Patent Description:
Local anesthetics is a class of drugs that can reversibly block the occurrence and transmission of sensory nerve impulses in the administration area. Under the condition that animals or humans are waking and conscious, it can locally and reversibly block the generation and signal conduction of sensory nerve impulse, resulting in the temporary sensory loss in the innervated area, and thereby reversibly causing the loss of local tissue pain. Generally, the effect of local anesthetics is limited to the administration site and disappears rapidly as the drug diffuses from the administration site. Local anesthetics block the generation of action potentials and the conduction of nerve impulses by directly inhibiting the related ion channels in nerve cells and fiber membranes, thereby producing local anesthesia. Currently, the well-known action mechanism for local anesthetics is blocking voltage-gated Na+ channels in nerve cell membranes, inhibiting nerve impulses, thereby producing local anesthesia.

The local anesthetics currently used in clinical practice are all hydrophobic compounds without electric charge, and they can easily enter nerve cells through cell membranes by diffusion and permeation, to reach the blocking site of sodium channels, and thereby interrupt the excitability of neurons by blocking sodium channels. In fact, although these local anesthetic molecules can easily enter nerve cells by diffusion to exert their actions, they also easily diffuse rapidly from the drug delivery site by diffusion, thereby escaping from nerve cells and resulting in that the local anesthetic effect cannot be kept for a long time. Even if the dosage is increased, the local anesthesia time can only be prolonged to a certain extent. These local anesthetic drugs cannot realize the ideal effect of long-time local anesthesia. At present, most of the local anesthetics commonly used in clinical have an action time of less than <NUM> hours. Because traditional local anesthetics last for a short period of time, analgesic pumps have to be used to maintain nerve block. The use of catheters in the spinal canal, nerve roots, and subcutaneous locations has greatly increased medical costs and the incidence of infection.

On the other hand, traditional local anesthetics do not have specific selectivity for nerve blocking. They block a variety of nerve fibers extensively during use, and affect various nerve functions such as sensation, pain, movement, and sympathetic nerves. This pharmacological feature greatly limits the wide application of local anesthetics in clinical practice. For example, early functional exercise and rehabilitation of patients after knee replacement is particularly important, however, there are no drugs that selectively block pain in the current local anesthetics. Most of surgical patients who use local anesthetics experience the motor nerves being blocked, unable to restore motor function, that limits postoperative rehabilitation. The study on local anesthetics urgently needs to introduce new research ideas and develop long-acting local anesthetics that selectively block sensory function, without affecting motor function, to meet clinical requirements.

The chemical structure of traditional local anesthetics generally contains at least one or more non-amide tertiary N atoms. When N is substituted, the corresponding quaternary ammonium compound will be obtained. The molecular structure of the quaternary ammonium compound has a positive charge, and the ability to penetrate the cell membrane is significantly reduced. For example, once the tertiary amine N atom in lidocaine is substituted with ethyl, a quaternary ammonium compound called QX-<NUM> will be obtained. Similar to QX-<NUM>, QX-<NUM> is also another quaternary ammonium salt having similar structure. Because the structures of QX-<NUM> and QX-<NUM> have positive charges, they cannot pass through cell membranes under normal conditions, and thus cannot quickly produce local anesthesia. But once it passes through the cell membrane, it can significantly inhibit sodium ion channels in nerve cells, resulting in a lasting local anesthetic effect (<NPL>). Current research has found that QX-<NUM> can easily enter nerve cells through the activation of TRPV1 channel with the assistance of capsaicin (transient receptor potential channel vanilloid subtype <NUM> agonist, i.e. TRPV1 Agonist), producing a long-time nerve block (<NPL>). However, the strong irritation of capsaicin makes it difficult to have application prospects.

Studies have further shown that the combination of QX314 and local anesthetics clinically used such as bupivacaine and lidocaine can quickly produce anesthesia and avoid the irritation of capsaicin. However, the synergistic use of the above drugs still cannot achieve the expected effect of local anesthesia. With the addition of surfactants, it can also help QX314 enter the cell membrane and cause local anesthesia for more than <NUM> hours (<NPL>). The current research has indicated that QX314 has some safety issues, which are mainly manifested as local nerve damage, and the death of experimental animals during intrathecal injection and so on. Based on QX-<NUM>, a series of long-chain compounds with surfactant structure have been developed, and they can realize a longer local anesthetic effect to a certain extent. However, since this kind of compounds have a surfactant-like structure, although they can produce long-acting effect at a certain degree, they will also cause serious muscle and nerve damage in local injection site, with poor safety. Meanwhile, similar compounds that have been reported so far do not have selective local anesthesia, and cannot meet clinical needs. Therefore, whether QX314 is used alone, or it is used in combination with other active drugs, or long-chain compounds of QX314 have structural characteristics of surfactant, have the disadvantages of poor safety and poor selectivity for local anesthesia. Therefore, it is of great significance to study a local anesthetic with fast onset, long-time action, good safety, and specific selectivity. <CIT>, <CIT> and <CIT> disclose compounds used as anesthetic drugs.

In view of above-mentioned problems, the present invention provides a new class of quaternary ammonium compounds, which have both long-acting and selective local anesthesia (the blocking time of sensory nerve is longer than that of motor nerve), and the compound has the advantages of fast onset, long-time local anesthetic action, good local anesthetic selectivity, less nerve damage, and high safety, compared with the existing QX314, QX314 compositions, and the long-chain compound with surfactant structure characteristics.

The present invention provides compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof:
<CHM>
wherein.

Further, said compound is as shown in formula II:
<CHM>
wherein.

Further, said compound is as shown in formula III:
<CHM>
wherein.

Further, said compound is as shown in formula IV:
<CHM>
wherein.

Further, the structure of the compound is one of the followings:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

The present invention also provides a use of a composition for preparing a local anesthetic medicine, and said composition is formed by the compound mentioned above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, together with a pharmaceutically acceptable carrier.

Further, said local anesthetic medicine makes the blocking time of sensory nerve longer than that of motor nerve; and/or.

The present invention also provides a drug, which is a composition formed by the compound mentioned above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, with the addition of pharmaceutically acceptable excipients.

The compounds and derivatives provided in the present invention can be named according to IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracting Service, Columbus, OH) naming system.

For the definition of the terms used in the present invention: unless otherwise specified, the initial definition provided for the group or the term herein is applicable to those in the whole specification; for terms not specifically defined herein, according to the disclosure content and the context, the term should have the meaning commonly given by those skilled in the field.

"Substitution" means that the hydrogen in a molecule is substituted by other different atoms or molecules.

Halogen is fluorine, chlorine, bromine, or iodine.

"Alkyl" is a hydrocarbon group formed by losing one hydrogen in an alkane molecule, such as methyl -CH<NUM>, ethyl -CH<NUM>CH<NUM>, etc. "C<NUM>-<NUM> alkyl" denotes a straight or branched hydrocarbon chain containing <NUM> to <NUM> carbon atoms.

"Alkylenyl" denotes the hydrocarbon group formed by losing two hydrogens in the alkane molecule, such as methylene -CH<NUM>-, ethylidene -CH<NUM>CH<NUM>-, etc. "C<NUM>-<NUM> alkylenyl" denotes a straight or branched hydrocarbon chain containing <NUM> to <NUM> carbon atoms.

"Substituted or unsubstituted C<NUM>-C<NUM> alkyl" denote C<NUM>-C<NUM> alkyl that can be substituted or not be substituted.

"L<NUM> is a substituted or unsubstituted C<NUM>~<NUM> alkylenyl; wherein, the main chain of said alkylenyl contains <NUM> to <NUM> heteroatoms" means a straight or branched hydrocarbon chain containing <NUM> to <NUM> carbon atoms; said hydrocarbon chain can be substituted or unsubstituted; "the main chain of said hydrocarbon contains heteroatoms" means that a carbon in the main chain is substituted with a heteroatom, which is O, S, or N substituted.

"Aryl" denotes all-carbon monocyclic or fused polycyclic (i.e. ring sharing adjacent carbon atom pairs) group with conjugated π electron system, such as phenyl and naphthyl. Said aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but can not contain heteroatoms such as nitrogen, oxygen, or sulfur. At the same time, the point connecting with the parent must be on the carbon in the ring having the conjugated π electron system. Aryls can be substituted or unsubstituted, i.e. aryls can be substituted by <NUM> to <NUM> deuterium, C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> alkoxy, C<NUM>-C<NUM> alkylthio, halogen, nitro, cyano, hydroxyl, carboxyl, amino, and so on.

The term "pharmaceutically acceptable salt" denotes the salt formed by the compound of the present invention and pharmaceutically acceptable inorganic and organic acids, which is suitable for contacting the tissue of the object (e.g. human) without undue side effects. Among them, the preferred inorganic acids include (but not limited to) hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid; the preferred organic acids include (but not limited to) formic acid, acetic acid, propionic acid, succinic acid, naphthalene disulfonic acid (<NUM>,<NUM>), asiatic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, niacin, isoniacin, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids.

The term "solvate" denotes the solvate formed by the compound of the present invention and pharmaceutically acceptable solvents, in which the pharmaceutically acceptable solvent includes (but not limited to) water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran, and dichloromethane.

The term "pharmaceutically acceptable stereoisomer" means that the chiral carbon atom involved in the compound of the present invention may be R-configuration, S-configuration, or a combination thereof.

The present invention provides a class of quaternary ammonium compounds with novel structures, as well as the preparation method and the use thereof. The compound has a fast onset of action, a long-time local anesthetic (more than <NUM> hours, and the local anesthesia time for most compounds exceeding <NUM> hours) effect after a single administration, a selectivity for nerve block (the blocking time of sensory nerve is longer than that of motor nerve, and the difference time is greater than or equal to <NUM> hours, and the difference time for most compounds is greater than <NUM> hours), and has both long-acting and selective local anesthetic effect, that significantly reduced the side effects of QX314, QX314 compositions, and the quaternary ammonium compound with surfactant structure characteristics. Moreover, the compound has better safety, that is, the compound of the present invention and its pharmaceutically acceptable salts can be used to prepare safe drugs with long-acting and selective local anesthesia, which has the advantages of long-time local anesthetic action, good local anesthetic selectivity, less nerve damage, and high safety.

By following specific examples of said embodiments, above content of the present invention is further illustrated. But it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples.

The starting materials and equipment used in the specific examples of the present invention are all known products and can be obtained by purchasing commercially available items.

Compound 1a (<NUM>, <NUM> mmol) was dissolved in <NUM>,<NUM>-dibromopropane (<NUM>), and the mixture was heated to <NUM> and reacted for <NUM>. The reaction was monitored by TLC (DCM: MeOH = <NUM>:<NUM>, Rf = <NUM>). A suitable amount of ethyl acetate was added to form a viscous syrupy substance. The supernatant was poured out, to obtain the residue of <NUM> crude product, which was dissolved in <NUM> methanol and mixed with silica gel. After dry loading, the crude product was purified by silica gel column chromatography, using eluent CH<NUM>Cl<NUM>:MeOH = <NUM>:<NUM>. The eluent was collected and concentrated to obtain <NUM> of crude product. The resultant product was recrystallized in ethyl acetate and dichloromethane, to prepare <NUM> of an off-white solid powder (1b) with a yield of <NUM>%, which was used in the next reaction. Intermediate 1b (<NUM>, <NUM> mmol) prepared above and N-(<NUM>,<NUM>-dimethylphenyl)-<NUM>-piperidinecarboxamide (<NUM>, <NUM> mmol,<NPL>) were dissolved in <NUM> ethanol, to which was added DIPEA (<NUM>, <NUM>, <NUM> mmol). The mixture was warmed to <NUM> and kept for <NUM> hours. Then, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent: CH<NUM>Cl<NUM>:MeOH = <NUM>:<NUM>. The eluate was collected and concentrated to obtain <NUM> of a white solid (<NUM>). Yield: <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

Compound 2a (<NUM>, <NUM> mmol) was dissolved in <NUM>-bromoethyl ether (<NUM>), and the mixture was heated to <NUM> and reacted for <NUM>. The reaction was monitored by TLC (DCM: MeOH = <NUM>:<NUM>, Rf = <NUM>). A suitable amount of ethyl acetate was added, then the reaction solution solidified to produce white solids, and <NUM> of crude product was filtered out as white solid, that was purified by silica gel column chromatography, using eluent CH<NUM>Cl<NUM>: MeOH = <NUM>:<NUM>. The eluent was collected and concentrated to obtain <NUM> of a white solid (intermediate 2b), with a yield of <NUM>%, which was used in the next reaction.

Intermediate 2b (<NUM>, <NUM> mmol) prepared above and N-(<NUM>,<NUM>-dimethylphenyl)-<NUM>-piperidinecarboxamide (<NUM>, <NUM> mmol, <NPL>) were dissolved in <NUM> ethanol, to which was added DIPEA (<NUM>, <NUM>, <NUM> mmol). The mixture was allowed to react for <NUM> days at the temperature of <NUM>. Then, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent CH<NUM>Cl<NUM>:MeOH = <NUM>:<NUM>. The eluate was collected and concentrated to obtain <NUM> of a solid as white powder (<NUM>). Yield: <NUM>%. <NUM> H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

Compound 3a (<NUM>, <NUM> mmol) and <NUM>,<NUM>-dibromotetradecane (<NUM>, <NUM> mmol) were dissolved in acetonitrile (<NUM>), and the mixture was heated to <NUM> and reacted for <NUM>. The reaction was monitored by TLC (DCM: MeOH = <NUM>:<NUM>, Rf = <NUM>). A suitable amount of ethyl acetate was added, then the reaction solution solidified to produce white solids, and <NUM> of crude product was filtered out as white solid, which was purified by silica gel column chromatography, using eluent CH<NUM>Cl<NUM>:MeOH = <NUM>:<NUM>. The eluent was collected and concentrated to obtain <NUM> of a white powder solid (3b), with a yield of <NUM>%, which was used in the next reaction.

Intermediates 3b (<NUM>, <NUM> mmol) and 3c (<NUM>, <NUM> mmol) prepared above were dissolved in the solvent mixture of <NUM> ethanol and <NUM> methanol, to which was added DIPEA (<NUM>, <NUM>, <NUM> mmol). The mixture was allowed to react for <NUM> days at the temperature of <NUM>. After completion of the reaction, the crude product was purified by silica gel column chromatography, using eluent CH<NUM>Cl<NUM>:MeOH = <NUM>:<NUM>. The eluate was collected and concentrated to obtain <NUM> white powder solid (<NUM>). Yield: <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM>(m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

Compound 4a (<NUM>, <NUM> mmol) was dissolved in bromo-PEG3-alcohol (<NUM>), and the mixture was heated to <NUM> and reacted for <NUM>. The reaction was monitored by TLC (DCM: MeOH = <NUM>:<NUM>). A suitable amount of ethyl acetate was added to form a viscous syrupy substance. The supernatant was poured out, and the residual solid was dissolved, mixed with silica gel, and purified by silica gel column chromatography, with eluent CH<NUM>Cl<NUM>:MeOH = <NUM>:<NUM>. The eluent was collected and concentrated to obtain <NUM> of crude product. The resultant product was recrystallized in ethyl acetate and dichloromethane, to prepare <NUM> of an off-white solid powder (4b), which was directly used in the next reaction.

Intermediates 4b (<NUM>, <NUM> mmol) and 4c (<NUM>, <NUM> mmol) prepared above were dissolved in <NUM> ethanol, to which was added DIPEA (<NUM>, <NUM> mmol). The mixture was heated to <NUM> and kept for <NUM> hours. Then, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent: CH<NUM>Cl<NUM>:MeOH = <NUM>:<NUM>. The eluate was collected and concentrated to obtain <NUM> of a white solid (<NUM>). Yield: <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

Compound 5a (<NUM>, <NUM> mmol) was dissolved in <NUM> of <NUM>,<NUM>-dibromooctane, and the mixture was heated to <NUM> and reacted. The reaction was monitored by TLC (DCM: MeOH = <NUM>:<NUM>). After completion of the reaction, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent CH<NUM>Cl<NUM>: MeOH = <NUM>: <NUM>. The eluent was collected and concentrated to obtain <NUM> of a dark brown compound (5b), with a yield of <NUM>%, which was used in the next reaction.

Intermediates 5b (<NUM>, <NUM> mmol) and 5c (<NUM>, <NUM> mmol) prepared above were dissolved in <NUM> ethanol, to which was added DIPEA (<NUM>, <NUM> mmol). The mixture was allowed to react for <NUM> days at the temperature of <NUM>, and the reaction was detected by TLC (DCM : MeOH = <NUM> : <NUM>). After completion of the reaction, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent CH<NUM>Cl<NUM>:MeOH = <NUM>:<NUM>. The eluate was collected and concentrated to obtain <NUM> of a white solid (<NUM>). Yield: <NUM>%. <NUM> H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>),<NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

Compound 6a (<NUM>, <NUM> mmol) was dissolved in <NUM>,<NUM>-dibromohexane (<NUM>), and the mixture was heated to <NUM> and reacted for <NUM>. The reaction was monitored by TLC (DCM: MeOH = <NUM>:<NUM>, Rf = <NUM>). A suitable amount of ethyl acetate was added to form a viscous syrupy substance. The supernatant was poured out, to obtain the residue of <NUM> of crude product, which was dissolved in <NUM> methanol and mixed with silica gel. After dry loading, the crude product was purified by silica gel column chromatography, with eluent CH<NUM>Cl<NUM>: MeOH = <NUM>:<NUM>. The eluent was collected and concentrated to obtain <NUM> of crude product. The resultant product was recrystallized in ethyl acetate and dichloromethane, to prepare <NUM> of an off-white solid powder (6b) with a yield of <NUM>%, which was used in the next reaction.

Intermediates 6b (<NUM>, <NUM> mmol) and 6c (<NUM>, <NUM> mmol) prepared above were dissolved in <NUM> ethanol, to which was added DIPEA (<NUM>, <NUM>, <NUM> mmol). The mixture was heated to <NUM> and kept for <NUM> hours. Then, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent: CH<NUM>Cl<NUM>:MeOH = <NUM>:<NUM>. The eluate was collected and concentrated to obtain <NUM> of a white solid (<NUM>). Yield: <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

Compound 7a (<NUM>, <NUM> mmol) was dissolved in <NUM>,<NUM>-dibromopentane (<NUM>), and the mixture was heated to <NUM> and reacted for <NUM>. The reaction was monitored by TLC (DCM: MeOH = <NUM>:<NUM>). A suitable amount of ethyl acetate was added to form a viscous syrupy substance. The supernatant was poured out, and the residue was dissolved and mixed with silica gel. After dry loading, the crude product was purified by silica gel column chromatography, with eluent CH<NUM>Cl<NUM>: MeOH = <NUM>:<NUM>. The eluent was collected and concentrated to obtain <NUM> crude product. The crude product was recrystallized in ethyl acetate and dichloromethane, to prepare <NUM> of an off-white solid powder (7b), which was used in the next reaction.

Intermediates 7b (<NUM>, <NUM> mmol) and 7c (<NUM>, <NUM> mmol) prepared above were dissolved in <NUM> ethanol, to which was added DIPEA (<NUM>, <NUM> mmol). The mixture was heated to <NUM> and kept for <NUM> hours. Then, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent: CH<NUM>Cl<NUM>:MeOH = <NUM>:<NUM>. The eluate was collected and concentrated to obtain <NUM> of a white solid (<NUM>). Yield: <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: [C<NUM>H<NUM>N<NUM>O<NUM>S] +, <NUM>.

Compound 8a (<NUM>, <NUM> mmol) was dissolved in <NUM>,<NUM>-dibromoheptane (<NUM>), and the mixture was heated to <NUM> and reacted for <NUM>. The reaction was monitored by TLC (DCM: MeOH = <NUM>:<NUM>, Rf = <NUM>). A suitable amount of ethyl acetate was added, then the reaction solution solidified to produce white solids, and <NUM> of crude product was filtered out as white solid, which was purified by silica gel column chromatography, using eluent CH<NUM>Cl<NUM>:MeOH = <NUM>:<NUM>. The eluent was collected and concentrated to obtain <NUM> of a white powder solid (8b), with a yield of <NUM>%, which was used in the next reaction.

Intermediates 8b (<NUM>, <NUM> mmol) and 8c (<NUM>, <NUM> mmol) prepared above were dissolved in the solvent mixture of <NUM> ethanol and <NUM> methanol, to which was added DIPEA (<NUM>, <NUM>, <NUM> mmol). The mixture was allowed to react for <NUM> days at the temperature of <NUM>. After completion of the reaction, the crude product was purified by silica gel column chromatography, using eluent CH<NUM>Cl<NUM>:MeOH = <NUM>:<NUM>. The eluate was collected and concentrated to obtain <NUM> of a white powder solid (<NUM>), with a yield of <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>ClN<NUM>O<NUM>S]+.

Compounds 9a (<NUM>, <NUM> mmol) and 9b (<NUM>, <NUM> mmol) was heated to <NUM> and reacted for <NUM>. The reaction was monitored by TLC (DCM: MeOH = <NUM>:<NUM>). A suitable amount of ethyl acetate was added to form a viscous syrupy substance. The supernatant was poured out, and the residue of the crude product (<NUM>) was dissolved in <NUM> methanol and mixed with silica gel. After dry loading, the crude product was purified by silica gel column chromatography, with eluent CH<NUM>Cl<NUM>: MeOH = <NUM>:<NUM>. The eluent was collected and concentrated to obtain <NUM> of crude product. The crude product was recrystallized in ethyl acetate and dichloromethane, to prepare <NUM> of an off-white solid powder (9c) with a yield of <NUM>%, which was used in the next reaction.

Intermediates 9c (<NUM>, <NUM> mmol) and 9d (<NUM>, <NUM> mmol) prepared above were dissolved in <NUM> ethanol, to which was added DIPEA (<NUM>, <NUM>, <NUM> mmol). The mixture was heated to <NUM> and kept for <NUM> hours. Then, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent CH<NUM>Cl<NUM>:MeOH = <NUM>:<NUM>. The eluate was collected and concentrated to obtain <NUM> of a white solid (<NUM>). Yield: <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>- <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>BrN<NUM>O<NUM>]+.

<NUM> of the product obtained in Example <NUM> was dissolved in <NUM> of dichloromethane, to which was added dropwise the solution of <NUM> mol/L hydrochloric acid-methanol at equal molar concention in an ice bath, and then the resultant solution was concentrated to dryness under reduced pressure. The residue was dried in vacuum to provide a pale yellow solid (<NUM>), with a yield of <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM> of the product obtained in Example <NUM> was dissolved in <NUM> of dichloromethane, to which was added <NUM> eq p-toluenesulfonic acid, and then the resultant solution was concentrated to dryness under reduced pressure. The residue was dried in vacuum to provide a pale yellow solid (<NUM>), with a yield of <NUM>%.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>BrN<NUM>O<NUM>]+.

With reference to the method in Example <NUM>, an off-white solid powder was obtained, with a yield of <NUM>%.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM>(m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM> H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (t, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

With reference to the method in Example <NUM>, a white solid powder was obtained, with a yield of <NUM>%.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM> H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM> H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM>,<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM> H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (t, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (t, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>S]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: [C<NUM>H<NUM>ClN<NUM>O<NUM>S] +, <NUM>.

<NUM> H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>- <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>N<NUM>O<NUM>]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>FN<NUM>O<NUM>S] +.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ (ppm): <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>- <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>). HRMS: m/z <NUM> [C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>]+.

In the following, the beneficial effects of the compounds of the present invention are illustrated by experimental examples.

Selected compounds <NUM>-<NUM> prepared in Examples, lidocaine (the positive control group), and levobupivacaine (the positive control group) were respectively assigned SD rats weighing <NUM>-<NUM> (half male and half female), and the rats were fully adapted to the experimental environment, <NUM> rats for each group.

Dosage: for lidocaine group, lidocaine was formulated with distilled water into a solution at the concentration of <NUM>% (<NUM> mmol/L); for levobupivacaine group, levobupivacaine was formulated with distilled water into a solution at the concentration of <NUM>% (<NUM> mmol/L); the compound of the present invention was formulated with distilled water into a solution at the concentration of <NUM> mmol/mL.

The injection volume for each rat was <NUM>, which was guided by a nerve locator and injected near the rat's sciatic nerve. Using von Frey stimulator, the rats were stimulated the soles of the feet in the injected side, to observe the effect of local anesthesia. Meanwhile, Postural Extensor Thrust (PET) was used to evaluate the motor function of the rat: the rat was lifted vertically and the hindlimb in the injected side pedaled on the platform of the electronic balance. At this time, the muscle strength of the rat's hindlimb was displayed by the value on the balance caused by pedal. When the limb was completely paralyzed, the reading was the limb's own weight, about <NUM>. If the measured value was more than half of the difference between the baseline and the limb weight, the motor function was regarded as recovery, and if the value was less than or equal to this difference, the motor function was regarded as loss.

Experimental results showed that the compounds of the present invention could produce local anesthesia lasting more than <NUM>, and the blocking time of the sensory nerve was significantly longer than that of the motor nerve, and the difference time is greater than or equal to <NUM>, wherein most of the compounds have a time difference of greater than or equal to <NUM>.

After the back of SD rat weighing <NUM> to <NUM> (half female and half male) was shaved and disinfected, a circle with a diameter of about <NUM> was drawn on the side of the exposed back, and the circle is divided into <NUM> equal parts. <NUM> solution containing a drug was subcutaneously injected into the skin of the center: using saline as the solvent, <NUM>% bupivacaine hydrochloride (<NUM> mmol/L), <NUM>% lidocaine hydrochloride (<NUM> mmol/L), the concentration of compounds <NUM>-<NUM> according to the present invention being <NUM> mmol/L, <NUM> rats for each group. Among the Von Frey fiber yarns, the one with a strength of <NUM> was bound to the needle for local skin stimulation. One minute After the drug was injected, the above method was used to stimulate in <NUM> divisions. If no back skin contraction behavior was observed in the same aliquot after three consecutive stimulations, the drug was considered to have positive effect. If back skin contraction was observed, the local anesthetic effect was considered as loss. If four or more areas in <NUM> aliquots showed positive local anesthesia, the local anesthesia of the drug was considered as effective, while if less than <NUM> areas in <NUM> aliquots showed positive, the local anesthesia was considered as failure. Each compound was tested with <NUM> rats.

Experimental results showed that this class of drugs could produce local anesthesia lasting more than <NUM> hours in the subcutaneous infiltration model of rat, wherein most compounds could produce local anesthesia for more than <NUM> hours.

The injection volume for each rat was <NUM>, which was injected near the rat's sciatic nerve. On day <NUM> and day <NUM> after injection near the sciatic nerve, the experimental rats were euthanized by injecting bupivacaine into the heart under isoflurane anesthesia. About <NUM> sciatic nerve was collected at the injection site, stored in <NUM>% formaldehyde solution for <NUM> hours, stained with HE, and cut into slices with <NUM> thickness.

The injection volume for each rat was <NUM>, which was injected under the skin of the back of the rat. On day <NUM> and day <NUM> after subcutaneous injection, the experimental rats were euthanized by injecting bupivacaine into the heart under isoflurane anesthesia. The skin tissue at the injection site was collected, stored in <NUM>% formaldehyde solution for <NUM> hours, stained with HE, and cut into slices with <NUM> thickness.

The evaluation of neuropathological damage showed that compared with the lidocaine positive control group and the levobupivacaine positive control group, the compounds of the Examples did not show significant differences in the aspects of nerve injury, vascular proliferation, demyelination, muscle inflammation, and connective tissue inflammation, and thus had good safety.

Claim 1:
A compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof:
<CHM>
wherein,
each of X and Y is independently selected from the group consisting of O and NR<NUM>, wherein R<NUM> is selected from the group consisting of H, deuterium, and C<NUM>-C<NUM> alkyl;
Z- is a pharmaceutically acceptable anion;
R<NUM> is n<NUM> R<NUM>-substituted aryls;
R<NUM> is n<NUM>' R<NUM>'-substituted aryls;
wherein, n<NUM> and n<NUM>' are each independently an integer of from <NUM> to <NUM>, and R<NUM> and R<NUM>' are each independently selected from the group consisting of deuterium, C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, and amino;
when the dotted line between R<NUM> and R<NUM> in Formula I is none, R<NUM> is a substituted C<NUM>-C<NUM> alkyl or unsubstituted C<NUM>-C<NUM> alkyl, and R<NUM> is independently a substituted or unsubstituted C<NUM>-C<NUM> alkyl, wherein said substituent is selected from the group consisting of deuterium, substituted or unsubstituted C<NUM>-C<NUM> alkoxy, halogen, nitro, cyano, hydroxyl, carboxy, amino, ester, C<NUM>-C<NUM> alkylthio, and mercapto; the substituent of said alkoxy is an hydroxyl;
when the dotted line between R<NUM> and R<NUM> in formula I is a bond, R<NUM> and R<NUM> are independently substituted or unsubstituted C<NUM>-C<NUM> alkylenes, and the substituent is C<NUM>-C<NUM> alkyl; wherein, the main chain of the alkylene contains <NUM> to <NUM> heteroatoms, and the heteroatom is selected from the group consisting of O, S, and NR<NUM>, wherein said R<NUM> is selected from the group consisting of hydrogen, deuterium, and C<NUM>-C<NUM> alkyl;
L<NUM> is a substituted or unsubstituted C<NUM>-C<NUM> alkylenyl; wherein the main chain of the alkylene contains <NUM> to <NUM> heteroatoms, and the heteroatom is selected from the group consisting of O, S, and NR<NUM>, wherein said R<NUM> is selected from the group consisting of hydrogen, deuterium, C<NUM>-C<NUM> alkyl, and C<NUM>-C<NUM> alkoxy; the substituent is selected from the group consisting of deuterium, C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> alkoxy, and halogen;
and L<NUM> is a substituted or unsubstituted C<NUM>-C<NUM> alkylenyl, and the substituent is selected from the group consisting of deuterium, C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> alkoxy, and halogen.