Flavonoid derivative as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention relates to the field of medical chemistry, and discloses a flavonoid derivative as well as a preparation method, a pharmaceutical composition and application thereof. The general structural formula of the flavonoid derivative is # imgabs0 #, 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; and R6 and R '6 are independently selected from-H,-OH or-OCH3. The flavonoid derivative is enhanced in fat solubility, is beneficial to penetrating through BBB, improving the concentration of drugs in the brain and maintaining the pharmacokinetic level, effectively retains the neuroprotective effects of oxidative stress resistance, inflammation resistance, nerve regeneration and the like, propofol is introduced into a flavonoid skeleton, the anesthetic effect is enhanced under the synergistic effect of propofol and propofol, and the flavonoid derivative can become a potential new anti-depression drug.

Description

Technical Field

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

[0002] Flavonoids are a large class of polyphenolic secondary metabolites widely found in nature. Their scientific and systematic research began in the mid-19th century. In 1814, French pharmacists Pelletier and Caventou first extracted a compound called "hesperidin" from citrus peels, which was an important milestone in the history of flavonoid research. After entering the 20th century, with the development of molecular biology, biochemistry, pharmacology and other disciplines, the research on flavonoids has become more in-depth. More and more flavonoids have been isolated and identified, and their biosynthetic pathways in plants and their wide range of biological activities have gradually been revealed, such as their significant effects in anti-oxidation, analgesia, anti-inflammatory, cardiovascular protection, and immune regulation.

[0003] Flavonoids mainly use 2-phenylchromone (Flavanone) as the parent core structure, including its open ring structure. The phenolic hydroxyl groups in its structure are the key groups for scavenging free radicals and antioxidant activity. Phenolic hydroxyl groups are highly reactive and can react with free radicals (such as superoxide anion radicals, hydroxyl radicals, alkoxy radicals, etc.) to generate relatively stable semiquinone free radicals, which prevent free radicals from damaging biological macromolecules (such as DNA, proteins, and lipids). In addition, flavonoids can reduce neuroinflammation by inhibiting the release of inflammatory factors and signal transduction pathways. For example, kaempferol can inhibit the production of nitric oxide synthase (NOS) and tumor necrosis factor-α (TNF-α) and block the COX-2 pathway, thereby achieving anti-inflammatory effects. In addition, some flavonoids can regulate the synthesis and release of neurotransmitters and improve the communication function between neurons. 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 have analgesic functions, and their mechanism may be related to calcium ion antagonism. By inhibiting the release of intracellular calcium ions or inhibiting the influx of extracellular calcium ions, the calcium ion concentration of nerve endings is reduced, the excitability of neurons is reduced, and the pain is relieved. Flavonoids can also reduce the transmission of pain signals by regulating the release of neurotransmitters or inhibiting the conduction pathway of pain signals, or can reduce tissue damage and pain caused by inflammatory reactions to achieve analgesic effects. For example, rutin flavonoid extract can significantly increase the threshold of mouse screaming stimulation, prolong the latency of mouse hot plate licking reaction, and effectively inhibit the twisting reaction of mice, showing an analgesic effect stronger than aspirin. At the same time, flavonoids have a certain antidepressant effect, and its mechanism may involve a variety of neurotransmitters and mechanisms. Studies have shown that flavonoids may exert 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 hypothalamus-pituitary-adrenal axis (HPA). The above two characteristics make flavonoids have potential in the development of new analgesics, anesthetics or antidepressants.

[0005] However, due to the rigidity of the polyphenol structure and 2-phenylchromone structure of flavonoids, they have poor lipid solubility, insufficient ability to pass through the blood-brain barrier (BBB), poor brain bioavailability and inability to maintain effective drug concentrations in the brain to exert their effects. Therefore, it is necessary to develop new flavonoids to overcome the above defects.

[0006] Therefore, the prior art 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 preparation methods, pharmaceutical compositions and applications thereof, aiming to solve the problem that the prior art lacks clinical anesthetics that reduce neurotoxicity and have high brain bioavailability.

[0008] The technical solution of the present invention is as follows:

[0009] In a first aspect of the present invention, a flavonoid derivative is provided, wherein the flavonoid derivative has 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 as shown in 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 to 90° C., and the reaction time is 6 to 36 hours.

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

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

[0025] (1) After reacting acetic acid with trifluoroacetic anhydride to generate activated anhydride, propofol was added to react to obtain compound 1b;

[0026] (2) dissolving aluminum chloride 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 hours. Preferably, the reaction temperature is 50-60°C, and the reaction time is 36-48 hours.

[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 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.

[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 flavonoids as the skeleton, introduces lipophilic groups, and performs structural modification similar to propofol according to the skeleton structure to obtain flavonoid derivatives, which have the following beneficial effects:

[0034] (1) Enhancing lipid solubility helps it pass through the BBB, increasing the drug concentration in the brain and maintaining the pharmacokinetic level. (2) The flavonoid core skeleton can effectively retain its anti-oxidative stress, anti-inflammatory and nerve regeneration functions to play a neuroprotective role, especially when 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 and the introduction of propofol structure can enhance the anesthetic effect (sedation, analgesia and muscle relaxation) under synergistic effect. (4) The flavonoids and propofol-like coupling can combine the drug effects 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 and preparation methods, pharmaceutical compositions and applications thereof. To make the purpose, technical solutions and effects of the present invention clearer and more specific, the present invention is further described in detail below. It should be understood that the specific embodiments described herein are only used to explain 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 a flavonoid derivative having a general structural formula as 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 helping them to penetrate the BBB, increase the drug concentration in the brain and maintain the pharmacokinetic level. The flavonoid core skeleton of the flavonoid derivatives can effectively retain its anti-oxidative stress, anti-inflammatory and nerve regeneration functions to play a neuroprotective role, and the flavonoid skeleton has the ability to target GABA A Receptor, while introducing propofol structure, can enhance the effect of anesthesia (sedation, analgesia and muscle relaxation) under synergistic effect. Normally, a certain dose of general anesthetic may accelerate postoperative dementia and AD process in some elderly surgical patients (especially AD and patients carrying AD susceptible genes), and the anesthetic currently used in clinical practice may have certain neurotoxicity. And the flavonoid derivatives provided by the present invention can reduce the neurotoxic effects on patients during surgical anesthesia or postoperatively, and have a direct protective effect on nerve cells, especially in response to common surgical problems such as hypoxia and ischemia, by reducing the damage of nerve cells, the stability of the nervous system is maintained. At the same time, by regulating the release of neurotransmitters and removing oxygen free radicals, damaged nerve cells are repaired and regenerated, nerve damage and postoperative cognitive impairment (POCD) during surgery are reduced, and damaged nerve cells are repaired.

[0045] In some specific embodiments, the flavonoid derivative is a compound as shown in the chemical structural 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) After reacting acetic acid with trifluoroacetic anhydride to generate activated anhydride, propofol was 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 as shown in the chemical structural formula FP-6 or FP-7:

[0059]

[0060] In some embodiments, the method for preparing the above 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 shown in 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] The embodiment of the present invention provides a pharmaceutical composition, which comprises the flavonoid derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier. The pharmaceutical carrier includes 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, but is not limited thereto. Exemplarily, the pharmaceutical carrier includes sugar, malt, starch, cellulose, gelatin, tragacanth powder, talc and vegetable oil, etc., but is not limited thereto.

[0064] In specific embodiments, the pharmaceutical carrier may be inert or it may have pharmaceutical benefits of its own. Some pharmaceutical carriers may be listed in more than one category, such as: vegetable oils (such as 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, diflubenzyl salicylate, 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, hydroxymethyl levorphan, pethidine, methadone, nalbuphine, oxycodone, oxymorphone, morphine, analgesic, propoxyphene, central analgesic 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, clexapine, olanzapine, quetiapine, risperidone, buspirone, ziprasidone, carbamazepine, gabapentin, lamotrigine, phenytoin, pregabalin, rivastigmine, galantamine, memantine, rivastigmine, homotaurine or their pharmaceutically active salts or prodrugs. Anesthetics may include ketamine, N2O, tramadol, midazolam, sevoflurane, isoflurane, fentanyl, sufentanil and etomidate, etc. Anti-inflammatory drugs can include aspirin, salsalate, diflunisal, 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. The above optional activating agent can be included in the pharmaceutical composition, which does not affect the activity of flavonoid derivatives substantially.

[0066] The pharmaceutical composition can be administered orally, topically, parenterally, by pulmonary inhalation or spray, sublingually, transdermally, by oral administration, rectal administration, as an ophthalmic solution, intravenous injection 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, atomizer, 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 its pharmaceutically acceptable salt in a unit dosage form 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.

[0067] The present invention provides an application 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. In the application, specifically, pain may include chronic pain and neuropathic pain; depression may include: bipolar depression and major depression; improving cognitive function includes preventing or treating Alzheimer's disease (AD) and Parkinson's disease, etc.

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

[0069] Example 1

[0070] Preparation of compound FP-2

[0071] The synthetic route is:

[0072]

[0073] The specific steps are: 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 under ice bath conditions and react for 2 hours, then continue to slowly add propofol 1a (5 g, 280 mmol, 1.0 equiv.) dropwise under ice bath conditions, and after the addition is complete, transfer the reaction bottle to room temperature, and the reaction system reacts at room temperature for 12 hours. 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 the organic phase was dried over anhydrous magnesium sulfate. After concentration, an appropriate amount of 200-300 mesh silica gel was added to mix the sample, and the sample was separated and purified by column chromatography (mobile phase ratio: petroleum ether / dichloromethane=10 / 1). The organic solvent was distilled 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] The ground aluminum chloride (3.88 g, 29 mmol, 1.6 equiv.) was placed in a 100 mL round-bottom flask and a rotor was placed therein, and nitrobenzene (12 mL) was added to dissolve it, and then the prepared intermediate 1b (4.0 g, 18 mmol, 1.0 equiv.) was added to the reaction bottle, and the reaction system was reacted at 50° C. for 2 days. After the reaction was completed by TLC monitoring, an appropriate amount of 200-300 mesh silica gel was added to mix the sample, and the sample was separated and purified by column chromatography (mobile phase ratio: petroleum ether / dichloromethane=2 / 1), and the organic solvent was distilled under reduced pressure to obtain a yellow solid 1c (2.8 g, yield 70%). 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] The prepared 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 raw materials. After the raw materials were dissolved, concentrated sulfuric acid (254 μL, 4.18 mmol, 4.0 equiv.) was added dropwise. The reaction system was reacted under the reflux condition of methanol (6 mL) for 16 h. TLC monitored the reaction, the reaction solvent was spin-dried and an appropriate amount of 200-300 mesh silica gel was added to mix the sample, and the sample was separated and purified by column chromatography (mobile phase ratio: dichloromethane / methanol = 100 / 1). The organic solvent was distilled under reduced pressure to obtain a yellow solid PF-2 (210 mg, yield 62%). 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 are as follows: accurately weigh the prepared intermediate 1c (152 mg, 1.0 mmol, 1.0 equiv.) and 4-hydroxy-3-methoxybenzaldehyde (330 mg, 1.50 mmol, 1.5 equiv.) into a 50 mL round-bottom flask and place a rotor, add methanol (6 mL) to dissolve, and after the raw materials are dissolved, add concentrated sulfuric acid (254 μL, 4.18 mmol, 4.0 equiv.), and the reaction system reacts for 16 hours under methanol reflux conditions. TLC monitors the reaction, spin-drys the reaction solvent, add an appropriate amount of 200-300 mesh silica gel to mix the sample, separate and purify by column chromatography (mobile phase ratio: dichloromethane / methanol=100 / 1), and distill the organic solvent under reduced pressure to obtain a yellow solid PF-3 (159 mg, yield 45%). 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 are as follows: accurately weigh the prepared intermediate 1c (60 mg, 0.27 mmol, 1.1 equiv.) and 4-hydroxy-3,5-diisopropylbenzaldehyde (51 mg, 0.25 mmol, 1.0 equiv.) into a 25 mL round-bottom flask and place a rotor, add methanol (3 mL) to dissolve, and after the raw materials are dissolved, add concentrated sulfuric acid (61 μL, 0.99 mmol, 4.0 equiv.), and the reaction system reacts under methanol reflux conditions for 16 hours. TLC monitors the reaction, spin-drys the reaction solvent, add an appropriate amount of 200-300 mesh silica gel to mix the sample, separate and purify by column chromatography (mobile phase ratio: petroleum ether / dichloromethane = 10 / 1), and the organic solvent is distilled under reduced pressure to obtain a yellow solid PF-4 (43 mg, yield 39%). 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 are as follows: accurately weigh 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.) in a 100 mL round-bottom flask and place a rotor, add methanol (12 mL) to dissolve, and after the raw materials are dissolved, add concentrated sulfuric acid (268 μL, 4.40 mmol, 4.0 equiv.), and the reaction system reacts under methanol reflux conditions for 16 hours. TLC monitors the reaction, spin-drys the reaction solvent, add an appropriate amount of 200-300 mesh silica gel to mix the sample, separate and purify by column chromatography (mobile phase ratio: petroleum ether / dichloromethane = 2 / 1), and obtain a light yellow solid PF-6 (271 mg, yield 76%) after reduced pressure distillation of the organic solvent. 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 are 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.) are accurately weighed in a 25 mL round-bottom flask and placed in a rotor, methanol (5 mL) is added for dissolution, concentrated sulfuric acid (220 μL, 3.61 mmol, 5.0 equiv.) is added dropwise after the raw materials are dissolved, and the reaction system is reacted under methanol reflux conditions for 16 h. TLC monitors the reaction, spin-drying the reaction solvent, adding an appropriate amount of 200-300 mesh silica gel to mix the sample, and separating and purifying by column chromatography (mobile phase ratio: petroleum ether / dichloromethane = 2 / 1), and the organic solvent is distilled under reduced pressure to obtain a yellow solid PF-7 (271 mg, yield 53%). 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 with 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] The experimental KM mice were randomly assigned to the following groups: saline group, blank group (6.6% DMSO / 93.4% corn oil), positive control group, FP-2 group, FP-3 group, FP-4 group, FP-6 group, and FP-7 group. There were 6 mice in each group, and all were intraperitoneally injected.

[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 the large intestine, small intestine and other organs from being damaged 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 pierce the abdominal cavity at a 45° angle between the needle and the skin. At this time, there is a sense of emptiness.

[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, and the judgment indicators were 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 compound, multiple screenings of different system solvents were conducted, such as the "DMSO / Solutol HS15 (polyoxyethylene stearyl ether) / normal saline" and "DMSO / ethanol / PEG-400 (polyethylene glycol) / normal saline" systems, in which the DMSO ratio was adjusted in the range of 10%-45%, the Solutol HS15 and PEG-400 ratio was 20%, the ethanol ratio was 10%, and the normal saline ratio was adjusted in the range of 25%-70%. Within the above adjustment ranges, the test compound could not be completely dissolved (emulsion, suspension or precipitation). The sample was injected intraperitoneally into mice as a suspension, and the mice were unable to absorb it, resulting in the inability to exert the drug effect. After 4 hours of observation, mice in each group of the FP series (compounds FP-2, FP-3, FP-4, FP-6, and FP-7) had no obvious anesthesia symptoms.

[0115] After the FP series compounds were dissolved in DMSO and corn oil was used as the dispersion medium, they were used for intraperitoneal injection in each group. The behavioral performance of mice in the FP-4 group was similar to that of the positive control group. About 20 minutes after injection, they showed nesting, slow movement, and drowsiness like the positive control mice, but to a lesser extent. The symptoms lasted for about 10 to 15 minutes before disappearing. Compounds FP-2, FP-3, FP-6, and FP-7 showed the above mild behaviors after about 30 minutes, and the symptoms lasted for about 4 to 6 minutes before disappearing.

[0116] Compared with the positive control group, the results of the animal behavior experiment in the above laboratory group show that corn oil as a diluent (dispersion medium) is not conducive to the absorption of drugs (including propofol) in mice. Due to the continuous metabolism and slow absorption of the drug, the blood drug concentration cannot reach the effect of complete deep anesthesia. Therefore, compounds FP-2, FP-3, FP-4, FP-6, and FP-7 all have certain anesthetic effects and are expected to be used to induce anesthesia, but a reliable and appropriate preparation solvent or structural modification needs to be explored in depth.

[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 produced by existing clinical anesthetics, thus 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 ordinary technicians in this field, 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 general structural formula of the flavonoid derivatives is shown in formula (I): 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; 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.

2. The flavonoid derivative according to claim 1, characterized in that The flavonoid derivatives are compounds shown in the chemical structural formula FP-2, FP-3, FP-4, FP-6 or FP-7:

3. The method for preparing flavonoid derivatives according to claim 2, characterized in that: include: 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; Wherein, the chemical formula of the compound 1c is: or, 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 shown in formula FP-6 or FP-7.

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

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

6. The method for preparing flavonoid derivatives according to claim 3, characterized in that: The compound 1c is prepared by the following steps: (1) After reacting acetic acid with trifluoroacetic anhydride to generate activated anhydride, propofol was added to react to obtain compound 1b; (2) dissolving aluminum chloride in nitrobenzene, adding the compound 1b, and reacting to obtain the compound 1c; Wherein, the chemical formula of the compound 1b is:

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

8. The method for preparing flavonoid derivatives according to claim 6, 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.

9. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the flavonoid 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 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.

10. Use of the flavonoid derivative according to claim 1 or 2 or the pharmaceutical composition according to claim 9 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.

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