Compounds for suppressing a peripheral nerve disorder induced by an anti-cancer agent

Abstract

The present invention provides a medicament that suppresses (or mitigates) various neurological symptoms caused by a peripheral nerve disorder induced by an anti-cancer agent.

1 . A method for suppressing a peripheral nerve disorder induced by an anti-cancer agent, which comprises administering a compound represented by the formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R is 
         (1) an aliphatic hydrocarbon group optionally having substituent(s), 
         (2) an aromatic hydrocarbon group optionally having substituent(s), 
         (3) a heterocyclic group optionally having substituent(s), 
         (4) a group represented by the formula: —OR 1  wherein R 1  is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), or 
         (5) a group represented by the formula: 
       
       
         
           
           
               
               
           
         
         wherein R 1b  and R 1c  are the same or different and each is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), 
         R 0  is a hydrogen atom or an aliphatic hydrocarbon group, or R and R 0  in combination may form a bond, 
         ring A 1  is a cycloalkene optionally substituted by 1 to 4 substituents selected from the group consisting of 
         (i) an aliphatic hydrocarbon group optionally having substituent(s), 
         (ii) an aromatic hydrocarbon group optionally having substituent(s), 
         (iii) a group represented by the formula: —OR 11  wherein R 11  is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), and 
         (iv) a halogen atom, 
         Ar is an aromatic hydrocarbon group optionally having substituent(s), 
         a group represented by the formula: 
       
       
         
           
           
               
               
           
         
         is a group represented by the formula: 
       
       
         
           
           
               
               
           
         
         and n is an integer of 1 to 4, 
         or a salt thereof or a prodrug thereof, or 
         a compound represented by the formula (II): 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1′  is 
         (1) an aliphatic hydrocarbon group optionally having substituent(s), 
         (2) an aromatic hydrocarbon group optionally having substituent(s), 
         (3) a heterocyclic group optionally having substituent(s), 
         (4) a group represented by the formula: —OR 1b′  wherein R 1b′  is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), or 
         (5) a group represented by the formula: 
       
       
         
           
           
               
               
           
         
         wherein R 1b′  and R 1c′  are the same or different and each is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), 
         X is methylene, NH, a sulfur atom or an oxygen atom, 
         Y is methylene optionally having substituent(s) or NH optionally having substituent(s), 
         ring A′ is a 5- to 8-membered ring optionally having 1 to 4 substituents selected from the group consisting of 
         (i) an aliphatic hydrocarbon group optionally having substituent(s), 
         (ii) an aromatic hydrocarbon group optionally having substituent(s), 
         (iii) a group represented by the formula: —OR 2′  wherein R 2′  is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), and 
         (iv) a halogen atom, 
         Ar′ is an aromatic hydrocarbon group optionally having substituent(s), 
         a group represented by the formula: 
       
       
         
           
           
               
               
           
         
         is a group represented by the formula: 
       
       
         
           
           
               
               
           
         
         s is an integer of 0 to 2, 
         t is an integer of 1 to 3, and 
         the total of s and t is 4 or less; 
         provided that when X is methylene, then Y should be methylene optionally having substituent(s), 
         or a salt thereof or a prodrug thereof, to a mammal in need thereof. 
       
     
     
         2 . A method for suppressing a peripheral nerve disorder induced by an anti-cancer agent, which comprises administering a compound represented by the formula (III): 
       
         
           
           
               
               
           
         
         wherein R 1aa  is C 1-6  alkyl, 
         X aa  is methylene or an oxygen atom, and 
         Ar aa  is phenyl optionally having 1 or 2 substituent(s) selected from a halogen atom, C 1-6  alkyl and C 1-6  alkoxy, 
         or a salt thereof or a prodrug thereof, to a mammal in need thereof. 
       
     
     
         3 . The method according to  claim 1 , wherein the compound is ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate or a salt thereof or a prodrug thereof. 
     
     
         4 . The method according to  claim 1 , wherein the compound is ethyl (3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carboxylate or a salt thereof or a prodrug thereof. 
     
     
         5 . The method according to  claim 1 , wherein the anti-cancer agent is selected from paclitaxel, docetaxel, vincristine, cisplatin, carboplatin and bortezomib. 
     
     
         6 . The method according to  claim 5 , wherein the anti-cancer agent is paclitaxel. 
     
     
         7 . The method according to  claim 1 , wherein the anti-cancer agent is selected from paclitaxel, docetaxel, vincristine, vinblastine, cisplatin, carboplatin, oxaliplatin and bortezomib. 
     
     
         8 . The method according to  claim 1 , wherein the compound is ethyl (−)-6-[(2-chloro-4-fluorobenzyl)sulfonyl]-1-cyclohexene-1-carboxylate or a salt thereof or a prodrug thereof. 
     
     
         9 . The method according to  claim 1 , wherein the compound is ethyl (+)-6-[(2-chloro-4-fluorobenzyl)sulfonyl]-1-cyclohexene-1-carboxylate or a salt thereof or a prodrug thereof. 
     
     
         10 . The method according to  claim 1 , wherein the anti-cancer agent is selected from taxane anti-cancer agents,  vinca  alkaloid anti-cancer agents, platinum preparations and molecular targeted drugs. 
     
     
         11 . The method according to  claim 10 , wherein the taxane anti-cancer agent is selected from paclitaxel and docetaxel. 
     
     
         12 . The method according to  claim 10 , wherein the vinca alkaloid anti-cancer agent is selected from vincristine and vinblastine. 
     
     
         13 . The method according to  claim 10 , wherein the platinum preparation is selected from cisplatin, carboplatin and oxaliplatin. 
     
     
         14 . The method according to  claim 10 , wherein the molecular targeted drug is bortezomib. 
     
     
         15 . The method according to  claim 1 , wherein the dosage form of the compound is subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection or drip infusion. 
     
     
         16 . The method according to  claim 1 , wherein the compound and the anti-cancer agent are administered to the mammal simultaneously or in a staggered manner. 
     
     
         17 . The method according to  claim 1 , wherein the compound is used in combination with other drugs that suppress side effects of the anti-cancer agent. 
     
     
         18 . The method according to  claim 17 , wherein the other drug is selected from pregabalin, gabapentin and morphine. 
     
     
         19 . The method according to  claim 2 , wherein the compound is ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate or a salt thereof or a prodrug thereof. 
     
     
         20 . The method according to  claim 2 , wherein the compound is ethyl (3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carboxylate or a salt thereof or a prodrug thereof. 
     
     
         21 . The method according to  claim 2 , wherein the anti-cancer agent is selected from paclitaxel, docetaxel, vincristine, cisplatin, carboplatin and bortezomib. 
     
     
         22 . The method according to  claim 21 , wherein the anti-cancer agent is paclitaxel. 
     
     
         23 . The method according to  claim 2 , wherein the anti-cancer agent is selected from paclitaxel, docetaxel, vincristine, vinblastine, cisplatin, carboplatin, oxaliplatin and bortezomib. 
     
     
         24 . The method according to  claim 2 , wherein the anti-cancer agent is selected from taxane anti-cancer agents, vinca alkaloid anti-cancer agents, platinum preparations and molecular targeted drugs. 
     
     
         25 . The method according to  claim 24 , wherein the taxane anti-cancer agent is selected from paclitaxel and docetaxel. 
     
     
         26 . The method according to  claim 24 , wherein the vinca alkaloid anti-cancer agent is selected from vincristine and vinblastine. 
     
     
         27 . The method according to  claim 24 , wherein the platinum preparation is selected from cisplatin, carboplatin and oxaliplatin. 
     
     
         28 . The method according to  claim 24 , wherein the molecular targeted drug is bortezomib. 
     
     
         29 . The method according to  claim 2 , wherein the dosage form of the compound is subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection or drip infusion. 
     
     
         30 . The method according to  claim 2 , wherein the compound and the anti-cancer agent are administered to the mammal simultaneously or in a staggered manner. 
     
     
         31 . The method according to  claim 2 , wherein the compound is used in combination with other drugs that suppress side effects of the anti-cancer agent. 
     
     
         32 . The method according to  claim 31 , wherein the other drug is selected from pregabalin, gabapentin and morphine.