Novel steroidal cyp17 inhibitors/antiandrogens

Abstract

Steroidal C-17 nitrogen-containing heterocycles of Formula I: wherein: the ABCD ring structure is the nucleus of a steroid, or an analog thereof; X is a group capable of coordinating a heme group of CYP17, and Y is an hydroxyl functionality, a suitable ester, or a prodrug group, for the treatment of urogenital and/or androgen-related cancers, such as castration-resistant prostate cancer. The invention provides methods of synthesizing new chemical entities and methods of using the same in treating urogenital and/or androgen-related cancers.

What is claimed is: 
     
         1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein:
 each position of the ABC ring structure is independently optionally substituted; 
 
         X is an aromatic group comprising at least 2 fused rings, a 10-electron aromatic system, and at least one nitrogen ring atom capable of coordinating a heme group of CYP17, wherein X is not benzimidazole and X is any one of: 
       
       
         
           
           
               
               
           
         
         
           wherein * is the point of attachment, and R is C 1 -C 6 -alkyl, and wherein any of the foregoing groups are optionally substituted; and 
           Y is OH, an ester, or a prodrug group, 
         
         or a pharmaceutically-acceptable salt or analog thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein each position of the ABC ring structure is independently optionally substituted with one or more of alkyl, halogenated alkyl, alkenyl, halogenated alkenyl, halogen, amino, aminoalkylene, hydroxyimino, and hydroxy. 
     
     
         3 . The compound of  claim 2 , wherein X is optionally substituted with one or more of halogen, amino, aminoalkylene, hydroxy, —SH, —S-alkyl, alkyl and halogenated C 1 -C 6 -alkyl. 
     
     
         4 . The compound of  claim 3 , wherein Y is OH. 
     
     
         5 . The compound of  claim 4  having the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R is C 1 -C 6 -alkyl, alkoxyalkyl, alkylaryl, aryl or heteroaryl. 
       
     
     
         6 . The compound of  claim 3 , wherein Y is a physiological precursor of a 3-hydroxyl group. 
     
     
         7 . The compound of  claim 6 , wherein Y is O-acetyl, O-propionyl, O-betaine, O-carnitine, an amino acid group, or a peptidyl group. 
     
     
         8 . The compound of  claim 7 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound represented by Formula II: 
       
         
           
           
               
               
           
         
         wherein:
 E is a ring containing 5, 6, or 7 atoms, which together with the F-ring forms an EF group comprising a 10-electron aromatic system; 
 U, Z, and Q are each independently C, CH, N, NH, oxygen, or sulfur; and 
 Y is OH, O-acetyl, or a physiological precursor of a 3-hydroxyl group. 
 
       
     
     
         10 . The compound of  claim 9 , wherein the EF group is 1-azaazulene, 2-alkylindazole, pyrazolo-[1,5-a]-pyridine, imidazo-[1,2-a]-pyridine, pyrrolo-[2,3-a]-pyrimidine, pyrrolo-[2,3-c]-pyrimidine, imidazo-[1,2-c]-pyrimidine, imidazo-[1,2-a]-pyrimidines4-alkylpyrazolo-[1,5-a]imidazole, 2,1-benzoxazoles, 2,1-benzthiazole, imidazo[2,1-b][1,3]oxazole, imidazo[2,1-b][1,3]thiazole, imidazo-[2,1-b][1,2]isoxazole, or cyclopenta[b]pyrrole, any of which is optionally substituted with halogen, amino, aminoalkylene, hydroxy, —SH, —S-alkyl, alkyl and halogenated C 1 -C 6 -alkyl. 
     
     
         11 . 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. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the composition is an oral dosage form. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the oral dosage form is a tablet, a caplet, or a capsule. 
     
     
         14 . The pharmaceutical composition of  claim 11 , wherein the amount of the compound is less than about 2000 mg. 
     
     
         15 . The pharmaceutical composition of  claim 11 , wherein the amount of the compound is from about 500 mg to about 1500 mg. 
     
     
         16 . The pharmaceutical composition of  claim 11 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R is C 1 -C 6 -alkyl, alkoxyalkyl, alkylaryl, aryl or heteroaryl. 
       
     
     
         17 . The pharmaceutical composition of  claim 11 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         18 . A method of treating a cancer 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 . 
     
     
         19 . The method of  claim 18 , wherein the cancer is a urogenital and/or androgen-related cancer. 
     
     
         20 . The method of  claim 19 , wherein the urogenital and/or androgen-related cancer is prostate cancer, breast cancer, ovarian cancer, other urogenital cancer, or prostate hyperplasia. 
     
     
         21 . The method of  claim 18 , 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. 
     
     
         22 . The method of  claim 18 , wherein the amount is less than about 2000 mg. 
     
     
         23 . The method of  claim 18 , wherein the amount is from about 100 to about 500 mg. 
     
     
         24 . The method of  claim 18 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R is C 1 -C 6 -alkyl, alkoxyalkyl, alkylaryl, aryl or heteroaryl. 
       
     
     
         25 . The method of  claim 18 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         26 . A method of treating cancer 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. 
     
     
         27 . The method of  claim 26 , wherein the cancer comprises a urogenital and/or androgen-related cancer. 
     
     
         28 . The method of  claim 26 , wherein the urogenital and/or androgen-related cancer is prostate cancer, breast cancer, ovarian cancer, other urogenital cancer, or prostate hyperplasia. 
     
     
         29 . The method of  claim 26 , wherein the amount is less than about 2000 mg. 
     
     
         30 . The method of  claim 26 , wherein the amount is from about 100 to about 500 mg. 
     
     
         31 . The method of  claim 26 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R is C 1 -C 6 -alkyl, alkoxyalkyl, alkylaryl, aryl or heteroaryl. 
       
     
     
         32 . The method of  claim 26 , wherein the compound is: