8-hydroxy-3H-quinazolin-4-(thi)one derivatives; ability to enter CNS, sequester transition metals Cu, Zn and Fe from various amiloid beta entities, reducing their toxicity; neurodegenerative disorders; Alzheimer's, Parkinson's, Cruetzfeldt-Jacob diseases, amyotrophic lateral sclerosis, cataract
Inventors
Kok, Gaik Beng • Leung, Brenda Kwan Yi
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-8084459-B2
Publication Date
2011-12-27
Expiration Date
Abstract
Compounds of the formula or salts, tautomers or isomers thereof, are useful for treating neurological conditions, especially neurodegenerative disorders, such as Alzheimer's disease.
Core Innovation
The invention relates to compounds defined by Formula I, including pharmaceutically acceptable salts, tautomers, and stereoisomers thereof. The compounds are characterized by X = O, R2 as CH2NR1 or CH2NR1R4, R1 and R4 independently selected from H and C1-3 alkyl, R3 as optionally substituted C1-4 alkyl, and R5 and R7 as chloro.
The disclosed compounds include quinazolin-4-one and quinazolin-4-thione related scaffolds, with 2,3-disubstituted-3H-quinazolin-4-ones, 8-hydroxy quinazolinone derivatives, and related intermediates exemplified. The disclosure further describes prodrug and derivative concepts in which an 8-hydroxy group is esterified or otherwise masked to protect against glucuronidation while enabling CNS activation via blood brain barrier esterases.
It also links the compounds to physicochemical property modulation, pharmacokinetics, metal chelation, and amyloid disaggregation, including plaque disaggregation. Example compounds and intermediates are characterized by analytical data, and the disclosure reports biological assessment assays and expanded characterization of physicochemical and blood-brain barrier-related properties.
Claims Coverage
The consolidated claim coverage centers on a formula I compound class with X = O and defined substituent-variable constraints, including R2 as CH2NR1 or CH2NR1R4, R1 and R4 independently selected from H and C1-3 alkyl, R3 as optionally substituted C1-4 alkyl, and R5 and R7 as chloro. Dependent claims narrow R1 to methyl or ethyl and progressively restrict R3 from C1-3 alkyl to C2-3 alkyl and then to methyl, and the claim set also includes a pharmaceutical or veterinary composition with an effective amount and an acceptable carrier.
Formula I compound with defined substituent variables and X = O
A compound of the formula, including pharmaceutically acceptable salts, tautomers, or stereoisomers thereof, in which R2 is CH2NR1 or CH2NR1R4, R1 and R4 are independently selected from H and C1-3 alkyl, R3 is optionally substituted C1-4 alkyl, R5 and R7 are chloro, and X is O.
Restricted R1 to methyl or ethyl with R3 constrained to C1-3 alkyl range
A compound wherein R2 is CH2NHR1 with R1 being methyl or ethyl, R3 being C1-3 alkyl, R5 and R7 being chloro, and X being O, or a pharmaceutically acceptable salt thereof.
Tighter R3 selection to C2-3 alkyl while maintaining methyl or ethyl R1
A compound wherein R2 is CH2NHR1 with R1 being methyl or ethyl, R3 being C2-3 alkyl, R5 and R7 being chloro, and X being O, or a pharmaceutically acceptable salt thereof.
Single-value R3 substituent methyl
A compound wherein R2 is CH2NHR1 with R1 being methyl or ethyl, R3 is methyl, R5 and R7 are chloro, and X is O, or a pharmaceutically acceptable salt thereof.
Pharmaceutical or veterinary composition with effective amount and acceptable carrier
A pharmaceutical or veterinary composition containing an effective amount of the compound of formula I, or its pharmaceutically acceptable salts, tautomers, or stereoisomers, together with a pharmaceutically or veterinarly acceptable carrier.
Overall, the claims define a formula I compound class characterized by X = O, chloro substituents at R5 and R7, and specific R2 motifs with R1 and R4 limited to H or C1-3 alkyl. The dependent claims narrow R1 to methyl or ethyl and restrict R3 from C1-3 alkyl to C2-3 alkyl and then to methyl, and a further dependent claim extends the scope to pharmaceutical or veterinary compositions containing an effective amount with an acceptable carrier.
Stated Advantages
Very good disaggregation is described for exemplified compounds, including compound 1100, compound 1101, and compound 1128.
The esterified 8-hydroxy prodrug approach is described as protecting against glucuronidation and enabling CNS activation via blood brain barrier esterases.
Enhancing metal chelation is described, including transition metals such as Cu, Zn, and Fe.
Amyloid disaggregation, including plaque disaggregation, is described.
CNS/BBB-active transport is described, supported by a CNS-penetrant design and an optional prodrug strategy masking the 8-hydroxy moiety.
Documented Applications
Biological assessment assays for compounds of Formula I, including a fluorometric assay for Aβ/H2O2 generation inhibition, neurotoxicity and cell-viability testing, Aβ neurotoxicity/protection testing, apoptosis-related testing, lipid peroxidation assays, amyloid solubilisation and disaggregation assays, extensive in vivo characterization in transgenic APP2576 studies, physicochemical property characterization, and blood-brain barrier penetration assessment.
Therapeutic context is described for Alzheimer’s disease, including reference to an amyloidogenic protein and use of the ADAS-cog test.
Use in connection with neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis.
Pharmaceutical use via pharmaceutical compositions comprising an effective amount and a pharmaceutically acceptable carrier.
Veterinary use via veterinary compositions comprising an effective amount and a veterinarly acceptable carrier.
Interested in licensing this patent?