Imatinib derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of drug synthesis, and provides an imatinib derivative and a preparation method and application thereof, the imatinib derivative provided by the invention has a new structure, and can reduce tumor interstitial fluid pressure, enhance drug permeability and improve drug curative effect. The specific preparation method comprises the following steps: mixing 4-mercaptobenzoic acid, N, N-dimethylformamide, N-hydroxysuccinimide and an N, N '-dicyclohexylcarbodiimide solution to obtain an activation system; and mixing the active system with imatinib amine for reaction to obtain the imatinib derivative. According to the preparation method, the synthesis reaction process is simple and easy to control, and the price is low.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to an imatinib derivative and a preparation method and application thereof. Background Art

[0002] Malignant tumors are one of the leading causes of death worldwide. Their development is an extremely complex process involving multiple stages and multiple factors. As cancer cells grow, the environment surrounding them undergoes tremendous changes. Compared with the internal environment of a healthy human body, the formation of a tumor microenvironment accelerates the occurrence, development, and metastasis of malignant tumors. Tumor interstitial fluid pressure plays an important role in this process. Increased tumor interstitial fluid pressure not only promotes the growth, survival, and metastasis of cancer cells, but also hinders drug penetration, thereby reducing the effectiveness of chemotherapy and targeted therapy. Therefore, the treatment of malignant tumors has always been a difficult problem in the world.

[0003] Lung cancer is one of the most common cancers worldwide, with non-small cell lung cancer accounting for 80-85% of lung cancer cases. Genetic mutations, signaling pathway aberrations, and environmental changes promote tumor angiogenesis, tumor cell proliferation, and survival. Various factors can increase tumor interstitial fluid pressure, thereby impairing drug penetration and reducing therapeutic efficacy. Therefore, a novel compound that can reduce tumor interstitial fluid pressure was designed and synthesized in the hope of mitigating adverse drug reactions and improving drug efficacy. Summary of the Invention

[0004] The purpose of the present invention is to overcome the defects in the prior art and provide an imatinib derivative and a preparation method and application thereof.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides an imatinib derivative, the structure of which is shown below:

[0007]

[0008] The present invention also provides a method for preparing the imatinib derivative, comprising the following steps:

[0009] (1) mixing 4-mercaptobenzoic acid, N,N-dimethylformamide, N-hydroxysuccinimide and N,N'-dicyclohexylcarbodiimide solution to obtain an activation system;

[0010] (2) The active system and imatinib are mixed and reacted to obtain the imatinib derivative.

[0011] Preferably, the mass volume ratio of 4-mercaptobenzoic acid and N,N-dimethylformamide in step (1) is 0.05-0.1 g: 3-6 mL.

[0012] Preferably, the N,N'-dicyclohexylcarbodiimide solution in step (1) comprises N,N'-dicyclohexylcarbodiimide and N,N-dimethylformamide;

[0013] The mass volume ratio of N,N'-dicyclohexylcarbodiimide and N,N-dimethylformamide is 0.1-0.2 g:1-2 mL.

[0014] Preferably, in step (1), the mass ratio of 4-mercaptobenzoic acid, N-hydroxysuccinimide and N,N'-dicyclohexylcarbodiimide is 0.05-0.1:0.05-0.1:0.1-0.2.

[0015] Preferably, the mixing temperature in step (1) is 20-30° C. and the mixing time is 1-2 h.

[0016] Preferably, the molar ratio of the imamine in step (2) to the 4-mercaptobenzoic acid in step (1) is 0.5-1.5:0.5-1.5.

[0017] Preferably, the reaction temperature in step (2) is 20-30° C. and the reaction time is 45-55 h.

[0018] The present invention also provides the use of the imatinib derivative in preparing drugs for treating tumors.

[0019] The present invention provides an imatinib derivative. This imatinib derivative has a novel structure and can reduce tumor interstitial fluid pressure, enhance drug permeability, and improve drug efficacy. The specific preparation method is as follows: 4-mercaptobenzoic acid, N,N-dimethylformamide, N-hydroxysuccinimide, and N,N'-dicyclohexylcarbodiimide solution are mixed to obtain an activated system; the activated system is mixed with imatinib and reacted to obtain the imatinib derivative. The preparation method provided by the present invention has a simple, easily controllable synthetic reaction process and is inexpensive. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is the UV scanning result of the reaction solution in Example 1;

[0021] Figure 2 is the characteristic band diagram of the imatinib derivative in Example 1;

[0022] Figure 3 is the H NMR spectrum of the imatinib derivative in Example 1;

[0023] Figure 4 is the NMR carbon spectrum of the imatinib derivative in Example 1;

[0024] Figure 5 is a high-resolution mass spectrum of the imatinib derivative in Example 1;

[0025] Figure 6 Figure 2 is the change of TIFP in each group of mice before and after drug administration;

[0026] Figure 7 The figure shows the immunofluorescence staining results of PDGFR-β in tumor tissue;

[0027] Figure 8 The relative fluorescence intensity results of PDGFR-β in each group are shown;

[0028] Figure 9 Figure 1 is the immunofluorescence staining result of p-PDGFR-β in tumor tissue;

[0029] Figure 10 The graph shows the relative fluorescence intensity of p-PDGFR-β in each group. DETAILED DESCRIPTION

[0030] The present invention provides an imatinib derivative, the structure of which is shown below:

[0031]

[0032] The present invention provides a method for preparing the imatinib derivative, comprising the following steps:

[0033] (1) mixing 4-mercaptobenzoic acid, N,N-dimethylformamide, N-hydroxysuccinimide and N,N'-dicyclohexylcarbodiimide solution to obtain an activation system;

[0034] (2) The active system and imatinib are mixed and reacted to obtain the imatinib derivative.

[0035] In the present invention, the mass volume ratio of 4-mercaptobenzoic acid and N,N-dimethylformamide in step (1) is preferably 0.05-0.1 g:3-6 mL, more preferably 0.06-0.09 g:3.5-5.5 mL, and more preferably 0.07-0.08 g:4-5 mL.

[0036] In the present invention, the N,N'-dicyclohexylcarbodiimide solution in step (1) comprises N,N'-dicyclohexylcarbodiimide and N,N-dimethylformamide.

[0037] In the present invention, the mass volume ratio of N,N'-dicyclohexylcarbodiimide to N,N-dimethylformamide is preferably 0.1-0.2 g:1-2 mL, more preferably 0.12-0.18 g:1.2-1.8 mL, and even more preferably 0.14-0.16 g:1.4-1.6 mL.

[0038] In the present invention, the mass ratio of 4-mercaptobenzoic acid, N-hydroxysuccinimide and N,N'-dicyclohexylcarbodiimide in step (1) is preferably 0.05-0.1:0.05-0.1:0.1-0.2, more preferably 0.06-0.09:0.06-0.09:0.12-0.18, and more preferably 0.07-0.08:0.07-0.08:0.14-0.16.

[0039] In the present invention, 4-mercaptobenzoic acid and N,N-dimethylformamide are first mixed, and the mixing of 4-mercaptobenzoic acid and N,N-dimethylformamide is carried out in a nitrogen atmosphere. After 4-mercaptobenzoic acid is completely dissolved, N-hydroxysuccinimide and N,N'-dicyclohexylcarbodiimide solution are added to carry out the mixing in step (1).

[0040] In the present invention, the mixing in step (1) is carried out under a nitrogen atmosphere and in the dark; the mixing temperature in step (1) is preferably 20 to 30°C, more preferably 22 to 28°C, and more preferably 24 to 26°C; the mixing time is preferably 1 to 2 hours, more preferably 1.2 to 1.8 hours, and more preferably 1.4 to 1.6 hours.

[0041] In the present invention, the molar ratio of the imamine in step (2) to the 4-mercaptobenzoic acid in step (1) is preferably 0.5-1.5:0.5-1.5, more preferably 0.6-1.4:0.6-1.4, and more preferably 0.8-1.2:0.8-1.2.

[0042] In the present invention, the reaction temperature in step (2) is preferably 20-30°C, more preferably 22-28°C, and more preferably 24-26°C; the reaction time is preferably 45-55h, more preferably 46-54h, and more preferably 48-52h.

[0043] In the present invention, water is added after the reaction in step (2) to terminate the reaction. The volume mass ratio of water to 4-mercaptobenzoic acid in step (1) is preferably 40-60 mL: 0.05-0.1 g, more preferably 45-55 mL: 0.06-0.09 g, and more preferably 46-54 mL: 0.07-0.08 g.

[0044] In the present invention, the system obtained by terminating the reaction is eluted, and the elution flow rate is preferably 2-3 mL / min, more preferably 2.2-2.8 mL / min, and more preferably 2.4-2.6 mL / min; the reaction solution is extracted with ethyl acetate, and the number of extractions is preferably ≥3 times, more preferably ≥4 times, and more preferably ≥5 times; the volume mass ratio of ethyl acetate and 4-mercaptobenzoic acid in a single extraction is preferably 20-40 mL: 0.05-0.1 g, more preferably 25-35 mL: 0.06-0.09 g, and more preferably 28-32 mL: 0.07-0.08 g. The extract is collected and subjected to reduced pressure rotary evaporation, wherein the temperature of the reduced pressure rotary evaporation is preferably 40-50° C., more preferably 42-48° C., and more preferably 44-46° C.; after evaporation to dryness, methanol is added for ultrasonic dissolution, wherein the volume mass ratio of methanol to 4-mercaptobenzoic acid is preferably 2-3 mL:0.05-0.1 g, more preferably 2.2-2.8 mL:0.06-0.09 mL, and more preferably 2.4-2.6 mL:0.07-0.08 mL; and then filtered using an organic filter membrane, wherein the pore size of the organic filter membrane is preferably ≤0.22 μm, more preferably ≤0.21 μm, and more preferably ≤0.20 μm. After filtration, a sample is collected, and polar impurities in the sample are removed using methanol, and then primary purification and secondary purification are performed in sequence.

[0045] In the present invention, the initial purification is first performed by rotary evaporation, and the rotary evaporation temperature is preferably 40-60°C, more preferably 45-55°C, more preferably 48-52°C, and the time is preferably 20-40 min, more preferably 25-35 min, more preferably 28-32 min; after the rotary evaporation to remove methanol, the mixed liquid is collected and freeze-dried, and the freeze-drying temperature is preferably -70--80°C, more preferably -72--78°C, more preferably -74--76°C; after freeze-drying to remove water, the primary purified product is obtained.

[0046] In the present invention, the initially purified product is mixed and redissolved with a solvent comprising methanol and chloroform, with the volumes of methanol and chloroform being equal. The mass-to-volume ratio of the initially purified product to the solvent is preferably 5-15 mg:1-3 mL, more preferably 6-14 mg:1.5-2.5 mL, and even more preferably 8-12 mg:1.8-2.2 mL. After redissolution, the sample is evenly applied to a silica gel plate 1.5 cm from the bottom using a pipette. Multiple bands are observed under a 254 nm UV light analyzer. The darkest band is circled with a pencil, scraped off the silica gel, and then soaked in ethyl acetate and ultrasonically extracted to extract the target product. After natural sedimentation, the supernatant is filtered with a filter head, and a developing agent is prepared. The developing agent comprises methanol and chloroform, and the volume ratio of methanol to chloroform is preferably 1:10-20, more preferably 1:12-18, and more preferably 1:14-16; the silica gel precipitate and the filter head are repeatedly rinsed with the developing agent, and finally the solvent in the filtrate is removed by rotary evaporation, and the product solid is dried to obtain the imatinib derivative.

[0047] The present invention also provides the use of the imatinib derivative in preparing drugs for treating tumors.

[0048] The technical solutions provided by the present invention are described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0049] Example 1

[0050] Place a magnetic rod at the bottom of a flask with a branched tube. Wrap the flask in tinfoil and secure it to a magnetic stirrer. Close the stopcock of the branched tube and secure a nitrogen-filled balloon to the end of the tube. Then open the stopcock to fill the flask with nitrogen. Add 4-mercaptobenzoic acid (0.082 g, 0.5 mmol) and stir to dissolve it in 4 mL of N,N-dimethylformamide. Mix N,N'-dicyclohexylcarbodiimide (0.157 g, 0.75 mmol) with 1 mL of N,N-dimethylformamide to obtain an N,N'-dicyclohexylcarbodiimide solution. Place the reaction flask in an ice bath. Add N-hydroxysuccinimide (0.089 g, 0.75 mmol) and the N,N'-dicyclohexylcarbodiimide solution to the dissolved 4-mercaptobenzoic acid solution. Stir at 25°C under a nitrogen atmosphere in the dark for 1 hour to obtain an activated system. Add imamidine (0.142 g, 0.5 mmol) to the activated system, seal the bottle with a sealing film, and stir at 25°C for 48 hours; after stirring, add 50 mL of purified water to terminate the reaction to obtain a reaction solution. The reaction solution was subjected to UV scanning, and the results were as follows: Figure 1 As shown, it was found that there were maximum absorption at 206 nm and 244 nm, but the interference was relatively large. Therefore, 278 nm where a shoulder peak appeared was selected as the detection wavelength for the semi-preparative liquid phase collected samples.

[0051] UV detector: Shimadzu SPD-20A; chromatographic column: Agilent ChromCore 120C18 (5 μm, 10×250 mm); flow rate: 2.5 mL / min; detection wavelength: 278 nm; injection volume: 100 μL.

[0052] The reaction solution was extracted three times with 30 mL of ethyl acetate, and the extract was evaporated under reduced pressure at 45°C. After spin-drying, 2 mL of methanol was added for ultrasonic dissolution, and the extract was filtered through a 0.22 μm organic filter membrane as a liquid sample.

[0053] The sample was collected by isocratic elution, and the eluent was collected for 23 to 28 minutes by semi-preparative liquid phase and then 100% methanol was used to remove the less polar impurities in the sample remaining in the chromatographic column.

[0054] The eluate was placed in a flask and evaporated under reduced pressure at 50°C for about 30 minutes to remove the methanol. The mixed liquid of solid and water precipitated in the collection bottle was frozen in a -80°C refrigerator and freeze-dried to remove the water in the sample to obtain the primary purified product.

[0055] For every 10 mg of the initially purified product, add 2 mL of a mixture of methanol and chloroform in equal proportions to dissolve it. Avoid the sides of the thin layer plate and apply it evenly with a 200 μL pipette at a distance of 1.5 cm from the bottom of the silica gel plate. Under the 254 nm light of the ultraviolet analyzer, the sample is observed to develop multiple bands, such as Figure 2 As shown; circle the darkest band with a pencil and scrape off the silica gel. Soak in ethyl acetate and extract the target product using ultrasound. After natural sedimentation, filter the supernatant using a filter. Rinse the silica gel precipitate and filter repeatedly with a developing solvent (methanol:chloroform in a 1:15 volume ratio). Finally, remove the solvent from the filtrate by rotary evaporation and dry to obtain the solid product, which is an imatinib derivative.

[0056] The spectral data of the imatinib derivative prepared in this example are: 1 H-NMR(401MHz,DMSO-d6)δ:10.22(s,2H),9.26(s,2H),8.97(s,2H),8.67(s,2H),8.59-8.38(m,4H),8.06 (s,2H),7.95(d,J=7.0Hz,4H),7.78-7.60(m,6H),7.62-7.34(m,4H),7.20(d,J=8.1Hz,2H),2.21(t,6H). 13C-NMR(101MHz,DMSO-d6)δ:166.07,162.08,161.63,159.94,151.85,148.66,138.30,137.48,134.89,132.67,130.64,130.53,1 29.25,128.20,126.92,126.71,124.25,117.62,117.16,108.02,52.71,40.63,40.42,40.22,40.01,39.80,39.59,39.38,18.11.

[0057] High-resolution mass spectrometer: Waters Xevo G2-XS QTof; dual electrospray ionization source (ESI): LockSpray; temperature: 120°C; capillary voltage: 2.02 kV (+); cone voltage: 40 V; cone gas flow rate: 50 L / h; nebulizer gas flow rate: 997 L / h. E Data acquisition was performed in ESI+ mode; low collision energy: 6.0 V; high collision energy: 15.0-45.0 V; scanning range m / z: 50-1200 Da. Leucine enkephalin solution (200 ng / mL) was used as a lock mass reference, and [M+H] + The ion (m / z 556.2771) was used for mass calibration. All samples were analyzed by liquid chromatography coupled to mass spectrometry (LC-MS).

[0058] Ionization mode: ESI+; Column: Waters ACQUITY UPLC BEH C18 column (2.1 mm × 100 mm, 1.7 μm); Flow rate: 0.2 mL / min; Mobile phase A: Water; Mobile phase B: Acetonitrile; Column temperature: 30°C; Injection volume: 2 μL. Gradient elution was performed over 5 min. The volume percentage (%) of acetonitrile in the mobile phase changes over time as shown in Table 1.

[0059] Table 1 The proportion of acetonitrile in the mobile phase changes with time

[0060]

[0061] A small amount of product powder was re-dissolved in MS-grade methanol and passed through a 0.22 μm organic filter membrane as a high-resolution mass spectrometry sample.

[0062] The adduct ion peaks and related information of the corresponding bands of imatinib derivatives measured by preparative thin layer chromatography are shown in Table 2.

[0063] Table 2 Adduct ion peak information

[0064]

[0065]

[0066] The results in Table 2 show that the mass error of the adduct ion peak of the target compound band measured for imatinib derivatives and its related information is less than 5ppm, and the data quality is good.

[0067] The H NMR spectrum of the imatinib derivative prepared in this example is as follows: Figure 3 As shown, the NMR carbon spectrum is as follows Figure 4 As shown in the high-resolution mass spectrum Figure 5 shown.

[0068] Experimental determination

[0069] Effects of imatinib derivatives on tumor interstitial fluid pressure (TIFP).

[0070] Grouping and dose setting

[0071] The phosphate buffered saline (PBS) group served as a negative control, and the imatinib (IMT) group was administered at a dose of 20 mg / kg as a positive control. Two experiments were conducted with the imatinib derivative (AP825) group prepared in this example. First, mice were administered an imatinib derivative at a dose equivalent to half the amount of IMT, i.e., 16.7 mg / kg, referred to as the halfAP825 group. TIFP measurements were performed in the AP825 group 72 hours apart, and mice were administered an AP825 dose equivalent to IMT, i.e., 33.4 mg / kg. Following the above steps, 5.33 mg of IMT, 4.45 mg of AP825, and 8.90 mg of AP825 were weighed, respectively, to prepare three drug solutions. Each group of mice received an injection volume of 150 μL per 20 g (body weight).

[0072] Preparation of drug solution

[0073] The drug was administered by tail vein injection. Due to the poor water solubility of AP825, polyoxyethylene 35 castor oil (CrEL35) was used as a solubilizer. The required weight of drug and 80 mg of CrEL35 (PBS group was pure CrEL35) were accurately weighed, dissolved in anhydrous ethanol, and placed in a flask for mixing. Anhydrous ethanol was added to a total volume of 6 mL. The ethanol was removed by vacuum evaporation at 50°C. A nearly transparent film formed in the flask. 2 mL of sterile PBS was added and vortexed to hydrate the film. The film was filtered through a 0.22 μm membrane as an intravenous injection sample and prepared immediately before use. The amount of CrEL35 added to the intravenous injection solution can reach 5-10%. The CrEL35 content of all drugs prepared in the experiment and the intravenous injection solution of the control group were within the safe range.

[0074] Detecting tumor interstitial fluid pressure

[0075] Tumor interstitial fluid pressure (TIFP) is measured using the pressure measurement mode of the BL-420A biosignal acquisition system. After repeated testing and optimization, the TIFP measurement device consists of a sensor, a three-way valve, and a side-hole needle connected in sequence. A 25U / mL heparin solution is prepared by diluting 12,500 units of sodium heparin with 500 mL of normal saline.

[0076] The dose was calculated based on body weight, and the prepared drug solution was injected intravenously into each group. Because the injection solution contained a certain amount of CrEL35, the injection should be slow and careful to avoid bubbles. Before drug administration, the TIFP data for each group of mice was measured as the 0-hour TIFP data. TIFP data were measured 2, 26, and 50 hours after intravenous injection. Mice were anesthetized with isoflurane and placed in lateral recumbency to expose the tumor-inoculated side. Sodium heparin solution was injected into the cavity between the sensor and the three-way valve using a syringe, filling the cavity and the interior of the side-port needle with heparin. The BL-420A biosignal acquisition system (signal transmission device and accompanying software) was turned on, and the pressure measurement program was run. The side-port needle was inserted into the tumor, ensuring that the side opening of the needle was fully inserted into the tumor. The position was adjusted until the real-time pressure curve was stable. The needle was removed, and the wound was quickly and lightly pressed with a sterile cotton ball. The stable reading segment was selected with the mouse, and the average pressure value of that segment was recorded as the TIFP measurement result. After each measurement, the side-port needle was removed, connected to a syringe, and flushed with sodium heparin solution to remove any residual tumor fluid from the needle tip before the next measurement was performed.

[0077] The measurement results are as follows Figure 6 As shown, there were no significant differences in TIFP among the groups before administration. Two hours after administration, TIFP levels were significantly different in the IMT group (P < 0.0001), the halfAP825 group (P < 0.001), and the AP825 group (P < 0.0001) compared with the PBS group. This indicates that both IMT and AP825 significantly reduce TIFP within 2 hours of intravenous administration. Furthermore, the TIFP-reducing effects of IMT and AP825 do not persist for 50 hours. To achieve a sustained TIFP-reducing effect at the current dose concentration, administration should be repeated at least every 24 hours.

[0078] Analysis of PDGFR-β and p-PDGFR-β staining results

[0079] Paraffin sections of tumor tissue were sliced ​​and immunofluorescence was used to observe the staining results of PDGFR-β and p-PDGFR-β. The results of PDGFR-β immunofluorescence staining are shown in Figure 7 The relative fluorescence intensity of PDGFR-β in each group is shown in Figure 8 ; p-PDGFR-β immunofluorescence staining results are shown in Figure 9 The relative fluorescence intensity of p-PDGFR-β in each group is shown in Figure 10 .

[0080] The results showed that the PDGFR-β contents in tumor tissues of the IMT group (P < 0.001) and the AP825 group (P < 0.0001) were significantly higher than those in the PBS group, indicating that the mechanism by which IMT and AP825 reduce TIFP may be by inhibiting the activation of PDGFR-β to p-PDGFR-β. The p-PDGFR-β contents in tumor tissues of the IMT group (P < 0.0001) and the AP825 group (P < 0.001) were significantly lower than those in the PBS group, indicating that most of the PDGFR-β in the PBS group was activated to p-PDGFR-β, so the PDGFR-β content in the tumor tissue was low; the PDGFR-β activation in the tumor tissues of the IMT group and the AP825 group was inhibited, resulting in higher contents than those in the PBS group.

[0081] It can be seen from the above examples that the imatinib derivatives provided by the present invention have a new structure, can reduce the pressure of tumor interstitial fluid, enhance the permeability of drugs, and improve the efficacy of drugs.

[0082] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. An imatinib derivative, characterized in that The structure of the imatinib derivative is shown below:

2. The method for preparing the imatinib derivative according to claim 1, characterized in that: It includes the following steps: (1) mixing 4-mercaptobenzoic acid, N,N-dimethylformamide, N-hydroxysuccinimide and N,N'-dicyclohexylcarbodiimide solution to obtain an activation system; (2) The active system and imatinib are mixed and reacted to obtain the imatinib derivative.

3. The method for preparing the imatinib derivative according to claim 2, wherein: The mass volume ratio of 4-mercaptobenzoic acid and N,N-dimethylformamide in step (1) is 0.05-0.1 g: 3-6 mL.

4. The method for preparing an imatinib derivative according to claim 3, wherein: The N,N'-dicyclohexylcarbodiimide solution in step (1) comprises N,N'-dicyclohexylcarbodiimide and N,N-dimethylformamide; The mass volume ratio of N,N'-dicyclohexylcarbodiimide and N,N-dimethylformamide is 0.1-0.2 g:1-2 mL.

5. The method for preparing the imatinib derivative according to claim 4, wherein: In step (1), the mass ratio of 4-mercaptobenzoic acid, N-hydroxysuccinimide and N,N'-dicyclohexylcarbodiimide is 0.05-0.1:0.05-0.1:0.1-0.

2.

6. The method for preparing the imatinib derivative according to claim 5, wherein: The mixing temperature in step (1) is 20-30° C. and the mixing time is 1-2 h.

7. The method for preparing the imatinib derivative according to claim 6, wherein: The molar ratio of the imamine in step (2) to the 4-mercaptobenzoic acid in step (1) is 0.5-1.5:0.5-1.

5.

8. The method for preparing the imatinib derivative according to claim 7, wherein: The reaction temperature in step (2) is 20-30° C. and the reaction time is 45-55 h.

9. Use of the imatinib derivative according to claim 1 in the preparation of drugs for treating tumors.

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