2-beta-naphthyl-acetic acid analogs as akr1c3 inhibitors and methods of using same

Abstract

The invention includes 2-β-naphthyl-acetic acid derivatives, which are selective AKR1C3 inhibitors. In certain embodiments, the compounds of the invention are R-naproxen analogs. The invention further includes methods of treating cancer, such as prostate cancer and/or castration-resistant prostate cancer, using at least one compound of the invention.

What is claimed is: 
     
         1 . A compound of formula (I), or a salt, solvate, or stereoisomer thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of OH, —NHSO 2 (C 1 -C 6  alkyl), C 1 -C 6  alkoxy, and C 3 -C 8  cycloalkoxy, wherein the alkyl, alkoxy or cycloalkoxy group is optionally substituted with at least one substituent selected from C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, optionally substituted aryl, OH, C 1 -C 6  alkoxy, halogen, and —CN; 
 R 2  and R 3  are independently selected from the group consisting of H, C 1 -C 6  alkyl, and C 3 -C 8  cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with at least one selected from the group consisting of C 1 -C 6  alkyl and C 3 -C 8  cycloalkyl; 
 R 4  is selected from the group consisting of C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 6  alkoxy, C 3 -C 8  cycloalkoxy, —S(C 1 -C 6  alkyl), —S(C 3 -C 8  cycloalkyl), —S(═O)(C 1 -C 6  alkyl), —S(═O)(C 3 -C 8  cycloalkyl), —S(═O) 2 (C 1 -C 6  alkyl), and —S(═O) 2 (C 3 -C 8  cycloalkyl); 
 wherein the compound is not a compound wherein R 1  is OH, one of R 2  and R 3  is methyl and the other is H, and R 4  is methoxy. 
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of OH and C 1 -C 6  alkoxy, wherein the alkoxy group is optionally substituted with at least one substituent selected from C 1 -C 6  alkyl, optionally substituted aryl, OH, C 1 -C 6  alkoxy, halogen, and —CN. 
     
     
         3 . The compound of  claim 1 , wherein Ri is selected from the group consisting of OH and C 1 -C 6  alkoxy. 
     
     
         4 . The compound of  claim 1 , wherein Ri is OH, methoxy, ethoxy, i-propoxy, n-propoxy, n-butoxy, i-butoxy, sec-butoxy or t-butoxy. 
     
     
         5 . The compound of  claim 1 , wherein
 R 2  is H, and R 3  is selected from the group consisting of H, C 1 -C 6  alkyl, and C 3 -C 8  cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with at least one selected from the group consisting of C 1 -C 6  alkyl and C 3 -C 8  cycloalkyl, or   (ii) R 3  is H, and R 2  is selected from the group consisting of H, C 1 -C 6  alkyl, and C 3 -C 8  cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with at least one selected from the group consisting of C 1 -C 6  alkyl and C 3 -C 8  cycloalkyl.   
     
     
         6 . The compound of  claim 1 , wherein
 (i) R 2  is H, and R 3  is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or t-butyl, or   (ii) R 3  is H and R 2  is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or t-butyl.   
     
     
         7 . The compound of  claim 1 , wherein R 4  is selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —S(C 1 -C 6  alkyl), —S(═O)(C 1 -C 6  alkyl), and —S(═O) 2 (C 1 -C 6  alkyl). 
     
     
         8 . The compound of  claim 1 , wherein R 4  is methyl, methoxy, ethyl, ethoxy, thiomethyl, thioethyl, —S(═O)CH 3 , S(═O) 2 CH 3 , —S(═O)CH 2 CH 3 , or —S(═O) 2 CH 2 CH 3 . 
     
     
         9 . The compound of  claim 1 , which is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , which is one of the following:
 (a) the compound of formula (Ia), or a salt or solvate thereof:   
       
         
           
           
               
               
           
         
         which has the (R) configuration at the carbon center linked to R2; 
         (b) the compound of formula (Ib), or a salt or solvate thereof: 
       
       
         
           
           
               
               
           
         
         which has the (S) configuration at the carbon center linked to R2. 
       
     
     
         11 . The compound of  claim 1 , which is selected from the group consisting of:
 2(R)-(6-ethylnaphthalen-2-yl)propanoic acid;   2(R)-(6-ethoxynaphthalen-2-yl)propanoic acid;   2(R)-(6-(methylthio)naphthalen-2-yl)propanoic acid;   2(R)-(6-(methylsulfinyl)naphthalen-2-yl)propanoic acid;   2(R)-(6-(methylsulfonyl)naphthalen-2-yl)propanoic acid;   2(R)-(6-methoxynaphthalen-2-yl)-N-(methylsulfonyl)butanamide; and   2(R)-(6-methoxynaphthalen-2-yl)butanoic acid.   
     
     
         12 . The compound of  claim 1 , which is 2(R)-(6-methoxynaphthalen-2-yl) butanoic acid 
       
         
           
           
               
               
           
         
       
       or a salt or solvate thereof 
     
     
         13 . A pharmaceutical composition comprising at least one compound of  claim 1  and further comprising at least one pharmaceutically acceptable carrier, optionally further comprising at least one additional agent that treats or ameliorates cancer. 
     
     
         14 . A method of treating or ameliorating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one compound of  claim 1 , wherein the cancer comprises prostate cancer or castration-resistant prostate cancer, optionally wherein the subject is human. 
     
     
         15 . The method of  claim 14 , the method further comprising administering to the subject at least one therapeutic agent selected from the group consisting of indomethacin, desatinib, selegiline, seliciclib, TOK-001, SAHA, docetaxel, bevacizumab, taxotere, thalidomide, prednisone, Sipuleucel-T, cabazitaxel, enzalutamide, ARN-509, abiraterone, temozolomide, salts thereof, solvates thereof, and any mixtures thereof, optionally wherein the compound and the at least one therapeutic agent are administered concomitantly to the subject, optionally wherein the compound and the at least one therapeutic agent are coformulated. 
     
     
         16 . The method of  claim 14 , wherein at least one of the following applies:
 (a) the compound is a substrate-selective inhibitor of endocannabinoid oxygenation by cyclooxygenase-2 (COX-2);   (b) the compound promotes analgesia in the subject suffering from prostate cancer or metastatic prostate cancer;   (c) the compound is administered to the subject by a nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, or intravenous route.   
     
     
         17 . A method of inhibiting aldo-keto reductase family 1, member C3 (AKR1C3) in a mammalian cell, the method comprising contacting the cell with an effective amount of at least one compound of  claim 1 . 
     
     
         18 . The method of  claim 17 , wherein the contacting does not significantly inhibit aldo-keto reductase family 1, member C1 (AKR1C1) r aldo-keto reductase family 1, member C2 (AKR1C2) in the cell, optionally wherein the contacting inhibits less than about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% of AKR1C1 or AKR1C2 in the cell. 
     
     
         19 . The method of  claim 17 , wherein at least one of the following applies:
 (a) the cell comprises a prostate cell;   (b) the cell comprises a castration-resistant prostate cancer cell;   (c) the cell is in vivo in the mammal, optionally the mammal being human;   (d) the cell is in vivo in the mammal and the compound is administered to the subject by a nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, or intravenous route.