3-(ethoxydifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-α]pyrazine as an ion channel modulator
Inventors
Griffin, Andrew Mark • Marron, Brian Edward • MARTINEZ BOTELLA, Gabriel
Assignees
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Publication Number
US-12325711-B2
Publication Date
2025-06-10
Expiration Date
Abstract
The present invention is directed to, in part, a compound having the structure: or a pharmaceutically acceptable salt thereof, useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, and neuromuscular disorders are also provided herein.
Core Innovation
The invention provides compounds for modulating sodium ion channel activity, including late sodium current (INaL) modulation, in a subject in need thereof. The disclosed compound family includes Formula I-d and subsequent embodiments including Formulas V-IX, with variable substituents such as R1, R2, R3, R4, R5, R6, and t, and related fused heteroaryl motifs and triazolo[4,3-a]pyrazine derivatives.
The disclosure further describes fluorinated and halogenated heteroaryl intermediates and products, with synthetic preparation, late-stage transformations, cross-coupling, and related synthetic steps for forming fused triazolo-pyrazine scaffolds and related azine/triazolo-pyrazine fused structures. Representative compounds and intermediates are characterized by 1H NMR, LCMS, XRPD, and DSC, including crystallinity peak information and melting point onset values.
The document also describes crystalline solid forms of the compounds and pharmaceutical compositions comprising the compound or a pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier. Therapeutic use is described for epilepsy and epilepsy syndromes, with genetic subtypes, and additional contexts including neurodevelopmental disorders, pain, and neuromuscular disorders.
Claims Coverage
The document includes two independent claims. The claims cover sodium ion channel activity modulation by administering a therapeutically effective amount of the specified compound or pharmaceutically acceptable salt, either directly or as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier; dependent claims further specify neurological and psychiatric conditions, especially epilepsy-related syndromes and genetic variants.
Administering a therapeutically effective amount for sodium ion channel modulation
A method for modulating sodium ion channel activity in a subject in need thereof by administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof.
Administering a pharmaceutical composition for sodium ion channel modulation
A method for modulating sodium ion channel activity in a subject in need thereof by administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound, or a pharmaceutically acceptable salt thereof.
The inventive scope is sodium ion channel modulation via administration of the specified compound, including pharmaceutically acceptable salts, with one independent claim directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier. Dependent claim coverage refines the subject’s condition toward epilepsy and epilepsy syndromes/encephalopathies, including specified genetic constraints such as SCN1A, SCN2A, SCN3A, SCN8A, and human subjects.
Stated Advantages
Preventing and/or treating diseases involving aberrant voltage-gated sodium ion channel function, including conditions associated with abnormal late/persistent sodium current (INaL).
Providing therapeutic utility for sodium-channel-related disorders and related epilepsy syndromes, including neurological disorders such as Dravet syndrome and epilepsy.
Documented Applications
Preventing and/or treating diseases involving aberrant voltage-gated sodium ion channel function, particularly abnormal late/persistent sodium current (INaL).
Preventing and/or treating sodium-channel-related disorders and related epilepsy syndromes, including Dravet syndrome and epilepsy.
Treatment context includes neurological disorders and epilepsy categories specifically identified such as autosomal dominant nocturnal frontal lobe epilepsy and sudden unexpected death in epilepsy (SUDEP).
Late sodium current (INaL) modulation assessed qualitatively in HEK-293 cells expressing human NaV1.6 or NaV1.2 with ATX-II using PatchXpress.
XRPD and DSC crystallinity analyses with peak information and melting point onset values.
Electrophysiology INa inhibition assessed using peak and ramp datasets.
Mouse MES seizure model with latency data and reported in vivo outcomes within a seizure/survival and pain endpoints framework.
Treatment or use for epilepsy and epilepsy syndromes, including genetic subtypes.
Treatment or use for neurodevelopmental disorders.
Treatment or use for pain.
Treatment or use for neuromuscular disorders.
Use in pharmaceutical composition and combination-therapy discussion is referenced in the document content.
Crystalline solid forms are characterized with XRPD peak sets, supporting identification/characterization of the compounds described.
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