Diaryl glycoluril tetramer derivative and application thereof

Abstract

The invention relates to application of two diaryl glycoluril tetramer derivatives. Specifically, the invention discloses two diaryl glycoluril tetramer derivatives as shown in a formula A-1 and a formula A-2 and application of a pharmaceutical composition containing any one of the diaryl glycoluril tetramer derivatives and the pharmaceutical composition containing any one of the diaryl glycoluril tetramer derivatives. The compound can be used for antagonizing clinically used non-depolarized muscle relaxants (such as cis-atracurium besylate and rocuronium bromide), and under the same dosage, the antagonistic activity of the diaryl glycoluril tetramer on rocuronium bromide is obviously superior to that of sugammadex sodium, and the antagonistic activity is far higher than that of neostigmine. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medicine, and specifically relates to the use of two diaryl glycoluril tetramer derivatives and a composition thereof for antagonizing multiple muscle relaxants. Background Art

[0002] Neuromuscular blockers or muscle relaxants (hereinafter referred to as muscle relaxants) are widely used in clinical anesthesia practice to paralyze skeletal muscles, thereby facilitating intubation and improving surgical conditions. Every year, more than 400 million patients worldwide receive muscle relaxant medication during anesthesia in operating rooms and intensive care units. Among them, non-depolarizing muscle relaxants, such as ammonium steroids rocuronium bromide and cisatracurium besylate, have fewer side effects than depolarizing muscle relaxants and are more widely used in clinical practice. The medium-acting cisatracurium besylate has the advantages of fast onset, strong effect, fast recovery speed, no histamine release, small cardiovascular side effects, no accumulation in the body, non-toxic metabolites and no muscle relaxant effect, and no dependence on renal excretion. It accounts for about 60% of the domestic muscle blocker market. Rocuronium, which is also a medium-acting muscle relaxant, accounts for about 30% of the domestic market. However, the incidence of postoperative "residual quiver toxicity" caused by the residual long-acting upper muscle relaxants in clinical practice is very high, leading to postoperative respiratory complications such as impaired upper respiratory function, airway obstruction and pulmonary respiratory dysfunction, and in severe cases, causing death of patients. A prospective, multicenter and single-blind observational study published in my country in 2016 found that the total incidence of residual muscle relaxants when the endotracheal tube was removed was as high as 57.8%, and artificial intervention with antagonists was required to eliminate "residual quiver toxicity" to help patients recover muscle motor function as soon as possible. Therefore, rapid and efficient antagonism of residual excess muscle relaxants is of great clinical significance, which is not only conducive to reducing the postoperative risks of patients, but also conducive to early extubation and rehabilitation of patients, accelerating operating room turnover and reducing surgical costs.

[0003] In current clinical practice, neostigmine restores paralyzed nerves and muscles by inhibiting cholinesterase activity, but the antagonism efficiency is generally low, and it is impossible to achieve rapid reversal of muscle relaxants, and it is impossible to reverse deep muscle relaxation. Sugandex sodium binds specifically to its hydrophobic inner cavity of γ-cyclodextrin, and uses the capture principle to achieve rapid isolation and reversal of rocuronium bromide, but it cannot antagonize cisatracurium besylate. Cisatracurium besylate is the muscle relaxant with the highest proportion of clinical use in China, and it is irreplaceable in many clinical practices: for example, patients at risk of acute respiratory distress syndrome are recommended to use cisatracurium besylate as a muscle relaxant for surgery, and patients with renal insufficiency are recommended to use it as a general anesthesia drug. Cisatracurium besylate is one of the most commonly used muscle relaxants in intensive care units. Therefore, there is an important and urgent unmet clinical need to develop antagonists that quickly antagonize cisatracurium besylate.

[0004] Isaacs et al. reported that diphenyl glycoluril tetramer with four sulfonate side chains can achieve a certain reversal of cis-atracurium besylate, but the antagonistic activity is low, and at high doses it has only moderate antagonistic activity against rocuronium bromide. An ideal specific muscle relaxant reversal agent needs to have three most basic properties: high activity (rapid specific reversal), high biosafety, and high water solubility. High water solubility is conducive to rapid injection and rapid onset of action in clinical practice, and high biosafety will significantly affect the safe therapeutic concentration of the antagonist. Antagonists with high antagonistic activity are worth clinical development. Given that cis-atracurium besylate and rocuronium bromide account for a wide market share in China (about 90%), the development of a new specific reversal agent that can antagonize these two muscle relaxants and has high biosafety, high water solubility, and drugability has important clinical value and is also a very challenging task.

[0005] In summary, there is an urgent need in this field to develop a class of antagonist drugs with high biological safety that can quickly antagonize cisatracurium besylate and rocuronium bromide. Summary of the invention

[0006] One object of the present invention is to provide an antagonist drug which has high biological safety and can quickly antagonize steroidal quaternary ammonium salt muscle relaxants and tetrahydroisoquinoline quaternary ammonium salt muscle relaxants.

[0007] In a first aspect of the present invention, there is provided a diaryl glycoluril tetramer derivative represented by formula A-1 and formula A-2, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in preparing a muscle relaxant antagonist;

[0008]

[0009] In another preferred embodiment, the muscle relaxant is a non-depolarizing muscle relaxant.

[0010] In another preferred embodiment, the muscle relaxant further comprises a depolarizing muscle relaxant.

[0011] In another preferred embodiment, the non-depolarizing muscle relaxant is selected from the following group: steroidal quaternary ammonium salt muscle relaxants, tetrahydroisoquinoline quaternary ammonium salt muscle relaxants, or a combination thereof.

[0012] In another preferred embodiment, the non-depolarizing muscle relaxant is selected from the following group: rocuronium bromide, cisatracurium besylate, or a combination thereof.

[0013] In a second aspect of the present invention, a pharmaceutical composition for antagonizing muscle relaxants is provided, the composition comprising:

[0014] (a) a compound represented by formula A-1 and / or formula A-2, or a pharmaceutically acceptable salt, hydrate or solvate thereof as the first active ingredient;

[0015]

[0016] (b) a pharmaceutically acceptable carrier or excipient.

[0017] 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%.

[0018] In another preferred embodiment, the dosage form of the pharmaceutical composition is injection, tablet, capsule, pill, suspension or emulsion; preferably injection.

[0019] In another preferred embodiment, the injection is an aqueous solution, a sodium chloride aqueous solution or a glucose aqueous solution, wherein the concentration of component (a) as the first active ingredient is 0.1-5000 mg / mL; preferably, it is a physiological saline solution.

[0020] In another preferred embodiment, the dosage of the injection is 0.1-5000 mg / kg, based on the body weight of the rat.

[0021] In a third aspect of the present invention, a pharmaceutical composition for antagonizing muscle relaxants is provided, the composition comprising:

[0022] (a) a compound represented by formula A-1 and / or formula A-2, or a pharmaceutically acceptable salt, hydrate or solvate thereof as the first active ingredient;

[0023]

[0024] (b) as a second active ingredient, an ingredient having an antagonistic effect on non-depolarizing muscle relaxants selected from the group consisting of neostigmine, sugammadex sodium, or a combination thereof; and

[0025] (c) a pharmaceutically acceptable carrier or excipient.

[0026] 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 %.

[0027] In another preferred embodiment, the pharmaceutical composition is in the form of an injection, tablet, capsule, pill, suspension or emulsion.

[0028] In another preferred embodiment, the injection is an aqueous solution, a sodium chloride aqueous solution or a glucose aqueous solution, wherein the concentration of component (a) as the first active ingredient is 0.1-5000 mg / mL.

[0029] In another preferred embodiment, the dosage of the injection is 0.1-5000 mg / kg, based on the body weight of the rat.

[0030] In a fourth aspect of the present invention, a kit is provided, comprising:

[0031] (a) a first container, and a compound of formula A-1 and / or formula A-2 as an active ingredient, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the second or third aspect of the present invention, located in the first container; and / or

[0032] (b) a second container, and a muscle relaxant in the second container; the muscle relaxant is a non-depolarizing muscle relaxant selected from the group consisting of steroidal quaternary ammonium salt muscle relaxants, tetrahydroisoquinoline quaternary ammonium salt muscle relaxants, or a combination thereof; and / or

[0033] (c) a third container, and a muscle relaxant antagonist in the third container, wherein the muscle relaxant antagonist is selected from the group consisting of neostigmine, sugammadex sodium, or a combination thereof; and / or

[0034] (d) Optional instructions for use.

[0035] In another preferred embodiment, the instructions for use are used to explain the method of using the kit, including the administration method, frequency, dosage, etc.

[0036] In another preferred embodiment, the non-depolarizing muscle relaxant is cisatracurium besylate, rocuronium bromide, or a combination thereof.

[0037] In another preferred embodiment, the kit is used to antagonize muscle relaxants.

[0038] In the fifth aspect of the present invention, a method for antagonizing muscle relaxants is provided, wherein a therapeutically effective amount of a compound of formula A-1 or formula A-2 as described in the first aspect of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is administered to a subject in need, thereby antagonizing "residual quiver toxicity" in the subject's body.

[0039] In another preferred embodiment, the method is in vitro.

[0040] In another preferred embodiment, the method is non-diagnostic and non-therapeutic.

[0041] In another preferred embodiment, the subject is a mammal.

[0042] In another preferred embodiment, the subject is a human.

[0043] 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

[0044] The inventors have developed a class of diaryl glycoluril tetramer derivatives with rapid antagonistic activity against steroidal quaternary ammonium salt muscle relaxants (such as rocuronium bromide) and tetrahydroisoquinoline quaternary ammonium salt muscle relaxants (such as cisatracurium besylate) through extensive and in-depth systematic research. The derivatives also have high water solubility and high biological safety. Based on this, the inventors have completed the present invention.

[0045] definition

[0046] 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.

[0047] 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.).

[0048] 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".

[0049] As used herein, the term "active ingredient" refers to a diaryl glycoluril tetramer derivative or a composition thereof. It should be understood that the term also includes mixtures of such compounds.

[0050] As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.

[0051] 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.

[0052] As used herein, the term "aryl" refers to a monovalent aromatic carbocyclic group of 6 carbon atoms, and preferred aryl groups include cyclopentaphenyl and 3,4-dimethylphenyl.

[0053] The animal activity test and acute toxicity test in the present invention are carried out using SD rats.

[0054] The diaryl glycoluril tetramer derivative or its composition of the present invention can be prepared by methods well known to those skilled in the art in the prior art, and there is no particular restriction on the reaction parameters of each step. In addition, the typical compound of the present invention can be obtained by commercial means.

[0055] As used herein, "quiver toxicity" refers to the symptom that a patient cannot recover spontaneous breathing due to neuromuscular blockade caused by residual muscle relaxants after surgery. Because the symptoms are like the use of quiver alkaloids, it is called "quiver toxicity".

[0056] The animal activity test and acute toxicity test in the present invention are carried out using SD rats.

[0057] Neuromuscular blockers or muscle relaxants

[0058] Neuromuscular blockers or muscle relaxants (abbreviated as muscle relaxants) are widely used in clinical practice to relax skeletal muscles, which is conducive to intubation and improves 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 clinically are mainly divided into steroidal quaternary ammonium salt derivatives (such as rocuronium bromide) and benzyl tetrahydroisoquinoline derivatives (such as cisatracurium besylate) according to their different chemical structures.

[0059] Muscle relaxant antagonists - diaryl glycoluril tetramers

[0060]

[0061]

[0062] The present invention provides a use of a diaryl glycoluril tetramer derivative having a structure shown in formula A-1 and A-2, which is used for rapidly antagonizing steroidal quaternary ammonium salts (such as rocuronium bromide) and tetrahydroisoquinoline quaternary ammonium salts (such as cisatracurium besylate) as muscle relaxants.

[0063] The diaryl glycoluril tetramer described in the present invention has a pre-organized "C" conformation, which constitutes a hydrophobic inner cavity and can drive the binding of the aforementioned muscle relaxant through hydrophobic interaction, thereby antagonizing its muscle relaxant activity.

[0064] The diaryl glycoluril tetramer described in the present invention introduces anionic sulfonate side chains at both ends, and the electrostatic interaction thereof can exert a synergistic effect with the hydrophobic effect of the tetramer "C" conformation, thereby quickly and efficiently binding to the muscle relaxant and thereby antagonizing its muscle relaxant activity.

[0065] In the present invention, diaryl glycoluril tetramer is used as a highly active muscle relaxant antagonist. Rat experiments support that this application can achieve rapid antagonism of cisatracurium besylate and rocuronium bromide. This class of compounds exhibits high water solubility and high biosafety and has significant clinical practicality.

[0066] Control experiments support that this new class of compounds can achieve faster antagonism of rocuronium than the clinically used drug sugammadex sodium. Rat experiments support that this application can achieve rapid antagonism of cisatracurium besylate. Control experiments support that this new class of compounds can achieve faster antagonism of rocuronium than the clinically used drug sugammadex sodium.

[0067] Pharmaceutical composition

[0068] 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 per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0069] The "active ingredient" described in the present invention refers to the compounds of formula A-1 and formula A-2 described in the present invention or their pharmaceutically acceptable salts, hydrates or solvates.

[0070] 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.

[0071] "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.

[0072] 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.

[0073] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0083] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0084] 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.

[0085] Compared with the prior art, the main advantages of the present invention include:

[0086] (1) Controlled trials support that, compared with the clinically used antagonist neostigmine, the compounds of the present invention can antagonize the benzylisoquinoline muscle relaxant cisatracurium besylate and the aminosteroid muscle relaxant rocuronium bromide more quickly.

[0087] (2) Controlled trials support that the compounds of the present invention can antagonize the aminosteroidal muscle relaxant rocuronium bromide more quickly than the clinically used antagonist sugammadex sodium. The compounds of the present invention can rapidly antagonize the benzylisoquinoline muscle relaxant cisatracurium besylate, while sugammadex sodium cannot antagonize this type of muscle relaxant.

[0088] (3) Control experiments show that, compared with the disclosed dibenzoglycoluril tetramer, the compound of the present invention has higher antagonistic activity against the above two non-depolarizing muscle relaxants, and at the same time has high water solubility and high biological safety.

[0089] 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.

[0090] 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.

[0091] Example 1: Synthesis of Compound A-1

[0092]

[0093] Add 2,3-propylene-1,4-dioxane (2.07 g, 13.78 mmol) to a 250 mL single-mouth bottle, add NaOH aqueous solution (1.38 g 34.45 mmol, dissolved in 37.5 mL H2O), and stir at room temperature for 30 min. Subsequently, add 1,3-propane sultone dioxane solution (5.05 g, 41.34 mmol, dissolved in 60 mL 1,4-dioxane) to the system under stirring. After reacting at room temperature for 12 hours, the raw material reacted completely. After the reaction was completed, centrifuge and wash the obtained solid with EtOH (60 mL × 2). The solid crude product was recrystallized with EtOH / H2O at 90 ° C to obtain a light brown solid powder 1-4 (3.7520 g, 70%). 1 H NMR(500MHz,D2O)δ6.85(s,2H),4.15(t,J=6.3Hz,4H),3.14–3.00(m,4H),2.88(t,J=7.4Hz,4H),2.18(dq,J=12.6,6.3Hz,4H),2.08(p,J=7.7Hz,2H). 13 C NMR(126MHz,D2O)δ149.18,134.92,112.52,67.89,47.89,29.45,24.51,24.36.HRMS(ESI)calcd:[M-Na] - ,415.0503,found 415.0501.

[0094] Add dimethyl glycoluril tetramer (1.50g, 1.79mmol) and trifluoroacetic acid (7.0mL) to a 50mL single-mouth bottle in sequence, stir to dissolve, then add acetic anhydride (7.0mL) and compound 1-4 (2.35g, 5.35mmol) to the reaction system in sequence, stir to dissolve. Heat the system to 50°C and react for 12 hours. After the reaction system is cooled, add the reaction solution dropwise to 140mL of ethanol, precipitate a light yellow solid, centrifuge, and collect the solid. Wash the solid twice with 150mL of ethanol and centrifuge again. The resulting solid is recrystallized with water and ethanol at 70°C. After vacuum drying, compound A-1 (1.60g, 59%) is obtained as a white powdery solid. 1 H NMR (400MHz, D2O): δ5.68(d,J=15.3Hz,2H),5.56(d,J=15.7Hz,4H),5.43(d,J=9.0Hz,2H ),5.35(d,J=9.0Hz,2H),5.18(d,J=15.9Hz,4H),4.31(dd,J=59.0,15.9Hz,8H),4.08(td, J=11.5,10.9,5.7Hz,6H),3.87(q,J=8.3,7.5Hz,4H),3.12(dd,J=20.4,14.4,7.2Hz,8H) ,2.47(d,J=19.8Hz,8H),2.16(s,8H),1.77(d,J=19.7Hz,12H),1.43(s,2H),1.31(s,2H). 13 C NMR (101MHz, D2O): δ156.71,156.19,148.31,138.21,128.65,78.70,77.66,71.8 8,71.51,71.16,52.93,48.52,48.12,36.08,30.36,25.58,25.03,16.80,15.71.

[0095] Example 2

[0096] Evaluation of antagonistic muscle relaxant activity: Taking the reversal of neuromuscular blockade induced by cisatracurium besylate by compound A-1 in SD rats as an example, the process of the in vivo reversal experiment of neuromuscular blockade by diaryl glycoluril tetramer derivatives is explained.

[0097] Specific operation process: SD rats weighing 170 to 240 g were selected as biological models to test the reversal effect of compound A-1. Three male rats and three female rats were selected for each group of experiments (the same below). During the test, the neuromuscular blocker injection solution was prepared using physiological saline as the solvent, and all injection operations were completed within 5 seconds. Rats were anesthetized with isoflurane, with an induction dose of 5% and a maintenance dose of 1.5%; 10% Na2S solution was used to remove the right hind leg and nearby hair of the mouse; an airway was inserted into the rat's trachea and connected to a small animal ventilator, with the tidal volume set to 8 and the frequency set to 80; 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 rat's tibia, and the electrode was fixed to the rat's right hind leg through a patch, and then calibrated using the Cal mode, and switched to the TOF mode (TOF is the abbreviation of train of four, four train stimulations) after the data stabilized. If the TOF data was stable ≥90, the next step of the experiment was performed; cisatracurium besylate solution was injected into the rat through the tail vein and the timing was started, with a dose of 0.6 mg / kg, and then the TOF value change was recorded; after the TOF value decreased to 0, the rat was injected with compound A-1 injection, and the injection time was recorded, and then the TOF value change was recorded, and the time it recovered to ≥90 was recorded as the neuromuscular blockade reversal time.

[0098] As shown in Tables 1 and 2, by comparing the antagonistic activities, it can be found that compounds A-1 and A-2 can quickly reverse the effects of cisatracurium besylate, which cannot be reversed by the clinical drug sugammadex sodium, and also have rapid reversal activity against rocuronium bromide.

[0099] The control compound A-3 at a high dose of 150 mg / kg had a TOF recovery time of only 84 seconds for reversing cisatracurium besylate, and the compound A-3 at a high dose of 90 mg / kg had a TOF recovery time of 87 seconds for reversing rocuronium bromide (Hoffmann et al., Anesthesiology 2013, 119, 317-325). The compounds A-1 and A-2 disclosed in the present invention have significantly better activities on cisatracurium besylate and rocuronium than the control compound A-3.

[0100]

[0101] The antagonistic activity of compounds A-1 and A-2 on cisatracurium besylate was significantly higher than that of neostigmine. Compared with the control compound A-3, compounds A-1 and A-2 were able to reverse the neuromuscular blockade caused by cisatracurium besylate more quickly at lower doses (80 and 100 mg / kg). Continuing to increase the dosage of compounds A-1 and A-2, the time of reversing the neuromuscular blockade induced by cisatracurium besylate can be further shortened to about 20 seconds.

[0102] When the dose of Compound A-1 and A-2 is 25 mg / kg, the TOF recovery time of antagonizing rocuronium is about 20 seconds, and its antagonistic activity is significantly higher than that of commercial sugammadex sodium at the same dose, and much higher than that of neostigmine. Continuing to increase the dosage of Compound A-1 and A-2, the neuromuscular blockade time induced by rocuronium can be further shortened to about 15 seconds.

[0103] The above results show that the activities of compounds A-1 and A-2 are significantly better than that of the dibenzoglycoluril tetramer derivative A-3 reported in the literature, and have better antagonistic activity than neostigmine and sugammadex sodium.

[0104] The antagonism data of neostigmine and sugammadex sodium in the table are derived from the literature (Liu et al., Journal of Medicinal Chemistry, 2022, 65, 16893-16901). All doses are the maximum doses for rats converted from the clinical adult dose (1:6.25).

[0105] Table 1. Compound A-1 (100-150 mg / kg), Compound A-2 (80-120 mg / kg) and Neostigmine (0.24 mg / kg) antagonize TOF→0.9 time of cisatracurium besylate

[0106]

[0107]

[0108] Table 2. Compounds A-1, A-2 (25-80 mg / kg), sugammadex sodium at the same dose (25 mg / kg) and neostigmine (0.24 mg / kg) antagonize the TOF→0.9 time of rocuronium

[0109]

[0110] Example 3

[0111] Water solubility test: Weigh about 100 mg of the above compound in a graduated test tube, and gradually add deionized water until it is completely dissolved. Measure the volume to calculate the solubility, and the solubility of compound A-1 and A-2 is 520 and 500 mg / mL, respectively, both of which meet the solubility requirements for rapid injection of muscle relaxants to exert their effects.

[0112] The structure of compound A-2 is as follows (prepared according to the literature method: Zhang et al., Journal of Medicinal Chemistry, 2014, 57, 9554-9563).

[0113]

[0114] Example 4

[0115] Acute toxicity test in mice: The present invention uses ICR mice (17-24g) to carry out acute toxicity experiments, with 4-6 mice per group, half male and half female. Taking compound A-1 as an example, a single injection through the tail vein is used, with a slow push injection (90s) and an injection volume of about 0.5mL. A saline blank control group is set. After injection, observation is carried out for 7 days, and deaths are recorded.

[0116] The experimental results showed that the maximum tolerated doses of Compound A-1 and A-2 in mice were 1800 mg / kg and 900 mg / kg, which were 12-18 times and 7.5-11.3 times of their effective doses (Compound A-1: ​​100-150 mg / kg, Compound A-2: 80-120 mg / kg), respectively. This indicates that Compound A-1 and Compound A-2 also have high biosafety.

[0117] The results of Examples 2-4 above show that Compounds A-1 and A-2 not only have high muscle relaxant antagonist activity, but also have high biological safety and high water solubility.

[0118] 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. Use of diaryl glycoluril tetramer derivatives represented by formula A-1 and formula A-2, or pharmaceutically acceptable salts, hydrates or solvates thereof, characterized in that: For the preparation of muscle relaxant antagonists; 2. The use according to claim 1, characterized in that The muscle relaxant is a non-depolarizing muscle relaxant.

3. The use according to claim 1, characterized in that The non-depolarizing muscle relaxant is selected from the following group: steroidal quaternary ammonium salt muscle relaxants, tetrahydroisoquinoline quaternary ammonium salt muscle relaxants, or a combination thereof.

4. The use according to claim 1, characterized in that The non-depolarizing muscle relaxant is selected from the group consisting of rocuronium bromide, cisatracurium besylate, or a combination thereof.

5. A pharmaceutical composition for antagonizing muscle relaxants, characterized in that: The composition comprises: (a) a compound represented by formula A-1 and / or formula A-2, or a pharmaceutically acceptable salt, hydrate or solvate thereof as the first active ingredient; (b) a pharmaceutically acceptable carrier or excipient.

6. The pharmaceutical composition according to claim 5, characterized in that The dosage form of the pharmaceutical composition is injection, tablet, capsule, pill, suspension or emulsion; preferably injection.

7. The pharmaceutical composition according to claim 6, characterized in that The injection is an aqueous solution, a sodium chloride aqueous solution or a glucose aqueous solution, wherein the concentration of component (a) as the first active ingredient is 0.1-5000 mg / mL; preferably, it is a physiological saline solution.

8. A pharmaceutical composition for antagonizing muscle relaxants, characterized in that: The composition comprises: (a) a compound represented by formula A-1 and / or formula A-2, or a pharmaceutically acceptable salt, hydrate or solvate thereof as the first active ingredient; (b) as a second active ingredient, an ingredient having an antagonistic effect on non-depolarizing muscle relaxants selected from the group consisting of neostigmine, sugammadex sodium, or a combination thereof; and (c) a pharmaceutically acceptable carrier or excipient.

9. A kit, characterized in that: Include: (a) a first container, and a compound of formula A-1 and / or formula A-2 as an active ingredient, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 4 or 5, located in the first container; and / or (b) a second container, and a muscle relaxant in the second container; the muscle relaxant is a non-depolarizing muscle relaxant selected from the group consisting of steroidal quaternary ammonium salt muscle relaxants, tetrahydroisoquinoline quaternary ammonium salt muscle relaxants, or a combination thereof; and / or (c) a third container, and a muscle relaxant antagonist in the third container, wherein the muscle relaxant antagonist is selected from the group consisting of neostigmine, sugammadex sodium, or a combination thereof; and / or (d) Optional instructions for use.

10. A method for antagonizing muscle relaxants, characterized in that: A therapeutically effective amount of the compound of formula A-1 or A-2 according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is administered to a subject in need thereof, thereby antagonizing "residual quiver toxicity" in the subject.

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