Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-03-20
1997-03-04
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514255, 514278, 514327, 514328, 514329, 514331, 514607, 514627, 544168, 544389, 544390, 544391, 546216, 564181, 564207, A61K 31535, A61K 31495, C07D29512
Patent
active
056079311
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to 1,2-disubstituted ethyl amides useful 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 amides have been reported as being useful in lowering cholesterol and/or in inhibiting the formation of cholesterol-containing lesions in mammalian arterial walls. U.S. Pat. No. 3,784,577 to Fukurmaru et al discloses fatty acid amide derivatives of the formula R-CONHR.sup.1 wherein RCO is a fatty acid radical and R.sup.1 is 1-.alpha.-benzylbenzyl.
U.S. Pat. No. 4,603,145 to De Vries et al discloses diaryl alkanamides of the formula ##STR2## wherein R.sup.3 and R.sup.4 independently include benzyl and phenethyl.
U.S. Pat. No. 4,420,475 to Damon et al discloses silicon-bearing amides of the formula ##STR3## wherein R.sup.1, R.sup.2 and R.sup.3 independently can be alkyl, phenyl, benzyl or phenethyl and R can be 1-.alpha.-benzylbenzyl optionally substituted in the phenyl rings. U.S. Pat. No. 4,434,161 to Barcza discloses similar compounds having a sulfur atom in the chain between the silicon atom and the carbonyl group.
U.S. Pat. No. 4,456,619 to Kathawala discloses amides of 2-alkynoic acids of the formula ##STR4## wherein A is alkyl, alkenyl or cyclopropanyl-substituted alkyl and B can be 1-.alpha.-benzylbenzyl, optionally substituted in the phenyl rings.
U.S. Pat. No. 4,716,175 to Hoefle et al discloses fatty acid amides of the formula ##STR5## wherein A is an alkyl chain, R.sup.1 and R.sup.2 can each be phenylmethyl, and B can be phenyl, benzyl, pyrimidinyl or pyridyl.
U.S. Pat. No. 4,518,789 to Yu et al discloses dermatologically useful phenyl alpha-acyloxyacetamides of the formula ##STR6## wherein R.sup.1 and R.sup.2 can be hydrogen, alkyl or araikyl and R.sup.3 and R.sup.4 can be hydrogen, alkyl, aralkyl or aryl.
While some of these diphenylethylamides 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. 5,149,709 discloses compounds, having in vivo anti-atherosclerotic activity, of the formula ##STR7## wherein R.sub.1 and R.sub.2 are independently a heteroaryl group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, triazinyl, imidazolyl, thiophenyl, oxazolyl and furanyl; X-substituted heteroaryl wherein X is 1 to 3 substituents independently selected from the group consisting of halogeno, lower alkyl, hydroxy, lower alkoxy, amino, lower alkylamino, lower dialkylamino, acetamido, methanesulfonyl-amino, 2-(trimethylsilyl)ethoxymethyl, carboxy and lower alkoxycarbonyl; X-substituted phenyl; or N-substituted triazinyl or N-substituted imidazolyl wherein the N-substituents are selected from the group consisting of lower alkyl, 2-(trimethylsilyl)ethoxymethyl and R.sub.5 CO-- wherein R is lower alkyl, phenyl, benzyl or 2,2-dimethylpropyl; other can be phenyl; saturated or containing one or more double bonds; an alkyl chain as defined substituted by one or more substituents selected from the group consisting of phenyl, X-subst
REFERENCES:
patent: 3784577 (1974-01-01), Fukumaru et al.
patent: 4248893 (1981-02-01), Kathawala et al.
patent: 4251438 (1981-02-01), Moon
patent: 4420475 (1983-12-01), Damon, II
patent: 4434161 (1984-01-01), Barcza
patent: 4456619 (1984-06-01), Kathawala
patent: 4518789 (1985-05-01), Yu et al.
patent: 4603145 (1986-07-01), DeVries et al.
patent: 4611063 (1986-09-01), Damon, II
patent: 4716175 (1987-12-01), Hoefle et al.
patent: 5149709 (1992-09-01), Clader et al.
Nishida et al. "Purpactins, new inhibitors of ACAT" Biol. Abstracts 91:129161 (1991).
DeVries et al. "Potential antiatherosclerotic agents" J. Med. Chem. v.32 2318-2325 (1989).
Chang Ceila
Dicker Eric S.
Magatti Anita W.
Schering Corporation
Thompson Paul A.
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