Modified saccharides with improved stability in water

FIELD: chemistry.

SUBSTANCE: invention pertains to modified polysaccharide in particular to modified polysaccharide Neisseria meningitidis of serogroup A, which preserves immunogenicity, but has improved stability. The modified polysaccharide is obtained from reaction of capsular polysaccharide, or its fragment - oligosaccharide, with CDI type bifunctional reagent, accompanied by reaction with an amino-compound, such as dimethylamine. Description is also given of modified polysaccharide conjugates and vaccines, which are obtained from such conjugates.

EFFECT: obtaining modified saccharide.

70 cl, 17 dwg

 

The text descriptions are given in facsimile form.

1. The modified capsular saccharide containing a blocking group in the position of the hydroxyl group on at least one monosaccharide link corresponding native of capsular saccharide, where capsular saccharide contains phosphodiester bond and where the blocking group is electron-withdrawing group.

2. The modified capsular saccharide according to claim 1, in which at least one monosaccharide link is nonterminal monosaccharide link.

3. The modified capsular saccharide according to claim 1, which includes at least one free hydroxyl group, or amino group.

4. The modified capsular saccharide according to claim 2, which includes at least one free hydroxyl group, or amino group.

5. The modified capsular saccharide according to claim 3, in which at least one free hydroxyl group is a terminal anomeric hydroxyl group.

6. The modified capsular saccharide according to claim 4, in which at least one free hydroxyl group is a terminal anomeric hydroxyl group.

7. The modified capsular saccharide according to claim 1, in which the blocking group is of the formula:

-O-X-Y or3where

X represents S(O), (S)O or SO2;

Y represents a C1-12alkyl, C1-12alkoxyl,3-12cycloalkyl,5-12aryl or5-12aryl-C1-6alkyl, each of which may be optionally substituted by 1, 2 or 3 groups independently selected from F, Cl, Br, CO2H, CO2(C1-6alkyl), CN, CF3or CCl3; or Y represents NR1R2;

R1and R2independently selected from H, C1-12of alkyl, C3-12cycloalkyl, C5-12aryl, C5-12aryl-C1-6of alkyl; or R1and R2may b the th United with the formation of C 3-12saturated heterocyclic group;

R3represents a C1-12alkyl or C3-12cycloalkyl, each of which may optionally be substituted by 1, 2 or 3 groups independently selected from F, Cl, Br, CO2(C1-6alkyl), CN, CF3or CCl3; or R3represents a C5-12aryl or5-12aryl-C1-6alkyl, each of which may be optionally substituted by 1, 2, 3, 4, or 5 groups selected from F, Cl, Br, CO2H, CO2(C1-6alkyl), CN, CF3or CCl3.

8. The modified capsular saccharide according to claim 2, in which the blocking group is of the formula:

-O-X-Y or3,

where X represents S(O), (S)O or SO2;

Y represents a C1-12alkyl, C1-12alkoxyl,3-12cycloalkyl,5-12aryl or5-12aryl-C1-6alkyl, each of which may be optionally substituted by 1, 2 or 3 groups independently selected from F, Cl, Br, CO2H, CO2(C1-6alkyl), CN, CF3or CCl3;

or Y represents NR1R2;

R1and R2independently selected from H, C1-12of alkyl, C3-12cycloalkyl,5-12aryl, C5-12aryl-C1-6of alkyl; or R1and R2can be combined with education3-12saturated heterocyclic group;

R3represents a C1-12alkyl or C3-12cycloalkyl, each of which may optionally be substituted by 1, 2 or 3 groups independently selected from F, Cl, Br, CO2(C1-6alkyl), CN, CF3or CCl3; or R3represents a C5-12aryl or5-12aryl-C1-6alkyl, each of which may be optionally substituted by 1, 2, 3, 4, or 5 groups selected from F, Cl, Br, CO2H, CO2(C1-6alkyl), CN, CF3or CCl3.

9. The modified capsular saccharide according to claim 3, in which the blocking group is-OC(O)NR1R2or-OC(O)CF3.

10. The modified capsular saccharide according to claim 4, in which the blocking group is-OC(O)NR1R2or-OC(O)CF3.

11. The modified capsular saccharide according to claim 5, in which the blocking group is-OC(O)NR1R2and R1and R2are independently selected from C1-6-alkyl.

12. The modified capsular saccharide according to claim 6, in which the blocking group is-OC(O)NR1R2and R1and R2are independently selected from C1-6the alkyl.

13. The modified capsular saccharide according to claim 1 in which both R1and R2represent methyl.

14. The modified capsular saccharide according to any one of claims 1 to 13, in which at least 10% monosaccharide the links include a blocking group.

15. The modified capsular saccharide according to any one of claims 1 to 13, in which the corresponding capsular saccharide includes monosaccharide units linked phosphodieterase connections.

16. The modified capsular saccharide according to 14, in which the corresponding capsular saccharide includes monosaccharide units linked phosphodieterase connections.

17. The modified capsular saccharide according to § 15, in which the corresponding capsular saccharide is a saccharide of Neisseria meningitidis serogroup A.

18. The modified capsular saccharide according to clause 16, in which the corresponding capsular saccharide is a saccharide of Neisseria meningitidis serogroup A.

19. The modified capsular saccharide according to any one of p and 18, in which the blocking group is in any of the 4 - and/or 3-positions of the corresponding saccharide of Neisseria meningitidis serogroup A.

20. The modified capsular saccharide according to any one of p and 18, in which the blocking group is in any of positions 4-the corresponding saccharide of Neisseria meningitidis serogroup A.

21. The modified capsular saccharide according to any one of claims 1 to 13, 16-18, which is an oligosaccharide.

22. The modified capsular saccharide according to 14, which represents an oligosaccharide.

23. The modified capsular saccharide according to § 15, which is an oligosaccharide.

24. The modified capsular saccharide according to claim 19, which represents an oligosaccharide.

25. The modified capsular saccharide according to claim 20, which represents an oligosaccharide.

26. The modified capsular saccharide according to any one of claims 1 to 13, 16-18, 22-25, for use as pharmaceuticals.

27. The modified capsular saccharide according to 14, for use as pharmaceuticals.

28. The modified capsular saccharide according to § 15, for use as a medicine,

29. The modified capsular saccharide according to claim 19, for use as pharmaceuticals.

30. The modified capsular saccharide according to claim 20, for use as pharmaceuticals.

31. The modified capsular saccharide according to item 21, for use as pharmaceuticals.

32. The saccharide of the formula:

where T has the formula (A) or (B)

n is an integer from 1 to 100;

each group Z is independently selected from HE, or a blocking group as defined in claim 1, 7-13; and

each group Q is independently selected from HE, or a blocking group as defined in claim 1, 7-13;

W is selected from-HE or a blocking group as defined in claim 1, 7-13;

V is selected from-NH2, -NH-E, where E is a protecting group of the nitrogen;

and where more than about 7% of the group Q represents a blocking group.

33. Saccharide on p, in which at least 50% of the groups Z are SLA.

34. Saccharide on p or 33, in which n is an integer from 15 to 25.

35. Saccharide on p or 33, in which at least 10% of the group Q represents a blocking group.

36. Saccharide according to clause 34, in which at least 10% of the group Q represents a blocking group.

37. Modified saccharide on p or 33, for use as pharmaceuticals.

38. Modified saccharide at 34, for use as pharmaceuticals.

39. The method of obtaining modified saccharide according to claim 1, which includes stages:

(a) providing the capsular saccharide having at least one hydroxyl group per monosaccharide link; and

(b) converting at least one of the mentioned hydroxyl group in the blocking group;

where capsular saccharide contains fosfodiesterazu communication and where the blocking group is electron-withdrawing group.

40. The modification of the capsular saccharide containing stages:

(a) providing the capsular saccharide having at least one hydroxyl group on mono is charignon link;

(b) converting at least one of the mentioned hydroxyl group in the blocking group-OC(O)NR1R2by (b1) interaction of the capsular saccharide with a bifunctional reagent in an organic solvent, and (b2) the interaction of the product of stage (b1) with aminoguanidinium formula (I)

where bifunctional reagent is selected from 1,1'-carbonyldiimidazole (CDI), carbonelli-1,2,4-triazole (CDT), carbonelli-1,2,3-benzotriazole (CDB), diphenylcarbonate, bromine cyan, phosgene or triphosgene, and

where R1and R2independently selected from H, C1-12of alkyl, C3-12cycloalkyl,5-12aryl, C5-12aryl-C1-6of alkyl; or R1and R2can be combined with education3-12saturated heterocyclic group.

41. The method according to § 39 or 42, in which the blocking group is defined in any of claims 1, 7-13.

42. The method according to paragraph 41, in which the organic solvent is an aprotic solvent.

43. The method according to § 42, in which the aprotic solvent is selected from dimethyl sulfoxide (DMSO), dimethylformamide (DMF), formamide, hexamethylphosphoramide (NMRA), hexamethylphosphorotriamide (NMRT), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) or dimethylacetamide (DMAC).

44. The method according to § 42 or 43, in which the aprotic solvent is DMSO.

So on p.43, in which the bifunctional reagent is selected from 1,1'-carbonyldiimidazole (CDI), carbonelli-1,2,4-triazole (CDT), carbonelli-1,2,3-benzotriazole (CDB), diphenylcarbonate, bromine cyan, phosgene or triphosgene.

46. The method according to item 44, in which the bifunctional reagent is selected from 1,1'-carbonyldiimidazole (CDI), carbonelli-1,2,4-triazole (CDT), carbonelli-1,2,3-benzotriazole (CDB), diphenylcarbonate, bromine cyan, phosgene or triphosgene.

47. The method according to item 45 or 46 in which the bifunctional reagent is CDI.

48. The method according to any of p, 40, 42, 43, 45 and 46, in which the modified capsular saccharide is a modified capsular oligosaccharide.

49. The method according to paragraph 41, in which the modified capsular saccharide is a modified capsular oligosaccharide.

50. The method according to item 44, in which the modified capsular saccharide is a modified capsular oligosaccharide.

51. The method according to p, in which the modified capsular saccharide is a modified capsular oligosaccharide.

52. The method according to p in which capsular saccharide at the stage (a) is capsular oligosaccharide obtained by sorting according to the size of the corresponding native capsular polysaccharide.

53. The method according to any of p-51, in which capsular saccharide at the stage (a) is capsular oligosaccharide, receiving the NYM sorting by size corresponding native capsular polysaccharide.

54. The method according to p in which capsular saccharide at the stage (a) is the native capsular polysaccharide, and the method further includes a step (C), where the product of stage (b) is sorted according to size, providing, thus, a modified capsular oligosaccharide.

55. The method according to any of p-51, in which capsular saccharide at the stage (a) is the native capsular polysaccharide, and the method further includes a step (C), where the product of stage (b) is sorted according to size, providing, thus, a modified capsular oligosaccharide.

56. Modification of polysaccharide of Neisseria meningitidis serogroup a, which includes stages:

(a) providing native polysaccharide of Neisseria meningitidis serogroup a;

(b) sizing of the above-mentioned polysaccharide to provide oligosaccharide; and

(c) converting at least one hydroxyl group of the oligosaccharide in protective group in accordance with p.

57. Modification of polysaccharide of Neisseria meningitidis serogroup a, which includes stages:

(a) providing native polysaccharide of Neisseria meningitidis serogroup a;

(b) converting at least one hydroxyl group of the polysaccharide in the blocking group in accordance with p; and

(c) sorting the sizes of the obtained polysaccharide.

58. Saha is ID-protein conjugate of a modified saccharide according to any one of claims 1 to 36 and the protein carrier, where the protein carrier is a bacterial toxin or toxoid and where the saccharide-protein conjugate is obtained by conjugation of the protein carrier with modified saccharide through terminal hydroxyl group or through a terminal amino group.

59. The conjugate according to § 58, in which a bacterial toxin or toxoid is diphtheria toxin or toxoid.

60. The conjugate according to § 58, in which a bacterial toxin or toxoid is CRM197.

61. The conjugate according to any one of p-60 for use as a medicine.

62. Pharmaceutical composition having immunogenic activity against mammalian, including (a) a modified saccharide according to any one of claims 1 to 36, and/or saccharide-protein conjugate according to any one of p-60, and (b) a pharmaceutically acceptable carrier.

63. The composition according to item 62, further comprising charigny antigen from N.Meningitidis one or more of serogroups C, W135 and Y, saccharide, need not oligosaccharide and need not be conjugated to a protein carrier.

64. The composition according to item 62 or 63, further comprising a vaccine adjuvant.

65. The composition according to p, in which the adjuvant is aluminum phosphate.

66. Composition according to any one of p, 63 or 65, which is a vaccine against disease caused by Neisseria meningitidis.

67. Songs which I p, which is a vaccine against disease caused by Neisseria meningitidis.

68. Method for enhancing antibody responses in a mammal, comprising the introduction of a pharmaceutical composition according to any one of p-67 mammal.

69. The use of a modified polysaccharide according to any one of claims 1 to 36 or conjugate according to any one of p-60 for the manufacture of a medicinal product for preventing or treating diseases caused by one or more capsular bacteria.

70. Use p, where the disease is bacterial meningitis.



 

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