Carboxamides as modulators of sodium channels
Inventors
Thomson, Stephen Andrew • Ahmad, Nadia • Anderson, Corey • Arumugam, Vijayalaksmi • Asgian, Iuliana Luci • CAMP, Joanne Louise • Fanning, Lev Tyler Dewey • Hadida Ruah, Sara Sabina • Hurley, Dennis • Schmidt, Yvonne • Shaw, David • PATEL, Urvi • Carvalho Meireles, Lidio Marx
Assignees
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Publication Number
US-12441703-B2
Publication Date
2025-10-14
Expiration Date
Abstract
Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.
Core Innovation
The invention describes carboxamide compounds of formula (I) or (II), and pharmaceutically acceptable salts thereof, as modulators of voltage-gated sodium channels. The chemical scaffold encompasses substituted benzoyl-amino heteroaryl carboxamides, including pyridine-2-carboxamide and pyrimidine-carboxamide derivatives bearing substituted phenoxy or diaryl ether scaffolds. Defined substituent alternatives and ring structures include specified options for hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, heterocyclyl, cycloalkyl, cycloalkenyl, alkynyl, phenyl, alkylsulfanyl, and aminoalkoxy moieties.
The disclosure further describes deuterated analogs, specific diastereomers, and compounds selected from depicted structural series acting as NaV1.8 inhibitors. Reported compounds demonstrate NaV1.8 inhibitory activity in an E-VIPR assay, wherein NaV1.8 selectivity is proposed to improve the therapeutic window relative to nonselective sodium channel inhibitors in the treatment of pain. Disclosed compounds and pharmaceutical compositions relate to treating or lessening the severity of conditions including various pain states, multiple sclerosis, and cardiac arrhythmia.
Claims Coverage
The claims identify three independent claims representing three inventive features: claim 1, directed to a chemical genus of formula (I) or (II), and claims 18 and 19, directed to sets of selected chemical structures.
Compounds of formula (I) or (II)
Claim 1 covers a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, with defined alternatives for substituents and ring structures, including specified hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, and phenyl groups, as well as defined linked substituent groups and ring-forming options for positions R5 through R8.
Compounds selected from depicted structures in claim 18
Claim 18 covers a compound selected from structures depicted in the claim, or a pharmaceutically acceptable salt thereof.
Compounds selected from depicted structures in claim 19
Claim 19 covers a compound selected from structures referenced or depicted in the claim, or a pharmaceutically acceptable salt thereof.
The independent claims encompass the formula (I) and (II) compound scaffolds with recited substituent patterns, as well as distinct sets of depicted chemical structures and their pharmaceutically acceptable salts.
Stated Advantages
NaV1.8 selectivity is proposed to improve the therapeutic window relative to nonselective sodium channel inhibitors.
Documented Applications
Treating or lessening the severity of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia in a subject.
Pharmaceutical compositions comprising a claimed compound or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or vehicles, and optional combination therapy.
Use of the compounds to inhibit NaV1.8, including in biological samples.
Combination therapies and implantable-device coatings containing the disclosed compounds.
Radiolabeled analogs for assays, including tissue-distribution studies.
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