Adsorption of immunopotentiators to insoluble metal salts
Immunopotentiators can be adsorbed to insoluble metal salts, such as aluminum salts, to modify their pharmacokinetics, pharmacodynamics, intramuscular retention time, and/or immunostimulatory effect. Immunopotentiators are modified to introduce a moiety, such as a phosphonate group, which can mediate adsorption. These modified compounds can retain or improve their in vivo immunological activity even when delivered in an adsorbed form.
1. A composition, comprising a TLR7 agonist of formula (C) and an insoluble metal salt, wherein at least 50% by mass of the TLR7 agonist of formula (C) is adsorbed to the metal salt, and wherein formula (C) is:
wherein:
P 3 is selected from H, C 1 -C 6 alkyl, CF 3 , —((CH 2 ) p O) q (CH 2 ) p O s — and —Y-L-X—P(O)(OR X )(OR Y ); and P 4 is selected from H, C 1 -C 6 alkyl, —C 1 -C 6 alkylaryl and —Y-L-X—P(O)(OR X )(OR Y ); with the proviso that at least one of P 3 and P 4 is —Y-L-X—P(O)(OR X )(OR Y );
R X and R Y are independently selected from H and C 1 -C 6 alkyl;
R C is selected from H and C 1 -C 6 alkyl;
X C is selected from CH and N;
X is selected from a covalent bond, O and NH;
Y is selected from a covalent bond, O, C(O), S and NH;
L is selected from, a covalent bond, C 1 -C 6 alkylene, C 1 -C 6 alkenylene, arylene, heteroarylene, C 1 -C 6 alkyleneoxy and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, —OP(O)(OH) 2 and —P(O)(OH) 2 ;
each p is independently selected from 1, 2, 3, 4, 5 and 6;
q is selected from 1, 2, 3 and 4; and
s is selected from 0 and 1.
2. The composition of claim 1 , wherein the compound of formula (C) is one of the following compounds:
3. The composition of claim 1 , wherein P 3 is selected from C 1 -C 6 alkyl, CF 3 , —((CH 2 ) p O) q (CH 2 ) p O s — and —Y-L-X—P(O)(OR X )(OR Y ); P 4 is selected from —C 1 -C 6 alkylaryl and —Y-L-X—P(O)(OR X )(OR Y ); X C is CH; X is a covalent bond; L is selected from C 1 -C 6 alkylene and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, —OP(O)(OH) 2 and —P(O)(OH) 2 ; each p is independently selected from 1, 2 and 3; q is 1 or 2.
4. The composition of claim 1 , wherein P 3 is selected from C 1 -C 6 alkyl, CF 3 , —((CH 2 ) p O) q (CH 2 ) p O s — and —Y-L-X—P(O)(OR X )(OR Y ); P 4 is selected from —C 1 -C 6 alkylaryl and —Y-L-X—P(O) (OR X )(OR Y ); X C is N; X is a covalent bond; L is selected from C 1 -C 6 alkylene and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, —OP(O)(OH) 2 and —P(O)(OH) 2 ; each p is independently selected from 1, 2 and 3; q is selected from 1 and 2.
5. The composition of claim 1 , wherein the compound of formula (C) is not a compound in which P 4 is —Y-L-X—P(O)(OR X )(OR Y ).
6. The composition of claim 1 , wherein P 4 is selected from H, C 1 -C 6 alkyl, —C 1 -C 6 alkylaryl.
7. The composition of claim 1 , wherein X is O; L is selected from C 1 -C 6 alkylene and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, —OP(O)(OH) 2 and —P(O)(OH) 2 ; each p is independently selected from 1, 2 and 3; and q is selected from 1 and 2.
8. The composition of claim 1 , wherein X is a covalent bond; L is selected from C 1 -C 6 alkylene and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, —OP(O)(OH) 2 and —P(O)(OH) 2 ; each p is independently selected from 1, 2 and 3; and q is selected from 1 and 2.
9. The composition of claim 1 , wherein the compound of formula (C) has a structure according to formula (C′), shown below:
wherein:
P 3 is selected from H, C 1 -C 6 alkyl, CF 3 , —((CH 2 ) p O) q (CH 2 ) p O s — and —Y-L-X—P(O)(OR X )(OR Y ); and P 4 is selected from H, C 1 -C 6 alkyl, —C 1 -C 6 alkylaryl and —Y-L-X—P(O)(OR X )(OR Y ); with the proviso that at least one of P 3 and P 4 is —Y-L-X—P(O)(OR X )(OR Y );
R X and R Y are independently selected from H and C 1 -C 6 alkyl;
X C is selected from CH and N;
X is selected from a covalent bond, O and NH;
Y is selected from a covalent bond, O, C(O), S and NH;
L is selected from a covalent bond, C 1 -C 6 alkylene, C 1 -C 6 alkenylene, arylene, heteroarylene, C 1 -C 6 alkyleneoxy and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, —OP(O)(OH) 2 and —P(O)(OH) 2 ;
each p is independently selected from 1, 2, 3, 4, 5 and 6;
q is selected from 1, 2, 3 and 4; and
s is selected from 0 and 1.
10. The composition of claim 9 , wherein P 3 is selected from C 1 -C 6 alkyl, CF 3 , —((CH 2 ) p O) q (CH 2 ) p O s — and —Y-L-X—P(O)(OR X )(OR Y ); P 4 is selected from —C 1 -C 6 alkylaryl and —Y-L-X—P(O)(OR X )(OR Y ); X C is CH; X is a covalent bond; L is selected from C 1 -C 6 alkylene and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, —OP(O)(OH) 2 and —P(O)(OH) 2 ; each p is independently selected from 1, 2 and 3; q is 1 or 2.
11. The composition of claim 9 , wherein P 3 is selected from C 1 -C 6 alkyl, CF 3 , —((CH 2 ) p O) q (CH 2 ) p O s — and —Y-L-X—P(O)(OR X )(OR Y ); P 4 is selected from —C 1 -C 6 alkylaryl and —Y-L-X—P(O)(OR X )(OR Y ); X C is N; X is a covalent bond; L is selected from C 1 -C 6 alkylene and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, —OP(O)(OH) 2 and —P(O)(OH) 2 ; each p is independently selected from 1, 2 and 3; q is selected from 1 and 2.
12. The TLR7 agonist as claimed in claim 9 , selected from formulae (D) or (D′), wherein P 5 is selected from C 1 -C 6 alkyl, and —Y-L-X—P(O)(OR X )(OR Y ).
13. The TLR7 agonist as claimed in claim 9 , selected from formulae (E) or (E′), wherein X E is CH 2 , P 8 is C 1 -C 6 alkoxy optionally substituted with —Y-L-X—P(O)(OR X )(OR Y ).
14. The TLR7 agonist as claimed in claim 9 , selected from formula (E) or (E′), wherein P 9 is —NHC 1 -C 6 alkyl optionally substituted with OH and C 1 -C 6 alkyl, and —Y-L-X—P(O)(OR X )(OR Y ).
15. The composition of claim 9 , selected from formulae (C) or (C′), which is not a compound in which P 4 is —Y-L-X—P(O)(OR X )(OR Y ).
16. The composition of claim 9 , wherein P 4 is selected from H, C 1 -C 6 alkyl, —C 1 -C 6 alkylaryl.
17. The composition of claim 9 , wherein X is O; L is selected from C 1 -C 6 alkylene and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, —OP(O)(OH) 2 and —P(O)(OH) 2 ; each p is independently selected from 1, 2 and 3; and q is selected from 1 and 2.
18. The composition of claim 9 , wherein X is a covalent bond; L is selected from C 1 -C 6 alkylene and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, —OP(O)(OH) 2 and —P(O)(OH) 2 ; each p is independently selected from 1, 2 and 3; and q is selected from 1 and 2.