Hydroxy and (halo)alkoxy substituted tetrahydrofurans as modulators of sodium channels
Inventors
Beck, Elizabeth Mary • Pullin, Robert • Etxebarria Jardi, Gorka • Stamos, Dean • Schmidt, Yvonne • Pontillo, Joseph • Thomson, Stephen Andrew • Shaw, David Matthew • Ahmad, Nadia M. • Carvalho Meireles, Lidio Marx • Skerratt, Sarah • Hadida Ruah, Sara S. • Neubert, Timothy Donald • Hurley, Dennis James • Durrant, Steven John • WRAY, Christopher • Virani, Anisa Nizarali • North, Kiri • Galan, Bhairavi • Knegtel, Ronald Marcellus • Chudyk, Ewa Iwona • Pinder, Joanne Louise • SOUSA, Bruno Artur • Pierard, Francoise
Assignees
Incorporated Vertex Pharmaceuticals • Vertex Pharmaceuticals Inc
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Publication Number
US-12662470-B2
Publication Date
2026-06-23
Expiration Date
Abstract
Compounds of formula I 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 disclosure relates to tetrahydrofuran carboxamides of formula (I) and pharmaceutically acceptable salts thereof, which possess defined alternatives for ring atoms and substituents. These compounds function as voltage-gated sodium-channel inhibitors, specifically targeting NaV1.8. The disclosure further describes stereochemical subfamilies, specific compound structures, pharmaceutical compositions, combination therapies, radiolabeled analogs, dosage forms, and synthetic intermediates.
Analytical characterization discloses formula (I)-type tetrahydrofuran carboxamides, including picolinamides, substituted aminopyridine amides, and amorphous compounds characterized by XRPD. The disclosure provides E-VIPR screening results demonstrating NaV1.8 inhibition across stated IC50 ranges. Documented therapeutic methods employ these compounds to inhibit NaV1.8 and to treat or lessen the severity of various pain disorders, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, and cardiac arrhythmia.
Claims Coverage
The claims cover four inventive features directed to compounds of formula (I), selected compound structures, pharmaceutical compositions, and methods of treatment.
Compounds of formula (I)
Independent claim 1 covers a compound of formula (I) or a pharmaceutically acceptable salt thereof, with defined alternatives for ring atoms and substituents. The claim limits the permitted ring atom identities, including X2a, X3a, X4a, X5a, and X6a as N, N+—O−, or C—R, alongside defined substituents including hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl groups, subject to stated structural provisos on nitrogen and N+—O− atoms.
Selected compounds
Claim 13 covers a compound selected from recited structures, or a pharmaceutically acceptable salt thereof, wherein the specific structures are not visible in the supplied claim text.
Pharmaceutical compositions
Recited claims cover a pharmaceutical composition comprising a compound of formula (I), optionally in a therapeutically effective amount, and one or more pharmaceutically acceptable carriers or vehicles.
Methods of NaV1.8 inhibition and treatment
Recited claims cover methods of inhibiting NaV1.8 and methods of treating or lessening the severity of listed conditions in a subject by administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the conditions include chronic, gut, neuropathic, musculoskeletal, acute, inflammatory, cancer, idiopathic, postsurgical, and visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, and cardiac arrhythmia.
The claims center on the defined formula (I) chemical genus and selected compounds, as well as associated pharmaceutical compositions and therapeutic methods for NaV1.8 inhibition and disease treatment.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Inhibiting voltage-gated sodium channels, particularly NaV1.8, in a subject using a compound of formula (I) or a pharmaceutically acceptable salt thereof.
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.
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