Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-10-17
1999-09-28
Huang, Evelyn
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514303, 514352, 546113, 546119, 546309, A61K 3144, A61K 31435, C07D21372, C07D47104
Patent
active
059589442
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel benzamide compounds useful as pharmaceutical agents, isomers thereof, pharmaceutically acceptable acid addition salts thereof and pharmaceutical use thereof.
BACKGROUND OF THE INVENTION
One pathogenetic cause of hypertension and coronary cerebral circulatory disturbances (e.g., angina pectoris, cerebral infarction and the like) which pose serious social problems as adult diseases is considered to be an abnormal contraction of smooth muscle. The contraction and relaxation of smooth muscle are mainly controlled by increase and decrease of intracellular calcium. The calcium which has flowed into smooth muscle cells binds with calmodulin to activate myosin light chain phosphorylation enzyme. As a result, myosin light chain is phosphorylated to cause contraction of smooth muscles (myosin phosphorylation theory). Taking note of this theory, various calcium antagonists have been developed which reduce intracellular calcium and distend blood vessels, and widely used for the therapy of hypertension, angina pectoris and the like.
Inasmuch as a sustained contraction of smooth muscle of blood vessel, trachea and the like, which is characteristic of smooth muscle, is inexplicable by myosin phosphorylation theory alone, an involvement of contraction mechanism which is independent of intracellular calcium level, and calcium sensitivity reinforcing mechanism, have been suggested in recent years. Such involvement is supported by the occurrence of contraction of smooth muscle and diseases (e.g., cerebral vasospasm, asthma and the like) on which calcium antagonists are ineffective. Therefore, a pharmaceutical agent which only reduces intracellular calcium is insufficient to treat diseases caused by contraction of smooth muscle, and the development of a new smooth muscle relaxant has been awaited.
Benzamide compounds as cardiotonics have been reported in Japanese Patent Unexamined Publication Nos. 158252/1987 and 158253/1987; as antiulcer agents in J. Med. Chem., 14, 963 (1971); and as intestinal peristaltic movement inhibitors in Spanish patent No. 456,989. Yet, no reports have documented their smooth muscle relaxing action.
On the other hand, WO 93/05021 discloses that 4-amino(alkyl)-cyclohexane-1-carboxamide compounds are useful as potent and longacting anti-hypertensive agents, agents for prevention and treatment of circulatory diseases of coronary, cerebral, renal and peripheral arteries, and therapeutic agents for asthma.
It is therefore an object of the present invention to provide an agent which can be administered orally, which has strong smooth muscle relaxing action, hypotensive action and cerebral coronary vasodilating action like conventional calcium antagonists, as well as sustained renal and peripheral circulation improving action, and which also suppresses, unlike calcium antagonists, vasoconstriction caused by various agonists.
DISCLOSURE OF THE INVENTION
The present inventors have conducted intensive studies and found that the benzamide compounds of the present invention, isomers thereof and pharmaceutically acceptable acid addition salts thereof can accomplish the above-mentioned objects and completed the present invention.
It has been also found that the compound of the present invention has anti-asthma action based on the inhibitory action on experimental asthma in guinea pig which was induced by histamin inhalation, and on the inhibitory action on the contraction induced by acetylcholine in tracheal specimens extracted from guinea pig.
Thus, the present invention relates to benzamide compounds of the formula ##STR2## wherein R is a hydrogen, an alkyl, or a cycloalkyl, a cycloalkylalkyl, a phenyl or an aralkyl, which optionally has a substituent on a ring, or a group of the formula ##STR3## wherein R.sup.6 is hydrogen, alkyl or the formula: --NR.sup.8 R.sup.9 wherein R.sup.8 and R.sup.9 are the same or different and each is hydrogen, alkyl, aralkyl or phenyl, and R.sup.7 combinedly form a heterocycle optionally having oxygen atom, sulfur atom or optionally subs
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Arita Masafumi
Minoguchi Masanori
Saitoh Tadamasa
Satoh Hiroyuki
Yamagami Keiji
Huang Evelyn
Yoshitomi Pharmaceutical Industries Ltd.
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