Use of aryl nitrone compounds in methods for treating neuropathic pain

Abstract

3,4,5-trisubstituted aryl nitrone compounds having the formula: where R 1 -R 4 are as defined in the specification are useful as therapeutics for neuropathic pain conditions in mammals.

1 - 35  (Canceled)  
     
     
         36 : A method for treating neuropathic pain in a patient comprising administering an effective neuropathic pain-treating dose of a pharmaceutical composition comprising a compound of formula I:  
       
         
           
           
               
               
           
         
         wherein  
         R 1  is selected from the group consisting of hydrogen, and  
         
           
             
             
                 
                 
             
           
         
         each R 2  is independently selected from a group of the formula:  
         
           
             
             
                 
                 
             
           
         
         R 3  is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl;  
         R 4  is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;  
         R 5  is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;  
         R 10  is selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl; or R 1  and R 10  can be joined to form an alkylene, substituted alkylene, —C(O)—, —S(O)— or —S(O) 2 — group;  
         R 11  and R 12  are independently selected from the group consisting of lower alkyl and lower cycloalkyl; or R 11  and R 12  can be joined to form an alkylene group having from 2 to 10 carbon atoms; and  
         W is oxygen or sulfur; or a pharmaceutically-acceptable salt thereof.  
       
     
     
         37 : The method of  claim 36 , wherein W is oxygen.  
     
     
         38 : The method of  claim 37 , wherein R 3  is hydrogen or lower alkyl.  
     
     
         39 : The method of  claim 38 , wherein R 3  is hydrogen.  
     
     
         40 : The method of  claim 39 , wherein R 4  is selected from the group consisting of alkyl, substituted alkyl and cycloalkyl.  
     
     
         41 : The method of  claim 40 , wherein R 4  is selected from the group consisting of methyl, n-propyl, isopropyl, 1-hydroxy-2-methylprop-2-yl, n-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy)but-1-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl.  
     
     
         42 : The method of  claim 39 , wherein R 5  is selected from the group consisting of alkyl and cycloalkyl.  
     
     
         43 : The method of  claim 42 , wherein R 5  is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and n-butyl.  
     
     
         44 : The method of  claim 39 , wherein R 10 , R 11  and R 12  are independently lower alkyl.  
     
     
         45 : The method of  claim 44 , wherein R 10 , R 11  and R 12  are methyl.  
     
     
         46 : The method of  claim 36 , wherein the compound is of formula IA:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 4  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl.  
 
     
     
         47 : The method of  claim 46 , wherein R 4  is an alkyl of from 3 to 8 carbon atoms.  
     
     
         48 : The method of  claim 47 , wherein R 4  is tert-butyl.  
     
     
         49 : The method of  claim 47 , wherein R 4  is tert-octyl.  
     
     
         50 : The method of  claim 36 , wherein the compound is of formula II:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 5  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and  
 R 4  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl;  
 or a pharmaceutically-acceptable salt thereof.  
 
     
     
         51  The method of  claim 46 , wherein R 5  is lower alkyl and R 4  is selected from the group consisting of alkyl, substituted alkyl and cycloalkyl.  
     
     
         52  The method of  claim 36 , wherein the compound is selected from the group consisting of: 
 α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone  
 α-(4-isobutanoyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone  
 α-(4-n-butanoyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone  
 α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-isopropylnitrone  
 α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-1-hydroxy-2-methylprop-2-ylnitrone  
 α-(4-n-pentanoyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone  
 α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-4-trifluoromethylbenzylnitrone  
 α-(4-propionyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone  
 α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-methylnitrone  
 α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-3,4,5-trimethoxybenzylnitrone  
 α-(4-hydroxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone  
 α-(4-hydroxy-3,5-di-tert-butylphenyl)-N-tert-octylnitrone  
 α-(4-hydroxy-3,5-dimethoxyphenyl)-N-tert-butylnitrone  
 α-(4-hydroxy-3,5-dimethoxyphenyl)-N-tert-butylnitrone  
 α-(4-hydroxy-3,5-dimethylphenyl)-N-hexylnitrone  
 α-(4-hydroxy-3,5-dimethylphenyl)-N-tert-butylnitrone  
 α-(4-hydroxy-3,5-di-tert-butylphenyl)-N-(1,1-dimethyl-2-hydroxyethyl)nitrone  
 α-(4-hydroxy-3,5-di-tert-butylphenyl)-N-(1,1-dimethylpropyl)nitrone  
 α-(4-hydroxy-3,5-di-tert-butylphenyl)-N-(1-methylethyl)nitrone  
 α-(4-hydroxy-3,5-di-tert-butylphenyl)-N-benzylnitrone 
 and pharmaceutically acceptable salts thereof.  
 
 
     
     
         53 : The method of  claim 36 , wherein the compound is α-(4-hydroxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone  
     
     
         54 : The method of  claim 36 , wherein the compound is α-(4-hydroxy-3,5-di-tert-butylphenyl)-N-tert-octylnitrone  
     
     
         55 : The method of  claim 36 , wherein the compound is α-(4-acetoxy-3,5-di-tert-butylphenyl)-N-tert-octylnitrone  
     
     
         56 : The method of  claim 36 , wherein the compound is α-(4-n-butanoyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone  
     
     
         57 : A pharmaceutical composition for the treatment of neuropathic pain comprising a pharmaceutically acceptable carrier and a pharmaceutically effective neuropathic pain-treating amount of a compound of formula I:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is selected from the group consisting of hydrogen and  
                     
 each R 2  is independently selected from a group of the formula:  
                     
 R 3  is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl;  
 R 4  is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;  
 R 5  is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;  
 R 10  is selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl; or R 1  and R 10  can be joined to form an alkylene, substituted alkylene, —C(O)——S(O)— or —S(O) 2 — group;  
 R 11  and R 12  are independently selected from the group consisting of lower alkyl and lower cycloalkyl; or R 11  and R 12  can be joined to form an alkylene group having from 2 to 10 carbon atoms; and  
 W is oxygen or sulfur;  
 or a pharmaceutically-acceptable salt thereof.  
 
     
     
         58 : The pharmaceutical composition of  claim 57 , wherein the compound is α-(4-hydroxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone.  
     
     
         59 : The pharmaceutical composition of  claim 57 , wherein the compound is α-(4-hydroxy-3,5-di-tert-butylphenyl)-N-tert-octylnitrone.