Isolated compounds from turmeric oil and methods of use
Inventors
Rishton, Gilbert M. • Catalano, Susan
Assignees
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Publication Number
US-9499462-B2
Publication Date
2016-11-22
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 for treatment, inhibition, 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 compounds comprising Formula I-0, Formula I-1, or Formula I-2, including pharmaceutically acceptable salts, where the structural scope is defined by a bond selected from a single bond and a double bond, R1 selected from F, Cl, Br, CF3, and OCF3, R2 selected from CH2C(CH3)2OH and CH=C(CH3)2, and R3 fixed as NHCH2CH(CH3)2. The disclosure also presents chemically stable, structurally diverse lead-like arrays for screening and references synthetic Scheme 4a and Scheme 5 for accessing styrene-derived intermediates and related intermediates described within the schemes.
The document further describes conversion steps and intermediates including formation and rearrangement of cyclohexa-1,4-diene to cyclohexa-1,3-diene, and transformations to alcohol intermediates and amine intermediates. It also describes stereoselective transformations leading to bromides, Grignard reagents, aldehyde addition, imine reduction, and preparation of stereoisomers of target amines, together with guidance for modifying functional groups while remaining within Formula I.
A therapeutic use is described for administering Formula I-0, Formula I-1, or Formula I-2 compounds, including specific enumerated stereoisomers and individual examples, to treat cognitive decline and/or Alzheimer’s disease. The described mechanisms target amyloid-related processes including Abeta oligomer binding, amyloid aggregation, assembly, deposition, beta-secretase activity, APP and amyloid processing, with experimental support including neuron-related assays, binding and inhibition assays, intracellular formazan vesicle effects, exocytosis modulation, fear conditioning, and pharmacokinetic data.
Claims Coverage
The provided independent claims cover three families of compounds (Formula I-0, Formula I-1, and Formula I-2) and three corresponding pharmaceutical composition claims, for a total of six independent claim positions. Across these, the inventive scope is primarily defined by the formula-based structural constraints for bond selection and R-group selection, with salt inclusion, and by the therapeutically effective amount plus pharmaceutically acceptable carrier for the composition claims.
Compound defined by Formula I-0
A compound comprising Formula I-0 (or a pharmaceutically acceptable salt thereof) where the bond is selected from a single bond and a double bond, R1 is selected from F, Cl, Br, CF3, and OCF3, R2 is selected from CH2C(CH3)2OH and CH=C(CH3)2, and R3 is NHCH2CH(CH3)2.
Compound defined by Formula I-1
A compound comprising Formula I-1 (or a pharmaceutically acceptable salt thereof) where the bond is selected from a single bond and a double bond, R1 is selected from F, Cl, Br, CF3, and OCF3, R2 is selected from CH2C(CH3)2OH and CH=C(CH3)2, and R3 is NHCH2CH(CH3)2.
Compound defined by Formula I-2
A compound comprising Formula I-2 (or a pharmaceutically acceptable salt thereof) where the bond is selected from a single bond and a double bond, R1 is selected from F, Cl, Br, CF3, and OCF3, R2 is selected from CH2C(CH3)2OH and CH=C(CH3)2, and R3 is NHCH2CH(CH3)2.
Pharmaceutical composition with Formula I-0 compound
A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I-0 (or a pharmaceutically acceptable salt thereof) where the bond is selected from a single bond and a double bond, R1 is selected from F, Cl, Br, CF3, and OCF3, R2 is selected from CH2C(CH3)2OH and CH=C(CH3)2, and R3 is NHCH2CH(CH3)2, together with a pharmaceutically acceptable carrier.
Pharmaceutical composition with Formula I-1 compound
A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I-1 (or a pharmaceutically acceptable salt thereof) where the bond is selected from a single bond and a double bond, R1 is selected from F, Cl, Br, CF3, and OCF3, R2 is selected from CH2C(CH3)2OH and CH=C(CH3)2, and R3 is NHCH2CH(CH3)2, together with a pharmaceutically acceptable carrier.
Pharmaceutical composition with Formula I-2 compound
A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I-2 (or a pharmaceutically acceptable salt thereof) where the bond is selected from a single bond and a double bond, R1 is selected from F, Cl, Br, CF3, and OCF3, R2 is selected from CH2C(CH3)2OH and CH=C(CH3)2, and R3 is NHCH2CH(CH3)2, together with a pharmaceutically acceptable carrier.
Overall, the claim set covers compounds defined by formulas I-0, I-1, and I-2 with enumerated structural constraints and corresponding pharmaceutical composition claims that combine those compounds, or their pharmaceutically acceptable salts, with a therapeutically effective amount and a pharmaceutically acceptable carrier.
Stated Advantages
Treating cognitive decline and/or Alzheimer’s disease.
Targeting amyloid-related processes including Abeta oligomer binding and amyloid aggregation, assembly, deposition, amyloid precursor protein (APP) and amyloid processing, and beta-secretase activity.
Dose-dependent blockade of Abeta42 oligomer-induced intracellular formazan vesicle effects.
Prevention and treatment effectiveness with similar EC50s irrespective of dosing order.
Complete blockage of Abeta oligomer-induced memory deficits in fear conditioning, without compound-alone effects or adverse behavioral changes as described.
Differing purity/potency and pharmacokinetics between stereoisomers and diastereomeric isolates, with competitive interaction characterized by Schild analysis (slope about 1) and Ki about 0.57 µM.
Chemically stable, structurally diverse lead-like arrays for screening.
Addresses neurodegeneration and restoration of long term potentiation.
Documented Applications
Treatment of cognitive decline and/or Alzheimer’s disease by administering Formula I-0, Formula I-1, or Formula I-2 compounds, including specified stereoisomers and individual examples, and pharmaceutically acceptable compositions.
Alzheimer’s-related functional assays using intracellular formazan-filled vesicle effects and exocytosis modulation in hippocampal neurons, including prevention and treatment formats.
Fear conditioning application reporting Abeta oligomer-induced memory deficits and inhibition or blockade by CT0109 and CT0093.
Membrane trafficking assays used to evaluate inhibition with stereoisomeric and diastereomeric isolates.
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