Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-01-25
1996-07-23
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514381, 514382, 514397, 514400, 5462751, 546256, 5462697, 5462704, 548252, 5483151, 5483154, 5483411, 5483421, A61K 3144, A61K 31415, C07D40112, C07D23354
Patent
active
055389872
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/01909 filed Jul. 20, 1993.
The present invention relates to imidazole ethers and thioethers 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 hormon 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 hormon 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 hormon, 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 derivatives having a not-peptide structure were described to have II antagonist activity.
Examples of these compounds are reported in EP 253,310, EP 324,377, EP 424,317, EP 419,048, EP 446,062, EP 403,159, EP 427,463, EP 434,249 and in papers by J. V. Duncia et al. , J. Med. Chem. 33, 1312, (1990), 33, 1330 (1990), 34, 2525 (1991); J. Weinstock et al., J. Med. Chem. 34, 1514 (1991); A. P. Thomas et al., J. Med. Chem., 35, 877 (1992); D. Middlemiss et al., Bioorg. Med. Chem. Lett. 1, 711 (1991).
The present invention relates to novel imidazole derivatives having an aryl (heteroaryl)oxy (thio) alkyl or aryl (heteroaryl) alkoxy (alkylthio) alkyl moiety at the 5-position.
These novel compounds have A II antagonist properties and therefore they can be used in various cardiovascular disorders, such as hypertension, acute and chronic cardiac decompensations, intraocular hypertension, and in some renal diseases.
The compounds of the invention have general formula (I): ##STR3## wherein:
E is O or S;
R is C.sub.1 -C.sub.5 straight, branched or cyclic alkyl or C.sub.2 -C.sub.5 alkenyl;
X can be H, F, Cl, Br, I, CF.sub.3 ;
n is an integer 1 to 4;
m is an integer 0 to 4;
A and B are 5- or 6-membered aromatic carbocyclic rings optionally containing one or more heteroatoms selected from N, O, S and carrying the substituents R.sub.1, R.sub.2 and R.sub.3, respectively;
R.sub.1 can be hydrogen, halogen, C.sub.1 -C.sub.5 alkyl, alkoxy, hydroxyl, carboxyl, C.sub.1 -C.sub.4 alkoxycarbonyl, a sulfonic group or a tetrazole group of formula ##STR4## wherein R.sub.4 can be hydrogen or C.sub.1 -C.sub.5 alkyl; R.sub.2 can be hydrogen or a COOR.sub.4 group (wherein R.sub.4 is hydrogen or C.sub.1 -C.sub.5 alkyl), CN, SO.sub.3 H, PO.sub.3 H or a tetrazole group;
R.sub.3 can be hydrogen or a moiety of formula II
B',R'.sub.2 have the same meanings reported above for B and R.sub.2, R'.sub.3 is H; with the proviso that when A is phenyl, R.sub.1 is different from H.
This invention also relates to the salts of the compounds of formula I with organic and inorganic acids and bases. 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; preferably butyl.
Examples of C.
REFERENCES:
patent: 5187271 (1993-02-01), Bovy et al.
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 252, No. 2, Feb. 1990, pp. 711-718, A. T. Chie, et al, "Nonpeptide angiotensin II receptor antagonists. VII. Cellular and biochemical pharmacology of DuP 753, an orally antihypertensive agent"--See p. 711, Table 1 (Baltimore, MD, U.S.A.).
Canevotti Renato
Mizrahi Jacques
Salimbeni Aldo
Scolastico Carlo
Istituto Luso Farmaco D'Italia S.p.A.
Ramsuer Robert W.
Stockton Laura L.
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