Application of benzenesulfonamide compound in preparation of medicine for regulating sleep

Abstract

The invention discloses an application of a benzenesulfonamide compound in preparation of a medicine for regulating sleep, and the structure of the benzenesulfonamide compound is as shown in the following formula: # imgabs0. The invention provides the application of the benzenesulfonamide compound in preparation of the medicine for regulating sleep for the first time. By intravenously injecting the benzenesulfonamide compound into the tail of the mouse, the sleep of the mouse can be promoted, the ratio of waking time of the mouse can be remarkably reduced, and the ratio of non-rapid eye movement sleep time and the ratio of rapid eye movement sleep time are increased.

Description

Technical Field

[0001] The present invention relates to use of a benzenesulfonamide compound in preparing a medicine for regulating sleep, and in particular to use of a benzenesulfonamide compound or a pharmaceutically acceptable derivative thereof in preparing a medicine for regulating sleep, and belongs to the field of medical technology. Background Art

[0002] Sleep is a necessary activity to maintain basic life functions of human beings. About one-third of a person's life is spent in sleep. Sleep mainly includes two types: rapid eye movement sleep (REM) and non-rapid eye movement sleep (NREM). The former is essential for the recovery of energy, and the latter is crucial for the recovery of physical strength. Insufficient sleep time will directly have many adverse effects on the body, such as: affecting the growth and development of adolescents and children; affecting thinking and reducing work efficiency; leading to a decrease in the body's immunity; leading to endocrine disorders; causing negative emotions such as anxiety and depression; causing cardiovascular and cerebrovascular diseases, etc. Existing drugs for the treatment of insomnia are mainly benzodiazepines or non-benzodiazepine sedative hypnotics and some antidepressants / antipsychotics. Long-term use is prone to side effects such as drowsiness, fatigue, addiction, and withdrawal. Therefore, the development of drugs based on new targets that can regulate sleep is of great practical significance. Summary of the invention

[0003] The main purpose of the present invention is to provide a use of a benzenesulfonamide compound in the preparation of a drug for regulating sleep, so as to make up for the shortcomings of existing treatment methods.

[0004] Another object of the present invention is to provide a pharmaceutical composition for regulating sleep.

[0005] In order to achieve the above-mentioned invention object, the technical solution adopted by the present invention includes:

[0006] An embodiment of the present invention provides a use of a benzenesulfonamide compound in the preparation of a drug for regulating sleep, wherein the structure of the benzenesulfonamide compound is shown in formula (I):

[0007]

[0008] The embodiment of the present invention also provides a pharmaceutical composition for regulating sleep, which comprises a benzenesulfonamide compound represented by formula (I) or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient;

[0009]

[0010] Wherein, the pharmaceutically acceptable derivative is selected from at least one of pharmaceutically acceptable salts, polymorphs, co-crystals, radiolabeled forms and combinations thereof.

[0011] Compared with the prior art, the beneficial effect of the present invention is that: the present invention proposes for the first time the use of benzenesulfonamide compounds in the preparation of drugs for regulating sleep. Animal experiments show that injection of benzenesulfonamide compounds into the tail vein of mice can promote the sleep of mice. Specifically, the administration of the aforementioned compounds can significantly reduce the proportion of the mice's wake time, and increase the proportion of non-rapid eye movement sleep (NREM) time and the proportion of rapid eye movement sleep (REM) time. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0013] Figure 1a-1b This is a typical EEG analysis example diagram of the effects of NS and SZ0232 on sleep in mice in a typical embodiment of the present invention;

[0014] Figure 2a-2b This is a graph showing the percentage of wake time of NS and SZ0232 mice in a typical embodiment of the present invention;

[0015] Figure 3a-Figure 3b This is a graph showing the proportion of non-rapid eye movement sleep (NREM) time in NS and SZ0232 mice in a typical embodiment of the present invention;

[0016] Figure 4a-4b This is a graph showing the effect of NS and SZ0232 on the duration of rapid eye movement (REM) sleep in mice in a typical embodiment of the present invention. DETAILED DESCRIPTION

[0017] In view of the defects of the prior art, the inventor of this case has proposed the technical solution of the present invention after long-term research and extensive practice. The technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0018] Specifically, as one aspect of the technical solution of the present invention, it involves the use of a benzenesulfonamide compound or a pharmaceutically acceptable derivative thereof in the preparation of a drug for regulating sleep, wherein the structure of the benzenesulfonamide compound is shown in formula (I):

[0019]

[0020] Wherein, the pharmaceutically acceptable derivative is selected from at least one of pharmaceutically acceptable salts, polymorphs, co-crystals, radiolabeled forms and combinations thereof.

[0021] Furthermore, the benzenesulfonamide compound is recorded as SZ0232.

[0022] In some preferred embodiments, the sleep refers to sleep in a natural state.

[0023] In some preferred embodiments, when the drug acts on a mouse model, the drug can at least reduce the proportion of the mouse's wakefulness time.

[0024] In some preferred embodiments, when the drug acts on a mouse model, the drug can at least increase the proportion of non-rapid eye movement sleep time of the mouse.

[0025] In some preferred embodiments, when the drug acts on a mouse model, the drug can at least increase the proportion of rapid eye movement sleep time of the mouse.

[0026] In some preferred embodiments, when the drug acts on a mouse model, the effective dosage range of the benzenesulfonamide compound in the drug is 2.5 to 50 mg / kg.

[0027] Furthermore, when the drug acts on a mouse model, the effective dosage range of the benzenesulfonamide compound in the drug is 10 to 20 mg / kg.

[0028] The sleep described in the present invention is the sleep in a natural state recorded in mice. Animal experiments show that injection of SZ0232 into the tail vein of mice can promote sleep in mice, specifically: administration of the aforementioned compound can significantly reduce the proportion of wake time in mice and increase the proportion of non-rapid eye movement sleep (NREM) time. The above experiments show that benzenesulfonamide compounds can regulate sleep, which is of great significance for the future development and preparation of drugs for regulating sleep.

[0029] Another aspect of the embodiments of the present invention further provides a pharmaceutical composition for regulating sleep, comprising a benzenesulfonamide compound represented by formula (I) or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient;

[0030]

[0031] Wherein, the pharmaceutically acceptable derivative is selected from at least one of pharmaceutically acceptable salts, polymorphs, co-crystals, radiolabeled forms and combinations thereof.

[0032] Further, the carrier and / or excipient can be any known pharmaceutically acceptable carrier and excipient for those skilled in the art suitable for such use. The "pharmaceutical carrier" described in this specification has a meaning well known to those skilled in the art, and can include any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, similar substances and combinations thereof.

[0033] In some preferred embodiments, the pharmaceutical composition can at least reduce the proportion of wakefulness time of normal mice.

[0034] In some preferred embodiments, the pharmaceutical composition is at least capable of increasing the proportion of non-rapid eye movement sleep time in mice.

[0035] In some preferred embodiments, when the pharmaceutical composition acts on a mouse model, the effective amount of the benzenesulfonamide compound in the pharmaceutical composition ranges from 2.5 to 50 mg / kg.

[0036] Furthermore, the effective dosage range of the benzenesulfonamide compound in the pharmaceutical composition is 10 to 20 mg / kg.

[0037] Furthermore, the dosage form of the pharmaceutical composition includes injection, oral solution, capsule, tablet or granule.

[0038] The term "pharmaceutically acceptable salt" as used herein refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction or other problems or complications within the scope of sound medical judgment, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, and the contents are incorporated by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic acids and bases and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or salts formed by using other methods in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, gluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hydroiodide, 2-hydroxyethanesulfonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like.

[0039] As used herein, "pharmaceutically acceptable salts" refer to forms of the disclosed compounds in which the parent compound is modified by preparing acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, such as those formed from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid.

[0040] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic sites by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used.

[0041] The term "pharmaceutically acceptable derivative" includes any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound that, when administered to a subject, is capable of providing (directly or indirectly) a compound of formula (I) or a metabolite or residue having antibacterial activity.

[0042] Salts of the compounds of formula (I) are preferably pharmaceutically acceptable, but non-pharmaceutically acceptable salts are also acceptable within the scope of the invention since these are useful intermediates for preparing pharmaceutically acceptable salts.

[0043] The compounds of the present disclosure provided herein also include all polymorphs and pseudopolymorphs of the compounds of formula (I). "Polymorphs" are known in the art (see, e.g., J. Thermal Anal. Cal. 64: 37-60 (2001)) and are considered to be different crystalline phases in which the compounds of formula (I) can exist. Crystalline phases can have different molecular arrangements ("packing polymorphism") and / or conformations ("conformational polymorphism") in the crystal lattice. For example, in two different polymorphs of the compound of formula (I), each polymorph may have molecules arranged in a different basic crystal system - triclinic, monoclinic, orthorhombic, tetragonal, trigonal, hexagonal or cubic.

[0044] The compounds of the present disclosure provided herein also include all co-crystals of the compound of formula (I). "Co-crystals" are known in the art, and co-crystals are considered to be structurally homogeneous crystalline materials that contain two or more neutral building blocks present in a well-defined stoichiometry, for example, a compound of formula (I) and a co-forming material. Mol. Pharmaceutics 4(3): 317-322 (2007). As used herein, "co-crystals" include all polymorphs of the co-crystal, i.e., all different crystalline phases of the co-crystal. The main difference between solvates and co-crystals is the physical state of the isolated pure substance.

[0045] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the technical solution of the present invention is further described in detail below in conjunction with the accompanying drawings and several preferred embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0046] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0047] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources, for example:

[0048] 1. Experimental steps

[0049] 1. Experimental Animals:

[0050] C57BL / 6J mice were purchased from Changzhou Cavens Laboratory Animal Technology Co., Ltd. and bred at Xuzhou Medical University. Mice were housed in a standard animal room with a temperature of 23±2°C and a humidity of 40±10%, a 12h / 12h (lighting on at 8:00), and free access to food. This experiment was approved by the Animal Ethics Committee of Xuzhou Medical University and was performed in strict accordance with the Guide for the Care and Use of Laboratory Animals.

[0051] 2. Reagents:

[0052] Physiological saline was purchased from Shandong Kelun Pharmaceutical Co., Ltd.

[0053] 3. Experimental design:

[0054] Mice were randomly divided into a normal saline group (NS group) and an inhibitor group (SZ0232 group), and were adapted to the sleep recording box for 24 hours in advance. Mice had free access to food during the entire experiment. At 20:00 on the day of the experiment, SZ0232 was systemically administered by tail vein injection at a dose of 10 mg / kg. Mice were immediately connected to the EEG interface after the injection and continuous multi-lead EEG signal recording began 5 minutes later. The entire recording process lasted for 3 hours.

[0055] 4. EEG acquisition and analysis:

[0056] One week in advance, a multi-channel EEG electrode holder was implanted in the skull of mice and embedded with bone cement. After implantation, the mice were returned to the cage for recovery. 24 hours before recording, the mice were placed in a sleep recording box to adapt. The environment in the sleep recording box was set to a circadian rhythm of 12 hours of light on (8:00-20:00) and 12 hours of light off (20:00-8:00), and sufficient food was provided. NS or SZ0232 was injected into the tail vein at 20:00 on the evening of the recording. After the injection, the EEG electrode holder embedded at the head end was connected to the Pinnacle EEG recording system through a preamplifier and its connecting wire. After that, the EEG signals of the mice could be continuously recorded throughout the whole process, with a sampling rate of 400Hz, a preamplification factor of 100 times, and an EEG low-pass filter of 0-45Hz. The EEG signals were analyzed using SleepSign forAnimal and Matlab R2016a software. The Delta wave frequency band is defined as 0.5-2.7Hz, the Theta wave frequency band is defined as 2.7-8Hz, the Alpha wave frequency band is defined as 8-12Hz, and the Beta wave frequency band is defined as 12-30Hz. The continuous EEG signal is divided into small segments of 4 seconds, and the segment is comprehensively determined as wakefulness (Wake), non-rapid eye movement sleep (NREM) or rapid eye movement sleep (REM) based on the spectrum analysis results of the EEG waves and the electromyography signal value. The proportion of sleep states every half hour is counted and finally the overall sleep phase within 3 hours is statistically analyzed.

[0057] 5. Data Analysis:

[0058] All values ​​are expressed as mean ± standard deviation. All data were tested for normality, and the two groups with normal distribution were compared using a two-sided independent sample t test. P < 0.05 was considered statistically significant.

[0059] 2. Experimental Results

[0060] 1. Example of typical EEG analysis of SZ0232 affecting sleep in mice

[0061] Figure 1a and Figure 1b The following are typical sleep recordings and analysis details of a single mouse within 3 hours after NS and SZ0232 were administered via the tail vein. From top to bottom, they are EEG spectrum, EEG original trajectory, electromyographic integration, and sleep phase. The results showed that compared with the NS group, the SZ0232 group had a shorter awake time and an increased sleep time.

[0062] 2. SZ0232 reduces the proportion of wake time in mice

[0063] When the brain waves are dominated by high-frequency waves and the electromyography is in a high activity state, the mouse can be judged to be in the awake period. This indicator was separated from the brain / electromyography signals of mice injected with NS or SZ0232 by tail vein, and the results were as follows: Figure 2a-2b As shown: Compared with the mice injected with normal saline, the proportion of wakefulness period in the mice injected with SZ0232 was significantly reduced, indicating that systemic administration of SZ0232 can reduce the wakefulness time of mice.

[0064] 3. SZ0232 increases the proportion of non-rapid eye movement sleep (NREM) in mice

[0065] When the brain waves are dominated by low-frequency waves and the electromyography is in a low activity state, the mouse can be judged to be in the non-rapid eye movement sleep (NREM) period, which is the main sleep state of mice and humans. This indicator was separated from the brain / electromyography signals of mice injected with NS or SZ0232 by tail vein, and the results were as follows Figure 3a-Figure 3b As shown: Compared with the mice injected with normal saline, the proportion of NREM in the mice injected with SZ0232 was significantly increased, indicating that systemic administration of SZ0232 can increase the non-rapid eye movement sleep time of mice.

[0066] 4. SZ0232 increases the proportion of rapid eye movement (REM) sleep in mice

[0067] When the brain waves are dominated by higher frequency waves but the electromyography is in a low activity state, the mouse can be judged to be in the rapid eye movement (REM) sleep period, also known as "paradoxical sleep", which generally accounts for a small proportion of sleep. This indicator was separated from the brain / electromyography signals of mice injected with NS or SZ0232 by the tail vein. The results are as follows Figure 4a-4b As shown: Compared with the mice injected with normal saline, the REM proportion of mice injected with SZ0232 increased, indicating that systemic administration of SZ0232 can increase the REM sleep time of mice.

[0068] At the same time, the inventor of this case also conducted experiments with dosages of 2.5 mg / kg, 15 mg / kg, 20 mg / kg, and 50 mg / kg, and achieved similar results. When the dosage was 10 mg / kg, 15 mg / kg, and 20 mg / kg, the effect was better than that with a dosage of 2.5 mg / kg and 50 mg / kg.

[0069] In addition, the inventors of this case also referred to the aforementioned embodiments and conducted experiments with other raw materials, process operations, and process conditions described in this specification, and obtained relatively ideal results.

[0070] It should be understood that the technical solution of the present invention is not limited to the above-mentioned specific implementation cases. Any technical deformation made according to the technical solution of the present invention without departing from the scope of protection of the purpose of the present invention and the claims shall fall within the protection scope of the present invention.

Claims

1. Use of a benzenesulfonamide compound in the preparation of a drug for regulating sleep, wherein the structure of the benzenesulfonamide compound is shown in formula (I):

2. The use according to claim 1, characterized in that: The sleep described herein refers to sleep in a natural state.

3. The use according to claim 1, characterized in that: When the drug acts on a mouse model, the drug can at least reduce the proportion of the mouse's wakefulness time.

4. The use according to claim 1, characterized in that: When the drug acts on a mouse model, the drug can at least increase the proportion of non-rapid eye movement sleep time of the mouse; And / or, when the drug acts on a mouse model, the drug can at least increase the proportion of rapid eye movement sleep time of the mouse.

5. The use according to claim 1, characterized in that: When the drug acts on a mouse model, the effective dosage range of the benzenesulfonamide compound in the drug is 2.5 to 50 mg / kg.

6. A pharmaceutical composition for regulating sleep, characterized in that: It comprises a benzenesulfonamide compound represented by formula (I) or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient; Wherein, the pharmaceutically acceptable derivative is selected from at least one of pharmaceutically acceptable salts, polymorphs, co-crystals, radiolabeled forms and combinations thereof.

7. The pharmaceutical composition according to claim 6, characterized in that: The pharmaceutical composition can at least reduce the proportion of wakefulness time of normal mice.

8. The pharmaceutical composition according to claim 6, characterized in that: The pharmaceutical composition can at least increase the proportion of non-rapid eye movement sleep duration in mice; And / or, when the drug acts on a mouse model, the drug can at least increase the proportion of rapid eye movement sleep time of the mouse.

9. The pharmaceutical composition according to claim 6, characterized in that: When the pharmaceutical composition acts on a mouse model, the effective dosage range of the benzenesulfonamide compound in the pharmaceutical composition is 2.5 to 50 mg / kg.

10. The pharmaceutical composition according to claim 6, characterized in that: The dosage form of the pharmaceutical composition includes any one of injection, oral solution, capsule, tablet and granule.

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