Granted Patent B2

US 12,187,756 · App. 17/296,194 · Granted Jan 7, 2025

Inventors: Madhu Emmadi (Berlin, DE); Marilda P. Lisboa (Berlin, DE); Daniel Knopp (Berlin, DE); Bopanna Monnanda (Berlin, DE); Arne Von Bonin (Allschwil, CH); Claney Lebev Pereira (Berlin, DE)

Assignee: IDORSIA PHARMACEUTICALS LTD

C07H17/04A61K47/646

Abstract

Claims (174)

1. A saccharide of general formula (I)

wherein

n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

T*- is —P(═O)(OH) 2 , —P(═O)(O − )(OH) or —PO 3 2− ;

Z is selected from

L is a linker;

E is —NH 2 , —N 3 , —CN, —O—NH 2 , —CH═CH 2 , —C≡CH, —Br, —Cl, —I, —CO 2 R′, —CONH—NH 2 , —SH, —OH or —SAc; and

R′ is —H, —Me, Et, 4-nitrophenyl, pentafluorophenyl, or N-succinimidyl;

or a diastereoisomer or a pharmaceutically acceptable salt thereof.

2. The saccharide according to claim 1 ,

wherein Z is

or a pharmaceutically acceptable salt thereof.

3. The saccharide according to claim 1 , wherein

-L- is -L a -, -L a -L e -, -L a -L b -L e -, or -L a -L d -L e -;

-L a - is —(CH 2 ) o —, —(CH 2 —CH 2 —O) o —C 2 H 4 —, or —(CH 2 —CH 2 —O) o —CH 2 ;

-L b - is —O—;

-L d - is —(CH 2 ) q —, —(CH(OH)) q —, —(CF 2 ) q —, —(CH 2 —CH 2 —O) q —C 2 H 4 —, or —(CH 2 —CH 2 —O) q —CH 2 —;

-L e - is —(CH 2 ) p1 —, —(CF 2 ) p1 —, —C 2 H 4 —(O—CH 2 —CH 2 ) p1 —, —CH 2 —(O—CH 2 —CH 2 ) p1 — or —(CH 2 ) p1 —O—(CH 2 ) p2 —; and

o, q, p1 and p2 are independently of each other an integer selected from 1, 2, 3, 4, 5, or 6,

or a pharmaceutically acceptable salt thereof.

4. The saccharide according to claim 1 selected from the group consisting of:

wherein Z is selected from

or a pharmaceutically acceptable salt thereof.

5. The saccharide according to claim 4 of formula (l′a-4) or formula (I′b-4),

wherein Z is

or a pharmaceutically acceptable salt thereof.

6. A conjugate comprising a saccharide of general formula (I)

wherein

n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

T*- is —P(═O)(OH) 2 , —P(═O)(O − )(OH) or —PO 3 2− ;

Z is selected from

L is a linker;

E is —NH 2 , —N 3 , —CN, —O—NH 2 , —CH═CH 2 , —C≡CH, —Br, —Cl, —I, —CO 2 R′, —CONH—NH 2 , —SH, —OH or —SAc; and

R′ is —H, —Me, —Et, 4-nitrophenyl, pentafluorophenyl, or N-succinimidyl;

or a diastereoisomer or a pharmaceutically acceptable salt thereof;

covalently linked to an immunogenic carrier through the residue E of the —O-L-E group,

or a pharmaceutically acceptable salt thereof.

7. A conjugate of general formula (IV)

wherein

c is between 2 and 18;

-E 1 - is a covalent bond, —NH—, —O—NH—, —O—, —S—, —CO—, —CH═CH—, —CONH—, —CO—NHNH—,

—W— is selected from:

a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

b is an integer selected from 1, 2, 3 or 4,

CP is a carrier protein;

n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

T*- is —P(═O)(OH) 2 , —P (═O)(O − )(OH) or —PO 3 2− ;

Z is selected from

L is a linker,

or a pharmaceutically acceptable salt thereof.

8. The conjugate according to claim 7 , wherein the conjugate has any one of the following formulae (IV-2) or (IV-4)

wherein L, E 1 , W, c, CP, and n have the same meanings as defined in claim 7 ,

or a pharmaceutically acceptable salt thereof.

9. The conjugate according to claim 7 , wherein the conjugate is of formula (V-2)

wherein L is —(CH 2 ) 5 —,

E1 is —NH—,

n is an integer selected from 1 or 2,

c and W have the meaning as defined in claim 8 ,

or a pharmaceutically acceptable salt thereof.

10. The conjugate according to claim 9 , wherein —W— is

and

a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

or a pharmaceutically acceptable salt thereof.

11. A method for detecting antibodies against bacteria containing in their cell-wall polysaccharides one of the following saccharide fragments:

-6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1-;

-3)-α-D-Man-(1, 6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1;

-4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1, 6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1;

-4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1, 6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1; and

-3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1, 6)-β-D-Glc-(1,

the method comprising contacting a saccharide according to claim 1 , or a pharmaceutically acceptable salt thereof, as a binding marker in an immunological assay.

12. A method for raising a protective immune response in a human and/or animal host, the method comprising administering the conjugate according to claim 7 , or a pharmaceutically acceptable salt thereof, as a vaccine to the human and/or animal host in need thereof.

13. The method according to claim 12 , wherein the conjugate is of formula (V-2)

wherein L is —(CH 2 ) 5 —,

E 1 is —NH—,

n is an integer selected from 1 or 2,

c is between 2 and 18,

—W— is:

and

a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

or a pharmaceutically acceptable salt thereof.

14. A method for the prevention and/or treatment of diseases caused by bacteria containing in their cell-wall polysaccharides one of the following saccharide fragments:

-6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1-;

-3)-α-D-Man-(1, 6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1;

-4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1, 6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1;

-4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1, 6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1; and

-3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1, 6)-β-D-Glc-(1,

the method comprising administering the conjugate according to claim 7 , or a pharmaceutically acceptable salt thereof, as a vaccine to a subject in need thereof.

15. The method according to claim 14 , wherein the conjugate is of formula (V-2)

wherein L is —(CH 2 ) 5 —,

E 1 is —NH—,

n is an integer selected from 1 or 2,

c is between 2 and 18,

—W— is:

and

a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

or a pharmaceutically acceptable salt thereof.

16. The method according to claim 14 , wherein the bacterium is Clostridium difficile.

17. A pharmaceutical composition comprising the conjugate according to claim 7 , or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable adjuvant and/or excipient.

18. The pharmaceutical composition according to claim 17 , wherein the conjugate is of formula (V-2)

wherein L is —(CH 2 ) 5 —,

E 1 is —NH—,

n is an integer selected from 1 or 2,

c is between 2 and 18,

—W— is:

and

a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

or a pharmaceutically acceptable salt thereof.

19. A conjugate, wherein the conjugate is of formula (V-2)

wherein L is —(CH 2 ) 5 —,

E 1 is —NH—,

n is 1,

—W— is

a is 4, and

c is selected from 2 to 18;

or a pharmaceutically acceptable salt thereof.

20. A conjugate having the following, wherein the conjugate is of formula (V-2)

wherein L is —(CH 2 ) 5 —,

E 1 is —NH—,

n is 2,

—W— is

a is 4, and

c is selected from 2 to 18;

or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising the conjugate according to claim 19 , or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable adjuvant and/or excipient.

22. A pharmaceutical composition comprising the conjugate according to claim 20 , or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable adjuvant and/or excipient.

23. A method for raising a protective immune response in a human and/or animal host, the method comprising administering the conjugate according to claim 19 , or a pharmaceutically acceptable salt thereof, as a vaccine to the human and/or animal host in need thereof.

24. A method for raising a protective immune response in a human and/or animal host, the method comprising administering the conjugate according to claim 20 , or a pharmaceutically acceptable salt thereof, as a vaccine to the human and/or animal host in need thereof.

25. A method for the prevention and/or treatment of diseases caused by bacteria containing in their cell-wall polysaccharides one of the following saccharide fragments:

-6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1-;

-3)-α-D-Man-(1, 6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1;

-4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1, 6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1;

-4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1, 6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1; and

-3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1, 6)-β-D-Glc-(1,

the method comprising administering the conjugate according to claim 19 , or a pharmaceutically acceptable salt thereof, as a vaccine to a subject in need thereof.

26. The method according to claim 25 , wherein the bacterium is Clostridium difficile.

27. A method for the prevention and/or treatment of diseases caused by bacteria containing in their cell-wall polysaccharides one of the following saccharide fragments:

-6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1-;

-3)-α-D-Man-(1, 6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1;

-4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1, 6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1;

-4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1, 6)-β-D-Glc-(1, 3)-β-D-GalNAc-(1; and

-3)-β-D-GalNAc-(1, 4)-α-D-Glc-(1, 4)-[β-D-Glc-(1, 3)]-β-D-GalNAc-(1, 3)-α-D-Man-(1, 6)-β-D-Glc-(1,

the method comprising administering the conjugate according to claim 20 , or a pharmaceutically acceptable salt thereof, as a vaccine to a subject in need thereof.

28. The method according to claim 27 , wherein the bacterium is Clostridium difficile.

29. The conjugate according to claim 7 , wherein

n is an integer selected from 1, 2 or 3;

-L- is -L a -, -L a -L e -, -L a -L b -L e -, or -L a -L d -L e -;

-L a - is —(CH 2 ) o —, —(CH 2 —CH 2 —O) o —C 2 H 4 —, or —(CH 2 —CH 2 —O) o —CH 2 ;

-L b - is —O—;

-L d - is —(CH 2 ) q —, —(CF 2 ) q —, —(CH 2 —CH 2 —O) q —C 2 H 4 —, or —(CH 2 —CH 2 —O) q —CH 2 ;

-L e - is —(CH 2 ) p1 —, —(CF 2 ) p1 —, —C 2 H 4 —(O—CH 2 —CH 2 ) p1 —, —CH 2 —(O—CH 2 —CH 2 ) p1 —or —(CH 2 ) p1 —O—(CH 2 ) p2 —;

o, q, p1 and p2 are independently of each other an integer selected from 1, 2, 3, 4, 5, or 6;

—W— is:

and

a is an integer selected from 2, 3, 4, 5 or 6;

or a pharmaceutically acceptable salt thereof.

30. The conjugate according to claim 8 , wherein

n is an integer selected from 1, 2 or 3;

-L- is -L a -, -L a -L e -, -L a -L b -L e -, or -L a -L d -L e -;

-L a - is —(CH 2 ) o —, —(CH 2 —CH 2 —O) o —C 2 H 4 —, or —(CH 2 —CH 2 —O) o —CH 2 ;

-L b - is —O—;

-L d - is —(CH 2 ) q —, —(CF 2 ) q —, —(CH 2 —CH 2 —O) q —C 2 H 4 —, or —(CH 2 —CH 2 —O) q —CH 2 ;

-L e - is —(CH 2 ) p1 —, —(CF 2 ) p1 —, —C 2 H 4 —(O—CH 2 —CH 2 ) p1 —, —CH 2 —(O—CH 2 —CH 2 ) p1 —or —(CH 2 ) p1 —O—(CH 2 ) p2 —;

o, q, p1 and p2 are independently of each other an integer selected from 1, 2, 3, 4, 5, or 6;

—W— is:

and

a is an integer selected from 2, 3, 4, 5 or 6;

or a pharmaceutically acceptable salt thereof.

31. The conjugate according to claim 29 , wherein CP is CRM 197 ;

or a pharmaceutically acceptable salt thereof.

32. The conjugate according to claim 30 , wherein CP is CRM 197 ;

or a pharmaceutically acceptable salt thereof.

33. The conjugate according to claim 10 , wherein

a is an integer selected from 2, 3, 4, 5 or 6;

or a pharmaceutically acceptable salt thereof.

Assignments (6)

Priority Claims (1)

Continuity (1)

References Cited (48)