Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-03-17
1996-12-24
McKane, Joseph K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514381, 514382, 514396, 548252, 548253, 548254, 5483351, 5483435, 5483461, 5462741, 5462727, A61K 3144, A61K 31415, C07D23356, C07D40106
Patent
active
055873901
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/02024 filed Jul. 29, 1995.
The present invention relates to imidazole derivatives having A II antagonist activity, the processes for the preparation thereof, pharmaceutical compositions containing them and the use thereof as therapeutical agents.
The renin-angiotensin system (RAS) is a proteolytic chain which plays a paramount role in the control of blood pressure and is apparently involved in the onset and the maintainement of some cardiovascular disorders, such as hypertension and cardiac decompensation.
The octapeptide hormone angiotensin II (A II), the final product from RAS, mainly forms in the blood following to the degradation of angiotensin I, carried out by the ACE enzyme, which is located in endothelium of blood vessels, lungs, kidney and many other organs. Such an hormone exerts a strong vasoconstricting action on arteries, due to its interaction with specific receptors located on the cell membranes.
One of the possible ways to control RAS is the A II antagonism at the receptor level. Some peptide analogues of A II (for example saralasin, sarmesin) are known to competitively block the interactions of said hormone, however the use thereof, both experimentally and clinically, is restricted by a partial agonist activity and by the lack of activity by the oral route.
Recently, a number of compounds having a non-peptide structure, deriving from 5-membered heterocycles, were described to have II antagonist activity. Examples of these compounds are claimed in patents EP 253,310, EP 324,377, PCT 91/00277, PCT 91/00281 PCT 91/14367, PCT 91/15206, PCT 92/00977.
A common characteristic of these compounds is that they have a completely substituted imidazole ring.
The present invention relates to imidazole derivatives, of general formula (I), having an aryl or heteroaryl group, which can be unsubstituted or functionalized at the 4- or 5-position of the imidazole ring. In the compounds of the invention, an hydrogen atom on the imidazole ring and a biphenylmethyl moiety linked to the imidazole by a nitrogen-carbon bond are always present.
These novel derivatives have A II antagonist properties and they in various can be used in various cardiovascular disorders, such as hypertension, cardiac decompensation, in the myocardial ischemia post-treatment or in intraocular hypertension, glaucoma, some renal diseases and hyperaldosteronism.
The compounds of the invention have general formula (I): ##STR1## wherein: n can be 0, 1 or 2 ##STR2## wherein Z can be C or N, whereas Y can be H, when Z is the same as C or can be oxygen or it can be not present, when Z is the same as N; C.sub.2 -C.sub.5 alkenyl group; tetrazole group of general formula (IIa) or (IIb): ##STR3## R.sub.3, R.sub.4 can independently be H, halogen, CN, NO.sub.2, NH.sub.2, COR.sub.7, OR.sub.8, CH.sub.2 OR.sub.8, C.sub.1 -C.sub.5 straight or branched alkyl;
The compounds of the invention form salts with various acids and bases, both inorganic and organic, and these also are an object of this invention. Said salts include ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline-earth metals such as calcium and magnesium, salts with organic bases such as dicyclohexylamine, N-methyl-D-glucamine, salts with amino acids such as arginine, lysine and the like. The salts with organic and inorganic acids comprise hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic acids and the like.
Examples of C.sub.1 -C.sub.5 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl; preferably methyl, propyl and butyl.
Examples of C.sub.2 -C.sub.5 alkenyl groups are vinyl, allyl, isoprenyl, 2-butenyl, 3-pentenyl.
Examples of --COOR.sub.5 groups are carbomethoxy, carbethoxy, carbopropoxy, carboisobutoxy, carbotertbutoxy, carbobenzyloxy; preferably carbomethoxy.
Examples of --OR.sub.8 groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy.
Exa
REFERENCES:
CA 115:8809j Preparation . . . Blockers. Ardecky et al. p. 863, 1991.
CA 116:66252x Treatment . . . Antagonists, Carini et al., p. 67, 1992.
CA 120:270398t Imidazole . . . Activity. Salimbemi et al., p. 1070, 1994.
Mizrahi Jacques
Paleari Fabio
Salimbeni Aldo
Scolastico Carlo
Istituto Luso Farmaco D'Italia S.p.A.
McKane Joseph K.
Schneider Walter H.
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