Deuterated diaryl glycoluril tetramer compounds and uses thereof

Abstract

Disclosed are deuterated glycoluril tetramer compounds having aryl groups incorporated at both ends represented by formula (1), pharmaceutical compositions containing the compounds. The deuterated compounds are useful for antagonizing clinically used non-depolarizing muscle relaxants, and have significantly superior antagonistic activity against rocuronium and vecuronium to sugammadex at the same dose, and significantly superior antagonistic activity against cisatracurium and rocuronium to a non-deuterated control molecule.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a deuterated diarylglycourea tetramer compound or a composition thereof capable of antagonizing a variety of muscle relaxants. Background Technology

[0002] Since 1942, neuromuscular blocking agents or muscle relaxants (hereinafter referred to as muscle relaxants) have been widely used in clinical anesthesia practice to relax skeletal muscles, thereby facilitating intubation and improving surgical conditions. Globally, more than 400 million patients receive muscle relaxant treatment during anesthesia in operating rooms and intensive care units each year. Among them, non-depolarizing muscle relaxants, such as ammonium steroids like rocuronium bromide, vecuronium bromide, and pancuronium bromide, and benzyl isoquinoline derivatives like atracurium besylate, are more widely used in clinical practice due to their fewer side effects compared to depolarizing muscle relaxants. The intermediate-acting muscle relaxant atracurium besylate, due to its advantages such as rapid onset of action, strong effect, rapid recovery, no histamine release, few cardiovascular side effects, no accumulation in the body, non-toxic metabolites, no muscle-relaxing effect, and independence from renal excretion, accounts for approximately 30% of the global neuromuscular blocking agent market and approximately 70% of the domestic market. Furthermore, rocuronium and vecuronium, which belong to the same intermediate-acting muscle relaxant class as atracurium besylate, account for approximately 50% of the global market and about 30% of the domestic market. Pancuronium, a long-acting muscle relaxant, accounts for about 1%, but the absolute number of cases remains high. However, the incidence of postoperative "residual quiver toxicity" caused by residual intermediate- and long-acting muscle relaxants is high in clinical practice, leading to postoperative respiratory complications such as upper airway dysfunction, airway obstruction, and pulmonary respiratory dysfunction, which can even result in death in severe cases. Therefore, rapid and effective antagonism of residual excess muscle relaxants is of significant clinical importance. It not only helps reduce postoperative risks for patients but also facilitates early extubation and recovery, accelerates operating room turnover, and reduces surgical costs.

[0003] A prospective, multicenter, single-blind observational study published in my country in 2016 found that the overall incidence of residual muscle relaxants after extubation was as high as 57.8%, requiring intervention with antagonists to eliminate "residual quiver toxicity" and help patients recover muscle function as quickly as possible. In current clinical practice, muscle relaxant antagonists are divided into two categories: (1) those that inhibit cholinesterase activity using anticholinesterase drugs, and (2) those that bind and isolate muscle relaxants using the principle of direct capture. The representative of the first type of antagonist is neostigmine, which requires the use of adjuvant drugs such as glycopyrronium bromide or alotridine to reduce the side effects of muscarinic toxicity. Neostigmine generally has low antagonistic efficiency, cannot achieve rapid reversal of muscle relaxants, and cannot reverse deep muscle relaxation. Therefore, neostigmine is not an ideal muscle relaxant antagonist. The representative drug in clinical practice of the second type of antagonist is sugammadextrin sodium, which can rapidly reverse the muscle relaxant activity of rocuronium bromide and vecuronium bromide through its specific binding to the hydrophobic cavities of γ-cyclodextrin. However, sugammadextrose sodium cannot antagonize cisatracurium and pancuronium bromide. Cisatracurium is widely used clinically and is the most commonly used muscle relaxant in China, playing an irreplaceable role in many clinical practices: it is recommended as a surgical muscle relaxant for patients at risk of acute respiratory distress syndrome, as a general anesthesia drug for patients with renal insufficiency, and is one of the most commonly used muscle relaxants in intensive care units. Pancuronium bromide, as a long-acting muscle relaxant, is still widely used clinically. Therefore, there is an important and urgent unresolved clinical need to develop antagonists that rapidly antagonize cisatracurium and pancuronium bromide, or broad-spectrum, rapidly acting antagonists against all of the aforementioned muscle relaxants.

[0004] Hoffmann et al. reported that diphenylglyuretetramers with four sulfonate side chains have high biocompatibility, but low antagonistic activity against muscle relaxants. Liu et al. reported that cucurbit[8]urea macrocycles with introduced sulfonate side chains have good antagonistic activity against muscle relaxants and good biocompatibility, but these cucurbit[8]urea derivatives are mixtures with uncertain composition and low drugability. Xue et al. reported that columnar[6] sulfonates have high binding affinity to cis-atracurium besylate, but their actual antagonistic activity is unknown, and the synthesis yield of columnar[6] sulfonates is low. Furthermore, the separation of these sulfonates requires complex gel chromatography techniques. Therefore, although the development of broad-spectrum antagonistic drugs that can rapidly reverse muscle relaxants is beneficial in clinical practice, discovering novel druggable compounds with rapid antagonistic activity and high biocompatibility is a very challenging task.

[0005] In summary, there is an urgent need in this field to develop a class of broad-spectrum antagonist drugs with high biological safety that can rapidly antagonize steroidal quaternary ammonium salts and tetrahydroisoquinoline quaternary ammonium salt muscle relaxants. Summary of the Invention

[0006] The purpose of this invention is to provide a deuterated diaryl glycourea tetramer compound with broad-spectrum and rapid antagonistic activity against muscle relaxants such as steroidal quaternary ammonium salts (rocuronium bromide, vecuronium bromide, pancuronium bromide) and tetrahydroisoquinoline quaternary ammonium salts (cis-sulfotracurium), and its uses.

[0007] In a first aspect, the present invention provides a deuterated diaryl glycourea tetramer compound of formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0008]

[0009] in,

[0010] Each Z is independently an amino group substituted with O, S, Se, Te, C1-C4 alkylene, -NH- or C1-C4 alkyl;

[0011] Each M is independently Na + K + Li + Mg 2+ Ca 2+ NH4 + or one or more C1-C4 alkyl-substituted ammonium salts;

[0012] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 and R 28 Each can be either deuterium or hydrogen independently;

[0013] R 9 R 10 R 11 and R 12 Each is independently an undeuterated, partially deuterated, or fully deuterated straight-chain or branched C1-C20 alkyl group, or R 9 and R10 R 11 and R 12 Each of them, together with the carbon atoms they are attached to, forms a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of: C3-C20 cycloalkyl, 3-20 heterocyclic, C5-C20 aryl, or 5-20 heteroaryl.

[0014] R 29 R 30 R 31 or R 32 Each of the following groups is independently non-deuterated, partially deuterated, or fully deuterated: straight-chain or branched C1-C20 alkylene, C3-C20 cycloalkylene, straight-chain or branched 1-20 heteroalkylene containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen, or 3-20 heterocyclic group containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen;

[0015] R 33 R 34 R 35 and R 36 Each group independently being deuterium, hydrogen, or non-deuterated, partially deuterated, or fully deuterated, selected from the group consisting of: straight-chain or branched C1-C20 alkyl, C3-C20 cycloalkyl, straight-chain or branched C1-C20 alkoxy, straight-chain or branched C1-C20 alkylthio, straight-chain or branched C1-C20 aldehyde, straight-chain or branched C1-C20 ester, carbonyl-containing straight-chain or branched C1-C20 alkyl, or R 33 With R 34 R 35 With R 36 Each of the carbon atoms attached to it forms a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of: C3-C20 saturated carbon rings, C3-C20 saturated spiro rings, saturated 3-20-membered heterocycles containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen, C5-C20 aromatic rings, or 5-20-membered heteroaromatic rings containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen.

[0016] The additional condition is: R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 33 R 34 R 35 and R 36 At least one of them is deuterium, or R 9 R 10 R 11 R 12 R 29 R 30 R 31 R 32 R 33 R 34 R 35 and R 36 At least one of them is deuterated or deuterated.

[0017] In another preferred embodiment, Z is an amino group substituted with O, S, Se, Te, methylene, NH, or C1-C4 alkyl.

[0018] In another preferred embodiment, M is Na. + .

[0019] In another preferred embodiment, R 1 R 2 R 3 R 4 Each can be H or D independently.

[0020] In another preferred embodiment, R 1 R 2 R 3 R 4 At least one of them is D.

[0021] In another preferred embodiment, R 1 R 2 R 3 R 4 Each is D independently.

[0022] In another preferred embodiment, R 5 R 6 R 7 and R 8 Each is either deuterium or hydrogen.

[0023] In another preferred embodiment, R 5 R 6 R 7 and R 8Each is independently hydrogen.

[0024] In another preferred embodiment, R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 Each can be H or D independently.

[0025] In another preferred embodiment, R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 At least one of them is D.

[0026] In another preferred embodiment, R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 Each is D independently.

[0027] In another preferred embodiment, R 13 R 14 R 15 R 16 R 17 R 18 R 19 R20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 Each is independently represented by H.

[0028] In another preferred embodiment, R 1 R 2 R 3 R 4 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 Each can be H or D independently.

[0029] In another preferred embodiment, R 1 R 2 R 3 R 4 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 At least 1, 2, 4, 6, 8, or 10 of them are D.

[0030] In another preferred embodiment, R 1 R 2 R 3 R 4 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 Each is D independently.

[0031] In another preferred embodiment, R 9 R 10 R 11 and R 12 Each is independently an undeuterated, partially deuterated, or fully deuterated straight-chain or branched C1-C10 alkyl group, or R9 and R 10 R 11 and R 12 Each of them, together with the carbon atoms they are attached to, forms a group selected from the group consisting of: C3-C10 cycloalkyl, 3-10 heterocyclic, C6-C10 aryl, or 5-10 heteroaryl.

[0032] In another preferred embodiment, R 9 R 10 R 11 and R 12 Each is independently an undeuterated, partially deuterated, or fully deuterated straight-chain or branched C1-C7 alkyl group, or R 9 and R 10 R 11 and R 12 Each of them, together with the carbon atoms they are attached to, forms a C3-C7 cycloalkyl group, a 3-7 membered heterocyclic group, a C6-C8 aryl group, or a 5-7 membered heteroaryl group.

[0033] In another preferred embodiment, R 9 R 10 R 11 and R 12 Each is independently an undeuterated, partially deuterated, or fully deuterated straight-chain or branched C1-C4 alkyl group, or R 9 and R 10 R 11 and R 12 Each of them, together with the carbon atoms they are attached to, forms a C5-C7 cycloalkyl group.

[0034] In another preferred embodiment, R 9 R 10 R 11 and R 12 Each is independently an undeuterated, partially deuterated, or fully deuterated straight-chain or branched C1-C4 alkyl group.

[0035] In another preferred embodiment, R 9 R 10 R 11 and R 12 Each is independently CD3 or CH3.

[0036] In another preferred embodiment, R 29 R 30 R 31 Or R 32Each of the following groups is independently non-deuterated, partially deuterated, or fully deuterated: straight-chain or branched C1-C10 alkylene groups, C3-C10 cycloalkylene groups, straight-chain or branched 1-10 heteroalkylene groups containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen, or 3-10 heterocyclic groups containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen.

[0037] In another preferred embodiment, R 29 R 30 R 31 Or R 32 Each of the following groups is independently non-deuterated, partially deuterated, or fully deuterated: straight-chain or branched C1-C6 alkyl groups, or straight-chain or branched 1-6 alkyl groups containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen.

[0038] In another preferred embodiment, R 29 R 30 R 31 Or R 32 Each of the following groups is independently non-deuterated, partially deuterated, or fully deuterated: straight-chain or branched C1-C4 alkylene groups, or straight-chain or branched 1-4 heteroalkylene groups containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen.

[0039] In another preferred embodiment, R 29 R 30 R 31 Or R 32 Each can be independently non-deuterated, partially deuterated, or fully deuterated propyl.

[0040] In another preferred embodiment, R 33 R 34 R 35 and R 36 Each group independently being deuterium, hydrogen, or non-deuterated, partially deuterated, or fully deuterated, selected from the group consisting of: straight-chain or branched C1-C10 alkyl, C3-C10 cycloalkyl, straight-chain or branched C1-C10 alkoxy, straight-chain or branched C1-C10 alkylthio, straight-chain or branched C1-C10 aldehyde, straight-chain or branched C1-C10 ester, carbonyl-containing straight-chain or branched C1-C10 alkyl, or R 33 With R 34 R 35 With R 36 Each of the groups, together with the carbon atoms they are attached to, forms a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of: C3-C10 saturated carbon rings, C3-C10 saturated spiro rings, saturated 3-10-membered heterocycles containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen, C5-C10 aromatic rings, or 5-10-membered heteroaromatic rings containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen.

[0041] In another preferred embodiment, R 33 R 34 R 35 and R 36 Each group independently being deuterium, hydrogen, or non-deuterated, partially deuterated, or fully deuterated, selected from the group consisting of: straight-chain or branched C1-C6 alkyl, C3-C7 cycloalkyl, straight-chain or branched C1-C6 alkoxy, straight-chain or branched C1-C6 alkylthio, straight-chain or branched C1-C6 aldehyde, straight-chain or branched C1-C6 ester, carbonyl-containing straight-chain or branched C1-C6 alkyl, or R 33 With R 34 R 35 With R 36 Each of the groups, together with the carbon atoms they are attached to, forms non-deuterated, partially deuterated, or fully deuterated groups selected from the group consisting of: C3-C7 saturated carbon rings, C3-C7 saturated spiro rings, saturated 3-7 membered heterocycles containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen, C6-C10 aromatic rings, or 5-8 membered heteroaromatic rings containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen.

[0042] In another preferred embodiment, R 33 R 34 R 35 and R 36 Each group is independently deuterium, hydrogen, or non-deuterated, partially deuterated, or fully deuterated, selected from the group consisting of: straight-chain or branched C1-C6 alkyl, C3-C7 cycloalkyl, or R 33 With R 34 R 35 With R 36 Each of them, together with the carbon atoms they are attached to, forms a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of C3-C7 saturated carbon rings or benzene rings.

[0043] In another preferred embodiment, R 33 R 34 R 35 and R 36 Each group is independently deuterium, hydrogen, or non-deuterated, partially deuterated, or fully deuterated, selected from the group consisting of: straight-chain or branched C1-C5 alkyl groups, or R 33 With R 34 R 35 With R 36 Each of them, together with the carbon atoms they are attached to, forms a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of C5-C7 saturated carbon rings or benzene rings.

[0044] In another preferred embodiment, R 33 R 34 R 35 and R 36Each can be independently deuterium, hydrogen, CD3 or CH3, or R. 33 With R 3 R 35 With R 36 Each carbon atom, together with its attached carbon atom, forms a five-membered carbon ring or a benzene ring.

[0045] In another preferred embodiment, the ratio of deuterium atoms to the sum of deuterium and hydrogen atoms (D / (D+H)) in the compound is ≥0.015% (natural deuterium isotope content); more preferably, ≥10%; more preferably, ≥30%; more preferably, ≥75%; more preferably, ≥95%; and most preferably, ≥98%.

[0046] In another preferred embodiment, the compound contains at least 1 deuterium atom; more preferably, 2 deuterium atoms; more preferably, 4 deuterium atoms; more preferably, 6 deuterium atoms; more preferably, 8 deuterium atoms; more preferably, 12 deuterium atoms; and most preferably, 20 deuterium atoms.

[0047] In another preferred embodiment, the compound does not include non-deuterated or deuterium-free compounds.

[0048] In another preferred embodiment, the compound is selected from the group consisting of:

[0049]

[0050]

[0051]

[0052] In another preferred embodiment, the compound is

[0053] A second aspect of the present invention provides a pharmaceutical composition comprising: (a) a compound of 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, component (a) comprises 0.001-99.999 wt% of the total weight of the composition; more preferably 0.01-99.99 wt%; and even more preferably 0.1-90 wt%.

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

[0056] In another preferred embodiment, the injection is an aqueous solution, an aqueous sodium chloride solution, or an aqueous glucose solution, wherein the concentration of the compound of the first aspect of the present invention as the active ingredient is 0.1-5000 mg / mL.

[0057] In another preferred embodiment, the dosage of the injection is 0.1-5000 mg / kg, based on the weight of the rat.

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

[0059] (a) The compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as the first active ingredient;

[0060] (b) as a second active ingredient an ingredient selected from the group consisting of non-depolarizing muscle relaxants: neostigmine, sugammadextrose sodium, or combinations thereof; and

[0061] (c) Pharmaceutically acceptable carriers or excipients.

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

[0063] In a fourth aspect of the invention, a pharmaceutical composition is provided, the composition comprising:

[0064] (a) The compound of the first aspect of the present invention as the first active ingredient, or a pharmaceutically acceptable salt, hydrate or solvate thereof;

[0065] (b) a non-deuterated aryl tetramer compound having the structure shown in the first aspect of the invention as a second active ingredient; and

[0066] (c) Pharmaceutically acceptable carriers or excipients.

[0067] In another preferred embodiment, the dosage form of the pharmaceutical composition is an injection, tablet, capsule, pill, suspension, or emulsion.

[0068] In another preferred embodiment, the non-deuterated aryl tetramer compound having the structure shown in the first aspect of the invention is as follows:

[0069]

[0070] Each Z is independently an amino group substituted with O, S, Se, Te, C1-C4 alkylene, -NH- or C1-C4 alkyl;

[0071] Each M is independently Na + K + Li + Mg 2+ Ca 2+ NH4 +or one or more C1-C4 alkyl-substituted ammonium salts;

[0072] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 and R 28 Each is independently hydrogen;

[0073] R 9 R 10 R 11 and R 12 Each is independently a non-deuterated straight-chain or branched C1-C20 alkyl group, or R 9 and R 10 R 11 and R 12 Each of them, together with the carbon atoms they are attached to, forms a non-deuterated group selected from the following groups: C3-C20 cycloalkyl, 3-20 heterocyclic, C5-C20 aryl, or 5-20 heteroaryl;

[0074] R 29 R 30 R 31 or R 32 Each of the following groups is independently non-deuterated and selected from the group consisting of: straight-chain or branched C1-C20 alkylene groups, C3-C20 cycloalkylene groups, straight-chain or branched 1-20 heteroalkylene groups containing one or more heteroatoms selected from oxygen, sulfur or nitrogen, or 3-20 heterocyclic groups containing one or more heteroatoms selected from oxygen, sulfur or nitrogen.

[0075] R 33 R 34 R 35 and R 36Each of the following groups is independently hydrogen or non-deuterated and selected from the group consisting of: straight-chain or branched C1-C20 alkyl, C3-C20 cycloalkyl, straight-chain or branched C1-C20 alkoxy, straight-chain or branched C1-C20 alkylthio, straight-chain or branched C1-C20 aldehyde, straight-chain or branched C1-C20 ester, carbonyl-containing straight-chain or branched C1-C20 alkyl, or R 33 With R 34 R 35 With R 36 Each of the groups, together with the carbon atoms they are attached to, forms a non-deuterated group selected from the following groups: C3-C20 saturated carbon rings, C3-C20 saturated spiro rings, saturated 3-20-membered heterocycles containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen, C5-C20 aromatic rings, or 5-20-membered heteroaromatic rings containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen.

[0076] In a fifth aspect of the invention, a kit is provided, comprising:

[0077] (a) A first container, and a compound of the first aspect of the present invention as an active ingredient, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of the second aspect of the present invention, located within the first container; and / or

[0078] (b) A second container, and a muscle relaxant located in the second container; said muscle relaxant is selected from the group consisting of steroidal quaternary ammonium salts, tetrahydroisoquinoline quaternary ammonium salts, benzylisoquinoline derivatives, or combinations thereof; and / or

[0079] (c) the nth container, and the nth pharmaceutical ingredient located in the nth container, wherein n is any positive integer from 3 to 30; wherein the nth pharmaceutical ingredient is selected from the compounds described in the first aspect of the invention; and / or

[0080] (4) Optional instruction manual.

[0081] In another preferred embodiment, the non-depolarizing muscle relaxant is succinate atracurium besylate, pancuronium bromide, rocuronium bromide, vecuronium bromide, or a combination thereof.

[0082] In another preferred embodiment, the kit is used to antagonize a muscle relaxant.

[0083] In another preferred embodiment, the non-depolarizing muscle relaxant is selected from the group consisting of steroidal quaternary ammonium salts, tetrahydroisoquinoline quaternary ammonium salts, benzylisoquinoline derivative muscle relaxants, or combinations thereof.

[0084] In a sixth aspect of the invention, the use of the compound described in the first aspect of the invention, or the pharmaceutical composition described in the second aspect of the invention, or the pharmaceutical composition described in the third aspect of the invention, or the pharmaceutical composition described in the fourth aspect of the invention, for antagonizing a muscle relaxant is provided.

[0085] In a seventh aspect of the invention, a method for antagonizing a muscle relaxant is provided, wherein a therapeutically effective amount of the compound described in the first aspect of the 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.

[0086] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described 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 described in detail here. Detailed Implementation

[0087] Through extensive, in-depth, and systematic research, the inventors have developed a class of deuterated diarylglycourea tetramers with broad-spectrum and rapid antagonistic activity against steroidal quaternary ammonium salts (rocuronium bromide, vecuronium bromide, pancuronium bromide) and tetrahydroisoquinoline quaternary ammonium salts (cissulfonamide) muscle relaxants. These compounds also exhibit high water solubility and high biocompatibility. At the same dosage, compared with non-deuterated control molecules and sugammadextrose sodium, the deuterated compounds of this invention exhibit significantly enhanced antagonistic activity. Based on this, the inventors completed this invention.

[0088] definition

[0089] Unless otherwise defined, 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 pertains.

[0090] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated values. 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.).

[0091] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0092] Deuterium is a stable isotope of hydrogen. CD bonds are more stable than CH bonds, therefore they are less prone to breakage and may have a longer half-life. The acidity and hydrophobicity of CD bonds differ from those of CH bonds, leading to variations in their hydrophobic-driven accumulation, clustering, or aggregation in vivo, as well as their stability and selectivity in binding with living matter. The metabolic processes of living systems are complex, and the metabolic and excretion kinetics of deuterated molecules are influenced by many factors, exhibiting corresponding complexity. Therefore, compared to non-deuterated molecules, the biological activity of deuterated molecules exhibits great randomness and unpredictability; deuteration at many sites can reduce or degrade the molecule's biological activity. Furthermore, certain hydrogen sites in organic molecules are difficult or impossible to deuterate due to limitations in synthetic methods. Therefore, deuteration of organic molecules is not arbitrary; the sites of deuteration are unpredictable, and their biological activity is also unpredictable.

[0093] As used herein, “C1-C20 alkyl” refers to a straight-chain or branched alkyl group comprising 1-20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc., or similar groups.

[0094] As used in this article, "1-20 heteroalkyl" refers to C 1-20 One or more carbon atoms in the alkyl chain are replaced by heteroatoms selected from nitrogen, oxygen and sulfur. For example, 1-8 heteroalkyl refers to CH3-CH2-CH2-CH2-O-CH2-CH2-CH2- or similar groups such as CH3-CH2-CH2-CH2-O-CH2-CH2-O-.

[0095] As used herein, “2-20 heteroalkenyl” refers to a group in which one or more carbon atoms in a C2-20 alkenyl chain are replaced by heteroatoms selected from nitrogen, oxygen and sulfur. For example, 1-7 heteroalkenyl refers to groups such as CH3-CH2-CH2-O-CH2-CH=CH- or CH3-S-CH2-CH2-O-CH=CH-.

[0096] As used in this article, "2-20 heteroyne group" refers to a group in which one or more carbon atoms in a C2-20 alkynyl chain are replaced by heteroatoms selected from nitrogen, oxygen and sulfur. For example, 1-7 heteroyne group refers to CH3-CH2-CH2-O-CH2-C≡C- or similar groups such as CH3-S-CH2-CH2-OC≡C-.

[0097] As used in this article, "C1-C" 20 "Alkyl chain" refers to a straight or branched alkyl chain (CH2) consisting of 1-20 carbon atoms. n (n = 1 to 20).

[0098] As used herein, "C3-C20 cycloalkyl" refers to cycloalkyl groups containing 3-20 carbon atoms or cycloalkyl groups with side chains, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The term "C3-C..." 20 "" refers to a cycloalkyl group containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The cycloalkyl group is preferably C3-C. 14 Cycloalkyl, more preferably C3-C 10 Cycloalkyl groups, more preferably C3-C6 monocyclic cycloalkyl groups, C7-C 10 Bicyclic or tricyclic cycloalkyl. "Substituted cycloalkyl" means that one or more positions in a cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.

[0099] As used herein, “carbocyclic” refers to a fully saturated or partially unsaturated (preferably fully saturated) cyclic hydrocarbon compound group, including cycloalkenyl, cycloalkyl, and cycloynyl groups.

[0100] In this invention, the term "heterocyclic group (or heterocycle)" refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, 3-7 membered monocyclic, 4-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic or polycyclic systems), wherein at least one heteroatom is present in a ring with at least one carbon atom. The term "4-20 membered heterocyclic group" refers to a heterocyclic group containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms. "Heterocyclic group" has the same meaning as "saturated or unsaturated heterocyclic group". The "heterocyclic group" is preferably a 4-14 membered heterocyclic group (including but not limited to 4-6 membered monocyclic, 7-10 membered bicyclic, or 8-14 membered tricyclic or polycyclic systems), more preferably a 4-12 membered heterocyclic group, even more preferably a 4-10 membered heterocyclic group, such as a 4-6 membered monocyclic heterocyclic group, a 7-11 membered bicyclic or tricyclic heterocyclic group, even more preferably a 4-8 membered heterocyclic group, and even more preferably a 4-6 membered heterocyclic group. Each heterocyclic group contains a heterocycle with 1, 2, 3, or 4 heteroatoms, each of which is independently selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom may be oxidized or quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom residue of the ring or ring system molecule, preferably to an N or C atom of the ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, nitrogen-containing heterocyclic butyl, pyrrolyl, oxoheterocyclic butyl, pyrazolinyl, imidazolinyl, imidazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, hexahydroacoxaneyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxaneyl, and tetrahydro-1,1-dioxothiophene, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring; the heterocyclic group can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuteralkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylic acid ester groups.

[0101] As used herein, “deuterated” means that one or more hydrogen atoms in a compound or group are replaced by deuterium. Deuteration can be monosubstituted, disubstituted, polysubstituted, or total substituted. The terms “one or more deuterated” and “one or more deuterated” are used interchangeably.

[0102] As used in this article, "non-deuterated" means that the proportion of deuterium isotopes in each hydrogen atom is no higher than the natural deuterium isotope content (approximately 0.015%).

[0103] As used herein, the term "active ingredient" refers to a deuterated diarylglycourea tetramer compound. It should be understood that the term also includes mixtures of such compounds.

[0104] As used herein, the term "hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0105] As used herein, the term "solvent complex" refers to a complex of the compound of the present invention coordinated with a solvent molecule in a specific ratio.

[0106] As used herein, the term "aryl (or aromatic ring)" refers to a monovalent aromatic carbocyclic group of 5 to 20 (preferably 6 to 14) carbon atoms, having a monocyclic (e.g., phenyl) or fused (e.g., naphthyl or anthracene) ring. If the bonding point is on an aromatic carbon atom, the fused ring may be non-aromatic (e.g., 2-benzoxazolone, 2H-1,4-benzoxazine-3(4H)-one-7-yl, etc.). Preferred aryl groups include phenyl and naphthyl.

[0107] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having 3 to 12 (preferably 3 to 10) carbon atoms and being monocyclic or polycyclic (including fused, bridged, and spirocyclic systems). In fused-ring systems, one or more rings may be cycloalkyl, heterocyclic, aryl, or heteroaryl, as long as the linking site is a ring through a cycloalkyl group. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.

[0108] The term "heteroaryl" refers to an aromatic cyclic hydrocarbon group comprising 1-4 heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur. Specifically, "5-14 membered heteroaryl" refers to a heteroaromatic system comprising 1-4 heteroatoms and 5-14 ring atoms. The heteroaryl is monocyclic (e.g., pyridinyl or furanyl) or fused-ring (e.g., indolizinyl or benzothiophene). The fused ring may be non-aromatic and / or contain one heteroatom, as long as the connecting point is through an atom of an aromatic heteroaryl group. The heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrroloyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and tetrazolyl. The "heteroaryl" group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, deuteralkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylic acid ester groups. In one embodiment, the nitrogen and / or sulfur atom of the heteroaryl ring is optionally oxidized to N-oxide (NO), sulfinyl, or sulfonyl. Preferably, the heteroaryl group includes pyridyl, pyrroleyl, indolyl, thiophenyl, and furanyl.

[0109] As used herein, the term "substituted heteroaryl" refers to a heteroaryl group substituted by 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the same substituents as defined for substituted aryl.

[0110] The animal activity tests and acute toxicity tests in this invention were conducted using SD rats.

[0111] As used herein, unless otherwise specified, substitution refers to the replacement of a hydrogen atom in a group with one or more groups selected from the group consisting of: halogen, nitro, amino, cyano, hydroxy, amide, trifluoromethyl, C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic groups, C 1-6 Alkoxycarbonyl group.

[0112] As used herein, if a deuterated diaryl urea tetramer compound contains a chiral carbon atom, the chiral carbon atom may be in the R-configuration, S-configuration, or a mixture of both.

[0113] The deuterated diarylglycourea tetramer compounds or compositions thereof of the present invention can be prepared using methods well known to those skilled in the art, and there are no particular limitations on the reaction parameters of each step. Furthermore, the typical compounds of the present invention are commercially available.

[0114] As used in this article, "quiver toxicity" refers to the symptoms that occur after surgery due to neuromuscular blockade caused by residual muscle relaxants, preventing the patient from regaining spontaneous breathing. It is called "quiver toxicity" because the symptoms resemble those caused by quiver alkaloids.

[0115] The animal activity tests and acute toxicity tests in this invention were conducted using SD rats.

[0116] Neuromuscular blocking agents or muscle relaxants

[0117] Neuromuscular blocking agents, or muscle relaxants (simply referred to as muscle relaxants), are widely used in clinical practice to relax skeletal muscles, thereby facilitating intubation and improving surgical conditions. Based on their mechanisms of action, muscle relaxants are classified into depolarizing and non-depolarizing types: depolarizing muscle relaxants bind to N2 cholinergic receptors on the motor nerve endplate membrane, weakening or eliminating the muscle cell's response to acetylcholine; non-depolarizing muscle relaxants compete with acetylcholine for N2 cholinergic receptors on the skeletal muscle motor endplate membrane, leading to skeletal muscle relaxation. The most commonly used non-depolarizing muscle relaxants in clinical practice are further classified according to their chemical structure into aminosteroid derivatives (such as rocuronium bromide, vecuronium bromide, and pancuronium bromide) and benzylisoquinoline derivatives (such as cis-atracurium besylate).

[0118] Muscle relaxant antagonist – deuterated diarylglycourea tetramer

[0119] The present invention provides a deuterated diaryl glycourea tetramer with the structure shown in Formula I.

[0120]

[0121] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 The definition is as described above.

[0122] The deuterated diaryl glycourea tetramer described in this invention has a pre-organized "C" conformation that forms a hydrophobic cavity that can drive the binding of the aforementioned muscle relaxant through hydrophobic interaction, thereby antagonizing its muscle relaxation activity.

[0123] The deuterated diaryl glycourea tetramer described in this invention has anionic sulfonate side chains introduced at both ends. The electrostatic interaction of these chains can synergistically work with the hydrophobic effect of the tetramer's "C" conformation, thereby rapidly and efficiently binding to muscle relaxants and antagonizing their muscle-relaxing activity.

[0124] In this invention, deuterated diarylglycourea tetramers are used as broad-spectrum muscle relaxant antagonists. Rat studies support that this application can achieve rapid antagonism against cis-sulfatracurium and rocuronium bromide, as well as vecuronium bromide and panvecuronium bromide muscle relaxants. These deuterated compounds exhibit high water solubility and high biocompatibility, demonstrating significant clinical applicability.

[0125] Controlled experiments support that these novel deuterated compounds achieve faster antagonism against rocuronium bromide and vecuronium bromide than the clinically used drug sugammadex. Controlled experiments with non-deuterated compounds support that these deuterated compounds significantly enhance the antagonistic activity against atracurium besylate. The deuterated diarylglycourea tetramer, compared to its corresponding non-deuterated counterpart, serves as a broad-spectrum muscle relaxant antagonist. Rat studies support that this application achieves rapid antagonism against atracurium besylate and pancuronium bromide. Controlled experiments support that these novel deuterated compounds achieve faster antagonism against rocuronium bromide and vecuronium bromide than the clinically used drug sugammadex. These deuterated compounds possess high water solubility and high biocompatibility, demonstrating significant clinical applicability.

[0126] Preparation method

[0127] The preparation methods of the compounds of formula (I) of the present invention are described in more detail below, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0128] The deuterated diaryl glycourea tetramer described in this invention is prepared by electrophilic substitution reaction with two aromatic ring molecules with different functional groups, using the open-ring glycourea tetramer as a rigid pre-organized framework.

[0129] In this invention, the preparation of the deuterated diarylglycourea tetramer and the corresponding starting materials is mostly carried out under acidic conditions, at room temperature to reflux temperature (e.g., 0–100°C, preferably 0–60°C). The reaction time is typically 0.1 h–60 h, preferably 0.5–48 h. The following general preparation route can be used to synthesize compounds of formula (I) of this invention:

[0130]

[0131] Synthetic route 1: where Z represents O, S, Se, Te, methylene, amino, and substituted amino groups;

[0132] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 The definition is as described above.

[0133] As shown in the first synthetic route, the compounds of the present invention are synthesized in a convergent manner. (a) First, a diketone compound A with different substituents undergoes a cyclization condensation reaction with urea to generate a glycourea compound B with different substituents. Subsequently, it undergoes a further cyclization condensation reaction with paraformaldehyde or deuterated paraformaldehyde C to obtain a glycourea dimer D and a tetracyclic glycourea diether structure E, respectively. D and E undergo further condensation reactions to obtain a tetramer F with different substituents; (b) An aryl compound G with different substituents undergoes a nucleophilic substitution reaction with propane sulfonyl lactone H to generate a non-deuterated aryl sulfonate I or J. I further undergoes a deuteration reaction to obtain a deuterated aryl sulfonate J; (c) Finally, the non-deuterated or deuterated aryl sulfonate J converges with the tetramer F and generates the compound (I) of the present invention through an electrophilic substitution reaction.

[0134] The deuterated diaryl urea tetramer described in this invention can be prepared using three key intermediates: a deuterated or non-deuterated dimer intermediate, a deuterated or non-deuterated tetramer intermediate, and a deuterated or non-deuterated sulfonate intermediate.

[0135] Deuterated or non-deuterated dimer intermediates;

[0136] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7 and R 8 Each can be either deuterium or hydrogen independently;

[0137] Furthermore, the structure of the deuterated or non-deuterated dimer intermediate is shown below:

[0138]

[0139] Deuterated or non-deuterated tetramers;

[0140] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R21 R 22 R 23 R 24 R 25 R 26 R 27 and R 28 Each is independently either deuterium or hydrogen; R 9 R 10 R 11 and R 12 Each is an undeuterated, partially deuterated, or fully deuterated straight-chain or branched C1-C20 alkyl group, or two adjacent groups together with the carbon atom they are connected to form an undeuterated, partially deuterated, or fully deuterated C3-C20 cycloalkyl group.

[0141] Furthermore, the structure of the deuterated or non-deuterated tetrameric intermediate is shown below:

[0142]

[0143] Deuterated or non-deuterated sulfonate intermediates;

[0144] In the formula, Z represents O, S, Se, Te, methylene, amino, or a substituted amino group; M represents Na. + ;

[0145] R 29 R 30 R 31 or R 32 Each of the following groups is independently non-deuterated, partially deuterated, or fully deuterated: straight-chain or branched C1-C20 alkyl, C3-C20 cycloalkyl, straight-chain or branched C1-C20 alkyl containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen, or C3-C20 cycloalkyl containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen;

[0146] R 33 R 34 R 35 and R 36 Each group is independently deuterium, hydrogen, or a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of: straight-chain or branched C1-C20 alkyl, C3-C20 cycloalkyl, straight-chain or branched C1-C20 alkoxy, straight-chain or branched C1-C20 alkylthio, straight-chain or branched C1-C20 aldehyde, straight-chain or branched C1-C20 ester, carbonyl-containing straight-chain or branched C1-C20 alkyl, or R 33 With R 34 R 35 With R 36Each of them, together with the carbon atoms they are attached to, forms a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of: C3-C20 saturated carbon rings, C3-C20 saturated spiro rings, saturated 3-20 membered heterocycles containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen, or C3-C20 aromatic rings.

[0147] Furthermore, the sulfonate intermediate is selected from the group consisting of:

[0148]

[0149] Pharmaceutical Composition

[0150] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to 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 or tablet.

[0151] The "active ingredient" referred to in this invention refers to the compound of general formula I described in this invention or its pharmaceutically acceptable salt, hydrate or solvate.

[0152] As used herein, the term "pharmaceutically acceptable salt" refers to a nontoxic acid or alkaline earth metal salt of a compound of formula I. These salts can be prepared in situ during the final isolation and purification of the compound of formula I, or by reacting a suitable organic or inorganic acid or base with a basic or acidic functional group. Representative salts include, but are not limited to: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, butates, camphorates, camphorsulfonates, diglucose, cyclopentanepropionates, dodecyl sulfates, ethanesulfonates, gluconate-heptate, glycerol phosphates, hemisulfates, heptate, hexanoates, fumarates, hydrochlorides, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactates, maleates, methanesulfonates, nicotinates, 2-naphthylsulfonate, oxalates, dihydroxynaphthyl salts, pectates, thiocyanates, 3-phenylpropionates, picrates, neopentate, propionates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, and undecanoates. Furthermore, nitrogen-containing basic groups can be quaternized with reagents such as: alkyl halides, such as chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl groups; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and dipentyl sulfates; long-chain halides, such as chlorides, bromides, and iodides of decyl, lauryl, myristyl, and stearyl groups; and aralkyl halides, such as benzyl and phenethyl bromides. This yields 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 separation and purification of compounds of general formula I, or by reacting the carboxylic acid moiety 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, alkali metal and alkaline earth metal-based cations, such as salts of sodium, lithium, potassium, calcium, magnesium, and aluminum, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Other representative organic amines used to form base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine.

[0153] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that 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 and with the compounds of the present invention without significantly reducing the efficacy of the compounds. 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, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0154] Suitable pharmaceutically acceptable carriers or excipients include processing agents and drug delivery modifiers and accelerators, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, low-melting-point waxes, ion exchange resins, and any combination of two or more thereof. Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol, and various oils, including petroleum, animal, vegetable, or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil, etc. 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, MackPub.Co., New Jersey (1991), and are incorporated herein by reference.

[0155] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0156] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0157] 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 components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0158] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0159] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0160] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0161] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0162] 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.

[0163] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0164] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antitumor drugs).

[0165] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0166] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0167] Compared with the prior art, the main advantages of the present invention include:

[0168] (1) Controlled trials support that, compared with the clinically used antagonist neostigmine, the preferred examples of the compounds of the present invention can antagonize the benzyl isoquinoline muscle relaxant atracurium besylate and the aminosteroid muscle relaxants pancuronium bromide, rocuronium bromide and vecuronium bromide more quickly.

[0169] (2) Controlled trials support the fact that, compared with the clinically used antagonist sugammadex sodium, preferred examples of the compounds of the present invention can antagonize the aminosteroid muscle relaxants rocuronium bromide and vecuronium bromide more rapidly. Preferred examples of the compounds of the present invention can rapidly antagonize the benzyl isoquinoline muscle relaxant sisatracurium besylate and the aminosteroid muscle relaxant pancuronium bromide, while sugammadex sodium cannot antagonize these two types of muscle relaxants.

[0170] (3) Control experiments support that, compared with the previously disclosed non-deuterated dibenzoglyurea tetramer, the preferred examples of the compounds of the present invention have higher antagonistic activity against the above four non-depolarizing muscle relaxants, and at the same time have high water solubility and high biocompatibility.

[0171] (4) Control experiments support that, compared with the previously disclosed non-deuterated dimethyl-substituted dibenzoglyurea tetramers, the deuterated compounds of the present invention have significantly improved antagonistic activity against cis-sulfatracurium and rocuronium bromide.

[0172] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0173] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0174] Example 1: Synthesis of Compound I-5

[0175]

[0176] Under rapid mechanical stirring, 80 mL of 8M hydrochloric acid was added to a 500 mL double-necked flask. Glycourea (compound 4, 49.3 g, 0.36 mol) was added in batches, maintaining the oil bath temperature at 50°C. Subsequently, a deuterated paraformaldehyde solution (compound 6, 10.7 g, 0.36 mol, dissolved in 40 mL of 8M hydrochloric acid) was slowly added dropwise through a constant-pressure dropping funnel. After the addition was complete, stirring continued for 48 hours (the reaction system remained heterogeneous throughout). After centrifugation, the supernatant was transferred back to the double-necked flask. The solid was dispersed in 2 mL of 8M hydrochloric acid, and then dissolved in 2 mL of deionized water to prepare a 4M solution. After shaking and centrifugation, the upper yellow clear liquid was transferred to the aforementioned double-necked flask. The solutions were combined and the reaction continued at 50°C for 48 hours. Subsequently, the "centrifugation-washing with 4M hydrochloric acid-transfer and combining of supernatants" operation was repeated 3 times. Finally, the solids were combined, dispersed with deionized water, and centrifuged again. The "washing with deionized water-centrifugation" operation was repeated 4 times until the pH of the supernatant was close to neutral. A white compound 8 (20.1 g, 37%) was obtained. ¹H NMR (400 MHz, DMSO-d⁶): δ 7.64 (s, 4H), 5.36 (d, J = 8.6 Hz, 2H), 5.23 (d, J = 8.7 Hz, 2H). ¹³C NMR (101 MHz, DMSO-d⁶): δ 158.38, 74.46, 60.63. HRMS (ESI): calcd for [M+H]⁺, 313.1306, found 313.1306.

[0177] Methylsulfonic acid (50 mL) was added to a 250 mL three-necked flask, and the oil bath temperature was raised to 50 °C. Then, solid compound 8 (10.0 g, 32.0 mmol) was added in portions, and the mixture was mechanically stirred until the system became clear. Subsequently, solid compound 7 (24.4 g, 96.1 mmol) was added in portions, and the reaction was carried out at 50 °C for 5 hours with mechanical stirring. After the reaction was completed and cooled to room temperature, the reaction mixture was added dropwise to water (500 mL), producing a large amount of white precipitate. After centrifugation, the lower solid layer was collected and washed with deionized water (200 mL) until neutral. The precipitate was transferred to a round-bottom flask and dried under vacuum to obtain white solid compound 9 (15.0 g, 60%). 1H NMR (400MHz, DMSO-d6) δ5.54–5.45(m,6H),5.34(d,J=9.1Hz,2H),5.12(d,J=11.3Hz ,4H),4.79(d,J=10.7Hz,4H),4.18(d,J=15.4Hz,4H),1.76(s,6H),1.59(s,6H).13C NMR (101MHz, DMSO-d6): δ155.22,154.67,77.03,72.29,70.46,70.03,48.32,17.63,15.59. HRMS(ESI):calcd for[M+H]+,785.3125,found 785.3127.

[0178]

[0179] Dimeric compound 9 (15.5 g, 19.8 mmol) was weighed and dissolved in trifluoroacetic acid (75 mL). Acetic anhydride (75 mL) and sodium 2,3-dimethyl-1,4-propanesulfonate (compound 12, 23.6 g, 59.3 mmol) were added sequentially, and the mixture was reacted at 50 °C for 12 hours. After the reaction was completed, the reaction solution was added dropwise to ethanol (1.3 L) under rapid stirring. After stirring for half an hour, the mixture was centrifuged. The solid was washed with ethanol (30 mL × 5) in centrifuge tubes. After the washing was completed, the solid was dissolved in water (20 mL), filtered, and the filtrate was evaporated to dryness. The solid residue was recrystallized from the solid residue with ethanol and water. The crystals were allowed to stand overnight at 4 °C and then filtered. The filter cake was washed with an ethanol-water solution (5 mL, 4:1 v / v). The resulting white solid was dissolved in water (6 mL) and filtered. The filtrate was evaporated at 70 °C to remove water. After vacuum drying, a white solid compound I-5 (19.1 g, 60%) was obtained. 1H NMR (400MHz, D2O): δ5.42(d,J=15.7Hz,4H),5.34-5.20(m,4H),5.01(d,J=16.5Hz,4H),4.22(d,J=16.2Hz,4H),4.12(d, J=15.6Hz,4H),3.88-3.76(m,4H),3.67-3.54(m,4H),3.02(q,J=7.0Hz,8H),2.09(t,J=7.3Hz,8H),1.73-1.56(m,24H). 13C NMR (101MHz, D2O): δ156.87,156.23,150.34,131.58,128.31,78.69,77.63,72.81,71.25,48.56,48.06,36.31,25.01,16.52,15.47,12.60. HRMS(ESI):Calcd for[M+2Na]2+:823.1707,Found:823.1696.

[0180] Example 2: Synthesis of Compound I-1

[0181] The method described in Example 1 differs in that sodium 1,4-phenoxy-dipropyl sulfonate is used instead of sodium 2,3-dimethyl-1,4-phenoxy-dipropyl sulfonate.

[0182] 1.0 g (1.26 mmol) of tetradeuterated dimethylglyurea tetramer was dissolved in 6 mL of trifluoroacetic acid. Acetic anhydride (6 mL) and sodium 1,4-phenoxy-dipropyl sulfonate (1.52 g, 3.82 mmol) were added sequentially, and the mixture was reacted at 50 °C for 12 hours. After the reaction was complete, the reaction solution was added dropwise to 200 mL of rapidly stirred ethanol. After stirring for half an hour, the mixture was centrifuged. The solid was washed with ethanol (30 mL × 5) in centrifuge tubes and centrifuged. The solid was then dissolved in 20 mL of water, filtered, and the solid residue after evaporation was dried was recrystallized from the filtrate with ethanol and water. The crystals were allowed to stand overnight at 4 °C and then filtered. The filter cake was washed with an ethanol-water solution (5 mL, 4:1 v / v) and recrystallized again with ethanol / water. The resulting white solid was dissolved in 8 mL of water and filtered. The filtrate was evaporated at 70 °C to remove water and then dried under vacuum to obtain white solid I-1 (1.1 g, 56%). 1H NMR (400MHz, D2O): δ6.78 (s, 4H), 5.56 (d, J = 15.4Hz, 4H), 5.46 -5.38(m,4H),5.34(d,J=16.1Hz,4H),4.26(d,J=15.3Hz,8H),4.03-3.95(m,4H),3.9 2-3.84(m,4H),3.19-3.06(m,8H),2.18(d,J=6.2Hz,8H),1.77(d,J=15.6Hz,12H).13C NMR (101MHz, D2O): δ156.75,156.43,150.12,127.78,114.94,78.88,77.69,71.16,71.01,68.69,48.48,48.21,35.26,24.68,16.46,15.38. HRMS(ESI):Calcdfor[M+2Na]2+:795.1394,Found:795.1382.

[0183] Example 3: Synthesis of Compound I-2

[0184] The method described in Example 1 differs in that sodium 2,3-dimethyl-1,4-phenoxy-dipropyl sulfonate is replaced with deuterated compound 3-4.

[0185]

[0186] 820.0 mg (5 mmol) of 4,7-dihydroxy-1-indanone (synthesized according to literature method) was weighed into a 50 mL single-necked flask. 500.9 mg (12.5 mmol) of NaOH was dissolved in 10.0 mL of H₂O and added to the system with stirring. The brown solid turned into a dark green liquid. The mixture was stirred at room temperature for 30 min. 1.8330 g (15 mmol) of 1,3-propanesulfonyl lactone was dissolved in 20.0 mL of 1,4-dioxane and added to the system with stirring. The reaction was allowed to proceed overnight at room temperature until the reactants were fully reacted. The reaction solution was concentrated and added dropwise to 100 mL of EtOH. A brown precipitate formed, which was obtained by centrifugation, leaving a brown solid on the surface of the black solid. The obtained solid was washed twice with 60 mL of EtOH. The crude solid product was recrystallized from EtOH / H₂O at 90 °C to obtain a light brown solid powder 3-2 (701.2 mg, 31%). 1H NMR(400MHz,D2O)δ7.26(d,J=8.8Hz,1H),6.92(d,J=9.2Hz,1H),4.19(m,J=6.4,14.4Hz,4H),3.0 7(q,J=8.0Hz,4H),3.01(t,J=5.6Hz,2H),2.69(t,J=5.6Hz,2H),2.21(m,J=12.0,6.0Hz,4H).13C NMR(101MHz, 298K): δ207.12,148.26,146.51,144.58,122.45,117.68,108.69,64.93,64.64,45.76,45.67,34.28,22.28,21.90,19.75. HRMS(ESI):cacld for[M-Na]-,429.0295; found,429.0323.

[0187] Sodium benzocyclopentanone sulfonate (452.2 mg, 1.0 mmol) was weighed into a 25 mL single-necked flask, and potassium carbonate (13.8 mg, 0.1 mmol) was added to 2 mL of deuterium water. The mixture was heated under reflux for 4 h. After the reaction was completed, the reaction mixture was poured into 20 mL of ethanol, and a precipitate formed. After centrifugation and drying, a light brown deuterated sodium benzocyclopentanone sulfonate (439.5 mg, 97%) was obtained. ¹H NMR (400 MHz, D₂O) δ 7.17 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.14 (m, J = 6.4, 14.0 Hz, 4H), 3.07 (m, J = 7.6, 15.2 Hz, 4H), 3.01 (s, 2H), 2.17 (m, J = 9.6, 15.2 Hz, 4H). ¹³C NMR(101MHz,D2O,298K)δ210.03,150.66,148.89,147.36,125.06,120.66,111.27,67.45,6 6.94,47.85,47.74,35.97,24.36,23.95,21.88.HRMS(ESI)calcd:[M-Na]-415.0415,found 415.0421;calcd:[M-2Na]2-204.0264,found204.0277.

[0188] Add sodium deuterated benzocyclopentane sulfonate (454.2 mg, 1.0 mmol) to a 50 mL single-necked flask, followed by (1.14 g, 10 mmol) TFA. The solution turns orange-red, and the mixture is stirred at room temperature for 15 min. Then, slowly add HSiEt3 (288.15 mg, 2.5 mmol) dropwise to the above system. React for 4 h. After the reaction is complete, distill the reaction system under reduced pressure to remove unreacted TFA and HSiEt3. The resulting crude solid product is recrystallized from water and ethanol to obtain a white powdery solid product, sodium deuterated benzocyclopentane sulfonate 3-4 (396.4 mg, 90%). 1H NMR(400MHz,D2O)δ6.80(s,1H),4.09(t,J=6.0Hz,4H),3.03(m,J=5.6,8.0Hz,4H),2.8(s,2H),2.12(m,J=6.0,14.0Hz,4H).M / Z=197.0368.13C NMR (101MHz, D2O, 298K) δ149.24,134.91,112.46,67.88,47.98,29.42,29.33,24.45. HRMS(ESI)calcd:[M-2Na]2-,197.0368, found 197.0402; [M-2Na+H]-,395.0809, found395.0806.

[0189]

[0190] Methyltetramer (189.0 mg, 0.25 mmol) and a TFA / Ac₂O mixed solvent (2 mL / 2 mL) were added sequentially to a 25 mL single-necked flask and stirred until dissolved. Then, deuterated benzocyclopentane sulfonate (286.0 mg, 0.625 mmol) was added to the system, and the temperature was raised to 50 °C and the reaction was carried out for 12 h. After the reaction was complete, the reaction system was slowly added dropwise to 80 mL of rapidly stirred ethanol, resulting in precipitation. The crude product was obtained by centrifugation. The crude product was recrystallized at 70 °C using a mixed solvent of EtOH and H₂O to give a white powdery solid target product I-2 (80.2 mg, 19.5%). NMR(400MHz,D2O)δ5.64(d,J=15.2Hz,2H),5.52(d,J=15.6Hz,4H),5.34(m,J=8.8,31 .2Hz,4H),5.15(d,J=9.2Hz,4H),4.31(d,J=16.0Hz,4H),4.20(d,J=15.6Hz,4H),4.0 2(m,J=10.0,15.2Hz,6H),3.81(m,J=6.0,15.6Hz,8H),3.08(m,J=18.0,8.4Hz,8H),2 .45(d,J=26.4,16.0Hz,8H),2.13(m,J=15.6,8.8Hz,8H),1.73(d,J=13.6Hz,12H).13C NMR(101MHz, ): δ156.60,156.12,148.23,138.11,128.67,78.68,77.59,71.78,71.50,71.10,36.00,30.17,24.99,17.28,16.79,15.82,15.81. HRMS(ESI): Calcd for[M+Na+H]2+:842.1789; found:824.1798.

[0191] Example 4: Synthesis of Compound I-3

[0192] The method described in Example 1 differs in that compound 4-2 is used instead of sodium 2,3-dimethyl-1,4-phenoxy-dipropyl sulfonate.

[0193]

[0194] 2,5-Dihydroxytoluene (29.79 g, 10 mmol) was added to a 2 L reaction flask, followed by the addition of NaOH solution (36.92 g, 38.5 mmol, dissolved in 370 mL of deionized water). The pale yellow solid turned into a dark green solution, and the mixture was stirred at room temperature for 30 minutes. A solution of 1,3-propanesulfonyl lactone in dioxane (72.41 g, 24.7 mmol, dissolved in 60 mL of dioxane) was added dropwise to the reaction system, and the reaction was continued at room temperature for 12 hours. As the reaction proceeded, a large amount of precipitate formed, and the reaction mixture gradually changed from black to brown. After the reaction was complete, the pale yellow solid was collected by filtration and then washed successively with ethanol (50 mL) and acetone (50 mL). The obtained solid was recrystallized from water and ethanol at 90 °C, and dried under vacuum to give a pale yellow solid compound 4-2 (64.29 g, 73%). ¹H NMR (400 MHz, ): δ6.89(d,J=8.8Hz,1H),6.80(s,1H),6.75(dd,J1=8.8Hz,J2=2.8Hz,1H),4.01(t,J1=7.2Hz,4H),2.98(m,4H),2.13-2.03(m,4H),2.11(s,3H). 13C NMR(101MHz, ): δ149.21,134.74,112.25,67.77,48.00,29.50,24.47. HRMS(ESI):Calcd:[M-Na]-,389.0346,Found:389.0406.

[0195]

[0196] Methyl tetramer (1.0 g, 1.275 mmol) was added to a 50 mL single-necked flask, followed by 5.0 mL of acetic anhydride and 5.0 mL of trifluoroacetic acid. After stirring to dissolve, compound 4-2 (1.5772 g, 3.825 mmol) was added to the reaction system and stirred until dissolved. The system was heated to 50 °C and reacted for 12 hours. After the reaction was complete, the reaction mixture was added dropwise to 80 mL of ethanol, resulting in the precipitation of a brown solid. After centrifugation, the lower precipitate was washed twice with 100 mL of ethanol, refluxed under MeOH for 3 hours, and then hot-filtered. The filter cake was collected and purified by diffusion using a water / acetone and tetrahydrofuran system to obtain a white solid product I-3 (200.8 mg, 10%). 1H NMR(400MHz,D2O)δ6.80(d,J=9.6Hz,2H),5.60(d,J=15.7Hz,4H),5.46(d,J=9.0Hz,2H),5.41(d,J=9.0Hz,2H),5 .35(dd,J=16.3,9.5Hz,2H),5.21(d,J=5.8Hz,1H),5.17(d,J=5.8Hz,1H),4.37(s,1H),4.34(s,1H),4.28(s,2H), 4.24(s,3H),4.21(s,1H),4.17(t,J=8.4Hz,4H),4.04(d,J=5.4Hz,3H),3.94(s,2H),3.22–3.11(m,8H),2.29–2. 20(m,8H),2.15(s,6H),1.82(s,6H),1.77(s,6H).HRMS(ESI):Calcd:[M–4Na+2H]2-,741.1947,Found:741.1881.

[0197] Example 5: Synthesis of Compound I-4

[0198] The method described in Example 1 differs in that sodium 2,3-dimethyl-1,4-phenoxy-dipropyl sulfonate is replaced with compound 5-2.

[0199]

[0200] 10 g of NaH was slowly added to 50 mL of heavy water with constant stirring. After the reaction was complete, anhydrous Na2SO4 dried hexane was added to extract the residual paraffin oil. The mixture was separated three times to prepare a sodium deuterium oxide solution. Dimethylphenoxydisulfonate (0.85 g, 2.0 mmol) and NaOD (100 mL) were added to a high-pressure reactor. The reactor was sealed and placed in an oil bath at 190 °C, and the mixture was stirred for 20 h. After the reaction was complete, the mixture was cooled to room temperature, filtered to collect the solid, washed with ethanol (2 mL), and the solid was dried under vacuum to obtain a white solid 5-2 (0.71 g, yield 81%, deuteration rate 98%). ¹H NMR (400 MHz, D2O): δ 4.05 (t, J = 6.4 Hz, 4H), 2.15 (t, J = 6.4 Hz, 4H).

[0201]

[0202] A tetradeuterated dimethyl tetramer (0.418 g, 0.5 mmol) was dissolved in trifluoroacetic acid (2 mL). Acetic anhydride (2 mL) and icoserodeuterated 2,3-dimethyl-1,4-phenoxy-dipropylsulfonate sodium (0.65 g, 1.5 mmol) were added sequentially, and the mixture was reacted in an oil bath at 50 °C for 12 h. After the reaction was complete, the reaction solution was added dropwise to ethanol (30 mL), stirred for 30 min, and then centrifuged. The solid was repeatedly washed with ethanol (3 mL × 4) in centrifuge tubes until the supernatant was essentially colorless. The solid was transferred to a 50 mL round-bottom flask to remove the solvent. The obtained solid was recrystallized from ethanol and water. After filtration, the solid was washed with a small amount of ethanol / water mixture (4:1) and dried under vacuum to obtain a white solid powder I-4 (0.398 g, 49%). 1H NMR (400MHz, D2O): δ5.64(d,J=15.4Hz,2H),5.54(d,J=16Hz,4H),5.42(d,J=9.2Hz,4H),5.35(d,J=9.2Hz,4H),5.13(d,J=16Hz ,4H),4.34(d,J=16Hz,4H),4.24(d,J=16Hz,4H),4.07(d,J=15.2Hz,2H),3.91(s,4H),3.70(s,4H),2.17(s,4H),1.74(d,12H). HRMS(ESI):Calcd:[M–4Na+2NH4]2-,780.2871, Found:780.4344.

[0203] Example 6: Synthesis of Compound I-6

[0204] The method described in Example 1 differs in that sodium 2,3-dimethyl-1,4-phenoxy-dipropyl sulfonate is replaced with compound 6-4.

[0205]

[0206] Add a magnetic flux and propenyl-1,3-sulfonyl lactone (310.0 mg, 2.5 mmol) to a 100 ml thick-walled pressure-resistant tube, add 50.0 ml of diethyl ether and stir to dissolve. Add 10% Pd / C (110.3 mg). Evacuate the autoclave and purge with deuterium to 0.6 MPa. Initiate the reaction at room temperature and stop when the pressure inside the autoclave no longer changes. After the reaction is complete, filter palladium on carbon using diatomaceous earth, wash three times with 10.0 ml of diethyl ether, and remove the solvent by rotary evaporation to obtain a light yellow oily liquid, namely 1,2-dideuteranesulfonyl lactone 6-2 (0.31 g, quantitative reaction). No further purification is required; proceed directly to the next step. 1 H NMR (400MHz, CDCl3) δ4.43 (dd, J=6.8, 1.6Hz, 2H), 3.24–3.15 (m, 1H), 2.57 (dtd, J=9.0, 6.9, 3.4Hz, 1H). 13 C NMR (101MHz, CDCl3) δ77.61,77.29,76.97,69.15,69.06,44.20,44.12,44.07,43. 94,43.85,43.71,43.63,23.64,23.57,23.45,23.36,23.24,23.15.FIMS(FI)calcd for[M]:124.0162,found124.0161.

[0207] Compound 6-3 (754.4 mg, 5 mmol) was added to a 50 mL single-necked flask. NaOH (508.8 mg, 12.5 mmol) was dissolved in 6.0 mL of H₂O and added to the above system. The reaction system changed from a white solid to a dark green solution. The mixture was stirred at room temperature for 30 min. Compound 6-2 (1.8624 g, 15 mmol) was dissolved in 12.0 mL of dioxane and added to the above system. The reaction was allowed to proceed overnight at room temperature. During the reaction, a large amount of brown precipitate was formed, and the reaction system changed from a black solution to a brown suspension. After the reaction was complete, the brown solid was obtained by filtration and washed with a small amount of ethanol and acetone. The solid was transferred to a 50 mL single-necked flask and recrystallized from it using water and ethanol at 90 °C. Product 6-4 was a light yellow powder (1.2397 g, 60%). 1 H NMR (400MHz, D2O): δ6.78 (s, 2H), 4.06 (d, J = 6.2Hz, 4H), 3.01 (dd, J = 9.0, 6.7Hz, 2H), 2.80 (t, J = 7.5Hz, 4H), 2.22–2.05 (m, 2H), 2.04 (d, J = 7.5Hz, 2H).13 C NMR(101MHz,D2O)δ149.17,134.95,112.51,67.79,47.78,47.68,47.48,47.27,29.44,24.56,24.12,23.93,23.74.HRMS(ESI)calcd for[M-2Na] 2+ :198.0431,found 198.0427.

[0208]

[0209] Methyl tetramer (782.3 mg, 1 mmol) was added to a 25 mL single-necked flask, followed by 7.0 mL of acetic anhydride and 7.0 mL of trifluoroacetic acid. After stirring to dissolve, compound 6-4 (1.2397 g, 3 mmol) was added to the reaction system and stirred until dissolved. The system was heated to 50 °C and reacted for 12 hours. After the reaction was completed, the reaction solution was added dropwise to 140 mL of ethanol, resulting in the precipitation of a brown solid. After centrifugation, the lower precipitate was washed twice with 100 mL of ethanol. The lower solid was then recrystallized from the precipitate at 70 °C using water and ethanol. The recrystallized product was evaporated to dryness using an oil pump to obtain a white powdery solid I-6 (0.6 g, 37%). 1 H NMR(500MHz,D2O)δ5.66(d,J=15.3Hz,2H),5.54(d,J=15.7Hz,4H),5.46–5.3 3(m,4H),5.16(d,J=15.9Hz,4H),4.34(d,J=15.9Hz,4H),4.24(d,J=15.6Hz,4 H),4.11–4.04(m,6H),3.87(d,J=8.2Hz,4H),3.07(dd,J=19.3,10.4Hz,4H), 2.51(s,8H),2.13(s,4H),1.75(d,J=24.7Hz,12H),1.50(s,2H),1.37(s,2H). 13 C NMR(101MHz,D2O)δ156.71,156.15,147.23,138.15,128.58,78.63,77.62,71.76,71.43 ,71.09,52.84,48.45,47.66,36.03,30.30,25.57,24.59,17.23,15.69.HRMS(ESI)calcd for[M-4Na+2H] 2- :769.2229,found 769.2243.

[0210] Example 7: Synthesis of Compound I-7

[0211] The method described in Example 1 differs in that sodium 2,3-dimethyl-1,4-phenoxy-dipropyl sulfonate is replaced with compound 7-4.

[0212]

[0213] 2,3-Propylene-1,4-benzenediol (prepared according to literature method, 2.07 g, 13.78 mmol) was added to a 250 mL single-necked flask, followed by an aqueous solution of NaOH (1.38 g, 34.45 mmol, dissolved in 37.5 mL H₂O). The mixture was stirred at room temperature for 30 min. Subsequently, a dioxane solution of 1,3-propanesulfonyl lactone (5.05 g, 41.34 mmol, dissolved in 60 mL 1,4-dioxane) was added to the system with stirring. After reacting at room temperature for 12 hours, the reaction proceeded to completion. After the reaction was complete, the mixture was centrifuged, and the resulting solid was washed with EtOH (60 mL × 2). The crude solid product was recrystallized from EtOH / H₂O at 90 °C to obtain a light brown solid powder 7-4 (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 CNMR(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.

[0214]

[0215] Tetradeuterated dimethylglyurea tetramer (1.53 g, 1.79 mmol) and acetic anhydride (7.0 mL) were added sequentially to a 50 mL single-necked flask and stirred until dissolved. Then, trifluoroacetic acid (7.0 mL) and sodium 2,3-propylidene-1,4-phenoxy-dipropyl sulfonate (2.35 g, 5.35 mmol) were added sequentially and stirred until dissolved. The system was heated to 50 °C and reacted for 12 hours. After the reaction was completed, the reaction solution was added dropwise to 140 mL of ethanol, and a pale yellow solid precipitated. After centrifugation, the lower solid was washed twice with 150 mL of ethanol. The lower solid was then recrystallized from the solid with water and ethanol at 70 °C. The recrystallized product was dried under vacuum to obtain a white powdery solid I-7 (1.61 g, 59%).1 H NMR(500MHz,D2O)δ5.50(d,J=15.7Hz,4H),5.38(d,J=9.1Hz,2H),5.31(d,J=9.0Hz, 2H),5.12(d,J=16.0Hz,4H),4.31(d,J=16.0Hz,4H),4.19(d,J=15.7Hz,4H),4.04(q ,J=7.2Hz,4H),3.82(q,J=7.9,7.3Hz,4H),3.05(tt,J=14.0,6.8Hz,8H),2.43(d,J= 18.3Hz,8H),2.23–2.03(m,8H),1.71(d,J=21.8Hz,12H),1.40(s,2H),1.28(s,2H). 13 C NMR(101MHz,D2O)δ156.74,156.20,148.32,138.21,128.60,78.67,77.69,71.89,71.31,71 .17,48.50,48.12,36.12,30.36,25.61,25.03,17.32,15.74.HRMS(ESI):Calcd:[M–3Na+H] 2- ,778.2013,Found:778.1961.

[0216] Example 8: Synthesis of Compound I-8

[0217] The method described in Example 1 differs in that sodium 2,3-dimethyl-1,4-phenoxy-dipropyl sulfonate is replaced with compound 8-2.

[0218]

[0219] 1,2-Dideuterium propanesulfonate was prepared according to the method described in Example 6. 3,4-Dimethylhydroquinone (0.35 g, 2.51 mmol) was added to a reaction flask, followed by the addition of 10% NaOH solution (0.25 g, 3.47 mmol, dissolved in 1.67 mL of deionized water). The pale yellow solid turned into a dark green solution, and the mixture was stirred at room temperature for 30 minutes. A dioxane solution of 1,2-dideuterium propanesulfonate (0.92 g, 7.53 mmol, dissolved in 4.2 L of dioxane) was added dropwise to the reaction system, and the reaction was continued at room temperature for 12 hours. As the reaction proceeded, a large amount of precipitate formed, and the reaction mixture gradually changed from black to brown. After the reaction was complete, the pale yellow solid was collected by filtration and then washed successively with ethanol (5 mL × 2) and acetone (5 mL × 2). The obtained solid was recrystallized from water and ethanol at 90 °C, and dried under vacuum to obtain a pale yellow solid compound 12 (0.55 g, 51%). 1 H NMR (400MHz, D2O) δ6.85 (s, 2H), 4.05 (d, J = 6.0Hz, 4H), 3.08 (dd, J1 = 9.0Hz, J2 = 12.8Hz, 2H), 2.19 (dd, J1 = 9.0Hz, J2 = 12.8Hz, 2H), 2.14 (s, 6H). 13 C NMR (101MHz, D2O): δ150.90,128.12,112.18,68.47,47.89,47.68,47.47,24.30,24.10,23.9011.10. HRMS(ESI)calcd for[M-2Na] 2- ,192.0516,found 192.0426;calcd for[M-2Na+H] - :385.0994,found 385.0934;calcd for[M-Na] - ,407.0744,found 407.0754.

[0220]

[0221] A tetradeuterated dimethyl tetramer (0.32 g, 0.387 mmol) was dissolved in trifluoroacetic acid (2 mL). Acetic anhydride (2 mL) and tetradeuterated 2,3-dimethyl-1,4-phenoxy-dipropylsulfonate sodium (0.5 g, 1.16 mmol) were added sequentially, and the reaction was carried out in an oil bath at 50 °C for 12 h. After the reaction was completed, the reaction solution was added dropwise to ethanol (30 mL), stirred for 30 min, and then centrifuged. The solid was repeatedly washed with ethanol (2 mL × 4) in centrifuge tubes until the supernatant was basically colorless. The solid was transferred to a 50 mL round-bottom flask to remove the solvent. The obtained solid was recrystallized from ethanol and water. After filtration, the solid was washed with a small amount of ethanol / water mixture (4:1) and dried under vacuum to obtain a white solid powder I-8 (0.323 g, 52%). 1 H NMR (400MHz, D2O): δ5.66(d,J=15.2Hz,2H),5.57(d,J=15.2Hz,4H),5.44(d,J=9.2Hz,4H),5.37(d,J=15.2Hz,4H),5.15(d,J=16Hz,4H),4.34(d,J=1 6Hz,4H),4.26(d,J=15.2Hz,4H),4.09(d,J=15.2Hz,2H),3.93(s,4H),3.7 1(s,4H),3.10(s,4H),2.16(s,4H),1.77(s,4H),1.74(s,4H),1.69(s,4H). HRMS(ESI):Calcd for[M-3Na+H] 2+ :768.2138,Found:768.2083.

[0222] Example 9: Synthesis of Compound I-9

[0223] The method described in Example 1 differs in that sodium 1,4-naphthoxy-dipropyl sulfonate is used instead of sodium 2,3-dimethyl-1,4-phenoxy-dipropyl sulfonate.

[0224]

[0225] A tetradeuterated dimethylglyurea tetramer (1.0 g, 1.26 mmol) was dissolved in trifluoroacetic acid (6 mL), followed by the addition of acetic anhydride (6 mL) and sodium 1,4-naphthoxy-dipropyl sulfonate (1.71 g, 3.50 mmol). The reaction was carried out at 50 °C for 12 hours. After the reaction was completed, the reaction solution was added dropwise to ethanol (200 mL) under rapid stirring. After stirring for half an hour, the mixture was centrifuged. The solid was washed with ethanol (30 mL × 5) in centrifuge tubes. After the washing was completed, the solid was dissolved in hot water (20 mL), filtered, and the solid residue after evaporation was dried was recrystallized from the filtrate with ethanol and water. The crystals were allowed to stand overnight at 4 °C and then filtered. The filter cake was washed with an ethanol-water solution (5 mL, 4:1 v / v) and recrystallized again with ethanol / water. The resulting white solid was dissolved in water (8 mL) and filtered. The filtrate was evaporated at 70 °C to remove water, yielding a white solid powder I-9 (0.98 g, 47%). 1H NMR (400MHz, DMSO-d6): δ7.78 (dd, J1=6.3, J2=3.1Hz, 4H), 7.25 (dd, J1=6.1, J2=2.5Hz, 4H), 5.58 (d, J=15.2Hz, 4H), 5.47–5.29 (m ,8H),4.54(d,J=16.4Hz,4H),4.25(t,J=12.9Hz,8H),4.02–3.90(m,4H),3.31–3.14(m,8H),2.32(d,J=7.2Hz,8H),1.84(s,12H). 13C NMR (101MHz, D2O): δ156.79,156.37,148.26,127.76,127.05,126.15,122.31, 78.68,77.69,74.25,71.44,71.28,48.58,48.06,36.59,25.17,16.57,15.37. HRMS(ESI):Calcd for[M+2Na]2+:845.1551,Found:845.1535.

[0226] Example 10: Synthesis of Compound I-10

[0227] The method described in Example 1 differs in that: hexadeuterated butanedione is used instead of non-deuterated butanedione, and non-deuterated glycourea dimer is used instead of deuterated dimer.

[0228]

[0229] Urea (23.3 g, 0.388 mol) was dissolved in 0.3 M hydrochloric acid (56 mL). Deuterated butanedione (10.8 g, 0.117 mol) was slowly added dropwise with stirring. The mixture was stirred at room temperature for 12 h. After the reaction was complete, the mixture was filtered, and the solid was washed with deionized water (10 mL × 2). After vacuum drying, a white solid of hexadeuterated dimethylglyurea (19.8 g, 96%) was obtained. 1 HNMR (400MHz, DMSO-d6): δ7.09 (s, 4H). 13 C NMR(101MHz,DMSO-d6):δ159.29,74.98.HRMS(ESI):Calcd for[M+H] + :177.1253,Found:177.1250.

[0230] Hexadeuterated dimethylglyurethane (10.0 g, 56.8 mmol) and paraformaldehyde (8.6 g, 286.7 mmol) were weighed into a 250 mL round-bottom flask, and 9 M hydrochloric acid (60 mL) was added. The mixture was stirred at room temperature for 24 h, and then deionized water (224 mL) was added, with stirring continuing for 12 h. After the reaction was complete, the mixture was filtered. The collected solid was washed with deionized water (50 mL × 3) and ethanol (50 mL × 3), respectively, and dried under vacuum to obtain hexadeuterated dimethylglyurethane diether-d6, a white solid (10.2 g, 69%). 1 H NMR (400MHz, DMSO-d6): δ5.20 (d, J = 11.4Hz, 4H), 4.99 (d, J = 11.4Hz, 4H). 13 C NMR(101MHz,DMSO-d6):δ157.98,73.77,70.72.HRMS(ESI):Calcd for[M+H] + :261.1464,Found:261.1463.

[0231] 1.88 g (6.10 mmol) of glycoure dimer was dissolved in 11 mL of methanesulfonic acid under sonication. Dimethylglycoure diether-d6 (4.76 g, 18.3 mmol) was added to the system, and the mixture was reacted at 50 °C for 5 h under mechanical stirring. After the reaction was complete and cooled to room temperature, the reaction solution was added dropwise to 110 mL of ice water, resulting in the formation of a large white precipitate. The precipitate was centrifuged and washed with water until neutral. The solid was redissolved in 6 mL of trifluoroacetic acid and cooled to 0 °C. Water (30 mL) was then slowly added dropwise to the solution, producing a large white precipitate. The precipitate was centrifuged, washed with water until neutral, and lyophilized to obtain a dodecyl deuterated glycoure tetramer as a white solid powder (1.98 g, 41%). 1HNMR (400MHz, DMSO-d6): δ5.69(d,J=11.0Hz,2H),5.54(d,J=15.1Hz,6H),5.41(d ,J=9.1Hz,2H),5.16(d,J=10.9Hz,4H),4.83(d,J=11.2Hz,4H),4.26–4.15(m,6H). 13 C NMR(101MHz,DMSO-d6):δ155.18,154.68,76.84,72.12,70.63,70.40,70.02,52.82,48.34.HRMS(ESI):Calcd for[M+Na] + :815.3446,Found:815.3436.Calcd for[M+H] + :793.3627,Found:793.3619.

[0232]

[0233] A 1.0 g (1.26 mmol) dodecyl dimethyl tetramer was dissolved in 6 mL trifluoroacetic acid. Acetic anhydride (6 mL) and sodium 2,3-dimethyl-1,4-phenoxy-dipropylsulfonate (compound 12, 1.6 g, 3.75 mmol) were added sequentially, and the mixture was reacted in an oil bath at 50 °C for 12 h. After the reaction was complete, the reaction mixture was added dropwise to 300 mL ethanol. After stirring for 30 min, the mixture was centrifuged. The solid was repeatedly washed with ethanol (10 mL × 4) in centrifuge tubes until the supernatant was essentially colorless. The solid was transferred to a 50 mL round-bottom flask to remove the solvent. The obtained solid was recrystallized from ethanol and water. After filtration, the solid was washed with a small amount of ethanol / water mixture (4:1) and dried under vacuum to obtain compound I-10 (1.36 g, 67%) as a white solid powder. 1 H NMR (400MHz, D2O): δ5.62(d,J=15.4Hz,2H),5.52(d,J=15.4Hz,4H),5.46–5.34(m,4H),5.10(d,J=15.9Hz,4H),4.32(d,J=16 .8Hz,4H),4.23(d,J=15.9Hz,4H),4.09(d,J=15.4Hz,2H),3.91(s,4H),3.69(s,4H),3.11(s,8H),2.18(s,8H),1.81(s,12H). 13C NMR (101MHz, D2O): δ156.74,156.15,150.23,131.48,128.22,78.46,77.39,72 .79,71.32,71.06,52.60,48.43,47.97,36.21,24.89,12.49.HRMS(ESI):Calcd for[M+2Na] 2+ :827.1959,Found:827.1950.

[0234] Example 11:

[0235] Compound I-7-4H was synthesized according to the method described in Example 7, except that a non-deuterated glycouretetramer was used instead of a tetradeuterated glycouretetramer.

[0236]

[0237] Dimethylglyurea tetramer (1.50 g, 1.79 mmol) and trifluoroacetic acid (7.0 mL) were added sequentially to a 50 mL single-necked flask and stirred until dissolved. Then, acetic anhydride (7.0 mL) and sodium 2,3-propylidene-1,4-phenoxy-dipropyl sulfonate (2.35 g, 5.35 mmol) were added sequentially and stirred until dissolved. The system was heated to 50 °C and reacted for 12 hours. After the reaction system cooled, the reaction mixture was added dropwise to 140 mL of ethanol, precipitating a pale yellow solid. The solid was collected by centrifugation. The solid was washed twice with 150 mL of ethanol and centrifuged again. The resulting solid was recrystallized from water and ethanol at 70 °C and dried under vacuum to obtain a white powdery solid I-7-4H (1.60 g, 59%). 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). 13C 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.

[0238] Example 12

[0239] Water solubility test: Weigh approximately 100 mg of the above deuterated compounds into a graduated fine-mesh test tube, and gradually add deionized water until completely dissolved. Calculate the solubility by volume, expressed in mg / mL (see Table 1). As can be seen from the table, although there are slight differences in solubility, 1-1, I-5, and I-7 have high water solubility, which meets the solubility requirements for rapid injection.

[0240] Table 1. Solubility (mg / mL) of the compounds of this invention

[0241]

[0242] Example 13

[0243] Evaluation of the activity of antagonistic muscle relaxants: Taking the reversal of neuromuscular blockade induced by cis-sulfotracurium in vivo by I-1, I-5, and I-7 in SD rats as an example, this study illustrates the process of reversing neuromuscular blockade in vivo by deuterated diaryl glycourea tetramer compounds.

[0244] Specific procedures: SD rats weighing 170 to 240 grams were selected as biological models to test the I-5 reversal effect. Each experimental group used 3 male rats and 3 female rats (the same below). During the test, the neuromuscular blocking agent injection solution was prepared using physiological saline as a solvent, and all injection operations were completed within 5 seconds. Rats were anesthetized with isoflurane at a dose of 5% for induction and 1.5% for maintenance. Hair was removed from the right hind leg and surrounding area of ​​the rats using a 10% Na2S solution. An airway was inserted into the rat's trachea and connected to a small animal ventilator with a tidal volume of 8 and a frequency of 80 bpm. A muscle relaxation monitor was used to test the neuromuscular blockade of the quadriceps femoris muscle in the rats. The sensor was fixed to the rat's tibia, and the electrode was fixed to the right hind leg via a patch. Cal mode was used for calibration, and after the data stabilized, it was switched to TOF mode (TOF stands for train of four, four stimuli in sequence). If the TOF data was stable at ≥90, the next step of the experiment was performed. Cissine atracurium solution was injected into the rats via the tail vein at a dose of 0.6 mg / kg, and the TOF value changes were recorded. After the TOF value decreased to 0, I-5 injection was injected into the rats, and the injection time was recorded. The TOF value changes were then recorded, and the time to recover to ≥90 was recorded as the neuromuscular blockade reversal time.

[0245] The antagonistic effects of the non-deuterated control compounds I-5-4H and I-7-4H on cis-sulfotracurium and rocuronium bromide under the same dosage conditions are shown in Tables 2 and 3.

[0246]

[0247]

[0248] By comparing the antagonistic activities of compounds I-1, I-5, I-7 and the corresponding non-deuterated compounds I-1-4H, I-5-4H, I-7-4H, it can be found that the deuterated compounds have enhanced antagonistic activities (see Tables 2 and 3).

[0249] The non-deuterated control compound I-1-4H, at a high dose of 150 mg / kg, reversed the TOF recovery time of atracurium besylate in 84 seconds, while at a dose of 30 mg / kg, I-1-4H reversed the TOF recovery time of rocuronium bromide in greater than 300 seconds (Hoffmann et al., Anesthesiology 2013, 119, 317-325). Deuterated I-1, at relatively lower doses (80 mg / kg and 25 mg / kg), significantly enhanced the reversal activity of atracurium besylate and rocuronium bromide, with TOF recovery times of 24 seconds and 208 seconds, respectively.

[0250] The deuterated I-7 showed significantly enhanced reversal activity against atracurium besylate compared to I-7-4H, while maintaining rapid reversal activity against rocuronium bromide. Similarly, the deuterated I-5 showed significantly enhanced reversal activity against atracurium besylate, achieving rapid reversal against both atracurium besylate and rocuronium bromide, and exhibited higher activity than the undeuterated sample at the same dosage. Therefore, at the same dosage, the antagonistic activity of I-5 was significantly superior to that of the undeuterated I-5-4H.

[0251] Comparison of the activities of deuterated compounds revealed that, at the same dosage, compound I-5 exhibited excellent antagonistic activity against both cis-sulfatracurium and rocuronium bromide, with the highest antagonistic activity (see Tables 2 and 3).

[0252] When the dose of I-5 was 80 mg / kg, the average time to reverse the effects of atracurium besylate (see Table 2) and pancuronium bromide (see Table 5) was 19 seconds and 20 seconds, respectively; when the dose of I-5 was 25 mg / kg, the average time to reverse the effects of rocuronium bromide (see Table 3) and vecuronium bromide (Table 4) was 9 seconds and 20 seconds, respectively, indicating that I-5 can rapidly and efficiently reverse the neuromuscular blockade induced by the above four muscle relaxants in vivo.

[0253] The above in vivo rat antagonistic activity experiments confirmed that I-5 can achieve rapid reversal within 20 seconds. Compared with the commercially available reagent neostigmine (the experimental dose in rats was calculated based on the maximum permissible clinical dose), I-5 increased the efficiency of reversing neuromuscular blockade induced by atracurium besylate, rocuronium bromide, vecuronium bromide, and pancuronium bromide by 10-17 times, 18 times, 32 times, and 67 times, respectively. Compared with the commercially available reagent sugammadex, at the same dose, I-5 can rapidly reverse neuromuscular blockade induced by atracurium besylate and pancuronium bromide that is clinically irreversible with sugammadex. Its activity in reversing neuromuscular blockade induced by rocuronium bromide and vecuronium bromide is also significantly higher than that of sugammadex. The time for TOF to recover to 0.9 was shortened from 52 seconds and 18 seconds to 18 seconds and 9 seconds, respectively, which is equivalent to an increase in antagonistic activity of approximately 1.9 times and 1.0 times.

[0254] As an example of the composition, at the same dose as deuterated I-5 (80 mg / kg), the composition of deuterated I-5 and non-deuterated I-5-4H (50% by mass) also showed good antagonistic activity with an antagonistic time of about 30 seconds (see Table 6).

[0255] The antagonistic data of neostigmine and sugammadextrose sodium in the table are from the literature (Liu et al., Journal of Medicinal Chemistry, 2022, 65, 16893-16901), and all doses are the maximum rat dose converted from the clinical adult dose (1:6.25).

[0256] Table 2. Time to TOF → 0.9 between compounds IC (I-1, I-5, I-7) and IC-4H (I-5-4H, I-7-4H) and neostigmine (0.24 mg / kg) at the same dose (80 mg / kg) for antagonizing atracurium besylate.

[0257]

[0258] Table 3. Time to TOF → 0.9 for compounds IC (I-1, I-5, I-7) and IC-4H (I-5-4H, I-7-4H) and sugammadextrose (25 mg / kg) and neostigmine (0.24 mg / kg) to antagonize rocuronium bromide.

[0259]

[0260] Table 4. Time to TOF → 0.9 for antagonism of vecuronium bromide by compound I-5 and sugammadex sodium (25 mg / kg) and neostigmine (0.24 mg / kg) at the same dose.

[0261]

[0262]

[0263] Table 5. Time to 0.9 for TOF antagonism of pancuronium by I-5 (80 mg / kg) and neostigmine (0.24 mg / kg).

[0264]

[0265] Table 6. The TOF→0.9 time of the combination of compounds I-5 and I-5-4H (80 mg / kg, 50% by mass each) antagonizing cis-sultracurium besylate.

[0266]

[0267] Example 14

[0268] Blood pharmacokinetics and excretion: Deuterated diarylglycourea tetramers exert their effects through blood injection. This invention uses the half-life and excretion of compound I-5 in SD rats as an example to illustrate the pharmacokinetics of deuterated diarylglycourea tetramers in vivo.

[0269] This invention uses SD rats (180-220g) as an experimental model, with 3 males and 3 females. A deuterated diarylglycourea tetramer compound (80mg / kg) was injected via the tail vein. Blood samples were collected within 1 hour via jugular vein (total volume 0.4mL, containing 0.05mL of 3.8% sodium citrate), and urine was collected within 24 hours via metabolic cages. The blood drug concentration analysis procedure was as follows: blood samples were collected at 0, 1, 5, 10, 20, 20 minutes, and 60 minutes, followed by centrifugation at 3000 rpm (4℃, 10 minutes) to collect the supernatant. 0.25mL of acetonitrile was added to the plasma, and the mixture was shaken to precipitate proteins. The supernatant was collected after centrifugation at 10000 rpm (4℃) for 10 minutes and allowed to evaporate at room temperature to remove as much acetonitrile as possible.

[0270] Subsequently, deionized water was added to bring the volume to 0.5 mL, and the mixture was centrifuged again at 10,000 rpm (4℃, 10 min). The supernatant was collected, and the blood drug concentration at different time points was analyzed and quantified by high-performance liquid chromatography (HPLC). The drug excretion analysis was performed as follows: After tail vein injection of the deuterated diarylglycourea tetramer (80 mg / kg), rats were placed in metabolic cages and fed and watered normally. Urine was collected every 4 hours for 6-7 times. The urine was centrifuged in ultrafiltration centrifuge tubes (10 kDa) to remove urinary protein, and the excretion of the compound in the urine over 24 hours was analyzed by HPLC.

[0271] Experimental results showed that the half-life of compound I-5 in rat blood was 10 minutes, indicating its rapid elimination or clearance in vivo. Compound I-5 was mainly excreted unchanged in urine, with over 70% of the compound being excreted within 24 hours, indicating its rapid excretion primarily through the kidneys.

[0272] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A deuterated diaryl urea tetramer compound of formula I, or a pharmaceutically acceptable salt thereof, in, Each Z is independently either O or S; Each M is independently Na + K + Li + or NH4 + ; R 1 R 2 R 3 and R 4 All are D; R 5 R 6 R 7 and R 8 Each is independently hydrogen; R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 and R 28 Each can be H or D independently; R 9 R 10 R 11 and R 12 Each is independently an undeuterated, partially deuterated, or fully deuterated straight-chain or branched C1-C4 alkyl group; R 29 R 30 R 31 Or R 32 Each group is independently non-deuterated, partially deuterated, or fully deuterated and selected from the group consisting of straight-chain C1-C4 alkylene groups; R 33 R 34 R 35 and R 36 Each group independently being deuterium, hydrogen, or non-deuterated, partially deuterated, or fully deuterated, selected from the group consisting of: straight-chain or branched C1-C4 alkyl groups, or R 33 With R 34 R 35 With R 36 Each of them, together with the carbon atoms they are attached to, forms a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of a five-membered carbon ring or a benzene ring.

2. The compound according to claim 1, characterized in that, Z is O.

3. The compound according to claim 1, characterized in that, The compound contains at least eight deuterium atoms.

4. The compound according to claim 1, characterized in that, The compound contains at least 12 deuterium atoms.

5. The compound according to claim 1, characterized in that, R 33 R 34 R 35 and R 36 Each can be independently deuterium, hydrogen, CD3 or CH3, or R. 33 With R 34 R 35 With R 36 Each carbon atom, together with its attached carbon atom, forms a five-membered carbon ring or a benzene ring.

6. The compound according to claim 1, characterized in that, The compounds are selected from the following group:

7. The compound according to claim 1, characterized in that, The compound is 8. A pharmaceutical composition, characterized in that, include: (a) the compound of claim 1 as an active ingredient, or a pharmaceutically acceptable salt thereof; (b) a pharmaceutically acceptable carrier.

9. A pharmaceutical composition, characterized in that, The composition contains: (a) The compound of claim 1, or a pharmaceutically acceptable salt thereof, as the first active ingredient; (b) as a second active ingredient an ingredient selected from the group consisting of non-depolarizing muscle relaxants: neostigmine, sugammadextrose sodium, or combinations thereof; and (c) Pharmaceutically acceptable carriers or excipients.

10. A pharmaceutical composition, characterized in that, The composition contains: (a) The compound of claim 1, or a pharmaceutically acceptable salt thereof, as the first active ingredient; (b) a non-deuterated aryl tetramer compound having the structure of claim 1 as a second active ingredient; and (c) Pharmaceutically acceptable carriers or excipients.

11. A reagent kit, characterized in that, include: (a) A first container, and the compound of claim 1 as an active ingredient, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8, located in the first container; (b) a second container, and a muscle relaxant located in the second container; said muscle relaxant is selected from the group consisting of: atracurium besylate, pancuronium bromide, rocuronium bromide, vecuronium bromide, or combinations thereof; and (c) Optional instruction manual.

12. The use of the compound of claim 1, or the pharmaceutical composition of claim 9, or the pharmaceutical composition of claim 10, characterized in that, Drugs used to prepare antagonistic muscle relaxants.

13. The use as described in claim 12, characterized in that, The muscle relaxant is selected from the group consisting of: atracurium besylate, pancuronium bromide, rocuronium bromide, vecuronium bromide, or combinations thereof.

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