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US 10,328,141 B2Granted
Synthetic vaccines against Streptococcus pneumoniae type 1
AssigneeMax-Planck-Gesellschaft zur Forderung der Wissenschaften e.V.
InventorsPeter H. Seeberger, Claney Lebev Pereira, Chakkumkal Anish, Benjamin Schumann
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Abstract
The present invention relates to the total synthesis of saccharide structures contained in the capsular polysaccharide of Streptococcus pneumoniae type 1, to glycoconjugates containing said saccharide structures obtained by total synthesis and to use of such glycoconjugates and pharmaceutical compositions thereof in the immunization against diseases associated with bacteria containing said saccharide structures in their capsular polysaccharide, and more specifically associated with Streptococcus pneumoniae.
Claims7
A saccharide of general formula (I):
- wherein A represents —(CH2)o1—;
- o1 represents an integer selected from 1, 2, 3, 4, 5 and 6;
- M, N and P represent independently of each other one of the following sugar fragments:
- wherein the sugar fragments S1, S2, S3 are connected to each other and to —O-A-SH fragment via O-glycosidic bonds, each sugar fragment S1, S2, and S3 is not more than once present in the general formula (I), sugar fragment Si cannot be simultaneously connected to —O-A-SH and sugar fragment S3, sugar fragment S3 cannot be simultaneously connected to —O-A-SH and sugar fragment S2, and sugar fragment S2 cannot be simultaneously connected to —O-A-SH and sugar fragment S1, and n1, n2 and n3 are integers selected from 0 and 1, wherein at least one of the integers n1, n2 and n3 is 1
- and pharmaceutically acceptable salts of these saccharides.
2 more elements
A synthesis of the saccharide of the general formula (I):
- wherein A represents (CH2)o1;
- o1 represents an integer selected from 1, 2, 3, 4, 5 and 6;
- M, N and P represent independently of each other one of the following sugar fragments:
- wherein the sugar fragments S1, S2, S3 are connected to each other and to —O-A-SH fragment via O-glycosidic bonds, each sugar fragment S1, S2, and S3 is not more than once present in the general formula (I), sugar fragment Si cannot be simultaneously connected to —O-A-SH and sugar fragment S3, sugar fragment S3 cannot be simultaneously connected to —O-A-SH and sugar fragment S2, and sugar fragment S2cannot be simultaneously connected to —O-A-SH and sugar fragment S1, and n1, n2 and n3 are integers selected from 0 and 1, wherein at least one of the integers n1, n2 and n3 is 1
- and comprising :
- A1) Reacting the compound 2 of the formula:
- wherein P1-P3 represent protecting groups,
- with the compound 3 of the formula
- wherein P4 represents a protecting group, in order to obtain compound 4 of general formula:
- wherein P1-P4 and A are defined as above;
- and
- performing removal of protecting groups P1-P4 on compound 4 to afford monosaccharide disulfide 5 of general formula:
- wherein A is defined as above, and wherein monosaccharide disulfide 5 is further treated with a reducing agent to afford monosaccharide 6 of general formula:
- wherein A is defined as above;
- or
- performing selective deprotection on compound 4 to afford compound 7 of general formula
- wherein P5 is a protecting group and P1, P3, P4 and A are defined as above;
- or
- A2) Reacting compound 8 of general formula
- wherein P6 and P7 represent protecting groups, with compound 3 to afford compound 9 of general formula
- wherein P6, P7 and A are defined as above;
- and
- performing conversion of the azido group to acetamido group and removal of the protecting groups P4, P6 and P7 on compound 9 to afford monosaccharide disulfide 10 of general formula:
- wherein A is defined as above, and wherein monosaccharide disulfide 10 is further treated with a reducing agent to afford monosaccharide 11 of general formula:
- wherein A is defined as above;
- or
- performing selective deprotection on compound 9 to afford compound 12 of general formula:
- wherein P4, P7 and A are defined as above;
- or
- A3) Reacting compound 13 of general formula
- wherein P8-P11 represent protecting groups, with compound 3 to afford compound 14 of general formula:
- wherein P4, P8-P11 are defined as above;
- and
- performing selective deprotection of compound 14 to afford compound 15 of general formula:
- wherein P4, P8, P9, P11 and A are defined as above;
- and
- B1) Reacting compound 7 with compound 13 to afford compound 16 of general formula:
- wherein P1, P3-P5, P8-P11 and A are defined as above;
- and
- performing removal of protecting groups P1 P3-P5, P8-P11 on compound 16 to afford disaccharide disulfide 17 of general formula:
- wherein A is defined as above and wherein disaccharide disulfide 17 is further treated with a reducing agent to afford disaccharide 18 of general formula:
- wherein A is defined as above;
- or
- performing selective removal of protecting group P10 on compound 16 to afford compound 19of general formula:
- wherein P1, P3-P5, P8, P9, P11 and A are defined as above;
- or
- B2) Reacting compound 15 with compound 8 to afford compound 20 of general formula:
- wherein P4, P6-P9, P11 and A are defined as above;
- and
- performing conversion of the azido group to acetamido group and removal of the protecting groups P4, P6-P9, P11 on compound 20 to afford disaccharide disulfide 21 of general formula:
- wherein A is defined as above and wherein disaccharide disulfide 21 is treated with a reducing agent to afford disaccharide 22 of general formula:
- wherein A is defined as above;
- or
- performing selective removal of protecting group P6 on compound 20 to afford compound 23of general formula:
- wherein P4, P7-P9, P11 and A are defined as above;
- or
- B3) Reacting compound 12 with compound 2 to afford compound 24 of general formula:
- wherein P1-P4, P7 and A are defined as above,
- and
- performing conversion of the azido group to acetamido group and removal of protecting groups P1-P4 and P7 on compound 24 to afford disaccharide disulfide 25 of general formula:
- wherein A is defined as above, and wherein disaccharide disulfide 25 is further treated with a reducing agent to afford disaccharide 26 of general formula:
- wherein A is defined as above;
- or
- performing selective deprotection on compound 24 to afford compound 27 of general formula:
- wherein P12 is a protecting group and P1, P3, P4, P7 and A are defined as above;
- and
- C1) Reacting compound 19 with compound 8 to afford compound 28 of general formula:
- wherein P1, P3-P9, P11 and A are defined as above;
- and
- wherein protecting group P6 is replaced with protecting group P13 in order to obtain compound 29 of the following chemical formula:
- wherein P1, P3-P5, P7-P9, P11, P13 and A are defined as above;
- and
- conversion of compound 29 to trisaccharide disulfide 30 by conversion of the azido group in the acetamido group and cleavage of the protecting group P1, P3-P5, P7-P9, P11, 13, wherein compound 30 is of general formula:
- and wherein A is defined as above;
- and
- conversion of trisaccharide disulfide 30 to trisaccharide 31 by treatment with a reducing agent, wherein compound 31 is of general formula:
- and wherein A is defined as above;
- or
- C2) Reacting compound 23 with compound 2 to afford compound 32 of general formula:
- wherein P1-P4, P7-P9, P11 and A are defined as above;
- and
- conversion of compound 32 to trisaccharide disulfide 33 by conversion of the azido group in the acetamido group and cleavage of the protecting group P1-P4, P7-P9, P11, wherein compound 33 is of general formula:
- wherein A is defined as above;
- and
- conversion of trisaccharide disulfide 33 to trisaccharide 34 by treatment with a reducing agent, wherein compound 34 is of general formula:
- wherein A is defined as above;
- or
- C3) Reacting compound 27 with compound 13 to afford compound 35 of general formula:
- wherein P1, P3, P4, P7-P11 and A are defined as above;
- and
- conversion of compound 35 to trisaccharide disulfide 36 by conversion of the azido group in the acetamido group and cleavage of the protecting group P1, P3, P4, P7-P11 wherein compound 36 is of general formula:
- wherein A is defined as above;
- and
- conversion of trisaccharide disulfide 36 to trisaccharide 37 by treatment with a reducing agent, wherein compound 37 is of general formula:
- wherein A is defined as above.
92 more elements
Dependencies are inferred from the claim text.