Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-11-12
2001-02-13
Kifle, Bruck (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S521000
Reexamination Certificate
active
06187772
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel pyrroloazepine compounds. More specifically, this invention is concerned with pyrrolo[3,2-c]azepine compounds, pyrrolo-[3,4-c]azepine compounds and salts thereof, said compounds and salts having strong &agr;
1
-blocking action and serotonin-2 receptor antagonistic action and being useful as pharmaceuticals for use in the prevention or treatment of circulatory diseases such as hypertension, heart failure, ischemic heart diseases such as angina pectoris, myocardial infarction and post-PTCA restenosis, cerebrovascular disturbances such as cerebral infarction and cerebral sequelae after sub-arachnoid hemorrhage, and peripheral circulatory disturbances such as arteriosclerosis obliterans, thromboangiitis obliterans, Raynaud disease and Buerger disease; their preparation process; and pharmaceuticals containing them as effective ingredients.
BACKGROUND ART
As pharmaceuticals which act on the circulatory system, many products are known to date, including a variety of products developed as vasodilators.
Among such vasodilators, &agr;
1
-blockers led by prazosin are the targets of active developments, because they have advantages such that (1) their anti-hypertensive action is strong and reliable, (2) they do not adversely affect lipometabolism or saccharometabolism and (3) they can be used easily for hypertensives suffering from complication. As &agr;
1
-blockers which are currently in clinical use, bunazosin, terazosin, urapidil, doxazosin and the like can be mentioned in addition to prazosin. Further, medicines having &agr;
1
-blocking action and anti-serotonin action in combination are expected to become still better therapeutics for hypertension, because they have possibility to reduce side effects, such as orthostatic hypotension and reflex tachycardia, induced by antihypertensive action which is based on &agr;
1
-blocking action.
Further, a hypertensive is considered to be prone to an ischemic heart disease or peripheral circulatory disturbance, since his or her platelet aggregating ability has been generally potentiated to have higher thrombophilia. As one of those taking part in thrombosis, serotonin is known. Serotonin is a compound contained abundantly in platelets, which are a blood component, and in a central nervous system, on the other hand, it acts as a neurotransmitter. In platelets, it is released upon stimulation by thromboxane A
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 &agr;
1
receptors, thereby inducing strong platelet aggregation and vasoconstriction [P.M. Vanhoutte, “Journal of Cardiovascular Pharmacology”, Vol. 17 (Suppl. 5), S6-S12 (1991)].
Serotonin is also known to potentiate proliferation of vascular smooth muscle cells [S. Araki et al., “Atherosclerosis”, Vol. 83, 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 to myocardial, cerebral and peripheral organs [P. Golino et al., “The New 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.
From the foregoing, a medicine having &agr;
1
-blocking action and serotonin-2 receptor antagonistic action in combination is expected to have vasodilative action, antiplatelet action and vascular smooth muscle proliferation inhibiting action, and is considered to become a medicine extremely effective for the prevention or treatment of not only hypertension but also general circulatory diseases such as heart failure, ischemic heart diseases such as angina pectoris, myocardial infarction and post-PTCA restenosis, cerebrovascular disturbances such as cerebral infarction and cerebral sequelae after subarachnoid hemorrhage, and peripheral circulatory disturbances such as arteriosclerosis obliterans, thromboangiitis obliterans, Raynaud disease and Buerger disease.
Until today, several medicines have been reported to have &agr;
1
-blocking action and serotonin-2 receptor antagonistic action in combination. They are however still accompanied with many problems to be improved in potency, selectivity to other receptors, toxicity, side effects and the like. There is hence an outstanding desire for the provision of a still better compound.
DISCLOSURE OF THE INVENTION
In view of the foregoing circumstances, the present inventors have proceeded with extensive research, resulting in the finding of pyrrolo[3,2-c]azepine compounds and pyrrolo[3,4-c]azepine compounds which have strong &agr;
1
-blocking action and serotonin-2 receptor antagonistic action in combination, have low toxicity and less side effects, and are useful for the prevention and treatment of general circulatory diseases such as hypertension, heart failure, ischemic heart diseases, cerebrovascular disturbances and peripheral circulatory disturbances.
The present invention has been completed based on the above described findings. A first object of the present invention is to provide a pyrroloazepine compound or a salt thereof, said pyrroloazepine compound being represented by the following formula (I):
wherein the ring P represented by
means a pyrrole ring represented by the following structure:
in which A represents an alkylene group, an alkenylene group or an alkynylene group, and Y represents a group
in which W represents CH, C= or a nitrogen atom; and, when W represents CH, m stands for 0 or 1, B represents an oxygen atom, a sulfur atom, a carbonyl group, a sulfinyl group, a sulfonyl group, an alkylene group, an alkenylene group, a group —C(OH)R
1
— in which R
1
represents a substituted or unsubstituted aryl group, a group —CHR
2
— in which R
2
represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted, cyclic or acyclic acetal group; when W represents C=, m stands for 1, B represents a group
in which the double bond is coupled with W and R
3
represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group; when W represents a nitrogen atom, m stands for 0 or 1, and B represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group —CHR
4
— in which R
4
represents a substituted or unsubstituted aryl group; E
1
and E
2
each independently represents a hydrogen atom or a lower alkyl group; and D represents a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group;
the dashed line indicates the presence or absence of a bond; and, when the bond indicated by the dashed line is present, Z
2
is not present and Z
1
represents a hydrogen atom but, when the bond indicated by the dashed line is absent, Z
1
and Z
2
both represent hydrogen atoms; Z
1
represents a hydrogen atom and Z
2
represents a hydroxyl group; Z
1
and Z
2
both represent groups SR
5
in which R
5
represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group; or Z
1
and Z
2
are combined together to represent an oxygen atom, a group NOR
6
in which R
6
represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group, or a group
in which G represents stituted or unsubstituted ethylene group
Inomata Norio
Kamei Tomoe
Mizuno Akira
Shibata Makoto
Kifle Bruck
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Suntory Limited
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