Suntory Limited

Daiichi Suntory Pharma Co., Ltd.

Tomoe Iwamori

Akira Mizuno

Makoto Shibata

Norio Inomata

Kyoko Nakanishi

Tetsuo Shimamoto

Masahiro Imoto

Pyrroloazepine derivatives

Benzothiazine derivative

Disclosed are benzothiazine derivatives represented by the following formula (I):

An intermediate represented by the following formula (XVIII),

Thiopyran derivatives

A method for treating a circulatory disease or condition in a mammal, which entails administering to the mammal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof:

A thiopyran derivative represented by the following formula (I) or (I'), or the salt thereof. ##STR1## wherein A is S or --CH.dbd.CH--; the dotted line indicates that the bond may be either present or absent; Z and Z' are typically ##STR2## L is an ethylene or trimethylene group; Y is CH or N; n is 2; B is a carbonyl group; m is 0 or 1; D is a phenyl group; and E.sub.1 and E.sub.2 are hydrogen atoms. These compounds exhibit a strong serotonin-2 blocking action and highly safe. Some compounds also exhibit an .alpha..sub.1 -blocking action and therefore are useful as an antihypertensive agent with less side effects. Thus, the thiopyran derivatives are useful as drugs for the treatment of circulatory diseases in general such as hypertension, ischemic heart disease, cerebrovascular disturbance, and peripheral circulatory disturbance.

Disclosed are benzothiazine derivatives represented by the following formula (I): ##STR1## wherein the dashed line indicates the presence or absence of a bond; Z represents one of the following groups: ##STR2## in which R.sub.1 and R.sub.2 individually represent alkyl, aralkyl or the like, R.sub.3 represents H, alkyl or the like, R.sub.4 represents H, aralkyl or the like, X.sub.1, X.sub.2 and X.sub.3 individually represent O or S, and G represents substituted or unsubstituted ethylene, trimethylene or the like; Q.sub.1 and Q.sub.2 individually represent H, OH, halogen, alkoxy or the like; A represents alkylene, alkenylene or the like; Y represents CH, C.dbd. or N; when Y is CH, m stands for 0 or 1, n stands for 1 or 2, B represents O, S, carbonyl or the like, when Y is C.dbd., m stands for 1, n stands for 1 or 2, B represents: ##STR3## in which the double bond is linked to Y, R.sub.6 represents substituted or unsubstituted aryl or the like; when Y is N, m stands for 0 or 1, n stands for 2 or 3 and B represents carbonyl, sulfonyl or the like, E.sub.1 and E.sub.2 individually represent H or lower alkyl; and D represents an aromatic hydrocarbon group or an aromatic heterocyclic group; and salts thereof. The benzothiazine derivatives (I) and their salts according to the present invention have strong serotonin-2 blocking action, have excellent selectivity to this action against .alpha..sub.1 blocking action and have high safety. Accordingly, the present invention has made it possible to provide pharmaceuticals making use of antagonistic action against serotonin-2 receptors, for example, therapeutics for various circulatory diseases such as ishemic heart diseases, cerebrovascular disturbances and peripheral circulatory disturbances.

Disclosed are benzothiazine derivatives represented by the following formula (I): ##STR1## The benzothiazine derivatives (I) and their salts according to the present invention have strong serotonin-2 blocking action, have excellent selectivity to this action against .alpha..sub.1 blocking action and have high safety. Accordingly, the present invention has made it possible to provide pharmaceuticals making use of antagonistic action against serotonin-2 receptors, for example, therapeutics for various circulatory diseases such as ischemic heart diseases, cerebrovascular disturbances and peripheral circulatory disturbances.

A simple and industrially viable process for preparing a 1-substituted pyrrole-3-carboxylic acid derivative of formula (I) is provided. The process comprises reacting a compound of formula (II), a compound of formula (III), and an acid anhydride according to the following reaction, ##STR1## wherein R.sub.1 and R.sub.2 individually represent an alkyl, aralkyl, or aryl group.

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Ibaraki, Japan

Tomoe Iwamori