Carboxamides as modulators of sodium channels
Inventors
Ahmad, Nadia M. • 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 • Thomson, Stephen Andrew • Carvalho Meireles, Lidio Marx
Assignees
Vertex Pharmaceuticals Europe Ltd • Vertex Pharmaceuticals Inc
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Publication Number
US-12281057-B2
Publication Date
2025-04-22
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 relates to compounds of formula (II) and pharmaceutically acceptable salts thereof. The compounds are defined by structural constraints in which L is O and multiple ring positions X1b through X11 are each N or CR, with each R independently H or CH3. The substituents R1b through R13 are defined by position-specific options including H, halo, OH, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, and —W—(CH2)n—Rw, together with ring-forming alternatives for selected pairs of substituents.
Further structural limitations define R8 as H or —O—(CH2)n—Rw, Y1, Y2, Z1, and Z2 as each independently O or C(R14)2, W as independently O or a single bond, Rw as independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl optionally substituted with 1-3 substituents selected from halo, C1-C6 alkyl, and C1-C6 haloalkyl, and n as 0 or 1. The structural definition imposes explicit limits on nitrogen placement across X1b-X4b, X5-X7, and X9-X11, and when R8 is H, at least one of X5, X6, and X7 is not N or CH.
The disclosure also describes fluorinated benzamide and pyridine carboxamide embodiments, including phenoxy-substituted analogs, deuterated analogs, and specific named examples within the broader formula (II) framework. These examples are presented with synthesis and characterization data and share a common scaffold with amide-linked heteroaryl and aryl substitution patterns.
Claims Coverage
The consolidated claim coverage is centered on one independent compound claim for formula (II) or a pharmaceutically acceptable salt thereof, with extensive structural constraints on L, X1b-X11, R, and the position-specific substituent sets. The provided material also includes dependent coverage for narrower structural embodiments and methods of inhibiting a voltage-gated sodium channel and treating pain and additional conditions.
Compound of formula (II) with constrained ring positions
A compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein L is O; each of X1b, X2b, X3b, X4b, X5, X6, X7, X9, X10, and X11 is N or CR; and each R is independently H or CH3.
Position-specific substituent options for R1b to R4b
R1b, R2b, R3b, and R4b are each independently H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
Substituent framework for R5 to R7 and ring-forming alternatives
R5, R6, and R7 are each independently H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, or —W—(CH2)n—Rw, with specified ring-forming alternatives for selected pairs of these substituents.
Definitions for R8 to R13, Y1 to Y2, Z1 to Z2, W, Rw, and n
R8 is H or —O—(CH2)n—Rw; R9, R10, and R11 are each independently H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or —W—(CH2)n—Rw; R12 and R13 are each independently selected from the same option set or together form a ring of formula; Y1, Y2, Z1, and Z2 are each independently O or C(R14)2; W is independently O or a single bond; Rw is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl optionally substituted with 1-3 substituents selected from halo, C1-C6 alkyl, and C1-C6 haloalkyl; and n is 0 or 1.
Conditional nitrogen placement constraints
When R8 is H, at least one of X5, X6, and X7 is not N or CH; no more than two of X1b, X2b, X3b, and X4b is N; no more than one of X5, X6, and X7 is N; and no more than one of X9, X10, and X11 is N.
Inhibiting a voltage-gated sodium channel
A method of inhibiting a voltage-gated sodium channel in a subject by administering the compound of claim 1 or a pharmaceutically acceptable salt thereof, optionally specifically inhibiting Nav1.8.
Treating pain and additional conditions
A method for treating or reducing severity of pain conditions and for treating incontinence, pathological cough, or cardiac arrhythmia by administering an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a subject.
Combination therapy with additional therapeutic agents
The subject is treated with one or more additional therapeutic agents given concurrently with, before, or after treatment with the compound or its pharmaceutically acceptable salt.
The claim coverage is anchored by the formula (II) compound genus with detailed substituent definitions, ring-forming options, and explicit limits on nitrogen placement. The provided material also extends the claim set to methods of sodium-channel inhibition, pain treatment, and combination therapy with additional therapeutic agents.
Stated Advantages
Inhibits a voltage-gated sodium channel, optionally Nav1.8.
Treats or reduces severity of pain conditions.
Treats incontinence, pathological cough, or cardiac arrhythmia.
Combination therapy is provided with one or more additional therapeutic agents concurrently with, before, or after treatment with the compound.
Documented Applications
Inhibiting a voltage-gated sodium channel in a subject, optionally specifically inhibiting Nav1.8.
Treating or reducing severity of pain conditions, including chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, and Charcot-Marie-Tooth syndrome.
Treating incontinence, pathological cough, or cardiac arrhythmia.
Combination treatment with one or more additional therapeutic agents given concurrently with, before, or after treatment with the compound.
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