Ferulic acid ester derivatives and preparation methods, pharmaceutical compositions and applications thereof

Abstract

The present invention relates to the field of medicinal chemistry, and discloses ferulic acid ester derivatives, preparation methods, pharmaceutical compositions, and applications thereof. The ferulic acid ester derivatives have the general structural formula: #imgabs0# R2 is selected from -H, -CH3, or -OCH3; R3 and R5 are independently selected from -H, -CH3, -OCH3, -CH(CH3)2, or -CH(CH2)2; R4 is selected from -H or -CH3; R6 is selected from -H, -CH3, or -OCH3; hydrogen atoms are independently selected from protium, deuterium, or tritium; oxygen atoms are independently selected from 16 O. 17 O or 18 O; carbon atoms are independently selected from 11 C. 12 C. 13 C or 14 C. The present invention obtains a ferulic acid ester derivative by esterification coupling ferulic acid and propofol, which enhances chemical stability and improves the ability to penetrate the blood-brain barrier. Ferulic acid and propofol are simultaneously released in the brain, maintaining the same pharmacokinetics, combining the efficacy of ferulic acid and propofol, and having a neuroprotective effect.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to ferulic acid ester derivatives, preparation methods thereof, pharmaceutical compositions and applications thereof. Background Art

[0002] Ferulic acid is a naturally occurring phenolic acid compound first isolated and extracted from Ferula foetida regei by German researcher Hlasweta H in 1866. This organic acid is named "ferulic acid" for its source. Subsequently, it was discovered to be widely distributed in the seeds and leaves of various plants, including angelica sinensis, Chuanxiong rhizome, asafoetida, Cimicifuga heracleifolia, and Ziziphus jujuba seeds. Studies have shown that ferulic acid possesses excellent antioxidant properties, scavenging free radicals and inhibiting tyrosinase activity, thereby reducing melanin formation in the body. It also possesses antibacterial properties, with inhibitory effects against Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and yeast. It can inhibit collagen- and ADP-induced platelet aggregation, suppress the release of thromboxane-like substances, and selectively inhibit the activity of thromboxane synthase, thereby preventing thrombosis and improving cardiovascular health. Based on the diverse pharmacological effects of ferulic acid, scientists have begun developing it into various drugs. For example, sodium ferulate injection is used to treat ischemic cardiovascular and cerebrovascular diseases, and piperazine ferulate tablets are used as an adjunctive treatment for glomerular diseases associated with microscopic hematuria and hypercoagulability.

[0003] Ferulic acid-related drugs have also demonstrated advantages and potential in the fields of neuroprotection and antidepressant effects. For example, sodium ferulate has strong antioxidant capacity, scavenging free radicals in the body and reducing damage to the nervous system caused by oxidative stress and inflammatory responses. Furthermore, it is an NMDAR (N-methyl-D-aspartate receptor) antagonist, inhibiting excitotoxicity caused by overactivation of the glutamate system, thereby protecting nerve cells from damage. Furthermore, sodium ferulate can promote the proliferation of neurons and neural stem cells, increase the expression of brain-derived neurotrophic factor (BDNF) and its downstream target genes, improve neuronal atrophy, and reduce neuronal apoptosis. BDNF plays a key role in memory formation and storage, and increasing its levels can help alleviate depressive symptoms. Furthermore, sodium ferulate can affect the levels of monoamine neurotransmitters such as serotonin (5-HT), norepinephrine (NE), and dopamine (DA), which regulate mood and behavior, and has demonstrated significant antidepressant-like effects in animal models. These research results of ferulic acid show that it has excellent prospects in neuroprotection and anti-depression, and is of great significance for the prevention and treatment of various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and depression.

[0004] According to ChemDraw calculation, the Log P value of ferulic acid is 1.42, and the topological polar surface area (tPSA) is Therefore, its chemical polarity is relatively large, its passive diffusion permeability is low, and its absorption and ability to pass through the blood-brain barrier are poor. It needs to be chemically modified to retain its excellent properties in neuroprotection and antidepressant properties. Therefore, starting from ferulic acid, the clinically mature intravenous anesthetic drug propofol is coupled through chemical synthesis to develop a neuroprotective anesthetic and a potential new antidepressant drug, which has important research significance for the discovery of a new generation of anesthetics. It should also be noted that propofol is a short-acting intravenous anesthetic. Since it was officially put into clinical use in 1986, it has been widely used in general anesthesia and small operations or examinations with short surgical time due to its good sedative and hypnotic effects. In recent years, researchers have found that propofol often makes patients feel happy and relaxed while bringing hypnosis and sedation. This phenomenon has attracted the attention of researchers to the antidepressant potential of propofol. By systematically screening the effects of propofol on different neurotransmitter systems in the brain, the researchers found that propofol can specifically bind to dopamine transporters, partially blocking the reuptake process of dopamine molecules, thereby causing an increase in dopamine levels in the nucleus accumbens, the brain's reward center, and regulating the activity of specific neurons, thereby participating in the formation of pleasure.

[0005] Studies have shown that certain doses of general anesthetics may accelerate the progression of postoperative dementia and AD in some elderly surgical patients (especially those with AD and those with AD-susceptibility genes). Currently used anesthetics in clinical practice may have certain neurotoxic properties. Therefore, there is a need to develop new anesthetics with potential neuroprotective properties to reduce the neurotoxicity of clinically used anesthetics and provide a foundation for subsequent in-depth clinical research and mechanism exploration.

[0006] Therefore, the existing technology still needs to be improved and developed. Summary of the Invention

[0007] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide ferulic acid ester derivatives and their preparation methods, pharmaceutical compositions and applications, aiming to solve the problem that the prior art lacks new anesthetics with neuroprotective functions to reduce the neurotoxicity of anesthetics used clinically.

[0008] The technical solutions of the present invention are as follows:

[0009] The first aspect of the present invention provides a ferulic acid ester derivative, wherein the general structural formula of the ferulic acid ester derivative is shown in formula (I):

[0010]

[0011] wherein R2 is selected from -H, -CH3 or -OCH3; R3 is selected from -H, -CH3, -OCH3, -CH(CH3)2 or -CH(CH2)2; R4 is selected from -H or -CH3; R5 is selected from -H, -CH3, -OCH3, -CH(CH3)2 or -CH(CH2)2; R6 is selected from -H, -CH3 or -OCH3;

[0012] In the formula, all hydrogen atoms are independently selected from protium, deuterium or tritium; all oxygen atoms are independently selected from 16 O. 17 O or 18 O; all carbon atoms are independently selected from 11 C. 12 C. 13 C or 14 C.

[0013] Optionally, the ferulic acid ester derivative is a compound represented by formula FPE-1, FPE-2, FPE-3 and FPE-4:

[0014]

[0015] The second aspect of the present invention provides a method for preparing the ferulic acid ester derivative, comprising the steps of:

[0016] S1. Compound a and malonic acid are dissolved in pyridine and reacted under the catalysis of piperidine to obtain compound b;

[0017] S2, the compound b and tert-butyldimethylsilyl chloride are dissolved in dichloromethane, and reacted under the alkaline condition of N,N-diisopropylethylamine to obtain compound c;

[0018] S3, dissolving the compound c in tetrahydrofuran, adding potassium carbonate, and reacting to obtain compound d;

[0019] S4, dissolving the compound d, N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine in dichloromethane, adding propofol, and reacting to obtain compound e;

[0020] S5, dissolving the compound e and tetrabutylammonium fluoride in tetrahydrofuran, and reacting to obtain the ferulic acid ester derivative;

[0021] Wherein, the chemical structural formulas of the compounds a to e are:

[0022]

[0023]

[0024] In the above chemical structure, R2 is selected from -H, -CH3 or -OCH3; R3 is selected from -H, -CH3, -OCH3, -CH(CH3)2 or -CH(CH2)2; R4 is selected from -H or -CH3; R5 is selected from -H, -CH3, -OCH3, -CH(CH3)2 or -CH(CH2)2; R6 is selected from -H, -CH3 or -OCH3; R x Selected from -TBS or -CH3; in the structural formula, all hydrogen atoms are independently selected from protium, deuterium or tritium; all oxygen atoms are independently selected from 16 O. 17 O or 18 O; all carbon atoms are independently selected from 11 C. 12 C. 13 C or 14 C.

[0025] Optionally, in step S1, the reaction temperature is 45-90° C., and the reaction time is 1-3 hours.

[0026] Optionally, in step S2, the reaction temperature is 20-30° C., and the reaction time is 12-24 h; and / or the molar ratio of the tert-butyldimethylsilyl chloride to the compound b is (2-4):1.

[0027] Optionally, in step S3, the reaction temperature is 20-30° C., and the reaction time is 2-8 h; and / or the molar ratio of potassium carbonate to compound c is (2-3):1.

[0028] Optionally, in step S4, the reaction temperature is 20-30° C., and the reaction time is 24-72 h; and / or the molar ratio of propofol to compound d is (0.8-3):1.

[0029] Optionally, in step S5, the reaction temperature is 20-30° C., and the reaction time is 0.5-2 h; and / or the molar ratio of tetrabutylammonium fluoride to compound e is (1.5-2):1.

[0030] The third aspect of the present invention provides a pharmaceutical composition, which comprises the ferulic acid ester derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier; the pharmaceutical carrier comprises one or more of a tabletting agent, a binder, a stabilizer, a buffer, a colorant, a diluent, a disintegrant, an emulsifier, a flavoring agent, a glidant, a lubricant, a preservative, a surfactant and a wetting agent.

[0031] The fourth aspect of the present invention provides a use of the ferulic acid ester derivative or the pharmaceutical composition in the preparation of a drug for inducing anesthesia, improving cognitive function, anti-inflammation, neuroprotection, antithrombosis, antidepression or improving anxiety.

[0032] The present invention has the following beneficial effects:

[0033] The invention uses ferulic acid and propofol as pharmacophores, uses dicyclohexylcarbodiimide (DCC) as a dehydration condensation agent to perform esterification coupling on the two to form a novel propofol ferulate (FPE), and then performs structural modification to obtain the ferulic ester derivative. The ferulic acid ester derivative provided by the present invention achieves the following by covalently coupling ferulic acid and propofol: 1) Ferulic acid is chemically unstable and has poor lipid solubility, and esterification of its carboxylic acid group can enhance its chemical stability, reduce the polarity of the compound, and improve its ability to penetrate the blood-brain barrier; 2) The ester bond of FPE is easily degraded under the catalysis of esterase, releasing ferulic acid and propofol simultaneously in the brain, and maintaining the same pharmacokinetics of the two; 3) The pharmacological effects of ferulic acid and propofol are combined. By combining the strong anti-oxidative stress, anti-inflammatory, and antidepressant effects of ferulic acid with the anesthetic or antidepressant effects of propofol, a potential new anesthetic or antidepressant with neuroprotective function is obtained, which can reduce neurotoxic effects on patients during surgical anesthesia or post-operative surgery. DETAILED DESCRIPTION

[0034] The present invention provides ferulic acid ester derivatives and their preparation methods, pharmaceutical compositions, and applications. To make the objectives, technical solutions, and effects of the present invention more clear and explicit, the present invention is further described below in detail. It should be understood that the specific embodiments described herein are intended only to illustrate the present invention and are not intended to limit the present invention.

[0035] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0036] An embodiment of the present invention provides a ferulic acid ester derivative, the general structural formula of the ferulic acid ester derivative is shown in Formula (I):

[0037]

[0038] wherein R2 is selected from -H, -CH3 or -OCH3; R3 is selected from -H, -CH3, -OCH3, -CH(CH3)2 or -CH(CH2)2; R4 is selected from -H or -CH3; R5 is selected from -H, -CH3, -OCH3, -CH(CH3)2 or -CH(CH2)2; R6 is selected from -H, -CH3 or -OCH3;

[0039] In formula (I), all hydrogen atoms are independently selected from protium, deuterium or tritium; all oxygen atoms are independently selected from 16 O. 17 O or 18 O; all carbon atoms are independently selected from 11 C. 12 C. 13 C or 14 C.

[0040] The present invention also provides a method for preparing the ferulic acid ester derivative, comprising the steps of:

[0041] a), compound a and malonic acid are dissolved in pyridine, and reacted under the catalysis of piperidine to obtain compound b;

[0042] b), the compound b and tert-butyldimethylsilyl chloride (TBSCl) are dissolved in dichloromethane (DCM), and reacted under alkaline conditions of N,N-diisopropylethylamine (DIPEA) to obtain compound c;

[0043] c), dissolving the compound c in tetrahydrofuran (THF), adding potassium carbonate, and reacting to obtain compound d;

[0044] d), dissolving the compound d, N,N'-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) in dichloromethane, adding propofol, and reacting to obtain compound e;

[0045] e), dissolving the compound e and tetrabutylammonium fluoride (TBAF) in tetrahydrofuran, and reacting to obtain the ferulic acid ester derivative;

[0046] Wherein, the chemical structural formulas of the compounds a to e are:

[0047]

[0048] The synthetic route of the ferulic acid ester derivative is as follows:

[0049]

[0050] In the structural formulas shown in a to e above, R2 is selected from -H, -CH3 or -OCH3; R3 is selected from -H, -CH3, -OCH3, -CH(CH3)2 or -CH(CH2)2; R4 is selected from -H or -CH3; R5 is selected from -H, -CH3, -OCH3, -CH(CH3)2 or -CH(CH2)2; R6 is selected from -H, -CH3 or -OCH3; R x Selected from -TBS or -CH3; in the structural formula, all hydrogen atoms are independently selected from protium, deuterium or tritium; all oxygen atoms are independently selected from 16 O. 17 O or 18 O; all carbon atoms are independently selected from 11 C. 12 C. 13 C or 14 C.

[0051] The present invention uses ferulic acid and propofol as pharmacophores, and uses dicyclohexylcarbodiimide (DCC) as a dehydration condensation agent to esterify and couple the two to form a novel propofol ferulate (FPE), which is then structurally modified to obtain the ferulic acid ester derivative. Ferulic acid itself is chemically unstable and has poor lipid solubility. Esterification of its carboxylic acid group can enhance the chemical stability of the compound and reduce its polarity, thereby improving its ability to penetrate the blood-brain barrier. Furthermore, the ester bond in the ferulic acid ester derivative is easily degraded under the catalysis of esterases, releasing ferulic acid and propofol simultaneously in the brain, maintaining the same pharmacokinetics of the two. Furthermore, the ferulic acid ester derivative combines the pharmacological effects of ferulic acid and propofol. By combining the strong anti-oxidative stress, anti-inflammatory, and antidepressant effects of ferulic acid with the anesthetic or antidepressant effects of propofol, a potential new anesthetic or antidepressant with neuroprotective function is obtained, which reduces neurotoxic effects on patients during anesthesia or postoperative surgery.

[0052] In a specific embodiment, the ferulic acid ester derivative is a compound represented by the following formula FPE-1, FPE-2, FPE-3 and FPE-4:

[0053]

[0054] In some embodiments, in step S1, the reaction temperature is 45-90° C., and the reaction time is 1-3 hours.

[0055] In some embodiments, in step S2, the reaction temperature is 20-30° C., and the reaction time is 12-24 h; and / or the molar ratio of the tert-butyldimethylsilyl chloride to the compound b is (2-4):1.

[0056] In some embodiments, in step S3, the reaction temperature is 20-30° C., the reaction time is 2-8 h; and / or the molar ratio of potassium carbonate to compound c is (2-3):1.

[0057] In some embodiments, in step S4, the reaction temperature is 20-30° C., and the reaction time is 24-72 h; and / or the molar ratio of propofol to compound d is (0.8-3):1.

[0058] In some embodiments, in step S5, the reaction temperature is 20-30° C., the reaction time is 0.5-2 h; and / or the molar ratio of tetrabutylammonium fluoride to compound e is (1.5-2):1.

[0059] An embodiment of the present invention provides a pharmaceutical composition, comprising the ferulic acid ester derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier; the pharmaceutical carrier comprises one or more of a tabletting agent, a binder, a stabilizer, a buffer, a colorant, a diluent, a disintegrant, an emulsifier, a flavoring agent, a glidant, a lubricant, a preservative, a surfactant, and a wetting agent.

[0060] In specific embodiments, pharmaceutical carriers must be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the patient to be treated. Exemplary pharmaceutical carriers include, but are not limited to, sugars, malt, starch, cellulose, gelatin, tragacanth powder, talc, and vegetable oils. Some pharmaceutical carriers may also be listed in more than one category, e.g., vegetable oils (e.g., corn oil, castor oil, etc.) may be used as lubricants in some formulations and as diluents in others.

[0061] In a specific embodiment, in the pharmaceutical composition, the ferulic acid ester derivative can also be optionally administered together with other active agents, such as anesthetics, AD drugs, anti-inflammatory drugs, antithrombotic drugs, antidepressants, etc. For example, the anesthetic may be selected from ketamine, N2O, tramadol, midazolam, sevoflurane, isoflurane, fentanyl, sufentanil, etomidate; AD drugs may be selected from donepezil, rivastigmine, galantamine, memantine; anti-inflammatory drugs may be selected from aspirin, salsalate, diflunisal, para-aminosalicylic acid, phenacetin, acetaminophen, acemetacin, indomethacin, tolmetin, diclofenac sodium, indomethacin, ibuprofen, flurbiprofen axetil, naproxen, piroxicam, meloxicam, nabumetone, etc., sulindac, such as celecoxib, such as rofecoxib, hydrocortisone, dexamethasone acetate, prednisone methylprednisolone, dexamethasone; antithrombotic drugs may be selected from aspirin, clopidogrel, ticagrelor, dapoxetine ... Antidepressants can be selected from paroxetine, escitalopram oxalate, atomoxetine, feloctin, duloxetine, sertraline, citalopram, bupropion, venlafaxine, duloxetine, naltrexone, mirtazapine, venlafaxine, bupropion, doxepin, amitriptyline, clomipramine, clozapine, nortriptyline, aripiprazole, cetirizine, olanzapine, quetiapine, risperidone, buspirone, ziprasidone, carbamazepine, gabapentin, lamotrigine, phenytoin, pregabalin, rivastigmine, galantamine, memantine, rivastigmine, homotaurine or their pharmaceutically active salts or prodrugs. The above-mentioned optional activating agent does not substantially affect the activity of the ferulic acid ester derivatives in the pharmaceutical composition.

[0062] In some embodiments, the pharmaceutical composition is an oral dosage form comprising about 0.1 mg to about 900 mg, about 1 mg to about 600 mg, or about 10 mg to about 300 mg of the ferulic acid ester derivative or a pharmaceutically acceptable salt thereof and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 700 mg, or about 200 mg to about 500 mg of the other active agent in a unit dosage form.

[0063] The fourth aspect of the present invention provides a use of the ferulic acid ester derivative or the pharmaceutical composition in the preparation of a drug for inducing anesthesia, improving cognitive function, anti-inflammation, neuroprotection, antithrombosis, antidepression or improving anxiety.

[0064] In the application, the drug can be administered orally, topically, parenterally, by pulmonary inhalation or spray, sublingually, transdermally, orally, rectally, as an ophthalmic solution, intravenously, or by other means in a dosage unit formulation containing a conventional pharmaceutical carrier. The dosage form can be prepared according to conventional production methods in the pharmaceutical field, and the drug can also be formulated into any pharmaceutical form, such as: submicron emulsion, atomizer, tablet, cream, gel, pill, capsule, syrup, transdermal patch, injection, or ophthalmic solution. The present invention has developed a new type of anesthetic with neuroprotective function, which can reduce the neurotoxicity of anesthetics used clinically and provide a basis for subsequent in-depth clinical research and mechanism exploration.

[0065] The following describes it in detail through specific examples.

[0066] Example 1

[0067] Preparation of compound FPE-1

[0068] The synthetic route is:

[0069]

[0070] The specific steps were as follows: 1a (200 mg, 0.97 mmol, 1.0 equiv.) was accurately weighed into a 10 mL eggplant flask and placed in a rotor. Piperidine (29 μL, 0.29 mmol, 0.3 equiv.) and pyridine (1 mL) were added. After 10 minutes, malonic acid (152 mg, 1.45 mmol, 1.5 equiv.) was added, and the reaction system was stirred at 80°C for 1.5 hours. After completion of the reaction, the reaction was monitored by TLC, diluted with 20 mL of water, cooled to room temperature, and the pH was adjusted to 2-3 with 1N HCl to precipitate the crude product. The crude product was filtered through a Shaxi funnel, and the filter cake was dissolved in dichloromethane and dried over anhydrous magnesium sulfate. The organic phase was concentrated to approximately 1 mL. An appropriate amount of petroleum ether was added to precipitate the product, which was then filtered and dried in vacuo to afford 1b (226 mg, 90% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ=7.75(d,J=16Hz,1H),7.28(s,2H),6.33(d,J=16Hz,1H),5.13(br,1H),3.15(hept,J=5.8Hz,2H),1.29(d,J=5.8Hz,12H)ppm; 13 C NMR (100MHz, CDCl3): δ=172.9,152.8,147.8,134.3,126.6,124.4,114.0,27.2,22.6ppm.

[0071] Intermediate 1b (230 mg, 0.93 mmol, 1.0 equiv.) was accurately weighed into a 10 mL eggplant flask and placed on a rotor. N,N-diisopropylethylamine (483 μL, 2.79 mmol, 3.0 equiv.) and dichloromethane (2 mL) were added. Once the mixture was completely dissolved, tert-butyldimethylsilyl chloride (560 mg, 3.72 mmol, 4.0 equiv.) was slowly added portionwise. The reaction was stirred at room temperature for 20 h. After completion of the reaction, the dichloromethane was evaporated and ethyl acetate (30 mL) was added. The organic phase was washed with 1N HCl (2 × 15 mL) and saturated sodium chloride solution (15 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford the disilylated product 1c (432 mg, 98% yield) as a brown oil. 1 H NMR (400MHz, CDCl3): δ=7.57(d,J=15.6Hz,1H),7.22(s,2H),6.28(d,J=15.6Hz,1H),3.28(hept,( d,J=6.8Hz,2H),1.18(d,(d,J=6.8Hz,12H),1.01(d,J=6.8Hz,18H),0.33(s,6H),0.20(s,6H)ppm; 13 CNMR (100MHz, CDCl3): δ=167.4,151.7,145.8,139.8,128.0,123.9,117.4,26.7,26.1,25.8,23.3,18.9,17.9,-3.3,-4.6ppm.

[0072] Intermediate 1c (432 mg, 0.91 mmol, 1.0 equiv.) was accurately weighed into a 25 mL round-bottom flask and placed in a rotor. Potassium carbonate (330 mg, 2.41 mmol, 2.7 equiv.) and tetrahydrofuran (3 mL) were added, and the reaction system was stirred at room temperature for 6 h. After completion of the reaction, the tetrahydrofuran was dried by spin drying, and ethyl acetate (60 mL) was added. The organic phase was washed with 1N HCl (2 x 30 mL) and saturated sodium chloride solution (30 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford 1d (294 mg, 89% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ=7.76 (dd, J=16Hz, J=2Hz, 1H), 7.28 (s, 2H), 6.34 (dd, J=16Hz, J=2 Hz,1H),3.29(hept,J=5.2Hz,2H),1.18(d,J=5.2Hz,12H),1.03(s,9H),0.21(s,6H)ppm; 13C NMR (100MHz, CDCl3): δ=172.9,152.2,147.8,139.9,127.7,124.2,114.5,26.7,26.1,23.2,19.0,-3.3ppm.

[0073] Intermediate 1d (294 mg, 0.81 mmol, 1.0 equiv.) was accurately weighed into a 25 mL round-bottom flask and placed in a rotor. DCC N,N'-dicyclohexylcarbodiimide (184 mg, 0.89 mmol, 1.1 equiv.), 4-dimethylaminopyridine (10 mg, 0.08 mmol, 0.1 equiv.), and dichloromethane (6 mL) were added. After 30 minutes, propofol (312 μL, 1.62 mmol, 2.0 equiv.) was added, and the reaction system was stirred at room temperature for 48 hours. After completion of the reaction, monitored by TLC, an appropriate amount of 200-300 mesh silica gel was added and the sample was separated and purified by column chromatography (mobile phase ratio: petroleum ether / dichloromethane = 10 / 1) to afford 1e (240 mg, 57% yield), a white solid powder. 1 H NMR (400MHz, CDCl3): δ = 7.88 (d, J = 16.0Hz, 1H), 7.34 (s, 2H), 7.23-7.17 (m, 3H), 6.60 (d, J = 16.0Hz, 1H), 3.31 (hept, J=6.8Hz,2H),3.0(hept,J=6.8Hz,2H),1.21(d,J=6.8Hz,12H),1.20(d,J=6.8Hz,12H),1.03(s,9H),0.22(s,6H)ppm; 13 C NMR (100MHz, CDCl3): δ=166.1,152.2,147.2 145.7,140.7,140.1,127.8,126.4,124.2,123.9,114.2,27.5,26.7 26.1,23.3,19.0,-3.2ppm.

[0074] Intermediate 1e (240 mg, 0.46 mmol, 1.0 equiv.) was accurately weighed into a 10 mL round-bottom flask and placed in a rotor. Tetrahydrofuran (2 mL) was added, and after dissolution, 1N TBAF (1 mL, 0.92 mmol, 2.0 equiv.) was slowly added dropwise. The reaction system was stirred at room temperature for 1 h. After completion of the reaction, the tetrahydrofuran was dried by spin-drying, and ethyl acetate (60 mL) was added. The organic phase was washed with purified water (2 × 30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, and concentrated. An appropriate amount of 200-300 mesh silica gel was added and the sample was separated and purified by column chromatography (mobile phase ratio: petroleum ether / dichloromethane = 10 / 1). The organic solvent was evaporated under reduced pressure to obtain FPE-1 (182 mg, 97% yield) as a pale yellow solid. 1 H NMR (400MHz, CDCl3): δ=7.87(d,J=16.0Hz,1H),7.34(s,2H),7.23-7.17(m,3H),6.58(d,J=16.0Hz,1H),5.19( s,1H),3.17(hept,J=6.8Hz,2H),3.01(hept,J=6.8Hz,2H),1.30(d,J=6.8Hz,12H),1.21(d,J=6.8Hz,12H)ppm; 13 C NMR (100MHz, CDCl3): δ=166.1,152.7,147.3,145.7,140.6,134.3,126.7,126.4,124.3,123.9,113.8,27.5,27.2,22.6ppm. ESI + -HRMS: 431.2552[M+Na] + .

[0075] Example 2

[0076] Preparation of compound FPE-2

[0077] The synthetic route is:

[0078]

[0079] The specific steps were as follows: 2b (2.5 g, 12.87 mmol, 1.0 equiv.) was accurately weighed into a 100 mL round-bottom flask and placed in a rotor. N,N-diisopropylethylamine (6.7 mL, 38.60 mmol, 3.0 equiv.) and dichloromethane (17 mL) were added. Once the solution was completely dissolved, tert-butyldimethylsilyl chloride (5.6 mL, 32.20 mmol, 2.5 equiv.) was slowly added portionwise. The reaction system was stirred at room temperature for 20 h. After completion of the reaction, the dichloromethane was evaporated and ethyl acetate (60 mL) was added. The organic phase was washed with 1N HCl (2 × 30 mL) and saturated sodium chloride solution (30 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield the disilylated product as a brown oil. The bissilyl compound was placed in a 100 mL round-bottom flask and placed in a rotor. Potassium carbonate (2.0 g, 14.49 mmol, 1.1 equiv.) and tetrahydrofuran (20 mL) were added, and the reaction system was stirred at room temperature for 6 h. After completion of the reaction, the tetrahydrofuran was dried by spin drying and ethyl acetate (60 mL) was added. The organic phase was washed with purified water (40 mL), 1N HCl (30 mL), and saturated sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, and concentrated. An appropriate amount of 200-300 mesh silica gel was added and the sample was separated and purified by column chromatography (mobile phase ratio: dichloromethane / methanol = 100 / 1). The organic solvent was evaporated under reduced pressure to obtain 2d as a white solid (2.2 g, 55% yield). 1 H NMR (400MHz, CDCl3): δ=7.60 (d, J=15.2Hz, 1H), 7.00-6.96 (m, 3H), 6.83 (d, J= 8.0Hz, 1H), 6.59 (d, J = 15.2Hz, 1H), 3.81 (s, 3H), 1.00 (s, 9H), 0.17 (s, 6H) ppm.

[0080] Intermediate 2d (400 mg, 1.30 mmol, 1.2 equiv.) was accurately weighed into a 25 mL round-bottom flask and placed in a rotor. DCC N,N'-dicyclohexylcarbodiimide (268 mg, 1.30 mmol, 1.2 equiv.), 4-dimethylaminopyridine (13 mg, 0.11 mmol, 0.1 equiv.), and dichloromethane (7 mL) were added. After 30 minutes, propofol (200 μL, 1.08 mmol, 1.0 equiv.) was added, and the reaction system was stirred at room temperature for 48 hours. After completion of the reaction, monitored by TLC, an appropriate amount of 200-300 mesh silica gel was added and the sample was separated and purified by column chromatography (mobile phase ratio: petroleum ether / dichloromethane = 10 / 1) to afford 2e (270 mg, 44% yield) as a white solid. 1H NMR (400MHz, CDCl3): δ = 7.85 (d, J = 16.0Hz, 1H), 7.24-7.17 (m, 3H), 7.13-7.11 (m, 2H), 6.89 (d, J = 8.4Hz, 1H), 6.5 7(d,J=16.0Hz,1H),3.87(s,3H),2.99(hept,J=6.8Hz,2H),1.21(d,J=6.8Hz,12H),1.01(s,9H),0.19(s,6H)ppm; 13 C NMR (100MHz, CDCl3): δ=165.9,151.4,148.0,146.6,145.7,140.6,128.1,126 .5,123.9,122.7,121.3,114.7,111.0,55.5,27.6,25.7,23.2,18.5,-4.6ppm.

[0081] Intermediate 2e (260 mg, 0.55 mmol, 1.0 equiv.) was accurately weighed into a 25 mL round-bottom flask and placed in a rotor. Tetrahydrofuran (4 mL) was added, and after dissolution, 1N TBAF (1.1 mL, 1.11 mmol, 2.0 equiv.) was slowly added dropwise. The reaction system was stirred at room temperature for 1 h. After completion of the reaction, the tetrahydrofuran was dried by spin-drying, and ethyl acetate (60 mL) was added. The organic phase was washed with purified water (3 × 30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, and concentrated. An appropriate amount of 200-300 mesh silica gel was added and the sample was separated and purified by column chromatography (mobile phase ratio: petroleum ether / dichloromethane = 10 / 1). The organic solvent was evaporated under reduced pressure to afford FPE-2 (190 mg, 97% yield) as a pale yellow solid. 1 H NMR (400MHz, CDCl3): δ = 7.84 (d, J = 16.0Hz, 1H), 7.24-7.16 (m, 4H), 7.13 (s, 1H), 6.96 (d, J = 8.0Hz, 1H) ,6.56(d,J=16.0Hz,1H),5.93(s,1H),3.96(s,3H),2.99(d,J=6.8Hz,2H),1.21(d,J=6.8Hz,12H)ppm; 13 C NMR (100MHz, CDCl3): δ=165.9,148.4,146.9,146.7,145.7,140.6,126.8,126.5,123.9,123.5,114.9,114.3,109.6,56.0,27.6,23.0ppm. ESI + -HRMS: 377.1723 [M+Na]+ ,731.3558[2M+Na] + .

[0082] Example 3

[0083] Preparation of compound FPE-3

[0084] The synthetic route is:

[0085]

[0086] The specific steps were as follows: 3b (2.5 g, 15.20 mmol, 1.0 equiv.) was accurately weighed into a 100 mL round-bottom flask and placed in a rotor. N,N-diisopropylethylamine (8.0 mL, 45.60 mmol, 3.0 equiv.) and dichloromethane (17 mL) were added. Once the solution was completely dissolved, tert-butyldimethylsilyl chloride (5.74 g, 38.10 mmol, 2.5 equiv.) was slowly added portionwise. The reaction system was stirred at room temperature for 20 h. After completion of the reaction, the dichloromethane was evaporated and ethyl acetate (80 mL) was added. The organic phase was washed with 1N HCl (2 × 30 mL) and saturated sodium chloride solution (30 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield the disilylated product as a brown oil. The bissilyl compound was placed in a 100 mL round-bottom flask with a rotor, and potassium carbonate (2.2 g, 15.94 mmol, 1.1 equiv.) and tetrahydrofuran (20 mL) were added. The reaction system was stirred at room temperature for 6 h. After completion of the reaction, the tetrahydrofuran was dried by spin drying and ethyl acetate (60 mL) was added. The organic phase was washed with purified water (40 mL), 1N HCl (30 mL), and saturated sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, and concentrated. An appropriate amount of 200-300 mesh silica gel was added and the sample was separated and purified by column chromatography (mobile phase ratio: dichloromethane / methanol = 100 / 1). The organic solvent was evaporated under reduced pressure to obtain 3d (3.64 g, 89% yield) as a white solid. 1 H NMR (400MHz, CDCl3): δ = 7.74 (d, J = 16.0Hz, 1H), 7.45 (d, J = 8.8Hz, 2H), 6.86 (d, J = 8.8Hz, 2H), 6.32 (d, J = 16.0Hz, 1H), 0.99 (s, 9H), 0.23 (s, 6H) ppm; 13 C NMR (100MHz, CDCl3): δ = 172.9, 158.3, 146.8, 130.1, 127.4, 120.6, 115.0, 25.6, 18.3, -4.4ppm.

[0087] Intermediate 3d (700 mg, 2.51 mmol, 1.0 equiv.) was accurately weighed into a 100 mL round-bottom flask and placed in a rotor. DCC N,N'-dicyclohexylcarbodiimide (570 mg, 2.77 mmol, 1.1 equiv.), 4-dimethylaminopyridine (31 mg, 0.25 mmol, 0.1 equiv.), and dichloromethane (12.5 mL) were added. After 30 minutes, propofol (0.96 mL, 5.03 mmol, 2.0 equiv.) was added, and the reaction system was stirred at room temperature for 48 hours. After completion of the reaction, 200-300 mesh silica gel was added and the sample was purified by column chromatography (mobile phase ratio: petroleum ether / dichloromethane = 10 / 1) to afford 3e (515 mg, 47% yield) as a white solid. 1 H NMR (400MHz, CDCl3): δ=7.86 (d, J=16.0Hz, 1H), 7.52 (d, J=8.8Hz, 2H), 7.25-7.17 (m, 3H), 6.89 (d, J=8.8Hz, 2H),6.58(d,J=8.8Hz,1H),2.98(hept,J=6.8Hz,2H),1.21(d,J=6.8Hz,12H),1.00(s,9H),0.24(s,6H)ppm; 13 CNMR (100MHz, CDCl3): δ=165.9,158.3,146.3,145.8,140.6,130.1,127.6,126.5,123.9,120.7,114.7,27.6,25.7,23.2,18.3,-4.3ppm.

[0088] Intermediate 3e (1.05 g, 2.39 mmol, 1.0 equiv.) was accurately weighed into a 25 mL round-bottom flask and placed in a rotor. Tetrahydrofuran (5 mL) was added, and after dissolution, 1NTBAF (4.8 mL, 4.79 mmol, 2.0 equiv.) was slowly added dropwise. The reaction system was stirred at room temperature for 1 h. After completion of the reaction, the tetrahydrofuran was dried by spin drying and ethyl acetate (60 mL) was added. The organic phase was washed with purified water (2 x 30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, concentrated, and then added with 200-300 mesh silica gel. The sample was then purified by column chromatography (mobile phase ratio: petroleum ether / dichloromethane = 1 / 1). The organic solvent was evaporated under reduced pressure to afford FPE-3 (542 mg, 70% yield) as a pale yellow solid. 1H NMR (400MHz, CDCl3): δ=7.86 (d, J=16.0Hz, 1H), 7.50 (d, J=8.4Hz, 2H), 7.24-7.17 (m, 3H), 6.83 (d, J=8 .4Hz,2H),6.57(d,J=16.0Hz,1H),5.65(s,1H),2.98(hept,J=6.8Hz,2H),1,21(d,J=6.8Hz,12H)ppm; 13 C NMR (100MHz, CDCl3): δ=166.6,158.4,146.8,145.7,140.6,130.4,126.7,126.6,124.0,116.0,114.0,27.6,23.2ppm. ESI + -HRMS: 347.1620 [M+Na] + ,671.3351[2M+Na] + .

[0089] Example 4

[0090] Preparation of compound FPE-4

[0091] The synthetic route is:

[0092]

[0093] The specific steps were as follows: 4b (300 mg, 1.68 mmol, 1.0 equiv.) was accurately weighed into a 25 mL round-bottom flask and placed in a rotor. DCC N,N'-dicyclohexylcarbodiimide (381 mg, 1.85 mmol, 1.1 equiv.), 4-dimethylaminopyridine (21 mg, 0.17 mmol, 0.1 equiv.), and dichloromethane (6 mL) were added. After 30 minutes, propofol (972 μL, 5.04 mmol, 3.0 equiv.) was added, and the reaction system was stirred at room temperature for 48 hours. After completion of the reaction, an appropriate amount of 200-300 mesh silica gel was added, and the sample was separated and purified by column chromatography (mobile phase ratio: petroleum ether / dichloromethane = 10 / 1) to obtain FPE-4 (490 mg, 86% yield), a white solid powder. 1 H NMR (400MHz, CDCl3): δ=7.87(d,J=16.0Hz,1H),7.57(d,J=8.8Hz,2H),7.25-7.17(m,3H),6.95(d,J=8 .8Hz,2H),6.58(d,J=16.0Hz,1H),3.89(s,3H),2.99(hept,J=6.8Hz,2H),1.21(d,J=6.8Hz,12H)ppm;13 C NMR (100MHz, CDCl3): δ=165.9,161.8,146.3,145.7,140.6,130.1,127.0,126.4,123.9,114.5,114.4,55.4,27.6,22.9ppm. ESI + -HRMS: 431.2555[M+Na] + ,839.5218[2M+Na] + .

[0094] The experiment on inducing general anesthesia in KM mice using the ferulic acid ester derivatives prepared in Examples 1 to 4 above specifically included the following:

[0095] 1. Experimental reagents and materials

[0096] SPF adult male KM mice weighing 25 g to 30 g were selected. The FPE series compounds (ferulate ester derivatives FPE-1, FPE-2, FPE-3, and FPE-4 prepared in Examples 1 to 4) were prepared in 6.6% DMSO / 93.4% corn oil at a test compound concentration of 50 mg / mL. The positive control, propofol, was prepared at a concentration of 50 mg / mL and the injection dose was 300 mg / kg.

[0097] 2. Animal grouping settings

[0098] KM mice were randomly assigned to the following groups: saline, blank (6.6% DMSO / 93.4% corn oil), positive control, FPE-1, FPE-2, FPE-3, and FPE-4. Six mice per group received the drug via intraperitoneal injection.

[0099] 3. Intraperitoneal injection steps

[0100] 1) Grab the experimental mouse with your left hand, with the abdomen facing upwards and the head lower than the tail, to prevent damage to the large intestine, small intestine and other organs when the syringe is inserted;

[0101] 2) Disinfect the mouse abdomen with 75% alcohol cotton balls;

[0102] 3) Hold the syringe in your right hand and insert the needle into the subcutaneous tissue slightly to the left or right of the linea alba;

[0103] 4) After the needle reaches the subcutaneous tissue, push it forward about 3-5 mm, and then insert the syringe needle into the abdominal cavity at a 45° angle to the skin. You will feel a sense of emptiness at this point.

[0104] 5) Fix the needle, keep the needle tip still, withdraw the needle plug, and if there is no reflux, slowly inject the drug solution;

[0105] 6) After removing the needle, press the puncture site to prevent leakage of the drug solution and promote drug absorption.

[0106] 4. Evaluation methods and results

[0107] The induction period, anesthesia period, and recovery period of KM mice after drug injection were recorded. The judgment indicators were as follows: induction period: from injection to the disappearance of the rat's righting reflex; anesthesia period: from the disappearance of the righting reflex to the recovery of its righting reflex; recovery period: from the recovery of the righting reflex to the rat's ability to stand and walk independently.

[0108] 5. Results Analysis

[0109] Before selecting the "DMSO / corn oil" system as the preparation solvent for the test compound, multiple solvent screenings were conducted using different systems, such as the "DMSO / Solutol HS15 (polyoxyethylene stearyl ether) / normal saline" and "DMSO / ethanol / PEG-400 (polyethylene glycol) / normal saline" systems. The DMSO ratio was adjusted from 10% to 45%, the Solutol HS15 and PEG-400 ratio was 20%, the ethanol ratio was 10%, and the normal saline ratio was adjusted from 25% to 70%. Within these adjustment ranges, the test compound could not be completely dissolved (emulsion, suspension, or precipitation). When the test compound was injected intraperitoneally into mice as a suspension, the mice were unable to absorb the drug, resulting in a lack of efficacy. After 4 hours of observation, no obvious symptoms of anesthesia were observed in the mice in the FPE series.

[0110] After dissolving the FPE compounds (FPE-1, FPE-2, FPE-3, and FPE-4) in DMSO and injecting them intraperitoneally with corn oil as the dispersion medium, mice in the FPE-1 group exhibited behaviorally nearly identical to the positive control group. Approximately 25 minutes after injection, mice exhibited nesting, slowed movement, lethargy, and lameness, similar to the positive control mice. These symptoms persisted for approximately 25-30 minutes before disappearing. FPE-2 / -3 / -4 exhibited these behavioral symptoms approximately 45 minutes after injection, lasting for approximately 5-8 minutes before disappearing.

[0111] Compared to the positive control group, the results of the animal behavioral experiments in the laboratory group above indicate that using corn oil as a diluent (dispersion medium) is not conducive to drug absorption (including propofol) in mice. Due to the drug's continuous metabolism and slow absorption, the blood drug concentration cannot reach a complete deep anesthesia effect. Therefore, compounds FPE-1, FPE-2, FPE-3, and FPE-4 all have a certain anesthetic effect and are promising for inducing anesthesia, but further exploration of reliable and appropriate preparation solvents or structural modifications is required.

[0112] Therefore, the present invention has developed a new type of anesthetic with neuroprotective function, which can reduce the neurotoxicity of anesthetics used in clinical practice and provide a basis for subsequent in-depth clinical research and mechanism exploration.

[0113] It should be understood that the application of the present invention is not limited to the above examples. For those skilled in the art, improvements or changes can be made based on the above description. All these improvements and changes should fall within the scope of protection of the claims attached to the present invention.

Claims

1. A ferulic acid ester derivative, characterized in that The general structural formula of the ferulic acid ester derivative is shown in formula (I): （I）； Wherein, R2 is selected from -H, -CH3 or -OCH3; R3 is selected from -H, -CH3, -OCH3 or -CH(CH3)2; R4 is selected from -H or -CH3; R5 is selected from -H, -CH3, -OCH3 or -CH(CH3)2; R6 is selected from -H, -CH3 or -OCH3.

2. The ferulic acid ester derivative according to claim 1, characterized in that The ferulic acid ester derivatives are compounds represented by formulas FPE-1, FPE-2, FPE-3 and FPE-4: 。 3. A method for preparing a ferulic acid ester derivative according to claim 1 or 2, characterized in that: Including steps: S1. Compound a and malonic acid are dissolved in pyridine and reacted under the catalysis of piperidine to obtain compound b; S2, the compound b and tert-butyldimethylsilyl chloride are dissolved in dichloromethane, and reacted under the alkaline condition of N, N-diisopropylethylamine to obtain compound c; S3, dissolving the compound c in tetrahydrofuran, adding potassium carbonate, and reacting to obtain compound d; S4, dissolving the compound d, N, N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine in dichloromethane, adding propofol, and reacting to obtain compound e; S5, dissolving the compound e and tetrabutylammonium fluoride in tetrahydrofuran, and reacting to obtain the ferulic acid ester derivative; Wherein, the chemical structural formulas of the compounds a to e are respectively: ； In the above chemical structure, R2 is selected from -H, -CH3 or -OCH3; R3 is selected from -H, -CH3, -OCH3 or -CH(CH3)2; R4 is selected from -H or -CH3; R5 is selected from -H, -CH3, -OCH3 or -CH(CH3)2; R6 is selected from -H, -CH3 or -OCH3; R x Selected from -TBS or -CH3.

4. The method for preparing a ferulic acid ester derivative according to claim 3, wherein: In step S1, the reaction temperature is 45-90° C., and the reaction time is 1-3 h.

5. The method for preparing a ferulic acid ester derivative according to claim 3, wherein: In step S2, the reaction temperature is 20-30° C., and the reaction time is 12-24 h; and / or the molar ratio of tert-butyldimethylsilyl chloride to compound b is (2-4):

1.

6. The method for preparing a ferulic acid ester derivative according to claim 3, wherein: In step S3, the reaction temperature is 20-30° C., and the reaction time is 2-8 h; and / or the molar ratio of potassium carbonate to compound c is (2-3):

1.

7. The method for preparing a ferulic acid ester derivative according to claim 3, wherein: In step S4, the reaction temperature is 20-30° C., and the reaction time is 24-72 h; and / or the molar ratio of propofol to compound d is (0.8-3):

1.

8. The method for preparing a ferulic acid ester derivative according to claim 3, wherein: In step S5, the reaction temperature is 20-30° C., and the reaction time is 0.5-2 h; and / or the molar ratio of tetrabutylammonium fluoride to compound e is (1.5-2):

1.

9. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the ferulic acid ester derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 and a pharmaceutical carrier; the pharmaceutical carrier comprises one or more of a binder, a stabilizer, a buffer, a colorant, a diluent, a disintegrant, an emulsifier, a flavoring agent, a glidant, a lubricant, a preservative, a surfactant and a wetting agent.

10. Use of the ferulic acid ester derivative according to claim 1 or 2 or the pharmaceutical composition according to claim 9 in the preparation of anesthesia-inducing drugs.

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