Enzyme inhibitors, their synthesis, and methods for use

Abstract

Novel compounds are provided that are effective to inhibit the activity of DHUDase or UrdPase. Such compounds have the general formulawhere X is S or Se; Y is <INS-S DATE="20020402" ID="INS-S-00001"/>H, <INS-E ID="INS-S-00001"/>I, F, Cl, Br, methoxy, benzyl, selenenylphenyl, or thiophenyl, and R1 is <INS-S DATE="20020402" ID="INS-S-00002"/>H or <INS-E ID="INS-S-00002"/>an acyclo tail having the general formulawhere R2 is H, CH2 OH or CH2 NH2; R3 is OH, NH2, or OCOCH2CH2CO2H; and R4 is O, S, or CH2.The compounds can be used in pharmaceutical compositions, along with various chemotherapeutic agents to increase the efficacy of the treatment. These compounds can also be used in methods of treating patients by coadministering or sequentially administering the enzyme inhibiting compounds with a chemotherapeutic agent effective to treat cancers, or viral, fungal, bacterial, or parasitic infections. The compounds have further utility in enhancing imaging. Further, they can be administered alone to prevent and/or treat disorders of pyrimidine catabolism and other physiological disorders.

What is claimed is:  
     
       1. A compound represented by the formula                    
       where X is S or Se; Y is H, I, F, Cl, Br, methoxy, benzyl, selenenylphenyl, or thiophenyl, and R 1  is H or an acyclo tail having the general formula                    
       where R 2  is H, CH 2 OH, or CH 2 NH 2 ; R 3  is OH, NH 2  or OCOCH 2 CH 2 CO 2 H; and R 4  is O, S, or CH 2 , provided when Y is H, then R 1    is an acyclo tail as above or when R   1    is H, then Y is I, F, Cl, Br, methoxy, or benzyl.    
     
     
       2. 5-(phenylselenenyl)uracil (PSU). 
     
     
       3. The compound of  claim 1  which is 1-[(2-hydroxyethoxy)methyl]-5-(phenylselenenyl)uracil (PSAU). 
     
     
       4. The compound of  claim 1  which is  5-(phenylselenenyl)-2,4-bis(benzyloxy)pyrimidine. 
     
     
       5. The compound of  claim 1  which is 1-(ethoxymethyl)-5-(phenylselenenyl)uracil. 
     
     
       6. 5-(phenylthio)uracil (PTU). 
     
     
       7. The compound of  claim 1  which is 1-[(2-hydroxyethoxy)methyl]-5-(phenylthio)uracil. (PTAU). 
     
     
       8. The compound of  claim 1  which is  5-(phenylthio)-2,4-bis(benzyloxy)pyrimidine. 
     
     
       9. 5-(phenylselenenyl)barbituric acid. 
     
     
       10. The compound of claim  1   17 which is 1-[2-(hydroxy-ethoxy)methyl]-5-(phenylselenenyl)barbituric acid. 
     
     
       11. The compound of  claim 1  which is  5-(phenylselenenyl)-2,4-bis(benzyloxy)barbituric acid. 
     
     
       12. The compound of  claim 1  which is  1-(ethoxymethyl)-5-(phenylselenenyl)barbituric acid. 
     
     
       13. 5-(phenylthio)barbituric acid. 
     
     
       14. The compound of claim  1   17 which is 1-[(2-hydroxy-ethoxy)methyl]-5-(phenylthio)barbituric acid. 
     
     
       15. The compound of  claim 1  which is  5-(phenylthio)-2,4-bis(benzyloxy)barbituric acid. 
     
     
       16. A pharmaceutical composition comprising a compound represented by the formula                                      
       where X is S or Se; Y is H, I, F, Cl, Br, methoxy, benzyl, selenenylphenyl, or thiophenyl, and R 1  is H or an a cyclo  acyclo tail having the general formula                    
       where R 2  is H, CH 2 OH, or CH 2 NH 2 ; R 5  is OH, NH 2  or OCOCH 2 CH 2 CO 2 H; and R 4  is O, S, or CH 2 , provided when Y is H, then R 1    is an acyclo tail as above or when R   1    is H, then Y is I, F, Cl, Br, methoxy, or benzyl  and a pharmaceutically acceptable carrier. 
     
     
       17. A compound represented by the formula                    
       
         where X is S or Se; Y is H, I, F, Cl, Br, methoxy, benzyl, selenenylphenyl, or thiophenyl, and R 
         1  
         is H or an acyclo tail having the formula  
         
           
           
               
               
           
         
       
       
         where R 
         2  
         is H, CH 
         2 
         OH, or CH 
         2 
         NH 
         2 
         ; R 
         3  
         is OH, NH 
         2  
         or OCOCH 
         2 
         CO 
         2 
         H; and R 
         4  
         is O, S, or CH 
         2 
         , provided when Y is H, then R 
         1  
         is an acyclo tail as above or when R 
         1  
         is H, then Y is I, F, Cl, Br, methoxy, benzyl, selenenylphenyl, or thiophenyl. 
       
     
     
       18. A pharmaceutical composition comprising a compound represented by the formula                    
       
         where X is S or Se; Y is H, I, F, Cl, Br, methoxy, benzyl, selenenylphenyl, or thiophenyl, and R 
         1  
         is H or an acyclo tail having the formula  
         
           
           
               
               
           
         
       
       
         where R 
         2  
         is H, CH 
         2 
         OH, or CH 
         2 
         NH 
         2 
         ; R 
         3  
         is OH, NH 
         2  
         or OCOCH 
         2 
         CO 
         2 
         H; and R 
         4  
         is O, S, or CH 
         2 
         , provided when Y is H, then R 
         1  
         is an acyclo tail as above or when R 
         1  
         is H, then Y is I, F, Cl, Br, methoxy, benzyl, selenenylphenyl, or thiophenyl and a pharmaceutically acceptable carrier.