Pegylated imidazoquinolines as TLR7 and TLR8 agonists
The present invention provides novel phospholipidated imidazoquinolines as TLR7 and TLR8 agonists, pharmaceutical compositions, therapeutic uses and processes for preparing the same.
1. A compound, or a pharmaceutically acceptable salt thereof, of formula (I):
wherein
R 1 is selected from H, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 3-6 cycloalkylC 1-6 alkyl, C 3-6 cycloalkylC 1-6 alkylamino, C 3-6 cycloalkylC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkylamino and C 1-6 alkoxyC 1-6 alkoxy; wherein the C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 3-6 cycloalkylC 1-6 alkyl, C 3-6 cycloalkylC 1-6 alkylamino, C 3-6 cycloalkylC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkylamino or C 1-6 alkoxyC 1-6 alkoxy is branched or unbranched and optionally terminally substituted with a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl, or maleimido group;
Z is selected from C 2 -C 6 alkyl and C 2 -C 6 alkenyl, wherein the C 2 -C 6 alkyl or C 2 -C 6 alkenyl is unsubstituted or terminally substituted by —(O—C 2 -C 6 alkyl) 1-6 -;
X is O or S;
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;
R 2 is H or a straight or branched, optionally unsaturated, C 4 -C 24 alkyl, or a straight or branched, optionally unsaturated, C 4 -C 24 , acyl;
R 3 is a straight or branched, optionally unsaturated, C 4 -C 24 alkyl or a straight or branched, optionally unsaturated, C 4 -C 24 acyl.
2. The compound or pharmaceutically acceptable salt according to claim 1 wherein R 1 is selected from H, C 1-6 alkyl, C 1-6 alkylamino and C 1-6 alkoxy wherein the C 1-6 alkyl, C 1-6 alkylamino or C 1-6 alkoxy is branched or unbranched and optionally terminally substituted with a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl, or maleimido group.
3. The compound or pharmaceutically acceptable salt according to claim 1 wherein R 1 is n-butyl.
4. The compound or pharmaceutically acceptable salt of claim 1 wherein Z is (CH 2 ) 2 .
5. The compound or pharmaceutically acceptable salt of claim 1 wherein X is O.
6. The compound or pharmaceutically acceptable salt of claim 1 wherein n is selected from 3 or 6.
7. The compound or pharmaceutically acceptable salt of claim 1 wherein R 2 is a straight or branched, optionally unsaturated, C 4 -C 24 acyl.
8. The compound or pharmaceutically acceptable salt of claim 1 wherein R 3 is a straight or branched, optionally unsaturated, C 4 -C 24 acyl.
9. The compound or pharmaceutically acceptable salt of claim 1 wherein R 2 is unbranched C 16 acyl (palmitoyl, COC 15 H 31 ).
10. The compound or pharmaceutically acceptable salt of claim 1 wherein R 3 is unbranched C 16 acyl (palmitoyl, COC 15 H 31 ).
11. The compound of claim 1 wherein R 1 =n-butyl; Z is (CH 2 ) 2 ; n is selected from 3, 6 and 9; R 2 is unbranched C 16 acyl (palmitoyl, COC 15 H 31 ) and R 3 is unbranched C 16 acyl (palmitoyl, COC 15 H 31 ).
12. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.