Application of aryl olefine acid schisandra phenolic ester in preparation of medicine for treating depression and prepared anti-depression medicine

Abstract

The invention provides an application of aryl olefine acid schisandra chinensis phenolic ester (O-dihydroxyphenyl) hernandezine and a derivative thereof in preparation of a medicine for treating depression and an anti-depression medicine prepared from the O-dihydroxyphenyl hernandezine and the derivative of the O-dihydroxyphenyl hernandezine and the derivative of the O-dihydroxyphenyl hernandezine. The application dosage is 0.01-30 mg of aryl olefine acid schisandra phenolic ester or the derivative thereof per kilogram of body weight, and the anti-depression effect can be achieved within 60 minutes after administration. After the medicine is administrated for 5 days, a remarkable anti-depression effect can be generated at a high dosage. A research result shows that in a mammal mouse tail suspension experiment, the aryl olefine acid schisandra phenolic ester or the derivative thereof has a rapid anti-depression effect and is more effective than a conventional anti-depression drug fluoxetine. According to the invention, a forced swimming experiment and a mouse tail suspension experiment are adopted as drug screening experiments, and meanwhile, an open field test is carried out on the mouse, so that the autonomous activity of the mouse is detected, and the interference of central excitation drugs is avoided. The anti-depression drug has the advantages of being remarkable in anti-depression effect, quick in effect taking, small in dosage, small in side effect and the like, and is expected to become a new anti-depression drug which is quick, efficient and novel in mechanism.

Description

Technical Field

[0001] The invention belongs to the field of medical technology and relates to the application of aryl olefinic acid schisandrin ester (O-dihydroxyphenylHernandezine) and its derivatives in the preparation of drugs for treating depression and the prepared antidepressant drugs. Background Art

[0002] Major depressive disorder (MDD) is a severe, recurrent, disabling mental illness. There are approximately 300 million people with depression worldwide. The incidence of depression in China is 4.2%, with approximately 56 million people suffering from depression. Depression is the second leading cause of life lost due to disability (years) and has become a major public health issue that urgently needs to be addressed. Clinically, depression can be seen as low mood, depressed emotions, inferiority and depression, and even pessimism and world-weariness, and there may be suicidal attempts or behaviors. Currently, the first-line antidepressants in clinical practice mainly include selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, etc., but these drugs have a slow onset, a narrow spectrum of action, and are prone to relapse after discontinuation of medication. Although a variety of antidepressant drugs are used for treatment, about 30% of patients will still become refractory depression (TRD). This type of refractory depression patient has a higher risk of social burden and suicide. Therefore, there is a great clinical need to find new antidepressant drugs with good compliance, fewer side effects and novel pharmacological mechanisms, which is also a hot topic in current international research.

[0003] Schisandrin (schisanhenol; Schizanhenol; Gomisin K3; (+)-Gomisin K3; NSC330515), also known as (+)-Gomisin K3 and nordeoxyschisandrin, is a biphenylcyclooctene-type lignin component extracted and separated from various Schisandraceae plants.

[0004] The molecular formula of Schisandrin is C 23 H 30 O6, molecular weight is 402.48, melting point is 132-133℃, soluble in ethanol, ether, ethyl acetate, DMSO and other solvents, almost insoluble in water. Existing studies have shown that schisandra chinensis phenol has an antioxidant effect, can inhibit cell damage caused by a variety of chemical inductions, and has a significant protective effect on cell mitochondrial swelling and reduced membrane fluidity. At the same time, schisandra chinensis phenol has anti-coagulant fibrinolysis, inhibits platelet aggregation and dilates blood vessels. It has therapeutic and protective effects on cerebral infarction and brain function and morphology, and is a candidate drug for the treatment of ischemic stroke.

[0005] The present invention introduces an o-dihydroxyphenyl structure based on the structure of schisandra chinensis phenol, aiming to further enhance the antioxidant and antidepressant activities. The synthesized structural formula is C 32 H 36 O9, molecular weight is 564.2, slightly soluble in ethyl acetate, acetonitrile, methanol, water, soluble in DMF, DMSO and other solvents.

[0006] Subacute toxicity experiments have shown that schisandrin aryl oleate has no significant effect on the functions of rats' bone marrow, liver, and kidney. Currently, there are no reports on the use of schisandrin aryl oleate as an active ingredient to prevent and treat depression. Summary of the invention

[0007] The invention aims to provide an application of aryl olefinic acid schisandrin esters in the preparation of a drug for treating depression. The drug has the advantages of significant antidepressant effect, rapid onset, small dosage, small side effects and the like.

[0008] The present invention provides the use of aryl olefinic acid schisandra phenol esters of formula (I) or derivatives thereof in the preparation of drugs for treating depression.

[0009]

[0010] Furthermore, the derivatives include sodium salt or potassium salt of aryl olefinic acid schisandra phenol esters.

[0011] Furthermore, the present invention also discloses a method for preparing the compound of the present invention, comprising the following steps:

[0012]

[0013] i: condensation; ii: hydrolysis

[0014] A. Schisandrin reacts with the compound of formula (II) in a solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide at 10°C-30°C under alkaline conditions such as organic bases such as pyridine, piperidine, diisopropylamine, ethylenediamine, triethylamine, N,N-diisopropylethylamine, etc.; inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, etc.; in the presence of condensation agents such as carbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-hydroxybenzotriazole (HOBt), etc., to generate a compound of formula (III);

[0015] B. The compound of formula (III) is reacted under acidic conditions, such as hydrochloric acid, sulfuric acid, nitric acid, camphorsulfonic acid, p-toluenesulfonic acid, pyridine p-toluenesulfonate, pyridinium hydrofluoride; or alkaline conditions, organic bases, such as pyridine, piperidine, diisopropylamine, ethylenediamine, triethylamine, N,N-diisopropylethylamine, etc.; inorganic bases, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, etc.; or by hydrogenation reaction, 0-valent Pd catalytic reaction to remove the protecting group to obtain the compound of formula (I)

[0016] Compounds;

[0017] Wherein R1 is selected from hydrogen, methoxycarbonyl, acetyl, methanesulfonyl, methyl, ethyl, trifluoromethyl, methoxymethyleneoxy, benzyl, p-methoxybenzyl, tert-butyldimethylsilyl, and allyl;

[0018] X is selected from hydroxy, chloro, tert-butoxy.

[0019] Furthermore, the application dosage is 0.01-30 mg of aryl olefinic acid schisandra chinensis phenol ester or its derivatives per kilogram of body weight.

[0020] The present invention also provides an antidepressant drug, the drug ingredients comprising: arylene acid schisandrin ester or its derivatives, and pharmaceutically acceptable auxiliary ingredients.

[0021] The pharmaceutical ingredients also include pharmaceutical ingredients that have a positive effect on treating depression after simultaneous administration.

[0022] Furthermore, the drug ingredients that have a positive effect on the treatment of depression after simultaneous administration include: monoamine oxidase inhibitors MAOI, tricyclic antidepressants TCA, selective serotonin reuptake inhibitors SSRI, serotonin and norepinephrine reuptake inhibitors SNRI, noradrenergic and specific 5-HT receptor antagonists NASSA, 5-HT antagonists and reuptake inhibitors, or melatonin and 5-HT2C receptor antagonists.

[0023] Furthermore, the tricyclic antidepressants (TCA) include amitriptyline, imipramine, chlorpromazine, doxepin and clomipramine, etc.; the selective serotonin reuptake inhibitors (SSRIs) include fluoxetine (Prozac), paroxetine (Celexa), fluvoxamine (fluvoxamine, Lanshi), sertraline (sertraline, Zoloft), citalopram (citalopram, Xipumi), escitalopram (escitalopram, Lexapro), etc.; the serotonin and norepinephrine reuptake inhibitors (SNRIs) include venlafaxine, duloxetine, etc.; the noradrenergic and specific 5-HT receptor antagonists (NASSAs) include mirtazapine, etc.; the 5-HT antagonists and reuptake inhibitors include nefazodone and trazodone; the melatonin and 5-HT2C receptor antagonists include agomelatine.

[0024] Furthermore, the drug ingredients that have a positive effect on treating depression after simultaneous administration are herbal medicines, such as St. John's wort, tianeptine, vortioxetine (also known as Vortioxetine), bupropion, and the like.

[0025] Furthermore, the drug ingredients that have a positive effect on treating depression after simultaneous administration are: ketamines, and the ketamines include S-ketamine or ketamine nasogastric solution.

[0026] Furthermore, the effective dose of the drug is 0.01-30 mg of aryl olefinic acid schisandrin ester per kilogram of body weight.

[0027] The above-mentioned drug dosage form is powder, granule, tablet, capsule, pill, solution, suspension or injection.

[0028] Aryl olefinic acid schisandra chinensis phenol esters are light yellow granular crystals or light yellow crystalline powders, HRESI-MS565.2430m / z[M+H] + , suggesting that its molecular formula is C 32 H 37 O9.

[0029] 1H NMR (400MHz, CDCl3) δ7.45(d,J=15.8Hz,1H),6.94(s,1H),6.77(d,J=8.2Hz,1H),6.73(d,J=8.5Hz,2 H),6.49(s,1H),6.11(d,J=15.8Hz,1H),3.91(s,3H),3.85(s,3H),3.80(s,3H),3.75(s,3H),3.58(s ,3H),2.64(dd,J=13.6,7.4Hz,1H),2.54(d,J=15.7Hz,0H),2.32(dd,J=13.4,9.6Hz,1H),2.03(d,J= 13.4Hz,1H),1.92(t,J=6.8Hz,1H),1.83–1.72(m,1H),0.98(d,J=7.1Hz,3H),0.78(d,J=7.1Hz,3H).

[0030] 13 C NMR (100MHz, CDCl3) δ165.4,152.9,151.5,151.0,147.0,146.5,144.3,142.2,140.4,139.3,139.1,134.3,12 7.0,123.5,122.3,120.8,115.4,114.4,113.9,113.0,107.6,56.1,55.8,40.6,39.2,34.6,33.8,21.7,12.2.

[0031] The drug of the present invention can be administered in a unit dosage form, and the dosage form can be a liquid dosage form or a solid dosage form. For example, the liquid dosage form can be a true solution, a colloid, a microparticle dosage form, an emulsion dosage form, or a suspension dosage form. Other dosage forms include tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injections, and the like.

[0032] The administration route can be enteral or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum.

[0033] The administration route of the drug of the present invention can be injection, which includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection.

[0034] The medicine of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0035] In order to prepare a unit dosage form into tablets, a wide variety of carriers known in the art can be used. In the carrier: diluents and absorbents, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, etc.; wetting agents and binders, such as water, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methylcellulose, potassium phosphate, polyvinyl pyrrolidone, etc.; disintegrants, such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium dodecyl sulfate, methylcellulose, ethyl cellulose, etc.; disintegration inhibitors, such as sucrose, tristearin, cocoa butter, hydrogenated oil, etc.; absorption promoters, such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants, such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0036] In order to make the dosing unit into a pill, various carriers known in the art can be widely used. Carriers include: for example, diluents and absorbents, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinyl pyrrolidone, Gelucire, kaolin, talc, etc.; binders, such as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or flour paste, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.

[0037] In order to prepare the administration unit into a suppository, various carriers known in the art can be widely used, such as polyethylene glycol, lecithin, cocoa butter, higher alcohols, enzymes of higher alcohols, gelatin, semi-synthetic glycerol enzymes, etc.

[0038] In order to prepare the dosing unit into capsules, the active ingredient is mixed with the above-mentioned various carriers, and the resulting mixture is placed in a hard gelatin capsule or a soft capsule. The active ingredient can also be prepared into microcapsules, suspended in an aqueous medium to form a suspension, or can be loaded into a hard capsule or prepared into an injection for use.

[0039] For example, the composition of the present invention is made into an injection preparation, such as a solution, a suspension solution, an emulsion, or a freeze-dried powder injection. This preparation can be aqueous or non-aqueous, and can contain one and / or more pharmacodynamically acceptable carriers, diluents, adhesives, lubricants, preservatives, surfactants, or dispersants. For example, the diluent can be selected from water, ethanol, polyethylene glycol, 1,3-propylene glycol, ethoxylated isostearyl alcohol, polyoxygenated isostearyl alcohol, polyoxyethylene sorbitol fatty acid enzyme, etc. In addition, in order to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose, or glycerol can be added to the injection preparation. In addition, conventional cosolvents, buffers, pH regulators, etc. can also be added. These adjuvants are commonly used in the art.

[0040] Furthermore, if necessary, colorants, preservatives, perfumes, flavoring agents, sweeteners or other materials may be added to the pharmaceutical preparations.

[0041] The dosage of the pharmaceutical composition of the present invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the number of administrations, etc., so the therapeutic dose of the present invention can vary widely. Generally speaking, the dosage of the compound of the present invention is well known to those skilled in the art. It can be appropriately adjusted according to the actual amount of effective drugs contained in the final preparation of the pharmaceutical composition of the present invention to achieve the requirements of its therapeutically effective amount, and complete the application of the present invention in the treatment of obesity, impaired glucose tolerance, hyperlipidemia, diabetes and its complications; and chronic inflammation, insulin resistance, cerebrovascular disease and atherosclerosis involved in the above-mentioned diseases.

[0042] Usually for patients weighing about 75 kg, the daily dose of the compound of the present invention is 0.001 mg / kg body weight to 200 mg / kg body weight, preferably 1 mg / kg body weight to 100 mg / kg body weight. The above dosage can be administered in a single dosage form or divided into several, such as two, three or four dosage forms, which is limited by the clinical experience of the doctor administering the drug and the dosage regimen. The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs.

[0043] The antidepressant provided by the present invention includes two stages: prevention and treatment. The dosage of the antidepressant is: 0.01-30 mg of aryl olefine acid schisandrin ester per kilogram of body weight per day. The antidepressant is administered orally, by nasal spray, drip or injection; and the subject of administration is a mammal, including a human.

[0044] The antidepressant provided by the present invention has an administration dosage of 0.01-30 mg of aryl olefine acid schisandrin phenol ester per kilogram of body weight; an antidepressant effect can be produced within 60 minutes after administration. After 5 days of administration, high doses all produce significant antidepressant effects. The drug has the advantages of significant antidepressant effect, rapid onset, small dosage, and small side effects. In a forced swimming experiment of mammalian mice, the antidepressant effect of aryl olefine acid schisandrin phenol ester is more significant than that of the conventional antidepressant fluoxetine.

[0045] Compared with the prior art, the beneficial technical effects of the present invention are:

[0046] 1. The present invention provides the use of schisandra chinensis phenol esters or their derivatives in the preparation of antidepressant drugs. The research results of the present invention show that in the tail suspension test of mammalian mice, schisandra chinensis phenol esters or their derivatives have a rapid antidepressant effect and are more effective than the conventional antidepressant fluoxetine.

[0047] 2. The present invention uses the forced swimming test and the mouse tail suspension test as drug screening experiments. The forced swimming test and the mouse tail suspension test are two commonly used animal behavior despair depression model experiments, which can better ensure the reliability of the screening results. The mouse forced swimming test has been used to screen many antidepressant drugs. Moreover, most antidepressants with clinical therapeutic effects have also been proven to effectively reduce the immobility time in the forced swimming test.

[0048] The so-called immobility means that "the animal stops struggling in the water, or is in a floating state, with only the nostrils exposed to breathe, and only small limb movements to keep the head floating on the water surface". The drug to be screened is given before the experiment. Because the animals are forced to swim, they cannot escape from the harsh environment, resulting in desperate behavior. This model method is simple and reliable, and has been widely used in the screening and evaluation of antidepressant drugs. The mouse tail suspension test is that the mouse no longer struggles in the tail suspension state, presenting a unique quiet and immobile state. Antidepressants can significantly shorten the duration of the immobile state. During the test, the mouse's tail is fixed and hung upside down. Do not twist or fold the mouse's tail. Record the immobility time. The immobility index is: "the animal's limbs and body do not twist and struggle". The tail suspension test is very sensitive to various antidepressants, and avoids the interference of temperature and animal motor dysfunction in the swimming test. Therefore, when using some mouse species to screen antidepressants, it can effectively verify and supplement the results of the forced swimming test.

[0049] 3. It shows comparable antidepressant effect than fluoxetine. In the tail suspension experiment of mouse animal model, it was found that the depressive symptoms of mice in the high-dose group of aryl olefine schisandrin phenol ester (10 mg / kg) began to ease 60 minutes after injection, that is, the activity became more and more frequent compared with the DMSO control group, and the immobility time was significantly shortened. Five days after injection, aryl olefine schisandrin phenol ester began to significantly shorten the immobility time of tail suspension. When the dose (10 mg / kg) of aryl olefine schisandrin phenol ester is equal to that of fluoxetine (10 mg / kg), it shows comparable antidepressant effect to fluoxetine.

[0050] 4. The present invention also carries out an open field test on mice to test the autonomous activity of mice and avoid the interference of central stimulants. Since the shortening of the immobility time of animals in the classic depression animal model may be caused by the central excitatory effect of the drug, the present invention also carries out an open field test on mice at the same time. The results show that compared with the control group, the high concentration of aryl olefine acid schisandra chinensis phenol ester has no significant effect on the autonomous activity of mice, so the possibility of stimulants causing mania can be ruled out, proving that aryl olefine acid schisandra chinensis phenol ester does have a significant antidepressant effect.

[0051] 5. The antidepressant drug of the present invention, which uses arylene acid schisandra chinensis phenol esters or their derivatives as active ingredients, is expected to become a new antidepressant drug with rapid, high efficiency and new mechanism. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] The drawings of this application are used to provide further description of this application. The illustrative embodiments of this application and their descriptions are used to explain this application and do not constitute improper limitations on this application.

[0053] Figure 1 .Aryl olefinic acid schisandra phenol ester structure

[0054] Figure 2 .Aryl olefin esters of schisandra chinensis 1 H NMR

[0055] Figure 3 .Aryl olefin esters of schisandra chinensis 13 C NMR

[0056] Figure 4 .MS of schisandra chinensis phenol esters

[0057] Figure 5 Effects of WWZF-5 on the tail suspension test in mice one hour after injection

[0058] Vertical axis: immobility time (s) of mice in tail suspension experiment; horizontal axis: from left to right: DMSO control group, WWZF-5 low-dose group (WWZF-5 low, 5 mg / kg), WWZF-5 high-dose group (WWZF-5 high, 10 mg / kg), fluoxetine positive control group (10 mg / kg).

[0059] Results: After 60 minutes of intraperitoneal injection of different doses of WWZF-5 into C57BL / 6 male mice, the high-dose group (10

[0060] mg / kg) showed significant antidepressant effect in the mouse tail suspension test (N=8 animals per group, ANOVA test P<0.05,

[0061] **P<0.01).

[0062] Figure 6 Effects of WWZF-5 on the swimming test of mice 5 days after injection

[0063] Vertical axis: immobility time of mice in forced swimming test (s); horizontal axis: from left to right: DMSO control group, WWZF-5 low-dose group (WWZF-5 low, 5 mg / kg), WWZF-5 high-dose group (WWZF-5 high, 10 mg / kg), fluoxetine positive control group (FLX, 10 mg / kg),

[0064] Results: After five days of intraperitoneal injection of different doses of WWZF-5 into C57BL / 6 male mice, the mice showed a very significant antidepressant effect in the forced swimming test. This antidepressant effect was comparable to that of the traditional antidepressant fluoxetine (N=8 animals per group, t-test *P<0.05, **P<0.01). DETAILED DESCRIPTION

[0065] To further illustrate the present invention, the present invention is described in detail with specific examples below. These embodiments are purely illustrative and are intended to specifically describe the present invention, but are not intended to limit the exemplary implementation methods according to the present application.

[0066] The starting materials used are known compounds or are prepared according to known methods.

[0067] Step A:

[0068] Schisandrin (50 mg, 0.12 mmol), acetyl-protected caffeic acid (50 mg, 0.19 mmol), EDCI 60 mg, in 5 ml of dichloromethane, stirred at 25 ° C for 40 h, ethyl acetate and water were added, the liquids were separated, the organic phase was taken, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (PE: EA = 5: 1) was performed to obtain 63 mg of compound 3 as a yellow solidified oil. The yield was 78.2%.

[0069]

[0070] 1 H NMR (400MHz, CDCl3) δ7.52(d,J=15.9Hz,1H),7.26(d,J=2.1Hz,1H),7.10(d,J=8.5Hz,1H),7.04(d,J=2.1Hz,1H),7.02(d,J=1. 9Hz,0H),6.70(s,1H),6.47(s,1H),6.24(d,J=15.9Hz,1H),5.24(s,2H),5.20(s,2H),3.91(s,3H),3.84(s,3H),3.81(s,3H),3. 75(s,3H),3.57(s,2H),3.49(s,3H),3.49(s,4H),2.63(dd,J=13.7,7.4Hz,1H),2.56(d,J=2.1Hz,1H),2.52(d,J=2.1Hz,0H),2. 32(dd,J=13.3,9.6Hz,1H),2.04(m,1H),1.92(d,J=7.3Hz,0H),1.84–1.72(m,0H),0.99(d,J=7.1Hz,2H),0.79(d,J=7.1Hz,2H).

[0071] 13 C NMR (100MHz, CDCl3) δ164.6,153.0,151.5,151.2,149.2,147.4,145.2,142.3,140.2,139.6,139.4,133.9,128.8,123.6,12 0.9,116.1,115.7,115.5,112.9,107.4,95.5,95.1,61.0,60.7,56.3,56.3,56.1,55.8,40.6,39.2,35.4,33.8,21.7,12.9.

[0072] Embodiment 1:

[0073] Step B:

[0074] Compound 3 (60 mg, 0.1 mmol) was dissolved in 2 ml of tetrahydrofuran, and 0.2 ml of hydrochloric acid in tetrahydrofuran was added dropwise. The mixture was stirred at 25°C-60°C for 10 h and concentrated to obtain 50 mg of compound (I) with a yield of 88.6%.

[0075]

[0076] 1 H NMR (400MHz, CDCl3) δ7.45(d,J=15.8Hz,1H),6.94(s,1H),6.77(d,J=8.2Hz,1H),6.73(d,J=8.5Hz,2 H),6.49(s,1H),6.11(d,J=15.8Hz,1H),3.91(s,3H),3.85(s,3H),3.80(s,3H),3.75(s,3H),3.58(s ,3H),2.64(dd,J=13.6,7.4Hz,1H),2.54(d,J=15.7Hz,0H),2.32(dd,J=13.4,9.6Hz,1H),2.03(d,J= 13.4Hz,1H),1.92(t,J=6.8Hz,1H),1.83–1.72(m,1H),0.98(d,J=7.1Hz,3H),0.78(d,J=7.1Hz,3H).

[0077] 13 C NMR (100MHz, CDCl3) δ165.4,152.9,151.5,151.0,147.0,146.5,144.3,142.2,140.4,139.3,139.1,134.3,12 7.0,123.5,122.3,120.8,115.4,114.4,113.9,113.0,107.6,56.1,55.8,40.6,39.2,34.6,33.8,21.7,12.2.

[0078] Embodiment 2:

[0079] Take 150g of schisandra chinensis phenol ester and appropriate amount of auxiliary materials, sieve, mix, and put into capsules to prepare 1000 schisandra chinensis phenol ester capsules. The content of schisandra chinensis phenol ester is obtained by quantitative analysis and used as the basis for dosage.

[0080] Embodiment 3:

[0081] Take 150g of schisandra chinensis phenol ester, dilute with water and use stevioside to make a 10% liquid medicine, and prepare schisandra chinensis phenol ester oral liquid. The content of schisandra chinensis phenol ester is obtained by quantitative analysis, which is used as the basis for the dosage.

[0082] Embodiment 4:

[0083] Aryl olefine schisandrae phenol ester sodium salt is added with injection water according to the conventional method, and then finely filtered, sealed and sterilized to prepare the injection solution.

[0084] Embodiment 5:

[0085] Aryl olefinic acid schisandra phenol ester potassium salt is dissolved in sterile water for injection, excipients are added, stirred to dissolve, filtered with a sterile suction filter funnel, and then sterile fine filtration is performed, divided into 2 ampoules, and freeze-dried at low temperature, sterilized and sealed to obtain powder injection.

[0086] Embodiment 6:

[0087] Aryl olefinic acid schisandra chinensis phenol ester is added to the excipient at a weight ratio of 9:1 to the excipient to prepare a powder.

[0088] Embodiment 7:

[0089] Aryl olefinic acid schisandra chinensis phenol ester is added to the excipient in a weight ratio of 1:5-1:10, and granulation and tableting are performed.

[0090] Embodiment 8:

[0091] Aryl olefinic acid schisandra chinensis phenol sodium salt is prepared into oral liquid according to the conventional oral liquid preparation method.

[0092] Embodiment 9:

[0093] Aryl olefinic acid schisandra chinensis phenol ester is added to the excipient in a weight ratio of 5:1 to prepare capsules, granules or granules.

[0094] Embodiment 10:

[0095] Aryl olefinic acid schisandra phenol ester potassium salt is added to the excipient in a weight ratio of 3:1 to prepare capsules, granules or granules.

[0096] Embodiment 11:

[0097] 46.6 g of sodium salt of aryl olefine schisandra phenol esters is added with 600 g of starch, 200 g of lactose, 3 g of menthol and 152 g of sodium carboxymethyl starch to prepare lozenges as a functional food.

[0098] Experimental Example 1. Effect of schisandra chinensis phenol esters on the tail suspension test of animal depression model

[0099] Experimental animals: C57BL / 6 mice, male, weighing 20-30 g, provided by Weitonglihua (Beijing) Biotechnology Co., Ltd., license number: SYXK (Beijing) 2017-0033. Animals were housed in separate cages, with a light / dark cycle of 12 h / 12 ​​h, room temperature of 20-22 °C, free access to food and water, and feed provided by Huilin Zegu Experimental Animal Center.

[0100] Experimental drugs: Aryl olefinic acid schisandra chinensis phenol esters were extracted from the Institute of Materia Medica, Chinese Academy of Medical Sciences. Their chemical purity and structural analysis are as follows: Figure 2 , 3 , 4. Fluoxetine hydrochloride is a product of Aladdin Company, with item number F189157-25g and batch number F2104323.

[0101] Experimental equipment: horizontal bar; tape; camera (Huawei mobile phone); JUNSO multi-function timer.

[0102] Experimental procedures: Male C57BL / 6 mice were adaptively fed for one week and divided into 4 groups, 8 mice in each group. They were DMSO control group (DMSO dissolved in DMSO), low-dose group of aryl olefine acid schisandrin ester (aryl olefine acid schisandrin ester-L, 5mg / kg, dissolved in DMSO), high-dose group of aryl olefine acid schisandrin ester (aryl olefine acid schisandrin ester-H, 10mg / kg, dissolved in DMSO), and positive control group of traditional antidepressant fluoxetine (10mg / kg fluoxetine, dissolved in DMSO). At 10 am, the mice were intraperitoneally injected with 0.15ml / 30g body weight. 60 minutes after the injection, 8 mice in each group were subjected to the tail suspension test; in the mouse tail suspension test, the mouse tail was glued to a horizontal bar 2 cm away from the tail tip with adhesive tape, so that the animal was in an upside-down state, and its head was about 15 cm away from the table. Observe for 6 minutes, and record the cumulative immobility time within the next 4 minutes.

[0103] The immobility indicator is: the animal's limbs and body do not struggle.

[0104] Statistical methods: The experimental results were expressed as mean ± SE, and four samples were tested using ANOVA.

[0105] The depressive symptoms of mice in the high-dose group of aryl olefine schisandrin esters and the fluoxetine positive control group began to ease 60 minutes after injection, that is, the struggling activities became more frequent and the immobility time was significantly shortened compared with the control group. Figure 5 As shown, the immobility time of mice in the high-dose group of aryl olefine acid schisandrin esters and the fluoxetine positive control group was reduced from 76.84±31.40s to 47.49±20.39s and 35.00±24.56s (P<0.01) compared with that in the DMSO control group.

[0106] The results showed that schisandrin aryl oleate esters could take effect in a very short time and could counteract the symptoms of depression and despair caused by forced tail suspension in mice.

[0107] Experimental Example 2. Effects of schisandra chinensis phenol esters on the forced swimming test of animal depression model

[0108] Experimental animals: C57BL / 6 mice, male, provided by Weitonglihua (Beijing) Biotechnology Co., Ltd., license number: SYXK (Beijing) 2017-0033. One week before the experiment, the animals were housed in separate cages, with a light / dark cycle of 12h / 12h, room temperature of 20-22℃, free access to food and water, and feed provided by Huilin Zegu Experimental Animal Center.

[0109] Experimental drugs: arylene schisandrin esters. Positive control fluoxetine hydrochloride is a product of Aladdin Company, with item number F189157-25g and batch number F2104323.

[0110] Experimental instruments: glass cylinder (40 cm high, 14 cm in diameter); mouse open box (50 cm in length and width, 40 cm high, with 16 equal parts at the bottom); thermometer; JUNSO multifunctional timer.

[0111] Experimental steps: Drug preparation is the same as the tail suspension test. Animal drug injection: C57BL / 6 mice, 7-8 weeks old, weighing 20-30 grams, began the experiment after one week of acclimatization. The animals were randomly divided into 4 groups, with 8 animals in each group. Intraperitoneal injection began at 10 am every day. The injection volume was 0.15 ml / 30 grams, once a day, and the forced swimming test began five days after the injection.

[0112] Forced swimming test: Each group of C57BL / 6 mice was placed vertically in a plexiglass cylinder (40 cm high × 14 cm diameter) with a water depth of 25 cm and a water temperature of 21-23°C. Each drug-treated group and control group were recorded for 6 minutes, and the cumulative immobility time of mice in each group in the last 4 minutes was compared.

[0113] Determination of immobility time: The mouse floats on the water surface, does not make any effort to climb out of the cylinder, and only performs some movements that are necessary to keep its head above the water surface.

[0114] Statistical analysis method: The experimental results were expressed as mean ± SE, and four samples were tested using ANOVA.

[0115] The results are as follows Figure 6As shown, compared with the DMSO control group, the immobility time of mice in the high-dose group of aryl olefinic acid schisandrin phenol esters was significantly shortened within 4 minutes of forced swimming. Compared with the 1% DMSO control group, the immobility time of mice in the high-dose group of aryl olefinic acid schisandrin phenol esters was reduced from 99.08±22.96s to 82.37±14.56s (P<0.05), shortened by 16.87%. In mice treated with the traditional antidepressant fluoxetine (10 mg / kg), the immobility time was reduced from 99.08±22.96s to 71.64±11.67s (P<0.01), reduced by 27.69%. Compared with fluoxetine, the antidepressant effect of aryl olefinic acid schisandrin phenol esters was comparable (P>0.05).

[0116] Experimental Example 3. Open field experiment on mice

[0117] Since the shortened immobility time in the classic depression animal model may be caused by the central excitatory effect of the drug, we conducted an open field experiment in mice to examine the central excitatory effect of arylene schisandrin esters.

[0118] The experimental results showed that after the mice entered the open box for 10 minutes, the total distance they moved in the open box was counted by ANY-maze software. There was no significant change (Anova, P>0.05, N=32) compared with the control group (24.35±4.83m) after high-dose treatment with schisandrin aryl olefine acid esters (25.23±3.20m) and low-dose treatment (28.05±5.44m). Therefore, the possibility of inducing manic state can be ruled out. Therefore, schisandrin aryl olefine acid esters do have a significant antidepressant effect.

[0119] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution, which should be included in the scope of the claims of the present invention.

Claims

1. Use of schisandra chinensis phenol ester of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of an antidepressant drug, 2. The use according to claim 1, characterized in that: The pharmaceutically acceptable salt is selected from the group consisting of sodium salt or potassium salt of arylene schisandrin ester.

3. The use according to claim 1, characterized in that: The application dosage is 0.01-30 mg of schisandra chinensis phenol or a pharmaceutically acceptable salt thereof per kilogram of body weight.

4. An antidepressant pharmaceutical composition, characterized in that: The drug component comprises the arylene acid schisandrin ester or a pharmaceutically acceptable salt thereof as claimed in claim 1, and pharmaceutically acceptable auxiliary components.

5. The antidepressant pharmaceutical composition according to claim 4, characterized in that: The pharmaceutical ingredients also include pharmaceutical ingredients that have a positive effect on treating depression after simultaneous administration.

6. The antidepressant pharmaceutical composition according to claim 5, characterized in that: The drug ingredients that have a positive effect on treating depression after simultaneous administration include: monoamine oxidase inhibitors MAOI, tricyclic antidepressants TCA, selective serotonin reuptake inhibitors SSRI, serotonin and norepinephrine reuptake inhibitors SNRI, noradrenergic and specific 5-HT receptor antagonists NASSA, 5-HT antagonists and reuptake inhibitors or melatonin and 5-HT2C receptor antagonists.

7. The antidepressant pharmaceutical composition according to claim 6, characterized in that: The tricyclic antidepressants include: amitriptyline, imipramine, chlorpromazine, doxepin or clomipramine; the selective serotonin reuptake inhibitors include: fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram or escitalopram; the serotonin and norepinephrine reuptake inhibitors include: venlafaxine or duloxetine; the noradrenergic and specific 5-HT receptor antagonist NASSA includes mirtazapine; the 5-HT antagonist and reuptake inhibitors include: nefazodone or trazodone; The melatonin and 5-HT2C receptor antagonist include agomelatine.

8. The antidepressant pharmaceutical composition according to claim 5, characterized in that: The drug ingredients that have a positive effect on treating depression after simultaneous administration include herbal medicines, such as St. John's wort, tianeptine, vortioxetine or bupropion.

9. The antidepressant pharmaceutical composition according to claim 5, characterized in that: The drug components that have a positive effect on treating depression after simultaneous administration include ketamines, which are S-ketamine or ketamine nasogastric administration.

10. The antidepressant pharmaceutical composition according to claim 4, 5, 6, 7, 8 or 9, characterized in that: The pharmaceutical dosage form is powder, granule, tablet, capsule, pill, solution, suspension or injection.

11. A method for preparing the compound according to claim 1-2, characterized in that: The following steps are involved: i: condensation; ii :hydrolysis A. Schisandrin reacts with the compound of formula (II) under alkaline conditions to generate a compound of formula (III); B. removing the protecting group of the compound of formula (III) under acidic conditions, alkaline conditions or by hydrogenation to obtain the compound of formula (I); Wherein R1 is selected from hydrogen, methoxycarbonyl, acetyl, methanesulfonyl, methyl, ethyl, trifluoromethyl, methoxymethyleneoxy, benzyl, p-methoxybenzyl, tert-butyldimethylsilyl, and allyl; X is selected from hydroxy, chloro, tert-butoxy.

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