Carboxylic acid derivatives, their preparation and their use

Details Carboxylic acid derivatives, their preparation and their use Carboxylic acid derivatives, their preparation and their use

1998-02-24

1999-12-21

Raymond, Richard L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514277, 514311, 514314, 514356, 514363, 514365, 514372, 514374, 514378, 514382, 514415, 514438, 514443, 514452, 514456, 514461, 514464, 514466, 514468, 514469, 514471, 514520, 514569, 514570, 514335, 546174, 546342, 548136, 548204, A61K 3119, A61K 31275, A61K 3141, C07C 5964, C07D25704

Patent

active

06004988&

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel carboxylic acid derivatives, their preparation and 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. Endothelin or ET hereinafter indicates one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a great effect on vascular tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).
Increased or abnormal release of endothelin causes persistent vasoconstriction in peripheral, renal and cerebral blood vessels, which may lead to diseases. As reported in the literature, elevated levels of endothelin in plasma have been found in patients with hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome, atherosclerosis and in the airways of asthmatics (Japan J. Hypertension, 12, 79 (1989), J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990)).
Accordingly, substances which specifically inhibit the binding of endothelin to the receptor should also antagonize the various abovementioned physiological effects of endothelin and therefore be valuable drugs.
It has been found (WO 94/02474) that certain carboxylic acid derivatives with the general formula Q are good inhibitors of endothelin receptors ##STR2##
However, this related mainly to compounds with a double bond in the molecule. Besides R.sup.A and R.sup.B, a maximum of one hydrogen atom is permitted on the .beta. center.
It has now been found, surprisingly, that this hydrogen atom can be replaced by alkyl radicals. This results in a quaternary .beta. center with, at the same time, a large increase in the activity with regard to endothelin receptors (see Examples).
The invention relates to carboxylic acid derivatives of the formula I ##STR3## where R.sup.1 is a tetrazole [sic], nitrile [sic], COOH or a radical which can be hydrolyzed to COOH, and the other substituents have the following meanings: radicals: halogen, cyano, NO.sub.2 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, benzyloxy, C.sub.1 -C.sub.4 -alkylamino or C.sub.1 -C.sub.4 -dialkylamino; or direct linkage, a methylene, ethylene or ethenylene group, or an oxygen or sulfur atom; indanyl, indolyl, pyridyl, benzopyranyl, furanyl, benzofuranyl, isooxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, pyrimidinyl, 2,3-dihydrobenzofuranyl, benzothienyl, quinolinyl, C.sub.3 -C.sub.7 -cycloalkyl, thienyl, oxazolyl, thiazolyl, each of which can be substituted by one or more of the following radicals: halogen, cyano, hydroxyl, NO.sub.2, 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, benzyloxy, C.sub.1 -C.sub.4 -alkylamino or C.sub.1 -C.sub.4 -dialkylamino, it being possible for the alkyl radicals together to form a ring; -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, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -alkylthio, C.sub.1 -C.sub.4 -alkylamino, di-C.sub.1 -C.sub.4 -alkylamino; which can be substituted by one or more of the following radicals: halogen, cyano, hydroxyl, amino, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, phenoxy, C.sub.1 -C.sub.4 -alkylthio, dioxomethylene [sic] or dioxoethylene [sic];
The compounds, and the intermediates for preparing them, such as Va, may have one or more asymmetric substituted carbon atoms. Compounds of this type may be in the form of pure enantiomers or pure diastereomers or of a mixture thereof. The use of an enantiomerically pure compound as agent is preferred.
The invention furthermore relates to the use of the abovementioned carboxylic acid derivative

REFERENCES:
Tanaka et al., Chem. Pharm. Gull., vol. 26, pp. 1558-1569, 1978.

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