Novel guanidinyl-substituted hydroxy-6-phenylphenanthridines as effective phosphodiesterase (pde) 4 inhibitors

A compound of formula 1

• in which
• R1 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-4C-alkoxy,
• R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-4C-alkoxy,
• or in which
• R1 and R2 together are a 1-2C-alkylenedioxy group,
• R3 is hydrogen or 1-4C-alkyl,
• R31 is hydrogen or 1-4C-alkyl,
• either, in a first embodiment (embodiment a),
• R4 is —O—R41, in which
• R41 is hydrogen, 1-4C-alkyl, completely or predominantly fluorine-substituted 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-2-4C-alkyl or 1-7C-alkylcarbonyl, and
• R5 is hydrogen or 1-4C-alkyl,
• or, in a second embodiment (embodiment b),
• R4 is hydrogen or 1-4C-alkyl, and
• R5 is —O—R51, in which
• R51 is hydrogen, 1-4C-alkyl, completely or predominantly fluorine-substituted 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-2-4C-alkyl or 1-7C-alkylcarbonyl,
• R6 is hydrogen, halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy,
• R7 is a radical of formulae (a), (b), (c) or (d)
• in which
• if R7 is a radical of the formula (b),
• either
• R8, R9, R10 and R11 independently of one another are hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, cyano, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or R28,
• or
• R8 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or R28,
• R9 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or R28, and
• R10 and R11, together and including the nitrogen atom to which both are bonded, are a pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, azocan-1-yl, azonan-1-yl, azecan-1-yl, morpholin-4-yl, tetrahydroisoquinolin-2-yl, tetrahydro-6,7-dimethoxyisoquinolin-2-yl, 3,5-dimethyl-pyrazol-1-yl, pyrazol-1-yl, 2,6-dimethylmorpholin-4-yl, 2,6-dimethyl-piperidin-1-yl, 4-benzylpiperidin-1-yl, thiomorpholin-4-yl or 1H-1,2,4-triazol-1-yl radical, or a piperazin-1-yl radical substituted in 4-position by R19,
• or
• R8 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or R28,
• R9 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or R28,
• R10 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or R28, and
• R11 is Aryl1, naphthyl, phenyl, phenyl substituted by R20 and/or R21, phenyl-1-4C-alkyl or phenyl-1-4C-alkyl substituted by R22 and R23,
• in which
• if R7 is a radical of the formula (c),
• either
• R12, R13, R14 and R15 independently of one another are hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or R28,
• or
• R12 and R13 independently of one another are hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or R28, and
• R14 and R15, together and including the nitrogen atom to which both are bonded, are a pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, azocan-1-yl, azonan-1-yl, azecan-1-yl, morpholin-4-yl, tetrahydroisoquinolin-2-yl, tetrahydro-6,7-dimethoxyisoquinolin-2-yl, 3,5-dimethyl-pyrazol-1-yl, pyrazol-1-yl, 2,6-dimethylmorpholin-4-yl, 2,6-dimethyl-piperidin-1-yl, 4-benzylpiperidin-1-yl, thiomorpholin-4-yl or 1H-1,2,4-triazol-1-yl radical, or a piperazin-1-yl radical substituted in 4-position by R19,
• or
• R12 and R13, together and including the nitrogen atom to which both are bonded, are a pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholino-4-yl, 4-(1-4C-alkyl-)-piperazin-1-yl, 2,6-dimethyl-morpholin-4-yl, 2,6-dimethyl-piperidin-1-yl, 4-benzyl-piperidin-1-yl or thiomorpholin-4-yl radical, and
• R14 and R15, together and including the nitrogen atom to which both are bonded, are a pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholino-4-yl, 4-(1-4C-alkyl-)-piperazin-1-yl, 2,6-dimethyl-morpholin-4-yl, 2,6-dimethyl-piperidin-1-yl, 4-benzyl-piperidin-1-yl or thiomorpholin-4-yl radical,
• or
• R12 and R15 independently of one another are hydrogen or 1-4C-alkyl, and
• R13 and R14, together and with inclusion of the N—C(═)—N structure to which they are bonded, are a hexahydropyrimidin-2-ylidene or imidazolidin-2-ylidene radical,
• in which
• if R7 is a radical of the formula (d),
• R16 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or R28, and
• R17 and R18, together and with inclusion of the N—C(—)—N structure to which they are bonded are Aryl2,
• Aryl1 is 4-methylthiazol-2-yl, benzimidazol-2-yl, 5-nitrobenzimidazol-2-yl, 5-chlorobenzimidazol-2-yl, 5-methylbenzimidazol-2-yl, 4-methylquinazolin-2-yl, benzothiazol-2-yl, benzoxazol-2-yl or pyrimidin-2-yl,
• Aryl2 is 1-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl, imidazol-2-yl, 4,5-dicyano-imidazol-2-yl, 4-methylimidazol-2-yl, 4-ethyl-benzimidazol-2-yl, 4-acetylimidazol-2-yl, 1H-[1,2,4]triazol-3-yl, benzimidazol-2-yl, 1-methyl-benzimidazol-2-yl, 1-ethyl-benzimidazol-2-yl, 5,6-dimethyl-benzimidazol-2-yl, purin-8-yl, 6-amino-7-methyl-7H-purine-8-yl, 1,6-dimethylimidazo[4,5-b]pyridin-2-yl, 1,5,6-trimethylimidazo[4,5-b]pyridin-2-yl, 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione-8-yl, 7-ethyl-3-methyl-3,7-dihydro-purine-2,6-dione-8-yl, 1,3,7-trimethyl-3,7-dihydro-purine-2,6-dione-8-yl, thiadiazolyl, 1,4-dihydrotetrazol-5-yl, 1H-[1,2,4]triazol-3-yl, 1,3-dihydrobenzimidazol-5-yl, 1H-tetrazol-5-yl, pyrimidin-2-yl or 4,6-dimethylpyrimidin-2-yl,
• R19 is 1-4C-alkyl, formyl, 3-7C-cycloalkyl, 3-7Ccycloalkylmethyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, 1-4C-alkylcarbonyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, hydroxy-2-4C-alkoxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkoxy-2-4C-alkyl, phenyl, phenyl substituted by R24 and/or R25, [benzo(1,3)dioxol]-5-ylmethyl, phenyl-1-4C-alkyl or phenyl-1-4C-alkyl substituted in the phenyl moiety by R26 and/or R27,
• R20 is halogen, nitro, carboxyl, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy,
• R21 is halogen, 1-4C-alkyl or 1-4C-alkoxy,
• R22 is halogen, nitro, carboxyl, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy,
• R23 is halogen, 1-4C-alkyl or 1-4C-alkoxy,
• R24 is halogen, nitro, carboxyl, 1-4C-alkyl, 1-4C-alkylcarbonyl, trifluoromethyl or 1-4C-alkoxy,
• R25 is halogen, 1-4C-alkyl or 1-4C-alkoxy,
• R26 is halogen, nitro, carboxyl, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy,
• R27 is halogen, 1-4C-alkyl or 1-4C-alkoxy, R28 is R29(R30)N-2-4C-alkyl wherein
• R29 and R30, together and including the nitrogen atom to which both are bonded, are a pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-(1-4C-alkyl)piperazin-1-yl, azepan-1yl, azocan-1-yl, azonan-1-yl, azecan-1-yl, tetrahydroisoquinolin-2-yl, tetrahydro-6,7-dimethoxyisoquinolin-2-yl, 3,5-dimethyl-pyrazol-1-yl, pyrazol-1-yl, morpholin-4-yl, 2,6-dimethylmorpholin-4-yl, 2,6-dimethyl-piperidin-1-yl, 4-benzylpiperidin-1-yl, thiomorpholin-4-yl or 1H-1,2,4-triazol-1-yl radical,
• or a salt, N-oxide, salt of the N-oxide, enantiomer, salt of the enantiomer, E/Z isomer, salt of the E/Z isomer, tautomer or salt of the tautomer thereof.