Cancer targeting using carbonic anhydrase isoform ix inhibitors

Abstract

The present invention concerns novel carbonic anhydrase IX inhibitors comprising a nitroimidazole moiety and their use in therapy of hypoxic conditions, in particular cancer treatment, especially chemotherapy and radiotherapy. The compounds of the invention have an increased specificity for the carbonic anhydrase IX enzyme compared to the art. The present invention relates to novel nitroimidazole derivates represented by formula (1), wherein R 1 , R 2 , and Z are as defined herein:

1 - 35 . (canceled) 
     
     
         36 . A method of treating a subject afflicted with a disease characterized by overexpression of one or more carbonic anhydrase enzymes, comprising administering to the subject an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of formula (1): 
       
         
           
           
               
               
           
         
         wherein Z is Z 1  with formula (2a): 
       
       
         
           
           
               
               
           
         
         or Z is Z 2  with formula (2b): (CH 2 )nCH 2 X, where X=sulfonamide, sulfamate or sulfamide; or 
         or Z is Z 3  with formula (2c): 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are, each independently, H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, cyano or halogen atom; 
         R 3 , R 4 , R 6  and R 7  are, each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, halogen atom, cyano, alkoxy, sulfonamide, sulfamate or sulfamide; 
         R 5  is sulfonamide, sulfamate or sulfamide; 
         Y=O or S; and 
         n=0, 1, 2, 3, 4 or 5. 
       
     
     
         37 . A method of treating a subject afflicted with a disease characterized by overexpression of one or more carbonic anhydrase enzymes, comprising administering to the subject an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of formula (1), 
       
         
           
           
               
               
           
         
         wherein the compound is a compound of formula (3a) 
       
       
         
           
           
               
               
           
         
         a compound of formula (3b) 
       
       
         
           
           
               
               
           
         
       
       wherein X=sulfonamide, sulfamate or sulfamide;
 or a compound of formula (3c) 
 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are, each independently, H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, cyano or halogen atom; 
         R 3 , R 4 , R 6  and R 7  are, each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, halogen atom, cyano, alkoxy, sulfonamide, sulfamate or sulfamide; 
         R 5  is sulfonamide, sulfamate or sulfamide; 
         Y=O or S; and 
         n=0, 1, 2, 3, 4 or 5. 
       
     
     
         38 . The method according to  claim 36 , wherein the disease is a pre-cancerous or cancerous disease, wherein said disease is characterized by overexpression of MN/CA IX protein. 
     
     
         39 . The method according to  claim 38 , wherein the cancerous disease is a cancer of breast, brain, kidney, colorectal, lung, head and neck or bladder. 
     
     
         40 . The method according to  claim 38 , wherein the cancer is colorectal cancer. 
     
     
         41 . The method according to  claim 36 , wherein R 1  and R 2  are, each independently, H or CH 3 . 
     
     
         42 . The method according to  claim 36 , wherein R 1 =R 2 =H. 
     
     
         43 . The method according to  claim 36 , wherein R 3 =R 4 =R 7 . 
     
     
         44 . The method according to  claim 36 , wherein R 3 =R 4 =R 7 =H. 
     
     
         45 . The method according to  claim 36 , wherein R 5  or R 6  is sulfonamide. 
     
     
         46 . The method according to  claim 36 , wherein n=0, 1 or 2. 
     
     
         47 . The method according to  claim 36 , wherein R 1 =H and R 2 =CH 3 . 
     
     
         48 . The method according to  claim 36 , wherein n=1. 
     
     
         49 . The method according to  claim 36 , wherein Z is Z 2  with formula (2b), wherein X is sulfamate or sulfamide. 
     
     
         50 . The method according to  claim 36 , wherein Y=S. 
     
     
         51 . A method of treating a subject afflicted with a disease characterized by overexpression of one or more carbonic anhydrase enzymes, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound or salt of  claim 36  and a pharmaceutically acceptable carrier.