High adamantane phloroglucinol compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly discloses a high adamantane phloroglucinol compound as well as a preparation method and application thereof. The high adamantane phloroglucinol compound Hyperhoissin C provided by the invention has remarkable anti-depression activity, is superior to positive drugs fluoxetine and luteotai, and can be used for developing drugs for treating depression.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and more specifically, relates to a preparation method of a homoadamantane-type phloroglucinol compound, a pharmaceutical composition and application of the same in antidepressant drugs. Background Art

[0002] The phloroglucinol component of the homoadamantane type is a phloroglucinol component containing a homoadamantane carbon frame in the parent core skeleton. This type of component has a "diamond-like" cage core and a common tricyclic [4.3.1.1] undecane core skeleton. This type of skeleton is based on the dicyclopolyisopentenyl-substituted acylphloroglucinol skeleton. The isoprenyl substituent side chain C-7a at the C-7 position attacks the C-3 on the parent core to undergo an intramolecular cyclization reaction to form a caged adamantane type.

[0003] The inventors isolated a homoadamantane-type phloroglucinol compound, Hyperichoisin C, from the dried aerial parts of Hypericum perforatum and found that it has significant antidepressant activity, which is superior to positive drugs Fluoxetine and Neurostan, and can be used to treat depression. Summary of the invention

[0004] In view of the deficiencies in the prior art, the present invention provides a homoadamantane-type phloroglucinol compound and a preparation method, a pharmaceutical composition and application thereof.

[0005] To achieve the above object, the technical solution of the present invention is as follows:

[0006] A homoadamantane-type phloroglucinol compound (referred to as compound Hyperichoisin C) has a structure as shown in the following formula (1):

[0007]

[0008] Among them, the tautomers or pharmaceutically acceptable salts of the phloroglucinol compounds also fall within the protection scope of the present invention.

[0009] Another aspect of the present invention provides a method for preparing the phloroglucinol compound Hyperichoisin C. The phloroglucinol compound is obtained by extraction and separation from Hypericum perforatum.

[0010] In the above technical solution, the preparation method of the phloroglucinol compound comprises the following steps:

[0011] S1. Take the dried aerial part of Hypericum perforatum, add a solvent for reflux extraction, combine the extracts and concentrate to obtain an extract;

[0012] S2, adding the extract to water for suspension, and then extracting with petroleum ether to obtain an extract;

[0013] S3, gradient eluting the extract by silica gel column chromatography using petroleum ether-ethyl acetate solution to obtain fraction C; when identified by silica gel thin layer chromatography, the Rf value corresponding to fraction C is 0.75-0.77;

[0014] S4, using a petroleum ether-ethyl acetate mixed solution to gradiently elute fraction C through silica gel column chromatography to obtain fraction C4; when detected by silica gel thin layer chromatography, the Rf value corresponding to fraction C4 is 0.72-0.74;

[0015] S5. Fraction C4 is subjected to gradient elution by MCI column chromatography using methanol-water solution to obtain fraction C4C. When fraction C4C is identified by silica gel thin layer chromatography, the Rf value corresponding to fraction C4C is 0.58-0.62;

[0016] S6. Separating a homoadamantane-type phloroglucinol compound having a structure as shown in formula (1) from fraction C4C by HPLC; the mobile phase used in HPLC is a methanol-water mixed solution.

[0017] The Rf values ​​in this application refer to the Rf values ​​of the fluorescent spots observed at scanning wavelengths of 254 nm and 365 nm.

[0018] Further, in step S6, according to the characteristic ultraviolet absorption (λ max =220, 280nm) to further separate the fraction C4C; the retention time of the obtained phloroglucinol compounds is 28-33min;

[0019] Furthermore, in step S6, the volume ratio of methanol to water in the methanol-water mixed solution is (83:17)-(87:13); preferably 85:15.

[0020] Furthermore, in step S3, based on the total volume of 100, the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate solution when fraction C is washed out (i.e. corresponding to fraction C) is (75:25)-(85:15); preferably, the volume ratio of petroleum ether to ethyl acetate is 80:20.

[0021] Furthermore, in step S4, based on the total volume of 100, the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate mixed solution when fraction C4 is washed out (i.e., corresponding to fraction C4) is (65:35)-(75:25); preferably, the volume ratio of petroleum ether to ethyl acetate is 70:30.

[0022] Furthermore, in step S5, the volume ratio of methanol to water in the methanol-water solution when washing out fraction C4C (i.e., corresponding to fraction C4C) is (77:23)-(85:15); preferably, the volume ratio of methanol to water is 80:20.

[0023] Furthermore, in step S1, the solvent is an 88-98V% ethanol aqueous solution, and the added mass is 8-10 times that of Hypericum perforatum, the number of reflux extractions is 1-3, and each extraction lasts 1-3 hours.

[0024] Furthermore, in step S2, the extract is added to 8-15 times the mass of water for suspension, and then extracted with petroleum ether.

[0025] In another aspect, the present invention provides a pharmaceutical composition containing the phloroglucinol compound Hyperichoisin C.

[0026] Furthermore, the pharmaceutical composition comprises a synergist and a pharmacodynamically acceptable carrier or excipient.

[0027] That is to say, the pharmaceutical composition containing the homoadamantane-type phloroglucinol compound of the present invention as an active ingredient and conventional pharmaceutical excipients or adjuvants or carriers is also included in the present invention.

[0028] Furthermore, the synergist is one or more of the following substances:

[0029] Fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, escitalopram, venlafaxine, duloxetine, mirtazapine, bupropion, agomelatine, trazodone, reboxetine, imipramine, amitriptyline, clomipramine, doxepin, maprotiline, moclobemide, Shugan Jieyu capsule, St. John's wort extract, flupentixol-melitracen.

[0030] Furthermore, the dosage form of the pharmaceutical composition is tablets, capsules, granules, oral liquid, granules, pills or micropills.

[0031] In another aspect, the present invention also provides the use of the phloroglucinol compound Hyperichoisin C in antidepressant drugs.

[0032] Compared with the prior art, the present invention has the following advantages:

[0033] (1) The present invention provides a method for extracting a homoadamantane-type phloroglucinol compound, Hyperichoisin C, from Hypericum perforatum, which has simple operation, good reproducibility and high extraction purity;

[0034] (2) The experimental results show that the homoadamantane-type phloroglucinol compound Hyperichoisin C provided by the present invention has a neuroprotective effect on SH-SY5Y cells induced by corticosterone, which is superior to the positive drugs fluoxetine and rulotide, and can be used to develop drugs for the treatment of depression. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 The Hyperichoisin C prepared in Example 1 of the present invention 1 H NMR spectrum (400 MHz, CDCl3);

[0036] Figure 2 The Hyperichoisin C prepared in Example 1 of the present invention 13 C NMR spectrum (100 MHz, CDCl3). DETAILED DESCRIPTION

[0037] In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In the embodiments, unless otherwise specified, the means used are conventional means in the art. The terms "comprising", "including" or any other variations thereof used herein are intended to cover non-exclusive inclusions.

[0038] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0039] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0040] In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0041] Example 1

[0042] This embodiment discloses a method for preparing a homoadamantane-type phloroglucinol compound, comprising the following steps:

[0043] S1. Take the dried aerial part of Hypericum perforatum, add a solvent for reflux extraction, combine the extracts and concentrate to obtain an extract; wherein the solvent is an 88-98V% ethanol aqueous solution, and the added mass is 8-10 times that of Hypericum perforatum, the number of reflux extractions is 1-3, and each extraction is 1-3h.

[0044] Preferably, a 95% ethanol aqueous solution having a mass 10 times that of Hypericum perforatum is added as a solvent and refluxed for extraction three times, each extraction for 2 hours, and the extracts are combined and concentrated to obtain an extract.

[0045] S2, adding the extract to 8-15 times the mass of water for suspension, and then extracting with petroleum ether to obtain an extract. Further preferably, adding the extract to 10 times the mass of water for suspension, and then extracting with 1.5 times the volume of the suspension of petroleum ether, extracting 3 times, to obtain a petroleum ether extract.

[0046] S3. Use petroleum ether-ethyl acetate solution to gradiently elute the extract through silica gel column chromatography to obtain fraction C; when detected by silica gel thin layer chromatography, the Rf value corresponding to fraction C is 0.75-0.77. Based on the total volume of 100, the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate solution when fraction C is eluted (i.e., corresponding to fraction C) is (75:25)-(85:15); preferably, the volume ratio of petroleum ether to ethyl acetate is 80:20.

[0047] It should be noted that during gradient elution, petroleum ether-ethyl acetate solutions with a volume ratio of (75:25)-(85:15) can elute fraction C. Using silica gel thin layer chromatography, the fraction with an Rf value of 0.75-0.77 is fraction C. Among them, the petroleum ether-ethyl acetate solution with a volume ratio of 80:20 has the highest elution efficiency. The "preferably" principle described in the following gradient elution process is the same.

[0048] The specific operation includes: subjecting the petroleum ether extract to silica gel column chromatography, using a petroleum ether-ethyl acetate gradient elution with a volume ratio of 100:0, 90:10, 80:20, 60:40, 50:50, 40:60, 30:70, 20:80, 10:90, 0:100, to obtain 56 fractions, 1-8, 9-18, 19-25, 26-29, 30-40, 41-44, 45-47, 48-51, 52-53, 54-56, and then using silica gel thin layer chromatography to identify the Rf values ​​at 254 nm and 365 nm, which are 0.81-0.83 (fraction 1-8), 0.78-0.80 (fraction 1-8), and 0.81-0.83 (fraction 1-8). The fluorescent spot results of fractions 9-18), 0.75-0.77 (fraction 19-25), 0.72-0.74 (fraction 26-29), 0.65-0.68 (fraction 30-40), 0.64-0.63 (fraction 41-44), 0.57-0.62 (fraction 45-47), 0.52-0.54 (fraction 48-51), 0.46-0.47 (fraction 52-53), and 0.35-0.39 (fraction 54-56) were merged with similar fractions to obtain 10 fractions, which were named A, B, C, D, E, F, G, H, I and J respectively; among them, fraction 19-25 was combined to obtain fraction C.

[0049] S4. Use a petroleum ether-ethyl acetate mixed solution to perform gradient elution on fraction C through silica gel column chromatography to obtain fraction C4; when detected by silica gel thin layer chromatography, the Rf value corresponding to fraction C4 is 0.72-0.74; when eluting fraction C4 (i.e., the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate mixed solution (i.e., corresponding to fraction C4) is (65:35)-(75:25); preferably, the volume ratio of petroleum ether to ethyl acetate is 70:30.

[0050] The specific steps include: analyzing the characteristic ultraviolet absorption (λ max=220, 280nm) Fraction C was selected for the next separation. Fraction C was subjected to silica gel column chromatography, using a gradient elution of petroleum ether-ethyl acetate with a volume ratio of 100:0, 90:10, 80:20, 70:30, 60:40, 40:60, 50:50, 30:70, 20:80, 10:90, 0:100, to obtain 1-10, 11-27, 28-35, 36-56, 57-61, 62-65, 66-70, 71-75, 76-80, 81-90, 91-111, a total of 111 fractions, and then detected by silica gel thin layer chromatography. According to the observation of fluorescent spot Rf values ​​at wavelengths of 254nm and 365nm, they were 0.85-0.82 (fractions 1-10) , 0.79-0.81 (fraction 11-27), 0.75-0.78 (fraction 28-35), 0.72-0.74 (fraction 36-56), 0.68-0.70 (fraction 57-61), 0.65-0.67 (fraction 62-65), 0.63-0.64 (fraction 66-70), 0.60-0.62 (fraction 71-75), 0.50-0.52 (fraction 76-80), 0.45-0.49 (fraction 81-90), 0.38-0.39 (fraction 91-111) were combined to obtain 11 fractions from C1 to C11; among them, fraction 36-56 was combined to obtain fraction C4.

[0051] S5. Fraction C4 is gradient eluted by MCI column chromatography using a methanol-water solution to obtain fraction C4C; when detected by silica gel thin layer chromatography, the Rf value corresponding to fraction C4C is 0.58-0.62; the volume ratio of methanol to water in the methanol-water solution when fraction C4C is eluted (i.e., corresponding to fraction C4C) is (77:23)-(85:15); preferably, the volume ratio of methanol to water is 80:20.

[0052] The specific operations are as follows:

[0053] According to the characteristic ultraviolet absorption (λ max =220, 280nm) select C4 for further separation.

[0054] Fraction C4 was subjected to MCI column chromatography, using a methanol-water gradient elution with a volume ratio of 70:30, 75:25, 80:20, 85:15, 90:10, 95:5, 100:0, and 35 fractions were collected in sequence, including 1-3, 4-10, 11-17, 18-23, 24-25, 26-30, and 31-35. The fractions were identified by silica gel thin layer chromatography, and the fluorescent spots were observed at wavelengths of 254 nm and 365 nm. The Rf values ​​were 0.31-0.34 (fractions 1-3), 0.47-0.49 (fractions 4-10), 0.58-0.62 (fractions 11-17), 0.65-0.69 (fractions 18-23), 0.70-0.73 (fractions 24-25), 0.76-0.78 (fractions 26-30), and 0.80-0.82 (fractions 31-35), respectively, and a total of 7 fractions C4A to C4G were obtained. Among them, fractions 11-17 were combined to obtain fraction C4C.

[0055] S6. Using HPLC to separate the homoadamantane-type phloroglucinol compound having the structure shown in formula (1) from fraction C4C; the mobile phase used in the HPLC method is a methanol-water mixed solution. The volume ratio of methanol to water in the methanol-water mixed solution is (83:17)-(87:13).

[0056] According to the characteristic ultraviolet absorption (λ max =220, 280nm) select fraction C4C for the next separation; the retention time of the obtained alkyl-type phloroglucinol compounds is 28-33min;

[0057] More preferably, the volume ratio of methanol to water in the methanol-water mixed solution is 85:15. The compound Hyperichoisin C prepared in fraction C4C has a retention time of 31 min (purity 99%).

[0058] The Rf values ​​in this application refer to the Rf values ​​of the fluorescent spots observed at scanning wavelengths of 254 nm and 365 nm.

[0059] The structure, physical properties and test data of the compound Hyperichoisin C prepared in Example 1 are as follows:

[0060] Colorless oily liquid. HR-ESI-MS m / z:587.3692[M+H] + , indicating that the molecular formula of the compound is C 32 H 46 O5.

[0061] like Figure 1 As shown, in 1In the H NMR (CDCl3, 400MHz) spectrum, δ H 7.40 (1H, t, J = 7.4 Hz, H-10d), 7.29 (2H, m, H-10c / e), 7.07 (2H, d, J = 7.3 Hz, H-10b / f) are proton signals on the benzene ring; 5.25 (1H, t, J = 7.4 Hz, H-5b), 5.06 (1H, t, J = 6.5 Hz, H-5g) are proton signals on two double bonds; δ H 2.75 (1H, dd, J = 12.6, 7.5 Hz, H-3a), 2.23 (1H, d, J = 13.3 Hz, H-3a'), 2.18 (1H, m, H-3b) are the proton signals of the methylene and methine groups on the five-membered ring; δ H 2.61 (1H, m, H-5a), 2.60 (1H, m, H-5a'), 2.49 (1H, dd, J = 14.7, 6.8 Hz, H-6), 2.19 (1H, m, H-6'), 2.05 (5H, m, H-5d / f, 7a), 1.75 (1H, m, H-7a') are proton signals on the methylene groups on the ring and side chains; δ H 2.29 (1H, J = 12.0, 7.5 Hz, H-7b), 1.75 (1H, m, H-7) are the proton signals on the methine; δ H 1.66 (6H, s, H-5i / e), 1.59 (3H, s, H-5j), 1.41 (1H, s, H-11), 1.39 (1H, s, H-12), 1.36 (6H, s, H-3d / e), 1.21 (1H, s, H-7e), and 1.07 (1H, s, H-7d) are proton signals on the methyl group.

[0062] like Figure 2 As shown, in 13 C NMR (CDCl3, 100MHz) spectrum, δ C 205.8 (C-9), 204.6 (C-4), 204.4 (C-2), 193.0 (C-10) are four carbonyl carbon signals; δ C 135.1 (C-10a), 132.4 (C-10d), 128.6 (C-10b / f), 128.4 (C-10c / e) are carbon signals on the benzene ring; δ C 139.2 (C-5c), 131.6 (C-5h), 124.3 (C-5g), 118.9 (C-5b) are the double bond carbon signals on the side chain; δ C81.7 (C-1), 73.4 (C-3c), 73.3 (C-3), 67.9 (C-5), 47.8 (C-8), 46.9 (C-7c) are quaternary carbon signals; δ C 59.2 (C-3b), 54.9 (C-7b), 42.5 (C-7) are the quarterly carbon signals of the ring; δ C 40.2 (C-5d), 35.3 (C-6), 31.3 (C-3a), 29.2 (C-5a), 26.7 (C-5f), 25.0 (C-7a) are secondary carbon signals; C 31.8 (C-3e), 30.5 (C-3d), 27.7 (C-7d), 27.1 (C-7e), 25.9 (C-5i), 25.3 (C-11), 22.1 (C-12), 17.8 (C-5j), 16.5 (C-5e) are methyl carbon signals. The above data identified the compound as Hyperichoisin C.

[0063] 1 H NMR, 13 The signal assignments of C NMR are shown in Table 1.

[0064] Table 1 NMR data of compound 1 δ (ppm)

[0065]

[0066]

[0067] In summary, the structure of the new compound 1 (compound Hyperichoisin C) was determined as follows:

[0068]

[0069] Comparative Example 1

[0070] Comparative Example 1 of the present invention provides a method for preparing a homoadamantane-type phloroglucinol compound, and its steps are similar to those of Example 1, except that in step S5, when fraction C4 is subjected to MCI column chromatography, methanol-water is used for elution, and the volume ratio of methanol-water is less than (77:23) or greater than (85:15).

[0071] The results showed that compound 1 could not be prepared.

[0072] Comparative Example 2

[0073] Comparative Example 2 of the present invention provides a method for preparing a homoadamantane-type phloroglucinol compound, and its steps are similar to those of Example 1, except that in step S6, in the mobile phase used for separating the C4C fraction by HPLC, the volume ratio of methanol to water is less than (83:17) or greater than (87:13).

[0074] The results showed that compound 1 could not be prepared.

[0075] In order to better understand the essence of the present invention, the new application of the above-mentioned phloroglucinol compounds in the pharmaceutical field is explained below in combination with pharmacological tests and results.

[0076] Test example

[0077] This test example discloses an experiment on the antidepressant activity of the above compound Hyperichoisin C in SH-SY5Y cells (a commonly used cell model for antidepressants) induced by corticosterone.

[0078] (1) Experimental materials and instruments

[0079] Human neuroblastoma SH-SY5Y was purchased from the Institute of Basic Research, Chinese Academy of Medical Sciences;

[0080] DMEM medium, PBS buffer, fetal bovine serum (FBS), and trypsin were purchased from Gibco, USA;

[0081] Fluoxetine (Shanghai Yuanye Biotechnology Co., Ltd.);

[0082] Luyoutai (Dr. Weimar Shupe Pharmaceuticals, Germany);

[0083] CCK-8 cell activity detection kit (Elabscience);

[0084] Corticosterone, DMSO (Sigma, USA);

[0085] 96-well plate (Corning, USA);

[0086] Carbon dioxide cell culture incubator (Thermo Fisher Scientific, USA);

[0087] Full wavelength microplate reader (Thermo Fisher Scientific, USA);

[0088] BIOFUGE STRATOS centrifuge (Thermo Fisher Scientific, USA);

[0089] IX73 inverted electron microscope (Olympus, Japan);

[0090] Pipette (Eppendorf, Germany);

[0091] Electronic balance (Sartorius, Germany);

[0092] Clean bench, centrifuge tubes, pipettes and other related consumables.

[0093] (2) Cell recovery and culture

[0094] Take out the marked SH-SY5Y cell cryopreservation tube from liquid nitrogen and immediately put it into a 37°C water bath, and try to complete rapid thawing within 1 minute; after disinfecting the cryopreservation tube with alcohol, transfer the cryopreservation solution in the tube into a 15mL sterile centrifuge tube, add the corresponding culture medium, mix it, and then centrifuge to remove the supernatant; repeat the above steps once for washing, then add 10mL of culture medium to mix and resuspend the cells, then transfer them to a 10mL culture dish, and culture them in a constant temperature incubator at 37°C and 5% CO2.

[0095] When the cell density reaches 70%-80%, it is passaged; first, the old culture medium is aspirated, PBS is added to wash twice, trypsin containing EDTA is added to the culture dish and placed in a 37°C incubator for 3 minutes, then culture medium is added to terminate digestion, centrifuged at 1000rpm for 5 minutes, the digestion solution is aspirated, and the serum-containing culture medium is re-added and the cells are repeatedly blown to form a cell suspension. Finally, according to the number of cells, they are transferred to a new culture dish to complete cell passage.

[0096] (3) Drug administration and CCK-8 method to evaluate cell viability

[0097] SH-SY5Y cells were cultured at 1×10 5 The cells / well were plated in a 96-well plate, with 6 replicate wells in each group, 80 μL / well, and cultured for 24 hours after plating. The positive drugs fluoxetine, rulothione, hyperforin, and tetrahydrohyperforin were dissolved and diluted to 10 μM. The compound Hyperichoisin C was dissolved and diluted to 5 μM and 10 μM, respectively, and treated with 10 μL / well for 1 hour. Then, 10 μL of 25 μM corticosterone was added, and cultured at 37°C for 48 hours. Then, 10 μL of CCK-8 was added. After 1 hour, the absorbance at 450 nm was detected using an enzyme reader, and the cell survival rate was calculated.

[0098] Cell viability (%) = [(A control - A sample) / (A control - A blank)] x 100%.

[0099] (4) Experimental results

[0100] The experimental results (Table 2) showed that compared with the model group, low and high doses of Hyperichoisin C (5μM, 10μM) had a significant protective effect on corticosterone-induced SH-SY5Y neuronal cell damage. The neuroprotective activity of low-dose Hyperichoisin C was significantly better than that of positive drugs Luyoutai (the first natural herbal medicine for antidepressants in the world, 10μM), hyperforin (10μM) and tetrahydrohyperforin (10μM); the neuroprotective activity of high-dose Hyperichoisin C was better than that of positive drug fluoxetine (a first-line chemical drug for clinical treatment of depression, 10μM).

[0101] Table 2 Neuroprotective effects of compounds on SH-SY5Y cell injury induced by corticosterone ( n=5)

[0102] Group Concentration (μM) Cell survival rate (%) blank 0 100.00±7.89 Model 0 <![CDATA[52.49±2.10 #### ]]> Fluoxetine 10 <![CDATA[65.79±2.33 ** ]]> Lu Youtai 10 <![CDATA[60.03±3.33 * ]]> Hyperforin 10 55.83±2.71 Tetrahydrohyperforin 10 <![CDATA[58.03±3.33 * ]]> Hyperichoisin C 5 <![CDATA[62.52±3.59 ** ]]> Hyperichoisin C 10 <![CDATA[67.52±6.59 *** ]]>

[0103] Note: Compared with the blank group: #### P<0.0001; compared with the model group: * P<0.05, ** P<0.01, *** P<0.001

[0104] In summary, the Hyperichoisin C described in the present invention exhibits significant antidepressant activity and is superior to the first-line antidepressant drugs fluoxetine and Luyoutai, and can be used as a drug for treating depression.

[0105] Application Example 1

[0106] The application example of the present invention discloses a capsule preparation using Hyperichoisin C as a raw material drug, and the components thereof are as follows:

[0107] Hyperichoisin C18.0 mg

[0108] Starch 6.0g

[0109] Sodium metabisulfite 0.2g

[0110] Magnesium stearate 0.2g

[0111] Anhydrous ethanol

[0112] Makes 100 tablets.

[0113] The specific preparation process is as follows:

[0114] Hyperichoisin C, starch and sodium metabisulfite were mixed evenly, anhydrous ethanol was added to make a soft material, the mixture was passed through a 24-mesh sieve to make granules, the mixture was dried, magnesium stearate was added, the mixture was mixed evenly and the mixture was put into capsules.

[0115] Application Example 2

[0116] The application example of the present invention discloses a granule preparation using the compound Hyperichoisin C as a raw material drug, and the components thereof are as follows:

[0117] Hyperichoisin C35.0 mg

[0118] Starch 6.0g

[0119] Sodium bisulfite 0.2g

[0120] Magnesium stearate 0.2g

[0121] Anhydrous ethanol

[0122] Makes 100 bags.

[0123] The specific preparation process is as follows:

[0124] Hyperichoisin C was mixed with starch and sodium bisulfite, and then anhydrous ethanol was added to make a soft material. The mixture was passed through a 24-mesh sieve to form granules, which were dried. Magnesium stearate was added, the mixture was mixed, and the mixture was bagged.

[0125] Application Example 3

[0126] The application example of the present invention discloses an oral liquid with the compound Hyperichoisin C as a raw material drug, and its components are as follows:

[0127] Hyperichoisin C25.0 mg

[0128]

[0129]

[0130] The specific preparation process is as follows:

[0131] After the above components are mixed evenly, they can be packaged using a conventional oral liquid preparation method.

[0132] Application Example 4

[0133] The application example of the present invention discloses an injection with the compound Hyperichoisin C as the raw material drug, and its components are as follows:

[0134] Hyperichoisin C45.0 mg

[0135] Vitamin C 0.2g

[0136] Sodium chloride 6.0g

[0137] Sodium bicarbonate 0.1g

[0138] Water for injection 1000mL

[0139] Made into 100 pieces.

[0140] The specific preparation process is as follows:

[0141] After the above components are mixed evenly, 100 vials can be obtained using a conventional injection preparation method.

[0142] Application Example 5

[0143] The application example of the present invention discloses a tablet with the compound Hyperichoisin C and fluoxetine as raw materials, and its components are as follows:

[0144] Hyperichoisin C 20.0mg

[0145] Fluoxetine 5g

[0146] Hydroxypropyl methylcellulose 18g

[0147] Talc 0.4g

[0148] Lactose 0.2g

[0149] Magnesium stearate 0.2g

[0150] Anhydrous ethanol

[0151] Makes 100 pieces.

[0152] The specific preparation process is as follows:

[0153] Take Hyperichoisin C, fluoxetine, hydroxypropyl methylcellulose, talc, lactose and magnesium stearate, mix them evenly, add anhydrous ethanol to make a soft material, pass through a 24-mesh sieve, make granules, dry, add magnesium stearate, mix well, and press into tablets.

[0154] Application Example 6

[0155] The application example of the present invention discloses a capsule preparation using the compound Hyperichoisin C and sertraline as raw materials, and the components thereof are as follows:

[0156] Hyperichoisin C18.0 mg

[0157] Sertraline 2.0g

[0158] Starch 6.0g

[0159] Sodium metabisulfite 0.2g

[0160] Magnesium stearate 0.2g

[0161] Anhydrous ethanol

[0162] Makes 100 tablets.

[0163] The specific preparation process is as follows:

[0164] Hyperichoisin C, sertraline, starch and sodium metabisulfite were mixed, anhydrous ethanol was added to make a soft material, the mixture was passed through a 24-mesh sieve to make granules, the mixture was dried, magnesium stearate was added, the mixture was mixed, and the mixture was put into capsules.

[0165] Application Example 7

[0166] The application example of the present invention discloses an injection with the compound Hyperichoisin C and escitalopram as raw materials, and its components are as follows:

[0167] Hyperichoisin C 30.0mg

[0168] Escitalopram 2.0g

[0169] Vitamin C 0.2g

[0170] Sodium chloride 6.0g

[0171] Sodium bicarbonate 0.1g

[0172] Water for injection 1000mL

[0173] Made into 100 pieces.

[0174] The specific preparation process is as follows:

[0175] After the above components are mixed evenly, 100 vials can be obtained using a conventional injection preparation method.

[0176] The above-mentioned embodiments only express several implementation modes of the present invention, and the description thereof is relatively specific and detailed, but it should not be understood as limiting the scope of the invention patent.

[0177] It should be noted that, for those skilled in the art, several modifications and improvements can be made without departing from the concept of the present invention, and these modifications and improvements all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A homoadamantane-type phloroglucinol compound, characterized in that: It has the structure shown in formula (1):

2. A method for preparing the phloroglucinol compound according to claim 1, characterized in that: The phloroglucinol compounds are obtained by extraction and separation from Hypericum perforatum.

3. The preparation method according to claim 2, characterized in that: The following steps are involved: S1. Take the dried aerial part of Hypericum perforatum, add a solvent for reflux extraction, combine the extracts and concentrate to obtain an extract; S2, adding the extract to water for suspension, and then extracting with petroleum ether to obtain an extract; S3, gradient eluting the extract by silica gel column chromatography using petroleum ether-ethyl acetate solution to obtain fraction C; when identified by silica gel thin layer chromatography, the Rf value corresponding to fraction C is 0.75-0.77; S4, using a petroleum ether-ethyl acetate mixed solution to gradiently elute fraction C through silica gel column chromatography to obtain fraction C4; when detected by silica gel thin layer chromatography, the Rf value corresponding to fraction C4 is 0.72-0.74; S5. Fraction C4 is subjected to gradient elution by MCI column chromatography using methanol-water solution to obtain fraction C4C. When fraction C4C is identified by silica gel thin layer chromatography, the Rf value corresponding to fraction C4C is 0.58-0.62; S6, separating and obtaining a homoadamantane-type phloroglucinol compound having a structure as shown in formula (1) from fraction C4C by HPLC; The mobile phase used in HPLC was a methanol-water mixture.

4. The preparation method according to claim 3, characterized in that: In step S6, fraction C4C is selected for further separation based on the characteristic ultraviolet absorption of phloroglucinol observed by HPLC analysis; The retention time of the obtained alkyl-type phloroglucinol compounds is 28-33 minutes.

5. The preparation method according to claim 3, characterized in that: In step S6, the volume ratio of methanol to water in the methanol-water mixed solution is (83:17)-(87:13).

6. The preparation method according to claim 3, characterized in that: In step S3, based on the total volume of 100, the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate solution when fraction C is eluted is (75:25)-(85:15).

7. The preparation method according to claim 3, characterized in that: In step S3, based on the total volume of 100, the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate solution when fraction C is washed out is 80:

20.

8. The preparation method according to claim 3, characterized in that: In step S4, the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate mixed solution when fraction C4 is washed out is (65:35)-(75:25).

9. The preparation method according to claim 3, characterized in that: In step S4, the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate mixed solution when fraction C4 is washed out is 70:

30.

10. The preparation method according to claim 3, characterized in that: In step S5, the volume ratio of methanol to water in the methanol-water solution when washing out fraction C4C is (77:23)-(85:15).

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