Pyrimidinone derivatives

Details Pyrimidinone derivatives Pyrimidinone derivatives

1997-04-25

1999-02-09

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514210, 514212, 5142278, 5142358, 514269, 514274, 540481, 540601, 544 60, 544123, 544310, 544313, 544319, C07D23936, C07D40310, C07D41314, A61K 31505

Patent

active

058694765

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/KR95/00121 filed Sep. 25, 1995.


BACKGROUND OF THE INVENTION

This invention relates to novel pyrimidinone derivatives and the pharmaceutically acceptable salts thereof. This invention also relates to process for preparing of the novel pyrimidinone derivatives and pharmaceutical composition containing the pyrimidinone derivatives.
The compounds of this invention and the pharmaceutically acceptable salts thereof are useful as angiotensin II antagonists especially, in treatment of various cardiovascular diseases caused by angiotensin II.
Renin-angiotensin system plays a central role in the regulation of blood pressure in human body. Angiotensin II, consisting of eight amino acids, is produced during the cleavage of angiotensin I by angiotensin converting enzyme(ACE) localized on the arterial blood vessels of lung, etc., and then involved in hypertension development. Angiotensin II, the final product of Renin-angiotensin system, exerts its action to elevate blood pressure and increase electrolyte concentration by interacting with specific receptors present in blood vessel, smooth muscle, kidney or adrenal gland. Thus, as a way of controlling hypertension several antagonistic compounds have been explored to inhibit the effect of angiotensin II by blocking its receptors.
Peptide antagonists analogous to angiotensin II are known, but their clinical applications have been limited because of their short half-life, extensive inactivation after oral administration and above all the partial agonistic activity.
Recently, several non-peptide compounds have been reported as angiotensin II antagonists. European Patent Application Laying-Open Publication Nos. 028,834 and 253310 disclose Imidazole derivatives substituted by biphenyl (for example, Losartan) and European Patent Application Laying-Open Publication No. 245,637, imidazopyridine derivatives (for example, L158,809) as potent angiotensin II antagonists.
In European Patent Application Laying-Open Publication Nos. 407,342, 419,048 and 445,811, pyrimidinone compounds similar to the compounds of this invention in their 6 membered heterocyclic ring structure are disclosed inclusively as a general formula without illustrative enough to support it. Further, the compounds described therein show relatively low activities(10.sup.-6 mol for 60.about.70% inhibition in in vitro blood vessel dilation study) than imidazole derivatives known in the above mentioned application.


DESCRIPTION OF THE INVENTION

In search of novel pyrimidinone compounds having at least 100 times more enhanced activities than the pyrimidinones disclosed in the prior art, the inventors of this invention have manufactured extensive pyrimidinones substituted by variety of functional groups and then investigated their angiotensin II antagonist activity.
The object of the invention, therefore, is to provide with novel pyrimidinone derivatives and the pharmaceutically acceptable salts thereof which inhibit the action of angiotensin II effectively.
Other object of the invention is to provide with process for preparing novel pyrimidinone derivatives and the pharmaceutically acceptable salts thereof which inhibit the action of angiotensin II effectively.
Another object of the invention is to provide with a pharmaceutical composition for treating hypertension including the novel pyrimidinone derivatives and the pharmaceutically acceptable salts thereof which inhibit the action of angiotensin II effectively.
In order to achieve the aforementioned objects, the present invention provides with pyrimidinone derivatives having the general formula (I): ##STR1## wherein: R.sup.1 is C.sub.1 .about.C.sub.4 alkyl, cycloalkyl, C.sub.1 .about.C.sub.4 alkoxy or C.sub.1 .about.C.sub.4 alkylmercapto; C.sub.1 .about.C.sub.4 alkyl being optionally substituted by H, halogen, hydroxy, C.sub.1 .about.C.sub.4 alkoxy, amino, alkylamino, dialkylamino(each alkyl having C.sub.1 .about.C.sub.5), C.sub.1 .about.C.sub.4 alkoxycarbonyl, carboxy or substituted aminocarbonyl, or C.sub.1 .about.C.sub.4 alkyl o

REFERENCES:
Chemical Abstracts, vol. 117, No. 25, 21 Dec. 1992 (Columbus, Ohio, USA), p. 694, col. 2, abstract No. 251363z, Shidara, Naganori et al., "Preparation of pyrimidine derivatives as angiotensin II receptor antagonists".

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