Flavonoid derivatives, preparation methods, pharmaceutical compositions and applications thereof

Abstract

The present invention relates to the field of pharmaceutical chemistry, and discloses flavonoid derivatives, preparation methods thereof, pharmaceutical compositions, and applications thereof. The general structural formula of the flavonoid derivatives is: wherein R2 and R'2 are independently selected from -H, -OH, or -OCH3; R3 and R'3 are independently selected from -H, -CH3, -OCH3, -CH(CH3)2, or -CH(CH2)2; R5 and R'5 are independently selected from -H, -CH3, -OCH3, -CH(CH3)2, or -CH(CH2)2; R6 and R'6 are independently selected from -H, -OH, or -OCH3. The flavonoid derivatives have enhanced lipid solubility, facilitate BBB penetration, increase drug concentration in the brain, maintain pharmacokinetic levels, effectively retain neuroprotective effects such as anti-oxidative stress, anti-inflammatory, and neuroregeneration, and introduce propofol into the flavonoid skeleton to enhance the anesthetic effect under the synergistic effect of the two, making them a potential new antidepressant drug.

Description

Technical Field

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

[0002] Flavonoids, a broad class of polyphenolic secondary metabolites found widely in nature, have been systematically studied since the mid-19th century. In 1814, French pharmacists Pelletier and Caventou first extracted hesperidin from citrus peel, marking a significant milestone in flavonoid research. The 20th century saw the advancement of molecular biology, biochemistry, and pharmacology, further deepening the study of flavonoids. An increasing number of flavonoids have been isolated and identified, revealing their biosynthetic pathways in plants and their diverse biological activities, including antioxidant, analgesic, anti-inflammatory, cardiovascular, and immune-modulating properties.

[0003] Flavonoids primarily have 2-phenylchromone as their core structure, including its open-ring structure. The phenolic hydroxyl groups within these structures are key groups in their free radical scavenging and antioxidant activities. Phenolic hydroxyl groups are highly reactive and can react with free radicals (such as superoxide anion radicals, hydroxyl radicals, and alkoxy radicals) to generate relatively stable semiquinone radicals, which prevent free radical damage to biomacromolecules (such as DNA, proteins, and lipids). Furthermore, flavonoids can alleviate neuroinflammation by inhibiting the release of inflammatory factors and signaling pathways. For example, kaempferol inhibits the production of nitric oxide synthase (NOS) and tumor necrosis factor-α (TNF-α), thereby blocking the COX-2 pathway and achieving anti-inflammatory effects. Furthermore, some flavonoids can regulate the synthesis and release of neurotransmitters, improving interneuronal communication. Studies have shown that flavonoids can affect a variety of cell signaling pathways, such as PI3K / Akt, AMPK, etc. These pathways play an important role in the survival, proliferation and metabolism of nerve cells. By regulating the activity of these pathways, flavonoids can enhance the stress resistance of nerve cells and promote the repair and regeneration of damaged nerve cells. Therefore, flavonoids have great potential for neuroprotection, especially during surgical anesthesia, through strong anti-oxidative stress and anti-inflammatory functions to reduce problems such as postoperative cognitive dysfunction (POCD) caused by neuronal damage. It is worth mentioning that flavonoids also have the effect of resisting amyloid deposition, which can prevent the aggregation of amyloid in nerve cells, thereby slowing the progression of neurodegenerative diseases such as Alzheimer's disease (AD).

[0004] Flavonoids also possess analgesic properties, the mechanism of which may be related to calcium ion antagonism. By inhibiting the release of intracellular calcium ions or the influx of extracellular calcium ions, they reduce calcium ion concentrations at nerve endings, lower neuronal excitability, and thus alleviate pain. Flavonoids can also reduce the transmission of pain signals by regulating the release of neurotransmitters or inhibiting pain signal transmission pathways, or they can reduce tissue damage and pain caused by inflammatory responses, achieving an analgesic effect. For example, rutin flavonoid extract can significantly increase the screaming threshold of mice, prolong the latency of their hot plate licking response, and effectively inhibit their writhing response, demonstrating an analgesic effect stronger than that of aspirin. Flavonoids also have certain antidepressant effects, the mechanism of which may involve multiple neurotransmitters and mechanisms. Studies have shown that flavonoids may exert their antidepressant effects by regulating the levels of neurotransmitters such as norepinephrine (NE), 5-hydroxytryptamine (5-HT), and dopamine (DA), affecting neuroplasticity, and regulating the function of the hypothalamic-pituitary-adrenal (HPA) axis. The above two characteristics make flavonoids have potential in the development of new analgesic anesthetics or antidepressants.

[0005] However, due to the rigidity of the polyphenolic structures and 2-phenylchromone structures of flavonoids, they have poor lipid solubility and inadequate ability to cross the blood-brain barrier (BBB). Consequently, their bioavailability in the brain is poor, preventing them from maintaining effective drug concentrations in the brain. Therefore, the development of novel flavonoids is needed to overcome these limitations.

[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 purpose of the present invention is to provide flavonoid derivatives and their preparation methods, pharmaceutical compositions and applications, aiming to solve the problem that the prior art lacks clinical anesthetics with reduced neurotoxicity and high brain bioavailability.

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

[0009] The first aspect of the present invention provides a flavonoid derivative having a general structural formula as shown in formula (I):

[0010]

[0011] wherein R2 and R'2 are independently selected from -H, -OH or -OCH3;

[0012] R3 and R'3 are independently selected from -H, -CH3, -OCH3, -CH(CH3)2 or -CH(CH2)2;

[0013] R5 and R'5 are independently selected from -H, -CH3, -OCH3, -CH(CH3)2 or -CH(CH2)2;

[0014] R6 and R'6 are independently selected from -H, -OH or -OCH3;

[0015] In the general 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.

[0016] Optionally, the flavonoid derivative is a compound represented by the chemical structural formula FP-2, FP-3 or FP-4:

[0017]

[0018] The second aspect of the present invention further provides a method for preparing the flavonoid derivatives, comprising the steps of:

[0019] Dissolving compound 1c and p-hydroxybenzaldehyde or 4-hydroxy-3-methoxybenzaldehyde or 4-hydroxy-3,5-diisopropylbenzaldehyde in methanol, adding concentrated sulfuric acid, and reacting to obtain the flavonoid derivative represented by formula FP-2, FP-3 or FP-4;

[0020] Wherein, the chemical formula of the compound 1c is:

[0021] Alternatively, p-hydroxyacetophenone or 4-hydroxy-3-methoxyacetophenone and 4-hydroxy-3,5-diisopropylbenzaldehyde are dissolved in methanol, and concentrated sulfuric acid is added to react to obtain the flavonoid derivative represented by formula FP-6 or FP-7.

[0022] Optionally, the reaction temperature is 60-90° C., and the reaction time is 6-36 hours.

[0023] Preferably, the reaction temperature is 75-85° C., and the reaction time is 16-24 h.

[0024] Alternatively, the compound 1c is prepared by the following steps:

[0025] (1) Acetic acid is reacted with trifluoroacetic anhydride to generate activated anhydride, and propofol is added to react to obtain compound 1b;

[0026] (2) dissolving aluminum trichloride in nitrobenzene, adding the compound 1b, and reacting to obtain the compound 1c;

[0027] Wherein, the chemical formula of the compound 1b is:

[0028] Optionally, in step (1), the reaction temperature is 0-25°C, and the reaction time is 6-24 hours. Preferably, the reaction temperature is 0-25°C, and the reaction time is 10-12 hours.

[0029] Optionally, in step (2), the reaction temperature is 40-70° C., and the reaction time is 36-72 h. Preferably, the reaction temperature is 50-60° C., and the reaction time is 36-48 h.

[0030] Optionally, in step (1), the molar ratio of the acetic acid to the propofol is (1-1.3):1, and the molar ratio of the trifluoroacetic anhydride to the propofol is (1.3-1.5):1.

[0031] The third aspect of the present invention provides a pharmaceutical composition, which comprises the flavonoid derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier; wherein the pharmaceutical carrier includes one or more of a tableting 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.

[0032] The fourth aspect of the present invention provides a use of the flavonoid derivative or the pharmaceutical composition in the preparation of drugs for inducing anesthesia, analgesia, anti-inflammation, improving cognitive function, neuroprotection, anti-depression, improving anxiety, post-traumatic stress syndrome or complex regional pain syndrome.

[0033] The present invention uses flavonoid as the skeleton, introduces lipophilic groups, and modifies the skeleton structure to be similar to propofol to obtain flavonoid derivatives with the following beneficial effects:

[0034] (1) Enhancing lipid solubility helps it pass through the BBB, increasing drug concentration in the brain and maintaining pharmacokinetic levels. (2) The flavonoid core skeleton can effectively retain its antioxidant stress, anti-inflammatory and nerve regeneration functions to play a neuroprotective role, especially in dealing with common surgical problems such as hypoxia and ischemia, by reducing nerve cell damage and maintaining the stability of the nervous system. (3) The flavonoid skeleton in flavonoid derivatives has the ability to target GABA AThe receptors are synthesized by the propofol structure, which can enhance the anesthetic effect (sedation, analgesia and muscle relaxation) under synergistic effects. (4) The flavonoids and propofol-like coupling can combine the pharmacodynamics and become a potential new antidepressant. Therefore, the present invention provides a basis for subsequent in-depth clinical research and mechanism exploration. DETAILED DESCRIPTION

[0035] The present invention provides flavonoid derivatives, preparation methods, pharmaceutical compositions, and applications thereof. To clarify the objectives, technical solutions, and effects of the present invention, the present invention is described in further detail below. 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.

[0036] 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.

[0037] The present invention provides flavonoid derivatives having the general structural formula shown in formula (I):

[0038]

[0039] wherein R2 and R'2 are independently selected from -H, -OH or -OCH3;

[0040] R3 and R'3 are independently selected from -H, -CH3, -OCH3, -CH(CH3)2 or -CH(CH2)2;

[0041] R5 and R'5 are independently selected from -H, -CH3, -OCH3, -CH(CH3)2 or -CH(CH2)2;

[0042] R6 and R'6 are independently selected from -H, -OH or -OCH3;

[0043] In the general 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.

[0044] The flavonoid derivatives provided in the embodiments of the present invention can enhance lipid solubility, thereby facilitating their penetration through the BBB, increasing drug concentration in the brain and maintaining pharmacokinetic levels. The flavonoid core skeleton of the flavonoid derivatives can effectively retain their antioxidant, anti-inflammatory and neuroregenerative functions to play a neuroprotective role, and the flavonoid skeleton has the ability to target GABA. A Receptor, while introducing propofol structure, can enhance its anesthetic effect (sedation, analgesia and muscle relaxation) under synergistic action.Under normal circumstances, a certain dose of general anesthetic may accelerate postoperative dementia and AD process in some elderly surgical patients (especially AD and patients carrying AD susceptibility genes), and the anesthetic used in current clinical practice may possess certain neurotoxicity.And the flavonoid derivatives provided by the present invention can reduce the neurotoxic effect on the patient during surgical anesthesia or postoperatively, and have a direct protective effect on nerve cells, particularly when dealing with common surgical problems such as hypoxia and ischemia, by reducing the damage of nerve cells, maintaining the stability of the nervous system.Meanwhile, by regulating the release of neurotransmitters and scavenging oxygen free radicals, repairing and regenerating damaged nerve cells, alleviating nerve damage and postoperative cognitive impairment (POCD) during surgery, repairing damaged nerve cells.

[0045] In some specific embodiments, the flavonoid derivative is a compound represented by the chemical formula FP-2, FP-3 or FP-4:

[0046]

[0047] The present invention provides a method for preparing the above-mentioned flavonoid derivatives, comprising the steps of:

[0048] (1) Acetic acid is reacted with trifluoroacetic anhydride to generate activated anhydride, and propofol is added to react to obtain compound 1b;

[0049] (2) dissolving aluminum chloride in nitrobenzene and adding the compound 1b to react to obtain compound 1c;

[0050] (3) dissolving the compound 1c and p-hydroxybenzaldehyde or 4-hydroxy-3-methoxybenzaldehyde or 4-hydroxy-3,5-diisopropylbenzaldehyde in methanol, adding concentrated sulfuric acid, and reacting to obtain the flavonoid derivative represented by formula FP-2, FP-3, or FP-4;

[0051] The chemical formulas of compound 1b and compound 1c are as follows:

[0052]

[0053] In some embodiments, in step (1), the reaction temperature is 0-25°C, and the reaction time is 6-24 hours. In a preferred embodiment, the reaction temperature is 0-25°C, and the reaction time is 10-12 hours.

[0054] In some embodiments, in step (2), the reaction temperature is 40-70°C, and the reaction time is 36-72 hours. In a preferred embodiment, the reaction temperature is 50-60°C, and the reaction time is 36-48 hours.

[0055] In some embodiments, in step (3), the reaction temperature is 60-90°C, and the reaction time is 6-36 hours. In a preferred embodiment, the reaction temperature is 75-85°C, and the reaction time is 16-24 hours.

[0056] In some embodiments, in step (1), the molar ratio of the acetic acid to the propofol is (1-1.3):1, and the molar ratio of the trifluoroacetic anhydride to the propofol is (1.3-1.5):1.

[0057] In some embodiments, in step (3), the molar ratio of the sulfuric acid to the compound 1c is (4-5):1, and the molar ratio of the aldehyde compound to the compound 1c is (0.5-3):1.

[0058] In some specific embodiments, the flavonoid derivative is also a compound represented by the chemical formula FP-6 or FP-7:

[0059]

[0060] In some embodiments, the method for preparing the flavonoid derivatives comprises the steps of:

[0061] After dissolving p-hydroxyacetophenone or 4-hydroxy-3-methoxyacetophenone and 4-hydroxy-3,5-diisopropylbenzaldehyde in methanol, concentrated sulfuric acid is added to react to obtain the flavonoid derivative represented by formula FP-6 or FP-7.

[0062] In some embodiments, the reaction temperature is 60-90°C, and the reaction time is 6-36 hours. In a preferred embodiment, the reaction temperature is 75-85°C, and the reaction time is 16-24 hours.

[0063] An embodiment of the present invention provides a pharmaceutical composition comprising the flavonoid derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier. The pharmaceutical carrier includes one or more of, but is not limited to, 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. Exemplary pharmaceutical carriers include, but are not limited to, sugar, malt, starch, cellulose, gelatin, tragacanth powder, talc, and vegetable oil.

[0064] In specific embodiments, the pharmaceutical carrier may be inert or it may itself have pharmaceutical benefits. Some pharmaceutical carriers may 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 other formulations.

[0065] In addition, the pharmaceutical composition may further include at least one active agent other than flavonoid derivatives, such as analgesics, anesthetics, AD drugs, anti-inflammatory drugs, antidepressants, etc. Among them, analgesics may include aspirin, acetaminophen, diclofenac, diflunisal, etodolac, fenoprofen, ibuprofen, mefenamic acid, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, meloxicam, naproxen, oxaprozin, piroxicam, sulindac, nabumetone, phenylbutazone, Cox-2 inhibitors such as celecoxib, and anesthetic pain drugs, such as buprenorphine, hydrocodone, butorphanol, hydromorphone, codeine, levorphanol, pethidine, methadone, nalbuphine, oxycodone, oxymorphone, morphine, fenvalerate, propoxyphene, central analgesia tramadol, etc. Antidepressants include 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 pharmaceutically active salts or prodrugs thereof. Anesthetics may include ketamine, N2O, tramadol, midazolam, sevoflurane, isoflurane, fentanyl, sufentanil, and etomidate. Anti-inflammatory drugs can include 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. AD drugs can include donepezil, rivastigmine, galantamine, memantine etc. Above-mentioned optional activating agent can be included in the pharmaceutical composition, and it does not affect the activity of flavonoid derivatives basically.

[0066] The pharmaceutical composition can be administered orally, topically, parenterally, by pulmonary inhalation or spray, sublingually, transdermally, orally, rectally, as an ophthalmic solution, intravenously, or by other means, wherein the dosage form can be prepared according to conventional production methods in the pharmaceutical field, and the pharmaceutical composition can also be formulated into any pharmaceutical form, such as: submicron emulsion, aerosol, tablet, cream, gel, pill, capsule, syrup, transdermal patch, injection or ophthalmic solution. In some embodiments, the pharmaceutical composition can be an oral dosage form containing 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 flavonoid derivative or a pharmaceutically acceptable salt thereof and 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 other active agents in a unit dosage form.

[0067] The present invention provides an embodiment of the present invention for use of the flavonoid derivative or pharmaceutical composition in the preparation of a drug for inducing anesthesia, relieving pain, combating inflammation, improving cognitive function, protecting neurons, combating depression, improving anxiety, post-traumatic stress syndrome, or complex regional pain syndrome. Specifically, pain in these applications may include chronic pain and neuropathic pain; depression may include bipolar disorder and major depressive disorder; and improving cognitive function may include preventing or treating Alzheimer's disease (AD) and Parkinson's disease.

[0068] The following describes it in detail through specific examples.

[0069] Example 1

[0070] Preparation of compound FP-2

[0071] The synthetic route is:

[0072]

[0073] The specific steps are as follows: accurately pipette acetic acid (2.1 mL, 37 mmol, 1.3 equiv.) into a 50 mL round-bottom flask and place a rotor. Add trifluoroacetic anhydride (5.9 mL, 42 mmol, 1.5 equiv.) dropwise in an ice bath and react for 2 h. Then, slowly add propofol 1a (5 g, 280 mmol, 1.0 equiv.) dropwise in an ice bath. After the addition is complete, transfer the reaction flask to room temperature and allow the reaction system to react at room temperature for 12 h. After the reaction was completed as monitored by TLC, an appropriate amount of crushed ice (50 g) was added and extracted with dichloromethane (3×80 mL). The organic phase was washed with a saturated sodium chloride solution (2×50 mL) and dried over anhydrous magnesium sulfate. After concentration, an appropriate amount of 200-300 mesh silica gel was added and the sample was mixed. The sample was separated and purified by column chromatography (mobile phase ratio: petroleum ether / dichloromethane = 10 / 1). The organic solvent was distilled off under reduced pressure to obtain a yellow liquid 1b (4.72 g, yield 76%). 1 HNMR (400MHz, CDCl3): δ=7.23-7.14(m,3H),2.92(hept,J=6.8Hz,2H),2.35(s,3H),1.20(d,J=6.8Hz,12H)ppm; 13 C NMR (100MHz, CDCl3): δ = 169.7, 145.6, 140.3, 126.5, 123.9, 27.6, 23.4, 20.7ppm.

[0074] Powdered aluminum trichloride (3.88 g, 29 mmol, 1.6 equiv.) was placed in a 100 mL round-bottom flask with a rotor. Nitrobenzene (12 mL) was added to dissolve the product. The prepared intermediate 1b (4.0 g, 18 mmol, 1.0 equiv.) was then added to the reaction flask and the reaction system was allowed to react at 50°C for 2 days. 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 = 2 / 1). The organic solvent was evaporated under reduced pressure to afford 1c (2.8 g, 70% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ = 7.73 (s, 2H), 5.99 (s, 1H), 3.23 (hept, J = 6.8Hz, 2H), 2.58 (s, 3H), 1.29 (d, J = 6.8Hz, 12H) ppm; 13 C NMR (100MHz, CDCl3): δ=198.0, 155.0, 133.9, 130.0, 124.7, 27.1, 26.3, 22.6ppm.

[0075] Intermediate 1c (230 mg, 1.04 mmol, 1.0 equiv.) and p-hydroxybenzaldehyde (153 mg, 1.25 mmol, 1.2 equiv.) were accurately weighed into a 25 mL round-bottom flask and placed in a rotor. Methanol was added to dissolve the starting materials. After dissolution, concentrated sulfuric acid (254 μL, 4.18 mmol, 4.0 equiv.) was added dropwise. The reaction system was allowed to react under reflux conditions of methanol (6 mL) for 16 h. The reaction was monitored by TLC. The reaction solvent was evaporated and an appropriate amount of 200-300 mesh silica gel was added to the sample. The sample was then separated and purified by column chromatography (mobile phase ratio: dichloromethane / methanol = 100 / 1). The organic solvent was evaporated under reduced pressure to obtain PF-2 (210 mg, 62% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ = 7.79 (s, 2H), 7.77 (d, J = 15.6Hz, 2H), 7.55 (d, J = 8.4Hz, 2H), 7.42 (d, J=15.6Hz,1H),6.91(d,J=8.4Hz,2H),3.20(hept,J=6.8Hz,2H),1.32(d,J=6.8Hz,12H)ppm; 13 C NMR (100MHz, CDCl3): δ=190.8,158.8,154.9,144.8,133.9,130.9,130.5,127.4,125.1,119.5,116.2,27.3,22.6ppm. ESI + -HRMS: 347.1614 [M+Na] + ,671.3344[2M+Na] + .

[0076] Example 2

[0077] Preparation of compound FP-3

[0078] The synthetic route is:

[0079]

[0080] The specific steps were as follows: Intermediate 1c (152 mg, 1.0 mmol, 1.0 equiv.) and 4-hydroxy-3-methoxybenzaldehyde (330 mg, 1.50 mmol, 1.5 equiv.) were accurately weighed into a 50 mL round-bottom flask and placed in a rotor. Methanol (6 mL) was added to dissolve the starting materials. After dissolution, concentrated sulfuric acid (254 μL, 4.18 mmol, 4.0 equiv.) was added dropwise. The reaction system was allowed to react under reflux conditions for 16 h. The reaction was monitored by TLC. The reaction solvent was dried and an appropriate amount of 200-300 mesh silica gel was added to the sample. The sample was then separated and purified by column chromatography (mobile phase ratio: dichloromethane / methanol = 100 / 1). The organic solvent was then distilled off under reduced pressure to obtain PF-3 (159 mg, 45% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ = 7.77 (s, 2H), 7.73 (d, J = 15.6Hz, 1H), 7.37 (d, J = 15.6Hz, 1H), 7.24 (dd, J = 8.0Hz, J = 2.0Hz, 1H), 7.12 (d, J = 2.0Hz,1H),6.97(d,J=8.0Hz,1H),5.89(br,1H),5.33(br,1H),3.97(s,3H),3.20(hept,J=6.8Hz,2H),1.33(d,J=6.8Hz,12H)ppm; 13 C NMR (100MHz, CDCl3): δ=189.9,154.6,148.1,146.8,144.2,133.8,131.1,127.8,124.88,122.7,120.1,114.9,110.6,56.0,27.3,22.7ppm. ESI + -HRMS: 377.1920 [M+Na] + ,731.3552[2M+Na] + .

[0081] Example 3

[0082] Preparation of compound FP-4

[0083] The synthetic route is:

[0084]

[0085] The specific steps were as follows: Intermediate 1c (60 mg, 0.27 mmol, 1.1 equiv.) and 4-hydroxy-3,5-diisopropylbenzaldehyde (51 mg, 0.25 mmol, 1.0 equiv.) were accurately weighed into a 25 mL round-bottom flask and placed in a rotor. Methanol (3 mL) was added to dissolve the starting materials. After dissolution, concentrated sulfuric acid (61 μL, 0.99 mmol, 4.0 equiv.) was added dropwise. The reaction system was allowed to react under reflux conditions for 16 h. The reaction was monitored by TLC. The reaction solvent was evaporated, and an appropriate amount of 200-300 mesh silica gel was added to the sample. The sample was then separated and purified by column chromatography (mobile phase ratio: petroleum ether / dichloromethane = 10 / 1). The organic solvent was then distilled off under reduced pressure to obtain PF-4 (43 mg, 39% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ=7.81(s,2H),7.78(d,J=15.6Hz,1H),7.40(d,J=15.6Hz,1H),7.38(s,2H),7.38(s,2H),5.51( s,1H),5.32(s,1H),3.24(d,J=7.2Hz,2H),3.21(d,J=7.2Hz,2H),1.35(d,J=7.2Hz,12H),1.34(d,J=7.2Hz,12H)ppm; 13 C NMR (100MHz, CDCl3): δ=190.4,154.4,152.6,145.1,134.3,134.3,133.7,133.7,131.3,127.7,124.9,124.32,119.8,27.4,27.3,22.6ppm. ESI + -HRMS: 431.2555[M+Na] + ,839.5218[2M+Na] + .

[0086] Example 4

[0087] Preparation of compound FP-6

[0088] The synthetic route is:

[0089]

[0090] The specific steps were as follows: 4-Hydroxy-3,5-diisopropylbenzaldehyde 1d (454 mg, 2.20 mmol, 2.0 equiv.) and p-hydroxyacetophenone (150 mg, 1.10 mmol, 1.0 equiv.) were accurately weighed into a 100 mL round-bottom flask and placed in a rotor. Methanol (12 mL) was added to dissolve the mixture. After dissolution, concentrated sulfuric acid (268 μL, 4.40 mmol, 4.0 equiv.) was added dropwise. The reaction system was allowed to react under reflux for 16 h. The reaction was monitored by TLC. The solvent was then dried and added to an appropriate amount of 200-300 mesh silica gel. The sample was then separated and purified by column chromatography (mobile phase ratio: petroleum ether / dichloromethane = 2 / 1). The organic solvent was then distilled off under reduced pressure to obtain PF-6 (271 mg, 76% yield) as a pale yellow solid. 1 H NMR (400MHz, MeOD-d4): δ=8.03(d,J=8.8Hz,2H),7.74(d,J=15.6Hz,1H),7.57(d,J=15.6Hz,1 H),7.43(s,2H),6.92(d,J=8.8Hz,2H),3.34(hept,J=6.8Hz,2H),1.29(d,J=6.8Hz,12H)ppm; 13 C NMR (100MHz, MeOD-d4): δ=189.9,162.3,153.9,145.6,135.7,130.83,129.9,126.8124.14,117.8,114.96,26.6,21.9ppm. ESI + -HRMS: 347.1616 [M+Na] + ,671.3344[2M+Na] + .

[0091] Example 5

[0092] Preparation of compound FP-7

[0093] The synthetic route is:

[0094]

[0095] The specific steps were as follows: 4-Hydroxy-3,5-diisopropylbenzaldehyde 1d (268 mg, 1.30 mmol, 1.8 equiv.) and 4-hydroxy-3-methoxyacetophenone (120 mg, 0.72 mmol, 1.0 equiv.) were accurately weighed into a 25 mL round-bottom flask and placed in a rotor. Methanol (5 mL) was added to dissolve the raw materials. After dissolution, concentrated sulfuric acid (220 μL, 3.61 mmol, 5.0 equiv.) was added dropwise. The reaction system was allowed to react under reflux conditions for 16 h. The reaction was monitored by TLC. The reaction solvent was dried by spin drying and then added to an appropriate amount of 200-300 mesh silica gel. The sample was then separated and purified by column chromatography (mobile phase ratio: petroleum ether / dichloromethane = 2 / 1). The organic solvent was then distilled off under reduced pressure to obtain PF-7 (271 mg, 53% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ = 7.81 (d, J = 15.6Hz, 1H), 7.69-7.66 (m, 2H), 7.42 (d, J = 15.6Hz, 1H), 7.39 (d, J = 8.0Hz, 1H), 7.38 (s ,1H),7.03(d,J=8.0Hz,1H),6.12(s,1H),5.22(s,1H),4.01(s,3H),3.20(hept,J=6.8Hz,2H),1.33(d,J=6.8Hz,12H)ppm; 13 C NMR (100MHz, CDCl3): δ=189.1,152.7,150.2,146.9,145.3,134.4,131.4,127.5,124.4,123.6,118.8,113.7,110.6,56.1,27.2,22.7ppm. ESI + -HRMS: 377.1720 [M+Na] + ,731.3552[2M+Na] + .

[0096] The test of the compounds in Examples 1 to 5 of the present invention in inducing general anesthesia in KM mice specifically includes:

[0097] 1. Experimental reagents and materials

[0098] SPF adult male KM mice weighing between 25g and 30g were selected. The experimental FEP series compounds were prepared in 6.6% DMSO / 93.4% corn oil. The concentration of the test compound was 50mg / mL. The positive control propofol was prepared at a concentration of 50mg / mL and the injection dose was 300mg / kg.

[0099] 2. Animal grouping settings

[0100] KM mice were randomly assigned to the following groups: saline, blank (6.6% DMSO / 93.4% corn oil), positive control, FP-2, FP-3, FP-4, FP-6, and FP-7. Six mice per group received the drug via intraperitoneal injection.

[0101] 3. Intraperitoneal injection steps

[0102] 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;

[0103] 2) Disinfect the mouse abdomen with 75% alcohol cotton balls;

[0104] 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;

[0105] 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.

[0106] 5) Fix the needle, keep the needle tip still, withdraw the needle plug, and if there is no reflux, slowly inject the drug solution;

[0107] 6) After removing the needle, press the puncture site to prevent leakage of the drug solution and promote drug absorption.

[0108] 4. Evaluation methods and results

[0109] The induction period, anesthesia period, and recovery period of KM mice after injection were recorded. The evaluation indicators are as follows:

[0110] Induction period: from injection to the disappearance of the rat's righting reflex;

[0111] Anesthesia period: from the disappearance of righting reflex to the recovery of righting reflex;

[0112] Awakening period: from the recovery of righting reflex to the rat being able to stand and walk independently.

[0113] 5. Results Analysis

[0114] Before selecting the "DMSO / corn oil" system as the preparation solvent for the test compounds, 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 the above adjustment ranges, the test compounds could not be completely dissolved (emulsion, suspension, or precipitation). The samples were injected intraperitoneally into mice as a suspension, but the mice were unable to absorb the sample, resulting in the drug's inability to exert its efficacy. After 4 hours of observation, no obvious anesthesia symptoms were observed in the mice in the FP series (compounds FP-2, FP-3, FP-4, FP-6, and FP-7) groups.

[0115] After dissolving the FP series compounds in DMSO and using corn oil as the dispersion medium, they were injected intraperitoneally into each group. The FP-4 group exhibited behavioral changes similar to those in the positive control group. Approximately 20 minutes after injection, mice exhibited nesting, slowed movement, and lethargy, similar to the positive control mice, but to a lesser degree. These symptoms persisted for approximately 10-15 minutes before disappearing. Compounds FP-2, FP-3, FP-6, and FP-7 exhibited these mild behaviors after approximately 30 minutes, lasting for approximately 4-6 minutes before disappearing.

[0116] 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 continuous metabolism and slow absorption of the drug, the blood drug concentration cannot reach a complete deep anesthesia effect. Therefore, compounds FP-2, FP-3, FP-4, FP-6, and FP-7 all have certain anesthetic effects and are promising for inducing anesthesia, but further exploration of reliable and appropriate preparation solvents or structural modifications is needed.

[0117] The present invention develops a new type of anesthetic with neuroprotective function, which has a direct protective effect on nerve cells and can avoid the neurotoxicity caused by existing clinical anesthetics, providing a basis for subsequent in-depth clinical research and mechanism exploration.

[0118] 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 flavonoid derivative, characterized in that: The flavonoid derivative is a compound as shown in the chemical structural formula FP-4: 。 2. The method for preparing flavonoid derivatives according to claim 1, wherein: include: Compound 1c and 4-hydroxy-3,5-diisopropylbenzaldehyde were dissolved in methanol, and concentrated sulfuric acid was added to react to obtain the flavonoid derivative of formula FP-4; Wherein, the chemical formula of the compound 1c is: .

3. The method for preparing flavonoid derivatives according to claim 2, characterized in that: The reaction temperature is 60-90° C., and the reaction time is 6-36 h.

4. The method for preparing flavonoid derivatives according to claim 3, characterized in that: The reaction temperature is 75-85° C., and the reaction time is 16-24 h.

5. The method for preparing flavonoid derivatives according to claim 2, characterized in that: The compound 1c was prepared by the following steps: (1) Acetic acid is reacted with trifluoroacetic anhydride to generate activated anhydride, and propofol is added to react to obtain compound 1b; (2) dissolving aluminum trichloride in nitrobenzene, adding the compound 1b, and reacting to obtain the compound 1c; Wherein, the chemical formula of the compound 1b is: .

6. The method for preparing flavonoid derivatives according to claim 5, characterized in that: In step (1), the reaction temperature is 0-25°C, and the reaction time is 6-24 h; in step (2), the reaction temperature is 40-70°C, and the reaction time is 36-72 h.

7. The method for preparing flavonoid derivatives according to claim 5, characterized in that: In step (1), the molar ratio of the acetic acid to the propofol is (1-1.3):1, and the molar ratio of the trifluoroacetic anhydride to the propofol is (1.3-1.5):

1.

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the flavonoid derivative or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutical carrier; the pharmaceutical carrier is selected from one or more of a tableting 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.

9. Use of the flavonoid derivative according to claim 1 or the pharmaceutical composition according to claim 8 in the preparation of anesthesia-inducing drugs.

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