Deuterated diaryl glycoluril tetramer compound and application thereof

Abstract

The invention discloses a deuterated glycoluril tetramer compound with aryl groups incorporated at two ends as shown in a formula (1), and a pharmaceutical composition containing the compound. The deuterated compound can be used for antagonizing a clinically used non-depolarized muscle relaxant, the antagonistic activity on rocuronium bromide and vecuronium bromide is remarkably superior to that of sugammadex sodium under the same dosage, and the antagonistic activity on cisatracurium besilate and rocuronium bromide is remarkably superior to that of a non-deuterated control molecule. # imgabs0 #

Description

Deuterated diaryl glycoluril tetramer compound and its use Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a deuterated diaryl glycoluril tetramer compound capable of antagonizing multiple muscle relaxants or a composition thereof. Background Art

[0002] Since 1942, neuromuscular blockers 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, over 400 million patients receive muscle relaxant medications during anesthesia in operating rooms and intensive care units each year. Among them, non-depolarizing muscle relaxants, such as the ammonium steroids rocuronium, vecuronium, and pancuronium, and the benzylisoquinoline cisatracurium besylate, have been more widely used in clinical practice due to their fewer side effects than depolarizing muscle relaxants. The medium-acting muscle relaxant cisatracurium besylate accounts for approximately 30% of the global neuromuscular blocker market and approximately 70% of the domestic market due to its advantages such as rapid onset, strong effect, rapid recovery, no histamine release, minimal cardiovascular side effects, no accumulation in the body, non-toxic metabolites with no muscle relaxant effect, and independence from renal excretion. In addition, rocuronium and vecuronium, which are medium-acting muscle relaxants like cisatracurium besylate, account for approximately 50% of the global market and about 30% of the domestic market. Long-acting pancuronium accounts for about 1%, but the absolute number of cases is still very high. However, clinically, the incidence of postoperative "residual quiver toxicity" caused by residual medium- and long-acting muscle relaxants is very high, leading to postoperative respiratory complications such as impaired upper respiratory tract function, airway obstruction, and pulmonary respiratory dysfunction, and in severe cases, death. Therefore, rapid and efficient antagonism of excess residual muscle relaxants is of great clinical significance. It not only helps reduce patients' postoperative risks, 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 2016 in my country found that the overall incidence of residual muscle relaxants when the endotracheal tube was removed was as high as 57.8%, and antagonists were needed to eliminate "residual quiver toxicity" to help patients recover muscle motor function as soon as possible. In current clinical practice, muscle relaxant antagonists are divided into two categories: (1) using anticholinesterase drugs to inhibit cholinesterase activity, and (2) using direct capture principles to bind and isolate muscle relaxants. The first type of antagonist is represented by neostigmine, which needs to be combined with adjuvants such as glycopyrrolate or alotropine to reduce muscarinic side effects. Neostigmine's antagonistic efficiency is generally low, and it cannot achieve rapid reversal of muscle relaxants, and it cannot reverse deep muscle relaxation. Therefore, neostigmine is not an ideal muscle relaxant antagonist. The second type of antagonist is represented by sugammadex sodium in clinical practice. It can quickly reverse the muscle relaxant activity of rocuronium and vecuronium through its specific binding to the hydrophobic inner cavity of γ-cyclodextrin. However, sugammadex sodium cannot antagonize cisatracurium besylate and pancuronium bromide. Cisatracurium besylate is widely used in clinical practice and is the most commonly used muscle relaxant in China. It is irreplaceable in many clinical practices: patients at risk of acute respiratory distress syndrome are recommended to use cisatracurium besylate as a muscle relaxant for surgery, and patients with renal insufficiency are recommended to use it as a general anesthesia drug. Cisatracurium besylate is one of the most commonly used muscle relaxants in intensive care units. Pancuronium bromide is still widely used in clinical practice as a long-acting muscle relaxant. Therefore, there is an important and urgent unmet clinical need to develop antagonists that quickly antagonize cisatracurium besylate and pancuronium bromide, or broad-spectrum, fast-acting antagonists for all the aforementioned muscle relaxants.

[0004] Hoffmann et al. reported that diphenyl glycoluril tetramers with four sulfonate side chains have high biosafety, but low activity against muscle relaxants. Liu et al. reported that cucurbit[8]uril macrocycles with sulfonate side chains have good activity and biosafety against muscle relaxants, but these cucurbit[8]uril derivatives are mixtures with unidentified components and low drugability. Xue et al. reported that columnar[6]arene sulfonates have a high binding capacity for cis-atracurium besylate, but their actual antagonistic activity is unknown, and the synthetic yield of columnar[6]arene is low. The separation of these sulfonates also requires complex gel chromatography technology. Therefore, although the development of broad-spectrum antagonists that can rapidly reverse muscle relaxants is clinically beneficial, discovering new drugable compounds with rapid antagonistic activity and high biosafety is a very challenging task.

[0005] In summary, there is an urgent need in this field to develop a broad-spectrum antagonist drug with high biological safety that can quickly antagonize steroid quaternary ammonium salts and tetrahydroisoquinoline quaternary ammonium salt muscle relaxants.

[0006] Summary of the Invention

[0007] The object of the present invention is to provide a deuterated diaryl glycoluril tetramer compound having a broad-spectrum rapid antagonistic activity against steroidal quaternary ammonium salts (rocuronium bromide, vecuronium bromide, pancuronium bromide), tetrahydroisoquinoline quaternary ammonium salts (cis-atracurium besylate), muscle relaxants, and the like, and its use.

[0008] The first aspect of the present invention provides a deuterated diaryl glycoluril tetramer compound represented by formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0009] in,

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

[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 independently deuterium or hydrogen;

[0013] R 9 、R 10 、R 11 and R 12 are each independently an undeuterated, partially deuterated or fully deuterated linear or branched C1-C20 alkyl group, or R 9 and R 10 , R11 and R 12 Each of the carbon atoms to which it is attached together forms a non-deuterated, partially deuterated or fully deuterated group selected from the group consisting of a C3-C20 cycloalkyl group, a 3-20 membered heterocyclyl group, a C5-C20 aryl group or a 5-20 membered heteroaryl group;

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

[0015] R 33 、R 34 、R 35 and R 36 are each independently deuterium, hydrogen, or a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of a linear or branched C1-C20 alkyl group, a C3-C20 cycloalkyl group, a linear or branched C1-C20 alkoxy group, a linear or branched C1-C20 alkylthio group, a linear or branched C1-C20 aldehyde group, a linear or branched C1-C20 ester group, a linear or branched C1-C20 alkyl group containing a carbonyl group, or R 33 With R 34 、R 35 With R 36 Each of the carbon atoms to which it is attached together forms a non-deuterated, partially deuterated or fully deuterated group selected from the group consisting of a C3-C20 saturated carbocycle, a C3-C20 saturated spirocycle, a saturated 3-20 membered heterocycle containing one or more heteroatoms selected from oxygen, sulfur or nitrogen, a C5-C20 aromatic ring, or a 5-20 membered heteroaromatic ring 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 、R 21 、R22 、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 O, S, Se, Te, methylene, NH or amino substituted with C1-C4 alkyl.

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

[0019] In another preferred embodiment, R 1 、R 2 、R 3 、R 4 are each independently H or D.

[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 independently D.

[0022] In another preferred embodiment, R 5 、R 6 、R 7 and R 8 are each independently deuterium or hydrogen.

[0023] In another preferred embodiment, R 5 、R 6 、R 7 and R 8 are each 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 are each independently H or D.

[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 independently D.

[0027] 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 independently 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 are each independently H or D.

[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 the above numbers 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 independently D.

[0031] In another preferred embodiment, R 9 、R 10 、R 11 and R 12 are each independently an undeuterated, partially deuterated or fully deuterated linear or branched C1-C10 alkyl group, or R 9 and R 10 , R11 and R 12 The carbon atom to which each is attached together forms a group selected from the group consisting of a C3-C10 cycloalkyl group, a 3-10 membered heterocyclyl group, a C6-C10 aryl group, or a 5-10 membered heteroaryl group.

[0032] In another preferred embodiment, R 9 、R 10 、R 11 and R 12 are each independently an undeuterated, partially deuterated or fully deuterated linear or branched C1-C7 alkyl group, or R 9 and R 10 , R 11 and R 12 The carbon atom to which each is attached together forms a C3-C7 cycloalkyl group, a 3-7 membered heterocyclyl 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 are each independently an undeuterated, partially deuterated or fully deuterated linear or branched C1-C4 alkyl group, or R 9 and R 10 , R 11 and R 12 The carbon atom to which each is attached together 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 32 Each is independently non-deuterated, partially deuterated or fully deuterated and is selected from the group consisting of a straight chain or branched C1-C10 alkylene group, a C3-C10 cycloalkylene group, a straight chain or branched 1-10 membered heteroalkylene group containing one or more heteroatoms selected from oxygen, sulfur or nitrogen, or a 3-10 membered heterocyclylene group 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 is independently non-deuterated, partially deuterated or fully deuterated and is selected from the group consisting of a linear or branched C1-C6 alkyl group, and a linear or branched 1-6 membered alkyl group 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 is independently non-deuterated, partially deuterated or fully deuterated and is selected from the group consisting of a straight chain or branched C1-C4 alkylene group, and a straight chain or branched 1-4 membered heteroalkylene group 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 is independently a non-deuterated, partially deuterated or fully deuterated propyl group.

[0040] In another preferred embodiment, R 33 、R 34 、R 35 and R 36 are each independently deuterium, hydrogen, or a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of a linear or branched C1-C10 alkyl group, a C3-C10 cycloalkyl group, a linear or branched C1-C10 alkoxy group, a linear or branched C1-C10 alkylthio group, a linear or branched C1-C10 aldehyde group, a linear or branched C1-C10 ester group, a linear or branched C1-C10 alkyl group containing a carbonyl group, or R 33 With R 34 , R 35 With R 36 Each of the carbon atoms to which it is attached together forms a non-deuterated, partially deuterated or fully deuterated group selected from the following group: a C3-C10 saturated carbocycle, a C3-C10 saturated spirocycle, a saturated 3-10 membered heterocycle containing one or more heteroatoms selected from oxygen, sulfur or nitrogen, a C5-C10 aromatic ring, or a 5-10 membered heteroaromatic ring containing one or more heteroatoms selected from oxygen, sulfur or nitrogen.

[0041] In another preferred embodiment, R 33 、R 34 、R 35 and R 36are each independently deuterium, hydrogen, or a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of a linear or branched C1-C6 alkyl group, a C3-C7 cycloalkyl group, a linear or branched C1-C6 alkoxy group, a linear or branched C1-C6 alkylthio group, a linear or branched C1-C6 aldehyde group, a linear or branched C1-C6 ester group, a linear or branched C1-C6 alkyl group containing a carbonyl group, or R 33 With R 34 , R 35 With R 36 Each of the carbon atoms to which it is attached together forms a non-deuterated, partially deuterated or fully deuterated group selected from the following group: a C3-C7 saturated carbocycle, a C3-C7 saturated spirocycle, a saturated 3-7 membered heterocycle containing one or more heteroatoms selected from oxygen, sulfur or nitrogen, a C6-C10 aromatic ring, or a 5-8 membered heteroaromatic ring 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 are each independently deuterium, hydrogen, or a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of a linear or branched C1-C6 alkyl group, a C3-C7 cycloalkyl group, or R 33 With R 34 , R 35 With R 36 The carbon atoms to which they are attached together form a non-deuterated, partially deuterated or fully deuterated group selected from the group consisting of a C3-C7 saturated carbon ring or a benzene ring.

[0043] In another preferred embodiment, R 33 、R 34 、R 35 and R 36 are each independently deuterium, hydrogen, or a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of a linear or branched C1-C5 alkyl group, or R 33 With R 34 、R 35 With R 36 The carbon atoms to which they are attached together form a non-deuterated, partially deuterated or fully deuterated group selected from the group consisting of a C5-C7 saturated carbon ring or a benzene ring.

[0044] In another preferred embodiment, R 33 、R 34 、R 35 and R 36 are each independently deuterium, hydrogen, CD3 or CH3, or R 33 With R 3 , R 35 With R 36The carbon atoms to which they are attached together form a five-membered carbon ring or a benzene ring.

[0045] In another preferred embodiment, in the compound, the ratio of deuterium atoms to the sum of deuterium atoms and hydrogen atoms (D / (D+H)) is ≥0.015% (natural deuterium isotope content); 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; 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 following group:

[0049] In another preferred embodiment, the compound is

[0050] The second aspect of the present invention provides a pharmaceutical composition comprising: (a) the compound described in 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.

[0051] In another preferred embodiment, in the composition, component (a) accounts for 0.001-99.999 wt% of the total weight of the composition; preferably 0.01-99.99 wt%; more preferably 0.1-90 wt%.

[0052] In another preferred embodiment, the pharmaceutical composition is in the form of an injection, tablet, capsule, pill, suspension or emulsion.

[0053] In another preferred embodiment, the injection is an aqueous solution, a sodium chloride aqueous solution or a glucose aqueous solution, wherein the concentration of the compound described in the first aspect of the present invention as an active ingredient is 0.1-5000 mg / mL.

[0054] In another preferred embodiment, the dosage of the injection is 0.1-5000 mg / kg, based on the body weight of the rat.

[0055] In a third aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0056] (a) as the first active ingredient, the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof;

[0057] (b) as a second active ingredient, an ingredient having an antagonistic effect on non-depolarizing muscle relaxants selected from the group consisting of neostigmine, sugammadex sodium, or a combination thereof; and

[0058] (c) a pharmaceutically acceptable carrier or excipient.

[0059] In another preferred embodiment, the pharmaceutical composition is in the form of an injection, tablet, capsule, pill, suspension or emulsion.

[0060] In a fourth aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0061] (a) as the first active ingredient, a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof;

[0062] (b) a non-deuterated aryl tetramer compound having the structure shown in the first aspect of the present invention as a second active ingredient; and

[0063] (c) a pharmaceutically acceptable carrier or excipient.

[0064] In another preferred embodiment, the pharmaceutical composition is in the form of an injection, tablet, capsule, pill, suspension or emulsion.

[0065] In another preferred embodiment, the non-deuterated aryl tetramer compound having the structure shown in the first aspect of the present invention is as follows:

[0066] wherein each Z is independently O, S, Se, Te, C1-C4 alkylene, -NH-, or C1-C4 alkyl-substituted amino;

[0067] Each M is independently Na + , K + 、Li + Mg 2+ , Ca 2+ NH4 + , or one or more C1-C4 alkyl-substituted ammonium salts;

[0068] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R13 、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 are each independently hydrogen;

[0069] R 9 、R 10 、R 11 and R 12 are each independently a non-deuterated straight or branched C1-C20 alkyl group, or R 9 and R 10 , R 11 and R 12 Each of the carbon atoms to which it is attached together forms a non-deuterated group selected from the group consisting of a C3-C20 cycloalkyl group, a 3-20 membered heterocyclyl group, a C5-C20 aryl group, or a 5-20 membered heteroaryl group;

[0070] R 29 、R 30 、R 31 or R 32 Each independently non-deuterated group selected from the group consisting of a straight or branched C1-C20 alkylene group, a C3-C20 cycloalkylene group, a straight or branched 1-20 membered heteroalkylene group containing one or more heteroatoms selected from oxygen, sulfur or nitrogen, or a 3-20 membered heterocyclylene group containing one or more heteroatoms selected from oxygen, sulfur or nitrogen;

[0071] R 33 、R 34 、R 35 and R 36 are each independently hydrogen, or a non-deuterated group selected from the group consisting of a linear or branched C1-C20 alkyl group, a C3-C20 cycloalkyl group, a linear or branched C1-C20 alkoxy group, a linear or branched C1-C20 alkylthio group, a linear or branched C1-C20 aldehyde group, a linear or branched C1-C20 ester group, a linear or branched C1-C20 alkyl group containing a carbonyl group, or R 33 With R 34 、R 35 With R 36The carbon atoms to which they are attached together form a non-deuterated group selected from the following group: a C3-C20 saturated carbocyclic ring, a C3-C20 saturated spirocyclic ring, a saturated 3-20 membered heterocyclic ring containing one or more heteroatoms selected from oxygen, sulfur or nitrogen, a C5-C20 aromatic ring, or a 5-20 membered heteroaromatic ring containing one or more heteroatoms selected from oxygen, sulfur or nitrogen.

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

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

[0074] (b) a second container, and a muscle relaxant in the second container; the muscle relaxant is selected from the group consisting of steroidal quaternary ammonium salts, tetrahydroisoquinoline quaternary ammonium salts, benzylisoquinoline derivatives, or combinations thereof; and / or

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

[0076] (4) Optional instruction manual.

[0077] In another preferred embodiment, the non-depolarizing muscle relaxant is cisatracurium besylate, pancuronium bromide, rocuronium bromide, vecuronium bromide, or a combination thereof.

[0078] In another preferred embodiment, the kit is used to antagonize muscle relaxants.

[0079] In another preferred embodiment, the non-depolarizing muscle relaxant is selected from the following group: steroidal quaternary ammonium salts, tetrahydroisoquinoline quaternary ammonium salts, benzylisoquinoline derivative muscle relaxants, or a combination thereof.

[0080] In the sixth aspect of the present invention, there is provided a use of the compound described in the first aspect of the present invention, or the pharmaceutical composition described in the second aspect of the present invention, or the pharmaceutical composition described in the third aspect of the present invention, or the pharmaceutical composition described in the fourth aspect of the present invention for antagonizing muscle relaxants.

[0081] In the seventh aspect of the present invention, a method for antagonizing muscle relaxants is provided, wherein a therapeutically effective amount of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is administered to a subject in need, thereby antagonizing "residual quiver toxicity" in the subject's body.

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

[0083] After extensive, in-depth, and systematic research, the inventors have developed a class of deuterated diaryl glycoluril tetramer compounds with broad-spectrum, rapid antagonistic activity against muscle relaxants, such as steroidal quaternary ammonium salts (rocuronium, vecuronium, and pancuronium), tetrahydroisoquinoline quaternary ammonium salts (cisatracurium besylate), and other muscle relaxants. These compounds also exhibit high water solubility and high biosafety. At the same dose, the deuterated compounds of the present invention exhibit significantly enhanced antagonistic activity compared to non-deuterated control molecules and sugammadex sodium. Based on this, the inventors completed the present invention.

[0084] definition

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

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

[0087] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0088] Deuterium is a stable isotope of hydrogen. CD bonds are more stable than C-H bonds, making them less susceptible to cleavage and potentially extending their half-lives. The acidic and hydrophobic properties of CD bonds differ from those of C-H bonds, leading to differences in their hydrophobic interactions in vivo, such as their accumulation, clustering, or aggregation, and potentially different binding stability and selectivity with biological substances. The metabolic processes of living systems are complex, and the metabolism and excretion dynamics of deuterated molecules are influenced by multiple factors, leading to correspondingly complex expectations. Therefore, compared to non-deuterated molecules, the biological activity of deuterated molecules is highly sporadic and unpredictable, with deuteration at many sites reducing or degrading their biological activity. Furthermore, hydrogen at certain positions in organic molecules is difficult or challenging to deuterate due to limitations in synthetic methods. Therefore, deuteration in organic molecules is not arbitrary; the sites that can be deuterated are unpredictable, and their biological activity is also unpredictable.

[0089] As used herein, "C1-C20 alkyl" refers to a straight or branched chain alkyl group comprising 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc., or the like.

[0090] As used herein, "1-20 membered heteroalkyl" refers to a C 1-20 One or more carbon atoms in the alkyl chain are substituted by a heteroatom selected from nitrogen, oxygen and sulfur, for example, a 1-8 membered heteroalkyl group refers to CH3-CH2-CH2-CH2-O-CH2-CH2-CH2-, or CH3-CH2-CH2-CH2-O-CH2-CH2-O- and the like.

[0091] As used herein, “2-20 membered heteroalkenyl” refers to a group in which one or more carbon atoms in the C2-20 alkenyl chain are substituted by a heteroatom selected from nitrogen, oxygen and sulfur. For example, a 1-7 membered heteroalkenyl group refers to CH3-CH2-CH2-O-CH2-CH=CH-, or CH3-S-CH2-CH2-O-CH=CH- and the like.

[0092] As used herein, “2-20-membered heteroalkynyl” refers to a group in which one or more carbon atoms in the C2-20 alkynyl chain are substituted by a heteroatom selected from nitrogen, oxygen and sulfur. For example, a 1-7-membered heteroalkynyl group refers to CH3-CH2-CH2-O-CH2-C≡C-, or CH3-S-CH2-CH2-OC≡C- and the like.

[0093] As used herein, “C1-C 20 "Alkyl chain" refers to a straight or branched alkyl chain (CH2) containing 1 to 20 carbon atoms. n (n=1~20).

[0094] As used herein, "C3-C20 cycloalkyl" refers to a cycloalkyl group containing 3 to 20 carbon atoms or a cycloalkyl group with a side chain, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The term "C3-C20 cycloalkyl" refers to a cycloalkyl group containing 3 to 20 carbon atoms or a cycloalkyl group with a side chain, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc 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, more preferably C3-C6 monocyclic cycloalkyl, C7-C 10 Bicyclic or tricyclic cycloalkyl groups. "Substituted cycloalkyl" refers to a cycloalkyl group that is substituted at one or more positions, particularly 1 to 4 substituents, and the substitutions may be at any position.

[0095] As used herein, "carbocycle" refers to a fully saturated or partially unsaturated (preferably fully saturated) cyclic hydrocarbon compound group, including cycloalkenyl, cycloalkyl and cycloalkynyl.

[0096] In the present invention, the term "heterocyclyl (or heterocycle)" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to a 3-7 membered monocyclic ring, a 4-7 membered monocyclic ring, a 6-11 membered bicyclic ring, or an 8-16 membered tricyclic or polycyclic ring system), wherein at least one heteroatom is present in the ring having at least one carbon atom. The term "4-20 membered heterocyclyl" refers to a heterocyclyl containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms. "Heterocyclyl" has the same meaning as "saturated or unsaturated heterocyclyl". "Heterocyclyl" is preferably a 4-14 membered heterocyclyl (including but not limited to a 4-6 membered monocyclic, 7-10 membered bicyclic or 8-14 membered tricyclic or polycyclic ring system), more preferably a 4-12 membered heterocyclyl, more preferably a 4-10 membered heterocyclyl, such as a 4-6 membered monocyclic heterocyclyl, a 7-11 membered bicyclic or tricyclic heterocyclyl, more preferably a 4-8 membered heterocyclyl, more preferably a 4-6 membered heterocyclyl. Each heterocyclic ring containing a heteroatom may have 1, 2, 3 or 4 heteroatoms, each of which is independently selected from a nitrogen atom, an oxygen atom or a sulfur atom, wherein the nitrogen atom or sulfur atom may be oxidized and the nitrogen atom may be quaternized. The heterocyclic group may be attached to the residue of any heteroatom or carbon atom of the ring or ring system, preferably to an N or C atom of the ring or ring system. Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl, and tetrahydro-1,1-dioxythiophene, and the like. Polycyclic heterocyclic groups include spirocyclic, fused and bridged heterocyclic groups; wherein the spirocyclic, fused and bridged heterocyclic groups are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring; the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, thiol, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.

[0097] As used herein, "deuterated" refers to a compound or group in which one or more hydrogen atoms are replaced by deuterium. Deuteration can be monosubstituted, disubstituted, polysubstituted, or persubstituted. The terms "deuterated one or more" and "deuterated one or more times" are used interchangeably.

[0098] As used herein, "non-deuterated" means that the deuterium isotope ratio of each hydrogen atom is no greater than the natural deuterium isotope content (about 0.015%).

[0099] As used herein, the term "active ingredient" refers to a deuterated diaryl glycoluril tetramer compound. It should be understood that the term also includes mixtures of such compounds.

[0100] As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.

[0101] As used herein, the term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0102] 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, which may have a single ring (e.g., phenyl) or a fused ring (e.g., naphthyl or anthracenyl). If the point of attachment is at the aromatic carbon atom, the fused ring may be non-aromatic (e.g., 2-benzoxazolone, 2H-1,4-benzoxazin-3(4H)-on-7-yl, etc.). Preferred aryl groups include phenyl and naphthyl.

[0103] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having 3 to 12 (preferably 3 to 10) carbon atoms, having a single or multiple rings (including fused, bridged, and spiro ring systems). In a fused ring system, one or more rings may be cycloalkyl, heterocyclic, aryl, or heteroaryl, as long as the point of attachment is through the cycloalkyl ring. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.

[0104] The term "heteroaryl" refers to an aromatic cyclic hydrocarbon group containing 1-4 heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. Among them, "5-14 membered heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms. The heteroaryl is a monocyclic ring (such as pyridyl or furyl) or a fused ring (such as indolizinyl or benzothienyl). Among them, the fused ring can be non-aromatic and / or contain one heteroatom, as long as the point of attachment is through the atom of the aromatic heteroaryl. The heteroaryl is preferably a 5- to 10-membered ring, more preferably a 5- or 6-membered ring, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl. "Heteroaryl" may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, sulfhydryl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate. In one embodiment, the ring nitrogen and / or sulfur atoms of the heteroaryl are optionally oxidized to N-oxide (NO), sulfinyl, or sulfonyl. Preferred heteroaryl groups include pyridyl, pyrrolyl, indolyl, thienyl, and furyl.

[0105] As used herein, the term "substituted heteroaryl" refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the same substituents as defined for substituted aryl.

[0106] The animal activity test and acute toxicity test in the present invention were conducted using SD rats.

[0107] As used herein, unless otherwise specified, the substitution refers to the substitution of hydrogen on a group by one or more groups selected from the group consisting of halogen, nitro, amino, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl.

[0108] As used herein, the deuterated diaryl glycoluril tetramer compound, if a chiral carbon atom is present, can be in the R-configuration, the S-configuration, or a mixture of the two.

[0109] The deuterated diaryl glycoluril tetramer compound or its composition of the present invention can be prepared by methods well known to those skilled in the art, and there is no particular limitation on the reaction parameters of each step. In addition, the typical compound of the present invention can be obtained through commercial means.

[0110] As used herein, "quiver toxicity" refers to the condition in which a patient is unable to recover spontaneous breathing after surgery due to neuromuscular blockade caused by residual muscle relaxants. Because the symptoms resemble those of quiver alkaloids, they are called "quiver toxicity."

[0111] The animal activity test and acute toxicity test in the present invention were conducted using SD rats.

[0112] neuromuscular blockers or muscle relaxants

[0113] Neuromuscular blockers or muscle relaxants (abbreviated as muscle relaxants) are widely used in clinical practice to relax skeletal muscles, thereby facilitating intubation and improving surgical conditions. Based on their mechanism of action, muscle relaxants are categorized as depolarizing and nondepolarizing. Depolarizing muscle relaxants bind to N2 cholinergic receptors on the motor nerve endplate membrane, weakening or eliminating the muscle cell's response to acetylcholine. Nondepolarizing muscle relaxants compete with acetylcholine for N2 cholinergic receptors on the motor endplate membrane of skeletal muscle, leading to skeletal muscle relaxation. The most commonly used nondepolarizing muscle relaxants in clinical practice are classified, based on their chemical structure, into aminosteroid derivatives (such as rocuronium, vecuronium, and pancuronium) and benzylisoquinoline derivatives (such as cisatracurium besylate).

[0114] Muscle relaxant antagonists - deuterated diaryl glycoluril tetramers

[0115] The present invention provides a deuterated diaryl glycoluril tetramer having a structure shown in formula I.

[0116] 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 、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 of is as mentioned above.

[0117] The deuterated diaryl glycoluril tetramer described in the present invention has a pre-organized "C" conformation, which constitutes a hydrophobic inner cavity and can drive the binding of the aforementioned muscle relaxant through hydrophobic interaction, thereby antagonizing its muscle relaxant activity.

[0118] The deuterated diaryl glycoluril tetramer described in the present invention has anionic sulfonate side chains introduced at both ends. The electrostatic interaction of these two chains can exert a synergistic effect with the hydrophobic effect of the tetramer "C" conformation, thereby quickly and efficiently binding to the muscle relaxant and thereby antagonizing its muscle relaxant activity.

[0119] In the present invention, deuterated diaryl glycoluril tetramers are used as broad-spectrum muscle relaxant antagonists. Rat studies have shown that this application can rapidly antagonize cisatracurium besylate and rocuronium bromide, as well as the muscle relaxants vecuronium and panvecuronium bromide. These deuterated compounds can exhibit high water solubility and biosafety, demonstrating significant clinical utility.

[0120] Control experiments support that this new class of deuterated compounds can achieve faster antagonism against rocuronium and vecuronium than the clinically used drug sugammadex sodium. Control experiments compared with non-deuterated compounds support that this class of deuterated compounds have significantly improved antagonistic activity against cisatracurium besylate. Deuterated diaryl glycoluril tetramers are used as broad-spectrum muscle relaxant antagonists compared to corresponding non-deuterated compounds. Rat experiments support that this application can achieve rapid antagonism against cisatracurium besylate and pancuronium. Control experiments support that this new class of deuterated compounds can achieve faster antagonism against rocuronium and vecuronium than the clinically used drug sugammadex sodium. This class of deuterated compounds can have high water solubility and high biosafety, and have significant clinical practicality.

[0121] Preparation method

[0122] The preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be prepared by combining various synthetic methods described in this specification or known in the art, and such combination can be easily carried out by those skilled in the art.

[0123] The deuterated diaryl glycoluril tetramer described in the present invention is prepared by using the ring-opened glycoluril tetramer as a rigid pre-organized skeleton and undergoing electrophilic substitution reaction with two aromatic ring molecules with different functional groups.

[0124] The preparation of the deuterated diaryl glycoluril tetramer and the corresponding raw materials in the present invention is generally carried out under acidic conditions, at room temperature to reflux temperature (e.g., 0-100°C, preferably 0-60°C). The reaction time is generally 0.1 hour to 60 hours, preferably 0.5-48 hours. The following general preparation route can be used to synthesize the compound of formula (I) of the present invention:

[0125] Synthesis route 1: wherein Z is O, S, Se, Te, methylene, amino, and substituted amino;

[0126] 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 of is as mentioned above.

[0127] As shown in Synthesis Scheme 1, the compounds of the present invention are synthesized using a convergent approach. (a) First, a diketone compound A with different substituents undergoes a cyclocondensation reaction with urea to produce a glycoluril compound B with different substituents. This is then subjected to a further cyclocondensation reaction with paraformaldehyde or deuterated paraformaldehyde C to produce a glycoluril dimer D and a tetracyclic glycoluril diether structure E, respectively. D and E undergo further condensation reactions to produce a tetramer F with different substituents. (b) An aryl compound G with different substituents undergoes a nucleophilic substitution reaction with propane sultone H to produce a non-deuterated aryl sulfonate I or J. I further undergoes a deuteration reaction to produce a deuterated aryl sulfonate J. (c) Finally, the non-deuterated or deuterated aryl sulfonate J converges with the tetramer F to produce the compound (I) of the present invention through an electrophilic substitution reaction.

[0128] The deuterated diaryl glycoluril tetramer described in the present invention can be prepared using three key intermediates, namely a deuterated or non-deuterated dimer intermediate, a deuterated or non-deuterated tetramer intermediate, and a deuterated or non-deuterated sulfonate intermediate.

[0129] Deuterated or non-deuterated dimer intermediates;

[0130] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 each independently deuterium or hydrogen;

[0131] Furthermore, the structure of the deuterated or non-deuterated dimer intermediate is as follows:

[0132] Deuterated or non-deuterated tetramers;

[0133] 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 、R 21 、R 22、R 23 、R 24 、R 25 、R 26 、R 27 and R 28 are each independently deuterium or hydrogen; 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 two adjacent groups and the carbon atom to which they are commonly attached together form an undeuterated, partially deuterated or fully deuterated C3-C20 cycloalkyl group;

[0134] Furthermore, the structure of the deuterated or non-deuterated tetramer intermediate is as follows:

[0135] Deuterated or non-deuterated sulfonate intermediates;

[0136] Wherein, Z is O, S, Se, Te, methylene, amino or substituted amino; M is Na + ;

[0137] R 29 、R 30 、R 31 or R 32 each independently a non-deuterated, partially deuterated or fully deuterated group selected from the group consisting of a linear or branched C1-C20 alkyl group, a C3-C20 cycloalkyl group, a linear or branched C1-C20 alkyl group containing one or more heteroatoms selected from oxygen, sulfur or nitrogen, or a C3-C20 cycloalkyl group containing one or more heteroatoms selected from oxygen, sulfur or nitrogen;

[0138] R 33 、R 34 、R 35 and R 36 are each independently deuterium, hydrogen, or a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of a linear or branched C1-C20 alkyl group, a C3-C20 cycloalkyl group, a linear or branched C1-C20 alkoxy group, a linear or branched C1-C20 alkylthio group, a linear or branched C1-C20 aldehyde group, a linear or branched C1-C20 ester group, a linear or branched C1-C20 alkyl group containing a carbonyl group, or R 33 With R 34 、R 35 With R 36Each of the carbon atoms to which it is attached together forms a non-deuterated, partially deuterated or fully deuterated group selected from the group consisting of a C3-C20 saturated carbocycle, a C3-C20 saturated spirocycle, a saturated 3-20 membered heterocycle containing one or more heteroatoms selected from oxygen, sulfur or nitrogen, or a C3-C20 aromatic ring;

[0139] Furthermore, the sulfonate intermediate is selected from the following group:

[0140] Pharmaceutical composition

[0141] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0142] The "active ingredient" described in the present invention refers to the compound of formula I described in the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0143] As used herein, the term "pharmaceutically acceptable salts" refers to non-toxic acid or alkaline earth metal salts of compounds of Formula I. These salts can be prepared in situ during the final isolation and purification of the compounds of Formula I, or by reacting a suitable organic or inorganic acid or base with a basic or acidic functional group, respectively. Representative salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, gluconate heptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthylsulfonate, oxalate, pamoate, pectinate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, and undecanoate. In addition, nitrogen-containing basic groups can be quaternized with the following reagents: alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long-chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, such as benzyl and phenethyl bromides, etc. This results in water-soluble, oil-soluble, or dispersible products. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, and citric acid. Base addition salts can be prepared in situ during the final isolation and purification of the compound of Formula I, or by reacting the carboxylic acid moiety with a suitable base (such as a pharmaceutically acceptable metal cation hydroxide, carbonate, or bicarbonate), ammonia, or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, salts based on alkali and alkaline earth metal cations, such as sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0144] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0145] Suitable pharmaceutically acceptable carriers or excipients include, for example, treating agents and drug delivery modifiers and accelerators, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting point waxes, ion exchange resins, and combinations of any two or more thereof. Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including petroleum, animal oils, vegetable oils, or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous glucose solutions, and ethylene glycol. Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[0146] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0147] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0148] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0149] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0150] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0151] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0152] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0153] 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.

[0154] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0155] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0156] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0157] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0158] Compared with the prior art, the main advantages of the present invention include:

[0159] (1) Controlled trials have shown that, compared with the clinically used antagonist neostigmine, the preferred examples of the compounds of the present invention can antagonize the benzylisoquinoline muscle relaxant cisatracurium besylate and the aminosteroid muscle relaxants pancuronium, rocuronium, and vecuronium more quickly.

[0160] (2) Controlled trials support that preferred examples of the compounds of the present invention can antagonize the aminosteroidal muscle relaxants rocuronium and vecuronium more rapidly than the clinically used antagonist sugammadex sodium. Preferred examples of the compounds of the present invention can rapidly antagonize the benzylisoquinoline muscle relaxant cisatracurium besylate and the aminosteroidal muscle relaxant pancuronium bromide, whereas sugammadex sodium cannot antagonize these two types of muscle relaxants.

[0161] (3) Control experiments show that, compared with the disclosed non-deuterated dibenzoglycoluril 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 biosafety.

[0162] (4) Control experiments show that the deuterated compounds of the present invention have significantly improved antagonistic activities against both cis-atracurium besylate and rocuronium bromide compared to the previously disclosed non-deuterated dimethyl-substituted dibenzoglycoluril tetramers.

[0163] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, were generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0164] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0165] Example 1: Synthesis of Compound I-5

[0166] Under rapid mechanical stirring, hydrochloric acid (8M, 80mL) was added to a 500mL two-necked flask, and glycoluril (compound 4, 49.3g, 0.36mol) was added in batches. The oil bath temperature was controlled to 50°C. Subsequently, a deuterated paraformaldehyde solution (compound 6, 10.7g, 0.36mol, dissolved in 40mL of 8M hydrochloric acid) was slowly added dropwise through a constant pressure dropping funnel. After the addition was completed, stirring was continued for 48 hours (the reaction system was not clear and was heterogeneous from beginning to end). After the reaction system was centrifuged, the supernatant was transferred back to the two-necked flask; the solid was dispersed with 8M hydrochloric acid (2mL) and deionized water (2mL) was added to make a 4M solution. After shaking, the upper yellow clear liquid was centrifuged and transferred to the above-mentioned two-necked flask. After merging, the reaction was continued at 50°C for 48 hours. Subsequently, the "centrifugation-4 M hydrochloric acid wash-transfer and combine supernatants" procedure was repeated three times. Finally, the solids were combined, dispersed with deionized water, and centrifuged. The "deionized water wash-centrifugation" procedure was repeated four times until the pH of the supernatant was close to neutral. Compound 8 (20.1 g, 37%) was obtained as a white product. 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.

[0167] Methanesulfonic acid (50 mL) was added to a 250 mL three-necked flask. The oil bath temperature was raised to 50°C, followed by the addition of solid compound 8 (10.0 g, 32.0 mmol) in portions, with mechanical stirring until the system clarified. Solid compound 7 (24.4 g, 96.1 mmol) was then added in portions, and the mixture was stirred at 50°C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature and 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 5) until neutral. The mixture was then transferred to an eggplant-shaped flask and vacuum-dried to yield compound 9 (15.0 g, 60%) as a white solid. 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.

[0168] The dimer 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 in sequence and reacted at 50°C for 12 hours. After the reaction, the reaction solution was added dropwise to rapidly stirred ethanol (1.3 L), stirred for half an hour and then centrifuged. The solid was washed with ethanol in a centrifuge tube (30 mL × 5). After the reaction, the solid was dissolved in water (20 mL) and filtered. The filtrate was dried and the solid residue was recrystallized with ethanol and water. The crystals were allowed to stand in a refrigerator at 4°C overnight and then filtered. The filter cake was washed with ethanol-water solution (5 mL, 4:1 v / v). The obtained white solid was dissolved in water (6 mL) and filtered. The filtrate was evaporated at 70°C to remove water and dried in vacuo to obtain white solid compound I-5 (19.1 g, 60%). 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.

[0169] Example 2: Synthesis of Compound I-1

[0170] The method described in Example 1 was followed, except that sodium 1,4-phenoxy-dipropyl alkanesulfonate was used instead of sodium 2,3-dimethyl-1,4-phenoxy-dipropyl alkanesulfonate.

[0171] Tetradeuterated dimethyl glycoluril tetramer (1.0 g, 1.26 mmol) was weighed and dissolved in trifluoroacetic acid (6 mL). Acetic anhydride (6 mL) and sodium 1,4-phenoxy-dipropyl alkanesulfonate (1.52 g, 3.82 mmol) were added sequentially and reacted at 50°C for 12 hours. After completion of the reaction, the reaction solution was added dropwise to rapidly stirring ethanol (200 mL). After stirring for half an hour, the mixture was centrifuged. The solid was washed with ethanol (30 mL x 5) in a centrifuge tube and centrifuged again. The solid was then dissolved in water (20 mL) and filtered. The filtrate was then dried by rotary evaporation. The solid residue was recrystallized from ethanol and water. The crystals were allowed to stand overnight in a refrigerator at 4°C and then filtered. The filter cake was washed with ethanol-water (5 mL, 4:1 v / v) and recrystallized again from ethanol / water. The resulting white solid was dissolved in water (8 mL) and filtered. The filtrate was rotary evaporation at 70°C to remove water and then dried under vacuum to yield I-1 (1.1 g, 56%) as a white solid. 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):Calcd for[M+2Na]2+:795.1394,Found:795.1382.

[0172] Example 3: Synthesis of Compound I-2

[0173] The method described in Example 1 was followed, except that deuterated compound 3-4 was used instead of sodium 2,3-dimethyl-1,4-phenoxy-dipropyl alkanesulfonate.

[0174] Compound 4,7-dihydroxy-1-indanone (synthesized according to a literature method, 820.0 mg 5 mmol) 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 and stirred at room temperature for 30 min. 1.8330 g (15 mmol) of 1,3-propane sultone 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 starting materials reacted completely. The reaction solution was concentrated and added dropwise to 100 ml of EtOH. A brown precipitate formed. Centrifugation afforded a brown solid on a black surface. The resulting solid was washed twice with 60 mL of EtOH. The crude solid was recrystallized from EtOH / H₂O at 90°C to yield 3-2 (701.2 mg, 31%) as a light brown solid powder. 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.

[0175] Sodium benzocyclopentanone sulfonate (452.2 mg, 1.0 mmol) was weighed into a 25 ml single-necked flask. Potassium carbonate (13.8 mg, 0.1 mmol) was added to 2 ml of deuterated water and heated under reflux for 4 h. After completion of the reaction, the reaction system was poured into 20 ml of ethanol, and a precipitate formed. After centrifugation and drying, light brown sodium deuterated 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.

[0176] To a 50 mL single-necked flask, sodium deuterated benzocyclopentanone sulfonate (454.2 mg, 1.0 mmol) was added, followed by TFA (1.14 g, 10 mmol). The solution turned orange-red and stirred at room temperature for 15 minutes. HSiEt3 (288.15 mg, 2.5 mmol) was slowly added dropwise. The reaction was allowed to proceed for 4 hours. After completion, the reaction system was distilled under reduced pressure to remove unreacted TFA and HSiEt3. The resulting crude solid product was recrystallized from water and ethanol. Sodium deuterated benzocyclopentane sulfonate 3-4 (396.4 mg, 90%) was obtained as a white powder. 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, found 395.0806.

[0177] Methyl tetramer (189.0 mg, 0.25 mmol) and a TFA / Ac2O mixed solvent (2 mL / 2 mL) were added to a 25 mL single-necked bottle and stirred to dissolve. Deuterated benzocyclopentane sulfonate (286.0 mg, 0.625 mmol) was then added to the system, the system was heated to 50°C and reacted for 12 h. After the reaction was completed, the reaction system was slowly added dropwise to 80 mL of rapidly stirred ethanol. A precipitate was precipitated and the crude product was obtained by centrifugation. The crude product was recrystallized at 70°C using a mixed solvent of EtOH / and H2O to obtain the target product I-2 (80.2 mg, 19.5%) as a white powder. 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.

[0178] Example 4: Synthesis of Compound I-3

[0179] The method described in Example 1 was followed, except that compound 4-2 was used instead of sodium 2,3-dimethyl-1,4-phenoxy-dipropyl alkanesulfonate.

[0180] 2,5-Dihydroxytoluene (29.79 g, 10 mmol) was added to a 2L reaction flask, followed by NaOH solution (36.92 g, 38.5 mmol, dissolved in 370 mL of deionized water). The light yellow solid turned into a dark green solution and was stirred at room temperature for 30 minutes. A dioxane solution of 1,3-propane sultone (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 appeared in the system, and the reaction system gradually changed from the initial black to brown. After the reaction was completed, the light yellow solid was collected by filtration and then washed with ethanol (50 mL 2) and acetone (50 mL 2) in sequence. The obtained solid was recrystallized with water and ethanol at 90°C and dried in vacuo to obtain a light 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.

[0181] To a 50ml single-necked flask, add methyl tetramer (1.0g, 1.275mmol), 5.0ml acetic anhydride and 5.0ml trifluoroacetic acid, stir to dissolve, then add compound 4-2 (1.5772g, 3.825mmol) to the reaction system and stir to dissolve. The system was heated to 50°C and reacted for 12 hours. After the reaction, the reaction solution was added dropwise to 80ml ethanol. A brown solid precipitated. After centrifugation, the lower precipitate was washed twice with 100ml ethanol. After reflux with MeOH for 3h, it was hot filtered and the filter cake was taken and purified by diffusion with a water / acetone and tetrahydrofuran system to obtain a white solid product I-3 (200.8mg, 10%). 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.

[0182] Example 5: Synthesis of Compound I-4

[0183] The method described in Example 1 was followed, except that compound 5-2 was used instead of sodium 2,3-dimethyl-1,4-phenoxy-dipropyl alkanesulfonate.

[0184] Weigh 10g of NaH and slowly add it to 50mL of heavy water with constant stirring. After the reaction, add anhydrous Na2SO4 and dry n-hexane. Extract the remaining paraffin oil and separate the mixture three times to obtain a sodium deuteride solution. Add dimethylphenoxydisulfonate (0.85g, 2.0mmol) and NaOD (100mL) to an autoclave, seal the autoclave, and place it in an oil bath at 190°C with stirring for 20h. After the reaction, cool to room temperature, collect the solid by filtration, and wash with ethanol (2mL). The resulting solid is vacuum-dried to obtain 5-2 (0.71g, 81% yield, 98% deuteration) as a white solid. 1H NMR (400MHz, D2O): δ4.05 (t, J = 6.4Hz, 4H), 2.15 (t, J = 6.4Hz, 4H).

[0185] Tetradeuterated dimethyl tetramer (0.418 g, 0.5 mmol) was dissolved in trifluoroacetic acid (2 mL). Acetic anhydride (2 mL) and 20-deuterated sodium 2,3-dimethyl-1,4-phenoxy-dipropylsulfonate (0.65 g, 1.5 mmol) were added sequentially. The mixture was then reacted in an oil bath at 50°C for 12 h. After completion of the reaction, 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 x 4) in a centrifuge tube until the supernatant was essentially colorless. The solid was transferred to a 50 mL eggplant flask to remove the solvent, and the resulting solid was recrystallized from ethanol and water. The solid was filtered, washed with a small amount of ethanol / water (4:1), and dried under vacuum to yield I-4 (0.398 g, 49%) as a white solid powder. 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.

[0186] Example 6: Synthesis of Compound I-6

[0187] The method described in Example 1 was followed, except that compound 6-4 was used instead of sodium 2,3-dimethyl-1,4-phenoxy-dipropyl alkanesulfonate.

[0188] To a 100ml thick-walled pressure-resistant tube, add a magnetron and propenyl-1,3-sultone (310.0mg, 2.5mmol). Add 50.0ml of ether and stir to dissolve. Then add 10% Pd / C (110.3mg). The autoclave is evacuated and filled with deuterium gas to 0.6MPa. The reaction is allowed to proceed at room temperature until the pressure in the autoclave stabilizes. After the reaction, the palladium-carbon is filtered through celite, washed three times with 10.0ml of ether, and the solvent is removed by rotary evaporation. The product, 1,2-dideuteriopropane sultone 6-2 (0.31g, quantitative reaction), is obtained as a light yellow oily liquid. This product is used directly in the next step without further purification. 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, found 124.0161.

[0189] 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 and stirred at room temperature for 30 minutes. 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 generated, and the reaction system changed from a black solution to a brown suspension. After the reaction was completed, the brown solid was filtered and washed with a small amount of ethanol and acetone. The solid was transferred to a 50 ml single-necked flask and recrystallized from water and ethanol at 90°C. The product 6-4 was a beige powdery solid (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). 13C 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.

[0190] To a 25ml single-necked flask, add methyl tetramer (782.3mg, 1mmol), 7.0ml acetic anhydride, and 7.0ml trifluoroacetic acid. Stir to dissolve. Then add compound 6-4 (1.2397g, 3mmol) to the reaction system and stir to dissolve. The system is heated to 50°C and allowed to react for 12 hours. After the reaction is complete, the reaction solution is added dropwise to 140ml of ethanol. A brown solid precipitates. After centrifugation, the lower precipitate is washed twice with 100ml of ethanol. The lower solid is removed and recrystallized from water and ethanol at 70°C. The recrystallized product is dried using an oil pump to yield I-6 (0.6g, 37%) as a white powder. 1 H NMR(500MHz,D2O)δ5.66(d,J=15.3Hz,2H),5.54(d,J=15.7Hz,4H),5.46–5.33(m,4H),5.16(d,J=15.9Hz,4H),4.34(d,J=15.9Hz,4H),4.24(d ,J=15.6Hz,4H),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.

[0191] Example 7: Synthesis of Compound I-7

[0192] The method described in Example 1 was followed, except that compound 7-4 was used instead of sodium 2,3-dimethyl-1,4-phenoxy-dipropyl alkanesulfonate.

[0193] To a 250 mL single-necked flask, 2,3-propylene-1,4-diol (prepared according to a literature method, 2.07 g, 13.78 mmol) was added, along with a sodium hydroxide solution (1.38 g, 34.45 mmol, dissolved in 37.5 mL of H₂O) and stirred at room temperature for 30 min. Subsequently, a solution of 1,3-propane sultone in dioxane (5.05 g, 41.34 mmol, dissolved in 60 mL of 1,4-dioxane) was added with stirring. The reaction was allowed to proceed at room temperature for 12 hours, leading to complete reaction. After completion of the reaction, the reaction was centrifuged, and the resulting solid was washed with EtOH (60 mL x 2). The crude solid was recrystallized from EtOH / H₂O at 90°C to yield 7-4 (3.7520 g, 70%) as a light brown solid powder. 1 H NMR(500MHz,D2O)δ6.85(s,2H),4.15(t,J=6.3Hz,4H),3.14–3.00(m,4H),2.88(t,J=7.4Hz,4H),2.18(dq,J=12.6,6.3Hz,4H),2.08(p,J=7.7Hz,2H). 13 C NMR(126MHz,D2O)δ149.18,134.92,112.52,67.89,47.89,29.45,24.51,24.36.HRMS(ESI)calcd:[M-Na] - ,415.0503,found 415.0501.

[0194] To a 50 mL single-necked flask, tetradeuterated dimethyl glycoluril tetramer (1.53 g, 1.79 mmol) and acetic anhydride (7.0 mL) were added sequentially and stirred to dissolve. Trifluoroacetic acid (7.0 mL) and sodium 2,3-propylene-1,4-phenoxy-dipropyl alkanesulfonate (2.35 g, 5.35 mmol) were then added sequentially to the reaction system and stirred to dissolve. The system was heated to 50°C and allowed to react for 12 hours. After completion of the reaction, the reaction solution was added dropwise to 140 mL of ethanol, resulting in the precipitation of a light yellow solid. After centrifugation, the lower layer of solid was washed twice with 150 mL of ethanol and then recrystallized at 70°C with water and ethanol. The recrystallized product was vacuum dried to yield I-7 (1.61 g, 59%) as a white powder. 1H 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.

[0195] Example 8: Synthesis of Compound I-8

[0196] The method described in Example 1 was followed, except that compound 8-2 was used instead of sodium 2,3-dimethyl-1,4-phenoxy-dipropyl alkanesulfonate.

[0197] 1,2-Dideuteriopropane sultone 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 a 10% NaOH solution (0.25 g, 3.47 mmol, dissolved in 1.67 mL of deionized water). The light yellow solid turned into a dark green solution, and stirring was continued at room temperature for 30 minutes. A solution of 1,2-dideuteriopropane sultone in dioxane (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 system gradually changed from the initial black color to brown. After the reaction was completed, the light yellow solid was collected by filtration and then washed with ethanol (5 mL x 2) and acetone (5 mL x 2). The resulting solid was recrystallized from water and ethanol at 90°C and dried in vacuo to yield Compound 12 (0.55 g, 51%) as a light yellow solid. 1H 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.

[0198] Tetradeuterated dimethyl tetramer (0.32 g, 0.387 mmol) was dissolved in trifluoroacetic acid (2 mL). Acetic anhydride (2 mL) and tetradeuterated sodium 2,3-dimethyl-1,4-phenoxy-dipropylsulfonate (0.5 g, 1.16 mmol) were added sequentially. The mixture was then reacted in an oil bath at 50°C for 12 h. After completion of the reaction, 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 x 4) in a centrifuge tube until the supernatant was essentially colorless. The solid was transferred to a 50 mL eggplant flask to remove the solvent, and the resulting solid was recrystallized from ethanol and water. The solid was filtered, washed with a small amount of ethanol / water (4:1), and dried under vacuum to yield I-8 (0.323 g, 52%) as a white solid powder. 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.

[0199] Example 9: Synthesis of Compound I-9

[0200] The method described in Example 1 was followed, except that sodium 1,4-naphthyloxy-dipropyl alkanesulfonate was used instead of sodium 2,3-dimethyl-1,4-phenoxy-dipropyl alkanesulfonate.

[0201] Tetradeuterated dimethyl glycoluril tetramer (1.0 g, 1.26 mmol) was weighed and dissolved in trifluoroacetic acid (6 mL). Acetic anhydride (6 mL) and sodium 1,4-naphthyloxy-dipropyl alkanesulfonate (1.71 g, 3.50 mmol) were added sequentially and reacted at 50°C for 12 hours. After completion of the reaction, the reaction solution was added dropwise to rapidly stirred ethanol (200 mL). After stirring for half an hour, the mixture was centrifuged. The solid was washed with ethanol (30 mL x 5) in a centrifuge tube. After completion, the solid was dissolved in hot water (20 mL) and filtered. The filtrate was dried and the solid residue was recrystallized from ethanol and water. The crystals were allowed to stand in a refrigerator at 4°C overnight and then filtered. The filter cake was washed with ethanol-water (5 mL, 4:1 v / v) and recrystallized again from ethanol / water. The resulting white solid was dissolved in water (8 mL) and filtered. The filtrate was then evaporated at 70°C to remove water to obtain I-9 (0.98 g, 47%) as a white solid powder. 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.

[0202] Example 10: Synthesis of Compound I-10

[0203] The method described in Example 1 was followed, except that hexadeuterated diacetyl was used instead of non-deuterated diacetyl, and non-deuterated glycoluril dimer was used instead of deuterated dimer.

[0204] Weigh 23.3 g of urea, 0.388 mol, and dissolve it in 56 mL of 0.3 M hydrochloric acid. Add deuterated butanedione (prepared according to a literature method, 10.8 g, 0.117 mol) slowly dropwise with stirring. Stir at room temperature for 12 h. After the reaction, filter the solid, wash it with deionized water (10 mL x 2), and vacuum dry it to obtain a white hexadeuterated dimethyl glycoluril solid (19.8 g, 96%). 1 H NMR (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.

[0205] Hexadeuterated dimethyl glycoluril (10.0 g, 56.8 mmol) and paraformaldehyde (8.6 g, 286.7 mmol) were weighed into a 250 mL eggplant flask. 9 M hydrochloric acid (60 mL) was added and stirred at room temperature for 24 h. Deionized water (224 mL) was then added and stirring continued for 12 h. After the reaction, the mixture was filtered. The collected solid was washed with deionized water (50 mL × 3) and ethanol (50 mL × 3) and dried under vacuum to yield hexadeuterated dimethyl glycoluril-d6 as 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.

[0206] Glycoluril dimer (1.88 g, 6.10 mmol) was weighed and dissolved in methanesulfonic acid (11 mL) under ultrasonication. Dimethyl glycoluril diether-d6 (4.76 g, 18.3 mmol) was added to the system and reacted at 50°C with mechanical stirring for 5 h. After the reaction was completed and cooled to room temperature, the reaction solution was added dropwise to ice water (110 mL), resulting in the formation of a large white precipitate. The solution was centrifuged and washed with water in a centrifuge tube until neutral. The solid was redissolved in trifluoroacetic acid (6 mL) and cooled to 0°C. Water (30 mL) was then slowly added dropwise to the solution, resulting in a large white precipitate. The solution was centrifuged, washed with water until neutral, and lyophilized to obtain the dodeutero-substituted glycoluril tetramer as a white solid powder (1.98 g, 41%). 1 H NMR (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.

[0207] The dodeutero-substituted dimethyl tetramer (1.0 g, 1.26 mmol) was dissolved in trifluoroacetic acid (6 mL). Acetic anhydride (6 mL) and sodium 2,3-dimethyl-1,4-phenoxy-dipropylsulfonate (Compound 12, 1.6 g, 3.75 mmol) were added sequentially. The mixture was then allowed to react in an oil bath at 50°C for 12 h. After completion of the reaction, the reaction solution was added dropwise to ethanol (300 mL), stirred for 30 min, and then centrifuged. The solid was repeatedly washed with ethanol (10 mL x 4) in a centrifuge tube until the supernatant was essentially colorless. The solid was transferred to a 50 mL eggplant flask to remove the solvent, and the resulting solid was recrystallized from ethanol and water. The solid was filtered and washed with a small amount of ethanol / water mixture (4:1). After vacuum drying, compound I-10 (1.36 g, 67%) was obtained as a white solid powder. 1H 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). 13 C 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.

[0208] Example 11:

[0209] Compound I-7-4H was synthesized according to the method described in Example 7, except that non-deuterated glycoluril tetramer was used instead of tetradeuterated glycoluril tetramer.

[0210] To a 50 mL single-necked flask, dimethyl glycoluril tetramer (1.50 g, 1.79 mmol) and trifluoroacetic acid (7.0 mL) were added sequentially and stirred to dissolve. Acetic anhydride (7.0 mL) and sodium 2,3-propylene-1,4-phenoxy-dipropyl alkanesulfonate (2.35 g, 5.35 mmol) were then added sequentially and stirred to dissolve. The system was heated to 50°C and reacted for 12 hours. After the reaction system cooled, the reaction solution was added dropwise to 140 mL of ethanol. A light yellow solid precipitated and 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 in vacuo to yield I-7-4H (1.60 g, 59%) as a white powder. 1H NMR (400MHz, D2O): δ5.68(d,J=15.3Hz,2H),5.56(d,J=15.7Hz,4H),5.43(d,J=9.0Hz,2H ),5.35(d,J=9.0Hz,2H),5.18(d,J=15.9Hz,4H),4.31(dd,J=59.0,15.9Hz,8H),4.08(td, J=11.5,10.9,5.7Hz,6H),3.87(q,J=8.3,7.5Hz,4H),3.12(dd,J=20.4,14.4,7.2Hz,8H) ,2.47(d,J=19.8Hz,8H),2.16(s,8H),1.77(d,J=19.7Hz,12H),1.43(s,2H),1.31(s,2H). 13 C NMR (101MHz, D2O): δ156.71,156.19,148.31,138.21,128.65,78.70,77.66,71.8 8,71.51,71.16,52.93,48.52,48.12,36.08,30.36,25.58,25.03,16.80,15.71.

[0211] Example 12

[0212] Water Solubility Testing: Approximately 100 mg of the above deuterated compounds were weighed into a graduated capillary test tube and deionized water was gradually added until completely dissolved. The solubility was calculated based on the volume and expressed in mg / mL (see Table 1). As can be seen from the table, despite slight differences in solubility, 1-1, I-5, and I-7 exhibit high water solubility, meeting the solubility requirements for rapid bolus injection.

[0213] Table 1. Solubility of the compounds of the present invention (mg / mL)

[0214] Example 13

[0215] Evaluation of antagonistic muscle relaxant activity: Taking the reversal of neuromuscular blockade induced by cisatracurium besylate in SD rats by I-1, I-5, and I-7 as an example, the experimental process of reversal of neuromuscular blockade by deuterated diaryl glycoluril tetramer compounds in vivo is explained.

[0216] Specific Procedure: Sprague-Dawley rats weighing 170 to 240 grams were used as a biological model to test the reversal effect of I-5. Three male and three female rats were used in each experimental group (the same applies below). The neuromuscular blocking agent injection was prepared using normal saline as the solvent, and all injections were completed within 5 seconds. Rats were anesthetized with isoflurane at an induction dose of 5% and a maintenance dose of 1.5%. The hair on the right hind leg and surrounding area of ​​the rats was removed 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. A muscle relaxation monitor was used to test quadriceps neuromuscular blockade in the rats. The sensor was fixed to the rat's tibia and the electrode was fixed to the rat's right hind leg via a patch. Calibration was then performed using the Cal mode. After the data stabilized, the mode was switched to the Time of Flight (TOF) mode (train of four). If the TOF data was stable at ≥90, the next step of the experiment was performed. The rats were injected with atracurium besylate solution via the tail vein at a dose of 0.6 mg / kg and a timer was started. The TOF value was then recorded. After the TOF value decreased to 0, the rats were injected with I-5 injection, and the injection time was recorded. The TOF value was then recorded, and the time it took for the TOF value to recover to ≥90 was recorded as the reversal time of neuromuscular blockade.

[0217] The antagonistic effects of non-deuterated control compounds I-5-4H and I-7-4H on cisatracurium besylate and rocuronium bromide at the same dose are shown in Tables 2 and 3.

[0218] 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).

[0219] At a high dose of 150 mg / kg, the non-deuterated control compound I-1-4H reversed the TOF recovery time of 84 seconds for cisatracurium besylate, while I-1-4H reversed the TOF recovery time of rocuronium bromide at a dose of 30 mg / kg in excess of 300 seconds (Hoffmann et al., Anesthesiology 2013, 119, 317-325). Deuterated I-1 significantly enhanced the reversal activity of cisatracurium besylate and rocuronium bromide at relatively lower doses (80 mg / kg and 25 mg / kg), with TOF recovery times of 24 seconds and 208 seconds, respectively.

[0220] Deuterated I-7 showed significantly improved reversal activity against cis-atracurium besylate compared to I-7-4H, while also maintaining rapid reversal activity against rocuronium bromide. Deuterated I-5 also showed significantly improved reversal activity against cis-atracurium besylate, achieving rapid reversal against cis-atracurium besylate while maintaining rapid reversal activity against rocuronium bromide. Furthermore, the activity was higher than that of the non-deuterated sample at the same dose. Therefore, at the same dose, the antagonistic activity of I-5 was significantly superior to that of the non-deuterated I-5-4H.

[0221] Comparing the activities of the deuterated compounds, it was found that at the same dose, compound I-5 exhibited excellent antagonistic activity against both cisatracurium besylate and rocuronium bromide, with the highest antagonistic activity (see Tables 2 and 3).

[0222] When the dose of I-5 was 80 mg / kg, the average time for reversal of cisatracurium 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 for reversal of rocuronium bromide (see Table 3) and vecuronium bromide (Table 4) was 9 seconds and 20 seconds, respectively, indicating that I-5 can quickly and efficiently reverse the neuromuscular blockade induced by the above four muscle relaxants in vivo.

[0223] The above-mentioned in vivo antagonist activity experiments in rats confirmed that I-5 can achieve rapid reversal within 20 seconds. Compared with the commercially available reagent neostigmine (the experimental dose in rats was converted from the clinical maximum allowable dose), the efficiency of I-5 in reversing neuromuscular blockade induced by cisatracurium besylate, rocuronium bromide, vecuronium bromide, and pancuronium bromide was increased by 10 to 17 times, 18 times, 32 times, and 67 times, respectively; compared with the commercially available reagent sugammadex sodium, at the same dose, I-5 can rapidly reverse the neuromuscular blockade induced by cisatracurium besylate and pancuronium bromide, which is clinically irreversible with sugammadex sodium. Its activity in reversing neuromuscular blockade induced by rocuronium bromide and vecuronium bromide is also significantly higher than that of sugammadex sodium. The time for TOF to recover to 0.9 was shortened from 52 seconds and 18 seconds to 18 seconds and 9 seconds, respectively, equivalent to an increase in antagonist activity of approximately 1.9 times and 1.0 times.

[0224] As an example of a composition, at the same dose as deuterated I-5 (80 mg / kg), a combination of deuterated I-5 and non-deuterated I-5-4H (50% by mass each) also showed good antagonistic activity, with an antagonistic time of about 30 seconds (see Table 6).

[0225] The antagonism data of neostigmine and sugammadex sodium in the table are derived from the literature (Liu et al., Journal of Medicinal Chemistry, 2022, 65, 16893-16901). All doses are the maximum doses for rats converted from the clinical adult dose (1:6.25).

[0226] Table 2. Compounds IC (I-1, I-5, I-7) and IC-4H (I-5-4H, I-7-4H) antagonize the TOF→0.9 time of cisatracurium besylate at the same dose (80 mg / kg) as neostigmine (0.24 mg / kg).

[0227] Table 3. Compounds IC (I-1, I-5, I-7) and IC-4H (I-5-4H, I-7-4H) antagonize the TOF→0.9 time of rocuronium at the same dose as sugammadex (25 mg / kg) and neostigmine (0.24 mg / kg).

[0228] Table 4. Compound I-5 and sugammadex sodium at the same dose (25 mg / kg) and neostigmine (0.24 mg / kg) antagonized the TOF→0.9 time of vecuronium bromide.

[0229] Table 5. I-5 (80 mg / kg) and neostigmine (0.24 mg / kg) antagonize the TOF→0.9 time of pancuronium bromide

[0230] Table 6. Antagonism of the TOF→0.9 time of cisatracurium besylate by the combination of compounds I-5 and I-5-4H (80 mg / kg, 50% by mass for each).

[0231] Example 14

[0232] Blood pharmacokinetics and excretion: Deuterated diaryl glycoluril tetramer compounds exert their effects through blood injection. The present invention uses the half-life and excretion of compound I-5 in SD rats as an example to illustrate the pharmacokinetic process of deuterated diaryl glycoluril tetramer compounds in vivo.

[0233] The present invention uses SD rats (180-220 g) as an experimental model, with three males and three females. A deuterated diaryl glycoluril tetramer compound (80 mg / kg) is injected via the tail vein. Blood samples are collected within one hour via jugular vein blood sampling (total volume 0.4 mL, containing 0.05 mL of 3.8% sodium citrate), and urine is collected within 24 hours using a metabolic cage. The blood drug concentration analysis test process is as follows: blood is collected at 0 minutes, 1 minute, 5 minutes, 10 minutes, 20 minutes, 20 minutes, and 60 minutes, followed by centrifugation at 3000 rpm (4°C, 10 minutes) to collect the upper plasma layer. 0.25 mL of acetonitrile is added to the plasma, shaken to precipitate protein, and the supernatant is collected by centrifugation at 10,000 rpm (4°C) for 10 minutes. The supernatant is evaporated at room temperature to remove as much acetonitrile as possible.

[0234] Subsequently, deionized water was added to the volume to 0.5 mL, and the supernatant was collected again by centrifugation at 10,000 rpm (4°C, 10 minutes). The blood drug concentration at different times was analyzed and quantified by high-performance liquid chromatography. The drug excretion analysis test process is as follows: After tail vein injection of a deuterated diaryl glycoluril tetramer compound (80 mg / kg), the rats were placed in a metabolic cage and fed and watered normally. Urine was collected every 4 hours for 6-7 collections. The urine was centrifuged in an ultrafiltration centrifuge tube (10KD) to remove urine protein, and the excretion of the compound through urine over a 24-hour period was analyzed by high-performance liquid chromatography.

[0235] Experimental results showed that Compound I-5 had a plasma concentration half-life of 10 minutes in rats, indicating rapid elimination or clearance. Compound I-5 was primarily excreted unchanged in the urine, with over 70% excreted within 24 hours, indicating rapid excretion primarily through the kidneys.

[0236] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A deuterated diaryl glycoluril tetramer compound of formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in, Each Z is independently O, S, Se, Te, C1-C4 alkylene, -NH- or C1-C4 alkyl-substituted amino; Each M is independently Na + , K + , Li + Mg 2+ , Ca 2+ NH4 + , or one or more C1-C4 alkyl substituted ammonium salts; 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 independently is deuterium or hydrogen; R 9 , R 10 , R 11 and R 12 are each independently an undeuterated, partially deuterated or fully deuterated straight or branched C1-C20 alkyl group, or R 9 and R 10 , R 11 and R 12 The carbon atoms to which they are attached together form a non-deuterated, partially deuterated or fully deuterated group selected from the group consisting of a C3-C20 cycloalkyl group, a 3-20 membered heterocyclyl group, a C5-C20 aryl group or a 5-20 membered heteroaryl group; R 29 , R 30 , R 31 or R 32 Each is independently a non-deuterated, partially deuterated or fully deuterated group selected from the group consisting of a straight chain or branched C1-C20 alkylene group, a C3-C20 cycloalkylene group, a straight chain or branched 1-20 membered heteroalkylene group containing one or more heteroatoms selected from oxygen, sulfur or nitrogen, or a 3-20 membered heterocyclylene group containing one or more heteroatoms selected from oxygen, sulfur or nitrogen; R 33 , R 34 , R 35 and R 36 Each is independently deuterium, hydrogen, or a non-deuterated, partially deuterated or fully deuterated group selected from the group consisting of a linear or branched C1-C20 alkyl group, a C3-C20 cycloalkyl group, a linear or branched C1-C20 alkoxy group, a linear or branched C1-C20 alkylthio group, a linear or branched C1-C20 aldehyde group, a linear or branched C1-C20 ester group, a linear or branched C1-C20 alkyl group containing a carbonyl group, or R 33 With R 34 , R 35 With R 36 The carbon atoms to which they are attached together form a non-deuterated, partially deuterated or fully deuterated group selected from the group consisting of a C3-C20 saturated carbocyclic ring, a C3-C20 saturated spirocyclic ring, a ring containing one or more selected from oxygen, sulfur or nitrogen. a saturated 3-20-membered heterocyclic ring containing a heteroatom, a C5-C20 aromatic ring, or a 5-20-membered heteroaromatic ring containing one or more heteroatoms selected from oxygen, sulfur or nitrogen; 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 , R 21 , 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.

2. The compound according to claim 1, characterized in that In the compound, the ratio of deuterium atoms to the sum of deuterium atoms and hydrogen atoms (D / (D+H)) is ≥0.015% (natural deuterium isotope content); preferably, ≥10%; more preferably, ≥30%; more preferably, ≥75%; more preferably; ≥95%; and most preferably, ≥98%.

3. The compound according to claim 1, characterized in that Z is O, S, Se, Te, methylene, NH or amino substituted by C1-C4 alkyl; R 1 , R 2 , R 3 , R 4 Each independently represents H or D; R 5 , R 6 , R 7 and R 8 are each independently hydrogen; R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 Each is independently H or D.

4. The compound according to claim 1, characterized in that R 9 , R 10 , R 11 and R 12 are each independently an undeuterated, partially deuterated or fully deuterated straight or branched C1-C10 alkyl group, or R 9 and R 10 , R 11 and R 12 The carbon atom to which each is attached together forms a group selected from the group consisting of a C3-C10 cycloalkyl group, a 3-10 membered heterocyclyl group, a C6-C10 aryl group, or a 5-10 membered heteroaryl group; R 29 , R 30 , R 31 or R 32 Each is independently a non-deuterated, partially deuterated or fully deuterated group selected from the group consisting of a straight chain or branched C1-C10 alkylene group, a C3-C10 cycloalkylene group, a straight chain or branched 1-10 membered heteroalkylene group containing one or more heteroatoms selected from oxygen, sulfur or nitrogen, or a 3-10 membered heterocyclylene group containing one or more heteroatoms selected from oxygen, sulfur or nitrogen; R 33 , R 34 , R 35 and R 36 Each independently represents deuterium, hydrogen, or a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of a linear or branched C1-C10 alkyl group, a C3-C10 cycloalkyl group, a linear or branched C1-C10 alkoxy group, a linear or branched C1-C10 alkylthio group, a linear or branched C1-C10 aldehyde group, a linear or branched C1-C10 ester group, a linear or branched C1-C10 alkyl group containing a carbonyl group, or R 33 With R 34 , R 35 With R 36 The carbon atoms to which they are attached together form a non-deuterated, partially deuterated or fully deuterated group selected from the following group: a C3-C10 saturated carbocyclic ring, a C3-C10 saturated spirocyclic ring, a saturated 3-10 membered heterocyclic ring containing one or more heteroatoms selected from oxygen, sulfur or nitrogen, a C5-C10 aromatic ring, or a 5-10 membered heteroaromatic ring containing one or more heteroatoms selected from oxygen, sulfur or nitrogen.

5. The compound according to claim 1, characterized in that R 9 , R 10 , R 11 and R 12 are each independently an undeuterated, partially deuterated or fully deuterated straight or branched C1-C7 alkyl group, or R 9 and R 10 , R 11 and R 12 The carbon atoms to which they are attached together form a C3-C7 cycloalkyl group, a 3-7 membered heterocyclyl group, a C6-C8 aryl group or a 5-7 membered heteroaryl group; R 29 , R 30 , R 31 or R 32 Each is independently a non-deuterated, partially deuterated or fully deuterated group selected from the group consisting of a straight chain or branched C1-C6 alkylene group, a straight chain or branched 1-6 membered heteroalkylene group containing one or more heteroatoms selected from oxygen, sulfur or nitrogen; R 33 , R 34 , R 35 and R 36 are each independently deuterium, hydrogen, or a non-deuterated, partially deuterated, or fully deuterated group selected from the group consisting of a straight or branched C1-C6 alkyl group, a C3-C7 cycloalkyl group, or R 33 With R 34 , R 35 With R 36 The carbon atoms to which they are attached together form a non-deuterated, partially deuterated or fully deuterated group selected from the group consisting of a C3-C7 saturated carbon ring or a benzene ring.

6. The compound according to claim 1, characterized in that R 9 , R 10 , R 11 and R 12 are each independently an undeuterated, partially deuterated or fully deuterated straight or branched C1-C4 alkyl group, or R 9 and R 10 , R 11 and R 12 The carbon atoms to which they are attached together form a C5-C7 cycloalkyl group; R 29 , R 30 , R 31 or R 32 Each is independently a non-deuterated, partially deuterated or fully deuterated group selected from the group consisting of a straight chain or branched C1-C4 alkylene group, a straight chain or branched 1-4 membered heteroalkylene group containing one or more heteroatoms selected from oxygen, sulfur or nitrogen; R 33 , R 34 , R 35 and R 36 are each independently deuterium, hydrogen, CD3 or CH3, or R 33 With R 3 , R 35 With R 36 The carbon atoms to which they are attached together form a five-membered carbon ring or a benzene ring.

7. The compound according to claim 1, characterized in that The compound contains at least 1 deuterium atom; 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.

8. The compound according to claim 1, characterized in that R 33 , R 34 , R 35 and R 36 are each independently deuterium, hydrogen, CD3 or CH3, or R 33 With R 3 , R 35 With R 36 The carbon atoms to which they are attached together form a five-membered carbon ring or a benzene ring.

9. The compound according to claim 1, characterized in that The compound is selected from the following group:

10. The compound according to claim 1, characterized in that The compound is 11. A pharmaceutical composition, characterized in that include: (a) the compound according to claim 1 as an active ingredient, or a pharmaceutically acceptable salt, hydrate or solvate thereof; (b) a pharmaceutically acceptable carrier.

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

13. A pharmaceutical composition, characterized in that The composition comprises: (a) as the first active ingredient, a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof; (b) a non-deuterated aryl tetramer compound having the structure shown in claim 1 as a second active ingredient; and (c) a pharmaceutically acceptable carrier or excipient.

14. A kit, characterized in that: include: (a) a first container, and the compound of claim 1 as an active ingredient, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition of claim 10, located in the first container; and / or (b) a second container, and a muscle relaxant in the second container; the muscle relaxant is selected from the group consisting of steroidal quaternary ammonium salts, tetrahydroisoquinoline quaternary ammonium salts, benzylisoquinoline derivatives, or a combination thereof; and / or (c) an nth container, and an nth pharmaceutical ingredient in the nth container, wherein n is any positive integer from 3 to 30; wherein the nth pharmaceutical ingredient is selected from the compound of claim 1; and / or (4) Optional instruction manual.

15. The compound according to claim 1, or the pharmaceutical composition according to claim 11, or the use of the pharmaceutical composition according to claim 12, characterized in that: Used to antagonize muscle relaxants.

Images