Neoseptins: small molecule adjuvants
View Patent ↗A MD-2:TLR4 complex agonist compound is disclosed whose structure corresponds to Formula (I), as defined within. Also disclosed are a method of its preparation and use, as well as a pharmaceutical composition containing the same.
1. A compound that corresponds in structure to Formula I, below, or a pharmaceutically acceptable salt thereof
wherein
X is O, S, NR 1 , CH 2 , where R 1 is H, or a C 1 -C 4 hydrocarbyl, or X is absent and two atoms link the depicted phenyl rings;
Y is O, S, NR 2 , or CH 2 , wherein R 2 is H, or a C 1 -C 4 hydrocarbyl group;
R 3 is a C 1 -C 6 hydrocarbyl group;
R 4 and R 5 are hydrido or hydroxyl but only one of R 4 and R 5 is hydrido, or both of R 4 and R 5 are hydroxyl;
W is a single 6-membered hydrocarbyl ring structure said ring structure W optionally containing one or more substituent groups bonded to one or more ring atoms, in which said one or more substituents contain a total of up to 8 atoms, selected from the group consisting of fluorine, chlorine, carbon, nitrogen, oxygen, sulfur, and mixtures thereof; and
a dotted line (----) represents one or more optional double bonds.
2. The compound according to claim 1 , wherein X is absent or O.
3. The compound according to claim 1 , wherein Y is CH 2 .
4. The compound according to claim 1 , wherein R 3 is a bulky hydrocarbyl group containing 4-6 carbon atoms.
5. The compound according to claim 1 , wherein ring structure W contains a substituent selected from the group consisting of azido, fluoro, methyl, methoxy and trifluoromethyl groups, and said substituent is present at the 4-position of a 6-membered ring counting from the position of attachment to the remainder of the molecule.
6. A compound that corresponds in structure to Formula III or Formula IV, below, or pharmaceutically acceptable salts thereof
wherein ring W ring is phenyl that optionally contains one or more substituent groups bonded to one or more ring atoms, in which said one or more substituents contain a total of up to 8 atoms, selected from the group consisting of fluorine, chlorine, carbon, nitrogen, oxygen, sulfur, and mixtures thereof, and R 3 is a bulky hydrocarbyl group containing 4-6 carbon atoms.
7. The compound according to claim 6 , wherein R 3 is a tert-butyl group, a neopentyl group, a cyclopentyl group or a cyclohexyl group.
8. A compound corresponding in structure to the structural formula below, or a pharmaceutically acceptable salt thereof
9. A compound corresponding in structure to the structural formula below, or a pharmaceutically acceptable salt thereof
10. A pharmaceutical composition that comprises an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof dissolved or dispersed in a physiologically acceptable carrier.
11. The pharmaceutical composition according to claim 10 wherein said effective amount is an adjuvant effective amount.
12. The pharmaceutical composition according to claim 10 wherein said effective amount is a TLR4 agonist effective amount.
13. A method of vaccination wherein mammalian cells in need of vaccination are contacted with an immunizing composition that comprises an effective amount of an immunogen and an effective amount of an adjuvant, wherein the adjuvant is a compound or a pharmaceutically acceptable compound salt of Formula I in claim 1 .
14. The method according to claim 13 , wherein said immunogen and said adjuvant are administered in the same composition.