Compositions and methods for altering second messenger signaling

Patent metadata

Field	Value
Publication number	US-10131686-B2
Application number	US-201715836763-A
Country	US
Kind code	B2
Filing date	Dec 8, 2017
Priority date	Apr 29, 2013
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

Abstract

The invention relates to compositions, methods, kits, and assays related to the use and/or exploitation of isomers of cGAMP as well as the structure of the enzyme cGAS.

First claim

We claim:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
Ring A is selected from the group consisting of:

Ring B is selected from the group consisting of:

each X 1 and X 2 is independently —CH— or —N—;
X 3 is —NH—;
X a and X b are independently —O— or —S—;
X a1 and X b1 are —CH—;
one of X c or X d is sulfur and the other of X c or X d is sulfur or oxygen optionally substituted with cyanoethyl;
each X e and X f is —O—;
each W is P;
each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, —NH 2 , and —OR a , wherein R a is an oxygen protecting group or hydrogen;
each R 3 , R 4 , R 5 , R 6 , and R 7 is independently selected from the group consisting of hydrogen, halogen, —NH 2 , —OR wherein R is hydrogen or C 1-6 alkyl, —SR wherein R is hydrogen or C 1-6 alkyl, and —NHC(O)R wherein R is hydrogen, C 1-6 alkyl, or phenyl;
each R 10 and R 11 is independently hydrogen or C 1-2 alkyl; and
the subindex of the carbon atoms to which each R 8 and R 9 is attached is 0.

2. The compound of claim 1 , wherein Ring A is

3. The compound of claim 1 , wherein Ring B is

4. The compound of claim 1 , wherein Ring B

5. The compound of claim 1 , wherein each X 1 and X 2 is —N—.

6. The compound of claim 1 , wherein X a and X b are —O—.

7. The compound of claim 1 , wherein X c and X d are both sulfur.

8. The compound of claim 1 , wherein R 1 is selected from the group consisting of hydrogen, halogen, and —OH.

9. The compound of claim 1 , wherein R 2 is selected from the group consisting of hydrogen, halogen, and —OH.

10. The compound of claim 1 , wherein each of R 3 , R 5 , and R 7 is hydrogen.

11. The compound of claim 1 , wherein R 4 and R 6 are each —NH 2 .

12. The compound of claim 1 , wherein R 10 and R 11 are each hydrogen.

13. The compound of claim 1 , wherein the compound is of formula I-a:

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein the compound is of formula III, VII, or IX:

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14 , wherein X c and X d are both sulfur.

16. The compound of claim 14 , wherein R 1 is selected from the group consisting of hydrogen, halogen, and —OH.

17. The compound of claim 14 , wherein R 2 is selected from the group consisting of hydrogen, halogen, and —OH.

18. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

19. A method for treatment or prevention of cancer, comprising administering to a subject in need thereof the pharmaceutical composition of claim 18 .

Assignees

• Memorial Sloan Kettering Cancer Center
• Univ Rockefeller
• Univ Rutgers
• Univ Of Bonn

Inventors

• Patel Dinshaw J
• Tuschl Thomas
• Ascano Jr Manuel
• Wu Yang
• Liu Yizhou
• Barchet Winfried
• Hartmann Gunther
• Zillinger Thomas
• Jones Roger
• Gaffney Barbara L
• Gao Pu

Classifications

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title