Aryloxypropanolamine derivatives, method of preparation and applications thereof

Abstract

The invention concerns aryloxypropanolamnine derivatives having at least an anti-diabetic and anti-fat activity and their methods of preparation and applications, particularly as human and veterinary medicine and animal food additive. These derivatives comply with the general formula (I) in which R 2 represents one of the following groups: —CH 2 —, —CH 2 —CH 2 , —CH(CH 3 )—CH 2 —C(CH 3 )—CH—, —C(CH 3 ) 2 —CH 2 — or a bond; Q represents: (i) a phenyl radical 3,4-substituted alkylene dioxy determining with the phenyl radical, a non-substituted benaodioxane unit, a non-substituted benzodioxol unit, or a 2-substituted benzodioxol unit, (ii) a phenyl radical 3 and/or 4-substituted, by a O—(CH 2 ) x —COOR 5 group, (iii) a condensed polycyclic hydrocarbon comprising at least two condensed cycles, (iv) a cyclic hydrocarbon system, optionally cross-linked, and constituting a cycloalkane comprising 1, 2 or 3 cycles.

1 . Compounds of general formula I below:  
       
         
           
           
               
               
           
         
       
       in which: 
 R 1 , a substituent in the 2-, 3-or 4-position of the phenyl group, is a hydrogen atom, a halogen atom or one of the following groups: hydroxyl; C 1 —C 10  lower alkyl selected in particular from methyl, ethyl, propyl, isopropyl, butyl and tert-butyl groups; C 1 -C 10 -alkoxy; benzyloxy; nitro; cyano; trifluoromethyl; or amino optionally substituted (monosubstituted or disubstituted) by 1 or 2 lower alkyl radicals as defined above;  
 R 2  is one of the following groups: —CH 2 —, —CH 2 —CH 2 —, —CH(CH 3 )—CH 2 —, —C(CH 3 )═CH—, —C(CH 3 ) 2 —CH 2 —, or a bond; and  
 Q is: 
 (i) a phenyl radical 3,4-disubstituted by alkylenedioxy, which forms, with the phenyl radical, an unsubstituted benzodioxane unit, an unsubstituted benzodioxole unit or a benzodioxole unit 2-substituted by two radicals R 3  and R according to the following formula:  
                     
 in which R 3  and R 4  are independently selected from the group comprising a hydrogen atom and a hydroxymethyl group;  
 
 (ii) a 3-and/or 4-substituted phenyl radical of formula II below:  
                     
 in which:  
 R 5  is a hydrogen atom or a linear or branched C 1 -C 6  lower alkyl radical; x is an integer between 1 and 3; and  
 y is 0 or 1;  
 (iii) a fused polycyclic hydrocarbon comprising at least two fused rings and selected from the following units: indene, indacene, naphthalene, azulene, biphenylene, acenaphthylene, fluorene, phenalene, phenanthrene and anthracene; or  
 (iv) an optionally bridged, cyclic hydrocarbon system which consists of a cyclo- alkane comprising 1, 2 or 3 rings optionally containing substituents selected from methyl, ethyl, isopropyl, propyl, butyl and tert-butyl groups, the main ring containing 5 or 6 members.  
 
     
     
         2 . Compound according to  claim 1 , characterized in that it has the following formula:  
       
         
           
           
               
               
           
         
       
       in which R 1  is a hydrogen atom, a methoxy or a chlorine atom in the para position, or a chlorine atom, a hydroxyl group, a nitro group, a cyano group or a trifluoromethyl group in the meta position.  
     
     
         3 . Compound according to  claim 1 , characterized in that it has the following formula:  
       
         
           
           
               
               
           
         
       
       in which R 1  is a hydrogen atom or a methoxy group in the para position.  
     
     
         4 . Compound according to  claim 1 , characterized in that it has the following formula:  
       
         
           
           
               
               
           
         
       
       in which R 1  is a hydrogen atom.  
     
     
         5 . Compound according to  claim 1 , characterized in that it has the following formula:  
       
         
           
           
               
               
           
         
       
       in which R 1  is a hydrogen atom.  
     
     
         6 . Compounds according to  claim 1 , characterized in that: 
 R 1  is a hydrogen atom, a 4-O-methyl, a 3-OH or a trifluoromethyl group;    R 2  is a bond or one of the following groups: —CH 2 — or —CH 2 —CH 2 —; and    Q is a fluorene group or a cyclic hydrocarbon system.    
     
     
         7 . Process for the preparation of a compound of formula (1) according to any one of  claims 1  to  6 , characterized in that it comprises reacting: 
 a phenoxyepoxypropane compound of formula III:  
                     
 in which R 1  is as defined above, with  
 a primary amine of formula (IV):  
                     
 in which R 2  and Q are as defined above.  
 
     
     
         8 . Process according to  claim 7 , characterized in that the intermediates of formula (III) and of formula (IV), NH 2 -R 2 -Q, are coupled by heating (in the crude form or dissolved in a polar solvent such as anhydrous dimethylformamide) for 12 to 14 hours, at a temperature between 70 and 100° C., to give compounds of formula (I).  
     
     
         9 . Process according to  claim 7  or  claim 8 , characterized in that if said compounds of formula (I) contain one or two ester groups, said esterified compounds are brought into contact respectively with 6 N HCl at 80° C. for 12 hours and with 1 N NaOH at room temperature for 12 to 48 hours to give the corresponding carboxylic acid salt.  
     
     
         10 . Drug, characterized in that it comprises at least one of the compounds according to any one of  claims 1  to  6 , in the pure state or in the form of salts with pharmaceutically acceptable acids or bases, and at least one pharmaceutically acceptable vehicle.  
     
     
         11 . Drug, characterized in that it comprises at least one of the compounds according to any one of  claims 1  to  6 , in the pure state or in the form of salts with pharmaceutically acceptable acids or bases, and at least one pharmaceutically acceptable vehicle, for combating weight problems and/or metabolic function disorders.  
     
     
         12 . Feed additive for animal rearing, characterized in that it comprises at least one compound according to any one of  claims 1  to  6 .