Pyrimidine compounds and methods for making and using the same

Abstract

This invention discloses compounds, and pharmaceutically acceptable salts, solvates and prodrugs thereof, useful in therapeutically and/or prophylactically treating patients with an illness. Such illnesses include cancer, and secondary infections caused by Pneumocystis carinii, Toxoplasma gondii, Mycobacterium tuberculosis, and Mycobacterium avium. The compounds themselves, methods of making these compounds, and methods of using these compounds are all disclosed. The compounds include 5-thiapyrimidines.

What is claimed is:  
     
         1 . A compound, and pharmaceutically acceptable salts thereof, having formula (1):  
       
         
           
           
               
               
           
         
         wherein R is an aryl ring or alkylaryl ring optionally substituted with one or more substituents independently selected from C 1-6  alkyl groups, C 2-6 alkenyl groups, C 2-6  alkynyl groups, C 1-6  alkoxy groups, halogens, nitro groups, aryl groups, C 1-6  acyl groups, carboxylic acids, carboxylic esters, hydroxyl groups, mercapto groups, polycarbo groups, and p-aroyl-L-glutamate;  
         wherein Z is S, Se, O, NH, CH 2 ; and  
         wherein R 1  is H or a straight, branched or cyclic alkyl group having up to about six carbons optionally substituted with one or more halogen, hydroxyl or amine groups; but when Z is S or Se, R is not p-aroyl-L-glutamate.  
       
     
     
         2 . The compound of  claim 1 , wherein Z is S.  
     
     
         3 . The compound of  claim 2 , wherein R is substituted or unsubstituted aryl.  
     
     
         4 . The compound of  claim 3 , wherein R is naphthyl.  
     
     
         5 . The compound of  claim 3 , wherein R is 2,5-dimethyoxyphenyl.  
     
     
         6 . A method of treating a patient for an illness by inhibiting dihydrofolate reductase and/or thymidylate synthase comprising: 
 administering an effective amount of a compound having formula (1):                          wherein R is an aryl ring or alkylaryl ring optionally substituted with one or more substituents independently selected from C 1-6  alkyl groups, C 2-6  alkenyl groups, C 2-6 alkynyl groups, C 1-6  alkoxy groups, halogens, nitro groups, aryl groups, C 1-6  acyl groups, carboxylic acids, carboxylic esters, hydroxyl groups, mercapto groups, polycarbo groups, and p-aroyl-L-glutamate;    wherein Z is S, Se, O, NH, CH 2 ; and    wherein R 1  is H or a straight, branched or cyclic alkyl group having up to about six carbons optionally substituted with one or more halogen, hydroxyl or amine group to said patient.    
     
     
         7 . The method of  claim 6 , wherein said compound is incorporated in a suitable pharmaceutical carrier.  
     
     
         8 . The method of  claim 6 , wherein said illness is cancer.  
     
     
         9 . The method of  claim 6 , wherein said illness is selected from the group consisting of infection caused by  Pneumocystis carinii, Toxoplasma gondii, Mycobacterium tuberculosis  and  Mycobacterium avium.    
     
     
         10 . The method of  claim 7 , wherein said carrier is selected from the group consisting of physiologic saline and 5% dextrose for injection.  
     
     
         11 . The method of  claim 7 , including administering said compound by a method selected from the group consisting of parenteral administration, oral administration and topical administration.  
     
     
         12 . The method of  claim 6 , wherein Z is S.  
     
     
         13 . The method of  claim 12 , wherein R is substituted or unsubstituted aryl.  
     
     
         14 . The method of  claim 13 , wherein R is naphthyl.  
     
     
         15 . The method of  claim 13 , wherein R is 2,5-dimethyoxyphenyl.  
     
     
         16 . A method for synthesizing a thiapyrimidine compound comprising: 
 a) mixing 2,4-diamino-6-oxopyrimidine with a sulfur containing substituent;    b) refluxing the mixture of step a);    c) adding iodine to the refluxed mixture of step b);    d) refluxing the mixture of step c);    e) cooling the mixture of step d); and    f) removing the precipitate that forms upon cooling;    wherein the molar ratio of 2,4-diamino-6-oxopyrimidine to sulfur containing substituent is between about 1:1 and 1:3 and the molar ratio of 2,4-diamino-6-oxopyrimidine to iodine is between about 1:2 and 1:4.    
     
     
         17 . The method of  claim 16 , wherein said sulfur containing substituent is contained in a solvent.  
     
     
         18 . The method of  claim 16 , wherein the precipitate recovered in step f) is further washed with ethyl acetate, ethanol and ethyl ether.  
     
     
         19 . The method of  claim 18 , wherein said washed precipitate is further mixed with a solvent, refluxed for at least two minutes, cooled, and the precipitate that forms upon cooling is removed.  
     
     
         20 . A method for synthesizing a compound of formula (1)  
       
         
           
           
               
               
           
         
         wherein R is an aryl ring or alkylaryl ring optionally substituted with one or more substituents independently selected from C 1-6  alkyl groups, C 2-6 alkenyl groups, C 2-6  alkynyl groups, C 1-6  alkoxy groups, halogens, nitro groups, aryl groups, C 1-6  acyl groups, carboxylic acids, carboxylic esters, hydroxyl groups, mercapto groups, polycarbo groups, and p-aroyl-L-glutamate;  
         wherein Z is O or NH; and  
         wherein R 1  is H or a straight, branched or cyclic alkyl group having up to about six carbons optionally substituted with one or more halogen, hydroxyl or amine groups comprising: 
 a) refluxing 2,4-diamino-6-oxopyrimidine with EtSH;  
 b) adding iodine to the mixture of step a);  
 c) refluxing the mixture of step b);  
 d) cooling the reflux mixture of step c);  
 e) collecting the product resulting from step d);  
 f) mixing the product of step e) with an oxone; and  
 g) mixing the product of step f) with H—Z—R, wherein Z and R are as described above.