Benzylamine analogues

Abstract

A compound of the formula (I): wherein R 1 represents a C 1 -C 6 alkyl, (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 the same or different and represent hydrogen or a C 1 -C 6 alkyl; R a represents hydrogen, C 1 -C 6 alkyl or C 2 -C 6 alkenyl or together with R 2 represents a C 1 -C 3 alkylene; Arom represents a heteroaryl; A represents a C 1 -C6 alkylene; E represents a single bond, oxygen, sulphur or R 4 NR 4 —, wherein R 4 is hydrogen or C 1 -C 7 alkenoyl; X 1 and X 2 both represent oxygen; X 2 is attached at the 3-position or the 4-position; or a pharmacologically acceptable salt or ester thereof. The compound has superior acetylcholinesterase inhibitory action and selective serotonin reuptake inhibitory action, and is useful for treating Alzheimer's disease, depression, Huntington's chorea, Pick's disease, tardive dyskinesia, compulsive disorders or panic disorders.

1 . A compound of the formula (I): 
     
       
         
         
             
             
         
       
       wherein
 R 1  represents a C 1 -C 6  alkyl 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 represent a hydrogen atom or a C 1 -C 6  alkyl group; 
 Arom represents a heteroaryl group which is unsubstituted or is substituted at from 1 to 3 positions by one or more substituents, which are the same or different, 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; 
 said heteroaryl group is a 5 to 10 membered aromatic heterocyclic group containing 1 to 3 sulfur, oxygen and/or nitrogen atoms; 
 A represents a C 1 -C 6  alkylene group; 
 R a  represents a hydrogen atom, a C 1 -C 6  alkyl group or a C 2 -C 6  alkenyl group or together with R 2 , represents a C 1 -C 3  alkylene group, wherein in the case of a C 2 -C 3  alkylene group, said alkylene group may contain a double bond; 
 E represents 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; 
 X 1  and X 2  both represent an oxygen atom; 
 and X 2  is attached at the 3-position or the 4-position; 
 
       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: R 1 —C(═X 1 )— is a (C 1 -C 4  alkyl)carbamoyl group or a di(C 1 -C 4  alkyl)carbamoyl group. 
   
   
       3 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein the group of the formula: R 1 —C(═X 1 )— is a di(C 1 -C 4  alkyl)carbamoyl group. 
   
   
       4 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein the group of the formula: R 1 —C(═X 1 )— is a dimethylcarbamoyl group or an ethylmethylcarbamoyl group. 
   
   
       5 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein a group of the formula: R 1 —C(═X 1 )— is a dimethylcarbamoyl group, 
   
   
       6 . 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. 
   
   
       7 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein R 2  is a hydrogen atom or a C 1 -C 6  alkyl group. 
   
   
       8 . 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. 
   
   
       9 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein R a  together with R 2  is a C 1 -C 3  alkylene group. 
   
   
       10 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein R a , together with R 2 , is a C 2 -C 3  alkylene group which may contain a double bond. 
   
   
       11 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein R a , together with R 2 , is a C 3  alkylene group which contains a double bond. 
   
   
       12 . 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. 
   
   
       13 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein the heteroaryl group of Arom is selected from the group consisting of furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and quinolyl 
   
   
       14 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein the heteroaryl group of Arom is pyridyl group. 
   
   
       15 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein A is a methylene group or an ethylene group. 
   
   
       16 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein A is an ethylene group. 
   
   
       17 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein E is an oxygen atom or a single bond. 
   
   
       18 . The compound or the pharmacologically acceptable salt or ester thereof according to  claim 1 , wherein E is an oxygen atom. 
   
   
       19 . A pharmaceutical composition containing a pharmaceutically effective amount of a compound or a pharmacologically acceptable salt or ester thereof according to  claim 1  in combination with a pharmacologically acceptable carrier. 
   
   
       20 . A method of treating Alzheimer's disease, depression, Huntington's chorea, Pick's disease, tardive dyskinesia, compulsive disorders or panic disorders in a human comprising administering to said human a pharmaceutically effective amount of a compound or a pharmacologically acceptable salt or ester thereof according to  claim 1 . 
   
   
       21 . A method according to  claim 20 , wherein the method is for treating Alzheimer's disease.