Novel C-17-Heteroaryl Steroidal Cyp17 Inhibitors/Antiandrogens, 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 CYP 17 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 metabolite of a compound of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       2 . The metabolite of  claim 1 , wherein the metabolite comprises one or more biological properties that are about the same as an analogous biological property of a compound of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       3 . The metabolite of  claim 2 , wherein the biological property comprises inhibition of CYP17 enzyme, inhibition of tumor growth, inhibition of LNCaP prostate cancer cells, inhibition of LAPC4 prostate cancer cells, or androgen receptor antagonism.