Compounds having angiotensine II antagonistic activity

Details Compounds having angiotensine II antagonistic activity Compounds having angiotensine II antagonistic activity

1994-03-21

1996-10-15

Ford, John M.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514272, 514274, 544310, 544316, 544319, 544321, C07D40110, A61K 31505

Patent

active

055654649

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP92/01753, filed Aug. 3, 1992.


FIELD OF THE INVENTION

The present invention refers to heterocyclic compounds having angiotensine II antagonistic activity.


BACKGROUND OF THE INVENTION

The renin-angiotensine system (RAS) is a proteolytic cascade playing a fundamental role in regulating blood pressure and is apparently involved in the onset and maintenance of some cardiovascular pathologies, such as hypertension or heart failure.
The octapeptide hormone angiotensine II (AII) final product of RAS, is mainly formed in blood by the degradation of angiotensine I by the ACE enzyme which is localized in the endothelium of blood vessels, lungs, kidneys and many other organs. This hormone exerts on the arteries a powerful vasoconstrictive action as a consequence of its interaction with specific receptors, present on the cell membranes.
One of the possible control modes of RAS is the AII antagonism at the receptorial level. Some peptide analogues of AII (e.g. saralasine, sarmesine) are known to antagonize competitively the interactions of the hormone, but their clinical or experimental use has been limited by a partial agonist activity and by the lack of oral activity.
Recently, several non-peptide 5-or 6-membered heterocyclic compounds were disclosed as AII receptor antagonists. Example of these compounds are claimed in EP 253310, EP 323841, EP 324377, EP 409332, EP 411507, EP 412594 A, EP 419048 A.


SUMMARY OF THE INVENTION

The present invention relates to heterocyclic derivatives having AII antagonist properties which may be therefore used for the treatment of different cardiovascular pathologies such as hypertension, heart failure and intraocular hypertension. The compounds of the invention have the general formula I ##STR2## wherein:
R is C.sub.1-4 linear or branched alkyl;
R.sub.1 is hydrogen; C.sub.1-4 linear or branched alkyl; aryl or arylalkyl wherein aryl is phenyl, naphthyl, 2-thienyl, 2-furanyl optionally substituted by one or more halogens, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, carboxy or C.sub.1-4 linear or branched alkoxycarbonyl groups; when N and X are connected by a double bond, R.sub.1 is obviously not present;
R.sub.2 is hydrogen, C.sub.1-4 linear or branched alkyl, hydroxy, amino, aryl, wherein aryl is as defined above, or a group of formula NHA wherein A is C.sub.2 -C.sub.7 acyl, CN, NO.sub.2, CONHB or CSNHB wherein B is hydrogen, C.sub.1 -C.sub.4 linear or branched alkyl, C.sub.3-7 cycloalkyl, aryl as defined above;
R.sub.3 is hydrogen or one o more halogen atoms;
X is CO or a C--R.sub.4 group wherein R.sub.4 may be OR.sub.1 (wherein R.sub.1 must be obviously present and has the above mentioned meanings), aryl optionally substituted by carboxy or hydroxy groups or CH.sub.2 OR.sub.5 wherein R.sub.5 is hydrogen, lower alkyl, arylalkyl wherein the aryl portion is as defined above;
Z is a COOR.sub.6 group wherein R.sub.6 is hydrogen or C.sub.1-4 linear or branched alkyl or a tetrazol-5-yl group of formula ##STR3## wherein R.sub.7 is hydrogen or C.sub.1-4 alkyl with the proviso that, when X is CO and R.sub.1 =H, phenyl or phenethyl, R.sub.2 is different from hydrogen or alkyl.
The disclaimed compounds are known from EP 0435827.
Preferred compounds of formula I are those wherein X is CO;
R.sub.1 is preferably hydrogen; C.sub.1 -C.sub.4 alkyl; phenyl, benzyl, thienyl or furanyl optionally substituted by carboxy or C.sub.1 -C.sub.4 alkoxycarbonyl groups;
R.sub.2 is preferally hydrogen; C.sub.1 -C.sub.4 alkyl; amino; phenyl, 2-thienyl, 2-furanyl optionally substituted by carboxy or C.sub.1 -C.sub.4 alkoxycarbonyl groups;
R.sub.3 is preferably hydrogen.
Another group of preferred compounds, is that where R.sub.2 is hydrogen or C.sub.1-4 alkyl and R.sub.1 is C.sub.1-4 alkyl, phenyl, benzyl, furanyl or thienyl optionally, substituted by carboxy or alkoxy carbonyl group. Particularly preferred are the compounds wherein R.sub.2 is amino. Particularly preferred compounds are: 4-butyl-1-[(2-carboxyphenyl) methyl]-2-methyl-5-[[2'-(1H-tetrazol-5-yl) biphenyl-4-]meth

REFERENCES:
patent: 5166206 (1992-11-01), Allen

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