Benzenesulfonamide compounds and their use as therapeutic agents
Inventors
Andrez, Jean-Christophe • Burford, Kristen Nicole • Chowdhury, Sultan • Cohen, Charles Jay • Dehnhardt, Christoph Martin • Devita, Robert Joseph • Empfield, James Roy • Focken, Thilo • GRIMWOOD, Michael Edward • Hasan, Syed Abid • Johnson, JR., James Philip • Zenova, Alla Yurevna
Assignees
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Publication Number
US-11299490-B2
Publication Date
2022-04-12
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.
Core Innovation
The invention relates to 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. The method comprises administering to the patient a therapeutically effective amount of a compound having a defined multi-parameter chemical formula with specified R-group definitions and optional substituents, including optionally substituted phenyl or optionally substituted pyridyl at R1 and optionally substituted thiazolyl, thiadiazolyl, isothiazolyl, or pyridinyl at R2.
The compound formula further defines R3 as —O— or —N(R13)—, with R4, R5, and R13 independently selected from hydrogen, alkyl, and haloalkyl, each R6 independently selected from hydrogen, halo, alkyl, and haloalkyl, R7 as halo, each R8 independently selected from hydrogen, alkyl, and haloalkyl, and m and n each being 1 or 2. The compounds are administered as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof, or as a pharmaceutically acceptable salt or solvate.
The disclosed compound series includes sulfonamide-linked aryl-heterocycle compounds and specific stereochemically defined benzenesulfonamide embodiments, including thiazolyl and isothiazolyl substituents and fluorinated aryl substitution patterns. Activity is linked to NaV1.6 modulation, preferably inhibition, relative to NaV1.5 and NaV1.1.
Claims Coverage
The independent claim covers a method of treating epilepsy or epileptic seizure disorder associated with aberrant Nav1.6 activity by administering a therapeutically effective amount of a compound defined by a multi-parameter chemical formula. Across the consolidated claim set, the inventive coverage includes the treatment indication, the defined R-group framework, stereochemical form scope, and pharmaceutically acceptable salt or solvate forms; dependent claims further narrow the indication to SCN8A developmental and epileptic encephalopathy and the patient context to SCN8A mutation.
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.
Administering a therapeutically effective amount of a defined compound formula
Administering to the patient a therapeutically effective amount of a compound in which R1 is an optionally substituted phenyl or optionally substituted pyridyl; R2 is an optionally substituted thiazolyl, thiadiazolyl, isothiazolyl, or pyridinyl; R3 is —O— or —N(R13)—; R4, R5, and R13 are each independently selected from hydrogen, alkyl, and haloalkyl; each R6 is independently selected from hydrogen, halo, alkyl, and haloalkyl; R7 is halo; each R8 is independently selected from hydrogen, alkyl, and haloalkyl; and m and n are each 1 or 2.
Stereoisomeric and salt/solvate forms
The compound is administered as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof, or as a pharmaceutically acceptable salt or solvate thereof.
Narrowing to SCN8A developmental and epileptic encephalopathy
The method is carried out where the disease or condition is SCN8A developmental and epileptic encephalopathy (SCN8A-DEE).
Patient having an SCN8A mutation
The method is carried out for a patient who has an SCN8A mutation.
Specified (S)-stereochemical thiazolyl benzenesulfonamide embodiment
The method is carried out using (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide, or a pharmaceutically acceptable salt or solvate thereof.
Specified (S)-stereochemical isothiazolyl benzenesulfonamide embodiment
The method is carried out using (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isothiazol-3-yl)-5-methylbenzenesulfonamide.
Claim coverage centers on a broad method-of-treatment claim for epilepsy or epileptic seizure disorder associated with aberrant Nav1.6 activity using a therapeutically effective amount of a structurally defined compound. The core inventive features are the defined multi-parameter formula, the stereochemical and salt/solvate scope, and dependent narrowing to SCN8A developmental and epileptic encephalopathy, SCN8A mutation, and specific named (S)-stereochemical embodiments.
Stated Advantages
Modulation of NaV1.6 activity, preferably inhibition, is stated.
Selective activity toward NaV1.6 relative to NaV1.5 and NaV1.1 is stated.
Therapeutic treatment of epilepsy or epileptic seizure disorder associated with aberrant Nav1.6 activity is stated.
Selective inhibition is stated to reduce side effects associated with activity at other sodium channel isoforms.
Documented Applications
Treating a disease or condition associated with aberrant Nav1.6 activity, wherein the disease or condition is epilepsy or epileptic seizure disorder.
Treating SCN8A developmental and epileptic encephalopathy (SCN8A-DEE).
Use in a patient having an SCN8A mutation.
Treating epilepsy or epileptic seizure disorder in a patient with aberrant NaV1.6 activity.
Use in patients having an SCN8A mutation.
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