Use of carboxylic acid derivatives as drugs

Details Use of carboxylic acid derivatives as drugs Use of carboxylic acid derivatives as drugs

1996-09-30

1998-11-24

Travers, Russell

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514276, A01N 4366

Patent

active

058407227

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP95/01094 filed on Mar. 23, 1995.


BACKGROUND OF THE INVENTION

The present invention relates to the use of certain carboxylic acid derivatives as drugs.
Endothelin is a peptide which is composed of 21 amino acids and which is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. "Endothelin" or "ET" hereinafter means one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a potent effect on vascular tone. It is known that this vasoconstriction is caused by binding of endothelin to its receptor (Nature 332 (1988) 411-415; FEBS Letters 231 (1988) 440-444, and Biochem. Biophys. Res. Commun. 154 (1988) 868-875).
Increased or abnormal release of endothelin causes persistent vasoconstriction in peripheral, renal and cerebral vessels, which may lead to pathological states. It is reported in the literature that elevated plasma endothelin levels are found in patients with hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome or atherosclerosis and in the airways of asthmatics (Japan J. Hypertension 12 (1989) 79, J. Vascular Med. Biology 2 (1990) 207, J. Am. Med. Association 264 (1990) 2868).
Accordingly, substances -which specifically inhibit the binding of endothelin to the receptor should also antagonize the various physiological effects of endothelin mentioned above and therefore be valuable drugs.


SUMMARY OF THE INVENTION

We have found that certain carboxylic acid derivatives are good inhibitors of endothelin receptors.
The invention relates to the use of carboxylic acid derivatives with the formula I which is described hereinafter for the production of drugs, in particular for the production of inhibitors of endothelin receptors.
Carboxylic acid derivatives of the general formula I ##STR2## where R is formyl, CO.sub.2 H or a radical which can be hydrolyzed to COOH, and the remaining substituents have the following meanings: C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -haloalkoxy or C.sub.1 -C.sub.4 -alkylthio; R.sup.3, forms a 3- or 4-membered alkylene or alkenylene chain in which, in each case, one methylene group is replaced by oxygen; C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -haloalkoxy, C.sub.1 -C.sub.4 -alkylthio or R.sup.3 is linked to R.sup.14 as indicated above to form a 5- or 6-membered ring; halogen atoms and/or one of the following radicals: C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -alkylthio, cyano, C.sub.1 -C.sub.8 -alkylcarbonyl, C.sub.1 -C.sub.8 -alkoxy-carbonyl, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals in turn can carry from one to five halogen atoms and/or from one to three of the following radicals: C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -haloalkyl, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -haloalkoxy and/or C.sub.1 -C.sub.4 -alkylthio;
C.sub.1 -C.sub.10 -alkyl which can carry from one to five halogen atoms and carries one of the following radicals: a five-membered heteroaromatic ring which contains from one to three nitrogen atoms and/or one sulfur or oxygen atom and which can carry from one to four halogen atoms and/or one or two of the following radicals: C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -haloalkyl, C.sub.1 -C.sub.4 -alkoxy,
C.sub.1 -C.sub.4 -haloalkoxy, C.sub.1 -C.sub.4 -alkylthio and/or phenyl;
C.sub.3 -C.sub.2 -cycloalkyl or C.sub.3 -C.sub.2 -Cycloalkenyl, each of which can contain one oxygen or sulfur atom and can carry from one to five halogen atoms and/or one of the following radicals: C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -alkylthio, cyano, C.sub.1 -C.sub.8 -alkyl-carbonyl, C.sub.1 -C.sub.8 -alkoxycarbonyl, phenyl, phenoxy or phenyl-carbonyl, where the phenyl radicals in turn can carry from one to five halogen atoms and/or from one to three of the following radicals: C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -haloalkyl, C.sub.l -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -haloalkoxy and/or C.sub.1 -C.sub.4 -alkylthio; C.sub.3 -C6-alkenyl or C.sub.3 -C.sub.46 -alkynyl, each of whic

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