Patent EA-000909-B1 (EA)
Title: 1-(1,2-disubstituted piperidinyl)-4-substituted piperazine derivatives
Inventor: JANSSENS FRANS EDUARD
IPC: A61P29/00
Filed: 1996-10-25
Abstract: 1. A compound of formula   it's 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;  p is 1 or 2; =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>C1-6alkyl or diAr<1>C1-6alkyl, wherein each C1-6alkyl group is optionally substituted with hydroxy,  C1-4alkyloxy, oxo or a ketalized oxosubstituent of formula -O-CH2-CH2-O- or -O-CH2-CH2-CH2-O-; R<2> is Ar<2>, Ar<2>C1-6alkyl, Het<1> or Het<1>C1-6 alkyl; R<3> is hydrogen or C1-6alkyl; L is hydrogen; Ar<3>; C1-6alkyl; C1-6alkyl, substituted with 1 or 2 substituents, selected from hydroxy, C1-6alkyloxy, Ar<3>; Ar<3>C1-6alkyloxy and Het<2>; C3-6alkenyl; Ar<3>C3-6alkenyl; diAr<3>C3-6alkenyl or a radical of formula     wherein each q independently is 2, 3 or 4; each r is 0, 1,2,3 or 4; each Y<1> independently is a covalent bond, -O- or NR<3>; Y<2> is a covalent bond, C1-4alkanediyl or C1-4alkylNR<3>-; each -A=B- independently is a bivalent radical of formula -CH=CH-, -N=CH- or -CH=N-; each R<4> independently is hydrogen, C1-6alkyl, Ar<2> or Ar<2>C1-6alkyl;  R<5> is hydrogen, C1-6alkyl or Ar<3>; R<6> is C1-6alkyl, Ar<3>, Ar<3>C1-6alkyl, di(Ar<3>)C1-6alkyl, Ar<3> -C3-7cycloalkyl or indolyl; R<7> is Ar<3>  ; Ar<3>C1-6alkyl; di(Ar<3>)C1-6alkyl; C1-6alkyl; C3-7cycloalkyl; C3-7cycloalkyl, substituted with Ar<3>; oxazolyl; oxazolyl, substituted with halo or C1-6alkyl; thiazolyl; thiazolyl, substituted with halo or C1-6alkyl; imidazolyl; imidazolyl, substituted with Ar<3>, C1-6alkyl, Ar<3>C1-6alkyl or halo; indolinyl; indolinyl, substituted with C1-4alkyl; 2,3,4-trihydroquinolinyl; pyrrolidinyl or furanyl; each R<8> independently is hydrogen, C1-6alkyl, C3-7cycloalkyl or a radical of formula  -Alk-R<11>                                (b-1) or   -Alk-Z-R<12>                          (b-2); wherein Alk is C1-6alkanediyl; Z is a bivalent radical of formula -O-, -S- or -NR<3>-; R<11> 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 hydroxyC1-6alkyl; 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<12> is C1-6alkyl or C1-6alkyl, substituted with hydroxy, carboxyl or C1-6alkyloxycarbonyl; Ar<1> is phenyl; phenyl, substituted with 1, 2 or 3 substituents each independently selected from halo, C1-4alkyl, haloC1-4alkyl, 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, haloC1-4alkyl, C1-4alkyloxy, halo C1-4alkyloxy, carboxyl, C1-4alkyloxycarbonyl, aminocarbonyl and mono- or di(C1-4alkyl)aminocarbonyl;  Ar<3> is phenyl or phenyl substituted with 1, 2 or 3 substituents selected from halo, hydroxy, amino, nitro, aminocarbonyl, C1-6alkyl, haloC1-6alkyl or C1-6alkyloxy; Het<1> is a monocyclic heterocycle selected from pyrrolyl, pyrrazolyl, 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; where each monocyclic and bicyclic heterocycle can optionally be substituted on a carbon atom by 1 or 2 substituents selected from halo, C1-4alkyl or mono-, di- or tri(halo)methyl; and Het<2> is a heterocycle selected from 1,4-dihydro-5-oxotetrazol-1-yl, imidazo[l ,2-a]pyridinyl, oxazolyl or imidazolyl; where each of said heterocycles can be substituted with 1 or where it is possible 2 substituents selected from C1-4alkyl and Ar<3>. 2. A compound according to claim 1 wherein L is hydrogen; C1-6alkyl; C1-6alkyl, substituted with hydroxy; C3-6alkenyl; Ar<3>; Ar<3>C1-6alkyl; di(Ar<3>)C1-6alkyl; Ar<3>C3-6alkenyl; di(Ar<3>)C1-6alkenyl or a radical of formula (a-1), (a-2), (a-4) or (a-5) wherein R<7> is Ar<3>; Ar<3>C1-6alkyl; di(Ar<3>)C1-6alkyl; C1-6alkyl; C3-7cycloalkyl; C3-7cycloalkyl, substituted with Ar<3> ; oxazolyl; oxazolyl, substituted with halo or C1-6alkyl; thiazolyl; thiazolyl, substituted with halo or C1-6alkyl; imidazolyl; imidazolyl, substituted with Ar<3> , C1-6alkyl, Ar<3>C1-6alkyl or halo; pyrrolidinyl or furanyl;  Ar<3> is phenyl or phenyl, substituted with 1,2 or 3 substituents selected from halo, hydroxy, amino, aminocarbonyl, C1-6alkyl, haloC1-6alkyl or C1-6alkyloxy; Het<1> 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; where each monocyclic and bicyclic heterocycle can 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 as claimed in claim 1 or 2, wherein R<1> is Ar<1>C1-6alkyl, R<2> is phenyl substituted with 2 substituents selected from methyl and trifluoromethyl, X is a covalent bond and =Q is =O. 4. A compound as claimed in any of claims 1-3, wherein n and m are 1 and p are 1 or 2. 5. A compound as claimed in any one of claims 1-4, wherein R<1> is phenylmethyl; R<2>  is phenyl, substituted with 2 substituents selected from methyl or trifluoromethyl; n, m and p are 1; X is a covalent bond and =Q is =O. 6. A compound as claimed in any one of claims 1-4, wherein L is a radical of formula (a-2), wherein R<4> is hydrogen or phenyl; r is 0 or 1; Y<1> is a covalent bond, -O- or -NH-; R<7> is pyrrolidinyl; furanyl; 1-phenylcyclohexanyl; diphenylmethyl or phenyl, substituted with 1, 2 or 3 substituents each independently selected from methyl, methoxy or chloro. 7. A compound as claimed in claim 5 or 6, wherein the compound has the transconfiguration. 8. A compound as claimed in claim 5 or 6 wherein the compound has the cisconfiguration. 9. A compound as claimed in claim 1, wherein L is hydrogen. 10. A compound as claimed in claim 1, wherein the compound is 4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6 dimethylphenyl)-l-piperazineacetamide; 4-[1-[3,5-bis(trifluoromethyl]benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(1-phenylcyclohexyl)-1-piperazineacetamide; 1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-[ α -(1-pyrrolidinylcarbonyl)benzyl]-1-piperazinyl] piperidine; 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]-1-piperazinyl]-2-(phenylmethyl)piperidine;  4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(4-trifluoromethylphenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide;  4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide. 11. A compound as claimed in claim 10, wherein the compound is  (+)-(B)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide; (-)-(B)-cis-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1- piperazineacetamide or (+)-(B)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1- piperazineacetamide as (L)-malic acid (1:1) salt. 12. A composition comprising a pharmaceutically acceptable carrier as active ingredient a therapeutically effective amount of a compound as claimed in any of claims 1-11. 13. A process of preparing a composition as claimed in claim 12, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as claimed in any of claims 1-11. 14. A compound as claimed in any of claims 1-11 for use as a medicine. 15. A process of preparing a compound as claimed in claim 1, including a) reducing N-alkylating of an intermediate product of formula (III), wherein L and p are defined in claim 1, by an intermediate product of formula (II)   where R<1>, R<2>, X, Q, n and m are defined as in claim 1, in a reaction-inert solvent, in the presence of an appropriate reducing agent and optionally in the presence of a suitable complex-forming agent; b) reaction of an intermediate product of formula (IV), wherein R<2>, X and Q are defined as in claim 1, and W<1> is an appropriate leaving group with an intermediate product of formula (V)   where wherein R<1>, L, n, m and p are defined as in claim 1, in a reaction-inert solvent and in the presence of a suitable base; c) reducing N-alkylating a piperazine derivative of formula (VII) wherein p is defined as in claim 1, and p<1> is a protective group, with an intermediate product 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 an appropriate reducing agent and optionally in the presence of a suitable complex-forming agent, with forming a compound of formula (I-c); d) reducing N-alkylating a piperazine derivative of formula (VII) wherein p is defined as in claim 1, and p<1> is a protective group, with an intermediate product of formula (VIII)   wherein R<1>, n and m are defined as in claim l, in a reaction-inert solvent and in the presence of a suitable base, thus forming an intermediate product of formula (XI); which may subsequently be reacted with an intermediate product of formula (IV)   wherein W<1> is an appropriate leaving group, and X,