Disclosed are novel A 2B adenosine receptor antagonists having the structure of Formula I or Formula II: The compounds are particularly useful for treating asthma, inflammatory gastrointestinal tract disorders, cardiovascular diseases, neurological disorders, and diseases related to undesirable angiogenesis.
1. A compound of Formula I or Formula II:
wherein:
R 1 and R 2 are independently chosen from hydrogen or optionally substituted alkyl;
R 3 is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;
X is optionally substituted arylene or heteroarylene that is attached to the purine ring at a carbon atom;
Y is a covalent bond or alkylene in which one carbon atom can be optionally replaced by —O—, —S—, or —NH—; and
Z is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl;
with the proviso that when X is optionally substituted arylene, Z is optionally substituted monocyclic heteroaryl.
2. The compound of claim 1 wherein:
R 3 is hydrogen; and
X is optionally substituted arylene.
3. The compound of claim 2 wherein R 1 and R 2 are independently lower alkyl optionally substituted by cycloalkyl.
4. The compound of claim 3 , wherein:
X is optionally substituted phenylene; and
Y is a covalent bond or lower alkylene in which one carbon atom can be optionally replaced by —O—, —S—, or —NH—.
5. The compound of claim 4 , wherein R 1 and R 2 are n-propyl and Y is —OCH 2 —.
6. The compound of claim 5 , wherein Z is optionally substituted oxadiazole.
7. The compound of claim 6 , wherein Z is 3-(2-methylphenyl)-(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(2-methylphenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
8. The compound of claim 6 , wherein Z is 3-(3-methylphenyl)-(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(3-methylphenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
9. The compound of claim 6 , wherein Z is 3-(4-methylphenyl)-(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(4-methylphenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
10. The compound of claim 6 , wherein Z is 3-(2-methoxyphenyl)-(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(2-methoxyphenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
11. The compound of claim 6 , wherein Z is 3-(3-methoxyphenyl)-(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(3-methoxyphenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
12. The compound of claim 6 , wherein Z is 3-(4-methoxylphenyl)-(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(4-methoxyphenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
13. The compound of claim 6 , wherein Z is 3-(2-chlorophenyl)-(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(2-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
14. The compound of claim 6 , wherein Z is 3-(3-chlorophenyl)-(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(3-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
15. The compound of claim 6 , wherein Z is 3-(4-chlorophenyl)-(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
16. The compound of claim 6 , wherein Z is 3-(2-fluorophenyl)-(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(2-fluorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
17. The compound of claim 6 , wherein Z is 3-(3-fluorophenyl)-(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(3-fluorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
18. The compound of claim 6 , wherein Z is 3-(4-fluorophenyl)(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(4-fluorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
19. The compound of claim 6 , wherein Z is 3-(2-trifluoromethylphenyl)(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(2-trifluoromethylphenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
20. The compound of claim 6 , wherein Z is 3-(3-trifluoromethylphenyl)(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(3-trifluoromethylphenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
21. The compound of claim 6 , wherein Z is 3-(4-trifluoromethylphenyl)(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(4-trifluoromethylphenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
22. The compound of claim 6 , wherein Z is 3-(4-cyanophenyl)(1,2,4-oxadiazol-5-yl), namely 8-(4-{[3-(4-cyanophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
23. The compound of claim 6 , wherein Z is 5-(2-methylphenyl)-(1,2,4-oxadiazol-3-yl), namely 8-(4-{[5-(2-methylphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
24. The compound of claim 6 , wherein Z is 5-(3-methylphenyl)-(1,2,4-oxadiazol-3-yl), namely 8-(4-{[5-(3-methylphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
25. The compound of claim 6 , wherein Z is 5-(4-methylphenyl)-(1,2,4-oxadiazol-3-yl), namely 8-(4-{[5-(4-methylphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
26. The compound of claim 6 , wherein Z is 5-(4-methoxylphenyl)-(1,2,4-oxadiazol-3-yl), namely 8-(4-{[5-(4-methoxyphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
27. The compound of claim 6 , wherein Z is 5-(2-chlorophenyl)-(1,2,4-oxadiazol-3-yl), namely 8-(4-{[5-(2-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
28. The compound of claim 6 , wherein Z is 5-(3-chlorophenyl)-(1,2,4-oxadiazol-3-yl), namely 8-(4-{[5-(3-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
29. The compound of claim 6 , wherein Z is 5-(4-chlorophenyl)-(1,2,4-oxadiazol-3-yl), namely 8-(4-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
30. The compound of claim 6 , wherein Z is 5-(2-fluorophenyl)-(1,2,4-oxadiazol-3-yl), namely 8-(4-{[5-(2-fluorophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
31. The compound of claim 6 , wherein Z is 5-(3-fluorophenyl)-(1,2,4-oxadiazol-3-yl), namely 8-(4-{[3-(5-fluorophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
32. The compound of claim 6 , wherein Z is 5-(2-trifluoromethylphenyl)(1,2,4-oxadiazol-3-yl), namely 8-(4-{[5-(2-trifluoromethylphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
33. The compound of claim 6 , wherein Z is 5-(3-trifluoromethylphenyl)(1,2,4-oxadiazol-3-yl), namely 8-(4-{[5-(3-trifluoromethylphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
34. The compound of claim 6 , wherein Z is 5-(4-trifluoromethylphenyl)(1,2,4-oxadiazol-3-yl), namely 8-(4-{[5-(4-trifluoromethylphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
35. The compound of claim 6 , wherein Z is 5-(4-cyanophenyl)(1,2,4-oxadiazol-3-yl), namely 8-(4-{[5-(4-cyanophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
36. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1 .