Application of tanshinol borneol ester related substances in treatment of ischemic brain and cardiovascular diseases

Abstract

The application relates to application of Danshensu borneol ester related substances in treatment of ischemic brain and cardiovascular diseases. In particular, the application relates to use of Danshensu borneol ester isomers and derivatives thereof in preparation of medicines for preventing and treating ischemic cerebrovascular diseases and cardiovascular diseases, and belongs to the technical field of medicines.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to the application of tanshinone borneol ester in the preparation of drugs for the prevention and treatment of ischemic cerebrovascular diseases and cardiovascular diseases. Background Technology

[0002] Tanshinone borneol ester (DBZ) has four isomers. The DBZ racemic compound (composed of DD-DBZ and LD-DBZ in a mass ratio of approximately 1:1) has been shown to have cardiovascular protective effects (CN200610042787.3). The effects of esters formed by the α-hydroxyl groups of DD-DBZ and LL-DBZ with organic acids on cerebral or cardiac ischemia have not been reported in the literature. Summary of the Invention

[0003] To address the shortcomings in the activity and toxicity of racemic DBZ, the inventors conducted in-depth research on various chiral isomers of DBZ, as well as α-hydroxy esters of DD-DBZ and LL-DBZ.

[0004] Thrombosis is a clinicopathological manifestation of ischemic cerebral or cardiovascular diseases of varying degrees and is an important cause of disease exacerbation. Improving cerebral thrombosis and cardiac thrombosis are important methods and strategies for the prevention and treatment of related diseases.

[0005] The inventors used a zebrafish thrombosis model to demonstrate the antithrombotic effects of various isomers of tanshinone borneol ester and its derivatives. The experiment induced a zebrafish cerebral thrombosis model using the tyrosine kinase inhibitor ponatinib, simulating the pathological state of impaired cerebral blood flow caused by cerebral artery occlusion. The efficacy of tanshinone borneol ester isomers and their derivatives in preventing cerebral thrombosis was evaluated using two quantitative methods: first, measuring the thrombus area and erythrocyte staining intensity in the zebrafish brain to evaluate the compound's antithrombotic activity; second, measuring the erythrocyte staining area and staining intensity in the zebrafish heart to verify the compound's antithrombotic activity. The results showed that all isomers of tanshinone borneol ester and their derivatives exhibited antithrombotic effects. Among them, the activities of levotanshinone levotanshinone borneol ester (LL-DBZ), α-O-tanshinone-derxane-dextrin-dexane-borneol ester (DSS-DD-DBZ), and α-O-tanshinone-derxane-levotanshinone levotanshinone borneol ester (DSS-LL-DBZ) were particularly significant. They could significantly improve the cerebral thrombosis induced by ponatinib in zebrafish, and no obvious toxic side effects were observed.

[0006] Based on new research findings, this invention provides the application of tanshinone borneol ester isomers in the preparation of drugs for the prevention and treatment of ischemic cerebrovascular diseases and ischemic cardiovascular diseases; the various isomers of tanshinone borneol ester are selected from one of the following structures:

[0007]

[0008] This invention also provides the application of tanshinone borneol ester derivatives in the preparation of drugs for the prevention and treatment of ischemic cerebrovascular diseases and ischemic cardiovascular diseases; the tanshinone borneol ester derivatives are selected from one of the following structures:

[0009]

[0010] Based on the above research results, this invention was completed. The study of this invention shows that the four isomers of tanshinone borneol and their derivatives achieve neuroprotection and cardiac protection through at least antithrombotic effects, thus they can be used alone or as active ingredients in the prevention and treatment of ischemic cerebrovascular and cardiovascular diseases in clinical practice. The ischemic cerebrovascular diseases include cerebral thrombosis, ischemic stroke, ischemic cerebellar disease, transient ischemic attack, cerebral infarction, cerebral steal syndrome, vertebrobasilar insufficiency, recovery period of cerebral hemorrhage, sequelae of traumatic brain injury, and posterior circulation ischemia. The ischemic cardiovascular diseases include myocardial infarction, coronary atherosclerotic heart disease, and angina pectoris.

[0011] In this invention, the various isomers of tanshinone borneol ester and their derivatives (AC-DD-DBZ, DSS-DD-DBZ, AC-LL-DBZ, and DSS-LL-DBZ) can be formulated into pharmaceutical compositions with any pharmaceutically permissible excipient, or into compound preparations with other therapeutic agents that do not antagonize them. These preparations can be any pharmaceutically permissible type, including but not limited to tablets, granules, pills, oral liquids, injections, films, capsules, liposomes, and nanoformulations. The concentration of the active substance in the drug, namely the various isomers of tanshinone borneol ester or their derivatives described in this invention, is 0.1-800 μmol / L. Specifically, the dosage can vary depending on the route of administration, patient age, weight, body surface area, type and severity of the disease being treated, and can be used once or multiple times.

[0012] The significant advantage of this invention lies in the comparative study of the antithrombotic activity of four isomers of tanshinone borneol ester and their derivatives. The study further confirmed the significant antithrombotic activity of the tanshinone borneol ester isomers and their derivatives, while also exhibiting low toxicity, indicating broad prospects for clinical application. Attached Figure Description

[0013] Figure 1 The statistical results of staining area and intensity of hemocytes in the brain and heart of zebrafish were obtained from four isomers of tanshinone borneol ester and their derivatives; (A) staining area of ​​hemocytes in brain vessels; (B) staining intensity of hemocytes in brain vessels; (C) staining area of ​​hemocytes in heart vessels; (D) staining intensity of hemocytes in heart vessels; n=10, 3 replicates per group, compared with the normal group, ### p < 0.001; compared with the model group,* For p < 0.05, ** For p < 0.01, *** p < 0.001;

[0014] Figure 2 Representative images of zebrafish brain hemocytosis stained by four isomers of tanshinone borneol ester and their derivatives;

[0015] Figure 3 Representative images of zebrafish heart hemocytosis staining using four isomers of tanshinone borneol ester and its derivatives. Detailed Implementation

[0016] Unless otherwise specified, the scientific and technical terms used herein are for the understanding of those skilled in the art. To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially. Unless otherwise stated, the terminology used herein is for the understanding of those skilled in the art.

[0017] The concentration range of the various isomers of tanshinone borneol and their derivatives involved in this invention for antithrombotic effects is 0.1-800 μmol / L.

[0018] DD-DBZ: Dextrorotatory tanshinone, dextrorotatory borneol ester;

[0019] LD-DBZ: L-tanshinone and D-borneol ester;

[0020] DL-DBZ: Dextrorotatory tanshinone, L-borneol ester;

[0021] LL-DBZ: L-tanshinone, L-borneol ester;

[0022] AC-DD-DBZ: α-O-acetyl-dextrin-dextrin-borneol ester;

[0023] DSS-DD-DBZ: α-O-tanshinone-based dextrorotatory tanshinone dextrorotatory borneol ester;

[0024] AC-LL-DBZ: α-O-acetyl-L-tanshinone-L-borneol ester;

[0025] DSS-LL-DBZ: α-O-tanshinone-based levtanshinone-levonorgestrel;

[0026] DMAP: 4-Dimethylaminopyridine

[0027] Unless otherwise stated, all raw materials, reagents, and experimental materials used in the following examples are commercially available products.

[0028] Example 1: Synthesis of DD-DBZ

[0029] D-tanshinone (10.00 g, 50.46 mmol), dextrorotatory borneol (11.68 g, 75.69 mmol), p-toluenesulfonic acid monohydrate (3.84 g, 20.18 mmol), DMAP (0.62 g, 5.1 mmol), and tetrahydrofuran (40 mL) were added to a single-necked flask and refluxed for 24 hours. After concentration, the reaction solution was separated by silica gel column chromatography to obtain a white solid DD-DBZ (5.2 g, yield: 30.8%). The NMR data of the product are as follows: 1 H NMR(400MHz,DMSO-d6)δ8.65(d,J=27.8Hz,2H),6.65-6.54(m,2H),6.44(dd,J=8.0,2.0Hz,1H), 5.42(s,1H),4.69(d,J=8.8Hz,1H),4.17(t,J=6.3Hz,1H),2.72(d,J=6.6Hz,2H),2.16(ddd,J=13 .7,9.8,5.2Hz,1H),1.78(ddd,J=13.0,9.3,4.1Hz,1H),1.61(dt,J=17.3,3.9Hz,2H),1.24-1.17 (m,1H),1.11-1.03(m,1H),0.84(s,3H),0.82(s,3H),0.76(s,3H),0.70(dd,J=13.6,3.4Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ173.82,144.81,143.71,127.98,119.98,116.76,115.1 6,79.07,71.53,47.34,44.14,39.87,35.87,27.37,26.63,19.48,18.57,13.34.

[0030] Example 2: Synthesis of LD-DBZ

[0031] L-tanshinone (10.00 g, 50.46 mmol), dextrorotatory borneol (11.68 g, 75.69 mmol), p-toluenesulfonic acid monohydrate (3.84 g, 20.18 mmol), DMAP (0.62 g, 5.1 mmol), and tetrahydrofuran (40 mL) were added to a single-necked flask and refluxed for 24 hours. After concentration, the reaction solution was separated by silica gel column chromatography to obtain a white solid DD-DBZ (4.4 g, yield: 26.1%). The NMR data of the product are as follows: 1H NMR(400MHz,DMSO-d6)δ8.65(s,2H),6.64-6.55(m,2H),6.43(dd,J=8.0,2.0Hz,1H ),5.44(s,1H),4.73(d,J=8.7Hz,1H),4.14(t,J=6.5Hz,1H),2.79-2.63(m,2H),2.2 4(ddt,J=9.8,7.9,4.0Hz,1H),1.87-1.77(m,1H),1.66(dt,J=16.3,4.0Hz,2H),1.2 4-1.13(m,2H),0.91-0.86(m,1H),0.86(d,J=3.6Hz,3H),0.83(s,3H),0.68(s,3H). 13 C NMR (101MHz, DMSO-d6) δ173.78,144.84,143.72,128.05,116.71,115.20,78.96,71.91,48.40,47.40,39.86,27.56,26.56,19.50,18.59,13.18.

[0032] Example 3: Synthesis of DL-DBZ

[0033] D-tanshinone (10.00 g, 50.46 mmol), levoborneol (11.68 g, 75.69 mmol), p-toluenesulfonic acid monohydrate (3.84 g, 20.18 mmol), DMAP (0.62 g, 5.1 mmol), and tetrahydrofuran (40 mL) were added to a single-necked flask and refluxed for 24 hours. After concentration, the reaction solution was separated by silica gel column chromatography to obtain a white solid DD-DBZ (5.9 g, yield: 35.0%). The NMR data of the product are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.65(d,J=30.1Hz,2H),6.59(d,J=8.0Hz,2H),6.44(dd,J=8.0,1.8 Hz,1H),5.43(d,J=6.0Hz,1H),4.74(d,J=8.8Hz,1H),4.14(q,J=6.2Hz,1H),2.79-2.63(m,2 H),2.24(ddt,J=9.7,7.9,3.9Hz,1H),1.86-1.77(m,1H),1.74-1.65(m,1H),1.65-1.61(m, 1H),1.24-1.14(m,2H),0.91-0.86(m,1H),0.86(d,J=4.2Hz,3H),0.83(s,3H),0.68(s,3H). 13C NMR(101MHz,DMSO-d6)δ173.78,144.84,143.72,128.06,119.93,116.72,115.21,7 8.97,71.91,48.40,47.41,44.21,39.87,36.11,27.57,26.56,19.49,18.59,13.18.

[0034] Example 4: Synthesis of LL-DBZ

[0035] L-tanshinone (10.00 g, 50.46 mmol), levoborneol (11.68 g, 75.69 mmol), p-toluenesulfonic acid monohydrate (3.84 g, 20.18 mmol), DMAP (0.62 g, 5.1 mmol), and tetrahydrofuran (40 mL) were added to a single-necked flask and refluxed for 24 hours. After concentration, the reaction solution was separated by silica gel column chromatography to obtain a white solid DD-DBZ (3.6 g, yield: 21.3%). The NMR data of the product are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.66 (s, 2H), 6.63-6.57 (m, 2H), 6.44 (dd, J = 8.0, 2.0Hz, 1H), 5.43 (s, 1 H),4.69(d,J=8.8Hz,1H),4.17(t,J=6.5Hz,1H),2.72(d,J=6.6Hz,2H),2.15(ddd,J=13.7,9.8, 5.1Hz,1H),1.78(ddd,J=13.0,9.3,4.2Hz,1H),1.68-1.57(m,2H),1.23-1.17(m,1H),1.07(td, J=11.6,11.2,4.1Hz,1H),0.84(s,3H),0.82(s,3H),0.75(s,3H),0.70(dd,J=13.7,3.4Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ173.84,144.82,127.99,119.99,116.76,115.16,79.08 ,71.54,48.29,47.35,44.14,39.88,35.88,27.38,26.63,19.49,18.58,13.35.

[0036] Example 5: Synthesis of AC-DD-DBZ

[0037] DD-DBZ (5.00 g, 15.0 mmol), p-toluenesulfonic acid monohydrate (2.84 g, 15.0 mmol), and ethyl acetate (50 mL) were added to a single-necked flask and refluxed for 72 hours. The reaction mixture was concentrated and separated by silica gel column chromatography to obtain a white solid AC-DD-DBZ (0.83 g, yield: 14.8%). The NMR data of the product are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.77 (d, J=16.8Hz, 2H), 6.63 (dd, J=5.0, 2.9Hz, 2H), 6. 47(dd,J=8.0,1.9Hz,1H),5.00(t,J=6.6Hz,1H),4.70(d,J=8.9Hz,1H),2.90(q d,J=14.2,6.7Hz,2H),2.14(m,1H),2.05(s,3H),1.73-1.58(m,3H),1.27-1.19 (m,1H),1.08-1.01(m,1H),0.82(s,3H),0.81(s,3H),0.72(s,3H),0.68(m,1H). 13 C NMR(101MHz,DMSO-d6)δ169.99,169.53,145.07,144.22,126.26,120.09,116.68,115.42,79.9 3,73.26,48.45,47.40,44.16,39.62,36.10,35.62,27.37,26.65,20.38,19.48,18.57,13.18.

[0038] Example 6: Synthesis of DSS-DD-DBZ

[0039] DD-DBZ (5.00 g, 15.0 mmol), DD-DSS (4.44 g, 22.4 mmol), p-toluenesulfonic acid monohydrate (1.42 g, 7.48 mmol), DMAP (0.37 g, 3.0 mmol), and tetrahydrofuran (40 mL) were added to a single-necked flask and refluxed for 72 hours. After concentration, the reaction mixture was separated by silica gel column chromatography to obtain an oily product, DSS-DD-DBZ (1.2 g, yield: 15.6%). The NMR data of the product are as follows: 1H NMR (400MHz, DMSO-d6) δ8.72 (d, J=37.8Hz, 4H), 6.66-6.59 (m, 4H), 6.50 (dd, J=8.0, 1.8Hz, 1H), 6.43 (dd, J=8.0, 1.8Hz, 1H),5.51(d,J=6.6Hz,1H),5.06(t,J=6.6Hz,1H),4.75(d,J=9.1Hz,1H),4.13(dt,J=5.8,3.0Hz,1H),2.95(dq,J=15.2, 8.0,7.5Hz,2H),2.86(dd,J=13.8,3.3Hz,1H),2.55(dd,J=14.0,9.3Hz,1H),2.15(ddd,J=13.6,9.8,4.0Hz,1H),1.75-1 .59(m,3H),1.21(d,J=12.7Hz,1H),1.06(d,J=7.0Hz,1H),0.83(s,3H),0.81(s,3H),0.73(s,3H),0.71(d,J=3.4Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ173.26,169.34,145.09,144.86,144.24,143.77,128.76,126.20,120.24,119.99,116.81, 115.41,115.32,80.03,73.24,71.46,48.51,47.49,44.15,39.24,36.27,35.58,27.38,26.63,19.51,18.58,13.22.

[0040] Example 7: Synthesis of AC-LL-DBZ

[0041] AC-LL-DBZ was synthesized according to Example 5. LL-DBZ (100 mg, 299.0 μmol), p-toluenesulfonic acid monohydrate (56.9 mg, 299.0 μmol), and ethyl acetate (30 mL) were added to a single-necked flask and refluxed for 72 hours to give a white solid (36 mg, yield: 32%). The MS m / z of the product was [M-1]: 375.2.

[0042] Example 8: Synthesis of DSS-LL-DBZ

[0043] LL-DBZ (100 mg, 299.0 μmol), DD-DSS (88.9 mg, 449.6 μmol), p-toluenesulfonic acid monohydrate (28 mg, 150 μmol), DMAP (7.3 mg, 60 μmol), and tetrahydrofuran (20 mL) were added to a single-necked flask and refluxed for 72 hours to give an oil (42 mg, yield: 27%). The MS m / z of the product was [M-1]: 513.2.

[0044] Example 9: Study on the toxic effects of the DBZ isomers and related derivatives prepared in the above examples on zebrafish.

[0045] 1. Experimental Methods:

[0046] Well-developed 2dpf AB strain zebrafish were selected and cultured in sterile 24-well plates. Ten different concentration groups of the test compound were set up (5, 10, 25, 50, 75, 100, 150, 200, 300, 800 μmol / L). The control group was treated with DMSO in the same volume as the highest concentration group. The final volume of the solution system in each well was 2 mL. After the drug was added, 15 juvenile fish were added to the corresponding well, and the plates were capped and labeled. After the drug was added, the culture plates were placed in a light incubator. The fish were observed every 4 hours, the number of dead fish was recorded, and dead juvenile fish were removed. The results were recorded 24 hours after drug administration. The experiment was repeated three times.

[0047] 2. Experimental Results:

[0048] Table 1 shows that the maximum tolerated concentration (MTC) of DD-DBZ is 50 μmol / L; DL-DBZ: MTC is 50 μmol / L; LD-DBZ: MTC is 50 μmol / L; LL-DBZ: MTC is 50 μmol / L; AC-DD-DBZ: MTC is 20 μmol / L; DSS-DD-DBZ: MTC is 50 μmol / L; AC-LL-DBZ: MTC is 20 μmol / L; and DSS-LL-DBZ: MTC is 50 μmol / L. This indicates that DBZ isomers and their derivatives (AC-DD-DBZ, DSS-DD-DBZ, AC-LL-DBZ, and DSS-LL-DBZ) are non-toxic to zebrafish model organisms at concentrations below 10 μmol / L.

[0049] Table 1. Maximum tolerable concentrations (MTCs) of DBZ and its derivatives in 3-day-per-fed zebrafish juveniles. a

[0050] DD-DBZ 50 DL-DBZ 50 LD-DBZ 50 LL-DBZ 50 AC-DD-DBZ 20 DSS-DD-DBZ 50 AC-LL-DBZ 20 DSS-LL-DBZ 50

[0051] a MTC:maximum tolerated concentration

[0052] Example 10: Study on the anti-cerebral thrombotic activity of various DBZ isomers and related derivatives in a ponatinib-induced zebrafish thrombosis model.

[0053] 1. Principle:

[0054] Ischemic cerebrovascular diseases are mainly caused by narrowing or occlusion of cerebral arteries, leading to impaired blood flow to the brain, which in turn causes ischemic and hypoxic necrosis of some brain tissue, ultimately resulting in neurological dysfunction. The cardiovascular system of zebrafish shares over 85% homology with that of humans and other mammals in terms of molecular signal transduction pathways. Therefore, zebrafish are widely used in research on cardiovascular diseases, including heart failure, thrombosis, arrhythmia, cardiomyopathy, and atherosclerosis.

[0055] Ponatinib, a tyrosine kinase inhibitor, has been found to cause myocardial infarction, stroke, and other diseases. After entering the human body, ponatinib inhibits vascular endothelial cell proliferation, migration, and angiogenesis by disrupting the vascular endothelial growth factor receptor pathway, affecting nitric oxide synthesis, causing vascular endothelial damage, and thus leading to vascular occlusion and cerebral thrombosis. Zebrafish brains exhibit typical vertebrate brain morphology and possess clotting factors and platelet receptors; therefore, ingestion of large amounts of ponatinib can also induce cerebral ischemia and cerebral thrombosis. After specific erythrocyte staining (ortho-anisidine staining), thrombi in the head of zebrafish with cerebral ischemia are significantly higher than in normal zebrafish. Due to the relatively transparent nature of juvenile zebrafish, these thrombi can be clearly observed, and the staining area and intensity can indirectly reflect the thrombosis status.

[0056] 2. Experimental Methods:

[0057] Before the formal experiment, adult fish were mated and spawned. Six hours after collecting the fertilized eggs, PTU (1 mg / mL) was added at a ratio of 30 μL / mL to inhibit melanin growth, ensure the fish were transparent, and avoid statistical errors. AB strain zebrafish embryos at 2 dpf were placed in culture dishes. Under a stereomicroscope, normally developing embryos were selected and transferred to 24-well culture plates, 10 embryos per well.

[0058] The experiment included a normal control group, a model group, a positive control group (aspirin), and different concentrations (5, 10 μmol / L) of DD-DBZ+LD-DBZ (mass ratio 1:1), DD-DBZ, DL-DBZ, LD-DBZ, LL-DBZ, AC-DD-DBZ, DSS-DD-DBZ, AC-LL-DBZ, and DSS-LL-DBZ, with 3 replicate wells in each group.

[0059] This study used a combination of modeling and therapeutic drugs. The normal control group did not receive ponatinib for modeling. The model group, positive control group, and treatment group all received an equal amount of ponatinib (1 μg / mL). 60 μL of ponatinib (PTU) was added to each well to inhibit melanin production, resulting in a final solution volume of 2 mL for each well. After drug addition, the solutions were transferred to a light incubator and incubated in the dark for 24 h at a temperature controlled at 28.5℃ ± 0.5℃.

[0060] During the drug treatment, the fish were observed every 4 hours. Juvenile fish that died due to chance were removed to avoid water pollution affecting the statistical results. Once the zebrafish reached 3 days post-flour (dpf), they were stained with 1 mg / mL o-anisidine solution for 15 min in the dark, then washed three times with DMSO and fixed overnight in 4% paraformaldehyde (PFA) at 4°C. Thrombosis in each group of zebrafish was observed and photographed using a ZEISS microscope (AXIO ZOOM.V16). The staining intensity of erythrocytes in the zebrafish brain and heart was quantitatively analyzed using IPP 5.1 image processing software.

[0061] Zebral cerebral thrombosis was induced by vascular occlusion caused by the ingestion of 1 μg / mL ponatinib in 2dpf wild-type AB zebrafish. The incidence of cerebral thrombosis was defined as the number of zebrafish with cerebral thrombosis in each test group / the total number of zebrafish in each test group, denoted as I. The efficacy of cerebral thrombosis improvement was defined as I(model group) - I(administered group) / I(model group) × 100%.

[0062] 3. Experimental Results

[0063] From Table 2 and Figure 1 It was found that DD-DBZ+LD-DBZ, DD-DBZ, DL-DBZ, LD-DBZ, LL-DBZ, AC-DD-DBZ, DSS-DD-DBZ, AC-LL-DBZ, and DSS-LL-DBZ all possessed anti-cerebral thrombotic activity. At a dosage concentration of 10 μmol / L, the anti-cerebral thrombotic effects of DD-DBZ, DL-DBZ, LD-DBZ, LL-DBZ, AC-DD-DBZ, DSS-DD-DBZ, AC-LL-DBZ, and DSS-LL-DBZ were significantly superior to those of the positive control drug aspirin and the mixed DBZ (DD-DBZ+LD-DBZ) group.

[0064] Figure 2 and Figure 3This directly demonstrates that DD-DBZ, DL-DBZ, LD-DBZ, LL-DBZ, AC-DD-DBZ, and DSS-DD-DBZ possess antithrombotic effects, superior to the positive control drug aspirin. Among them, levotanshinone-levoborneol ester (LL-DBZ) and α-O-tanshinone-yldextrin-devoborneol ester (DSS-DD-DBZ) exhibit relatively better activity, significantly improving zebrafish cerebral thrombosis induced by ponatinib without significant toxic side effects.

[0065] Table 2 Evaluation of the efficacy of DBZ isomers and their impurities in improving cerebral thrombosis in zebrafish (n=20)

[0066]

[0067]

Claims

1. The application of tanshinone borneol ester derivatives in the preparation of drugs for the prevention and treatment of ischemic cerebrovascular diseases; wherein the tanshinone borneol ester derivative is selected from one of the following structures: 。 2. The application according to claim 1, characterized in that, The ischemic cerebrovascular diseases mentioned are cerebral thrombosis, ischemic stroke, transient ischemic attack, and cerebral infarction.

3. The application according to claim 1, characterized in that, The concentration of tanshinone borneol derivative in the drug is 0.1-800 mg / L. μ mol / L.

4. The application according to claim 1, characterized in that, The drug is in the form of pills, capsules, tablets, or granules.

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