Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-04-30
1998-07-14
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514 75, 514 80, 514309, 514314, 514337, 514378, 514381, 514385, 514418, 514443, 514616, 546 22, 546141, 546175, 5462774, 548112, 548247, 548253, 5483121, 548413, 548485, 548486, 548492, 548494, 548495, 549 6, 549 57, 549 58, 564 15, 564155, A61K 3140, A61K 3147, A61K 3144, C07D40112, C07D21538, C07D20912, C07D33302, C07C23300
Patent
active
057804982
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/03418 filed Oct. 17, 1994.
BACKGROUND OF THE INVENTION
1. Field 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.
2. Description of Related Art
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, gastrointestinal, 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-intlammatory. ETs have regulatory functions on hormone- or peptide-secretion, neurotransmission, ion-transport and metabolism.
EP 436189A describes endothelin antagonistic cyclic pentapeptides. EP 457195A describes endothelin antagonistic oligopeptides comprising L-leucine and D-tryptophan. They could not be orally administered. EP 460679A describes endothelin antagonistic peptide derivatives, specifically tripeptides are disclosed. WO 92/20706 describes endothelin antagonists, specifically hexapeptides are disclosed. EP 526708 describes endothelin antagonistic benzosulfonamide derivatives. EP 510526A also describes endothelin antagonistic benzosulfonamide derivatives. Although the benzosulfonamide derivatives can be administered orally, their antagonistic activity is not high. In EP 13891A dipeptide derivatives of phenylalanine and trypthophan are disclosed having tumor tissue destroying properties. FR 2294694 describes phenylalanylphenylalanyl derivatives having antiulcer effects.
SUMMARY OF THE INVENTION
The present invention provides novel compounds represented by the general formula I: ##STR2## wherein R.sub.1 is a straight or branched lower alkyl, a cycloalkyl-lower alkyl, an aryl-lower alkyl, a cycloalkyl, an aryl, an aryl-cycloalkyl, lower alkoxy, an aryloxy, or a heteroaryl; cycloalkyl-lower alkyl; a straight or branched lower alkyl, a cycloalkyl, an aryl-lower alkyl, an aryl, or a heteroaryl; or --(CH.sub.2).sub.n -- wherein n is an integer of 1, 2 or 3; or --(CH.sub.2).sub.p --Ar-- or --Ar--(CH.sub.2).sub.p --, respectively, wherein p is zero or an integer of 1 or 2, and Ar is an arylene or heteroarylene; C.dbd.NH--OH, or CH.sub.2 ; or or 3; and Ar' is an aryl, or a heteroaryl; and tetrazole, CH.sub.2 OH, CN, or hydrogen; lower alkoxy; R.sub.3 is phenyl; R.sub.3 ' and R.sub.3 " each are hydrogen; X is oxygen; Y is NH; R.sub.4 is 4-hydroxybenzyl; R.sub.5 is carboxy; R.sub.2 is different from hydrogen; and phenyl; R.sub.3 ' and R.sub.3 " each are hydrogen; X is oxygen; Y is NH; R.sub.4 is indol-3-ylmethyl; R.sub.5 is carboxy; carbamoyl, or carbamoyl which is mono- or di-substituted by lower alkyl; R.sub.2 is different from hydrogen; or a pharmaceutically acceptable salt thereof.
All of the compounds of the present invention possess two or more chiral centers and each center 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. Preferred are those compounds of formula I, in which Y is different from CH.sub.2 and the carbon atom, to which the struc
REFERENCES:
Breu et al., Third International Conference on Endothelin, Feb. 15-17, 1993, pp. 11 and 17.
Doherty et al., Journal of Medicinal Chemistry, vol. 36, No. 18, pp. 2585-2594 (1993).
Steinke et al., Formation of Peptide Bonds by Carboxypeptidase c from Orange Leaves, Enzyme Microbial Technology, vol. 13, No. 3, pp. 262-266, Mar. 1991.
Imai et al., Photoaffinity Heterobifunctional Cross-Linking Reagents Based on N-(Azidobenzoyl)tyrosines, Bioconjugate Chemistry, vol. 1, No. 2, pp. 138-143, Mar. 1990.
Fruh Thomas
Murata Toshiki
Okada Toshikazu
Pitterna Thomas
Saika Hideyuki
Ciba-Geigy (Japan) Limited
Coleman Brenda
Shah Mukund J.
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