Agent for preventing or treating neuropathy

Abstract

The present invention provides an agent for preventing or treating neuropathy having superior action and low toxicity. This agent comprises a compound represented by the formula: wherein ring A is a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may further have substituent(s); B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a divalent acyclic hydrocarbon group; Z is —O—, —S—, —NR 2 —, —CONR 2 — or —NR 2 CO— (R 2 is a hydrogen atom or an optionally substituted alkyl group); Y is a bond or a divalent acyclic hydrocarbon group; R 1 is an optionally substituted cyclic group, an optionally substituted amino group or an optionally substituted acyl group, provided that when the 5-membered aromatic heterocycle represented by ring A is imidazole, then Z should not be —O—, or a salt thereof.

1 - 30 . (canceled) 
   
   
       31 . An agent for preventing or treating neuropathy, which comprises a compound represented by the formula: 
     
       
         
         
             
             
         
       
       wherein 
       ring A is a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may further have substituent(s); 
       B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; 
       X is a divalent acyclic hydrocarbon group; 
       Z is —O—, —S—, —NR 2 —, —CONR 2 — or —NR 2 CO— (R 2  is a hydrogen atom or an optionally substituted alkyl group); 
       Y is a bond or a divalent acyclic hydrocarbon group; and 
       R 1  is an optionally substituted cyclic group, an optionally substituted amino group or an optionally substituted acyl group, 
       provided that when the 5-membered aromatic heterocycle represented by ring A is imidazole, then Z should not be —O—, 
       or a salt thereof. 
     
   
   
       32 . The agent of  claim 31 , wherein the 5-membered aromatic heterocycle represented by ring A is a pyrazole, oxadiazole, thiadiazole, triazole or tetrazole ring. 
   
   
       33 . The agent of  claim 31 , wherein the optionally substituted cyclic group represented by R 1  is a group represented by the formula: 
     
       
         
         
             
             
         
       
       wherein D is a ring optionally further having substituents; Y 1  is a bond or a divalent acyclic hydrocarbon group; R 3′  is a group of the formula: —SO 2 R 4 , —SOR 4  or —PO 3 R 4 R 5  wherein R 4  and R 5  are the same or different and each is a hydrogen atom, a hydrocarbon group or a heterocyclic group, and R 4  and R 5  may form a heterocycle together with the adjacent oxo-substituted phosphorus atom and two oxygen atoms, or an optionally substituted heterocyclic group. 
     
   
   
       34 . An agent for promoting production or secretion of a neurotrophic factor, which comprises a compound of the formula 
     
       
         
         
             
             
         
       
       wherein 
       ring A is a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may further have substituent(s); 
       B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; 
       X is a divalent acyclic hydrocarbon group; 
       Z is —O—, —S—, —NR 2 —, —CONR 2 — or —NR 2 CO— (R 2  is a hydrogen atom or an optionally substituted alkyl group); 
       Y is a bond or a divalent acyclic hydrocarbon group; and 
       R 1  is an optionally substituted cyclic group, an optionally substituted amino group or an optionally substituted acyl group, 
       provided that when the 5-membered aromatic heterocycle represented by ring A is imidazole, then Z should not be —O—, 
       or a salt thereof. 
     
   
   
       35 . The agent of  claim 34 , wherein the 5-membered aromatic heterocycle represented by ring A is a pyrazole, oxadiazole, thiadiazole, triazole or tetrazole ring. 
   
   
       36 . An agent for ameliorating pain comprising a compound represented by the formula: 
     
       
         
         
             
             
         
       
       wherein 
       ring A is a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may further have substituent(s); 
       B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; 
       X is a divalent acyclic hydrocarbon group; 
       Z is —O—, —S—, —NR 2 —, —CONR 2 — or —NR 2 CO— (R 2  is a hydrogen atom or an optionally substituted alkyl group); 
       Y is a bond or a divalent acyclic hydrocarbon group; and 
       R 1  is an optionally substituted cyclic group, an optionally substituted amino group or an optionally substituted acyl group, 
       provided that when the 5-membered aromatic heterocycle represented by ring A is imidazole, then Z should not be —O—, 
       or a salt thereof. 
     
   
   
       37 . The agent of  claim 36 , wherein the 5-membered aromatic heterocycle represented by ring A is a pyrazole, oxadiazole, thiadiazole, triazole or tetrazole ring. 
   
   
       38 . A neuroprotective agent comprising a compound represented by the formula: 
     
       
         
         
             
             
         
       
       wherein 
       ring A is a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may further have substituent(s); 
       B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; 
       X is a divalent acyclic hydrocarbon group; 
       Z is —O—, —S—, —NR 2 —, —CONR 2 — or —NR 2 CO— (R 2  is a hydrogen atom or an optionally substituted alkyl group); 
       Y is a bond or a divalent acyclic hydrocarbon group; and 
       R 1  is an optionally substituted cyclic group, an optionally substituted amino group or an optionally substituted acyl group, 
       provided that when the 5-membered aromatic heterocycle represented by ring A is imidazole, then Z should not be —O—, 
       or a salt thereof. 
     
   
   
       39 . A compound represented by the formula 
     
       
         
         
             
             
         
       
       wherein 
       ring A is a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may further have substituent(s); 
       B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; 
       X is a divalent acyclic hydrocarbon group; 
       Z is —O—, —S—, —NR 2 —, —CONR 2 — or —NR 2 CO— (R 2  is a hydrogen atom or an optionally substituted alkyl group); 
       Y and Y 1  are the same or different and each is a bond or a divalent acyclic hydrocarbon group; and 
       D is a ring optionally further having substituent(s); 
       R 3  is an optionally substituted acyl group or an optionally substituted heterocyclic group, 
       provided that when the 5-membered aromatic heterocycle represented by ring A is imidazole, then Z should not be —O—, 
       and provided that when the 5-membered aromatic heterocycle represented by ring A is pyrazole, X is methylene, Z is —S— and Y is a bond, then the ring represented by D should not be oxadiazole, 
       or a salt thereof. 
     
   
   
       40 . The compound of  claim 39 , wherein the 5-membered aromatic heterocycle represented by ring A is a pyrazole, oxadiazole, thiadiazole, triazole or tetrazole ring. 
   
   
       41 . The compound of  claim 39 , wherein the optionally substituted acyl group represented by R 3  is a group of the formula: —SO 2 R 4 , —SOR 4  or —PO 3 R 4 R 5  wherein R 4  and R 5  are the same or different and each is a hydrogen atom, a hydrocarbon group or a heterocyclic group, and R 4  and R 5  may form a heterocycle together with the adjacent oxo-substituted phosphorus atom and two oxygen atoms. 
   
   
       42 . The compound of  claim 39 , wherein the 5-membered aromatic heterocycle represented by ring A is a pyrazole ring. 
   
   
       43 . The compound of  claim 39 , wherein B is an optionally substituted aromatic hydrocarbon group or an optionally substituted aromatic heterocyclic group. 
   
   
       44 . The compound of  claim 39 , wherein X is a divalent C 1-8  aliphatic hydrocarbon group. 
   
   
       45 . The compound of  claim 39 , wherein Z is —CONR 2 — (R 2  is a hydrogen atom or an optionally substituted alkyl group). 
   
   
       46 . The compound of  claim 39 , wherein Y is a bond or a C 1-4  alkylene. 
   
   
       47 . The compound of  claim 39 , wherein Y 1  is a bond or a C 1-4  alkylene. 
   
   
       48 . The compound of  claim 39 , wherein the ring represented by D is a C 6-14  aromatic hydrocarbon ring. 
   
   
       49 . The compound of  claim 39 , which is 
     (2E)-N-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide; 
     (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-[4-(1H-imidazol-1-ylmethyl)phenyl]acrylamide; 
     (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-[4-(1H-pyrazol-1-ylmethyl)phenyl]acrylamide; 
     diethyl [4-({(2E)-3-[1-methyl-5-(2-thienyl)-1H-pyrazol-4-yl]prop-2-enoyl}amino)benzyl]phosphonate; 
     (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-{4-[(3-methyl-2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}acrylamide; 
     (2E)-N-[4-(1H-benzimidazol-1-ylmethyl)phenyl]-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide; 
     (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-{4-[(methylsulfonyl)methyl]phenyl}acrylamide; 
     (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-{4-[hydroxy(2-pyridinyl)methyl]phenyl}acrylamide; 
     (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-[4-(4-morpholinylmethyl)phenyl]acrylamide; or 
     (2E)-N-{4-[(ethylsulfonyl)methyl]phenyl}-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide. 
   
   
       50 . A pharmaceutical agent comprising the compound of  claim 39  or a prodrug thereof. 
   
   
       51 . A method for preventing or treating neuropathy in a mammal, which comprises administering a compound represented by the formula: 
     
       
         
         
             
             
         
       
       wherein 
       ring A is a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may further have substituent(s); 
       B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; 
       X is a divalent acyclic hydrocarbon group; 
       Z is —O—, —S—, —NR 2 —, —CONR 2 — or —NR 2 CO— (R 2  is a hydrogen atom or an optionally substituted alkyl group); 
       Y is a bond or a divalent acyclic hydrocarbon group; and 
       R 1  is an optionally substituted cyclic group, an optionally substituted amino group or an optionally substituted acyl group, 
       provided that when the 5-membered aromatic heterocycle represented by ring A is imidazole, then Z should not be —O—, 
       or a salt thereof, to said mammal. 
     
   
   
       52 . A method for promoting production or secretion of a neurotrophic factor in a mammal, which comprises administering a compound represented by the formula: 
     
       
         
         
             
             
         
       
       wherein 
       ring A is a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may further have substituent(s); 
       B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; 
       X is a divalent acyclic hydrocarbon group; 
       Z is —O—, —S—, —NR 2 —, —CONR 2 — or —NR 2 CO— (R 2  is a hydrogen atom or an optionally substituted alkyl group); 
       Y is a bond or a divalent acyclic hydrocarbon group; and 
       R 1  is an optionally substituted cyclic group, an optionally substituted amino group or an optionally substituted acyl group, 
       provided that when the 5-membered aromatic heterocycle represented by ring A is imidazole, then Z should not be —O—, 
       or a salt thereof, to said mammal. 
     
   
   
       53 . A method for ameliorating pain in a mammal, which comprises administering a compound represented by the formula: 
     
       
         
         
             
             
         
       
       wherein 
       ring A is a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may further have substituent(s); 
       B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; 
       X is a divalent acyclic hydrocarbon group; 
       Z is —O—, —S—, —NR 2 —, —CONR 2 — or —NR 2 CO— (R 2  is a hydrogen atom or an optionally substituted alkyl group); 
       Y is a bond or a divalent acyclic hydrocarbon group; and 
       R 1  is an optionally substituted cyclic group, an optionally substituted amino group or an optionally substituted acyl group, 
       provided that when the 5-membered aromatic heterocycle represented by ring A is imidazole, then Z should not be —O—, 
       or a salt thereof, to said mammal. 
     
   
   
       54 . A method for protecting a nerve in a mammal, which comprises administering a compound represented by the formula: 
     
       
         
         
             
             
         
       
       wherein 
       ring A is a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may further have substituent(s); 
       B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; 
       X is a divalent acyclic hydrocarbon group; 
       Z is —O—, —S—, —NR 2 —, —CONR 2 — or —NR 2 CO— (R 2  is a hydrogen atom or an optionally substituted alkyl group); 
       Y is a bond or a divalent acyclic hydrocarbon group; and 
       R 1  is an optionally substituted cyclic group, an optionally substituted amino group or an optionally substituted acyl group, 
       provided that when the 5-membered aromatic heterocycle represented by ring A is imidazole, then Z should not be —O—, 
       or a salt thereof, to said mammal. 
     
   
   
       55 . A production method of a compound represented by the formula: 
     
       
         
         
             
             
         
       
       wherein 
       ring A is a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may further have substituent(s); 
       B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; 
       X is a divalent acyclic hydrocarbon group; 
       R 2  is a hydrogen atom or an optionally substituted alkyl group; 
       Y and Y 1  are the same or different and each is a bond or a divalent acyclic hydrocarbon group; 
       D is a ring optionally further having substituent(s); and 
       R 3  is an optionally substituted acyl group or an optionally substituted heterocyclic group, 
       or a salt thereof, which comprises reacting a compound represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein each symbol is as defined above, or a salt thereof, with a compound represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein each symbol is as defined above, or a salt thereof. 
     
   
   
       56 . A production method of a compound represented by the formula: 
     
       
         
         
             
             
         
       
       wherein 
       B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and 
       alk 4  is a C 1-6  alkyl group or a C 7-13  aralkyl group, 
       or a salt thereof, which comprises reacting a compound represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein W is —OH or —N(alk 2 )(alk 3 ) wherein alk 2  and alk 3  are the same or different and each is a C 1-6  alkyl group, and B is as defined above, or a salt thereof, with a C 1-6  alkylhydrazine or a C 7-13  aralkylhydrazine in the presence of an acid.