Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-09-25
1998-01-13
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514260, 544291, 544293, C07D40300, C07D40302, C07D23994, A61K 31505
Patent
active
057079986
DESCRIPTION:
BRIEF SUMMARY
This a national stage application filed under 35 U.S.C. .sctn.371 of PCT/JP94/00446, filed Mar. 18,1994.
FIELD OF INDUSTRIAL APPLICATION
The present invention relates to a nitrogenous fused-heterocycle compound which exhibits an excellent activity as a drug.
BACKGROUND OF THE INVENTION AND PRIOR ART
Angina pectoris which is one of ischemic heart diseases has been known as a disease which often attacks the aged. Nitrates, nitrites, calcium antagonists and .beta.-blockers have been used as a remedy therefor, but they are still poorly effective in treating angina pectoris and in preventing the evolution thereof to myocardial infarction. Further, there have recently been observed lowering in the age of a patient with angina pectoris and complication in the symptoms thereof which are caused by stress enhanced by changes in the life style and complication in the social system and so on. Under these circumstances, the development of a new type of excellent drug has been expected.
It is believed in respect of the nitrate and nitrite compounds among the above current angina pectoris remedies that cyclic GMP (hereinafter abbreviated to "cGMP")among the cyclic nucleotides known as the intracellular second messenger participates in the action of these compounds. Further, cGMP is well known to have a relaxant activity on the smooth muscle of the vessel or bronchus. Although the mechanism of action of the above remedy is not always apparent, it is generally believed that the relaxant activity of cGMP is due to the synthesis of cGMP accelerated by the activation of guanylate cyclase. However, the above remedies exhibit a low bioavailability and a relatively short reaction time. Further, it has been reported that they give rise to tolerance when administered repeatedly, which poses a clinical problem.
Under these circumstances, the inventors of the present invention have started studies to develop a new type of more excellent drug.
Namely, the inventors of the present invention directed their attention to cGMP phosphodiesterase (hereinafter abbreviated to "cGMP-PDE) inhibitory activity and have made intensive studies on compounds having such an activity for many years. As a result of the studies, the inventors of the present invention have found that a nitrogenous fused-heterocycle compound which will be described below has a cGMP-PDE inhibitory activity and is efficacious against various ischemic heat diseases. The present invention has been accomplished on the basis of this finding.
Quinazoline derivatives useful as drugs are disclosed in, e.g., Japanese Patent Application "Kohyo" (Published Japanese Translation of PCT Patent Application) No. 502462/1990, but they are different from the compounds of the present invention in structure and activity.
DISCLOSURE OF THE INVENTION
The present invention relates to a nitrogenous fused-heterocycle compound represented by the following general formula (I) and pharmacologically acceptable salts thereof: ##STR4## wherein ring A represents a benzene, pyridine or cyclohexane ring and ring B represents a pyridine, imidazole or pyrimidine ring, with the proviso that rings A and B are bonded to each other with two atoms being shared by them, and the shared atoms may be any of carbon and nitrogen atoms; (wherein R.sup.4 and R.sup.5 may be the same or different from each other and each represent a hydrogen atom, a lower alkyl or acyl group or a carboxyl group which may be protected, or alternatively R.sup.4 and R.sup.5 may form a ring together with the nitrogen atom to which they are bonded, provided that the ring may be substituted), or a heteroaryl group which has one or two nitrogen atoms and may be substituted; ##STR5## (wherein R.sup.8 represents a carboxyl or tetrazolyl group which may be protected), or a halogen atom; and ##STR6## (wherein R.sup.6 and R.sup.7 each represent a hydrogen or halogen atom or a lower alkoxy group, or alternatively R.sup.6 and R.sup.7 may together form a methylenedioxy or ethylenedioxy group).
In the definition of the general formula (I), the low
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Adachi Hideyuki
Ishihara Hiroki
Kodama Kohtaro
Saeki Takao
Souda Shigeru
Eisai Co. Ltd.
Grumbling Matthew V.
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