Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2003-04-24
2004-06-01
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
active
06743913
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel pyrrolesulfonamide compounds. More specifically, this invention is concerned with pyrrolo[2,3-e][1,2]thiazine compounds, pyrrolo[3,4-e][1,2]thiazine compounds, pyrrolo[2,3-f][1,2]thiazepine compounds and pyrrolo[3,4-f][1,2]thiazepine 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 the prevention or treatment of 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, peripheral circulatory disturbances such as arteriosclerosis obliterans, thrombo-angiitis obliterans and Raynaud disease; their preparation processes; and pharmaceuticals containing them as effective ingredients.
BACKGROUND ART
Conventionally, many compounds are known as medicines which act on the circulatory system, including a variety of compounds developed as vasodilators.
Among such vasodilators, &agr;
1
-blockers represented by prazosin are the subject of a great deal of active development work for their merits in that (1) their antihypertensive action is strong and positive, (2) they give no adverse effect to the metabolism of lipids and carbohydrates and (3) they can be easily used even for hypertensives suffering from complication. Examples of &agr;
1
-blockers which are clinically used these days can include, in addition to prazosin, bunazosin, tetrazosin, urapidil and doxazosin. Further, medicines equipped with &agr;
1
-blocking action and anti-serotonin action in combination have possibility to reduce side effects induced by hypotensive action based on the &agr;
1
-blocking action, such as orthostatic hypotension and reflex tachycardia, and are hence expected to become superior hypertension therapeutics.
Further, hypertensives generally have potentiated platelet-aggregating ability and tend to form thrombi, so that they are considered to develop ischemic heart diseases or peripheral circulatory disturbances. As one of factors which take part in the formation of thrombi, serotonin is known. 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.
With the foregoing in view, medicines which have &agr;
1
-blocking action and serotonin-2 receptor antagonistic action in combination are expected to have vasodilating action, anti-platelet action and vascular smooth muscle cell proliferation inhibitory action and are considered to become extremely effective medicines for the prevention and treatment of not only hypertension but also all circulator diseases, for example, 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, peripheral circulatory disturbances such as arteriosclerosis obliterans, thrombo-angiitis obliterans and Raynaud disease.
To date, 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/or the like. There is accordingly an outstanding demand for the provision of still better compounds.
DISCLOSURE OF THE INVENTION
In view of the foregoing circumstances, the present inventors have proceeded with extensive research toward compounds which have strong &agr;
1
-blocking action and serotonin-2 receptor antagonistic action in combination and also have low toxicity and less side effects and are thus useful for the prevention and treatment of all circulatory diseases such as hypertension, heart failure, ischemic heart diseases, cerebrovascular disturbances and peripheral circulatory disturbances. As a result, it has been found that pyrrolo[2,3-e]thiazine compounds, pyrrolo[3,4-e]thiazine compounds, pyrrolo[2,3-f]thiazepine compounds and pyrrolo[3,4-f]thiazepine compounds can satisfy such conditions.
Incidentally, pharmaceuticals having the pyrrolo[2,3-e]thiazine skeleton, pyrrolo[3,4-e]thiazine skeleton, pyrrolo[2,3-f]thiazepine skeleton or pyrrolo[3,4-f]thiazepine skeleton did not exist in the past, to say nothing of reports even on the synthesis of compounds having these skeletons.
The present invention has been completed based on the above described findings. A first object of the present invention is to provide a pyrrolesulfonamide compound or a salt thereof, said pyrrolesulfonamide 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 a substituted or unsubstituted alkylene group, a substituted or unsubstituted alkenylene group or a substituted or unsubstituted alkynylene group; 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 a carbonyl 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;
l represents 0 or 1;
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
re
Fukami Harukazu
Inomata Norio
Kamei Tomoe
Mizuno Akira
Shibata Makoto
Daiichi Suntory Pharma Co., Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Stockton Laura L.
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