Synthesis of new sialooligosaccharide derivatives

Abstract

The invention relates to a method for the synthesis of compounds of general formula (1A) and salts thereof wherein one of the R groups is an α-sialyl moiety and the other is H, X 1 represents a carbohydrate linker, A is a D -glucopyranosyl unit optionally substituted with fucosyl, R 1 is a protecting group that is removable by hydrogenolysis, the integer in is 0 or 1, by a transsialidation reaction.

1 - 10 . (canceled) 
     
     
         11 . Compounds of general formula 1A′ and salts thereof 
       
         
           
           
               
               
           
         
         wherein one of the R groups is an α-sialyl moiety and the other is H, R 1  is a protecting group that is removable by hydrogenolysis, A is a  D -glucopyranosyl unit optionally substituted with fucosyl, integer m is 0 or 1, and X 1  represents a carbohydrate linker, provided that 1-O-β-benzyl and 1-O-β-(4,5-dimethoxy-2-nitro)-benzyl glycosides of 3′-O-(N-acetyl-neuraminosyl)-lactose sodium salt, and 1-O-β-benzyl glycoside of 6′-O-(N-acetyl-neuraminosyl)-lactose sodium salt are excluded. 
       
     
     
         12 . A compound according to  claim 11 , wherein compounds of general formula 1A′ and salts thereof are characterized by general formula 1′-3A and salts thereof 
       
         
           
           
               
               
           
         
         wherein SA is an α-sialyl moiety, R 1 , A, X 1  and m are defined in  claim 11 . 
       
     
     
         13 . A compound according to  claim 12 , wherein compounds of general formula 1′-3A and salts thereof are characterized by general formulae 1′-3B or 1′-3C and salts thereof 
       
         
           
           
               
               
           
         
         wherein R 3  is fucosyl or H, B is an N-acetyl-glucosaminopyranosyl unit optionally substituted with fucosyl and/or sialyl, and linker X 2  means a mono-, di-, tri-, tetra-, penta- or oligosaccharide representing a linear or a branched structure having the monosaccharide building units selected from glucose, N-acetyl-glucosamine, galactose, fucose and sialic acid, R 1  and A are defined in  claim 11 . 
       
     
     
         14 . A compound according to  claim 13 , wherein compounds of general formulae 1′-3B or 1′-3C and salts thereof are human milk oligosaccharides of general formula 1′-3D and salts thereof 
       
         
           
           
               
               
           
         
         wherein Y is independently an N-acetyl-lactosaminyl group optionally substituted with a sialyl and/or fucosyl residue, integer p is independently 0, 1 or 2, R 4′  is selected from the groups characterized by general formulae 3-3 and 4-3, 
       
       
         
           
           
               
               
           
         
         wherein R 6  is H or fucosyl residue, R 7  H or α-sialyl moiety, SA is α-sialyl moiety, and R 5′  is selected from H, α-sialyl moiety, a group of general formula 3-3 and a group of general formula 4-3. 
       
     
     
         15 . A compound according to  claim 13  or  claim 11 , wherein compounds of general formula 1′-3B or 1′-3C and salts thereof are selected from the group consisiting of R 1 -glycosides of lactose, lacto-N-neotetraose, para-lacto-N-hexaose, para-lacto-N-neohexaose, lacto-N-neohexaose, para-lacto-N-octaose and lacto-N-neooctaose, lacto-N-tetraose, lacto-N-hexaose, lacto-N-octaose, iso-lacto-N-octaose, lacto-N-decaose and lacto-N-neodecaose optionally substituted with one or more sialyl and/or fucosyl residue and having sialyl substituent in 3-OH of a terminal galactosyl residue, and salts thereof. 
     
     
         16 . A compound according to  claim 15 , wherein the compounds are selected from the group consisting of R′-glycosides of Neu5Acα2-3Galβ1-4Glc (3′-O-(N-acetyl-neuraminosyl)-lactose), Neu5Acα2-3Galβ1-4(Fucα1-3)Glc (3-O-fucosyl-3′-O-(N-acetyl-neuraminosyl)-lactose), Neu5Acα2-3Galβ1-3GlcNAcβ1-3Galβ1-4Glc (LST a), Neu5Acα2-3Galβ1-4GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (FLST a), Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAc131-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4Glc (DSLNT), Neu5Acα2-3Galβ1-3(Neu5Acα2-6)(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (FDSLNT I), Neu5Acα2-3Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (FDSLNT II), Neu5Acα2-3Galβ1-4GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc and salts thereof. 
     
     
         17 . A compound according to  claim 11 , wherein R 1  is selected from the group consisting of benzyl or 2-naphthylmethyl groups optionally substituted with at least one group selected from the group consisting of phenyl, alkyl or halogen. 
     
     
         18 . Compounds of general formula 2A′ and salts thereof 
       
         
           
           
               
               
           
         
         wherein A is a  D -glucopyranosyl unit optionally substituted with fucosyl, R′ is a protecting group that is removable by hydrogenolysis, X 1  represents a carbohydrate linker, integer m is 0 or 1, provided that a) when m is 0, then group A is substituted with fucosyl, and b) 1-O-β-benzyl-LNT, 1-O-β-(4-hydroxymethylbenzyl)-LNnT and 1-O-β-benzyl-LNnT are excluded. 
       
     
     
         19 . A compound according to  claim 18 , wherein compounds of general formula 2A′ and salts thereof are characterized by general formulae 2B′ or 2C′ and salts thereof 
       
         
           
           
               
               
           
         
         wherein R 3  is fucosyl, B is an N-acetyl-glucosaminopyranosyl unit optionally substituted with fucosyl and/or sialyl, and linker X 2  means a mono-, di-, tri-, tetra-, penta- or oligosaccharide representing a linear or a branched structure having the monosaccharide building units selected from glucose, N-acetyl-glucosamine, galactose, fucose and sialic acid, R 1  and A are as defined in  claim 18 . 
       
     
     
         20 . A compound according to  claim 19 , wherein compounds of general formulae formulae 2B′ or 2C′ and salts thereof are human milk oligosaccharide derivatives of general formula 2D′ or salts thereof 
       
         
           
           
               
               
           
         
         wherein R 1  is a group removable by hydrogenolysis, R 3  is H or fucosyl unit, Y is independently an N-acetyl-lactosaminyl group optionally substituted with a sialyl and/or fucosyl residue, integer p is independently 0, 1 or 2, R 8  is selected form the groups characterized by general formulae 5 and 6, 
       
       
         
           
           
               
               
           
         
         wherein R 6  is H or fucosyl residue, R 7  is H or α-sialyl moiety, 
         and R 9  is selected from H, α-sialyl moiety, a group of general formula 5 and a group of general formula 6. 
       
     
     
         21 . A compound according to  claim 19 , wherein compounds of 2B′ or 2C′ and salts thereof are selected from the group consisting of R 1 -glycosides of lacto-N-neotetraose, para-lacto-N-hexaose, para-lacto-N-neohexaose, lacto-N-neohexaose, para-lacto-N-octaose and lacto-N-neooctaose, lacto-N-tetraose, lacto-N-hexaose, lacto-N-octaose, iso-lacto-N-octaose, lacto-N-decaose and lacto-N-neodecaose optionally substituted with one or more sialyl and/or fucosyl residues and having an unsubstituted terminal galactosyl residue, and salts thereof. 
     
     
         22 . A compound of according to  claim 18 , wherein the compounds are selected from the group consisting of R 1 -glycosides of Galβ1-4(Fucα1-3)Glc (3-O-fucosyllactose), Galβ1-3GlcNAcβ1-3Galβ1-4Glc (LNT), Galβ1-4GlcNAcβ1-3Galβ1-4Glc (LNnT), Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (LNFP II), Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc (LNFP III), Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (LNFP V), Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (LNDFH II), Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4Glc (LSTb), Galβ1-3(Neu5Acα2-6)(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc, Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Galβ1-4GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (LNDFH III), or salts thereof. 
     
     
         23 . A compound according to  claim 18 , wherein R 1  is selected from the group consisting of benzyl or 2-naphthylmethyl groups optionally substituted with at least one group selected from the group consisting of phenyl, alkyl or halogen.