Diarylhydantoin compounds

Abstract

The present invention relates to diarylhydantoin compounds, including diarylthiohydantoins, and methods for synthesizing them and using them in the treatment of hormone refractory prostate cancer.

1 - 51 . (canceled) 
     
     
         52 . A method of synthesizing the compound 
       
         
           
           
               
               
           
         
         comprising 
         mixing N-methyl-2-fluoro-4-(1,1-dimethyl-cyanomethyl)-aminobenzamide and 4-isothiocyanato-2-trifluoromethylbenzonitrile to form a mixture; and 
         reacting the mixture to form the compound. 
       
     
     
         53 . The method of claim  1 , comprising synthesizing the N-methyl-2-fluoro-4-(1,1-dimethyl-cyanomethyl)-aminobenzamide by reacting N-methyl-2-fluoro-4-aminobenzamide with acetone cyanohydrin. 
     
     
         54 . The method of claim  2 , comprising synthesizing N-methyl-2-fluoro-4-aminobenzamide by reacting N-methyl-2-fluoro-4-nitrobenzamide with acetic acid. 
     
     
         55 . The method of claim  3 , comprising synthesizing N-methyl-2-fluoro-4-nitrobenzamide by reacting 2-fluoro-4-nitrobenzoic acid with methylamine. 
     
     
         56 . The method of claim  4 , comprising synthesizing 2-fluoro-4-nitrobenzoic acid by oxidizing 2-fluoro-4-nitrotoluene. 
     
     
         57 . The method of claim  5 , wherein the 2-fluoro-4-nitrotoluene is oxidized by reaction with chromium trioxide. 
     
     
         58 . The method of claim  1 , comprising synthesizing the 4-isothiocyanato-2-trifluoromethylbenzonitrile by reacting 4-amino-2-trifluoromethylbenzonitrile with thiophosgene. 
     
     
         59 . The method of claim  1 , wherein the mixture comprises a solvent. 
     
     
         60 . The method of claim  1 , wherein the solvent is a polar solvent. 
     
     
         61 . The method of claim  1 , wherein the solvent is an aprotic solvent. 
     
     
         62 . The method of claim  1 , wherein the solvent is dimethylformamide. 
     
     
         63 . The method of claim  1 , further comprising adding an alcohol and an acid to the mixture. 
     
     
         64 . The method of claim  8 , wherein the alcohol is methanol. 
     
     
         65 . The method of claim  8 , wherein the acid is hydrochloric acid. 
     
     
         66 . A method of synthesizing the compound 
       
         
           
           
               
               
           
         
       
       comprising
 mixing N-methyl-2-fluoro-4-(1,1-dimethyl-cyanomethyl)-aminobenzamide and 4-isothiocyanato-2-trifluoromethylbenzonitrile in DMF and heating to form a first mixture; and 
 adding an alcohol and an acid to the first mixture and reacting to, form the compound. 
 
     
     
         67 . The method of claim  15 ,
 wherein the alcohol is methanol and   wherein the acid is hydrochloric acid.   
     
     
         68 . A method of synthesizing the compound 
       
         
           
           
               
               
           
         
       
       comprising
 mixing N-methyl-2-fluoro-4-(1,1-dimethyl-cyanomethyl)-aminobenzamide and 4-isothiocyanato-2-trifluoromethylbenzonitrile in DMF and heating to form a first mixture; 
 adding an alcohol and an acid to the first mixture to form a second mixture; 
 refluxing the second mixture; 
 cooling the second mixture, 
 combining the second mixture with water and extracting an organic layer; 
 isolating the compound from the organic layer. 
 
     
     
         69 . The method of claim  17 ,
 wherein the alcohol is methanol and   wherein the acid is hydrochloric acid.