Novel Difluoroethoxy-Substituted Hydroxy-6-Phenylphenanthridines and Their Use as Pde4 Inhibitors

1 . A compound of formula I

in which

either, in a first aspect (aspect 1),

R1 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-4C-alkoxy, and

R2 is 2,2-difluoroethoxy,

or, in a second aspect (aspect 2),

R1 is 2,2-difluoroethoxy, and

R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-4C-alkoxy,

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, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, halogen, nitro, cyano, hydroxyl, 1-4C-alkylcarbonyloxy, amino, mono- or di-1-4C-alkylamino, phenyl, phenyl-1-4C-alkyl, 1-4C-alkylcarbonylamino, phenoxy, 1-4C-alkylcarbonyl, or C(O)OR61, wherein

R61 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl,

R7 is hydrogen, 1-4C-alkyl, hydroxyl, halogen, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or C(O)OR61,

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

either, in a first aspect (aspect 1),

R1 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy, and

R2 is 2,2-difluoroethoxy,

or, in a second aspect (aspect 2),

R1 is 2,2-difluoroethoxy, and

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 -0-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 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, 3-7C-cycloalkylmethoxy, halogen, nitro, cyano, hydroxyl, 1-4C-alkylcarbonyloxy, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, phenoxy or C(O)OR61, wherein

R61 is hydrogen or 1-4C-alkyl,

R7 is hydrogen, halogen, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, or 3-7C-cycloalkylmethoxy,

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

either, in a first aspect (aspect 1),

R1 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy, and

R2 is 2,2-difluoroethoxy,

or, in a second aspect (aspect 2),

R1 is 2,2-difluoroethoxy, and

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 or 1-4C-alkylcarbonyl,

R5 is hydrogen,

R6 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, 3-7C-cycloalkylmethoxy, halogen, nitro, cyano, hydroxyl, 1-4C-alkylcarbonyloxy, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, phenoxy or C(O)OR61, wherein

R61 is hydrogen or 1-4C-alkyl,

R7 is hydrogen, halogen, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, or 3-7C-cycloalkylmethoxy,

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

either, in a first aspect (aspect 1),

R1 is 1-2C-alkoxy, and

R2 is 2,2-difluoroethoxy,

or, in a second aspect (aspect 2),

R1 is 2,2-difluoroethoxy, and

R2 is 1-2C-alkoxy,

R3 is hydrogen,

R31 is hydrogen,

R4 is -0-R41, in which

R41 is hydrogen,

R5 is hydrogen,

R6 is halogen,

R7 is hydrogen,

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, and

R2 is 2,2-difluoroethoxy,

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 1-2C-alkoxy,

R2 is 2,2-difluoroethoxy,

R3 is hydrogen,

R31 is hydrogen,

R4 is —O—R41, in which

R41 is hydrogen,

R5 is hydrogen,

R6 is cyano or halogen,

R7 is hydrogen,

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 , 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.

8 . A compound of formula I according to any of the preceding claims, 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.

9 . (canceled)

10 . A pharmaceutical composition comprising one or more compounds of formula I as claimed in claim 1 , or a pharmaceutically aceeptable 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.

11 .- 12 . (canceled)

13 . 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.

14 . 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.

15 . 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.