Antagonists of endothelin receptors

Details Antagonists of endothelin receptors Antagonists of endothelin receptors

1996-09-25

1997-12-30

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514383, 514419, 548247, 5482664, 548467, 548496, 548497, C07D26106, A61K 3142

Patent

active

057031061

DESCRIPTION:

BRIEF SUMMARY
This application is a filing under 35 U.S.C.371 of PCT/EP95/01013, filed Mar. 17, 1995.


BACKGROUND OF THE INVENTION

The present invention relates to novel compounds as antagonists of endothelin (ET) receptors, processes for their preparation, their use and pharmaceutical compositions.
ETs are a family of vasoactive peptides with 21 amino acid residues and two intramolecular disulfide bonds. They comprise ET-1, the original ET isolated from the culture media of porcine endothelial cells, ET-2 and ET-3.
ETs, of which biosynthesis is enhanced by many biological and pathological factors, are widely distributed in both peripheral and brain tissues of mammalians, and elicit a number of biological responses by binding to at least two distinct ET receptor subtypes, ET.sub.A and ET.sub.B receptors.
ET receptors are present in cardiovascular, renal, hepatic and neural tissues. ET receptors are also found in the respiratory, gastro-intestinal, endocrine, central nervous and genito-urinary systems, the blood and blood forming organs, the sensory organs, and other tissues in the body.
ETs are the most potent and longest acting endogeneous constrictors of blood vessels identified to date. ETs also cause contraction of various non-vascular smooth muscles including the air-way, and the cardiac muscle. In addition, ETs are ulcerogenic and pro-inflammatory. ETs have regulatory functions on hormone- or peptide-secretion, neurotransmission, ion-transport and metabolism.


SUMMARY OF THE INVENTION

The present invention provides novel compounds represented by the general formula I ##STR2## wherein Ar represents a direct bond or arylene; m is 0, 1, 2, or 3; cycloalkyl, aryl, aryl-cycloalkyl, lower alkoxy, or aryloxy; cycloalkyl-lower alkyl; cycloalkyl, or aryl-lower alkyl, provided that Ar is a direct bond, or represents aryl; or aryl; or direct bond; --CH.sub.2).sub.n -- wherein n is an integer of 1, 2 or 3; or --(CH.sub.2).sub.o --Ar.sub.1 -- or --Ar.sub.1 --(CH.sub.2).sub.o --, respectively, wherein o is zero or an integer of 1 or 2, and Ar.sub.1 is arylene; C(.dbd.X) is C(.dbd.O), C(.dbd.S), C(.dbd.NH), C(.dbd.N-lower alkyl); C.dbd.NH--OH, or CH.sub.2 ; and Y is a direct bond, --NH--, ##STR3## oxygen, or methylene; or C(.dbd.X) is CHOH and Y is a direct bond or methylene; aryl-lower alkenyl, or aryl; cycloalkyl-lower alkyl; acyloxy-lower alkyl, lower alkoxy-lower alkyl, aryloxy-lower alkyl, aryl-lower alkyl, lower alkenyl, lower alkenyl which substituted by at least one substituent selected from the group consisting of carboxy, lower alkoxycarbonyl, hydroxy, lower alkoxy, amino, lower alkylamino and di-lower alkylamino, or represents aryl-lower alkenyl, aryl or lower alkyl which is substituted by carboxy or lower alkoxycarbonyl and also by amino, lower alkylamino or di-lower alkylamino; or --(CH.sub.2).sub.p -- wherein p is an integer of 3-5, or together form a group represented by the formulae: --(CH.sub.2).sub.q --Ar.sub.1 -- or --Ar.sub.1 --(CH.sub.2).sub.q --, wherein q is zero or an integer of 1 or 2, and Ar.sub.1 is arylene; and --NH--CO--O--or --NH--SO.sub.2 ; and respectively, represents, in each case, a corresponding carbocyclic or heterocyclic aryl radical or aryl moiety, respectively; and salts thereof; the compounds of formula I and salts thereof.
All of the compounds of the present invention possess two or more chiral centers which may exist e.g. in the R(D), S(L), S,R and/or S,S configuration. The present invention includes all essentially pure enantiomeric and diastereomeric forms as well as appropriate mixtures of corresponding enantiomers and diastereomers, e.g. racemates.
Aryl represents a corresponding carbocyclic or heterocyclic aryl radical or aryl moiety, respectively.
Carbocyclic aryl, if not defined differently, generally represents, for example, phenyl, and naphthyl such as 2-naphthyl or 3-naphthyl. Carbocyclic aryl may be unsubstituted or poly-substituted, for example, di- or tri-substituted.
Heterocyclic aryl, if not defined differently, in particular represents an appropriate 5- or 6-membered

REFERENCES:
patent: 5284828 (1994-02-01), Hemmi et al.

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