Phenylacetic acid benzylamides

Abstract

Phenylacetic acid benzylamides having the following general structurewherein the substituents are defined herein, are disclosed, which compounds are hypoglcemic agents.

We claim:  
     
       1. A compound of the formula:                    
       wherein 
       R 1  represents an unbranched alkyleneimino group with 4 to 6 carbon atoms optionally mono- or di-(alkyl of 1 to 3 carbon atoms)-substituted;  
       R 2  represents a hydrogen or halogen atom or a methyl or methoxy group;  
       R 3  represents a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a phenyl group optionally substituted by a halogen atom or a methyl or methoxy group, an alkyl group with 1 or 2 carbon atoms substituted by a hydroxy, alkoxy, alkanoyloxy, tetrahydrofuranyl, tetrahydropyranyl, cyclocalkyl or phenyl group, in which the alkoxy part can contain from 1 to 3 carbon atoms, the alkanoyloxy part can contain 2 or 3 carbon atoms and the cycloalkyl part can contain 3 to 7 carbon atoms, an alkenyl group with 3 to 6 carbon atoms, an alkynyl group with 3 to 5 carbon atoms, a carboxy group or an alkoxycarbonyl group with a total of 2 to 5 carbon atoms;  
       R 4  represents a hydrogen atom, a methyl, ethyl or allyl group; and  
       W represents a methyl, hydroxymethyl, formyl, carboxyl, alkoxycarbonyl, cyanomethyl, 2-cyanoethyl, 2-carboxyethenyl, alkoxycarbonylmethyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonylethenyl group, in which each alkoxy part can contain from 1 to 4 carbon atoms and can be substituted by a phenyl group; and  
       when R 3  is other then hydrogen and/or the radical R 1  contains an optically active carbon atom, the enantiomeres and the diastereomeres thereof or their mixtures; when W is carboxyl, a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt thereof formed by an inorganic or organic acid with the amino function in the R 1 -position.  
     
     
       2. A compound of claim  1 , wherein 
       R 1  represents a pyrrolidino, piperidino, 4-methyl-piperidino, 3-methyl-piperidino, 3,3-dimethyl-piperidino, 3,5-dimethyl-piperidino or hexamethyleneimino group;  
       R 2  represents a hydrogen, fluorine or chlorine atom;  
       R 3  represents hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a phenyl, methyl-phenyl, chloro-phenyl, methoxy-phenyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydrofuran-2-yl-methyl, tetrahydropyran-2-yl-methyl, propargyl, hydroxymethyl, ethoxymethyl, acetoxymethyl, propionyloxymethyl, carboxy, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl group or an alkenyl group with 3 or 4 carbon atoms;  
       R 4  represents a methyl, ethyl or allyl group; and  
       W represents a methyl, hydroxymethyl, formyl, carbonyl, benzyloxycarbonyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, cyanomethyl, 2-carboxy-ethyl, 2-ethoxycarbonyl-ethyl, 2-cyano-ethyl, 2-carboxy-ethenyl, 2-ethoxycarbonyl-ethenyl or 2-cyano-ethenyl group or an alkoxycarbonyl group with 1 to 4 carbon atoms in the alkoxy part; and  
       when R 3  is other then hydrogen and/or R 1  represents the 3-methyl-piperidino group, the enantiomeres and the diastereomeres thereof or their mixtures; when W is carboxyl, a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt thereof formed by an inorganic or organic acid with the amino function in the R 1 -position.  
     
     
       3. A compound of claim  1 , wherein 
       R 1  represents a piperidino group;  
       R 2  represents a hydrogen atom;  
       R 3  represents an alkyl group with 1 to 6 carbon atoms, an alkenyl group with 3 or 4 carbon atoms, a phenyl, tetrahydropyran-2-yl-methyl, cyclopropylmethyl or cyclohexylmethyl group;  
       R 4  represents a methyl, ethyl or allyl group; and  
       W represents a carboxyl, methoxycarbonyl, ethoxycarbonyl or cyanomethyl group; and  
       the enantiomeres thereof or their mixtures; when W is carboxyl, a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt thereof formed by an inorganic or organic acid with the piperidino function.  
     
     
       4. A compound of claim  1 , wherein 
       R 1  represents a piperidino group;  
       R 2  represents a hydrogen atom;  
       R 3  represents an alkyl group with 3 to 6 carbon atoms, an alkenyl group with 3 or 4 carbon atoms, a phenyl, cyclopropylmethyl or cyclohexylmethyl group;  
       R 4  represents a methyl or ethyl group; and  
       W represents a carboxyl group; and  
       the enantiomeres thereof or their mixtures; a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt thereof formed by an inorganic or organic acid with the piperidino function.  
     
     
       5. A compound of claim  1 , wherein 
       R 1  represents a piperidino group;  
       R 2  represents a hydrogen atom;  
       R 3  represents an alkyl group with 3 to 6 carbon atoms, a 2-methyl-1-propen-1-yl, cyclomethylpropyl or cyclohexylmethyl group;  
       R 4  represents a methyl or ethyl group; and  
       W represents a carboxyl group; and  
       the enantiomeres thereof or their mixtures; a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt thereof formed by an inorganic or organic acid with the piperidino function.  
     
     
       6. A compound of claim  5 , wherein 
       R 3  represents a n-propyl, n-butyl, isobutyl, sec.butyl, n-pentyl, 2-methyl-1-propen-1-yl, cyclomethylpropyl or cyclohexylmethyl group;  
       the enantiomeres thereof or their mixtures; a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt thereof formed by an inorganic or organic acid with the piperidino function.  
     
     
       7. A compound of claim  5 , wherein 
       R 3  represents a n-propyl, n-butyl, isobutyl, sec.butyl or n-pentyl group; and  
       the enantiomeres thereof or their mixtures; a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt thereof salt thereof formed by an inorganic or organic acid with the piperidino function.  
     
     
       8. The compound of claim  5 , which is 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid; the enantiomeres thereof or their mixtures; a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt formed by an inorganic or organic acid with the piperidino function. 
     
     
       9. The compound of claim  5 , which is 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzoic acid; the enantiomeres thereof or their mixtures; a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt formed by an inorganic or organic acid with the piperidino function. 
     
     
       10. The compound of claim  5 , which is form (A) of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid, recrystallized from acetone/petroleum ether, having a melting point of 90°-92° C. 
     
     
       11. The compound of claim  5 , which is form (B) of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid, recrystallized from ethanol/water, having a melting point of 140°-142° C. 
     
     
       12. The compound of claim  5 , which is form (C) of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid, recrystallized from methanol, having a melting point of 74°-85° C. 
     
     
       13. The compound of claim  5 , which is 2-ethoxy-4-[N-(α-cyclohexylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid; the enantiomeres thereof or their mixtures; a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt formed by an inorganic or organic acid with the piperidino function. 
     
     
       14. The (S)-enantiomer of a compound as claimed in anyone of the claims  1  to  13 ; when W is carboxy, a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt formed by an inorganic or organic acid with the amino function in the R 1 -position. 
     
     
       15. A hypoglycemic pharmaceutical composition consisting essentially of an inert pharmaceutical carrier and an effective hypoglycemic amount of a compound of claim  1 .