Adenosine receptor antagonists and uses thereof
Inventors
Assignees
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Publication Number
US-11124515-B2
Publication Date
2021-09-21
Expiration Date
Abstract
Disclosed herein are compounds of Formula (III), compositions and formulations thereof,and methods for modulating the A22B adenosine receptor for treatment of A2B adenosine receptor mediated diseases or conditions.
Core Innovation
The invention relates to adenosine receptor antagonists, including A2B adenosine receptor antagonists, and to compounds represented by Formula (A), Formula (B), Formula (III), and related Formulae I-III and II/IIa. The compounds are defined by substituent variables R1-R12 and additional substituent and ring parameters, with explicit structural motifs and variable-specific restrictions within the formula definitions. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, and prodrug-related forms are included within the disclosed chemical scope.
The substituent definitions include hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted and unsubstituted phenyl, and substituted phenyl options including halogen, —CN, and C1-C4 fluoroalkyl. Additional classes are stated for alkyl, alkyl-(substituted or unsubstituted heterocycloalkyl), —(CH2CH2O)n—R11, and —(C(R10)2)p—OR11, together with carbonyl-, phosphonooxy-, ester-type, and phosphate-type substituent groupings. The disclosure also includes explicit examples of substituent patterns such as ethyl, n-propyl, and 3-(trifluoromethyl)phenyl.
The disclosed framework includes parameter constraints for n and p each limited to 1, 2, 3, 4, 5, or 6. The document also places these A2B receptor antagonists in downstream therapeutic context, including cancer and fibrosis therapy, and identifies exemplified compounds such as Compound BB, Compound CC, Compound DD, Compound EE, Compound FF, and Compound GG.
Claims Coverage
The claim coverage is concentrated on chemical-structure scope: a Formula (III) compound with defined substituent classes and bounded integer parameters, plus additional structure-defined compound claims that include pharmaceutically acceptable salts and, in one case, solvates. Dependent claim coverage further narrows substituents and adds pharmaceutical composition features, including administration routes, dosage forms, and excipients.
Formula (III) A2B antagonist compound scaffold with constrained substituent variables
A compound represented by Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R2 are each independently selected from hydrogen and substituted or unsubstituted C1-C6 alkyl; R3 is selected from substituted and unsubstituted phenyl with substitution options limited to halogen, —CN, and C1-C4 fluoroalkyl; R5 is hydrogen or R7; R7 is substituted or unsubstituted C1-C6 alkyl, alkyl-(substituted or unsubstituted heterocycloalkyl), —(CH2CH2O)n—R11, or —(C(R10)2)p—OR11; each R9 is independently selected from hydrogen and C1-C6 alkyl; each R10 is independently selected from hydrogen and C1-C6 alkyl; R11 is hydrogen, substituted or unsubstituted alkyl, —C(=O)R12, or —P(=O)(OR9)2; R12 is hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C10 cycloalkyl; and n and p are each 1, 2, 3, 4, 5, or 6.
Compound of structure with pharmaceutically acceptable salt or solvate
A compound of structure, or a pharmaceutically acceptable salt or solvate thereof.
Compound of structure with pharmaceutically acceptable salt
A compound of structure, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition including the claimed compound
A pharmaceutical composition that includes the compound of the claim or a pharmaceutically acceptable salt thereof, including formulation for administration to a mammal via oral, intravenous, or subcutaneous routes and dosage forms such as tablet, pill, capsule, liquid, suspension, dispersion, solution, or emulsion, with at least one pharmaceutically acceptable excipient.
Overall, the claim coverage is concentrated on chemical-structure scope: a Formula (III) compound with defined substituent classes and bounded integer parameters, plus additional structure-defined compound claims that include pharmaceutically acceptable salts and, in one case, solvates. Dependent claim coverage further narrows substituents and adds pharmaceutical composition features, including administration routes, dosage forms, and excipients.
Stated Advantages
Improved bioavailability is stated as a motivation in view of some A2B antagonists being relatively insoluble and difficult to formulate.
Documented Applications
A2B adenosine receptor antagonists intended to address solubility and formulation challenges.
Cancer therapy.
Fibrosis therapy.
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