Novel prodrugs of steroidal cyp17 inhibitors/antiandrogens

Abstract

Prodrugs of C-17-heterocyclic-steroidal drugs providing improved oral bioavailability and pharmacokinetics are described. The drugs are inhibitors of human CYP 17 enzyme, as well as potent antagonists of both wild type and mutant androgen receptors (AR), and are useful for the treatment of urogenital and/or androgen-related cancers, diseases and/or conditions, such as human prostate cancer, breast cancer, and prostate hyperplasia. The disclosure describes methods of synthesizing and using the prodrugs in cancer therapy.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 the ABC ring structure is optionally substituted independently at each position and wherein hydrogen substituents on adjacent carbon atoms of the ABC ring structure are optionally removed and replaced by a pi-bond between the adjacent carbon atoms; 
 Y is Z-L-C(═O)O—; and 
 either
 X is an optionally substituted heterocycle that is a pyridine, pyrazine, pyrimidine, pyridazine, benzimidazole, benzotriazole, pyrimidinoimidazole, or pyrimidinotriazole group, wherein the benzimidazole, benzotriazole, pyrimidinoimidazole or pyrimidinotriazole group is bonded to the C17 position through a nitrogen atom on a 5-membered ring of the heterocycle, and the pyridine, pyrazine, pyrimidine, or pyridazine group is bonded to the C17 position through a carbon atom of the heterocycle; 
 L is C 1 -C 12 -alkyl, fluoro-C 2 -C 6 -alkyl, aryl, arylalkyl, alkylaryl, alkoxyalkyl, polyalkoxyalkyl, or heteroaryl, any of which is optionally cyclic or together with Z forms a ring, wherein L is optionally substituted with one or more of alkyl, arylalkyl, alkylaryl, alkylheteroaryl, halogen, hydroxyl, alkoxy, and mercaptan; and 
 Z is a charged group that is charged under normal physiological conditions, wherein the charged group is a sulfonic acid; a phosphonic acid; a fluoroalkanol; or an acidic hydroxyl group, 
 
 or
 X is an optionally-substituted pyridine group; 
 L is C 1 -C 12 -alkyl, fluoro-C 2 -C 6 -alkyl, aryl, arylalkyl, alkylaryl, alkoxyalkyl, polyalkoxyalkyl, or heteroaryl, any of which is optionally cyclic or together with Z forms a ring, wherein L is optionally substituted with one or more of alkyl, arylalkyl, alkylaryl, alkylheteroaryl, halogen, hydroxyl, alkoxy, alkylamino, and mercaptan; and 
 Z is a charged group that is charged under normal physiological conditions, wherein the charged group is a quaternary ammonium group of the formula (R 3 N + )—, wherein each R group is independently C 1 -C 7 -branched alkyl, C 1 -C 7 -straight-chain alkyl, aryl, alkylaryl, aralkyl, heteroaryl, or two or more R groups together form a ring; a sulfonic acid; a phosphonic acid; a fluoroalkanol; or an acidic hydroxyl group, 
 
 
       or a pharmaceutically-acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , wherein X is optionally substituted with one or more of halogen, amino, aminoalkylene, hydroxy, —SH, —S—C 1 -C 6 -alkyl, C 1 -C 6 -alkyl and halogenated C 1 -C 6 -alkyl. 
     
     
         3 . The compound of  claim 2 , wherein the pyridine, pyrazine, pyrimidine, pyridazine, benzimidazole, benzotriazole, pyrimidinoimidazole, and pyrimidinotriazole groups are, respectively. 
       
         
           
           
               
               
           
         
       
       wherein each * indicates a point of attachment to the C17 position. 
     
     
         4 . The compound of  claim 3 , wherein the ABC ring structure is optionally substituted with one or more of C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, halogenated C 1 -C 6 -alkenyl, halogen, amino, aminoalkylene, hydroxyimino, and hydroxyl. 
     
     
         5 . The compound of  claim 4 , wherein Z is a quaternary ammonium group, wherein the quaternary ammonium group is trimethyl ammonium, triethyl ammonium, triphenyl ammonium, benzyldimethyl ammonium, benzyldiethyl ammonium, N-methylpiperidinium, N-ethylpiperidinium, or tribenzyl ammonium. 
     
     
         6 . The compound of  claim 4 , wherein Z is a sulfonic acid, and L is C 1 -C 6 -alkyl. 
     
     
         7 . The compound of  claim 4 , wherein Z is a phosphonic acid, and L is C 1 -C 6 -alkyl. 
     
     
         8 . The compound of  claim 4 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 8 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       wherein R is C 1 -C 6 -alkyl, aryl, heteroaryl, arylalkyl, or alkylaryl; R 1  is H, C 1 -C 8 -alkyl, aryl, aralkyl, alkylaryl, or alkylheteroaryl; and n is from 1 to 49. 
     
     
         10 . A pharmaceutical composition comprising a therapeutically-effective amount of one or more compounds of  claim 1  and one or more pharmaceutically-acceptable excipients, bulking agents, binders, flow agents, release agents, carriers or diluents. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the composition is an oral dosage form. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the oral dosage form is a tablet, a caplet, or a capsule. 
     
     
         13 . The pharmaceutical composition of  claim 10 , wherein the amount of the compound is less than about 2000 mg. 
     
     
         14 . The pharmaceutical composition of  claim 10 , wherein the amount of the compound is from about 500 mg to about 1500 mg. 
     
     
         15 . The pharmaceutical composition of  claim 10 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       wherein R is C 1 -C 6 -alkyl, aryl, heteroaryl, arylalkyl, or alkylaryl; and R 1  is H, C 1 -C 8 -alkyl, aryl, aralkyl, alkylaryl, or alkylheteroaryl; and n is from 1 to 49. 
     
     
         16 . A method of treating a cancer or a urogenital disease in a subject in need or want thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein the cancer is a urogenital and/or androgen-related cancer. 
     
     
         18 . The method of  claim 16 , wherein the cancer or urogenital disease is prostate cancer, breast cancer, ovarian cancer, other urogenital cancer, or prostate hyperplasia. 
     
     
         19 . The method of  claim 16 , further comprising administering to the subject a therapeutically-effective amount of one or more of an anti-androgen, a CYP17 inhibitor, a luteinizing hormone-releasing hormone agonist, a drug for preventing androgen production, an estrogen, and a chemotherapy drug. 
     
     
         20 . The method of  claim 16 , wherein the amount is less than about 2000 mg. 
     
     
         21 . The method of  claim 16 , wherein the amount is from about 500 to about 1500 mg. 
     
     
         22 . The method of  claim 16 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       wherein R is C 1 -C 6 -alkyl, aryl, heteroaryl, arylalkyl, or alkylaryl; and R 1  is H, C 1 -C 8 -alkyl, aryl, aralkyl, alkylaryl, or alkylheteroaryl; and n is from 1 to 49. 
     
     
         23 . A method of treating a cancer or a urogenital disease in a subject in need or want thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of  claim 1 , in combination with a hormone therapy, a chemotherapy, a radiation therapy, an immunotherapy, or surgery. 
     
     
         24 . The method of  claim 23 , wherein the cancer comprises a urogenital and/or androgen-related cancer. 
     
     
         25 . The method of  claim 23 , wherein the cancer or urogenital disease is prostate cancer, breast cancer, ovarian cancer, other urogenital cancer, or prostate hyperplasia. 
     
     
         26 . The method of  claim 23 , wherein the amount is less than about 2000 mg. 
     
     
         27 . The method of  claim 23 , wherein the amount is from about 500 to about 1500 mg. 
     
     
         28 . The method of  claim 23 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       wherein R is C 1 -C 6 -alkyl, aryl, heteroaryl, arylalkyl, or alkylaryl; and R 1  is H, C 1 -C 8 -alkyl, aryl, aralkyl, alkylaryl, or alkylheteroaryl; and n is from 1 to 49.