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

Imidazolium salt macrocyclic compound and its preparation method and use Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a class of imidazolium salt macrocyclic compounds, a preparation method thereof, and an 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, enable rapid intubation, and provide safe surgical conditions. Hundreds of millions of patients worldwide receive muscle relaxant treatment during surgery each year. Among them, non-depolarizing muscle relaxants, such as rocuronium, cisatracurium besylate, vecuronium, and pancuronium, have fewer side effects and a longer duration of effectiveness than depolarizing muscle relaxants. Therefore, they are more widely used in clinical practice, accounting for over 95% of clinical use.

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

[0004] In theory, if a muscle relaxant can produce a sufficiently long effective muscle relaxation time, it is possible to achieve a single injection of muscle relaxant for one surgery, avoiding the above-mentioned intermittent or continuous additional administration and the resulting increase in comprehensive economic costs. Under 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 during 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 and cannot meet the single administration requirements for surgeries lasting more than 75 minutes. It also has 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 achieves long-acting muscle relaxation + rapid antagonism. The research and development of combination drugs that meet the above performance is a very challenging task.

[0005] The muscle relaxants currently used clinically are all different types of tetraalkyl ammonium salt derivatives. Long-acting muscle relaxants generally have a slow onset of action, and achieving rapid onset can be achieved through two approaches. One is to increase the dosage of the muscle relaxant. This method is the simplest to administer and does not require combination with other muscle relaxants, avoiding possible side effects caused by muscle relaxant interactions, but the muscle relaxant requires a wider dosage window. The other is to combine it with currently used clinically rapid-acting muscle relaxants such as rocuronium bromide. This strategy does not require increasing the dosage of long-acting muscle relaxants, and this combination strategy of muscle relaxants with different pharmacological effects has been widely used in clinical practice. If a muscle relaxant with safety, rapid onset, and long-term effect can be obtained, antagonists that specifically antagonize it can be designed based on its structural characteristics, ultimately achieving rapid antagonism in the clinic. As a key first step in the development of the above-mentioned new combination drug type of long-acting muscle relaxant + rapid antagonist partner, it is necessary to first develop a safe muscle relaxant with rapid onset and long-term effect to 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.

[0007] Summary of the Invention

[0008] One object of the present invention is to provide a muscle relaxant with rapid onset, long-lasting effect and high safety.

[0009] Another object of the present invention is to provide a pharmaceutical composition of a muscle relaxant and a muscle relaxant antagonist.

[0010] 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,

[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 C 1-20alkyl, 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, 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 3-20 Cycloalkyl, substituted or unsubstituted C 6-20 aryl, a substituted or unsubstituted 3-20-membered heterocyclic group containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, or a 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: none, substituted or unsubstituted C 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 zero, C 6-10 Arylene or 5-8 membered heteroarylene;

[0016] X is a pharmaceutically acceptable anion that is balanced with the tetravalent 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 a group by a group selected from the group consisting of halogen, nitro, amino, 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 C1-10 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] Wherein, the substitution refers to the substitution of one or more hydrogens on the group by a group selected from the group consisting of halogen, nitro, amino, 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] Wherein, the substitution refers to the substitution of one or more hydrogens on the group by a group selected from the group consisting of halogen, nitro, amino, 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 1-6 alkyl, substituted or unsubstituted 1-6 membered heteroalkyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-6Alkenyl, substituted or unsubstituted C 3-7 Cycloalkyl;

[0023] Wherein, the substitution refers to the substitution of one or more hydrogens on the group by a group selected from the group consisting of halogen, nitro, amino, 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 groups: 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, a substituted or unsubstituted 3- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or a substituted or unsubstituted 5- to 10-membered heteroaryl group containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur;

[0025] Wherein, the substitution refers to the substitution of one or more hydrogens on the group by a group selected from the group consisting of halogen, nitro, amino, 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 groups: 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 2-6Alkynyl, 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, a substituted or unsubstituted 3-7 membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or a substituted or unsubstituted 5-7 membered heteroaryl group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur;

[0027] Wherein, the substitution refers to the substitution of one or more hydrogens on the group by a group selected from the group consisting of halogen, nitro, amino, 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 groups: 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, 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 phenyl;

[0029] Wherein, the substitution refers to the substitution of one or more hydrogens on the group by a group selected from the group consisting of halogen, nitro, amino, 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 groups: 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] Wherein, the substitution refers to the substitution of one or more hydrogens on the group by a group selected from the group consisting of halogen, nitro, amino, 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: 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 1-10Alkyl, Ar is a substituted or unsubstituted 5-7 membered aryl group or a substituted or unsubstituted 5-7 membered heteroaryl group 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 means that the hydrogen of the group is replaced 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 groups: 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 the substitution of one or more hydrogen atoms on the group by a group selected from the group consisting of: C 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, and 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] Wherein, X is an anion paired with the tetravalent cation imidazolium salt macrocycle, and the anion is selected from the following group: Cl - Br - , I - 、SO4 2- 、HSO4 - PO43- 、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,

[0047] 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, amino, 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.

[0048] In another preferred embodiment, the compound is Wherein, X is an anion paired with the tetravalent cation 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, and S;

[0049] Wherein, the substitution refers to the substitution of one or more hydrogens on the group by a group selected from the group consisting of halogen, nitro, amino, 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.

[0050] In another preferred embodiment, the compound is selected from the following group:

[0051] In another preferred embodiment, the compound is

[0052] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising:

[0053] (a) 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 (b) a pharmaceutically acceptable carrier.

[0054] In another preferred embodiment, in the composition, component (a) accounts for 0.001-99.999 wt% of the total weight of the composition; preferably 0.01-99.99 wt%; more preferably 0.1-90 wt%.

[0055] In another preferred embodiment, the pharmaceutical composition is in the form of an injection, tablet, capsule, pill, suspension or emulsion.

[0056] In a third aspect of the present invention, there is provided a pharmaceutical composition comprising:

[0057] (a) the imidazolium salt macrocyclic compound according to the first aspect of the present invention as the first active ingredient;

[0058] (b) as a second active ingredient, an ingredient having a muscle relaxant effect selected from the group consisting of rocuronium bromide, vecuronium bromide, cisatracurium besylate, pancuronium bromide, or a combination thereof; and

[0059] (c) a pharmaceutically acceptable carrier or excipient.

[0060] In another preferred embodiment, the pharmaceutical composition is in the form of an injection, tablet, capsule, pill, suspension or emulsion.

[0061] In a 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:

[0062] (1) using an excess of imidazole unit Im and dihalide MCH2YCH2M to undergo substitution reaction to obtain an imidazole intermediate;

[0063] (2) subjecting the imidazole intermediate to intermolecular and intramolecular substitution reactions with a dihalide MCH2ZCH2M to obtain a tetravalent cationic imidazolium salt macrocyclic compound;

[0064] (3) the tetravalent cationic imidazolium salt macrocyclic compound is exchanged with an anion X to obtain the corresponding salt;

[0065] 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.

[0066] In another preferred embodiment, the dihalide MCH2YCH2M and the dihalide MCH2ZCH2M can react interchangeably.

[0067] In another preferred embodiment, the dihalide MCH2YCH2M and the dihalide MCH2ZCH2M are the same or different.

[0068] 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.

[0069] In a sixth aspect of the present invention, a kit is provided, comprising:

[0070] (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

[0071] (b) a second container, and a muscle relaxant antagonist located in the second container: neostigmine, sugammadex sodium, or a combination thereof;

[0072] (c) an nth container, and an nth pharmaceutical ingredient located in the nth container, where 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

[0073] (d) Optional instructions.

[0074] In another preferred embodiment, the kit is used for relaxing skeletal muscle.

[0075] 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.

[0076] In another preferred embodiment, the subject is a mammal, preferably a rodent or a primate, more preferably a mouse, a rat or a human.

[0077] In another preferred embodiment, the method is in vitro.

[0078] In another preferred embodiment, the method is non-diagnostic and non-therapeutic.

[0079] 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 described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0080] After extensive and in-depth research, the inventors have for the first time provided a structurally novel macrocyclic compound incorporating four imidazolium salt groups, which is used as a muscle relaxant. The compound of the present invention carries a positive charge and has rapid and long-lasting muscle relaxation. Animal model experiments on SD rats have shown that the imidazolium salt macrocyclic compound described in the present invention has high muscle relaxant activity, and increasing the dosage can prolong the muscle relaxation time to 5 hours. Theoretically, converted to an adult dose, it can achieve muscle relaxation for more than 10 hours, covering more than 95% of surgical patients and achieving rapid onset of action. Based on this, the inventors completed the present invention.

[0081] the term

[0082] 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.

[0083] As used herein, when used in reference to a specific recited 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.).

[0084] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0085] As used herein, “C 1-20 "Alkyl" refers to a straight or branched chain alkyl group (CH2) containing 1 to 20 carbon atoms n-1 CH3 (n=1-20), such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc., or similar groups.

[0086] 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 a heteroatom 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.

[0087] 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.

[0088] 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 group refers to CH3-CH2-CH2-O-CH2-C≡C-, or CH3-S-CH2-CH2-OC≡C- and the like.

[0089] 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.

[0090] 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.

[0091] As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.

[0092] 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.

[0093] As used herein, the term "aryl" refers to a monovalent aromatic carbocyclic group of 6 to 20 (preferably 6 to 14) carbon atoms, which may have a single ring (e.g., phenyl) or a fused ring (e.g., naphthyl or anthracenyl). If the point of attachment is at an aromatic carbon atom, the fused ring may be non-aromatic (e.g., 2-benzoxazolone, 2H-1,4-benzoxazin-3(4H)-on-7-yl, etc.). Preferred aryl groups include phenyl and naphthyl.

[0094] 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 or multiple rings (including fused, bridged, 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.

[0095] 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 within the ring. Such heteroaryl groups can be monocyclic (e.g., pyridyl or furyl) or fused rings (e.g., indolizinyl or benzothienyl), wherein the fused rings can be non-aromatic and / or contain one heteroatom, as long as the point of attachment is through an aromatic heteroaryl atom. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to N-oxide (NO), sulfinyl, or sulfonyl. Preferred heteroaryl groups include pyridyl, pyrrolyl, indolyl, thienyl, and furanyl. In one embodiment, heteroaryl refers to a 3-14-membered heteroaryl group, preferably a 5-12-membered heteroaryl group.

[0096] 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.

[0097] The animal activity test and acute toxicity test in the present invention were conducted using SD rats.

[0098] 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, amino, 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.

[0099] As used herein, the compound of formula I of the present invention is composed of a tetravalent cationic imidazolium salt macrocycle and an anion X coordinated with the tetravalent 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, and S; wherein the substitution means that one or more hydrogen atoms on the group are replaced by a group selected from the group consisting of halogen, nitro, amino, 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 total valence of the anions is 4, thereby balancing the tetravalent cation imidazolium salt macrocycle. The anions represented by X can be four monovalent anions, two divalent anions, one divalent anion and two monovalent anions, or one monovalent anion and one trivalent anion. The monovalent anions in the four monovalent anions can be the same or different, and the divalent anions in the two divalent anions can be the same or different.

[0100] neuromuscular blockers or muscle relaxants

[0101] 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. Based on their mechanism of action, muscle relaxants are categorized as depolarizing and nondepolarizing. Depolarizing muscle relaxants bind to N2 cholinergic receptors on the motor nerve endplate membrane, weakening or eliminating the muscle cell's response to acetylcholine. Nondepolarizing muscle relaxants compete with acetylcholine for N2 cholinergic receptors on the motor endplate membrane of skeletal muscle, leading to skeletal muscle relaxation. The most commonly used nondepolarizing muscle relaxants in clinical practice are classified, based on their chemical structure, into aminosteroid derivatives (such as rocuronium, vecuronium, and pancuronium) and benzylisoquinoline derivatives (such as cisatracurium besylate).

[0102] 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.

[0103] Wherein, each of R1, R2, Z, Y, and X is as described in the first aspect of the present invention.

[0104] In another preferred embodiment, R1 is H, D, substituted or unsubstituted C 1-3 Alkyl, allyl; wherein, the substitution means that the hydrogen of the group is replaced by one or more C 1-4 Alkyl or halogen substituted.

[0105] In another preferred embodiment, Selected from Wherein, n=1, 2; G is H, or one or more groups selected from the following groups: C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxycarbonyl.

[0106] In another preferred embodiment, each of Y and Z is independently zero, substituted or unsubstituted and is selected from the group consisting of: Wherein, the substitution refers to the substitution of one or more hydrogen atoms on the group by a group selected from the group consisting of: C 1-6 Alkyl, halogen, C 1-6 an alkoxycarbonyl group or an amide group.

[0107] In another preferred embodiment, the halogen is fluorine, chlorine, bromine or iodine.

[0108] In another preferred embodiment, each R1 is independently selected from the group consisting of H, methyl, and ethyl.

[0109] 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.

[0110] Preparation method

[0111] 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 by combining various synthetic methods described in this specification or known in the art, and such combination can be easily carried out by those skilled in the art.

[0112] The present invention discloses a class of macrocyclic compounds incorporating four imidazolium salt groups and a method for preparing the same. Animal experiments demonstrate that the compounds exhibit highly effective neuromuscular blocking activity with rapid onset and long-lasting efficacy.

[0113] (1) using an excess of imidazole unit Im and dihalide MCH2YCH2M to undergo substitution reaction to obtain an imidazole intermediate;

[0114] (2) subjecting the imidazole intermediate to intermolecular and intramolecular substitution reactions with a dihalide MCH2ZCH2M to obtain a tetravalent cationic imidazolium salt macrocyclic compound;

[0115] (3) the tetravalent cationic imidazolium salt macrocyclic compound is exchanged with an anion X to obtain the corresponding salt;

[0116] 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.

[0117] In another preferred embodiment, the dihalide MCH2YCH2M and the dihalide MCH2ZCH2M react interchangeably.

[0118] In another preferred embodiment, the dihalide MCH2YCH2M is the same as or different from the dihalide MCH2ZCH2M.

[0119] Pharmaceutical composition

[0120] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule, tablet, or injection.

[0121] 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.

[0122] As used herein, the term "pharmaceutically acceptable salts" 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 with the following reagents: alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long-chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, such as benzyl and phenethyl bromides, etc. This results in water-soluble, oil-soluble, or dispersible products. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, and 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 moiety with a suitable base (such as a pharmaceutically acceptable metal cation hydroxide, carbonate, or bicarbonate), 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, as well as 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 useful for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0123] "Pharmaceutically acceptable carriers" refer 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 Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0124] Suitable pharmaceutically acceptable carriers or excipients include, for example, treating agents and drug delivery modifiers and accelerators, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting point waxes, ion exchange resins, and combinations of any two or more thereof. Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including petroleum, animal oils, vegetable oils, or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Preferred liquid carriers, particularly 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.

[0125] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0126] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0127] 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 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.

[0128] Solid dosage forms such as tablets, dragees, 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 opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0129] 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, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0130] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0131] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0132] Compositions for parenteral injection may comprise 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.

[0133] Dosage forms for topical administration of the compounds of this 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.

[0134] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0135] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0136] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0137] Compared with the prior art, the main advantages of the present invention include:

[0138] (1) The imidazolium salt macrocyclic compound of the present invention has high muscle relaxant activity and high safety.

[0139] (2) The imidazolium salt macrocyclic compound of the present invention can provide rapid and long-lasting non-depolarizing muscle relaxant effect, which meets the needs of clinical use.

[0140] 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, for which specific conditions are not specified, were 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 according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0141] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0142] Example 1

[0143] Taking IMC-1 as an example, the imidazolium salt macrocyclic compound of the present invention adopts the general preparation route shown below:

[0144] Compound 1a (1.43 g, 21 mmol) was dissolved in 200 mL of acetonitrile and stirred at room temperature. Sodium hydroxide (1.6 g, 40 mmol) was added and stirring continued for 2 h. Compound 2a (2.64 g, 10 mmol) was dissolved in 30 mL of acetonitrile and added dropwise to the acetonitrile solution. Stirring continued at room temperature for 2 h. Filter, spin-dry the filtrate, and dissolve completely in 100 mL of dichloromethane. Wash repeatedly with deionized water until the washings were neutral. Add an appropriate amount of anhydrous sodium sulfate to the dichloromethane solution. After complete drying, filter, spin-dry the filtrate to yield 1.96 g of a white solid (82% yield), which was used in the next reaction. The intermediate prepared above (0.48 g, 2 mmol) was dissolved in 300 mL of acetonitrile and heated to 80°C with thorough stirring. Compound 2b (0.68 g, 2 mmol) was dissolved in 80 mL of acetonitrile and added dropwise to the acetonitrile solution. The reaction was continued at 80°C for 48 h. The reaction solution solvent was evaporated under reduced pressure, and the obtained crude product was separated and purified by column chromatography using methanol / water / saturated ammonium chloride aqueous solution (12:7:1) as eluent. The eluate was collected, the solvent was evaporated under reduced pressure, and an appropriate amount of deionized water was added to make a saturated aqueous solution. Saturated ammonium hexafluorophosphonate aqueous solution was added dropwise, and a large amount of white solid precipitated. The addition was continued until the white solid was completely precipitated. The mixture was filtered, the filter residue was dried, and an appropriate amount of acetonitrile was added to make a saturated acetonitrile solution. Saturated tetrabutylammonium chloride acetonitrile solution was added dropwise, and a large amount of white solid precipitated. The addition was continued until the white solid was completely precipitated. The mixture was filtered, the filter residue was dried, and 192 mg of white powdery solid IMC-1 was obtained 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).

[0145] Example 2

[0146] IMC-2 was prepared by first reacting compound 1a with compound 2c, followed by compound 2b, following the same steps as for IMC-1. Yield: 19%. 1H NMR (400 MHz, Deuterium Oxide) δ 8.90 (s, 4H), 7.59 (s, 6H), 7.47 (d, J = 2.0 Hz, 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).

[0147] Example 3

[0148] IMC-3 was prepared by first reacting compound 1a with compound 2b, followed by compound 2d, following the same steps as for IMC-1, with a yield of 13%. 1H NMR (400 MHz, Deuterium Oxide) δ 8.94 (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).

[0149] Example 4

[0150] IMC-3 was hydrolyzed to obtain carboxyl-substituted IMC-4. The specific steps were as follows: IMC-3 (0.01 g, 0.088 mmol) was dissolved in a mixture of 2 mL of methanol and 2 mL of deionized water. Sodium hydroxide (0.014 g, 0.35 mmol) was added and stirred at room temperature for 12 hours. The reaction solution was then spin-dried to dryness and dissolved in 5 mL of deionized water. 2 M hydrochloric acid was then added dropwise, resulting in the formation of a white precipitate. This addition was continued until a solid was completely precipitated. The residue was filtered and dried to yield 79 mg of IMC-4 as a white solid, 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).

[0151] Example 5

[0152] Similar to the preparation of IMC-1, compound 1a was reacted with compound 2a, and then with compound 2e to separate the tetravalent imidazolium macrocyclic compound IMC-5 (yield 6%) and the divalent bisimidazolium cyclic compound IMC-5' (yield 8%). IMC-5: 1H NMR (400 MHz, Deuterium Oxide) δ 8.71 (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).

[0153] Example 6

[0154] IMC-6 was prepared by first reacting compound 1a with compound 2c, followed by compound 2e, following the same steps as for IMC-1, yielding 26%. 1H NMR (400 MHz, Deuterium Oxide) δ 8.29 (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).

[0155] Example 7

[0156] IMC-7 was prepared by first reacting compound 1a with compound 2a, followed by reaction with compound 2f, following the same steps as for IMC-1, yielding 7%. 1H NMR (400 MHz, Deuterium Oxide) δ 8.80 (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).

[0157] Example 8

[0158] IMC-8 was prepared by first reacting compound 1a with compound 2c, followed by compound 2f, following the same steps as for IMC-1, yielding 16%. 1H NMR (400 MHz, Deuterium Oxide) δ 8.81 (s, 4H), 7.59–7.52 (m, 6H), 7.41 (d, J = 1.9 Hz, 4H), 7.39 (d, J = 1.9 Hz, 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).

[0159] Example 9

[0160] IMC-8 was placed in deuterated water and allowed to stand at room temperature for 2 h to obtain the deuterated product IMC-8-d4 in 100% yield. 1H NMR (400 MHz, Deuterium Oxide) δ 7.59–7.52 (m, 6H), 7.41 (d, J = 1.9 Hz, 4H), 7.39 (d, J = 1.9 Hz, 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).

[0161] Example 10

[0162] IMC-9 was prepared by first reacting compound 1a with compound 2f, followed by compound 2d, following the same steps as for IMC-1. Yield: 18%. H NMR (400 MHz, Deuterium Oxide) δ 8.87 (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).

[0163] Example 11

[0164] IMC-10 is the hydrolysis product of IMC-9. The specific preparation steps are the same as IMC-4, with a yield of 84%. 1H NMR (400 MHz, Deuterium Oxide) δ 8.83 (s, 4H), 7.94 (d, J = 1.6 Hz, 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).

[0165] Example 12

[0166] IMC-11 was prepared by first reacting compound 1b with compound 2c, followed by compound 2f, following the same steps as for IMC-1, with a yield of 13%. 1H NMR (400 MHz, Deuterium Oxide) δ 7.52–7.48 (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).

[0167] Example 13

[0168] IMC-12 was prepared by first reacting compound 1a with compound 2g, followed by compound 2f, following the same steps as for IMC-1. Yield: 16%. 1H NMR (400 MHz, Deuterium Oxide) δ 8.93 (s, 4H), 7.49–7.39 (m, 16H), 7.02 (brs, 8H), 6.65 (s, 4H), 5.40–5.35 (m, 16H).

[0169] Example 14

[0170] IMC-13 was prepared by first reacting compound 1a with compound 3b, followed by reaction with compound 2f, following the same steps as for IMC-1, with a yield of 14%. 1H NMR (400 MHz, Deuterium Oxide) δ 8.86 (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).

[0171] Example 15

[0172] IMC-14 was prepared by first reacting compound 1b with compound 3b, followed by compound 2f, following the same steps as for IMC-1, with a yield of 13%. 1H NMR (400 MHz, Deuterium Oxide) δ 7.32 (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).

[0173] Example 16

[0174] IMC-15 was prepared by first reacting compound 1c with compound 3b, followed by reaction with compound 2f, following the same steps as for IMC-1, yielding 15%. 1H NMR (400 MHz, Deuterium Oxide) δ 7.41 (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).

[0175] Example 17

[0176] IMC-16 was prepared by first reacting compound 1d with compound 3b, followed by compound 2f, following the same steps as for IMC-1, with a yield of 14%. 1H NMR (400 MHz, Deuterium Oxide) δ 7.60–7.55 (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 = 6.2 Hz, 8H), 2.11–2.04 (m, 8H), 1.35–1.27 (m, 4H).

[0177] Example 18

[0178] IMC-17 was prepared by first reacting compound 1b with compound 3a, followed by reaction with compound 2f, following the same steps as for IMC-1, yielding 14%. 1H NMR (400 MHz, Deuterium Oxide) δ 7.43 (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).

[0179] Example 19

[0180] IMC-18 was prepared by first reacting compound 1b with compound 3c, followed by reaction with compound 2f, following the same steps as for IMC-1. Yield: 14%. 1H NMR (400 MHz, Deuterium Oxide) δ 7.37 (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).

[0181] Example 20

[0182] IMC-19 was prepared by first reacting compound 1b with compound 3d, followed by compound 2f, following the same steps as for IMC-1. Yield: 16%. 1H NMR (400 MHz, Deuterium Oxide) δ 7.33–7.29 (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).

[0183] Example 21

[0184] IMC-20 was prepared by first reacting compound 1b with CH2Cl2, followed by reaction with compound 2f. The specific steps for preparing IMC-1 were the same, with a yield of 14%. 1H NMR (400 MHz, Deuterium Oxide) δ 7.73 (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).

[0185] Example 22: Effects of different dosages of imidazolium salt macrocyclic compounds on neuromuscular blocking effects

[0186] 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 using distilled water as the solvent, with a concentration of 0.8 μg / mL-16 μg / mL; SD rats weighing 170 to 240 grams were selected as test subjects, and 2, 13, 16, 20, and 40 μg / kg dose groups were set, with 2 male and 2 female animals in each group. The same applies to the following experimental examples.

[0187] The operation process is as follows: rats are anesthetized with isoflurane, with an induction dose of 4% and a maintenance dose of 1%; the right hind leg and surrounding hair of the rats are removed with 10% Na2S solution; an airway is 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 breaths / min; a muscle relaxation monitor is used to test the neuromuscular blockade of the rat's quadriceps femoris, wherein the sensor is fixed to the rat's tibia and the electrode is fixed to the rat's right hind leg through a patch. The device is then calibrated using the Cal mode and switched to the single stimulation mode (ST) after the data stabilizes. When the ST value stabilizes ≥90, 10 ST data are recorded continuously, and the average value is calculated, which is recorded as the baseline mean ST0; according to the experimental protocol, IMC-19 injection is injected through the rat's tail vein, and the injection volume is adjusted according to the rat's body weight. The injection operation is completed within 5 seconds. After the injection is completed, the timer is started and the ST value change is recorded; when the ST value drops to the lowest point, 5 ST data are recorded continuously, and the average value is calculated, which is recorded as ST min , (ST0-ST min ) / ST0 is the maximum muscle blocking rate of the imidazolium salt macrocyclic compound at this dose.

[0188] The experimental results are listed in Table 1. The results showed that IMC-19 had no blocking effect at a dosage of 2 μg / kg. As the dosage increased, the maximum muscle blocking rate gradually increased. At a dosage of 16 μg / kg, the maximum muscle blocking rate was higher than 90%, and at a dosage of 40 μg / kg, the maximum muscle blocking rate reached 100%.

[0189] Table 1. Dose dependence of IMC-19 muscle relaxant activity

[0190] Example 23: ED95 test of muscle relaxant activity of imidazolium salt macrocyclic compounds

[0191] 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 was prepared as an injection using distilled water as a solvent, with concentrations of 0.8 μg / mL-16 μg / mL; 2 μg / kg, 10 μg / kg, 13 μg / kg, 16 μg / kg, 20 μg / kg and 40 μg / kg dose groups were set, with 2 male and female animals in each group. The actual injection volume was calculated based on the rat body weight and injection concentration. The operation process was the same as in Example 22, and the maximum muscle blockade 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.

[0192] Example 24: Screening of neuromuscular blocking effects at specific dosages

[0193] The neuromuscular blocking effect of imidazolium macrocyclic compounds at specific dosages was screened.

[0194] Specifically, the imidazolium salt macrocyclic compound was prepared as an injection using distilled water as a solvent, and a 20 μg / kg-1800 μg / kg administration dose group was set, with 2 animals of both sexes in each dose group. The operation process was the same as in Example 22. After the injection was completed, the timing was started and the ST value changes were recorded: when the ST value dropped to 95% ST0, the time t1 was recorded; when the ST value recovered to 25% ST0, the time t2 was recorded; when the ST value recovered to 90% ST0, the time t3 was recorded, t1 was the onset time of muscle relaxation, t2-t1 was the duration of muscle relaxation, and t3-t2 was the recovery time of muscle relaxation; and the maximum muscle blockade rate was recorded; all results were taken as the average of 4 animals in each group.

[0195] The experimental results are shown in Table 2. At certain doses, IMC-1, IMC-5, IMC-7, IMC-8, IMC-10, IMC-11, and IMC-13 achieved greater than 90% muscle blockade. IMC-14, IMC-15, IMC-17, IMC-18, and IMC-19 achieved 100% muscle blockade at relatively low doses of 20 μg / kg to 40 μg / kg. The bisimidazolium cyclic compound IMC-5' achieved a maximum blockade rate of only 23.3% at a dose of 2000 μg / kg, demonstrating that the muscle blocking activity of tetravalent imidazolium macrocyclic compounds is far superior to that of divalent cyclic compounds.

[0196] Table 2. Dosage of imidazolium salt macrocyclic compounds and maximum neuromuscular blockade rate

[0197] Example 25: Testing of the onset and duration of action of imidazolium salt macrocyclic compounds

[0198] Using the experimental conditions described in Example 24, the onset and duration of muscle relaxation were further monitored for imidazolium macrocyclic compounds that achieved a maximum muscle blockade rate of 100%. The results are listed in Table 3. These results demonstrate that at high doses, imidazolium macrocyclic compounds can achieve rapid onset (0.24 minutes) and long-lasting muscle relaxation (5 hours).

[0199] Table 3. Onset and duration of muscle relaxation at different doses of imidazolium macrocyclic compounds

[0200] Example 26: Imidazolium Macrocyclic Compound Antagonism Test

[0201] Taking IMC-19 as an example, neostigmine was used as an antagonist to detect the antagonistic effect of cholinesterase inhibitors on imidazolium macrocyclic compounds.

[0202] Specifically, the imidazolium macrocyclic compound was prepared as an injection using distilled water as the solvent at a concentration of 8.0 μg / mL; neostigmine was prepared as an injection using distilled water as the solvent at a concentration of 48 μg / mL; the IMC-19 dosage was 20 μg / kg, and the antagonist dosage was 240 μg / kg. The actual injection volume was calculated based on the rat weight and injection concentration. Two male and two female animals were included in each group, and the results were averaged. The operation process was the same as in Example 22. After the injection was completed, the timer was started and the ST value change was recorded. When the ST value dropped to the lowest point and the monitoring data stabilized, the rat was injected with the neostigmine solution via the tail vein. After the injection was completed, the time and ST value change were recorded.

[0203] Experimental results demonstrate that neostigmine rapidly antagonizes muscle blockade induced by imidazolium macrocyclic compounds. Because neostigmine is a cholinesterase inhibitor, it inhibits the hydrolysis of acetylcholine in vivo, thereby enriching acetylcholine. This competitively crowds out imidazolium macrocyclic compounds from acetylcholine receptors, thereby restoring neuromuscular excitation and ultimately reversing the muscle relaxant effect.

[0204] The experimental results show that imidazolium macrocyclic compounds are a class of competitive N2 cholinergic receptor inhibitors, which are consistent with the characteristics of non-depolarizing muscle relaxants and also indicate that they have high safety.

[0205] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

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, substituted or unsubstituted a 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 connected together form a group selected from the group consisting of: 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 group.

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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