Hydrogen sulfide donor compounds, pharmaceutical compositions containing hydrogen sulfide donor compounds, and methods of synthesis and use

Abstract

The application belongs to the technical field of medicine research, and particularly relates to a hydrogen sulfide donor compound, a medicine composition containing the hydrogen sulfide donor compound, and a synthesis method and application thereof. The hydrogen sulfide donor compound has a structure as shown in general formula (I). The hydrogen sulfide donor compound can release H2S responsively 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 excellent biocompatibility. In animal experiments, the compound can reduce the incidence of aortic dissection and improve Alzheimer's disease and Parkinson's disease, has potential application value for prevention and treatment of cardiovascular diseases and neurodegenerative diseases, and also has expansion potential for other diseases related to oxidative stress.

Description

Technical Field

[0001] This invention belongs to the field of drug research and bioactive small molecule design technology, specifically relating to a class of donor compounds that can responsively release hydrogen sulfide (H2S) under physiological conditions, their synthesis methods, pharmaceutical compositions containing the compounds, and their application in the treatment of diseases related to decreased H2S levels. Background Technology

[0002] Hydrogen sulfide (H2S) is the third gaseous signaling molecule discovered after nitric oxide (NO) and carbon monoxide (CO). It is widely involved in vital processes such as vasodilation, anti-oxidative stress, apoptosis regulation, mitochondrial metabolic regulation, and neuroprotection. Numerous studies have shown that H2S plays multiple protective roles in the cardiovascular and nervous systems, and its deficiency or signaling is closely related to the occurrence of many major diseases, especially cardiovascular diseases and neurodegenerative diseases (Physiol Rev, 2012, 92, 791–896; Nat Rev Cardiol, 2023, 20, 109–125).

[0003] Currently developed H2S donors mainly include: (1) inorganic donors, such as NaHS and Na2S, where H2S release is too rapid and blood drug concentration is difficult to control; (2) small organic molecule donors, such as ADT-OH and its derivatives, which have high stability but poor release kinetics; (3) responsive donors, such as GYY4137, NSHD, and COS precursor molecules, which can be released in a controlled manner but have complex structures, are difficult to synthesize, and often lack sustainable modification capabilities; (4) polymeric or nanocarrier-type donors, which have targeting potential but limited H2S release sites and poor dose accuracy. Existing donors generally lack structural universality and broad-spectrum indication expansion capabilities, and no products have entered international Phase III clinical trials, reflecting that there are still bottlenecks in the development of H2S donor drugs. Therefore, it is urgent to develop a new type of H2S donor with abundant structural sites, a clear release mechanism, controllable pharmacokinetic behavior, and potential for indication expansion, in order to break through the current limitations of H2S drug development. Summary of the Invention

[0004] To address the problems of uncontrollable release, limited indications, and insufficient clinical translation of existing H2S donors, this invention proposes a novel class of H2S donor compounds with strong structural versatility and tunable responsiveness. These compounds can sustainably release H2S under physiological conditions, particularly in the presence of endogenous thiols, through a mild and efficient nucleophilic addition / exchange reaction, thereby achieving continuous and effective H2S therapy.

[0005] The H2S donor compound has the following characteristics and advantages: (1) Strong structural versatility and customizability: By adjusting the chemical properties of acyl substituents (R' or R1) and alkynyl substituents (R2), the key pharmacological properties of compounds, such as water solubility, H2S release rate and biomembrane permeability, can be flexibly controlled to meet the needs of different administration routes and indications.

[0006] (2) Clear response mechanism: Its H2S release mechanism is clear, which is achieved through nucleophilic addition or exchange reaction triggered by endogenous thiols. The process is mild and efficient, avoiding interference caused by metabolic byproducts. (3) Great potential for functional expansion: The substituents (R' or R1, R2) of the compound can be connected to drug molecule fragments with cardiovascular, nervous system or metabolic regulatory pharmacological activities, so as to achieve synergistic release or synergistic effect between the main skeleton and the active drug fragment, thereby supporting the construction of a composite H2S donor with multi-target effect. (4) Mild and efficient synthesis method: The synthetic route adopted is simple, the conditions are mild, the reaction is efficient, and it can be compatible with multiple functional groups, which is conducive to large-scale production and subsequent formulation development; (5) Experiments on its broad-spectrum disease intervention capabilities have demonstrated that it can significantly reduce the incidence of aortic dissection and improve myocardial ischemia-reperfusion injury, showing its outstanding application value in cardiovascular diseases, while also having the potential to be extended to other oxidative stress-related diseases.

[0007] This invention also provides a method for synthesizing the aforementioned H2S donor compound, a pharmaceutical composition containing the compound, and its application in the prevention and treatment of the said disease. The pharmaceutical composition can be further used in synergy with one or more therapeutic agents selected from statins, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, monoamine oxidase B (MAO-B) inhibitors, or cholinesterase inhibitors to achieve a more comprehensive disease intervention effect.

[0008] The specific technical solution provided by this invention is as follows: In a first aspect, the present invention provides a class of hydrogen sulfide donor compounds, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, said hydrogen sulfide donor compounds having a structure as shown in general formula (I): ; In the formula: the curves on both sides of the S atom represent cis-trans isomerism; X is C, S, S=O, Se, Se=O or P; When X is C, S, S=O, Se, Se=O, R' does not exist; R' and R1 are each independently selected from H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, -C3-C6 cycloalkyl, substituted or unsubstituted aryl, cyanoaryl, heteroaryl, haloaryl, haloheteroaryl, nitroalkyl, nitroaryl, nitroheteroaryl, halonitroaryl, halonitroheteroaryl, silyl, -C1-C6 haloalkyl, -C2-C6 haloalkenyl, -C3-C6 halocycloalkyl, substituted or unsubstituted phenoxy, 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 halocyclic alkyl, -O-C3-C7 halocyclic alkyl, cycloalkyl or heterocyclic alkyl or heteroaryl formed by cyclization of linked carbon atoms, L-arginine, -OH, -NH2, -NR3R4, -R5-NO y For any one of the following, y = 2 or 3; R2 is selected from H, -C1-C6 substituted or unsubstituted alkyl, -C2-C6 alkenyl, -C3-C6 cycloalkyl, -C1-C6-OH hydroxyalkyl, -C1-C6-COOH carboxylalkyl, substituted or unsubstituted aryl, heteroaryl, haloaryl, haloheteroaryl, nitro, cyano, trifluoromethyl, trifluoromethylaryl, cyanophenyl, nitroalkyl, nitroaryl, nitroheteroaryl, halonitroaryl, halonitroheteroaryl, silyl, -C1-C6 haloalkyl, -C2-C6 haloalkenyl, -C3-C6 halocycloalkyl, -O-C3-C6 cycloalkyl, -O-C3-C7 heterocycloalkyl, -O-C3-C6 halocycloalkyl, -O-C3-C7 haloheterocycloalkyl, and the carbon atom linked to the alkyl group. The cycloalkyl, heterocycloalkyl, or heteroaryl group formed by cyclization; or selected from -X'=O, with -R6R7 attached to X', wherein X' is taken from C, S, S=O, Se, Se=O, or P; when X' is C, S, S=O, Se, or Se=O, R6 is absent; R6 and R7 are independently taken from H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, aryl, cyanophenyl, heteroaryl, haloaryl, haloheteroaryl, nitroalkyl, nitroaryl, nitroheteroaryl, halonitroaryl, halonitroheteroaryl, silyl, -C1-C6 haloalkyl, -C2-C6 haloalkenyl, -C3-C6 halocycloalkyl, -O-C1-C6 alkoxy, - O-C2-C6 alkenyloxy, -O-C3-C6 alkynyloxy, -O-C3-C7 heterocyclic alkyl, -O-C3-C6 halocyclic alkyl, -O-C3-C7 halocyclic alkyl, substituted or unsubstituted phenoxy, substituted or unsubstituted benzyloxy, cycloalkyl or heterocyclic alkyl or heteroaryl formed by cyclization of linked carbon atoms, -OH, -NH2, -NR8R9, -R 10 -NOy’ y' = 2 or 3; R3, R4, R8, and R9 are each independently selected from H, substituted or unsubstituted -C1-C6 alkyl, -C2-C6 alkenyl, -C3-C6 cycloalkyl, -C1-C6-OH hydroxyalkyl, -C1-C6-NH2 aminoalkyl, -C1-C6-COOH carboxylalkyl, substituted or unsubstituted aryl, cyanophenyl, heteroaryl, halogen, haloaryl, haloheteroaryl, nitroalkyl, nitroaryl, nitroheteroaryl, halonitroaryl, halonitroheteroaryl, -C1-C6 haloalkyl, -C2-C6 haloalkenyl, -C3-C6 halocycloalkyl, cycloalkyl or heterocycloalkyl or heteroaryl formed by cyclization of linked carbon atoms; R5-NO y R 10 -NO y’ It is independently selected from any one of isosorbide mononitrate, glyceryl dinitrate, glyceryl mononitrate, nipridil, ethylene glycol mononitrate, propylene glycol mononitrate, butylene glycol mononitrate, pentylene glycol mononitrate, hexanediol mononitrate, ethylene glycol mononitrite, propylene glycol mononitrite, butylene glycol mononitrite, pentylene glycol mononitrite, hexanediol mononitrite, aminoethyl mononitrate, aminoethyl mononitrite, S-nitrosoglutathione, and S-nitroso-N-acetylpenicillamine.

[0009] The R' or R1, R2 groups in the compounds of this invention can also be selected from functionalized derivatives of the active structures of cardiovascular and cerebrovascular drugs. Without affecting their activity, they can be attached to the main skeleton by means of acylation, etherification, esterification, amination, etc., thereby achieving dual-function release.

[0010] In a preferred embodiment of the present invention, R' and R1 are each independently selected from H, -C1-C4 alkyl, -C2-C4 alkenyl, -C3-C6 cycloalkyl, substituted or unsubstituted aryl, cyanophenyl, heteroaryl, haloaryl, haloheteroaryl, nitroaryl, nitroheteroaryl, substituted or unsubstituted phenoxy, substituted or unsubstituted benzyloxy, -O-C1-C4 substituted or unsubstituted alkoxy, -O-C2-C4 alkenyloxy, cycloalkyl or heterocycloalkyl or heteroaryl formed by cyclization of linked carbon atoms, -OH, -NH2, -NR3R4, -R5-NO y For any one of the following, y = 2 or 3; R2 is selected from any one of H, -C1-C4 alkyl, -C2-C4 alkenyl, -C1-C6-OH hydroxyalkyl, -C1-C6-COOH carboxylalkyl, phenyl, haloaryl, haloheteroaryl, trifluoromethyl, trifluoromethylaryl, nitro, cyano, cyanophenyl, nitroalkyl, nitroaryl, nitroheteroaryl, -O-C3-C6 cycloalkyl, -O-C3-C7 heterocycloalkyl, cycloalkyl or heterocycloalkyl or heteroaryl formed by cyclization of connected carbon atoms; R3 and R4 are independently selected from H, substituted or unsubstituted -C1-C4 alkyl, -C2-C4 alkenyl, -C3-C6 cycloalkyl, -C1-C4-OH hydroxyalkyl, -C1-C4-NH2 aminoalkyl, -C1-C3-COOH carboxylalkyl, substituted or unsubstituted aryl, heteroaryl, haloaryl, cyanophenyl, haloheteroaryl, nitroalkyl, nitroaryl, nitroheteroaryl, cycloalkyl or heterocycloalkyl or heteroaryl formed by cyclization of linked carbon atoms; R5-NO y It is independently selected from any one of isosorbide mononitrate, glyceryl dinitrate, glyceryl mononitrate, ethylene glycol mononitrate, nipridil, aminoethyl mononitrate, aminoethyl mononitrite, S-nitrosoglutathione, and S-nitroso-N-acetylpenicillamine.

[0011] More preferably, R' and R1 are each independently selected from H, methyl, ethyl, substituted or unsubstituted phenyl, haloaryl, nitroaryl, nitroheteroaryl, substituted or unsubstituted phenoxy, substituted or unsubstituted benzyloxy, -O-C1-C4 alkoxy, OH, -NH2, -NR3R4, -R5-NO y For any one of the following, y = 2 or 3; R2 is selected from any one of H, methyl, ethyl, -C1-C4-OH hydroxyalkyl, -C1-C4-COOH carboxylalkyl, phenyl, halophenyl, cyanophenyl, haloheteroaryl, nitro, cyano, trifluoromethyl, nitroaryl, and nitroheteroaryl. R3 and R4 are independently selected from any one of H, methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, aminoethyl, aminopropyl, carboxymethyl, carboxyethyl, phenyl, pyridyl, imidazolyl, p-fluorophenyl, and trifluoromethylphenyl. R5-NO y It is independently selected from any one of isosorbide mononitrate, glyceryl dinitrate, glyceryl mononitrate, S-nitrosoglutathione, and S-nitroso-N-acetylpenicillamine.

[0012] More preferably, R' and R1 are each independently selected from H, methyl, ethyl, phenyl, p-fluorophenyl, nitrophenyl, cyanophenyl, trifluoromethylphenyl, methoxy, ethoxy, OH, -NH2, -NR3R4, -R5-NO y For any one of the following, y = 2 or 3; R2 is selected from any one of H, methyl, ethyl, hydroxymethyl, hydroxyethyl, carboxymethyl, carboxyethyl, phenyl, p-fluorophenyl, cyanophenyl, nitrophenyl, nitro, cyano, and trifluoromethyl. R3 and R4 are independently selected from any one of H, methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, aminoethyl, carboxymethyl, and carboxyethyl; R5-NO y It is independently selected from any one of isosorbide mononitrate, glyceryl dinitrate, and S-nitrosoglutathione.

[0013] In a second aspect, the present invention provides a method for synthesizing the hydrogen sulfide donor compound, comprising the following steps: In the presence of an alkaline catalyst, the compound shown in formula (II) is subjected to sulfidation coupling to obtain the compound shown in formula (I).

[0014] ; The groups selected for R', R1, R2, and X in the compound shown in formula (II) are the same as those selected for R', R1, R2, and X in the compound shown in formula (I).

[0015] In a preferred embodiment of the present invention, the sulfidation coupling reaction is carried out by adding a sulfur source to the compound shown in formula (II) under the action of an alkaline catalyst. The sulfur source is selected from any one of elemental sulfur, hydrogen sulfide, sodium sulfide, sodium hydrosulfide, calcium sulfide, calcium hydrosulfide, lithium polysulfide, sodium persulfide, potassium polysulfide, and calcium polysulfide.

[0016] More preferably, the sulfur source is any one of hydrogen sulfide, sodium sulfide, and sodium hydrosulfide.

[0017] More preferably, the sulfur source is hydrogen sulfide or sodium sulfide.

[0018] 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.

[0019] 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.

[0020] In a preferred embodiment of the present invention, the vulcanization addition time is 0.1 min to 6 h.

[0021] In a third aspect, the present invention provides a pharmaceutical composition comprising the aforementioned hydrogen sulfide donor compound or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvation thereof.

[0022] In a preferred embodiment of the present invention, the pharmaceutical composition is a combination of the hydrogen sulfide donor compound and donepezil.

[0023] More preferably, the mass ratio of the hydrogen sulfide donor compound to donepezil is 4~10:1.

[0024] In a preferred embodiment of the present invention, the pharmaceutical composition further includes a pharmaceutically acceptable carrier, sustained-release excipient, or targeted delivery system. In preparing the pharmaceutical composition, a compound of general formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvation thereof, is typically mixed with a pharmaceutically acceptable carrier, excipient, diluent, or targeted delivery system.

[0025] In a third 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 associated with decreased H2S levels in the body.

[0026] As a preferred embodiment of the present invention, the diseases associated with a decrease in H2S levels in the body are cardiovascular and cerebrovascular diseases, neurodegenerative diseases, or metabolic syndromes.

[0027] More preferably, the diseases associated with decreased H2S levels in the body are myocardial infarction, heart failure, aortic dissection, hypertension, cerebral ischemia, stroke, Alzheimer's disease, Parkinson's disease, type 2 diabetes, or type 2 diabetes-related vascular complications.

[0028] The effective dose of the compound represented by general formula (I) of the present invention, or its pharmaceutically acceptable salt, or its hydrate or solvation, is 0.01 to 25 mg / kg body weight / day. This dose may be adjusted according to individual differences and clinical progression. Preferably, it is 0.1 to 15 mg / kg body weight / day, more preferably 0.2 to 10 mg / kg body weight / day.

[0029] In this invention, the term "halogen" refers to fluorine, chlorine, bromine, iodine, etc., preferably fluorine, chlorine, and bromine, and more preferably fluorine and chlorine.

[0030] 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 fusion with a benzene ring, a pyridine ring, or a pyrrole ring. The heteroaryl groups include, but are not limited to, furanyl, thiophene, pyrroloyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophene, benzothiadiazolyl, benzothiazolyl, benzoimidazolyl, indolyl, isoindolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,2-b]pyridyl, pyrrolo[2,3-b]pyrazinyl, indololin-2-one, preferably pyridyl, thiophene, and benzofuranyl.

[0031] The term "pharmaceutically acceptable salt" in this invention refers to an acid addition salt or base addition salt of a relatively non-toxic compound of this invention. The acid addition salt is a salt formed by a compound of general formula (I) of this invention with a suitable inorganic or organic acid. These salts can be prepared during the final separation and purification process of the compound, or by reacting a purified compound of general formula (I) in its free base form with a suitable organic or inorganic acid. Representative acid addition salts include, but are not limited to: acetates, valerates, oxalates, phosphates, hydrogen phosphates, lactates, benzoates, hydrobroms, hydrochlorides, sulfates, hydrogen sulfates, sulfites, methanesulfonates, p-toluenesulfonates, citrates, maleates, fumarates, succinates, gluconates, oleates, palmitates, stearates, borates, carbonates, bicarbonates, toluene, tartrates, benzoates, lactobionates, and lauryl sulfonates, etc. The base addition salt is a salt formed by the compound of general formula (I) with a suitable inorganic or organic base, including, for example, salts formed with alkali metals, alkaline earth metals, or quaternary ammonium cations, such as potassium salts, lithium salts, sodium salts, calcium salts, magnesium salts, tetramethyl quaternary ammonium salts, tetraethyl quaternary ammonium salts, etc.; amine salts, including salts formed with ammonia (NH3), primary amines, secondary amines, or tertiary amines, such as ethylamine salts, methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, etc.

[0032] The compounds represented by general formula (I) of the present invention, their pharmaceutically acceptable salts or hydrates or solvates thereof, may be administered to mammals, including humans, by oral, rectal, parenteral (intravenous, intramuscular or subcutaneous) administration, or topical administration (powder, ointment or drops, etc.).

[0033] The compounds of general formula (I) of the present invention, their pharmaceutically acceptable salts or their hydrates or solvates can be formulated into solid dosage forms for oral administration, including but not limited to capsules, tablets, pills, powders and granules. In these solid dosage forms, the compounds of general formula (I) of the present invention, their pharmaceutically acceptable salts or their hydrates or solvates are mixed as active ingredients with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (1) fillers or compatibilizers, such as starch, sucrose, lactose, mannitol, glucose and silicic acid; (2) binders, such as hydroxymethyl cellulose, gelatin, alginate, sucrose, polyvinylpyrrolidone and gum arabic; 3) Humectants, such as glycerin; (4) Disintegrants, such as agar, alginic acid, calcium carbonate, potato starch or cassava starch, certain complex silicates and sodium carbonate; (5) Slow solvents, such as paraffin; (6) Absorption accelerators, such as quaternary ammonium compounds; (7) Wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) Adsorbents, such as kaolin; and (9) Lubricants, such as talc, calcium stearate, sodium dodecyl sulfate, magnesium stearate, solid polyethylene glycol or mixtures thereof. Buffers may also be included in capsules, tablets and pills.

[0034] The solid dosage forms, such as tablets, sugar pills, capsules, pellets, and granules, can be coated or microencapsulated with coating and shell materials, such as enteric coatings and other materials known in the art. They may contain opaque agents, and the release of the active ingredient in such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the compounds of the present invention or pharmaceutically acceptable salts thereof may also be formed into microcapsules with one or more of the excipients described above.

[0035] The compounds represented by general formula (I) of this invention, or their pharmaceutically acceptable salts, hydrates, or solvates, can be formulated into liquid dosage forms for oral administration, including but not limited to pharmaceutically acceptable suspensions, emulsions, solutions, syrups, and tinctures. In addition to the compounds represented by general formula (I) or their pharmaceutically acceptable salts, hydrates, or solvates as active ingredients, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water and other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, propylene glycol, ethyl carbonate, 1,3-butanediol, ethyl acetate, dimethylformamide, and oils, particularly corn germ oil, cottonseed oil, olive oil, peanut oil, castor oil, and sesame oil, or mixtures thereof. Besides these inert diluents, the liquid dosage forms of this invention may also contain conventional adjuvants, such as wetting agents, emulsifiers, sweeteners, suspending agents, flavoring agents, and fragrances.

[0036] In addition to the compounds represented by general formula (I) of the present invention or their pharmaceutically acceptable salts or their hydrates or solvates, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures thereof.

[0037] The compounds of general formula (I) of this invention, or pharmaceutically acceptable salts thereof, or hydrates thereof, or solvates thereof, can be formulated into dosage forms for parenteral injection, including but not limited to physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable carriers, diluents, solvents, or excipients that may be added during preparation include water, ethanol, polyols, and suitable mixtures thereof.

[0038] The compounds of general formula (I) of the present invention, or their pharmaceutically acceptable salts, hydrates, or solvates, can also be formulated into dosage forms for topical administration, including ointments, suppositories, powders, drops, sprays, and inhalers. The compounds of general formula (I) of the present invention, or their pharmaceutically acceptable salts, hydrates, or solvates, as active ingredients, may contain a carrier conventionally used in the art that is sterile and physiologically acceptable, and optionally a preservative, buffer, or, if necessary, a propellant.

[0039] The compounds provided by this invention, or their pharmaceutically acceptable salts, hydrates, or solvates, can be administered alone or in combination with other pharmaceutically acceptable therapeutic agents, particularly with other anti-cardiovascular and cerebrovascular drugs. These therapeutic agents include, but are not limited to: antianginal drugs, such as isosorbide mononitrate and nitroglycerin; antiarrhythmic drugs, such as metoprolol and propranolol; antihypertensive drugs, such as amlodipine and felodipine; β-receptor agonists, such as dobutamine and pibuterol; vasodilators, such as minoxidil and nifedipine; β-receptor blockers; statins; dopamine receptor agonists; monoamine oxidase B (MAO B) inhibitors; catechol-O-methyltransferase (also known as COMT) inhibitors; adenosine receptor antagonists (A2A receptor antagonists); and cholinesterase inhibitors. The components to be combined can be administered simultaneously or sequentially, in single-component formulations or in separate formulations. The combination includes not only the combination of the compound of the present invention and one other active agent, but also the combination of the compound of the present invention and two or more other active agents.

[0040] The compounds provided by this invention are obtained by the addition of H2S from an acyl-yne or hetero-yne compound and a sulfur source. The resulting diacyl ethynyl sulfide unit can responsively release a single sulfur-containing H2S species in the presence of bio-thiols (GSH, cysteine, etc.). The H2S release rate can be regulated by changing the substituent attached to the acetyl group (i.e., R2), and the activity of the addition reaction between the acetyl group and the sulfur source-provided H2S, as well as the functionality of the resulting product (such as water solubility, NO release, etc.), can be regulated by changing the substituent attached to the acyl or hetero-yne group (i.e., R' or R1). Experimental results show that these compounds have good biocompatibility and stable release behavior, maintain H2S concentrations well in mice and rats, significantly reduce the incidence of aortic dissection, and improve myocardial ischemia-reperfusion injury, showing outstanding application prospects for cardiovascular diseases. They also have broad intervention potential for other oxidative stress-related diseases. Attached Figure Description

[0041] Figure 1 The curves of H2S concentration versus time under different microenvironment conditions simulated in vitro by different donor compounds of the present invention confirm that different substituents affect the H2S release rate, and the thiol responsiveness of the characteristic structure (diacyl alkenyl thioether) of the compound of the present invention.

[0042] Figure 2 The acute toxicity and tolerability of the compounds of this invention in mice demonstrate that the compounds of this invention have excellent biocompatibility at conventional doses.

[0043] Figure 3 The curve showing the change in blood H2S concentration over time after the compound of the present invention was injected into rats confirms that the compound of the present invention can effectively and sustainably release H2S in vivo.

[0044] Figure 4 The curve of blood H2S concentration change over time after the compound of the present invention is injected into TAD mice. Compared with the normal group and the TAD model group, the compound of the present invention can effectively release H2S and restore the H2S concentration of mice with decreased H2S levels.

[0045] Figure 5 In animal experiments with TAD, EPS affected the aortic rupture rate in the BAPN-induced TAD model.

[0046] Figure 6 In animal experiments on TAD, EPS improved the survival rate of BAPN-induced TAD models.

[0047] Figure 7 In TAD animal experiments, HE, Masson, and EVG staining showed improved vascular wall structure.

[0048] Figure 8 In animal experiments on Alzheimer's disease (AD), the effects of EPS and its combination with AD drugs on the behavioral improvement of mice were investigated.

[0049] Figure 9 : In PD animal experiments, EPS improved the behavior of mice. Detailed Implementation

[0050] 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.

[0051] In the embodiments of the present invention, the abbreviations used have common meanings in the art, such as: TEA (triethylamine), DMAP (4-dimethylaminopyridine), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DIPEA (N,N-diisopropylethylamine), DABCO (1,4-diazabicyclo[2.2.2]octane), TMS (trimethylsilyl), DMF (N,N-dimethylformamide), THF (tetrahydrofuran), DCM (dichloromethane), etc.

[0052] All raw materials and solvents used in the reactions are commercially available analytical grade and are used directly without special treatment, unless otherwise stated.

[0053] The general synthetic route of the compounds of this invention includes two steps: (1) constructing a monomer containing an alkyne structure; (2) undergoing a sulfidation addition reaction with a sulfur source (such as H2S, Na2S, NaSH) in the presence of an alkaline catalyst to form a diacyl alkene sulfide or similar response unit, thereby completing the construction of the target donor.

[0054] 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.

[0055] Example 1 Ethyl propargyl ester (2 mmol) was dissolved in 20 mL of tetrahydrofuran, and 0.1 mmol of triethylamine was added. Hydrogen sulfide gas was bubbled into the solution under an ice-water bath at a flow rate of 1–10 mL / min for 4 h. The solution was then allowed to cool naturally to room temperature. The solvent was evaporated to dryness, yielding a pale yellow oil. MS (ESI): 253.05 [M + Na] +

[0056] 1 H-NMR (400MHz, CDCl3, δ): 7.7–5.97 (6 doublets, 2H, from 3 pairs of cis-trans isomers), 4.21 (q, 2H), 1.30 (t, 3H).

[0057] Example 2 Propynic acid (2 mmol) was dissolved in 20 mL of deionized water, and 2 mmol of sodium hydroxide was added. Anhydrous sodium sulfide (2.2 mmol) was then added under ice-water bath conditions. The mixture was stirred for 4 h and then allowed to cool naturally to room temperature. After the reaction was complete, acid was added to precipitate the product, which was then freeze-dried to obtain a white product, designated as compound 1. MS (ESI): 196.99 [M+Na] +

[0058] Example 3 2 mmol of 3-butyn-2-one was dissolved in 20 mL of tetrahydrofuran, and 0.1 mmol of triethylamine was added. Hydrogen sulfide gas was bubbled into the solution under an ice-water bath at a flow rate of 1–10 mL / min for 4 h. The solution was then allowed to cool naturally to room temperature. The solvent was evaporated to dryness, yielding a pale yellow oil. MS (ESI): 221.06 [M + Na] +

[0059] Example 4 This embodiment demonstrates a synthetic pathway for incorporating isosorbide mononitrate (ISMN) drug fragments into the main scaffold to form a donor structure, and verifies the functional extensibility and druggability of the donor structure.

[0060] The compound was prepared by the following steps: 1) Isosorbide 5-mononitrate (1 mmol) and propargyl acid (1.5 mmol) were mixed in dichloromethane, and 0.1 mmol DCC and 0.15 mmol DMAP were added. After stirring at room temperature for 12 h, insoluble matter was removed, and the mixture was subjected to column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a pale brownish-yellow oil. MS (ESI): 266.03 [M+Na] +

[0061] 0) The above product (0.5 mmol) was dissolved in dichloromethane, and 0.01 mmol of TEA was added. Hydrogen sulfide gas was bubbled into the solution under an ice-water bath at a flow rate of 1–10 mL / min for 6 h. The solution was then allowed to cool naturally to room temperature. After the reaction was complete, the solvent was evaporated to obtain a pale yellow product. MS (ESI): 543.05 [M+Na]+

[0062] Example 5 Dissolve 4-hydroxybut-2-ynoic acid (1 mmol) in 20 mL of tetrahydrofuran, add 0.6 mmol of aqueous sodium sulfide solution, stir and react at room temperature for 2.5 h. After the reaction, add hydrochloric acid to precipitate. Obtain a light yellow powder after drying. MS (ESI): 257.01 [M+Na] +

[0063] Example 6 Dissolve methyl 3-(4-fluorophenyl)propiolate (1 mmol) in 20 mL of tetrahydrofuran, add 0.02 mmol of DBU, and introduce hydrogen sulfide gas into it under an ice-water bath. Control the gas flow rate within the range of 1-10 mL / min, and carry out the gas-phase reaction for 4 h. Naturally warm up to room temperature. Evaporate the solvent to dryness to obtain a light yellow powder.

[0064] MS (ESI): 413.06 [M+Na] + Example 7 Dissolve ethyl 4,4,4-trifluoro-2-butynoate (1 mmol) in 20 mL of dichloromethane, add 0.01 mmol of DBU, and introduce hydrogen sulfide gas into it under an ice-water bath. Control the gas flow rate within the range of 1-10 mL / min, and carry out the gas-phase reaction for 4 h. Naturally warm up to room temperature. Evaporate the solvent to dryness to obtain a light yellow oil.

[0065] MS (ESI): 389.02 [M+Na] + Example 8 Dissolve 2-phenylethynesulfonamide (1 mmol) in a mixed solution of 20 mL of acetonitrile and DMSO, add 0.05 mmol of triethylamine, and introduce hydrogen sulfide gas into it under an ice-water bath. Control the gas flow rate within the range of 1-10 mL / min, and carry out the gas-phase reaction for 4 h. Naturally warm up to room temperature. Evaporate the solvent to dryness to obtain a yellow solid.

[0066] MS (ESI): 419.02 [M+Na] + Example 9 Dissolve bis(dibenzylphosphonate)acetylene (1 mmol) in 20 mL of THF, add 0.01 mmol of triethylamine, and introduce hydrogen sulfide gas into it under an ice-water bath. Control the gas flow rate within the range of 1 - 10 mL / min, carry out the gas-phase reaction for 4 h, and naturally warm up to room temperature. Rotate to dry the solvent to obtain a light yellow oily substance.

[0067] MS (ESI): 629.13 [M+Na] + Example 10 Dissolve ethynyl(diphenyl)phosphine oxide (1 mmol) in 20 mL of acetonitrile, add 0.05 mmol of triethylamine, and introduce hydrogen sulfide gas into it under an ice-water bath. Control the gas flow rate within the range of 1 - 10 mL / min, carry out the gas-phase reaction for 4 h, and naturally warm up to room temperature. Rotate to dry the solvent to obtain a light yellow solid.

[0068] MS (ESI): 509.09 [M+Na] + Example 11 Dissolve diethyl acetylenephosphonate (1 mmol) in 20 mL of THF, add 0.02 mmol of triethylamine, and introduce hydrogen sulfide gas into it under an ice-water bath. Control the gas flow rate within the range of 1 - 10 mL / min, carry out the gas-phase reaction for 4 h, and naturally warm up to room temperature. Rotate to dry the solvent to obtain a yellow liquid. MS (ESI): 381.07 [M+Na] +

[0069] Experimental Example 1 H2S in vitro release ability of the compounds of the present invention This experiment aims to evaluate the hydrogen sulfide release ability of the compounds of the present invention under physiological conditions. The classical methylene blue method (reference: 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.) is used in the present invention to quantitatively determine the H2S release ability of the donor compounds of the present invention under simulated physiological microenvironment conditions.

[0070] The experimental conditions are as follows: The buffer is PBS (10 mM) with a pH of 7.4, or 0.5 mM cysteine is added as a physiological thiol model. After dissolving the compound of the present invention, it is incubated at 37 °C. Samples are taken at different time points and the absorbance change of methylene blue is measured to calculate the release amount of H2S.

[0071] The conditions for each group are as follows: A is the release of the compound of Example 1 in PBS buffer without Cys; B is the release of the compound of Example 1 in PBS buffer containing 0.5 mM Cys; C is the release of the compound of Example 1 in PBS buffer containing 1.0 mM Cys; D is the release of the compound of Example 3 in PBS buffer without Cys; E is the release of the compound of Example 3 in PBS buffer containing 0.5 mM Cys; F is the release of the compound of Example 4 in PBS buffer containing 0.5 mM Cys.

[0072] The experimental results (see Figure 1 ) show that the compounds of the present invention have significant thiol responsiveness, with no release in buffer without Cys, but significant release in buffer containing different concentrations of Cys. They can continuously release H2S under the simulated in vivo microenvironment, and the release curve shows a sustained-release characteristic. Moreover, the release rates are different in buffer containing different concentrations of Cys, indicating that the synthesized hydrogen sulfide donor compounds have excellent Cys concentration dependence and may have different responses to different lesion microenvironments (curves A, B, and C). Further comparison reveals that different substituents have a significant impact on the H2S release rate, with some substituents being able to accelerate the initial release rate (curves B, E, and F).

[0073] The above results indicate that the compounds of the present invention have stable and controllable H2S release performance under physiological conditions, which can not only meet the demand for continuous supply in the long-term treatment of chronic diseases, but also provide an experimental basis and a direction for optimizing the drug structure for designing different H2S donors according to different disease characteristics.

[0074] Experimental Example 2 The acute toxicity and tolerance of the H2S of the compounds of the present invention in vivo This experiment aims to evaluate the acute toxicity and tolerance of the compound of Example 1 of the present invention in vivo. Male C57BL / 6 mice (6 - 8 weeks old, weighing 20 - 25 g) are randomly divided into a low-dose group (0.5 mg / kg), a medium-low-dose group (1 mg / kg), a medium-dose group (2 mg / kg), a medium-high-dose group (4 mg / kg), a high-dose group (8 mg / kg), and a control group (equal volume of PBS solution). After a single intraperitoneal injection, they are continuously observed for 7 days.

[0075] The results show ( Figure 2 ), in the low-dose and medium-dose groups, no mice died, the body weight growth curve was comparable to that of the control group, and the behavioral state was normal; in the high-dose group, some mice showed reduced activity and piloerection in a short time after administration, but recovered within 24 h and no deaths occurred. The body weight statistics showed that there was no significant difference in the body weight index between the low- and medium-dose groups and the control group, while the body weight in the high-dose group decreased. The comprehensive results indicate that the H2S donor compound of the present invention exhibits good tolerance and low acute toxicity in mice, has no obvious adverse effects within the conventional dosing range (0.5 - 4 mg / kg), has good in vivo safety, and is suitable for further pharmacodynamic and long-term dosing studies.

[0076] Experimental Example 3 H2S release ability of the compound of Example 1 of the present invention in vivo This experiment aims to evaluate the hydrogen sulfide release ability of the compounds of the present invention under physiological conditions. The classical liquid chromatography-mass spectrometry method (also known as the MBB method, reference: Shanshan Luo, Chuiyu Kong, Shuang Zhao and etal., Endothelial HDAC1-ZEB2-NuRD Complex Drives Aortic Aneurysm and Dissection Through Regulation of Protein S-Sulfhydration, Circulation. 2023;147:1382–1403.) was used in the present invention to determine the H2S release ability of the donors of the present invention in rats.

[0077] The test animals were Wistar rats (male, body weight 200 - 250 g, n = 5), and they were adaptively fed for 1 week before the experiment. The compounds of the present invention were dissolved in PBS containing a small amount of co-solvent (DMSO ≤ 0.1%, Tween-80 ≤ 1%), and were freshly prepared before use. Administration method: intraperitoneal injection (i.p.). Administration dose: 1, 2, 4 mg / kg (single administration). Blood samples of about 50 - 100 μL were collected from the orbital cavity at different time points (0, 0.3, 0.5, 1, 2, 4, 6, 8, 12, and 24 h) after administration, and the specific sample treatment method is described in the above-mentioned literature.

[0078] The results are as Figure 3As shown: The compound of the present invention can significantly increase the plasma H2S level in rats. The blood H2S levels of both groups of animals showed a typical pharmacokinetic curve of first increasing and then gradually decreasing. Among them, the 2 mg / kg group reached the peak (6.6 µM) at about 3 - 4 h after administration, and then slowly decreased, still higher than the basal level (about 4 µM) at 24 h; the 4 mg / kg group increased faster, reached the peak (12.8 µM) at 3 - 4 h, and its peak concentration was about 1.9 times higher than that of the lower dose group, and remained at a relatively high level of 6 - 7 µM within 12 - 24 h. The results indicate that the H2S donor of the present invention exhibits dose-dependence and significant sustained-release characteristics in vivo, can achieve continuous and stable H2S release, and has the advantages of rapid onset and long-term maintenance. This characteristic provides important pharmacokinetic support for the long-term intervention of subsequent multi-system chronic diseases (such as heart failure, neurodegenerative diseases, etc.).

[0079] Experimental Example 4 In this experiment, a BAPN-induced TAD mouse model was used to evaluate the therapeutic effect of the compound of Example 1 of the present invention (hereinafter referred to as EPS) in aortic dissection (TAD). By comparing the survival rate and aortic rupture rate of mice in the EPS treatment group and the control group, the role of the compound of the present invention in the intervention of aortic dissection disease was further verified. 1. Establishment of animal model

[0080] Four-week-old male C57BL / 6J mice were selected and randomly divided into 3 groups (n = 15 in each group): 1) Control group: normal drinking water + saline injection; 2) BAPN group: drinking 0.25% BAPN aqueous solution + saline injection; 3) BAPN+EPS group: drinking 0.25% BAPN aqueous solution + EPS intraperitoneal injection. All mice were continuously treated for 28 days. 2. Administration and treatment:

[0081] From the day of modeling, mice in the BAPN group and the BAPN+EPS group continuously drank 0.25% BAPN solution. Mice in the EPS group were given intraperitoneal injection of EPS (4 mg / kg) once a day for 28 days. The control group and the BAPN group were injected with the same volume of saline during the same period.

[0082] 3. Evaluation of aortic rupture: 1) At the end of the experiment, mice were examined by B-ultrasound (VEVO 2100) to detect the diameter of the thoracic aorta and judge whether dissection formation occurred. b) Dead or dying mice were dissected after the experiment to observe whether the aorta was ruptured, and the rupture location, size and cause of death were recorded. c) The aortic rupture rate was the number of ruptured mice / total number of mice, and the aortic rupture rate of each group of mice was statistically analyzed. 4. Results <The results showed that the serum H2S level in the BAPN group was significantly lower than that in the normal group. After injection of Compound 1 of the present embodiment, the blood H2S level recovered to the normal level at about 4 h and remained at the normal level for a long time ( Figure 4 ). Compared with the BAPN group, the aortic rupture rate of mice in the EPS group was significantly reduced (for example, the rupture rate in the BAPN group was about 60%, and that in the EPS group was reduced to about 25%, P<0.05) ( Figure 5 ); in addition, the survival rate of mice in the EPS treatment group was significantly increased, and the survival rate was increased by 35% compared with the BAPN group ( Figure 6 ). The results indicate that the compound of the present invention can effectively inhibit the occurrence and rupture of BAPN-induced aortic dissection and has good cardiovascular protective effects.

[0084] Experimental Example 5 This experiment aimed to evaluate the effect of EPS on the vascular structure in a mouse model of TAD, especially the repair effect on the destruction of aortic structure and matrix degradation caused by inflammation. The effect of EPS treatment on the aortic vascular wall was detected by HE staining, EVG staining and Masson staining.

[0085] Steps: (1) The animal model and experimental groups were the same as in Experimental Example 4; (2) The administration and treatment of EPS were the same as in Experimental Example 4; (3) Histological analysis: At the end of the mouse experiment, the aorta was taken out and tissue-fixed, fixed with 4% paraformaldehyde and then embedded in paraffin. The section thickness was 5 µm, and HE staining, Masson trichrome staining and EVG staining were performed. Among them, HE staining was used to observe the structural changes of the vascular wall; Masson staining was used to detect the deposition of collagen fibers; EVG staining was used to observe the integrity and degree of fracture of elastic fibers.

[0086] As Figure 7 shown, the aortic vascular wall of mice in the BAPN group was significantly damaged, and the HE staining results showed that the intima of the vascular wall peeled off, the middle layer fractured, and the inner and outer layers separated, and the elastic fibers (EVG staining) were significantly fractured. The Masson staining results showed excessive collagen deposition, which further aggravated the pathological remodeling of the vascular wall. In the EPS treatment group, the vascular wall structure was relatively stable, the HE staining showed that the thickness of the vascular wall was relatively uniform, the intima was not significantly peeled off, the elastic fibers (EVG staining) were less fractured, and the amount of collagen deposition was lower.

[0087] Experimental Example 6 The protective effect of the compound of the present invention in a mouse model of Alzheimer's disease In some experiments, reported H2S donors (such as GYY4137 or NaHS) can also be set as positive controls to verify the relative effects of the compounds of the present invention. In this experiment, an Alzheimer's disease (AD) model was established using APP / PS1 double transgenic mice to evaluate the therapeutic effects of Compound 1 of the present invention and its combination with the AD drug Donepezil in AD.

[0088] (1) Establishment and grouping of animal models: Six-month-old male APP / PS1 mice were selected and randomly divided into 3 groups (n = 12 in each group): 1) Normal control group: C57BL / 6J mice + saline treatment; 2) AD group: APP / PS1 mice + saline treatment; 3) AD+EPS group (labeled as AD+H2S donor group): APP / PS1 mice + EPS intraperitoneal injection; 4) AD+ Donepezil group (labeled as AD+drug group): APP / PS1 mice + Donepezil intraperitoneal injection; 5) AD+EPS+Donepezil group (labeled as AD+drug+H2S donor group): APP / PS1 mice + EPS intraperitoneal injection.

[0089] (2) Administration and treatment: Mice in the AD+EPS group were given intraperitoneal injection of EPS (4 mg / kg), mice in the EPS+Donepezil group were given intraperitoneal injection of EPS (4 mg / kg) and Donepezil (0.5 mg / kg), mice in the AD+ Donepezil group were given intraperitoneal injection of Donepezil (0.5 mg / kg), and the control group and the AD group were given the same volume of saline at the same time. Once a day for 8 consecutive weeks.

[0090] (3) Behavioral evaluation: After the administration, the Morris water maze experiment was carried out. Training was carried out for 5 days, and the escape latency was recorded.

[0091] As Figure 8 shown, compared with the AD group, the escape latency of mice in the AD+EPS+Donepezil group was significantly shortened. On the 5th day, the average escape latency of mice in the AD group was about 50 s, that in the EPS group was shortened to 24.9 s, while that in the AD+EPS+Donepezil group was shortened to nearly 20 s of the normal control group, with an improvement amplitude of about 60%. The results show that the compound of the present invention alone may significantly improve the learning and memory disorders of AD mice, and when combined with AD drugs, the effect is better, showing a good cognitive function protection effect.

[0092] Experimental Example 7 In this experiment, a Parkinson's disease (PD) mouse model was established by MPTP treatment to evaluate the effect of Compound 1 of the present invention in improving motor disorders.

[0093] (1) Establishment and grouping of animal models: Male C57BL / 6J mice at 8 weeks of age were selected and randomly divided into 3 groups (n = 12 in each group): 1) Normal control group: Treated with normal saline; 2) PD group: Treated with MPTP + injected with normal saline; 3) PD+EPS group: Treated with MPTP + intraperitoneal injection of EPS.

[0094] (2) Administration and treatment: Mice in the PD+EPS group were given intraperitoneal injection of EPS (4 mg / kg) once a day for 14 consecutive days during the MPTP treatment. The control group and the PD group were given the same volume of normal saline during the same period.

[0095] (3) Behavioral evaluation: After the last administration, the total movement distance, the number of rearing, the rotarod test and the tail suspension test were carried out.

[0096] Results ( Figure 9 ): Compared with the PD group, the total movement distance and the number of rearing of mice in the PD+EPS group were significantly increased, and were restored to about 90% of the normal group level respectively (about 40% of the normal group in the PD group); in the rotarod test, the retention time of the EPS group was extended to about 135 s, while that of the PD group was only about 90 s, and the improvement amplitude was about 50% (P<0.05); in the tail suspension test, the stationary time of the EPS group decreased to about 70 s, while that of the PD group was about 160 s, and the decrease amplitude was about 56% (P<0.05). The results show that the compound of the present invention can significantly improve the motor disorders and depression-like behaviors of PD model mice and has good neuroprotective effects.

[0097] Based on the above results, the donor of the present invention is applicable to multiple clinical cardiovascular disease indications including acute and chronic cardiovascular events.

Claims

1. A class of hydrogen sulfide donor compounds or pharmaceutically acceptable salts thereof, characterized in that, The structure of the hydrogen sulfide donor compound is as follows: or 。 2. A pharmaceutical composition, characterized in that, It comprises the hydrogen sulfide donor compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2, characterized in that, It is a compound of the hydrogen sulfide donor compound as described in claim 1 and donepezil.

4. The pharmaceutical composition according to claim 3, characterized in that, The mass ratio of the hydrogen sulfide donor compound to donepezil is 4~10:

1.

5. The pharmaceutical composition according to claim 2, characterized in that, It also includes one or more pharmaceutically acceptable carriers, sustained-release excipients, or targeted delivery systems.

6. The use of a class of hydrogen sulfide donor compounds or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 2, characterized in that, The application refers to its use in the preparation of medicaments for treating diseases associated with decreased H2S levels in the body, wherein the hydrogen sulfide donor compound has a structure as shown in general formula (I): In the formula: the curves on both sides of the S atom represent cis-trans isomerism; R1 is methyl or ethoxy; R2 is H or methyl; Alternatively, the hydrogen sulfide donor compound may be as follows: 。 7. The application according to claim 6, characterized in that, The method for synthesizing hydrogen sulfide donor compounds includes the following steps: In the presence of an alkaline catalyst, a sulfur source is added to the compound shown in formula (II) to undergo sulfidation addition, thereby obtaining the compound shown in formula (I). 。 8. The application according to claim 7, characterized in that, The sulfur source is selected from any one of hydrogen sulfide, sodium sulfide, and sodium hydrosulfide.

9. The application according to claim 7, characterized in that, The reaction time for the sulfidation addition is 0.1 min to 6 h.

10. The application according to claim 7, characterized in that, 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, and dimethylphenylphosphine; the reaction time of the sulfidation addition is 0.1 min to 6 h.

11. The application according to claim 6, characterized in that, The diseases associated with decreased H2S levels in the body are cardiovascular and cerebrovascular diseases, neurodegenerative diseases, or metabolic syndromes.

12. The application according to claim 6, characterized in that, The diseases associated with decreased H2S levels in the body are myocardial infarction, heart failure, aortic dissection, hypertension, cerebral ischemia, stroke, Alzheimer's disease, Parkinson's disease, type 2 diabetes or type 2 diabetes-related vascular complications.

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