Patent EA-001247-B1 (EA)
Title: N-acyl-2-substituted -4-(benzimidazolyl- or imidazopyridinyl-substituted residues)-piperidines as tachykinin antagonists
Inventor: JANSSENS FRANS EDUARD
IPC: C07D401/12
Filed: 1996-12-20
Abstract: 1. A compound of formula:   a N-oxide form, a 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; X is a covalent bond or a bivalent radical of formula -O-, -S-, -NR<3>-; =Q is =O or=NR<3>; R<1> is Ar<1>, Ar<1> C1-6alkyl or di(Ar<1>) C1-6alkyl wherein the 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-CH2-CH2-O-; R<2> is Ar<2>, Ar<2> C1-6alkyl, Het or Het C1-6alkyl; L is a radical of formula:   or wherein p is 0, 1 or 2; =y- is a bivalent radical of formula -CH2-, -CH(OH)-, -C(=O)-,-O-,-S-, -S(=O)-,-S(=O)2-, -NR<3>-, -CH2-NR<3>- or -C(=O)-NR<3>-; or a trivalent radical of formula =CH-;  -A=B- is a bivalent radical of formula -CH=CH-, -N=CH- or -CH=N-; R<3> independently is hydrogen or C1-6alkyl; R<4> is hydrogen, C1-6alkyl, C3-7cycloalkyl or a radical of formula  -Alk-R<7> 		(c-1) or  -Alk-Z-R<8> 	(c-2); wherein Alk is C1-6alkanediyl; Z is a bivalent radical of formula -O-, -S- or -NR<3>-; R<7> is phenyl, phenyl substituted with 1 or 2 substituents selected from halo, C1-6alkyl or C1-6alkyloxy; furanyl; furanyl substituted with 1 or 2 substituents selected from C1-6alkyl or hydroxy C1-6alkyl; thienyl; thienyl substituted with 1 or 2 substituents selected from halo or C1-6alkyl; oxazolyl; oxazolyl substituted with 1 or 2 C1-6alkyl substituents; thiazolyl; thiazolyl substituted with 1 or 2 C1-6alkyl substituents; pyridinyl or pyridinyl substituted with 1 or 2 C1-6alkyl substituents; R<8> is C1-6alkyl or C1-6alkyl substituted with hydroxy, carboxyl or C1-6alkyloxycarbonyl; R<5> is hydrogen, halo, hydroxy or C1-6alkyloxy; R<6> is hydrogen, C1-6alkyl or Ar<1> C1-6alkyl; Ar<1> is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, C1-4alkyl, halo C1-4alkyl, cyano, aminocarbonyl, C1-4alkyloxy or halo C1-4alkyloxy; 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, halo C1-4alkyl, C1-4alkyloxy, halo C1-4alkyloxy, 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, benzisoxazo1yl, 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 L is a radical of formula (A) 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, 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 wherein L is a radical of formula (B) 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, 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. 4. A compound according any one of claims 1 to 3 wherein L is a radical of formula (A) and p is 0 or 1. 5. A compound according any one of claims 1 to 4 wherein L is a radical of formula (B), n is 1 or 2, and m is 1 or 2, provided that if m is 2, then n is 1. 6. A compound according any one of claims 1 to 5 wherein R<1> is Ar<1> C1-6alkyl, R<2> is phenyl substituted with 2 substituents selected from methyl or trifluoromethyl, X is a covalent bond and =Q is =O. 7. A compound according any one of claims 1 to 6 wherein  is -NH- or -O-; -A=B- is -CH=CH- or -N=CH-; R4 is a radical of formula (c-1) wherein R<7> is oxazolyl substituted with 1 or 2 C1-6alkyl substituents, furanyl substituted wit h C1-6alkyl or hydroxy C1-6alkyl; or R<4> is a radical of formula (c-2) wherein Z is a bivalent radical of formula -O-, and R<8> is C1-6alkyl; R<5> is hydrogen; and R<6> is hydrogen. 8. A compound according to claim 1 selected from 1-[1,3-bis(trifluoromethyl)benzoyl]-4-[4-[[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-(phenylmethyl)piperidine; 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-(phenylmethyl)piperidine; 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-[[3-(5-methyl-2-furanyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinyl]-2-(phenylmethyl)piperidine; 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[3-[[3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-pyrrolidinyl]-2-(phenylmethyl)piperidine; 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4[1-[(5-methyl-2-furanyl)methyl]-lH-benzimidazol-2-yl]amino]-1-piperidinyl]piperidine; 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[[1-(2-ethoxyethyl)-lH-benzimidazol-2-yl]amino]-2-(phenylmethyl)piperidine; 1-[3 ,5-bis(trifluoromethyl)benzoyl]-4-[[1-[(2-methyl-4-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-2-(phenylmethyl)piperidine; 1-[3,5-bis(trifluoromethyl)benzoy]-4-[[1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-yl]armino]-2-(phenylmethyl)piperidine; and also stereoisomeric forms or a pharmaceutically acceptable acid addition salt thereof.  9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound as claimed in any one of claims 1 to 8. 10. A process of preparing a composition as claimed in claim 9, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as claimed in any one claims 1 to 8. 11. A compound as claimed in any one of claims 1 to 8 for use as a medicine. 12. A process of preparing a compound as claimed in claim 1, characterized by  a) reacting an intermediate of formula (II) wherein R<2>, X and Q are defined as in claim 1 and W<1> is an appropriate leaving group, with an intermediate of formula (III):   wherein n, m, L and R<1> are defined as in claim 1, in a reaction-inert solvent, a nd in the presence of a suitable base;  b) reductively N-alkylating an intermediate of formula (V) wherein p, ,-A=B -, R<4>, R<5> and R<6> are defined as in claim 1, with an intermediate of formula (IV):   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 catalyst; thus forming a compound of formula (I-A);  c) reductively N-alkylating an intermediate of formula (VI) wherein -A=B-, R<3>, R<4> and R<5> are defined as in claim 1, with an intermediate of formula (IV):   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 catalyst; thus forming a compound of formula (I-B-1); d) reacting an intermediate of formula (VII) wherein R<1>, R<2>, R<3>, X, Q, n and m are defined as in claim 1 with an intermediate of formula (VIII):   wherein W<2> is an appropriate leaving group and -A=B-, R<4> and R<5> are defined as in claim 1, in the presence of a suitable catalyst and optionally in a reactioninert solvent; thus forming a compound of formula (I-B-1);  e) reacting an intermediate of formula (IX) wherein W<3> is a suitable leaving group and R<1>, R<2>, X, Q, n and m are defined as in claim 1, with an intermediate of formula (X):   wherein -A=B-, R<4> and R<5> are defined as in claim 1, in a reaction-inert solvent, and in the presence of a suitable base; thus forming a compound of formula (I-B-2);  f) reacting an intermediate of formula (XI) wherein R<1>,R<2>, X, Q, n and m are defined as in claim 1, with an intermediate of formula (VIII)    wherein W<2> is an appropriate leaving group and -A=B-, R<4> and R<5> are defined as in claim 1, in a reaction-inert solvent and in the presence of a suitable base; thus forming a compound of formula (I-B-3); 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, converting 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 forms thereof.