Deuterated diaryl glycoluril tetramer compound and application thereof

Abstract

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

Description

Technical Field

[0001] The invention belongs to the field of medicine, and in particular relates to a deuterated diaryl glycoluril tetramer compound or a composition thereof which can antagonize multiple muscle relaxants. 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. Every year, more than 400 million patients worldwide receive muscle relaxant medication during anesthesia in operating rooms and intensive care units. Among them, non-depolarizing muscle relaxants, such as ammonium steroids such as rocuronium, vecuronium and pancuronium and benzylisoquinoline-based cisatracurium besylate, have fewer side effects than depolarizing muscle relaxants and are more widely used in clinical practice. The medium-acting muscle relaxant cisatracurium besylate accounts for about 30% of the global neuromuscular blocker market and about 70% of the domestic market due to its advantages of rapid onset, strong effect, fast recovery speed, no histamine release, small cardiovascular side effects, no accumulation in the body, non-toxic metabolites and no muscle relaxant effect, and no dependence on renal excretion. In addition, rocuronium and vecuronium, which are medium-acting muscle relaxants like cisatracurium besylate, account for about 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, which can cause death in severe cases. Therefore, rapid and efficient antagonism of residual excess muscle relaxants is of great clinical significance, which is not only conducive to reducing the postoperative risks of patients, but also conducive to early extubation and rehabilitation of patients, accelerating operating room turnover, and reducing surgical costs.

[0003] A prospective, multicenter, single-blind observational study published in 2016 in my country found that the total 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 the direct capture principle 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. The antagonistic efficiency of neostigmine 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. Through its specific binding to the hydrophobic inner cavity of γ-cyclodextrin, it can quickly reverse the muscle relaxant activity of rocuronium and vecuronium. However, sugammadex sodium cannot antagonize cisatracurium besylate and pancuronium bromide. Cisatracurium besylate is widely used in clinical practice and is the muscle relaxant with the highest clinical usage 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 clinically as a long-acting muscle relaxant. Therefore, there is an important and urgent unmet clinical need to develop antagonists that rapidly antagonize cisatracurium besylate and pancuronium, or broad-spectrum, rapid-acting antagonists for all of 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 against muscle relaxants and biosafety, but these cucurbit[8]uril derivatives are mixtures with uncertain composition and low drugability. Xue et al. reported that columnar[6]arene sulfonates have high binding capacity for cis-atracurium besylate, but their actual antagonistic activity is unknown, and the synthetic yield of columnar[6]arene is low, and the separation of these sulfonates requires complex gel chromatography technology. Therefore, although the development of broad-spectrum antagonists that can rapidly reverse muscle relaxants is clinically beneficial, it is very challenging to discover new drugable compounds with rapid antagonistic activity and high biosafety.

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

[0006] 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, vecuronium, pancuronium), tetrahydroisoquinoline quaternary ammonium salts (cis-atracurium besylate), muscle relaxants and the like, and uses thereof.

[0007] In a first aspect of the present invention, there is provided a deuterated diaryl glycoluril tetramer compound as shown in Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0008]

[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 is deuterium or hydrogen;

[0013] 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 R10 , 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;

[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 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 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;

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

[0017] In another preferred embodiment, Z is 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 Each is 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 8are 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 Each is 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 , R20 , 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 Each is 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 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 straight or branched C1-C10 alkyl group, or R9 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.

[0032] In another preferred embodiment, 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.

[0033] In another preferred embodiment, 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 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 or branched C1-C4 alkyl group.

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

[0036] In another preferred embodiment, R 29 , R 30 , R 31 or R 32Each 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.

[0037] In another preferred embodiment, 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 alkyl group, and a straight chain 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 a non-deuterated, partially deuterated or fully deuterated group 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 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.

[0041] In another preferred embodiment, 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-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 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-C7 saturated carbocyclic ring, a C3-C7 saturated spirocyclic ring, a saturated 3-7 membered heterocyclic ring 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 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.

[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 36are 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.

[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%; 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]

[0050]

[0051]

[0052] In another preferred embodiment, the compound is

[0053] The second aspect of the present invention provides a pharmaceutical composition comprising: (a) as an active ingredient, the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable carrier.

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

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

[0056] 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.

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

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

[0059] (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;

[0060] (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

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

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

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

[0064] (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;

[0065] (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

[0066] (c) a pharmaceutically acceptable carrier or excipient.

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

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

[0069]

[0070] wherein each Z is independently O, S, Se, Te, C1-C4 alkylene, -NH- or C1-C4 alkyl-substituted amino;

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

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

[0073] 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 The carbon atoms to which they are attached together form 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;

[0074] 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;

[0075] R 33 , R 34 , R 35 and R 36are each independently hydrogen, or a non-deuterated group selected from the group consisting of a straight chain or branched C1-C20 alkyl group, a C3-C20 cycloalkyl group, a straight chain or branched C1-C20 alkoxy group, a straight chain or branched C1-C20 alkylthio group, a straight chain or branched C1-C20 aldehyde group, a straight chain or branched C1-C20 ester group, a straight chain 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 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.

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

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

[0078] (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

[0079] (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

[0080] (4) Optional instruction manual.

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

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

[0083] 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.

[0084] In the sixth aspect of the present invention, there is provided the 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.

[0085] 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.

[0086] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0087] 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 steroidal quaternary ammonium salts (rocuronium, vecuronium, pancuronium), tetrahydroisoquinoline quaternary ammonium salts (cis-atracurium besylate) muscle relaxants, etc., and the compounds also have high water solubility and high biosafety. At the same dose, compared with non-deuterated control molecules and sugammadex sodium, the deuterated compounds of the present invention have significantly enhanced antagonistic activity. On this basis, the inventors have completed the present invention.

[0088] definition

[0089] 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.

[0090] As used herein, when used in reference to a specific recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0091] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0092] Deuterium is a stable isotope of hydrogen. CD bonds are more stable than CH bonds, so CD bonds are less likely to break than CH bonds, and their half-life may be extended. The acidity and hydrophobicity of CD bonds are different from those of CH bonds. Their accumulation, clustering or aggregation driven by hydrophobic effects in the body, and the stability and selectivity of binding to living substances may all be different. The metabolic process of living systems is complex, and the metabolism and excretion dynamics of deuterated molecules in living bodies are affected by many factors, and are expected to show corresponding complexity. Therefore, compared with non-deuterated molecules, the biological activity of deuterated molecules shows great randomness and unpredictability, and deuteration at many sites will reduce or degrade the biological activity of molecules. In addition, hydrogen at certain positions of organic molecules is not easy or difficult to be deuterated due to limitations of the synthesis method. Therefore, the deuteration of organic molecules is not arbitrary, the sites that can be deuterated are unpredictable, and their biological activity is also unpredictable.

[0093] As used herein, "C1-C20 alkyl" refers to a straight or branched alkyl group including 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc., or the like.

[0094] As used herein, "1-20 membered heteroalkyl" refers to a C 1-20 One or more carbon atoms in the alkyl chain are substituted by heteroatoms selected from nitrogen, oxygen and sulfur. For example, a 1-8 membered heteroalkyl group refers to CH3-CH2-CH2-CH2-O-CH2-CH2-CH2-, or CH3-CH2-CH2-CH2-O-CH2-CH2-O- and the like.

[0095] 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.

[0096] 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.

[0097] 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).

[0098] As used herein, "C3-C20 cycloalkyl" refers to a cycloalkyl group containing 3 to 20 carbon atoms or a cycloalkyl group having a side chain, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0099] As used herein, "deuterated" refers to one or more hydrogens in a compound or group being replaced by deuterium. Deuterated can be monosubstituted, disubstituted, polysubstituted or fully substituted. The term "one or more deuterated" and "one or more deuterated" can be used interchangeably.

[0100] 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%).

[0101] 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.

[0102] As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.

[0103] 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.

[0104] As used herein, the term "aryl" refers to a monovalent aromatic carbocyclic group of 6 to 20 (preferably 6-14) carbon atoms, which has a single ring (such as phenyl) or a condensed ring (such as naphthyl or anthracenyl). If the point of attachment is on the aromatic carbon atom, the condensed ring may be non-aromatic (such as 2-benzoxazolone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, etc.). Preferred aryl groups include phenyl and naphthyl.

[0105] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having 3 to 12 (preferably 3 to 10) carbon atoms, having a single ring or multiple rings (including fused systems, bridged ring systems and spiro ring systems). In a fused ring system, one or more rings may be cycloalkyl, heterocyclic, aryl or heteroaryl, as long as the point of attachment is through the cycloalkyl ring. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl.

[0106] As used herein, the term "heteroaryl" refers to an aromatic group having 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring, such heteroaryl groups may be monocyclic (such as pyridyl or furanyl) or fused rings (such as indolizinyl or benzothienyl), wherein the fused ring may be non-aromatic and / or contain one heteroatom, as long as the point of attachment is through the atom of the aromatic heteroaryl. In one embodiment, the ring atoms nitrogen and / or sulfur of the heteroaryl are optionally oxidized to N-oxide (NO), sulfinyl or sulfonyl. Preferably, heteroaryl groups include pyridyl, pyrrolyl, indolyl, thienyl and furanyl. In one embodiment, heteroaryl refers to 3-14 membered heteroaryl, preferably 5-12 membered heteroaryl.

[0107] 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.

[0108] The animal activity test and acute toxicity test in the present invention are carried out using SD rats.

[0109] As used herein, unless otherwise specified, the substitution refers to the substitution of hydrogen on the group by one or more groups selected from the group consisting of halogen, nitro, amine, cyano, hydroxyl, amide, trifluoromethyl, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclic group, C 1-6 Alkoxycarbonyl.

[0110] 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.

[0111] 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 in the prior art, and there is no particular restriction on the reaction parameters of each step. In addition, the typical compound of the present invention can be obtained by commercial means.

[0112] As used herein, "quiver toxicity" refers to the symptom that a patient cannot recover spontaneous breathing due to neuromuscular blockade caused by residual muscle relaxants after surgery. Because the symptoms are like the use of quiver alkaloids, it is called "quiver toxicity".

[0113] The animal activity test and acute toxicity test in the present invention are carried out using SD rats.

[0114] Neuromuscular blockers or muscle relaxants

[0115] Neuromuscular blockers or muscle relaxants (abbreviated as muscle relaxants) are widely used in clinical practice to relax skeletal muscles, which is conducive to intubation and improves surgical conditions. According to different mechanisms of action, muscle relaxants are divided into depolarizing and non-depolarizing types: depolarizing muscle relaxants bind to the N2 choline receptors on the motor nerve end plate membrane, weakening or eliminating the response of muscle cells to acetylcholine; non-depolarizing muscle relaxants compete with acetylcholine for the N2 choline receptors on the motor end plate membrane of skeletal muscle, leading to skeletal muscle relaxation. The non-depolarizing muscle relaxants used more frequently in clinical practice are divided into aminosteroid derivatives (such as rocuronium, vecuronium and pancuronium) and benzylisoquinoline derivatives (such as cisatracurium besylate) according to their different chemical structures.

[0116] Muscle relaxant antagonists: deuterated diaryl glycoluril tetramers

[0117] The present invention provides a deuterated diaryl glycoluril tetramer having a structure shown in formula I.

[0118]

[0119] 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.

[0120] 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.

[0121] The deuterated diaryl glycoluril tetramer described in the present invention has anionic sulfonate side chains introduced at both ends, and the electrostatic interaction thereof can exert a synergistic effect with the hydrophobic effect of the tetramer "C" conformation, thereby quickly and efficiently binding to the muscle relaxant and thereby antagonizing its muscle relaxant activity.

[0122] In the present invention, deuterated diaryl glycoluril tetramers are used as broad-spectrum muscle relaxant antagonists. Rat experiments support that this application can achieve rapid antagonism of cisatracurium besylate and rocuronium bromide, and can also quickly antagonize vecuronium bromide and panvecuronium bromide muscle relaxants. Such deuterated compounds can have high water solubility and high biosafety, and have significant clinical practicality.

[0123] Control experiments support that this type of new deuterated compound can achieve faster antagonism against rocuronium and vecuronium than the clinically used drug sugammadex sodium. Control experiments with non-deuterated compounds support that this type of deuterated compound has significantly improved antagonistic activity against cis-atracurium 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 cis-atracurium besylate and pancuronium. Control experiments support that this type of new deuterated compound can achieve faster antagonism against rocuronium and vecuronium than the clinically used drug sugammadex sodium. This type of deuterated compound can have high water solubility and high biosafety, and has significant clinical practicality.

[0124] Preparation method

[0125] The preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be prepared conveniently by combining various synthetic methods described in this specification or known in the art, and such combination can be easily carried out by a technician in the field to which the present invention belongs.

[0126] 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.

[0127] The preparation of the deuterated diaryl glycoluril tetramer and the corresponding raw materials in the present invention is mostly carried out under acidic conditions, at room temperature to reflux temperature (such as 0 to 100° C., preferably 0 to 60° C.). The reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours. The following general preparation route can be used to synthesize the compound of the formula (I) structure of the present invention:

[0128]

[0129] Synthesis route 1: wherein Z is O, S, Se, Te, methylene, amino and substituted amino;

[0130] 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.

[0131] As shown in the first synthetic route, the compounds of the present invention are synthesized in a convergent manner. (a) First, a diketone compound A with different substituents undergoes a cyclocondensation reaction with urea to generate a glycoluril compound B with different substituents. Subsequently, a further cyclocondensation reaction occurs with paraformaldehyde or deuterated paraformaldehyde C to obtain a glycoluril dimer D and a tetracyclic glycoluril diether structure E, respectively. D and E undergo a further condensation reaction to obtain a tetramer F with different substituents; (b) an aryl compound G with different substituents undergoes a nucleophilic substitution reaction with propane sultone H to generate a non-deuterated aryl sulfonate I or J, and I further undergoes a deuteration reaction to obtain a deuterated aryl sulfonate J; (c) finally, the non-deuterated or deuterated aryl sulfonate J converges with the tetramer F to generate the compound (I) of the present invention through an electrophilic substitution reaction.

[0132] 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.

[0133] Deuterated or non-deuterated dimer intermediates;

[0134] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 each independently is deuterium or hydrogen;

[0135] Furthermore, the structure of the deuterated or non-deuterated dimer intermediate is as follows:

[0136]

[0137] Deuterated or non-deuterated tetramers;

[0138] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 and R 28 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 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;

[0139] Furthermore, the structure of the deuterated or non-deuterated tetramer intermediate is as follows:

[0140]

[0141] Deuterated or non-deuterated sulfonate intermediates;

[0142] In the formula, Z is O, S, Se, Te, methylene, amino or substituted amino; M is Na + ;

[0143] 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 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;

[0144] 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 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 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, or a C3-C20 aromatic ring;

[0145] Furthermore, the sulfonate intermediate is selected from the following group:

[0146]

[0147] Pharmaceutical composition

[0148] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0149] 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.

[0150] As used herein, the term "pharmaceutically acceptable salt" refers to non-toxic acid or alkaline earth metal salts of compounds of Formula I. These salts can be prepared in situ during the final isolation and purification of the compounds of Formula I, or by reacting a suitable organic or inorganic acid or base with a basic or acidic functional group, respectively. Representative salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, gluconate heptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthylsulfonate, oxalate, pamoate, pectinate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, and undecanoate. In addition, nitrogen-containing basic groups can be quaternized by the following reagents: alkyl halides, such as chlorides, bromides and iodides of methyl, ethyl, propyl, butyl; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates; long-chain halides such as chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl; aralkyl halides such as benzyl and phenethyl bromides, etc. Water-soluble or oil-soluble or dispersible products are thus obtained. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, citric acid. Base addition salts can be prepared in situ during the final isolation and purification of the compound of formula I, or by reacting the carboxylic acid portion with a suitable base (such as a pharmaceutically acceptable metal cation hydroxide, carbonate or bicarbonate) or ammonia, or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, salts based on alkali and alkaline earth metal cations, such as sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, and non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0151] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0152] Suitable pharmaceutically acceptable carriers or excipients include: such as treating agents and drug delivery modifiers and promoters, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting point wax, ion exchange resins, etc., and any combination of two or more thereof. Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils, including petroleum, animal oil, vegetable oil or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly carriers for injectable solutions, include water, saline, aqueous glucose solutions and ethylene glycol. Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[0153] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0154] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0155] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0156] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0157] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0158] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0159] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0160] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0161] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0162] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0163] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0164] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0165] Compared with the prior art, the main advantages of the present invention include:

[0166] (1) Controlled trials support that, compared with the clinically used antagonist neostigmine, the preferred examples of the compounds of the present invention can antagonize the benzylisoquinoline muscle relaxant cisatracurium besylate and the aminosteroid muscle relaxants pancuronium, rocuronium and vecuronium more quickly.

[0167] (2) Control experiments support that, compared with the clinically used antagonist sugammadex sodium, the preferred examples of the compounds of the present invention can antagonize the aminosteroidal muscle relaxants rocuronium and vecuronium more quickly. The preferred examples of the compounds of the present invention can quickly antagonize the benzylisoquinoline muscle relaxant cisatracurium besylate and the aminosteroidal muscle relaxant pancuronium, while sugammadex sodium cannot antagonize these two types of muscle relaxants.

[0168] (3) Control experiments support 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 biological safety.

[0169] (4) Control experiments show that, compared with the previously disclosed non-deuterated dimethyl-substituted dibenzoglycoluril tetramer, the deuterated compounds of the present invention have significantly improved antagonistic activities against both cisatracurium besylate and rocuronium bromide.

[0170] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0171] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0172] Example 1: Synthesis of Compound I-5

[0173]

[0174] Under rapid mechanical stirring, hydrochloric acid (8M, 80mL) was added to a 500mL two-necked bottle, and glycoluril (compound 4, 49.3g, 0.36mol) was added in batches, and the oil bath temperature was controlled to 50°C. Subsequently, a deuterated polyformaldehyde 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 bottle; the solid was dispersed with 8M hydrochloric acid (2mL) and deionized water (2mL) was added to make a 4M solution, shaken and centrifuged, and the upper yellow clear liquid was transferred to the above two-necked bottle, and the reaction was continued at 50°C for 48 hours after merging. Subsequently, the operation of "centrifugation-washing with 4M hydrochloric acid-transferring and combining the supernatant" was repeated 3 times, and finally the solids were combined and dispersed with deionized water and centrifuged, and the operation of "washing with deionized water-centrifugation" was repeated 4 times until the pH value of the supernatant was close to neutral. White compound 8 (20.1 g, 37%) was obtained. 1H NMR (400MHz, DMSO-d6): δ7.64 (s, 4H), 5.36 (d, J=8.6Hz, 2H), 5.23 (d, J=8.7Hz, 2H). 13C NMR (101MHz, DMSO-d6): δ158.38, 74.46, 60.63. HRMS (ESI): calcd for [M+H]+, 313.1306, found 313.1306.

[0175] Add methylsulfonic acid (50 mL) to a 250 mL three-necked flask, raise the oil bath temperature to 50 ° C, then add solid compound 8 (10.0 g, 32.0 mmol) in batches, and use mechanical stirring until the system is clear. Then add solid compound 7 (24.4 g, 96.1 mmol) in batches and react at 50 ° C for 5 hours under mechanical stirring. After the reaction is completed, cool to room temperature, and add the reaction solution dropwise to water (500 mL) to produce a large amount of white precipitate. After centrifugation, collect the lower layer of solid, wash with deionized water (200 mL 5) until neutral, transfer to an eggplant-shaped bottle, and obtain white solid compound 9 (15.0 g, 60%) after vacuum drying. 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.

[0176]

[0177] Weigh the dimer compound 9 (15.5 g, 19.8 mmol) and dissolve it in trifluoroacetic acid (75 mL), add acetic anhydride (75 mL) and sodium 2,3-dimethyl-1,4-propane sulfonate (compound 12, 23.6 g, 59.3 mmol) in turn, and react at 50 ° C for 12 hours. After the reaction, the reaction solution was added dropwise to the rapidly stirred ethanol (1.3 L), stirred for half an hour and then centrifuged. The solid was washed with ethanol (30 mL × 5) in a centrifuge tube. After the reaction, the solid was dissolved in water (20 mL), filtered, and the solid residue after the filtrate was dried 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 aqueous solution (5 mL, 4: 1 v / v), and the obtained white solid was dissolved in water (6 mL) and filtered. The filtrate was evaporated at 70 ° C to remove water, and the white solid compound I-5 (19.1 g, 60%) was obtained after vacuum drying. 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.

[0178] Example 2: Synthesis of Compound I-1

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

[0180] Weigh tetradeuterated dimethyl glycoluril tetramer (1.0 g, 1.26 mmol) and dissolve it in trifluoroacetic acid (6 mL), add acetic anhydride (6 mL), 1,4-phenoxy-dipropyl alkane sulfonate sodium (1.52 g, 3.82 mmol) in sequence, and react at 50 ° C for 12 hours. After the reaction is completed, the reaction solution is added dropwise to rapidly stirred ethanol (200 mL), stirred for half an hour and then centrifuged. The solid is washed with ethanol in a centrifuge tube (30 mL×5) and centrifuged. The solid is then dissolved in water (20 mL), filtered, and the solid residue after the filtrate is dried is recrystallized with ethanol and water. The crystals are allowed to stand in a refrigerator at 4 ° C overnight and then filtered. The filter cake is washed with ethanol aqueous solution (5 mL, 4:1 v / v) and then recrystallized again with ethanol / water. The obtained white solid is dissolved in water (8 mL) and filtered. The filtrate is evaporated at 70 ° C to remove water and then vacuum dried to obtain white solid I-1 (1.1 g, 56%). 1H NMR (400MHz, D2O): δ6.78 (s, 4H), 5.56 (d, J = 15.4Hz, 4H), 5.46 -5.38(m,4H),5.34(d,J=16.1Hz,4H),4.26(d,J=15.3Hz,8H),4.03-3.95(m,4H),3.9 2-3.84(m,4H),3.19-3.06(m,8H),2.18(d,J=6.2Hz,8H),1.77(d,J=15.6Hz,12H).13C NMR (101MHz, D2O): δ156.75,156.43,150.12,127.78,114.94,78.88,77.69,71.16,71.01,68.69,48.48,48.21,35.26,24.68,16.46,15.38. HRMS(ESI):Calcdfor[M+2Na]2+:795.1394,Found:795.1382.

[0181] Example 3: Synthesis of Compound I-2

[0182] 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 alkane sulfonate.

[0183]

[0184] Weigh the compound 4,7-dihydroxy-1-indanone (synthesized according to the literature method, 820.0 mg 5 mmol) into a 50 ml single-mouth bottle, dissolve 500.9 mg (12.5 mmol) of NaOH in 10.0 ml of H2O, add it to the system under stirring, the brown solid turns into a dark green liquid, and stir at room temperature for 30 min. Dissolve 1.8330 g (15 mmol) of 1,3-propane sultone in 20.0 ml of 1,4-dioxane and add it to the system under stirring. React overnight at room temperature, and the raw materials react completely. Concentrate the reaction solution and add it dropwise to 100 ml of EtOH, a brown precipitate is precipitated, and centrifuge to obtain a brown solid on the surface of the black solid. The obtained solid is washed twice with 60 mL of EtOH. The solid crude product is recrystallized with EtOH / H2O at 90 ° C to obtain a light brown solid powder 3-2 (701.2 mg, 31%). 1H NMR(400MHz,D2O)δ7.26(d,J=8.8Hz,1H),6.92(d,J=9.2Hz,1H),4.19(m,J=6.4,14.4Hz,4H),3.0 7(q,J=8.0Hz,4H),3.01(t,J=5.6Hz,2H),2.69(t,J=5.6Hz,2H),2.21(m,J=12.0,6.0Hz,4H).13C NMR(101MHz, 298K): δ207.12,148.26,146.51,144.58,122.45,117.68,108.69,64.93,64.64,45.76,45.67,34.28,22.28,21.90,19.75. HRMS(ESI):cacld for[M-Na]-,429.0295; found,429.0323.

[0185] Weigh sodium benzocyclopentanone sulfonate (452.2 mg, 1.0 mmol) in a 25 ml single-mouth bottle, add 2 ml of deuterated water to potassium carbonate (13.8 mg, 0.1 mmol), and heat under reflux for 4 h. After the reaction is completed, pour the reaction system into 20 ml of ethanol, and a precipitate is generated. Centrifuge and dry to obtain light brown deuterated sodium benzocyclopentanone sulfonate (439.5 mg, 97%). 1H NMR (400 MHz, D2O) δ7.17 (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.

[0186] Add deuterated sodium benzocyclopentane sulfonate (454.2 mg, 1.0 mmol) to a 50 mL single-mouth bottle, then add (1.14 g, 10 mmol) TFA, the solution turns orange-red, and stir at room temperature for 15 min. Slowly drop HSiEt3 (288.15 mg, 2.5 mmol) into the above system. React for 4 h. After the reaction is completed, the reaction system is distilled under reduced pressure to remove the unreacted TFA and HSiEt3. The obtained solid crude product is recrystallized using water and ethanol. The white powder solid product deuterated sodium benzocyclopentane sulfonate 3-4 (396.4 mg, 90%) is obtained. 1H NMR(400MHz,D2O)δ6.80(s,1H),4.09(t,J=6.0Hz,4H),3.03(m,J=5.6,8.0Hz,4H),2.8(s,2H),2.12(m,J=6.0,14.0Hz,4H).M / Z=197.0368.13C NMR (101MHz, D2O, 298K) δ149.24,134.91,112.46,67.88,47.98,29.42,29.33,24.45. HRMS(ESI)calcd:[M-2Na]2-,197.0368, found 197.0402; [M-2Na+H]-,395.0809, found395.0806.

[0187]

[0188] Methyl tetramer (189.0 mg, 0.25 mmol) and TFA / Ac2O mixed solvent (2 mL / 2 mL) were added to a 25 mL single-mouth 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 ethanol that was stirred rapidly. A precipitate was precipitated and the crude product was obtained by centrifugation. The crude product was recrystallized at 70°C with a mixed solvent of EtOH / and H2O to obtain the target product I-2 (80.2 mg, 19.5%) as a white powder solid. 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.

[0189] Example 4: Synthesis of Compound I-3

[0190] 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 alkane sulfonate.

[0191]

[0192] 2,5-dihydroxytoluene (29.79 g, 10 mmol) was added to a 2L reaction bottle, followed by NaOH solution (36.92 g, 38.5 mmol, dissolved in 370 mL of deionized water), and the light yellow solid turned into a dark green solution. Stirring was continued 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 precipitation 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 suction filtration and then washed with ethanol (50 mL 2) and acetone (50 mL 2) in turn. The obtained solid was recrystallized with water and ethanol at 90 ° C, and after vacuum drying, a light yellow solid compound 4-2 (64.29 g, 73%) was obtained. 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.

[0193]

[0194] Add methyl tetramer (1.0g, 1.275mmol) to a 50ml single-mouth bottle, add 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, stir to dissolve. Heat the system to 50°C and react for 12 hours. After the reaction is completed, add the reaction solution dropwise to 80ml ethanol, and a brown solid precipitates. After centrifugation, wash the lower precipitate twice with 100ml ethanol, reflux MeOH for 3h, and then filter hot. Take the filter cake and diffuse and purify it with a water / acetone and tetrahydrofuran system to obtain a white solid product I-3 (200.8mg, 10%). 1H NMR(400MHz,D2O)δ6.80(d,J=9.6Hz,2H),5.60(d,J=15.7Hz,4H),5.46(d,J=9.0Hz,2H),5.41(d,J=9.0Hz,2H),5 .35(dd,J=16.3,9.5Hz,2H),5.21(d,J=5.8Hz,1H),5.17(d,J=5.8Hz,1H),4.37(s,1H),4.34(s,1H),4.28(s,2H), 4.24(s,3H),4.21(s,1H),4.17(t,J=8.4Hz,4H),4.04(d,J=5.4Hz,3H),3.94(s,2H),3.22–3.11(m,8H),2.29–2. 20(m,8H),2.15(s,6H),1.82(s,6H),1.77(s,6H).HRMS(ESI):Calcd:[M–4Na+2H]2-,741.1947,Found:741.1881.

[0195] Example 5: Synthesis of Compound I-4

[0196] 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 alkane sulfonate.

[0197]

[0198] Weigh 10g NaH and slowly add it to 50mL heavy water, stirring continuously. After the reaction is completed, add anhydrous Na2SO4 dried n-hexane, extract the residual paraffin oil, separate the liquid three times, and prepare a sodium deuteride solution. Add dimethylphenoxy disulfonate (0.85g, 2.0mmol) and NaOD (100mL) to the autoclave, seal it and place it in an oil bath at 190℃, stir and react for 20h. After the reaction is completed, cool it to room temperature, filter and collect the solid, wash it with ethanol (2mL 2), and the obtained solid is vacuum dried to obtain a white solid 5-2 (0.71g, yield 81%, deuteration rate 98%). 1H NMR (400MHz, D2O): δ4.05 (t, J=6.4Hz, 4H), 2.15 (t, J=6.4Hz, 4H).

[0199]

[0200] Weigh the tetradeuterated dimethyl tetramer (0.418 g, 0.5 mmol) and dissolve it in trifluoroacetic acid (2 mL). Then add acetic anhydride (2 mL) and 20-deuterated 2,3-dimethyl-1,4-phenoxy-dipropyl sulfonate sodium (0.65 g, 1.5 mmol) in turn, and then set the oil bath temperature to 50 ° C for 12 hours. After the reaction is completed, the reaction solution is added dropwise to ethanol (30 mL), stirred for 30 minutes, and then centrifuged. The solid is repeatedly washed with ethanol in a centrifuge tube (3 mL × 4) until the supernatant is basically colorless. The solid is transferred to a 50 mL eggplant flask to remove the solvent, and the obtained solid is recrystallized using ethanol and water. Filter, wash the solid with a small amount of ethanol / water mixed solution (4:1), and vacuum dry to obtain a white solid powder I-4 (0.398 g, 49%). 1H NMR (400MHz, D2O): δ5.64(d,J=15.4Hz,2H),5.54(d,J=16Hz,4H),5.42(d,J=9.2Hz,4H),5.35(d,J=9.2Hz,4H),5.13(d,J=16Hz ,4H),4.34(d,J=16Hz,4H),4.24(d,J=16Hz,4H),4.07(d,J=15.2Hz,2H),3.91(s,4H),3.70(s,4H),2.17(s,4H),1.74(d,12H). HRMS(ESI):Calcd:[M–4Na+2NH4]2-,780.2871, Found:780.4344.

[0201] Example 6: Synthesis of Compound I-6

[0202] 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 alkane sulfonate.

[0203]

[0204] Add magnetron, propenyl-1,3-sultone (310.0 mg, 2.5 mmol) to a 100 ml thick-walled pressure-resistant tube, add 50.0 ml of ether and stir to dissolve, add 10% Pd / C (110.3 mg). Evacuate the autoclave, fill it with deuterium gas to 0.6 MPa, start the reaction at room temperature, and stop the reaction when the pressure in the reactor no longer changes. After the reaction is completed, filter the palladium carbon with diatomaceous earth, wash it three times with 10.0 ml of ether, and remove the solvent by rotary evaporation to obtain the product as a light yellow oily liquid, i.e., 1,2-dideuterium propane sultone 6-2 (0.31 g, quantitative reaction), which can be directly used for 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.

[0205] Add compound 6-3 (754.4 mg, 5 mmol) to a 50 ml single-mouth bottle. Dissolve NaOH (508.8 mg, 12.5 mmol) in 6.0 ml H2O and add the above system. The reaction system changes from a white solid to a dark green solution and is stirred at room temperature for 30 min. Dissolve compound 6-2 (1.8624 g, 15 mmol) in 12.0 mL dioxane and add the above system. React overnight at room temperature. A large amount of brown precipitate is generated during the reaction, and the reaction system changes from a black solution to a brown suspension. After the reaction is completed, filter out the brown solid and wash it with a small amount of ethanol and acetone. Transfer the solid to a 50 ml single-mouth bottle and recrystallize it with water and ethanol at 90 ° C. The product 6-4 is 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).13 C NMR(101MHz,D2O)δ149.17,134.95,112.51,67.79,47.78,47.68,47.48,47.27,29.44,24.56,24.12,23.93,23.74.HRMS(ESI)calcd for[M-2Na] 2+ :198.0431, found 198.0427.

[0206]

[0207] Add methyl tetramer (782.3 mg, 1 mmol) to a 25 ml single-mouth bottle, add 7.0 ml acetic anhydride and 7.0 ml trifluoroacetic acid, stir to dissolve, then add compound 6-4 (1.2397 g, 3 mmol) to the reaction system, stir to dissolve. Heat the system to 50 ° C and react for 12 hours. After the reaction is completed, add the reaction solution dropwise to 140 ml ethanol, and a brown solid precipitates. After centrifugation, wash the lower precipitate with 100 ml ethanol twice, take the lower solid and recrystallize it with water and ethanol at 70 ° C. After recrystallization, the product is dried with an oil pump to obtain a white powder solid I-6 (0.6 g, 37%). 1 H NMR(500MHz,D2O)δ5.66(d,J=15.3Hz,2H),5.54(d,J=15.7Hz,4H),5.46–5.3 3(m,4H),5.16(d,J=15.9Hz,4H),4.34(d,J=15.9Hz,4H),4.24(d,J=15.6Hz,4 H),4.11–4.04(m,6H),3.87(d,J=8.2Hz,4H),3.07(dd,J=19.3,10.4Hz,4H), 2.51(s,8H),2.13(s,4H),1.75(d,J=24.7Hz,12H),1.50(s,2H),1.37(s,2H). 13 C NMR(101MHz,D2O)δ156.71,156.15,147.23,138.15,128.58,78.63,77.62,71.76,71.43 ,71.09,52.84,48.45,47.66,36.03,30.30,25.57,24.59,17.23,15.69.HRMS(ESI)calcd for[M-4Na+2H] 2- :769.2229, found 769.2243.

[0208] Example 7: Synthesis of Compound I-7

[0209] 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 alkane sulfonate.

[0210]

[0211] Add 2,3-propylene-1,4-diol (prepared according to the literature method, 2.07g, 13.78mmol) to a 250mL single-mouth bottle, add NaOH aqueous solution (1.38g 34.45mmol, dissolved in 37.5mL H2O), and stir at room temperature for 30min. Subsequently, add 1,3-propane sultone dioxane solution (5.05g, 41.34mmol, dissolved in 60mL 1,4-dioxane) to the system under stirring. After reacting at room temperature for 12 hours, the raw material reacted completely. After the reaction was completed, centrifugation was performed and the obtained solid was washed with EtOH (60mL×2). The solid crude product was recrystallized with EtOH / H2O at 90°C to obtain a light brown solid powder 7-4 (3.7520g, 70%). 1 H NMR(500MHz,D2O)δ6.85(s,2H),4.15(t,J=6.3Hz,4H),3.14–3.00(m,4H),2.88(t,J=7.4Hz,4H),2.18(dq,J=12.6,6.3Hz,4H),2.08(p,J=7.7Hz,2H). 13 CNMR(126MHz,D2O)δ149.18,134.92,112.52,67.89,47.89,29.45,24.51,24.36.HRMS(ESI)calcd:[M-Na] - ,415.0503,found 415.0501.

[0212]

[0213] Add tetradeuterated dimethyl glycoluril tetramer (1.53 g, 1.79 mmol) and acetic anhydride (7.0 mL) to a 50 mL single-mouth bottle, stir and dissolve, then add trifluoroacetic acid (7.0 mL) and sodium 2,3-propylene-1,4-phenoxy-dipropyl alkanesulfonate (2.35 g, 5.35 mmol) to the reaction system, stir and dissolve. Heat the system to 50 ° C and react for 12 hours. After the reaction is completed, add the reaction solution dropwise to 140 mL of ethanol, and a light yellow solid precipitates. After centrifugation, wash the lower layer of solid with 150 mL of ethanol twice, take the lower layer of solid and recrystallize it with water and ethanol at 70 ° C. After recrystallization, the product is vacuum dried to obtain a white powder solid I-7 (1.61 g, 59%).1 H NMR(500MHz,D2O)δ5.50(d,J=15.7Hz,4H),5.38(d,J=9.1Hz,2H),5.31(d,J=9.0Hz, 2H),5.12(d,J=16.0Hz,4H),4.31(d,J=16.0Hz,4H),4.19(d,J=15.7Hz,4H),4.04(q ,J=7.2Hz,4H),3.82(q,J=7.9,7.3Hz,4H),3.05(tt,J=14.0,6.8Hz,8H),2.43(d,J= 18.3Hz,8H),2.23–2.03(m,8H),1.71(d,J=21.8Hz,12H),1.40(s,2H),1.28(s,2H). 13 C NMR(101MHz,D2O)δ156.74,156.20,148.32,138.21,128.60,78.67,77.69,71.89,71.31,71 .17,48.50,48.12,36.12,30.36,25.61,25.03,17.32,15.74.HRMS(ESI):Calcd:[M–3Na+H] 2- ,778.2013,Found:778.1961.

[0214] Example 8: Synthesis of Compound I-8

[0215] 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 alkane sulfonate.

[0216]

[0217] 1,2-Dideuterium propane sultone was prepared according to the method in Example 6. 3,4-Dimethylhydroquinone (0.35 g, 2.51 mmol) was added to the reaction bottle, followed by 10% NaOH solution (0.25 g, 3.47 mmol, dissolved in 1.67 mL of deionized water), and the light yellow solid turned into a dark green solution. Stirring was continued at room temperature for 30 minutes. A dioxane solution of 1,2-dideuterium propane sultone (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 precipitation 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 suction filtration, and then washed with ethanol (5 mL × 2) and acetone (5 mL × 2) in turn. The obtained solid was recrystallized with water and ethanol at 90 ° C, and after vacuum drying, a light yellow solid compound 12 (0.55 g, 51%) was obtained. 1 H NMR (400MHz, D2O) δ6.85 (s, 2H), 4.05 (d, J = 6.0Hz, 4H), 3.08 (dd, J1 = 9.0Hz, J2 = 12.8Hz, 2H), 2.19 (dd, J1 = 9.0Hz, J2 = 12.8Hz, 2H), 2.14 (s, 6H). 13 C NMR (101MHz, D2O): δ150.90,128.12,112.18,68.47,47.89,47.68,47.47,24.30,24.10,23.9011.10. HRMS(ESI)calcd for[M-2Na] 2- ,192.0516,found 192.0426;calcd for[M-2Na+H] - :385.0994,found 385.0934;calcd for[M-Na] - ,407.0744,found 407.0754.

[0218]

[0219] Weigh the tetradeuterated dimethyl tetramer (0.32 g, 0.387 mmol) and dissolve it in trifluoroacetic acid (2 mL). Then add acetic anhydride (2 mL) and tetradeuterated 2,3-dimethyl-1,4-phenoxy-dipropyl sulfonate sodium (0.5 g, 1.16 mmol) in turn, and then set the oil bath temperature to 50 ° C for 12 hours. After the reaction is completed, the reaction solution is added dropwise to ethanol (30 mL), stirred for 30 minutes, and then centrifuged. The solid is repeatedly washed with ethanol in a centrifuge tube (2 mL × 4) until the supernatant is basically colorless. The solid is transferred to a 50 mL eggplant flask to remove the solvent, and the obtained solid is recrystallized using ethanol and water. Filter, wash the solid with a small amount of ethanol / water mixed solution (4:1), and vacuum dry to obtain a white solid powder I-8 (0.323 g, 52%). 1 H NMR (400MHz, D2O): δ5.66(d,J=15.2Hz,2H),5.57(d,J=15.2Hz,4H),5.44(d,J=9.2Hz,4H),5.37(d,J=15.2Hz,4H),5.15(d,J=16Hz,4H),4.34(d,J=1 6Hz,4H),4.26(d,J=15.2Hz,4H),4.09(d,J=15.2Hz,2H),3.93(s,4H),3.7 1(s,4H),3.10(s,4H),2.16(s,4H),1.77(s,4H),1.74(s,4H),1.69(s,4H). HRMS(ESI):Calcd for[M-3Na+H] 2+ :768.2138,Found:768.2083.

[0220] Example 9: Synthesis of Compound I-9

[0221] The method described in Example 1 was followed except that sodium 1,4-naphthyloxy-dipropyl alkane sulfonate was used instead of sodium 2,3-dimethyl-1,4-phenoxy-dipropyl alkane sulfonate.

[0222]

[0223] Weigh tetradeuterated dimethyl glycoluril tetramer (1.0 g, 1.26 mmol) and dissolve it in trifluoroacetic acid (6 mL), add acetic anhydride (6 mL) and sodium 1,4-naphthyloxy-dipropyl alkane sulfonate (1.71 g, 3.50 mmol) in sequence, and react at 50°C for 12 hours. After the reaction, add the reaction solution dropwise to rapidly stirred ethanol (200 mL), stir for half an hour and then centrifuge. The solid is washed with ethanol (30 mL×5) in a centrifuge tube. After the reaction, the solid is dissolved with hot water (20 mL), filtered, and the solid residue after the filtrate is dried by rotary evaporation is recrystallized with ethanol and water. The crystals are allowed to stand in a refrigerator at 4°C overnight and then filtered. The filter cake is washed with ethanol-water solution (5 mL, 4:1 v / v) and then recrystallized again with ethanol / water. The obtained white solid is dissolved in water (8 mL) and filtered. The filtrate is rotary evaporated at 70°C to remove water to obtain white solid powder I-9 (0.98 g, 47%). 1H NMR (400MHz, DMSO-d6): δ7.78 (dd, J1=6.3, J2=3.1Hz, 4H), 7.25 (dd, J1=6.1, J2=2.5Hz, 4H), 5.58 (d, J=15.2Hz, 4H), 5.47–5.29 (m ,8H),4.54(d,J=16.4Hz,4H),4.25(t,J=12.9Hz,8H),4.02–3.90(m,4H),3.31–3.14(m,8H),2.32(d,J=7.2Hz,8H),1.84(s,12H). 13C NMR (101MHz, D2O): δ156.79,156.37,148.26,127.76,127.05,126.15,122.31, 78.68,77.69,74.25,71.44,71.28,48.58,48.06,36.59,25.17,16.57,15.37. HRMS(ESI):Calcd for[M+2Na]2+:845.1551,Found:845.1535.

[0224] Example 10: Synthesis of Compound I-10

[0225] The method described in Example 1 is followed, except that hexadeuterated butanedione is used to replace the non-deuterated butanedione, and non-deuterated glycoluril dimer is used to replace the deuterated dimer.

[0226]

[0227] Weigh urea (23.3 g, 0.388 mol) and dissolve it in 0.3 M hydrochloric acid (56 mL). Add deuterated diacetyl (prepared according to the literature method, 10.8 g, 0.117 mol) slowly under stirring, and stir at room temperature for 12 hours. After the reaction is completed, filter and wash the solid with deionized water (10 mL × 2). After vacuum drying, a white hexadeuterated dimethyl glycoluril solid (19.8 g, 96%) is obtained. 1 HNMR (400MHz, DMSO-d6): δ7.09 (s, 4H). 13 C NMR(101MHz,DMSO-d6):δ159.29,74.98.HRMS(ESI):Calcd for[M+H] + :177.1253,Found:177.1250.

[0228] Weigh hexadeuterated dimethyl glycoluril (10.0 g, 56.8 mmol) and paraformaldehyde (8.6 g, 286.7 mmol) in a 250 mL eggplant-shaped bottle, add 9 M hydrochloric acid (60 mL), stir at room temperature for 24 h, then add deionized water (224 mL) and continue stirring for 12 h. Filter after the reaction. The collected solids are washed with deionized water (50 mL × 3) and ethanol (50 mL × 3) respectively, and after vacuum drying, hexadeuterated dimethyl glycoluril diether-d6 is obtained 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.

[0229] Weigh glycoluril dimer (1.88 g, 6.10 mmol) and dissolve it in methanesulfonic acid (11 mL) under ultrasound. Add dimethyl glycoluril diether-d6 (4.76 g, 18.3 mmol) to the system and react at 50 ° C for 5 h under mechanical stirring. After the reaction is completed, cool to room temperature, add the reaction solution dropwise to ice water (110 mL) to generate a large amount of white precipitate, centrifuge. Wash with water in a centrifuge tube until neutral. Dissolve the solid in trifluoroacetic acid (6 mL) and cool to 0 ° C, then slowly add water (30 mL) to the solution to generate a large amount of white precipitate, centrifuge, wash with water until neutral, and freeze-dry to obtain dodeuterated glycoluril tetramer as a white solid powder (1.98 g, 41%). 1H 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.

[0230]

[0231] Weigh the dodeuterated dimethyl tetramer (1.0 g, 1.26 mmol) and dissolve it in trifluoroacetic acid (6 mL). Then add acetic anhydride (6 mL) and 2,3-dimethyl-1,4-phenoxy-dipropyl sodium sulfonate (compound 12, 1.6 g, 3.75 mmol) in turn, and then set the oil bath temperature to 50 ° C for 12 hours. After the reaction is completed, the reaction solution is added dropwise to ethanol (300 mL), stirred for 30 minutes, and then centrifuged. The solid is repeatedly washed with ethanol in a centrifuge tube (10 mL × 4) until the supernatant is basically colorless. The solid is transferred to a 50 mL eggplant flask to remove the solvent, and the obtained solid is recrystallized using ethanol and water. Filter, wash the solid with a small amount of ethanol / water mixed solution (4:1), and after vacuum drying, compound I-10 (1.36 g, 67%) is obtained as a white solid powder. 1 H NMR (400MHz, D2O): δ5.62(d,J=15.4Hz,2H),5.52(d,J=15.4Hz,4H),5.46–5.34(m,4H),5.10(d,J=15.9Hz,4H),4.32(d,J=16 .8Hz,4H),4.23(d,J=15.9Hz,4H),4.09(d,J=15.4Hz,2H),3.91(s,4H),3.69(s,4H),3.11(s,8H),2.18(s,8H),1.81(s,12H). 13C NMR (101MHz, D2O): δ156.74,156.15,150.23,131.48,128.22,78.46,77.39,72 .79,71.32,71.06,52.60,48.43,47.97,36.21,24.89,12.49.HRMS(ESI):Calcd for[M+2Na] 2+ :827.1959,Found:827.1950.

[0232] Embodiment 11:

[0233] 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.

[0234]

[0235] Add dimethyl glycoluril tetramer (1.50 g, 1.79 mmol) and trifluoroacetic acid (7.0 mL) to a 50 mL single-mouth bottle, stir and dissolve, then add acetic anhydride (7.0 mL) and sodium 2,3-propylene-1,4-phenoxy-dipropyl alkanesulfonate (2.35 g, 5.35 mmol) to the reaction system, stir and dissolve. Heat the system to 50 ° C and react for 12 hours. After the reaction system is cooled, add the reaction solution dropwise to 140 mL of ethanol, precipitate a light yellow solid, centrifuge, and collect the solid. Wash the solid twice with 150 mL of ethanol and centrifuge again. The obtained solid is recrystallized with water and ethanol at 70 ° C, and vacuum dried to obtain a white powder solid I-7-4H (1.60 g, 59%). 1 H NMR (400MHz, D2O): δ5.68(d,J=15.3Hz,2H),5.56(d,J=15.7Hz,4H),5.43(d,J=9.0Hz,2H ),5.35(d,J=9.0Hz,2H),5.18(d,J=15.9Hz,4H),4.31(dd,J=59.0,15.9Hz,8H),4.08(td, J=11.5,10.9,5.7Hz,6H),3.87(q,J=8.3,7.5Hz,4H),3.12(dd,J=20.4,14.4,7.2Hz,8H) ,2.47(d,J=19.8Hz,8H),2.16(s,8H),1.77(d,J=19.7Hz,12H),1.43(s,2H),1.31(s,2H). 13C NMR (101MHz, D2O): δ156.71,156.19,148.31,138.21,128.65,78.70,77.66,71.8 8,71.51,71.16,52.93,48.52,48.12,36.08,30.36,25.58,25.03,16.80,15.71.

[0236] Example 12

[0237] Water solubility test: Weigh about 100 mg of the above deuterated compound into a graduated capillary test tube, and gradually add deionized water until it is completely dissolved. Measure the volume to calculate the solubility, expressed in mg / mL (see Table 1). As can be seen from the table, although the solubility is slightly different, 1-1, I-5 and I-7 have high water solubility and can meet the solubility requirements for rapid injection.

[0238] Table 1. Solubility of the compounds of the present invention (mg / mL)

[0239] medium I-1 I-5 I-7 Deionized water 510 582 600

[0240] Example 13

[0241] 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 process of the deuterated diaryl glycoluril tetramer compound reversing neuromuscular blockade in vivo was explained.

[0242] Specific operation process: SD rats weighing 170 to 240 grams were selected as biological models to test the reversal effect of I-5. Three male rats and three female rats were selected for each group of experiments (the same below). During the test, the neuromuscular blocker injection solution was prepared using physiological saline as the solvent, and all injection operations were completed within 5 seconds. Rats were anesthetized with isoflurane, with an induction dose of 5% and a maintenance dose of 1.5%; 10% Na2S solution was used to remove the right hind leg and nearby hair of the rat; an airway was inserted into the rat's trachea and connected to a small animal ventilator, with the tidal volume set to 8 and the frequency set to 80; a muscle relaxation monitor was used to test the neuromuscular blockade of the quadriceps femoris of the rat, wherein the sensor was fixed to the rat's tibia, and the electrode was fixed to the rat's right hind leg through a patch, and then the Cal mode was used for calibration, and the TOF mode (TOF is the abbreviation of train of four, four train stimulations) was switched to after the data stabilized. If the TOF data was stable ≥90, the next step of the experiment was performed; cisatracurium besylate solution was injected into the rat through the tail vein and the timing was started, with a dose of 0.6 mg / kg, and then the TOF value change was recorded; after the TOF value decreased to 0, the rat was injected with I-5 injection, and the injection time was recorded, and then the TOF value change was recorded, and the time it recovered to ≥90 was recorded as the neuromuscular block reversal time.

[0243] 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.

[0244]

[0245]

[0246] 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).

[0247] The non-deuterated control compound I-1-4H reversed the TOF recovery time of 84 seconds at a high dose of 150 mg / kg for cisatracurium besylate, and the TOF recovery time of I-1-4H at a dose of 30 mg / kg for rocuronium bromide was greater than 300 seconds (Hoffmann et al., Anesthesiology 2013, 119, 317-325). The deuterated I-1 reversed cisatracurium besylate and rocuronium bromide at relatively lower doses (80 mg / kg and 25 mg / kg), and the activity was greatly improved, with TOF recovery times of 24 seconds and 208 seconds, respectively.

[0248] Deuterated I-7 has significantly improved reversal activity on cis-atracurium besylate compared to I-7-4H, and also maintains rapid reversal activity on rocuronium bromide; deuterated I-5 has significantly improved reversal activity on cis-atracurium besylate, achieved rapid reversal on cis-atracurium besylate, and also maintains rapid reversal activity on rocuronium bromide, and the activity is higher than the non-deuterated sample of the same dose. Therefore, the antagonistic activity of I-5 is significantly better than that of non-deuterated I-5-4H at the same dose.

[0249] By comparing the activities of deuterated compounds, it was found that at the same dose, compound I-5 showed excellent antagonistic activity against both cis-atracurium besylate and rocuronium bromide, and the antagonistic activity was the highest (see Tables 2 and 3).

[0250] When the dose of I-5 was 80 mg / kg, the average time for reversing 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 reversing 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.

[0251] The above in vivo antagonist activity experiment in rats confirmed that I-5 can achieve rapid reversal within 20 seconds. Compared with the commercially available reagent neostigmine (the experimental dose of rats was obtained by converting 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 quickly reverse the neuromuscular blockade induced by cisatracurium besylate and pancuronium bromide that cannot be reversed by sugammadex sodium in clinical practice, and its activity in reversing neuromuscular blockade induced by rocuronium bromide and vecuronium bromide is also significantly higher than that of sugammadex sodium, and the time for TOF to recover to 0.9 is shortened from 52 seconds and 18 seconds to 18 seconds and 9 seconds, respectively, which is equivalent to an increase of about 1.9 times and 1.0 times in antagonist activity.

[0252] As an example of a composition, at the same dose as deuterated I-5 (80 mg / kg), the composition of deuterated I-5 and non-deuterated I-5-4H (50% by mass each) also showed good antagonistic activity, with an antagonistic time of about 30 seconds (see Table 6).

[0253] 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).

[0254] 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) and neostigmine (0.24 mg / kg).

[0255]

[0256] Table 3. Compounds IC (I-1, I-5, I-7) and IC-4H (I-5-4H, I-7-4H) and sugammadex at the same dose (25 mg / kg) and neostigmine (0.24 mg / kg) antagonize the TOF→0.9 time of rocuronium.

[0257]

[0258] 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.

[0259]

[0260]

[0261] Table 5. I-5 (80 mg / kg) and neostigmine (0.24 mg / kg) antagonize the TOF→0.9 time of pancuronium bromide

[0262]

[0263] Table 6. The combination of compounds I-5 and I-5-4H (80 mg / kg, 50% by mass for each) antagonizes the TOF→0.9 time of cisatracurium besylate.

[0264]

[0265] Embodiment 14

[0266] Blood pharmacokinetics and excretion: Deuterated diaryl glycoluril tetramer compounds exert their effects through blood injection. The present invention takes 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.

[0267] The present invention uses SD rats (180-220g) as an experimental model, 3 males and 3 females, and injects a deuterated diaryl glycoluril tetramer compound (80mg / kg) through the tail vein, collects blood samples within 1 hour through jugular vein blood sampling (total volume 0.4mL, containing 0.05mL3.8% sodium citrate), and collects urine within 24 hours through a metabolic cage. The analysis and testing process of blood drug concentration is as follows: blood is collected at 0 minutes, 1 minutes, 5 minutes, 10 minutes, 20 minutes, 20 minutes, and 60 minutes, and then centrifuged at 3000 rpm (4°C, 10 minutes) to collect the upper plasma. 0.25mL acetonitrile is added to the plasma, shaken to precipitate protein, and centrifuged at 10000 rpm for 10 minutes (4°C) to collect the supernatant, and evaporated at room temperature to remove acetonitrile as much as possible.

[0268] Subsequently, deionized water was added to make the volume 0.5 mL, and the supernatant was collected 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 analytical test process of drug excretion is as follows: After the tail vein injection of deuterated diaryl glycoluril tetramer compound (80 mg / kg), the rats were placed in a metabolic cage, fed and watered normally, and urine was collected every 4 hours for 6-7 times. The urine was centrifuged in an ultrafiltration centrifuge tube (10KD) to remove urine protein, and the excretion of compounds through urine within 24 hours was analyzed by high performance liquid chromatography.

[0269] The experimental results show that the half-life of the blood drug concentration of compound I-5 in rats is 10 minutes, indicating that it has the characteristics of rapid elimination or clearance in the body. Compound I-5 is mainly excreted through urine in the form of prototype, and more than 70% of the compound is excreted within 24 hours, indicating that it has the characteristics of rapid excretion mainly through the kidneys.

[0270] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. 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 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; 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.

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