Substituted pyrimidines as vaccine adjuvants
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.
1. A method of inducing or enhancing an antigen-specific immune reaction in a mammal, wherein the method comprises administering to the mammal in need thereof an effective amount of a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the antigen is a pathogen-derived antigen or a tumor antigen.
3. The method of claim 1 , wherein the antigen is a peptide or a protein.
4. The method of claim 1 , wherein the compound activates a toll-like receptor in the mammal.
5. The method of claim 1 , wherein:
(i) the compound activates toll-like receptor (TLR7) in the mammal; or
(ii) the compound activates toll-like receptor 8 (TLR8) in the mammal; or
(iii) the compound activates toll-like receptor 7 (TLR7) and toll-like receptor 8 (TLR8) in the mammal.
6. The method of claim 1 , wherein:
(a) the antigen-specific immune reaction in the mammal comprises an increase in CD4+ T lymphocytes in the mammal relative to a control; or
(b) the antigen-specific immune reaction in the mammal comprises an increase in CD8+ T lymphocytes in the mammal relative to a control.
7. The method of claim 6 , wherein the CD8+ T lymphocytes are effector memory CD8+ T lymphocytes.
8. The method of claim 1 , wherein the mammal has cancer.
9. The method of claim 1 , wherein the mammal has an infectious disease.
10. A method of inducing or enhancing an antigen-specific immune reaction in a mammal, wherein the method comprises administering to the mammal in need thereof an effective amount of a compound which is:
or a pharmaceutically acceptable salt thereof.
11. The method of claim 10 , wherein the antigen is a pathogen-derived antigen or a tumor antigen.
12. The method of claim 10 , wherein the antigen is a peptide or a protein.
13. The method of claim 10 , wherein the compound activates a toll-like receptor in the mammal.
14. The method of claim 10 , wherein:
(i) the compound activates toll-like receptor 7 (TLR7) in the mammal; or
(ii) the compound activates toll-like receptor 8 (TLR8) in the mammal; or
(iii) the compound activates toll-like receptor 7 (TLR7) and toll-like receptor 8 (TLR8) in the mammal.
15. The method of claim 10 , wherein:
(a) the antigen-specific immune reaction in the mammal comprises an increase in CD4+ T lymphocytes in the mammal relative to a control; or
(b) the antigen-specific immune reaction in the mammal comprises an increase in CD8+ T lymphocytes in the mammal relative to a control.
16. The method of claim 15 , wherein the CD8+ T lymphocytes are effector memory CD8+ T lymphocytes.
17. The method of claim 10 , wherein the mammal has cancer.
18. The method of claim 10 , wherein the mammal has an infectious disease.
19. A method of inducing or enhancing an antigen-specific immune reaction in a mammal, wherein the method comprises administering to the mammal in need thereof an effective amount of a compound which is:
or a pharmaceutically acceptable salt thereof.
20. The method of claim 19 , wherein the antigen is a pathogen-derived antigen or a tumor antigen.
21. The method of claim 19 , wherein the antigen is a peptide or a protein.
22. The method of claim 19 , wherein the compound activates a toll-like receptor in the mammal.
23. The method of claim 19 , wherein:
(i) the compound activates toll-like receptor 7 (TLR 7 ) in the mammal; or
(ii) the compound activates toll-like receptor 8 (TLR 8 ) in the mammal; or
(iii) the compound activates toll-like receptor 7 (TLR 7 ) and toll-like receptor 8 (TLR8) in the mammal.
24. The method of claim 19 , wherein:
(a) the antigen-specific immune reaction in the mammal comprises an increase in CD4+ T lymphocytes in the mammal relative to a control; or
(b) the antigen-specific immune reaction in the mammal comprises an increase in CD8+ T lymphocytes in the mammal relative to a control.
25. The method of claim 24 , wherein the CD8+ T lymphocytes are effector memory CD8+ T lymphocytes.
26. The method of claim 19 , wherein the mammal has cancer.
27. The method of claim 19 , wherein the mammal has an infectious disease.