Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1986-04-07
1988-04-12
Jiles, Henry R.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514333, 514341, 546256, 546257, 546258, 546263, 546278, A61K 31455, C07D40112
Patent
active
047375060
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel 1,4-dihydropyridine-3,5-dicarboxylate derivatives, and more specifically to 1,4-dihydropyridine-3,5-dicarboxylate derivatives each of which is represented by the following general formula (I): ##STR5## wherein R means is imidazolyl or pyridyl group, R.sub.1 denotes a hydrogen or halogen atom or a nitro or trifluoromethyl group, R.sub.2 is a lower alkyl group, X is CH or N, A means a lower alkylene group, ##STR6## B being a lower alkylene or O-lower alkylene group, ##STR7## R.sub.4 being a hydrogen atom or lower alkyl group, or ##STR8## m denotes a number of 1-3, and n stands for 1 or 2.
BACKGROUND ART
It has already been known that certain derivatives of 1,4-dihydropyridine-3,5-dicarboxylic acid have pharmacological effects such as vasodilative effects. A variety derivatives of 1,4-dihydropyridine-3,5-dicarboxylic acid have heretofore been synthesized, pharmacological effects of which have also been studied. For example, nifedipine [Vater, W. et al, Arzneim. Forsch., 22, 1(1972)] and nicardipine [Takenaka, T. et al, Arzneim. Forsch., 26, 2172(1976)] have already been put as pharmaceutical products on the market.
These conventional derivatives of 1,4-dihydropyridine-3,5-dicarboxylic acid are however not fully satisfactory. There is thus an outstanding demand for the development of derivatives having still better pharmacological effects.
SUMMARY OF THE INVENTION
The present inventors have carried out an extensive research under the above-described circumstances. As a result, it has been found that the novel 1,4-dihydropyridine-3,5-dicarboxylate derivatives represented by the general formula (I) have excellent pharmacological effects.
Namely, the compounds (I) of this invention have vasodilative effects, hyperkinemic effects, platelet aggregation inhibitory effects, thromboxane A.sub.2 formation inhibitory effects and so on, and are hence useful as pharmaceutical products such as vasodilators, antihypertensives, antithrombotic agents, anti-arteriosclerotic agents, etc. The compounds (I) of this invention are advantageous particularly as therapeutic agents for arteriosclerosis as they have both coronary hyperkinemic effects and thromboxane A.sub.2 formation inhibitory effects. In addition, compared with the above-mentioned nifedipine and nicardipine, the compounds (I) of this invention have such advantageous features that they show hyperkinemic effects for the coronary artery and vertebral artery over longer periods of time and weaker heart-beat increasing effects.
The compounds (I) of this invention can be prepared, for example, in accordance with any one of the following Processes A-D:
Process A
Using the Hantzsch Pyridine Synthesis [Annalen der Chemie, 215, 1, 72(1882)] or its modified process, the compounds (I) of this invention can be prepared in accordance with the following reaction scheme, in which all symbols have the same meaning as defined above. ##STR9##
Of the above-illustrated Processes A-1-A-7, A-1 is the Hantzsch Pyridine Synthesis while Processes A-2-A-7 are its modifications.
The reactions of Process A-1-A-7 may be effected by heating their respective reactants in a solvent or without using any solvent, at 30.degree.-180.degree. C. or preferably 50.degree.-130.degree. C. and for 2-24 hours. As the solvent, it is possible to use a lower alcohol such as ethanol, propanol, isopropanol or n-butanol, a halogenated hydrocarbon such as chloroform, dichloroethane or trichloroethane, benzene, pyridine or the like.
Process B
##STR10##
By the reaction between the compound (IX) and the compound (X), the compound (I) of this invention can be prepared. This reaction may be carried out by reacting the compound (IX) with N,N'-carbonyldiimidazole and then with the compound (X), for example, in an inert solvent. Upon conducting this reaction, it is possible to use 1,8-diazabicyclo-[5.4.0]-7-undecene (hereinafter called "DBU"), sodium alcoholate, alkali metal imidazole or the like as a reaction accelerator. As the inert solvent, may be used tetrahydro
REFERENCES:
patent: 4656181 (1987-04-01), Sunkel et al.
Derwert Abstract 85-307998/49.
Ishihama Hiroshi
Ishiwata Hiroyuki
Ohta Tomio
Shimizu Noboru
Uchida Yasumi
Bjorkman Dale A.
Jiles Henry R.
Kowa Co. Ltd.
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