Phenoxyalkylamine derivatives useful as opioid delta receptor ligands

Abstract

A medicament useful for preventive and/or therapeutic treatment of nerve system diseases which comprises, as an active ingredient, a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof: wherein, X represents a group represented by the following general formula (II), (III), (IV), (V), or (VI), “A” represents a saturated or unsaturated 3- to 6-membered carbocyclic group and the like, “B” represents CH 2 and the like, “n” represents 0 to 2, R 1 represents a hydrogen atom, a halogen atom and the like, R 2 , R 3 , and R 7 to R 14 represent a hydrogen atom, a lower alkyl group which may be substituted and the like, R 4 represents a hydrogen atom, a lower alkyl group which may be substituted and the like, R 5 represents a hydrogen atom, a halogen atom and the like, R 6 represents a saturated or unsaturated monocyclic or bicyclic carbocyclic group and the like, and R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , or R 11 and R 12 may bind to each other to form a cyclic structure.

1 . A compound represented by the following general formula (I) of a salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein, X represents the following group (II), (III), (IV), (V), or (VI),  
       
         
           
           
               
               
           
         
         “A” represents a saturated or unsaturated 3- to 6-membered carbocyclic group,  
         “B” represents —CH 2 — or a single bond,  
         “n” represents 0, 1 or 2,  
         R 1  represents a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a lower alkoxy group which may be substituted, a hydroxy group, a cyano group, an amino group, a N,N-di(lower alkyl)amino group, a N,N-di(substituted lower alkyl)amino group, a nitro group, a carbamoyl group, a N,N-di(lower alkyl)carbamoyl group, a N,N-di(substituted lower alkyl)carbamoyl group, a carboxyl group, a lower alkoxycarbonyl group which may be substituted or a lower alkylcarbonyl group which may be substituted,  
         R 2 , R 3 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14  independently represent a hydrogen atom, a lower alkyl group which may be substituted or a lower alkenyl group which may be substituted,  
         R 4  represents a hydrogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, or a lower alkoxy group which may be substituted,  
         R 5  represents a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a lower alkoxy group which may be substituted, a hydroxy group, a cyano group, an amino group, a N,N-di(lower alkyl)amino group, a N,N-di(substituted lower alkyl)amino group, a carbamoyl group, a N,N-di(lower alkyl)carbamoyl group, a N,N-di(substituted lower alkyl)carbamoyl group, a carboxyl group, a lower alkoxycarbonyl group which may be substituted, or a lower alkylcarbonyl group which may be substituted,  
         R 6  represents a saturated or unsaturated monocyclic or bicyclic carbocyclic group, a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing one or more hetero atoms or a N-(lower alkyl)carbonyl-N-(substituted or unsubstituted phenyl)amino group.  
       
     
     
         2 . The compound or a salt thereof according to  claim 1 , wherein R 6  represents the following group (VII):  
       
         
           
           
               
               
           
         
       
       wherein,  
       
         
           
           
               
               
           
         
       
       represents a single bond or a double bond, 
 R 15  represents a hydrogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, or oxo group,  
 R 16  represents a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted; a lower alkenyl group which may be substituted, a lower alkoxy group which may be substituted, a hydroxy group, a cyano group, an amino group, a N,N-di(lower alkyl)amino group, a N,N-di(substituted lower alkyl)amino group, a nitro group, a carbamoyl group, a N,N-di(lower alkyl)carbamoyl group, a N,N-di(substituted lower alkyl)carbamoyl group, carboxyl group, a lower alkoxycarbonyl group which may be substituted, or a lower alkylcarbonyl group which may be substituted.  
 
     
     
         3 . The compound or a salt thereof according to  claim 1 , wherein X represents the group (II), (III), (V), or (VI), 
 “A” represents a residue derived from a ring selected from the group consisting of benzene, and cyclohexane,    “B” represents —CH 2 — or a single bond,    “n” represents 0, 1, or 2,    R 1  represents a hydrogen atom or a lower alkoxy group,    R 2 , R 3 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14  each independently represent a hydrogen atom or a lower alkyl group which may be substituted,    R 4  represents a hydrogen atom or a lower alkyl group which may be substituted,    R 5  represents a hydrogen atom or a lower alkylcarbonyl group which may be substituted,    R 6  represents a residue of a ring selected from the group consisting of benzene, naphthalene, indane, benzofuran, imidazole, benzimidazole, indole, quinoline, benzotriazole, benzimidazole, benzisothiazole, benzisoxazole, quinazoline, isoquinoline and benzoxazine wherein a hydrogen atom on ring may be replaced with halogen, oxo, lower alkyl, hydroxymethyl, lower alkoxy or benzyl.    
     
     
         4 . The compound or a salt thereof according to  claim 1 , wherein X represents the group (II).  
     
     
         5 . The compound or a salt thereof according to  claim 2 , wherein X represents the group (II).  
     
     
         6 . A pharmaceutical composition, said pharmaceutical composition comprising at least one compound of formula (I) according to  claim 1 .  
     
     
         7 . The pharmaceutical composition according to  claim 6 , wherein the composition further comprises one or more pharmaceutical additives.  
     
     
         8 . The pharmaceutical composition according to  claim 6 , which has affinity for an opioid δ receptor.  
     
     
         9 . A method for therapeutic treatment of a central nerve system disease selected from the group consisting of schizophrenia, depression, cerebral apoplexy, epilepsy, Alzheimer's disease, and Parkinson's disease, which comprises administering a therapeutically effective amount of at least one compound according to  claim 1  or a pharmacologically acceptable salt thereof to a mammal.  
     
     
         10 . A method for therapeutic treatment of pain of diseases of the peripheral nerve system, which comprises administering therapeutically effective amount of at least one compound according to  claim 1  or a pharmacologically acceptable salt thereof to a mammal.