Aryl substituted pyridines, pyrimidines, pyrazines and triazines and the use thereof

Abstract

This invention relates aryl substituted pyridines, pyrimidines, pyrazines and triazines of Formula I: or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein A 1 , A 2 , A 3 , R 1 —R 4 , X and Y are set in the specification. The invention is also directed to the use of compounds of Formula I for the treatment of neuronal damage following global and focal ischemia, for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), and for the treatment, prevention or amelioration of both acute or chronic pain, as antitinnitus agents, as anticonvulsants, and as antimanic depressants, as local anesthetics, as antiarrhythmics and for the treatment or prevention of diabetic neuropathy.

1 - 58 . (Cancelled).  
     
     
         59 . A compound having the Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: 
 Y is  
                     
 or R 7 ,  
 provided that when Y is R 7 , R 1  is aminocarbonyl;  
 A 1 , A 2  and A 3  are each CR 2 ; or A 2  is N and A 1  and A 3  are CR 2 ; or A 1  and A 3  are N and A 2  is CR 2 ; or A 1  and A 2  are N and A 3  is CR 2 ; or A 2  and A 3  are N and A 1  is CR 2 ;  
 R 1  is selected from the group consisting an optionally substituted alkyl, amino, alkylthiol, C(O)R 8 , SO 2 R 8 , OC(O)NH 2 , 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;  
 each R 2  is selected from the group consisting of hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino; or R 1  and R 2  are taken together with the carbon atoms to which they are attached to form a heterocyclic ring;  
 R 3 , R 4 , R 5 , and R 6  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;  
 R 7  is an optionally substituted alkyl;  
 R 8  is selected from the group consisting of alkyl, alkenyl, alkynyl, OR 9 , amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino, alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted, provided that R 8  is not OR 9  when R 1  is SO 2 R 8 ; wherein  
 R 9  is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkali metal; and  
 X is one of O, S, NH, or CH 2  when Y is other than R 7 ; or  
 X is one of O, S, NH, CH 2  or absent when Y is R 7 ;  
 with the provisos that:  
 1) R 2  is not methoxy if R 5  is trifluoromethyl, R 6  is H, X is O and R 1  is SO 2 CH 2 Ph;  
 2) R 2  is not NH 2  if R 1  is methylthio, X is O and two of A 1 , A 2  and A 3  are N;  
 3) R 2  is not methyl if R 1  is SO 2 R 8 , wherein R 8  is methylphenyl, R 3  and R 4  are methoxy, X is S and two of A 1 , A 2  and A 3  are N;  
 4) R 2  is not CCl 3  if R 1  is CCl 3 , X is S and two of A 1 , A 2  and A 3  are N; or  
 5) R 1  and R 2  are not both NH 2  if X is O or S and two of A 1 , A 2  and A 3  are N.  
 
     
     
         60 . A compound having the Formula II:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: 
 A 1 , A 2  and A 3  are each CR 2 ; or A 2  is N and A 1  and A 3  are CR 2 ; or A 1  and A 3  are N and A 2  is CR 2 ; or A 1  and A 2  are N and A 3  is CR 2 ; or A 2  and A 3  are N and A 1  is CR 2 ;  
 R 1  is selected from the group consisting an optionally substituted alkyl, amino, alkylthiol, C(O)R 8 , SO 2 R 8 , OC(O)NH 2 , 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;  
 each R 2  is selected from the group consisting of hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino; or R 1  and R 2  are taken together with the carbon atoms to which they are attached to form a heterocyclic ring;  
 R 3 , R 4 , R 5 , and R 6  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol; and  
 R 8  is selected from the group consisting of alkyl, alkenyl, alkynyl, OR 9 , amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino, alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted, provided that R 8  is not OR 9  when R 1  is SO 2 R 8 ; wherein  
 R 9  is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkali metal; and  
 X is one of O, S, NH, or CH 2 ;  
 with the provisos that:  
 1) R 2  is not methoxy if R 5  is trifluoromethyl, R 6  is H, X is O and R 1  is SO 2 CH 2 Ph;  
 2) R 2  is not NH 2  if R 1  is methylthio, X is O and two of A 1 , A 2  and A 3  are N;  
 3) R 2  is not methyl if R 1  is SO 2 R 8 , wherein R 8  is methylphenyl, R 3  and R 4  are methoxy, X is S and two of A 1 , A 2  and A 3  are N;  
 4) R 2  is not CCl 3  if R 1  is CCl 3 , X is S and two of A 1 , A 2  and A 3  are N; or  
 5) R 1  and R 2  are not both NH 2  if X is O or S and two of A 1 , A 2  and A 3  are N.  
 
     
     
         61 . The compound of  claim 60 , wherein A 1 , A 2  and A 3  are each CR 2 ; or A 2  is N and A 1  and A 3  are CR 2 ; or A 1  and A 3  are N and A 2  is CR 2 .  
     
     
         62 . The compound of  claim 60 , wherein R 1  is selected from the group consisting of an alkyl optionally substituted by halogen or hydroxy, C(O)R 8 , SO 2 R 8 , 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, and 5-isoxazolyl, wherein R 8  is as defined in  claim 60 , provided that R 8  is not OR 9  when R 1  is SO 2 R 8 .  
     
     
         63 . The compound of  claim 62 , wherein R 8  is selected from the group consisting of alkyl, alkenyl, OR 9 , amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, and heterocycloalkylamino, all of which can be optionally substituted.  
     
     
         64 . The compound of  claim 60 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aminoalkyl, amino, hydroxyalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino.  
     
     
         65 . The compound of  claim 64 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, alkoxy, aminoalkyl and aminocarbonyl.  
     
     
         66 . The compound of  claim 60 , wherein R 3 , R 4 , R 5 , and R 6  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, and cyano.  
     
     
         67 . The compound of  claim 66 , wherein R 3  and R 4  are both hydrogen and R 5  and R 6  are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, and nitro.  
     
     
         68 . The compound of  claim 60 , wherein X is O or S.  
     
     
         69 . The compound of  claim 68 , wherein X is O.  
     
     
         70 . The compound of  claim 60 , wherein R 2  is hydrogen, X is O or S and R 1  is aminocarbonyl.  
     
     
         71 . The compound of  claim 60 , wherein A 2  is CR 2 , wherein R 2  is other than H and A 1  and A 3  are each CH.  
     
     
         72 . The compound of  claim 60 , wherein A 2  is N, A 1  is CR 2 , wherein R 2  is other than H, and A 3  is CH.  
     
     
         73 . The compound of  claim 60 , having the Formula III:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein;  
         A 1 -A 3 , R 2 —R 6 , R 8  and X are as defined in  claim 60 .  
       
     
     
         74 . The compound of  claim 73 , wherein A 1 , A 2  and A 3  are each CR 2 ; or A 2  is N and A 1  and A 3  are CR 2 ; or A 1  and A 3  are N and A 2  is CR 2 .  
     
     
         75 . The compound of  claim 73 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aminoalkyl, amino, hydroxyalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino.  
     
     
         76 . The compound of  claim 75 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, alkoxy, aminoalkyl and aminocarbonyl.  
     
     
         77 . The compound of  claim 73 , wherein R 3 , R 4 , R 5 , and R 6  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, and cyano.  
     
     
         78 . The compound of  claim 77 , wherein R 3  and R 4  are both hydrogen and R 5  and R 6  are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, and nitro.  
     
     
         79 . The compound of  claim 73 , wherein R 8  is selected from the group consisting of alkyl, alkenyl, OR 9 , amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, and heterocycloalkylamino, all of which can be optionally substituted, provided that R 8  is not OR 9  when R 1  is SO 2 R 8 , and wherein R 9  is as defined in  claim 73 .  
     
     
         80 . The compound of  claim 73 , wherein X is O or S.  
     
     
         81 . The compound of  claim 80 , wherein X is O.  
     
     
         82 . The compound of  claim 73 , wherein 
 X is O;    A 1 , A 2  and A 3  are each CR 2 ; or A 2  is N and A 1  and A 3  are CR 2 ; or A 1  and A 3  are N and A 2  is CR 2 ; wherein    R 2  is selected from the group consisting of hydrogen, alkyl, alkoxy, aminoalkyl, and aminocarbonyl;    R 3  and R 4  are both hydrogen;    R 5  and R 6  are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, and nitro; and    R 8  is amino.    
     
     
         83 . The compound of  claim 73 , wherein A 2  is CR 2 , wherein R 2  is other than H and A 1  and A 3  are each CH.  
     
     
         84 . The compound of  claim 73 , wherein A 2  is N, A 1  is CR 2 , wherein R 2  is other than H, and A 3  is CH.  
     
     
         85 . The compound of  claim 60 , having Formula IV:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or solvate thereof; wherein:  
         A 1 -A 3 , R 2 —R 6 , and X are as defined in  claim 60  and  
         R 8  is selected from the group consisting of alkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted.  
       
     
     
         86 . The compound of  claim 85 , wherein A 1 , A 2  and A 3  are each CR 2 ; or A 2  is N and A 1  and A 3  are CR 2 ; or A 1  and A 3  are N and A 2  is CR 2 , and R 2  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aminoalkyl, amino, hydroxyalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino.  
     
     
         87 . The compound of  claim 86 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, alkoxy, aminoalkyl and aminocarbonyl.  
     
     
         88 . The compound of  claim 85 , wherein R 3 , R 4 , R 5 , and R 6  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, and cyano.  
     
     
         89 . The compound of  claim 88 , wherein R 3  and R 4  are both hydrogen and R 5  and R 6  are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, and nitro.  
     
     
         90 . The compound of  claim 85 , wherein R 8  is selected from the group consisting of alkyl, alkenyl, amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, and heterocycloalkylamino, all of which can be optionally substituted.  
     
     
         91 . The compound of  claim 85 , wherein X is O or S.  
     
     
         92 . The compound of  claim 91 , wherein X is O.  
     
     
         93 . A compound of  claim 60 , wherein said compound is: 
 2-methyl-6-(4-phenoxyphenyl)pyridine;    6-(4-phenoxyphenyl)pyridine-2-carboxamide;    2-methyl-6-[4-(4-fluorophenoxy)phenyl]pyridine;    6-(4-phenoxyphenyl)pyridine-2-carboxylic acid;    6-(4-phenoxyphenyl)pyridine-2-carboxylic acid methylamide;    6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxamide;    6-[4-(2,4-difluorophenoxy)phenyl]pyridine-2-carboxamide;    6-[4-(4-chloro-2-fluorophenoxy)phenyl]pyridine-2-carboxamide;    6-[4-(4-fluorophenoxy)-3-fluorophenyl]pyridine-2-carboxamide;    6-[4-(4-trifluoromethylphenoxy)phenyl]pyridine-2-carboxamide;    6-(4-phenoxyphenyl)pyrazine-2-carboxamide;    3,5-diamino-6-(4-phenoxyphenyl)pyrazine-2-carboxamide; or    2-[4-(4-nitrophenoxy)phenyl]-4-methyl-[1,3,5]-triazine,    or a pharmaceutically acceptable salt, prodrug or solvate thereof.    
     
     
         94 . A compound of  claim 59 , wherein said compound is: 
 6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid N-piperidinylethylamide;    6-(4-tert-butylphenyl)pyridine-2-carboxamide;    6-(4-n-butylphenyl)pyridine-2-carboxamide;    6-(4-i-propylphenyl)pyridine-2-carboxamide;    6-(4-thiomethylphenyl)pyridine-2-carboxamide;    6-(4-ethoxyphenyl)pyridine-2-carboxamide; or    6-(4-methoxyphenyl)pyridine-2-carboxamide,    or a pharmaceutically acceptable salt, prodrug or solvate thereof.    
     
     
         95 . The compound of  claim 59 , having the Formula V:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein;  
         A 1 -A 3 , R 2 —R 4 , and R 7  are as defined in  claim 59;  and  
         X is one of O, S, NH, CH 2  or absent.  
       
     
     
         96 . The compound of  claim 95 , wherein A 1 , A 2  and A 3  are each CR 2 ; or A 2  is N and A 1  and A 3  are CR 2 ; or A 1  and A 3  are N and A 2  is CR 2 .  
     
     
         97 . The compound of  claim 95 , wherein R 7  is a C 1-6  alkyl optionally substituted with one or more of halogen, hydroxy, nitro, amino, cyano and alkoxy.  
     
     
         98 . The compound of  claim 95 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, alkoxy, aminoalkyl and aminocarbonyl.  
     
     
         99 . The compound of  claim 95 , wherein R 3  and R 4  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, and cyano.  
     
     
         100 . The compound of  claim 99 , wherein R 3  and R 4  are both hydrogen.  
     
     
         101 . The compound of  claim 95 , wherein X is O or S.  
     
     
         102 . The compound of  claim 101 , wherein X is O.  
     
     
         103 . A compound of  claim 95 , wherein said compound is 6-[(4-trifluoromethoxy)phenyl]pyridine-2-carboxamide or a pharmaceutically acceptable salt, prodrug or solvate thereof.  
     
     
         104 . A pharmaceutical composition, comprising the compound of formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:  
         Y is  
         
           
             
             
                 
                 
             
           
         
          or R 7 , provided that when Y is R 7 , R 1  is aminocarbonyl;  
         A 1 , A 2  and A 3  are each CR 2 ; or A 2  is N and A 1  and A 3  are CR 2 ; or A 1  and A 3  are N and A 2  is CR 2 ; or A 1  and A 2  are N and A 3  is CR 2 ; or A 2  and A 3  are N and A 1  is CR 2 ;  
         R 1  is selected from the group consisting an optionally substituted alkyl, amino, alkylthiol, C(O)R8, SO 2 R 8 , OC(O)NH 2 , 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;  
         each R 2  is selected from the group consisting of hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino; or R 1  and R 2  are taken together with the carbon atoms to which they are attached to form a heterocyclic ring;  
         R 3 , R 4 , R 5 , and R 6  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;  
         R 7  is an optionally substituted alkyl;  
         R 8  is selected from the group consisting of alkyl, alkenyl, alkynyl, OR 9 , amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino, alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted, provided that R8 is not OR 9  when R 1  is SO 2 R 8 ; wherein  
         R 9  is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkali metal; and  
         X is one of O, S, NH, or CH 2  when Y is other than R 7 ; or  
         X is one of O, S, NH, CH 2  or absent when Y is R 7 ; and a pharmaceutically acceptable carrier or diluent;  
         with the proviso that R 1  and R 2  are not both NH 2  if X is O or S and two of A 1 , A 2  and A 3  are N.  
       
     
     
         105 . A pharmaceutical composition, comprising a compound as claimed in  claim 59  or  60 , and a pharmaceutically acceptable carrier or diluent.  
     
     
         106 . A method of treating a disorder responsive to the blockade of sodium channels in a mammal suffering therefrom, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:  
         Y is  
         
           
             
             
                 
                 
             
           
         
         or R 7 ,  
         provided that when Y is R 7 , R 1  is aminocarbonyl;  
         A 1 , A 2  and A 3  are each CR 2 ; or A 2  is N and A 1  and A 3  are CR 2 ; or A 1  and A 3  are N and A 2  is CR 2 ; or A 1  and A 2  are N and A 3  is CR 2 ; or A 2  and A 3  are N and A 1  is CR 2 ;  
         R 1  is selected from the group consisting an optionally substituted alkyl, amino, alkylthiol, C(O)R 8 , SO 2 R 8 , OC(O)NH 2 , 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;  
         each R 2  is selected from the group consisting of hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino; or R 1  and R 2  are taken together with the carbon atoms to which they are attached to form a heterocyclic ring;  
         R 3 , R 4 , R 5 , and R 6  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;  
         R 7  is an optionally substituted alkyl;  
         R 8  is selected from the group consisting of alkyl, alkenyl, alkynyl, OR 9 , amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino, alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted, provided that R 8  is not OR 9  when R 1  is SO 2 R 8 ; wherein  
         R 9  is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkali metal; and  
         X is one of O, S, NH, or CH 2  when Y is other than R 7 ; or  
         X is one of O, S, NH, CH 2  or absent when Y is R 7 .  
       
     
     
         107 . A method of treating a disorder responsive to the blockade of sodium channels in a mammal suffering therefrom, comprising administering to a mammal in need of such treatment an effective amount of a compound as claimed in  claim 59  or  60 .  
     
     
         108 . A method for treating, preventing or ameliorating neuronal loss following global and focal ischemia; treating, preventing or ameliorating neurodegenerative conditions; treating, preventing or ameliorating pain or tinnitus; treating, preventing or ameliorating manic depression; providing local anesthesia; or treating arrhythmias, or treating convulsions, comprising administering to a mammal in need of such treatment an effective amount of a compound formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:  
         Y is  
         
           
             
             
                 
                 
             
           
         
         or R 7 ,  
         provided that when Y is R 7 , R 1  is aminocarbonyl;  
         A 1 , A 2  and A 3  are each CR 2 ; or A 2  is N and A 1  and A 3  are CR 2 ; or A 1  and A 3  are N and A 2  is CR 2 ; or A 1  and A 2  are N and A 3  is CR 2 ; or A 2  and A 3  are N and A 1  is CR 2 ;  
         R 1  is selected from the group consisting an optionally substituted alkyl, amino, alkylthiol, C(O)R 8 , SO 2 R 8 , OC(O)NH 2 , 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;  
         each R 2  is selected from the group consisting of hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino; or R 1  and R 2  are taken together with the carbon atoms to which they are attached to form a heterocyclic ring;  
         R 3 , R 4 , R 5 , and R 6  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;  
         R 7  is an optionally substituted alkyl;  
         R 8  is selected from the group consisting of alkyl, alkenyl, alkynyl, OR 9 , amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino, alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted, provided that R 8  is not OR 9  when R 1  is SO 2 R 8 ; wherein  
         R 9  is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkali metal; and  
         X is one of O, S, NH, or CH 2  when Y is other than R 7 ; or  
         X is one of O, S, NH, CH 2  or absent when Y is R 7 .  
       
     
     
         109 . A method for treating, preventing or ameliorating neuronal loss following global and focal ischemia; treating, preventing or ameliorating neurodegenerative conditions; treating, preventing or ameliorating pain or tinnitus; treating, preventing or ameliorating manic depression; providing local anesthesia; or treating arrhythmias, or treating convulsions, comprising administering to a mammal in need of such treatment an effective amount of a compound as claimed in  claim 59  or  60 .  
     
     
         110 . The method of  claim 108 , wherein the method is for treating, preventing or ameliorating pain and said pain is one of neuropathic pain, surgical pain or chronic pain.  
     
     
         111 . A method of alleviating or preventing seizure activity in an animal subject, comprising administering to said animal in need of such treatment an effective amount of a compound of formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:  
         Y is  
         
           
             
             
                 
                 
             
           
         
         or R 7 ,  
         provided that when Y is R 7 , R 1  is aminocarbonyl;  
         A 1 , A 2  and A 3  are each CR 2 ; or A 2  is N and A 1  and A 3  are CR 2 ; or A 1  and A 3  are N and A 2  is CR 2 ; or A 1  and A 2  are N and A 3  is CR 2 ; or A 2  and A 3  are N and A 1  is CR 2 ;  
         R 1  is selected from the group consisting an optionally substituted alkyl, amino, alkylthiol, C(O)R 8 , SO 2 R 8 , OC(O)NH 2 , 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;  
         each R 2  is selected from the group consisting of hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino; or R 1  and R 2  are taken together with the carbon atoms to which they are attached to form a heterocyclic ring;  
         R 3 , R 4 , R 5 , and R 6  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;  
         R 7  is an optionally substituted alkyl;  
         R 8  is selected from the group consisting of alkyl, alkenyl, alkynyl, OR 9 , amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino, alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted, provided that R 8  is not OR 9  when R 1  is SO 2 R 8 ; wherein  
         R 9  is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkali metal; and  
         X is one of O, S, NH, or CH 2  when Y is other than R 7 ; or  
         X is one of O, S, NH, CH 2  or absent when Y is R 7 .  
       
     
     
         112 . A method of alleviating or preventing seizure activity in an animal subject, comprising administering to said animal in need of such treatment an effective amount of a compound as claimed in  claim 59  or  60 .