Sequence-controllable polymer hydrogen sulfide donor, pharmaceutical composition, synthesis method and application

Abstract

The application belongs to the technical field of medicine research, and particularly relates to a sequence-controllable high-molecular hydrogen sulfide donor, a pharmaceutical composition, and a synthesis method and application. The high-molecular hydrogen sulfide donor has a structure as shown in general formula (I). The high-molecular hydrogen sulfide donor compound can release H2S in a long-acting and slow-releasing manner under physiological conditions, especially in the presence of endogenous mercaptan, and can realize bifunctional release by introducing a drug active fragment. Experimental results show that the H2S release behavior of the compound is stable and has good biocompatibility, can significantly reduce the incidence of aortic dissection, and also has the potential for expansion to other diseases related to oxidative stress.

Description

Technical Field

[0001] This invention relates to the field of controlled click polymerization of polymeric hydrogen sulfide donors, specifically to a class of controlled click polymerization polymeric hydrogen sulfide (H2S) donor compounds, their synthesis methods, pharmaceutical compositions, and their application in the preparation of drugs for treating diseases related to oxidative stress. Background Technology

[0002] Hydrogen sulfide (H2S) is the third endogenous gaseous signaling molecule discovered after nitric oxide (NO) and carbon monoxide (CO), playing a crucial regulatory role in cardiovascular, neurological, immune, and metabolic physiological and pathological processes. Studies have shown that H2S has significant effects in antioxidation, anti-inflammation, regulation of vascular tone, and inhibition of apoptosis, demonstrating broad application prospects in the treatment of diseases such as aortic dissection, myocardial infarction, ischemia-reperfusion injury, Alzheimer's disease, Parkinson's disease, diabetes, and diabetic wound repair (Physiol Rev, 2012, 92, 791–896; Nat Rev Cardiol, 2023, 20, 109–125). However, due to the high activity and extremely low physiological concentration (sub-micromolar level) of H2S, its clinical application places extremely stringent requirements on the donor release rate and dosage control.

[0003] Existing H2S donors mainly include small molecule compounds such as thioethers, thiocarbonyl compounds, and thioesters. However, these compounds are rapidly metabolized in vivo, making it difficult to maintain stable H2S levels. Furthermore, they produce complex byproducts, some of which may interfere with normal physiological processes. To prolong the duration of action, researchers have attempted to combine small molecule donors with polymers to form polymer-coupled drugs (PCDs) or polyprodrugs. PCDs, due to their low drug loading capacity, typically require higher doses to maintain blood H2S levels. While the polyprodrug strategy can polymerize hydrogen sulfide donor units into polymers, the polymerization reaction and the structure of the hydrogen sulfide releasing units limit the precise release of hydrogen sulfide from the resulting polymers, making it difficult to control the release and meet the clinical need for precise controlled release.

[0004] Therefore, developing a class of high molecular weight hydrogen sulfide donors with high drug loading capacity, long blood circulation time, and controllable release is of great significance for breaking through the key bottlenecks in the clinical translation of H2S, promoting the development of H2S-related medical agents, and facilitating the actual clinical application of H2S. Summary of the Invention

[0005] Based on the above technical problems, this invention proposes a novel polymeric H2S donor compound constructed by precisely embedding a diacyl olefin sulfide unit that can release H2S in response to bio-thiols into the polymer backbone through a sequence-controlled polymerization method. This compound exhibits highly tunable H2S release performance, and under physiological conditions, especially in the presence of endogenous thiols such as glutathione (GSH) or cysteine, it can responsively and sustainably release H2S. By rationally designing the connection mode between the comonomer and the H2S donor unit, this invention achieves control over the long-term release behavior of H2S and can further introduce drug-active fragments to achieve dual-function synergistic delivery of H2S and drugs, significantly improving the disease intervention effect. The polymeric donor of this invention can be selected from various polymeric backbones according to application requirements, including biocompatible PEG, PLGA, PCL, PLA, PU, ​​etc., to achieve tunable solubility, degradability, and biocompatibility.

[0006] The specific technical solution provided by this invention is as follows: In a first aspect, the present invention provides a sequence-controllable polymeric hydrogen sulfide donor compound, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, which can release H2S in response in vivo, said polymeric hydrogen sulfide donor compound having a structure as shown in formula (I): ; In the formula: The curves on both sides of the S atom represent cis-trans isomerism; R is selected from any one of O=CC=O, X=O, O=X-R4-X=O, O=X-R5[(-X=O)-CH=CH(R6)]-X=O (R5 is attached to three -X=O groups, and CH=CH-R6 is attached to the third -X=O group), and X is any one of C, S, S=O, Se, Se=O, and R3-P=O; R1 and R2 are each independently selected from H, -C1-C6 alkyl, -C2-C6 alkenyl, -C3-C6 cycloalkyl, -C1-C6-OH hydroxyalkyl, -C1-C6-COOH carboxylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitro, cyano, trifluoromethyl, silyl, cycloalkyl or heterocycloalkyl or heteroaryl formed by cyclization of linked carbon atoms; R3 is selected from H, -C1-C6 substituted or unsubstituted alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted benzyloxy, -O-C1-C6 substituted or unsubstituted alkoxy, -O-C2-C6 alkenyloxy, -O-C3-C6 alkynyloxy, -O-C3-C7 heterocyclic alkyl, -O-C3-C6 substituted or unsubstituted cycloalkyl, -O-C3-C7 substituted or unsubstituted heterocyclic alkyl, cycloalkyl or heterocyclic alkyl or heteroaryl formed by cyclization of linked carbon atoms, L-arginine, -OH, -NH2, -NR7R8, -R9-NO y For any one of the following, y = 2 or 3; R4 is selected from -O-C2-C6-O-dialkoxy, -O-C4-C6O-dienyloxy, -NH-C2-C6-NH-dialkylamine, -NH-C4-C6-NH-dienylamine, and -O(CH2CH2O). n -Polyethylene glycol chain, -NH(CH2CH2NH) n - Linear polyethyleneimine chain, -O (CH2CH2CH2O) n Polypropylene glycol chain, -O (CH2CH2O) n -(CH2CH2CH2O) m - Poly(ethylene glycol-co-propylene glycol) chain, PDMS polydimethylsiloxane chain, polyetheramine chain, PCL polycaprolactone chain, polylactic acid (PLA) chain, polyglycolic acid (PGA) chain, polyurethane (PU) chain, PLGA polylactic acid-glycolic acid copolymer chain, PVP hydroxyl-terminated polyvinylpyrrolidone chain, PEEK hydroxyl-terminated polyetheretherketone chain, -OR 10 -N + (R 11 R 12 Y - )-R 13 -N + (R 14 R 15 Z - )-R 16 -O-、-O-CH=CH(R 17 )-(X=O)-R 18 -(X=O)-CH=CH(R 19 Any one of )-O-; R5 is selected from any one of glycerol, trimethylolethane, trimethylolpropane, phloroglucinol, resveratrol, hydroquinone, and 1,2-dihydroxyethylphenol; R6 is selected from any one of the following: amino acids or polypeptides containing a single thiol group, cysteine, N-acetylcysteine, thioglycerol, thioglycolic acid, thioethanol, thiolactic acid, monothiol cyclodextrin, isosorbide mononitrate, captopril, mercaptopurine, amifostine, D-penicillamine, thiol polyethylene glycol, thiol-terminated PLGA, and thiol-containing RGD peptides. R7, R8, R 11 R 12 R 14 R 15 Each of the following is independently selected from H, -C1-C6 substituted or unsubstituted alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, substituted or unsubstituted aryl, heteroaryl, hydroxymethyl, hydroxyethyl, hydroxypropyl, aminoethyl, carboxymethyl, carboxyethyl, sulfonic acid methyl, sulfonic acid ethyl, phosphoric acid methyl, phosphoric acid ethyl, nitrate methyl, nitrate ethyl, nitrite methyl, and nitrite ethyl; R9-NO y It is selected from any one of isosorbide mononitrate, glyceryl dinitrate, glyceryl mononitrate, nipridil, -O-C2-C6-NO3, -O-C2-C6-NO2, -NH-C2-NO3, -NH-C2-NO2, S-nitrosoglutathione, and S-nitroso-N-acetylpenicillamine; R 10 R 13 R 16 Each is independently selected from any one of -C2-C6-alkyl, -C4-C6-alkenyl, -C4-C6-ynyl, -C3-C6-cycloalkyl, -Ar-aryl, -C2-C6-nitroalkyl, -C2-C6-haloalkyl, and -C2-C6-haloalkenyl; Y - and Z - It is independently selected from any one of the following: halide anion, tetrafluoroborate, hexafluorophosphate, p-toluenesulfonate, acetate, trifluoroacetate, hydrogen sulfate, bicarbonate, dihydrogen phosphate, trifluoromethanesulfonate, dicyandiamide, bis(trifluoromethanesulfonyl)imide anion, and bis(fluorosulfonyl)imide anion. R 17 R 19 Each of the following is independently selected from H, -C1-C6 alkyl, -C2-C6 alkenyl, -C3-C6 cycloalkyl, -C1-C6-OH hydroxyalkyl, -C1-C6-COOH carboxylalkyl, aryl, heteroaryl, nitro, cyano, trifluoromethyl, and silyl; R 18Selected from -O-C2-C6-O-dialkoxy, -O-C4-C6O-dienyloxy, -NH-C2-C6-NH-dialkylamine, -NH-C4-C6-NH-dienylamine, -O(CH2CH2O) n -Polyethylene glycol chain, -O(CH2CH2CH2O) n - Polypropylene glycol chain, -O(CH2CH2O) n -(CH2CH2CH2O) m - Any one of the following chains: poly(ethylene glycol-co-propylene glycol) chain, polydimethylsiloxane chain, polyetheramine chain, polycaprolactone chain, polylactic acid (PLA) chain, polyglycolic acid (PGA) chain, polyurethane (PU) chain, PLGA polylactic acid-glycolic acid copolymer chain, PVP hydroxyl-terminated polyvinylpyrrolidone chain, and PEEK hydroxyl-terminated polyetheretherketone chain; n=2~1000, -O(CH2CH2O) n -(CH2CH2CH2O) m - In the poly(ethylene glycol-co-propylene glycol) chain, n+m=2~1000.

[0007] The R1, R2, or R3 groups in the compounds of this invention can also be selected from functionalized derivatives of the active structures of cardiovascular and cerebrovascular drugs. These derivatives can be incorporated into the polymer backbone through acylation, etherification, esterification, amination, etc., without affecting the activity of the parent drug, thereby achieving bifunctional release of H2S and the drug.

[0008] In a preferred embodiment of the present invention, R1 and R2 are each independently selected from H, -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6-OH hydroxyalkyl, -C1-C6-COOH carboxylalkyl, substituted or unsubstituted aryl, trifluoromethyl, silyl; R3 is selected from H, -C1-C6 substituted or unsubstituted alkyl, -C3-C6 cycloalkyl, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted benzyloxy, -O-C1-C6 substituted or unsubstituted alkoxy, -O-C3-C7 heterocyclic alkyl, -O-C3-C6 substituted or unsubstituted cycloalkyl, -O-C3-C7 substituted or unsubstituted heterocyclic alkyl, -OH, -NH2, -NR7R8, -R9-NO y For any one of the following, y = 2 or 3; R4 is selected from -O-C2-C6-O-dialkoxy, -NH-C2-C6-NH-dialkylamine, -NH-C4-C6-NH-dienylamine, and -O(CH2CH2O). n -Polyethylene glycol chain, -NH(CH2CH2NH) n- Linear polyethyleneimine chain, PCL polycaprolactone chain, polylactic acid (PLA) chain, polyglycolic acid (PGA) chain, polyurethane (PU) chain, PLGA polylactic acid-glycolic acid copolymer chain, PVP hydroxyl-terminated polyvinylpyrrolidone chain, PEEK hydroxyl-terminated polyetheretherketone chain, -OR 10 -N + (R 11 R 12 Y - )-R 13 -N + (R 14 R 15 Z - )-R 16 -O-、-O-CH=CH(R 17 )-(X=O)-R 18 -(X=O)-CH=CH(R 19 Any one of )-O-; n=2~1000 R5 is selected from any one of glycerol, trimethylolethane, trimethylolpropane, resveratrol, and phloroglucinol; R6 is selected from any one of the following: amino acids or polypeptides containing a single thiol group, thioglycerol, thioglycolic acid, thioethanol, thiolactic acid, monothiol cyclodextrin, isosorbide mononitrate, captopril, amifostine, D-penicillamine, thiol polyethylene glycol, thiol-terminated PLGA, and thiol-containing RGD peptides. R7, R8, R 11 R 12 R 14 R 15 Each of the following is independently selected from H, -C1-C6 substituted or unsubstituted alkyl groups, -C2-C6 alkenyl groups, hydroxymethyl, hydroxyethyl, hydroxypropyl, aminoethyl, carboxymethyl, carboxyethyl, sulfonylmethyl, sulfonylethyl, phosphatemethyl, phosphateethyl, nitratemethyl, nitrateethyl, nitritemethyl, and nitriteethyl. R9-NO y Selected from any one of isosorbide mononitrate, nipridil, -O-C2-C6-NO3, -O-C2-C6-NO2, S-nitrosoglutathione, and S-nitroso-N-acetylpenicillamine; R 10 R 13 R 16 Each is independently selected from any one of -C2-C6-alkyl, -C3-C6-cycloalkyl, -Ar-aryl, -C2-C6-nitroalkyl, and -C2-C6-haloalkyl; Y - and Z- Each of the following is independently selected from any one of the following: halide anions, tetrafluoroborate, hexafluorophosphate, p-toluenesulfonate, acetate, trifluoroacetate, bisulfate, bicarbonate, and dihydrogen phosphate. R 17 R 19 Each of the following is independently selected from H, -C1-C6 alkyl, -C1-C6-OH hydroxyalkyl, -C1-C6-COOH carboxylalkyl, aryl, heteroaryl, trifluoromethyl, and silyl; R 18 Selected from -O-C2-C6-O-dialkoxy, -O-C4-C6O-dienyloxy, -NH-C2-C6-NH-dialkylamine, -NH-C4-C6-NH-dienylamine, -O(CH2CH2O) n - Any one of the following chains: polyethylene glycol (n=2~1000), polycaprolactone, polylactic acid (PLA), polyglycolic acid (PGA), polyurethane (PU), PLGA polylactic acid-glycolic acid copolymer, PVP hydroxyl-terminated polyvinylpyrrolidone, and PEEK hydroxyl-terminated polyether ether ketone.

[0009] More preferably, R1 and R2 are each independently selected from H, -C1-C6 alkyl, substituted or unsubstituted aryl, trifluoromethyl, silyl; R3 is selected from H, methyl, ethyl, substituted or unsubstituted phenyl, haloaryl, nitroaryl, nitroheteroaryl, phenoxy, benzyloxy, -O-C1-C4 alkoxy, -OH, -NH2, -NR7R8, -R9-NO y For any one of the following, y = 2 or 3; R4 is selected from -O-C2-C6-O-dialkoxy, -NH-C2-C6-NH-dialkylamine, and -O(CH2CH2O). n - Polyethylene glycol chain (n=2~1000), polylactic acid (PLA) chain, polyurethane (PU) chain, PLGA lactic acid-glycolic acid copolymer chain, - OR 10 -N + (R 11 R 12 Y - )-R 13 -N + (R 14 R 15 Z - )-R 16 -O-、-O-CH=CH(R 17 )-(X=O)-R 18 -(X=O)-CH=CH(R 19 Any one of )-O-; R5 is selected from any one of glycerol, trimethylolethane, trimethylolpropane, and resveratrol; R6 is selected from any one of the following: cysteine, glutathione, thioglycerol, mercaptoacetic acid, mercaptoethanol, thiolactic acid, isosorbide mononitrate, captopril, amifostine, D-penicillamine, and mercaptopolyethylene glycol. R7, R8, R 11 R 12 R 14 R 15 Each of them is independently selected from any one of H, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, aminoethyl, carboxymethyl, carboxyethyl, sulfonic acid methyl, sulfonic acid ethyl, and nitrate ethyl; R9-NO y Selected from any one of isosorbide mononitrate, nipridil, -O-C2-C6-NO3, and S-nitrosoglutathione; R 10 R 13 R 16 Each is independently selected from any one of -C2-C6-alkyl, -C3-C6-cycloalkyl, and -C2-C6-haloalkyl; Y - and Z - Each of the following is independently selected from any one of the following: halide anions, tetrafluoroborate, hexafluorophosphate, p-toluenesulfonate, acetate, bicarbonate, and dihydrogen phosphate. R 17 R 19 Each of the following is independently selected from H, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, carboxymethyl, carboxyethyl, trifluoromethyl, and silyl. R 18 Selected from -O-C2-C6-O-dialkoxy, -NH-C2-C6-NH-dialkylamine, -O(CH2CH2O) n - Any one of polyethylene glycol chain (n=2~1000) or PLGA lactic acid-glycolic acid copolymer chain.

[0010] More preferably, R1 and R2 are each independently selected from H, methyl, ethyl, propyl, butyl, phenyl, trifluoromethyl, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, and tert-butyldiphenylsilyl. R3 is selected from H, methyl, ethyl, phenyl, nitrophenyl, phenoxy, nitrophenoxy, benzyloxy, -O-C1-C4 alkoxy, -NR7R8, -R9-NO. y For any one of the following, y = 2 or 3; R4 is selected from -O-C2-C6-O-dialkoxy, -NH-C2-C6-NH-dialkylamine, and -O(CH2CH2O). n -Polyethylene glycol chain (n=2~1000), -OR 10 -N + (R 11 R 12 Y - )-R 13 -N + (R 14 R 15 Z - )-R 16 -O-、-O-CH=CH(R 17 )-(X=O)-R 18 -(X=O)-CH=CH(R 19 Any one of )-O-; R5 is selected from any one of glycerol, trimethylolethane, and trimethylolpropane; R6 is selected from any one of the following: cysteine, glutathione, thioglycerol, mercaptoacetic acid, mercaptoethanol, thiolactic acid, isosorbide mononitrate, captopril, and mercaptopolyethylene glycol. R7, R8, R 11 R 12 R 14 R 15 Each of them is independently selected from any one of H, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, aminoethyl, carboxymethyl, carboxyethyl, and sulfonic acid ethyl; R9-NO y Selected from any one of isosorbide mononitrate, -O-C2-C6-NO3, and S-nitrosoglutathione; R 10 R 13 R 16 Each is independently selected from either -C2-C6-alkyl or -C3-C6-cycloalkyl; Y - and Z - Each is independently selected from any one of the following: halide anions, p-toluenesulfonate, acetate, bicarbonate, and dihydrogen phosphate. R 17 R 19 Each of the following is independently selected from H, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, carboxymethyl, carboxyethyl, trifluoromethyl, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, and tert-butyldiphenylsilyl; R 18Selected from -O-C2-C6-O-dialkoxy, -NH-C2-C6-NH-dialkylamine, -O(CH2CH2O) n - Any of the following polyethylene glycol chains (n=2~1000):

[0011] The present invention also provides a method for synthesizing the aforementioned polymeric hydrogen sulfide donor compound, comprising the following steps: In organic solvents or water, and under the action of a base catalyst or autocatalysis, the compound shown in formula (II) and a sulfur source are used as raw materials to obtain the compound shown in formula (I) through an addition polymerization reaction. The synthetic route is as follows: ; In the compound shown in formula (II), R' is defined in the same way as R4 in the compound shown in formula (I); or In an organic solvent, and in the presence of an alkaline catalyst and / or a dehydrating agent, the compound shown in formula (III) and the compound shown in formula (IV) are used as starting materials to obtain the compound shown in formula (I) through a polycondensation reaction. The synthetic route is as follows: ; In the compound shown in formula (III), X, R1, R2 and the curve are defined in the same way as X, R1, R2 and the curve in the compound shown in formula (I), and Y is selected from any one of OH, Cl and Br; R' in the compound shown in formula (IV) is the same as R in the compound shown in formula (I). 10 Same definition; X' is taken from -OH, -NH2, or -NHR''; R'' is selected from -C2-C6-alkyl, -C4-C6-alkenyl, -C4-C6-ynyl, -C3-C6-cycloalkyl, and -(CH2CH2O). n -Polyethylene glycol chain, -(CH2CH2CH2O) n - Polypropylene glycol chain, (CH2CH2O) n -(CH2CH2CH2O) m Any one of the following chains: poly(ethylene glycol-co-propylene glycol), polydimethylsiloxane, polyetheramine, polycaprolactone, polylactic acid (PLA), polyglycolic acid (PGA), polyurethane (PU), PLGA, PVP, and PEEK. n=2~1000, (CH2CH2O) n -(CH2CH2CH2O) m In the poly(ethylene glycol-co-propylene glycol) chain, n+m = 2~1000; or In an organic solvent or water, and in the presence of a base catalyst, compounds of formula (V) and (VI) were used as starting materials to obtain compound (I) via addition polymerization. The synthetic route is as follows: ; In the compound shown in formula (V), R1, R2, X and the curve are defined in the same way as those in the compound shown in formula (I); R' in the compound shown in formula (VI) is the same as R in the compound shown in formula (I). 18 Same definition; or In an organic solvent or water, and in the presence of a base catalyst or under autocatalysis, the compounds shown in formula (VI) and (VII) are used as starting materials to obtain the compound shown in formula (I) through an addition polymerization reaction. The synthetic route is as follows: ; In formula (VI), compounds R1, R2, X and curves are defined in the same way as those in formula (I). R' is selected from any one of -O-C2-C6-alkyl, -O-C4-C6-alkenyl, -O-C4-C6-ynyl, -O-C3-C6-cycloalkyl, -NH-C2-C6-alkyl, -NH-C4-C6-alkenyl, and -NH-C4-C6-ynyl. Z is selected from Cl, Br or I. In the compound shown in formula (VII), R 3’ R 4’ R 5’ R 6’ R in the compound shown in formula (I) 11 R 12 R 14 R 15 The definitions are the same, R is the same as R in the compound shown in formula (I), and R'' is the same as R in the compound shown in formula (I). 13 same.

[0012] In a preferred embodiment of the present invention, both the addition polymerization reaction and the condensation polymerization reaction are carried out at -20°C to 120°C for 1 min to 96 h.

[0013] More preferably, both the addition polymerization reaction and the condensation polymerization reaction are carried out at 0°C to 80°C for 1 h to 72 h.

[0014] More preferably, both the addition polymerization reaction and the condensation polymerization reaction are carried out at 0°C to 60°C for 1 h to 48 h.

[0015] In a preferred embodiment of the present invention, the molar ratio of the compound shown in formula (II) and the sulfur source, the compound shown in formula (III) and the compound shown in formula (IV), the compound shown in formula (V) and the compound shown in formula (VI), and the compound shown in formula (VI) and the compound shown in formula (VII) are all 1:1 to 1.5.

[0016] In a preferred embodiment of the present invention, the sulfur source includes, but is not limited to, elemental sulfur, hydrogen sulfide, sodium sulfide, sodium hydrosulfide, calcium sulfide, calcium hydrosulfide, lithium polysulfide, sodium persulfide, potassium polysulfide, and calcium polysulfide, with hydrogen sulfide, sodium sulfide, and sodium hydrosulfide being preferred, and hydrogen sulfide and sodium sulfide being more preferred.

[0017] In a preferred embodiment of the present invention, the alkaline catalyst is selected from any one of trimethylamine, triethylamine, tripropylamine, tributylamine, trihexylamine, tetramethylethylenediamine, pentamethyldiethylenetriamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 4-dimethylaminopyridine (DMAP), 2,6-di-tert-butylpyridine, hexamethylenetetramine, dimethylphenylphosphine, triphenylphosphine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, and alumina.

[0018] More preferably, the base catalyst is selected from any one of triethylamine, 1,4-diazabicyclo[2.2.2]octane, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene. The selection of these catalysts further improves regioselectivity and reaction efficiency.

[0019] As a preferred embodiment of the present invention, the dehydrating agent includes, but is not limited to, DCC (N,N'-dicyclohexylcarbodiimide), EDC / EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide), DIC (N,N'-diisopropylcarbodiimide), DIC (N,N'-diisopropylcarbodiimide), P2O5 (phosphorus pentoxide), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate), HBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate), and PyBOP (benzotriazoloxytripyrrolidinylphosphine hexafluorophosphate).

[0020] In a preferred embodiment of the present invention, the amount of base catalyst used in each reaction is 0.01% to 200% of the molar amount of the monomer compound.

[0021] In a preferred embodiment of the present invention, the organic solvent is selected from one or more commonly used organic solvents such as n-hexane, cyclohexane, toluene, xylene, dichloromethane, chloroform, dichloroethane, methyl tert-butyl ether, methanol, ethanol, acetonitrile, diethyl ether, ethyl acetate, tetrahydrofuran, acetone, isopropanol, dioxane, N,N'-dimethylformamide, N,N'-dimethylacetamide, formamide, acetamide, dimethyl sulfoxide, and N-methylpyrrolidone.

[0022] In a third aspect, the present invention provides a pharmaceutical composition comprising the aforementioned high molecular weight hydrogen sulfide donor compound or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof.

[0023] In a fourth aspect, the present invention provides the use of a compound of general formula (1) or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof or the pharmaceutical composition thereof in the preparation of a medicament for treating diseases related to a decrease in H2S concentration in the body.

[0024] As a preferred embodiment of the present invention, the diseases that lead to a decrease in H2S concentration in the body are cardiovascular and cerebrovascular diseases, neurodegenerative diseases or metabolic syndromes.

[0025] More preferably, the high molecular weight hydrogen sulfide donor compound, its pharmaceutically acceptable salt or its hydrate or solvate, or the pharmaceutical composition is used to prepare a medicament for treating aortic dissection.

[0026] In this invention, the term "halogen" refers to fluorine, chlorine, bromine, iodine, etc., preferably fluorine, chlorine, or bromine, and more preferably fluorine or chlorine.

[0027] In this invention, the term "heteroaryl" refers to a 5- to 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, S, or O, or a bicyclic heteroaryl formed by fused with a benzene ring, pyridine ring, or pyrrole ring. The heteroaryl includes, but is not limited to, furanyl, thiophene, pyrrole, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and preferably pyridinyl, thiophene, and benzofuranyl.

[0028] The compounds provided by this invention are obtained by addition polymerization of compounds containing acyl-yne or hetero-acyl-yne groups with H2S provided by a sulfur source, or by polycondensation or addition polymerization of compounds containing diacyl olefin sulfide units with comonomers. The diacyl olefin sulfide units in the polymer structure can responsively release single H2S in the presence of bio-thiols (GSH, cysteine, etc.). Experimental results show that these compounds have good biocompatibility and stable release behavior, effectively maintain H2S concentrations in mice and rats, significantly reduce the incidence of aortic dissection, and demonstrate outstanding application prospects for cardiovascular diseases. They also possess broad intervention potential for other oxidative stress-related diseases.

[0029] Compared with existing H2S donors, the present invention has the following outstanding advantages: (1) The polymer skeleton is covalently linked by clickable linking units to form a hydrogen sulfide donor with diene sulfide units, which realizes the sequence controllability of the polymer H2S donor structure and avoids the problem of unpredictable release rate caused by random connection between donor and skeleton in traditional methods.

[0030] (2) Different polymer skeletons can be designed according to the characteristics of the disease to achieve precise regulation of H2S release rate and pharmacokinetic behavior.

[0031] (3) Active drug fragments can be flexibly introduced to form a dual-function H2S and drug delivery system, which has unique advantages in the synergistic treatment of cardiovascular, neurological and metabolic diseases. (4) The compounds of the present invention have good biocompatibility and strong degradability, and are feasible for industrial preparation.

[0032] (5) Compared with traditional synthesis methods, the synthesis method of the polymeric hydrogen sulfide donor compound provided by this invention achieves controllable and precise arrangement of the hydrogen sulfide donor unit sequence on the polymer backbone, thereby solving the problems of difficulty in editing hydrogen sulfide releasing units and precise control of release behavior in the prior art. In addition, this strategy also significantly enriches the structure and properties of polymeric hydrogen sulfide donors, and polymeric hydrogen sulfide donors with different properties can be designed as needed.

[0033] In summary, this invention, through innovative polymer design and controllable synthesis strategies, constructs a polymer platform that combines tunable H2S release performance with drug co-delivery function. This overcomes the problems of short half-life of small molecule donors, insufficient sustained-release capacity, and uncontrollable polymer backbone in existing technologies, providing a new technical solution for the development of novel multifunctional gas therapy drugs and broad-spectrum intervention strategies. Attached Figure Description

[0034] Figure 1 1H NMR spectrum of 3,3'-thiodiacrylic acid. Figure 2 : The hydrogen NMR spectrum of DSG12. Figure 3 Fourier transform infrared (FTIR) spectrum of DSG12.

[0035] Figure 4 The gel permeation chromatography (GPC) spectrum of DSG12 indicates that it has a high molecular weight and a relatively narrow molecular weight distribution.

[0036] Figure 5 The H2S release response curves of DSG12 at different GSH concentrations show its good biothiol response characteristics. Figure 6 The curves showing the change in H2S concentration over time in mice of different groups after DSG12 injection. Surface DSG12 can effectively restore blood H2S levels in TAD mice.

[0037] Figure 7 Results of CCK-8 assay for the cytotoxicity of DG12 against HUVECs.

[0038] Figure 8 Results of CCK-8 assay for the cytotoxicity of DSG12 on HUVEC cells.

[0039] Figure 9 Results of CCK-8 assay for the cytotoxicity of DG12 against L929 cells.

[0040] Figure 10 Results of CCK-8 assay for the cytotoxicity of DSG12 on L929 cells.

[0041] Figure 11 Results of CCK-8 assay for the cytotoxicity of DG12 against A7R5 cells.

[0042] Figure 12 Results of CCK-8 assay for the cytotoxicity of DSG12 against A7R5 cells.

[0043] Figure 13 Fluorescence imaging of ROS levels in endothelial cells treated with DSG12 under TNF-α stimulation, indicating that it has excellent antioxidant capacity.

[0044] Figure 14 Fluorescence imaging quantitative analysis of the changes in ROS levels in endothelial cells treated with DSG12 under TNF-α stimulation showed that it has excellent antioxidant capacity.

[0045] Figure 15 Fluorescent imaging of DSG12’s protective effect against TNF-α-induced apoptosis in HUVEC cells indicates its antioxidant capacity.

[0046] Figure 16 Fluorescence imaging of the protective effect of DSG12 against TNF-α-induced apoptosis in HUVEC cells ( Figure 15 Quantitative analysis of ).

[0047] Figure 17 Experimental results on the enhancement of TNF-α-induced Transwell migration ability by DSG12.

[0048] Figure 18 Quantitative analysis of experimental results on the enhancement of Transwell migration ability induced by DSG12 by TNF-α.

[0049] Figure 19 DSG12 enhanced TNF-α-induced cell proliferation. Results are expressed as mean ± standard deviation, n=3, *P<0.05, **P<0.01; Figure 20 In animal experiments on TAD, DSG12 improved the aortic rupture rate in the BAPN-induced TAD model.

[0050] Figure 21 The results of DSG12 improving the survival rate of BAPN-induced TAD model mice in animal experiments.

[0051] Figure 22 Representative images of the aorta from different groups in TAD animal experiments. Figure 23 : Changes in aortic diameter in different groups of mice detected by ultrasound in TAD animal experiments.

[0052] Figure 24 In TAD animal experiments, HE, Masson, and EVG staining of mice in different groups showed improved vascular wall structure.

[0053] Figure 25 Quantitative results of differences in histone cleavage in TAD animal experiments.

[0054] Figure 26 Quantitative analysis of collagen content in different groups in TAD animal experiments, n=3, *P<0.05, **P<0.01; Figure 27 In TAD animal experiments, MMP-9 immunofluorescence staining images in aortic tissues of different groups reflect the inhibitory effect on matrix degradation.

[0055] Figure 28 Quantitative analysis of MMP-9 immunofluorescence intensity in aortic tissue of different groups in TAD animal experiments, n=3, *P<0.05, **P<0.01; Figure 29 In TAD animal experiments, the levels of blood routine parameters in different groups showed that DSG12 had no significant toxic effects. n=3, *P<0.05, **P<0.01.

[0056] Figure 30 In TAD animal experiments, HE staining results of major organs in different groups showed that DSG12 had no significant toxic effects. Detailed Implementation

[0057] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, parts and percentages are parts by weight and weight percentages, respectively.

[0058] In the embodiments, the abbreviations have meanings known in the art, for example; TEA and NEt3 represent triethylamine; DMAP represents 4-dimethylaminopyridine; DBU represents 1,8-diazabicyclo[5.4.0]undec-7-ene; DIPEA represents N,N-diisopropylethylamine; DABCO represents 1,4-diazabicyclo[2.2.2]octane; TMS represents trimethylsilyl; DMF represents N,N-dimethylformamide; THF represents tetrahydrofuran; DCM represents dichloromethane; OEt represents ethoxy, etc.

[0059] All raw materials and solvents used in the reactions are commercially available analytical grade and are used directly without special treatment, unless otherwise stated.

[0060] It is worth noting that the alkynyl or acyl sites can be pre-introduced with drug-active functional groups or targeting groups to modulate the release behavior, hydrophilicity, or bioavailability of the compound, thereby meeting the needs of different indications for H2S delivery strategies.

[0061] Example 1: 10 mmol of triethylene glycol and 60 mmol of propargyl acid were dissolved in 100 ml of toluene, and 5 drops of concentrated sulfuric acid were added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralizing the reaction solution with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation. After dilution with dichloromethane, the unreacted propargyl acid and triethylene glycol were removed by repeated washing with 5% sodium bicarbonate aqueous solution. The organic phase was then dried by rotary evaporation to obtain triethylene glycol dipropargyl ester (denoted as DG3).

[0062] Dissolve 1 mmol of triethylene glycol dipropynate in 20 mL of tetrahydrofuran, add 0.1 mmol of triethylamine, and pass hydrogen sulfide gas into the mixture under an ice-water bath, controlling the gas flow rate to be within the range of 1-10 mL / min. Continue the reaction for 4 hours, then allow it to naturally warm to room temperature. Reduce the solvent by rotary evaporation to obtain a pale yellow oil.

[0063] GPC:M n = 6.2×10 5 Example 2: 10 mmol of hexaethylene glycol and 60 mmol of propargyl acid were dissolved in 100 ml of toluene, and 5 drops of concentrated sulfuric acid were added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralizing the reaction solution with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation, diluted with dichloromethane, and repeatedly washed with 5% sodium bicarbonate aqueous solution to remove unreacted propargyl acid and hexaethylene glycol. The organic phase was then dried by rotary evaporation to obtain hexaethylene glycol dipropargyl ester (denoted as DG6).

[0064] Dissolve 1 mmol of hexaethylene glycol dipropynate in 20 mL of tetrahydrofuran, add 0.1 mmol of triethylamine, and pass hydrogen sulfide gas into the mixture under an ice-water bath, controlling the gas flow rate to be within the range of 1-10 mL / min. Continue the reaction for 4 h, then allow the mixture to naturally warm to room temperature. Reduce the solvent by rotary evaporation to obtain a pale yellow oil.

[0065] GPC:M n = 4.3 × 10 4 Example 3: 10 mmol of nonaethylene glycol and 60 mmol of propargyl acid were dissolved in 100 ml of toluene, and 5 drops of concentrated sulfuric acid were added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralizing the reaction solution with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation. After dilution with dichloromethane, the unreacted propargyl acid and nonaethylene glycol were removed by repeated washing with 5% sodium bicarbonate aqueous solution. The organic phase was then dried by rotary evaporation to obtain nonaethylene glycol dipropargyl ester (denoted as DG9).

[0066] Dissolve 1 mmol of nonaethylene glycol dipropynate in 20 mL of tetrahydrofuran, add 0.1 mmol of triethylamine, and pass hydrogen sulfide gas into the mixture under an ice-water bath, controlling the gas flow rate to be within the range of 1-10 mL / min. Continue the reaction for 4 h, then allow it to naturally warm to room temperature. Reduce the solvent by rotary evaporation to obtain a pale yellow oil.

[0067] GPC:M n = 4.5 × 10 4 Example 4: 10 mmol of dodecaethylene glycol and 60 mmol of propargyl acid were dissolved in 100 ml of toluene, and 5 drops of concentrated sulfuric acid were added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralizing the reaction solution with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation. After dilution with dichloromethane, the unreacted propargyl acid and dodecaethylene glycol were removed by repeated washing with 5% sodium bicarbonate aqueous solution. The organic phase was then evaporated to dryness to obtain dodecaethylene dipropargyl ester (denoted as DG12).

[0068] Dissolve 1 mmol of dodecaethylene glycol dipropynate in 20 mL of tetrahydrofuran, add 0.1 mmol of triethylamine, and pass hydrogen sulfide gas into the mixture under an ice-water bath, controlling the gas flow rate to be within the range of 1–10 mL / min. Continue the reaction for 4 h, then allow the mixture to naturally warm to room temperature. Remove the solvent by rotary evaporation to obtain a pale yellow oil, labeled DSG12.

[0069] GPC:M n = 3.5×10 4 Example 5: 20 mmol of propynic acid was dissolved in tetrahydrofuran and mixed with 10 mmol of sodium sulfide aqueous solution. Then, 1 mmol of triethylamine was added as a catalyst under magnetic stirring. After the reaction was completed, hydrochloric acid was added to precipitate the product, and the product was washed with a small amount of ethanol to obtain 3,3'-thiodiacrylic acid.

[0070] 1 mmol of 3,3'-thiodiacrylic acid and 1 mmol of triethylene glycol dipropynate were dissolved in 20 ml of tetrahydrofuran, and 0.1 mmol of DABCO was added as a catalyst. The mixture was stirred at room temperature for 4 h, the solvent was evaporated, dialyzed for 48 h, and then freeze-dried to obtain a light yellow oil.

[0071] GPC:M n = 1.7×10 4 Example 6: 20 mmol of propynic acid was dissolved in tetrahydrofuran and mixed with 10 mmol of sodium sulfide aqueous solution. Then, 1 mmol of triethylamine was added as a catalyst under magnetic stirring. After the reaction was completed, hydrochloric acid was added to precipitate the product, and the product was washed with a small amount of ethanol to obtain 3,3'-thiodiacrylic acid.

[0072] 1 mmol of 3,3'-thiodiacrylic acid and 1 mmol of honokiol dipropynate were dissolved in 20 ml of tetrahydrofuran. 0.1 mmol of DABCO was added as a catalyst. The mixture was stirred at room temperature for 4 h, the solvent was evaporated, dialyzed for 48 h, and then freeze-dried to obtain a brown oily substance.

[0073] GPC: Mn = 8.3 × 10 4 Example 7: 10 mmol of 2-bromoethanol and 22 mmol of propargyl acid were dissolved in 100 ml of toluene, and 1 mmol of p-toluenesulfonic acid was added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralization with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation, diluted with dichloromethane, and repeatedly washed with 5% sodium bicarbonate aqueous solution to remove unreacted propargyl acid and bromoethanol. The final product was obtained by column chromatography.

[0074] Dissolve 5 mmol of ethyl propynate in 20 mL of tetrahydrofuran, add 0.1 mmol of triethylamine, and pass hydrogen sulfide gas into the solution under an ice-water bath, controlling the gas flow rate to be within the range of 1–10 mL / min. Allow the reaction to proceed for 4 hours, then allow it to naturally warm to room temperature. Reverse the solvent to obtain a pale yellow oily substance, which is bis(2-bromoethyl) 3,3'-thiodiacrylate.

[0075] 1 mmol of bis(2-bromoethyl) 3,3'-thiodiacrylate was dissolved in 50 ml of acetonitrile. 0.8 mmol of tetramethylethylenediamine dissolved in 50 ml of acetonitrile was added dropwise through a constant pressure dropping funnel under ice-water bath. The mixture was allowed to cool naturally to room temperature, then heated to 45 °C and stirred for 12 h. After the reaction solution was evaporated to dryness, it was dialyzed for 48 hours to obtain a brown viscous substance.

[0076] GPC:M n = 3.1×10 4 Example 8: 10 mmol of 2-bromoethanol and 22 mmol of propargyl acid were dissolved in 100 ml of toluene, and 1 mmol of p-toluenesulfonic acid was added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralization with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation, diluted with dichloromethane, and repeatedly washed with 5% sodium bicarbonate aqueous solution to remove unreacted propargyl acid and bromoethanol. The final product was obtained by column chromatography.

[0077] Dissolve 5 mmol of ethyl propynate in 20 mL of tetrahydrofuran, add 0.1 mmol of triethylamine, and pass hydrogen sulfide gas into the solution under an ice-water bath, controlling the gas flow rate to be within the range of 1–10 mL / min. Allow the reaction to proceed for 4 h, then allow it to naturally warm to room temperature. Reverse the solvent to obtain a pale yellow oily substance, which is bis(2-bromoethyl) 3,3'-thiodiacrylate.

[0078] 1 mmol of bis(2-bromoethyl) 3,3'-thiodiacrylate and 1 mmol of N,N,N',N'-tetramethylbutanediamine were dissolved in 20 ml of acetonitrile. The mixture was heated and stirred overnight at 45 degrees Celsius. After the reaction solution was evaporated to dryness, it was dialyzed for 48 hours to obtain a brown viscous substance.

[0079] GPC:M n = 2.2×10 4 Example 9: 10 mmol of 2-bromoethanol and 22 mmol of propargyl acid were dissolved in 100 ml of toluene, and 1 mmol of p-toluenesulfonic acid was added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralization with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation, diluted with dichloromethane, and repeatedly washed with 5% sodium bicarbonate aqueous solution to remove unreacted propargyl acid and bromoethanol. The final product was obtained by column chromatography.

[0080] Dissolve 5 mmol of ethyl propynate in 20 mL of tetrahydrofuran, add 0.1 mmol of triethylamine, and pass hydrogen sulfide gas into the solution under an ice-water bath, controlling the gas flow rate to be within the range of 1–10 mL / min. Allow the reaction to proceed for 4 h, then allow it to naturally warm to room temperature. Reverse the solvent to obtain a pale yellow oily substance, which is bis(2-bromoethyl) 3,3'-thiodiacrylate.

[0081] 1 mmol of bis(2-bromoethyl) 3,3'-thiodiacrylate and 1 mmol of N,N,N',N'-tetramethylhexanediamine were dissolved in 20 ml of acetonitrile. The mixture was heated and stirred overnight at 45 degrees Celsius. After the reaction solution was evaporated to dryness, it was dialyzed for 48 hours to obtain a brown viscous substance.

[0082] GPC:M n = 1.8 × 10 4 Example 10: 10 mmol of 2-bromoethanol and 22 mmol of propargyl acid were dissolved in 100 ml of toluene, and 1 mmol of p-toluenesulfonic acid was added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralization with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation, diluted with dichloromethane, and repeatedly washed with 5% sodium bicarbonate aqueous solution to remove unreacted propargyl acid and bromoethanol. The final product was obtained by column chromatography.

[0083] Dissolve 5 mmol of ethyl propynate in 20 mL of tetrahydrofuran, add 0.1 mmol of triethylamine, and pass hydrogen sulfide gas into the solution under an ice-water bath, controlling the gas flow rate to be within the range of 1–10 mL / min. Allow the reaction to proceed for 4 h, then allow it to naturally warm to room temperature. Reverse the solvent to obtain a pale yellow oily substance, which is bis(2-bromoethyl) 3,3'-thiodiacrylate.

[0084] 1 mmol of bis(2-bromoethyl) 3,3'-thiodiacrylate and 1 mmol of 2,3-dimethoxy-1,4-bis(dimethylamino)butane were dissolved in 20 ml of acetonitrile. The mixture was heated and stirred overnight at 45 degrees Celsius. After the reaction solution was evaporated to dryness, it was dialyzed for 48 hours to obtain a brown viscous substance.

[0085] GPC:M n = 2.7 × 10 4 Example 11: 10 mmol of 2-bromoethanol and 22 mmol of propargyl acid were dissolved in 100 ml of toluene, and 1 mmol of p-toluenesulfonic acid was added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralization with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation, diluted with dichloromethane, and repeatedly washed with 5% sodium bicarbonate aqueous solution to remove unreacted propargyl acid and bromoethanol. The final product was obtained by column chromatography.

[0086] Dissolve 5 mmol of ethyl propynate in 20 mL of tetrahydrofuran, add 0.1 mmol of triethylamine, and pass hydrogen sulfide gas into the solution under an ice-water bath, controlling the gas flow rate to be within the range of 1–10 mL / min. Allow the reaction to proceed for 4 h, then allow it to naturally warm to room temperature. Reverse the solvent to obtain a pale yellow oily substance, which is bis(2-bromoethyl) 3,3'-thiodiacrylate.

[0087] 1 mmol of bis(2-bromoethyl) 3,3'-thiodiacrylate and 1 mmol of 1,3-bis(dimethylamino)-2-propanol were dissolved in 20 ml of acetonitrile. The mixture was heated and stirred overnight at 45 degrees Celsius. After the reaction solution was evaporated to dryness, it was dialyzed for 48 hours to obtain a brown viscous substance.

[0088] GPC:M n = 5.7 × 10 4 Example 12: 10 mmol of 2-bromoethanol and 22 mmol of propargyl acid were dissolved in 100 ml of toluene, and 1 mmol of p-toluenesulfonic acid was added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralization with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation, diluted with dichloromethane, and repeatedly washed with 5% sodium bicarbonate aqueous solution to remove unreacted propargyl acid and bromoethanol. The final product was obtained by column chromatography.

[0089] Dissolve 5 mmol of ethyl propynate in 20 mL of tetrahydrofuran, add 0.1 mmol of triethylamine, and pass hydrogen sulfide gas into the solution under an ice-water bath, controlling the gas flow rate to be within the range of 1–10 mL / min. Allow the reaction to proceed for 4 h, then allow it to naturally warm to room temperature. Reverse the solvent to obtain a pale yellow oily substance, which is bis(2-bromoethyl) 3,3'-thiodiacrylate.

[0090] 1 mmol of bis(2-bromoethyl) 3,3'-thiodiacrylate and 1 mmol of di(dimethylamino)methoxymethane were dissolved in 20 ml of acetonitrile. The mixture was heated and stirred overnight at 45 degrees Celsius. After the reaction solution was evaporated to dryness, it was dialyzed for 48 hours to obtain a brown viscous substance.

[0091] GPC:M n = 3.8 × 104 Example 13: 10 mmol of 2-bromoethanol and 22 mmol of propargyl acid were dissolved in 100 ml of toluene, and 1 mmol of p-toluenesulfonic acid was added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralization with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation, diluted with dichloromethane, and repeatedly washed with 5% sodium bicarbonate aqueous solution to remove unreacted propargyl acid and bromoethanol. The final product was obtained by column chromatography.

[0092] Dissolve 5 mmol of ethyl propynate in 20 mL of tetrahydrofuran, add 0.1 mmol of triethylamine, and pass hydrogen sulfide gas into the solution under an ice-water bath, controlling the gas flow rate to be within the range of 1–10 mL / min. Allow the reaction to proceed for 4 h, then allow it to naturally warm to room temperature. Reverse the solvent to obtain a pale yellow oily substance, which is bis(2-bromoethyl) 3,3'-thiodiacrylate.

[0093] 1 mmol of bis(2-bromoethyl) 3,3'-thiodiacrylate and 1 mmol of bis(dimethylamino)tert-butoxymethane were dissolved in 20 ml of acetonitrile. The mixture was heated and stirred overnight at 45 degrees Celsius. After the reaction solution was evaporated to dryness, it was dialyzed for 48 hours to obtain a brown viscous substance.

[0094] GPC:M n = 2.1×10 4 Example 14: 10 mmol of 2-bromoethanol and 22 mmol of propargyl acid were dissolved in 100 ml of toluene, and 1 mmol of p-toluenesulfonic acid was added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralization with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation, diluted with dichloromethane, and repeatedly washed with 5% sodium bicarbonate aqueous solution to remove unreacted propargyl acid and bromoethanol. The final product was obtained by column chromatography.

[0095] Dissolve 5 mmol of ethyl propynate in 20 mL of tetrahydrofuran, add 0.1 mmol of triethylamine, and pass hydrogen sulfide gas into the solution under an ice-water bath, controlling the gas flow rate to be within the range of 1–10 mL / min. Allow the reaction to proceed for 4 h, then allow it to naturally warm to room temperature. Reverse the solvent to obtain a pale yellow oily substance, which is bis(2-bromoethyl) 3,3'-thiodiacrylate.

[0096] 1 mmol of bis(2-bromoethyl) 3,3'-thiodiacrylate and 1 mmol of bis(2-dimethylaminoethyl) ether were dissolved in 20 ml of acetonitrile. The mixture was heated and stirred overnight at 45 degrees Celsius. After the reaction solution was evaporated to dryness, it was dialyzed for 48 hours to obtain a brown viscous substance.

[0097] GPC:M n = 3.9×10 4 Example 15: 10 mmol of trimethylolethane and 60 mmol of propargyl acid were dissolved in 100 ml of toluene, and 5 drops of concentrated sulfuric acid were added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralizing the reaction solution with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation, diluted with dichloromethane, and repeatedly washed with 5% sodium bicarbonate aqueous solution to remove unreacted propargyl acid and dodecaethylene glycol. The organic phase was then dried by rotary evaporation and recrystallized to obtain trimethylolethane tripropargyl ester.

[0098] 5 mmol of trimethylolpropynate and 5.5 mmol of thioglycerol were simultaneously dissolved in 50 mL of tetrahydrofuran. 0.1 mmol of triethylamine was added as a catalyst, and the mixture was reacted at room temperature with stirring for 12 h. After the reaction was complete, hydrogen sulfide gas was introduced into the mixture under an ice-water bath at a flow rate of 1–10 mL / min for 4 h, followed by natural warming to room temperature. The reaction solution was evaporated to dryness and dialyzed for 48 h to obtain a brown viscous substance.

[0099] GPC:M n = 5.2 × 10 4 Example 16: 10 mmol of trimethylolethane and 60 mmol of propargyl acid were dissolved in 100 ml of toluene, and 5 drops of concentrated sulfuric acid were added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralizing the reaction solution with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation, diluted with dichloromethane, and repeatedly washed with 5% sodium bicarbonate aqueous solution to remove unreacted propargyl acid and dodecaethylene glycol. The organic phase was then dried by rotary evaporation and recrystallized to obtain trimethylolethane tripropargyl ester.

[0100] 1 mmol of trimethylolpropynate and 1.1 mmol of captopril were simultaneously dissolved in 50 mL of DMF, and 0.1 mmol of triethylamine was added as a catalyst. The reaction was carried out at room temperature with stirring for 12 h. After the reaction was completed, hydrogen sulfide gas was introduced into the mixture under an ice-water bath at a flow rate of 1–10 mL / min for 4 h, followed by natural warming to room temperature. The reaction solution was evaporated to dryness and dialyzed for 48 h to obtain a brown viscous substance.

[0101] GPC:M n = 2.3×10 4 Example 17: 10 mmol of trimethylolethane and 60 mmol of propargyl acid were dissolved in 100 ml of toluene, and 5 drops of concentrated sulfuric acid were added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralizing the reaction solution with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation, diluted with dichloromethane, and repeatedly washed with 5% sodium bicarbonate aqueous solution to remove unreacted propargyl acid and dodecaethylene glycol. The organic phase was then dried by rotary evaporation and recrystallized to obtain trimethylolethane tripropargyl ester.

[0102] 1 mmol of trimethylolpropynate and 1.1 mmol of cysteine ​​were simultaneously dissolved in 50 mL of a mixed solvent of dimethylformamide and water (45:5). 0.1 mmol of triethylamine was added as a catalyst, and the reaction was carried out at room temperature with stirring for 12 h. After the reaction was complete, hydrogen sulfide gas was introduced into the solution under an ice-water bath at a flow rate of 1–10 mL / min for 4 h, followed by natural warming to room temperature. The reaction solution was evaporated to dryness and dialyzed for 48 h to obtain a brown viscous substance.

[0103] GPC:M n = 8.5 × 10 3 Example 18: 10 mmol of trimethylolethane and 60 mmol of propargyl acid were dissolved in 100 ml of toluene, and 5 drops of concentrated sulfuric acid were added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralizing the reaction solution with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation, diluted with dichloromethane, and repeatedly washed with 5% sodium bicarbonate aqueous solution to remove unreacted propargyl acid and dodecaethylene glycol. The organic phase was then dried by rotary evaporation and recrystallized to obtain trimethylolethane tripropargyl ester.

[0104] 1 mmol of trimethylolpropynate and 1.1 mmol of glutathione were simultaneously dissolved in 50 mL of dimethylformamide and reacted with stirring at room temperature for 12 h. After the reaction was complete, hydrogen sulfide gas was introduced into the mixture under an ice-water bath at a flow rate of 1–10 mL / min for 4 h, followed by natural warming to room temperature. The reaction solution was evaporated to dryness and dialyzed for 48 h to obtain a brown viscous substance.

[0105] GPC:M n = 1.5×10 4 Example 19: 10 mmol of trimethylolethane and 60 mmol of propargyl acid were dissolved in 100 ml of toluene, and 5 drops of concentrated sulfuric acid were added as a catalyst. The mixture was then refluxed at 130 °C for 24 h using a water separator. After neutralizing the reaction solution with saturated sodium bicarbonate, the organic phase was concentrated by rotary evaporation, diluted with dichloromethane, and repeatedly washed with 5% sodium bicarbonate aqueous solution to remove unreacted propargyl acid and dodecaethylene glycol. The organic phase was then dried by rotary evaporation and recrystallized to obtain trimethylolethane tripropargyl ester.

[0106] 1 mmol of trimethylolpropynate and 1.1 mmol of isosorbide mononitrate were simultaneously dissolved in 50 mL of dimethylformamide. 0.1 mmol of triethylamine was added as a catalyst, and the reaction was carried out at room temperature with stirring for 12 h. After the reaction was complete, hydrogen sulfide gas was introduced into the solution under an ice-water bath at a flow rate of 1–10 mL / min for 4 h, followed by natural warming to room temperature. The reaction solution was evaporated to dryness and dialyzed for 48 h to obtain a brown viscous substance.

[0107] GPC:M n = 9.2 × 10 3 Since the compounds of the general formula (I) provided by this invention have stable H2S release behavior and excellent biocompatibility, and can significantly reduce the incidence of aortic dissection, and are also applicable to other diseases related to oxidative stress, this invention only uses the compound prepared in Example 4 (hereinafter referred to as DSG12) as an example to illustrate the effect.

[0108] Experimental Example 1: In vitro release capacity of the compound H2S of this invention This experiment aims to evaluate the hydrogen sulfide release capacity of the compounds of this invention under physiological conditions. The classic methylene blue method (see Pramod K. Yadav, Michael Martinov, Victor Vitvitsky et al. Biosynthesis and Reactivity of Cysteine ​​Persulfides in Signaling. J. Am. Chem. Soc. 2016, 138, 1, 289-299.) was used to quantitatively determine the H2S release capacity of the donor compounds of this invention under simulated physiological microenvironment conditions.

[0109] The experimental conditions were as follows: the buffer was PBS (10 mM) at pH 7.4, or 0.5 mM cysteine ​​was added as a physiological thiol model. The compound of this invention was dissolved and incubated at 37 °C. Samples were taken at different time points, and the absorbance changes of methylene blue were measured to calculate the amount of H2S released.

[0110] Procedure: 50 µM of compound 1 (hereinafter referred to as DSG12) at different concentrations were dissolved in PBS 7.4 buffer with GSH concentrations of 0, 1, and 2 mM (12 groups in total). After incubation at 37°C for 5 hours, the H2S concentration in the solution was determined using the methylene blue method described above to evaluate its release under different microenvironments.

[0111] Experimental results (see) Figure 5 The results show that the compounds of this invention exhibit significant thiol responsiveness, with no release in GSH-free buffers, but significant and gradually increasing release in buffers containing different concentrations of Cys. These results demonstrate that the compounds of this invention possess stable and controllable H2S release performance under physiological conditions, which not only meets the continuous supply requirements for long-term treatment of chronic diseases but also provides experimental evidence and directions for drug structure optimization for designing differentiated H2S donors based on different disease characteristics.

[0112] Experimental Example 2 In vivo H2S release capacity of compound DSG12 of the present invention This experiment aims to evaluate the hydrogen sulfide release capacity of the compounds of this invention under physiological conditions. The classic liquid chromatography-mass spectrometry (LC-MS / MS) method (also known as the MBB method, see reference Shanshan Luo, Chuiyu Kong, Shuang Zhao et al. Endothelial HDAC1-ZEB2-NuRD Complex Drives Aortic Aneurysm and DissectionThrough Regulation of Protein S-Sulfhydration, Circulation. 2023;147:1382–1403.) was used to determine the H2S release capacity of the donors of this invention in rats.

[0113] The experimental animals were C57BL / 6J mice (male, n = 5), which were acclimatized for one week before the experiment. The compound of this invention was dissolved in PBS and freshly prepared before use. C57BL / 6J mice were intraperitoneally injected with DSG12 (60 mg / kg), and plasma samples were collected at 1, 2, 4, 6, 8, 10, and 12 hours after administration. Plasma H2S concentration was determined using the MBB method described above. A control group (normal drinking water) and a BAPN group (TAD model) were set up for comparison to evaluate the ability of DSG12 to increase and maintain H2S levels in vivo.

[0114] Experimental results ( Figure 6The results showed that in animal release experiments, after a single intraperitoneal injection of 60 mg / kg, the plasma H2S concentration in mice reached a peak of 704.368 nM at about 5 hours, which was 115.586 nM higher than that in the BAPN-induced TAD model control group, and remained above 630 nM for 12 hours, demonstrating a sustained and stable in vivo release capacity.

[0115] Experimental Example 3: DSG12 exhibits good biocompatibility with a variety of cell types. To systematically evaluate the in vitro biosafety of DSG12, the CCK-8 cell viability assay was used to investigate its effects on three cell types under different concentrations. The cytotoxicity differences between DSG12 and its precursor molecule DG12 in HUVECs (human umbilical vein endothelial cells), L929 (mouse fibroblasts), and A7R5 (rat aortic smooth muscle cells) were compared and analyzed to clarify its biocompatibility advantages. In the cell compatibility and toxicology evaluation, DG12 was used as a control, and DSG12 was used as the test sample. All figure captions and text descriptions are consistent with this. The steps are as follows:

[0116] (1) Cell culture: HUVEC (immortalized human umbilical vein endothelial cell line) and A7R5 (rat aortic smooth muscle cell line) were obtained from the American Type Culture Collection (ATCC) in the United States. L929 (mouse fibroblast cell line) cells were obtained from Procell in China. A7R5 cells were stored in DMEM (high glucose) supplemented with 10% bovine serum, 0.08 mg / mL streptomycin and 80 U / mL penicillin at 37°C and 5% CO2. HUVEC cells were placed in EGM-2 MV (Lonza) containing 5% fetal bovine serum (FBS), 0.1 ng / mL vascular endothelial growth factor (VEGF), 5 ng / mL epidermal growth factor (EGF), 10 ng / mL fibroblast growth factor-2 (FGF-2), 1 µg / mL hydrocortisone, 50 µg / mL gentamicin and 0.05 mg / mL amphotericin B and maintained at 37°C and 5% CO2. L929 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum, 0.08 mg / mL streptomycin, and 80 U / mL penicillin, under the same environmental conditions as above.

[0117] (2) Drug dissolution and treatment: The lyophilized DSG12 and DG12 were dissolved in sterile PBS to prepare a series of concentrations. The control group was treated with the same volume of PBS.

[0118] (3) CCK-8 cell viability assay: Cells were seeded at 5 × 10³ cells / well in 96-well plates. After 24 hours, different concentrations of compound solutions were added. After another 24 hours of incubation, 10 µL of CCK-8 working solution was added, and incubation was continued for 1 hour. The absorbance (OD) was read at 450 nm. Five replicate wells were set up for each group, and three independent replicate experiments were performed.

[0119] Experimental results are as follows Figures 7-12 As shown, DG12 exhibited good biocompatibility in all three cell models, demonstrating that cell activity remained at a high level even under high concentration conditions.

[0120] In HUVEC cells, DG12 treatment up to 400 µM maintained >85% cell viability, and no concentration-related toxicity was observed; however, DSG12 activity began to decline after 100 µM, and the activity was below 30% at 300 µM.

[0121] In L929 cells, the activity of DG12 remained stable at all concentrations, while the DSG12 group showed significant inhibition of cell activity at ≥100 µM and decreased to <20% at 300 µM.

[0122] In A7R5 cells, DG12 showed no significant toxicity in the concentration range of 0–300 µM, with a small amount of toxicity at 400 µM; however, DSG12 showed a decrease in activity from 75 µM onwards, and almost no cell viability at 300 µM, demonstrating a significant concentration-dependent inhibitory effect.

[0123] Statistical analysis showed that the DSG12 group was significantly different from the control group at medium and high concentrations (≥100 µM) (P<0.01), while the DG12 group showed no statistically significant difference from the control group at the full concentration range except for a small amount of toxicity to A7R5 at 400 µM (P>0.05).

[0124] Experiment Example 4: DSG12 can inhibit ROS production in endothelial cells and has anti-apoptotic effects. This experiment aimed to evaluate the protective effect of DSG12 on endothelial cells under oxidative stress, focusing on whether it could protect endothelial cell homeostasis by inhibiting reactive oxygen species (ROS) generation and inhibiting apoptosis. To this end, HUVEC cells were stimulated with TNF-α to simulate an inflammatory injury model, and the ROS levels, cell viability, and apoptosis rate after treatment were analyzed. The steps are as follows:

[0125] (1) Cell culture: Same as in Experiment 3; (2) Experimental group setup: Three groups were set up in the experiment: control group (no treatment), TNF-α group (TNF-α stimulation, 10 ng / mL), and TNF-α + drug group (TNF-α stimulation + 50 µM DSG12 treatment). (3) ROS detection: First, ROS levels were labeled using the DCFH-DA fluorescent probe (2',7'-dichlorodifluorofluorescein diacetate). After treatment in each group, HUVEC cells were treated with the DCFH-DA probe (10 µM) and incubated at 37°C for 30 minutes. Fluorescence intensity was detected by flow cytometry to analyze the ROS generation level in each group. Second, ROS fluorescence intensity was calculated using quantitative analysis software, and the results are expressed in relative units.

[0126] (4) Apoptosis detection: First, apoptosis was detected using Calcein-AM (cell viability marker) and PI (cell death marker) double staining. After treatment, cells in each group were stained with Calcein-AM and PI, and the ratio of viable cells to dead cells was observed under a fluorescence microscope. Second, cell viability and apoptosis ratio were quantitatively analyzed by flow cytometry.

[0127] The results are as follows Figures 13-16 As shown, the ROS level of HUVEC cells in the TNF-α stimulation group was significantly increased, the DCFH-DA fluorescence intensity was significantly increased, and the proportion of apoptotic cells was high. In contrast, after DSG12 treatment, the ROS level was significantly decreased, the fluorescence intensity was reduced, and the proportion of Calcein-AM-labeled surviving cells was significantly increased. Quantitative analysis results indicate that the cell survival rate in the DSG12 treatment group was significantly higher than that in the TNF-α stimulation group, while the proportion of apoptotic cells was significantly reduced.

[0128] Experimental Example 5: DSG12 can promote endothelial cell migration and proliferation. To further evaluate the role of DSG12 in promoting vascular endothelial function repair, this experiment used Transwell migration assays and WST-1 cell proliferation assays to examine its effects on the migration and proliferation abilities of HUVEC cells under inflammatory stimulation. This experiment aims to verify that the material of this invention not only possesses cell-protective functions but also actively promotes the endothelial repair process after injury. The steps are as follows:

[0129] (1) Cell preparation and treatment: Logarithmically growing HUVEC cells were seeded in 96-well plates (for WST-1) or Transwell chambers (for migration experiments) and cultured at 37°C and 5% CO2 until approximately 80% confluence. The cell treatment groups were set up as follows: control group: no treatment; TNF-α group: incubated with 10 ng / mL TNF-α for 24 hours; TNF-α + DSG12 group: incubated with TNF-α (10 ng / mL) + DSG12 (50 µM) simultaneously for 24 hours.

[0130] (2) Transwell cell migration experiment: First, add 1×10⁻⁶ cells to the upper chamber of the Transwell chamber. 5 After treatment, HUVEC cells were incubated in complete culture medium containing 10% FBS as a chemokine. After 24 hours of incubation, unmigrated cells in the upper chamber were removed, fixed with 4% paraformaldehyde, stained with crystal violet, and photographed and counted under a light microscope. Finally, three replicates were set up for each group, and the number of migrating cells per field of view was counted, with the average taken as an indicator of migration ability.

[0131] (3) WST-1 cell proliferation assay: First, after the cells in each group were treated, 10 µL of WST-1 reagent (Roche) was added to the well containing 100 µL of culture medium; Second, after incubation at 37°C for 1 hour, the absorbance (OD) was measured at a wavelength of 450 nm. 450 This reflects cellular metabolic activity and proliferation levels. The third step involves setting up 5 parallel wells for each group, and repeating the experiment 3 times.

[0132] The results are as follows Figures 17-19 As shown, the migration ability of HUVEC cells in the TNF-α group was significantly decreased, with the number of migrating cells reduced by approximately 50% compared to the control group. However, after DSG12 treatment, the migration ability was significantly improved, and the number of migrating cells recovered to the control group level, or even slightly increased, demonstrating a significant cell migration-promoting effect. Statistical analysis showed a statistically significant difference between the TNF-α + DSG12 group and the TNF-α group (P<0.01). In WST-1 assays, TNF-α significantly inhibited cell proliferation (OD value decreased by approximately 35%), while DSG12 treatment significantly increased OD value. 450 The absorbance value suggests that it can reverse the inhibitory effect of TNF-α and restore cell vitality.

[0133] Experimental Example 6: DSG12 can significantly reduce the aortic rupture rate in TAD animal models. This experiment used a BAPN-induced TAD mouse model to evaluate the therapeutic effect of DSG12 in aortic dissection (TAD). By comparing the aortic rupture rate between the DSG12-treated group and the control group, the role of the material of this invention in the intervention of aortic dissection was further verified. The steps are as follows:

[0134] (1) Animal model establishment: Four-week-old male C57BL / 6J mice were randomly divided into three groups (n = 15 in each group): control group: normal drinking water + physiological saline injection; BAPN group: drinking 0.25% β-aminopropionitrile (BAPN) aqueous solution + physiological saline injection; BAPN + DSG12 group: drinking 0.25% β-aminopropionitrile (BAPN) aqueous solution + DSG12 intraperitoneal injection.

[0135] (2) Administration and treatment: From the day of modeling, DSG12 was administered intraperitoneally at a dose of 60 mg / kg twice daily for 28 days. Mice in the BAPN drinking water group drank 0.25% BAPN aqueous solution for 28 days, and continued to be administered the drug after the model was established.

[0136] (3) Aortic rupture assessment: a) At the end of the experiment, mice were examined by ultrasound (VEVO 2100) to measure the diameter of the thoracic aorta and determine whether dissection had occurred. b) Dead or terminally ill mice were dissected after the experiment to observe whether the aorta had ruptured and to record the location, size and cause of death of the rupture. c) The aortic rupture rate was the number of ruptured mice / the total number of mice. The aortic rupture rate of each group of mice was calculated.

[0137] The results are as follows Figures 20-21 As shown, in the BAPN-induced TAD mouse model, the aortic rupture rate was 53.3% in the untreated BAPN group, while it was significantly reduced to 20% in the DSG12-treated group (P<0.01). No such significant change was observed in other control groups (including the BAPN group). Furthermore, the survival rate of mice in the DSG12-treated group was significantly improved, increasing by 30% compared to the BAPN group. These results indicate that DSG12 can effectively reduce the aortic rupture rate in TAD mice and significantly prolong their survival time.

[0138] Experiment Example 7: DSG12 can improve vascular structure destruction and matrix degradation in TAD models. This experiment aimed to evaluate the effects of DSG12 on vascular structure in a TAD mouse model, particularly its repair effect on inflammation-induced aortic structural damage and matrix degradation. The effects of DSG12 treatment on aortic wall stability, elastic fiber integrity, and matrix-degrading enzyme (MMP-9) expression were detected using ultrasound diameter measurement, HE staining, EVG staining, and MMP-9 immunofluorescence analysis. The steps are as follows:

[0139] (1) Animal model and experimental group setup: Same as in Experiment 6; (2) DSG12 administration and treatment: same as in Experiment 6; (3) Ultrasonic diameter measurement: On days 0, 14, and 28 of the experiment, B-mode ultrasound scans were performed using the VEVO 2100 ultrasound system to measure the changes in the diameter of the mouse thoracic aorta. The stability of the vascular wall was assessed by periodically monitoring changes in the vascular diameter.

[0140] (4) Histological analysis: At the end of the mouse experiment, the aorta was removed and the tissue was fixed in 4% paraformaldehyde and then embedded in paraffin. The section thickness was 5 µm, and HE staining, Masson's trichrome staining and EVG staining were performed. HE staining was used to observe structural changes in the blood vessel wall; Masson's staining was used to detect collagen fiber deposition; and EVG staining was used to observe the integrity and degree of breakage of elastic fibers.

[0141] (5) MMP-9 immunofluorescence staining: First, aortic tissue taken from mice was embedded in an OCT complex and rapidly frozen. Second, 5 µm thick sections were used for MMP-9 immunofluorescence staining, and matrix metalloproteinase 9 expression was labeled with anti-MMP-9 antibody (Abcam, 1:200 dilution). Third, the staining results were observed using a fluorescence microscope, and the MMP-9 expression intensity of different groups of mice was analyzed.

[0142] The results are as follows Figures 22-28 As shown, the aortic vessel wall of mice in the BAPN group was significantly damaged. HE staining results showed intimal detachment, medial rupture, and separation of the inner and outer layers, with significant breakage of elastic fibers (EVG staining). Masson staining results indicated excessive collagen deposition, further exacerbating the pathological remodeling of the vessel wall. In the DSG12 treatment group, the vessel wall structure was relatively stable. HE staining showed a more uniform vessel wall thickness, no significant intimal detachment, fewer elastic fiber (EVG staining) breaks, and lower collagen deposition. Ultrasound examination showed that the aortic diameter of mice in the DSG12 treatment group changed less, indicating that the stability of the vessel wall was effectively improved. MMP-9 immunofluorescence results showed that MMP-9 expression was significantly increased in the BAPN group mice, while MMP-9 expression was significantly downregulated in the DSG12 treatment group, indicating that DSG12 can effectively inhibit matrix degradation, reduce matrix metalloproteinase 9 activity, and thus slow down the vascular remodeling process.

[0143] Experimental Example 8 DSG12 has no obvious toxicity or organ damage in vivo. To systematically evaluate the in vivo biosafety of the material DSG12 of this invention, this experiment examined its effects on the function and morphology of major organs in mice at multiple levels. By detecting serum liver and kidney function biochemical indicators and HE staining results of major organs such as the heart, liver, spleen, lungs, and kidneys, it was determined whether it caused organ structural damage or toxic reactions. The steps are as follows:

[0144] (1) Experimental animals and grouping: Same as in Experiment Example 6; (2) DSG12 dosing regimen: same as in Experiment 6; (3) Serum biochemical index detection: After the experiment on day 28, mice were anesthetized, and whole blood was collected from the heart. Serum was obtained by centrifugation, and the following indicators were detected using a fully automated biochemical analyzer: Liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST). Kidney function: urea (UREA), creatinine (CREA). Other systemic indicators: lactate dehydrogenase (LDH), uric acid (UA). Blood cell parameters: white blood cells (WBC), red blood cells (RBC), platelets (PLT), mean corpuscular hemoglobin concentration (MCHC).

[0145] (4) Organ histological evaluation: After euthanizing the mice, organs such as heart, liver, spleen, lung, and kidney were fixed (4% paraformaldehyde, 24 hours), dehydrated, embedded, and sectioned (5 µm) for hematoxylin-eosin (HE) staining. Two independent pathologists performed histological scoring in a blinded state to determine the presence of pathological manifestations such as cell degeneration, inflammation, necrosis, or fibrosis.

[0146] The results are as follows Figure 29 As shown, there were no significant differences in ALT, AST, UREA, CREA, LDH, and UA between the DSG12 treatment group and the control group (P>0.05), indicating that DSG12 has no significant effect on liver and kidney function. In routine blood tests, WBC, RBC, PLT, and MCHC levels were all within the normal physiological range, with no significant abnormalities.

[0147] HE staining results ( Figure 30 The results showed that the heart, liver, spleen, lungs, kidneys and other organs of mice in all treatment groups had intact tissue structures and regular cell arrangement. No toxicity-related changes such as inflammatory infiltration, necrosis, swelling or fibrosis were observed, indicating that DSG12 did not cause tissue damage in vivo.

[0148] Although specific embodiments of the invention have been illustrated and described in detail herein, the invention is not limited thereto. The above detailed description is provided as an example of the invention and should not be construed as limiting the invention in any way. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of the invention will be included within the scope of the claims.

Claims

1. A class of sequence-controllable high-molecular-weight hydrogen sulfide donor compounds, their pharmaceutically acceptable salts, or their hydrates or solvates, characterized in that, The high molecular weight hydrogen sulfide donor compound has a structure as shown in formula (I): ； In the formula: The curves on both sides of the S atom represent cis-trans isomerism; R is selected from any one of O=CC=O, X=O, O=X-R4-X=O, O=X-R5[(-X=O)-CH=CH(R6)]-X=O, and X is any one of C, S, S=O, Se, Se=O, R3-P=O; R1 and R2 are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 hydroxyalkyl, C1-C6 carboxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitro, cyano, trifluoromethyl, and silyl. R3 is selected from H, substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted benzyloxy, -O-substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyloxy, C3-C6 alkynyl, -O-substituted or unsubstituted C3-C6 cycloalkyl, -O-substituted or unsubstituted C3-C7 heterocyclic alkyl, L-arginine, -OH, -NH2, -NR7R8, -R9-NO y For any one of the following, y = 2 or 3; R4 is selected from -O-(C2-C6 alkylene)-O-, -O-(C4-C6 alkenyl)-O-, -NH-(C2-C6 alkylene)-NH-, -NH-(C4-C6 alkenyl)-NH-, polyethylene glycol chain, linear polyethyleneimine chain, polypropylene glycol chain, and -O-(CH2CH2O). n -(CH2CH2CH2O) m - Polydimethylsiloxane chain, polyetheramine chain, polycaprolactone chain, polylactic acid chain, polyglycolic acid chain, polyurethane chain, polylactic acid-glycolic acid copolymer chain, hydroxyl-terminated polyvinylpyrrolidone chain, hydroxyl-terminated polyetheretherketone chain, -OR 10 -N + (R 11 R 12 Y - )-R 13 -N + (R 14 R 15 Z - )-R 16 -O-、-O-(R 17 C=CH-(X=O)-R 18 -(X=O)-CH=C(R 19 Any one of -O-; -O-(CH2CH2O) n -(CH2CH2CH2O) m - In the range n+m=2~1000, X is any one of C, S, S=O, Se, Se=O, R3-P=O; R5 is a trivalent linker, and its three linking sites are respectively connected to the three -X=O groups in formula (I) through oxygen atoms; R5 is selected from any one of 1,2,3-triyl of glycerol, trimethylolethane-1,1,1-triyl, trimethylolpropane-1,1,1-triyl, 3,5,4'-triyl of resveratrol, 1,2,3-triyl of phloroglucinol, triyl of hydroxymethylbenzene, and triyl of 1,2-dihydroxyethylphenol; R6 is selected from any one of the following: amino acids or polypeptides containing a single thiol group, cysteine, thioglycerol, thioglycolic acid, thioethanol, thiolactic acid, monothiol cyclodextrin, isosorbide mononitrate, captopril, mercaptopurine, amifostine, mercaptopolyethylene glycol, and mercapto-terminated PLGA. R7, R8, R 11 R 12 R 14 R 15 Each of the following is independently selected from H, substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, substituted or unsubstituted aryl, heteroaryl, hydroxymethyl, hydroxyethyl, hydroxypropyl, aminoethyl, carboxymethyl, carboxyethyl, sulfonic acid methyl, sulfonic acid ethyl, phosphoric acid methyl, phosphoric acid ethyl, nitrate methyl, nitrate ethyl, nitrite methyl, and nitrite ethyl; R9-NO y It is selected from any one of isosorbide mononitrate, glyceryl dinitrate, glyceryl mononitrate, nipridil, -O-(C2-C6 alkylene)-NO3, -O-(C2-C6 alkylene)-NO2, -NH-CH2CH2-NO3, -NH-CH2CH2-NO2, S-nitrosoglutathione, and S-nitroso-N-acetylpenicillamine; R 10 R 13 R 16 Each of them is independently selected from any one of C2-C6 alkylene, C4-C6 alkenylene, C4-C6 alkyneene, C3-C6 cycloalkylene, arylene, nitro-substituted C2-C6 alkylene, halo-C2-C6 alkylene, and halo-C2-C6 alkenyl. Y - and Z - Each of the following is independently selected from any one of the following: halide anion, tetrafluoroborate, hexafluorophosphate, p-toluenesulfonate, acetate, trifluoroacetate, hydrogen sulfate, bicarbonate, dihydrogen phosphate, trifluoromethanesulfonate, dicyandiamide, bis(trifluoromethanesulfonyl)imide anion, and bis(fluorosulfonyl)imide anion. R 17 R 19 Each of the following is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 hydroxyalkyl, C1-C6 carboxyalkyl, aryl, heteroaryl, nitro, cyano, trifluoromethyl, and silyl; R 18 Selected from -O-(C2-C6 alkylene)-O-, -O-(C4-C6 alkenyl)-O-, -NH-(C2-C6 alkylene)-NH-, -NH-(C4-C6 alkenyl)-NH-, polyethylene glycol chain, polypropylene glycol chain, -O-(CH2CH2O). n -(CH2CH2CH2O) m - Any one of the following: hydroxyl-terminated polydimethylsiloxane chain, hydroxyl-terminated polyetheramine chain, hydroxyl-terminated polycaprolactone chain, hydroxyl-terminated polylactic acid chain, hydroxyl-terminated polyglycolic acid chain, amino-terminated polyurethane chain, -O-poly(lactic-glycolic acid) copolymer -O-, -O-polyvinylpyrrolidone chain -O-, or hydroxyl-terminated polyetheretherketone chain; -O-(CH2CH2O) n -(CH2CH2CH2O) m - In the equation, n+m=2~1000, n=2~1000.

2. The polymeric hydrogen sulfide donor compound according to claim 1, its pharmaceutically acceptable salt, or its hydrate or solvate, characterized in that, R1 and R2 are each independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 hydroxyalkyl, C1-C6 carboxyalkyl, substituted or unsubstituted aryl, trifluoromethyl, silyl; R3 is selected from H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted benzyloxy, -O-substituted or unsubstituted C1-C6 alkyl, -O-C3-C6 substituted or unsubstituted cycloalkyl, -O-substituted or unsubstituted C3-C7 heterocycloalkyl, -OH, -NH2, -NR7R8, -R9-NO y For any one of the following, y = 2 or 3; R4 is selected from -O-(C2-C6 alkylene)-O-, -NH-(C2-C6 alkylene)-NH-, -NH-(C4-C6 alkenyl)-NH-, polyethylene glycol chain, linear polyethyleneimine chain, hydroxyl-terminated polycaprolactone chain, hydroxyl-terminated polylactic acid chain, hydroxyl-terminated polyglycolic acid chain, hydroxyl-terminated polyglycolic acid chain, hydroxyl-terminated polylactic acid-glycolic acid copolymer chain, hydroxyl-terminated polyvinylpyrrolidone chain, hydroxyl-terminated polyetheretherketone chain, -OR 10 -N + (R 11 R 12 Y - )-R 13 -N + (R 14 R 15 Z - )-R 16 -O-、-O-CH=CH(R 17 )-(X=O)-R 18 -(X=O)-CH=CH(R 19 X is any one of C, S, S=O, Se, Se=O, and R3-P=O; R5 is a trivalent linker, and its three linking sites are respectively connected to the three -X=O groups in formula (I) through oxygen atoms; R5 is selected from any one of 1,2,3-triyl of glycerol, trimethylolethane-1,1,1-triyl, trimethylolpropane-1,1,1-triyl, 3,5,4'-triyl of resveratrol, and 1,2,3-triyl of phloroglucinol; R6 is selected from any one of the following: amino acids or polypeptides containing a single thiol group, thioglycerol, thioglycolic acid, thioethanol, thiolactic acid, monothiol cyclodextrin, isosorbide mononitrate, captopril, amifostine, thiol polyethylene glycol, and thiol-terminated PLGA. R7, R8, R 11 R 12 R 14 R 15 Each is independently selected from H, substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, aminoethyl, carboxymethyl, carboxyethyl, sulfonylmethyl, sulfonylethyl, phosphatemethyl, phosphateethyl, nitratemethyl, nitrateethyl, nitritemethyl, and nitriteethyl. R9-NO y Selected from any one of isosorbide mononitrate, nipridil, -O-(C2-C6 alkylene)-NO3, -O-(C2-C6 alkylene)-NO2, S-nitrosoglutathione, and S-nitroso-N-acetylpenicillamine; R 10 R 13 R 16 Each is independently selected from any one of C2-C6 alkylene, C3-C6 cycloalkylene, aryl, nitro-substituted C2-C6 alkylene, and halo-C2-C6 alkylene; Y - and Z - Each of the following is independently selected from any one of the following: halide anions, tetrafluoroborate, hexafluorophosphate, p-toluenesulfonate, acetate, trifluoroacetate, bisulfate, bicarbonate, and dihydrogen phosphate. R 17 R 19 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 carboxylalkyl, aryl, heteroaryl, trifluoromethyl, and silyl; R 18 It is selected from any one of -O-(C2-C6 alkylene)-O-, -O-(C4-C6 alkenyl)-O-, -NH-(C2-C6 alkylene)-NH-, -NH-(C4-C6 alkenyl)-NH-, polyethylene glycol chain, hydroxyl-terminated polycaprolactone chain, hydroxyl-terminated polylactic acid chain, hydroxyl-terminated polyglycolic acid chain, hydroxyl-terminated polyglycolic acid chain, hydroxyl-terminated polyurethane chain, -O-poly(lactic acid-glycolic acid) copolymer-O-, -O-polyvinylpyrrolidone chain-O-, and hydroxyl-terminated polyetheretherketone chain.

3. The polymeric hydrogen sulfide donor compound according to claim 2, its pharmaceutically acceptable salt, or its hydrate or solvate, characterized in that, R1 and R2 are each independently selected from H, C1-C6 alkyl, substituted or unsubstituted aryl, trifluoromethyl, silyl; R3 is selected from H, methyl, ethyl, substituted or unsubstituted phenyl, haloaryl, nitroaryl, nitroheteroaryl, substituted or unsubstituted phenoxy, benzyloxy, C1-C4 alkoxy, -OH, -NH2, -NR7R8, -R9-NO y For any one of the following, y = 2 or 3; R4 is selected from -O-(C2-C6 alkylene)-O-, -NH-(C2-C6 alkylene)-NH-, polyethylene glycol chain, hydroxyl-terminated polylactic acid chain, hydroxyl-terminated polyurethane chain, hydroxyl-terminated lactic acid-glycolic acid copolymer chain, and -OR. 10 -N + (R 11 R 12 Y - )-R 13 -N + (R 14 R 15 Z - )-R 16 -O-、-O-CH=CH(R 17 )-(X=O)-R 18 -(X=O)-CH=CH(R 19 X is any one of C, S, S=O, Se, Se=O, and R3-P=O; R5 is a trivalent linker, and its three linking sites are respectively connected to the three -X=O groups in formula (I) through oxygen atoms; R5 is selected from any one of 1,2,3-triyl of glycerol, trimethylolethane-1,1,1-triyl, trimethylolpropane-1,1,1-triyl, and 3,5,4'-triyl of resveratrol. R6 is selected from any one of the following: cysteine, glutathione, thioglycerol, mercaptoacetic acid, mercaptoethanol, thiolactic acid, isosorbide mononitrate, captopril, amifostine, and mercaptopolyethylene glycol. R7, R8, R 11 R 12 R 14 R 15 Each of them is independently selected from any one of H, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, aminoethyl, carboxymethyl, carboxyethyl, sulfonic acid methyl, sulfonic acid ethyl, and nitrate ethyl; R9-NO y Selected from any one of isosorbide mononitrate, nipridil, -O-(C2-C6 alkylene)-NO3, and S-nitrosoglutathione; R 10 R 13 R 16 Each is independently selected from any one of C2-C6 alkylene, C3-C6 cycloalkylene, and halo-C2-C6 alkylene; Y - and Z - Each of the following is independently selected from any one of the following: halide anions, tetrafluoroborate, hexafluorophosphate, p-toluenesulfonate, acetate, bicarbonate, and dihydrogen phosphate. R 17 R 19 It is independently selected from any one of H, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, carboxymethyl, carboxyethyl, trifluoromethyl, and silyl; R 18 It is selected from any one of -O-(C2-C6 alkylene)-O-, -NH-(C2-C6 alkylene)-NH-, polyethylene glycol chain, and -O-poly(lactic acid-glycolic acid) copolymer-O-.

4. The polymeric hydrogen sulfide donor compound according to claim 3, its pharmaceutically acceptable salt, or its hydrate or solvate, characterized in that, R1 and R2 are each independently selected from H, methyl, ethyl, propyl, butyl, phenyl, trifluoromethyl, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, and tert-butyldiphenylsilyl. R3 is selected from H, methyl, ethyl, phenyl, nitrophenyl, phenoxy, nitrophenoxy, benzyloxy, C1-C4 alkoxy, -NR7R8, -R9-NO. y For any one of the following, y = 2 or 3; R4 is selected from -O-(C2-C6 alkylene)-O-, -NH-(C2-C6 alkylene)-NH-, polyethylene glycol chain, -OR 10 -N + (R 11 R 12 Y - )-R 13 -N + (R 14 R 15 Z - )-R 16 -O-、-O-CH=CH(R 17 )-(X=O)-R 18 -(X=O)-CH=CH(R 19 X is any one of C, S, S=O, Se, Se=O, and R3-P=O; R5 is a trivalent linker, and its three linking sites are respectively connected to the three -X=O groups in formula (I) through oxygen atoms; R5 is selected from any one of 1,2,3-triyl glycerol, trimethylolethane-1,1,1-triyl, and trimethylolpropane-1,1,1-triyl. R6 is selected from any one of the following: cysteine, glutathione, thioglycerol, mercaptoacetic acid, mercaptoethanol, thiolactic acid, isosorbide mononitrate, captopril, and mercaptopolyethylene glycol. R7, R8, R 11 R 12 R 14 R 15 Each of them is independently selected from any one of H, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, aminoethyl, carboxymethyl, carboxyethyl, and sulfonic acid ethyl; R9-NO y Selected from any one of isosorbide mononitrate, -O-(C2-C6 alkylene)-NO3, and S-nitrosoglutathione; R 10 R 13 R 16 Each is independently selected from C2-C6 alkylene or C3-C6 cycloalkylene; Y - and Z - Each is independently selected from any one of the following: halide anions, p-toluenesulfonate, acetate, bicarbonate, and dihydrogen phosphate. R 17 R 19 Each of the following is independently selected from H, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, carboxymethyl, carboxyethyl, trifluoromethyl, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, and tert-butyldiphenylsilyl; R 18 It is selected from any one of -O-(C2-C6 alkylene)-O-, -NH-(C2-C6 alkylene)-NH-, and polyethylene glycol chains.

5. A method for synthesizing the polymeric hydrogen sulfide donor compound according to claim 1, characterized in that, Includes the following steps: Under the action of an alkaline catalyst, using the compound shown in formula (II) and a sulfur source as raw materials, the compound shown in formula (I) is obtained through an addition polymerization reaction. The synthetic route is as follows: ； In the compound shown in formula (II), R' is defined in the same way as R4 in the compound shown in formula (I); or In the presence of an alkaline catalyst and / or a dehydrating agent, using the compounds shown in formula (III) and (IV) as raw materials, the compound shown in formula (I) is obtained through a polycondensation reaction. The synthetic route is as follows: ； In the compound shown in formula (III), X, R1, R2 and the curve are defined in the same way as X, R1, R2 and the curve in the compound shown in formula (I), and Y is selected from any one of OH, Cl and Br; R' in the compound shown in formula (IV) is the same as R in the compound shown in formula (I). 10 Same definition; X' is taken from -OH, -NH2, or -NHR''; R'' is selected from C2-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl, C3-C6 cycloalkyl, polyethylene glycol chain, polypropylene glycol chain, and -O(CH2CH2O). n -(CH2CH2CH2O) m - Any one of the following chains: polydimethylsiloxane, polyetheramine, polycaprolactone, polylactic acid, polyglycolic acid, polylactic acid, polyurethane, polyvinylpyrrolidone, or polyetheretherketone; -O(CH2CH2O) n -(CH2CH2CH2O) m - In this context, n+m=2~1000, n=2~1000; or In the presence of a base catalyst, using the compounds shown in formula (V) and formula (VI) as starting materials, the compound shown in formula (I) is obtained through an addition polymerization reaction. The synthetic route is as follows: ； In the compound shown in formula (V), R1, R2, X and the curve are defined in the same way as those in the compound shown in formula (I); R' in the compound shown in formula (VI) is the same as R in the compound shown in formula (I). 18 Same definition; or In the presence of a base catalyst or under autocatalysis, the compound shown in formula (VI) and the compound shown in formula (VII) were used as starting materials to obtain the compound shown in formula (I) through an addition polymerization reaction. The synthetic route is as follows: ； Wherein, the compounds R1, R2, X and curves shown in formula (VI) are defined in the same way as those in the compounds shown in formula (I), R' is selected from any one of -O-C2-C6 alkylene, -O-C4-C6 alkenylene, -O-C4-C6 alkyneide, -O-C3-C6 cycloalkylene, -NH-C2-C6 alkylene, -NH-C4-C6 alkenylene, and -NH-C4-C6 alkyneide, and Z is selected from Cl, Br or I; In equation (I), R4 is selected from -OR 10 -N + (R 11 R 12 Y - )-R 13 -N + (R 14 R 15 Z - )-R 16 -O-, and R in the compound shown in formula (VII) 3’ R 4’ R 5’ R 6’ R in the compound shown in formula (I) 11 R 12 R 14 R 15 Having the same meaning, R is the same as R in the compound shown in formula (I), and R'' is the same as R in the compound shown in formula (I). 13 same.

6. The method for synthesizing the polymeric hydrogen sulfide donor compound according to claim 5, characterized in that, Both the addition polymerization and the condensation polymerization are carried out at -20℃ to 120℃ for 1 min to 96 h.

7. The method for synthesizing the polymeric hydrogen sulfide donor compound according to claim 5, characterized in that, The molar ratios of the compound shown in formula (II) and the sulfur source, the compound shown in formula (III) and the compound shown in formula (IV), the compound shown in formula (V) and the compound shown in formula (VI), and the compound shown in formula (VI) and the compound shown in formula (VII) are all 1:1 to 1.

5.

8. The method for synthesizing the polymeric hydrogen sulfide donor compound according to claim 5, characterized in that, The sulfur source is elemental sulfur, hydrogen sulfide, sodium sulfide, sodium hydrosulfide, calcium sulfide, calcium hydrosulfide, lithium polysulfide, sodium persulfide, potassium polysulfide, or calcium polysulfide. The alkaline catalyst is selected from any one of trimethylamine, triethylamine, tripropylamine, tributylamine, trihexylamine, tetramethylethylenediamine, pentamethyldiethylenetriamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, 4-dimethylaminopyridine, 2,6-di-tert-butylpyridine, hexamethylenetetramine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and cesium hydroxide; The dehydrating agent is selected from any one of N,N'-dicyclohexylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, N,N'-diisopropylcarbodiimide, phosphorus pentoxide, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, and benzotriazoloxytripyrrolidinylphosphine hexafluorophosphate.

9. A pharmaceutical composition, characterized in that, It includes the high molecular weight hydrogen sulfide donor compound as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a hydrate or solvation thereof.

10. The use of a high molecular weight hydrogen sulfide donor compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for treating aortic dissection.

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