Conjugated TLR7 and/or TLR8 and TLR2 agonists
A conjugated compound of formula Q-Z—R 4 wherein Q is a TLR7 and/or TLR8 agonist and Z—R 4 is a TLR2 agonist, and the uses thereof in the treatment of infection, cancer or immune disorders or for use in vaccines.
1. A conjugated compound of Formula I:
Q-Z—R 4 Formula I
wherein Q is a purine derivative agonist of TLR7 and/or TLR8 and Z—R 4 is a TLR2 agonist,
said conjugated compound being chosen among compounds of Formula II:
a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or tautomer,
wherein:
R 2 is a C 1 -C 10 alkylamino;
X is a phenylene;
and
Z—R 4 is a TLR2 agonist selected from the group consisting of:
wherein:
R 5 is the specific side chain of L or D isomers of alanine, valine, leucine, isoleuciane, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, proline and histidine;
n is 0 or 1;
W is —C(O)—;
m is an integer from 1 to 4;
R 6 is H, OH, —O—C 1 -C 30 alkyl, —NH—C 1 -C 30 alkyl, —S—C 1 -C 30 alkyl, or —O—C 2 -C 30 alkylenyl;
R 4 is a lipid of formula V:
wherein:
R 7 and R 8 are independently from each other H, C 1 -C 30 alkyl, C 2 -C 30 alkylenyl, —C(O)—C 1 -C 30 alkyl, —C(O)—C 2 -C 30 alkylenyl, or —C(O)—O—C 1 -C 30 alkyl;
R 9 is C 1 -C 30 alkyl or C 2 -C 30 alkylenyl;
R 10 is C 1 -C 30 alkyl or C 2 -C 30 alkylenyl;
L 1 is either absent, or —OC(O)—, 13 O—,—NR 11 C(O)—,—OC(O)NR 11 —or —CH 2 wherein R 11 is H, C 1 -C 30 alkyl or C 2 -C 30 alkylenyl;
L 2 is —CH 2 OC(O)—,—CH 2 O—,—CH 2 NR 11 C(O)— or —CH 2 —, or if L 1 is absent, L 2 is —OC(O)—, —O—, —NR 11 C(O)—, —NR 10 R 11 , —OC(O)NR 11 — or —CH 2 — wherein R 11 is as H, C 1 -C 30 alkyl or C 2 -C 30 alkylenyl.
2. The conjugated compound according to claim 1 , wherein R 2 is a C 1 -C 6 alkylamino.
3. The conjugated compound according to claim 1 , wherein —Z— is absent.
4. The conjugated compound according to claim 1 , wherein —Z—R 4 is of Formula III,
wherein n=1.
5. The conjugated compound according to claim 1 , wherein —Z—R 4 is of Formula IV,
wherein
m=1, 2, 3 or 4,
W is —C(O)—, and
R 6 is —OH, —O—C 1 -C 30 alkyl, or —NH—C 1 C 30 alkyl.
6. The conjugated compound according to claim 1 , wherein R 4 is a lipid of formula V:
wherein:
R 7 and R 8 are independently from each other H or —C(O)—C 1 -C 30 alkyl;
R 9 and R 10 are independently from each other C 1 -C 30 alkyl; and
L 1 is absent and L 2 is —OC(O)—; or
L 1 is —OC(O)— and L 2 is —CH 2 OC(O)—.
7. The conjugated compound according to claim 1 , wherein:
R 2 is a C 1 -C 6 alkylamino,
X is a phenylene,
Z—R 4 is of Formula III, wherein:
n=0 or n=1 and R 5 is the specific side chain of L or D isormers of alanine, valine, leucine, isoleucine, phenylalanine, tryptophan,methionine, glycine, serince, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, proline and histidine
R 4 is a lipid of Formula V, wherein:
R 7 and R 8 are both a hydrogen atom,
R 9 and R 10 are independently from each other C 1 -C 30 alkyl; and
L 1 is absent and L 2 is —OC(O)—; or
L 1 is —OC(O)— and L 2 is —CH 2 OC(O)—.
8. The conjugated compound according to claim 1 , wherein said compound is selected from the group consisting of:
(R)-3-(2-amino-3-(4-((6-amino-2-(butylamino)-8-hydroxy-9H-purin-9-yl)methyl)phenyl amino)-3-oxopropylthio)propane-1,2-diyl dipalmitate,
3-((R)-2-amino-3-((S)-1-(4-((6-amino-2-(butylamino)-8-hydroxy-9H-purin-9-yl)methyl)phenylamino)-3-hydroxy-1-oxopropan-2-ylamino)-3-oxopropylthio)propane-1,2-diyl dipalmitate,
(R)-3-(3-(4-((6-amino-2-(butylamino)-8-hydroxy-9H-purin-9-yl)methyl)phenylamino)-3-oxo-2-palmitamidopropylthio)propane-1,2-diyl dipalmitate,
(R)-2-(2-amino-3-(4-((6-amino-2-(butylamino)-8-hydroxy-9H-purin-9yl)methyl)phenylamino)-3-oxopropylthio)ethyl tetradecanoate,
(R)-2-(2-amino-3-(4-((6-amino-2-(butylamino)-8-hydroxy-9H-purin-9yl)methyl)phenylamino)-3-oxopropylthio)ethyl palmitate,
(R)-2-(2-amino-3-(4-((6-amino-2-(butylamino)-8-hydroxy-9H-purin-9yl)methyl)phenylamino)-3-oxopropylthio)ethyl stearate,
2-((S)-2-amino-3-((S)-1-(4-((6-amino-2-(butylamino)-8-hydroxy-9H-purin-9-yl)methyl)phenylamino)-3-hydroxy-1-oxopropan-2-ylamino)-3-oxopropylthio)ethyl tetradecanoate,
2-((S)-2-amino-3-((S)-1-(4-((6-amino-2-(butylamino)-8-hydroxy-9H-purin-9-yl)methyl)phenylamino)-3-hydroxy-1-oxopropan-2-ylamino)-3-oxopropylthio)ethyl palmitate,
2-((S)-2-amino-3-((S)-1-(4-((6-amino-2-(butylamino)-8-hydroxy-9H-purin-9-yl)methyl)phenylamino)-3-hydroxy-1-oxopropan-2-ylamino)-3-oxopropylthio)ethyl stearate,
2-((R)-2-amino-3-((S)-5-(4-((6-amino-2-(butylamino)-8-hydroxy-9H-purin-9-yl)methyl)phenylamino)-1-methoxy-1,5-dioxopentan-2-ylamino)-3-oxopropylthio)ethyl tetradecanoate, and
a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or tautomer.
9. A pharmaceutical composition comprising the conjugated compound according to claim 1 and a pharmaceutically acceptable excipient or carrier.
10. A vaccine comprising the conjugated compound according to claim 1 .