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 . A pharmaceutical composition comprising a pharmaceutical compound having the following structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof, and a physiologically acceptable vehicle, wherein the pharmaceutical compound is formulated to provide, after administration to a subject, a concentration of the compound of at least 10 μg/mL in a tissue of the subject; and
 wherein the concentration of the compound is measured by reverse phase HPLC using a C18 column; a mobile phase composition of water/MeOH/CH 3 CN in a ratio of 35:35:30 v/v/v, additionally comprising 200 IA of triethylamine and 0.77 g of NH 4 OAc per 1000 mL of mobile phase; and a flow rate of 1 mL/min. 
 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical compound is present in an amount sufficient to treat one or more symptoms associated with a prostate disease. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the composition is in a solid dosage form. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the solid dosage form is a tablet. 
     
     
         5 . The pharmaceutical composition of  claim 3 , wherein the solid dosage form is a capsule. 
     
     
         6 . The pharmaceutical composition of  claim 1  or  claim 3 , wherein the composition is
 formulated to deliver from about 1 mg to about 500 mg of the compound after administration to a subject. 
 
     
     
         7 . The pharmaceutical composition of  claim 1  or  claim 3 , wherein the composition is
 formulated to deliver from about 50 mg to about 150 mg of the compound after administration to a subject. 
 
     
     
         8 . The pharmaceutical composition of  claim 1  or  claim 4 , wherein the pharmaceutical compound is in a single crystalline form having a melting point of 189-190 degrees Celsius, and wherein the crystalline form is obtained from a crystallization using ethyl acetate and methanol. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the tissue is tumor, liver, testes, or blood.