4-amino(alkyl)cyclohexane-1-carboxamide compound and use thereof

Details 4-amino(alkyl)cyclohexane-1-carboxamide compound and use thereof 4-amino(alkyl)cyclohexane-1-carboxamide compound and use thereof

1994-03-07

1995-12-26

Dentz, Bernard

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514303, 546113, 546119, A61K 31435, C07D47104

Patent

active

054788382

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP92/01139 filed Sep. 4, 1992.
1. Technical Field
The present invention relates to novel and pharmaceutically useful 4-amino(alkyl)cyclohexane-1-carboxamide compounds, isomers thereof and pharmaceutically acceptable acid addition salts thereof.
2. Background Art
It is known that one of the causes of hypertensions and coronary or cerebral circulatory diseases, which constitute a major social problem as adult diseases, is the abnormal contraction of smooth muscles, which is caused by a rise in intracellular concentrations of calcium ion. The rise of the intracellular concentrations of calcium ion is caused, for example, 1) through the membrane potential-dependent calcium channel, 2) by release of calcium from the intracellular organella where it is stored and 3) through the receptor-dependent channel, and therefore its origin is uneven. Further, it is recognized that the excessive calcium ions induce twitches of the coronary artery and the cerebrovascular artery and these vascular twitches constitute one of the causes of angina pectoris, myocardial infarction and cerebral infarction.
Incidentally, calcium antagonists have been recently employed for the treatment of hypertension or coronary, cerebral and peripheral circulatory diseases. While the calcium antagonists show antagonistic activity against the membrane potential-dependent calcium channel, they scarcely show antagonistic activities against other influx of calcium ion into the cell and liberation of calcium ion from the storage organella.
As compounds having intracellular calcium antagonistic action as well as inhibitory action against membrane potential-dependent smooth muscle contraction which conventional calcium antagonists inhibit, WO 90/05723 discloses that certain trans-4-amino(alkyl)-pyridylcarbamoylcyclohexane compounds, optical isomers thereof and pharmaceutically acceptable acid addition salts thereof have long-lasting coronary, cerebral and renal blood flow-increasing actions and are useful as an antihypertensive agent and an agent for the prevention and treatment of coronary, cerebral and renal circulatory diseases.


DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a compound having a potent and long-lasting blood flow-increasing action in the coronary, cerebral, renal and peripheral arteries, which is less toxic than conventional compounds.
Under these circumstances, the present inventors have made intensive studies and found that 4-amino(alkyl)cyclohexane-1-carboxamide compounds, isomers thereof and pharmaceutically acceptable acid addition salts thereof can achieve the aforementioned objects, and completed the present invention.
Moreover, the compounds of the present invention exhibit inhibitory action on histamine inhalation-induced experimental asthma in guinea pig and acetylcholine-induced inhibitory action on contraction of extirpated guinea pig trachea, thus showing the anti-asthma action of the compound of the invention.
That is, the present invention relates to: ##STR2## wherein: R.sup.1 and R.sup.2 are the same or different and each is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl, aralkyl, piperidyl or pyrrolidinyl, which may have substituent on the ring, or a group of the formula ##STR3## [wherein; R is hydrogen, alkyl, --NR'R" (where R' and R" are the same or different and each is hydrogen, alkyl, aralkyl or phenyl), R.sup.0 is hydrogen, alkyl, aralkyl, phenyl, nitro or cyano, or R and R.sup.0 may combinedly form a heterocyclic ring which may have, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom], or therewith, a heterocyclic ring which may have, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom;


______________________________________ --CRa.dbd.CRb-- (a), --NRa--C(.dbd.Rb)-- (b), --N.dbd.CRb-- (c), --C(=Ra)--NRb-- (d), --CRa.dbd.N-- (e) or --NRa-- (f) ______________________________________ halogen, alkyl, alkoxy, aralkyl, haloalkyl, nitro, --NRcRd (wherein Rc and Rd are the

REFERENCES:
patent: 4997834 (1991-03-01), Muro et al.
Muro et al., "Preparation of (Pyridylcarbamoyl)Cyclohexane Derivatives As Antihypertensive Agents", Chemical Abstracts, vol. 116, No. 15, 1992, Abstract No. 151571b.
CIP Abstract 89-110631/15 (corresponding to JP-A-64-56661) (1989).

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