Benzodioxole or benzodioxepine heterocyclic compounds as phosphodiesterase inhibitors
Compounds of the general formula (I) wherein each of m and n is independently 0 or 1; R 1 and R 2 , together with the carbon atom to which they are attached, form a heterocyclic ring comprising one or two heteroatoms selected from oxygen, sulfur, —S(O)— and —S(O) 2 —; R 3 is —CHF 2 , —CF 3 , —OCHF 2 , —OCF 3 , —SCHF 2 or —SCF 3 ; X is a bond, —CH 2 —, or —NH—; A is aryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkenyl, optionally substituted with one or more, same or different substituents selected from R 4 ; and R 4 is hydrogen, amino, thioxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, halogen, oxo, thia, or hydroxy; or pharmaceutically acceptable salts, hydrates or solvates thereof, have been found to exhibit PDE4 inhibiting activity, and may therefore be useful in the treatment of inflammatory diseases and disorders.
1. A compound of general formula IIb
wherein
each of m and n is independently 0 or 1;
R 1 and R 2 , together with the carbon atom to which they are attached, form a heterocyclic ring comprising one or two heteroatoms selected from oxygen, sulfur, —S(O)— and —S(O) 2 —; and
R 3 is —OCHF 2 , or —OCF 3 ;
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
2. A compound according to claim 1 , wherein m and n are both 0.
3. A compound according to claim 1 , wherein m and n are both 1.
4. A compound according to claim 1 , wherein R 3 is —OCHF 2 .
5. A compound according to claim 1 , wherein R 1 and R 2 , together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclic ring.
6. A compound according to claim 5 , wherein the heterocyclic ring is tetrahydropyran, oxetane, [1,3]dioxolane, [1,3]dioxane, tetrahydrothiopyran, tetrahydrothiopyran-1,1-dioxide, tetrahydrothiopyran-1-oxide, tetrahydrothiophene, [1,3]-dithiane, thietane, [1,3]-dithiane-1,3-dioxide, thietane-1-oxide, or thiethane-1,1-dioxide.
7. A compound according to claim 5 , wherein the heterocyclic ring comprises one heteroatom.
8. A compound according to claim 7 , wherein the heteroatom is oxygen or —S(O) 2 .
9. A compound according to claim 1 , selected from the group consisting of
2-(3,5-Dichloro-1-oxido-pyridin-4-yl)-1-{9-difluoromethoxy-spiro[2H-1,5-benzodioxepin-3(4H),3′ -oxetane]-6-yl}ethanone (compound 102);
2-(3,5-Dichloro-1-oxido-pyridin-4-yl)-1- {9-difluoromethoxy-spiro[2H-1,5-benzodioxepin-3(4H),4′-tetrahydropyran]-6-yl}ethanone (compound 104);
2-(3,5-Dichloro-1-oxido-pyridine-4-yl)-1-(7-difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-pyran]-4-yl)ethanone (compound 106); and
2-(3,5-Dichloro-1-oxido-pyridine-4-yl)-1-(7-difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2, 4 ′-(4H)-thiopyran-1′,1 ′-dioxide]-4-yl)ethanone(compound 108), or a pharmaceutically acceptable salt, hydrate or solvate thereof.
10. A pharmaceutical composition comprising, as a therapeutically active ingredient, a compound according to claim 1 and a pharmaceutically acceptable carrier or vehicle.
11. A composition according to claim 10 , wherein the pharmaceutically acceptable carrier or vehicle is one that is suitable for oral administration.
12. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridin-4-yl)-1-{9-difluoromethoxy-spiro[2H-1,5-benzodioxepin-3(4H),3′-oxetane]-6-yl}ethanone (compound 102), or a pharmaceutically acceptable hydrate or solvate thereof.
13. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridin-4-yl)-1-{9-difluoromethoxy-spiro[2H-1,5-benzodioxepin-3(4H),4 ′-tetrahydropyran]-6-yl}ethanone (compound 104), or a pharmaceutically acceptable hydrate or solvate thereof.
14. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridine-4-yl)-1-(7-difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-pyran]-4-yl)ethanone (compound 106), or a pharmaceutically acceptable hydrate or solvate thereof.
15. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridine-4-yl)-1-(7-difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2, 4′-(4H)-thiopyran-1′,1′-dioxide]-4-yl)ethanone (compound 108), or a pharmaceutically acceptable hydrate or solvate thereof.
16. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridin-4-yl)-1-{9-difluoromethoxy-spiro[2H-1,5-benzodioxepin-3(4H),3′-oxetane]-6-yl}ethanone (compound 102).
17. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridin-4-yl)-1-{9-difluoromethoxy-spiro[2H-1,5-benzodioxepin-3(4H),4′-tetrahydropyran]-6-yl}ethanone (compound 104).
18. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridine-4-yl)-1-(7-difluoromethoxy-2′,3 ′,5′,6′tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-pyran]-4-yl)ethanone (compound 106).
19. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridine-4-yl)-1-(7-difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2, 4′-(4H)-thiopyran-1′,1′-dioxide]-4-yl)ethanone (compound 108).
20. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridin-4-yl)-1-{9-difluoromethoxy-spiro[2H-1,5-benzodioxepin-3(4H),3′-oxetane]-6-yl}ethanone (compound 102), or a pharmaceutically acceptable hydrate thereof.
21. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridin-4-yl)-1-{9-difluoromethoxy-spiro[2H-1,5-benzodioxepin-3(4H),4′-tetrahydropyran]-6-yl}ethanone (compound 104), or a pharmaceutically acceptable hydrate thereof.
22. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridine-4-yl)-1-(7-difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-pyran]-4-yl)ethanone (compound 106), or a pharmaceutically acceptable hydrate thereof.
23. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridine-4-yl)-1-(7-difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2, 4′-(4H)-thiopyran-1′,1′-dioxide]-4-yl)ethanone (compound 108), or a pharmaceutically acceptable hydrate thereof.
24. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridin-4-yl)-1-{9-difluoromethoxy-spiro[2H-1,5-benzodioxepin-3(4H),3 ′-oxetane]-6-yl}ethanone (compound 102), or a pharmaceutically acceptable solvate thereof.
25. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridin-4-yl)-1-{9-difluoromethoxy-spiro[2H-1,5-benzodioxepin-3(4H),4 ′-tetrahydropyran]-6-yl}ethanone (compound 104), or a pharmaceutically acceptable solvate thereof.
26. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridine-4-yl)-1-(7-difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-pyran]-4-yl)ethanone (compound 106), or a pharmaceutically acceptable solvate thereof.
27. A compound according to claim 1 which is 2-(3,5-Dichloro-1-oxido-pyridine-4-yl)-1-(7-difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2, 4′-(4H)-thiopyran-1′,1′-dioxide]-4-yl)ethanone (compound 108), or a pharmaceutically acceptable solvate thereof.
28. A pharmaceutically composition comprising, as a therapeutically active ingredient, a compound according to claim 12 and a pharmaceutically acceptable carrier or vehicle.
29. A pharmaceutically composition comprising, as a therapeutically active ingredient, a compound according to claim 13 and a pharmaceutically acceptable carrier or vehicle.
30. A pharmaceutically composition comprising, as a therapeutically active ingredient, a compound according to claim 14 and a pharmaceutically acceptable carrier or vehicle.
31. A pharmaceutically composition comprising, as a therapeutically active ingredient, a compound according to claim 15 and a pharmaceutically acceptable carrier or vehicle.
32. A composition according to claim 28 , wherein the pharmaceutically acceptable carrier or vehicle is one that is suitable for oral administration.
33. A composition according to claim 29 , wherein the pharmaceutically acceptable carrier or vehicle is one that is suitable for oral administration.
34. A composition according to claim 30 , wherein the pharmaceutically acceptable carrier or vehicle is one that is suitable for oral administration.
35. A composition according to claim 31 , wherein the pharmaceutically acceptable carrier or vehicle is one that is suitable for oral administration.