Thienylazolylalkoxyethanamines, their preparation and their application as medicaments

Abstract

The thienylazolylalkoxyethanamines (I) where R1 is a hydrogen atom, a halogen atom or a lower alkyl radical; R2, R3 and R4 represent, independently, a hydrogen atom or a lower alkyl radical; and Az represents a five-member nitrogenated hetercyclic aromatic group, N-methyl-substituted, that contains from one to three nitrogen atoms. They have analgesic activity in mammals, including humans. The compounds (I) can be obtained, for example, by reaction of a derivative of hydroxy-thienylazol (IV) with a derivative of a suitable N-(ethyl)amine. The compounds (IV) are useful intermediates in the synthesis of the compounds (I). The compounds (I) have an application in human and/or veterinary medicine.

1 . A derivative of thienylazolylalkoxyethanamine of general formula (I)  
       
         
           
           
               
               
           
         
         in which 
 R1 is a hydrogen or halogen atom, or an alkyl radical of 1 to 4 carbon atoms;  
 R2, R3 and R4 represent, independently, an atom of hydrogen or an alkyl radical of 1 to 4 carbon atoms; and  
 Az represents a nitrogenated heterocyclic aromatic five-member ring, N-methyl substituted, that contains from one to three atoms of nitrogen, of general formula (III)  
                     
 
         in which Z1, Z2 and Z3, independently, represent an atom of nitrogen or CH, and its physiologically acceptable salts:  
       
     
     
         2 . A compound according to  claim 1 , in which the halogen atom represents a fluorine, chlorine, or bromine atom.  
     
     
         3 . A compound according to  claim 1 , selected from the following group: 
 [1] 5-{α-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;    [2] Citrate of 5-{α-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;    [3] 5-{α-[2-(dimethylamino)ethoxy]-3-thienylmethyl}-1-methyl-1H-pyrazol;    [4] 2-{α-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-imidazol;    [5] 5-{α-[2-(dimethylamino)ethoxy]-3-methyl-2-thienylmethyl-}-1-methyl-1H-pyrazol;    [6] 5-{α-[2-(dimethylamino)ethoxy]-5-methyl-2-thienylmethyl }-1-methyl-1H-pyrazol;    [7] 5-{α-[2-(dimethylamino)ethoxy]-5-bromo-2-thienylmethyl}-1-methyl-1H-pyrazol;    [8] 5-{α-[2-(dimethylamino)ethoxy]-4-bromo-2-thienylmethyl}-1-methyl-1H-pyrazol;    [9] 5-{1-[2-(dimethylamino)ethoxy]-1-(2-thienyl)ethyl}-1-methyl-1H-pyrazol;    [10] (+)-5-{α-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;    [11] (−)-5-{α-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;    [12] Citrate of (+)-5-{α-[2-(dimethylamino)ethoxy]-2-thienylmethyl)}-1-methyl-1H-pyrazol;    [13] Citrate of (−)-5-{α-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;    [14] D-toluoyltartrate of (+)-5-{α-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol; and    [15] D-toluoyltartrate of (−)-5-{α-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol.    
     
     
         4 . Procedure for obtaining a derivative of thienylazolylalkoxyethanamine of general formula (I), according to  claim 1 , which comprises making a compound of general formula (IV)  
       
         
           
           
               
               
           
         
         in which R1, R2 and Az have the meaning indicated in  claim 1;   
         with a compound of general formula (V)  
         
           
             
             
                 
                 
             
           
         
         in which R3 and R4 have the meaning indicated in  claim 1 , and X represents a halogen atom or a leaving group.  
       
     
     
         5 . Procedure for obtaining a derivative of thienylazolylalkoxyethanamine of general formula (I), according to  claim 1 , which comprises making a compound of general formula (VI) react  
       
         
           
           
               
               
           
         
         in which R1 and R2 have the meaning indicated in  claim 1 , and Y represents a halogen atom. a leaving group or a hydroxyl group;  
         with a compound of general formula (VII)  
         
           
             
             
                 
                 
             
           
         
         in which R3 and R4 have the meaning indicated in  claim 1 .  
       
     
     
         6 . Procedure for obtaining a derivative of thienylazolylalkoxyethanamine of general formula (I), according to  claim 1 , enantiomerically pure, that comprises effecting the resolution of the racemic mixtures of general formula (I), by forming a salt with an enantiomerically pure acid.  
     
     
         7 . Procedure for obtaining a physiologically acceptable salt of a derivative of thienylazolylalkoxyethanamine of general formula (I), according to  claim 1 , that comprises making react a compound of general formula (I) with an inorganic acid or with an organic acid in the presence of a solvent.  
     
     
         8 . A pharmaceutical composition characterised because it contains, at least, one derivative of thienylazolylalkoxyethanamine of general formula (I), or one of its physiologically acceptable salts, according to any of the  claims 1  to  3 , and a pharmaceutically acceptable excipient.  
     
     
         9 . Use of a thienylazolylalkoxyethanamine of general formula (I), or one of its physiologically acceptable salts, according to any of the  claims 1  to  3 , in the elaboration of a medicament with analgesic activity in mammals, including man.  
     
     
         10 . A compound of general formula (IV), as an intermediate for the preparation of a compound of general formula (I), according to  claim 1   
       
         
           
           
               
               
           
         
         in which R1 and R2 have the meanings mentioned in  claim 1  and Az represents N-methylpyrazol.  
       
     
     
         11 . A compound according to  claim 10 , selected from the following group: 
 [16] 5-(α-hydroxy-2-thienylmethyl)-1-methyl-1H-pyrazol;    [17] 5-(α-hydroxy-3-methyl-2-thienylmethyl)-1-methyl-1H-pyrazol;    [18] 5-(α-hydroxy-5-methyl-2-thienylmethyl)-1-methyl-1H-pyrazol;    [19] 5-(α-hydroxy-5-bromo-2-thienylmethyl)-1-methyl-1H-pyrazol;    [20] 5-(α-hydroxy-4-bromo-2-thienylmethyl)-1-methyl-1H-pyrazol; and    [21] 5-[1-hydroxy-1-(2-thienyl)ethyl]-1-methyl-1H-pyrazol.    
     
     
         12 . Procedure for obtaining a compound of general formula (IV), according to  claim 10 , in which R2 represents a hydrogen atom, that comprises effecting the reduction of a compound of general formula (VIII)  
       
         
           
           
               
               
           
         
       
       in which R1 has the meaning indicated in  claim 1 , and Az represents N-methylpyrazol.  
     
     
         13 . Procedure according to  claim 12 , in which said reduction is effected by the use of a reducing agent selected from the group formed by metallic hydrides or with hydrogen in the presence of a catalyst.  
     
     
         14 . Procedure for obtaining a compound of general formula (IV), according to  claim 10 , that comprises adding to a carbonyl compound of general formula (IX)  
       
         
           
           
               
               
           
         
         in which R1 and R2 have the meaning indicated in  claim 1;   
         an or2anometallic reagent of general formula 
         Az-M 
         in which Az represents N-methylpyrazol, and M represents a lithium atom or the MgX function of the Grignard reagents, where X represents a halogen.  
       
     
     
         15 . Procedure for obtaining a compound of general formula (IV), according to  claim 10 , that comprises adding to carbonyl compound of general formula (X)  
       
         
           
           
               
               
           
         
         in which R2 has the meaning indicated in  claim 1  and Az represents N-methylpyrazol,  
         an organometallic reagent of general formula (XI)  
         
           
             
             
                 
                 
             
           
         
         in which R1 has the meaning indicated in  claim 1 , and M represents a lithium atom or the MgX function of the Grignard reagents, where X represents a halogen.