Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases
Inventors
Griffioen, Gerard • VAN DOOREN, Tom • ROJAS DE LA PARRA, Veronica • Marchand, Arnaud • Allasia, Sara • Kilonda, Amuri • Chaltin, Patrick
Assignees
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Publication Number
US-10117850-B2
Publication Date
2018-11-06
Expiration Date
Abstract
This invention provides novel compounds and the novel compounds for use as a medicine, more in particular for the prevention or treatment of neurodegenerative disorders, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, and disorders characterized by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such neurodegenerative disorders. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds.
Core Innovation
The invention relates to methods for the treatment of neurodegenerative disorders in a subject by administering an effective amount of a compound of formula (AA1) or formula (A1), including stereoisomers, enantiomers, tautomers, and in some cases solvates, hydrates, salts, or prodrugs thereof, or a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of the compound. The compounds are defined by a maximum of two dotted lines selected from five dotted lines being a double bond, together with variable selections for E1, E2, E3, Q, Ra, Rb, L, and related substituent groups.
The structural scope further defines ring-forming and linkage relationships, including Ra and Rb being hydrogen or together forming a substituted or unsubstituted 4, 5, 6, 7 or 8 membered ring containing one N atom, and L being selected from —O—, —NH—, —NR10—, and C1-6 alkylene, C1-6 alkenylene, or C1-6 alkynylene variants with optional heteroatoms and optional substitution. X, Y, T, W and V form with the dotted lines one of a listed set of structural cycles, with the left side attached to Q and the right side attached to L, and in some cases Q is further constrained for particular cycle arrangements.
The treated neurodegenerative disorder is selected from Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism linked to chromosome 17 (FTDP-17), Parkinson’s disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, and multiple system atrophy. The disclosure includes an explicit exclusion of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(4-ethylphenyl)-2-oxopyrrolidine-3-carboxamide.
Claims Coverage
The independent claims cover methods for treating neurodegenerative disorders by administering effective amounts of compounds defined by formula (AA1) or formula (A1), including stereoisomers, enantiomers, tautomers, and in some claims solvates, hydrates, salts, or pharmaceutical compositions. Across the claims, the inventive features are the constrained scaffold definition, the capped double-bond rule, the defined substituent and ring-forming variables, the cycle-forming X/Y/T/W/V arrangements, and the treatment of a specified set of neurodegenerative disorders.
Treatment of neurodegenerative disorders with formula (AA1) compounds
A method for the treatment of a neurodegenerative disorder in a subject comprising administering an effective amount of a compound of formula (AA1) or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of the compound of formula (AA1), with a maximum of two dotted lines selected from five dotted lines being a double bond and with defined structural formulae, substituent selections, and an explicit exclusion of a named compound.
Treatment of neurodegenerative disorders with formula (A1) compounds
A method for the treatment of a neurodegenerative disorder in a subject comprising administering an effective amount of a compound according to formula (A1) or a stereoisomer, enantiomer or tautomer thereof, and in some claims a solvate, hydrate, or salt thereof, with a maximum of two dotted lines selected from five dotted lines being a double bond and with defined substituent, ring-forming, linkage, and cycle-forming constraints, together with an explicit exclusion of a named compound.
Cycle-forming scaffold with defined linkage and ring constraints
X, Y, T, W and V form with the dotted lines one of the listed structural cycles, the left side of each structure is attached to Q and the right side is attached to L, and Q, Ra, Rb, L, B, R1, R2, R3, R4, R5, R6, R8, n, m, Z, and related variables are defined by broad chemical classes and ring-forming options.
The independent claims collectively cover treatment methods for neurodegenerative disorders by administering structurally defined formula (AA1) or (A1) compounds, including specified related forms and pharmaceutical compositions. The core inventive scope is the constrained scaffold with limited double bonds, defined substituent and ring relationships, cycle-forming X/Y/T/W/V arrangements, and the stated disorder list with exclusion of a named compound.
Stated Advantages
Efficiently inhibiting tau-aggregation-induced toxicity.
Addressing drug limitations related to physicochemical and ADME-Tox properties.
Documented Applications
Treatment of a neurodegenerative disorder in a subject, where the disorder is selected from Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism linked to chromosome 17 (FTDP-17), Parkinson’s disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, and multiple system atrophy.
Prevention or treatment of tauopathies and cytotoxic α-synuclein amyloidogenesis (α-synucleinopathy).
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