Agent for regeneration and/or protection of nerves

Abstract

An EP2 agonist which may have an EP3 agonistic effect has an effect of regenerating and/or protecting nerves, and is therefore useful as a therapeutic agent for a disease of the peripheral nervous system, such as a lower or upper motor neuron disease, a nerve root disease, plexopathy, thoracic outlet compression syndrome, peripheral neuropathy, neurofibromatosis and neuromuscular transmission disease. An EP2 agonist which has an EP3 agonistic effect is a safe and effective agent for the regeneration and/or protection of nerves which has little influence on the circulatory system.

1 . An agent for regeneration and/or protection of nerves comprising an EP2 agonist which may have an EP3 agonistic effect. 
     
     
         2 . The agent for the regeneration and/or protection of nerves according to  claim 1 , comprising an EP2 agonist having an EP3 agonistic effect. 
     
     
         3 . The agent according to  claim 2 , wherein the EP2 agonist having an EP3 agonistic effect is a compound represented by formula (I): 
       
         
           
           
               
               
           
         
         wherein ring A is a 5 or 6-membered ring which may comprise 1 to 3 hetero atom(s) selected from nitrogen, oxygen and sulfur in addition to X and Y, and furthermore may have a substituent(s), 
         X and Y are each independently nitrogen or carbon, 
         D is hydrocarbon which may have a substituent(s), 
         E is a bond, oxygen or optionally oxidized sulfur, 
         G is a bond, hydrocarbon which may have a substituent(s) or hetero ring which may have a substituent(s), 
         J is an acidic group which may be protected, 
         W is hydrocarbon which may have a substituent(s), a salt thereof, an N-oxide thereof, an S-oxide thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin clathrate thereof. 
       
     
     
         4 . The agent according to  claim 3 , wherein the compound represented by formula (I) is a compound represented by formula (I-1): 
       
         
           
           
               
               
           
         
         wherein ring A 1  is 5 or 6 membered ring which may comprise 1 to 3 hetero atom(s) selected from nitrogen, oxygen and sulfur in addition to X and Y, and may have more substituent(s), 
         E 1  is oxygen or optionally oxidized sulfur, 
         R is hydrogen or C1-8 aliphatic hydrocarbon group, and 
         the other symbols have the same meanings as those described in the  claim 3 . 
       
     
     
         5 . The agent according to  claim 4 , wherein the compound represented by formula (I-1) is a compound represented by (1-5): 
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen or C1-4 aliphatic hydrocarbon group, R 2  is hydrocarbon group which may have a substituent(s),   is β-configuration, and the other symbols have the same meanings as those described in the  claim 4 . 
       
     
     
         6 . A medicament combined an EP2 agonist having an EP3 agonistic effect, with one or more selected from an EP2 agonist and an EP3 agonist. 
     
     
         7 . The agent according to  claim 1 , wherein the regeneration and/or protection of nerves is a prevention and/or a treatment for a disease of the peripheral nervous system. 
     
     
         8 . A medicament comprising an EP2 agonist which may have an EP3 agonistic effect, and one or more species selected from prostaglandins, prostaglandin derivatives, nonsteroidal anti-inflammatory drugs, vitamins, muscle relaxants, antidepressants, nitric oxide synthase inhibitors, aldose reductase inhibitors, poly ADP-ribose polymerase inhibitors, excitatory amino acid receptor antagonists, radical scavengers, astrocyte modulators, phosphodiesterase inhibitor and immunosuppressive agent in combination. 
     
     
         9 . A method for the regeneration and/or protection of nerves, which comprises administering to a mammal an effective amount of an EP2 agonist which may have an EP3 agonistic effect. 
     
     
         10 . A use of an EP2 agonist which may have an EP3 agonistic effect, for the manufacture of an agent for regeneration and/or protection of nerves. 
     
     
         11 . A compound represented by formula (I-2): 
       
         
           
           
               
               
           
         
         wherein ring A 2  is a 5 or 6-membered ring which may comprise 1 to 3 hetero atom(s) selected from nitrogen, oxygen and sulfur, and may have more substituent(s), and 
         the other symbols have the same meanings as those described in the  claim 4 , excluding 
         2-[(2-{(1R,2R)-2-[(1E,3S,5S)-3-hydroxy-5-methyl-1-nonenyl]-5-oxocyclopentyl}ethyl)sulfanyl]-1,3-thiazole-4-carboxylic acid, 
         2-[(2-{(1R,2R)-2-[(1E,3R)-3-hydroxy-4,4-dimethyl-1-octenyl]-5-oxocyclopentyl}ethyl)sulfanyl]-1,3-thiazole-4-carboxylic acid, 
         2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4-methyl-1-nonenyl]-5-oxocyclopentyl}ethyl)sulfanyl]-1,3-thiazole-4-carboxylic acid, 
         2-[(2-{(1R,2R)-2-[(1E)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-oxocyclopentyl}ethyl)sulfanyl]-1,3-thiazole-4-carboxylic acid and 
         2-[(2-{(1R,2R)-2-[(1E)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-oxocyclopentyl}ethyl)sulfonyl]-1,3-thiazole-4-carboxylic acid, 
         a salt thereof, an N-oxide thereof, an S-oxide thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin clathrate thereof. 
       
     
     
         12 . The compound according to  claim 11 , which is represented by formula (I-3): 
       
         
           
           
               
               
           
         
         wherein   is α-configuration, and the other symbols have the same meanings as those described in the  claim 4  and  claim 5 . 
       
     
     
         13 . The compound according to  claim 12 , wherein R 1  is hydrogen or C1-4 alkyl group, R 2  is C1-8 aliphatic hydrocarbon group which may have a substituent(s), or (C3-8 cycloalkyl)-(C1-4 aliphatic hydrocarbon) group which may have a substituent(s). 
     
     
         14 . The compound according to  claim 11 , which is selected from
 2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclohexyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid,   2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4,8-dimethyl-1,7-nonadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid,   2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4,7-dimethyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid,   2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-4-methyl-1-nonen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid,   2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid,   2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-4,8-dimethyl-1-nonen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid,   2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid,   2-[(2-{(1R,2R)-2-[(1E,4S)-6-cyclobutyl-4-hydroxy-4-methyl-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid,   2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-4-methyl-1-decen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid,   2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-7-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid and   2-[(2-{(1R,2R)-2-[(1E,4S)-6-cyclobutyl-4-hydroxy-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid.   
     
     
         15 . 2-[(2-{(2R)-2-[(1E)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid,
 2-[(2-{(2R)-2-[(1E)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid,   2-[(2-{(2R)-2-[(1E)-4-hydroxy-4-methyl-1-decen-5-yn-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid,   2-[(2-{(2R)-2-[(1E,4R)-4-hydroxy-4-methyl-1-decen-5-yn-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid,   2-[(2-{(2R)-2-[(1E,4S)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid or   2-[(2-{(2R)-2-[(1E,4S)-4-hydroxy-4,7-dimethyl-1,7-octadien-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid,   a salt thereof, an N-oxide thereof, an S-oxide thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin clathrate thereof.   
     
     
         16 . An agent for the regeneration and/or protection of nerves, or an agent to increase cauda equina blood flow comprising the compound which is represented by formula (I-2) or the compound according to  claim 15 , the salt thereof, the N-oxide thereof, the S-oxide thereof, the solvate thereof or the prodrug thereof, or the cyclodextrin clathrate thereof. 
     
     
         17 . The agent according to  claim 16 , which is a preventive and/or a therapeutic agent for spinal canal stenosis and/or cervical vertebra symptom.