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WO2025129167A1 - Inhibiteurs de l'expression de surface du canal ionique sodique dépendant de la tension 1,7 (nav1.7) et leurs utilisations thérapeutiques - Google Patents

Inhibiteurs de l'expression de surface du canal ionique sodique dépendant de la tension 1,7 (nav1.7) et leurs utilisations thérapeutiques Download PDF

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Publication number
WO2025129167A1
WO2025129167A1 PCT/US2024/060335 US2024060335W WO2025129167A1 WO 2025129167 A1 WO2025129167 A1 WO 2025129167A1 US 2024060335 W US2024060335 W US 2024060335W WO 2025129167 A1 WO2025129167 A1 WO 2025129167A1
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Prior art keywords
methyl
phenyl
pain
mmol
fluorophenyl
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Inventor
Ganesha RAI BANTUKALLU
Shyh Ming YANG
Xin Hu
Se In Son
Kwong Tai CHENG
Natalia Julia MARTINEZ
Matthew David HALL
Rajesh Khanna
Samantha PEREZ-MILLER
Marcel Patek
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Regulonix LLC
US Department of Health and Human Services
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Regulonix LLC
US Department of Health and Human Services
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Na V 1.7 is usually expressed at high levels at the endings of pain-sensing neurons (nociceptors) whose cell bodies are located in the dorsal root ganglia (DRG) or the trigeminal ganglia, and in sympathetic ganglia neurons of the autonomic nervous system. Stimulation of nociceptor nerve endings produces a “generator potential” that is amplified by Na V 1.7. When the membrane potential difference reaches a certain threshold, the nociceptive neurons fire. Therefore, Na V 1.7 plays a critical role in the transmission of acute pain and chronic pain. [0004] For example, chemotherapy and nerve injury often induce chronic peripheral neuropathy.
  • Na V 1.7 is expressed at high levels in peripheral nerve tissues and plays a critical role in the transmission of acute and chronic neuropathic pain.
  • a selective blocker of Na V 1.7 can potentially be safely used systemically for pain relief without affecting cardiac electrical activity and without causing addiction or physical dependence.
  • direct blockers of Na V 1.7 that bind to Na V 1.7 have not succeeded in clinical trials to date, in part because many of them also block other voltage-gated sodium ion channels and thus have significant side effects.
  • the present disclosure describes compounds that indirectly inhibit Na V 1.7 by selectively inhibiting the expression of Na V 1.7 on the surface of nociceptive neurons.
  • the compounds selectively inhibit conjugation of the protein small ubiquitin-like modifier 2 (SUMO2) to the cytosolic collapsin response mediator protein 2 (CRMP2) by the E2 SUMO-conjugating enzyme Ubc9.
  • SUMO2 protein small ubiquitin-like modifier 2
  • CRMP2 cytosolic collapsin response mediator protein 2
  • Ubc9 E2 SUMO-conjugating enzyme
  • the compounds By selectively inhibiting CRMP2 SUMOylation and hence trafficking of Na V 1.7 to the plasma membrane of nociceptive neurons, the compounds selectively inhibit Na V 1.7 currents and thus pain signaling without affecting the function of other voltage-gated sodium ion channels including Na V 1.1, Na V 1.2, Na V 1.3, Na V 1.4, Na V 1.5, Na V 1.6, Na V 1.8 and Na V 1.9.
  • the compounds can be used to treat a wide variety of pain and pain-associated disorders. Compared to opioids, the compounds described herein have much less potential to cause addiction or physical dependence.
  • Figs.1A-D show that 10 mg/kg of intraperitoneally (i.p.) administered Compound 193 and Compound 215 markedly reduced both tactile allodynia (Figs.1A and B) and cold allodynia (Figs.1C and D) in 8 week-old, male C57BL/6J mice in a model of neuropathic pain. Compound 193 and Compound 215 reduced the tactile and cold allodynia in male neuropathic mice.
  • Fig. 1A Effect of the intraperitoneal administration of compounds on the tactile allodynia.
  • Fig.1B Area under the curve of the antiallodynic effect induced by compounds.
  • Fig.1C Effect of the intraperitoneal administration of compounds on the cold allodynia.
  • Fig.2A Effect of the intraperitoneal administration of compounds on the tactile allodynia.
  • Fig.2B Area under the curve of the antiallodynic effect induced by compounds.
  • Fig.2C Effect of the intraperitoneal administration of compounds on the cold allodynia.
  • Fig.2D Area under the curve of the antiallodynic effect induced by compounds.
  • Figs.3A-D show that i.p. administered Compound 193 reduced both tactile allodynia (Figs.3A and B) and cold allodynia (Figs.3C and D) in male mice in a dose-dependent manner. Compound 193 reduced the tactile and cold allodynia in a dose-dependent manner in male neuropathic mice.
  • Fig.3A Effect of the intraperitoneal administration of Compound 193 on the tactile allodynia.
  • Fig.3B Area under the curve of the antiallodynic effect induced by Compound 193.
  • Fig.3C Effect of the intraperitoneal administration of Compound 193 on the cold allodynia.
  • Fig.5A-D show that i.p. administered Compound 193 reduced both tactile allodynia (Figs.5A and B) and cold allodynia (Figs.5C and D) in female mice in a dose-dependent manner.
  • Compound 193 reduced the tactile and cold allodynia in a dose-dependent manner in female neuropathic mice.
  • Fig.5A Effect of the intraperitoneal administration of Compound 193 on the tactile allodynia.
  • Fig.5B Area under the curve of the antiallodynic effect induced by Compound 193.
  • Fig.5C Effect of the intraperitoneal administration of Compound 193 on the cold allodynia.
  • Fig.6A Effect of the intraperitoneal administration of compounds on the tactile allodynia.
  • Fig.6B Area under the curve of the antiallodynic effect induced by compounds.
  • Fig.6C Effect of the intraperitoneal administration of compounds on the cold allodynia.
  • Figs.7A-D show that Compound 193 and Compound 261 reduced the tactile and cold allodynia in a comparison with Gabapentin (30 mg/kg) in male neuropathic mice.
  • Fig.7A Effect of the intraperitoneal administration of compounds on the tactile allodynia
  • Fig.7B Area under the curve of the antiallodynic effect induced by compounds.
  • Fig.7C Effect of the intraperitoneal administration of compounds on the cold allodynia.
  • the present disclosure encompasses analogs, derivatives, prodrugs, metabolites, salts, solvates, hydrates, clathrates, isotopes, or isotopic forms including deuterated and tritiated forms, and polymorphs of all the compounds/substances disclosed herein, as appropriate.
  • the present disclosure encompasses all possible tautomers, all possible regioisomers, and all possible stereoisomers, including both enantiomers and all possible diastereomers in substantially pure form and mixtures of both enantiomers in any ratio (including a racemic mixture of enantiomers) and mixtures of two or more diastereomers in any ratio, of the compounds/substances described herein as appropriate, and not only the specific tautomers, regioisomers and stereoisomers as indicated by drawn structure or nomenclature. Some embodiments of the disclosure relate to the specific tautomers, regioisomers and stereoisomers indicated by drawn structure or nomenclature.
  • the indefinite articles “a” and “an” and the definite article “the” can include plural referents as well as singular referents unless specifically stated otherwise or the context clearly indicates otherwise.
  • the terms “or/and” and “and/or” mean “either ... or ..., or both ... and ...” when referring to two elements, and mean “either ..., ... or ..., or any combination or all thereof” when referring to three or more elements.
  • the phrase “A or/and B” means “either A or B, or both A and B”
  • the phrase “A, B or/and C” means “either A, B or C, or any combination or all thereof”.
  • transitional terms such as “comprising”, “containing”, “having”, “including”, “possessing”, “holding”, “carrying”, “bearing”, “composed of”, “characterized by” and the like are open-ended and inclusive, that is, mean including but not limited to and do not exclude additional, unrecited element(s) or method step(s). Only the transitional term “consisting of” is closed, that is, excludes any additional, unrecited element or method step, and the transitional term “consisting essentially of” is semi-closed, that is, only allows inclusion of additional, unrecited element(s) or method step(s) that do not materially affect the basic and novel characteristic(s) of that particular embodiment.
  • exemplary means “serving as an example, instance or illustration”. Any embodiment or feature characterized herein as “exemplary” should not be construed as preferred or advantageous over other embodiments or features.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within one standard deviation.
  • the term “about” or “approximately” means that range which would encompass the recited value and the range which would be included by rounding up or down to the recited value as well, taking into account significant figures. In certain embodiments, the term “about” or “approximately” means within ⁇ 10% or 5% of the specified value.
  • the term “substantially free” means no more than about 10%, 5%, 4%, 3%, 2% or 1% by weight or molarity, or no more than about 1000 ppm, 500 ppm, 400 ppm, 300 ppm, 200 ppm or 100 ppm.
  • the term “substantially pure” means at least about 90%, 95%, 96%, 97%, 98% or 99% pure.
  • -aryl- refers to a divalent aryl group.
  • An aryl group and an -aryl- group can optionally be substituted with one or more substituents as described herein.
  • heteroaryl refers to a monocyclic aromatic group or a multicyclic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, N and S.
  • the heteroaromatic ring may be attached or fused to one or more saturated, partially unsaturated or aromatic rings that may contain only ring carbon atoms or that may contain one or more ring heteroatoms.
  • the compounds of the disclosure indirectly inhibit the function of the voltage-gated sodium ion channel 1.7 (Na V 1.7) by selectively inhibiting SUMOylation of collapsin response mediator protein 2 (CRMP2) and hence trafficking of Na V 1.7 to the plasma membrane of nociceptive neurons.
  • CRMP2 collapsin response mediator protein 2
  • the optionally substituted R 2 group is selected from phenyl, pyrrolyl, furanyl (furyl), thiophenyl (thienyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl (pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, 2-pyridinonyl, 3- pyridinonyl and 4-pyridinonyl, wherein the R 2 group can be connected to ring A directly or via - CH 2 -, -NH-, -NCH 3 -, -O- or -S-, and wherein R 2 is not connected via -NH-, -NCH 3 -, -O- or -S-, to the nitrogen of ring A.
  • R 4 is selected from -CHF 2 , -CH 2 CHF 2 , cyclopropyl, -CH 2 - cyclopropyl, -CH 2 CH 2 -cyclopropyl, cis or trans -CH 2 -3-OH-cyclobutane, -CH 2 -(3,3-diF- cyclobutane), , , -CH 2 -tetrahydropyran-4-yl, -CH 2 CH 2 - tetrahydropyran-4-yl, -CH 2 -phenyl, -CH 2 -(3-F-phenyl), -CH(CH 3 )-phenyl, -CH(CH 3 )-(3-F- phenyl), -CF 2 -phenyl, -CF 2 -(3-F-phenyl), -CH 2 -pyridin-2-yl and -CH(CH 3 )-pyri
  • Non-limiting examples of organic amines useful for forming base addition salts include chloroprocaine, choline, cyclohexylamine, dibenzylamine, N,N’-dibenzylethylenediamine, dicyclohexylamine, diethanolamine, ethylenediamine, N-ethylpiperidine, histidine, isopropylamine, N-methylglucamine, procaine, pyrazine, triethylamine, trimethylamine and tromethamine.
  • Pharmaceutically acceptable salts are discussed in detail in Handbook of Pharmaceutical Salts, Properties, Selection and Use, P. Stahl and C. Wermuth, Eds., Wiley-VCH (2011).
  • compositions comprising an indirect Na V 1.7 inhibitor described herein (“Na V 1.7 inhibitor” for brevity), or a tautomer, pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof, and one or more pharmaceutically acceptable excipients or carriers.
  • the compositions can optionally contain an additional therapeutic agent such as an additional analgesic.
  • a pharmaceutical composition contains a therapeutically effective amount, or any appropriate fraction thereof, of a NaV1.7 inhibitor, one or more pharmaceutically acceptable excipients or carriers and optionally a therapeutically effective amount of an additional therapeutic agent, and is formulated for administration to a subject for therapeutic use.
  • a pharmaceutical composition contains a Na V 1.7 inhibitor and optionally an additional therapeutic agent in substantially pure form.
  • the purity of the Na V 1.7 inhibitor and the optional additional therapeutic agent independently is at least about 95%, 96%, 97%, 98% or 99%.
  • a pharmaceutical composition is substantially free of contaminants or impurities.
  • the level of contaminants or impurities other than residual solvent in a pharmaceutical composition is no more than about 5%, 4%, 3%, 2% or 1% relative to the combined weight of the intended active and inactive ingredients.
  • compositions generally are prepared according to current good manufacturing practice (GMP), as recommended or required by, e.g., the Federal Food, Drug, and Cosmetic Act ⁇ 501(a)(2)(B) and the International Conference on Harmonisation Q7 Guideline.
  • GMP current good manufacturing practice
  • Pharmaceutical compositions/formulations can be prepared in sterile form.
  • pharmaceutical compositions/formulations for parenteral administration by injection or infusion generally are sterile.
  • Sterile pharmaceutical compositions/formulations are compounded or manufactured according to pharmaceutical-grade sterilization standards known to those of skill in the art, such as those disclosed in or required by the United States Pharmacopeia Chapters 797, 1072 and 1211, and 21 Code of Federal Regulations 211.
  • compositions and carriers include pharmaceutically acceptable substances, materials and vehicles.
  • types of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersing agents, disintegration agents, emulsifying agents, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption-delaying agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweetening agents, flavoring agents, coloring agents, encapsulating materials and coating materials.
  • oils e.g., vegetable oils such as olive oil and sesame oil
  • aqueous solvents e.g., saline, buffered saline (e.g., phosphate-buffered saline [PBS]) and isotonic solutions (e.g., Ringer’s solution) ⁇
  • organic solvents e.g., dimethyl sulfoxide [DMSO] and alcohols [e.g., ethanol, glycerol and propylene glycol]
  • the disclosure encompasses the use of conventional excipients and carriers in formulations containing Na V 1.7 inhibitors. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania) (2005); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Pre-formulation and Formulation, Gibson, Ed., CRC Press (Boca Raton, Florida) (2004).
  • Appropriate formulation can depend on various factors, such as the route of administration chosen.
  • Potential routes of administration of pharmaceutical compositions comprising Na V 1.7 inhibitors include without limitation oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intra-arterial, intraperitoneal, intracavitary, intramedullary, intrathecal and topical), and topical (including dermal/epicutaneous, transdermal, mucosal, transmucosal, intranasal [e.g., by nasal spray or drop], ocular/intraocular [e.g., by eye drop], pulmonary [e.g., by oral or nasal inhalation], buccal, sublingual, rectal [e.g., by suppository], and vaginal [e.g., by suppository]).
  • parenteral including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intra-arterial, intraperitoneal, intracavitary, intra
  • Topical formulations can be designed to produce a local or systemic therapeutic effect.
  • formulations of Na V 1.7 inhibitors suitable for oral administration can be presented in discrete units adapted for instant, controlled or sustained release as, e.g., boluses; capsules (including push-fit capsules and soft capsules), tablets, pills, cachets or lozenges; as powders or granules; as semisolids, electuaries, pastes or gels; as solutions or suspensions in an aqueous liquid or/and a non-aqueous liquid; or as oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • Push-fit capsules or two-piece hard gelatin capsules can contain a Na V 1.7 inhibitor in admixture with, e.g., a filler or inert solid diluent (e.g., calcium carbonate, calcium phosphate, kaolin or lactose), a binder (e.g., a starch), a glidant or lubricant (e.g., talc or magnesium stearate), and a disintegrant (e.g., crospovidone), and optionally a stabilizer or/and a preservative.
  • a filler or inert solid diluent e.g., calcium carbonate, calcium phosphate, kaolin or lactose
  • a binder e.g., a starch
  • a glidant or lubricant e.g., talc or magnesium stearate
  • a disintegrant e.g., crospovidone
  • a Na V 1.7 inhibitor can be dissolved or suspended in a suitable liquid (e.g., liquid polyethylene glycol or an oil medium, such as a fatty oil, peanut oil, olive oil or liquid paraffin), and the liquid-filled capsules can contain one or more other liquid excipients or/and semi-solid excipients, such as a stabilizer or/and an amphiphilic agent (e.g., a fatty acid ester of glycerol, propylene glycol or sorbitol).
  • a suitable liquid e.g., liquid polyethylene glycol or an oil medium, such as a fatty oil, peanut oil, olive oil or liquid paraffin
  • an amphiphilic agent e.g., a fatty acid ester of glycerol, propylene glycol or sorbitol.
  • Tablets can contain a Na V 1.7 inhibitor in admixture with, e.g., a filler or inert diluent (e.g., calcium carbonate, calcium phosphate, lactose, mannitol or microcrystalline cellulose), a binding agent (e.g., a starch, gelatin, acacia, alginic acid or a salt thereof, or microcrystalline cellulose), a lubricating agent (e.g., stearic acid, magnesium stearate, talc or silicon dioxide), and a disintegrating agent (e.g., crospovidone, croscarmellose sodium or colloidal silica), and optionally a surfactant (e.g., sodium lauryl sulfate).
  • a filler or inert diluent e.g., calcium carbonate, calcium phosphate, lactose, mannitol or microcrystalline cellulose
  • a binding agent e.g.,
  • compositions for oral administration can also be formulated as solutions or suspensions in an aqueous liquid and/or a non-aqueous liquid, or as oil-in-water liquid emulsions or water-in- oil liquid emulsions.
  • Dispersible powder or granules of a Na V 1.7 inhibitor can be mixed with any suitable combination of an aqueous liquid, an organic solvent or/and an oil and any suitable excipients (e.g., any combination of a dispersing agent, a wetting agent, a suspending agent, an emulsifying agent or/and a preservative) to form a solution, suspension or emulsion.
  • Na V 1.7 inhibitors can also be formulated for parenteral administration by injection or infusion to circumvent gastrointestinal absorption and first-pass metabolism. An exemplary parenteral route is intravenous.
  • Formulations for injection or infusion can be in the form of, e.g., solutions, suspensions or emulsions in oily or aqueous vehicles, and can contain excipients such as suspending agents, dispersing agents or/and stabilizing agents.
  • aqueous or non-aqueous (e.g., oily) sterile injection solutions can contain a Na V 1.7 inhibitor along with excipients such as an antioxidant, a buffer, a bacteriostat and solutes that render the formulation isotonic with the blood of the subject.
  • Aqueous or non-aqueous sterile suspensions can contain a Na V 1.7 inhibitor along with excipients such as a suspending agent and a thickening agent, and optionally a stabilizer and an agent that increases the solubility of the NaV1.7 inhibitor to allow for the preparation of a more concentrated solution or suspension.
  • excipients such as a suspending agent and a thickening agent, and optionally a stabilizer and an agent that increases the solubility of the NaV1.7 inhibitor to allow for the preparation of a more concentrated solution or suspension.
  • a sterile aqueous solution for injection or infusion can contain a Na V 1.7 inhibitor, an isotonic agent (e.g., sodium chloride), a buffering agent (e.g., sodium citrate), a preservative (e.g., meta-cresol), and optionally a base (e.g., NaOH) or/and an acid (e.g., HCl) to adjust pH.
  • Topical formulations for application to the skin or mucosa can be useful for transdermal or transmucosal administration of a therapeutic agent to the local target site of action, or into the blood for systemic distribution.
  • Advantages of topical administration can include circumvention of the GI tract (including enzymes and acid in the GI tract and absorption through it) and first- pass metabolism; delivery of a therapeutic agent with a short half-life, a small therapeutic index or/and low oral bioavailability; controlled, continuous and sustained release of the therapeutic agent; a more uniform plasma level or delivery profile of the therapeutic agent; lower dose and less frequent dosing of the therapeutic agent; reduction of systemic side effects (e.g., side effects caused by a temporary overdose or an overly high peak plasma drug concentration); minimal or no invasiveness; ease of self-administration; and increased patient compliance.
  • circumvention of the GI tract including enzymes and acid in the GI tract and absorption through it
  • first- pass metabolism delivery of a therapeutic agent with a short half-life, a small therapeutic index or/and low oral bioavailability
  • controlled, continuous and sustained release of the therapeutic agent a more uniform plasma level or delivery profile of the therapeutic agent
  • lower dose and less frequent dosing of the therapeutic agent reduction of system
  • compositions suitable for topical administration include without limitation liquid or semi-liquid preparations such as sprays, gels, liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, foams, ointments and pastes, and solutions or suspensions such as drops (e.g., eye drops, nose drops and ear drops).
  • liquid or semi-liquid preparations such as sprays, gels, liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, foams, ointments and pastes, and solutions or suspensions such as drops (e.g., eye drops, nose drops and ear drops).
  • drops e.g., eye drops, nose drops and ear drops.
  • solvents including a suitable amount of an alcohol, can be used to solubilize the active agent.
  • excipients include without limitation gelling agents, thickening agents, emulsifiers, surfactants, stabilizers, buffers, antioxidants, preservatives, cooling agents (e.g. menthol), opacifiers, fragrances and colorants.
  • a topical formulation can contain a chemical permeation enhancer (e.g., a fatty acid ester [e.g., isopropyl myristate or isopropyl palmitate], a fatty acid [e.g., palmitic acid, oleic acid or palmitoleic acid], or/and an alcohol [e.g., propylene glycol or a fatty alcohol such as geraniol or farnesol]) to increase the permeation of the active agent through the skin or mucosal tissue.
  • a chemical permeation enhancer e.g., a fatty acid ester [e.g., isopropyl myristate or isopropyl palmitate], a fatty acid [e.g., palmitic acid, oleic acid or palmitoleic acid], or/and an alcohol [e.g., propylene glycol or a fatty alcohol such as geraniol or farnesol]
  • a topical formulation can also contain an irritation-mitigating excipient that reduces any irritation to the skin or mucosa caused by the active agent, the chemical permeation enhancer or any other component of the formulation.
  • a topical composition comprises a therapeutic agent dissolved, dispersed or suspended in a carrier.
  • the carrier can be in the form of, e.g., a solution, a suspension, an emulsion, an ointment or a gel base, and can contain, e.g., petrolatum, lanolin, a wax (e.g., bee wax), mineral oil, a long-chain alcohol, polyethylene glycol or polypropylene glycol, a diluent (e.g., water or/and an alcohol [e.g., ethanol or propylene glycol]), a gel, an emulsifier, a thickening agent, a stabilizer or a preservative, or any combination thereof.
  • petrolatum e.g., petrolatum, lanolin
  • a wax e.g., bee wax
  • mineral oil e.g., mineral oil
  • a long-chain alcohol e.g., polyethylene glycol or polypropylene glycol
  • a diluent e.g., water or/and an alcohol [
  • a topical formulation can be administered by means of, e.g., a transdermal or transmucosal delivery device, such as a transdermal patch, a microneedle patch or an iontophoresis device.
  • a topical composition can deliver a drug transdermally or transmucosally via a concentration gradient (with or without the use of a chemical permeation enhancer) or an active mechanism (e.g., iontophoresis or microneedles).
  • a Na V 1.7 inhibitor can be formulated as, e.g., a buccal or sublingual tablet or pill.
  • a buccal or sublingual tablet or pill include avoidance of gastrointestinal absorption and first-pass metabolism, and rapid absorption into systemic circulation.
  • a buccal or sublingual tablet or pill can be designed to provide faster release of the Na V 1.7 inhibitor for more rapid uptake of it into systemic circulation.
  • the buccal or sublingual tablet or pill can contain suitable excipients, including without limitation any combination of fillers and diluents (e.g., mannitol and sorbitol), binding agents (e.g., sodium carbonate), wetting agents (e.g., sodium carbonate), disintegrants (e.g., crospovidone and croscarmellose sodium), lubricants (e.g., silicon dioxide [including colloidal silicon dioxide] and sodium stearyl fumarate), stabilizers (e.g., sodium bicarbonate), flavoring agents (e.g., spearmint flavor), sweetening agents (e.g., sucralose), and coloring agents (e.g., yellow iron oxide).
  • suitable excipients including without limitation any combination of fillers and diluents (e.g., mannitol and sorbitol), binding agents (e.g., sodium carbonate), wetting agents (e.g., sodium carbonate), disintegrants (e.g
  • Na V 1.7 inhibitors can also be formulated for intranasal administration.
  • the nasal mucosa provides a big surface area, a porous endothelium, a highly vascular subepithelial layer and a high absorption rate, and hence allows for high bioavailability.
  • intranasal administration avoids first-pass metabolism.
  • An intranasal formulation can comprise a Na V 1.7 inhibitor along with excipients, such as a solubility enhancer (e.g., propylene glycol), a humectant (e.g., mannitol or sorbitol), a buffer and water, and optionally a preservative (e.g., benzalkonium chloride), a mucoadhesive agent (e.g., hydroxyethyl cellulose) or/and a penetration enhancer.
  • a solubility enhancer e.g., propylene glycol
  • a humectant e.g., mannitol or sorbitol
  • a buffer and water e.g., a buffer and water
  • a preservative e.g., benzalkonium chloride
  • a mucoadhesive agent e.g., hydroxyethyl cellulose
  • An intranasal solution or suspension formulation can be administered to the nasal cavity by any suitable means, including but not limited to a dropper, a pipette, or a spray using, e.g., a metering atomizing spray pump.
  • Table 3 shows exemplary excipients of nasal-spray formulations.
  • An additional mode of topical administration of Na V 1.7 inhibitors is pulmonary, including by oral inhalation and nasal inhalation.
  • a pulmonarily administered drug can treat a lung disease or/and a systemic disease, as the lungs serve as a portal to the systemic circulation.
  • Advantages of pulmonary drug delivery include, for example: 1) avoidance of first-pass metabolism; 2) fast drug action; 3) large surface area of the alveolar region for absorption, high permeability of the lungs (thin air-blood barrier), and profuse vasculature of the airways; 4) reduced extracellular enzyme levels compared to the GI tract due to the large alveolar surface area; and 5) smaller doses to achieve equivalent therapeutic effect compared to other oral routes, and hence reduced systemic side effects.
  • An advantage of oral inhalation over nasal inhalation includes deeper penetration/deposition of the drug into the lungs, although nasal inhalation can deliver the drug into systemic circulation transmucosally in the nasal cavity as well as in the lungs.
  • a drug can be embedded in a matrix that swells to form a gel through which the drug exits. Sustained release can also be achieved by way of a single-layer or multi-layer osmotic controlled-release oral delivery system (OROS).
  • OROS osmotic controlled-release oral delivery system
  • An OROS is a tablet with a semi-permeable outer membrane and one or more small laser-drilled holes in it. As the tablet passes through the body, water is absorbed through the semi-permeable membrane via osmosis, and the resulting osmotic pressure pushes the drug out through the hole(s) in the tablet and into the GI tract where it can be absorbed.
  • Types of pain that can be treated using the Na V 1.7 inhibitors disclosed herein include without limitation acute pain, chronic pain, neuropathic pain, inflammatory pain, mechanical pain, pressure pain, tactile pain, thermal pain, cold pain, post-surgical pain, cancer pain, musculoskeletal pain (e.g., neck pain, spinal cord-related pain, lower back pain, hip pain, knee pain and joint pain), and spinal cord injury-related pain, wherein each of the preceding types of pain includes allodynia, algesia and hyperalgesia.
  • a Na V 1.7 inhibitor is used to treat acute pain.
  • a Na V 1.7 inhibitor is used to treat post-surgical pain.
  • a Na V 1.7 inhibitor is used to treat cancer pain.
  • a Na V 1.7 inhibitor is used to treat acute or chronic neuropathic pain.
  • the Na V 1.7 inhibitors disclosed herein can be used to treat all forms of neuropathic pain, including without limitation chemotherapy-induced peripheral neuropathy, diabetic neuropathy, spinal cord injury- related pain, fibromyalgia and chronic regional pain syndrome.
  • Pain-associated disorders that can be treated using the Na V 1.7 inhibitors disclosed herein include without limitation fibromyalgia, neuralgia, neuropathies (e.g., diabetic neuropathy), peripheral neuropathies (e.g., PNs induced by chemotherapy and nerve injury), chronic regional pain syndrome, musculoskeletal disorders (e.g., degenerative ones such as rheumatoid arthritis, osteoarthritis and spondylosis), headaches (e.g., migraine and tension headache), and disorders resulting from mutations in the gene encoding Na V 1.7 (e.g., primary erythromelalgia and paroxysmal extreme pain disorder).
  • neuropathies e.g., diabetic neuropathy
  • peripheral neuropathies e.g., PNs induced by chemotherapy and nerve injury
  • chronic regional pain syndrome e.g., musculoskeletal disorders (e.g., degenerative ones such as rheumatoid arthritis, osteoarthritis and spondylos
  • the therapeutically effective amount and frequency of administration of a Na V 1.7 inhibitor may depend on various factors, including the type of pain or the pain-associated disorder being treated, the severity of the condition, the potency of the compound, the route of administration, the age, body weight, general health, gender and diet of the subject, and the response of the subject to the treatment, and can be determined by the treating physician.
  • the effective dose (e.g., maintenance dose) of a NaV1.7 inhibitor per day is about 1-500 mg, 1-100 mg, 100-200 mg, 200-300 mg, 300-400 mg or 400-500 mg, or as deemed appropriate by the treating physician, which can be administered in a single dose or in divided doses (e.g., 2, 3 or 4 times daily).
  • the effective dose (e.g., maintenance dose) of a Na V 1.7 inhibitor per day is about 1-200 mg, 1-50 mg, 50-100 mg, 100-150 mg or 150- 200 mg.
  • the dosing frequency may depend on, e.g., the route of administration chosen. For example, dosing by pulmonary administration (e.g., by oral inhalation) may occur more frequently (e.g., 2, 3 or 4 times daily).
  • a loading dose of the inhibitor that is greater (e.g., about 2- or 3-fold greater) than the maintenance dose can be administered at the beginning (e.g., in the first three days) of treatment followed by administration of the maintenance dose.
  • the length of treatment with a Na V 1.7 inhibitor can be determined by the treating physician to achieve alleviation of or relief from pain.
  • an Na V 1.7 inhibitor is administered for at least about 1 week, 2 weeks, 3 weeks or 4 weeks (1 month).
  • a Na V 1.7 inhibitor is administered for at least about 6 weeks, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years or longer.
  • a Na V 1.7 inhibitor can be taken pro re nata (as needed). For instance, a Na V 1.7 inhibitor can be taken until relief from pain is achieved, when dosing of the Na V 1.7 inhibitor can optionally be discontinued. If pain returns, use of the Na V 1.7 inhibitor can be resumed.
  • the dose of a Na V 1.7 inhibitor or/and its dosing frequency can be reduced upon alleviation of pain and then can be increased (e.g., to the previously effective dose or/and dosing frequency) if pain subsequently worsens.
  • the appropriate dosage of, frequency of dosing of and length of treatment with a Na V 1.7 inhibitor to treat pain or a pain-associated disorder can be determined by the treating physician.
  • a Na V 1.7 inhibitor can be administered via any suitable route, which may depend on, e.g., the type of pain or the pain-associated disorder being treated and its location and the pharmacokinetics of the inhibitor.
  • Potential routes of administration of a Na V 1.7 inhibitor include without limitation oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intra-arterial, intraperitoneal, intracavitary, intramedullary, intrathecal and topical), and topical (including dermal/epicutaneous, transdermal, mucosal, transmucosal, intranasal [e.g., by nasal spray or drop], ocular/intraocular [e.g., by eye drop], pulmonary [e.g., by oral or nasal inhalation], buccal, sublingual, rectal [e.g., by suppository], and vaginal [e.g., by suppository]).
  • parenteral including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intra-arterial, intraperitoneal, intracavitary, intramedullary, intrathecal and topical
  • topical including dermal/epicutaneous, trans
  • a Na V 1.7 inhibitor is administered orally. In other embodiments, a Na V 1.7 inhibitor is administered parenterally, such as intravenously, subcutaneously or intramuscularly. In further embodiments, a Na V 1.7 inhibitor is administered topically, such as sublingually, transdermally (e.g., via a transdermal patch), by oral inhalation or by rectal suppository. [0115] In some embodiments, a Na V 1.7 inhibitor is used in combination with one or more additional therapeutic agents to treat pain or a pain-associated disorder. In certain embodiments, the one or more additional therapeutic agents comprise one or more additional analgesics.
  • a NaV1.7 inhibitor may have a synergistic analgesic effect when used in combination with an additional analgesic such as an opioid (e.g., morphine, oxycodone or hydrocodone) or/and an NSAID (e.g., ibuprofen, naproxen or a COX-2 inhibitor).
  • an opioid e.g., morphine, oxycodone or hydrocodone
  • an NSAID e.g., ibuprofen, naproxen or a COX-2 inhibitor
  • Analgesics that can be used in combination with a Na V 1.7 inhibitor to treat pain or a pain- associated disorder include without limitation: acetaminophen (paracetamol); non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, ibuprofen, naproxen, and cyclo-oxygenase 2 (COX-2) inhibitors (e.g., apricoxib, celecoxib, etoricoxib, firocoxib, fluorocoxibs [e.g., fluorocoxibs A-C], lumiracoxib, mavacoxib, parecoxib, rofecoxib, tilmacoxib and valdecoxib); opioids, such as morphine, dihydromorphine, codeine, oxycodone, hydrocodone, pethidine and piritramide; other agonists of the ⁇ -opioid receptor, such as buprenorphine
  • analgesics that are used to treat primarily neuropathic pain include anticonvulsants (e.g., carbamazepine, gabapentin, pregabalin and phenibut) and tricyclic antidepressants (e.g., amitriptyline).
  • anticonvulsants e.g., carbamazepine, gabapentin, pregabalin and phenibut
  • tricyclic antidepressants e.g., amitriptyline
  • Examples The following examples are intended only to illustrate the disclosure. Other synthetic processes, assays, studies, protocols, procedures, methodologies, techniques, reagents and conditions may alternatively be used as appropriate. Synthesis of Compounds [0119] All air- or moisture-sensitive reactions were performed under a positive pressure of nitrogen with oven-dried glassware. Chemical reagents and anhydrous solvents were obtained from commercial sources and used as is.
  • Method 2 Analysis was performed on an Agilent 1260 with a 7 minute gradient of 4% to 100% acetonitrile (containing 0.025% TFA) in water (containing 0.05% TFA) over 8 minute run time at a flow rate of 1 mL/min.
  • Purity determination was performed using an Agilent Diode Array Detector for both Method 1 and Method 2.
  • Mass determination was performed using an Agilent 6130 mass spectrometer with electrospray ionization in the positive mode.
  • reaction mixture was sealed and heated up to 90 °C and then stirred for overnight. After cooling to rt, the mixture was diluted with EtOAc (20 mL) and washed with H 2 O (20 mL x3). The organic layer was dried (Na 2 SO 4 ) and filtered.
  • STEP 2 The title compound was prepared from methyl 1-(3-fluorophenyl)-1H-indazole- 5-carboxylate following a similar procedure as described in the synthesis of Int-15 (STEP-2).
  • the title compound was prepared from methyl 2-(3-fluorophenyl)-2H-indazole-5- carboxylate following a similar procedure as described in the synthesis of Int-15 (STEP-2).
  • Example 2 (4-(1-(3-fluorobenzyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)(4-((3- fluorophenyl)amino)quinazolin-7-yl)methanone, TFA (Cpd 2)
  • Cpd 2 STEP 1 Synthesis of methyl 4-((3-fluorophenyl)amino)quinazoline-7-carboxylate [0231] To a suspension of methyl 4-chloroquinazoline-7-carboxylate (0.668 g, 3 mmol) in 2- propanol (6 ml) was added 3-fluoroaniline (0.367 g, 3.30 mmol) and then Hunig's base (0.786 ml, 4.50 mmol).
  • STEP 2 Synthesis of 4-((3-fluorophenyl)amino)quinazoline-7-carboxylic acid [0232] To a suspension of methyl 4-((3-fluorophenyl)amino)quinazoline-7-carboxylate (700 mg, 2.0 mmol) in THF (8 ml)/MeOH (2 ml) was added 1 N NaOH (aq) (8 mL, 8 mmol, 4 equiv). The mixture was stirred at 50 °C for 1.5 hr. After cooling to rt, 1N HCl (aq) was added dropwise until the pH of aqueous layer was ca 5.
  • Example 51 (1-(3-fluorophenyl)-1H-indazol-5-yl)(4-(1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)- 1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methanone (Cpd 51) Cpd 51 [0297]
  • the title compound was prepared from 1-(3-fluorophenyl)-1H-indazole-5-carboxylic acid and 2-(piperidin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 1.
  • Example 52 4-((1-(1-(3-fluorobenzyl)-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)oxy)-7-(3- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (Cpd 52)
  • Cpd 52 STEP 1 Synthesis of 4-chloro-7-(3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine [0298] The material, 4-chloro-7-(3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine, was prepared from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 1-bromo-3-fluorobenzene following a similar procedure as described in the synthesis of Int-71 (STEP 1).
  • STEP 2 Synthesis of 4-((1-(1-(3-fluorobenzyl)-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)oxy)-7- (3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (Cpd 52) [0299]
  • the title compound was prepared from 4-chloro-7-(3-fluorophenyl)-7H-pyrrolo[2,3- d]pyrimidine and 1-(1-(3-fluorobenzyl)-1H-benzo[d]imidazol-2-yl)piperidin-4-ol following a similar procedure as described in Example 49 (STEP-2).
  • Example 54 (4-(1-(3-fluorobenzyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)(3-(3- fluorophenyl)-1-methyl-1H-indazol-7-yl)methanone (Cpd 54) Cpd 54 [0301]
  • the title compound was prepared from 3-(3-fluorophenyl)-1-methyl-1H-indazole-7- carboxylic acid and 1-(3-fluorobenzyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 1.
  • Example 56 (3-(3-fluorophenyl)-1-methyl-1H-indazol-6-yl)(4-(1-((3-methyloxetan-3- yl)methyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methanone (Cpd 56) Cpd 56 [0303]
  • the title compound was prepared from (4-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)(3- (3-fluorophenyl)-1-methyl-1H-indazol-6-yl)methanone and 3-(bromomethyl)-3-methyloxetane following a similar procedure as described in Example 22 (STEP-2).
  • Example 67 (3-(3-fluorophenyl)-1-methyl-1H-indazol-6-yl)(4-(1-((tetrahydro-2H-pyran-4- yl)methyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methanone (Cpd 67) Cpd 67 [0314]
  • the title compound was prepared from (4-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)(3- (3-fluorophenyl)-1-methyl-1H-indazol-6-yl)methanone and 4-(bromomethyl)tetrahydro-2H- pyran following a similar procedure as described in Example 22 (STEP-2).
  • Example 78 6-((4-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1- yl)methyl)-3-(3-fluorophenyl)-1-methyl-1H-indazole (Cpd 78) [0326]
  • the title compound was prepared from 3-(3-fluorophenyl)-1-methyl-1H-indazole-6- carbaldehyde and 1-(cyclopropylmethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 154 2-(1-((3-(3-fluorophenyl)-1-methyl-1H-indazol-6-yl)methyl)piperidin-4- yl)isoindolin-1-one (Cpd 154)
  • Cpd 154 [0420] The title compound was prepared from 3-(3-fluorophenyl)-1-methyl-1H-indazole-6- carbaldehyde and 2-(piperidin-4-yl)isoindolin-1-one, HCl following a similar procedure as described in Example 53.
  • Example 155 3-(2-fluorophenyl)-1-methyl-6-((4-(1-(1-phenylethyl)-1H-benzo[d]imidazol- 2-yl)piperidin-1-yl)methyl)-1H-indazole (Cpd 155)
  • Cpd 155 [0421] The title compound was prepared from 3-(2-fluorophenyl)-1-methyl-1H-indazole-6- carbaldehyde and 1-(1-phenylethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 156 4-((1-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)oxy)- 7-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (Cpd 156)
  • Cpd 156 STEP 1 Synthesis of 4-chloro-7-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine [0422]
  • the material, 4-chloro-7-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine was prepared from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 1-bromo-2-fluorobenzene following a similar procedure as described in Int-71 (STEP 1).
  • Example 158 1-(cyclopropylmethyl)-2-(1-((3-(2-fluorophenyl)-1-methyl-1H-indol-6- yl)methyl)piperidin-4-yl)-1H-benzo[d]imidazole (Cpd 158)
  • Cpd 158 [0426] The title compound was prepared from 3-(2-fluorophenyl)-1-methyl-1H-indole-6- carbaldehyde and 1-(cyclopropylmethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 159 1-(cyclopropylmethyl)-2-(1-((1-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4- yl)methyl)piperidin-4-yl)-1H-benzo[d]imidazole, 2TFA (Cpd 159)
  • Cpd 159 STEP 1 Synthesis of methyl 1-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate [0427] The material, methyl 1-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate, was prepared from methyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate and 1-bromo-3-fluorobenzene following a similar procedure as described in the synthesis of Int-71 (STEP 1).
  • Example 160 6-((4-(1-((3,3-difluorocyclobutyl)methyl)-1H-benzo[d]imidazol-2- yl)piperidin-1-yl)methyl)-3-(3-fluorophenyl)-1-methyl-1H-indazole (Cpd 160) F [0430] The title compound was prepared from 3-(3-fluorophenyl)-1-methyl-1H-indazole-6- carbaldehyde and 1-((3,3-difluorocyclobutyl)methyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 161 6-((4-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-benzo[d]imidazol-2- yl)piperidin-1-yl)methyl)-3-(3-fluorophenyl)-1-methyl-1H-indazole (Cpd 161) [0431] The title compound was prepared from 3-(3-fluorophenyl)-1-methyl-1H-indazole-6- carbaldehyde and 1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-2-(piperidin-4-yl)-1H- benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 162 (4-(1-(2,2-difluoroethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)(3-(3- fluorophenyl)-1-methyl-1H-indazol-6-yl)methanone (Cpd 162) Cpd 162 [0432] The title compound was prepared from (4-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)(3- (3-fluorophenyl)-1-methyl-1H-indazol-6-yl)methanone and 1,1-difluoro-2-iodoethane following a similar procedure as described in Example 22 (STEP 2).
  • Example 163 (4-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)(3-(3- fluorophenyl)-1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)methanone (Cpd 163) Cpd 163 [0433]
  • the title compound was prepared from 3-(3-fluorophenyl)-1-methyl-1H-pyrazolo[4,3- b]pyridine-6-carboxylic acid and 1-(cyclopropylmethyl)-2-(piperidin-4-yl)-1H- benzo[d]imidazole, 2HCl following a similar procedure as described in Example 1.
  • Example 164 7-((4-(1-(3-fluorobenzyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methyl)-3- (2-fluorophenyl)-1-methyl-1H-indazole (Cpd 164)
  • Cpd 164 [0434] The title compound was prepared from 3-(2-fluorophenyl)-1-methyl-1H-indazole-7- carbaldehyde and 1-(3-fluorobenzyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 165 (4-(1-(3-fluorobenzyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)(3-(3- fluorophenyl)-1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)methanone (Cpd 165)
  • F Cpd 165 [0435]
  • the title compound was prepared from 3-(3-fluorophenyl)-1-methyl-1H-pyrazolo[4,3- b]pyridine-6-carboxylic acid and 1-(3-fluorobenzyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 1.
  • Example 166 1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-2-(1-((3-(3-fluorophenyl)-1- methyl-1H-indol-6-yl)methyl)piperidin-4-yl)-1H-benzo[d]imidazole (Cpd 166)
  • Cpd 166 [0436]
  • the title compound was prepared from 3-(3-fluorophenyl)-1-methyl-1H-indole-6- carbaldehyde and 1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-2-(piperidin-4-yl)-1H- benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 168 1-((3,3-difluorocyclobutyl)methyl)-2-(1-((3-(3-fluorophenyl)-1-methyl-1H- indol-6-yl)methyl)piperidin- F Cpd 168 [0438]
  • the title compound was prepared from 3-(3-fluorophenyl)-1-methyl-1H-indole-6- carbaldehyde and 1-((3,3-difluorocyclobutyl)methyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 169 7-((4-(1-(3-fluorobenzyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methyl)-1- methyl-3-(o-tolyl)-1H-indazole (Cpd 169)
  • Cpd 169 [0439] The title compound was prepared from 1-methyl-3-(o-tolyl)-1H-indazole-7-carbaldehyde and 1-(3-fluorobenzyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 170 6-(1-(4-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1- yl)ethyl)-3-(3-fluorophenyl)-1-methyl-1H-indazole (Cpd 170) Cpd 170 [0440] To a mixture of 1-(3-(3-fluorophenyl)-1-methyl-1H-indazol-6-yl)ethan-1-one (53.7 mg, 0.2 mmol) and 1-(cyclopropylmethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl (65.7 mg, 0.200 mmol) in CH2Cl2 (1.5 ml) was added Et3N (0.056 ml, 0.40 mmol) and stirred for 5 min.
  • titanium(IV) isopropoxide (0.176 ml, 0.60 mmol) was added.
  • sodium triacetoxyborohydride (212 mg, 1.0 mmol) was added and stirred at rt for overnight.
  • the mixture was poured into EtOAc/2N Na 2 CO 3 (aq) (10 mL/10 mL).
  • the aqueous layer was extracted with EtOAc (5 mL x 2).
  • the combined organic layer was dried (Na 2 SO 4 ) and filtered.
  • Example 171 (4-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)(1-(3- fluorophenyl)-1H-indazol-4-yl)methanone (Cpd 171) F Cpd 171 [0441]
  • the title compound was prepared from 1-(3-fluorophenyl)-1H-indazole-4-carboxylic acid and 1-(cyclopropylmethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 1.
  • Example 172 6-((4-(1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methyl)- 3-(3-fluorophenyl)-1-methyl-1H-pyrazolo[4,3-b]pyridine (Cpd 172) Cpd 172 [0442]
  • the title compound was prepared from 3-(3-fluorophenyl)-1-methyl-1H-pyrazolo[4,3- b]pyridine-6-carbaldehyde and 1-(difluoromethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 173 5-((4-(1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methyl)- 1-(2-fluorophenyl)-3-methyl-1H-indazole (Cpd 173) Cpd 173 [0443]
  • the title compound was prepared from 1-(2-fluorophenyl)-3-methyl-1H-indazole-5- carbaldehyde and 1-(difluoromethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 174 1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-2-(1-((3-(2-fluorophenyl)-1- methyl-1H-indol-6-yl)methyl)piperidin-4-yl)-1H-benzo[d]imidazole (Cpd 174)
  • Cpd 174 [0444] The title compound was prepared from 3-(2-fluorophenyl)-1-methyl-1H-indole-6- carbaldehyde and 1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-2-(piperidin-4-yl)-1H- benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 175. 6-((4-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1- yl)methyl)-3-(3-fluorophenyl)-1-methyl-1H-pyrazolo[4,3-b]pyridine (Cpd 175) Cpd 175 [0445]
  • the title compound was prepared from 3-(3-fluorophenyl)-1-methyl-1H-pyrazolo[4,3- b]pyridine-6-carbaldehyde and 1-(cyclopropylmethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 176 5-((4-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-benzo[d]imidazol-2- yl)piperidin-1-yl)methyl)-1-(2-fluorophenyl)-3-methyl-1H-indazole (Cpd 176)
  • Cpd 176 [0446] The title compound was prepared from 1-(2-fluorophenyl)-3-methyl-1H-indazole-5- carbaldehyde and 1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-2-(piperidin-4-yl)-1H- benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 177 (4-(1-(3-fluorobenzyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)(1-(3- fluorophenyl)-1H-indazol-4-yl)methanone (Cpd 177)
  • Cpd 177 F Cpd 177 [0447]
  • the title compound was prepared from 1-(3-fluorophenyl)-1H-indazole-4-carboxylic acid and 1-(3-fluorobenzyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 1.
  • Example 178 (4-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)(1-(3- fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone (Cpd 178) Cpd 178 [0448]
  • the title compound was prepared from 1-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-4- carboxylic acid and 1-(cyclopropylmethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 1.
  • Example 179 4-((4-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1- yl)methyl)-1-(3-fluorophenyl)-1H-indazole (Cpd 179) F Cpd 179 [0449] The title compound was prepared from 1-(3-fluorophenyl)-1H-indazole-4-carbaldehyde and 1-(cyclopropylmethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 180 6-(1-(4-(1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)- 3-(3-fluorophenyl)-1-methyl-1H-indazole (Cpd 180) [0450]
  • the title compound was prepared from 1-(3-(3-fluorophenyl)-1-methyl-1H-indazol-6- yl)ethan-1-one and 1-(difluoromethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 170.
  • Example 181 7-((4-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-benzo[d]imidazol-2- yl)piperidin-1-yl)methyl)-3-(3-fluorophenyl)-1-methyl-1H-indazole (Cpd 181) Cpd 181 [0451]
  • the title compound was prepared from 3-(3-fluorophenyl)-1-methyl-1H-indazole-7- carbaldehyde and 1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-2-(piperidin-4-yl)-1H- benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 182 6-((4-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-benzo[d]imidazol-2- yl)piperidin-1-yl)methyl)-3-(2-fluorophenyl)-1-methyl-1H-indazole (Cpd 182) [0452]
  • the title compound was prepared from 3-(2-fluorophenyl)-1-methyl-1H-indazole-6- carbaldehyde and 1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-2-(piperidin-4-yl)-1H- benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 183 (1s,3s)-3-((2-(1-((3-(2-fluorophenyl)-1-methyl-1H-indol-6- yl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)cyclobutan-1-ol (Cpd 183)
  • Cpd 183 [0453]
  • the title compound was prepared from 3-(2-fluorophenyl)-1-methyl-1H-indole-6- carbaldehyde and (1s,3s)-3-((2-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)cyclobutan-1- ol, 2HCl following a similar procedure as described in Example 53.
  • Example 184 5-((4-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1- yl)methyl)-6-fluoro-1-(2-fluorophenyl)-1H-indazole (Cpd 184)
  • Cpd 184 STEP 1 Synthesis of methyl 6-fluoro-1-(2-fluorophenyl)-1H-indazole-5-carboxylate
  • the material, methyl 6-fluoro-1-(2-fluorophenyl)-1H-indazole-5-carboxylate was prepared from methyl 6-fluoro-1H-indazole-5-carboxylate and 1-bromo-2-fluorobenzene following a similar procedure as described in the synthesis of Int-71 (STEP 1).
  • STEP 3 Synthesis of 5-((4-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1- yl)methyl)-6-fluoro-1-(2-fluorophenyl)-1H-indazole (Cpd 184) [0456] The title compound was prepared from 6-fluoro-1-(2-fluorophenyl)-1H-indazole-5- carbaldehyde and 1-(cyclopropylmethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 185 6-chloro-5-((4-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1- yl)methyl)-1-(2-fluorophenyl)-1H-indazole (Cpd 185)
  • Cpd 185 STEP 1 Synthesis of methyl 6-chloro-1-(2-fluorophenyl)-1H-indazole-5-carboxylate
  • the material, methyl 6-chloro-1-(2-fluorophenyl)-1H-indazole-5-carboxylate was prepared from methyl 6-chloro-1H-indazole-5-carboxylate and 1-bromo-2-fluorobenzene following a similar procedure as described in the synthesis of Int-71 (STEP 1).
  • STEP 3 Synthesis of 6-chloro-5-((4-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2- yl)piperidin-1-yl)methyl)-1-(2-fluorophenyl)-1H-indazole (Cpd 185) [0459] The title compound was prepared from 6-chloro-1-(2-fluorophenyl)-1H-indazole-5- carbaldehyde and 1-(cyclopropylmethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 53.
  • Example 186 (4-(1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)(1-(3- fluorophenyl)-3-methyl-1H-indazol-5-yl)methanone (Cpd 186) O Cpd 186 [0460]
  • the title compound was prepared from 1-(3-fluorophenyl)-3-methyl-1H-indazole-5- carboxylic acid and 1-(difluoromethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 1.
  • Example 187 (4-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)(1-(3- fluorophenyl)-3-methyl-1H-indazol-5-yl)methanone (Cpd 187)
  • Cpd 187 [0461] The title compound was prepared from 1-(3-fluorophenyl)-3-methyl-1H-indazole-5- carboxylic acid and 1-(cyclopropylmethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 1.
  • Example 195 (4-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)(1- (cyclopropylmethyl)-3-(3-fluorophenyl)-1H-indazol-6-yl)methanone (Cpd 195)
  • Cpd 195 [0470] The title compound was prepared from 1-(cyclopropylmethyl)-3-(3-fluorophenyl)-1H- indazole-6-carboxylic acid and 1-(cyclopropylmethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl following a similar procedure as described in Example 1.
  • Example 196 (1s,3s)-3-((2-(1-((1-(3-fluorophenyl)-3-methyl-1H-indazol-5- yl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)cyclobutan-1-ol (Cpd 196) OH Cpd 196 [0471]
  • the title compound was prepared from 1-(3-fluorophenyl)-3-methyl-1H-indazole-5- carbaldehyde and (1s,3s)-3-((2-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)cyclobutan-1- ol, 2HCl following a similar procedure as in Example 53.
  • Example 197 6-(1-(4-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)- 2,2,2-trifluoroethyl)-3-(3-fluorophenyl)-1-methyl-1H-indazole (Cpd 197)
  • Cpd 197 [0472] In a microwave tube was placed 1-(cyclopropylmethyl)-2-(piperidin-4-yl)-1H- benzo[d]imidazole (0.077 g, 0.3 mmol) and sodium iodide (4.50 mg, 0.03 mmol).
  • Example 199 6-((1-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)oxy)- 3-(3-fluorophenyl)-1-methyl-1H-indazole (Cpd 199) Cpd 199 [0476]
  • the title compound was prepared from 3-(3-fluorophenyl)-1-methyl-6-(piperidin-4- yloxy)-1H-indazole, HCl and 2-chloro-1-(cyclopropylmethyl)-1H-benzo[d]imidazole following a similar procedure as described in Example 102.
  • Example 200 6-((1-(1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)oxy)-3-(3- fluorophenyl)-1-methyl-1H-indazole (Cpd 200) [0477]
  • the title compound was prepared from 3-(3-fluorophenyl)-1-methyl-6-(piperidin-4- yloxy)-1H-indazole, HCl and 2-chloro-1-(difluoromethyl)-1H-benzo[d]imidazole following a similar procedure as described in Example 102.
  • Example 209 N-(1-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)-3-(3- fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Cpd 209) Cpd 209 [0487] The title compound was prepared from 3-(3-fluorophenyl)-1-methyl-N-(piperidin-4-yl)- 1H-pyrazolo[3,4-d]pyrimidin-6-amine, 2HCl and 2-chloro-1-(cyclopropylmethyl)-1H- benzo[d]imidazole following a similar procedure as described in Example 102.
  • Example 210 6-((1-(1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)oxy)-3-(3- fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (Cpd 210) Cpd 210 [0488]
  • the title compound was prepared from 3-(3-fluorophenyl)-1-methyl-6-(piperidin-4- yloxy)-1H-pyrazolo[3,4-d]pyrimidine, 2HCl and 2-chloro-1-(difluoromethyl)-1H- benzo[d]imidazole following a similar procedure as described in Example 102.
  • Example 211 N-(1-(1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)-3-(3- fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Cpd 211) Cpd 211 [0489]
  • the title compound was prepared from 3-(3-fluorophenyl)-1-methyl-N-(piperidin-4-yl)- 1H-pyrazolo[3,4-d]pyrimidin-6-amine, 2HCl and 2-chloro-1-(difluoromethyl)-1H- benzo[d]imidazole following a similar procedure as described in Example 102.
  • Example 212 (3-(3-fluorophenyl)-1-methyl-1H-indazol-6-yl)(4-(1-(tetrahydro-2H-pyran-4- yl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methanone, TFA (Cpd 212) Cpd 212 [0490]
  • the title compound was prepared from (4-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)(3- (3-fluorophenyl)-1-methyl-1H-indazol-6-yl)methanone and tetrahydro-2H-pyran-4-yl methanesulfonate following a similar procedure as described in Example 22 (STEP 2).
  • STEP 2 Synthesis of 5-((1-(1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)oxy)- 1-(3-fluorophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine (Cpd 224) [0507] The title compound was prepared from 1-(3-fluorophenyl)-3-methyl-5-(piperidin-4- yloxy)-1H-pyrazolo[3,4-b]pyridine, 2HCl and 2-chloro-1-(difluoromethyl)-1H- benzo[d]imidazole following a similar procedure as described in Example 223 (STEP 4).
  • Example 250 1-(cyclopropylmethyl)-N-(1-(1-(difluoromethyl)-1H-benzo[d]imidazol-2- yl)piperidin-4-yl)-3-(3-fluorophenyl)-N-(trifluoromethyl)-1H-indazol-6-amine (Cpd 250) Cpd 250 [0535] To a mixture of 1-(cyclopropylmethyl)-N-(1-(1-(difluoromethyl)-1H-benzo[d]imidazol-2- yl)piperidin-4-yl)-3-(3-fluorophenyl)-1H-indazol-6-amine (106 mg, 0.2 mmol) and tetramethylammonium trifluoromethanethiolate (70.1 mg, 0.40 mmol) was added MeCN (1 ml).

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Abstract

La divulgation concerne des composés qui interfèrent indirectement avec la fonction de canal ionique sodique dépendant de la tension 1,7 (NaV1,7) par modulation sélective du trafic de NaV1.7 à la membrane plasmique de neurones nociceptifs. Contrairement aux bloqueurs directs de NaV1.7 qui se lient à NaV1.7, les composés selon la divulgation n'affectent pas la fonction d'autres canaux ioniques sodiques sensibles à la tension. Les composés peuvent être utilisés pour traiter plusieurs types de douleurs et de troubles associés à la douleur. Par rapport aux opioïdes, les composés ont beaucoup moins de potentiel pour provoquer une dépendance ou une dépendance physique.
PCT/US2024/060335 2023-12-15 2024-12-16 Inhibiteurs de l'expression de surface du canal ionique sodique dépendant de la tension 1,7 (nav1.7) et leurs utilisations thérapeutiques Pending WO2025129167A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4144317A (en) 1975-05-30 1979-03-13 Alza Corporation Device consisting of copolymer having acetoxy groups for delivering drugs
US5797898A (en) 1996-07-02 1998-08-25 Massachusetts Institute Of Technology Microchip drug delivery devices
WO2018144900A1 (fr) * 2017-02-03 2018-08-09 Arizona Board Of Regents On Behalf Of The University Of Arizona Antagonistes à petites molécules de la modification liée au sumo de crmp2 et leurs utilisations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4144317A (en) 1975-05-30 1979-03-13 Alza Corporation Device consisting of copolymer having acetoxy groups for delivering drugs
US5797898A (en) 1996-07-02 1998-08-25 Massachusetts Institute Of Technology Microchip drug delivery devices
WO2018144900A1 (fr) * 2017-02-03 2018-08-09 Arizona Board Of Regents On Behalf Of The University Of Arizona Antagonistes à petites molécules de la modification liée au sumo de crmp2 et leurs utilisations

Non-Patent Citations (6)

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Title
"Handbook of Pharmaceutical Additives", 2007, GOWER PUBLISHING CO.
"Handbook of Pharmaceutical Salts, Properties, Selection and Use", 2011, WILEY-VCH
"Pharmaceutical Pre-formulation and Formulation", 2004, CRC PRESS
"Remington: The Science and Practice of Pharmacy", 2005, THE PHARMACEUTICAL PRESS AND THE AMERICAN PHARMACEUTICAL ASSOCIATION
BRADEN ET AL.: "Neurobiol. Pain", vol. 11, 2022, pages: 100082
NELSON TSSINHA GPSANTOS DFSJUKKOLA PPRASOON PWINTER MK ET AL.: "Spinal neuropeptide Y Y1 receptor-expressing neurons are a pharmacotherapeutic target for the alleviation of neuropathic pain.", PROC NATL ACAD SCI U S A., vol. 119, no. 46, 2022, pages e2204515119

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