A rosmarinic acid derivative based on proteolysis-targeting chimeras, its preparation method and applications

Abstract

The present invention belongs to the field of biomedicine, and particularly relates to a rosmarinic acid derivative based on proteolysis targeting chimera and its preparation method and application. The structural formula of the rosmarinic acid derivative is: #imgabs0# or #imgabs1#. The rosmarinic acid derivative based on the proteolysis targeting chimera technology provided by the present invention has higher pharmacological activity than the prototype drug, effectively improving the effect of the traditional Chinese medicine monomer in inhibiting NEU1; moreover, its preparation process is simple, the materials are easy to obtain, the cost is low, and it is easy to promote, and it has good application prospects in the aspect of modifying and optimizing the structure of traditional Chinese medicine monomers.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to a rosmarinic acid derivative based on proteolysis targeting chimera and its preparation method and application. Background Art

[0002] NEU1 is one of the most important subtypes of neuraminidase in mammals and is closely related to cardiovascular diseases and the like. It is extremely important to discover NEU1 inhibitors for the treatment of diseases. Salvianolic acid B has been confirmed to be a natural inhibitor of NEU1 protein. However, salvianolic acid B has unstable structure, large molecular weight and low bioavailability in vivo. It is partially metabolized into the natural product rosmarinic acid in vivo. Rosmarinic acid has a more stable structure and a lower molecular weight, and there is room for structural optimization. It is of great significance to optimize rosmarinic acid to improve its inhibitory effect on NEU1 protein.

[0003] PROTAC is a ternary complex formed by a ligand that binds to a target protein, an E3 ligase ligand, and an appropriate linker that connects these two compounds. Among them, small molecules can attract the target protein, and the E3 ligand at the other end, such as VHL and CRBN, attracts the E3 ubiquitin ligase to degrade the target protein, which can improve the oral bioavailability of drugs and promote the transformation of small molecule drugs into clinical applications. Natural products are an important source for the synthesis and modification of PROTAC.

[0004] The solubility of rosmarinic acid in hydrophobic media is relatively low, which to a certain extent limits its ability to cross lipid-rich cell membranes. Based on this, how to structurally modify and optimize rosmarinic acid to improve its biological activity and inhibitory effect on NEU1 has become an urgent problem to be solved. Summary of the Invention

[0005] Aiming at the problems existing in the prior art, the present invention provides a rosmarinic acid derivative based on proteolysis targeting chimera. The compound prepared by the present invention can effectively improve the pharmacological effects of traditional Chinese medicine monomer prototype drugs and has good application prospects in the transformation and optimization of traditional Chinese medicine monomer structures.

[0006] The present invention further provides a preparation method of the above rosmarinic acid derivative.

[0007] Another object of the present invention is to provide the application of the above rosmarinic acid derivative.

[0008] In order to achieve the above object, the technical solution of the present invention is as follows:

[0009] The present invention discloses a rosmarinic acid derivative based on proteolysis targeting chimera, and the structural formula of the rosmarinic acid derivative is:

[0010] Formula I:

[0011] or

[0012] Formula Ⅱ ;

[0013] When in Formula Ⅰ, n is 1, 2 or 3; when in Formula Ⅱ, n is 1, 2 or 3.

[0014] The present invention also discloses a preparation method of the above rosmarinic acid derivative based on the targeted protein degradation chimera, comprising the following steps:

[0015] (1) Add DIEA to the NMP solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindole-1,3-dione (Compound a) and Compound b to obtain a mixture; heat the mixture under reflux for reaction, after completion, filter the reactants to obtain a filtrate, and purify the filtrate by reverse-phase high performance liquid chromatography to obtain Compound c in the form of a yellow solid;

[0016] (2) Add TFA to the DCM solution of Compound c, stir for reaction, after completion, concentrate the reactants under vacuum to obtain Compound d in the form of a yellow oil;

[0017] (3) Add DIEA, EDCI and HOBt to the DMF solution of Compound d and rosmarinic acid (Compound e), stir for reaction, and purify the crude product by preparative high performance liquid chromatography to obtain the rosmarinic acid derivative in the form of a yellow solid.

[0018] Preferably, in step (1), in terms of molar ratio, 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindole-1,3-dione (Compound a) and Compound b:DIEA = 1:1:3; the heating under reflux reaction is carried out at 70-100 °C for 4-6 h.

[0019] Preferably, in step (1),

[0020] The structural formula of Compound b is: , n is 1, 2 or 3; or , n is 1, 2 or 3.

[0021] Preferably, in step (2), in terms of molar ratio, Compound c:TFA = 1:50; the stirring reaction is carried out at room temperature for 4-6 h.

[0022] Preferably, in step (2),

[0023] The structural formula of Compound c is: , n is 1, 2 or 3; or , n is 1, 2 or 3.

[0024] Preferably, in step (3), in terms of molar ratio, compound d: rosmarinic acid: DIEA: EDCI: HOBt = 1: 1.5: 4: 1.5: 1.5; the stirring reaction is carried out at room temperature of 15 - 25 °C for 4 - 6 h.

[0025] Preferably, in step (3),

[0026] The structural formula of compound d is: , n is 1, 2 or 3; or , n is 1, 2 or 3.

[0027] Another object of the present invention is to provide the application of the above rosmarinic acid derivative in the preparation of a drug as a NEU1 inhibitor.

[0028] The reaction process for preparing the rosmarinic acid derivative of the present invention is:

[0029] ;

[0030] .

[0031] Compared with the traditional Chinese medicine monomer prototype drug, the beneficial effects of the present invention are as follows:

[0032] (1) The rosmarinic acid derivative based on the targeted protein degradation chimera technology provided by the present invention has higher pharmacological activity than the prototype drug, effectively improving the effect of the traditional Chinese medicine monomer in inhibiting NEU1;

[0033] (2) The rosmarinic acid derivative provided by the present invention has a simple preparation process, easily available materials, low cost, and is easy to promote, and has good application prospects in modifying and optimizing the structure of traditional Chinese medicine monomers. Description of the Drawings

[0034] Figure 1 1H NMR spectrum of the rosmarinic acid derivative (RP-1) based on the protein-targeted degradation chimera;

[0035] Figure 2 13C NMR spectrum of the rosmarinic acid derivative (RP-1) based on the protein-targeted degradation chimera;

[0036] Figure 3 1H NMR spectrum of the rosmarinic acid derivative (RP-2) based on the protein-targeted degradation chimera;

[0037] Figure 4 13C NMR spectrum of the rosmarinic acid derivative (RP-2) based on the protein-targeted degradation chimera;

[0038] Figure 5 1H NMR spectrum of the rosmarinic acid derivative (RP-3) based on the protein-targeted degradation chimera;

[0039] Figure 6 13C NMR spectrum of rosmarinic acid derivative (RP-3) based on proteolysis targeting chimera;

[0040] Figure 7 1H NMR spectrum of rosmarinic acid derivative (RP-4) based on proteolysis targeting chimera;

[0041] Figure 8 13C NMR spectrum of rosmarinic acid derivative (RP-4) based on proteolysis targeting chimera;

[0042] Figure 9 1H NMR spectrum of rosmarinic acid derivative (RP-5) based on proteolysis targeting chimera;

[0043] Figure 10 13C NMR spectrum of rosmarinic acid derivative (RP-5) based on proteolysis targeting chimera;

[0044] Figure 11 1H NMR spectrum of rosmarinic acid derivative (RP-6) based on proteolysis targeting chimera;

[0045] Figure 12 13C NMR spectrum of rosmarinic acid derivative (RP-6) based on proteolysis targeting chimera;

[0046] Figure 13 Rosmarinic acid derivatives based on proteolysis targeting chimera improve the migration dysfunction of HUVECs caused by overexpression of NEU1; wherein, A is the scratch assay at different times (6 h, 12 h, 24 h, 48 h); B is the statistical analysis of the scratch assay at different times (6 h, 12 h); C is the statistical analysis of the scratch assay at different times (24 h, 48 h).

[0047] Figure 14 Fluorescence images of the NEU1 degradation effect of rosmarinic acid derivatives based on proteolysis targeting chimera; wherein, A is the fluorescence intensity of different rosmarinic acid derivatives on the degradation of NEU1; B is the statistical analysis of the fluorescence intensity of different rosmarinic acid derivatives on the degradation of NEU1. Detailed implementation manners

[0048] The following will describe the implementation schemes of the present invention in detail in combination with specific examples and drawings. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present application. For those not specified in the examples, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. For the reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0049] The first aspect of the present invention is to provide a rosmarinic acid derivative based on proteolysis targeting chimera, and its structural formula is:

[0050]

[0051] 。

[0052] When detecting the degradation degree of NEU1 protein by the rosmarinic acid derivative prepared in the present invention, the specific detection steps are as follows: overexpress the NEU1 protein in the cells to be tested, intervene with six rosmarinic acid derivatives based on the proteolysis targeting chimera technology, and set up a control group and a model group. Detect the fluorescence intensity of each group on a confocal microscope to detect the degradation effect of the rosmarinic acid derivative based on the proteolysis targeting chimera technology on the NEU1 protein.

[0053] Among them, the lower the fluorescence intensity, the higher the degradation degree of the NEU1 protein indicates.

[0054] Example 1 Synthesis of rosmarinic acid derivative (RP-1) based on proteolysis targeting chimera

[0055] (l) Add DIEA (842 mg) to a solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindole-1,3-dione (Compound a, 600 mg) and tert-butyl N-(4-aminobutyl)carbamate (Compound b1, 449.84 mg) in NMP (5 mL). React the mixture at 80 °C for 5 h. After completion, filter the reactant through a syringe-driven filter to obtain a filtrate. The crude product was purified by reverse-phase high performance liquid chromatography (column: CD18-Welch Utimate C18 150*40*7um; mobile phase: Phase A: water (containing 0.1% TFA)-Phase B: acetonitrile; gradient: 27%-57% B within 10 minutes) to obtain Compound c1 (240 mg) in the form of a yellow solid;

[0056] (2) Add TFA (1.54 g) to a solution of Compound c1 (200 mg) in DCM (2 mL), and stir the mixture at 25 °C for 6 h. After completion, concentrate the mixture in vacuo to obtain Compound d1 (200 mg) in the form of a yellow oil;

[0057] (3) To a solution of compound d1 (200 mg), rosmarinic acid (compound e, 235 mg), and DMF (2 mL) was added DIEA (225 mg), EDCI (125 mg), and HOBt (88.4 mg). The mixture was stirred at 25 °C for 6 h. The crude product was purified by preparative high performance liquid chromatography (column: CD24-XPT C18 150*25*7um; mobile phase: phase A: water (containing 0.1% FA) - phase B: acetonitrile; gradient: 16% - 46% B, 10 min), to obtain RP-1 (90.1 mg) as a yellow solid.

[0058] The chemical structure of the rosmarinic acid derivative (RP-1) based on the proteolysis targeting chimera is: ;

[0059] The 1H NMR spectrum of RP-1 is shown in Figure 1 , and the 13C NMR spectrum is shown in Figure 2 .

[0060] Example 2 Synthesis of rosmarinic acid derivative (RP-2) based on the proteolysis targeting chimera

[0061] (1) To a solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindole-1,3-dione (compound a, 600 mg) and tert-butyl N-(5-aminopentyl)carbamate (compound b2, 483 mg) in NMP (5 mL) was added DIEA (842 mg). The mixture was reacted at 80 °C for 5 h. After completion, the reactant was filtered through a syringe-driven filter to obtain a filtrate, which was purified by reverse-phase high performance liquid chromatography (column: CD18-Welch Utimate C18 150*40*7um; mobile phase: phase A: water (containing 0.1% TFA) - phase B: acetonitrile; gradient: 27% - 57% B in 10 min), to obtain compound c2 (226 mg) as a yellow solid;

[0062] (2) To a DCM (2 mL) solution of compound c2 (200 mg) was added TFA (2.46 g). The mixture was stirred at 25 °C for 6 h. The mixture was concentrated in vacuo to obtain compound d2 (200 mg) as a yellow oil;

[0063] (3) DIEA (218 mg), HOBt (85.8 mg), and EDCI (121 mg) were added to a solution of compound d2 (200 mg) and rosmarinic acid (228 mg) in DMF (2 mL). The mixture was stirred at 25 °C for 6 h. The crude product was purified by preparative high-performance liquid chromatography (column: CD04 Welch Utimate C18 150*25*7um; mobile phase: phase A: water (containing 0.1% FA) - phase B: acetonitrile; gradient: 14% - 44% B, 15 min), and yellow solid RP-2 (72.7 mg) was obtained.

[0064] The chemical structure of the rosmarinic acid derivative (RP-2) based on the proteolysis targeting chimera is as follows: ;

[0065] The 1H NMR spectrum of RP-2 is shown in Figure 3 , and the 13C NMR spectrum is shown in Figure 4 .

[0066] Example 3 Synthesis of rosmarinic acid derivative (RP-3) based on the proteolysis targeting chimera

[0067] (1) DIEA (842 mg) was added to a solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindole-1,3-dione (compound a, 600 mg) and tert-butyl N-(5-aminopentyl)carbamate (compound b3, 516 mg) in NMP (5 mL). The mixture was reacted at 80 °C for 5 h. After completion, the reactant was filtered through a syringe-driven filter to obtain a filtrate, which was purified by reverse-phase high-performance liquid chromatography (column: CD18-Welch Utimate C18 150*40*7um; mobile phase: phase A: water (containing 0.1% TFA) - phase B: acetonitrile; gradient: 27% - 57% B in 10 min), and yellow solid compound c3 (170 mg) was obtained;

[0068] (2) TFA (1.78 g) was added to a DCM (1 mL) solution of compound c3 (145 mg). The mixture was stirred at 25 °C for 6 h, and the mixture was concentrated in vacuo to obtain yellow oily compound d3 (140 mg);

[0069] (3) To a solution of compound d3 (140 mg) and rosmarinic acid (compound e, 155 mg) in DMF (1.5 mL) were added DIEA (148 mg), HOBt (58.3 mg), and EDCI (82.7 mg). The mixture was stirred at 25 °C for 6 h. The crude product was purified by preparative high-performance liquid chromatography (column: CD04 Welch Utimate C18 150*25*7um; mobile phase A: water (containing 0.1% TFA) - B: acetonitrile; gradient: 14% - 44% B, 15 min), to obtain the yellow solid RP-3 (52.0 mg).

[0070] The chemical structure of the rosmarinic acid derivative (RP-3) based on the protein-targeting degrader chimera is as follows:

[0071] ;

[0072] The 1H NMR spectrum of RP-3 is shown in Figure 5 , and the 13C NMR spectrum is shown in Figure 6 .

[0073] Example 4 Synthesis of the rosmarinic acid derivative (RP-4) based on the protein-targeting degrader chimera

[0074] (1) To a solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindole-1,3-dione (compound a, 600 mg) in NMP (10 mL) were added DIEA (842 mg) and tert-butyl N-[2-(2-aminoethoxy)ethyl]carbamate (compound b4, 465 mg). The mixture was reacted at 80 °C for 5 h. After completion, it was purified by reversed-phase high-performance liquid chromatography (column: CD18-Welch Utimate C18 150*40*7um; mobile phase: A: water (containing 0.1% TFA) - B: acetonitrile; gradient: 27% - 57% B in 10 min), to obtain the yellow solid compound c4 (470 mg).

[0075] (2) To a DCM (2 mL) solution of compound c4 (150 mg) was added TFA (1.54 g). The mixture was stirred at 25 °C for 6 h. The mixture was concentrated in vacuo to obtain the yellow oil compound d4 (150 mg).

[0076] (3) To a solution of compound d4 (200 mg) and rosmarinic acid (compound e, 227 mg) in DMF (2 mL) were added DIEA (217 mg), HOBt (85.4 mg), and EDCI (121 mg), and the mixture was stirred at 25 °C for 6 h. After completion, it was purified by preparative high performance liquid chromatography (column: CD24-XPT C18 150*25*7um; mobile phase: phase A: water (containing 0.1% TFA) - phase B: acetonitrile; gradient: 16% - 46% B in 10 minutes), and yellow solid RP-4 (100 mg) was obtained.

[0077] The chemical structure of rosmarinic acid derivative (RP-4) based on proteolysis targeting chimera is:

[0078] ;

[0079] The 1H NMR spectrum of RP-4 is shown in Figure 7 , and the 13C NMR spectrum is shown in Figure 8 .

[0080] Example 5 Synthesis of rosmarinic acid derivative (RP-5) based on proteolysis targeting chimera

[0081] (1) To a solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindole-1,3-dione (compound a, 600 mg) in NMP (10 mL) were added DIEA (842 mg) and tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (compound b5, 566 mg), and the mixture was reacted at 80 °C for 5 h. After completion, it was purified by reversed-phase high performance liquid chromatography (column: CD18-Welch Utimate C18 150*40*7um; mobile phase: phase A: water (containing 0.1% TFA) - phase B: acetonitrile; gradient: 27% - 57% B in 10 minutes), and yellow solid compound c5 (470 mg) was obtained.

[0082] (2) To a DCM (2 mL) solution of compound c5 (100 mg) was added TFA (1.54 g), and the mixture was stirred at 25 °C for 6 h. The mixture was concentrated in vacuo to obtain yellow oily compound d5 (100 mg).

[0083] (3) To a solution of compound d5 (100 mg) and rosmarinic acid (compound e, 104 mg) in DMF (2 mL), DIEA (99.7 mg), HOBt (39.1 mg), and EDCI (55.4 mg) were added. The mixture was stirred at 25 °C for 6 h. After completion, it was purified by preparative high-performance liquid chromatography (column: CD24-XPT C18 150*25*7um; mobile phase: phase A: water (containing 0.1% TFA) - phase B: acetonitrile; gradient: 16% - 46% B, 10 min), and yellow solid RP-5 (45.9 mg) was obtained.

[0084] The chemical structure of the rosmarinic acid derivative (RP-5) based on the proteolysis targeting chimera is as follows:

[0085] ;

[0086] The 1H NMR spectrum of RP-5 is shown in Figure 9 , and the 13C NMR spectrum is shown in Figure 10 .

[0087] Example 6 Synthesis of rosmarinic acid derivative (RP-6) based on the proteolysis targeting chimera

[0088] (1) To a solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindole-1,3-dione (compound a, 600 mg) in NMP (10 mL), DIEA (842 mg) and N-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]carbamic acid tert-butyl ester (compound b6, 666 mg) were added. The mixture was reacted at 80 °C for 5 h. After completion, it was purified by reversed-phase high-performance liquid chromatography (column: CD18-Welch Utimate C18 150*40*7um; mobile phase: phase A: water (containing 0.1% TFA) - phase B: acetonitrile; gradient: 27% - 57% B within 10 min), and yellow solid compound c6 (500 mg) was obtained.

[0089] (2) To a DCM (2 mL) solution of compound c6 (150 mg), TFA (1.54 g) was added. The mixture was stirred at 25 °C for 6 h, and the mixture was concentrated in vacuo to obtain yellow oily compound d6 (150 mg).

[0090] (3) To a solution of compound d6 (150 mg) and rosmarinic acid (compound e, 144 mg) in DMF (1.5 mL) were added DIEA (137 mg), HOBt (54 mg) and EDCI (76.6 mg), and the mixture was stirred at 25 °C for 6 h. After completion, it was purified by preparative high performance liquid chromatography (column: CD24-XPT C18 150*25*7um; mobile phase: phase A: water (containing 0.1% TFA) - phase B: acetonitrile; gradient: 14% - 44% B, 10 min) to obtain RP-6 (81.5 mg) as a yellow solid.

[0091] The chemical structure of the rosmarinic acid derivative (RP-6) based on the proteolysis targeting chimera is as follows:

[0092] ;

[0093] The 1H NMR spectrum of RP-6 is shown in Figure 11 , and the 13C NMR spectrum is shown in Figure 12 .

[0094] Effect Example 1 Improvement of the migration function of HUVECs induced by overexpression of NEU1 by rosmarinic acid derivatives (RP-1 to RP-6) based on proteolysis targeting chimeras

[0095] The cell migration assay is an intuitive experiment to evaluate the function of vascular endothelial cells. A cell scratch assay was performed on HUVECs to test the in vitro efficacy of rosmarinic acid derivatives (RP-1 to RP-6) based on proteolysis targeting chimeras.

[0096] HUVECs in the logarithmic growth phase were seeded into 6-well plates at a density of approximately 5 × 10 5 / well and cultured in a 37 °C, 5% CO2 incubator for 24 h. After 24 h of culture, each group was treated with RP-1 to RP-6 (10 µM) for 24 h. The confluent monolayer cells were carefully scraped vertically with the tip of a sterile 10 μL pipette, and the suspended cell debris was washed with PBS and the medium was replaced. Images were immediately taken at 0 h under an inverted fluorescence microscope. The cells were placed in the incubator and photographed at 6, 12, 24, and 48 h to record the cell migration in the scratched area. The Image J software was used to quantitatively calculate and evaluate the experimental results.

[0097] As Figure 13As shown in A, B, and C: During the four observed time periods, the performance trends of each compound maintained relative stability. At the 12-hour observation point, significant differences were found between each treatment group and the untreated model group, with RP-5 showing particularly prominent performance. Within 1 to 2 days after the intervention, there were no significant differences between RP-5 and RP-6 compared to the model group, indicating that they had little effect on cell migration in the short term. Further observation found that there were also no significant differences between RP-5 and the normal group at the 24-hour and 48-hour time points, further demonstrating its significant pharmacological effect.

[0098] Effect Example 2 Study on the Degradation of NEU1 Protein by Rosmarinic Acid Derivatives (RP-1~RP-6) Based on Proteolysis-Targeting Chimeras

[0099] Take logarithmically growing HUVEC cells and seed them in 6-well culture plates. When the cells grow and reach 70% confluence, perform cell transfection according to the Lipofectamine 3000 instruction manual. Mix 3 μg of plasmid DNA with 6 μL of Lipofectamine 3000 reagent in each well and incubate at room temperature for 15 min to form a DNA-liposome complex. Subsequently, add this complex dropwise to the cell culture medium, gently shake the culture plate to ensure uniform distribution, and continue to culture the cells in a 37°C, 5% CO2 incubator for 6 h, then change the medium and administer drugs in groups: oseltamivir, salvianolic acid B, rosmarinic acid, RP-1~RP-6 at 10 μM each, and continue to culture for 24 h. Using the fluorescence intensity value of endothelial cells as the measurement standard, evaluate the degradation effect of rosmarinic acid derivatives based on proteolysis-targeting chimeras on NEU1 protein, and use Image J software to process the images and measure the fluorescence intensity. See Figure 14 A and B in, RP-4~RP-6 significantly degraded NEU1 while maintaining cell viability.

Claims

1. A rosmarinic acid derivative based on proteolysis targeting chimera, characterized in that, The structural formula of the rosmarinic acid derivative is as follows: Formula I: ； or Formula II: ； When it is Formula I, n is 1, 2 or 3; when it is Formula II, n is 1, 2 or 3.

2. A preparation method of a rosmarinic acid derivative based on a target protein degradation chimera as described in claim 1, characterized in that, It includes the following steps: (1) Add DIEA to the NMP solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindole-1,3-dione and compound b to obtain a mixture; heat the mixture under reflux for reaction. After completion, filter the reactants to obtain a filtrate, and purify the filtrate by reverse-phase high-performance liquid chromatography to obtain a yellow solid compound c; (2) Add TFA to the DCM solution of compound c and stir for reaction. After completion, concentrate the reactants in vacuo to obtain a yellow oily compound d; (3) Add DIEA, EDCI and HOBt to the DMF solution of compound d and rosmarinic acid, stir for reaction, and purify the crude product by preparative high-performance liquid chromatography to obtain a yellow solid rosmarinic acid derivative; The structural formula of compound b is as follows: , where n is 1, 2 or 3; or , where n is 1, 2 or 3; The structural formula of compound c is as follows: , where n is 1, 2, or 3; or , where n is 1, 2, or 3; The structural formula of compound d is as follows: , where n is 1, 2 or 3; or , where n is 1, 2 or 3.

3. The preparation method according to claim 2, characterized in that, In step (1), in terms of molar ratio, 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindole-1,3-dione, compound b:DIEA = 1:1:3; the heating under reflux reaction is carried out at 70-100 °C for 4-6 h.

4. The preparation method according to claim 2, characterized in that, In step (2), in terms of molar ratio, compound c:TFA = 1:50; the stirring reaction is carried out at room temperature for 4-6 h.

5. The preparation method according to claim 2, wherein In step (3), in terms of molar ratio, compound d:rosmarinic acid:DIEA:EDCI:HOBt = 1:1.5:4:1.5:1.5; the stirring reaction is carried out at room temperature of 15-25 °C for 4-6 h.

6. Use of a rosmarinic acid derivative as described in claim 1 in the preparation of a drug as a NEU1 inhibitor.

Images