Tunicamycin analogues

Patent metadata

Field	Value
Publication number	US-10954262-B2
Application number	US-201816619504-A
Country	US
Kind code	B2
Filing date	Jun 6, 2018
Priority date	Jun 6, 2017
Publication date	Mar 23, 2021
Grant date	Mar 23, 2021

Abstract

The invention relates to tunicamycin analogues which are compounds according to Formula (I), or pharmaceutically acceptable salts thereof, (I) Wherein [Base] and R 1 to R 9 are as defined herein. The tunicamycin analogues are useful in the prevention or treatment of bacterial infection, in particular of tuberculosis.

First claim

The invention claimed is:

1. An oligosaccharide which is a compound according to Formula (I), or a pharmaceutically acceptable salt thereof,

wherein:
[Base] is a natural nucleobase selected from adenine, cytosine, guanine, thymine and uracil;
each R 1 , which may be the same or different, is independently H, OH, —OPO(OH) 2 , or halogen;
each R 2 , which may be the same or different, is independently H, halogen, or C 1 to C 2 alkyl;
R 3 and R 4 , which may be the same or different, are each independently H, OH, halogen, C 1 to C 2 alkyl, C 1 to C 2 alkoxy, or —NR 10 R 11 ;
each R 5 , which may be the same or different, is independently H, halogen, or C 1 to C 2 alkyl;
each R 6 , which may be the same or different, is independently OH, halogen, —OPO(OH) 2 , —OCO 2 CH 3 , —NHCOCH 3 or C 1 to C 2 alkoxy;
one or more R 7 and/or one or more R 8 is a group —NHC(O)R 9 ; the remaining groups R 7 , which may be the same or different, are independently H, halogen, or C 1 to C 2 alkyl; and the remaining groups R 8 , which may be the same or different, are independently OH, halogen, —OPO(OH) 2 , —OCO 2 CH 3 , —NHCOCH 3 or C 1 to C 2 alkoxy;
each R 9 , which may be the same or different, is independently C 3 to C 20 alkyl, C 3 to C 20 alkenyl, or C 3 to C 20 alkynyl, wherein R 9 may be unsubstituted or may be substituted by from 1 to 6 substituents selected from halogen, OH, C 1 to C 4 alkoxy and —NR 10 R 11 ; and
each R 10 and R 11 , which may be the same or different, is independently H or C 1 to C 4 alkyl.

2. An oligosaccharide according to claim 1 which is a compound according to Formula (II), or a pharmaceutically acceptable salt thereof

wherein R 1 to R 11 and [Base] are as defined in claim 1 .

3. An oligosaccharide according to claim 1 wherein [Base] is thymine or uracil.

4. An oligosaccharide according to claim 1 wherein each R 1 , which may be the same or different, is independently OH or —OPO(OH) 2 .

5. An oligosaccharide according to claim 1 wherein each R 2 , which may be the same or different, is independently H or methyl.

6. An oligosaccharide according to claim 1 wherein R 3 and R 4 are each H.

7. An oligosaccharide according to claim 1 wherein each R 5 , which may be the same or different, is independently H or C 1 to C 2 alkyl.

8. An oligosaccharide according to claim 1 wherein each R 6 , which may be the same or different, is independently OH, —NHCOCH 3 or —OPO(OH) 2 .

9. An oligosaccharide according to claim 1 wherein one of the R 7 and/or R 8 groups which are —NHC(O)R 9 is bonded to the C2″ carbon.

10. An oligosaccharide according to claim 1 wherein the total number of R 7 and R 8 groups which are —NHC(O)R 9 is from 1 to 3; the remaining groups R 7 , which may be the same or different, are independently H or C 1 to C 2 alkyl, and the remaining groups R 8 , which may be the same or different, are independently OH, —NHCOCH 3 or —OPO(OH) 2 .

11. An oligosaccharide according to claim 10 wherein one group R 8 is —NHC(O)R 9 ; the groups R 7 , which may be the same or different, are independently H or C 1 to C 2 alkyl; and the remaining groups R 8 , which may be the same or different, are independently OH, —NHCOCH 3 or —OPO(OH) 2 , according to Formula (IV)

12. An oligosaccharide according to claim 1 wherein each R 9 , which may be the same or different, is independently C 4 to C 16 alkyl, or C 4 to C 16 alkenyl, wherein R 9 is unsubstituted or substituted by from 1 to 4 substituents selected from halogen, OH, C 1 to C 4 alkoxy, and —NR 10 R 11 .

13. An oligosaccharide according to claim 1 wherein each R 9 , which may be the same or different, is independently an unsubstituted C 7 to C 9 alkyl group.

14. An oligosaccharide according to claim 1 having a structure according to Formula (III)

wherein each R 9 , which may be the same or different, is independently C 3 to C 20 alkyl, C 3 to C 20 alkenyl or C 3 to C 20 alkynyl, wherein R 9 may be unsubstituted or may be substituted by from 1 to 6 substituents selected from Mogen, OH, C 1 to C 4 alkoxy and —NR 10 R 11 ; and each R 10 and R 11 , which may be the same or different, is independently H or C 1 to C 4 alkyl.

15. An oligosaccharide according to claim 14 wherein R 9 is selected from

16. A pharmaceutical composition comprising an oligosaccharide according to claim 1 and a pharmaceutically acceptable carrier or diluent.

17. A method of treating a subject suffering from or susceptible to a bacterial infection, which method comprises administering an effective amount of an oligosaccharide according to claim 1 , or a pharmaceutical composition comprising an oligosaccharide according to claim 1 and a pharmaceutically acceptable carrier or diluent, to said subject.

18. The method according to claim 17 , wherein the bacterial infection is caused by Bacillus, Pseudomonas, Mycobacterium, Staphylococcus , or Escherichia.

19. The method according to claim 18 , wherein the bacterial infection is caused by Mycobacterium tuberculosis.

20. The method according to claim 17 , wherein the oligosaccharide or pharmaceutical composition is for use in treating or preventing tuberculosis.

Assignees

• Univ Oxford Innovation Ltd

Inventors

• Davis Benjamin Guy
• Wyszynski Filip
• Wang Hua

Classifications

• A61K31/7072

  having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine · CPC title

• C07H19/067 Primary

  with ribosyl as the saccharide radical · CPC title

• A61P31/06

  for tuberculosis · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61K31/7068

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title