Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1990-06-19
1991-07-30
Bond, Robert T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540481, A61K 3155, C07D28536
Patent
active
050360655
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel benzothiadiazepine derivatives, pharmaceutically acceptable salts thereof and antiarrhythmic compositions comprising the derivative or salt.
BACKGROUND ART
Benzothiadiazepine derivatives are described in U.S. Pat. No. 3,453,266 and JP-B-21617/1966, whereas the pharmaceutical actions of these compounds heretofore found are limited only to antispasmodic action, hypoglycemic action, central depressant action, sedative action, hypnotic action, diuretic action, tranquillizer action and antihypertensive action. Although the compounds of the present invention have antiarrhythmic action, local anesthetic action and calcium antagonistic action, nothing has been mentioned about these actions.
An object of the present invention is to provide novel benzothiadiazepine derivatives and pharmaceutically acceptable salts thereof which have excellent antiarrhythmic action, local anesthetic action and calcium antagonistic action and which are very useful as cardiovascular agents such as antiarrhythmic agents and the like.
DISCLOSURE OF THE INVENTION
The present invention provides benzothiadiazepine derivatives represented by the formula below and pharmaceutically acceptable salts thereof ##STR4## wherein R.sup.1 is lower alkyl or ##STR5## R.sup.3 is hydrogen atom, lower alkoxyl or halogen atom, one or 2 to 3 same or different substituents represented by R.sup.3 may be used, R.sup.2 is ##STR6## or --(CH.sub.2)nCO.sub.2 R.sup.6, n is an integer of 1 to 4, R.sup.4 and R.sup.5 are same of different and are each hydrogen atom or lower alkyl, R.sup.4 and R.sup.5 may link together to form a ring and the ring may include oxygen atom or nitrogen atom, R.sup.6 is hydrogen atom or lower alkyl.
In the above formula (1), as the lower alkyl groups of R.sup.1, R.sup.4, R.sup.5 and R.sup.6 are enumerated straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms. Examples thereof are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. Examples of the lower alkoxyl groups as defined in R.sup.3 are straight-chain or branched-chain alkoxyl groups having 1 to 3 carbon atoms, such as methoxy, ethoxy, propoxy and isopropoxy. Examples of the halogen atoms are fluorine, chlorine, bromine and iodine. Examples of the rings formed by linkage of R.sup.4 and R.sup.5 which contain optionally oxygen atom or nitrogen atom are pyrrolidine, piperidine, morpholine, piperazine, N-lower alkyl substituted piperazine and hydroxypiperidine.
As salts of the present compound are enumerated, for example, salts of inorganic acid such as hydrochloric acid, sulfuric acid and nitric acid, salts of aliphatic saturated monocarboxylic acid such as formic acid and acetic acid, salts of aliphatic unsaturated dicarboxylic acid such as maleic acid and fumaric acid, salts of aliphatic saturated dicarboxylic acid such as oxalic acid and malonic acid, salts of sulfonic acid such as tosilic acid and methanesulfonic acid, salts of organic acid such as picric acid, and like pharmaceutically acceptable salts. Further, in the dicarboxylic acids, also are included monoamides such as oxalic acid monoamide. As salts of the compound in which R.sup.2 is --(CH.sub.2)nCO.sub.2 H are enumerated salts of alkali metal such as sodium, potassium and lithium, salts of alkaline earth metal such as calcium and magnesium and salts of basic amino acid such as lysine, alginine and histidine. Further, the present compound includes hydrates and optical isomers of the benzothiadiazepine derivatives of the formula (1).
Among the compounds of the formula (1), preferable are compounds in which, R.sup.1 is methyl, benzyl, 4-methoxybenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl or 2-fluoro-4-bromobenzyl, R.sup.2 is --(CH.sub.2)nNR.sup.4 R.sup.5 (n is 2 or 3, R.sup.4 and R.sup.5 are same or different and are each hydrogen atom, lower alkyl or link together with nitrogen atom to form pyrrolidine, piperidine, morpholine, N-methylpiperazine or 4-hydroxypiperidine ring), --CH.sub.
REFERENCES:
patent: 3453266 (1969-07-01), Wei et al.
Matsushita Yoh-ichi
Ogawa Kazuo
Bond Robert T.
Taiho Pharmaceutical Company Limited
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