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Publication Number
US-9815770-B2
Publication Date
2017-11-14
Expiration Date
Abstract
Compounds that are central nervous system drug candidates for the treatment of cognitive decline and, more particularly, Alzheimer's disease are provided. Methods of treating, inhibiting, and/or abatement of cognitive decline and/or Alzheimer's disease with a compound or pharmaceutically acceptable salt of the invention are also provided. Also provided are methods of preparing the compounds/compositions of the invention.
Core Innovation
The invention relates to inhibitors of cognitive decline and Alzheimer’s disease and describes CNS-active compounds derived from turmeric oil (Curcuma longa) by chemical conditioning. The disclosure describes conditioning of biological extracts in which ketones and aldehydes are converted into nitrogen-containing amines via reductive amination, including formation of imines and/or enamines followed by hydride reduction, and into alcohol derivatives through hydride reduction.
The conditioned derivatives are described within a structure-variability framework for compounds of Formula I and variants identified as I-0/I/Ia/Ib, together with defined R groups including R3a/R3b, and R1, R2, R3, and R4. Purification and isolation of conditioned extract products are mentioned, and schematic examples illustrate conversion of extract components into amines and alcohols using amines and hydride reducing agents, together with quenching agents.
The conditioned extracts and derivatives are screened for central nervous system activity and biological activity testing using beta-secretase and neuron/amyloid-related assays is described. The document states that the compounds address amyloid production, amyloid assembly, amyloid aggregation, amyloid deposition, and binding, including effects on beta-amyloid (Abeta) oligomers, and references beta-secretase activity, long term potentiation, and neurodegeneration-related effects.
Claims Coverage
The provided independent claims cover specific amine compounds, specific alcohol compounds, and pharmaceutical compositions comprising those selected compounds together with a carrier. Across the independent claims, the inventive features are centered on the defined compound selection, stereoisomers at (6S)/(6R), pharmaceutically acceptable salts, and formulation with a carrier.
Selected amine compounds and pharmaceutically acceptable salts
A compound selected from the named N-isobutyl substituted hept-2-en-4-amine structures, including stereoisomers at (6S)/(6R), and corresponding pharmaceutically acceptable salts thereof.
Selected alcohol compounds and pharmaceutically acceptable salts
A compound selected from the named 2-methyl substituted hept-2-en-4-ol structures, including stereoisomers at (6S)/(6R), and corresponding pharmaceutically acceptable salts thereof.
Pharmaceutical composition of selected amine compounds with a carrier
A pharmaceutical composition comprising a compound selected from the group of the named N-isobutyl hept-2-en-4-amine structures, including stereoisomers at (6S)/(6R), or a pharmaceutically acceptable salt thereof, and a carrier.
Pharmaceutical composition of selected alcohol compounds with a carrier
A pharmaceutical composition comprising a compound selected from the group of the named 2-methyl hept-2-en-4-ol structures, including stereoisomers at (6S)/(6R), or a pharmaceutically acceptable salt thereof, and a carrier.
Overall, the independent claim coverage is directed to tightly defined small-molecule selections, including amine stereoisomer variants or alcohol stereoisomer variants, their pharmaceutically acceptable salts, and pharmaceutical compositions with pharmaceutically acceptable carriers.
Stated Advantages
Conditioned extracts/derivatives may inhibit beta-secretase.
Conditioned extracts/derivatives may reduce amyloid processes relevant to Alzheimer’s disease, including amyloid production, amyloid assembly, amyloid aggregation, and amyloid oligomer binding and deposition.
Inhibiting cognitive decline and Alzheimer’s disease.
Targeting beta-secretase activity.
Modulating amyloid-related pathways including amyloid production, assembly, aggregation, deposition, and binding.
Affecting beta-amyloid (Abeta) oligomers, with references to long term potentiation and neurodegeneration-related effects.
Documented Applications
Screening conditioned extracts/derivatives for central nervous system activity.
Potential use in relation to Alzheimer’s disease amyloid processes, including beta-secretase inhibition and reduction of amyloid production, assembly, aggregation, and amyloid oligomer binding and deposition.
Neuronal MTT/exocytosis and binding assays using Abeta/neurons and Abeta 1-42 oligomers.
Pharmacokinetic and functional assessment including fear conditioning.
Therapeutic use for cognitive decline and Alzheimer’s disease.
Treatment or inhibition of amyloid-related pathways, including beta-secretase activity and effects on beta-amyloid (Abeta) oligomers as well as amyloid production, assembly, aggregation, deposition, and binding.
Biological activity testing referenced for beta-secretase and neuron/amyloid-related assays in connection with conditioned extract products.
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