Adsorption of immunopotentiators to insoluble metal salts

Patent metadata

Field	Value
Publication number	US-9315530-B2
Application number	US-201113820370-A
Country	US
Kind code	B2
Filing date	Sep 1, 2011
Priority date	Sep 1, 2010
Publication date	Apr 19, 2016
Grant date	Apr 19, 2016

Abstract

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.

First claim

The invention claimed is:

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.

Assignees

• Singh Manmohan
• Skibinski David A G
• Wu Tom Yao-Hsiang
• Li Yongkai
• Cortez Alex
• Zhang Xiaoyue
• Zou Yefen
• Hoffman Timothy Z
• Pan Jianfeng
• Yue Kathy
• Novartis Ag

Inventors

• Singh Manmohan
• Skibinski David A G
• Wu Tom Yao-Hsiang
• Li Yongkai
• Cortez Alex
• Zhang Xiaoyue
• Zou Yefen
• Hoffman Timothy Z
• Pan Jianfeng
• Yue Kathy

Classifications

• A61K31/661 Primary

  Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion {or mevinphos} · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K39/08

  Clostridium, e.g. Clostridium tetani · CPC title

• A61K39/05

  Actinobacteria, e.g. Actinomyces, Streptomyces, Nocardia, Bifidobacterium, Gardnerella}, Corynebacterium; Propionibacterium {(Mycobacterium A61K39/04) · CPC title