Etomidate derivatives, preparation methods thereof, and use thereof in preparing anesthetic drugs

Abstract

The present invention provides an etomidate derivative and a preparation method thereof and use thereof in preparing anesthetic drugs, belonging to the field of chemical medicine. The structure of the etomidate derivative is shown in Formula I. Compared with etomidate, the compound of the present invention significantly shortens the anesthesia time. Shortening the anesthesia time helps to alleviate some side effects after anesthesia; is conducive to the rapid recovery of the patient's important organs' autonomous regulation ability and postoperative care; and reduces the risk of delayed awakening. The etomidate derivative of the present invention has good application prospects in the preparation of anesthetic drugs that shorten the anesthesia time. .

Description

Technical Field

[0001] The invention belongs to the field of chemical medicine, and specifically relates to etomidate derivatives and preparation methods thereof and uses thereof in preparing anesthetic drugs. Background Art

[0002] General anaesthetics, also known as general anesthetics, are the cornerstone of modern surgery. Currently, propofol, etomidate, dexmedetomidine, and benzodiazepines are commonly used in clinical practice. Compared with other general anesthetics, etomidate has less effect on blood pressure and heart rate. Therefore, etomidate is more suitable for patients with hemodynamic instability, heart disease, and cerebrovascular disease.

[0003] However, continuous infusion of etomidate will prolong the awakening time and extubation time. Studies have found that with the increase in the dosage of etomidate, the patient's respiratory recovery time, eye opening time and extubation time are progressively prolonged. This may be because the amount of etomidate used gradually increases, desensitizing the γ-aminobutyric acid (GABA) receptors, thereby gradually increasing the GABA content in the synaptic cleft, prolonging the time of nerve blockade, and ultimately disinhibiting the subcortex. The probability of myoclonus when using etomidate during the induction phase of general anesthesia is as high as 50%~80%. Etomidate can competitively bind to dopamine receptors in the substantia nigra, striatum and other parts of the midbrain, reducing the production of endogenous dopamine and leading to the occurrence of myoclonus.

[0004] Shortening the anesthesia time can reduce the time patients occupy the operating room, thereby improving the operating efficiency of the operating room; it can help alleviate some side effects after anesthesia, such as drowsiness, poor brain function, etc., especially for elderly patients, it can restore cognitive function faster; it can reduce the patient's stay time in the recovery room, allowing patients to leave the recovery room faster, improving patient comfort and satisfaction; it is conducive to the rapid recovery of the patient's important organs' autonomous regulation ability and postoperative care; it can reduce the risk of delayed awakening, which is especially important for patients with liver and kidney dysfunction or other metabolic disorders.

[0005] Therefore, in order to better meet clinical needs, it is of great significance to develop anesthetic drugs that can shorten anesthesia time. Summary of the invention

[0006] In order to solve the above problems existing in the prior art, the object of the present invention is to provide an etomidate derivative and a preparation method thereof and use thereof in the preparation of anesthetic drugs.

[0007] In order to achieve the above object, the present invention adopts the following technical solution:

[0008] The present invention provides an etomidate derivative or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the structure of the etomidate derivative is shown in Formula I:

[0009] ;

[0010] R1 is selected from H, C 1-6 alkyl, ; R4 is selected from C 1-6 alkyl;

[0011] R2 and R3 are each independently selected from H, C 1-6 Alkyl or C 1-6 Alkoxy, and R1, R2, and R3 are not hydrogen at the same time.

[0012] Furthermore, the structure of the etomidate derivative is shown in Formula I-E:

[0013] ;

[0014] R2 and R3 are each independently selected from H, methyl or methoxy, and R2 and R3 are not hydrogen at the same time.

[0015] Furthermore, the structure of the etomidate derivative is shown in Formula ⅠⅠ-C:

[0016] ;

[0017] R1 is selected from or .

[0018] Furthermore, the structure of the etomidate derivative is as follows:

[0019] .

[0020] The present invention also provides a method for preparing the above-mentioned etomidate derivative, which specifically comprises the following steps:

[0021] ;

[0022] R2 and R3 are each independently selected from H, methyl or methoxy, and R2 and R3 are not hydrogen at the same time;

[0023] (a) Compound IA reacts with a reducing agent under inert gas protection to obtain compound IB; (b) Compound IB reacts with an oxidizing agent to obtain compound IC; (c) Compound IC reacts with a Grignard reagent under inert gas protection to obtain compound ID; (d) Compound ID reacts with 3 H -Ethyl imidazole-5-carboxylate, triphenylphosphine and diisopropyl azodicarboxylate react under the protection of inert gas to obtain compound IE.

[0024] Further, in step (a), the reducing agent is LiAlH4; the inert gas is nitrogen; the reaction temperature is 0 ℃ ~ 25 ℃; the reaction solvent is tetrahydrofuran; the molar ratio of the compound IA to the reducing agent is 1:1; the reaction time is 6 h; in step (b), the oxidizing agent is Dess-Martin reagent; the reaction temperature is 25 ℃; the reaction solvent is dichloromethane; the molar ratio of the compound IB to the oxidizing agent is 1:1.5; the reaction time is 2 h; in step (c), the Grignard reagent is methylmagnesium chloride; the reaction temperature is 0 ℃ ~ 25 ℃; the inert gas is nitrogen; the reaction solvent is tetrahydrofuran; the molar ratio of the compound IC to the Grignard reagent is 1:1.5; the reaction time is 6 h; in step (d), the reaction temperature is 0 ℃ ~ 25 ℃; the inert gas is nitrogen; the reaction solvent is tetrahydrofuran; the compounds ID, 3 H The molar ratio of ethyl imidazole-5-carboxylate, triphenylphosphine and diisopropyl azodicarboxylate is 1: 1: 1.2: 1.2; the reaction time is 6 h.

[0025] The present invention also provides a method for preparing the above-mentioned etomidate derivative, which specifically comprises the following steps:

[0026] ;

[0027] R1 is selected from or ;

[0028] (a) Compound II-A reacts with an alkaline reagent to obtain compound II-B; (b) Compound II-B reacts with an alkaline reagent and an electrophilic reagent to obtain compound II-C.

[0029] Furthermore, in step (a), the alkaline reagent is LiOH; the reaction temperature is 25°C; the reaction solvent is methanol; the molar ratio of the compound II-A to the alkaline reagent is 1:4; and the reaction time is 12 hours; in step (b), the alkaline reagent is K2CO3; the electrophilic reagent is 1-bromo-2-(2-methoxyethoxy)ethane or 1-bromo-2-(2-ethoxyethoxy)ethane; the reaction temperature is 25°C; the molar ratio of the compound II-B, the alkaline reagent and the electrophilic reagent is 1:2.5:1.2; and the reaction time is 12 hours.

[0030] The present invention also provides a pharmaceutical composition for anesthesia, wherein the pharmaceutical composition is prepared by using the above-mentioned etomidate derivative or its pharmaceutically acceptable salt, stereoisomer or solvate as an active ingredient and adding pharmaceutically acceptable excipients.

[0031] The present invention also provides the use of the etomidate derivative or its pharmaceutically acceptable salt, stereoisomer or solvate in the preparation of anesthetic drugs.

[0032] Furthermore, the anesthetic drug is a short-acting anesthetic drug.

[0033] The present invention has achieved the following beneficial effects:

[0034] The present invention provides an etomidate derivative shown in formula I, a preparation method thereof, and medical uses thereof. Compared with etomidate, the compounds I-2, II-1, and II-2 of the present invention significantly shorten the anesthesia time. Shortening the anesthesia time helps to alleviate some side effects after anesthesia; is beneficial to the rapid recovery of the patient's important organs' autonomous regulation ability and postoperative care; and reduces the risk of delayed awakening. The etomidate derivative of the present invention has good application prospects in the preparation of anesthetic drugs that shorten the anesthesia time.

[0035] In the present invention, the compounds and derivatives provided are named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0036] Definitions of terms used in the present invention: Unless otherwise specified, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms that are not specifically defined in the present invention, the meanings that can be given to them by those skilled in the art should be given according to the disclosure and context. Among them:

[0037] Unless otherwise specified, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure; for example, R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of these compounds are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0038] Unless otherwise specified, the structures depicted in the present invention are also meant to include solvates of the structures, which refers to the physical association of the compounds of the present invention with one or more solvent molecules; the physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding; non-limiting examples of suitable solvents include, but are not limited to, isopropanol, ethanol, methanol, polyethylene glycol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine; "hydrate" is a solvate in which the solvent molecule is H2O;

[0039] The term "pharmaceutically acceptable" means that a carrier, excipient, diluent, adjuvant, and / or applicable salt is generally chemically and physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0040] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final separation and purification of the compound. It can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base appropriately (e.g., equivalent). These salts may form a precipitate in the solution and be collected by filtration, or be recovered after solvent evaporation, or be obtained by freeze-drying after reaction in an aqueous medium. In the present invention, the salt can be a hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.

[0041] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0042] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0043] The reagents and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercially available products.

[0044] In a specific embodiment of the present invention, stirring overnight refers to stirring for 12 hours.

[0045] Example 1: Preparation of 1-(1-(2,3-dimethylphenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (I-1)

[0046] Step 1: Preparation of intermediate 2,3-dimethylbenzyl alcohol

[0047]

[0048] Place 1.5 g (10 mmol) of 2,3-dimethylbenzoic acid in a 100 ml two-necked bottle and inject 40 ml of tetrahydrofuran. Under nitrogen protection, add 4 ml of LiAlH4 THF solution (2.5 mol / L in THF) at 0°C, stir under the reaction conditions for 30 minutes, and move to room temperature for reaction for 6 hours. After the reaction is completed by TLC monitoring, slowly add 0.4 ml of water at 0°C, then slowly add 1.2 ml of 15% NaOH solution, and finally add 0.4 ml of water, warm to room temperature and stir for 15 minutes. Filter and wash the filter cake with ethyl acetate 2-3 times. Pour the filtrate into a separatory funnel, extract with ethyl acetate 2-3 times, dry with anhydrous Na2SO4, filter, and distill under reduced pressure to dry to obtain a light yellow oily liquid 2,3-dimethylbenzyl alcohol, 1.2 g, with a yield of 89%.

[0049] Step 2: Preparation of 2,3-dimethylbenzaldehyde

[0050]

[0051] Place 955 mg (7.0 mmol) of 2,3-dimethylbenzyl alcohol in a 100 ml eggplant-shaped bottle and add 20 ml of dichloromethane. Add 4.45 g of Dess-Martin reagent (10.5 mmol) at room temperature and stir under the reaction conditions for 2 hours. After the reaction is completed by TLC monitoring, add saturated sodium thiosulfate solution dropwise at room temperature and stir at room temperature for 10 minutes. Pour the filtrate into a separatory funnel, extract with dichloromethane 2-3 times, dry with anhydrous Na2SO4, filter, distill and dry under reduced pressure, and purify the residue with silica gel column chromatography (petroleum ether: ethyl acetate = 19:1, v / v) to obtain 2,3-dimethylbenzaldehyde as a light yellow oily liquid, 900 mg, with a yield of 95.6%.

[0052] Step 3: Preparation of 1-(2,3-dimethylphenyl)-1-ethanol

[0053]

[0054] Place 536 mg (4 mmol) of 2,3-dimethylbenzaldehyde in a 100 ml two-necked bottle and add 40 ml of tetrahydrofuran. Under nitrogen protection, add 2 ml of methylmagnesium chloride THF solution (3 mol / L in THF) at 0°C, stir under the reaction conditions for 30 minutes, and move to room temperature for 6 hours. After the reaction is completed by TLC monitoring, add saturated sodium bicarbonate solution dropwise at room temperature and stir at room temperature for 10 minutes. Pour the filtrate into a separatory funnel, extract with ethyl acetate 2-3 times, dry over anhydrous Na2SO4, filter, and distill under reduced pressure to dryness to obtain 540 mg of 1-(2,3-dimethylphenyl)-1-ethanol as a light yellow oily liquid with a yield of 90%.

[0055] Step 4: Preparation of ethyl 1-(1-(2,3-dimethylphenyl)ethyl)-1H-imidazole-5-carboxylate

[0056]

[0057] Place 1.1 g (4.2 mmol) of triphenylphosphine in a 100 ml two-necked bottle and add 40 ml of anhydrous tetrahydrofuran. Under nitrogen protection, slowly add 849.28 mg (4.2 mmol) of diisopropyl azodicarboxylate at 0°C. Stir for 15 minutes under the reaction conditions. After a white solid appears, add 3 H 490 mg (3.5 mmol) of tetrahydrofuran solution of ethyl imidazole-5-carboxylate was stirred for 5 minutes, and then 1-(2,3-dimethylphenyl)-1-ethanol (3.5 mmol) was slowly added dropwise, and finally the mixture was moved to room temperature for 6 hours. After the reaction was completed by TLC monitoring, the reaction solution was poured into a separatory funnel, water was added, and the mixture was extracted with ethyl acetate 2-3 times, dried over anhydrous Na2SO4, filtered, and distilled under reduced pressure to dryness. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain 524 mg of 1-(1-(2,3-dimethylphenyl)ethyl)-1H-imidazole-5-carboxylate as an oil, with a yield of 55%.

[0058] 1H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J = 1.1Hz, 1H), 7.68 (d, J= 1.1 Hz, 1H), 7.22 – 7.17 (m, 2H), 7.13 (d, J = 8.3 Hz, 1H), 6.34 (q, J =7.1 Hz, 1H), 4.34 – 4.20 (m, 2H), 2.89 (p, J = 6.9 Hz, 1H), 1.84 (d, J =7.1Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H), 1.24 (s, 3H), 1.22 (s, 3H).

[0059] Example 2: Preparation of 1-(1-(o-tolyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (I-2)

[0060]

[0061] Referring to the method of Example 1, the only difference is that the raw material 2,3-dimethylbenzoic acid in Step 1 of Example 1 is replaced by 2-methylbenzoic acid to prepare 1-(1-(o-tolyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (Ⅰ-2).

[0062] 1 H NMR (400 MHz, Methanol- d 4) δ 9.24 (s, 1H), 8.34 (s, 1H), 7.28 –7.18 (m, 3H), 6.92 (d, J = 7.2 Hz, 1H), 6.66 (q, J = 6.9 Hz, 1H), 4.39 – 4.23 (m,2H), 2.41 (s, 3H), 1.91 (d, J = 7.0 Hz, 3H), 1.28 (t, J = 7.1 Hz, 4H).

[0063] Example 3: Preparation of 1-(1-(2,5-dimethoxyphenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (I-3)

[0064]

[0065] Referring to the method of Example 1, the only difference is that the raw material 2,3-dimethylbenzoic acid in Step 1 of Example 1 is replaced by 2,5-dimethoxybenzoic acid to prepare 1-(1-(2,5-dimethoxyphenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (Ⅰ-3).

[0066] 1 H NMR (400 MHz, Chloroform- d ) δ 8.05 (s, 1H), 7.96 (s, 1H), 6.93(dd, J = 2.0, 1.0 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 6.77 (dd, J = 7.4, 1.9 Hz,1H), 5.79 (qd, J = 6.8, 1.0 Hz, 1H), 4.45 – 4.32 (m, 2H), 3.80 (s, 3H), 3.71(s,3H), 1.73 (d, J = 6.8 Hz, 3H), 1.36 (t, J = 8.1 Hz, 3H).

[0067] Example 4: Preparation of 1-(1-(2,5-dimethylphenyl)ethyl)-1H-imidazole-4-carboxylic acid ethyl ester (I-4)

[0068]

[0069] Referring to the method of Example 1, the only difference is that the raw material 2,3-dimethylbenzoic acid in Step 1 of Example 1 is replaced by 2,5-dimethylbenzoic acid to prepare 1-(1-(2,5-dimethylphenyl)ethyl)-1H-imidazole-4-carboxylic acid ethyl ester (Ⅰ-4).

[0070] 1 H NMR (400 MHz, Methanol- d 4) δ 9.21 (s, 1H), 8.34 (s, 1H), 7.16 –7.03 (m, 2H), 6.77 (s, 1H), 6.63 (q, J = 6.9 Hz, 1H), 4.38 – 4.27 (m, 2H), 2.33(s, 3H), 2.26 (s, 3H), 1.89 (d, J = 6.9 Hz, 3H), 1.29 (t, J= 7.1 Hz, 3H).

[0071] Example 5: Preparation of 1-(1-(2,4-dimethylphenyl)ethyl)-1H-imidazole-4-carboxylic acid ethyl ester (I-5)

[0072]

[0073] Referring to the method of Example 1, the only difference is that the raw material 2,3-dimethylbenzoic acid in Step 1 of Example 1 is replaced by 2,4-dimethylbenzoic acid to prepare 1-(1-(2,4-dimethylphenyl)ethyl)-1H-imidazole-4-carboxylic acid ethyl ester (Ⅰ-5).

[0074] 1 H NMR (400 MHz, Methanol- d 4) δ 9.15 (s, 1H), 8.33 (s, 1H), 7.10 –7.01 (m, 2H), 6.87 (d, J = 7.9 Hz, 1H), 6.63 (q, J = 6.8 Hz, 1H), 4.41 – 4.26 (m,2H), 2.33 (s, 3H), 2.29 (s, 3H), 1.89 (d, J = 6.9 Hz, 3H), 1.30 (t, J = 7.1 Hz,3H).

[0075] Example 6: Preparation of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid 2-(2-methoxyethoxy)ethyl ester (II-1)

[0076] Step 1: Preparation of intermediate (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid (ET-COOH)

[0077]

[0078] Take 2.44 g (10 mmol, 1eq) of commercially available etomidate API and place it in a 100 mL round-bottom flask, add 30 mL of methanol to dissolve it, and then add 10 mL (4M) of LiOH aqueous solution dropwise under stirring at room temperature. Stir overnight at room temperature and monitor by TLC. After the reaction is complete, evaporate the excess methanol and add 50 mL of water, then extract with dichloromethane to remove impurities, and then adjust the pH of the solution to about 3 with dilute hydrochloric acid after leaving the aqueous phase, and a large amount of white solid precipitates, and then extract twice with ethyl acetate, combine the organic phases, wash the organic phases with water twice, dry, and evaporate to dryness to obtain the crude product of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid, which is directly carried out to the next step.

[0079] Step 2: Preparation of Compound II-1

[0080]

[0081] ET-COOH (410 mg, 2 mmol) was dissolved in 5 mL DMF, and K2CO3 powder (690 mg, 5 mmol) was added. After stirring at room temperature for 10 min, 1-bromo-2-(2-methoxyethoxy)ethane (439 mg, 2.4 mmol) was added dropwise. After the addition was complete, stirring was continued at room temperature overnight and monitored by TLC. After the reaction was complete, 50 mL of water was added to the system, and then extracted twice with 50 mL of ethyl acetate. The organic phases were combined and washed twice with water. The organic phase was retained, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a colorless oil, namely (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid 2-(2-methoxyethoxy)ethyl ester (Ⅱ-1), about 510 mg, with a yield of 79.4%.

[0082] 1 H NMR (400 MHz, Chloroform- d ) δ 7.81 (d, J = 1.0 Hz, 1H), 7.72 (s,1H), 7.37 – 7.28(m, 3H), 7.21 – 7.15 (m, 2H), 6.34 (q, J = 7.1 Hz, 1H), 4.42 –4.32 (m, 2H), 3.76 (t, J = 4.8 Hz, 2H), 3.65 (dd, J = 5.7, 3.6 Hz, 2H), 3.54 (dd, J = 5.6, 3.6 Hz, 2H), 3.37 (s, 3H), 1.86 (d, J= 7.1 Hz, 3H).

[0083] Example 7: Preparation of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid 2-(2-ethoxyethoxy)ethyl ester (II-2)

[0084]

[0085] Referring to the method of Example 6, the only difference is that the electrophilic reagent 1-bromo-2-(2-methoxyethoxy)ethane is replaced by 1-bromo-2-(2-ethoxyethoxy)ethane to prepare (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid 2-(2-ethoxyethoxy)ethyl ester (II-2).

[0086] 1 H NMR (400 MHz, Chloroform- d ) δ 7.83 – 7.78 (m, 1H), 7.72 (d, J = 1.0Hz, 1H), 7.37 – 7.27 (m, 3H), 7.21 – 7.16 (m, 2H), 6.34 (q, J = 7.1 Hz, 1H),4.37 (q, J = 4.7 Hz, 2H), 3.76 (t, J = 4.9 Hz, 2H), 3.66 (dd, J = 6.0, 3.5 Hz, 2H),3.58 (dd, J = 6.0, 3.5 Hz, 2H), 3.52 (q, J = 7.0 Hz, 2H), 1.86 (d, J = 7.1 Hz, 3H),1.20 (t, J = 7.0 Hz, 3H).

[0087] The beneficial effects of the present invention are demonstrated by experimental examples below.

[0088] Experimental Example 1: Effect of etomidate derivatives of the present invention on ED in mice 50 Test pre-experiment

[0089] Experimental method: Accurately weigh 5 mg of each of the 7 target compounds of Examples 1-7, place them in 1.5 mL centrifuge tubes, add 100 μL DMSO, 30 μL Tween 80, and 870 μL saline, respectively, to prepare 5 mg / mL, sonicate in an ultrasound machine for several minutes, and dilute according to the anesthesia of the mice before use. The disappearance of the righting reflex is used as an indicator of drug efficacy. Inject 0.2 mL of solution into each mouse. If the mouse is anesthetized, halve the dose and continue to administer the drug until the mouse is no longer anesthetized. This anesthetized dose and non-anesthetized dose are used as the ED for subsequent experiments. 50 The maximum and minimum concentration values.

[0090] Table 1 Preliminary experimental results of the ED50 test of etomidate derivatives of the present invention in mice

[0091]

[0092] The experimental results are shown in Table 1. Except for compounds Ⅰ-1, Ⅰ-2, Ⅱ-1 and Ⅱ-2 of the present invention, the compounds prepared in other examples had no anesthetic effect at a dose of 50 mg / kg. Therefore, Ⅰ-1, Ⅰ-2, Ⅱ-1 and Ⅱ-2 were selected for the next experiment.

[0093] Experimental Example 2: Effect of etomidate derivatives of the present invention on ED in mice 50 test

[0094] Experimental method: 20 mg of Ⅰ-1, 5 mg of Ⅱ-1, and 4 mg of Ⅱ-2 were accurately weighed and placed in 5 ml centrifuge tubes, 400 μL of DMSO, 100 μL of Tween 80, and 3500 μL of normal saline were added, and ultrasonicated for several minutes in an ultrasonicator, and five groups of solutions with different concentrations and arranged in equal proportions were prepared (the concentration of each compound in Table 1 is the highest dose, and the concentration without anesthesia is the lowest dose, with a common ratio of 2 1 / 4 Set a concentration gradient). The disappearance of the righting reflex was used as the indicator of drug efficacy. Each mouse was injected with 0.2 mL of the solution, and the drug was administered starting from the middle dose. If the mouse was anesthetized, the dose was reduced by one; if the mouse was not anesthetized, the dose was increased by one, and the sequential method was used until six cycles occurred (anesthesia-no anesthesia or no anesthesia-anesthesia is a group of cycles). The ED was calculated according to the following formula 50 :lgED 50 =lgX0+lgq(A / N±0.5), where X0 is the middle dose concentration (mg / kg), q is the common ratio, A is the sum of a×d, a is the number of positives at each dose, d is the group distance; N is the sum of a. 50 Calculate 2 times ED 50 , at 2×ED 50The anesthesia and awakening conditions of mice were recorded after a single administration of the dose, and the anesthesia latency time and anesthesia duration time were calculated according to the formula.

[0095] The formula for calculating the anesthesia latency time is: (ΣS a ) / n±(Σ((ΣS a ) / (n-1)-S a ) 2 ) 1 / 2 ;The calculation formula for the duration of anesthesia is: (ΣS b ) / n±(Σ((ΣS b ) / (n-1)-S b ) 2 ) 1 / 2 (Where S a = the time from when the mouse was given the drug to when it was anesthetized, S b = the time from when mice were anesthetized to when they woke up, n=6).

[0096] Table 2 ED of mice of etomidate derivatives of the present invention 50 Test results

[0097]

[0098] The experimental results are shown in Table 2. Compound Ⅰ-1 exhibits a shorter incubation period and a longer duration; compounds Ⅱ-1 and Ⅱ-2 exhibit a shorter incubation period and a shorter duration.

[0099] Experimental Example 3: Effect of etomidate derivatives of the present invention on ED in rats 50 Test pre-experiment

[0100] Experimental method: 50 mg of each of Ⅰ-1, Ⅰ-2, Ⅱ-1, and Ⅱ-2 were accurately weighed and placed in 5 ml centrifuge tubes. 200 ul DMSO, 100 ul Tween 80, and 2200 ul normal saline were added respectively. Ultrasonication was performed in an ultrasound machine for several minutes. The solution was diluted according to the anesthesia of the rat before use. The disappearance of the righting reflex was used as an indicator of drug efficacy. 0.2 ml of solution was injected into each rat. If the rat was anesthetized, the dose was halved and continued until the rat was no longer anesthetized. This anesthetized dose and the non-anesthetized dose were used as the ED test for subsequent experiments. 50 The maximum and minimum concentration values.

[0101] Table 3 ED of etomidate derivatives of the present invention in rats 50 Test pre-experiment results

[0102]

[0103] The experimental results are shown in Table 3. 50The dose range was 8.4-16.82 mg / kg, and the ED in the Ⅰ-2 pilot study was 50 The dose range was 20-40 mg / kg, and the ED in the II-1 pilot study was 50 The dose range is 10-20 mg / kg, and the ED in the II-2 pilot study 50 The dose range was 6-12 mg / kg, from which the further experiments were carried out.

[0104] Experimental Example 4: Effect of etomidate derivatives of the present invention on ED in rats 50 test

[0105] Experimental method: 20 mg of Ⅰ-1, 40 mg of Ⅰ-2, 20 mg of Ⅱ-1, and 20 mg of Ⅱ-2 were accurately weighed and placed in 10 ml centrifuge tubes, respectively, and prepared into 20 mg / mL stock solutions according to DMSO: Tween 80: physiological saline = 1:0.4:8.6, sonicated in an ultrasonic instrument for several minutes, and prepared into five groups of solutions with different concentrations and arranged in equal proportions (the anesthetic concentration in Table 3 is set as the maximum concentration, the non-anesthetic concentration is set as the minimum concentration, and the common ratio is 2 1 / 4 Set the concentration gradient). The disappearance of the righting reflex was used as the index of drug efficacy. Each rat was injected with 0.2 mL of the solution, and the drug was administered starting from the middle dose. If the rat was anesthetized, the dose was reduced by one; if the rat was not anesthetized, the dose was increased by one, and the sequential method was used until six cycles occurred. According to the calculation formula (same as ED in Experimental Example 2), 50 Calculation formula) Calculate ED 50 . According to ED 50 Calculate 2 times ED 50 , at 2×ED 50 The anesthesia and awakening conditions of the rats were recorded after a single administration of the dose. The anesthesia latency time and anesthesia duration time were calculated according to the formula.

[0106] The formula for calculating the anesthesia latency time is: (ΣS a ) / n±(Σ((ΣS a ) / (n-1)-S a ) 2 ) 1 / 2 ;The calculation formula for the duration of anesthesia is: (ΣS b ) / n±(Σ((ΣS b ) / (n-1)-S b ) 2 ) 1 / 2 (Where S a = the time from when the rat was given the drug to when it was anesthetized, S b = the time from anesthesia to awakening of rats, n=6).

[0107] Table 4 Determination of the latency and duration of anesthesia in rats of etomidate derivatives of the present invention

[0108]

[0109] The experimental results are shown in Table 4. The duration of Ⅰ-1 is longer than that of etomidate; however, the duration of Ⅰ-2 is 183±23.52 s, the duration of Ⅱ-1 is 248.2±32.35 s, and the duration of Ⅱ-2 is 261.3±39.68 s, which are all significantly lower than the duration of etomidate of 630.53±138.92 s.

[0110] In summary, the present invention develops etomidate derivatives and their preparation methods and medical uses. Compared with etomidate, compounds I-2, II-1 and II-2 of the present invention significantly shorten the anesthesia time. Shortening the anesthesia time helps to alleviate some side effects after anesthesia; it is beneficial to the rapid recovery of the patient's important organs' self-regulation ability and postoperative care; and it reduces the risk of delayed awakening. The etomidate derivatives of the present invention have good application prospects in the preparation of anesthetic drugs that shorten the anesthesia time.

Claims

1. An etomidate derivative or a pharmaceutically acceptable salt thereof, characterized in that: The structure of the etomidate derivative is selected from the following structures:

2. A method for preparing an etomidate derivative I-2, characterized in that: The specific steps include: (a) Compound IA reacts with a reducing agent under inert gas protection to obtain Compound IB; (b) Compound IB reacts with an oxidizing agent to obtain Compound IC; (c) Compound IC reacts with a Grignard reagent under inert gas protection to obtain Compound ID; (d) Compound ID is reacted with ethyl 3H-imidazole-5-carboxylate, triphenylphosphine and diisopropyl azodicarboxylate under inert gas protection to obtain etomidate derivative I-2.

3. The preparation method according to claim 2, characterized in that: In step (a), the reducing agent is LiAlH4; the inert gas is nitrogen; the reaction temperature is 0°C to 25°C; the reaction solvent is tetrahydrofuran; the molar ratio of compound IA to the reducing agent is 1:1; and the reaction time is 6 hours; In step (b), the oxidizing agent is Dess-Martin reagent; the reaction temperature is 25° C.; the reaction solvent is dichloromethane; the molar ratio of compound IB to the oxidizing agent is 1:1.5; and the reaction time is 2 h; In step (c), the Grignard reagent is methylmagnesium chloride; the reaction temperature is 0°C to 25°C; the inert gas is nitrogen; the solvent of the reaction is tetrahydrofuran; the molar ratio of compound IC to the Grignard reagent is 1:1.5; and the reaction time is 6 hours; In step (d), the reaction temperature is 0°C to 25°C; the inert gas is nitrogen; the reaction solvent is tetrahydrofuran; the molar ratio of compound ID, 3H-imidazole-5-carboxylic acid ethyl ester, triphenylphosphine and diisopropyl azodicarboxylate is 1:1:1.2:1.2; and the reaction time is 6 hours.

4. A method for preparing an etomidate derivative II-C, characterized in that: The specific steps include: R1 is selected from (a) Compound II-A reacts with an alkaline reagent to obtain compound II-B; (b) Compound II-B reacts with a basic reagent and an electrophilic reagent to obtain etomidate derivative II-C.

5. The preparation method according to claim 4, characterized in that: In step (a), the alkaline reagent is LiOH; the reaction temperature is 25° C.; the reaction solvent is methanol; the molar ratio of compound II-A to the alkaline reagent is 1:4; and the reaction time is 12 hours; In step (b), the alkaline reagent is K2CO3; the electrophilic reagent is 1-bromo-2-(2-methoxyethoxy)ethane or 1-bromo-2-(2-ethoxyethoxy)ethane; the reaction temperature is 25°C; the molar ratio of compound II-B, the alkaline reagent and the electrophilic reagent is 1:2.5:1.2; and the reaction time is 12 hours.

6. A pharmaceutical composition for anesthesia, characterized in that: The pharmaceutical composition is prepared by using the etomidate derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 as an active ingredient and adding pharmaceutically acceptable excipients.

7. Use of the etomidate derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of anesthetic drugs.

Images