US 2014/0234364 A1Published application

Total synthesis and immunological evaluation of saccharide moieties of the lipopolysaccharide from neisseria meningitidis

AssigneeMax-Planck-Gesellschaft zur Forderung der Wissenschaften e.V.

InventorsPeter H. Seeberger, You Yang, Chakkumkal Anish, Anika Reinhardt

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Abstract

The present invention relates to the total chemical synthesis of the monosaccharide 35# (R′═H), the disaccharide 36# (R′≠H; R″═H), the trisaccharide 37# (R′≠H; R″≠H; R′″≠H) and the tetrasaccharide 1# (R′≠H; R″≠H; R′″≠H) of the following general formula wherein R represents —Y—NH2Y represents a linker R′ is H or R″ is H or R′″ is H or of the lipopolysaccharide from Neisseria meningitidis, as well as to the trisaccharide 37# and the tetrasaccharide 1#, to vaccines containing at least one of the saccharides 1#, 35#, 36#, and 37# and to the use of such vaccine for immunization against diseases caused by infection with bacteria containing the tetrasaccharide α-GlcNAc-(1→2)-α-Hep-(1→3)-α-Hep-(1→5)-α-Kdo or the trisaccharide α-Hep-(1→3)-α-Hep-(1→5)-α-Kdo or α-GlcNAc-(1→2)-α-Hep-(1→3)-α-Hep, especially for immunization against meningitis, septicaemia, pneumonia and nasopharyngitis caused by Neisseria meningitidis.

Claims25

Dependent claims

Synthesis of synthetic saccharides of general formula (I)

wherein
R represents —Y—NH2
Y represents a linker
R′ represents
H or
R″ represents
H or
R′″
represents H
or
comprising or consisting of the steps:
A1) Reacting compound 26* with a compound HO—Y—NP14P15,
wherein P1, P13, P14 and P15 are protecting groups and Y is defined as above, yielding a compound of the formula 28#
A2) Performing deprotection reactions with compound 28# yielding a monosaccharide 35#,
wherein R is defined as above,
or
converting compound 28# to compound 7#,
wherein P6 and P7 are protecting groups, and Y, P13, P14 and P15 are defined as above;
B1) Reacting compound 6* of the formula
wherein
P8-P12 represent protecting groups
with compound 7# in order to obtain a compound 31# of the following chemical formula
wherein Y and P6 to P15 are defined as above;
B2) Performing deprotection reactions with compound 31# yielding a disaccharide 36#,
wherein R is defined as above,
or
performing a selective deprotection yielding a compound of the formula 3#,
Wherein P6 to P8, P10 to P15 and Y are defined as above;
C1) Reacting compound 3# with a compound of the formula 38#
wherein P2-P5 and P16 are protecting groups,
yielding a compound of the formula 39#,
wherein P2-P8, P10-P16 and Y are defined as above,
and
D1) Performing deprotection reactions with compound 39# yielding a trisaccharide 37#
wherein R is defined as above,
or
C2) Reacting the compound 4* of the formula
wherein
the groups P1 represent the same protecting group
with the compound 5* of the following chemical formula
wherein
P2-P5 are defined as above
and
Ar represents an aromatic ring or aromatic ring system
in order to obtain compound 30* of the following chemical formula
wherein
the group —SAr is converted to the group —O—C(═NPh)-CF3 in order to obtain compound 2* of the following chemical formula
wherein P1-P5 are defined as above,
Reacting compound 3# with a compound 2*,
yielding a compound of the formula 32#,
wherein P1-P8, P10-P15 and Y are defined as above,
and
D2) Converting the azide group of compound 32# into an acetamide group and performing deprotection reactions yielding a tetrasaccharide 1#
wherein R is defined as above.

51 more elements

Saccharide selected from the following group comprising the following compounds:

tetrasaccharide 1:
2-N-acetyl-2-deoxy-α-D-glucopyranosyl-(1→2)-L-glycero-α-D-manno-heptopyranosyl-(1→3)-L-glycero-α-D-manno-heptopyranosyl-(1→5)-2-(5-amino)pentyl-3-deoxy-α-D-manno-oct-2-ulopyranosidonic acid
mono-saccharide 35:
2-(5-amino)pentyl-3-deoxy-a-D-manno-oct-2-ulopyranosidonic acid
disaccharide 36:
L-glycero-a-D-manno-heptopyranosyl-(1→5)-2-(5-amino) pentyl-3-deoxy-a-D-manno-oct-2-ulopyranosidonic acid
trisaccharide 37:
L-glycero-α-D-manno-heptopyranosyl-(1→3)-L-glycero-α-D-manno-heptopyranosyl-(1→5)-2-(5-amino)pentyl-3-deoxy-α-D-manno-oct-2-ulopyranosidonic acid
compound 42:
2-(2-amino)ethyl-3-deoxy-a-D-manno-oct-2-ulopyranosidonic acid
compound 45:
2-(22-amino)docosanyl-3-deoxy-a-D-manno-oct-2-ulopyranosidonic acid
compound 48:
2-2-(2-aminoethoxy)ethyl-3-deoxy-a-D-manno-oct-2-ulpyrano sidonic acid
compound 51:
2-2-(5-aminomethyl)pyrrolidin-2-yl)ethyl-3-deoxy-a-D-man no-oct-2-ulpyranosidonic acid
compound 54:
2-4-(2-aminoethoxy)benzyl-3-deoxy-a-D-manno-oct-2-ulpyranosidonic acid
compound 59:
L-glycero-a-D-manno-heptopyranosyl-(1→5)-2-(38-amino-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxaoctatriacontanyl)-3-deoxy-a-D-manno-oct-2-ulopyranosidonic acid
compound 64:
L-glycero-a-D-manno-heptopyranosyl-(1→5)-2-(((aminomethyl)disulfanyl)methyl)-3-deoxy-a-D-manno-oct-2-ulopyranosidonic acid
compound 69:
L-glycero-a-D-manno-heptopyranosyl-(1→5)-2-(2-((2-aminoethyl)(methyl)amino)ethyl)-3-deoxy-a-D-manno-oct-2-ulopyranosidonic acid
compound 74:
L-glycero-a-D-manno-heptopyranosyl-(1→5)-2-(2-(aminomethoxy)phenoxy)methyl-3-deoxy-a-D-manno-oct-2-ulopyranosidonic acid
compound 79:
L-glycero-a-D-manno-heptopyranosyl-(1→5)-2-(3-(6-(aminomethyl)piperidin-2-yl)propanyl)-3-deoxy-a-D-manno-oct-2-ulopyranosidonic acid
compound 86:
L-glycero-α-D-manno-heptopyranosyl-(1→3)-L-glycero-α-D-manno-heptopyranosyl-(1→5)-2-(40-amino)tetracontanyl-3-deoxy-α-D-manno-oct-2-ulopyranosidonic acid
compound 93:
L-glycero-α-D-manno-heptopyranosyl-(1→3)-L-glycero-α-D-manno-heptopyranosyl-(1→5)-2-(2-(4-aminophenoxy)ethyl-3-deoxy-α-D-manno-oct-2-ulopyranosidonic acid
compound 100:
L-glycero-α-D-manno-heptopyranosyl-(1→3)-L-glycero-α-D-manno-heptopyranosyl-(1→5)-2-(2-(4-(2-aminoethyl)-2-methoxyphenyl)ethyl)-3-deoxy-α-D-manno-oct-2-ulopyranosidonic acid
compound 107:
L-glycero-α-D-manno-heptopyranosyl-(1→3)-L-glycero-α-D-manno-heptopyranosyl-(1→5)-2-(4-(2-aminoacetyl)phenyl)-3-deoxy-α-D-manno-oct-2-ulopyranosidonic acid
compound 114:
L-glycero-α-D-manno-heptopyranosyl-(1→3)-L-glycero-α-D-manno-heptopyranosyl-(1→5)-2-(6-amino-3-oxo)hexyl-3-deoxy-α-D-manno-oct-2-ulopyranosidonic acid
compound 121:
2-N-acetyl-2-deoxy-α-D-glucopyranosyl-(1→2)-L-glycero-α-D-manno-heptopyranosyl-(1→3)-L-glycero-α-D-manno-heptopyranosyl-(1→5)-2-(8-amino-2,2-dimethyl)octyl-3-deoxy-α-D-manno-oct-2-ulopyranosidonic acid
compound 128:
2-N-acetyl-2-deoxy-α-D-glucopyranosyl-(1→2)-L-glycero-α-D-manno-heptopyranosyl-(1→3)-L-glycero-α-D-manno-heptopyranosyl-(1→5)-2-(2-((aminomethyl)thio)ethyl)-3-deoxy-α-D-manno-oct-2-ulopyranosidonic acid
compound 135:
2-N-acetyl-2-deoxy-α-D-glucopyranosyl-(1→2)-L-glycero-α-D-manno-heptopyranosyl-(1→3)-L-glycero-α-D-manno-heptopyranosyl-(1→5)-2-(3-(3-aminopropyl)ureido)methyl-3-deoxy-α-D-manno-oct-2-ulopyranosidonic acid
compound 142:
2-N-acetyl-2-deoxy-α-D-glucopyranosyl-(1→2)-L-glycero-α-D-manno-heptopyranosyl-(1→3)-L-glycero-α-D-manno-heptopyranosyl-(1→5)-2-(5-(2-aminoethyl)-1-methylpiperidin-2-yl)methyl-3-deoxy-α-D-manno-oct-2-ulopyranosidonic acid
compound 149:
2-N-acetyl-2-deoxy-α-D-glucopyranosyl-(1→2)-L-glycero-α-D-manno-heptopyranosyl-(1→3)-L-glycero-α-D-manno-heptopyranosyl-(1→5)-2-(4-(3-aminopropyl)phenyl)-3-deoxy-α-D-manno-oct-2-ulopyranosidonic acid

45 more elements

Dependencies are inferred from the claim text.