Novel C-17-Heteroaryl Steroidal Cyp17 Inhibitors/Antiandrogens: Synehesis, 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 method for treating an androgen dependent prostate disease the method comprising contacting a human cell with a compound that inhibits CYP17 enzyme in the cell and antagonizes androgen receptors in the cell. 
   
   
       2 . The method of  claim 1 , wherein the compound reduces the volume of a tumor in a subject. 
   
   
       3 . A method of inhibiting the growth of prostate cancer cells in a subject, the method comprising administering to the subject a compound that inhibits CYP17 enzyme and antagonizes an androgen receptor. 
   
   
       4 . The method of  claim 1 ,  2  or  3 , wherein the compound is a C-17 heteroaryl steroid compound of compound of formula 1: 
     
       
         
         
             
             
         
       
     
     wherein:
 the ABC ring structure is the A, B and C ring portions of a steroid or analog thereof having a structure based on 3β-hydroxy-androsta-5,16-diene or 3-oxo-androsta-5,16-diene or such structures wherein the AB rings are one of the following structures: 
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     which are optionally substituted;
 the    
 
     bond at the 16, 17 position is a double bond or, when the compound is 17-(1H-benzimidazol-1-yl)androst-3-one, a single bond; and
 X is an optionally substituted benzimidazole, benzotriazole, pyrimidinoimidazole, pyrimidinotriazole or diazine; the benzimidazole, benzotriazole, and pyrimidinoimidazole groups being bonded to the steroid residue through a nitrogen atom on the 5-membered ring; and, the diazine groups being bonded to the steroid residue through a carbon atom on the diazine ring; 
 or a pharmaceutically acceptable salt of one of these compounds. 
 
   
   
       5 . The method of  claim 4 , wherein the compound is not 3,3-difluoro-17-(1H-benzimidazol-1-yl)-androsta-1,4,16-triene. 
   
   
       6 . The method of  claim 4 , wherein the optional substituents for the ABC ring structure are selected from one or more of: alkyl and halogenated alkyl; alkenyl and halogenated alkenyl; halogen; amino; aminoalkylene; hydroxyimino; and hydroxy; optionally, hydrogen substituents on adjacent carbon atoms of the ABC ring structure are removed and replaced by an additional bond between the adjacent carbon atoms to result in a double bond between these carbons in the ring structure; and the optional substituents for the benzimidazole, benzotriazole, pyrimidinoimidazole, pyrimidinotriazole or diazine structures are selected from: halogen, amino, aminoalkylene, hydroxy, —SH, —S-alkyl, alkyl and halogenated alkyl; these optional substituents being on ring carbon atoms of the benzimidazole, benzotriazole, pyrimidinoimidazole, pyrimidinotriazole or diazine structures. 
   
   
       7 . The method of  claim 4 , wherein the benzimidazole, benzotriazole, pyrimidinoimidazole, pyrimidinotriazole or diazine structures are of the 
     
       
         
         
             
             
         
       
     
     following formulae, respectively; wherein the * indicates the point of attachment to the steroid residue. 
   
   
       8 . The method of  claim 4 , wherein the ABC ring structure has a C ring substituted by alkyl, particularly methyl, at the carbon shared with the D ring which is adjacent the attachment to the C-17 heteroaryl substitution. 
   
   
       9 . The method of  claim 4 , wherein the compound is 
     
       
         
         
             
             
         
       
     
   
   
       10 . The method of  claim 4 , wherein the compound is one of the following compounds:
 3β-Hydroxy-3α-methyl-17-(1H-benzimidazol-1-yl)-an-drosta-5,16-diene,   3β-Fluoro-17-(1H-benzimidazol-1-yl)-androsta-5,16-diene,   3β-Chloro-17-(1H-benzimidazol-1-yl)-androsta-5,16-diene,   3β-Bromo-17-(1H-benzimidazol-1-yl)-androsta-5,16-diene,   3β-Iodo-17-(1H-benzimidazol-1-yl)-androsta-5,16-diene,   3β-Amino-17-(1H-benzimidazol-1-yl)-androsta-5,16-diene,   17-(1H-benzimidazol-1-yl)-androsta-3,5,16-triene,   17-(1H-benzimidazol-1-yl)-androsta-2,4,16-triene,   17-(1H-benzimidazol-1-yl)-3-methyleneandrosta-5,16-triene,   17-(1H-benzimidazol-1-yl)-3-methyleneandrosta-4,16-triene,   3,3-Difluoro-17-(1H-benzimidazol-1-yl)-androsta-5,16-diene,   3,3-Difluoro-17-(1H-benzimidazol-1-yl)-androsta-4,16-diene,   17-(1H-benzimidazol-1-yl)-3-methyleneandrosta-2,4,16-triene,   17-(1H-benzimidazol-1-yl)-3-methyleneandrosta-2,4,6,16-tetraene,   3-Hydroxyimino-17-(1H-benzimidazol-1-yl)-androsta-5,16-diene,   3-Hydroxyimino-17-(1H-benzimidazol-1-yl)-androsta-4,16-diene,   3-Hydroxyimino-17-(1H-benzimidazol-1-yl)-androsta-2,4,16-triene,   3-Hydroxyimino-17-(1H-benzimidazol-1-yl)-androsta-2,4,6,16-diene,   3-Hydroxy-17-(1H-benzimidazol-1-yl)-estra-1,3,5(10),16-tetraene,   3-Fluoro-17-(1H-benzimidazol-1-yl)-estra-1,3,5(10),16-tetraene,   3-Chloro-17-(1H-benzimidazol-1-yl)-estra-1,3,5(10),16-tetraene,   3-Bromo-17-(1H-benzimidazol-1-yl)-estra-1,3,5(10),16-tetraene,   3-Iodo-17-(1H-benzimidazol-1-yl)-estra-1,3,5(10),16-tetraene, or   3,3-difluoro-17-(1H-benzimidazol-1-yl)-androsta-2,4,16-triene.   
   
   
       11 . The method of  claim 1  or  3 , wherein the compound possesses an IC 50  value of less than about 900 nM for CYP17. 
   
   
       12 . The method of  claim 1  or  3 , wherein the compound possesses an IC 50  value of between about 300 nM and about 900 nM for CYP17. 
   
   
       13 . The method of  claim 1  or  3 , wherein the compound possesses an IC 50  value of less than about 300 nM for CYP17. 
   
   
       14 . The method of  claim 1  or  3 , wherein the compound possesses an IC 50  value of less than about 900 nM for CYP17 and inhibition of androgen receptors of less than about 1-2 μM. 
   
   
       15 . The method of  claim 1  or  3 , wherein the compound inhibits one or both of human 5-alpha reductase type one and type two. 
   
   
       16 . The method of  claim 1  or  3 , wherein the compound possesses a terminal half-life of approximately 45 minutes after administration to a subject. 
   
   
       17 . The method of  claim 1  or  3 , wherein the compound possesses a terminal half-life of greater than approximately 45 minutes after administration to a subject. 
   
   
       18 . The method of  claim 1  or  3 , wherein the compound possesses a terminal half-life of approximately 45 minutes, an elimination rate constant of 56 min −1 , a maximum concentration of about 17 μg/mL, and a volume of distribution of about 2099 mL/kg after administration to a subject. 
   
   
       19 . A substituted androstane compound that inhibits CYP17 enzyme and antagonizes human androgen at the androgen receptor: 
   
   
       20 . A compound according to  claim 19 , wherein the androstene compound is a 3β-hydroxy-androsta-5,16-diene compound.