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Publication Number
US-9365491-B2
Publication Date
2016-06-14
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 document describes chemical conditioning to derive different Formula I derivatives and nitrogen-containing conditioned extracts from a biological extract, exemplified by ginger oil or ginger oleoresin. Functional reactive groups in electrophilic natural components are converted into different chemical structures through chemical conditioning using reductive amination with selected amines and hydride reducing agents. The conditioned extract is isolated and purified and subjected to biological screening, including endpoints related to Abeta oligomers, amyloid assembly, and amyloid aggregation/binding.
The chemical conditioning approach converts electrophilic natural components having reactive electrophilic groups such as ketones or aldehydes into conditioned nitrogen-containing derivatives, with reductive amination proceeding through imine and enamine intermediates. The resulting compounds are represented as Formula I derivatives, and representative substituted phenol/benzylamino compounds are linked to potential central nervous system drug-like activity. The document connects these Formula I members to Alzheimer’s disease-related biological activity, including inhibition of Abeta oligomer effects, inhibition of amyloid deposition/aggregation/binding, and beta-secretase activity.
The document further describes treating Alzheimer’s disease by administering therapeutically effective amounts of compounds according to Formula I or pharmaceutically acceptable salts. It also describes inhibiting or abating binding of one or more Abeta oligomers to a neuronal cell and/or abating Abeta oligomer-associated membrane trafficking deficits, including long-term potentiation-related outcomes. Example compounds are presented in the context of assay endpoints and reported thresholds, including EC50 and IC50 values and control comparisons such as memantine and anti-Abeta antibody 6E10.
Claims Coverage
The independent claims cover treating Alzheimer’s disease with Formula I compounds, inhibiting or abating binding and/or activity/effects of Abeta oligomers on neuronal cells, and administering a composition that includes a Formula I compound plus a pharmaceutically acceptable carrier. Across these claims, the defining inventive elements are the Formula I compound structures defined by extensive R-group ranges and the specified Alzheimer’s/Abeta oligomer-related biological effects.
Alzheimer’s disease treatment with Formula I amyloid beta oligomer inhibitory compounds
A method of treating Alzheimer's disease in a patient by administering a therapeutically effective amount of a compound according to Formula I or a pharmaceutically acceptable salt, with extensive R-group definitions and a proviso restricting selections when R1 is a moiety of (A1).
Inhibiting or abating Abeta oligomer binding to neuronal cells with Formula I compounds
A method of inhibiting or abating binding of one or more Abeta oligomers to a neuronal cell by contacting the neuronal cell with an effective amount of an amyloid beta oligomer inhibitory compound according to Formula I or a pharmaceutically acceptable salt, with extensive R-group definitions and a proviso restricting selections when R1 is a moiety of (A1).
Composition administration for inhibiting or abating Abeta oligomer activity/effects on neuronal cells
A method to inhibit, treat, or abate the activity or effect of an Abeta oligomer on a neuronal cell by administering an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, with the same Formula I substituent selections and proviso.
Alzheimer’s disease treatment with two named Formula I compounds
A method of treating Alzheimer's disease in a patient by administering a therapeutically effective amount of 4-(3-(4-chlorobenzylamino)butyl)-2-methoxyphenol or 4-(3-(4-(trifluoromethyl)benzylamino)butyl)-2-methoxyphenol, or a pharmaceutically acceptable salt thereof.
Overall, the claim set focuses on Formula I amyloid beta oligomer inhibitory compounds with defined substitution patterns and optional salts for Alzheimer’s disease treatment and for inhibiting or abating Abeta oligomer binding and related effects on neuronal cells, including approaches using a pharmaceutically acceptable carrier and specific named Formula I embodiments.
Stated Advantages
Restoration of long-term potentiation.
Inhibition or abatement of binding of Abeta oligomers to neuronal cells.
Inhibition or abatement of Abeta oligomer activity or effect on neuronal cells.
Inhibition or abatement of Abeta-mediated membrane trafficking effects associated with exposure to soluble Abeta oligomers.
The compound does not significantly alter membrane trafficking when dosed in the absence of Abeta oligomers.
Inhibits or abates neurodegeneration.
Documented Applications
CNS-active treatment of cognitive decline and Alzheimer's disease.
Inhibition or abatement of binding of Abeta oligomers to a neuronal cell by contacting the neuronal cell with an effective amount of an amyloid beta oligomer inhibitory compound.
Inhibiting, treating, or abating the activity or effect of an Abeta oligomer on a neuronal cell by administering a composition comprising a Formula I compound and a pharmaceutically acceptable carrier.
Restoration of long-term potentiation and inhibition or abatement of neurodegeneration, Abeta oligomer binding, and Abeta-mediated membrane trafficking effects in connection with exposure to soluble Abeta oligomers.
Generation of structurally diverse, chemically stable nitrogen-containing derivatives from biological extracts, including ginger oil/gingerol, via a chemical conditioning approach described as reductive amination with conditioned extract workflows.
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