A berberine-trimetazidine conjugate, a preparation method and application thereof

Abstract

The application discloses a berberine-triamterene conjugate and a preparation method and application thereof, and aims to provide a berberine-triamterene conjugate with anti-myocardial ischemia activity. The C-9 position and the C-13 position of berberine are reformed, and different length halogenated alkanes are connected to the C-9 position and the C-13 position respectively, then the halogenated alkanes are combined with triamterene to obtain multiple berberine-triamterene conjugates, the berberine-triamterene conjugates have good anti-myocardial ischemia reperfusion injury activity, and can be used for preparing anti-myocardial ischemia reperfusion injury drugs. The application relates to the technical field of medicinal chemistry.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to a berberine-trimetazidine conjugate. The present invention also relates to a preparation method and application of the berberine-trimetazidine conjugate. Background Art

[0002] Coronary heart disease and acute myocardial infarction are critical cardiovascular diseases. Not only are their incidence rates increasing year by year, but they are also showing a significant trend of younger patients. Current clinical treatments focus on thrombolysis or percutaneous coronary intervention to open blocked blood vessels, but the reperfusion process may cause secondary damage, namely myocardial ischemia-reperfusion injury. Although reperfusion therapy significantly reduces patient mortality, complications such as postoperative arrhythmias, metabolic disorders, and sudden cardiac death still seriously affect patient prognosis. This shows that the research and development of drugs for coronary heart disease, acute myocardial infarction, and postoperative myocardial ischemia-reperfusion injury is of extremely important research value, and actively developing cardioprotective drugs is a top priority.

[0003] Myocardial ischemia-reperfusion injury is closely related to mitochondrial function. Mitochondria provide energy for the normal functioning of cardiomyocytes and participate in and regulate multiple aspects of normal cellular physiological activities. Trimetazidine, a piperazine derivative, mediates mitochondrial protection of the heart and is clinically used to treat coronary artery disease. Trimetazidine inhibits the activity of key enzymes in fatty acid β-oxidation, enhancing glucose oxidation energy supply to optimize myocardial metabolism, increase ATP synthesis efficiency, alleviate acidosis in hypoxic myocardium, and maintain cellular function.

[0004] Natural products are valuable resources in drug development. Berberine, an isoquinoline alkaloid derived from plants in the Ranunculaceae family, such as Coptis chinensis, has been shown to possess multi-target activities, including anti-myocardial ischemia. Summary of the Invention

[0005] One of the objectives of the present invention is to obtain a berberine-trimetazidine conjugate with cardioprotective activity by optimizing the structures of berberine C-9 and C-13 and connecting trimetazidine with different connecting carbon chains.

[0006] A second object of the present invention is to provide a method for preparing a berberine-trimetazidine conjugate.

[0007] The third object of the present invention is to provide the use of berberine-trimetazidine conjugate in the preparation of cardioprotective drugs to prepare highly effective drugs for treating myocardial ischemia-reperfusion injury.

[0008] To this end, the first technical solution provided by the present invention is a berberine-trimetazidine conjugate having the general structural formula shown in Formula 1:

[0009]

[0010] Formula 1;

[0011] wherein:

[0012] R1 is one of hydrogen, 4-[ (2,3,4-trimethoxyphenyl) methyl] piperazin-1- propyl, 4-[ (2,3,4-trimethoxyphenyl) methyl] piperazin-1-pentyl, 4-[ (2,3,4- trimethoxyphenyl) methyl] piperazin-1-hexyl, 4-[ (2,3,4-trimethoxyphenyl) methyl] piperazin-1-octyl;

[0013] R2 is one of methyl, 4-[ (2,3,4-trimethoxyphenyl) methyl] piperazin-1-propyl, 4-[ (2,3,4-trimethoxyphenyl) methyl] piperazin-1-pentyl, 4-[ (2,3,4- trimethoxyphenyl) methyl] piperazin-1-hexyl, 4-[ (2,3,4-trimethoxyphenyl) methyl] piperazin-1-heptyl, 4-[ (2,3,4-trimethoxyphenyl) methyl] piperazin-1-octyl, 4-[ (2,3,4-trimethoxyphenyl) methyl] piperazin-1-nonyl, 4-[ (2,3,4-trimethoxyphenyl) methyl] piperazin-1-decyl;

[0014] X is one of chlorine, bromine, iodine.

[0015] Further, the above-mentioned berberine-telmisartan conjugate is one of the following compounds shown in the following chemical structural formula:

[0016] ;

[0017] 3a 3b 3c

[0018] ;

[0019] 3d 5a

[0020] ;

[0021] 5b

[0022] ;

[0023] 5c

[0024] ;

[0025] 5d

[0026] ;

[0027] 5e

[0028] ;

[0029] 5f

[0030] ;

[0031] 5g.

[0032] The second technical solution of the present application is to provide a preparation method of the above-mentioned berberine-tetramethylazine conjugate, which comprises the following steps in sequence:

[0033] 1) Dissolving hydrochloric acid berberine in sodium hydroxide solution, then adding acetone dropwise, and reacting for 0.8-1.2 h to generate compound 2;

[0034] 2) Dissolving the compound 2 prepared in step 1) in acetonitrile, then adding diiodo alkane compound, heating to 60-70°C under inert atmosphere and reacting for 7-9 h; then adding tetramethylazine and potassium carbonate dissolved in acetonitrile solution, and continuing to react at 60-70°C for 1.5-2.5 h to obtain one of the compounds shown in chemical structural formula 3a-3d;

[0035] The molar ratio of hydrochloric acid berberine to sodium hydroxide is 0.8-1.2:14;

[0036] The molar ratio of compound 2, diiodo alkane compound, potassium carbonate, and tetramethylazine is 0.8-1.2:5:2:1.5.

[0037] Further, it specifically comprises the following steps:

[0038] (1) Synthesis of compound 2

[0039] Dissolve 2.0 g of hydrochloric acid berberine in 10 ml of sodium hydroxide solution. Under stirring conditions, add acetone dropwise to the mixture. Maintain the obtained reaction mixture under stirring for about 1 h, or monitor the reaction to completion by thin layer chromatography (TLC). After the reaction is completed, filter the reaction mixture. Wash the obtained solid with 90% methanol aqueous solution to obtain compound 2;

[0040] (2) Synthesis of compound 3a-3d

[0041] Dissolve 1 mmol of compound 2 in 5 ml of acetonitrile, and add 5 mmol of a diiodoalkane. Heat the reaction mixture to approximately 65°C under an inert atmosphere and maintain stirring for 8 hours. After completion, add 1.5 mmol of trimetazidine and 2 mmol of potassium carbonate dissolved in 5 ml of acetonitrile. Heat the reaction mixture to approximately 65°C under an inert atmosphere and maintain stirring for 2 hours. Monitor the reaction by thin-layer chromatography (TLC) until completion. After completion, add an extractant, collect the organic layer, dry it at room temperature, and concentrate it for separation and purification to obtain compounds 3a-3d.

[0042] Its synthetic route is as follows:

[0043]

[0044] Furthermore, in the above-mentioned method for preparing the berberine-trimetazidine conjugate, the diiodoalkane compound is at least one of 1,3-diiodopropane, 1,5-diiodopentane, 1,6-diiodohexane and 1,8-diiodooctane.

[0045] Another method for preparing the berberine-trimetazidine conjugate comprises the following steps in sequence:

[0046] 1) Berberine hydrochloride was added to a vacuum reactor and thermally decomposed at 190-200°C for 1.5-2.5 h to produce compound 4;

[0047] 2) Compound 4 prepared in step 1) and potassium carbonate were dissolved in acetonitrile solution, and a brominated alkane compound was added dropwise, and the reaction was carried out at 68-72°C for 10-14 hours. Then, a solution of trimetazidine, potassium carbonate, and triethylamine dissolved in N,N-dimethylformamide was added, and the reaction was carried out at 75-85°C for 3-5 hours to obtain one of compounds 5a-5g;

[0048] The molar ratio of compound 4, potassium carbonate, and brominated alkane compound is 0.8-1.2:2.5:2.5;

[0049] The molar ratio of compound 4, trimetazidine and triethylamine is 0.8-1.2:1.5:1.5.

[0050] Furthermore, it specifically includes the following steps:

[0051] (1) Synthesis of compound 4

[0052] 3.0 g of berberine hydrochloride was added to a vacuum reactor and thermally decomposed at 195 ± 5°C for 2 h. During the reaction, the color of the material was observed to change from yellow to dark red. After completion of the reaction, 2.67 g of a dark red solid product was obtained, yielding compound 4.

[0053] (2) Synthesis of compounds 5a-5g

[0054] Dissolve 1 mmol of compound 4 and 2 mmol of potassium carbonate in 2.5 ml of anhydrous acetonitrile solvent, and slowly drop 2.5 mmol of bromoalkane compound under mechanical stirring. The reaction system is refluxed in an oil bath at 70±2℃ for 12h. After the reaction is completed, dissolve 1.5 mmol of trimetazidine, 2 mmol of potassium carbonate and 1.5 mmol of triethylamine in 2.5 ml of acetonitrile, and stir the reaction at 80±5℃ for 4h. Monitor the reaction progress by thin layer chromatography (TLC), and after the raw material is completely converted, the reaction is completed, an extractant is added for extraction, the organic layer is collected, dried at room temperature, concentrated, separated and purified to obtain a series of compounds 5a-5g.

[0055] The synthesis route is as follows:

[0056] Further, in the preparation method of the above berberine-trimetazidine conjugate, the bromoalkane compound is one of 1,3-dibromopropane, 1,5-dibromopentane, 1,6-dibromohexane, 1,7-dibromoheptane, 1,8-dibromooctane, 1,9-dibromononane and 1,10-dibromodecane.

[0057] The last technical solution provided by the present application is the use of the above berberine-trimetazidine conjugate in the preparation of a heart protection active drug.

[0058] The present application also provides a heart protection active drug, which comprises the berberine-trimetazidine conjugate described in the first technical solution.

[0059] More preferably, the drug further comprises at least one of a pharmaceutically acceptable adjuvant, a disintegrant, a lubricant, a filler, a surfactant, an antioxidant or a pH regulator.

[0060] The dosage form of the drug is injection, tablet, oral liquid, granules or capsule.

[0061] Compared with the prior art, the technical solution provided by the present application has the following technical advantages:

[0062] 1) The technical solution provided by the present application connects different lengths of halogenated alkanes to the C-9 and C-13 positions of berberine, respectively, and further combines with trimetazidine to obtain multiple berberine-trimetazidine conjugates, which have good anti-myocardial ischemia-reperfusion injury activity, can significantly improve cell oxidative stress damage, ischemia-reperfusion cell survival rate, zebra fish damaged heart deformation, and improve heart systolic and diastolic function.

[0063] 2) The technical solution provided by the application has the advantages that the anti-ischemia-reperfusion activity of the berberine-trimetazidine conjugate is significantly better than that of berberine, trimetazidine or a combination of berberine and trimetazidine, and the berberine-trimetazidine conjugate can be used as a high-efficiency drug for treating myocardial ischemia-reperfusion injury. BRIEF DESCRIPTION OF DRAWINGS

[0064] Figure 1 is a 1H NMR spectrum of compound 3b synthesized in Example 1. 1 H NMR spectrum;

[0065] Figure 2 is a 1H NMR spectrum of compound 3b synthesized in Example 1. 13 C NMR spectrum;

[0066] Figure 3 is a 1H NMR spectrum of compound 3c synthesized in Example 1. 1 H NMR spectrum;

[0067] Figure 4 is a 1H NMR spectrum of compound 3c synthesized in Example 1. 13 C NMR spectrum;

[0068] Figure 5 is a 1H NMR spectrum of compound 5a synthesized in Example 2. 1 H NMR spectrum;

[0069] Figure 6 is a 1H NMR spectrum of compound 5a synthesized in Example 2. 13 C NMR spectrum;

[0070] Figure 7 is a 1H NMR spectrum of compound 5b synthesized in Example 2.

[0071] Figure 8 is a 1H NMR spectrum of compound 5b synthesized in Example 2. 13 C NMR spectrum;

[0072] Figure 9 is a 1H NMR spectrum of compound 5c synthesized in Example 2.

[0073] Figure 10 is a 1H NMR spectrum of compound 5c synthesized in Example 2. 13 C NMR spectrum;

[0074] Figure 11 is an effect of an excellent berberine-trimetazidine conjugate on cell survival rate of H9c2 ischemia-reperfusion at different concentrations;

[0075] Figure 12 is a zebrafish embryo heart function evaluation of an excellent berberine-trimetazidine conjugate on ischemia-reperfusion. DETAILED DESCRIPTION

[0076] The present invention will be further explained below in conjunction with implementation and accompanying drawings, but implementation does not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art. Unless otherwise specified, the reagents and materials used in the present invention are commercially available.

[0077] Example 1 Synthesis of Compounds 3a-3d

[0078] The synthesis of compounds 3a-3d is shown in Synthesis Route 1. Berberine hydrochloride is used as the starting material to react in sodium hydroxide solution and acetone to produce compound 2. Then, under nitrogen protection, compound 2 is reacted with a halogenated alkane in acetonitrile solvent, and then reacted with potassium carbonate and trimetazidine in acetonitrile solvent to obtain compounds 3a-3d.

[0079] Reaction conditions and reagents in synthetic route 1: (i) sodium hydroxide, acetone, 1 h; (ii) ① acetonitrile, diiodoalkane, 65°C, 8 h, acetonitrile; ② trimetazidine, potassium carbonate, 65°C, 2 h.

[0080]

[0081] Synthesis Route 1

[0082] The specific steps are as follows:

[0083] (1) Synthesis of compound 2

[0084] Dissolve 2.0 g of berberine hydrochloride in 10 ml of sodium hydroxide solution (1 mol / ml) to obtain a mixture. Add 1 ml of acetone dropwise to the mixture while stirring. Maintain stirring and react for 1 hour (monitored by thin-layer chromatography (TLC) until completion). After completion, filter the reaction mixture. Wash the resulting solid with 90% (volume fraction) methanol-water solution to obtain compound 2.

[0085] (2) Synthesis of compounds 3a-3d

[0086] 1) Dissolve 1 mmol of compound 2 prepared in step (1) in 5 ml of acetonitrile, add 5 mmol of diiodoalkane compound, heat to 65°C under an inert atmosphere, and maintain stirring for 8 hours to obtain reactant A;

[0087] 2) Dissolve 1.5 mmol of trimetazidine and 2 mmol of potassium carbonate in 5 ml of acetonitrile to obtain mixture A; add all of mixture A to the reactant A of step 2), heat to about 65°C under inert atmosphere and maintain stirring for 2 h, monitor by thin layer chromatography (TLC) until the reaction is complete. After the reaction is complete, extract with a volume ratio of 1:10 dichloromethane to saturated aqueous sodium chloride solution, collect the organic layer, dry at room temperature and concentrate, separate and purify to obtain compounds 3a-3d series.

[0088] wherein, compound 3a adopts diiodoalkane compound 1,3-diiodopropane; compound 3b adopts diiodoalkane compound 1,5-diiodopentane; compound 3c adopts diiodoalkane compound 1,6-diiodohexane; compound 3d adopts diiodoalkane compound 1,8-diiodooctane.

[0089] The structure, appearance, nuclear magnetic resonance spectrum data of compounds 3a-3d are as follows:

[0090] The structural formula of compound 3a is as follows:

[0091]

[0092] 3a. Yellow solid (24 mg, 6%) 1 H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H,H-8),7.94 (d, J = 9.3 Hz, 1H,H-2), 7.78 (d, J = 9.3 Hz, 1H,H-1), 7.05 (s, 1H,H-3),6.94 (d, J = 8.5 Hz, 1H,1''), 6.82 (s, 1H,H-5), 6.57 (d, J = 8.5 Hz, 1H.H-2''), 6.04 (s, 2H,OCH2O-4), 5.00 (s, 2H,CH2-6), 4.30 (s, 3H,OCH3-9), 4.01 (s,3H,OCH3-10), 3.81 (s, 3H,OCH3), 3.80 (s, 3H,OCH3), 3.78 (s, 3H,OCH3), 3.47 (s,2H,NCH2-3''), 3.31 (t, J = 7.8 Hz, 2H, linker-CH2-3''), 3.16 (t, J= 5.5 Hz,2H, CH2-6), 2.64 – 2.46 (overlapping, 10H,C4H 10 N2,4×CH 2, linker-CH2), 1.96 (s, 2H, linker-CH2). 13 C NMR (101 MHz, CDCl3) δ 151.9, 151.1, 151.0, 149.9, 147.8,147.1, 143.0, 140.5, 137.0, 134.6, 133.4, 132.7, 124.4, 123.9, 122.8, 122.4,122.2, 122.0, 109.9, 109.2, 108.0, 101.6, 62.3, 60.8, 60.1, 59.3, 58.5, 56.5,56.4, 55.1, 52.9, 52.2, 29.3, 28.2, 25.8.

[0093] The structural formula of compound 3b is as follows:

[0094]

[0095] 3b. Yellow solid (28 mg, 7%); 1 H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H,H-8),8.01 (d, J = 9.3 Hz, 1H,H-2), 7.93 (d, J = 9.3 Hz, 1H,H-1), 7.08 (s, 1H,H-3),7.02 (d, J = 8.4 Hz, 1H,H-1''), 6.89 (s, 1H,H-5), 6.64 (d, J = 8.5 Hz, 1H,H-2''), 6.11 (s, 2H,OCH2O-4), 5.01 (s, 2H,CH2-6), 4.34 (s, 3H,OCH3-9)), 4.08 (s,3H,OCH3-10), 3.87 (s, 3H,OCH3), 3.86 (s, 3H,OCH3), 3.85 (s, 3H,OCH3), 3.59 (s,2H,NCH2-3''), 3.35 (d, J = 7.5 Hz, 2H, linker-CH2-5''), 3.26 (d, J= 5.8 Hz,2H, CH2-6), 2.88-2.66 (overlapping, 10H,C4H 10 N2,4×CH 2, linker-CH2), 1.83 (d, J = 14.0Hz, 2H,linker-CH2), 1.77-1.68 (m, 2H,linker-CH2), 1.44 (q, J = 7.6 Hz, 2H,linker-CH2). 13 C NMR (101 MHz, CDCl3) δ 152.6, 150.4, 149.9, 147.3, 145.7,144.9, 142.2, 136.2, 134.3, 133.4, 133.0, 125.6, 121.9, 120.6, 120.3, 109.2,108.5, 107.1, 102.2, 62.9, 61.3, 58.0, 57.4, 57.0, 56.0, 55.8, 50.8, 30.6,29.7, 28.4, 26.6; 1 H NMR spectrum see 1; 13 C NMR spectrum reference Figure 2 .

[0096] The structural formula of compound 3c is as follows:

[0097]

[0098] 3c. Yellow solid (35 mg, 9%) 1 H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H,H-8),8.02 (d, J = 9.4 Hz, 1H,H-2), 7.99 (d, J = 9.3 Hz, 1H,H-1), 7.08 (s, 1H,H-3),7.02 (d, J = 8.5 Hz, 1H,H-1''), 6.90 (s, 1H,H-5), 6.64 (d, J= 8.5 Hz, 1H,H-2''), 6.11 (s, 2H,OCH2O-4), 5.04 (s, 2H,CH2-6), 4.32 (s, 3H,OCH3-9), 4.08 (s,3H,OCH3-10), 3.88 (s, 3H,OCH3), 3.86 (s, 3H,OCH3), 3.85 (s, 3H,OCH3), 3.60 (s,2H,NCH2-3''), 3.32 (t, J = 8.0 Hz, 2H, linker-CH2-6''), 3.24-3.17 (m, 2H,CH2-6), 2.97-2.66 (overlapping, 10H,C4H 10 N2,4×CH 2, linker-CH2), 1.85 (d, J = 8.1 Hz,2H,linker-CH2), 1.71 (t, J = 8.2 Hz, 2H,linker-CH2), 1.49 (t, J = 7.4 Hz, 4H,linker-2×CH2). 13 C NMR (101 MHz, CDCl3) δ 153.5, 152.6, 150.4, 149.8, 147.3,145.6, 144.8, 142.2, 136.1, 134.4, 133.4, 133.0, 125.9, 125.6, 121.8, 120.7,120.3, 109.2, 108.1, 107.1, 102.2, 62.9, 61.2, 60.8, 58.0, 57.5, 57.0, 56.0,55.8, 52.1, 50.7, 31.9, 30.7, 29.8, 29.6, 28.7, 28.5, 26.4, 14.0; 1 For H NMR spectra, see 3; 13 C NMR spectrum reference Figure 4 .

[0099] The structural formula of compound 3d is as follows:

[0100]

[0101] 3d. Yellow solid (30 mg, 7%) 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H,H-8),7.96-7.88 (m, 2H,H-1,H-2), 7.10 (s, 1H,H-3), 6.99 (d, J = 8.5 Hz, 1H,H-1''),6.90 (s, 1H,H-5), 6.63 (d, J = 8.5 Hz, 1H,H-2''), 6.11 (s, 2H,OCH2O-4), 5.10(s, 2H,CH2-6), 4.37 (s, 3H,OCH3-9), 4.08 (s, 3H,OCH3-10), 3.88 (s, 3H,OCH3),3.87 (s, 3H,OCH3), 3.85 (s, 3H,OCH3), 3.54 (s, 2H, linker-CH2-8''), 3.28 (t, J = 8.2 Hz, 2H,NCH2-3''), 3.21 (t, J = 5.8 Hz, 2H, CH2-6), 2.55-2.45 (overlapping, 10H,C4H 10 N2, 4×CH 2, linker-CH2), 1.85 (s, 2H, linker-CH2), 1.67-1.35 (overlapping, 10H, linker-5×CH2). 13 C NMR (101 MHz, CDCl3) δ 153.1, 149.7, 145.1, 134.4, 133.5,125.6, 125.4, 120.3, 109.1, 108.6, 107.0, 102.1, 63.1, 61.2, 60.8, 58.3,58.1, 57.0, 56.1, 56.0, 52.8, 51.9, 31.1, 30.0, 29.7, 29.4, 29.2, 28.8, 28.5,27.2, 26.1.

[0102] Example 2 Synthesis of Compounds 5a-5g

[0103] As shown in Synthesis Route 2, berberine hydrochloride is used as the starting material. Compound 4 is reacted under high temperature and high pressure to generate compound 4. Compound 4 is reacted with a haloalkane in acetonitrile solvent, and then reacted with potassium carbonate, triethylamine, and trimethoprim in N,N-dimethylformamide solvent to obtain compounds 5a-5g.

[0104] Reaction conditions and reagents in synthetic route 2: (III) vacuum, 195±5°C, 2 h; (vi) ① potassium carbonate, acetonitrile, dibromoalkane compound, 70±2°C, 12 h; ② trimetazidine, potassium carbonate, acetonitrile, 80±5°C, 4 h.

[0105]

[0106] Synthesis Route 2

[0107] The specific steps are as follows:

[0108] (1) Synthesis of compound 4

[0109] 3.0 g of berberine hydrochloride was added into a vacuum reactor and -4 The thermal decomposition reaction was carried out at pa and 195±5°C for 2h. During the reaction, the color of the material was observed to change from yellow to dark red. After the reaction was completed, 2.67 g of a dark red solid product was obtained to obtain compound 4.

[0110] (2) Synthesis of compounds 5a-5g

[0111] 1) Dissolve 1 mmol of compound 4 and 2 mmol of potassium carbonate in 2.5 ml of anhydrous acetonitrile. Slowly add 2.5 mmol of a bromoalkane compound dropwise under mechanical stirring. Reflux in an oil bath at 70 ± 2°C for 12 h to obtain reactant B.

[0112] 2) Dissolve 1.5 mmol of trimetazidine, 2 mmol of potassium carbonate, and 1.5 mmol of triethylamine in 2.5 ml of acetonitrile to obtain a mixture B. Add all of this mixture B to reactant B from step 1) and stir at 80±5°C for 4 h. Monitor the reaction progress by thin-layer chromatography (TLC). After complete conversion of the starting materials and completion of the reaction, extract with a 1:10 volume ratio of dichloromethane to saturated saline solution. Collect the organic layer, dry it at room temperature, and concentrate it. Separate and purify the resulting compounds 5a-5g.

[0113] Among them, the brominated alkane compound used in compound 5a is 1,3-dibromopropane; the brominated alkane compound used in compound 5b is 1,5-dibromopentane; the brominated alkane compound used in compound 5c is 1,6-dibromohexane; the brominated alkane compound used in compound 5d is 1,7-dibromoheptane; the brominated alkane compound used in compound 5e is 1,8-dibromooctane; the brominated alkane compound used in compound 5f is 1,9-dibromononane; and the brominated alkane compound used in compound 5g is 1,10-dibromodecane. The structures, appearance, and nuclear magnetic resonance spectrum data of compounds 5a-5g are shown below:

[0114] The structural formula of compound 5a is as follows:

[0115]

[0116] 5a. Yellow solid (23 mg, 8%) 1 H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H, H-9), 8.38 (s, 1H, H-3), 7.91 (d, J = 9.0 Hz, 1H, H-2), 7.66 (d, J = 9.0 Hz, 1H, H-1), 7.32 (s, 1H,H-4)), 7.01 (d, J = 8.5 Hz, 1H, H-1′′), 6.73 (s, 1H, H-6), 6.64 (d, J = 8.6 Hz, 1H, H-2′′), 6.01 (s, 2H, OCH2O-5), 5.19 (t, J = 6.1 Hz,2H,CH2-7), 4.46 (t, J = 6.1 Hz, 2H linker-CH2-1′), 3.94 (s, 3H,OCH3-10), 3.88(s, 3H,OCH3-), 3.87 (s, 3H,OCH3-), 3.85 (s, 3H,OCH3-), 3.55 (s, 2H,NCH2-3′′),3.25 (t, J = 6.3 Hz, 2H,CH2-8), 3.11 – 2.65 (overlapping, 10H,4×CH2,C4H 10 N2,linker-CH2), 2.33 (p, J = 6.2, 5.6 Hz, 2H, linker-CH2-2′). 13 C NMR (101 MHz, CDCl3) δ 153.1, 152.6, 150.3, 150.0, 148.0, 146.0, 143.6, 142.2, 137.2, 133.1, 130.0,125.6, 125.4, 123.2, 122.9, 121.6, 120.1, 119.7, 108.2, 107.0, 105.4, 102.1,72.6, 61.2, 60.8, 56.9, 55.9, 54.4, 52.6, 51.5, 27.3, 26.8. ;1 For H NMR spectra, see 5; 13 C NMR spectrum reference Figure 6 .

[0117] The structural formula of compound 5b is as follows:

[0118]

[0119] 5b. Yellow solid (21 mg, 7%) 1 H NMR (400 MHz, CDCl3) δ 10.16 (s, 1H,H-9),8.36 (s, 1H,H-3), 7.89 (d, J = 9.0 Hz, 1H,H-2), 7.74 (d, J = 9.0 Hz, 1H,H-1),7.37 (s, 1H,H-4), 6.99 (d, J = 8.5 Hz, 1H,H-1''), 6.77 (s, 1H,H-6), 6.63 (d, J = 8.6 Hz, 1H,H-2''), 6.06 (s, 2H,OCH2O-5), 5.32 (t, J = 6.5 Hz, 2H,CH2-7),4.45 (t, J = 6.5 Hz, 2H,linker-CH2-5'), 4.01 (s, 3H,OCH3-10), 3.87 (s, 3H,OCH3-), 3.86 (s, 3H,OCH3-), 3.85 (s, 3H,OCH3-), 3.57 (s, 2H,NCH2-3′′), 3.30(t, J = 6.3 Hz, 2H,CH2-8), 3.19-2.80 (overlapping, 10H,4×CH2,C4H 10 N2,linker-CH2),2.08-1.93 (m, 4H,linker-2×CH2), 1.70 (p, J = 7.6 Hz, 2H, linker-CH2-3′). 13CNMR (101 MHz, CDCl3) δ 153.3, 152.6, 150.5, 150.3, 148.2, 146.2, 144.3,142.2, 137.6, 133.3, 130.4, 125.9, 125.4, 122.8, 122.0, 120.2, 119.7, 108.4,107.1, 105.3, 102.1, 61.3, 60.8, 57.4, 57.0, 56.4, 56.0, 55.8, 52.2, 50.2,29.4, 27.5, 24.3, 23.3. 1 For H NMR spectra, see 7; 13 C NMR spectrum reference Figure 8 .

[0120] The structural formula of compound 5c is as follows:

[0121]

[0122] 5c. Yellow solid (25 mg, 9%) 1 H NMR (400 MHz, CD4O) δ 9.62 (s, 1H,H-9), 8.57 (s, 1H,H-3), 8.01 (d, J = 9.1 Hz, 1H,H-2), 7.91 (d, J = 9.1 Hz, 1H,H-1), 7.52(s, 1H,H-4), 7.00 (d, J = 8.6 Hz, 1H,H-1''), 6.90 (s,1H,H-6), 6.74 (d, J =8.6 Hz, 1H,H-2''),6.06 (s, 2H,OCH2O-5), 4.94 (t, J = 6.3 Hz, 2H,CH2-7), 4.34(t, J = 6.8 Hz, 2H,linker-CH2-6'), 4.04 (s,3H,OCH3-10), 3.85 (s, 3H,OCH3-),3.82 (s, 3H,OCH3-), 3.80 (s, 3H,OCH3-)3.57 (s,2H,CH2-8),3.24 (t, J = 6.3 Hz,2H,linker-CH2-1′), 2.92-2.59 (m,8H,C4H 10N2,4×CH2), 1.92 (p, J = 6.9 Hz, 2H, linker-CH2), 1.69-1.50 (m, 4H, linker-2×CH2), 1.43-1.35 (m, 4H, linker-2×CH2). 13 C NMR (101 MHz, CDCl3) δ 153.1, 152.6, 150.4, 150.4, 148.1, 146.0,144.1, 142.2, 137.5, 133.3, 130.3, 125.9, 125.4, 123.2, 122.8, 122.1, 120.2,120.0, 108.3, 107.0, 105.4, 102.0, 60.7, 57.8, 56.9, 56.1, 55.9, 52.5, 51.2,30.1, 29.7, 27.5, 26.7, 25.1, 25.2.; 1 For H NMR spectra, see 9; 13 C NMR spectrum reference Figure 10 .

[0123] The structural formula of compound 5d is as follows:

[0124]

[0125] 5d. Yellow solid (22 mg, 8%) 1 H NMR (400 MHz, CDCl3) δ 10.16 (s, 1H,H-9),8.31 (s, 1H,H-3), 7.87 (d, J = 9.0 Hz, 1H,H-2), 7.76 (d, J = 9.0 Hz, 1H,H-1),7.36 (s, 1H,H-4), 6.99 (d, J = 8.6 Hz, 1H,H-1''), 6.80 (s, 1H,H-6), 6.63 (d, J = 8.5 Hz, 1H,H-2''), 6.07 (s, 2H,OCH2O-5), 5.28 (t, J = 6.4 Hz, 2H,CH2-7),4.46 (t, J= 6.8 Hz, 2H,linker-CH2-1'), 4.03 (s, 3H,OCH3-10), 3.87 (s, 3H,OCH3-), 3.86 (s, 3H,OCH3-), 3.85 (s, 3H,OCH3-), 3.55 (s, 2H,NCH2-3′′),3.33(t, J =6.3Hz,2H,CH2-8), 2.91-2.62 (overlapping, 10H, ,C4H 10 N2,4×CH 2, linker-CH2), 2.00 (p, J = 5.6 Hz, 2H,linker-CH2), 1.76-1.41 (overlapping, 10H,linker-CH2×5). 13 C NMR (101MHz, CDCl3) δ 153.2, 152.6, 150.5, 150.4, 148.2, 146.1, 144.2, 142.2, 137.6,133.3, 130.4, 126.0, 125.4, 123.1, 122.2, 120.2, 119.9, 108.4, 107.0, 105.4,102.1, 61.2, 60.7, 58.0, 56.9, 56.1, 55.9, 52.5, 51.3, 31.4, 30.1, 29.9,29.6, 28.8, 27.5, 27.0, 25.4.

[0126] The structural formula of compound 5e is as follows:

[0127]

[0128] 5e. Yellow solid (28 mg, 11%) 1 H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H,H-9),8.42 (s, 1H,H-3), 7.95 (d, J = 9.0 Hz, 1H,H-2), 7.74 (d, J = 9.0 Hz, 1H,H-1)), 7.39 (s, 1H,H-4), 7.01 (d, J = 8.5 Hz, 1H,H-1''), 6.78 (s, 1H,H-6), 6.64(d, J= 8.5 Hz, 1H,H-2''), 6.05 (s, 2H,OCH2O-5), 5.24 (t, J = 6.4 Hz, 2H,CH2-7), 4.43 (t, J = 6.8 Hz, 2H,linker-CH2-1'), 4.01 (s, 3H,OCH3-10), 3.88 (s, 3H,OCH3-),3.86(s, 3H,OCH3-),3.85(s,3H,OCH3-), 3.57 (s, 2H,NCH2-3′),3.33(t, J = 6.3 Hz, 2H, CH2-8), 2.93-2.57 (overlapping, 10H, C4H 10 N2,4×CH 2, linker-CH2), 1.98 (q, J = 7.6Hz, 2H,linker-CH 2) , 1.67-1.34 (overlapping,10H,linker-CH2×5). 13 C NMR (101 MHz, CDCl3) δ 153.2, 152.6, 150.5, 148.2, 146.0, 144.4, 142.2, 137.5, 133.4,130.3, 126.0, 125.5, 123.0, 122.2, 120.2, 119.8, 108.4, 107.0, 105.4, 102.1,61.2, 60.8, 58.0, 56.9, 56.4, 56.0, 52.4, 51.2, 31.9, 30.0, 29.6, 29.0, 27.5,27.0, 25.5, 25.4, 22.6.

[0129] The structural formula of compound 5f is as follows:

[0130]

[0131] 5f. Yellow solid (24 mg, 10%) 1 H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H,H-9),8.46 (s, 1H,H-3), 7.97 (d, J = 7.0 Hz, 1H,H-2), 7.75 (d, J= 21.2 Hz, 1H,H-1), 7.40 (s, 1H,H-4), 7.01 (d, J = 8.0 Hz, 1H,H-1''), 6.77 (s, 1H,H-6), 6.64(d, J = 8.3 Hz, 1H,H-2''), 6.04 (s, 2H,OCH2O-5), 5.34-5.03 (m, 2H,CH2-7), 4.41(t, J = 5.0 Hz, 2H,linker-CH2-2'), 4.01 (s, 3H,OCH3-10), 3.92-3.80 (overlapping, 9H,3×OCH3), 3.58 (s, 2H,NCH2-3'), 3.35-3.28 (m, 2H,linker-CH2),2.73 (overlapping, 10H,C4H 10 N2,4×CH 2, linker-CH2),1.94(s,2H , linker-CH2), 1.71-1.33 (overlapping, 12H, linker-CH2×6). 13 C NMR (101 MHz, CDCl3) δ 153.3, 152.6, 150.4, 148.2, 145.9, 144.2,142.2, 137.5, 133.4, 130.2, 125.9, 125.5, 123.1, 122.1, 120.2, 119.9, 108.4,107.0, 105.4, 102.1, 61.2, 60.8, 57.9, 56.9, 56.4, 56.0, 55.9, 52.3, 51.0,31.4, 30.1, 29.6, 29.2, 29.1, 27.5, 27.1, 25.6, 25.3.

[0132] The structural formula of compound 5g is as follows:

[0133]

[0134] 5 g. Yellow solid (27 mg, 9%) 1H NMR (400 MHz, CD4O) δ 9.67 (s, 1H, H-9),8.70 (s, 1H, H-3), 8.11 (d, J = 9.1 Hz, 1H,H-2), 7.99 (d, J = 9.1 Hz, 1H, H-1), 7.66 (s, 1H, H-4), 7.00 (d, J = 8.6 Hz, 1H, H-1''), 6.96 (s, 1H, H-6),6.74 (d, J = 8.5 Hz, 1H, H-2''), 6.10 (s, 2H, OCH2O-5), 4.93 (t, J = 6.3 Hz,2H, CH2-7), 4.39 (t, J = 6.8 Hz, 2H, linker-CH 2- 1'), 4.09 (s, 3H,OCH3-10),3.85(s,3H,OCH 3- ),3.83(s,3H,OCH 3- ),3.81(s,3H,OCH 3- ),3.52(s,2H,NCH 2- 3′),

[0135] 3.25 (t, J = 6.4 Hz, 2H, linker-CH2), 2.77-2.30 (overlapping, 10H, C4H 10 N2,4×CH2,linkerCH2),1.92(overlapping,4H,linkerCH2×2),

[0136] 1.60-1.34 (overlapping, 14H, linker-CH2×7). 13 C NMR (101 MHz, CDCl3) δ 153.0,152.5, 150.3, 150.3, 148.1, 145.4, 143.8, 142.2, 137.2, 133.3, 129.9, 125.8,125.3, 123.4, 122.9, 121.9, 120.2, 108.2, 107.0, 105.6, 102.0, 75.1, 61.1,60.7, 58.3, 56.9, 56.4, 56.0, 55.9, 52.7, 51.8, 30.1, 29.4, 29.3, 29.3, 27.4,27.3, 26.0, 25.7.

[0137] In order to demonstrate the advantages of the technical solution provided by this application, an embodiment of the technical solution provided by this application is given below.

[0138] Experimental Example 1 Verification of the protective activity of berberine-trimetazidine conjugate against TBHP-induced oxidative stress damage in HT-22 cells

[0139] (1) Cell culture: After cell recovery, resuspend the cells in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin and inoculate them into cell culture dishes at 37°C and 5% CO2. Observe the cell morphology during the culture period. After the cell morphology is stable and the density reaches 80%, proceed with subsequent experiments.

[0140] (2) Screening of drug cell activity: A certain number of cells were taken, mixed with complete culture medium, and plated in a 96-well plate. 8,000 cells were plated in 100 μL of solution per well. After 12 hours of culture, the solution in the plate was discarded, and 90 μL of complete culture medium and 10 μL of the test compound were added. After 24 hours of treatment, the medium containing 200 μM TBHP was added as a replacement. After 48 hours of treatment, the medium containing 10% CCK8 was added as a replacement. After 4 hours of culture, the absorbance at 570 nm was measured using a microplate reader.

[0141] As shown in Table 1, preliminary activity screening results indicate that the berberine-trimetazidine conjugate exhibited significantly enhanced cardioprotective activity at both 0.1 μM and 1 μM test concentrations compared to berberine alone, trimetazidine alone, and the berberine and trimetazidine combination at the same concentration (p<0.05). Compound 5b was particularly noteworthy, achieving a cardiomyocyte viability of 78.3±1.5% at 0.1 μM and further increasing to 89.0±1.0% at 1 μM. These data strongly support the effectiveness of the berberine-mediated mitochondrial targeting strategy to enhance compound efficacy.

[0142] Table 1 Protective effect of berberine-trimetazidine conjugate on TBHP-induced oxidative stress

[0143]

[0144] Mean ± standard deviation (SD). Cell viability was assessed 24 h after treatment. *p<0.05, **p<0.01, **p<0.001.

[0145] Experimental Example 2 Evaluation of the Protection of Berberine-Trimetazidine Conjugate 5b against H9c2 Induced by H / R

[0146] (1) Cell culture and H / R protection evaluation: A certain number of cells were taken, mixed with complete culture medium, and plated in a 96-well plate. Among them, 8000 cells were plated in 100 μL solution per well. After culturing for 12 hours, the solution in the well plate was discarded, and 90 μL complete culture medium and 10 μL test compound were added. The hypoxic treatment conditions were 1% CO2, 37°C for 3 hours, and reoxygenation for 1 hour. The cell survival rate of the model group was controlled at 52.3±3.1%. The cells were pretreated with 5b, berberine, trimetazidine, berberine + trimetazidine, 15g, 11h (0.01, 0.1, 1, 10 μM) for 24 hours, and then hypoxia and reoxygenation were performed. After 24 hours of treatment, the medium containing 10% CCK8 was added as a replacement medium. After culturing for 4 hours, the absorbance at 570nm was measured in an enzyme reader.

[0147] The results are as follows Figure 11 (Evaluation of the protective effect of the berberine-trimetazidine conjugate 5b on H9c2 cells induced by H / R (values ​​expressed as mean ± standard deviation, n = 3)) This study successfully established an H9c2 cell model of ischemia-reperfusion injury using a 3-hour hypoxia followed by a 1-hour reoxygenation intervention. The cell survival rate in the model group was significantly reduced to 52.3±3.1% (compared with the normal control group, P < 0.01, n = 6). After 24 hours of pretreatment with different drugs (5b, berberine, trimetazidine, and berberine + trimetazidine), significant differences in cell survival were observed among the intervention groups. Notably, 5b exhibited the most potent protective effect at a concentration of 1 μM, with a cell survival rate of 86.5±4.1% (compared with the model group, P < 0.001; compared with 68.2±3.5% in the trimetazidine group and 71.4±2.8% in the berberine group, both P < 0.01). The results indicate that 5b has significant advantages in improving ischemia-reperfusion injury.

[0148] Experimental Example 3 Evaluation of the protective effect of berberine-trimetazidine conjugate 5b on H / R-induced zebrafish heart

[0149] (1) Animal Source and Animal Husbandry: AB zebrafish (3-12 months old) were purchased from the National Zebrafish Resource Center (CZRC-AB-2023-001) and maintained in a recirculating aquaculture system (Pentair Aquatic Habitats, ZM-300). System parameters were set as follows: a 14 h:10 h light:dark cycle, a constant water temperature of 28.5 ± 0.5 °C, and a dissolved oxygen concentration of ≥ 6 mg / L. Live Artemia salina (salinity 30‰) filtered through a 0.22 μm filter were fed twice daily at a rate of 3%-5% of the fish's body weight.

[0150] (2) Breeding and embryo collection: Sexually mature zebrafish (sex-to-male ratio 1:1) were selected and placed in an independent spawning tank the night before spawning. Fertilized eggs were collected within 2 h after the start of light the next day. The embryos were rinsed three times with 0.3× Holtfreter buffer (pH 7.2±0.1, NaCl 34.8 mM, KCl 0.6 mM, CaCl2 1.0 mM, NaHCO3 2.0 mM) and then transferred to a constant temperature incubator (Binder CB-170) for incubation at 28.5±0.5℃ in still water.

[0151] (3) Embryo screening and quality control: After 24 hours of incubation, embryo development was screened using a stereo microscope (Leica M205 C, 10× objective lens). Unfertilized eggs (blastomeres not split), malformed embryos (pericardial edema, body axis curvature), and developmentally delayed individuals (number of somites <20) were eliminated. Qualified embryos (n ≥ 200 / batch) were selected and cultured to the desired developmental stage. The entire process followed the Zebrafish International Guideline (2022).

[0152] (4) Construction of myocardial hypoxia zebrafish model and cardiac function evaluation method: This study used 3-day-old (3 dpf) myel genotype zebrafish as experimental subjects and randomly divided them into a blank control group (n=20 / well) and a model group (n=20 / well), and cultured them in 6-well plates. The zebrafish in the blank control group were placed in a constant temperature and humidity incubator (temperature 28±0.5℃, humidity 8±1%) for routine culture, while the zebrafish in the model group were transferred to a hypoxic culture device (O2 concentration <1%) for 1.5-4.5 hours of hypoxia intervention.

[0153] Cardiac function assessment in the zebrafish model of myocardial hypoxia: Zebrafish specimens were fixed in 0.8% methylcellulose solution, and 60-second continuous cardiac beat videos were acquired using an upright microscope (Nikon Eclipse Ni). Video data were frame-rate normalized using Premiere Pro (Adobe, v2022), and cardiac function parameters were quantitatively analyzed using Image-Pro Plus (Media Cybernetics, v6.0). These parameters included: ① Heart rate (HR), calculated based on the complete 60-second cardiac cycle count; ② Fractional contraction (FS%), calculated as (EDW - ESW) / EDW × 100%, where EDW represents the end-diastolic ventricular width and ESW represents the end-systolic ventricular width; ③ Stroke volume (SV), calculated using the modified ellipsoid volume formula: SV = 0.523 × (EDL × EDW² - ESL × ESW²), where EDL and ESL represent the end-diastolic and end-systolic ventricular long axis lengths, respectively; and ④ Stroke volume (CO), calculated by multiplying HR and SV. The model validation criteria are: compared with the blank control group, the above cardiac function indicators in the model group must show statistically significant differences (p < 0.05, t-test), thereby confirming the successful construction of the myocardial hypoxia model. Analysis of drug intervention effects in myocardial hypoxia model. Figure 12 As shown in Figures (A) and (B), the cardioprotective effect of berberine-trimetazidine conjugate 5b on H / R-induced zebrafish is shown in Figures (A) and (B). Figure 12 As shown in (A); the histogram statistics of heart rate, short-axis contraction rate, stroke volume and stroke volume are as follows Figure 12 As shown in (B) (values ​​are expressed as mean ± SD, n = 3; **p < 0.01, ***p < 0.001 compared with the control group; #p < 0.05, ##p < 0.01, ###p < 0.001 compared with the H / R group; &p < 0.05, &&p < 0.01 compared with the trimetazidine (15 μM) group). It can be seen that compared with the normal control group, the zebrafish in the hypoxia model group showed significant cardiac function damage: heart rate (HR) decreased by 41.6% (p < 0.001, t-test), ventricular short-axis contraction fraction (FS%) decreased by 62.5% (p < 0.0001), and stroke volume (SV) decreased by 62.9% (p < 0.0001). Compound 5b exhibited a dose-dependent protective effect after treatment, with a 10 μM concentration restoring HR, FS%, and SV to 93.4%, 81.2%, and 78.6% of the normal group, respectively (all p<0.01 compared to the model group). Notably, while pretreatment with the positive control drug trimetazidine significantly increased HR to 118.3% of the normal group (p<0.001 compared to the normal group), it also induced tachycardia-like pathological changes. In contrast, HR in the 5b treatment group remained within the normal physiological range (98.5-103.2%).

[0154] The above experimental results show that the compound of the present invention has a significant cardioprotective effect. It inhibits cellular oxidative stress, improves cell survival rate, restores and improves the heart rate, stroke volume, ventricular short-axis contraction fraction, and cardiac short-axis contraction rate, thereby preventing myocardial ischemia-reperfusion injury. It can be developed as a potential candidate drug for cardioprotection clinical trials.

Claims

1. A berberine-trimetazidine conjugate, characterized in that: It has the general structural formula 1: ； Formula 1; in: R1 is one of hydrogen, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-propyl, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-pentyl, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-hexyl, and 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-octyl; R2 is one of 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-propyl, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-pentyl, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-hexyl, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-heptyl, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-octyl, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-nonyl, and 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-decyl; X is one of chlorine, bromine and iodine.

2. A berberine-trimetazidine conjugate, characterized in that: It has the general structural formula 1: ； Formula 1; in: R1 is one of 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-propyl, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-pentyl, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-hexyl, and 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-octyl; R2 is one of methyl, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-propyl, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-pentyl, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-hexyl, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-heptyl, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-octyl, 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-nonyl, and 4-[(2,3,4-trimethoxyphenyl)methyl]piperazine-1-decyl; X is one of chlorine, bromine and iodine.

3. A berberine-trimetazidine conjugate, characterized in that: The berberine-trimetazidine conjugate is one of the compounds represented by the following chemical formula: ； 3a 3b 3c ； 3d 5a ； 5b ； 5c ； 5d ； 5e ； 5f ； 5g。 4. The method for preparing the berberine-trimetazidine conjugate according to claim 3, wherein: The method includes the following steps in sequence: 1) Dissolve berberine hydrochloride in sodium hydroxide solution, then add acetone dropwise and react for 0.8-1.2 h to produce compound 2; The structure of compound 2 is as follows: ; 2) dissolving compound 2 prepared in step 1) in acetonitrile, adding a diiodoalkane compound, and heating to 60-70°C under an inert atmosphere for 7-9 hours; then adding an acetonitrile solution containing trimetazidine and potassium carbonate, and continuing the reaction at 60-70°C for 1.5-2.5 hours to obtain one of the compounds represented by chemical formulas 3a-3d; The molar ratio of berberine hydrochloride to sodium hydroxide is 0.8-1.2:14; The molar ratio of the compound 2, the diiodoalkane compound, potassium carbonate, and trimetazidine is 0.8-1.2:5:2:1.5; The diiodoalkane compound is at least one of 1,3-diiodopropane, 1,5-diiodopentane, 1,6-diiodohexane and 1,8-diiodooctane.

5. The method for preparing the berberine-trimetazidine conjugate according to claim 3, characterized in that: 1) Berberine hydrochloride was added to a vacuum reactor and thermally decomposed at 190-200°C for 1.5-2.5 h to produce compound 4; The structural formula of the compound 4 is as follows: ; 2) Compound 4 prepared in step 1) and potassium carbonate were dissolved in acetonitrile solution, and a brominated alkane compound was added dropwise, and the reaction was carried out at 68-72°C for 10-14 hours. Then, a solution of trimetazidine, potassium carbonate, and triethylamine dissolved in N,N-dimethylformamide was added, and the reaction was carried out at 75-85°C for 3-5 hours to obtain one of compounds 5a-5g; The molar ratio of compound 4, potassium carbonate, and brominated alkane compound is 0.8-1.2:2.5:2.5; The molar ratio of compound 4, trimetazidine and triethylamine is 0.8-1.2:1.5:1.5; The brominated alkane compound is one of 1,3-dibromopropane, 1,5-dibromopentane, 1,6-dibromohexane, 1,7-dibromoheptane, 1,8-dibromooctane, 1,9-dibromononane and 1,10-dibromodecane.

6. Use of the berberine-trimetazidine conjugate according to claim 1 or 2 in the preparation of a cardioprotective drug.

7. A cardioprotective drug, characterized in that Including the berberine-trimetazidine conjugate according to claim 1 or 2.

8. A cardioprotective drug according to claim 7, characterized in that: Pharmaceutically acceptable excipients are also included.

9. A cardioprotective drug according to claim 8, characterized in that: The auxiliary material is at least one of a binder, a disintegrant, a lubricant, a filler, a surfactant, an antioxidant or a pH adjuster; The dosage form of the medicine is injection, tablet, oral solution, granule or capsule.

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