Indole derivatives useful as endothelin receptor antagonists

Details Indole derivatives useful as endothelin receptor antagonists Indole derivatives useful as endothelin receptor antagonists

1998-10-05

2000-01-25

McKane, Joseph K.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514415, 514419, 548454, 548455, 548494, 548495, 548496, A61K 3140, C07D40502

Patent

active

060179457

DESCRIPTION:

BRIEF SUMMARY
This invention relates to indole derivatives useful in the treatment of a variety of diseases including restenosis, renal failure and pulmonary hypertension, and to pharmaceutical formulations containing such compounds.
International Patent Application WO 94/14434 discloses indole derivatives which are indicated as endothelin receptor antagonists. European Patent Application 617001 discloses a large number of phenoxyphenylacetic acid derivatives which are also indicated as endothelin receptor antagonists.
Bergman et al. Tetrahedron. Vol 31. N.sup.o 17, 1975, pages 2063-2073, disclose a number of indole-3-acetic acids. Similar compounds are disclosed by Rusinova et al. Khim Geterotsikl Soedin, 1974, (2), 211-213 (see also Chemical Abstracts, Vol 81, N.sup.o 7, 19 August 1974, abstract N.sup.o 37455a). and Yarovenko et al. J Gen Chem USSR (English translation), Vol 39, 1969, page 2039 (see also Beilstein, Registry Number 431619). These compounds are not indicated in any kind of therapy, and proviso (i) below relates to them.
Julian et al. J Chem Soc. Chemical Communications. N.sup.o 1, 1973, disclose an N-p-chlorobenzoylindole derivative as a by-product of a photo-addition reaction. The compound is not indicated in any kind of therapy, and proviso (ii) below relates to it.
Yamamoto et al. Japanese Patent N.sup.o 70 041 381 (see also Chemical Abstracts. Vol 75. N.sup.o 3, 1971. abstract N.sup.o 20189v), disclose an N-p-chlorobenzoylindole derivative which is indicated as an anti-inflammatory. Proviso (iii) below relates to it.
According to the present invention, there is provided a compound of formula I. ##STR2## wherein R.sup.1 and R.sup.2 are optional substituents and independently represent C.sub.1-6 alkyl, C.sub.2-6 alkenyl [optionally substituted by CO.sub.2 H or CO.sub.2 (C.sub.1-6 alkyl)], C.sub.2-6 alkynyl, halogen, C.sub.1-3 perfluoroalkyl, (CH.sub.2).sub.m Ar.sup.1, (CH.sub.2).sub.m Het.sup.1, (CH.sub.2).sub.m CONR.sup.7 R.sup.8, (CH.sub.2).sub.m CO.sub.2 R.sup.8, O(CH.sub.2).sub.q CO.sub.2 R.sup.8, (CH.sub.2).sub.m COR.sup.8, (CH.sub.2).sub.m OR.sup.8, O(CH.sub.2).sub.p OR.sup.8, (CH.sub.2).sub.m NR.sup.7 R.sup.8, CO.sub.2 (CH.sub.2).sub.q NR.sup.7 R.sup.8, (CH.sub.2).sub.m CN, S(O).sub.n R.sup.8, SO.sub.2 NR.sup.7 R.sup.8, CONH(CH.sub.2).sub.m Ar.sup.1 or CONH(CH.sub.2).sub.m Het.sup.1 ; SO.sub.2 R.sup.10, SO.sub.2 NR.sup.9 R.sup.10, (CH.sub.2).sub.m COR.sup.10, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.m CONR.sup.9 R.sup.10, (CH.sub.2).sub.m CO.sub.2 R.sup.10, (CH.sub.2).sub.p CN, (CH.sub.2).sub.p R.sup.10 or (CH.sub.2).sub.p OR.sup.10 ; or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, S and O, the group as a whole being optionally substituted by one or more groups selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy and halogen, and wherein any members of the heterocyclic ring which are S may be substituted by one or two oxygen atoms; Het.sup.2 or C.sub.1-6 alkyl substituted by Ar.sup.2 or Het.sup.2 ; alkyl), CO.sub.2 Ar.sup.3, CO.sub.2 (C.sub.1-6 alkyl), tetrazol-5-yl, CONHSO.sub.2 Ar.sup.3, CONHSO.sub.2 (CH.sub.2).sub.q Ar.sup.3 or CONHSO.sub.2 (C.sub.1-6 alkyl); heterocycle having 5 or 6 ring members up to 4 of which are selected from N, S and O, which aromatic heterocycle is optionally fused to a benzene ring, and which phenyl group is optionally fused to an aromatic heterocycle as defined immediately above, the group as a whole being optionally substituted by one or more groups falling within the definition of R.sup.1 above; and Het.sup.1 and Het.sup.2 independently represent a non-aromatic heterocycle having 5 or 6 ring members up to 4 of which are selected from N, S and O, which group is optionally substituted by one or more groups falling within the definition of R.sup.1 above, and is further optionally substituted by .dbd.O or .dbd.S; provided that: R.sup.3 represents H, R.sup.4 represents H, methyl or ethyl, and R.sup.6 represents unsubstituted phenyl, then Z does not represent CO.sub.2 H or CO.sub.2 (C.sub.1-6 alkyl); H.sub.4), R.sup.4 represents H,

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