Vaccines against Streptococcus pneumoniae serotype 5

Patent metadata

Field	Value
Publication number	US-10596272-B2
Application number	US-201615580069-A
Country	US
Kind code	B2
Filing date	Jan 26, 2016
Priority date	Jun 8, 2015
Publication date	Mar 24, 2020
Grant date	Mar 24, 2020

Abstract

The present invention relates to well-defined synthetic saccharides of general formula (I) that are related to the repeating unit of Streptococcus pneumoniae serotype 5 capsular polysaccharide and conjugates thereof. The conjugates and pharmaceutical compositions containing said conjugates are useful for prevention and/or treatment of diseases associated with Streptococcus pneumoniae , and more specifically against diseases associated with Streptococcus pneumoniae serotype 5. Furthermore, the synthetic saccharides of general formula (I) are useful as marker in immunological assays for detection of antibodies against Streptococcus pneumoniae bacteria.

First claim

The invention claimed is:

1. A saccharide of general formula (I)

wherein
R 1 is selected from —R 2 , —R 4 ,

R 2 represents

R 3 is selected from —H, —CH 3 , —C 2 H 5 , —C 3 H 7 , —C 4 H 9 and —CF 3 ;
R 4 represents R 6 or

R 5 represents —H or

R 6 represents —O-L-NH 2 ;
R 7 and R 8 are independently of each other selected from —H and —OH and cannot be simultaneously —H;
R 7 and R 8 can form together with the carbon atom to which they are attached to a carbonyl group C═O;
R 23 is selected from —H, —C(O)CH 3 , —C(O)CF 3 and —C(O)CCl 3 ;
-L- is selected from: —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 —, —(CH 2 ) 6 —, —(CH 2 ) 7 —, —(CH 2 ) 8 —, —(CH 2 ) 9 —, —(CH 2 ) 10 —, —CF 2 —, —(CF 2 ) 2 —, —(CF 2 ) 3 —, —(CF 2 ) 4 —, —(CF 2 ) 5 —, —(CF 2 ) 6 —, —(CF 2 ) 7 —, —(CF 2 ) 8 —, —(CF 2 ) 9 —, —(CF 2 ) 10 —, —(CH 2 ) 2 —O—(CH 2 ) 2 —, —CH 2 —O—(CH 2 ) 3 —, —(CH 2 ) 3 —O—CH 2 —, —CH 2 —O—(CH 2 ) 2 —, —(CH 2 ) 2 —O—CH 2 —, —(CH 2 ) 3 —O—(CH 2 ) 2 —, —(CH 2 ) 2 —O—(CH 2 ) 3 —, —(CH 2 ) 4 —O—CH 2 —, —CH 2 —O—(CH 2 ) 4 —, -L a -, -L a -L e -, -L a -L b -L e -, -L a -L b -L d -L c -L e , -L a -L d -L e ;
wherein
-L a - is selected from: —(CH 2 ) m , —(CF 2 ) m , —(CH 2 —CH 2 —O) m —C 2 H 4 —, —(CH 2 —CH 2 —O) m —CH 2 —, —(CR 10 R 11 ) m —,

-L b - and -L c - are independently of each other selected from: —O—, —S—, —NH—C(O)—NH—, —NH—C(S)—NH—, —NH—C(O)—, —C(O)—NH—, —NH—C(O)—O—, —NR 9 —, —NR 18 —, —SO 2 —,

-L d - represents —(CH 2 ) n —, —(CF 2 ) n —, —(CR 12 R 13 ) n —, —(CH 2 —CH 2 —O) n —C 2 H 4 —, —(CH 2 —CH 2 —O) n —CH 2 —,

-L e - is selected from: —(CH 2 ) p1 —, —(CF 2 ) p1 —, —C 2 H 4 —(O—CH 2 —CH 2 ) p1 —, —CH 2 —(O—CH 2 —CH 2 ) p1 —, —(CH 2 ) p1 —O—(CH 2 ) p2 —, —(CH 2 ) p1 —S—(CH 2 ) p2 —, —(CR 14 R 15 ) p1 —, —(CR 14 R 15 ) p1 —O—(CR 21 R 22 ) p2 —, —(CR 14 R 15 ) p1 —S—(CR 21 R 22 ) p2 —,

R 9 and R 18 are independently of each other selected from: —CH 3 , —C 2 H 5 , —C 3 H 7 , and —C(O)CH 3 ;
R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , R 21 and R 22 are independently of each other selected from: —H, —F, —Cl, —CH 3 , —C 2 H 5 , —C 3 H 7 , —C 5 H 9 , —C 6 H 13 , —OCH 3 , —OC 2 H 5 , —CH 2 F, —CHF 2 , —CF 3 , —C(O)—NH 2 , —SCH 3 , —SC 2 H 5 , —NHC(O)CH 3 , —N(CH 3 ) 2 and —N(C 2 H 5 ) 2 ;
m, n, p1 and p2 are independently of each other an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
and pharmaceutically acceptable salts thereof.

2. The saccharide according to claim 1 , wherein R 1 represents

and R 2 and R 3 have the meanings as defined in claim 1 .

3. The saccharide according to claim 1 , wherein R 4 represents R 6 .

4. The saccharide according to claim 1 of general formula (III)

wherein R 3 , R 5 , R 6 and R 23 have the meanings as defined in claim 1 .

5. The saccharide according to claim 1 of the formula 72

wherein L, R 7 , R 8 and R 23 have the meanings as defined in claim 1 .

6. The saccharide according to claim 1 , wherein R 3 represents —H and R 23 represents —C(O)CH 3 .

7. The saccharide according to claim 1 selected from the group consisting of:
5-amino-pentanyl 2-N-acetyl-α-L-pneumosaminopyranosyl-(1→2)-β- D -glucopyranosyluronate (27*),
5-amino-pentanyl 2-N-acetyl-α-L-pneumosaminopyranosyl-(1→2)-β- D -glucopyranosyluronate-(1→3)-2-N-acetyl-α-L-fucosaminopyranosyl-(1→3)-2-N-acetyl-β- D -fucosaminopyranoside (33*),
5-amino-pentanyl 2-N-acetyl-α-L-pneumosaminopyranosyl-(1→2)-β- D -glucopyranosyluronate-(1→3)-2-N-acetyl-α-L-fucosaminopyranosyl-(1→3)-[β- D -glucopyranosyl-(1→4)]-2-N-acetyl-β- D -fucosaminopyranoside (73*),
5-amino-pentanyl 2-N-acetyl-α-L-pneumosaminopyranosyl-(1→2)-β- D D-glucopyranosyluronate-(1→3)-2-N-acetyl-α-L-fucosaminopyranosyl-(1→3)-β- D -glucopyranosyl-(1→4)]-2-N-acetyl-3- D -quinovosaminopyranoside (85*), and
5-amino-pentanyl 2-N-acetyl-α-L-pneumosaminopyranosyl-(1→2)-β- D -glucopyranosyluronate-(1→3)-2-N-acetyl-α-L-fucosaminopyranosyl-(1→3)-[β- D -glucopyranosyl-(1→4)]-2-acetamido-2,5-dideoxy-β- D -xylo-hexos-4-uloside (88*).

8. An intermediate compound of formula (IX), 36, 41, 63, 68*, 70 or 70a:

wherein
R 24 is selected from

—F, —Cl, —Br, —I, —SR 28 , —SeR 29 , —OPO 3 R 30 2 ;
R 25 is selected from —N 3 , -NBn 2 , -NBnCbz;
R 26 and R 27 are independently of each other selected from —H, -Bn,

Si(CH 3 ) 3 , —Si(CH 2 CH 3 ) 3 , —C(O)CH 3 , —C(O)Ph,

or R 26 and R 27 can form together

R 28 is selected from: —CH 3 , —CH 2 CH 3 , -Ph,

R 29 represents -Ph;
R 30 represents —CH 2 CH 2 CH 2 CH 3 ;

wherein L has the meanings as defined in claim 1 ;

wherein L and R 23 have the meanings as defined in claim 1 ;

wherein L has the meanings as defined in claim 1 ;

wherein L has the meanings as defined in claim 1 ;
or

wherein L has the meanings as defined in claim 1 .

9. The intermediate according to claim 8 is selected from the group consisting of the saccharides 36, 41, 63, 70, 70a, wherein L is —C 5 H 10 — and/or R 23 is CH 3 CO—.

10. A conjugate comprising the sacc

Assignees

• Max Planck Gesellschaft

Inventors

• Anish Chakkumkal
• Lisboa Marilda
• Martin Christopher
• Pereira Claney Lebev
• Seeberger Peter H
• Khan Naeem

Classifications

• A61K39/09

  {Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus}, streptococcus · CPC title

• C07H15/04

  attached to an oxygen atom of the saccharide radical · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K47/646 Primary

  the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines · CPC title

• A61K47/6415

  Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins · CPC title