Cyclic dinucleotides as agonists of stimulator of interferon gene dependent signalling

Patent metadata

Field	Value
Publication number	US-12036231-B2
Application number	US-202217809190-A
Country	US
Kind code	B2
Filing date	Jun 27, 2022
Priority date	Feb 21, 2017
Publication date	Jul 16, 2024
Grant date	Jul 16, 2024

Abstract

Disclosed herein are new cyclic dinucleotide compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of modulation of immune response to disease, and induce Stimulator of Interferon Genes (STING) dependent type I interferon production and co-regulated genes in a human or animal subject are also provided for the treatment diseases such as cancer, particularly metastatic solid tumors and lymphomas, inflammation, allergic and autoimmune disease, infectious disease, and for use as anti-viral agents and vaccine adjuvants.

First claim

What is claimed is:

1. A compound of structural Formula:

or a salt, ester, tautomer, or prodrug thereof, wherein:
R 2 is selected from the group consisting of OH, Cl, N 3 , and NH 2 ; and
R 3 is selected from the group consisting of OH, Cl, N 3 , and NH 2 , with the proviso that:
when R 2 is OH, R 3 is not OH; and
when R 3 is OH, R 2 is not OH.

2. The compound of claim 1 , or a salt, ester, tautomer, or prodrug thereof, wherein R 2 is —Cl.

3. The compound of claim 1 , or a salt, ester, tautomer, or prodrug thereof, wherein R 2 is —N 3 .

4. The compound of claim 1 , or a salt, ester, tautomer, or prodrug thereof, wherein R 2 is —NH 2 .

5. The compound of claim 1 , or a salt, ester, tautomer, or prodrug thereof, wherein R 3 is —OH, and R 2 is —Cl.

6. The compound of claim 1 , or a salt, ester, tautomer, or prodrug thereof, wherein R 3 is —OH, and R 2 is —N 3 .

7. The compound of claim 1 , or a salt, ester, tautomer, or prodrug thereof, wherein R 3 is —OH, and R 2 is —NH 2 .

8. A drug delivery vehicle comprising a compound of structural Formula:

or a salt, ester, tautomer, or prodrug thereof,
which is conjugated to a targeting moiety,
wherein
R 2 is selected from the group consisting of OH, F, Cl, N 3 , and NH 2 ; and
R 3 is selected from the group consisting of OH, F, Cl, N 3 , and NH 2 , with the proviso that:
when R 2 is OH, R 3 is not OH; and
when R 3 is OH, R 2 is not OH.

9. The drug delivery vehicle of claim 8 , wherein R 3 is —OH, and R 2 is —F.

10. The drug delivery vehicle of claim 8 , or a salt, ester, tautomer, or prodrug thereof, wherein the compound is:

11. The drug delivery vehicle of claim 8 , or a salt, ester, tautomer, or prodrug thereof, wherein the compound is:

12. The drug delivery vehicle of claim 8 , wherein the targeting moiety is selected from the group consisting of a peptide, biotin or a biotin analog, a protein, transferrin, an antibody, a monoclonal antibody, and a nanoparticle.

13. The drug delivery vehicle of claim 8 contained with a container moiety.

14. The drug delivery vehicle of claim 8 , wherein the container moiety is selected from the group consisting of a nanoparticle, a liposome, a micelle, and a vesicle.

15. A pharmaceutical composition comprising a compound of claim 1 , or a salt, ester, tautomer, or prodrug thereof, and a pharmaceutically acceptable carrier.

16. A method of agonism of STING comprising contacting STING with a compound of claim 1 , or a salt, ester, tautomer, or prodrug thereof.

17. A method of treatment of a STING-mediated disease comprising administration of a therapeutically effective amount of a compound of claim 1 , or a salt, ester, tautomer, or prodrug thereof, to a patient in need thereof, wherein treatment means ameliorating a disease so as to reduce, ameliorate, or eliminate its cause, its progression, its severity, or one or more of its symptoms.

18. The method of claim 17 , wherein the disease is a STING-mediated tumor, a STING-mediated inflammatory disease, a STING-mediated autoimmune disease, or a STING-mediated infectious disease.

19. A method for achieving an effect in a patient comprising administration of a therapeutically effective amount of a compound of claim 1 , or a salt, ester, tautomer, or prodrug thereof, to a patient in need thereof, wherein said effect is selected from the group consisting of induction of transcription of host defense genes, production of a cytokine, release of chemokines, and priming of antigen-specific T-cells.

20. A method of inducing STING-dependent type interferon I production in a patient comprising administration of a therapeutically effective amount of a compound of claim 1 , or a salt, ester, tautomer, or prodrug thereof, to a patient in need thereof.

Assignees

• Univ Texas

Inventors

• Di Francesco Maria Emilia
• Jones Philip
• Curran Michael A

Classifications

• C07D473/26

  with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both · CPC title

• C07D473/32

  Nitrogen atom · CPC title

• C07D473/16

  two nitrogen atoms · CPC title

• C07D473/34

  attached in position 6, e.g. adenine · CPC title

• C07D473/02

  with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 · CPC title