A benzene sulfonamide derivative and its use in the preparation of antidepressant drugs

Abstract

The application belongs to the technical field of biomedicine, and particularly relates to a benzene sulfonamide derivative and application thereof in antidepressant drugs. The structural general formula of the compound is (I). The compound or a pharmaceutically acceptable salt thereof has agonistic activity on 5-hydroxytryptamine 2A type receptors. The compound is determined to have good antidepressant activity through a mouse tail suspension test model, an open field test model and a forced swimming test model, is a novel antidepressant compound with wide application prospect, has no hallucinogenic effect, and can be developed into an antidepressant therapeutic drug.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a benzenesulfonamide derivative and its application in antidepressants. Background Technology

[0002] The core symptoms of depression include low mood, slowed thinking, and reduced willpower. It is often accompanied by cognitive impairment and somatic symptoms (such as sleep disorders and pain), which seriously affect patients' normal work and life and increase their economic burden. It has now become one of the major public health problems in the world.

[0003] The core symptoms of depression are low mood, slowed thinking, and reduced willpower, often accompanied by cognitive impairment and somatization symptoms. It seriously affects the patient's social function and increases the economic burden, and has now become a major concern.

[0004] Existing antidepressants are mainly based on the monoamine neurotransmitter hypothesis, exerting their effects by regulating the serotonin (5-HT), norepinephrine, and dopamine systems. They can be divided into five major categories: (1) tricyclic antidepressants (TCAs); (2) monoamine oxidase inhibitors (MAOIs); (3) selective serotonin reuptake inhibitors (SSRIs); (4) serotonin norepinephrine reuptake inhibitors (SNRIs); and (5) atypical antidepressants (such as mirtazapine, bupropion, ketamine, etc.). However, these drugs generally suffer from delayed onset of action (usually requiring 2 to 4 weeks), low treatment response rates (only about 30% to 50% of patients experience significant relief), and significant side effects.

[0005] Antidepressants play a vital role in treating depression, but their side effects remain a significant challenge in the field of psychiatry. Common anticholinergic side effects of TCAs include dry mouth, constipation, blurred vision, urinary retention, and facial flushing; they may also cause drowsiness, tremors, confusion, seizures, hallucinations, delusions, orthostatic hypotension, tachycardia, and arrhythmias. MAOIs may cause hypertensive crisis, serotonin syndrome, nausea, vomiting, and arrhythmias. Common side effects of SSRIs and SNRIs include nausea, diarrhea, insomnia, drowsiness, headache, and sexual dysfunction. Atypical antidepressants may cause drowsiness, weight gain, nausea, and headaches; while ketamine has a rapid onset of action, it has limitations such as addictiveness and neurotoxicity. Antidepressants based on the monoamine neurotransmitter hypothesis and atypical antidepressants have significant side effects, which seriously affect patient treatment adherence and quality of life. Therefore, the development of novel target antidepressants is urgent.

[0006] In recent years, targeting serotonin 2A 5-hydroxytryptaime 2A receptor, 5-HT 2A Novel antidepressant strategies targeting 5-HT receptors have become a research hotspot. This receptor exerts its antidepressant effect by regulating neural plasticity, such as promoting synaptic regeneration, neural network remodeling, and modulating mood-related neural circuits, such as the prefrontal cortex-amygdala pathway. Agonists targeting this receptor, such as psilocybin (Pcb), have been reported to have rapid and long-lasting antidepressant effects, demonstrating rapid (within 24 hours) and sustained (effect lasting more than 3 months) antidepressant effects in clinical trials. Its mechanism may be related to remodeling the dynamics of cortical neuronal clusters, such as inhibiting fear-related neurons and enhancing extinction-related neural plasticity. However, it has hallucinogenic side effects, such as perceptual distortion and hallucinations, which severely limit its clinical application. Therefore, developing 5-HT receptor-targeting agents is crucial. 2A Novel antidepressant compounds with 5-HT agonist activity, rapid onset of action, and no hallucinogenic effects have become a core target in current drug development, and will be of great significance for the development of new antidepressant drugs. Currently, we have discovered a class of compounds with 5-HT agonist activity through high-throughput screening. 2A No literature reports have been found on the use of compounds with R agonist activity in antidepressant applications. Summary of the Invention

[0007] The purpose of this invention is to provide a derivative with antidepressant effects and its applications. The benzenesulfonamide derivative of this invention has an effect on 5-HT... 2A R has strong agonist activity, significant antidepressant effect, and no hallucinogenic effect. It is a novel antidepressant compound with broad application prospects.

[0008] The present invention is achieved through the following technical solution.

[0009] In a first aspect, the present invention provides the use of a benzenesulfonamide derivative in the preparation of an antidepressant, said derivative being a compound of formula I or a pharmaceutically acceptable salt thereof:

[0010]

[0011] In Formula I, R1, R2, and R3 are independent of each other; R1, R2, and R3 are selected from benzene and its derivatives in which 1 to 5 H atoms are substituted, and the substituents of the derivatives include any one or more combinations of halogen, alkoxy, nitro, and alkyl groups.

[0012] Preferably, when there are two substituents, the substituents can be para, meta, or ortho.

[0013] Preferably, the derivatives include the compounds listed in Table 1;

[0014] The compounds CP-A, CP-B, CP-C, CP-D, CP-E, CP-F, CP-G, CP-H, and CP-I belong to the benzenesulfonamide class of compounds and have a 5-HT group. 2A It exhibits R-agonist activity and has antidepressant effects.

[0015] Table 1. Benzenesulfonamide derivatives

[0016]

[0017] Secondly, the present invention also provides a pharmaceutical composition having the above-mentioned derivative as an active ingredient and containing one or more pharmaceutically acceptable carriers, diluents, excipients, etc.

[0018] The above-mentioned compounds and pharmaceutical compositions can be used in the preparation of antidepressant drugs.

[0019] Preferably, the pharmaceutically acceptable carrier, diluent, or excipient includes water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil, and polyalkylene glycol.

[0020] Preferably, the pharmaceutical composition is administered orally, by injection, or by spray.

[0021] Furthermore, the dosage of the active ingredient administered is 10 mg / kg to 20 mg / kg.

[0022] Preferably, the pharmaceutical composition is a tablet, capsule, solution, suspension, injection, patch, or spray.

[0023] The beneficial effects of this invention are:

[0024] This invention provides the application of benzenesulfonamide compounds in the preparation of antidepressant drugs. The benzenesulfonamide compound is a 5-HT2... A R agonists, for 5-HT 2A R exhibits significant agonistic activity. These compounds effectively alleviated or eliminated depressive symptoms in mouse tail suspension, open field, and forced swimming models, demonstrating strong antidepressant effects. These compounds have no hallucinogenic effects and represent a novel class of 5-HT compounds with broad application prospects. 2A R agonists have the potential to be developed into antidepressant treatments. Attached Figure Description

[0025] Figure 1 It represents 5-HT 2A A agonist dose-response relationship diagram of the 5-HT agonist.

[0026] Figure 2 This indicates the effect of the control compound Pcb on 5-HT. 2A The dose-response relationship of R.

[0027] Figure 3 This refers to the effect of the benzenesulfonamide compounds of the present invention on 5-HT. 2A Diagram of the agonistic activity of R.

[0028] Figure 4 This refers to the CP-I of the present invention for 5-HT 2A The dose-response relationship of R.

[0029] Figure 5 This diagram illustrates the evaluation of a mouse depression model using the tail suspension test.

[0030] Figure 6 This diagram illustrates the evaluation of a mouse depression model using a spontaneous activity experiment.

[0031] Figure 7 The diagram shows the antidepressant effect of CP-I on mice, evaluated using a tail suspension test.

[0032] Figure 8 The graph shows the antidepressant effect of CP-I on mice as evaluated using an open field test.

[0033] Figure 9 The graph shows the effect of CP-I on the antidepressant effect in mice, evaluated using a forced swimming test. Detailed Implementation

[0034] The following will describe in detail the specific embodiments of the present invention with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are only for illustrating and explaining the present invention, and are not used to limit the present invention.

[0035] There is no particular limitation on the compounds described in the present invention. Those skilled in the art can prepare them according to the common knowledge in the art or obtain the compounds described in the present invention through commercial sources.

[0036] The following will describe the present invention in detail through examples.

[0037] In the following examples, unless otherwise specified, all kinds of reagents and materials used are from commercial sources.

[0038] In the following examples, the agonist effects of the compounds [5-HT, Pcb, CP-A, CP-B, CP-C, CP-D, CP-E, CP-F, CP-G, CP-H, CP-I] on 5-HT 2A R were detected by a FLIPR instrument (Molecular Devices). The FLIPR detection method is a homogeneous, dynamic, fluorescence detection method at the cellular level. After a stable 5-HT 2A R cell line was incubated with a calcium-sensitive fluorescent dye for a period of time, the dye entered the cells. When a compound with 5-HT 2A R agonist activity binds to 5-HT 2A R on the cell surface, it can cause a change in the intracellular calcium ion concentration, and then cause an increase in the fluorescence signal of the calcium-sensitive fluorescent dye. According to the increase in the fluorescence signal, the agonist activity of the compound can be detected in real time.

[0039] In the following examples, corticosterone was used to replace drinking water to feed mice for 21 days to construct an animal depression model. The mouse tail suspension test (TST) and spontaneous activity test (SAT) were used to confirm the successful construction of the depression model. The antidepressant effects of the compounds were determined by TST, open field test (OFT), and forced swim test (FST).

[0040] In the following examples, the experimental C57 BL / 6J mice used were all purchased from Beijing Huafukang Biotech Co., Ltd., license number: SCXK (Beijing) 2019-0008, male, weighing 18-22 g, and 8 weeks old.

[0041] Example 1: Dose-effect relationship diagram of the agonist 5-HT 2A R of 5-HT agonist.

[0042] Stable transfection with 5-HT 2A R's 5-HT 2A R-CHO cells were seeded at 10,000 cells / well in 384-well black-bottomed permeable culture plates, with 20 μL of culture medium added to each well. The plates were then incubated at 37°C and 5% CO2 for 24 h. When the cell confluence reached 80%, the culture medium was removed, and 20 μL of FLIPR calcium-sensitive fluorescent dye was added to each well. The plates were then incubated at 37°C in the dark for 1 h.

[0043] 5-HT is known to have 5-HT 2A In this embodiment, the compound with R-agonist activity is used as a 5-HT agonist. 2A Evaluation of representative agonist of R: 5-HT 2A The activity of R, i.e., assessing 5-HT 2A The response activity of R to its agonist is used to demonstrate the biological activity of the receptor, proving the 5-HT response in this embodiment. 2A R recombinant cells (5-HT) 2A R-CHO has pharmacological functions. Freshly prepared serially diluted 5-HT was added to the wells of the compound (maximum concentration 370 nmol / L, serially diluted 3-fold to a total of 9 concentrations, with 3 replicates for each concentration). Different concentrations of 5-HT were added to the 384-well cell plate using a FLIPR automated sample loading system and incubated for 20 min. Fluorescence was read according to the parameter settings: excitation wavelength 470–495 nm, emission wavelength 515–575 nm, exposure time 0.2 s, data collected once per second for 120 s. The changes in fluorescence signal over time caused by different concentrations of 5-HT were detected by real-time sample loading and recording.

[0044] according to Figure 1 Different concentrations of 5-HT induced S-shaped changes in fluorescence signals, exhibiting a clear dose-response relationship. The effect of 5-HT on 5-HT... 2A R cell agonistic effect EC 50 The value was 3.33 ± 0.69 nmol·L⁻¹. These results indicate that 5-HT… 2A The R-cell model can well reflect the effect of compounds on 5-HT. 2A The agonistic effect of R is applicable to the reaction of compounds with 5-HT. 2A Evaluation of the in vitro activity of R-agonists.

[0045] Example 2: Control compound Pcb against 5-HT 2A The agonist dose-response relationship of R.

[0046] Stable transfection with 5-HT 2AR's 5-HT 2A R-CHO cells were seeded at 10,000 cells / well in 384-well black-bottomed permeable culture plates, with 20 μL of culture medium added to each well. The plates were then incubated at 37°C and 5% CO2 for 24 h. When the cell confluence reached 80%, the culture medium was removed, and 20 μL of FLIPR calcium-sensitive fluorescent dye was added to each well. The plates were then incubated at 37°C in the dark for 1 h.

[0047] Pcb is known to possess 5-HT 2A In this embodiment, an antidepressant compound with R-agonist activity was used as a positive control compound with antidepressant activity. Freshly prepared serially diluted Pcb was added to the well plates (maximum concentration 18 μmol / L, serially diluted 3-fold to obtain 8 concentrations, with 3 replicates for each concentration). Different concentrations of Pcb were added to 384-well cell culture plates using a FLIPR automated loading system and incubated for 20 min. Fluorescence was then read according to the parameters set: excitation wavelength 470–495 nm, emission wavelength 515–575 nm, exposure time 0.2 s, data collected once per second for 120 s. Real-time loading and recording were used to detect changes in fluorescence signal over time caused by different concentrations of Pcb.

[0048] according to Figure 2 Different concentrations of Pcb induced S-shaped curves in the fluorescence signal, exhibiting a clear dose-response relationship. Pcb also affected 5-HT... 2A R cell agonistic effect EC 50 The value was 0.83 ± 0.10 μmol·L⁻¹. These results indicate that the positive control compound... 2A It exhibits receptor-agonistic activity in R cell models, making it suitable as a positive control drug and a potential candidate for drugs with 5-HT receptor activity. 2A Reference standards of compounds with R-agonist activity were used for in vitro activity evaluation.

[0049] Example 3: The effect of the benzenesulfonamide compounds of the present invention on 5-HT 2A The agonistic activity of R.

[0050] Stable transfection with 5-HT 2A R's 5-HT 2A R-CHO cells were seeded at 10,000 cells / well in 384-well black-bottomed permeable culture plates, with 20 μL of culture medium added to each well. The plates were then incubated at 37°C and 5% CO2 for 24 h. When the cell confluence reached 80%, the culture medium was removed, and 20 μL of FLIPR calcium-sensitive fluorescent dye was added to each well. The plates were then incubated at 37°C in the dark for 1 h.

[0051] Freshly prepared Pcb and benzenesulfonamide compounds were added to compound plates (Pcb concentration 1 μmol·L⁻¹, benzenesulfonamide compound concentration 10 μmol·L⁻¹), with three replicate wells for each compound. Using a FLIPR automated sample loading system, Pcb and benzenesulfonamide compounds were added to 384-well cell plates and incubated for 20 min. Fluorescence was then read according to the parameters set: excitation wavelength 470–495 nm, emission wavelength 515–575 nm, exposure time 0.2 s, data collected once per second for 120 s. Real-time sample loading and recording were used to detect changes in fluorescence signals induced by Pcb and benzenesulfonamide compounds.

[0052] according to Figure 3 Compared with the control group, the fluorescence signals of Pcb and various benzenesulfonamide compounds increased by 4.4, 2.7, 3.0, 3.6, 3.3, 5.1, 3.3, 3.0, 3.4, and 9.0 times, respectively (p<0.01 or p<0.001). Taking the fluorescence signal enhancement caused by Pcb as 100%, the percentage changes in fluorescence signal enhancement caused by benzenesulfonamide compounds were 61.36±6.82%, 68.18±13.64%, 81.82±13.64%, 75.00±6.82%, 115.91±2.27%, 75.00±6.82%, 68.18±4.55%, 77.27±15.75%, and 204.55±4.55%. Among them, CP-I significantly increased the fluorescence signal of 5-HT. 2A R cells exhibit the greatest agonistic activity, indicating that their agonistic activity is strongest when detected by in vitro experimental methods.

[0053] Example 4: Compound CP-I [N-(5-chloro-2-methoxyphenyl)-N-{2-[4-(2-fluorophenyl)-1-piperazinyl]-2-oxoethyl}-3,4-dimethoxybenzenesulfonamide] for 5-HT 2A The agonist dose-response relationship of R.

[0054] Stable transfection with 5-HT 2A R's 5-HT 2A R-CHO cells were seeded at 10,000 cells / well in 384-well black-bottomed permeable culture plates, with 20 μL of culture medium added to each well. The plates were then incubated at 37°C and 5% CO2 for 24 h. When the cell confluence reached 80%, the culture medium was removed, and 20 μL of FLIPR calcium-sensitive fluorescent dye was added to each well. The plates were then incubated at 37°C in the dark for 1 h.

[0055] Freshly prepared serially diluted CP-I was added to the well plates (maximum concentration 100 μmol / L, serially diluted 3-fold to obtain 12 concentrations, with 3 replicates for each concentration). Different concentrations of CP-I were added to the 384-well cell plates using an automated FLIPR loading system and incubated for 20 min. Fluorescence was then read according to the parameters set: excitation wavelength 470–495 nm, emission wavelength 515–575 nm, exposure time 0.2 s, and data collected once per second for 120 s. The changes in fluorescence signal over time caused by different concentrations of CP-I were detected using real-time loading and recording.

[0056] according to Figure 4 The fluorescence signal changes induced by different concentrations of CP-I exhibited an "S"-shaped curve, with a clear dose-response relationship. CP-I also affected 5-HT. 2A R cell agonistic effect EC 50 The value was 0.89 ± 0.12 μmol / L.

[0057] The above results indicate that CP-I is a 5-HT 2A R agonist, and 5-HT 2A R exhibits good agonistic activity.

[0058] Example 5: Tail suspension test to evaluate mouse depression model.

[0059] Establishment of a mouse model of depression: 100 mg of corticosterone (CORT) powder was dissolved in 10 mL of anhydrous ethanol, sonicated for 5–10 minutes until completely dissolved, and then diluted with 990 mL of drinking water to a concentration of 0.1 mg / mL. This solution was prepared fresh daily for 21 consecutive days, with the CORT solution being changed once daily. The experiment included a control group (Con, given drinking water) of 8 mice and a model group (Model, given CORT solution) of 120 mice.

[0060] Evaluation of the TST mouse depression model: Twenty-one days after model establishment, the TST test was used to evaluate the establishment of the depression model in mice. Individual mice were fixed to the top support of a tail-hanging box with medical tape approximately 1-2 cm from the tail tip, placing the mice in an inverted position with their heads about 5 cm above the bottom of the box. Recording was performed continuously for 6 minutes, and the immobility time at the last 4 minutes was recorded. The TST test results after model establishment (day 21) are as follows: Figure 5 As shown, compared with the Con group, the immobility time of mice in the Model group increased by 5.5% in the TST experiment (p<0.05), showing a significant difference. Therefore, the mouse depression model was successfully established by replacing drinking water with 0.1 mg / mL corticosterone.

[0061] Example 6: Spontaneous activity experiment to evaluate a mouse depression model.

[0062] Establishment of a mouse depression model: 100 mg of CORT powder was dissolved in 10 mL of anhydrous ethanol and sonicated for 5–10 minutes until completely dissolved. The solution was then diluted to 0.1 mg / mL with 990 mL of drinking water. This solution was prepared fresh daily for 21 consecutive days, with the CORT solution being changed once daily. The experiment included a control group (Con, given drinking water) of 8 mice and a model group (Model, given CORT solution) of 120 mice.

[0063] Evaluation of the SAT mouse depression model: On day 22 after model establishment, the Laboras system was used to detect the spontaneous activity ability of the mice to assess the establishment of the depression model. The Laboras system records stress changes caused by behaviors such as crawling, standing, grooming, licking, drinking, and eating through carbon fiber plates, thereby accurately measuring stress and frequency changes and enabling the identification and recording of parameters such as mouse movement time, foraging time, climbing time, activity speed, and activity trajectory. Figure 6 As shown, compared with the Con group, the Model group mice had a 15.5% reduction in movement time (p<0.05) and a 53.5% reduction in foraging time (p<0.0001), both of which were statistically significant. These results indicate that the mouse depression model was successfully established.

[0064] Example 7: The antidepressant effect of CP-I on mice was evaluated using the tail suspension test.

[0065] Mice that successfully established a depression model after TST and SAT experiments were randomly assigned to three groups of eight mice each: a Model group (solvent composed of 5% DMSO: 45% PEG400: 5% Tween80: 45% saline), a positive control group (Pcb, 1 mg / kg), and CP-I compound groups (10 and 20 mg / kg). All groups received a single intraperitoneal injection of 20 μL / 100 g body weight. The antidepressant effect of the compound was evaluated using the TST experiment 2 hours after administration. Mice were suspended by their tails on a tail suspension device with their heads down for 6 minutes, and immobility time was recorded for the last 4 minutes. The immobility time of each compound group was compared with that of the Model group to evaluate the dose-response relationship of CP-I in antidepressant efficacy. Experimental data are expressed as mean ± standard deviation (Mean ± SD). There are 8 groups. One-way ANOVA in GraphPad Prism 9.5 was used to analyze differences between groups. *p<0.05 and ****p<0.0001 were used to indicate significance.

[0066] In the TST experiment, the results are shown below. Figure 7Compared with the Model, CP-I at doses of 10 and 20 mg / kg significantly reduced immobility time in the TST test (p<0.05, p<0.0001), indicating that all CP-I dosage groups had significant antidepressant effects. Compared with the 10 mg / kg CP-I dosage group, the 20 mg / kg group showed a significantly reduced immobility time in the TST (p<0.05), indicating that the antidepressant activity of CP-I is dose-dependent, with the 20 mg / kg CP-I dosage group exhibiting a stronger antidepressant effect. Compared with Pcb, the 20 mg / kg dose of CP-I showed a stronger antidepressant effect, with an activity increase of 5.8% (p<0.05).

[0067] Example 8: The open field test was used to evaluate the antidepressant effect of CP-I on mice.

[0068] Mice exhibiting depressive symptoms as assessed by the TST and SAT tests were randomly assigned to three groups of eight mice each: a Model group (solvent composed of 5% DMSO: 45% PEG400: 5% Tween80: 45% saline), a positive control group (Pcb, 1 mg / kg), and a CP-I compound group (10 and 20 mg / kg). All groups received a single intraperitoneal injection (20 μL / 100 g body weight). The antidepressant effect of the compounds was evaluated using the OFT test 4 hours post-administration. Mice were placed in an open field chamber with the walls adhered to the chamber, and their activity was observed over 5 minutes using an automated observation and analysis imaging system. The number of times mice in each compound group and the Model group shuttled through the center of the open field was compared to evaluate the dose-response relationship of CP-I in antidepressant effects. Experimental data are expressed as mean ± standard deviation (Mean ± SD). There are 8 groups. One-way ANOVA in GraphPad Prism 9.5 was used to analyze differences between groups. *p<0.05, **p<0.01, ****p<0.0001 were used to indicate significance.

[0069] In the OFT experiment, the effect of different CP-I dosage groups on the number of central shuttles showed a clear dose-response relationship. The results are as follows: Figure 8As shown, compared with Model, CP-I at doses of 10 and 20 mg / kg significantly increased central shuttle number (p<0.01, p<0.0001), indicating that all CP-I dosage groups had significant antidepressant effects. Compared with the 10 mg / kg CP-I dosage group, the 20 mg / kg group showed a significantly increased central shuttle number (p<0.05), indicating that the antidepressant activity of CP-I is dose-dependent, with the 20 mg / kg CP-I dosage group exhibiting a stronger antidepressant effect. Compared with Pcb, the 20 mg / kg dose of CP-I showed a stronger antidepressant effect, with an activity increase of 44.7% (p<0.05).

[0070] Example 9: The forced swimming test was used to evaluate the antidepressant effect of CP-I on mice.

[0071] Mice exhibiting depressive symptoms as assessed by the TST and SAT tests were randomly assigned to three groups of eight mice each: a Model group (solvent composed of 5% DMSO: 45% PEG400: 5% Tween80: 45% saline), a positive control group (Pcb, 1 mg / kg), and CP-I compound groups (10 and 20 mg / kg). All groups received a single intraperitoneal injection of 20 μL / 100 g body weight. The antidepressant effect of the compounds was evaluated using the FST test 6 hours after administration. Mice were placed in a transparent glass tank (15 cm in diameter, 22 cm in height) at 24°C and 16 cm in depth, and immobility was recorded for 6 minutes, followed by 4 minutes. The immobility time of each compound group (Pcb 1 mg / kg, and different doses of CP-I 10 and 20 mg / kg) was compared with that of the Model group to evaluate the dose-response relationship of CP-I in antidepressant efficacy. Experimental data are expressed as mean ± standard deviation (Mean ± SD). There are 8 groups. One-way ANOVA in GraphPad Prism 9.5 was used to analyze differences between groups. *p<0.05, ***p<0.001, and ****p<0.0001 were used to indicate significance.

[0072] In the FST experiment, such as Figure 9As shown, compared with Model, CP-I at doses of 10 and 20 mg / kg significantly reduced immobility time in FST (p<0.0001), indicating that all CP-I administration groups had significant antidepressant effects. There was no significant difference in immobility time between the 20 mg / kg and 10 mg / kg CP-I dose groups, but a dose-dependent effect was observed, with the 20 mg / kg CP-I dose group showing a stronger antidepressant effect. Compared with Pcb, the activity of the 10 mg / kg CP-I group increased by 42.4% (p<0.05), and the activity of the 20 mg / kg CP-I group increased by 45.3% (p<0.05).

[0073] As can be seen from the results of the above embodiments, the benzenesulfonamide compounds of the present invention are effective against 5-HT. 2A The receptor exhibits significant agonistic activity and can significantly improve depressive symptoms in a mouse depression model established using CORT, without revealing any hallucinogenic effects. This invention confirmed the successful establishment of the depression model using TST and SAT experiments, and confirmed the significant antidepressant effect of the representative compound CP-I using TST, OFT, and FST experiments. The benzenesulfonamide compounds described in this invention can be used in the preparation of drugs for the prevention or treatment of depression.

Claims

1. The use of a group of benzenesulfonamide derivatives in the preparation of antidepressant drugs, characterized in that, The benzenesulfonamide derivatives are: N-(5-chloro-2-methoxyphenyl)-N-{2-[4-(3-chlorophenyl)-1-piperazinyl-2-oxoethyl}-3,4-dimethoxybenzenesulfonamide, N-(3,5-dimethylphenyl)-N-{2-[4-(4-fluorophenyl)-1-piperazinyl]-2-oxoethyl}-3,4-dimethoxybenzenesulfonamide, N-(2,4-dimethoxyphenyl)-2-nitro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxoethyl}benzenesulfonamide, N-{2-[4-(4-fluorophenyl)-1-piperazinyl]-2-oxoethyl}-3,4-dimethoxy-N-(4-methoxyphenyl)benzenesulfonamide, N-{2-[4-(4-fluorophenyl)-1-piperazinyl]-2-oxoethyl}-3,4-dimethoxy-N-(4-methoxyphenyl)benzenesulfonamide, N-(2,4-dimethoxyphenyl)-2-nitro-N ... 2-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxoethyl}benzenesulfonamide, N-(2,4-dimethoxyphenyl)-N-[2-oxo-2-(4-phenyl-1-piperazinyl)ethyl]benzenesulfonamide, N-{2-[4-(2-fluorophenyl)-1-piperazinyl]-2-oxoethyl}-3,4-dimethoxy-N-(4-methoxyphenyl)benzenesulfonamide, N-(2,5-dimethoxyphenyl)-N-[2-oxo-2-(4-phenyl-1-piperazinyl)ethyl]benzenesulfonamide, N-(5-chloro-2-methoxyphenyl)-N-{2-[4-(2-fluorophenyl)-1-piperazinyl]-2-oxoethyl}-3,4-dimethoxyphenylsulfonamide; The structural formula is: 。 2. The use of the benzenesulfonamide derivative according to claim 1 in the preparation of antidepressant drugs, characterized in that, The antidepressant is a pharmaceutical composition comprising at least one of the benzenesulfonamide derivatives, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

3. The use of the benzenesulfonamide derivative according to claim 2 in the preparation of antidepressant drugs, characterized in that, Pharmaceutically acceptable carriers, diluents, or excipients include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil, and polyalkylene glycols.

4. The use of the benzenesulfonamide derivative according to claim 2 in the preparation of antidepressant drugs, characterized in that, The pharmaceutical composition can be administered orally, by injection, or by spray.

5. The use of the benzenesulfonamide derivative according to claim 2 in the preparation of antidepressant drugs, characterized in that, The dosage of the active ingredient in the pharmaceutical composition is 10 mg / kg to 20 mg / kg.

6. The use of the benzenesulfonamide derivative according to claim 2 in the preparation of antidepressant drugs, characterized in that, The pharmaceutical composition is in the form of tablets, capsules, solutions, suspensions, injections, patches, or sprays.

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