Isothiazole dioxides as CXC- and CC-chemokine receptor ligands
View Patent ↗Disclosed are novel compounds of the formula: and the pharmaceutically acceptable salts and solvates thereof. D and E are different groups wherein one is N and the other is CR 50 . Examples of groups comprising Substituent A include heteroaryl, aryl, heterocycloalkyl, cycloalkyl, aryl, alkynyl, alkenyl, aminoalkyl, alkyl or amino. Examples of groups comprising Substituent B include aryl and heteroaryl. Also disclosed is a method of treating a chemokine mediated diseases, such as, cancer, angiogenisis, angiogenic ocular diseases, pulmonary diseases, multiple sclerosis, rheumatoid arthritis, osteoarthritis, stroke and cardiac reperfusion injury, pain (e.g., acute pain, acute and chronic inflammatory pain, and neuropathic pain) using a compound of formula IA.
1. A compound of the formula:
or a pharmaceutically acceptable salts thereof, wherein:
D and E are independently selected from the group consisting of: N and CR 50 , provided that D and E are not the same;
R 50 is selected from the group consisting of: H, —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —S(O) 2 NR 13 R 14 , —CF 3 , —CN, —NO 2 , —NR 13 R 14 , R 13 and halo;
A is selected from the group consisting of:
wherein the A (2) group is substituted with at least one alkyl group;
B is
R 2 is OH;
R 3 is —C(O)NR 13 14 ;
R 4 is hydrogen;
R 5 and R 6 are hydrogen;
each R 7 and R 8 is independently selected from the group consisting of: H, and unsubstituted alkyl and;
each R 13 and R 14 is independently selected from the group consisting of: H, and unsubstituted alkyl.
2. The compound of claim 1 wherein substituent A is unsubstituted or substituted with 1 or 2 alkyl groups wherein each alkyl group is independently selected, R 7 is alkyl and R 8 is H.
3. The compound of claim 1 wherein substituent A is substituted with 1 or 2 alkyl groups independently selected from the group consisting of methyl, ethyl and isopropyl, R 7 is selected from the group consisting of: ethyl, isopropyl and t-butyl, and R 8 is H.
4. The compound of claim 1 wherein A is selected from the group consisting of:
5. The compound of claim 1 wherein A is selected from the group consisting of:
6. The compound of claim 1 wherein substituent A is selected from the group consisting of:
7. The compound of claim 1 wherein B is:
8. The compound of claim 1 wherein said compound of formula IA is a compound of formula IA.1:
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 wherein said compound of formula IA is a compound of formula IA.2:
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 wherein R 50 is H.
11. The compound of claim 1 wherein R 50 is —C(O)R 13 .
12. The compound of claim 1 wherein R 50 is —C(O)OR 13 .
13. The compound of claim 1 wherein R 50 is —C(O)NR 13 R 14 .
14. The compound of claim 1 wherein R 50 is —S(O) 2 NR 13 R 14 .
15. The compound of claim 1 wherein R 50 is —CF 3 .
16. The compound of claim 1 wherein R 50 is —CN.
17. The compound of claim 1 wherein R 50 is —NO 2 .
18. The compound of claim 1 wherein R 50 is —NR 13 R 14 .
19. The compound of claim 1 wherein R 50 is halo.
20. The compound of claim 1 wherein substituent A in formula IA is unsubstituted, or substituted with 1 to 3 substituents independently selected from the group consisting of: alkyl; R 7 is selected from the group consisting of: H, methyl, ethyl, isopropyl, and t-butyl; and R 8 is H.
21. The compound of claim 1 wherein:
substituent A in formula IA is selected from the group consisting of:
R 13 and R 14 are independently selected from the group consisting of H and methyl.
22. The compound of claim 1 wherein substituent A is selected from the group consisting of:
and substituent B is:
23. A pharmaceutically acceptable salt of a compound of claim 1 .
24. A sodium salt of a compound of claim 1 .
25. A calcium salt of a compound of claim 1 .
26. The compound of claim 1 selected from the group consisting of
and the pharmaceutically acceptable salts thereof.
27. The compound of claim 1 selected from the group consisting of
and the pharmaceutically acceptable salts thereof.
28. The compound of claim 1 selected from the group consisting of
and the pharmaceutically acceptable salts thereof.
29. The compound of claim 1 wherein said compound is
or a pharmaceutically acceptable salt thereof.
30. The compound of claim 1 wherein said compound is
or a pharmaceutically acceptable salt thereof.
31. The compound of claim 1 wherein said compound is
or a pharmaceutically acceptable salt thereof.
32. The compound of claim 1 wherein said compound is
or a pharmaceutically acceptable salt thereof.
33. The compound of claim 1 wherein said compound is
or a pharmaceutically acceptable salt thereof.
34. The compound of claim 1 wherein said compound is
or a pharmaceutically acceptable salt thereof.
35. The compound of claim 1 wherein said compound is
or a pharmaceutically acceptable salt thereof.
36. The compound of claim 1 wherein said compound is
or a pharmaceutically acceptable salt thereof.
37. The compound of claim 1 in isolated and pure form.
38. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
39. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one other agent, medicament, antibody and/or inhibitor for treating a chemokine mediated disease, in combination with a pharmaceutically acceptable carrier.