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 crystalline form of a compound of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       18 . The crystalline form of  claim 17 , wherein the crystalline form is a free base form. 
   
   
       19 . The crystalline form of  claim 17 , wherein the crystalline form is a non-solvate form. 
   
   
       20 . The crystalline form of  claim 17 , wherein the crystalline form has a melting point of about 189-190 degrees Celsius. 
   
   
       21 . The crystalline form of  claim 17 , made by contacting the compound with an alcohol and an organic solvent. 
   
   
       22 . The crystalline form of  claim 21 , wherein the organic solvent is ethyl acetate. 
   
   
       23 . The crystalline form of  claim 21 , wherein the alcohol is methanol, ethanol, n-butanol, tert-butanol, isobutanol, sec-butanol, n-propanol, 2-propanol, or a mixture thereof. 
   
   
       24 . The crystalline form of  claim 23 , wherein the alcohol is methanol. 
   
   
       25 . The crystalline form of  claim 17 , in the form of a pharmaceutical composition. 
   
   
       26 . The crystalline form of  claim 25 , wherein the pharmaceutical composition is a solid dosage form. 
   
   
       27 . The crystalline form of  claim 26 , wherein the solid dosage form is a tablet. 
   
   
       28 . The crystalline form of  claim 26 , wherein the solid dosage form is a capsule. 
   
   
       29 . A method of making a crystalline form of a compound of the formula: 
     
       
         
         
             
             
         
       
     
     ,comprising the step of contacting the compound with an alcohol and an organic solvent. 
   
   
       30 . The method of  claim 29 , wherein the organic solvent is ethyl acetate. 
   
   
       31 . A method according to  claim 29 , wherein the alcohol is methanol, ethanol, n-butanol, tert-butanol, isobutanol, sec-butanol, n-propanol, 2-propanol, or a mixture thereof. 
   
   
       32 . A method according to  claim 29 , wherein the alcohol is methanol. 
   
   
       33 . A method according to  claim 29 , comprising contacting a freebase form with methanol/ethyl acetate.