NOVEL 3,4,4A,10B-TETRAHYDRO-1H-THIOPYRANO[4,3-C] ISOQUINOLINE COMPOUNDS

1 . A compound of formula (1)

wherein

A is S, S(O) or S(O) 2 ,

X is C(O) and is attached either in ortho, meta or para position to the phenyl,

R1 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy predominantly or completely substituted by fluorine,

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

or

R1 and R2 together form a 1-2C-alkylenedioxy group,

R3 is unsubstituted phenyl, phenyl substituted by R4 and R5 or phenyl substituted by R4, R5 and R6, wherein

R4 is 1-4C-alkyl, 1-4C-alkoxy or halogen,

R5 is 1-4C-alkyl, 1-4C-alkoxy or halogen and

R6 is 1-4Calkyl, 1-4C-alkoxy or halogen,

R7 is unsubstituted phenyl, phenyl substituted by R8 or phenyl substituted by R8 and R9, wherein

R8 is 1-4C-alkyl, 1-4C-alkoxy or halogen and

R9 is 1-4C-alkyl, 1-4C-alkoxy or halogen

or

R8 and R9 together form a 1-2C-alkylenedioxy group,

or a stereoisomer of the compound.

2 . A compound of formula (1) according to claim 1 ,

wherein

A is S, S(O) or S(O) 2 ,

X is C(O) and is attached either in meta or para position to the phenyl,

R1 is 1-4C-alkoxy or 1-4C-alkoxy predominantly or completely substituted by fluorine,

R2 is 1-4C-alkoxy or 1-4C-alkoxy predominantly or completely substituted by fluorine,

or

R1 and R2 together form a 1-2C-alkylenedioxy group,

R3 is unsubstituted phenyl, phenyl substituted by R4 and R5 or phenyl substituted by R4, R5 and R6, wherein

R4 is 1-4C-alkyl, 1-4C-alkoxy or halogen,

R5 is 1-4C-alkoxy or halogen and

R6 is 1-4C-alkoxy or halogen,

R7 is unsubstituted phenyl, phenyl substituted by R8 or phenyl substituted by R8 and R9, wherein

R8 is 1-4C-alkoxy or halogen and

R9 is 1-4C-alkyl, 1-4C-alkoxy or halogen,

or

R8 and R9 together form a 1-2C-alkylenedioxy group,

or a stereoisomer of the compound.

3 . A compound of formula (1) according to claim 1 ,

wherein

A is S, S(O) or S(O) 2 ,

X is C(O) and is attached either in meta or para position to the phenyl,

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

R2 is 1-2C-alkoxy or 1-2C-alkoxy predominantly or completely substituted by fluorine,

or

R1 and R2 together form a 1-2C-alkylenedioxy group,

R3 is unsubstituted phenyl, phenyl substituted by R4 and R5 or phenyl substituted by R4, R5 and R6, wherein

R4 is 1-4C-alkyl, 1-4C-alkoxy or halogen,

R5 is 1-4C-alkoxy or halogen and

R6 is 1-4C-alkoxy or halogen,

R7 is unsubstituted phenyl, phenyl substituted by R8 or phenyl substituted by R8 and R9, wherein

R8 is 1-2C-alkoxy, fluorine, chlorine or bromine and

R9 is 1-2C-alkyl, 1-2C-alkoxy, fluorine, chlorine or bromine,

or

R8 and R9 together form a 1-2C-alkylenedioxy group,

or a stereoisomer of the compound.

4 . A compound of formula (1) according to claim 3 , wherein

A is S, S(O) or S(O) 2 ,

X is C(O) and is attached either in meta or para position to the phenyl,

R1 is ethoxy,

R2 is methoxy,

R3 is unsubstituted phenyl, phenyl substituted by R4 and R5 or phenyl substituted by R4, R5 and R6, wherein

R4 is 1-2C-alkyl, 1-2C-alkoxy, fluorine, chlorine or bromine,

R5 is 1-2C-alkoxy, fluorine, chlorine or bromine and

R6 is 1-2C-alkoxy, fluorine, chlorine or bromine,

R7 is unsubstituted phenyl, phenyl substituted by R8 or phenyl substituted by R8 and R9, wherein

R8 is methoxy or fluorine and

R9 is methyl, methoxy or fluorine

or

R8 and R9 together form a methylenedioxy group,

or a stereoisomer of the compound.

5 . A compound of formula (1) according to claim 4 , wherein

A is S, S(O) or S(O) 2 ,

X is C(O) and is attached either in meta or para position to the phenyl,

R1 is ethoxy,

R2 is methoxy,

R3 is phenyl substituted by R4 and R5 or phenyl substituted by R4, R5 and R6,

wherein

R4 is methyl, methoxy or fluorine,

R5 is methoxy or fluorine and

R6 is methoxy or fluorine,

R7 is unsubstituted phenyl, phenyl substituted by R8 or phenyl substituted by R8 and R9, wherein

R8 is methoxy or fluorine,

R9 is methyl, methoxy or fluorine,

or

R8 and R9 together form a methylenedioxy group,

or a stereoisomer of the compound.

6 . A compound of formula (1) according to claim 5 , which is selected from the group consisting of

3-(1-{4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoyl}piperidin-4-yl)-1-(3-fluoro-4-methoxybenzyl)-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 3-[1-({3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-1-(3-fluoro-4-methoxybenzyl)-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 1-(3,5-difluoro-4-methoxybenzyl)-3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 1-(2,3-difluoro-4-methoxybenzyl)-3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-1-(2-fluoro-4,5-dimethoxy-benzyl)-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-1-(3-fluoro-4-methylbenzyl)-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 1-benzyl-3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 6-(1,3-benzodioxol-5-yl)-3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thio-pyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-1-(3-fluoro-4-methoxybenzyl) thieno-[3,2-d]pyrimidine-2,4(1H,3H)-dione; 3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-1-(3-fluoro-4-methoxybenzyl)-6-(4-fluoro-2-methoxyphenyl) thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]-phenyl}carbonyl)piperidin-4-yl]-1-(3-fluoro-4-methoxybenzyl)-6-(5-fluoro-2-methoxyphenyl)-thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; dimethoxyphenyl)-3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)-piperidin-4-yl]-1-(3-fluoro-4-methoxybenzyl) thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]-phenyl}carbonyl)piperidin-4-yl]-1-(3-fluoro-4-methoxybenzyl)-6-(2-fluorophenyl)thieno[3,2-d]-pyrimidine-2,4(1H,3H)-dione; 3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-1-(3-fluoro-4-methoxy-benzyl)-6-(4-fluorophenyl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 1-(3,5-difluoro-4-methoxybenzyl)-3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]-isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-6-(4-fluoro-2-methoxyphenyl)thieno[3,2-d]-pyrimidine-2,4(1H,3H)-dione; 1-(2,3-difluoro-4-methoxybenzyl)-3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-6-(4-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)-piperidin-4-yl]-6-(4-fluoro-2-methoxyphenyl)-1-(3-fluoro-4-methylbenzyl) thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 1-benzyl-3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-6-(4-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-1-(3-fluoro-4-methoxybenzyl)-6-(4-fluoro-2-methylphenyl) thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]-phenyl}carbonyl)piperidin-4-yl]-1-(3-fluoro-4-methoxybenzyl)-6-(2-methoxyphenyl)thieno[3,2-d]-pyrimidine-2,4(1H,3H)-dione, 6-(1,3-benzodioxol-5-yl)-3-[1-({3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-1-(3-fluoro-4-methoxybenzyl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione and 1-(3,5-difluoro-4-methoxy-benzyl)-3-[1-({3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]-isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione.

7 . A compound of formulae (3) or (4)

wherein R3 and R7 have the meanings as defined in claim 1 and the salts of compounds of formula (3).

8 . (canceled)

9 . A pharmaceutical composition comprising at least one of the compounds of formula (1) or a stereoisomer thereof according to claim 1 , together with at least one pharmaceutically acceptable auxiliary.

10 . A non-fixed combination comprising at least one compound of formula (1) or a stereoisomer thereof according to claim 1 , at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, β 2 -adreno-receptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, 5-lipoxygenase inhibitors, endothelin receptor antagonists, prostacyclines, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, type 5 phosphodiesterase inhibitors, immuno-suppressants, vitamin D analogues, HMG-CoA reductase-inhibitors, PPARγ agonists, ACE inhibitors, angiotensin II-receptor antagonists, lung surfactants, antibiotics, guanylyl-cyclase activators/stimulators, tetrahydrobiopterin, tetrahydrobiopterin derivatives, anticoagulants, diuretics, pirfenidone and digitalis glycosides, and at least one pharmaceutically acceptable auxiliary.

11 . (canceled)

12 . A method of treating or preventing an acute or chronic airway disease in a patient, comprising administering to a patient in need thereof a compound of formula (1) or a stereoisomer thereof according to claim 1 .

13 . The method according to claim 12 , wherein the acute or chronic airway disease is selected from the group consisting of interstitial lung disease, pulmonary fibrosis, cystic fibrosis, bronchial asthma, chronic bronchitis, emphysema, chronic obstructive pulmonary disease (COPD) and COPD associated with pulmonary hypertension.

14 . (canceled)

15 . (canceled)

16 . A method of treating or preventing a disease, which is alleviated by inhibition of the type 4 and type 5 phosphodiesterase, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula 1 or a stereoisomer of the compound according to claim 1 .