Application of danshensu bornyl ester related substances in treatment of ischemic cerebral and cardiovascular diseases

Abstract

The invention relates to application of tanshinol bornyl ester related substances in treatment of ischemic cerebral and cardiovascular diseases. The invention relates to application of salvianic acid bornyl ester isomers and derivatives thereof in preparation of drugs for preventing and treating ischemic cerebrovascular diseases and cardiovascular diseases independently or as effective components, and belongs to the technical field of medicines.

Description

Technical Field

[0001] The invention belongs to the field of medical technology and relates to the application of danshensu borneol ester in preparing medicines for preventing and treating ischemic cerebrovascular diseases and cardiovascular diseases. Background Art

[0002] Danshensu borneol ester (DBZ) has four isomers, and it has been proven that DBZ racemate (composed of DD-DBZ and LD-DBZ, with a mass ratio of about 1:1) has the effect of protecting cardiovascular and cerebrovascular vessels (CN200610042787.3). The effect of DD-DBZ and LL-DBZ α-hydroxyl groups forming esters with organic acids on brain or heart ischemia has not been reported in the literature. Summary of the invention

[0003] In view of the insufficient activity and toxicity of racemic DBZ, the inventors conducted in-depth research on the chiral isomers of DBZ and DD-DBZ and LL-DBZ α-hydroxy ester compounds.

[0004] Thrombosis is the clinical pathological manifestation of ischemic brain or cardiovascular diseases of varying degrees and is an important cause of disease deterioration. Improving cerebral thrombosis and cardiac thrombosis is an important method and strategy for the prevention and treatment of related diseases.

[0005] The inventors used the zebrafish thrombosis model to illustrate that the various isomers of danshensu borneol ester and its derivatives have anti-thrombotic effects. The experiment induced a zebrafish cerebral thrombosis model by using the tyrosine kinase inhibitor ponatinib, simulating the pathological state of cerebral blood supply obstruction caused by cerebral artery lumen occlusion. The efficacy of danshensu borneol ester isomers and its derivatives in anti-cerebral thrombosis was evaluated, specifically through the following two quantitative determination methods: one is to measure the thrombus area of ​​zebrafish brain and the staining intensity of brain red blood cells to evaluate the anti-thrombotic activity of the compound; the other is to measure the staining area and staining intensity of zebrafish heart red blood cells to verify the anti-thrombotic activity of the compound. The research results showed that all isomers of danshensu borneol ester and their derivatives exhibited anti-thrombotic effects, among which the activities of levorotatory danshensu borneol ester (LL-DBZ), α-O-danshensu dextrorotatory danshensu borneol ester (DSS-DD-DBZ) and α-O-danshensu levorotatory danshensu borneol ester (DSS-LL-DBZ) were particularly significant, and they could significantly improve the cerebral thrombosis in zebrafish caused by ponatinib without obvious toxic side effects.

[0006] Based on new research findings, the present invention provides the use of danshensu borneol isomers for preparing drugs for preventing and treating ischemic cerebrovascular diseases and ischemic cardiovascular diseases; each danshensu borneol isomer is selected from one of the following structures:

[0007]

[0008] The present invention also provides the use of danshensu borneol ester derivatives for preparing drugs for preventing and treating ischemic cerebrovascular diseases and ischemic cardiovascular diseases; the danshensu borneol ester derivatives are selected from one of the following structures:

[0009]

[0010] The present invention was completed based on the above research results. The research of the present invention shows that the four isomers of danshensu borneol ester and its derivatives can at least achieve brain protection and heart protection through anti-thrombotic effects, so they can be used alone or as an effective ingredient in the prevention and treatment of clinical ischemic cerebrovascular diseases and ischemic cardiovascular diseases. The ischemic cerebrovascular diseases include cerebral thrombosis, ischemic stroke, ischemic cerebellar disease, transient ischemic attack, cerebral infarction, cerebral artery steal syndrome, vertebral basilar artery insufficiency, cerebral hemorrhage recovery period, sequelae of craniocerebral injury and posterior circulation ischemia. The ischemic cardiovascular diseases include myocardial infarction, coronary atherosclerotic heart disease and angina pectoris.

[0011] In the present invention, each isomer of danshensu borneol ester and its derivatives (AC-DD-DBZ, DSS-DD-DBZ, AC-LL-DBZ and DSS-LL-DBZ) can be made into a pharmaceutical composition with any pharmaceutically permitted excipient, or can be composed of a compound preparation with other therapeutic drugs that do not antagonize with it. These preparations can be of any type pharmaceutically permitted, including but not limited to tablets, granules, pills, oral liquids, injections, films, capsules, liposomes, nano preparations, etc. The concentration of the active substance in the drug, i.e., each isomer of danshensu borneol ester or its derivatives described in the present invention, is 0.1-800 μmol / L. Specifically, it can be changed according to the route of administration, patient age, weight, body surface area, type of disease to be treated and severity, and can be used once or multiple times.

[0012] The significant advantage of the present invention is that the antithrombotic activity of four isomers of danshensu borneol ester and their derivatives was compared and studied. The study further confirmed that danshensu borneol ester isomers and their derivatives have significant antithrombotic activity and exhibit low toxicity, indicating that they have broad prospects in clinical application. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The statistical results of the staining area and intensity of blood cells in the brain and heart of zebrafish by four isomers of danshinone bornyl ester and their derivatives; (A) Staining area of ​​blood cells in brain blood vessels; (B) Staining intensity of blood cells in brain blood vessels; (C) Staining area of ​​blood cells in heart; (D) Staining intensity of blood cells in heart; n = 10, 3 replicates per group, compared with the normal group, ### p<0.001; compared with the model group,* p<0.05, ** p<0.01, *** p<0.001;

[0014] Figure 2 Representative pictures of zebrafish brain blood cells stained by four isomers of danshinone bornyl ester and their derivatives;

[0015] Figure 3 Representative images of zebrafish heart blood cells stained by four isomers of danshinone borneol and their derivatives. DETAILED DESCRIPTION

[0016] Unless otherwise specified, the scientific and technical terms in this article are understood according to the knowledge of ordinary technicians in the relevant fields. In order to make the purpose, 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. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially. Unless otherwise specified, the terms in this article are understood according to the conventional knowledge of those skilled in the art.

[0017] The concentration range of the danshensu bornyl ester isomers and derivatives thereof in the anti-thrombotic effect is 0.1-800 μmol / L.

[0018] DD-DBZ: dextro-danshinone dextro-bornyl ester;

[0019] LD-DBZ: L-danshinone D-bornyl;

[0020] DL-DBZ: dextro-danshinone-levo-bornyl ester;

[0021] LL-DBZ: L-danshinone L-bornyl;

[0022] AC-DD-DBZ: α-O-acetyl-D-danshinone-D-bornyl;

[0023] DSS-DD-DBZ: α-O-danshinol-based dextran danshinol-based dextran borneol ester;

[0024] AC-LL-DBZ: α-O-acetyl-L-danshinone-L-bornyl;

[0025] DSS-LL-DBZ: α-O-danshinol-based levorotatory danshinol-bornyl;

[0026] DMAP: 4-dimethylaminopyridine

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

[0028] Example 1: Synthesis of DD-DBZ

[0029] D-danshensu (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-mouth bottle and refluxed for 24 hours; after the reaction solution was concentrated, it was separated by silica gel column chromatography to obtain a white solid DD-DBZ (5.2 g, yield: 30.8%). The product NMR data are: 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-danshensu (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-mouth bottle and refluxed for 24 hours; after the reaction solution was concentrated, it was separated by silica gel column chromatography to obtain a white solid DD-DBZ (4.4 g, yield: 26.1%). The product NMR data are: 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-danshensu (10.00 g, 50.46 mmol), 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-mouth bottle and refluxed for 24 hours; after the reaction solution was concentrated, it was separated by silica gel column chromatography to obtain a white solid DD-DBZ (5.9 g, yield: 35.0%). The product NMR data are: 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-danshensu (10.00 g, 50.46 mmol), 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-mouth bottle and refluxed for 24 hours; after the reaction solution was concentrated, it was separated by silica gel column chromatography to obtain white solid DD-DBZ (3.6 g, yield: 21.3%). The product NMR data are: 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-mouth bottle and refluxed for 72 hours; after the reaction solution was concentrated, it was separated by silica gel column chromatography to obtain a white solid AC-DD-DBZ (0.83 g, yield: 14.8%). The product NMR data are: 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 bottle and refluxed for 72 hours; after the reaction solution was concentrated, it was separated by silica gel column chromatography to obtain an oily substance DSS-DD-DBZ (1.2 g, yield: 15.6%). The product NMR data are: 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] According to Example 5, AC-LL-DBZ was synthesized. 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 bottle and refluxed for 72 hours to obtain a white solid (36 mg, yield: 32%). Product MS m / z = [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 bottle and refluxed for 72 hours to obtain an oily substance (42 mg, yield: 27%). Product MS m / z = [M-1]: 513.2.

[0044] Example 9: Study on the toxic effects of 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 test compound administration concentration groups (5, 10, 25, 50, 75, 100, 150, 200, 300, 800 μmol / L) were set up, and DMSO was added to the control group, and its volume was the same as the highest concentration group. The final volume of the solution system in each well was 2mL. After the addition of the drug, 15 fry were added to the corresponding wells, covered and marked; after the addition of the drug, the culture plate was placed in a light incubator, observed every 4 hours, recorded the number of deaths and removed the dead fry, and the statistics were terminated 24 hours after the administration, and the experiment was repeated three times.

[0047] 2. Experimental results:

[0048] As shown in Table 1, 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; DSS-LL-DBZ: MTC is 50 μmol / L; This shows 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 animals below 10 μmol / L.

[0049] Table 1 Maximum tolerable concentrations (MTCs) of DBZ and its derivatives in 3dpf zebrafish larvae a

[0050] Test compound MTCs (μmol / L) 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 DBZ isomers and related derivatives in the zebrafish thrombosis model induced by Ponatinib

[0053] 1. Principle:

[0054] Ischemic cerebrovascular disease is mainly caused by stenosis or occlusion of the cerebral artery lumen, which leads to obstruction of cerebral blood supply, and then causes ischemic hypoxic necrosis of some brain tissues, and finally leads to neurological dysfunction. The cardiovascular system of zebrafish has a high degree of homology with humans and mammals in molecular signal transduction pathways, exceeding 85%. Therefore, zebrafish are widely used in the study of cardiovascular diseases, including heart failure, thrombosis, arrhythmia, myocardial lesions, and atherosclerosis.

[0055] As a tyrosine kinase inhibitor, studies have found that ponatinib can cause myocardial infarction, stroke and other diseases. After entering the human body, ponatinib destroys the vascular endothelial growth factor receptor pathway, inhibits endothelial cell proliferation, migration and angiogenesis, affects nitric oxide synthesis, causes endothelial damage, and thus causes blood vessel blockage and induces cerebral thrombosis. The zebrafish brain has typical vertebrate brain morphological characteristics, and has coagulation factors and platelet receptors. After taking a large amount of ponatinib, it will also induce cerebral ischemia and cerebral thrombosis. After red blood cell-specific staining (o-dianisidine staining), the head thrombosis of zebrafish with cerebral ischemia will be significantly higher than that of normal zebrafish. Due to the relatively transparent characteristics of zebrafish larvae, it can be clearly observed, and the staining area and staining intensity can indirectly reflect the thrombosis situation.

[0056] 2. Experimental methods:

[0057] Before the formal experiment, adult fish mated and laid eggs. After collecting fertilized eggs for 6 hours, PTU (1 mg / mL) was added at a ratio of 30 μL / mL to inhibit the growth of melanin, ensure the transparency of the fish body, and avoid statistical errors. 2dpf AB zebrafish embryos were placed in a culture dish, and normal embryos were selected under a stereomicroscope and transferred to a 24-well culture plate, with 10 per well.

[0058] The experiment set up a normal control group, a model group, a positive 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 drug-dosing groups, with 3 replicate wells in each group.

[0059] This study used modeling drugs and therapeutic drugs for co-treatment. The normal control group did not take ponatinib for modeling, and the model group, positive group and drug-treated group all took the same amount of ponatinib (1μg / mL). 60μL of ponatinib PTU was added to each well to inhibit melanin production, and the final volume of each well solution system was 2mL. After the addition of drugs, the cells were transferred to a light incubator for incubation in the dark for 24 hours, and the incubator temperature was controlled at 28.5℃±0.5℃.

[0060] During the drug administration process, observations were made every 4 hours, and juvenile fish that died due to accidental errors were removed to avoid water pollution affecting the statistical results. When the zebrafish developed to 3 dpf, they were stained with 1 mg / mL o-dianisidine staining solution for 15 min in the dark, then washed 3 times with DMSO, and fixed in 4% paraformaldehyde (PFA) at 4°C overnight. The thrombosis of zebrafish in each group was observed and photographed using a ZEISS microscope (AXIO ZOOM.V16), and the staining intensity of red blood cells in the zebrafish brain and heart was quantitatively analyzed using the IPP 5.1 image processing software.

[0061] Zebrafish cerebral thrombosis was caused by 2dpf wild-type AB zebrafish ingesting 1μg / mL ponatinib, which caused vascular blockage and induced cerebral thrombosis; the incidence of cerebral thrombosis refers to the number of cerebral thrombosis in zebrafish in each test group / the total number of zebrafish in each test group, recorded as Ⅰ; the efficacy of improving cerebral thrombosis refers to Ⅰ (model group) - Ⅰ (drug treatment group) / Ⅰ (model group) × 100%.

[0062] 3. Experimental results

[0063] From Table 2 and Figure 1 It can be seen 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 have anti-cerebral thrombotic activity. At a 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 better than those of the positive drug aspirin and mixed DBZ (DD-DBZ+LD-DBZ) group.

[0064] Figure 2 and Figure 3It can be directly shown that DD-DBZ, DL-DBZ, LD-DBZ, LL-DBZ, AC-DD-DBZ, and DSS-DD-DBZ have antithrombotic effects and are superior to the positive drug aspirin. Among them: levorotatory danshensu levorotatory bornyl ester (LL-DBZ) and α-O-danshensu dextrorotatory danshensu dextrorotatory bornyl ester (DSS-DD-DBZ) have relatively good activity and can significantly improve zebrafish cerebral thrombosis caused by Ponatinib without obvious toxic side effects.

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

[0066]

[0067]

Claims

1. Use of danshensu borneol isomers for preparing drugs for preventing and treating ischemic cerebrovascular diseases and ischemic cardiovascular diseases; each danshensu borneol isomer is selected from one of the following structures:

2. The use of danshensu borneol ester derivatives for preparing drugs for preventing and treating ischemic cerebrovascular diseases and ischemic cardiovascular diseases; the danshensu borneol ester derivatives are selected from one of the following structures:

3. The use according to claim 1 or 2, characterized in that: The ischemic cerebrovascular diseases include cerebral thrombosis, ischemic stroke, ischemic cerebellar disease, transient ischemic attack, cerebral infarction, cerebral artery steal syndrome, vertebral basilar artery insufficiency, cerebral hemorrhage recovery period, sequelae of craniocerebral injury and posterior circulation ischemia.

4. The use according to claim 1 or 2, characterized in that: The ischemic cardiovascular diseases include myocardial infarction, coronary atherosclerotic heart disease and angina pectoris.

5. The use according to claim 1 or 2, characterized in that: The concentration of each isomer of danshensu bornyl ester or its derivatives in the medicine is 0.1-800 μmol / L.

6. The use according to claim 1 or 2, characterized in that: The medicine is in the form of pills, capsules, tablets, dispersible tablets, granules or dry suspensions.

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