Benzene-condensed heterocyclic derivatives and their uses

Details Benzene-condensed heterocyclic derivatives and their uses Benzene-condensed heterocyclic derivatives and their uses

1997-06-26

2000-03-28

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514444, 514469, 548235, 549 60, 549462, 549467, 549471, C07D30779, C07D30780, C07D30781, A61K 3134

Patent

active

060432640

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a novel benzene-condensed heterocyclic derivative and to an antagonist against thromboxane A.sub.2 (hereinafter referred to as "TXA.sub.2 ") receptor, comprising the compound as an active ingredient.


BACKGROUND ART

TXA.sub.2 discovered by Samuelsson et al. in 1975 has a strong platelet aggregation activity as well as vascular smooth muscle-contracting activity and bronchial smooth muscle-contracting activity (Proc. Natl. Acad. Sci. U.S.A., 72, 2994 (1975)). On the other hand, plastaglandin I.sub.2 (PGI.sub.2) is known as a compound having activities opposite to the above-mentioned activities, that is, as a compound having a strong platelet aggregation inhibiting activity and vasodilation activity (Nature, 263, 663(1976)). Since these two compounds are synthesized from arachidonic acid in the body and since their activities are strong, it is said that the balance between TXA.sub.2 and PGI.sub.2 i s important for keeping the homeostasis of circulatory system. Therefore, if this balance is inclined to the side of TXA.sub.2, activation of platelets and subsequent thrombus formation and vasoconstriction are caused, which is thought to be a cause of circulatory disorders including ischemic heart diseases such as angina pectoris and myocardial infarction, cerebrovascular diseases, renal disorders and the like. Further, since TXA.sub.2 has a strong bronchial smooth muscle-contracting activity, it is thought that TXA.sub.2 also has a relationship to bronchial asthma. Thus, inhibition of activities of TXA.sub.2 is thought to be effective for therapies of circulatory disorders including ischemic heart diseases such as angina pectoris and myocardial infarction, cerebrovascular diseases and renal disorders, as well as bronchial asthma. So far, as the drugs to inhibit the activities of TXA.sub.2, a TXA.sub.2 receptor antagonist (Circulation, 81, Suppl. I, I-69(1990); Medicinal Research Reviews, 11, 503(1991)), and an inhibitor of TXA.sub.2 synthetase have been reported.
However, no drugs which sufficiently inhibit the activities of TXA.sub.2 have been obtained yet.


DISCLOSURE OF THE INVENTION

Accordingly, an object of the present invention is to provide an excellent TXA.sub.2 receptor antagonist.
The present inventors searched a TXA.sub.2 receptor antagonist having a novel structure to discover benzene-condensed heterocyclic derivatives having strong TXA.sub.2 receptor antagonist activities, thereby completing the present invention.
That is, the present invention provides a benzene-condensed heterocyclic derivative of the formula (I): ##STR2## (wherein R.sup.1 is --X--(CH.sub.2).sub.n COOR.sup.3 (wherein X is --O--, --S-- or --CH.sub.2 --, R.sup.3 is hydrogen, C.sub.1 -C.sub.5 lower alkyl, or an atom or group which gives a pharmaceutically acceptable salt, and n is an integer of 1 to 3); substituted) described above) described above) above) described above), or ##STR3## R.sup.8 is 1) phenyl, thienyl, furyl, naphthyl or C.sub.3 -C.sub.8 cycloalkyl, substituted naphthyl, selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C.sub.3 -C.sub.8 cycloalkyl and phenoxy; substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C.sub.3 -C.sub.8 cycloalkyl and phenoxy; substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C.sub.3 -C.sub.8 cycloalkyl and phenoxy; substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C.sub.3 -C.sub.8 cycloalkyl and phenoxy; substituents selected from the group consisting of phenyl (which may be substituted), thieny

REFERENCES:
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patent: 5703121 (1997-12-01), Lesieur et al.
FitzGerald, Prostaglandins and related compounds, Cecil Textbook of Medicine, 20th Edition, vol. 2, pp. 1187-1194, 1996.

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