New medical use of triazine derivatives

Abstract

Compounds of formula (I): especially where R 1 is an optionally substituted alkyl, aralkyl or heterocyclyl-alkyl group, are shown to have activity as sodium channel blockers or as antifolates. Some novel compounds where R 1 is an aralkyl or heterocyclyl-alkyl are disclosed.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a salt or solvate thereof, in which
 R 1  is C 1-3 alkylaryl or C 1-3  alkyl-heterocyclyl, which is optionally substituted by any one of halogen, halo C 1-6  alkyl, C 1-6  alkyl or C 1-6 alkoxy, excluding unsubstituted benzyl; 
 R 2  is selected from halogen, C 1-6  alkyl, alkenyl, alkynyl or alkoxy, amino, mono- or di-substituted amino, alkenyloxy, acyl, acyloxy, cyano, nitro, aryl and alkylthio groups; and 
 R 3  to R 6  are independently selected from hydrogen, halogen, C 1-6  alkyl, alkenyl, alkynyl or alkoxy, amino, mono- or di-substituted amino, alkenyloxy, acyl, acyloxy, cyano, nitro, aryl and alkylthio groups. 
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is substituted benzyl, piperidinyl-methyl, furyl-methyl, or thienyl-methyl. 
     
     
         3 . The compound of  claim 2 , wherein R 1  is substituted benzyl, in which the phenyl group is optionally substituted by one or more of halogen, halo C 1-6  alkyl, or C 1-6  alkoxy. 
     
     
         4 . The compound of  claim 1 , wherein R 2  to R 6  are independently selected from hydrogen and halogen. 
     
     
         5 . The compound of  claim 4 , wherein the halogen is chloride. 
     
     
         6 . The compound of  claim 1 , selected from
 5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(2′-fluorophenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(3′-fluorophenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(4′-fluorophenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(2′,3′-fluorophenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(3′-chlorophenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(4′-chlorophenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(4′-methylphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(2′-methoxyphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(3′-methoxyphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(4′-methoxyphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(2′-chlorophenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(2′-trifluoromethylphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(3′-trifluoromethylphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(4′-trifluoromethylphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(2′-fluoro-3′-trifluoromethylphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(3-thienyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(3-furyl-methyl)-1,2,4-triazine; and   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(piperidin-4-yl-methyl)-1,2,4-triazine.   
     
     
         7 . A method for the treatment of epilepsy, multiple sclerosis, glaucoma and uveitis, cerebral traumas and cerebral ischaemias, stroke, head injury, spinal cord injury, surgical trauma, neurodegenerative disorders, motorneurone disease, Alzheimer's disease, Parkinson's disease, chronic inflammatory pain, neuropathic pain, migraine, bipolar disorder, mood, anxiety and cognitive disorders, schizophrenia or trigeminal autonomic cephalalgias in a patient suffering from one of said disorders, comprising administering to said patient an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a salt or solvate thereof, in which
 R 1  is C 1-3  alkylaryl or C 1-3  alkyl-heterocyclyl, which is optionally substituted by any one of halogen, halo C 1-6  alkyl, C 1-6  alkyl or C 1-6  alkoxy, excluding unsubstituted benzyl; 
 R 2  is selected from halogen, C 1-6  alkyl, alkenyl, alkynyl or alkoxy, amino, mono- or di-substituted amino, alkenyloxy, acyl, acyloxy, cyano, nitro, aryl and alkylthio groups; and 
 R 3  to R 6  are independently selected from hydrogen, halogen, C 1-6  alkyl, alkenyl, alkynyl or alkoxy, amino, mono- or di-substituted amino, alkenyloxy, acyl, acyloxy, cyano, nitro, aryl and alkylthio groups. 
 
     
     
         8 . The method of  claim 7 , wherein R 1  is substituted benzyl, piperidinyl-methyl, furyl-methyl, or thienyl-methyl. 
     
     
         9 . The method of  claim 8 , wherein R 1  is substituted benzyl, in which the phenyl group is optionally substituted by one or more halogen, halo C 1-6  alkyl, or C 1-6  alkoxy. 
     
     
         10 . The method of  claim 7 , wherein R 2  to R 6  are independently selected from hydrogen and halogen. 
     
     
         11 . The method of  claim 10 , wherein the halogen is chloride. 
     
     
         12 . The method of  claim 7 , wherein the compound of formula (I) is selected from
 5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(2′-fluorophenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(3′-fluorophenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(4′-fluorophenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(2′,3′-fluorophenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(3′-chlorophenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(4′-chlorophenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(4′-methylphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(2′-methoxyphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(3′-methoxyphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(4′-methoxyphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(2′-chlorophenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(2′-trifluoromethylphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(3′-trifluoromethylphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(4′-trifluoromethylphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(2′-fluoro-3′-trifluoromethylphenyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(3-thienyl-methyl)-1,2,4-triazine;   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(3-furyl-methyl)-1,2,4-triazine; and   5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(piperidin-4-yl-methyl)-1,2,4-triazine.