Toll-like receptor ligands
Toll-like receptor (TLR) ligands having an allose-based core are stable in aqueous formulation and are useful in treating, preventing, or reducing susceptibility to diseases or conditions mediated by TLRs, such as cancer, infectious disease, allergy, autoimmune disease, sepsis, and ischemia reperfusion.
1. A method of eliciting or enhancing, or modifying an immune response in a subject comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I-a), or a pharmaceutically acceptable salt thereof,
wherein,
R 2a , R 2b , and R 2c are each independently-CH(R 10 )(R 11 );
R 3a is-OP(O)(OH) 2 , —OSO 3 H, or —OCH 2 P(O)(OH) 2 ;
R 3b is hydrogen or COOH, or an ester thereof;
R 10 , at each occurrence, is independently C 8-14 alkyl;
R 11 , at each occurrence, is independently —O—C(═O)C 1-15 alkyl, —O—C(═O)C 1-15 alkylene-Z 2 , —O—C 2-16 alkylene-Z 2 , or —O—C 2-16 alkyl; and
Z 2 , at each occurrence, is independently phenyl or a 5- to 6-membered heteroaryl, wherein Z 2 is optionally substituted with 1-5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, —OC 1-4 alkyl, —OC 1-4 haloalkyl, cyano, and halogen.
2. The method of claim 1 , wherein the immune response treats a cancer, an infectious disease, or an allergy in the subject.
3. The method of claim 1 , wherein the immune response treats an infectious disease in the subject.
4. The method of claim 3 , wherein the infectious disease is a bacterial, viral, fungal or prion infection.
5. The method of claim 1 , wherein the immune response treats an allergy in the subject.
6. A method of treating an allergy, an infectious disease, or cancer in a subject comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I-a), or a pharmaceutically acceptable salt thereof,
wherein,
R 2a , R 2b , and R 2c are each independently-CH(R 10 )(R 11 );
R 3a is-OP(O)(OH) 2 , —OSO 3 H, or —OCH 2 P(O)(OH) 2 ;
R 3b is hydrogen or COOH, or an ester thereof;
R 10 , at each occurrence, is independently C 8-14 alkyl;
R 11 , at each occurrence, is independently-O—C(═O)C 1-15 alkyl, —O—C(═O)C 1-15 alkylene-Z 2 , —O—C 2-16 alkylene-Z 2 , or —O—C 2-16 alkyl; and
Z 2 , at each occurrence, is independently phenyl or a 5- to 6-membered heteroaryl, wherein Z 2 is optionally substituted with 1-5 substituents independently selected from C 1-4 alkyl, C 1 -4 haloalkyl, —OC 1-4 alkyl, —OC 1 -4 haloalkyl, cyano, and halogen.
7. The method of claim 1 , wherein the administering to the subject is by intramuscular, intradermal, subcutaneous, topical, intravenous or mucosal administration.
8. The method of claim 1 , further comprising administering to the subject a therapeutically effective amount of radiation therapy or an additional therapeutic agent selected from a chemotherapeutic agent and an immune modulatory agent such as an immune checkpoint inhibitor or tumor phagocytosis-inducing agent.
9. The method of claim 1 , further comprising administering to the subject an immunogenic quantity of an antigen.
10. The method according to claim 1 , wherein the method produces an IgA immune response.
11. The method according to claim 1 , wherein the method produces an IgG immune response.
12. The method of claim 1 , wherein the compound of formula (Ia) is
13. The method of claim 1 , wherein the compound of formula (Ia) is
14. The method of claim 6 , wherein the compound of formula (Ia) is
15. The method of claim 6 , wherein the compound of formula (Ia) is
16. The method of claim 14 , wherein the method is the method of treating an allergy.
17. The method of claim 14 , wherein the method is the method of treating an infectious disease.
18. The method of claim 14 , wherein the method is the method of treating cancer.
19. The method of claim 15 , wherein the method is the method of treating an allergy.
20. The method of claim 15 , wherein the method is the method of treating an infectious disease.
21. The method of claim 15 , wherein the method is the method of treating cancer.
22. A method of reducing the susceptibility to an allergy, an infectious disease, or cancer in a subject comprising administering to a subject in need thereof, an immunogenic quantity of an antigen and a therapeutically effective amount of the compound of formula (I-a), or a pharmaceutically acceptable salt thereof,
wherein,
R 2a , R 2b , and R 2c are each independently —CH(R 10 )(R 11 );
R 3a is —OP(O)(OH) 2 , —OSO 3 H, or —OCH 2 P(O)(OH) 2 ;
R 3b is hydrogen or COOH, or an ester thereof;
R 10 , at each occurrence, is independently C 8-14 alkyl;
R 11 , at each occurrence, is independently-O—C(═O)C 1-15 alkyl, —O—C(═O)C 1-16 alkylene-Z 2 , —O—C 2-16 alkylene-Z 2 , or —O—C 2-16 alkyl; and
Z 2 , at each occurrence, is independently phenyl or a 5- to 6-membered heteroaryl, wherein Z 2 is optionally substituted with 1-5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, —OC 1-4 alkyl, —OC 1 -4 haloalkyl, cyano, and halogen.
23. The method of claim 22 , wherein the compound of formula (Ia) is
24. The method of claim 22 , wherein the compound of formula (Ia) is
25. The method of claim 23 , wherein the method is the method of reducing the susceptibility to an allergy.
26. The method of claim 23 , wherein the method is the method of reducing the susceptibility to an infectious disease.
27. The method of claim 23 , wherein the method is the method of reducing the susceptibility to cancer.
28. The method of claim 24 , wherein the method is the method of reducing the susceptibility to an allergy.
29. The method of claim 24 , wherein the method is the method of reducing the susceptibility to an infectious disease.
30. The method of claim 24 , wherein the method is the method of reducing the susceptibility to cancer.