Pyrimidine compounds and their use as vaccine adjuvants

Patent metadata

Field	Value
Publication number	US-10632192-B2
Application number	US-201615766560-A
Country	US
Kind code	B2
Filing date	Oct 6, 2016
Priority date	Oct 7, 2015
Publication date	Apr 28, 2020
Grant date	Apr 28, 2020

Abstract

The present invention provides a compound of the formula (1):

wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y 1 , Y 2 , L, and m are as defined in the description, and a pharmaceutically acceptable salt thereof, which are useful as a vaccine adjuvant.

First claim

The invention claimed is:

1. A compound of the formula (1):

or a pharmaceutically acceptable salt thereof, wherein:
X is —CH 2 —;
R 1 and R 2 are independently H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of hydroxy, halogen, and C 1-6 alkoxy;
R 3 is C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylthio;
R 4 is H, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, or cyano;
Y 1 is a single bond or —(CR 9 R 10 ) p —;
Y 2 is a single bond or —C(O)—;
L is a straight chain C 2-6 alkylene, wherein the C 2-6 alkylene is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C 1-5 alkyl, hydroxy, and halogen;
R 5 and R 6 are independently H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of hydroxy and halogen;
or R 5 and R 6 are taken together with —N-L-N—, to form piperazin-1,4-diyl, wherein the piperazin-1,4-diyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, oxo, hydroxy, and halogen;
R 9 and R 10 are independently selected from H and C 1-4 alkyl;
m is 1;
p is 1; and
each is a double bond.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 1 is a single bond; and Y 2 is —C(O)—.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 1 is —(CR 9 R 10 ) p —; and Y 2 is a single bond.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is an unsubstituted straight chain C 2-3 alkylene.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are independently H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of hydroxy and halogen;
R 3 is C 1-6 alkyl; and
R 4 is H, halogen, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy.

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2, 3, or 4 hydroxy;
R 2 is H or an unsubstituted C 1-6 alkyl;
R 3 is C 1-3 alkyl;
R 4 is H, halogen, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy;
Y 1 is a single bond or —CH 2 —;
L is an unsubstituted straight chain C 2-3 alkylene; and
R 5 and R 6 are independently H or an unsubstituted C 1-3 alkyl;
or R 5 and R 6 , taken together with —N-L-N—, form piperazin-1,4-diyl, wherein the piperazin-1,4-diyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of hydroxy and halogen.

7. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or excipients and a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition according to claim 11 , wherein the pharmaceutical composition further comprises an antigen.

13. The pharmaceutical composition according to claim 12 , wherein the antigen is selected from the group consisting of a pathogen-derived antigen and a tumor antigen.

14. The pharmaceutical composition according to claim 12 , wherein the antigen is selected from the group consisting of a peptide and a protein.

15. An immunogenic composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

16. A kit, comprising:
a) a compound according to claim 1 , or a pharmaceutically acceptable salt thereof; and
b) an antigen.

17. A method of inducing or enhancing an antigen-specific immune reaction in a mammal, comprising administering to the mammal an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

18. The method of claim 17 , wherein the antigen is a pathogen-derived antigen or a tumor antigen.

19. The method of claim 17 , wherein the antigen is a peptide or a protein.

20. The method of claim 17 wherein the compound activates a Toll-like Receptor.

21. The method of claim 17 wherein the compound activates one or both of TLR 7 and TLR 8.

22. The method of claim 17 wherein the antigen-specific immune reaction comprises:
a) an increase in CD4+ T lymphocytes relative to a control; or
b) an increase in CD8+ T lymphocytes relative to a control.

23. The method of claim 22 wherein the CD8+ T lymphocytes are CD8+ effector memory T lymphocytes.

24. The method of claim 17 , wherein the method is a method of treating or preventing cancer.

25. The method of claim 17 , wherein the method is a method of preventing an infectious disease.

Assignees

• Sumitomo Dainippon Pharma Co Ltd

Inventors

• Kimura Hidenori
• Ban Hitoshi
• Isobe Yoshiaki
• Watanabe Hitoshi

Classifications

• C07D239/49

  with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• A61K39/39 Primary

  characterised by the immunostimulating additives, e.g. chemical adjuvants · CPC title

• A61P37/04 Primary

  Immunostimulants · CPC title

• A61K31/505 Primary

  Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim · CPC title