Rufinamide and derivatives and their use in modulating the gating process of human voltage-gated sodium channels

Abstract

The present invention provides compounds of formula I or a salt, solvate, or stereoisomer thereof, wherein X is H, or an electron withdrawing group such as a halogen, NH 2 , NO 2 , SO 2 , CN, or a C 1 -C 6 alkyl group; Alk is C 1 -C 3 alkyl; R 1 is H, C 1 -C 6 alkyl, which may be substituted with OH, NH 2 , acyl, sulfonyl, and cyano groups; and R 2 , is C 1 -C 6 alkyl, which may be substituted with OH, NH 2 , acyl, sulfonyl, and cyano groups. Pharmaceutical compositions comprising these compounds and/or rufinamide are also provided. Methods for prevention and treatment of epilepsy disorders such as Lennox-Gastaut Syndrome (LGS), and modulation of voltage-gated sodium (Nay) channels are Nav1.1 channels by administration of these compounds and/or rufinamide are also provided.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a salt, solvate, or stereoisomer thereof, 
         wherein X is H, or an electron withdrawing group such as a halogen, NH 2 , NO 2 , SO 2 , CN, or a C 1 -C 6  alkyl group; 
         Alk is C 1 -C 3  alkyl; 
         R 1  is H, C 1 -C 6  alkyl, which may be substituted with OH, NH 2 , amido, acyl, sulfonyl, and cyano groups; and 
         R 2 , is C 1 -C 6  alkyl, which may be substituted with OH, NH 2 , amido, acyl, sulfonyl, and cyano groups. 
       
     
     
         2 . The compound of  claim 1 , wherein X is F, Cl or Br. 
     
     
         3 . The compound of  claim 1 , wherein X is F and is in the 2, 3, 4, 5, or 6 position on the phenyl ring. 
     
     
         4 . The compound of  claim 3 , wherein F is on the 4 or 5 position on the phenyl ring. 
     
     
         5 . The compound of  claim 1 , wherein Alk is methyl. 
     
     
         6 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of H, CH 3  and NH 2 . 
     
     
         7 . The compound of  claim 1 , wherein R 2  is CH 2 OH or CONH 2 . 
     
     
         8 . The compound of  claim 1 , wherein the compounds are selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt, solvate, or stereoisomer thereof. 
       
     
     
         9 . A pharmaceutical composition comprising a compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a salt, solvate, or stereoisomer thereof,
 wherein X is H, or an electron withdrawing group such as a halogen, NH 2 , NO 2 , SO 2 , CN, or a C 1 -C 6  alkyl group; 
 Alk is C 1 -C 3  alkyl; R 1  is H, C 1 -C 6  alkyl, which may be substituted with OH, NH 2 , amido, acyl, sulfonyl, and cyano groups; and 
 R 2 , is C 1 -C 6  alkyl, and alkenyl, which may be substituted with OH, NH 2 , amido, acyl, sulfonyl, and cyano groups; and 
 a pharmaceutically acceptable carrier, in an effective amount, for use as a medicament, preferably for use in modulating the opening of one or more voltage-gated sodium (Nav) channels in one or more neurons of a subject, or for use in treating an epilepsy disorder in a subject. 
 
     
     
         10 . A pharmaceutical composition comprising at least one compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt, solvate, or stereoisomer thereof, and 
         a pharmaceutically acceptable carrier, in an effective amount, for use as a medicament, preferably for use in modulating the opening of one or more voltage-gated sodium (Nav) channels in one or more neurons of a subject, or for use in treating an epilepsy disorder in a subject. 
       
     
     
         11 . The pharmaceutical composition of  claim 9 , wherein the composition further comprises at least one additional therapeutic agent. 
     
     
         12 . The pharmaceutical composition of  claim 9 , wherein the at least one additional therapeutic agent is selected from the group consisting of lamotrigine, valproic acid, topiramate, felbamate, and clobazam. 
     
     
         13 . A method for for modulating the opening of one or more voltage-gated sodium (Nav) channels in one or more neurons of a subject comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 9 . 
     
     
         14 . The method of  claim 13 , wherein the one or more voltage-gated sodium (Nav) channels are selected from the group consisting of Nav1.1, Nav1.2, Nav1.3 and Nav1.6 channels. 
     
     
         15 . The method of  claim 14 , wherein the one or more voltage-gated sodium (Nav) channels are Nav1.1 channels. 
     
     
         16 . The method of  claim 14 , wherein the modulation comprises inhibition of Nav1.1 channel activation. 
     
     
         17 . A method for for treating an epilepsy disorder in a subject comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 9 . 
     
     
         18 . The method of  claim 17 , wherein the epilepsy disorder is Lennox-Gastaut Syndrome (LGS). 
     
     
         19 . A method for for treating seizure in a subject comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 9 .