Composition comprising an antigen and a substituted imidazo[1,2-a]pyrimidine for enhancing human immune response

Patent metadata

Field	Value
Publication number	US-11730810-B2
Application number	US-201816763847-A
Country	US
Kind code	B2
Filing date	Nov 14, 2018
Priority date	Nov 14, 2017
Publication date	Aug 22, 2023
Grant date	Aug 22, 2023

Abstract

Provided herein are imidazopyrimidine compounds, such as compounds of Formula (I), for use in enhancing human immune response and/or as adjuvants in vaccines.

First claim

What is claimed is:

1. A composition comprising an antigen and a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is hydrogen, halogen, C 1-6 alkyl, N(R a1 ) 2 , or OR a ;
R 1A is benzyl, phenyl, or 6-membered heteroaryl;
wherein the —CH 2 — portion of the benzyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, N(R a1 ) 2 , and OR a ;
wherein each C 1-6 alkyl substituent of the —CH 2 — portion of the benzyl is optionally and independently substituted with 1, 2, or 3 independently selected OR a substituents;
wherein the phenyl portion of the benzyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, NO 2 , alkyl, haloalkyl, alkenyl, alkynyl, C(O)R a , C(O)N(R a1 ) 2 , C(O)OR a , N(R a1 ) 2 , OR a , SR a , carbocyclyl, heterocyclyl, aryl, and heteroaryl; and
wherein the phenyl or 6-membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, NO 2 , alkyl, haloalkyl, alkenyl, alkynyl, C(O)R a , C(O)N(R a1 ) 2 , C(O)OR a , N(R a1 ) 2 , OR a , SR a , carbocyclyl, heterocyclyl, aryl, and heteroaryl;

each R A is independently halogen, CN, NO 2 , alkyl, alkenyl, alkynyl, C(O)R a , C(O)N(R a1 ) 2 , C(O)OR a , N(R a1 ) 2 , OR a , SR a , carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each R B is independently halogen, CN, NO 2 , alkyl, alkenyl, alkynyl, C(O)R a , C(O)N(R a1 ) 2 , C(O)OR a , N(R a1 ) 2 , OR a , SR a , carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each R a is independently hydrogen, alkyl, alkenyl, alkynyl, acyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each R a1 is independently hydrogen, alkyl, alkenyl, alkynyl, acyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or
any two R a1 , together with the nitrogen atom to which they are attached, independently form a heterocyclyl or heteroaryl;
a is 0, 1, 2, or 3; and
b is 0, 1, 2, or 3.

2. The composition of claim 1 , wherein the composition is a vaccine composition.

3. The composition of claim 2 , wherein the compound of Formula (I) is an adjuvant.

4. The composition of claim 1 , wherein the compound of Formula (I) is lipidated.

5. The composition of claim 1 , wherein the compound of Formula (I) is conjugated to the antigen.

6. The composition of claim 1 , wherein:
(a) the antigen comprises a polypeptide; or
(b) the antigen comprises a protein.

7. The composition of claim 1 , wherein:
(a) the antigen comprises a nucleic acid encoding a polypeptide; or
(b) the antigen comprises a nucleic acid encoding a protein.

8. The composition of claim 1 , wherein the antigen is a cancer-specific antigen.

9. The composition of claim 1 , wherein the antigen is from a microbial pathogen.

10. The composition of claim 1 , wherein the compound of Formula (I) is any one of the following formulae:

or a pharmaceutically acceptable salt thereof,
wherein:
each R 2 is independently hydrogen, halogen, C 1-6 alkyl, N(R a1 ) 2 , or OR a , wherein each C 1-6 alkyl is optionally and independently substituted with 1, 2, or 3 independently selected OR a substituents;
each R C is independently halogen, CN, NO 2 , alkyl, haloalkyl, alkenyl, alkynyl, C(O)R a , C(O)N(R a1 ) 2 , C(O)OR a , N(R a1 ) 2 , OR a , SR a , carbocyclyl, heterocyclyl, aryl, or heteroaryl; and
c is 0, 1, 2, 3, 4, or 5.

11. The composition of claim 1 , wherein the compound of Formula (I) is of the following formula:

or a pharmaceutically acceptable salt thereof,
wherein:
each R 2 is independently hydrogen, halogen, C 1-6 alkyl, N(R a1 ) 2 , or OR a , wherein each C 1-6 alkyl is optionally and independently substituted with 1, 2, or 3 independently selected OR a substituents;
each R C is independently halogen, CN, NO 2 , alkyl, haloalkyl, alkenyl, alkynyl, C(O)R a , C(O)N(R a1 ) 2 , C(O)OR a , N(R a1 ) 2 , OR a , SR a , carbocyclyl, heterocyclyl, aryl, or heteroaryl; and
c is 0, 1, 2, 3, 4, or 5.

12. The composition of claim 1 , wherein the compound of Formula (I) is of the following formula:

or a pharmaceutically acceptable salt thereof,
wherein:
each R C is independently halogen, CN, NO 2 , alkyl, haloalkyl, alkenyl, alkynyl, C(O)R a , C(O)N(R a1 ) 2 , C(O)OR a , N(R a1 ) 2 , OR a , SR a , carbocyclyl, heterocyclyl, aryl, or heteroaryl; and
c is 0, 1, 2, 3, 4, or 5.

13. The composition of claim 1 , wherein the compound of Formula (I) is of the following formula:

or a pharmaceutically acceptable salt thereof,
wherein:
each R C is independently halogen, CN, NO 2 , alkyl, haloalkyl, alkenyl, alkynyl, C(O)R a , C(O)N(R a1 ) 2 , C(O)OR a , N(R a1 ) 2 , OR′, SR a , carbocyclyl, heterocyclyl, aryl, or heteroaryl.

14. The composition of claim 1 , wherein the compound of Formula (I) is of the following formula:

or a pharmaceutically acceptable salt thereof,
wherein:
each R C is independently halogen, CN, NO 2 , alkyl, haloalkyl, alkenyl, alkynyl, C(O)R a , C(O)N(R a1 ) 2 , C(O)OR a , N(R a1 ) 2 , OR′, SR a , carbocyclyl, heterocyclyl, aryl, or heteroaryl; and
c is 0, 1, 2, 3, 4, or 5.

15. The composition of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

16. The composition of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

17. A method for enhancing an immune response in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of the composition of claim 1 .

18. The method of claim 17 , wherein the subject has a disease which requires an immune response.

19. The method of claim 17 , wherein the immune response is an innate immune response.

20. A method for enhancing an immune response to an antigen in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of the composition of claim 1 .

Assignees

• Childrens Medical Center
• Dana Farber Cancer Inst Inc

Inventors

• Levy Ofer
• Dowling David J
• Borriello Francesco
• Scott David A
• Brightman Spencer E
• Feru Frederic

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61K39/39 Primary

  characterised by the immunostimulating additives, e.g. chemical adjuvants · CPC title

• A61K9/127

  Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant · CPC title

• A61K39/0003

  Invertebrate antigens · CPC title

• A61K39/008

  Leishmania antigens · CPC title