N-aroylamino acid amides as endothelin inhibitors

Details N-aroylamino acid amides as endothelin inhibitors N-aroylamino acid amides as endothelin inhibitors

1997-10-21

1999-11-02

Tsang, Cecilia J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

562445, A61K 3805

Patent

active

059770759

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to acyl-amino acid derivatives of formula I below useful as endothelin (ET) receptor antagonists, in particular ET-1 antagonists, methods for preparation thereof, pharmaceutical compositions comprising said compounds, a method of inhibiting endothelin activity in mammals and a method of treating endothelin dependent diseases or conditions in mammals using such compounds or pharmaceutical compositions comprising such compounds.
Endothelin has been implicated in the pathogenesis of various diseases and elevated levels of endothelin have been reported in such diseases. Endothelin is a potent vasoconstrictor and is also known to be, inter alia, a potent constrictor of mammalian bronchial tissue.
Thus the endothelin receptor antagonists of the instant invention can be used for the treatment of endothelin dependent diseases, including various cardiovascular diseases such as cerebral and coronary vasospasm, cerebral and coronary ischemia, subarachinoidal hemorrhage, various types of hypertension, pulmonary hypertension, cardiac failure, Raynaud-syndrome, diabetes, artherosclerosis or restenosis following angioplasty, and also for the treatment of asthma, renal failure, dialysis, glomerular injury, hepatic failure, stomach and duodenal ulcer, ulcus cruris, various brain dysfunctions including migraine, benign prostatic hyperplasia, and ocular diseases such as glaucoma.


DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the compounds of formula I ##STR2## wherein R is carboxy, esterified carboxy, carbamoyl, N-(alkyl or aryl)-carbamoyl, cyano, 5-tetrazolyl or CONH--SO.sub.2 --R.sub.4 ; alkyl; carbon and nitrogen atoms to which they are attached an azacycloalkane ring; substituted by oxo, alkylenedioxy, hydroxy, acyloxy, lower alkoxy; or Y is 5-10 membered cycloalkylidenyl fused to a saturated or unsaturated carbocyclic 5- or 6-membered ring; or Y is 5 to 8 membered oxacycloalkylidenyl, 5 to 8 membered (thia-, oxothia- or dioxothia-) cycloalkylidenyl, or 5- to 8-membered azacycloalkylidenyl optionally N-substituted by lower alkyl or aryl-lower alkyl; aryl, cycloalkyl, (carbocyclic aryl, heterocyclic aryl, cycloalkyl, hydroxy, acyloxy, or lower alkoxy)-lower alkyl, lower alkyl substituted by carboxyl, by esterified carboxyl or by amidated carboxyl; acceptable salts thereof.
The compounds of the present invention possess one or more chiral centers. The instant invention includes the possible isomers and enantiomers. Preferred are the compounds of formula I in which the carbon atom to which R.sub.2 and R.sub.3 are attached has the R-configuration corresponding to the D-amino acid.
The definitions as such or in combination as used herein, unless denoted otherwise, have the following meanings within the scope of the present invention.
Aryl represents carbocyclic or heterocyclic aryl, either monocyclic or bicyclic.
Monocyclic carbocyclic aryl represents optionally substituted phenyl, being preferably phenyl or phenyl substituted by one to three substituents, such being advantageously lower alkyl, hydroxy, lower alkoxy, acyloxy, halogen, cyano, trifluoromethyl, amino, lower alkanoylamino, lower alkyl-(thio, sulfinyl or sulfonyl), lower alkoxycarbonyl, mono- or di-lower alkylcarbamoyl, mono- or di-lower alkylamino, pyrrolidino, piperidino, morpholino.
Bicyclic carbocyclic aryl represents 1- or 2-naphthyl or 1- or 2-naphthyl preferably substituted by lower alkyl, lower alkoxy or halogen.
Heterocyclic aryl represents, for example, mono- or bicyclic heteroaryl having up to and including 4 identical or different hetero atoms such as nitrogen, oxygen or sulfur, preferably one, two, three, or four nitrogen atoms, a nitrogen and an oxygen or a sulfur, an oxygen or a sulfur atom. Preferred are corresponding 5- or 6-membered monocyclic heteroaryl radicals which may also be attached to a carbocyclic aryl radical, especially phenyl. Appropriate monocyclic 5-membered heteroaryl radicals are, for example, monoaza-, diaza-, -triaza-, tetraaza-, monooxa-, monothia-, oxaza- or thiaza-cycl

REFERENCES:
patent: 4339534 (1982-07-01), Johansen
patent: 5273990 (1993-12-01), De Lombaert
Derwent Abstract DE 3332633 A1 of Apr. 4, 1985, and pp. 18-22 of DE 3332633 (see formulae I and II referred to in abstract).
Jordan, et al., Heterocycles, vol. 33, No. 8, Apr. 1992, pp. 657-671.
Derwent Abstract 85-087758[15], 1986.

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