Patent EA-001374-B1 (EA)
Title: 1-(1,2-disubstituted piperidinyl)-4-(fused imidazole)-piperidine derivatives
Inventor: JANSSENS FRANS EDUARD
IPC: A61K31/395
Filed: 1996-12-20
Abstract: 1. A compound of formula    a N-oxide form, pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein n is 0,1 or 2; m is 1 or 2, provided that if m is 2, then n is 1; =Q is =O or =NR<3>; X is a covalent bond or a bivalent radical of formula -O-, -S-, -NR<3>-; R<1> is Ar<1>, Ar<1>C1-6a1kyl or di(Ar<1>)C1-6alkyl, wherein each C1-6alkyl group is optionally substituted with hydroxy, C1-4alkyloxy, oxo or a ketalized oxo substituent of formula -O-CH2-CH2-O- or -O-CH2- H2-CH2-O-; R<2> is Ar<2>, Ar<2>C1-6alkyl, Het or HetC1-6alkyl; R<3> is hydrogen or C1-6alkyl; L is a radical of formula   wherein the dotted line is an optional bond;  each -A-B- independently is a bivalent radical of formula  -Y-CR<7>=CH- (b-1); -CH=CR<7>-Y- (b-2); -CH=CH-CH=CH- (c-3); -CH=CR<7>-CH=CH- (b-4); -CH=CH-CR<7>=CH- (b-5); or -CH=CH-CH=CR<7>- (b-6); wherein each Y independently is a bivalent radical of formula -O-,-S- or NR<8>-; each R<7> independently is C1-6alkyl; halo; ethenyl substituted with carboxyl or C1-6alkyloxycarbonyl; hydroxy C1-66alkyl; formyl; carboxyl or hydroxycarbonyl C1-6alkyl; or R<7> is hydrogen in case -A-B- is radical of formula (b-1) or (b-2); R<8> is hydrogen, C1-6alkyl or C1-6alkylcarbonyl; each Z independently is Z<1> or Z<2>; wherein Z<1> is a bivalent radical of formula -CH2-, -CH2-CH2- or -CH=CH-; provided that when L is a radical of formula (a-1) and the dotted line is an extra bond, then Z<1> is other than -CH2-; Z<2> is a bivalent radical of formula -CH2-CHOH-, -CH2-O-, -CH2-C(=O)- or -CH2-C(=NOH)-, provided that the -CH2- moiety of said bivalent radicals is connected to the nitrogen of the imidazole ring; each R<4> independently is hydrogen; C1-6alkyl; halo; ethenyl substituted with carboxyl or C1-6alkyloxycarbonyl; C1-6alkyl substituted with carboxyl or C1-6alkyloxycarbonyl; hydroxyC1-6alkyl; formyl or carboxyl; each R<5> independently is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, Ar<1> or halo; or R<4> and R<5> taken together may form a bivalent radical of formula CH=CH-CH=CH- or-CH2-CH2-CH2-CH2; each R<6> is hydrogen, C1-6alkyl or Ar<1>C1-6alkyl; Ar<1> is phenyl; phenyl substituted with 1, 2 or 3 substituents each independentl y selected from halo, C1-4alkyl, haloC1-4alkyl, cyano, aminocarbonyl, C1-4alkyloxy or haloC1-4alkyloxy; Ar<2> is naphtalenyl; phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from hydroxy, halo, cyano, nitro, amino, mono- or di(C1-4alkyl)amino, C1-4alkyl, haloC1-4alkyl, C1-4alkyloxy, haloC1-4alkyloxy, carboxyl, C1-4alkyloxycarbonyl, aminocarbonyl and mono- or di(C1-4alkyl)-aminocarbonyl; and Het is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom by 1 or 2 substituents selected from halo, C1-4alkyl or mono-, di- or tri(halo)methyl. 2. A compound according to claim 1 wherein Het is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, benzimidazo1yl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom by 1 or 2 substituents selected from halo, C1-4alkyl or mono-, di- or tri(halo)methyl. 3. A compound according to claim 1 or 2 wherein R<1> is Ar<1> C1-6alky, R<2> is phenyl substituted with 2 substituents selected from methyl or trifluoromethyl, X is a covalent bond and =Q is =O. 4. A compound according to any one of claims 1 to 3 wherein R<1> is phenylmethyl; R<2> is phenyl substituted with 2 substituents selected from methyl or trifluoromethyl; n, m are 1; X is a covalent bond; and =Q is =O. 5. A compound according to any one of claims 1 to 4 wherein L is a radical of formula (a-1) wherein -A-B- is a radical of formula (b-1) wherein Y is -S-; and R7 is hydrogen; or -A-B- is a radical of formula (b-2) wherein Y is -NCH3-; and R<7> is hydrogen; or -A-B-is a radical of formula (b-3); Z is a bivalent radical of formula -CH2- or -CH2-CH2-, provided that when the dotted line is an extra bond, then Z is other than -CH2-; R<4> is formyl; and R<5> is hydrogen; R<6> is hydrogen; or L is a radical of formula (a-2) wherein -A-B- is a radical of formula (b-3); Z is a bivalent radical of formula -CH2-CH<2>  -; R<4>, R<5> and R<6> are hydrogen. 6. A compound according to claim 1, wherein the compound is  1-[3,5-bis(trifluoromethyl)benzoyl]-4-(5,6-dihydrospiro[11H-imidazo[2,1-b][3]benza-zepine-11,4'-piperidin]-1-yl)-2-(phenylmethyl)piperidine; 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(5,6,9,10-tetrahydro-imidazo[1,2-a]thieno-[2,3-d]azepin-10-ylidene)-1-piperidinyl]-2-(phenylmethyl)piperidine; 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(5,6,7,10-tetrahydro-7-methylimidazo[1,2-a]-pyrrolo[3,2-d]azepin-10-ylidene)-1-piperidinyl]-2-(phenylmethyl)piperidine; and  1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(3-formyl-5,6-dihydro-11H-imidazo[2,1-b][3]benzazepin-11-ylidene)-1-piperidinyl]-2-(phenylmethyl)piperidine; 4-[4-(5,6,7,10-tetrahydro-7-methylimidazo[1,2-a]pyrrolo[3,2-d]azepin-10-ylidene) 1-piperidinyl]-1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)piperidine; and  4-[4-(5,6-dihydro-6-oxo-10H-imidazo[1,2-a]thieno[3,2-d]azepin-10-ylidene)-1-piperidinyl]-1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)piperidine; a stereoisomeric form, or a pharmaceutically acceptable acid addition salt thereof. 7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier , and as active ingredient a therapeutically effective amount of a compound as described in any one of claims 1 to 6. 8. A process of preparing a composition as claimed in claim 7, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as described in any one claims 1 to 6. 9. A compound as claimed in any one of claims 1 to 6 for use as a medicine. 10. A process of preparing a compound as claimed in claim 1, characterized by,  a) reductively N-alkylating an intermediate of formula (III) wherein L is defined as in claim 1, with an intermediate of formula (II)    wherein R<1>, R<2>, X, Q, n and m are defined as in claim 1, in a reaction-inert solvent, in the presence of a reducing agent and optionally in the presence of a suitable ca talyst; b) reacting an intermediate of formula (IV) wherein R2, X and Q are defined as in claim 1 and W<1> is an appropriate leaving group with an intermediate of formula (V)    wherein R<1>, L, n and m are defined as in claim 1, in a reaction-inert solvent an d in the presence of a suitable base; and, if desired, converting compounds of formula (I) into each other following art-known transformations, and further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active non-toxic base addition salt by treatment with a base, or conversely, coupling the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and, if desired, preparing stereochemically isomeric forms or N-oxide form s thereof.