Hydroxy-6-heteroarylphenanthridines and their use as PDE4 inhibitors
View Patent ↗Compounds of the formula Ia***** in which the substituents have the definitions provided in the specification, are novel, effective PDE4 inhibitors, useful in the treatment of psoriasis.
1. A method of treating psoriasis in a patient, comprising administering to said patient a compound of formula Ia*****
wherein
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,
R41 is hydrogen,
R5 is hydrogen,
Har is optionally substituted by R6 and/or R7 and is a pyridinyl, isoxazolyl, imidazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyrazinyl or pyridazinyl radical, in which
R6 is 1-4C-alkyl, 1-4C-alkoxy, pyridyl or morpholin-4-yl, and
R7 is 1-4C-alkoxy,
or a pharmaceutically acceptable salt thereof.
2. The method of treating psoriasis in a patient according to claim 1 , comprising administering to said patient a compound of formula Ia*****,
wherein
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,
R41 is hydrogen,
R5 is hydrogen,
Har is 6-(morpholin-4-yl)-pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, isoxazol-5-yl, 1-methyl-imidazol-2-yl, 1-methyl-imidazol-5-yl, 2-(pyridin-3-yl)-thiazol-4-yl, 2,6-dimethoxy-pyridin-4-yl or 2,6-dimethoxy-pyridin-3-yl, or a pharmaceutically acceptable salt thereof.
3. The method of treating psoriasis in a patient according to claim 1 , comprising administering to said patient a compound of formula Ia*****,
wherein
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,
R41 is hydrogen,
R5 is hydrogen,
Har is a pyridinyl radical bi-substituted by 1-4C-alkoxy,
or a pharmaceutically acceptable salt thereof.
4. The method of treating psoriasis in a patient according to claim 1 , comprising administering to said patient a compound of formula Ia*****,
wherein
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,
R41 is hydrogen,
R5 is hydrogen,
Har is 2,6-dimethoxypyridin-3-yl,
or a pharmaceutically acceptable salt thereof.
5. The method of treating psoriasis in a patient according to claim 1 , comprising administering to said patient a compound of formula Ia*****,
which is selected from the group consisting of
(2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol and a pharmaceutically acceptable salt thereof.
6. The method of treating psoriasis in a patient according to claim 1 , comprising administering to said patient a compound of formula Ia*****,
which is (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol.