Adenine conjugate compounds and their use as vaccine adjuvants
The present specification relates to adenine conjugate compounds represented by the formula (1), wherein A, L 1 , L 2 , X 1 , R 1 , R 2 , R 3 , and m are as defined herein, or their pharmaceutically acceptable salts. Compounds of formula (1) have immunostimulating properties and may therefore be useful in therapy, for example as vaccine adjuvants. The present specification also relates to a process for preparing adenine conjugate compounds and pharmaceutically acceptable salts thereof, and to pharmaceutical compositions comprising adenine conjugate compounds and their pharmaceutically acceptable salts.
1. A compound of formula (1):
or a pharmaceutically acceptable salt thereof, wherein:
L 1 and L 2 are independently alkylene;
R 1 is hydrogen atom or alkyl;
R 2 is optionally substituted alkyl;
R 3 is hydrogen atom, halogen atom, alkyl or alkoxy;
X 1 is single bond, oxygen atom, sulfur atom, SO, SO 2 , NR 4 or CONR 4 ;
R 4 is hydrogen atom or alkyl;
A is a monocyclic aromatic carbocycle, a 5-membered aromatic heterocycle which includes 1 to 2 heteroatoms selected from the group consisting of 1 to 2 nitrogen atoms, an oxygen atom, and a sulfur atom, or a 6-membered aromatic heterocycle which includes 1 to 3 heteroatoms selected from the group consisting of 1 to 3 nitrogen atoms, an oxygen atom, and a sulfur atom;
m is 0 or 1; and
each bond described by
independently represents a single bond or a double bond.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
L 1 is C 1-4 alkylene;
L 2 is C 1-4 alkylene;
R 1 is hydrogen atom or C 1-4 alkyl;
R 2 is C 1-6 alkyl optionally substituted by 1 to 4 groups that may be the same or different selected from hydroxy, halogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino optionally substituted by one or two C 1-6 alkyl that may be the same or different, and carboxy;
R 3 is hydrogen atom, halogen atom, C 1-4 alkyl or C 1-4 alkoxy;
X 1 is single bond, oxygen atom, sulfur atom, SO, SO 2 , NR 4 or CONR 4 ; and
R 4 is hydrogen atom or C 1-4 alkyl.
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-6 alkyl optionally substituted by 1 to 3 groups that may be the same or different selected from hydroxy, halogen atom, C 1-6 alkoxy and C 1-6 haloalkoxy.
4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is benzene ring or pyridine ring.
5. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein A is benzene ring.
6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is methylene.
7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-4 alkyl, C 1-4 hydroxy-alkyl, or C 1-4 alkoxy-C 1-4 alkyl.
8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is C 1-3 alkylene, and R 1 is hydrogen atom or C 1-3 alkyl.
9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein all of the bonds described by
represent a single bond, or all of the bonds described by
represent a double bond.
10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen atom or methyl.
11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
L 1 is methylene;
L 2 is methylene;
R 1 is hydrogen atom or methyl;
R 2 is C 1-6 alkyl, C 1-3 alkoxy-C 2-4 alkyl or C 2-6 alkyl substituted by 1 to 4 hydroxy groups wherein two or more hydroxy groups are attached to different carbon atoms;
R 3 is hydrogen atom, C 1-3 alkyl, C 1-3 alkoxy, or halogen atom;
X 1 is single bond, oxygen atom, NR 4 or CONR 4 ;
R 4 is hydrogen atom or C 1-3 alkyl;
A is benzene ring or pyridine ring; and
all of the bonds described by
represent a single bond, or all of the bonds described by
represent a double bond.
12. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable diluents or carriers.
13. The pharmaceutical composition according to claim 12 wherein the pharmaceutical composition is an oil-in-water emulsion comprising squalene, and one or more surfactants selected from the group consisting of Sorbitan Trioleate, Poloxamer 188, and L-α-phosphatidylcholine.
14. The pharmaceutical composition according to claim 13 wherein the pharmaceutical composition comprises:
a) squalene, Sorbitan Trioleate, and Poloxamer 188; or
b) squalene, L-α-phosphatidylcholine, and Poloxamer 188.
15. The pharmaceutical composition according to claim 13 wherein the oil-in-water emulsion comprises droplets with a mean particle size of 10-1000 nm±10 nm.
16. The pharmaceutical composition according to claim 12 further comprising an antigen.
17. The pharmaceutical composition according to claim 16 , wherein the antigen is an antigen derived from a pathogen or is a tumor antigen.
18. The pharmaceutical composition according to claim 16 , wherein the antigen is a peptide or a protein.
19. A method of retaining or enhancing an immunostimulating activity of an antigen comprising administering an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a mammal in need thereof.
20. The method of claim 19 wherein the compound activates a Toll-like Receptor.
21. The method of claim 19 wherein the compound activates one or both of TLR 7 and TLR 8.
22. The compound according to claim 1 wherein the compound of formula (1) is selected from the group consisting of 6-amino-2-butoxy-9-[4-({[(4E,8E,12E,16E,20E)-4,8,12,17,21,25-hexamethylhexacosa-4,8,12,16,20,24-hexaen-1-yl](methyl)amino}methyl)benzyl]-9H-purin-8-ol; 6-amino-9-[4-({[(4E,8E,12E,16E,20E)-4,8,12,17,21,25-hexamethylhexacosa-4,8,12,16,20,24-hexaen-1-yl](methyl)amino}methyl)benzyl]-2-(2-methoxyethoxy)-9H-purin-8-ol; and 3-({6-amino-9-[4-({[(4E,8E,12E,16E,20E)-4,8,12,17,21,25-hexamethylhexacosa-4,8,12,16,20,24-hexaen-1-yl](methyl)amino}methyl)benzyl]-8-hydroxy-9H-purin-2-yl}-oxy)propane-1,2-diol; or a pharmaceutically acceptable salt thereof.
23. The pharmaceutical composition according to claim 12 wherein the compound of formula (1) is selected from the group consisting of 6-amino-2-butoxy-9-[4-({[(4E,8E,12E,16E,20E)-4,8,12,17,21,25-hexamethylhexacosa-4,8,12,16,20,24-hexaen-1-yl](methyl)amino}methyl)benzyl]-9H-purin-8-ol; 6-amino-9-[4-({[(4E,8E,12E,16E,20E)-4,8,12,17,21,25-hexamethylhexacosa-4,8,12,16,20,24-hexaen-1-yl](methyl)amino}methyl)benzyl]-2-(2-methoxyethoxy)-9H-purin-8-ol; and 3-({6-amino-9-[4-({[(4E,8E,12E,16E,20E)-4,8,12,17,21,25-hexamethylhexacosa-4,8,12,16,20,24-hexaen-1-yl](methyl)amino}methyl)benzyl]-8-hydroxy-9H-purin-2-yl}-oxy)propane-1,2-diol; or a pharmaceutically acceptable salt thereof.
24. A method of enhancing immunostimulating activity of an antigen, comprising a step of administering an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a mammal in need thereof.
25. The method according to claim 19 , wherein the antigen is an antigen derived from a pathogen or is a tumor antigen.
26. The method according to claim 19 , wherein the antigen is a peptide or a protein.