A2B Adenosine Receptor Antagonists

Abstract

Disclosed are novel compounds that are A 2B adenosine receptor antagonists, useful for treating various disease states, including asthma and diarrhea.

1 . A method of treating a disease state by inhibition of an adenosine receptor characterized as A 2B , comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are independently chosen from hydrogen, optionally substituted alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl, or optionally substituted alkynyl, with the proviso that when D is a covalent bond E cannot be alkoxy; 
 R 3  is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; 
 X is optionally substituted arylene or heteroarylene; 
 Y is a covalent bond or alkylene in which one carbon atom can be optionally replaced by —O—, —S—, or —NH—, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or —COR, in which R is hydroxy, alkoxy or amino; 
 
       with the proviso that when the optional substitution is hydroxy or amino said substitution cannot be present on a carbon atom adjacent to a heteroatom; and
 Z is hydrogen, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; 
 
       with the proviso that Z is hydrogen only when Y is a covalent bond and X is optionally substituted 1,4-pyrazolene attached to the purine ring by a carbon atom; and, 
       with the proviso that when X is optionally substituted arylene, Z is an optionally substituted monocyclic heteroaryl other than optionally substituted imidazole. 
     
     
         2 . The method of  claim 1 , wherein the disease state is chosen from atherosclerosis, angiogenesis, type II diabetes, diabetic retinopathy, cancer, and asthma. 
     
     
         3 . The method of  claim 2 , wherein the disease state is cancer. 
     
     
         4 . The method of  claim 2 , wherein the disease state is asthma. 
     
     
         5 . The method of  claim 2 , wherein the disease state is diabetic retinopathy. 
     
     
         6 . The method of  claim 1 , wherein the disease state is an inflammatory gastrointestinal tract disorder. 
     
     
         7 . The method of  claim 3 , wherein the inflammatory gastrointestinal tract disorder is diarrhea. 
     
     
         8 . The method of  claim 1 , wherein the disease state is a neurological disorder. 
     
     
         9 . The method of  claim 5 , wherein the neurological disorder is senile dementia, Alzheimer's disease, or Parkinson's disease. 
     
     
         10 . A method of treating a disease state by inhibition of an adenosine receptor characterized as A 2B , comprising administering to a mammal in need thereof a therapeutically effective dose of the compound 3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione. 
     
     
         11 . The method of  claim 1 , wherein the disease state is chosen from atherosclerosis, angiogenesis, type II diabetes, diabetic retinopathy, cancer, and asthma. 
     
     
         12 . The method of  claim 11 , wherein the disease state is cancer. 
     
     
         13 . The method of  claim 11 , wherein the disease state is asthma. 
     
     
         14 . The method of  claim 11 , wherein the disease state is diabetic retinopathy. 
     
     
         15 . The method of  claim 10 , wherein the disease state is an inflammatory gastrointestinal tract disorder. 
     
     
         16 . The method of  claim 15 , wherein the inflammatory gastrointestinal tract disorder is diarrhea. 
     
     
         17 . The method of  claim 10 , wherein the disease state is a neurological disorder. 
     
     
         18 . The method of  claim 17 , wherein the neurological disorder is senile dementia, Alzheimer's disease, or Parkinson's disease.