Imidazoquinoxaline compounds as immunomodulators
View Patent ↗The invention provides novel compositions comprising imidazoquinoxaline compounds of formula (I) and analogs thereof. Also provided are methods of administering the compositions in an effective amount to enhance the immune response of a subject. Further provided are novel compositions and methods of administering the compositions in combination with (an) other agent(s).
1. A compound of Formula (I):
wherein:
R 1 is selected from the group consisting of C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, hydroxy, hydroxyalkyl, halo, haloalkyl, amino, —OR 3 , —N(R 3 )(R 4 ), —NR 3 C(═O)R 4 , —NR 3 S(═O) p R 4 , —NR 3 C(═O)NR 4 R 5 , —NR 3 S(═O) p NR 4 R 5 , —C(═O)R 4 , —S(═O) p R 4 , —C(═O)NR 3 R 4 , —S(═O) p NR 3 R 4 and —C(═O)OR 4 ;
R 2 is selected from the group consisting of hydrogen, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxy, hydroxyalkyl, halo, haloalkyl, amino, —OR 3 , —N(R 3 )(R 4 ), —NR 3 C(═O)R 4 , —NR 3 S(═O) p R 4 , —NR 3 C(═O)NR 4 R 5 , —NR 3 S(═O) p NR 4 R 5 , —C(═O)R 4 , —S(═O) p R 4 , —C(═O)NR 3 R 4 , —S(═O) p NR 3 R 4 and —C(═O)OR 4 ;
R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxy, hydroxyalkyl, halo and haloalkyl;
R 6 is selected from the group consisting of hydrogen, halogen, hydroxy, —OR 3 , —N(R 3 )(R 4 ), C 1-3 haloalkyl, —O—C 1-3 haloalkyl, C 1-3 perhaloalkyl, —O—C 1-3 perhaloalkyl, C 1-3 hydroxyalkyl, —O—C 1-3 hydroxyalkyl, CN, —(CH 2 ) q C(═O)R 7 , —O—(CH 2 ) q C(═O)R 7 , —(CH 2 ) q N(R 8 )(R 9 ), —S—C 1-3 alkyl, —S(═O) 2 —R 10 and —S(═O) 2 N(R 8 )(R 9 );
q is 0, 1, 2 or 3;
R 7 is selected from hydrogen, hydroxy, C 1-3 alkyl or C 1-3 alkoxy; and
R 8 , R 9 and R 10 are each independently hydrogen or C 1-3 alkyl;
or a pharmaceutically acceptable salt thereof; a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer.
2. A compound of claim 1 , wherein R 1 is —N(R 3 )(R 4 ), C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, or substituted C 2 -C 12 alkenyl.
3. A compound of claim 1 , wherein R 1 is C 1 -C 12 alkyl or substituted C 1 -C 12 alkyl.
4. A compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl.
5. A compound of claim 1 , wherein R 2 is hydrogen, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, or hydroxyalkyl.
6. A compound of claim 1 , wherein R 2 is hydroxyalkyl.
7. A compound of claim 1 , wherein:
R 1 is —CH 2 —CH(CH 3 ) 2 ; and
R 2 is hydrogen or hydroxyalkyl.
8. A compound of claim 1 , wherein R 6 is hydrogen.
9. A compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
10. A compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
11. A method of inducing an immune response in a subject, comprising: administering a compound of claim 1 to the subject in an amount sufficient to induce an immune response in the subject.
12. The method of claim 11 , wherein the subject is suffering from a microbial infection.
13. The method of claim 11 , wherein the subject is suffering from a viral infection.
14. The method of claim 11 , wherein the subject is suffering from abnormal cellular proliferation or cancer.
15. The method of claim 11 , wherein the subject is suffering from allergic diseases.
16. The method of claim 11 , wherein the subject is suffering from asthma.
17. The method of claim 11 , wherein the subject is suffering from precancerous lesions, wherein the precancerous lesions are actinic keratosis.
18. The method of claim 11 wherein the compound is administered topically.
19. A method of enhancing the immune response to an antigen in a subject, comprising: administering to the subject a composition comprising a compound of claim 1 and an antigen, wherein the immune response to the antigen in the subject is enhanced.
20. A pharmaceutical composition, comprising: the compound of claim 1 and a pharmaceutically acceptable excipient.
21. A composition comprising the compound of claim 1 and an additional immunogenic composition or an antigen.
22. The composition of claim 21 , further comprising an adjuvant, wherein the adjuvant is MF59.
23. The composition of claim 21 , further comprising poly(lactide-co-glycolide) (PLG).
24. The composition of claim 21 , wherein the antigen is a bacterial antigen or a viral antigen.
25. The composition of claim 24 , wherein the antigen is a viral antigen from a virus selected from the group consisting of Hepatitis C virus, Human Immunodeficiency virus, Hepatitis B virus, Human Papilloma virus and Influenza virus.
26. The composition of claim 25 , wherein the antigen is an influenza antigen, and wherein the influenza antigen comprises haemagglutinin and/or neuraminidase surface proteins.
27. An immunogenic composition comprising an antigen and the compound of claim 1 effective to stimulate a cell mediated immune response to said antigen.