Sodium channel blockers

Abstract

The present invention relates to sodium channel blockers. The present invention also includes a variety of methods of treatment using these inventive sodium channel blockers.

1 . (canceled) 
     
     
         2 . A method of preparing a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a salt thereof, the method comprising a step of reacting a compound of the formula: 
       
       
         
           
           
               
               
           
         
         or a salt thereof, with a compound of the formula: HNR 3 R 4 , or a salt thereof, wherein:
 X is hydrogen, halogen, trifluoromethyl, lower alkyl, unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-lower alkyl-thio, lower alkyl-sulfonyl, or phenyl-lower alkyl-sulfonyl; 
 Y is hydrogen, hydroxyl, mercapto, lower alkoxy, lower alkyl-thio, halogen, lower alkyl, unsubstituted or substituted mononuclear aryl, or —N(R 2 ) 2 ; 
 R 1  is hydrogen or lower alkyl; 
 each R 2  is independently —R 7 , —(CH 2 ) m —OR 8 , —(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 R 10 , —(CH 2 ) n —(Z) g -R 7 , —(CH 2 ) m NR 10 -CH 2 (CHOR 8 )(CHOR 8 ) n CH 2 OR 8 , —(CH 2 ) n CO 2 R 7 , or 
 
       
       
         
           
           
               
               
           
         
         
           R 3  and R 4  are each independently hydrogen, a group represented by Formula (A), lower alkyl, hydroxyl lower alkyl, phenyl, phenyl-lower alkyl, (halophenyl)-lower alkyl, lower-(alkylphenylalkyl), lower (alkoxyphenyl)-lower alkyl, naphthyl-lower alkyl, or pyridyl-lower alkyl, with the proviso that at least one of R 3  and R 4  is a group represented by Formula (A): 
         
       
       
         
           
           
               
               
           
         
         and wherein:
 each R L  is independently —R 7 , —(CH 2 ) n —OR 8 , —O—(CH 2 ) m —OR 8 , —(CH 2 ) n —NR 7 R 10 , —O—(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —O—(CH 2 CH 2 O) m —R 8 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —O—(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 R 10 , —O—(CH 2 ) m —C(═O)NR 7 R 10 , —(CH 2 ) n —(Z) g —R 7 , —O—(CH 2 ) m —(Z) g —R 7 , —(CH 2 ) n —NR 10 -CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m —NR 10 -CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 ) n —CO 2 R 7 , —O—(CH 2 ) m —CO 2 R 7 , —OSO 3 H, —O-glucuronide, —O-glucose, 
 
       
       
         
           
           
               
               
           
         
         
           each o is independently an integer from 0 to 10; 
           each p is an integer from 0 to 10; 
           with the proviso that the sum of o and p in each contiguous chain is from 1 to 10; 
           each x is independently O, NR 10 , C(═O), CHOH, C(═N—R 10 ), CHNR 7 R 10 , or a single bond; 
           each R 5  is independently —(CH 2 ) m —OR 8 , —O—(CH 2 ) m —OR 8 , —(CH 2 ) n —NR 7 R 10 , —O—(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —O—(CH 2 CH 2 O) m —R 8 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —O—(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 R 10 , —O—(CH 2 ) m —C(═O)NR 7 R 10 , —(CH 2 ) n —(Z) g -R 7 , —O—(CH 2 ) m —(Z) g -R 7 , —(CH 2 ) n —NR 10 -CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m —NR 10 -CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 ) n —CO 2 R 7 , —O—(CH 2 ) m —CO 2 R 7 , —OSO 3 H, —O-glucuronide, —O-glucose, 
         
       
       
         
           
           
               
               
           
         
         
           each R 6  is independently —R 7 , —OR 11 , —N(R 7 ) 2 , —(CH 2 ) m —OR 8 , —O—(CH 2 ) m —OR 8 , —(CH 2 ) n —NR 7 R 10 , —O—(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —O—(CH 2 CH 2 O) m -R 8 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —O—(CH 2 CH 20 ) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 R 10 , —O—(CH 2 ) m —C(═O)NR 7 R 10 , —(CH 2 ) n —(Z) g -R 7 , —O—(CH 2 ) m —(Z) g -R 7 , —(CH 2 ) n —NR 10 -CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m —NR 10 -CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 ) n —CO 2 R 7 , —O—(CH 2 ) m —CO 2 R 7 , —OSO 3 H, —O-glucuronide, —O-glucose, 
         
       
       
         
           
           
               
               
           
         
         
           wherein when two R 6  are —OR 11  and are located adjacent to ech other on a phenyl ring, the alkyl moieties of the two R 6  may be bonded together to form a methylenedioxy group; 
           each R 7  is independently hydrogen or lower alkyl; 
           each R 8  is independently hydrogen, lower alkyl, —C(═O)-R 11 , glucuronide, 2-tetrahydropyranyl, or 
         
       
       
         
           
           
               
               
           
         
         
           each R 9  is independently —CO 2 R 7 , —CON(R 7 ) 2 , —SO 2 CH 3 , or C(═O)R 7 ; 
           each R 10  is independently —H, —SO 2 CH 3 , —CO 2 R 7 , —C(═O)NR 7 R 9 , —C(═O)R 7 , or CH 2 —(CHOH) n CH 2 OH; 
           each Z is independently CHOH, C(═O), CHNR 7 R 10 , C═NR 10 , or NR 10 ; 
           each R 11  is independently lower alkyl; 
           each g is independently an integer from 1 to 6; 
           each m is independently an integer from 1 to 7; 
           each n is independently an integer from 0 to 7; and 
           each Q is independently C—R 5  or C—R 6 , wherein one Q is C—R 5 . 
         
       
     
     
         3 . The method of  claim 2 , wherein the compound of the formula: 
       
         
           
           
               
               
           
         
         is of the formula: 
       
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         4 . The method of  claim 3 , wherein the compound of the formula: 
       
         
           
           
               
               
           
         
         is in the form of a hydroxide salt. 
       
     
     
         5 . The method of  claim 2 , wherein the reaction is carried out in the presence of a base. 
     
     
         6 . The method of  claim 5 , wherein the base is diisopropylethylamine or triethylamine. 
     
     
         7 . The method of  claim 2 , wherein the reaction is carried out in a solvent. 
     
     
         8 . The method of  claim 7 , wherein the solvent is THF or ethanol. 
     
     
         9 . The method of  claim 2 , wherein the reaction is carried out at elevated temperature. 
     
     
         10 . The method of  claim 8 , where the reaction is carried out at about 66° C. 
     
     
         11 . The method of  claim 2  further comprising a step of purifying the compound of Formula (I), or a salt thereof, via chromatography or recrystallization. 
     
     
         12 . The method of  claim 2 , wherein each instance of R 1 , R 2 , and R 3  is hydrogen. 
     
     
         13 . The method of  claim 2 , wherein X is chlorine. 
     
     
         14 . The method of  claim 2 , wherein Y is —NH 2 . 
     
     
         15 . The method of  claim 2 , wherein R 4  is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 2 , wherein R 4  is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 2 , wherein R 4  is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 2 , wherein:
 each instance of R 1 , R 2 , and R 3  is hydrogen;   R 4  is of the formula:   
       
         
           
           
               
               
           
         
       
       and x is a single bond. 
     
     
         19 . The method of  claim 18 , wherein X is chlorine. 
     
     
         20 . The method of  claim 18 , wherein Y is NH 2 . 
     
     
         21 . The method of  claim 18 , wherein R 5  is —O—(CH 2 ) m (Z) g -R 7 . 
     
     
         22 . The method of  claim 21 , wherein g is 1; and Z is NR 10 . 
     
     
         23 . The method of  claim 21 , wherein R 10  is CH 2 —(CHOH) n CH 2 OH.