Compounds for the treatment of epilepsy, neurodegenerative disorders and other CNS disorders
Inventors
Griffioen, Johan Gerard • Princen, Katrien • Van Dooren, Tom Francois L. • Marchand, Arnaud Didier Marie • Kilonda, Amuri • Allasia, Sara • Chaltin, Patrick
Assignees
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Publication Number
US-11548881-B2
Publication Date
2023-01-10
Expiration Date
Abstract
The present invention relates to a compound of formula (I) or a tautomer thereof, wherein R1, R2, R3, R4 and R5, have the same meaning as that defined in the claims and the description. The present invention also relates to compositions, in particular pharmaceuticals, comprising such compounds, and to uses of such compounds and compositions for the prevention and/or treatment of epilepsy and/or neurodegenerative diseases.
Core Innovation
The invention provides compounds of formula (I) for central nervous system indications, where each of R1, R2, R3, R4, and R5 is selected from hydrogen and F, with the proviso that at least one of R1, R2, R3, R4, or R5 is not hydrogen. The disclosed scope excludes N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-5-[(3-fluorophenyl)methyl]isoxazole-3-carboxamide, together with any tautomer, solvate, hydrate, salt, or prodrug thereof.
The disclosure defines related chemical forms for the compounds, including tautomers, solvates, hydrates, salts, and prodrugs, to capture variants of the same core chemical scaffold within the indicated scope. The patent describes fluorinated benzyl isoxazole-3-carboxamides comprising a 5-fluoro-1H-indol-3-yl ethyl substituent and provides analytical characterization for the described compounds.
For biological evaluation, the patent content describes testing TAU P301L using TAU-P301L overexpressing M17 neuroblastoma cells (BM17). Readouts include LDH-leakage toxicity and calcium dyshomeostasis assays using Fura-2, along with compound effects on neuronal calcium influx and VGCC activity.
Claims Coverage
The independent claims are directed to a compound of formula (I) with defined R-group selections and explicit exclusion, and to a pharmaceutical composition including pharmaceutically acceptable excipients and a therapeutically effective amount of a compound from claim 1. The claim set also specifies particular fluorination patterns and concrete fluorinated isoxazole-3-carboxamide derivative embodiments, while covering tautomers, solvates, hydrates, salts, and prodrugs.
Formula (I) with at least one non-hydrogen fluorine substitution
A compound of formula (I) wherein R1, R2, R3, R4, and R5 are each selected from hydrogen and F, with the proviso that at least one of R1, R2, R3, R4, or R5 is not hydrogen.
Exclusion of a specific isoxazole-3-carboxamide and its chemical forms
The compound of formula (I) is not N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-5-[(3-fluorophenyl)methyl]isoxazole-3-carboxamide, or a tautomer, a solvate, a hydrate, a salt or a prodrug thereof.
Specified fluorination pattern fixing which R groups are hydrogen versus F
The compound of claims 1 or 2 is specified such that R2, R3, R4, and R5 are hydrogen and R1 is F.
Alternative specified fluorination pattern fixing which R groups are hydrogen versus F
The compound of claims 1 or 2 is defined such that R1, R2, R4, and R5 are hydrogen and R3 is fluorine (F).
Concrete fluorinated isoxazole-3-carboxamide derivative embodiments
A compound of claim 1 is selected from a group of specific isoxazole-3-carboxamide derivatives containing fluorinated phenylmethyl and 5-fluoro-1H-indol-3-yl ethyl substituents.
Pharmaceutical composition with pharmaceutically acceptable excipients and therapeutically effective amount
A pharmaceutical composition that includes one or more pharmaceutically excipients together with a therapeutically effective amount of a compound from claim 1, including specified chemical forms such as tautomers, solvates, hydrates, salts, or prodrugs.
Overall, the claim set centers on a defined formula (I) scaffold with fluorine/hydrogen R-group selection, an explicit exclusion of a named isoxazole-3-carboxamide and its chemical forms, and additional narrowing to specific fluorination patterns and enumerated fluorinated derivative embodiments, with coverage extended to pharmaceutical compositions and to tautomers, solvates, hydrates, salts, and prodrugs.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Medicaments for the prevention and/or treatment of epilepsy and multiple neurodegenerative disorders including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Creutzfeld-Jacob's disease.
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