Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-08-21
1999-10-05
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540521, A61K 3155, C07D48704
Patent
active
059624485
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel pyrroloazepine derivatives. More derivatives, pyrrolo(3,4-c!azepine derivatives and salts thereof, said derivatives and salts having strong serotonin-2 receptor antagonistic action of excellent selectivity and being useful, for example, for the prevention or treatment of ischemic heart diseases such as angina pectoris, arrhythmia, myocardial infarction, congestive heart failure and post-PTCA restenosis, cerebrovascular disturbances such as cerebral infarction and cerebral sequelae after subarachnoid hemorrhage, peripheral circulatory disturbances such as arteriosclerosis obliterans, thromboangiitis obliterans, Raynaud disease and Buerger disease, hypertension; their preparation process; and therapeutics containing them as effective ingredients.
BACKGROUND ART
Serotonin is a compound contained abundantly in platelets, which are a blood component, and in a central nervous system, it acts as a neurotransmitter. In platelets, it is released upon stimulation by thromboxane A.sub.2, ADP, collagen or the like, and synergistically acts on release of various platelet aggregation factors through activation of serotonin-2 receptors in the platelets and vascular smooth muscle cells and also on vasoconstriction by norepinephrine through .alpha..sub.1 receptors, thereby inducing strong platelet aggregation and Pharmacology", Vol. 17 (Supple. 5), S6-S12 (1991)!.
Serotonin is also-known to potentiate proliferation of vascular smooth pp.29-34(1990)!. It has been considered that, particularly when endothelial cells are injured as in arteriosclerosis or myocardial infarction, the vasoconstricting action and thrombus forming action of serotonin are exasperated, thereby reducing or even stopping blood supply England Journal of Medicine", Vol. 324, No. 10, pp.641-648(1991), Y. Takiguchi et al., "Thrombosis and Haemostasis", Vol. 68(4), pp.460-463(1992), A. S . Weyrich et al., "American Journal of Physiology", Vol. 263, H349-H358(1992)!.
Being attracted by such actions of serotonin or serotonin-2 receptors, various attempts are now under way to use a serotonin-2 receptor antagonist as a pharmaceutical for ischemic diseases of the heart, the brain and peripheral tissues.
Several compounds, led by sarpogrelate, are known to have serotonin-2 receptor antagonistic action. They however do not include anything having Those known to have serotonin-2 receptor antagonistic action are accompanied with many problems to be improved in potency, toxicity, side effects or the like. On the other hand, medicines which have anti-serotonin action and .alpha..sub.1 -blocking action in combination are considered to become extremely effective medicines for the treatment and prevention of hypertension and ischemic heart diseases, because they have possibility to reduce side effects, such as orthostatic hypotension and reflex tachycardia, induced by antihypertensive action on the basis of the .alpha..sub.1 -blocking action and hypertension is a serious risk factor for ischemic heart diseases.
DISCLOSURE OF THE INVENTION
In view of the foregoing circumstances, the present inventors have proceeded with extensive research, resulting in the finding of pyrroloazepine derivatives which have strong serotonin-2 receptor antagonistic action and low toxicity and less side effects and are useful for the treatment and prevention of ischemic heart diseases, cerebrovascular disturbances and peripheral circulatory disturbances. It has also been found that the compounds according to the present invention include those also having .alpha..sub.1 -blocking action in combination and that such compounds are useful as antihypertensives or the like having less side effects and are widely usable for the treatment and prevention of circulatory diseases.
The present invention has been completed based on the above described findings. A first object of the present invention is to provide a pyrroloazepine derivative or a salt thereof, said pyrroloazepine derivative being represented by the following formula (I): ##STR3## where
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Inomata Norio
Iwamori Tomoe
Mizuno Akira
Nakanishi Kyoko
Shibata Makoto
Kifle Bruck
Shah Mukund J.
Suntory Limited
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