Treatment of length dependent neuropathy

Abstract

Compositions, and methods of use thereof, are provided for the treatment of painful neuropathy by local or topical delivery of compounds that interact with α-adrenergic receptors, especially an alpha 2 adrenergic agonist such as clonidine, to the entire painful area such that the need for systemic dosing is minimized. The compounds are delivered to or adjacent to painful areas in patients with painful length dependent neuropathy, and other neuropathies that affect the pain signaling fibers in the skin. A preferred compound for the treatment of patients with length dependent neuropathy is clonidine applied in a transdermal patch, gel, ointment, lotion, liposomal formulation, cream, or emulsion, wherein the concentration is sufficient to provide an effective dose in the painful area or immediately adjacent areas.

I claim: 
     
         1 . A method for the treatment of painful length dependent neuropathy in a patient in need thereof, comprising locally or topically administering an effective amount at the site of treatment and not systemically, a compound having the structure represented by formula I: 
       
         
           
           
               
               
           
         
         wherein A 4  may be selected from aryl, and heteroaryl, which may be substituted by one or more radicals selected from alkyl, branched alkyl, cycloalkyl, hydroxyl, alkoxy, cycloalkylalkyl, alkoxyalkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyano, halogen, thioalkyl, dialkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl or arylsulfonyl; wherein X is selected from thio, imino, or methylene; wherein R 7  is selected from hydrogen, lower alkyl, or oxygen-containing heterocycle; and wherein n is either 2 or 3; or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The method of  claim 1  wherein the compounds of Formula I consist of those compounds wherein A 4  is phenyl; wherein A 4  is substituted phenyl, on which positions 2 and 6 of the phenyl ring may be independently substituted by a radical selected from hydrogen, chloro, methyl, ethyl, or cycloalkyl, and positions 3, 4, and 5 may be independently substituted by a radical selected from hydrogen, methyl, trifluoromethyl, fluoro, or cyano; wherein A 4  is 3-thienyl, on which positions 2 and 4 are independently substituted by a radical selected from hydrogen, chloro, methyl, ethyl, or cycloalkyl; wherein A 4  is 1-naphthyl, 5,6,7,8-tetrahydronaphthyl-1-yl, pyrrolyl, oxazolyl, isoxazolyl, indol-3-yl, indazol-3-yl, quinolinyl, quinazolinyl, quinoxazolinyl, benzoxazolyl, and benzothiophen-3-yl; wherein A 4  is pyrimidin-4-yl, on which positions 3 and 5 are independently substituted by hydrogen, chloro, methyl, ethyl, cycloalkyl, or methoxy; wherein R 7  is either hydrogen or tetrahydropyran-2-yl; wherein X is thio or imino; and wherein n is 2. 
     
     
         3 . The method of  claim 1  wherein the compound is selected from the group consisting of compounds wherein A 4  is selected from phenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2,6-diethylphenyl, 3,4-dihydroxyphenyl, 3-fluoro-6-methylphenyl, 2-chloro-5-trifluoromethylphenyl, 2-chloro-4-methylphenyl, 3-chloro-4-methylthien-3-yl, 5,6,7,8-tetrahydronaphth-1-yl, and 4-chloro-5-methoxy-2-methylpyrimidin-4-yl; wherein R 7  is hydrogen or tetrahydropyran-2-yl; wherein X is thio or imino; and wherein n is 2. 
     
     
         4 . The method of  claim 1  wherein the compound is selected from the group consisting of xylazine, flutonidine, moxonidine, tramazoline, tolonidine, piclonidine, tiamenidine, and clonidine. 
     
     
         5 . The method of  claim 1  wherein the compound is formulated in a topical carrier selected from the group consisting of transdermal patches, gels, ointments, lotions, liposomal formulations, creams, and emulsions. 
     
     
         6 . The method of  claim 1  wherein 0.01% to 1.0% clonidine is applied to the painful area affected by the neuropathy. 
     
     
         7 . The method of  claim 1  wherein the clonidine is given anywhere from once a week to several times a day. 
     
     
         8 . The method of  claim 1  wherein the treatment is given to patients with neuropathy that stems from diabetes mellitus. 
     
     
         9 . The method of  claim 1  wherein the treatment is administered to patients with a sensory peripheral neuropathy in the painful region. 
     
     
         10 . The method of  claim 1  wherein the treatment is administered to a patient with a small fiber neuropathy in the painful region. 
     
     
         11 . The method of  claim 1  further comprising administering a therapy selected from the group consisting of opioids, anticonvulsants, membrane stabilizers, and psychoactive drugs such as anti-depressants. 
     
     
         12 . A dosage formulation comprising an amount of a compound to treat painful length dependent neuropathy in a patient in need thereof, comprising in a pharmaceutically acceptable carrier for local or topical administration selected from the group consisting of transdermal patches, gels, ointments, lotions, liposomal formulations, creams, and emulsions, a compound having the structure represented by formula I: 
       
         
           
           
               
               
           
         
         wherein A 4  may be selected from aryl, and heteroaryl, which may be substituted by one or more radicals selected from alkyl, branched alkyl, cycloalkyl, hydroxyl, alkoxy, cycloalkylalkyl, alkoxyalkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyano, halogen, thioalkyl, dialkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl or arylsulfonyl; wherein X is selected from thio, imino, or methylene; wherein R 7  is selected from hydrogen, lower alkyl, or oxygen-containing heterocycle; and wherein n is either 2 or 3; or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . The dosage formulation of  claim 12  wherein the compounds of Formula I consist of those compounds wherein A 4  is phenyl; wherein A 4  is substituted phenyl, on which positions 2 and 6 of the phenyl ring may be independently substituted by a radical selected from hydrogen, chloro, methyl, ethyl, or cycloalkyl, and positions 3, 4, and 5 may be independently substituted by a radical selected from hydrogen, methyl, trifluoromethyl, fluoro, or cyano; wherein A 4  is 3-thienyl, on which positions 2 and 4 are independently substituted by a radical selected from hydrogen, chloro, methyl, ethyl, or cycloalkyl; wherein A 4  is 1-naphthyl, 5,6,7,8-tetrahydronaphthyl-1-yl, pyrrolyl, oxazolyl, isoxazolyl, indol-3-yl, indazol-3-yl, quinolinyl, quinazolinyl, quinoxazolinyl, benzoxazolyl, and benzothiophen-3-yl; wherein A 4  is pyrimidin-4-yl, on which positions 3 and 5 are independently substituted by hydrogen, chloro, methyl, ethyl, cycloalkyl, or methoxy; wherein R 7  is either hydrogen or tetrahydropyran-2-yl; wherein X is thio or imino; and wherein n is 2. 
     
     
         14 . The dosage formulation of  claim 12  wherein the compound is selected from the group consisting of compounds wherein A 4  is selected from phenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2,6-diethylphenyl, 3,4-dihydroxyphenyl, 3-fluoro-6-methylphenyl, 2-chloro-5-trifluoromethylphenyl, 2-chloro-4-methylphenyl, 3-chloro-4-methylthien-3-yl, 5,6,7,8-tetrahydronaphth-1-yl, and 4-chloro-5-methoxy-2-methylpyrimidin-4-yl; wherein R 7  is hydrogen or tetrahydropyran-2-yl; wherein X is thio or imino; and wherein n is 2. 
     
     
         15 . The dosage formulation of  claim 12  wherein the compound is selected from the group consisting of xylazine, flutonidine, moxonidine, tramazoline, tolonidine, piclonidine, tiamenidine, and clonidine. 
     
     
         16 . The dosage formulation of  claim 12  comprising 0.1% to 1.0% clonidine. 
     
     
         17 . The dosage formulation of  claim 12  further comprising a therapeutic selected from the group consisting of opioids, anticonvulsants, membrane stabilizers, and psychoactive drugs.