Patent ID: 6265425
Filing Date: 2001-07-24
Classification: A61K,A61P

Abstract:
The combination of a tocopherol and a retinoic acid metabolism blocking agent of formula (I) or (II) ##STR14##an N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein:R.sup.1 represents hydrogen, hydroxy, C.sub.1-6 alkyl or aryl;R.sup.2 represents hydrogen; C.sub.1-12 alkyl; C.sub.3-7 cycloalkyl; 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;R.sup.3 represents hydrogen, C.sub.1-6 alkyl, aryl or C.sub.1-6 alkyl substituted with aryl;Het represents an unsaturated heterocycle selected from imidazolyl, 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; ##STR15##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 ##STR16##represents a radical of formula ##STR17##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;R.sup.4 and R.sup.5 each independently represent hydrogen, hydroxy, halo, 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;--R.sup.6 --R.sup.7 -- represents a bivalent radical of formula--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.dbd.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);--N.dbd.CR.sup.9 --CR.sup.9.dbd.N-- (b-11);--CR.sup.9.dbd.N--N.dbd.N-- (b-12);--N.dbd.CR.sup.9 --N.dbd.N-- (b-13);--N.dbd.N--CR.sup.9.dbd.N-- (b-14)or--N.dbd.N--N.dbd.CR.sup.9 -- (b-15);wherein each R.sup.9 independently represents hydrogen, hydroxy, halo, 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; andaryl represents phenyl or phenyl substituted with one, two or three substituents selected from hydroxy, halo, cyano, amino, mono- or di(C.sub.1-6 alkyl)amino, C.sub.1-6 alkyl, haloC.sub.1-6 alkyl, hydroxyC.sub.1-6 alkyl, C.sub.1-6 alkyloxy, formyl, carboxyl and C.sub.1-6 alkylcarbonyl; or two adjacent carbon atoms on said phenyl may be substituted by a single bivalent radical having the formula C.sub.1-12 alkanediyl or haloC.sub.1-12 alkanediyl;X represents O, S or NR.sup.13 ;R.sup.11 represents hydrogen, hydroxy, C.sub.1-6 alkyl or aryl.sup.1 ;R.sup.12 represents hydrogen; C.sub.1-12 alkyl; C.sub.3-7 cycloalkyl; C.sub.2-8 alkenyl; aryl.sup.1 ; Het.sup.2 ; 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- or di(aryl.sup.1 C.sub.1-4 alkyl)amino, di (aryl.sup.1 C.sub.1-4 alkyl) aminocarbonyloxy, (C.sub.1-4 alkyl) (aryl.sup.1 C.sub.1-4 alkyl) amino, mono- and di (aryl.sup.1) amino, (C.sub.1-4 alkyl)(di(C.sub.1-4 alkyl)aminoC.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.sup.1, aryl.sup.1 oxy and aryl.sup.1 thio;orR.sup.11 and R.sup.12 taken together may form a bivalent radical of formula --R.sup.11 --R .sup.12 -- wherein --R.sup.11 --R.sup.12 -- represents --(CH.sub.2).sub.n --wherein n is 2, 3, 4, 5 or 6;R.sup.13 represents hydrogen, C.sub.1-6 alkyl, aryl.sup.1, Het.sup.2 or C.sub.1-6 alkyl substituted with aryl.sup.1 or Het.sup.2 ;R.sup.14 represents hydrogen; hydroxy; mercapto; C.sub.1-6 alkyloxy; C.sub.1-6 alkylthio; aryl.sup.1 oxy; aryl.sup.1 thio; Het.sup.2 -oxy; Het.sup.2 -thio; C.sub.1-12 alkyl optionally substituted with one, two or three substituents each independently selected from halo, thiolanyl, thienyl, dioxolanyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, tetrahydropyranyl, pyranyl, morpholinyl and dioxanyl; each of said monocyclic heterocycles may be optionally substituted with one or two substituents each independently selected from C.sub.1-4 alkyl, hydroxy, amino, halo, aryl, arylcarbonyl or C.sub.1-4 alkyloxycarbonyl; or a bicyclic heterocycle selected from indolinyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, 2H-1-benzopyranyl, 3,4-dihydro-2H-1-benzopyranyl, benzthiazolyl, isoquinolinyl, quinolinyl, 3,4-dihydroquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, chromanyl, 1,4-benzodioxinyl, 1,4-benzoxathianyl, benzodioxanyl and benzodioxolanyl; each of said bicyclic heterocycles may be substituted with one or two substituents each independently selected from C.sub.1-4 alkyl, hydroxy, amino, halo, aryl, arylcarbonyl or C.sub.1-4 alkyloxycarbonyl.