Compounds for the treatment of neurodegenerative diseases
Inventors
Griffioen, Gerard • VAN DOOREN, Tom • Rojas De La Parra, Verónica • Marchand, Arnaud • Alassia, Sara • Kilonda, Amuri • Chaltin, Patrick
Assignees
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Publication Number
US-9284271-B2
Publication Date
2016-03-15
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. The compounds have the formula (A1), wherein R1, R2, R4, R5, R6, E, n, Y1, Y2, Y3, Y4, Y5, B, R8, and m are as defined in the claims.
Core Innovation
The invention relates to a compound of formula (A1) or a stereoisomer, enantiomer or tautomer thereof, including a solvate, hydrate, salt, pharmaceutically acceptable salt, or prodrug thereof. The structure is defined by selected variables including E, R1, R2, R3, R4, R5, R6, R8, R10, R11, R12, R13, Y1-Y5, B, m, and Z, with substituent groups expressly listed and with oxidation-state constraints for carbon and heteroatoms.
A shared structural theme is a fused bicyclic heteroaromatic core with an N-CH2/alkyl amide linkage to a second aromatic ring system. E is independently selected from CR3 and N, and the selected alkyl, alkenyl, alkynyl, aryl, and heterocycle moieties, and related arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene, and heterocycle-alkynylene moieties, are constrained to be unsubstituted or substituted with one or more Z groups.
The structural scope further constrains B as a cyclic structure selected from cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and heterocycle, with m selected from 0 to 5. Carbon and heteroatoms are unoxidized or oxidized to forms including C=O, C=S, N=O, N=S, S=O, and S(O)2, and the compound family is further defined by alternative structural formulas such as (A2/A3) and additional structural embodiments such as (I1-I4).
Claims Coverage
The consolidated claim coverage identifies one main independent compound claim defining formula (A1) with extensive structural constraints, and dependent claim content that refines the genus by alternative structural formulas, specific structural subsets, and pharmaceutical composition form. The inventive features center on formula-defined substituent selection, cyclic group B, parameter m, and explicit oxidation-state motifs.
Compound of formula (A1) with stereochemical and pharmaceutical-form coverage
A compound of formula (A1) or a stereoisomer, enantiomer or tautomer thereof, including a solvate, hydrate, salt, pharmaceutically acceptable salt, or prodrug thereof.
Defined substituent sets and oxidation-state rules
E is independently selected from CR3 and N, and the substituent positions R1, R2, R3, R4, R5, R6, and R8 and related groups are selected from expressly listed atoms and functional groups, with carbon and heteroatoms unoxidized or oxidized to C=O, C=S, N=O, N=S, S=O, or S(O)2.
Variable cyclic group B and linker parameter m
B is a cyclic structure selected from cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and heterocycle, and m is selected from 0, 1, 2, 3, 4, and 5.
Substitution constraints through Z and related positions
Selected alkyl, alkenyl, alkynyl, aryl, and heterocycle moieties are unsubstituted or substituted with one or more Z groups, with further constraints through Z1 and Z2 selections and related substituent sets.
Pharmaceutical composition including the claimed compound
A pharmaceutical composition that includes one or more pharmaceutically acceptable excipients and a therapeutically effective amount of the claimed compound.
The claims cover a broad formula-based compound genus under formula (A1), together with stereochemical and salt/solvate/prodrug forms, defined cyclic and substituent constraints, oxidation-state motifs, and pharmaceutical composition embodiments.
Stated Advantages
Unexpectedly inhibits tau-aggregation induced toxicity.
Documented Applications
Therapeutic use in neurodegenerative diseases, including tauopathies and α-synuclein amyloidogenesis or α-synucleopathy.
Use for preventing or treating Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism (FTDP-17), Parkinson’s disease, multiple system atrophy, amyotrophic lateral sclerosis, traumatic brain injury, Hallervorden-Spatz syndrome, Down syndrome, Niemann-Pick disease, and diffuse Lewy body disease.
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