CN114159438A

CN114159438A - Application of hypnagazine and derivatives thereof in preparation of medicaments for treating depression and prepared antidepressant medicaments

Info

Publication number: CN114159438A
Application number: CN202111444601.8A
Authority: CN
Inventors: 杜静; 吉腾飞; 阚伟京; 王刚
Original assignee: Institute of Materia Medica of CAMS; Beijing Anding Hospital
Current assignee: Institute of Materia Medica of CAMS; Beijing Anding Hospital
Priority date: 2021-11-30
Filing date: 2021-11-30
Publication date: 2022-03-11
Anticipated expiration: 2041-11-30
Also published as: CN114159438B

Abstract

The invention provides application of hyphenazine and derivatives thereof in preparing medicaments for treating depression and prepared antidepressant medicaments. The application dosage is 0.01-30mg of the hypanthazine or the derivative thereof per kilogram of body weight, and the antidepressant effect can be produced within 60 minutes after the administration. After 5 days of administration, both low and high doses produced significant antidepressant effects. The research result of the invention shows that the galanthamine or the derivative thereof has the effect of quickly resisting depression in the tail suspension experiment of a mammal mouse, and is more effective than the conventional antidepressant imipramine. The invention adopts forced swimming experiment and mouse tail suspension experiment as drug screening experiment, and simultaneously carries out mouse Open field test (Open field test) to test the autonomous activity of the mouse, thereby avoiding the interference of central stimulant. The antidepressant drug has the advantages of obvious antidepressant effect, quick response, small dosage, small side effect and the like, and is expected to become a new antidepressant drug with high speed, high efficiency and a new mechanism.

Description

Application of hypnagazine and derivatives thereof in preparation of medicaments for treating depression and prepared antidepressant medicaments

Technical Field

The invention belongs to the technical field of medicines, and relates to application of galanthamine (Hernandezine) and derivatives thereof in preparation of medicines for treating depression and prepared antidepressant medicines.

Background

Major Depressive Disorder (MDD) is a serious, recurrent disabling psychotic disorder. About 3 billion depression patients worldwide. The incidence of depression in china is 4.2%, with about 5600 ten thousand patients suffering depression. Depression is the second leading cause of life loss (years) due to disability, and has become a major public health problem that urgently needs to be solved. Depression is clinically manifested as depressed mood, hyposis, and even pessimistic and boredom, with suicide attempts or behaviors. The current first-line clinical antidepressants mainly comprise selective 5-hydroxytryptamine reuptake inhibitors, 5-hydroxytryptamine and norepinephrine reuptake inhibitors and the like. However, these drugs have slow onset of action, narrow spectrum of action, and are easy to recur after withdrawal of the drug. Despite the use of multiple antidepressant medications, about 30% of patients become refractory Depression (TRD). Patients with this type of refractory depression present a higher risk of social burden and risk of suicide. Therefore, the search for new antidepressant drugs with good compliance, few side effects and novel pharmacological mechanisms has great clinical requirements, and is also a hot spot of international research at present.

Hylandizine (Hernandezine), also known as thalictrine, is a dibenzylisoquinoline alkaloid isolated from the plant Thalictrum glandifolia (Thalictrum glandulosissimum) of the genus Thalictrum of the family Ranunculaceae. The molecular formula of the hypanthazine is C39H44N2O7, the molecular weight is 652.78, the melting point is 192-193 ℃, and the hypanthazine is soluble in ether and chloroform and hardly soluble in water. The hypanthazine has certain therapeutic effect on P388 leukemia mice, ascites type S180 and C26 colon cancer mice.

In vitro, the hypanthazine obviously inhibits the growth of mouse leukemia L1210 cells and human oral cancer KB cells, and has weak inhibition effect on mouse normal hematopoietic progenitor cells (CFU-GM).

Subacute toxicity experiments prove that the hypanthazine has no obvious influence on the functions of bone marrow, liver, kidney and the like of rats. At present, no report is found about the use of the galanthamine as an active ingredient for preventing and treating depression.

Disclosure of Invention

The invention aims to provide an application of the hyphenazine and the derivatives thereof in preparing a medicament for treating depression, and the medicament has the advantages of obvious anti-depression effect, quick response, small dosage, small side effect and the like.

The invention provides an application of the compound of formula (I) and the derivatives thereof in preparing the drug for treating depression,

further, the derivatives include: hydrochloride, sulfate, phosphate and other inorganic acid salts of the hypanthazine, and organic acid salts of oxalic acid, citric acid and other organic acid salts.

Further, the dosage for application is 0.01-30mg of the hypanthazine or the derivative thereof per kilogram of body weight.

The invention also provides an anti-depression drug, which comprises the following components: the compound is the compound of the galanthamine or the derivative thereof and auxiliary components acceptable in pharmacy.

The medicinal components also comprise medicinal components which have positive effects on treating depression after being simultaneously applied.

Further, the pharmaceutical ingredients having a positive effect on the treatment of depression after the simultaneous administration include: monoamine oxidase inhibitor MAOI, tricyclic antidepressant TCA, selective serotonin reuptake inhibitor SSRI, serotonin and norepinephrine reuptake inhibitor SNRI, noradrenergic and specific 5-HT receptor antagonist NASSA, 5-HT antagonist and reuptake inhibitor, or melatonin and 5-HT2C receptor antagonist.

Further, the tricyclic antidepressants (TCAs) include amitriptyline, imipramine, chlorpromazine, doxepin, clomipramine, and the like; such Selective Serotonin Reuptake Inhibitors (SSRIs) are for example: fluoxetine (banseolute), paroxetine (tyloxamine), fluvoxamine (lansoprazole), sertraline (levofloxacin), citalopram (citalopram, siberian), escitalopram (escitalopram), etc.; the Serotonin and Norepinephrine Reuptake Inhibitors (SNRI), e.g., venlafaxine, duloxetine, etc.; the noradrenergic and specific 5-HT receptor antagonists (NASSA), e.g., mirtazapine, etc.; the 5-HT antagonist and reuptake inhibitor: such as nefazodone and trazodone; the melatonin and 5-HT2C receptor antagonists: such as agomelatine.

Further, the pharmaceutical ingredients which have a positive effect on the treatment of depression after simultaneous administration are herbs such as: john's wort, and tianeptine, Vortioxetine (also known as Vortioxetine), Bupropion (bupapion), and the like.

Further, the pharmaceutical ingredients which have positive effects on treating depression after simultaneous administration are as follows: ketamines, including S-ketamine or ketamine nasal feeds.

Further, the effective dose of the drug is 0.01-30mg of the hypanthazine and the derivatives thereof per kilogram of body weight.

The above medicinal preparation is in the form of powder, granule, tablet, capsule, pill, solution, suspension or injection.

The hypanthazine is white powder, HRESI-MS M/z [ M + H ] +653.3221, and its molecular formula is C39H44N2O 7.

¹H NMR(400MHz,CDCl₃)δ7.32(d,J＝2.2Hz,1H),7.13(dd,J＝8.1,2.6Hz,2H),6.85(s,2H),6.78(dd,J＝8.3,2.6Hz,2H),6.54(s,2H),6.50(s,2H),6.29(dd,J＝8.3,2.2Hz,2H),5.99(s,2H),3.92(s,4H),3.80(s,4H),3.77(s,4H),3.44(d,J＝6.7Hz,1H),3.34(s,4H),3.23(s,4H),2.91(s,2H),2.85–2.69(m,3H),2.63(s,4H),2.51(d,J＝14.3Hz,0H),2.30(s,4H)。

¹³C NMR(100MHz,CDCl₃)δ153.80,149.41,145.58,144.35,143.81,134.98,132.64,130.19,122.88,121.95,120.27,116.12,112.67,111.55,63.86,60.91,60.59,60.54,56.16,55.69,45.22,42.58,42.41。

The medicament can be administered in unit dosage form, and the administration dosage form can be liquid dosage form or solid dosage form. For example, the liquid dosage form can be true solution, colloid, microparticle, emulsion, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.

The administration route can be intestinal or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosal, cutaneous, peritoneal or rectal.

The route of administration of the drug of the present invention may be administration by injection. The injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection, etc.

The medicine of the present invention may be prepared into common preparation, slow released preparation, controlled releasing preparation, targeting preparation and various particle medicine feeding system.

In order to prepare the unit dosage form into tablets, various carriers well known in the art can be widely used. In the vector: diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, and the like; 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, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.

For making the administration units into pills, a wide variety of carriers well known in the art can be used. In the vector: for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, polyvinylpyrrolidone, Gelucire, kaolin, talc, and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc.

For making the administration unit into a suppository, various carriers well known in the art can be widely used. In the vector: such as polyethylene glycol, lecithin, cocoa butter, higher alcohols, higher alcohol enzymes, gelatin, semisynthetic glyceroses, and the like.

To encapsulate the administration units, the active ingredient is mixed with the various carriers described above, and the mixture thus obtained is placed in hard gelatin capsules or soft gelatin capsules. Or making into microcapsule, suspending in aqueous medium to form suspension, or making into hard capsule or injection.

For example, the composition of the present invention is formulated into an injectable preparation, such as a solution, a suspension solution, an emulsion, a lyophilized powder, which may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid enzyme, etc. In addition, for the preparation of isotonic injection, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, pH adjusters and the like may also be added. These adjuvants are commonly used in the art.

In addition, if desired, colorants, preservatives, flavors, flavorings, sweeteners, or other materials may also be added to the pharmaceutical preparation.

The dose of the pharmaceutical composition of the present invention to be administered depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight, character and individual response of the patient or animal, the administration route, the number of administrations, etc., and thus the therapeutic dose of the present invention can be widely varied. Generally, the dosage of the compounds of the present invention used is well known to those skilled in the art. The actual effective amount of the drug contained in the final preparation of the medicinal composition can be properly adjusted according to the requirement of the effective amount of the drug so as to achieve the treatment of obesity, abnormal glucose tolerance, hyperlipidemia, diabetes, complications thereof and other diseases; and the use of chronic inflammation, insulin resistance, cerebrovascular disease and atherosclerosis in relation to the above mentioned diseases.

In general, for a patient weighing about 75 kg, the compounds of the present invention are administered in a daily dose of 0.001mg/kg body weight to 200mg/kg body weight, preferably 1mg/kg body weight to 100mg/kg body weight. The above-mentioned dosage may be administered in a single dosage form or divided into several, e.g., two, three or four dosage forms, which is limited by the clinical experience of the administering physician and the dosage regimen. The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents.

The invention provides an anti-depression drug, which comprises two stages of prevention and treatment. The dosage of the anti-depression drug is as follows: providing 0.01-30mg of Hailandizine and its derivatives per kilogram of body weight per day. The administration mode of the anti-depression drug is oral administration, nasal spray, instillation or injection; the subject to be administered is a mammal, including a human.

The anti-depression drug provided by the invention is an administration dosage of 0.01-30mg of the hypanthazine and the derivatives thereof per kilogram of body weight; the antidepressant effect can be achieved within 60 minutes after administration. After 5 days of administration, both low and high doses produced significant antidepressant effects. The medicine has the advantages of remarkable antidepressant effect, quick action, small dosage, small side effect and the like. In the forced swimming test of mammal mice, the anti-depression effect of the halauxin and the derivatives thereof is more obvious than that of the conventional antidepressant imipramine.

Compared with the prior art, the invention has the beneficial technical effects that:

1. the invention provides an application of hypanthazine or derivatives thereof in preparing an anti-depression drug. The research result of the invention shows that the galanthamine or the derivative thereof has the effect of quickly resisting depression in the tail suspension experiment of a mammal mouse, and is more effective than the conventional antidepressant imipramine.

2. The invention adopts forced swimming experiment and mouse tail suspension experiment as drug screening experiment. Forced swimming experiments and mouse tail suspension experiments are two common animal behavior despair depression model experiments, and can better ensure the reliability of screening results. Forced swimming experiments in mice have been used for screening of many antidepressants. Moreover, most of the antidepressants with clinical treatment effects are also proved to be effective in reducing immobility time in forced swimming experiments.

By immobile, it is meant that "the animal stops struggling in water, or is in a floating state, only exposing nostrils to keep breathing, and only having small limb movements to keep the head floating on the water". Drugs to be screened were administered prior to the assay. Animals cannot escape from the harsh environment due to downstream swimming in a forced state, resulting in despair behavior of the animals. The model method is simple, convenient and reliable, and is widely used for screening and evaluating the antidepressant. The tail suspension experiment of the mouse is that the mouse does not struggle under the tail suspension state and presents a special quiet immobility state, and the antidepressant can obviously shorten the duration time of the immobility state. During the test, the tail of the mouse is fixed and suspended upside down. The tail of the mouse is not twisted and folded. And recording the immobility time. The immobility indexes are as follows: animal limbs and trunk struggle without twisting. The tail suspension experiment is sensitive to various antidepressants, and avoids the interference of temperature and animal movement dysfunction in the swimming experiment, so that the results of the forced swimming experiment can be effectively verified and supplemented when some mice are used for screening the antidepressants.

3. Shows stronger antidepressant effect than imipramine. In a tail suspension experiment of a mouse animal model, the mice (10mg/kg) in a high-dose group of the galanthamine and derivatives thereof have the effect that depression symptoms begin to be relieved after 60 minutes of injection, namely, the activity amount is more and more frequent compared with that of a blank control group, and the immobility time is obviously shortened. The duration of immobility of tail suspension was significantly shortened by the onset of hylandizine and its derivatives 5 days after injection. The dose (10mg/kg) of the halazine and the derivatives thereof is lower than that of imipramine (15mg/kg), and the halazine and the derivatives thereof show stronger antidepressant effect than the imipramine.

4. The invention also carries out an Open field test (Open field test) of the mouse to check the autonomous activity of the mouse and avoid the interference of central stimulant. Since the shortening of the immobility time of animals in classical animal models of depression may be due to the central excitatory action of the drug, the present invention also simultaneously performs mouse open-field experiments. The result shows that the high concentration of the hyphenazine and the derivatives thereof have no obvious influence on the autonomous activity of mice compared with the control group, so that the possibility of causing mania by stimulant can be eliminated, and the hyphenazine and the derivatives thereof are proved to have obvious antidepressant effect indeed.

5. The antidepressant medicament taking the hyphenazine or the derivative thereof as the effective component is expected to become a new antidepressant medicament with high speed, high efficiency and a new mechanism.

Drawings

FIG. 1 is a structural formula of Hailandizine;

FIG. 2 preparation of Hailandizine¹H NMR；

FIG. 3 preparation of Hailandizine¹³C NMR；

FIG. 4 MS of Hailandizine;

FIG. 5 Effect of Hailandizine injection on mouse tail suspension experiment one hour later;

ordinate: tail suspension experiment mice immobility time(s), abscissa: a DMSO control group, a hyphenazine low-dose group (HWH-L, 5mg/kg), a hyphenazine high-dose group (HWH-H, 10mg/kg), a normal saline control group and an imipramine positive control group (15mg/kg) are arranged from left to right in sequence; as a result: the high dose group (10mg/kg) showed significant antidepressant effect in the mice tail suspension experiment 60 minutes after intraperitoneal injection of different doses of galanthamine in C57BL/6 male mice (animals per group N6-10, ANOVA test p < 0.05, p < 0.01).

FIG. 6 Effect of Hailandizine injection on mouse swimming test 5 days later

Ordinate: forced swimming test mice immobility time(s), abscissa: from left to right in sequence: DMSO control group, hylandizine low dose group (HWH-L, 5mg/kg), hylandizine high dose group (HWH-H, 10mg/kg), normal saline control group, imipramine positive control group (IMI, 15 mg/kg). As a result: five days after intraperitoneal injection of different doses of the landazine, C57BL/6 male mice show extremely remarkable antidepressant effect in a forced swimming experiment of the mice. This antidepressant effect is more pronounced than that of the traditional antidepressant drug imipramine (animals of each group)

N-8-10, t-test p < 0.05, p < 0.01).

Detailed Description

The present invention is described in detail below by way of specific examples, it being understood that the following examples are intended only by way of illustration and description and are not intended to limit the scope of the present invention in any way. In the following embodiments, the biochemical reagents not specifically described are all conventional reagents in the art, and may be prepared according to conventional methods in the art or commercially available, and may be of laboratory pure grade.

Hailandizine, CAS number: 6681-13-6, trade name: macklin, available from chemical industries, Inc. of Waverrucke, Beijing.

Example 1:

taking 150g of the Hailandizine and a proper amount of auxiliary materials, sieving, uniformly mixing, and encapsulating to prepare 1000 capsules of the Hailandizine. The content of the hylandizine is obtained according to quantitative analysis and is used as the basis of the dosage.

Example 2:

diluting 150g of Hailandizine with water, and flavoring with stevioside to obtain 10% liquid preparation, and making into oral liquid. The content of the hylandizine is obtained according to quantitative analysis and is used as the basis of the dosage.

Example 3:

adding water for injection into the hydrochloride of the Hailandizine, finely filtering, encapsulating and sterilizing according to the conventional method to prepare the injection.

Example 4:

dissolving the sodium alginate sulfate in sterile water for injection, adding excipient, stirring to dissolve, filtering with sterile filter funnel, performing aseptic fine filtration, packaging in 2 ampoules, freeze drying at low temperature, sterilizing, and sealing to obtain powder for injection.

Example 5:

adding excipient into the hypanthazine according to the weight ratio of the hypanthazine to the excipient of 9:1, and preparing into powder.

Example 6:

adding excipient into the hypanthazine according to the weight ratio of the hypanthazine to the excipient of 1:5-1:10, granulating and tabletting.

Example 7:

the compound Hailandizine phosphate is prepared into oral liquid according to a conventional oral liquid preparation method.

Example 8:

adding excipient into the hypanthazine according to the weight ratio of the hypanthazine to the excipient of 5:1, and making into capsule, granule or electuary.

Example 9:

adding excipient into the hypnagazine oxalic acid according to the weight ratio of the hypnagazine oxalic acid to the excipient of 3:1, and preparing into capsules, granules or electuary.

Example 10:

46.6 g of galanthamine citrate, 600 g of starch, 200 g of lactose, 3 g of menthol and 152 g of sodium carboxymethyl starch are added to prepare the buccal tablet which is used as a functional food.

Test example 1 Effect of Hailandizine on Tail suspension test of animal Depression model

Experimental animals: c57BL/6 mice, male, 30-40 grams in weight, supplied by sbefu (beijing) biotechnology limited, license number: SCXK (Jing) 2019-. The animals are raised in cages with the light and shade period of 12h/12h, the room temperature of 22-24 ℃, the water is free, and the feed is provided by the Huada protein experimental animal center.

Experimental drugs: the compound is extracted from the institute of pharmaceutical research of academy of Chinese medical science, and its chemical purity and structure analysis are shown in FIGS. 2, 3 and 4. Imipramine hydrochloride (Imipramine hydrochloride) is a product of Sigma company, the product number is I7379, and the batch number is O56K 1380. Experimental equipment: a cross bar; rubberized fabric; a camera (Hua as cell phone P40 Pro); JUNSO multifunctional timer.

The experimental steps are as follows: male C57BL/6 mice were acclimatized for one week and divided into 5 groups of 6-8 mice each. The control groups are dimethyl sulfoxide DMSO control group (DMSO is dissolved in normal saline), a low-dose group of the Hainandizime (Hainandizime-L is dissolved in DMSO at 5mg/kg), a high-dose group of the Hainandizime (Hainandizime-H is dissolved in DMSO at 10mg/kg), a positive control group of the traditional antidepressant drug imipramine (15mg/kg), and a normal saline control group. The medicine is administrated by intraperitoneal injection at 10 am according to 0.1ml/10g body weight, and after 60 minutes of injection, tail suspension experiments are carried out on 6-8 mice in each group; in the tail suspension experiment of the mouse, the tail of the mouse is stuck on a horizontal cross bar at a position 1 cm away from the tail tip by using an adhesive tape, so that the animal is in an inverted hanging state, and the head of the animal is 15 cm away from a table top. The observation time was 6 minutes and the cumulative immobility time was recorded over 4 minutes.

The immobility indexes are as follows: neither the animal's limbs nor body struggles.

The statistical method comprises the following steps: the results are expressed as mean ± SE and three samples were tested by ANOVA. The average comparison of the two samples (imipramine and saline) was performed using the t-test.

The mice in the high dose group of the galanthamine had initial relief of depression symptoms 60 minutes after injection, i.e., struggling activities were more and more frequent than in the blank control group, and immobility time was significantly shortened. The activity of the imipramine positive control group and the physiological saline control group is not enhanced to be obvious within 60 minutes after injection. Observed 60 minutes after injection, as shown in FIG. 5, the immobility time of the mice in the high and low dose groups of galanthamine was reduced from 197.70 + -4.20 s to 174.7 + -4.23 s (P < 0.05) and 173.2 + -6.40 s compared to the DMSO control group.

The result shows that the high-dose landazine can take effect within a short time, has obvious effect and can resist depression and despair symptoms caused by forced tail suspension of mice.

Test example 2 Effect of Hailandizine on forced swimming test in animal depression model

Experimental animals: c57BL/6 mice, male, offered by sbefu (beijing) biotechnology limited, license number: SCXK (Jing) 2019-. The animals are raised in cages with the light and shade period of 12h/12h, the room temperature of 22-24 ℃, the water is free, and the feed is provided by the Huada protein experimental animal center.

Experimental drugs: hailandizine. The positive control Imipramine hydrochloride (Imipramine hydrochloride) is a product of Sigma company, the product number is I7379, and the batch number is O56K 1380.

An experimental instrument: glass cylinder (height 40cm, diameter 14 cm); a mouse open box (the length and the width are 50cm, the height is 40cm, and the bottom is 16 equal parts); a thermometer; JUNSO multifunctional timer.

The experimental steps are as follows: drug preparation same tail suspension experiment. Animal drug injection: c57BL/6 mice, age 7 weeks, weigh 30-40 grams, acclimate for one week and begin the experiment. Animals were randomly grouped into 5 groups of 8-10 animals each. Intraperitoneal injections were started at 10 am each day. The injection amount is 0.3 ml/30 g, the injection is performed intraperitoneally once a day, and a forced swimming experiment is started five days after the injection. Forced swimming experiment: each group of C57BL/6 mice was placed individually vertically into a plexiglas cylinder (40cm height by 14cm diameter) at a water depth of 25cm and a water temperature of 21-23 ℃. The administration group and the control group were recorded for 6 minutes, and the cumulative immobility time in the following 4 minutes was compared for each group of mice.

And (3) judging the motionless time: the mouse floats on the water surface, does not try to climb out of the cylinder, and only does some action which is necessary to keep the head of the mouse on the water surface.

The statistical analysis method comprises the following steps: the results are expressed as means ± SE and the comparison of the mean of the two samples is performed by t-test. As shown in FIG. 6, compared with DMSO control group, the immobility time of the mice in both the high dose and low dose forms of Hailandin was significantly reduced within 4 minutes of forced swimming, and the immobility time of the mice in the high dose (10mg/kg) and low dose (5mg/kg) forms a reduction from 69.63 + -13.28 s to 32.57 + -6.53 s (p < 0.01) and 23.88 + -5.27 s (p < 0.01) in comparison with 1% DMSO control group, which are reduced by 53.22% and 65.70%, respectively. And the imipramine (15mg/kg) with the similar dosage is reduced to (57.17 +/-5.66 s) from (75.54 +/-6.06 s) of the normal saline control group, and is reduced by 24.3 percent, and compared with the imipramine which is a traditional antidepressant, the anti-depression effect of the halazine is stronger.

Test example 3 mouse open-field test

Since the reduction in immobility time of animals in classical animal models of depression is probably due to the central excitatory action of the drug, we performed a mouse open field experiment to examine the central excitability of the hylandizine.

The experimental results show that 6 minutes after the mice entered the open field, where the total distance traveled in the open box 5 minutes later was counted by the ANY-maze software, there was no significant change (Anova, p > 0.05, N ═ 19) after the high dose treatment of the hyaline (15.69 ± 3.14m), after the low dose treatment of the hyaline (15.45 ± 2.92m) compared to the DMSO control (15.85 ± 2.35m), so the possibility of inducing mania was excluded, and therefore, the hyaline did have significant antidepressant effect.

Finally, the above embodiments are only intended to illustrate the technical solutions of the present invention and not to limit the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions, and all of them should be covered by the claims of the present invention.

Claims

1. The application of the compound shown in the formula (I) and the derivatives thereof in preparing the medicament for treating depression,

2. the use according to claim 1, wherein the derivative comprises: a hydrochloride, sulfate, phosphate, oxalate or citrate salt of galanthamine.

3. Use according to claim 1, wherein the dose used is 0.01-30mg of hyphenazine or a derivative thereof per kg of body weight.

4. An anti-depression drug, wherein the drug comprises the following components: the compound is the compound of the galanthamine or the derivative thereof and auxiliary components acceptable in pharmacy.

5. The antidepressant as in claim 4, wherein said pharmaceutical components further comprise pharmaceutical components having a positive effect on the treatment of depression after the simultaneous administration.

6. The antidepressant as claimed in claim 5, characterized in that said pharmaceutical ingredients with a positive effect on the treatment of depression after the simultaneous administration comprise: monoamine oxidase inhibitor MAOI, tricyclic antidepressant TCA, selective serotonin reuptake inhibitor SSRI, serotonin and norepinephrine reuptake inhibitor SNRI, noradrenergic and specific 5-HT receptor antagonist NASSA, 5-HT antagonist and reuptake inhibitor or melatonin and 5-HT2C receptor antagonist.

7. The anti-depression drug of claim 6, wherein said tricyclic antidepressant comprises: amitriptyline, imipramine, chlorpromazine, doxepin or clomipramine; the selective serotonin reuptake inhibitor comprises: fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram or escitalopram; the serotonin and norepinephrine reuptake inhibitor comprises: venlafaxine or duloxetine; the noradrenergic and specific 5-HT receptor antagonist NASSA comprises mirtazapine; the 5-HT antagonist and reuptake inhibitor comprises: nefazodone or trazodone; the melatonin and 5-HT2C receptor antagonists include: agomelatine.

8. An antidepressant drug according to claim 5, characterized in that said pharmaceutical ingredients having a positive effect on the treatment of depression after the simultaneous administration comprise herbs which are St.

9. The antidepressant drug according to claim 5, characterized in that said pharmaceutical composition having a positive effect on the treatment of depression after the simultaneous administration comprises ketamine, which is S-ketamine or ketamine nasal feed.

10. The antidepressant as claimed in claim 3, 4, 5, 6, 7, 8 or 9, characterized in that said pharmaceutical form is a powder, granules, tablets, capsules, pills, solutions, suspensions or injections.