Pyrroloazepine derivatives

Details Pyrroloazepine derivatives Pyrroloazepine derivatives

2002-07-03

2004-03-30

Kifle, Bruck (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06713634

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel pyrroloazepine derivatives. More specifically, this invention is concerned with pyrrolo[3,2-c]azepine 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
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 (Supple. 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.
Several compounds, led by sarpogrelate, are known to have serotonin-2 receptor antagonistic action. They however do not include anything having the pyrrolo[3,2-c]azepine skeleton or the pyrrolo[3,4-c]azepine skeleton. 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 &agr;
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 &agr;
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 &agr;
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):
wherein
the ring P represented by:
 means a pyrrole ring represented by the following structure:
 in which R
1
represents an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group, and R
2
represents a hydrogen atom or an alkyl 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
are both hydrogen atoms; Z
1
represents a hydrogen atom and Z
2
represents a group OR
3
in which R
3
represents a hydrogen atom, a substituted or unsubstituted alkyl group or a substituted or unsubstituted aralkyl group; Z
1
and Z
2
both represent groups SR
4
in which R
4
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
5
in which R
5
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 L represents a substituted or unsubstituted ethylene group or a substituted or unsubstituted trimethylene group;
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, n stands for 1 or 2, G represents an oxygen atom, a sulfur atom, a carbonyl group, a sulfinyl group, a sulfonyl group, an alkylene group, an alkenylene group, a group;
 in which R
6
represents a substituted or unsubstituted aryl group, a group:
 in which R
7
represents a hydroxyl group, an alkoxy group or an aralkyloxy group, or a substituted or unsubstituted cyclic or acyclic acetal group; when W represents C═, m stands for 1, n stands for 1 or 2, G represents a group:
 in which the double bond is coupled with W and R
8
represents a substituted or unsubstituted alkyl group, 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, n stands for 2 or 3, and G represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group —CHR
9
— in which R
9
represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl 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.
Another object of the present invention is to provide a preparation process of the pyrroloazepine derivative (I) or its salt.
A further object of the present invention is to provide a pharmaceutical which comprises the pyrroloazepine derivative (I) or its pharmaceutically-acceptable salt as an effective ingredient and is usable for the treatment or the like of circulatory diseases.
BEST MODES FOR CARRYING OUT THE INVENTION
In the pyrroloazepine derivatives (I) of the present invention, the ring P represents any one of the following pyrrole rings:
wherein R
1
and R
2
have the same meanings as defined above.
Preferred examples of the group R
1
bonded to the nitrogen atom of the pyrrole ring can include linear or branched alkyl groups having 1-8 carbon atoms preferably, such

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