WO2024012397A1 - N-取代芳胺衍生物及其制备方法和用途 - Google Patents

N-取代芳胺衍生物及其制备方法和用途 Download PDF

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WO2024012397A1
WO2024012397A1 PCT/CN2023/106526 CN2023106526W WO2024012397A1 WO 2024012397 A1 WO2024012397 A1 WO 2024012397A1 CN 2023106526 W CN2023106526 W CN 2023106526W WO 2024012397 A1 WO2024012397 A1 WO 2024012397A1
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compound
anesthesia
pharmaceutically acceptable
formula
solution
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PCT/CN2023/106526
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English (en)
French (fr)
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李勤耕
陈捷
李长文
王凯
江帅
廖建
谭波
申义
董小虎
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江苏恩华络康药物研发有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
    • C07C271/64—Y being a hydrogen or a carbon atom, e.g. benzoylcarbamates

Definitions

  • the present application relates to N-substituted aromatic amine derivatives and their preparation methods as well as their uses in related medical treatment fields.
  • Local anesthetics block the conduction of various nerve impulses. They first inhibit the sense of touch, pressure and pain. When the concentration increases, they may also inhibit the function of motor nerves. Local anesthetics are applied locally to cause local loss of sensation and pain. The scope of anesthesia is small and it is mostly suitable for minor surgeries and intubation. Compared with general anesthetics, it has fewer adverse reactions and is safer.
  • Local anesthetics can be used in different parts to block sensory nerves and produce anesthetic effects. They can be divided into:
  • Topical anesthesia The anesthetic drug solution is directly dripped, applied, and sprayed on the mucosal surface to paralyze the sensory nerve endings under the mucosa. It is used for operations on the oral cavity, nose, pharynx, larynx, eyes, and urethral mucosa;
  • Block anesthesia Also known as conductive anesthesia, drug solution is injected near the peripheral nerve trunk to block nerve conduction and produce anesthesia in the area innervated by the nerve. It is often used for operations on limbs, face, mouth and other parts;
  • Subarachnoid space block anesthesia Also called spinal anesthesia, drug solution is injected into the subarachnoid space from the low lumbar intervertebral space to anesthetize the spinal nerve roots in this part. It is often used for lower abdominal and lower limb surgery;
  • Epidural anesthesia Also called epidural anesthesia, the drug solution is injected into the epidural space, allowing it to spread along the spinal nerve roots and enter the intervertebral foramen, blocking the nerve trunks in the intervertebral foramen. , to achieve anesthesia of a certain segment of the trunk, it can be used for surgeries from the neck to the lower limbs, and is especially suitable for abdominal surgeries.
  • Local anesthetics can be divided into categories such as esters and amides based on their chemical structure.
  • Common local anesthetics that are esters include procaine, cocaine, tetracaine, chloroprocaine, proparacaine, oxybuvacaine, benzocaine, etc.
  • Common local anesthetics belonging to the amide class include lidocaine, cinchaine, bupivacaine, mepivacaine, etivacaine, prilocaine, trimethocaine, ropivacaine, etc.
  • a single administration 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 drug in clinical practice.
  • Existing local anesthetic drugs often require repeated doses to maintain the local anesthetic effect in clinical practice, which is very inconvenient especially when long-term local anesthesia is required.
  • R A and R B are each independently hydrogen or methyl
  • R 1 is independently H, R 1a , R 1c or Rx2;
  • R 1a is a C1-C10 hydrocarbon group, which is 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 it is optionally substituted with a substituent selected from Rx2;
  • R 1c is where 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;
  • R 2 are each independently
  • R 2' are each independently H
  • 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.
  • a method for local anesthesia comprising 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 thereof or Solvates or polymorphs thereof or steps of pharmaceutical compositions according to the present disclosure.
  • the local anesthesia includes topical anesthesia, infiltration anesthesia, block anesthesia, subarachnoid block anesthesia and epidural block anesthesia.
  • R A and R B are each independently hydrogen or methyl
  • R 1 is independently H, R 1a , R 1c or Rx2;
  • R 1a is a C1-C10 hydrocarbon group, which is 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 it is optionally substituted with a substituent selected from Rx2;
  • R 1c is where 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;
  • R 2 are each independently as well as
  • R 2' are each independently H
  • hydrocarbon group refers to a saturated or unsaturated group composed of carbon and hydrogen atoms, which includes straight or branched chain hydrocarbon groups, alicyclic hydrocarbon groups, heterocyclic hydrocarbon groups, aromatic hydrocarbon groups or aromatic heterohydrocarbon groups.
  • C1-C10 hydrocarbyl includes C1-10 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl-, C2-10 alkenyl, C2-10 alkynyl and C6-10 aryl base.
  • the C1-10 alkyl group includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, pentyl, hexyl, heptyl, octyl, nonyl base, decyl base.
  • the C3-10 cycloalkyl group includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the C3-6 cycloalkyl-C1-C4 alkyl- is a hydrocarbon group composed of C3-6 cycloalkyl and C1-4 alkyl, such as cyclopropyl-methyl, cyclobutyl methyl-methyl, cyclopentyl-methyl, cyclohexyl-methyl and cycloheptyl-methyl.
  • the C2-10 alkenyl group includes, for example, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, and 3-pentenyl.
  • the C2-10 alkynyl group includes, for example, propargyl, 2-butynyl.
  • the C6-10 aryl group includes, for example, phenyl.
  • mark Indicates the position where the corresponding group is attached to other parts of the compound.
  • the term "pharmaceutically acceptable salt” refers to an acid addition salt or a base addition salt that is suitable for or compatible with the treatment of the subject.
  • the pharmaceutically acceptable salt may be the free base of a compound according to the present disclosure and one of a pharmaceutically acceptable inorganic acid and an organic acid. Or salts formed by combining two or more acids 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, and isethionulfonate.
  • 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, propylene glycol 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 Dicarboxylic acid, citric acid.
  • the free base of the compound of the present invention and the inorganic acid and organic acid in the addition salt may exist in stoichiometric or non-stoichiometric ratios.
  • the solvent in the solvate is selected from the group consisting of water, alcohol, acid, ester, ether, ketone, nitrile and halogenated hydrocarbon, and combinations thereof, and the amount of the solvent may be present in a stoichiometric or non-stoichiometric ratio.
  • the solvent in the solvate is selected from the group consisting of water, C1-C6 alcohols, C1-C6 acids, C3-C6 esters, C4-C6 ethers, C3-C6 ketones, C1-C6 nitriles and C1-C6 Halogenated hydrocarbons and combinations thereof.
  • the solvent in the solvate is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol , glycerin, acetic acid, propionic acid, butyric acid, ethyl acetate, methyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetone, butyl Ketones, acetonitrile, methylene chloride and chloroform and combinations thereof.
  • 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:
  • a method of preparing a compound according to the present disclosure or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a polymorph thereof.
  • an N-substituted-2,6-dimethylaniline derivative having a structure of Formula I, Formula II or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof or a polycrystalline thereof
  • the preparation method includes: 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.
  • R A and R B are each independently hydrogen or methyl
  • R 1 is independently R 1a or R 1c ;
  • R 1a is a C1-C10 hydrocarbon group, which is 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 it is optionally substituted with a substituent selected from Rx2;
  • R 1c is where 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;
  • R 2 are each independently as well as
  • X is a group that is easy to leave.
  • 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.
  • the sulfonic acid group includes, for example, methanesulfonic acid group, benzenesulfonic acid group, p-toluenesulfonic acid group, trifluoromethanesulfonic acid group.
  • carboxylic acid or substituted carboxylic acid groups include, for example, acetate, trifluoroacetate, trichloroacetate, pivaloate, and the like.
  • the acid binding agent is an inorganic base or an organic base
  • the inorganic base includes but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, hydrogenated Sodium, 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 organic bases include but are 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, magnesium ethoxide, magnesium tert-butoxid
  • a compound having a structure of Formula F or Formula F', or a stereoisomer thereof or an addition salt or solvate thereof or a polymorph thereof wherein said Formula F or Formula F'
  • the compound is prepared by the following route 2:
  • the method includes: (1) the compound of formula C reacts with benzyl chloroformate in the presence of an acid binding agent to obtain the compound of formula D; (2) the compound of formula D and formula B (1) or The compound of formula B (2) reacts in the presence of an acid binding agent to obtain the compound of formula E or formula E' respectively; and (3) the compound of formula E or formula E' is deprotected to obtain the compound of formula F or formula F', respectively.
  • the compound of route 2 includes: (1) the compound of formula C reacts with benzyl chloroformate in the presence of an acid binding agent to obtain the compound of formula D; (2) the compound of formula D and formula B (1) or The compound of formula B (2) reacts in the presence of an acid binding agent to obtain the compound of formula E or formula E' respectively; and (3) the compound of formula E or formula E' is deprotected to obtain the compound of formula F or formula F', respectively.
  • R 1 is independently R 1a or R 1c ;
  • R 1a is a C1-C10 hydrocarbon group, which is 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 it is optionally substituted with a substituent selected from Rx2;
  • R 1c is where 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;
  • R 3 is where R A and R B are each independently hydrogen or methyl
  • X is a group that is easy to leave.
  • 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.
  • the sulfonic acid group includes, for example, a methanesulfonic acid group, a benzenesulfonic acid group, a p-toluenesulfonic acid group, a trifluoromethanesulfonic acid group, and the like.
  • the carboxylic acid or substituted carboxylic acid group includes, for example, acetate, trifluoroacetate, trichloroacetate, pivaloate, etc.;
  • the acid binding agent is an inorganic base or an organic base
  • the inorganic base includes but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, hydrogenated Sodium, 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 organic bases include but are 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, magnesium ethoxide, magnesium tert-butoxid
  • an N-substituted-2,6-dimethylaniline derivative having the structure of Formula III or a stereoisomer thereof or an addition salt or solvate thereof or a polymorph thereof, wherein the compound is prepared by the following route 3:
  • the method includes: reacting the compound of formula A with the compound of formula B(3) in the presence of an acid binding agent to obtain the compound of formula III.
  • an acid binding agent to obtain the compound of formula III.
  • R A and R B are each independently hydrogen or methyl
  • R 1 is independently R 1a or R 1c ;
  • R 1a is a C1-C10 hydrocarbon group, which is 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 it is optionally substituted with a substituent selected from Rx2;
  • R 1c is where 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;
  • R 2 are each independently
  • Rx2 is and
  • X is a group that is easy to leave.
  • easily leaving groups X include, but are not limited to, chlorine, bromine, iodine, and sulfonic acid groups.
  • the sulfonic acid group includes, for example, methanesulfonic acid group, benzenesulfonic acid group, p-toluenesulfonic acid group, trifluoromethanesulfonic acid group, etc.
  • the acid binding agent is an inorganic base or an organic base
  • the inorganic base includes but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, hydrogenated Sodium, 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 organic bases include but are 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, magnesium ethoxide, magnesium tert-butoxid
  • a dry organic solvent Dissolve the compound of formula A in route 3 in a dry organic solvent.
  • alkali preferably containing metal compounds, 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, methane Magnesium bromide, methyl magnesium iodide,
  • the compound of formula B (3) in route 3 is slowly added to the above reaction system, and then the cold bath is removed and the temperature is raised to continue the reaction.
  • the reaction can be raised to no more than 50°C, preferably no more than 40°C. From a convenience perspective, a natural rise to ambient temperature response is usually chosen.
  • the reaction solution is purified using silica gel chromatography, alumina chromatography or preparative liquid phase to obtain the target compound.
  • the free base obtained in the above 1) is added with an alcoholic solvent.
  • the alcoholic solvent is preferably selected from methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, 1,2-propanediol, and 1,3-propanediol.
  • glycerol single solvent or two or more mixed solvents thereof after dissolving and filtering, hydrogen chloride gas is passed into the filtrate or an organic solution containing hydrogen chloride is added to obtain the hydrochloride.
  • the obtained hydrochloride can be crystallized by adding an ether solvent to the above-mentioned alcohol solvent to obtain a refined hydrochloride product.
  • Single caine substrates including lidocaine, mepivacaine, ropivacaine, bupivacaine, levobupivacaine, and 1-ethyl-2-(2,6-dimethylaminomethane Acyl) piperidine
  • a dry organic solvent such as drying in an external tube filled with desiccant or filled with inert gas (including nitrogen, argon, etc.), at low temperature (preferably below 0°C) , 0°C ⁇ -40°C can be selected according to the equipment conditions)
  • alkali preferably containing metal compounds, 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-butoxid
  • a bis-alkylation reagent with two excellent leaving groups (the leaving groups include chlorine, bromine, iodine, and sulfonate) into the above reaction system, where the relationship between the bis-alkylation reagent and the caine substrate is
  • the molar ratio 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.
  • the temperature can be raised to no more than 50°C for reaction, and preferably no more than 40°C for reaction. From a convenience point of view, the temperature is usually raised 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. Add a lower polar organic solvent for extraction to remove excess di-alkylation reagent.
  • the lower polar organic solvent includes ester solvents (including ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate) , Ether solvents (including diethyl ether, isopropyl ether, methyl tert-butyl ether), hydrocarbon solvents (including benzene, toluene, pentane, hexane, heptane, octane, cyclohexane, cyclopentane, petroleum ether), or a mixed solvent of two or more thereof. Neutralize the acidic solution to alkalinity and extract it with an organic solvent to obtain the monosubstituted intermediate.
  • ester solvents including ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate
  • Ether solvents including diethyl ether, isopropyl ether, methyl tert-butyl ether
  • the organic solvent includes halogenated hydrocarbons (dichloromethane, chloroform, dichloroethane, chlorobenzene), ester solvents (including ethyl acetate). ester, propyl acetate, isopropyl acetate, butyl acetate), ether solvents (including diethyl ether, isopropyl ether, methyl tert-butyl ether), hydrocarbon solvents (including benzene, toluene, xylene) or any of them A mixture of two or more solvents.
  • halogenated hydrocarbons diichloromethane, chloroform, dichloroethane, chlorobenzene
  • ester solvents including ethyl acetate. ester, propyl acetate, isopropyl acetate, butyl acetate
  • ether solvents including diethyl ether, isopropyl ether, methyl tert-butyl ether
  • step 1 Add single caine substrates different from those in step 1 (including lidocaine, mepivacaine, ropivacaine, bupivacaine, levobupivacaine, and 1-ethyl-2-(2, 6-Dimethylcarbamoyl)piperidine) is dissolved in a dry organic solvent.
  • alkali preferably containing metal compounds, 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, Methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, ethyl magnesium chloride, ethyl magnesium bromide, ethyl magnesium magnesium
  • 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 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, most preferably in the range of 0.8:1 to 1.2:1.
  • the temperature can be raised to no more than 50°C for reaction, and preferably no more than 40°C for reaction. From a convenience point of view, the temperature is usually raised to ambient temperature for reaction.
  • the reaction solution is subjected to post-treatment and purification methods to obtain the target product.
  • the purification methods include silica gel chromatography, alumina chromatography, preparative liquid phase separation or crystallization, or a combination of two or more of them.
  • a compound having the 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:
  • the method includes: 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.
  • a compound of formula C As shown in Route 4, the method includes: 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.
  • R 1 is independently R 1a or R 1c ;
  • R 1a is a C1-C10 hydrocarbon group, which is 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 it is optionally substituted with a substituent selected from Rx2;
  • R 1c is where 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;
  • R 3 is where R A and R B are each independently hydrogen or methyl
  • Rx2 is and
  • X is a group that is easy to leave.
  • X includes but is not limited to chlorine, bromine, iodine, and sulfonic acid groups.
  • the sulfonate group includes, for example, a methanesulfonate group, a benzenesulfonate group, a p-toluenesulfonate group, a trifluoromethanesulfonate group, and the like.
  • the acid binding agent is an inorganic base or an organic base
  • the inorganic base includes but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, hydrogenated Sodium, 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 organic bases include but are 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, magnesium ethoxide, magnesium tert-butoxid
  • Another aspect of the present disclosure provides a pharmaceutical composition
  • 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 excipients.
  • pharmaceutically acceptable carrier refers to a nontoxic solvent, dispersant, excipient, adjuvant or other material with which the active ingredient is mixed to form a pharmaceutical composition (ie, a dosage form capable of being administered to an individual).
  • the pharmaceutically acceptable carrier or excipient is physiological saline
  • a compound or composition of the present disclosure is administered parenterally.
  • the parenteral route may be selected from the group consisting of inhalation, intraperitoneal, intramuscular, subcutaneous, subarachnoid, epidural, mucosal and deep tissue or transocular, transdermal or superficial, and combinations thereof.
  • a solution of a compound of the present disclosure in a vehicle such as physiological saline can be administered by intraperitoneal, intramuscular, subcutaneous, subarachnoid, epidural, or epidural injection or infusion, or by instillation into the eye.
  • sterile solutions of the compounds of the invention are generally prepared and the pH of the solution appropriately adjusted and buffered.
  • the total concentration of solutes should be controlled so that the preparation is isotonic.
  • the droppable liquid may be administered, for example, via an ocular administration system known in the art (eg, applicator or dropper).
  • the diluent or carrier will be selected to be suitable for aerosol formation.
  • the compounds and/or compositions described herein are formulated for parenteral administration by injection, including using conventional catheterization or infusion.
  • injectable preparations are presented in unit dosage form, eg, in ampoules or multi-dose containers, with an added preservative.
  • the compositions or combinations take the form of a sterile suspension, solution or emulsion in an oily or aqueous vehicle, and contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the dosage form must be sterile and must be flowable to facilitate injection.
  • the compounds of the present disclosure are suitably in sterile powder form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) before use.
  • the composition or combination for inhalation is conveniently formulated as an aerosol.
  • the compounds described herein may be conveniently delivered as solutions, dry powder or granular formulations, or suspensions from pump spray containers that are squeezed or pumped by the patient, or as an aerosol spray
  • the form is delivered from a pressurized container or nebulizer.
  • Aerosol preparations generally contain a solution or fine suspension of the active material in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in sterile form in single or multiple doses in sealed containers, e.g. Comes in the form of a cartridge or refill for use with a nebulizing device.
  • 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 disposal after use.
  • the dosage form may contain a propellant, such as a compressed gas (such as compressed air) or an organic propellant (such as chlorofluorocarbons).
  • a propellant such as a compressed gas (such as compressed air) or an organic propellant (such as chlorofluorocarbons).
  • Suitable propellants include, but are not limited to, difluorodichloromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkane, carbon dioxide, or other suitable gases.
  • the dosage unit is suitably determined by providing a valve to deliver the metered quantity.
  • 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 pharmaceutical composition according to the present disclosure are for local anesthesia.
  • Yet another aspect of the present disclosure provides a method for local anesthesia, comprising administering to an individual in need thereof an effective dose of a compound according to the present disclosure, or a stereoisomer thereof, or an addition salt or solvate thereof, or Polymorphs thereof or steps of pharmaceutical compositions according to the present disclosure.
  • the local anesthesia includes topical anesthesia, infiltration anesthesia, block anesthesia, subarachnoid space block anesthesia, epidural space block anesthesia, and the like.
  • Compounds according to the present application may be administered using various dosage ranges depending on the site of administration and clinical needs.
  • anesthesia including topical anesthesia, infiltration anesthesia, block anesthesia, subarachnoid space block anesthesia and epidural space block
  • the compound or its three-dimensional Isomers or their pharmaceutically acceptable salts or solvates or their polymorphs can be used in accordance with 0.1% ⁇ 0.5%, 0.5% ⁇ 1%, 1% ⁇ 2%, 2% ⁇ 4%, 4% ⁇
  • the drug concentration ranges of 6%, 6% to 8%, and 8% to 10% are used for single or repeated administration in the drug dosage ranges of 1 to 50 mg, 50 to 100 mg, 100 to 200 mg, 200 to 400 mg, and 400 to 800 mg. To obtain good local anesthesia/analgesia.
  • the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is for topical anesthesia, wherein the compound or pharmaceutical composition is The solution form is directly dripped, applied or sprayed onto the mucosal surface to paralyze the sensory nerve endings under the mucosa. It is used for operations on the oral cavity, nose, pharynx, larynx, eyes and urethral mucosa.
  • the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is for infiltration anesthesia, wherein the compound or pharmaceutical composition is Solution dosage form, and the solution is injected into the skin, subcutaneous tissue or deep in the surgical field to block nerve conduction at the site of administration.
  • the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is for block anesthesia, wherein the compound or pharmaceutical composition It is a solution dosage form, and the solution is injected near the peripheral nerve trunk to block nerve conduction and produce anesthesia in the area innervated by the nerve. It is often used for surgeries on the body, limbs, face, mouth and other parts.
  • the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is for subarachnoid block anesthesia, wherein the compound Or the pharmaceutical composition is in the form of a solution, and the solution is injected into the subarachnoid space from the low lumbar intervertebral space to anesthetize the spinal nerve roots in this part, and is often used for lower abdominal and lower limb surgery.
  • the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is for epidural anesthesia, wherein said The compound or pharmaceutical composition is in the form of a solution, and the solution is injected into the epidural space, allowing it to spread along the spinal nerve roots and enter the intervertebral foramen, blocking the nerve trunks in the intervertebral foramen, and reaching a certain segment of the trunk.
  • Anesthesia can be used for surgeries from the neck to the lower limbs, and is especially suitable for abdominal surgeries.
  • Reference Example 1 was purified through a preparative column to obtain 0.57 g of colorless viscous oil with a purity of 99.1%.
  • lidocaine (468mg) and dissolve it in anhydrous tetrahydrofuran (10ml). Dry it in a drying tube and put it in an ice bath at -20°C for 5 minutes. Add sodium hydrogen (110mg) and keep stirring for 0.5h. Take n-valeryl chloride (480 ⁇ l) and dissolve it in anhydrous tetrahydrofuran (10ml). Water and tetrahydrofuran (15 ml) were slowly dropped into the system, and after 1 hour, the mixture was turned to room temperature and stirred overnight.
  • lidocaine (495 mg) and dissolve it in anhydrous tetrahydrofuran (15 ml). Dry in a drying tube at -10°C for 5 minutes. Add sodium hydrogen (117 mg) and keep stirring for 1 hour. Then add 1,4-dibromobutane (130 ⁇ l) Dissolve in anhydrous tetrahydrofuran (10 ml), slowly drop into the above reaction system, stir at room temperature overnight, filter the reaction solution through diatomaceous earth + anhydrous sodium sulfate, concentrate the filtrate and purify through preparative liquid phase to obtain 402 mg of the title compound, purity 99.1% .
  • the corresponding chloroformate was used as the acylating agent, and compounds B1-B10 were prepared using mepivacaine as the raw material; using 1-ethyl-2-(2,6-dimethylcarbamoyl ) Piperidine was used as the raw material to prepare compounds B43-B52; ropivacaine was used as the raw material to prepare compounds B54-B66; bupivacaine was used as the raw material to prepare compounds B79-B104:
  • the corresponding acid chloride is used as the acylating agent, and mepivacaine, 1-ethyl-2-(2,6-dimethylcarbamoyl)piperidine, racemic ropivacaine, and ropivacaine are used respectively.
  • the following compounds were prepared from pipevacaine, bupivacaine and levobupivacaine as raw materials:
  • reaction solution was filtered with diatomaceous earth + anhydrous sodium sulfate, spin-dried, and the crude product was dissolved in hydrochloric acid solution (0.1M), then extracted and washed twice with isopropyl ether, and the aqueous phase was adjusted to a weakly alkaline pH with saturated sodium bicarbonate solution. , then extracted with ethyl acetate three times, dried over anhydrous sodium sulfate for 1 hour, filtered, and concentrated to obtain a colorless oil (649 mg, HPLC purity 99%).
  • the corresponding alkylation reagents were used, including mepivacaine, 1-ethyl-2-(2,6-dimethylcarbamoyl)piperidine, racemic ropivacaine, and ropivacaine.
  • Caine, bupivacaine and levobupivacaine are prepared from raw materials to obtain the following compounds:
  • Example 8 and Example 9 use corresponding alkylation reagents, including mepivacaine, 1-ethyl-2-(2,6-dimethylcarbamoyl)piperidine, and racemic ropivacaine.
  • alkylation reagents including mepivacaine, 1-ethyl-2-(2,6-dimethylcarbamoyl)piperidine, and racemic ropivacaine.
  • the following compounds and their corresponding hydrochlorides were prepared from raw materials: ropivacaine, bupivacaine and levobupivacaine:
  • the corresponding halogenated hydrocarbyl amine or N-Boc-halogenated hydrocarbyl amine is used, and lidocaine, mepivacaine, ropivacaine, bupivacaine and levobupivacaine are used as raw materials respectively.
  • the dihydrochloride salt of the following compound was prepared:
  • Step 1 Add 250 mg of levobupivacaine in a 25 ml three-neck bottle, pass in N 2 , add 10 ml of dry tetrahydrofuran, cool to -10°C, add 45 mg of NaH (60%), react at -10°C for 1.5 hr, and drip at low temperature Add 10 ml of tetrahydrofuran solution of 2 g of 1,4-dibromobutane, and let the reaction last overnight at room temperature. Filter through diatomaceous earth. Slowly add hydrochloric acid solution to the filtrate in an ice bath until the pH of the solution is about 2. Extract with ethyl acetate three times.
  • Step 2 Add 215 mg of mepivacaine into a 25 ml three-neck bottle, pass N 2 through, add 10 ml of dry tetrahydrofuran, cool to -10°C, add 45 mg of NaH (60%), react at -10°C for 1.5 hr, and add dropwise at low temperature
  • the intermediate tetrahydrofuran solution in step 1 was dropped, heated to 30-40°C, and reacted for 72 hours.
  • lidocaine, bupivacaine, levobupivacaine, mepivacaine, ropivacaine and 1-ethyl-2-(2,6-dimethylcarbamoyl ) piperidine is used as raw material to prepare the following compounds:
  • Example 12 Preparation of improved compound B250 hydrochloride (optimized on the basis of Example 9)
  • Test Example 1 Test of local anesthesia by corneal method in rats
  • SD rats ⁇ , about 300 g, were purchased from the Experimental Animal Center of Chongqing Medical University. These rats were kept on a routine basis, with free access to food and water. During the period, the temperature was about 25-28°C and the humidity was about 65-85%.
  • lidocaine hydrochloride injection 5mL: 0.1g, batch number: 161207, Southwest Pharmaceutical Co., Ltd.
  • ⁇ Compound 174 solution (40.8 mg/mL, equimolar concentration with 2% lidocaine): Add 48.2 mg of compound 174 to 1.18 mL of physiological saline (Hualu, SD21032001), first use hydrochloric acid to dissolve it, and then Adjust pH to 5.14 with sodium hydroxide.
  • Compound 172 solution (38.6 mg/mL, equimolar concentration with 2% lidocaine): Add 52.2 mg of compound 172 to 1.35 mL of physiological saline (Hualu, SD21032001), first use hydrochloric acid to dissolve, and then Adjust pH to 5.17 with sodium hydroxide.
  • Compound 169 solution (22.5 mg/mL, equimolar concentration to Compound 1 hydrochloride solution 2): Add 30.2 mg of Compound 169 to 1.34 mL of physiological saline (Tiansheng, 522021703), dissolve it with hydrochloric acid, and then add hydrogen Sodium oxide adjusts the pH to 5.19.
  • Preliminary test Place the rat in a horizontal lying position, then take the solution with a pipette and instill it into the eyes, one drop every 30 seconds, a total of 3 drops. During this period, the ocular surface remains moistened with the drug. 30 seconds after the last eye instillation, absorb with filter paper. Remove the solution from the ocular surface, use cut rat whiskers to stimulate the cornea, and observe the corneal reflection. The results are shown in Table 1 below.
  • a guinea pig weighing 300-500g One day before the test, shave the hair on the back and sides of the guinea pig.
  • Injection solution 0.1-0.20mL. This will prevent the liquid from leaking out and forming pimples after the needle is pulled out.
  • Use an ink circle to mark the size. After injecting the drug, use acupuncture at different time points to test the feeling of the skin at the papule.
  • Test Example 3 Rat subcutaneous local anesthesia test
  • ⁇ Lidocaine hydrochloride 5 mg/mL (0.5%): Add 1 mL of lidocaine hydrochloride injection (Southwestern Pharmaceutical, 161207, 5 mL: 0.1 g) to 3 mL of normal saline (Tiansheng, 522021703), and dilute to 5mg/mL.
  • the rats were Baoding, and the two test drugs were infiltrated into the skin of the corresponding areas on both sides of the back of the same animal, and 0.6 mL was injected subcutaneously to form a skin mound, which was marked with a marker pen. At each time point, a total of 5 points were punctured in the middle and around the administration site (pill or bump). The acupuncture time interval was 3-5 seconds. No reaction after acupuncture was recorded (no skin muscle contraction or hissing). Case.
  • Test Example 4 Rat subcutaneous local anesthesia test
  • ⁇ Compound 172 solution (approximately 9mM): Add 9.6mg of compound 172 to 1.985mL of physiological saline (Tiansheng, 522021703), and adjust the pH to 5.16 with a small amount of hydrochloric acid/sodium hydroxide to dissolve.
  • the rats were Baoding, and the two test drugs were infiltrated into the skin of the corresponding areas on both sides of the back of the same animal, and 0.3 mL was injected subcutaneously to form a skin mound, which was marked with a marker pen. At each time point, a total of 5 points were punctured in the middle and around the administration site (pill or bump). The acupuncture time interval was 3-5 seconds. No reaction after acupuncture was recorded (no skin muscle contraction or hissing). Case.
  • mice were purchased from the Experimental Animal Center of Chongqing Medical University. During the entire test period, animals were allowed to eat and drink freely, with an ambient temperature of approximately 23-26°C and a humidity of 70-90%.
  • ⁇ Lidocaine hydrochloride solution Add 0.1mL of 2% lidocaine hydrochloride injection (2% lidocaine hydrochloride injection, 5mL: 0.1g, batch number: 161207, Southwest Pharmaceutical Co., Ltd.) into 0.9mL of physiological Dilute to 2mg/mL in saline.
  • Compound 1 solution 1) Disperse 7.2 mg of Compound 1 in 4.05 mL of physiological saline (Hualu, SD21032001), adjust the pH to 5.42 with hydrochloric acid/sodium hydroxide, and prepare a 1.78 mg/mL solution; 2) 8.6 mg of compound 1 was dispersed in 1.985 mL of physiological saline (Hualu, SD21032001), and the pH was adjusted to 5.32 with hydrochloric acid/sodium hydroxide to prepare a 4.33 mg/mL solution.
  • ⁇ Compound 169 solution i) Disperse 35.7 mg of compound 169 in 1.485 mL of physiological saline (Tiansheng, 522021703), first add hydrochloric acid to dissolve, then add sodium hydroxide to adjust the pH to 5.14, ii) Disperse 500 ⁇ L of i ) was added to 4.3 ml of physiological saline and diluted to obtain a 2.5 mg/ml solution.
  • Test Example 6 Test of intradermal local anesthesia in rats
  • ⁇ 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), add Dissolve the solution with hydrochloric acid, then adjust the pH to 5.31 with sodium hydroxide, and then filter with 0.22 ⁇ m.
  • the rats were restrained and administered intradermal infiltration anesthesia as shown in the figure below. 1 and 3 were administered with levobupivacaine hydrochloride, 2 and 4 were administered with compound B105 hydrochloride, and 0.1 mL was injected intradermally. Pichus are formed and marked with a marker.
  • the acupuncture time interval is 3-5s, and no reaction after acupuncture is recorded ( There is no point of skin muscle contraction or hissing).
  • the temperature is about 25°C
  • the humidity is about 70%.
  • ⁇ Compound 172 solution (4.6mM): Add 9.6mg of compound 172 to 1.985mL of normal saline (Tiansheng, 522021703), adjust the pH to 5.16 with a small amount of hydrochloric acid/sodium hydroxide to dissolve, take 1mL of this solution and add 1mL of normal saline (Tiansheng, 522021703), diluted to 2.42mg/mL.
  • the rat was Baoding, intradermal infiltration anesthesia was administered, and 0.3 mL was injected subcutaneously to form a cortical dome, which was marked with a marker pen. At each time point, a total of 5 points were punctured in the middle and around the administration site (pill or bump). The acupuncture time interval was 3-5 seconds. No reaction after acupuncture was recorded (no skin muscle contraction or hissing). Case.
  • mice were purchased from the Experimental Animal Center of Chongqing Medical University. During the entire test period, animals were allowed to eat and drink freely, with an ambient temperature of approximately 23-26°C and a humidity of 70-90%.
  • ⁇ Levobupivacaine hydrochloride solution prepared with physiological saline to a 1 mg/mL solution.
  • mice were injected into the tail vein at a constant speed for about 2-3 seconds, and the LD 50 value was observed and estimated.
  • the results are shown in Table 8 below.
  • a guinea pig weighing 800-1000g.
  • One day before the test shave the hair on the back line and both sides of the guinea pig.
  • Use a small needle to inject the liquid into the skin of the guinea pig at three locations in front, middle and back of the midline of the 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 medicinal solution. This will prevent the liquid from leaking out and forming a skin mound after the needle is pulled out. Mark its size with an ink circle.
  • acupuncture was used at different time points to test the sensation of the skin on the pichus, and normal skin outside the pichus was used as a control. Normal skin will experience skin muscle contraction after acupuncture.
  • the acupuncture test was performed 6 times at each time point, with an interval of 3-5 s between two times, and the total number of no reactions (no skin and muscle contraction) after acupuncture was recorded. If the needle is used to stimulate 6 times and no skin muscle contraction occurs ⁇ 3 times, it means that the subcutaneous infiltration of the drug is effective.
  • Table 10 The pain suppression at different time points after injection of bupivacaine and compound B105 into the back of guinea pigs is summarized in Table 10 below.
  • Test Example 10 Comparison of subcutaneous administration of bupivacaine and compound B246 to rats
  • Bupivacaine and compound B246 were prepared into equimolar concentration (10mM) solutions with physiological saline, and were injected subcutaneously into two SD rats respectively. Each rat was injected at two points, and the administration volume was 0.6mL/point. , the interval between each point is 5 hours, and the skin is taken 20 or 25 minutes after the last dose to detect the content. The results are shown in Table 14 below.
  • Test Example 11 Observation of local drug concentration after local administration of compound B246 to rats
  • Compound B246 was prepared into a 10 m M solution with physiological saline, and was injected subcutaneously into 7 SD rats respectively. Each rat was injected with one point on each side of the left and right sides, and the administration volume was 0.6 mL /point. Acupuncture was performed within the next 20 min to 120 hours (puncture one needle in each of the five areas above, below, left, right, and middle of the formed skin circle), and the number of times without response (that is, local anesthesia was effective) was recorded, and then The skin and subcutaneous tissue were taken to detect the drug concentration. The results are shown in Table 15 below.
  • Test Example 12 Observation of local drug concentration after local administration of compound B246 to rats until local anesthesia disappears
  • Compound B246 was prepared into a 10mM solution with physiological saline, and administered subcutaneously to SD rats. Each rat was injected with one point on each side of the left and right sides, and the administration volume was 0.6 mL/point. When the unresponsiveness of the administration site to acupuncture completely disappears (348-360 hours), samples were taken at different time points to detect the local drug concentration and blood drug concentration. The results are shown in Table 16 below.
  • Test Example 13 Preliminary test of rat sciatic nerve block
  • bupivacaine physiological saline solution Add 5.2mg bupivacaine to 1.8mL of physiological saline (Yuyuan, L23010707), adjust the pH to 5.80 with hydrochloric acid/sodium hydroxide, and dissolve.
  • Rat sciatic nerve block method Insert a needle at the midpoint of the line connecting the greater trochanter of the right femur and the ischial tubercle. After the needle tip touches the ischium, inject the drug.
  • test data in Table 17 shows that bupivacaine and compound 169 at a concentration of 10mM each have 0.2 mL each, and both have sciatic nerve blockade in rats.
  • the blocking effect of compound 169 is stronger than that of bupivacaine 1 hour after administration. because.
  • Test Example 14 Mouse hot plate foot licking test
  • mice ⁇ , SPF grade, Experimental Animal Center of Chongqing Medical University.
  • the mice were adaptively raised for 4 days, during which they had free access to food and water; the temperature during the test was 27.6°C and the humidity was 80%.
  • compound 169 physiological saline solution Add 5.1 mg of compound 169 to 5.1 mL of physiological saline (Yuyuan, L23010707), then adjust the pH to 5.58 with hydrochloric acid/sodium hydroxide and dissolve.
  • mice were injected with compound 169 through the tail vein at doses of 10mg/kg (1mg/mL, 0.1mL/10g), 5mg/kg (1mg/mL, 0.5mL/10g), and 0mg/kg (NS, 0.1mL/10g).
  • Physiological saline solution 10 minutes after administration, observe the foot licking time on the hot plate (55.0°C, the longest observed time is 60 seconds).
  • one animal each in the control group and the high and low dose groups of the test substance was administered and tested at the same time. The test results are shown in Table 18 below.
  • test data in Table 18 shows that after injection through the tail meridian, Compound 169 can prolong the foot licking time of mice on a 55.0°C hot plate in a dose-dependent manner.
  • the N-substituted aromatic amine derivative according to the present invention has local anesthetic effect. Compared with the drugs currently used clinically, it shows a significantly longer-lasting local anesthetic effect, can reduce the number of administrations, and is particularly suitable for long-term needs. In the case of local anesthesia, it has the advantages of long-lasting effect, safety and more controllable quality.

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Abstract

本发明涉及具有式I、式II、式III、式IV、式V或式VI结构的化合物或其立体异构体或药学可接受的盐，以及包含所述化合物的药物组合物及其用途。

Description

N-取代芳胺衍生物及其制备方法和用途 技术领域
本申请涉及N-取代芳胺衍生物及其制备方法以及其在相关医药治疗领域中的用途。
背景技术
局部麻醉药阻断各种神经冲动的传导，其首先抑制触觉、压觉和痛觉，在浓度增加时也可能抑制运动神经的功能。局部麻醉药应用于局部，使局部发生感觉和痛觉缺失的效果，其麻醉范围小，多适用于小型手术和插管，与全身麻醉药相比，其不良反应少，较安全。
局部麻醉药可用于不同部位以阻断感觉神经而产生麻醉作用，具体可分为：
(1)表面麻醉：将麻醉药物溶液直接点滴、涂抹、喷射于黏膜表面，使黏膜下的感觉神经末梢麻痹，用于口腔、鼻、咽、喉、眼及尿道黏膜等部位手术；
(2)浸润麻醉：将药物注射于皮内、皮下组织或手术野深部，以阻断用药部位的神经传导；
(3)阻滞麻醉：又称传导麻醉，将药物溶液注射于外周神经干附近，以阻断神经传导，使该神经所支配的区域产生麻醉作用，常用于四肢、面部、口腔等部位手术；
(4)蛛网膜下腔阻滞麻醉：又称腰麻，将药物溶液自低位腰椎间注入蛛网膜下腔内，麻醉该部的脊神经根，常用于下腹部和下肢手术；
(5)硬脊膜外腔阻滞麻醉：又称硬膜外麻醉，将药物溶液注入硬脊膜外腔，使其沿脊神经根扩散而进入椎间孔，阻滞椎间孔内的神经干，达到躯干某一节段的麻醉，从颈部至下肢的手术都可采用，特别适用于腹部手术。
局部麻醉药根据化学结构可划分为酯类和酰胺类等类别。
属于酯类的局部麻醉药常见的有普鲁卡因、可卡因、丁卡因、氯普鲁卡因、丙美卡因、奥布卡因、苯佐卡因等。属于酰胺类的局部麻醉药常见的有利多卡因、辛可卡因、布比卡因、甲哌卡因、依替卡因、丙胺卡因、三甲卡因、罗哌卡因等。现有局部麻醉药单次给药通常可以维持数十分钟至数小时的局部麻醉效果，利多卡因是目前临床使用最为广泛的局部麻醉药物。现有局部麻醉药物在临床实践中经常需要反复追加剂量以维持局部麻醉效果，特别是对于需要长时间局部麻醉的情况下，使用很不方便。
仍需要一种与现有临床所使用的药物相比具有明显更长时效的局部麻醉作用，可减少给药次数，特别适合需要长时间局部麻醉的情况的局部麻醉药。
发明内容
在本申请的一个方面中，提供具有式I、式II、式III、式IV、式V或式VI结构的化合物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物：

其中，
RA和RB各自独立地为氢或甲基；
R1分别独立地为H、R1a、R1c或Rx2；
R1a为C1-C10烃基，其选自C1-10烷基、C3-10环烷基、C3-6环烷基-C1-C4烷基-、C2-10烯基、C2-10炔基和C6-10芳基，并且其任选地被选自Rx2的取代基取代；
R1c为其中n为2-8的整数，m为1-6的整数，o为2或3，p为1或2，q为1-3的整数，以及RN1和RN2相互独立地为H或C1-C8烷基；
Rx2为
R2各自独立地为
R2’各自独立地为H、
根据本申请的另一个方面，提供一种药物组合物，其包含根据本公开的化合物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物，以及药学可接受的载体或赋形剂。
根据本申请的再一个方面，提供根据本公开的化合物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物在制备用于局部麻醉的药物中的用途。
根据本申请的再一个方面，提供一种用于局部麻醉的方法，其包括对有此需要的个体施予有效剂量的根据本公开的化合物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物或者根据本公开的药物组合物的步骤。
在本公开中，所述局部麻醉包括表面麻醉、浸润麻醉、阻滞麻醉、蛛网膜下腔阻滞麻醉和硬脊膜外腔阻滞麻醉。
具体实施方式
化合物
根据本申请的一个方面，提供具有式I、式II、式III、式IV、式V或式VI结构的化合物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物：
其中，
RA和RB各自独立地为氢或甲基；；
R1分别独立地为H、R1a、R1c或Rx2；
R1a为C1-C10烃基，其选自C1-10烷基、C3-10环烷基、C3-6环烷基-C1-C4烷基-、C2-10烯基、C2-10炔基和C6-10芳基，并且其任选地被选自Rx2的取代基取代；
R1c为其中n为2-8的整数，m为1-6的整数，o为2或3，p为1或2，q为1-3的整数，以及RN1和RN2相互独立地为H或C1-C8烷基；
Rx2为
R2各自独立为 以及
R2’各自独立地为H、
在本公开中，术语“烃基”是指有碳和氢原子组成的饱和或不饱和基团，其包括直连或支链烃基、脂环烃基、杂环烃基、芳烃基或芳杂烃基。例如，C1-C10烃基包括C1-10烷基、C3-10环烷基、C3-6环烷基-C1-4烷基-、C2-10烯基、C2-10炔基和C6-10芳基。
在一个实施方案中，所述C1-10烷基例如包括甲基、乙基、正丙基、异丙基、正丁基、2-丁基、戊基、己基、庚基、辛基、壬基、癸基。
在一个实施方案中，所述C3-10环烷基例如包括环丙基、环丁基、环戊基、环己基和环庚基。
在一个实施方案中，所述C3-6环烷基-C1-C4烷基-是由C3-6环烷基与C1-4烷基构成的烃基，例如包括环丙基-甲基、环丁基-甲基、环戊基-甲基、环己基-甲基和环庚基-甲基。
在一个实施方案中，所述C2-10烯基例如包括烯丙基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基。
在一个实施方案中，所述C2-10炔基例如包括炔丙基、2-丁炔基。
在一个实施方案中，所述C6-10芳基例如包括苯基。
在本公开中，标记表示相应基团与化合物之其他部分连接的位置。
术语“药学可接受的盐”是指适用于个体的治疗或与个体的治疗相容的酸加成盐或碱加成盐。例如，所述药学可接受的盐可以是根据本公开的化合物的游离碱与可药用无机酸和有机酸中的一种酸 或以任意比例组合的两种及以上的酸所形成的盐。所述可药用无机酸盐例如包括盐酸、氢溴酸、磷酸、硫酸；所述可药用有机酸盐例如包括甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、羟乙磺酸、甲酸、乙酸、氯乙酸、羟基乙酸、三氟乙酸、丙酸、丙烯酸、丁酸、异丁酸、戊酸、特戊酸、己酸、苯甲酸、苯乙酸、乙二酸、丙二酸、丁二酸、顺丁烯二酸、反丁烯二酸、d-酒石酸、l-酒石酸、dl-酒石酸、戊二酸、己二酸、邻苯二甲酸、间苯二甲酸、对苯二甲酸、柠檬酸。所述加成盐中本发明化合物的游离碱与无机酸和有机酸之间可以化学计量比或非化学计量比存在。
所述溶剂合物中的溶剂选自水、醇、酸、酯、醚、酮、腈和卤代烃及其组合，溶剂的量可以化学计量比或非化学计量比存在。根据一个实施方案，所述溶剂合物中的溶剂选自水、C1-C6醇、C1-C6酸、C3-C6酯、C4-C6醚、C3-C6酮、C1-C6腈和C1-C6卤代烃及其组合。根据一个实施方案，所述溶剂合物中的溶剂选自水、甲醇、乙醇、丙醇、异丙醇、正丁醇、叔丁醇、乙二醇、1,2-丙二醇、1,3丙二醇、丙三醇、乙酸、丙酸、丁酸、乙酸乙酯、乙酸甲酯、乙酸异丙酯、丙酸甲酯、丙酸乙酯、乙醚、甲基叔丁基醚、四氢呋喃、丙酮、丁酮、乙腈、二氯甲烷和氯仿及其组合。
在一个实施方案中，所述具有式I、式II、式III、式IV、式V或式VI结构的化合物是选自以下表中的化合物：








































化合物的制备
根据本公开的另一个方面，提供制备根据本公开的化合物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物的方法。
在一个实施方案中，提供具有式I、式II结构的N-取代-2,6-二甲基苯胺衍生物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物的制备方法，其中所述化合物通过如下路线1进行制备：
如路线1所示，所述制备方法包括：式A化合物与式B(1)或式B(2)化合物在缚酸剂存在条件下，发生反应分别得到式I或式II化合物。在上述路线1所涉及的化合物中，
RA和RB各自独立地为氢或甲基；
R1分别独立地为R1a或R1c；
R1a为C1-C10烃基，其选自C1-10烷基、C3-10环烷基、C3-6环烷基-C1-4烷基-、C2-10烯基、C2-10炔基和C6-10芳基，并且其任选地被选自Rx2的取代基取代；
R1c为其中n为2-8的整数，m为1-6的整数，o为2或3，p为1或2，q为1-3的整数，以及RN1和RN2相互独立地为H或C1-C8烷基；
Rx2为
R2各自独立为 以及
X为容易离去的基团。
在一个实施方案中，作为容易离去的基团的X包括但不限于氯、溴、碘、磺酸基、羧酸基或取代羧酸基。在一个实施方案中，磺酸基包括如甲磺酸基、苯磺酸基、对甲苯磺酸基、三氟甲磺酸 基等。在一个实施方案中，羧酸或取代羧酸基包括如乙酸基、三氟乙酸基、三氯乙酸基、特戊酸基等。
在一个实施方案中，所述缚酸剂为无机碱或有机碱，其中无机碱包括但不限于氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、氢氧化钙、氢氧化镁、氢化钠、氢化钾、氢化钙、氢化锂、碳酸氢锂、碳酸氢钠、碳酸氢钾、碳酸氢钙、碳酸锂、碳酸钠、碳酸钾、碳酸铯、碳酸镁、碳酸钙、磷酸钠、磷酸钾、磷酸氢二钠、磷酸氢二钾、磷酸氢钾钠，其中有机碱包括但不限于乙酸钠、丙酸钠、丁酸钠、甲醇钠、乙醇钠、叔丁醇钠、甲醇钾、乙醇钾、叔丁醇钾、甲醇镁、乙醇镁、叔丁醇镁、三甲胺、三乙胺、三丁胺、二异丙胺、二异丙基乙胺、叔丁胺、N,N-二甲基苯胺、四甲基乙二胺、DABCO、DBU、DBN、吡啶、DMAP、N-甲基吗啉、四甲基胍、正丁基锂、叔丁基锂、苯基锂、氨基钠、甲基氯化镁、甲基溴化镁、甲基碘化镁、乙基氯化镁、乙基溴化镁、乙基碘化镁、异丙基氯化镁、异丙基溴化镁、异丙基碘化镁、二甲基镁、二乙基镁、二异丙基镁等、LDA、NaHMDS、KHMDS、LiHMDS等。
根据本公开的另一个方面，提供具有式F或式F’结构的化合物或其立体异构体或其加成盐或溶剂合物或其多晶型物，其中所述式F或式F’的化合物通过如下路线2进行制备：
如路线2所示，所述方法包括：(1)式C化合物与氯甲酸苄酯在缚酸剂存在条件下发生反应，得到式D化合物；(2)式D化合物与式B(1)或式B(2)化合物在缚酸剂存在下发生反应，分别得到式E或式E’化合物；以及(3)式E或式E’化合物经过脱保护分别得到式F或式F’化合物。在路线2的化合物中，
R1分别独立地为R1a或R1c；
R1a为C1-C10烃基，其选自C1-10烷基、C3-10环烷基、C3-6环烷基-C1-4烷基-、C2-10烯基、C2-10炔基和C6-10芳基，并且其任选地被选自Rx2的取代基取代；
R1c为其中n为2-8的整数，m为1-6的整数，o为2或3，p为1或2，q为1-3的整数，以及RN1和RN2相互独立地为H或C1-C8烷基；
Rx2为
R3为其中RA和RB各自独立地为氢或甲基；以及
X为容易离去的基团。
在一个实施方案中，作为容易离去的基团的X包括但不限于氯、溴、碘、磺酸基、羧酸基或取代羧酸基。在一个实施方案中，所述磺酸基包括如甲磺酸基、苯磺酸基、对甲苯磺酸基、三氟甲磺酸基等。在一个实施方案中，所述羧酸或取代羧酸基包括如乙酸基、三氟乙酸基、三氯乙酸基、特戊酸基等；
在一个实施方案中，所述缚酸剂为无机碱或有机碱，其中无机碱包括但不限于氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、氢氧化钙、氢氧化镁、氢化钠、氢化钾、氢化钙、氢化锂、碳酸氢锂、碳酸氢钠、碳酸氢钾、碳酸氢钙、碳酸锂、碳酸钠、碳酸钾、碳酸铯、碳酸镁、碳酸钙、磷酸钠、磷酸钾、磷酸氢二钠、磷酸氢二钾、磷酸氢钾钠，其中有机碱包括但不限于乙酸钠、丙酸钠、丁酸钠、甲醇钠、乙醇钠、叔丁醇钠、甲醇钾、乙醇钾、叔丁醇钾、甲醇镁、乙醇镁、叔丁醇镁、三甲胺、三乙胺、三丁胺、二异丙胺、二异丙基乙胺、叔丁胺、N,N-二甲基苯胺、四甲基乙二胺、DABCO、DBU、DBN、吡啶、DMAP、N-甲基吗啉、四甲基胍、正丁基锂、叔丁基锂、苯基锂、氨基钠、甲基氯化镁、甲基溴化镁、甲基碘化镁、乙基氯化镁、乙基溴化镁、乙基碘化镁、异丙基氯化镁、异丙基溴化镁、异丙基碘化镁、二甲基镁、二乙基镁、二异丙基镁等、LDA、NaHMDS、KHMDS、LiHMDS等。
根据本公开的另一个方面，提供具有式III结构的N-取代-2,6-二甲基苯胺衍生物或其立体异构体或其加成盐或溶剂合物或其多晶型物，其中所述化合物通过如下路线3进行制备：
如路线3所示，所述方法包括：使式A化合物与式B(3)化合物在缚酸剂存在条件下发生反应，得到式III化合物。在路线3所涉及的化合物中，
RA和RB各自独立地为氢或甲基；
R1分别独立地为R1a或R1c；
R1a为C1-C10烃基，其选自C1-10烷基、C3-10环烷基、C3-6环烷基-C1-4烷基-、C2-10烯基、C2-10炔基和C6-10芳基，并且其任选地被选自Rx2的取代基取代；
R1c为其中n为2-8的整数，m为1-6的整数，o为2或3，p为1或2，q为1-3的整数，以及RN1和RN2相互独立地为H或C1-C8烷基；
R2各自独立为
Rx2为及
X为容易离去的基团。
在一个实施方案中，作为容易离去的基团X包括但不限于氯、溴、碘、磺酸基。在一个所述方案中，所述磺酸基包括如甲磺酸基、苯磺酸基、对甲苯磺酸基、三氟甲磺酸基等。
在一个实施方案中，所述缚酸剂为无机碱或有机碱，其中无机碱包括但不限于氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、氢氧化钙、氢氧化镁、氢化钠、氢化钾、氢化钙、氢化锂、碳酸氢锂、碳酸氢钠、碳酸氢钾、碳酸氢钙、碳酸锂、碳酸钠、碳酸钾、碳酸铯、碳酸镁、碳酸钙、磷酸钠、磷酸钾、磷酸氢二钠、磷酸氢二钾、磷酸氢钾钠，其中有机碱包括但不限于乙酸钠、丙酸钠、丁酸钠、甲醇钠、乙醇钠、叔丁醇钠、甲醇钾、乙醇钾、叔丁醇钾、甲醇镁、乙醇镁、叔丁醇镁、三甲胺、三乙胺、三丁胺、二异丙胺、二异丙基乙胺、叔丁胺、N,N-二甲基苯胺、四甲基乙二胺、DABCO、DBU、DBN、吡啶、DMAP、N-甲基吗啉、四甲基胍、正丁基锂、叔丁基锂、苯基锂、氨基钠、甲基氯化镁、甲基溴化镁、甲基碘化镁、乙基氯化镁、乙基溴化镁、乙基碘化镁、异丙基氯化镁、异丙基溴化镁、异丙基碘化镁、二甲基镁、二乙基镁、二异丙基镁等、LDA、NaHMDS、KHMDS、LiHMDS等。
在本发明化合物结构列表中，式B241-B264化合物及其相应的盐酸盐，通过如下方法进行制备得到高质量样品：
1)游离碱的制备
将路线3中式A化合物溶于干燥的有机溶剂中，在保持干燥的条件下，如外接填充干燥剂的管干燥或充入惰性气体(包括氮气、氩气等)，于低温下(优选0℃以下，根据设备情况可选择0℃～-40℃)，加入碱(优选含金属化物，包括氢化钠、氢化钾、氢化钙、氢化锂、碳酸钠、碳酸钾、碳酸铯、甲醇钠、乙醇钠、叔丁醇钠、甲醇钾、乙醇钾、叔丁醇钾、甲醇镁、乙醇镁、叔丁醇镁、正丁基锂、叔丁基锂、苯基锂、氨基钠、甲基氯化镁、甲基溴化镁、甲基碘化镁、乙基氯化镁、乙基溴化镁、乙基碘化镁、异丙基氯化镁、异丙基溴化镁、异丙基碘化镁、二甲基镁、二乙基镁、二异丙基镁、LDA、NaHMDS、KHMDS、LiHMDS)，于低温下保温反应一段时间。然后将路线3中式B(3)化合物缓慢加入上述反应体系，然后移除冷浴后升温继续反应，可升至不超过50℃反应，优选不超过40℃反应。从方便的角度，通常选择自然升至环境温度反应。反应液经过后处理后，采用硅胶层析、氧化铝层析或制备液相等方法进行纯化，得到目标物。
2)盐酸盐的制备
上述1)中得到的游离碱，加入醇类溶剂，所述醇类溶剂优选自甲醇、乙醇、丙醇、异丙醇、丁醇、乙二醇、1,2-丙二醇、1,3-丙二醇、丙三醇单一溶剂或其中的两种及以上的混合溶剂，经溶解、过滤，滤液中通入氯化氢气体或加入含氯化氢的有机溶液，得到盐酸盐。所得盐酸盐可以通过在上述的醇类溶剂中加入醚类溶剂结晶的方法，得到精制盐酸盐产品。
在本发明化合物结构列表中，式B241-B330以及式B355-B364化合物通过如下分步的方法进行制备得到：
步骤1：制备单取代中间体，
将单一卡因类底物(包括利多卡因、甲哌卡因、罗哌卡因、布比卡因、左布比卡因以及1-乙基-2-(2,6-二甲胺甲酰基)哌啶)溶于干燥的有机溶剂中，在保持干燥的条件下，如外接填充干燥剂的管干燥或充入惰性气体(包括氮气、氩气等)，于低温下(优选0℃以下，根据设备情况可选择0℃～-40℃)，加入碱(优选含金属化物，包括氢化钠、氢化钾、氢化钙、氢化锂、碳酸钠、碳酸钾、 碳酸铯、甲醇钠、乙醇钠、叔丁醇钠、甲醇钾、乙醇钾、叔丁醇钾、甲醇镁、乙醇镁、叔丁醇镁、正丁基锂、叔丁基锂、苯基锂、氨基钠、甲基氯化镁、甲基溴化镁、甲基碘化镁、乙基氯化镁、乙基溴化镁、乙基碘化镁、异丙基氯化镁、异丙基溴化镁、异丙基碘化镁、二甲基镁、二乙基镁、二异丙基镁、LDA、NaHMDS、KHMDS、LiHMDS)，于低温下保温反应一段时间。将具有两个优良离去基团的双烃基化试剂(所述离去基团包括氯、溴、碘、磺酸酯)缓慢加入上述反应体系，其中双烃基化试剂与卡因类底物的摩尔比不小于2:1，优选地，该摩尔比不小于5:1，更优选地，该摩尔比不小于10:1。加毕，移除冷浴后升温继续反应，可升至不超过50℃反应，优选不超过40℃反应，从方便的角度，通常选择自然升至环境温度反应。反应液经过滤除去不溶性盐，滤液中加入酸性水溶液，所述酸性水溶液包括盐酸溶液、硫酸溶液、磷酸溶液、硝酸溶液。加入较低极性的有机溶剂萃取，除去过量的双烃基化试剂，所述较低极性的有机溶剂包括酯类溶剂(包括乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯)、醚类溶剂(包括乙醚、异丙醚、甲基叔丁基醚)、烃类溶剂(包括苯、甲苯、戊烷、己烷、庚烷、辛烷、环己烷、环戊烷、石油醚)，或其中的两种及以上的混合溶剂。将酸性溶液中和至碱性，用有机溶剂提取得到单取代中间体，所述有机溶剂包括卤代烃(二氯甲烷、氯仿、二氯乙烷、氯苯)、酯类溶剂(包括乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯)、醚类溶剂(包括乙醚、异丙醚、甲基叔丁基醚)、烃类溶剂(包括苯、甲苯、二甲苯)或其中的两种及以上的混合溶剂。
步骤2：制备目标物
将与步骤1中不同的单一卡因类底物(包括利多卡因、甲哌卡因、罗哌卡因、布比卡因、左布比卡因以及1-乙基-2-(2,6-二甲胺甲酰基)哌啶)溶于干燥的有机溶剂中，在保持干燥的条件下，如外接填充干燥剂的管干燥或充入惰性气体(包括氮气、氩气等)，于低温下(优选0℃以下，根据设备情况可选择0℃～-40℃)，加入碱(优选含金属化物，包括氢化钠、氢化钾、氢化钙、氢化锂、碳酸钠、碳酸钾、碳酸铯、甲醇钠、乙醇钠、叔丁醇钠、甲醇钾、乙醇钾、叔丁醇钾、甲醇镁、乙醇镁、叔丁醇镁、正丁基锂、叔丁基锂、苯基锂、氨基钠、甲基氯化镁、甲基溴化镁、甲基碘化镁、乙基氯化镁、乙基溴化镁、乙基碘化镁、异丙基氯化镁、异丙基溴化镁、异丙基碘化镁、二甲基镁、二乙基镁、二异丙基镁、LDA、NaHMDS、KHMDS、LiHMDS)，于低温下保温反应一段时间。将步骤1中得到的单取代中间体的非水溶液缓慢加入上述反应体系，其中单一卡因类底物与单取代中间体的摩尔比优选地在0.5:1～2:1范围内，更优选地在0.7:1～1.5:1范围内，最优选地在0.8:1～1.2:1范围内。加毕，移除冷浴后升温继续反应，可升至不超过50℃反应，优选不超过40℃反应，从方便的角度，通常选择自然升至环境温度反应。反应液经后处理和纯化方法得到目标物，所述纯化方法包括硅胶层析、氧化铝层析、制备液相分离或者结晶，或其中的两种及以上的方法联合施用。
根据本公开的另一个方面，提供具有式H结构的化合物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物，其中所述化合物通过如下路线4进行制备：
如路线4所示，所述方法包括：式C化合物与式B(3)化合物在缚酸剂存在条件下发生反应，得到式H化合物。在路线4所涉及的化合物中，
R1分别独立地为R1a或R1c；
R1a为C1-C10烃基，其选自C1-10烷基、C3-10环烷基、C3-6环烷基-C1-4烷基-、C2-10烯基、C2-10炔基和C6-10芳基，并且其任选地被选自Rx2的取代基取代；
R1c为其中n为2-8的整数，m为1-6的整数，o为2或3，p为1或2，q为1-3的整数，以及RN1和RN2相互独立地为H或C1-C8烷基；
R3为其中RA和RB各自独立地为氢或甲基；
Rx2为及
X为容易离去的基团。
根据本申请的一个实施方案，X包括但不限于氯、溴、碘、磺酸基。在一个实施方案中，所述磺酸基包括例如甲磺酸基、苯磺酸基、对甲苯磺酸基、三氟甲磺酸基等。
在一个实施方案中，所述缚酸剂为无机碱或有机碱，其中无机碱包括但不限于氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、氢氧化钙、氢氧化镁、氢化钠、氢化钾、氢化钙、氢化锂、碳酸氢锂、碳酸氢钠、碳酸氢钾、碳酸氢钙、碳酸锂、碳酸钠、碳酸钾、碳酸铯、碳酸镁、碳酸钙、磷酸钠、磷酸钾、磷酸氢二钠、磷酸氢二钾、磷酸氢钾钠，其中有机碱包括但不限于乙酸钠、丙酸钠、丁酸钠、甲醇钠、乙醇钠、叔丁醇钠、甲醇钾、乙醇钾、叔丁醇钾、甲醇镁、乙醇镁、叔丁醇镁、三甲胺、三乙胺、三丁胺、二异丙胺、二异丙基乙胺、叔丁胺、N,N-二甲基苯胺、四甲基乙二胺、DABCO、DBU、DBN、吡啶、DMAP、N-甲基吗啉、四甲基胍、正丁基锂、叔丁基锂、苯基锂、氨基钠、甲基氯化镁、甲基溴化镁、甲基碘化镁、乙基氯化镁、乙基溴化镁、乙基碘化镁、异丙基氯化镁、异丙基溴化镁、异丙基碘化镁、二甲基镁、二乙基镁、二异丙基镁等、LDA、NaHMDS、KHMDS、LiHMDS等。
药物组合物及其应用
本公开的另一个方面提供一种药物组合物，其包含根据本公开的化合物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物，以及药学可接受的载体或赋形剂。
术语“药学可接受的载体”是指与活性成分混合以形成药物组合物(即，能够使个体施用的剂型)的无毒溶剂、分散剂、赋形剂、佐剂或其它材料。在一个实施方案中，所述药学可接受的载体或赋形剂是生理盐水
在一些实施方案中，本公开的化合物或组合物是肠胃外施用的。例如，所述肠胃外途径可选自吸入、腹膜内、肌内、皮下、蛛网膜下腔、硬脊膜外腔、黏膜及深部组织或经眼、经皮或表面及其组合。例如，本公开的化合物在诸如生理盐水的载体中的溶液可以经腹膜内、肌内、皮下、蛛网膜下腔、硬脊膜外腔注射或者输注给药，或者滴注于眼内。
本领域技术人员将知道如何根据具体的局部麻醉要求制备合适的制剂。对于肠胃外施用，通常制备本发明化合物的无菌溶液，并适当调节该溶液的pH并进行缓冲。对于静脉内使用，应控制溶质的总浓度，使制剂具有等渗性。对于眼部施用，可滴液体可以例如通过本领域已知的眼部施用系统(例如施用器或滴管)进行施用。对于肺内施用，稀释剂或载体将被选择为适合形成气溶胶。
在一些实施方案中，本文所述的化合物和/或组合物被配制为用于通过注射进行肠胃外施用，包括使用传统的导管插入术或输注。例如，注射用制剂以例如盛装在安瓿或多剂量容器中的单位剂型存在，其中添加防腐剂。在一些实施方案中，所述组合物或组合采用在油性或水性载体中的无菌混悬液、溶液或乳液等形式，并含有配制剂，例如悬浮剂、稳定剂和/或分散剂。在所有情况下，该剂型必须是无菌的，并且必须是流动的，以便于注射。或者，本公开的化合物适当地为无菌粉末形式，用于在使用前用合适的载体(例如，无菌无热原水)进行重构。
在一些实施方案中，用于吸入(任选地鼻腔施用)的组合物或组合被方便地配制为气雾剂。对于鼻内施用或通过吸入施用，本文所述的化合物可以方便地以溶液、干粉或颗粒制剂或悬浮液的形式从由患者挤压或泵送的泵式喷雾容器中递送，或者以气溶胶喷雾的形式从加压容器或雾化器中递送。气雾剂制剂通常包含活性物质在生理上可接受的水性或非水性溶剂中的溶液或精细悬浮液，并且通常以无菌形式以单剂量或多剂量存在于密封容器中，该密封容器为例如采用与雾化装置一起使用的药筒或填充物的形式。或者，该密封容器是单一的分配装置，例如单剂量鼻用吸入器或装有计量阀的气雾剂分配器，该计量阀用于在使用后进行处理。在剂型包括气雾剂分配器的情况下，它可包含推进剂，该推进剂例如是压缩气体(如压缩空气)或有机推进剂(如氟氯烃)。合适的推进剂包括但不限于二氟二氯甲烷、三氯一氟甲烷、二氯四氟乙烷、七氟烷烃(heptafluoroalkane)、二氧化碳或其它合适的气体。在加压气雾剂的情况下，通过提供输送计量数的阀门来适当地确定剂量单位。
在一个实施方案中，根据本公开的化合物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物以及根据本公开的药物组合物是用于局部麻醉。
本公开的再一个方面提供一种用于局部麻醉的方法，其包括对有此需要的个体施予有效剂量的根据本公开的化合物或其立体异构体或其加成盐或溶剂合物或其多晶型物或者根据本公开的药物组合物的步骤。
在本公开中，所述局部麻醉包括表面麻醉、浸润麻醉、阻滞麻醉、蛛网膜下腔阻滞麻醉和硬脊膜外腔阻滞麻醉等。
根据给药部位和临床需求，根据本申请的化合物可以使用不同的剂量范围进行给药。例如，对有局部麻醉或镇痛需求的受试者实施包括表面麻醉、浸润麻醉、阻滞麻醉、蛛网膜下腔阻滞麻醉和硬脊膜外腔阻滞麻醉时，所述化合物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物可分别按照0.1％～0.5％、0.5％～1％、1％～2％、2％～4％、4％～6％、6％～8％、8％～10％的药物浓度范围以1～50mg、50～100mg、100～200mg、200～400mg、400～800mg的药物剂量范围进行单次或重复给药，以获得良好的局部麻醉/镇痛效果。
根据一个实施方案，所述化合物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物或者药物组合物是用于表面麻醉，其中所述化合物或药物组合物为溶液剂型，直接点滴、涂抹、喷射于黏膜表面，使黏膜下的感觉神经末梢麻痹，用于口腔、鼻、咽、喉、眼及尿道黏膜等部位手术。
根据一个实施方案，所述化合物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物或者药物组合物是用于浸润麻醉，其中所述化合物或药物组合物为溶液剂型，并将所述溶液注射于皮内、皮下组织或手术野深部，以阻断用药部位的神经传导。
根据一个实施方案，所述化合物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物或者药物组合物是用于阻滞麻醉，其中所述化合物或药物组合物为溶液剂型，并将所述溶液注射于外周神经干附近，以阻断神经传导，使该神经所支配的区域产生麻醉作用，常用于躯体、四肢、面部、口腔等部位手术。
根据一个实施方案，所述化合物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物或者药物组合物是用于蛛网膜下腔阻滞麻醉，其中所述化合物或药物组合物为溶液剂型，并将所述溶液自低位腰椎间注入蛛网膜下腔内，麻醉该部的脊神经根，常用于下腹部和下肢手术。
根据一个实施方案，所述化合物或其立体异构体或其药学可接受的盐或溶剂合物或其多晶型物或者药物组合物是用于硬脊膜外腔阻滞麻醉，其中所述化合物或药物组合物为溶液剂型，并将所述溶液注入硬脊膜外腔，使其沿脊神经根扩散而进入椎间孔，阻滞椎间孔内的神经干，达到躯干某一节段的麻醉，从颈部至下肢的手术都可采用，特别适用于腹部手术。
实施例
为了使本发明的目的和技术方案更加清楚，下面对本发明的优选实施例进行详细的描述。要说明的是：以下实施例只用于对本发明进行进一步的说明，而不能理解为对本发明保护范围的限制。本领域的技术人员根据本发明的上述内容做出的一些非本质的改进和调整均属于本发明的保护范围。
实施例1:化合物1的制备
将0.5g利多卡因溶解在20ml无水四氢呋喃中，无水氯化钙保护，冰水浴冷却下，加入0.11g氢化钠(60％)。室温搅拌30min后，滴加含有0.52g氯甲酸丙酯的无水四氢呋喃溶液约10ml。室温反应2h，反应液直接用硅藻土和无水硫酸钠垫滤，浓缩滤液，得到的油状物直接通过制备液相纯化，得到无色油状物250mg，纯度99％，ESI-MS m/z[M+H]+＝321.0。
参照实施例1方法，制备得到以下化合物：


参照实施例1方法，制备得到以下化合物：


参照实施例1方法，以依替卡因为原料制备得到以下化合物：
实施例2:化合物53的制备
实施例2-1：化合物中间体1的制备
将1.0g丙胺卡因溶解在30ml二氯甲烷中，加入0.67gDMAP，冰水浴冷却下，滴加氯甲酸苄酯0.93g。滴加完毕后，室温搅拌2h。TLC监控反应完全。反应液依次用0.1M稀酸水(30ml*1)、水(30ml*2)、饱和碳酸氢钠(30ml*1)和饱和食盐水(30ml*1)洗涤。无水硫酸钠干燥，过滤、浓缩得到的粗品用硅胶柱纯化，得到无色油状物1.48g，纯度98.6％。
实施例2-2：化合物中间体2的制备：
参考实施例1经过制备柱纯化得到无色粘稠油状物0.57g，纯度99.1％。
实施例2-3：标题化合物的制备：
将中间体2溶解在20ml四氢呋喃中，加入60mg10％钯碳，氢气置换5次，室温加氢还原过夜。硅藻土滤除钯碳，浓缩滤液，经制备液柱纯化得到粘稠蜡状标题化合物0.37g，纯度98.6％，Mass(ESI+)[M+H]+＝307.0。
参照实施例2方法，制备得到以下化合物：

参照实施例2方法，以阿替卡因原料制备得到以下化合物：
实施例3:化合物159的制备
称取利多卡因(468mg)溶于无水四氢呋喃(10ml)，干燥管干燥，-20℃冰浴5min，加入钠氢(110mg)，保温搅拌0.5h，取正戊酰氯(480μl)溶于无水四氢呋喃(15ml)，缓慢滴入体系，1h后转室温搅拌过夜。反应液经硅藻土+无水硫酸钠过滤，浓缩滤液后经制备液相纯化，得417mg标题化合物，纯度98.9％，Mass(ESI+)[M+H]+＝319.1。
参照实施例3方法，以制备得到以下化合物：
实施例4：化合物172的制备
称取利多卡因(495mg)溶于无水四氢呋喃(15ml)，干燥管干燥，-10℃5min，加入钠氢(117mg)，保温搅拌1h，然后将1,4-二溴丁烷(130μl)溶于无水四氢呋喃(10ml)，缓慢滴入上述反应体系，室温搅拌过夜，反应液经硅藻土+无水硫酸钠过滤，浓缩滤液后经制备液相纯化，得标题化合物402mg，纯度99.1％。
Mass(ESI+)[M+H]+＝523.4。
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)。
13C-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.
参照实施例4方法，分别以利多卡因和依替卡因为原料制备得到以下化合物：

分别以丙胺卡因和阿替卡因为原料，先参照实施例2-1制备N-Cbz保护中间体，再参照实施例4制备烃基化物，最后参照实施例2-3脱除Cbz保护，制备得到以下化合物：
实施例5：化合物B53的制备
称取罗哌卡因(280mg)溶于无水四氢呋喃(20ml)，干燥管干燥，置于-10℃5min，加入钠氢(60mg)，保温搅拌0.5h后加入氯甲酸丙酯(220μl)，然后转室温反应过夜。反应液经硅藻土+无水硫酸钠过滤，旋干滤液后硅胶拌样，由约3cm高的硅胶垫中通过，用PE:乙酸乙酯＝15:1的洗脱液冲洗，TLC监控，收集浓缩得粗品，经制备液相分离纯化得到176mg标题化合物，纯度99.5％，ESI-MS m/z[M+H]+＝361.2。
参照实施例5方法，以相应的氯甲酸酯为酰化剂，分别以甲哌卡因为原料制备得到化合物B1-B10；以1-乙基-2-(2,6-二甲胺甲酰基)哌啶为原料制备得到化合物B43-B52；以罗哌卡因为原料制备得到化合物B54-B66；以布比卡因为原料制备得到化合物B79-B104：





参照实施例5方法，以(2S)-布比卡因原料制备得到以下化合物B105-B130：



参照实施例5方法，以(2R)-布比卡因原料制备得到以下化合物B131-B136：
实施例6:化合物B160的制备
将甲哌卡因(446mg)溶于无水四氢呋喃(10ml)，干燥管干燥，在-20℃冰浴中放置5min，加入钠氢(106mg)，保温搅拌0.5h，将正戊酰氯(470μl)溶于无水四氢呋喃(15ml)，缓慢滴入体系， 1h后转室温搅拌过夜。反应液经硅藻土+无水硫酸钠过滤，浓缩滤液后经制备液相纯化，得398mg油状标题化合物，纯度98.8％，ESI-MS m/z[M+H]+＝331.2。
参照实施例6方法，以相应酰氯为酰化剂，分别以甲哌卡因、1-乙基-2-(2,6-二甲胺甲酰基)哌啶、消旋罗哌卡因、罗哌卡因、布比卡因和左布比卡因为原料制备得到如下化合物：






实施例7:化合物169的制备
将利多卡因(500mg)溶于无水四氢呋喃(20ml)，外接无水氯化钙干燥管，于-10℃下搅拌10min，加入氢化钠(112mg)，保温搅拌0.5h，再将溴戊烷(530μl)加入体系，室温搅拌，HPLC监控至基本反应完全。反应液用硅藻土+无水硫酸钠过滤，旋干后粗品溶于盐酸溶液(0.1M)，然后用异丙醚萃洗2次，水相用饱和碳酸氢钠溶液调节pH至弱碱性，然后用乙酸乙酯萃取3次，无水硫酸钠干燥1h，过滤、浓缩得无色油(649mg，HPLC纯度99％)。
参照实施例7方法，分别以利多卡因和依替卡因为原料制备得到以下化合物：

以阿替卡因为原料，先参照实施例2-1制备N-Cbz保护中间体，再参照实施例7制备烃基化物，最后参照实施例2-3脱除Cbz保护，制备得到以下化合物：
参照实施例7方法，采用相应的烃化试剂，分别以甲哌卡因、1-乙基-2-(2,6-二甲胺甲酰基)哌啶、消旋罗哌卡因、罗哌卡因、布比卡因和左布比卡因为原料制备得到如下化合物：


实施例8:化合物B262的制备
将甲哌卡因(500mg)溶于无水四氢呋喃(15ml)，干燥管干燥，在-10℃下保持5min，加入钠氢(110mg)，保温搅拌1h，然后取1,4-二溴丁烷(150μl)溶于无水四氢呋喃(10ml)，缓慢滴入体系，室温搅拌过夜，反应液经硅藻土+无水硫酸钠过滤，浓缩滤液后经制备液相纯化，得392mg标题化合物，纯度99.3％，ESI-MS m/z[M+H]+＝547.3。
实施例9:化合物B250盐酸盐的制备
在25ml三口瓶中投布比卡因500mg，通N2，加入燥四氢呋喃10ml，降温至-10℃，加NaH(60％)96mg，于-10℃反应1.5hr，低温滴加1，4-二溴丁烷175mg的四氢呋喃溶液2ml，滴完之 后室温(23.8℃)搅拌2天，经硅藻土过滤，滤液浓缩，得粗品596mg。将粗品采用碱性氧化铝层析柱分离，碱性氧化铝量60g，洗脱剂为石油醚:乙酸乙酯＝2:1→1:2(v/v)，收集所需组份，浓缩得游离碱391mg，纯度93.74％。将所得游离碱再一次用碱性氧化铝层析柱分离，其中碱性氧化铝量40g，洗脱剂为石油醚:乙酸乙酯＝2:1→1:2(v/v)，收集所需组份，浓缩得游离碱326mg，纯度97.1％。加入甲醇10ml溶解所得游离碱，过滤，滤液室温滴加2.16％异丙醚盐酸液，pH2-3,浓缩，残余物中加入甲醇2ml溶清，室温下慢慢滴加甲基叔丁基醚6ml，搅拌1.0hr，过滤，烘干滤饼得到白色标题化合物125mg，纯度100％。滤液浓缩，残余物中加甲醇2ml，室温下滴加甲基叔丁基醚40ml，室温搅拌过夜，过滤，烘干滤饼得到另外一批白色标题化合物210mg，纯度100％。ESI-MS m/z[M-2Cl-H]+＝631.49。
参照实施例8和实施例9方法，采用相应的烃化试剂，分别以甲哌卡因、1-乙基-2-(2,6-二甲胺甲酰基)哌啶、消旋罗哌卡因、罗哌卡因、布比卡因和左布比卡因为原料制备得到如下化合物及其相应的盐酸盐：



实施例10:化合物D1二盐酸盐的制备
将左布比卡因300mg溶解在10ml无水DMF中，冷却至-5℃，加入氢化钠120mg，无水氯化钙保护，-5℃搅拌0.5h，加入二甲氨基溴乙烷盐酸盐360mg，室温反应过夜。加入30ml异丙醚，析出大量白色固体，室温搅拌10min，过滤。先减压蒸除滤液中的异丙醚，再用高真空减压蒸除DMF。得到粗品油状物，向其中加入40ml异丙醚，室温搅拌过夜。滤除固体，浓缩滤液，得到的淡黄色油状物，向其中加入8ml四氢呋喃溶解，用HCl/异丙醚溶液调pH≈3，浓缩至干，加入32ml四氢呋喃，室温搅拌过夜。过滤，烘干滤饼，得到210mg白色固体，纯度98％，ESI-MS m/z[M-Cl--HCl]+＝360.3。
参照实施例10方法，采用相应的卤代烃基胺或N-Boc-卤代烃基胺，分别以利多卡因、甲哌卡因、罗哌卡因、布比卡因和左布比卡因为原料制备得到如下化合物的二盐酸盐：


实施例11:化合物B360的制备
步骤1：在25ml三口瓶中投左布比卡因250mg，通入N2，加入干燥四氢呋喃10ml，降温至-10℃，加NaH(60％)45mg，于-10℃反应1.5hr，低温滴加1，4-二溴丁烷2g的四氢呋喃溶液10ml，滴毕，室温反应过夜，经硅藻土过滤，滤液于冰浴下缓慢加入盐酸溶液，至溶液约pH 2，乙酸乙酯萃取三次，冰浴下向水层中加入饱和碳酸氢钠溶液，至无气体放出，乙酸乙酯萃取三次，合并有机层，无水硫酸钠干燥，过滤、浓缩，将所得中间体溶于干燥四氢呋喃备用。得粗品596mg。
步骤2：在25ml三口瓶中投甲哌卡因215mg，通N2，加入干燥四氢呋喃10ml，降温至-10℃，加45mg的NaH(60％)，于-10℃反应1.5hr，低温滴加步骤1中所的中间体四氢呋喃溶液，滴毕，升温至30-40℃反应72h，反应液经硅藻土+无水硫酸钠过滤，滤液浓缩后经制备液相纯化，得419mg标题化合物，纯度99.5％，ESI-MS m/z[M+H]+＝589.4。
参照实施例11方法，分别以利多卡因、布比卡因、左布比卡因、甲哌卡因、罗哌卡因和1-乙基-2-(2,6-二甲胺甲酰基)哌啶为原料，制备得到如下化合物：




实施例12：改进的化合物B250盐酸盐的制备(在实施例9的基础上优化)
取布比卡因750mg，溶于无水THF(15ml)，干燥管干燥，-15℃冰浴，加入钠氢157mg，保温搅拌2h，加入1,4-二溴丁烷283mg，转至室温(25℃左右)搅拌。反应约48h，HPLC监控产物含量约70％，继续反应至无明显进展后，于-15℃冰浴下补加钠氢36mg，室温反应2h，再补加钠氢42mg反应过夜。向体系中加入1,4-二溴丁烷60mg，室温搅拌20h，补加钠氢28mg，继续反应6h，再补加钠氢17mg、1,4-二溴丁烷100mg，室温搅拌23h。加入酸乙酯稀释反应液，然后过一2-3cm高硅藻土垫，用乙酸乙酯冲洗至总体积约120ml。减压浓缩，残余物用甲醇溶解，加入盐酸乙醇溶液(10M，3ml)，振摇均匀。减压浓缩，残余物中加入甲醇6ml，室温下缓慢滴入甲基叔丁基醚90ml，室温搅拌过夜。过滤，滤饼用甲醇6ml溶解，室温下缓慢滴入甲基叔丁基醚36ml，室温搅拌2h，过滤，滤饼烘干，得到230mg标题化合物白色固体，纯度99.9％。
将母液转移至单口瓶中，用甲醇2ml润洗，然后缓慢滴入甲基叔丁基醚40ml，室温搅拌2h，分次滴入甲基叔丁基醚80ml，室温搅拌过夜。过滤，将滤饼用甲醇5ml溶解，缓慢滴入甲基叔丁基醚30ml，室温继续搅拌1.5h，补加甲基叔丁基醚70ml，搅拌2h。过滤，滤饼烘干，得到485mg标题化合物类白色固体，纯度99.3％。
两批产品合计总收率78.13％。
测试例1:大鼠角膜法局麻作用测试
1、试验动物
SD大鼠，♂，约300g，购自重庆医科大学实验动物中心。这些大鼠常规饲养，自由摄食饮水，期间温度约25-28℃，湿度约65-85％。
2、受试物
2.1、对照品
·2％盐酸利多卡因注射液，5mL：0.1g，批号：161207，西南药业股份有限公司。
2.2、受试品
·化合物1溶液1(27.36mg/mL)：将36.8mg的化合物1(纯度99％)加入1.345mL的生理盐水(华鲁，SD21032001)中，并用盐酸/氢氧化钠调pH为5.80。
·化合物159盐酸盐溶液(26.3mg/mL，与2％利多卡因等摩尔浓度)：将13.3mg的化合物159盐酸盐加入0.505mL的生理盐水(华鲁，SD21032001)中，并漩涡溶解。
·化合物174溶液(40.8mg/mL，与2％利多卡因等摩尔浓度)：将48.2mg的化合物174加入1.18mL的生理盐水(华鲁，SD21032001)中，先用盐酸调至溶清，再用氢氧化钠调pH为5.14。
·化合物172溶液(38.6mg/mL，与2％利多卡因等摩尔浓度)：将52.2mg的化合物172加入1.35mL的生理盐水(华鲁，SD21032001)中，先用盐酸调至溶清，再用氢氧化钠调pH为5.17。
·化合物172溶液(19.3mg/mL，2％利多卡因一半摩尔浓度)：取上述38.6mg/mL的化合物172溶液，按1:1加入生理盐水稀释。
·化合物1盐酸盐溶液2(26.4mg/mL，与2％利多卡因等摩尔浓度)：将33.0mg的化合物1盐酸盐加入1.25mL的生理盐水(天圣，522021703)中溶解，并用氢氧化钠调pH为5.27。
·化合物169溶液(22.5mg/mL，与化合物1盐酸盐溶液2等摩尔浓度)：将30.2mg的化合物169加入1.34mL的生理盐水(天圣，522021703)中，用盐酸溶解，再用氢氧化钠调pH为5.19。
3、方法与结果
(1)预试验：将大鼠保定在水平侧躺位，再经移液器取溶液点眼，每30s一滴，共3滴，期间眼表保持药物润湿状态，末次点眼后30s，用滤纸吸去眼表药液，用剪取的大鼠胡须刺激角膜，观察角膜反射情况，结果见下表1。
表1
以上表1中的结果显示给药后化合物1能有效抑制角膜反射。
进一步采用与上述相同方法对本发明化合物2、化合物3、化合物4、化合物5、化合物13、化合物14、化合物21、化合物24、化合物25、化合物176、化合物D1、化合物B285、B328和化合物B360进行测试，给药后均可有效抑制其角膜反射。这些试验结果显示，本发明化合物具有局部麻醉作用。
(2)化合物159盐酸盐、化合物172和化合物174与生理盐水和利多卡因的对比测试:
将大鼠保定在水平侧躺位，再经移液器取溶液点眼，每30s一滴，共3滴，期间眼表保持药物润湿状态，末次点眼后30s，用滤纸吸去眼表药液，在不同时间点用剪取的大鼠胡须刺激角膜，观察角膜反射情况，其结果总结于下表2中。
表2

上述表2中的试验结果显示，根据本发明的化合物的局部麻醉持续时间长于利多卡因。
(3)化合物1盐酸盐和化合物169的对比测试:
将大鼠保定在水平侧躺位，再经移液器取溶液点眼，每30s一滴，共3滴，期间眼表保持药物润湿状态，末次点眼后30s，用滤纸吸去眼表药液，在不同时间点用剪取的大鼠胡须刺激角膜，观察角膜反射情况，其结果总结于下表3中。
表3
测试例2:豚鼠局麻作用测试
选取体重300-500g豚鼠，于试验前一日，剃净豚鼠背部正在线及两侧的毛。在豚鼠背部正中线前、中、后3处皮肤，以小号针头，注射药液。先刺穿皮肤，再将针尖退后至皮肤中层，再斜插入皮内。注射药液0.1-0.20mL。这样可使拔针后药液不至漏出，形成丘疹，用墨水圈记其大小。注药后，在不同时间点，用针刺，测试丘疹部皮肤的感觉，用丘疹外正常皮肤作对照，正常皮肤用针刺后会出现皮肤肌肉收缩现象。每个时间点用针刺测试6次，两次间隔3-5s，记录针刺后无反应(未出现皮肤肌肉收缩)的总次数。如果用针刺激6次，未出现皮肤肌肉收缩次数≥3次，即代表药物皮下浸润有效。豚鼠背部注射化合物1盐酸盐溶液和盐酸利多卡因溶液后不同时间点的疼痛抑制率(％)的结果分别见下表4和5。
表4：豚鼠背部注射化合物1盐酸盐溶液后不同时间点的疼痛抑制率(％)

表5：豚鼠背部注射盐酸利多卡因溶液后不同时间点的疼痛抑制率(％)
从上述试验结果可知，本发明化合物1盐酸盐溶液(50mM)的局部麻醉效果可持续至少2小时，而盐酸利多卡因溶液(70mM)的局部麻醉效果只能持续不足30min。
测试例3：大鼠皮下局麻作用测试
1、试验动物
SD大鼠，3只，♂，SPF级，约300g，重庆医科大学实验动物中心。这些大鼠常规饲养，自由摄食饮水，温度约25℃，湿度约70％。
2、受试物
·盐酸利多卡因，5mg/mL(0.5％)：将1mL的盐酸利多卡因注射液(西南药业，161207，5mL:0.1g)加入3mL的生理盐水(天圣，522021703)中，稀释成5mg/mL。
·化合物172溶液(9.67mg/mL，与0.5％盐酸利多卡因等摩尔浓度)：将29.2mg的化合物172加入3.02mL的生理盐水(天圣，522021703)分散，用少量盐酸/氢氧化钠调pH 5.27溶解。
3、方法与结果
将大鼠保定，在同一动物背部两侧对应区域的皮内分别浸润给予两种受试药物，皮下注射0.6mL，形成皮丘，记号笔标记。各给药处(皮丘或隆起)在每个时间点，针刺中间和四周共计5个点，针刺时距3-5s，记录针刺后无反应(未出现皮肤肌肉收缩和嘶叫)的情况。
观察到的结果显示，0.5％盐酸利多卡因与等摩尔浓度的化合物172溶液在给药后2min即均已起 效；前者给药后局麻作用维持在约1.5-2小时，而后者则在给药后局麻作用时间长达142小时。
测试例4:大鼠皮下局麻作用测试
1、试验动物
SD大鼠，2只，♂，SPF级，约300g，重庆医科大学实验动物中心。这些大鼠常规饲养，自由摄食饮水，温度约25℃，湿度约70％。
2、受试物
·化合物172溶液(约9mM)：将9.6mg的化合物172加入1.985mL的生理盐水(天圣，522021703)中，用少量盐酸/氢氧化钠调pH 5.16溶解。
·化合物199溶液(约9mM)：将31mg的化合物199加入5.37mL的生理盐水(天圣，522021703)中，用少量盐酸/氢氧化钠调pH 5.07溶解。
3、方法与结果
将大鼠保定，在同一动物背部两侧对应区域的皮内分别浸润给予两种受试药物，皮下注射0.3mL，形成皮丘，记号笔标记。各给药处(皮丘或隆起)在每个时间点，针刺中间和四周共计5个点，针刺时距3-5s，记录针刺后无反应(未出现皮肤肌肉收缩和嘶叫)的情况。
观察到的结果显示，等摩尔浓度的化合物172溶液和化合物199溶液均在给药后2min即已起效；二者在给药后24小时仍有局麻作用。
在参照上述测试进行的试验中，皮下注射给药，给药浓度均为10mM，注射体积为0.6ml，对大鼠背部注射化合物B290、B360和B362与左布比卡因进行对比。观察到的结果显示，左布比卡因产生的局麻持续时间为2-4h，而化合物B290局麻持续时间为48-72h，化合物B360局麻时间>96h，化合物B362局麻持续时间为72-96h。这表明根据本发明的化合物的局麻作用时间远远超过左布比卡因。
测试例5:急性毒性测试
1、试验动物
KM小鼠，购自重庆医科大学实验动物中心。整个试验期间自由摄食饮水，环境温度约23-26℃、湿度70-90％。
2、对照品和供试品
·盐酸利多卡因溶液：将0.1mL的2％盐酸利多卡因注射液(2％盐酸利多卡因注射液，5mL：0.1g，批号：161207，西南药业股份有限公司)加入0.9mL的生理盐水中稀释成2mg/mL。
·化合物1溶液：1)将7.2mg的化合物1并分散于4.05mL的生理盐水(华鲁，SD21032001)中，用盐酸/氢氧化钠调pH为5.42，配制成1.78mg/mL溶液；2)将8.6mg的化合物1分散于1.985mL的生理盐水(华鲁，SD21032001)中，用盐酸/氢氧化钠调pH为5.32，配制成4.33mg/mL溶液。
·化合物169溶液：i)将35.7mg的化合物169并分散于1.485mL的生理盐水(天圣，522021703)中，先加盐酸溶解，再加氢氧化钠调pH为5.14，ii)将500μL的i)中所配溶液加入到4.3ml的生理盐水中稀释得2.5mg/ml溶液。
3、方法与结果
采用序贯法，小鼠尾静脉匀速注射给药上述化合物1溶液和化合物169溶液，时间约2-3s，观察并估算LD50值，结果如下以下表6所示。
表6
以上表6中的急性毒性试验结果显示，根据本发明的化合物的安全性优于盐酸利多卡因。
测试例6:大鼠皮内局麻作用测试
1、试验动物
SD大鼠，5只，♂，SPF级，约300g，重庆医科大学实验动物中心。这些大鼠常规饲养，自由摄食饮水，温度约25℃，湿度约70％。
2、受试物
2.1、对照品
·盐酸左布比卡因，0.25％(盐酸左布比卡因)溶液：将6.1mg的左布比卡因(20070801，游离碱)加入2.74mL的生理盐水(天圣，522021703)中，加盐酸溶清，再用氢氧化钠调pH 5.31，然后0.22μm过滤。
2.2、受试品
·化合物B105盐酸盐，0.315％溶液，与左布比等摩尔浓度：将8.6mg的化合物B105盐酸盐加入2.73mL的生理盐水(天圣，522021703)中溶解，pH为5.06，氢氧化钠调pH为5.15，然后0.22μm过滤。
3、方法与结果
将大鼠保定，皮内浸润麻醉给药，如下图所示给药，①、③为给药盐酸左布比卡因，②、④为给药化合物B105盐酸盐，皮内注射0.1mL，形成皮丘，记号笔标记。
各给药处(皮丘或隆起)在每个时间点，针刺中间和四周共计5个点(针刺位置如图所示)，针刺时距3-5s，记录针刺后无反应(未出现皮肤肌肉收缩和嘶叫)的点的情况。
结果显示，0.25％盐酸左布比卡因和等摩尔浓度化合物B105盐酸盐在给药后2min即已起效；盐酸左布比卡因溶液的维持时间在约4.5小时，化合物B105盐酸盐溶液(等摩尔浓度)的维持时间不低于6.5小时。本发明化合物的局麻时间更长。
测试例7大鼠皮下局麻作用测试
1、试验动物
SD大鼠，2只，♂，SPF级，约300g，重庆医科大学实验动物中心。
常规饲养，自由摄食饮水，温度约25℃，湿度约70％。
2、受试物
·化合物172溶液(4.6mM)：将9.6mg的化合物172加入1.985mL的生理盐水(天圣，522021703)中，用少量盐酸/氢氧化钠调pH 5.16溶解，取1mL该溶液并加入1mL生理盐水(天圣，522021703)，稀释成2.42mg/mL。
·化合物B246溶液(4.6mM)：将5.2mg的化合物B246二盐酸盐加入1.6mL的生理盐水(天圣，522021703)中溶解，并用少量氢氧化钠调pH为5.41。
3、方法与结果
将大鼠保定，皮内浸润麻醉给药，皮下注射0.3mL，形成皮丘，记号笔标记。各给药处(皮丘或隆起)在每个时间点，针刺中间和四周共计5个点，针刺时距3-5s，记录针刺后无反应(未出现皮肤肌肉收缩和嘶叫)的情况。
结果显示，浓度为4.6mM的化合物172溶液和等摩尔浓度的化合物B246溶液均在给药后2min即已起效；前者在给药后局麻作用持续约3h，而后者的局麻作用则持续19小时以上。
在参照上述测试进行的试验中，皮下注射给药，注射体积为0.3-0.6ml，对大鼠背部注射化合物B246、化合物B242、化合物B250、化合物B262和布比卡因对疼痛抑制的50％持续时间汇总于下表表7中。
表7
测试例8:急性毒性测试
1、试验动物
KM小鼠，购自重庆医科大学实验动物中心。整个试验期间自由摄食饮水，环境温度约23-26℃、湿度70-90％。
2、对照品和供试品
·左布比卡因盐酸盐溶液，用生理盐水配制成1mg/mL的溶液。
·化合物B105盐酸盐溶液，用生理盐水配制成6mg/mL的溶液。
3、方法与结果
采用序贯法，小鼠尾静脉匀速注射给药，时间约2-3s，观察并估算LD50值，结果如下表8所示。
表8
表8中的急性毒性试验结果显示，本发明化合物安全性优于左布比卡因。
参照上述方法，对化合物B246、B250、B242、罗哌卡因、B262以及甲哌卡因进行测试，将所得数据及相关文献值的对比列于下表9中。
表9
文献1：US Patent 3632766
由以上对比可以看出，本发明所提供的化合物安全性优于其各自对应的现有局麻药物。
测试例9：豚鼠局麻作用测试
选取体重800-1000g豚鼠，于试验前一日，剃净豚鼠背部正在线及两侧的毛。在豚鼠背部正中线前、中、后3处皮肤，以小号针头，注射药液。先刺穿皮肤，再将针尖退后至皮肤中层，再斜插入皮内。注射药液0.20mL。这样可使拔针后药液不至漏出，形成皮丘，用墨水圈记其大小。注药后，在不同时间点，用针刺，测试皮丘部皮肤的感觉，用皮丘外正常皮肤作对照，正常皮肤用针刺后会出现皮肤肌肉收缩现象。每个时间点用针刺测试6次，两次间隔3-5s，记录针刺后无反应(未出现皮肤肌肉收缩)的总次数。如果用针刺激6次，未出现皮肤肌肉收缩次数≥3次，即代表药物皮下浸润有效。豚鼠背部注射布比卡因和化合物B105后不同时间点的疼痛抑制情况总结于下表10中。
表10

从上述表10中的试验结果可知，本发明化合物B105溶液(7mM、14mM)的局部麻醉持续时间均显著长于布比卡因相应等摩尔浓度溶液。
参照上述测试，对豚鼠背部注射浓度均为10mM的化合物B246、化合物B250和化合物199。在注射后不同时间点的疼痛抑制情况总结于下表11中。
表11
参照上述测试，将皮内注射改为皮下注射给药，注射体积为0.6ml/点，对豚鼠背部注射化合物B246、化合物B242、化合物B250和布比卡因后，观察到的疼痛抑制情况总结于下表12中。
表12
从上述表12中的试验结果可知，本发明化合物局部麻醉持续时间显著长于布比卡因。
在参照上述测试进行的另一次试验中，皮下注射给药(10mM)，注射体积为0.6ml/点，对豚鼠背部注射化合物B246、化合物B242、化合物B250、化合物B262和布比卡因对疼痛抑制的50％有效时间如下表13所示。
表13
从上述表13中的试验结果可知，本发明化合物局部麻醉持续时间显著长于布比卡因。
测试例10:布比卡因和化合物B246大鼠皮下给药对比
将布比卡因和化合物B246用生理盐水配制成等摩尔浓度(10mM)溶液，分别在两只SD大鼠皮下注射给药，每只大鼠共注射两个点，给药体积0.6mL/点，每点间隔5h，末次给药后20或25min取皮检测含量，所得结果如下表14所示。
表14：布比卡因&化合物B246：大鼠皮下给药对比
测试例11：大鼠局部给予化合物B246后的局部药物浓度观察
将化合物B246用生理盐水配制成10mM溶液，分别在7只SD大鼠皮下注射给药，每只大鼠共注射左右两侧各一个点，给药体积0.6mL/点，于给药后20min-120h内进行针刺(在形成的皮丘圆圈内上、下、左、右、中五个区域各刺一针)，并记录无反应(即局麻有效)次数，再取皮肤及皮下组织检测药物浓度，所得结果如下表15所示。
表15
测试例12：大鼠局部给予化合物B246后至局麻作用消失后的局部药物浓度观察
将化合物B246用生理盐水配制成10mM溶液，分别在SD大鼠皮下注射给药，每只大鼠共注射左右两侧各一个点，给药体积0.6mL/点。当给药部位对针刺的无反应性完全消失后(348-360小时)，在不同时间点取样检测给药局部药物浓度和血药浓度，结果如下表16所示。
表16
测试例13:大鼠坐骨神经阻滞初步试验
1、受试物
·2.88mg/mL(10mM)布比卡因生理盐水溶液：将布比卡因5.2mg加入1.8mL的生理盐水(裕源，L23010707)中，用盐酸/氢氧化钠调pH为5.80，溶解。
·3.04mg/mL(10mM)化合物169生理盐水溶液：将6.1mg的化合物169加入2mL生理盐水(裕源，L23010707)中，然后用盐酸/氢氧化钠调pH为5.24，溶解。
2、试验方法与结果
1)试验动物：SD大鼠，♂，SPF级，购自重庆医科大学实验动物中心。给药时温度27.1℃、湿度84％。
2)大鼠坐骨神经阻滞方法：在右侧股骨大转子和坐骨结节连线中点进针，针尖抵坐骨后，注射药物。
3)观察在50℃水浴的缩足反应：将大鼠后足分别置于50℃热水中，记录缩足时间(回缩潜伏期)，>7s认为感觉阻滞，为防烫伤设置中断时间为12s。
表17：大鼠坐骨神经阻滞-方法与结果(50℃水浴缩足时间)
表17中的试验数据表明，分别给药10mM浓度的布比卡因和化合物169各自0.2mL，均对大鼠有坐骨神经阻滞作用，给药后1h化合物169的阻滞作用强于布比卡因。
测试例14:小鼠热板舔足测试
1、试验材料
1.1、试验动物
KM小鼠，♀，SPF级，重庆医科大学实验动物中心。小鼠适应性饲养4d，期间自由摄食饮水；测试时温度27.6℃，湿度80％。
1.2、试验仪器
RB-200智能热板仪，序列号：TM026-1905-003-020-004，生产日期：2019年05月，成都泰盟软件有限公司。
1.3、对照品与受试品
1.3.1、阴性对照
·生理盐水(NS)。
1.3.2、受试品
·1mg/mL的化合物169生理盐水溶液：将5.1mg的化合物169加入5.1mL的生理盐水(裕源，L23010707)中，然后用盐酸/氢氧化钠调pH为5.58，溶解。
2、试验方法和结果
小鼠按10mg/kg(1mg/mL，0.1mL/10g)、5mg/kg(1mg/mL，0.5mL/10g)、0mg/kg(NS，0.1mL/10g)的剂量尾静脉注射化合物169的生理盐水溶液，给药后10min考察热板舔足时间(55.0℃，最长观察到60s)。平行测试，每次对照组和受试物高低剂量组各1只动物同时给药和测试。测试结果如下表18所示。
表18：小鼠热板试验(iv)-结果(55.0℃-舔足时间s)
表18中的试验数据显示，经尾经脉注射后，化合物169可以延长小鼠对55.0℃热板的舔足时间，且有剂量依赖性特征。
根据本发明的N-取代芳胺衍生物具有局部麻醉效力，与现有临床所使用的药物相比，其显示出有明显更长时效的局部麻醉作用，可减少给药次数，特别适合需要长时间局部麻醉的情况，具有长效、安全性和质量更可控的优点。

Claims (14)

  1. 具有式I、式II、式III、式IV、式V或式VI结构的化合物或其立体异构体或药学可接受的盐，
    其中：RA和RB各自独立地为氢或甲基；；
    R1分别独立地为H、R1a、R1c或Rx2；
    R1a为C1-C10烃基，其选自C1-10烷基、C3-10环烷基、C3-6环烷基-甲基-、C2-10烯基、C2-10炔基和C6-10芳基，并且其任选地被选自Rx2的取代基取代；
    R1c为其中n为2-8的整数，m为1-6的整数，o为2或3，p为1或2，q为1-3的整数，以及RN1和RN2相互独立地为H或C1-C8烷基；
    Rx2为
    R2各自独立为 以及
    R2’各自独立为H、
  2. 根据权利要求1所述的化合物或其立体异构体或药学可接受的盐，其中所述化合物选自：








































  3. 根据权利要求2所述的化合物或其立体异构体或其药学可接受的盐，其中所述化合物选自：



  4. 根据权利要求1-3之一所述的化合物或其立体异构体或其药学可接受的盐，其中所述药学可接受的盐是盐酸盐。
  5. 一种药物组合物，其包含根据权利要求1-4之一所述的化合物或其立体异构体或其药学可接受的盐，以及药学可接受的载体或赋形剂。
  6. 根据权利要求5所述的药物组合物，其中所述药学可接受的载体或赋形剂是生理盐水。
  7. 根据权利要求5或6所述的药物组合物，其是用于肠胃外途径给药的剂型。
  8. 根据权利要求7所述的药物组合物，其中所述肠胃外途径选自吸入、腹膜内、肌内、皮下、蛛网膜下腔、硬脊膜外腔、黏膜及深部组织或经眼、经皮或表面及其组合。
  9. 根据权利要求1-4之一所述的化合物或其立体异构体或其药学可接受的盐在制备用于局部麻醉的药物中的用途。
  10. 根据权利要求9所述的用途，其中所述局部麻醉包括表面麻醉、浸润麻醉、阻滞麻醉、蛛网膜下腔阻滞麻醉和硬脊膜外腔阻滞麻醉。
  11. 根据权利要求1-4之一所述化合物或其立体异构体或其药学可接受的盐或者根据权利要求5-8之一所述的药物组合物，其用于局部麻醉。
  12. 根据权利要求11所述用途的药物组合物，其中所述局部麻醉包括表面麻醉、浸润麻醉、阻滞麻醉、蛛网膜下腔阻滞麻醉和硬脊膜外腔阻滞麻醉。
  13. 一种用于局部麻醉的方法，其包括对有此需要的个体施予有效剂量的根据权利要求1-4之一所述的化合物或其立体异构体或其药学可接受的盐或者根据权利要求5-8之一所述的药物组合物的步骤。
  14. 根据权利要求13所述的方法，其中所述局部麻醉包括表面麻醉、浸润麻醉、阻滞麻醉、蛛网膜下腔阻滞麻醉和硬脊膜外腔阻滞麻醉。
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