8-hydroxy quinoline derivatives
Inventors
Barnham, Kevin Jeffrey • Gautier, Elisabeth Colette Louise • Kok, Gaik Beng • Krippner, Guy
Assignees
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Publication Number
US-8975278-B2
Publication Date
2015-03-10
Expiration Date
Abstract
The present invention describes a method for the treatment of a neurological condition in a subject which comprises administering to a subject in need thereof a therapeutically effect amount of a compound of the formula or pharmaceutically acceptable salts, hydrates, or solvates thereof.
Core Innovation
The invention relates to a method for the treatment of Alzheimer’s disease in a subject which comprises administering to the subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof. The disclosed content also concerns substituted quinoline derivatives and related 8-hydroxyquinoline derivative compounds, including compound embodiments defined by formulae such as I, Ia-Ic, IIa-IIc, IIIa-IVc, Vb/Vc/VIb, and related substituted quinoline carboxaldehydes, hydroxyquinoline derivatives, and metal chelators.
The description includes prodrug and ester strategies, hydrate, salt, solvate, and optional antioxidant moieties, together with carrier and combination medicament context. It further describes treatment, amelioration, and prophylaxis of neurological conditions, in particular neurodegenerative amyloidosis such as Alzheimer’s disease, and indicates targeting of abnormal protein-metal interactions involving transition metals, oxidative stress, and reactive oxygen species.
The disclosed material also presents specific chemical structures and candidate compounds with associated identifiers, structural modifications, and measured or calculated properties such as clogP values, IC50 values, and activity categories. The compounds include chloro-, amino-, nitro-, methoxy-, formyl-, and other substituted quinoline-like aromatic structures, with examples and characterization data supporting the chemical scope associated with the Alzheimer’s disease treatment method.
Claims Coverage
The consolidated claim coverage centers on a method for the treatment of Alzheimer’s disease by administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, to a subject in need. Across the input items, four recurring dependent inventive features are identified: administration with a pharmaceutically acceptable carrier, co-administration with specified medicament classes, provision of the compound in hydrate form, and use of the compound with broader formulation context.
Method for the treatment of Alzheimer's disease by administering a therapeutically effective amount
A method for the treatment of Alzheimer's disease in a subject which comprises administering to the subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof.
Administration with a pharmaceutically acceptable carrier
The method includes administering the compound together with a pharmaceutically acceptable carrier.
Co-administration with a medicament selected from specified classes
The method includes administering the compound together with a medicament that is an acetyl cholinesterase active site inhibitor, an antioxidant, an anti-inflammatory agent, or an oestrogenic agent.
Compound provided in hydrate form
The method is characterized in that the compound is provided in hydrate form.
Overall, the claim coverage is directed to administering a therapeutically effective amount of a compound, or pharmaceutically acceptable salt thereof, for Alzheimer’s disease treatment, with dependent refinement to carrier administration, optional co-administration with specified medicament classes, and hydrate-form limitation.
Stated Advantages
Improved efficacy compared with clioquinol (CQ) through optimized metal chelation.
Increased aqueous solubility.
Reduced cell toxicity.
Improved amyloid dispersion.
Suitable membrane permeability for central nervous system entry.
Improved metabolic stability.
Provides effects on ADAS-cog cognition in moderately severe Alzheimer’s disease patients.
Provides plasma Aβ242 changes in connection with the Phase II trial of oral PBT-1.
Increases plasma Zn without corresponding Cu changes.
Documented Applications
Alzheimer’s disease treatment in a subject by administering a therapeutically effective amount of a specified compound or a pharmaceutically acceptable salt.
Treatment, amelioration, and prophylaxis of neurological conditions, especially neurodegenerative amyloidosis such as Alzheimer’s disease.
Treatment of Alzheimer’s disease in a subject, including a Phase II randomized double-blind placebo-controlled oral trial of PBT-1 in moderately severe patients with reported cognitive and plasma Aβ242/Zn outcomes.
Assessment for Alzheimer’s disease-related endpoints, including hydrogen peroxide IC50, Aβ2 plaque solubilisation, cell viability, and a BAS score [procedural detail omitted for safety].
Human brain amyloid solubilisation and metal partitioning assessment [procedural detail omitted for safety].
Blood-brain barrier (BBB) penetration and pharmacokinetic profile characterization [procedural detail omitted for safety].
In vivo/animal efficacy and development examples including testing PBT-1033 in Huntington’s disease mice and glioma tumor efficacy screening for compound 1033.
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