Phenethyldihydrobenzodioxolones and methods of use
Inventors
Williams, Russell B • Eldridge, Gary • Starks, Courtney M. • Guzzo, Peter Robert • Huang, Zhongping
Assignees
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Publication Number
US-9562031-B1
Publication Date
2017-02-07
Expiration Date
Abstract
The present invention generally relates to phenethyldihydrobenzodioxolone compounds and compositions useful for reducing or inhibiting tumor growth. It also relates to methods of use and the preparation of phenethyldihydrobenzodioxolone compounds.
Core Innovation
The invention relates to compounds, including stereoisomers and enantiomers, defined by chemical formulas in which multiple substituents are selected from specific groups and ring-position variables are constrained by enumerated chemical substituent sets. The compounds include benzo[d][1,3]dioxol-5(6H)-one scaffolds and related phenethyldihydrobenzodioxolone analogues, with variable substituents including R1, R2, R3, R4, and, in some embodiments, R5/R6/R7 or R8/R9. The scope includes explicit provisos that exclude particular combinations of substituent selections, together with pharmaceutically acceptable salts, solvates, and, in some instances, prodrugs.
Specific embodiments narrow the compound scope to selected members of substituted benzo[d][1,3]dioxol-5(6H)-one structures and phenethyldihydrobenzodioxolone analogues. These selected compounds vary by substituents on the aryl portion, including fluoro, hydroxy, methoxy, difluoro, and methylamino, and by substituents on the core ring system, including allyl, propyl, and but-3-en-2-yl. The document also includes explicit stereochemical specificity by selecting compounds as particular enantiomers, including the (+)-enantiomer.
The patent text also describes stereochemically defined benzo[d][1,3]dioxol-5(6H)-one derivatives and reports characterization and data for listed compounds. Beyond the compound examples, the document includes compound embodiments framed in pharmaceutical contexts by the inclusion of pharmaceutically acceptable salts and solvates.
Claims Coverage
The independent claims cover multiple compound- and structure-selection claims and one treatment claim. Across the claims, the inventive features are centered on formula-defined benzo[d][1,3]dioxol-5(6H)-one or related compounds with enumerated substituent options and conditional exclusions, plus selection of specific substituted compounds, explicit stereoisomer/enantiomer forms including (+)-enantiomer, and pharmaceutically acceptable salts, solvates, and in some cases prodrugs; one independent claim also recites treating cancer by administering an effective amount of a claimed compound.
Formula-defined compounds with enumerated substituents and exclusion proviso
A compound according to a formula, or stereoisomers thereof, wherein R1, R2, R3, and R4 are selected from enumerated groups, R8 and R9 are independently selected from enumerated groups, and a proviso excludes the combination where R2 is methoxy when R1 is methoxy, R3 is hydrogen, and R4 is 2-propenyl, with pharmaceutically acceptable salts, solvates, or prodrugs where stated.
Selected substituted benzo[d][1,3]dioxol-5(6H)-one compounds
A compound selected from a listed group of specific substituted benzo[d][1,3]dioxol-5(6H)-one structures, including variations in aryl substitution such as fluoro, hydroxy, methoxy, difluoro, and methylamino, and variations such as allyl, propyl, or but-3-en-2-yl on the core, together with pharmaceutically acceptable salts or solvates.
Enantiomer-inclusive compound selections
A compound selected from a stated group, or enantiomers thereof, or pharmaceutically acceptable salts, or solvates thereof, with some claims expressly narrowing the compound to the (+)-enantiomer.
Formula-defined compounds with additional substituent positions and conditional exclusions
A compound according to a formula, or stereoisomers thereof, wherein R1, R2, R3, R4, R6, and R7 are selected from enumerated groups, with conditional provisos governing when R2 is hydrogen, when only one of R6 or R7 is hydrogen, and additional exclusions linking R2, R1, R3, R5, R6, and R4.
Restricted R2, R3, and R4 substituent sets
A compound according to a formula or enantiomers thereof wherein R2 is selected from enumerated amide/oxy-linked alkyl or alkenyl variants, R3 is selected from hydrogen and fluoro, and R4 is selected from lower alkyl, lower alkenyl, lower alkynyl, alkyl ether, and thioalkyl ether categories, with pharmaceutically acceptable salts, solvates, or prodrugs where stated.
Cancer treatment by administering a claimed compound
A method of treating cancer in a patient by administering an effective amount of the compound of claim 1.
Overall, the claim coverage is concentrated on compound definitions built from enumerated substituent selections and explicit provisos, with additional independent claims covering selected substituted benzo[d][1,3]dioxol-5(6H)-one compounds and stereochemical forms, including the (+)-enantiomer. Pharmaceutically acceptable salts and solvates are included across multiple claims, and one independent claim adds a cancer treatment method based on administration of a claimed compound.
Stated Advantages
Inhibition of proliferation of cell lines is reported, with IC50 values for M14 and NCI-H460.
Certain aromatic substitutions, notably ortho fluorine, are described as enhancing potency while maintaining plasma bioavailability.
Documented Applications
Inhibition of proliferation of cell lines M14 and NCI-H460, with IC50 values reported.
Tumor growth inhibition and cancer treatment.
Combination therapy with other anticancer agents, including platinum-based anticancer agents.
Inflammatory disorder indications, including gout.
Plant/seed treatment.
A method of treating cancer in a patient by administering an effective amount of the compound of claim 1.
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