Prodrug of compound as sodium channel modulator and use thereof

Abstract

Disclosed in the present invention are a prodrug of a compound as a sodium channel modulator and the use thereof. Specifically, the present invention relates to a prodrug compound of formula I, which prodrug exhibits a good solubility and can be rapidly transformed into active ingredients in vivo. The compound of formula I can be used in the preparation of drugs for treating diseases such as intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence and arrhythmia, and has broad application prospects.

Description

A prodrug of a compound as a sodium channel modulator and its uses Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a prodrug of a compound used as a specific inhibitor of the voltage-gated sodium ion channel subtype Nav1.8 and its uses. Background Technology

[0002] Globally, the cost of pain management reaches $75 billion annually and continues to increase at a rate of 10%-20% per year. However, among the current mainstream analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) have problems such as insufficient analgesic efficacy and significant gastrointestinal side effects, while the addictive nature of opioid analgesics severely limits their clinical use.

[0003] There are nine sodium ion channels in humans, namely Nav1.1–Nav1.9. Nav1.5, Nav1.8, and Nav1.9 are sodium channels insensitive to tetrodotoxin (TTX). Among them, Nav1.8 is an important ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome, and is a highly selective target for pain treatment. Nav1.8 is mainly expressed in small-diameter pain-sensing neurons and participates in the action potentials and rhythmic firing of sensory neurons. Nav1.8 is regulated by inflammatory mediators and is upregulated in a sciatic nerve injury model. Gene knockout and silencing studies of Nav1.8 have shown its involvement in the regulation of neurogenic and inflammatory pain. Because Nav1.8 is mainly confined to pain-sensing neurons, selective Nav1.8 blockers are unlikely to induce the adverse reactions commonly seen with non-selective Nav1.8 blockers. Therefore, research on screening for specific inhibitors targeting Nav1.8 has become a hot topic in the field of pain management.

[0004] Most early Nav1.8 inhibitors were discontinued in preclinical or early clinical stages due to insufficient selectivity, poor pharmacokinetic data, and low bioavailability. VX-548, a Nav1.8 inhibitor developed by Vertex, met the primary endpoints in multiple Phase II and III clinical trials. The FDA recently approved Vertex's rolling submission of a New Drug Application (NDA) for VX-548 for the treatment of moderate to severe acute pain. However, VX-548 has poor solubility, making it difficult to develop into an injectable formulation, and its structure is not suitable for further prodrug modification.

[0005] WO2022121517 discloses a Nav1.8 inhibitor, wherein the preferred compound, namely the compound described in Example 114, can inhibit Nav1.8 with high activity and selectivity and has good oral exposure. However, the compound also has poor solubility, making it impossible to develop into a simple injectable formulation.

[0006] Injectable analgesics are widely used in perioperative analgesia and other fields, with significant clinical demand. However, there are currently few reports on the development of injectable Nav1.8 inhibitors. Therefore, the development of injectable solutions of Nav1.8 inhibitors with high affinity, high specificity, and especially good water solubility has great social and economic value. Summary of the Invention

[0007] The main technical problem solved by this invention is to provide a prodrug of a Nav1.8 inhibitor, which has excellent solubility and can be rapidly converted into the active ingredient in vivo.

[0008] To address the aforementioned technical problems, the present invention provides a compound as shown in Formula I, its stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts:

[0009] Among them, R1 is selected from H + Metal cations, HN + (R2)3;

[0010] Each time R2 appears, it is independently selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 heteroalkyl, and the substituent is selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxyamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ester, acyl, and amide.

[0011] Alternatively, any two R2s together with the nitrogen atom they are attached to form a substituted or unsubstituted five- to twelve-membered ring group containing at least one of C, N, O, or S atoms, and the remaining R2 is selected from unsubstituted, hydrogen-free, substituted or unsubstituted C1-C10 alkyl groups, or substituted or unsubstituted C1-C10 heteroalkyl groups; wherein the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxyamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ester, acyl, carbonyl, and amide groups.

[0012] In the present invention, "two R2s are selected together with the nitrogen attached to them to form a substituted or unsubstituted five- to twelve-membered ring group containing at least one of C, N, O, or S atoms", when the "five- to twelve-membered ring group" is an aromatic group, the remaining R2 is selected as "none"; when the "five- to twelve-membered ring group" is a non-aromatic group, the remaining R2 is selected as hydrogen, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 heteroalkyl group.

[0013] The metal cation is selected from K. + 1 / 2Ca 2+ Na+ 1 / 2Mg 2+ 1 / 2Zn 2+ .

[0014] Furthermore, the metal cation is selected from K + 1 / 2Ca 2+ Na + .

[0015] Furthermore, R1 is selected from a metal cation, wherein the metal cation is selected from Na. + .

[0016] Each time R2 appears, it is independently selected from hydrogen, substituted or unsubstituted C1-C5 alkyl, or substituted or unsubstituted C1-C5 heteroalkyl.

[0017] Furthermore, the substituent is selected from halogen, hydroxyl, amino, carboxyl, and amide groups.

[0018] Furthermore, each occurrence of R2 is independently selected from hydrogen and -(CH2). n OH, -(CH2) m CH(NH2)COOR3; n is selected from 1, 2, 3, 4 or 5; m is selected from 1, 2, 3, 4 or 5; R3 is selected from hydrogen or C1-C5 alkyl groups.

[0019] Furthermore, n is selected from 1, 2, or 3; m is selected from 3, 4, or 5.

[0020] Furthermore, R3 is selected from hydrogen, methyl, or ethyl.

[0021] The present invention also provides a pharmaceutical composition comprising a first therapeutic agent and a pharmaceutically acceptable excipient, wherein the first therapeutic agent is selected from one or more of the aforementioned compounds, their stereoisomers, solvates, hydrates or pharmaceutically acceptable salts.

[0022] This invention also provides the use of the compound of the invention or its stereoisomers, solvates, hydrates, pharmaceutically acceptable salts or eutectics in the preparation of sodium ion channel modulators.

[0023] Furthermore, the sodium ion channel modulator is a drug that inhibits Nav1.8.

[0024] The present invention also provides the use of the said compound, its stereoisomers, solvates, hydrates or pharmaceutically acceptable salts in the preparation of medicaments for the treatment or prevention of pain, pain-related diseases, pruritus, multiple sclerosis, Shama-Tutan syndrome, incontinence, pathological cough or arrhythmia.

[0025] The pain is selected from any one or more diseases including chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, and primary pain.

[0026] Furthermore, 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, neuropathic pain caused by drug therapy, neuropathic pain caused by cancer chemotherapy, neuropathic pain caused by antiretroviral therapy, post-spinal cord injury pain, primary small fiber neuropathy, primary sensory neuropathy, and trigeminal autonomic headache.

[0027] The musculoskeletal pain is selected from one or more of the following: osteoarthritis pain, back pain, cold pain, burn pain, and toothache.

[0028] The inflammatory pain is selected from rheumatoid arthritis pain and / or vulvar pain;

[0029] The primary pain is selected from fibromyalgia.

[0030] Pharmaceutical compositions containing the compounds of the present invention or their stereoisomers, solvates, hydrates, pharmaceutically acceptable salts or eutectics may contain pharmaceutically acceptable excipients.

[0031] The pharmaceutically acceptable excipients described in this invention are a general term for all additional materials in a drug other than the main drug. The excipients should have the following properties: (1) They are non-toxic to the human body and have almost no side effects; (2) They are chemically stable and not easily affected by temperature, pH, storage time, etc.; (3) They have no incompatibilities with the main drug and do not affect the efficacy and quality inspection of the main drug; (4) They do not interact with the packaging materials.

[0032] The excipients in this invention include, but are not limited to, fillers (diluents), lubricants (flow aids or anti-adhesion agents), dispersants, wetting agents, binders, regulators, solubilizers, antioxidants, antibacterial agents, emulsifiers, disintegrants, etc. Binders include syrups, gum arabic, gelatin, sorbitol, astragalus gum, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, or hydroxypropyl methyl cellulose, etc.), gelatin paste, syrup, starch paste, or polyvinylpyrrolidone, etc.; fillers include lactose, powdered sugar, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts (such as calcium sulfate, calcium phosphate, dicalcium phosphate, precipitated calcium carbonate, etc.), sorbitol, or glycine, etc.; lubricants include micronized silica gel, magnesium stearate, talc, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, etc.; disintegrants include starch and its derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, etc.). The ingredients include: pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.; polyvinylpyrrolidone or microcrystalline cellulose, etc.; humectants include sodium dodecyl sulfate, water or alcohol, etc.; antioxidants include sodium sulfite, sodium bisulfite, sodium metabisulfite, dibutylbenzoic acid, etc.; antibacterial agents include 0.5% phenol, 0.3% cresol, 0.5% chlorobutanol, etc.; regulators include hydrochloric acid, citric acid, potassium hydroxide (sodium), sodium citrate and buffers (including sodium dihydrogen phosphate and disodium hydrogen phosphate), etc.; emulsifiers include polysorbate-80, sorbitan, prorhonic F-68, lecithin, soybean lecithin, etc.; solubilizers include Tween-80, bile, glycerin, etc.

[0033] The term "salt" refers to a compound containing both cations and anions, which can be produced by protonation of an acceptable proton site and / or deprotonation of a proton-available site. Notably, protonation of the acceptable proton site results in the formation of a cation-like substance whose charge is balanced by the presence of a physiological anion, while deprotonation of the proton-available site results in the formation of an anionic substance whose charge is balanced by the presence of a physiological cation.

[0034] "Pharmaceutically acceptable salt" means that the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to:

[0035] Acids can form salts by reacting with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, gluconic acid, salicylic acid, benzenesulfonic acid, benzenesulfonic acid, etc.; or with acidic amino acids such as aspartic acid and glutamic acid.

[0036] A base addition salt is formed by reacting with the conjugate base of any of the above inorganic acids, wherein the conjugate base comprises a component selected from Na. + K + Mg 2+ Ca2+ The cationic component in. It should be understood that all pharmaceutically acceptable salts include the same acid addition salts in the solvation form (solvent) or crystalline form (polymorph) as defined herein.

[0037] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0038] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0039] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0040] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0041] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0042] In addition to the active compound, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0043] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0044] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0045] The compounds of this invention can also be used in injectable formulations. The injectable formulation is selected from liquid injections (water injections), sterile powders for injection (powder injections), or tablets for injection (referring to molded or machine-compressed tablets made by aseptic methods, dissolved in water for injection before use, for subcutaneous or intramuscular injection).

[0046] In addition to the aforementioned compounds, the injectable powder also contains at least an excipient. The excipients described in this invention are components intentionally added to the drug. They should not possess pharmacological properties in the amount used; however, excipients may contribute to drug processing, dissolution or release, drug delivery via targeted administration routes, or contribute to stability.

[0047] The term "treatment" as used in this application includes, but is not limited to, curing a patient's disease, reducing the severity of a disease, or slowing the progression of a disease.

[0048] The term "prevention" as used in this application refers to the intervention and defense taken in healthy groups or asymptomatic patients before the onset of a disease, so as to avoid the occurrence of the disease.

[0049] As used in this application, the term "prodrug" refers to a substance that is converted from an inert form of a drug into an active drug (parent drug) in vivo through a chemical or biological reaction.

[0050] Prodrugs are often useful because, in some embodiments, they can be administered or processed more easily than the parent drug. For example, prodrugs are more readily bioavailable via oral administration, while the parent drug is less so. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, after administration in vivo, the prodrug is chemically converted into a biologically, pharmaceutically, or therapeutically more effective form of the compound. In some embodiments, the prodrug is enzymatically metabolized through one or more steps or processes into a biologically, pharmaceutically, or therapeutically active form of the compound. To prepare a prodrug, the active drug is modified such that it will be regenerated after administration in vivo. Prodrugs are designed to alter the metabolic or transport characteristics of the drug, and in some embodiments, are also used to mask side effects.

[0051] As used in this application, the term "metabolite" refers to a compound produced in the body after a subject is given a drug that it requires.

[0052] A functional group isomer that is produced by the rapid movement of an atom in two positions within a molecule is called a tautomer.

[0053] A meso compound molecule contains asymmetric atoms, but has symmetric elements that make the total optical rotation within the molecule zero, i.e., it is optically inactive.

[0054] A racemic mixture is an equimolar mixture of an optically active (see optical isomerism) chiral molecule and its enantiomer.

[0055] Enantiomers are stereoisomers that are the real and mirror images of each other but cannot be superimposed. Enantiomers are optically active, one of which is left-handed and the other is right-handed. Therefore, enantiomers are also called optically active isomers.

[0056] Diastereoisomers are stereoisomers of molecules that have two or more chiral centers and are not mirror images of each other.

[0057] As used in this application, the term "inhibitor" refers to a product that reduces the biological activity of a protein, such as the compound of this invention, which can reduce the activity of the Nav1.8 ion channel, and is therefore a Nav1.8 inhibitor.

[0058] "Metal cations" are positively charged ions formed when a metal atom loses electrons. Common metal cations include Na. + K + NH4 + Mg 2+ Ca 2+ Ba 2+ Al3+ Fe 2+ Fe 3+ Zn 2+ Cu 2+ Ag + wait.

[0059] "Halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0060] "Hydroxy group" refers to -OH.

[0061] "Cyano" refers to -CN.

[0062] "Amino" refers to -NH2.

[0063] "Thiol group" refers to -SH.

[0064] "Nitro" refers to -NO2.

[0065] "Carboxyl group" refers to -alkyl-COOH.

[0066] "Hydroxyamino" refers to -NHOH.

[0067] "Alkyl" refers to an aliphatic hydrocarbon group, specifically a saturated hydrocarbon group. The alkyl part can be a straight-chain alkyl group or a branched alkyl group. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.

[0068] The C1 to Cn1 used in this application include C1 to C2, C1 to C3, C1 to 4 alkyl, C1 to 5 alkyl, C1 to 6 alkyl, C1 to 7 alkyl, C1 to 8 alkyl, C1 to 9 alkyl, ... C1 to Cn1, where n1 is an integer greater than one; the prefix used as a substituent indicates the minimum and maximum number of carbon atoms in the substituent, for example, "C1 to C10 alkyl" refers to a straight-chain or branched alkyl group containing one to ten carbon atoms.

[0069] "Heteroalkyl" refers to an alkyl group containing heteroatoms, including but not limited to O, S, N, P, Si, etc. Heteroalkyl groups include alkoxy groups, such as methoxy (CH3O-), ethoxy (C2H5O-), propoxy (C3H7O-), etc.

[0070] The "amide group" has a chemical structure with the formula -C(O)NHR or -NHC(O)R, where R can be selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc.

[0071] "Ester group" refers to a chemical structure with the formula -COOR, where R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc.

[0072] "Acyl" refers to a chemical structure with the formula -C(O)R, where R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc.

[0073] "Ring" refers to any covalently closed structure, including, for example, carbocyclic (e.g., aryl or cycloalkyl), heterocyclic (e.g., heteroaryl or heterocycloalkyl), aromatic (e.g., aryl or heteroaryl), and non-aromatic (e.g., cycloalkyl or heterocycloalkyl). The "ring" described in this application can be monocyclic or polycyclic, and can be fused, spirocyclic, or bridged.

[0074] "Cycloalkyl" refers to a substituent in a saturated or unsaturated cyclic hydrocarbon. Cycloalkyl groups are generally selected from ternary to decacyclic cycloalkyl groups.

[0075] Typical cycloalkyl groups include, but are not limited to:

[0076] Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.

[0077] "Heterocyclic alkyl" refers to a cyclic alkyl group containing at least one heteroatom in its ring skeleton. Heterocyclic alkyl groups are generally selected from ternary to decacyclic alkyl groups.

[0078] Typical heterocyclic alkyl groups include, but are not limited to:

[0079] "Aryl" refers to a planar ring with a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. Aryl rings can consist of five, six, seven, eight, nine, or more atoms. Aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthraceneyl, fluorenyl, and indeneyl.

[0080] "Heteroaryl" refers to an aryl group whose ring skeleton contains at least one heteroatom. Heteroaryl groups are generally selected from ternary to decaaryaryl groups.

[0081] Typical heteroaryl groups include, but are not limited to:

[0082] Unless otherwise specified, “substitution” means that the mentioned group can be substituted by one or more additional groups, each and independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxyamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ester, acyl, carbonyl, amide, etc.

[0083] The beneficial effects of this invention are: This invention provides a series of compounds that have a significant inhibitory effect on the activity of Nav1.8 ion channels, providing new solutions for the treatment of diseases targeting Nav1.8, such as chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, multiple sclerosis, Sharma-Tutankhamun syndrome, incontinence, or arrhythmia. These compounds can be used to prepare drugs for treating related diseases and have broad application prospects. Detailed Implementation

[0084] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0085] In this invention, the structures of the compounds were determined using mass spectrometry (MS) and / or nuclear magnetic resonance (¹H NMR) equipment. The chemical abbreviations have the following meanings: THF: Tetrahydrofuran; TCFH: N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate; NMI: N-methylimidazolium; TEMP: 2,2,6,6-Tetramethylpiperidine; n-BuLi: n-Butyllithium; t-BuOK: Potassium tert-butoxide.

[0086] Example 1

[0087] (4S)-4-[({4-[({5-chloro-2-[(4-fluoro-2-methylphenyl)oxy]-4-(trifluoromethyl)phenyl}carbonyl)amino]pyridin-2-yl}oxy)methyl]-2-oxo-2λ 5 -1,3,2-Dioxaphosphazene-2-ol sodium (compound A)

[0088] Step 1: Synthesis of (S)-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pyridine-4-amine

[0089] 2-Chloro-4-aminopyridine (1.30 g, 10.2 mmol) and 10 mL of (S)-(+)-glycerol acetal were mixed and stirred until homogeneous. Sodium metal (280 mg, 12.2 mmol) was added, and the mixture was stirred overnight at 130 °C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and then water was added. After stirring, the mixture was separated into aqueous and organic phases. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give 2.15 g of product, yield: 95%.

[0090] Step 2: Synthesis of methyl 5-chloro-2-fluoro-4-(trifluoromethyl)benzoate

[0091] 4.85 g (20.0 mmol) of 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid was dissolved in 20 mL of methanol, and 15 mL of thionyl chloride was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the system was evaporated to dryness, water was added, and the mixture was extracted twice with ethyl acetate. The organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give 4.10 g of product, yield: 80%.

[0092] Step 3: Synthesis of methyl 5-chloro-2-[(4-fluoro-2-methylphenyl)oxy]-4-(trifluoromethyl)benzoate

[0093] Methyl 5-chloro-2-fluoro-4-(trifluoromethyl)benzoate (4.10 g, 16.0 mmol) was dissolved in 35 mL of acetonitrile, followed by the addition of 4-fluoro-2-methylphenol (2.02 g, 16.0 mmol) and potassium carbonate (3.07 g, 24.0 mmol). After the addition was complete, the mixture was stirred at 70 °C for 3 hours. After the reaction was complete, the mixture was poured into water and extracted twice with ethyl acetate. The organic phase was backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain 4.25 g of crude product, which was used directly in the next step.

[0094] Step 4: Synthesis of 5-chloro-2-[(4-fluoro-2-methylphenyl)oxy]-4-(trifluoromethyl)benzoic acid

[0095] Methyl 5-chloro-2-[(4-fluoro-2-methylphenyl)oxy]-4-(trifluoromethyl)benzoate (4.25 g, 11.7 mmol) was dissolved in 20 mL of ethanol, followed by the addition of 4 mL of water and sodium hydroxide (1.9 g, 47.0 mmol). After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was poured into water, and the pH was adjusted to acidic under hydrochloric acid conditions. The mixture was extracted with ethyl acetate, and the organic phase was backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give 2.50 g of product. The two-step yield was 45%.

[0096] Step 5: Synthesis of (S)-5-chloro-N-(2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pyridin-4-yl)-2-(4-fluoro-2-methylphenoxy))-4-(trifluoromethyl)benzamide

[0097] Add 100 mg (0.29 mmol) of 5-chloro-2-[(4-fluoro-2-methylphenyl)oxy]-4-(trifluoromethyl)benzoic acid and 2 mL of thionyl chloride to a single-necked flask, stir at 60 °C for 2 hours, and then evaporate the mixture to dryness.

[0098] (S)-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pyridine-4-amine (70 mg, 0.31 mmol), triethylamine (88 mg, 0.87 mmol), and 2 mL THF were added to a single-necked flask. The THF solution of the previously evaporated residue was added dropwise with stirring. After the addition was complete, the mixture was reacted overnight at room temperature. The system was poured into water, extracted with ethyl acetate, backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC (dichloromethane / methanol = 20 / 1) to give 103 mg of product, yield: 65%.

[0099] Step 6: Synthesis of (R)-5-chloro-N-(2-(2,3-dihydroxypropoxy)pyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (Compound B)

[0100] (S)-5-chloro-N-(2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pyridin-4-yl)-2-(4-fluoro-2-methylphenoxy))-4-(trifluoromethyl)benzamide (103 mg, 0.19 mmol) was dissolved in 5 mL of methanol, and 2 mL of hydrogen chloride methanol solution (2 M) was added. The mixture was stirred at room temperature for 2 hours. The system was evaporated to dryness, water was added, and the mixture was extracted with ethyl acetate. The organic phase was backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was dissolved in 1 mL of dichloromethane, and 10 mL of petroleum ether was added. A solid precipitated, which was filtered. The filter cake was washed with petroleum ether and dried to give 76 mg of product. Yield: 80%.

[0101] LC / MS: m / z = 515.1 [M+H] + .

[0102] 1H NMR(400MHz,d6-DMSO)δ2.16(3H,s),3.40-3.43(2H,m),3.75-3.79(1H,m),4.09-4.13(1H,m),4.23-4.27(1H,m),4.64(1H,t, J=5.6Hz),4.92(1H,d,J=5.2Hz),7.09-7.16(5H,m),7.21(1H,d,J=9.2Hz),8.05(1H,d,J=5.6Hz),8.08(1H,s),10.94(1H,s).

[0103] Step 7: (4S)-4-[({4-[({5-chloro-2-[(4-fluoro-2-methylphenyl)oxy]-4-(trifluoromethyl)phenyl}carbonyl)amino]pyridin-2-yl}oxy)methyl]-2-oxo-2λ 5 Synthesis of sodium -1,3,2-dioxaphosphazene-2-ol (Compound A)

[0104] Phosphorus oxychloride (1.2 g, 7.80 mmol) was dissolved in THF (10 mL), cooled to -70°C, and then triethylamine (0.9 g, 8.78 mmol) was slowly added. After that, (R)-5-chloro-N-(2-(2,3-dihydroxypropoxy)pyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (1.0 g, 1.95 mmol) was slowly added. The temperature was kept below -65°C and the reaction was maintained at this temperature for two hours. The reaction system was then added to ice water, and sodium bicarbonate was added to adjust the pH to 8-9. The mixture was extracted with ethyl acetate, dried to dryness, and purified by Prep-HPLC (ACN / H2O = 1 / 3) to give 712 mg of white solid, yield: 61%.

[0105] LC / MS: m / z = 577.1 [M+H] + .

[0106] 1H NMR(400MHz,d6-DMSO)δ2.16(3H,s),3.65-3.71(1H,m),3.97-4.04(1H,m),4.24(2H,d,J =4.0Hz),4.37-4.42(1H,m),7.05-7.22(6H,m),8.04(1H,s),8.05(1H,s),11.18(1H,s).

[0107] Drugability testing

[0108] Experimental Example 1: Compound Solubility Test

[0109] 1. Experimental Procedure

[0110] 1.1 Specific Positioning Solution Method: Weigh 1 mg of compound B and place it in a 10 ml volumetric flask. Dissolve and dilute to the mark with diluent, and shake well to obtain the positioning solution stock solution. Accurately measure the positioning solution stock solution of compound B, place it in a 10 ml volumetric flask, dilute to the mark with diluent, and shake well. Transfer the solution to a liquid chromatograph for analysis.

[0111] 1.2 STD (control) preparation method: Weigh 3 mg of compound A, place it in a 10 ml volumetric flask, add diluent to dissolve and dilute to the mark, shake well, and transfer to a liquid chromatograph for analysis.

[0112] 1.3 Preparation method of compound A: Weigh 144.14 mg of compound A and place it in a 20 ml headspace vial. Add 5 ml of aqueous medium and shake well to form a supersaturated solution. Shake at 37°C (300 r / min) for 1 h. Measure the pH of the aqueous medium sample (approximately 8.73). Centrifuge 2 ml of the suspension (12000 r / min, 3 min). Take 1 ml of the supernatant and place it in a 100 ml volumetric flask. Dilute to the mark with diluent and shake well. Transfer to a liquid chromatograph for analysis.

[0113] 1.4 Preparation of Compound B: Weigh 31.14 mg of compound B and place it in a 20 ml headspace vial. Add 5 ml of aqueous medium and shake well to form a supersaturated solution. Shake at 37°C (300 rpm) for 1 h. Centrifuge 2 ml of the suspension (12000 rpm for 3 min). Take 1 ml of the supernatant and place it in a 2 ml volumetric flask. Dilute to the mark with diluent and shake well. Transfer the solution to a liquid chromatograph for analysis.

[0114] 2. Data Processing

[0115] Solubility = Measured sample concentration * Dilution volume; Measured sample concentration = Sample peak area / Reference response factor; Reference response factor = Reference peak area / Reference concentration; Reference concentration = Reference sample weight * Purity / 100 / Dilution factor.

[0116] Table 1: Results of solubility tests for compound pairs

[0117] Note: Compound A is a prodrug of compound B, which is the compound described in Example 114 of WO2022121517.

[0118] As can be seen from the data in Table 1, compound B has very low solubility, making it difficult to develop into a simple injectable formulation. In contrast, compound A, prepared in Example 1, has significantly higher solubility than compound B, thus meeting the requirements for developing a simple injectable formulation.

[0119] Experimental Example 2: Effects of Compounds on Human Na+ in HEK293 Cells V 1.8 Ion Channel Inhibitory Activity Assay

[0120] 1: Test compound formulation

[0121] All reagents, except for NaOH and KOH used in acid-base titrations, were purchased from Sigma (St. Louis, MO). The final concentrations of all test compounds were prepared on the same day and then dissolved in extracellular fluid. The extracellular fluid (mM) consisted of: NaCl, 137 g; KCl, 4 g; CaCl₂, 1.8 g; MgCl₂, 1 g; HEPES, 10 g; glucose, pH 7.4 (NaOH titration). The intracellular fluid (mM) consisted of: Aspartic acid, 140 g; MgCl₂, 2 g; EGTA, 11 g; HEPES, 10 g; pH 7.2 (CsOH titration). All test compound solutions contained 1 μM TTX.

[0122] The test compound was stored at a concentration of 3 mM. It was dissolved in dimethyl sulfoxide (DMSO). On the day of testing, it was dissolved in extracellular fluid to prepare the required concentration.

[0123] Test compound solvent

[0124] 2: Testing Method

[0125] 2.1: Cells

[0126] All experiments were conducted at room temperature. Each cell served as its own control.

[0127] 2.1.1: Compound Testing

[0128] All compounds were perfused using a gravity-based perfusion system. At least one cell was tested for each concentration. The inhibitory effect of the compound was calculated by comparing the changes in current before and after application, after the current stabilized (or after 5 minutes).

[0129] 2.1.2: Test Cells

[0130] HEK293 cells with steady-state expression of NaV1.8 ion channels.

[0131] 2.1.3: Experimental Apparatus

[0132] Patch clamp amplifier: PC-505B (WARNER instruments) / MultiClamp 700A (Axon instruments)

[0133] Digital-to-analog converters: Digidata 1440A (Axon CNS) / Digidata 1550A (Axon Instruments)

[0134] Microcontroller: MP-225 (SUTTER instrument)

[0135] Inverted microscope: TL4 (Olympus)

[0136] Glass microelectrode pulling instrument: PC-10 (NARISHIGE)

[0137] Microelectrode glass capillary: B12024F (Wuhan Microprobe Scientific Instruments Co., Ltd.)

[0138] 2.2: Electrophysiology

[0139] Cells were transferred to a perfusion tank and perfused with extracellular fluid. The intracellular fluid (mM) consisted of Aspartic acid, 140; MgCl2, 2; EGTA, 11; HEPES, 10; pH 7.2 (titrated with CsOH). Intracellular fluid was stored in batches at -80°C and thawed on the day of the experiment. Electrodes were fabricated using PC-10 (Narishige, Japan). Whole-cell patch-clamp recording was performed, and noise was filtered at one-fifth of the sampling frequency.

[0140] 2.3: Test Voltage Equation (resting) and Results

[0141] The cells were clamped at -80 mV and then depolarized to 10 mV using a square wave for 10 milliseconds to obtain Na. V 1.8 Current (see figure). This procedure is repeated every 5 seconds. The maximum current induced by the square wave is detected, and after it stabilizes, the test compound is perfused. Once the reaction stabilizes, the blocking strength is calculated.

[0142] Table 2: Inhibitory activity of compounds against Nav1.8

[0143] As can be seen from the data in Table 2, as a prodrug of compound B, compound A prepared in Example 1 itself has no inhibitory effect on Nav1.8, but its in vivo metabolite compound B (which can be demonstrated in Experiment 3) can significantly inhibit the activity of Nav1.8.

[0144] Experimental Example 3: Pharmacokinetic Test of Compound in Rats

[0145] Male SD rats (purchased from Chengdu Dashuo Experimental Animal Co., Ltd.) were used. The test compound (compound A) was administered to SD rats via a single intravenous injection (25 mg / kg, 3 rats per group) for pharmacokinetic studies. The test compound was prepared on the day of administration using 5% glucose injection to create the dosing system. Following tail vein administration, blood samples were collected via orbital sampling at the following time points: before administration, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-administration. Three whole blood samples (approximately 0.2 mL–0.3 mL) were collected at each time point and anticoagulated with heparin sodium. Blood samples were immediately placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 8000 rpm, 1 minute, room temperature). The collected plasma was stored at –80°C before analysis. Plasma samples were analyzed using liquid chromatography / mass spectrometry (LC / MS / MS) to determine the concentrations of compounds A and B, and pharmacokinetic (PK) analysis was performed on the plasma concentration and time data of the compounds.

[0146] Table 3: Blood concentrations of Compound A and Compound B after intravenous injection of Compound A (25 mg / kg)

[0147] Table 4: Pharmacokinetic Results of Compound A (25 mg / kg) after Intravenous Injection

[0148] As can be seen from the data in Tables 3 and 4, compound A is rapidly converted into the active ingredient (i.e., compound B) in vivo. Two hours after administration, the blood concentration of compound A is already less than 10% of that of compound B. The converted compound B is cleared more slowly and has a longer half-life.

[0149] The drug-likeness data above show that compound A prepared in Example 1 has excellent solubility and can be rapidly converted into the active ingredient (i.e., compound B) in vivo. The solubility of compound A meets the development requirements of a simple injectable formulation; the active ingredient (i.e., compound B) converted in vivo after injection has a significant inhibitory effect on Nav1.8 ion channel activity and can be used as a Nav1.8 inhibitor, showing broad application prospects in analgesia, atrial fibrillation, Budd-Chiari syndrome, and other fields.

Claims

1. A compound of Formula I, its stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts: in, R1 is selected from H + Metal cations, HN + (R2)3; Each time R2 appears, it is independently selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 heteroalkyl, and the substituent is selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxyamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ester, acyl, and amide. Alternatively, any two R2s together with the nitrogen atom they are attached to form a substituted or unsubstituted five- to twelve-membered ring group containing at least one of C, N, O, or S atoms, and the remaining R2 is selected from unsubstituted, hydrogen-free, substituted or unsubstituted C1-C10 alkyl groups, or substituted or unsubstituted C1-C10 heteroalkyl groups; wherein the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxyamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ester, acyl, carbonyl, and amide groups.

2. The compound, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt according to claim 1, characterized in that: The metal cation is selected from K. + 1 / 2Ca 2+ Na + 1 / 2Mg 2+ 1 / 2Zn 2+ .

3. The compound, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt according to claim 1, characterized in that: The metal cation is selected from K. + 1 / 2Ca 2+ Na + .

4. The compound, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt according to claim 1, characterized in that: R1 is selected from a metal cation, wherein the metal cation is selected from Na. + .

5. The compound, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt according to claim 1, characterized in that: Each time R2 appears, it is independently selected from hydrogen, substituted or unsubstituted C1-C5 alkyl, or substituted or unsubstituted C1-C5 heteroalkyl.

6. The compound, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt according to claim 1 or 5, characterized in that: The substituents are selected from halogens, hydroxyl groups, amino groups, carboxyl groups, and amide groups.

7. The compound, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt according to claim 1, characterized in that: Each time R2 appears, it is independently selected from hydrogen and -(CH2). n OH, -(CH2) m CH(NH2)COOR3; n is selected from 1, 2, 3, 4 or 5; m is selected from 1, 2, 3, 4 or 5; R3 is selected from hydrogen or C1-C5 alkyl groups.

8. The compound, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt according to claim 7, characterized in that: n is selected from 1, 2, or 3; m is selected from 3, 4, or 5.

9. The compound, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt according to claim 7, characterized in that... R3 is selected from hydrogen, methyl, or ethyl.

10. A pharmaceutical composition, characterized in that, It includes a first therapeutic agent and a pharmaceutically acceptable excipient, wherein the first therapeutic agent is selected from one or more of the compounds, stereoisomers, solvates, hydrates or pharmaceutically acceptable salts of any one of claims 1 to 9.

11. Use of the compound of claim 1, its stereoisomers, solvates, hydrates or pharmaceutically acceptable salts in the preparation of a medicament for inhibiting Nav1.

8.

12. The use according to claim 11, characterized in that: Use of the compound, its stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts in the preparation of medicaments for the treatment, relief, or prevention of pain and pain-related diseases, pruritus, multiple sclerosis, Shama-Tutan syndrome, incontinence, pathological cough, or arrhythmias.

13. The use according to claim 12, characterized in that: The pain is selected from any one or more diseases among chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, and primary pain.

14. The use according to claim 13, characterized in that, 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; The primary pain is selected from fibromyalgia.

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