Patent EA-000514-B1 (EA)
Title: Method of regulating lipoprotein profile of blood plasma in a mammal and pharmaceutical composition to perform thereof
Inventor: BOCAN THOMAS M A
IPC: A61K45/06
Filed: 1996-10-02
Abstract: 1. A method of regulating lipoprotein profile in a mammal in need of said treatment comprising administering a mammal therapeutically effective amounts of an acyl-CoA cholesterol O-acyltransferase (ACAT) inhibitor and an HMG-CoA reductase inhibitor. 2. A method according to Claim 1 wherein the ACAT inhibitor is [[2,4,6-tris(1-methylethyl)phenyl] acetyl]-2,6-bis(1-methylethyl)phenyl ester of sulfamic acid and the HMG-CoA reductase inhibitor is selected from rivastatin, lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin. 3. A method according to Claim 1 wherein as ACAT inhibitor [[2,4,6-tris(1-methylethyl)phenyl] acetyl]-2,6-bis(1-methylethyl)phenyl ester of sulfamic acid and as HMG-CoA reductase inhibitor atorvastatin are used. 4. A pharmaceutical composition for regulating lipoprotein profile in a mammal comprising a therapeutically effective amount of an acyl-CoA cholesterol O-acyltransferase (ACAT) inhibitor and an HMG-CoA reductase inhibitor. 5. A pharmaceutical composition according to Claim 4 wherein the ACAT inhibitor is a one or more compound selected from: sulfamic acid, [[2,4,6-tris(1-methylethyl)phenyl]acetyl]-2,6-bis[(1-meth;ylethyl)phenyl ester; 2,6-bis(l-methyl-ethyl)phenyl [ [2,6-bis(1-methylethyl)phenyl]sulfonyl]carbamate monosodium salt; N-(2,6-diiso-propyl-phenyl)-2-phenyl-malonamic acid dodecyl-ester; N-(2,6-diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl-acetamide; 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)-docecanamide; and N-[2,6-bis(1-methylethyl)-phenyl]-N'-[[1-[4-(dimethylamino)phenyl]-cyclopentyl]methyl urea monohydrochloride; and the HMG-CoA reductase inhibitor is one or more compounds selected from rivastatin, lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin. 6. A pharmaceutical composition according to Claim 4 wherein the ACAT inhibitor is one or more compounds selected from [[2,4,6-tris(1-methylethyl)phenyl] acetyl]-2,6-bis(1-methylethyl)phenyl ester of sulfamic acid, N-(2,6-diiso-propyl-phenyl)-2-phenyl-malonamic acid dodecylester, and N-(2,6-diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl-acetamide; and the HMG-CoA reductase inhibitor is one or more compounds selected from rivastatin, lovastatin, simvastatin, pravastatin, fluvastatin and atorvastatin. 7. A pharmaceutical composition according to Claim 4 wherein the ACAT inhibitor is [[2,4,6-tris(1-methylethyl)phenyl]acetyl]-2,6-bis(1-methylethyl)phenyl ether of sulfamic acid and the HMG-CoA reductase inhibitor is selected from rivastatin, lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin. 8. A pharmaceutical composition according to Claim 4 wherein the ACAT inhibitor is [[2,4,6-tris(1-methylethyl)phenyl] acetyl]-2,6-bis(1-methylethyl)phenyl ester of sulfamic acid and the HMG-CoA reductase inhibitor is atorvastatin. 9. A pharmaceutical composition according to Claim 4 further comprising a pharmaceutically acceptable carrier. 10. A method of restoring endogenous vascular endothelium-dependent activities selected from preventing coagulation of platelets, decreasing the adherent properties of blood vessel walls, and inducing vasodilation to modulate vascular tone and blood flow in a mammal which comprises administering a therapeutically effective amount of one or more ACAT inhibiting compounds and one or more HMG-CoA reductase inhibitors. 11. A method according to Claim 10 wherein the ACAT inhibitor is selected from: sulfamic acid, [[2,4,6-tris(methylethyl)phenyl]acetyl]-, 2,6-bis[(1-methylethyl)phenyl ester; 2,6-bis (1-methylethyl)phenyl-[[2,6-bis(1-methylethyl)-phenyl]sulfonyl] carbamate monosodium salt; N-(2,6-diisopropyl-phenyl)-2-phenyl-malonamic acid dodecyl ester; 2,2-dimethyl-N-(2,4,6-trimethoxy-phenyl)docecanamide; and N-[2,6-bis(1-methylethyl)phenyl]-N'-[[1-[4-(dimethylamino)phenyl]-cyclopentyl]methyl urea monohydrochloride; and the HMG-CoA reductase inhibitor is one or more compounds selected from rivastatin, lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin. 12. A method according to Claim 10 wherein the ACAT inhibitor is 2,6-bis(1-methylethyl)phenyl[[2,4,6-tris(1-methylethyl)phenyl]acetyl]sulfamate, and the HMG-CoA reductase inhibitor is one or more compounds selected from rivastatin, lovastatin, simvastatin, pravastatin, fluvastatin and atorvastatin. 13. A method according to Claim 10, wherein the ACAT inhibitor is [[2,4,6-tris(1-methylethyl)phenyl] acetyl]-2,6-bis(1-methylethyl)phenyl ester of sulfamic acid and the HMG-CoA reductase inhibitor is selected from simvastatin and atorvastatin. 14. A method according to Claim 7 wherein the therapeutically effective dose of ACAT inhibitor is 50 to 1500 mg per day, and the therapeutically effective dose of HMG-CoA reductase inhibitor is about 5 to about 80 mg/day. 15. A method of preventing and/or treating diseases associated with endothelial dysfunction selected from: angina pectoris, myocardial infarctions, coronary artery disease, hypertension, cerebrovascular accidents, transient ischemic attacks chronic obstructive pulmonary disease, chronic hypoxic lung disease, pulmonary hypertension, renal hypertension, chronic renal disease, microvascular complications of diabetes, and vasoocclusive complications of sickle cell anemia which comprises administering to a mammal a therapeutically effective amount of one or more ACAT inhibiting compounds and one or more HMG-CoA reductase inhibitors. 16. A method according to Claim 15 wherein the ACAT inhibitor is selected from: sulfamic acid, [[2,4,6-tris(methylethyl)phenyl]acetyl]-, 2,6-bis[(1-methylethyl)phenyl ester of sulfamic acid carbamate monosodium salt; N-(2,6-diisopropyl-phenyl)-2-phenyl-malonamic acid dodecylester; 5-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-ylbenzo [6]-thiopheno-2-carboxamide monosodium salt; 2,2-dimethyl-N-(2,4,6-trimethoxyphenyO-docecanamide; and N-[2,6-bis(1-methylethyl)-phenyl]-N'-[[1 -[4-(dimethylamino)phenyl]-cyclopentyl]methyl urea monohydrochloride; and the HMG-CoA reductase inhibitor is one or more compounds selected from rivastatin, lovastatin, simvastatin, pravastatin, fluvastatin and atorvastatin. 17. A method according to Claim 15 wherein the ACAT inhibitor is selected from: [[2,4,6-tris(methylethyl)phenyl]acetyl]-, 2,6-bis[(1-methylethyl)phenyl ester of sulfamic acid, N-(2,6-diisopropyl-phenyl)-2-phenyl-malonamic acid dodecyl- ester, and N-(2,6-diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl-acetamide; and the HMG-CoA reductase inhibitor is one or more compounds selected from rivastatin, lovastatin, simvastatin, pravastatin, fluvastatin and atorvastatin. 18. A method of stabilizing atherosclerotic lesion and preventing plaque rupture in a mammal with atherosclerosis comprising administering therapeutically effective amounts of acyl-CoA cholesterol 0-acyltransferase (ACAT) inhibitor and an HMG-CoA reductase inhibitor. 19. A method according to Claim 18 wherein the ACAT inhibitor is sulfamic acid, [[2,4,6-tris(methylethyl)phenyl]acetyl]-2,6-bis[(1-methylethyl)phenyl ester; 2,6-bis(1-methylethyl)phenyl[[2,6-bis(1-methylethyl)phenyl]-sulfonyl]carbamate monosodium salt; N-(2,6-diisopropyl-phenyl)-2-phenyl-malonamic acid dodecylester; 5-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-ylbenzo [6]thiopheno-2-carboxamide monosodium salt; 2,2-dimethyl-N-(2,4,6-trimethoxy phenyl)-docecanamide; and N-[2,6-bis (1-methylethyl)-phenyl]-N'-[[1-[4-(dimethyl amino)phenyl]-cyclopentyl]methyl urea monohydrochloride; and the HMG-CoA reductase inhibitor is one or more compounds selected from rivastatin, lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin. 20. A method according to Claim 18 wherein the ACAT inhibitor is one or more compounds selected from [[2,4,6-tris(1-methylethyl) phenyl]-acetyl]sulfamate 2,6-bis(1-methylethyl)-phenyl, N-(2,6-diisopropyl-phenyl)-2-phenyl-malonamic acid dodecylester, and N-(2,6-diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl) -2-phenyl-acetamide; and the HMG-CoA reductase inhibitor is one or more compounds selected from rivastatin, lovastatin, simvastatin, pravastatin, fluvastatin.