Application of chalcone compound in preparation of medicine for treating depression

Abstract

The invention provides application of a chalcone compound as well as a stereoisomer, a pharmaceutically acceptable salt or a solvate thereof in preparation of a medicament for treating depression. The depression is selected from mild depression, moderate depression, severe depression, persistent depressive disorder, depression associated with bipolar disorder, seasonal affective disorder, psychotic depression, postpartum depression, premenstrual anxiety disorder, encountering depression, pleasant sensation deficiency, melancholia, middle-year depression and late-year depression; depression caused by identifiable pressure factors, refractory depression, or a combination thereof. The compounds can treat mental symptoms of depression, such as depressive mood and loss of interest or fun in almost all activities.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical compound technology, specifically relating to the application of a chalcone compound in the preparation of a drug for treating depression. Background Technology

[0002] Depression is one of the most common psychopathologies. Symptoms of depression include depressed mood, decreased interest and pleasure. In 2000, the World Health Organization listed it as the fourth leading cause of global disease burden. Although many effective antidepressants are currently available, current treatments are often inadequate. Approximately two-thirds of patients with anxiety or depression respond to currently available treatments, but the degree of improvement remains disappointing. About one-third of treatment participants have unsatisfactory results. Therefore, it is essential to find new antidepressants with fewer side effects and better efficacy.

[0003] Chalcones are biological precursors of all known flavonoids and are abundant in edible plants. They include open-chain flavonoids, in which two aromatic rings are linked by a three-carbon α,β-unsaturated carbonyl system. They possess a wide range of biological properties, such as anticancer, anti-inflammatory, antimalarial, antifungal, and antiviral activity. In recent years, flavonoids have been reported to possess antidepressant-like activities. Furthermore, Yi et al. reported that apigenin (5,7,4-trihydroxyflavone) has antidepressant effects. Wang et al. also reported 10 natural flavonoids with antidepressant-like activities. Summary of the Invention

[0004] This invention provides the use of compounds of formula I, their stereoisomers, pharmaceutically acceptable salts, or solvates in the preparation of medicaments for treating depression. in:

[0005] R1 is

[0006] R2 is C 1-4 Alkyl; preferably methyl;

[0007] Each R3 may be the same or different, and is independently selected from C. 1-4 Alkyl; preferably, each R3 is identical and is methyl;

[0008] R4 is selected from C 1-4 Alkyl or C 1-4 Alkyloxy group; preferably C 1-4 alkyl.

[0009] In some preferred embodiments of the present invention, in formula I:

[0010] R1 is

[0011] R2 is C 1-4Alkyl; preferably methyl;

[0012] Each R3 may be the same or different, and is independently selected from C. 1-4 Alkyl; preferably, each R3 is identical and is methyl.

[0013] In some preferred embodiments of the present invention, in formula I:

[0014] R1 is

[0015] R2 is C 1-4 Alkyl; preferably methyl;

[0016] Each R3 may be the same or different, and is independently selected from C. 1-4 Alkyl; preferably, each R3 is identical and is methyl;

[0017] R4 is selected from C 1-4 Alkyl or C 1-4 Alkyloxy group; preferably C 1-4 alkyl.

[0018] In a preferred embodiment of the present invention, the compound of formula I is selected from...

[0019] The present invention also provides compounds of Formula I, their stereoisomers, pharmaceutically acceptable salts, or solvates for the treatment of depression. The compounds of Formula I are defined as described above.

[0020] The present invention also provides a pharmaceutical composition for treating depression, comprising a compound of Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt or solvate thereof.

[0021] The present invention also provides a method for treating depression, characterized in that a therapeutically effective amount of the compound of formula I, its stereoisomers, pharmaceutically acceptable salts or solvates, or a pharmaceutical composition containing the compound of formula I of the present invention, its stereoisomers, pharmaceutically acceptable salts or solvates is administered to a patient in need.

[0022] The present invention also provides the use or application of the compound of Formula I, its stereoisomers, pharmaceutically acceptable salts or solvates in the treatment of depression.

[0023] The present invention also provides a method for using the compound of Formula I, its stereoisomers, pharmaceutically acceptable salts or solvates in the treatment of depression.

[0024] The depression mentioned includes, but is not limited to, mild depression, moderate depression, severe depression, persistent depressive disorder, depression associated with bipolar disorder (also known as bipolar depression), seasonal affective disorder, psychotic depression, postpartum depression, premenstrual anxiety disorder, situational depression, anhedonia, melancholia, midlife depression, late-life depression, depression caused by identifiable stressors, treatment-resistant depression, or a combination thereof.

[0025] The treatment methods, applications, or uses described in this invention, as well as compounds of Formula I, their stereoisomers, pharmaceutically acceptable salts, or solvates, can be used to treat core (or psychiatric) symptoms of depression. These symptoms include depressed mood in almost all activities and loss of interest or pleasure.

[0026] The treatment methods, applications, or uses described in this invention, as well as compounds of formula I, their stereoisomers, pharmaceutically acceptable salts, or solvates, are intended for subjects or patients diagnosed with or exhibiting at least one symptom of depression, regardless of the type or underlying cause of the depression.

[0027] The drug or pharmaceutical composition further comprises a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is a variety of excipients commonly used or known in the pharmaceutical industry, including but not limited to: diluents, binders, antioxidants, pH adjusters, preservatives, lubricants, disintegrants, etc. Examples of diluents include: lactose, starch, cellulose derivatives, inorganic calcium salts, sorbitol, etc. Examples of binders include: starch, gelatin, sodium carboxymethyl cellulose, polyvinylpyrrolidone, etc. Examples of antioxidants include: vitamin E, sodium bisulfite, sodium sulfite, butylated hydroxyanisole, etc. Examples of pH adjusters include: hydrochloric acid, sodium hydroxide, citric acid, tartaric acid, Tris, acetic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, etc. Examples of preservatives include: methylparaben, ethylparaben, m-cresol, benzalkonium chloride, etc. Examples of lubricants include: magnesium stearate, micronized silica gel, talc, etc. Examples of disintegrants include: starch, methylcellulose, xanthan gum, croscarmellose sodium, etc.

[0028] The drug or drug composition may further contain other active compounds that treat or improve depressive states.

[0029] The amount of the drug or pharmaceutical composition containing a compound of formula I, its stereoisomers, a pharmaceutically acceptable salt or solvate, calculated as a compound of formula I, is 0.1-1000 mg, preferably 1-500 mg, more preferably 5-100 mg.

[0030] The dosage form of the drug or pharmaceutical composition may be an oral dosage form, such as tablets, capsules, pills, powders, granules, suspensions, syrups, etc.; or an injectable dosage form, such as an injection solution, powder for injection, etc., administered via intravenous, intraperitoneal, subcutaneous, or intramuscular routes. All dosage forms used are well known to those skilled in the art of pharmaceutical science.

[0031] The routes of administration of the drug or drug composition include, but are not limited to: oral; sublingual; sublingual; transdermal; pulmonary; rectal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous; and by implantation of a reservoir or infusion device.

[0032] The dosage of Formula I compound, its stereoisomers, pharmaceutically acceptable salts or solvates will depend on the recipient's age, health and weight, the type of concomitant medication, treatment frequency, route of administration, etc. The drug can be administered as a single daily dose, once daily, once every two days, once every three days, once every four days, or the total daily dose can be administered in two, three, or four separate doses per day. The dosage of Formula I compound, its stereoisomers, pharmaceutically acceptable salts or solvates, calculated based on Formula I compound, is 0.01-100 mg / kg / day, preferably 0.1-10 mg / kg / day, for example, 0.5 mg / kg / day, 1 mg / kg / day, 2 mg / kg / day, 5 mg / kg / day, etc.

[0033] Compounds of Formula I, their stereoisomers, pharmaceutically acceptable salts or solvates, or pharmaceuticals or pharmaceutical compositions containing compounds of Formula I, their stereoisomers, pharmaceutically acceptable salts or solvates, may be used in combination with other pharmaceuticals for treating or improving depressive states.

[0034] According to the present invention, other medications for treating or improving depressive states include, but are not limited to: sertraline, paroxetine, escitalopram, venlafaxine, fluvoxamine, imipramine, nortriptyline, estazolam, mirtazapine, olanzapine, etc.

[0035] In the treatment methods or applications described in this invention, the patient's response to the therapeutic drug and its maintenance can be determined by a clinician, psychiatrist, psychologist, or other suitable medical professional. Maintenance of the antidepressant response can be established, for example, by the absence of relapse of depression (or one or more symptoms of depression), the absence of a need for one or more additional or alternative treatments for depression, or the absence of worsening of depression. The physician may utilize any techniques known in the art, including but not limited to general patient assessments, diagnostic questionnaires, and assessments such as the Clinical Global Impression-Severity (CGI-S) scale, the Sheehan Disability Scale (SDS), the 30-item scale (IDS-C30), the MADRS questionnaire, the Hamilton Depression Rating Scale (HAM-D or HDRS), the Beck Depression Scale, or the Quick List of Depressive Symptoms (QIDS), etc.

[0036] The preparation of the compound of formula I of the present invention can be carried out by referring to the methods described in Chinese patent applications CN115636809A and CN117603175A. Attached Figure Description

[0037] Figure 1 Open field behavioral experiments were conducted on days 7 and 60 after the model group began restraint (i.e., the cumulative 49th day of restraint). The percentage of time spent in the central region in both the model and control groups is shown in the graph. * indicates P < 0.05 compared to the control group, ** indicates P < 0.01 compared to the control group, *** indicates P < 0.001 compared to the control group, and **** indicates P < 0.0001 compared to the control group.

[0038] Figure 2 The graph shows the percentage of time spent in the central region during the open field behavioral experiment in both the model group and the control group on days 7 and 60 after the start of restraint (i.e., the cumulative 49th day of restraint). In the graph, * represents a p-value < 0.05, ** represents a p-value < 0.01, *** represents a p-value < 0.001, and **** represents a p-value < 0.0001.

[0039] Figure 3 After the depression model was established (i.e., 60 days after the start of restraint), a forced swimming behavioral experiment was conducted. The percentage of rest time in the model group and the control group is shown in the graph. * represents P < 0.05 compared to the control group, ** represents P < 0.01 compared to the control group, *** represents P < 0.001 compared to the control group, and **** represents P < 0.000 compared to the control group.

[0040] Figure 4Twenty-four mice were selected for subsequent drug administration. The percentage of time spent at rest during forced swimming in the selected model group and control group at the end of depression modeling (i.e., day 60 after the start of restraint) is statistically analyzed in the graph. * represents P < 0.05 compared to the control group, ** represents P < 0.01 compared to the control group, *** represents P < 0.001 compared to the control group, and **** represents P < 0.0001 compared to the control group.

[0041] Figure 5 During WR010 administration, the percentage of time mice spent at rest during forced swimming was statistically analyzed in the model group + WR010, model group + solvent, and blank group + solvent groups. In the figure, * represents P < 0.05, ** represents P < 0.01, *** represents P < 0.001, and **** represents P < 0.0001.

[0042] Figure 6 After 7 days of continuous administration and 7 days of drug withdrawal with WR034, the percentage of time spent in the central region of the open field was statistically analyzed in each group of mice: model group + WR034, model group + solvent, and blank group + solvent. * indicates a p-value < 0.05 between the two groups, and ** indicates a p-value < 0.01 between the two groups.

[0043] Figure 7 After 7 days of continuous administration and 7 days of drug withdrawal with WR034, the static time of forced swimming behavior in mice of the model group + WR034, model group + solvent, and blank group + solvent were statistically analyzed. * indicates P < 0.05 between the two groups, and ** indicates P < 0.01 between the two groups.

[0044] Figure 8 After 7 days of continuous administration and 7 days of drug withdrawal with WR034, the percentage of mice in each group showing preference for sucrose solution was statistically analyzed in the following charts: model group + WR034, model group + solvent, and blank group + solvent. * indicates a p-value < 0.05 between the two groups, and ** indicates a p-value < 0.01 between the two groups.

[0045] Figure 9 After 7 days of continuous administration of WR034 followed by a 7-day withdrawal period, the following statistical graphs were generated for the tail suspension behavior of mice in the model group + WR034, model group + solvent, and blank group + solvent. * indicates a p-value < 0.05 between the two groups, and ** indicates a p-value < 0.01 between the two groups. Detailed Implementation

[0046] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0047] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0048] Example 1: Synthesis of compound WR010

[0049]

[0050] a) CuI, K2CO3, KI, DMF, 81%; b) N, N-Diethylaniline, 76%; c) NaH, DMF, 88%; d) Eu(fod)3, chloroform, 78%; e) NaH, CH3I, DMF, 89%; f) Benzaldehyde, NaOH, EtOH, 50°C, 86%; g) 1) Rose Bengal,MeOH,O2,hv,2)PPh3,RT,45%.

[0051] 1) Preparation of compounds 1-6

[0052]

[0053] Starting with 2,4-dihydroxyacetophenone, it reacts with 3-chloro-3-methyl-1-butyne under cuprous iodide and potassium iodide conditions to generate compound 2; compound 2 reacts with N,N-diethylaniline to generate compound 3; subsequently, compound 3 reacts with compound 4 under sodium hydride conditions to generate compound 5; finally, compound 5 reacts with Eu(fod)3 to obtain compound 6.

[0054] Compound 6: 1 H NMR (400MHz, CDCl3) δ12.84(s,1H),7.33(s,1H),6.71(d,J=10.0Hz,1H),5.57(d,J=10.0Hz ,1H),5.23(t,J=7.4Hz,1H),3.20(d,J=7.4Hz,2H),2.53(s,3H),1.73(s,6H),1.44(s,6H).

[0055] 13 C NMR (100MHz, CDCl3) δ202.75,158.14,157.62,132.49,130.84,127.95,122.4 1,120.75,116.16,113.30,109.00,77.56,28.26,27.91,26.21,25.81,17.92.

[0056] 2) Preparation of compound 7

[0057]

[0058] Compound 6 (0.6 g, 2.09 mmol) was dissolved in anhydrous tetrahydrofuran and placed in a 50 mL round-bottom flask with stirring. Iodomethane (0.26 mL, 4.19 mmol) and potassium carbonate (0.25 g, 6.28 mmol) were slowly added dropwise under ice bath conditions. After stirring for 30 minutes, the reaction system was placed at room temperature to continue the reaction. The reaction was monitored by TLC. After the reaction was complete, 200 mL of ethyl acetate was added to the system. The reaction solution was washed and extracted with saturated sodium chloride solution (100 mL × 3). The organic phase was collected, treated with anhydrous sodium sulfate as a drying agent, and then filtered and concentrated. The crude product was purified by rapid silica gel column chromatography to give compound 7 (559 mg, 89%) as a white solid.

[0059] 1 H NMR (400MHz, CDCl3) δ7.44(s,1H),6.59(d,J=10.0Hz,1H),5.67(d,J=10.0Hz,1H),5.24(t ,J=7.4Hz,1H),3.77(s,3H),3.23(d,J=7.4Hz,2H),2.59(s,3H),1.72(s,6H),1.44(s,6H).

[0060] 13 C NMR (100MHz, CDCl3) δ198.39,155.48,155.17,132.39,130.83,130.19,12 5.56,124.32,122.17,117.00,114.41,63.09,30.33,28.01,25.80,17.89.

[0061] 3) Preparation of compound WR022

[0062]

[0063] Compound 7 (330 mg, 1.681 mmol) and benzaldehyde (535.8 mg, 5.049 mmol) were dissolved in anhydrous tetrahydrofuran and placed in a 50 mL round-bottom flask with stirring. 4 M sodium hydroxide solution (0.841 mL, 3.367 mmol) was slowly added dropwise under ice bath conditions. After stirring for 30 minutes, the reaction mixture was allowed to continue reacting at room temperature. The reaction was monitored by TLC. After the reaction was complete, 200 mL of ethyl acetate was added to the system. The reaction mixture was washed and extracted with saturated sodium chloride solution (100 mL × 3). The organic phase was collected, treated with anhydrous sodium sulfate as a drying agent, and then filtered and concentrated. The crude product was purified by rapid silica gel column chromatography to give a pale yellow solid compound WR022 (698 mg, 86%).

[0064] 1 H NMR(400MHz, CDCl3)δ7.73(d,J=15.8Hz,1H),7.65–7.52(m,3H),7.45–7.32(m,4H),6.64(d,J=10.0Hz,1H), 5.69(d,J=10.0Hz,1H),5.27(t,J=7.4Hz,1H),3.73(s,3H),3.26(d,J=7.4Hz,2H),1.73(s,6H),1.46(s,6H).

[0065] 13 C NMR(100MHz,Chloroform-d)δ191.04,155.16,154.77,142.81,135.33,132.41,131.18,130.35,130.14,12 8.90,128.42,126.43,125.74,124.90,122.20,116.84,114.43,78.44,63.51,28.09,28.00,25.82,17.91.

[0066] 4) Preparation of compound WR010

[0067]

[0068] Compounds WR022 (370 mg, 0.953 mmol) and Rose bengal (97 mg, 0.095 mmol) were dissolved in anhydrous dichloromethane under ice bath conditions. The solution was then placed in a 50 mL round-bottom flask and stirred. The system was placed under 500 W incandescent light, and the reaction was monitored by TLC. After the reaction was complete, triphenylphosphine (374.8 mg, 1.43 mmol) was added to the system, and the reaction was monitored by TLC again. After the reaction was complete, 200 mL of ethyl acetate was added to the system. The reaction solution was washed and extracted with saturated sodium chloride solution (100 mL × 3). The organic phase was collected, treated with anhydrous sodium sulfate as a drying agent, and then filtered and concentrated. The crude product was purified by rapid silica gel column chromatography to give a white solid compound WR010 (180 mg, 45%).

[0069] Compound WR010: 1H NMR (400MHz, CDCl3) δ7.73(d,J=15.8Hz,1H),7.62(dd,J=6.7,2.9Hz,2H),7.55(d,J=15.9Hz ,1H),7.48(s,1H),7.40(dd,J=5.1,1.9Hz,3H),6.66(d,J=10.0Hz,1H),5.70(d,J=10.0Hz,1H ),4.99(d,J=1.9Hz,1H),4.85(t,J=1.7Hz,1H),4.31(dd,J=8.7,3.9Hz,1H),3.75(s,3H),2. 94(dd,J=13.8,3.9Hz,1H),2.71(dd,J=13.8,8.7Hz,1H),1.83(s,3H),1.49(d,J=4.7Hz,6H).

[0070] 13 C NMR (100MHz, CDCl3) δ190.84,147.17,143.17,139.90,135.23,132.81,130.25,130.21,128.93,128.45,1 26.26,125.13,122.47,120.72,116.78,114.58,110.77,75.51,70.24,63.53,36.46,28.28,28.13,18.18.

[0071] Example 2: Synthesis of compound WR034

[0072]

[0073] a) NaH, DMF, 88%; b) Eu(fod)3, chloroform, 78%; c) NaH, CH3I, DMF, 89%; d) Benzaldehyde, NaOH, EtOH, 50°C, 86%; e) 1-penten-3-one, Grubbs catalyst 2nd generation, DCM, 83%.

[0074] 1) Preparation of compound 12

[0075] Compounds 9-12 were prepared using intermediate 3 from Example 1 as the starting material and following the synthesis method of compounds 3-WR022 in Example 1. The NMR data of the compounds are as follows:

[0076]

[0077] 1H NMR(400MHz,Chloroform-d)δ7.53–7.41(m,1H),6.52(ddd,J=13.2,9.7,3.0Hz,2H),5.98(dddd,J=15.9,10.8,5.4,2.8Hz,1H),5.72–5.50(m,1H),5.35(ddd,J=17.1,3.0,1.5Hz,1H),5.20(ddd,J=10.5,3.0,1.5Hz,1H),4.29(dq,J=4.4,1.5Hz,2H),2.67–2.31(m,3H),1.59–0.87(m,6H).

[0078] 13 C NMR(100MHz,Chloroform-d)δ198.32,157.86,155.24,132.98,131.03,130.56,125.59,118.12,116.75,115.08,112.75,76.87,76.61,30.35,28.00.

[0079]

[0080] 1 H NMR(400MHz,Chloroform-d)δ12.87(d,J=3.2Hz,1H),7.33(d,J=3.1Hz,1H),6.71(d,J=9.6Hz,1H),5.94(ddd,J=16.9,6.9,3.6Hz,1H),5.58(d,J=9.7Hz,1H),5.27–4.82(m,2H),3.27(d,J=6.3Hz,2H),2.54(d,J=3.2Hz,3H),1.44(d,J=3.0Hz,6H).

[0081] 13 C NMR(100MHz,Chloroform-d)δ202.76,158.34,157.55,136.67,131.25,127.99,119.13,116.09,115.67,113.37,108.99,77.67,33.46,28.31,26.22.

[0082]

[0083] 1H NMR(400MHz,Chloroform-d)δ7.73(d,J=15.8Hz,1H),7.67–7.50(m,3H),7.46–7.36(m,4H),6.65(d,J=10.0Hz,1H), 6.03–5.87(m,1H),5.70(d,J=10.0Hz,1H),5.15–4.92(m,2H),3.74(s,3H),3.33(dd,J=6.6,1.6Hz,2H),1.46(s,6H).

[0084] 13 C NMR(100MHz,Chloroform-d)δ190.89,155.18,155.03,142.91,136.36,135.29,131.50,130.42,130.18 ,128.91,128.43,126.33,124.96,124.12,116.77,115.82,114.49,77.26,76.89,63.53,33.67,28.14.

[0085] 2) Preparation of compound WR034

[0086] Intermediate 12 (50 mg, 0.138 mmol) was dissolved in anhydrous dichloromethane and placed in a 50 mL round-bottom flask with stirring. 1-penten-3-one (20 μL, 0.207 mmol) and Grubbs second-generation catalyst (12 mg, 0.014 mmol) were slowly added dropwise under ice bath conditions. After stirring for 30 minutes, the reaction mixture was allowed to continue reacting at room temperature. The reaction was monitored by TLC. After the reaction was complete, 200 mL of ethyl acetate was added to the system. The reaction solution was washed and extracted with saturated sodium chloride solution (100 mL × 3). The organic phase was collected, treated with anhydrous sodium sulfate as a drying agent, and then filtered and concentrated. The crude product was purified by rapid silica gel column chromatography to give a white solid compound WR034 (47.95 mg, 83%).

[0087] 1H NMR (400MHz, CDCl3) δ7.79–7.51(m,4H),7.40(q,J=5.3,4.3Hz,4H),6.91(dd,J=15.9,6.5Hz,1H),6.63(dd,J=10.1,6.0Hz,1H),6.08(d,J=16. 2Hz,1H),5.74–5.65(m,1H),3.73(d,J=5.9Hz,3H),3.46(t,J=6.1Hz,2H),2.55(q,J=7.1Hz,2H),1.44(d,J=5.9Hz,6H),1.06(q,J=7.0Hz,3H).

[0088] 13 C NMR (100MHz, CDCl3) δ201.23,190.68,155.49,155.27,144.39,143.20,135.16,131.88,130.80,130.55,1 30.31,128.95,128.48,126.07,125.22,121.75,116.60,114.74,77.24,63.60,33.14,32.61,28.22,8.12.

[0089] Example 3: Experiment on the antidepressant activity of WR010

[0090] 1. Open field behavioral experiments

[0091] 1) Experimental materials

[0092] Animals: 60 SPF-grade C57 mice

[0093] Consumables: Binding tubing

[0094] 2) Experimental Procedure: Sixty mice were placed in an environment with a temperature of 24±1℃ and a relative humidity of 60-70%, maintaining a 12-hour light-dark cycle (light from 7:00 to 19:00) for one week to acclimatize. They were randomly divided into two groups:

[0095] Group A: Blank group (15 animals)

[0096] Group B: Model Group (55 animals)

[0097] The depression model group was subjected to the following restraints and intensified stimulation daily:

[0098] (1) Daytime (8:30-18:00): Restraint for 6 hours, room temperature 25℃

[0099] (2) Evening (18:00-8:30 the next day): Randomly enhanced stimulation (including: water restriction, food restriction, light stimulation, tilting of cage box and overnight wet mat)

[0100] The control group with depression was fed normally.

[0101] The model group was first restrained for 28 consecutive days, then fed normally for 11 days, and then restrained again for 21 days. Open field behavioral experiments were conducted on the 7th and 60th days after the model group began restraint.

[0102] Experimental procedure: After the mice have adapted to the environment, they are placed in an open field test chamber, and the data results are recorded within 5 minutes.

[0103] Experimental results are as follows Figure 1 As shown, there was no significant difference in the time spent in the center of the open field between the control group and the model group on the 7th day after the start of restraint, but a highly significant difference was found between the two groups on the 60th day after the start of restraint (i.e., the 49th day of cumulative restraint). For example... Figure 2 As shown, the model group exhibited a highly significant difference in the time spent in the center of the open field on day 60 (i.e., the cumulative 49th day of restraint) compared to the time spent in the center of the open field on day 7. This indicates that the depression model was successfully established.

[0104] After confirming the successful establishment of the depression model, the mice in the model group were no longer restrained, and subsequent behavioral experiments were carried out.

[0105] 2. After establishing the depression model, a forced swimming behavioral experiment was conducted.

[0106] The mice in the blank group and model group mentioned in point 1 above underwent a forced swimming behavioral experiment on the 60th day after the start of restraint.

[0107] Experimental procedure: The day before the experiment, mice were placed in water at approximately 25°C and swam for 5 minutes to acclimatize. The next day, mice were placed in water at approximately 25°C and swam for 6 minutes to perform forced swimming behavior, and the data for the last 5 minutes were recorded.

[0108] Experimental results are as follows Figure 3 As shown, there was a highly significant difference in the time spent at rest during forced swimming between the control group and the model group on day 60 of the initial restraint period. This indicates that the depression model was successfully established.

[0109] Then, eight mice were randomly selected from the control group and sixteen mice were randomly selected from the model group and randomly assigned to the WR010 group and the solvent group. The time spent in forced swimming at rest on day 60 of the initial restraint period was statistically analyzed. Results Figure 4 As shown, both the model + WR010 group and the model + solvent group were significantly different from the blank + solvent group, while there was no significant difference between the model + WR010 group and the model + solvent group.

[0110] Administration method: Drug: WR010; Solvent: DMSO (Sangon Biotech, A603039-0260), Tween 80 (Maclean's, T818928), normal saline; Consumables: 1mL syringe, gavage needle.

[0111] Drug solution preparation: DMSO and Tween 80 are prepared in a 1:2 ratio. The drug is dissolved to a concentration of 66.67 mg / ml and stored as a stock solution. Before gavage, it is diluted with physiological saline to a concentration of 6 mg / ml.

[0112] Mice in the model + WR010 group were administered WR010 drug at a dose of 20 mg / kg by gavage daily, while mice in the model + solvent group and the blank + solvent group were administered the same volume of solvent by gavage daily, with a gavage volume of 0.1 mL / 30 g. The administration was continued for 7 consecutive days.

[0113] Forced swimming behavioral experiments were conducted on the three groups of mice before drug administration, on day 1 of drug administration, day 7 of drug administration, and 7 days after drug withdrawal. The experimental results are as follows: Figure 5 As shown.

[0114] from Figure 5 As can be seen, before drug administration, there was no difference in the forced swimming quiescent time between the model + WR010 group and the model + solvent group, but both were different from the blank + solvent group. On day 1 of drug administration, there was no significant difference in the forced swimming quiescent time between the model + WR010 group and the model + solvent group, but both were still different from the blank + solvent group. On day 7 of drug administration, there was a difference in the forced swimming quiescent time between the model + WR010 group and the model + solvent group, and the model + WR010 group was not different from the blank + solvent group, while the model + solvent group was different from the blank + solvent group. Seven days after drug withdrawal, the differences in forced swimming quiescent time among the three groups of mice maintained the same trend.

[0115] The above experimental results indicate that the depression model is stable and WR010 is effective in treating depression.

[0116] Example 4: Antidepressant activity of WR034

[0117] The antidepressant activity of WR034 was tested according to the experimental method in Example 3. Six mice were randomly selected from the blank control group, and 12 mice were randomly selected from the established depression model group and randomly assigned to the WR034 group and the solvent group. Mice in the model + WR034 group were administered WR034 at a dose of 20 mg / kg by gavage daily. Mice in the model + solvent group and the blank + solvent group were administered the same volume of solvent by gavage daily, with a gavage volume of 0.1 mL / 30 g. The drug was dissolved in 5% DMSO + 40% PEG300 + 5% Tween 80 + 50% physiological saline in that order.

[0118] After 7 days of continuous administration followed by 7 days of drug withdrawal, open field behavioral experiments, forced swimming behavioral experiments, sucrose preference experiments, and tail suspension experiments were conducted.

[0119] The experimental results are as follows:

[0120] 1) Open field behavioral experiments

[0121] Post-drug administration behavior, central region dwell time, such as Figure 6 As shown, the dwell time in the central region of the open field for the model + WR034 group was significantly longer than that for the model + solvent group, but there was no significant difference compared to the blank + solvent group; the dwell time in the central region of the open field for the model + solvent group was significantly shorter than that for the blank + solvent group.

[0122] 2) Forced swimming behavioral experiment

[0123] Post-drug forced swimming behavioral resting time, such as Figure 7 As shown, the forced swimming stillness time of the model + WR034 group was significantly lower than that of the model + solvent group, but there was no significant difference compared with the blank + solvent group; the forced swimming stillness time of the model + solvent group was significantly higher than that of the blank + solvent group.

[0124] 3) Sugar water preference experiment

[0125] Experimental Methods: Adaptation Phase: Day 1: Two bottles of 1% sucrose solution were placed in each cage for 24 hours. Day 2: One bottle of 1% sucrose solution and one bottle of distilled water were placed in each cage for 24 hours. The water bottles were changed approximately every 2 hours. Day 3: Fasting and water restriction for 12 hours. During the sucrose-water preference behavior experiment, mice were allowed to access one bottle of 1% sucrose solution and one bottle of distilled water. After 12 hours, the mass of the sucrose solution and distilled water was weighed. The sucrose-water preference rate (%) was calculated as follows: [Sucrose solution consumption / (Sucrose solution consumption + Distilled water consumption)] × 100%. The percentage of mice with sucrose-water preference after administration is shown below. Figure 8 As shown, the preference for sugar water in the model + WR034 group was significantly higher than that in the model + solvent group, but there was no significant difference compared with the blank + solvent group; the preference for sugar water in the model + solvent group was significantly lower than that in the blank + solvent group.

[0126] 4) Tail Suspension Test

[0127] Experimental Methods: Mice were secured to the posterior third of their tails with tape and suspended from a support, with their heads 15 cm above the table surface. Video recordings were taken against a background that contrasted sharply with the mouse's fur color; black mice were recorded against a white background. The results of the tail suspension behavioral resting time experiment after drug administration are as follows: Figure 9 As shown, the tail suspension quiescence time of the model + WR034 group was significantly lower than that of the model + solvent group, but there was no significant difference compared with the blank + solvent group; the tail suspension quiescence time of the model + solvent group was significantly higher than that of the blank + solvent group.

[0128] The above experimental results indicate that WR0034 is effective in treating depression.

Claims

1. Compound of Formula I The use of its stereoisomers, pharmaceutically acceptable salts, or solvates in the preparation of drugs for treating depression, wherein: R1 is R2is C 1-4 alkyl; Each R3 may be the same or different, and is independently selected from C. 1-4 alkyl; R4 is selected from C 1-4 Alkyl or C 1-4 Alkyloxy group.

2. The application as described in claim 1, characterized in that, In Formula I: R1 is R2 is C 1-4 Alkyl; preferably methyl; Each R3 may be the same or different, and is independently selected from C. 1-4 Alkyl; preferably, each R3 is identical and is methyl.

3. The application as described in claim 1, characterized in that, In Formula I: R1 is R2 is C 1-4 Alkyl; preferably methyl; Each R3 may be the same or different, and is independently selected from C. 1-4 Alkyl; preferably, each R3 is identical and is methyl; R4 is selected from C 1-4 Alkyl or C 1-4 Alkyloxy group; preferably C 1-4 alkyl.

4. The application as described in claim 1, characterized in that, Compound I is selected from 5. The application as described in any one of claims 1-4, characterized in that, The depression is selected from mild depression, moderate depression, severe depression, persistent depressive disorder, depression associated with bipolar disorder, seasonal affective disorder, psychotic depression, postpartum depression, premenstrual anxiety disorder, situational depression, anhedonia, melancholia, midlife depression, late-life depression, depression caused by identifiable stressors, treatment-resistant depression, or a combination thereof.

6. The application as described in any one of claims 1-5, characterized in that, The medication is used to treat the mental symptoms of depression, which are depressed mood and loss of interest or pleasure in almost all activities.

7. A pharmaceutical composition, characterized in that, Compound containing formula I Its stereoisomers, pharmaceutically acceptable salts or solvates, and other antidepressants, including: R1 is R2 is C 1-4 alkyl; Each R3 may be the same or different, and is independently selected from C. 1-4 alkyl; R4 is selected from C 1-4 Alkyl or C 1-4 Alkyloxy group.

8. The pharmaceutical composition according to claim 7, characterized in that, In Formula I: R1 is R2 is C 1-4 Alkyl; preferably methyl; Each R3 may be the same or different, and is independently selected from C. 1-4 Alkyl; preferably, each R3 is identical and is methyl.

9. The pharmaceutical composition according to claim 7, characterized in that, In Formula I: R1 is R2 is C 1-4 Alkyl; preferably methyl; Each R3 may be the same or different, and is independently selected from C. 1-4 Alkyl; preferably, each R3 is identical and is methyl; R4 is selected from C 1-4 Alkyl or C 1-4 Alkyloxy group; preferably C 1-4 alkyl.

10. The pharmaceutical composition according to claim 7, characterized in that, Compound I is selected from

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