Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-11-12
2000-01-25
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514364, 548126, C07D28514, A01R 3191
Patent
active
060179392
DESCRIPTION:
BRIEF SUMMARY
The invention relates to compounds of the formula I ##STR2## in which ##STR3## R is or SO.sub.2 NH.sub.2, SO.sub.3 -A, SO.sub.2 NHA, CN or formyl, phenyl group which is unsubstituted or mono- or polysubstituted by Hal, OH, OA, O-alkylene-R.sup.5, A, S-A, S-OA, SO.sub.2 A, S-OR.sup.5, SO.sub.2 R.sup.5, NO.sub.2, NHA, NA.sub.2, NHacyl, NHSO.sub.2 A, NHSO.sub.2 R.sup.5, NASO.sub.2 A, NASO.sub.2 -R.sup.5, NH(CO)NH.sub.2, NH(CO)NHA, formyl, NH(CO)NHR.sup.5, NHCOOA, NAacyl, NHCOOCH.sub.2 R.sup.5, NHSO.sub.2 CH.sub.2 R.sup.5, NHCOO-alkylene-OA, NH(CO)NA.sub.2, 1-piperidinyl-CO-NH, 1-pyrrolidinyl-CONH, O(CH.sub.2).sub.n COOA, O(CH.sub.2).sub.n COOH, O(CH.sub.2).sub.n OH, O(CH.sub.2).sub.n OA, CH.sub.2 OH, CH.sub.2 OA, COOH, COOA, CH.sub.2 COOH or CH.sub.2 COOA, ##STR4## where R.sup.2 is additionally A or cycloalkyl, polysubstituted by Hal, OH, OA, A, S-A, NO.sub.2, NH.sub.2, NHA, NA.sub.2, NHacyl, NHSO.sub.2 A, NASO.sub.2 A, NH(CO)NH.sub.2, NH(CO)NHA, formyl, NHCOOA, NAacyl, NHCOO-alkylene-OA, NH(CO)NA.sub.2, N-piperidinyl-CO-NH, N-pyrrolidinyl-CONH, O(CH.sub.2).sub.n COOA, O(CH.sub.2).sub.n COOH, O(CH.sub.2).sub.n O, O(CH.sub.2).sub.n OA, CH.sub.2 OH, CH.sub.2 OA, COOH, COOA, CH.sub.2 COOH or CH.sub.2 COOA, replaced by O or S atoms or by --CR.sup.6 .dbd.CR.sup.6 groups and/or 1-7 H atoms can be replaced by F, A, all isomers.
The tautomeric ring-closed hydroxylactone form ##STR5## is present if the compounds of the formula I are isolated as carboxylic acids. If the compounds of the formula I are obtained as salts (carboxylates); the open-chain tautomer is obtained.
Similar compounds are disclosed in WO 95/05376.
The invention was based on the object of finding novel compounds having useful properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I and their salts have very useful pharmacological properties together with good tolerability. In particular, they show endothelin receptor-antagonistic properties and can therefore be employed for the treatment of diseases such as hypertension, cardiac insufficiency, coronary heart disease, renal, cerebral and myocardial ischaemia, renal insufficiency, cerebral infarct, subarachnoid haemorrhage, arteriosclerosis, pulmonary high blood pressure, infla nmations, asthma, prostate hyperplasia, endotoxic shock and in complications after the administration of substances such as, for example, cyclosporin, as well as other diseases associated with endothelin activities.
The compounds exhibit, inter alia, a high affinity for the endothelin subreceptors ET.sub.A and ET.sub.B. These actions can be determined by customary in vitro or in vivo methods, such as described, for example, by P. D. Stein et al., J. Med. Chem. 37, 1994, 329-331 and E. Ohlstein et al., Proc. Natl. Acad. Sci. USA 91, 1994, 8052-8056.
A suitable method for the determination of the hypotensive action is described, for example, by M. K. Bazil et al., J. Cardiovasc. Pharmacol. 22, 1993, 897-905 and J. Lange et al., Lab Animal 20, 1991, Appl. Note 1016.
The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine, in particular for the prophylaxis and/or therapy of cardiac, circulatory and vascular diseases, especially of hypertension and cardiac insufficiency.
The invention relates to the compounds of the formula I and their salts, and to a process for the preparation of these compounds and their salts, ##STR6## a) R is characterized in that a compound of the formula II ##STR7## in which R.sup.1, R.sup.3 and X have the meaning indicated in claim 1, and A is alkyl having 1-4 C atoms or benzyl, claim 1 and their salts, ##STR8## b) R is a compound of the formula IV ##STR9## in which R.sup.1, R.sup.4 and X have the meaning indicated in claim 1, and A is alkyl having 1-4 C atoms or benzyl, claim 1, and their salts, ##STR10## c) R is a compound of the formula V ##STR11## in which R.sup.3 and R.sup.4 have the meaning indicated in claim 1, and A is alkyl having 1-4 C atoms or benzyl, ##STR12#
Anzali Soheila
Christadler Maria
Dorsch Dieter
Mederski Werner
Osswald Mathias
Gerstl Robert
Merck Patent Gesellschaft
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