Carbinols for the treatment of neuropathic dysfunction

Abstract

Compositions and methods are provided for treating neuropathic pain or neuropathic dysfunction that include the administration of an effective amount of a defined carbinol or a pharmaceutically acceptable salt or prodrug thereof.

1 - 34 . (cancelled)  
     
     
         35 . A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with one or more other agents that are useful for the treatment of conventional neuropathic pain, wherein: 
 m is 1, 2 or 3;  
 R 1  is CH 3 , C 2 H 5 , n-C 3 H 7  or allyl;  
 R 2  and R 3  independently are H or alkyl of 1-4 carbon atoms; or R1 and R 2  taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms; or R 2  and R 3  taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 to 6 carbon atoms;  
 R 4  is: 
 (a) phenyl or  
                     
 wherein X is independently one or two substituents, selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms;  
 (b) 2-, 3-, or 4-biphenyl or 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different, selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, perfluoroalkoxy, arylthio, perfluoroalkyl-thio and dialkylamino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms;  
 (c) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above;  
 (e) 2-, 3-, or 4-pyridyl, or 2- or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms;  
 (f) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms; or  
 (g) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CF 3 ;  
 
 R 5  is alkyl of 1-4 carbon atoms, or is taken together with R 6  to form a branched or unbranched alkylene bridge of 3-11 carbon atoms;  
 R 6  is H, alkyl of 1-4 carbon atoms, or is taken together with R 5  to form a branched or unbranched alkylene bridge of 3-11 carbon atoms; and  
 R 7  is H, alkyl of 1-4 carbon atoms, alkanoyl of 1-4 carbon atoms, or —CH 2 phenyl; or a pharmaceutically salt or N-oxide thereof, provided that when 
 (i) R 1 , R 5  and R 6  are methyl, and R 2  and R 3  are H, then R 4  is not 3,4-F 2 C 6 H 3 , 3,4-C l2 C 6 H 3 , p-t-butylphenyl, 2,3-(MeO) 2 C 6 H 3 , 2,5-(MeO) 2 C 6 H 3 , or 3-pyridyl;  
 (ii) R 2 , R 5  and R are methyl or R 5  and R 6  are taken together as —(CH 2 ) 6 — and —(CH 2 ) 7 —, then R 4  is not 3-(MeO)C 6 H 4 .  
 
 
     
     
         36 . A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with one or more other agents that are useful for the treatment of conventional pain, wherein: 
 when m is 2;  
 R 1  is CH 3 , C 2 H 5 , n-C 3 H 7  or allyl;  
 R 2  and R3 independently are H or alkyl of 1-4 carbon atoms; or R1 and R2 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms; or R 2  and R 3  taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 to 6 carbon atoms;  
 R 4  is: 
 (a)  
                     
 (b) 1-naphthyl optionally substituted with one or two substituents, the same or different, selected from F, Cl, Br; perfluoroalkyl, alkylthio, alkoxy, phenoxy, alkyl, alkyl- or dialkylamino, said alkyl in the alkyl-containing groups being 1-12 carbon atoms,  
 (c) 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms,  
 (d) 2-, or 3-thienyl optionally substituted with Cl, Br, or alkyl of 1-4 carbon atoms, provided when 2-thienyl is substituted with alkyl it is other than the 5-position, or  
 (e) 2-, or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br or CF 3 ;  
 
 R 5  independently is alkyl of 1-4 carbon atoms or when taken together with R 6  is a branched or unbranched alkylene bridge of 3-11 carbon atoms;  
 R 6  independently is alkyl of 1-4 carbon atoms, or when taken together with R 5  is a branched or unbranched alkylene bridge of 3-11 carbon atoms;  
 R 7  is H, alkyl of 1-4 carbon atoms, alkanoyl, or —CH 2  phenyl.  
 
     
     
         37 . A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with one or more other agents that are useful for the treatment of conventional or neuropathic pain, wherein: 
 m is 1 or 3;  
 R 1  independently is CH 3 , C 2 H 5 , n-C 3 H 7 , or allyl;  
 R 2  and R 3  independently are H or alkyl of 1-4 carbon atoms; or R 1  and R 2  taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms; or R 2  and R 3  taken together is a branched or unbranched alkylene bridge where the bridge is of 3 to 6 carbon atoms;  
 R 4  is: 
 (a) phenyl or  
                     
 where X is one or two substituents the same or different selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms;  
 (b) 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamine, amino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms;  
 (c) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above;  
 (d) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms;  
 (e) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms; or  
 (f) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CF 3 ;  
 
 R 5  independently is alkyl of 1-4 carbon atoms, or when taken together with R 6  is a branched or unbranched alkylene bridge of 3-11 carbon atoms;  
 R 6  independently is H, alkyl of 1-4 carbon atoms, or when taken together with R 5  is a branched or unbranched alkylene bridge of 3-11 carbon atoms;  
 R 7  is H, alkyl of 1-4 carbon atoms, alkanoyl, or —CH 2 phenyl; or  
 a pharmaceutically suitable salt or N-oxide thereof.  
 
     
     
         38 . A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with one or more other agents that are useful for the treatment of conventional neuropathic pain, wherein: 
 m is 2;  
 R 6  is H;  
 R 1  independently is CH 3 , C 2 H 5 , n-C 3 H 7 , or allyl;  
 R 2  and R 3  independently are H or alkyl of 1-4 carbon atoms; or R1 and R 2  taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms; or R 2  and R 3  taken together is a branched or unbranched alkylene bridge where the bridge is of 3 to 6 carbon atoms;  
 R 4  is: 
 (a) phenyl or  
                     
 where X is one or two substituents the same or different selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms;  
 (b) 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamine, amino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms;  
 (c) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above;  
 (e) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms;  
 (f) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms; or  
 (g) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CF3;  
 
 R 5  independently is alkyl of 1-4 carbon atoms;  
 R 7  is H, alkyl of 1-4 carbon atoms, alkanoyl, or —CH 2 phenyl; or  
 a pharmaceutically suitable salt or N-oxide thereof.  
 
     
     
         39 . A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with one or more other agents that are useful for the treatment of conventional or neuropathic pain, wherein: 
 m is 2;  
 R 6  is H;  
 R 1  is methyl;  
 R 2  and R 3  independently are H or alkyl of 1-4 carbon atoms; or R 2  and R 3  taken together is a branched or unbranched alkylene bridge where the bridge is of 3 to 6 carbon atoms;  
 R 4  is: 
 (a)  
                     
 where X is one or two substituents the same or different selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms;  
 (b) 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamine, amino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms;  
 (c) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above;  
 (d) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms;  
 (e) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms; or  
 (f) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CF 3 ;  
 
 R 5  independently is alkyl of 1-4 carbon atoms;  
 R 7  is H, alkyl of 1-4 carbon atoms, alkanoyl, or —CH 2  phenyl; or  
 a pharmaceutically suitable salt or N-oxide thereof.  
 
     
     
         40 . A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with one or more other agents that are useful for the treatment of conventional or neuropathic pain, wherein: 
 m is 2;  
 R 1  is CH 3 ;  
 R 2  and R 3  are H;  
 R 4  is 2- or 3-thienyl,  
                     
  where X is Cl, Br, F, CF 3 ;  
 R 5  is CH 3 ;  
 R 6  is H or CH 3 ; and  
 R 7  is H.  
 
     
     
         41 . A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with one or more other agents that are useful for the treatment of conventional or neuropathic pain, wherein: 
 m is 1 or 3;  
 R 1  is CH 3 ;  
 R 2 , R 3  and R 7  are H;  
 R 4  is  
                     
  where X is Cl, Br, F or CF 3 ;  
 R 5  is CH 3 ; and  
 R is H or CH 3 .  
 
     
     
         42 . The method of  claim 35 , wherein the compound is selected from the group consisting of: 
 (a) 4-(3′-Thienyl)-α,α, 1-trimethyl-4-piperidinemethanol;    (b) 4-(3′-Chlorophenyl)-α, 1-dimethylpiperidinemethanol;    (c) 4-(3′-Chlorophenyl)-α,α, 1-trimethyl-4-piperidinemethanol;    (d) 4-(3′-Bromophenyl)-α, 1-dimethylpiperidinemethanol;    (e) 4-(3′-Bromophenyl)-α,α, 1-trimethyl-4-piperidinemethanol;    (f) 4-(2-Thienyl)-α, 1-dimethylpiperidinemethanol;    (g) 4-(3-Thienyl)-α, 1-dimethylpiperidinemethanol;    (h) 4-(3′-Chlorophenyl)-α, 1-dimethyl-2,3,4,5,6,7-hexahydro-1H-azepine-1-methanol;    (i) 3-(3′-Chlorophenyl)-α,α,1-trimethyl-3-pyrrolidinemethanol;    (j) 4(4′-Trifluoromethylphenyl)-α-1-dimethylpiperidinemethanol;    or a pharmaceutically suitable salt thereof.    
     
     
         43 . A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with one or more other agents that are useful for the treatment of conventional or neuropathic pain, wherein: 
 X 1  and X 2  are independently O or NR 2 ; and  
 R 1  is H, alkyl, lower alkyl alkenyl, alkynyl, acyl, —C(O)R 5 , —C(O)NR 5 R 6 , —C(O)OR 5 , —C(O)SR 5 , —C(S)R 5 , —C(S)NR 5 R 6 , —C(S)OR 5 , —C(S)SR 5 , —C(NR 7 )R 5 , —C(NR 7 )NR 5 R 6 , —C(NR 7 )OR 5 , —C(NR 7 )SR 5  or phosphate; and  
 R 2 , R 5 , R 6  and R 7  are independently H or alkyl.  
 
     
     
         44 - 67 . (Cancelled)  
     
     
         68 . The method according to  claim 43 , wherein the lower alkyl is C 1 -C 6  optionally substituted, branched or straight-chained alkyl.  
     
     
         69 . The method of  claim 35 , wherein the compound is in the form of a dosage unit.  
     
     
         70 . The method of  claim 69 , wherein the patient is a human.  
     
     
         71 . The method of  claim 69 , wherein the dosage is 50-1000 mg.  
     
     
         72 . The method of  claim 69 , wherein the dosage unit is an immediate release tablet, controlled release tablet, capsule, oral solution, oral suspension, pill, gel, or cream.  
     
     
         73 . The method of  claim 35 , wherein the compound is suitable for oral delivery.  
     
     
         74 . The method of  claim 35 , wherein the compound is suitable for parental delivery.  
     
     
         75 . The method of  claim 35 , wherein the compound is suitable for intravenous delivery or intranasal delivery.  
     
     
         76 . The method of  claim 35 , wherein the compound is suitable for transdermal delivery.  
     
     
         77 . The method of  claim 35 , wherein the compound is suitable for rectal suppository delivery or transmucosal delivery.  
     
     
         78 . The method of  claim 35 , wherein the neuropathic pain is caused by a disorder selected from carpal tunnel syndrome, cervical or lumbar radiculopathy, complex regional pain syndrome, spinal cord injury, or stump pain.  
     
     
         79 . The method of  claim 35 , wherein the neuropathic pain is caused by a disorder selected from metabolic or toxic diseases.  
     
     
         80 . The method of  claim 35 , wherein the neuropathic pain is caused by endocrinologic disorders.  
     
     
         81 . The method as in  claim 80 , wherein the endocrinologic disorder is selected from diabetes mellitus, diabetic neuropathy, amyloidosis, or amyloid polyneuropathy.  
     
     
         82 . The method as in  claim 35 , wherein the neuropathic pain is caused by a malignant tumor, Eosinophilia-myalgia syndrome, monoclonal gammopathy, mulitiple sclerosis, stroke, postherpetic neuralgia, neuropathy with monoclonal protein, vasculitic neuropathy, neuropathy associated with Guillain-Barré syndrome, neuropathy associated with Fabry's disease, entrapment due to anatomic abnormality, trigeminal, CNS neuralgia, malignancy, inflammatory condition, autoimmune disorder, idiopathic distal small-fiber neuropathy, toxin, drug, dietary or absorption abnormality, immuno-globulinemia, hereditary abnormality, mastectomy, or amputation.  
     
     
         83 . The method of  claim 35 , wherein the neuropathic pain is caused by a viral infection.  
     
     
         84 . The method of  claim 83 , wherein the viral infection is HIV infection or herpes.  
     
     
         85 . The method as in  claim 82 , wherein said autoimmune disorder is selected from the group consisting of demyelinating inflammatory disorders, rheumatoid arthritis, systemic lupus erythematosus, or Sjögren's syndrome.  
     
     
         86 . The method as in  claim 82 , wherein toxin or drug is selected from the group consisting of arsenic, lead, mercury, thallium, alcohol, vincrisitne, cisplatinum, or dideoxynucleo-side.  
     
     
         87 . The method of  claim 35 , wherein the compound inhibits uptake of serotonin, norepinephrine, or dopamine.  
     
     
         88 . The method of  claim 35 , wherein the compound inhibits ectopic activity.  
     
     
         89 . The method of  claim 35 , wherein the compound inhibits ectopic discharge in the peripheral nervous system pathways.  
     
     
         90 . The method of  claim 35 , wherein the compound inhibits ectopic discharge in the dorsal-root-ganglion cells of damaged afferent axons.  
     
     
         91 . The method of  claim 35 , wherein the treatment is a maintenance treatment to prevent the reoccurrence of neuropathic pain.  
     
     
         92 . The method of  claim 35 , wherein the other agents are at least one selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, pregabalin, phenytoin, carbamazepine, valproic acid, venlafaxine, paroxetine, amitriptyline HCl, nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine HCl, mexiletine HCl, tocainide, lidocaine, clomipramine, clonazepam, dexamethasone, morphine, methadone HCl, fentanyl, oxycodone, tramadol HCl and capsaicin.  
     
     
         93 . The method of  claim 36 , wherein the other agents are at least one selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, pregabalin, phenyloin, carbamazepine, valproic acid, venlafaxine, paroxetine, amitriptyline HCl, nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine HCl, mexiletine HCl, tocainide, lidocaine, clomipramine, clonazepam, dexamethasone, morphine, methadone HCl, fentanyl, oxycodone, tramadol HCl and capsaicin.  
     
     
         94 . The method of  claim 37 , wherein the other agents are at least one selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, pregabalin, phenyloin, carbamazepine, valproic acid, venlafaxine, paroxetine, amitriptyline HCl, nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine HCl, mexiletine HCl, tocainide, lidocaine, clomipramine, clonazepam, dexamethasone, morphine, methadone HCl, fentanyl, oxycodone, tramadol HCl and capsaicin.  
     
     
         95 . The method of  claim 38 , wherein the other agents are at least one selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, pregabalin, phenyloin, carbamazepine, valproic acid, venlafaxine, paroxetine, amitriptyline HCl, nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine HCl, mexiletine HCl, tocainide, lidocaine, clomipramine, clonazepam, dexamethasone, morphine, methadone HCl, fentanyl, oxycodone, tramadol HCl and capsaicin.  
     
     
         96 . The method of  claim 39 , wherein the other agents are at least one selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, pregabalin, phenyloin, carbamazepine, valproic acid, venlafaxine, paroxetine, amitriptyline HCl, nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine HCl, mexiletine HCl, tocainide, lidocaine, clomipramine, clonazepam, dexamethasone, morphine, methadone HCl, fentanyl, oxycodone, tramadol HCl and capsaicin.  
     
     
         97 . The method of  claim 40 , wherein the other agents are at least one selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, pregabalin, phenyloin, carbamazepine, valproic acid, venlafaxine, paroxetine, amitriptyline HCl, nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine HCl, mexiletine HCl, tocainide, lidocaine, clomipramine, clonazepam, dexamethasone, morphine, methadone HCl, fentanyl, oxycodone, tramadol HCl and capsaicin.  
     
     
         98 . The method of  claim 41 , wherein the other agents are at least one selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, pregabalin, phenyloin, carbamazepine, valproic acid, venlafaxine, paroxetine, amitriptyline HCl, nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine HCl, mexiletine HCl, tocainide, lidocaine, clomipramine, clonazepam, dexamethasone, morphine, methadone HCl, fentanyl, oxycodone, tramadol HCl and capsaicin.