Dioxolane analogues of uridine for the treatment of cancer

Abstract

The invention provides compounds of the formula:R1 is OR11, or NR5R5′;R2 is H or F;R5 is H, C1-C6alkyl, OH, C(═O)R6, O(C═O)R6 or O(C═O)OR6;R5′ is H or C1-C6alkyl;R6 is C1-C6alkyl or C3-C7cycloalkyl;R13 is H, phenyl, pyridyl, benzyl, indolyl or naphthyl wherein the phenyl, pyridyl, benzyl, indolyl and naphthyl is optionally substituted with 1, 2 or 3 R22;and the other variables are as defined in the claims,which are of use in the treatment of cancer, and related aspects.

1 .- 22 . (canceled) 
     
     
         23 . A method for the treatment of liver cancer, comprising the oral administration to a warm blooded animal of a therapeutically effective amount of a compound of the formula Ia: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is NH 2 ; 
         R 2  is H; 
         R 13  is phenyl, optionally substituted with 1, 2 or 3 R 22 ; 
         R 15  is methyl; 
         R 16  is 2-pentyl; 
         each R 22  is independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, phenyl, hydroxyC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylcarbonyl, C 3 -C 6 cycloalkylcarbonyl, carboxyC 1 -C 6 alkyl, hydroxy, amino CN, and NO 2 , or any two R 22  groups attached to adjacent ring carbon atoms can combine to form —O—(CR 23 R 23 ′) 1-6 —O—; 
         R 23  and R 23′  are independently H or C 1 -C 3 alkyl; 
         or a pharmaceutically acceptable salt and/or solvate thereof, 
         wherein the method further comprises therapy with radiofrequency ablation. 
       
     
     
         24 . The method according to  claim 23 , wherein R 13  is substituted with one or two R 22 . 
     
     
         25 . The method according to  claim 23 , wherein R 13  is unsubstituted phenyl. 
     
     
         26 . The method according to  claim 23 , wherein the compound of formula Ia is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         27 . The method according to  claim 23 , wherein the compound of formula Ia is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         28 . The method according to  claim 23 , wherein the compound of formula Ia is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         29 . The method according to  claim 23 , wherein the liver cancer is hepatocellular carcinoma. 
     
     
         30 . The method according to  claim 23 , wherein the liver cancer is a secondary liver cancer, that is a cancer that has originated in an organ elsewhere in the body and has metastasised to the liver. 
     
     
         31 . The method according to  claim 30 , wherein the cancer has metastasised to the liver from colon, lung or breast. 
     
     
         32 . The method according to  claim 23 , wherein the warm-blooded animal is a human. 
     
     
         33 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         34 . The compound according to  claim 33 , which is at least 90% diastereomerically pure.