CN111393342B - Alliin hydrogen sulfide donor compound and preparation method and application thereof - Google Patents

Abstract

The invention relates to an alliin hydrogen sulfide donor compound or a medicinal salt or hydrate thereof, a preparation method thereof and application thereof in preparing analgesic drugs. The structural formula of the compound is shown as a formula (I), wherein R₁Is a phenolic analgesic substance, R₂Is hydrogen or methyl. The compound of the invention can slowly release the parent drug and H in vivo₂S messenger, and can obviously improve the blood concentration of the pharmacological active form mother medicine.

Description

Alliin hydrogen sulfide donor compound and preparation method and application thereof

One, the technical field

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of an alliin hydrogen sulfide donor compound or a medicinal salt thereof or a hydrate or a solvate thereof and application of the alliin hydrogen sulfide donor compound or the medicinal salt thereof in preparation of an analgesic drug.

Second, background Art

The discovery of gas signaling molecules has opened a new field of biomedical research, hydrogen sulfide (H)₂S) as a third novel endogenous gas signaling molecule discovered following Nitric Oxide (NO) and carbon monoxide (CO), has complex biological activities, is widely involved in body pain and function regulation of various systems, has a protective effect on ischemia-reperfusion injury (I/RI) of multiple organs, and has received increasing attention in clinical research and therapeutic applications.

H₂Important targets of S for exerting analgesic biological effect include NMDA receptor, MAPK signal channel, NF-kB signal channel, PKC signal channel and various ion channels. Ion channels include ATP sensitivityPotassium channel (A)_l K_ATP)、Ca²⁺Channel, Cl^-Channels, large conductance calcium sensitive potassium channels, and transient voltage receptor cation channels (including TRPV and TRPA), among others. As a negative regulator of visceral pain sensation, H₂S is mainly through K_ATPChannel [ Clin Exp Pharmacol Physiol 2010,37 (7): 753-763]T type Ca²⁺Channel [ Gut,2009, 58 (6): 751-761]And TRPV₁To exert the analgesic biological effect.

At present, for H₂The regulatory role of S in pain has different views: h considered by scholars to be endogenous or exogenous₂S has pain-causing action at peripheral level, and H is considered by scholars₂S is directly acting on nociceptive neurons to produce analgesic effect [ Pain,2007, l30(3): 300-302.]. The Pain-causing effect of H2S may be due to induction of mechanical hyperalgesia after localized inflammatory response, or as a result of direct action on primary afferent nerves [ Pain,2007,132(1-2): 74-81]. Analgesia may be due to induction of presynaptic inhibition, reducing neurotransmitter release; or by postsynaptic inhibition to reduce the hyperpolarization of the postsynaptic membrane, etc., down-regulate the release of substance P and other neurotransmitters, thereby inhibiting hyperalgesia.

H₂S is the only endogenous vascular smooth muscle K discovered to date_ATPChannel openers, Sivarajah et al [ Shock,2006,26(2): 154-161]First proves the endogenous H₂S by adjusting K_ATPThe opening of sensitive channels exerts a protective effect on myocardial damage. Calvert et al [ Artificial Redox Signal,2010,12(10): 1203-1217]Research shows that endogenous H of mice is inhibited₂S production, which can exacerbate myocardial I/RI.

With H₂Clear release indication of S in organisms, researchers can design more H₂S-released donor targeted drugs. Currently, the group modification is carried out on the basis of the existing medicaments to release H₂S, is also a branch of contemporary drug development. For example, because of H₂The S donor can inhibit phosphatase, participate in the regulation of erectile dysfunction, and is specially developed into a hydrogen sulfide donor typeCTG-Pharma company of drugs, general Ltd₂The S donor compound is combined with sildenafil to synthesize sildenafil-anethol trithione which is used for relaxing cavernous smooth muscle of penis and has stronger inhibition on phosphatase than sildenafil [ bioinpir biomem, 2009,103(11): 1522-9)]. In order to reduce the adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the gastrointestinal tract, liver, kidney and blood system, researchers often refer to H₂The S donor group and NSAIDs are assembled to form a new chemical entity. Such as the company Antibe therapeutics H₂The S donor (4-hydroxythiobenzamide) and naproxen are combined to form a novel ester compound, which is expected to be used in a treatment for improving osteoarthritis. Compared with naproxen, the novel ester compound can inhibit COX-2 activity more effectively, reduce damage to gastrointestinal tract and accelerate healing of existing gastric ulcer focus [ Blumea,2010,159(6): 1236-46%]Currently, preclinical efficacy and toxicological testing are in progress.

At present, H₂The mechanism of S action has made a lot of progress in many areas of research, but there is still much room for further research and development of the physiological effects in different organ systems.

Exogenous H₂S donors mainly include 7 types: (1) na (Na)₂Sulfide-containing salts such as S, NaHS, CaS and the like; (2) lawson's reagent (dithiophosphate) derivatives (e.g., GYY 4137); (3) allicin (alliin, etc.) in natural products; (4) dithiothione derivatives (e.g., noranethotrithione); (5) n- (benzoyl) -thiobenzamide derivatives; (6) s-acetyl persulfides; (7) a thioamino acid compound.

The garlic contains various chemical components, mainly comprises sulfur-containing organic compounds and saponins, the sulfur-containing organic compounds are currently accepted as main active components of the garlic, and odorless and stable alliin is the most abundant sulfide contained in the intact garlic. Research shows that the incidence rate of acute myocardial ischemia is obviously negatively related to the quantity of garlic which is taken frequently, garlic sulfide can be the main reason for reducing the incidence rate of the acute myocardial ischemia, and garlic sulfur-containing compounds and gas signal molecule hydrogen sulfide (H) with obvious cardiovascular effect₂S) are closely related[Expert Rev Clin Pharmacol，2011，4(1)：123～133]. In the process of extracting the pilot plant alliin raw material medicine, the applicant researches the physicochemical properties and the activity characteristics of the alliin raw material medicine, and the basic information is as follows:

3.2.S.1.1 drug name

1) Chinese name: alliin

2) English name: allin

3) Spelling names: suan' ansean

4) Chinese culture name: (S) -3- (allylsulfinyl) -L-alanine

5) English chemical name: (S) -3- (Allylsulfophinyl) -L-alanine

6) CAS number: 556-27-4

Structure of 3.2.S.1.2

Structural formula (I)

The molecular formula is as follows: c₆H₁₁NO₃S

Relative molecular mass: 177.22

S.1.3 physicochemical Properties

1) Appearance and properties: white needle cluster crystal (50% acetone solution or 85% ethanol solution) without odor

2) And solubility: is easily soluble in water, slightly soluble in inorganic acid and alkali, and insoluble in diethyl ether, acetone, ethanol, and glacial acetic acid

3) Melting point: 164 ℃ to 166 DEG C

4) Isoelectric point: pI 4.86

5) And optical rotation: [ a ] A]D₂₀+63.5 ° (c ═ 2 aqueous solution)

Some phenol analgesic drugs used clinically, such as tapentadol hydrochloride, nalbuphine hydrochloride, butorphanol tartrate, pentazocine hydrochloride, dezocine, eptazocin hydrobromide, oxycodone hydrochloride, hydromorphone hydrochloride and oxymorphone hydrochloride, are compounds with phenolic hydroxyl groups, belong to the narcotic psychotropic drug control class, and have dependence and abuse potential. Like such substances, abuse is a particular problem with opioids suitable for the treatment of pain.

Not only does the combination of analgesic drugs increase the analgesic effect of different mechanisms, but also the resolution of abuse (i.e. ineffectiveness in vitro and difficulty in obtaining the original compound by general extraction) is a leading issue for developers.

Therefore, it is highly desirable to combine a single anesthetic or psychotropic analgesic drug molecule with a drug capable of slow release of H in vivo by enzymes₂S and at the same time slow release of anaesthetic or psychotropic analgesic drugs.

Third, the invention

The invention aims to solve the technical problem of finding safe and reliable hydrogen sulfide donor derivatives with good analgesic activity, taking a mother nucleus of anesthesia psychotropic analgesics containing phenolic hydroxyl groups which are clinically applied for many years as a lead compound, selecting alliin hydrogen sulfide donor derivatives with good activity by utilizing a splicing principle and an in vivo quantitative enzyme metabolism release activation principle, connecting the alliin hydrogen sulfide donor derivatives with good activity to phenol-OH of a molecular structure of the alliin hydrogen sulfide donor derivatives through a connecting group, and designing and synthesizing the spliced hydrogen sulfide donor derivatives with the general formula (I). The compound after being combined has better pharmaceutical activity.

In order to solve the technical problems, the invention provides the following technical scheme:

the first purpose of the invention is to provide an alliin hydrogen sulfide donor compound, which is a compound shown by the following general formula (I) or a medicinal salt thereof or a hydrate or a solvate thereof:

wherein R is₁Is a phenolic analgesic substance, the hydrogen atom of the phenolic hydroxyl group of which is bonded by replacing a covalent bond; r₂Is hydrogen or methyl, further, R₂Is methyl. The phenolic analgesic substance is selected from tapentadol, nalbuphine, butorphanol, pentazocine, dezocine, eptazocine, oxycodone, hydromorphone or oxymorphone, and further preferably has the following structure:

the pharmaceutically acceptable salt is hydrochloride, hydrobromide, hydroiodide, hydrofluoride, sulfate, nitrate, phosphate, formate, acetate, propionate, oxalate, malonate, butyrate, lactate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, maleate, benzoate, succinate, picrate, tartaric acid, citrate, fumarate, preferably hydrochloride.

The second purpose of the invention is to provide a preparation method of alliin hydrogen sulfide donor compound, which adopts the following technical scheme for synthesizing the compound:

wherein R is₁And R₂As defined above.

The above-mentioned production method is only one example of a method for producing the compound of the general formula (I) of the present invention. The method for producing the compound of the present invention is not limited to these methods, and the method for producing the compound of the present invention is more specifically described in the examples of the present specification, so that the compound of the general formula (I) or a salt thereof can be produced by a person skilled in the art by appropriately modifying the compound of the present invention as necessary based on the above description and the description of the specific examples.

The third objective of the present invention is to provide a pharmaceutical composition containing a therapeutically or prophylactically effective amount of an alliin hydrogen sulfide donor compound as an active ingredient, together with a pharmaceutically acceptable carrier. The above pharmaceutical composition is selected from solid, the donor compound is administered orally, and the dosage forms include tablet, dispersible tablet, chewable tablet, orally disintegrating tablet, granule, capsule and dry suspension; the oral preparation is prepared from an active raw material alliin hydrogen sulfide donor compound and auxiliary materials according to a general method in pharmaceutics, wherein the auxiliary materials comprise diluents, binders, disintegrants, lubricants, flavoring agents, aromatics or preservatives which are necessary in pharmaceutics. The pharmaceutical compositions of the invention generally contain a therapeutically effective amount of a compound of the invention. However, one skilled in the art will recognize that the pharmaceutical composition may contain more than a therapeutically effective amount (i.e., a bulk composition) or less than a therapeutically effective amount (i.e., separate unit doses designed for multiple administrations to achieve a therapeutically effective amount). Typically, such pharmaceutical compositions will contain from about 0.1 to about 95% by weight of a compound of formula (i) or a pharmaceutically acceptable salt thereof, including from about 5 to about 70% by weight; for example, from about 10 to about 60 weight percent of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The invention also provides the use of an alliin hydrogen sulfide donor compound or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the manufacture of a medicament for the treatment of pain, preferably acute pain, chronic pain, neuropathic pain, nociceptive pain, mild and severe pain relief, hyperalgesia, pain associated with central sensitization, allodynia or cancer pain.

The invention has the advantages that:

1) the external stability, few activated parent drugs, activation after internal administration, slow release of phenol analgesic substances under the action of in vivo enzyme, prevention of abuse and overuse;

2) after in vivo administration, the exogenous H is activated and slowly released under the action of in vivo enzyme₂S, synergistic effect, and the release mechanism is as follows:

3) the toxicity is reduced, the effect is enhanced, and the blood concentration of the parent drug in a pharmacological activity form can be obviously improved.

In a word, the compound prepared by the invention can better improve the membrane permeability and oral bioavailability of the phenol analgesic substance, simultaneously avoids the in vitro oxidability of the phenol analgesic substance, has stronger synergistic effect, and prevents abuse and overuse.

Fourth, detailed description of the invention

The following examples may further illustrate the present invention, however, these examples should not be construed as limiting the scope of the present invention.

Example 1 Tapentadol-3- (N-methyl-N- ((S) -3- (allylsulfinyl) -L-alanyl (methyl) amino)) ethylcarbamate (Compound I)₁) Preparation of

Step 1: preparation of intermediate 1

Alliin (265g, 1.5mol) was added to the reactor, 5L water and 10L acetone were added, cooled to 10-15 deg.C, 1.5 equivalents triethylamine was added with stirring, the temperature was controlled, and (Boc) was added slowly₂O (360g, 1.65mol), heating to 25-30 ℃, stirring for 5h, concentrating under reduced pressure at 40-45 ℃ to remove acetone, extracting the water layer with ethyl acetate (100mL × 3), and discarding. Adjusting pH of the water layer to 2-3 with 0.1N hydrochloric acid, extracting with ethyl acetate (300mL × 3), mixing the organic phases, washing with saturated sodium chloride solution, and removing anhydrous Na₂SO₄Drying, filtering to remove anhydrous Na₂SO₄The solvent was evaporated on a rotary evaporator and the residue was recrystallized from ethyl acetate-petroleum ether (1:2) to give 391g of a white crystalline solid with a yield of 94%.

Step 2: preparation of intermediate 2

Intermediate 1(390g, 1.4mol) and DMF 4000ml were dissolved by stirring at room temperature, 1-hydroxybenzotriazole (HOBt, 209g, 1.55mol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOT, 806g, 1.55mol) were added thereto, the mixture was stirred for 10min, diisopropylethylamine (582g, 4.5mol) was added thereto, the mixture was stirred for 15min, and CH was added dropwise₂-NH-CH₂-CH₂-N(CH₃) CBz (344g, 1.55mol) in 500mL DMF was stirred at room temperature for 3h, TLC was used to identify completion of the reaction, the mixture was poured into 350mL 0.5% aqueous acetic acid and stirred for 20min, celite was used to aid filtration, the filtrate was extracted with dichloromethane (400 mL. times.3), the organic phases were combined, washed with saturated sodium carbonate solution, saturated sodium chloride solution, anhydrousNa₂SO₄Drying, filtering to remove anhydrous Na₂SO₄The solvent was evaporated on a rotary evaporator to obtain 667g of off-white crystalline powder with a yield of 98.6%.

And step 3: preparation of intermediate 3

Putting the intermediate 2(660g, 1.37mol) and methanol into a hydrogenation kettle, and adding Pd-BaSO₄(34g)，N₂Replacement 3 times, H₂Replacing for 3 times, then heating to 40-45 ℃, and introducing H₂Hydrogenation to 2 atm until hydrogenation is complete, cooling to room temperature, filtration with celite, and concentration of the filtrate under reduced pressure to dryness to give 471g of intermediate 3 as a white waxy solid in 99.0% yield.

And 4, step 4: preparation of intermediate 4

The method comprises the steps of cooling tapentadol (self-made, 299g and 1.35mol) and 8L acetonitrile to 0-5 ℃, adding bis (4-nitrophenyl) carbonate (471g and 1.55mol), stirring for 10min, adding diisopropylethylamine (200g and 1.55mol) at the temperature, stirring for 15min, heating to room temperature, stirring for 5h to obtain a solution of an intermediate 4, and directly entering the next step.

And 5: preparation of intermediate 5

Cooling the solution of the intermediate 4 to 0-5 ℃, adding 3L dichloromethane solution of the intermediate 3(470g, 1.35mol) while stirring, adding diisopropylethylamine (100g, 0.88mol) after finishing dropping, heating to room temperature, stirring for 4h, identifying the completion of the reaction by TLC, adding 150mL acetic acid to quench the reaction, adding 5L dichloromethane to dilute the mixture, washing the mixture with water (300mL × 3), saturated sodium bicarbonate (400mL × 3) and saturated saline (400mL) in sequence, and adding anhydrous Na₂SO₄Drying, filtering to remove anhydrous Na₂SO₄The solvent was evaporated on a rotary evaporator to obtain 706g of off-white crystalline powder with a yield of 87.5%.

Step 6: compound I₁Preparation of

Intermediate 5(700g, 1.18mol), dichloromethane 1000mL, stirring at room temperature, adding trifluoroacetic acid 1000mL, stirring for 7h, identifying by TLC that the reaction is complete, diluting the mixture with 1L dichloromethane, and successively diluting the mixture with water (200 mL. times.3), saturated sodium bicarbonate (200 mL. times.3) and saturated brine (300mL)Washing with anhydrous Na₂SO₄Drying, filtering to remove anhydrous Na₂SO₄Evaporating the solvent on a rotary evaporator, adding 480ml of ethyl acetate, cooling to 0-5 ℃, stirring for 1h, filtering, washing the solid with a proper amount of cold ethyl acetate, and drying at 60 ℃ in vacuum for 3h to obtain 332g of off-white crystalline powder, wherein the yield is 56.6 percent, and the HPLC content is 98.6 percent.

¹H—NMR(500MHz，CDCl₃/TMS，ppm)：

δ：2.26(s，6H，CH ₃N-)，2.16(2H，d，J＝8.5Hz，CH ₂-N(CH₃)2)，1.84～1.86(1H，m，-CH-CH₃-CH-CH₂-)，0.96(3H，d，J＝8.5Hz，-CH-CH ₃-CH-CH₂-)，2.49(1H，m，-CH-CH₃-CH-CH₂-)，1.09～1.14(3H，t，J＝15.6Hz，CH ₃CH₂-CH-)，1.54(2H，m，CH₃CH ₂-CH-)，7.09～7.14(4H，m，J＝12.6Hz，Ar-H)，2.94～3.29(6H，m，J＝15.6Hz，-2N(CH ₃))，3.22～3.47(4H，t，J＝15.5Hz，-CH ₂CH ₂-)，2.95～3.19(2H，m，SO-CH ₂-CH-NH2)，3.61(1H，m，SO-CH₂-CH-NH2)，3.24(2H，m，SO-CH ₂-CH＝CH₂)，5.86(1H，m，SO-CH₂-CH＝CH₂)，5.07～5.44(2H，t，J＝15.6Hz，SO-CH₂-CH＝CH ₂)。

MS:m/z：[M+H⁺]495.8(100％)。

EXAMPLE 2 Compound I₁Preparation of hydrochloride salts

Compound I₁(495g, 1.0mol) and 5L of methanol are heated to 40-45 ℃ and stirred to be dissolved, hydrogen chloride gas is introduced until the pH value is 1-2, the mixture is stirred for 1h, cooled to 0-5 ℃, kept stand for 1h, filtered and dried for 3h at the temperature of 60 ℃ in vacuum, 467g of white crystalline powder is obtained, the yield is 87.8 percent, and the HPLC content is 99.3 percent.

Example 3 nalbuphine-3- (N-methyl-N- ((S) -3- (allylsulfinyl) -L-alanyl (methyl) amino)) ethylcarbamate(Compound I)₂) Preparation of

By the same procedure as in example 1, using nalbuphine in place of tapentadol, 46g of the target compound was synthesized in a total yield of 7.4%, HPLC content 98.1%, MS: m/z: [ M + H ]⁺]631.6 (calculated: 630.8).

EXAMPLE 4 Compound I₂Preparation of hydrochloride salts

In the same manner as in example 2, with Compound I₂In place of the compound I₁21g of the target compound was synthesized with a total yield of 81.2% and an HPLC content of 99.6%.

Example 5 pentazocine-3- (N-methyl-N- ((S) -3- (allylsulfinyl) -L-alanyl (methyl) amino)) ethylcarbamate (Compound I)₃) Preparation of

By the same procedure as in example 1, using pentazocine instead of tapentadol, 53g of the objective compound was synthesized in a total yield of 4.7%, HPLC content of 97.6%, MS: m/z: [ M + H ]⁺]559.9 (calculated value: 558.8).

Example 6 hydromorphone-3- (N-methyl-N- ((S) -3- (allylsulfinyl) -L-alanyl (methyl) amino)) ethylcarbamate (Compound I)₄) Preparation of

By the same procedure as in example 1, using hydromorphone instead of tapentadol, 5.8g of the objective compound was synthesized in a total yield of 3.1%, HPLC content 98.5%, MS: m/z: [ M + H ]⁺]559.4 (calculated value: 558.6).

Example 7 butorphanol-3- (N-methyl-N- ((S) -3- (allylsulfinyl) -L-alanyl (methyl) amino)) ethylcarbamate (Compound I)₄) Preparation of

By the same procedure as in example 1, using butorphanol in place of tapentadol, 3.7g of the target compound was synthesized with a total yield of 2.5%, an HPLC content of 98.0%, and an MS: m/z: [ M + H ]⁺]601.9 (calculated value: 600.8).

Example 8 in vitro activation stability

Preparing supersaturated aqueous solutions of the compound of the invention with three different pH values, placing the supersaturated aqueous solutions at room temperature for 24 hours, then heating the supersaturated aqueous solutions at 85-90 ℃ for 24 hours, and analyzing the content of the parent drug by an HPLC method, wherein the results are as follows:

the results show that the compound is very stable under severe in vitro conditions, and the parent drug compound can not be extracted generally, so that abuse is prevented.

Example 9 in vivo activation experiments

Selecting 30 healthy male Wistar rats with the weight of 220-280 g, and randomly dividing the rats into A-E groups and F-K groups, wherein each group comprises 3 rats. Single-cycle intragastric administration, with groups A-E each administered compound I₁Compound I₂Compound I₃Compound I₄And compounds I₅The F-K components are respectively administered with tapentadol, nalbuphine, pentazocine, hydromorphone and butorphanol, and the administration dosage is 15 mg/kg. Pre-dose (oh) and 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 12 or 24h post-dose, 0.5mL of blood was taken from the orbital vein of rats, placed in heparinized EP tubes, centrifuged for 5min (5000rpm), plasma separated, and frozen in a freezer at-20 ℃ to be tested. The fluconazole is taken as an internal standard, and the measurement results are shown in the following table through tandem mass spectrometry.

Gavage administration of tapentadol or B-F the compounds of examples 1-5 resulted in a significant increase in both Cmax and AUC for tapentadol in blood when the compounds of examples 1-5 were administered B-F, as compared to tapentadol.

It can be seen from this that the blood levels of pharmacologically active forms of tapentadol or analogues can be significantly increased after administration of the compounds of examples 1 to 5.

Compound (I)	AUC0～t(ng·h·mL-1)	Cmax(ng/mL)
			Compound I1	468.7±161.4	110.3±42.5
Tapentadol	159.4±46.3	37.8±9.4
			Compound I2	644.2±138.1	108.0 Shi 31.2
Nalbuphine	173.3±36.9	28.8±7.3
			Compound I3	764.7±193.5	179.4±76.3
Pentazocine	265.5±73.1	53.1±10.6
			Compound I4	546.7±112.3	152.3±47.8
Hydromorphone	509.4±153.8	136.1±63.9
			Compound I5	617.4±137.6	186.3±59.9
Butorphanol	295.4±69.8	58.3±12.7

The results of the experiments show that the compounds of the present invention are activated to the parent compound in vivo and that both Cmax and AUC in plasma are significantly increased. It can be seen that the compounds I₁Compound I₂Compound I₃Compound I₄And compounds I₅After administration, the blood concentration of the pharmacologically active form of the parent drug can be significantly increased.

Example 10 experiment of hydrogen sulfide release amount

Detecting the release amount of hydrogen sulfide from a hydrogen sulfide donor by adopting human umbilical vein endothelial cells and a methylene blue spectrophotometry, and preparing a microporous filter membrane adsorption device: sequentially adhering the microporous filter membrane on the inner side surface of the cover of the culture plate by using glue for 30min of ultraviolet irradiation; preparation of Na₂S, making a standard curve: na with concentration gradients of 100, 50, 25 and 12.5umol/L is formulated₂S solution, preparing Na₂And (2) taking 0.5mL of S as a standard curve, adding 2.5mL of deionized water into each tube, sequentially adding 0.5mL of 1% (mass fraction) zinc acetate, 0.5mL of 0.2% (mass fraction) N, N-dimethyl-p-phenylenediamine solution, adding 0.05mL of 10% (mass fraction) ferric ammonium sulfate solution, and standing at room temperature for 20 min. Deionized water for zero setting pipe to replace Na₂S solution, Optical Density (OD) was read at 670 nm.

The experiment is divided into a blank group, a solvent control group and a compound I₁Compound I₅Groups, each at 1000umo1/L human umbilical vein endothelial cells were plated in 12-well plates, 3 replicates per group. Blank group 2mmol/LL-Cys +0.5mmol/L pyridoxal 5-phosphate (PLP); solvent control group, L-Cys + PLP + DMSO 0.1%; sterilizing by passing 1% (mass fraction) zinc acetate solution through 0.2um filterThen, 500uL of the solution was added dropwise to each filter, and the mixture was left at 37 ℃ with 5% (volume fraction) CO₂Is incubated for 8 hours in the incubator. Measurement of hydrogen sulfide release amount: putting the filter membrane into a hose, adding 3mL of deionized water, 0.5mL of 0.2% (mass fraction) of N, N-dimethyl p-phenylenediamine solution into each hose, adding 0.05mL of 10% (mass fraction) of ammonium ferric sulfate solution, slightly shaking the hose, standing at room temperature for 20min, reading an OD value at 670nm after the reaction is completed, and calculating the cumulative yield of the hydrogen sulfide of the cells according to a standard curve, wherein the results are as follows:

compound (I)	Hydrogen sulfide evolution (umol/10)6cells)
		Compound I1	31
Compound I2	33
		Compound I3	34
Compound I4	32
		Compound I5	27

The compound of the invention slowly releases exogenous H under the action of in vivo enzyme₂S。

Claims (8)

1. An alliin hydrogen sulfide donor compound characterized in that: a compound represented by the following general formula (I):

wherein R is₁Is a phenolic analgesic substance, the hydrogen atom of the phenolic hydroxyl group of which is bonded by replacing a covalent bond; r₂Is hydrogen or methyl, the phenolic analgesic substance is tapentadol, nalbuphine, butorphanol, pentazocine, dezocine, etazocine, oxycodone, hydromorphone or oxymorphone.

2. The alliin hydrogen sulfide donor compound as claimed in claim 1, wherein: r₂Is methyl.

3. The alliin hydrogen sulfide donor compound as claimed in claim 1 or 2, wherein: the compound is tapentadol-3- (N-methyl-N- ((S) -3- (allylsulfinyl) -L-alanyl (methyl) amino)) ethylcarbamate, nalbuphine-3- (N-methyl-N- ((S) -3- (allylsulfinyl) -L-alanyl (methyl) amino)) ethylcarbamate, pentazocine-3- (N-methyl-N- ((S) -3- (allylsulfinyl) -L-alanyl (methyl) amino)) ethylcarbamate, hydromorphone-3- (N-methyl-N- ((S) -3- (allylsulfinyl) -L-alanyl (methyl) amino)) ethylcarbamate, or Butorphanol-3- (N-methyl-N- ((S) -3- (allylsulfinyl) -L-alanyl (methyl) amino)) ethyl carbamate.

4. The alliin hydrogen sulfide donor compound as claimed in claim 1, wherein: the medicinal salt is hydrochloride, hydrobromide, hydroiodide, hydrofluoride, sulfate, nitrate, phosphate, formate, acetate, propionate, oxalate, malonate, butyrate, lactate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, maleate, benzoate, succinate, picrate, tartaric acid, citrate or fumarate.

5. A preparation method of an alliin hydrogen sulfide donor compound is characterized by comprising the following technical routes:

wherein R is₁And R₂As claimed in claim 1.

6. A pharmaceutical composition characterized by: comprising as active ingredient a therapeutically or prophylactically effective amount of a compound according to any one of claims 1-4, in combination with a pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6, wherein: the pharmaceutical composition is formulated for oral administration to a patient.

8. Use of the alliin hydrogen sulfide donor compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 for the preparation of an analgesic drug.