A cycloheptenone adduct of a flavane and a stilbene compound

Abstract

A cycloheptenone adduct of flavanols and stilbene compounds as shown in formula (I), its preparation method, and its use in treating cerebral ischemia. The compound of this invention has a simple preparation method and exhibits good neuroprotective activity.

Description

A cycloheptenone adduct of flavanane and stilbene compounds Technical Field

[0001] This invention belongs to the field of medicine, specifically relating to a cycloheptenone adduct of flavanane and stilbene compounds, its synthesis method, and its use in treating ischemic cerebrovascular diseases. Background Technology

[0002] Ischemic cerebrovascular disease (ICVD) is a general term for cerebrovascular diseases of varying degrees, also known as ischemic brain disease. This disease has a high mortality rate during acute attacks and an extremely high rate of disability. [1] Currently, there are no highly effective treatments in clinical practice, and drug therapy has poor long-term efficacy and almost none of them can reduce neuronal damage. [2] Therefore, the development of highly effective and low-toxicity drugs for treating cerebral ischemia-reperfusion injury has always been a hot topic in the international pharmaceutical community.

[0003] Plant polyphenols are a collective term for a class of plant polyphenols containing di(tri)hydroxyphenyl structural fragments and their polymers. Studies have shown that this type of natural product has good antioxidant capacity, and its neuroprotective effects have received widespread attention and research. [3] Flavonoids (such as catechins and epicatechins) and stilbenes (such as resveratrol and stilbene) are two representative classes of plant polyphenols. Due to the tendency of plant polyphenols to polymerize, these two compounds can also react to form adducts. These adducts exhibit diverse linkages, forming complex structural frameworks. Pharmacological studies have shown that they possess neuroprotective, antioxidant, and antitumor activities. The low abundance of these compounds in plants results in high extraction and separation costs. Therefore, developing chemical synthesis methods for these components, especially biomimetic synthesis methods using flavanoids and stilbene units as substrates, is of great significance for new drug development. Summary of the Invention

[0004] The purpose of this invention is to provide a 5 / 6 / 7 tricyclic dimer compound in which flavananes and stilbene compounds are linked through a 2-cyclohepten-1-one skeleton.

[0005] Another object of the present invention is to provide a method for preparing such compounds.

[0006] Another object of the present invention is to provide a pharmaceutical composition comprising an adduct of an effective dose of a class of flavanes and stilbene compounds linked by a 2-cyclohepten-1-one skeleton, and a pharmaceutical carrier and / or excipient.

[0007] Another object of the present invention is to provide the use of an adduct of a class of flavananes and stilbene compounds linked by a 2-cyclohepten-1-one skeleton in the preparation of a medicament for the treatment and / or prevention of ischemic cerebrovascular diseases.

[0008] This invention provides the following technical solution:

[0009] The first aspect of this invention provides a class of 5 / 6 / 7 tricyclic cycloadducts of flavanes and stilbene compounds linked by a 2-cyclohepten-1-one skeleton, characterized in that they have the structure shown in general formula (I):

[0010]

[0011] in,

[0012] R A Selected from: hydrogen, hydroxyl group

[0013] R B Selected from hydrogen, hydroxyl, alkoxy, halogen, and cyano groups;

[0014] a is an integer selected from 0 to 5; b is an integer selected from 0 to 4; c is an integer selected from 0 to 5; d is an integer selected from 0 to 3.

[0015] Optionally, the halogen is selected from F, Cl, Br, and I;

[0016] Optionally, the alkyl group in "alkyl", "halogenated alkyl", or "alkyl sulfonyl" is C1-C2. 10 Straight-chain or branched alkyl groups, preferably C1-C7 straight-chain or branched alkyl groups, preferably C1-C5 straight-chain or branched alkyl groups, preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isopropyl... Hexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl.

[0017] Optionally, a is selected from an integer between 0 and 3; alternatively, a is 0, 1, 2, or 3.

[0018] Optionally, b is selected from an integer between 2 and 3; alternatively, b is 2 or 3.

[0019] Optionally, c is selected from an integer between 0 and 3; alternatively, c is 0, 1, 2, or 3.

[0020] Optionally, d can be 0, 1, 2, or 3.

[0021] Optionally, the compound with the structure shown in formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds:

[0022]

[0023] A second aspect of this invention provides a method for synthesizing a class of 5 / 6 / 7 tricyclic cycloadducts of flavanes and stilbene compounds linked by a 2-cyclohepten-1-one skeleton, the method comprising the following steps:

[0024] (1) Hydrobromic acid-catalyzed depolymerization into flavan monomer derivatives with thio groups at the 4-position.

[0025]

[0026] (2) Synthesis of an intermediate by silver trifluoroacetate-catalyzed substitution reaction of flavane linked at the 4-position to stilbene at the 2-position.

[0027]

[0028] (3) Synthesis of a class of 5 / 6 / 7 tricyclic cycloadducts of flavananes and stilbene compounds linked by a 2-cyclohepten-1-one skeleton using ferric iron or copper as catalysts.

[0029]

[0030] In each formula, R A R B The definitions of a, b, c, and d are as described above.

[0031] Further preparation methods include the following steps:

[0032] The dried rhizome of *Rhodiola rosea* was used as the primary medicinal material. The material was pulverized and extracted three times by reflux with 80% ethanol. The extracts were combined, filtered, and concentrated under reduced pressure to obtain an extract. After water precipitation, the precipitate was filtered, and the filtrate was concentrated under reduced pressure and then subjected to HP-20 macroporous adsorption resin column chromatography. Elution was performed using three gradients: pure water, 50% ethanol, and 95% ethanol. The eluent from the 50% ethanol fraction was concentrated under reduced pressure and freeze-dried to obtain the flavane polymer fraction of *Rhodiola rosea* (see Chinese Patent CN201010587820.7). This fraction was dissolved in methanol, and benzyl thiol, a thiopolymerization depolymerization reagent, and 48% hydrobromic acid aqueous solution were added. The reaction was carried out at 60°C for 6 hours to obtain benzyl thio-substituted flavane monomers. The benzyl thio-substituted flavane monomers were dissolved in ultra-dry N,N-dimethylformamide, stirred at -10°C, and then excess stilbene with different substituted styrene and silver trifluoroacetate were added sequentially. The reaction was stirred for 2 hours to obtain a flavane-stilbene coupling intermediate. The flavan stilbene coupling intermediate was dissolved in water, and copper sulfate pentahydrate was added and stirred at room temperature for 2 hours to obtain the target product.

[0033] A third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) having an effective dose of a drug, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

[0034] Typically, the pharmaceutical composition contains 0.1-95% by weight of a compound with the structure shown in formula (I) or a pharmaceutically acceptable salt thereof. In unit dosage forms, the compound of the present invention generally contains 0.1-100 mg, and in preferred unit dosage forms, the compound of the present invention generally contains 4-150 mg.

[0035] Pharmaceutical compositions of the compounds of the present invention can be prepared according to methods known in the art. For this purpose, if desired, the compounds of the present invention can be combined with one or more solid or liquid pharmaceutical excipients and / or adjuvants to formulate suitable administration or dosage forms for use as human or veterinary medicine.

[0036] The compounds of this invention or pharmaceutical compositions containing them can be administered in unit dose form via enteral or non-enteric routes, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum, or rectum.

[0037] The compounds of this invention or pharmaceutical compositions containing them can be administered via injection. Injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, and acupoint injection, etc.

[0038] The dosage form can be liquid or solid. Liquid dosage forms include true solutions, colloids, microparticles, emulsions, and suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, and lyophilized powders for injection. Tablets, capsules, pills, granules, oral liquids, and suspensions are preferred.

[0039] The compounds of this invention can be formulated into conventional formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0040] For example, various carriers known in the art can be widely used to formulate unit-dose dosage forms into tablets. Examples of carriers include diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and aluminum silicate; humectants and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrants such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, methylcellulose, and ethylcellulose; disintegration inhibitors such as sucrose, tristearate, cocoa butter, and hydrogenated oil; absorption promoters such as quaternary ammonium salts and sodium dodecyl sulfate; and lubricants such as talc, silica, corn starch, stearates, boric acid, liquid paraffin, and polyethylene glycol. Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0041] For example, various carriers known in the art can be widely used to formulate the drug delivery unit into pills. Examples of carriers include diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, glyceryl monostearate, kaolin, talc, etc.; binders such as gum arabic, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste, or flour paste, etc.; and disintegrants such as agar powder, dried starch, alginate, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc.

[0042] For example, to formulate the drug delivery unit into a capsule, the active ingredient, the compound of the present invention, is mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin capsule or a soft capsule. Alternatively, the active ingredient, the compound of the present invention, can be formulated as a microcapsule, suspended in an aqueous medium to form a suspension, or filled into a hard capsule or formulated as an injectable preparation for use.

[0043] For example, the compounds of this invention can be formulated into injectable formulations, such as solutions, suspensions, emulsions, and lyophilized powders for injection. These formulations can be aqueous or non-aqueous and may contain one or more pharmacodynamically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants, or dispersants. Diluents may be selected from water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxyethylene isostearyl alcohol, polyoxyethylene sorbitan esters, fatty acid esters, etc. Furthermore, to prepare isotonic injections, appropriate amounts of sodium chloride, glucose, or glycerol can be added to the injectable formulations. In addition, conventional solubilizers, buffers, pH adjusters, etc., may also be added. These excipients are commonly used in the art.

[0044] In addition, colorants, preservatives, flavorings, tasters, sweeteners or other materials may be added to pharmaceutical preparations if necessary.

[0045] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0046] The dosage of the pharmaceutical composition of the present invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the frequency of administration, and the therapeutic purpose. Therefore, the therapeutic dosage of the present invention can vary widely. Generally speaking, the dosage of the pharmaceutical components used in the present invention is well known to those skilled in the art. The actual amount of drug contained in the final formulation of the compound composition of the present invention can be appropriately adjusted to achieve the required therapeutic dose and fulfill the preventive or therapeutic purpose of the present invention. The suitable daily dosage range of the compounds of the present invention is: 0.001-100 mg / kg body weight, preferably 0.1-60 mg / kg body weight, more preferably 1-30 mg / kg body weight, and most preferably 2-15 mg / kg body weight. For adult patients, the daily dosage of the compounds of the present invention is 10-500 mg, preferably 20-100 mg, which can be taken once or divided into 2-3 doses; for children, the dosage is 5-30 mg / kg body weight, preferably 10-20 mg / kg body weight. The above dosage can be administered as a single dose or divided into several doses, such as two, three, or four doses, depending on the clinical experience of the attending physician and the dosing regimen of the treatment. The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs.

[0047] The fourth aspect of this invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for the prevention and / or treatment of ischemic cerebrovascular diseases. Optionally, the product is selected from pharmaceuticals and health products.

[0048] Beneficial effects:

[0049] 1. The present invention provides a class of 5 / 6 / 7 tricyclic cycloadducts of flavanes and stilbene compounds linked by a 2-cyclohepten-1-one skeleton, which have the potential to be further developed into new drugs for treating cerebral ischemia.

[0050] 2. The synthetic route of the 5 / 6 / 7 tricyclic cycloadduct of a class of flavanes and stilbene compounds linked by a 2-cyclohepten-1-one skeleton is mature, simple and easy to obtain.

[0051] 3. The method for preparing a class of flavanes and stilbene compounds linked by a 2-cyclohepten-1-one skeleton, a 5 / 6 / 7 tricyclic cycloadduct, is simple, has good stereoselectivity, and is easy to separate.

[0052] 4. The 5 / 6 / 7 tricyclic cycloadduct of flavanes and stilbene compounds of the present invention, which are linked by a 2-cyclohepten-1-one skeleton, has good anti-cerebral ischemia activity, and the anti-cerebral ischemia activity of this type of compound has not been reported before. Attached Figure Description

[0053] Figure 1 is a schematic diagram of the effect of compound 1 on the behavior of rats after middle cerebral artery occlusion injury (mean±SD);

[0054] Figure 2 is a schematic diagram showing the effect of compound 1 on the infarct volume (mean ± SD) in rats with middle cerebral artery occlusion. Detailed Implementation

[0055] The following will provide further details with specific examples, but the scope of protection of this invention is not limited thereto:

[0056] Example 1: Synthesis of Compound 1, with the following molecular structure:

[0057]

[0058] The preparation and detection of compound 1 are as follows:

[0059] 1. Obtaining the flavanane polymer fraction from Rhodiola rosea

[0060] The dried rhizomes of Rhodiola rosea were used as the primary drug. After being pulverized, they were extracted three times by reflux with 80% ethanol. The extracts were combined, filtered, and concentrated under reduced pressure to obtain an extract. After water precipitation, the precipitate was filtered, and the filtrate was concentrated under reduced pressure and then separated by HP-20 macroporous adsorption resin. The elution was carried out using three gradients: pure water, 50% ethanol, and 95% ethanol. The eluent of 50% ethanol was concentrated under reduced pressure and then freeze-dried to obtain the flavane polymer fraction of Rhodiola rosea (see Chinese Patent CN201010587820.7 for details).

[0061] 2. Synthesis of intermediate compound 1-1.

[0062]

[0063] A certain amount of the flavanane polymer fraction of Rhodiola rosea was dissolved in anhydrous methanol at a mass ratio of 1:30. A corresponding thioretin reagent was added at a mass ratio of 1:0.5, and a 48% HBr aqueous solution was added at a mass ratio of 1:0.5. The mixture was reacted at 60℃ for 4 hours. Distilled water at a mass ratio of 3:1 was added to the reaction solution for suspension. The mixture was extracted three times with ethyl acetate, and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then, reversed-phase rapid preparative column chromatography was performed sequentially. High-performance liquid chromatography (HPLC) at 60% (methanol / water volume ratio) yielded 4-(S)-(benzylthio)-epicatechin gallate, a white powder, as shown in Formula 1-1, with a yield of 41.5%.

[0064] HRESIMS(m / z 563.1018[MH]-,calcd,563.1012); 1 H NMR (500MHz, CD3OD)δ H :7.45-7.48(m,2H,2″′,6″′-H),7.28-7.33(m,2H,3″′,5″′-H),7.20′7.25(m,1H,4″′-H) ,6.90(s,2H,2″,6″-H),6.89(brs,1H,2′-H),6.67-6.71(m,2H,5′,6′-H),5.94(d,J=2.0H z,1H,8-H),5.93(d,J=2.0Hz,1H,6-H),5.49(brs,1H,2-H),5.38(dd,J=2.5,1.0Hz,1H,3 -H), 4.16 (d, J = 2.0Hz, 1H, 4-H), 4.11 (d, J = 13.5Hz, 1H, SCH), 4.03 (d, J = 13.5Hz, 1H, SCH).

[0065] 3. Synthesis of intermediate compound 2-1.

[0066]

[0067] 564 mg (1 mmol) of 4-benzylthioepicatechin gallate (compound 1-1) was weighed into a 100 mL round-bottom flask, and then 20 mL of N,N-dimethylformamide was added. After stirring and dissolving, 1220 mg (5 mmol) of paclitaxel and 1100 mg (5 mmol) of silver trifluoroacetate were added sequentially at -10 °C. The mixture was stirred at -10 °C for 4 h, and the reaction was monitored by high performance liquid chromatography (HPLC) to indicate completion. The reaction was terminated by adding 400 mL of distilled water to the reaction solution. The mixture was extracted with ethyl acetate (400 mL × 3 times), and the organic layers were combined. The organic layers were washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and separated by reversed-phase rapid preparative column chromatography (acetonitrile:water = 25:75) to obtain 233.9 mg of the product, with a yield of 34.2%.

[0068] HRESIMS (m / z 685.1551 [M+H]) + ,calcd,685.1552); 1 H NMR (500MHz, DMSO-d6)δ H :5.51(1H,brs,2-H),5.25(1H,m,3-H),4.59(1H,brs,4-H),5.74(1H,d,J=2.0Hz,6-H),5.97(1H,d,J=2.0Hz, 8-H),6.49(1H,d,J=2.0Hz,2′-H),6.72(1H,overlap,5′-H),6.66(1H,overlap,6′-H),6.88(2H,brs,2″,6″- H),6.08(1H,d,J=2.5Hz,4″′-H),6.31(1H,brs,6″′-H),7.62(1H,d,J=16.0Hz,7″′-H),6.45(1H,d,J=16.0Hz ,8″′-H),6.89(1H,d,J=8.5Hz,10″′-H),6.59(1H,overlap,13″′-H),7.00(1H,dd,J=2.0Hz,8.5Hz,14″′-H); 13 C NMR (125MHz, DMSO-d6)δ C:74.4(C-2),72.7(C-3),34.8(C-4),157.6(C-5),94.8(C-6),157.2(C-7),95.3(C-8),156.3(C-9),101.3(C-10),130.8(C-1 ′),115.8(C-2′),144.8(C-3′),145.0(C-4′),117.4(C-5′),119.1(C-6′),144.5(C-1″),108.8(C-2″,6″),146.4(C-3″,5″), 140.0(C-4″),165.3(C=O),142.5(C-1″′),117.4(C-2″′),156.8(C-3″′),103.0(C-4″′),156.4(C-5″′),105.3(C-6″′),125. 0(C-7″′), 129.7(C-8″′), 129.5(C-9″′), 115.1(C-10″′), 145.2(C-11″′), 145.5(C-12″′), 116.0(C-13″′), 119.5(C-14″′).

[0069] 4. Synthesis of Compound 1.

[0070]

[0071] 1231 mg (1.8 mmol) of compound 2-1 was weighed into a 250 mL round-bottom flask, and then 100 mL of distilled water was added. After stirring to dissolve, an aqueous solution of copper sulfate pentahydrate [153.4 mg (0.9 mmol) dissolved in 15 mL of distilled water] was added dropwise. The reaction was stirred at room temperature for 5 h, and the reaction was monitored by high performance liquid chromatography (HPLC) to indicate completion. The product was extracted with ethyl acetate (100 mL × 3 times), and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and separated by reversed-phase rapid preparative column chromatography (methanol:water = 25:75) to obtain 910 mg of the product, with a yield of 77.1%.

[0072] HRESIMS (m / z 657.1597 [M+H]) + ,calcd,657.1530); 1 H NMR (500MHz, DMSO-d6)δ H:5.14(2H,brs,2,3-H),3.81(1H,m,4-H),2.30(1H,d,J=13.5Hz,6a-H),3.31(1H,overlap,6b-H)5.58(1H,brs,8-H ),4.20(1H,td,J=10.0Hz,10.0Hz,10-H),6.80(1H,d,J=2.0Hz,2′-H),6.59(1H,overlap,5′-H),6.66(1H,overlap, 6′-H),6.79(2H,brs,2″,6″-H),5.93(1H,d,J=2.5Hz,4″′-H),5.69(1H,brs,6″′-H),3.81(1H,overlap,7″′-H),3.1 1(1H,m,8″′-H),6.65(1H,overlap,10″′-H),6.72(1H,d,J=8.5Hz,13″′-H),6.56(1H,dd,J=2.0Hz,8.5Hz,14″′-H); 13 C NMR (125MHz, DMSO-d6)δ C :80.9(C-2),71.9(C-3),43.1(C-4),50.5(C-6),197.1(C-7),111.0(C-8),175.9(C-9),46.0(C-10),138.1(C-1′),115. 7(C-2′),145.1(C-3′),145.2(C-4′),117.6(C-5′),119.3(C-6′),145.3(C-1″),108.8(C-2″,6″),145.5(C-3″,5″),138. 1(C-4″),164.3(C=O),143.9(C-1″′),135.7(C-2″′),154.8(C-3″′),100.9(C-4″′),158.2(C-5″′),101.1(C-6″′),55.1( C-7″′), 50.5(C-8″′), 127.9(C-9″′), 117.6(C-10″′), 145.6(C-11″′), 145.5(C-12″′), 118.5(C-13″′), 119.3(C-14″′).

[0073] Example 2: Synthesis of Compound 2, with the following molecular structure:

[0074]

[0075] The preparation and detection of compound 2 are as follows:

[0076] 1. Obtaining the flavanane polymer fraction of Rhodiola rosea, the synthesis of intermediate compound 1-1, and the synthesis of intermediate compound 2-1 are the same as in Example 1.

[0077] 2. Synthesis of intermediate 3-1

[0078]

[0079] 100 mg of compound 2-1 was weighed into a 50 mL round-bottom flask, 10 mL of distilled water was added, and the mixture was stirred to dissolve. After argon purging protection, 10 mg of tanninase was added at room temperature. The mixture was stirred at room temperature for 2 h, and the reaction was monitored by HPLC to indicate completion. The reaction solution was directly freeze-dried and separated by reversed-phase rapid preparative column chromatography (acetonitrile:water = 25:75) to obtain 69.6 mg of the product, with a yield of 89.5%.

[0080] HRESIMS(m / z 533.1309[M+H] + ,calcd,533.1369); 1 H NMR (500MHz, DMSO-d6)δ H :4.68(1H,d,J=5.0Hz,2-H),3.65(1H,m,3-H),4.49(1H,d,J=2.0Hz,4-H),5.83(1H,d,J=2.0Hz,6-H),5.90(1H ,d,J=2.0Hz,8-H),6.57(1H,d,J=2.0Hz,2′-H),6.70(1H,overlap,5′-H),6.41(1H,dd,J=2.0Hz,8.5Hz,6′-H) ,6.27(1H,d,J=2.5Hz,4″′-H),6.29(1H,d,J=2.5Hz,6″′-H),6.57(1H,d,J=16.0Hz,7″′-H),6.34(1H,d,J=16. 0Hz, 8″′-H), 6.53 (1H, overlap, 10″′-H), 6.70 (1H, overlap, 13″′-H), 6.38 (1H, dd, J = 2.0Hz, 8.5Hz, 14″′-H); 13 CNMR (125MHz, DMSO-d6)δ C:75.2(C-2),71.5(C-3),37.9(C-4),16.2(C-5),94.8(C-6),156.7(C-7),95.4(C-8),156.9(C-9),102.6 (C-10),130.9(C-1′),115.2(C-2′),145.1(C-3′),145.0(C-4′),117.4(C-5′),118.1(C-6′),139.8(C-1″ ′),116.0(C-2″′),157.3(C-3″′),105.4(C-4″′),157.2(C-5″′),103.4(C-6″′),125.8(C-7″′),124.5(C -8″′), 129.2(C-9″′), 115.4(C-10″′), 145.9(C-11″′), 145.8(C-12″′), 115.0(C-13″′), 119.1(C-14″′).

[0081] 5. Synthesis of Compound 2

[0082]

[0083] 86 mg (0.16 mmol) of compound 3-1 was weighed into a 50 mL round-bottom flask, and 15 mL of H2O was added. After stirring to dissolve, an aqueous solution of copper sulfate pentahydrate was added dropwise [20.0 mg (0.08 mmol) dissolved in 5 mL of H2O]. The reaction was stirred at room temperature for 4 h, and the reaction was monitored by high-performance liquid chromatography (HPLC) to indicate completion. The product precipitated as a white solid. After filtration and washing, 31.2 mg of crude product was obtained. The mother liquor was extracted with ethyl acetate (50 mL × 3 times). The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and combined with the filter residue. The mixture was then separated by reversed-phase rapid preparative column chromatography (methanol:water = 50:50) to obtain 28.0 mg of product, with a yield of 35.7%.

[0084] HRESIMS (m / z 505.1495 [M+H]) + ,calcd,505.1420); 1 H NMR (500MHz, DMSO-d6)δ H:5.44(1H,brs,2-H),4.11(2H,td,J=10.0Hz,10.0Hz,2.0Hz,3-H),3.64(1H,overlap,4-H),2.23(1H,m,6a-H),3.23( 1H,dd,J=13.0Hz,8.0Hz,6b-H),5.67(1H,brs,8-H),3.08(1H,m,10-H),6.78(1H,d,J=2.0Hz,2′-H),6.69(1H,overla p,5′-H),6.68(1H,overlap,6′-H),6.01(1H,d,J=2.5Hz,4″′-H),6.17(1H,brs,6″′-H),3.45(1H,m,7″′-H),3.69(1H ,overlap,8″′-H),6.57(1H,d,J=2.5Hz,10″′-H),6.64(1H,overlap,13″′-H),6.47(1H,dd,J=2.5Hz,8.5Hz,14″′-H); 13 C NMR (125MHz, DMSO-d6)δ C :83.2(C-2),72.5(C-3),45.9(C-4),45.4(C-6),197.5(C-7),102.7(C-8),177.3(C-9),51.0(C-10), 128.7(C-1′),115.6(C-2′),145.5(C-3′),145.8(C-4′),116.2(C-5′),118.8(C-6′),147.8(C-1″′),1 27.8(C-2″′),154.7(C-3″′),101.8(C-4″′),159.0(C-5″′),107.4(C-6″′),56.3(C-7″′),44.7(C-8″ ′), 133.9(C-9″′), 115.9(C-10″′), 145.5(C-11″′), 144.3(C-12″′), 116.2(C-13″′), 120.0(C-14″′).

[0085] Example 3: Synthesis of compound 3, with the following molecular structure:

[0086]

[0087] The preparation and detection of compound 3 are as follows:

[0088] 1. Obtaining the flavanane polymer fraction of Rhodiola rosea, and synthesizing intermediate compound 1-1 as in Example 1.

[0089] 2. Synthesis of Compound 3

[0090] Weigh 564 mg (1 mmol) of 4-benzylthioepicatechin gallate (compound 1-1) into a 100 mL round-bottom flask, then add 20 mL of N,N-dimethylformamide. After stirring to dissolve, add 1300 mg (5 mmol) of 5-[(1E)-2-(3,5-dihydroxyphenyl)vinyl]-1,2,3-benzylpyrogallol and 1100 mg (5 mmol) of silver trifluoroacetate sequentially at -10 °C. After stirring at -10 °C for 4 h, add 100 mL of distilled water and 62.4 mg (0.25 mmol) of copper sulfate pentahydrate directly to the reaction solution without monitoring. Stir at room temperature for 2 h and monitor the reaction to ensure it is complete using high performance liquid chromatography. Extracted with ethyl acetate (400 mL × 3 times), the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and separated by reversed-phase rapid preparative column chromatography (methanol:water = 25:75) to obtain 75.3 mg of product, with an overall yield of 11.2% for both steps.

[0091] HRESIMS (m / z 673.1550 [M+H]) + ,calcd,673.1552); 1 H NMR (500MHz, DMSO-d6)δ H :5.13(1H,overlap,2-H),5.13(1H,overlap,3-H),4.18(1H,t,J=9.0Hz,4-H),2.30(1H,d,6a-H),3.29(1H, dd,J=13.0Hz,7.5Hz,6b-H),5.72(1H,brs,8-H),3.01(1H,t,J=9.0Hz,10-H),6.79(1H,overlap,2′-H),6.6 4(1H,J=8.0Hz,2.0Hz,5′-H),6.59(1H,J=8.0Hz,6′-H),6.79(2H,overlap,4″,6″-H),5.58(1H,brs,6″′-H) ,3.76(1H,m,7″′-H),3.81(1H,overlap,8″′-H),6.21(2H,brs,10″′,14″′-H),5.93(1H,J=8.0Hz,12″′-H); 13 C NMR (125MHz, DMSO-d6)δ C:84.4(C-2),79.6(C-3),46.0(C-4),50.5(C-6),197.1(C-7),101.0(C-8),175.9(C-9),55.0(C-10),127.9(C-1′),114.5(C-2 ′),145.2(C-3′),145.2(C-4′),116.2(C-5′),115.0(C-6′),164.3(OC=O),120.0(C-1″),108.9(C-2″),145.5(C-3″),138.2(C- 4″),116.2(C-5″),108.9(C-6″),135.0(C-1″′),119.3(C-2″′),145.1(C-3″′),131.6(C-4″′),147.8(C-5″′),111.0(C-6″′), 56.8(C-7″′), 45.0(C-8″′), 145.7(C-9″′), 106.3(C-10″′), 154.8(C-11″′), 101.2(C-12″′), 158.3(C-13″′), 106.3(C-14″′).

[0092] Example 4: Synthesis of compound 4, with the following molecular structure:

[0093]

[0094] The preparation and detection of compound 4 are as follows:

[0095] 1. Obtaining the flavanane polymer fraction of Rhodiola rosea, and synthesizing intermediate compound 1-1 as in Example 1.

[0096] 2. Synthesis of intermediate compound 4-1.

[0097]

[0098] 564 mg (1 mmol) of 4-benzylthioepicatechin gallate (compound 1-1) was weighed into a 100 mL round-bottom flask, and then 20 mL of N,N-dimethylformamide was added. After stirring and dissolving, 1140 mg (5 mmol) of resveratrol and 1100 mg (5 mmol) of silver trifluoroacetate were added sequentially at -10 °C. The mixture was stirred at -10 °C for 4 h, and the reaction was monitored by high performance liquid chromatography (HPLC) to indicate completion. The reaction was terminated by adding 400 mL of distilled water to the reaction solution. The mixture was extracted with ethyl acetate (400 mL × 3 times), and the organic layers were combined. The organic layers were washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and separated by reversed-phase rapid preparative column chromatography (acetonitrile:water = 25:75) to obtain 278.6 mg of the product, with a yield of 41.7%.

[0099] HRESIMS (m / z 669.1602[M+H]) + ,calcd,669.1603); 1 H NMR (500MHz, DMSO-d6)δ H :5.51(1H,brs,2-H),5.24(1H,m,3-H),4.58(1H,brs,4-H),5.84(1H,d,J=2.0Hz,6-H),5.99(1H,d,J=2. 0Hz,8-H),6.49(1H,overlap,2′-H),6.74(1H,overlap,5′-H),6.66(1H,dd,J=8.0Hz,2.0Hz,6′-H),6.90 (2H,brs,2″,6″-H),6.49(1H,d,J=2.5Hz,4″′-H),6.61(1H,brs,6″′-H),7.68(1H,d,J=15.0Hz,7″′-H), 6.69(1H,d,J=15.0Hz,8″′-H),7.43(2H,d,J=8.5Hz,10″′,14″′-H),6.77(2H,d,J=8.5Hz,11″′,13″′-H); 13 C NMR (125MHz, DMSO-d6)δ C:73.9(C-2),72.5(C-3),36.0(C-4),156.9(C-5),94.5(C-6),157.2(C-7),95.9(C-8),155.9(C-9),101.5(C-10),130.3(C-1 ′),114.0(C-2′),144.6(C-3′),144.9(C-4′),115.2(C-5′),117.1(C-6′),119.5(C-1″),108.7(C-2″,6″),145.5(C-3″,5″), 139.9(C-4″),165.5(C=O),138.9(C-1″′),117.4(C-2″′),156.4(C-3″′),103.2(C-4″′),156.6(C-5″′),105.2(C-6″′),125. 0(C-7″′), 128.6(C-8″′), 129.5(C-9″′), 128.0(C-10″′), 115.6(C-11″′), 157.3(C-12″′), 115.6(C-13″′), 128.0(C-14″′).

[0100] 3. Synthesis of compound 4.

[0101]

[0102] 1202 mg (1.8 mmol) of compound 4-1 was weighed into a 250 mL round-bottom flask, and then 100 mL of distilled water was added. After stirring to dissolve, an aqueous solution of ferric chloride hexahydrate [243.3 mg (0.9 mmol) dissolved in 15 mL of distilled water] was added dropwise. The reaction was stirred at 35 °C for 22 h, and the reaction was monitored by high performance liquid chromatography (HPLC) to indicate completion. The product was extracted with ethyl acetate (100 mL × 3 times), and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and separated by reversed-phase rapid preparative column chromatography (methanol:water = 25:75) to obtain 186.6 mg of the product, with a yield of 16.2%.

[0103] HRESIMS (m / z 641.1654 [M+H]) + ,calcd,641.1640); 1 H NMR (500MHz, DMSO-d6)δ H:5.15(2H,brs,2,3-H),3.82(1H,s,4-H),2.29(1H,d,J=13.5Hz,6a-H),3.33(1H,overlap,6b-H)5.58(1H,brs ,8-H),4.21(1H,td,J=10.0Hz,2.0Hz,10-H),6.83(1H,d,J=2.0Hz,2′-H),6.58(1H,overlap,5′-H),6.66(1H,o verlap,6′-H),6.78(2H,brs,2″,6″-H),5.92(1H,d,J=2.0Hz,4″′-H),5.65(1H,d,J=2.0Hz,6″′-H),3.82(1H,o verlap,7″′-H),3.19(1H,m,8″′-H),7.08(2H,d,J=8.5Hz,10″′,14″′-H),6.76(2H,d,J=8.5Hz,11″′,13″′-H); 13 C NMR (125MHz, DMSO-d6)δ C :80.9(C-2),72.1(C-3),44.7(C-4),46.1(C-6),197.1(C-7),101.0(C-8),176.0(C-9),46.0(C-10),127.9(C-1′), 114.7(C-2′),145.1(C-3′),145.6(C-4′),114.9(C-5′),117.6(C-6′),119.4(C-1″),108.85(C-2″,6″),145.2(C-3 ″,5″),145.02(C-4″),164.3(C=O),128.8(C-1″′),119.6(C-2″),154.8(C-3″),100.9(C-4″′),156.0(C-5″′),110. 9(C-6″′), 50.4(C-7″′), 43.3(C-8″′), 135.0(C-9″′), 128.8(C-10″′,14″′), 115.5(C-11″′,13″′), 158.2(C-12″′).

[0104] Experimental Example 1: In vitro screening model: Screening for protective activity against neuronal cell damage induced by glutamate or hydrogen peroxide

[0105] L-Glutamate is a major excitatory neurotransmitter in the central nervous system, distributed in neurons of the cerebral cortex and hippocampus. Elevated glutamate levels can act as a neurotoxin, inducing severe neuronal damage. Glutamate-mediated overactivation or overstimulation of neurons can lead to cell death. Hydrogen peroxide is a strong oxidant that generates hydroxyl radicals, causing lipid peroxidation and amplifying free radical reactions, resulting in cell damage. Glutamate- or hydrogen peroxide-induced neuronal damage models have become effective research models for neuronal damage, contributing to the exploration of the neuroprotective effects and mechanisms of cycloheptenone, a class of flavanols and stilbene adducts, and its synthetic intermediates, as described in this invention.

[0106] 1. Materials and Methods

[0107] 1.1 Materials

[0108] Fetal bovine serum (FCS) and DMEM glucose-free culture medium were Invitrogen products; trypsin was purchased from Gibco; centrifuge tubes, 96-well cell culture plates, cell culture dishes, and cell culture flasks were Corning products; coverslips were DIAMOND products; and dimethyl sulfoxide was a product of Sinopharm Group. All other reagents were purchased from Sigma.

[0109] 1.2 Methods

[0110] PC-12 cells were grown at a concentration of 1.5 × 10⁻⁶. 4 Cells were seeded at a density of 100 μL / well in 96 culture plates. The experiment was divided into a blank group, a model group, a drug-treated group, and a positive control group. Before oxygen and glucose deprivation, the incubator was set to equilibration at 94% N2, 5% CO2, 1% O2, and 37℃ for 1 h. The original cell culture medium was discarded, and an equal volume of preheated sugar-free DMEM medium was added. The cells were then placed in an anoxic incubator for 2 h. Reoxygenation and glucose treatment were then performed under normal culture conditions. Simultaneously, 10 μM of the compound or edaravone was added to the drug-treated and positive control groups, while an equal volume of culture medium was added to the model group. Changes in cell morphology and viability were observed at 2 h of oxygen and glucose deprivation and at different time points after reoxygenation and reoxygenation.

[0111] PC-12 cells were grown at a concentration of 1.5 × 10⁻⁶. 4 At a density of 100 μL / mL, ELISA was seeded into each well of a 96 culture plate. The experiment was divided into a blank group, a model group, a drug-treated group, and a positive control group. Models were established for 2 hours using 120 μM H₂O₂ and 8 mM glutamate, respectively. The blank group was then cultured in complete culture medium, the positive control group was treated with 10 μM edaravone, and the drug-treated group was treated with 10 μM of the test compound. After incubation for 24 hours, 10 μL of CCK-8 was added to each well. The absorbance at 490 nm was measured using a microplate reader after 60 minutes, and the survival rate was calculated.

[0112] 2 Results

[0113] In vitro pharmacological experiments showed that most of these compounds and their intermediates possess neuroprotective activity. Among them, the flavan-stilbene adduct 1, with a 2-cyclohepten-1-one structure, exhibited good protective effects against glutamate and hydrogen peroxide-induced cell damage, increasing cell survival rates by 15.73% and 31.64%, respectively. Survival rate increase = (survival rate of the treated group - survival rate of the model group) / (survival rate of the model group). The structures and pharmacological activities of some of the more active compounds are shown in the table below.

[0114]

[0115] Table 1. Screening results of in vitro neuroprotective activity

[0116]

[0117] Experimental Example 2: In vivo screening model: Study on its preventive and therapeutic effects on cerebral ischemia-reperfusion injury.

[0118] The middle cerebral artery occlusion model is a classic animal model for studying ischemic stroke. This model involves inserting a suture through the internal carotid artery into the skull to block the blood supply to the contralateral anterior communicating artery of the brain, thus blocking the blood supply to the middle cerebral artery. This experiment has the advantages of being non-invasive, having a proven track record, and allowing for precise control of ischemia and reperfusion time.

[0119] 1. Materials and Methods

[0120] 1.1 Materials

[0121] (1) Test sample: Compound 1. Purity ≥90%, yellow solid powder, 560 mg in total, readily soluble in dimethyl sulfoxide (DMSO).

[0122] (2) Reagent: 2% TTC staining solution, purchased from Shanghai Yuanye Biotechnology Co., Ltd.

[0123] (3) Animals: 280-300g male SD rats, SPF grade, purchased from Spiford (Beijing) Biotechnology Co., Ltd.

[0124] (4) Equipment: rat operating table, surgical instruments, nylon suture plug (0.24 mm in diameter), sutures, etc.

[0125] 1.2 Methods

[0126] Middle cerebral artery occlusion model

[0127] The experimental subjects were male SD rats (280-300g). After anesthetizing the rats with isoflurane, the skin and subcutaneous tissue were cut along the midline of the neck to expose the ECA, CCA, and ICA vessels. Surgical sutures were used to ligate the proximal end of the CCA and the distal end of the ECA. Simultaneously, a slipknot was tied near the bifurcation of the ICA and ECA using surgical sutures, and the ICA was clamped with an arterial clamp. Then, an incision was made between the two ligatures on the ECA using microscissors. A suture plug (0.36±0.02mm in diameter) was gently inserted into the lumen of the ICA from the ECA to a position of approximately 18mm, blocking the blood flow on the contralateral side of the middle cerebral artery and inducing ischemia. After 90 minutes of ischemia, the suture plug was removed, and the neck was sutured. The sham group (Sham group) underwent the same surgical procedures except that the embolization procedure was not performed. After the rats regained consciousness, their neurological function was assessed. Rats without neurological deficits or subarachnoid hemorrhage were removed. The remaining rats were randomly divided into two groups: the model group (Vehicle group) and the drug administration group (Compound 1 group). The drug administration group was administered Compound 1 (30 mg / kg) by gavage, while the sham-operated and model groups were administered the same volume of physiological saline by gavage. Throughout the ischemic phase, the rats were placed on warming pads to maintain a body temperature of 37°C.

[0128] 2. Rats' neurological deficit scores

[0129] On days 1, 3, and 7 after middle cerebral artery occlusion modeling, the Longa scale was used to assess neurological deficits in rats, classifying the degree of deficit into five levels: rats with scores of 0 or 4 (indicating unsuccessful modeling) were excluded, while those with scores of 1-3 (indicating successful modeling) were excluded. Throughout the experiment, a single-blind approach was used to avoid random error. The results are shown in Figure 1.

[0130] 3TTC staining

[0131] After anesthetizing rats, the rats were quickly decapitated and their brains removed. The brain tissue was placed in a brain mold for coronal sectioning, with each section 2 mm thick, for a total of 6 sections. The brain sections were placed in 2% TTC staining solution and incubated at 37°C in the dark for 10-15 minutes. The brain sections were then removed, fixed with 4% paraformaldehyde, and photographed. Active brain tissue contains dehydrogenases that reduce TTC to red, thus staining red. Infarcted brain tissue lacks dehydrogenase activity and is therefore not stained. Therefore, the stained sections show two colors: normal brain tissue appears red, and infarcted areas appear white. ImageJ software was used to process the images and calculate the infarct volume.

[0132] 2 Experimental Results

[0133] (1) The results of the rat neurological deficit score are shown in Figure 1. It shows that compared with the sham-operated group, the model group rats showed obvious neurological damage. After one week of continuous administration, compound 1 can effectively restore the nerve function of rats.

[0134] (2) The TTC staining results are shown in Figure 2, which show that compound 1 can significantly reduce the volume of cerebral infarction, indicating that it has good anti-ischemic stroke activity.

[0135] The above embodiments are not intended to limit the present invention, and the present invention is not limited to the above embodiments. Any embodiment that meets the requirements of the present invention is within the protection scope of the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that, (I) Among them, R A Selected from: hydrogen, hydroxyl group (II); R B The following are selected from hydrogen, hydroxyl, alkoxy, halogen, and cyano; a is an integer selected from 0 to 5; b is an integer selected from 0 to 4; c is an integer selected from 0 to 5; and d is an integer selected from 0 to 3.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The halogen is selected from F, Cl, Br, and I; the alkyl group in "alkoxy" is C1-C. 10 Straight-chain or branched alkyl groups.

3. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, The alkyl group in the "alkoxy group" is a C1-C7 straight-chain or branched alkyl group.

4. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, The alkyl group in the "alkoxy group" is a C1-C5 straight-chain or branched alkyl group.

5. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, The alkyl group in the "alkoxy group" is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl.

6. A compound of formula (I) according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, characterized in that, a is an integer from 0 to 3; b is an integer from 2 to 3; c is an integer from 0 to 3; d is 0, 1, 2 or 3.

7. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, characterized in that, a can be 0, 1, 2, or 3.

8. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, characterized in that, b is 2 or 3.

9. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, characterized in that, c can be 0, 1, 2, or 3.

10. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, characterized in that, d can be 0, 1, 2, or 3.

11. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Selected from the following compounds: 1 2 3 4 。 12. A method for preparing a compound of formula (I) according to any one of claims 1-11 or a pharmaceutically acceptable salt thereof, characterized in that, The process includes the following steps: (1) hydrobromic acid-catalyzed depolymerization into flavan monomer derivatives with thio groups linked at the 4-position. (2) Synthesis of an intermediate in which flavanane is linked to stilbene at the 4-position and stilbene at the 2-position via a silver trifluoroacetate-catalyzed substitution reaction. (3) Synthesis of a class of flavanes and stilbene compounds linked by a 2-cyclohepten-1-one skeleton via ferric iron or copper catalysis: 5 / 6 / 7 tricyclic cycloadducts In each formula, R A R B The definitions of a, b, c, and d are as described in any one of claims 1-11.

13. A pharmaceutical composition, characterized in that, A compound containing an effective dose of the structure of formula (I) as described in any one of claims 1-11, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

14. The pharmaceutical composition according to claim 13, characterized in that, The dosage form of the pharmaceutical composition is selected from tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, and lyophilized powder injections.

15. The pharmaceutical composition according to claim 13, characterized in that, The dosage form of the pharmaceutical composition is selected from tablets, capsules, pills, granules, oral liquids, and suspensions.

16. The use of a compound of formula (I) according to any one of claims 1-11 or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition according to any one of claims 13-15 in the preparation of a product for the prevention and / or treatment of ischemic cerebrovascular diseases.

17. The use according to claim 16, characterized in that, The ischemic cerebrovascular disease mentioned is ischemic stroke.

18. The use according to claim 16 or 17, characterized in that, The products mentioned are selected from pharmaceuticals and health products.

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