Patchouli alcohol glucoside derivative as well as preparation method and application thereof

Abstract

The invention provides a patchouli alcohol glucoside derivative as well as a preparation method and application thereof, the structural formula of the patchouli alcohol glucoside derivative is shown as a formula I. The invention also provides a preparation method of the patchouli alcohol glucoside derivative and application of the patchouli alcohol glucoside derivative in preparation of antidepressant drugs. The dissolution rate of the patchouli alcohol glucoside derivative in water is increased by more than 1000 times compared with that of patchouli alcohol, pharmacological tests prove that the antidepressant activity of the patchouli alcohol glucoside derivative is obviously higher than that of patchouli alcohol, the patchouli alcohol glucoside derivative can be used for preparing antidepressant drugs, and a new choice is provided for the antidepressant drugs: in the formula, R is selected from any one of glucoside, rhamnoside and moss phenol glucoside.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and more specifically, to a baiqiu ruol glycoside derivative, its preparation method, and its application. Background Technology

[0002] Depression, also known as depressive disorder, is a mental disorder with a high incidence, high clinical cure rate but low treatment acceptance rate and high relapse rate. Its main characteristic is significant and persistent low mood. Some patients may engage in self-harm or suicidal behavior, and may even experience psychotic symptoms such as delusions and hallucinations.

[0003] With the accelerating pace of modern life and increasing social pressure, its incidence rate has been rising globally in recent years, becoming a significant global public health issue.

[0004] Currently, there are many treatments for depression, primarily using Western medicine. Commonly used Western medicines include serotonin reuptake inhibitors (STIs), monoamine oxidase inhibitors (MAOIs), norepinephrine reuptake inhibitors (NRIs), and tricyclic antidepressants. However, these drugs have drawbacks such as significant side effects, unstable efficacy, narrow antidepressant spectrum, and slow onset of action, limiting their clinical use. Patchouli oil is the main medicinal component of patchouli. In aromatherapy, patchouli oil is used to enhance libido and relieve depression and stress.

[0005] Patchouli alcohol, also known as patchouli alcohol, is a terpenoid compound. It is the main component of patchouli oil, accounting for up to 57% of its composition. Patchouli oil is the primary medicinal component of patchouli, and in aromatherapy, it is used to enhance libido and alleviate depression and stress. Studies have shown that the patchouli alcohol-type dichloromethane extract of Indian valerian containing patchouli alcohol has antidepressant effects. Furthermore, patchouli alcohol exhibits neuroprotective effects and protects against scopolamine-induced cognitive and memory impairment in mice. These studies suggest that patchouli alcohol may possess antidepressant properties. Additionally, previous research indicates that patchouli alcohol has low toxicity. Therefore, patchouli alcohol is likely a safe and effective antidepressant. However, its relatively low antidepressant activity and water insolubility limit its application. Summary of the Invention

[0006] To address the problems of existing technologies, this invention provides a baicaleol glycoside derivative, its preparation method, and its application. The baicaleol glycoside derivative is soluble in water and exhibits significantly higher antidepressant activity than baicaleol.

[0007] This invention is achieved through the following technical solution: Firstly, this invention provides a berberine glycoside derivative of Formula I:

[0008] In the formula, R is selected from any one of glucoside, rhamnoside, and styrophenol glucoside.

[0009] Preferably, the baiqiu plum alcohol glycoside derivative is any one of formula YZ-01, YZ-05, and YZ-08: .

[0010] Secondly, the present invention provides a method for preparing the above-mentioned baiqiu plum glycoside derivative, which includes the following steps: (1) Baiqiuli alcohol and ethyl bromoacetate were reacted in a polar aprotic solvent in the presence of a base to generate intermediate M1; (2) React intermediate M1 with a reducing agent in an organic solvent to generate intermediate M2; (3) Intermediate M2 is reacted with a sugar donor under glycosylation conditions to form an acetylated glycoside intermediate; (4) The acetylated glycoside intermediate obtained in step (3) is subjected to a deprotection reaction to obtain the baiqiuli alcohol glycoside derivative; The chemical structural formula of intermediate M1 is shown in Formula M1, and the chemical structural formula of intermediate M2 is shown in Formula M2: .

[0011] Preferably, the base in step (1) is potassium carbonate, the polar aprotic solvent is N,N-dimethylformamide, and the reaction conditions are stirring at room temperature for 2-3 hours, then heating to 60°C and stirring for 4.5-5.5 hours, with the molar ratio of baicalein, ethyl bromoacetate, and potassium carbonate being 1:1-2:1-2; the reducing agent in step (2) is lithium aluminum hydride, the organic solvent is tetrahydrofuran, and the reaction conditions are stirring at 0°C for 0.5-1 hours, then heating to room temperature and stirring for 2.5-3.5 hours, with the molar ratio of intermediate M1 to lithium aluminum hydride being 1:1-2.

[0012] Preferably, the sugar donor in step (3) is selected from tetraacetyl glucosamine trichloroacetylimine ester, tetraacetyl rhamnose or teurophenol tetraacetyl glucosinolate, and the molar ratio of intermediate M2 to sugar donor is 1:1.1 to 1.5; the glycosylation conditions include reaction in an organic solvent in the presence of a Lewis acid catalyst or coupling agent.

[0013] Preferably, when the sugar donor is tetraacetylglucosamine trichloroacetylimine ester or tetraacetyrhamnose, the Lewis acid catalyst is boron trifluoride diethyl ether, the organic solvent is dichloromethane, and the reaction conditions are stirring at 0°C for 3 h and then stirring at room temperature for 16 h.

[0014] Preferably, when the sugar donor is teurophenol tetraacetyl glucoside, the coupling agent is triphenylphosphine and diethyl azodicarbonate, the organic solvent is tetrahydrofuran, and the reaction conditions are stirring at 0°C for 3 h followed by stirring at room temperature for 16 h.

[0015] Preferably, the deprotection reaction in step (4) includes a reaction in methanol under alkaline conditions, followed by neutralization with an acidic resin to obtain a baicalein glycoside derivative, wherein the alkaline conditions are provided by sodium methoxide, the reaction temperature is 0°C, and the reaction time is 1 hour.

[0016] Thirdly, the present invention provides the use of the above-mentioned baicalein glycoside derivatives or pharmaceutically acceptable salts thereof in the preparation of antidepressant drugs.

[0017] Fourthly, the present invention provides an antidepressant pharmaceutical composition comprising the above-mentioned baicalein glycoside derivative or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients.

[0018] Preferably, the pharmaceutically acceptable excipients include any one or a combination of at least two of the following: sustained-release agents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, and lubricants. The combination of at least two is, for example, a combination of binders and excipients, a combination of binders and flavoring agents, a combination of binders and fillers, etc. Other combinations are also possible and will not be described in detail here.

[0019] Preferably, the drug dosage form is a tablet, capsule, granule, injection, oral liquid, pill, ointment, suspension, dispersant, syrup, suppository, gel, aerosol, or patch.

[0020] Compared with the prior art, the present invention has the following beneficial effects: The baicalein glycoside derivative provided by this invention has a water solubility that is more than 1,000 times higher than that of baicalein, and pharmacological tests have shown that its antidepressant activity is significantly higher than that of baicalein. It can be used to prepare antidepressant drugs, providing a new option for antidepressant medication. Detailed Implementation

[0021] The present invention will be further described in detail below with reference to embodiments, but this does not limit the present invention in any way. Any modifications or improvements made based on the teachings of the present invention shall fall within the protection scope of the present invention.

[0022] The processes, conditions, reagents, and experimental methods used in implementing this invention, except as specifically mentioned below, are all common knowledge and general knowledge in the field, and this invention does not have any particular limitations. Experimental methods in the embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer.

[0023] Unless otherwise stated, all technical terms and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. However, in the event of any conflict, the specification containing the definitions shall prevail.

[0024] Table 1 shows the sources and specifications of the main raw materials in the examples.

[0025] Table 1. Main raw material sources and specifications in the examples

[0026] Example 1: Preparation of intermediates M1 and M2 Its reaction pathway is as follows:

[0027] Step 1: Acetonide (SM1, 10.0 g, 44.97 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (100 mL), followed by the addition of ethyl bromoacetate (9.0 g, 53.96 mmol, 1.2 eq) and potassium carbonate (9.3 g, 67.45 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 3 h, then heated to 60 °C and stirred for another 5 h. The reaction mixture was cooled to room temperature and poured into water (300 mL). Extraction was performed with ethyl acetate (3 × 150 mL), and the organic layers were combined. The mixture was washed with saturated sodium chloride solution (1 × 100 mL), dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and subjected to column chromatography to obtain intermediate M1 (10.3 g), with a yield of 74%.

[0028] 1 H NMR (500 MHz, CDCl3): δ 4.11 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 2.01- 1.83 (m, 3H), 1.75 - 1.56 (m, 1H), 1.55 -1.15 (m, 11H), 1.07 (s, 3H), 1.04(s, 3H), 0.82 (s, 3H), 0.78 (s, 3H). HRMS(ESI) m / z Calcd. For C 19 H 33 O3+ [M+H] + =309.2424, found: 309.2430. Step 2: Intermediate M1 (10.0 g, 32.42 mmol, 1.0 eq) was dissolved in dry tetrahydrofuran (100 mL), and argon gas was purged three times. The mixture was cooled to 0 °C, and lithium aluminum hydride (1.5 g, 38.90 mmol, 1.2 eq) was slowly added in portions. The reaction was stirred at 0 °C for 0.5 h, then heated to room temperature and stirred for another 3 h. Water was slowly added dropwise to the reaction mixture until the solid was fluffy and the liquid was clear. The mixture was filtered, and the solid was washed with dry tetrahydrofuran (100 mL). The filtrate was dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and column chromatography was used to obtain intermediate M2 (7.1 g), with a yield of 82%.

[0029] 1 H NMR (500 MHz, CDCl3): δ 4.05 - 4.01 (m, 1H), 3.88 - 3.76 (m, 3H), 2.00 - 1.80 (m, 3H), 1.75 - 1.55 (m, 1H), 1.55 -1.15 (m, 9H), 1.06 (s, 3H), 1.04 (s, 3H), 0.82 (s, 3H), 0.78 (s, 3H).

[0030] HRMS(ESI) m / z Calcd. For C 17 H 31 O2 + [M+H] + =267.2319, found: 267.2324. Example 2: Preparation of compound YZ-01 Its reaction pathway is as follows:

[0031] Step 1: Intermediate M2 (2.0 g, 7.51 mmol, 1.0 eq) and tetraacetylglucose trichloroacetylimine ester (4.4 g, 9.01 mmol, 1.5 eq) were dissolved in dichloromethane (40 mL), purged with argon three times, cooled to 0 °C, and boron trifluoride diethyl ether (1.6 g, 11.26 mmol, 1.5 eq) was slowly added dropwise. The reaction was stirred at 0 °C for 3 h, then heated to room temperature and stirred for 16 h. The reaction mixture was poured into a saturated sodium bicarbonate solution (100 mL), stirred for 5 min, filtered, and the aqueous layer was extracted with dichloromethane (3 × 50 mL). The organic layers were combined and washed successively with saturated sodium bicarbonate solution (1 × 50 mL) and saturated sodium chloride solution (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to remove the solvent, yielding a solid compound that was directly used in the next step.

[0032] Step 2: Dissolve the solid obtained above in methanol (50 mL), cool to 0 °C, slowly add sodium methoxide (0.2 g), stir the reaction at 0 °C for 1 h, adjust the pH value to neutral with acidic resin, filter, concentrate to remove solvent, and purify the crude product by column chromatography to obtain solid YZ-01 (1.8 g), with a combined yield of 56%.

[0033] 1 H NMR (500 MHz, D2O): δ = 4.50 (d, J = 7.8 Hz, 1H), 4.02 - 3.98 (m, 1H), 3.92 (dd, J = 2.3, 12.2 Hz, 1H), 3.80 - 3.76 (m, 3H), 3.73 (dd, J = 6.1, 12.2 Hz, 1H), 3.51 (t, J = 9.1 Hz, 1H), 3.46 (m, 1H), 3.38 (t, J = 9.3 Hz, 1H), 3.32 (dd, J = 8.0, 9.3 Hz, 1H), 2.00 - 1.83 (m, 3H), 1.75 - 1.56 (m, 1H), 1.53 -1.15 (m,9H), 1.07 (s, 3H), 1.05 (s, 3H), 0.81 (s, 3H), 0.79 (s, 3H). HRMS (ESI) m / z Calculated. For C 23 H41 O7 + [M+H] + =429.2847, found: 429.2851. Example 3 Preparation of compound YZ-05 The reaction pathway is as follows:

[0034] Step 1: Intermediate M2 (2.0 g, 7.51 mmol, 1.0 eq) and tetraacetylrhamnose (3.0 g, 9.01 mmol, 1.5 eq) were dissolved in dichloromethane (40 mL), purged with argon three times, cooled to 0 °C, and boron trifluoride diethyl ether (1.6 g, 11.26 mmol, 1.5 eq) was slowly added dropwise. The reaction was stirred at 0 °C for 3 h, then heated to room temperature and stirred for 16 h. The reaction mixture was poured into a saturated sodium bicarbonate solution (100 mL), stirred for 5 min, filtered, and the aqueous layer was extracted with dichloromethane (3 × 50 mL). The organic layers were combined and washed successively with saturated sodium bicarbonate solution (1 × 50 mL) and saturated sodium chloride solution (1 × 50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to remove the solvent, yielding a solid compound that was directly used in the next step.

[0035] Step 2: Dissolve the solid obtained above in methanol (50 mL), cool to 0 °C, slowly add sodium methoxide (0.2 g), stir the reaction at 0 °C for 1 h, adjust the pH value to neutral with acidic resin, filter and concentrate to remove solvent, and purify the crude product by column chromatography to obtain solid YZ-05 (1.5 g), with a combined yield of 48%.

[0036] 1 H NMR (500 MHz, D2O) δ 4.56 (d, J = 1.7 Hz, 1H), 4.03 - 3.90 (m, 2H), 3.82 - 3.76 (m, 4H), 3.65 (dd, J = 3.6, 9.4 Hz, 1H), 3.58 - 3.52 (m, 1H), 1.28(d, J = 6.2 Hz, 3H), 2.03 - 1.81 (m, 3H), 1.76 - 1.57 (m, 1H), 1.54 - 1.16 (m,9H), 1.08 (s, 3H), 1.05 (s, 3H), 0.83 (s, 3H), 0.79 (s, 3H). HRMS (ESI) m / z Calculated. For C 23 H 41 O6 + [M+H] + =413.2898, found: 413.2906. Example 4: Preparation of compound YZ-08 The reaction pathway is as follows:

[0037] Step 1: Intermediate M2 (3.0 g, 11.26 mmol, 1.0 eq), teurophenol tetraacetyl glucoside (5.6 g, 12.39 mmol, 1.1 eq), and triphenylphosphine (4.4 g, 16.89 mmol, 1.5 eq) were dissolved in tetrahydrofuran (60 mL), purged with argon three times, cooled to 0 °C, and diethyl azodicarbonate (2.9 g, 16.89 mmol, 1.5 eq) was slowly added dropwise. The reaction was stirred at 0 °C for 3 h and then heated to room temperature and stirred for 16 h. The reaction mixture was poured into a saturated ammonium chloride solution (100 mL), stirred for 5 min, filtered, and the aqueous layer was extracted with ethyl acetate (3 × 70 mL). The organic layers were combined, washed with a saturated sodium chloride solution (1 × 100 mL), dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and column chromatography was performed to obtain a solid compound (3.3 g) which was used directly in the next step.

[0038] Step 2: Dissolve the solid obtained above in methanol (100 mL), cool to 0 °C, slowly add sodium methoxide (0.3 g), stir the reaction at 0 °C for 1 h, adjust the pH to neutral with acidic resin, filter and concentrate to remove solvent, and purify the crude product by column chromatography to obtain solid YZ-08 (1.9 g), with a combined yield of 32%.

[0039] 1 H NMR (500 MHz, D2O) δ 6.54 (t, J = 1.7 Hz, 1H), 6.48 (d, J = 1.9 Hz, 1H), 6.44 (t, J = 2.3 Hz, 1H), 5.04 (d, J = 7.8 Hz, 1H), 4.03 - 3.97 (m, 1H), 3.92(dd, J= 2.3, 12.5 Hz, 1H), 3.86 - 3.83 (m, 3H), 3.75 (dd, J = 5.7, 12.5 Hz, 1H),3.60 - 3.53 (m, 2H), 3.53 - 3.44 (m, 2H), 2.26 (s, 3H), 2.05 - 1.79 (m, 3H),1.72 - 1.53 (m, 1H), 1.50 -1.17 (m, 9H), 1.07 (s, 3H), 1.03 (s, 3H), 0.81 (s, 3H), 0.78 (s, 3H). HRMS (ESI) m / z Calculated. For C 30 H 47 O8 + [M+H] + =535.3265, found: 535.3273. Example 5 Preparation of intermediates M1 and M2 Step 1: Acetonide (SM1, 1.0 g, 4.50 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL). Ethyl bromoacetate (0.075 g, 4.50 mmol, 1.0 eq) and potassium carbonate (1.24 g, 8.99 mmol, 2.0 eq) were added. The reaction mixture was stirred at room temperature for 2 h, then heated to 60 °C and stirred for another 4.5 h. The reaction mixture was cooled to room temperature and poured into water (30 mL). Extraction was performed with ethyl acetate (3 × 15 mL). The organic layers were combined, washed with saturated sodium chloride solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and column chromatography was used to obtain intermediate M1 (0.78 g), with a yield of 56%.

[0040] Step 2: Intermediate M1 (0.7 g, 2.27 mmol, 1.0 eq) was dissolved in dry tetrahydrofuran (10 mL), and argon gas was purged three times. The mixture was cooled to 0 °C, and lithium aluminum hydride (0.17 g, 4.54 mmol, 2.0 eq) was slowly added in portions. The reaction was stirred at 0 °C for 1 h, then heated to room temperature and stirred for another 2.5 h. Water was slowly added dropwise to the reaction mixture until the solid was fluffy and the liquid was clear. The mixture was filtered, and the solid was washed with dry tetrahydrofuran (10 mL). The filtrate was dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and column chromatography was used to obtain intermediate M2 (0.46 g), with a yield of 76%.

[0041] Example 6 Preparation of intermediates M1 and M2 Step 1: Acetonide (SM1, 1.0 g, 4.50 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of ethyl bromoacetate (1.5 g, 8.99 mmol, 2.0 eq) and potassium carbonate (0.62 g, 4.50 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 2.5 h, then heated to 60 °C and stirred for another 5.5 h. The reaction mixture was cooled to room temperature and poured into water (30 mL). Extraction was performed with ethyl acetate (3 × 15 mL), and the organic layers were combined. The mixture was washed with saturated sodium chloride solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and subjected to column chromatography to obtain intermediate M1 (0.81 g), with a yield of 58%.

[0042] Step 2: Intermediate M1 (0.7 g, 2.27 mmol, 1.0 eq) was dissolved in dry tetrahydrofuran (10 mL), and argon gas was purged three times. The mixture was cooled to 0 °C, and lithium aluminum hydride (86 mg, 2.27 mmol, 1.0 eq) was slowly added in portions. The reaction was stirred at 0 °C for 1 h, then heated to room temperature and stirred for another 3.5 h. Water was slowly added dropwise to the reaction mixture until the solid was fluffy and the liquid was clear. The mixture was filtered, and the solid was washed with dry tetrahydrofuran (10 mL). The filtrate was dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and column chromatography was used to obtain intermediate M2 (0.43 g), with a yield of 71%.

[0043] Example 7 Simple Solubility Experiment According to Chemical Book data, the solubility of baicalein in water is approximately 41.8 mg / L (24 °C).

[0044] Take three test tubes, add 42 mg of the sample prepared in Examples 2-4 to each tube, add purified water at 24 ℃, sonicate for 20 seconds, and observe the dissolution. The experimental results are shown in Table 2.

[0045] Table 2 Solubility test results

[0046] Experimental results show that the solubility of the three compounds provided by this invention is greater than 42 mg / mL (24 ℃), indicating that the solubility of the three compounds provided by this invention is more than 1000 times higher than that of baicalein.

[0047] Example 8 Evaluation of antidepressant activity 1. Preparation of test sample and positive control Imipramine Hydrochloride: Dissolve the required amount of imipramine hydrochloride in normal saline to prepare a solution of 1.5 mg / mL, and prepare it freshly before each administration.

[0048] Patchouli alcohol: Weigh an appropriate amount of patchouli alcohol, dissolve it in 2% DMSO with a total volume, and dilute it with corn oil to prepare a solution of 2 mg / mL. ZY-01: Weigh an appropriate amount of ZY-01, dissolve it in normal saline, and prepare a solution with a concentration of 1 mg / mL, and prepare it freshly before use. ZY-05: Weigh an appropriate amount of ZY-05, dissolve it in normal saline, and prepare a solution with a concentration of 1 mg / mL, and prepare it freshly before use. ZY-08: Weigh an appropriate amount of ZY-08, dissolve it in normal saline, and prepare a solution with a concentration of 1 mg / mL, and prepare it freshly before use. 2. Experimental system 2.1 Animals Species, strain, and quality level: Mice, Kunming, specific pathogen free Gender and quantity: Male, 60 Animal body weight range: 25 - 30 g Animal source and certificate number: Beijing Speifo Laboratory Animal Center, SCXK (Beijing) 2024 - 000 2.2 Identification method of experimental animals After the animals arrive, receive them according to the company's operating procedures for receiving experimental animals, assign an independent batch number to each batch of animals, and mark the animals at the same time. Use the experimental animal number to identify them in the original data.

[0049] 2.3 Feeding, management, and environmental conditions of experimental animals The experimental animals are housed in an independent ventilated cage system (IVC) in the applicant's experimental animal house. The numbers of the experimental facilities are: 13 - 11 - 078 and 13 - 11 - 079, and the production date of the facilities is November 24, 2013. The feeding method is group feeding, with 5 animals in each cage. The cage specifications are: 330 * 215 * 160 mm. The room temperature is controlled at 20 - 25 °C, the humidity is 40 - 70%, the noise is <60 db, the illuminance is 170 Lux, with 12 h of lighting and 12 h of darkness, the light - on time: 7:00 am, and the light - off time: 19:00 pm. Change the cages and bedding twice a week.

[0050] 2.4 Feed and drinking water The experimental animals are fed with sterilized feed produced by Jiangsu Xietong Pharmaceutical Biotechnology Co., Ltd., and the feed certificate number is: Su Feed Certificate (2019) 01008. Feed is supplied to each cage once a day, and the drinking water bottle contains cool boiled water for the animals to drink freely.

[0051] 2.5 Animal numbering, marking, and experimental grouping Each experimental animal was assigned a unique experimental animal number, which was marked on the animal and its cage card. The mice were marked with a black marker on their tails and then randomly grouped into four groups using a simple random number sorting method in Excel: saline group, imipramine hydrochloride group, baicalein group, ZY-01 group, ZY-05 group, and ZY-08 group, with 10 animals in each group.

[0052] 3. Experimental Methods 3.1. Route and method of administration Route of administration: Intraperitoneal injection (ip).

[0053] Dosage volume: 0.1 mL / 10 g body weight.

[0054] Dosage frequency and time: once a day.

[0055] 3.2 Test Method Depressive behavior in mice was detected by tail suspension test and forced swimming.

[0056] (1) Tail suspension test (TST): The mouse is inverted and its tail is attached to the tail suspension device with tape 1 cm from the tail tip. The head is about 10 cm away from the table. The tail suspension test is performed for 6 minutes while the video is taken. The background of the video is in obvious contrast to the color of the mouse's fur. A black background is used for white mice.

[0057] Observation indicators: The tail suspension test lasted for 6 minutes, and the cumulative immobility time of mice was recorded in the first 2 minutes and the last 4 minutes. The immobility time in the last 4 minutes was used as the primary evaluation indicator. The criterion for judging immobility in mice was that the mice stopped struggling and were in a still state. Throughout the experiment, animal grouping and drug administration were performed by one person, while experimental procedures and data collection were performed by another person (blinding method). After all experiments were completed, the blinding was reversed, and data were statistically analyzed according to the grouping.

[0058] (2) Forced Swimming (FST): The standard operating procedure for forced swimming experiments in mice was followed: a cylindrical transparent glass tank with an inner diameter of 15 cm and a depth of 24 cm was used; the water temperature was 25 ± 1℃ and the water depth was 15 ± 1 cm. Before the experiment, the animals were placed in the behavioral laboratory for 1 hour to acclimatize. The animals were given intraperitoneal medication according to the experimental protocol, and then the forced swimming test was conducted for 6 minutes. The specific experimental procedure was as follows: the mice with confirmed numbers were gently held and slowly moved to the tank. The mice were gently placed into the water with their heads facing the tank wall. The timer was started as soon as the mice entered the water and entered the countdown state. There should be no debris within 0.5 m around the tank. The experimenter observed and recorded the mice's status from a distance of 1.5 m from the tank. If necessary, the water in the tank was changed and the tank was cleaned. After the forced swimming was completed, the mice were immediately removed from the tank, dried, and returned to their cages. The forced swimming was recorded using a DV camera.

[0059] Observation indicators: The forced swimming test lasted 6 minutes. The cumulative immobility time of the mice was recorded in the first 2 minutes and the last 4 minutes, with the immobility time in the last 4 minutes serving as the primary evaluation indicator. The criteria for defining immobility in the water were: the mouse stopped struggling and floated, occasionally making limb movements to keep its nostrils afloat. Throughout the experiment, animal grouping and drug administration were performed by one person, while experimental procedures and data collection were performed by another person (blinding method). After all experiments were completed, the blinding was reversed, and data were statistically analyzed according to the grouping results.

[0060] 3.3 Experimental Procedure 3.3.1 Evaluation of drug efficacy Experimental animals were given the drug once a day according to the experimental group. The tail suspension test was performed 0.5 h after the drug was administered. The drug was administered again on the second day. The forced swimming test was performed 0.5 h after the drug was administered. The immobility time of the mice in the tail suspension test and forced swimming was recorded using a blind method.

[0061] 3.3.2 Statistical Analysis One-way ANOVA was performed on the data using SPSS 22.0 software, followed by LSD (Least Significant Difference) comparisons between groups. P < 0.05 was considered statistically significant (P < 0.05 was denoted as *, P < 0.01 as **, and P < 0.001 as ***). All results are expressed as mean ± standard error (SE).

[0062] 4. Results 4.1 Results of mouse tail suspension test In the tail suspension test, as shown in Table 2, compared with the saline group, the immobility time of the animals in the positive control imipramine hydrochloride group (15 mg / kg) was significantly shortened (***P<0.001), indicating that the experimental system has good drug predictability. Compared with the saline group, the immobility time of the animals in the ZY-01 (10 mg / kg) group was significantly shortened (*P<0.05), the immobility time of the animals in the ZY-05 (10 mg / kg) group was significantly shortened (**P<0.01), the immobility time of the animals in the ZY-08 (10 mg / kg) group was significantly shortened (**P<0.01), and the immobility time of the animals in the baicalein (20 mg / kg) group was significantly shortened (*P<0.05). The immobility time shortening effect of ZY-08 was the best.

[0063] Table 2. Immobility time in mouse tail suspension test

[0064] Note: VS physiological saline, P<0.05*; P<0.01**; P<0.001***, one-way ANOVA. 5.2 Results of forced swimming in mice The drug was administered again 24 hours after the tail suspension test, and forced swimming was performed 0.5 hours later. The results are shown in Table 3.

[0065] In the forced swimming experiment, the positive control group (imipramine hydrochloride 15 mg / kg) showed a significantly shorter immobility time compared to the saline group (***P<0.001). Compared to the saline group, the immobility time of animals in the ZY-01 (10 mg / kg) group, ZY-05 (10 mg / kg) group, ZY-08 (10 mg / kg) group, and baicaleol (20 mg / kg) group was significantly shorter (*P<0.05), with ZY-08 showing the best effect in shortening the immobility time.

[0066] Table 3. Time of immobility during forced swimming in mice

[0067] Note: VS saline solution P <0.05*; P <0.01**; P <0.001***, One-way ANOVA 6. Conclusion In the tail suspension test and forced swimming test, the experimental system showed good drug predictive ability. Under this test system, ZY-01, ZY-05 and ZY-08 all showed better antidepressant activity than the baicalein group, and ZY-08 was better than ZY-01 and ZY-05.

[0068] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. The glycoside derivative of Prunus persica shown in Formula I: In the formula, R is selected from any one of glucoside, rhamnoside, and styrophenol glucoside.

2. The baiqiu plumol glycoside derivative according to claim 1, characterized in that, The baiqiu plum alcohol glycoside derivative is any one of formulas YZ-01, YZ-05, and YZ-08: 。 3. The method for preparing the baiqiu plumol glycoside derivative according to claim 1 or 2, characterized in that, Includes the following steps: (1) Baiqiuli alcohol and ethyl bromoacetate were reacted in a polar aprotic solvent in the presence of a base to generate intermediate M1; (2) React intermediate M1 with a reducing agent in an organic solvent to generate intermediate M2; (3) Intermediate M2 is reacted with a sugar donor under glycosylation conditions to form an acetylated glycoside intermediate; (4) The acetylated glycoside intermediate obtained in step (3) is subjected to a deprotection reaction to obtain the baiqiuli alcohol glycoside derivative; The chemical structural formula of intermediate M1 is shown in Formula M1, and the chemical structural formula of intermediate M2 is shown in Formula M2: 。 4. The method according to claim 3, characterized in that, In step (1), the base is potassium carbonate, the polar aprotic solvent is N,N-dimethylformamide, and the reaction conditions are: stirring at room temperature for 2-3 hours, then heating to 60°C and stirring for 4.5-5.5 hours. The molar ratio of baicalein, ethyl bromoacetate, and potassium carbonate is 1:1-2:1-2. In step (2), the reducing agent is lithium aluminum hydride, the organic solvent is tetrahydrofuran, and the reaction conditions are: stirring at 0°C for 0.5-1 hours, then heating to room temperature and stirring for 2.5-3.5 hours. The molar ratio of intermediate M1 to lithium aluminum hydride is 1:1-2.

5. The method according to claim 3, characterized in that, The sugar donor in step (3) is selected from tetraacetyl glucotrichloroacetylimine ester, tetraacetyl rhamnose or teurophenol tetraacetyl glucoside, and the molar ratio of intermediate M2 to sugar donor is 1:1.1-1.5; the glycosylation conditions include reaction in an organic solvent in the presence of a Lewis acid catalyst or coupling agent.

6. The method according to claim 5, characterized in that, When the sugar donor is tetraacetylglucosamine trichloroacetylimide ester or tetraacetyrhamnose, the Lewis acid catalyst is boron trifluoride diethyl ether, the organic solvent is dichloromethane, and the reaction conditions are stirring at 0°C for 3 h and then stirring at room temperature for 16 h.

7. The method as described in claim 5, characterized in that, When the sugar donor is teurophenol tetraacetyl glucoside, the coupling agent is triphenylphosphine and diethyl azodicarbonate, the organic solvent is tetrahydrofuran, and the reaction conditions are stirring at 0°C for 3 h and then stirring at room temperature for 16 h.

8. The method as described in claim 1, characterized in that, In step (4), the deprotection reaction includes a reaction in methanol under alkaline conditions, followed by neutralization with an acidic resin to obtain a baicalein glycoside derivative, wherein the alkaline conditions are provided by sodium methoxide, the reaction temperature is 0°C, and the reaction time is 1 hour.

9. The use of the baicalein glycoside derivatives described in 1 or 2 or pharmaceutically acceptable salts thereof in the preparation of antidepressant drugs.

10. An antidepressant pharmaceutical composition, characterized in that, Includes the baicalein glycoside derivative of claim 1 or 2 or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.

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