A cysteine ​​protease inhibitor composition and its preparation method and application

Abstract

This invention provides a cysteine ​​protease inhibitor composition, its preparation method, and its application, belonging to the field of pharmaceutical technology. The compound has a structure represented by one of the following formulas. The cysteine ​​protease inhibitor and composition prepared by this invention offer potential options for the preparation of highly effective drugs for the treatment of ischemic stroke, traumatic brain injury, spinal cord injury, neurodegenerative diseases, brain tumors, and myocardial tissue damage, possessing broad application prospects and research value. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a cysteine ​​protease inhibitor composition, a preparation method and an application thereof. Background Art

[0002] Cysteine ​​proteases include calpain, cathepsin, papain, etc., which are widely present in mammalian cells. For example, there are at least two calcium-activated cysteine ​​proteases in the brain. -6 mol / L calpain: Calcium can activate calpain I, 10 -3 Calcium at 1 mol / L activates calpain II. Calpain degrades a wide range of protein substrates, directly impacting physiological processes such as long-term memory, axonal terminal blockade, membrane protein fragmentation, cytoskeletal modification, and neuropolypeptide metabolism. Because of the important physiological functions of calpain, its inhibitors have potential applications in treating diseases associated with neurodegeneration, such as stroke, hemiplegia, Alzheimer's disease, and Parkinson's disease. Cathepsin B, implicated in pathologies such as myocardial tissue damage and tumor metastasis, also plays a crucial physiological role.

[0003] Peptide aldehydes have been reported to be more effective than amino acid ketoacids and ketoesters, while peptide trifluoromethyl ketones are the least effective. Certain peptide derivatives containing electrophilic carbonyl groups are inhibitors of cathepsin B. Some reported inhibitors have poor biological membrane permeability, lack specificity, and are carcinogenic (e.g., peptide diazomethyl ketone). Therefore, these compounds are not particularly useful for inhibiting calpain in native tissues. To date, no specific drugs have been found for the treatment of neurodegenerative diseases. Summary of the Invention

[0004] The present invention aims to provide a cysteine ​​protease inhibitor composition, its preparation method, and its application, which has a good inhibitory effect on calpain (including calpain I and calpain II), cathepsins, papain, cathepsin B, etc., providing an option for the preparation of potentially effective drugs for the treatment of ischemic stroke, traumatic brain injury, spinal cord injury, neurodegenerative diseases, brain tumors, and myocardial tissue damage, and has broad application prospects and research value.

[0005] The technical solution of the present invention is achieved as follows:

[0006] The present invention provides a cysteine ​​protease inhibitor, which is a compound having a structure as shown in Formula I or Formula II:

[0007]

[0008] Among them, R1=H, Ph, Bn, 4-OMePh.

[0009] As a further improvement of the present invention, the synthesis method of the compound represented by the structure of Formula I is as follows:

[0010] S1. p-Aminobenzyl chloride and sodium diselenide react to obtain intermediate 1, the structure of which is as follows:

[0011] S2. Intermediate 1 is reacted with diethyl 2-oxalopropionate, followed by secondary condensation in acetic acid, heated in an oil phase to form a ring, and hydrolyzed under alkaline conditions to obtain intermediate 2, the structure of which is as follows:

[0012] S3. The intermediate 2 is reacted with α-hydroxylamine and then oxidized to obtain a compound of the structure shown in Formula I.

[0013] As a further improvement of the present invention, the molar ratio of p-aminobenzyl chloride and sodium diselenide in step S1 is 1:2-3, the reaction temperature is room temperature, and the time is 4-7 hours; the molar ratio of intermediate 1 and diethyl 2-oxalopropionate in step S2 is 1:2.1-2.2, the reaction temperature is 45-50°C, the time is 5-7 hours, and the reaction is heated to 240-260°C for 20-40 minutes. The pH value of the alkaline conditions is 9.5-10.5, the temperature is 65-75°C, and the time is 1-3 hours; the molar ratio of intermediate 2 and α-hydroxyamine in step S3 is 1:2-2.1, and the oxidation adopts Dess-Martin oxidant, and the molar ratio of the Dess-Martin oxidant to intermediate 2 is 4-4.1:1.

[0014] As a further improvement of the present invention, the synthesis method of the compound represented by the structure of Formula II is as follows:

[0015] T1. p-Aminobenzyl chloride and sodium diselenide react to obtain intermediate 1, the structure of which is as follows:

[0016] T2. Intermediate 1 is reacted with sodium triacetoxyborohydride and iodomethane to obtain intermediate 3, the structure of which is as follows:

[0017] T3. Intermediate 3 is reacted with diethyl 2-oxalopropionate, followed by secondary condensation in acetic acid, heated in an oil phase to form a ring, and hydrolyzed under alkaline conditions to obtain intermediate 4, the structure of which is as follows:

[0018] T4. The intermediate 4 is reacted with α-hydroxylamine and then oxidized to obtain a compound of formula II.

[0019] As a further improvement of the present invention, the molar ratio of p-aminobenzyl chloride to sodium diselenide in step T1 is 1:2-3, the reaction temperature is room temperature, and the reaction time is 4-7 hours; the molar ratio of intermediate 1 to sodium triacetoxyborohydride and iodomethane in step T2 is 1:3-4:3-5; the molar ratio of intermediate 1 to diethyl 2-oxalopropionate in step T3 is 1:1.05-1.1, the reaction temperature is 45-50°C, the reaction time is 4-6 hours, and the reaction is heated to 240-260°C for 20-40 minutes. The pH value of the alkaline conditions is 9.5-10.5, the temperature is 65-75°C, and the reaction time is 1-3 hours; the molar ratio of intermediate 4 to α-hydroxyamine in step T4 is 1:1-1.1, and the oxidation is carried out using a Dess-Martin periodinane, with the molar ratio of the Dess-Martin periodinane to intermediate 4 being 2-2.1:1.

[0020] As a further improvement of the present invention, the preparation method of sodium diselenide is as follows: 2-3 parts by weight of sodium hydroxide are dissolved in 50 parts by weight of water, 2-4 parts by weight of selenium powder are added, and the mixture is stirred and mixed uniformly, 3-4 parts by weight of sodium bisulfite formaldehyde are added, and the mixture is heated to 55-65° C. and stirred for reaction for 0.5-1 hour. An equal volume of ethanol is added for precipitation, and the mixture is filtered, washed, and dried to obtain sodium diselenide.

[0021] As a further improvement of the present invention, the α-hydroxyamine is selected from one of the compounds of the following structural formula:

[0022] The present invention further protects a cysteine ​​protease inhibitor composition comprising compounds of the structures shown in Formula I and Formula II in a mass ratio of 5-7:2-4.

[0023] The present invention further protects a method for preparing the above-mentioned cysteine ​​protease inhibitor composition, which comprises uniformly mixing the compounds represented by formula I and formula II in proportion to prepare the cysteine ​​protease inhibitor composition.

[0024] The present invention further protects the use of the above-mentioned cysteine ​​protease inhibitor composition in the preparation of a drug for treating ischemic stroke, traumatic brain injury, spinal cord injury, neurodegenerative diseases, brain tumors, and myocardial tissue damage.

[0025] The present invention has the following beneficial effects: the present invention prepares α-ketoamide cysteine ​​protease inhibitors containing Se elements (compounds shown in formula I and compounds shown in formula II), which have good inhibitory effects on calpain (including calpain I and calpain II), cathepsin, papain, cathepsin B, etc. In the presence of Se elements, the anti-tumor and anti-inflammatory activities of the compounds can be significantly improved, and the inhibitory effect on proteases can be significantly improved, so that better inhibitory effects can be achieved at lower administration concentrations, and the biomembrane permeability is good, cytotoxicity is low, and there is a specific inhibitory effect on cysteine ​​proteases. The raw material sources are wide and the preparation cost is low.

[0026] In addition, the present invention has found that a composition prepared by mixing two compounds, including the compound represented by Formula I and the compound represented by Formula II, can further significantly improve the inhibitory effect within a suitable mass ratio range and has a synergistic effect.

[0027] The cysteine ​​protease inhibitors and compositions prepared by the present invention provide options for preparing potentially highly effective drugs for treating ischemic stroke, traumatic brain injury, spinal cord injury, neurodegenerative diseases, brain tumors, and myocardial tissue damage, and have broad application prospects and research value. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0029] Figure 1 The synthetic route of the compound of the structure shown in Formula I;

[0030] Figure 2 The synthetic route of the compound of the structure shown in formula II is shown in FIG. DETAILED DESCRIPTION

[0031] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0032] The preparation method of sodium diselenide is as follows: dissolve 2.5g of sodium hydroxide in 50mL of water, add 3g of selenium powder, stir and mix evenly, add 3.5g of sodium bisulfite formaldehyde, heat to 60°C, stir and react for 1h, add an equal volume of ethanol to precipitate, filter, wash, and dry to obtain sodium diselenide, then dissolve the sodium diselenide in water to prepare a solution containing 0.25mol of sodium diselenide.

[0033] Example 1 Synthesis of the compound having the structure shown in Formula I

[0034] like Figure 1 , the synthesis method is as follows:

[0035] S1. Dissolve 0.1 mol of p-aminobenzyl chloride in 50 mL of ethanol, add sodium hydroxide solution dropwise to adjust the pH to 9, add 20 mL of a solution containing 0.25 mol of sodium diselenide, and stir at room temperature for 5 h. Add hydrochloric acid dropwise to adjust the pH of the solution to 1.5, stir for 1 h, then adjust the pH of the solution to 6.2. Incubate at 4°C for 1 h to precipitate crystals, filter, wash, and dry to obtain intermediate 1; ESI-MS calculated value: C 14 H 17 N2Se2(M+H) + 372.96, found: 373.0, yield: 67%.

[0036] NMR results: 1 H NMR (300MHz, CDCl3) δ6.82 (d, J=6.7Hz, 4H), 6.31 (d, J=6.7Hz, 4H), 4.0 (br, 4H), 2.6 (s, 4H).

[0037] S2. 0.1 mol of intermediate 1 and 0.215 mol of diethyl 2-oxalylpropionate were dissolved in 100 mL of acetic acid, heated to 50° C., stirred and reacted for 6 h, the reaction liquid was neutralized, extracted with dichloromethane, washed with 0.5 mol / L hydrochloric acid, water, and 0.5 mol / L NaOH solution in sequence, dried, filtered, added to ethanol for recrystallization, filtered, washed with ethanol, the product was added to mineral oil at 250° C., stirred and reacted for 30 min, cooled to room temperature, filtered, washed with petroleum ether, and then added to 60 wt% ethanol solution, sodium hydroxide was added to adjust the solution pH to 10, stirred and reacted at 70° C. for 2 h, and then the solution pH was adjusted to 5.5, the solid precipitated, filtered, washed with water, and dried to obtain intermediate 2; ESI-MS calculated value: C 24 H 21 N206Se2(M+H) + 592.97, found: 593.0, yield: 69%.

[0038] NMR results: 1H NMR (300MHz, CDCl3) δ11.2 (br, 2H), 7.31 (s, 2H), 7.12 (d, J=5.9Hz, 2H), 6.49 (d, J=5.9Hz, 2H), 4.1 (br, 2H), 2.57 (s, 4H), 1.91 (s, 6H).

[0039] S3. 0.1 mol of intermediate 2 and 0.2 mol of α-hydroxyamine were dissolved in 200 mL of DMF, 0.3 mol of 1-hydroxybenzotriazole and 0.3 mol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide were added at 0°C, the mixture was stirred and mixed uniformly, the temperature was raised to room temperature, the mixture was stirred and reacted for 2 h, an equal volume of water was added, the mixture was filtered, the mixture was washed with ethanol, and the obtained product was dissolved in 200 mL of dichloromethane, 0.4 mol of Dess-Martin periodinane was added at 0°C, the mixture was stirred and reacted at room temperature for 5 h, 50 mL of 10 wt% sodium bisulfite solution was added, the organic phase was separated, and the mixture was washed with saturated sodium bicarbonate solution, water and saturated brine in sequence, dried, and precipitated by adding tetrahydrofuran. The mixture was filtered, washed, and dried to obtain a compound with the structure shown in Formula I.

[0040] Among them, when α-hydroxylamine is When the compound A with the structure shown in formula I is obtained, the structural formula is as follows: ESI-MS calculated value: C 44 H 41 N6O8Se2(M+H) + 941.12, found: 941.1, yield 75%.

[0041] NMR results: 1 H NMR (300MHz, CDCl3) δ8.0 (br, 2H), 7.32 (s, 2H), 7.10-7.22 (m, 12H), 6.51 (d, J=5.6Hz, 2 H), 6.0 (br, 4H), 4.81 (t, 2H), 4.0 (br, 2H), 3.22-3.37 (m, 4H), 2.57 (s, 4H), 1.91 (s, 6H).

[0042] Among them, when α-hydroxylamine is When the compound B with the structure shown in formula I is obtained, the structural formula is as follows: ESI-MS calculated value: C 56 H 49 N6O8Se2(M+H) + 1093.19, found: 1093.2, yield: 71%.

[0043] NMR results: 1H NMR (300MHz, CDCl3) δ8.0 (br, 2H), 7.65 (d, J=5.2Hz, 4H), 7.34 (s, 2H), 7.00-7.27 (m, 18H), 6.52 (d, J =5.6Hz, 2H), 6.03 (br, 2H), 4.84 (t, 2H), 4.02 (br, 2H), 3.22-3.39 (m, 4H), 2.55 (s, 4H), 1.92 (s, 6H).

[0044] Example 2 Synthesis of the compound represented by formula II

[0045] like Figure 2 , the synthesis method is as follows:

[0046] T1. Dissolve 0.1 mol of p-aminobenzyl chloride in 50 mL of ethanol, add sodium hydroxide solution dropwise to adjust the pH to 9, add 20 mL of a solution containing 0.25 mol of sodium diselenide, and stir at room temperature for 5 h. Add hydrochloric acid dropwise to adjust the pH of the solution to 1.5, stir for 1 h, then adjust the pH of the solution to 6.2. Incubate at 4°C for 1 h to precipitate crystals, filter, wash, and dry to obtain intermediate 1.

[0047] T2. Add 0.1 mol of intermediate 1 to a mixture of 200 mL of ethanol and water (volume ratio 1:1), adjust the pH to 8.5 with NaOH, add 0.35 mol of sodium triacetoxyborohydride, stir at room temperature for 20 min, add 0.4 mol of iodomethane, stir at room temperature for 30 min. After the reaction, adjust the pH of the solution to 7, add pyridine for precipitation, filter, wash, and dry to obtain intermediate 3; ESI-MS calculated value: C8H 12 NSe(M+H) + 202.01, found: 202.0, yield 86%.

[0048] NMR results: 1 H NMR (300MHz, CDCl3) δ6.87 (d, J=6.2Hz, 2H), 6.36 (d, J=6.2Hz, 2H), 4.0 (br, 2H), 2.69 (s, 2H), 0.92 (s, 3H).

[0049] T3. 0.1 mol of intermediate 3 and 0.11 mol of diethyl 2-oxalylpropionate were dissolved in 100 mL of acetic acid, heated to 50°C, stirred and reacted for 6 h. The reaction liquid was neutralized, extracted with dichloromethane, washed with 0.5 mol / L hydrochloric acid, water, and 0.5 mol / L NaOH solution in sequence, dried, filtered, and recrystallized by adding ethanol. The product was filtered and washed with ethanol. The product was added to mineral oil at 250°C, stirred and reacted for 30 min, cooled to room temperature, filtered, washed with petroleum ether, and then added to 60 wt% ethanol solution. Sodium hydroxide was added to adjust the solution pH to 10. The solution was stirred and reacted at 70°C for 2 h. The pH of the solution was then adjusted to 5.5. The precipitated solid was filtered, washed with water, and dried to obtain intermediate 4. ESI-MS calculated value: C 13 H 14 NO3Se(M+H) + 312.01, found: 312.0, yield: 72%.

[0050] NMR results: 1 H NMR (300MHz, CDCl3) δ11.0 (br, 1H), 7.32 (s, 1H), 7.10 (d, J=5.4Hz, 1H), 6.50 (d, J=5.4Hz, 1H), 4.0 (br, 1H), 2.63 (s, 2H), 1.91 (s, 3H), 0.94 (s, 3H).

[0051] T4. 0.1 mol of intermediate 4 and 0.1 mol of α-hydroxyamine were dissolved in 200 mL of DMF, 0.15 mol of 1-hydroxybenzotriazole and 0.15 mol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide were added at 0°C, and the mixture was stirred and mixed. The mixture was then warmed to room temperature and stirred for 2 h. An equal volume of water was added, the mixture was filtered, washed with ethanol, and dried. The obtained product was dissolved in 200 mL of dichloromethane, 0.2 mol of Dess-Martin periodinane was added at 0°C, and the mixture was stirred and reacted at room temperature for 5 h. Then, 50 mL of 10 wt% sodium bisulfite solution was added, the organic phase was separated, and the mixture was washed with saturated sodium bicarbonate solution, water, and saturated brine, dried, and precipitated with tetrahydrofuran. The mixture was filtered, washed, and dried to obtain a compound of formula II.

[0052] Among them, when α-hydroxylamine is When the compound A with the structure shown in formula II is obtained, the structural formula is as follows: ESI-MS calculated value: C 23 H 24 N304Se(M+H) + 486.09, found: 486.1, yield 81%.

[0053] NMR results:1 H NMR (300MHz, CDCl3) δ8.0 (br, 1H), 7.34 (s, 1H), 7.12-7.25 (m, 6H), 6.57 (d, J=5.1Hz, 1H), 6.0 (br, 2H), 4.85 (t, 1H), 4.0 (br, 1H), 3.21-3.34 (m, 2H), 2.64 (s, 2H), 1.94 (s, 3H), 0.91 (s, 3H).

[0054] Among them, when α-hydroxylamine is When the compound B with the structure shown in formula II is obtained, the structural formula is as follows: ESI-MS calculated value: C 29 H 28 N304Se(M+H) + 562.12, found: 562.1, yield 79%.

[0055] NMR results: 1 H NMR (300MHz, CDCl3) δ8.05 (br, 2H), 7.69 (d, J=5.2Hz, 2H), 7.37 (s, 1H), 7.05-7.22 (m, 9H), 6.54 (d, J=5.4Hz, 1H), 4.81 (t, 1H), 4.05 (br, 1H), 3.26-3.35 (m, 2H), 2.62 (s, 2H), 1.94 (s, 3H), 0.95 (s, 3H).

[0056] Example 3

[0057] A cysteine ​​protease inhibitor composition comprises compound A having a structure shown in formula I and compound A having a structure shown in formula II in a mass ratio of 5:2. The compounds are mixed uniformly according to the ratio to prepare the cysteine ​​protease inhibitor composition.

[0058] Example 4

[0059] A cysteine ​​protease inhibitor composition comprises compound B having a structure shown in formula I and compound B having a structure shown in formula II in a mass ratio of 7:4. The compounds are mixed uniformly in proportion to prepare the cysteine ​​protease inhibitor composition.

[0060] Example 5

[0061] A cysteine ​​protease inhibitor composition comprises compound A having a structure shown in formula I and compound B having a structure shown in formula II in a mass ratio of 6:3. The compounds are mixed uniformly according to the ratio to prepare the cysteine ​​protease inhibitor composition.

[0062] Example 6

[0063] A cysteine ​​protease inhibitor composition comprises compound B having a structure shown in formula I and compound A having a structure shown in formula II in a mass ratio of 6:3. The compounds are mixed uniformly according to the ratio to prepare the cysteine ​​protease inhibitor composition.

[0064] Example 7

[0065] A cysteine ​​protease inhibitor composition comprises compound A having a structure shown in formula I and compound A having a structure shown in formula II in a mass ratio of 6:3. The compounds are mixed uniformly according to the ratio to prepare the cysteine ​​protease inhibitor composition.

[0066] Example 8

[0067] A cysteine ​​protease inhibitor composition comprises compound B having a structure shown in formula I and compound B having a structure shown in formula II in a mass ratio of 6:3. The compounds are mixed uniformly according to the ratio to prepare the cysteine ​​protease inhibitor composition.

[0068] Example 9

[0069] Compared with Example 6, the difference is that the mass ratio of compound B with the structure shown in Formula I and compound A with the structure shown in Formula II is 20:1.

[0070] Example 10

[0071] Compared with Example 6, the difference is that the mass ratio of compound B with the structure shown in Formula I to compound A with the structure shown in Formula II is 1:20.

[0072] Test Example 1

[0073] Compound A of Formula I, Compound B of Formula I, Compound A of Formula II, Compound B of Formula II, the compositions of Examples 3-10, MDL 28170, and KYS-4516 were used as experimental subjects to test the inhibitory activity IC against calpair I, calpain II, μ-calpain enzyme, and cathepsin B. 50 The concentration of Suc-Leu-Tyr-AMC was determined by fluorescence spectrophotometry using Suc-Leu-Tyr-AMC as a fluorescent substrate (λ ex =380nm,λ em =440 nm), and the concentration of the cleavage product 7-amino-4-methylcoumarin was determined, with no enzyme added as a blank control.

[0074] The results are shown in Table 1.

[0075] Table 1

[0076]

[0077]

[0078] As can be seen from the above table, the compositions prepared by using compound A having a structure represented by formula I, compound B having a structure represented by formula I, compound A having a structure represented by formula II, compound B having a structure represented by formula II, and Examples 3-10 of the present invention all have excellent inhibitory activity against calpain I, calpain II, -calpainase, and cathepsin B, among which the composition of Example 6 has the best inhibitory activity.

[0079] Compared with Example 6, in Examples 9 and 10, the ratios of the two compounds are different, and the inhibitory effect obtained is greatly reduced. It can be seen that within the appropriate mass ratio range, the two compositions can further significantly improve the inhibitory effect and have a synergistic effect.

[0080] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A cysteine ​​protease inhibitor, characterized in that A compound having a structure as shown in Formula I or Formula II: Among them, R1=H, Ph, Bn, 4-OMePh.

2. A method for synthesizing a cysteine ​​protease inhibitor according to claim 1, characterized in that: The synthesis method of the compound of the structure shown in Formula I is as follows: S1. p-Aminobenzyl chloride and sodium diselenide react to obtain intermediate 1, the structure of which is as follows: S2. Intermediate 1 is reacted with diethyl 2-oxalopropionate, followed by condensation in acetic acid, heating in an oil phase to form a ring, and hydrolyzing under alkaline conditions to obtain intermediate 2, the structure of which is as follows: S3. The intermediate 2 is reacted with α-hydroxyamine and then oxidized to obtain a compound of the structure shown in Formula I; The α-hydroxylamine is selected from one of the compounds of the following structural formula:

3. The method for synthesizing a cysteine ​​protease inhibitor according to claim 2, characterized in that: In step S1, the molar ratio of p-aminobenzyl chloride to sodium diselenide is 1:2-3, the reaction temperature is room temperature, and the reaction time is 4-7 hours; in step S2, the molar ratio of intermediate 1 to diethyl 2-oxalopropionate is 1:2.1-2.2, the reaction temperature is 45-50°C, the reaction time is 5-7 hours, the heating to a temperature of 240-260°C, the time is 20-40 minutes, the pH value of the alkaline conditions is 9.5-10.5, the temperature is 65-75°C, and the time is 1-3 hours; in step S3, the molar ratio of intermediate 2 to α-hydroxyamine is 1:2-2.1, and the oxidation adopts Dess-Martin oxidant, and the molar ratio of the Dess-Martin oxidant to intermediate 2 is 4-4.1:

1.

4. The method for synthesizing a cysteine ​​protease inhibitor according to claim 1, characterized in that: The synthesis method of the compound of the structure shown in Formula II is as follows: T1. p-Aminobenzyl chloride and sodium diselenide react to obtain intermediate 1, the structure of which is as follows: T2. Intermediate 1 is reacted with sodium triacetoxyborohydride and iodomethane to obtain intermediate 3, the structure of which is as follows: T3. Intermediate 3 is reacted with diethyl 2-oxalopropionate, followed by condensation in acetic acid, heating in an oil phase to form a ring, and hydrolyzing under alkaline conditions to obtain intermediate 4, the structure of which is as follows: T4. The intermediate 4 is reacted with α-hydroxyamine and then oxidized to obtain a compound of formula II; The α-hydroxylamine is selected from one of the compounds of the following structural formula:

5. The method for synthesizing a cysteine ​​protease inhibitor according to claim 4, characterized in that: In step T1, the molar ratio of p-aminobenzyl chloride to sodium diselenide is 1:2-3, the reaction temperature is room temperature, and the reaction time is 4-7 hours; in step T2, the molar ratio of intermediate 1 to sodium triacetoxyborohydride and methyl iodide is 1:3-4:3-5; in step T3, the molar ratio of intermediate 1 to diethyl 2-oxalopropionate is 1:1.05-1.1, the reaction temperature is 45-50°C, and the reaction time is 4-6 hours. The heating to a temperature of 240-260°C is carried out for 20-40 minutes. The pH value of the alkaline conditions is 9.5-10.5, the temperature is 65-75°C, and the reaction time is 1-3 hours. In step T4, the molar ratio of intermediate 4 to α-hydroxyamine is 1:1-1.1, and the oxidation is carried out using a Dess-Martin oxidant. The molar ratio of the Dess-Martin oxidant to intermediate 4 is 2-2.1:

1.

6. The method for synthesizing a cysteine ​​protease inhibitor according to claim 2 or 4, characterized in that: The preparation method of sodium diselenide is as follows: dissolving 2-3 parts by weight of sodium hydroxide in 50 parts by weight of water, adding 2-4 parts by weight of selenium powder, stirring and mixing uniformly, adding 3-4 parts by weight of sodium bisulfite formaldehyde, heating to 55-65° C., stirring and reacting for 0.5-1 hour, adding an equal volume of ethanol for precipitation, filtering, washing, and drying to obtain sodium diselenide.

7. A cysteine ​​protease inhibitor composition, characterized in that: The compound comprises the structures shown in formula I and formula II as claimed in claim 1, with a mass ratio of 5-7:2-4.

8. A method for preparing the cysteine ​​protease inhibitor composition according to claim 7, characterized in that: The compounds represented by the structures of formula I and formula II as claimed in claim 1 are mixed uniformly in proportion to prepare a cysteine ​​protease inhibitor composition.

9. Use of the cysteine ​​protease inhibitor composition according to claim 7 in the preparation of a medicament for treating ischemic stroke, traumatic brain injury, spinal cord injury, neurodegenerative disease, brain tumor, and myocardial tissue damage.

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