Preparation method of cyclopentenone compound and salt thereof and application of cyclopentenone compound and salt thereof in treatment of cerebral apoplexy

Abstract

The invention belongs to the technical field of pharmacy, and relates to cyclopentenone compounds as shown in a formula I, in particular to application of cyclopentenone sodium salt as a medicine for treating cerebrovascular diseases, a preparation method of the cyclopentenone compounds, a composition containing one or more of the compounds, and application of the compounds as the medicine for treating diseases related to blood-brain barriers, such as blood-brain-barrier diseases, blood-brain-barrier diseases and blood-brain-barrier diseases. The invention also relates to application in preparation, prevention and / or treatment of cerebral apoplexy.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology. Specifically, the present invention relates to a cyclopentenone compound shown in formula I or a pharmaceutically acceptable salt thereof, and a preparation method thereof, a composition containing one or more such compounds, and the use of such compounds in preventing and / or treating cerebrovascular-related diseases. Background Art

[0002] Cerebrovascular disease is a group of diseases that occur in the blood vessels of the brain and cause damage to brain tissue due to impaired intracranial blood circulation. "Cerebral vascular accident", "stroke" and "cerebral infarction" in our daily life are all cerebrovascular diseases. Deaths from cerebrovascular diseases account for 22% of the total number of deaths among Chinese residents, and stroke has become the leading cause of death and disability in my country. Acute cerebrovascular disease is generally divided into two categories: ischemic and hemorrhagic. Among new cases of stroke, 62.4% are ischemic strokes. Although intravenous thrombolysis with recombinant tissue plasminogen activator and surgical thrombectomy can reperfuse ischemic brain tissue in time, inflammatory factors, excitatory amino acids and other harmful substances produced during the reperfusion process can cause damage to the blood-brain barrier and excessive immune inflammatory response, further aggravating its pathological damage and causing ischemia-reperfusion injury. Dysfunction of the blood-brain barrier is a typical feature of stroke. After ischemia-reperfusion treatment, the destruction of the blood-brain barrier and the resulting hemorrhagic transformation, cerebral edema, and neuroinflammation are directly related to poor clinical prognosis and severe disability sequelae. Therefore, maintaining the stability of the blood-brain barrier structure, slowing down the progression of neuroinflammation, and preventing the process of damage, thereby providing long-term protection against neurological deficits, is expected to become a treatment strategy for acute ischemic stroke.

[0003] The invention discloses a cyclopentenone compound or a pharmaceutically acceptable salt thereof, and a preparation method thereof, and a composition containing one or more of the compounds. The cyclopentenone compounds have higher stability, better water solubility and better in vivo pharmacological activity. Summary of the invention

[0004] The object of the present invention is to provide a cyclopentenone compound or a pharmaceutically acceptable salt thereof for treating cerebrovascular diseases, and a preparation method and application thereof.

[0005] In order to solve the technical problem of the present invention, the technical solution of the present invention provides a compound having a cyclopentenone structural core as shown in formula (I) or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in:

[0008] R1 is selected from hydrogen, saccharide, C 1-5 Alkyl, C 3-5Alkenyl, C 3-6 Cycloalkyl;

[0009] Preferably, the sugar group described in R1 is selected from glucose, xylose, galactose, and rhamnose, and the C 1-5 The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl; the C 3-5 The alkenyl group is selected from propenyl, butenyl, pentenyl, isopentenyl; the C 3-6 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0010] R2 is selected from hydrogen, C 1-5 Alkyl, C 3-5 Alkenyl, C 3-6 Cycloalkyl, aryl, 5-6 membered heterocycloalkane or aromatic heterocycle, wherein the phenyl-containing group may be optionally substituted with halogen;

[0011] Preferably, R2 is C 1-5 The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl; the C 3-5 The alkenyl group is selected from propenyl, butenyl, pentenyl, isopentenyl, and the C 3-6 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; the aryl group is selected from phenyl, benzyl, styryl, or styryl; the 5-6 membered heterocycloalkane or aromatic heterocycle contains 1 or 2 heteroatoms or heteroatom groups independently selected from O, NH, S, C(=O), and N; the phenyl group may be optionally substituted with 1, 2, or 3 halogens, hydroxyl groups, or methoxy groups;

[0012] Specifically, the preferred compounds according to the present invention are as follows:

[0013] The first aspect of the technical solution of the present invention provides a method for preparing the compound, which comprises the following route:

[0014] Route 1

[0015]

[0016] R2 is selected from hydrogen, C 1-5 Alkyl, C 3-5 Alkenyl, C 3-6 Cycloalkyl, aryl, 5-6 membered heterocycloalkane or aromatic heterocycle, wherein the benzene-containing group may be optionally substituted by halogen

[0017] Step a: Compound A is dissolved in an alcohol solution, an alkaline substance is added, and the mixture is heated under reflux to obtain a cyclopentenone compound B.

[0018] The alcohol solution is methanol, ethanol or isopropanol, preferably methanol, and the material-liquid mass ratio is 1:0.1-10, preferably 1:5-7.

[0019] The alkaline substance is sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate, sodium tartrate, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium bicarbonate, ammonium bicarbonate, ammonium carbonate or ammonia, preferably sodium methoxide. The concentration of the alkaline substance is 1% to 50%, preferably 30% to 40%.

[0020] The heating reflux temperature is 30-100°C, preferably 60°C.

[0021] The cyclopentenone compounds are prepared by separating the reaction solution after conversion through gel column chromatography.

[0022] Route 2

[0023]

[0024] R1 is selected from hydrogen, saccharide, C 1-5 Alkyl, C 3-5 Alkenyl, C 3-6 Cycloalkyl

[0025] R2 is selected from hydrogen, C 1-5 Alkyl, C 3-5 Alkenyl, C 3-6 Cycloalkyl, aryl, 5-6 membered heterocycloalkane or aromatic heterocycle, X is selected from halogen, hydroxyl, methoxy

[0026] Step b: Compound C reacts with a halide to generate compound D;

[0027] Step c: Compound D is oxidatively dearomatized in air using a catalyst to generate compound E;

[0028] Step d: Compound E undergoes a ring contraction reaction under alkaline conditions to generate a cyclopentenone compound F;

[0029] Step e: When R2 contains an aromatic group, compound F undergoes aldol condensation with a corresponding aldehyde compound under alkaline conditions to generate compound G.

[0030] In the step b, the reaction solvent is an aqueous solution such as KOH, NaOH, Na2CO3, etc., with a mass fraction of 1 to 30%, the reaction temperature is 0 to 50°C, and the reaction time is 0 to 4h;

[0031] In the step c, the reaction catalyst is Pb(OAc)2, CuSO4, etc., the reaction solvent is anhydrous methanol, ethanol, isopropanol, the reaction temperature is 0-50°C, and the reaction time is 0-4h;

[0032] In the step d, the reaction solvent is an aqueous solution such as KOH, NaOH, Na2CO3, etc., with a mass fraction of 1 to 30%, the reaction temperature is 0 to 50°C, and the reaction time is 0 to 4h;

[0033] In the step e, the reaction solvent is an ethanol solution of Ba(OH)2, the reaction temperature is 0 to 50°C, and the reaction time is 0 to 4h;

[0034] The second aspect of the technical solution of the present invention provides the cyclopentenone compounds and pharmaceutically acceptable salts thereof described in the first aspect.

[0035] The pharmaceutically acceptable salt refers to a salt that is pharmaceutically acceptable and has the pharmacological activity required by the parent compound, and can be a monovalent salt or a divalent salt. The monovalent salt is a sodium salt, potassium salt, lithium salt or ammonium salt, and the divalent salt is a calcium salt or magnesium salt.

[0036] The cyclopentenone monovalent salt compound is prepared by subjecting the cyclopentenone compound to sodium, potassium, lithium or ammonium cation exchange resin column chromatography, and the obtained cyclopentenone monovalent salt compound fraction is purified by dextran gel to obtain the cyclopentenone monovalent salt compound.

[0037] The cyclopentenone divalent salt compound is prepared by subjecting the cyclopentenone compound to calcium-type or magnesium-type cation exchange resin column chromatography, and the obtained cyclopentenone divalent salt compound fraction is purified by dextran gel to obtain the cyclopentenone divalent salt compound.

[0038] The invention relates to an application of the cyclopentenone salt compound in preparing medicine for treating cerebrovascular diseases.

[0039] Another aspect of the present invention provides a pharmaceutical composition containing a cyclopentenone compound or a salt thereof as an active ingredient. The pharmaceutical composition can be prepared according to methods known in the art. The cyclopentenone compound or a salt thereof of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants to prepare any dosage form suitable for human or animal use. The content of the compound of the present invention in its pharmaceutical composition is usually 0.1 to 95% by weight.

[0040] The cyclopentenone compound or its salt or the pharmaceutical composition containing it can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, etc. The dosage form can be a liquid dosage form, a solid dosage form or a semisolid dosage form. The liquid dosage form can be a solution (including a true solution and a colloid solution), an emulsion (including an o / w type, a w / o type and a multiple emulsion), a suspension, an injection (including a water injection, a powder injection and an infusion), etc.; the solid dosage form can be a tablet (including a common tablet, an enteric-coated tablet, a lozenge), a capsule (including a hard capsule, a soft capsule, an enteric-coated capsule), a granule, a powder, a micropill, a dripping pill, a spray, a freeze-dried powder injection, etc.; the semisolid dosage form can be an ointment, a gel, a paste, etc.

[0041] The compounds of the present invention can be made into ordinary preparations, or sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle delivery systems. These preparations are prepared according to methods well known to those skilled in the art. The auxiliary materials used to make tablets, capsules and coatings are conventional auxiliary agents, such as starch, gelatin, gum arabic, silica, polyethylene glycol, and the solvents used in liquid dosage forms are, for example, water, ethanol, propylene glycol, and vegetable oils such as corn oil, peanut oil, olive oil, etc. The preparations containing the compounds of the present invention may also contain other auxiliary agents, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, pigments, etc.

[0042] In order to prepare the compound of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and glidants. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc. The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0043] In order to prepare the dosing unit into a capsule, the active ingredient compound of the present invention can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient compound of the present invention can also be first prepared into granules or pellets with a diluent, a binder, and a disintegrant, and then placed in a hard capsule or a soft capsule. The diluents, binders, wetting agents, disintegrants, and glidants used to prepare tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

[0044] To prepare the compound of the present invention into an injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent and an appropriate amount of a solubilizer, cosolvent, pH adjuster, and osmotic pressure regulator commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjuster can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. If a lyophilized powder injection is prepared, mannitol, glucose, etc. can also be added as a support agent.

[0045] In order to achieve the purpose of medication and enhance the therapeutic effect, the compound or pharmaceutical composition of the present invention can be administered by any known administration method.

[0046] The dosage of the pharmaceutical composition of the compound of the present invention can vary widely according to the nature and severity of the disease to be prevented or treated, the individual conditions of the patient or animal, the route of administration and the dosage form. Generally speaking, the suitable daily dosage range of the compound of the present invention is 0.01 to 500 mg / kg body weight, preferably 0.1 to 300 mg / kg body weight. The above dosage can be administered in one dosage unit or divided into several dosage units, depending on the doctor's clinical experience and the dosage regimen including the use of other treatment means.

[0047] The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0048] The technical solution of the present invention provides the use of the cyclopentenone compound or its salt described in the present invention in the preparation of a drug for preventing and / or treating diseases and conditions related to the blood-brain barrier. The use is characterized in that the diseases and conditions related to the blood-brain barrier are selected from ischemic stroke or hemorrhagic stroke. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1. Effect of compound 1 on the survival rate of rats with ischemia-reperfusion injury.

[0050] Figure 2.Effect of compound 1 on the recovery of neurological function in rats with ischemia-reperfusion injury. Neurological function scores were performed on the 1st, 3rd and 7th days, n=7, and the results are mean±SEM, *p<0.05 versus the model group.

[0051] Figure 3. Effect of compound 1 on blood-brain barrier permeability in rats with ischemia-reperfusion injury. A: Photo of rat slices after Evans blue staining; B: Evans blue content in rat brain, n=5, results are mean±SEM, **p<0.01 versus model group.

[0052] Figure 4. Effects of compound 1 on brain water content in rats with ischemia-reperfusion injury. n = 5, results are mean ± SEM, *p < 0.05 versus model group.

[0053] Figure 5. Compound 1 reduces cerebral infarction volume in rat ischemia-reperfusion injury model. A: TTC staining of rats at 7 days of ischemia; B: Calculation of cerebral infarction volume of rats at 7 days. (n=7, *p<0.05) DETAILED DESCRIPTION

[0054] The present invention is further described below by means of specific embodiments, but the protection scope of the present invention includes but is not limited to these.

[0055]

[0056] Example 1 Preparation of Sodium 2-p-Hydroxycinnamoyl-3,4-dihydroxy-5-(glucosyl)cyclopent-2-enone

[0057]

[0058] Take 10 g of hydroxysafflor yellow A and dissolve it in 600 mL of anhydrous methanol, add 25 g of sodium methoxide solution, stir at room temperature for 6 h, add water to terminate the reaction after the reaction is completed, use 1 M hydrochloric acid to adjust the pH to about 7.0, concentrate the reaction solution, purify it by dextran gel chromatography, and dry it under reduced pressure to obtain 6.5 g of crude 2-p-hydroxycinnamoyl-3,4-dihydroxy-5-(glucose)cyclopent-2-enone.

[0059] The crude product of 2-p-hydroxycinnamoyl-3,4-dihydroxy-5-(glucosyl)cyclopent-2-enone was dissolved in water, and then separated by dextran gel column chromatography, with pure water as the elution solvent. The eluate was collected and dried under reduced pressure to obtain the pure product of 2-p-hydroxycinnamoyl-3,4-dihydroxy-5-(glucosyl)cyclopent-2-enone with a purity of 99%. Take 5g of pure 2-hydroxycinnamoyl-3,4-dihydroxy-5-(glucose)cyclopent-2-enone and dissolve it in pure water. Then slowly add it to the treated and balanced sodium ion exchange resin. The column diameter-to-height ratio is 1:10, the column volume is 1000mL, and deionized water is used for elution at a flow rate of 10mL / min. Collect the fraction containing sodium 2-hydroxycinnamoyl-3,4-dihydroxy-5-(glucose)cyclopent-2-enone and slowly add it to the dextran gel chromatography column. The column diameter-to-height ratio is 1:12 and the loading flow rate is 10mL per minute. After loading, deionized water is used for elution at a flow rate of 20mL per minute. The eluate is concentrated under reduced pressure at 60°C to obtain the title compound with a purity of 98.5%.

[0060] Other cyclopentenone salt compounds can be prepared in the same way.

[0061] 1 H NMR (500 MHz, DMSO-d6):δ H 8.11(1H,d,J=16.0Hz),7.40(2H,d,J=8.0Hz),7.35(1H,d,J=16.0Hz),6.79(2 H,d,J=8.0Hz),4.13(1H,d,J=5.5Hz),3.71(1H,dd,J=9.0,1.5Hz),3.54(1H,dd ,J=12.0,2.0Hz),3.39(1H,dd,J=12.0,5.0Hz),3.29(1H,t,J=9.0Hz),3.16(1H ,t,J=9.0Hz), 3.09(1H,t,J=9.0Hz), 2.99(1H,m), 2.59(1H,dd,J=5.5,1.5Hz). 13 C NMR (DMSO-d6, 125 MHz)δ C :201.5,198.8,183.0,159.0,137.8,129.4(2),126.9,124.9,115.8(2),80.3,78.9,76.2,71.3,70.1(2),61.0,53.0.

[0062] Example 2 Preparation of 2-acetyl-3,4-dihydroxy-5-isopentenylcyclopent-2-enone

[0063]

[0064] Step 1: Preparation of 2,4,6-trihydroxy-3,5-diisoprenylacetophenone

[0065]

[0066] In a 100ml round-bottom flask, add 2,4,6-trihydroxyacetophenone (1000mg, 5.96mmol) and potassium hydroxide (667mg, 11.92mmol), dissolve in 20ml water, slowly add isopentyl bromide (1370μL, 11.92mmol) dropwise in an ice bath, stir and react for 1h. After the reaction is completed, add dilute hydrochloric acid to the reaction solution to adjust the pH value of the reaction solution to about 3, extract with ethyl acetate, wash the organic layer with water, dry with anhydrous sodium sulfate, recover the solvent under reduced pressure, load on silica gel column, and elute with petroleum ether: ethyl acetate = 20:1 to obtain the title compound (636mg, yield 35.15%).

[0067] Step 2: Preparation of 2-acetyl-3,5,6-trihydroxy-4,6-diisopentenylcyclohexa-2,4-dienone

[0068]

[0069] In a 100mL round-bottom flask, add 2,4,6-trihydroxy-3,5-diisoprenylacetophenone (1900mg, 6.25mmol) and lead acetate trihydrate (2370mg, 6.25mmol), dissolve in 60ml methanol, and introduce air at a constant speed under constant stirring. Stir and react for 3 days. Remove the device for introducing air, let the reaction solution stand, and filter to collect the precipitate. Suspend the precipitate in 8% sodium hydroxide aqueous solution, add dilute hydrochloric acid to the alkali solution to adjust the pH value of the reaction solution to about 3, extract with ethyl acetate, wash the organic layer with water, dry with anhydrous sodium sulfate, recover the solvent under reduced pressure, load on a reverse phase column, and elute with methanol: water = 1:2 to obtain the title compound (914mg, yield 45.72%).

[0070] Step 3: Preparation of 2-acetyl-3,4-dihydroxy-5-isopentenylcyclopent-2-enone

[0071]

[0072] In a 100ml round-bottom flask, add 2-acetyl-3,5,6-trihydroxy-4,6-diisopentenylcyclohexa-2,4-dienone (640mg, 2mmol), suspend in 50mL 8% sodium hydroxide solution, heat and stir at 80℃, react for 30 minutes after a clear solution is formed. After the reaction is completed, cool to room temperature, add dilute hydrochloric acid to the reaction solution to adjust the pH value of the reaction solution to about 3, extract with ethyl acetate, wash the organic layer with water, dry with anhydrous sodium sulfate, recover the solvent under reduced pressure, load on a reverse phase column, and elute with methanol: water = 1:2 to obtain the title compound (180mg, yield 40.17%).

[0073] 1 H NMR (DMSO-d6, 500 MHz)δ H :1.61(3H,s),1.66(3H,s),2.27(1H,m),2.39(3H,s),2.45(1H,m),2.48(1H,m),4.08(1H,d,J=4Hz),5.12(1H,t,J=7.2Hz). 13 CNMR (DMSO-d6, 125MHz)δ C :17.7,25.6,26.2,26.8,52.0,73.2,112.9,120.3,133.3,195.9,197.4,199.1.HR-ESI-MS:m / z 225.1125[M+H] + ,calcd for C 12 H 17 O4,225.1121. Example 3 2-Butyryl-3,4-dihydroxy-5-isopentenylcyclopent-2-enone

[0074]

[0075] Step 1: Preparation of 1-(2,4,6-trihydroxy-3,5-diisopentenylphenyl)butanone

[0076]

[0077] According to the method of step 1 of Example 2, the title compound was synthesized from 1-(2,4,6-trihydroxyphenyl)butanone;

[0078] Step 2: Preparation of 2-butyryl-3,5,6-trihydroxy-4,6-diisoprenycyclohexa-2,4-dienone

[0079]

[0080] According to the method of step 2 of Example 2, the title compound was synthesized from 1-(2,4,6-trihydroxy-3,5-diisopentenylphenyl)butanone;

[0081] Step 3: Preparation of 2-butyryl-3,4-dihydroxy-5-isopentenylcyclopent-2-enone

[0082]

[0083] According to the method of step 3 of Example 2, the title compound was synthesized from 2-butyryl-3,5,6-trihydroxy-4,6-diisopentenylcyclohexa-2,4-dienone.

[0084] 1 H NMR (DMSO-d6, 400 MHz)δ H :0.87(3H,t,J=7.2Hz),1.53(2H,m),1.59(3H,s),1.64(3H,s),2.24(1H,m),2. 42(1H,m),2.46(1H,m),2.76(2H,m),4.06(1H,d,J=4Hz, 5.09(1H,t,J=7.2Hz). 13 C NMR (DMSO-d6, 100 MHz)δ C :13.6,16.9,17.7,25.6,26.3,40.9,51.9,73.0,112.7,120.3,133.3,197.3,198.9,199.2.HR-ESI-MS:m / z253.1441[M+H] + ,calcdfor C 14 H 21 O4,253.1434.

[0085] Example 4 Preparation of 2-(2-phenylacetyl)-3,4-dihydroxy-5-isopentenylcyclopent-2-enone

[0086]

[0087] Step 1: Preparation of 2-phenyl-1-(2,4,6-trihydroxy-3,5-diisopentenylphenyl)ethanone

[0088]

[0089] According to the method of step 1 of Example 2, the title compound was synthesized from 2-phenyl-1-(2,4,6-trihydroxyphenyl)ethanone; Step 2: Preparation of 2-(2-phenylacetyl)-3,5,6-trihydroxy-4,6-diisoprenycyclohexa-2,4-dienone

[0090]

[0091] According to the method of step 2 of Example 2, the title compound was synthesized from 2-phenyl-1-(2,4,6-trihydroxy-3,5-diisopentenylphenyl)ethanone;

[0092] Step 3: Preparation of 2-(2-phenylacetyl)-3,4-dihydroxy-5-isopentenylcyclopent-2-enone

[0093]

[0094] According to the method of step 3 of Example 2, the title compound was synthesized from 2-(2-phenylacetyl)-3,5,6-trihydroxy-4,6-diisopentenylcyclohexa-2,4-dienone.

[0095] 1 H NMR (DMSO-d6, 400 MHz)δ H :1.58(3H,s),1.63(3H,s),2.28(1H,m),2.42(1H,m),2.48(1H,m),4.09(1H,d, J=4Hz),4.13(2H,s),5.08(1H,t,J=7.2Hz),7.21(3H,m),7.27(2H,t,J=7.6Hz). 13 C NMR (DMSO-d6, 100 MHz)δ C :17.7,25.6,26.3,45.4,52.0,72.9,112.7,120.3,126.6,128.2(2),129 .7(2),133.4,134.6,195.9,197.0,198.8.HR-ESI-MS:m / z301.1441[M+H] + ,calcd for C 18 H 21 O4,301.1434.

[0096] Example 5 Preparation of 2-cinnamoyl-3,4-dihydroxy-5-isoprenyl-cyclopent-2-enone

[0097]

[0098] In a 100mL round-bottom flask, add 2-acetyl-3,4-dihydroxy-5-isopentenylcyclopent-2-enone (630mg, 2.172mmol), benzaldehyde (330μL, 4.08mmol), anhydrous barium hydroxide (466mg, 2.172mmol) and 50mL anhydrous ethanol, reflux and stir to react for 2 days, and after the reaction is completed, cool to room temperature. Add appropriate amount of water to the reaction solution, add dilute hydrochloric acid to adjust the pH value of the reaction solution to about 3, extract with ethyl acetate, wash the organic layer with water, dry with anhydrous sodium sulfate, recover the solvent under reduced pressure, and elute with gel column chromatography with methanol: water = 7:3 to obtain the title compound (368mg, yield 45.05%).

[0099] 1 H NMR (DMSO-d6, 500 MHz)δ H :1.60(3H,s),1.65(3H,s),2.34(1H,m),2.46(1H,m),2.59(1H,m),4.11(1H,d,J=5Hz),5.15 (1H,t,J=7.5Hz),7.49(3H,m),7.72(2H,m,H-2″),7.79(1H,d,J=16Hz),7.93(1H,d,J=16Hz). 13 C NMR (DMSO-d6, 125 MHz)δ C :17.7,25.6,26.1,52.9,74.3,110.4,119.6,120.5,128.9(2),129.2(2),131.5,133.2,134.1,145.7,180.6,201.3,202.3.HR-ESI-MS:m / z 313.1445[M+H] + ,calcd for C 19 H 21 O4,313.1434.

[0100] Example 6 2-(4-chlorocinnamoyl)-3,4-dihydroxy-5-isopentenylcyclopent-2-enone

[0101]

[0102] According to the method of Example 5, the title compound was synthesized from 2-acetyl-3,4-dihydroxy-5-isopentenylcyclopent-2-enone and 4-chlorobenzaldehyde.

[0103] 1 H NMR (DMSO-d6, 500 MHz)δ H:1.60(3H,s),1.64(3H,s),2.34(1H,m),2.47(1H,m),2.58(1H,m),4.11(1H,d,J=5.5Hz),5.15(1H,t ,J=7.5Hz),7.52(2H,d,J=8.5Hz),7.73(2H,d,J=8.5Hz),7.75(1H,d,J=16Hz),7.89(1H,d,J=16Hz). 13 CNMR (DMSO-d6, 125MHz)δ C :17.7,25.5,26.1,52.9,74.2,110.6,120.3,120.4,129.3(2),130.5(2),133 .0,133.2,136.0,144.0,180.5,201.1,202.1.HR-ESI-MS:m / z347.1042[M+H] + ,calcd for C 19 H 20 ClO4,347.1045.

[0104] Example 7 2-(4-bromocinnamoyl)-3,4-dihydroxy-5-isopentenylcyclopent-2-enone

[0105]

[0106] According to the method of Example 5, the title compound was synthesized from 2-acetyl-3,4-dihydroxy-5-isopentenylcyclopent-2-enone and 4-bromobenzaldehyde.

[0107] 1 H NMR (DMSO-d6, 500 MHz)δ H :1.60(3H,s),1.64(3H,s),2.34(1H,m),2.47(1H,m),2.60(1H,m),4.13(1H,d,J=5 Hz), 5.16 (1H, t, J = 7.5Hz), 7.62 (4H, m), 7.74 (1H, d, J = 16Hz), 7.85 (1H, d, J = 16Hz). 13 C NMR (DMSO-d6, 125 MHz)δ C :17.7,25.6,26.1,53.0,74.3,110.5,120.1,120.5,125.1,130.6(2),132.2(2),133.3,144.3,180.4,198.3,202.3.HR-ESI-MS:m / z 391.0546[M+H] +,calcd for C 19 H 20 BrO4,391.0539.

[0108] Example 8 2-(4-methoxycinnamoyl)-3,4-dihydroxy-5-isopentenylcyclopent-2-enone

[0109]

[0110] According to the method of Example 5, the title compound was synthesized from 2-acetyl-3,4-dihydroxy-5-isopentenylcyclopent-2-enone and 4-methoxybenzaldehyde.

[0111] 1 H NMR (DMSO-d6, 500 MHz)δ H :1.60(3H,s),1.65(3H,s),2.34(1H,m),2.47(1H,m),2.57(1H,m),3.82(3H,s),4.08(1H,d,J=5Hz),5.15 (1H,t,J=7.5Hz),7.05(2H,d,J=8.5Hz),7.65(1H,d,J=16Hz),7.70(2H,d,J=8.5Hz),7.96(1H,d,J=16Hz). 1 3C NMR (DMSO-d6, 125MHz)δ C :17.7,25.6,26.1,53.0,55.5,74.5,109.6,114.9(2),116.0,120.5,126 .7,131.3(2),133.2,146.6,162.4,180.0,201.9,203.1.HR-ESI-MS:m / z 343.1542[M+H] + ,calcd for C 20 H 23 O5,343.1540.

[0112] Example 9 Study on the pharmacological activity of compound 1 in treating ischemic stroke in rats

[0113] Male SD rats weighing 280-300 g, with a certificate number of No. 11400700293705, were purchased from Sibeifu (Beijing) Biotechnology Co., Ltd., with a license number of SYXK (Beijing) 2014-0023, and were kept in the SPF animal room of the Institute of Materia Medica, Chinese Academy of Medical Sciences. They were fed with normal diet and had free access to water.

[0114] An appropriate amount of the compound 1 prepared in Example 1 was accurately weighed and dissolved in physiological saline to prepare a 6 mg / mL solution for later use. In the same manner, edaravone was prepared into a 2 mg / mL solution for later use.

[0115] 80 SD male rats (SPF grade) weighing 280-300g were randomly divided into 4 groups, namely sham operation group, model group, drug administration group and positive drug group, with 20 rats in each group. The rat ischemia-reperfusion injury model used an improved middle cerebral artery suture occlusion method. The suture slowly entered the proximal end of the anterior cerebral artery from the right external carotid artery through the internal carotid artery to block the blood supply source on the opposite side of the middle cerebral artery. After 90 minutes of ischemia, the suture was withdrawn and the blood supply was restored, forming rat middle cerebral artery ischemia-reperfusion injury. The sham operation group was only anesthetized and vascular stripped, without ligating the blood vessels and introducing sutures. The drug administration group was intraperitoneally injected with 30mg / kg of compound 1, the positive drug group was intraperitoneally injected with 10mg / kg of edaravone, and the model group was intraperitoneally injected with the same volume of normal saline. The drugs were administered once a day for 7 consecutive days.

[0116] Three hours after the model was successfully prepared, the neurological function score was scored according to the Longa method on a 5-point scale: 0 points, no obvious neurological symptoms; 1 point, unable to fully extend the contralateral forelimb; 2 points, turning in circles to the contralateral side; 3 points, falling to the contralateral side when walking; 4 points, unable to walk independently. Rats with a score of 2 or 3 were included in the group, and the rest were excluded.

[0117] The Evans blue method was used to detect changes in the permeability of the blood-brain barrier in rats 72 hours after modeling. A 2% Evans blue solution was injected into the rats through the femoral vein, with a dosage of 4 mL / kg. The rats were deeply anesthetized 3 hours later, and precooled saline was used for perfusion before sampling to remove excess Evans blue in the blood. The brain was removed and weighed, homogenized with 50% trichloroacetic acid, centrifuged at 12,000 × g for 30 minutes, and the supernatant was diluted with 4 times the volume of ethanol, and the Evans blue content was detected at a wavelength of 620 nm.

[0118] Detection of brain water content in rats: 72 hours after modeling, the rats were anesthetized and the samples were taken, and the wet weights of the left and right cerebral hemispheres were weighed, and then freeze-dried, and the dry weights were weighed to calculate the brain water content.

[0119] Brain water content = 100 × (wet weight - dry weight) / wet weight

[0120] The 2,3,5-triphenyltetrazolium chloride staining method was used to detect the infarction volume of rats. After 7 days of drug administration, the rats were deeply anesthetized, and the brains were removed by decapitation. After being placed in a brain mold, 2 mm thick brain slices were cut along the coronal plane of the brain, and the brain slices were immersed in 2% 3,5-triphenyltetrazolium chloride staining solution and stained for 15 minutes in the dark. After being fixed overnight with 4% paraformaldehyde, the stained brain slices were scanned and the infarction volume was calculated.

Claims

1. A cyclopentenone compound as shown in general formula I or a pharmaceutically acceptable salt thereof, in: R1 is selected from hydrogen, saccharide, C 1-5 Alkyl, C 3-5 Alkenyl, C 3-6 Cycloalkyl; R2 is selected from hydrogen, C 1-5 Alkyl, C 3-5 Alkenyl, C 3-6 Cycloalkyl, aryl, 5-6 membered heterocycloalkane or aromatic heterocycle, wherein the phenyl-containing group may be optionally substituted by halogen.

2. The cyclopentenone compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The salt may be a monovalent salt or a divalent salt.

3. The cyclopentenone compound or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: The monovalent salt is a sodium salt, a potassium salt, a lithium salt or an ammonium salt.

4. The cyclopentenone compound or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: The divalent salt is a calcium salt or a magnesium salt.

5. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that The sugar group in R1 is selected from glucose, xylose, galactose, and rhamnose, and the C 1-5 The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl; the C 3-5 The alkenyl group is selected from propenyl, butenyl, pentenyl, isopentenyl; the C 3-6 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

6. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that Where R2 is C 1-5 The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl; the C 3-5 The alkenyl group is selected from propenyl, butenyl, pentenyl, isopentenyl; the C 3-6 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the aryl group is selected from phenyl, benzyl, styryl or styryl; the 5-6 membered heterocycloalkane or aromatic heterocycle contains 1 or 2 heteroatoms or heteroatom groups independently selected from O, NH, S, C(=O) and N; the phenyl group may be optionally substituted by 1, 2 or 3 halogens, hydroxyl or methoxy groups.

7. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the compound includes but is not limited to the following compounds 8. The method for preparing cyclopentenone compounds according to claim 1, wherein the preparation route is: Route 1 Step a: Compound A (hydroxysafflor yellow A) is dissolved in an alcohol solution, an alkaline substance is added, and the mixture is heated under reflux to obtain a cyclopentenone compound B. Route 2 Step b: Compound C reacts with a halide to generate compound D; Step c: Compound D is oxidatively dearomatized in air using a catalyst to generate compound E; Step d: Compound E undergoes a ring contraction reaction under alkaline conditions to generate a cyclopentenone compound F; Step e: When R2 contains an aromatic group, compound F undergoes aldol condensation with a corresponding aldehyde compound under alkaline conditions to generate compound G.

9. The preparation method according to claim 3, characterized in that: The cyclopentenone compound prepared in claim 7 is eluted through a sodium, potassium, lithium or ammonium cation exchange resin column, the eluate containing the cyclopentenone monovalent salt compound is collected, and purified through dextran gel to obtain the cyclopentenone monovalent salt compound.

10. The preparation method according to claim 4, characterized in that: The cyclopentenone compound prepared in claim 7 is eluted through a calcium-type or magnesium-type cation exchange resin column, the eluate containing the cyclopentenone divalent salt compound is collected, and purified through dextran gel to obtain the cyclopentenone divalent salt compound.

11. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises at least one compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier and / or excipient.

12. The pharmaceutical composition according to claim 10, characterized in that The pharmaceutical composition further comprises a pharmaceutically active ingredient other than the compound or a pharmaceutically acceptable salt thereof.

13. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to any one of claims 10 or 11 in the preparation of a medicament for preventing and / or treating cerebrovascular-related diseases.

14. Use of the cyclopentenone salt compound and pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or the pharmaceutical composition according to any one of claims 10 or 11 in the preparation of drugs for diseases related to the blood-brain barrier.

15. The use according to claim 12, characterized in that The cerebrovascular-related disease is selected from ischemic stroke and hemorrhagic stroke.

Images