Use of a compound in the preparation of a medicament for treating and / or preventing stroke

Abstract

The present invention discloses the use of a compound in the preparation of a medicament for treating and / or preventing stroke. The compound is 2,3-dihydronaphtho[1,2-b]furan-4,5-dione, and the stroke includes acute ischemic stroke or ischemic reperfusion brain injury. The compound can effectively treat or prevent acute ischemic stroke by alleviating the acute brain injury caused by acute ischemic stroke or ischemic reperfusion, reducing the volume of cerebral infarction after acute ischemic stroke, alleviating cerebral edema after stroke, and improving neurological function after stroke.

Description

Technical Field

[0001] The present invention relates to the use of a compound in the preparation of a drug for treating and / or preventing stroke, and specifically relates to the use of 2,3-dihydronaphtho[1,2-b]furan-4,5-dione in the preparation of a drug for treating and / or preventing stroke. Background Art

[0002] Stroke, also known as apoplexy, is a type of acute cerebrovascular disease caused by abnormal blood vessels in the brain, resulting in brain tissue damage, and is characterized by high incidence, high recurrence rate, high disability rate, and high mortality rate. Stroke is mainly divided into ischemic and hemorrhagic strokes. Among them, acute ischemic stroke (commonly known as cerebral infarction) is the most common clinical stroke type, accounting for about 62.4% of the total number of stroke patients. It is analyzed that the globally age-standardized incidence of ischemic stroke is expected to increase to 89.32 / 100,000 people by 2030 (Pu L, et al. Stroke. 2023, 54: 1330-1339).

[0003] Ischemic stroke is caused by various reasons such as cerebrovascular occlusion or stenosis, resulting in obstruction or reduction of local cerebral blood supply, and ischemia and hypoxia cause necrosis of related brain tissue (cerebral infarction). Patients will have long-term neurological deficits or even death. Its acute phase generally refers to within 1 week after the onset of mild cases and within 1 month after the onset of severe cases. The primary clinical treatment principle of acute ischemic stroke is to restore cerebral blood flow as soon as possible to achieve reperfusion, so that the ischemic brain tissue can regain the supply of oxygen, blood sugar, etc.

[0004] However, after cerebral ischemia and cerebral blood flow reperfusion, various forms of delayed death occur in nerve cells, cerebral microvascular endothelial cells, etc., leading to a progressive increase in pathological changes such as cerebral infarction volume and cerebral edema. Cerebral tissue infarction is the main pathological change after acute ischemic stroke, which will aggravate the neurological damage of patients, and survivors will have long-term sensory and motor function disorders and neuropsychiatric abnormalities (Sarraj A, et al. Stroke. 2021, 52: 838-849). Cerebral edema is another main pathological change after acute ischemic stroke and is an independent predictor of the mortality of stroke patients. Therefore, it is urgent to develop safe and effective therapeutic drugs to improve acute brain injury after stroke and reperfusion brain injury after stroke. Summary of the Invention

[0005] Object of the Invention: The object of the present invention is to provide the use of 2,3-dihydronaphtho[1,2-b]furan-4,5-dione in the preparation of a drug for treating and / or preventing stroke.

[0006] Technical solution: The application of the compound of the present invention in the preparation of a medicament for treating and / or preventing stroke, wherein the compound is 2,3-dihydronaphtho[1,2-b]furan-4,5-dione, and the structure is shown in Formula I:

[0007]

[0008] Among them, the stroke includes acute ischemic stroke or ischemic reperfusion brain injury, and the compound improves acute brain injury after stroke and reperfusion brain injury after stroke.

[0009] Among them, the compound alleviates acute brain injury caused by acute ischemic stroke or ischemic reperfusion and improves neurological deficit.

[0010] Among them, the dosage form of the medicament is tablet, powder, granule, capsule, oral liquid or injection.

[0011] Among them, the compound also includes its stereoisomers, pharmaceutically acceptable salts, precursors and solvates.

[0012] Among them, the compound is prepared from 7-methoxy-3,4-dihydroxynaphthalen-1(2H)-one as a raw material by the following reaction process:

[0013]

[0014] Among them, the specific preparation method of the compound is as follows:

[0015] (1) Using 7-methoxy-3,4-dihydroxynaphthalen-1(2H)-one as a raw material, reacting with tert-butanol and potassium tert-butoxide to obtain Compound II;

[0016] (2) Preparing a mixed solution of toluene, Compound II and potassium carbonate, dropping 3-bromoethylene dissolved in N,N-dimethylformamide, filtering, washing and recrystallizing to obtain Compound III;

[0017] (3) Preparing a mixed solution of N,N-dimethylformamide and Compound III, refluxing and reacting, and separating to obtain Compound IV;

[0018] (4) Preparing a mixed solution of dichloromethane, Compound IV and aluminum trichloride, reacting and separating to obtain Compound V;

[0019] (5) Preparing a mixed solution of acetonitrile and Compound V, adding potassium carbonate and p-methylbenzyl bromide, refluxing and reacting, and separating to obtain Compound I.

[0020] The present invention also discloses the application of a pharmaceutical composition containing the compound described in Claim 1 in the preparation of a medicament for treating and / or preventing stroke.

[0021] Among them, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, and the pharmaceutical excipient is selected from diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers or lubricants.

[0022] Among them, the pharmaceutical excipient further comprises a flavoring agent.

[0023] Principle of the invention: The compound 2,3-dihydronaphtho[1,2-b]furan-4,5-dione of formula I in this application can inhibit the programmed necrosis of nerve cells after oxygen-glucose deprivation, and can be used as a drug targeting programmed necrosis, overcoming problems such as easy drug resistance of a single molecular target. It has a strong therapeutic effect on ischemic stroke, significantly reduces the brain damage caused by acute ischemic stroke, improves the neurological deficit after stroke, and brings a strong brain protection effect.

[0024] Specifically, after cerebral ischemia, neurons undergo various forms of death, including irreversible necrosis and regulated cell death (such as programmed necrosis, apoptosis, pyroptosis, and ferroptosis, etc.), which cause progressive aggravation of cerebral infarction and brain edema, leading to long-term neurological deficits. And neuronal programmed necrosis occurs in the early stage of cerebral ischemia / reperfusion. The compound 2,3-dihydronaphtho[1,2-b]furan-4,5-dione can timely inhibit this type of regulated cell death and effectively block the pathological process after stroke.

[0025] Beneficial effects: Compared with the prior art, the present invention has the following advantages: The compound 2,3-dihydronaphtho[1,2-b]furan-4,5-dione is applied to the preparation of drugs for the treatment and / or prevention of stroke, especially as an anti-acute ischemic stroke drug, which can significantly reduce the brain damage caused by acute ischemic stroke and improve the neurological deficit after stroke. Description of the drawings

[0026] Figure 1 It is a result diagram of CPU-hl02 reducing the cerebral infarction lesion in mice with acute ischemic stroke. Among them, (A) is the observation of cerebral infarction lesions by TTC staining, and (B) is the statistical chart of cerebral infarction volume;

[0027] Figure 2 It is a result diagram of CPU-hl02 reducing the brain edema lesion in mice with acute ischemic stroke;

[0028] Figure 3 It is a result diagram of CPU-hl02 reducing the neurological deficit in mice with acute ischemic stroke. Detailed implementation manners

[0029] The technical solutions of the present invention will be further described below in conjunction with the drawings and embodiments. All materials can be obtained commercially.

[0030] Example 1

[0031] Synthesis of 2,3-dihydronaphtho[1,2-b]furan-4,5-dione compound (CPU-hl02):

[0032] (1) Synthesis of 2-hydroxy-7-methoxy-[1,4]naphthoquinone (II)

[0033]

[0034] Oxygen was continuously introduced into a mixture of 500 mL of tert-butanol and potassium tert-butoxide (446 mmol) for 30 min, 7-methoxy-3,4-dihydroxynaphthalen-1(2H)-one (56.8 mmol) was added, and then oxygen was continuously introduced for 4 h. The mixture was stirred at room temperature overnight. After the reaction was completed, it was cooled to 0 °C, and the organic layer was rinsed 3 times with 600 mL of 1 M hydrochloric acid. The organic layers were combined and rinsed 2 times with 500 mL of 1 M aqueous sodium hydroxide solution. The aqueous phase was acidified with 1 M hydrochloric acid solution and extracted 3 times with dichloromethane (500 mL), dried over magnesium sulfate, and filtered to recover the solvent to obtain Compound II. The yield was 62%, a yellow solid. 1 H NMR (500 MHz, DMSO) δ 11.55 (s, 1H, OH), 7.88 (d, J = 8.5 Hz, 1H, Ar-H), 7.42 (s, 1H, Ar-H), 7.35 (dd, J = 8.5, 2.4 Hz, 1H, Ar-H), 6.10 (s, 1H, CH), 3.91 (s, 3H, OCH3).

[0035] (2) Synthesis of 2-allyloxy-7-methoxynaphthalene-1,4-dione (III)

[0036]

[0037] Potassium carbonate (11.5 mmol) was added to a mixture of 15 mL of toluene and 2-hydroxy-7-methoxy-[1,4]naphthoquinone (11.5 mmol), and the mixture was stirred at room temperature for 15 min. Then, 3-bromoethylene (28.7 mmol) dissolved in 5 mL of N,N-dimethylformamide was slowly added dropwise over 15 min, and then the mixture was stirred at room temperature for 15 min and then at 45 °C for 6 h. After the reaction was completed, it was cooled to room temperature, filtered, 30 mL of dichloromethane was added, and the organic layer was rinsed 3 times with 20 mL of distilled water. The organic layers were combined and rinsed 2 times with 500 mL of 1 M aqueous sodium hydroxide solution, dried over magnesium sulfate, and filtered to recover the solvent. Recrystallization from dichloromethane / petroleum ether gave Compound III. The yield was 88%, yellow needle-like crystals. 11H NMR (500 MHz, DMSO) δ 7.91 (d, J = 8.6 Hz, 1H, Ar-H), 7.41 (d, J = 2.6 Hz, 1H, Ar-H), 7.36 (dd, J = 8.6, 2.6 Hz, 1H, Ar-H), 6.27 (s, 1H, CH), 3.92 (s, 3H, OCH3). 1 1H NMR (500 MHz, CDCl3) δ 8.10 (dd, J = 7.6, 1.3 Hz, 1H, Ar-H), 8.01 (dd, J = 7.6, 1.3 Hz, 1H, Ar-H), 7.73 (dt, J = 7.5, 1.0 Hz, 1H, Ar-H), 7.66 (dt, J = 7.5, 1.0 Hz, 1H, Ar-H), 7.25 (brs, 1H), 5.88–5.78 (m, 1H, CH), 5.11 (dd, J = 10, 1.4 Hz, 1H, CH), 5.00 (dd, J = 10, 1.4 Hz, 1H, CH), 3.92 (s, 3H, OCH3), 3.31 (d, J = 4.5 Hz, 2H, CH2).

[0038] (3) Synthesis of 7-methoxy-2-methyl-2,3-dihydronaphtho[1,2-b]furan-4,5-dione (IV)

[0039]

[0040] A mixture of 50 mL of N,N-dimethylformamide and 2-allyloxy-7-methoxynaphthalene-1,4-dione (8.19 mmol) was refluxed and stirred for 6 h. The solvent was recovered to obtain the crude product of 2-allyl-3-hydroxy-6-methoxynaphthalene-1,4-dione, which was directly dissolved in 30 mL of dry dichloromethane solution. Dry iron(III) chloride (40.9 mmol) was slowly added, and the reaction was stirred overnight. After the reaction was completed, a large amount of distilled water was added. The organic layer was recovered by solvent evaporation, and the compound IV was obtained by silica gel column chromatography with petroleum ether / ethyl acetate. The yield was 81%, and it was a reddish-brown powder. 1 1H NMR (500 MHz, CDCl3) δ 8.10 (dd, J = 7.6, 1.3 Hz, 1H, Ar-H), 8.01 (dd, J = 7.6, 1.3 Hz, 1H, Ar-H), 7.73 (dt, J = 7.5, 1.0 Hz, 1H, Ar-H), 7.66 (dt, J = 7.5, 1.0 Hz, 1H, Ar-H), 7.25 (brs, 1H), 5.88–5.78 (m, 1H, CH), 5.11 (dd, J = 10, 1.4 Hz, 1H, CH), 5.00 (dd, J = 10, 1.4 Hz, 1H, CH), 3.92 (s, 3H, OCH3), 3.31 (d, J = 4.5 Hz, 2H, CH2).

[0041] (4) Synthesis (V) of 7-hydroxy-2-methyl-2,3-dihydronaphtho[1,2-b]furan-4,5-dione

[0042]

[0043] To a mixture of dry 30 mL of dichloromethane and 7-methoxy-2-methyl-2,3-dihydronaphtho[1,2-b]furan-4,5-dione (4.09 mmol), aluminum trichloride (61.4 mmol) was added, and the mixture was refluxed and stirred for 48 h. After the reaction was completed, a large amount of dilute hydrochloric acid aqueous solution was added. The organic layer was recovered by solvent, and the compound V was obtained by passing through a silica gel column with petroleum ether / ethyl acetate, with a yield of 90%, as a reddish-brown powder. 1 H NMR (500 MHz, DMSO) δ 10.71 (s, 1H, OH), 7.47 (d, J = 8.3 Hz, 1H, Ar-H), 7.30 (d, J = 2.4 Hz, 1H, Ar-H), 7.06 (dd, J = 8.3, 2.5 Hz, 1H, Ar-H), 5.26 (dt, J = 9.4, 6.6 Hz, 1H, CH), 3.10 (dd, J = 14.7, 9.6 Hz, 1H, CH), 2.54 (dd, J = 14.8, 7.0 Hz, 1H, CH), 1.47 (d, J = 6.3 Hz, 3H, CH3).

[0044] (5) Synthesis (I) of 2-methyl-7-((4-methylbenzyl)oxy)-2,3-dihydronaphtho[1,2-b]furan-4,5-dione derivative

[0045]

[0046] To a mixture of 5 mL of acetonitrile and 7-hydroxy-2-methyl-2,3-dihydronaphtho[1,2-b]furan-4,5-dione (0.43 mmol), potassium carbonate (0.48 mmol) and p-methylbenzyl bromide (0.48 mmol) were added, and the mixture was refluxed and stirred for 10 h. The solvent was recovered, and the target compound I was obtained by passing through a silica gel column with petroleum ether / ethyl acetate.

[0047] Example 2

[0048] Preparation and purification of compound CPU-hl02:

[0049] The crude product was dissolved in a methanol-acetonitrile mixed solvent and purified by high performance liquid chromatography separation method with 0.1% formic acid / aqueous solution and acetonitrile as the mobile phase.

[0050] The structure confirmation data of the compound of formula I are as follows:

[0051] 11H NMR (500 MHz, DMSO) δ 7.58 (d, J = 8.4 Hz, 1H, Ar-H), 7.50 (d, J = 2.4 Hz, 1H, Ar-H), 7.38–7.35 (m, 3H, Ar-H), 7.23 (d, J = 7.8 Hz, 2H, Ar-H), 5.33–5.28 (m, 1H, CH), 5.24 (d, J = 15.2 Hz, 2H, CH2), 3.14 (dd, J = 14.8, 9.6 Hz, 1H, CH), 2.58 (dd, J = 14.8, 7.0 Hz, 1H, CH), 2.33 (s, 3H, CH3), 1.51 (d, J = 6.3 Hz, 3H, CH3). 13 13C NMR (126 MHz, DMSO) δ 180.57 (s), 174.76 (s), 168.79 (s), 161.22 (s), 137.28 (s), 133.03 (s), 132.41 (s), 128.95 (s), 127.72 (s), 126.05 (s), 120.14 (s), 119.73 (s), 115.12 (s), 112.84 (s), 84.27 (s), 69.71 (s), 32.82 (s), 21.54 (s), 20.66 (s). MS (ESI) m / z 335.1 [M+H] + ; HRMS (ESI) m / z 335.1280 [M+H] + (calcd for 335.1278, C 21 H 19 O4).

[0052] Example 3

[0053] Experimental verification of the therapeutic effect of CPU-hl02 on acute ischemic stroke in mice:

[0054] 1. Animals

[0055] Adult male C57BL / 6 mice, weighing 26 ± 4 g, SPF grade, provided by Shanghai Bikai Keyi Biotechnology Co., Ltd., license number SCXK (Shanghai) 2018-0006.

[0056] 2. Main reagents

[0057] Dimethyl sulfoxide (DMSO): purchased from Sigma-Aldrich Shanghai Trading Co., Ltd.

[0058] Castor oil polyoxyethylene ether: purchased from Shanghai Macklin Biochemical Co., Ltd.

[0059] CPU-hl02: Purified by the method described above, dissolved in DMSO to prepare a stock solution, and diluted with polyoxyethylene castor oil and normal saline to prepare a working solution before use.

[0060] Edaravone: Purchased from Shanghai Yuanye Bio-Technology Co., Ltd.

[0061] Isoflurane: Purchased from Shenzhen Rewod Life Science & Technology Co., Ltd.

[0062] Suture: Purchased from Guangzhou Jialing Biotechnology Co., Ltd.

[0063] 2,3,5-Triphenyltetrazolium Chloride (TTC): Purchased from Beijing Solarbio Science & Technology Co., Ltd.

[0064] 3. Instruments and Equipment

[0065] Mouse Anesthesia Machine: Purchased from Shanghai Yuyan Scientific Instruments Co., Ltd. (ABS type).

[0066] Mouse Brain Stereotaxic Instrument: Purchased from Beijing Zhongshi Dichuang Technology Development Co., Ltd. (Single-arm Digital Display Brain Stereotaxic Instrument).

[0067] Laser Speckle Flow Imaging System: Purchased from Jierdean Technology Co., Ltd. (FLP12).

[0068] 4. Animal Grouping

[0069] Animals were randomly divided into a solvent control group (n = 8), a low-dose CPU-hl02 treatment group (5 mg / kg / d; n = 7), a high-dose CPU-hl02 treatment group (10 mg / kg / d; n = 7), and an edaravone control group (5 mg / kg / d, n = 6). Solvent, CPU-hl02 (5, 10 mg / kg), or edaravone (5 mg / kg) was intraperitoneally injected 30 min after acute ischemic stroke / reperfusion, and then injected once a day for a total of three days.

[0070] 5. Experimental Methods

[0071] Establishment of mouse cerebral ischemia model:

[0072] An acute ischemic stroke model in mice was established by the middle cerebral artery occlusion method. The mice were anesthetized with isoflurane (induced with 3% isoflurane and maintained with 1%-1.5% isoflurane), then fixed in the supine position. A midline incision was made in the neck, and the right common carotid artery, internal carotid artery, and external carotid artery were separated one by one. The proximal end of the common carotid artery and the external carotid artery were ligated with threads respectively. The internal carotid artery was clamped with an artery clip. A small incision was made in the external carotid artery, and the thread embolism was carefully inserted. The artery clip on the internal carotid artery was removed, and the thread embolism was carefully delivered into the internal carotid artery to block the blood flow of the middle cerebral artery. After 60 minutes of ischemia, the thread embolism was removed to achieve reperfusion. During the operation, a laser speckle flow imaging system was used to monitor the changes in cerebral blood flow in mice. The body temperature of the mice was maintained at 37.0±0.5°C.

[0073] Detection of cerebral infarction by TTC staining:

[0074] At 72 hours after reperfusion following cerebral ischemia, the mice were sacrificed and the brain tissues were taken to make coronal sections with a thickness of 1 mm. The brain sections were transferred to a TTC solution (2%) for staining for 10 minutes (at a constant temperature of 37°C, protected from light), and then fixed with paraformaldehyde (4%) for 24 hours. The normal brain tissues on the contralateral side without ischemia showed red, and the white parts on the ischemic side were the infarction areas. The ImageJ (1.54f) image analysis software was used to calculate the cerebral infarction volume. Cerebral infarction volume (%) = (total volume of normal brain tissues on the contralateral side - volume of non-infarcted brain tissues on the ischemic side) / (2 × total volume of normal brain tissues on the contralateral side) × 100%.

[0075] Detection of brain edema by the brain water content analysis method:

[0076] The brain water content analysis method was used to detect brain edema. At 72 hours after ischemia-reperfusion, the left and right hemisphere tissues of the mice brains were taken respectively, the surface moisture was blotted, and the wet weight was measured. Then the tissues were placed in an oven at 110°C for 24 hours until constant weight, taken out and immediately weighed for dry weight, and the brain water content was calculated. Brain water content (%) = (wet weight - dry weight) / wet weight × 100%.

[0077] Modified neurological severity score (mNSS):

[0078] The mNSS was used to evaluate the degree of nerve function impairment such as movement, sensation, and balance in mice. The mNSS score range was 0-18 points, among which severe impairment was 13-18 points, moderate impairment was 7-12 points, and mild impairment was 1-6 points.

[0079] Data statistics:

[0080] Graphpad Prism software (8.0.2) was used to perform statistical analysis on the data. Measurement data were expressed as mean

[0081] ± standard deviation. One-way analysis of variance (one-way ANOVA with

[0082] Bonferroni post-hoc analysis). P < 0.05 was considered statistically significant.

[0083] Mice were intraperitoneally injected with solvent, CPU-hl02 (5, 10 mg / kg), or intravenously injected with the positive control drug edaravone (5 mg / kg) 30 min after ischemia-reperfusion, once a day for three consecutive days. Brain tissue sections were collected 72 h after ischemia-reperfusion. Data are presented as mean ± standard deviation (n = 8, 7, 7, 6). *** P < 0.001, **** P < 0.0001, one-way ANOVA.

[0084] As Figure 1 shown, it is the result graph of CPU-hl02 reducing the cerebral infarction lesions in mice with acute ischemic stroke in Example 3. The TTC staining results showed that compared with the solvent control group, the cerebral infarction volumes of the low-dose treatment group (5 mg / kg / d) and high-dose treatment group (10 mg / kg / d) of CPU-hl02 in mice were significantly reduced, and the differences were statistically significant ( *** P < 0.001; **** P < 0.0001); the cerebral infarction volume of the high-dose group of CPU-hl02 was lower than that of the edaravone positive control group, and the difference was statistically significant ( **** P < 0.0001), and the results indicate that the compound CPU-hl02 can effectively reduce the cerebral infarction volume after acute ischemic stroke.

[0085] Mice were intraperitoneally injected with solvent, CPU-hl02 (5, 10 mg / kg), or intravenously injected with edaravone (5 mg / kg) 30 min after ischemia-reperfusion, once a day for three consecutive days. The water content of brain tissue was detected 72 h after ischemia-reperfusion. Data are presented as mean ± standard deviation (n = 8, 7, 7, 6). # P < 0.05, #### P < 0.0001 compared with the contralateral side, *** P < 0.001, **** P < 0.0001 compared with the ischemic side of the solvent control group, ns indicates no statistically significant difference, one-way ANOVA.

[0086] As Figure 2 shown, it is the result graph of CPU-hl02 reducing the brain edema lesions in mice with acute ischemic stroke in Example 3. 72 h after ischemia-reperfusion, the water content of the ischemic side brain tissue of the solvent control group mice was significantly higher than that of the normal brain tissue on the contralateral side ( ####P < 0.0001); The cerebral water content on the ischemic side of the high-dose treatment group of CPU-hl02 (10 mg / kg / d) and the edaravone positive control group was significantly lower than that on the ischemic side of the solvent control group, and the differences were statistically significant ( **** P < 0.0001; *** P < 0.001), and it was still slightly higher than the water content of the normal brain tissue on the contralateral side of each group ( # P < 0.05; #### P < 0.0001). The results showed that CPU-hl02 effectively reduced cerebral edema after acute ischemic stroke.

[0087] Mice were intraperitoneally injected with solvent, CPU-hl02 (5, 10 mg / kg), or intravenously injected with edaravone (5 mg / kg) at 30 min after ischemia-reperfusion, once a day for three consecutive days, and neurological deficit scores were performed 72 h after ischemia-reperfusion. The data were mean ± standard deviation (n = 8, 7, 7, 6). ** P < 0.01, **** P < 0.0001, one-way ANOVA.

[0088] As Figure 3 shown, it is the result graph of the improvement of neurological deficit in mice with acute ischemic stroke by CPU-hl02 in Example 3. The mNSS score showed that compared with the solvent control group, the neurological deficit scores of the low-dose treatment group of CPU-hl02 (5 mg / kg / d) and the high-dose treatment group of CPU-hl02 (10 mg / kg / d) were significantly reduced, and the differences were statistically significant ( ** P < 0.01; **** P < 0.0001); The effect of the high-dose group of CPU-hl02 on improving neurological function was similar to that of the edaravone positive control group. The results showed that CPU-hl02 improved neurological function after acute ischemic stroke.

[0089] Therefore, the 2,3-dihydronaphtho[1,2-b]furan-4,5-dione compound of the present invention is applied to the preparation of drugs for treating and / or preventing stroke, such as anti-acute ischemic stroke drugs, which can effectively reduce acute brain injury, such as brain injury after acute ischemic stroke, and treat or improve neurological function.

Claims

1. Use of a compound in the preparation of a medicament for treating and / or preventing stroke, characterized in that, The stroke includes acute ischemic stroke or ischemic reperfusion brain injury, and the compound is 2,3-dihydronaphtho[1,2-b]furan-4,5-dione, with the structure shown in Formula I: 。 2. The application according to claim 1, characterized in that, The compound alleviates acute brain injury caused by acute ischemic stroke or ischemic reperfusion and improves neurological deficits.

3. The application according to claim 1, characterized in that, The dosage form of the drug is tablet, powder, granule, capsule, oral liquid or injection.

4. The application according to claim 1, wherein The compound also includes its stereoisomers, pharmaceutically acceptable salts, precursors and solvates.

5. The application according to claim 1, wherein The compound is prepared from 7-methoxy-3,4-dihydroxynaphthalen-1(2H)-one as a raw material by the following reaction process: 。 6. The application according to claim 5, wherein The specific preparation method of the compound is as follows: (1) Using 7-methoxy-3,4-dihydroxynaphthalen-1(2H)-one as a raw material, reacting with tert-butanol and potassium tert-butoxide to obtain Compound II; (2) Preparing a mixed solution of toluene, Compound II and potassium carbonate, dropping 3-bromoethylene dissolved in N,N-dimethylformamide for reaction, filtering, washing and recrystallizing to obtain Compound III; (3) Preparing a mixed solution of N,N-dimethylformamide and Compound III, refluxing for reaction, and separating to obtain Compound IV; (4) Preparing a mixed solution of dichloromethane, Compound IV and aluminum trichloride, reacting and separating to obtain Compound V; (5) Preparing a mixed solution of acetonitrile and Compound V, adding potassium carbonate and p-methylbenzyl bromide and refluxing for reaction, and separating to obtain Compound I.

7. Use of a pharmaceutical composition comprising the compound according to claim 1 in the preparation of a medicament for treating and / or preventing stroke, characterized in that The stroke includes acute ischemic stroke or ischemic reperfusion brain injury.

8. The application according to claim 7, wherein The pharmaceutical composition also contains pharmaceutically acceptable excipients, and the pharmaceutical excipients are selected from diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers or lubricants.

9. The application according to claim 7, wherein The pharmaceutical excipients also contain flavoring agents.

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