An N-acetanilide cationic compound, its preparation method and application

Abstract

This invention discloses an N-acetanilide cationic compound, its preparation method, and its applications, particularly in the pharmaceutical field. This cationic compound exhibits rapid onset of action, high potency, long duration of action, good safety profile, and strong nerve-blocking effect. It can exert a reversible and sustained local anesthetic effect in vivo and can be used as a long-acting and / or selectively blocking local anesthetic or analgesic, showing great promise and value.

Description

Technical Field

[0001] This invention relates to the field of chemical and pharmaceutical technology, specifically to an N-acetanilide cationic compound, its preparation method, and its applications, particularly in the pharmaceutical field. Background Technology

[0002] Local anesthetics are drugs that can temporarily, completely, and reversibly block nerve conduction within a limited area of ​​the body. That is, they can cause a part of the body to lose sensation without loss of consciousness, so as to facilitate surgical procedures. Their mechanism of action is to bind to certain sites on the sodium ion channels on the nerve membrane, thereby reducing the sodium ion concentration in the channels and changing the nerve membrane potential, which leads to the blockage of nerve impulse conduction and ultimately achieves an anesthetic effect.

[0003] Currently, all local anesthetics used clinically are uncharged molecules with a certain ability to penetrate tissues and cells. Their effects disappear rapidly as the drug diffuses from the administration site. To achieve a prolonged local anesthetic effect, the dosage needs to be increased; however, increasing the dosage only appropriately prolongs the duration of action and still cannot achieve the desired long-lasting local anesthetic effect. Currently, the duration of action of commonly used long-acting local anesthetics in clinical practice generally does not exceed 8 hours.

[0004] Local anesthetics generally contain at least one non-amide tertiary nitrogen atom. Further alkylation of this atom yields the corresponding quaternary ammonium salt. Alkylation imparts a charge to the entire molecule, making it less likely to cross cell membranes. For example, ethylation of the tertiary nitrogen atom in lidocaine yields a quaternary ammonium salt called QX-314. Similar to QX-314, QX-222 was also an earlier reported quaternary ammonium salt. Under specific conditions, both QX-314 and QX-222 can produce local anesthetic effects, but QX-314 exhibits significantly higher activity than QX-222. Therefore, there are far more literature reports on QX-314 than on QX-222.

[0005]

[0006] Because QX-314 molecules carry a charge, they cannot cross cell membranes, thus failing to produce rapid local anesthesia. However, once they cross the cell membrane, they can effectively inhibit sodium ion channels within the membrane, resulting in a prolonged anesthetic effect. Numerous studies have found that QX-314 can be used in combination with capsaicin (a transient receptor potential channel vanillic acid subtype 1 agonist, i.e., TRPV1 agonist) to produce long-lasting and motor-sensory dissociation blockade. However, the strong irritant properties of capsaicin limit the applicability of this combination. Although some studies have shown that QX314, when used in combination with clinically used local anesthetics such as bupivacaine and lidocaine, can rapidly produce a prolonged anesthetic effect and avoid the irritation of capsaicin, the safety concerns of QX314 itself remain. Current research has revealed that QX314's safety profile is not ideal, primarily manifesting as nerve damage, and intrathecal injection can cause death in experimental animals. Therefore, QX314, whether used alone or in combination with other active drugs, presents safety concerns.

[0007] To meet clinical needs, it is necessary to develop new long-acting local anesthetic active ingredients that separate sensory and motor blockade. Summary of the Invention

[0008] To overcome the shortcomings of the prior art, the present invention provides an N-acetanilide cationic compound, its preparation method and application.

[0009] In a first aspect of the present invention, an N-acetanilide cationic compound is provided, having the following structure:

[0010]

[0011]

[0012] in,

[0013] R1, R2, R3, R4, and R5 are selected independently. The structure, wherein Y is selected from: single bond (-), -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -NH-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -S(O)-, -S(O)2-, -SS-, and Z is selected from: H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, halogen;

[0014] R6 is an alkyl group, and R8 is selected from H or alkyl groups; or, R6 and R8 together with the atoms connected in the middle form a cyclic group.

[0015] R7 is an alkyl group;

[0016] R9 and R 10 Independently selected from: H, alkyl;

[0017] X - It is an anion.

[0018] In particular, the compounds represented by general formula I do not include the following compounds:

[0019]

[0020] Specifically, X is selected from: F, Cl, Br, I, methanesulfonate, ethylsulfonate, benzenesulfonate, citrate, lactate, succinate, fumarate, glutamate, citrate, salicylate, maleate, especially F, Cl, Br or I.

[0021] Specifically, Y can be selected from: single bond (-), -O-, -S-, -C(O)O-, -OC(O)-.

[0022] Specifically, Z can be selected from: H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl.

[0023] In one embodiment of the present invention, Y is a single bond (-) and Z is H, that is... For H.

[0024] Specifically, at least one (e.g., one, two, or three) of R1, R2, R3, R4, and R5 is not H.

[0025] In another embodiment of the present invention, Y is a single bond (-) and Z is an alkyl group, i.e. It is an alkyl group, such as C1-6 alkyl groups, such as methyl, ethyl, n-propyl, and isopropyl.

[0026] In another embodiment of the present invention, Y is -O- and Z is alkyl, i.e. It is an alkoxy group, such as C1-6 alkoxy groups, such as methoxy, ethoxy, and propoxy.

[0027] In another embodiment of the present invention, Y is -OC(O)-, and Z is an alkyl group, i.e. It is an alkyl acyloxy group, such as C2-6 alkyl acyloxy groups, such as acetoxy, propionyloxy, and butyryloxy groups.

[0028] In another embodiment of the present invention, Y is -O- and Z is an alkynyl group, i.e. It is an alkynyloxy group, such as C2-6 alkynyloxy groups, such as propynyloxy, butynyloxy, and pentylyoxy groups.

[0029] In another embodiment of the present invention, Y is -OC(O)-, and Z is an alkynyl group, i.e. It is an alkynyl acyloxy group, such as C3-6 alkynyl acyloxy groups, such as propynyloxy, butynyloxy, and pentynyloxy.

[0030] Specifically, R1, R2, R3, R4, and R5 are independently selected from: H, alkyl (e.g., C1-6 alkyl, such as methyl, ethyl, n-propyl, isopropyl), alkoxy (e.g., C1-6 alkoxy, such as methoxy, ethoxy, propoxy), alkylacyloxy (e.g., C2-6 alkylacyloxy, such as acetoxy, propionyloxy, butyryloxy), alkynoxy (e.g., C2-6 alkynoxy, such as propynoxy, butyryloxy, pentyryloxy), or alkynyloxy (e.g., C3-6 alkynyloxy, such as propynyloxy, butyryloxy, pentyryloxy).

[0031] In one embodiment of the present invention, R2, R3, R4, and R5 are all H, and R1 is H. And not H, wherein Y1 and Z1 have the definitions of Y and Z as described above. Specifically, R1 is selected from: alkyl (e.g., C1-6 alkyl, such as methyl, ethyl, n-propyl, isopropyl), alkoxy (e.g., C1-6 alkoxy, such as methoxy, ethoxy, propoxy), alkylacyloxy (e.g., C2-6 alkylacyloxy, such as acetoxy, propionyloxy, butyryloxy), alkynoxy (e.g., C2-6 alkynoxy, such as propynoxy, butyryloxy, pentyryloxy) or alkynyloxy (e.g., C3-6 alkynyloxy, such as propynyloxy, butyryloxy, pentyryloxy).

[0032] In one embodiment of the present invention, R1, R3, R4, and R5 are all H, and R2 is... And not H, wherein Y2 and Z2 have the definitions of Y and Z as described above. Specifically, R2 is selected from: alkyl (e.g., C1-6 alkyl, such as methyl, ethyl, n-propyl, isopropyl), alkoxy (e.g., C1-6 alkoxy, such as methoxy, ethoxy, propoxy), alkylacyloxy (e.g., C2-6 alkylacyloxy, such as acetoxy, propionyloxy, butyryloxy), alkynoxy (e.g., C2-6 alkynoxy, such as propynoxy, butyryloxy, pentyryloxy) or alkynyloxy (e.g., C3-6 alkynyloxy, such as propynyloxy, butyryloxy, pentyryloxy).

[0033] In one embodiment of the present invention, R1, R2, R4, and R5 are all H, and R3 is H. And not H, wherein Y3 and Z3 have the definitions of Y and Z as described above. Specifically, R3 is selected from: alkyl (e.g., C1-6 alkyl, such as methyl, ethyl, n-propyl, isopropyl), alkoxy (e.g., C1-6 alkoxy, such as methoxy, ethoxy, propoxy), alkylacyloxy (e.g., C2-6 alkylacyloxy, such as acetoxy, propionyloxy, butyryloxy), alkynoxy (e.g., C2-6 alkynoxy, such as propynoxy, butyryloxy, pentyryloxy), or alkynyloxy (e.g., C3-6 alkynyloxy, such as propynyloxy, butyryloxy, pentyryloxy).

[0034] In one embodiment of the present invention, R1, R4, and R5 are all H, and R2 is... And not H, R3 is And not H, wherein Y2 and Y3 independently have the definition of Y as described above, and Z2 and Z3 independently have the definition of Z as described above. R2 and R3 are independently selected from: alkyl (e.g., C1-6 alkyl, such as methyl, ethyl, n-propyl, isopropyl), alkoxy (e.g., C1-6 alkoxy, such as methoxy, ethoxy, propoxy), alkylacyloxy (e.g., C2-6 alkylacyloxy, such as acetoxy, propionyloxy, butyryloxy), alkynoxy (e.g., C2-6 alkynoxy, such as propynoxy, butyryloxy, pentyryloxy), or alkynyloxy (e.g., C3-6 alkynyloxy, such as propynyloxy, butyryloxy, pentyryloxy). More specifically, R2 is a C2-6 alkylacyloxy, and R3 is a C2-6 alkynoxy or a C3-6 alkynyloxy. In one embodiment of the invention, R2 is an acetoxy, and R3 is a propynyloxy.

[0035] In one embodiment of the present invention, R1 and R5 are both H, and R2 is... And not H, R3 is And not H, R4 is And not H, wherein Y2, Y3, and Y4 each independently have the definition of Y as described above, and Z2, Z3, and Z4 each independently have the definition of Z as described above. R2, R3, and R4 are independently selected from: alkyl (e.g., C1-6 alkyl, such as methyl, ethyl, n-propyl, isopropyl), alkoxy (e.g., C1-6 alkoxy, such as methoxy, ethoxy, propoxy), alkylacyloxy (e.g., C2-6 alkylacyloxy, such as acetoxy, propionyloxy, butyryloxy), alkynoxy (e.g., C2-6 alkynoxy, such as propynoxy, butyryloxy, pentyryloxy), or alkynyloxy (e.g., C3-6 alkynyloxy, such as propynyloxy, butyryloxy, pentyryloxy). More specifically, R3 is a C2-6 alkynoxy or a C3-6 alkynyloxy; or, R2 is a C2-6 alkynoxy or a C3-6 alkynyloxy. Further, R3 is a C2-6 alkynoxy or C3-6 alkynyl acyloxy, and R2 and R4 are independently selected from: C1-6 alkyl, C1-6 alkoxy, C2-6 alkyl acyloxy; or, R2 is a C2-6 alkynoxy or C3-6 alkynyl acyloxy, and R3 and R4 are independently selected from: C1-6 alkyl, C1-6 alkoxy, C2-6 alkyl acyloxy.

[0036] Specifically, R6 is a C1-6 alkyl group, such as methyl, ethyl, n-propyl, or n-butyl.

[0037] Specifically, R8 is selected from: H, C1-6 alkyl, such as methyl, ethyl, n-propyl, n-butyl.

[0038] In one embodiment of the invention, R6, R8, together with the atoms they are connected in the middle, form a 5-8 member heterocyclic group, particularly a 6 member heterocyclic group, preferably a piperidinyl group.

[0039] Specifically, R7 is a C1-6 alkyl group, such as methyl, ethyl, n-propyl, or n-butyl.

[0040] Specifically, R9 is selected from H, C1-6 alkyl, such as methyl, ethyl, n-propyl, n-butyl, and in particular, R9 is H or methyl.

[0041] Specifically, R 10 Selected from H, C1-6 alkyl, such as methyl, ethyl, n-propyl, n-butyl, especially R 10 It is H or methyl.

[0042] Specifically, the compound represented by general formula I can have the following structure:

[0043]

[0044]

[0045] More specifically, the compounds represented by general formula I can have the following structures:

[0046]

[0047] In some embodiments of the present invention, the compound represented by general formula I has the following structure:

[0048]

[0049]

[0050] In a second aspect of the invention, a stereoisomer of the compound described in the first aspect is provided, having the following structure:

[0051]

[0052] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 X has the corresponding definition described in the first aspect of the present invention.

[0053] Specifically, the above-mentioned stereoisomers have the following structure:

[0054]

[0055]

[0056] In some embodiments of the present invention, the above-described stereoisomers have the following structure:

[0057]

[0058]

[0059] In a third aspect of the invention, a prodrug and a solvate of the compound described in the first aspect are provided.

[0060] In a fourth aspect of the invention, a method for preparing the compound described in the first aspect is provided, comprising the step of reacting the compound of formula V with the compound of formula VI, wherein the reaction formula is as follows:

[0061]

[0062] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 X has the corresponding definition described in the first aspect of the present invention.

[0063] In some embodiments of the present invention, the compound represented by Formula V is ropivacaine, mepivacaine, bupivacaine, lidocaine, or eticaine, particularly ropivacaine.

[0064] Specifically, the reaction system also includes a reaction solvent; more specifically, the reaction solvent is a polar aprotic solvent, such as acetonitrile, dimethylformamide, dimethyl sulfoxide, etc., especially acetonitrile.

[0065] Specifically, the temperature of the above reaction is 40-75℃ (e.g., 40, 45, 50, 55, 60, 65, 70℃).

[0066] Specifically, the reaction time is 6-18 hours (e.g., 6, 8, 10, 12, 14, 16, 18 hours).

[0067] Specifically, the preparation method further includes a purification step; more specifically, the purification step includes: removing the reaction solvent, recrystallizing, drying, and obtaining the target product.

[0068] Specifically, the recrystallization solvent can be methyl tert-butyl ether, diethyl ether, ethyl acetate, etc., especially methyl tert-butyl ether.

[0069] In a fifth aspect of the invention, the use of the compound of formula VI in the structural modification of the compound of formula V is provided.

[0070] Specifically, the compound represented by Formula V is a local anesthetic, such as ropivacaine, mepivacaine, bupivacaine, lidocaine, or eticaine, especially ropivacaine.

[0071] Specifically, this structural modification can prolong the duration of the local anesthetic and analgesic effects of the compound shown in Formula V.

[0072] In a sixth aspect of the invention, a pharmaceutical composition is provided comprising the compound described in the first aspect, the stereoisomer described in the second aspect or the prodrug described in the third aspect, a solvate, and one or more pharmaceutically acceptable excipients.

[0073] Specifically, pharmaceutically acceptable excipients may be selected from one or more of the following: excipients, disintegrants, binders, lubricants, wetting agents, suspending agents, stabilizers, fillers, pH buffers, antioxidants, preservatives, flavoring agents, etc.

[0074] Specifically, the pharmaceutical composition can be administered via any suitable route of administration, such as gastrointestinal or non-gastrointestinal routes (e.g., intravenous, intramuscular, subcutaneous, intra-organ, intranasal, intradermal, intravenous drip, intracerebral, rectal, etc.).

[0075] Specifically, the pharmaceutical composition can be any suitable dosage form, such as gastrointestinal dosage forms, including, but not limited to, tablets, pills, powders, granules, capsules, lozenges, syrups, liquids, emulsions, suspensions, etc.; non-gastrointestinal dosage forms, such as injectable dosage forms: such as injections (e.g., for subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection); respiratory dosage forms: such as sprays, aerosols, powder inhalers, etc.; skin dosage forms: such as topical solutions, lotions, ointments, plasters, pastes, patches, etc.; mucosal dosage forms: such as eye drops, ophthalmic ointments, nasal drops, mouthwashes, sublingual tablets, etc.; cavity dosage forms: such as suppositories, aerosols, effervescent tablets, drops, pills, etc., for use in the rectum, vagina, urethra, nasal cavity, ear canal, etc.

[0076] Specifically, the pharmaceutical composition will comprise about 1 to about 99% by weight of the compound or its stereoisomers, prodrugs, solvates, and 99 to 1% by weight of suitable pharmaceutically acceptable excipients. For example, the pharmaceutical composition may comprise about 5 to 75% by weight (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%) of the compound or its stereoisomers, prodrugs, solvates, with the remainder being suitable pharmaceutically acceptable excipients.

[0077] In a seventh aspect of the invention, the use of the compound described in the first aspect, the stereoisomer described in the second aspect, the prodrug described in the third aspect, the solvate, and the pharmaceutical composition described in the sixth aspect of the invention in the preparation of an anesthetic is provided.

[0078] Specifically, the anesthetic is a local anesthetic, especially a long-acting local anesthetic (e.g., one that can provide effective anesthesia within 16 hours).

[0079] Specifically, this drug can be used for human or veterinary purposes.

[0080] In an eighth aspect of the invention, the use of the compound of the first aspect, the stereoisomer of the second aspect, the prodrug of the third aspect, the solvate, and the pharmaceutical composition of the sixth aspect of the invention in the preparation of a medicament for the prevention and / or treatment of pain is provided.

[0081] Specifically, pain can be acute or chronic.

[0082] Specifically, the pain can be neuropathic pain or inflammatory pain.

[0083] Specifically, pain can be caused by conditions or diseases selected from the following: congenital or hereditary diseases; trauma, surgery or burns; infections and / or parasitic diseases; metabolic diseases; inflammation; autoimmune diseases; poisoning; metabolic diseases; neurodegenerative and degenerative symptoms; functional disorders; mental disorders; tumors.

[0084] More specifically, pain can be selected from one or more of the following: injury to bones, joints, muscles, roots, or medulla; mechanical injury caused by radiation, surgery, or thermal, chemical, or electrical burns; osteoarthritis, rheumatoid arthritis; musculoskeletal pain, especially post-traumatic pain; toothache; headache, migraine; abdominal pain; cancer pain; postoperative pain; multiple sclerosis, amyotrophic lateral sclerosis; intervertebral disc rupture; diabetes, hypothyroidism, or hyperthyroidism; pain originating from repetitive strain injury; pain originating from congenital or hereditary diseases; pain originating from leprosy. Pain from diseases such as herpes zoster, acquired immunodeficiency syndrome (AIDS), and heavy metal poisoning; pain from afferent nerve block, central pain, phantom limb pain, burning pain, myelopathic pain, complex regional pain syndrome, myofascial pain syndrome, fibromyalgia, stump pain, reflex sympathetic dystrophy, postherpetic neuralgia, diabetic mononeuropathy, ischemic neuropathy, polyarteritis nodosa, post-radiation pain, polyneuropathy, multiple mononeuritis, infectious and neurodegenerative myelopathy, toxic neuropathy, vasculitis, and syringomyelia.

[0085] Specifically, this drug can be used for human or veterinary purposes.

[0086] In a ninth aspect of the invention, a method of anesthesia is provided, comprising the step of administering to a subject in need an effective amount of the compound of the first aspect, the stereoisomer of the second aspect, the prodrug of the third aspect, the solvate, or the pharmaceutical composition of the sixth aspect.

[0087] Specifically, the anesthesia is local anesthesia, especially long-acting local anesthesia (e.g., effective anesthesia within 16 hours).

[0088] Specifically, the subject was a mammal, particularly a human.

[0089] In a tenth aspect of the invention, a method for preventing and / or treating pain is provided, comprising the step of administering to a subject in need an effective amount of the compound of the first aspect, the stereoisomer of the second aspect, the prodrug of the third aspect, the solvate, or the pharmaceutical composition of the sixth aspect.

[0090] Specifically, pain has the corresponding definition described in the eighth aspect of the present invention.

[0091] Specifically, the subject was a mammal, particularly a human.

[0092] The N-acetanilide cationic compounds provided by this invention have the characteristics of rapid onset, strong efficacy, long duration of action, good safety and strong nerve blockade effect. They can exert reversible and long-lasting local anesthetic effects in vivo and can be used as long-acting and / or selectively blocking local anesthetics or analgesics, which have very good application prospects and value. Attached Figure Description

[0093] Figure 1 The mass spectrum of R-OME-1 is shown below.

[0094] Figure 2 The image shows the NMR spectrum of R-OME-1.

[0095] Figure 3 The mass spectrum of R-OME-2 is shown below.

[0096] Figure 4 The image shown is the NMR spectrum of R-OME-2.

[0097] Figure 5 The mass spectrum of R-OME-3 is shown below.

[0098] Figure 6 The image shown is the NMR spectrum of R-OME-3.

[0099] Figure 7 The mass spectrum of R-AC-1 is shown below.

[0100] Figure 8 The image shows the NMR spectrum of R-AC-1.

[0101] Figure 9 The mass spectrum of R-AC-2 is shown below.

[0102] Figure 10 The image shows the NMR spectrum of R-AC-2.

[0103] Figure 11 The mass spectrum of R-AC-3 is shown below.

[0104] Figure 12 The image shows the NMR spectrum of R-AC-3.

[0105] Figure 13 The image shown is the NMR spectrum of T4-9R. Detailed Implementation

[0106] Unless otherwise defined, all scientific and technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0107] The term "alkyl" refers to a straight-chain or branched hydrocarbon radical that does not contain unsaturated bonds and is connected to the rest of the molecule by single bonds. Typical alkyl groups contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12), 1 to 6, or 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. If the alkyl group is replaced by a cycloalkyl group, the corresponding radical is a "cycloalkylalkyl" radical, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. If the alkyl group is replaced by an aryl group, the corresponding radical is an "aralkyl" radical, such as benzyl, diphenylmethyl, or phenethyl. If the alkyl group is replaced by a heterocyclic group, the corresponding radical is a "heterocyclicalkyl" radical.

[0108] The term "alkenyl" refers to a straight-chain or branched hydrocarbon radical containing at least two carbon atoms and at least one unsaturated bond, with the hydrocarbon radical connected to the rest of the molecule by a single bond. Typical alkenyl groups contain 2 to 12, 2 to 8, or 2 to 6 carbon atoms, such as vinyl, 1-methyl-vinyl, 1-propenyl, 2-propenyl, or butenyl.

[0109] The term "alkynyl" refers to a straight-chain or branched hydrocarbon radical containing at least two carbon atoms and at least one carbon-carbon triple bond, with the hydrocarbon radical connected to other parts of the molecule by single bonds. Typical alkynyl groups contain 2 to 12, 2 to 8, or 2 to 6 carbon atoms, such as ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), butynyl (e.g., 1-butynyl, 2-butynyl, 3-butynyl), and pentyynyl (e.g., 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl).

[0110] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 monocyclic and / or fused rings, containing 3 to 18 carbon atoms, preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl.

[0111] The term "aryl" refers to monocyclic or polycyclic free radicals, including polycyclic free radicals containing monoaryl groups and / or fused aryl groups, such as those containing 1-3 monocyclic or fused rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms, such as phenyl, naphthyl, biphenyl, indene, etc.

[0112] The term "heterocyclic group" includes heteroaromatic groups and heterocyclic cyclic groups containing 1 to 3 monocyclic and / or fused rings and 3 to 18 ring atoms. Preferred heteroaromatic groups and heterocyclic cyclic groups contain 5 to 10 ring atoms. Suitable heteroaryl groups in the compounds of the present invention contain one, two, or three heteroatoms selected from N, O, or S atoms. These heteroaryl groups include, for example, coumarins, including 8-coumarins; quinolinyl groups, including 8-quinolinyl, isoquinolinyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrroloyl, thiopheneyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazoleyl, indolyl, isoyndolyl, indazoleyl, inazinyl, phthalazinyl, pteridinyl, purineyl, oxadiazolyl, thiadiazolyl, furazolidyl, pyridazinyl, triazinyl; cenolinyl, benzimidazolyl, benzofuranyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphridinyl, and furanopyridinyl. Suitable heterocyclic groups in the compounds of the present invention contain one, two, or three heteroatoms selected from N, O, or S atoms. These heterocyclic groups include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuran, tetrahydrothiophenyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, oxothiocyclohexyl, piperazine, aziridine, oxobutyl, thiobutyl, homopiperidinyl, oxopropane, thiopropane, acrylonitrile, oxazine, and dioxane. Acetyl, triacetyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentanyl, pyrazolinyl, dithiaalkyl, dithiopentanyl, dihydropyranyl, dihydrothiophenyl, pyrazolinyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinazinyl.

[0113] The term "halogen" refers to bromine, chlorine, iodine, or fluorine.

[0114] The term "solvent" should be understood to refer to any form of the compounds of the present invention, wherein the compounds are linked to another molecule (usually a polar solvent) by a non-covalent bond, particularly including hydrates and alcohols, such as methanols. Hydrates are preferred solvates.

[0115] The term "prodrug" is used in its broad sense and encompasses derivatives that can be converted into compounds of the present invention in vivo. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds of formula (I), including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable acylureas, and biohydrolyzable phosphate ester analogs. Prodrugs can generally be prepared by known methods, such as those described in Burger's "Medicinal Chemistry and Drug Discovery, 6th Edition" (Donald J. Abrahamed., 2001, Wiley) and "Design and Applications of Prodrugs" (H. Bundgaarded., 1985, Harwood Academic Publishers).

[0116] The term "pain treatment" includes eradicating, removing, reversing, relieving, altering, or controlling pain after it has occurred.

[0117] The term "pain prevention" refers to the ability to avoid, minimize, or prevent pain from occurring or developing before it occurs, through treatment.

[0118] The term "subject" refers to any animal or its cells treated according to the methods described herein, whether in vitro or in situ. Specifically, the aforementioned animals include mammals, such as wild animals, zoo animals, commercial animals (e.g., pigs, cattle, sheep, horses, donkeys, foxes, raccoon dogs, minks, camels, etc.), pets (e.g., dogs, cats, rabbits, rodents (e.g., guinea pigs, hamsters, gerbils, chinchillas, squirrels, etc.)), laboratory animals (e.g., monkeys, dogs, rabbits, cats, rodents (e.g., rats, mice)), and humans, especially humans.

[0119] All publications, patents, and published patent specifications cited in this article are incorporated herein in their entirety through citation.

[0120] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and 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.

[0121] Example 1: Synthesis of R-OME-1

[0122]

[0123] STEP 1:

[0124] 2-Methoxybenzyl alcohol (15.0 g, 0.109 mol) was dissolved in 150 mL of THF, and PBr3 (23.5 g, 0.087 mol) was slowly added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC until the reactants were completely reacted. The reaction was then quenched with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give 18.0 g of compound 1, with a yield of 82.4%.

[0125] STEP 2:

[0126] Compound 1 (5.0 g, 0.025 mol), free ropivacaine (6.9 g, 0.024 mol), and 25 mL of acetonitrile were stirred at 60 °C for 12 h. The reaction was monitored by HPLC. After the reaction was complete, the acetonitrile was evaporated to dryness. The crude product was recrystallized from methyl tert-butyl ether to give 3.5 g of R-OME-1, with a yield of 29.6%. Its mass spectrum and NMR spectrum are shown below. Figure 1 and 2 As shown. MS m / z(ESI): 395.3 [M]; 1 HNMR (300MHz, DMSO-d) 6 ): δ10.24(s,1H),7.57-7.51(m,1H),7.46-7.43(m,1H),7.21-7.07(m,5H),5.45-5.35(m,1H),4.94-4.90(m,1H),4.57-4.53(m,1H),3.85( s,3H),3.78-3.70(m,1H),3.23-3.21(m,3H),2.51-2.50(m,2H),2.30(s,6H),2.08-1.91(m,3H),1.68-1.66(m,3H),0.86(t,3H,J=6.9Hz).

[0127] Example 2: Synthesis of R-OME-2

[0128]

[0129] STEP 1:

[0130] 3-Methoxybenzyl alcohol (15.0 g, 0.109 mol) was dissolved in 150 mL of THF, and PBr3 (23.5 g, 0.087 mol) was slowly added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC until the reactants were completely reacted. The reaction was then quenched with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give 17.5 g of compound 2, with a yield of 81.8%.

[0131] STEP 2:

[0132] Compound 2 (5.0 g, 0.025 mol), free ropivacaine (6.9 g, 0.024 mol), and 25 mL of acetonitrile were stirred at 60 °C for 12 h. The reaction was monitored by HPLC. After the reaction was complete, the acetonitrile was evaporated to dryness. The crude product was recrystallized from methyl tert-butyl ether to give 3.6 g of R-OME-2, with a yield of 29.8%. Its mass spectrum and NMR spectrum are shown below. Figure 3 and 4 As shown. MS m / z(ESI): 395.3 [M]; 1 HNMR (300MHz, DMSO-d) 6 ): δ10.22(s,1H),7.47-7.42(m,1H),7.19-7.12(m,6H),5.22-5.17(m,1H),4.99-4.95(m,1H),4.58-4.54(m,1H),3.81(s,3H),3. 74-3.73(m,1H),3.38-3.25(m,3H),2.36-2.31(m,2H),2.20(s,6H),1.92-1.90(m,3H),1.80-1.72(m,3H),0.89(t,3H,J=6.9Hz).

[0133] Example 3: Synthesis of R-OME-3

[0134]

[0135] STEP 1:

[0136] 4-Methoxybenzyl alcohol (15.0 g, 0.109 mol) was dissolved in 150 mL of THF, and PBr3 (23.5 g, 0.087 mol) was slowly added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. Once the reaction was complete, water was added to quench the reaction, and the mixture was extracted with DCM, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give 18.4 g of compound 3, with a yield of 82.9%.

[0137] STEP 2:

[0138] Compound 3 (5.0 g, 0.025 mol), free ropivacaine (6.9 g, 0.024 mol), and 25 mL of acetonitrile were stirred at 60 °C for 12 h. The reaction was monitored by HPLC. After the reaction was complete, the acetonitrile was evaporated to dryness. The crude product was recrystallized from methyl tert-butyl ether to give 3.3 g of R-OME-1, with a yield of 29.2%. Its mass spectrum and NMR spectrum are shown below. Figure 5 and 6 As shown. MS m / z(ESI): 395.3 [M]; 1 HNMR (300MHz, DMSO-d)6 ): δ10.18(s,1H),7.50(d,1H,J=8.7Hz),7.16-7.05(m,6H),5.20-5.15(m,1H),4.98-4.93(m,1H),4.56-4.52(m,1H),3.81(s,3H), 3.53-3.62(m,1H),3.28-3.25(m,3H),2.39-2.28(m,2H),2.20(s,6H),1.92-1.89(m,3H),1.88-1.73(m,3H),0.87(t,3H,J=7.2Hz).

[0139] Example 4: Synthesis of R-AC-1

[0140]

[0141] STEP 1:

[0142] 2-Methylbenzyl alcohol (20.0 g, 0.185 mol) was dissolved in 200 mL of THF, and triethylamine (20.1 g, 0.204 mol) was added. The mixture was cooled to 5 °C, and AcCl (16.0 g, 0.204 mol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 h. TLC monitoring was performed until the reaction of the starting material was complete. The reaction was then quenched with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give 18.1 g of compound 4, with a yield of 64.8%.

[0143] STEP 2:

[0144] Compound 4 (18.0 g, 0.120 mol), NBS (32.0 g, 0.180 mol), and azobisisobutyronitrile were dissolved in 180 mL of chloroform and stirred at 60 °C for 1 h. TLC monitoring was performed. After the reaction was complete, the chloroform was evaporated to dryness. The crude product was purified by column chromatography to give 12.0 g of compound 5, with a yield of 43.7%.

[0145] STEP 3:

[0146] Compound 5 (5.0 g, 0.022 mol), free ropivacaine (6.1 g, 0.021 mol), and 25 mL of acetonitrile were stirred at 60 °C for 12 h. The reaction was monitored by HPLC. After the reaction was complete, the acetonitrile was evaporated to dryness. The crude product was recrystallized from methyl tert-butyl ether to give 3.5 g of R-AC-1, with a yield of 31.8%. Its mass spectrum and NMR spectrum are shown below. Figure 7 and 8 As shown. MS m / z(ESI): 423.4 [M]; 1 HNMR (300MHz, DMSO-d) 6): δ10.28(s,1H),7.65-7.57(m,2H),7.47-7.42(m,1H),7.36(t,1H,J=7.2Hz),7.17-7.16(m,3H),5.60-5.45(m,1H),5.06-4.92(m,1H),4 .64-4.60(m,1H),3.78-3.61(m,1H),3.33-3.29(m,2H),2.50-2.19(m,13H),1.97-1.89(m,3H),1.88-1.73(m,2H),0.87(t,3H,J=6.9Hz).

[0147] Example 5: Synthesis of R-AC-2

[0148]

[0149] STEP 1:

[0150] 20.0 g (0.164 mol) of 3-hydroxybenzaldehyde was dissolved in 200 mL of THF, and 18.2 g (0.180 mol) of triethylamine was added. The mixture was cooled to 5 °C, and 14.1 g (0.180 mol) of AcCl was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. Once the reaction was complete, water was added to quench the reaction, and the mixture was extracted with DCM, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give 21.0 g of compound 6, with a yield of 78.1%.

[0151] STEP 2:

[0152] Compound 6 (21.0 g, 0.128 mol) was dissolved in 210 mL of methanol, and NaBH4 was slowly added at room temperature. After the addition was complete, the mixture was stirred at room temperature for 1 h. TLC monitoring was performed, and the methanol was evaporated to dryness after the reaction was complete, yielding 19.3 g of compound 7, with a yield of 89.5%.

[0153] STEP 3:

[0154] Compound 7 (15.0 g, 0.109 mol) was dissolved in 190 mL of THF, and PBr3 (24.8 g, 0.091 mol) was slowly added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC until the reactants were completely reacted. The reaction was then quenched with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give 12.1 g of compound 8, with a yield of 45.8%.

[0155] STEP 4:

[0156] Compound 8 (5.0 g, 0.022 mol), free ropivacaine (6.1 g, 0.021 mol), and 25 mL of acetonitrile were stirred at 60 °C for 12 h. The reaction was monitored by HPLC. After the reaction was complete, the acetonitrile was evaporated to dryness. The crude product was recrystallized from methyl tert-butyl ether to give 3.2 g of R-AC-2, with a yield of 31.3%. Its mass spectrum and NMR spectrum are shown below. Figure 9 and 10 As shown. MS m / z(ESI): 423.4 [M]; 1 HNMR (300MHz, DMSO-d) 6 ): δ10.23(s,1H),7.60-7.32(m,4H),7.16-7.11(m,3H),5.29-5.24(m,1H),5.06-5.02(m,1H),4.62-4.60(m,1H),3. 74-3.55(m,1H),3.29-3.24(m,2H),2.50-2.20(m,13H),1.93-1.90(m,3H),1.80-1.72(m,2H),0.88(t,3H,J=6.9Hz).

[0157] Example 6: Synthesis of R-AC-3

[0158]

[0159] STEP 1:

[0160] 4-Hydroxybenzaldehyde (20.0 g, 0.164 mol) was dissolved in 200 mL of THF, and triethylamine (18.2 g, 0.180 mol) was added. The mixture was cooled to 5 °C, and AcCl (14.1 g, 0.180 mol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 h. TLC monitoring was performed until the reaction of the starting material was complete. The reaction was then quenched with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give 21.5 g of compound 9, with a yield of 78.8%.

[0161] STEP 2:

[0162] Compound 9 (21.0 g, 0.128 mol) was dissolved in 210 mL of methanol, and NaBH4 was slowly added at room temperature. After the addition was complete, the mixture was stirred at room temperature for 1 h. TLC monitoring was performed, and the methanol was evaporated to dryness after the reaction was complete, yielding 20 g of compound 10, with a yield of 90.7%.

[0163] STEP 3:

[0164] Compound 10 (15.0 g, 0.109 mol) was dissolved in 190 mL of THF, and PBr3 (24.8 g, 0.091 mol) was slowly added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. Once the reaction was complete, water was added to quench the reaction, and the mixture was extracted with DCM, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give 13 g of compound 11, with a yield of 46.1%.

[0165] STEP 4:

[0166] Compound 11 (5.0 g, 0.022 mol), free ropivacaine (6.1 g, 0.021 mol), and 25 mL of acetonitrile were stirred at 60 °C for 12 h. The reaction was monitored by HPLC. After the reaction was complete, the acetonitrile was evaporated to dryness. The crude product was recrystallized from methyl tert-butyl ether to give 3.5 g of R-AC-3, with a yield of 35.0%. Its mass spectrum and NMR spectrum are shown below. Figure 11 and 12 As shown. MS m / z(ESI): 423.4 [M]; 1 H NMR (300MHz, DMSO-d) 6 ): δ10.25(s,1H),7.64(d,2H,J=8.4Hz),7.29(d,2H,J=8.4Hz),7.16-7.11(m,3H),5.28-5.23(m,1H),5.05-5.01(m,1H),4.62-4. 60(m,1H),3.70-3.60(m,1H),3.33-3.24(m,2H),2.36-2.13(m,13H),1.93-1.90(m,3H),1.79-1.70(m,2H),0.89(t,3H,J=7.2Hz).

[0167] Example 7: Synthesis of T4-9R

[0168]

[0169] STEP 1:

[0170] In a three-necked flask, 66.5 g (1.67 mol, 2.3 eq) of NaH and 500 ml of a mixed solvent (DMSO:THF = 1:1) were added. Under nitrogen protection, the mixture was cooled to approximately 0°C in an ice-salt bath. T4-1 (100 g, 0.724 mol, 1 eq) (dissolved in 300 ml of the mixed solvent) was slowly added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 2 hours. The mixture was then cooled again to 0°C in an ice-water bath. Propylene bromide (103.5 g, 0.87 mol, 1.2 eq) was added dropwise. After the addition was complete, the mixture was allowed to rise to room temperature and stirred overnight. For post-treatment, the reaction solution was poured into ice water, and the pH was adjusted to 3-5 with 4N hydrochloric acid aqueous solution. The solution was extracted three times with ethyl acetate (600 ml * 3), dried over anhydrous sodium sulfate, and concentrated to obtain a gray solid crude product. This crude product was recrystallized from dichloromethane and dried to obtain 70 g of compound 12, with a yield of 55%.

[0171] STEP 2:

[0172] Compound 12 (66 g, 0.375 mol, 1 eq) was dissolved in 900 mL of dichloromethane. Triethylamine (114 g, 1.125 mol, 3 eq) was rapidly added dropwise under ice bath conditions. After the addition was complete, acetyl chloride (47 g, 0.6 mol, 1.6 eq) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and stirred overnight. After the reaction was complete, the mixture was poured into ice water, and the pH was adjusted to approximately 3-5 with 4N hydrochloric acid aqueous solution while stirring. The dichloromethane phase was separated, and the aqueous phase was extracted twice with dichloromethane (250 mL * 2). The dichloromethane phases were combined and washed twice with water (500 mL * 2). The mixture was dried over anhydrous sodium sulfate and concentrated to obtain 88 g of crude compound 13.

[0173] STEP 3:

[0174] Compound 13 (85.0 g, 0.39 mol, 1 eq) was dissolved in 1.2 L THF and cooled in an ice-water bath. Sodium borohydride (18 g, 0.468 mol, 1.2 eq) was added in batches, and the mixture was stirred at 0 °C for 2–3 h. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was poured into ice water, and the pH was adjusted to 3–5 with 4 N hydrochloric acid aqueous solution. The mixture was extracted three times with ethyl acetate, washed twice with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 65 g of compound 14. The crude product yield was 75.8%.

[0175] STEP 4:

[0176] Compound 14 (50.0 g, 0.227 mol, 1 eq) was dissolved in 600 mL of dichloromethane, cooled in an ice-salt bath under nitrogen protection, and phosphorus tribromide (0.36 mol, 1.6 eq) was added dropwise. After the addition was complete, the mixture was stirred in an ice-water bath for 2-3 h, and the reaction was monitored by TLC until completion. For post-processing, the reaction solution was added to the stirred ice-water bath, the organic phase was separated, and the aqueous phase was extracted twice with dichloromethane. The dichloro phases were combined, washed twice with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain 43 g of compound 15, with a yield of 67%.

[0177] STEP 5:

[0178] Ropivacaine base (38.7 g, 0.134 mol, 1.0 eq) and compound 15 (38 g, 0.134 mol, 1.0 eq) were added to a 1 L single-necked flask, followed by the addition of 400 mL of acetonitrile. The mixture was heated to 45 °C and stirred overnight. TLC monitoring was performed. The acetonitrile was evaporated to dryness, recrystallized from ethyl acetate, and dried to give 68 g of a white solid, T4-9R, with a yield of 88.8%. Its NMR spectrum is shown below. Figure 13 As shown. MS m / z(ESI): 477.3 [M]; 1 H NMR (300MHz, DMSO-d) 6 ): δ10.35(s,1H),7.42(s,1H),7.32-7.26(m,2H),7.23-7.14(m,3H),5.25-5.20(m,1H),5.05-5.01(m,1H),4.93(s,2H),4.76-4.72(m,1 H),3.70-3.68(m,1H),3.65(s,1H),3.33-3.24(m,2H),2.42-2.21(m,13H),2.08-1.91(m,3H),1.80-1.75(m,2H),0.91(t,3H,J=7.2Hz).

[0179] Example 8: Pharmacological Study

[0180] 1. Materials

[0181] Twenty-four male SD rats, weighing 260-280 grams, were used; ropivacaine hydrochloride injection and T4-9R injection were administered.

[0182] 2. Method

[0183] 2.1 Grouping and Modeling

[0184] SD rats with normal pain thresholds were randomly divided into three groups of eight each. A pain model was established using the Brennan method. The specific method was as follows: Rats were fasted for 6 hours and deprived of water for 1 hour before surgery. After the pain threshold was measured using the Fleisham method, the rats were placed in a sealed anesthesia box and induced with 1.5-2% isoflurane. After loss of consciousness, the animals were removed, and the right hind foot was disinfected with iodine. A 1cm incision was made from 0.5cm proximal to the toe on the sole of the foot. After incising the skin and fascia, the foot muscles were lifted with ophthalmic forceps and longitudinally cut (maintaining the origin, insertion, and attachment of the muscles). Hemostasis was achieved by applying pressure. Before suturing, each group of animals was injected into the incision with 0.5ml of physiological saline, 10mg / kg of ropivacaine hydrochloride, and 10mg / kg of T4-9R, respectively. After administration, the incision was sutured with 2-0 fine silk sutures, using two stitches. Throughout the surgery, the rats were maintained under anesthesia with the same concentration of isoflurane via a face mask.

[0185] 2.2 Von Frey Test and Result Statistics

[0186] After the animals regained consciousness and returned to normal condition (approximately 1 hour post-surgery), pain threshold determination was performed using the Fleishort method. Pain thresholds were then measured at 1, 2, 4, 8, 12, 16, and 24 hours post-surgery. During pain threshold measurement, the surgical paw of each rat model was stimulated with gradually increasing force using a filament, and the threshold value (g) at which the animal exhibited a paw withdrawal response was recorded. Measurements were taken 2-3 times, and the average value was recorded. Experimental results were analyzed using SPSS 17.0. One-way ANOVA was used for comparisons between groups. P < 0.05 was considered statistically significant. The experimental results are shown in Table 1 below.

[0187] Table 1 Experimental Results

[0188]

[0189]

[0190] 2.3 Discussion of Results

[0191] The results show that compounds T4-9R, R-AC-3, and R-OME-3 still have significant analgesic effects 16 hours after surgery, and their effects are significantly better than those of ropivacaine hydrochloride.

[0192] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

[0193] The foregoing embodiments and methods described in this invention may vary based on the capabilities, experience, and preferences of those skilled in the art.

[0194] Listing the steps of the method in a certain order in this invention does not constitute any restriction on the order of the method steps.

Claims

1. A compound or its stereoisomer, wherein the compound has the following structure: in, X - It is an anion; X is selected from: F, Cl, Br, I; R1, R2, R4, and R5 are all H, and R3 is selected from: C1-6 alkoxy, C2-6 alkylacyloxy; or, R1, R4, and R5 are all H, R2 is a C2-6 alkynyloxy group, and R3 is a C2-6 alkyl acyloxy group; or, R1, R2, R3, and R4 are all H, and R5 is selected from: C1-6 alkoxy, C2-6 alkylacyloxy; or, R1, R2, R3, and R5 are all H, and R4 is selected from C1-6 alkoxy and C2-6 alkyl acyloxy.

2. The compound according to claim 1, characterized in that, R1, R2, R4, and R5 are all H, and R3 is selected from: methoxy, ethoxy, propoxy, acetoxy, propionyloxy, and butyryloxy.

3. The compound according to claim 1, characterized in that, R1, R4, and R5 are all H, R2 is selected from propynoxy, butynoxy, and pentynoxy, and R3 is selected from acetoxy, propionyloxy, and butyryloxy.

4. The compound according to claim 1, characterized in that, R1, R2, R3, and R4 are all H, and R5 is selected from: methoxy, ethoxy, propoxy, acetoxy, propionyloxy, and butyryloxy.

5. The compound according to claim 1, characterized in that, R1, R2, R3, and R5 are all H, and R4 is selected from: methoxy, ethoxy, propoxy, acetoxy, propionyloxy, and butyryloxy.

6. The compound according to claim 1, characterized in that, The compound is selected from the following structures:

7. The compound according to any one of claims 1-6, characterized in that, The stereoisomer has the following structure:

8. A pharmaceutical composition comprising the compound or a stereoisomer thereof as claimed in any one of claims 1-7 and one or more pharmaceutically acceptable excipients.

9. Use of the compound or its stereoisomer according to any one of claims 1-7 in the preparation of anesthetics or medicaments for the prevention and / or treatment of pain.

10. The application as described in claim 9, characterized in that, The anesthetic drug is a local anesthetic drug.

11. The application as described in claim 9, characterized in that, The pain can be acute or chronic.

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