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 method of treating or ameliorating a dermal disease or condition, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula IIb, optionally together with a pharmaceutically acceptable carrier or one or more excipients, wherein the dermal disease and condition is selected from the group consisting of psoriasis, eczema, dermatitis, urticaria, and alopecia,
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. The method of claim 1 , wherein the compound of formula IIb 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).
3. The method of claim 1 , wherein the compound of formula IIb 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).
4. The method of claim 1 , wherein the compound of formula IIb 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).
5. The method of claim 1 , wherein the compound of formula IIb 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).
6. The method of claim 2 , wherein the dermal disease or condition is selected from the group consisting of psoriasis and dermatitis.
7. The method of claim 3 , wherein the dermal disease or condition is selected from the group consisting of psoriasis and dermatitis.
8. The method of claim 4 , wherein the dermal disease or condition is selected from the group consisting of psoriasis and dermatitis.
9. The method of claim 5 , wherein the dermal disease or condition is selected from the group consisting of psoriasis and dermatitis.
10. The method of claim 1 , wherein the compound is administered by the oral route.
11. The method of claim 2 , wherein the compound is administered by the oral route.
12. The method of claim 3 , wherein the compound is administered by the oral route.
13. The method of claim 4 , wherein the compound is administered by the oral route.
14. The method of claim 5 , wherein the compound is administered by the oral route.
15. The method of claim 6 , wherein the compound is administered by the oral route.
16. The method of claim 7 , wherein the compound is administered by the oral route.
17. The method of claim 8 , wherein the compound is administered by the oral route.
18. The method of claim 9 , wherein the compound is administered by the oral route.
19. The method of claim 1 , wherein the dermatitis is seborrheic dermatitis.
20. The method of claim 1 , wherein the dermatitis is contact dermatitis.
21. The method of claim 1 , wherein the dermatitis is atopic dermatitis.