Patent EA-003780-B1 (EA)
Title: Phenylphenanthridines with pde-iv inhibiting activity
Inventor: FLOCKERZI DIETER
IPC: A61P17/14
Filed: 2000-01-12
Abstract: 1. A compound of formula I in which R1 is hydroxyl, C1-4 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy or completely or predominantly fluorine-substituted C1-4 alkoxy, R2 is hydroxyl, C1-4 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy or completely or predominantly fluorine-substituted C1-4 alkoxy, or in which R1 and R2 together are a C1-2 alkylenedioxy group, R3 is hydrogen or C1-4 alkyl, R31 is hydrogen or C1-4, or in which R3 and R31 together are a C1-4 alkylene group, R4 is hydrogen or C1-4 alkyl, R5 is hydrogen, R51 is hydrogen, or in which R5 and R51 together represent an additional bond, R6 is O-R7, S-R8, C(O)-R9, CH2-R10, S(O)2-aryl, O-S(O)2-R11, pyrrolidin-1-yl, pyrrolidin-1-yl-2-one, pyrrolidin-1-yl-2,5-dione, piperidin-1-yl, piperidin-1-yl-2-one or piperidin-1-yl-2,6-dione, where R7 is C3-7 cycloalkyl, C3-7 cycloalkylmethyl, C1-4 alkoxy- C1-4 alkyl, aryl or phenyl- C1-4 alkyl, R8 is hydrogen, C1-4 alkyl, C1-4 alkylcarbonyl, arylcarbonyl, trifluoromethyl, difluoromethyl, trichloromethyl or phenyl, R9 is C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylmethyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, 4-morpholinyl or aryl, R10 is hydroxyl, halogen, cyano, carboxyl, C4-1 alkoxy, phenoxy, C1-4 alkoxycarbonyl, aminocarbonyl, mono- or di-C1-4 alkylaminocarbonyl, N(R15)R16 or C1-4 alkylcarbonylamino, and R11 is C1-4 alkyl, amino, mono- or di-C1-4 alkylamino or aryl, aryl is phenyl, pyridyl or R12-substituted phenyl, where R12 is hydroxyl, halogen, carboxyl, nitro, amino, cyano, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1-4 alkylcarbonyloxy or aminocarbonyl, R13 is hydrogen, hydroxyl, halogen, cyano, nitro, amino, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, completely or predominantly fluorine-substituted C1-4 alkoxy, phenyl, phenyl-C1-4 alkyl, C(O)-OR14, C(O)-N (R15)R16, N(R17)R18, S(O)2-R19, S(O)2-N(R15)R16 or has one of the meanings of R6, where R14 is hydrogen, C1-4 alkyl, C3-7 cycloalkyl or C3-7 cycloalkylmethyl, R15 is hydrogen, C1-4 alkyl, C3-7 cycloalkyl or C3-7 cycloalkylmethyl, R16 is hydrogen, C1-4 alkyl, C3-7 -cycloalkyl, C3-7 cycloalkylmethyl or aryl, or where R15 and R16, together and including the nitrogen atom to which both are bonded, represent a 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazin-1-yl, 1-hexahydroazepinyl or 4-morpholinyl radical, R17 is hydrogen, C1-4 alkyl, S(O)2-R19 or S(O)2-aryl, R18 is C1-4 alkyl, C1-4 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C3-7 cycloalkylmethylcarbonyl, S(O)2-R19 or S(O)2-aryl, and R19 is C1-4 alkyl, R20 is hydrogen, hydroxyl, halogen, nitro, amino, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, completely or predominantly fluorine-substituted C1-4 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy, CH2-R10, carboxyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonyloxy, C1-4 alkylcarbonylamino or aminocarbonyl, or a pharmaceutically acceptable salt, an N-oxide, or a salt of an N-oxide of this compound. 2. A compound of formula I as claimed in claim 1, in which R1 is C1-2 alkoxy, C3-5 cycloalkoxy, C3-5 cycloalkylmethoxy or completely or predominantly fluorine-substituted C1-2 alkoxy, R2 is C1-2 alkoxy, C3-5 cycloalkoxy, C3-5 cycloalkylmethoxy or completely or predominantly fluorine-substituted C1-2 alkoxy, R3 is hydrogen, R31 is hydrogen, R4 is hydrogen or C1-2 alkyl, R5 is hydrogen, R51 is hydrogen, or in which R5 and R51 together represent an additional bond, R6 is O-R7, S-R8, C(O)-R9, CH2-R10, SO2-aryl, O-S(O)2-R11, pyrrolidin-1-yl, pyrrolidin-1-yl-2-one or pyrrolidin-1-yl-2,5-dione, Where R7 is C3-7 cycloalkyl, C3-7 cycloalkylmethyl, C1-4 alkoxy- C1-4 alkyl, aryl or phenyl- C1-4 alkyl, R8 is hydrogen, C1-4 alkyl, acetyl, phenylcarbonyl, trifluoromethyl or phenyl, R9 is C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylmethyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, 4-morpholinyl or aryl, R10 is halogen, carboxyl, C1-4 alkoxy, phenoxy, C1-4 alkoxycarbonyl, aminocarbonyl, mono- or di-C1-4 alkylaminocarbonyl, N(R15)R16 or C1-4 alkylcarbonylamino, and R11 is C1-4 alkyl, mono- or di- C1-4 alkylamino or aryl, aryl is phenyl, pyridyl or R12-substituted phenyl, where R12 is halogen, carboxyl, nitro, amino, cyano, C1-4 alkyl, trifluoromethyl or C1-4 alkoxy, R13 is hydrogen, hydroxyl, halogen, cyano, nitro, amino, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, completely or predominantly fluorine-substituted C1-4 alkoxy, phenyl, phenyl- C1-4 alkyl, C(O)-OR14, C(O)-N(R15)R16, N(R17)R18, S(O)2-R19, S(O)2-N(R15)R16 or has one of the meanings of R6, where R14 is hydrogen or C1-4 alkyl, R15 is hydrogen or C1-4 alkyl, R16 is hydrogen, C1-4 alkyl or aryl, or where R15 and R16, together and including the nitrogen atom to which both are bonded, are a 1-piperidyl, 1-piperazinyl, 1-methylpiperazin-4-yl or 4-morpholinyl radical, R17 is hydrogen, C1-4 alkyl, S(O)2-R19 or S(O)2-aryl, R18 is C1-4 alkyl, C1-4 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C3-7 cycloalkylmethylcarbonyl, S(O)2-R19 or S(O)2-aryl, and R19 is C1-4 alkyl, R20 is hydrogen, hydroxyl, halogen, nitro, amino, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, completely or predominantly fluorine-substituted C1-4 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl-methoxy, carboxyl, C1-4 alkoxycarbonyl or C1-4 alkylcarbonyloxy, or a pharmaceutically acceptable salt, an N-oxide, or a salt of an N-oxide of this compound. 3. A compound of formula I as claimed in claim 1, in which R1 is C1-2 alkoxy, R2 is C1-2 alkoxy, R3, R31, R4, R5 and R51 are hydrogen, R6 is O-R7, S-R8, C(O)-R9, CH2-R10, S(O)2-phenyl, O-S(O)2-R11, pyrrolidin-1-yl, pyrrolidin-1-yl-2-one or pyrrolidin-1-yl-2,5-dione, where R7 is C3-5 cycloalkyl, C3-5 cycloalkylmethyl, C1-2 alkoxy- C1-2 alkyl, aryl or phenyl- C1-2 alkyl, R8 is phenyl, R9 is C1-4 alkyl, cycloalkylmethyl, 1-piperidinyl or aryl, R10 is halogen, C1-4 alkoxycarbonyl or N(R15)R16, and R11 is methyl or 4-methylphenyl, aryl is phenyl, pyridyl or R12-substituted phenyl, where R12 is C1-4 alkyl, C1-4 alkoxy, halogen, nitro or cyano, R15 is C1-4 alkyl, and R16 is C1-4 alkyl, or where R15 and R16, together and including the nitrogen atom to which both are bonded, are a 1-piperidinyl, 1-piperazinyl, 1-methylpiperazin-4-yl or 4-morpholinyl radical, and in which eitherR13 is hydrogen, C1-4 alkoxy, completely or predominantly fluorine-substituted C1-2 alkoxy, or C1-4 alkylcarbonylamino and R20 is hydrogen, or R13 is hydrogen and R20 is C3-5 cycloalkoxy or C3-5 cycloalkylmethoxy, or a pharmaceutically acceptable salt, an N-oxide, or a salt of an N-oxide of this compound. 4. A compound of formula I as claimed in claim 1, in which R1 is C1-2 alkoxy, R2 is C1-2 alkoxy, R3, R31, R4, R5 and R51 are hydrogen, R6 is O-R7, S-R8, C(O)-R9, CH2-R10, S(O)2-phenyl, O-S(O)2-R11, pyrrolidin-1-yl or pyrrolidin-1-yl-2-one, where R7 is cyclobutyl, cyclopentyl, cyclopropylmethyl, 2-methoxyethyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl or pyridyl, R8 is phenyl, R9 is methyl, ethyl, isobutyl, cyclopropylmethyl, 1-piperidinyl or aryl, R10 is methoxycarbonyl, morpholin-4-yl or 1-methylpiperazin-4-yl, and R11 is methyl or 4-methylphenyl, aryl is phenyl, pyridyl or R12-substituted phenyl, in which R12 is methoxy, halogen, nitro or cyano, and in which either R13 is hydrogen, methoxy, ethoxy, difluoromethoxy or acetylamino and R20 is hydrogen, or R13 is hydrogen and R20 is cyclopropylmethoxy, or a pharmaceutically acceptable salt, an N-oxide, or a salt of an N-oxide of this compound. 5. A compound of formula I as claimed in claim 1, in which R1 is hydroxyl, C1-4 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy or completely or predominantly fluorine-substituted C1-4 alkoxy, R2 is hydroxyl, C1-4 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy or completely or predominantly fluorine-substituted C1-4 alkoxy, or in which R1 and R2 together are a C1-2 alkylenedioxy group, R3 is hydrogen or C1-4 alkyl, R31 is hydrogen or C1-4 alkyl, or in which R3 and R31 together are a C1-4 alkylene group, R4 is hydrogen or C1-4 alkyl, R5 is hydrogen, R51 is hydrogen, or in which R5 and R51 together are an additional bond, R6 is O-R7, S-R8, C(O)-R9, CH2-R10 or O-S(O)2-R11, where R7 is C3-7 cycloalkyl, C3-7 cycloalkylmethyl, aryl or phenyl- C1-4 alkyl, R8 is hydrogen, C1-4 alkyl, C1-4 alkylcarbonyl, trifluoromethyl, difluoromethyl, trichloromethyl or phenyl, R9 is C1-4 alkyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, 4-morpholinyl or aryl, R10 is hydroxyl, halogen, cyano, carboxyl, C1-4 alkoxy, phenoxy, C1-4 alkoxycarbonyl, aminocarbonyl, mono- or di-C1-4 alkylaminocarbonyl, N(R15)R16 or C1-4 alkylcarbonylamino, and R11 is C1-4 alkyl, amino, mono- or di-C1-4 alkylamino or aryl, aryl is phenyl, pyridyl or R12-substituted phenyl, where R12 is hydroxyl, halogen, carboxyl, nitro, amino, cyano, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1-4 alkylcarbonyloxy or aminocarbonyl, R13 is hydrogen, hydroxyl, halogen, cyano, nitro, amino, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, completely or predominantly fluorine-substituted C1-4 alkoxy, phenyl, phenyl- C1-4 alkyl, C(O)-OR14, C(O)-N(R15)R16, N(R17)R18, S(O)2-R19, S(O)2-N(R15)R16 or has one of the meanings of R6, where R14 is hydrogen, C1-4 alkyl, C3-7 cycloalkyl or C3-7 cycloalkylmethyl, R15 is hydrogen, C1-4 alkyl, C3-7 cycloalkyl or C3-7 cycloalkylmethyl, R16 is hydrogen, C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylmethyl or aryl, or where R15 and R16, together and including the nitrogen atom to which both are bonded, are a 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazin-1-yl, 1-hexahydroazepinyl or 4-morpholinyl radical, R17 is hydrogen, C1-4 alkyl, S(O)2-R19 or S(O)2-aryl, R18 is C1-4 alkyl, C1-4 alkylcarbonyl or S(O)2-R19 or S(O)2-aryl, and R19 is C1-4 alkyl, R20 is hydrogen, hydroxyl, halogen, nitro, amino, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, completely or predominantly fluorine-substituted C1-4 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy, CH2-R10,