Benzoyl hydrazine antitumor compound as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicines, and particularly relates to a novel benzoyl hydrazine antitumor compound as well as a preparation method and application thereof. The benzoyl hydrazine compound with a novel structure is prepared by adopting a simple and efficient synthesis method, and the specific structural general formula of the benzoyl hydrazine compound is as follows: imgabs0 #. The research on the in-vitro anti-tumor activity of the compound shows that the novel benzoyl hydrazine compound has an obvious inhibition effect on the growth of human hepatoma cells (HepG-2), human gastric cancer cells (SGC-7901) and human breast cancer cells (MDA-MB-231); therefore, the benzoyl hydrazine compound can be used as a lead compound or a candidate compound for the development of antitumor drugs.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and specifically relates to a novel benzoylhydrazide anti-tumor compound and a preparation method and application thereof. Background Art

[0002] Cancer is the second leading cause of death in developing countries. Current chemotherapy drugs include alkylating agents (cyclophosphamide), antibiotics (doxorubicin), etc. Since these chemotherapy drugs have indiscriminate effects on tumors and normal cells, they have side effects such as neurotoxicity. Therefore, it is very necessary to develop new anti-tumor drugs with better efficacy and less toxic side effects. Erianin has antiviral, antibacterial and anti-colorectal cancer, gastric cancer, liver cancer, and leukemia activities; Compretin A4 is an effective microtubule polymerization inhibitor with strong inhibitory activity on tumor cell growth. Erianin and Compretin A4 have structural similarities, organically integrate benzohydrazide, and then modify its structure to obtain benzohydrazide compounds. It is of great research value to conduct activity research on them, which is conducive to the development of my country's independent intellectual property drugs. Summary of the invention

[0003] The present invention aims to provide a benzoylhydrazide compound with a novel structure and a simple preparation method; another object of the present invention is to provide the application of the benzoylhydrazide compound in anti-tumor drugs.

[0004] To achieve the above object, the general structural formula of the benzoyl hydrazide compound of the present invention is as follows:

[0005]

[0006] In the structure shown in the general formula I, R is selected from phenyl, p-ethylphenyl, 3,4,5-trimethoxyphenyl, p-nitrophenyl, p-chlorophenyl, p-methoxyphenyl, p-methylphenyl, p-bromophenyl, 3,4-dimethoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 2,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl

[0007] Preferably, the structure of the p-benzoylhydrazide compound is as follows:

[0008]

[0009] The present invention also provides a method for preparing the above-mentioned terephthalamide compounds, comprising the following steps: firstly, p-methoxybenzaldehyde and 3,4,5-trimethoxyaniline WCJ-01 are condensed in ethanol to generate a Schiff base, and then the Schiff base and sodium triacetoxyborohydride are reduced to generate an intermediate WCJ-02; the intermediate WCJ-02 and methyl 4-chloroformylbenzoate are condensed in dichloromethane to generate an intermediate WCJ-03; the intermediate WCJ-03 and a sodium hydroxide aqueous solution are hydrolyzed to generate an intermediate WCJ-04; and the intermediate WCJ-04 and various benzoyl hydrazides are condensed to generate the target product benzoyl hydrazide compounds.

[0010] The synthetic route is as follows:

[0011]

[0012] The various hydrazides are: benzohydrazide, p-ethylbenzohydrazide, 3,4,5-trimethoxybenzohydrazide, p-nitrobenzohydrazide, p-chlorobenzohydrazide, p-methoxybenzohydrazide, p-methylbenzohydrazide, p-bromobenzohydrazide, 3,4-dimethylbenzohydrazide, 3-fluorobenzohydrazide, 3-chlorobenzohydrazide, 2,4-dimethoxybenzohydrazide, 3,4-methylenedioxybenzohydrazide

[0013] The present invention also provides the use of any one of the above compounds in the preparation of tumor drugs. Preferably, the tumor is selected from human liver cancer, human gastric cancer and human breast cancer.

[0014] The present invention also provides an anti-tumor drug, comprising any one of the above-mentioned benzoyl hydrazide compounds and a pharmaceutically acceptable carrier, a pharmaceutically acceptable salt and an excipient.

[0015] The present invention has the following beneficial effects:

[0016] The invention provides a novel benzoyl hydrazide compound.

[0017] The invention provides a method for synthesizing a benzoyl hydrazide compound. The method is simple and safe to operate, has few reaction by-products, high yield, and is easy to separate and purify the product.

[0018] The in vitro antitumor activity experiment of the novel benzoyl hydrazide compounds of the present invention found that the compounds had strong inhibitory activity against human gastric cancer cells (SGC-7901), and the strongest inhibitory activity IC 50 The value is 15nM, which has broad application prospects in the preparation of anti-tumor drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0020] Figure 1 For compound (WCJ-02-1) 1 H-NMR

[0021] Figure 2 For compound (WCJ-02-1) 13 C-NMR

[0022] Figure 3 HRMS of compound (WCJ-02-1) DETAILED DESCRIPTION

[0023] The following will be clearly and completely described in conjunction with the technical solutions in the specific embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments. The following description of at least one exemplary embodiment is actually only illustrative and is by no means intended to limit the present invention and its application or use. Based on the embodiments of the present invention, other embodiments obtained by ordinary technicians in this field without creative work are all within the scope of protection of the present invention.

[0024] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR measurement uses a Bruker AV-500 nuclear magnetic spectrometer, the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). The chemical shift (δ) unit is ppm.

[0025] Examples of compound synthesis

[0026] Example 1: Preparation of 4-(2-benzoylhydrazide-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide (WCJ-02-1)

[0027] Preparation of 3,4,5-trimethoxy-N-(4-methoxybenzyl)aniline (WCJ-02)

[0028] In a 100 mL round-bottom flask, add 3,4,5-trimethoxyaniline (5.38 g, 29.39 mmol), p-methoxybenzaldehyde (4 g, 29.38 mmol) and 60 mL of ethanol and heat under reflux for 8 h. Distill under reduced pressure to obtain the crude compound, which is directly used in the next step without further purification.

[0029] To the 100 mL round-bottom flask containing the crude compound, add 50 mL of dichloromethane solution, cool to 0°C in an ice-water bath, add sodium triacetoxyborohydride (18 g, 88.14 mmol) three times and stir at room temperature. Monitor the reaction by TLC and stop the reaction. Adjust the pH to 9 with a saturated aqueous solution of sodium bicarbonate, extract with dichloromethane and saturated brine, retain the organic phase, dry over anhydrous sodium sulfate, distill under reduced pressure, and separate by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 8:1) to obtain intermediate WCJ-02.

[0030] Preparation of methyl 4-((4-methoxybenzyl)(3,4,5-trimethoxyphenyl)carbamoyl)benzoate (WCJ-03)

[0031] To a 100 mL round-bottom flask containing the intermediate WCJ-02 (5 g, 16.48 mmol), 50 mL of dichloromethane and N,N-diisopropylethylamine (5.74 mL, 32.96 mmol) were added. The mixture was cooled to 0°C in an ice-water bath. 10 mL of dichloromethane containing methyl 4-chloroformylbenzoate (3.6 g, 18.13 mmol) was slowly added dropwise and stirred for reaction. The reaction was monitored by TLC. The reaction was stopped and extracted with dichloromethane and saturated brine. The organic phase was retained and dried over anhydrous sodium sulfate, evaporated under reduced pressure, and separated by silica gel column chromatography (eluent: dichloromethane: methanol = 40:1) to obtain the intermediate WCJ-03 (6.2 g, 80%).

[0032] White solid, yield: 80%; mp116.9-117.9℃. 1 H NMR (500MHz, CDCl3) δ7.86 (d, J=8.0Hz, 2H), 7.40 (d, J=8.1Hz, 2H), 7.25 (s, 2H), 6.85 (d, J= 8.6Hz, 2H), 6.04(s, 2H), 5.01(s, 2H), 3.88(s, 3H), 3.80(s, 3H), 3.75(s, 3H), 3.56(s, 6H). 13C NMR (126MHz, CDCl3) δ169.45, 166.32, 159.10, 153.11, 140.69, 138.34, 137.02, 130.79, 130.16, 1 29.60, 129.05, 128.13, 113.87, 105.61, 60.96, 56.11, 55.26, 53.16, 52.24. HR-MS (ESI) m / z: calcd forC 26 H 27 NO7Na[M+Na] + 488.1685, found 488.1687.

[0033] Preparation of 4-((4-methoxybenzyl)(3,4,5-trimethoxyphenyl)carbamoyl)benzoic acid (WCJ-04)

[0034] To a 50 mL round-bottom flask containing the intermediate WCJ-03 (4 g, 8.59 mmol), 20 mL of methanol and 5 mL of water were added, stirred at room temperature to dissolve, 3 mL of sodium hydroxide (378 mg, 9.45 mmol) was added, and the reaction was stirred at room temperature. The reaction was completed after monitoring by TLC. The reaction was stopped and distilled under reduced pressure. Ethyl acetate and water were added to extract. The aqueous phase was retained, and the pH was adjusted to 1 with 1 M hydrochloric acid. The organic phase was extracted with dichloromethane and dried over anhydrous sodium sulfate. The intermediate WCJ-04 (3.5 g, 90%) was obtained by distillation under reduced pressure.

[0035] White solid, yield: 90%; 1 H NMR (500MHz, CDCl3) δ7.91 (d, J=7.9Hz, 2H), 7.43 (d, J=7.9Hz, 2H), 7.25 (s, 2H), 6.8 5(d, J=8.5Hz, 2H), 6.05(s, 2H), 5.02(s, 2H), 3.80(s, 3H), 3.75(s, 3H), 3.56(s, 6H). 13 C NMR (126MHz, CDCl3) δ170.64, 169.49, 159.13, 153.15, 141.35, 138.17, 137.12, 130.20, 130.0 9, 129.65, 129.47, 128.20, 113.90, 105.66, 60.98, 56.14, 55.28, 53.45. HR-MS (ESI) m / z: calcd for C 25 H 25 NO7Na[M+Na] + 474.1529, found 474.1522.

[0036] Preparation of 4-(2-benzoylhydrazide-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide (WCJ-02-1)

[0037] The intermediate WCJ-04 (250 mg, 553.74 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (143.83 mg, 609.11 μmol), and 1-hydroxybenzotriazole (68.32 mg, 609.11 μmol) were added to a 25 mL round-bottom flask containing 10 mL of dichloromethane and stirred at room temperature for 30 minutes. Benzoyl hydrazide (151 mg, 1.11 mmol) was added to react. The reaction was monitored by TLC. The reaction was stopped, and dichloromethane and water were added for extraction. The organic phase was retained, dried over anhydrous sodium sulfate, distilled under reduced pressure, and separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to obtain the white solid target product WCJ-02-1. White solid, yield: 67.7%; mp116.9-117.9℃. 1 H NMR (400MHz, CDCl3) δ9.41 (s, 2H), 7.83 (dd, J = 7.1, 1.8Hz, 2H), 7.68 (d, J = 7.9Hz, 2H), 7.58-7.52 (m, 1H), 7.44 (dd, J = 8.1 , 6.8Hz, 4H), 7.24 (d, J = 8.6Hz, 2H), 6.87-6.82 (m, 2H), 6.06 (s, 2H), 5.00 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.57 (s, 6H). 13 C NMR (101MHz, CDCl3) δ169.27, 164.74, 163.74, 159.14, 153.20, 140.15, 138.19, 137.14, 132.46, 132.03, 131.24, 13 0.22, 129.48, 128.73, 128.52, 127.34, 126.90, 113.89, 105.70, 60.98, 56.15, 55.28, 53.38. HR-MS (ESI) m / z: calcd forC 32 H 31 N3O7Na[M+Na] + 592.2064, found 592.2060.

[0038] Example 2: Preparation of 4-(2-(4-ethylbenzoyl)-hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)-benzamide (WCJ-02-2)

[0039] The intermediate WCJ-04 (250 mg, 553.74 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (143.83 mg, 609.11 μmol), and 1-hydroxybenzotriazole (68.32 mg, 609.11 μmol) were added to a 25 mL round-bottom flask containing 10 mL of dichloromethane and stirred at room temperature for 30 minutes. p-Ethylbenzohydrazide (182 mg, 1.11 mmol) was added to react. The reaction was monitored by TLC to complete. The reaction was stopped, and dichloromethane and water were added for extraction. The organic phase was retained, dried over anhydrous sodium sulfate, distilled under reduced pressure, and separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to obtain the white solid target product WCJ-02-2.

[0040] White solid, yield: 75%; mp97.1-98.1℃. 1 H NMR (400MHz, CDCl3) δ9.35 (s, 1H), 9.29 (s, 1H), 7.76 (d, J = 8.4Hz, 2H), 7.68 (d, J = 8.3Hz, 2H), 7.44 (d, J = 8.4Hz, 2H), 7.28 (s, 1H), 7.24 (d, J = 8. 9Hz, 3H), 6.84 (d, J = 8.8Hz, 2H), 6.06 (s, 2H), 5.00 (s, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.58 (s, 6H), 2.70 (q, J=7.6Hz, 2H), 1.25 (t, J=7.6Hz, 3H). 13 C NMR (101MHz, CDCl3) δ169.29, 164.82, 163.78, 159.12, 153.19, 149.27, 140.07, 138.20, 137.10, 132.11, 130.21, 129.49, 12 8.59, 128.50, 128.21, 127.43, 126.90, 113.87, 105.66, 60.98, 56.14, 55.28, 53.39, 28.86, 15.24. HR-MS (ESI) m / z: calcdfor C 34 H 35 N3O7Na[M+Na] + 620.2373, found 620.2373.

[0041] Example 3: Preparation of N-(4-methoxybenzyl)-4-(2-(3,4,5-trimethoxybenzoyl)hydrazine-1-carbonyl)-N-(3,4,5-trimethoxyphenyl)benzamide (WCJ-154-25)

[0042] 3,4,5-trimethoxybenzoic acid hydrazide was used to replace p-ethylbenzoic acid hydrazide. The preparation method was the same as that in Example 2.

[0043] White solid, yield: 72.8%; mp108.5-109.5℃. 1 H NMR (500MHz, CDCl3) δ9.81 (s, 1H), 9.36 (s, 1H), 7.68 (d, J = 7.9Hz, 2H), 7.44 (d, J = 7.9Hz, 2H), 7.25 (d, J = 7.6Hz, 2H), 7.10 ( s, 2H), 6.85 (d, J = 8.6Hz, 2H), 6.07 (s, 2H), 5.01 (s, 2H), 3.89 (s, 3H), 3.85 (s, 6H), 3.81 (s, 3H), 3.78 (s, 3H), 3.59 (s, 6H). 13 C NMR (126MHz, CDCl3) δ169.26, 165.04, 159.13, 153.18, 153.12, 141.52, 140.19, 138.16, 137.10, 132.05, 130.19, 129. 38, 128.50, 126.89, 126.15, 113.87, 105.67, 104.66, 60.95, 60.87, 56.16, 56.12, 55.27, 53.36. HR-MS (ESI) m / z: calcd for C 35 H 37 N3O 10 Na[M+Na] + 682.2383, found 682.2377.

[0044] Example 4: Preparation of N-(4-methoxybenzyl)-4-(2-(4-nitrobenzoyl)hydrazine-1-carbonyl)-N-(3,4,5-trimethoxyphenyl)benzamide (WCJ-02-4)

[0045] Use p-nitrobenzoyl hydrazide to replace p-ethylbenzoyl hydrazide, and the preparation method is the same as Example 2.

[0046] White solid, yield: 72%; mp109.2-110.2℃. 1H NMR (400MHz, CDCl3) δ9.89 (s, 1H), 9.27 (s, 1H), 8.25 (d, J = 8.9Hz, 2H), 8.01 (d, J = 8.9Hz, 2H), 7.61 (d, J = 8.4Hz, 2H), 7.41 (d, J=8.3Hz, 2H), 7.23 (d, J=8.5Hz, 2H), 6.84 (d, J=8.6Hz, 2H), 6.06 (s, 2H), 5.00 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.58 (s, 6H). 13 C NMR (101MHz, CDCl3) δ169.44, 164.70, 163.71, 159.19, 153.25, 149.95, 140.29, 137.98, 137.19, 136.68, 131.66, 13 0.09, 129.15, 128.81, 128.37, 127.02, 123.67, 113.92, 105.69, 60.94, 56.15, 55.28, 53.50. HR-MS (ESI) m / z: calcd for C 32 H 30 N4O9Na[M+Na] + 637.1910, found 637.1910.

[0047] Example 5: Preparation of 4-(2-(4-chlorobenzoyl)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide (WCJ-02-5)

[0048] Use p-chlorobenzoyl hydrazide to replace p-ethylbenzoyl hydrazide, and the preparation method is the same as Example 2.

[0049] White solid, yield: 56.9%; 1 H NMR (400MHz, CDCl3) δ9.56 (s, 1H), 9.33 (s, 1H), 7.77 (d, J = 8.6Hz, 2H), 7.65 (d, J = 8.1Hz, 2H), 7.41 (t, J = 8.9Hz, 4H ), 7.23 (d, J=8.1Hz, 2H), 6.84 (d, J=8.8Hz, 2H), 6.06 (s, 2H), 5.00 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.57 (s, 6H). 13CNMR (101MHz, CDCl3) δ169.34, 164.51, 164.34, 159.14, 153.21, 140.15, 138.69, 138.10, 137.13, 131.91, 130.2 0, 129.57, 129.37, 128.88, 128.42, 126.97, 113.89, 105.68, 60.97, 56.14, 55.28, 53.43. HR-MS (ESI) m / z: calcd for C 32 H 30 N3O7NaCl[M+Na] + 626.1671, found 626.1670.

[0050] Example 6: Preparation of 4-(2-(4-methoxybenzoyl)hydrazine-1-carbonyl)N-(4-methoxybenzyl)N-(3,4,5-trimethoxyphenyl)benzamide (WCJ-02-7)

[0051] Use p-methoxybenzoic acid hydrazide to replace p-ethylbenzoic acid hydrazide, and the preparation method is the same as Example 2.

[0052] White solid, yield: 42.4%; mp 98.7-99.7℃. 1 H NMR (400MHz, CDCl3) δ9.36 (s, 1H), 9.28 (d, J=6.0Hz, 1H), 7.80 (d, J=8.9Hz, 2H), 7.69 (s, 2H), 7.43 (d, J=8.4Hz, 2H), 7.24 (d, J=8.8H z, 2H), 6.92 (d, J = 9.0Hz, 2H), 6.84 (d, J = 8.8Hz, 2H), 6.06 (s, 2H), 5.00 (s, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.57 (s, 6H). 13 C NMR (101MHz, CDCl3) δ169.28, 164.52, 163.83, 162.93, 159.12, 153.19, 140.07, 138.21, 137.09, 132.15, 130.20, 129.5 0, 129.27, 128.50, 126.89, 123.42, 113.96, 113.88, 105.65, 60.98, 56.14, 55.46, 55.28, 53.38. HR-MS (ESI) m / z: calcd for C 33 H 33 N3O8Na[M+Na] +622.2168, found 622.2165.

[0053] Example 7: Preparation of N-(4-methoxybenzyl)-4-(2-(4-methylbenzoyl)hydrazine-1-carbonyl)N-(3,4,5-trimethoxyphenyl)benzamide (WCJ-02-8)

[0054] Use p-methylbenzoyl hydrazide to replace p-ethylbenzoyl hydrazide, and the preparation method is the same as Example 2.

[0055] White solid, yield: 18.3%; mp 98.0-99.0℃. 1 H NMR (400MHz, CDCl3) δ9.36 (s, 1H), 9.29 (d, J = 5.8Hz, 1H), 7.73 (d, J = 8.3Hz, 2H), 7.68 (d, J = 8.3Hz, 2H), 7.44 (d, J = 8.4Hz, 2H) , 7.25 (d, J=7.9Hz, 4H), 6.84 (d, J=8.8Hz, 2H), 6.06 (s, 2H), 5.00 (s, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.57 (s, 6H), 2.40 (s, 3H). 13 C NMR (101MHz, CDCl3) δ169.27, 164.74, 163.68, 159.12, 153.19, 143.10, 140.10, 138.21, 137.10, 132.09, 130.21, 129.5 0, 129.39, 128.50, 128.39, 127.32, 126.89, 113.87, 105.66, 60.98, 56.14, 55.28, 53.39, 21.56. HR-MS (ESI) m / z: calcd for C 33 H 33 N3O7Na[M+Na] + 606.2220, found 606.2216.

[0056] Example 8: Preparation of 4-(2-(4-bromobenzoyl)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)N-(3,4,5-trimethoxyphenyl)benzamide (WCJ-02-9)

[0057] Use p-bromobenzoylhydrazide to replace p-ethylbenzoylhydrazide, and the preparation method is the same as Example 2.

[0058] White solid, yield: 80.9%; mp 97.9-98.9℃. 1H NMR (400MHz, CDCl3) δ9.50 (d, J=5.8Hz, 1H), 9.26 (d, J=5.0Hz, 1H), 7.72, 7.68 (m, 2H), 7.65 (d, J=8.3Hz, 2H), 7.59, 7.55 (m, 2H), 7 .43 (d, J = 8.4Hz, 2H), 7.23 (d, J = 8.5Hz, 2H), 6.86, 6.82 (m, 2H), 6.06 (s, 2H), 5.00 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.57 (s, 6H). 13 C NMR (101MHz, CDCl3) δ169.32, 164.53, 164.46, 159.14, 153.21, 140.15, 138.10, 137.13, 131.90, 131.86, 130.20, 13 0.02, 129.36, 129.02, 128.42, 127.24, 126.97, 113.89, 105.68, 60.97, 56.15, 55.28, 53.45.HR--MS(ESI)m / z: calcd for C 32 H 30 N3O7NaBr[M+Na] + 670.1165, found 670.1165.

[0059] Example 9: Preparation of 4-(2-(3,4-dimethoxybenzoyl)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide (WCJ-02-11)

[0060] 3,4-dimethylbenzohydrazide was used to replace p-ethylbenzohydrazide. The preparation method was the same as that in Example 2.

[0061] White solid, yield: 37.4%; mp103.5-104.5℃. 1 H NMR (400MHz, CDCl3) δ9.36 (s, 1H), 9.27 (s, 1H), 7.68 (d, J = 8.4Hz, 2H), 7.46-7.41 (m, 3H), 7.39 (d, J = 2.1Hz, 1H), 7.24 (d, J = 8.5Hz, 2H), 6.88-6.82(m, 3H), 6.06(s, 2H), 5.00(s, 2H), 3.92(s, 3H), 3.90(s, 3H), 3.79(s, 3H), 3.76(s, 3H), 3.58(s, 6H). 13C NMR (101MHz, CDCl3) δ169.28, 165.02, 164.63, 159.12, 153.18, 152.45, 148.88, 140.07, 138.19, 137.08, 132.14, 130.19, 129.45, 1 28.46, 126.93, 123.59, 120.71, 113.87, 110.42, 110.28, 105.66, 60.95, 56.13, 56.02, 55.95, 55.27, 53.38. HR-MS (ESI) m / z: calcd for C 34 H 35 N3O9Na[M+Na] + 652.2274, found 652.2271.

[0062] Example 10: Preparation of 4-(2-(3-fluorobenzoyl)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide (WCJ-02-13)

[0063] 3-Fluorobenzoic acid hydrazide was used to replace p-ethylbenzoic acid hydrazide. The preparation method was the same as that in Example 2.

[0064] White solid, yield: 71.1%; mp100.2-101.2℃. 1 H NMR (400MHz, CDCl3) δ9.55 (d, J = 4.6 Hz, 1H), 9.29 (s, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 7.9 Hz, 1H), 7.55 (dt, J = 9.1, 2.1 Hz, 1H), 7.44-7.37(m, 3H), 7.26-7.20(m, 3H), 6.86-6.82(m, 2H), 6.06(s, 2H), 5.00(s, 2H), 3.79(s, 3H), 3.76(s, 3H), 3.57(s, 6H). 13C NMR (101MHz, CDCl3) δ169.31, 164.39, 163.99, 163.83, 161.36, 159.13, 15 3.21, 140.15, 138.11, 137.12, 133.39, 133.32, 131.86, 130.39, 130.31, 13 0.22, 129.39, 128.46, 126.95, 122.97, 122.94, 119.50, 119.29, 114.92, 1 14.69, 113.87, 105.68, 60.96, 56.12, 55.28, 53.47. HR-MS (ESI) m / z: calcd forC 32 H 30 N3O7NaF[M+Na] + 610.1968, found 610.1965.

[0065] Example 11: Preparation of 4-(2-(3-chlorobenzoyl)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide (WCJ-02-14)

[0066] 3-Chlorobenzoylhydrazide was used to replace p-ethylbenzoylhydrazide. The preparation method was the same as that in Example 2.

[0067] White solid, yield: 72.4%; mp 95.8-96.8℃. 1 H NMR (400MHz, CDCl3) δ9.97 (d, J=5.0Hz, 1H), 9.58 (s, 1H), 7.82 (t, J=1.9Hz, 1H) , 7.70 (dt, J = 7.8, 1.3Hz, 1H), 7.60 (d, J = 8.3Hz, 2H), 7.46 (ddd, J = 8.0, 2.1, 1.0H z, 1H), 7.37 (d, J = 8.3Hz, 2H), 7.30 (t, J = 7.9Hz, 1H), 7.22 (d, J = 8.3Hz, 2H), 6.84 -6.80(m,2H), 6.05(s,2H), 4.99(s,2H), 3.78(s,3H), 3.75(s,3H), 3.55(s,6H). 13C NMR (101MHz, CDCl3) δ169.33, 164.30, 163.89, 159.14, 153.21, 140.14, 138.08, 137.14, 134.84, 132.98, 132.38, 131.89, 130 .22, 129.95, 129.37, 128.47, 127.84, 126.96, 125.43, 113.87, 105.69, 60.97, 56.14, 55.28, 53.44. HR-MS (ESI) m / z: calcdfor C 32 H 30 N3O7NaCl[M+Na] + 626.1671, found 626.1670.

[0068] Example 12: Preparation of 4-(2-(2,4-dimethoxybenzoyl)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide (WCJ-02-15)

[0069] 2,4-dimethoxybenzoic acid hydrazide was used to replace p-ethylbenzoic acid hydrazide. The preparation method was the same as that in Example 2.

[0070] White solid, yield: 38.8%; mp 95.8-96.8℃. 1 H NMR (400MHz, CDCl3) δ10.76 (d, J=7.4Hz, 1H), 9.54 (d, J=7.4Hz, 1H), 8.12 (d, J=8 .8Hz, 1H), 7.71 (d, J=8.0Hz, 2H), 7.45 (d, J=8.1Hz, 2H), 7.25 (d, J=8.8Hz, 2H), 6 .88, 6.82 (m, 2H), 6.63 (dd, J = 8.8, 2.3Hz, 1H), 6.52 (d, J = 2.3Hz, 1H), 6.06 (s, 2H ), 5.01(s, 2H), 4.04(s, 3H), 3.87(s, 3H), 3.80(s, 3H), 3.76(s, 3H), 3.58(s, 6H). 13C NMR (101MHz, CDCl3) δ169.27, 164.24, 161.84, 160.75, 159.11, 159.04, 153.18, 139.95, 138.32, 137.09, 133.69, 132.38, 130.17, 129.59, 128.57, 126.75, 113.88, 111.58, 105.74, 105.62, 98.59, 61.01, 56.24, 56.15, 55.64, 55.28, 53.30. HR-MS (ESI) m / z: calcd for C 34 H 35 N3O9Na[M+Na] + 652.2275, found 652.2271.

[0071] Example 13: Preparation of 4-(2-(benzo[d][1,3]dioxazole-5-carbonyl)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide (WCJ-02-16)

[0072] 3,4-methylenedioxybenzohydrazide was used to replace p-ethylbenzohydrazide. The preparation method was the same as that in Example 2.

[0073] White solid, yield: 63.6%; mp107.8-108.8℃. 1 H NMR (400MHz, CDCl3) δ9.18 (s, 2H), 7.67 (d, J = 7.9Hz, 2H), 7.44 (d, J = 7.9Hz, 2H), 7.40 (dd, J = 8.1, 1.8Hz, 1H), 7.30 (d, J = 1.8Hz, 1H) , 7.24 (d, J = 8.7Hz, 2H), 6.84 (dd, J = 8.5, 2.5Hz, 3H), 6.06 (s, 2H), 6.04 (s, 2H), 5.00 (s, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.58 (s, 6H). 13 C NMR (101MHz, CDCl3) δ169.28, 165.02, 163.22, 159.15, 153.22, 151.41, 148.19, 140.27, 137.14, 135.92, 132.03, 130.24, 12 8.63, 126.78, 125.17, 122.31, 113.89, 108.30, 107.67, 105.66, 101.92, 61.01, 56.16, 55.29, 53.40. HR-MS (ESI) m / z: calcd for C33 H 31 N3O9Na[M+Na] + 636.1959, found 636.1958.

[0074] Application examples of compounds

[0075] In vitro anti-tumor activity test: Three cell lines were used using the CCK8 method, namely human liver cancer cells (HepG-2), human breast cancer cells (MDA-MB-231), and human gastric cancer cells (SGC-7901).

[0076] Collect cells in the logarithmic phase, adjust the concentration of the cell suspension, add 100 μL to each well, plate to adjust the cell density to be tested, and fill the edge wells of the 96-well plate with PBS. Incubate for 24 hours under 5% CO2, 37°C, and 90% humidity conditions until the cell monolayer covers the bottom of the 96-well plate. Add the drug synthesized by the present invention with a concentration gradient, set 9 concentrations, 200 μL in the mother well, set 3 replicate wells, incubate for 72 hours, observe under an inverted microscope, add 10 μL of CCK8 solution to each well, and continue to culture for 2 hours. Use an enzyme reader to measure the absorbance of each well at 450nm. Use GraphPad Prism 9.5 software to count the experimental results and calculate the IC 50 (μmol / L) values, the results are shown in Table 1 below.

[0077] Table 1 In vitro antitumor activity test results

[0078]

Claims

1. A novel benzoyl hydrazide compound, characterized in that: It has the structure described in general formula I: In the general formula I: R is phenyl, p-ethylphenyl, 3,4,5-trimethoxyphenyl, p-nitrophenyl, p-chlorophenyl, p-methoxyphenyl, p-methylphenyl, p-bromophenyl, 3,4-dimethoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 2,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl.

2. The benzoyl hydrazide compound according to claim 1, wherein: Select one of the following compounds:

3. The method for preparing the benzoyl hydrazide compound as claimed in claim 1, characterized in that: This is achieved through the following synthetic steps: First, p-methoxybenzaldehyde and 3,4,5-trimethoxyaniline WCJ-01 are condensed in ethanol to generate Schiff base, and then the Schiff base and sodium triacetoxyborohydride are reduced to generate intermediate WCJ-02; intermediate WCJ-02 and methyl 4-chloroformylbenzoate are condensed in dichloromethane to prepare intermediate WCJ-03; intermediate WCJ-03 and sodium hydroxide aqueous solution are hydrolyzed to prepare intermediate WCJ-04; intermediate WCJ.-04 and various benzoyl hydrazides are condensed to prepare target product benzoyl hydrazide compounds; The benzohydrazide compounds are: benzohydrazide, p-ethylbenzohydrazide, 3,4,5-trimethoxybenzohydrazide, p-nitrobenzohydrazide, p-chlorobenzohydrazide, p-methoxybenzohydrazide, p-methylbenzohydrazide, p-bromobenzohydrazide, 3,4-dimethylbenzohydrazide, 3-fluorobenzohydrazide, 3-chlorobenzohydrazide, 2,4-dimethoxybenzohydrazide and 3,4-methylenedioxybenzohydrazide.

4. The use of the benzoylhydrazide compound as claimed in claim 1 in drug preparation, characterized in that: The active ingredient is used for preparing drugs against breast cancer cells, gastric cancer cells or liver cancer cells.

5. An anti-tumor drug composition, characterized in that: The pharmaceutical composition uses the compound described in claim 1 as an active ingredient; the pharmaceutical composition also includes a pharmaceutically acceptable carrier, a pharmaceutically acceptable salt or an excipient.

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