Novel heterocycle-substituted hydroxy-6-phenylphenanthridines and their use as pde4 inhibitors
Compounds of the formula I in which the substituents have the definitions provided in the specification, are novel, effective PDE4 inhibitors.
1 . A compound of formula I
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, 1-4C-alkoxy-1-4C-alkyl, hydroxy-2-4C-alkyl, 1-7C-alkylcarbonyl, or completely or predominantly fluorine-substituted 1-4C-alkyl, 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, 1-4C-alkoxy-1-4C-alkyl, hydroxy-2-4C-alkyl, 1-7C-alkylcarbonyl, or completely or predominantly fluorine-substituted 1-4C-alkyl,
R6 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,
R7 is Het1, Het2, Har1, Het3 or Har2, in which
Het1 is optionally substituted by R71 and is a monocyclic 3- to 7-membered fully saturated heterocyclic ring radical comprising one to three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, in which
R71 is 1-4C-alkyl, 1-4C-alkoxy, or completely or partially fluorine-substituted 1-4C-alkyl,
Het2 is optionally substituted by R72 and is a monocyclic 5- to 7-membered saturated or unsaturated heterocyclic ring radical, which comprises one nitrogen atom and optionally one or two further heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, and to which ring one or two oxo substituents are bonded, in which
R72 is 1-4C-alkyl, 1-4C-alkoxy, or completely or partially fluorine-substituted 1-4C-alkyl,
Har1 is optionally substituted by R73 and is a monocyclic 5-membered fully unsaturated heterocyclic ring radical comprising one to four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, in which
R73 is 1-4C-alkyl, 1-4C-alkoxy, or completely or partially fluorine-substituted 1-4C-alkyl,
Het3 is optionally substituted by R74 and is a monocyclic 5- or 6-membered partially unsaturated heterocyclic ring radical comprising one nitrogen atom and optionally one further heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, in which
R74 is 1-4C-alkyl, 1-4C-alkoxy, or completely or partially fluorine-substituted 1-4C-alkyl,
Har2 is optionally substituted by R75 and/or R76 and stands for a monocyclic 6-membered fully unsaturated heterocyclic ring radical comprising one to three nitrogen atoms, in which
R75 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, halogen, hydroxyl, amino, mono- or di-1-4C-alkylamino, or completely or partially fluorine-substituted 1-4C-alkyl,
R76 is 1-4C-alkoxy, 1-4C-alkylthio, hydroxyl, amino or mono- or di-1-4C-alkylamino,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
2 . A compound of formula I according to claim 1 in which
R1 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R2 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R3 is hydrogen,
R31 is hydrogen,
either, in a first embodiment (embodiment a),
R4 is —O—R41, in which
R41 is hydrogen or 1-4C-alkylcarbonyl, and
R5 is hydrogen,
or, in a second embodiment (embodiment b),
R4 is hydrogen, and
R5 is —O—R51, in which
R51 is hydrogen or 1-4C-alkylcarbonyl,
R6 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,
R7 is Het1, Het2, Har1, Het3 or Har2, in which
Het1 is optionally substituted by R71 and is a monocyclic 3- to 7-membered fully saturated heterocyclic ring radical comprising one to three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, in which
R71 is 1-4C-alkyl, 1-4C-alkoxy, or completely or partially fluorine-substituted 1-4C-alkyl,
Het2 is optionally substituted by R72 and is a monocyclic 5- to 7-membered saturated or unsaturated heterocyclic ring radical, which comprises one nitrogen atom and optionally one or two further heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, and to which ring one or two oxo substituents are bonded, in which
R72 is 1-4C-alkyl, or completely or partially fluorine-substituted 1-4C-alkyl,
Har1 is optionally substituted by R73 and is a monocyclic 5-membered fully unsaturated heterocyclic ring radical comprising one to four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, in which
R73 is 1-4C-alkyl, 1-4C-alkoxy, or completely or partially fluorine-substituted 1-4C-alkyl,
Het3 is optionally substituted by R74 and is a monocyclic 5- or 6-membered partially unsaturated heterocyclic ring radical comprising one nitrogen atom and optionally one further heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, in which
R74 is 1-4C-alkyl, or completely or partially fluorine-substituted 1-4C-alkyl,
Har2 is optionally substituted by R75 and/or R76 and stands for a monocyclic 6-membered fully unsaturated heterocyclic ring radical comprising one to three nitrogen atoms, in which
R75 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, halogen, hydroxyl, amino, mono- or di-1-4C-alkylamino, or completely or partially fluorine-substituted 1-4C-alkyl,
R76 is 1-4C-alkoxy, 1-4C-alkylthio, hydroxyl, amino or mono- or di-1-4C-alkylamino,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
3 . A compound of formula I according to claim 1 in which
R1 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R2 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R3 is hydrogen,
R31 is hydrogen,
R4 is —O—R41, in which
R41 is 1-4C-alkylcarbonyl or hydrogen,
R5 is hydrogen,
R6 is hydrogen,
R7 is Het1, Har1, Het3 or Har2, in which
Het1 is optionally substituted by R71 and is a monocyclic 3- to 7-membered fully saturated heterocyclic ring radical comprising one nitrogen atom and optionally one or two further heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, in which
R71 is 1-4C-alkyl, or completely or partially fluorine-substituted 1-4C-alkyl,
Har1 is optionally substituted by R73 and is a monocyclic 5-membered fully unsaturated heterocyclic ring radical comprising one nitrogen atom and optionally up to three further heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, in which
R73 is 1-4C-alkyl, or completely or partially fluorine-substituted 1-4C-alkyl,
Het3 is optionally substituted by R74 and is a monocyclic 5-membered partially unsaturated heterocyclic ring radical comprising one nitrogen atom and one further heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, in which
R74 is 1-4C-alkyl, or completely or partially fluorine-substituted 1-4C-alkyl,
Har2 is optionally substituted by R75 and/or R76 and stands for a monocyclic 6-membered fully unsaturated heterocyclic ring radical comprising one or two nitrogen atoms, in which
R75 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, halogen, hydroxyl, amino, mono- or di-1-4C-alkylamino, or completely or partially fluorine-substituted 1-4C-alkyl,
R76 is 1-4C-alkoxy, 1-4C-alkylthio, hydroxyl, amino or mono- or di-1-4C-alkylamino,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
4 . A compound of formula I according to claim 1 in which
R1 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R2 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R3 is hydrogen,
R31 is hydrogen,
R4 is —O—R41; in which
R41 is hydrogen,
R5 is hydrogen,
R6 is hydrogen,
R7 is Het1, Har1, Het3 or Har2, in which
Het1 is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl or thiomorpholin-4-yl, or 4-N-(R71)-piperazin-1-yl or 4-N-(R71)-homopiperazin-1-yl, in which
R71 is 1-4C-alkyl, or completely or partially fluorine-substituted 1-2C-alkyl,
Har1 is optionally substituted by R73 and is a monocyclic 5-membered fully unsaturated heterocyclic ring radical comprising one nitrogen atom and optionally up to three further heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, in which
R73 is 1-4C-alkyl, or completely or partially fluorine-substituted 1-2C-alkyl,
Het3 is 1-N-(R74)-4,5-dihydro-1H-imidazol-2-yl, in which
R74 is 1-4C-alkyl, or completely or partially fluorine-substituted 1-2C-alkyl,
Har2 is optionally substituted by R75 and/or R76 and stands for a monocyclic 6-membered fully unsaturated heterocyclic ring radical comprising one or two nitrogen atoms, in which
R75 is 1-2C-alkyl, 1-4C-alkoxy, mono- or di-1-2C-alkylamino, or completely or partially fluorine-substituted 1-2C-alkyl,
R76 is 1-4C-alkoxy or mono- or di-1-2C-alkylamino,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
5 . A compound of formula I according to claim 1 in which
R1 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R2 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R3 is hydrogen,
R31 is hydrogen,
R4 is —O—R41, in which
R41 is hydrogen,
R5 is hydrogen,
R6 is hydrogen,
R7 is Het1, Har1, Het3 or Har2, in which
Het1 is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl or thiomorpholin-4-yl, or 4-N-(R71)-piperazin-1-yl or 4-N-(R71)-homopiperazin-1-yl, in which
R71 is 1-4C-alkyl, or completely or partially fluorine-substituted 1-2C-alkyl,
Har1 is optionally substituted by R73 and is pyrrolyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl, in which
R73 is 1-4C-alkyl, or completely or partially fluorine-substituted 1-2C-alkyl,
Het3 is 1-N-(R74)-4,5-dihydro-1H-imidazol-2-yl, in which
R74 is 1-4C-alkyl, or completely or partially fluorine-substituted 1-2C-alkyl,
Har2 is optionally substituted by R75 and/or R76 and is pyridinyl or pyrimidinyl, in which
R75 is 1-4C-alkoxy,
R76 is 1-4C-alkoxy,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
6 . A compound of formula I according to claim 1 in which
one of R1 and R2 is methoxy, and the other is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy, and
R3 and R31 are both hydrogen,
R4 is —O—R41, in which
R41 is hydrogen,
R5 is hydrogen,
R6 is hydrogen,
R7 is Het1, Har1 or Har2, in which
Het1 is morpholin-4-yl or 4-N-(R71)-piperazin-1-yl, in which
R71 is 1-4C-alkyl,
Har1 is optionally substituted by R73 and is 2H-tetrazol-5-yl, 1,2,3-thiadiazol-4-yl, imidazol-1-yl, thiazol-4-yl, oxazol-5-yl, 1,2,4-triazol-1-yl, or 1,2,4-oxadiazol-3-yl, in which
R73 is 1-4C-alkyl,
Har2 is optionally substituted by R75 and/or R76 and is pyridinyl or pyrimidinyl, in which
R75 is 1-4C-alkoxy,
R76 is 1-4C-alkoxy,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
7 . A compound of formula I according to claim 1 in which
R1 is methoxy, or ethoxy,
R2 is methoxy, ethoxy, difluoromethoxy, or 2,2-difluoroethoxy,
R3 is hydrogen,
R31 is hydrogen,
R4 is —O—R41, in which
R41 is hydrogen,
R5 is hydrogen,
R6 is hydrogen,
R7 is bonded to the meta or para position with respect to the binding position in which the phenyl ring is bonded, and is Het1, Har1 or Har2, in which
Het1 is morpholin-4-yl or 4-N-(R71)-piperazin-1-yl, in which
R71 is methyl,
Har1 is 2-(1-4C-alkyl)-2H-tetrazol-5-yl,
Har2 is optionally substituted by R75 and/or R76 and is pyridinyl or pyrimidinyl, in which
R75 is methoxy,
R76 is methoxy,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
8 . Compounds A compound of formula I according to claim 1 comprising one or more of the following:
R1 is methoxy or ethoxy,
R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy, and
R3 and R31 are both hydrogen, and
R4 is —O—R41, in which
R41 is hydrogen, or 1-4C-alkylcarbonyl, and
R5 is hydrogen,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
9 . A compound of formula I according to claim 1 comprising one or more of the following:
R1 is methoxy,
R2 is ethoxy, difluoromethoxy or 2,2-difluoroethoxy, and
R3 and R31 are both hydrogen,
R4 is —O—R41, in which
R41 is hydrogen, and
R5 is hydrogen, and
R7 is Har2, in which
Har2 is optionally substituted by R75 and/or R76, and is pyridinyl or pyrimidinyl,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
10 . compound of formula I according to claim 1 selected from the group consisting of
(2RS,4aRS,10bRS)-9-Ethoxy-6-(4-imidazol-1-yl-phenyl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2RS,4aRS,10bRS)-6-[4-(4,6-Dimethoxy-pyrimidin-2-yl)-phenyl]-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-(4-[1,2,3]thiadiazol-4-yl-phenyl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-(4-morpholin-4-yl-phenyl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2RS,4aRS,10bRS)-8,9-Dimethoxy-6-[4-(2-propyl-2H-tetrazol-5-yl)-phenyl]-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2RS,4aRS,10bRS)-8-(1,1-Difluoro-methoxy)-6-[4-(2-ethyl-2H-tetrazol-5-yl)-phenyl]-9-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2RS,4aRS,10bRS)-9-(1,1-Difluoro-methoxy)-6-[4-(2-ethyl-2H-tetrazol-5-yl)-phenyl]-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2RS,4aRS,10bRS)-9-(2,2-Difluoro-ethoxy)-8-methoxy-6-[3-(2-methyl-thiazol-4-yl)-phenyl]-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2RS,4aRS,10bRS)-9-(2,2-Difluoro-ethoxy)-6-[4-(2-ethyl-2H-tetrazol-5-yl)-phenyl]-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2RS,4aRS,10bRS)-9-(2,2-Difluoro-ethoxy)-8-methoxy-6-(4-oxazol-5-yl-phenyl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2RS,4aRS,10bRS)-9-(2,2-Difluoro-ethoxy)-8-methoxy-6-(4-[1,2,4]triazol-1-yl-phenyl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2RS,4aRS,10bRS)-9-(2,2-Difluoro-ethoxy)-6-(4-imidazol-1-yl-phenyl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2RS,4aRS,10bRS)-9-Ethoxy-6-[3-(2-ethyl-2H-tetrazol-5-yl)-phenyl]-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2R,4aR,10bR)-9-Ethoxy-6-(4-imidazol-1-yl-phenyl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2S,4aS,10bS)-9-Ethoxy-6-(4-imidazol-1-yl-phenyl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2R,4aR,10bR)-9-Ethoxy-6-[3-(2-ethyl-2H-tetrazol-5-yl)-phenyl]-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(2R,4aR,10bR)-9-(2,2-Difluoro-ethoxy)-6-[4-(2-ethyl-2H-tetrazol-5-yl)-phenyl]-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
(3SR,4aRS,10bRS)-9-Ethoxy-6-[3-(2-ethyl-2H-tetrazol-5-yl)-phenyl]-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-3-ol,
and the salts, enantiomers, N-oxides, salts of the N-oxides and enantiomers thereof.
11 . A compound of formula I according to claim 1 , which have with respect to the positions 4a and 10b the configuration shown in formula I*:
or a salt, N-oxide or salt of an N-oxide thereof.
12 . A compound of formula I according to claim 1 , which have with respect to the positions 2, 4a and 10b the configuration shown in formula Ia*****, or, which have with respect to the positions 3, 4a and 10b the configuration shown in formula Ib*****:
or a salt, N-oxide or salt of an N-oxide thereof.
13 . (canceled)
14 . A pharmaceutical composition comprising one or more compounds of formula I as claimed in claim 1 , or a pharmaceutically acceptable salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof, together with a pharmaceutically acceptable excipient and/or vehicle.
15 . (canceled)
16 . A method for treating an illness in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula I as claimed in claim 1 , or a pharmaceutically acceptable salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
17 . A method for treating an airway disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula I as claimed in claim 1 , or a pharmaceutically acceptable salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.