Novel C-17-Heteroaryl Steroidal CYP17 Inhibitors/Antiandrogens;Synthesis In Vitro Biological Activities, Pharmacokinetics and Antitumor Activity

Abstract

Described are steroidal C-17 benzoazoles, pyrimidinoazoles (azabenzoazoles) and diazines. Methods for their synthesis are also described, which include methods having a step of nucleophilic vinylic “addition-elimination” substitution reaction of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene or analogs thereof and benzoazole or pyrimidinoazole nucleophiles and methods having a palladium catalyzed cross-coupling reaction of 17-iodoandrosta-5,16-dien-3β-ol or analogs thereof with tributylstannyl diazines. The compounds are potent inhibitors of human CYP17 enzyme as well as potent antagonists of both wild type and mutant androgen receptors (AR). The compounds are useful for the treatment of human prostate cancer.

1 . A method comprising the step of nucleophilic vinylic addition-elimination substitution of a compound of the formula: 
     
       
         
         
             
             
         
       
     
     or analogue thereof, with a benzoazole nucleophile to produce a first product. 
   
   
       2 . The method of  claim 1 , comprising contacting a mixture comprising a compound of the formula: 
     
       
         
         
             
             
         
       
     
     or analogue thereof, with a benzoazole nucleophile of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       3 . The method of  claim 2 , wherein the mixture comprises DMF and potassium carbonate. 
   
   
       4 . The method of  claim 2 , wherein the first product comprises a compound of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       5 . The method of  claim 4 , further comprising contacting the first product with palladium on charcoal to produce a second product comprising the formula: 
     
       
         
         
             
             
         
       
     
   
   
       6 . The method of  claim 5 , further comprising contacting the second product with methanolic potassium hydroxide to produce a third product comprising the formula: