Imidazolium salt macrocyclic compound as well as preparation method and application thereof

Abstract

The invention provides an imidazolium salt macrocyclic compound as well as a preparation method and application thereof. Specifically disclosed are macrocyclic compounds represented by formula (I) or pharmaceutically acceptable salts, hydrates or solvates thereof, and applications of the macrocyclic compounds or pharmaceutically acceptable salts, hydrates or solvates thereof and a composition formed by the macrocyclic compounds or pharmaceutically acceptable salts, hydrates or solvates thereof and pharmaceutically acceptable carriers in preparation of muscle relaxant. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular, relates to a class of imidazolium salt macrocyclic compounds and a preparation method thereof and application thereof as a muscle relaxant. Background Art

[0002] Neuromuscular blockers (also known as muscle relaxants) are widely used in clinical anesthesia surgery to relax skeletal muscles, achieve rapid intubation and provide safe surgical conditions. Hundreds of millions of patients worldwide receive muscle relaxant treatment during surgery every year. Among them, non-depolarizing muscle relaxants, such as rocuronium, cisatracurium besylate, vecuronium and pancuronium, have fewer side effects and longer effective time than depolarizing muscle relaxants, so they are more widely used in clinical practice, accounting for more than 95% of clinical use.

[0003] Medium-acting non-depolarizing muscle relaxants, such as rocuronium, vecuronium, and cisatracurium besylate, are injected at a dose of 2 times the ED95 for adult patients, and the effective muscle relaxation time is 30-45 minutes. Injecting a dose of 2 times the ED95 dose of pancuronium bromide, a long-acting muscle relaxant, can maintain effective muscle relaxation for about 75 minutes in adult patients. For general anesthesia surgeries that last longer than the above effective muscle relaxation time, patients need to be given single or multiple additional injections or continuous injections of muscle relaxants, which increases the cost of medication to varying degrees. In addition, single or multiple additional injections of muscle relaxants require determination of the appropriate injection dose and injection time, but may still cause fluctuations or abnormalities in muscle relaxation. Continuous injections also require determination of an appropriate maintenance dose. Both methods require a high degree of reliance on multiple types of medical equipment monitoring, the experience and professional skills of anesthesiologists and nurses, increase or prolong the workload of anesthesiologists and nurses, and result in higher surgical costs.

[0004] Theoretically, if a muscle relaxant can produce a sufficiently long effective muscle relaxation time, it is possible to achieve a single injection of muscle relaxant in one surgery, avoiding the above-mentioned intermittent or continuous additional administration and the resulting increase in comprehensive economic costs. On the premise of ensuring safety, if rapid onset and rapid antagonism after surgery can be further achieved, the complexity of the muscle relaxant medication process in surgical anesthesia will be significantly reduced, the surgical efficiency and medical resource utilization rate will be improved, and ultimately the cost of surgery will be reduced, benefiting patients. The long-acting muscle relaxant pancuronium bromide currently used in clinical practice has a relatively short duration of action, which cannot meet the single administration of surgery lasting more than 75 minutes. There are also a variety of side effects and contraindications, and there is no rapid antagonist that specifically binds to it. Therefore, there is no clinical combination of drugs that achieve long-acting muscle relaxation + rapid antagonism. The development of a combination drug that meets the above performance is an extremely challenging task.

[0005] The muscle relaxants currently used in clinical practice are all tetraalkyl ammonium salt derivatives of different types. Long-acting muscle relaxants generally take effect slowly, and their rapid onset can be achieved through two ways. One is to increase the dosage of muscle relaxants. This method is the simplest to administer, and does not need to be used in combination with other muscle relaxants, avoiding possible side effects caused by the interaction of muscle relaxants, but muscle relaxants need to have a wider dosage window. The other is to be used in combination with fast-acting muscle relaxants currently used in clinical practice, such as rocuronium bromide. This strategy does not require increasing the dose of long-acting muscle relaxants, and this strategy of combined use of muscle relaxants with different efficacy has been widely used in clinical practice. If a safe, fast-acting and long-acting muscle relaxant can be obtained, an antagonist that specifically antagonizes it can be designed based on its structural characteristics, and ultimately achieve rapid antagonism in clinical practice. As the key first step in the development of the above-mentioned new combination drug of long-acting muscle relaxant + rapid antagonist partner type, it is first necessary to develop safe muscle relaxants that can take effect quickly and for a long time, and provide candidate structures for further development of specific rapid antagonists.

[0006] Therefore, there is an urgent need in the art to develop a muscle relaxant that can achieve rapid onset of action, long-term effectiveness, and high safety to meet the needs of clinical use. Summary of the invention

[0007] One object of the present invention is to provide a muscle relaxant with rapid onset, long-term effect and high safety.

[0008] Another object of the present invention is to provide a pharmaceutical composition of a muscle relaxant and a muscle relaxant antagonist.

[0009] In the first aspect of the present invention, there is provided an imidazolium salt macrocyclic compound of formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0010]

[0011] Each R1 is independently selected from the group consisting of H, D, substituted or unsubstituted C 1-20 alkyl, substituted or unsubstituted 1-20 membered heteroalkyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 alkenyl, substituted or unsubstituted 2-20 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkynyl, substituted or unsubstituted 2-20 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted 3-20 membered heterocyclic group containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur;

[0012] Each R2 is independently selected from the group consisting of H, substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted 1-20 membered heteroalkyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 alkenyl, substituted or unsubstituted 2-20 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkynyl, substituted or unsubstituted 2-20 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-20 a cycloalkyl group, a substituted or unsubstituted 3-20 membered heterocyclic group containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, or two adjacent R2 together with the carbon atom to which they are attached form a group selected from the group consisting of: a substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted 3-20-membered heterocyclic group containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, or substituted or unsubstituted 5-20-membered heteroaryl group containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur;

[0013] Each Y and Z is independently selected from the group consisting of: 1-20 Alkylene, substituted or unsubstituted C containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur 1-20 Alkylene, substituted or unsubstituted C 3-20 Cycloalkylene, substituted or unsubstituted C 5-20 Arylene, substituted or unsubstituted Ar1-L-Ar2, substituted or unsubstituted 5-20 membered heteroarylene;

[0014] L is selected from the following group: None, O, NH, C 1-10 Alkylene, S, phenylene;

[0015] Ar1 and Ar2 are each independently null, C 6-10 Arylene or 5-8 membered heteroarylene;

[0016] X is a pharmaceutically acceptable anion that is balanced with the 4-valent cationic imidazolium salt macrocycle in the structure of Formula I;

[0017] Unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group by a group selected from the group consisting of halogen, nitro, amine, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl.

[0018] In another preferred embodiment, each R1 is independently selected from the following group: H, D, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted 1-10 membered heteroalkyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted 2-10 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-10 Alkynyl, substituted or unsubstituted 2-10 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur;

[0019] The substitution refers to the substitution of one or more hydrogen atoms on the group by a group selected from the group consisting of halogen, nitro, amine, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl.

[0020] In another preferred embodiment, each R1 is independently selected from the following group: H, D, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 1-6 membered heteroalkyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted 2-6 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 2-6 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur;

[0021] The substitution refers to the substitution of one or more hydrogen atoms on the group by a group selected from the group consisting of halogen, nitro, amine, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl.

[0022] In another preferred embodiment, each R1 is independently selected from the following group: H, D, substituted or unsubstituted C 1-6alkyl, substituted or unsubstituted 1-6 membered heteroalkyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 3-7 Cycloalkyl;

[0023] The substitution refers to the substitution of one or more hydrogen atoms on the group by a group selected from the group consisting of halogen, nitro, amine, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl.

[0024] In another preferred embodiment, each R2 is independently selected from the following group: H, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted 1-10 membered heteroalkyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted 2-10 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-10 Alkynyl, substituted or unsubstituted 2-10 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or two adjacent R2 together with the carbon atom to which they are attached form a group selected from the group consisting of: substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 3-10 membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or substituted or unsubstituted 5-10 membered heteroaryl group containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur;

[0025] The substitution refers to the substitution of one or more hydrogen atoms on the group by a group selected from the group consisting of halogen, nitro, amine, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl.

[0026] In another preferred embodiment, each R2 is independently selected from the following group: H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 1-6 membered heteroalkyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted 2-6 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C2-6 Alkynyl, substituted or unsubstituted 2-6 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or two adjacent R2 together with the carbon atom to which they are attached form a group selected from the group consisting of: substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 3-7 membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or substituted or unsubstituted 5-7 membered heteroaryl group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur;

[0027] The substitution refers to the substitution of one or more hydrogen atoms on the group by a group selected from the group consisting of halogen, nitro, amine, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl.

[0028] In another preferred embodiment, each R2 is independently selected from the following group: H, substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted 1-6 membered heteroalkyl group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or two adjacent R2 and the carbon atom to which they are attached together form a group selected from the group consisting of: a substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted phenyl;

[0029] The substitution refers to the substitution of one or more hydrogen atoms on the group by a group selected from the group consisting of halogen, nitro, amine, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl.

[0030] In another preferred embodiment, each Y and Z is independently selected from the following group: 1-10 alkylene, substituted or unsubstituted 1-10 membered heteroalkylene containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-10 Cycloalkylene, substituted or unsubstituted C 5-10 Arylene, substituted or unsubstituted Ar1-L-Ar2, substituted or unsubstituted 5-10 membered heteroaryl;

[0031] L is selected from the following group: None, O, S, NH, C 1-6 Alkylene, phenylene;

[0032] Ar1 and Ar2 are each independently null, phenylene or a five-membered heteroarylene group.

[0033] In another preferred embodiment, each Y and Z is independently zero, substituted or unsubstituted C 1-7 alkylene, substituted or unsubstituted 1-7 membered heteroalkylene containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-7 Cycloalkylene, substituted or unsubstituted phenyl, substituted or unsubstituted Ar1-L-Ar2, substituted or unsubstituted 5-8 membered heteroaryl;

[0034] L is selected from the following group: None, O, S, NH, C 1-6 Alkylene, phenylene;

[0035] Ar1, Ar2 are each independently null, phenylene or five-membered heteroarylene;

[0036] The substitution refers to the substitution of one or more hydrogen atoms on the group by a group selected from the group consisting of halogen, nitro, amine, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl.

[0037] In another preferred embodiment, X is selected from the following group: - Br - ,I - 、SO4 2- 、HSO4 - PO4 3- 、HOPO3 2- 、(HO)2PO2 - 、R'CO2 - , - O2C(CH2) n CO2 - (n = 0-20), ArCO2 - 、R'SO3 - 、ArSO3 - 、R'PO3 - 、ArPO3 - , alginate, citrate, aspartate, camphorate, camphorsulfonate, digluconate, glycerophosphate, fumarate, taurine, 2-hydroxyethanesulfonate, lactate, maleate, nicotinate, pamoate, pectinate, thiocyanate, 3-phenylpropionate, picrate, tartrate. Where R' is a substituted or unsubstituted C 1-10Alkyl, Ar is a substituted or unsubstituted 5-7 membered aryl or a substituted or unsubstituted 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S. Preferably it is a chloride ion.

[0038] In another preferred embodiment, R'SO3 - Selected from CH3SO3 - 、PhSO3 - 、CH3PhSO3 - .

[0039] In another preferred embodiment, R1 is H, D, substituted or unsubstituted C 1-3 Alkyl, allyl; wherein the substitution refers to the replacement of the hydrogen of the group by one or more C 1-4 Alkyl or halogen substituted.

[0040] In another preferred embodiment, Selected from Wherein, n=1, 2; G is H, or one or more groups selected from the following group: C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxycarbonyl.

[0041] In another preferred embodiment, each Y and Z is independently zero, or a substituted or unsubstituted group selected from the following group: Wherein, the substitution refers to that one or more hydrogen atoms on the group are replaced by a group selected from the following group: 1-6 Alkyl, halogen, C 1-6 an alkoxycarbonyl group or an amide group.

[0042] In another preferred embodiment, the halogen is fluorine, chlorine, bromine or iodine.

[0043] In another preferred embodiment, each R1 is independently selected from the following group: H, methyl, ethyl.

[0044] In another preferred embodiment, each R2 is independently hydrogen, or two adjacent R2 and the carbon atom to which they are connected together form a substituted or unsubstituted benzene ring, cyclopentyl or cyclohexyl group.

[0045] In another preferred embodiment, the compound is selected from the following group:

[0046]

[0047] Wherein, X is an anion paired with the 4-valent cationic imidazolium salt macrocycle, and the anion is selected from the following group: Cl - Br - ,I - 、SO4 2- 、HSO4- PO4 3- 、HOPO3 2- 、(HO)2PO2 - 、R'CO2 - , - O2C(CH2) n CO2 - (n = 0-20), ArCO2 - 、R'SO3 - 、ArSO3 - 、R'PO3 - 、ArPO3 - , alginate, citrate, aspartate, camphorate, camphorsulfonate, digluconate, glycerophosphate, fumarate, taurine, 2-hydroxyethanesulfonate, lactate, maleate, nicotinate, pamoate, pectinate, thiocyanate, 3-phenylpropionate, picrate, tartrate; wherein R' is substituted or unsubstituted C 1-10 Alkyl, Ar is substituted or unsubstituted C 5-7 aryl or substituted or unsubstituted 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S,

[0048] Wherein, the substitution refers to the substitution of hydrogen on the group by one or more groups selected from the group consisting of halogen, nitro, amine, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl.

[0049] In another preferred embodiment, the compound is Wherein, X is an anion paired with the 4-valent cationic imidazolium salt macrocycle, and the anion is selected from the following group: Cl - Br - ,I - 、SO4 2- 、HSO4 - PO4 3- 、HOPO3 2- 、(HO)2PO2 - 、R'CO2 - , - O2C(CH2) n CO2 - (n = 0-20), ArCO2 - 、R'SO3 - 、ArSO3 - 、R'PO3 -、ArPO3 - , alginate, citrate, aspartate, camphorate, camphorsulfonate, digluconate, glycerophosphate, fumarate, taurine, 2-hydroxyethanesulfonate, lactate, maleate, nicotinate, pamoate, pectinate, thiocyanate, 3-phenylpropionate, picrate, tartrate; wherein R' is substituted or unsubstituted C 1-10 Alkyl, Ar is substituted or unsubstituted C 5-7 Aryl or substituted or unsubstituted 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S;

[0050] The substitution refers to the substitution of one or more hydrogen atoms on the group by a group selected from the group consisting of halogen, nitro, amine, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl.

[0051] In another preferred embodiment, the compound is selected from the following group:

[0052]

[0053] In another preferred embodiment, the compound is

[0054] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0055] (a) as an active ingredient, the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and (b) a pharmaceutically acceptable carrier.

[0056] In another preferred embodiment, in the composition, component (a) accounts for 0.001-99.999wt% of the total weight of the composition; preferably 0.01-99.99wt%; more preferably 0.1-90wt%.

[0057] In another preferred embodiment, the pharmaceutical composition is in the form of an injection, tablet, capsule, pill, suspension or emulsion.

[0058] In a third aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0059] (a) the imidazolium salt macrocyclic compound according to the first aspect of the present invention as the first active ingredient;

[0060] (b) as a second active ingredient, an ingredient having a muscle relaxant effect selected from the group consisting of rocuronium, vecuronium, cisatracurium besylate, pancuronium, or a combination thereof; and

[0061] (c) a pharmaceutically acceptable carrier or excipient.

[0062] In another preferred embodiment, the pharmaceutical composition is in the form of an injection, tablet, capsule, pill, suspension or emulsion.

[0063] In the fourth aspect of the present invention, there is provided a method for preparing the compound according to the first aspect of the present invention, comprising the following steps:

[0064]

[0065] (1) using an excess of imidazole unit Im and a dihalide MCH2YCH2M to undergo a substitution reaction to obtain an imidazole intermediate;

[0066] (2) subjecting the imidazole intermediate to intermolecular and intramolecular substitution reactions with a dihalide MCH2ZCH2M to obtain a tetravalent cationic imidazolium salt macrocyclic compound;

[0067] (3) The 4-valent cationic imidazolium salt macrocyclic compound is exchanged with anion X to obtain the corresponding salt;

[0068] Wherein, each of R1, R2, X, Y, and Z is as described in the first aspect of the present invention; and M is a halogen.

[0069] In another preferred embodiment, the dihalide MCH2YCH2M and the dihalide MCH2ZCH2M can react interchangeably.

[0070] In another preferred embodiment, the dihalide MCH2YCH2M and the dihalide MCH2ZCH2M are the same or different.

[0071] In the fifth aspect of the present invention, there is provided a use of the compound described in the first aspect of the present invention, the pharmaceutical composition described in the second aspect of the present invention, or the pharmaceutical composition described in the third aspect of the present invention as a muscle relaxant.

[0072] In a sixth aspect of the present invention, a kit is provided, comprising:

[0073] (a) a first container, and the compound according to the first aspect of the present invention as an active ingredient, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and / or

[0074] (b) a second container, and a muscle relaxant antagonist located in the second container: neostigmine, sugammadex sodium, or a combination thereof;

[0075] (c) an nth container, and an nth pharmaceutical ingredient in the nth container, wherein n is any positive integer from 3 to 30; wherein the nth pharmaceutical ingredient is the compound according to the first aspect of the present invention, or the pharmaceutical composition according to the second aspect of the present invention, or the pharmaceutical composition according to the third aspect of the present invention; and / or

[0076] (d) Optional instructions.

[0077] In another preferred embodiment, the kit is used for relaxing skeletal muscle.

[0078] In the seventh aspect of the present invention, a method for relaxing skeletal muscle is provided, comprising the steps of administering a therapeutically effective amount of the compound described in the first aspect of the present invention, the pharmaceutical composition described in the second aspect of the present invention, or the pharmaceutical composition described in the third aspect of the present invention to a subject in need thereof, so as to relax the skeletal muscle.

[0079] In another preferred embodiment, the subject is a mammal, preferably a rodent or a primate, more preferably a mouse, a rat or a human.

[0080] In another preferred embodiment, the method is in vitro.

[0081] In another preferred embodiment, the method is non-diagnostic and non-therapeutic.

[0082] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0083] After extensive and in-depth research, the inventors have provided for the first time a macrocyclic compound with a completely new structure incorporating four imidazolium salt groups, and used it as a muscle relaxant. The compound of the present invention carries a positive charge and has a rapid and long-lasting muscle relaxation function. The SD rat animal model test shows that the imidazolium salt macrocyclic compound of the present invention has high muscle relaxant activity, and increasing the dosage can extend the muscle relaxation time to 5 hours. In theory, more than 10 hours of muscle relaxation can be achieved when converted to an adult dose, which can cover more than 95% of surgical patients and achieve rapid onset. Based on this, the inventors have completed the present invention.

[0084] the term

[0085] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0086] As used herein, when used in reference to a specific recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0087] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0088] As used herein, “C 1-20 "Alkyl" refers to a straight or branched chain alkyl group containing 1 to 20 carbon atoms - (CH2) n-1 CH3 (n=1-20), for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc., or the like.

[0089] As used herein, "1-20 membered heteroalkyl" refers to a C 1-20 One or more carbon atoms in the alkyl chain are substituted by heteroatoms selected from nitrogen, oxygen and sulfur. For example, a 1-8 membered heteroalkyl group refers to CH3-CH2-CH2-CH2-O-CH2-CH2-CH2-, or CH3-CH2-CH2-CH2-O-CH2-CH2-O- and the like.

[0090] As used herein, “2-20 membered heteroalkenyl” refers to a group in which one or more carbon atoms in the C2-20 alkenyl chain are substituted by a heteroatom selected from nitrogen, oxygen and sulfur. For example, a 2-7 membered heteroalkenyl group refers to CH3-CH2-CH2-O-CH2-CH=CH-, or CH3-S-CH2-CH2-O-CH=CH- and the like.

[0091] As used herein, “2-20-membered heteroalkynyl” refers to a group in which one or more carbon atoms in the C2-20 alkynyl chain are substituted by a heteroatom selected from nitrogen, oxygen and sulfur. For example, a 2-7-membered heteroalkynyl refers to CH3-CH2-CH2-O-CH2-C≡C-, or CH3-S-CH2-CH2-OC≡C- and the like.

[0092] As used herein, “C 3-20 The term "cycloalkyl" refers to a cycloalkyl group containing 3 to 20 carbon atoms or a cycloalkyl group with a side chain, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0093] As used herein, the term "active ingredient" refers to an imidazolium salt macrocyclic compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof. It should be understood that the active ingredient also includes a mixture of such compounds.

[0094] As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.

[0095] As used herein, the term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0096] As used herein, the term "aryl" refers to a monovalent aromatic carbocyclic group of 6 to 20 (preferably 6-14) carbon atoms, which has a single ring (such as phenyl) or a condensed ring (such as naphthyl or anthracenyl). If the point of attachment is on the aromatic carbon atom, the condensed ring may be non-aromatic (such as 2-benzoxazolone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, etc.). Preferred aryl groups include phenyl and naphthyl.

[0097] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having 3 to 12 (preferably 3 to 10) carbon atoms, having a single ring or multiple rings (including fused systems, bridged ring systems and spiro ring systems). In a fused ring system, one or more rings may be cycloalkyl, heterocyclic, aryl or heteroaryl, as long as the point of attachment is through the cycloalkyl ring. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl.

[0098] As used herein, the term "heteroaryl" refers to an aromatic group having 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring, such heteroaryl groups may be monocyclic (such as pyridyl or furanyl) or fused rings (such as indolizinyl or benzothienyl), wherein the fused ring may be non-aromatic and / or contain one heteroatom, as long as the point of attachment is through the atom of the aromatic heteroaryl. In one embodiment, the ring atoms nitrogen and / or sulfur of the heteroaryl are optionally oxidized to N-oxide (NO), sulfinyl or sulfonyl. Preferably, heteroaryl groups include pyridyl, pyrrolyl, indolyl, thienyl and furanyl. In one embodiment, heteroaryl refers to 3-14 membered heteroaryl, preferably 5-12 membered heteroaryl.

[0099] As used herein, the term "substituted heteroaryl" refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the same substituents as defined for substituted aryl.

[0100] The animal activity test and acute toxicity test in the present invention are carried out using SD rats.

[0101] As used herein, unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on a group by a group selected from the group consisting of halogen, nitro, amine, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl.

[0102] As used herein, the compound of formula I of the present invention is composed of a 4-valent cationic imidazolium salt macrocycle and an anion X that is balanced with the 4-valent cationic imidazolium salt macrocycle; wherein X is one or more anions selected from the group consisting of: Cl - Br - ,I - 、SO4 2- 、HSO4 - PO4 3- 、HOPO3 2- 、(HO)2PO2 - 、R'CO2 - , - O2C(CH2) n CO2 - (n = 0-20), ArCO2 - 、R'SO3 - 、ArSO3 - 、R'PO3 - 、ArPO3 - , alginate, citrate, aspartate, camphorate, camphorsulfonate, digluconate, glycerophosphate, fumarate, taurine, 2-hydroxyethanesulfonate, lactate, maleate, nicotinate, pamoate, pectinate, thiocyanate, 3-phenylpropionate, picrate, tartrate; wherein R' is substituted or unsubstituted C 1-10 Alkyl, Ar is substituted or unsubstituted C 5-7 Aryl or substituted or unsubstituted 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S; wherein the substitution means that one or more hydrogens on the group are replaced by a group selected from the group consisting of halogen, nitro, amine, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl. X indicates that the sum of the valence states of the anions is 4, so as to be balanced with the tetravalent cationic imidazolium salt macrocycle. The anions represented by X can be 4 monovalent anions, 2 divalent anions, 1 divalent anion and 2 monovalent anions; or one monovalent anion and one trivalent anion; wherein the monovalent anions in the 4 monovalent anions can be the same or different, and the divalent anions in the 2 divalent anions can be the same or different.

[0103] Neuromuscular blockers or muscle relaxants

[0104] Neuromuscular blockers or muscle relaxants (abbreviated as muscle relaxants) are widely used in clinical practice to relax skeletal muscles, thereby facilitating intubation or improving surgical conditions. According to different mechanisms of action, muscle relaxants are divided into depolarizing and non-depolarizing types: depolarizing muscle relaxants bind to the N2 choline receptors on the motor nerve end plate membrane, weakening or eliminating the response of muscle cells to acetylcholine; non-depolarizing muscle relaxants compete with acetylcholine for the N2 choline receptors on the motor end plate membrane of skeletal muscle, leading to skeletal muscle relaxation. The non-depolarizing muscle relaxants used more frequently in clinical practice are divided into aminosteroid derivatives (such as rocuronium, vecuronium, and pancuronium) and benzylisoquinoline derivatives (such as cisatracurium besylate) according to their different chemical structures.

[0105] Different from the tetraalkyl ammonium salt derivatives of clinically used muscle relaxants, the present invention provides a macrocyclic compound represented by formula I incorporating four imidazolium salt groups, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0106]

[0107] Wherein, each of R1, R2, Z, Y, and X is as described in the first aspect of the present invention.

[0108] In another preferred embodiment, R1 is H, D, substituted or unsubstituted C 1-3 Alkyl, allyl; wherein the substitution refers to the replacement of the hydrogen of the group by one or more C 1-4 Alkyl or halogen substituted.

[0109] In another preferred embodiment, Selected from Wherein, n=1, 2; G is H, or one or more groups selected from the following group: C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxycarbonyl.

[0110] In another preferred embodiment, each Y and Z is independently zero, or a substituted or unsubstituted group selected from the following group: Wherein, the substitution refers to that one or more hydrogen atoms on the group are replaced by a group selected from the following group: 1-6 Alkyl, halogen, C 1-6 an alkoxycarbonyl group or an amide group.

[0111] In another preferred embodiment, the halogen is fluorine, chlorine, bromine or iodine.

[0112] In another preferred embodiment, each R1 is independently selected from the group consisting of H, methyl, and ethyl.

[0113] In another preferred embodiment, each R2 is independently hydrogen, or two adjacent R2 and the carbon atom to which they are connected together form a substituted or unsubstituted benzene ring, cyclopentyl or cyclohexyl group.

[0114] Preparation method

[0115] The preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be prepared conveniently by combining various synthetic methods described in this specification or known in the art, and such combination can be easily carried out by a technician in the field to which the present invention belongs.

[0116] The invention discloses a macrocyclic compound incorporating four imidazolium salt groups and a preparation method thereof. Animal experiments support that the compound has highly effective neuromuscular blocking activity and has the characteristics of rapid onset and long-term effect.

[0117]

[0118] (1) using an excess of imidazole unit Im and a dihalide MCH2YCH2M to undergo a substitution reaction to obtain an imidazole intermediate;

[0119] (2) subjecting the imidazole intermediate to intermolecular and intramolecular substitution reactions with a dihalide MCH2ZCH2M to obtain a tetravalent cationic imidazolium salt macrocyclic compound;

[0120] (3) The 4-valent cationic imidazolium salt macrocyclic compound is exchanged with anion X to obtain the corresponding salt;

[0121] Wherein, each of R1, R2, X, Y, and Z is as described in the first aspect of the present invention; and M is a halogen.

[0122] In another preferred embodiment, the dihalide MCH2YCH2M and the dihalide MCH2ZCH2M can react interchangeably.

[0123] In another preferred embodiment, the dihalide MCH2YCH2M is the same as or different from the dihalide MCH2ZCH2M.

[0124] Pharmaceutical composition

[0125] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention / dose, more preferably, 10-1000 mg of the compound of the present invention / dose. Preferably, the "one dose" is a capsule or tablet or injection.

[0126] The "active ingredient" described in the present invention refers to the compound of formula I described in the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0127] As used herein, the term "pharmaceutically acceptable salt" refers to non-toxic acid or alkaline earth metal salts of compounds of Formula I. These salts can be prepared in situ during the final isolation and purification of the compounds of Formula I, or by reacting a suitable organic or inorganic acid or base with a basic or acidic functional group, respectively. Representative salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, gluconate heptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthylsulfonate, oxalate, pamoate, pectinate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, and undecanoate. In addition, nitrogen-containing basic groups can be quaternized by the following reagents: alkyl halides, such as chlorides, bromides and iodides of methyl, ethyl, propyl, butyl; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates; long-chain halides such as chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl; aralkyl halides such as benzyl and phenethyl bromides, etc. Water-soluble or oil-soluble or dispersible products are thus obtained. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, citric acid. Base addition salts can be prepared in situ during the final isolation and purification of the compound of formula I, or by reacting the carboxylic acid portion with a suitable base (such as a pharmaceutically acceptable metal cation hydroxide, carbonate or bicarbonate) or ammonia, or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, salts based on alkali and alkaline earth metal cations, such as sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, and non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0128] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0129] Suitable pharmaceutically acceptable carriers or excipients include: such as treating agents and drug delivery modifiers and promoters, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting point wax, ion exchange resins, etc., and any combination of two or more thereof. Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils, including petroleum, animal oil, vegetable oil or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly carriers for injectable solutions, include water, saline, aqueous glucose solutions and ethylene glycol. Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[0130] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0131] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0132] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0133] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0134] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0135] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0136] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0137] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0138] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0139] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0140] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0141] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0142] Compared with the prior art, the main advantages of the present invention include:

[0143] (1) The imidazolium salt macrocyclic compound of the present invention has high muscle relaxant activity and high safety.

[0144] (2) The imidazolium salt macrocyclic compound of the present invention can provide rapid and long-lasting non-depolarizing muscle relaxant effect, which meets the requirements of clinical use.

[0145] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0146] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0147] Example 1

[0148] Taking IMC-1 as an example, the imidazolium salt macrocyclic compound of the present invention adopts the general preparation route shown below:

[0149]

[0150] Dissolve compound 1a (1.43 g, 21 mmol) in 200 mL of acetonitrile, stir at room temperature, add sodium hydroxide (1.6 g, 40 mmol), and continue stirring for 2 h. Dissolve compound 2a (2.64 g, 10 mmol) in 30 mL of acetonitrile, add dropwise to the above acetonitrile solution, and continue stirring at room temperature for 2 h. Filter by suction, spin dry the filtrate, add 100 mL of dichloromethane to completely dissolve, and wash repeatedly with deionized water until the washing liquid is neutral. Add an appropriate amount of anhydrous sodium sulfate to the dichloromethane solution, dry it completely, filter by suction, spin dry the filtrate, and obtain 1.96 g of white solid (yield 82%) for the next reaction. Dissolve the intermediate (0.48 g, 2 mmol) prepared above in 300 mL of acetonitrile, heat to 80 ° C and stir thoroughly. Dissolve compound 2b (0.68 g, 2 mmol) in 80 mL of acetonitrile, add dropwise to the acetonitrile solution of the intermediate, and react at 80 ° C for 48 h. The solvent of the reaction solution was evaporated under reduced pressure, and the crude product was separated and purified by column chromatography using methanol / water / saturated ammonium chloride aqueous solution (12:7:1) as the eluent. The eluent was collected, the solvent was evaporated under reduced pressure, and an appropriate amount of deionized water was added to prepare a saturated aqueous solution. Saturated ammonium hexafluorophosphonate aqueous solution was added dropwise, and a large amount of white solid precipitated. Continue to add dropwise until the white solid precipitated completely. Filter by suction, dry the filter residue, add an appropriate amount of acetonitrile to prepare a saturated acetonitrile solution. Saturated tetrabutylammonium chloride acetonitrile solution was added dropwise, and a large amount of white solid precipitated. Continue to add dropwise until the white solid precipitated completely. Filter by suction, dry the filter residue, and obtain 192 mg of white powdered solid IMC-1 with a yield of 20%. 1H NMR(400MHz,Deuterium Oxide)δ8.84(s,4H),7.57(d,J=1.8Hz,4H),7.44(s,8H),7.39(d,J=1.7Hz,4H),7.32–7.30(m,8H),7.24–7.22(m,8H),5.42(s,8H),5.33(s,8H).

[0151] Example 2

[0152]

[0153] The preparation of IMC-2 was firstly to react compound 1a with compound 2c, and then with compound 2b. The specific steps were the same as those for the preparation of IMC-1, and the yield was 19%. 1H NMR (400MHz, Deuterium Oxide) δ8.90 (s, 4H), 7.59 (s, 6H), 7.47 (d, J=2.0Hz, 4H), 7.34–7.32 (m, 12H), 7.26–7.24 (m, 8H), 7.00 (s, 2H), 5.45 (s, 8H), 5.28 (s, 8H).

[0154] Example 3

[0155]

[0156] The preparation of IMC-3 was firstly to react compound 1a with compound 2b, and then with compound 2d. The specific steps were the same as those for the preparation of IMC-1, with a yield of 13%. 1H NMR (400MHz, Deuterium Oxide) δ8.94 (s, 4H), 8.17 (d, J = 1.7 Hz, 4H), 7.51 (d, J = 2.1 Hz, 4H), 7.38 (d, J = 2.0 Hz, 4H), 7.36–7.34 (m, 8H), 7.29–7.28 (m, 10H), 5.53 (s, 8H), 5.31 (s, 8H), 3.92 (s, 6H).

[0157] Example 4

[0158]

[0159] IMC-3 was hydrolyzed to obtain carboxyl-substituted IMC-4, and the specific steps were as follows: IMC-3 (0.01 g, 0.088 mmol) was dissolved in a mixed solvent of 2 mL methanol and 2 mL deionized water, sodium hydroxide (0.014 g, 0.35 mmol) was added, and stirred at room temperature for 12 h. The reaction solution solvent was spin-dried, 5 mL deionized water was added to dissolve, and 2 M hydrochloric acid solution was added dropwise, and a white precipitate was generated. The addition was continued until the solid was completely precipitated. Filtered by suction, the filter residue was dried, and 79 mg of white solid IMC-4 was obtained, with a yield of 84%. 1H NMR (400MHz, Deuterium Oxide) δ8.92(s,4H),8.16(s,4H),7.48(s,4H),7.37–7.34(m,12H),7.27–7.23(m,10H),5.51(s,8H),5.29(s,8H).

[0160] Example 5

[0161]

[0162] The same preparation method as IMC-1 was used, compound 1a was reacted with compound 2a, and then with compound 2e to separate the tetravalent imidazolium salt macrocyclic compound IMC-5 (yield 6%) and the divalent bisimidazolium salt cyclic compound IMC-5' (yield 8%). IMC-5: 1H NMR (400MHz, Deuterium Oxide) δ8.71 (s, 4H), 7.51 (d, J = 2.0 Hz, 4H), 7.45 (d, J = 2.0 Hz, 4H), 7.37 (s, 8H), 7.11 (ABq, J = 8.0 Hz, 16H), 5.37 (s, 8H), 5.30 (s, 8H), 3.76 (s, 4H). IMC-5': 1H NMR (400MHz, Deuterium Oxide) δ7.67(s,2H),7.58(s,2H),7.33-7.28(m,8H),7.18(s,4H),5.33(s,4H),5.31(s,4H),3.91(s,2H).

[0163] Example 6

[0164]

[0165] The preparation of IMC-6 was firstly to react compound 1a with compound 2c, and then with compound 2e. The specific steps were the same as those for the preparation of IMC-1, with a yield of 26%. 1H NMR (400MHz, Deuterium Oxide) δ8.29 (s, 4H), 7.68 (d, J = 2.0 Hz, 4H), 7.57 (d, J = 2.1 Hz, 4H), 7.47–7.43 (m, 10H), 7.38–7.35 (m, 12H), 7.11 (s, 2H), 5.30 (s, 8H), 5.26 (s, 8H), 3.99 (s, 4H).

[0166] Example 7

[0167]

[0168] The preparation of IMC-7 was firstly to react compound 1a with compound 2a, and then with compound 2f. The specific steps were the same as those for the preparation of IMC-1, and the yield was 7%. 1H NMR (400MHz, Deuterium Oxide) δ8.80 (s, 4H), 7.56 (d, J = 1.8 Hz, 4H), 7.50 (d, J = 1.6 Hz, 4H), 7.44 (s, 8H), 7.32–7.30 (m, 8H), 6.95–6.93 (m, 8H), 5.43 (s, 8H), 5.36 (s, 8H).

[0169] Example 8

[0170]

[0171] The preparation of IMC-8 was firstly to react compound 1a with compound 2c, and then with compound 2f. The specific steps were the same as those for the preparation of IMC-1, and the yield was 16%. 1H NMR (400MHz, Deuterium Oxide) δ8.81 (s, 4H), 7.59–7.52 (m, 6H), 7.41 (d, J=1.9Hz, 4H), 7.39 (d, J=1.9Hz, 4H), 7.28–7.26 (m, 8H), 7.06 (s, 2H), 6.87–6.84 (m, 8H), 5.40 (s, 8H), 5.32 (s, 8H).

[0172] Example 9

[0173]

[0174] IMC-8 was placed in heavy water and placed at room temperature for 2 hours to obtain the deuterated product IMC-8-d4 with a yield of 100%. 1H NMR (400MHz, Deuterium Oxide) δ7.59–7.52 (m, 6H), 7.41 (d, J=1.9Hz, 4H), 7.39 (d, J=1.9Hz, 4H), 7.28–7.26 (m, 8H), 7.06 (s, 2H), 6.87–6.84 (m, 8H), 5.40 (s, 8H), 5.32 (s, 8H).

[0175] Example 10

[0176]

[0177] The preparation of IMC-9 was firstly to react compound 1a with compound 2f, and then with compound 2d. The specific steps were the same as those for the preparation of IMC-1. Yield: 18%. 1H NMR (400MHz, Deuterium Oxide) δ8.87 (s, 4H), 8.09 (s, 4H), 7.48–7.46 (m, 8H), 7.39 (s, 2H), 7.32–7.30 (m, 8H), 6.89–6.87 (m, 8H), 5.50 (s, 8H), 5.36 (s, 8H), 3.89 (s, 6H).

[0178] Embodiment 11

[0179]

[0180] IMC-10 is the hydrolysis product of IMC-9, and the specific steps are the same as those of IMC-4, with a yield of 84%. 1H NMR (400MHz, Deuterium Oxide) δ8.83 (s, 4H), 7.94 (d, J=1.6Hz, 4H), 7.46–7.44 (m, 8H), 7.30–7.28 (m, 8H), 7.26 (s, 2H), 6.86–6.84 (m, 8H), 5.46 (s, 8H), 5.34 (s, 8H).

[0181] Example 12

[0182]

[0183] The preparation of IMC-11 was firstly to react compound 1b with compound 2c, and then with compound 2f. The specific steps were the same as those for the preparation of IMC-1, with a yield of 13%. 1H NMR (400MHz, Deuterium Oxide) δ7.52–7.48 (m, 2H), 7.42–7.40 (m, 4H), 7.33 (s, 4H), 7.24–7.21 (m, 12H), 6.88–6.86 (m, 8H), 6.52 (s, 2H), 5.33 (s, 8H), 5.26 (s, 8H), 2.40 (s, 12H).

[0184] Example 13

[0185]

[0186] The preparation of IMC-12 was firstly to react compound 1a with compound 2g, and then with compound 2f. The specific steps were the same as those for the preparation of IMC-1, with a yield of 16%. 1H NMR (400MHz, Deuterium Oxide) δ8.93 (s, 4H), 7.49–7.39 (m, 16H), 7.02 (brs, 8H), 6.65 (s, 4H), 5.40–5.35 (m, 16H).

[0187] Embodiment 14

[0188]

[0189] The preparation of IMC-13 was firstly to react compound 1a with compound 3b, and then with compound 2f. The specific steps were the same as those for the preparation of IMC-1, and the yield was 14%. 1H NMR (400MHz, Deuterium Oxide) δ8.86 (s, 4H), 7.43 (d, J = 1.9 Hz, 4H), 7.37 (d, J = 1.9 Hz, 4H), 7.36–7.34 (m, 8H), 6.96–6.93 (m, 8H), 5.33 (s, 8H), 4.18 (t, J = 6.5 Hz, 8H), 1.88–1.83 (m, 8H), 1.11–1.03 (m, 4H).

[0190] Embodiment 15

[0191]

[0192] The preparation of IMC-14 was firstly to react compound 1b with compound 3b, and then with compound 2f. The specific steps were the same as those for the preparation of IMC-1, with a yield of 13%. 1H NMR (400MHz, Deuterium Oxide) δ7.32 (d, J = 2.2 Hz, 4H), 7.27–7.25 (m, 12H), 6.96–6.93 (m, 8H), 5.29 (s, 8H), 4.14 (t, J = 6.3 Hz, 8H), 2.55 (s, 12H), 1.85–1.78 (m, 8H), 1.10–1.03 (m, 4H).

[0193] Example 16

[0194]

[0195] The preparation of IMC-15 was firstly to react compound 1c with compound 3b, and then with compound 2f. The specific steps were the same as those for the preparation of IMC-1, and the yield was 15%. 1H NMR (400MHz, Deuterium Oxide) δ7.41 (d, J = 2.2 Hz, 4H), 7.35 (d, J = 2.2 Hz, 4H), 7.26–7.24 (m, 8H), 6.96–6.92 (m, 8H), 5.33 (s, 8H), 4.18 (t, J = 6.2 Hz, 8H), 3.01 (q, J = 7.6 Hz, 8H), 1.95–1.88 (m, 8H), 1.13–1.05 (m, 4H), 1.01 (t, J = 7.6 Hz, 12H).

[0196] Embodiment 17

[0197]

[0198] The preparation of IMC-16 was firstly to react compound 1d with compound 3b, and then with compound 2f. The specific steps were the same as those for the preparation of IMC-1, with a yield of 14%. 1H NMR (400MHz, Deuterium Oxide) δ7.60–7.55 (m, 8H), 7.45–7.36 (m, 8H), 7.00–6.97 (m, 8H), 6.42–6.38 (m, 8H), 5.58 (s, 8H), 4.56 (t, J=6.2Hz, 8H), 2.11–2.04 (m, 8H), 1.35–1.27 (m, 4H).

[0199] Embodiment 18

[0200]

[0201] The preparation of IMC-17 was firstly to react compound 1b with compound 3a, and then with compound 2f. The specific steps were the same as those for the preparation of IMC-1, and the yield was 14%. 1H NMR (400MHz, Deuterium Oxide) δ7.43 (d, J = 2.2 Hz, 4H), 7.39 (d, J = 2.2 Hz, 4H), 7.26–7.22 (m, 8H), 6.82–6.78 (m, 8H), 5.29 (s, 8H), 4.07 (t, J = 6.8 Hz, 8H), 2.56 (s, 12H), 1.65 (t, J = 6.8 Hz, 8H), 1.10 (brs, 12H).

[0202] Embodiment 19

[0203]

[0204] The preparation of IMC-18 was firstly to react compound 1b with compound 3c, and then with compound 2f. The specific steps were the same as those for the preparation of IMC-1, and the yield was 14%. 1H NMR (400MHz, Deuterium Oxide) δ7.37 (d, J = 2.2 Hz, 4H), 7.35 (d, J = 2.2 Hz, 4H), 7.23–7.19 (m, 8H), 6.89–6.85 (m, 8H), 5.33 (s, 8H), 4.18 (t, J = 5.2 Hz, 8H), 2.48 (s, 12H), 1.70–1.66 (m, 8H).

[0205] Embodiment 20

[0206]

[0207] The preparation of IMC-19 was firstly to react compound 1b with compound 3d, and then with compound 2f. The specific steps were the same as those for the preparation of IMC-1, with a yield of 16%. 1H NMR (400MHz, Deuterium Oxide) δ7.33–7.29 (m, 12H), 7.07–7.03 (m, 12H), 5.26 (s, 8H), 4.33 (t, J = 6.3 Hz, 8H), 2.57 (s, 12H), 2.53 (t, J = 6.4 Hz, 4H).

[0208] Embodiment 21

[0209]

[0210] The preparation of IMC-20 is to first react compound 1b with compound CH2Cl2, and then react with compound 2f. The specific steps are the same as those for the preparation of IMC-1. The yield is 14%. 1H NMR (400MHz, Deuterium Oxide) δ7.73 (d, J = 2.3 Hz, 4H), 7.64 (d, J = 2.3 Hz, 4H), 7.26 (d, J = 8.3 Hz, 8H), 7.01 (d, J = 8.3 Hz, 8H), 6.69 (s, 4H), 5.41 (s, 8H), 2.65 (s, 12H).

[0211] Example 22: Effects of different dosages of imidazolium salt macrocyclic compounds on neuromuscular blocking effects

[0212] Taking IMC-19 as an example, SD rats were used as a model to test the muscle relaxant effect. Specifically, IMC-19 was prepared as an injection with distilled water as the solvent, and the concentration was 0.8μg / mL-16μg / mL; SD rats weighing 170 to 240 grams were selected as test subjects, and 2, 13, 16, 20 and 40μg / kg dosage groups were set, with 2 male and 2 female animals in each group, and the same was true for the following test examples.

[0213] The operation process is as follows: rats were anesthetized with isoflurane, with an induction dose of 4% and a maintenance dose of 1%; 10% Na2S solution was used to remove the right hind leg and nearby hair of the rat; an airway was inserted into the rat's trachea and connected to a small animal ventilator, with a tidal volume of 1.7 mL and a respiratory rate of 80 times / min; a muscle relaxation monitor was used to test the neuromuscular blockade of the quadriceps femoris of the rat, wherein the sensor was fixed to the tibia of the rat, and the electrode was fixed to the right hind leg of the rat through a patch, and then the Cal mode was used for calibration, and the single stimulation mode (ST) was switched to after the data stabilized. When the ST value was stable ≥90, 10 ST data were recorded continuously, and the average value was calculated, which was recorded as the baseline mean ST0; according to the experimental protocol, IMC-19 injection was injected through the rat's tail vein, and the injection volume was adjusted according to the rat's weight. The injection operation was completed within 5 seconds. After the injection was completed, the timing was started and the ST value change was recorded; when the ST value dropped to the lowest point, 5 ST data were recorded continuously, and the average value was calculated, which was recorded as ST min , (ST0-ST min ) / ST0 is the maximum muscle blocking rate of the imidazolium salt macrocyclic compound at this dose.

[0214] The experimental results are listed in Table 1. The results showed that when the dosage of IMC-19 was 2 μg / kg, there was no blocking effect. As the dosage increased, the maximum muscle blocking rate gradually increased. When the dosage reached 16 μg / kg, the maximum muscle blocking rate was higher than 90%. When the dosage reached 40 μg / kg, the maximum muscle blocking rate reached 100%.

[0215] Table 1. Dose dependence of IMC-19 muscle relaxant activity

[0216]

[0217]

[0218] Example 23: ED95 test of muscle relaxant activity of imidazolium salt macrocyclic compounds

[0219] Taking IMC-19 as an example, SD rats were used as a model to determine the ED95 of the muscle relaxant activity of imidazolium salt macrocyclic compounds. The specific implementation process is: IMC-19 is prepared as an injection with distilled water as the solvent, and the concentrations are 0.8μg / mL-16μg / mL; 2μg / kg, 10μg / kg, 13μg / kg, 16μg / kg, 20μg / kg and 40μg / kg dosage groups are set, with 2 male and female animals in each group. The actual injection volume is calculated according to the rat body weight and the injection concentration. The operation process is the same as Example 22, and the maximum muscle blocking rate (ST0-ST min ) / ST0, the experimental results were fitted with the drug inhibition curve using GraphPad Prism software, and the ED95 of IMC-19 was calculated to be approximately 17.5 μg / kg.

[0220] Example 24: Screening of neuromuscular blocking effect at a specific dosage

[0221] The neuromuscular blocking effect of imidazolium macrocyclic compounds at specific dosages was screened.

[0222] Specifically, the imidazolium salt macrocyclic compound is prepared as an injection with distilled water as the solvent, and the dosage group of 20 μg / kg-1800 μg / kg is set, and each dosage group has 2 animals of both sexes. The operation process is the same as Example 22. After the injection is completed, the timing is started and the changes in ST value are recorded: when the ST value decreases to 95% ST0, the time t1 is recorded; when the ST value recovers to 25% ST0, the time t2 is recorded; when the ST value recovers to 90% ST0, the time t3 is recorded, t1 is the onset time of muscle relaxation, t2-t1 is the duration of muscle relaxation, and t3-t2 is the recovery time of muscle relaxation; and the maximum muscle blocking rate is recorded; all results are taken as the average value of 4 animals in each group.

[0223] The experimental results are shown in Table 2. IMC-1, IMC-5, IMC-7, IMC-8, IMC-10, IMC-11, and IMC-13 can achieve more than 90% muscle blockade at a certain dosage, and IMC-14, IMC-15, IMC-17, IMC-18, and IMC-19 can achieve 100% muscle blockade at a lower dosage of 20 μg / kg-40 μg / kg. The maximum blocking rate of the bisimidazolium salt cyclic compound IMC-5' at a dose of 2000 μg / kg is only 23.3%, which shows that the muscle blocking activity of the tetravalent imidazolium salt macrocyclic compound is much higher than that of the divalent cyclic compound.

[0224] Table 2. Dosage of imidazolium salt macrocyclic compounds and maximum neuromuscular blocking rate

[0225]

[0226]

[0227] Example 25: Testing of onset and duration of action of imidazolium salt macrocyclic compounds

[0228] Using the test conditions described in Example 24, the imidazolium salt macrocyclic compound with a maximum muscle blocking rate of 100% was further monitored for the onset time and duration of muscle relaxation. The results are listed in Table 3. The test results show that the imidazolium salt macrocyclic compound can achieve rapid onset (0.24min) and long-lasting muscle relaxation (5 hours) at high doses.

[0229] Table 3. Onset and duration of muscle relaxant effect at different doses of imidazolium macrocyclic compounds

[0230]

[0231] Example 26: Imidazolium macrocyclic compound antagonism test

[0232] Taking IMC-19 as an example, neostigmine was used as an antagonist to detect the antagonistic effect of cholinesterase inhibitors on imidazolium macrocyclic compounds.

[0233] Specifically: the imidazolium salt macrocyclic compound is prepared as an injection with distilled water as solvent, and the concentration is 8.0μg / mL; neostigmine is prepared as an injection with distilled water as solvent, and the concentration is 48μg / mL; the dosage of IMC-19 is 20μg / kg, and the dosage of antagonist is 240μg / kg. The actual injection volume is calculated according to the rat body weight and the injection concentration. There are 2 male and female animals in each group, and the results are averaged. The operation process is the same as in Example 22. After the injection is completed, the timing is started and the ST value change is recorded; when the ST value drops to the lowest point, after the monitoring data is stable, the neostigmine solution is injected into the rat through the tail vein, and the time and ST value change are recorded after the injection is completed.

[0234] The experimental results show that neostigmine can rapidly antagonize muscle blockade caused by imidazolium salt macrocyclic compounds. Since neostigmine is a cholinesterase inhibitor, it inhibits the hydrolysis of acetylcholine in the body, thereby achieving the enrichment of acetylcholine, and then competitively squeezes out the imidazolium salt macrocyclic compounds on the acetylcholine receptor, thereby restoring the transmission of neuromuscular excitation and ultimately achieving the reversal of the muscle relaxant effect.

[0235] The experimental results show that imidazolium macrocyclic compounds are a class of competitive N2 cholinergic receptor inhibitors, which meet the characteristics of non-depolarizing muscle relaxants and indicate that they have high safety.

[0236] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. An imidazolium salt macrocyclic compound of formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that: Each R1 is independently selected from the group consisting of H, D, substituted or unsubstituted C 1-20 alkyl, substituted or unsubstituted 1-20 membered heteroalkyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 alkenyl, substituted or unsubstituted 2-20 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkynyl, substituted or unsubstituted 2-20 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted 3-20 membered heterocyclic group containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur; Each R2 is independently selected from the group consisting of H, substituted or unsubstituted C 1-20 alkyl, substituted or unsubstituted 1-20 membered heteroalkyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 alkenyl, substituted or unsubstituted 2-20 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkynyl, substituted or unsubstituted 2-20 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-20 a cycloalkyl group, a substituted or unsubstituted 3-20 membered heterocyclic group containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, or two adjacent R2 together with the carbon atom to which they are attached form a group selected from the group consisting of: a substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted 3-20-membered heterocyclic group containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, or substituted or unsubstituted 5-20-membered heteroaryl group containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur; Each Y and Z is independently selected from the group consisting of: 1-20 Alkylene, substituted or unsubstituted C containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur 1-20 Alkylene, substituted or unsubstituted C 3-20 Cycloalkylene, substituted or unsubstituted C 5-20 Arylene, substituted or unsubstituted Ar1-L-Ar2, substituted or unsubstituted 5-20 membered heteroarylene; L is selected from the following group: None, O, NH, C 1-10 Alkylene, S, phenylene; Ar1 and Ar2 are each independently zero, C 6-10 Arylene or 5-8 membered heteroarylene; X is a pharmaceutically acceptable anion that is balanced with the 4-valent cationic imidazolium salt macrocycle in the structure of Formula I; Unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group by a group selected from the group consisting of halogen, nitro, amine, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl.

2. The compound according to claim 1, characterized in that Each R1 is independently selected from the group consisting of H, D, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 1-6 membered heteroalkyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted 2-6 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 2-6 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur; Each R2 is independently selected from the following group: Each R2 is independently selected from the following group: H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 1-6 membered heteroalkyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted 2-6 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 2-6 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or two adjacent R2 together with the carbon atom to which they are attached form a group selected from the group consisting of: substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 3-7 membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or substituted or unsubstituted 5-7 membered heteroaryl group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur; Each Y and Z is independently selected from the group consisting of: 1-10 alkylene, substituted or unsubstituted 1-10 membered heteroalkylene containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-10 Cycloalkylene, substituted or unsubstituted C 5-10 Arylene, substituted or unsubstituted Ar1-L-Ar2, substituted or unsubstituted 5-10 membered heteroaryl; L is selected from the following group: None, O, S, NH, C 1-6 Alkylene, phenylene; Ar1 and Ar2 are each independently null, phenylene or a five-membered heteroarylene group.

3. The compound according to claim 1, characterized in that Each R1 is independently selected from the group consisting of H, D, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 1-6 membered heteroalkyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 3-7 Cycloalkyl; Each R2 is independently selected from the group consisting of H, substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted 1-6 membered heteroalkyl group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or two adjacent R2 and the carbon atom to which they are attached together form a group selected from the group consisting of: a substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted phenyl; Each Y and Z is independently zero, substituted or unsubstituted C 1-7 alkylene, substituted or unsubstituted 1-7 membered heteroalkylene containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-7 Cycloalkylene, substituted or unsubstituted phenyl, substituted or unsubstituted Ar1-L-Ar2, substituted or unsubstituted 5-8 membered heteroaryl; L is selected from the following group: None, O, S, NH, C 1-6 Alkylene, phenylene; Ar1 and Ar2 are each independently null, phenylene or a five-membered heteroarylene group.

4. The compound according to claim 1, characterized in that R1 is H, D, substituted or unsubstituted C 1-3 Alkyl, allyl; wherein the substitution refers to the replacement of the hydrogen of the group by one or more C 1-4 Alkyl or halogen substituted.

5. The compound according to claim 1, characterized in that Selected from Wherein, n=1, 2; G is H, or one or more groups selected from the following group: C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxycarbonyl.

6. The compound according to claim 1, characterized in that Each Y and Z is independently zero, or a substituted or unsubstituted group selected from the following group: Wherein, the substitution refers to that one or more hydrogen atoms on the group are replaced by a group selected from the following group: 1-6 Alkyl, halogen, C 1-6 an alkoxycarbonyl group or an amide group.

7. The compound according to claim 1, characterized in that Each R2 is independently hydrogen, or two adjacent R2 and the carbon atom to which they are connected together form a substituted or unsubstituted benzene ring, cyclopentyl or cyclohexyl.

8. The compound according to claim 1, characterized in that The 4-valent cationic imidazolium salt macrocycle in the compound is selected from the following group: Wherein, X is an anion paired with the 4-valent cationic imidazolium salt macrocycle, and the anions are independently selected from the following group: Cl - Br - ,I - 、SO4 2- 、HSO4 - PO4 3- 、HOPO3 2- 、(HO)2PO2 - 、R'CO2 - , - O2C(CH2) n CO2 - (n = 0-20), ArCO2 - 、R'SO3 - 、ArSO3 - 、R'PO3 - 、ArPO3 - , alginate, citrate, aspartate, camphorate, camphorsulfonate, digluconate, glycerophosphate, fumarate, taurine, 2-hydroxyethanesulfonate, lactate, maleate, nicotinate, pamoate, pectinate, thiocyanate, 3-phenylpropionate, picrate, tartrate; wherein R' is substituted or unsubstituted C 1-10 Alkyl, Ar is substituted or unsubstituted C 5-7 Aryl or substituted or unsubstituted 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S; The substitution refers to the substitution of one or more hydrogen atoms on the group by a group selected from the group consisting of halogen, nitro, amine, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl.

9. A pharmaceutical composition, characterized in that include: (a) the compound according to claim 1 as an active ingredient, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and (b) a pharmaceutically acceptable carrier.

10. A pharmaceutical composition, characterized in that include: (a) the imidazolium salt macrocyclic compound according to claim 1 as the first active ingredient; (b) as a second active ingredient, an ingredient having a muscle relaxant effect selected from the group consisting of rocuronium, vecuronium, cisatracurium besylate, pancuronium, or a combination thereof; and (c) a pharmaceutically acceptable carrier or excipient.

11. A method for preparing the compound according to claim 1, characterized in that: The steps include: (1) using an excess of imidazole unit Im and a dihalide MCH2YCH2M to undergo a substitution reaction to obtain an imidazole intermediate shown in formula II; (2) subjecting the imidazole intermediate to intermolecular and intramolecular substitution reactions with a dihalide MCH2ZCH2M to obtain a tetravalent cationic imidazolium salt macrocyclic compound; as well as (3) The 4-valent cationic imidazolium salt macrocyclic compound is exchanged with anion X to obtain the corresponding salt; Wherein, each of R1, R2, X, Y, and Z is as described in claim 1; and M is a halogen.

12. Use of the compound of claim 1, the pharmaceutical composition of claim 9, or the pharmaceutical composition of claim 10 as a muscle relaxant.

13. A kit, characterized in that: include: (a) a first container, and the compound according to claim 1 as an active ingredient, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and / or (b) a second container, and a muscle relaxant antagonist located in the second container: neostigmine, sugammadex sodium, or a combination thereof; (c) an nth container, and an nth pharmaceutical ingredient in the nth container, wherein n is any positive integer from 3 to 30; wherein the nth pharmaceutical ingredient is the compound according to claim 1, or the pharmaceutical composition according to claim 9, or the pharmaceutical composition according to claim 10; and / or (d) Optional instructions.

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