N-[4-(Heteroarylmethyl)phenyl]-heteroarylamines

Details N-[4-(Heteroarylmethyl)phenyl]-heteroarylamines N-[4-(Heteroarylmethyl)phenyl]-heteroarylamines

1999-04-29

2000-09-26

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514367, 514370, 514372, 514373, 5142315, 5142338, 5142352, 5142355, 5142358, 5142368, 51425213, 51425401, 51425404, 514315, 514323, 514324, 514326, 548152, 548190, 548206, 548208, 548212, 548214, 546197, 546198, 546202, 546208, 546209, 546229, 544133, 544135, 544139, 544141, 544367, 544368, 544369, 544370, 544372, 540602, 540603, A61K 31426, A61P 1706, C07D27722, C07D27760, C07D41710

Patent

active

061243302

DESCRIPTION:

BRIEF SUMMARY
The present invention concerns N-[4-(heteroaryl-methyl)phenyl]-heteroarylamines, their N-oxides and addition salts; it further relates to processes for their preparation, and compositions comprising them. The compounds of the present invention are potent inhibitors of the retinoic acid-metabolism, and hence, their use as a medicine is also described.
EP-A-0,260,744, published on Mar. 23, 1988, discloses (1H-imidazol-1-ylmethyl) substituted benzimidazoles as inhibitors of the androgen formation from C.sub.21 -steroids, as inhibitors of the biosynthesis of thromboxane A.sub.2, and also having the capability to increase the excretion of ureic acid. EP-A-0,371,559, published on Jun. 6, 1990, discloses said benzimidazoles and analogous benzotriazoles as potent suppressers of the plasma elimination of endogenously or exogenously administered retinoic acid.
Retinoic acid (RA) is a key molecule in the regulation of growth and differentiation of epithelial tissues. However, RA is very rapidly metabolized by a series of enzymatic reactions, which results in its deactivation. Inhibition of RA-metabolism leads to enhanced RA levels in plasma and tissue. Therefore, compounds with such an inhibitory action, also called retinoic mimetic activity, have therapeutic and/or preventive potential in the field of dermatology and oncology.
The novel compounds of the present invention have retinoic mimetic activity and, moreover, show little or no endocrinological side-effects.
The present invention is concerned with compounds of formula ##STR3## the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein: C.sub.2-8 alkenyl; aryl; pyrrolidinyl optionally substituted with C.sub.1-4 alkyl or C.sub.1-4 alkyloxycarbonyl; or C.sub.1-12 alkyl substituted with one or two substituents selected from C.sub.3-7 cycloalkyl, hydroxy, C.sub.1-4 alkyloxy, cyano, amino, mono- and di(C.sub.1-4 alkyl)amino, mono- and di(aryl)-amino, arylC.sub.1-4 alkylamino, (C.sub.1-4 alkyl)(arylC.sub.1-4 alkyl)amino, pyrrolidinyl, piperidinyl, piperazinyl optionally substituted with C.sub.1-4 alkyl, morpholinyl, perhydro-azepinyl, carboxyl, C.sub.1-4 alkyloxycarbonyl, aminocarbonyl, mono- and di(C.sub.1-4 alkyl)aminocarbonyl, aryl, aryloxy and arylthio; substituted with aryl; triazolyl, tetrazolyl and pyridinyl; each of said unsaturated heterocycles may optionally be substituted with amino, mercapto, C.sub.1-6 alkyl, C.sub.1-6 alkylthio or aryl; ##STR4## represents an unsaturated mono- or bicyclic heterocycle selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, purinyl, phtalazinyl, cinnolinyl, quinazolinyl and quinoxalinyl; each of said unsaturated mono- or bicyclic heterocycles may optionally be substituted with one, two or three substituents selected from hydroxy, halo, nitro, amino, C.sub.1-6 alkyl, hydroxyC.sub.1-6 alkyl, haloC.sub.1-6 alkyl, C.sub.1-6 alkyloxy, C.sub.1-6 alkylthio, formyl, carboxyl, mono- or di(C.sub.1-6 alkyl)amino, C.sub.1-6 alkyloxycarbonyl or aryl; or ##STR5## represents a radical of formula ##STR6## wherein: each X independently represents NR.sup.8, O, S, S(.dbd.O) or S(.dbd.O).sub.2 ; wherein R.sup.8 is hydrogen, C.sub.1-6 alkyl, aryl or arylC.sub.1-6 alkyl; cyano, nitro, amino, C.sub.1-6 alkyl, hydroxyC.sub.1-6 alkyl, haloC.sub.1-6 alkyl, C.sub.1-6 alkyloxy, formyl, carboxyl, mono- or di(C.sub.1-6 alkyl)amino, C.sub.1-6 alkyloxycarbonyl or aryl;


______________________________________ --CR.sup.9 .dbd.CR.sup.9 --CR.sup.9 .dbd.CR.sup.9 -- (b-1); --N.dbd.CR.sup.9 --CR.sup.9 .dbd.CR.sup.9 -- (b-2); --CR.sup.9 .dbd.N--CR.sup.9 .dbd.CR.sup.9 -- (b-3); --CR.sup.9 .dbd.CR.sup.9 --N.dbd.CR.sup.9 -- (b-4); --CR.sup.9 .dbd.CR.sup.9 --CR.sup.9 .dbd.N-- (b-5); --CR.sup.9 .dbd.N--N.dbd.CR.sup.9 -- (b-6); --CR.sup.9 --N--CR.sup.9 .dbd.N-- (b-7); --CR.sup.9 .dbd.CR.sup.9 --N.dbd.N-- (b-8); --N.dbd.N--CR.sup.9 .dbd.CR.sup.9 -- (b-9); --N.dbd.CR.sup.9 --N.dbd.CR.sup.9 -- (b-10)

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