N-substituted arylamine derivative as well as preparation method and application thereof

Abstract

The invention relates to a compound with a structure as shown in a formula I, a formula II, a formula III, a formula IV, a formula V or a formula VI or a stereoisomer or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound and application of the pharmaceutical composition. # imgabs0 #

Description

N-substituted aromatic amine derivatives and preparation methods and uses thereof Technical Field

[0001] The present application relates to N-substituted aromatic amine derivatives, preparation methods thereof, and uses thereof in related medical treatment fields. Background Art

[0002] Local anesthetics block the conduction of various nerve impulses, primarily suppressing touch, pressure, and pain. At higher concentrations, they may also inhibit motor nerve function. Local anesthetics are applied to a local area, causing loss of sensation and pain. They provide a narrow anesthesia range and are primarily suitable for minor surgeries and intubation. Compared to general anesthetics, they have fewer adverse reactions and are safer.

[0003] Local anesthetics can be used in different areas to block sensory nerves and produce anesthesia. They can be divided into:

[0004] (1) Surface anesthesia: Anesthetic solution is directly dripped, smeared, or sprayed on the surface of the mucosa to paralyze the sensory nerve endings under the mucosa. It is used for surgeries on the oral cavity, nose, pharynx, larynx, eyes, and urethra mucosa.

[0005] (2) Infiltration anesthesia: injecting drugs into the skin, subcutaneous tissue or deep into the surgical field to block nerve conduction at the medication site;

[0006] (3) Block anesthesia: also known as conduction anesthesia, the drug solution is injected near the peripheral nerve trunk to block nerve conduction, so that the area controlled by the nerve produces anesthesia. It is often used in surgeries on the limbs, face, mouth, etc.

[0007] (4) Subarachnoid block anesthesia: also known as spinal anesthesia, the drug solution is injected into the subarachnoid space from the lower lumbar intervertebral space to anesthetize the spinal nerve roots in that area. It is commonly used in lower abdominal and lower limb surgery.

[0008] (5) Epidural block anesthesia: also known as epidural anesthesia, the drug solution is injected into the epidural space, allowing it to diffuse along the spinal nerve roots and enter the intervertebral foramen, blocking the nerve trunk in the intervertebral foramen to achieve anesthesia in a certain segment of the trunk. It can be used for surgeries from the neck to the lower limbs, and is particularly suitable for abdominal surgery.

[0009] Local anesthetics can be divided into categories such as esters and amides based on their chemical structure.

[0010] Common local anesthetics belonging to the ester class include procaine, cocaine, tetracaine, chloroprocaine, proparacaine, oxybuprocaine, benzocaine, etc. Common local anesthetics belonging to the amide class include lidocaine, cinchocaine, bupivacaine, mepivacaine, etidocaine, prilocaine, trimecaine, ropivacaine, etc. A single dose of existing local anesthetics can usually maintain the local anesthetic effect for tens of minutes to several hours. Lidocaine is currently the most widely used local anesthetic in clinical practice. Existing local anesthetics often require repeated additional doses in clinical practice to maintain the local anesthetic effect, which is very inconvenient to use, especially in situations where long-term local anesthesia is required.

[0011] There is still a need for a local anesthetic that has a significantly longer duration of local anesthetic effect than existing drugs used in clinical practice, can reduce the number of administrations, and is particularly suitable for situations where prolonged local anesthesia is required.

[0012] Summary of the Invention

[0013] In one aspect of the present application, a compound having a structure of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a polymorph thereof is provided:

[0014] in,

[0015] R A and R B are each independently hydrogen or methyl;

[0016] R 1 H, R 1a 、R 1c or Rx2;

[0017] R 1a is a C1-C10 hydrocarbon group selected from C1-10 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-C4 alkyl-, C2-10 alkenyl, C2-10 alkynyl and C6-10 aryl, and is optionally substituted with a substituent selected from Rx2;

[0018] R 1c for wherein n is an integer from 2 to 8, m is an integer from 1 to 6, o is 2 or 3, p is 1 or 2, q is an integer from 1 to 3, and R N 1 and R N 2 are independently H or C1-C8 alkyl;

[0019] Rx2 is

[0020] R 2Each independently

[0021] R 2’ Each independently is H,

[0022] According to another aspect of the present application, a pharmaceutical composition is provided, comprising a compound according to the present disclosure or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof or a polymorph thereof, and a pharmaceutically acceptable carrier or excipient.

[0023] According to yet another aspect of the present application, provided is use of the compound according to the present disclosure, or its stereoisomer, or its pharmaceutically acceptable salt, or solvate, or its polymorph, in the preparation of a medicament for local anesthesia.

[0024] According to yet another aspect of the present application, a method for local anesthesia is provided, comprising the step of administering to an individual in need thereof an effective dose of a compound according to the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a polymorph thereof, or a pharmaceutical composition according to the present disclosure.

[0025] In the present disclosure, the local anesthesia includes topical anesthesia, infiltration anesthesia, block anesthesia, subarachnoid block anesthesia and epidural block anesthesia. DETAILED DESCRIPTION

[0026] Compound

[0027] According to one aspect of the present application, a compound having a structure of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a polymorph thereof is provided:

[0028] in,

[0029] R A and R B are each independently hydrogen or methyl;

[0030] R 1 H, R 1a 、R 1c or Rx2;

[0031] R 1a is a C1-C10 hydrocarbon group selected from C1-10 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-C4 alkyl-, C2-10 alkenyl, C2-10 alkynyl and C6-10 aryl, and is optionally substituted with a substituent selected from Rx2;

[0032] R 1c for wherein n is an integer from 2 to 8, m is an integer from 1 to 6, o is 2 or 3, p is 1 or 2, q is an integer from 1 to 3, and R N 1 and R N 2 are independently H or C1-C8 alkyl;

[0033] Rx2 is

[0034] R 2 Each is independent as well as

[0035] R 2’ Each independently is H,

[0036] In the present disclosure, the term "hydrocarbon group" refers to a saturated or unsaturated group consisting of carbon and hydrogen atoms, including straight or branched chain hydrocarbon groups, alicyclic hydrocarbon groups, heterocyclic hydrocarbon groups, aromatic hydrocarbon groups, or aromatic heterohydrocarbon groups. For example, C1-C10 hydrocarbon groups include C1-10 alkyl groups, C3-10 cycloalkyl groups, C3-6 cycloalkyl-C1-4 alkyl groups, C2-10 alkenyl groups, C2-10 alkynyl groups, and C6-10 aryl groups.

[0037] In one embodiment, the C1-10 alkyl group includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0038] In one embodiment, the C3-10 cycloalkyl group includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0039] In one embodiment, the C3-6 cycloalkyl-C1-C4 alkyl- is a hydrocarbon group composed of a C3-6 cycloalkyl and a C1-4 alkyl, for example including cyclopropyl-methyl, cyclobutyl-methyl, cyclopentyl-methyl, cyclohexyl-methyl and cycloheptyl-methyl.

[0040] In one embodiment, the C2-10 alkenyl group includes, for example, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, and 3-pentenyl.

[0041] In one embodiment, the C2-10 alkynyl group includes, for example, propargyl and 2-butynyl.

[0042] In one embodiment, the C6-10 aryl group includes, for example, a phenyl group.

[0043] In this disclosure, the mark It indicates the position at which the corresponding group is attached to the rest of the compound.

[0044] The term "pharmaceutically acceptable salt" refers to an acid addition salt or base addition salt that is suitable for or compatible with the treatment of an individual. For example, the pharmaceutically acceptable salt can be a salt formed by the free base of a compound according to the present disclosure and one or more of a pharmaceutically acceptable inorganic acid and an organic acid in any proportion. The pharmaceutically acceptable inorganic acid salts include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid; the pharmaceutically acceptable organic acid salts include, for example, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, isethionic acid, formic acid, acetic acid, chloroacetic acid, glycolic acid, trifluoroacetic acid, propionic acid, acrylic acid, butyric acid, isobutyric acid, valeric acid, pivalic acid, hexanoic acid, benzoic acid, phenylacetic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, d-tartaric acid, l-tartaric acid, dl-tartaric acid, glutaric acid, adipic acid, phthalic acid, isophthalic acid, terephthalic acid, and citric acid. The free base of the compound of the present invention and the inorganic and organic acids in the addition salts may be present in a stoichiometric or non-stoichiometric ratio.

[0045] The solvent in the solvate is selected from water, alcohol, acid, ester, ether, ketone, nitrile and halogenated hydrocarbon and a combination thereof, and the amount of the solvent can be present in a stoichiometric ratio or a non-stoichiometric ratio. According to one embodiment, the solvent in the solvate is selected from water, C1-C6 alcohol, C1-C6 acid, C3-C6 ester, C4-C6 ether, C3-C6 ketone, C1-C6 nitrile and C1-C6 halogenated hydrocarbon and a combination thereof. According to one embodiment, the solvent in the solvate is selected from water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, glycerol, acetic acid, propionic acid, butyric acid, ethyl acetate, methyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, ethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetone, butanone, acetonitrile, dichloromethane and chloroform and a combination thereof.

[0046] In one embodiment, the compound having the structure of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI is a compound selected from the following table:

[0047] Preparation of compounds

[0048] According to another aspect of the present disclosure, there is provided a method for preparing the compound according to the present disclosure or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof or a polymorph thereof.

[0049] In one embodiment, a method for preparing an N-substituted-2,6-dimethylaniline derivative having a structure of Formula I or Formula II, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a polymorph thereof, is provided, wherein the compound is prepared by the following route 1:

[0050] As shown in Route 1, the preparation method comprises: reacting a compound of Formula A with a compound of Formula B (1) or Formula B (2) in the presence of an acid-binding agent to obtain a compound of Formula I or Formula II, respectively.

[0051] R A and R B are each independently hydrogen or methyl;

[0052] R 1 R 1a or R 1c ;

[0053] R 1a is a C1-C10 hydrocarbon group selected from C1-10 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl-, C2-10 alkenyl, C2-10 alkynyl and C6-10 aryl, and which is optionally substituted by a substituent selected from Rx2;

[0054] R 1c for wherein n is an integer from 2 to 8, m is an integer from 1 to 6, o is 2 or 3, p is 1 or 2, q is an integer from 1 to 3, and R N 1 and R N 2 are independently H or C1-C8 alkyl;

[0055] Rx2 is

[0056] R 2 Each is independent as well as

[0057] X is a group that easily leaves.

[0058] In one embodiment, X as an easily leaving group includes but is not limited to chlorine, bromine, iodine, sulfonic acid group, carboxylic acid group or substituted carboxylic acid group. In one embodiment, sulfonic acid group includes such as methanesulfonic acid group, benzenesulfonic acid group, p-toluenesulfonic acid group, trifluoromethanesulfonic acid group etc. In one embodiment, carboxylic acid or substituted carboxylic acid group includes such as acetic acid group, trifluoroacetic acid group, trichloroacetic acid group, pivaloyl group etc.

[0059] In one embodiment, the acid binding agent is an inorganic base or an organic base, wherein the inorganic base includes but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, sodium hydride, potassium hydride, calcium hydride, lithium hydride, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium potassium hydrogen phosphate, wherein the organic base includes but is not limited to sodium acetate, sodium propionate, sodium butyrate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, magnesium methoxide, ethyl acetate ... Magnesium alkoxide, magnesium tert-butoxide, trimethylamine, triethylamine, tributylamine, diisopropylamine, diisopropylethylamine, tert-butylamine, N,N-dimethylaniline, tetramethylethylenediamine, DABCO, DBU, DBN, pyridine, DMAP, N-methylmorpholine, tetramethylguanidine, n-butyllithium, tert-butyllithium, phenyllithium, sodium amide, methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, ethylmagnesium iodide, isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, dimethylmagnesium, diethylmagnesium, diisopropylmagnesium, etc., LDA, NaHMDS, KHMDS, LiHMDS, etc.

[0060] According to another aspect of the present disclosure, a compound having a structure of Formula F or Formula F' or a stereoisomer thereof or an addition salt thereof or a solvate thereof or a polymorph thereof is provided, wherein the compound of Formula F or Formula F' is prepared by the following route 2:

[0061] As shown in Scheme 2, the method comprises: (1) reacting a compound of Formula C with benzyl chloroformate in the presence of an acid-binding agent to obtain a compound of Formula D; (2) reacting a compound of Formula D with a compound of Formula B(1) or Formula B(2) in the presence of an acid-binding agent to obtain a compound of Formula E or Formula E', respectively; and (3) deprotecting the compound of Formula E or Formula E' to obtain a compound of Formula F or Formula F', respectively. In the compound of Scheme 2,

[0062] R 1 R 1a or R 1c ;

[0063] R 1a is a C1-C10 hydrocarbon group selected from C1-10 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl-, C2-10 alkenyl, C2-10 alkynyl and C6-10 aryl, and which is optionally substituted by a substituent selected from Rx2;

[0064] R 1c for wherein n is an integer from 2 to 8, m is an integer from 1 to 6, o is 2 or 3, p is 1 or 2, q is an integer from 1 to 3, and R N 1 and R N 2 are independently H or C1-C8 alkyl;

[0065] Rx2 is

[0066] R 3 for where R A and R B are each independently hydrogen or methyl; and

[0067] X is a group that easily leaves.

[0068] In one embodiment, X as an easily leaving group includes, but is not limited to, chlorine, bromine, iodine, sulfonic acid group, carboxylic acid group or substituted carboxylic acid group. In one embodiment, the sulfonic acid group includes, for example, methanesulfonic acid group, benzenesulfonic acid group, p-toluenesulfonic acid group, trifluoromethanesulfonic acid group, etc. In one embodiment, the carboxylic acid or substituted carboxylic acid group includes, for example, acetic acid group, trifluoroacetic acid group, trichloroacetic acid group, pivalic acid group, etc.;

[0069] In one embodiment, the acid binding agent is an inorganic base or an organic base, wherein the inorganic base includes but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, sodium hydride, potassium hydride, calcium hydride, lithium hydride, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium potassium hydrogen phosphate, wherein the organic base includes but is not limited to sodium acetate, sodium propionate, sodium butyrate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, magnesium methoxide, ethyl acetate ... Magnesium alkoxide, magnesium tert-butoxide, trimethylamine, triethylamine, tributylamine, diisopropylamine, diisopropylethylamine, tert-butylamine, N,N-dimethylaniline, tetramethylethylenediamine, DABCO, DBU, DBN, pyridine, DMAP, N-methylmorpholine, tetramethylguanidine, n-butyllithium, tert-butyllithium, phenyllithium, sodium amide, methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, ethylmagnesium iodide, isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, dimethylmagnesium, diethylmagnesium, diisopropylmagnesium, etc., LDA, NaHMDS, KHMDS, LiHMDS, etc.

[0070] According to another aspect of the present disclosure, there is provided an N-substituted-2,6-dimethylaniline derivative having a structure of Formula III, or a stereoisomer thereof, or an addition salt thereof, or a solvate thereof, or a polymorph thereof, wherein the compound is prepared by the following route 3:

[0071] As shown in Scheme 3, the method comprises: reacting a compound of Formula A with a compound of Formula B (3) in the presence of an acid-binding agent to obtain a compound of Formula III.

[0072] R A and R B are each independently hydrogen or methyl;

[0073] R 1 R 1a or R 1c ;

[0074] R 1a is a C1-C10 hydrocarbon group selected from C1-10 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl-, C2-10 alkenyl, C2-10 alkynyl and C6-10 aryl, and which is optionally substituted by a substituent selected from Rx2;

[0075] R 1c for wherein n is an integer from 2 to 8, m is an integer from 1 to 6, o is 2 or 3, p is 1 or 2, q is an integer from 1 to 3, and RN 1 and R N 2 are independently H or C1-C8 alkyl;

[0076] R 2 Each is independent

[0077] Rx2 is and

[0078] X is a group that easily leaves.

[0079] In one embodiment, the easily leaving group X includes but is not limited to chlorine, bromine, iodine, and sulfonic acid. In one embodiment, the sulfonic acid group includes methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, etc.

[0080] In one embodiment, the acid binding agent is an inorganic base or an organic base, wherein the inorganic base includes but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, sodium hydride, potassium hydride, calcium hydride, lithium hydride, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium potassium hydrogen phosphate, wherein the organic base includes but is not limited to sodium acetate, sodium propionate, sodium butyrate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, magnesium methoxide, ethyl acetate ... Magnesium alkoxide, magnesium tert-butoxide, trimethylamine, triethylamine, tributylamine, diisopropylamine, diisopropylethylamine, tert-butylamine, N,N-dimethylaniline, tetramethylethylenediamine, DABCO, DBU, DBN, pyridine, DMAP, N-methylmorpholine, tetramethylguanidine, n-butyllithium, tert-butyllithium, phenyllithium, sodium amide, methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, ethylmagnesium iodide, isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, dimethylmagnesium, diethylmagnesium, diisopropylmagnesium, etc., LDA, NaHMDS, KHMDS, LiHMDS, etc.

[0081] In the structure list of the compounds of the present invention, compounds of formula B241-B264 and their corresponding hydrochlorides were prepared by the following method to obtain high-quality samples:

[0082] 1) Preparation of free base

[0083] The compound of formula A in route 3 is dissolved in a dry organic solvent. Under dry conditions, such as drying with an external desiccant-filled tube or filling with an inert gas (including nitrogen, argon, etc.), a base (preferably a metal compound, including sodium hydride, potassium hydride, calcium hydride, lithium hydride, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, n-butyllithium, tert-butyllithium, phenyllithium, sodium amide, methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, ethylmagnesium iodide, isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, dimethylmagnesium, diethylmagnesium, diisopropylmagnesium, LDA, NaHMDS, KHMDS, LiHMDS) is added at low temperature and the reaction is kept at low temperature for a period of time. The compound of formula B (3) in Scheme 3 is then slowly added to the above reaction system. The cooling bath is then removed and the temperature is raised to continue the reaction. The temperature may be raised to no more than 50°C, preferably no more than 40°C. For convenience, the reaction is usually carried out naturally at ambient temperature. The reaction solution is post-treated and purified by silica gel chromatography, alumina chromatography, or preparative liquid chromatography to obtain the target compound.

[0084] 2) Preparation of hydrochloride

[0085] The free base obtained in 1) above is added to an alcohol solvent, preferably a single solvent selected from methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, glycerol, or a mixture of two or more thereof, and dissolved and filtered. Hydrogen chloride gas is passed into the filtrate or an organic solution containing hydrogen chloride is added to obtain a hydrochloride. The obtained hydrochloride can be crystallized by adding an ether solvent to the above-mentioned alcohol solvent to obtain a refined hydrochloride product.

[0086] In the structure list of the compounds of the present invention, compounds of formula B241-B330 and formula B355-B364 were prepared by the following step-by-step method:

[0087] Step 1: Preparation of monosubstituted intermediates,

[0088] A single caine substrate (including lidocaine, mepivacaine, ropivacaine, bupivacaine, levobupivacaine and 1-ethyl-2-(2,6-dimethylaminoformyl)piperidine) is dissolved in a dry organic solvent, and kept dry, such as by drying with an external tube filled with a desiccant or by filling with an inert gas (including nitrogen, argon, etc.), at low temperature (preferably below 0°C, 0°C to -40°C depending on the equipment), a base (preferably containing a metal compound, including sodium hydride, potassium hydride, calcium hydride, lithium hydride, sodium carbonate, potassium carbonate, Cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, n-butyllithium, tert-butyllithium, phenyllithium, sodium amide, methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, ethylmagnesium iodide, isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, dimethylmagnesium, diethylmagnesium, diisopropylmagnesium, LDA, NaHMDS, KHMDS, LiHMDS) are heated at low temperature for a period of time. A dialkylating agent having two excellent leaving groups (the leaving groups include chlorine, bromine, iodine, and sulfonate) is slowly added to the above reaction system, wherein the molar ratio of the dialkylating agent to the caine substrate is not less than 2:1, preferably, the molar ratio is not less than 5:1, and more preferably, the molar ratio is not less than 10:1. After the addition is completed, the temperature is raised after removing the cold bath to continue the reaction. The temperature can be raised to no more than 50°C for reaction, preferably no more than 40°C for reaction. From a convenient point of view, it is usually selected to naturally rise to ambient temperature for reaction. The reaction solution is filtered to remove insoluble salts, and an acidic aqueous solution is added to the filtrate. The acidic aqueous solution includes hydrochloric acid solution, sulfuric acid solution, phosphoric acid solution, and nitric acid solution. An organic solvent with lower polarity is added for extraction to remove excess dialkylation reagent. The organic solvent with lower polarity includes an ester solvent (including ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate), an ether solvent (including diethyl ether, isopropyl ether, methyl tert-butyl ether), a hydrocarbon solvent (including benzene, toluene, pentane, hexane, heptane, octane, cyclohexane, cyclopentane, petroleum ether), or a mixed solvent of two or more thereof. The acidic solution is neutralized to alkaline, and the monosubstituted intermediate is extracted with an organic solvent, wherein the organic solvent includes a halogenated hydrocarbon (dichloromethane, chloroform, dichloroethane, chlorobenzene), an ester solvent (including ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate), an ether solvent (including diethyl ether, isopropyl ether, methyl tert-butyl ether), a hydrocarbon solvent (including benzene, toluene, xylene) or a mixed solvent of two or more thereof.

[0089] Step 2: Prepare the target

[0090] A single caine-based substrate different from that in step 1 (including lidocaine, mepivacaine, ropivacaine, bupivacaine, levobupivacaine and 1-ethyl-2-(2,6-dimethylaminoformyl)piperidine) is dissolved in a dry organic solvent. Under dry conditions, such as drying with an external tube filled with a desiccant or filling with an inert gas (including nitrogen, argon, etc.), a base (preferably containing a metal compound, including sodium hydride, potassium hydride, calcium hydride, lithium hydride, etc.) is added at low temperature (preferably below 0°C, and can be selected from 0°C to -40°C depending on the equipment) to obtain a caine-based substrate. Sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, n-butyllithium, tert-butyllithium, phenyllithium, sodium amide, methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, ethylmagnesium iodide, isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, dimethylmagnesium, diethylmagnesium, diisopropylmagnesium, LDA, NaHMDS, KHMDS, LiHMDS), and the reaction is carried out at low temperature for a period of time. The non-aqueous solution of the monosubstituted intermediate obtained in step 1 is slowly added to the above reaction system, wherein the molar ratio of the single caine-like substrate to the monosubstituted intermediate is preferably in the range of 0.5:1 to 2:1, more preferably in the range of 0.7:1 to 1.5:1, and most preferably in the range of 0.8:1 to 1.2:1. After the addition is complete, the cooling bath is removed and the temperature is raised to continue the reaction. The temperature may be raised to no more than 50°C, preferably no more than 40°C. For convenience, the reaction is generally allowed to rise naturally to ambient temperature. The reaction solution is post-treated and purified by methods including silica gel chromatography, alumina chromatography, preparative liquid separation, or crystallization, or a combination of two or more thereof to obtain the desired product.

[0091] According to another aspect of the present disclosure, there is provided a compound having a structure of Formula H or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof or a polymorph thereof, wherein the compound is prepared by the following route 4:

[0092] As shown in Scheme 4, the method comprises: reacting a compound of Formula C with a compound of Formula B (3) in the presence of an acid-binding agent to obtain a compound of Formula H. Among the compounds involved in Scheme 4,

[0093] R 1 R 1a or R 1c ;

[0094] R 1a is a C1-C10 hydrocarbon group selected from C1-10 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl-, C2-10 alkenyl, C2-10 alkynyl and C6-10 aryl, and which is optionally substituted by a substituent selected from Rx2;

[0095] R 1c for wherein n is an integer from 2 to 8, m is an integer from 1 to 6, o is 2 or 3, p is 1 or 2, q is an integer from 1 to 3, and R N 1 and R N 2 are independently H or C1-C8 alkyl;

[0096] R 3 for where R A and R B are each independently hydrogen or methyl;

[0097] Rx2 is and

[0098] X is a group that easily leaves.

[0099] According to one embodiment of the present application, X includes but is not limited to chlorine, bromine, iodine, and sulfonic acid groups. In one embodiment, the sulfonic acid group includes, for example, methanesulfonic acid group, benzenesulfonic acid group, p-toluenesulfonic acid group, trifluoromethanesulfonic acid group, and the like.

[0100] In one embodiment, the acid binding agent is an inorganic base or an organic base, wherein the inorganic base includes but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, sodium hydride, potassium hydride, calcium hydride, lithium hydride, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium potassium hydrogen phosphate, wherein the organic base includes but is not limited to sodium acetate, sodium propionate, sodium butyrate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, magnesium methoxide, ethyl acetate ... Magnesium alkoxide, magnesium tert-butoxide, trimethylamine, triethylamine, tributylamine, diisopropylamine, diisopropylethylamine, tert-butylamine, N,N-dimethylaniline, tetramethylethylenediamine, DABCO, DBU, DBN, pyridine, DMAP, N-methylmorpholine, tetramethylguanidine, n-butyllithium, tert-butyllithium, phenyllithium, sodium amide, methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, ethylmagnesium iodide, isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, dimethylmagnesium, diethylmagnesium, diisopropylmagnesium, etc., LDA, NaHMDS, KHMDS, LiHMDS, etc.

[0101] Pharmaceutical composition and its application

[0102] Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound according to the present disclosure or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof or a polymorph thereof, and a pharmaceutically acceptable carrier or excipient.

[0103] The term "pharmaceutically acceptable carrier" refers to a non-toxic solvent, dispersant, excipient, adjuvant or other material that is mixed with the active ingredient to form a pharmaceutical composition (i.e., a dosage form that can be administered to an individual). In one embodiment, the pharmaceutically acceptable carrier or excipient is saline.

[0104] In some embodiments, the compounds or compositions of the present disclosure are administered parenterally. For example, the parenteral route can be selected from inhalation, intraperitoneal, intramuscular, subcutaneous, subarachnoid, epidural, mucosal and deep tissue or transocular, transdermal or surface and combinations thereof. For example, a solution of the compounds of the present disclosure in a carrier such as normal saline can be administered by intraperitoneal, intramuscular, subcutaneous, subarachnoid, epidural injection or infusion, or instilled into the eye.

[0105] Those skilled in the art will know how to prepare suitable preparations according to specific local anesthesia requirements. For parenteral administration, a sterile solution of the compounds of this invention is generally prepared, and the pH of the solution is appropriately adjusted and buffered. For intravenous use, the total concentration of the solute should be controlled so that the preparation has isotonicity. For ocular administration, dropwise liquids can be administered, for example, by an ocular administration system known in the art (e.g., an applicator or dropper). For intrapulmonary administration, a diluent or carrier will be selected to be suitable for forming an aerosol.

[0106] In some embodiments, the compounds and / or compositions described herein are formulated for parenteral administration by injection, including the use of traditional catheterization or infusion. For example, the formulation for injection is present in a unit dosage form, for example, contained in an ampoule or a multidose container, to which a preservative is added. In some embodiments, the composition or combination is in the form of a sterile suspension, solution, or emulsion in an oily or aqueous vehicle, and contains a preparaton, such as a suspending agent, a stabilizer, and / or a dispersant. In all cases, the dosage form must be sterile and must be flowable for ease of injection. Alternatively, the compound of the present disclosure is suitably in the form of a sterile powder for reconstitution with a suitable carrier (e.g., sterile pyrogen-free water) prior to use.

[0107] In some embodiments, the composition or combination for inhalation (optionally nasal administration) is conveniently formulated as an aerosol. For intranasal administration or administration by inhalation, the compounds described herein can be conveniently delivered in the form of a solution, dry powder or granular formulation or suspension from a pump spray container squeezed or pumped by the patient, or delivered in the form of an aerosol spray from a pressurized container or a nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent, and are typically present in a sealed container in a sterile form in a single dose or multiple doses, the sealed container being, for example, in the form of a cartridge or filler for use with an atomizing device. Alternatively, the sealed container is a single dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve for handling after use. In the case where the dosage form includes an aerosol dispenser, it can include a propellant, which is, for example, a compressed gas (such as compressed air) or an organic propellant (such as a fluorochlorocarbon). Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichloromonofluoromethane, dichlorotetrafluoroethane, heptafluoroalkane, carbon dioxide or other suitable gases.In the case of a pressurized aerosol, the dosage unit may be appropriately determined by providing a valve to deliver a metered amount.

[0108] In one embodiment, the compound according to the present disclosure or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorphic form and the pharmaceutical composition according to the present disclosure are for use in local anesthesia.

[0109] Another aspect of the present disclosure provides a method for local anesthesia, comprising the step of administering an effective dose of the compound according to the present disclosure or its stereoisomer or addition salt or solvate or polymorph thereof, or the pharmaceutical composition according to the present disclosure to a subject in need thereof.

[0110] In the present disclosure, the local anesthesia includes topical anesthesia, infiltration anesthesia, block anesthesia, subarachnoid block anesthesia and epidural block anesthesia, etc.

[0111] Depending on the site of administration and clinical needs, the compounds of the present application can be administered using different dosage ranges. For example, when a subject with local anesthesia or analgesia needs is subjected to topical anesthesia, infiltration anesthesia, block anesthesia, subarachnoid block anesthesia and epidural block anesthesia, the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph can be administered in a single or repeated dose in a drug dosage range of 1 to 50 mg, 50 to 100 mg, 100 to 200 mg, 200 to 400 mg, or 400 to 800 mg according to a drug concentration range of 0.1% to 0.5%, 0.5% to 1%, 1% to 2%, 2% to 4%, 4% to 6%, 6% to 8%, or 8% to 10%, respectively, to obtain a good local anesthesia / analgesia effect.

[0112] According to one embodiment, the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is used for surface anesthesia, wherein the compound or pharmaceutical composition is in the form of a solution, which is directly dripped, applied or sprayed on the mucosal surface to paralyze the sensory nerve endings under the mucosa, and is used for surgery on the oral cavity, nose, pharynx, larynx, eye and urethra mucosa.

[0113] According to one embodiment, the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is used for infiltration anesthesia, wherein the compound or pharmaceutical composition is in the form of a solution, and the solution is injected into the skin, subcutaneous tissue or deep into the surgical field to block nerve conduction at the medication site.

[0114] According to one embodiment, the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is used for block anesthesia, wherein the compound or pharmaceutical composition is in solution dosage form, and the solution is injected near the peripheral nerve trunk to block nerve conduction, thereby producing an anesthetic effect in the area innervated by the nerve, and is commonly used in surgeries on the body, limbs, face, oral cavity, etc.

[0115] According to one embodiment, the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is used for subarachnoid block anesthesia, wherein the compound or pharmaceutical composition is in the form of a solution, and the solution is injected into the subarachnoid space from the lower lumbar intervertebral space to anesthetize the spinal nerve roots in that area, which is commonly used in lower abdominal and lower limb surgery.

[0116] According to one embodiment, the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is used for epidural block anesthesia, wherein the compound or pharmaceutical composition is in the form of a solution, and the solution is injected into the epidural space, allowing it to diffuse along the spinal nerve roots and enter the intervertebral foramen, blocking the nerve trunk in the intervertebral foramen to achieve anesthesia of a certain segment of the trunk. It can be used in surgeries from the neck to the lower limbs, and is particularly suitable for abdominal surgery.

[0117] Example

[0118] In order to make the purpose and technical solution of the present invention clearer, the preferred embodiments of the present invention are described in detail below. It should be noted that the following embodiments are only used to further illustrate the present invention and are not to be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by those skilled in the art based on the above content fall within the scope of protection of the present invention.

[0119] Example 1: Preparation of Compound 1

[0120] Dissolve 0.5 g of lidocaine in 20 ml of anhydrous tetrahydrofuran, protect with anhydrous calcium chloride, and cool in an ice-water bath. Add 0.11 g of sodium hydride (60%). After stirring at room temperature for 30 min, add dropwise approximately 10 ml of an anhydrous tetrahydrofuran solution containing 0.52 g of propyl chloroformate. Allow to react at room temperature for 2 h. Filter the reaction solution directly through a pad of celite and anhydrous sodium sulfate. Concentrate the filtrate, and purify the resulting oil directly by preparative liquid chromatography to yield 250 mg of a colorless oil with a purity of 99%. ESI-MS m / z [M+H]+ = 321.0.

[0121] Referring to the method of Example 1, the following compound was prepared:

[0122] Referring to the method of Example 1, the following compound was prepared:

[0123] Referring to the method of Example 1, the following compound was prepared using etidocaine as a raw material:

[0124] Example 2: Preparation of Compound 53

[0125] Example 2-1: Preparation of compound intermediate 1

[0126] Dissolve 1.0g of prilocaine in 30ml of dichloromethane, add 0.67g of DMAP, and cool in an ice-water bath. Add 0.93g of benzyl chloroformate dropwise. After the addition is complete, stir at room temperature for 2 hours. Monitor the reaction for completion by TLC. The reaction solution is washed sequentially with 0.1M dilute acid solution (30ml / 1), water (30ml / 2), saturated sodium bicarbonate (30ml / 1), and saturated brine (30ml / 1). Dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product, which is purified on a silica gel column to yield 1.48g of a colorless oil with a purity of 98.6%.

[0127] Example 2-2: Preparation of compound intermediate 2:

[0128] The residue of Reference Example 1 was purified by preparative column to obtain 0.57 g of a colorless viscous oil with a purity of 99.1%.

[0129] Example 2-3: Preparation of the title compound:

[0130] Dissolve intermediate 2 in 20 ml of tetrahydrofuran, add 60 mg of 10% palladium carbon, replace the hydrogen atmosphere 5 times, and reduce with hydrogen at room temperature overnight. Filter the palladium carbon through diatomaceous earth, concentrate the filtrate, and purify it by preparative column chromatography to obtain 0.37 g of the viscous waxy title compound with a purity of 98.6%. Mass (ESI + )[M+H] + =307.0.

[0131] Referring to the method of Example 2, the following compound was prepared:

[0132] With reference to the method of Example 2, the following compound was prepared using articaine raw material:

[0133] Example 3: Preparation of Compound 159

[0134] Weigh lidocaine (468 mg) and dissolve it in anhydrous tetrahydrofuran (10 ml), dry it in a drying tube, ice-bath at -20°C for 5 minutes, add sodium hydroxide (110 mg), keep warm and stir for 0.5 hours, take n-valeryl chloride (480 μl) and dissolve it in anhydrous tetrahydrofuran (15 ml), slowly add it dropwise to the system, and after 1 hour, stir it at room temperature overnight. The reaction solution was filtered through celite + anhydrous sodium sulfate, and the filtrate was concentrated and purified by preparative liquid phase to obtain 417 mg of the title compound with a purity of 98.9%. Mass (ESI + )[M+H] + =319.1.

[0135] Referring to the method of Example 3, the following compound was prepared:

[0136] Example 4: Preparation of Compound 172

[0137] Weigh lidocaine (495 mg) and dissolve it in anhydrous tetrahydrofuran (15 ml), dry it in a drying tube, and incubate at -10°C for 5 min. Add sodium hydroxide (117 mg) and stir at this temperature for 1 h. Then, dissolve 1,4-dibromobutane (130 μl) in anhydrous tetrahydrofuran (10 ml) and slowly add it dropwise to the above reaction system. Stir at room temperature overnight. The reaction solution is filtered through celite + anhydrous sodium sulfate. The filtrate is concentrated and purified by preparative liquid phase to obtain 402 mg of the title compound with a purity of 99.1%.

[0138] Mass (ESI + )[M+H] + =523.4.

[0139] H-NMR(600MHz, CDCl3)δ:7.08-7.01(m,6H),3.43-3.41(t(br),4H),2.70(s,4H) ,2.47-2.44(dd,8H),2.11(s,12H),1.45-1.43(m(br),4H),0.82-0.80(t,12H).

[0140] 13 C-NMR(150MHz, CDCl3):169.74,138.62,134.96,128.04,127.00,53.46,47.68,46.38,24.57,17.25,10.97.

[0141] Referring to the method of Example 4, the following compounds were prepared using lidocaine and etidocaine as raw materials:

[0142] Prilocaine and articaine were used as raw materials, respectively, and the N-Cbz protected intermediate was first prepared according to Example 2-1, and then the alkyl compound was prepared according to Example 4. Finally, the Cbz protection was removed according to Example 2-3 to prepare the following compounds:

[0143] Example 5: Preparation of Compound B53

[0144] Weigh 280 mg of ropivacaine and dissolve it in anhydrous tetrahydrofuran (20 ml), dry it with a drying tube, and place it at -10°C for 5 minutes. Then, add sodium hydroxide (60 mg). After stirring for 0.5 hours, add propyl chloroformate (220 μl), and then return to room temperature to react overnight. The reaction solution is filtered through celite and anhydrous sodium sulfate. The filtrate is dried and then mixed with silica gel. The sample is passed through a silica gel pad approximately 3 cm high and rinsed with a 15:1 PE:ethyl acetate eluent. Monitor by TLC. The crude product is collected and concentrated to obtain 176 mg of the title compound, which is purified by preparative liquid phase separation. The purity is 99.5%. ESI-MS m / z [M+H] + =361.2.

[0145] Referring to the method of Example 5, the corresponding chloroformate was used as the acylating agent, and mepivacaine was used as the raw material to prepare compounds B1-B10; 1-ethyl-2-(2,6-dimethylaminoformyl)piperidine was used as the raw material to prepare compounds B43-B52; ropivacaine was used as the raw material to prepare compounds B54-B66; and bupivacaine was used as the raw material to prepare compounds B79-B104:

[0146] Referring to the method of Example 5, the following compounds B105-B130 were prepared using (2S)-bupivacaine as the starting material:

[0147] Referring to the method of Example 5, the following compounds B131-B136 were prepared using (2R)-bupivacaine as the starting material:

[0148] Example 6: Preparation of Compound B160

[0149] Mepivacaine (446 mg) was dissolved in anhydrous tetrahydrofuran (10 ml), dried using a drying tube, and placed in an ice bath at -20°C for 5 min. Sodium hydroxide (106 mg) was added and stirred at this temperature for 0.5 h. Valeryl chloride (470 μl) was dissolved in anhydrous tetrahydrofuran (15 ml) and slowly added dropwise. After 1 h, the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite and anhydrous sodium sulfate. The filtrate was concentrated and purified by preparative liquid chromatography to yield 398 mg of the title compound as an oil with a purity of 98.8%. ESI-MS m / z [M+H]+ = 331.2.

[0150] Referring to the method of Example 6, the corresponding acyl chloride was used as the acylating agent, and mepivacaine, 1-ethyl-2-(2,6-dimethylaminoformyl)piperidine, racemic ropivacaine, ropivacaine, bupivacaine, and levobupivacaine were used as raw materials to prepare the following compounds:

[0151] Example 7: Preparation of Compound 169

[0152] Lidocaine (500 mg) was dissolved in anhydrous tetrahydrofuran (20 ml) and connected to an anhydrous calcium chloride drying tube. The mixture was stirred at -10°C for 10 min, sodium hydride (112 mg) was added, and the mixture was stirred at this temperature for 0.5 h. Bromopentane (530 μl) was then added to the system, and the mixture was stirred at room temperature. The reaction was monitored by HPLC until the reaction was substantially complete. The reaction solution was filtered through diatomaceous earth + anhydrous sodium sulfate, and the crude product was dissolved in hydrochloric acid solution (0.1 M) after spin drying. The product was then washed twice with isopropyl ether. The pH of the aqueous phase was adjusted to a weak alkaline state with saturated sodium bicarbonate solution, and then extracted three times with ethyl acetate. The product was dried over anhydrous sodium sulfate for 1 h, filtered, and concentrated to obtain a colorless oil (649 mg, HPLC purity 99%).

[0153] Referring to the method of Example 7, the following compounds were prepared using lidocaine and etidocaine as raw materials:

[0154] Using articaine as a raw material, first prepare an N-Cbz protected intermediate according to Example 2-1, then prepare an alkyl compound according to Example 7, and finally remove the Cbz protection according to Example 2-3 to prepare the following compound:

[0155] Referring to the method of Example 7, the corresponding alkylating agents were used to prepare the following compounds using mepivacaine, 1-ethyl-2-(2,6-dimethylaminoformyl)piperidine, racemic ropivacaine, ropivacaine, bupivacaine and levobupivacaine as raw materials:

[0156] Example 8: Preparation of Compound B262

[0157] Mepivacaine (500 mg) was dissolved in anhydrous tetrahydrofuran (15 ml), dried with a drying tube, and maintained at -10°C for 5 min. Sodium hydroxide (110 mg) was added and the mixture was stirred at this temperature for 1 h. Then, 1,4-dibromobutane (150 μl) was dissolved in anhydrous tetrahydrofuran (10 ml) and slowly added dropwise to the system. The mixture was stirred at room temperature overnight. The reaction solution was filtered through celite + anhydrous sodium sulfate. The filtrate was concentrated and purified by preparative liquid chromatography to obtain 392 mg of the title compound with a purity of 99.3%. ESI-MS m / z [M+H] + =547.3.

[0158] Example 9: Preparation of Compound B250 Hydrochloride

[0159] In a 25ml three-necked flask, 500mg of bupivacaine was placed under N2 pressure. 10ml of dry tetrahydrofuran was added and the temperature was cooled to -10°C. 96mg of 60% NaH was added and the mixture was allowed to react at -10°C for 1.5 hours. A 2ml solution of 175mg of 1,4-dibromobutane in tetrahydrofuran was then added dropwise at low temperature. After completion of the addition, the mixture was stirred at room temperature (23.8°C) for 2 days, filtered through celite, and the filtrate was concentrated to obtain 596mg of crude product. The crude product was separated using a basic alumina column (60g of basic alumina) and an eluent of petroleum ether:ethyl acetate = 2:1 → 1:2 (v / v). The desired fractions were collected and concentrated to obtain 391mg of the free base with a purity of 93.74%. The resulting free base was again separated using a basic alumina column chromatography column with 40 g of basic alumina and a 2:1 to 1:2 (v / v) ratio of petroleum ether to ethyl acetate. The desired fractions were collected and concentrated to yield 326 mg of the free base with a purity of 97.1%. The resulting free base was dissolved in 10 ml of methanol and filtered. The filtrate was then added dropwise with 2.16% isopropyl ether hydrochloric acid at room temperature to a pH of 2-3. The residue was concentrated. 2 ml of methanol was added to the residue to dissolve the residue. 6 ml of methyl tert-butyl ether was slowly added dropwise at room temperature, stirred for 1.0 hr, filtered, and the filter cake dried to yield 125 mg of the title compound as a white product with a purity of 100%. The filtrate was concentrated, 2 ml of methanol was added to the residue, and 40 ml of methyl tert-butyl ether was added dropwise at room temperature. The mixture was stirred overnight at room temperature, filtered, and the filter cake dried to yield another 210 mg of the title compound as a white product with a purity of 100%. ESI-MS m / z [M-2Cl-H] + =631.49.

[0160] Referring to the methods of Examples 8 and 9, the following compounds and their corresponding hydrochlorides were prepared using corresponding alkylating agents, respectively, with mepivacaine, 1-ethyl-2-(2,6-dimethylaminoformyl)piperidine, racemic ropivacaine, ropivacaine, bupivacaine, and levobupivacaine as raw materials:

[0161] Example 10: Preparation of Compound D1 Dihydrochloride

[0162] Dissolve 300 mg of levobupivacaine in 10 ml of anhydrous DMF, cool to -5°C, add 120 mg of sodium hydride, and protect with anhydrous calcium chloride. Stir at -5°C for 0.5 h, then add 360 mg of dimethylaminoethyl bromide hydrochloride and react at room temperature overnight. Add 30 ml of isopropyl ether to precipitate a large amount of white solid. Stir at room temperature for 10 min and filter. First, remove the isopropyl ether from the filtrate under reduced pressure, then remove the DMF under high vacuum. A crude oil is obtained, to which 40 ml of isopropyl ether is added and stirred at room temperature overnight. Filter the solid and concentrate the filtrate to obtain a pale yellow oil. Add 8 ml of tetrahydrofuran to dissolve the oil, adjust the pH to ≈ 3 with HCl / isopropyl ether solution, concentrate to dryness, add 32 ml of tetrahydrofuran, and stir at room temperature overnight. Filter and dry the filter cake to obtain 210 mg of a white solid with a purity of 98%. ESI-MS m / z [M-Cl - -HCl]+=360.3.

[0163] Referring to the method of Example 10, the corresponding halogenated alkylamine or N-Boc-halogenated alkylamine was used, respectively, with lidocaine, mepivacaine, ropivacaine, bupivacaine and levobupivacaine as raw materials to prepare the dihydrochloride of the following compound:

[0164] Example 11: Preparation of Compound B360

[0165] Step 1: 250 mg of levobupivacaine was added to a 25 ml three-necked flask, and the mixture was purged with N2. 10 ml of dry tetrahydrofuran was added, and the temperature was cooled to -10°C. 45 mg of 60% NaH was added, and the mixture was allowed to react at -10°C for 1.5 hours. A solution of 2 g of 1,4-dibromobutane in tetrahydrofuran (10 ml) was then added dropwise at low temperature. The reaction was allowed to proceed overnight at room temperature, and the mixture was filtered through celite. Hydrochloric acid solution was slowly added to the filtrate under an ice bath until the solution reached a pH of approximately 2. The mixture was extracted three times with ethyl acetate. Saturated sodium bicarbonate solution was added to the aqueous layer under an ice bath until gas evolution ceased. The mixture was extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting intermediate was dissolved in dry tetrahydrofuran and set aside. 596 mg of crude product was obtained.

[0166] Step 2: 215 mg of mepivacaine was placed in a 25 ml three-necked flask, and N2 was passed through. 10 ml of dry tetrahydrofuran was added, and the temperature was cooled to -10°C. 45 mg of NaH (60%) was added and the reaction was carried out at -10°C for 1.5 hours. The tetrahydrofuran solution of the intermediate obtained in step 1 was added dropwise at low temperature. After the addition was completed, the temperature was raised to 30-40°C and the reaction was carried out for 72 hours. The reaction solution was filtered through celite and anhydrous sodium sulfate. The filtrate was concentrated and purified by preparative liquid chromatography to obtain 419 mg of the title compound with a purity of 99.5%. ESI-MS m / z [M+H] + =589.4.

[0167] Referring to the method of Example 11, the following compounds were prepared using lidocaine, bupivacaine, levobupivacaine, mepivacaine, ropivacaine and 1-ethyl-2-(2,6-dimethylaminoformyl)piperidine as raw materials:

[0168] Example 12: Preparation of Improved Compound B250 Hydrochloride (Optimized Based on Example 9)

[0169] Dissolve 750mg of bupivacaine in 15ml of anhydrous THF, dry under a drying tube, and cool to -15°C. Add 157mg of sodium hydride, stir at this temperature for 2 hours, then add 283mg of 1,4-dibromobutane. Allow to cool to room temperature (around 25°C) and stir. Allow to react for approximately 48 hours, with product content at approximately 70% as monitored by HPLC. Continue the reaction until no further progress is observed. Then, add 36mg of sodium hydride in a -15°C ice bath, allow to react at room temperature for 2 hours, and then add 42mg of sodium hydride and allow to react overnight. Add 60mg of 1,4-dibromobutane, stir at room temperature for 20 hours, then add 28mg of sodium hydride, continue the reaction for 6 hours, then add 17mg of sodium hydride and 100mg of 1,4-dibromobutane, and stir at room temperature for 23 hours. Dilute the reaction solution with ethyl acetate, then pass through a 2-3cm high pad of celite and rinse with ethyl acetate to a total volume of approximately 120ml. The product was concentrated under reduced pressure, and the residue was dissolved in methanol. 3 ml of 10 M ethanolic hydrochloric acid solution was added and shaken evenly. The product was concentrated under reduced pressure, and 6 ml of methanol was added to the residue. 90 ml of methyl tert-butyl ether was slowly added dropwise at room temperature and stirred overnight at room temperature. The product was filtered, and the filter cake was dissolved in 6 ml of methanol. 36 ml of methyl tert-butyl ether was slowly added dropwise at room temperature and stirred at room temperature for 2 h. The product was filtered and the filter cake was dried to obtain 230 mg of the title compound as a white solid with a purity of 99.9%.

[0170] Transfer the mother liquor to a single-necked flask and rinse with 2 ml of methanol. Then, slowly add 40 ml of methyl tert-butyl ether dropwise. Stir at room temperature for 2 hours. Then, add 80 ml of methyl tert-butyl ether dropwise in portions and stir at room temperature overnight. Filter, dissolve the filter cake in 5 ml of methanol, slowly add 30 ml of methyl tert-butyl ether dropwise, continue stirring at room temperature for 1.5 hours, add an additional 70 ml of methyl tert-butyl ether, and stir for 2 hours. Filter, and dry the filter cake to obtain 485 mg of the title compound as an off-white solid with a purity of 99.3%.

[0171] The total yield of the two batches of products was 78.13%.

[0172] Test Example 1: Rat corneal local anesthetic effect test

[0173] 1. Experimental Animals

[0174] SD rats (♂, approximately 300 g) were purchased from the Experimental Animal Center of Chongqing Medical University. These rats were housed in a conventional manner with free access to food and water at a temperature of approximately 25-28°C and a humidity of approximately 65-85%.

[0175] 2. Test substance

[0176] 2.1. Reference substances

[0177] 2% lidocaine hydrochloride injection, 5 mL: 0.1 g, batch number: 161207, Southwest Pharmaceutical Co., Ltd.

[0178] 2.2 Test Article

[0179] Compound 1 solution 1 (27.36 mg / mL): 36.8 mg of compound 1 (purity 99%) was added to 1.345 mL of normal saline (Hualu, SD21032001), and the pH was adjusted to 5.80 with hydrochloric acid / sodium hydroxide.

[0180] Compound 159 hydrochloride solution (26.3 mg / mL, equimolar concentration with 2% lidocaine): 13.3 mg of compound 159 hydrochloride was added to 0.505 mL of normal saline (Hua Lu, SD21032001) and vortexed to dissolve.

[0181] Compound 174 solution (40.8 mg / mL, equimolar concentration with 2% lidocaine): 48.2 mg of compound 174 was added to 1.18 mL of normal saline (Hualu, SD21032001), first adjusted to dissolve with hydrochloric acid, and then adjusted to pH 5.14 with sodium hydroxide.

[0182] Compound 172 solution (38.6 mg / mL, equimolar concentration with 2% lidocaine): 52.2 mg of compound 172 was added to 1.35 mL of normal saline (Hualu, SD21032001), first adjusted to dissolve with hydrochloric acid, and then adjusted to pH 5.17 with sodium hydroxide.

[0183] Compound 172 solution (19.3 mg / mL, 2% lidocaine half molar concentration): Take the above 38.6 mg / mL compound 172 solution and dilute it with normal saline at a ratio of 1:1.

[0184] Compound 1 hydrochloride solution 2 (26.4 mg / mL, equimolar concentration with 2% lidocaine): 33.0 mg of Compound 1 hydrochloride was dissolved in 1.25 mL of normal saline (Tiansheng, 522021703), and the pH was adjusted to 5.27 with sodium hydroxide.

[0185] Compound 169 solution (22.5 mg / mL, equimolar concentration with compound 1 hydrochloride solution 2): 30.2 mg of compound 169 was added to 1.34 mL of normal saline (Tiansheng, 522021703), dissolved with hydrochloric acid, and then adjusted to pH 5.19 with sodium hydroxide.

[0186] 3. Methods and Results

[0187] (1) Preliminary test: The rats were restrained in a horizontal side-lying position, and the solution was then administered into the eyes using a pipette, one drop every 30 seconds, for a total of 3 drops. During this period, the ocular surface was kept moist with the drug. 30 seconds after the last eye drop, the ocular surface solution was removed with filter paper, and the cornea was stimulated with clipped rat whiskers to observe the corneal reflex. The results are shown in Table 1 below.

[0188] Table 1

[0189] The results in Table 1 above show that compound 1 can effectively inhibit corneal reflex after administration.

[0190] Compounds 2, 3, 4, 5, 13, 14, 21, 24, 25, 176, D1, B285, B328, and B360 were tested using the same method. The results showed that the compounds of the present invention effectively inhibited the corneal reflex after administration. These test results show that the compounds of the present invention have a local anesthetic effect.

[0191] (2) Comparative test of compound 159 hydrochloride, compound 172 and compound 174 with normal saline and lidocaine:

[0192] The rats were restrained in a horizontal side-lying position, and the solution was then administered into the eyes using a pipette, one drop every 30 seconds, for a total of 3 drops. During this period, the ocular surface was kept moist with the drug. 30 seconds after the last eye drop, the ocular surface solution was removed with filter paper. At different time points, the cornea was stimulated with clipped rat whiskers, and the corneal reflex was observed. The results are summarized in Table 2 below.

[0193] Table 2

[0194] The test results in Table 2 above show that the duration of local anesthesia of the compound according to the present invention is longer than that of lidocaine.

[0195] (3) Comparative test of compound 1 hydrochloride and compound 169:

[0196] The rats were restrained in a horizontal side-lying position, and the solution was then administered into the eyes using a pipette, one drop every 30 seconds, for a total of 3 drops. During this period, the ocular surface was kept moist with the drug. 30 seconds after the last eye drop, the ocular surface solution was removed with filter paper. At different time points, the cornea was stimulated with clipped rat whiskers, and the corneal reflex was observed. The results are summarized in Table 3 below.

[0197] Table 3

[0198] Test Example 2: Guinea Pig Local Anesthesia Test

[0199] Select guinea pigs weighing 300-500g. Shave the hair on the back and both sides of the guinea pigs one day before the experiment. Use a small needle to inject the drug solution into the skin at three locations in front, middle and back of the midline of the guinea pig's back. First pierce the skin, then withdraw the needle tip to the middle layer of the skin, and then insert it obliquely into the skin. Inject 0.1-0.20mL of drug solution. This will prevent the drug solution from leaking out after the needle is removed, forming a papule, and use an ink circle to mark its size. After injection, use a needle to test the sensation of the skin at the papule at different time points, and use normal skin outside the papule as a control. Normal skin will experience skin muscle contraction after acupuncture of normal skin. Use acupuncture to test 6 times at each time point, with an interval of 3-5s between two times, and record the total number of no reaction (no skin muscle contraction) after acupuncture. If the needle is stimulated 6 times and no skin muscle contraction occurs ≥ 3 times, it means that the drug has effectively penetrated subcutaneously. The results of pain inhibition rate (%) at different time points after injection of Compound 1 hydrochloride solution and lidocaine hydrochloride solution into the back of guinea pigs are shown in Tables 4 and 5 below, respectively.

[0200] Table 4: Pain inhibition rate (%) at different time points after injection of compound 1 hydrochloride solution into the back of guinea pigs

[0201] Table 5: Pain inhibition rate (%) at different time points after injection of lidocaine hydrochloride solution into the back of guinea pigs

[0202] From the above test results, it can be seen that the local anesthetic effect of the hydrochloride solution (50 mM) of the present compound 1 can last for at least 2 hours, while the local anesthetic effect of the lidocaine hydrochloride solution (70 mM) can only last for less than 30 minutes.

[0203] Test Example 3: Subcutaneous local anesthesia test in rats

[0204] 1. Experimental Animals

[0205] Three Sprague-Dawley rats (♂, SPF grade, approximately 300 g) were housed in the Experimental Animal Center of Chongqing Medical University. These rats were housed in a conventional manner with free access to food and water at a temperature of approximately 25°C and a humidity of approximately 70%.

[0206] 2. Test substance

[0207] Lidocaine hydrochloride, 5 mg / mL (0.5%): Add 1 mL of lidocaine hydrochloride injection (Southwest Pharmaceutical, 161207, 5 mL: 0.1 g) to 3 mL of normal saline (Tiansheng, 522021703) and dilute to 5 mg / mL.

[0208] Compound 172 solution (9.67 mg / mL, equimolar concentration with 0.5% lidocaine hydrochloride): 29.2 mg of compound 172 was dispersed in 3.02 mL of normal saline (Tiansheng, 522021703), and dissolved by adjusting the pH to 5.27 with a small amount of hydrochloric acid / sodium hydroxide.

[0209] 3. Methods and Results

[0210] Rats were restrained and the two test drugs were administered intradermally in corresponding areas on both sides of the back. 0.6 mL was then injected subcutaneously to form a skin bump, which was marked with a marker. At each time point, acupuncture was performed at the center and periphery of each dosing site (skin bump or elevation) for a total of five points, with a needling interval of 3-5 seconds. No response (absence of skin muscle contraction or neighing) after acupuncture was recorded.

[0211] The observed results showed that 0.5% lidocaine hydrochloride and equimolar concentration of compound 172 solution both took effect 2 minutes after administration; the local anesthetic effect of the former lasted for about 1.5-2 hours after administration, while the local anesthetic effect of the latter lasted for up to 142 hours after administration.

[0212] Test Example 4: Subcutaneous local anesthesia test in rats

[0213] 1. Experimental Animals

[0214] Two Sprague-Dawley rats (♂, SPF grade, approximately 300 g) were housed in the Experimental Animal Center of Chongqing Medical University. These rats were housed in a conventional manner with free access to food and water at a temperature of approximately 25°C and a humidity of approximately 70%.

[0215] 2. Test substance

[0216] Compound 172 solution (about 9 mM): 9.6 mg of compound 172 was added to 1.985 mL of normal saline (Tiansheng, 522021703), and the pH was adjusted to 5.16 with a small amount of hydrochloric acid / sodium hydroxide to dissolve.

[0217] Compound 199 solution (about 9 mM): 31 mg of compound 199 was added to 5.37 mL of normal saline (Tiansheng, 522021703), and the pH was adjusted to 5.07 with a small amount of hydrochloric acid / sodium hydroxide to dissolve.

[0218] 3. Methods and Results

[0219] Rats were restrained and the two test drugs were administered intradermally in corresponding areas on both sides of the back. 0.3 mL was then injected subcutaneously to form a skin bump, which was marked with a marker. At each time point, acupuncture was performed at the center and periphery of each dosing site (skin bump or elevation) for a total of five points, with a needling interval of 3-5 seconds. The absence of a response (absence of skin muscle contraction or neighing) after acupuncture was recorded.

[0220] The observed results showed that solutions of compound 172 and compound 199 with equimolar concentrations took effect 2 minutes after administration; both solutions still had local anesthetic effects 24 hours after administration.

[0221] In experiments conducted in accordance with the aforementioned test, compounds B290, B360, and B362 were compared with levobupivacaine by subcutaneous injection into the back of rats at a 10 mM concentration in a 0.6 ml injection volume. The observed results showed that levobupivacaine produced a local anesthetic duration of 2-4 hours, while compound B290 had a local anesthetic duration of 48-72 hours, compound B360 had a local anesthetic duration of >96 hours, and compound B362 had a local anesthetic duration of 72-96 hours. This indicates that the compounds according to the present invention have a local anesthetic effect that far exceeds that of levobupivacaine.

[0222] Test Example 5: Acute toxicity test

[0223] 1. Experimental Animals

[0224] KM mice were purchased from the Experimental Animal Center of Chongqing Medical University. They had free access to food and water during the entire experimental period. The ambient temperature was approximately 23-26°C and the humidity was 70-90%.

[0225] 2. Reference substances and test substances

[0226] Lidocaine hydrochloride solution: Add 0.1 mL of 2% lidocaine hydrochloride injection (2% lidocaine hydrochloride injection, 5 mL: 0.1 g, batch number: 161207, Southwest Pharmaceutical Co., Ltd.) to 0.9 mL of normal saline and dilute to 2 mg / mL.

[0227] Compound 1 solution: 1) Disperse 7.2 mg of compound 1 in 4.05 mL of normal saline (Hualu, SD21032001) and adjust the pH to 5.42 with hydrochloric acid / sodium hydroxide to prepare a 1.78 mg / mL solution. 2) Disperse 8.6 mg of compound 1 in 1.985 mL of normal saline (Hualu, SD21032001) and adjust the pH to 5.32 with hydrochloric acid / sodium hydroxide to prepare a 4.33 mg / mL solution.

[0228] Compound 169 solution: i) Disperse 35.7 mg of compound 169 in 1.485 mL of normal saline (Tiansheng, 522021703), dissolve in hydrochloric acid, and adjust the pH to 5.14 with sodium hydroxide. ii) Add 500 μL of the solution prepared in i) to 4.3 mL of normal saline to dilute to a 2.5 mg / mL solution.

[0229] 3. Methods and Results

[0230] The compound 1 solution and the compound 169 solution were injected into the tail vein of mice at a constant speed for about 2-3 seconds. The LD 50 The results are shown in Table 6 below.

[0231] Table 6

[0232] The acute toxicity test results in Table 6 above show that the compound according to the present invention is safer than lidocaine hydrochloride.

[0233] Test Example 6: Intradermal local anesthesia test in rats

[0234] 1. Experimental Animals

[0235] Five Sprague-Dawley rats (SD rats, ♂, SPF grade, approximately 300 g) were housed in the Experimental Animal Center of Chongqing Medical University. These rats were housed in a conventional manner with free access to food and water at a temperature of approximately 25°C and a humidity of approximately 70%.

[0236] 2. Test substance

[0237] 2.1. Reference substances

[0238] Levobupivacaine hydrochloride, 0.25% (levobupivacaine hydrochloride) solution: Add 6.1 mg of levobupivacaine (20070801, free base) to 2.74 mL of normal saline (Tiansheng, 522021703), dissolve with hydrochloric acid, adjust the pH to 5.31 with sodium hydroxide, and filter through 0.22 μm.

[0239] 2.2 Test Article

[0240] Compound B105 hydrochloride, 0.315% solution, equimolar concentration with Levobucil: 8.6 mg of Compound B105 hydrochloride was dissolved in 2.73 mL of normal saline (Tiansheng, 522021703), pH 5.06, adjusted to pH 5.15 with sodium hydroxide, and then filtered through 0.22 μm.

[0241] 3. Methods and Results

[0242] The rats were restrained and anesthetized by intradermal infiltration. The drugs were administered as shown in the figure below. ① and ③ were administered with levobupivacaine hydrochloride, and ② and ④ were administered with compound B105 hydrochloride. 0.1 mL was injected intradermally to form a skin bump, which was marked with a marker.

[0243] At each time point, acupuncture was performed at 5 points in the middle and around each dosing site (skin bump or bulge) (the acupuncture positions are shown in the figure), with a needling interval of 3-5 seconds. The points with no response (no skin muscle contraction or screaming) after acupuncture were recorded.

[0244] Results showed that 0.25% levobupivacaine hydrochloride and an equimolar concentration of Compound B105 hydrochloride had an onset of effect within 2 minutes of administration; the levobupivacaine hydrochloride solution maintained its effect for approximately 4.5 hours, while the equimolar concentration of Compound B105 hydrochloride solution maintained its effect for no less than 6.5 hours. The compounds of the present invention exhibited a prolonged local anesthetic effect.

[0245] Test Example 7: Subcutaneous local anesthesia test in rats

[0246] 1. Experimental Animals

[0247] Two SD rats, ♂, SPF grade, approximately 300 g, obtained from the Experimental Animal Center of Chongqing Medical University.

[0248] The rats were raised in a conventional manner with free access to food and water, a temperature of about 25°C, and a humidity of about 70%.

[0249] 2. Test substance

[0250] Compound 172 solution (4.6 mM): 9.6 mg of compound 172 was added to 1.985 mL of normal saline (Tiansheng, 522021703), and the pH was adjusted to 5.16 with a small amount of hydrochloric acid / sodium hydroxide to dissolve. 1 mL of this solution was taken and added with 1 mL of normal saline (Tiansheng, 522021703) to dilute to 2.42 mg / mL.

[0251] Compound B246 solution (4.6 mM): 5.2 mg of compound B246 dihydrochloride was dissolved in 1.6 mL of normal saline (Tiansheng, 522021703), and the pH was adjusted to 5.41 with a small amount of sodium hydroxide.

[0252] 3. Methods and Results

[0253] Rats were restrained and anesthetized by intradermal infiltration. 0.3 mL of the drug was injected subcutaneously to form a skin bump, which was marked with a marker. At each time point, acupuncture was performed at five points, including the center and periphery of each injection site (skin bump or elevation), with a needling interval of 3-5 seconds. No response (absence of skin muscle contraction or neighing) after acupuncture was recorded.

[0254] The results showed that both the 4.6 mM solution of compound 172 and the equimolar solution of compound B246 took effect 2 minutes after administration; the local anesthetic effect of the former lasted for about 3 hours after administration, while the local anesthetic effect of the latter lasted for more than 19 hours.

[0255] In the experiment conducted with reference to the above test, subcutaneous injection with an injection volume of 0.3-0.6 ml was performed on the back of rats. The 50% duration of pain inhibition by injection of compound B246, compound B242, compound B250, compound B262 and bupivacaine is summarized in Table 7 below.

[0256] Table 7

[0257] Test Example 8: Acute toxicity test

[0258] 1. Experimental Animals

[0259] KM mice were purchased from the Experimental Animal Center of Chongqing Medical University. They had free access to food and water during the entire experimental period. The ambient temperature was approximately 23-26°C and the humidity was 70-90%.

[0260] 2. Reference substances and test substances

[0261] Levobupivacaine hydrochloride solution: Prepare a 1 mg / mL solution in normal saline.

[0262] Compound B105 hydrochloride solution was prepared in normal saline to a concentration of 6 mg / mL.

[0263] 3. Methods and Results

[0264] The drug was administered by sequential injection into the tail vein of mice at a constant speed for about 2-3 seconds, and the LD was observed and estimated. 50 The results are shown in Table 8 below.

[0265] Table 8

[0266] The acute toxicity test results in Table 8 show that the compound of the present invention is safer than levobupivacaine.

[0267] Referring to the above method, compounds B246, B250, B242, ropivacaine, B262 and mepivacaine were tested, and the obtained data were compared with the relevant literature values ​​in Table 9 below.

[0268] Table 9

[0269] Document 1: US Patent 3632766

[0270] From the above comparison, it can be seen that the compounds provided by the present invention are safer than their respective corresponding existing local anesthetics.

[0271] Test Example 9: Guinea Pig Local Anesthesia Test

[0272] Select guinea pigs weighing 800-1000g, and shave the hair on the back of the guinea pigs in the middle and on both sides one day before the experiment. Use a small needle to inject the drug solution into the skin of the guinea pig's back midline, front, middle, and back. First pierce the skin, then withdraw the needle tip to the middle layer of the skin, and then insert it obliquely into the skin. Inject 0.20mL of the drug solution. This will prevent the drug from leaking out after the needle is removed, forming a skin bump, and use an ink circle to mark its size. After injection, at different time points, use acupuncture to test the sensation of the skin of the skin bump. Use normal skin outside the skin bump as a control. After acupuncture of normal skin, skin muscle contraction will occur. Each time point is tested with acupuncture 6 times, with an interval of 3-5s between two times, and the total number of no reaction (no skin muscle contraction) after acupuncture is recorded. If the number of skin muscle contractions does not occur ≥ 3 times after 6 needle stimulations, it means that the drug subcutaneous infiltration is effective. The pain suppression at different time points after injection of bupivacaine and compound B105 on the guinea pig back is summarized in the following table 10.

[0273] Table 10

[0274] From the test results in Table 10 above, it can be seen that the duration of local anesthesia of the solutions of the compound B105 of the present invention (7 mM, 14 mM) is significantly longer than that of the corresponding equimolar concentration solutions of bupivacaine.

[0275] Referring to the above test, guinea pigs were injected with 10 mM concentrations of Compound B246, Compound B250, and Compound 199 on their backs. The pain suppression at different time points after injection is summarized in Table 11 below.

[0276] Table 11

[0277] Referring to the above test, intradermal injection was changed to subcutaneous injection with an injection volume of 0.6 ml / point. After injection of compound B246, compound B242, compound B250 and bupivacaine into the back of guinea pigs, the pain inhibition observed was summarized in the following Table 12.

[0278] Table 12

[0279] From the test results in Table 12 above, it can be seen that the duration of local anesthesia of the compound of the present invention is significantly longer than that of bupivacaine.

[0280] In another experiment conducted with reference to the above test, subcutaneous injection (10 mM) with an injection volume of 0.6 ml / point was performed on the back of guinea pigs. The 50% effective time for pain inhibition of compound B246, compound B242, compound B250, compound B262 and bupivacaine is shown in Table 13 below.

[0281] Table 13

[0282] From the test results in Table 13 above, it can be seen that the duration of local anesthesia of the compound of the present invention is significantly longer than that of bupivacaine.

[0283] Test Example 10: Comparison of subcutaneous administration of bupivacaine and compound B246 in rats

[0284] Bupivacaine and compound B246 were prepared into equimolar concentration (10 mM) solutions in physiological saline and administered subcutaneously to two SD rats. Each rat was injected at two sites with a dosing volume of 0.6 mL / site, with an interval of 5 hours between each site. The skin was sampled and the content was detected 20 or 25 minutes after the last dose. The results are shown in Table 14 below.

[0285] Table 14: Bupivacaine & Compound B246: Comparison of subcutaneous administration in rats

[0286] Test Example 11: Observation of local drug concentration after topical administration of compound B246 in rats

[0287] Compound B246 was prepared with normal saline to 10 m M solution was subcutaneously injected into 7 SD rats, with each rat injected at one point on both sides, with a volume of 0.6 mL / point, 20 m i n Acupuncture was performed within 120 hours (one needle was inserted in each of the upper, lower, left, right, and middle areas of the formed skin hillock circle), and the number of no reactions (i.e., effective local anesthesia) was recorded. The skin and subcutaneous tissue were then sampled for drug concentration testing. The results are shown in Table 15 below.

[0288] Table 15

[0289] Test Example 12: Observation of local drug concentration in rats after topical administration of compound B246 until the local anesthetic effect disappears

[0290] Compound B246 was prepared into a 10 mM solution in physiological saline and administered subcutaneously to SD rats. Each rat received a single injection at each site, with a volume of 0.6 mL per site. After the complete disappearance of acupuncture-induced unresponsiveness at the injection site (348-360 hours), samples were collected at various time points to measure local and plasma drug concentrations. The results are shown in Table 16 below.

[0291] Table 16

[0292] Test Example 13: Preliminary Experiment on Sciatic Nerve Block in Rats

[0293] 1. Test substance

[0294] 2.88 mg / mL (10 mM) bupivacaine in normal saline: Add 5.2 mg of bupivacaine to 1.8 mL of normal saline (Yuyuan, L23010707), adjust the pH to 5.80 with hydrochloric acid / sodium hydroxide, and dissolve.

[0295] 3.04 mg / mL (10 mM) solution of compound 169 in normal saline: 6.1 mg of compound 169 was added to 2 mL of normal saline (Yuyuan, L23010707), and then the pH was adjusted to 5.24 with hydrochloric acid / sodium hydroxide and dissolved.

[0296] 2. Test methods and results

[0297] 1) Experimental Animals: SD rats, grade ♂, SPF, purchased from the Experimental Animal Center of Chongqing Medical University. The temperature at the time of administration was 27.1°C and the humidity was 84%.

[0298] 2) Sciatic nerve block method in rats: insert the needle into the midpoint of the line connecting the greater trochanter of the right femur and the ischial tuberosity, and inject the drug after the needle tip reaches the ischium.

[0299] 3) Observation of paw withdrawal in a 50°C water bath: The rat's hind paws were placed in 50°C hot water and the withdrawal time (withdrawal latency) was recorded. A withdrawal latency > 7 seconds was considered sensory block. To prevent burns, a 12-second pause was set.

[0300] Table 17: Rat sciatic nerve block - method and results (50°C water bath paw withdrawal time)

[0301] The experimental data in Table 17 show that administration of 10 mM concentration of bupivacaine and 0.2 mL of compound 169, respectively, both had sciatic nerve blocking effects on rats. One hour after administration, the blocking effect of compound 169 was stronger than that of bupivacaine.

[0302] Test Example 14: Mouse hot plate licking test

[0303] 1. Test materials

[0304] 1.1 Experimental Animals

[0305] KM mice (♀, SPF grade) were obtained from the Experimental Animal Center of Chongqing Medical University. Mice were acclimated for 4 days with free access to food and water. The temperature during testing was 27.6°C and the humidity was 80%.

[0306] 1.2 Test Instruments

[0307] RB-200 intelligent hot plate analyzer, serial number: TM026-1905-003-020-004, production date: May 2019, Chengdu Taimeng Software Co., Ltd.

[0308] 1.3. Reference Article and Test Article

[0309] 1.3.1 Negative Control

[0310] Normal saline (NS).

[0311] 1.3.2 Test Article

[0312] 1 mg / mL saline solution of compound 169: 5.1 mg of compound 169 was added to 5.1 mL of saline (Yuyuan, L23010707), and then the pH was adjusted to 5.58 with hydrochloric acid / sodium hydroxide and dissolved.

[0313] 2. Test methods and results

[0314] Mice were injected with compound 169 in normal saline solution via the tail vein at doses of 10 mg / kg (1 mg / mL, 0.1 mL / 10 g), 5 mg / kg (1 mg / mL, 0.5 mL / 10 g), and 0 mg / kg (NS, 0.1 mL / 10 g). Hot plate licking time (55.0°C, maximum observed time of 60 seconds) was measured 10 minutes after administration. Parallel testing was performed, with one animal in each of the control group, high-dose group, and low-dose group receiving the test compound being administered and tested simultaneously. The results are shown in Table 18 below.

[0315] Table 18: Mouse hot plate test (iv) - results (55.0°C - paw licking time s)

[0316] The experimental data in Table 18 show that after injection into the tail vein, compound 169 can prolong the licking time of mice on the 55.0°C hot plate in a dose-dependent manner.

[0317] The N-substituted aromatic amine derivatives according to the present invention have local anesthetic efficacy. Compared with existing drugs used in clinical practice, they show a significantly longer-lasting local anesthetic effect, can reduce the number of administrations, are particularly suitable for situations where long-term local anesthesia is required, and have the advantages of long-term effect, safety and more controllable quality.

Claims

1. A compound having a structure of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, or a stereoisomer or a pharmaceutically acceptable salt thereof, in: R A and R B are each independently hydrogen or methyl; R 1 H, R 1a 、R 1c or Rx2; R 1a is a C1-C10 hydrocarbon group selected from C1-10 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-methyl-, C2-10 alkenyl, C2-10 alkynyl and C6-10 aryl, and is optionally substituted with a substituent selected from Rx2; R 1c for wherein n is an integer from 2 to 8, m is an integer from 1 to 6, o is 2 or 3, p is 1 or 2, q is an integer from 1 to 3, and R N 1 and R N 2 are independently H or C1-C8 alkyl; Rx2 is R 2 Each is independent as well as R 2’ Each is independently H, 2. The compound according to claim 1 or its stereoisomer or pharmaceutically acceptable salt, wherein the compound is selected from:

3. The compound according to claim 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 4 . The compound according to claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is hydrochloride.

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition according to claim 5 , wherein the pharmaceutically acceptable carrier or excipient is physiological saline.

7. The pharmaceutical composition according to claim 5 or 6, which is in a dosage form for parenteral administration.

8. The pharmaceutical composition according to claim 7, wherein the parenteral route is selected from the group consisting of inhalation, intraperitoneal, intramuscular, subcutaneous, subarachnoid, epidural, mucosal and deep tissue or ocular, transdermal or topical and combinations thereof.

9. Use of the compound according to any one of claims 1 to 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for local anesthesia.

10. The use according to claim 9, wherein the local anesthesia includes topical anesthesia, infiltration anesthesia, block anesthesia, subarachnoid block anesthesia and epidural block anesthesia.

11. The compound according to any one of claims 1 to 4 or its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 5 to 8, for use in local anesthesia.

12. The pharmaceutical composition for use according to claim 11, wherein the local anesthesia includes topical anesthesia, infiltration anesthesia, block anesthesia, subarachnoid block anesthesia and epidural block anesthesia.

13. A method for local anesthesia, comprising the step of administering to a subject in need thereof an effective dose of the compound according to any one of claims 1 to 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 5 to 8.

14. The method according to claim 13, wherein the local anesthesia comprises topical anesthesia, infiltration anesthesia, block anesthesia, subarachnoid block anesthesia and epidural block anesthesia.

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