WO2022037590A1 - 一种用于麻醉的季铵盐类化合物及其制备方法和用途 - Google Patents

一种用于麻醉的季铵盐类化合物及其制备方法和用途 Download PDF

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WO2022037590A1
WO2022037590A1 PCT/CN2021/113091 CN2021113091W WO2022037590A1 WO 2022037590 A1 WO2022037590 A1 WO 2022037590A1 CN 2021113091 W CN2021113091 W CN 2021113091W WO 2022037590 A1 WO2022037590 A1 WO 2022037590A1
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alkyl
group
deuterium
alkoxy
halogen
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French (fr)
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柯博文
刘进
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四川大学华西医院
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a quaternary ammonium salt compound used for anesthesia and a preparation method and application thereof.
  • Local anesthetics are a class of drugs that can reversibly block the generation and transmission of sensory nerve impulses in the local area of medication, referred to as "local anesthetics".
  • the effects of local anesthetics are localized to the site of administration and disappear rapidly as the drug diffuses from the site of administration.
  • Local anesthetics produce local anesthesia by directly inhibiting the related ion channels on nerve cells and fiber membranes, blocking the generation of action potentials and the conduction of nerve impulses.
  • the currently recognized mechanism of action of local anesthetics is to block the voltage-gated Na + channels on the nerve cell membrane, thereby blocking the conduction of nerve impulses, thereby producing a local anesthetic effect.
  • the local anesthetics currently used clinically are all hydrophobic compounds with no charge, so it is easy to enter the nerve cells through the cell membrane by means of diffusion and penetration to reach the blocking site of the sodium channel. These anesthetics block sodium channels and thus block neuronal excitability.
  • these local anesthetic molecules are easy to diffuse into nerve cells to play their role, they are also easy to diffuse rapidly from the administration site by diffusion, dissociating nerve cells, so that the local anesthetic effect cannot be sustained for a long time. Even if the dose is increased, the local anesthesia time can only be prolonged to a certain extent, and these local anesthesia drugs cannot obtain the ideal long-term local anesthesia effect.
  • the duration of action of local anesthetics commonly used in clinical practice is usually less than 4 hours. Due to the short duration of action of traditional local anesthetics, analgesic pumps have to be used to maintain nerve block, and catheters in the spinal canal, nerve root, subcutaneous and other parts are used, which greatly increases the medical cost and the incidence of infection.
  • the purpose of the present invention is to provide a quaternary ammonium salt compound for anesthesia and its preparation method and use.
  • the present invention provides the compound represented by formula I, or its salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite:
  • Z - is a pharmaceutically acceptable anion
  • n is selected from an integer from 0 to 8;
  • R 1 is selected from hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, C 1-8 alkoxy, hydroxyl, amino, nitro, ester, cyano, carboxyl, mercapto or Wherein, the substituent of the alkyl group is selected from deuterium, halogen, hydroxyl, carboxyl, amino, nitro, cyano, mercapto or ester;
  • R 2 is selected from H, substituted or unsubstituted C 1-8 alkyl, C 1-8 alkoxy or Wherein, the substituent of the alkyl group is selected from deuterium, C 1-8 alkoxy, halogen, hydroxyl, carboxyl, amino, cyano, mercapto, ester or
  • R 4 is selected from n 1 R 11 substituted aryl groups
  • X is selected from O, S or NR 10 ;
  • R 10 is selected from H, deuterium, C 1-8 alkyl or C 1-8 alkoxy;
  • n 1 is an integer selected from 0 to 5;
  • R 11 is selected from deuterium, C 1-8 alkyl, C 1-8 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto or ester;
  • R 3 is selected from -NR 12 R 13 or -OR 14 ;
  • R 12 and R 13 are independently selected from hydrogen, deuterium, substituted or unsubstituted C 1-8 alkyl, C 1-8 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto, ester
  • the substituent of the alkyl group is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, ester, -OC(O)R 17 , -C(O)SR 15 ;
  • Y is selected from O, S or NR 16 ;
  • R 15 and R 16 are independently selected from hydrogen, deuterium, C 1-8 alkyl, C 1-8 alkoxy, halogen, substituted or unsubstituted 3- to 8-membered unsaturated heterocyclic group, substituted or unsubstituted 3- to 8-membered unsaturated cycloalkyl;
  • the substituent of the unsaturated heterocyclic group is selected from C 1-8 alkyl, C 1-8 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino , mercapto, ester;
  • the substituent of the unsaturated cycloalkyl is selected from C 1-8 alkyl, C 1-8 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, mercapto, ester, Amino group;
  • the heteroatom of the heterocyclic group is 1 to 3, and the heteroatom is N, O or S;
  • R 17 is selected from substituted or unsubstituted 3-8 membered unsaturated cycloalkyl; the substituent of the unsaturated cycloalkyl is selected from C 1-8 alkyl, C 1-8 alkoxy, halogen, nitro , cyano group, hydroxyl group, carboxyl group, mercapto group, ester group, amino group, -NR 18 R 19 ;
  • R 18 and R 19 are independently selected from hydrogen and C 1-8 alkyl
  • R 12 and R 13 are connected to form a substituted or unsubstituted 3-11-membered saturated heterocyclic group;
  • the substituent of the saturated heterocyclic group is selected from deuterium, C 1-8 alkyl, C 1-8 alkoxy , halogen, nitro, cyano, hydroxyl, carboxyl, mercapto, ester, amino,
  • the heteroatom of the heterocyclic group is 1-3, and the heteroatom is N, O or S;
  • R 14 is selected from -C(O)R 20 , substituted or unsubstituted 3- to 8-membered unsaturated cycloalkyl; the substituent of the unsaturated cycloalkyl is -C(O)(CH 2 ) m R 21 ;
  • R 20 is selected from substituted or unsubstituted 3- to 8-membered unsaturated cycloalkyl; the substituents of the unsaturated cycloalkyl are C 1-8 alkoxy, -NR 18 R 19 ;
  • n is selected from an integer from 0 to 8.
  • R 21 is selected from a 3- to 8-membered saturated heterocyclic group; the heteroatom of the heterocyclic group is 1 to 3, and the heteroatom is N, O or S;
  • L 1 is selected from substituted or unsubstituted C 1-16 alkylene; wherein, the alkylene main chain contains 0-4 heteroatoms, and the heteroatom is selected from O, S, NR 22 ; the The substituent of the alkylene group is selected from deuterium, C 1-8 alkyl, C 1-8 alkoxy, halogen;
  • L 11 is selected from substituted or unsubstituted C 1-7 alkylene, wherein the main chain of the alkylene contains 0-4 heteroatoms, and the heteroatom is selected from S, NR 22 ; the alkylene The substituent of the group is selected from deuterium, C 1-8 alkyl, C 1-8 alkoxy, halogen;
  • R 22 is selected from hydrogen, deuterium, C 1-4 alkyl, and C 1-4 alkoxy.
  • R 4 is selected from
  • n 1 is an integer selected from 0 to 5;
  • R 11 is selected from deuterium, C 1-8 alkyl, C 1-8 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto or ester.
  • R 3 is selected from the following groups substituted or unsubstituted:
  • substituents include substituted or unsubstituted C 1-8 alkyl, C 1-4 alkoxy, and further substituents deuterium, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto, ester group.
  • Z - is a pharmaceutically acceptable anion
  • n is selected from an integer from 0 to 4.
  • R 1 is selected from hydrogen, halogen, substituted or unsubstituted C 1-5 alkyl, C 1-4 alkoxy, hydroxyl, amino, nitro, methyl formate, ethyl formate, ethyl acetate or Wherein, the substituent of the alkyl group is selected from deuterium, halogen, hydroxyl, carboxyl, amino, nitro, cyano, mercapto, methyl formate, ethyl formate or ethyl acetate;
  • R 2 is selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, C 1-4 alkoxy or Wherein, the substituent of the alkyl group is selected from deuterium, C 1-4 alkoxy, halogen, hydroxyl, carboxyl, amino, cyano, mercapto, methyl formate, ethyl formate, and ethyl acetate;
  • X is selected from O, S or NR 10 ;
  • R 10 is selected from H, deuterium, C 1-4 alkyl or C 1-4 alkoxy;
  • n 1 is an integer selected from 0 to 4.
  • R 11 is selected from deuterium, C 1-4 alkyl, C 1-4 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto, methyl formate, ethyl formate or ethyl acetate base;
  • R 3 is selected from -NR 12 R 13 or -OR 14 ;
  • R 12 and R 13 are independently selected from hydrogen, deuterium, substituted or unsubstituted C 1-8 alkyl, C 1-4 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto, methyl formate Ester group, ethyl formate group, ethyl acetate group; the substituent of the alkyl group is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, methyl formate, ethyl formate, Ethyl acetate, -C(O)NR 15 R 16 , -OC(O)R 17 , -C(O)SR 15 ;
  • R 15 and R 16 are independently selected from hydrogen, deuterium, C 1-8 alkyl, C 1-4 alkoxy, halogen, substituted or unsubstituted thienyl, and substituted or unsubstituted phenyl; the thienyl
  • the substituent is selected from C 1-4 alkyl, C 1-4 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, methyl formate, ethyl formate or ethyl acetate;
  • the substituent of the phenyl group is selected from C 1-4 alkyl, C 1-4 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, mercapto, methyl formate, ethyl formate, ethyl acetate base, amino;
  • R 17 is selected from substituted or unsubstituted phenyl; the substituent of the phenyl is selected from C 1-4 alkyl, C 1-4 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, mercapto, methyl formate, ethyl formate, ethyl formate, -NR 18 R 19 ;
  • R 18 and R 19 are independently selected from hydrogen and C 1-4 alkyl
  • R 12 and R 13 are connected to form a substituted or unsubstituted 3-8 membered saturated heterocyclic group; the substituent of the saturated heterocyclic group is selected from C 1-8 alkyl, C 1-4 alkoxy, halogen , nitro, cyano, hydroxyl, carboxyl, mercapto, ester, amino, -C(O)NR 15 R 16 ; the number of heteroatoms in the saturated heterocyclic group is 1;
  • R 14 is selected from -C(O)R 20 , phenyl; the substituent of the phenyl group is -C(O)(CH 2 ) m R 21 ;
  • R 20 is selected from substituted or unsubstituted phenyl; the substituents of the phenyl are C 1-4 alkoxy, -NR 18 R 19 ;
  • n is selected from an integer from 0 to 3;
  • R 21 is selected from piperidinyl
  • L 1 is selected from substituted or unsubstituted C 1-16 alkylene; wherein, the alkylene main chain contains 0-4 heteroatoms, and the heteroatom is selected from O, S, NR 22 ; the The substituent of the alkylene group is selected from deuterium, C 1-4 alkyl, C 1-4 alkoxy, halogen;
  • L 11 is selected from substituted or unsubstituted C 1-6 alkylene, wherein the alkylene main chain contains 0-4 heteroatoms, and the heteroatom is selected from S, NR 22 ; the alkylene The substituent of the group is selected from deuterium, C 1-8 alkyl, C 1-8 alkoxy, halogen;
  • R 22 is selected from hydrogen, deuterium, C 1-4 alkyl, and C 1-4 alkoxy.
  • the pharmaceutically acceptable anion Z- is halogen anion, sulfate, acetate, tartrate, p - toluenesulfonate, mesylate, citrate;
  • the pharmaceutically acceptable anion Z- is a halogen anion
  • the pharmaceutically acceptable anion Z - is Br - or I - .
  • the salt is a pharmaceutically acceptable salt
  • the pharmaceutically acceptable salt refers to the formation of the compound represented by formula I and a pharmaceutically acceptable inorganic acid or organic acid;
  • the inorganic or organic acid is hydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, succinic acid, carbonic acid, tartaric acid, lauric acid, maleic acid, citric acid or benzene formic acid.
  • n is selected from an integer from 0 to 4.
  • R 1 is selected from hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl group, C 1-8 alkoxy group, hydroxyl group, amino group, nitro group, ester group, cyano group, carboxyl group, mercapto group; wherein, the alkyl group The substituent of the group is selected from deuterium, halogen, hydroxyl, carboxyl, amino, nitro, cyano, mercapto or ester;
  • R 2 is selected from H, substituted or unsubstituted C 1-8 alkyl, C 1-8 alkoxy; wherein, the alkyl substituent is selected from deuterium, C 1-8 alkoxy, halogen, hydroxyl, Carboxyl, amino, cyano, mercapto, ester;
  • X is selected from O, S or NR 10 ;
  • R 10 is selected from hydrogen, deuterium, C 1-8 alkyl or C 1-8 alkoxy;
  • n 1 , n 1 ' are each independently selected from an integer from 0 to 5;
  • R 11 , R 11 ' are each independently selected from deuterium, C 1-8 alkyl, C 1-8 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto or ester;
  • L 2 is selected from a substituted or unsubstituted C 1-8 alkylene group, and the substituents of the alkylene group are deuterium, C 1-4 alkyl group, C 1-4 alkoxy group, halogen;
  • Y is selected from O, S or NR 16 ;
  • R 16 is selected from hydrogen, deuterium, C 1-8 alkyl, C 1-8 alkoxy;
  • L 1 is selected from substituted or unsubstituted C 1-16 alkylene; wherein, the alkylene main chain contains 0-4 heteroatoms, and the heteroatom is selected from O, S, NR 22 ; the The substituent of the alkylene group is selected from deuterium, C 1-8 alkyl, C 1-8 alkoxy, halogen;
  • R 22 is selected from hydrogen, deuterium, C 1-4 alkyl, and C 1-4 alkoxy.
  • n is selected from an integer from 0 to 4.
  • R 1 is selected from hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl group, C 1-8 alkoxy group, hydroxyl group, amino group, nitro group, ester group, cyano group, carboxyl group, mercapto group; wherein, the alkyl group The substituent of the group is selected from deuterium, halogen, hydroxyl, carboxyl, amino, nitro, cyano, mercapto or ester;
  • R 2 is selected from H, substituted or unsubstituted C 1-8 alkyl, C 1-8 alkoxy; wherein, the alkyl substituent is selected from deuterium, C 1-8 alkoxy, halogen, hydroxyl, Carboxyl, amino, cyano, mercapto, ester;
  • X is selected from O, S or NR 10 ;
  • R 10 is selected from H, deuterium or C 1-4 alkyl
  • n 1 , n 1 ' are each independently selected from an integer from 0 to 4;
  • R 11 and R 11 ' are each independently selected from deuterium, C 1-4 alkyl, C 1-4 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto, methyl formate, ethyl formate Ester or ethyl acetate;
  • L 2 is selected from substituted or unsubstituted C 1-8 alkylene groups, and the substituents of the alkylene groups are deuterium, C 1-4 alkyl groups, and C 1-4 alkoxy groups;
  • Y is selected from O, S or NR 16 ;
  • R 16 is selected from hydrogen, deuterium, C 1-8 alkyl, C 1-4 alkoxy;
  • L 1 is selected from substituted or unsubstituted C 1-16 alkylene; wherein, the alkylene main chain contains 0-4 heteroatoms, and the heteroatom is selected from O, S, NR 22 ; the The substituent of the alkylene group is selected from deuterium, C 1-4 alkyl, C 1-4 alkoxy, halogen;
  • R 22 is selected from hydrogen, deuterium, C 1-4 alkyl, and C 1-4 alkoxy.
  • X is selected from NR 10 ;
  • R 10 is selected from H, deuterium or C 1-4 alkyl
  • Y is selected from NR 16 ;
  • R 16 is selected from H, deuterium or C 1-4 alkyl
  • R 1 is selected from hydrogen, halogen, substituted or unsubstituted C 1-5 alkyl, C 1-4 alkoxy, and the alkyl substituent is selected from deuterium, halogen, hydroxyl, carboxyl, amino, mercapto, ester group ;
  • n is selected from an integer from 0 to 4.
  • R 11 , R 11 ' are selected from deuterium, C 1-3 alkyl, methoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto or ester;
  • n 1 and n 1 ' are each independently selected from an integer of 2 to 3;
  • L 2 is selected from substituted or unsubstituted C 2-6 alkylene groups, and the substituents are methyl and methoxy;
  • L 1 is selected from C 3-14 alkylene groups; wherein, the alkylene main chain contains 0-2 heteroatoms, and the heteroatoms are selected from O, S, NR 22 ;
  • R 22 is selected from hydrogen, deuterium.
  • the compound is one of the following compounds:
  • the compound is one of the following compounds:
  • n is selected from an integer from 0 to 4.
  • R 1 is selected from hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl group, C 1-8 alkoxy group, hydroxyl group, amino group, nitro group, ester group, cyano group, carboxyl group, mercapto group; wherein, the alkyl group The substituent of the group is selected from deuterium, halogen, hydroxyl, carboxyl, amino, nitro, cyano, mercapto or ester;
  • R 2 is selected from H, substituted or unsubstituted C 1-8 alkyl, C 1-8 alkoxy; wherein, the substituent of the alkyl is selected from deuterium, C 1-8 alkoxy, halogen, hydroxyl , carboxyl group, amino group, cyano group, mercapto group, ester group;
  • X is selected from O, S or NR 10 ;
  • R 10 is selected from H, deuterium, C 1-8 alkyl or C 1-8 alkoxy;
  • n 1 , n 1 ' are each independently selected from an integer from 0 to 5;
  • R 11 , R 11 ' are each independently selected from deuterium, C 1-8 alkyl, C 1-8 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto or ester;
  • L 2 is selected from hydrogen, deuterium, substituted or unsubstituted C 1-8 alkyl, C 1-8 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto, ester; the alkane
  • the substituent of the group is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, ester group;
  • Y is selected from O, S or NR 16 ;
  • R 16 is selected from H, deuterium, C 1-8 alkyl or C 1-8 alkoxy;
  • L 1 is selected from substituted or unsubstituted C 1-16 alkylene; wherein, the alkylene main chain contains 0-4 heteroatoms, and the heteroatom is selected from O, S, NR 22 ; the The substituent of the alkylene group is selected from deuterium, C 1-8 alkyl, C 1-8 alkoxy, halogen;
  • R 22 is selected from hydrogen, deuterium, C 1-4 alkyl, C 1-4 alkoxy;
  • n is selected from an integer from 0 to 4.
  • R 1 is selected from hydrogen, halogen, substituted or unsubstituted C 1-5 alkyl, C 1-4 alkoxy, hydroxyl, amino, nitro, methyl formate, ethyl formate and ethyl acetate; Wherein, the substituent of the alkyl is selected from deuterium, halogen, hydroxyl, carboxyl, amino, nitro, cyano, mercapto, methyl formate, ethyl formate or ethyl formate;
  • R 2 is selected from H, substituted or unsubstituted C 1-8 alkyl, C 1-4 alkoxy; wherein, the substituent of the alkyl is selected from deuterium, C 1-4 alkoxy, halogen, hydroxyl , carboxyl, amino, cyano, mercapto, methyl formate, ethyl formate, ethyl acetate;
  • X is selected from O, S or NR 10 ;
  • R 10 is selected from H, deuterium or C 1-4 alkyl
  • n 1 , n 1 ' are each independently selected from an integer from 0 to 4;
  • R 11 and R 11 ' are each independently selected from deuterium, C 1-4 alkyl, C 1-4 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto, methyl formate, ethyl formate Ester or ethyl acetate;
  • L 2 is selected from hydrogen, deuterium, substituted or unsubstituted C 1-8 alkyl, C 1-4 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto, methyl formate, formic acid Ethyl ester group, ethyl acetate group; the substituent of the alkyl group is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, methyl formate, ethyl formate, ethyl acetate ;
  • R 16 is selected from hydrogen, deuterium, C 1-8 alkyl, C 1-4 alkoxy;
  • L 1 is selected from substituted or unsubstituted C 1-16 alkylene; wherein, the alkylene main chain contains 0-4 heteroatoms, and the heteroatom is selected from O, S, NR 22 ; the The substituent of the alkylene group is selected from deuterium, C 1-4 alkyl, C 1-4 alkoxy, halogen;
  • R 22 is selected from hydrogen, deuterium, C 1-4 alkyl, and C 1-4 alkoxy.
  • X is selected from NR 10 ;
  • R 10 is selected from H, deuterium or C 1-4 alkyl
  • Y is selected from NR 16 ;
  • R 16 is selected from H, deuterium or C 1-4 alkyl
  • R 1 is selected from hydrogen, substituted or unsubstituted C 1-5 alkyl, C 1-4 alkoxy, and the alkyl substituent is selected from deuterium, halogen, hydroxyl, carboxyl, amino, mercapto, and ester;
  • n is selected from an integer from 0 to 4.
  • R 11 , R 11 ' are selected from deuterium, C 1 alkyl, methoxy, halogen;
  • n 1 and n 1 ' are each independently selected from an integer of 2 to 5;
  • L 2 is selected from hydrogen, deuterium, and C 1-8 alkylene
  • L 1 is selected from C 2-10 alkylene groups; wherein, the alkylene main chain contains 0-2 heteroatoms, and the heteroatoms are selected from O, S, NR 22 ;
  • R 22 is selected from hydrogen, deuterium.
  • the compound is one of the following compounds:
  • n is selected from an integer from 0 to 5;
  • R 1 is selected from hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl group, C 1-8 alkoxy group, hydroxyl group, amino group, nitro group, ester group, cyano group, carboxyl group, mercapto group; wherein, the alkyl group The substituent of the group is selected from deuterium, halogen, hydroxyl, carboxyl, amino, nitro, cyano, mercapto or ester;
  • X is selected from O, S or NR 10 ;
  • R 10 is selected from H, deuterium or C 1-8 alkyl, C 1-8 alkoxy;
  • n 1 , n 1 ' are each independently selected from an integer from 0 to 5;
  • R 11 , R 11 ' are each independently selected from deuterium, C 1-8 alkyl, C 1-8 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto or ester;
  • L 2 is selected from substituted or unsubstituted C 1-8 alkylene, and the substituents of the alkylene are deuterium, C 1-4 alkyl, C 1-4 alkoxy, halogen;
  • Y is selected from O, S or NR 16 ;
  • R 16 is selected from hydrogen, deuterium, C 1-8 alkyl, C 1-8 alkoxy;
  • L 1 is selected from substituted or unsubstituted C 1-16 alkylene; wherein, the alkylene main chain contains 0-4 heteroatoms, and the heteroatom is selected from O, S, NR 22 ; the The substituent of the alkylene group is selected from deuterium, C 1-8 alkyl, C 1-8 alkoxy, halogen;
  • R 22 is selected from hydrogen, deuterium, C 1-4 alkyl, C 1-4 alkoxy;
  • n is selected from an integer from 0 to 4.
  • R 1 is selected from hydrogen, halogen, substituted or unsubstituted C 1-5 alkyl, C 1-4 alkoxy, hydroxyl, amino, nitro, methyl formate, ethyl formate, and ethyl acetate; Wherein, the substituent of the alkyl group is selected from deuterium, halogen, hydroxyl, carboxyl, amino, nitro, cyano, mercapto, methyl formate, ethyl formate or ethyl acetate;
  • X is selected from O, S or NR 10 ;
  • R 10 is selected from H, deuterium or C 1-4 alkyl
  • n 1 , n 1 ' are each independently selected from an integer from 0 to 4;
  • R 11 and R 11 ' are each independently selected from deuterium, C 1-4 alkyl, C 1-4 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto, methyl formate, ethyl formate Ester or ethyl acetate;
  • L 2 is selected from a substituted or unsubstituted C 1-8 alkylene group, and the substituents of the alkylene group are deuterium, C 1-4 alkyl group, C 1-4 alkoxy group, halogen;
  • R 16 is selected from hydrogen, deuterium, C 1-8 alkyl, C 1-4 alkoxy;
  • L 1 is selected from substituted or unsubstituted C 1-16 alkylene; wherein, the alkylene main chain contains 0-4 heteroatoms, and the heteroatom is selected from O, S, NR 22 ; the The substituent of the alkylene group is selected from deuterium, C 1-4 alkyl, C 1-4 alkoxy, halogen;
  • R 22 is selected from hydrogen, deuterium, C 1-4 alkyl, and C 1-4 alkoxy.
  • X is selected from NR 10 ;
  • R 10 is selected from H, deuterium or C 1-4 alkyl
  • Y is selected from NR 16 ;
  • R 16 is selected from H, deuterium or C 1-4 alkyl
  • R 1 is selected from hydrogen, substituted or unsubstituted C 1-5 alkyl, C 1-4 alkoxy, and the alkyl substituent is selected from deuterium, halogen, hydroxyl, carboxyl, amino, mercapto, and ester;
  • n is selected from an integer from 0 to 5;
  • R 11 , R 11 ' are selected from deuterium, C 1-3 alkyl, methoxy, halogen, nitro, cyano, carboxyl, hydroxyl, amino, mercapto, and ester;
  • n 1 and n 1 ' are each independently selected from an integer of 2 to 3;
  • L 2 is selected from substituted or unsubstituted C 2-6 alkylene groups, and the substituents of the alkylene groups are methyl and methoxy;
  • L 1 is selected from C 3-14 alkylene groups; wherein, the alkylene main chain contains 0-2 hetero atoms, and the hetero atoms are selected from O, S, NR 22 ;
  • R 22 is selected from hydrogen, deuterium.
  • the compound is one of the following compounds:
  • n is selected from an integer from 0 to 5;
  • R 1 is selected from hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl group, C 1-8 alkoxy group, hydroxyl group, amino group, nitro group, ester group, cyano group, carboxyl group, mercapto group; wherein, the alkyl group The substituent of the group is selected from deuterium, halogen, hydroxyl, carboxyl, amino, nitro, cyano, mercapto or ester;
  • X is selected from O, S or NR 10 ;
  • R 10 is selected from H, deuterium or C 1-8 alkyl, C 1-8 alkoxy;
  • n 1 , n 1 ' are each independently selected from an integer from 0 to 5;
  • R 11 , R 11 ' are each independently selected from deuterium, C 1-8 alkyl, C 1-8 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto or ester;
  • L 2 is selected from hydrogen, deuterium, substituted or unsubstituted C 1-8 alkyl, C 1-8 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto, ester; the alkane
  • the substituent of the group is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, ester group;
  • Y is selected from O, S or NR 16 ;
  • R 16 is selected from H, deuterium or C 1-8 alkyl, C 1-8 alkoxy;
  • L 1 is selected from substituted or unsubstituted C 1-16 alkylene; wherein, the alkylene main chain contains 0-4 heteroatoms, and the heteroatom is selected from O, S, NR 22 ; the The substituent of the alkylene group is selected from deuterium, C 1-8 alkyl, C 1-8 alkoxy, halogen;
  • R 22 is selected from hydrogen, deuterium, C 1-4 alkyl, C 1-4 alkoxy;
  • n is selected from an integer from 0 to 4.
  • R 1 is selected from hydrogen, halogen, substituted or unsubstituted C 1-5 alkyl, C 1-4 alkoxy, hydroxyl, amino, nitro, methyl formate, ethyl formate, and ethyl acetate; Wherein, the substituent of the alkyl group is selected from deuterium, halogen, hydroxyl, carboxyl, amino, nitro, cyano, mercapto, methyl formate, ethyl formate or ethyl acetate;
  • X is selected from O, S or NR 10 ;
  • R 10 is selected from H, deuterium or C 1-4 alkyl
  • n 1 , n 1 ' are each independently selected from an integer from 0 to 4;
  • R 11 and R 11 ' are each independently selected from deuterium, C 1-4 alkyl, C 1-4 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto, methyl formate, ethyl formate Ester or ethyl acetate;
  • L 2 is selected from hydrogen, deuterium, substituted or unsubstituted C 1-8 alkyl, C 1-4 alkoxy, halogen, nitro, cyano, hydroxyl, carboxyl, amino, mercapto, methyl formate, formic acid Ethyl ester group, ethyl acetate group; the substituent of the alkyl group is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, methyl formate, ethyl formate, ethyl acetate ;
  • R 16 is independently selected from hydrogen, deuterium, C 1-8 alkyl, and C 1-4 alkoxy;
  • L 1 is selected from substituted or unsubstituted C 1-16 alkylene; wherein, the alkylene main chain contains 0-4 heteroatoms, and the heteroatom is selected from O, S, NR 22 ; the The substituent of the alkylene group is selected from deuterium, C 1-4 alkyl, C 1-4 alkoxy, halogen;
  • R 22 is selected from hydrogen, deuterium, C 1-4 alkyl, and C 1-4 alkoxy.
  • X is selected from NR 10 ;
  • R 10 is selected from H, deuterium or C 1-4 alkyl
  • Y is selected from NR 16 ;
  • R 16 is selected from H, deuterium or C 1-4 alkyl
  • R 1 is selected from hydrogen, substituted or unsubstituted C 1-5 alkyl, C 1-4 alkoxy, and the alkyl substituent is selected from deuterium, halogen, hydroxyl, carboxyl, amino, mercapto, and ester;
  • n is selected from an integer from 0 to 5;
  • R 11 , R 11 ' are selected from deuterium, C 1-3 alkyl, methoxy, halogen;
  • n 1 and n 1 ' are each independently selected from an integer of 2 to 5;
  • L 2 is selected from hydrogen, deuterium, and C 1-8 alkylene
  • L 1 is selected from C 2-10 alkylene groups; wherein, the alkylene main chain contains 0-2 heteroatoms, and the heteroatoms are selected from O, S, NR 22 ;
  • R 22 is selected from hydrogen, deuterium.
  • the compound is one of the following compounds:
  • the present invention also provides a compound, or its salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, and the structure of said compound is shown in formula VI-A:
  • X 1 and Y 1 are independently selected from CHR 4 or O, and only one of X 1 and Y 1 is O;
  • R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl
  • R 3 is selected from hydrogen, halogen, C 1 -C 3 alkyl
  • n 1 is an integer from 0 to 3;
  • n 2 are independently selected from integers from 1 to 8;
  • Z - is a pharmaceutically acceptable anion
  • R 1 and R 2 are independently selected from substituted or unsubstituted C 1-3 alkyl groups; the substituents of the alkyl groups are selected from
  • Y is selected from NR 6 ;
  • R 6 is selected from hydrogen, C 1-3 alkyl
  • R 5 is selected from a substituted or unsubstituted phenyl group; the substituent of the phenyl group is a C 1-3 alkyl group;
  • R 1 and R 2 are connected to form a substituted or unsubstituted 6-membered saturated heterocyclic group; the substituent of the saturated heterocyclic group is selected from The heteroatom of the heterocyclyl group is 1, and the heteroatom is N;
  • R 3 and R 4 are independently selected from hydrogen, halogen, and C 1 -C 3 alkyl
  • n 2 are independently selected from integers from 1 to 8;
  • Z - is a pharmaceutically acceptable anion
  • R 1 and R 2 are independently selected from substituted or unsubstituted C 1-3 alkyl groups; the substituents of the alkyl groups are selected from
  • Y is selected from NR 6 ;
  • R 6 is selected from hydrogen, C 1-3 alkyl
  • R 5 is selected from a substituted or unsubstituted phenyl group; the substituent of the phenyl group is a C 1-3 alkyl group.
  • the compound is one of the following compounds:
  • the present invention also provides the use of the aforementioned compounds, or their salts, or their stereoisomers, or their solvates, or their prodrugs, or their metabolites, in the preparation of anesthetics;
  • the anesthetic is a local anesthetic.
  • the local anesthetic makes the sensory nerve block time longer than the motor nerve block time
  • the sensory nerve block time of the local anesthetic is longer than the motor nerve block time by more than 10 hours.
  • the local anesthetic is long-acting local anesthesia and/or selective local anesthesia
  • the anesthesia time of the local anesthetic is more than 30 hours.
  • the present invention also provides a medicine, which uses the aforementioned compound, or its salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite as an active ingredient, plus the medicine Preparations prepared from the above acceptable excipients.
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • Alkyl is a hydrocarbon group formed by missing one hydrogen atom in an alkane molecule, such as methyl-CH 3 , ethyl-CH 3 CH 2 and the like.
  • C 1-4 alkyl refers to a straight or branched hydrocarbon chain containing one to four carbon atoms.
  • Alkylene refers to a hydrocarbon group formed by missing two hydrogen atoms in an alkane molecule, such as methylene-CH 2 -, ethylene-CH 2 CH 2 - and the like.
  • C 1-4 alkylene refers to a straight or branched hydrocarbon chain containing one to four carbon atoms.
  • C 1-8 alkoxy refers to an alkoxy group containing one to eight carbon atoms.
  • the structural formula of "NR 10” is The structural formula of "NR 12 R 13 " is The structural formula of "OR 14 " is The structural formula of "-OC(O)R 17 " is The structural formula of “-C(O)SR 15 ” is The structural formula of “-C(O)R 20 “ is The structural formula of “-C(O)(CH 2 ) m R 21 ” is m is an integer of 0-8.
  • Substituted or unsubstituted C 1-8 alkyl group means that the C 1-8 alkyl group may be substituted or unsubstituted.
  • L 1 is selected from substituted or unsubstituted C 1-16 alkylene; wherein, the alkylene main chain contains 0-4 heteroatoms" refers to a straight chain or a straight chain containing one to sixteen carbon atoms.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, such as phenyl and naphthyl.
  • the aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be in a conjugated pi-electron system on the carbon atom of the ring.
  • Aryl can be substituted or unsubstituted, that is, can be replaced by 0-4 deuterium, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halogen, nitro, cyano , hydroxyl, carboxyl, amino and other substituents.
  • 3- to 8-membered unsaturated cycloalkyl group refers to a cycloalkyl group composed of 3-8 carbon atoms containing at least one double bond;
  • 3- to 8-membered unsaturated heterocyclic group refers to at least one carbon atom is Unsaturated cycloalkyl substituted with a heteroatom which is O, S or N.
  • salts refers to salts of compounds of the present invention with pharmaceutically acceptable inorganic and organic acids that are suitable for contact with the tissue of a subject (eg, a human) without undue adverse effects.
  • preferred inorganic acids include (but are not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid;
  • preferred organic acids include (but are not limited to): formic acid, acetic acid, propionic acid, succinic acid, naphthalene Disulfonic acid (1,5), succinic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, hexamethylene diacid acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, as
  • solvate refers to a compound of the present invention forming a solvate with a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent includes, but is not limited to, water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran , Dichloromethane.
  • stereoisomer means that the chiral carbon atoms involved in the compounds of the present invention may be in the R configuration, or the S configuration, or a combination thereof.
  • the quaternary ammonium salt compounds of the present invention have quick onset of action when used for local anesthesia, long anesthesia time after single administration, and longer sensory nerve block time than motor nerve block time, and have both long-acting local anesthesia and selective local anesthesia It can significantly reduce the side effects of the local anesthetics in the prior art, and has better safety.
  • the quaternary ammonium salt compound of the present invention can be used for preparing safe medicines with long-term local anesthesia and selective local anesthesia, and has the advantages of long local anesthesia action time, good local anesthesia selectivity, less nerve damage and high safety .
  • the raw materials and equipment used in the specific embodiments of the present invention are all known products, which are obtained by purchasing commercially available products.
  • the compounds of the examples were selected, and the lidocaine positive control group and the levobupivacaine positive control group were respectively administered to the test rats fully adapted to the experimental environment, with 8 rats in each group.
  • the administration doses were as follows: lidocaine group concentration was 2% aqueous solution, levobupivacaine group concentration was 0.75% aqueous solution, and the concentration of the drug to be tested was 20 mmol/mL aqueous solution.
  • each rat is 0.5ml, which is guided and positioned by the nerve localizer, and injected near the sciatic nerve of the rat.
  • the von Frey stimulator was used to stimulate the lateral sole of the rat to inject the drug, and the effect of local anesthesia was observed.
  • the motor function of the rat was evaluated by the hindlimb pedaling test (Postural Extensor Thrust, PET): the rat was lifted vertically and the hindlimb on the injection side was pedaled on the electronic platform. and the displayed numerical value. When the limb is completely paralyzed, the reading is the limb's own weight, about 20g. A measured value greater than half of the difference between the baseline and the limb weight was considered motor function recovery, and less than or equal to this value was considered motor function loss.
  • the experimental results show that the drugs can produce local anesthesia for more than 30 hours in the rat subcutaneous infiltration model.
  • Dosages were as follows: Lido concentration was 2% aqueous solution, levobupivacaine group concentration was 0.75% aqueous solution, and the drug concentration to be tested was 20 mmol/L aqueous solution.
  • the injection volume of each rat or control was 0.5 mL, and it was injected near the sciatic nerve of the rat.
  • experimental rats were euthanized by cardiac injection of bupivacaine under isoflurane anesthesia.
  • the sciatic nerve of about 1.5 cm at the injection site was taken, stored in 10% formaldehyde solution for 48 h, stained with HE and cut into 5 ⁇ m thick sections.
  • the administration doses were as follows: lidocaine group concentration was 2% aqueous solution, levobupivacaine group concentration was 0.75% aqueous solution, and the drug concentration to be tested was 6mmol/L aqueous solution.
  • the injection volume of each rat was 0.5 ml, and it was injected subcutaneously on the back of the rat.
  • experimental rats were euthanized by intracardiac injection of bupivacaine under isoflurane anesthesia.
  • the skin tissue at the injection site was taken, stored in 10% formaldehyde solution for 48 hours, stained with HE and cut into 5 ⁇ m thick sections.
  • the evaluation of neuropathological damage showed that: the compounds of Examples 1-13 and 201-207 were compared with the lidocaine positive control group and the levobupivacaine positive control group in nerve injury, vascular proliferation, degree of demyelination, muscle inflammation, There was no significant difference in the degree of connective tissue inflammation, with a good safety profile.
  • the quaternary ammonium salt compounds of the present invention have a fast onset of action when used for local anesthesia, a long anesthesia time after a single administration, and the sensory nerve block time is longer than the motor nerve block time. It has the effect of local anesthesia, significantly reduces the side effects of the local anesthesia drugs in the prior art, and has better safety.
  • the quaternary ammonium salt compound of the present invention can be used for preparing safe medicines with long-term local anesthesia and selective local anesthesia, and has the advantages of long local anesthesia action time, good local anesthesia selectivity, less nerve damage and high safety .

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Abstract

提供了一种用于麻醉的季铵盐类化合物及其制备方法和用途，属于医药化学领域。该季铵盐类化合物是式I所示的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物。所述季铵盐类化合物用于局部麻醉时起效快，单次给药后麻醉时间长，并且感觉神经阻滞时间大于运动神经阻滞时间，兼具长效局部麻醉作用和选择性局部麻醉作用，显著降低了现有技术中局麻药物的副作用，具有更好的安全性。

Description

一种用于麻醉的季铵盐类化合物及其制备方法和用途 技术领域
本发明属于医药化学领域，具体涉及一种用于麻醉的季铵盐类化合物及其制备方法和用途。
背景技术
局部麻醉药(Local anesthetics，局麻药)是一类能在用药局部可逆性的阻断感觉神经冲动发生与传递的药品，简称“局麻药”。在动物或人意识清醒的条件下，在局部可逆的阻断感觉神经冲动产生与信号传导，使有关神经支配的部位出现暂时性感觉丧失，从而可逆的引起局部组织痛觉消失的一类药物。一般的，局麻药的作用局限于给药部位并随药物从给药部位扩散而迅速消失。局部麻醉药通过直接抑制神经细胞和纤维膜上的相关离子通道，阻滞动作电位的产生和神经冲动的传导，从而产生局部麻醉作用。目前公认的局麻药作用机制，是阻断神经细胞膜上的电压门控性Na +通道，使神经冲动传导阻滞，从而产生局部麻醉作用。
临床目前所使用的局麻药均为不具备电荷的疏水性化合物，因此容易通过扩散和渗透方式通过细胞膜进入神经细胞达到钠通道的阻断位点。这些麻醉药阻断钠通道从而阻断神经元的兴奋性。实际上，这些局部麻醉药分子虽然容易通过扩散进入神经细胞内发挥作用，但同时也容易通过扩散作用从给药部位迅速扩散，游离出神经细胞，导致局部麻醉作用无法长时间持续。即使加大使用剂量也只能在一定程度内延长局部麻醉时间，这些局部麻醉药物，无法获得理想的长时间局部麻醉作用。目前临床常用的局部麻醉药物作用时间大多不超过4小时。由于传统局部麻醉药的作用维持时间较短，不得不使用镇痛泵来维持神经阻滞，采取椎管内、神经根、皮下等部位的置管，大大增加了医疗成本和感染的发生率。
另一方面，传统局部麻醉药物对神经的阻滞并不具有特异的选择性，在使用过程中广泛地阻滞多种神经纤维，影响感觉、痛觉、运动以及交感神经等多种神经功能，这一药理特点极大的限制了局部麻醉药在临床中的广泛应用。例如膝关节置换术后患者早期的功能锻炼康复尤为重要，但是目前使用的局麻药中并无选择性阻滞痛觉的药物，大部分手术患者由于使用局部麻醉药，导致患者的运动神经被阻滞，无法恢复运动功能从而使得术后康复受限。局部麻醉药研究急需引入新的研究思路，开发选择性阻滞感觉功能而不影响运动功能的长效局部麻醉药物以满足临床需求。
发明内容
本发明的目的是提供一种用于麻醉的季铵盐类化合物及其制备方法和用途。
本发明提供了式I所示的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物：
Figure PCTCN2021113091-appb-000001
式中，
Z -为药学上可接受的阴离子；
n选自0～8的整数；
R 1选自氢、卤素、取代或未取代的C 1～8烷基、C 1～8烷氧基、羟基、氨基、硝基、酯基、氰基、羧基、巯基或
Figure PCTCN2021113091-appb-000002
其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基或酯基；
R 2选自H、取代或未取代的C 1～8烷基、C 1～8烷氧基或
Figure PCTCN2021113091-appb-000003
其中，所述烷基的取代基选自氘、C 1～8烷氧基、卤素、羟基、羧基、氨基、氰基、巯基、酯基或
Figure PCTCN2021113091-appb-000004
R 4选自n 1个R 11取代的芳基；
X选自O、S或NR 10；
R 10选自H、氘、C 1～8烷基或C 1～8烷氧基；
n 1选自0～5的整数；
R 11选自氘、C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基或酯基；
R 3选自-NR 12R 13或-OR 14；
R 12、R 13分别独立选自氢、氘、取代或未取代的C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、酯基；所述烷基的取代基选 自氘、卤素、氨基、硝基、氰基、羧基、羟基、巯基、酯基、
Figure PCTCN2021113091-appb-000005
Figure PCTCN2021113091-appb-000006
-OC(O)R 17、-C(O)SR 15；
Y选自O、S或NR 16；
R 15、R 16分别独立选自氢、氘、C 1～8烷基、C 1～8烷氧基、卤素、取代或未取代的3～8元不饱和杂环基、取代或未取代的3～8元不饱和环烷基；所述不饱和杂环基的取代基选自C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、酯基；所述不饱和环烷基的取代基选自C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、巯基、酯基、氨基；所述杂环基的杂原子为1～3个，所述杂原子为N、O或S；
R 17选自取代或未取代的3～8元不饱和环烷基；所述不饱和环烷基的取代基选自C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、巯基、酯基、氨基、-NR 18R 19；
R 18、R 19分别独立选自氢、C 1～8烷基；
或者，R 12和R 13连接形成取代或未取代的3～11元饱和杂环基；所述饱和杂环基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、巯基、酯基、氨基、
Figure PCTCN2021113091-appb-000007
所述杂环基的杂原子为1～3个，所述杂原子为N、O或S；
R 14选自-C(O)R 20、取代或未取代的3～8元不饱和环烷基；所述不饱和环烷基的取代基为-C(O)(CH 2) mR 21；
R 20选自取代或未取代的3～8元不饱和环烷基；所述不饱和环烷基的取代基为C 1～8烷氧基、-NR 18R 19；
m选自0～8的整数；
R 21选自3～8元饱和杂环基；所述杂环基的杂原子为1～3个，所述杂原子为N、O或S；
L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素；
L 11选自取代或未取代的C 1～7亚烷基，其中，所述亚烷基主链中含有0～4 个杂原子，所述杂原子选自S、NR 22；所述亚烷基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素；
R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基。
进一步地，
R 4选自
Figure PCTCN2021113091-appb-000008
n 1选自0～5的整数；
R 11选自氘、C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基或酯基。
进一步地，所述R 3选自取代或未取代的如下基团：
Figure PCTCN2021113091-appb-000009
Figure PCTCN2021113091-appb-000010
其中，所述取代基包括取代或未取代的C 1～8烷基、C 1～4烷氧基，以及进一步的取代基氘、卤素、硝基、氰基、羟基、羧基、氨基、巯基、酯基。
进一步地，
Z -为药学上可接受的阴离子；
n选自0～4的整数；
R 1选自氢、卤素、取代或未取代的C 1～5烷基、C 1～4烷氧基、羟基、氨基、硝基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基或
Figure PCTCN2021113091-appb-000011
其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
R 2选自氢、取代或未取代的C 1～8烷基、C 1～4烷氧基或
Figure PCTCN2021113091-appb-000012
其中，所述烷基的取代基选自氘、C 1～4烷氧基、卤素、羟基、羧基、氨基、氰基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；
X选自O、S或NR 10；
R 10选自H、氘、C 1～4烷基或C 1～4烷氧基；
n 1选自0～4的整数；
R 11选自氘、C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
R 3选自-NR 12R 13或-OR 14；
R 12、R 13分别独立选自氢、氘、取代或未取代C 1～8烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；所述烷基的取代基选自氘、卤素、氨基、硝基、氰基、羧基、羟基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基、-C(O)NR 15R 16、
Figure PCTCN2021113091-appb-000013
-OC(O)R 17、-C(O)SR 15；
R 15、R 16分别独立选自氢、氘、C 1～8烷基、C 1～4烷氧基、卤素、取代或未取代的噻吩基、取代或未取代的苯基；所述噻吩基的取代基选自C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；所述苯基的取代基选自C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基、氨基；
R 17选自取代或未取代的苯基；所述苯基的取代基选自C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基、-NR 18R 19；
R 18、R 19分别独立选自氢、C 1～4烷基；
或者，R 12和R 13连接形成取代或未取代的3～8元饱和杂环基；所述饱和杂环基的取代基选自C 1～8烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、巯基、酯基、氨基、-C(O)NR 15R 16；所述饱和杂环基的杂原子个数为1；
R 14选自-C(O)R 20、苯基；所述苯基的取代基为-C(O)(CH 2) mR 21；
R 20选自取代或未取代的苯基；所述苯基的取代基为C 1～4烷氧基、-NR 18R 19；
m选自0～3的整数；
R 21选自哌啶基；
L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～4烷基、C 1～4烷氧基、卤素；
L 11选自取代或未取代的C 1～6亚烷基，其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自S、NR 22；所述亚烷基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素；
R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基。
进一步地，所述药学上可接受的阴离子Z -为卤素阴离子、硫酸根、醋酸根、酒石酸根、对甲苯磺酸根、甲磺酸根、枸橼酸根；
优选地，所述药学上可接受的阴离子Z -为卤素阴离子；
更优选地，所述药学上可接受的阴离子Z -为Br -或I -。
进一步地，所述盐为药学上可接受的盐；
优选地，所述药学上可接受的盐是指由式I所示化合物与药学上可接受的无机酸或有机酸形成；
更优选地，所述无机酸或有机酸为盐酸、氢溴酸、乙酸、硫酸、甲磺酸、对甲苯磺酸、琥珀酸、碳酸、酒石酸、月桂酸、马来酸、枸橼酸或苯甲酸。
进一步地，所述化合物如式Ⅱ所示：
Figure PCTCN2021113091-appb-000014
式中，
n选自0～4的整数；
R 1选自氢、卤素、取代或未取代的C 1～8烷基、C 1～8烷氧基、羟基、氨基、硝基、酯基、氰基、羧基、巯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基或酯基；
R 2选自H、取代或未取代的C 1～8烷基、C 1～8烷氧基；其中，所述烷基取代基选自氘、C 1～8烷氧基、卤素、羟基、羧基、氨基、氰基、巯基、酯基；
X选自O、S或NR 10；
R 10选自氢、氘、C 1～8烷基或C 1～8烷氧基；
n 1、n 1’各自独立选自0～5的整数；
R 11、R 11’各自独立选自氘、C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、 羟基、羧基、氨基、巯基或酯基；
L 2选自取代或未取代的C 1～8的亚烷基，所述亚烷基的取代基为氘、C 1～4烷基、C 1～4烷氧基、卤素；
Y选自O、S或NR 16；
R 16选自氢、氘、C 1～8烷基、C 1～8烷氧基；
L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素；
R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基。
进一步地，
n选自0～4的整数；
R 1选自氢、卤素、取代或未取代的C 1～8烷基、C 1～8烷氧基、羟基、氨基、硝基、酯基、氰基、羧基、巯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基或酯基；
R 2选自H、取代或未取代的C 1～8烷基、C 1～8烷氧基；其中，所述烷基取代基选自氘、C 1～8烷氧基、卤素、羟基、羧基、氨基、氰基、巯基、酯基；
X选自O、S或NR 10；
R 10选自H、氘或C 1～4烷基；
n 1、n 1’各自独立选自0～4的整数；
R 11、R 11’各自独立选自氘、C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
L 2选自取代或未取代的C 1～8的亚烷基，所述亚烷基的取代基为氘、C 1～4烷基、C 1～4烷氧基；
Y选自O、S或NR 16；
R 16选自氢、氘、C 1～8烷基、C 1～4烷氧基；
L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～4烷基、C 1～4烷氧基、卤素；
R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基。
进一步地，
X选自NR 10；
R 10选自H、氘或C 1～4的烷基；
Y选自NR 16；
R 16选自H、氘或C 1～4的烷基；
R 1选自氢、卤素，取代或未取代的C 1～5烷基、C 1～4烷氧基，所述烷基取 代基选自氘、卤素、羟基、羧基、氨基、巯基、酯基；
n选自0～4的整数；
R 11、R 11’选自氘、C 1～3烷基、甲氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基或酯基；
n 1、n 1’各自独立选自2～3的整数；
L 2选自取代或未取代的C 2～6的亚烷基，所述取代基为甲基、甲氧基；
L 1选自C 3～14的亚烷基；其中，所述亚烷基主链中含有0～2个杂原子，所述杂原子选自O、S、NR 22；
R 22选自氢、氘。
进一步地，所述化合物为如下化合物之一：
Figure PCTCN2021113091-appb-000015
Figure PCTCN2021113091-appb-000016
进一步地，所述化合物为如下化合物之一：
Figure PCTCN2021113091-appb-000017
Figure PCTCN2021113091-appb-000018
进一步地，所述化合物如式Ⅲ所示：
Figure PCTCN2021113091-appb-000019
式中，
n选自0～4的整数；
R 1选自氢、卤素、取代或未取代的C 1～8烷基、C 1～8烷氧基、羟基、氨基、硝基、酯基、氰基、羧基、巯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基或酯基；
R 2选自H、取代或未取代的C 1～8烷基、C 1～8烷氧基；其中，所述烷基的取代基选自氘、C 1～8烷氧基、卤素、羟基、羧基、氨基、氰基、巯基、酯基；
X选自O、S或NR 10；
R 10选自H、氘、C 1～8烷基或C 1～8烷氧基；
n 1、n 1’各自独立选自0～5的整数；
R 11、R 11’各自独立选自氘、C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基或酯基；
L 2选自氢、氘、取代或未取代的C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、酯基；所述烷基的取代基选自氘、卤素、氨基、硝基、氰基、羧基、羟基、巯基、酯基；
Y选自O、S或NR 16；
R 16选自H、氘、C 1～8烷基或C 1～8烷氧基；
L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素；
R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基；
优选地，
n选自0～4的整数；
R 1选自氢、卤素、取代或未取代的C 1～5烷基、C 1～4烷氧基、羟基、氨基、硝基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
R 2选自H、取代或未取代的C 1～8烷基、C 1～4烷氧基；其中，所述烷基的取代基选自氘、C 1～4烷氧基、卤素、羟基、羧基、氨基、氰基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；
X选自O、S或NR 10；
R 10选自H、氘或C 1～4烷基；
n 1、n 1’各自独立选自0～4的整数；
R 11、R 11’各自独立选自氘、C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
L 2选自氢、氘、取代或未取代的C 1～8烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；所述烷基的取代基选自氘、卤素、氨基、硝基、氰基、羧基、羟基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；
R 16选自氢、氘、C 1～8烷基、C 1～4烷氧基；
L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～4烷基、C 1～4烷氧基、卤素；
R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基。
进一步地，
X选自NR 10；
R 10选自H、氘或C 1～4烷基；
Y选自NR 16；
R 16选自H、氘或C 1～4烷基；
R 1选自氢，取代或未取代的C 1～5烷基、C 1～4烷氧基，所述烷基取代基选自氘、卤素、羟基、羧基、氨基、巯基、酯基；
n选自0～4的整数；
R 11、R 11’选自氘、C 1烷基、甲氧基、卤素；
n 1、n 1’各自独立选自2～5的整数；
L 2选自氢、氘、C 1～8的亚烷基；
L 1选自C 2～10的亚烷基；其中，所述亚烷基主链中含有0～2个杂原子，所述杂原子选自O、S、NR 22；
R 22选自氢、氘。
进一步地，所述化合物为如下化合物之一：
Figure PCTCN2021113091-appb-000020
Figure PCTCN2021113091-appb-000021
进一步地，所述化合物如式Ⅳ所示：
Figure PCTCN2021113091-appb-000022
式中，
n选自0～5的整数；
R 1选自氢、卤素、取代或未取代的C 1～8烷基、C 1～8烷氧基、羟基、氨基、硝基、酯基、氰基、羧基、巯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基或酯基；
X选自O、S或NR 10；
R 10选自H、氘或C 1～8烷基、C 1～8烷氧基；
n 1、n 1’各自独立选自0～5的整数；
R 11、R 11’各自独立选自氘、C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基或酯基；
L 2选自取代或未取代的C 1～8亚烷基，所述亚烷基的取代基为氘、C 1～4烷基、C 1～4烷氧基、卤素；
Y选自O、S或NR 16；
R 16选自氢、氘、C 1～8烷基、C 1～8烷氧基；
L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4 个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素；
R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基；
优选地，
n选自0～4的整数；
R 1选自氢、卤素、取代或未取代的C 1～5烷基、C 1～4烷氧基、羟基、氨基、硝基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
X选自O、S或NR 10；
R 10选自H、氘或C 1～4烷基；
n 1、n 1’各自独立选自0～4的整数；
R 11、R 11’各自独立选自氘、C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
L 2选自取代或未取代的C 1～8的亚烷基，所述亚烷基的取代基为氘、C 1～4烷基、C 1～4烷氧基、卤素；
R 16选自氢、氘、C 1～8烷基、C 1～4烷氧基；
L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～4烷基、C 1～4烷氧基、卤素；
R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基。
进一步地，
X选自NR 10；
R 10选自H、氘或C 1～4烷基；
Y选自NR 16；
R 16选自H、氘或C 1～4烷基；
R 1选自氢，取代或未取代的C 1～5烷基、C 1～4烷氧基，所述烷基取代基选自氘、卤素、羟基、羧基、氨基、巯基、酯基；
n选自0～5的整数；
R 11、R 11’选自氘、C 1～3烷基、甲氧基、卤素、硝基、氰基、羧基、羟基、氨基、巯基、酯基；
n 1、n 1’各自独立选自2～3的整数；
L 2选自取代或未取代的C 2～6亚烷基，所述亚烷基的取代基为甲基、甲氧基；
L 1选自C 3～14的亚烷基；其中，所述亚烷基主链中含有0～2个杂原子， 所述杂原子选自O、S、NR 22；
R 22选自氢、氘。
进一步地，所述化合物为如下化合物之一：
Figure PCTCN2021113091-appb-000023
Figure PCTCN2021113091-appb-000024
进一步地，所述化合物如式V所示：
Figure PCTCN2021113091-appb-000025
式中，
n选自0～5的整数；
R 1选自氢、卤素、取代或未取代的C 1～8烷基、C 1～8烷氧基、羟基、氨基、硝基、酯基、氰基、羧基、巯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基或酯基；
X选自O、S或NR 10；
R 10选自H、氘或C 1～8烷基、C 1～8烷氧基；
n 1、n 1’各自独立选自0～5的整数；
R 11、R 11’各自独立选自氘、C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基或酯基；
L 2选自氢、氘、取代或未取代的C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、酯基；所述烷基的取代基选自氘、卤素、氨基、硝基、氰基、羧基、羟基、巯基、酯基；
Y选自O、S或NR 16；
R 16选自H、氘或C 1～8烷基、C 1～8烷氧基；
L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素；
R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基；
优选地，
n选自0～4的整数；
R 1选自氢、卤素、取代或未取代的C 1～5烷基、C 1～4烷氧基、羟基、氨基、硝基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
X选自O、S或NR 10；
R 10选自H、氘或C 1～4烷基；
n 1、n 1’各自独立选自0～4的整数；
R 11、R 11’各自独立选自氘、C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
L 2选自氢、氘、取代或未取代的C 1～8烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；所述烷基的取代基选自氘、卤素、氨基、硝基、氰基、羧基、羟基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；
R 16分别独立选自氢、氘、C 1～8烷基、C 1～4烷氧基；
L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～4烷基、C 1～4烷氧基、卤素；
R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基。
进一步地，
X选自NR 10；
R 10选自H、氘或C 1～4烷基；
Y选自NR 16；
R 16选自H、氘或C 1～4烷基；
R 1选自氢，取代或未取代的C 1～5烷基、C 1～4烷氧基，所述烷基取代基选自氘、卤素、羟基、羧基、氨基、巯基、酯基；
n选自0～5的整数；
R 11、R 11’选自氘、C 1～3烷基、甲氧基、卤素；
n 1、n 1’各自独立选自2～5的整数；
L 2选自氢、氘、C 1～8的亚烷基；
L 1选自C 2～10的亚烷基；其中，所述亚烷基主链中含有0～2个杂原子，所述杂原子选自O、S、NR 22；
R 22选自氢、氘。
进一步地，所述化合物为如下化合物之一：
Figure PCTCN2021113091-appb-000026
Figure PCTCN2021113091-appb-000027
本发明还提供了一种化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，所述化合物的结构如式VI-A所示：
Figure PCTCN2021113091-appb-000028
其中，
X 1、Y 1分别独立选自CHR 4或O，且X 1、Y 1中有且只有1个为O；
R 4选自氢、卤素、C 1～C 3烷基；
R 3选自氢、卤素、C 1～C 3烷基；
m 1为0～3的整数；
m 2分别独立选自1～8的整数；
Z -为药学上可接受的阴离子；
R 1、R 2分别独立选自取代或未取代的C 1～3烷基；所述烷基的取代基选自
Figure PCTCN2021113091-appb-000029
Y选自NR 6；
R 6选自氢、C 1～3烷基；
R 5选自取代或未取代的苯基；所述苯基的取代基为C 1～3烷基；
或者，R 1和R 2连接形成取代或未取代的6元饱和杂环基；所述饱和杂环基的取代基选自
Figure PCTCN2021113091-appb-000030
所述杂环基的杂原子为1个，所述杂原子为N；
或者，所述化合物的结构如式VI-B所示：
Figure PCTCN2021113091-appb-000031
R 3、R 4分别独立选自氢、卤素、C 1～C 3烷基；
m 2分别独立选自1～8的整数；
Z -为药学上可接受的阴离子；
R 1、R 2分别独立选自取代或未取代的C 1～3烷基；所述烷基的取代基选自
Figure PCTCN2021113091-appb-000032
Y选自NR 6；
R 6选自氢、C 1～3烷基；
R 5选自取代或未取代的苯基；所述苯基的取代基为C 1～3烷基。
进一步地，所述化合物为如下化合物之一：
Figure PCTCN2021113091-appb-000033
本发明还提供了前述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物在制备麻醉药物中的用途；
优选地，所述麻醉药物为局部麻醉药物。
进一步地，所述局部麻醉药物使得感觉神经阻滞时间长于运动神经阻滞时间；
优选地，所述局部麻醉药物的感觉神经阻滞时间长于运动神经阻滞时间超过10小时。
进一步地，所述局部麻醉药物为长效局部麻醉和/或选择性局部麻药物；
优选地，所述局部麻醉药物的麻醉时间超过30小时。
本发明还提供了一种药物，它是以前述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物为活性成分，加上药物上可接受的辅料制备而成的制剂。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
卤素为氟、氯、溴或碘。
“烷基”是烷烃分子中少掉一个氢原子而成的烃基，例如甲基-CH 3、乙基-CH 3CH 2等。C 1～4烷基是指含有一个至四个碳原子的直链或支链的烃链。
“亚烷基”是指烷烃分子中少掉两个氢原子而成的烃基，例如亚甲基-CH 2-、亚乙基-CH 2CH 2-等。“C 1～4亚烷基”是指含有一个至四个碳原子的直链或支链的烃链。
“C 1～8烷氧基”是指含有一至八个碳原子的烷氧基。
“NR 10”的结构式为
Figure PCTCN2021113091-appb-000034
“NR 12R 13”的结构式为
Figure PCTCN2021113091-appb-000035
“OR 14”的结构式为
Figure PCTCN2021113091-appb-000036
“-OC(O)R 17”的结构式为
Figure PCTCN2021113091-appb-000037
“-C(O)SR 15”的结构式为
Figure PCTCN2021113091-appb-000038
“-C(O)R 20”的结构式为
Figure PCTCN2021113091-appb-000039
“-C(O)(CH 2) mR 21”的结构式为
Figure PCTCN2021113091-appb-000040
m为0～8的整数。
“取代或未取代的C 1～8烷基”是指C 1～8烷基可以是被取代的，也可以没有取代基的。
“L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子”是指含有一个至十六个碳原子的直链或支链的烃链；该烃链可以是取代的，也可以是未取代的；该烃链的主链上含有杂原子，杂原子为O、S或取代的N。
“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环)，但不能含有杂原子如氮，氧，或硫，同时连接母 体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的，即可以被0～4个氘、C1～4的烷基、C1～4的烷氧基、C1～4的烷硫基、卤素、硝基、氰基、羟基、羧基、氨基等取代基取代。
“3～8元不饱和环烷基”是指至少含有一个双键的由3～8个碳原子构成的环烷基；“3～8元不饱和杂环基”是指至少一个碳原子被杂原子替代的不饱和环烷基，所述杂原子为O、S或N。
术语“药学上可接受的盐”指本发明化合物与药学上可接受的无机酸和有机酸所形成的盐，适合与对象(例如，人)的组织接触，而不会产生不适度的副作用的盐。其中，优选的无机酸包括(但并不限于)：盐酸、氢溴酸、磷酸、硝酸、硫酸；优选的有机酸包括(但并不限于)：甲酸、乙酸、丙酸、丁二酸、萘二磺酸(1,5)、亚细亚酸、草酸、酒石酸、乳酸、水杨酸、苯甲酸、戊酸、二乙基乙酸、丙二酸、琥珀酸、富马酸、庚二酸、己二酸、马来酸、苹果酸、氨基磺酸、苯丙酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸、对甲苯磺酸、柠檬酸，以及氨基酸。
术语“溶剂合物”指本发明化合物与药学上可接受的溶剂形成溶剂合物，其中，所述药学上可接受的溶剂包括但并不限于水、乙醇、甲醇、异丙醇、丙二醇、四氢呋喃、二氯甲烷。
术语“立体异构体”指本发明化合物所涉及手性碳原子可以为R构型，也可以为S构型，或其组合。
本发明季铵盐类化合物用于局部麻醉时起效快，单次给药后麻醉时间长，并且感觉神经阻滞时间大于运动神经阻滞时间，兼具长效局部麻醉作用和选择性局部麻醉作用，显著降低了现有技术中局麻药物的副作用，具有更好的安全性。本发明季铵盐类化合物可用于制备安全的、具有长时间局部麻醉和选择性局部麻醉作用的药物，具有局部麻醉作用时间长、局部麻醉选择性好、神经损伤更小、安全性高的优点。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1、本发明化合物的制备
Figure PCTCN2021113091-appb-000041
化合物1a(10.0g,40.59mmol)溶于15mL的1,3-二溴丙烷，加热至70℃反应48h，TLC监测(DCM:MeOH＝10:1,v/v,R f＝0.3)。加入适量的石油醚，生成粘稠的糖浆状物质，倾出上层清液，剩余粗产品13.5g，使用25mL的甲醇溶解后与硅胶进行拌样，干法上样后硅胶柱柱层析纯化。洗脱剂：DCM:MeOH＝10:1，v/v，收集洗脱液，浓缩得粗产品9g。乙酸乙酯和二氯甲烷重结晶，制备得到8.8g类白色固体粉末(中间体1b)，产率58.9％，用于下一步反应。
将上述制备得到的中间体1b(1.00g，2.17mmol)，S-N-(2,6-二甲基苯基)-2-哌啶甲酰胺(0.505g,2.17mmol)溶于10mL的乙醇中，加入DIPEA(0.99g,0.78mL,4.74mmol)，升温至80℃，加热48h，蒸干溶剂，粗产品用硅胶柱柱层析纯化，洗脱剂：DCM:MeOH＝10:1，v/v，收集洗脱液，浓缩得530mg白色固体(1)。产率46.7％。 1H NMR(400MHz,CDCl 3)δ9.66(s,1H),8.02(dd,J＝43.2,15.2Hz,1H),7.18–6.93(m,6H),5.90(d,J＝35.2Hz,1H),4.10–3.72(m,2H),3.66–3.20(m,4H),3.00(ddd,J＝83.2,31.4,11.0Hz,2H),2.84–2.70(m,1H),2.33(dd,J＝18.8,14.2Hz,2H),2.10–2.01(m,13H),2.14–1.97(m,3H),1.88(s,3H),1.70(m,J＝25.2,12.5Hz,7H),1.47–1.30(m,4H),1.02–0.92(m,3H).
实施例2、本发明化合物的制备
Figure PCTCN2021113091-appb-000042
化合物2a(10.0g,40.59mmol)溶于15mL的1,5-二溴戊烷，加热至75℃反应36h，TLC监测(DCM:MeOH＝10:1,v/v,R f＝0.3)。加入适量的石油醚，生成粘稠的糖浆状物质，倾出上层清液，剩余粗产品14.5g，使用25mL的甲醇溶解后与硅胶进行拌样，干法上样后硅胶柱柱层析纯化。洗脱剂：DCM:MeOH＝10:1，v/v，收集洗脱液，浓缩得粗产品11g。乙酸乙酯和二氯甲烷重结晶，制备得到10.1g类白色固体粉末(中间体2b)，产率62.8％，用于下一步反应。
将上述制备得到的中间体2b(1.00g，2.52mmol)，S-N-(2,6-二甲基苯基)-2-哌啶甲酰胺(0.585g,2.28mmol)溶于10mL的乙醇中，加入DIPEA(0.99g,0.78mL,4.74mmol)，升温至80℃，加热48h，蒸干溶剂，粗产品用硅胶柱柱层析纯化，洗脱剂：DCM:MeOH＝10:1，v/v，收集洗脱液，浓缩得630mg白色固体(2)。产率45.6％。 1H NMR(400MHz,CDCl3)δ10.35 (s,1H),7.15–6.98(m,6H),5.03–4.83(m,2H),3.96(s,2H),3.82–3.63(m,2H),3.43(s,2H),3.16(t,J＝17.2Hz,1H),2.80(s,1H),2.40(s,1H),2.29–2.20(m,12H),2.11(s,5H),1.94–1.52(m,14H),1.46–1.28(m,5H).
实施例3、本发明化合物的制备
Figure PCTCN2021113091-appb-000043
化合物3a(10.0g,34.67mmol)溶于15mL的1,5-二溴戊烷，加热至75℃反应48h，TLC监测(DCM:MeOH＝10:1,v/v,R f＝0.3)。加入适量的石油醚，生成粘稠的糖浆状物质，倾出上层清液，剩余粗产品14g，使用25mL的甲醇溶解后与硅胶进行拌样，干法上样后硅胶柱柱层析纯化。洗脱剂：DCM:MeOH＝10:1，v/v，收集洗脱液，浓缩得粗产品9g。乙酸乙酯和二氯甲烷重结晶，制备得到8.6g类白色固体粉末(中间体3b)，产率56.7％，用于下一步反应。
将上述制备得到的中间体3b(1.00g，2.28mmol)，S-N-(2,6-二甲基苯基)-2-哌啶甲酰胺(0.530g,2.28mmol)溶于10mL的乙醇中，加入DIPEA(0.99g,0.78mL,4.74mmol)，升温至80℃，加热48h，蒸干溶剂，粗产品用硅胶柱柱层析纯化，洗脱剂：DCM:MeOH＝10:1，v/v，收集洗脱液，浓缩得550mg白色固体(3)。产率40.9％。 1H NMR(400MHz,CDCl 3)δ9.80(s,1H),8.04(dd,J＝43.2,15.2Hz,1H),7.14–6.97(m,6H),5.97(d,J＝35.2Hz,1H),4.15–3.76(m,2H),3.63–3.29(m,4H),3.09(ddd,J＝83.2,31.4,11.0Hz,2H),2.89–2.74(m,1H),2.41(dd,J＝18.8,14.2Hz,2H),2.35–2.20(m,13H),2.11–1.93(m,5H),1.87(s,3H),1.74(dd,J＝25.2,12.5Hz,9H),1.44–1.33(m,4H),1.06–0.97(m,3H).
实施例4、本发明化合物的制备
Figure PCTCN2021113091-appb-000044
化合物4a(4g，13.87mmol)溶于10mL的1,4-二溴丁烷，加热至90℃反应48h，TLC监测(DCM:MeOH＝10:1,v/v,R f＝0.3)。加入适量的石油醚，生成粘稠的糖浆状物质，倾出上层清液，剩余粗产品5g，使用25mL的二氯甲烷溶解后与硅胶进行拌样，干法上样后硅胶柱柱层析纯化。洗脱剂：DCM:MeOH＝20:1，v/v，收集洗脱液，浓缩得粗产品3.5g。乙酸乙酯和二氯甲烷重结晶，制备得到3.3g类白色固体粉末(中间体4b)，产率47.1％，用于下一步反应。
将上述制备得到的中间体4b(950mg，1.88mmol)，S-N-(2,6-二甲基苯 基)-2-哌啶甲酰胺(464mg，2.00mmol)溶于30mL的乙醇中，加入碳酸氢钠(335mg，3.99mmol)，升温至80℃，加热48h，蒸干溶剂，粗产品用硅胶柱柱层析纯化，洗脱剂：DCM:MeOH＝20:1，v/v，收集洗脱液，浓缩得448mg类白色固体(4)。产率36.4％。 1H NMR(400MHz,D 2O)δ7.24–7.05(m,6H),4.39(dd,J＝11.4,6.2Hz,1H),4.17(dd,J＝24.9,12.6Hz,1H),3.95–3.57(m,4H),3.54–3.42(m,2H),3.39–3.22(m,2H),3.21–3.02(m,2H),2.40(d,J＝9.3Hz,2H),2.28(s,1H),2.10(d,J＝9.5Hz,12H),1.90(d,J＝34.5Hz,11H),1.75–1.61(m,4H),1.38–1.24(m,2H),0.90(dd,J＝16.1,8.3Hz,3H).
实施例5、本发明化合物的制备
Figure PCTCN2021113091-appb-000045
化合物5a(10g，36.44mmol)溶于25mL的1,4-二溴丁烷，加热至90℃反应48h，TLC监测(DCM:MeOH＝10:1,v/v,R f＝0.3)。加入适量的石油醚，生成粘稠的糖浆状物质，倾出上层清液，剩余粗产品11g，使用30mL的二氯甲烷溶解后与硅胶进行拌样，干法上样后硅胶柱柱层析纯化。洗脱剂：DCM:MeOH＝20:1，v/v，收集洗脱液，浓缩得粗产品9.5g。乙酸乙酯和二氯甲烷重结晶，制备得到8.8g类白色固体粉末(中间体5b)，产率49.2％，用于下一步反应。
将上述制备得到的中间体5b(1.00g，2.04mmol)，S-N-(2,6-二甲基苯基)-2-哌啶甲酰胺(379mg，1.63mmol)溶于30mL的N，N-二甲基甲酰胺中，加入碳酸氢钠(343mg，4.08mmol)，升温至80℃，加热48h，减压浓缩溶剂，加入适量二氯甲烷，用水洗3次，有机层用无水硫酸钠干燥，过滤，溶剂减压浓缩。粗产品用硅胶柱柱层析纯化，洗脱剂：DCM:MeOH＝20:1，v/v，收集洗脱液，浓缩得520mg类白色固体(5)。产率39.6％。 1H NMR(400MHz,D 2O)δ7.23–7.03(m,6H),4.41(dd,J＝11.4,6.2Hz,1H),4.20(dd,J＝24.9,12.6Hz,1H),3.97–3.54(m,4H),3.54–3.42(m,2H),3.37–3.22(m,2H),3.20–3.02(m,2H),2.44(d,J＝9.3Hz,2H),2.27(s,1H),2.11(d,J＝9.5Hz,12H),1.88(d,J＝34.5Hz,9H),1.75–1.60(m,4H),1.35–1.25(m,2H),0.88(dd,J＝16.1,8.3Hz,3H).
实施例6、本发明化合物的制备
Figure PCTCN2021113091-appb-000046
化合物6a(8.0g,32.47mmol)溶于15mL的1,4-二溴丁烷，加热至80℃反应30h，TLC监测(DCM:MeOH＝10:1,v/v,R f＝0.3)。加入适量的石油醚，生成粘稠的糖浆状物质，倾出上层清液，剩余粗产品11.1g，使用25mL 的二氯甲烷溶解后与硅胶进行拌样，干法上样后硅胶柱柱层析纯化。洗脱剂：DCM:MeOH＝20:1，v/v，收集洗脱液，浓缩得粗产品10g。乙酸乙酯和二氯甲烷重结晶，制备得到9.5g类白色固体粉末(中间体6b)，产率63.3％，用于下一步反应。
将上述制备得到的中间体6b(1.50g，3.24mmol)，N-去甲利多卡因(602mg,2.92mmol)溶于10mL的N，N-二甲基甲酰胺中，加入碳酸氢钠(545mg,6.49mmol)，升温至80℃，加热36h，减压浓缩溶剂，加入适量二氯甲烷，用水洗3次，有机层用无水硫酸钠干燥，过滤，溶剂减压浓缩。粗产品用硅胶柱柱层析纯化，洗脱剂：DCM:MeOH＝10:1，v/v，收集洗脱液，浓缩得715mg白色固体(6)。产率41.6％。 1H NMR(400MHz,D 2O)δ7.20–7.04(m,6H),4.37(s,2H),4.29(s,2H),3.65(d,J＝12.4Hz,4H),3.53–3.43(m,2H),3.33(dd,J＝13.5,6.4Hz,4H),2.09(d,J＝7.6Hz,12H),1.95–1.79(m,8H),1.72–1.60(m,2H),1.30(t,J＝7.1Hz,3H).
实施例7、本发明化合物的制备
Figure PCTCN2021113091-appb-000047
化合物7a(10g，36.44mmol)溶于25mL的2,2’-二溴二乙醚，加热至100℃反应24h，TLC监测(DCM:MeOH＝10:1,v/v,R f＝0.3)。加入适量的乙醚，生成粘稠的糖浆状物质，倾出上层清液，剩余粗产品12g，使用30mL的二氯甲烷溶解后与硅胶进行拌样，干法上样后硅胶柱柱层析纯化。洗脱剂：DCM:MeOH＝20:1，v/v，收集洗脱液，浓缩得粗产品10.0g。乙酸乙酯和二氯甲烷重结晶，制备得到8.8g类白色固体粉末(中间体7b)，产率48.9％，用于下一步反应。
将上述制备得到的中间体7b(1.00g，1.92mmol)，S-N-(2,6-二甲基苯基)-2-哌啶甲酰胺(402mg，1.73mmol)溶于30mL的N，N-二甲基甲酰胺中，加入碳酸钾(531mg，3.84mmol)，升温至80℃，加热48h，减压浓缩溶剂，加入适量二氯甲烷，用水洗3次，有机层用无水硫酸钠干燥，过滤，溶剂减压浓缩。粗产品用硅胶柱柱层析纯化，洗脱剂：DCM:MeOH＝20:1，v/v，收集洗脱液，浓缩得520mg类白色固体(7)。产率39.6％。 1H NMR(400MHz,D 2O)δ7.23–6.93(m,6H),4.58(s,1H),4.23(d,J＝11.0Hz,1H),4.10(d,J＝9.2Hz,1H),3.97–3.76(m,6H),3.60(t,J＝7.6Hz,2H),3.40(d,J＝15.6Hz,3H),3.11(t,J＝10.9Hz,1H),2.38(d,J＝10.9Hz,2H),2.19(d,J＝7.9Hz,2H),2.11–1.81(m,18H),1.79–1.61(m,5H),1.40–1.24(m,2H),0.90(t,J＝7.0Hz,3H).
实施例8、本发明化合物的制备
Figure PCTCN2021113091-appb-000048
将8a(1g，3.27mmol)溶解于N，N-二甲基甲酰胺中，滴加25％氨水(0.91mL，9.80mmol)，加入碳酸钾(903mg，6.53mmol)，60℃反应3h。蒸干溶剂，粗产品用硅胶柱柱层析纯化，洗脱剂：DCM:MeOH＝20:1，v/v，收集洗脱液，浓缩得436mg白色固体(中间体8b)。产率55.1％。
将上述实施例6制备得到的中间体6b(800mg，1.73mmol)，中间体8b(466mg，1.92mmol)溶于10mL的N，N-二甲基甲酰胺中，加入碳酸钾(545mg,3.95mmol)，升温至80℃，加热24h，减压浓缩溶剂，加入适量二氯甲烷，用水洗3次，有机层用无水硫酸钠干燥，过滤，溶剂减压浓缩。粗产品用硅胶柱柱层析纯化，洗脱剂：DCM:MeOH＝10:1，v/v，收集洗脱液，浓缩得400mg白色固体(8)。产率37.0％。 1H NMR(400MHz,D 2O)δ7.37(dd,J＝2.1,0.8Hz,1H),7.17–7.04(m,3H),4.43–4.31(m,2H),4.25(q,J＝6.8Hz,1H),3.67(dd,J＝15.1,4.2Hz,7H),3.53–3.43(m,2H),3.18(dt,J＝12.2,7.5Hz,1H),3.04(dt,J＝12.2,7.6Hz,1H),2.07(s,6H),1.97(s,3H),1.94–1.84(m,6H),1.81–1.73(m,2H),1.71–1.57(m,5H).
实施例9、本发明化合物的制备
Figure PCTCN2021113091-appb-000049
将9a(5.0g，21.07mmol)溶解于N，N-二甲基甲酰胺中，滴加2-溴乙醇(1.64mL，23.18mmol)，加入碳酸钾(5.83g，42.15mmol)，60℃反应24h。蒸干溶剂，粗产品用硅胶柱柱层析纯化，洗脱剂：PE:EA＝10:1，v/v，收集洗脱液，浓缩得7.0g白色固体(中间体9b)。产率96.5％。
将上述制备得到的中间体9b(5.0g，14.53mmol)溶解于N，N-二甲基甲酰胺中，滴加乙胺(0.889mL，15.98mmol)，加入碳酸钾(4.02g，29.05mmol)，50℃反应24h。减压浓缩溶剂，加入适量二氯甲烷，用水洗3次，有机层用无水硫酸钠干燥，过滤，溶剂减压浓缩。粗产品用硅胶柱柱层析纯化，洗脱剂：DCM:MeOH＝20:1，v/v，收集洗脱液，浓缩得4.2g无色油状物(中间体9c)。产率93.8％。
将上述实施例4制备得到的中间体4b(1.8g，3.57mmol)，中间体9c(1.0g，3.24mmol)溶于10mL的N，N-二甲基甲酰胺中，加入碳酸钾(896mg,6.49mmol)，升温至80℃，加热24h，减压浓缩溶剂，加入适量二氯甲烷，用水洗3次，有机层用无水硫酸钠干燥，过滤，溶剂减压浓缩。粗产品用硅胶柱柱层析纯化，洗脱剂：DCM:MeOH＝10:1，v/v，收集洗脱液，浓 缩得818mg白色固体(9)。产率39.9％。 1H NMR(400MHz,D 2O)δ10.06(s,1H),7.96(d,J＝8.2Hz,2H),7.30–7.02(m,5H),4.38(s,2H),3.64(s,6H),3.45(s,2H),3.35(dd,J＝12.0,6.3Hz,4H),2.16(dd,J＝13.6,5.1Hz,6H),1.97–1.61(m,10H),1.31(dt,J＝17.9,9.1Hz,3H).
实施例10、本发明化合物的制备
Figure PCTCN2021113091-appb-000050
将实施例2产物200mg溶解于二氯甲烷10mL，冰浴下滴加等物质的量浓度的氢溴酸溶液，减压浓缩至干。真空干燥，得到白色固体(10)。
实施例11、本发明化合物的制备
Figure PCTCN2021113091-appb-000051
将实施例4产物200mg溶解于二氯甲烷10mL，冰浴下滴加等物质的量浓度0.1mol/L的盐酸-甲醇溶液，减压浓缩至干。真空干燥，得到白色固体(11)。
实施例12、本发明化合物的制备
Figure PCTCN2021113091-appb-000052
将实施例7产物200mg溶解于二氯甲烷10mL，加入1eq的对甲苯磺酸，减压浓缩至干。真空干燥，得到白色固体(12)。
实施例13、本发明化合物的制备
Figure PCTCN2021113091-appb-000053
将实施例8产物200mg溶解于二氯甲烷10mL，加入1eq的对甲苯磺酸，减压浓缩至干。真空干燥，得到白色固体(13)。
按照上述实施例的方法，得到以下实施例化合物：
Figure PCTCN2021113091-appb-000054
Figure PCTCN2021113091-appb-000055
Figure PCTCN2021113091-appb-000056
Figure PCTCN2021113091-appb-000057
Figure PCTCN2021113091-appb-000058
Figure PCTCN2021113091-appb-000059
Figure PCTCN2021113091-appb-000060
Figure PCTCN2021113091-appb-000061
Figure PCTCN2021113091-appb-000062
Figure PCTCN2021113091-appb-000063
Figure PCTCN2021113091-appb-000064
以下利用实验例的方式来说明本发明化合物的有益效果
实验例1、本发明化合物局部麻醉效果的研究
选取实施例化合物，利多卡因阳性对照组、左布比卡因阳性对照组分别给予完全适应实验环境的受试大鼠，每组8只。
给药剂量为：利多卡因组浓度为2％水溶液，左布比卡因组浓度为0.75％水溶液，待测药物浓度均为20mmol/mL的水溶液。
每只大鼠给药或对照的注射体积为0.5ml，通过神经定位器导向定位，注射于大鼠坐骨神经附近。通过von Frey刺激仪，刺激大鼠注射药物体侧足底，观测局部麻醉效果。同时，由后肢蹬踏试验(Postural Extensor Thrust，PET)评价大鼠运动功能情况：垂直提起大鼠并使注射侧后肢蹬在电子天平台面上，此时大鼠后肢肌力由肢体蹬踏天平而显示出的数值表示。肢体完全麻痹时，读数为肢体自身重量，约20g。测量值超过基线与肢体重量差值的 一半视为运动功能恢复，小于或等于该值视为运动功能丧失。
表1本发明化合物的坐骨神经局部麻醉效果
Figure PCTCN2021113091-appb-000065
Figure PCTCN2021113091-appb-000066
Figure PCTCN2021113091-appb-000067
Figure PCTCN2021113091-appb-000068
实验结果表明，该类药物在坐骨神经阻滞模型中能够产生大于30小时的局部麻醉作用，同时感觉神经阻滞时间显著大于运动神经阻滞时间，且相差时间大于10小时。
实验例2、本发明化合物局部麻醉效果的研究
250～300克体重的大鼠背部剃毛消毒后，在裸露的背部一侧画出直径约1.5厘米圆形，并将圆形进行6等分。在中心的皮肤处皮下注射含有本发明实施例化合物或利多卡因或左布比卡因的溶液0.5mL(以水为溶剂，左布比卡因浓度为23mmol/L，本发明化合物浓度为6mmol/L，利多卡因浓度为2％)。将Von Frey纤维丝中100克力度的纤维丝与针头绑定进行皮肤局部刺激。药物注射5min后，使用上述方法在6个划分范围内进行刺激，若在同一等分范围内的连续3次刺激均未出现背部皮肤收缩行为，视为药效效应阳性，若出现背部皮肤收缩则视为局部麻醉效应消失。6个等分范围中有3个或3个以上区域显示局部麻醉阳性，则视为药物的局部麻醉有效，6个等分范围中少于3个区域显示阳性，视为局部麻醉失效。每种化合物使用10只大鼠进行实验。
表2本发明化合物的皮下浸润局部麻醉效果
Figure PCTCN2021113091-appb-000069
Figure PCTCN2021113091-appb-000070
实验结果表明，该类药物在大鼠皮下浸润模型中能够产生大于30小时的局部麻醉作用。
实验例3、本发明化合对神经病理损伤的研究
选取实施例1-13、201-207化合物，利多卡因阳性对照、左布比卡因阳性对照组分别给予完全适应实验环境的受试大鼠，每组8只。
给药剂量为：利多浓度为2％水溶液，左布比卡因组浓度为0.75％水溶液，待测药物浓度均为20mmol/L的水溶液。每只大鼠给药或对照的注射体积为0.5mL，注射于大鼠坐骨神经附近。在坐骨神经注射后第7天和第14天，将实验大鼠异氟醚麻醉下心脏注射布比卡因安乐死。取注射部位坐骨神经约1.5cm，存于10％甲醛溶液中48h，HE染色并切成5μm厚度的切片。
给药剂量为：利多卡因组浓度为2％水溶液，左布比卡因组浓度为0.75％水溶液，待测药物浓度均为6mmol/L的水溶液。每只大鼠给药或对照的注射体积为0.5ml，注射于大鼠背部皮下。在皮下注射后第7天和第14天，将实验大鼠异氟醚麻醉下心脏注射布比卡因安乐死。取注射部位皮肤组织，保存于10％甲醛溶液中48h，HE染色并切成5μm厚度的切片。
神经病理损伤评估显示：实施例1-13、201-207化合物与利多卡因阳性对照组、左布比卡因阳性对照组相比，在神经损伤、血管增生、脱髓鞘程度、肌肉炎症、结缔组织炎症程度方面都没有显著差异，具有良好的安全性。
综上，本发明季铵盐类化合物用于局部麻醉时起效快，单次给药后麻醉时间长，并且感觉神经阻滞时间大于运动神经阻滞时间，兼具长效局部麻醉作用和选择性局部麻醉作用，显著降低了现有技术中局麻药物的副作用，具有更好的安全性。本发明季铵盐类化合物可用于制备安全的、具有长时间局部麻醉和选择性局部麻醉作用的药物，具有局部麻醉作用时间长、局部麻醉选择性好、神经损伤更小、安全性高的优点。

Claims (26)

  1. 式I所示的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物：
    Figure PCTCN2021113091-appb-100001
    式中，
    Z -为药学上可接受的阴离子；
    n选自0～8的整数；
    R 1选自氢、卤素、取代或未取代的C 1～8烷基、C 1～8烷氧基、羟基、氨基、硝基、酯基、氰基、羧基、巯基或
    Figure PCTCN2021113091-appb-100002
    其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基或酯基；
    R 2选自H、取代或未取代的C 1～8烷基、C 1～8烷氧基或
    Figure PCTCN2021113091-appb-100003
    其中，所述烷基的取代基选自氘、C 1～8烷氧基、卤素、羟基、羧基、氨基、氰基、巯基、酯基或
    Figure PCTCN2021113091-appb-100004
    R 4选自n 1个R 11取代的芳基；
    X选自O、S或NR 10；
    R 10选自H、氘、C 1～8烷基或C 1～8烷氧基；
    n 1选自0～5的整数；
    R 11选自氘、C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基或酯基；
    R 3选自-NR 12R 13或-OR 14；
    R 12、R 13分别独立选自氢、氘、取代或未取代的C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、酯基；所述烷基的取代基选自氘、卤素、氨基、硝基、氰基、羧基、羟基、巯基、酯基、
    Figure PCTCN2021113091-appb-100005
    Figure PCTCN2021113091-appb-100006
    -OC(O)R 17、-C(O)SR 15；
    Y选自O、S或NR 16；
    R 15、R 16分别独立选自氢、氘、C 1～8烷基、C 1～8烷氧基、卤素、取代或未取代的3～8元不饱和杂环基、取代或未取代的3～8元不饱和环烷基；所述不饱和杂环基的取代基选自C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、酯基；所述不饱和环烷基的取代基选自C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、巯基、酯基、氨基；所述杂环基的杂原子为1～3个，所述杂原子为N、O或S；
    R 17选自取代或未取代的3～8元不饱和环烷基；所述不饱和环烷基的取代基选自C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、巯基、酯基、氨基、-NR 18R 19；
    R 18、R 19分别独立选自氢、C 1～8烷基；
    或者，R 12和R 13连接形成取代或未取代的3～11元饱和杂环基；所述饱和杂环基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、巯基、酯基、氨基、
    Figure PCTCN2021113091-appb-100007
    所述杂环基的杂原子为1～3个，所述杂原子为N、O或S；
    R 14选自-C(O)R 20、取代或未取代的3～8元不饱和环烷基；所述不饱和环烷基的取代基为-C(O)(CH 2) mR 21；
    R 20选自取代或未取代的3～8元不饱和环烷基；所述不饱和环烷基的取代基为C 1～8烷氧基、-NR 18R 19；
    m选自0～8的整数；
    R 21选自3～8元饱和杂环基；所述杂环基的杂原子为1～3个，所述杂原子为N、O或S；
    L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素；
    L 11选自取代或未取代的C 1～7亚烷基，其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自S、NR 22；所述亚烷基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素；
    R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基。
  2. 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    R 4选自
    Figure PCTCN2021113091-appb-100008
    n 1选自0～5的整数；
    R 11选自氘、C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基或酯基。
  3. 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述R 3选自取代或未取代的如下基团：
    Figure PCTCN2021113091-appb-100009
    Figure PCTCN2021113091-appb-100010
    其中，所述取代基包括取代或未取代的C 1～8烷基、C 1～4烷氧基，以及进一步的取代基氘、卤素、硝基、氰基、羟基、羧基、氨基、巯基、酯基。
  4. 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    Z -为药学上可接受的阴离子；
    n选自0～4的整数；
    R 1选自氢、卤素、取代或未取代的C 1～5烷基、C 1～4烷氧基、羟基、氨基、硝基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基或
    Figure PCTCN2021113091-appb-100011
    其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
    R 2选自氢、取代或未取代的C 1～8烷基、C 1～4烷氧基或
    Figure PCTCN2021113091-appb-100012
    其中，所述烷基的取代基选自氘、C 1～4烷氧基、卤素、羟基、羧基、氨基、 氰基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；
    X选自O、S或NR 10；
    R 10选自H、氘、C 1～4烷基或C 1～4烷氧基；
    n 1选自0～4的整数；
    R 11选自氘、C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
    R 3选自-NR 12R 13或-OR 14；
    R 12、R 13分别独立选自氢、氘、取代或未取代C 1～8烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；所述烷基的取代基选自氘、卤素、氨基、硝基、氰基、羧基、羟基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基、-C(O)NR 15R 16、
    Figure PCTCN2021113091-appb-100013
    -OC(O)R 17、-C(O)SR 15；
    R 15、R 16分别独立选自氢、氘、C 1～8烷基、C 1～4烷氧基、卤素、取代或未取代的噻吩基、取代或未取代的苯基；所述噻吩基的取代基选自C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；所述苯基的取代基选自C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基、氨基；
    R 17选自取代或未取代的苯基；所述苯基的取代基选自C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基、-NR 18R 19；
    R 18、R 19分别独立选自氢、C 1～4烷基；
    或者，R 12和R 13连接形成取代或未取代的3～8元饱和杂环基；所述饱和杂环基的取代基选自C 1～8烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、巯基、酯基、氨基、-C(O)NR 15R 16；所述饱和杂环基的杂原子个数为1；
    R 14选自-C(O)R 20、苯基；所述苯基的取代基为-C(O)(CH 2) mR 21；
    R 20选自取代或未取代的苯基；所述苯基的取代基为C 1～4烷氧基、-NR 18R 19；
    m选自0～3的整数；
    R 21选自哌啶基；
    L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～4 烷基、C 1～4烷氧基、卤素；
    L 11选自取代或未取代的C 1～6亚烷基，其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自S、NR 22；所述亚烷基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素；
    R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基。
  5. 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述药学上可接受的阴离子Z -为卤素阴离子、硫酸根、醋酸根、酒石酸根、对甲苯磺酸根、甲磺酸根、枸橼酸根；
    优选地，所述药学上可接受的阴离子Z -为卤素阴离子；
    更优选地，所述药学上可接受的阴离子Z -为Br -或I -。
  6. 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述盐为药学上可接受的盐；
    优选地，所述药学上可接受的盐是指由式I所示化合物与药学上可接受的无机酸或有机酸形成；
    更优选地，所述无机酸或有机酸为盐酸、氢溴酸、乙酸、硫酸、甲磺酸、对甲苯磺酸、琥珀酸、碳酸、酒石酸、月桂酸、马来酸、枸橼酸或苯甲酸。
  7. 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物如式Ⅱ所示：
    Figure PCTCN2021113091-appb-100014
    式中，
    n选自0～4的整数；
    R 1选自氢、卤素、取代或未取代的C 1～8烷基、C 1～8烷氧基、羟基、氨基、硝基、酯基、氰基、羧基、巯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基或酯基；
    R 2选自H、取代或未取代的C 1～8烷基、C 1～8烷氧基；其中，所述烷基取代基选自氘、C 1～8烷氧基、卤素、羟基、羧基、氨基、氰基、巯基、酯基；
    X选自O、S或NR 10；
    R 10选自氢、氘、C 1～8烷基或C 1～8烷氧基；
    n 1、n 1’各自独立选自0～5的整数；
    R 11、R 11’各自独立选自氘、C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基或酯基；
    L 2选自取代或未取代的C 1～8的亚烷基，所述亚烷基的取代基为氘、C 1～4烷基、C 1～4烷氧基、卤素；
    Y选自O、S或NR 16；
    R 16选自氢、氘、C 1～8烷基、C 1～8烷氧基；
    L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素；
    R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基。
  8. 根据权利要求7所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    n选自0～4的整数；
    R 1选自氢、卤素、取代或未取代的C 1～8烷基、C 1～8烷氧基、羟基、氨基、硝基、酯基、氰基、羧基、巯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基或酯基；
    R 2选自H、取代或未取代的C 1～8烷基、C 1～8烷氧基；其中，所述烷基取代基选自氘、C 1～8烷氧基、卤素、羟基、羧基、氨基、氰基、巯基、酯基；
    X选自O、S或NR 10；
    R 10选自H、氘或C 1～4烷基；
    n 1、n 1’各自独立选自0～4的整数；
    R 11、R 11’各自独立选自氘、C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
    L 2选自取代或未取代的C 1～8的亚烷基，所述亚烷基的取代基为氘、C 1～4烷基、C 1～4烷氧基；
    Y选自O、S或NR 16；
    R 16选自氢、氘、C 1～8烷基、C 1～4烷氧基；
    L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～4烷基、C 1～4烷氧基、卤素；
    R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基。
  9. 根据权利要求8所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    X选自NR 10；
    R 10选自H、氘或C 1～4的烷基；
    Y选自NR 16；
    R 16选自H、氘或C 1～4的烷基；
    R 1选自氢、卤素，取代或未取代的C 1～5烷基、C 1～4烷氧基，所述烷基取代基选自氘、卤素、羟基、羧基、氨基、巯基、酯基；
    n选自0～4的整数；
    R 11、R 11’选自氘、C 1～3烷基、甲氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基或酯基；
    n 1、n 1’各自独立选自2～3的整数；
    L 2选自取代或未取代的C 2～6的亚烷基，所述取代基为甲基、甲氧基；
    L 1选自C 3～14的亚烷基；其中，所述亚烷基主链中含有0～2个杂原子，所述杂原子选自O、S、NR 22；
    R 22选自氢、氘。
  10. 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物为如下化合物之一：
    Figure PCTCN2021113091-appb-100015
    Figure PCTCN2021113091-appb-100016
  11. 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物为如下化合物之一：
    Figure PCTCN2021113091-appb-100017
    Figure PCTCN2021113091-appb-100018
  12. 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物如式Ⅲ所示：
    Figure PCTCN2021113091-appb-100019
    式中，
    n选自0～4的整数；
    R 1选自氢、卤素、取代或未取代的C 1～8烷基、C 1～8烷氧基、羟基、氨基、 硝基、酯基、氰基、羧基、巯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基或酯基；
    R 2选自H、取代或未取代的C 1～8烷基、C 1～8烷氧基；其中，所述烷基的取代基选自氘、C 1～8烷氧基、卤素、羟基、羧基、氨基、氰基、巯基、酯基；
    X选自O、S或NR 10；
    R 10选自H、氘、C 1～8烷基或C 1～8烷氧基；
    n 1、n 1’各自独立选自0～5的整数；
    R 11、R 11’各自独立选自氘、C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基或酯基；
    L 2选自氢、氘、取代或未取代的C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、酯基；所述烷基的取代基选自氘、卤素、氨基、硝基、氰基、羧基、羟基、巯基、酯基；
    Y选自O、S或NR 16；
    R 16选自H、氘、C 1～8烷基或C 1～8烷氧基；
    L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素；
    R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基；
    优选地，
    n选自0～4的整数；
    R 1选自氢、卤素、取代或未取代的C 1～5烷基、C 1～4烷氧基、羟基、氨基、硝基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
    R 2选自H、取代或未取代的C 1～8烷基、C 1～4烷氧基；其中，所述烷基的取代基选自氘、C 1～4烷氧基、卤素、羟基、羧基、氨基、氰基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；
    X选自O、S或NR 10；
    R 10选自H、氘或C 1～4烷基；
    n 1、n 1’各自独立选自0～4的整数；
    R 11、R 11’各自独立选自氘、C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
    L 2选自氢、氘、取代或未取代的C 1～8烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；所述烷基的取代基选自氘、卤素、氨基、硝基、氰基、羧基、羟基、巯基、 甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；
    R 16选自氢、氘、C 1～8烷基、C 1～4烷氧基；
    L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～4烷基、C 1～4烷氧基、卤素；
    R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基。
  13. 根据权利要求12所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    X选自NR 10；
    R 10选自H、氘或C 1～4烷基；
    Y选自NR 16；
    R 16选自H、氘或C 1～4烷基；
    R 1选自氢，取代或未取代的C 1～5烷基、C 1～4烷氧基，所述烷基取代基选自氘、卤素、羟基、羧基、氨基、巯基、酯基；
    n选自0～4的整数；
    R 11、R 11’选自氘、C 1烷基、甲氧基、卤素；
    n 1、n 1’各自独立选自2～5的整数；
    L 2选自氢、氘、C 1～8的亚烷基；
    L 1选自C 2～10的亚烷基；其中，所述亚烷基主链中含有0～2个杂原子，所述杂原子选自O、S、NR 22；
    R 22选自氢、氘。
  14. 据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物为如下化合物之一：
    Figure PCTCN2021113091-appb-100020
    Figure PCTCN2021113091-appb-100021
  15. 据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物如式Ⅳ所示：
    Figure PCTCN2021113091-appb-100022
    式中，
    n选自0～5的整数；
    R 1选自氢、卤素、取代或未取代的C 1～8烷基、C 1～8烷氧基、羟基、氨基、硝基、酯基、氰基、羧基、巯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基或酯基；
    X选自O、S或NR 10；
    R 10选自H、氘或C 1～8烷基、C 1～8烷氧基；
    n 1、n 1’各自独立选自0～5的整数；
    R 11、R 11’各自独立选自氘、C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基或酯基；
    L 2选自取代或未取代的C 1～8亚烷基，所述亚烷基的取代基为氘、C 1～4烷基、C 1～4烷氧基、卤素；
    Y选自O、S或NR 16；
    R 16选自氢、氘、C 1～8烷基、C 1～8烷氧基；
    L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素；
    R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基；
    优选地，
    n选自0～4的整数；
    R 1选自氢、卤素、取代或未取代的C 1～5烷基、C 1～4烷氧基、羟基、氨基、硝基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
    X选自O、S或NR 10；
    R 10选自H、氘或C 1～4烷基；
    n 1、n 1’各自独立选自0～4的整数；
    R 11、R 11’各自独立选自氘、C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
    L 2选自取代或未取代的C 1～8的亚烷基，所述亚烷基的取代基为氘、C 1～4烷基、C 1～4烷氧基、卤素；
    R 16选自氢、氘、C 1～8烷基、C 1～4烷氧基；
    L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～4烷基、C 1～4烷氧基、卤素；
    R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基。
  16. 据权利要求15所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    X选自NR 10；
    R 10选自H、氘或C 1～4烷基；
    Y选自NR 16；
    R 16选自H、氘或C 1～4烷基；
    R 1选自氢，取代或未取代的C 1～5烷基、C 1～4烷氧基，所述烷基取代基选自氘、卤素、羟基、羧基、氨基、巯基、酯基；
    n选自0～5的整数；
    R 11、R 11’选自氘、C 1～3烷基、甲氧基、卤素、硝基、氰基、羧基、羟基、氨基、巯基、酯基；
    n 1、n 1’各自独立选自2～3的整数；
    L 2选自取代或未取代的C 2～6亚烷基，所述亚烷基的取代基为甲基、甲氧基；
    L 1选自C 3～14的亚烷基；其中，所述亚烷基主链中含有0～2个杂原子，所述杂原子选自O、S、NR 22；
    R 22选自氢、氘。
  17. 据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物为如下化合物之一：
    Figure PCTCN2021113091-appb-100023
    Figure PCTCN2021113091-appb-100024
  18. 据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物如式V所示：
    Figure PCTCN2021113091-appb-100025
    式中，
    n选自0～5的整数；
    R 1选自氢、卤素、取代或未取代的C 1～8烷基、C 1～8烷氧基、羟基、氨基、硝基、酯基、氰基、羧基、巯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基或酯基；
    X选自O、S或NR 10；
    R 10选自H、氘或C 1～8烷基、C 1～8烷氧基；
    n 1、n 1’各自独立选自0～5的整数；
    R 11、R 11’各自独立选自氘、C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基或酯基；
    L 2选自氢、氘、取代或未取代的C 1～8烷基、C 1～8烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、酯基；所述烷基的取代基选自氘、卤素、氨基、硝基、氰基、羧基、羟基、巯基、酯基；
    Y选自O、S或NR 16；
    R 16选自H、氘或C 1～8烷基、C 1～8烷氧基；
    L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～8烷基、C 1～8烷氧基、卤素；
    R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基；
    优选地，
    n选自0～4的整数；
    R 1选自氢、卤素、取代或未取代的C 1～5烷基、C 1～4烷氧基、羟基、氨基、硝基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；其中，所述烷基的取代基选自氘、卤素、羟基、羧基、氨基、硝基、氰基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
    X选自O、S或NR 10；
    R 10选自H、氘或C 1～4烷基；
    n 1、n 1’各自独立选自0～4的整数；
    R 11、R 11’各自独立选自氘、C 1～4烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基或乙酸乙酯基；
    L 2选自氢、氘、取代或未取代的C 1～8烷基、C 1～4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；所述烷基的取代基选自氘、卤素、氨基、硝基、氰基、羧基、羟基、巯基、甲酸甲酯基、甲酸乙酯基、乙酸乙酯基；
    R 16分别独立选自氢、氘、C 1～8烷基、C 1～4烷氧基；
    L 1选自取代或未取代的C 1～16亚烷基；其中，所述亚烷基主链中含有0～4个杂原子，所述杂原子选自O、S、NR 22；所述亚烷基的取代基选自氘、C 1～4烷基、C 1～4烷氧基、卤素；
    R 22选自氢、氘、C 1～4烷基、C 1～4烷氧基。
  19. 据权利要求18所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    X选自NR 10；
    R 10选自H、氘或C 1～4烷基；
    Y选自NR 16；
    R 16选自H、氘或C 1～4烷基；
    R 1选自氢，取代或未取代的C 1～5烷基、C 1～4烷氧基，所述烷基取代基选自氘、卤素、羟基、羧基、氨基、巯基、酯基；
    n选自0～5的整数；
    R 11、R 11’选自氘、C 1～3烷基、甲氧基、卤素；
    n 1、n 1’各自独立选自2～5的整数；
    L 2选自氢、氘、C 1～8的亚烷基；
    L 1选自C 2～10的亚烷基；其中，所述亚烷基主链中含有0～2个杂原子，所述杂原子选自O、S、NR 22；
    R 22选自氢、氘。
  20. 据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物为如下化合物之一：
    Figure PCTCN2021113091-appb-100026
    Figure PCTCN2021113091-appb-100027
  21. 一种化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物的结构如式VI-A所示：
    Figure PCTCN2021113091-appb-100028
    其中，
    X 1、Y 1分别独立选自CHR 4或O，且X 1、Y 1中有且只有1个为O；
    R 4选自氢、卤素、C 1～C 3烷基；
    R 3选自氢、卤素、C 1～C 3烷基；
    m 1为0～3的整数；
    m 2分别独立选自1～8的整数；
    Z -为药学上可接受的阴离子；
    R 1、R 2分别独立选自取代或未取代的C 1～3烷基；所述烷基的取代基选自
    Figure PCTCN2021113091-appb-100029
    Y选自NR 6；
    R 6选自氢、C 1～3烷基；
    R 5选自取代或未取代的苯基；所述苯基的取代基为C 1～3烷基；
    或者，R 1和R 2连接形成取代或未取代的6元饱和杂环基；所述饱和杂环基的取代基选自
    Figure PCTCN2021113091-appb-100030
    所述杂环基的杂原子为1个，所述杂原子为N；
    或者，所述化合物的结构如式VI-B所示：
    Figure PCTCN2021113091-appb-100031
    R 3、R 4分别独立选自氢、卤素、C 1～C 3烷基；
    m 2分别独立选自1～8的整数；
    Z -为药学上可接受的阴离子；
    R 1、R 2分别独立选自取代或未取代的C 1～3烷基；所述烷基的取代基选自
    Figure PCTCN2021113091-appb-100032
    Y选自NR 6；
    R 6选自氢、C 1～3烷基；
    R 5选自取代或未取代的苯基；所述苯基的取代基为C 1～3烷基。
  22. 根据权利要求21所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物为如下化合物之一：
    Figure PCTCN2021113091-appb-100033
  23. 权利要求1～22任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物在制备麻醉药物中的用途；
    优选地，所述麻醉药物为局部麻醉药物。
  24. 根据权利要求23所述的用途，其特征在于：所述局部麻醉药物使得感觉神经阻滞时间长于运动神经阻滞时间；
    优选地，所述局部麻醉药物的感觉神经阻滞时间长于运动神经阻滞时间超过10小时。
  25. 根据权利要求23所述的用途，其特征在于：所述局部麻醉药物为长效局部麻醉和/或选择性局部麻药物；
    优选地，所述局部麻醉药物的麻醉时间超过30小时。
  26. 一种药物，其特征在于：它是以权利要求1～22任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物为活性成分，加上药物上可接受的辅料制备而成的制剂。
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