Beta-eudesmol glucoside derivative as well as preparation method and application thereof

Abstract

The invention discloses a beta-eudesmol glucoside derivative as well as a preparation method and application thereof, the structural formula of the beta-eudesmol glucoside derivative is shown as a formula I. The invention further provides the preparation method of the beta-eudesmol glucoside derivative and application of the beta-eudesmol glucoside derivative in preparation of antidepressant drugs. The dissolution rate of the beta-eudesmol glucoside derivative in water is increased by more than 1000 times compared with that of beta-eudesmol, pharmacological tests prove that the anti-depression activity of the beta-eudesmol glucoside derivative is obviously higher than that of the beta-eudesmol, and the beta-eudesmol glucoside derivative can be used for preparing anti-depression drugs. In the formula, R is selected from any one of glucoside, rhamnoside and aurenol glucoside. The invention also provides a new choice for antidepressant drugs, wherein R is selected from any one of glucoside, rhamnoside and aurenol glucoside.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a β-eucalyptol 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 rate, a high clinical cure rate but a low treatment acceptance rate and a high relapse rate.

[0003] With the accelerating pace of modern life and increasing social pressure, the incidence of depression has been rising globally in recent years, becoming a significant global public health issue. According to the World Health Organization (WHO), the global prevalence of depression is approximately 11%, meaning about 340 million people worldwide suffer from it. In China, the situation is equally serious. Data from the "2022 National Depression Blue Book" shows that the number of people with depression in China has reached 95 million, roughly one in 14 people, making it the country with the highest number of people with depression globally. Furthermore, according to domestic research, the lifetime prevalence of depressive disorders among Chinese adults is 6.8%, with a prevalence of depression as low as 3.4%. These data indicate that depression has become one of the most significant diseases affecting public health in China.

[0004] Currently, there are many treatments for depression, mainly based on Western medicine. Commonly used Western medicines include serotonin reuptake inhibitors, monoamine oxidase inhibitors, norepinephrine reuptake inhibitors, and tricyclic antidepressants. However, these drugs have disadvantages such as large toxic side effects, unstable efficacy, narrow antidepressant spectrum, and slow onset of action, which limit their clinical use.

[0005] β-Eudesmol is a characteristic component of Atractylodes lancea volatile oil and is often used as a marker for quality control of Atractylodes lancea. Atractylodis Rhizoma First recorded in the *Shennong Bencao Jing* (Shennong's Classic of Materia Medica), Atractylodes lancea is considered a superior herb for "lightening the body, invigorating qi, and prolonging life," holding an important place in traditional Chinese medicine theory since ancient times. Clinically, it is widely used in the treatment of gastrointestinal disorders, immune and metabolic diseases, and many other areas. Atractylodes lancea and its active ingredient β-cineole possess central nervous system pharmacological effects such as sedation, analgesia, anti-epileptic seizures, and antidepressant properties. Therefore, β-cineole is likely a safe and effective antidepressant. However, β-cineole's antidepressant activity is relatively low, and its insolubility in water limits its application. Summary of the Invention

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

[0007] This invention is achieved through the following technical solution: In a first aspect, the present invention provides a β-eucalyptol glycoside derivative of Formula I: .

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

[0009] Preferably, the β-eucalyptol glycoside derivative is any one of formulas YZ-13, YZ-14, and YZ-15: . Secondly, the present invention provides a method for preparing the above-mentioned β-eucalyptol glycoside derivative, comprising the following steps: (1) β-Cephaloyl 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 β-eucalyptol 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: .

[0010] Preferably, the base in step (1) is potassium tert-butoxide, the polar aprotic solvent is N,N-dimethylformamide, the reaction conditions are stirring at 0°C for 2-3 hours, then heating to room temperature and stirring for 16-17 hours, and the molar ratio of β-eucalyptol, ethyl bromoacetate, and potassium tert-butoxide is 1:1-2:1-2; the reducing agent in step (2) is lithium aluminum hydride, the organic solvent is tetrahydrofuran, the reaction conditions are stirring at 0°C for 0.5-1 hours, then heating to room temperature and stirring for 2.5-3 hours, and the molar ratio of intermediate M1 to lithium aluminum hydride is 1:1-2.

[0011] Preferably, the sugar donor in step (3) is selected from tetraacetyl glucosamine trichloroacetylimine ester, tetraacetyl rhamnose or teurophenol tetraacetyl glucoside, and the molar ratio of intermediate M2 to sugar donor is 1:1.1-2; the glycosylation conditions include reaction in an organic solvent in the presence of a Lewis acid catalyst or coupling agent.

[0012] 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 2-3 hours and then stirring at room temperature for 16-17 hours.

[0013] 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 2-3 hours and then stirring at room temperature for 16-17 hours.

[0014] Preferably, in step (4), the deprotection reaction includes reacting in methanol under alkaline conditions and then neutralizing with an acidic resin to obtain a β-eucalyptol glycoside derivative, wherein the alkaline conditions are provided by sodium methoxide, the reaction temperature is 0°C, and the reaction time is 1-2 h.

[0015] Thirdly, the present invention provides the use of the above-mentioned β-eudesminol glycoside derivatives or pharmaceutically acceptable salts thereof in the preparation of antidepressant drugs.

[0016] Fourthly, the present invention provides an antidepressant pharmaceutical composition comprising the above-mentioned β-cineole glycoside derivative or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.

[0017] 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 elaborated here.

[0018] Preferably, the drug dosage form is a tablet, capsule, granule, injection, oral liquid, pill, ointment, suspension, dispersant, syrup, suppository, gel, aerosol, or patch.

[0019] Compared with the prior art, the present invention has the following beneficial effects: The β-cineole glycoside derivative provided by this invention has a water solubility that is more than 1,000 times higher than that of β-cineole, and pharmacological tests have shown that its antidepressant activity is significantly higher than that of β-cineole. It can be used to prepare antidepressant drugs, providing a new option for antidepressant medication. Detailed Implementation

[0020] The present invention will be further described in detail below with reference to specific 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.

[0021] 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.

[0022] 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.

[0023] Table 1 shows the source and specifications of the main raw materials in the examples.

[0024] Table 1. Main raw material sources and specifications in the examples

[0025] Example 1: Preparation of intermediates M1 and M2 Its reaction pathway is as follows:

[0026] Step 1: β-Cephalotaxel (SM1, 30.0 g, 134.91 mmol) was dissolved in N,N-dimethylformamide (300 mL), cooled to 0 °C, and ethyl bromoacetate (27.0 g, 161.89 mmol) and potassium tert-butoxide (19.7 g, 175.38 mmol) were added. The reaction mixture was stirred at 0 °C for 3 h, then heated to room temperature and stirred for another 16 h. The reaction mixture was cooled to room temperature, poured into water (1000 mL), extracted with ethyl acetate (3 × 300 mL), and the organic layers were combined. The mixture was washed with sodium chloride solution (1 × 300 mL), dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and column chromatography was used to obtain intermediate M1 (22.5 g), yield 54%.

[0027] 1 H NMR (500 MHz, CDCl3): δ. 4.71 (d, J = 1.9 Hz, 1H), 4.44 (d, J =1.8 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 4.11 (s, 2H), 2.34 - 2.27 (m, 1H), 2.04- 1.94 (m, 1H), 1.80 - 1.73 (m, 1H), 1.67 - 1.54 (m, 6H), 1.45 - 1.41 (m,1H), 1.39 - 1.35 (m, 1H), 1.34 - 1.15 (m, 12H), 0.70 (s, 3H). HRMS (ESI) m / z Calculated. For C 19 H 33 O3 + [M+H] + =309.2424, found: 309.2433. Step 2: Intermediate M1 (20.0 g, 64.84 mmol) was dissolved in dry tetrahydrofuran (200 mL), and argon gas was purged three times. The temperature was lowered to 0 °C, and lithium aluminum hydride (3.0 g, 77.81 mmol) 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 solution until the solid was fluffy and the liquid was clear. The mixture was filtered, and the solid was washed with dry tetrahydrofuran (200 mL). The filtrate was dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and column chromatography was used to obtain intermediate M2 (14.2 g), with a yield of 82%.

[0028] The spectral identification data are as follows: 1 H NMR (500 MHz, CDCl3): δ 4.70 (d, J = 1.8 Hz, 1H), 4.43 (d, J = 1.8Hz, 1H), 4.04 - 4.00 (m, 1H), 3.88 - 3.75 (m, 3H), 2.35 - 2.28 (m, 1H), 0.71 (s, 3H). HRMS (ESI) m / z Calculated. For C 17 H 31 O2 + [M+H]+ =267.2319, found: 267.2327. Example 2: Preparation of compound YZ-13 Its reaction pathway is as follows:

[0029] Step 1: Intermediate M2 (2.0 g, 7.51 mmol) and tetraacetylglucose trichloroacetylimine ester (4.4 g, 9.01 mmol) 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) 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 solution 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.

[0030] 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 to neutral with acidic resin, filter, concentrate to remove solvent, and purify the crude product by column chromatography to obtain solid YZ-13 (1.9 g), with a combined yield of 59%.

[0031] The spectral identification data are as follows: 1 H NMR (500 MHz, D2O): δ = 4.70 (d, J = 1.8 Hz, 1H), 4.50 (d, J = 7.8Hz, 1H), 4.43 (d, J = 1.8 Hz, 1H), 4.03 - 3.99 (m, 1H), 3.93 (dd, J = 2.4,12.1 Hz, 1H), 3.79 – 3.77 (m, 3H), 3.74 (dd, J = 6.2, 12.1 Hz, 1H), 3.50 (t, J = 9.0 Hz, 1H), 3.45 (m, 1H), 3.38 (t, J = 9.1 Hz, 1H), 3.32 (dd, J= 8.0, 9.1Hz, 1H), 2.34 - 2.25 (m, 1H), 2.04 - 1.93 (m, 1H), 1.80 - 1.72 (m, 1H), 1.66 -1.53 ​​(m, 6H), 1.44 - 1.40 (m, 1H), 1.38 - 1.34 (m, 1H), 1.32 - 1.17 (m, 9H), 0.71 (s, 3H). HRMS (ESI) m / z Calculated. For C 23 H 41 O7 + [M+H] + =429.2847, found: 429.2850. Example 3: Preparation of compound YZ-14 Its reaction pathway is as follows:

[0032] Step 1: Intermediate M2 (2.0 g, 7.51 mmol) and tetraacetylrhamnose (3.0 g, 9.01 mmol) 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) 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.

[0033] 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 to neutral with acidic resin, filter, concentrate to remove solvent, and purify the crude product by column chromatography to obtain solid YZ-14 (1.6 g), with a combined yield of 52%.

[0034] The spectral identification data are as follows: 1 H NMR (500 MHz, D2O) δ 4.70 (d, J = 1.8 Hz, 1H), 4.57 (d, J= 1.7 Hz,1H), 4.03 - 4.43 (d, J = 1.8 Hz, 1H), 3.93 -3.90 (m, 2H), 3.81 - 3.75 (m,4H), 3.66 (dd, J = 3.7, 9.3 Hz, 1H), 3.59 - 3.52 (m, 1H), 2.35 - 2.27 (m, 1H), 2.06 - 1.95 (m, 1H), 1.82 - 1.75 (m, 1H), 1.67 - 1.55 (m, 6H), 1.44 - 1.41(m, 1H), 1.38 - 1.35 (m, 1H), 1.32 - 1.17 (m, 12H), 0.70 (s, 3H). HRMS (ESI) m / z Calculated. For C 23 H 41 O6 + [M+H] + =413.2898, found: 413.2904 Example 4: Preparation of compound YZ-15 Its reaction pathway is as follows:

[0035] Step 1: Intermediate M2 (3.0 g, 11.26 mmol), teurophenol tetraacetyl glucoside (5.6 g, 12.39 mmol), and triphenylphosphine (4.4 g, 16.89 mmol) were dissolved in tetrahydrofuran (60 mL), purged with argon three times, cooled to 0 °C, and diethyl azodicarbonate (2.9 g, 16.89 mmol) was slowly added dropwise. The reaction mixture 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 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 (3.2 g), which was used directly in the next step.

[0036] Step 2: Dissolve the solid obtained above in methanol (100 mL), cool to 0℃, slowly add sodium methoxide (0.3 g), stir the reaction at 0℃ 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-15 (1.8 g), with a combined yield of 30%.

[0037] The spectral identification data are as follows: 1 H NMR (500 MHz, D2O) δ 6.55 (t, J = 1.8 Hz, 1H), 6.47 (d, J = 1.8 Hz, 1H), 6.44 (t, J = 2.3 Hz, 1H), 5.03 (d, J = 7.8 Hz, 1H), 4.70 (d, J = 1.8 Hz, 1H), 4.43 (d, J = 1.8 Hz, 1H), 4.03 (m, 1H), 3.92 (dd, J = 2.3, 12.5 Hz, 1H), 3.83 (m, 3H), 3.75 (dd, J = 5.7, 12.5 Hz, 1H), 3.60 - 3.55 (m, 2H), 3.53 -3.44 (m, 2H), 2.34 - 2.27 (m, 4H), 2.03 - 1.94 (m, 1H), 1.80 - 1.72 (m, 1H),1.65 - 1.53 (m, 6H), 1.45 - 1.41 (m, 1H), 1.39 - 1.35 (m, 1H), 1.32 - 1.17(m, 9H), 0.71 (s, 3H). HRMS (ESI) m / z Calculated. For C 30 H 47 O8 + [M+H] + =535.3265, found: 535.3270. Example 5 Preparation of intermediates M1 and M2 Step 1: β-Cephalotaxel (SM1, 3.0 g, 13.5 mmol) was dissolved in N,N-dimethylformamide (30 mL), cooled to 0 °C, and ethyl bromoacetate (2.5 g, 14.8 mmol) and potassium tert-butoxide (1.8 g, 16.2 mmol) were added. The reaction mixture was stirred at 0 °C for 2 h, then heated to room temperature and stirred for another 17 h. The reaction mixture was cooled to room temperature, poured into water (100 mL), extracted with ethyl acetate (3 × 30 mL), and the organic layers were combined. The mixture was washed with sodium chloride solution (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and column chromatography was used to obtain intermediate M1 (1.1 g), with a yield of 26%.

[0038] Step 2: Intermediate M1 (1.0 g, 3.2 mmol) 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 (123 mg, 3.2 mmol) 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 (20 mL). The filtrate was dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and column chromatography was used to obtain intermediate M2 (0.6 g), with a yield of 69%.

[0039] Example 5 Preparation of intermediates M1 and M2 Step 1: β-Cephalotaxel (SM1, 3.0 g, 13.5 mmol) was dissolved in N,N-dimethylformamide (30 mL), cooled to 0 °C, and ethyl bromoacetate (4.5 g, 26.9 mmol) and potassium tert-butoxide (3.0 g, 26.9 mmol) were added. The reaction mixture was stirred at 0 °C for 2 h, then heated to room temperature and stirred for another 17 h. The reaction mixture was cooled to room temperature, poured into water (100 mL), extracted with ethyl acetate (3 × 30 mL), and the organic layers were combined. The mixture was washed with sodium chloride solution (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and column chromatography was used to obtain intermediate M1 (2.1 g), with a yield of 50%.

[0040] Step 2: Intermediate M1 (1.0 g, 3.2 mmol) 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 (246 mg, 6.5 mmol) 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 (20 mL). The filtrate was dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and column chromatography was used to obtain intermediate M2 (0.73 g), with a yield of 85%.

[0041] Example 6 Preparation of compound YZ-13 Step 1: Intermediate M2 (0.5 g, 1.9 mmol) and tetraacetylglucose trichloroacetylimine ester (1.8 g, 3.7 mmol) were dissolved in dichloromethane (5 mL), purged with argon three times, cooled to 0 °C, and boron trifluoride diethyl ether (0.5 g, 3.7 mmol) was slowly added dropwise. The reaction was stirred at 0 °C for 2 h, then heated to room temperature and stirred for 17 h. The reaction solution was poured into a saturated sodium bicarbonate solution (10 mL), stirred for 5 min, filtered, and the aqueous layer was extracted with dichloromethane (3 × 5 mL). The organic layers were combined and washed successively with saturated sodium bicarbonate solution (1 × 5 mL) and saturated sodium chloride solution (1 × 5 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.

[0042] Step 2: Dissolve the solid obtained above in methanol (5 mL), cool to 0 °C, slowly add sodium methoxide (0.05 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-13 (0.43 g), with a combined yield of 53%.

[0043] Example 7 Preparation of compound YZ-14 Step 1: Intermediate M2 (0.5 g, 1.9 mmol) and tetraacetylrhamnose (1.3 g, 3.8 mmol) were dissolved in dichloromethane (5 mL), purged with argon three times, cooled to 0 °C, and boron trifluoride diethyl ether (0.6 g, 3.8 mmol) was slowly added dropwise. The reaction mixture 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 (10 mL), stirred for 5 min, filtered, and the aqueous layer was extracted with dichloromethane (3 × 5 mL). The organic layers were combined and washed successively with saturated sodium bicarbonate solution (1 × 5 mL) and saturated sodium chloride solution (1 × 5 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.

[0044] Step 2: Dissolve the solid obtained above in methanol (5 mL), cool to 0 °C, slowly add sodium methoxide (0.05 g), stir the reaction at 0 °C for 2 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-14 (0.41 g), with a combined yield of 53%.

[0045] Example 8 Preparation of compound YZ-15 Step 1: Intermediate M2 (0.5 g, 1.9 mmol), teurophenol tetraacetyl glucoside (1.7 g, 3.8 mmol), and triphenylphosphine (1.0 g, 3.8 mmol) were dissolved in tetrahydrofuran (10 mL), purged with argon three times, cooled to 0 °C, and diethyl azodicarbonate (0.7 g, 3.8 mmol) was slowly added dropwise. The reaction mixture 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 ammonium chloride solution (10 mL), stirred for 5 min, filtered, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, washed with a saturated sodium chloride solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and column chromatography was performed to obtain a solid compound which was directly used in the next step.

[0046] Step 2: Dissolve the solid obtained above in methanol (10 mL), cool to 0 °C, slowly add sodium methoxide (0.05 g), stir the reaction at 0 °C for 2 h, adjust the pH to neutral with acidic resin, filter, concentrate to remove solvent, and purify the crude product by column chromatography to obtain solid YZ-15 (0.38 g), with a combined yield of 38%.

[0047] Example 9: Simple Solubility Experiment According to the literature {Anurak Cheoymang, Kessrs Na-Bangchang, Lipophilicity, aqueous solubility, and degree of ionization of atractylodin and β-eudesmol, the bioactive compounds isolated from atractylodes lancea, Int J Pharm PharmSci, Vol 13, Issue 6, 17-22}, the solubility of β-eudesmol in water is approximately 32.48 μg / mL.

[0048] Take three test tubes, add 33 mg of the sample prepared in Examples 2-4 to each tube, add purified water, sonicate for 20 seconds, and observe the dissolution. The experimental results are shown in Table 2 below.

[0049] Table 2 Solubility test results

[0050] Experimental results show that the solubility of the three compounds provided by this invention is greater than 33 mg / mL, indicating that the solubility of the three compounds provided by this invention is more than 1000 times that of β-eucalyptol.

[0051] Example 10 Evaluation of antidepressant activity 1. Preparation of test sample and positive control Imipramine hydrochloride: Dissolve the required amount of imipramine hydrochloride in physiological saline to prepare a 1.5 mg / ml solution. Prepare fresh before each administration.

[0052] β-Cephalophyllin: Weigh an appropriate amount of β-Cephalophyllin, dissolve it in 2% DMSO, dilute it with corn oil, and prepare a 2 mg / ml solution.

[0053] ZY-13: Weigh an appropriate amount of ZY-13, dissolve it in physiological saline, and prepare a solution with a concentration of 1 mg / ml. Prepare and use immediately.

[0054] ZY-14: Weigh an appropriate amount of ZY-14, dissolve it in physiological saline, and prepare a solution with a concentration of 1 mg / ml. Prepare and use immediately.

[0055] ZY-15: Weigh an appropriate amount of ZY-15, dissolve it in physiological saline, and prepare a solution with a concentration of 1 mg / ml. Prepare and use immediately.

[0056] 2. Experimental System (1) Animals Species, strain, quality level: Mouse, Kunming, specific pathogen free (SPF); Sex and quantity: Male, 60; Animal body weight range: 25 - 30 g; Animal source and certificate number: Beijing Spey Foster Laboratory Animal Center, SCXK(Beijing)2024 - 000

[0057] (2)Identification method of experimental animals After the animals arrive, they are received according to the company's operating procedures for receiving experimental animals. An independent batch number is assigned to each batch of animals, and at the same time, the animals are marked. The experimental animal numbers are used for identification in the original materials.

[0058] (3)Feeding, management and environmental conditions of experimental animals The experimental animals are housed in an independent ventilated cage system (IVC) in the company's experimental animal house. The numbers of the experimental facilities are: 13 - 11 - 080 and 13 - 11 - 081, and the production date of the facilities is November 24, 2013. The feeding method is group housing, 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, and a 12 - hour light and 12 - hour dark cycle is adopted. The light - on time is 7:00 am, and the light - off time is 19:00 pm. The cages and bedding are changed twice a week.

[0059] (4)Feed and drinking water The experimental animals are fed with sterilized feed produced by Jiangsu Xietong Pharmaceutical Biotechnology Co., Ltd. The feed certificate number is: Su Feed Certificate (2019)01008. Each cage is supplied with feed once a day, and the drinking water bottle contains cold boiled water for the animals to drink freely.

[0060] (5)Animal numbering, marking and experimental grouping A unique experimental animal number is assigned to each experimental animal, and the animal number is marked on the animal and the cage card. A black marker pen is used to mark the tails of the mice. The experimental animals are randomly grouped using the simple random number sorting method in Excel into a normal saline group, an imipramine hydrochloride group, a β - eudesmol group, a ZY - 13 group, a ZY - 14 group and a ZY - 15 group, with 10 animals in each group.

[0061] 3. Experimental methods (1)Administration route and method Administration route: Intraperitoneal injection (i.p); Administration volume: 0.1 ml / 10 g body weight; Administration frequency and time: Once a day; (2)Testing method Depressive behavior in mice was detected by tail suspension test and forced swimming.

[0062] 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 should be in obvious contrast to the color of the mouse's fur. A black background is used for white mice.

[0063] 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.

[0064] 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 then administered intraperitoneally according to the established experimental protocol, followed by a 6-minute forced swimming test. The specific experimental procedure was as follows: the identified numbered mice were gently held and slowly moved to the tank. The mice were then gently lowered into the water, head up and facing the tank wall. A timer was started immediately upon entry, initiating a countdown. There should be no debris within 0.5 m of the tank. The experimenter observed and recorded the mice's condition from a distance of 1.5 m. The tank was changed and cleaned as needed. After the forced swimming test, the mice were immediately removed from the tank, dried, and returned to their cages. The forced swimming was recorded using a DV camera.

[0065] 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.

[0066] 3.3 Experimental Procedure (1) Evaluation of 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.

[0067] (2) Statistical analysis One-way ANOVA was performed using SPSS 22.0 software, followed by LSD (Least Significant Difference) for inter-group comparisons. 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).

[0068] 4. Results (1) Results of mouse tail suspension test The results of the tail suspension test are shown in Table 3. It can be seen that, 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 predictive ability. Compared with the saline group, the immobility time of the animals in the ZY-13 (10 mg / kg) group was significantly shortened (*P<0.05), the immobility time of the animals in the ZY-14 (10 mg / kg) group was significantly shortened (**P<0.01), the immobility time of the animals in the ZY-15 (10 mg / kg) group was significantly shortened (**P<0.01), and the immobility time of the animals in the β-eucalyptol (20 mg / kg) group was significantly shortened (*P<0.05). The immobility time shortening effect of ZY-15 was the best.

[0069] Table 3. Immobility time in mouse tail suspension test

[0070] Note: Compared with normal saline, P<0.05*; P<0.01**; P<0.001***, One-way ANOVA (2) Results of forced swimming in mice The drug was administered again 24 h after the tail suspension test, and forced swimming was performed 0.5 h later. The results are shown in Table 4 below.

[0071] 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-13 (10 mg / kg) group, ZY-14 (10 mg / kg) group, ZY-15 (10 mg / kg) group, and β-eucalyptol (20 mg / kg) group was significantly shorter (*P<0.05), with ZY-15 showing the best effect in shortening the immobility time.

[0072] Table 4. Time of immobility during forced swimming in mice

[0073] Note: VS saline solution P <0.05*; P <0.01**; P <0.001***, One-way ANOVA 5. Conclusion In the tail suspension test and forced swimming test, the experimental system showed good drug predictive ability. Under this test system, ZY-13, ZY-14 and ZY-15 all showed better antidepressant activity than the β-eucalyptol group, and ZY-15 was superior to ZY-13 and ZY-14.

[0074] 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. A β-eudesmol glycoside derivative represented by Formula I: ###0001### Formula I wherein R is selected from any one of glucoside, rhamnoside, or orsellinic acid glucoside. The β-eudesmol glycoside derivative is any one of Formula YZ-13, YZ-14, or YZ-15: ###0002### Formula YZ-13 Formula YZ-14 Formula YZ-15 2. The β-eudesmol glycoside derivative according to claim 1, characterized by, comprising the following steps: 。 3. A process for the preparation of the β-eudesmol glycoside derivative according to claim 1 or 2, characterized in that, (1) reacting β-eudesmol with ethyl bromoacetate in the presence of a base in a polar aprotic solvent to form an intermediate M1; (2) reacting the intermediate M1 with a reducing agent in an organic solvent to form an intermediate M2; (3) reacting the intermediate M2 with a sugar donor under glycosylation conditions to form an acetylated glycoside intermediate; (4) deprotecting the acetylated glycoside intermediate obtained in step (3) to obtain the β-eudesmol glycoside derivative; the chemical structure of the intermediate M1 is represented by Formula M1 and the chemical structure of the intermediate M2 is represented by Formula M2: in step (1), the base is potassium tert-butoxide and the polar aprotic solvent is N,N-dimethylformamide, the reaction condition is stirring at 0 °C for 2-3 h and then stirring at room temperature for 16-17 h, and the molar ratio of β-eudesmol, ethyl bromoacetate, and potassium tert-butoxide is 1:1-2:1-2; in step (2), the reducing agent is lithium aluminum hydride and the organic solvent is tetrahydrofuran, the reaction condition is stirring at 0 °C for 0.5-1 h and then stirring at room temperature for 2.5-3 h, and the molar ratio of the intermediate M1 and lithium aluminum hydride is 1:1-2. 。 4. The method of claim 3, wherein, in step (3), the sugar donor is selected from tetraacetylglucose trichloroacetimidate, tetraacetyl rhamnose, or orsellinic acid tetraacetyl glucoside, and the molar ratio of the intermediate M2 and the sugar donor is 1:1.1-2; the glycosylation conditions include reacting in the presence of a Lewis acid catalyst or a coupling agent in an organic solvent.

5. The method of claim 3, wherein, when the sugar donor is tetraacetylglucose trichloroacetimidate or tetraacetyl rhamnose, the Lewis acid catalyst is boron trifluoride etherate and the organic solvent is dichloromethane, and the reaction condition is stirring at 0 °C for 2-3 h and then stirring at room temperature for 16-17 h.

6. The method of claim 5, wherein, when the sugar donor is orsellinic acid tetraacetyl glucoside, the coupling agent is triphenylphosphine and diethyl azodicarboxylate, the organic solvent is tetrahydrofuran, and the reaction condition is stirring at 0 °C for 2-3 h and then stirring at room temperature for 16-17 h.

7. The method of claim 5, wherein, in step (4), the deprotection reaction includes reacting in a basic condition in methanol and then neutralizing with an acidic resin to obtain the β-eudesmol glycoside derivative, wherein the basic condition is provided by sodium methoxide, the reaction temperature is 0 °C, and the reaction time is 1-2 h.

8. The method of claim 3, wherein, 9. Use of the β-eudesmol glycoside derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of an antidepressant drug. The β-eudesmol glycoside derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 and a pharmaceutically acceptable adjuvant.

10. An antidepressant pharmaceutical composition, characterized by, ​

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