Methylene dimethylamino-modified curcumin analogues, methods of making and uses thereof

Abstract

The application discloses a methylenedimethylamino-modified curcumin analogue as well as a preparation method and application thereof. A structural formula of the curcumin analogue is shown as formula I. The application introduces a methylenedimethylamino into a curcumin molecule, chemically synthesizes a series of curcumin analogues, and then combines the compounds with hydrochloric acid to form hydrochloride, so that water solubility of the curcumin analogue is greatly improved. Some of the compounds show more excellent anti-inflammatory activity and antioxidant activity compared with curcumin. Through structural modification of curcumin, the curcumin analogue synthesized in the application is superior to curcumin in water solubility and pharmacological activity, and is expected to be applied in development of new anti-inflammatory drugs and anti-tumor drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic chemical synthesis and medicine, and particularly relates to methylenedimethylamino-modified curcumin analogues and a preparation method and application thereof. BACKGROUND

[0002] Curcumin is a natural product isolated from Curcuma aromatica Salisb. and C. longa L. It is an orange-yellow crystalline powder and has multiple pharmacological activities such as inhibiting inflammatory response, antioxidation, inhibiting tumor growth, anti-diabetes, and neuroprotection. A large number of studies have proved that curcumin does not show obvious toxicity at a high dose. However, the solubility of curcumin in water and various buffer aqueous solutions is poor, which greatly limits the clinical application of curcumin. Therefore, a large number of studies focus on improving the water solubility of curcumin, improving the pharmacokinetic properties of curcumin, and increasing the bioavailability thereof. Salification is also a very important method for improving the solubility of a drug. Sildenafil, a drug for treating erectile dysfunction, is a lead compound whose solubility is insufficient. After a methylpiperazine sulfonyl group is introduced, the water solubility of the compound is greatly improved after salification with citric acid. Inspired by this, the inventors of the present application expect to improve the structure of curcumin to obtain a curcumin analogue with significantly improved water solubility and activity. SUMMARY

[0003] The purpose of the present application is to provide a curcumin analogue. The inventors introduce a methylenedimethylamino group to one side of the benzene ring of curcumin, and design and synthesize a series of curcumin analogues by changing the substituents of the other side of the benzene ring. Due to the presence of the methylenedimethylamino group, these analogues can be salified with common acids, greatly improving the water solubility of curcumin. The in vitro anti-inflammatory and antioxidant activities of the obtained curcumin analogues are evaluated, and it is found that the anti-inflammatory activity of the compounds is significantly better than that of curcumin, and the antioxidant activity of the compounds is significantly better than that of curcumin.

[0004] The curcumin analogue provided by the present application or a pharmaceutically acceptable salt thereof has the structural general formula as shown in formula I:

[0005]

[0006] Further, R in formula I is selected from any of the following groups:

[0007]

[0008] The above R substituents 1-15 correspond to compounds 1-15 in formula I, respectively.

[0009] The carbon atom in the curcumin analogue of formula I is selected from at least one of 12C, 14C; and the hydrogen atom is selected from at least one of 1H, 2H, 3H.

[0010] The above-mentioned "pharmaceutically acceptable salt" refers to a salt which is within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response and the like, and commensurate with a reasonable benefit / risk ratio. The pharmaceutically acceptable salts of the compound of formula I are well known in the art, and include but are not limited to hydrochloride, nitrate, sulfate, bisulfate, phosphate, hydrogen phosphate, acetate, oxalate, lactate, citrate, tartrate, maleate and the like.

[0011] The present application also provides a preparation method of the curcumin analogue of formula I or the pharmaceutically acceptable salt thereof.

[0012] The preparation method of the curcumin analogue of formula I or the pharmaceutically acceptable salt thereof provided by the present application comprises the following steps:

[0013] 1) condensing the compound of formula II with 2,4-pentanedione in the presence of diboron trioxide and trimethyl borate to obtain the compound of formula III;

[0014]

[0015] wherein R in the compound of formula II is defined the same as R in formula I;

[0016] 2) reacting vanillin, dimethylamine and formaldehyde to obtain the compound of formula IV;

[0017]

[0018] 3) condensing the compound of formula III with the compound of formula IV in the presence of diboron trioxide and trimethyl borate to obtain the compound of formula I.

[0019] In the above-mentioned step 1) of the method, the molar ratio of the compound of formula II to 2,4-pentanedione is 1:(0.8-1.2).

[0020] In the above-mentioned step 1) of the method, the molar ratio of the compound of formula II to diboron trioxide, trimethyl borate is 1:(2-4):(2-4).

[0021] In the above-mentioned step 1) of the method, the reaction is carried out in a solvent, which can be ethyl acetate.

[0022] In the above-mentioned step 1) of the method, the reaction condition of the condensation reaction is heating.

[0023] The step 1) further comprises a step of separating the product by silica gel column chromatography after the reaction, and the eluent E (ethyl acetate):P (petroleum ether) =1:40-1:5 (v / v).

[0024] Specifically, the reaction operation of the step 1) is as follows: adding boric oxide into ethyl acetate solution of 2,4-pentanedione, and stirring the obtained solution at 70-90 °C for 0.5-2 h; adding trimethyl borate and ethyl acetate solution of the compound shown in formula II, and stirring at 70-90 °C for 0.5-2 h after completion of the addition; adding n-butylamine (to initiate the condensation reaction of acetylacetone-boron complex and aldehyde), and stirring at 90-110 °C for 0.5-2 h; adding 1N hydrochloric acid into the system, and stirring at 40-60 °C for 0.5-2 h; adding water, and extracting the aqueous phase with ethyl acetate for 3 times; combining the organic phases, adding anhydrous Na2SO4 for drying, filtering and concentrating to obtain the crude product; separating the crude product by silica gel column chromatography, and using eluent E (ethyl acetate):P (petroleum ether) =1:40-1:5 (v / v) to obtain the compound shown in formula III after purification.

[0025] In the step 2) of the method, the molar ratio of the vanillin, dimethylamine and formaldehyde is 1:(2-4):(4-6).

[0026] In the step 2) of the method, the reaction is carried out in a solvent, and the solvent can be methanol.

[0027] In the step 2) of the method, the reaction condition is heating.

[0028] The step 2) further comprises a step of separating the product by silica gel column chromatography after the reaction, and the eluent E (ethyl acetate):P (petroleum ether) =1:50-1:3 (v / v).

[0029] In the step 3) of the method, the molar ratio of the compound shown in formula III and the compound shown in formula IV is 1:

[0030] (0.8-1.2).

[0031] In the step 3) of the method, the molar ratio of the compound shown in formula III, boric oxide and trimethyl borate is 1:(2-4):(2-4).

[0032] In the step 3) of the method, the reaction is carried out in a solvent, and the solvent can be ethyl acetate.

[0033] In the step 3) of the method, the reaction condition of the condensation reaction is heating.

[0034] The step 3) further comprises a step of separating the product by silica gel column chromatography after the reaction, and the eluent E (ethyl acetate):P (petroleum ether) =1:40-1:5 (v / v).

[0035] Specifically, the reaction operation of step 3) is as follows: add boric oxide to the ethyl acetate solution of the compound shown in formula IV, stir the obtained solution at 70-90℃ for 0.5h-2h; add the ethyl acetate solution of trimethyl borate and vanillin, stir at 70-90℃ for 0.5h-2h after addition; add piperidine, stir at 90-110℃ for 0.5h-2h; add 1N hydrochloric acid to the system, stir at 40-60℃ for 0.5h-2h, add water, extract the aqueous phase with ethyl acetate for 3 times, combine the organic phases, dry with anhydrous Na2SO4, filter and concentrate to obtain the crude product; separate the crude product by silica gel column chromatography, eluent E (ethyl acetate): P (petroleum ether) = 1:40-1:5 (v / v) to obtain the compound shown in formula I after purification.

[0036] The application also provides the use of the curcumin analogues shown in formula I or pharmaceutically acceptable salts thereof.

[0037] The use includes at least one of the following aspects: 1) use in the preparation of anti-inflammatory drugs; 2) use in the preparation of antioxidant drugs; 3) use in the preparation of antitumor drugs.

[0038] The anti-inflammatory drugs or antioxidant drugs prepared by using the compound shown in formula I as the active ingredient also belong to the protection scope of the present application.

[0039] The application also provides a pharmaceutical preparation.

[0040] The pharmaceutical preparation provided by the present application contains a therapeutically effective amount of the curcumin analogue shown in formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0041] In the above pharmaceutical preparation, the curcumin analogue shown in formula I or a pharmaceutically acceptable salt thereof can be used as one of the effective components or as the only effective component.

[0042] The above pharmaceutically acceptable carrier includes but is not limited to water-soluble carrier materials (such as polyethylene glycol, polyvinylpyrrolidone, organic acid, etc.), poorly soluble carrier materials (such as ethyl cellulose, cholesteryl stearate, etc.), enteric soluble carrier materials (such as cellulose acetate phthalate and carboxymethyl cellulose, etc.). Using these materials can be made into various dosage forms, including but not limited to tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations, buccal tablets, suppositories, freeze-dried powder injections, etc. It can be ordinary preparation, sustained-release preparation, controlled-release preparation and various microparticle drug delivery systems.

[0043] For the preparation of tablets, various carriers known in the art can be widely used. Examples of the carriers are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, white clay, microcrystalline cellulose, aluminum silicate, etc.; humectants and binders such as water, glycerol, polyethylene glycol, ethanol, propanol, starch paste, dextrin, sugar syrup, honey, glucose solution, acacia paste, gelatin paste, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrants such as dry starch, alginate, agar powder, alginic acid, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glycerol triestearate, cocoa butter, hydrogenated oil, etc.; absorption accelerators such as quaternary ammonium salt, sodium dodecylsulfate, etc.; lubricants such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. The tablets can be further prepared as coated tablets such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets. For the preparation of pills, various carriers known in the art can be widely used. Examples of the carriers are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, etc.; binders such as acacia, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or wheat paste, etc.; disintegrants such as agar powder, dry starch, alginate, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc. For the preparation of suppositories, various carriers known in the art can be widely used. Examples of the carriers are, for example, polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc. For the preparation of injection preparations such as solutions, emulsions, lyophilized powders and suspensions, all diluents commonly used in the art can be used, for example, water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxyethylated sorbitol fatty acid ester, etc. In addition, for the preparation of isotonic injection solutions, an appropriate amount of sodium chloride, glucose or glycerol can be added to the injection preparations, and in addition, conventional co-solvents, buffers, pH adjustors, etc. can be added. In addition, if necessary, coloring agents, preservatives, fragrances, flavoring agents, sweetening agents or other materials can be added to the pharmaceutical preparations. The above dosage forms can be administered by injection, including subcutaneous injection, intravenous injection, intramuscular injection and intracavitary injection, etc.; cavity administration such as rectal and vaginal administration; respiratory tract administration such as nasal cavity; mucosal administration.

[0044] The present application synthesizes a new curcumin analogue by structural modification of curcumin. The curcumin analogue or its pharmaceutically acceptable salt has better solubility in water than curcumin, and its anti-inflammatory activity and antioxidant activity are also better than curcumin, and is expected to be applied in the development of new anti-inflammatory drugs and anti-tumor drugs. BRIEF DESCRIPTION OF DRAWINGS

[0045] Figure 1 A synthesis route map of the curcumin analogue represented by formula I of the present application;

[0046] Figure 2 A C NMR spectrum of compound 1; 13

[0047] Figure 3 A H NMR spectrum of compound 1; 1

[0048] Figure 4 A C NMR spectrum of compound 2; 13

[0049] Figure 5 A H NMR spectrum of compound 2; 1

[0050] Figure 6 A C NMR spectrum of compound 3; 13

[0051] Figure 7 A H NMR spectrum of compound 3; 1

[0052] Figure 8 A C NMR spectrum of compound 4; 13

[0053] Figure 9 A H NMR spectrum of compound 4; 1

[0054] Figure 10 A C NMR spectrum of compound 5; 13

[0055] Figure 11 A H NMR spectrum of compound 5; 1

[0056] Figure 12 A C NMR spectrum of compound 6; 13

[0057] Figure 13 A H NMR spectrum of compound 6; 1

[0058] ​​​​​​​​​​​​Figure 14 Compound 7 13 H NMR spectrum;

[0059] Figure 15 Compound 7 1 H NMR spectrum;

[0060] Figure 16 Compound 8 13 H NMR spectrum;

[0061] Figure 17 Compound 8 1 H NMR spectrum;

[0062] Figure 18 Compound 9 13 H NMR spectrum;

[0063] Figure 19 Compound 9 1 H NMR spectrum;

[0064] Figure 20 Compound 10 13 H NMR spectrum;

[0065] Figure 21 Compound 10 1 H NMR spectrum;

[0066] Figure 22 Compound 11 13 H NMR spectrum;

[0067] Figure 23 Compound 11 1 H NMR spectrum;

[0068] Figure 24 Compound 12 13 H NMR spectrum;

[0069] Figure 25 Compound 12 1 H NMR spectrum;

[0070] Figure 26 Compound 13 13 H NMR spectrum;

[0071] Figure 27 Compound 13 1 H NMR spectrum;

[0072] Figure 28 Compound 14 13 H NMR spectrum;

[0073] Figure 29 Compound 14 is 1 H NMR spectrum;

[0074] Figure 30 Compound 15 is 13 C NMR spectrum;

[0075] Figure 31 Compound 15 is 1 H NMR spectrum;

[0076] Figure 32 In vitro anti-inflammatory activity data of curcumin analogues;

[0077] Figure 33 In vitro antioxidant activity data of curcumin analogues. DETAILED DESCRIPTION

[0078] The present application will be further described in conjunction with specific examples, but the present application is not limited to the following examples. The methods are all conventional methods unless otherwise specified. The raw materials are all commercially available unless otherwise specified.

[0079] Example 1, synthesis of compound 15

[0080] Compound 15 is a compound of formula I, wherein R is .

[0081] a) To a solution of 2,4-pentanedione (0.9 g) in ethyl acetate was added boron trioxide (0.21 g) and the resulting solution was stirred at 80 °C for 0.5 h. A solution of trimethyl borate (0.31 g) and vanillin (0.5 g) in ethyl acetate (8 ml) was added and the resulting solution was stirred at 80 °C for 0.5 h. n-Butylamine (0.22 g) was added and the resulting solution was stirred at 100 °C for 1 h. 5 ml of 1 N hydrochloric acid was added to the solution and the resulting solution was stirred at 50 °C for 0.5 h. 20 ml of water was added to the solution and the aqueous phase was extracted with ethyl acetate (20 ml x 3) three times. The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give 1 g of crude product. The crude product was separated by column chromatography on silica gel using E:P = 1:40-1:5 (v / v) as eluent to give 0.6 g of the target product (corresponding to compound of formula III).

[0082] b) Mix dimethylamine (40%, 10 g) and formaldehyde (37%, 10.67 g) and stir at 70°C for 0.5 h. Add a solution of vanillin (10 g) in 80 ml of methanol and stir at 70°C for 12 h. Concentrate the reaction solution under reduced pressure to remove methanol and extract the aqueous phase with ethyl acetate three times (20 ml*3). Combine the organic phases, dry over anhydrous Na2SO4, filter and concentrate to obtain 11.2 g of crude product. The crude product is separated by silica gel column chromatography using eluent E:P = 1:50-1:3 (v / v) to obtain 6.6 g of the target product 3-((dimethylamino)methyl)-4-hydroxy-5-methoxybenzaldehyde (compound shown in Formula IV).

[0083]

[0084] c) Add boric oxide (28 mg) to a solution of 3-((dimethylamino)methyl)-4-hydroxy-5-methoxybenzaldehyde (0.1 g) prepared in step b) in ethyl acetate and stir the resulting solution at 80°C for 0.5 h. Add a solution of trimethyl borate (50 mg) and vanillin (67 mg) in ethyl acetate (2 ml) and stir at 80°C for 0.5 h. Add piperidine (41 mg) and stir at 100°C for 1 h. Add 2 ml of 1N hydrochloric acid to the system and stir at 50°C for 0.5 h. Add 10 ml of water and extract the aqueous phase with ethyl acetate three times (10 ml*3). Combine the organic phases, dry over anhydrous Na2SO4, filter and concentrate to obtain 35 mg of crude product. The crude product is separated by silica gel column chromatography using eluent E:P = 1:40-1:5 to obtain 12 mg of the target product (compound 15).

[0085] The structure identification results of compound 1 are shown in Figures 2-31 .

[0086] Solubility in water: The solubility of curcumin in water is only 13.76 μg / ml, and the solubility of compound 5 and the hydrochloride salt of compound 11 is 117 mg / ml and 285 mg / ml, respectively, which is greatly improved.

[0087] Other compounds 1-14 can be prepared according to the preparation method of compound 15.

[0088] The structure identification results of compound 1 are shown in Figures 2-3 ;

[0089] The structure identification results of compound 2 are shown in Figures 4-5 ;

[0090] The structure identification results of compound 3 are shown in Figures 6-7 ;

[0091] The structure identification results of compound 4 are shown in Figures 8-9 ;

[0092] The structural identification results of compound 5 are shown in Figures 10-11 ;

[0093] The structural identification results of compound 6 are shown in Figures 12-13 ;

[0094] The structural identification results of compound 7 are shown in Figures 14-15 ;

[0095] The structural identification results of compound 8 are shown in Figures 16-17 ;

[0096] The structural identification results of compound 9 are shown in Figures 18-19 ;

[0097] The structural identification results of compound 10 are shown in Figures 20-21 ;

[0098] The structural identification results of compound 11 are shown in Figures 22-23 ;

[0099] The structural identification results of compound 12 are shown in Figures 24-25 ;

[0100] The structural identification results of compound 13 are shown in Figures 26-27 ;

[0101] The structural identification results of compound 14 are shown in Figures 28-29 ;

[0102] The structural identification results of compound 15 are shown in Figures 30-31 .

[0103] Example 2: Inhibition of LPS-induced NO release in RAW264.7 cells by curcumin analogs (compounds 1-15)

[0104] Nitric oxide (NO) is an important gaseous signal and effector molecule, which participates in a variety of biological effects and physiological and pathological processes as a second messenger.

[0105] The mouse monocyte macrophage RAW264.7 was cultured with DMEM medium (containing 10% domestic fetal bovine serum and 1% double-antibiotic), and after being placed in a 37℃, 5% CO2 incubator for 24 h, the logarithmic growth phase RAW264.7 cells were digested and centrifuged, and the number of cells was 3×10 4Cells were seeded at a density of 80 μL per well in 96-well plates and cultured in a cell culture incubator at 37°C and 5% CO2. After 24 h of cell adhesion observed under a microscope, the cells were divided into a blank control group, a model group (LPS group), a curcumin treatment group, and a curcumin analog treatment group, with three replicates in each group. In the curcumin treatment group, 10 μL of 10 μM curcumin solution was added first. In the curcumin analog treatment group, 10 μL of sample solutions of different concentrations (final concentrations of 5, 10, and 20 μM) were added first. Then, except for the blank control group, 10 μL of LPS with a final concentration of 1 μg / ml was added to each well for inflammatory stimulation. Finally, 20 μL of DMEM culture medium was added to each well in the blank control group and 10 μL of DMEM culture medium was added to each well in the model group, resulting in a final volume of 100 μL per well. Continue incubation at constant temperature for 24 h, and determine NO content using a nitric oxide kit. Take 50 μL of cell supernatant and NaNO2 standard (0, 1.56, 3.13, 6.25, 12.5, 25, 50, 100, 200 μM) per well into a 96-well plate, add 50 μL of Griess R1 reagent to each well, incubate at room temperature in the dark for 5 min, then add 50 μL of Griess R2 reagent, and incubate at room temperature in the dark for another 5 min. Measure the absorbance of each well at 540 nm using a microplate reader within 30 minutes.

[0106] Preparation of the standard curve: The average absorbance (OD value) was plotted on the x-axis, and the NO concentration of the standard was plotted on the y-axis using Excel, yielding the standard curve formula (y = 161.64x - 9.4822). The NO concentration was calculated by substituting the OD values ​​from each group into the standard curve. Results are shown below. Figure 32 .

[0107] Depend on Figure 32 It can be seen that compounds 1, 5, 6, 7, 8, 10, 11, and 12 exhibited superior anti-inflammatory activity compared to curcumin at a concentration of 20 μM.

[0108] Example 3: Protective effect of curcumin analogues (compounds 1-15) against H2O2-induced damage to PC12 cells

[0109] PC12 cells were cultured in DMEM medium (containing 5% imported fetal bovine serum, 10% horse serum, and 1% penicillin antibiotics) and incubated at 37°C in a 5% CO2 incubator for 24 hours. PC12 cells in the logarithmic growth phase were then digested and centrifuged to a cell count of 8 × 10⁻⁶ cells / cells. 3The density of 80 μL per well was used to inoculate the 96-well plate, and the cells were cultured in a cell incubator at 37°C and 5% CO2. After 24 hours of cell adhesion under a microscope, the cells were divided into a blank group, an oxidative damage model group, and a drug treatment group (curcumin group and compound 1-15 group), each group was set up in triplicate. In the drug treatment group, 10 μL of different concentrations of sample solution (final concentrations were 5, 10, and 20 μM, respectively) were added first, then 10 μL of H2O2 with a final concentration of 140 μM was added to each well except the blank group to construct an oxidative damage cell model, finally 20 μL of DMEM culture medium was added to each well of the blank group and 10 μL to each well of the model group, and the final volume of each well was 100 μL. After 24 hours of constant temperature culture, the cell viability was detected by the CCK8 method, and after 2 hours of placement in a 37°C CO2 incubator, the absorbance of each well was determined by a microplate reader at 450 nm wavelength. The survival rate of each group of cells was calculated according to the cell survival rate calculation formula (A / A0*100%, A is the average absorbance of this group, and A0 is the average absorbance of the blank group). The results are shown in Figure 33 .

[0110] It can be seen from Figure 33 that the antioxidant activity of compounds 5 and 11 at concentrations of 5 μM, 10 μM, and 20 μM is significantly better than that of curcumin.

Claims

1. A curcumin analogue or a pharmaceutically acceptable salt thereof, having a general structure as shown in Formula I: ###0001### Formula I wherein R is selected from any of the following groups: ###0002### 3. A method for preparing the curcumin analogue or a pharmaceutically acceptable salt thereof according to claim 1 or 2, comprising the following steps: 1) condensing a compound shown in Formula II with 2,4-pentanedione in the presence of boron trioxide and trimethyl borate to obtain a compound shown in Formula III; ###0003### Formula II Formula III wherein R is defined as R in Formula I of claim 1; 2) reacting vanillin, dimethylamine and formaldehyde to obtain a compound shown in Formula IV; ###0004### Formula IV 3) condensing the compound shown in Formula III with the compound shown in Formula IV in the presence of boron trioxide and trimethyl borate to obtain the compound shown in Formula I. 。 2. The curcumin analog or pharmaceutically acceptable salt thereof according to claim 1, characterized by: The carbon atoms in said formula I are selected from at least one of the following: 12 C, 14 C; the hydrogen atoms are selected from at least one of the following: 1 H, 2 H, 3 H. In step 1), the molar ratio of the compound shown in Formula II to 2,4-pentanedione is 1:(0.8-1.2); or, the molar ratio of the compound shown in Formula II to boron trioxide, trimethyl borate is 1:(2-4):(2-4); or, the reaction is carried out in a solvent, and the solvent is ethyl acetate; or, the reaction condition of the condensation reaction is heating; or, step 1) further comprises a step of separating the product by silica gel column chromatography after the reaction is completed, and the eluent E (ethyl acetate):P (petroleum ether) =1:40-1:5 (v / v). In step 2), the molar ratio of vanillin, dimethylamine and formaldehyde is 1:(2-4):(4-6); or, the reaction is carried out in a solvent, and the solvent is methanol; or, the reaction condition is heating; or, step 2) further comprises a step of separating the product by silica gel column chromatography after the reaction is completed, and the eluent E (ethyl acetate):P (petroleum ether) =1:50-1:3 (v / v). wherein In step 3), the molar ratio of the compound shown in Formula III to the compound shown in Formula IV is 1:(0.8-1.2); or, the molar ratio of the compound shown in Formula III to boron trioxide, trimethyl borate is 1:(2-4):(2-4); or, the reaction is carried out in a solvent, and the solvent is ethyl acetate; or, the reaction condition of the condensation reaction is heating; or, step 3) further comprises a step of separating the product by silica gel column chromatography after the reaction is completed, and the eluent E (ethyl acetate):P (petroleum ether) =1:40-1:5 (v / v).

7. Use of the curcumin analogue shown in Formula I or a pharmaceutically acceptable salt thereof according to claim 1 in at least one of the following aspects: 1) in the preparation of an anti-inflammatory drug; 2) in the preparation of an antioxidant drug; 3) in the preparation of an anti-tumor drug.

8. A pharmaceutical preparation comprising a therapeutically effective amount of the curcumin analogue shown in Formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2 and a pharmaceutically acceptable carrier.

4. The method of claim 3, wherein: The pharmaceutical preparation has at least one of the following effects: 1) anti-inflammatory; 2) antioxidant; 3) anti-tumor. ​ ​ ​ ​ 5. The method of claim 3, wherein: ​ ​ ​ ​ 6. The method of claim 3, wherein: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 9. The pharmaceutical preparation according to claim 8, characterized in that: ​

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