Compounds for the treatment of peripheral neuropathies

Abstract

A compound of formula A1 or A2 for use in the treatment of a demyelinating peripheral neuropathy: wherein A is COOR 5 , OPO(OR 5 ) 2 , PO(OR 5 ) 2 , SO 2 OR 5 , POR 5 OR 5 or 1H-tetrazol-5-yl, R 5 being H or an ester-forming group, optionally C 1-6 alkyl; W is a bond, C 1-3 alkylene or C 2-3 alkenylene; Y is C 6-10 aryl or C 2-9 heteroaryl eg C 3-9 heteroaryl, optionally substituted by 1 to 3 radicals selected from halogen, OH, NO 2 , C 1-6 alkyl, C 1-6 alkoxy; halo-substituted C 1-6 alkyl and halo-substituted C 1-6 alkoxy; Z is chosen from: wherein the asterisks of Z indicate the point of attachment between —C(R 3 )(R 4 )— and A of Formula Ia or Ib, respectively; R 6 is chosen from hydrogen and C 1-6 alkyl; and J 1 and J 2 are independently methylene or a heteroatom chosen from S, O and NR 5 ; wherein R 5 is chosen from hydrogen and C 1-6 alkyl; and any alkylene of Z can be further substituted by one to three radicals chosen from halo, hydroxy, C 1-6 alkyl; or R 6 can be attached to a carbon atom of Y to form a 5-7 member ring; R 1 is C 6-10 aryl or C 2-9 heteroaryl eg C 3-9 heteroaryl, optionally substituted by C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-4 alkyl, C 3-9 heteroaryl, C 3-9 heteroarylC 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-4 alkyl, C 3-8 heterocycloalkyl or C 3-8 heterocycloalkylC 1-4 alkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 1 may be substituted by 1 to 5 groups selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and halo substituted-C 1-6 alkyl or —C 1-6 alkoxy; R 2 is H, C 1-6 alkyl, halo substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; and each of R 3 and R 4 , independently, is H, halogen, OH, C 1-6 alkyl, C 1-6 alkoxy or halo substituted C 1-6 alkyl or C 1-6 alkoxy; and the N-oxide derivatives thereof or prodrugs thereof, or a pharmacologically acceptable salt, solvate or hydrate thereof.

1 . A compound of formula A1 or A2 for use in the treatment of a demyelinating peripheral neuropathy: 
       
         
           
           
               
               
           
         
         wherein 
         A is COOR 5 , OPO(OR 5 ) 2 , PO(OR 5 ) 2 , SO 2 OR 5 , POR 5 OR 5  or 1H-tetrazol-5-yl, R 5  being H or an ester-forming group, optionally C 1-6 alkyl; 
         W is a bond, C 1-3 alkylene or C 2-3 alkenylene; 
         Y is C 6-10 aryl or C 2-9 heteroaryl eg C 3-9 heteroaryl, optionally substituted by 1 to 3 radicals selected from halogen, OH, NO 2 , C 1-6 alkyl, C 1-6 alkoxy; halo-substituted C 1-6 alkyl and halo-substituted C 1-6 alkoxy; 
         Z is chosen from: 
       
       
         
           
           
               
               
           
         
         wherein the left and right asterisks of Z indicate the point of attachment between —C(R 3 )(R 4 )— and A of Formula Ia or Ib, respectively; R 6  is chosen from hydrogen and C 1-6 alkyl; and J 1  and J 2  are independently methylene or a heteroatom chosen from S, O and NR 5 ; wherein R 5  is chosen from hydrogen and C 1-6 alkyl; and any alkylene of Z can be further substituted by one to three radicals chosen from halo, hydroxy, C 1-6 alkyl; or R 6  can be attached to a carbon atom of Y to form a 5-7 member ring; 
         R 1  is C 6-10 aryl or C 2-9 heteroaryl eg C 3-9 heteroaryl, optionally substituted by C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-4 alkyl, C 3-9 heteroaryl, C 3-9 heteroarylC 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-4 alkyl, C 3-8 heterocycloalkyl or C 3-8 heterocycloalkylC 1-4 alkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 1  may be substituted by 1 to 5 groups selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and halo substituted-C 1-6 alkyl or -C 1-6 alkoxy; 
         R 2  is H, C 1-6 alkyl, halo substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; and 
         each of R 3  and R 4 , independently, is H, halogen, OH, C 1-6 alkyl, C 1-6 alkoxy or halo substituted C 1-6 alkyl or C 1-6 alkoxy; 
         and the N-oxide derivatives thereof or prodrugs thereof, 
         or a pharmacologically acceptable salt, solvate or hydrate thereof. 
       
     
     
         2 . A compound of  claim 1 , wherein the neuropathy is Guillain-Barré syndrome. 
     
     
         3 . A compound of  claim 1 , wherein the neuropathy is chronic inflammatory demyelinating polyradiculoneuropathy. 
     
     
         4 . A compound of  claim 1 , wherein the neuropathy is multifocal motor neuropathy with conduction block. 
     
     
         5 . A compound of  claim 1 , wherein the neuropathy is paraproteinaemic demyelinating peripheral neuropathy. 
     
     
         6 . A compound of any preceding claim, wherein A is COOR 5 . 
     
     
         7 . A compound of  claim 6 , wherein A is COOH. 
     
     
         8 . A compound of any preceding claim, wherein W is ethylene. 
     
     
         9 . A compound of any preceding claim, wherein Y is optionally substituted phenyl or C 6 heteroaryl. 
     
     
         10 . A compound of any of  claims 1  to  8 , wherein Y is C 6-10 aryl or C 3-9 heteroaryl, substituted with a single C 1-6 alkyl substituent. 
     
     
         11 . A compound of  claim 10 , wherein Y is phenyl optionally substituted by ethyl. 
     
     
         12 . A compound of any preceding claim, wherein Z is selected from the heterocycles azetidine, pyrrolidine or piperidine, joined to the remainder of the molecule at the 1- and 3-positions; or piperidine joined to the remainder of the molecule at the 1- and 4-positions; optionally wherein the heterocycle is N-substituted (1-substituted) by moiety A and substituted at the 3 or, as the case may be, 4-position by —C(R 3 )(R 4 )—. 
     
     
         13 . A compound of any preceding claim, wherein R 1  is optionally substituted phenyl or optionally substituted C 6 heteroaryl. 
     
     
         14 . A compound of any preceding claim, wherein R 1  has two substituents selected from optionally halo-substituted alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, optionally halo-substituted phenyl and optionally halo-substituted C 3-8 cycloalkyl. 
     
     
         15 . A compound of  claim 14  wherein R 1  is phenyl or C 6 heteroaryl. 
     
     
         16 . A compound of  claim 15 , wherein R 1  has one optionally halo-substituted alkyl group and one optionally halo-substituted cyclic moiety selected from phenyl and C 3-8 cycloalkyl groups. 
     
     
         17 . A compound of any preceding claim, wherein R 2  is methyl. 
     
     
         18 . A compound of any preceding claim, wherein R 3  and R 4  are each independently H, halogen, methyl or halo-substituted methyl. 
     
     
         19 . A compound of  claim 18 , wherein R 3  and R 4  are both H. 
     
     
         20 . A compound of any of  claims 1  to  5 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 . A compound of any of  claims 1  to  5 , wherein the compound is 1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid: 
       
         
           
           
               
               
           
         
       
     
     
         22 . A method of treating a subject having a demyelinating peripheral neuropathy comprising administering to the subject an effective amount of a compound having a structure defined in any of  claims 1  and  6  to  21 . 
     
     
         23 . A method of alleviating a symptom of, delaying the progression of, or prolonging time to relapse of a demyelinating peripheral neuropathy comprising administering to the subject an effective amount of a compound having a structure defined in any of  claims 1  and  6  to  21 . 
     
     
         24 . A method of improving or maintaining, or delaying the deterioration of, the status of a subject having a demyelinating peripheral neuropathy comprising administering to the subject an effective amount of a compound having a structure defined in any of  claims 1  and  6  to  21 . 
     
     
         25 . A method of  claim 22 ,  23  or  24 , wherein the neuropathy is Guillain-Barré syndrome. 
     
     
         26 . A method of  claim 22 ,  23  or  24 , wherein the neuropathy is chronic inflammatory demyelinating polyradiculoneuropathy. 
     
     
         27 . A method of  claim 22 ,  23  or  24 , wherein the neuropathy is multifocal motor neuropathy with conduction block. 
     
     
         28 . A method of  claim 22 ,  23  or  24 , wherein the neuropathy is paraproteinaemic demyelinating peripheral neuropathy. 
     
     
         29 . A pharmaceutical formulation comprising a compound having a structure defined in any of  claims 1  and  6  to  21  in combination with at least one further therapeutic agent useful for treating a patient having a demyelinating peripheral neuropathy. 
     
     
         30 . A formulation of  claim 29 , wherein the at least one further therapeutic agent is selected from an immunosuppresant (e.g., cyclosporin A, cyclosporin G, FK-506, ABT-281, ASM981, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin, a corticosteroid, cyclophosphamide, azathioprine, methotrexate, leflunomide, mizoribine, mycophenolate mofetil, or 15-deoxyspergualine), a steroid (e.g., prednisone or hydrocortisone), an immunoglobulin, or type 1 interferon. 
     
     
         31 . A compound having a structure defined in any of  claims 1  and  6  to  21  for simultaneous, separate or sequential co-administration with at least one further agent as defined in  claim 29  or  30 .