Pharmaceutical application of N, N-diethyl-2-hydroxyphenylacetamide

Abstract

The invention relates to a new application of N, N-diethyl-2-hydroxyphenylacetamide. It is unexpectedly found that N, N-diethyl-2-hydroxyphenylacetamide or a derivative thereof of the present application has a sedative effect, so that N, N-diethyl-2-hydroxyphenylacetamide or a derivative thereof can be used for sedation or prevention and / or treatment of diseases or conditions associated with a non-sedative state. According to the present invention, the N, N-diethyl-2-hydroxyphenylacetamide or the derivative thereof can be adopted as the active component of the sedative drug, and can provide significant sedative and hypnotic effects on mice, and the research results show that DEM has significant inhibition effects on the L-Glu content in the cerebral cortex and other parts of the brain, such that more choices can be provided for the development of the sedative drug.

Description

Technical Field

[0001] This article relates to the technical field of pharmaceutical compounds, and particularly to the use of N,N - diethyl - 2 - hydroxybenzeneacetamide or its derivatives in sedation and hypnosis. Background Art

[0002] Sedatives are drugs that mildly inhibit the cerebral cortex, can reduce central nervous excitability, relieve agitation, eliminate restlessness, and restore a quiet mood. Depending on the dose of the drug, different clinical effects can be produced. Small doses produce a preliminary sedative effect, medium doses can produce physiological sleep, and large doses have anticonvulsant and anesthetic effects. Commonly used sedative drugs include barbiturates, benzodiazepines, antihistamines, and other types. There is a need to develop compounds and their derivatives with sedative effects suitable for different situations.

[0003] DEM, with the chemical name N,N - diethyl - 2 - hydroxybenzeneacetamide, has the chemical structure shown in Formula I below:

[0004]

[0005] Its 2 - position is a chiral carbon atom and usually exists as a mixture of enantiomers. In the prior art, it has been reported that DEM has good anthelmintic activity and significant efficacy against diseases transmitted by arthropods. However, there are few reports on its other uses. Summary of the Invention

[0006] This application provides a new use of N,N - diethyl - 2 - hydroxybenzeneacetamide (DEM).

[0007] On the one hand, this application provides the use of N,N - diethyl - 2 - hydroxybenzeneacetamide or its derivatives in the preparation of drugs for sedation.

[0008] On the other hand, this application provides N,N - diethyl - 2 - hydroxybenzeneacetamide or its derivatives for sedative use.

[0009] On the other hand, this application provides a method for inducing or maintaining general anesthesia or sedation in a subject, the method comprising administering to the subject a pharmaceutically effective amount of N,N - diethyl - 2 - hydroxybenzeneacetamide or its derivatives.

[0010] In some embodiments, the N,N - diethyl - 2 - hydroxybenzeneacetamide or its derivatives described herein are the S - configuration enantiomer, the R - configuration enantiomer, or a mixture of the S - configuration enantiomer and the R - configuration enantiomer.

[0011] The present application provides the use of N,N - diethyl - 2 - hydroxybenzeneacetamide or its derivatives, or its stereoisomers, pharmaceutically acceptable salts or prodrugs in the preparation of a drug having effects such as anti - anxiety, anti - convulsion, sedation, hypnosis, anesthesia or muscle relaxation.

[0012] In one variant, the present application provides the use of N,N - diethyl - 2 - hydroxybenzeneacetamide or its derivatives, or its stereoisomers, pharmaceutically acceptable salts or prodrugs in the preparation of a drug for inducing or maintaining general anesthesia or sedation in a mammal.

[0013] The present application provides the use of N,N - diethyl - 2 - hydroxybenzeneacetamide or its derivatives in combination with one or more other active ingredients other than N,N - diethyl - 2 - hydroxybenzeneacetamide or its derivatives in the preparation of a drug having effects such as anti - anxiety, anti - convulsion, sedation, hypnosis, anesthesia or muscle relaxation, and the other active ingredients have the effects of sedation, hypnosis or anesthesia assistance. In one variant, there is provided the use of N,N - diethyl - 2 - hydroxybenzeneacetamide or its derivatives in combination with one or more intravenous anesthetics and / or anesthesia adjuvants other than N,N - diethyl - 2 - hydroxybenzeneacetamide or its derivatives in the preparation of a drug for inducing or maintaining general anesthesia or analgesia in a mammal.

[0014] So far, the prior art has not studied the sedative use of N,N - diethyl - 2 - hydroxybenzeneacetamide or its derivatives. The applicant unexpectedly found that N,N - diethyl - 2 - hydroxybenzeneacetamide or its derivatives of the present application have a sedative effect, and thus can be used for sedation or prevention and / or treatment of diseases or disorders related to a non - sedated state. It should be understood that N,N - diethyl - 2 - hydroxybenzeneacetamide or its derivatives can be used as the active component of a sedative drug, and have a significant sedative and hypnotic effect on mice. The optimal dosage is 750 mg / kg, and the safe dosage is less than 1000 mg / kg. The study found that DEM has a significant inhibitory effect on the content of L - glutamate (L - Glu) in the cerebral cortex and the rest of the brain, which will provide more choices for the development of sedative drugs.

[0015] Other features and advantages of the present application will be described in the subsequent specification, and in part will be obvious from the specification, or will be understood by implementing the present application. Other advantages of the present application can be realized and obtained through the solutions described in the specification and the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The drawings are used to provide an understanding of the technical solutions of the present application, and constitute a part of the specification. Together with the embodiments of the present application, they are used to explain the technical solutions of the present application, and do not constitute a limitation to the technical solutions of the present application.

[0017] Figure 1 This is a photograph of the survival status of mice in the acute toxicity assay in Example 2 of the present application. Among them, the surviving mice are in the cage, and the dead mice are on the iron stand.

[0018] Figure 2 This is a result graph of the survival rate of mice in the acute toxicity assay in Example 2 of the present application.

[0019] Figure 3 This is a result graph of the survival rate of mice under different doses of DEM in Example 3 of the present application.

[0020] Figure 4 This is a result graph of the content of γ-aminobutyric acid in the mouse brain tissue in Example 4 of the present application.

[0021] Figure 5 This is a result graph of the content of L-Glu in the mouse brain tissue in Example 4 of the present application. Detailed implementation manners

[0022] Unless otherwise specified, the technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present application belongs. When a quantity, concentration, or other value or parameter is expressed in the form of a range, a preferred range, or a preferred upper limit of a value and a preferred lower limit of a value, it should be understood that any range is specifically disclosed by combining any pair of the upper limit of the range or the preferred value with any lower limit of the range or the preferred value, regardless of whether the range is specifically disclosed. Unless otherwise specified, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range.

[0023] The terms "about" and "approximately", when used in combination with numerical variables, generally refer to the value of the variable and all values of the variable within the experimental error (e.g., within the 95% confidence interval for the average value) or within ±10% of the specified value, or within a wider range.

[0024] The expression "comprising" or similar expressions synonymous therewith, such as "including", "containing", and "having", etc., are open-ended and do not exclude additional unlisted elements, steps, or components. The expression "consisting of" excludes any unstated elements, steps, or components. The expression "consisting essentially of" means that the scope is limited to the specified elements, steps, or components, plus optionally existing elements, steps, or components that do not substantially affect the basic and novel features of the claimed subject matter. It should be understood that the expression "comprising" encompasses the expressions "consisting essentially of" and "consisting of".

[0025] The expression "at least one (piece)" or "one (piece) or more (pieces)" means 1, 2, 3, 4, 5, 6, 7, 8, 9 pieces (pieces) or more.

[0026] As used herein, DEM-RS is the racemate of N,N-diethyl-2-hydroxybenzeneacetamide, DEM-R is the R-configurational enantiomer of N,N-diethyl-2-hydroxybenzeneacetamide, and DEM-S is the S-configurational enantiomer of N,N-diethyl-2-hydroxybenzeneacetamide.

[0027] In one aspect, the present application provides the use of N,N-diethyl-2-hydroxybenzeneacetamide or a derivative thereof in the preparation of a medicament for sedation.

[0028] The present application provides the use of N,N-diethyl-2-hydroxybenzeneacetamide or a derivative thereof, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof in the preparation of a medicament having effects such as anti-anxiety, anti-convulsion, sedation, hypnosis, anesthesia or muscle relaxation.

[0029] In a variant, the present application provides the use of N,N-diethyl-2-hydroxybenzeneacetamide or a derivative thereof, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof in the preparation of a medicament for inducing or maintaining general anesthesia or sedation in a mammal.

[0030] In some embodiments, the N,N-diethyl-2-hydroxybenzeneacetamide or a derivative thereof described herein is the S-configurational enantiomer, the R-configurational enantiomer, or a mixture of the S-configurational enantiomer and the R-configurational enantiomer.

[0031] In some embodiments, the N,N-diethyl-2-hydroxybenzeneacetamide or a derivative thereof described herein is the S-configurational enantiomer; or the N,N-diethyl-2-hydroxybenzeneacetamide or a derivative thereof described herein is the R-configurational enantiomer; or the N,N-diethyl-2-hydroxybenzeneacetamide or a derivative thereof described herein is a mixture of the S-configurational enantiomer and the R-configurational enantiomer, optionally, the S-configurational enantiomer and the R-configurational enantiomer in the mixture can be mixed in any molar ratio. In some embodiments, the molar ratio of the S-configurational enantiomer to the R-configurational enantiomer in the mixture is 1:1, i.e., the racemate.

[0032] The present application provides the use of N,N-diethyl-2-hydroxybenzeneacetamide or a derivative thereof in combination with one or more other active ingredients other than N,N-diethyl-2-hydroxybenzeneacetamide or a derivative thereof in the preparation of a medicament having effects such as anti-anxiety, anti-convulsion, sedation, hypnosis, anesthesia or muscle relaxation, and the other active ingredients have the effect of sedation, hypnosis or anesthesia assistance. In a variant, there is provided the use of N,N-diethyl-2-hydroxybenzeneacetamide or a derivative thereof in combination with one or more intravenous anesthetics and / or anesthesia adjuvants other than N,N-diethyl-2-hydroxybenzeneacetamide or a derivative thereof in the preparation of a medicament for inducing or maintaining general anesthesia or analgesia in a mammal.

[0033] In some embodiments, the drugs described herein further comprise other active ingredients in addition to N,N-diethyl-2-hydroxybenzeneacetamide or its derivatives, and the other active ingredients are selected from drugs having sedative-hypnotic or anesthesia-assisting effects; preferably, the other active ingredients are selected from intravenous anesthetics, inhaled anesthetics or anesthesia adjuvants.

[0034] The combination of N,N-diethyl-2-hydroxybenzeneacetamide or its derivatives with one or more intravenous anesthetics and / or anesthesia adjuvants other than N,N-diethyl-2-hydroxybenzeneacetamide or its derivatives provides excellent effects, such as: improving the quality of anesthesia, reducing the dosage of N,N-diethyl-2-hydroxybenzeneacetamide or its derivatives during the perioperative period, increasing safety, patient compliance, reducing the incidence of adverse reactions, reducing the number of drug administrations by anesthesiologists, and making the anesthesia induction process more convenient.

[0035] In some embodiments, the intravenous anesthetics are selected from propofol, fospropofol disodium, midazolam, ketamine, thiopental sodium, sodium oxybate or etomidate, including their pharmaceutically acceptable salts; the inhaled anesthetics are selected from sevoflurane, isoflurane, enflurane, desflurane, methoxyflurane or nitrous oxide; the anesthesia adjuvants are selected from sedative-hypnotics, anticholinergics, muscle relaxants, antiemetics, local anesthetics or analgesics.

[0036] Those skilled in the art will understand that many factors can affect the effective amount administered and / or the maintenance dose. For example, inducing or maintaining general anesthesia or sedation in a patient may be related to whether the patient is a human or a non-human mammal; it may also be related to the patient's age, weight, gender, diet, health status or mental state, etc. In actual application, anesthesiologists, veterinarians or other medical or healthcare practitioners in this field select and adjust the effective amount and / or the maintenance dose based on the above influencing factors and the reactivity changes of the patient to achieve a relatively stable blood drug concentration, and to achieve the purpose of stable anesthesia depth, strong controllability, good awakening quality and stable vital signs.

[0037] A range of doses can be selected, which depends to a large extent on the level and depth of general anesthesia or sedation or hypnosis to be achieved.

[0038] In some embodiments, when administered to a subject, the effective dose of N,N - diethyl - 2 - hydroxybenzamide or its derivatives is about 10 - 1000 mg / kg based on the body weight of the subject. In some embodiments, when administered to a subject, the effective dose of N,N - diethyl - 2 - hydroxybenzamide or its derivatives is about 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 150 mg / kg, 200 mg / kg, 250 mg / kg, 300 mg / kg, 350 mg / kg, 400 mg / kg, 450 mg / kg, 500 mg / kg, 550 mg / kg, 600 mg / kg, 650 mg / kg, 700 mg / kg, 750 mg / kg, 800 mg / kg, 850 mg / kg, 900 mg / kg, 950 mg / kg or 1000 mg / kg based on the body weight of the subject.

[0039] In some embodiments, the administration time of the drugs described herein is within 10 minutes; preferably, the administration time of the drugs described herein is within 2 minutes. The administration time of the maintenance dose is determined according to the time for maintaining general anesthesia or sedation or hypnosis in mammals. The forms of drug administration include one or more of single administration, multiple administrations, continuous administration, and targeted infusion.

[0040] According to the characteristics of clinical medication, the effective amount for inducing general anesthesia or sedation or hypnosis is mostly administered by single injection. The maintenance dose for maintaining general anesthesia or sedation or hypnosis can be administered by multiple injections, but the blood drug concentration will show saw - tooth - like fluctuations with this method, and the depth of anesthesia in the patient will also fluctuate accordingly. Therefore, in clinical practice, the maintenance dose is mostly administered by continuous infusion or targeted infusion, avoiding the ups and downs of the peak and trough of the blood drug concentration after fractional administration, and the depth of anesthesia is easy to control and the anesthesia process is stable.

[0041] In some embodiments, the dosage forms of the drugs described herein are selected from one or more of the following: capsules, tablets, pills, liquids, powders, granules, fine granules, film - coated agents, pills, lozenges, sublingual agents, colloidal solvents, buccal preparations, pastes, syrups, suspensions, elixirs, emulsions, coating agents, ointments, plasters, cataplasms, transdermal preparations, lotions, inhalants, aerosols, injections, and suppositories.

[0042] In some embodiments, the drugs described herein further comprise a pharmaceutically acceptable excipient, and the excipient is selected from one or more of the following: granulating agents, binders, lubricants, disintegrants, sweeteners, glidants, anti-adhesives, antistatic agents, surfactants, antioxidants, gums, coating agents, colorants, flavoring agents, plasticizers, preservatives, suspending agents, emulsifying agents, antimicrobial agents, plant cellulose materials, and spheronizing agents, and any combination thereof.

[0043] In some embodiments, the drugs described herein are administered by intravenous, oral, intradermal, transdermal, intrathecal, intraarterial, intraperitoneal, intranasal, intravaginal, rectal, intravesical, intratumoral, topical, intramuscular, subcutaneous, mucosal, inhalation, injection, infusion, or any combination thereof.

[0044] In some embodiments, the subject described herein is a mammal; optionally, the subject described herein is a human, rat, mouse, cat, dog, horse, sheep, cow, or monkey; preferably, the subject described herein is a human.

[0045] This application also provides a method for general anesthesia, sedation, or hypnosis of a mammal, the method comprising administering an effective amount of N,N-diethyl-2-hydroxybenzeneacetamide or a derivative thereof, a pharmaceutically acceptable salt, or a prodrug to a subject.

[0046] This application describes a number of embodiments, but the description is exemplary rather than restrictive, and it will be apparent to those of ordinary skill in the art that there can be more embodiments and implementation schemes within the scope of the embodiments described in this application. Although many possible combinations of features are shown in the drawings and discussed in the detailed description, many other combinations of the disclosed features are also possible. Unless specifically restricted, any feature of any embodiment can be combined with any other feature in any other embodiment, or can replace any other feature in any other embodiment.

[0047] This application includes and contemplates combinations with features known to those of ordinary skill in the art. The embodiments and features already disclosed in this application can also be combined with any conventional features to form a unique inventive solution defined by the claims. Any feature of any embodiment can also be combined with features from other inventive solutions to form another unique inventive solution defined by the claims. Therefore, it should be understood that any feature shown and / or discussed in this application can be implemented alone or in any suitable combination. Therefore, the embodiments are not subject to other limitations except those made in accordance with the appended claims and their equivalents. In addition, various modifications and changes can be made within the scope of the appended claims.

[0048] In addition, when describing representative embodiments, the specification may have presented the method and / or process as a specific sequence of steps. However, to the extent that the method or process does not depend on the specific order of the steps described herein, the method or process should not be limited to the specific order of steps described. As those of ordinary skill in the art will understand, other step orders are possible. Therefore, the specific order of steps set forth in the specification should not be construed as a limitation on the claims. In addition, the claims directed to the method and / or process should not be limited to performing their steps in the order written, as those skilled in the art can readily understand that these orders can vary and still remain within the spirit and scope of the embodiments of the present application.

[0049] For the experimental methods without specific conditions noted in the following examples, they are generally determined according to national standards. For the experimental materials without sources noted in the following examples, they are all commercially available raw materials. The equipment used in each step of the following examples is all conventional equipment. If there is no corresponding national standard, it is carried out according to general international standards, conventional conditions, or the conditions recommended by the manufacturer. Unless otherwise defined or explained, all professional and scientific terms used in this application have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the described content can be applied to the methods of this application.

[0050] Example

[0051] The relevant materials used in the examples are as follows:

[0052] 1. Reagents, materials

[0053] DEM-RS, DEM-R, DEM-S, 1,2-propanediol, dimethyl sulfoxide, γ-aminobutyric acid, LPS (lipopolysaccharide), diazepam, caffeic acid phenethyl ester were all purchased from Sigma-Aldrich (Shanghai) Trading Co., Ltd.; the BALB / c mice used in the experiment were purchased from the Animal Department of Peking University Health Science Center; mouse γ-aminobutyric acid (GABA) ELISA kit (YJ-E-30510M-48T, Beijing Green Source Kewi Biotechnology Co., Ltd.); L-glutamic acid (L-Glu) Elisa kit (RE2396-96T, Baoru Yi (Beijing) Biotechnology Co., Ltd.)

[0054] 2. Instruments

[0055] Patch Clamp System 700B (Molecular Devices, USA), FlexStation 3 Multifunctional Microplate Reader (Molecular Devices, USA)

[0056] Example 1 Preliminary Exploration of Drug Administration Dosage

[0057] In this experiment, 100 NIH mice were used and randomly divided into 10 groups according to body weight. They were the vehicle control group, and the low, medium, and high dose groups of racemate DEM-RS, DEM-R, and DEM-S (the doses of the 3 test substances were all set at 100, 250, and 625 mg / kg), with 10 animals in each group, all female. Each group of animals was given a single intragastric administration with a dosing volume of 10 ml / kg (0.1 mL / 10 g). The vehicle control group was given DMSO, and the dose groups of DEM-RS, DEM-R, and DEM-S were given the test substance solutions at different concentrations (the concentrations were 10, 25, and 62.5 mg / ml) respectively. 30 minutes after the administration of each group was completed, a 0.5% sodium pentobarbital solution was intraperitoneally injected at a dose of 50 mg / kg body weight, and the injection volume was 10 ml / kg (0.1 mL / 10 g). The time from the injection of the sodium pentobarbital solution to the disappearance of the righting reflex in the mice was the sleep latency, and the time from the disappearance of the righting reflex to the recovery of the righting reflex was the sleep time (the longest monitoring time was up to 150 minutes after the disappearance of the righting reflex, and the record for those whose righting reflex did not recover after more than 150 minutes was 150 minutes).

[0058] The sleep situation was evaluated by detecting the righting reflex of the mice, and the results are shown in Table 1 below:

[0059] Table 1

[0060]

[0061] *The longest monitoring time was 150 minutes.

[0062] The results showed that the compound N,N-diethyl-2-hydroxybenzeneacetamide and its chiral isomers exhibited obvious sedative and hypnotic activities.

[0063] Example 2 Acute Toxicity Determination

[0064] Twenty NIH mice were selected and randomly divided into 4 groups, with 5 animals in each group, all female. They were orally administered four different doses (500, 1000, 1500, and 2000 mg / kg) of racemate DEM-RS, and the number of surviving mice was monitored within 1 hour. The results are as Figure 1 shown. It can be seen that 2 mice died in the 1000 mg / kg group, 3 mice died in the 1500 mg / kg group, and all 5 mice in the 2000 mg / kg group died. The survival rates of the mice at each dose are as Figure 2 shown.

[0065] The results showed that the compound N,N-diethyl-2-hydroxybenzeneacetamide showed toxicity at doses above 1000 mg / kg, and all mice died when the dose reached 2000 mg / kg.

[0066] Determination of the Optimal Sedative Dose and Sleep Time in Example 3

[0067] In this experiment, 50 BALB / c mice were randomly divided into 5 groups according to body weight, namely the vehicle control group and 4 dose groups of racemic DEM-RS (500, 600, 750, and 900 mg / kg), with 10 animals in each group, all of which were female. Each group of animals was given a single intragastric administration with a dosing volume of 10 ml / kg (0.1 mL / 10 g). The vehicle control group was given 1,2-propanediol, and the DEM-RS dose groups were given the test substance solutions at different concentrations (concentrations were 50, 60, 75, and 90 mg / ml) respectively. The time from the disappearance of the righting reflex to its recovery after drug administration in each group was the sleep time.

[0068] The survival rate results at the above doses are as Figure 3 shown, and the sleep time results are shown in Table 2 below:

[0069] Table 2

[0070]

[0071] *For those exceeding 12 hours, it is counted as 12 hours.

[0072] According to the experimental results, it can be seen that the optimal dose for N,N-diethyl-2-hydroxybenzeneacetamide to exert sedative-hypnotic activity is 750 mg / kg.

[0073] Example 4 Exploration of the Sedative Activity Mechanism of N,N-Diethyl-2-hydroxybenzeneacetamide

[0074] In the pharmacodynamic study of N,N-diethyl-2-hydroxybenzeneacetamide, it was found to have sedative-hypnotic activity. Multiple signaling factors in the brain tissue are involved in the sedative-hypnotic effect, among which the effects of serotonin (5-HT), gamma-aminobutyric acid (GABA), norepinephrine (NE), and excitatory amino acid (L-Glu) are the most significant. The effects of DEM on the above factors are likely to be related to its sedative-hypnotic activity.

[0075] 1. Determination of the effect of N,N-diethyl-2-hydroxybenzeneacetamide on the content of gamma-aminobutyric acid in brain tissue:

[0076] Twenty BALB / c mice were used in this experiment and randomly divided into 4 groups according to body weight, namely the vehicle control group, DEM-RS, DEM-R, and DEM-S groups (with a dose of 600 mg / kg for all), and 5 females in each group. Each group of animals was given a single intragastric administration with a dosing volume of 10 ml / kg (0.1 mL / 10 g). The vehicle control group was given 1,2-propanediol, and the DEM-RS, DEM-R, and DEM-S groups were given the test substance solution with a concentration of 60 mg / ml respectively. Three hours after dosing, the mice were sacrificed, and their brain tissues were placed on ice. An equal amount of brain tissue was weighed from each group and ground using an electric tissue grinder, with attention paid to controlling the temperature during the process. The brain tissue homogenate was lysed using cell lysate, and the total protein was obtained by centrifugation at 12,000 rpm at 4°C. The content of γ-aminobutyric acid in each group was measured using a γ-aminobutyric acid Elisa kit according to the method of the kit.

[0077] The results are as Figure 4 shown in

[0078] Table 3

[0079] Blank (μM) DEM-RS (μM) DEM-R (μM) DEM-S (μM) 1 1.89 1.89 1.75 1.78 2 1.82 1.86 1.73 1.69 3 1.77 1.81 1.74 1.76 4 1.73 1.80 1.76 1.78 5 1.78 1.79 1.75 1.73 Mean ± sd 1.80±0.05 1.83±0.04 1.75±0.01 1.75±0.03

[0080] The results showed that N,N-diethyl-2-hydroxybenzeneacetamide had no effect on the content of GABA in the mouse brain.

[0081] 2. Determination of the effect on the GABAa receptor:

[0082] The voltage stimulation protocol for recording GABA receptor currents using the whole-cell patch clamp was as follows: When a whole-cell seal was formed, the cell membrane voltage was clamped at -70 mV. Agonist administration method: Recorded in the Gap-free mode, and the peak current was given after sequentially spraying the test substance with increasing concentrations and 300 μΜ GABA on the cell surface. Allosteric modulation administration method: Recorded in the Gap-free mode, and the peak current was given after sequentially spraying 3 μΜ GABA, the test substance, and a mixture of the test substance and 3 μM GABA on the cell surface. Test substance administration method: Each concentration of the test substance was given 1 - 2 times, and then rinsed with extracellular fluid for 1 min before detecting the next concentration. The experimental data were collected by an EPC-10 amplifier (HEKA) and stored in the PatchMaster (HEKA) software.

[0083] The results are as follows:

[0084] In this study, the patch clamp technique was used to detect the concentration-effect relationship of the test substances (DEM-RS, DEM-R, and DEM-S) on the A (α1β2γ2) receptor current. The experimental results are summarized as follows:

[0085] The direct agonist effects of the test substances (DEM-RS, DEM-R, and DEM-S) on the GABA A (α1β2γ2) receptor are shown in Table 4 as follows:

[0086] Table 4

[0087]

[0088] The results showed that the test substances DEM-RS, DEM-R, and DEM-S had no obvious direct agonist effects on the GABA A (α1β2γ2) receptor.

[0089] The allosteric modulation effects of the test substances (DEM-RS, DEM-R, and DEM-S) on the GABA A (α1β2γ2) receptor are shown in Table 5 as follows:

[0090] Table 5

[0091]

[0092] The results showed that the test substances DEM-RS, DEM-R, and DEM-S had no obvious allosteric modulation effects on the GABA A (α1β2γ2) receptor.

[0093] 3. Determination of the effect of N,N-diethyl-2-hydroxybenzamide on the content of the excitatory amino acid L-glutamate (L-Glu) in the brain tissue:

[0094] In this experiment, 10 BALB / c mice were used and randomly divided into 2 groups according to body weight, namely the vehicle control group and the DEM-R group (both at a dose of 600 mg / kg), with 5 females in each group. Each group of animals was given a single intragastric administration at a dosing volume of 10 ml / kg (0.1 mL / 10 g). The vehicle control group was given 1,2-propanediol, and the DEM-R group was given the test substance solution at a concentration of 60 mg / ml. The mice were sacrificed uniformly 3 h after dosing. The mouse brain tissues were taken and placed on ice, and the cerebral cortex and the remaining brain tissues were separated for subsequent experiments. An equal amount of brain tissue was weighed in each group and ground using an electric tissue grinder, with temperature control during the process. The brain tissue homogenate was lysed using cell lysate, and the total protein was obtained by centrifugation at 12,000 rpm at 4°C. The content of L-glutamate in the cerebral cortex and the remaining brain tissues of each group was measured using an L-glutamate Elisa kit according to the method of the kit.

[0095] The content of L-glutamate in the cerebral cortex and other parts of the brain is as Figure 5 , shown in Table 6 and Table 7:

[0096] Table 6

[0097]

[0098] Table 7

[0099]

[0100]

[0101] The results showed that N,N - diethyl - 2 - hydroxybenzeneacetamide had a significant effect on the concentration of L - Glu in the cerebral cortex and the whole brain.

[0102] The results of this application showed that N,N - diethyl - 2 - hydroxybenzeneacetamide and its chiral isomers (DEM - R & DEM - S) had a significant sedative - hypnotic effect on mice. The optimal dosage was about 750 mg / kg, and the safe dosage was less than about 1000 mg / kg. The study on the sedative - hypnotic mechanism of N,N - diethyl - 2 - hydroxybenzeneacetamide showed that using patch - clamp to measure N,N - diethyl - 2 - hydroxybenzeneacetamide and its chiral isomers (DEM - R & DEM - S) had no obvious agonist effect on the GABA A (α1β2γ2) receptor and no allosteric regulatory effect. However, N,N - diethyl - 2 - hydroxybenzeneacetamide had a significant inhibitory effect on the content of L - glu in the cerebral cortex and the rest of the brain.

Claims

1. Use of N,N-diethyl-2-hydroxyphenylacetamide or its derivatives in the preparation of sedative drugs.

2. The use according to claim 1, wherein The N,N-diethyl-2-hydroxyphenylacetamide or its derivative is an S-configuration enantiomer, an R-configuration enantiomer, or a mixture of an S-configuration enantiomer and an R-configuration enantiomer.

3. The use according to claim 1 or 2, wherein When administered to a subject, the effective dose of the N,N-diethyl-2-hydroxyphenylacetamide or a derivative thereof is about 10-1000 mg / kg based on the subject's body weight.

4. The use according to any one of claims 1 to 3, wherein The drug further comprises other active ingredients besides N,N-diethyl-2-hydroxyphenylacetamide or its derivatives, and the other active ingredients are selected from drugs with sedative, hypnotic or anesthetic auxiliary effects; preferably, the other active ingredients are selected from intravenous anesthetics, inhalation anesthetics or anesthetic auxiliary agents.

5. The use according to any one of claims 1 to 4, wherein The dosage form of the drug is selected from one or more of the following: capsules, tablets, pills, liquids, powders, granules, fine granules, film coatings, pills, lozenges, sublingual agents, peptizers, buccal preparations, pastes, syrups, suspensions, elixirs, emulsions, coatings, ointments, plasters, poultices, transdermal preparations, lotions, inhalants, aerosols, injections and suppositories.

6. The use according to any one of claims 1 to 5, wherein The medicament further comprises a pharmaceutically acceptable excipient selected from one or more of the following: a granulating agent, a binder, a lubricant, a disintegrant, a sweetener, a glidant, an anti-adherent, an antistatic agent, a surfactant, an antioxidant, a gum, a coating agent, a colorant, a flavoring agent, a plasticizer, a preservative, a suspending agent, an emulsifier, an antimicrobial agent, a plant cellulose material, and a spheronizing agent, and any combination thereof.

7. The use according to any one of claims 1 to 6, wherein The form of administering the drug is selected from one or more of single administration, multiple administration, continuous administration and targeted infusion.

8. The use according to any one of claims 1 to 7, wherein The drug is administered intravenously, orally, intradermally, transdermally, intrathecally, intraarterially, intraperitoneally, intranasally, intravaginally, intrarectally, intravesically, intratumorally, topically, intramuscularly, subcutaneously, mucosally, by inhalation, injection, infusion, or any combination thereof.

9. The use according to any one of claims 1 to 8, wherein The subject is a mammal; optionally, the mammal is a human, rat, mouse, cat, dog, horse, sheep, cow or monkey.

10. The use according to claim 9, wherein The subject is a human.

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