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 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 pharmaceutical compound having the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       18 . A pharmaceutical composition comprising the pharmaceutical compound of  claim 17  and a physiologically acceptable vehicle. 
   
   
       19 . The pharmaceutical composition of  claim 18 , wherein the pharmaceutical compound of  claim 17  is present in an amount sufficient to treat one or more symptoms associated with a prostate disease. 
   
   
       20 . The pharmaceutical composition of  claim 18  in a solid dosage form. 
   
   
       21 . The pharmaceutical composition of  claim 20 , wherein the solid dosage form is a tablet. 
   
   
       22 . The pharmaceutical composition of  claim 20 , wherein the solid dosage form is a capsule. 
   
   
       23 . The pharmaceutical composition of  claim 18  or  claim 21 , wherein the composition is formulated to deliver from about 1 mg to about 500 mg of the compound after administration to a subject. 
   
   
       24 . The pharmaceutical composition of  claim 18  or  claim 21 , wherein the composition is formulated to deliver from about 50 mg to about 150 mg of the compound after administration to a subject. 
   
   
       25 . The pharmaceutical composition of  claim 18  or  claim 21 , wherein the composition is formulated to deliver more than about 0.15 mmol/kg of the compound after administration to a subject. 
   
   
       26 . The pharmaceutical composition of  claim 18  or  claim 21 , wherein the composition is formulated to deliver less than about 0.15 mmol/kg of the compound after administration to a subject. 
   
   
       27 . The pharmaceutical composition of  claim 18  or  claim 21 , wherein the composition is formulated to deliver from about 0.15 mmol/kg to about 0.30 mmol/kg of the compound after administration to a subject. 
   
   
       28 . The pharmaceutical composition of  claim 18  or  claim 21 , wherein the compound is in a crystalline form. 
   
   
       29 . The pharmaceutical composition of  claim 18 , wherein the compound is in a free base form. 
   
   
       30 . The pharmaceutical composition of  claim 18 , wherein the compound is in a non-solvate form. 
   
   
       31 . The pharmaceutical composition of  claim 28 , wherein the crystalline form has a melting point of about 189-190 degrees C. 
   
   
       32 . The pharmaceutical composition of  claim 18  or  claim 21 , wherein the compound binds CYP17.