Thiopyran derivatives

Details Thiopyran derivatives Thiopyran derivatives

2000-03-17

2001-09-25

Berch, Mark L. (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S023000, C549S027000

Reexamination Certificate

active

06294677

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention:
The present invention relates to novel thiopyran derivatives. More specifically, this invention is concerned with benzothiopyran derivatives, thienothiopyran derivatives and salts thereof, said derivatives and salts being useful 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 disturbance such as arteriosclerosis obliterans, thromboangina oblite, Raynaud disease, Buerger disease, and/or hypertension; their preparation processes; and pharmaceuticals comprising them as effective ingredients.
2. Discussion of the Background
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 various platelet aggregation factors or vasoconstrictors through activation of serotonin-2 receptors in the platelets and vascular smooth muscle cells, 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, p29-p34(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, p641-p648 (1991), Y. Takiguchi et al., “Thrombosis and Haemostasis”, Vol. 68(4), p460-p463 (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 such as sarpogrerate are known to possess the serotonin-2-receptor antagonistic action. These compounds still exhibit many problems to be solved, such as the intensity of the activity, toxicity, and side effects. A drug exhibiting both the anti-serotonin action and the &agr;
1
blocking action has a possibility of alleviating side effects such as orthostatic hypotension and reflex pulsus frequens which involve antihypertensive action due to the &agr;
1
blocking action. In addition, because hypertension is a major risk factor in ischemic heart diseases, the drug exhibiting both the anti-serotonin action and the &agr;
1
blocking action has the potential of being extremely effective for the treatment and prevention of hypertension and ischemic heart diseases.
In view of this situation, the inventors of the present invention have undertaken extensive studies and discovered thiopyran derivatives exhibiting a strong serotonin-2-recepter antagonistic action and useful as a drug for preventing or treating ischemic heart diseases, cerebrovascular disturbance, and peripheral circulatory disturbance, with minimal toxic or side effects. In addition, some of the compounds among the thiopyran derivatives were found to also possess the &agr;
1
blocking action and are thus useful as antihypertensive agents with less side effects, and can therefore be widely used in the treatment and prevention of circulatory diseases.
SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is to provide a thiopyran derivative or the salt thereof represented by the following formula (I) or (I′),
wherein,
A represents a sulfur atom or the group —CH═CH—;
the dotted line indicates that the bond may be either present or absent;
when the dotted line indicates that the bond is present, Z represents the group,
and when the dotted line indicates that the bond is absent, Z represents one of the following groups,
(wherein R
1
is an alkyl group which may be substituted, an aryl group which may be substituted, or an aralkyl group which may be substituted, R
2
is a hydrogen atom, an alkyl group which may be substituted, an aryl group which may be substituted, or an aralkyl group which may be substituted, R
3
is a hydrogen atom, an alkyl group which may be substituted, or an aralkyl group which may be substituted, X
1
, X
2
, and X
3
individually represent an oxygen atom or a sulfur atom, and G represents an ethylene group, of which one or more hydrogen atoms may be replaced by a halogen atom, alkyl group, aryl group, aralkyl group, or alkylidene group, or a trimethylene group, of which one or more hydrogen atoms may be replaced by a halogen atom, alkyl group, aryl group, aralkyl group, or alkylidene group);
Z′ represents the group;
(wherein G has the same meaning as defined above);
L is an alkylene group which may be substituted, an alkenylene group which may be substituted, or an alkynylene group which may be substituted;
Y represents the group CH, the group C═, or a nitrogen atom;
when Y is the group CH, m is 0 or 1, n is 1 or 2, and B is an oxygen atom, a sulfur atom, a carbonyl group, a sulfinyl group, a sulfonyl group, an alkylene group, an alkenylene group, a hydroxymethylene group which may be substituted, a group —CHR
4
— (wherein R
4
is an alkyl group which may be substituted, an aryl group which may be substituted, or an aralkyl group which may be substituted), or a cyclic or acyclic acetal group which may be substituted;
when Y is the group C═, m is 1, n is 1 or 2, and B is the group,
(wherein the double bond is linked to Y and R
5
is an alkyl group which may be substituted, an aryl group which may be substituted, or an aralkyl group which may be substituted); and
when Y is a nitrogen atom, m is 0 or 1, n is 2 or 3, and B is a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group, or a group —CHR
6
— (wherein R
6
is an alkyl group which may be substituted, an aryl group which may be substituted, or an aralkyl group which may be substituted);
E
1
and E
2
individually represent a hydrogen atom or a lower alkyl group; and
D represents an aromatic hydrocarbon group which may be substituted or an aromatic heterocyclic group which may be substituted.
Another object of the present invention is to provide a process for preparing said thiopyran derivative (I) or (I′), or the salt thereof.
Still another object of the present invention is to provide a drug composition for circulatory diseases comprising said thiopyran derivative (I) or (I′), or a pharmaceutically acceptable salt thereof, as an effective component.
Other objects, features and advantages of the invention will hereinafter become more readily apparent from the following description.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
In the thiopyran derivative (I) or (I′) of the present invention, given as preferred examples of R
1
are alkyl group having 1 to 4 carbon atoms which may be branched, such as methyl or ethyl; aryl groups having 6 to 14 carbon atoms such as phenyl or naphthyl; and aralkyl groups having 7 to 22 carbon atoms such as benzyl or phenethyl. These groups may be substituted by one or more of a halogen atom such as fluorine, chlorine, or bromine; an alkyl group having preferably 1 to 4 carbon atoms, such as methyl or ethyl; or an alkoxy group having preferably 1 to 4 carbon atoms such as methoxy or ethoxy. In this instance, as preferred examples of the group R
1
X
1
, such groups as methoxy, methylthio, ethoxy, and ethylthio are given.
The following groups,
are given as preferred examples of the group,
One or more hydrogens of the above groups may be repla

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