Hydrazino 1H-imidazoquinolin-4-amines and conjugates made therefrom
View Patent ↗1H-Imidazo[4,5-c]quinolin-4-amines substituted at the 1-position with a substituent bearing a hydrazinobenzamide or hydrazinonicotinamide, a salt thereof, or a protected hydrazinobenzamide or hydrazinonicotinamide and conjugates made from such compounds are disclosed. Pharmaceutical compositions containing the compound or the conjugate, methods of making a conjugate, and methods of use of the compounds or conjugates as immunomodulators for inducing cytokine biosynthesis in an animal and for vaccinating an animal are also disclosed.
1. A compound of formula:
wherein:
X is alkylene having up to 8 carbon atoms optionally interrupted or terminated by —O—;
R 2 is hydrogen, alkyl, alkoxyalkylenyl, alkylaminoalkylenyl, or hydroxyalkylenyl;
P is an amino group, a protected amino group, or NH 3 + Y − , wherein Y − is a counter anion;
A is CH or N;
R is halogen, hydroxyl, alkyl, haloalkyl, or alkoxy; and
n is an integer from 0 to 4;
or a pharmaceutically acceptable salt thereof.
2. The compound or salt of claim 1 , wherein P is an amino group.
3. The compound or salt of claim 1 , wherein n is 0.
4. The compound or salt of claim 1 , wherein R 2 is methyl, ethyl, propyl, butyl, ethoxymethyl, methoxymethyl, ethylaminomethyl, or 2-methoxyethyl.
5. The compound or salt of claim 1 , wherein X is —O—C 3-8 alkylene.
6. The compound or salt of claim 1 , which is of formula:
or a pharmaceutically acceptable salt thereof.
7. The compound or salt of claim 1 , wherein X is C 3-8 alkylene.
8. A conjugate comprising a reaction product of the compound or salt of claim 1 and an aldehyde-bearing antigen.
9. The conjugate of claim 8 , wherein the aldehyde-bearing antigen is an aldehyde-bearing protein.
10. The conjugate of claim 9 , wherein to provide the reaction product, a ratio of the compound or salt to the aldehyde-bearing protein is in a range from 30:1 to 1:3.
11. The conjugate of claim 8 , wherein the aldehyde-bearing antigen is an aldehyde-bearing lipid.
12. A conjugate of an antigen, the conjugate having at least one segment represented by formula:
wherein:
X is alkylene having up to 8 carbon atoms optionally interrupted or terminated by —O—;
R 2 is hydrogen, alkyl, alkoxyalkylenyl, alkylaminoalkylenyl, or hydroxyalkylenyl;
A is CH or N:
R is halogen, hydroxyl, alkyl, haloalkyl, or alkoxy;
n is an integer from 0 to 4;
Z is a bond or —C(O)—NH—(CH 2 CH 2 O) p —CH 2 CH 2 —, wherein p is in a range from 1 to 50; and
the nitrogen atom indicated by N* is covalently bonded to the antigen;
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a conjugate of claim 8 .
14. A method of vaccinating an animal, the method comprising administering an effective amount of the conjugate of claim 8 to the animal.
15. A method of inducing cytokine biosynthesis in an animal, the method comprising administering an effective amount of the conjugate of claim 8 to the animal.
16. A composition comprising the compound or salt of claim 1 , an aldehyde-bearing antigen, and a pharmaceutically acceptable carrier.
17. A method of making a conjugate, the method comprising:
combining a compound or salt of claim 1 , wherein P is a protected amino group; an aldehyde-bearing antigen; and a carrier under conditions where the protected amino group is deprotected and the conjugate is formed.
18. The conjugate of claim 12 , wherein Z is a bond.
19. The conjugate of claim 12 , wherein Z is —C(O)—NH—(CH 2 CH 2 O) p —CH 2 CH 2 —, wherein p is in a range from 1 to 50.
20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a conjugate of claim 12 .