Tetrahydrothiopy ranphthalazinone derivatives as PDE4 inhibitors

1. A compound selected from the group consisting of:

(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one;

(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-11 6 -thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one;

(cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1I 4 -thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one;

(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one;

(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-11 4 -thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one;

(cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l 6 -thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one;

(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1l 6 -thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one;

(4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-11 6 -thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one;

(4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-11 6 -thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one;

(cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-11 6 -thiopyran-4-yl)-4a,5,8,8a -tetrahydro-2H-phthalazin-1-one;

and hydrates, solvates, salts, hydrates of the salts, or solvates of the salts of these compounds.

2. A pharmaceutical composition comprising one or more compounds as claimed in claim 1 , or a pharmaceutically acceptable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof, together with pharmaceutical auxiliaries and/or carrier materials.

3. A method for treating a disease or disorder in a patient comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds according to claim 1 , wherein the disease or disorder is selected from the group consisting of asthma, COPD, allergic rhinitis, rheumatoid arthritis, dermatoses, Crohn's disease and ulcerative colitis.

4. A pharmaceutical composition containing one or more compounds of formula I

in which

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

A represents S(O) (sulfoxide) or S(O) 2 (sulfone),

Ar represents a benzene derivative of formula (a) or (b)

wherein

R3 is halogen, 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,

R4 is halogen, 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,

R5 is halogen, 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,

R6 is 1-4C-alkyl and

R7 is hydrogen or 1-4C-alkyl,

or wherein

R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,

or a pharmaceutically acceptable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof, together with pharmaceutical auxiliaries and/or carrier materials.

5. A pharmaceutical composition containing one or more compounds of formula I as claimed in claim 4 ,

in which

R1 and R2 together form an additional bond,

Ar represents a benzene derivative of formula (a) or (b)

wherein

R3 is methoxy or ethoxy,

R4 is chlorine, methoxy, ethoxy or cyclopentyloxy,

R5 is methoxy,

R6 is methyl,

R7 is hydrogen,

or wherein

R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane or cyclohexane ring,

or a pharmaceutically acceptable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof, together with pharmaceutical auxiliaries and/or carrier materials.

6. A pharmaceutical composition containing one or more compounds of formula I as claimed in claim 4 ,

in which

R1 and R2 together form an additional bond,

Ar represents a benzene derivative of formula (a)

wherein

R3 is methoxy,

R4 is methoxy,

or a pharmaceutically acceptable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof, together with pharmaceutical auxiliaries and/or carrier materials.

7. A pharmaceutical composition containing one or more compounds of formula I as claimed in claim 4 , in which the hydrogen atoms in the positions 4a and 8a are cis-configured, together with pharmaceutical auxiliaries and/or carrier materials.

8. A pharmaceutical composition containing one or more compounds of formula I as claimed in claim 4 , in which the absolute configuration (according to the rules of Cahn, Ingold and Prelog) is S in the position 4a and R in the position 8a, together with pharmaceutical auxiliaries and/or carrier materials.

9. A pharmaceutical composition containing one or more compounds of formula I

in which

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

A represents S (sulfur),

Ar represents a benzene derivative of formula (a) or (b)

wherein

R3 is 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,

R4 is halogen,

R5 is halogen, 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,

R6 is 1-4C-alkyl and

R7 is hydrogen or 1-4C-alkyl,

or wherein

R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,

or a pharmaceutically acceptable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof, together with pharmaceutical auxiliaries and/or carrier materials.

10. A pharmaceutical composition containing one or more compounds of formula I as claimed in claim 9 , in which

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

Ar represents a benzene derivative of formula (b)

wherein

R5 is halogen, 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,

R6 is 1-4C-alkyl and

R7 is hydrogen or 1-4C-alkyl,

or wherein

R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,

or a pharmaceutically acceptable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof, together with pharmaceutical auxiliaries and/or carrier materials.

11. A pharmaceutical composition containing one or more compounds of formula I as claimed in claim 9 , in which

R1 and R2 together form an additional bond,

Ar represents a benzene derivative of formula (b)

wherein

R5 is methoxy,

R6 is methyl and

R7 is hydrogen,

or a pharmaceutically acceptable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof, together with pharmaceutical auxiliaries and/or carrier materials.

12. A pharmaceutical composition containing one or more compounds of formula I as claimed in claim 9 , in which the hydrogen atoms in the positions 4a and 8a are cis-configured, together with pharmaceutical auxiliaries and/or carrier materials.

13. A pharmaceutical composition containing one or more compounds of formula I as claimed in claim 9 , in which the absolute configuration (according to the rules of Cahn, Ingold and Prelog) is S in the position 4a and R in the position 8a, together with pharmaceutical auxiliaries and/or carrier materials.

14. A method for treating a disease or disorder in a patient comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds of formula I

wherein, in the compound of formula I,

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

A represents S(O) (sulfoxide) or S(O) 2 (sulfone),

Ar represents a benzene derivative of formula (a) or (b)

wherein

R3 is halogen, 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,

R4 is halogen, 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,

R5 is halogen, 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,

R6 is 1-4C-alkyl and

R7 is hydrogen or 1-4C-alkyl,

or wherein

R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,

or a pharmaceutically acceptable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof, wherein the disease or disorder is selected from the group consisting of asthma, COPD, allergic rhinitis, rheumatoid arthritis, dermatoses, Crohn's disease and ulcerative colitis.

15. The method according to claim 14 , wherein, in the compound of formula I,

R1 and R2 together form an additional bond,

Ar represents a benzene derivative of formula (a) or (b)

wherein

R3 is methoxy or ethoxy,

R4 is chlorine, methoxy, ethoxy or cyclopentyloxy,

R5 is methoxy,

R6 is methyl,

R7 is hydrogen,

or wherein

R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane or cyclohexane ring,

or a pharmaceutically acceptable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof.

16. The method according to claim 14 , wherein, in the compound of formula I,

R1 and R2 together form an additional bond,

Ar represents a benzene derivative of formula (a)

wherein

R3 is methoxy,

R4 is methoxy,

or a pharmaceutically acceptable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof.

17. The method according to claim 14 , wherein, in the compound of formula I, the hydrogen atoms in the positions 4a and 8a are cis-configured.

18. The method according to claim 14 , wherein, in the compound of formula I, the absolute configuration (according to the rules of Cahn, Ingold and Prelog) is S in the position 4a and R in the position 8a.

19. A method for treating a disease or disorder in a patient comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds of formula I

wherein, in the compound of formula I,

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

A represents S (sulfur),

Ar represents a benzene derivative of formula (a) or (b)

wherein

R3 is 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,

R4 is halogen,

R5 is halogen, 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,

R6 is 1-4C-alkyl and

R7 is hydrogen or 1-4C-alkyl,

or wherein

R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,

or a pharmaceutically acceptable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof, wherein the disease or disorder is selected from the group consisting of asthma, COPD, allergic rhinitis, rheumatoid arthritis, dermatoses, Crohn's disease and ulcerative colitis.

20. The method according to claim 19 , wherein, in the compound of formula I,

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

Ar represents a benzene derivative of formula (b)

wherein

R5 is halogen, 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,

R6 is 1-4C-alkyl and

R7 is hydrogen or 1-4C-alkyl,

or wherein

R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,

or a pharmaceutically acceptable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof.

21. The method according to claim 19 , wherein, in the compound of formula I,

R1 and R2 together form an additional bond,

A represents S (sulfur),

Ar represents a benzene derivative of formula (b)

wherein

R5 is methoxy,

R6 is methyl and

R7 is hydrogen,

or a pharmaceutically acceptable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof.

22. The method according to claim 19 , wherein, in the compound of formula I, the hydrogen atoms in the positions 4a and 8a are cis-configured.

23. The method according to claim 19 , wherein, in the compound of formula I, the absolute configuration (according to the rules of Cahn, Ingold and Prelog) is S in the position 4a and R in the position 8a.