Bicyclic amides as inhibitors of acyl-coenzyme A: cholesterol ac

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...

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514357, 514456, 514596, 514619, 514621, 514622, 514625, 514627, 514630, 546337, 549399, 549400, 549404, 564 55, 564163, 564165, 564166, 564167, 564168, 564170, 564174, 564177, 564179, 564181, 564182, 564200, 564202, 564207, 564218, C07C23311, A61K 31165, A61K 3144, A61K 3135

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054161185

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BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The present invention relates to bicyclic amides and to pharmaceutical compositions containing such compounds, for use in the treatment and prevention of atherosclerosis.
Atherosclerotic coronary heart disease represents the major cause for death and cardiovascular morbidity in the western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes mellitus, family history, male sex, cigarette smoking and serum cholesterol. A total cholesterol level in excess of 225-250 mg/dl is associated with significant elevation of risk.
Cholesterol esters are a major component of atherosclerotic lesions and the major storage form of cholesterol in arterial wall cells. Formation of cholesterol esters is also a key step in the intestinal absorption of dietary cholesterol. The intracellular esterification of cholesterol is catalyzed by the enzyme acyl CoA:cholesterol acyl transferase (ACAT, EC 2.3.1.26). Thus, inhibition of ACAT is likely to inhibit the progression of atherosclerotic lesion formation, decrease the accumulation of cholesterol esters in the arterial wall, and block the intestinal absorption of dietary cholesterol.
A number of bicyclic amides have been reported as being useful in lowering cholesterol and/or inhibiting formation of cholesterol-containing lesions in mammalian arterial walls. U.S. Pat. No. 4,456,619 to Kathawala discloses compounds of the formula ##STR2## wherein R.sup.1 and R.sup.2 are independently H, lower alkyl, lower alkoxy or halo; j is an integer of from 1 to 3; and R.sup.3 is an alkyl chain of 1 to 23 carbon atoms, saturated or unsaturated, or an alkyl chain as defined wherein each unsaturated ethylenic group is replaced by a cyclopropanyl group.
U.S. Pat. No. 4,248,893 to Kathawala et al discloses compounds of formula ##STR3## wherein j is an integer of from 1 to 3; R.sup.1 and R.sup.2 are independently H, halo, lower alkyl or lower alkoxy; and --C(O)--R is a 7-23 C unsaturated fatty acid radical in which each ethylenic group is replaced by a cyclopropanyl group.
While some of these bicyclic amides have shown in vitro ACAT inhibitory activity, none have been reported to show significant activity in whole animal models of atherosclerosis.
In addition, U.S. Pat. No. 3,704,323 to Krapcho discloses CNS stimulant 2-methyl-2-phenylindanamines of the formula ##STR4## wherein X is H, OH, lower alkyl, halogen, lower alkoxy, amino or dialkylamino; Y is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --O-- or --S--; n is 1, 2 or 3; m is 0 or 1; R.sup.1 is phenyl, pyridyl, or X-substituted phenyl or pyridyl; R.sup.2 is lower alkyl or X-substituted aryl; and R is lower alkyl or hydroxy- or phenyl-substituted lower alkyl.
European Patent Application 250,077 to Evans et al discloses hypotensive compounds of the formula ##STR5## wherein R is alkyl; R.sup.1 is alkoxy or acyloxy; R.sup.2 is lower alkyl; and R.sup.3 is lower alkyl, aryl or heteroaryl.


SUMMARY OF THE INVENTION

Novel compounds of the present invention which show significant in vivo anti-atherosclerotic activity are represented by the formula ##STR6## wherein Ar.sup.1 and Ar.sup.2 are independently selected from the group consisting of phenyl, R.sup.2 -substituted phenyl, heteroaryl or R.sup.2 -substituted heteroaryl, wherein R.sup.2 is 1 to 3 substituents independently selected from the group consisting of halogeno, hydroxy, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino and lower dialkylamino;
X, Y and Z are independently selected from the group consisting of --CH.sub.2 --, --CH(alkyl)--, --C(alkyl).sub.2 --, --NH--, --N(alkyl)--, --O-- and --SO.sub.r, wherein r is 0, 1 or 2, and m, n and p are 0 or 1, such that 0<(m+n+p)<4, provided that only one of X,Y or Z is --NH--, --N(alkyl)--, --O-- or --SO.sub.r ;
R.sup.1 is an alkyl chain of 1 to 25 carbon atoms, branched or straight, saturated or containing one or more double bonds; an alkyl chain of 1 to 25 carbon atoms as defined substituted by one or more substituents selected from the group consisting of phenyl, R.sup

REFERENCES:
patent: 3704323 (1972-11-01), Krapcho
patent: 4248893 (1981-02-01), Kathawala et al.
patent: 4456619 (1984-06-01), Kathawala
patent: 4888355 (1989-12-01), Clemence et al.
patent: 5071875 (1991-12-01), Horn et al.
Derwent Abstract 50885B/28: BE 873,365 (1979).
Chemical Abstracts 59: 611c (1962), Takahashi et al.
Chemical Abstracts 64: 19517b (1966), Olin Mathieson.
Gopinath et al, J. Chem. Soc., (1957), pp. 4760-4765.
Broquet et al, Comptes Rendus, 258, 6 (1964), pp. 1820-1823.
Kametani et al, Chem. Pharm. Bull., 19, 6 (1971), pp. 1150-1157.
Yamaguchi, et al, Bull. Chem. Soc. Japan, 41, 9 (1968), pp. 2073-2077.
Ishii et al, Chem. Pharm. Bull., 31, 9 (1983), pp. 3056-3073.

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