Substituted phenol compound as well as preparation method and application thereof

Abstract

The invention discloses a substituted phenol compound as well as a preparation method and application thereof. According to the present invention, the propofol is subjected to structure optimization to obtain the compound having the structure represented by the formula (I), such that the safety is significantly improved, the anesthetic effect is excellent, various preparation forms can be conveniently prepared, the clinical application in various drug delivery forms can be easily achieved, the structure is novel, and the preparation method is simple. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a substituted phenol compound and a preparation method and use thereof, and in particular to a substituted phenol compound with sedative, hypnotic, analgesic or anesthetic effects and a preparation method and use thereof. Background Art

[0002] Propofol (2,6-diisopropylphenol, Propofol, formula A) is a widely used systemic intravenous anesthetic, particularly suitable for induction and maintenance of surgical anesthesia, outpatient biopsy and various types of surgery, and can also be used for long-term sedation treatment of cardiac, pediatric, neurosurgery and intensive care patients.

[0003]

[0004] Since propofol is a fat-soluble compound and is poorly soluble in water, fat emulsions are currently widely used. However, when fat emulsions are used for intravenous anesthesia, they usually cause adverse reactions such as hypotension, apnea due to respiratory suppression, local pain during injection, hypertriglyceridemia, secondary acute pancreatitis, hyperglycemia, and ketone bodies in urine, making their therapeutic window narrower. In addition, the lipid components can aggravate the hypotension caused by propofol or cause bacterial infection and allergic reactions due to contamination, which also limits the clinical application of propofol to a certain extent. Summary of the invention

[0005] Objectives of the invention: The first objective of the present invention is to provide a substituted phenol compound with propofol as the basic structure, the second objective is to provide a method for preparing the compound, the third objective is to provide a pharmaceutical composition composed of the compound, and the fourth objective is to provide a pharmaceutical use of the compound and its pharmaceutical composition.

[0006] Technical solution: The substituted phenol compound of the present invention has a structure of formula (I), and the compound includes a pharmaceutically acceptable salt thereof.

[0007]

[0008] in:

[0009] p, q are independently selected from 1, 2 or 3;

[0010] R 1 , R 2 are independently selected from halogen, substituted C 1 ~C 6 Alkyl, substituted C 2 ~C 6 Alkenyl, substituted C 1 ~C 3 Alkoxy or substituted C 3 ~C6 Cycloalkyl; the substituent is selected from hydrogen, C 1 ~C 3 Alkyl, OH, C 1 ~C 6 Alkoxy, halogen, nitro, cyano, C 3 ~C 6 Cycloalkyl or four to seven membered heterocycloalkyl, wherein the heterocycloalkyl is selected from a four-membered, five-membered, six-membered or seven-membered saturated or unsaturated heterocyclic ring containing 1 to 2 O, N or S ring heteroatoms; the substituent is monosubstituted or polysubstituted;

[0011] X is selected from Where R 3 , R 4 are each independently selected from hydrogen, halogen, cyano, nitro, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, three to six membered heterocycloalkyl, COOR a , COR b , OR c or CH 2 COOR d ; R 5 Selected from hydrogen, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, three to six membered heterocycloalkyl, COOR a , COR b or CH 2 COOR d ; R a , R b , R c , R d are each independently selected from hydrogen, -NH 2 , C 1 ~C 3 Alkyl, C 3 ~C 6 Cycloalkyl or four to seven membered heterocycloalkyl; the heterocycloalkyl is selected from four-membered, five-membered, six-membered or seven-membered saturated or unsaturated heterocyclic ring containing 1 to 2 O, N or S ring heteroatoms.

[0012] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group is connected to other fragments and groups in the compound shown in Formula I through this site.

[0013] Preferably, in the structure:

[0014] p, q are independently selected from 1, 2 or 3;

[0015] R 1 , R 2 are independently selected from halogen, substituted C 1 ~C 3 Alkyl, substituted C 2 ~C 4 Alkenyl, substituted C 1 ~C 3 Alkoxy or substituted C 3 ~C 5 Cycloalkyl; the substituent is selected from hydrogen, methyl, ethyl, OH, methoxy, ethoxy, F, Cl, Br, I, cyano, cyclopropyl, cyclobutyl, cyclopentyl, aziridine-1-yl, acridin-1-yl or pyrrolidin-1-yl, and the substituent is monosubstituted or polysubstituted.

[0016] Preferably, in the structure:

[0017] X is selected from Where R 3 , R 4 Each is independently selected from hydrogen, halogen, methyl, ethyl, cyclopropyl, cyclobutyl, cycloalkyl, aziridine-1-yl, acridin-1-yl, pyrrolidin-1-yl, COOCH 3 、COOCH 2 CH 3 、COCH 3 ,CONH 2 、OCH 3 、OCH 2 CH 3 , CH 2 COOCH 3 or CH 2 COOCH 2 CH 3 ; R 5 Selected from hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, cycloalkyl, COOCH 3 、COOCH 2 CH 3 、COCH 3 ,CONH 2 , CH 2 COOCH 3 or CH 2 COOCH 2 CH 3 .

[0018] Preferably, in the structure:

[0019] R 1 , R 2Each of the following is independently selected from halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, vinyl, propenyl, allyl, propen-2-yl, n-butenyl, 2-methylpropen-1-yl, 2-methylallyl, methoxy, ethoxy, n-propoxy, isopropoxy, 2-methylpropoxy, methoxymethyl, ethoxymethyl, isopropoxymethyl, cyclopropyl, cyclobutyl, cycloalkyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, aziridine-1-yl, acridin-1-yl or pyrrolidin-1-yl.

[0020] Preferably, in the structure:

[0021] X is selected from -O- or Where R 3 , R 4 are each independently selected from hydrogen, halogen, methyl, cyclopropyl, cyclobutyl, cycloalkyl, aziridine-1-yl, acridin-1-yl, pyrrolidin-1-yl, COOCH 3 、COOCH 2 CH 3 ,CONH 2 , CH 2 COOCH 3 or CH 2 COOCH 2 CH 3 ; R 5 Selected from hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, cycloalkyl, COOCH 3 、COOCH 2 CH 3 ,CONH 2 , CH 2 COOCH 3 or CH 2 COOCH 2 CH 3 .

[0022] Preferably, the substituted phenol compound of the present invention is selected from any one of the following compounds:

[0023]

[0024]

[0025]

[0026] The pharmaceutically acceptable salts described in the present invention are salts formed by the substituted phenol compounds described in the present invention and any one of the following acids or bases: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, malic acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ferulic acid, alkaline earth metal cation base or alkali metal cation base.

[0027] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents discovered by the present invention with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates, sulfuric acid (forming sulfates or bisulfates), hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, Citric acid, tartaric acid and methanesulfonic acid and similar acids; organic acid salts also include amino acids (such as arginine, etc.), glucuronic acid and other organic acid salts. Certain specific compounds of the present invention contain basic and acidic functional groups, and can be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubility in polar solvents.

[0028] The "pharmaceutically acceptable salts" of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0029] The preparation method of the substituted phenol compound of the present invention is to prepare the compound I by bromination, hydroxyl protection, coupling and dehydroxyl protection reaction of compound II.

[0030]

[0031] Where p, q, R 1 , R 2 , X is defined as above; R h is a protecting group for a phenolic hydroxyl group, specifically selected from benzyl (Bn), p-methoxybenzyl (PMB), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS) or triisopropylsilyl (TIPS).

[0032] Specifically, compound III is prepared from compound II by dissolving compound II in a solvent and adding a brominating agent to carry out a substitution reaction. The brominating agent used is selected from bromine, N-bromosuccinimide (NBS), dibromohydantoin, preferably NBS. The solvent is selected from methanol, ethanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or a mixed solvent of any two of them, preferably acetonitrile.

[0033] The preparation of IV from compound III is to dissolve compound III in a solvent, add R h -X(R h is a hydroxyl protecting group) and an acid binding agent through a substitution reaction. h -X is selected from Bn-Br, PMB-Cl, TMS-Cl, TES-Cl, TBDMS-Cl, TIPS-Cl, etc., preferably Bn-Br; the acid binding agent used is selected from N,N-diisopropylethylamine (DIEA), triethylamine, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, potassium carbonate, sodium carbonate, cesium carbonate or sodium bicarbonate, preferably potassium carbonate; the solvent used is selected from acetone, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or a mixed solvent of any two thereof, preferably acetone.

[0034] The preparation of VI from compound IV is to dissolve compound IV and V in a solvent, add a catalyst, a ligand and a base to carry out a Buchwald coupling reaction under heating. The base used is selected from N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, potassium carbonate, sodium carbonate, cesium carbonate or sodium bicarbonate, preferably sodium tert-butoxide; the catalyst used is selected from tris(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium, 1,1-bis(diphenylphosphine)diferropalladium dichloride (DPPF palladium dichloride), palladium acetate or dichlorobis[(1,2,3)-1-phenyl-2-propylene]dipalladium, preferably dichlorobis[(1,2,3)-1-phenyl-2-propylene]dipalladium; the ligand used is selected from 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-(dicyclohexylphosphine)-3,6-di Methoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine or 5-di-tert-butylphosphino-1',3',5'-triphenyl-1'H-[1,4']dipyrazole, preferably 5-di-tert-butylphosphino-1',3',5'-triphenyl-1'H-[1,4']dipyrazole; the solvent used is selected from toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or a mixed solvent of any two thereof, preferably toluene; the reaction temperature is preferably 60-80°C.

[0035] Compound I is prepared from compound VI by dissolving compound VI in a solvent and then adding a corresponding deprotection reagent to react. h When Bn is used, the deprotection agent is preferably H 2 / Pd / C; the solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or a mixed solvent of any two thereof, preferably methanol.

[0036] The compound I prepared by the above method is salified with a pharmaceutically acceptable acid or base to obtain the pharmaceutically acceptable salt.

[0037] The pharmaceutical composition of the present invention contains the substituted phenol compound of the present invention and a pharmaceutically acceptable carrier.

[0038] The pharmaceutically acceptable carrier can be an adjuvant widely used in the field of drug production. The adjuvant is mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical adjuvant can be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical adjuvant can include one or more of the following adjuvants: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0039] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0040] The pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be a controlled release or sustained release dosage form (e.g., liposomes or microspheres). Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of preparations for parenteral administration include, but are not limited to, solutions for injection, dry powder preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0041] The substituted phenol compound or the pharmaceutical composition thereof described in the present invention is used for preparing sedative, hypnotic, analgesic and anesthetic drugs.

[0042] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0043] The compound designed in the present invention significantly improves safety by optimizing the structure of propofol, and has excellent anesthetic effect, is easy to prepare into various preparation forms, is conducive to clinical application in various administration forms, has a novel structure, and is simple in preparation method. DETAILED DESCRIPTION

[0044] The technical solution of the present invention is further described below in conjunction with embodiments.

[0045] Example 1: Synthesis of 4-(1,4-diazepan-1-yl)-2,6-diisopropylphenol (I-1)

[0046] Synthesis of 4-bromo-2,6-diisopropylphenol (III-1)

[0047] Propofol (25.00 g, 0.14 mol) was dissolved in acetonitrile (200 mL), cooled and stirred at 0°C for 30 min, and NBS (24.91 g, 0.14 mol) was slowly added in batches. The reaction solution gradually changed from colorless and clear to yellow turbid. After the addition was completed, it was stirred at 0°C for 2 h. TLC (V 石油醚 :V 乙酸乙酯 =20:1) After monitoring the reaction of the raw materials, water (100 mL) was added to the reaction system to quench the reaction. Ethyl acetate (100 mL × 3) was extracted three times, water (100 mL × 3) was washed three times, and saturated brine (200 mL) was washed once. The organic layers were combined, dried over anhydrous sodium sulfate, purified by silica gel column chromatography (petroleum ether), and concentrated under reduced pressure to remove the solvent to obtain 28.37 g of a yellow oil, with a yield of 78.8%. 1 H NMR (400MHz, Chloroform-d) δ7.74 (s, 1H), 7.14 (s, 2H), 3.17-3.05 (m, 2H), 1.24 (d, J = 6.8Hz, 12H).

[0048] Synthesis of 2-Benzyloxy-5-bromo-1,3-diisopropylbenzene (IV-1)

[0049] III-1 (14.70 g, 0.06 mol) was added to a 250 mL three-necked flask and dissolved in 100 mL of acetone. The reaction solution was yellow and clear. K 2 CO 3 (11.80 g, 0.09 mol), stirred at room temperature for 10 min, added BnBr (10.26 g, 0.06 mol) to the reaction solution, heated to reflux for 1.5 h, TLC (V 石油醚 :V 乙酸乙酯 =20:1) monitor the reaction completion of the raw materials, add ethyl acetate (100 mL) to dilute, add water (100 mL) and ethyl acetate (100 mL×3) to extract three times, combine the organic layers, wash once with saturated brine (300 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, recrystallize from n-hexane (100 mL), cool and crystallize, filter and dry to obtain 18.98 g of a yellow solid, yield: 95.6%. 1H NMR (300 MHz, DMSO-d 6 )δ8.74(s,1H),7.50-7.32(m,5H),6.47(s,2H),4.66(s,2H),3.66(t,J=5.0Hz,2H),3.47(t,J =5.9Hz,2H),3.31-3.21(m,4H),3.17-3.10(m,2H),2.11-2.00(m,2H),1.19(d,J=6.8Hz,12H).

[0050] Synthesis of 1-(4-Benzyloxy)-3,5-diisopropylphenyl)-1,4-diazepane (VI-1)

[0051] IV-1 (5.00 g, 14.45 mmol), 1,4-diazacycloheptane (V-1) (1.70 g, 17.33 mmol), sodium tert-butoxide (2.79 g, 0.03 mol), dichlorobis[(1,2,3)-1-phenyl-2-propylene]dipalladium (362 mg, 0.70 mmol), 5-di-tert-butylphosphine-1',3',5'-triphenyl-1'H-[1,4']dipyrazole (725 mg, 1.43 mmol) were added to a 250 mL three-necked flask, 60 mL of toluene was added to dissolve, and N 2 The air was replaced three times, and the reaction was heated at 60°C for 2 h. TLC (V 二氯甲烷 :V 甲醇 =10:1) to monitor the reaction of the raw materials, filter with diatomaceous earth, wash the filter cake with ethyl acetate (30 mL) three times, combine the organic layers, add water (80 mL) to dilute, extract with ethyl acetate (50 mL×3) three times, combine the organic layers, wash three times with water (100 mL×3), wash once with saturated sodium chloride aqueous solution (150 mL), dry over anhydrous sodium sulfate, and purify by silica gel column chromatography (V 二氯甲烷 :V 甲醇 =60:1~30:1), and concentrated under reduced pressure to remove the solvent to obtain 3.87 g of brown solid. The yield is 73.3%. 1 H NMR (300 MHz, DMSO-d 6 )δ8.74(s,1H),7.50-7.32(m,5H),6.47(s,2H),4.66(s,2H),3.66(t,J=5.0Hz,2H),3.47(t,J =5.9Hz,2H),3.31-3.21(m,4H),3.17-3.10(m,2H),2.11-2.00(m,2H),1.19(d,J=6.8Hz,12H).

[0052] Synthesis of 4-(1,4-diazepan-1-yl)-2,6-diisopropylphenol (I-1)

[0053] VI-1 (300 mg, 0.82 mmol) was added to a 50 mL three-necked bottle, and anhydrous methanol (6 mL) was added to dissolve. The reaction solution was yellow and clear. 10% Pd / C (30 mg) and H 2 The air was replaced three times, and the mixture was stirred at room temperature for 12 hours. TLC (V 二氯甲烷 :V 甲醇 =20:1) to monitor the complete reaction of the raw materials, filter with diatomaceous earth, wash the filter cake with ethyl acetate (5 mL×3) three times, and purify it by silica gel column chromatography (V 二氯甲烷 :V 甲醇 =40:1~20:1), and concentrated under reduced pressure to remove the solvent to obtain 206 mg of a yellow solid. The yield was 91.2%. 1 H NMR (300 MHz, DMSO-d 6 )δ9.10(s,1H),6.92-6.84(m,1H),6.70(s,2H),3.52(t,J=7.1Hz,2H),3.33 -3.14(m,4H),2.87-2.64(m,4H),1.91-1.75(m,2H),1.18(d,J=6.8Hz,12H).

[0054] The synthesis of compounds I-2, I-3, I-4, I-5, I-6, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23 is as follows:

[0055]

[0056]

[0057] Example 2: Evaluation of the anesthetic effect of compounds

[0058] 1. Experimental Animals

[0059] Grade and strain: SPF grade ICR mice;

[0060] Animal management: Animals are raised and managed by personnel who have obtained the qualification of laboratory animal management;

[0061] Age, number, and sex at the time of purchase: SPF-grade ICR male mice, 4-6 weeks, 18-22 g, manufacturer: Hangzhou Medical College, animal quality certificate: SCXK (Su) 2024-0001;

[0062] Breeding unit: Experimental Animal Center, China Pharmaceutical University, use license number: SYXK(Su)2023-0019;

[0063] Quarantine process: Animal quarantine observation is 3 to 5 days, during which the animal's appearance, behavioral activities, weight, diet and other indicators are observed.

[0064] 2. Experimental methods

[0065] Pharmacodynamic study of some compounds of the present invention in mice: Before the experiment, the ICR mice were fasted for 12 hours and allowed to drink water freely. Propofol and each test compound were administered by tail vein injection of mice, the dosage was set to 26 mg / kg, the administration speed was controlled to be completed in 10 seconds, and there were 5 mice in each group. After successful tail vein administration, the loss of righting reflex (LORR) phenomenon of mice for more than 30 seconds was regarded as induced anesthesia; if the mouse was able to right itself twice, it was regarded as the return of righting reflex (RRR) phenomenon, and it was regarded as recovery; when the animal woke up and had purposeful exploration, it was regarded as recovery (Recovery). During the experiment, the behavioral activities, respiratory changes and more significant adverse reactions of the mice during the experiment were observed. The administration time, onset time (i.e., the time it takes for the LORR phenomenon to occur after the tail vein injection of the mouse), duration time (i.e., the time it takes for the mouse to experience the LORR phenomenon and the RRR phenomenon) and recovery time (i.e., the time it takes for the mouse to experience the RRR phenomenon and fully recover) of the ICR mice were recorded. Propofol and each compound were dissolved and prepared into the required concentration using 5% to 10% DMSO, 5% to 15% solutol (HS-15) and 75% to 90% saline.

[0066] 3. Experimental results

[0067] The anesthetic onset time, average duration, and average recovery time of propofol and each test compound are shown in Table 1.

[0068] Table 1 Experimental data of mouse anesthetic activity test

[0069] drug Onset time(s) Average duration (s) Average recovery time (s) I-2 5～10 320±16 634±32 I-3 20～75 145±12 312±11 I-8 60～95 110±10 70±5 I-9 43～134 192±12 212±15 I-10 35～88 174±11 197±17 Propofol 0～5 366±21 723±32

[0070] The results in Table 1 show that many compounds of the present invention have excellent anesthetic effects.

[0071] Example 3: Safety evaluation of compounds

[0072] 1. Experimental Animals

[0073] Grade and strain: SPF grade ICR mice;

[0074] Animal management: Animals are raised and managed by personnel who have obtained the qualification of laboratory animal management;

[0075] Age, number, and sex at the time of purchase: SPF-grade ICR male mice, 4-6 weeks, 18-22 g; SPF-grade ICR female mice, 4-6 weeks, 18-20 g; manufacturer: Hangzhou Medical College; animal quality certificate: SCXK (Su) 2024-0001;

[0076] Breeding unit: Experimental Animal Center, China Pharmaceutical University, use license number: SYXK(Su)2023-0019;

[0077] Quarantine process: Animal quarantine observation is 3 to 5 days, during which the animal's appearance, behavioral activities, weight, diet and other indicators are observed.

[0078] 2. Experimental methods

[0079] Safety study of some compounds of the present invention in mice: Before the experiment, the ICR mice were divided into 12 groups, half male and half female, with 6 mice in each group. The female mice in the 6 groups were injected with propofol and compound I-2 at a dose of 20 mg / kg, 40 mg / kg and 80 mg / kg, respectively, and the male mice in the 6 groups were also injected with propofol and compound I-2 at a dose of 20 mg / kg, 40 mg / kg and 80 mg / kg. The mice were observed for 7 consecutive days, and the survival of each group of mice was recorded. The LD 50 =log -1 [X m -i(Σp-0.5)] to calculate the LD of propofol and the tested compounds 50 , where Xm is the logarithm of the dose in the maximum mortality group; i is the logarithm of the ratio of adjacent doses; Σp is the sum of the mortality rates of each group. Propofol and each compound were dissolved and prepared into the required concentration using 5% to 10% DMSO, 5% to 15% solutol (HS-15) and 75% to 90% saline.

[0080] 3. Experimental results

[0081] LD of propofol and test compound I-2 50 As shown in Table 2.

[0082] Table 2 Experimental data of safety test of propofol and compound I-2 in mice

[0083] drug <![CDATA[LD 50 (mg / kg)]]> I-2 77.62 Propofol 40

[0084] The results in Table 2 show that the safety of compound I-2 of the present invention is better than that of propofol.

Claims

1. A substituted phenol compound, characterized in that: Having the structure of formula (I), the compound includes a pharmaceutically acceptable salt thereof, in: p, q are independently selected from 1, 2 or 3; R 1 , R 2 Each of the substituents is independently selected from halogen, substituted C1-C6 alkyl, substituted C2-C6 alkenyl, substituted C1-C3 alkoxy or substituted C3-C6 cycloalkyl; the substituent is selected from hydrogen, C1-C3 alkyl, OH, C1-C6 alkoxy, halogen, nitro, cyano, C3-C6 cycloalkyl or four- to seven-membered heterocycloalkyl, the heterocycloalkyl is selected from a four-, five-, six- or seven-membered saturated or unsaturated heterocycle containing 1 to 2 O, N or S ring heteroatoms; the substituent is monosubstituted or polysubstituted; X is selected from Where R 3 , R 4 Each is independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C3-C6 cycloalkyl, three- to six-membered heterocycloalkyl, COOR a , COR b , OR c or CH2COOR d ; R 5 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, three- to six-membered heterocycloalkyl, COOR a , COR b or CH2COOR d ; R a , R b , R c , R d Each is independently selected from hydrogen, -NH2, C1-C3 alkyl, C3-C6 cycloalkyl or four to seven membered heterocycloalkyl; the heterocycloalkyl is selected from a four-membered, five-membered, six-membered or seven-membered saturated or unsaturated heterocycle containing 1 to 2 O, N or S ring heteroatoms.

2. The substituted phenol compound according to claim 1, characterized in that In the structure: p, q are independently selected from 1, 2 or 3; R 1 , R 2 They are independently selected from halogen, substituted C1-C3 alkyl, substituted C2-C4 alkenyl, substituted C1-C3 alkoxy or substituted C3-C5 cycloalkyl; the substituents are selected from hydrogen, methyl, ethyl, OH, methoxy, ethoxy, F, Cl, Βr, Ι, cyano, cyclopropyl, cyclobutyl, cyclopentyl, aziridine-1-yl, acridin-1-yl or pyrrolidin-1-yl, and the substituents are monosubstituted or polysubstituted.

3. The substituted phenol compound according to claim 1 or 2, characterized in that: In the structure: X is selected from Where R 3 , R 4 R is independently selected from hydrogen, halogen, methyl, ethyl, cyclopropyl, cyclobutyl, cycloalkyl, aziridine-1-yl, acridin-1-yl, pyrrolidin-1-yl, COOCH3, COOCH2CH3, COCH3, CONH2, OCH3, OCH2CH3, CH2COOCH3 or CH2COOCH2CH3; 5 is selected from hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, cycloalkyl, COOCH3, COOCH2CH3, COCH3, CONH2, CH2COOCH3 or CH2COOCH2CH3.

4. The substituted phenol compound according to claim 1 or 2, characterized in that: In the structure: R 1 , R 2 Each of the following is independently selected from halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, vinyl, propenyl, allyl, propen-2-yl, n-butenyl, 2-methylpropen-1-yl, 2-methylallyl, methoxy, ethoxy, n-propoxy, isopropoxy, 2-methylpropoxy, methoxymethyl, ethoxymethyl, isopropoxymethyl, cyclopropyl, cyclobutyl, cycloalkyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, aziridine-1-yl, acridin-1-yl or pyrrolidin-1-yl.

5. The substituted phenol compound according to claim 1 or 2, characterized in that: In the structure: X is selected from Where R 3 , R 4 R is independently selected from hydrogen, halogen, methyl, cyclopropyl, cyclobutyl, cycloalkyl, aziridine-1-yl, acridin-1-yl, pyrrolidin-1-yl, COOCH3, COOCH2CH3, CONH2, CH2COOCH3 or CH2COOCH2CH3; 5 Selected from hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, cycloalkyl, COOCH3, COOCH2CH3, CONH2, CH2COOCH3 or CH2COOCH2CH3.

6. The substituted phenol compound according to claim 1 or 2, characterized in that: Any one of the following compounds: 4-(1,4-diazepan-1-yl)-2,6-diisopropylphenol (I-1), 4-(4,4-difluoropiperidin-1-yl)-2,6-diisopropylphenol (I-2), 4-(3,3-difluoropiperidin-1-yl)-2,6-diisopropylphenol (I-3), 1-(4-hydroxy-3,5-diisopropylphenyl)azetidine-3-carboxylic acid methyl ester (I-4), 1-(4-hydroxy-3,5-diisopropylphenyl)azetidine-3-carboxylic acid ethyl ester (I-5), 2,6-diisopropyl-4-(4-methylpiperidin-1-yl)phenol (I-6), 4-(3,3-difluoropyrrolidin-1-yl)-2,6-diisopropylphenol (I-7), 2,6-diisopropyl-4-(4-methyl-1,4-diazepan-1-yl)phenol (I-8), 2,6-diisopropyl-4-(3-methylazetidin-1-yl)phenol (I-9), 4-(azetidin-1-yl)-2,6-diisopropylphenol (I-10), 2,6-di-tert-butyl-4-(4,4-difluoropiperidin-1-yl)phenol (I-11), 2,6-di-tert-butyl-4-(3-methylazetidin-1-yl)phenol (I-12), 2,6-di-tert-butyl-4-(1,4-diazepan-1-yl)phenol (I-13), 2,6-diisopropyl-4-morpholinylphenol (I-14), 2-(4-(4-hydroxy-3,5-diisopropylphenyl)-1,4-diazepan-1-yl)acetic acid methyl ester (I-15), Cyclopropyl (4-(4-hydroxy-3,5-diisopropylphenyl)-1,4-diazepan-1-yl)methanone (I-16), 1-(4-(4-hydroxy-3,5-diisopropylphenyl)-1,4-diazepan-1-yl)ethan-1-one (I-17), 2-allyl-6-(tert-butyl)-4-(4,4-difluoropiperidin-1-yl)phenol (I-18), 2-Cyclopropyl-4-(4,4-difluoropiperidin-1-yl)-6-isopropylphenol (I-19), 2-Cyclopropyl-4-(3,3-difluoropiperidin-1-yl)-6-isopropylphenol (I-20), 4-(4,4-difluoropiperidin-1-yl)-2-isopropyl-6-(trifluoromethoxy)phenol (I-21), 4-(4,4-difluoropiperidin-1-yl)-2-isopropyl-6-(trifluoromethyl)phenol (I-22), 4-(3,3-Difluoropiperidin-1-yl)-2-isopropyl-6-(trifluoromethyl)phenol (I-23).

7. The substituted phenol compound according to claim 1 or 2, characterized in that: The pharmaceutically acceptable salt is a salt formed by the compound and any one of the following acids or bases: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, malic acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ferulic acid, alkaline earth metal cation base or alkali metal cation base.

8. A method for preparing a substituted phenol compound according to claim 1, characterized in that: Compound I is prepared from compound II through bromination, hydroxy protection, coupling and dehydroxy protection reactions. Where p, q, R 1 , R 2 , X is defined as in claim 1, R h is selected from benzyl, p-methoxybenzyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl or triisopropylsilyl; The compound I prepared by the above method is salified with a pharmaceutically acceptable acid or base to obtain the pharmaceutically acceptable salt.

9. A pharmaceutical composition, characterized in that Contains the substituted phenol compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.

10. Use of the substituted phenol compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 9 in the preparation of sedative, hypnotic, analgesic and anesthetic drugs.

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