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-11939324-B2
Publication Date
2024-03-26
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 disclosed subject matter relates to a method of treatment in which a disease is treated by administering an effective amount of a compound of formula (I), or a tautomer thereof. The compounds of formula (I) are defined by substituent groups R1 to R5 selected from hydrogen and halogens (F, Cl, and Br), with the proviso that at least one of R1 to R5 is not hydrogen, and with explicit exclusion of a specific named compound and its derivatives, including solvate, hydrate, salt, or prodrug forms.
The disease category is selected from epilepsy and neurodegenerative disorders, as well as pain disorders, anxiety disorders, depression, bipolar disorder, psychosis, drug withdrawal, tobacco withdrawal, memory loss, dementia, schizophrenia, and panic. The provided examples focus on substituted isoxazole-3-carboxamide derivatives bearing fluorinated indole-ethyl substituents and difluorobenzyl or fluorobenzyl substituents, including specific named examples.
The disclosed biological evaluation uses TAU P301L overexpressing neuroblastoma cells and primary neuron/circuit models, with results reported as reduction of TAU-driven cytotoxicity and mitigation of cytosolic calcium dyshomeostasis. The evaluation further reports inhibition of VGCC activity, improved amyloid beta (Aβo) toxicity outcomes ex vivo, reduced TAU phosphorylation in APP/PS1 mice, improved cognition in APP mice as assessed by the Morris water maze, normalization of neuronal hyperactivation ex vivo, and anti-epileptic effects in a kainate model.
Claims Coverage
The document includes one independent method claim directed to administering a compound of formula (I) or a tautomer thereof for treatment of a disease, with multiple dependent claims that narrow the treated disease set and structural embodiments of the compound.
Administering a formula (I) compound for disease treatment
A method of treatment comprising administering an effective amount of a compound of formula (I) or a tautomer thereof, where the disease is selected from epilepsy, neurodegenerative disorders, pain disorders, anxiety disorders, depression, bipolar disorder, psychosis, drug withdrawal, tobacco withdrawal, memory loss, dementia, schizophrenia, and panic.
Halogen-substituted formula (I) with at least one non-hydrogen substituent
The compound of formula (I) has R1, R2, R3, R4, and R5 selected from hydrogen; F, Cl, and Br, with the proviso that at least one of R1, R2, R3, R4, or R5 is not hydrogen.
Excluding a specific named prior compound and derivatives
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 solvate, hydrate, a salt, or a prodrug thereof.
Treating specifically enumerated epilepsy and seizure phenotypes
The disease is an epilepsy selected from a group comprising refractory epilepsy and multiple named epilepsy syndromes and seizure forms, including West syndrome, Doose syndrome, benign rolandic epilepsy, Rasmussen's syndrome, Lennox-Gastaut syndrome, juvenile myoclonic epilepsy, childhood absence epilepsy, idiopathic localization-related epilepsies, temporal lobe epilepsy, and seizure types including partial seizures, simple partial seizures, tonic seizures, tonic-clonic seizures, clonic seizures, myoclonic seizures, absence seizures, atonic seizures, and frontal lobe epilepsy, as well as epilepsy with grand-mal seizures, generalized epilepsy, idiopathic epilepsy, symptomatic epilepsy, and cryptogenic epilepsy.
Treating specifically enumerated neurodegenerative disorders
The disease is a neurodegenerative disorder selected from a list including Parkinson's disease, Alzheimer's disease, diffuse Lewy body disease, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, multiple system atrophy, Huntington's disease, frontotemporal lobar degeneration (FTLD), cystic fibrosis, and Creutz-Jacob's disease.
Alternative chemical embodiments of formula (II) through (VI)
The compound has at least one chemical embodiment corresponding to formula (II), (III), (IV), (V), or (VI), where R1, R2, R3, and R4 have the same meanings as defined.
Constrained substituent pattern (R2–R5 hydrogen; R1 halogen)
R2, R3, R4, and R5 are hydrogen and R1 is selected from F, Cl, and Br.
Specific administered isoxazole-3-carboxamide structures
The compound used is selected from substituted isoxazole-3-carboxamides bearing difluorophenyl and fluorinated indole-ethyl substituents, including structures such as 5-[(2,4-difluorophenyl)methyl]-N-[2-(5-fluoro-1H-indol-3-yl)ethyl]isoxazole-3-carboxamide and N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-5-[(4-fluorophenyl)methyl]isoxazole-3-carboxamide, among the enumerated difluorophenyl positional isomers.
Overall claim coverage centers on a method of treatment by administering an effective amount of a specific halogen-substituted formula (I) or tautomer, expressly excluding a named prior compound and its derivatives. Dependent claims narrow the target diseases to enumerated epilepsy subtypes and seizure forms and enumerated neurodegenerative disorders, and further narrow structural scope via alternative formula embodiments (II–VI), constrained substituent patterns, and enumerated specific substituted isoxazole-3-carboxamide structures.
Stated Advantages
Reduces TAU-driven cytotoxicity.
Mitigates cytosolic calcium dyshomeostasis.
Inhibits VGCC activity.
Improves Aβo toxicity outcomes ex vivo.
Reduces TAU phosphorylation in APP/PS1 mice.
Improves cognition in APP mice (Morris water maze).
Normalizes neuronal hyperactivation ex vivo.
Shows anti-epileptic effects in a kainate model.
Documented Applications
Treatment of epilepsy, including effects evaluated in a kainate epilepsy model.
Treatment of neurodegenerative disorder models involving TAU P301L overexpression and APP/PS1 and APP mice, including reduced TAU phosphorylation and improved cognition.
Ex vivo outcomes reported for TAU-driven cytotoxicity, neuronal hyperactivation, and Aβo toxicity outcomes.
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