CCR4 antagonists
View Patent ↗Compounds, compositions and methods are provided that are useful in the treatment of chemokine receptor-mediated conditions and diseases. In particular, the invention provides compounds which modulate CCR4 function or a CCR4-mediated response. The subject compounds and compositions are useful for the treatment or prevention of inflammatory conditions and diseases.
1. A compound having the formula (I):
or a pharmaceutically acceptable salt or prodrug thereof, wherein
W is substituted indolyl;
X is S;
Y is N(R 5 );
Z is N;
R 1 is unsubstituted (C 1 –C 8 )alkyl or (C 1 –C 8 )alkyl substituted with NR′R″ in which R′ and R″ are independently selected from the group consisting of aryl (C 1 –C 4 )alkyl and unsubstituted (C 1 –C 8 )alkyl, and wherein, optionally, R′ and R″ are combined with the nitrogen atom to which they are attached to form a 5-, 6- or 7-membered ring;
R 2 is H or (C 1 –C 8 )alkyl; and
optionally, R 1 and R 2 combine to form a 5- to 8-membered ring; and
R 5 is selected from the group consisting of H, (C 1 –C 8 )alkyl, heteroatkyl, aryl and heteroaryl.
2. The compound of claim 1 , wherein R 1 is unsubstituted (C 1 –C 8 )alkyl.
3. The compound of claim 1 , wherein R 1 is (C 1 –C 8 )alkyl substituted with NR′R″.
4. The compound of claim 1 , having the formula:
5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 1 .
6. A method of treating an inflammatory condition or disease mediated by CCR4, comprising administering to a subject having the inflammatory condition or disease a therapeutically effective amount of a compound of claim 1 , and wherein said inflammatory condition or disease is selected from the group consisting of allergic disease, psoriasis, atopic dermatitis, eczema, allergic rhinitis, asthma, inflammatory bowel disease, arthritis, multiple sclerosis and atherosclerosis.
7. The method of claim 6 , wherein the inflammatory condition or disease is arthritis.
8. The method of claim 6 , wherein the inflammatory condition or disease is an allergic disease.
9. The method of claim 6 , wherein the inflammatory condition or disease is psoriasis, atopic dermatitis, or eczema.
10. The method of claim 6 , wherein the inflammatory condition or disease is asthma.
11. The method of claim 6 , wherein the inflammatory condition or disease is inflammatory bowel disease.
12. The method of claim 6 , wherein the inflammatory condition or disease is multiple sclerosis.
13. The method of claim 6 , wherein the inflammatory condition or disease is atherosclerosis.
14. The method of claim 6 , wherein the subject is human.
15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 2 .
16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 3 .
17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 4 .
18. A method of treating an inflammatory condition or disease mediated by CCR 4 , comprising administering to a subject having said inflammatory condition or disease a therapeutically effective amount of a compound of claim 2 and wherein the inflammatory condition or disease is selected from the group consisting of allergic disease, psoriasis, atopic dermatitis, eczema, allergic rhinitis, asthma, inflammatory bowel disease, arthritis, multiple sclerosis and atherosclerosis.
19. The method of claim 18 , wherein the inflammatory condition or disease is arthritis.
20. The method of claim 18 , wherein the inflammatory condition or disease is an allergic disease.
21. The method of claim 18 , wherein the inflammatory condition or disease is psoriasis, atopic dermatitis, or eczema.
22. The method of claim 18 , wherein the inflammatory condition or disease is asthma.
23. The method of claim 18 , wherein the inflammatory condition or disease is inflammatory bowel disease.
24. The method of claim 18 , wherein the inflammatory condition or disease is multiple sclerosis.
25. The method of claim 18 , wherein the inflammatory condition or disease is atherosclerosis.
26. The method of claim 18 , wherein the subject is human.
27. A method of treating an inflammatory condition or disease mediated by CCR 4 , comprising administering to a subject having said inflammatory condition or disease a therapeutically effective amount of a compound of claim 3 and wherein the inflammatory condition or disease is selected from the group consisting of allergic disease, psoriasis, atopic dermatitis, eczema, allergic rhinitis, asthma, inflammatory bowel disease, arthritis, multiple sclerosis and atherosclerosis.
28. The method of claim 27 , wherein the inflammatory condition or disease is arthritis.
29. The method of claim 27 , wherein the inflammatory condition or disease is an allergic disease.
30. The method of claim 27 , wherein the inflammatory condition or disease is psoriasis, atopic dermatitis, or eczema.
31. The method of claim 27 , wherein the inflammatory condition or disease is asthma.
32. The method of claim 27 , wherein the inflammatory condition or disease is inflammatory bowel disease.
33. The method of claim 27 , wherein the inflammatory condition or disease is multiple sclerosis.
34. The method of claim 27 , wherein the inflammatory condition or disease is atherosclerosis.
35. The method of claim 27 , wherein the subject is human.
36. A method of treating an inflammatory condition or disease mediated by CCR 4 , comprising administering to a subject having said inflammatory condition or disease a therapeutically effective amount of a compound of claim 4 and wherein the inflammatory condition or disease is selected from the group consisting of allergic disease, psoriasis, atopic dermatitis, eczema, allergic rhinitis, asthma, inflammatory bowel disease, arthritis, multiple sclerosis and atherosclerosis.
37. The method of claim 36 , wherein the inflammatory condition or disease is arthritis.
38. The method of claim 36 , wherein the inflammatory condition or disease is an allergic disease.
39. The method of claim 36 , wherein the inflammatory condition or disease is psoriasis, atopic dermatitis, or eczema.
40. The method of claim 36 , wherein the inflammatory condition or disease is asthma.
41. The method of claim 36 , wherein the inflammatory condition or disease is inflammatory bowel disease.
42. The method of claim 36 , wherein the inflammatory condition or disease is multiple sclerosis.
43. The method of claim 36 , wherein the inflammatory condition or disease is atherosclerosis.
44. The method of claim 36 , wherein the subject is human.