Compositions and methods for treating and preventing neurodegenerative disorders
Inventors
Kocis, Petr • TOLAR, Martin • Hey, John
Assignees
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Publication Number
US-11053192-B2
Publication Date
2021-07-06
Expiration Date
Abstract
Compounds, pharmaceutical compositions, methods and kits are described for treating or preventing neurodegenerative diseases such as Alzheimer's disease.
Core Innovation
The disclosure relates to compounds selected from listed formulae and pharmaceutically acceptable salts, including Formula I, Ia/Ib, II, III, IV, V, IV-1/IV-2a/IV-2b/IV-3a/IV-3b variants, VIa-VId, VIIa-VIIb, and VIIIa-VIIIo and VIIIaa-VIIIoo. The chemical scope includes substituents, ring selections, stereoisomers, enantiomers, non-aromatic carbocyclic or heterocyclic ring scaffolds, amino-acid or dipeptide functionalities, deuterium, sulfonic acid motifs, cis-proline based compounds, trans-proline based compounds, and cyclopentyl-containing cores.
The disclosure further includes heterocyclic substituent examples such as morpholinyl, piperazinyl, and piperidinyl, together with sulfonic acid, carboxylic acid, amide, and amine functionalities and protecting-group variants such as Boc, Cbz, t-BuO, and HCl salts. It also presents multiple compound sets and intermediates identified by example labels and compound IDs, with analytical characterization such as NMR and MS.
The patent presents a therapeutic rationale for Alzheimer’s disease and other neurodegenerative disorder pathology. The disclosed compounds are stated to bind amyloid-beta (Aβ) and to provide amyloid anti-aggregation activity together with plaque-reduction and plaque clearance effects, including effects relevant to beta-amyloid plaques and soluble oligomeric Aβ and fibrillar Aβ. The context also references treatment and/or prevention, blood-brain barrier considerations, and treatment in ApoE4-positive patients and patients homozygous for ApoE4.
Claims Coverage
The consolidated claim coverage centers on formula-defined compounds and pharmaceutically acceptable salts, with pharmaceutical composition and Alzheimer’s disease treatment claims. Across the items, five inventive features recur, and the treatment claims are narrowed to ApoE4-positive patients and patients homozygous for ApoE4.
Selected compounds from listed formulae and pharmaceutically acceptable salts
A compound selected from any one of the listed formulae, or a pharmaceutically acceptable salt of any of the foregoing.
Pharmaceutical composition including the claimed compound and a carrier
A pharmaceutical composition including the claimed compound or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
Alzheimer’s disease treatment by patient administration
A method of treating Alzheimer’s disease by administering to a patient the claimed compound or a pharmaceutically acceptable salt.
Treatment in ApoE4-positive patients
The method is performed in a patient who is ApoE4-positive.
Treatment in homozygous ApoE4 patients
The method is used for a patient who is homozygous for ApoE4.
Overall, the claim coverage is broad at the compound level and extends to pharmaceutical compositions and treatment of Alzheimer’s disease by administering the claimed compound, with additional restriction to ApoE4-positive and homozygous ApoE4 patient subpopulations.
Stated Advantages
Amyloid anti-aggregation activity and plaque-reduction/clearance effects are stated for binding amyloid-beta (Aβ).
Treatment and/or prevention of neurodegenerative disorder pathology is stated in the context of Alzheimer’s disease.
Patient stratification based on ApoE4 status is stated as part of the treatment approach.
Treating Alzheimer’s disease.
Documented Applications
Treating Alzheimer’s disease by administering a compound selected from the listed formulae, including treatment in ApoE4-positive patients and in patients homozygous for ApoE4.
Treatment and/or prevention of neurodegenerative disorder pathology in the Alzheimer’s disease context.
Use in methods for treating Alzheimer’s disease by administering the claimed compound or a pharmaceutically acceptable salt to a patient.
Treatment of Alzheimer’s disease in ApoE4-positive patients.
Treatment of Alzheimer’s disease in patients homozygous for ApoE4.
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