Fluorinated 2-amino-4-(benzylamino)phenylcarbamate derivatives

Abstract

The invention relates to fluorinated compounds and their use as anti-epileptic, muscle-relaxing, fever-reducing and peripherally analgesically acting medications and as imaging agents. Novel fluorinated 2-amino-4-(benzylamino)phenyl carbamate derivatives of ezogabine and pharmaceutically acceptable salts or solvates thereof and their use are described.

What is claimed: 
     
         1 . A compound of formula A: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein:
 X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8  are each independently selected from hydrogen, deuterium, and F; 
 X 9  and X 10  are each independently selected from hydrogen and deuterium; and 
 n is 1, 2, or 3, 
 
         provided that when X 6  is F, then X 1 , X 2 , X 3 , X 4 , X 5 , X 7  and X 8  are not all hydrogen. 
       
     
     
         2 . The compound of  claim 1  of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein:
 X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7  and X 8  are each independently selected from hydrogen, deuterium, and F, wherein at least one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7  and X 8  is F, provided that when X 6  is F, then X 1 , X 2 , X 3 , X 4 , X 5 , X 7  and X 8  are not all hydrogen. 
 
       
     
     
         3 . The compound of  claim 2 , wherein two of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7  and X 8  are F. 
     
     
         4 . The compound of  claim 2 , wherein three of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7  and X 8  are F. 
     
     
         5 . The compound of  claim 1  of formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein:
 X 1 , X 2 , X 3 , and X 6  are each independently selected from hydrogen, deuterium, and F, provided that when X 6  is F, then X 1 , X 2 , and X 3  are not all hydrogen. 
 
       
     
     
         6 . The compound of  claim 5 , wherein at least one of X 1 , X 2 , and X 3  is fluorine. 
     
     
         7 . The compound of  claim 5 , wherein X 6  is fluorine and one of X 1 , X 2 , and X 3  is fluorine. 
     
     
         8 . A compound of  claim 1  selected from 
       
         
           
                 
                 
               
                     
                 
                   Compound # 
                   Chemical Structure 
                 
                     
                 
                    2A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    3A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    4A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   and 
                 
                     
                 
                   10A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         9 . A pharmaceutical composition comprising at least one compound according to  claim 1  or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable carrier or excipient. 
     
     
         10 . A method of treating a subject suffering from or susceptible to conditions ameliorated by KCNQ2/3 potassium channel opening, comprising administering to the subject an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         11 . A method of treating or preventing a disease or disorder selected from epilepsy, neurodegenerative disorder, cognitive disorder, cancer, inflammatory disease, ophthalmic disease, migraine, bipolar disorder, unipolar depression, functional bowel disorder, or tinnitus in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         12 . The method of  claim 11 , wherein the disease is epilepsy. 
     
     
         13 . An 18F compound of formula V: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 A is N or C—X 3 ; 
 X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8  are each independently selected from hydrogen, 19F and 18F; and 
 n is 2 or 3, 
 
         provided that one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8  is 18F. 
       
     
     
         14 . The 18F compound of  claim 13 , wherein at least one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8  is 19F. 
     
     
         15 . The 18F compound of  claim 13  of formula VII: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 X 1 , X 2 , X 3 , and X 6  are each independently selected from hydrogen, 18F, and 19F, provided that one of X 1 , X 2 , X 3 , and X 6  is 18F. 
 
       
     
     
         16 . The 18F compound of  claim 15 , wherein at least one of X 1 , X 2 , and X 3  is 19F. 
     
     
         17 . The 18F compound of  claim 15 , wherein X 6  is 19F or 18F. 
     
     
         18 . The 18F compound of  claim 13  selected from 
       
         
           
                 
                 
               
                     
                 
                   Compound # 
                   Chemical Structure 
                 
                     
                 
                   5A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   6A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   7A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   8A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   and 
                 
                     
                 
                   9A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . A pharmaceutical composition comprising at least one 18F compound according to  claim 13  or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier or excipient. 
     
     
         20 . A method of imaging (1) the functional status of the KCNQ2/3 potassium channel, (2) the biodistribution of an 18F compound according to  claim 13 , or (3) a disorder or disease selected from a neurotransmission disorder, CNS disorder, cognitive disorder, and neurodegenerative disease in a subject in need thereof, comprising administering to the subject an effective amount of an 18F compound according to  claim 13  or a pharmaceutically acceptable salt thereof and imaging the subject using positron emission tomography.