Novel isoamido-substituted hydroxy-6-phenylphenanthridines
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,
wherein 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,
R61 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl,
R7 is Het1, Har1, 3-7C-cycloalkyl, or 1-4C-alkyl substituted by R8, in which
Het1 is optionally substituted by R71 and is a monocyclic monocylic 3- to 7-membered fully saturated heterocyclic ring radical,
which is bonded via a ring carbon atom to the carbonyl moiety of the —C(O)N(R61)- group, and
which comprises one nitrogen atom and optionally one further heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and, optionally,
to which ring one or two oxo groups are bonded, in which
R71 is 1-4C-alkyl, or completely or partially fluorine-substituted 1-4C-alkyl,
Har1 is optionally substituted by R72 and/or R73, and is a 5- or 6-membered monocyclic unsaturated heteroaryl radical comprising 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, in which
R72 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, 1-4C-alkylthio, cyano, 1-4C-alkoxycarbonyl, carboxyl, hydroxyl, -A-N(R721)R722, pyridyl, or completely or partially fluorine-substituted 1-4C-alkyl, in which
A is a bond or 1-4C-alkylene,
R721 is hydrogen or 1-4C-alkyl,
R722 is hydrogen or 1-4C-alkyl,
or R721 and R722 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het2, in which
Het2 is optionally substituted by R723, and is a 3- to 7-membered saturated or unsaturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R721 and R722 are bonded, and optionally one to three further heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, in which
R723 is 1-4C-alkyl,
R73 is halogen, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, 1-4C-alkylthio, hydroxyl, amino or mono- or di-1-4C-alkylamino,
R8 is 1-4C-alkoxy, carbamoyl, carboxyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylaminocarbonyl or —N(R81)R82, in which
R81 is hydrogen, 1-4C-alkyl, carbamoyl, amidino or 1-4C-alkylcarbonyl,
R82 is hydrogen or 1-4C-alkyl,
or R81 and R82 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het3, in which
Het3 is optionally substituted by R811, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R81 and R82 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R811 is 1-4C-alkyl,
or an enantiomer, salt, N-oxide, salt of an N-oxide or enantiomer of an N-oxide 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,
wherein 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,
R61 is hydrogen,
R7 is Het1, Har1, 3-7C-cycloalkyl, or 1-4C-alkyl substituted by R8, in which
Het1 is optionally substituted by R71 and is a monocyclic 5- to 7-membered fully saturated heterocyclic ring radical, which is bonded via a ring carbon atom to the carbonyl moiety of the —C(O)N(R61)- group, and which comprises one nitrogen atom and optionally one further heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and, optionally, to which ring one or two oxo groups are bonded, in which
R71 is 1-4C-alkyl, or completely or partially fluorine-substituted 1-4C-alkyl,
Har1 is optionally substituted by R72 and/or R73, and is either a 6-membered monocyclic unsaturated heteroaryl radical comprising one or two nitrogen atoms, or a 5-membered monocyclic unsaturated heteroaryl radical comprising 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, in which
R72 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,1-4C-alkylthio, cyano, 1-4C-alkoxycarbonyl, carboxyl, hydroxyl, -A-N(R721)R722, pyridyl, or completely or partially fluorine-substituted 1-4C-alkyl, in which
A is a bond or 1-4C-alkylene,
R721 is hydrogen or 1-4C-alkyl,
R722 is hydrogen or 1-4C-alkyl,
or R721 and R722 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het2, in which
Het2 is optionally substituted by R723, and is a 3- to 7-membered saturated or unsaturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R721 and R722 are bonded, and optionally one to three further heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, in which
R723 is 1-4C-alkyl,
R73 is halogen, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, 1-4C-alkylthio, hydroxyl, amino or mono- or di-1-4C-alkylamino,
R8 is 1-4C-alkoxy, carbamoyl, mono- or di-1-4C-alkylaminocarbonyl or —N(R81)R82, in which
R81 is hydrogen, 1-4C-alkyl, carbamoyl, amidino or 1-4C-alkylcarbonyl,
R82 is hydrogen or 1-4C-alkyl,
or R81 and R82 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het3, in which
Het3 is optionally substituted by R811, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R81 and R82 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R811 is 1-4C-alkyl,
or an enantiomer, salt, N-oxide, salt of an N-oxide or enantiomer of an N-oxide 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,
R61 is hydrogen,
R7 is Het1, Har1, 3-7C-cycloalkyl, or 1-4C-alkyl substituted by R8, in which
Het1 is optionally substituted by R71 and is a monocyclic 5- to 7-membered fully saturated heterocyclic ring radical,
which is bonded via a ring carbon atom to the carbonyl moiety of the —C(O)N(R61)- group, and
which comprises one nitrogen atom, and, optionally, to which ring one oxo group is bonded, in which
R71 is 1-4C-alkyl, or completely or partially fluorine-substituted1-2C-alkyl,
Har1 is optionally substituted by R72 and/or R73, and is a 6-membered monocyclic unsaturated heteroaryl radical comprising one or two nitrogen atoms, in which
R72 is halogen, 1-4C-alkoxy, 1-4C-alkoxy-ethoxy, 1-2C-alkylthio, hydroxyl, amino or mono- or di-1-2C-alkylamino,
R73 is halogen, 1-4C-alkoxy, 1-2C-alkoxy-ethoxy, 1-2C-alkylthio, hydroxyl, amino or mono- or di-1-2C-alkylamino,
R8 is 1-4C-alkoxy, carbamoyl, mono- or di-1-4C-alkylaminocarbonyl or —N(R81)R82, in which
R81 is hydrogen, 1-4C-alkyl, carbamoyl or 1-4C-alkylcarbonyl,
R82 is hydrogen or 1-4C-alkyl,
or R81 and R82 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het3, in which
Het3 is optionally substituted by R811, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R81 and R82 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R811 is 1-2C-alkyl,
or an enantiomer, salt, N-oxide, salt of an N-oxide or enantiomer of an N-oxide 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,
R61 is hydrogen,
R7 is Het1, Har1, 3-5C-cycloalkyl, or 1-4C-alkyl substituted by R8, in which
Het1 is 1-N—(R71)-piperdin-4-yl or pyrrolidin-2-on-5-yl, in which
R71 is 1-4C-alkyl,
Har1 is optionally substituted by R72 and/or R73, and is pyridinyl, in which
R72 is 1-4C-alkoxy,
R73 is 1-4C-alkoxy,
R8 is 1-4C-alkoxy, carbamoyl, mono- or di-1-4C-alkylaminocarbonyl or —N(R81)R82, in which
R81 is 1-4C-alkyl, carbamoyl or 1-4C-alkylcarbonyl,
R82 is hydrogen or 1-4C-alkyl,
or R81 and R82 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het3, in which
Het3 is piperidin-1-yl, pyrrolidin-1-yl, 4-N—(R811)-piperazin-1-yl, 4-N—(R81l)-homopiperazin-1-yl, homopiperidin-1-yl, morpholin-4-yl or thiomorpholin-4-yl, in which
R811 is 1-2C-alkyl,
or an enantiomer, salt, N-oxide, salt of an N-oxide or enantiomer of an N-oxide 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-substituted1-2C-alkoxy,
R3 is hydrogen,
R31 is hydrogen,
R4 is —O—R41, in which
R41 is hydrogen,
R5 is hydrogen,
R6 is hydrogen,
R61 is hydrogen,
R7 is Het1, Har1, 3-5C-cycloalkyl, or 1-4C-alkyl substituted by R8, in which
Het1 is 1-N—(R71)-piperdin-4-yl or pyrrolidin-2-on-5-yl, in which
R71 is 1-4C-alkyl,
Har1 is 2,6-dimethoxypyridin-3-yl,
R8 is 1-4C-alkoxy, carbamoyl, mono- or di-1-4C-alkylaminocarbonyl or —N(R81)R82, in which
R81 is 1-4C-alkyl, carbamoyl or 1-4C-alkylcarbonyl,
R82 is hydrogen or 1-4C-alkyl,
or R81 and R82 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het3, in which
Het3 is piperidin-1-yl,
or an enantiomer, salt, N-oxide, salt of an N-oxide or enantiomer of an N-oxide thereof.
6 . 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,
R61 is hydrogen,
R7 is Het1, Har1, cyclopropyl, or 1-4C-alkyl substituted by R8, in which
Het1 is 1-N—(R71)-piperdin-4-yl or pyrrolidin-2-on-5-yl, in which
R71 is methyl,
Har1 is 2,6-dimethoxypyridin-3-yl,
R8 is methoxy, carbamoyl, dimethylaminocarbonyl or —N(R81)R82, in which
R81 is methyl, carbamoyl or acetyl,
R82 is hydrogen or methyl,
or R81 and R82 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het3, in which
Het3 is piperidin-1-yl,
or an enantiomer, salt, N-oxide, salt of an N-oxide or enantiomer of an N-oxide thereof.
7 . A compound of formula I according to claim 1 comprising one or more of the following:
R1 is methoxy,
R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy, and
R3 and R31 are hydrogen,
R4 is —O—R41, in which
R41 is hydrogen, and
R5 is hydrogen,
R6 is hydrogen,
R61 is hydrogen,
the radical R7C(O)N(R61)- is bonded to the meta or para position with respect to the binding position at which the phenyl group is bonded or an enantiomer, salt, N-oxide, salt of an N-oxide or enantiomer of an N-oxide thereof.
8 . A compound of formula I according to claim 1 selected from the group consisting of
N-[3-((2RS,4aRS,10bRS)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-2-methoxy-acetamide,
N-[4-((2RS,4aRS,10bRS)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-3-methoxy-propionamide,
Cyclopropanecarboxylic acid [3-((2RS,4aRS,10bRS)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-amide,
N-[4-((2RS,4aRS,10bRS)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-3-piperidin-1-yl-propionamide,
N-[4-((2RS,4aRS,10bRS)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-N′,N′-dimethyl-succinamide,
1-Methyl-piperidine-4-carboxylic acid [4-((2RS,4aRS, 10bRS)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-amide,
Cyclopropanecarboxylic acid [4-((2RS,4aRS,10bRS)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-amide,
N-[3-((2RS,4aRS,10bRS)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-3-methoxy-propionamide,
N-[4-((2RS,4aRS,10bRS)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-2-methoxy-acetamide,
N-[3-((2RS,4aRS,10bRS)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-3-piperidin-1-yl-propionamide,
1-Methyl-piperidine-4-carboxylic acid [3-((2RS,4aRS,10bRS)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-amide,
N-[3-((2RS,4aRS,10bRS)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-N′,N′-dimethyl-succinamide,
Dimethylamino-N-[4-((2RS,4aRS,10bRS)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-butyramide,
Dimethylamino-N-[3-((2RS,4aRS,10bRS)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-butyramide,
2-Acetylamino-N-[3-((2RS,4aRS,10bRS)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-acetamide,
5-Oxo-pyrrolidine-2-carboxylic acid [3-((2RS,4aRS,10bRS)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-amide,
N-[3-((2RS,4aRS,10bRS)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-2,6-dimethoxy-nicotinamide,
(2RS,4aRS,10bRS)-6-[3-(3-carbamoyl-propanoylamino)-phenyl]-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol,
N-[3-((2RS,4aRS,10bRS)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-3-ureido-propionamide,
Cyclopropanecarboxylic acid [3-((3SR,4aRS,10bRS)-9-ethoxy-3-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-amide and
the enantiomers, N-oxides, salts of the N-oxides and enantiomers of the N-oxides thereof.
9 . A compound of formula I according to claim 1 which has 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.
10 . A compound of formula I according to claim 1 which has with respect to the positions 2, 4a and 10b the configuration shown in formula Ia*****, or, which has 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.
11 . (canceled)
12 . 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 of an N-oxide thereof, together with a pharmaceutically acceptable excipient and/or vehicle.
13 - 14 . (canceled)
15 . 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 of an N-oxide thereof.
16 . 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 of an N-oxide thereof.
17 . A method for treating a PDE-mediated 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 of an N-oxide thereof.