Use of a benzenesulfonamide compound for the manufacture of a medicament for the modulation of sleep

Abstract

The application discloses a use of a benzene sulfonamide compound in preparation of a medicine for regulating sleep, and the benzene sulfonamide compound has the following structure: the application first proposes the use of the benzene sulfonamide compound in preparation of the medicine for regulating sleep, and animal experiments show that tail vein injection of the benzene sulfonamide compound into mice can promote sleep of the mice, can significantly reduce a proportion of wake time of the mice, and can increase proportions of non-rapid eye movement sleep time and rapid eye movement sleep time.

Description

TECHNICAL FIELD

[0001] The present application relates to the use of a benzene sulfonamide compound in the preparation of a drug for regulating sleep, in particular to the use of a benzene sulfonamide compound or a pharmaceutically acceptable derivative thereof in the preparation of a drug for regulating sleep, and belongs to the technical field of medicine. BACKGROUND

[0002] Sleep is a necessary activity for maintaining the basic life functions of human beings, and human beings spend about one-third of their lives in sleep. Sleep mainly includes two types of 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 will directly have many adverse effects on the body, such as affecting the growth and development of adolescents and children, affecting the operation of thinking and reducing work efficiency, causing the body's immunity to decline, causing endocrine disorders, causing negative emotions such as anxiety and depression, and causing cardiovascular and cerebrovascular diseases. The existing drugs for treating insomnia are mainly benzodiazepines or non-benzodiazepine sedative hypnotics and some antidepressants / antipsychotic drugs, and long-term use is easy to cause side effects such as drowsiness, fatigue, addiction, and withdrawal. Therefore, it is of great practical significance to develop drugs based on new targets that can have the effect of regulating sleep. SUMMARY

[0003] The main purpose of the present application is to provide the use of a benzene sulfonamide compound in the preparation of a drug for regulating sleep to make up for the shortcomings of the existing treatment methods.

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

[0005] To achieve the aforementioned purposes of the application, the technical solutions adopted by the present application include:

[0006] The present application provides the use of a benzene sulfonamide compound in the preparation of a drug for regulating sleep, and the structure of the benzene sulfonamide compound is shown in formula (I):

[0007]

[0008] The present application also provides a pharmaceutical composition for regulating sleep, which comprises a benzene sulfonamide compound shown in formula (I) or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient.

[0009]

[0010] The pharmaceutically acceptable derivative is selected from at least one of a pharmaceutically acceptable salt, a polymorph, a co-crystal, a radio-labeled form, and a combination thereof.

[0011] Compared with the prior art, the beneficial effects of the present application are that the present application first proposes the use of benzene sulfonamide compounds in the preparation of drugs for regulating sleep, animal experiments show that intravenous injection of benzene sulfonamide compounds into the tail vein of mice can promote the sleep of mice, and the specific performance is that the administration of the aforementioned compounds can significantly reduce the proportion of wake time of mice, 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 DRAWINGS

[0012] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed to be used in the embodiments or the prior art description will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments described in the present application, and other drawings can also be obtained by those skilled in the art without creative labor on the basis of these drawings.

[0013] Figures 1a-1b is a typical brain wave analysis example of the effect of NS and SZ0232 on mouse sleep in a typical embodiment of the present application;

[0014] Figures 2a-2b is a typical embodiment of the present application, the proportion of NS and SZ0232 mouse wake (Wake) time;

[0015] Figures 3a-3b is a typical embodiment of the present application, the proportion of NS and SZ0232 mouse non-rapid eye movement sleep (NREM) time;

[0016] Figures 4a-4b is a typical embodiment of the present application, the proportion of NS and SZ0232 mouse rapid eye movement sleep (REM) time. DETAILED DESCRIPTION

[0017] In view of the defects of the prior art, the present inventors have long-term research and a large number of practices, and have proposed the technical solutions of the present application. The technical solutions of the present application will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0018] Specifically, as one aspect of the technical solutions of the present application, the use of a benzene sulfonamide compound or a pharmaceutically acceptable derivative thereof in the preparation of a drug for regulating sleep, the structure of the benzene sulfonamide compound is shown in formula (I):

[0019]

[0020] The pharmaceutically acceptable derivative is at least one selected from the group consisting of a pharmaceutically acceptable salt, a polymorph, a co-crystal, a radiolabeled form and a combination thereof.

[0021] Further, the benzene sulfonamide compound is denoted 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 wake time of the mouse.

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

[0026] In some preferred embodiments, when the drug acts on a mouse model, the effective amount of the benzene sulfonamide compound in the drug ranges from 2.5 to 50 mg / kg.

[0027] Further, when the drug acts on a mouse model, the effective amount of the benzene sulfonamide compound in the drug ranges from 10 to 20 mg / kg.

[0028] The sleep in the present application refers to sleep in a natural state recorded on a mouse. Animal experiments show that the tail vein injection of SZ0232 into a mouse can promote the sleep of the mouse, which is specifically manifested as follows: the administration of the aforementioned compound can significantly reduce the proportion of the wake time of the mouse and increase the proportion of the non-rapid eye movement sleep time. The above experiments show that the benzene sulfonamide compound can play a role in regulating sleep, which has very important significance for the development and preparation of drugs for regulating sleep in the future.

[0029] Another aspect of the embodiment of the present application further provides a pharmaceutical composition for regulating sleep, which comprises a benzene sulfonamide compound shown in formula (I) or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient.

[0030]

[0031] The pharmaceutically acceptable derivative is at least one selected from the group consisting of a pharmaceutically acceptable salt, a polymorph, a co-crystal, a radiolabeled form and a combination thereof.

[0032] Further, the carrier and / or excipient can be any known pharmaceutically acceptable carrier and excipient suitable for such use by those skilled in the art. "Pharmaceutically acceptable carrier" as described in the specification has the meaning well known to those skilled in the art, which 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, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, similar substances that are physiologically compatible; and combinations thereof.

[0033] In some preferred embodiments, the pharmaceutical composition is at least capable of reducing the percentage of the length of the wakefulness of normal mice.

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

[0035] In some preferred embodiments, when the pharmaceutical composition acts on a mouse model, the effective amount of the benzene sulfonamide compound in the pharmaceutical composition is in the range of 2.5-50 mg / kg.

[0036] Further, the effective amount of the benzene sulfonamide compound in the pharmaceutical composition is in the range of 10-20 mg / kg.

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

[0038] The term "pharmaceutically acceptable salt" as used herein, refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and other problem or complication, commensurate with a reasonable benefit / risk ratio, and are effective for their intended use. Pharmaceutically acceptable salts are well known in the art. For example, S M Berge et al. describe pharmaceutically acceptable salts in detail, J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this application include those derived from suitable inorganic or organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acid, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by using other methods such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, glucoheptonate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, 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 salts, and the like.

[0039] As used herein, "pharmaceutically acceptable salt" refers to a form of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, nitric and phosphoric acids; and the like.

[0040] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like 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 which, upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula (I) or a metabolite or residue thereof which is active anti-bacterial.

[0042] Salts of the compounds of formula (I) are pharmaceutically preferably accepted, but non-pharmaceutically acceptable salts should also fall within the scope of the present application and are acceptable in that they are useful as intermediates in 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 recognized as different crystalline phases in which the compound of formula (I) can exist. The crystalline phases can have different molecular arrangements in the crystal lattice ("packing polymorphism") and / or conformation ("conformational polymorphism"). For example, in two different polymorphs of the compound of formula (I), each polymorph can have the 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 compounds of formula (I). "Co-crystals" are known in the art and are recognized as structurally uniform crystalline materials composed of two or more neutral molecular components that are present in the crystal lattice in a definite stoichiometric ratio, e.g., a compound of formula (I) and a co-former material. Mol. Pharmaceutics 4(3): 317-322 (2007). As used herein, "co-crystals" include all polymorphs of the co-crystals, i.e., all different crystalline phases of the co-crystals. The main difference between solvates and co-crystals is the physical state of the isolated pure substance.

[0045] In order to make the objects, technical solutions and advantages of the present application clearer, the technical solutions of the present application are further described in detail below in combination with the drawings and several preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based upon the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative effort should fall within the scope of the present application.

[0046] The experimental methods used in the following examples are all conventional methods unless otherwise specified.

[0047] The materials, reagents, etc. used in the following examples are all commercially available unless otherwise specified, for example:

[0048] I. Experimental procedures

[0049] 1. Experimental animals:

[0050] C57BL / 6J mice were purchased from Changzhou Cavens Experimental Animal Technology Co., Ltd. and bred in Xuzhou Medical University. The mice were raised in a standard animal room with a temperature of 23±2℃ and humidity of 40±10%, with a 12h / 12h (8:00 illumination) circadian rhythm, and free access to food. This experiment was approved by the Animal Ethics Committee of Xuzhou Medical University and was strictly in accordance with the Laboratory Animal Care and Use Guidelines.

[0051] 2. Reagents:

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

[0053] 3. Experimental design:

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

[0055] 4. Electroencephalogram acquisition and analysis:

[0056] The multi-channel brain electrical electrode seat was implanted on the skull of mice one week in advance, and the bone cement was embedded. After the implantation was completed, the mice were released to the cage for recovery. The mice were placed in the sleep recording box for 24 hours before recording to adapt to the environment. The sleep recording box was set to a 12-hour light (8:00-20:00) and 12-hour dark (20:00-8:00) circadian rhythm, and sufficient food was supplied. At 20:00 on the recording night, NS or SZ0232 was injected into the tail vein, respectively. After the injection was completed, the head-end embedded brain electrical electrode seat was connected to the Pinnacle brain electrical recording system through the preamplifier and its connecting line, and then the brain electrical signal of the mouse could be recorded continuously. The sampling rate was 400 Hz, the preamplification multiple was 100 times, and the EEG low-pass filter was 0-45 Hz. The brain electrical signal was analyzed by SleepSign for Animal and Matlab R2016a software. The Delta wave frequency band was defined as 0.5-2.7 Hz, the Theta wave frequency band was defined as 2.7-8 Hz, the Alpha wave frequency band was defined as 8-12 Hz, and the Beta wave frequency band was defined as 12-30 Hz. The continuous brain electrical signal was divided into 4-second segments, and the sleep state was determined as wake, non-rapid eye movement sleep (NREM) or rapid eye movement sleep (REM) according to the spectrum analysis results of the brain electrical wave and the electromyogram signal value. The sleep state ratio per half hour was calculated and the overall sleep phase in 3 hours was statistically analyzed.

[0057] 5. Data analysis:

[0058] All numerical values are represented by mean (Mean) ± standard deviation (SD). Normality test was performed on all data, and two independent sample t test was used for data comparison between two groups with normal distribution. P<0.05 was considered to have statistical significance.

[0059] II. Experimental results

[0060] 1. Analysis of typical brain electrical waves of SZ0232 affecting mouse sleep

[0061] Figure 1a and Figure 1b are respectively the typical sleep recording chart and analysis details of a single mouse within 3 hours after tail vein injection of NS and SZ0232. From top to bottom, they are brain electrical spectrum chart, brain electrical original trajectory chart, electromyogram integration chart and sleep phase staging chart. The results show that compared with the NS group of mice, the wake time of the SZ0232 group of mice is reduced, and the sleep time is increased.

[0062] 2. SZ0232 reduces the proportion of mouse wake (Wake) time

[0063] When the brain waves are dominated by high frequency waves and the muscle electricity is in high activity, the mouse can be determined to be in the wake period. This indicator is separated from the brain / muscle electricity signals of the mice injected with NS or SZ0232 in the tail vein respectively, and the results are shown in Figures 2a-2b As compared with the mice injected with physiological saline, the proportion of the wake period of the mice injected with SZ0232 is significantly reduced, indicating that the system administered SZ0232 can reduce the wake time of the mice.

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

[0065] When the brain waves are dominated by low frequency waves and the muscle electricity is in low activity, the mouse can be determined to be in the non-rapid eye movement sleep (NREM) period, which is the main sleep state of the mouse and human. This indicator is separated from the brain / muscle electricity signals of the mice injected with NS or SZ0232 in the tail vein respectively, and the results are shown in Figures 3a-3b As compared with the mice injected with physiological saline, the proportion of NREM of the mice injected with SZ0232 is significantly increased, indicating that the system administered SZ0232 can increase the non-rapid eye movement sleep time of the mice.

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

[0067] When the brain waves are dominated by higher frequency waves but the muscle electricity is in lower activity, the mouse can be determined to be in the rapid eye movement sleep (REM) period, also called "paradoxical sleep", which is generally less than the proportion of this sleep phase. This indicator is separated from the brain / muscle electricity signals of the mice injected with NS or SZ0232 in the tail vein respectively, and the results are shown in Figures 4a-4b As compared with the mice injected with physiological saline, the proportion of REM of the mice injected with SZ0232 is increased, indicating that the system administered SZ0232 can increase the rapid eye movement sleep time of the mice.

[0068] Meanwhile, the present inventors also conducted experiments with a drug amount of 2.5 mg / kg, 15 mg / kg, 20 mg / kg, and 50 mg / kg, and obtained similar effects, and when the drug amount is 10 mg / kg, 15 mg / kg, and 20 mg / kg, the effect is better than that when the drug amount is 2.5 mg / kg and 50 mg / kg.

[0069] In addition, the present inventors also conducted experiments by referring to the foregoing examples, using other raw materials, process operations, and process conditions described in the specification, and all obtained relatively ideal results.

[0070] It should be understood that the technical solutions of the present application are not limited to the above specific implementation cases, and any technical modification made according to the technical solutions of the present application without departing from the purpose of the present application and the scope protected by the claims falls within the protection scope of the present application.

Claims

1. Use of a benzene sulfonamide compound in the preparation of a medicament for modulating sleep, the benzene sulfonamide compound having a structure according to Formula (I): ###0001### Formula (I) wherein: R1 is H, CH3, or CH2CH3; R2 is H, CH3, or CH2CH3; R3 is H, CH3, or CH2CH3; R4 is H, CH3, or CH2CH3; R5 is H, CH3, or CH2CH3; R6 is H, CH3, or CH2CH3; R7 is H, CH3, or CH2CH3; R8 is H, CH3, or CH2CH3; R9 is H, CH3, or CH2CH3; R10 is H, CH3, or CH2CH3; R11 is H, CH3, or CH2CH3; R12 is H, CH3, or CH2CH3; R13 is H, CH3, or CH2CH3; R14 is H, CH3, or CH2CH3; R15 is H, CH3, or CH2CH3; R16 is H, CH3, or CH2CH3; R17 is H, CH3, or CH2CH3; R18 is H, CH3, or CH2CH3; R19 is H, CH3, or CH2CH3; R20 is H, CH3, or CH2CH3; R21 is H, CH3, or CH2CH3; R22 is H, CH3, or CH2CH3; R23 is H, CH3, or CH2CH3; R24 is H, CH3, or CH2CH3; R25 is H, CH3, or CH2CH3; R26 is H, CH3, or Formula (I).

2. Use according to claim 1, characterized in that: ​ 3. Use according to claim 1, characterized in that: ​ 4. Use according to claim 1, characterized in that: ​ ​ 5. Use according to claim 1, characterized in that: ​

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