Compositions and methods for altering second messenger signaling

Patent metadata

Field	Value
Publication number	US-10385091-B2
Application number	US-201715718753-A
Country	US
Kind code	B2
Filing date	Sep 28, 2017
Priority date	Apr 29, 2013
Publication date	Aug 20, 2019
Grant date	Aug 20, 2019

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 pharmaceutical composition comprising a compound of Formula II:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
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 —CR— or —N—, wherein each R is independently hydrogen or C 1-6 aliphatic;
X 3 is —NH—;
X a and X b are independently —O— or —S—;
X a1 and X b1 are —CH;
X c and X d are independently oxygen or sulfur;
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, —CN, —OR a wherein R a is hydrogen or C 1-6 aliphatic, —N(R) 2 wherein each R is independently hydrogen or C 1-6 aliphatic, and C 1-12 aliphatic optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OR ∘ , and —N(R ∘ ) 2 , wherein each R ∘ is independently hydrogen or C 1-6 aliphatic;
each R 3 , R 4 , R 5 , R 6 , and R 7 is independently selected from the group consisting of hydrogen, halogen, —CN, —OR wherein R is hydrogen or C 1-6 aliphatic, —SR wherein R is hydrogen or C 1-6 aliphatic, —N(R) 2 wherein each R is independently hydrogen or C 1-6 aliphatic, —C(O)N(R) 2 wherein each R is independently hydrogen or C 1-6 aliphatic, —NHC(O)R wherein R is hydrogen, C 1-6 aliphatic, or phenyl, and C 1-12 aliphatic optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OR ∘ , and —N(R ∘ ) 2 , wherein each R ∘ is independently hydrogen or C 1-6 aliphatic;
the subindex of the carbon atoms to which each R 8 and R 9 is attached is 0; and
each R 10 and R 11 is independently hydrogen or C 1-2 alkyl.

2. The pharmaceutical composition of claim 1 , wherein Ring A is

3. The pharmaceutical composition of claim 2 , wherein Ring B is

4. The pharmaceutical composition of claim 1 , wherein Ring B is

5. The pharmaceutical composition of claim 1 , wherein each X 1 is —N—.

6. The pharmaceutical composition of claim 1 , wherein each X 2 is —N—.

7. The pharmaceutical composition of claim 1 , wherein X a is —O—.

8. The pharmaceutical composition of claim 1 , wherein X b is —O—.

9. The pharmaceutical composition of claim 1 , wherein X c and X d are both oxygen.

10. The pharmaceutical composition of claim 1 , wherein X c and X d are both sulfur.

11. The pharmaceutical composition of claim 1 , wherein 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 hydrogen or C 1-6 alkyl.

12. The pharmaceutical composition of claim 11 , wherein at least one of R 1 and R 2 is —OH.

13. The pharmaceutical composition of claim 1 , wherein 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 hydrogen or C 1-6 alkyl; and each R 10 and R 11 is hydrogen.

14. The pharmaceutical composition of claim 1 , wherein each R 3 , R 4 , R 5 , R 6 , and R 7 is independently selected from the group consisting of hydrogen, halogen, —OH, —SH, —NH 2 , and —C(O)NH 2 .

15. The pharmaceutical composition of claim 14 , wherein 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 hydrogen or C 1-6 alkyl.

16. The pharmaceutical composition of claim 1 , wherein each R 3 , R 5 , and R 7 is independently selected from the group consisting of hydrogen and halogen.

17. The pharmaceutical composition of claim 16 , wherein each R 3 , R 5 , and R 7 is hydrogen.

18. The pharmaceutical composition of claim 1 , wherein each R 4 and R 6 is independently selected from the group consisting of hydrogen, halogen, and —NH 2 .

19. The pharmaceutical composition of claim 18 , wherein R 4 and R 6 are each —NH 2 .

20. The pharmaceutical composition of claim 1 , wherein R 10 and R 11 are hydrogen.

21. The pharmaceutical composition of claim 1 , wherein the compound is of formula II-a:

or a pharmaceutically acceptable salt thereof.

22. The pharmaceutical composition of claim 1 , wherein the compound is of formula X, XI, XII, XIII, XIV, XV, or XVI:

or a pharmaceutically acceptable salt thereof.

23. The pharmaceutical composition of claim 21 , wherein:
Ring A is

wherein each X 1 is —N—, R 3 and R 5 are hydrogen, and
R 4 is —NH 2 ;
X a and X b are —O—;
R 1 and R 2 are —OH; and
R 10 and R 11 are hydrogen.

24. The pharmaceutical composition of claim 23 , wherein at least one of X c and X d is sulfur.

25. The pharmaceutical composition of claim 23 , wherein both of X c and X d are oxygen.

26. The pharmaceutical composition of claim 23 , wherein both of X c and X d are sulfur.

27. The pharmaceutical composition of claim 1 , wherein the compound is of formula XIV:

or a pharmaceutically acceptable salt thereof,
wherein:
each R 3 , R 5 , and R 7 are independently hydrogen or halogen;
each R 4 and R 6 are independently hydrogen, halogen, or —NH 2 ; and
each R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, —NH 2 , and —OR a , wherein R a is hydrogen or C 1-6 alkyl.

28. The pharmaceutical composition of claim 1 , wherein the compound is of formula XVI:

or a pharmaceutically acceptable salt thereof,
wherein:
each R 3 , R 5 , and R 7 are independently hydrogen or halogen;
each R 4 and R 6 are independently hydrogen, halogen, or —NH 2 ; and
each R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, —NH 2 , and —OR a , wherein R a is hydrogen or C 1-6 alkyl.

29. The pharmaceutical composition of claim 1 ,
wherein at least one of X c and X d is sulfur.

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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

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

• A61P37/02

  Immunomodulators · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title