Polyhydroxyalkylpyrazine derivatives, their preparation and medicaments comprising them

Abstract

The present invention relates to compounds of formula (I) in which R 1 is any of the stereoisomeric forms of the chain —(CHOH) 3 —CH 2 OH  (II) and either (A) R 2 is a hydrogen atom and R 3 is any of the stereoisomeric forms of the chain —CH 2 —(CHOH) 2 —CH 2 OH  (III) or (B) R 2 is any of the stereoisomeric forms of the chains —(CHOH) 3 —CH 2 OH  (II) and —CH 2 —(CHOH) 2 —CH 2 OH  (III) and R 3 is a hydrogen atom, or their salts with an inorganic or organic acid, in a pharmaceutically acceptable vehicle, provided, however, that said compound is not fructosazine of formula deoxyfructosazine of formula a compound of formula and to methods of making such compounds, as well as to a method for the treatment or prevention of diabetes or complications of diabetes, this method comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I).

1 . A pharmaceutical composition comprising at least one compound of general formula:  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  represents the stereoisomeric forms of the chain 
 —(CHOH) 3 —CH 2 OH   (II) 
 and either (A) R 2  represents a hydrogen atom and R 3  represents the stereoisomeric forms of the chain 
 —CH 2  —(CHOH) 2 —CH 2 OH  (III) 
 or (B) R 2  represents the stereoisomeric forms of the chains 
 —(CHOH) 3 —CH 2 OH   (II) 
 or 
 —CH 2 —(CHOH) 2 —CH 2 OH  (III) 
 and R 3  represents a hydrogen atom, or a salt thereof with an organic or inorganic acid, provided however, that said compound is not  
 fructosazine of formula  
                     
 deoxyfructosazine of formula  
                     
 or the compound of formula  
                     
 
     
     
         2 . A pharmaceutical composition according to  claim 1  comprising a compound selected from the group consisting of: 
 1-[5-(1R,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol  
 1-[5-(1R,2R,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol  
 1-[5-(1R,2S,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol  
 1-[5-(1S,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol  
 1-[5-(1S,2R,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol  
 1-[5-(1S,2S,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol  
 1-[5-(1S,2S,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol  
 1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol  
 1-[5-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol  
 1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol  
 1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol  
 1-[5-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol  
 1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol  
 1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol  
 1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol  
 1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol  
 1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol  
 1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol  
 1-[6-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol  
 1-[6-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol 
 or a salt of such a compound with an inorganic or organic acid.  
 
 
     
     
         3 . A compound of formula:  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  represents the stereoisomeric forms of the chain 
 —(CHOH) 3 —CH 2 OH  (II) 
 and either (A) R 2  represents a hydrogen atom and R 3  represents the stereoisomeric forms of the chain 
 —CH 2 —(CHOH) 2 —CH 2 OH  (III) 
 or (B) R 2  represents the stereoisomeric forms of the chains 
 —(CHOH) 3 —CH 2 OH   (II) 
 or 
 —CH 2 —(CHOH) 2 —CH 2 OH  (III) 
 and R 3  represents a hydrogen atom, or a salt thereof with an inorganic or organic acid, provided, however, that said compound is not a compound having any of the following structures:  
                                       
 
     
     
         4 . A compound according to  claim 3  selected from the group consisting of: 
 1-[5-(1R,2R,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol  
 1-[5-(1S,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol  
 1-[5-(1S,2S,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol  
 1-[5-(1S,2S,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol  
 1-[5-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol  
 1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol  
 1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol  
 1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol  
 1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol  
 1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol  
 1-[6-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol or a salt of such a compound with an inorganic or organic acid.  
 
     
     
         5 . A compound according to  claim 3  selected from the group consisting of: 
 1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol  
 1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol  
 1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol 
 and their salts with an inorganic or organic acid.  
 
 
     
     
         6 . A process for the preparation of a compound according to  claim 3  in which R, of formula (I) represents the stereoisomeric forms of the —(CHOH) 3 —CH 2 OH chain (II), R 2  represents a hydrogen atom and R 3  represents the stereoisomeric forms of the —CH 2 —(CHOH) 2 —CH 2 OH chain (III), said process comprising reacting ammonium formate with an aldose, or a mixture of two aldoses, of the dextrorotatory or levorotatory series, of general formula: 
       CHO—CHOH—R 1   (X) 
       in which R 1  has the same meaning as in  claim 3 , isolating the product and optionally converting it to a salt.  
     
     
         7 . A process according to  claim 6  in which the aldose is selected from D-gulose, D-galactose, D-allose, D-altrose, D-idose, D-talose, L-glucose, L-mannose, L-galactose, L-allose, L-altrose, L-idose, L-talose and L-gulose.  
     
     
         8 . A process for the preparation of a compound according to  claim 3  in which R 1  of formula (I) represents the stereoisomeric forms of the —(CHOH) 3 —CH 2 OH chain (II), R 2  represents the stereoisomeric forms of the —(CHOH) 3 —CH 2 OH chains (II) and R 3  represents a hydrogen atom, said process comprising treating aminoaldose, or a mixture of 2 aminoaldoses, of general formula CHO—CH(NH 2 )—R 1  (XI) in which R 1  has the same meaning as in  claim 3 , isolating the product and optionally converting it to a salt with an inorganic or organic acid.  
     
     
         9 . The process according to  claim 8  in which said aminoaldose is D-galactosamine.  
     
     
         10 . A process for the preparation of a compound according to  claim 3  in which R 1  of formula (I) represents the stereoisomeric forms of the —(CHOH) 3 —CH 2 OH chain (II), R 2  represents the stereoisomeric forms of the —CH 2 —(CHOH) 2 —CH 2 OH chain (III) and R 3  represents a hydrogen atom, said process comprising treating an aminoaldose, or a mixture of two aminoaldoses of general formula CHO—CH(NH 2 )—R 1  (XI), in which R 1  has the same meaning as in  claim 3 , in acidic medium, isolating the product and optionally converting it to a salt with an inorganic or organic acid.  
     
     
         11 . A process according to  claim 10  in which said aminoaldoses or mixture of aminoaldoses comprises D-galactosamine.  
     
     
         12 . A process for the preparation of a compound according to  claim 3  in which R 1  of formula (I) is a stereoisomeric form of —(CHOH) 3 —CH 2 OH chain (II), R 2  is a stereoisomeric form of —CH 2 —(CHOH) 2 —CH 2 OH chain (III) and R 3  is a hydrogen atom, said process comprising reacting a ketose, or a mixture of two ketoses, of general formula HOCH 2 —CO—R 1  (XII) in which R 1  has the same meaning as in  claim 3 , with ammonium formate and isolating the product and optionally converting the product to a salt with an inorganic or organic acid.  
     
     
         13 . A process according to  claim 12  wherein said ketose of formula (XII) is selected from D-psicose, D-sorbose, D-tagatose, L-psicose, L-fructose, L-sorbose and L-tagatose.  
     
     
         14 . A method for the treatment or prevention of diabetes or complications of diabetes, this method comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  is any of the stereoisomeric forms of the chain 
 —(CHOH) 3 —CH 2 OH   (II) 
 and either (A) R 2  is a hydrogen atom and R 3  is any of the stereoisomeric forms of the chain 
 —CH 2 —(CHOH) 2 —CH 2 OH  (III) 
 or (B) R 2  is any of the stereoisomeric forms of the chains 
 —(CHOH) 3 —CH 2 OH  (II) 
 and 
 —CH 2 —(CHOH) 2 —CH 2 OH  (III) 
 and R 3  is a hydrogen atom, or their salts with an inorganic or organic acid, in a pharmaceutically acceptable vehicle, provided, however, that said compound is not  
 fructosazine of formula  
                     
 deoxyfructosazine of formula  
                     
 a compound of formula