Benzylamine analogues

Abstract

A compound of the formula (I): wherein R 1 is C 1 -C 6 alkyl, amino, (C 1 -C 6 alkyl)amino, di(C 1 -C 6 alkyl)amino or a nitrogen-containing saturated heterocyclic; R 2 and R 3 are hydrogen or C 1 -C 6 alkyl; Arom is phenyl, idenyl, napthyl, phenanthrenyl, furyl, thiolyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3 oxadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or quinolyl; A is C 1 -C 6 alkylene; R a is hydrogen, C 1 -C 6 alkyl or C 2 -C 6 alkenyl; E is a single bond, oxygen, sulfur or —NR 4 —, wherein R 4 is hydrogen or C 1 -C 7 alkanoyl; X 1 and X 2 are oxygen or sulfur; or a pharmacologically acceptable salt or ester thereof.

1 . A compound of the formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is a C 1 -C 6  alkyl group, an amino group, a (C 1 -C 6  alkyl)amino group, a di(C 1 -C 6  alkyl)amino group or a nitrogen-containing saturated heterocyclic group; 
 R 2  and R 3  are the same or different and are a hydrogen atom or a C 1 -C 6  alkyl group; 
 Arom is an unsubstituted aryl group, a substituted aryl group which is substituted at 1 to 5 positions, an unsubstituted heteroaryl group or a substituted heteroaryl group which is substituted at 1 to 3 positions;
 wherein the unsubstituted or substituted aryl group of Arom is selected from the group consisting of phenyl, indenyl, naphthyl, phenanthrenyl and anthracenyl; 
 wherein the unsubstituted or substituted heteroaryl group of Arom is selected from the group consisting of furyl, thiolyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3 oxadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and quinolyl; 
 wherein the substituents of the substituted aryl group and of the substituted heteroaryl group are independently selected from the group consisting of a halogen atom, a C 1 -C 6  alkyl group, a halogeno C 1 -C 6  alkyl group, a C 1 -C 6  alkoxy group, a C 1 -C 6  alkylthio group, a C 1 -C 3  alkylenedioxy group, a C 1 -C 7  alkanoyl group, a C 2 -C 7  alkyloxycarbonyl group, an amino group, a C 1 -C 7  alkanoylamino group, a hydroxyl group, a mercapto group, a cyano group, a nitro group and a carboxyl group; 
 
 A is an C 1 -C 6  alkylene group; 
 R a  is a hydrogen atom, a C 1 -C 6  alkyl group or a C 2 -C 6  alkenyl group; 
 E is a single bond, an oxygen atom, a sulfur atom or a group of the formula: —NR 4 —, wherein R 4  represents a hydrogen atom or a C 1 -C 7  alkanoyl group; and 
 X 1  and X 2  are the same or different and are an oxygen atom or a sulfur atom; 
 
       or a pharmacologically acceptable salt or ester thereof. 
     
     
         2 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein the group of the formula: 
       
         
           
           
               
               
           
         
       
       is a carbamoyl group, a (C 1 -C 4  alkyl)carbamoyl group, a di(C 1 -C 4  alkyl)carbamoyl group, a thiocarbamoyl group, a (C 1 -C 4  alkyl)thiocarbamoyl group or a di(C 1 -C 4  alkyl)thiocarbamoyl group. 
     
     
         3 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein the group of the formula: 
       
         
           
           
               
               
           
         
       
       is a (C 1 -C 4  alkyl)carbamoyl group, a di(C 1 -C 4  alkyl)carbamoyl group, a (C 1 -C 4  alkyl)thiocarbamoyl group or a di(C 1 -C 4  alkyl)thiocarbamoyl group. 
     
     
         4 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein the group of the formula: 
       
         
           
           
               
               
           
         
       
       is a (C 1 -C 4  alkyl)carbamoyl group or a di(C 1 -C 4  alkyl)carbamoyl group. 
     
     
         5 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein the group of the formula: 
       
         
           
           
               
               
           
         
       
       a di(C 1 -C 4  alkyl)carbamoyl group. 
     
     
         6 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein the group of the formula: 
       
         
           
           
               
               
           
         
       
       is a dimethylcarbamoyl group or an ethylmethylcarbamoyl group. 
     
     
         7 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein the group of the formula: 
       
         
           
           
               
               
           
         
       
       is a dimethylcarbamoyl group, 
     
     
         8 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein R 3  is a C 1 -C 6  alkyl group. 
     
     
         9 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein R 3  is a methyl group or an ethyl group. 
     
     
         10 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein R 3  is a methyl group. 
     
     
         11 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein R 2  is a hydrogen atom, a methyl group or an ethyl group. 
     
     
         12 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein R 2  is a hydrogen atom or a methyl group. 
     
     
         13 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein R a  is a hydrogen atom or a methyl group. 
     
     
         14 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein R a  is a hydrogen atom. 
     
     
         15 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein Arom is an unsubstituted or substituted phenyl group or an unsubstituted or substituted pyridyl group;
 and wherein the phenyl group is substituted at from 1 to 3 positions and the pyridyl group is substituted at one position; and   wherein the substituents of the phenyl group and the pyridyl group are independently selected from the group consisting of a halogen atom, a C 1 -C 6  alkyl group, a halogeno C 1 -C 6  alkyl group, a C 1 -C 6  alkoxy group, a C 1 -C 6  alkylthio group, a C 1 -C 3  alkylenedioxy group, a C 1 -C 7  alkanoyl group, a C 2 -C 7  alkyloxycarbonyl group, an amino, C 1 -C 7  alkanoylamino group, a hydroxyl group, a mercapto group, a cyano group, a nitro group and a carboxy group.   
     
     
         16 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein Arom is an unsubstituted phenyl group or a phenyl group substituted at from 1 to 3 positions by substituent(s), which are independently selected from the group consisting of a halogen atom, a C 1 -C 6  alkyl group, a halogeno C 1 -C 6  alkyl group, a C 1 -C 6  alkoxy group, a C 1 -C 6  alkylthio group, a C 1 -C 3  alkylenedioxy group, a C 1 -C 7  alkanoyl group, a C 2 -C 7  alkyloxycarbonyl group, an amino group, a C 1 -C 7  alkanoylamino group, a hydroxyl group, a mercapto group, a cyano group, a nitro group and a carboxyl group. 
     
     
         17 . The compound or the pharmacologically acceptable salt thereof according to  claim 1 , wherein Arom is a phenyl group substituted at three positions by halogen atoms or is a phenyl group substituted at one or two positions by substituent(s) which are independently selected from the group consisting of a halogen group, a C 1 -C 4  alkyl group, a C 1 -C 4  alkyl group substituted by from 1 to 3 fluorine atoms, a C 1 -C 4  alkoxy group, a C 1 -C 4  alkylthio group, a methylenedioxy group, an ethylenedioxy group, a C 1 -C 4  alkanoyl group, a cyano group and a nitro group. 
     
     
         18 . The compound or the pharmacologically acceptable salt thereof according to  claim 1 , wherein Arom is a phenyl group substituted at three positions by a fluorine atom or a chlorine atom or is a phenyl group substituted at one or two positions by substituent(s) which are independently selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl, methoxy, methylthio, acetyl, cyano and nitro. 
     
     
         19 . The compound or the pharmacologically acceptable salt thereof according to  claim 1 , wherein Arom is a phenyl group substituted at three positions by fluorine atoms or is a phenyl group substituted at one or two positions by substituent(s) which are independently selected from the group consisting of a fluorine atom, a chlorine atom, a methylthio group, an acetyl group, a cyano group and a nitro group. 
     
     
         20 . The compound or the pharmacologically acceptable salt thereof according to  claim 1 , wherein Arom is a phenyl group substituted at three positions by fluorine atoms or is a phenyl group substituted at one or two positions by substituent(s), which are independently selected from the group consisting of a fluorine atom, a chlorine atom, a methylthio group and a nitro group. 
     
     
         21 . The compound or the pharmacologically acceptable salt thereof according to  claim 1 , wherein Arom is a phenyl group substituted at one position by a fluorine atom, a chlorine atom or a nitro group or a phenyl group substituted at two positions by fluorine atoms. 
     
     
         22 . The compound or the pharmacologically acceptable salt thereof according to  claim 1 , wherein Arom is a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-nitrophenyl group or a 3,4-difluorophenyl group. 
     
     
         23 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein A is a C 1 -C 4  alkylene group. 
     
     
         24 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein A is an ethylene group. 
     
     
         25 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein E is an oxygen atom or a single bond. 
     
     
         26 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein E is an oxygen atom. 
     
     
         27 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein X 1  is an oxygen atom. 
     
     
         28 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein X 2  is an oxygen atom. 
     
     
         29 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein R 1  is an amino group, a (C 1 -C 6  alkyl)amino group or a di(C 1 -C 6  alkyl)amino group. 
     
     
         30 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein R 1  is an amino group, a (C 1 -C 4  alkyl)amino group or a di(C 1 -C 4  alkyl)amino group. 
     
     
         31 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein R 1  is a (C 1 -C 4  alkyl)amino group or a di(C 1 -C 4  alkyl)amino group. 
     
     
         32 . A pharmaceutical composition containing a pharmaceutically effective amount of a compound or a pharmacologically acceptable salt or ester thereof according to  claim 1 . 
     
     
         33 . A method of treating or preventing Alzheimer's disease, depression, Huntington's chorea, Pick's disease, tardive dyskinesia, compulsive disorders or panic disorders in a mammal comprising administering to a mammal a pharmaceutically effective amount of a compound or a pharmacologically acceptable salt or ester thereof according to  claim 1 . 
     
     
         34 . The method according to  claim 33  for treating or preventing Alzheimer's disease. 
     
     
         35 . A method according to  claim 33 , wherein the mammal is a human. 
     
     
         36 . The method according to  claim 34 , wherein the mammal is a human.