Tetrahydrofuran-formamide sodium channel modulator and use thereof in medicine

Abstract

The present invention provides a substituted tetrahydrofuran-formamide derivative, a salt or stereoisomer, a pharmaceutical composition containing same, a use thereof as a Nav inhibitor, and a use thereof in preparation of a drug for treating and / or alleviating pain and pain-related diseases. The compound provided in the present invention has the advantages of high metabolic stability, high oral absorption, better bioavailability, better activity, higher selectivity, better pharmacokinetic properties, faster onset of action, and low central nervous system side effects.

Description

Tetrahydrofuran carboxamide sodium channel modulators and their pharmaceutical applications

[0001] This application claims priority to Chinese patent application 202411641321X, filed on 2024 / 11 / 18. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention provides a class of substituted tetrahydrofuran carboxamide derivatives, salts, or stereochemical isomers and pharmaceutical compositions containing them. In particular, this invention discloses the use of a Nav inhibitor and its use in the preparation of medicaments for treating and / or alleviating aches and pains-related disorders. Background Technology

[0003] Pain is a sensation produced when the human body is subjected to various noxious stimuli. It is a complex physiological and psychological activity, as well as a defensive mechanism to protect the body from harm. Clinically, it is one of the most common symptoms. The International Association for the Study of Pain (IASP) classifies pain into nociceptive pain, neuropathic pain, and psychogenic pain. Neuropathic pain typically includes pain caused by systemic metabolic damage and pain caused by discrete nerve damage.

[0004] Voltage-gated sodium channels are mainly distributed in the nervous system, excitable neurons, and play an important biophysical role in the transmission of pain-related signals. They transmit electrical signals through the generation and propagation of action potentials (APs) in the peripheral nervous system (PNS) and central nervous system (CNS). There are nine types of sodium ion channels in humans, namely Nav1.1 to Nav1.9, each of which is formed by an α subunit and one or more β subunits. Despite their high structural and sequence similarity, different subtypes of Nav channels not only have specific tissue distributions, but also have different voltage dependencies and activation, inactivation, and recovery kinetics (Xiaoshuang H, et al. Proceedings of the National Academy of Sciences of the United States of America, 2022, 119(30); Eleonora S, et al. Cardiovascular research, 2014, 104(2):355-63). Studies have shown that mutations, changes in expression, or inappropriate regulation of these channels can lead to electrical instability of the cell membrane and abnormal spontaneous activity observed under pathological conditions (Chahine M, et al. CNS & Neurological Disorders-Drug Targets, 2008, 7(2): 144-158).

[0005] Nav1.8 is a tetrodotoxin (TTX)-insensitive sodium channel encoded by SCN10A, primarily expressed in sensory neurons, located in the 3p21-22 region of human chromosomes, and mainly encoding the α subunit. Studies have shown that Nav1.8 plays an important role in neuropathic and chronic inflammatory pain, such as regulating malondialdehyde (a key factor in diabetic pain) and tumor necrosis factor-α (TNF-α) (Huang Q, et al. Metabolism, 2016, 65(4):463-474; He XH, Zang Y, Chen X, et al. Pain. 2010 Nov; 151(2):266-279.). Based on a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 can be used to treat various types of pain, including inflammatory pain, neuropathic pain, postoperative pain, and cancer pain, becoming a novel analgesic therapy. Therefore, Nav1.8 blockers are expected to become a new generation of ideal drugs for the treatment of neuropathic and inflammatory pain.

[0006] Clinically used Nav inhibitors, lacking subtype selectivity, inhibit sodium ion channels expressed in the heart and central nervous system, resulting in a narrow therapeutic window and limited application. Nav1.8 is primarily distributed in the peripheral nervous system, so selective inhibition of Nav1.8 can effectively reduce side effects. Therefore, it is necessary to develop Nav1.8 inhibitors with better activity, higher selectivity, better pharmacokinetic properties, faster onset of action, and fewer side effects. Summary of the Invention

[0007] This invention provides a substituted tetrahydrofuran carboxamide derivative, its salt or stereochemical isomer thereof, and a pharmaceutical composition containing the derivative, wherein the tetrahydrofuran carboxamide derivative preferably has a structure shown in any of the following structural formulas:

[0008] The compounds of the present invention are typically used in the form of free acids or free bases. Alternatively, the compounds of the present invention may be used in the form of acid or base salts. Acid adduct salts of the free amino compounds of the present invention can be prepared using methods known in the art, and can be prepared from organic and inorganic acids.

[0009] Suitable organic acids include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, phenylacetic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, and benzenesulfonic acid. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptate, glyceryl phosphate, gluconate, hemisulfate, heptaate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Basic salts include salts formed with carboxylate anions, and also include salts formed with organic and inorganic cations such as those selected from alkali metal ions, alkaline earth metal ions (e.g., lithium, sodium, potassium, magnesium, barium, calcium), and ammonium ions, as well as their substituted derivatives (e.g., dibenzylamine, benzylamine, 2-hydroxyethylamine, etc.). Therefore, the term "pharmaceutical-acceptable salt" should include all acceptable salt forms.

[0010] Furthermore, prodrugs are also included within the scope of this invention. A prodrug is any covalently bound carrier that releases the accepted compound in vivo when administered to a patient. Prodrugs are typically prepared by modifying functional groups in a way that allows the modification to be resolved by conventional exchange or in vivo to yield the parent compound. Prodrugs include compounds of this invention, for example, hydroxyl, amino, or thiol groups combined with any group, wherein the group is detached upon administration to a patient to yield a hydroxyl, amino, or thiol group.

[0011] Therefore, representative examples of prodrugs include (but are not limited to) derivatives of acetates (esters), formates (esters), and benzoate salts of the alcohol and amine functional groups of the compounds of this application. Furthermore, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, etc., may be included. In the case of hydroxyl groups, mixed acid anhydrides such as methoxy, ethoxy, propoxy, tert-butoxy, etc., may be included.

[0012] For stereoisomers, the compounds of this application may have a chiral center and may exist as racemates, racemic mixtures, and individual enantiomers or diastereomers. All isomeric forms are included within the scope of this invention, including mixtures thereof. Furthermore, certain crystalline forms of the compounds of this application may exist in polymorphic forms, which are also included within the scope of this invention. Some of the compounds of this application may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.

[0013] Those skilled in the art will understand that any compound may contain atomic isotopes in non-natural proportions on one or more of the atoms constituting the compound. As used in this invention, in the specification and claims, H refers to hydrogen and includes any stable isotope of hydrogen, i.e. 1 H and D. In embodiments where the atom is designated as H, no work was performed to enrich specific isotopic hydrogen atoms, and therefore those skilled in the art will understand that such hydrogen atoms may be present at approximately the natural abundance concentration of hydrogen. In the tetrahydrofuran carboxamide derivatives involved in this invention, deuteration means that the atoms at the relevant sites of the compound contain deuterium atoms in a proportion exceeding the natural abundance (i.e., exceeding the natural abundance of deuterium). Therefore, any tetrahydrofuran carboxamide derivative containing deuterium atoms at the relevant sites in a proportion exceeding the natural abundance of deuterium is within the scope of protection of this invention. For example, it can be understood that corresponding tetrahydrofuran carboxamide derivatives with corresponding deuteration rates or deuterium contents obtained by introducing deuterium atoms using commercially available deuterating agents through the same or similar chemical synthesis methods shown in the embodiments of this invention are within the scope of protection of this invention. The chemical synthesis methods and deuterated reagents mentioned herein are not limited to those exemplified in the examples, but should be understood as all synthetic methods or routes that can be used in the art to obtain the compounds of the present invention, and all deuterated reagents that can be used in conjunction with the aforementioned synthetic methods or routes to introduce deuterium atoms into the target molecule.

[0014] Isotope-labeled compounds and salts can be used in a variety of advantageous ways, including as pharmaceuticals. In some embodiments, the isotope-labeled compounds and salts are deuterium (D)-labeled. Deuterium (D)-labeled compounds and salts are therapeutically useful, possessing potential therapeutic advantages over unlabeled compounds. Generally, due to the kinetic isotope effect described below, deuterium (D)-labeled compounds and salts can exhibit higher metabolic stability compared to unlabeled compounds and salts. Higher metabolic stability directly translates to prolonged in vivo half-life or reduced dose, which in most cases will represent preferred embodiments of the invention. Isotope-labeled compounds and salts can generally be prepared by performing the procedures disclosed in the synthetic schemes, examples, and related descriptions, replacing the unlabeled reactants with readily available isotope-labeled reactants. Deuterium (D)-labeled compounds and salts can manipulate the oxidative metabolic rate of said compounds through primary kinetic isotope effects. Primary kinetic isotope effects are rate changes in chemical reactions resulting from isotopic nuclear exchange, which in turn is caused by changes in the ground-state energy of the covalent bonds involved in the reaction. Exchange with heavier isotopes typically lowers the ground-state energy of chemical bonds and thus reduces the rate-limiting bond breaking. If bond breaking occurs in or near a saddle point region along the coordinates of a multi-product reaction, it can substantially alter the product distribution ratio.

[0015] Based on the specific embodiments disclosed below according to the present invention, those skilled in the art can use the same or similar principles and methods to prepare the specific compounds involved in the tetrahydrofuran carboxamide derivatives of the present invention.

[0016] The present invention further provides the use of tetrahydrofuran carboxamide derivatives, their stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts thereof, or prodrugs as shown in this application, in the preparation of sodium ion channel modulators. Further, the sodium ion channel modulator is a Nav1.8 inhibitor.

[0017] The present invention further provides the use of tetrahydrofuran carboxamide derivatives, their stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof as shown in this application, in the preparation of medicaments for treating diseases causing Nav1.8 overexpression.

[0018] The present invention further provides the use of tetrahydrofuran carboxamide derivatives, their stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof as shown in this application in the preparation of medicaments for treating diseases caused by Nav1.8 overexpression.

[0019] The present invention further provides the use of tetrahydrofuran carboxamide derivatives, their stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts thereof, or their prodrugs as shown in this application, in the preparation of medicaments for treating any one or more of the following diseases: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, and arrhythmias.

[0020] Further, the neuropathic pain is selected from one or more of the following: postherpetic neuralgia, diabetic neuropathic pain, painful HIV-related sensory neuropathy, trigeminal neuralgia, oral burn syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve compression injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug-induced neuropathic pain, cancer chemotherapy-induced neuropathic pain, antiretroviral therapy-induced neuropathic pain, post-spinal cord injury pain, primary small fiber neuropathy, primary sensory neuropathy, and trigeminal autonomic headache; the musculoskeletal pain is selected from one or more of the following: osteoarthritis pain, back pain, cold pain, burn pain, and toothache; the inflammatory pain is selected from rheumatoid arthritis pain and / or vulvar pain; and the primary pain is selected from fibromyalgia.

[0021] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a tetrahydrofuran carboxamide derivative, its stereoisomer, hydrate, solvate, polymorph, active metabolite, pharmaceutically acceptable salt thereof or a prodrug thereof, as shown in this application, and a pharmaceutically acceptable carrier.

[0022] The compounds of the present invention, or their pharmaceutically acceptable salts, in pure form or suitable pharmaceutical compositions, can be administered in any acceptable mode of administration to a similarly effective agent. The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable carriers, diluents, or excipients, and can be formulated into solid, semi-solid, liquid, or gaseous formulations, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalers, gels, microspheres, and aerosols. Typical routes of administration of the pharmaceutical compositions include (but are not limited to) oral, topical, transdermal, inhalation, non-enteric, sublingual, buccal, rectal, vaginal, and intranasal administration. As used herein, the term non-enteric includes subcutaneous injection, intravenous, intramuscular, intrasternal injection, or infusion techniques. The pharmaceutical compositions of the present invention are formulated to allow the bioavailability of the contained clean components after administration to a patient. The composition to be administered to an individual or patient may be in the form of one or more dose units, wherein, for example, a tablet may be a single dose unit, while a container containing the compound of the invention in aerosol form may hold multiple dose units. The actual methods for preparing the dosage form are known to, or will be known to, those skilled in the art. The composition to be administered will in any case contain a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof, in order to treat the disease or condition of interest according to the teachings of the invention.

[0023] The pharmaceutical compositions of the present invention can be in solid or liquid form. On one hand, the carrier is a microparticle, so that the composition is in the form of, for example, tablets or powders. The carrier can be a liquid, and the composition is, for example, an oral syrup, an injectable liquid, or an aerosol suitable for, for example, inhalation. When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, wherein semi-solid, semi-liquid, suspension, and gel forms are included in forms considered solid or liquid herein. For oral solid compositions, the pharmaceutical composition can be formulated into powders, granules, compressed tablets, pills, capsules, chewable tablets, powder tablets, etc. Such solid compositions typically contain one or more inert diluents or edible carriers. In addition, one or more of the following substances may be present: binders, such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, yellow tartar glue, or gelatin; excipients, such as starch, lactose, or dextrin; disintegrants, such as alginate, sodium alginate, Primogel, corn starch, etc.; lubricants, such as magnesium stearate or hydrogenated vegetable oil (Sterotex); flow aids, such as colloidal silica; sweeteners, such as sucrose or saccharin; flavoring agents, such as peppermint, methyl salicylate, or sweet orange flavoring; and coloring agents.

[0024] In preparing compositions for oral administration, any common pharmaceutical medium can be used, such as water, glycols, oils, alcohols, etc., in the case of oral liquid compositions (e.g., suspensions, syrups, free radicals, emulsions, and solutions); or solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc., in the case of solid compositions. For parenteral compositions, the carrier will typically consist of at least predominantly sterile water, but other components such as solubilizers, emulsifiers, or additional adjuvants may be added. Injectable solutions can be prepared in which the carrier includes physiological saline, glucose solution, or a mixture of both. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents, etc., can be used. Solid formulations intended to be converted into liquid form shortly before use are also included, such as powders for reconstitution.

[0025] When the pharmaceutical composition is in capsule form, such as a gelatin capsule, it may contain a liquid carrier, such as polyethylene glycol or oil, in addition to the substances described above. The pharmaceutical composition may be in liquid form, such as a tincture, syrup, solution, emulsion, or suspension. This liquid may be administered orally or by injection, as two examples. When intended for oral administration, the composition preferably contains one or more of the following in addition to the compounds of the present invention: a sweetener, a preservative, a dye / coloring agent, and a flavor enhancer. In compositions intended for injection, one or more of the following may be included: a surfactant, a preservative, a wetting agent, a dispersant, a suspending agent, a buffer, a stabilizer, and an isotonic agent.

[0026] Regardless of whether it is a solution, suspension, or other similar form, the liquid pharmaceutical composition of the present invention may include one or more of the following adjuvants: a sterile diluent, such as water for injection, physiological saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, non-volatile oils (e.g., synthetic mono- or diglycerides, which can be used as solvents or suspension media), polyethylene glycol, glycerol, propylene glycol, etc.; an antibacterial agent, such as benzyl alcohol or methylparaben; an antioxidant, such as ascorbic acid or sodium bisulfite; a chelating agent, such as ethylenediaminetetraacetic acid; a buffer, such as acetate, citrate, or phosphate; and a tonic agent, such as sodium oxide or dextran. Enteral preparations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

[0027] Liquid pharmaceutical compositions of the present invention intended for oral or intestinal administration should contain an amount of the compounds of the present invention to achieve a suitable dosage. Pharmaceutical compositions of the present invention may be intended for topical administration, in which case the carrier preferably comprises a solution, emulsion, ointment, or gel matrix. For example, this matrix may comprise one or more of the following: paraffin oil, lanolin, polyethylene glycol, beeswax, mineral oil, diluents (e.g., water and alcohol), and emulsifiers and stabilizers. Thickeners may be present in pharmaceutical compositions intended for topical administration. If intended for transdermal administration, the composition may comprise a transdermal patch or an iontophoresis device.

[0028] The pharmaceutical compositions of this invention can be administered rectally, for example in suppository form, where they melt in the rectum and release the drug. The compositions for rectal administration may contain an oily matrix as a suitable non-irritating excipient. The matrix includes (but is not limited to) lanolin, cocoa butter, and polyethylene glycol.

[0029] The pharmaceutical compositions of the present invention may include various substances in physical form that alter the dosage units of solids or liquids. For example, the composition may include a substance that forms a coating around the active ingredient. The substance forming the coating is generally inert and may be selected from, for example, sugars, shellac, and other enteric coatings. Alternatively, the active ingredient may be encapsulated in a gelatin capsule.

[0030] Pharmaceutical compositions of the present invention in solid or liquid form may include an agent that binds to and thereby facilitates the delivery of the compound. Suitable agents with this capability include monoclonal or polyclonal antibodies, proteins, or liposomes.

[0031] The pharmaceutical compositions of the present invention can consist of dosage units that can be administered in aerosol form. The term aerosol is used to refer to a variety of systems, ranging from gel-like forms to systems consisting of pressurized packaging. Delivery can be carried out by liquefied or compressed gas, or by a suitable pump system dispensing the active ingredient. The aerosols of the compounds of the present invention can be delivered in a single-phase, two-phase, or three-phase system to deliver the active ingredient. Aerosol delivery includes necessary containers, initiators, valves, sub-containers, etc., which together form a kit. Preferred aerosols can be determined by those skilled in the art without extensive experimentation.

[0032] The pharmaceutical compositions of the present invention can be prepared using methods well-known in the pharmaceutical industry. For example, a pharmaceutical composition intended for injection can be prepared by combining the compounds of the present invention with sterile distilled water to form a solution. Surfactants can be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compounds of the present invention, thereby promoting the dissolution or homogeneous suspension of the compounds in an aqueous delivery system. A solution can be formed by combining the compounds of the present invention with an acceptable solvent or medium, such as water, Ringer's solution, or isotonic sodium chloride solution. The sterile injectable formulation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream by local large-volume injection. Alternatively, it is preferable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the DeltecCADD-PLUS™ 5400 intravenous infusion pump.

[0033] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral-acceptable, non-toxic diluents or solvents. Furthermore, sterile fixative oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil may be used. Additionally, fatty acids may also be used to prepare injectable formulations.

[0034] The compounds, salts, and pharmaceutically acceptable compositions of the present invention can be used in combination therapies, i.e., said compounds, salts, and pharmaceutically acceptable compositions can be administered simultaneously, before, or after one or more other desired therapeutic agents or medical procedures. The specific combination of therapies (therapeutic agents or procedures) employed in a combination regimen will take into account the compatibility of the desired therapeutic agents and / or procedures and the desired therapeutic effect to be achieved. It should also be understood that the therapies employed may achieve the desired effect on the same condition (e.g., the compounds of the present invention may be administered simultaneously with another agent for treating the same condition), or they may achieve different effects (e.g., control of any adverse reactions).

[0035] As used herein, an additional therapeutic agent typically administered for the treatment or prevention of a particular disease or condition is referred to as “suitable for the disease or condition being treated.” For example, other exemplary therapeutic agents include, but are not limited to: non-opioid analgesics (indoles, such as etodolac, indomethacin, sulindac, tolmetin; naphthylalkanones, such as nabumetone; oxicams, such as piroxicam; para-aminophenol derivatives, such as acetaminophen; propionic acid, such as fenofofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprazine; salicylates, such as aspirin, choline magnesium trisalicylate). trisalicylate, diflunisal; fenamates, such as meclofenamic acid, mefenamic acid; and pyrazoles, such as phenylbutazone; or opioid (anesthetic) agonists (such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine). The compounds include enorphine, butorphanol, dezocine, nalbuphine, and pentazocine. Alternatively, non-pharmacological analgesic methods can be used in conjunction with the administration of one or more compounds of the present invention. For example, anesthetic (spinal infusion, nerve block), neurosurgical (neurolysis of the CNS pathway), neurostimulation (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiological (physiotherapy, orthopedic devices, diathermy), or psychological (cognitive methods—hypnosis, biofeedback, or behavioral methods) methods can also be used.

[0036] The compounds of the present invention or their pharmaceutically acceptable salts are administered in therapeutically effective amounts, which will vary depending on a variety of factors, including the activity of the particular compound used; the metabolic stability and duration of action of the compound; the patient's age, weight, general health status, sex, and diet; the administration pattern and timing; the rate of excretion; the combination of drugs; the severity of the particular disease or symptom; and the individual receiving the therapy.

[0037] The compounds of the present invention or pharmaceutically acceptable salts thereof may also be administered concurrently with, before, or after administration of one or more other therapeutic agents. This combination therapy includes administration of a single pharmaceutical formulation containing the compound of the present invention and one or more other active agents, as well as administration of separate pharmaceutical formulations containing the compound of the present invention and each active agent individually. For example, the compound of the present invention and another active agent may be administered to the patient as a single oral composition (e.g., tablets or capsules), or each agent may be administered as a separate oral formulation. In the case of using separate formulations, the compound of the present invention and one or more additional active agents may be administered substantially at the same time (i.e., simultaneously) or at separately staggered times (i.e., sequentially); combination therapy should be understood to include all of these options.

[0038] The compounds and salts of the present invention, or pharmaceutically acceptable compositions thereof, can also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents, and catheters. Thus, in another aspect, the present invention comprises compositions for coating implantable devices comprising the compounds or salts of the present invention as generally described above, as well as the classes and subclasses herein, and carriers suitable for coating said implantable devices. Still in another aspect, the present invention comprises implantable devices coated with compositions comprising the compounds or salts of the present invention as generally described above, as well as the classes and subclasses herein, and carriers suitable for coating said implantable devices. The coating is typically a biocompatible polymeric material, such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be further coated with a suitable topcoat of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid, or combinations thereof to impart controlled-release properties to the composition.

[0039] As a general guideline, the active compounds disclosed herein are preferably administered in unit dose form, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compounds or compositions may be expressed as tablets, capsules, sachets, bottled liquids, powders, granules, lozenges, suppositories, regenerated powders, or liquid formulations. Suitable unit doses may range from 0.1 to 1000 mg.

[0040] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients, wherein the excipients are selected from the following components: fillers (diluents), binders, wetting agents, disintegrants, or excipients, etc. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0041] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0042] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients. The tablets contain the active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0043] This invention relates to tetrahydrofuran carboxamide derivatives and their prodrugs and their deuterated compounds as shown in this application, and pharmaceutical compositions containing the same, as well as a method of using the composition to inhibit a voltage-gated sodium channel in a subject, wherein the voltage-gated sodium channel is Nav1.8.

[0044] The present invention is characterized by compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in treating subjects with acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, plastic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy, epileptic symptoms, neurodegenerative diseases, mental disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, and irritable bowel syndrome of the central nervous system. Pathological pain, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, hernia repair pain, bunion removal pain, or abdominoplasty pain), cancer pain, including chronic and breakthrough cancer pain, stroke (e.g., post-stroke central nervous system pathological pain), and more. Whiplash injury-related conditions, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteogenesis imperfecta, polymyalgia rheumatica, pyoderma gangrenosa, chronic widespread pain, diffuse idiopathic osteophyte formation, intervertebral disc degeneration / hernia pain, radiculopathy, facet joint syndrome, syndrome of failed back surgery, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, intervertebral discitis, transverse myelitis, Ehlers-Donlow syndrome, Fabry disease Mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, vertebral detachment, vertebral displacement, chemotherapy-induced stomatitis, Charcot neuropathic osteoarthritis, temporomandibular joint disorders, painful arthroplasty, non-cardiac chest pain, genital pain, renal colic, biliary tract disease, vascular leg ulcers, pain from Parkinson's disease, pain from Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or methods to reduce the severity of gastrointestinal motility disorders.

[0045] On the other hand, the present invention is characterized in that the compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof are used to treat subjects with femoral cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic lower back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, pancreatic pain, IBS pain, chronic and acute headaches, migraines, tension headaches, cluster headaches, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal neuralgia, and Charcot-Marie-Tooth disease. Disease), hereditary sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal and distal discharges, nerve root lesions, chemotherapy-induced neuropathic pain, radiation-induced neuropathic pain, persistent / chronic postoperative pain (e.g., after amputation, after thoracotomy, after cardiac surgery), post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom limb pain (e.g., after amputation of the lower limb, upper limb, or breast), intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, joint pain, mechanical lower back pain, neck pain, tendinitis, injury pain, movement pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic, acute labor pain, labor pain, cesarean section pain, acute inflammation Pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, oral and facial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behcet's disease pain, painful obesity, phlebitis pain, Guillain-Barré syndrome pain, leg and toe pain, Haglund syndrome, erythromelalgia, Fabry disease pain, bladder and genitourinary disorders, urinary incontinence, pathological cough, overactive bladder, bladder pain syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, generalized pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain or methods to reduce its severity.

[0046] On the other hand, the present invention is characterized by the use of the compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof for treating subjects with trigeminal neuralgia, migraine treated with botulinum toxin, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus lesions, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, iliolingual neuralgia, pudendal neuralgia, femoral neuropathy, paresthesia of the femoral nerve, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexus lesions, traumatic neuroma stump pain, or post-amputation pain, or by reducing the severity thereof.

[0047] A method for treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or arrhythmia in a subject, said method comprising administering to the subject an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0048] Treat the subject for or reduce the severity of any of the following: one or more of the following neuropathic pain, optionally one or more of postherpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy, or diabetic neuropathy; musculoskeletal pain, optionally osteoarthritis pain; acute pain, acute postoperative pain; postoperative pain, optionally one or more of the following: bunion excision pain, abdominoplasty pain, or hernia repair pain; or visceral pain.

[0049] The compounds provided by this invention possess advantages such as high metabolic stability, high oral absorption, superior bioavailability, better activity, higher selectivity, better pharmacokinetic properties, faster onset of action, and lower side effects and central nervous system side effects. Therefore, the compounds of this invention have excellent pharmaceutical properties.

[0050] Unless otherwise specified, all reagents and raw materials used in this invention are commercially available.

[0051] Unless otherwise specified, the compounds of this invention are named manually or using chemical structure software, and commercially available compounds are named according to the supplier's catalog.

[0052] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention. Detailed Implementation

[0053] Certain preferred embodiments of the present invention are illustrated in the following non-limiting examples. Experimental methods not specifically described in the following examples are performed according to conventional methods and conditions, or as selected according to the trade instructions. Raw materials may be commercially available, or prepared by methods known in the art, or according to the methods described herein.

[0054] Example 1.

[0055] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(2-methoxyethoxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridineamide

[0056] The synthesis route is as follows:

[0057] Preparation of intermediate 5:

[0058] It was prepared from ethyl 2-diaza-3-oxovalerate (intermediate 1) using the method disclosed in Example 3 on page 231 of patent application "WO2021113627". Intermediate 5:

[0059] 1 ¹H NMR (400MHz, chloroform-d) δ 6.89–6.80 (m, 2H), 4.18–4.10 (m, 2H), 3.91 (s, 3H), 3.77–3.46 (m, 1H), 1.68 (s, 3H), 1.14 (t, 3H), 1.07 (dd, 3H) ppm, ESI-MS m / z 381.02 [M+1] + .

[0060] Preparation of intermediate 6:

[0061] Intermediate 5 (220 g, 486 mmol) was dissolved in DCM (600 mL), stirred, and cooled to 0 °C. BBr3 (740 mL, 1 M, 370.0 mmol) solution was added dropwise, and the reaction was stirred. The reaction was quenched by adding sodium bicarbonate aqueous solution at 0 °C. The mixture was extracted with DCM, dried over anhydrous NaSO4, and concentrated under reduced pressure. The product was dissolved in DCM (800 mL), and trifluoroacetic acid (80 mL, 1038 mmol) was added dropwise. The reaction mixture was then heated to 45 °C. After the reaction was complete, sodium bicarbonate aqueous solution was added to quench the reaction, followed by extraction with DCM, drying over anhydrous NaSO4, and concentration under reduced pressure to obtain the desired product in the mixture of diastereomers. The crude DCM-heptane was recrystallized twice, filtered, and dried to obtain 124 g of solid as intermediate 6. ESI-MS m / z 321.5 [M+1] + .

[0062] Preparation of intermediate 7:

[0063] In a hydrogenation reactor, a MeOH suspension of intermediate 6 (90 g, 281.07 mmol) in 1800 mL was added, followed by a MeOH suspension of Pd(OH)₂ (185.5 g, 20% w / w, 58.2 mmol) in 400 mL. The reactor was pressurized with hydrogen and stirred at 60 psi for 8 hours. The reaction was monitored by TCL to ensure complete reaction. The suspension was filtered through diatomaceous earth under a nitrogen atmosphere, washed with MeOH and EtOAc, and the filtrate was concentrated under reduced pressure to obtain intermediate (91.2 g).

[0064] The above intermediate (91.2 g, 257.4 mmol) was dissolved in THF (1000 mL), and the solution was cooled to 0 °C. Potassium tert-butoxide (97.6 g, 869.6 mmol) was added in portions. The reaction mixture was stirred at 0 °C for 10 min, then heated to 10 °C and stirred for 1 hr. After cooling to 5 °C, 2 M HCl was added to adjust the pH to 1. Water was added, and the mixture was extracted with EtOAc. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure to give intermediate 7 (78.3 g). 1 ¹H NMR (400MHz, methanol-d⁴) δ 6.98 (m, 1H), 6.67 (m, 1H), 4.96 (m, 1H), 4.16 (m, 1H), 2.80 (m, 1H), 1.57 (m, 3H), 0.75 (m, 3H) ppm. ESI-MS m / z 339.0 [M⁻¹] - .

[0065] Preparation of intermediate 8:

[0066] 1-Bromo-2-(2-methoxyethoxy)ethane (54.5 g, 298.0 mmol) was dissolved in 200 mL of acetonitrile, and added dropwise to a suspension of intermediate 7 (20 g, 58.8 mmol) and cesium carbonate (96 g, 298.0 mmol) in 800 mL of acetonitrile. The mixture was stirred at 70 °C for 24 h, filtered, and concentrated under reduced pressure to obtain the intermediate, which was then used directly in the next step of the reaction.

[0067] The above intermediate was dissolved in ethanol (600 mL), and 2 M LiOH solution (30 mL, 60 mmol) was added dropwise. The mixture was stirred at room temperature for 8 hours. Acidification was achieved by adding 3 M HCl in MeOH (20 mL), followed by filtration and concentration under reduced pressure to obtain intermediate 8 (18.1 g). ESI-MS m / z 441.1 [M⁻¹] - .

[0068] Preparation of compound 1:

[0069] Intermediate 8 (2.2 g, 5 mmol) was dissolved in 20 mL of DCM, cooled to 2 °C, and oxaloyl chloride (2.2 mL, 25 mmol) and DMF (35.5 μL, 0.5 mmol) were added dropwise to the reaction solution. The mixture was stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, and then 10 mL of DCM was added for further concentration under reduced pressure. The concentrate was dissolved in 20 mL of DCM and added dropwise at room temperature to a DCM solution of methyl 4-aminopyridinecarboxylate (1.15 g, 7.62 mmol), DMAP (35.6 mg, 0.3 mmol), and Et3N (2.2 mL, 15.5 mmol). The mixture was stirred for 8 hr, concentrated under reduced pressure, and extracted with water using DCM. The extract was dried over anhydrous sodium sulfate. The solution was purified by rapid silica gel column chromatography with a methanol-dichloromethane gradient elution to obtain the intermediate, which was used directly in the next reaction.

[0070] The above intermediate was dissolved in methanol-ammonia (38.5 mL, 7 M, 269.2 mmol), and the mixture was stirred at room temperature for 24 h. The reaction solution was concentrated under reduced pressure and purified by reversed-phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) to give 1.3 g of compound 1. 1 H NMR (400MHz, chloroform-d) δ8.85(s,1H),8.41(m,1H),8.14(m,1H),7.94(m,1H),7.81(m,1H),7.08(m,1H),6.89(m,1H),5.76(m ,1H),4.98(m,1H),4.38-4.11(m,3H),3.77-3.40(m,6H),3.24(s,3H),2.84(m,1H),1.68(s,3H),0.76(m,3H)ppm.ESI-MS m / z 562.5[M+1] + .

[0071] Example 2.

[0072] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(2-hydroxyethoxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridineamide

[0073] The synthesis route is as follows:

[0074] Preparation of intermediate 9:

[0075] In a hydrogenation reactor, a MeOH suspension of intermediate 6 (90 g, 281.07 mmol) in 1800 mL was added, followed by a MeOH suspension of Pd(OH)₂ (185.5 g, 20% w / w, 58.2 mmol) in 400 mL. The reactor was pressurized with hydrogen and stirred at 60 psi for 8 hours. The reaction was monitored by TCL to ensure complete reaction. The suspension was filtered through diatomaceous earth under a nitrogen atmosphere, washed with MeOH and EtOAc, and the filtrate was concentrated under reduced pressure to obtain intermediate 9 (91.2 g).

[0076] Preparation of intermediate 10:

[0077] Under nitrogen protection and at room temperature, intermediate 9 (2 g, 5.64 mmol) was dissolved in 20 mL of acetonitrile. Potassium carbonate (4 g, 28.8 mmol) was added, followed by the addition of methyl iodoform (3.7 g, 26 mmol) in portions. The mixture was stirred for 24 hours. MTBE was added, and the mixture was filtered through diatomaceous earth. The filtrate was washed with MTBE, and the filtrate was concentrated under reduced pressure to obtain intermediate 10 (1.8 g) as a solid. ESI-MS m / z 369.1 [M+1] + .

[0078] Preparation of intermediate 11:

[0079] Under nitrogen protection and at room temperature, intermediate 10 (49 g, 133 mmol) was dissolved in 500 ml THF, and sodium methoxide (30% methanol solution, 3.2 mL, 14 mmol) was added to the reaction solution. The mixture was stirred for 4.5 hours.

[0080] Add 50 mL of MeOH-50 mL of water solution dropwise to the reaction mixture, stir for 30 min, then add lithium hydroxide monohydrate (8.4 g, 200 mmol), and stir for 8 h. After the reaction is complete as detected by TLC, add 1 M hydrochloric acid (220 mL), extract with MTBE, wash the organic layer with saturated NaCl, dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure. Dissolve the residue in toluene (4 L) and concentrate under vacuum, then dissolve in MTBE (4 L) and concentrate again under vacuum to obtain oily intermediate 11, which can be used directly in the next reaction.

[0081] Preparation of intermediate 12 (control compound CP):

[0082] Intermediate 11 (1.8 g, 5 mmol) was dissolved in 20 mL of DCM, cooled to 2 °C, and oxaloyl chloride (2.2 mL, 25 mmol) and DMF (35.5 μL, 0.5 mmol) were added dropwise to the reaction solution. The mixture was stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, and then 10 mL of DCM was added for further concentration under reduced pressure. The concentrate was dissolved in 20 mL of DCM and added dropwise at room temperature to a DCM solution of methyl 4-aminopyridinecarboxylate (1.15 g, 7.62 mmol), DMAP (35.6 mg, 0.3 mmol), and Et3N (2.2 mL, 15.5 mmol). The mixture was stirred for 8 hr, concentrated under reduced pressure, and extracted with water using DCM. The extract was dried over anhydrous sodium sulfate. The solution was purified by rapid silica gel column chromatography with a methanol-dichloromethane gradient elution to obtain the intermediate, which was used directly in the next reaction.

[0083] The above intermediate was dissolved in methanol-ammonia (38.5 mL, 7 M, 269.2 mmol), and the reaction mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and EtOAc (10 mL) was added. The mixture was heated to 60 °C to dissolve the intermediate. The solution was cooled to 50 °C, and 6 mL of heptane was added dropwise to give 1.0 g of intermediate 12. ESI-MS m / z 474.4 [M+1] + .

[0084] Preparation of intermediate 13:

[0085] Intermediate 12 (3.4 g, 7.08 mmol) was dissolved in DCM (70 mL), stirred, and cooled to 0 °C. BBr3 (10 mL, 1 M, 10 mmol) solution was added dropwise, and the reaction was stirred for 12 hours. The reaction was quenched by adding sodium bicarbonate aqueous solution at 0 °C. Extraction was performed with DCM, and the organic layer was dried over anhydrous NaSO4 and concentrated under reduced pressure. Purification was achieved by rapid silica gel column chromatography with ethyl acetate-petroleum ether gradient elution to give intermediate 13 (2.2 g). ESI-MS m / z 458.8 [M⁻¹] - .

[0086] Preparation of compound 2:

[0087] Intermediate 13 (0.4 g, 0.9 mmol) and cesium carbonate (1 g, 3 mmol) suspension were added to acetonitrile (120 mL). (2-(2-bromoethoxy)ethoxy)-tert-butyl-dimethylsilane (0.53 g, 1.86 mmol) dissolved in 10 mL of acetonitrile was added dropwise to the above reaction solution. The mixture was stirred at 65 °C for 12 h, concentrated under reduced pressure to obtain the intermediate, and 50 mL of THF was added. TBAF (20 mL, 1 M THF solution) was added to the above solution, and the mixture was stirred for 2 h. The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with DCM. The organic layer was concentrated under reduced pressure and purified by reversed-phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) to give 0.2 g of compound 2. 1 H NMR (400MHz, chloroform-d) δ8.86(s,1H),8.42(m,1H),8.09(m,1H),7.95(m,1H),7.08(m,1H),6.90(m,1H),4.99(m,1H ),4.38-4.05(m,6H),3.85(s,2H),2.76(m,1H),2.36(s,1H),1.66-1.56(m,3H),0.76-0.72(m,3H)ppm.ESI-MS m / z 548.2[M+1] + .

[0088] Example 3.

[0089] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridineamide

[0090] The synthesis route is as follows:

[0091] Preparation of intermediate 18:

[0092] Under nitrogen protection, dissolve 145 mL of isopropyl magnesium chloride (290 mmol in 2 M THF) in 150 mL of THF, heat to 40 °C, and add 28 g (117 mmol) of 6-bromo-2,3-difluoroanisole in portions, stirring for 30 min. Cool the reaction solution to 0 °C, and add dropwise a solution of 46 mL (410 mmol) of tripentyl borate in 100 mL of THF. Adjust the pH to 1 with 2 N hydrochloric acid, extract with DCM, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Add n-hexane and stir thoroughly to obtain the solid intermediate 18 (15 g).

[0093] Preparation of intermediate 4:

[0094] It was prepared using ethyl 2-diaza-3-oxovalerate (intermediate 1) as the raw material, according to the method disclosed in Example 3 on page 231 of the specification of patent application "WO2021113627".

[0095] Preparation of intermediate 14:

[0096] Under a nitrogen atmosphere, intermediate 4 (78 g, 201.93 mmol) was dissolved in 400 mL of toluene. Intermediate 18 (45.6 g, 223.5 mmol) was added to the solution, and the mixture was stirred. K3PO4 (300 mL, 2 M, 600 mmol) was then added, followed by tetrakis(triphenylphosphine)palladium(0) (12 g, 10.38 mmol). The mixture was heated to 100 °C and stirred for 3 hours. The reaction was quenched with water, extracted with EtOAc, and the combined organic layers were concentrated under reduced pressure. The mixture was then purified by rapid silica gel column chromatography with an EtOAc / petroleum ether gradient elution to give intermediate 14 (72 g). ESI-MS m / z 397.1 [M+1] + .

[0097] Preparation of intermediate 15:

[0098] Intermediate 14 (11 g, 24.3 mmol) was dissolved in DCM (30 mL), stirred, and cooled to 0 °C. BBr3 (37 mL, 1 M, 18.5 mmol) solution was added dropwise, and the reaction was stirred. The reaction was quenched by adding sodium bicarbonate aqueous solution at 0 °C. The mixture was extracted with DCM, dried over anhydrous NaSO4, and concentrated under reduced pressure. The product was dissolved in DCM (40 mL), and trifluoroacetic acid (4 mL, 52 mmol) was added dropwise. The reaction mixture was then heated to 45 °C. After the reaction was complete, sodium bicarbonate aqueous solution was added to quench the reaction, followed by extraction with DCM, drying over anhydrous NaSO4, and concentration under reduced pressure to obtain the desired product in the mixture of diastereomers. The crude DCM-heptane was recrystallized twice, filtered, and dried to obtain 5.5 g of solid as intermediate 15. ESI-MS m / z 337.0 [M+1] + .

[0099] Preparation of intermediate 16:

[0100] In a hydrogenation reactor, a MeOH suspension of intermediate 15 (9.4 g, 28.11 mmol) in 180 mL was added, followed by a MeOH suspension of Pd(OH)2 (18.6 g, 20% w / w, 5.82 mmol) in 40 mL. The reactor was pressurized with hydrogen and stirred at 60 psi for 4 hours. Then, Pd(OH)2 (18.6 g, 20% w / w, 5.82 mmol) was added, and the reactor was pressurized with hydrogen and stirred at 80 psi for another 4 hours. The reaction was monitored by TCL to ensure complete reaction. The suspension was filtered through diatomaceous earth under a nitrogen atmosphere, washed with MeOH and EtOAc, and the filtrate was concentrated under reduced pressure to obtain intermediate 16 (8.3 g).

[0101] Preparation of intermediate 17:

[0102] Under nitrogen protection and at room temperature, intermediate 16 (1 g, 2.82 mmol) was dissolved in 15 mL of acetonitrile. Potassium carbonate (2 g, 14.4 mmol) was added, followed by the addition of methyl iodoform (1.85 g, 13 mmol) in portions. The mixture was stirred for 24 hours. MTBE was added, and the mixture was filtered through diatomaceous earth. The filtrate was washed with MTBE, and the filtrate was concentrated under reduced pressure to obtain intermediate 17 (0.9 g) as a solid. ESI-MS m / z 385.1 [M+1] + .

[0103] Preparation of compound 3:

[0104] Under nitrogen protection and at room temperature, intermediate 17 (5.1 g, 13.3 mmol) was dissolved in 50 mL of THF, and sodium methoxide (30% methanol solution, 0.32 mL, 1.3 mmol) was added to the reaction solution. The mixture was stirred for 5 hours.

[0105] Add 5 ml of MeOH-5 ml of water solution dropwise to the reaction mixture, stir for 30 min, then add lithium hydroxide monohydrate (0.84 g, 20 mmol), and stir for 8 h. After the reaction is complete as detected by TLC, add 1 M hydrochloric acid (20 ml), extract with MTBE, wash the organic layer with saturated NaCl, dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure. Dissolve the residue in toluene and concentrate under vacuum, then dissolve it in MTBE and concentrate again under vacuum to obtain an intermediate, which can be used directly in the next reaction.

[0106] The intermediate from the previous step (1.9 g, 5 mmol) was dissolved in 20 mL of DCM, cooled to 2 °C, and oxaloyl chloride (2.2 mL, 25 mmol) and DMF (35.5 μL, 0.5 mmol) were added dropwise to the reaction solution. The mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and then 10 mL of DCM was added for further concentration under reduced pressure. The concentrate was dissolved in 20 mL of DCM and added dropwise at room temperature to a DCM solution of methyl 4-aminopyridinecarboxylate (1.15 g, 7.62 mmol), DMAP (35.6 mg, 0.3 mmol), and Et3N (2.2 mL, 15.5 mmol) in 40 mL of DCM. The mixture was stirred for 8 hours, concentrated under reduced pressure, and extracted with water using DCM. The extract was dried over anhydrous sodium sulfate. The solution was purified by rapid silica gel column chromatography with methanol-dichloromethane gradient elution to obtain the intermediate, which was used directly in the next reaction.

[0107] The intermediate from the previous step was dissolved in methanol-ammonia (38.5 mL, 7 M, 269.2 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and EtOAc (10 mL) was added. The mixture was heated to 60 °C to dissolve the solid. The solution was cooled to 50 °C, and 6 mL of heptane was added dropwise. The solid precipitated and was purified by reversed-phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) to give 0.9 g of compound 3. 1 ¹H NMR (400MHz, methanol-d⁴) δ 8.81 (m, 1H), 8.57 (m, 1H), 8.21 (m, 1H), 7.46–7.20 (m, 2H), 5.12 (m, 1H), 4.56 (m, 1H), 3.14 (m, 1H), 2.78 (m, 3H), 1.93 (m, 3H), 0.91 (m, 3H) ppm. ESI-MS m / z 490.2 [M+1] + .

[0108] Example 4.

[0109] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylsulfoxide)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridineamide

[0110] The synthesis route is as follows:

[0111] Preparation of compound 4:

[0112] Compound 3 (1 g, 2 mmol) was dissolved in 15 mL of THF, and cyanuric chloride (0.15 g, 0.8 mmol) and H₂O₂ (0.2 g, 35%, 2 mmol) were added. The mixture was stirred at room temperature for 1.5 hr, then NaHCO₃ solution was added, and the mixture was extracted with DCM and dried over anhydrous sodium sulfate. The solution was purified by rapid silica gel column chromatography with a methanol-dichloromethane gradient elution to give 0.6 g of compound 4. ESI-MS m / z 506.2 [M+1] + .

[0113] Example 5.

[0114] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridineamide

[0115] The synthesis route is as follows:

[0116] Preparation of compound 5:

[0117] Intermediate 13 (0.4 g, 0.9 mmol) and cesium carbonate (1 g, 3 mmol) suspension were added to acetonitrile (120 mL). (S)-3-iodotetrahydrofuran (0.37 g, 1.86 mmol) was dissolved in 10 mL of acetonitrile and added dropwise to the above reaction solution. The mixture was stirred at 65 °C for 12 h, concentrated under reduced pressure to obtain the intermediate, and 50 mL of THF was added. TBAF (20 mL, 1 M THF solution) was added to the above solution, and the mixture was stirred for 2 h. The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with DCM. The organic layer was concentrated under reduced pressure and purified by reversed-phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) to obtain 0.22 g of compound 5. 1 H NMR (400MHz, chloroform-d) δ8.83(s,1H),8.39(m,1H),8.06(m,1H),7.92(m,1H),7.05(m,1H),6.87(m,1H),4.95(m,1 H),4.35-4.05(m,4H),3.85-3.64(m,2H),2.79-2.21(m,3H),1.64-1.55(m,3H),0.78-0.70(m,3H)ppm.ESI-MS m / z 530.2[M+1] + .

[0118] Example 6.

[0119] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridineamide

[0120] The synthesis route is as follows:

[0121] Preparation of compound 6:

[0122] Intermediate 13 (0.4 g, 0.9 mmol) and cesium carbonate (1 g, 3 mmol) suspension were added to acetonitrile (120 mL). (R)-3-iodotetrahydrofuran (0.37 g, 1.86 mmol) was dissolved in 10 mL of acetonitrile and added dropwise to the above reaction solution. The mixture was stirred at 65 °C for 12 h, concentrated under reduced pressure to obtain the intermediate, and 50 mL of THF was added. TBAF (20 mL, 1 M THF solution) was added to the above solution, and the mixture was stirred for 2 h. The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with DCM. The organic layer was concentrated under reduced pressure and purified by reversed-phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) to give 0.20 g of compound 6. 1 ¹H NMR (400MHz, chloroform-d)δ 1 H NMR (400MHz, chloroform-d) δ8.89(s,1H),8.47(m,1H),8.13(m,1H),7.99(m,1H),7.12(m,1H),6.94(m,1H),5.01(m,1 H),4.39-4.06(m,4H),3.89-3.65(m,2H),2.84-2.23(m,3H),1.72-1.61(m,3H),0.84-0.72(m,3H)ppm.ESI-MS m / z 530.2[M+1] + .

[0123] Example 7.

[0124] 4-((2R,3S,4S,5R)-3-(4-fluoro-2,3-dihydrobenzo[b]thiophene-7-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridineamide

[0125] The synthesis route is as follows:

[0126] Preparation of intermediate 19:

[0127] Under nitrogen protection, dissolve magnesium isopropyl chloride (145 mL, 2 M THF, 290 mmol) in 150 mL of THF, heat to 40 °C, and add 1-bromo-4-fluoro-2,3-dihydrobenzo[b]thiophene (27.3 g, 117 mmol) in portions, stirring for 30 min. Cool the reaction solution to 0 °C, and add a solution of tripentyl borate (46 mL, 410 mmol) in 100 mL of THF dropwise. Adjust the pH to 1 with 2 N hydrochloric acid, extract with DCM, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Add n-hexane and stir thoroughly to obtain the solid intermediate 19 (18.3 g).

[0128] Preparation of intermediate 20:

[0129] Under a nitrogen atmosphere, intermediate 4 (15.6 g, 40.39 mmol) was dissolved in 400 mL of toluene. Intermediate 19 (8.85 g, 44.7 mmol) was added to the solution, and the mixture was stirred. K3PO4 (60 mL, 2 M, 120 mmol) was then added, followed by tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2.1 mmol). The mixture was heated to 100 °C and stirred for 3 hours. The reaction was quenched with water, extracted with EtOAc, and the combined organic layers were concentrated under reduced pressure. The mixture was then purified by rapid silica gel column chromatography with an EtOAc / petroleum ether gradient elution to give intermediate 20 (72 g). ESI-MS m / z 391.1 [M+1] + .

[0130] Preparation of intermediate 21:

[0131] Compound 20 (30 g, 76.25 mmol) was dissolved in 100 mL of ethanol. Pd / C (10% loading, 100 g, 94 mmol) was added, and the mixture was purged with hydrogen at room temperature for 10 hours. Pd / C (10% loading, 100 g, 94 mmol) was then added again, and the mixture was purged with hydrogen for another 10 hours. The mixture was filtered through diatomaceous earth, washed with DCM, and extracted with water using DCM. The combined organic layers were concentrated under reduced pressure. The mixture was then purified by rapid silica gel column chromatography with an EtOAc / petroleum ether gradient elution and used directly in the next step.

[0132] The above intermediate (7.8 g, 20 mmol) and potassium tert-butoxide (6.5 g, 58 mmol) were dissolved in tert-butanol (250 mL), and the reaction was stirred for 6 h. The reaction was quenched with saturated NH4Cl aqueous solution, subjected to 2N hydrochloric acid at pH 1, and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The mixture was purified by rapid silica gel column chromatography with an EtOAc / petroleum ether gradient elution to give intermediate 21 (6.1 g). ESI-MS m / z 363.3 [M⁻¹] - .

[0133] Preparation of compound 7:

[0134] Intermediate 21 (3.7 g, 10 mmol) was dissolved in 40 mL of DCM, cooled to 2 °C, and oxaloyl chloride (4.4 mL, 50 mmol) and DMF (71 μL, 1 mmol) were added dropwise to the reaction solution. The mixture was stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, and then concentrated again under reduced pressure by adding 20 mL of DCM. The concentrate was dissolved in 40 mL of DCM and added dropwise at room temperature to a solution of methyl 4-aminopyridinecarboxylate (2.3 g, 14.5 mmol), DMAP (70 mg, 0.6 mmol), and Et3N (4.4 mL, 31 mmol) in DCM (80 mL). The mixture was stirred for 8 hr, concentrated under reduced pressure, and extracted with water using DCM. The extract was dried over anhydrous sodium sulfate. The solution was purified by rapid silica gel column chromatography with methanol-dichloromethane gradient elution to obtain the intermediate, which was used directly in the next reaction.

[0135] The above intermediate was dissolved in methanol-ammonia (77 mL, 7 M, 538 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and EtOAc (20 mL) was added. The mixture was heated to 60 °C to dissolve the intermediate. The solution was cooled to 50 °C, and 12 mL of heptane was added dropwise to obtain the intermediate. The intermediate was purified by reversed-phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) to give 1.5 g of compound 7. 1 ¹H NMR (400MHz, methanol-d⁴) δ 8.85 (m, 1H), 8.62 (m, 1H), 8.26 (m, 1H), 7.51–7.24 (m, 2H), 5.16 (m, 1H), 4.61 (m, 1H), 3.29 (m, 5H), 1.97 (m, 3H), 0.95 (m, 3H) ppm. ESI-MS m / z 484.2 [M+1] + .

[0136] Example 8.

[0137] 4-((2R,3S,4S,5R)-3-(4-fluoro-1-oxo-2,3-dihydrobenzo[b]thiophene-7-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridineamide

[0138] The synthesis route is as follows:

[0139] Preparation of compound 8:

[0140] Compound 7 (1 g, 2 mmol) was dissolved in 15 mL of THF, and cyanuric chloride (0.15 g, 0.8 mmol) and H₂O₂ (0.2 g, 35%, 2 mmol) were added. The mixture was stirred at room temperature for 1.5 hr, then NaHCO₃ solution was added, and the mixture was extracted with DCM and dried over anhydrous sodium sulfate. The solution was purified by rapid silica gel column chromatography with a methanol-dichloromethane gradient elution to give 0.5 g of compound 8. ESI-MS m / z 500.1 [M+1] + .

[0141] Example 9.

[0142] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(2-hydroxyethoxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridineamide

[0143] The synthesis route is as follows:

[0144] Preparation of compound 9:

[0145] Intermediate 13 (0.4 g, 0.9 mmol) and cesium carbonate (1 g, 3 mmol) suspension were placed in acetonitrile (120 mL). 2-Iodo-1,1,1-trifluoroethane (0.39 g, 1.86 mmol) dissolved in 10 mL of acetonitrile was added dropwise to the above reaction solution. The mixture was stirred at 65 °C for 12 h, concentrated under reduced pressure, and the intermediate was obtained. 50 mL of THF was added to the intermediate. TBAF (20 mL, 1 M THF solution) was added to the above solution, and the mixture was stirred for 2 h. The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with DCM. The organic layer was concentrated under reduced pressure and purified by reversed-phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) to give 0.18 g of compound 9. ESI-MS m / z 542.2 [M+1] + .

[0146] Example 1: Determination of Nav1.8 inhibitory activity and ion channel selectivity

[0147] The in vitro test examples investigated the effects of the compounds on the Nav1.8, Nav1.4, and Nav1.6 ion channels. The Nav1.8 ion channel was expressed in HEK293 cells, while the Nav1.4 and Nav1.6 ion channels were expressed in HEK293 or ND7 / 23 cells, respectively. After the Nav1.8 and Nav1.4 / Nav1.6 currents stabilized, the magnitudes of the corresponding ion channel currents before and after compound application were compared to determine the inhibitory activity and selectivity of the compounds on the Nav1.8 ion channel.

[0148] 1. Experimental apparatus

[0149] 1) Patch clamp amplifier: PC-505B (WARNER instruments) / MultiClamp 700A (Axon instruments)

[0150] 2) Digital-to-analog converters: Digidata 1440A (Axon CNS) / Digidata 1550A (Axon Instruments)

[0151] 3) Microcontroller: MP-225 (SUTTER instrument)

[0152] 4) Inverted microscope: TL4 (Olympus)

[0153] 5) Glass microelectrode pulling instrument: PC-10 (NARISHIGE)

[0154] 6) Microelectrode glass capillary: B12024F

[0155] 2. Experimental Procedure

[0156] 2.1 Preparation of experimental compounds and intracellular / extracellular solutions

[0157] All test and control compounds (CP) were dissolved in dimethyl sulfoxide (DMSO) and stored at a concentration of 10 mM. The compound solutions used for Nav1.8 inhibitory activity assays contained 1 μM tetrodotoxin (TTX, Affix Scientific). They were diluted with extracellular fluid, prepared fresh for each use, and diluted to the required concentration using the fractional dilution method.

[0158] Preparation of intracellular and extracellular fluids:

[0159] Intracellular fluid (mM): Aspartic acid, 140; MgCl2, 2; EGTA, 11; HEPES, 10; pH 7.2 (CsOH titration).

[0160] Extracellular fluid (mM): NaCl, 137; KCl, 4; CaCl2, 1.8; MgCl2, 1; HEPES, 10; glucose, 10; pH 7.4 (NaOH titration).

[0161] 2.2 Electrophysiology

[0162] 1) After the compound is prepared into a solution of a specified concentration, add the solution to each pipe in order of increasing concentration and label each pipe.

[0163] 2) Transfer the cells to the perfusion tank, apply positive pressure to the electrode, and bring the electrode tip into contact with the cell. Adjust the three-way valve of the suction device to the three-way position, and then apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cell. Continue to apply negative pressure to rupture the cell membrane and form a current pathway.

[0164] 3) After the cell membrane rupture current stabilizes, perform perfusion at different concentrations sequentially. If the current stabilizes for at least one minute, proceed to the next concentration. The perfusion time for each concentration should not exceed five minutes.

[0165] 4) Clean the perfusion tank. Rinse with the drug solution from high to low concentration, rinsing for 20 seconds for each concentration. Finally, rinse with extracellular fluid for 1 minute.

[0166] 3. Pilot-scale design (resting state)

[0167] Cells were clamped at -80 mV and then depolarized to 10 mV using a square wave lasting 10 milliseconds to obtain Nav1.8, Nav1.4, and Nav1.6 currents. This procedure was repeated every 5 seconds. The maximum current induced by the square wave was detected, and after it stabilized, the test compound was perfused. Once the reaction stabilized, the strength of the blockade was calculated.

[0168] 4. Data Analysis

[0169] Data acquisition and analysis will be performed using pCLAMP10 (Molecular Devices, Union City, CA). Current stability refers to the current changing within a finite range over time. The magnitude of the stable current is used to calculate the effect of the compound at that solubility.

[0170] The inhibitory activity of the compounds in the examples against Nav1.8, Nav1.4, and Nav1.6 was determined by the above experiments, and the measured IC50 values ​​were... 50 Value and SI (Therapeutic Index), SI 1.4 = (Nav1.4 IC) 50 ) / (Nav1.8 IC 50 SI 1.6 = (Nav1.6 IC) 50 ) / (Nav1.8 IC 50 The experimental results are shown in Table 1.

[0171] Table 1: IC50 values ​​of the compounds in the examples for inhibiting Nav1.8 channel activity 50 and the treatment index SI

[0172] The results above show that all tested compounds exhibited relatively high inhibitory effects on Nav1.8 channel activity and high selectivity indices (therapeutic indices). In particular, compounds 3 and 7 showed approximately 10 times the inhibitory effect on Nav1.8 compared to the control compound CP, and the Nav1.4 therapeutic indices of compounds 3 and 7 were greater than 15 times that of the control compound CP; the Nav1.6 therapeutic indices of compounds 1 and 3 were greater than 19 times that of the control compound CP. Nav1.6 is expressed in central nervous system cells, while Nav1.4 is expressed in skeletal muscle cells. While Nav1.6 and Nav1.4 ion channels are not involved in inflammatory pain or neuropathic pain processes, they can cause adverse reactions. Therefore, the compounds in this example can be formulated as pharmaceutical remedies for the prevention / treatment of symptoms / diseases caused by Nav1.8 overexpression, with higher therapeutic indices and lower central nervous system side effects.

[0173] Example 2: Pharmacokinetic Evaluation

[0174] Using SD rats as test animals, the plasma drug concentration at different time points after gavage administration of the compound described in the examples to SD rats was determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in SD rats was investigated, and its pharmacokinetic characteristics were evaluated.

[0175] 1) Test drugs

[0176] Examples: Compound 1, Compound 3 and Compound 7.

[0177] 2) Experimental animals

[0178] Sixteen SD rats were used, divided into four groups of half males and half females. After fasting for one night but with free access to water, the drugs were administered by gavage.

[0179] 3) Drug preparation

[0180] Weigh out a certain amount of each of the compound from the examples, add lysozyme: 5% DMSO + 10% Solutol + 85% physiological saline, and prepare a homogeneous solution of 0.2 mg / mL.

[0181] 4) Administration

[0182] The dosage is 2 mg / kg, and the administration volume is 10.0 mL / kg.

[0183] 5) Operation

[0184] Blood samples of 0.2 mL were collected from the orbital cavity before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours after administration. The samples were placed in EDTA-K2 anticoagulant tubes and centrifuged at 10,000 rpm for 1 minute (4°C). Plasma was separated within 1 hour and stored at -20°C for analysis. The entire process, from blood collection to centrifugation, was performed under ice bath conditions. Patients ate 2 hours after administration.

[0185] Determination of the content of the target compound in the plasma of SD rats after administration of different drug concentrations: Plasma samples from SD rats at various time points after drug administration were taken, diluted 10-fold with acetonitrile solution containing internal standard, vortexed, and centrifuged at 3700 rpm for 10 minutes. The supernatant was mixed with water at a 1:1 ratio, and 0.5 μL of the supernatant was analyzed by LC / MS / MS.

[0186] 6) The results of the pharmacokinetic parameters are shown in Table 2.

[0187] Table 2: Pharmacokinetic parameters of the compounds in the examples in SD rats

[0188] The experiment revealed significant gender differences in metabolic parameters between the control and control compounds, while compounds 1, 3, and 7 showed no significant gender differences. These results indicate that all tested compounds offered superior exposure levels compared to the control compounds. Compound 3C, in particular, showed superior exposure. max It is 1.6 times that of the control compound, and compound 1 AUC 0-t It is 2.2 times that of the control compound. The experimental results show that the compound in the examples has better metabolic parameters, and the metabolic parameters have no gender difference, which means it can be used in a wider range of clinical populations and has higher drug safety.

[0189] Example 3: Efficacy evaluation of a mouse incision pain model

[0190] Using mice as test animals, the efficacy of the compound disclosed herein in a mouse model of incision pain was studied by gavage administration, and its in vivo efficacy was evaluated.

[0191] 1) Modeling:

[0192] Grouping: BALB / c mice were used as experimental animals, with 8 mice per group (half male and half female). Before modeling, 8 mice were randomly selected as the sham-operated group after removing abnormal animals based on baseline pain threshold (PWT). 8 mice were then used in each of the drug-treated groups for surgical modeling. After surgery, the animals were regrouped based on their pre-drug pain threshold (PWT).

[0193] Anesthetized with isoflurane, a 0.5 cm long longitudinal skin incision was made on the left hind foot, approximately 0.2 cm distal to the tibiotalar joint, extending towards the toes. The plantar muscles were dissected, slightly elevated, and then longitudinally incised, taking care not to damage the muscle's origin and insertion. The incision was closed with interrupted horizontal sutures (2 stitches) using 5-0 nylon sutures, serving as the model group and efficacy evaluation group; additionally, healthy normal mice were selected as the normal group.

[0194] 2) Solvent: The solvent used for the compound in the examples and the control compound CP was 5% DMSO + 10% Solutol + 85% Saline.

[0195] 3) Administration method and frequency:

[0196] Model group: The solvent was administered orally once daily.

[0197] Normal group: The solvent was administered orally once daily.

[0198] Experimental group: Oral administration, once daily, dose: 60 mpk.

[0199] 4) Mechanical pain threshold measurement: The mechanical pain threshold was measured before modeling; 2.5 h after modeling, the mechanical pain threshold was measured before drug administration. After the measurement, the drug was administered orally, and the mechanical pain threshold was measured again 2 h after drug administration. The measurement site was inside the surgical incision site. Each animal was measured 3 times, with an interval of 3-5 minutes between each measurement, and the average value was taken. The experimental results are shown in Table 3.

[0200] 5) Data Analysis: The relevant data were organized in GraphPad Prism 6.0 and analyzed using One-way ANOVA. The Tukey test was used to test the significance of differences between groups.

[0201] Table 3: Efficacy results of the compounds in the examples on a mouse model of incision pain.

[0202] The above results demonstrate that the compounds in the examples all exhibit excellent analgesic effects. Furthermore, the analgesic effects of the compounds in the examples are superior to those of the control compound CP. The experimental results indicate that the compounds in the examples offer better analgesic efficacy, lower dosage, and fewer central nervous system side effects compared to existing clinical treatments.

[0203] For those skilled in the art, this disclosure is not limited to the foregoing illustrative embodiments and can be embodied in other specific forms without departing from its essential attributes. Therefore, it is intended that all aspects be considered illustrative rather than restrictive, that references be made to the appended claims rather than the foregoing embodiments, that references be made only to the appended claims and not to the foregoing examples, and that all variations falling within the meaning and scope of claim equivalence are therefore intended to be included herein.

[0204] All patents, patent applications, and references listed in this specification are incorporated herein by reference in their entirety. In case of inconsistencies, this disclosure, including its definitions, will be considered more persuasive.

Claims

1. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by any one of the following structural formulas:

2. A pharmaceutical composition comprising an effective amount of the compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

3. Use of the pharmaceutical composition according to claim 2 or the compound according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of a medicament for treating, preventing or alleviating voltage-gated sodium channel-related diseases.

4. Use according to claim 3; characterized in that, The relevant diseases are selected from chronic pain or acute pain.

5. Use according to claim 3; characterized in that, The relevant diseases are selected from intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, peroneal muscular atrophy, incontinence, pathological cough, or arrhythmia.

6. Use according to claim 3; characterized in that, The relevant diseases are selected from one or more of the neuropathic pain, postherpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy, or diabetic neuropathy.

7. Use according to claim 3; characterized in that, The relevant diseases are selected from musculoskeletal pain, postoperative pain, or visceral pain.

8. Use according to claim 7; characterized in that, The relevant disease, wherein the musculoskeletal pain is selected from osteoarthritis pain.

9. Use according to claim 4; characterized in that, The relevant disease, wherein the acute pain is selected from acute postoperative pain.

10. Use according to claim 7; characterized in that, The relevant diseases, wherein the postoperative pain is selected from pain after bunion excision, pain after abdominoplasty, or pain after hernia repair.

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