Sting agonistic compound
Inventors
HANADA, Ryosuke • Kokubo, Masaya • KURONO, Masakuni • KOUDA, Kenichi • Hagiya, Hiroshi
Assignees
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Publication Number
US-11919917-B2
Publication Date
2024-03-05
Expiration Date
Abstract
A drug or agent containing a compound having an agonistic activity to STING as an active ingredient, where the compound is represented by the following general formula (I-1):wherein all symbols represent the same meanings as described in the specification, and the compound can be used as an active ingredient of an agent for suppressing the progression of, suppressing the recurrence of and/or treating cancer or infectious disease.
Core Innovation
The invention relates to compounds of formula (I-1) and their pharmaceutically acceptable salts or solvates, including hydrates, N-oxides and prodrugs. The compounds are defined by specified ring systems, linker groups, and substituent variables, where Ring A is a 5 to 7-membered monocycle and Ring B is a 5 to 7-membered monocycle or 8 to 10-membered bicycle. The structural definitions restrict X, Y, Z, T, the allowable bonding patterns L1 and L2, and substituents including R1, R2c, R2d, R2e, R3, R4a, R5, R6a, R7, and the bonding position of Ring B b.
The invention further specifies a phosphonooxyalkyl substituent represented by RFR within the compound scaffold, together with constraints on the permissible values of q and the substituents (RFa) and (RFb). In particular, the claim language includes a proviso that two or more of R2d, R4a, and R6a are not simultaneously RFR, and it includes extensive lists of allowable substituent types and heterocyclic options for the rings and positions. Ring A is selected from pyrazole, triazole, tetrazole, oxazole, isoxazole, imidazole, thiazole, or isothiazole.
The disclosed examples provide characterization data using LCMS and 1H-NMR for multiple variants differing in aryl sulfur/acyl substituents, and include downstream reference to biological activity testing and in vivo colon cancer tumor suppression data for specified examples. The document states that the structural class is previously unreported and connects the compounds to STING activation in relation to cGAS and cGAMP, including stimulation of type I interferon (IFN) and innate immunity pathways relevant to tumor immunity and infectious disease.
Claims Coverage
The claim coverage includes three independent claims: a broad compound class of formula (I-1) with constrained structural variables, a specific alkali metal salt/solvate of a named dihydrogen phosphate compound, and a pharmaceutical composition containing that named compound plus a pharmaceutically acceptable carrier. Across these claims, the main inventive coverage centers on the formula (I-1) scaffold definition, phosphorous-containing group constraints, and specific salt/composition embodiments explicitly tied to a dihydrogen phosphate compound.
Constrained compound of formula (I-1)
A compound of formula (I-1) with defined ring sizes and heteroatoms, where Ring A is a 5 to 7-membered monocycle and Ring B is a 5 to 7-membered monocycle or 8 to 10-membered bicycle; specified linker options L1 and L2; defined substituent constraints for X, Y, Z, T, R1, R2c, R2d, R2e, R3, R4a, R5, R6a, and R7; a defined RFR group with proviso that two or more of R2d, R4a, and R6a are not simultaneously RFR; including a pharmaceutically acceptable salt or solvate thereof.
Phosphonooxyalkyl substituent RFR
RFR represents —(CRFb2)qOP(=O)(ORFa)2, where (RFa)s are independently hydrogen atom, C1-4 alkyl group, C3-6 cycloalkyl group, —(CH2)2OH, or —CH2OCO2CH(CH3)2; (RFb)s are independently hydrogen atom or methyl group; and q is an integer of 1 or 2 with possible repetition of (RFb)s.
Alkali metal salt of a substituted dihydrogen phosphate
An alkali metal salt of (4-(4-(5-acetyl-4-amino-2-fluorophenyl)-3-aminoisoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate or a solvate thereof.
Pharmaceutical composition with named dihydrogen phosphate and carrier
A pharmaceutical composition comprising (4-(4-(5-acetyl-4-amino-2-fluorophenyl)-3-aminoisoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier.
Overall, the claim coverage includes a broad scaffold definition (formula (I-1)) with detailed structural constraints, and it also specifically covers a particular alkali metal salt/solvate and a pharmaceutical composition containing a corresponding named dihydrogen phosphate compound with a pharmaceutically acceptable carrier.
Stated Advantages
STING agonist activity enabling suppression of cancer progression and/or recurrence and/or treatment of cancer.
STING agonist activity enabling treatment of infectious disease.
Documented Applications
Treating colon cancer disease in a subject, including suppressing progression and suppressing recurrence, by administering the compound of formula (I-1) (or pharmaceutically acceptable salt/solvate).
STING agonist-based pharmaceutical use for treating/suppressing progression or recurrence of cancer and/or progression of infectious disease.
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