Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-07-06
1996-10-08
Chan, Nicky
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549388, 549392, 549 60, 549 27, 549 26, A61K 3135, C07D31190
Patent
active
055631690
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP92/01164 filed Sep. 11, 1992.
TECHNICAL FIELD
The present invention relates to tricyclic heterocyclyl compounds which have excellent activity in the inhibition of acyl-CoA: cholesterol acyltransferase.
BACKGROUND ART
Atherosclerosis is an important cause of ischemic cardiac insufficiency such as angina, myocardial infarction and the like. It has been considered that a major cause of atherosclerosis is the accumulation of cholesterol esters by foam cells which are present under the endodermis cell layer of blood vessels.
Inhibitors of acyl-CoA: cholesterol acyltransferase (hereinafter referred as ACAT) inhibit the synthesis of cholesterol esters in the foam cells and they diminish the accumulation of cholesterol esters, thereby inhibiting the formation and development of atherosclerosis caused by the accumulation of cholesterol esters.
It has also been established that atherosclerosis is linked with hypercholesterolemia. Cholesterols in food are absorbed as free cholesterol in the intestinal mucosal cell tract, esterified by ACAT and then enter the blood. Therefore, an inhibitor of ACAT will also prevent a rise in the cholesterol concentration in the blood by inhibiting the absorption of food cholesterol into the blood.
For this reason, compounds which are active in the inhibition of ACAT are useful for the treatment and prophylaxis of atherosclerosis.
Tricyclic heterocyclyl compounds which inhibit ACAT are known and, for example, a compound having the formula: ##STR2## has been disclosed in Japanese Patent Kokai Application No. Hei 2-6457.
However, it is still desired to develop a therapeutic agent having more potent activity.
DISCLOSURE OF INVENTION
The present inventors have studied the synthesis of a series of tricyclic heterocyclyl compounds and the pharmacological activity thereof for many years. As a result, they have discovered that tricyclic heterocyclyl compounds having specific substituents exhibit excellent activity in the inhibition of ACAT, and thus the present invention was accomplished.
CONSTITUTION OF INVENTION
Tricyclic heterocyclyl compounds according to the invention have a general formula I: ##STR3##
In the above formula, R.sup.1 and R.sup.2 are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom or a halogeno-lower alkyl group;
R.sup.3 represents a hydrogen atom or a lower alkyl group;
R.sup.4 represents a phenyl or naphthyl group, which has 1 to 3 substituents and may optionally be condensed 5- or 6-membered heterocyclyl group (the said substituent represents a lower alkyl, halogeno-lower alkyl, lower alkoxy(lower alkyl), lower alkylthio(lower alkyl), aralkyl, lower alkenyl, lower alkoxy, aryloxy, aralkyloxy, lower alkylthio, arylthio, aralkylthio, carboxy, lower alkoxycarbonyl, lower alkylsulfinyl, arylsulfinyl, aralkylsulfinyl, lower alkylsulfonyl, arylsulfonyl or aralkylsulfonyl group, a halogen atom, a cyano or nitro group);
R.sup.5 represents a hydrogen atom or a lower alkyl group;
A represents a lower alkylene group;
B represents an oxygen or sulfur atom; and
n is 0 or 1.
Where R.sup.1 and R.sup.2 each represents a lower alkyl or halogeno-lower alkyl group; R.sup.3 represents a lower alkyl group; a substituent of a phenyl or naphthyl group represented by R.sup.4 is a lower alkyl, halogeno-lower alkyl, lower alkoxy(lower alkyl), lower alkylthio(lower alkyl), lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group; and R.sup.5 represents a lower alkyl group, the term "lower alkyl moiety" is here defined mean a straight or branched C.sub.1 -C.sub.6 alkyl group such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl, preferably a C.sub.1 -C.sub.4 alkyl group, and more preferably a methyl or ethyl group.
Where R.sup.1 and R.sup.2 each represents a lower alkoxy; and a substituent of a phenyl or naphthyl group represented by R.sup.4 is a lower alkoxy, lower alkoxyalkyl or lower alkoxycarbonyl group, the alkyl moiety of the said lower
REFERENCES:
patent: 4489090 (1984-12-01), DeVries et al.
patent: 4999373 (1991-03-01), Trivedi
Hasegawa Kazuo
Kasai Takashi
Koga Teiichiro
Oda Kozo
Yoshida Akira
Chan Nicky
Sankyo Company Limited
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