Pyrrolidinedione substituted piperidine-phthalazones as PDE4 inhibitors

1. A compound of formula I

in which

R1 and R2 are both hydrogen or together form an additional bond,

R3 represents a phenyl derivative of formulae (a) or (b)

wherein

R4 is 1–4C-alkoxy or 1–4C-alkoxy which is completely or predominantly substituted by fluorine,

R5 is 1–4C-alkoxy, 3–7C-cycloalkoxy, 3–7C-cycloalkylmethoxy, or 1–4C-alkoxy which is completely or predominantly substituted by fluorine,

R6 is 1–4C-alkoxy or 1–4C-alkoxy which is completely or predominantly substituted by fluorine,

R7 is 1–4C-alkyl and

R8 is hydrogen or 1–4C-alkyl, or wherein

R7 and R8 together, and with inclusion of the two carbon atoms to which they are bonded, form a spiro-linked 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen or sulfur atom,

R9 is —C(O)—(CH 2 ) n -R10,

wherein

R10 is pyrrolidine-2,5-dione-1-yl,

n is an integer from 1 to 4,

or a salt thereof.

2. A compound of formula I according to claim 1 in which

R1 and R2 are both hydrogen or together form an additional bond,

R3 represents a phenyl derivative of formulae (a) or (b)

wherein

R4 is 1–2C-alkoxy or 1–2C-alkoxy which is completely or predominantly substituted by fluorine,

R5 is 1–2C-alkoxy or 1–2C-alkoxy which is completely or predominantly substituted by fluorine,

R6 is 1–2C-alkoxy or 1–2C-alkoxy which is completely or predominantly substituted by fluorine,

R7 is methyl and

R8 is hydrogen,

or wherein

R7 and R8 together, and with inclusion of the two carbon atoms to which they are bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofurane or tetrahydropyran ring,

R9 is —C(O)—(CH 2 ) n -R10,

wherein

R10 is pyrrolidine-2,5-dione-1-yl,

n is an integer from 1 to 2, or a salt thereof.

3. A compound of formula I according to claim 1 in which

R1 and R2 together form an additional bond,

R3 represents a phenyl derivative of formula (a)

wherein

R4 is 1–2C-alkoxy,

R5 is 1–2C-alkoxy,

R9 is —C(O)—(CH 2 ) n R10,

wherein

R10 is pyrrolidine-2,5-dione-1-yl and

n is 1,

or a salt thereof.

4. A compound of formula I according to claim 1 in which

R1 and R2 together form an additional bond,

R3 represents a phenyl derivative of formula (a)

wherein

R4 is methoxy,

R5 is methoxy,

R9 is —C(O)—(CH 2 ) n -R10,

wherein

R10 is pyrrolidine-2,5-dione-1-yl and

n is 1,

or a salt thereof.

5. A compound of formula I according to claim 1 , in which the hydrogen atoms in the positions 4a and 8a are cisconfigurated, or a salt thereof.

6. A compound of formula I according to claim 1 , in which the absolute configuration is S in the position 4a and R in the position 8a, or a salt thereof.

7. A compound of formula I according to claim 1 with the chemical formula

8. A compound of formula I according to claim 1 with the chemical formula

or a salt thereof.

9. A compound of formula I according to claim 1 with the chemical name 1-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1 H-phthalazin-2yl]-piperidin-1-yl}-2-oxo-ethyl)-pyrrolidine-2,5-dione.

10. A compound of formula I according to claim 1 with the chemical name 1-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2-oxo-ethyl)-pyrrolidine-2,5-dione or a salt thereof.

11. A process of preparing a compound comprising reacting (4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one hydrochloride with 1-(2chloro-ethanoyl)pyrrolidine-2,5-dione in the presence of a base.

12. A process of preparing 1-(2-{4[(4aS, 8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2yl]-piperidin-1-yl}-2oxo-ethyl)-pyrrolidine-2,5-dione comprising reacting (4aS, 8aR)-4-(3,4-Dimethoxy-phenyl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one hydrochloride with 1-(2-chloro-ethanoyl)-pyrrolidine-2,5-dione in the presence of a base.

13. A pharmaceutical composition comprising one or more compounds of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, together with a suitable pharmaceutical auxiliary and/or excipient.

14. A method for treating airway disorders 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 thereof.

15. A compound of formula I according to claim 2 , in which the hydrogen atoms in the positions 4a and 8a are cis-configurated, or a salt thereof.

16. A compound of formula I according to claim 2 , in which the absolute configuration is S in the position 4a and R in the position 8a, or a salt thereof.

17. A compound of formula I according to claim 3 , in which the hydrogen atoms in the positions 4a and 8a are cisconfigurated, or a salt thereof.

18. A compound of formula I according to claim 3 , in which the absolute configuration is S in the position 4a and R in the position 8a, or a salt thereof.

19. A compound of formula I according to claim 4 , in which the hydrogen atoms in the positions 4a and 8a are cis-configurated, or a salt thereof.

20. A compound of formula I according to claim 4 , in which the absolute configuration is S in the position 4a and R in the position 8a, or a salt thereof.

21. The method according to claim 14 , wherein the airway disorder is selected from the group consisting of bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD and allergic rhinitis.

22. A method for treating dermatoses 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 thereof.

23. The method according to claim 22 , wherein the dermatose is selected from the group consisting of psoriasis and atopic eczema.

24. A pharmaceutical composition comprising the compound of claim 7 together with a suitable pharmaceutical auxiliary and/or excipient.

25. A pharmaceutical composition comprising the compound of claim 8 , or a pharmaceutically acceptable salt thereof, together with a suitable pharmaceutical auxiliary and/or excipient.

26. A method for treating airway disorders in a patient comprising administering to said patient a therapeutically effective amount of the compound of claim 7 .

27. A method for treating airway disorders in a patient comprising administering to said patient a therapeutically effective amount of the compound of claim 8 or a pharmaceutically acceptable salt thereof.

28. The method according to claim 26 , wherein the airway disorder is selected from the group consisting of bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD and allergic rhinitis.

29. The method according to claim 27 , wherein the airway disorder is selected from the group consisting of bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD and allergic rhinitis.

30. A method for treating dermatoses in a patient comprising administering to said patient a therapeutically effective amount of the compound of claim 7 .

31. A method for treating dermatoses in a patient comprising administering to said patient a therapeutically effective amount of the compound of claim 8 or a pharmaceutically acceptable salt thereof.

32. The method according to claim 30 , wherein the dermatose is selected from the group consisting of psoriasis and atopic eczema.

33. The method according to claim 31 , wherein the dermatose is selected from the group consisting of psoriasis and atopic eczema.