Diterpenoid alkaloid 3-acetyl aconitine, pharmaceutical composition and application

Abstract

The invention relates to the technical field of medicines, and discloses diterpenoid alkaloid 3-acetyl aconitine as well as a pharmaceutical composition and application of the diterpenoid alkaloid 3-acetyl aconitine. The C19 type diterpenoid alkaloid 3-acetyl aconitine provided by the invention shows remarkable anti-depression activity in a mouse behavioral despair model experiment, is obviously superior to a positive drug fluoxetine, and can be used for developing anti-depression drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and more particularly relates to a C 19 type diterpene alkaloid 3-acetylaconitine, a pharmaceutical composition and application in preparation of antidepressant drugs. BACKGROUND

[0002] Nowadays, the society competition is increasingly fierce, and the high-intensity and high-pressure life has a serious impact on people's physical and mental health, and the depression gradually increases and seriously affects people's normal work and life. At present, the drugs for treating depression generally have large side effects and have certain limitations in clinical application.

[0003] The inventors prepared 3-acetylaconitine from aconite, found that it showed significant antidepressant activity in a mouse behavioral despair model experiment, which was better than the positive drug fluoxetine (Fluoxetine), and could be used for developing antidepressant drugs. SUMMARY

[0004] In view of the deficiencies of the prior art, the present application provides a C 19 type diterpene alkaloid 3-acetylaconitine, a preparation method, a pharmaceutical composition and application in antidepressant drugs. And, the present application is a divisional application of the invention patent application No. 2024110665310, entitled "Preparation method of diterpene alkaloid 3-acetylaconitine", filed on August 5, 2024.

[0005] To achieve the above-mentioned purpose, the technical scheme of the present application is as follows:

[0006] A diterpene alkaloid 3-acetylaconitine has a structure shown in formula (1):

[0007]

[0008] It should be noted that the diterpene alkaloid 3-acetylaconitine can be a compound including the structure shown in formula (1), a stereoisomer, a tautomer or a pharmaceutically acceptable salt. That is, the compound including the structure shown in formula (1), its stereoisomer, tautomer and pharmaceutically acceptable salt are all within the protection scope of the present application.

[0009] The present application further provides a preparation method of the diterpene alkaloid 3-acetylaconitine, which is obtained by extraction and separation from aconite.

[0010] In the above technical scheme, the preparation method of the diterpene alkaloid 3-acetylaconitine comprises the following steps:

[0011] S1, taking dry Fuzi, adding solvent to reflux extraction, combining the extract and then concentrating to obtain the extract;

[0012] S2, adding the extract to dilute hydrochloric acid to fully dissolve and suspend, then filtering to remove impurities to obtain an acid aqueous solution; once extracting the acid aqueous solution with dichloromethane, filtering out the first extract to obtain a filtered acid aqueous solution; adjusting the pH of the filtered acid aqueous solution to be alkaline; then twice extracting with dichloromethane to obtain a second extract;

[0013] S3, gradient eluting the second extract with dichloromethane-methanol solution to obtain fraction B; when using silica gel thin layer chromatography, the Rf value corresponding to fraction B is 0.76-0.80;

[0014] S4, gradient eluting fraction B with methanol-water mixed solution to obtain fraction B4;

[0015] When using silica gel thin layer chromatography, the Rf value corresponding to fraction B4 is 0.61-0.69;

[0016] S5, gradient eluting fraction B4 with methanol-water solution to obtain fraction L3;

[0017] When using silica gel thin layer chromatography, the Rf value corresponding to fraction L3 is 0.66-0.75;

[0018] S6, separating the diterpene alkaloid 3-acetylhellebrin from fraction L3 by RP-HPLC (i.e. reverse phase high performance liquid chromatography);

[0019] The mobile phase used in RP-HPLC is a mixture of acetonitrile and water.

[0020] Further, in step S2, the filtered acid aqueous solution is adjusted to pH 8-11 with sodium hydroxide; preferably, to pH=9.

[0021] Further, in step S2, the extract is added to 8-15 times the mass of dilute hydrochloric acid to fully dissolve and suspend, then filtering to remove impurities to obtain an acid aqueous solution.

[0022] Further, the concentration of the dilute hydrochloric acid is 0.1-1.0%; preferably 0.5%.

[0023] Further, in step S3, the second extract is separated by silica gel column chromatography to obtain fraction B; based on a total volume of 100, the volume ratio of dichloromethane to methanol in the dichloromethane-methanol solution when washing out (i.e. corresponding to) fraction B is (97:3)-(93:7).

[0024] Preferably, in step S3, the volume ratio of dichloromethane to methanol in the dichloromethane-methanol solution (i.e. corresponding to the elution of fraction B) is 95:5.

[0025] Further, in step S4, the fraction B is separated by ODS column chromatography to obtain fraction B4; and the volume ratio of methanol to water in the methanol-water mixed solution (i.e. corresponding to the elution of fraction B4) is (45:55)-(55:45) based on a total volume of 100.

[0026] Preferably, in step S4, the volume ratio of methanol to water in the methanol-water mixed solution is 50:50.

[0027] Further, in step S4, the methanol-water mixed solution contains 0.01-0.1V% formic acid.

[0028] Preferably, in step S4, the methanol-water mixed solution contains 0.05V% formic acid.

[0029] Further, in step S5, the fraction B4 is separated by gel column chromatography to obtain fraction L3; and the volume ratio of methanol to water in the methanol-water solution (i.e. corresponding to the elution of fraction L3) is (65:35)-(75:25) based on a total volume of 100.

[0030] Preferably, in step S5, the volume ratio of methanol to water in the methanol-water solution is 70:30.

[0031] Further, in step S6, the volume ratio of acetonitrile to water in the acetonitrile-water mixed solution is (50:50)-(55:45); and the acetonitrile-water mixed solution contains 0.01-0.5V% trifluoroacetic acid.

[0032] Further, in step S6, the volume ratio of acetonitrile to water in the acetonitrile-water mixed solution is 52:48.

[0033] Further, in step S6, the acetonitrile-water mixed solution contains 0.1V% trifluoroacetic acid.

[0034] Further, in step S1, the solvent is 88-98V% aqueous ethanol, the solvent is added in an amount of 8-10 times the mass of the appendage, and the reflux extraction is performed 2-4 times, each time for 1-3h.

[0035] In another aspect, the present application also provides a pharmaceutical composition comprising the above-mentioned diterpene alkaloid 3-acetylaconitine.

[0036] Further, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0037] Further, the pharmaceutical composition further comprises a synergist.

[0038] The synergist is one or several of the following:

[0039] fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, escitalopram, venlafaxine, duloxetine, mirtazapine, bupropion, agomelatine, trazodone, reboxetine, imipramine, clomipramine, desipramine, maprotiline, moclobemide, Shugan Jieyu Capsule, St. John's wort extract, flupentixol melitracen, etc.

[0040] That is, the pharmaceutical composition containing the 3-acetylaconine of the present application as an active ingredient and conventional pharmaceutical excipients or adjuvants or carriers is also included in the present application.

[0041] Further, the dosage form of the pharmaceutical composition is tablet, capsule, granule, oral liquid, powder, dripping pill or pellet.

[0042] The present application further provides the use of the above-mentioned diterpene alkaloid 3-acetylaconine and / or the pharmaceutical composition in antidepressant drugs.

[0043] Compared with the prior art, the present application has the following advantages:

[0044] (1) The experimental results show that the C 19 type diterpene alkaloid 3-acetylaconine provided by the present application shows significant antidepressant activity in the tail suspension test of the mouse behavioral despair model, which is superior to the positive drug fluoxetine, and can be used for developing antidepressant drugs.

[0045] (2) The present application provides a method for preparing the C 19 type diterpene alkaloid 3-acetylaconine, which can be obtained from aconite with simple operation, good reproducibility and high extraction purity. 19 type diterpene alkaloid 3-acetylaconine. DETAILED DESCRIPTION

[0046] In order to make the purpose, technical scheme and advantages of the present application clearer, the present application will be further described in detail below in combination with embodiments.

[0047] It should be understood that the specific embodiments described herein are only used to explain the present application and do not limit the present application.

[0048] In the embodiments, unless otherwise specified, the means used are conventional means in the art.

[0049] As used herein the terms "comprises", "comprising", or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but can include other elements not expressly listed or inherent to such composition, step, method, article, or apparatus.

[0050] Unless otherwise indicated, technical or conditions in the examples were carried out according to techniques or conditions described in the literature or according to the manufacturer's instructions. Unless otherwise indicated, reagents or instruments were commercially available and were used according to the manufacturer's instructions.

[0051] The endpoints of the ranges and any values described herein are not limited to the precise values stated. The ranges and values should be construed to be approximations that allow for significant error and variations. Various ranges of values that overlap, overlap with each other, and / or are adjacent to each other are considered to be encompassed by a particular value or range.

[0052] Further, the various features of the application described below in individual embodiments can be combined with each other as long as no conflict arises.

[0053] Example 1

[0054] The present embodiment discloses a preparation method of C 19 type diterpenoid alkaloid 3-acetylaconitine, and the C 19 type diterpenoid alkaloid 3-acetylaconitine is obtained by extraction and separation from aconite.

[0055] The present embodiment discloses a preparation method of C 19 type diterpenoid alkaloid 3-acetylaconitine, and the C

[0056] S1, taking dry aconite, adding solvent to reflux extraction, and then combining the extraction liquid and concentrating to obtain an extract;

[0057] Specifically, taking dry aconite, and taking 95% ethanol aqueous solution with a mass of 10 times of the aconite as the solvent, reflux extraction for three times, each time for 2 hours, combining the extraction liquid and concentrating to obtain the extract;

[0058] S2, adding the extract into dilute hydrochloric acid to fully dissolve and suspend, filtering to remove impurities to obtain an acid aqueous solution; extracting the acid aqueous solution with dichloromethane once, filtering out the first extraction to obtain a filtered acid aqueous solution; adjusting the pH of the filtered acid aqueous solution to be alkaline; and then extracting with dichloromethane twice to obtain a second extraction.

[0059] Specifically, the extract is added to 10 times the mass of 0.5% dilute hydrochloric acid, fully dissolved and suspended, and then filtered to remove impurities. The filtered acid aqueous solution is extracted with 1.5 times the volume of dichloromethane three times to obtain an acidified dichloromethane extract (first extract, discarded) and an acid water layer, which is the filtered acid aqueous solution;

[0060] The filtered acid aqueous solution is adjusted to pH = 9 with sodium hydroxide, and then extracted twice with dichloromethane. The second dichloromethane extract is obtained.

[0061] S3, gradient elution of the second extract with dichloromethane-methanol solution to obtain fraction B; when using silica gel thin layer chromatography, the corresponding brick red spot of fraction B shows an Rf value of 0.76-0.80; based on a total volume of 100, the volume ratio of dichloromethane to methanol in the dichloromethane-methanol solution used to elute fraction B (i.e. corresponding to fraction B) is (97:3)-(93:7).

[0062] Specifically, the second extract is subjected to silica gel column chromatography, and gradient elution is performed with dichloromethane-methanol in a volume ratio of 100:0, 95:5, 92:8, 90:10, 85:15, 75:25, 65:35, 50:50, and 0:100, respectively, to obtain fractions 1-10, 11-20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, and 81-90, respectively.

[0063] The Rf values of the corresponding brick red spots of fractions 1-10, 11-20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, and 81-90 are 0.82-0.86, 0.76-0.80, 0.72-0.75, 0.65-0.70, 0.56-0.62, 0.50-0.54, 0.42-0.48, 0.30-0.38, and 0.25-0.28, respectively, when using silica gel thin layer chromatography. Similar fractions are combined to obtain fractions A, B, C, D, E, F, G, H, and I, respectively. Fractions 11-20 are combined to obtain fraction B.

[0064] S4, gradient elution of fraction B with a methanol-water mixed solution to obtain fraction B4; when using silica gel thin layer chromatography, the Rf value of fraction B4 is 0.61-0.69. Based on a total volume of 100, the volume ratio of methanol to water in the methanol-water mixed solution used to elute fraction B4 (i.e. corresponding to fraction B4) is (45:55)-(55:45). The methanol-water mixed solution contains 0.01-0.1 V% formic acid.

[0065] i.e. fraction B was selected for further separation according to the brick-red spot shown by the bismuth potassium iodide reagent and the characteristic UV absorption (λ max = 230 nm) observed by HPLC analysis.

[0066] Specifically, fraction B was subjected to ODS column chromatography and gradient elution using methanol-water mixed solutions (containing 0.05 V% formic acid in the methanol-water mixed solution) with volume ratios of 20:80, 30:70, 40:60, 50:50, 60:40, 80:20, and 100:0. Then, fractions 1-6, 7-15, 16-23, 24-36, 37-45, 46-57, and 58-68 were obtained in sequence, and a total of 68 fractions were collected.

[0067] Using silica gel thin layer chromatography, the Rf values were 0.35-0.44 (fractions 1-6), 0.45-0.49 (fractions 7-15), 0.50-0.60 (fractions 16-23), 0.61-0.69 (fractions 24-36), 0.70-0.74 (fractions 37-45), 0.75-0.79 (fractions 46-57), and 0.80-0.89 (fractions 58-68) according to the brick-red spot shown by the bismuth potassium iodide reagent, and similar fractions were combined into seven fractions B1-B7. Among them, fractions 24-36 were combined to obtain fraction B4.

[0068] S5, fraction B4 was subjected to gradient elution using a methanol-water solution to obtain fraction L3; when subjected to silica gel thin layer chromatography, the Rf value corresponding to fraction L3 was 0.66-0.75; and the volume ratio of methanol to water in the methanol-water solution when eluting fraction L3 was (65:35)-(75:25).

[0069] i.e. fraction B4 was selected for further separation according to the brick-red spot shown by the bismuth potassium iodide reagent and the characteristic UV absorption (λ max = 230 nm) observed by HPLC analysis.

[0070] Specific operation includes: fraction B4 through gel column chromatography, using volume ratio of methanol-water gradient elution of 0:100, 30:70, 70:30, 100:0, collected fraction 1-6, 7-15, 16-21, 22-25, a total of 25 fractions, then using silica gel thin layer chromatography, according to the brick red spot observed by bismuth potassium iodide reagent Rf value is 0.35-0.52 (fraction 1-6), 0.53-0.65 (fraction 7-15), 0.66-0.75 (fraction 16-21), 0.75-0.85 (fraction 22-25), combined similar fractions into four fractions L1~L4; fraction 16-21 combined to obtain fraction L3. The Rf value of fraction L3 is 0.66-0.75.

[0071] According to the brick red spot observed by bismuth potassium iodide reagent and the characteristic ultraviolet absorption (λ max =230nm) observed by HPLC analysis, fraction L3 is selected for next step separation.

[0072] S6, using RP-HPLC method from fraction L3 to separate the diterpene alkaloid 3-acetylhypaconine, defined as compound 1.

[0073] The mobile phase used in RP-HPLC method is acetonitrile-water mixed solution; the volume ratio of acetonitrile to water in acetonitrile-water mixed solution is (50:50)-(55:45), preferably 52:48; wherein the acetonitrile-water mixed solution contains 0.01-0.5V% trifluoroacetic acid.

[0074] Specifically, in the mobile phase used in RP-HPLC method for separating fraction L3, the volume ratio of acetonitrile to water is 52:48, and contains 0.1% trifluoroacetic acid; using C 18 Chromatographic column in fraction L3 to prepare C 19 type diterpene alkaloid 3-acetylhypaconine (t R =28.2min, purity 98%).

[0075] The physical properties and detection data of compound 1 prepared in Example 1 are as follows:

[0076] White amorphous powder, easily soluble in methanol. High resolution mass spectrometry (HR-ESI-MS) m / z 688.3335 ([M+H] + The calculated value is 688.3328), combined with nuclear magnetic data, to determine the molecular formula of C 36 H 49 NO 12 , the unsaturation is calculated to be 13, and the nuclear magnetic data is as follows:

[0077] 1HNMR (400 MHz, CDC13) δ: 3.09 (IH, dd, J = 10.6, 6.8 Hz, H-I), 2.09 (IH, m, H-2β), 2.34 (IH, m, H-2α), 4.91 (IH, dd, J = 13.8, 5.3 Hz, H-3β), 2.26 (IH, m, H-5β), 4.07 (IH, d, J = 6.8 Hz, H-6β), 2.73 (IH, br s, H-7), 2.70 (IH, m, H-9), 2.21 (IH, m, H-10), 2.12 (IH, m, H-12α), 2.89 (IH, dd, J = 12.2, 5.7 Hz, H-12β), 4.86 (IH, d, J = 5.2 Hz, H-14β), 4.45 (IH, dd, J = 5.2, 2.7 Hz, H-15β), 3.31 (IH, d, J = 5.3 Hz, H-16), 2.82 (IH, s, H-17), 4.05 (IH, d, J = 8.0 Hz, H-18β), 3.79 (IH, d, J = 8.4 Hz, H-18α), 2.27 (IH, d, J = 11.0 Hz, H-19β), 2.49 (IH, d, J = 11.0 Hz, H-19α), 1.09 (3H, t, J = 7.1 Hz, NCH2CH3), 2.43 (IH, m, NCH2αCH3), 2.95 (IH, m, NCH2βCH3), 1.36 (3H, s, 8-COCH3), 2.05 (3H, s, 3-COCH3), 3.18 (3H, s, 1-OCH3), 3.17 (3H, s, 6-OCH3), 3.71 (3H, s, 16-OCH3), 3.23 (3H, s, 18-OCH3), 8.04

[0078] (2H, d, J = 7.1 Hz, H-2', 6'), 7.55 (IH, t, J = 7.3 Hz, H-4'), 7.44 (2H, t, J = 7.5 Hz, H-3', 5');

[0079] 13CNMR (100 MHz, CDC13) δ: 83.7 (C-l), 32.2 (C-2), 71.9 (C-3), 42.5 (C-4), 46.1 (C-5), 82.4 (C-6), 45.5 (C-7), 92.2 (C-8), 44.8 (C-9), 40.7 (C-10), 49.9 (C-l l), 36.7 (C-12), 74.5 (C-13), 79.1 (C-14), 78.9 (C-15), 90.4 (C-16), 61.4 (C-17), 71.7 (C-18), 49.4 (C-19), 47.3 (NCH2CH3), 13.7 (NCH2CH3), 172.6 (8-COCH3), 21.4 (8-COCH3), 170.5 (3-COCH3), 21.6 (3-COCH3), 56.7 (1-OCH3), 58.6 (6-OCH3), 60.9 (16-OCH3), 58.9 (18-OCH3), 166.3 (OCO), 130.0 (C-l'), 129.8 (C-2',6'), 128.8 (C-3',5'), 133.5 (C-4').

[0080] The C 19 The structural formula of the C

[0081]

[0082] Comparative Example 1

[0083] Comparative Example 1 of the present application provides a preparation method of the C 19 The preparation method of the C

[0084] The compound prepared in Comparative Example 1 has a serious peak tailing in the preparation process, and the analysis of the liquid phase after preparation shows that it contains a large amount of impurities, and the purity of the prepared compound 1 is less than 50%.

[0085] Comparative Example 2

[0086] Comparative Example 2 of the present application provides a preparation method of the C 19 The preparation method of the C

[0087] Comparative Example 2 cannot detect the compound in the subsequent fraction preparation process; Comparative Example 2 cannot detect the compound in the subsequent fraction preparation process;

[0088] The results show that compound 1 cannot be prepared.

[0089] Test Example 1

[0090] This test example discloses the antidepressant effect of compound 3-acetylaconine in a mouse behavioral despair model experiment (the gold standard for screening antidepressants).

[0091] 1. Experimental materials and instruments

[0092] Fluoxetine hydrochloride was purchased from Shanghai Yuan Ye Biotechnology Co., Ltd.; methylcytisine, norlaudanosine were purchased from Shanghai Shidan Standard Technology Service Co., Ltd.; total alkaloids of Fuzi; 3-acetylaconine.

[0093] ZIL-2 type mouse autonomous activity box (Shanghai Xinman Teaching Equipment Co., Ltd.); YLS-18A type mouse tail suspension instrument (Anhui Zhenghua Biological Instrument Equipment Co., Ltd.); electronic balance (Sartorius Scientific Instruments (Beijing) Co., Ltd.).

[0094] 2. Experimental animals

[0095] ICR mice, male, body weight 18-22 g, SPF level, provided by Weitong Lihua, animal license number: SYXK(Jing)2023-0001 The animals were bred in an environment with a temperature of 23±2℃ and a humidity of 50±10%, and the lighting time was 12h per day (lighting from 7:00 to 19:00). The animals were bred for 3d, and then the experiments were performed. The animals were fasted for 6h before the behavioral experiment, and free water was provided.

[0096] 3. Experimental method

[0097] 70 ICR male mice were arranged in a snake shape in descending order of the number of autonomous activities in animal screening, and divided into 7 groups, namely the blank group (same volume of physiological saline), the positive drug fluoxetine group (10 mg / kg), the methylcytisine group (10 mg / kg), the norlaudanosine group (10 mg / kg), the total alkaloids of Fuzi group (10 mg / kg), the 3-acetylaconine low-dose group (0.03 mg / kg), and the 3-acetylaconine high-dose group (0.3 mg / kg), 10 mice in each group, and numbered respectively. The drugs were added to physiological saline to prepare a solution, and each group was given intragastrical administration once a day, with a drug volume of 0.1 ml / 10 g of body weight. After 3 days of continuous administration, the autonomous activity experiment was performed on the 4th day, and the tail suspension experiment was performed on the 5th day.

[0098] 3. Experimental results

[0099] As shown in Table 1, compared with the blank group, the 3-acetylaconine high-dose group (0.3 mg / kg) can significantly shorten the immobility time of the mice in the tail suspension test, and shows an obvious antidepressant effect better than the positive drugs fluoxetine (10 mg / kg, a first-line chemical drug for clinical treatment of depression), methylcytisine (10 mg / kg), norlaudanosine (10 mg / kg) and aconite total alkaloids (10 mg / kg).

[0100] Table 1 Influence of 3-acetylaconine on the immobility time of the mice in the tail suspension test of the behavior despair model

[0101]

[0102] (compared with the blank group, * P<0.05, *** P<0.001)

[0103] As shown in Table 2, compared with the blank group, the open field test shows that the self-activity of the mice in each administration group has no significant influence, which indicates that the effect of the immobility time of the mice in the tail suspension test is irrelevant to the nerve excitability.

[0104] Table 2 Influence of 3-acetylaconine on the horizontal movement distance of the mice in the open field test of the behavior despair model

[0105]

[0106] In summary, the C 19 The diterpene alkaloid 3-acetylaconine has an antidepressant activity significantly better than fluoxetine, a first-line drug for depression, and can be applied as a drug precursor for treating depression.

[0107] Application Example 1

[0108] The application example of the present application discloses a capsule with 3-acetylaconine as a raw drug, and the components are as follows:

[0109]

[0110] The specific preparation process is as follows:

[0111] 3-acetylaconine, starch and sodium pyrosulfite are uniformly mixed, anhydrous ethanol is added to form a soft material, the soft material is passed through a 24-mesh sieve to form granules, the granules are dried, magnesium stearate is added, and the mixture is uniformly mixed and loaded into a capsule.

[0112] Application Example 2

[0113] The application example of the present application discloses a granule with 3-acetylaconine as a raw drug, and the components are as follows:

[0114] 3-acetylaconine 4.0 mg

[0115] Starch 6.0g

[0116] Sodium bisulfite 0.2g

[0117] Magnesium stearate 0.2g

[0118] Anhydrous ethanol q.s.

[0119] Make 100 bags.

[0120] The specific preparation process is as follows:

[0121] Take 3-acetylaconine and starch, sodium bisulfite, mix evenly, add anhydrous ethanol to make soft material, pass through 24 mesh sieve, make granules, dry, add magnesium stearate, mix evenly, bag.

[0122] Application Example 3

[0123] The application example of the application discloses an oral liquid taking compound 3-acetylaconine as raw material, and its components are as follows:

[0124]

[0125] The specific preparation process is as follows:

[0126] After mixing the above components, the conventional preparation method of oral liquid is adopted, and it can be divided and packaged.

[0127] Application Example 4

[0128] The application example of the application discloses an injection taking compound 3-acetylaconine as raw material, and its components are as follows:

[0129] 3-acetylaconine 4.0mg

[0130] Vitamin C 0.2g

[0131] Sodium chloride 6.0g

[0132] Sodium bicarbonate 0.5g

[0133] Water for injection 1000.0mL

[0134] Make 100.

[0135] The specific preparation process is as follows:

[0136] After mixing the above components, the conventional preparation method of injection is adopted, and 100 injections can be obtained.

[0137] Application Example 5

[0138] The application example of the application discloses a tablet taking compound 3-acetylaconine and fluoxetine as raw material, and its components are as follows:

[0139] 3-acetylaconine 3.5mg

[0140] fluoxetine 20mg

[0141] hydroxypropyl methyl cellulose 18g

[0142] talc 0.4g

[0143] lactose 0.2g

[0144] magnesium stearate 0.2g

[0145] absolute ethyl alcohol proper amount

[0146] 100 tablets are made.

[0147] The specific preparation process is as follows:

[0148] 3-acetylaconine, fluoxetine and hydroxypropyl methyl cellulose, talc, lactose, magnesium stearate are uniformly mixed, absolute ethyl alcohol is added to make a soft material, which is sieved through a 24-mesh sieve, granulated, dried, and then magnesium stearate is added and uniformly mixed, and then compressed into tablets.

[0149] Application Example 6

[0150] The application example of the present application discloses a capsule using compound 3-acetylaconine and Luoyoutei as raw drugs, and the components are as follows:

[0151] 3-acetylaconine 3.5mg

[0152] Luoyoutei 300.0mg

[0153] starch 6.0g

[0154] sodium metabisulfite 0.2g

[0155] magnesium stearate 0.2g

[0156] absolute ethyl alcohol proper amount

[0157] 100 capsules are made.

[0158] The specific preparation process is as follows:

[0159] 3-acetylaconine, Luoyoutei and sodium metabisulfite are uniformly mixed, absolute ethyl alcohol is added to make a soft material, which is sieved through a 24-mesh sieve, granulated, dried, and then magnesium stearate is added and uniformly mixed, and then loaded into capsules.

[0160] Application Example 7

[0161] The application example of the present application discloses an injection using compound 3-acetylaconine and paroxetine as raw drugs, and the components are as follows:

[0162] 3-acetylaconine 5.0 mg

[0163] Paroxetine 20.0 mg

[0164] Vitamin C 0.2 g

[0165] Sodium chloride 6.0 g

[0166] Sodium bicarbonate 0.5 g

[0167] Water for injection 1000.0 mL;

[0168] Make 100.

[0169] The specific preparation process is as follows:

[0170] After the above components are mixed, 100 are obtained by using the conventional preparation method of injection.

[0171] The above examples only express several embodiments of the present application, and the description is more specific and detailed, but it cannot be understood as the limitation of the scope of the patent right of the application.

[0172] It should be noted that for those skilled in the art, without departing from the concept of the present application, several modifications and improvements can be made, which belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application should be subject to the appended claims.

Claims

1. A diterpenoid alkaloid compound, 3-acetyl aconitine, characterized in that, It has the structure shown in equation (1):

2. A pharmaceutical composition, characterized in that, It includes the diterpenoid alkaloid 3-acetyl aconitine as described in claim 1.

3. The pharmaceutical composition according to claim 2, characterized in that, The pharmaceutical composition also includes a pharmacodynamically acceptable carrier or excipient.

4. The pharmaceutical composition according to claim 2, characterized in that, The pharmaceutical composition also includes an synergist; The synergist is one or more of the following substances: Fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, escitalopram, venlafaxine, duloxetine, mirtazapine, bupropion, agomelatine, trazodone, reboxetine, imipramine, amitriptyline, clomipramine, doxepin, maprotiline, moclobemide, liver-soothing and mood-regulating capsules, St. John's wort extract, flupentixol melitracen.

5. The pharmaceutical composition according to claim 2, characterized in that, The dosage form of the pharmaceutical composition is tablets, capsules, granules, oral liquids, powders, drops, or micro-pellets.

6. The use of the diterpenoid alkaloid 3-acetyl aconitine according to claim 1 or the pharmaceutical composition according to any one of claims 2-5 in the preparation of an antidepressant.

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