Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-10-08
2000-08-15
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514274, 514312, 514345, 514348, 514349, 544302, 544314, 544319, 546141, 546157, 546158, 546296, 546301, 546302, A61K 3144, A61K 31505, C07D21368, C07D23934
Patent
active
06103732&
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel carboxylic acid derivatives, to their preparation and to their use.
Endothelin is a peptide which is composed of 21 amino acids and is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following text, "Endothelin" or "ET" signifies one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a potent effect on vessel 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 und Biochem. Biophys. Res. Commun., 154, 1988, 868-875).
Increased or abnormal release of endothelin causes persistent vasoconstriction in the peripheral, renal and cerebral blood vessels, which may lead to illnesses. It has been reported in the literature that elevated plasma levels of endothelin were found in patients with hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome, 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 ought also to antagonize the various abovementioned physiological effects of endothelin and therefore be valuable drugs.
We have found that certain carboxylic acid derivatives are good inhibitors of endothelin receptors.
The invention relates to carboxylic derivatives of the formula I ##STR2## where R is tetrazole, nitrile, a group COOH or a radical which can be hydrolyzed to COOH, and the other substituents have the following meanings: N(C.sub.1 -C.sub.4 -alkyl).sub.2, halogen, 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 or C.sub.1 -C.sub.4 -alkylthio, or CR.sup.2 is linked to CR.sup.12 as indicated below to form a 5- or 6-membered ring; CR.sup.12 forms together with CR.sup.2 or CR.sup.3 a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C.sub.1-4 -alkyl groups and in which in each case one methylene group can be replaced by oxygen, sulfur, --NH or --NC.sub.1-4 -alkyl; N(C.sub.1 -C.sub.4 -alkyl).sub.2, halogen, 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, --NH--O--C.sub.1-4 -alkyl, C.sub.1 -C.sub.4 -alkylthio; or CR.sup.3 is linked to CR.sup.12 as indicated above to form a 5- or 6-membered ring; following radicals: halogen, nitro, cyano, hydroxyl, 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, phenoxy, C.sub.1 -C.sub.4 -alkylthio, amino, C.sub.1 -C.sub.4 -alkylamino or C.sub.1 -C.sub.4 -dialkylamino; or direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO.sub.2 --, NH-- or N-alkyl group, or C.sub.3 -C.sub.7 -cycloalkyl; C.sub.3 -C.sub.6 -alkynyl or C.sub.3 -C.sub.8 -cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C.sub.1 -C.sub.4 -alkoxy, C.sub.3 -C.sub.6 -alkenyloxy, C.sub.3 -C.sub.6 -alkynyloxy, C.sub.1 -C.sub.4 -alkylthio, C.sub.1 -C.sub.4 -haloalkoxy, C.sub.1 -C.sub.4 -alkylcarbonyl, C.sub.1 -C.sub.4 -alkoxycarbonyl, C.sub.3-8 -alkylcarbonylalkyl, C.sub.1 -C.sub.4 -alkylamino, di-C.sub.1 -C.sub.4 -alkylamino, phenyl or phenoxy or phenyl, substituted one or more times, e.g. once to three times, by halogen, nitro, cyano, 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 or C.sub.1 -C.sub.4 -alkylthio; following radicals: halogen, nitro, cyano, hydroxyl, amino, 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, phenoxy, C.sub.1 -C.sub.4 -alkylthio, C.sub.1 -C.sub.4 -alkylamino, C.sub.1 -C.sub.4 -dialkylamino, dioxomethylene or dioxoethylene; nitrogen atoms and/or one s
Amberg Wilhelm
Baumann Ernst
Hergenroder Stefan
Kling Andreas
Klinge Dagmar
Balasubramanian V.
BASF - Aktiengesellschaft
Shah Mukund J.
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