Methods of Treating Neuropathic Pain with Benzimidazole Derivative Agonists of PPARgamma

Abstract

Embodiments of the invention relate to the treatment of neuropathic pain in mammals. Embodiments of the invention include methods for treating neuropathic pain with benzimidazole derivatives with PPARgamma agonist activity, as well as methods for preparing medicaments used in such treatments of mammalian pain.

We claim: 
     
         1 . A method of treating neuropathic pain, comprising administering a pharmaceutical composition to a mammal in need of such treatment, wherein the pharmaceutical composition comprises a therapeutically effective amount of an agonist of PPARγ of Formula I: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents a hydrogen atom, an arylsulfonyl group, or a lower alkyl group; said lower alkyl group may be substituted by an aryl group or an aryl group substituted by one or two substituents selected from a halogen atom, a haloaryl group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a cyano group, an aryl group, an aryl-lower alkyloxy group, an arylsulfonyl-lower alkyl group, an aryl-lower alkyl group, a haloaryl-lower alkyloxy group, an arylsulfonylamino group, an arylcarbonylamino group, an arylcarbonyl group, an arylalkenyl group, a cyanoaryl group, and a heterocyclic group, or by a heterocyclic group; 
         R 2  represents a hydrogen atom, a lower cycloalkyl group, a hydroxyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group, an amino group, a lower alkylamino group, a carboxyl group, an aryl group, or a lower alkyl group; said lower alkyl group may be substituted by a halogen atom, a lower alkoxy group, a cyano group, a halocarbonyl group, an aryl group, or a heterocyclic group; 
         R 25  represents an alkyl group having up to 8 carbon atoms, a lower cycloalkyl group, a halo-lower alkyl group, a tri-lower alkylsilyl-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, an aryl group, a heterocyclic group, an aryl-lower alkyl group, or a hydroxy-lower alkyl group; said aryl group may be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a nitro group; 
         R 26  represents a hydrogen atom or a lower alkyl group; provided that, when R 25  and R 26  are both lower alkyl groups, they may be bonded together to form a ring; 
         Y represents a carbonyl group or a lower alkylene group; 
         A represents a single bond, or a lower alkylene or alkenylene group; 
         R 4 ′ represents a hydrocarbon group or a halogenated hydrocarbon group; and 
         n means an integer from 0 to 3;
 wherein 
 the arylsulfonyl group is selected from a benzenesulfonyl group, a toluenesulfonyl group, and a naphthalenesulfonyl group; 
 the term “lower” indicates that the group has from 1 to 6 carbon atoms, unless otherwise specifically indicated; 
 the aryl group is selected from a phenyl group and a naphthyl group, which may optionally be substituted by one or more substituents selected from a halogen atom, a lower alkyl group, a cyano group, a nitro group and a trifluoromethyl group; 
 the halo-lower alkyl group is a linear or branched alkyl group having up to 8 carbon atoms, which is substituted with one or more halogen atoms; 
 the heterocyclic group is selected from a pyridyl group, a quinolyl group, an isoquiriolyl group, a thiazolyl group, a thiadiazolyl group, a benzofuranyl group, a dibenzofuranyl group, a thianaphthalenyl group, a 1H-1,2,3-triazolyl group, a 1,2,4-triazolyl group, a tetrazolyl group, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrimidinyl group, an indolyl group, a benzimidazolyl group, which groups may optionally be substituted by one or more substituents of halogen atoms and lower alkyl groups; and 
 the lower cycloalkyl group is a cycloalkyl group having from 3 to 7 carbon atoms 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         2 . The method of treating neuropathic pain of  claim 1 , wherein the mammal is a human. 
     
     
         3 . The method of treating neuropathic pain of  claim 2 , wherein the agonist of PPARγ is 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The method of treating neuropathic pain of  claim 2 , wherein the agonist of PPARγ is a compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         R 27  represents a hydrogen atom, a lower alkyl group, an arylsulfonyl group or an aryl-lower alkyl group; wherein the aromatic ring moiety in said aryl-lower alkyl group may be substituted by one or two substituents selected from a halogen atom, a lower alkyl group, a halo-lower alkyl group, a cyanoaryl group, an amino group, a lower alkoxy group, a nitro group, a cyano group, an aryl group, a haloaryl group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, an aryl-lower alkyloxy group, an aryl-lower alkyl group, a heterocyclic group, an arylcarbonyl group, an arylcarbonylamino group, and an aryl-lower alkyloxy group substituted by one or two halogen atoms; 
         R 28  represents a hydrogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy-lower alkyl group, a lower cycloalkyl group, an aryl group, an aryl-lower alkyl group, a lower alkylamino group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, a mercapto group, an amino group, or a carboxyl group; 
         R 25  represents an alkyl group having up to 8 carbon atoms, a halo-lower alkyl group, a tri-lower alkylsilyl-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, an aryl group, a heterocyclic group, an aryl-lower alkyl group, or a hydroxy-lower alkyl group; said aryl group may be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a nitro group; 
         R 26  represents a hydrogen atom or a lower alkyl group; provided that, when R 25  and R 26  are both lower alkyl groups, they may be bonded together to form a ring; 
         Y represents a carbonyl group or a lower alkylene group; 
         A represents a single bond, or a lower alkylene or alkenylene group; and 
         R 29  represents a hydrogen atom or a lower alkyl group. 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The method of treating neuropathic pain of  claim 4 , wherein
 R 27  represents an aryllower alkyl group whose aryl moiety may be substituted by one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, a halo-lower alkyl group, a cyanoaryl group, an amino group, a lower alkoxy group, a nitro group, a cyano group, an aryl group, a haloaryl group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, an aryl-lower alkyloxy group, an aryl-lower alkyl group, a heterocyclic group, an arylcarbonyl group, an arylcarbonylamino group, and an aryl-lower alkyloxy group substituted by one or two halogen atoms;   Y represents a carbonyl group; and   A represents a single bond.   
     
     
         6 . The method of treating neuropathic pain of  claim 5 , wherein
 R 27  represents an aryl lower alkyl group whose aryl moiety may be substituted by one or two substituents selected from a halogen atom or an aryl group;   R 28  represents a lower alkyl group or a lower cycloalkyl group;   R 25  represents an alkyl group having up to 8 carbon atoms or an aryl group;   Y represents a carbonyl group; and   A represents a single bond.   
     
     
         7 . The method of treating neuropathic pain of  claim 2 , wherein the agonist of PPARγ is selected from the group consisting of 6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole, 1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole, 1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-ethylbenzimidazole, 6-benzenesulfonylcarbamoyl-2-cyclopropyl-1-(2-fluorobenzyl)-benzimidazole, 6-benzenesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 6-benzenesulfonylcarbamoyl-1-(2,4-difluorobenzyl)-2-methylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, and pharmaceutically acceptable salts thereof. 
     
     
         8 . A method of treating pain associated with postherpetic neuralgia, trigeminal neuralgia, AIDS-related neuropathy, causalgia, diabetic neuropathy, chronic low back pain, back or neck pain with neuropathic involvement, phantom limb pain, atypical facial pain or cancer neuropathy, comprising administering a pharmaceutical composition to a mammal in need of such treatment, wherein the pharmaceutical composition comprises a therapeutically effective amount of an agonist of PPARγ of Formula I: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents a hydrogen atom, an arylsulfonyl group, or a lower alkyl group; said lower alkyl group may be substituted by an aryl group or an aryl group substituted by one or two substituents selected from a halogen atom, a haloaryl group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a cyano group, an aryl group, an aryl-lower alkyloxy group, an arylsulfonyl-lower alkyl group, an aryl-lower alkyl group, a haloaryl-lower alkyloxy group, an arylsulfonylamino group, an arylcarbonylamino group, an arylcarbonyl group, an arylalkenyl group, a cyanoaryl group, and a heterocyclic group, or by a heterocyclic group; 
         R 2  represents a hydrogen atom, a lower cycloalkyl group, a hydroxyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group, an amino group, a lower alkylamino group, a carboxyl group, an aryl group, or a lower alkyl group; said lower alkyl group may be substituted by a halogen atom, a lower alkoxy group, a cyano group, a halocarbonyl group, an aryl group, or a heterocyclic group; 
         R 25  represents an alkyl group having up to 8 carbon atoms, a lower cycloalkyl group, a halo-lower alkyl group, a tri-lower alkylsilyl-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, an aryl group, a heterocyclic group, an aryl-lower alkyl group, or a hydroxy-lower alkyl group; said aryl group may be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a nitro group; 
         R 26  represents a hydrogen atom or a lower alkyl group; provided that, when R 25  and R 26  are both lower alkyl groups, they may be bonded together to form a ring; 
         Y represents a carbonyl group or a lower alkylene group; 
         A represents a single bond, or a lower alkylene or alkenylene group; 
         R 4 ′ represents a hydrocarbon group or a halogenated hydrocarbon group; and 
         n means an integer from 0 to 3;
 wherein 
 the arylsulfonyl group is selected from a benzenesulfonyl group, a toluenesulfonyl group, and a naphthalenesulfonyl group; 
 the term “lower” indicates that the group has from 1 to 6 carbon atoms, unless otherwise specifically indicated; 
 the aryl group is selected from a phenyl group and a naphthyl group, which may optionally be substituted by one or more substituents selected from a halogen atom, a lower alkyl group, a cyano group, a nitro group and a trifluoromethyl group; 
 the halo-lower alkyl group is a linear or branched alkyl group having up to 8 carbon atoms, which is substituted with one or more halogen atoms; 
 the heterocyclic group is selected from a pyridyl group, a quinolyl group, an isoquiriolyl group, a thiazolyl group, a thiadiazolyl group, a benzofuranyl group, a dibenzofuranyl group, a thianaphthalenyl group, a 1H-1,2,3-triazolyl group, a 1,2,4-triazolyl group, a tetrazolyl group, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrimidinyl group, an indolyl group, a benzimidazolyl group, which groups may optionally be substituted by one or more substituents of halogen atoms and lower alkyl groups; and 
 the lower cycloalkyl group is a cycloalkyl group having from 3 to 7 carbon atoms 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         9 . The method of treating pain of  claim 8 , wherein the mammal is a human. 
     
     
         10 . The method of treating pain of  claim 9 , wherein the agonist of PPARγ is 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method of treating pain of  claim 9 , wherein the agonist of PPARγ is a compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         R 27  represents a hydrogen atom, a lower alkyl group, an arylsulfonyl group or an aryl-lower alkyl group; wherein the aromatic ring moiety in said aryl-lower alkyl group may be substituted by one or two substituents selected from a halogen atom, a lower alkyl group, a halo-lower alkyl group, a cyanoaryl group, an amino group, a lower alkoxy group, a nitro group, a cyano group, an aryl group, a haloaryl group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, an aryl-lower alkyloxy group, an aryl-lower alkyl group, a heterocyclic group, an arylcarbonyl group, an arylcarbonylamino group, and an aryl-lower alkyloxy group substituted by one or two halogen atoms; 
         R 28  represents a hydrogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy-lower alkyl group, a lower cycloalkyl group, an aryl group, an aryl-lower alkyl group, a lower alkylamino group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, a mercapto group, an amino group, or a carboxyl group; 
         R 25  represents an alkyl group having up to 8 carbon atoms, a halo-lower alkyl group, a tri-lower alkylsilyl-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, an aryl group, a heterocyclic group, an aryl-lower alkyl group, or a hydroxy-lower alkyl group; said aryl group may be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a nitro group; 
         R 26  represents a hydrogen atom or a lower alkyl group; provided that, when R 25  and R 26  are both lower alkyl groups, they may be bonded together to form a ring; 
         Y represents a carbonyl group or a lower alkylene group; 
         A represents a single bond, or a lower alkylene or alkenylene group; and 
         R 29  represents a hydrogen atom or a lower alkyl group. 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The method of treating pain of  claim 11 , wherein
 R 27  represents an aryllower alkyl group whose aryl moiety may be substituted by one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, a halo-lower alkyl group, a cyanoaryl group, an amino group, a lower alkoxy group, a nitro group, a cyano group, an aryl group, a haloaryl group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, an aryl-lower alkyloxy group, an aryl-lower alkyl group, a heterocyclic group, an arylcarbonyl group, an arylcarbonylamino group, and an aryl-lower alkyloxy group substituted by one or two halogen atoms;   Y represents a carbonyl group; and   A represents a single bond.   
     
     
         13 . The method of treating neuropathic pain of  claim 12 , wherein
 R 27  represents an aryl lower alkyl group whose aryl moiety may be substituted by one or two substituents selected from a halogen atom or an aryl group;   R 28  represents a lower alkyl group or a lower cycloalkyl group;   R 25  represents an alkyl group having up to 8 carbon atoms or an aryl group;   Y represents a carbonyl group; and   A represents a single bond.   
     
     
         14 . The method of treating neuropathic pain of  claim 9 , wherein the agonist of PPARγ is selected from the group consisting of 6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole, 1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole, 1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-ethylbenzimidazole, 6-benzenesulfonylcarbamoyl-2-cyclopropyl-1-(2-fluorobenzyl)-benzimidazole, 6-benzenesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 6-benzenesulfonylcarbamoyl-1-(2,4-difluorobenzyl)-2-methylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, and pharmaceutically acceptable salts thereof.