Pro-drugs of A2B Adenosine Receptor Antagonists

Abstract

Disclosed are prodrugs of A 2B adenosine receptor antagonists, 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-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 in a mammal that is alleviable by treatment with an A 2B  adenosine receptor antagonist, 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 14 , wherein the disease state is chosen from atherosclerosis, angiogenesis, diabetic retinopathy, cancer, chronic obstructive pulmonary disease, and asthma. 
     
     
         16 . The method of  claim 15 , wherein the disease state is asthma. 
     
     
         17 . The method of  claim 14 , wherein the disease state is an inflammatory gastrointestinal tract disorder. 
     
     
         18 . The method of  claim 17 , wherein the inflammatory gastrointestinal tract disorder is diarrhea. 
     
     
         19 . The method of  claim 14 , wherein the disease state is a neurological disorder. 
     
     
         20 . The method of  claim 19 , wherein the neurological disorder is senile dementia, Alzheimer's disease, or Parkinson's disease. 
     
     
         21 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of  claim 1 .