Benzenesulfonamide compounds and their use as therapeutic agents
Inventors
Burford, Kristen Nicole • Focken, Thilo • Lofstrand, Verner Alexander • Wilson, Michael Scott • Zenova, Alla Yurevna
Assignees
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Publication Number
US-11325902-B2
Publication Date
2022-05-10
Expiration Date
Abstract
This invention is directed to benzenesulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy and/or epileptic seizure disorders.
Core Innovation
The invention relates to methods of treating a disease or a condition associated with aberrant Nav1.6 activity in a patient, wherein the disease or condition is epilepsy or epileptic seizure disorder. The method comprises administering a therapeutically effective amount of a compound of formula (I), including an individual stereoisomer, enantiomer or tautomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof.
The compound of formula (I) is defined by structural constraints including q being 1 or 2, r being 1 or 2, R1 being hydrogen or alkyl, R2 being thiazolyl, isothiazolyl or isoxazolyl, R3a and R3b each independently being hydrogen or alkyl, each R4 independently being halo or alkyl, R5 being halo, each R6 independently being halo or alkoxy, and R7 being azabicyclo[2.2.1]heptanylalkyl or ((methyl)(prop-2-yl)amino)alkyl when r is 2 and at least one R6 is alkoxy.
The description further relates the compounds to Nav1.6 activity and epilepsy by providing compound structure depictions, multiple Nav1.6-targeting sulfonamide/thiazole derivatives and salts, and enantiomeric forms resolved into (S) and (R). The document also outlines sodium-channel electrophysiological and sodium influx assays, with representative sodium-channel assay results across Nav1.1, Nav1.5, and Nav1.6 summarized as IC50 values, and electrical stimulation seizure assay models including a 6 Hz psychomotor seizure assay and maximal electroshock seizure (MES) models.
Claims Coverage
The patent contains one independent method claim directed to treating a disease or condition associated with aberrant Nav1.6 activity. The independent claim is supported by dependent claims that refine the treated indication and narrow the compound scope using structural constraints and stereochemical and salt/solvate forms.
Treating epilepsy or epileptic seizure disorder associated with aberrant Nav1.6 activity
A method of treating a disease or condition associated with aberrant Nav1.6 activity in a patient, wherein the disease or condition is epilepsy or epileptic seizure disorder, comprising administering a therapeutically effective amount of a compound of formula (I).
Formula (I) substituent scope
The compound of formula (I) is defined such that q is 1 or 2; r is 1 or 2; R1 is hydrogen or alkyl; R2 is thiazolyl, isothiazolyl or isoxazolyl; R3a and R3b are each independently hydrogen or alkyl; each R4 is independently halo or alkyl; R5 is halo; each R6 is independently halo or alkoxy; and R7 is azabicyclo[2.2.1]heptanylalkyl or ((methyl)(prop-2-yl)amino)alkyl when r is 2 and at least one R6 is alkoxy.
Stereochemical and salt/solvate coverage
The compound of formula (I) is administered as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof, or as a pharmaceutically acceptable salt or solvate thereof.
Overall claim coverage centers on treating epilepsy or epileptic seizure disorder linked to aberrant Nav1.6 activity using formula (I) compounds with constrained substituent variables, together with defined stereoisomer, enantiomer, tautomer, salt and solvate variants.
Stated Advantages
Selective inhibition of the voltage-gated sodium channel NaV1.6 over NaV1.5 and/or NaV1.1.
Documented Applications
Treating epilepsy in a patient with aberrant Nav1.6 activity using compounds of formula (I).
Treating epileptic seizure disorder in a patient with aberrant Nav1.6 activity using compounds of formula (I).
Treatment of SCN8A developmental and epileptic encephalopathy (SCN8A-DEE) using the method of claim 1.
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