Disclosed are prodrugs of A 2B adenosine receptor antagonists, having the following structure 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 lower alkyl; or
Y is —P(O)(OR 5 ) 2 , in which R 5 is hydrogen or lower alkyl;
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. The compound of claim 5 , wherein Y is —C(O)R.
7. The compound of claim 6 , wherein R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, or n-pentyl.
8. The compound of claim 7 , wherein R is methyl, namely [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurin-7-yl]methyl acetate.
9. The compound of claim 7 , wherein R is n-propyl, namely [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurin-7-yl]methyl butanoate.
10. The compound of claim 7 , wherein R is t-butyl, namely [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurin-7-yl]methyl 2,2-dimethylpropanoate.
11. The compound of claim 5 , wherein Y is —P(O)(OR 5 ) 2 .
12. The compound of claim 11 , wherein R 5 is hydrogen, namely [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}-pyrazol-4-yl)(1,3,7-trihydropurin-7-yl)]methyl dihydrogen phosphate.
13. A method of treating a disease state chosen from diarrhea and asthma in a mammal, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of claim 1 .
14. The method of claim 13 , wherein the compound of claim 1 is chosen 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 acetate,
[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurin-7-yl]methyl butanoate,
[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurin-7-yl]methyl 2,2-dimethylpropanoate, and
[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}-pyrazol-4-yl)(1,3,7-trihydropurin-7-yl)]methyl dihydrogen phosphate.
15. The method of claim 13 , wherein the disease state is asthma.
16. The method of claim 13 , wherein the disease state is diarrhea.
17. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 1 .