Cyclic amide-containing pyridyl xanthines as A2B antagonists
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Publication Number
US-12269828-B2
Publication Date
2025-04-08
Expiration Date
Abstract
Described herein are cyclic amide-containing pyridyl-xanthines of formula I and pharmaceutical compositions thereof that are useful as antagonists of A2B adenosine receptors.
Core Innovation
The invention relates to compounds of formula I for use in treating an adenosine A2B receptor associated state in a subject by administering an effective amount of a compound of formula I, or a stereoisomer, or a pharmaceutically acceptable salt thereof. The formula I compounds are defined by a shared structural framework with Ring A selected from phenyl, naphthyl, and a 5-10 membered heteroaryl, a variable (CH2)n group, and substituents R1 through R7 and p, including embodiments with amide-containing groups and alternatives where R4 and R5 are absent with Ring A replicated by a selected group.
The disclosure further includes deuterium-enriched variants in which H is replaced by D within Ring A substituents, including Formula I_A through I_C, and representative compounds are described as active A2B antagonists. The structural scope further includes substitution patterns involving C1-6 alkyl, C3-6 cycloalkyl, substituted alkylene-cycloalkyl motifs, and alternative selection rules for (CH2)n-R3.
The method is directed to inhibiting the adenosine A2B receptor associated state and/or relieving the adenosine A2B receptor associated state and/or ameliorating a symptom of the adenosine A2B receptor associated state. The adenosine A2B receptor associated state is identified as asthma, bronchoconstriction, pain, diabetic retinopathy, bladder cancer, and breast cancer, with a specific example of breast cancer in the human breast cancer cell line MDA-MB-231 and an analgesic adjuvant combination approach.
Claims Coverage
The independent claim coverage centers on a method for treating an adenosine A2B receptor associated state by administering an effective amount of a compound of formula I, including stereoisomers and pharmaceutically acceptable salts. The claim set combines defined formula I structural limitations with explicit therapeutic outcomes, and includes dependent refinements that narrow the compound selection, target state, deuterium-enriched embodiments, and combination use.
Treating an adenosine A2B receptor associated state with formula I compounds
A method for treating an adenosine A2B receptor associated state in a subject by administering an effective amount of a compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein treatment inhibits the adenosine A2B receptor associated state and/or relieves the adenosine A2B receptor associated state and/or ameliorates a symptom.
Defined formula I structure with Ring A, linker, and substituent selections
A compound of formula I is defined with Ring A selected from phenyl, naphthyl, and a 5-10 membered heteroaryl, n selected from 1-10, and R1, R2, R3, R4, R5, R6, R7, and p selected from enumerated groups, including alternative embodiments where R4 and R5 are absent and Ring A is replicated by a group selected from specified alternatives.
Amide-containing constraint within R1 or R2
At least one of R1 and R2 is an amide-containing group independently selected from specified amide-containing moieties.
Deuterium-enriched Formula I embodiments
Deuterium-enriched variants of Formula I are provided, including Formula I_A through Formula I_C, in which H is replaced by D within Ring A substituents.
Therapeutic target states within adenosine A2B receptor associated states
The adenosine A2B receptor associated state is asthma, bronchoconstriction, pain, diabetic retinopathy, bladder cancer, and breast cancer, with a specific narrowing to breast cancer in the human breast cancer cell line MDA-MB-231.
A2B antagonist as an analgesic adjuvant
A compound of formula I is administered together with a therapeutically effective amount of an analgesic to a subject needing analgesia, with the compound serving as an A2B antagonist analgesic adjuvant.
Analgesic selected from opioid or non-steroidal anti-inflammatory drug
In the analgesic-adjuvant combination, the analgesic is selected from an opioid or a non-steroidal anti-inflammatory drug.
The claims cover treatment of adenosine A2B receptor associated states using formula I compounds, including stereoisomers, pharmaceutically acceptable salts, and deuterium-enriched variants, with extensive structural definitions and an amide-containing limitation. The coverage also includes the listed disease states, a specific breast cancer narrowing to MDA-MB-231, and combination use as an A2B antagonist analgesic adjuvant with an opioid or a non-steroidal anti-inflammatory drug.
Stated Advantages
Inhibiting the adenosine A2B receptor associated state and/or relieving the adenosine A2B receptor associated state and/or ameliorating a symptom of the adenosine A2B receptor associated state.
Provides A2B antagonism.
Improves prior A2B xanthine antagonists described as having low solubility, low bioavailability, and poor tissue penetration.
Documented Applications
Treatment of an adenosine A2B receptor associated state in a subject, including asthma, bronchoconstriction, pain, diabetic retinopathy, bladder cancer, and breast cancer.
Breast cancer application narrowed to the human breast cancer cell line MDA-MB-231.
Analgesic adjuvant application in which a compound of formula I is administered together with an analgesic to a subject needing analgesia.
Representative compounds are described as active A2B antagonists with percent inhibition of NECA in an A2B receptor assay using HEK293 cells.
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