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Publication Number
US-9145375-B2
Publication Date
2015-09-29
Expiration Date
Abstract
The present invention relates to quinazolinone compounds, processes for their preparation and their use as pharmaceutical agents for the treatment of Parkinson's disease (PD). The quinazolinone compounds are of general formula (I).
Core Innovation
The patent describes compounds of Formula I, Formula Ia, Formula Ib, Formula Ic, and Formula II, including quinazolinone-containing compounds, quinazolinone/condensed diazine-containing compounds, and 2,3-disubstituted 8-hydroxy-3H-quinazolin-4-one derivatives, together with pharmaceutically acceptable salts and prodrugs. The disclosure also includes representative compound embodiments, HBr salts and HCl salts, and characterization by NMR and mass spectrometry data.
The invention defines compound classes by selectable substituent frameworks, including R1 and R2 selected from H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, or together with the N atom an optionally substituted 5- or 6-membered heterocyclyl containing ring heteroatoms selected from N and O. R3 is defined across the claim sets as methylene cyclopropyl or as constrained alkyl, cycloalkyl, aryl, or heterocyclyl selections depending on the specific formula or claim language.
The disclosure is directed to treatment of Parkinson's disease, with method language administering an effective amount of a Formula II compound or selected compound embodiments to a patient in need thereof. The document also presents biological assessment context including H2O2 inhibition assay framework using horseradish peroxidase and fluorescence readout, in vitro efficacy/property assessments, human liver microsome metabolism, CYP450 inhibition assay context, blood-brain barrier penetration context using LCMS/brain homogenate, and Parkinson's disease animal model sections including 6-OHDA lesion and MPTP models.
Claims Coverage
The independent claims cover methods of treating Parkinson's disease by administering an effective amount of compounds of Formula II or selected specific compound embodiments, including pharmaceutically acceptable salts. The claimed inventive features are centered on the defined substituent selections for R1, R2, and R3, with multiple claim sets narrowing those selections or reciting specific compound lists. Six inventive features are reflected in the consolidated claim coverage.
Formula II for Parkinson's disease treatment
A method for the treatment of Parkinson's disease comprising administering to a patient in need thereof an effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof.
R1 and R2 substituent framework with methylene cyclopropyl R3
R1 and R2 are independently selected from H, optionally substituted C1-6 alkyl, and optionally substituted C2-6 alkynyl provided that at least one of R1 and R2 is other than H; or R1 and R2 together with the N atom form an optionally substituted 5- or 6-membered heterocyclyl containing further ring heteroatoms selected from N and O; and R3 is methylene cyclopropyl or optionally substituted C3-6 cycloalkyl.
N-containing heterocyclyl option with alkyl or cycloalkyl R3
R1 and R2 together with the N atom form an optionally substituted 5- or 6-membered heterocyclyl with the nitrogen atom being a ring heteroatom and containing at least one further ring heteroatom selected from N and O; and R3 is selected from optionally substituted C1-6 alkyl and optionally substituted C3-6 cycloalkyl.
Constrained substituent ranges for Formula II
R1 is C1-4 alkyl; R2 is selected from C1-4 alkyl optionally substituted with optionally substituted aryl or C2-6 alkynyl; or R1 and R2 together with the N atom form an optionally substituted 5- or 6-membered heterocyclyl containing at least one further ring heteroatom selected from N and O; and R3 is C1-4 alkyl.
Selected compound embodiments
A method of treating Parkinson's disease comprising administering a compound selected from a specified set of named or identified compounds, or pharmaceutically acceptable salts thereof.
R1c, R2c, and R3c selection set
R1c is selected from H and C1-4 alkyl; R2c is selected from C1-4 alkyl, C2-6 cycloalkyl methyl substituted with optionally substituted aryl, and C2-4 alkynyl; or R1c and R2c together with the N atom form an optionally substituted 5- or 6-membered heterocyclyl containing at least one further heteroatom selected from N and O; and R3c is selected from optionally substituted C3-6 cycloalkyl, optionally substituted aryl, and optionally substituted 5- or 6-membered heterocyclyl containing at least one heteroatom selected from N and O.
Overall, the claim coverage is centered on Parkinson's disease treatment by administration of Formula II compounds or selected compound embodiments, with the inventive scope defined by the permitted R1/R2 substituent classes, optional N-containing heterocyclyl formation, and the defined R3 selections, including methylene cyclopropyl or other constrained alkyl/cycloalkyl/aryl/heterocyclyl options.
Stated Advantages
Improves biologically available ionic iron (Fe) management by associating with Fe and reducing its intracellular uptake.
Documented Applications
Use of Formula I, Formula Ia, Formula Ib, Formula Ic, and Formula II compounds for the treatment of Parkinson's disease by administering to a patient in need thereof.
Pharmaceutical compositions and medicament manufacture comprising the Formula I and Formula II compounds and pharmaceutically acceptable salts for Parkinson's disease treatment.
H2O2 inhibition assay framework using horseradish peroxidase and fluorescence readout.
In vitro efficacy/property assessments, including metal transport/metal uptake, cytotoxicity, in vitro metabolism in human liver microsomes, and CYP450 inhibition assay context.
Blood-brain barrier penetration context using LCMS/brain homogenate.
Treatment of Parkinson's disease, including 6-OHDA lesion and MPTP animal model contexts with behavioral readouts and efficacy-related tables.
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