Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1986-04-10
1988-06-07
Schwartz, Richard A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514218, 514252, 514255, 540575, 544359, 544360, 544363, 544380, 544393, A61K 3138, A61K 31495, C07D24102, C07D40104
Patent
active
047497033
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel tricyclic or tetracyclic compounds having .omega.-[4-substituted-1-(homo)piperazinyl]alkanoylamino group which have a calcium antagonistic activity and hence are useful as a medicament, a process for preparing the compounds, and a pharmaceutical composition containing the compound as an active ingredient.
BACKGROUND ART
With recent elucidation of physiological roles of calcium, various calcium antagonists having various chemical structures have been studied and have been come into the market. There have now been used the calcium antagonists such as nifedipine, diltiazem hydrochloride, etc. for the prophylaxis and treatment of various diseases such as ischemic heart disease, hypertension and the like. These medicaments have, however, comparatively short duration of action, and hence, it has been desired to find a medicament having more prolonged activity.
As far as the present inventors know, there is no report that a tricyclic or tetracyclic compound having .omega.-[4-substituted-1-(homo)piperazinyl]alkanoylamino group has a calcium antagonistic activity.
The present inventors have intensively studied in order to obtain novel compounds having a chemical structure different from the known calcium antagonists and having superior activity to the latter, and have found that tricyclic or tetracyclic compounds having .omega.-[4-substituted-1-(homo)piperazinyl]alkanoylamino group show potent calcium antagonistic activity when they satisfy the following conditions:
(i) the substituent at 4-position of the (homo)piperazinyl group contains at least one aromatic hydrocarbon group or aromatic heterocyclic group, and
(ii) the middle ring of the tricyclic or tetracyclic group is a seven-membered ring, and further that some of them show more prolonged antihypertensive activity than that of the commercially available calcium antagonists.
DISCLOSURE OF INVENTION
The present invention provides compounds of the formula (I): ##STR4## wherein A means a C.sub.1-10 alkylene; Y-Z means ##STR5## --CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, or ##STR6## R.sub.1 groups are the same or different and are each hydrogen atom, a halogen atom, a C.sub.1-6 alkyl, a C.sub.1-6 alkoxy, a C.sub.1-6 alkylthio, or cyano; R.sub.2 groups are the same or different and are each hydrogen atom, a halogen atom, a C.sub.1-6 alkyl, a C.sub.1-6 alkoxy, a C.sub.1-6 alkylthio, or cyano; R.sub.3 is hydrogen atom, a C.sub.1-6 alkyl, or a C.sub.1-6 alkoxy; R.sub.4 is phenyl, a phenyl-C.sub.1-10 alkyl wherein the alkyl moiety may optionally be substituted by one hydroxy, a phenyl-C.sub.3-5 alkenyl, diphenylmethyl, naphthyl, thiazolyl, a pyridyl which may optionally be substituted by a C.sub.1-6 alkoxycarbonyl, a pyrimidinyl which may optionally be substituted by a C.sub.1-6 alkyl, quinolyl, a benzoyl-C.sub.1-5 alkyl, benzoyl, furoyl, thenoyl, phenyloxycarbonyl, phenyloxysulfonyl, or phenylsulfonyl; a is 2 or 3, b and c are each 1 or 2, and d is an integer of 0 to 2, provided that the phenyl, phenyl moiety and naphthyl in the above definition may optionally be substituted by one or two members selected from the group consisting of a halogen atom, hydroxy, nitro, a C.sub.1-6 alkyl, trifluoromethyl and a C.sub.1-6 alkoxy, and when two substituents are contained, both may be the same or different, and a pharmaceutically acceptable salt thereof, a process of the preparation of the compounds, and a pharmaceutical compposition containing the compounds as an active ingredient.
The pharmaceutically acceptable salts of the compounds (I) include, for example, inorganic acid addition salts (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.) and organic acid addition salts (e.g. oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, etc.) The compounds (I) and salts thereof may optionally be present in the form of a hydrate or a solvate, and these hydrate and solvate are also included in the present invention.
Besides, the compounds (I) may have one or more asym
REFERENCES:
patent: 3849410 (1974-11-01), Nakanishi et al.
patent: 4278796 (1981-07-01), Corvi-Mora
patent: 4457931 (1984-07-01), Milani et al.
Thomas et al., J. of Cardiovascular Pharm. 6, 1170-1176, 1984, Raven Press, N.Y.
Meyer, Calcium Antagonists and Cardiovascular Disease, Raven Press, N.Y., 1984, pp. 165-173.
Rajsner et al., CA vol. 101, 1984, 101:54944h, p. 608.
Hatano Naonobu
Kurokawa Mikio
Sato Fuminori
Uno Hitoshi
Dainippon Pharmaceutical Co., Ltd.
Mullins J. G.
Schwartz Richard A.
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