New compounds with local anesthetic and general deep sedative functions and medical uses

Abstract

The application provides a new compound with local anesthesia and general deep sedation function and medical use. The new compound has the structure shown in the following formula: The compound has local anesthesia and also exhibits a unique general sedative effect, suggesting that it has general anesthesia potential, and its rapid onset and recovery characteristics make it possible to be used for developing a new intravenous anesthetic.

Description

Technical Field

[0001] This application specifically relates to a novel compound with dual functions of local anesthesia and deep systemic sedation, and its pharmaceutical uses, belonging to the field of pharmaceutical technology. Background Technology

[0002] Prilocaine, an amide-type local anesthetic, is commonly used for local infiltration anesthesia, nerve blocks, and surface anesthesia due to its rapid onset, moderate duration of action, and low toxicity. Its molecular structure contains aromatic amine groups and amide bonds, exerting its local anesthetic effect by blocking voltage-gated sodium channels. However, prilocaine only provides local anesthetic effects, making its function relatively limited. Summary of the Invention

[0003] The main objective of this application is to provide a novel compound with dual functions of local anesthesia and deep systemic sedation, and its pharmaceutical uses, in order to overcome the shortcomings of the prior art.

[0004] To achieve the above-mentioned objectives, this application adopts the technical solution described below.

[0005] According to the first aspect of this application, the use of at least one of the compounds of Formula I and their stereoisomers, pharmaceutically acceptable salts and solvates in the preparation of medicaments for anesthesia and / or sedation is provided. Formula I.

[0006] In one embodiment, the drug is a drug for local anesthesia.

[0007] In one embodiment, the drug is a drug for deep sedation.

[0008] In one embodiment, the drug is a drug for local anesthesia and deep sedation, particularly a drug for local anesthesia and general deep sedation.

[0009] In one embodiment, the dosage form of the drug may include, but is not limited to, a gastrointestinal dosage form, an injectable dosage form, a respiratory dosage form, a skin dosage form, a mucosal dosage form, or a cavity dosage form.

[0010] Preferably, the dosage form of the drug is selected from intravenous injection dosage forms.

[0011] Furthermore, the drug comprises a separate solid portion and a liquid portion, wherein the solid portion comprises at least one of a therapeutically effective amount of the compound of Formula 1 and its stereoisomers, a pharmaceutically acceptable salt, and a solvate, and the liquid portion is a pharmaceutically acceptable solvent.

[0012] Furthermore, the pharmaceutically acceptable solvent may include, but is not limited to, sterile water, decarbonated water, ethanol, aqueous sorbitol solution or physiological saline.

[0013] Furthermore, the drug is an intravenous anesthetic.

[0014] According to a second aspect of this application, a pharmaceutical composition is provided, comprising: At least one of the compounds represented by Formula I and their stereoisomers, pharmaceutically acceptable salts and solvates; And, pharmaceutically acceptable carriers.

[0015] The pharmaceutically acceptable carrier can also be referred to as a pharmaceutical excipient, which is all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient. These can mainly be excipients and additives. For details, please refer to the *Pharmacopoeia of the People's Republic of China (2020 Edition)* and *Handbook of Pharmaceutical Excipients* (Paul J Sheskey, Bruno Chancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0016] According to a third aspect of this application, the use of the pharmaceutical composition in the preparation of a medicament for inducing or maintaining anesthesia or sedation in mammals is provided.

[0017] Furthermore, the drug is used to induce or maintain local anesthesia and / or deep sedation in mammals.

[0018] Preferably, the drug is used to induce or maintain deep sedation throughout the body in mammals.

[0019] The mammals mentioned include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0020] Compared with existing technologies, the amide compounds of Formula I provided in this application not only have local anesthetic activity comparable to prilocaine, but also exhibit unique systemic sedative effects. Under strictly controlled environmental interference conditions, after tail vein injection of an effective dose, mice can rapidly enter a deep sedative state of motion stillness and stable breathing within seconds, demonstrating the potential for general anesthesia. Furthermore, they also have the characteristics of rapid onset and recovery, providing new clues for the development of novel intravenous anesthetics. Attached Figure Description

[0021] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0022] Figure 1 This is the result of the tail pinching experiment in Embodiment 2 of this application; Figure 2 This is a schematic diagram of the hot plate experiment in Embodiment 2 of this application; Figure 3 These are the hot plate experiment results from Embodiment 2 of this application; Figure 4 This is a schematic diagram of the mechanical pain threshold test in Embodiment 2 of this application; Figure 5 This is the mechanical pain threshold test result in Embodiment 2 of this application; Figure 6 This is the result of the deep sedation effect test when the drug concentration was 0.25% in Example 3 of this application; Figure 7 This is the result of the deep sedation effect test when the drug concentration was 0.5% in Example 3 of this application; Figure 8 This is the result of the deep sedation effect test when the drug concentration was 1% in Example 3 of this application. Detailed Implementation

[0023] The technical solutions of this application will be described in detail below with reference to embodiments and accompanying drawings. Unless otherwise stated, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. When a quantity, concentration, or other value or parameter is expressed in the form of a range, preferred range, or preferred upper and lower numerical limits, it should be understood that this is equivalent to specifically disclosing any range by combining any pair of upper or preferred numerical limits with any lower or preferred numerical limit, regardless of whether the range is specifically disclosed. Unless otherwise stated, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within that range.

[0024] When used with a numerical variable, the terms "about" or "approximately" usually mean that the value of the variable and all values ​​of the variable are within the experimental error (e.g., within a 95% confidence interval for the mean) or within ±10% of the specified value, or a wider range.

[0025] The expression "comprising," or similar expressions such as "including," "containing," and "having," is open-ended and does not exclude additional unlisted elements, steps, or components. The expression "consisting of," excludes any unspecified elements, steps, or components. The expression "substantially consisting of," limits the scope to the specified elements, steps, or components, plus optional elements, steps, or components that do not materially affect the essential and novel features of the claimed subject matter. It should be understood that the expression "comprising" encompasses both the expressions "substantially consisting of" and "consisting of."

[0026] The expression "at least one" or "one or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0027] Example 1: Synthesis and Characterization of Four Amide Compounds In a nitrogen-filled glove box, a 4 mL oven-dried vial equipped with a magnetic stir bar was loaded with catalyst A1 (9.2 mg, 0.005 mmol, 5.0 mol%), catalyst B (0.9 mg, 0.0025 mmol, 2.5 mol%), olefin (0.1 mmol, 1.0 equivalent), and alkyl chloride (0.3 mmol, 3 equivalent). Then, MTBE (0.6 mL) and HFIP (0.4 mL) were added to the vial. After sealing the vial, it was removed from the glove box and irradiated at room temperature with a 370 nm LED (40 W × 2) for 4 hours with vigorous stirring. After the reaction was complete, the solvent was removed under vacuum, and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the ATRA product.

[0028] An oven-dried vial (8 mL) was placed in a magnetic stir bar, and ATRA product (0.1 mmol, 1 equivalent), nPrNH2 (41 μL, 0.5 mmol, 5 equivalent), potassium carbonate (27.6 mg, 0.2 mmol, 2 equivalent), and anhydrous formonitrile (1 mL) were added. The resulting mixture was stirred at 80 °C for 24 hours. The crude product was purified by flash column chromatography using petroleum ether and ethyl acetate as eluents.

[0029] The specific synthesis route in this embodiment is as follows: Catalyst A1 (cat.A1) is: .

[0030] Catalyst B (cat.B) is: .

[0031] For target product 1 (the compound shown in Formula I, 4,4-dimethyl-2-(propylamino)- N -(o-tolyl)pentanamide (colorless oil), the corresponding alkyl chloride (R-Cl) is tert-butane chloride.

[0032] Formula I The characterization data of the target product 1 are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 9.60 (s, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 3.15 (dd, J = 8.5, 2.0 Hz, 1H), 2.71 – 2.62 (m, 1H), 2.63 – 2.53 (m, 1H), 2.28 (s, 3H), 1.86 (dd, J = 14.5, 2.0 Hz, 1H), 1.57 – 1.51 (m, 3H), 1.37 – 1.30 (m, 1H), 1.03 (s, 9H), 0.95 (t, J = 7.4 Hz, 3H).

[0033] 13 C NMR (126 MHz, Chloroform- d ) δ 173.7, 136.2, 130.2, 126.9, 126.9, 123.9, 120.7, 62.2, 51.1, 48.6, 31.1, 29.9, 23.6, 17.7, 11.7.

[0034] IR(ATR): ν = 3244, 2989, 1690, 1660, 1588, 1528, 1276, 1261, 764, 750cm -1 .

[0035] HRMS (ESI) calcd. for C 17 H 29N2O [M+H] + : 277.2274, found: 277.2271.

[0036] For target product 2 (the compound shown in Formula II, 2-(propylamino)- N -(o-tolyl)heptanamide (colorless oil), the corresponding alkyl chloride (R-Cl) is chlorobutane.

[0037] Formula II The characterization data of the target product 2 are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 9.52 (s, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 3.23– 3.12 (m, 1H), 2.71 – 2.56 (m, 2H), 2.28 (s, 3H), 1.92 – 1.80 (m, 1H), 1.69 –1.49 (m, 4H), 1.48 – 1.38 (m, 2H), 1.37 – 1.28 (m, 4H), 0.96 (t, J = 7.4 Hz, 3H), 0.93 – 0.84 (m, 3H).

[0038] 13 C NMR (126 MHz, Chloroform- d ) δ 172.6, 136.0, 130.3, 127.3, 126.8,124.1, 121.0, 64.0, 51.2, 33.9, 31.7, 25.7, 23.4, 22.4, 17.7, 14.0, 11.7.

[0039] IR (ATR): ν = 3304, 2956, 2927, 1680, 1587, 1522, 1454, 1250, 1046,752 cm -1 .

[0040] HRMS (ESI) calcd. for C 17 H 29 N2O [M+H] + : 277.2274, found: 277.2266.

[0041] For target product 3 (the compound shown in Formula III, 4-methyl-2-(propylamino)- N -(o-tolyl)pentanamide (colorless oil), the corresponding alkyl chloride (R-Cl) is chloroisopropane.

[0042] Formula III The characterization data of the target product 3 are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 9.53 (s, 1H), 8.16 – 8.09 (m, 1H), 7.25 – 7.19 (m, 1H), 7.18 – 7.15 (m, 1H), 7.06 – 6.99 (m, 1H), 3.29 – 3.20 (m, 1H), 2.72 – 2.57 (m, 2H), 2.28 (s, 3H), 1.79 – 1.69 (m, 3H), 1.61 – 1.52 (m, 2H), 1.52 – 1.45 (m, 1H), 1.02 – 0.97 (m, 6H), 0.96 (t, J = 7.4 Hz, 3H).

[0043] 13 C NMR (126 MHz, Chloroform- d ) δ 173.0, 136.1, 130.3, 127.3, 126.8,124.1, 121.0, 62.4, 51.1, 43.1, 25.3, 23.4, 23.2, 21.9, 17.7, 11.7.

[0044] IR (ATR): ν = 3303, 2957, 2929, 1680, 1587, 1522, 1454, 1137, 1047,742 cm -1 .

[0045] HRMS (ESI) calcd. for C 16 H27 N2O [M+H] + : 263.2118, found: 263.2099.

[0046] For target product 4 (the compound shown in Formula IV, 6,6,6-trifluoro-2-(propylamino)- N -(o-tolyl)hexanamide (colorless oil), the corresponding alkyl chloride (R-Cl) is CF3(CH2)2CH2Cl.

[0047] Formula IV The characterization data of target product 4 are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 9.47 (s, 1H), 8.13 – 8.06 (m, 1H), 7.25 – 7.20 (m, 1H), 7.18 (d, J = 7.5 Hz, 1H), 7.09 – 7.02 (m, 1H), 3.20 (t, J =5.9 Hz, 1H), 2.74 – 2.57 (m, 2H), 2.28 (s, 3H), 2.20 – 2.07 (m, 2H), 1.97 –1.86 (m, 1H), 1.82 – 1.67 (m, 3H), 1.63 – 1.48 (m, 3H), 0.97 (t, J = 7.4 Hz, 3H).

[0048] 19 F NMR (471 MHz, CDCl3) δ -66.22.

[0049] 13 C NMR (126 MHz, Chloroform- d ) δ 171.7, 135.8, 130.3, 127.4, 126.9 (q, J = 276.3 Hz), 126.9, 124.4, 121.1, 63.3, 51.1, 33.6 (q, J = 28.8 Hz), 32.9, 23.5, 18.6 (q, J = 3.1 Hz), 17.6, 11.6.

[0050] IR(ATR): ν = 3294, 2960, 2932, 1678, 1587, 1521, 1455, 1253, 1135,752 cm -1 .

[0051] HRMS (ESI) calcd. for C 16 H 24 F3N2O [M+H] + : 317.1835, found: 317.1830.

[0052] Example 2: Local Anesthesia Effect Test Experiment 1. Eighteen male C57BL / 6J mice (20-25g) with similar health status and weight were selected and divided into four groups: a negative control group, a positive control group, a modification drug group (Group 1), a modification drug group (Group 2), a modification drug group (Group 3), and a modification drug group (Group 4), with three mice in each group. All animals were placed in an acclimatization environment with constant temperature (22-25℃), humidity (45%-60%), and a 12-hour light / 12-hour dark cycle for 3-5 days. During this period, they had free access to food and water to minimize the impact of environmental stress on the experimental results.

[0053] 2. Mice in the negative control group were subcutaneously injected with saline into their tails, while mice in the positive control group were subcutaneously injected with 0.5% prilocaine into their tails. Additionally, mice in the No. 1, No. 2, No. 3, and No. 4 modified drug groups were subcutaneously injected with compounds of Formula II, Formula III, Formula IV, and Formula I, respectively, at a concentration of 0.5%.

[0054] The specific routes of administration for each group were as follows: intradermal injection at the base of the mouse tail (the tail nerves are regularly distributed and superficial). Mice were properly restrained with a fixator and disinfected with 75% alcohol. An intradermal injection was performed on the dorsal side of the tail base using a fine needle, forming a clear wheal. The injection volume was 100 μl.

[0055] The preparation methods for the injections in the positive control group and drug modification groups 1-4 are as follows: First, place 5 mg of drug powder in a centrifuge tube, add 200 μL of DMSO, and gently vortex until the drug is completely dissolved. Then, add 200 μL of Tween 80 and mix thoroughly with a vortex mixer for 1 minute to form a homogeneous DMSO-Tween 80 mixture. Next, slowly add physiological saline to the mixture while gently vortexing to avoid rapid pouring which could cause excessive local concentration precipitation. Finally, bring the volume to 2 mL and vortex again for 30 seconds to ensure the solution is homogeneous and transparent.

[0056] The aforementioned injectable medications should be prepared and used immediately to ensure sterility and accurate concentration.

[0057] 3. Place each group of mice individually into a transparent observation box, place it on a metal grid, and close the lid. Allow the mice to move freely and adapt to the environment for 15-30 minutes (observe the mice's behavior during this time; if they exhibit persistent restlessness, curling up, or other abnormalities, replace the animal or extend the adaptation time). Begin testing after the adaptation period.

[0058] 4. Tail pinching test The experimental method was as follows: blunt-tipped tweezers were used to pinch the distal, middle and proximal segments of the tail of each group of mice with constant force (avoiding the injection site).

[0059] Indicators: Record the mice's escape responses such as tail retraction and hissing. Sensory blockage was graded into 4 levels: Level 0: Normal, rapid escape response; Level 1: Slow or diminished response; Level 2: Only reacts to strong pinching; Level 3: No response at all.

[0060] The results of the tail pinch test for each group of mice are as follows: Figure 1 As shown in the figure, sham, 0, 1, 2, 3, and 4 correspond to the negative control group, positive control group, drug 1 modification group, drug 2 modification group, drug 3 modification group, and drug 4 modification group, respectively.

[0061] 5. Hot plate test Turn on the hot plate apparatus and set the target temperature (commonly 52±0.5℃ or 55±0.5℃, adjusted according to the analgesic strength of the drug: choose 52℃ for weak analgesia and 55℃ for strong analgesia). After the temperature stabilizes, verify the actual surface temperature of the hot plate with a thermometer, ensuring the error is ≤0.5℃, and record the calibration data.

[0062] like Figure 2 As shown, each group of mice was placed individually in the transparent observation hood of the hot plate apparatus (to avoid group stress), and the timing was started. The time at which the mice first licked their hind paws, jumped, or withdrew their paws was observed and recorded (i.e., the pain threshold latency). Each mouse was tested 3 times, with an interval of ≥10 minutes between tests to avoid heat adaptation; after the test, the mice were returned to their original cages.

[0063] The results of the hot plate test for each group of mice are as follows: Figure 3 As shown in the figure, sham, 0, 1, 2, 3, and 4 correspond to the negative control group, positive control group, drug 1 modification group, drug 2 modification group, drug 3 modification group, and drug 4 modification group, respectively.

[0064] 6. Mechanical pain threshold test Select the middle of the sole of the hind paw of each group of mice (avoiding the toes, the edge of the pad, and areas of ulceration and redness; the test paws of each group of mice must be consistent, and the right hind paw should be tested).

[0065] like Figure 4 As shown, using an electronic Von Frey device, hold the Von Frey fiber perpendicular to the skin of the foot and slowly apply pressure until the fiber bends and remains bent for 1-2 seconds. If the mouse exhibits a clear avoidance response within 1-2 seconds (withdrawing paw, raising paw, licking the stimulation site, or fleeing the stimulation area), record it as a "positive response (√)"; if there is no such response, record it as a "negative response (×)". The interval between consecutive stimulations of the same site should be ≥5 minutes to avoid local sensory adaptation. Initial stimulation intensity: Select a fiber of medium intensity (e.g., 0.4g) as the initial stimulus. Gradient adjustment rules: If the current stimulus is "positive (×)": use a fiber of one level lower intensity for the next stimulation; if the current stimulus is "negative (√)": use a fiber of one level higher intensity for the next stimulation; if the mouse actively moves during stimulation, causing the stimulation to be interrupted, it is considered an "invalid stimulus" and the stimulation of that intensity should be repeated after 1 minute (maximum 2 repetitions). Termination criteria: After the first "positive response" is observed, stimulation is continued according to the rules until five clear response inflection points are recorded (i.e., points where "+" and "-" alternate, such as "-→+" and "+→-"). The mouse test is then stopped. Each mouse is tested three times on the same hind paw, with each test 10 minutes apart. The average of the three test results is taken as the mouse's mechanorepain threshold.

[0066] After each mouse test, it was returned to its original cage, and the observation box and metal mesh were wiped with 75% alcohol to prevent residual odor from affecting the next mouse.

[0067] The results of the mechanical pain threshold test for each group of mice are as follows: Figure 5 As shown in the figure, sham, 0, 1, 2, 3, and 4 correspond to the negative control group, positive control group, drug 1 modification group, drug 2 modification group, drug 3 modification group, and drug 4 modification group, respectively.

[0068] Based on the above test results, it can be seen that the compound shown in Formula I has a better local anesthetic effect than the compounds shown in Formulas II-IV. From the results of tail pinch and mechanical pain threshold tests, its local anesthetic activity is comparable to that of prilocaine, and from the results of hot plate tests, its local anesthetic activity is even better than that of prilocaine.

[0069] Example 3: Deep Sedation Effect Test Experiment 1. Select male C57BL / 6J mice (20-25g) with similar health status and weight, and randomly divide them into a negative control group, a positive control group, and a modified drug group, with 3 animals in each group. All animals were placed in an acclimatization environment with constant temperature (22-25℃), humidity (45%-60%), and a 12h light / 12h dark light cycle for 3-5 days, during which they had free access to food and water to reduce the impact of environmental stress on the experimental results.

[0070] 2. Based on the experimental animal weight and drug concentration requirements, and referring to the preparation method of the injection preparation in Example 2, prilocaine injection preparations with concentrations of 0.25%, 0.5%, and 1% were prepared, and modified drug injection preparations with concentrations of 0.25%, 0.5%, and 1% were prepared using the compound shown in Formula I.

[0071] 3. Tail vein injection procedure: Negative control group: Mice were injected with saline via tail vein injection at a dose of 0.1 ml per 20g as a negative control group.

[0072] Positive control group: The prepared prilocaine injection solution was injected via the tail vein in the same manner, and 0.1 ml of the solution was injected at a dosage of 20g.

[0073] Modified drug group: The modified drug was injected via tail vein using the same method, with a dosage of 0.1 ml per 20g as the experimental group.

[0074] 4. Once the experimental animals have reached a stable and sedated state, remove them from their temporary cages and gently place them in the center of the bottom of the open-field test chamber. Simultaneously, activate the video acquisition system and start timing. Four mice are tested each time, with a test duration of 20-30 minutes. During the test, maintain a quiet experimental environment, avoiding external interference such as personnel movement and noise. Keep the light intensity constant, and the experimenter should observe from a distance outside the test chamber to avoid directly looking at the animals and affecting their behavior.

[0075] 5. Cleaning and spacing between groups: After each group of animals is tested, immediately remove them and place them in a clean temporary cage. Thoroughly wipe the inner wall and bottom of the test chamber with 75% alcohol to remove residual odors and excrement from the animals. After the alcohol has completely evaporated, the next group of animals will be tested to ensure that there is no cross-interference between groups.

[0076] 6. Behavioral indicator analysis: The activity trajectories of each group of animals were extracted and recorded using an open field experiment video analysis system.

[0077] The results of the deep sedation effect test for each group of mice are as follows: Figures 6-8As shown, under tail vein injection, compared with the negative control group and the positive control group (prilocaine group), the modified drug (the compound shown in Formula I) could produce deep sedation in mice at three concentration gradients of 0.25%, 0.5%, and 1%. The sedative effect was relatively weak in the 0.25% concentration group; the sedative effect was the best in the 0.5% concentration group, and the duration of sedation was the longest; the mice in the 1% concentration group showed toxic reactions other than deep sedation.

[0078] Although this application has been described with reference to illustrative embodiments, those skilled in the art will understand that various other changes, omissions, and / or additions may be made without departing from the spirit and scope of this application, and that elements of the described embodiments may be substituted with substantially equivalents. Furthermore, many modifications may be made without departing from the scope of this application to adapt particular situations or materials to the teachings of this application. Therefore, this application is not intended to be limited to the specific embodiments disclosed for carrying out this application, but rather is intended to include all embodiments falling within the scope of the appended claims.

Claims

1. Use of at least one of the compounds of Formula I and their stereoisomers, pharmaceutically acceptable salts and solvates in the preparation of medicaments for anesthesia and / or sedation; Equation I.

2. The use according to claim 1, characterized in that: The drug is a drug used for local anesthesia or a drug used for deep sedation.

3. The use according to claim 1, characterized in that: The drug is used for local anesthesia and deep sedation.

4. The use according to any one of claims 1-3, characterized in that: The dosage forms of the drug include those administered via the gastrointestinal tract, injection, inhalation, skin, mucosa, or body cavity.

5. The application according to claim 4, characterized in that: The dosage form of the drug is selected from intravenous injection dosage forms.

6. The application according to claim 4, characterized in that: The drug comprises a separate solid portion and a liquid portion, wherein the solid portion comprises at least one of a therapeutically effective amount of a compound of Formula 1 and its stereoisomers, a pharmaceutically acceptable salt, and a solvate, and the liquid portion is a pharmaceutically acceptable solvent.

7. The application according to claim 6, characterized in that, Pharmaceutically acceptable solvents include sterile water, decarbonated water, ethanol, sorbitol aqueous solution, or physiological saline.

8. A pharmaceutical composition, characterized in that, include: An effective dose of at least one of the compounds of Formula I and their stereoisomers, pharmaceutically acceptable salts and solvates; And, pharmaceutically acceptable carriers; Equation I.

9. Use of the pharmaceutical composition of claim 8 in the preparation of a medicament for inducing or maintaining local anesthesia and / or deep sedation in mammals.

10. The use according to claim 9, characterized in that: The drug is used to induce or maintain deep sedation throughout the body in mammals.

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