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Publication Number
US-8889695-B2
Publication Date
2014-11-18
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 invention provides compounds of general formula I and pharmaceutically acceptable salts thereof, with R1, R2, and R3 selected from specified alkyl, cycloalkyl, and alkynyl groups. In one embodiment, R1 and R2 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. The disclosure also includes formula Ib and formula Ic variants with additional substituent options and explicit general term definitions for alkyl, cycloalkyl, aryl, heterocyclyl, and halo.
The document further relates to quinazolin-4-one derivatives and describes 2,3-disubstituted 8-hydroxy-3H-quinazolin-4-ones, including representative example compounds and analytical characterization for multiple HCl and HBr salt forms. The text includes structural depictions, spectrometric support using 1H NMR and mass spectrometry, and preparation narrative for substituted quinazolinone framework intermediates and final salt forms.
The patent text additionally includes process descriptions for forming compounds of formula I by cyclisation and aminating steps. One route proceeds from formula III to formula IV and then to formula I, and another route proceeds from formula V to formula VI and then to formula I, with deprotecting included when a protecting group is present. The text also states administration of compounds of formula I for treatment of Parkinson’s disease and includes pharmaceutical composition and application categories.
Claims Coverage
Across the provided claim set, the document includes independent claim groups covering compounds of general formula I, a selected compound set, and two process claims for preparing compounds of formula I. The independent features center on structural definitions for formula I and on cyclisation/aminating routes to form formula I, with pharmaceutically acceptable salts included.
General formula I Parkinson’s-relevant compounds
A compound of general formula I in which R1 is selected from H, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl and optionally substituted C2-6 alkynyl; R2 is optionally substituted C2-6 alkynyl; or R1 and R2 together with the N atom to which they are attached form an optionally substituted 5- or 6-membered heterocyclyl which may contain at least one further heteroatom selected from N and O; and R3 is selected from optionally substituted C1-6 alkyl and optionally substituted C3-6 cycloalkyl; or pharmaceutically acceptable salts thereof.
Selected compounds list
A compound which is selected from the following or pharmaceutically acceptable salts thereof.
Process: cyclisation of formula III then aminating to form formula I
A process for the preparation of the compound of formula I which comprises cyclisation of a compound of formula III in the presence of a source of a leaving group to prepare a compound of formula IV, and aminating the compound of formula IV with a source of NR1R2 and deprotecting when R8 is a protecting group, thereby forming a compound of formula I.
Process: cyclisation of formula V using a source of NR3 then aminating to form formula I
A process for the preparation of the compound of formula I which comprises cyclisation of a compound of formula V in the presence of a source of NR3 in which LG is a leaving group to prepare a compound of formula VI, and aminating the compound of formula VI with a source of NR1R2, thereby forming a compound of formula I.
The claim coverage is directed to compounds of general formula I defined by selectable R1, R2, and R3 patterns, including the option that R1 and R2 together with the attached N form an optionally substituted 5- or 6-membered heterocyclyl containing N and/or O. In parallel, the process claims define formation of formula I via cyclisation to intermediates formula IV or VI followed by aminating, with deprotecting included in the formula III route.
Stated Advantages
The compounds are described as addressing dopamine deficiency and dopaminergic neuron degeneration in Parkinson’s disease, in particular in the substantia nigra.
The approach is described as selectively associating the compounds with ionic iron (Fe) in the substantia nigra to prevent excessive neuronal uptake and to reduce intracellular Fe.
Documented Applications
Treatment of Parkinson’s disease.
Pharmaceutical compositions including compounds of formula I and pharmaceutically acceptable carriers.
Drug eluting stents are listed among the pharmaceutical composition/application categories described in the partial content.
Analytical characterization and structural depiction of multiple HCl/HBr salt forms of quinazolin-4-one derivative compounds using 1H NMR and mass spectrometry.
Preparation narrative for 2,3-disubstituted 8-hydroxy-3H-quinazolin-4-ones involving transformation steps described in the provided text.
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