Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-06-12
1999-03-23
Clardy, S. Mark
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142395, 514319, 514370, 514426, 514408, 514510, 548194, 5483315, 548557, 548569, 546206, 544162, 564167, 562440, 560 49, 560 20, 560 34, 560 35, C07D27718, C07D29514, C07D23324, C07C25718, C07C27918, A61K 31245
Patent
active
058859900
DESCRIPTION:
BRIEF SUMMARY
This application has been filed under 35 USC 371 as a national stage application of PCT/JP95/02723 filed Dec. 27, 1995.
INDUSTRIAL FIELD OF THE INVENTION
The present invention relates to substituted amidinonaphthyl ester derivatives and pharmaceutical compositions containing the same as an active ingredient. The present invention further relates to intermediates for producing the said derivatives.
PRIOR ART
A clot formed in the heart or blood vessels due to coagulation of blood is called thrombus, and state of disease caused by the formation of thrombus is called thrombosis. Thrombosis includes various diseases such as cerebral infarction, myocardial infarction, pulmonary infarction and the like.
The methods for treatment of thrombosis is roughly classified into two methods from the point of action. That is, one is anti-thrombotic method which inhibits formation of thrombus and another is thrombolysis method according to which the formed thrombi are resolved.
It is considered that according to the thrombolysis method, plasminogen which is a precursor of fibrinolysis regulatory factor is activated into plasmin by giving a thrombolysis and this plasmin decomposes fibrin which forms thrombi in blood vessel whereby thrombi are resolved to open occluded parts. Medicines used for the thrombolysis method include, for example, tissue plasminogen activators (t-PA) which are plasminogen activators activating plasminogen into plasmin, substances in living body such as urokinase (UK) and the like, substances produced by cells such as staphylokinase, streptokinase and the like, and recombinants thereof.
Problems to be Solved by the Invention
However, the above t-PA and others are generally considered to be effective when intravenously administered. Since they are short in half-life in blood and rapidly removed from liver and, furthermore, inhibitors are present in living bodies, they must be administered in a large dosage to develop the thrombolysis action at the part where thrombi have been produced. The high dosage of the thrombus resolvent given in a short time is expected to markedly enhance the thrombus-resolving action systemically and open the occluded parts, and, on the other hand, it has been reported that it causes serious bleeding. Moreover, it has been reported as a result of animal experiments and clinical trials that even if the occluded parts are temporarily opened by the administration of the thrombolytic agents, the parts are apt to be reoccluded. This is a serious problem. Another problem in administration is that since the thrombolytic agents are injections, if they are administered for a long period of time, it gives a heavy burden to patients.
For the above reasons, development of medicines which have thrombolytic activity action and can be orally administered has been desired to reduce the burden for patients.
Means for Solving the Problems
The inventors have found that compounds represented by the following formula (I) have fibrinolysis promoting action and excellent thrombolysis action. As a result, the above problems have been solved and the present invention has been accomplished. That is, the present invention relates to a compound represented by the formula (I): ##STR3## (wherein R.sub.1 represents (4,5-dihydro-1H-imidazol-2-yl)amino group, (4,5-dihydro-1,3-thiazol-2-yl)amino group, amidino group, morpholinomethyl group, nitro group, amino group, dimethylamino group, ##STR4## R.sub.3 represents hydrogen, methoxy group, hydroxyl group, acetylamino group, morpholino group, piperidino group, 1-pyrrolidinyl group or dimethylamino group, or R.sub.5 OOC(CH.sub.2).sub.n --, group, and
The present invention further relates to pharmaceutical compositions containing the above compound (I).
Furthermore, the present invention relates to a compound represented by the formula (II) useful as an intermediate for the production of the compound (I): ##STR5## (wherein R.sub.2 represents NH.sub.2 CO(CH.sub.2).sub.n --, 2-(carbamoyl)vinyl group or R.sub.5 OOC(CH.sub.2).sub.n --, group, and excluded).
REFERENCES:
Aoyama et al. (CA 104:19396, abstract of Chem. Pharm. Bull. (1985), 33(4), 1458-71).
Chemical Pharmaceutical Bulletin, vol. 33, No. 4 (1985), Takuo Aoyama, et al. "Synthesis and structure-activity study of protease inhibitors. IV. Amidinonaphthols and related acyl derivatives.", pp. 1458-1471.
Kawamura Hiroyuki
Nakayama Toyoo
Uchiyama Hiroyuki
Clardy S. Mark
Qazi Sabiha N.
Torii Pharmaceutical Co., Ltd.
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