Diarylthiohydantoin compounds

Abstract

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

1 . A compound having the formula 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently methyl or, together with the carbon to which they are linked, a cycloalkyl group of 4 to 5 carbon atoms, 
         wherein R 3  is dialkylcarbamoylpropyl, and 
         wherein R 4  is hydrogen or fluorine, or 
         a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         3 - 9 . (canceled) 
     
     
         10 . A method for treating a hyperproliferative disorder comprising administering a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, thereby treating the hyperproliferative disorder. 
     
     
         11 . The pharmaceutically acceptable composition of  claim 2 , wherein the composition has a form selected from the group consisting of a solution, dispersion, suspension, powder, capsule, tablet, pill, time release capsule, time release tablet, and time release pill. 
     
     
         12 . The method of  claim 10 , wherein the compound is administered by intravenous injection, by injection into tissue, intraperitoneally, orally, or nasally. 
     
     
         13 . The method of  claim 10 , wherein the compound is administered at a dosage of the compound in the range of from about 0.001 mg per kg body weight per day to about 100 mg per kg body weight per day. 
     
     
         14 . The method of  claim 10 , wherein the compound is administered at a dosage of the compound in the range of from about 0.01 mg per kg body weight per day to about 100 mg per kg body weight per day. 
     
     
         15 . The method of  claim 10 , wherein the compound is administered at a dosage of the compound in the range of from about 0.1 mg per kg body weight per day to about 10 mg per kg body weight per day. 
     
     
         16 . The method of  claim 10 , wherein the compound is administered at a dosage of the compound of about 1 mg per kg body weight per day. 
     
     
         17 . A method for treating hormone refractory prostate cancer comprising administering a composition according to  claim 2  to a subject in need of such treatment, thereby treating the hormone refractory prostate cancer. 
     
     
         18 . A method comprising contacting a mammalian cell capable of expressing prostate specific antigen with a sufficient amount of a compound according to  claim 1  to interfere with the transcription of prostate specific antigen mRNA. 
     
     
         19 . A method comprising contacting a mammalian cell with a sufficient amount of a compound according to  claim 1  to prevent nuclear translocation of an androgen receptor protein. 
     
     
         20 . A method comprising contacting a mammalian cell with a sufficient amount of a compound according to  claim 1  to destabilize an androgen receptor protein. 
     
     
         21 - 24 . (canceled) 
     
     
         25 . A method of synthesizing a diaryl compound of formula: 
       
         
           
           
               
               
           
         
         comprising mixing Compound I 
       
       
         
           
           
               
               
           
         
         with Compound II 
       
       
         
           
           
               
               
           
         
         in a first polar solvent to form a mixture, 
         heating the mixture, 
         adding a second polar solvent, the same as or different from the first polar solvent, and an aqueous acid to the mixture, 
         refluxing the mixture, 
         cooling the mixture and combining with water, and 
         separating the diaryl compound from the mixture, 
         wherein R51 comprises an alkyl chain of from 1 to 4 carbon atoms, R52 is dialkylcarbamoylpropyl, and R53 is selected from the group consisting of F and H. 
       
     
     
         26 . The method of  claim 25 , wherein R51 comprises an alkyl chain of from 1 to 2 carbon atoms, and R53 is F. 
     
     
         27 - 48 . (canceled) 
     
     
         49 . The compound of  claim 1 , wherein R 3  is not dimethylcarbamoylpropyl. 
     
     
         50 . The method of  claim 10 , wherein the hyperproliferative disorder is selected from the group consisting of a cancer, a metastatic cancer, a hormone refractory cancer, breast cancer, hormone refractory breast cancer, and ovarian cancer. 
     
     
         51 . The method of  claim 10 , wherein the hyperproliferative disorder is prostate cancer. 
     
     
         52 . The method of  claim 10 , wherein the hyperproliferative disorder is hormone refractory prostate cancer. 
     
     
         53 . The method of  claim 10 , wherein the hyperproliferative disorder is hormone sensitive prostate cancer. 
     
     
         54 . The method of  claim 10 , further comprising administering a hormone therapy to the subject before the therapeutically effective amount of the compound is administered. 
     
     
         55 . A method comprising contacting a mammalian cell with a sufficient amount of a compound according to  claim 1  to prevent formation of a transcription complex on a prostate specific antigen gene. 
     
     
         56 . A method comprising contacting a mammalian cell with a sufficient amount of a compound according to  claim 1  to prevent an androgen receptor protein from complexing with a prostate specific antigen gene. 
     
     
         57 . A method comprising contacting a mammalian cell with a sufficient amount of a compound according to  claim 1  to prevent an RNA polymerase II from complexing with a prostate specific antigen gene.