COMPOSITIONS AND METHODS FOR ALTERING SECOND MESSENGER SIGNALING

• US 20190330257A1
• Filed: 06/28/2019
• Published: 10/31/2019
• Est. Priority Date: 04/29/2013
• Status: Active Grant

• Current Assignee: Bond University, Memorial Sloan-Kettering Cancer Center, Rockefeller University, Rutgers University
• Original Assignee: Bond University, Memorial Sloan-Kettering Cancer Center, Rockefeller University, Rutgers University
• 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
• Granted Patent: US 11,014,956 B2
• Time in Patent Office: Days
• 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

1-2. -2. (canceled)

3. A compound of Formula II:

79. The compound of claim 3, wherein Ring A is selected from the group consisting of:

80. The compound of claim 79, wherein R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, —

OR^a, or —

NH₂.

81. The compound of claim 80, wherein each R³, R⁵, and R⁷ is independently selected from the group consisting of hydrogen and halogen, and wherein each of R⁴ and R⁶ is independently selected from the group consisting of hydrogen, halogen, and —

NH₂.

82. The compound of claim 81, wherein each X¹ is —

N—

, each X² is —

N—

, and each X³ is —

NH—

.

83. The compound of claim 82, wherein each X^e and X^f is —

O—

;

X^a and X^b are —

O—

; and

X^a1 and X^b1 are —

CH—

.

84. The compound of claim 83, wherein R¹⁰ and R¹¹ are hydrogen, and wherein the subindex of the carbon atoms to which each R⁸ and R⁹ is attached is 0.

85. The compound of claim 84, wherein R^a is R, and each R is hydrogen.

86. The compound of claim 85, wherein one of X^c and X^d is sulfur.

87. The compound of claim 86, wherein one of X^c and X^d is sulfur, and the other of X^c and X^d is oxygen or sulfur.

88. The compound of claim 87, wherein X^c and X^d are both sulfur.

89. The compound of claim 3, wherein:

Ring A is selected from the group consisting of;

90. The compound of claim 89, wherein each optionally substituted group of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹ and R is independently optionally substituted with one or more of halogen, C_1-6 alkyl, —

OR^∘

, —

SR^∘

, or —

N(R^∘

)₂, wherein R^∘

is hydrogen or C_1-6 alkyl.

91. The compound of claim 90, wherein:

each X¹ and X² is independently —

CR—

or —

N—

, wherein each R is independently hydrogen or C_1-6 aliphatic;

X³ is —

NH—

;

X^a and X^b are independently —

O—

or —

S—

;

X^a1 and X^b1 are independently —

CH—

;

each X^e and X^f is —

O—

, —

S—

, or —

NH—

;

each R¹ and R² is independently selected from the group consisting of hydrogen, halogen, —

CN, —

OR^a, —

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 of halogen, —

OR^∘

, and —

N(R^∘

)₂;

each R³, R⁴, R⁵, R⁶, and R⁷ 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, —

N(H)C(O)R wherein R is hydrogen, C_1-6 aliphatic, or phenyl, and C_1-12 aliphatic optionally substituted with one or more of halogen, —

OR^∘

, and —

N(R^∘

)₂;

each R¹⁰ and R¹¹ is independently hydrogen or C_1-2 alkyl;

R^a is an oxygen protecting group, hydrogen, or C_1-6 aliphatic; and

each R^∘

is independently hydrogen or C_1-6 aliphatic.

92. The compound of claim 91, wherein:

each X¹ and X² is independently —

CH—

or —

N;

one of X^c and X^d is sulfur, and the other of X^c and X^d is oxygen or sulfur;

each X^e and X^f is —

O—

;

each R¹ and R² is independently selected from the group consisting of hydrogen, halogen, —

OR^a, or —

NH₂;

each R³, R⁴, R⁵, R⁶, and R⁷ is independently selected from the group consisting of hydrogen, halogen, —

OR wherein R is hydrogen or C_1-6 alkyl, —

SR wherein R is hydrogen or C_1-6 alkyl, —

NH₂, and —

N(H)C(O)R wherein R is hydrogen, C_1-6 alkyl, or phenyl; and

R^a is an oxygen protecting group or hydrogen.

93. The compound of claim 3, wherein the compound is of formula II-a:

94. The compound of claim 93, wherein the compound is of formula X, XIV, or XVI:

95. The compound of claim 93, wherein:

Ring A is

96. The compound of claim 93, wherein:

Ring A is

97. A pharmaceutical composition comprising the compound claim 3 and a pharmaceutically acceptable carrier.

98. A method for treatment or prevention of cancer, comprising administering to a subject in need thereof the compound of claim 3.

4-78. -78. (canceled)