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 - 16 . (canceled) 
   
   
       17 . A method for inhibiting CYP17 enzyme in a cell, the method comprising contacting the cell with a compound of the formula: 
     
       
         
         
             
             
         
       
     
     or a metabolite thereof. 
   
   
       18 . The method of  claim 17 , wherein the cell is human. 
   
   
       19 . A method for antagonizing an androgen receptor in a cell, the method comprising contacting the cell with a compound of the formula: 
     
       
         
         
             
             
         
       
     
     or a metabolite thereof. 
   
   
       20 . The method of  claim 19 , wherein the cell is human. 
   
   
       21 . A method of reducing the volume of a tumor in a subject, the method comprising administering to the subject a compound of the formula: 
     
       
         
         
             
             
         
       
     
     or a metabolite thereof. 
   
   
       22 . A method of inhibiting the growth of LAPC4 prostate cancer cells in a subject, the method comprising administering to the subject a compound of the formula: 
     
       
         
         
             
             
         
       
     
     or a metabolite thereof. 
   
   
       23 . A method of inhibiting the growth of LNCaP prostate cancer cells in a subject, the method comprising administering to the subject a compound of the formula: 
     
       
         
         
             
             
         
       
     
     or a metabolite thereof.