CN115215760B - Aryl-containing quaternary ammonium salt derivative and application thereof in preparation of local anesthetic drugs - Google Patents

Aryl-containing quaternary ammonium salt derivative and application thereof in preparation of local anesthetic drugs Download PDF

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CN115215760B
CN115215760B CN202210390452.XA CN202210390452A CN115215760B CN 115215760 B CN115215760 B CN 115215760B CN 202210390452 A CN202210390452 A CN 202210390452A CN 115215760 B CN115215760 B CN 115215760B
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CN115215760A (en
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柯博文
刘进
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West China Hospital of Sichuan University
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Abstract

The invention provides a quaternary ammonium salt derivative containing aryl and application thereof in preparing local anesthetic medicaments, belonging to the field of medicinal chemistry. The structure of the quaternary ammonium salt derivative is shown as a formula I. The quaternary ammonium salt derivative has quick response when being used for local anesthesia, long anesthesia duration after single administration, and the sensory nerve blocking time is obviously longer than the motor nerve blocking time, has long-acting local anesthesia effect and selective local anesthesia effect, obviously reduces the side effect of local anesthesia medicaments in the prior art, and has better safety. The quaternary ammonium salt derivative can be used forThe preparation method of the medicine has the advantages of safety, long local anesthesia time, good local anesthesia selectivity, small nerve injury and high safety. The invention provides a new choice for long-acting local anesthetic and selective local anesthetic.

Description

Aryl-containing quaternary ammonium salt derivative and application thereof in preparation of local anesthetic drugs
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a quaternary ammonium salt derivative containing aryl and application thereof in preparing local anesthetic medicaments.
Background
Local anesthetics (Local anesthetics, local anesthetics for short) are a class of drugs that can block the occurrence and transmission of sensory nerve impulses in a locally reversible manner when administered. It is a kind of medicine which can reversibly block the impulse of sensory nerve to generate and signal transmission under the condition of consciousness and consciousness of animal or human, and can make the relevant innervation position produce temporary sensory loss so as to reversibly produce local tissue pain and disappearance. In general, the effect of local anesthetics is limited to the site of administration and rapidly disappears as the drug diffuses from the site of administration. Local anesthetics produce local anesthetic effects by directly inhibiting the associated ion channels on nerve cells and fibrous membranes, blocking the generation of action potentials and the conduction of nerve impulses. The currently accepted mechanism of action of local anesthetics is to block voltage-gated Na on nerve cell membranes + The channel blocks nerve impulses, thereby producing local anesthetic action.
Local anesthetics currently used in clinic are all uncharged hydrophobic compounds, and thus readily penetrate the cell membrane into nerve cells by diffusion and osmosis to reach the blocking site of sodium channels. These anesthetics block sodium channels and thus block neuronal excitability. However, these local anesthetic molecules are likely to act by diffusing into nerve cells, but are also likely to rapidly diffuse from the site of administration by diffusion, and release nerve cells, so that the local anesthetic action cannot be continued for a long period of time. Even if the dosage is increased, the local anesthesia time can be prolonged to a certain extent, and the ideal long-time local anesthesia effect can not be obtained. The action time of the local anesthetic which is commonly used in clinic at present is mostly not more than 4 hours. Because the traditional local anesthetic has shorter action and maintenance time, an analgesic pump is required to maintain nerve block, and the position tubes of the parts such as the vertebral canal, the nerve root, the subcutaneous part and the like are adopted, the medical cost and the incidence rate of infection are greatly increased.
On the other hand, the traditional local anesthetic does not have specific selectivity on nerve blocking, and various nerve fibers are widely blocked in the using process, so that various nerve functions such as sense, pain sense, movement and sympathetic nerves are affected, and the pharmacological feature greatly limits the wide application of the local anesthetic in clinic. For example, early functional exercise of a patient after knee joint replacement is particularly important for rehabilitation, but no drug for selectively blocking pain sense exists in the local anesthetic used clinically at present, and most of operation patients can not recover the motor function due to blocking of the motor nerve caused by using the local anesthetic, so that postoperative rehabilitation is limited. The research of local anesthetics is urgently needed to introduce new research ideas, and long-acting local anesthetics which selectively block sensory functions without affecting motor functions are developed to meet clinical demands.
Disclosure of Invention
The invention aims to provide a quaternary ammonium salt derivative containing aryl and application thereof in preparing local anesthetic drugs.
The invention provides a compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated compound thereof, wherein the structure of the compound is shown as a formula I:
in the formula I, Z - Is a pharmaceutically acceptable anion;
the A ring is selected from 5-6 membered aryl, 5-6 membered heteroaryl, condensed ring alkyl and hetero condensed ring group;
n is an integer from 0 to 5;
R d each independently selected from hydrogen, halogen, C 1～6 Alkyl, C 1～6 Alkoxy, NR e1 R e2 ；R e1 、R e2 Each independently selected from hydrogen, C 1～6 An alkyl group;
x is selected from O, NH;
L 1 selected from substituted or unsubstituted C 1～4 An alkylene group; the substituents are each independently selected from C 1～4 Alkyl, halogen, hydroxy;
R 2 、R 3 each independently selected from C 1～6 An alkyl group;
L 2 selected from C 1～12 Alkylene or C 1～12 1 to 2 CH in the alkylene backbone 2 Quilt R L A group obtained after replacement; r is R L Selected from O, S, COO, OCOO;
m is selected fromY、NR 0 ；
R 0 Selected from hydrogen, C 1～6 Alkyl and 3-8 membered saturated cycloalkyl; r is R 4 Selected from hydrogen, C 1～6 An alkyl group; alternatively, R 0 、R 4 Connected into a ring;
y is selected from L 3 R y ；L 3 Selected from the group consisting of unsubstituted, substituted or unsubstituted C 1～4 Alkylene, said substituents being selected from C 1～4 An alkyl group; r is R y Selected from O, NH, CO, CONH, NHCO, OCO, COO;
the B ring is selected from 5-6 membered aryl, 5-6 membered heteroaryl, condensed ring alkyl and hetero condensed ring group;
m is selected from integers of 0 to 5;
R c each independently selected from hydrogen, substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 1～6 Alkoxy, halogen, hydroxy, COOR e3 、NR e1 R e2 The method comprises the steps of carrying out a first treatment on the surface of the The substituent is selected from 3-6 membered saturated cycloalkyl and 3-6 membered saturated heterocyclic group; r is R e1 、R e2 、R e3 Each independently selected from hydrogen, C 1～6 An alkyl group;
or, the structure of the compound is shown as a formula II:
in the formula II, Z - Is a pharmaceutically acceptable anion;
the C ring is selected from 5-6 membered aryl and 5-6 membered heteroaryl;
r is an integer from 0 to 5;
R a each independently selected from hydrogen, C 1～6 Alkyl, C 1～6 Alkoxy, halogen, hydroxy, NR e4 R e5 、COOR e6 ；R e4 、R e5 、R e6 Each independently selected from hydrogen, C 1～6 An alkyl group;
R 11 selected from hydrogen, substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 1～6 An alkoxy group; the substituents are selected from halogen, C 1～6 An alkoxy group;
R 6 selected from C 1～6 An alkyl group;
R 7 、R 8 each independently selected from substituted or unsubstituted C 1～10 Alkyl, said substituents being selected from hydroxy, halogen, unsubstituted or hydroxy-substituted C 1～6 Alkoxy, amino, carboxyl, cyano, nitro, mercapto, COOR 12 ，R 12 Selected from C 1～6 An alkyl group;
L 4 selected from C 1～14 Alkylene or C 1～14 1 to 2 CH in the alkylene backbone 2 Quilt R L After replacement ofThe resulting group; r is R L Selected from O, S, COO, OCOO;
R 5 selected from the group consisting of
R 9 Selected from hydrogen, C 1～6 Alkyl, unsubstituted or substituted by R 9a Substituted 3-8 membered saturated cycloalkyl, unsubstituted or substituted by R 9a Substituted 3-8 membered heterocycloalkyl, R 9a Selected from C 1～6 An alkyl group; r is R 10 Selected from hydrogen, C 1～6 An alkyl group; or R is 9 、R 10 Connected into a ring; w is L 5 Q；L 5 Selected from the group consisting of unsubstituted, substituted or unsubstituted C 1～4 Alkylene, said substituents being selected from C 1～6 An alkyl group; q is selected from O, NH, CO, CONH, NHCO, OCO, COO;
p is an integer from 0 to 5;
R a1 selected from hydrogen, C 1～6 Alkyl, C 1～6 Alkoxy, halogen, hydroxy, NR e4 R e5 、COOR e6 、COOL 6 NR e4 R e5 、OL 7 R e7 ；L 6 Selected from C 1～2 Alkylene group, R e4 、R e5 、R e6 Each independently selected from hydrogen, C 1～6 Alkyl, L 7 Selected from C 1～3 Alkylene group, R e7 Is selected from 3-6 membered saturated heterocyclic groups.
Further, the structure of the compound shown in the formula I is shown in the formula III:
wherein Z is - Is a pharmaceutically acceptable anion;
R d1 、R d2 each independently selected from hydrogen, halogen, C 1～4 Alkyl, C 1～4 Alkoxy, NR e1 R e2 ；R e1 、R e2 Each independently selected from hydrogen, C 1～4 An alkyl group;
L 1 selected from C 2～3 An alkylene group;
R 2 、R 3 each independently selected from C 1～3 An alkyl group;
L 2 selected from C 4～6 An alkylene group;
R 0 selected from hydrogen, C 1～4 An alkyl group;
R 4 selected from hydrogen, C 1～4 An alkyl group;
R c1 、R c2 each independently selected from hydrogen, C 1～4 Alkyl, C 1～4 Alkoxy, halogen, hydroxy, COOR e3 ；R e3 Selected from hydrogen, C 1～4 An alkyl group.
Further, in the formula III,the structure of (2) is->
Further, the structure of the compound shown in the formula I is shown in the formula IV:
wherein Z is - Is a pharmaceutically acceptable anion;
R d1 、R d2 each independently selected from hydrogen, halogen, C 1～4 Alkyl, C 1～4 Alkoxy, NR e1 R e2 ；R e1 、R e2 Each independently selected from hydrogen, C 1～4 An alkyl group;
L 1 selected from substituted or unsubstituted C 2～3 An alkylene group; the substituents are each independently selected from C 1～2 An alkyl group;
R 2 、R 3 each independently selectFrom C 1～4 An alkyl group;
L 2 selected from C 2～9 Alkylene or C 2～9 1 to 2 CH in the alkylene backbone 2 A group obtained after replacement by O;
R 0 selected from hydrogen, C 1～4 An alkyl group; r is R 4 Selected from hydrogen, C 1～4 An alkyl group; alternatively, R 0 、R 4 Is connected into a ring, and the ring is preferably a 4-6 membered saturated nitrogen ring;
y is selected from L 3 R y ；L 3 Selected from the group consisting of unsubstituted, substituted or unsubstituted methylene groups, said substituents being selected from C 1～2 An alkyl group; r is R y Selected from O, NH, CONH, NHCO, OCO, COO;
m is selected from integers of 0 to 3;
R c3 each independently selected from hydrogen, C 1～4 Alkyl, C 1～4 Alkoxy, halogen, hydroxy, COOR e3 、NR e1 R e2 ；R e1 、R e2 、R e3 Each independently selected from hydrogen, C 1～4 An alkyl group.
Further, in the formula I,the structure of (2) is selected from: />
Further, the structure of the compound shown in the formula II is shown in a formula V:
wherein R is d3 、R d4 Each independently selected from hydrogen, C 1～6 Alkyl, C 1～6 Alkoxy, halogen, hydroxy, NR e4 R e5 、COOR e6 ；R e4 、R e5 、R e6 Each independently selected from hydrogen, C 1～6 An alkyl group;
R 11 selected from hydrogen, substituted or unsubstituted C 1～4 Alkyl, substituted or unsubstituted C 1～4 An alkoxy group; the substituents are selected from halogen, C 1～4 An alkoxy group;
R 6 selected from C 1～2 An alkyl group;
R 7 、R 8 each independently selected from substituted or unsubstituted C 1～10 Alkyl, said substituents being selected from hydroxy, halogen, unsubstituted or hydroxy-substituted C 1～4 Alkoxy, amino, carboxyl, cyano, nitro, mercapto, COOR 12 ，R 12 Selected from C 1～2 An alkyl group;
L 4 selected from C 1～14 Alkylene or C 1～14 1 to 2 CH in the alkylene backbone 2 Quilt R L A group obtained after replacement; r is R L Selected from O, S, COO, OCOO;
R 9 selected from hydrogen, C 1～6 Alkyl, unsubstituted or substituted by C 1～3 Alkyl-substituted 3-to 8-membered saturated cycloalkyl, unsubstituted or C-substituted 1～3 Alkyl substituted 3-8 membered heterocycloalkyl, R 10 Selected from hydrogen, C 1～6 An alkyl group; or R is 9 、R 10 Is connected into a ring, and the ring is preferably a 4-8 membered saturated nitrogen ring;
w is L 5 Q；L 5 Selected from the group consisting of unsubstituted, substituted or unsubstituted C 1～3 Alkylene, said substituents being selected from C 1～3 An alkyl group; q is selected from O, NH, CO, CONH, NHCO, OCO, COO;
p is selected from integers from 0 to 5, preferably from 0 to 3;
R a1 each independently selected from hydrogen, C 1～6 Alkyl, C 1～6 Alkoxy, halogen, hydroxy, NR e4 R e5 、COOR e6 ；R e4 、R e5 、R e6 Each independently selected from hydrogen, C 1～6 An alkyl group.
Further, the Z - Selected from halogen anions, sulfateAcetate, tartrate, p-toluenesulfonate, methanesulfonate, citrate;
preferably, the halide anion is Cl - 、Br - Or I - 。
Further, the pharmaceutically acceptable salt is a salt of the compound with a pharmaceutically acceptable inorganic or organic acid;
preferably, the inorganic or organic acid is hydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, tartaric acid, lauric acid, maleic acid, citric acid, succinic acid, benzoic acid or pamoic acid.
Further, it is selected from one of the following structures:
the invention also provides application of the compound, or pharmaceutically acceptable salt, or stereoisomer, or solvate, or prodrug, or metabolite, or deuterated compound thereof in preparing local anesthetic.
Further, the local anesthetic is a long-acting local anesthetic and/or a selective local anesthetic.
Further, the local anesthetic causes a longer sensory nerve block time than a motor nerve block time; preferably, the local anesthetic causes a sensory nerve block time longer than a motor nerve block time by more than 10 hours;
and/or the anesthetic time of the local anesthetic is more than 30 hours.
The invention also provides a local anesthetic which is a preparation prepared by taking the compound, or pharmaceutically acceptable salt, or stereoisomer, or solvate, or prodrug, or metabolite, or deuterated compound thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
The minimum and maximum values of the carbon atom content of the hydrocarbon groups are indicated by a prefix, e.g. prefix C a～b Alkyl means any alkyl group containing from "a" to "b" carbon atoms. For example, C 1～8 Alkyl refers to straight or branched chain alkyl groups containing 1 to 8 carbon atoms. For example, C 1～12 Alkylene refers to straight or branched chain alkylene groups containing 1 to 12 carbon atoms.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the invention with pharmaceutically acceptable inorganic and organic acids, suitable for contact with the tissues of a subject (e.g., a human) without undue adverse effects. Among the preferred mineral acids include (but are not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid; preferred organic acids include (but are not limited to): formic acid, acetic acid, propionic acid, succinic acid, naphthalene disulfonic acid (1, 5), asiatic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethyl acetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids.
"pharmaceutically acceptable anions" means including, but not limited to, halide anions, sulfate, acetate, tartrate, p-toluenesulfonate, methanesulfonate, citrate.
"halogen" is fluorine, chlorine, bromine or iodine.
"solvate" means a solvate of a compound of the invention with a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent includes, but is not limited to, water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran, dichloromethane.
"stereoisomers" refers to the chiral carbon atoms involved in the compounds of the present invention that may be in the R configuration, or in the S configuration, or a combination thereof.
"deuterated compound" refers to a compound obtained by substituting one or more hydrogens in the compound of the present invention with deuterium.
"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings) but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be at a carbon atom on the ring with a conjugated pi-electron system. Aryl groups may be substituted or unsubstituted. For example, "5-to 6-membered aryl" refers to an aryl group having 5 to 6 ring atoms.
"heteroaryl" refers to a heteroaromatic group containing one to more heteroatoms. Heteroatoms as referred to herein include oxygen, sulfur and nitrogen. Such as furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted. For example, "5-to 6-membered heteroaryl" refers to heteroaryl groups having 5 to 6 ring atoms.
"cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be a single ring or multiple rings. "saturated cycloalkyl" refers to saturated cycloalkyl. For example, "3-to 8-membered saturated cycloalkyl" refers to a saturated cycloalkyl group having 3 to 8 ring carbon atoms.
"heterocyclyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic and carry at least one ring heteroatom (including but not limited to O, S or N). "saturated heterocyclyl" refers to a saturated heterocyclyl. For example, the "3-to 8-membered saturated heterocyclic group" means a saturated heterocyclic group having 3 to 8 ring carbon atoms.
"fused ring alkyl" refers to a polycyclic cycloalkyl group in which two rings share two adjacent carbon atoms.
"heterofused ring group" refers to a polycyclic heterocyclic group having two rings sharing two adjacent carbon or heteroatom. For example:
"an integer of 0 to 5" means 0, 1,2, 3, 4 or 5. "an integer of 0 to 3" means 0, 1,2 or 3.
The quaternary ammonium salt derivative provided by the invention has the advantages that the quaternary ammonium salt derivative has quick effect when being used for local anesthesia, the anesthesia duration time after single administration is long, the sensory nerve blocking time is obviously longer than the motor nerve blocking time, the quaternary ammonium salt derivative has long-acting local anesthesia effect and selective local anesthesia effect, the side effect of local anesthesia medicaments in the prior art is obviously reduced, and the quaternary ammonium salt derivative has better safety. The quaternary ammonium salt derivative can be used for preparing safe medicines with long-time local anesthesia and selective local anesthesia, and has the advantages of long local anesthesia time, good local anesthesia selectivity, more nerve injury and high safety.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The materials and equipment used in the embodiments of the present invention are all known products and are obtained by purchasing commercially available products.
Unless otherwise specified, the liquid ratio referred to in the examples of the present invention is a volume ratio.
EXAMPLE 1 preparation of Compound 1 of the invention
1a (5.0 g,41.26 mmol) was dissolved in 100mL of DCM, 11.4g of potassium carbonate was added, 2-bromobutyryl bromide (14.2 g,61.89 mmol) dissolved in 20mL of DCM was added dropwise at 0deg.C, and the reaction was stirred at room temperature for 3h and monitored by TLC. After the reaction was substantially completed, the solvent was dried under reduced pressure, petroleum ether and methylene chloride were recrystallized to prepare 10.8g of an off-white solid powder 1b in 97% yield. 1 H NMR(400MHz,CDCl 3 )δ8.82(s,1H),7.12–7.06(m,1H),7.06–7.01(m,2H),4.58(t,J＝5.8Hz,1H),2.12–1.95(m,2H),1.03(t,J＝6.7Hz,3H).
Compound 1b (2.0 g,7.40 mmol) and potassium carbonate (2.1 g,14.81 mmol) were added to 30mL of DMF, di-n-propylamine (0.749 g,7.40 mmol) was added with stirring, the reaction was stirred at 50℃for 3h, the reaction mixture was dried under reduced pressure, and the crude product was purified by column chromatography on silica gel, eluent: DCM: meoh=20:1, which gives 1.8g of colorless oil 1c after purification. The yield thereof was found to be 84%. 1 H NMR(400MHz,CDCl 3 )δ8.64(s,1H),7.12–7.06(m,1H),7.06–7.01(m,2H),3.48(t,J＝5.8Hz,1H),2.64(dt,J＝12.2,6.6Hz,2H),2.53(dt,J＝12.2,6.6Hz,2H),2.19(s,5H),1.98–1.78(m,2H),1.52(dtd,J＝14.2,7.7,6.5Hz,4H),0.94(dt,J＝18.3,7.7Hz,9H).
Compound 1c (1.8 g,6.20 mmol) was dissolved in 10mL of 1, 4-dibromobutane and heated to 90℃for 20h, monitored by TLC (DCM: meOH=10:1). An appropriate amount of dehydrated ether was added to give a viscous syrup-like substance, the supernatant was decanted, and 2.6g of the crude product remained, and the crude product was purified by silica gel column chromatography. Eluent: DCM, meoh=10:1, the eluate was collected and concentrated to give 1.9g of crude product. Petroleum ether and methylene dichloride are recrystallized to prepare 1.7g of off-white solid powder 1d with the yield of 54 percent, which is directly used in the next reaction.
Compound 1b (2.0 g,7.40 mmol) and potassium carbonate (2.1 g,14.81 mmol) were added to 30mL of DMF, ethylamine (0.334 g,7.40 mmol) was added with stirring, the reaction was stirred at normal temperature for 5h, the reaction solution was dried under reduced pressure, the crude product was purified by silica gel column chromatography, eluent: DCM: meoh=20:1, which gives 1.6g of colorless oil 1f after purification. The yield was 92%. 1 H NMR(400MHz,CDCl 3 )δ8.34(s,1H),7.12–7.01(m,3H),3.53(dt,J＝7.5,3.6Hz,1H),3.45(dt,J＝7.7,4.2Hz,1H),2.88–2.72(m,3H),1.75(qdd,J＝7.2,4.2,1.5Hz,3H),1.20(t,J＝6.2Hz,4H),0.94(t,J＝7.1Hz,4H).
Intermediate 1d (1.7 g,3.36 mmol) prepared above, 1f (0.787 g,3.36 mmol) was dissolved in 20mL of acetonitrile, 0.5g sodium bicarbonate was added, the temperature was raised to 80 ℃, heating was carried out for 24h, the solvent was evaporated, the crude product was purified by column chromatography on silica gel, eluent: DCM: meoh=10:1, the eluate was collected and concentrated to give 1.5g of white solid 1. The yield was 68%. 1 H NMR(400MHz,CDCl 3 )δ9.40(s,1H),8.64(s,1H),7.13–7.06(m,2H),7.06–7.01(m,4H),4.50(t,J＝4.1Hz,1H),3.62(t,J＝8.7Hz,2H),3.62–3.56(m,2H),3.59–3.52(m,2H),3.46(t,J＝5.4Hz,1H),2.79–2.71(m,1H),2.74–2.68(m,1H),2.63(dq,J＝12.6,7.6Hz,1H),2.56(dt,J＝12.3,5.5Hz,1H),2.19(t,J＝0.7Hz,11H),2.07(qdd,J＝8.8,4.0,1.2Hz,2H),1.96–1.78(m,2H),1.77–1.60(m,6H),1.63–1.55(m,1H),1.58–1.48(m,1H),1.16–1.05(m,11H),0.96(t,J＝7.9Hz,3H).
EXAMPLE 2 preparation of Compound 2 of the invention
Compound 2a (8.0 g,28.94 mmol) was dissolved in 20mL of 1, 3-dibromopropane and heated to 70℃for 44h with TLC monitoring (DCM: meOH=15:1). Adding petroleum ether to obtain viscous syrup, pouring out supernatant, and purifying with silica gel column chromatography to obtain 10.6g of crude product. Eluent: DCM, meoh=10:1, the eluate was collected and concentrated to give 8.7g of crude product. Ethyl acetate and methylene chloride were recrystallized to prepare 7.7g of off-white solid powder 2b in 55.6% yield, which was directly used in the next reaction.
Intermediate 2b (2.00 g,4.18 mmol) prepared above, S-N- (2, 6-dimethylphenyl) -2-piperidinecarboxamide (1.94 g,8.36 mmol) was dissolved in 20mL of acetonitrile, 1.0g of sodium bicarbonate was added, the temperature was raised to 80 ℃, heating was carried out for 44h, the solvent was evaporated, and the crude product was purified by column chromatography on silica gel eluting with eluent: DCM: meoh=10:1, the eluate was collected and concentrated to give 1.54g of white solid 2. The yield was 58.5%. 1 H NMR(400MHz,CDCl 3 )δ9.24(s,1H),8.12(s,1H),7.17–6.87(m,6H),5.85(t,J＝35.2Hz,1H),4.10–3.72(m,3H),3.66–3.20(m,4H),2.84–2.70(m,4H),2.10–2.01(m,13H),1.99–1.87(m,7H),1.70(m,J＝25.2,12.5Hz,4H),1.47–1.30(m,3H),1.02–0.92(m,6H).
EXAMPLE 3 preparation of Compound 3 of the invention
3a (6.0 g,35.04 mmol) was dissolved in 100mL DCM, 10.0g potassium carbonate was added, 2-bromopropionyl bromide (11.35 g,52.57 mmol) dissolved in 20mL DCM was added dropwise at 0deg.C, and the reaction was stirred at room temperature for 3h and monitored by TLC. After the reaction was substantially completed, the solvent was dried under reduced pressure, petroleum ether and methylene chloride were recrystallized to prepare 10.2g of an off-white solid powder 3b in 95% yield, which was directly acted on the next step. 1 H NMR(400MHz,CDCl 3 )δ9.54(s,1H),6.98(s,1H),4.70(q,J＝6.7Hz,1H),3.91(s,3H),2.25(d,J＝0.7Hz,4H),1.83(s,2H).
3b (1.0 g,3.27 mmol) was dissolved in DMF and 25% aqueous ammonia (0.91 mL,9.80 mmol) was added dropwise, 1.1g of potassium carbonate was added and reacted at 60℃for 3h. Evaporating the solvent, purifying the crude product by silica gel column chromatography, elutingThe preparation method comprises the following steps: DCM: meoh=20:1, the eluate was collected and concentrated to 0.44g of white solid 3c. The yield was 55%. 1 H NMR(400MHz,CDCl 3 )δ9.53(s,1H),6.98(s,1H),4.05(m,1H),3.91(s,2H),3.52(dd,J＝7.8,5.6Hz,1H),3.29(dd,J＝7.9,5.5Hz,1H),1.35(d,J＝5.1Hz,3H).
Intermediate 2b (0.86 g,1.80 mmol) and 3c (0.44 g,1.80 mmol) prepared above were dissolved in 20mL of acetonitrile, 0.5g of sodium bicarbonate was added, heated to 80℃for 24h, the solvent was evaporated, and the crude product was purified by column chromatography on silica gel, eluent: DCM: meoh=10:1, the eluate was collected and concentrated to 0.87g of white solid 3. The yield was 76%. 1 H NMR(400MHz,CDCl 3 )δ9.85(s,1H),9.40(s,1H),7.12–7.06(m,1H),7.06–7.01(m,2H),6.98(s,1H),5.35(dt,J＝7.0,4.7Hz,1H),4.48(t,J＝3.8Hz,1H),3.91(s,2H),3.80(dq,J＝7.0,5.5Hz,1H),3.68–3.49(m,6H),2.83(td,J＝6.8,4.6Hz,2H),2.25(d,J＝0.7Hz,3H),2.19(d,J＝0.6Hz,6H),2.07(qdd,J＝8.8,3.8,1.4Hz,2H),1.92(dtt,J＝11.8,8.3,6.7Hz,2H),1.76–1.61(m,2H),1.33–1.24(m,6H),1.10(dt,J＝21.6,8.7Hz,6H).
EXAMPLE 4 preparation of Compound 4 of the invention
1 (1.0 g,1.52 mmol) and sodium hydride (0.11 g,4.55 mmol) were dissolved in 30mL anhydrous Tetrahydrofuran (THF), and bromoethane (0.17 g,1.52 mmol) dissolved in 10mL anhydrous tetrahydrofuran was added dropwise at 0deg.C under nitrogen. The reaction was carried out at room temperature for 5 hours. The reaction was monitored by TLC. After the reaction was substantially complete, water was added dropwise with stirring under ice bath to 100mL. THF was evaporated under reduced pressure, extracted with DCM (100 mL. Times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and the solvent evaporated. Purifying the crude product by silica gel column chromatography, eluting with an eluent: DCM: meoh=10:1, the eluate was collected and concentrated to 0.64g of white solid 3. The yield was 62%. 1 H NMR(400MHz,CDCl 3 )δ7.12–7.01(m,2H),3.66–3.54(m,2H),3.49–3.29(m,1H),2.79–2.51(m,1H),2.20(d,J＝8.6Hz,4H),2.13–2.03(m,1H),1.96–1.78(m,1H),1.77–1.62(m,2H),1.66–1.48(m,1H),1.24(t,J＝7.5Hz,1H),1.16–1.05(m,4H),0.96(t,J＝7.9Hz,1H).
EXAMPLE 5 preparation of Compound 5 of the invention
5a (2.0 g,16.56 mmol) was dissolved in 100mL DCM, and an aqueous solution containing 0.88g sodium hydroxide, di-tert-butyl dicarbonate (5.42 g,24.84 mmol) were added sequentially and the reaction was stirred at room temperature overnight and monitored by TLC. After the reaction was substantially completed, the reaction mixture was concentrated, and then, an appropriate amount of water was added thereto, and after the pH was adjusted to about 3.0 with 2mol/L of diluted hydrochloric acid, a white solid was precipitated, and 4.2g of a white powdery solid 5b was obtained by filtration. The yield was 90% and was directly used in the next step.
Compound 5b (3.8 g,13.51 mmol) was dissolved in DCM, EDCI (4.0 g,20.86 mmol) and DMAP (0.18 g,1.51 mmol) were added, and then bromoethanol (2.5 g,20.26 mmol) was added and the reaction was stirred at room temperature overnight and monitored by TLC. After the reaction was completed, the reaction solution was concentrated, a proper amount of water was added, extracted with DCM (100 ml×3), and the organic phase was dried over anhydrous sodium sulfate, filtered and dried by spin-drying, followed by purification by column chromatography to give 4.5g of a white powdery solid 5c. The yield was 86%. 1 H NMR(400MHz,CDCl 3 )δ8.37(d,J＝2.2Hz,1H),7.63(dd,J＝8.8,2.2Hz,1H),7.10(d,J＝8.9Hz,1H),6.34(s,1H),4.55(t,J＝3.6Hz,2H),4.11(q,J＝6.2Hz,2H),3.65(t,J＝3.7Hz,2H),1.42(t,J＝6.3Hz,3H).
Compound 5c (2.0 g,5.15 mmol) and 2.0g potassium carbonate were added to 30mL DMF, ethylamine (0.232 g,5.15 mmol) was added with stirring, the reaction was stirred at normal temperature for 5h, the reaction solution was dried under reduced pressure, the crude product was purified by silica gel column chromatography, eluent: DCM meoh=20:1, giving after purification 1.32g of a colorless oil 5d. The yield thereof was found to be 73%. 1 H NMR(400MHz,CDCl 3 )δ8.37(d,J＝2.2Hz,1H),7.63(dd,J＝8.8,2.2Hz,1H),7.10(d,J＝8.9Hz,1H),6.34(s,1H),4.26(t,J＝4.5Hz,2H),4.11(q,J＝6.2Hz,2H),3.74(tt,J＝5.5,3.9Hz,1H),3.09(dt,J＝5.5,4.5Hz,2H),2.98(qd,J＝6.1,3.9Hz,2H),1.42(t,J＝6.3Hz,3H),1.18(t,J＝6.0Hz,3H).
Will be combinedThe reaction mixture 1b (2.0 g,7.40 mmol) and potassium carbonate (2.1 g,14.81 mmol) were added to 30mL of DMF, N-ethyl-N-propylamine (0.853 g,7.40 mmol) was added under stirring, stirred at room temperature for 5h, the reaction mixture was dried under reduced pressure, the crude product was purified by silica gel column chromatography, eluent: DCM meoh=20:1, giving after purification 2.0g of a colorless oil 5e. The yield was 89%. 1 HNMR(400MHz,CDCl 3 )δ8.64(s,1H),7.12–7.06(m,1H),7.06–7.01(m,2H),3.47(t,J＝5.8Hz,1H),2.68(dtd,J＝12.2,6.6,4.3Hz,2H),2.51(dtd,J＝12.3,6.6,4.7Hz,2H),2.19(s,5H),1.98–1.78(m,2H),1.58–1.41(m,4H),1.39–1.28(m,2H),1.00–0.89(m,9H).
Compound 5e (2.0 g,6.57 mmol) was dissolved in 15mL of 1, 2-dibromoethane and heated to 80℃for 24h, monitored by TLC (DCM: meOH=15:1). Adding petroleum ether to obtain viscous syrup, pouring out supernatant, dissolving the rest crude product 3.6g with 15mL methanol, mixing with silica gel, dry loading, and purifying by silica gel column chromatography. Eluent: DCM, meoh=10:1, the eluate was collected and concentrated to give 2.7g of crude product. Ethyl acetate and methylene chloride were recrystallized to prepare 2.2g of off-white solid powder 5f in 68% yield, which was directly used in the next reaction.
Intermediate 5f (2.0 g,4.06 mmol) prepared above, 5d (1.15 g,3.25 mmol) was dissolved in 20mL of acetonitrile, 1.0g sodium bicarbonate was added, the temperature was raised to 80 ℃, heating was carried out for 24h, the solvent was evaporated, the crude product was purified by column chromatography on silica gel, eluent: DCM: meoh=10:1, the eluate was collected, concentrated, and the solid was dissolved in 30mL of methanol solution, added with methanol hydrochloride solution, and stirred overnight at room temperature. Spin-drying the solvent and concentrating to give 2.1g of white solid 5. The yield was 62%. 1 HNMR(400MHz,CDCl 3 )δ9.32(s,1H),7.48(dd,J＝8.5,2.3Hz,1H),7.40(d,J＝2.2Hz,1H),7.12–7.06(m,1H),7.06–7.01(m,2H),6.96(d,J＝8.5Hz,1H),4.49(t,J＝4.0Hz,1H),4.31(t,J＝5.6Hz,2H),4.20(s,2H),4.03(q,J＝6.3Hz,2H),3.75–3.69(m,2H),3.62(td,J＝9.1,1.2Hz,2H),3.57(td,J＝4.9,2.6Hz,2H),3.24(dt,J＝13.4,4.5Hz,1H),3.14(dt,J＝13.5,4.6Hz,1H),2.89(t,J＝5.6Hz,2H),2.63(q,J＝7.0Hz,2H),2.19(d,J＝0.7Hz,6H),2.07(qdd,J＝8.8,4.1,2.1Hz,2H),1.76–1.39(m,10H),1.16–1.01(m,9H),0.98(t,J＝6.6Hz,3H).
EXAMPLE 6 preparation of Compound 6 of the invention
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1a (5.0 g,41.26 mmol) was dissolved in 100mL of DCM, 11.4g of potassium carbonate was added, 2-bromopropionyl bromide (13.4 g,61.89 mmol) dissolved in 20mL of DCM was added dropwise at 0℃and the reaction was stirred at room temperature for 3h and monitored by TLC. After the reaction was substantially completed, the solvent was dried under reduced pressure, petroleum ether and methylene chloride were recrystallized to prepare 10.0g of an off-white solid powder 6b in 95% yield. 1 H NMR(400MHz,CDCl 3 )δ8.90(s,1H),7.12–7.01(m,4H),4.72(q,J＝6.7Hz,1H),1.82(d,J＝6.6Hz,4H).
Compound 6b (2.0 g,7.81 mmol) and potassium carbonate (2.1 g,14.81 mmol) were added to 30mL of DMF, N-ethyl-N-propylamine (0.681 g,7.40 mmol) was added with stirring, the reaction was stirred at 50℃for 3h, the reaction mixture was dried under reduced pressure, and the crude product was purified by silica gel column chromatography, eluent: DCM: meoh=20:1, which gave after purification a white solid 6c (1.7 g, 83%). 1 H NMR(400MHz,CDCl 3 )δ8.80(s,1H),7.12–7.01(m,3H),3.41(q,J＝6.3Hz,1H),2.74(qd,J＝7.2,1.6Hz,2H),2.68(dt,J＝12.1,5.9Hz,1H),2.59(dt,J＝12.0,5.8Hz,1H),1.52(qt,J＝7.6,5.8Hz,2H),1.29(d,J＝6.4Hz,3H),1.10(t,J＝7.1Hz,3H),0.93(t,J＝7.6Hz,3H).
Compound 6c (1.7 g,6.48 mmol) was dissolved in 15mL of 4-bromo-1-butanol and heated to 80℃for 24h, monitored by TLC (DCM: meOH=15:1). An appropriate amount of dehydrated ether was added to give a white solid, which was filtered and dried to give 1.5g of an off-white solid powder 6d in 56% yield. 1 HNMR(400MHz,CDCl 3 )δ7.12–7.01(m,1H),3.74–3.63(m,1H),3.66–3.60(m,1H),3.62–3.49(m,1H),2.19(d,J＝0.7Hz,2H),1.80–1.66(m,1H),1.69–1.58(m,1H),1.55(d,J＝4.7Hz,1H),1.30(t,J＝5.4Hz,1H),1.13(t,J＝8.5Hz,1H).
6d (1.5 g,3.61 mmol) was added to 30mL of acetone solution, and triphosgene (0.79 g,3.61 mmol) and 0.40g pyridine were added under nitrogen at 0deg.C. The reaction mixture was stirred at room temperature overnight and concentrated by filtration. Yield 6e was used directly in the next step.
Intermediate 6e and N- (2, 6-dimethylphenyl) -2- (propylamine) butanamide (0.897 g,3.61 mmol) prepared above were dissolved in 20mL of acetonitrile, 1.0g sodium bicarbonate was added, the temperature was raised to 80 ℃, heating was carried out for 24h, the solvent was evaporated, the crude product was purified by column chromatography on silica gel, eluent: DCM: meoh=10:1, the eluate was collected and concentrated to give 1.12g of white solid 6. The yield was 45%. 1 HNMR(400MHz,CDCl 3 )δ9.60(s,1H),8.60(s,1H),7.13–7.06(m,2H),7.05(s,1H),7.06–7.01(m,3H),4.37(q,J＝4.6Hz,1H),4.30(t,J＝6.0Hz,1H),4.18(t,J＝5.7Hz,2H),3.74–3.48(m,6H),3.27–3.12(m,2H),2.37–2.25(m,1H),2.19(t,J＝0.7Hz,12H),2.09–1.97(m,1H),1.91–1.81(m,1H),1.84–1.71(m,3H),1.74–1.56(m,5H),1.55(d,J＝4.7Hz,3H),1.30(t,J＝5.4Hz,3H),1.13(t,J＝8.5Hz,3H),0.99(t,J＝7.8Hz,3H),0.88(t,J＝7.6Hz,3H).
EXAMPLE 7 preparation of Compound 7 of the invention
200mg of Compound 1 was dissolved in 20mL of methanol, and a hydrochloric acid-methanol solution having an amount concentration of 0.1mol/L of the substance was added dropwise under ice bath, followed by concentration under reduced pressure until it was dried. Drying in vacuo afforded white solid 7.
EXAMPLE 8 preparation of Compound 8 of the invention
200mg of Compound 2 was dissolved in 20mL of methanol, and hydrobromic acid solution having an amount concentration of the substance was added dropwise under ice bath, and concentrated to dryness under reduced pressure. Drying in vacuo afforded white solid 8.
EXAMPLE 9 preparation of Compound 9 of the invention
200mg of Compound 3 was dissolved in 20mL of methanol, 1eq of methanesulfonic acid was added, and the mixture was concentrated to dryness under reduced pressure. Drying in vacuo afforded white solid 9.
With reference to the procedure of the above examples, the following examples of compounds 10-69 were prepared by corresponding replacement of the starting materials:
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the beneficial effects of the compounds of the present invention are described below by way of examples
Experimental example 1 investigation of local anesthetic Effect of the Compounds of the invention in a ischial nerve block model
(1) Experimental method
The compounds 1-69, lidocaine hydrochloride (positive control) and levobupivacaine hydrochloride (positive control) prepared in the examples were selected and administered to the rats to be tested, each group of which was 8 rats, which were fully adapted to the experimental environment.
The dosage is as follows: the lidocaine hydrochloride has a concentration of 2% aqueous solution, the levobupivacaine hydrochloride has a concentration of 0.75% aqueous solution, and the compounds 1-69 have a concentration of 20mmol/mL aqueous solution.
The injection volume of each rat was 0.5ml, and the rats were injected near the sciatic nerve by guiding and positioning with a nerve positioner. The rat is stimulated by a von Frey stimulator to inject the medicine to the sole of the body side, and the local anesthetic effect is observed. Meanwhile, the motor function of rats was evaluated by hind limb pedaling test (Postural Extensor Thrust, PET): the rat was lifted vertically and the injection side hind limb was allowed to ride on the electronic balance table, at which time the rat hind limb muscle strength was represented by the value displayed by the limb riding on the balance. When the limb is fully paralyzed, the reading is about 20g of the weight of the limb. A measurement that exceeds half the difference between baseline and limb weight is considered motor function recovery, and a value less than or equal to this value is considered motor function loss.
(2) Experimental results
TABLE 1 local anesthetic effect of the Compounds of the invention on sciatic nerve
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Experimental results show that the compounds 1-69 of the invention have quick effect in a sciatic nerve block model, can generate local anesthetic effect for more than 30 hours, and have obviously longer sensory nerve block time than motor nerve block time and a difference time of more than 10 hours.
Experimental example 2 investigation of local anesthetic Effect of the Compounds of the invention in a rat subcutaneous infiltration model
(1) Experimental method
After shaving and disinfecting the backs of rats weighing 250-300 g, a circle with a diameter of about 1.5cm was drawn on the exposed back side and the circle was divided 6 equal. 0.5mL of a solution containing the compounds 1-8, 35-42, 61-68 or levobupivacaine hydrochloride of the present invention (water was used as a solvent, the concentration of levobupivacaine hydrochloride was 23mmol/L, and the concentration of the compound of the present invention was 6 mmol/L) was subcutaneously injected at the skin of the center, respectively. Binding 100 gram-force fiber filaments in the Von Frey fiber filaments with a needle head for local skin stimulation. After the medicine is injected for 5min, the stimulation is carried out in 6 divided ranges by using the method, if the back skin contraction behavior does not appear in the continuous 3 times of stimulation in the same divided range, the medicine effect is positive, and if the back skin contraction appears, the local anesthetic effect is disappeared. If 3 or more areas in the 6 divided areas show positive local anesthesia, the medicine is considered to be effective in local anesthesia, and less than 3 areas in the 6 divided areas show positive and the medicine is considered to be ineffective in local anesthesia. Experiments were performed using 10 rats for each drug.
(2) Experimental results
TABLE 2 subcutaneous invasive local anesthetic effect of the compounds of the invention
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Experimental results show that the compound provided by the embodiment of the invention has a fast effect in a rat subcutaneous infiltration model, and can generate local anesthetic effect for more than 30 hours.
Experimental results of experimental examples 1 and 2 show that the compound of the invention has quick response when being used for local anesthesia, long anesthesia duration after single administration, and obviously longer sensory nerve blocking time than motor nerve blocking time, and has long-acting local anesthesia effect and selective local anesthesia effect. The safety of the compounds of the present invention is further evaluated as follows.
Experimental example 3 investigation of the Compounds of the invention on neuropathological injury
(1) Experimental method
Compounds 1-8, 35-42, 61-68, lidocaine hydrochloride (positive control), levobupivacaine hydrochloride (positive control) were selected and administered to the rats tested, each group of 8 rats, which were fully adapted to the experimental environment.
The administration dose of the sciatic nerve of the rat is as follows: the lidocaine hydrochloride concentration is 2% aqueous solution, the levobupivacaine hydrochloride concentration is 0.75% aqueous solution, and the concentrations of the compounds 1-8, 35-42 and 61-68 are all 20mmol/L aqueous solution. Each rat was administered at an injection volume of 0.5mL, injected near the sciatic nerve of the rat. The experimental rats were euthanized by bupivacaine under isoflurane anesthesia at day 7 and day 14 post sciatic nerve injection. The sciatic nerve at the injection site was taken at about 1.5cm, placed in 10% formaldehyde solution for 48h, HE stained and sectioned into 5 μm thick sections.
The subcutaneous administration dose of the back of the rat is as follows: the lidocaine hydrochloride concentration is 2% aqueous solution, the levobupivacaine hydrochloride concentration is 0.75% aqueous solution, and the concentrations of the compounds 1-8, 35-42 and 61-68 are all 6mmol/L aqueous solution. The injection volume of each rat was 0.5ml and was injected subcutaneously in the backs of the rats. On days 7 and 14 after subcutaneous injection, experimental rats were euthanized with bupivacaine under isoflurane anesthesia. Skin tissue at the injection site was taken, stored in 10% formaldehyde solution for 48h, HE stained and cut into 5 μm thick sections.
(2) Experimental results
The evaluation of the neuropathological injury shows that: compared with the positive control of lidocaine hydrochloride and the positive control of levobupivacaine hydrochloride, the compounds 1-8, 35-42 and 61-68 have no obvious difference in the aspects of nerve injury, vascular hyperplasia, demyelination degree, muscle inflammation and connective tissue inflammation degree, and have good safety.
In summary, the invention provides a quaternary ammonium salt derivative containing aryl and application thereof in preparing local anesthetic drugs. The quaternary ammonium salt derivative has quick response when being used for local anesthesia, long anesthesia duration after single administration, and the sensory nerve blocking time is obviously longer than the motor nerve blocking time, has long-acting local anesthesia effect and selective local anesthesia effect, obviously reduces the side effect of local anesthesia medicaments in the prior art, and has better safety. The quaternary ammonium salt derivative can be used for preparing safe medicines with long-time local anesthesia and selective local anesthesia, and has the advantages of long local anesthesia time, good local anesthesia selectivity, small nerve injury and high safety. The invention provides a new choice for long-acting local anesthetic and selective local anesthetic.

Claims (12)

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: the structure of the compound is shown in a formula IV:
wherein Z is - Is a pharmaceutically acceptable anion;
R d1 、R d2 each independently selected from hydrogen, halogen, C 1～4 Alkoxy, NR e1 R e2 ；R e1 、R e2 Each independently selected from hydrogen, C 1～4 An alkyl group;
L 1 selected from substituted or unsubstituted C 2～3 An alkylene group; the substituents are each independently selected from C 1～2 An alkyl group;
R 2 、R 3 each independently selected from C 1～4 An alkyl group;
L 2 selected from C 2～9 Alkylene or C 2～9 1 to 2 CH in the alkylene backbone 2 A group obtained after replacement by O;
R 0 selected from hydrogen, C 1～4 An alkyl group; r is R 4 Selected from hydrogen, C 1～4 An alkyl group; alternatively, R 0 、R 4 A ring is formed by connection, and the ring is a 6-membered saturated nitrogen ring;
y is selected from L 3 R y ；L 3 Selected from the group consisting of unsubstituted, substituted or unsubstituted methylene groups, said substituents being selected from C 1～2 An alkyl group; r is R y Selected from CONH and OCO;
m is selected from integers of 0 to 3;
R c3 each independently selected from hydrogen, C 1～4 Alkyl, C 1～4 Alkoxy, COOR e3 、NR e1 R e2 ；R e1 、R e2 、R e3 Each independently selected from hydrogen, C 1～4 An alkyl group.
2. A compound or a pharmaceutically acceptable salt thereof, characterized in that: the structure of the compound is shown in a formula V:
wherein Z-is a pharmaceutically acceptable anion;
R d3 、R d4 are all methyl groups;
R 11 selected from hydrogen, substituted or unsubstituted C 1～4 Alkyl, substituted or unsubstituted C 1～4 An alkoxy group; the substituents are selected from halogen, C 1～4 An alkoxy group;
R 6 selected from C 1～2 An alkyl group;
R 7 、R 8 each independently selected from substituted or unsubstituted C 1～10 Alkyl, said substituents being selected from hydroxy, halogen, unsubstituted or hydroxy-substituted C 1～4 Alkoxy, amino, carboxyl, cyano, nitro, mercapto, COOR 12 ，R 12 Selected from C 1～2 An alkyl group;
L 4 selected from C 1～14 Alkylene or C 1～14 1 to 2 CH in the alkylene backbone 2 Quilt R L A group obtained after replacement; r is R L Selected from O, S, COO, OCOO;
R 9 selected from hydrogen, C 1～6 Alkyl, unsubstituted or substituted by C 1～3 Alkyl substituted 3-8 membered saturated cycloalkyl, R 10 Selected from hydrogen, C 1～6 An alkyl group; or R is 9 、R 10 The two rings are connected to form a ring, and the ring is a 4-8 membered saturated nitrogen ring;
w is L 5 Q；L 5 Selected from the group consisting of unsubstituted, substituted or unsubstituted C 1～3 Alkylene, said substituents being selected from C 1～3 An alkyl group; q is selected from CONH and OCO;
p is an integer from 0 to 3;
R a1 each independently selected from hydrogen, C 1～6 Alkyl, C 1～6 Alkoxy, NR e4 R e5 、COOR e6 ；R e4 、R e5 、R e6 Each independently selected from hydrogen, C 1～6 An alkyl group.
3. A compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein: the Z is - Selected from the group consisting of halide anions, sulfate, acetate, tartrate, p-toluenesulfonate, methanesulfonate, citrate.
4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein: the halogen anion is Cl-, br-or I-.
5. A compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutically acceptable salts are salts of the compounds with pharmaceutically acceptable inorganic or organic acids.
6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein:
the inorganic acid or organic acid is hydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, tartaric acid, lauric acid, maleic acid, citric acid, succinic acid, benzoic acid or pamoic acid.
7. A compound or a pharmaceutically acceptable salt thereof, characterized in that: it is selected from one of the following structures
8. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for local anesthesia.
9. Use according to claim 8, characterized in that: the local anesthetic is a long-acting local anesthetic and/or a selective local anesthetic.
10. Use according to claim 9, characterized in that: the sensory nerve blocking time caused by the local anesthetic is longer than the motor nerve blocking time;
and/or the anesthetic time of the local anesthetic is more than 30 hours.
11. Use according to claim 10, characterized in that: the local anesthetic causes a sensory nerve block time longer than a motor nerve block time by more than 10 hours.
12. A local anesthetic, characterized in that: a preparation prepared by adding pharmaceutically acceptable auxiliary materials into the compound or pharmaceutically acceptable salt thereof as active ingredient in any one of claims 1 to 7.
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