Halogenated compounds for cancer imaging and treatment and methods for their use

Abstract

Compounds having a structure of Formula I: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , X 3 and X 4 are are as defined herein, and wherein the compound comprises at least one F, Cl, Br, I or 123 I moiety, are provided. Uses of such compounds for imaging diagnostics in cancer and therapeutics methods for treatment of subjects in need thereof, including prostate cancer as well as methods and intermediates for preparing such compounds are also provided.

1 . A compound having a structure of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
 R 1  and R 2  are each independently_H or C 1 -C 10  alkyl, or R 1  and R 2 , together with the carbon atom to which they are bound, are taken together to form a carbocyclic or heterocyclic ring; 
 R 3 , R 4  and R 5  are each independently H, C 1 -C 10  alkyl or C 1 -C 10  alkylcarbonyl; and 
 X 1 , X 2 , X 3  and X 4  are each independently H, F, Cl, Br, I or  123 I, 
 wherein at least one of X 1 , X 2 , X 3  or X 4  is F, Cl, Br, I or  123 I. 
 
     
     
         2 . The compound of  claim 1 , wherein the compound has one of the following structures (Ia), (Ib), (Id), (Ie), (Ig) or (Ih): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein three of x 1 , X 2 , X 3  and X 4  are H, and the remaining X 1 , X 2 , X 3  or X 4  is F, Cl, Br, I or  123 I. 
     
     
         5 . The compound of  claim 1 , wherein X 1  is  123 I. 
     
     
         6 . The compound of  claim 1 , wherein X 3  is  123 I. 
     
     
         7 .- 11 . (canceled) 
     
     
         12 . The compound of  claim 1 , wherein R 1  and R 2  are each H or methyl. 
     
     
         13 .- 15 . (canceled) 
     
     
         16 . The compound of any one of  claims 1 - 15 , wherein at least one of R 3 , R 4  or R 5  is H. 
     
     
         17 . (canceled) 
     
     
         18 . The compound of  claim 1 , wherein R 3 , R 4  and R 5  are each H. 
     
     
         19 . The compound of  claim 1 , wherein at least one of R 3 , R 4  or R 5  is C 1 -C 10  alkyl. 
     
     
         20 .- 22 . (canceled) 
     
     
         23 . The compound of  claim 19 , wherein C 1 -C 10  alkyl is methyl, isopropyl, n-butyl or propargyl. 
     
     
         24 .- 25 . (canceled) 
     
     
         26 . The compound of  claim 1 , wherein at least one of R 3 , R 4  or R 5  is C 1 -C 10  alkylcarbonyl. 
     
     
         27 . (canceled) 
     
     
         28 . The compound of  claim 1 , wherein R 3 , R 4  and R 5  are each C 1 -C 10  alkylcarbonyl. 
     
     
         29 . The compound of  claim 26 , wherein C 1 -C 10  alkylcarbonyl is methyl carbonyl. 
     
     
         30 . The compound of  claim 1 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         31 . A pharmaceutical composition comprising a compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         32 . A method of imaging cancer, the method comprising administering a compound of  claim 1  to a subject and detecting the presence or absence of cancer by use of SPECT or PET. 
     
     
         33 . The method of  claim 32 , wherein the method identifies the presence or absence of a tumor. 
     
     
         34 . The method of  claim 32 , wherein the method identifies the location of a tumor. 
     
     
         35 . The method of  claim 32 , wherein the cancer is prostate cancer. 
     
     
         36 . The method of  claim 35 , wherein the prostate cancer is castration resistant prostate cancer or androgen-dependent prostate cancer. 
     
     
         37 . (canceled) 
     
     
         38 . The method of  claim 32 , wherein the method detects the presence of splice variants, mutants and/or species which comprise the AR NTD. 
     
     
         39 . A method of imaging prostate, the method comprising administering a compound of  claim 1  to a subject and detecting the prostate by use of SPECT or PET 
     
     
         40 .- 44 . (canceled) 
     
     
         45 . A method for modulating androgen receptor (AR) activity, the method comprising administering to a mammalian cell a compound of  claim 1 . 
     
     
         46 . (canceled) 
     
     
         47 . The method of  claim 45 , wherein modulating androgen receptor (AR) activity is for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age related macular degeneration. 
     
     
         48 . The method of  claim 47 , wherein the indication is prostate cancer. 
     
     
         49 .- 51 . (canceled) 
     
     
         52 . A method of modulating androgen receptor (AR) activity, the method comprising administering a compound of  claim 1  to a subject in need thereof. 
     
     
         53 . The method of  claim 52 , wherein modulating androgen receptor (AR) activity is for the treatment of one or more of the following: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age related macular degeneration. 
     
     
         54 . (canceled) 
     
     
         55 . A pharmaceutical composition comprising a compound of  claim 1 , an additional therapeutic agent and a pharmaceutically acceptable carrier. 
     
     
         56 . (canceled) 
     
     
         57 . The pharmaceutical composition of  claim 55 , wherein the additional therapeutic agent is enzalutamide, galeterone, ODM-201, ARN-509, abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX 011, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF 105,111 or related compounds thereof. 
     
     
         58 . The method of  claim 52 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or stereoisomer thereof.