Patent EA-001559-B1 (EA)
Title: 1-(1,2-disubstitutedpiperidinyl)-4-substituted piperidine derivatives as tachykini receptorn
Inventor: JANSSENS FRANS EDUARD
IPC: A61K31/00
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 m=n=1; p is 0, 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 di(Ar<1>)C1-6alkyl, wherein each C1-6alkyl group is optionally substituted with hydroxy, C1-4alkyloxy-substituent, oxo-substituent 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 HetC1-6alkyl; R<3> is hydrogen or C1-6alkyl; R<4> is hydrogen; C1-4alkyl; C1-4alkyloxy-C1-4alkyl; hydroxy-C1-4alkyl; carboxyl, C1-4alkyloxycarbonyl or Ar<3>; R<5> is hydrogen; hydroxyl; Ar<3>; Ar<3>C1-6alkyloxy-group; di(Ar<3>)C1-6alkyloxy-group; Ar<3>C1-6alkylthio-group; di(Ar<3>)C1-6alkylthio-group; Ar<3>C1-6alkylsulfoxy-group; di(Ar<3>)C1-6alkylsulfoxy-group; Ar<3>C1-6alkylsulfonyl; di(Ar<3>)C1-6alkylsulfonyl; -NR<7>R<8>; C1-6alkyl substituted with -NR<7>R<8>; or a radical of formula:   wherein R<7> is hydrogen; C1-6alkyl; pyridinyl or Ar<3>; R<8> is hydrogen; C1-6alkyl; Ar<3>C1-6alkyl; di(Ar<3>)C1-6alkyl; imidazolyl substituted with Ar<3>, C1-6alkyl or Ar<3>C1-6alkyl; benzoxazolyl or benzothiazolyl; R<9> is hydrogen; hydroxyl; C1-6alkyl; C1-6alkyloxy-group; Ar<3>; Ar<3>C1-6alkyl; di(Ar<3>)C1-6alkyl; amino-group; mono- or di-C1-6alkylamino-group; imidazolyl; imidazolyl substituted with Ar<3>, C1-6alkyl or Ar<3>C1-6alkyl; pyrrolidinyl; piperidinyl; homopiperidinyl; morpholinyl or thiomorpholinyl; R<10> is hydrogen or C1-6alkylcarbonyl; R<11> is hydrogen; halo or mono-, di- or trihalomethyl; Y is Y<1> or Y<2>, wherein Y<1> is a covalent bond; C1-6alkanediyl; -NR<7>- or -C1-6alkanediyl-NR<7>-; or Y<2> is -O-, provided that R<9> is other than hydroxyl or C1-6alkyloxy-group; R<4> and R<5> may also be taken together to form a bivalent radical of formula -O-CH2-CH2-O or -C(=O)-NR<3>-CH2-NR<7>-; R<6> is hydrogen; hydroxy; C1-6alkyloxy-group; C1-6alkyl or Ar<3>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-group, aminocarbonyl, C1-4alkyloxy-group, halo-C1-4alkyloxy-group; Ar<2> is naphtalinyl; phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from hydroxyl, halo, cyano-group, nitro-group, amino-group, mono- or di(C1-4alkyl)amino-group, C1-4alkyl, halo-C1-4alkyl, C1-4alkyloxy-group, halo-C1-4alkyloxy-group, 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, hydroxyl, amino-group, nitro-group, aminocarbonyl, C1-6alkyl, halo-C1-6alkyl or C1-6alkyloxy; 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 as claimed in claim 1 wherein R<8> is hydrogen; C1-6alkyl; Ar<3>C1-6alkyl; di(Ar<3>)-C1-6alkyl; benzoxazolyl or benzothiazolyl; R<9> is hydrogen; hydroxyl; C1-6alkyl; C1-6alkyloxy-group; Ar<3>; Ar<3>C1-6alkyl; di(Ar<3>)-C1-6alkyl: amino; mono- or di-(C1-6alkyl)amino-group; pyrrolidinyl; piperidinyl; homopiperidinyl; morpholinyl or thiomorpholinyl; 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. 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 or trifluoromethyl, X is a covalent bond and =Q is =0. 4. A compound as claimed in any one of claims 1 to 3 wherein p is 1. 5. A compound as claimed in any one of claims 1 to 4 wherein R<4> is hydrogen; C1-4alkyloxy-C1-4alkyl, phenyl or phenyl substituted with halo; R<5> is phenyl; amino-group substituted with phenyl or substituted with imidazolyl; or phenyl substituted with halo; or R<5> is a radical of formula (a-1) wherein Y is Y<1> or Y<2> wherein Y<1> is a covalent bond, -NR<7> or -CH2-NR<7>-; wherein R<7> is hydrogen or phenyl optionally substituted with halo; Y<2> is -O-; R<9> is C1-6alkyl, C1-6alkyloxy-group, pyrrolidinyl, phenyl-C1-6alkyl, imidazolyl substituted with phenyl-C1-6alkyl or Ar<3>; or R<5> is a radical of formula (a-2) wherein R<10> is hydrogen or C1-6alkylcarbonyl; R<11> is hydrogen; or R<4> and R<5> are taken together to form a bivalent radical of formula -C(=O)-NR<3>-CH2-NR<7>- wherein each R<7> independently is selected from hydrogen or phenyl; and R<6> is hydrogen. 6. A compound as claimed in claim 1 is: 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]-2-(phenylmethyl)piperidine; 1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-phenyl-4-(1-pyrrolidinylcarbonyl)-1-piperidinyl]piperidine; N-[[1-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-4-phenyl-4-piperidinyl]methyl]acetamide; or 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl]-2-(phenylmethyl)piperidine; 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-phenyl-4-(1-pyrrolidinylcarbonyl)-1-piperidinyl]-2-[[4-(trifluoromethyl)phenyl]methyl]piperidine; and 1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3,4-difluorophenyl)methyl]-4-[4-phenyl-4-(1-pyrrolidinylcarbonyl)-1-piperidinyl]piperidine; stereoisomeric and pharmaceutically acceptable acid addition salts thereof. 7. A compound as claimed in any one of claims 1 to 6 for use as a medicine. 8. 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 6. 9. A process of preparing a composition as claimed in claim 8, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as claimed in any one of claims 1 to 6. 10. A process of preparing a compound as claimed in claim 1, characterized by reductively N-alkylating an intermediate of formula (III) wherein R<4>, R<5> and R<6> are defined as in claim 1, with an intermediate of formula (II):   wherein R<1>, R<2>, X, =Q, n, m and p 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. 11. A process of preparing a compound as claimed in claim 1, characterized by reacting an intermediate 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 of formula (V)   wherein R<1>, R<4>, R<5>, R<6>, X, =Q, n, m and p are defined as in claim 1, in a reaction-inert solvent and in the presence of a suitable base; 12. A process of preparing a compound as claimed in claim 1, characterized by reacting a piperidinone derivative of formula (VI) wherein R<1>, R<2>, R<6>, X, =Q, n, m and p are defined as in claim 1, with an intermediate of formula (VII):   wherein M is an appropriate organometallic part and R<4>' is the same as R<4> as defined in claim 1 but other than hydrogen; 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 salts by treatment with an acid, or conversely, converting the acid addition salt form into the free base by treatment with alkali; and, if desired, preparing stereochemically isomeric forms or N-oxide forms thereof.