Compositions and methods for altering second messenger signaling

• US 10,385,091 B2
• Filed: 09/28/2017
• Issued: 08/20/2019
• Est. Priority Date: 04/29/2013
• Status: Active Grant

• Current Assignee: Bond University, Memorial Sloan-Kettering Cancer Center, Rockefeller University, Rutgers University
• Original Assignee: Memorial Sloan-Kettering Cancer Center
• 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
• Primary Examiner(s): Murray, Jeffrey H
• Application Number:
  US15/718,753
• Publication Number:
  US 20180118777A1
• Time in Patent Office: 691 Days
• Field of Search: 514 47
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07F 9/65746 : the molecule containing more than one cyclic phosphorus atom
• CPC Class Codes: C07H 21/00 : Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12Q 1/485 : involving kinase
• CPC Class Codes: C12Y 207/07 : Nucleotidyltransferases (2.7.7)
• CPC Class Codes: G01N 2500/04 : Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 2500/10 : involving cells
• CPC Class Codes: G06V 20/698 : Matching; Classification
• CPC Class Codes: G16B 15/00 : ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
• CPC Class Codes: G16B 20/00 : ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/30 : Detection of binding sites or motifs
• CPC Class Codes: G16B 20/50 : Mutagenesis

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.

Claims

1. A pharmaceutical composition comprising a compound of Formula II:

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 X¹ is —

N—

.

6. The pharmaceutical composition of claim 1, wherein each X² 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 R¹ and R² is independently selected from the group consisting of hydrogen, halogen, —

NH₂, 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 R¹ and R² is —

OH.

13. The pharmaceutical composition of claim 1, wherein each R¹ and R² is independently selected from the group consisting of hydrogen, halogen, —

NH₂, and —

OR^a, wherein R^a is hydrogen or C_1-6 alkyl; and

each R¹⁰ and R¹¹ is hydrogen.

14. The pharmaceutical composition of claim 1, wherein each R³, R⁴, R⁵, R⁶, and R⁷ is independently selected from the group consisting of hydrogen, halogen, —

OH, —

SH, —

NH₂, and —

C(O)NH₂.

15. The pharmaceutical composition of claim 14, wherein each R¹ and R² is independently selected from the group consisting of hydrogen, halogen, —

NH₂, and —

OR^a, wherein R^a is hydrogen or C_1-6 alkyl.

16. The pharmaceutical composition of claim 1, wherein each R³, R⁵, and R⁷ is independently selected from the group consisting of hydrogen and halogen.

17. The pharmaceutical composition of claim 16, wherein each R³, R⁵, and R⁷ is hydrogen.

18. The pharmaceutical composition of claim 1, wherein each R⁴ and R⁶ is independently selected from the group consisting of hydrogen, halogen, and —

NH₂.

19. The pharmaceutical composition of claim 18, wherein R⁴ and R⁶ are each —

NH₂.

20. The pharmaceutical composition of claim 1, wherein R¹⁰ and R¹¹ are hydrogen.

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

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

23. The pharmaceutical composition of claim 21, wherein:

Ring A is

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:

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

29. The pharmaceutical composition of claim 1,

wherein at least one of X^c and X^d is sulfur.