutyl] alanyl] hexahydro-2-indolincarboxylic acid, 1-ethyl Esters, compounds with tert-butylamine (1: 1), for example ACEON® tablets available from Solvay); Quinapril (e.g. [3S- [2 [R * (R *)], 3R *]]-2- [2-[[1- (ethoxycarbonyl) -3-phenylpropyl] amino] -1- Oxopropyl] -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, monohydrochloride such as ACCURETIC® tablets available from Parke-Davis); Ramipril (eg, 2-aza-bicyclo [3.3.0] -octane-3-carboxylic acid derivatives such as the ALTACE® capsules available from Monarch); Enalapril maleate (e.g. (S) -1- [N- [1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl] -L-proline, (Z) -2-butene Dioate salt (1: 1), for example VASOTEC® tablets available from Merck); Ricinopril (eg, (S) -1- [N-2- (1-carboxy-3-phenylpropyl) -L-lysyl] -L-proline dihydrate, eg PRINZIDE® tablets available from Merck) ); Delapril (which may be prepared as described in US Patent No. 4,385,051); And spirapril (which may be prepared as described in US Patent No. 4,470,972); Benazeprillat (1H-1-benzazepine-1-acetic acid, 3-[[(1S) -1-carboxy-3-phenylpropyl] amino] -2,3,4,5-tetrahydro-2- Oxo-, (3S) -CAS RN 86541-78-8); Delapril hydrochloride (glycine, N-[(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl-N- (2,3-dihydro-1H-indene-2- Il)-, monohydrochloride CAS RN 83435-67-0); Posinopril sodium (L-proline, 4-cyclohexyl-1-[[(R)-[(1S) -2-methyl-1- (1-oxopropoxy) propoxy] (4-phenylbutyl) force Finyl] acetyl]-, sodium salt, (4S) -CAS RN88889-14-9); Ribenzapril (1H-1-benzazepine-1-acetic acid, 3-[[(1S) -5-amino-1-carboxypentyl] amino] -2,3,4,5-tetrahydro-2-oxo -, (3S) -CAS RN 109214-55-3); Pentopril (1H-indole-1-pentanoic acid, 2-carboxy-2,3-dihydro-alpha, gamma-dimethyl-delta-oxo-, alpha-ethyl ester, (alpha R, gamma R, 2S) -CAS RN 82924-03-6); Perindopril (1H-indole-2-carboxylic acid, 1-[(2S) -2-[[(1S) -1- (ethoxycarbonyl) butyl] amino] -1-oxopropyl] octahydro-, ( 2S, 3aS, 7aS) -CAS RN 82834-16-0); Quinapryl hydrochloride (3-isoquinolinecarboxylic acid, 2-[(2S) -2-[[(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] amino] -1-oxopropyl] -1 , 2,3,4-tetrahydro-, monohydrochloride, (3S) -CAS RN 82586-55-8); Quinaprylat (3-isoquinolinecarboxylic acid, 2-[(2S) -2-[[(1S) -1-carboxy-3-phenylpropyl] amino] -1-oxopropyl] -1,2,3,4 -Tetrahydro-, (3S) -CAS RN 82768-85-2); Spirapril hydrochloride (1,4-dithia-7-azaspiro [4.4] nonane-8-carboxylic acid, 7-[(2S) -2-[[(1S) -1- (ethoxycarbonyl) -3 -Phenylpropyl] amino] -1-oxopropyl]-, monohydrochloride, (8S) -CAS RN 94841-17-5); Spirapril (1,4-dithia-7-azaspiro [4.4] nonane-8-carboxylic acid, 7-[(2S) -2-[[(1S) -1-carboxy-3-phenylpropyl] amino] -1-oxopropyl]-, (8S) -CAS RN 83602-05-5); Teprotide (bradykinin agonist BPP9a CAS RN 35115-60-7); Ricinopril (L-proline, N2-[(1S) -1-carboxy-3-phenylpropyl] -L-lysyl-CAS RN 76547-98-3); Zofenopril (L-proline, 1-[(2S) -3-benzoylthio) -2-methyl-1-oxopropyl] -4- (phenylthio)-, calcium salt (2: 1), (4S) CAS RN 81938-43-4), but is not limited thereto.
[30] "Calcium channel blockers" are chemically diverse classes of compounds that have important therapeutic value in controlling various diseases, including some cardiovascular disorders such as hypertension, angina, and heart failure. Fleckenstein, Cir. Res. V. 52 (suppl. 1), p. 13-16 (1983); Fleckenstein, Experimental Facts and Therapeutic Prospects, John Wiley, New York (1983); McCall, D., Curr. Pract Cardiol., V. 10, p. 1-11 (1985); Each of which is incorporated herein by reference]. Calcium channel blockers are a heterogeneous group of drugs that modulate cellular calcium channels to prevent or slow the influx of calcium into cells [Remington, The Science and Practice of Pharmacy, Nineteenth Edition, Mack Publishing Company, Eaton, PA, p. 963 (1995); Incorporated herein by reference. Calcium channel blockers useful in the present invention include the besylate salt of amlodipine, such as 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro -6-methyl-3,5-pyridinedicarboxylate benzenesulfonate, for example NORVASC® available from Pfizer); Clentiazem maleate (1,5-benzothiazepin-4 (5H) -one, 3- (acetyloxy) -8-chloro-5- [2- (dimethylamino) ethyl] -2,3-dihydro -2- (4-methoxyphenyl)-(2S-cis)-, (Z) -2-butenedioate (1: 1), see US Pat. No. 4,567,195); Isradin (3,5-pyridinedicarboxylic acid, 4- (4-benzofurazanyl) -1,4-dihydro-2,6-dimethyl-, methyl 1-methylethyl ester, (±) -4 (4 -Benzofurazanyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate, see US Pat. No. 4,466,972); Nimodipine such as isopropyl (2-methoxyethyl) -1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridine-dicarboxylate, for example , NIMOTOP® available from Bayer); Pelodipine (eg, ethyl methyl 4- (2,3-dichlorophenyl) -1,4-dihydro-2.6-dimethyl-3,5-pyridinedicarboxylate, for example PLENDIL® extensions available from AstraZeneca LP) -Release tablets); Nilbadipine (3,5-pyridinedicarboxylic acid, 2-cyano-1,4-dihydro-6-methyl-4- (3-nitrophenyl)-, 3-methyl 5- (1-methylethyl) ester , US Pat. No. 3,799,934); Nifedipine (eg 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl)-, dimethyl ester such as PROCARDIA XL® extension available from Pfizer -Release tablets); Diltiazem hydrochloride such as 1,5-benzothiazepin-4 (5H) -one, 3- (acetyloxy) -5 [2- (dimethylamino) ethyl] -2,3-dihydro-2 ( 4-methoxyphenyl)-, monohydrochloride, (+)-cis, for example TIZAC® capsules available from Forest); Verapamil hydrochloride such as benzeneacetonitrile, (alpha)-[[3-[[2- (3,4-dimethoxyphenyl) ethyl] methylamino] propyl] -3,4-dimethoxy- (alpha) -(1-methylethyl) hydrochloride such as ISOPTIN® SR tablets available from Knoll Labs); Tellurine hydrochloride (3,5-pyridinedicarboxylic acid, 2-[(dimethylamino) methyl] -4- [2-[(1E) -3- (1,1-dimethylethoxy) -3-oxo- 1-propenyl] phenyl] -1,4-dihydro-6-methyl-, diethyl ester, mono hydrochloride, CAS RN 108700-03-4); Velfosdil (phosphonic acid, [2- (2-phenoxyethyl) -1,3-propanediyl] bis-, tetrabutyl ester CAS RN 103486-79-9); Postedil (phosphonic acid, [[4- (2-benzothiazolyl) phenyl] methyl-, diethyl ester CAS RN 75889-62-2)), including but not limited to.
[31] The cardiovascular preparations of the present invention which also serve as "antianginal agents" are useful in the present invention. Angina includes symptoms that occur when myocardial oxygen availability is insufficient to meet myocardial oxygen demand. Non-limiting examples of these agents include: Ranolazine hydrochloride (1-piperazinacetamide, N- (2,6-dimethylphenyl) -4- [2-hydroxy-3- (2- Methoxyphenoxy) propyl]-, dihydrochloride CAS RN 95635-56-6); Betaxolol hydrochloride (2-propanol, 1- [4- [2- (cyclopropylmethoxy) ethyl] phenoxy] -3-[(1-methylethyl) amino]-, hydrochloride CAS RN 63659-19 -8); Butoprozin hydrochloride (methanone, [4- [3 (dibutylamino) propoxy] phenyl] (2-ethyl-3-indolizinyl)-, monohydrochloride CAS RN 62134-34-3); Cinepazate maleate (1-piperazinacetic acid, 4- [1-oxo-3- (3,4,5-trimethoxyphenyl) -2-propenyl]-, ethyl ester, (2Z) -2- Butenedioate (1: 1) CAS RN 50679-07-7); Tocifen (benzenesulfonamide, 4-methyl-N-[[[(1S) -1-methyl-2-phenylethyl] amino] carbonyl] -CASRN 32295-18-4); Verapamil hydrochloride (benzeneacetonitrile, alpha- [3-[[2- (3,4-dimethoxyphenyl) ethyl] methylamino] propyl] -3,4-dimethoxy-alpha- (1-methylethyl)- , Monohydrochloride CAS RN 152-11-4); Molardomin (1,2,3-oxadiazolium, 5-[(ethoxycarbonyl) amino] -3- (4-morpholinyl)-, internal salt CAS RN 25717-80-0); Ranolazine hydrochloride (1-piperazinacetamide, N- (2,6-dimethylphenyl) -4- [2-hydroxy-3- (2-methoxyphenoxy) propyl]-, dihydrochloride CAS RN 95635-56-6); Tocifen (benzenesulfonamide, 4-methyl-N-[[[(1S) -1-methyl-2-phenylethyl] amino] carbonyl]-CAS RN 32295-18-4).
[32] "Coronary vasodilators" can act to lower the angina system by increasing oxygen supply to the heart. Coronary vasodilators useful in the present invention include diltiazem hydrochloride, such as 1,5-benzothiazepin-4 (5H) -one, 3- (acetyloxy) -5 [2- (dimethylamino) ethyl] -2 , 3-dihydro-2 (4-methoxyphenyl)-, monohydrochloride, (+)-cis, for example TIZAC® capsules available from Forest); Isosorbide dinitrate (eg, 1,4: 3,6- dianhydro-D-glucinitol 2,5-dinithrate, eg, ISORDIL® TITRADOSE® tablets available from Wyeth-Ayerst); Sorbide mononitrate (eg, 1,4: 3,6-dianhydro-D-glucitol, 5-nitrate, organic nitrates such as Isomo® tablets available from Wyeth-Ayerst); Nitroglycerin (eg 2,3-propanetriol trinitrate, such as NITROSTAT® tablets available from Parke-Davis); Verapamil hydrochloride (benzeneacetonitrile, (±)-(alpha)-[3-[[2- (3,4-dimethoxyphenyl) ethyl] methylamino] propyl] -3,4-dimethoxy- (alpha) -(1-methylethyl) hydrochloride such as COVERA HS® extended-release tablets available from Searle); Chromonear (which may be prepared as described in US Patent No. 3,282,938); Clonitate (Annalen 1870 155); Droprenylamine (which may be prepared as described in German Patent No. 2,521,113); Lidofrazine (which may be prepared as described in US Pat. No. 3,267,104); Prenylamine (which may be prepared as described in US Patent No. 3,152, 173); Propatyl nitrate (which may be prepared as described in French Patent No. 1,103,113); Myopazine hydrochloride (1-piperazinacetamide, 3- (aminocarbonyl) -4- [4,4-bis (4-fluorophenyl) butyl] -N- (2,6-dichlorophenyl)- , Dihydrochloride CAS RN 83898-67-3); Mixidine (benzeneethanamine, 3,4-dihydroxy-N- (1-methyl-2-pyrrolidinylidene) -pyrrolidine, 2-[(3,4-dimethoxyphenethyl) imino ] -1-methyl-1-methyl-2-[(3,4-dimethoxyphenethyl) imino] pyrrolidine CAS RN 27737-38-8); Molardomin (1,2,3-oxadiazolium, 5-[(ethoxycarbonyl) amino] -3- (4-morpholinyl)-, internal salt CAS RN 25717-80-0); Isosorbide mononitrate (D-glucitol, 1,4: 3,6-dianhydro-, 5-nitrate CAS RN 16051-77-7); Erytrityl tetranitrate (1,2,3,4-butanetetrol, tetranitrate, (2R, 3S) -rel-CAS RN 7297-25-8); Clonitrate (1,2-propanediol, 3-chloro-, dinitrate (7Cl, 8Cl, 9Cl) CAS RN 2612-33-1); Dipyridamole ethanol (2,2 ', 2 ", 2'"-[(4,8-di-1-piperidinylpyrimido [5,4-d] pyrimidine-2,6-diyl) dinitrile Rho] tetrakis-CAS RN 58-32-2); Nicorandil (CAS RN 65141-46-03-); Pyridinecarboxamide (N- [2- (nitrooxy) ethyl]-; nisoldipine (3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) Methyl 2-methylpropyl ester CAS RN 63675-72-9), nifedipine (3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl)-, Dimethyl ester CAS RN 21829-25-4); perhexylmaleate (piperidine, 2- (2,2-dicyclohexylethyl)-, (2Z) -2-butenedioate (1: 1) CAS RN 6724-53-4); oxprenolol hydrochloride (2-propanol, 1-[(1-methylethyl) amino] -3- [2- (2-propenyloxy) phenoxy]-, hydrochloride CAS RN 6452-73-9); pentrinitrol (1,3-propanediol, 2,2-bis [(nitrooxy) methyl]-, mononitrate (ester) CAS RN 1607-17-6); verapamil (benzene Acetonitrile, alpha- [3-[[2- (3,4-dimethoxyphenyl) ethyl] methylamino] propyl] -3,4-dimethoxy-alpha- (1-methylethyl) -CAS RN 52-53 -9), but This is not restrictive.
[33] The term "diuretic" includes compounds that increase the release of solutes (primarily NaCl) and water. In general, the main purpose of diuretic therapy is to reduce the extracellular fluid dose to lower blood pressure or to remove excess interstitial fluid (edema) from the body. Non-limiting examples of diuretics that can be used within the scope of the present invention include althiazide (which may be prepared as described in British Patent No. 902,658); Benzthiazide (which may be prepared as described in US Patent No. 3,108,097); Butiazide (which may be prepared as described in British Patent No. 861,367); Chlorothiazide, which may be prepared as described in US Patent No. 2,809,194; Spironolactone (CAS No. 52-01-7); And triamterene (CAS No. 396-01-0).
[34] "Adrenergic agonist stimulants" useful as cardiovascular agents in the present invention include guanfacin hydrochloride (e.g., N-amidino-2- (2,6-dichlorophenyl) acetamide hydrochloride, such as available from Robins TENEX® tablets); Methyldopa-hydrochlorothiane in combination with hydrochlorothiazide (eg 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide) Zide (eg, levo-3- (3,4-dihydroxyphenyl) -2-methylalanine) (eg, combinations as ALDORIL® tablets available from Merck); Methyldopa-chlorothiazide (eg 6-chloro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide and methyldopa as mentioned above, for example from Merck Available ALDOCLORr® tablets); Clonidine hydrochloride (e.g. 2- (2,6-dichlorophenylamino) -2-imidazoline hydrochloride and chlortalidone (e.g. 2-chloro-5- (1-hydroxy-3-oxo-1-) Isoindolinyl) benzenesulfonamide), eg, COMBIPRES® tablets available from Boehringer Ingelheim); Clonidine hydrochloride (eg, 2- (2,6-dichlorophenylamino) -2-imidazoline hydrochloride, for example CATAPRES® tablets available from Boehringer Ingelheim); Clonidine (1H-imidazol-2-amine, N- (2,6-dichlorophenyl) -4,5-dihydro-CAS RN 4205-90-7), including but not limited to.
[35] In general, the total dosage of the above-mentioned agents or medicaments is 1 to 3,000 mg / day, preferably about 1 to 1,000 mg / day, more preferably about 1 to 200 mg / day, which is administered in a single dose or Or divided into two to four doses.
[36] Cardiovascular agents useful for treating vascular diseases are administered in a therapeutically effective amount for treating the diseases specified above, for example, the daily dose is preferably from about 1 to about 3000 mg, more preferably from about 5 to about It may range from 200 mg, which is administered in a single dose or divided into two to four doses. However, the exact dose is determined by the attending physician, which depends on the efficacy of the compound administered, the age, weight, condition and response of the patient.
[37] The term "therapeutically effective amount" refers to amelioration of a disease or disease symptom to be treated, including the prevention of the disease (eg, vascular disease as discussed above), and slowing or stopping its progression. The amount of therapeutic agent in the composition, such as a cardiovascular agent, sterol absorption, that will elicit a biological or medical response in a particular tissue, system, animal or mammal that a woman (e.g., a researcher, doctor or veterinarian) seeks. The amount of inhibitor and other pharmacological or therapeutic agents described below.
[38] As used herein, a “combination therapy” or “therapeutic combination” is used to prevent vascular disease, such as hyperlipidemia (eg, atherosclerosis, hypercholesterolemia or cytosterolemia), stroke, diabetes, obesity or To treat and / or lower the level of sterols in plasma, it is meant to administer two or more different therapeutic agents, such as cardiovascular agents and inhibitors of sterol absorption. As used herein, “vascular” includes cardiovascular, cerebrovascular and combinations thereof. Such administration may be effected together in a substantially simultaneous manner, eg, in a single tablet or capsule with a fixed ratio of active ingredient, or together in separate multiple capsules for each therapeutic agent. It is included. Such administration also includes the use of each type of therapeutic agent in a sequential manner. In either case, treatment with combination therapy will provide favorable results for treating vascular diseases and other diseases as mentioned above. A potential advantage of the combination therapies discussed herein is the ability to reduce the total amount of therapeutic compound or the amount of individual therapeutic compound required to treat a vascular disease. By using a combination of therapeutic agents, it is easy to obtain patient consent since the side effects of the individual compounds can be reduced compared to a single therapy. In addition, the therapeutic agents may be selected to provide a wide range of complementary effects or complementary modes of action.
[39] As discussed above, the compositions, pharmaceutical compositions and therapeutic combinations of the present invention may comprise one or more sterol absorption inhibitors, such as substituted azetidinone sterol absorption inhibitors or substituted β-lactam sterol absorption inhibitors, discussed in detail below. Include. As used herein, a "sterol absorption inhibitor" is one or more sterols [cholesterol, phytosterols (eg, cytosterols, camphorsterols) when administered to a mammal or human in a therapeutically effective amount (inhibiting sterol absorption) Stigmasterol and avenosterol), 5α-stanol (eg, but not limited to cholestanol, 5α-campestanol, 5α-cytostanol) and mixtures thereof] Means a compound.
[40] In a preferred embodiment, the sterol absorption inhibitors useful in the compositions, therapeutic combinations and methods of the present invention are compounds of formula I, isomers of compounds of formula I, pharmaceutically acceptable salts of compounds of formula I or isomers thereof, or As a solvate or a prodrug of a compound of formula (I) or an isomer, salt or solvate of a compound of formula (I):
[41]
[42] In the above formula,
[43] Ar ¹ and Ar ² are independently selected from the group consisting of aryl and R ⁴ -substituted aryl;
[44] Ar ³ is aryl or R ⁵ -substituted aryl;
[45] X, Y and Z are independently selected from the group consisting of -CH _2- , -CH (lower alkyl)-and -C (di-lower alkyl)-;
[46] R and R ² are independently selected from the group consisting of —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ^9, and —O (CO) NR ⁶ R ⁷ ;
[47] R ¹ and R ³ are independently selected from the group consisting of hydrogen, lower alkyl and aryl;
[48] q is 0 or 1;
[49] r is 0 or 1;
[50] m, n and p are independently selected from 0, 1, 2, 3 or 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; when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5;
[51] R ⁴ is lower alkyl, -OR ⁶ , -O (CO) R ⁶ , -O (CO) OR ⁹ , -O (CH ₂ ) _1-5 OR ⁶ , -O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , -(Lower alkylene) COOR ⁶ , -CH = CH-COOR ⁶ , -CF ₃ , -CN, -NO _2, and 1 to 5 substituents independently selected from the group consisting of halogen;
[52] R ⁵ is -OR ⁶ , -O (CO) R ⁶ , -O (CO) OR ⁹ , -O (CH ₂ ) _1-5 OR ⁶ , -O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ ,-(low) Alkylene) COOR ⁶ and -CH = CH-COOR ⁶ ; 1 to 5 substituents independently selected from the group consisting of;
[53] R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
[54] R ⁹ is lower alkyl, aryl or aryl-substituted lower alkyl.
[55] Preferably, R ⁴ is one to three independently selected substituents and R ⁵ is preferably one to three independently selected substituents.
[56] As used herein, the term "alkyl" or "lower alkyl" refers to straight or branched chain alkyl of 1 to 6 carbon atoms, and "alkoxy" similarly refers to an alkoxy group of 1 to 6 carbon atoms. Non-limiting examples of suitable lower alkyl groups are methyl, ethyl, propyl and butyl groups.
[57] "Alkenyl" means a carbon straight or branched chain having one or more double bonds in the chain, either conjugated or unconjugated. Similarly, "alkynyl" means a carbon straight or branched chain having one or more triple bonds in the chain. When the alkyl, alkenyl or alkynyl chain is divalent in combination with two other variables, the terms alkylene, alkenylene and alkynylene are used.
[58] "Cycloalkyl" refers to a saturated carbon ring of 3 to 6 carbon atoms, while "cycloalkylene" refers to a corresponding divalent ring, including all positional isomers at the point of attachment to the other group.
[59] "Halogeno" refers to a fluorine, chlorine, bromine or iodine radical.
[60] "Aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl or indanyl.
[61] "Phenylene" means a divalent phenyl group including ortho, meta and para-substituted.
[62] For example, R, R ^1, R ² and R information, a ^trivalent noted that selected independently from the substituent groups R, R ^1, R ² and R ³ are only means that independently selected, but R, R ¹ , R ² and R ³ variables exist one or more times in the molecule, each time independently selected (e.g., if R is -OR ⁶ and R ⁶ is hydrogen, R ² is -OR ⁶ and R ⁶ may be lower alkyl). Those skilled in the art will recognize that the size and type of substituent (s) will be affected by the number of substituents that may be present.
[63] Since the compounds of the present invention have one or more asymmetric carbon atoms, all isomers (if any), including enantiomers, stereoisomers, rotamers, tautomers, racemates, of the compounds of Formulas I-XI are present Is considered as part of the invention. The present invention encompasses both d and l isomers in pure form and mixture forms (including racemic mixtures). Isomers may be prepared using conventional techniques by reacting optically pure or optically rich starting materials or by separating the isomers of the compounds of Formulas I-XI. Isomers may also include geometric isomers, for example when a double bond is present.
[64] Those skilled in the art will appreciate that in some cases of the compounds of Formulas I-XI, one isomer will exhibit greater pharmacological activity than the other isomer.
[65] Compounds of the invention having amino groups are capable of forming pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation include hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, methanesulfonic acid, and other inorganics well known to those skilled in the art. Acids and carboxylic acids. Salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt. This free base form can be regenerated by treating the salt with a suitable dilute aqueous base solution, for example dilute aqueous sodium bicarbonate. The free base forms differ somewhat from their respective salt forms in terms of their specific physical properties, e.g. solubility in polar solvents, but the salts are equivalent to their respective free base forms for the purposes of the present invention.
[66] Certain compounds of the present invention are acidic (eg, compounds having carboxyl groups). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
[67] The term “solvate,” as used herein, refers to a molecule or ion of a solvent and a solute (eg, one or more compounds of Formulas I-XI, isomers of compounds of Formulas I-XI, and compounds of Formulas I-XI) Prodrug) means a molecular or ionic complex with a molecule or ion. Non-limiting examples of useful solvents are polar protic solvents such as water and alcohols such as methanol.
[68] As used herein, the term “prodrug” refers to a drug precursor compound that, after being administered to a patient, releases the drug in vivo through some chemical or physiological process (eg, at physiological pH or Through enzymatic action, the prodrug is converted into the desired drug form).
[69] Preferred are compounds of formula I, wherein Ar ¹ is phenyl or R ⁴ -substituted phenyl, more preferably (4-R ⁴ ) -substituted phenyl. Ar ² is preferably phenyl or R ⁴ -substituted phenyl, more preferably (4-R ⁴ ) -substituted phenyl. Ar ³ is preferably R ⁵ -substituted phenyl, more preferably (4-R ⁵ ) -substituted phenyl. When Ar ¹ is (4-R ⁴ ) -substituted phenyl, R ⁴ is preferably halogen. When Ar ² and Ar ³ are each R ⁴ -and R ⁵ -substituted phenyl, R ⁴ is preferably halogen or -OR ⁶ and R ⁵ is preferably -OR ⁶ , and R ⁶ is lower alkyl or hydrogen to be. Particular preference is given to compounds in which Ar ¹ and Ar ² are each 4-fluorophenyl and Ar ³ is 4-hydroxyphenyl or 4-methoxyphenyl.
[70] X, Y and Z are each preferably -CH _2- . R ¹ and R ³ are each preferably hydrogen. R and R ² are preferably -OR ⁶ , and R ⁶ is hydrogen or a group readily metabolizable to hydroxyl (eg, -O (CO) R ⁶ , -O (CO) OR ^{9 as} defined above). And -O (CO) NR ⁶ R ⁷ ).
[71] The sum of m, n, p, q and r is preferably 2, 3 or 4, more preferably 3. Preferred are compounds in which m, n and r are each 0, q is 1 and p is 2.
[72] Preference is furthermore given to compounds of the formula I in which p, q and n are each 0, r is 1 and m is 2 or 3. More preferred are compounds in which m, n and r are each 0, q is 1, p is 2, Z is -CH _2- , R is -OR ⁶ , in particular R ⁶ is hydrogen.
[73] Further preferred are compounds in which p, q and n are each 0, r is 1, m is 2, X is -CH _2- , R ² is -OR ⁶ , in particular R ⁶ is hydrogen.
[74] Another group of preferred compounds of formula I are compounds wherein Ar ¹ is phenyl or R ⁴ -substituted phenyl, Ar ² is phenyl or R ⁴ -substituted phenyl and Ar ³ is R ⁵ -substituted phenyl. In addition, Ar ¹ is phenyl or R ⁴ -substituted phenyl, Ar ² is phenyl or R ⁴ -substituted phenyl, Ar ³ is R ⁵ -substituted phenyl, and the sum of m, n, p, q and r Preferred are 2, 3 or 4, more particularly 3 compounds. Ar ¹ is phenyl or R ⁴ -substituted phenyl, Ar ² is phenyl or R ⁴ -substituted phenyl, Ar ³ is R ⁵ -substituted phenyl, m, n and r are each 0, q is 1 More preferably, p is 2 or p, q and n are each 0, r is 1 and m is 2 or 3.
[75] In a preferred embodiment, the sterol absorption inhibitor of formula (I) useful in the compositions, therapeutic combinations and methods of the present invention is a compound of formula (II) (Ezetimibe), a pharmaceutically acceptable salt or solvate of the compound of formula Or as a prodrug of a compound of Formula II or a salt or solvate of a compound of Formula II:
[76]
[77] Compounds of formula (I) can be prepared by various methods well known to those skilled in the art, for example, U.S. Pat. And PCT International Publication No. WO 93/02048, each of which is incorporated herein by reference, and the methods as described in the following examples. For example, suitable compounds of formula (I)
[78] (a) the following structure
[79]
[80] [Wherein R 'and R ^2' are each R and R ² or a suitably protected hydroxy group; Ar ¹⁰ is Ar ¹ , suitably protected hydroxy-substituted aryl or suitably protected amino-substituted aryl; The remaining variables are as defined for Formula I above, provided that in the lactone of structure B, if n and r are each 0, p is 1-4;
[81] (b) the product of step (a)
[82]
[83] [Wherein Ar ²⁰ is Ar ² , suitably protected hydroxy-substituted aryl or suitably protected amino-substituted aryl; Ar ³⁰ is Ar ³ , suitably protected hydroxy-substituted aryl or suitably protected amino-substituted aryl;
[84] (c) quenching the reaction with an acid;
[85] (d) optionally, if present, removing the protecting group from R ′, R ^{2 ′} , Ar ¹⁰ , Ar ²⁰ and Ar ³⁰ ;
[86] (e) optionally functionalizing a hydroxy or amino substituent at R, R ² , Ar ¹ , Ar ^2, and Ar ³
[87] It can manufacture by the method containing.
[88] Using the lactones set forth above, the compounds of formulas IA and IB are obtained as follows:
[89]
[90]
[91] Wherein the variables are as defined above.
[92] Still other sterol absorption inhibitors useful in the compositions, therapeutic combinations and methods of the present invention are compounds of formula III, isomers of compounds of formula III, pharmaceutically acceptable salts or solvates of compounds of formula III or isomers thereof Or as a prodrug of a compound of Formula III or an isomer, salt or solvate of a compound of Formula III:
[93]
[94] In the above formula,
[95] Ar ¹ is R ³ -substituted aryl;
[96] Ar ² is R ⁴ -substituted aryl;
[97] Ar ³ is R ⁵ -substituted aryl;
[98] Y and Z are independently selected from the group consisting of -CH _2- , -CH (lower alkyl)-and -C (di-lower alkyl)-;
[99] A is -O-, -S-, -S (O)-or -S (O) _2- ;
[100] R ¹ is selected from the group consisting of —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ^9, and —O (CO) NR ⁶ R ⁷ ; R ² is selected from the group consisting of hydrogen, lower alkyl and aryl, or R ¹ and R ² together are ═O;
[101] q is 1, 2 or 3;
[102] p is 0, 1, 2, 3 or 4;
[103] R ⁵ is -OR ⁶ , -O (CO) R ⁶ , -O (CO) OR ⁹ , -O (CH ₂ ) _1-5 OR ⁹ , -O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ -lower alkyl, -NR ⁶ SO ₂ -aryl, -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 -alkyl, S (O) _0-2 -aryl, -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl,-(lower alkylene) -COOR ⁶ and -CH = CH-COOR ⁶ 1 to 3 substituents independently selected from the group consisting of;
[104] R ³ and R ⁴ are independently 1 to 3 substituents independently selected from the group consisting of R ⁵ , hydrogen, p-lower alkyl, aryl, —NO ₂ , —CF ₃ and p-halogeno;
[105] R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
[106] R ⁹ is lower alkyl, aryl or aryl-substituted lower alkyl.
[107] Preferred compounds of formula III include those wherein Ar ¹ is R ³ -substituted phenyl, in particular (4-R ³ ) -substituted phenyl. Ar ² is preferably R ⁴ -substituted phenyl, in particular (4-R ⁴ ) -substituted phenyl. Ar ³ is preferably R ⁵ -substituted phenyl, in particular (4-R ⁵ ) -substituted phenyl. Preferred monocyclic rings of Ar ¹ , Ar ² and Ar ³ are preferred.
[108] Y and Z are each preferably -CH _2- . R ² is preferably hydrogen. R ¹ is preferably -OR ⁶ and R ⁶ is hydrogen or a group readily metabolizable to hydroxyl (e.g., -O (CO) R ⁶ , -O (CO) OR ⁹ and-as defined above). O (CO) NR ⁶ R ⁷ ). Also preferred are compounds in which R ¹ and R ² together are = O.
[109] The sum of q and p is preferably 1 or 2, more preferably 1. Preference is given to compounds in which p is 0 and q is 1. More preferred are compounds wherein p is 0, q is 1, Y is -CH ₂ -and R ¹ is -OR ⁶ , in particular R ⁶ is hydrogen.
[110] Another preferred compound group is a compound wherein Ar ¹ is R ³ -substituted phenyl, Ar ² is R ⁴ -substituted phenyl, and Ar ³ is R ⁵ -substituted phenyl.
[111] Further, compounds in which Ar ¹ is R ³ -substituted phenyl, Ar ² is R ⁴ -substituted phenyl, Ar ³ is R ⁵ -substituted phenyl, and the sum of p and q are 1 or 2, especially 1 desirable. More preferred are compounds wherein Ar ¹ is R ³ -substituted phenyl, Ar ² is R ⁴ -substituted phenyl, Ar ³ is R ⁵ -substituted phenyl, p is 0 and q is 1.
[112] A is preferably -O-.
[113] R ³ is preferably -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 -alkyl, S (O) _0-2 -aryl, NO ₂ Or halogeno. A more preferred definition for R ³ is halogeno, in particular fluoro or chloro.
[114] R ⁴ is preferably hydrogen, lower alkyl, —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ⁹ , —O (C 0) NR ⁶ R ⁷ , —NR ⁶ R ⁷ , COR ⁶ or Halogen, R ⁶ and R ⁷ are preferably independently hydrogen or lower alkyl, and R ⁹ is preferably lower alkyl. A more preferred definition for R ⁴ is hydrogen or halogeno, in particular fluoro or chloro.
[115] R ⁵ is preferably -OR ⁶ , -O (CO) R ⁶ , -O (CO) OR ⁹ , -O (C0) NR ⁶ R ⁷ , -NR ⁶ R ⁷ ,-(lower alkylene) -COOR ⁶ or —CH═CH—COOR ⁶ , R ⁶ and R ⁷ are preferably independently hydrogen or lower alkyl, and R ⁹ is preferably lower alkyl. More preferred definitions for R ⁵ are —OR ⁶ , — (lower alkylene) -COOR ⁶ or —CH═CH—COOR ⁶ , with R ⁶ being preferably hydrogen or lower alkyl.
[116] Methods of preparing compounds of formula III are well known to those skilled in the art. Non-limiting examples of suitable methods are described in US Pat. No. 5,688,990, which is incorporated herein by reference.
[117] In another embodiment, a sterol absorption inhibitor useful in the compositions, therapeutic combinations and methods of the present invention is a compound of formula IV, an isomer of a compound of formula IV, a pharmaceutically acceptable salt of a compound of formula IV or an isomer thereof Or as a solvate, or a prodrug of a compound of formula IV or an isomer, salt or solvate of a compound of formula IV:
[118]
[119] In the above formula,
[120] A is R ² - is selected from the group consisting of a substituted benzo fused heteroaryl, substituted heterocycloalkyl, R ² - substituted heteroaryl, R ² - - a substituted benzo fused heterocycloalkyl, and R ^2;
[121] Ar ¹ is aryl or R ³ -substituted aryl;
[122] Ar ² is aryl or R ⁴ -substituted aryl;
[123] Q is a spiro group, either as a bond or with the 3-position ring carbon of the corresponding azetidinone To form;
[124] R ¹ is
[125] -(CH ₂ ) _q -wherein q is 2 to 6, provided that Q may be 0 or 1 if Q forms a spiro ring;
[126] -(CH ₂ ) _e -G- (CH ₂ ) _r -wherein G is -O-, -C (O)-, phenylene, -NR ⁸ -or -S (O) _0-2- , e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
[127] -(C ₂ -C ₆ alkenylene)-; And
[128] -(CH ₂ ) _f -V- (CH ₂ ) _g- [where V is C ₃ -C ₆ cycloalkylene, f is 1 to 5 and g is 0 to 5, provided the sum of f and g is 1 to 6];
[129] Is selected from;
[130] R ⁶ and R ⁷ are -CH _2- , -CH (C ₁ -C ₆ alkyl)-, -C (di- (C ₁ -C ₆ ) alkyl), -CH = CH- and -C (C _1- C ₆ alkyl) is independently selected from the group consisting of CH-, or R ⁵ together with adjacent R ⁶ or R ⁵ together with adjacent R ⁷ -CH = CH- or -CH = C (C ₁ -C ₆ alkyl)-form a group;
[131] a and b are independently 0, 1, 2 or 3, provided that both are not 0; R ⁶ is a -CH = CH- or -C (C ₁ -C ₆ alkyl) = CH-, a is 1; If R ⁷ is —CH═CH— or —C (C ₁ -C ₆ alkyl) = CH—, b is 1; when a is 2 or 3, R ⁶ may be the same or different; when b is 2 or 3, R ⁷ may be the same or different;
[132] If Q is a bond, then R ¹ is also
[133] Can be selected from;
[134] M is -O-, -S-, -S (O)-or -S (O) _2- ;
[135] X, Y and Z are independently selected from the group consisting of -CH _2- , -CH (C ₁ -C ₆ alkyl)-and -C (di- (C ₁ -C ₆ ) alkyl);
[136] R ¹⁰ and R ¹² are independently selected from the group consisting of —OR ¹⁴ , —O (CO) R ¹⁴ , —O (CO) OR ^16, and —O (CO) NR ¹⁴ R ¹⁵ ;
[137] R ¹¹ and R ¹³ are independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl and aryl, or R ¹⁰ and R ¹¹ together are ═O or R ¹² and R ¹³ together are ═O Is;
[138] d is 1, 2 or 3;
[139] h is 0, 1, 2, 3 or 4;
[140] s is 0 or 1; t is 0 or 1; m, n and p are independently 0 to 4, provided that at least one of s and t is 1 and the sum of m, n, p, s and t is 1 to 6; when p is 0 and t is 1, the sum of m, s and n is 1 to 5; when p is 0 and s is 1, the sum of m, t and n is 1 to 5;
[141] v is 0 or 1;
[142] j and k are independently 1 to 5, provided that the sum of j, k and v is 1 to 5;
[143] R ² is hydrogen, (C ₁ -C ₁₀ ) alkyl, (C ₂ -C ₁₀ ) alkenyl, (C ₂ -C ₁₀ ) alkynyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ Cycloalkenyl, R ¹⁷ -substituted aryl, R ¹⁷ -substituted benzyl, R ¹⁷ -substituted benzyloxy, R ¹⁷ -substituted aryloxy, halogeno, -NR ¹⁴ R ¹⁵ , NR ¹⁴ R ¹⁵ (C ₁ -C ₆ alkylene)-, NR ¹⁴ R ¹⁵ C (O) (C ₁ -C ₆ alkylene)-, -NHC (O) R ¹⁶ , OH, C ₁ -C ₆ alkoxy, -OC (O) R ¹⁶ , -COR ¹⁴ , hydroxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, NO ₂ , -S (O) _0-2 R ¹⁶ ,- 1 to 3 substituents on a ring carbon atom selected from the group consisting of SO ₂ NR ¹⁴ R ¹⁵ and-(C ₁ -C ₆ alkylene) COOR ¹⁴ ; When R ² is a substituent on a heterocycloalkyl ring, R ² is as defined or = O or ego; When R ² is a substituent on a substitutable ring nitrogen, it is hydrogen, (C ₁ -C ₆ ) alkyl, aryl, (C ₁ -C ₆ ) alkoxy, aryloxy, (C ₁ -C ₆ ) alkylcarbonyl, aryl Carbonyl, hydroxy,-(CH ₂ ) _1-6 CONR ¹⁸ R ¹⁸ , Is; J is -O-, -NH-, -NR ¹⁸ -or -CH _2- ;
[144] R ³ and R ⁴ are (C ₁ -C ₆ ) alkyl, -OR ¹⁴ , -O (CO) R ¹⁴ , -O (CO) OR ¹⁶ , -O (CH ₂ ) _1-5 OR ¹⁴ , -O ( CO) NR ¹⁴ R ¹⁵ , -NR ¹⁴ R ¹⁵ , -NR ¹⁴ (CO) R ¹⁵ , -NR ¹⁴ (CO) OR ¹⁶ , -NR ¹⁴ (CO) NR ¹⁵ R ¹⁹ , -NR ¹⁴ SO ₂ R ¹⁶ , -COOR ¹⁴ , -CONR ¹⁴ R ¹⁵ , -COR ¹⁴ , -SO ₂ NR ¹⁴ R ¹⁵ , S (O) _0-2 R ¹⁶ , -O (CH ₂ ) _1-10 -COOR ¹⁴ , -O (CH ₂ ) _1-10 CONR ¹⁴ R ¹⁵ ,-(C ₁ -C ₆ alkylene) -COOR ¹⁴ , -CH = CH-COOR ¹⁴ , -CF ₃ , -CN, -NO ₂ and independently selected from the group consisting of halogen Independently selected from the group consisting of 1 to 3 substituents;
[145] R ⁸ is hydrogen, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, —C (O) R ¹⁴ or —COOR ¹⁴ ;
[146] R ⁹ and R ¹⁷ are independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, -COOH, NO ₂ , -NR ¹⁴ R ¹⁵ , OH and halogeno 1 to 3 groups selected from;
[147] R ¹⁴ and R ¹⁵ are independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, aryl and aryl-substituted (C ₁ -C ₆ ) alkyl;
[148] R ¹⁶ is (C ₁ -C ₆ ) alkyl, aryl or R ¹⁷ -substituted aryl;
[149] R ¹⁸ is hydrogen or (C ₁ -C ₆ ) alkyl;
[150] R ¹⁹ is hydrogen, hydroxy or (C ₁ -C ₆ ) alkoxy.
[151] As used in Formula IV above, "A" is preferably an R ² -substituted 6-membered heterocycloalkyl ring containing 1 or 2 nitrogen atoms. Preferred heterocycloalkyl rings are piperidinyl, piperazinyl and morpholinyl groups. Ring “A” is preferably linked to the phenyl ring via ring nitrogen. Preferred R ² substituents are hydrogen and lower alkyl. R ¹⁹ is preferably hydrogen.
[152] Ar ² is preferably phenyl or R ⁴ -phenyl, in particular (4-R ⁴ ) -substituted phenyl. Preferred definitions for R ⁴ are lower alkoxy, in particular methoxy, and halogeno, especially fluoro.
[153] Ar ¹ is preferably phenyl or R ³ -substituted phenyl, in particular (4-R ³ ) -substituted phenyl.
[154] Some preferred definitions for the -R ¹ -Q- combination variable are as follows:
[155] Q is a bond and R ¹ is lower alkylene, preferably propylene;
[156] Q is a spiro group as defined above, preferably R ⁶ and R ⁷ are each ethylene and R ⁵ is Is;
[157] Q is a bond and R ¹ is Wherein the variables are selected such that R ¹ is —O—CH ₂ —CH (OH) —;
[158] Q is a bond and R ¹ is Wherein the variables are selected such that R ¹ is —CH (OH) — (CH ₂ ) ₂ —;
[159] Q is a bond and R ¹ is Wherein the variables are selected such that R ¹ is —CH (OH) —CH ₂ —S (O) _0-2 —.
[160] Methods of preparing compounds of formula IV are well known to those skilled in the art. Non-limiting examples of suitable methods are described in US Pat. No. 5,656,624, which is incorporated herein by reference.
[161] In another embodiment, sterol absorption inhibitors useful in the compositions, therapeutic combinations and methods of the present invention are compounds of formula (V), isomers of compounds of formula (V), pharmaceutically acceptable salts of compounds of formula (V) or isomers thereof Or as a solvate or a prodrug of a compound of formula (V) or an isomer, salt or solvate of a compound of formula (V):
[162]
[163] In the above formula,
[164] Ar ¹ is aryl, R ¹⁰ -substituted aryl or heteroaryl;
[165] Ar ² is aryl or R ⁴ -substituted aryl;
[166] Ar ³ is aryl or R ⁵ -substituted aryl;
[167] X and Y are independently selected from the group consisting of -CH _2- , -CH (lower alkyl)-and -C (di-lower alkyl)-;
[168] R is —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ⁹ or —O (CO) NR ⁶ R ⁷ ; R ¹ is hydrogen, lower alkyl or aryl or R and R ¹ together are ═O;
[169] q is 0 or 1;
[170] r is 0, 1 or 2;
[171] m and n are independently 0, 1, 2, 3, 4 or 5, provided that the sum of m, n and q is 1, 2, 3, 4 or 5;
[172] R ⁴ is lower alkyl, -OR ⁶ , -O (CO) R ⁶ , -O (CO) OR ⁹ , -O (CH ₂ ) _1-5 OR ⁶ , -O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , -(Lower alkylene) 1-5 substituents independently selected from the group consisting of COOR ⁶ and -CH = CH-COOR ⁶ ;
[173] R ⁵ is -OR ⁶ , -O (CO) R ⁶ , -O (CO) OR ⁹ , -O (CH ₂ ) _1-5 OR ⁶ , -O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , -CF ₃ , 1 -5 substituents independently selected from the group consisting of -CN, -NO ₂ , halogen,-(lower alkylene) COOR ⁶ and -CH = CH-COOR ⁶ ;
[174] R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
[175] R ⁹ is lower alkyl, aryl or aryl-substituted lower alkyl;
[176] R ¹⁰ is lower alkyl, —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ⁹ , —O (CH ₂ ) _1-5 OR ⁶ , —O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , And 1 to 5 substituents independently selected from the group consisting of —CF ₃ , —CN, —NO ₂ and halogen.
[177] Within the scope of formula (V) there are two preferred structures. In formula VA, q is 0 and the remaining variables are as defined above, and in formula VB, q is 1 and the remaining variables are as defined above:
[178]
[179]
[180] R ⁴ , R ⁵ and R ¹⁰ are each preferably one to three independently selected substituents as set forth above. Preferred are compounds of formula V, wherein Ar ¹ is phenyl, R ¹⁰ -substituted phenyl or thienyl, in particular (4-R ¹⁰ ) -substituted phenyl or thienyl. Ar ² is preferably R ⁴ -substituted phenyl, in particular (4-R ⁴ ) -substituted phenyl. Ar ³ is preferably phenyl or R ⁵ -substituted phenyl, in particular (4-R ⁵ ) -substituted phenyl. When Ar ¹ is R ¹⁰ -substituted phenyl, R ¹⁰ is preferably halogeno, in particular fluoro. When Ar ² is R ⁴ -substituted phenyl, R ⁴ is preferably -OR ⁶ , in particular R ⁶ is hydrogen or lower alkyl. When Ar ³ is R ⁵ -substituted phenyl, R ⁵ is preferably halogeno, in particular fluoro. Particular preference is given to compounds of the formula V, in which Ar ¹ is phenyl, 4-fluorophenyl or thienyl, Ar ² is 4- (alkoxy or hydroxy) phenyl and Ar ³ is phenyl or 4-fluorophenyl.
[181] X and Y are each preferably -CH _2- . The sum of m, n and q is preferably 2, 3 or 4, more preferably 2. When q is 1, n is preferably 1-5.
[182] Preferred definitions for X, Y, Ar ¹ , Ar ² and Ar ³ are the same for each of formulas VA and VB.
[183] In the compound of formula VA, the sum of m and n is preferably 2, 3 or 4, more preferably 2. Also preferred are compounds in which the sum of m and n is 2 and r is 0 or 1.
[184] In the compounds of the formula VB, the sum of m and n is preferably 1, 2 or 3, more preferably 1. Particularly preferred are compounds wherein m is 0 and n is 1. R ¹ is preferably hydrogen, R is preferably —OR ⁶ , and R ⁶ is a group readily metabolizable to hydrogen or hydroxyl (eg, —O (CO) R ⁶ , — as defined above). O (CO) OR ⁹ and -O (CO) NR ⁶ R ⁷ ), or R and R ¹ together form a ═O group.
[185] Processes for the preparation of compounds of formula V are well known to those skilled in the art. Non-limiting examples of suitable methods are described in US Pat. No. 5,624,920, which is incorporated herein by reference.
[186] In another embodiment, a sterol absorption inhibitor useful in the compositions, therapeutic combinations and methods of the present invention is a compound of Formula VI, an isomer of a compound of Formula VI, a pharmaceutically acceptable salt of a compound of Formula VI, or an isomer thereof Or as a solvate, or a prodrug of a compound of formula VI or an isomer, salt or solvate of a compound of formula VI:
[187]
[188] In the above formula,
[189]
[190] R ₂ and R ₃ are independently selected from the group consisting of -CH _2- , -CH (lower alkyl)-, -C (di-lower alkyl), -CH = CH- and -C (lower alkyl) = CH- Or R ₁ together with adjacent R ₂ or R ₁ together with adjacent R _{3 form a} —CH═CH— or —CH═C (lower alkyl) — group;
[191] u and v are independently 0, 1, 2 or 3, provided that both are not 0;
[192] Provided that when R ₂ is —CH═CH— or —C (lower alkyl) ═CH—, v is 1;
[193] If R ₃ is -CH = CH- or -C (lower alkyl) = CH-, u is 1;
[194] if v is 2 or 3, R₂May be the same or different;
[195] if u is 2 or 3, R ₃ may be the same or different;
[196] R ₄ is B- (CH ₂ ) _m C (O) —, wherein m is 0, 1, 2, 3, 4 or 5;
[197] B- (CH ₂ ) _q -where q is 0, 1, 2, 3, 4, 5 or 6;
[198] B- (CH ₂ ) _e -Z- (CH ₂ ) _r- [where Z is -O-, -C (O)-, phenylene, -N (R ₈ ) _-or -S (O) _{0- 2-} , 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 r is 0, 1, 2, 3, 4, 5 or 6;
[199] B- (C ₂ -C ₆ alkenylene)-;
[200] B- (C ₄ -C ₆ alkadienylene)-;
[201] B- (CH ₂ ) _t -Z- (C ₂ -C ₆ alkenylene)-[where Z is as defined above and t is 0, 1, 2 or 3, provided that the carbon atoms in the alkenylene chain The sum of t and t is 2, 3, 4, 5 or 6;
[202] B- (CH ₂ ) _f -V- (CH ₂ ) _g- [where V is C ₃ -C ₆ cycloalkylene, f is 1, 2, 3, 4 or 5 and g is 0, 1, 2 , 3, 4 or 5, provided that the sum of f and g is 1, 2, 3, 4, 5 or 6;
[203] B- (CH ₂ ) _t -V- (C ₂ -C ₆ alkenylene)-or
[204] B- (C ₂ -C ₆ alkenylene) -V- (CH ₂ ) _t- [where V and t are as defined above, provided that the sum of the number of carbon atoms and t in the alkenylene chain is 2, 3, 4, 5 or 6;
[205] B- (CH ₂ ) _a -Z- (CH ₂ ) _b -V- (CH ₂ ) _d- [where Z and V are as defined above and a, b and d are independently 0, 1, 2 , 3, 4, 5 or 6, provided the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; or
[206] T- (CH ₂ ) _s -wherein T is cycloalkyl having 3 to 6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6; or
[207] R ₁ and R ₄ together, group To form;
[208] B is indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl or W-substituted heteroaryl, where heteroaryl is pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl , Thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and in the case of nitrogen-containing heteroaryl, its N-oxide or Is;
[209] W is lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower alkoxyimino) -lower alkyl, lower alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, -CF ₃ , -OCF ₃ , benzyl, R ₇ -benzyl, benzyloxy, R ₇ -benzyloxy, phenoxy, R ₇ -phenoxy, dioxolanyl, NO ₂ , -N (R ₈ ) (R ₉ ), N (R ₈ ) (R ₉ ) -lower alkylene-, N (R ₈ ) (R ₉ ) -lower alkylenyloxy-, OH, halogeno, -CN, -N ₃ , -NHC (O) OR ₁₀ , -NHC (O) R ₁₀ , R ₁₁ O ₂ SNH-, (R ₁₁ O ₂ S) ₂ N-, -S (O) ₂ NH ₂ , -S (O) _0-2 R ₈ , tert-butyl Dimethylsilyloxymethyl, -C (O) R ₁₂ , -COOR ₁₉ , -CON (R ₈ ) (R ₉ ), -CH = CHC (O) R ₁₂ , -lower alkylene-C (O) R ₁₂ , R ₁₀ C (O) (lower alkylenyloxy)-, N (R ₈ ) (R ₉ ) C (O) (lower alkylenyloxy)-and 1 to 3 substituents independently selected from the group consisting of (when substituted on a ring carbon atom), wherein the substituent on the substituted heteroaryl ring nitrogen atom, if present, lower alkyl, lower alkoxy, -C (O) OR ₁₀ , -C (O) R ₁₀ , OH, N (R ₈ ) (R ₉ ) -lower alkylene-, N (R ₈ ) (R ₉ ) -lower alkylenyloxy-, -S (O) ₂ NH ₂ and 2- (trimethylsilyl) -ethoxymethyl;
[210] R ₇ is 1 to 3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, —COOH, NO ₂ , —N (R ₈ ) (R ₉ ), OH and halogeno;
[211] R ₈ and R ₉ are independently selected from H or lower alkyl;
[212] R ₁₀ is selected from lower alkyl, phenyl, R ₇ -phenyl, benzyl or R ₇ -benzyl;
[213] R ₁₁ is selected from OH, lower alkyl, phenyl, benzyl, R ₇ -phenyl or R ₇ -benzyl;
[214] R ₁₂ is H, OH, alkoxy, phenoxy, benzyloxy, , -N (R ₈ ) (R ₉ ), lower alkyl, phenyl or R ₇ -phenyl;
[215] R ₁₃ is selected from —O—, —CH ₂ —, —NH—, —N (lower alkyl) — or —NC (O) R ₁₉ ;
[216] R ₁₅ , R ₁₆ and R ₁₇ are H; And independently selected from the group consisting of groups defined for W, or R ₁₅ is hydrogen and R ₁₆ and R ₁₇ together with adjacent carbon atoms attached thereto form a dioxolanyl ring;
[217] R ₁₉ is H, lower alkyl, phenyl or phenyl lower alkyl;
[218] R ₂₀ and R ₂₁ are phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzo Independently selected from the group consisting of fused heteroaryl, W-substituted benzofused heteroaryl and cyclopropyl, wherein heteroaryl is as defined above.
[219] One group of preferred compounds of formula VI is that R ₂₁ is phenyl, W-substituted phenyl, indanyl, benzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl or cyclo Profile
[220] W is lower alkyl, lower alkoxy, OH, halogeno, -N (R ₈ ) (R ₉ ), -NHC (O) OR ₁₀ , -NHC (O) R ₁₀ , NO ₂ , -CN, -N ₃ , -SH, -S (O) _0-2- (lower alkyl), -COOR ₁₉ , -CON (R ₈ ) (R ₉ ), -COR ₁₂ , phenoxy, benzyloxy, -OCF ₃ , -CH = C (O) R ₁₂ or tert-butyldimethylsilyloxy, and R ₈ , R ₉ , R ₁₀ , R ₁₂ and R ₁₉ are compounds as defined for Formula VI. When W is 2 or 3 substituents, these substituents may be the same or different.
[221] Another group of preferred compounds of formula VI are those wherein R ₂₀ is phenyl or W-substituted phenyl and the preferred meaning of W is as defined for the preferred definition of R ₂₁ above.
[222] More preferred compounds of formula VI are those wherein R ₂₀ is phenyl or W-substituted phenyl, R ₂₁ is phenyl, W-substituted phenyl, indanyl, benzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl, pyra Genyl, pyrimidinyl, quinolyl or cyclopropyl, W is lower alkyl, lower alkoxy, OH, halogeno, -N (R ₈ ) (R ₉ ), -NHC (O) OR ₁₀ , -NHC (O) R ₁₀ , NO ₂ , -CN, -N ₃ , -SH, -S (O) _0-2- (lower alkyl), -COOR ₁₉ , -CON (R ₈ ) (R ₉ ), -COR ₁₂ , phenoxy Is benzyloxy, -CH = CHC (O) R ₁₂ , -OCF ₃ or tert-butyldimethylsilyloxy, and when W is 2 or 3 substituents, these substituents can be the same or different and R ₈ , R ₉ , R ₁₀ , R ₁₂ and R ₁₉ are compounds as defined for Formula VI.
[223] Further, preferred compounds of formula (VI) R ₁ is Phosphorus compound.
[224] Another group of preferred compounds of formula VI are compounds wherein R ₂ and R ₃ are each -CH _2- , the sum of u and v is 2, 3 or 4, more preferably u = v = 2.
[225] R ₄ is preferably B- (CH ₂ ) _q -or B- (CH ₂ ) _e -Z- (CH ₂ ) _r -wherein B, Z, q, e and r are as defined above; to be. B is preferably Wherein R ₁₆ and R ₁₇ are each hydrogen and R ₁₅ is preferably H, OH, lower alkoxy, in particular methoxy, or halogeno, in particular chloro.
[226] Preferably, Z is -O-, e is 0 and r is 0.
[227] Preferably, q is 0-2.
[228] R ₂₀ is preferably phenyl or W-substituted phenyl.
[229] Preferred W substituents for R ₂₀ are lower alkoxy, in particular methoxy and ethoxy, OH and —C (O) R _12, wherein R ₁₂ is preferably lower alkoxy.
[230] Preferred definitions for R ₂₁ are phenyl, lower alkoxy-substituted phenyl and F-phenyl.
[231] Particularly preferred compounds of formula VI are those wherein R ₁ R ₂ and R ₃ are each -CH _2- , u = v = 2, R ₄ is B- (CH ₂ ) _q- , B is phenyl or phenyl substituted by lower alkoxy or chloro and q is 0 to 2, R ₂₀ is phenyl, OH-phenyl, lower alkoxy-substituted phenyl or lower alkoxycarbonyl-substituted phenyl, and R ₂₁ is phenyl, lower alkoxy-substituted phenyl or F-phenyl Compound.
[232] Methods for the preparation of compounds of formula VI are well known to those skilled in the art. Non-limiting examples of suitable methods are described in US Pat. No. 5,698,548, which is incorporated herein by reference.
[233] In another embodiment, sterol absorption inhibitors useful in the compositions, therapeutic combinations and methods of the present invention are compounds of formula VIIA and VIIB, isomers of compounds of formula VIIA or VIIB, compounds of formula VIIA or VIIB, or isomers thereof As a pharmaceutically acceptable salt or solvate, or as a prodrug of a compound of formula VIIA or VIIB or an isomer, salt or solvate of a compound of formula VIIA or VIIB:
[234]
[235]
[236] In the above formula,
[237] A is -CH = CH-, -C≡C- or-(CH ₂ ) _p- , where p is 0, 1 or 2;
[238]
[239] D is-(CH ₂ ) _m C (O)-or-(CH ₂ ) _q -where m is 1, 2, 3 or 4 and q is 2, 3 or 4;
[240] E is C ₁₀ to C ₂₀ alkyl or -C (O)-(C ₉ to C ₁₉ ) -alkyl, wherein alkyl contains straight or branched saturated or one or more double bonds;
[241] R is hydrogen, C ₁ -C ₁₅ alkyl (either straight or branched, saturated or containing one or more double bonds), or B- (CH ₂ ) _r- [where r is 0, 1, 2 or 3 ]ego;
[242] R ₁ , R ₂ , R ₃ , R _{1 '} , R _2' and R _{3 '} are hydrogen, lower alkyl, lower alkoxy, carboxy, NO ₂ , NH ₂ , OH, halogeno, lower alkylamino, di-lower alkyl Independently selected from the group consisting of amino, -NHC (O) OR ₅ , R ₆ O ₂ SNH-, and -S (O) ₂ NH ₂ ;
[243] Where n is 0, 1, 2 or 3;
[244] R ₅ is lower alkyl;
[245] R ₆ is OH, lower alkyl, phenyl, benzyl or substituted phenyl [wherein the substituents consist of lower alkyl, lower alkoxy, carboxy, NO ₂ , NH ₂ , OH, halogeno, lower alkylamino and di-lower alkylamino One to three groups independently selected from the group.
[246] Preferred are compounds of formula VIIA, wherein R is hydrogen, saturated or mono-unsaturated C ₁ -C ₁₀ alkyl or phenyl. Another group of preferred compounds of formula VIIA are those wherein D is propyl [ie,-(CH ₂ ) _q -where q is 3]. A third group in the preferred compound of formula VIIA is a compound wherein R ₄ is p-methoxyphenyl or 2,4,6-trimethoxyphenyl. Another group of preferred compounds of formula VIIA are compounds wherein A is ethylene or a bond [ie,-(CH ₂ ) _p -where p is 0. R _{1 '} , R _2' and R _{3 '} are each preferably hydrogen, preferably R ₁ is hydrogen, hydroxy, nitro, lower alkoxy, amino or t-butoxycarbonyl-amino and R ₂ And R ₃ are each hydrogen.
[247] R _{1 '} , R _2' and R _{3 '} are each hydrogen; R ₁ is hydrogen, hydroxy, nitro, lower alkoxy, amino or t-butoxycarbonyl-amino and R ₂ and R ₃ are each hydrogen; R is hydrogen, ethyl or phenyl; D is propyl; R ₄ is p-methoxyphenyl or 2,4,6-trimethoxyphenyl; Especially preferred are compounds of formula VIIA, wherein A is ethylene or a bond.
[248] Preferred compounds of formula VIIA wherein B 'is phenyl are shown in the following table:
[249]
[250] More preferred are the first-listed compounds of the above table with (3R, 4S) absolute stereochemistry.
[251] Preferred compounds of formula VIIB are those wherein R is hydrogen, methyl, ethyl, phenyl or phenylpropyl. Another group of preferred compounds of formula VIIB are those wherein R ₄ is p-methoxyphenyl or 2,4,6-trimethoxyphenyl. Another group of preferred compounds of formula VIIB are those wherein A is ethylene or a bond. Another group of preferred compounds of formula VIIB are those wherein E is decyl, oleoyl or 7-Z-hexadecenyl. Preferably, R ₁ , R ₂ and R ₃ are each hydrogen.
[252] Particularly preferred compounds of formula VIIB are those in which R is hydrogen, methyl, ethyl, phenyl or phenylpropyl; R ₄ is p-methoxyphenyl or 2,4,6-trimethoxyphenyl; A is ethylene or a bond; E is decyl, oleoyl or 7-Z-hexadecenyl; R ₁ , R ₂ and R ₃ are each hydrogen.
[253] Particularly preferred compounds of formula VIIB are those wherein E is decyl, R is hydrogen, BA is phenyl, and R ₄ is p-methoxyphenyl.
[254] In another embodiment, a sterol absorption inhibitor useful in the compositions, therapeutic combinations and methods of the present invention is a compound of Formula VIII, an isomer of a compound of Formula VIII, a pharmaceutically acceptable salt of a compound of Formula VIII or an isomer thereof Or as a solvate, or a prodrug of a compound of formula VIII or an isomer, salt or solvate of a compound of formula VIII:
[255]
[256] In the above formula,
[257] R ²⁶ is H or OG ¹ ;
[258] G and G ¹ are
[259] Independently selected from the group consisting of provided that when R ²⁶ is H or OH, G is not H;
[260] R, R ^a and R ^b are independently selected from the group consisting of H, -OH, halogeno, -NH ₂ , azido, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkoxy or -WR ³⁰ Become;
[261] W is -NH-C (O)-, -OC (O)-, -OC (O) -N (R ³¹ )-, -NH-C (O) -N (R ³¹ )-, and -OC (S ) -N (R ³¹ )-is independently selected from the group consisting of;
[262] R ² and R ⁶ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl and aryl (C ₁ -C ₆ ) alkyl;
[263] R ³ , R ⁴ , R ⁵ , R ⁷ , R ^3a and R ^4a are H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, -C (O) (C ₁ -C ₆ Independently selected from the group consisting of alkyl and -C (O) aryl;
[264] R ³⁰ is R ³² -substituted T, R ³² -substituted-T- (C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₂ -C ₄ ) alkenyl, R ³² -substituted- ( Group consisting of C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl and R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₆ ) alkyl Is selected from;
[265] R ³¹ is selected from the group consisting of H and (C ₁ -C ₄ ) alkyl;
[266] T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
[267] R ³² is halogeno, (C ₁ -C ₄ ) alkyl, -OH, phenoxy, -CF ₃ , -NO ₂ , (C ₁ -C ₄ ) alkoxy, methylenedioxy, oxo, (C ₁ -C ₄ ) Alkylsulfanyl, (C ₁ -C ₄ ) alkylsulfinyl, (C ₁ -C ₄ ) alkylsulfonyl, -N (CH ₃ ) ₂ , -C (O) -NH (C ₁ -C ₄ ) alkyl , -C (O) -N ((C ₁ -C ₄ ) alkyl) ₂ , -C (O)-(C ₁ -C ₄ ) alkyl, -C (O)-(C ₁ -C ₄ ) alkoxy and Independently selected from 1 to 3 substituents independently selected from the group consisting of pyrrolidinylcarbonyl; Or R ³² is a covalent bond and nitrogen attached R ³¹ together with R ³² are pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl groups, or (C ₁ -C ₄ ) alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl groups;
[268] Ar ¹ is aryl or R ¹⁰ -substituted aryl;
[269] Ar ² is aryl or R ¹¹ -substituted aryl;
[270] Q is a spiro group, either as a bond or with the 3-position ring carbon of azetidinone To form;
[271] R ¹ is
[272] -(CH ₂ ) _q -wherein q is 2 to 6, provided that Q may be 0 or 1 if Q forms a spiro ring;
[273] -(CH ₂ ) _e -E- (CH ₂ ) _r -wherein E is -O-, -C (O)-, phenylene, -NR ²² -or -S (O) _0-2- , e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
[274] -(C ₂ -C ₆ ) alkenylene-; And
[275] -(CH ₂ ) _f -V- (CH ₂ ) _g- [where V is C ₃ -C ₆ cycloalkylene, f is 1 to 5 and g is 0 to 5, provided the sum of f and g is 1 to 6];
[276] Is;
[277] R ¹³ and R ¹⁴ are -CH _2- , -CH (C ₁ -C ₆ alkyl)-, -C (di- (C ₁ -C ₆ ) alkyl), -CH = CH- and -C (C _1- Independently selected from the group consisting of C ₆ alkyl) ═CH—; Or R ¹² together with adjacent R ¹³ , or R ¹² together with adjacent R ¹⁴ , form a —CH═CH— or —CH═C (C ₁ -C ₆ alkyl) — group;
[278] a and b are independently 0, 1, 2 or 3, provided that both are not zero;
[279] However, when R ¹³ is -CH = CH- or = CH- -C (C ₁ -C ₆ alkyl), a is 1;
[280] When R ¹⁴ is —CH═CH— or —C (C ₁ -C ₆ alkyl) = CH—, b is 1;
[281] when a is 2 or 3, R ¹³ may be the same or different;
[282] when b is 2 or 3, R ¹⁴ may be the same or different;
[283] When Q is a bond, R ¹ is also
[284] Can be;
[285] M is -O-, -S-, -S (O)-or -S (O) _2- ;
[286] X, Y and Z are independently selected from the group consisting of -CH _2- , -CH (C ₁ -C ₆ ) alkyl- and -C (di- (C ₁ -C ₆ ) alkyl);
[287] R ¹⁰ and R ¹¹ are (C ₁ -C ₆ ) alkyl, -OR ¹⁹ , -O (CO) R ¹⁹ , -O (CO) OR ²¹ , -O (CH ₂ ) _1-5 OR ¹⁹ , -O ( CO) NR ¹⁹ R ²⁰ , -NR ¹⁹ R ²⁰ , -NR ¹⁹ (CO) R ²⁰ , -NR ¹⁹ (CO) OR ²¹ , -NR ¹⁹ (CO) NR ²⁰ R ²⁵ , -NR ¹⁹ SO ₂ R ²¹ , -COOR ¹⁹ , -CONR ¹⁹ R ²⁰ , -COR ¹⁹ , -SO ₂ NR ¹⁹ R ²⁰ , S (O) _0-2 R ²¹ , -O (CH ₂ ) _1-10 -COOR ¹⁹ , -O (CH ₂ ) _1-10 CONR ¹⁹ R ²⁰ ,-(C ₁ -C ₆ alkylene) -COOR ¹⁹ , -CH = CH-COOR ¹⁹ , -CF ₃ , -CN, -NO ₂ and halogen independently selected from the group Independently selected from the group consisting of 1 to 3 substituents;
[288] R ¹⁵ and R ¹⁷ are independently selected from the group consisting of —OR ¹⁹ , —O (CO) R ¹⁹ , —O (CO) OR ^21, and —O (CO) NR ¹⁹ R ²⁰ ;
[289] R ¹⁶ and R ¹⁸ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl and aryl, or R ¹⁵ and R ¹⁶ together are ═O or R ¹⁷ and R ¹⁸ together are ═O Is;
[290] d is 1, 2 or 3;
[291] h is 0, 1, 2, 3 or 4;
[292] s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4,
[293] Provided that at least one of s and t is 1 and the sum of m, n, p, s and t is 1 to 6;
[294] when p is 0 and t is 1, the sum of m, s and n is 1 to 5;
[295] when p is 0 and s is 1, the sum of m, t and n is 1 to 5;
[296] v is 0 or 1;
[297] j and k are independently 1 to 5, provided that the sum of j, k and v is 1 to 5;
[298] Q is a bond and R ¹ is If, Ar ¹ may also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
[299] R ¹⁹ and R ²⁰ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl and aryl-substituted (C ₁ -C ₆ ) alkyl;
[300] R ²¹ is (C ₁ -C ₆ ) alkyl, aryl or R ²⁴ -substituted aryl;
[301] R ²² is H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, —C (O) R ¹⁹ or —COOR ¹⁹ ;
[302] R ²³ and R ²⁴ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, -COOH, NO ₂ , -NR ¹⁹ R ²⁰ , -OH and halogeno One to three groups independently selected;
[303] R ²⁵ is H, —OH or (C ₁ -C ₆ ) alkoxy.
[304] Ar ² is preferably phenyl or R ¹¹ -phenyl, in particular (4-R ¹¹ ) -substituted phenyl. Preferred definitions for R ¹¹ are lower alkoxy, in particular methoxy, and halogeno, especially fluoro.
[305] Ar ¹ is preferably phenyl or R ¹⁰ -substituted phenyl, in particular (4-R ¹⁰ ) -substituted phenyl. A preferred definition of R ¹⁰ is halogeno, in particular fluoro.
[306] Some preferred definitions for the -R ¹ -Q- combination variable are as follows:
[307] Q is a bond and R ¹ is lower alkylene, preferably propylene;
[308] Q is a spiro group as defined above, preferably R ¹³ and R ¹⁴ are each ethylene and R ¹² is And R ¹ is — (CH ₂ ) _q where q is 0 to 6;
[309] Q is a bond and R ¹ is Wherein the variables are selected such that R ¹ is —O—CH ₂ —CH (OH) —;
[310] Q is a bond and R ¹ is Wherein the variables are selected such that R ¹ is —CH (OH) — (CH ₂ ) ₂ —;
[311] Q is a bond and R ¹ is Wherein the variables are selected such that R ¹ is —CH (OH) —CH ₂ —S (O) _0-2 —.
[312] Thus, preferred compounds of formula VIII are those wherein G and G ¹ are as defined above and the remaining variables have the following definitions:
[313] Ar ¹ is phenyl or R ¹⁰ -substituted phenyl, R ¹⁰ is halogeno;
[314] Ar ² is phenyl or R ¹¹ -phenyl, R ¹¹ is 1 to 3 substituents independently selected from the group consisting of C ₁ -C ₆ alkoxy and halogeno;
[315] Q is a bond and R ¹ is lower alkylene; Q is a group together with the 3-position ring carbon of azetidinone And preferably R ¹³ and R ¹⁴ are each ethylene, a and b are each 1, and R ¹² is Or; Q is a bond and R ¹ is -O-CH ₂ -CH (OH)-; Q is a bond and R ¹ is -CH (OH)-(CH ₂ ) _2- ; Or Q is a bond and R ¹ is -CH (OH) -CH ₂ -S (O) _0-2- .
[316] Structure
[317] Preferred variables for the G and G ¹ groups of are as follows:
[318] R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, benzyl and acetyl.
[319] Structure
[320] Preferred variables for the G and G ¹ groups of are as follows:
[321] R ³ , R ^3a , R ⁴ and R ^4a are selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, benzyl and acetyl;
[322] R, R ^a and R ^b are independently selected from the group consisting of H, -OH, halogeno, -NH ₂ , azido, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) -alkoxy and -WR ³⁰ Selected,
[323] W is -OC (O)-or -OC (O) -N (R ³¹ )-, R ³¹ is H, R ³⁰ is (C ₁ -C ₆ ) alkyl, -C (O)-(C ₁ -C ₄ ) alkoxy (C ₁ -C ₆ ) alkyl, T, T- (C ₁ -C ₆ ) alkyl, or T or T- (C ₁ -C ₆ ) alkyl [where T is one or two Halogeno or (C ₁ -C ₆ ) alkyl group.
[324] Preferred R ³⁰ substituents are 2-fluorophenyl, 2,4-difluoro-phenyl, 2,6-dichlorophenyl, 2-methylphenyl, 2-thienylmethyl, 2-methoxy-carbonylethyl, thiazole- 2-yl-methyl, 2-furyl, 2-methoxycarbonylbutyl and phenyl.
[325] Preferred combinations of R, R ^a and R ^b are as follows:
[326] 1) R, R ^a and R ^b are independently -OH or -OC (O) -NH-R ³⁰ , in particular R ^a is -OH and R and R ^b are -OC (O) -NH-R ³⁰ R ³⁰ is selected from the preferred substituents specified above or R and R ^a are each -OH, R ^b is -OC (0) -NH-R ³⁰ and R ³⁰ is 2-fluorophenyl, 2,4- Difluorophenyl, 2,6-dichlorophenyl;
[327] 2) R ^a is —OH, halogeno, azido or (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkoxy, and R ^b is H, halogeno, azido or (C ₁ -C ₆ ) Alkoxy (C ₁ -C ₆ ) alkoxy and R is —OC (O) —NH—R ³⁰ , in particular R ^a is —OH, R ^b is H and R ³⁰ is 2-fluorophenyl;
[328] 3) R, R ^a and R ^b are independently —OH or —OC (O) —R ³⁰ and R ³⁰ is (C ₁ -C ₆ ) alkyl, T, or 1 or 2 halogeno or (C T is substituted by _1- C ₆ ) alkyl group, in particular R is -OH, R ^a and R ^b are -OC (O) -R ³⁰ and R ³⁰ is 2-furyl;
[329] 4) R, R ^a and R ^b are independently —OH or halogeno. Three additional classes of preferred compounds are C ^{1 ′} anomeric oxyga beta, C ^{2 ′} anomeric oxyga beta, and R groups are alpha compounds.
[330] G and G ¹ groups are preferably selected from the following structures:
[331]
[332] In the above structure,
[333] Ac is acetyl and Ph is phenyl.
[334] Preferably, R ²⁶ is H or OH, more preferably H. The -OG substituent is preferably at the 4-position of the phenyl ring attached thereto.
[335] In another embodiment, sterol absorption inhibitors useful in the compositions, therapeutic combinations and methods of the present invention include compounds of formula (IX), isomers of compounds of formula (IX), pharmaceutically acceptable salts of compounds of formula (IX) or isomers thereof Or as a solvate or a prodrug of a compound of formula (IX) or an isomer, salt or solvate of a compound of formula (IX):
[336]
[337] In the above formula,
[338] R ²⁶ is
[339] (a) OH;
[340] (b) OCH ₃ ;
[341] (c) fluorine and
[342] (d) chlorine
[343] It is selected from the group consisting of;
[344] R ¹ is
[345] , -SO ₃ H; Natural and non-natural amino acids;
[346] R, R ^a and R ^b are independently selected from the group consisting of H, -OH, halogeno, -NH ₂ , azido, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) -alkoxy and -WR ³⁰ Selected;
[347] W is -NH-C (O)-, -OC (O)-, -OC (O) -N (R ³¹ )-, -NH-C (O) -N (R ³¹ )-, and -OC (S ) -N (R ³¹ )-is independently selected from the group consisting of;
[348] R ² and R ⁶ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl and aryl (C ₁ -C ₆ ) alkyl;
[349] R ³ , R ⁴ , R ⁵ , R ⁷ , R ^3a and R ^4a are H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, -C (O) (C ₁ -C ₆ Independently selected from the group consisting of alkyl and -C (O) aryl;
[350] R ³⁰ is R ³² -substituted T, R ³² -substituted-T- (C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₂ -C ₄ ) alkenyl, R ³² -substituted- ( Group consisting of C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl and R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₆ ) alkyl Independently selected from;
[351] R ³¹ is independently selected from the group consisting of H and (C ₁ -C ₄ ) alkyl;
[352] T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl Become;
[353] R ³² is H, halogeno, (C ₁ -C ₄ ) alkyl, -OH, phenoxy, -CF ₃ , -NO ₂ , (C ₁ -C ₄ ) alkoxy, methylenedioxy, oxo, (C _1- C ₄ ) alkylsulfanyl, (C ₁ -C ₄ ) alkylsulfinyl, (C ₁ -C ₄ ) alkylsulfonyl, -N (CH ₃ ) ₂ , -C (O) -NH (C ₁ -C ₄ ) Alkyl, -C (O) -N ((C ₁ -C ₄ ) alkyl) ₂ , -C (O)-(C ₁ -C ₄ ) alkyl, -C (O)-(C ₁ -C ₄ ) Independently selected from 1 to 3 substituents independently selected from the group consisting of alkoxy and pyrrolidinylcarbonyl; Or R ³² is a covalent bond and nitrogen attached R ³¹ together with R ³² are pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl groups, or (C ₁ -C ₄ ) alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl groups;
[354] Ar ¹ is aryl or R ¹⁰ -substituted aryl;
[355] Ar ² is aryl or R ¹¹ -substituted aryl;
[356] Q is-(CH ₂ ) _q- [where q is 2 to 6], or together with the 3-position ring carbon of azetidinone, a spiro group To form;
[357] Is;
[358] R ¹³ and R ¹⁴ are -CH _2- , -CH (C ₁ -C ₆ alkyl)-, -C (di- (C ₁ -C ₆ ) alkyl), -CH = CH- and -C (C _1- Independently selected from the group consisting of C ₆ alkyl) ═CH—; Or R ¹² together with adjacent R ¹³ or R ¹² together with adjacent R ^{14 form a} —CH═CH— or —CH—C (C ₁ -C ₆ alkyl) — group;
[359] a and b are independently 0, 1, 2 or 3, provided that both are not zero; When the R ¹³ is -CH = CH- or = CH- -C (C ₁ -C ₆ alkyl), a is 1; When R ¹⁴ is —CH═CH— or —C (C ₁ -C ₆ alkyl) = CH—, b is 1; when a is 2 or 3, R ¹³ may be the same or different; when b is 2 or 3, R ¹⁴ may be the same or different;
[360] R ¹⁰ and R ¹¹ are (C ₁ -C ₆ ) alkyl, -OR ¹⁹ , -O (CO) R ¹⁹ , -O (CO) OR ²¹ , -O (CH ₂ ) _1-5 OR ¹⁹ , -O ( CO) NR ¹⁹ R ²⁰ , -NR ¹⁹ R ²⁰ , -NR ¹⁹ (CO) R ²⁰ , -NR ¹⁹ (CO) OR ²¹ , -NR ¹⁹ (CO) NR ²⁰ R ²⁵ , -NR ¹⁹ SO ₂ R ²¹ , -COOR ¹⁹ , -CONR ¹⁹ R ²⁰ , -COR ¹⁹ , -SO ₂ NR ¹⁹ R ²⁰ , S (O) _0-2 R ²¹ , -O (CH ₂ ) _1-10 -COOR ¹⁹ , -O (CH ₂ ) _1-10 CONR ¹⁹ R ²⁰ ,-(C ₁ -C ₆ alkylene) -COOR ¹⁹ , -CH = CH-COOR ¹⁹ , -CF ₃ , -CN, -NO ₂ and halogen independently selected from the group Independently selected from the group consisting of 1 to 3 substituents;
[361] Ar ¹ may also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
[362] R ¹⁹ and R ²⁰ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl and aryl-substituted (C ₁ -C ₆ ) alkyl;
[363] R ²¹ is (C ₁ -C ₆ ) alkyl, aryl or R ²⁴ -substituted aryl;
[364] R ²² is H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, —C (O) R ¹⁹ or —COOR ¹⁹ ;
[365] R ²³ and R ²⁴ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, -COOH, NO ₂ , -NR ¹⁹ R ²⁰ , -OH and halogeno One to three groups independently selected;
[366] R ²⁵ is H, —OH or (C ₁ -C ₆ ) alkoxy.
[367] Ar ² is preferably phenyl or R ¹¹ -phenyl, in particular (4-R ¹¹ ) -substituted phenyl. Preferred definitions for R ¹¹ are lower alkoxy, in particular methoxy, and halogeno, especially fluoro.
[368] Ar ¹ is preferably phenyl or R ¹⁰ -substituted phenyl, in particular (4-R ¹⁰ ) -substituted phenyl. A preferred definition of R ¹⁰ is halogeno, in particular fluoro.
[369] Preferably, Q is lower alkyl or a spiro group as defined above, preferably R ¹³ and R ¹⁴ are each ethylene and R ¹² is to be.
[370] Thus, preferred compounds of formula (IX) are those compounds wherein R ¹ is as defined above and the remaining variables have the following definitions:
[371] Ar ¹ is phenyl or R ¹⁰ -substituted phenyl, R ¹⁰ is halogeno;
[372] Ar ² is phenyl or R ¹¹ -phenyl, R ¹¹ is 1 to 3 substituents independently selected from the group consisting of C ₁ -C ₆ alkoxy and halogeno;
[373] Q is lower alkyl (ie, C-1 to C-2), where Q = C-2 is preferred, or Q is a group together with the 3-position ring carbon of azetidinone And preferably R ¹³ and R ¹⁴ are each ethylene, a and b are each 1, and R ¹² is to be.
[374] Structure
[375] Preferred variables for the R ¹ group of are as follows:
[376] R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, benzyl and acetyl.
[377] Structure
[378] Preferred variables for the R ¹ group of are as follows:
[379] R ³ , R ^3a , R ⁴ and R ^4a are selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, benzyl and acetyl;
[380] R, R ^a and R ^b are independently selected from the group consisting of H, -OH, halogeno, -NH ₂ , azido, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) -alkoxy and -WR ³⁰ Is selected, W is -OC (O)-or -OC (O) -N (R ³¹ )-, R ³¹ is H, R ³⁰ is (C ₁ -C ₆ ) alkyl, -C (O)- (C ₁ -C ₄ ) alkoxy (C ₁ -C ₆ ) alkyl, T, T- (C ₁ -C ₆ ) alkyl, or T or T- (C ₁ -C ₆ ) alkyl [where T is 1 Or substituted by two halogeno or (C ₁ -C ₆ ) alkyl groups.
[381] Preferred R ³⁰ substituents are 2-fluorophenyl, 2,4-difluoro-phenyl, 2,6-dichlorophenyl, 2-methylphenyl, 2-thienylmethyl, 2-methoxy-carbonylethyl, thiazole- 2-yl-methyl, 2-furyl, 2-methoxycarbonylbutyl and phenyl. Preferred combinations of R, R ^a and R ^b are as follows: 1) R, R ^a and R ^b are independently -OH or ^{-OC (O) -NH-R 30} , particularly R ^a is -OH and R And R ^b is —OC (O) —NH—R ³⁰ , R ³⁰ is selected from the preferred substituents specified above or R and R ^a is —OH, R ^b is —OC (0) —NH—R ³⁰ and , R ³⁰ is 2-fluorophenyl, 2,4-difluorophenyl, 2,6-dichlorophenyl; 2) R ^a is —OH, halogeno, azido or (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkoxy, R ^b is H, halogeno, azido or (C ₁ -C ₆ ) Alkoxy (C ₁ -C ₆ ) alkoxy and R is —OC (O) —NH—R ³⁰ , in particular R ^a is —OH, R ^b is H and R ³⁰ is 2-fluorophenyl; 3) R, R ^a and R ^b are independently —OH or —OC (O) —R ³⁰ and R ³⁰ is (C ₁ -C ₆ ) alkyl, T, or 1 or 2 halogeno or (C T is substituted by _1- C ₆ ) alkyl group, in particular R is -OH, R ^a and R ^b are -OC (O) -R ³⁰ and R ³⁰ is 2-furyl; 4) R, R ^a and R ^b are independently —OH or halogeno. Three additional classes of preferred compounds are C ^{1 ′} anomeric oxyga beta, C ^{2 ′} anomeric oxyga beta, and R groups are alpha compounds.
[382] R ¹ is preferably selected from the following structures:
[383]
[384] In the above structure,
[385] Ac is acetyl and Ph is phenyl.
[386] One example of a useful compound of the present invention is a compound of formula X, a pharmaceutically acceptable salt or solvate of a compound of formula X, or a prodrug of a compound of formula X or a salt or solvate of a compound of formula X As a prodrug of:
[387]
[388] In the above formula,
[389] R ¹ is as defined above.
[390] More preferred compounds are represented by the following compounds of formula (XI), pharmaceutically acceptable salts or solvates of compounds of formula (XI), or prodrugs of compounds of formula (XI) or salts or solvates of compounds of formula (XI) will be:
[391]
[392] In another embodiment, (a) a first amount of one or more cardiovascular agents; And (b) a second amount of one or more sterol absorption inhibitors, pharmaceutically acceptable salts or solvates thereof, or prodrugs of said sterol absorption inhibitors or salts or solvates of sterol absorption inhibitors, wherein The first and second doses, whether administered at the same time or continuously, may be used in amounts that are therapeutically effective to treat or prevent vascular disease, diabetes, obesity, or to lower the concentration of sterols in mammalian plasma. Including compositions, pharmaceutical compositions, therapeutic combinations, kits and methods of treatment as mentioned above are provided. Suitable sterol absorption inhibitors include substituted azetidinone compounds or substituted β-lactam compounds, isomers of the substituted azetidinone compounds or substituted β-lactam compounds, such as any of the compounds of formulas I-XI mentioned above, Salts or solvates of such substituted azetidinone compounds or substituted β-lactam compounds or isomers thereof, or prodrol or substituted azetidinone compounds or substitutions of the substituted azetidinone compounds or substituted β-lactam compounds Prodrugs of isomers, salts or solvates of β-lactam compounds. Other useful substituted azetidinone compounds include N-sulfonyl-2-azetidinone as described in US Pat. No. 4,983,597, and Ram et al., Indian J. Chem. Sect. B. 29B, 12 (1990), p. 1134-7; Ethyl 4- (2-oxoazetidin-4-yl) phenoxy-alkanoate as described herein by reference.
[393] Compounds of formulas (I)-(XI) can be prepared by known methods, for example WO 93/02048 discloses -R ¹ -Q- is alkylene; Alkenylene or alkylene interrupted by hetero atoms; Phenylene; Or a method for preparing a compound that is cycloalkylene; WO 94/17038 describes methods for the preparation of compounds wherein Q is a spirocyclic group; WO 95/08532 describes methods for the preparation of compounds wherein -R ¹ -Q- is a hydroxy-substituted alkylene group; PCT / US 95/03196 describes compounds wherein -R ¹ -Q- is a hydroxy-substituted alkylene attached to an Ar ¹ residue via an -O- or S (O) _0-2 -group; United States Patent Application No. 08/463 619 No. (Application 1995. 6. 5 characters), the -R ¹ -Q-, -S (O) a hydroxyl attached to the azetidine ring tea dinon by _{O-2-group-substituted} Processes for the preparation of compounds which are alkylene groups are described.
[394] The daily dose of the sterol absorption inhibitor may range from about 0.1 to about 1000 mg, preferably from about 0.25 to about 50 mg, more preferably about 10 mg, which is administered in a single dose or divided into two to four doses. However, the exact dose is determined by the attending physician, which depends on the efficacy of the compound administered, the age, weight, condition and response of the patient.
[395] When administering a pharmaceutically acceptable salt of the compound, the indicated weight refers to the weight of the acid or base equivalent of the therapeutic compound derived from such salt.
[396] In one aspect of the invention, the composition or therapeutic combination may further comprise one or more pharmacological or therapeutic agents or drugs, eg, lipid lowering agents and / or cholesterol biosynthesis inhibitors, discussed below. .
[397] Non-limiting examples of cholesterol biosynthesis inhibitors for use in the compositions, therapeutic combinations and methods of the present invention include competitive inhibitors of HMG CoA reductase, squalene synthase inhibitors, squalene epoxidase inhibitors and the rate-limiting stages of cholesterol biosynthesis and Mixtures thereof. Non-limiting examples of suitable HMG CoA reductase inhibitors include statins such as lovastatin (such as MEVACOR® available from Merck & Co.), pravastatin (PRAVACHOL® available from Bristol Meyers Squibb), fluvastatin, simvastatin (ZOCOR® available from Merck & Co.), atorvastatin, cerivastatin, rosuvastatin, rivastatin (sodium 7- (4-fluorophenyl) -2,6-diisopropyl-5-methoxymethylpyridine -3-yl) -3,5-dihydroxy-6-heptanoate), CI-981 and pitavastatin (eg NK-104 from Negma Kowa of Japan); HMG CoA synthetase inhibitors such as L-659,699 ((E, E) -11- [3'R- (hydroxy-methyl) -4'-oxo-2'R-oxetanyl] -3, 5,7R-trimethyl-2,4-undecdienoic acid); Squalene synthesis inhibitors such as squalenestatin 1; And squalene epoxidase inhibitors such as NB-598 ((E) -N-ethyl-N- (6,6-dimethyl-2-hepten-4-ynyl) -3-[(3,3'-bar Thiophen-5-yl) methoxy] benzene-methanamine hydrochloride), and other sterol biosynthesis inhibitors such as DMP-565. Preferred HMG CoA reductase inhibitors include lovastatin, pravastatin and simvastatin. The most preferred HMG CoA reductase inhibitor is simvastatin.
[398] In general, the total daily dose of a cholesterol biosynthesis inhibitor is about 0.1 to about 160 mg / day, preferably about 0.2 to about 80 mg / day, which may be administered in a single dose or divided into two to three doses. .
[399] In another preferred embodiment, the composition or therapeutic agent comprises a compound of Formula (II) in combination with one or more cardiovascular agents and one or more cholesterol biosynthesis inhibitors. Preferably, the cholesterol biosynthesis inhibitor comprises one or more HMG CoA reductase inhibitors, for example lovastatin, pravastatin and / or simvastatin.
[400] In another alternative embodiment, the compositions or therapeutics of the present invention further comprise or combine with nicotinic acid (niacin) and / or derivatives thereof for administration with the cardiovascular agent and sterol absorption inhibitors discussed above. It can be included as.
[401] As used herein, a “nicotinic acid derivative”, if available, comprises a pyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure, including acid forms, salts, esters, zwitterions and tautomers Means. Examples of nicotinic acid derivatives include niceritrol, nicofuranose and acipimox (5-methyl pyrazine-2-carboxylic acid 4-oxide). Nicotinic acid and its derivatives inhibit the production of VLDL and its metabolite LDL in the liver and increase HDL and apo A-1 levels. An example of a suitable nicotinic acid product is NIASPAN® (niacin extended-release tablet) available from Kos.
[402] Generally, the total daily dose of nicotinic acid or derivatives thereof is about 500 to about 10,000 mg / day, preferably about 1000 to about 8000 mg / day, more preferably about 3000 to about 6000 mg / day, which is a single dose It may be administered in several portions or divided into several portions.
[403] In another alternative embodiment, the compositions or therapies of the present invention comprise one or more acylCoA: cholesterol O-acyltransferase (“ACAT”) inhibitors that can lower LDL and VLDL levels, the cardiovascular agents and sterols discussed above. It may be further included for administration with an absorption inhibitor or further included in combination with them. ACAT is an enzyme involved in esterifying excess intracellular cholesterol, which can reduce the synthesis of cholesterol esterification product VLDL and overproduction of apo B-100-containing lipoproteins.
[404] Non-limiting examples of useful ACAT inhibitors include abashimibe ([[2,4,6-tris (1-methylethyl) phenyl] acetyl] sulfonic acid, 2,6-bis (1-methylethyl) phenyl ester; Is known as CI-1011), HL-004, Resividide (DuP-128) and CL-277082 (N- (2,4-difluorophenyl) -N-[[4- (2,2- Dimethylpropyl) phenyl] methyl] -N-heptylurea), P. Chang et al., "Current, New and Future Treatments in Dyslipidaemia and Atherosclerosis", Drugs 2000 Jul; 60 (1); 55-93; Incorporated herein by reference.
[405] In another alternative embodiment, the compositions or therapeutics of the present invention discuss probucol or derivatives thereof that can lower LDL levels, such as AGI-1067 and other derivatives described in US Pat. Nos. 6,121,319 and 6,147,250, as discussed above. It can be further included or further combined with it for administration with a cardiovascular agent and a sterol absorption inhibitor.
[406] Generally, the total daily dose of probucol or its derivatives is about 10 to about 2000 mg / day, preferably about 500 to about 1500 mg / day, which will be administered in a single dose or divided into 2 to 4 doses. Can be.
[407] In another alternative embodiment, the compositions or therapeutics of the present invention further comprise, or in combination with, a low density lipoprotein (LDL) receptor activator for administration with a cardiovascular agent and a sterol absorption inhibitor discussed above. It may include. Non-limiting examples of suitable LDL-receptor activators include HOE-402, an imidazolidinyl-pyrimidine derivative that directly stimulates LDL receptor activity. See M. Huettinger et al., "Hypolipidemic activity of HOE. -42 is Mediated by Stimulation of the LDL Receptor Pathway ", Arterioscler. Thromb. 1993; 13: 1005-12.
[408] In general, the total daily dose of LDL receptor activator is from about 1 to about 1000 mg / day, which may be administered in a single dose or divided into 2 to 4 doses.
[409] In another alternative embodiment, the compositions or therapeutics of the present invention comprise fish oil containing omega 3 fatty acids (3-PUFA), which can lower VLDL and triglyceride levels, the cardiovascular preparations discussed above and It may be further included for administration with a sterol absorption inhibitor or further in combination with them. Generally, the total daily dose of fish oil or omega 3 fatty acids is from about 1 to about 30 g / day, which may be administered in a single dose or divided into 2 to 4 doses.
[410] In another alternative embodiment, the compositions or therapeutics of the present invention comprise natural water soluble fibers, such as psyllium, guar, oat and pectin, which can lower cholesterol levels, the cardiovascular agents and sterols discussed above. It may be further included for administration with an absorption inhibitor or further included in combination with them. Generally, the total daily dose of natural water soluble fiber is from about 0.1 to about 10 g / day, which may be administered in a single dose or divided into two to four doses.
[411] In another alternative embodiment, the compositions or therapeutics of the invention may be used in fatty acid esters of plant sterols, plant stanols and / or plant stanols, such as BENECOL® margarine, which may lower cholesterol levels. Knoll esters may be further included or further combined with them for administration with the cardiovascular agents and sterol absorption inhibitors discussed above. Generally, the total daily dose of plant sterols, plant stanols and / or fatty acid esters of plant stanols is from about 0.5 to about 20 g / day, which can be administered in a single dose or divided into two to four doses. have.
[412] In another alternative embodiment, the compositions or therapies of the invention may contain antioxidants such as probucol, tocopherol, ascorbic acid, β-carotene and selenium, or vitamins such as vitamin B ₆ or vitamin B ₁₂ It may be further included in combination with or in combination with the cardiovascular agent and sterol absorption inhibitors discussed above. Generally, the total daily dose of antioxidant or vitamin is about 0.05 to about 10 g / day, which may be administered in a single dose or divided into two to four doses.
[413] In another alternative embodiment, the compositions, therapeutic combinations or methods of the present invention further comprise one or more bile acid sequestrants (insoluble anion exchange resins) for administration with the cardiovascular agents and sterol absorption inhibitors discussed above. Or in combination with these.
[414] Bile acid sequestrants bind bile acids in the intestine, disrupting the enterohepatic circulation of bile acids and increasing fecal excretion of steroids. It is desirable to use bile acid sequestrants because of their non-systemic mode of action. Bile acid sequestrants can lower hepatic cholesterol levels and enhance the synthesis of apo B / E (LDL) receptors that bind to LDL from plasma and further lower blood cholesterol levels.
[415] Non-limiting examples of suitable bile acid sequestrants include cholestyramine [styrene-divinylbenzene copolymers containing quaternary ammonium cationic groups capable of binding bile acids, such as QUESTRAN® available from Bristol-Myers Squibb. Or QUESTRAN LIGHT®], cholestipol [copolymers of diethylenetriamine and 1-chloro-2,3-epoxypropane, for example COLESTID® tablets available from Pharmacia], Colesevelam hydrochloride [eg For example, WelChol® tablets available from Sankyo (poly (allylamine hydrochloride) crosslinked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl) -trimethylammonium bromide), water soluble derivatives, For example, 3,3-ioenes, N- (cycloalkyl) alkylamines and polyglusams, insoluble quaternized polystyrenes, saponins, and mixtures thereof. Lize is described in PCT International Publications WO 97/11345 and WO 98/57652, and US Pat. Nos. 3,692,895 and 5,703,188, which are incorporated herein by reference. Silates plus montmorillonite clay, aluminum hydroxide and calcium carbonate antacids.
[416] Generally, the total daily dose of bile acid sequestrant is about 1 to about 50 g, preferably about 2 to about 16 g per day, which is administered in a single dose or divided into two to four doses.
[417] Also useful in the present invention are compositions and therapeutic combinations that may further include one or more activators for the peroxisomal growth factor-activated receptor (PPAR). These activators act as agonists for the peroxisomal growth factor-activated receptor. Three subtypes of PPARs have been identified, these as peroxysomal growth factor-activated receptor alpha (PPARα), peroxysomal growth factor-activated receptor gamma (PPARγ) and peroxysomal growth factor-activated receptor delta (PPARδ). It is named. PPARδ is sometimes referred to in the art as PPARβ and as NUC1, and it should be recognized that each of these names refers to the same receptor.
[418] PPARα regulates lipid metabolism. PPARα is activated by fibrate and numerous heavy and long chain fatty acids, which are involved in stimulating the β-oxidation reaction of fatty acids. PPARγ receptor subtypes are involved in activating adipocyte differentiation programs but not in stimulating peroxysomal proliferation in the liver. PPARδ has been identified as useful for increasing high density lipoprotein (HDL) levels in humans (WO 97/28149).
[419] PPARα activator compounds are particularly useful for lowering triglyceride levels, moderately lowering LDL levels and increasing HDL levels. Useful examples of PPARα activators include the fibrates mentioned above.
[420] Other examples of PPARα activators useful in the practice of the present invention include suitable fluorophenyl compounds as described in US Pat. No. 6,028,109, which is incorporated herein by reference; Certain substituted phenylpropionic compounds as described in WO 00/75103, which is incorporated herein by reference; And PPARα activator compounds as described in WO 98/43081, which is incorporated herein by reference.
[421] Non-limiting examples of PPARγ activators include suitable derivatives of glitazones or thiazolidinediones, such as troglitazones [eg REZULIN® troglitazone (-5-[[4- [3,4] available from Parke-Davis. -Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione)]; Rosiglitazone [e.g. AVANDIA® rosiglitazone maleate (-5-[[4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl] methyl] -2,4-thiazolidinedione available from SmithKline Beecham , (Z) -2-butenedioate) (1: 1)]; And pioglitazone [eg, ACTOS ™ pioglitazone hydrochloride (5-[[4- [2- (5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl] -2,4-] thiazoli commercially available from Takeda Pharmaceuticals Dindione monohydrochloride)]. Other useful thiazolidinediones include cyglitazone, englitazone, darglitazone and BRL 49653 as described in WO 98/05331, which is incorporated herein by reference; PPARγ activator compounds as described in WO 00/76488, which is incorporated herein by reference; And PPARγ activator compounds as described in US Pat. No. 5,994,554, which is incorporated herein by reference.
[422] Other useful PPARγ activator compounds include certain acetylphenols as described in US Pat. No. 5,859,051, which is incorporated herein by reference; Certain quinoline phenyl compounds as described in WO 99/20275, which is incorporated herein by reference; Aryl compounds as described in WO 99/38845, which is incorporated herein by reference; Certain 1,4-disubstituted phenyl compounds as described in WO 00/63161; Certain aryl compounds as described in WO 01/00579, which is incorporated herein by reference; Benzoic acid compounds as described in WO 01/12612 and WO 01/12187, which are incorporated herein by reference; And substituted 4-hydroxy-phenylalconic acid compounds as described in WO 97/31907, which is incorporated herein by reference.
[423] PPARδ compounds are particularly useful for lowering triglyceride levels or increasing HDL levels. Non-limiting examples of suitable PPARδ activators useful in the compositions of the present invention include suitable thiazole and oxazole derivatives as described in WO 01/00603, which is incorporated herein by reference (e.g. CAS Registry No. 317318-32). -4); Certain fluoro, chloro or thiophenoxy phenylacetic acid as described in WO 97/28149, which is incorporated herein by reference; Suitable non-β-oxidizable fatty acid homologs as described in US Pat. No. 5,093,365, which is incorporated herein by reference; And PPARδ activator compounds as described in WO 99/04815, which is incorporated herein by reference.
[424] Moreover, compounds having multiple functional groups for activating various combinations of PPARα, PPARγ and PPARδ are also useful in the compositions of the present invention. Non-limiting examples include US Pat. No. 6,248,781; WO 00/23416; WO 00/23415; WO 00/23425; WO 00/23445; WO 00/23451; And certain substituted aryl compounds as described in WO 00/63153, all of which are incorporated herein by reference, which are described as useful PPARα and / or PPARγ activator compounds. Other non-limiting examples of useful PPARα and / or PPARγ activator compounds include activator compounds as described in WO 97/25042, which is incorporated herein by reference; Activator compounds as described in WO 00/63190, which is incorporated herein by reference; Activator compounds as described in WO 01/21181, which is incorporated herein by reference; Biaryl-oxa (thia) azole compounds as described in WO 01/16120, which is incorporated herein by reference; Compounds as described in WO 00/63196 and WO 00/63209, which are incorporated herein by reference; Substituted 5-aryl-2,4-thiazolidinedione compounds as described in US Pat. No. 6,008,237, which is incorporated herein by reference; Arylthiazolidinedione and aryloxazolidinedione compounds as described in WO 00/78312 and WO 00 / 78313G, which are incorporated herein by reference; GW2331 or (2- (4- [difluorophenyl] -1-heptylureido) ethyl] phenoxy) -2-methylbutyric acid compound as described in WO 98/05331, which is incorporated herein by reference. ; Aryl compounds as described in US Pat. No. 6,166,049, which is incorporated herein by reference; Oxazole compounds as described in WO 01/17994, which is incorporated herein by reference; And dithiolane compounds as described in WO 01/25225 and WO 01/25226, which are incorporated herein by reference.
[425] Other useful PPAR activator compounds include substituted benzylthiazolidine-2,4-dione compounds as described in WO 01/14349, WO 01/14350 and WO 01/04351, which are incorporated herein by reference; Mercaptocarboxyl compounds as described in WO 00/50392, which is incorporated herein by reference; Ascofuranone compounds as described in WO 00/53563, which is incorporated herein by reference; Carboxylic compounds as described in WO 99/46232, which is incorporated herein by reference; Compounds as described in WO 99/12534, which is incorporated herein by reference; Benzene compounds as described in WO 99/15520, which is incorporated herein by reference; O-anisamide compounds as described in WO 01/21578, which is incorporated herein by reference; And PPAR activator compounds as described in WO 01/40192, which is incorporated herein by reference.
[426] Peroxysomal growth factor-activated receptor activators are administered in a therapeutically effective amount for treating the diseases specified above, for example, preferably from about 50 to about 3000 mg per day, more preferably from about 50 to 1 day. About 2000 mg are administered in a single dose or divided into two to four doses. However, the exact dose is determined by the attending physician, which depends on factors such as the efficacy of the compound administered, the age, weight, condition and response of the patient.
[427] The compositions or therapeutics of the present invention may comprise one or more ileal bile acid transport ("IBAT") inhibitors (or apical sodium co-dependent bile acid transport ("ASBT") inhibitors) as discussed above with cardiovascular agents and sterol absorption inhibitors. It may be further included in combination with (s) or further in combination with them. IBAT inhibitors can inhibit bile acid transport and lower LDL cholesterol levels. Non-limiting examples of suitable IBAT inhibitors include, but are not limited to, benzothiene, for example 2,3,4,5-tetrahydro- as described in PCT Publication WO 00/38727, which is incorporated herein by reference. Included are therapeutic compounds comprising a 1-benzothiene 1,1-dioxide structure.
[428] In general, the total daily dose of an IBAT inhibitor is about 0.01 to about 1000 mg / day, preferably about 0.1 to about 50 mg / day, which may be administered in a single dose or divided into two to four doses.
[429] The compositions or therapeutics of the invention further comprise or combine in combination with one or more cholesteryl ester transfer protein ("CETP") inhibitors for administration with the cardiovascular agent and sterol absorption inhibitors discussed above. CETP is involved in the exchange or transfer of cholesteryl esters that carry triglycerides and HDL in VLDL.
[430] Non-limiting examples of suitable CETP inhibitors are described in PCT Publication WO 00/38721 and US Pat. No. 6,147,090, which is incorporated herein by reference. Pancreatic cholesteryl ester hydrolase (pCEH) inhibitors, such as WAY-121898, are also further included for administration with the peroxysomal growth factor-activated receptor activator and sterol uptake inhibitor discussed above, or Or in combination with these.
[431] Generally, the total daily dose of CETP inhibitor is about 0.01 to about 1000 mg / day, preferably about 0.5 to about 20 mg / day, which may be administered in a single dose or divided into several doses.
[432] The compositions or therapies of the present invention include probucols or derivatives thereof that can lower LDL and HDL levels, such as AGI-1067 and other derivatives described in US Pat. Nos. 6,121,319 and 6,147,250, and the cardiovascular systems discussed above. It may be further included in combination with the agent and the sterol absorption inhibitor, or further in combination with it.
[433] Compositions or therapies of the invention include monocyte and macrophage inhibitors such as polyunsaturated fatty acids (PUFAs); Thyroid hormones including troxin homologues such as CGS-26214 (a thyroxine compound having a fluorinated ring); And may further comprise recombinant proteins of gene therapy and use, eg, recombinant apo E. In general, the total daily dose of these formulations is about 0.01 to about 1000 mg / day, which may be administered in a single dose or divided into 2-4 servings.
[434] Compositions or therapeutic combinations further comprising hormone replacements and hormone replacement compositions are also useful in the present invention. Hormonal agents and compositions useful in the hormone replacement therapy of the present invention include androgens, estrogens, progestins, pharmaceutically acceptable salts and derivatives thereof. Combinations of these agents and compositions are also useful.
[435] The dosage of the androgen and estrogen combination preferably varies from about 1 mg to about 4 mg androgen and from about 1 mg to about 3 mg estrogen. Examples thereof include esterified estrogens (sodium estrone sulfate and sodium aquiline sulfate) and methyltestosterone (17-hydroxy-17-methyl, available from Solvay Pharmaceuticals, Inc. (Marietta, GA) under the trade name Estratest. Combinations of androgens and estrogens, such as, but not limited to, combinations of (17B) -androst-4-en-3-one).
[436] The estrogen and estrogen combination may vary from a dosage of 0.01 to 8 mg or less, preferably about 0.3 to about 3.0 mg. Examples of useful estrogens and estrogen combinations include:
[437] (a) sodium estrone sulfate, sodium aquilin sulfate, sodium 17α-dihydroequiline sulfate, sodium 17α-estradiol sulfate, available from Duramed Pharmaceuticals, Inc. (Cincinnati, OH) under the trademark Cenestin, Of nine synthetic estrogenous substances, including sodium 17β-dihydroequiline sulfate, sodium 17α-dihydroequilenine sulfate, sodium 17β-dihydroequilenine sulfate, sodium equilenin sulfate and sodium 17β-estradiol sulfate Blends;
[438] (b) Ethinyl estradiol (19-nor-17α-pregna-1,3,5 (10) -triene-20-, available from Schering Plough Corporation (Kenilworth, NJ) under the trade name Estinyl. Phosphorus-3,17-diol;
[439] (c) esterified estrogen combinations, such as sodium estrone sulfate and sodium, available from Solvay under the tradename Estratab and available from Monarch Pharmaceuticals (Bristol, TN) under the trade name Menest. Aquilin sulfate;
[440] (d) available from Pharmacia & Upjohn (Peapack, NJ) under the trade name Ogen and from Women First Health Care, Inc. (San Diego, CA) under the trade name Ortho-Est, Estropiate (piperazine estra-1,3,5 (10) -trien-17-one, 3- (sulfooxy) -estrone sulfate); And
[441] (e) conjugated estrogens (17α-dihydroequilin, 17α-estradiol, and 17β-dihydroequilin) available from Wyeth-Ayerst Pharmaceuticals (Philadelphia, PA) under the trade name Premarin.
[442] Progestins and estrogens may also be administered in various dosages of generally about 0.05 to about 2.0 mg progestin and about 0.001 to about 2 mg estrogen, preferably about 0.1 to about 1 mg progestin and about 0.01 to about 0.5 mg estrogen. Examples of progestin and estrogen combinations that may vary in dosage and regimen include:
[443] (a) Estradiol (estra-1,3,5 (10) -triene-3,17β-diol hemihydrate) and norde available from Pharmacia & Upjohn (Peapack, NJ) under the trade name Actella A combination of ethynrone (17β-acetoxy-19-nor-17α-pregan-4-ene-20-yn-3-one);
[444] (b) available from Wyeth-Ayerst under the trade name Alesse, from Watson Laboratories, Inc. (Corona, CA) under the trade names Levora and Trivora; Levonorgestrel (d (-)-13β-ethyl-17α-ethynyl-17β-hydroxy, available from Monarch Pharmaceuticals under the tradename Nordette and available from Wyeth-Ayerst under the trade name Triphasil). Gon-4-en-3-one) and ethynyl estradiol;
[445] (c) under the trade name Demulen, G.D. Ethinodiol diacetate (19-nor-17α-pregin-4-ene-20-yn-3β, available from Searle & Co. (Chicago, IL) and available from Watson under the trade name Zovia. , 17-diol diacetate) and a combination of ethynyl estradiol;
[446] (d) Desogenestrel, available from Organon under the trade names Desogen and Mircette and available from Ortho-McNeil Pharmaceutical (Raritan, NJ) under the trade name Ortho-Cept. 13-ethyl-11-methylene-18,19-dinonor-17α-pregin-4-ene-20-yn-17-ol) and a combination of ethynyl estradiol;
[447] (e) available from Parke-Davis (Morris Plains, NJ) under the trade names Estrostep and femhrt, and include Microgestin, Necon and Tri-Norinyl ( Tri-Norinyl, available from Watson under the tradename Modicon and Ortho-Novum, available from Ortho-McNeil, under the trade name Obv under Warner Chilcott Laboratories (Rockaway, A combination of noethine drone and ethynyl estradiol available from NJ);
[448] (f) available from Wyeth-Ayerst under the trade names Ovral and Lo / Ovral, and from Watson under the trade names Ogestrel and Low-Ogestrel. Of available norgestrel ((±) -13-ethyl-17-hydroxy-18,19-dinor-17α-preg-4-ene-20-yn-3-one) and ethynyl estradiol Combinations;
[449] (g) noethine drone, ethynyl estradiol and mestranol (3-methoxy-19-nor-17α-pregnna-1, available from Watson under the trade names Brevicon and Norinyl); , 3,5 (10) -trien-20-in-17-ol);
[450] (h) finely divided with 17β-estradiol (estra-1,3,5 (10) -triene-3,17β-diol), available from Ortho-McNeil under the trade name Ortho-Prefest. A combination of norgestimate (17α-17- (acetyloxy) -13-ethyl-18,19-dinonorpregan-4-ene-20-yn-3-one-3-oxime);
[451] (i) Norgestimate (18,19-dinonor-17-pregine-4, available from Ortho-McNeil under the trade names Ortho Cyclen and Ortho Tri-Cyclen); -En-20-yn-3-one, 17- (acetyloxy) -13-ethyl-, oxime, a combination of (17 (α)-(+)-) with ethynyl estradiol; and
[452] (j) Conjugated estrogens (sodium estrone sulfate and sodium aquiline sulfate) and hydroxyprogesterone acetate (20-dione, 17- (acetyl), available from Wyeth-Ayerst under the trade names Premphase and Prempro. Oxy) -6-methyl-, a combination of (6 (α))-pregin-4-ene-3).
[453] In general, the dosage of progestin may vary from about 0.05 to about 10 mg or up to about 200 mg when finely divided progesterone is administered. Examples of progestins are available from ESI Lederle, Inc. (Philadelphia, PA) under the trade name Aygestin, and available from Ortho-McNeil under the trade name Micronor, Nor-QD Noethyne drone, available from Watson under the tradename; Norgestrel, available from Wyeth-Ayerst under the trademark Orvrette; Finely divided progesterone (pregan-4-ene-3,20-dione) available from Solvay under the trade name Prometrium; And hydroxyprogesterone acetate available from Pharmacia & Upjohn under the trade name Provera.
[454] The compositions, therapeutic combinations or methods of the invention may further comprise one or more obesity control drugs. Useful obesity control drugs include, but are not limited to, drugs that reduce energy absorption or suppress appetite, drugs that increase energy expenditure and nutrient-distributing agents. Suitable obesity control drugs include noradrenergic agonists (eg, diethylpropion, mardol, phenylpropanolamine, phentermine, pendimethazine, pendamine tartrate, methamphetamine, pendimethazine and tartrate); Serotonin agonist agents such as sibutramine, fenfluramine, dexfenfluramine, fluorcetin, fluvoxamine and paroxin; Pyrogenic agents such as ephedrine, caffeine, theophylline and optional β3-adrenergic agonists; Alpha-blockers; Kinite or AMPA receptor antagonists; Leptin lipolysis stimulated receptors; Phosphodiesterase enzyme inhibitors; Compounds having the nucleotide sequence of a mahogany gene; Fibroblast growth factor-10 polypeptide; Monoamine oxidase inhibitors (e.g. befloxatone, moclobemid, broparomin, phenoxatine, esupron, bepol, toloxatone, pyrrindole, amiflavin, cerchlorremin, panzaphrine, lazabe Mead, millasemide and caroxazone); And compounds for increasing lipid metabolism (eg, evodiamine compounds); And lipase inhibitors such as orlistat. In general, the total daily dose of the aforementioned obesity control drug is 1 to 3,000 mg / day, preferably about 1 to 1,000 mg / day, more preferably about 1 to 200 mg / day, which is a single dose. It may be administered or divided into 2 to 4 doses.
[455] The compositions, therapeutic combinations or methods of the invention add one or more blood modifiers that are chemically or structurally different from the sterol absorption inhibitors discussed above (eg, compounds of Formulas I-XI) and cardiovascular agents discussed above. For example, they contain one or more different atoms and have different atomic arrangements or different numbers of one or more atoms than the sterol absorption inhibitors and cardiovascular agents presented above. Different blood control agents include anticoagulants (argatroban, vivalidin, dalteparin sodium, decirudine, dicoumarol, liafolate sodium, napamosat mesylate, fenprocomon, tinzaparin sodium, warfarin salt); Antithrombotic agents (anagrelide hydrochloride, vivalirudin, cilostazol, dalteparin sodium, danaparoid sodium, dazociben hydrochloride, epegatran sulfate, enoxaparin sodium, fluretophene, efetro Half, Ifetroban Sodium, Ramipiban, Lotrafiban Hydrochloride, Naxatran, Orbopiban Acetate, Roxypiban Acetate, Sibrapivan, Tinzaparin Sodium, Trifenagrel, Apsisimab, Zolimomab Arytox); Fibrinogen receptor antagonists (Roxypiban acetate, pradapiban, orbopiban, rotrapibane hydrochloride, tyropiban, semmilapiban, monoclonal antibody 7E3, sibrapivan); Platelet inhibitors (cilostazol, clopidogrel bisulfate, epoprostenol, epoprostenol sodium, ticlopidine hydrochloride, aspirin, ibuprofen, naproxen, sulphonic acid, idometacin, mefenamate, drocampam, diclofenac Sulfinpyrazone, pyroxycam, dipyridamole); Platelet aggregation inhibitors (acadesin, veraprost, veraprost sodium, cyprosten calcium, itazigrel, rifarizine, rotrapibane hydrochloride, orbopiban acetate, oxagrelate, pradapiban, orbopiban, tyropiban , Semmilapiban); Blood flow agents (pentoxyphylline); Lipoprotein-related coagulation inhibitors; Factor VIIa inhibitors (4H-3,1-benzoxazine-4-one, 4H-3,1-benzoxazine-4-thione, quinazolin-4-one, quinazolin-4-thione, benzothiazine-4- On, imidazolyl-boronic acid-derived peptide-like TFPI-derived peptide, naphthalene-2-sulfonic acid {1- [3- (aminoiminomethyl) -benzyl] -2-oxo-pyrrolidine-3- (S) -yl} amide trifluoroacetate, dibenzofuran-2-sulfonic acid {1- [3- (aminomethyl) -benzyl] -5-oxo-pyrrolidin-3-yl} -amide, toluene 4-Sulfonic acid {1- [3- (aminoiminomethyl) -benzyl] -2-oxo-pyrrolidin-3- (S) -yl} -amide trifluoroacetate, 3,4-dihydro- 1H-isoquinoline-2-sulfonic acid {1- [3- (aminoiminomethyl) -benzyl] -2-oxo-pyrroline-3- (S) -yl} -amide trifluoroacetate); Factor Xa inhibitors (disubstituted pyrazolines, disubstituted triazolines, substituted n-[(aminoiminomethyl) phenyl] propylamides, substituted n-[(aminomethyl) phenyl] propylamides, tissue factor pathway inhibitors (TFPI) , Low molecular weight heparin, heparinoid, benzimidazolin, benzoxazolinone, benzopiperazinone, indanone, divalent (amidinoaryl) propanoic acid derivatives, amidinophenyl-pyrrolidine, amidinophenyl Pyrroline, amidinophenyl-isoxazolidine, amidinoindole, amidinoazole, bis-arylsulfonylaminobenzamide derivatives, peptidic factor Xa inhibitors).
[456] Compositions, therapeutic combinations or methods of the invention may further comprise one or more antidiabetic agents for lowering blood glucose levels in humans. Different antidiabetic agents include, but are not limited to, drugs that reduce energy absorption or suppress appetite, drugs that increase energy expenditure and nutrient-distributing agents. Suitable antidiabetic agents include sulfonylureas (e.g. acetohexamide, chlorpropamide, glyamide, glyclazide, glymepiride, glipidide, glyburide, glybenclamide, tolazamide and tolbutamide) ); Meglitinides (e.g. repaglinide and nateglinides), biguanides (e.g. metformin and buformin), alpha-glucosidase inhibitors (e.g. acarbose, miglitol, camiglibose and bolglides Bose), certain peptides (eg, amphetides, pramtinides, exendin, and GLP-1 agonistic peptides), and insulins or insulin compositions for oral administration for intestinal delivery thereof. In general, the total dose of the antidiabetic agent mentioned above is 0.1 to 1,000 mg / day, which may be administered in a single dose or divided into 2 to 4 doses.
[457] All mixtures of the aforementioned pharmacological or therapeutic agents can be used in the compositions and therapeutic combinations of the present invention.
[458] The compositions and therapeutic combinations of the invention may be administered to a mammal in need thereof in a therapeutically effective amount for treating vascular disease, such as hypertension. The compositions and therapeutics of the present invention may be administered by any suitable means for bringing these compounds into contact with a site of action in the mammalian or human body, such as plasma, liver or small intestine.
[459] The daily doses for the various compositions and therapeutic combinations mentioned above may be administered to a patient in a single dose or, if desired, in divided doses. Small doses may be administered, for example, 2 to 6 times a day. Sustained release dosage forms can be used. When the cardiovascular agent and the sterol absorption inhibitor are administered in separate dosage forms, the frequency of administration of each component provided per day does not necessarily need to be the same, for example, when one component has a longer active period, It will not be necessary to administer it frequently.
[460] The pharmaceutical therapeutic compositions and therapeutic combinations of the present invention may further comprise one or more pharmaceutically acceptable carriers, one or more excipients and / or one or more additives. Non-limiting examples of pharmaceutically suitable carriers include solids and / or liquids such as ethanol, glycerol, water and the like. The amount of carrier in the therapeutic composition may range from about 5 to about 99 weight percent based on the total weight of the therapeutic composition or therapeutic combination. Non-limiting examples of suitable pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders such as starch, disintegrants, buffers, preservatives, antioxidants, lubricants, flavors, thickeners, colorants , Emulsifiers and the like. The amount of excipient or additive may range from about 0.1 to about 90 weight percent based on the total weight of the therapeutic composition or therapeutic combination. Those skilled in the art will appreciate that amounts of carriers, excipients and additives (if present) may vary.
[461] The therapeutic compositions of the invention may be administered in all conventional dosage forms, preferably in oral dosage forms such as capsules, tablets, powders, cassettes, suspensions or solutions. Formulations and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable and conventional techniques. Some examples of how to prepare a dosage form are provided below.
[462] The following formulations illustrate some dosage forms of the invention. In each formulation, the term "active compound I" refers to a sterol absorption inhibitor and the term "active compound II" refers to the cardiovascular agent mentioned above.
[463] Example-Tablet
[464] numberingredientmg / tablet
[465] 1 active compound I 10
[466] 2 Lactose Monohydrate NF 55
[467] 3 Microcrystalline Cellulose 20
[468] 4 povidone (K29-32) USP 4
[469] 5 Croscarmellose Sodium NF 8
[470] 6 Sodium Lauryl Sulfate 2
[471] 7 Magnesium Stearate NF 1
[472] Total 100
[473] In the present invention, the above-mentioned tablets may be administered in combination with tablets, capsules and the like comprising the active compound II, for example, a dose of the cardiovascular agent as mentioned above.
[474] Manufacturing method:
[475] Item 4 is mixed with purified water in a suitable mixer to form a binder solution. This binder solution is followed by spraying water onto a fluidization processor onto items 1, 2, 6 and a portion of item 5 to granulate the components. Continuous fluidization to dry the wet granules. The dried granules are screened and mixed with item 3 and the remaining amount of item 5. Add item 7 and mix. The mixture is compressed to the appropriate size and weighed on a suitable purifier.
[476] Representative formulations comprising cholesterol absorption inhibitors as discussed above for administration together in separate tablets or capsules are well known in the art and representative formulations comprising cardiovascular agents as discussed above are known in the art. It is well known. When the two active ingredients are administered as a single composition, it is contemplated that dosage forms for sterol absorption inhibitors can be readily modified using the knowledge of those skilled in the art.
[477] The present invention relates to reducing plasma sterols (particularly cholesterol) concentrations or levels by treating with a combination of active ingredients, wherein the active ingredients may be administered separately, or to treating vascular disease, stroke or obesity. As such, the invention also relates to combining separate pharmaceutical compositions in kit form. That is, kits are contemplated that combine two separate units, a pharmaceutical composition comprising one or more cardiovascular agents, and a separate pharmaceutical composition comprising one or more sterol absorption inhibitors as mentioned above. The kit will preferably include instructions for the administration of the separate component. The kit form is particularly advantageous when the separate components must be administered in different dosage forms (eg oral and parenteral) or at different dosage intervals.
[478] Therapeutic compositions and therapeutic combinations of the present invention can inhibit intestinal absorption of cholesterol in mammals, as shown in the following examples, and include vascular diseases such as vascular inflammation, atherosclerosis, hypercholesterolemia and cytosterolemia, It may be useful for treating and / or preventing stroke, obesity and lowering cholesterol plasma levels in mammals, particularly humans.
[479] In another aspect of the invention, the compositions and therapeutic combinations of the invention comprise phytosterols such as cytosterol, campestrol, stigmasterol and avenosterol, 5α-stanols such as cholestanol, 5α-campestanol , 5α-cytostanol), cholesterol, and mixtures thereof, may lower the plasma concentration of one or more sterols selected from the group consisting of and / or inhibit sterol absorption. The plasma concentration may be lowered by administering to a mammal in need thereof an effective amount of one or more therapeutic compositions or therapeutic combinations comprising one or more cardiovascular agents and one or more sterol absorption inhibitors discussed above. The rate of reduction of sterol concentration in plasma may range from about 1 to about 70%, preferably from about 10 to about 50%. Methods of measuring serum total blood cholesterol and total LDL cholesterol are well known to those skilled in the art and include, for example, those described in PCT WO 99/38498 (page 11), incorporated herein by reference. Methods for determining the levels of other sterols in serum are described in H. Gylling et al., "Serum Sterols During Stanol Ester Feeding in a Mildly Hypercholesterolemic Population", J. Lipid Res. 40: 593-600 (1999); Incorporated herein by reference.
[480] Although the present invention is illustrated by the following examples, this does not limit the scope of the invention. Unless otherwise indicated, all parts and percentages mentioned throughout the specification as well as the following examples are by weight.
[481] Preparation of Compound of Formula (II)
[482] Step 1): 4-dimethylaminopyridine (2.5 g, 0.02 mol) and triethylamine in a solution of (S) -4-phenyl-2-oxazolidinone (41 g, 0.25 mol) in CH ₂ Cl ₂ (200 ml) (84.7 ml, 0.61 mol) is added and the reaction mixture is cooled to 0 ° C. Methyl-4- (chloroformyl) butyrate (50 g, 0.3 mol) is added dropwise over 1 hour as a solution in CH ₂ Cl ₂ (375 ml) and the reaction is warmed to 22 ° C. After 17 h, water and H ₂ S0 ₄ (2N, 100 ml) are added, the charge is separated and the organic layer is washed sequentially with NaOH (10%), NaCl (saturated) and water. The organic layer is dried over MgSO ₄ and concentrated to give a semi-crystalline product.
[483] Step 2): Titanium isopropoxide (16.5 ml, 0.055 mol) is added to a solution of TiCl ₄ (18.2 ml, 0.165 mol) in CH ₂ Cl ₂ (600 ml) at 0 ° C. After 15 minutes, the product of step 1 (49.0 g, 0.17 mol) is added as a solution in CH ₂ Cl ₂ (100 ml). After 5 minutes, diisopropylethylamine (DIPEA) (65.2 ml, 0.37 mol) is added and the reaction mixture is stirred at 0 ° C. for 1 hour, the reaction mixture is cooled to −20 ° C. and 4-benzyloxybenzyl Lidine (4-fluoro) aniline (114.3 g, 0.37 mol) is added as a solid. The reaction mixture was stirred vigorously at -20 ° C. for 4 hours, then acetic acid was added dropwise over 15 minutes as a solution in CH ₂ Cl ₂ , the reaction mixture was warmed to 0 ° C. and H ₂ SO ₄ (2N) was added. Add. The reaction mixture is stirred for an additional hour, the layers are separated, washed with water, separated and the organic layer is dried. The crude product is crystallized from ethanol / water to give pure intermediate.
[484] Step 3): N, O-bis (trimethylsilyl) acetamide (BSA) (7.50 ml, 30.3 mmol) was added to a solution of the product of step 2 (8.9 g, 14.9 mmol) in toluene (100 ml) at 50 ° C. . After 0.5 h, solid TBAF (0.39 g, 1.5 mmol) is added and the reaction mixture is further stirred at 50 ° C. for 3 h. The reaction mixture is cooled to 22 ° C. and CH ₃ OH (10 ml) is added. The reaction mixture is washed with HCl (1N), NaHCO ₃ (1N) and NaCl (saturated), and the organic layer is dried over MgSO ₄ .
[485] Step 4): To a solution of the product of step 3 (0.94 g, 2.2 mmol) in CH ₃ OH (3 ml) is added water (1 ml) and LiOH.H ₂ O (102 mg, 2.4 mmol). The reaction mixture is stirred at 22 ° C. for 1 hour, then additional LiOH.H ₂ O (54 mg, 1.3 mmol) is added. After a total of 2 hours, HCl (IN) and EtOAc are added, the layers are separated, and the organic layer is dried and concentrated in vacuo. To the resulting solution of product (0.91 g, 2.2 mmol) in CH ₂ Cl ₂ at 22 ° C. is added ClCOCOCl (0.29 ml, 3.3 mmol) and the mixture is stirred for 16 h. The solvent is removed in vacuo.
[486] Step 5): Effectively stirred 4-fluorophenylzinc chloride prepared from 4-fluorophenylmagnesium bromide (1M in THF, 4.4 ml, 4.4 mmol) and ZnCl ₂ (0.6 g, 4.4 mmol) at 4 ° C. To a suspension of 4.4 mmol) tetrakis (triphenyl-phosphine) palladium (0.25 g, 0.21 mmol) is added, followed by the product of step 4 (0.94 g, 2.2 mmol) as a solution in THF (2 ml). The reaction is stirred at 0 ° C. for 1 hour and then at 22 ° C. for 0.5 hour. HCl (1N, 5 ml) is added and the mixture is extracted with EtOAc. The organic layer was concentrated to an oil and purified by silica gel chromatography to give 1- (4-fluorophenyl) -4 (S)-(4-hydroxyphenyl) -3 (R)-(3-oxo-3- Phenylpropyl) -2-azetidinone: HRMS calcd for C ₂₄ H ₁₉ F ₂ NO ₃ : 408.1429. Found: 408.1411.
[487] Step 6): (R) -tetrahydro-1-methyl-3,3-diphenyl-1H, 3H-pyrrolo- [1,2 to the product of step 5 (0.95 g, 1.91 mmol) in THF (3 ml). -c] [1,3,2] oxazaborole (120 mg, 0.43 mmol) is added and the mixture is cooled to -20 ° C. After 5 minutes, the borohydride-dimethylsulfide complex (2M in THF, 0.85 ml, 1.7 mmol) is added dropwise over 0.5 hour. After a total of 1.5 hours, CH ₃ OH was added, then HCl (1N) was added, and the reaction mixture was extracted with EtOAc 1- (4-fluorophenyl) -3 (R)-[3 (S)-(4- Fluorophenyl) -3-hydroxypropyl)]-4 (S)-[4- (phenylmethoxy) phenyl] -2-azetidinone (Compound 6A-1) is obtained as an oil. ¹ H in CDCl ₃ d H ₃ = 4.68. J = 2.3 Hz. Cl (M + H) 500.
[488] (S) -Tetrahydro-1-methyl-3,3-diphenyl-1H, 3H-pyrrolo- [1,2-c] [1,3,2] oxazaborole with corresponding 3 (R ) -Hydroxypropyl azetidinone (compound 6B-1) is obtained. ¹ H (in CDCl ₃ d) H ₃ = 4.69. J = 2.3 Hz. Cl (M + H) 500.
[489] To a solution of compound 6A-1 (0.4 g, 0.8 mmol) in ethanol (2 ml) is added 10% Pd / C (0.03 g) and the reaction mixture is stirred for 16 h under H ₂ gas pressure (60 psi). The reaction mixture is filtered and the solvent is concentrated to give compound 6A: melting point 164-166 ° C .; Cl (M + H) 410.
[490] [a] _D ²⁵ = -28.1 ° (c 3, CH ₃ OH). Elemental analysis for C ₂₄ H ₂₁ F ₂ NO ₃ : Calcd: C 70.41; H 5.17; N 3.42; Found: C 70.25; H 5.19; N 3.54.
[491] Compound 6B-1 is treated similarly to give compound 6B: melting point 129.5-132.5 ° C .; Cl (M + H) 410. Elemental analysis for C ₂₄ H ₂₁ F ₂ NO ₃ : Calcd: C 70.41; H 5.17; N 3.42; Found: C 70.30; H 5.14; N 3.52.
[492] Step 6 ′ (alternative): To the solution of the product of step 5 (0.14 g, 0.3 mmol) in ethanol (2 ml) was added 10% Pd / C (0.03 g) and the reaction was carried out under H ₂ gas pressure (60 psi) for 16 h. Stir while. The reaction mixture is filtered and the solvent is concentrated to give a 1: 1 mixture of compounds 6A and 6B.
[493] Those skilled in the art will recognize that changes may be made to the above-mentioned aspects without departing from the broad inventive concept of the invention. Accordingly, the invention is not limited to the specific embodiments mentioned, but encompasses modifications within the scope and spirit of the invention as defined by the appended claims.

权利要求:
Claims (49)
[1" claim-type="Currently amended] (a) at least one sterol absorption inhibitor, a pharmaceutically acceptable salt or solvate thereof, or a prodrug of said at least one sterol absorption inhibitor or a salt or solvate of at least one sterol absorption inhibitor; And
(b) one or more cardiovascular agents for treating vascular diseases that are different from the one or more sterol absorption inhibitors
Composition comprising a.
[2" claim-type="Currently amended] The compound of claim 1, wherein the at least one sterol absorption inhibitor is a compound of formula I, an isomer of a compound of formula I, a pharmaceutically acceptable salt or solvate of a compound of formula I, or an isomer thereof, or a compound of formula I Compositions represented as prodrugs of or prodrugs of isomers, salts or solvates of compounds of formula (I):
Formula I

In the above formula,
Ar ¹ and Ar ² are independently selected from the group consisting of aryl and R ⁴ -substituted aryl;
Ar ³ is aryl or R ⁵ -substituted aryl;
X, Y and Z are independently selected from the group consisting of -CH _2- , -CH (lower alkyl)-and -C (di-lower alkyl)-;
R and R ² are independently selected from the group consisting of —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ^9, and —O (CO) NR ⁶ R ⁷ ;
R ¹ and R ³ are independently selected from the group consisting of hydrogen, lower alkyl and aryl;
q is 0 or 1;
r is 0 or 1;
m, n and p are independently selected from 0, 1, 2, 3 or 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; when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5;
R ⁴ is lower alkyl, -OR ⁶ , -O (CO) R ⁶ , -O (CO) OR ⁹ , -O (CH ₂ ) _1-5 OR ⁶ , -O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , -(Lower alkylene) COOR ⁶ , -CH = CH-COOR ⁶ , -CF ₃ , -CN, -NO _2, and 1 to 5 substituents independently selected from the group consisting of halogen;
R ⁵ is -OR ⁶ , -O (CO) R ⁶ , -O (CO) OR ⁹ , -O (CH ₂ ) _1-5 OR ⁶ , -O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ ,-(low) Alkylene) COOR ⁶ and -CH = CH-COOR ⁶ ; 1 to 5 substituents independently selected from the group consisting of;
R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
R ⁹ is lower alkyl, aryl or aryl-substituted lower alkyl.
[3" claim-type="Currently amended] The method of claim 2, wherein the at least one sterol absorption inhibitor is selected from the group consisting of the following compounds of formula II, pharmaceutically acceptable salts or solvates thereof, or prodrugs of compounds of formula II or Compositions Represented by Drugs:
Formula II

[4" claim-type="Currently amended] The compound of claim 1, wherein the at least one sterol absorption inhibitor is a compound of formula III, an isomer of a compound of formula III, a pharmaceutically acceptable salt or solvate of a compound of formula III or an isomer thereof, or a compound of formula III A composition represented as a prodrug of or a prodrug of an isomer, salt or solvate of a compound of formula III:
Formula III

In the above formula,
Ar ¹ is R ³ -substituted aryl;
Ar ² is R ⁴ -substituted aryl;
Ar ³ is R ⁵ -substituted aryl;
Y and Z are independently selected from the group consisting of -CH _2- , -CH (lower alkyl)-and -C (di-lower alkyl)-;
A is -O-, -S-, -S (O)-or -S (O) _2- ;
R ¹ is selected from the group consisting of —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ^9, and —O (CO) NR ⁶ R ⁷ ; R ² is selected from the group consisting of hydrogen, lower alkyl and aryl, or R ¹ and R ² together are ═O;
q is 1, 2 or 3;
p is 0, 1, 2, 3 or 4;
R ⁵ is -OR ⁶ , -O (CO) R ⁶ , -O (CO) OR ⁹ , -O (CH ₂ ) _1-5 OR ⁹ , -O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ -lower alkyl, -NR ⁶ SO ₂ -aryl, -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 -alkyl, S (O) _0-2 -aryl, -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl,-(lower alkylene) -COOR ⁶ and -CH = CH-COOR ⁶ 1 to 3 substituents independently selected from the group consisting of;
R ³ and R ⁴ are independently 1 to 3 substituents independently selected from the group consisting of R ⁵ , hydrogen, p-lower alkyl, aryl, —NO ₂ , —CF ₃ and p-halogeno;
R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
R ⁹ is lower alkyl, aryl or aryl-substituted lower alkyl.
[5" claim-type="Currently amended] The compound of claim 1, wherein the at least one sterol absorption inhibitor is a compound of formula IV, an isomer of a compound of formula IV, a pharmaceutically acceptable salt or solvate of the compound of formula IV or an isomer thereof, or a compound of formula IV A composition represented as a prodrug of or a prodrug of an isomer, salt or solvate of a compound of formula IV:
Formula IV

In the above formula,
A is R ² - is selected from the group consisting of a substituted benzo fused heteroaryl, substituted heterocycloalkyl, R ² - substituted heteroaryl, R ² - - a substituted benzo fused heterocycloalkyl, and R ^2;
Ar ¹ is aryl or R ³ -substituted aryl;
Ar ² is aryl or R ⁴ -substituted aryl;
Q is a spiro group, either as a bond or with the 3-position ring carbon of the corresponding azetidinone To form;
R ¹ is
-(CH ₂ ) _q -wherein q is 2 to 6, provided that Q may be 0 or 1 if Q forms a spiro ring;
-(CH ₂ ) _e -G- (CH ₂ ) _r -wherein G is -O-, -C (O)-, phenylene, -NR ⁸ -or -S (O) _0-2- , e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
-(C ₂ -C ₆ alkenylene)-; And
-(CH ₂ ) _f -V- (CH ₂ ) _g- [where V is C ₃ -C ₆ cycloalkylene, f is 1 to 5 and g is 0 to 5, provided the sum of f and g is 1 to 6];
Is selected from;
R ⁶ and R ⁷ are -CH _2- , -CH (C ₁ -C ₆ alkyl)-, -C (di- (C ₁ -C ₆ ) alkyl), -CH = CH- and -C (C _1- C ₆ alkyl) is independently selected from the group consisting of CH-, or R ⁵ together with adjacent R ⁶ or R ⁵ together with adjacent R ⁷ -CH = CH- or -CH = C (C ₁ -C ₆ alkyl)-form a group;
a and b are independently 0, 1, 2 or 3, provided that both are not 0; R ⁶ is a -CH = CH- or -C (C ₁ -C ₆ alkyl) = CH-, a is 1; If R ⁷ is —CH═CH— or —C (C ₁ -C ₆ alkyl) = CH—, b is 1; when a is 2 or 3, R ⁶ may be the same or different; when b is 2 or 3, R ⁷ may be the same or different;
If Q is a bond, then R ¹ is also
Can be selected from;
M is -O-, -S-, -S (O)-or -S (O) _2- ;
X, Y and Z are independently selected from the group consisting of -CH _2- , -CH (C ₁ -C ₆ alkyl)-and -C (di- (C ₁ -C ₆ ) alkyl);
R ¹⁰ and R ¹² are independently selected from the group consisting of —OR ¹⁴ , —O (CO) R ¹⁴ , —O (CO) OR ^16, and —O (CO) NR ¹⁴ R ¹⁵ ;
R ¹¹ and R ¹³ are independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl and aryl, or R ¹⁰ and R ¹¹ together are ═O or R ¹² and R ¹³ together are ═O Is;
d is 1, 2 or 3;
h is 0, 1, 2, 3 or 4;
s is 0 or 1; t is 0 or 1; m, n and p are independently 0 to 4, provided that at least one of s and t is 1 and the sum of m, n, p, s and t is 1 to 6; when p is 0 and t is 1, the sum of m, s and n is 1 to 5; when p is 0 and s is 1, the sum of m, t and n is 1 to 5;
v is 0 or 1;
j and k are independently 1 to 5, provided that the sum of j, k and v is 1 to 5;
R ² is hydrogen, (C ₁ -C ₁₀ ) alkyl, (C ₂ -C ₁₀ ) alkenyl, (C ₂ -C ₁₀ ) alkynyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ Cycloalkenyl, R ¹⁷ -substituted aryl, R ¹⁷ -substituted benzyl, R ¹⁷ -substituted benzyloxy, R ¹⁷ -substituted aryloxy, halogeno, -NR ¹⁴ R ¹⁵ , NR ¹⁴ R ¹⁵ (C ₁ -C ₆ alkylene)-, NR ¹⁴ R ¹⁵ C (O) (C ₁ -C ₆ alkylene)-, -NHC (O) R ¹⁶ , OH, C ₁ -C ₆ alkoxy, -OC (O) R ¹⁶ , -COR ¹⁴ , hydroxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, NO ₂ , -S (O) _0-2 R ¹⁶ ,- 1 to 3 substituents on a ring carbon atom selected from the group consisting of SO ₂ NR ¹⁴ R ¹⁵ and-(C ₁ -C ₆ alkylene) COOR ¹⁴ ; When R ² is a substituent on a heterocycloalkyl ring, R ² is as defined or = O or ego; When R ² is a substituent on a substitutable ring nitrogen, it is hydrogen, (C ₁ -C ₆ ) alkyl, aryl, (C ₁ -C ₆ ) alkoxy, aryloxy, (C ₁ -C ₆ ) alkylcarbonyl, aryl Carbonyl, hydroxy,-(CH ₂ ) _1-6 CONR ¹⁸ R ¹⁸ , Is; J is -O-, -NH-, -NR ¹⁸ -or -CH _2- ;
R ³ and R ⁴ are (C ₁ -C ₆ ) alkyl, -OR ¹⁴ , -O (CO) R ¹⁴ , -O (CO) OR ¹⁶ , -O (CH ₂ ) _1-5 OR ¹⁴ , -O ( CO) NR ¹⁴ R ¹⁵ , -NR ¹⁴ R ¹⁵ , -NR ¹⁴ (CO) R ¹⁵ , -NR ¹⁴ (CO) OR ¹⁶ , -NR ¹⁴ (CO) NR ¹⁵ R ¹⁹ , -NR ¹⁴ SO ₂ R ¹⁶ , -COOR ¹⁴ , -CONR ¹⁴ R ¹⁵ , -COR ¹⁴ , -SO ₂ NR ¹⁴ R ¹⁵ , S (O) _0-2 R ¹⁶ , -O (CH ₂ ) _1-10 -COOR ¹⁴ , -O (CH ₂ ) _1-10 CONR ¹⁴ R ¹⁵ , independently selected from the group consisting of-(C ₁ -C ₆ alkylene) -COOR ¹⁴ , -CH = CH-COOR ¹⁴ , -CF ₃ , -CN, -NO ₂ and halogen Independently selected from the group consisting of 1 to 3 substituents;
R ⁸ is hydrogen, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, —C (O) R ¹⁴ or —COOR ¹⁴ ;
R ⁹ and R ¹⁷ are independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, -COOH, NO ₂ , -NR ¹⁴ R ¹⁵ , OH and halogeno 1 to 3 groups selected from;
R ¹⁴ and R ¹⁵ are independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, aryl and aryl-substituted (C ₁ -C ₆ ) alkyl;
R ¹⁶ is (C ₁ -C ₆ ) alkyl, aryl or R ¹⁷ -substituted aryl;
R ¹⁸ is hydrogen or (C ₁ -C ₆ ) alkyl;
R ¹⁹ is hydrogen, hydroxy or (C ₁ -C ₆ ) alkoxy.
[6" claim-type="Currently amended] The compound of claim 1, wherein the at least one sterol absorption inhibitor is a compound of formula V, an isomer of a compound of formula V, a pharmaceutically acceptable salt or solvate of the compound of formula V or an isomer thereof, or a compound of formula V A composition represented as a prodrug of or as a prodrug of an isomer, salt or solvate of a compound of formula V:
Formula V

In the above formula,
Ar ¹ is aryl, R ¹⁰ -substituted aryl or heteroaryl;
Ar ² is aryl or R ⁴ -substituted aryl;
Ar ³ is aryl or R ⁵ -substituted aryl;
X and Y are independently selected from the group consisting of -CH _2- , -CH (lower alkyl)-and -C (di-lower alkyl)-;
R is —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ⁹ or —O (CO) NR ⁶ R ⁷ ; R ¹ is hydrogen, lower alkyl or aryl or R and R ¹ together are ═O;
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 the sum of m, n and q is 1,2, 3, 4 or 5;
R ⁴ is lower alkyl, -OR ⁶ , -O (CO) R ⁶ , -O (CO) OR ⁹ , -O (CH ₂ ) _1-5 OR ⁶ , -O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , -(Lower alkylene) 1-5 substituents independently selected from the group consisting of COOR ⁶ and -CH = CH-COOR ⁶ ;
R ⁵ is -OR ⁶ , -O (CO) R ⁶ , -O (CO) OR ⁹ , -O (CH ₂ ) _1-5 OR ⁶ , -O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , -CF ₃ , 1 -5 substituents independently selected from the group consisting of -CN, -NO ₂ , halogen,-(lower alkylene) COOR ⁶ and -CH = CH-COOR ⁶ ;
R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
R ⁹ is lower alkyl, aryl or aryl-substituted lower alkyl;
R ¹⁰ is lower alkyl, —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ⁹ , —O (CH ₂ ) _1-5 OR ⁶ , —O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , And 1 to 5 substituents independently selected from the group consisting of —CF ₃ , —CN, —NO ₂ and halogen.
[7" claim-type="Currently amended] The compound of claim 1, wherein the at least one sterol absorption inhibitor is a compound of Formula VI, an isomer of a compound of Formula VI, a pharmaceutically acceptable salt or solvate of the compound of Formula VI, or an isomer thereof, or a compound of Formula VI A composition represented as a prodrug of or as a prodrug of an isomer, salt or solvate of a compound of formula VI:
Formula VI

In the above formula,

R ₂ and R ₃ are independently selected from the group consisting of -CH _2- , -CH (lower alkyl)-, -C (di-lower alkyl), -CH = CH- and -C (lower alkyl) = CH- Or R ₁ together with adjacent R ₂ or R ₁ together with adjacent R _{3 form a} —CH═CH— or —CH═C (lower alkyl) — group;
u and v are independently 0, 1, 2 or 3, provided that both are not 0;
Provided that when R ₂ is —CH═CH— or —C (lower alkyl) ═CH—, v is 1;
If R ₃ is -CH = CH- or -C (lower alkyl) = CH-, u is 1;
if v is 2 or 3, R₂May be the same or different;
if u is 2 or 3, R ₃ may be the same or different;
R ₄ is B- (CH ₂ ) _m C (O) —, wherein m is 0, 1, 2, 3, 4 or 5;
B- (CH ₂ ) _q -where q is 0, 1, 2, 3, 4, 5 or 6;
B- (CH ₂ ) _e -Z- (CH ₂ ) _r- [where Z is -O-, -C (O)-, phenylene, -N (R ₈ ) _-or -S (O) _{0- 2-} , 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 r is 0, 1, 2, 3, 4, 5 or 6;
B- (C ₂ -C ₆ alkenylene)-;
B- (C ₄ -C ₆ alkadienylene)-;
B- (CH ₂ ) _t -Z- (C ₂ -C ₆ alkenylene)-[where Z is as defined above and t is 0, 1, 2 or 3, provided that the carbon atoms in the alkenylene chain The sum of t and t is 2, 3, 4, 5 or 6;
B- (CH ₂ ) _f -V- (CH ₂ ) _g- [where V is C ₃ -C ₆ cycloalkylene, f is 1, 2, 3, 4 or 5 and g is 0, 1, 2 , 3, 4 or 5, provided that the sum of f and g is 1, 2, 3, 4, 5 or 6;
B- (CH ₂ ) _t -V- (C ₂ -C ₆ alkenylene)-or
B- (C ₂ -C ₆ alkenylene) -V- (CH ₂ ) _t- [where V and t are as defined above, provided that the sum of the number of carbon atoms and t in the alkenylene chain is 2, 3, 4, 5 or 6;
B- (CH ₂ ) _a -Z- (CH ₂ ) _b -V- (CH ₂ ) _d- [where Z and V are as defined above and a, b and d are independently 0, 1, 2 , 3, 4, 5 or 6, provided the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; or
T- (CH ₂ ) _s -wherein T is cycloalkyl having 3 to 6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6; or
R ₁ and R ₄ together, group To form;
B is indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl or W-substituted heteroaryl, where heteroaryl is pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl , Thiazolyl, pyrazolyl, thienyl, oxazolyl and furanillo, and in the case of nitrogen-containing heteroaryl, its N-oxide or Is;
W is lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower alkoxyimino) -lower alkyl, lower alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, -CF ₃ , -OCF ₃ , benzyl, R ₇ -benzyl, benzyloxy, R ₇ -benzyloxy, phenoxy, R ₇ -phenoxy, dioxolanyl, NO ₂ , -N (R ₈ ) (R ₉ ), N (R ₈ ) (R ₉ ) -lower alkylene-, N (R ₈ ) (R ₉ ) -lower alkylenyloxy-, OH, halogeno, -CN, -N ₃ , -NHC (O) OR ₁₀ , -NHC (O) R ₁₀ , R ₁₁ O ₂ SNH-, (R ₁₁ O ₂ S) ₂ N-, -S (O) ₂ NH ₂ , -S (O) _0-2 R ₈ , tert-butyl Dimethylsilyloxymethyl, -C (O) R ₁₂ , -COOR ₁₉ , -CON (R ₈ ) (R ₉ ), -CH = CHC (O) R ₁₂ , -lower alkylene-C (O) R ₁₂ , R ₁₀ C (O) (lower alkylenyloxy)-, N (R ₈ ) (R ₉ ) C (O) (lower alkylenyloxy)-and 1 to 3 substituents independently selected from the group consisting of (when substituted on a ring carbon atom), wherein the substituent on the substituted heteroaryl ring nitrogen atom, if present, lower alkyl, lower alkoxy, -C (O) OR ₁₀ , -C (O) R ₁₀ , OH, N (R ₈ ) (R ₉ ) -lower alkylene-, N (R ₈ ) (R ₉ ) -lower alkylenyloxy-, -S (O) ₂ NH ₂ and 2- (trimethylsilyl) -ethoxymethyl;
R ₇ is 1 to 3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, —COOH, NO ₂ , —N (R ₈ ) (R ₉ ), OH and halogeno;
R ₈ and R ₉ are independently selected from H or lower alkyl;
R ₁₀ is selected from lower alkyl, phenyl, R ₇ -phenyl, benzyl or R ₇ -benzyl;
R ₁₁ is selected from OH, lower alkyl, phenyl, benzyl, R ₇ -phenyl or R ₇ -benzyl;
R ₁₂ is H, OH, alkoxy, phenoxy, benzyloxy, , -N (R ₈ ) (R ₉ ), lower alkyl, phenyl or R ₇ -phenyl;
R ₁₃ is selected from —O—, —CH ₂ —, —NH—, —N (lower alkyl) — or —NC (O) R ₁₉ ;
R ₁₅ , R ₁₆ and R ₁₇ are H; And independently selected from the group consisting of groups defined for W, or R ₁₅ is hydrogen and R ₁₆ and R ₁₇ together with adjacent carbon atoms attached thereto form a dioxolanyl ring;
R ₁₉ is H, lower alkyl, phenyl or phenyl lower alkyl;
R ₂₀ and R ₂₁ are phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzo Independently selected from the group consisting of fused heteroaryl, W-substituted benzofused heteroaryl and cyclopropyl, wherein heteroaryl is as defined above.
[8" claim-type="Currently amended] The compound of claim 1, wherein the one or more sterol absorption inhibitors is a compound of formula VIIA or VIIB, an isomer of a compound of formula VIIA or VIIB, a pharmaceutically acceptable salt or solvate of the compound of formula VIIA or VIIB, or an isomer thereof, Or as a prodrug of a compound of formula VIIA or VIIB or a prodrug of an isomer, salt or solvate of a compound of formula VIIA or VIIB:
Formula VIIA

Formula VIIB

In the above formula,
A is -CH = CH-, -C≡C- or-(CH ₂ ) _p- , where p is 0, 1 or 2;

D is-(CH ₂ ) _m C (O)-or-(CH ₂ ) _q -where m is 1, 2, 3 or 4 and q is 2, 3 or 4;
E is C ₁₀ to C ₂₀ alkyl or -C (O)-(C ₉ to C ₁₉ ) -alkyl, wherein alkyl contains straight or branched saturated or one or more double bonds;
R is hydrogen, C ₁ -C ₁₅ alkyl (either straight or branched, saturated or containing one or more double bonds), or B- (CH ₂ ) _r- [where r is 0, 1, 2 or 3 ]ego;
R ₁ , R ₂ , R ₃ , R _{1 '} , R _2' and R _{3 '} are hydrogen, lower alkyl, lower alkoxy, carboxy, NO ₂ , NH ₂ , OH, halogeno, lower alkylamino, di-lower alkyl Independently selected from the group consisting of amino, -NHC (O) OR ₅ , R ₆ O ₂ SNH-, and -S (O) ₂ NH ₂ ;
Where n is 0, 1, 2 or 3;
R ₅ is lower alkyl;
R ₆ is OH, lower alkyl, phenyl, benzyl or substituted phenyl [wherein the substituents consist of lower alkyl, lower alkoxy, carboxy, NO ₂ , NH ₂ , OH, halogeno, lower alkylamino and di-lower alkylamino One to three groups independently selected from the group.
[9" claim-type="Currently amended] The compound of claim 1, wherein the at least one sterol absorption inhibitor is a compound of Formula VIII, an isomer of a compound of Formula VIII, a pharmaceutically acceptable salt or solvate of the compound of Formula VIII or an isomer thereof, or a compound of Formula VIII A composition represented as a prodrug of or as a prodrug of an isomer, salt or solvate of a compound of formula VIII:
Formula VIII

In the above formula,
R ²⁶ is H or OG ¹ ;
G and G ¹ are
Independently selected from the group consisting of provided that when R ²⁶ is H or OH, G is not H;
R, R ^a and R ^b are independently selected from the group consisting of H, -OH, halogeno, -NH ₂ , azido, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkoxy or -WR ³⁰ Become;
W is -NH-C (O)-, -OC (O)-, -OC (O) -N (R ³¹ )-, -NH-C (O) -N (R ³¹ )-, and -OC (S ) -N (R ³¹ )-is independently selected from the group consisting of;
R ² and R ⁶ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl and aryl (C ₁ -C ₆ ) alkyl;
R ³ , R ⁴ , R ⁵ , R ⁷ , R ^3a and R ^4a are H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, -C (O) (C ₁ -C ₆ Independently selected from the group consisting of alkyl and -C (O) aryl;
R ³⁰ is R ³² -substituted T, R ³² -substituted-T- (C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₂ -C ₄ ) alkenyl, R ³² -substituted- ( Group consisting of C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl and R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₆ ) alkyl Is selected from;
R ³¹ is selected from the group consisting of H and (C ₁ -C ₄ ) alkyl;
T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R ³² is halogeno, (C ₁ -C ₄ ) alkyl, -OH, phenoxy, -CF ₃ , -NO ₂ , (C ₁ -C ₄ ) alkoxy, methylenedioxy, oxo, (C ₁ -C ₄ ) Alkylsulfanyl, (C ₁ -C ₄ ) alkylsulfinyl, (C ₁ -C ₄ ) alkylsulfonyl, -N (CH ₃ ) ₂ , -C (O) -NH (C ₁ -C ₄ ) alkyl , -C (O) -N ((C ₁ -C ₄ ) alkyl) ₂ , -C (O)-(C ₁ -C ₄ ) alkyl, -C (O)-(C ₁ -C ₄ ) alkoxy and Independently selected from 1 to 3 substituents independently selected from the group consisting of pyrrolidinylcarbonyl; Or R ³² is a covalent bond and nitrogen attached R ³¹ together with R ³² are pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl groups, or (C ₁ -C ₄ ) alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl groups;
Ar ¹ is aryl or R ¹⁰ -substituted aryl;
Ar ² is aryl or R ¹¹ -substituted aryl;
Q is a spiro group, either as a bond or with the 3-position ring carbon of azetidinone To form;
R ¹ is
-(CH ₂ ) _q -wherein q is 2 to 6, provided that Q may be 0 or 1 if Q forms a spiro ring;
-(CH ₂ ) _e -E- (CH ₂ ) _r -wherein E is -O-, -C (O)-, phenylene, -NR ²² -or -S (O) _0-2- , e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
-(C ₂ -C ₆ ) alkenylene-; And
-(CH ₂ ) _f -V- (CH ₂ ) _g- [where V is C ₃ -C ₆ cycloalkylene, f is 1 to 5 and g is 0 to 5, provided the sum of f and g is 1 to 6];
Is;
R ¹³ and R ¹⁴ are -CH _2- , -CH (C ₁ -C ₆ alkyl)-, -C (di- (C ₁ -C ₆ ) alkyl), -CH = CH- and -C (C _1- Independently selected from the group consisting of C ₆ alkyl) ═CH—; Or R ¹² together with adjacent R ¹³ , or R ¹² together with adjacent R ¹⁴ , form a —CH═CH— or —CH═C (C ₁ -C ₆ alkyl) — group;
a and b are independently 0, 1, 2 or 3, provided that both are not zero;
However, when R ¹³ is -CH = CH- or = CH- -C (C ₁ -C ₆ alkyl), a is 1;
When R ¹⁴ is —CH═CH— or —C (C ₁ -C ₆ alkyl) = CH—, b is 1;
when a is 2 or 3, R ¹³ may be the same or different;
when b is 2 or 3, R ¹⁴ may be the same or different;
When Q is a bond, R ¹ is also
Can be;
M is -O-, -S-, -S (O)-or -S (O) _2- ;
X, Y and Z are independently selected from the group consisting of -CH _2- , -CH (C ₁ -C ₆ ) alkyl- and -C (di- (C ₁ -C ₆ ) alkyl);
R ¹⁰ and R ¹¹ are (C ₁ -C ₆ ) alkyl, -OR ¹⁹ , -O (CO) R ¹⁹ , -O (CO) OR ²¹ , -O (CH ₂ ) _1-5 OR ¹⁹ , -O ( CO) NR ¹⁹ R ²⁰ , -NR ¹⁹ R ²⁰ , -NR ¹⁹ (CO) R ²⁰ , -NR ¹⁹ (CO) OR ²¹ , -NR ¹⁹ (CO) NR ²⁰ R ²⁵ , -NR ¹⁹ SO ₂ R ²¹ , -COOR ¹⁹ , -CONR ¹⁹ R ²⁰ , -COR ¹⁹ , -SO ₂ NR ¹⁹ R ²⁰ , S (O) _0-2 R ²¹ , -O (CH ₂ ) _1-10 -COOR ¹⁹ , -O (CH ₂ ) _1-10 CONR ¹⁹ R ²⁰ ,-(C ₁ -C ₆ alkylene) -COOR ¹⁹ , -CH = CH-COOR ¹⁹ , -CF ₃ , -CN, -NO ₂ and halogen independently selected from the group Independently selected from the group consisting of 1 to 3 substituents;
R ¹⁵ and R ¹⁷ are independently selected from the group consisting of —OR ¹⁹ , —O (CO) R ¹⁹ , —O (CO) OR ^21, and —O (CO) NR ¹⁹ R ²⁰ ;
R ¹⁶ and R ¹⁸ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl and aryl, or R ¹⁵ and R ¹⁶ together are ═O or R ¹⁷ and R ¹⁸ together are ═O Is;
d is 1, 2 or 3;
h is 0, 1, 2, 3 or 4;
s is 0 or 1; t is 0 or 1; m, n and p are 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 to 6;
when p is 0 and t is 1, the sum of m, s and n is 1 to 5;
when p is 0 and s is 1, the sum of m, t and n is 1 to 5;
v is 0 or 1;
j and k are independently 1 to 5, provided that the sum of j, k and v is 1 to 5;
Q is a bond and R ¹ is If, Ar ¹ may also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
R ¹⁹ and R ²⁰ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl and aryl-substituted (C ₁ -C ₆ ) alkyl;
R ²¹ is (C ₁ -C ₆ ) alkyl, aryl or R ²⁴ -substituted aryl;
R ²² is H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, —C (O) R ¹⁹ or —COOR ¹⁹ ;
R ²³ and R ²⁴ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, -COOH, NO ₂ , -NR ¹⁹ R ²⁰ , -OH and halogeno One to three groups independently selected;
R ²⁵ is H, —OH or (C ₁ -C ₆ ) alkoxy.
[10" claim-type="Currently amended] The compound of claim 1, wherein the at least one sterol absorption inhibitor is a compound of formula IX, an isomer of a compound of formula IX, a pharmaceutically acceptable salt or solvate of the compound of formula IX or an isomer thereof, or a compound of formula IX A composition represented as a prodrug of or a prodrug of an isomer, salt or solvate of a compound of formula (IX):
Formula IX

In the above formula,
R ²⁶ is
(a) OH;
(b) OCH ₃ ;
(c) fluorine and
(d) chlorine
It is selected from the group consisting of;
R ¹ is
, -SO ₃ H; Natural and non-natural amino acids;
R, R ^a and R ^b are independently selected from the group consisting of H, -OH, halogeno, -NH ₂ , azido, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) -alkoxy and -WR ³⁰ Selected;
W is -NH-C (O)-, -OC (O)-, -OC (O) -N (R ³¹ )-, -NH-C (O) -N (R ³¹ )-, and -OC (S ) -N (R ³¹ )-is independently selected from the group consisting of;
R ² and R ⁶ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl and aryl (C ₁ -C ₆ ) alkyl;
R ³ , R ⁴ , R ⁵ , R ⁷ , R ^3a and R ^4a are H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, -C (O) (C ₁ -C ₆ Independently selected from the group consisting of alkyl and -C (O) aryl;
R ³⁰ is R ³² -substituted T, R ³² -substituted-T- (C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₂ -C ₄ ) alkenyl, R ³² -substituted- ( Group consisting of C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl and R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₆ ) alkyl Independently selected from;
R ³¹ is independently selected from the group consisting of H and (C ₁ -C ₄ ) alkyl;
T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl Become;
R ³² is H, halogeno, (C ₁ -C ₄ ) alkyl, -OH, phenoxy, -CF ₃ , -NO ₂ , (C ₁ -C ₄ ) alkoxy, methylenedioxy, oxo, (C _1- C ₄ ) alkylsulfanyl, (C ₁ -C ₄ ) alkylsulfinyl, (C ₁ -C ₄ ) alkylsulfonyl, -N (CH ₃ ) ₂ , -C (O) -NH (C ₁ -C ₄ ) Alkyl, -C (O) -N ((C ₁ -C ₄ ) alkyl) ₂ , -C (O)-(C ₁ -C ₄ ) alkyl, -C (O)-(C ₁ -C ₄ ) Independently selected from 1 to 3 substituents independently selected from the group consisting of alkoxy and pyrrolidinylcarbonyl; Or R ³² is a covalent bond and R ³¹ with nitrogen is attached to R ³² together with pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or (C ₁ -C ₄ ) alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl groups;
Ar ¹ is aryl, R ¹⁰ -substituted aryl; Pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
Ar ² is aryl or R ¹¹ -substituted aryl;
Q is-(CH ₂ ) _q- [where q is 2 to 6], or together with the 3-position ring carbon of azetidinone, a spiro group To form;

R ¹³ and R ¹⁴ are -CH _2- , -CH (C ₁ -C ₆ alkyl)-, -C (di- (C ₁ -C ₆ ) alkyl), -CH = CH- and -C (C _1- Independently selected from the group consisting of C ₆ alkyl) ═CH—; Or R ¹² together with adjacent R ¹³ or R ¹² together with adjacent R ^{14 form a} —CH═CH— or —CH—C (C ₁ -C ₆ alkyl) — group;
a and b are independently 0, 1, 2 or 3, provided that both are not zero; When the R ¹³ is -CH = CH- or = CH- -C (C ₁ -C ₆ alkyl), a is 1; When R ¹⁴ is —CH═CH— or —C (C ₁ -C ₆ alkyl) = CH—, b is 1; when a is 2 or 3, R ¹³ may be the same or different; when b is 2 or 3, R ¹⁴ may be the same or different;
R ¹⁰ and R ¹¹ are (C ₁ -C ₆ ) alkyl, -OR ¹⁹ , -O (CO) R ¹⁹ , -O (CO) OR ²¹ , -O (CH ₂ ) _1-5 OR ¹⁹ , -O ( CO) NR ¹⁹ R ²⁰ , -NR ¹⁹ R ²⁰ , -NR ¹⁹ (CO) R ²⁰ , -NR ¹⁹ (CO) OR ²¹ , -NR ¹⁹ (CO) NR ²⁰ R ²⁵ , -NR ¹⁹ SO ₂ R ²¹ , -COOR ¹⁹ , -CONR ¹⁹ R ²⁰ , -COR ¹⁹ , -SO ₂ NR ¹⁹ R ²⁰ , S (O) _0-2 R ²¹ , -O (CH ₂ ) _1-10 -COOR ¹⁹ , -O (CH ₂ ) _1-10 CONR ¹⁹ R ²⁰ ,-(C ₁ -C ₆ alkylene) -COOR ¹⁹ , -CH = CH-COOR ¹⁹ , -CF ₃ , -CN, -NO ₂ and halogen independently selected from the group Independently selected from the group consisting of 1 to 3 substituents;
R ¹⁹ and R ²⁰ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl and aryl-substituted (C ₁ -C ₆ ) alkyl;
R ²¹ is (C ₁ -C ₆ ) alkyl, aryl or R ²⁴ -substituted aryl;
R ²² is H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, —C (O) R ¹⁹ or —COOR ¹⁹ ;
R ²³ and R ²⁴ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, -COOH, NO ₂ , -NR ¹⁹ R ²⁰ , -OH and halogeno One to three groups independently selected;
R ²⁵ is H, —OH or (C ₁ -C ₆ ) alkoxy.
[11" claim-type="Currently amended] The method of claim 1, wherein the one or more cardiovascular agents for treating vascular disease are calcium channel blockers, adrenergic agonists, adrenergic stimulators, angiotensin-converting enzyme (ACE) inhibitors, blood pressure lowering agents, angiotensin II receptor antagonists, anti Composition selected from the group consisting of angina, coronary vasodilators, diuretics, and combinations thereof.
[12" claim-type="Currently amended] The composition of claim 11, wherein the at least one cardiovascular agent is an adrenergic blocker.
[13" claim-type="Currently amended] 13. The composition of claim 12, wherein the adrenergic blocker is an α-receptor inhibitor selected from the group consisting of penpyred hydrochloride, labetalol hydrochloride, prooxane, alfuzosin hydrochloride, and combinations thereof.
[14" claim-type="Currently amended] 13. The method of claim 12, wherein the adrenergic blocker is selected from acebutolol, acebutolol hydrochloride, alprenolol hydrochloride, atenolol, bunolol hydrochloride, carteolol hydrochloride, celiprolol hydrochloride, cetamolol hydrochloride, Cycloprolol hydrochloride, dexpropranolol hydrochloride, diacetolol hydrochloride, dilevalol hydrochloride, esmolol hydrochloride, exaprolol hydrochloride, pestolol sulfate, labetalol hydrochloride, levotaxolol hydrochloride, Levobunol hydrochloride, metalol hydrochloride, metoprolol, metoprolol tartrate, nadolol, parmatolol sulfate, fenbutolol sulfate, fructolol, propranolol hydrochloride Β-receptor selected from the group consisting of rolides, sotalol hydrochloride, timolol, timolol maleate, thiprenolol hydrochloride, tolamolol, bisoprolol, bisoprolol fumarate, nebivolol and combinations thereof A composition that is an inhibitor.
[15" claim-type="Currently amended] 13. The method of claim 12, wherein the adrenergic blocker is brethlium tosylate, dihydroergotamine mesylate, pentolamin mesylate, solipertin tartrate, zoletin hydrochloride, carvedilol, labetalol hydrochloride and these The composition is selected from the group consisting of combinations of.
[16" claim-type="Currently amended] The composition of claim 11, wherein the at least one cardiovascular agent is a calcium channel blocker.
[17" claim-type="Currently amended] The method of claim 16, wherein the calcium channel blocker is Clentiazem maleate, amlodipine besylate, isradipine, nimodipine, felodipine, nilvadipine, nifedipine, telluride hydrochloride, diltiazem hydrochloride, belfos A composition selected from the group consisting of dill, verapamil hydrochloride, postedil and combinations thereof.
[18" claim-type="Currently amended] The composition of claim 11, wherein the at least one cardiovascular agent is an angiotensin-converting enzyme (ACE) inhibitor.
[19" claim-type="Currently amended] 19. The method of claim 18, wherein the angiotensin converting enzyme inhibitor is benazepril hydrochloride, benaziprilat, captopril, delapril hydrochloride, fosinopril sodium, ribenzapril, moexipril hydrochloride, pentopril, perindo Prills, quinapril hydrochloride, quinapril, ramipril, spirapril hydrochloride, spirapril, teprotide, enalapril maleate, ricinopril, jofenopril calcium, perindopril erbumin and combinations thereof The composition is selected from the group consisting of water.
[20" claim-type="Currently amended] The composition of claim 11, wherein the at least one cardiovascular agent is an adrenergic stimulant.
[21" claim-type="Currently amended] 21. The combination product of claim 20, wherein the adrenergic stimulator is a combination product of chlorothiazide and methyldopa, a combination product of methyldopa hydrochlorothiazide and methyldopa, a combination product of clonidine hydrochloride, clonidine, chlortalidone and clonidine hydrochloride. , Guanfacin hydrochloride and combinations thereof.
[22" claim-type="Currently amended] The composition of claim 11, wherein the at least one cardiovascular agent is a blood pressure lowering agent.
[23" claim-type="Currently amended] 23. The method of claim 22, wherein the blood pressure lowering agent is althiazide, benzthiazide, captopril, carvedilol, chlorothiazide sodium, clonidine hydrochloride, cyclothiazide, delapril hydrochloride, dilevalol hydrochloride, doxazosin mesylate , Posinopril Sodium, Guanfasin Hydrochloride, Methyldopa, Metoprolol Succinate, Moexipril Hydrochloride, Monatefil Maleate, Perlanserine Hydrochloride, Phenoxybenzamine Hydrochloride, Prazosin Hydrochloride, Primidolol, Quinapril Hydrochloride, quinaprililat, ramipril, terrazosin hydrochloride, candesartan, candesartan cilexetil, telmisartan, amlodipine besylate, amlodipine maleate, bevantolol hydrochloride and combinations thereof Choose books that composition.
[24" claim-type="Currently amended] The composition of claim 11, wherein the at least one cardiovascular agent is an angiotensin II receptor antagonist.
[25" claim-type="Currently amended] The composition of claim 24, wherein the angiotensin II receptor antagonist is selected from the group consisting of candesartan, irbesartan, losartan potassium, candesartan cilexetil, telmisartan, and combinations thereof.
[26" claim-type="Currently amended] The composition of claim 11, wherein the one or more cardiovascular agents are antianginal agents.
[27" claim-type="Currently amended] 27. The method of claim 26, wherein the antianginal agent is amlodipine besylate, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozin hydrochloride, carvedilol, cinefazette maleate, metoprolol succinate, molsidomine , Monatefil maleate, primidolol, ranolazine hydrochloride, tocifen, verapamil hydrochloride, and combinations thereof.
[28" claim-type="Currently amended] The composition of claim 11, wherein the at least one cardiovascular agent is a coronary vasodilator.
[29" claim-type="Currently amended] 29. The method of claim 28, wherein the coronary vasodilator is postedil, azaclozin hydrochloride, chromonar hydrochloride, clonitrate, diltiazem hydrochloride, dipyridamole, droprenilamine, erythritol tetranitrate , Isosorbide dinitrate, isosorbide mononitrate, lidofrazine, myoflavin hydrochloride, mixidine, molsidomine, nicorandil, nifedipine, nisoldipine, nitroglycerin, oxprenolol hydrochloride, pent A composition selected from the group consisting of linitrol, perhexyl maleate, prenylamine, propargyl nitrate, terodilin hydrochloride, tolamolol, verapamil, and combinations thereof.
[30" claim-type="Currently amended] The composition of claim 11, wherein the at least one cardiovascular agent is a diuretic.
[31" claim-type="Currently amended] 31. The composition of claim 30, wherein the diuretic is selected from the group consisting of a combination product of hydrochlorothiazide and spironolactone and a combination product of hydrochlorothiazide and triamterene.
[32" claim-type="Currently amended] The composition of claim 1, wherein the at least one cardiovascular agent is rabetalol hydrochloride.
[33" claim-type="Currently amended] The composition of claim 1, wherein the one or more cardiovascular agents for treating vascular disease are administered to the mammal in an amount ranging from about 50 to about 3000 mg per day.
[34" claim-type="Currently amended] The composition of claim 1, wherein the one or more sterol absorption inhibitors are administered to the mammal in an amount ranging from about 0.1 to about 1000 mg per day.
[35" claim-type="Currently amended] The composition of claim 1 further comprising one or more cholesterol biosynthesis inhibitors.
[36" claim-type="Currently amended] 36. The composition of claim 35, wherein the at least one cholesterol biosynthesis inhibitor comprises at least one HMG CoA reductase inhibitor.
[37" claim-type="Currently amended] The composition of claim 36, wherein the one or more HMG CoA reductase inhibitors comprise lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, rosuvastatin, rivastatin, cerivastatin, and mixtures thereof.
[38" claim-type="Currently amended] The composition of claim 37, wherein the at least one HMG CoA reductase inhibitor comprises simvastatin.
[39" claim-type="Currently amended] The composition of claim 1 further comprising one or more bile acid sequestrants.
[40" claim-type="Currently amended] The composition of claim 1, further comprising one or more acylCoA: cholesterol O-acyltransferase inhibitors.
[41" claim-type="Currently amended] The composition of claim 1 further comprising probucol or a derivative thereof.
[42" claim-type="Currently amended] The composition of claim 1 further comprising one or more low density lipoprotein receptor activators.
[43" claim-type="Currently amended] The composition of claim 1 further comprising at least one omega 3 fatty acid.
[44" claim-type="Currently amended] The composition of claim 1 further comprising at least one natural water soluble fiber.
[45" claim-type="Currently amended] The composition of claim 1 further comprising one or more antioxidants or vitamins.
[46" claim-type="Currently amended] A pharmaceutical composition for treating or preventing vascular disease, obesity, diabetes, or lowering the concentration of sterols in mammalian plasma, comprising a therapeutically effective amount of the composition of claim 1 and a pharmaceutically acceptable carrier.
[47" claim-type="Currently amended] For mammals in need of treatment,
(a) an effective amount of at least one sterol absorption inhibitor, a pharmaceutically acceptable salt or solvate thereof, or a prodrug of said at least one sterol absorption inhibitor or a salt or solvate of at least one sterol absorption inhibitor; And
(b) an effective amount of at least one cardiovascular agent different from the sterol absorption inhibitor
A method of treating or preventing vascular disease, diabetes, obesity, or lowering the concentration of sterols in the plasma of a mammal, comprising administering a.
[48" claim-type="Currently amended] 48. The method of claim 47, wherein the vascular disease is hyperlipidemia.
[49" claim-type="Currently amended] (a) a first amount of at least one sterol absorption inhibitor, a pharmaceutically acceptable salt or solvate thereof, or a prodrug of the at least one sterol absorption inhibitor or a salt or solvate thereof; And
(b) a second amount of at least one cardiovascular agent that is different from the at least one sterol absorption inhibitor, wherein the first amount and the second amount are together to treat or prevent vascular disease, obesity, diabetes, or Or a therapeutically effective amount for lowering the concentration of sterols in the plasma of a mammal).

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-01-26|Priority to US60/264,275

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2001-01-26|Priority to US26460001P

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2001-01-26|Priority to US26427501P

---

2001-01-26|Priority to US26439601P

---

2001-01-26|Priority to US60/264,600

---

2001-01-26|Priority to US60/264,396

---

2001-09-21|Priority to US32384201P

---

2001-09-21|Priority to US60/323,842

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2002-01-25|Application filed by 쉐링 코포레이션

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2002-01-25|Priority to PCT/US2002/001196

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2004-03-26|Publication of KR20040025889A

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2006-07-24|First worldwide family litigation filed

优先权:

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申请号 | 申请日 | 专利标题

---

US26460001P| true| 2001-01-26|2001-01-26|

---

US26427501P| true| 2001-01-26|2001-01-26|

---

US26439601P| true| 2001-01-26|2001-01-26|

---

US60/264,600|2001-01-26|

---

US60/264,396|2001-01-26|

---

US60/264,275|2001-01-26|

---

US32384201P| true| 2001-09-21|2001-09-21|

---

US60/323,842|2001-09-21|

---

PCT/US2002/001196|WO2002058731A2|2001-01-26|2002-01-25|Combinations of sterol absorption inhibitor with cardiovascular agent for the treatment of vascular conditions|