Aryloxy amine compounds and their use as sodium channel modulators

Abstract

The present invention relates generally to the field of therapeutic treatment and compounds having utility therefor, in particular the therapy or management of conditions associated with excessive, unwanted or undesirable sodium ion passage through cellular membranes via voltage-gated sodium channels. In one embodiment the invention is concerned with the treatment of neuropathic pain. The invention contemplates to aryloxy-substituted amines, as sodium channel blockers or modulators. In further embodiments, the invention also relates to compounds which may advantageously have dual sodium channel blocker/modulating and antioxidative (free-radical scavenging) effects. Methods for their manufacture and compositions containing the compounds are also contemplated.

1 - 17 . (canceled) 
     
     
         18 . A method of preventing sodium ion influx into a cell by blocking or modulating a sodium channel, said method comprising contacting said sodium channel with a compound of Formula (I):
   A-O-L 1 -NR-L 2 -B   wherein   A is an optionally substituted cyclopentadi-2,4-en-1-yl or phenyl group, an optionally substituted 5-6-membered monocyclic heteroaryl group, an optionally substituted napthyl group or an optionally substituted 9-10-membered bicyclic heteroaryl group;   L 1  is an optionally substituted C 1-4  alkylene group, an optionally substituted C 2-4  alkenylene group or an optionally substituted C 2 -C 4  alkynylene group;   L 2  is an optionally substituted C 1-4  alkylene group, an optionally substituted C 2-4  alkenylene group or an optionally substituted C 2 -C 4  alkynylene group or a CO 2  group;   R is hydrogen or a C 1-6 alkyl group; and   B is a group of formula (a) below:   
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently selected from hydrogen, C 1-6  alkyl and C 3-6 cycloalkyl; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         19 . A method for treating a condition in which excessive or undesirable sodium channel activity is implicated, in a subject in need thereof, comprising administering to said subject a compound of Formula (I):
   A-O-L 1 -NR-L 2 -B   wherein   A is an optionally substituted cyclopentadi-2,4-en-1-yl or phenyl group, an optionally substituted 5-6-membered monocyclic heteroaryl group, an optionally substituted napthyl group or an optionally substituted 9-10-membered bicyclic heteroaryl group;   L 1  is an optionally substituted C 1-4  alkylene group, an optionally substituted C 2-4  alkenylene group or an optionally substituted C 2 -C 4  alkynylene group;   L 2  is an optionally substituted C 1-4  alkylene group, an optionally substituted C 2-4  alkenylene group or an optionally substituted C 2 -C 4  alkynylene group or a CO 2  group;   R is hydrogen or a C 1-6 alkyl group; and   B is a group of formula (a) below:   
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently selected from hydrogen, C 1-6  alkyl and C 3-6 cycloalkyl; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         20 . The method of  claim 19 , wherein the condition in which excessive or undesirable sodium channel activity is implicated is neuroinflammatory disease. 
     
     
         21 . The method of  claim 19 , wherein the condition in which excessive or undesirable sodium channel activity is implicated is neuropathic pain. 
     
     
         22 . The method of  claim 19 , wherein the condition in which excessive or undesirable sodium channel activity is implicated is spinal cord injury. 
     
     
         23 . The method of  claim 19 , wherein the condition in which excessive or undesirable sodium channel activity is implicated is axonal loss, degeneration or damage. 
     
     
         24 . The method of  claim 19 , wherein the condition in which excessive or undesirable sodium channel activity is implicated is a demyelinating disease. 
     
     
         25 . The method of  claim 19 , wherein condition in which excessive or undesirable sodium channel activity is implicated is a central or peripheral neuropathy. 
     
     
         26 . The method of  claim 18  or  19 , wherein one of R 1  and R 2  is hydrogen and the other is C 1-6 alkyl or C 3-6 cycloalkyl. 
     
     
         27 . The method of  claim 18  or  19 , wherein R 1  and R 2  are independently C 1-6 alkyl or C 3-6 cycloalkyl. 
     
     
         28 . The method of  claim 26  wherein C 1-6 alkyl is t-butyl. 
     
     
         29 . The method of  claim 27  wherein C 1-6 alkyl is t-butyl. 
     
     
         30 . The method of  claim 18  or  19 , wherein A is substituted or unsubstituted phenyl or substituted or unsubstituted 6-membered heteroaryl. 
     
     
         31 . The method of  claim 18  or  19 , wherein L 1  and L 2  are independently selected from substituted or unsubstituted C 1-4 alkylene. 
     
     
         32 . The method of  claim 31  wherein L 1  and L 2  are unsubstituted. 
     
     
         33 . The method of  claim 32  wherein L 1  is unsubstituted ethylene or propylene and L 2  is unsubstituted methylene.