Claims
- 1. A method for lowering the plasma cholesterol level in a patient by administration of a compound of formula (1) ##STR14## wherein: R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are each independently a C.sub.1 -C.sub.6 alkyl group;
- Z is a thio, oxy or methylene group;
- A is a C.sub.1 -C.sub.4 alkylene group; and
- R.sub.5 is a C.sub.1 -C.sub.6 alkyl or --(CH.sub.2).sub.n --(Ar)
- wherein n is an integer 0, 1, 2 or 3; and Ar is phenyl or napthyl unsubstituted or substituted with one to three substituents selected from the group consisting of hydroxy, methoxy, ethoxy, chloro, fluoro or C.sub.1 -C.sub.6 alkyl group.
- 2. The method according to claim 1, wherein R.sub.1 and R.sub.2 are C.sub.4 alkyl group.
- 3. The method according to claim 2, wherein Z is thio.
- 4. The method according to claim 2, wherein R.sub.3 and R.sub.4 are C.sub.1.
- 5. The method according to claim 4, wherein R.sub.5 is --(CH.sub.2).sub.n --(Ar).
- 6. The method according to claim 5, wherein Ar is phenyl.
- 7. The method according to claim 6, wherein Ar is phenyl substituted with one to three C.sub.1 -C.sub.6 alkyl substituents.
- 8. The method according to claim 6, wherein Ar is phenyl substituted with one to three methoxy substituents.
- 9. The method according to claim 6, wherein Ar is phenyl substituted with one to three chloro or fluoro substituents.
- 10. The method according to claim 6, wherein Ar is phenyl unsubstituted.
- 11. The method according to claim 5, wherein n is an integer 0.
- 12. The method according to claim 2, wherein Z is oxy.
- 13. The method according to claim 12, wherein R.sub.3 and R.sub.4 are C.sub.1.
- 14. The method according to claim 13, wherein R.sub.5 is --(CH.sub.2).sub.n --(Ar).
- 15. The method according to claim 14, wherein Ar is phenyl.
- 16. The method according to claim 15, wherein Ar is phenyl substituted with one to three C.sub.1 -C.sub.6 alkyl substituents.
- 17. The method according to claim 16, wherein Ar is phenyl substituted with one to three methoxy substituents.
- 18. The method according to claim 17, wherein Ar is phenyl substituted with one to three chloro or fluoro substituents.
- 19. The method according to claim 15, wherein Ar is phenyl unsubstituted.
- 20. The method according to claim 1, wherein n is an integer 0.
- 21. The method according to claim 1, wherein R.sub.1 and R.sub.2 are C.sub.1 alkyl group.
- 22. The method according to claim 21, wherein Z is oxy.
- 23. The method according to claim 22, wherein R.sub.3 and R.sub.4 are C.sub.1.
- 24. The method according to claim 1, wherein one of R.sub.1 and R.sub.2 is C.sub.1 and one of R.sub.1 and R.sub.2 is C.sub.4.
- 25. The method according to claim 1, wherein A is C.sub.4.
- 26. The method according to claim 1, wherein R.sub.1 and R.sub.2 are C.sub.4 alkyl group.
- 27. The method according to claim 1, wherein R.sub.3 and R.sub.4 are C.sub.1 alkyl group.
- 28. The method according to claim 1, wherein Ar is napthyl.
- 29. The method according to claim 1, wherein R.sub.5 is --(CH.sub.2).sub.n --(Ar).
- 30. The method according to claim 29, wherein n is 0.
- 31. The method according to claim 29, wherein Ar is phenyl unsubstituted or substituted with one to three substituents selected from the group consisting of hydroxy, methoxy, ethoxy, chloro, fluoro or C.sub.1 -C.sub.6 alkyl group.
- 32. A method for lowering the plasma cholesterol level in a patient by administration of a compound selected from the group consisting of 2,6-Di-t-butyl-4�(dimethylphenylsilyl)methylthio!phenol, 2,6-Di-t-butyl-4�(dimethyldodecylsilyl)methylthio!phenol, 2,6-Di-t-butyl-4�(trimethylsilyl)methylthio!phenol, 2,6-Dimethyl-4�(trimethylsilyl)methyloxy!phenol, 2,6 Di-t-butyl-4�(4-chlorophenyldimethylsilyl)methyloxy!phenol, 2,6 Di-t-butyl-4�dimethyl-4-fluorophenylsilyl)methyloxy!phenol, 2,6-Di-t-butyl-4�dimethylphenylsilyl)methyloxy!phenol, 2,6-Di-t-butyl-4�(dimethyl-4-methoxy phenylsilyl)methyloxy!phenol, 2,6-Dimethyl-4�(dimethylphenylsilyl)methyloxy!phenol, 2-t-butyl-6-methyl-4�(dimethylphenylsilyl)methylthio!phenol, 2,6-Di-t-butyl-4�(dimethy 1-2-methoxyphenylsilyl)methyloxy!phenol, 2, 6-Di-t-butyl-4-�(dimethyl-2,5-dimethoxyphenylsilyl) methyloxy!phenol, 2,6-Di-t-butyl-4-�(dimethyl-2,3-dimethoxyphenylsilyl) methyloxy!phenol, 2,6-Di-t-butyl-4-�(dimethyl-4-t-butylphenylsilyl) methyloxy!phenol, and 2,6-Di-t-butyl-4-�(benzyldimethylsilyl) methyloxy!phenol.
- 33. The method according to claim 32, wherein the compound is of 2,6-Di-t-butyl-4�(dimethylphenylsilyl)methylthio!phenol.
- 34. The method according to claim 32, wherein the compound is 2,6-Di-t-butyl-4�(dimethyldodecylsilyl)methylthio!phenol.
- 35. The method according to claim 32, wherein the compound is 2,6-Di-t-butyl-4�(trimethylsilyl)methylthio!phenol.
- 36. The method according to claim 32, wherein the compound is 2,6-Dimethyl-4�(trimethylsilyl)methyloxy!phenol.
- 37. The method according to claim 32, wherein the compound is 2,6 Di-t-butyl-4�(4-chlorophenyldimethylsilyl)methyloxy!phenol.
- 38. The method according to claim 32, wherein the compound is 2,6 Di-t-butyl-4�dimethyl-4-fluorophenylsilyl)methyloxy!phenol.
- 39. The method according to claim 32, wherein the compound is 2,6-Di-t-butyl-4�dimethylphenylsilyl)methyloxy!phenol.
- 40. The method according to claim 32, wherein the compound is 2,6-Di-t-butyl-4�(dimethyl-4-methoxy phenylsilyl)methyloxy!phenol.
- 41. The method according to claim 32, wherein the compound is 2,6-Dimethyl-(dimethylphenylsilyl)methyloxy!phenol.
- 42. The method according to claim 32, wherein the compound is 2-t-butyl-6-methyl-4�(dimethylphenylsilyl)methylthio!phenol.
- 43. The method according to claim 32, wherein the compound is 2,6-Di-t-butyl-�(dimethy 1-2-methoxyphenylsilyl)methyloxy!phenol.
- 44. The method according to claim 32, wherein the compound is 2,6-Di-t-butyl-�( dimethyl-2,5-dimethoxyphenylsilyl) methyloxy !phenol.
- 45. The method according to claim 32, wherein the compound is 2,6-Di-t-butyl-�(dimethyl-2,3-dimethoxyphenylsilyl) methyloxy!phenol.
- 46. The method according to claim 32, wherein the compound is 2,6-Di-t-butyl-4-�(dimethyl-4-t-butylphenylsilyl) methyloxy!phenol.
- 47. The method according to claim 32, wherein the compound is 2,6-Di-t-butyl-4-�(benzyldimethylsilyl) methyloxy!phenol.
Parent Case Info
This application is a continuation-in-part application of U.S. Ser. No. 08/409,104 filed Mar. 27, 1995 now abandoned, which is a continuation of application Ser. No. 08/165,281, filed Dec. 10, 1993, now abandoned.
Coronary heart disease (CHD) remains the leading cause of death in the industrialized countries. Despite recent declines in CHD mortality, CHD is still responsible for more than 500,000 deaths in the U.S. annually. It is estimated that CHD, directly and indirectly, costs the U.S. more than $100 billion a year. The primary cause of CHD is atherosclerosis, a disease characterized by the deposition of lipids in the arterial vessel wall, resulting in a narrowing of the vessel passages and ultimately hardening the vascular system.
Atherosclerosis as manifested in its major clinical complication, ischaemic heart disease, is thought to begin with local injury to the arterial endothelium followed by proliferation of arterial smooth muscle cells from the medial layer to the intimal layer along with deposition of lipid and accumulation of foam cells in the lesion. As the atherosclerotic plaque develops, it progressively occludes more and more blood vessel and can eventually lead to ischaemia or infarction. Therefore, it is desirable to provide a method of inhibiting the progression of atherosclerosis in patients in need thereof.
Hypercholesterolemia is an important risk factor associated with CHD. For example, in December 1984, a National Institute of Health Consensus Development Conference Panel concluded that lowering plasma cholesterol levels (specifically blood levels of low-density lipoprotein cholesterol) will definitely reduce the risk of heart attacks due to CHD. Serum lipoproteins are the carriers for lipids in the circulation. They are classified according to their density: chylomicrons, very low-density lipoproteins (VLDL), low density lipoproteins (LDL) and high-density lipoproteins (HDL). Chylomicrons mainly participate in transporting dietary triglycerides and cholesterol from the intestine to adipose tissue and liver. VLDL deliver endogenously synthesized triglycerides from liver to adipose and other tissues. LDL transports cholesterol to peripheral tissues and regulate endogenous cholesterol levels in those tissues. HDL transports cholesterol from peripheral tissues to the liver. Arterial wall cholesterol is derived almost exclusively from LDL (Brown and Goldstein, Ann. Rev. Biochem. 52, 223 (1983); Miller, Ann. Rev. Med. 31, 97 (1980)). In patients with low levels of LDL, the development of atheroscherosis is rare. Accordingly, it is desirable to provide a method for reducing plasma cholesterol in patients with hypercholesterolemia or at risk of developing hypercholesterolemia.
Elevated cholesterol levels are also associated with a number of disease states, including restenosis, angina, cerebral arteriosclerosis, and xanthoma. It is desirable to provide a method for reducing plasma cholesterol in patients with, or at risk of developing, restenosis, angina, cerebral arteriosclerosis, xanthoma, and other disease states associated with elevated cholesterol levels.
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Continuations (1)
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Parent |
165281 |
Dec 1993 |
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Continuation in Parts (1)
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409104 |
Mar 1995 |
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