Disclosed are prodrugs of A 2B adenosine receptor antagonists of the formula: wherein R 1 and R 2 are independently lower alkyl; R 4 is optionally substituted phenyl; X is hydrogen or methyl; and Y is —C(O)R, in which R is optionally substituted aryl or optionally substituted heteroaryl or a pharmaceutically acceptable salt thereof, and their use in treating mammals for various disease states.
1. A compound of the formula:
wherein:
R 1 and R 2 are independently lower alkyl;
R 4 is optionally substituted phenyl;
X is hydrogen or methyl; and
Y is —C(O)R, in which R is optionally substituted aryl or optionally substituted heteroaryl or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 1 and R 2 are independently ethyl or n-propyl.
3. The compound of claim 1 , wherein R 4 is 3-(trifluoromethyl)phenyl.
4. The compound of claim 3 , wherein R 1 is n-propyl and R 2 is ethyl.
5. The compound of claim 4 , wherein X is hydrogen.
6. A method of treating diarrhea in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective dose of a compound of claim 1 .
7. A method of treating asthma in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective dose of a compound of claim 1 .
8. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 1 .
9. The compound of claim 5 , wherein R is phenyl or pyridyl.
10. The compound of claim 1 , selected from the group consisting of [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurin-7-yl]methyl benzoate; [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurin-7-yl]methyl 3-(trifluoromethyl)benzoate; [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurin-7-yl]methyl 4-piperazinylbenzoate; [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurin-7-yl]methyl 4-morpholin-4-ylbenzoate and [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurin-7-yl]methylpyridine-3-carboxylate.