Synthesis and application of benzoyl hydrazone derivative

Abstract

The invention relates to a synthesis method of a benzoyl hydrazone derivative and an antitumor activity research of the benzoyl hydrazone derivative. A series of benzoyl hydrazone derivatives are synthesized by modifying benzamide and hydrazone. The synthesis method is simple, convenient and efficient, and has better selectivity and yield. In-vitro cell experiments show that the synthesized derivatives have remarkable anti-tumor activity, and especially in the aspect of inhibiting the growth of U87 (human brain astroblastoma cells), SGC-7901 (human gastric cancer cells) and HepG2 (human liver cancer cells), part of the derivatives show a low nanomole-level IC50 value. Researches show that the benzoyl hydrazone derivatives may play an anti-tumor role by inhibiting tumor cell proliferation, inducing apoptosis and other mechanisms, and have the potential to become novel anti-tumor drugs. The synthesis method of the compound, the antitumor activity and the mechanism research of the compound provide effective thinking and basis for developing new antitumor drugs, and the compound has a wide application prospect.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a synthesis method and application of a series of benzoylhydrazone derivatives. Background Art

[0002] Tumors are one of the major diseases that threaten human health worldwide. According to statistics from the World Health Organization (WHO) in 2022, cancer causes nearly 10 million deaths each year, and the incidence and mortality rates continue to rise. The occurrence of tumors is due to an imbalance between cell proliferation and apoptosis. Its core mechanism involves multiple factors such as gene mutations (such as inactivation of tumor suppressor genes, activation of oncogenes), epigenetic abnormalities, microenvironmental disorders, and immune escape. Research on anti-tumor drug therapy requires the exploration of new drug targets and treatment strategies. By continuously advancing the research on cancer drug therapy, it is expected to provide cancer patients with more effective and safer treatment options. Therefore, the development of new, highly effective cancer drugs with fewer side effects has become the focus of current medical research. Summary of the Invention

[0003] The present invention aims to provide a benzoylhydrazone derivative with antitumor activity, a preparation method of the benzoylhydrazone derivative, and an application of the benzoylhydrazone derivative in antitumor activities.

[0004] Technical solution: The benzoylhydrazone derivative of the present invention has a structural formula as shown in Formula I:

[0005]

[0006] wherein R is selected from 4-fluoro, 4-methoxy, 4-bromo, 4-chloro, 3,4-dimethoxy, 4-nitro, 3,4,5-trimethoxy, 2-chloro, 3-fluoro, 3-chloro, 3-bromo, pyridyl, naphthyl, 4-methoxy-3-nitro, and methyl.

[0007] The preparation method of the benzoylhydrazone derivative of the present invention has the following synthetic route:

[0008]

[0009] a) aromatic alcohol, EtOH, reflux; b) sodium triacetoxyborohydride, DCM, 0°C; c) methyl 4-chlorocarbonylbenzoate, Dipea, DCM, 0°C; d) hydrazine hydrate, EtOH, reflux; e) aldehyde, EtOH, reflux.

[0010] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The benzoylhydrazone derivatives described in the present invention are a new type of compound; (2) The preparation method of the benzoylhydrazone derivatives described in the present invention has a novel and efficient reaction, simple operation, and readily available raw materials; (3) The benzoylhydrazone derivatives described in the present invention can effectively inhibit the proliferation of tumor cells and can be used as potential new anti-tumor drug candidate molecules. DETAILED DESCRIPTION

[0011] The following will be a clear and complete description of the technical solutions in the specific embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. The following description of at least one exemplary embodiment is actually only illustrative and is in no way 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 making creative work are all within the scope of protection of the present invention.

[0012] Example 1

[0013] The benzoylhydrazone derivative Q-1 has the chemical name (E)-4-(2-benzylidenehydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide, and the English name is (E)-4-(2-benzylidenehydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide, with the structural formula as follows:

[0014]

[0015] Preparation method: 3,4,5-Trimethoxyaniline (5.38 g, 29.38 mmol) and p-anisaldehyde (4 g, 29.38 mmol) were added to 30 mL of ethanol and refluxed for 8 hours. The reaction was monitored for completion by thin-layer chromatography. The crude product was distilled under reduced pressure to obtain the crude product. The crude product was directly dissolved in dichloromethane (100 mL). Sodium triacetoxyborohydride (18.6 g, 87.77 mmol) was added in three portions at 0°C and stirred for 5 hours. The reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and purified by column chromatography (PE:EA = 10:1) to obtain the intermediate 3,4,5-trimethoxy-N-(4-methoxybenzyl)aniline (8.85 g, 29.38 mmol).

[0016] Methyl 4-chloroformylbenzoate (3.6 g, 18.13 mmol) was dissolved in dichloromethane (20 ml) and added dropwise to a mixed solution containing 3,4,5-trimethoxy-N-(4-methoxybenzyl)aniline (5 g, 16.48 mmol) and N-ethyl-N-isopropylpropane-2-amine (5.73 ml, 32.96 mmol). The mixture was stirred at room temperature for 8 hours. The reaction was monitored for completion by thin-layer chromatography. The mixture was evaporated under reduced pressure and purified by column chromatography (PE:EA = 6:1) to yield the intermediate methyl 4-(4-methoxybenzyl)(3,4,5-trimethoxyphenyl)carbamoyl)benzoate (6.90 g, 16.48 mmol).

[0017] Methyl 4-(4-methoxybenzyl)(3,4,5-trimethoxyphenyl)carbamoyl)benzoate (6 g, 12.89 mmol) was dissolved in ethanol (20 ml), and hydrazine hydrate (2.58 g, 51.56 mmol) was added. The mixture was heated to reflux for 48 hours, and the reaction was complete after monitoring with thin-layer chromatography. The mixture was evaporated under reduced pressure, extracted with ethyl acetate, dried, evaporated under reduced pressure, and purified by column chromatography (PE:EA = 6:1) to obtain the intermediate 4-(hydrazinecarbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide (5.10 g, 10.96 mmol).

[0018] 4-(Hydrazinecarbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide (200 mg, 0.429 mmol) was dissolved in ethanol (10 ml), and aromatic aldehyde (0.644 mmol) was added. The mixture was heated to reflux for 8 hours, and the reaction was complete after monitoring by thin-layer chromatography. The mixture was evaporated under reduced pressure, extracted with ethyl acetate, dried, evaporated under reduced pressure, and purified by column chromatography (PE:EA = 6:1) to obtain the final product 6, the target compound Q-1.

[0019] Yield of target compound Q-1: 80%; mp: 98.2-99.2°C. 1H NMR (500 MHz, CDCl 3 ) δ 10.10 (s, 1H), 8.35 (s, 1H), 7.84-7.68 (m, 2H), 7.69-7.59 (m, 2H), 7.37 (d, J = 1.4 Hz, 2H), 7.36 (s, 1H), 7.30 (d, J = 6.7 Hz, 2H), 7.25-7.20 (m, 2H), 6.83 (d, J = 8.2 Hz, 2H), 6.06 (d, J = 27.4 Hz, 2H), 5.01 (s, 2H), 3.78 (s, 3H), 3.75 (s, 3H), 3.53 (s, 6H). 13C NMR (101MHz, CDCl3) δ169.74, 163.61, 159.18, 153.20, 149.19, 139.21, 138.08, 137.06, 134.31, 133 .72, 130.48, 130.00, 128.64, 128.16, 127.75, 127.18, 113.96, 105.65, 60.97, 56.16, 55.29, 53.35.

[0020] Example 2

[0021] The benzoylhydrazone derivative Q-2, R = 4-methoxy, has the chemical name (E)-N-(4-methoxybenzyl)-4-(2-(4-methoxybenzylidene)hydrazine-1-carbonyl)-N-(3,4,5-trimethoxyphenyl)benzamide, and the English name is (E)-N-(4-methoxybenzyl)-4-(2-(4-methoxybenzylidene)hydrazine-1-carbonyl)-N-(3,4,5-trimethoxyphenyl)benzamide. The structural formula is as follows:

[0022]

[0023] The preparation method is as described in Example 1. The yield of the target compound Q-2 was 73%; mp 94.0-95.0°C. 1H NMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 8.24 (s, 1H), 7.70-7.62 (m, 4H), 7.36 (d, J = 7.4 Hz, 2H), 7.23 (s, 2H), 6.90 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.05 (s, 2H), 5.01 (s, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H), 3.55 (s, 6H). 13C NMR (101MHz, CDCl3) δ169.74, 163.48, 161.56, 159.18, 153.20, 149.01, 139.16, 138.17, 137.05, 134.43 , 130.01, 129.39, 128.16, 127.10, 126.37, 114.13, 113.95, 105.65, 60.97, 56.15, 55.37, 55.28, 53.32.

[0024] Example 3

[0025] The benzoylhydrazone derivative Q-3, R = 4-fluoro, has the chemical name (E)-4-(2-(4-fluorobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide and the English name (E)-4-(2-(4-fluorobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide. The structural formula is as follows:

[0026]

[0027] The preparation method is as described in Example 1. The yield of the target compound Q-3 was 78%; mp 96.0-97.0°C. 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.35 (s, 1H), 7.64 (d, J = 21.6 Hz, 4H), 7.45 (s, 1H), 7.23 (d, J = 8.3 Hz, 3H), 7.04 (t, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 6.04 (s, 2H), 5.01 (s, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.53 (s, 6H). 13C NMR (101MHz, CDCl3) δ169.81, 165.31, 163.66, 162.81, 159.21, 154.30, 153.21, 147.98, 139.19, 138.02, 137.08, 134 .24, 129.91, 129.63, 129.55, 129.14, 128.09, 127.20, 115.91, 115.69, 113.98, 105.63, 60.96, 56.15, 55.28, 53.35.

[0028] Example 4

[0029] The benzoylhydrazone derivative Q-4, R = 4-bromo, has the chemical name (E)-4-(2-(4-bromobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide and the English name (E)-4-(2-(4-bromobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide. The structural formula is as follows:

[0030]

[0031] The preparation method is as described in Example 1. The yield of the target compound Q-4 was 67%; mp 102.0-103.0°C. 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 8.31 (s, 1H), 7.62 (s, 2H), 7.57 (d, J = 7.1 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 6.0 Hz, 2H), 7.24 (s, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.04 (s, 2H), 5.02 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.55 (s, 6H). 13C NMR (101MHz, CDCl3) δ169.84, 163.69, 159.21, 153.21, 147.90, 139.19, 138.03, 137.07, 134.17, 132 .74, 131.87, 129.87, 129.04, 128.07, 127.23, 124.72, 113.98, 105.60, 60.95, 56.14, 55.28, 53.36.

[0032] Example 5

[0033] The benzoylhydrazone derivative Q-5, R = 3,4-dimethoxy. Its chemical name is (E)-4-(2-(3,4-dimethoxybenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide, and its English name is (E)-4-(2-(3,4-dimethoxybenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide. Its structural formula is as follows:

[0034]

[0035] The preparation method is as described in Example 1. The yield of the target compound Q-5 was 85%; mp 99.0-100.0°C. 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.28 (s, 1H), 7.64 (d, J = 7.9 Hz, 2H), 7.45 (s, 1H), 7.30 (d, J = 7.0 Hz, 2H), 7.23 (d, J = 7.5 Hz, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 8.3 Hz, 3H), 6.03 (s, 2H), 5.01 (s, 2H), 3.90 (s, 6H), 3.79 (s, 3H), 3.75 (s, 3H), 3.53 (s, 6H). 13C NMR (101MHz, CDCl3) δ169.76, 163.53, 159.18, 153.20, 151.38, 149.42, 149.30, 139.17, 138.10, 137.04, 134.40, 13 0.01, 129.27, 128.14, 127.10, 126.74, 122.94, 117.54, 113.96, 105.65, 60.96, 56.15, 56.10, 55.93, 55.28, 53.31.

[0036] Example 6

[0037] The benzoylhydrazone derivative Q-6, R = 4-nitro, has the chemical name (E)-N-(4-methoxybenzyl)-4-(2-(4-nitrobenzylidene)hydrazine-1-carbonyl)-N-(3,4,5-trimethoxyphenyl)benzamide and the English name (E)-N-(4-methoxybenzyl)-4-(2-(4-nitrobenzylidene)hydrazine-1-carbonyl)-N-(3,4,5-trimethoxyphenyl)benzamide. The structural formula is as follows:

[0038]

[0039] The preparation method is as described in Example 1. The yield of the target compound Q-6 was 74%; mp 193.8-194.8°C. 1H NMR (400 MHz, CDCl3) δ 10.93 (s, 1H), 8.50 (s, 1H), 8.19 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 9.0 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.24 (s, 4H), 6.84 (d, J = 8.4 Hz, 2H), 6.05 (s, 2H), 5.04 (s, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 3.54 (s, 6H). 13C NMR (101MHz, CDCl3) δ169.96, 163.89, 159.28, 153.26, 148.54, 146.23, 139.93, 139.33, 137 .21, 133.91, 129.71, 128.11, 127.37, 123.91, 114.05, 105.61, 60.97, 56.17, 55.29, 53.38.

[0040] Example 7

[0041] The benzoylhydrazone derivative Q-7, R = 3,4,5-trimethoxy. Its chemical name is (E)-N-(4-methoxybenzyl)-4-(2-(3,4,5-trimethoxybenzylidene)hydrazine-1-carbonyl)-N-(3,4,5-trimethoxyphenyl)benzamide, and its English name is (E)-N-(4-methoxybenzyl)-4-(2-(3,4,5-trimethoxybenzylidene)hydrazine-1-carbonyl)-N-(3,4,5-trimethoxyphenyl)benzamide. Its structural formula is as follows:

[0042]

[0043] The preparation method is as described in Example 1. The yield of the target compound Q-7 was 78%; mp 108.0-109.0°C. 1H NMR (400 MHz, CDCl3) δ 10.37 (s, 1H), 8.33 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.92 (s, 1H), 6.83 (d, J = 8.5 Hz, 2H), 6.03 (s, 2H), 5.01 (s, 2H), 3.86 (s, 2H), 3.83 (s, 4H), 3.78 (s, 3H), 3.75 (s, 2H), 3.53 (s, 5H). 13C NMR (101MHz, CDCl3) δ169.81, 163.67, 159.23, 153.43, 153.21, 149.15, 140.25, 139.21, 137.96, 137.11, 13 4.33, 130.02, 129.21, 128.14, 127.17, 113.99, 105.69, 104.86, 60.96, 60.93, 56.26, 56.17, 55.28, 53.30.

[0044] Example 8

[0045] The benzoylhydrazone derivative Q-8, R = 4-chloro, has the chemical name (E)-4-(2-(4-chlorobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide and the English name (E)-4-(2-(4-chlorobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide, and has the structural formula shown below:

[0046]

[0047] The preparation method is as described in Example 1. The yield of the target compound Q-8 is 69%; mp 105.0-106.0°C. 1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 8.34 (s, 1H), 7.65-7.57 (m, 4H), 7.33 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 10.3 Hz, 4H), 6.83 (d, J = 8.5 Hz, 2H), 6.03 (s, 2H), 5.01 (s, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.53 (s, 6H). 13C NMR (101MHz, CDCl3) δ169.87, 163.75, 159.22, 153.21, 147.88, 139.20, 137.99, 137.08, 136.31, 134 .19, 132.33, 129.87, 128.91, 128.84, 128.05, 127.26, 113.99, 105.62, 60.95, 56.15, 55.29, 53.35.

[0048] Example 9

[0049] The benzoylhydrazone derivative Q-9, R = pyridyl, has the chemical name (E)-N-(4-methoxybenzyl)-4-(2-(pyridin-4-ylmethylene)hydrazine-1-carbonyl)-N-(3,4,5-trimethoxyphenyl)benzamide and the English name (E)-N-(4-methoxybenzyl)-4-(2-(pyridin-4-ylmethylene)hydrazine-1-carbonyl)-N-(3,4,5-trimethoxyphenyl)benzamide. Its structural formula is as follows:

[0050]

[0051] The preparation method is as described in Example 1. The yield of the target compound Q-9 was 77%; mp 180.0-181.0°C. 1H NMR (400 MHz, CDCl3) δ 10.73 (s, 1H), 8.62 (d, J = 5.3 Hz, 2H), 8.41 (s, 1H), 7.64 (s, 2H), 7.51 (s, 2H), 7.23 (d, J = 9.4 Hz, 4H), 6.84 (d, J = 8.6 Hz, 2H), 6.05 (s, 2H), 5.03 (s, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.54 (s, 6H). 13C NMR (101MHz, CDCl3) δ169.85, 163.94, 159.26, 153.24, 150.22, 146.32, 141.25, 139.37, 137.93 , 137.18, 133.90, 129.81, 128.03, 127.35, 121.33, 114.03, 105.63, 60.96, 56.16, 55.30, 53.40.

[0052] Example 10

[0053] The benzoylhydrazone derivative Q-10, R = 3-bromo, has the chemical name (E)-4-(2-(3-bromobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide and the English name (E)-4-(2-(3-bromobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide. The structural formula is as follows:

[0054]

[0055] The preparation method is as described in Example 1. The yield of the target compound Q-10 was 71%; mp 101.5-102.5°C. 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.34 (s, 1H), 7.83 (s, 1H), 7.61 (s, 3H), 7.50 (dt, J = 8.0, 1.5 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 6.84 (d, J = 8.8 Hz, 5H), 6.04 (s, 2H), 5.02 (s, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.54 (s, 6H). 13C NMR (101MHz, CDCl3) δ169.84, 163.69, 159.23, 153.23, 147.39, 139.24, 138.01, 137.12, 135.89, 134.15, 133 .25, 130.41, 130.19, 129.89, 129.08, 128.09, 127.24, 126.15, 114.03, 105.62, 60.98, 56.16, 55.30, 53.41.

[0056] Example 11

[0057] The benzoylhydrazone derivative Q-11, R = 3-chloro, has the chemical name (E)-4-(2-(3-chlorobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide and the English name (E)-4-(2-(3-chlorobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide, and has the following structural formula:

[0058]

[0059] The preparation method is as described in Example 1. The yield of the target compound Q-11 was 76%; mp 99.0-100.0°C. 1H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 8.36 (s, 1H), 7.67-7.60 (m, 3H), 7.54 (s, 1H), 7.36-7.30 (m, 2H), 7.29 (s, 1H), 7.23 (d, J = 11.0 Hz, 3H), 6.84 (d, J = 8.6 Hz, 2H), 6.04 (s, 2H), 5.02 (s, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.54 (s, 6H). 13C NMR (101MHz, CDCl3) δ169.86, 163.70, 159.22, 153.22, 147.53, 139.22, 138.02, 137.11, 135.66, 134.73, 134 .17, 130.32, 129.88, 129.05, 128.07, 127.52, 127.24, 125.68, 114.01, 105.61, 60.97, 56.15, 55.29, 53.38.

[0060] Example 12

[0061] The benzoylhydrazone derivative Q-12, R = 3-fluoro, has the chemical name (E)-4-(2-(3-fluorobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide and the English name (E)-4-(2-(3-fluorobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide. The structural formula is as follows:

[0062]

[0063] The preparation method is as described in Example 1. The yield of target compound Q-12 is 62%; mp 89.0-90.0°C. 1H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 8.38 (s, 1H), 7.62 (s, 2H), 7.40 (s, 2H), 7.35-7.30 (m, 1H), 7.24 (s, 4H), 7.10-7.03 (m, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.04 (s, 2H), 5.02 (s, 2H), 3.78 (s, 3H), 3.75 (s, 3H), 3.54 (s, 6H). 13C NMR (101MHz, CDCl3) δ169.88, 164.14, 163.71, 161.69, 159.23, 153.23, 147.81, 139.22, 138.01, 137.11, 136.16, 134 .19, 130.23, 129.88, 129.08, 128.10, 127.25, 123.55, 117.41, 117.19, 114.00, 105.63, 60.97, 56.15, 55.28, 53.37.

[0064] Example 13

[0065] The benzoylhydrazone derivative Q-13, R = 2-chloro, has the chemical name (E)-4-(2-(2-chlorobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide and the English name (E)-4-(2-(2-chlorobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide. Its structural formula is as follows:

[0066]

[0067] The preparation method is as described in Example 1. The yield of the target compound Q-13 was 59%; mp 100.0-101.0°C. 1H NMR (400 MHz, CDCl3) δ 10.37 (s, 1H), 8.76 (s, 1H), 8.15 (s, 1H), 7.67 (s, 2H), 7.32 (ddq, J = 14.8, 4.8, 2.3 Hz, 5H), 7.23 (d, J = 6.0 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.04 (s, 2H), 5.02 (s, 2H), 3.78 (s, 3H), 3.75 (s, 3H), 3.54 (s, 6H). 13C NMR (101MHz, CDCl3) δ169.77, 163.64, 159.15, 153.19, 145.39, 139.34, 138.02, 137.10, 134.27, 134.00, 131 .28, 130.06, 129.63, 129.24, 128.11, 127.95, 127.26, 127.12, 113.91, 105.66, 60.97, 56.12, 55.27, 53.34.

[0068] Example 14

[0069] The benzoylhydrazone derivative Q-14, R = 4-methoxy-3-nitro. Its chemical name is (E)-4-(2-(4-methoxy-3-nitrobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide, and its English name is (E)-4-(2-(4-methoxy-3-nitrobenzylidene)hydrazine-1-carbonyl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)benzamide. Its structural formula is as follows:

[0070]

[0071] The preparation method is as described in Example 1. The yield of target compound Q-14 is 65%; mp is 114.5-115.5°C. 1H NMR (400 MHz, CDCl3) δ 10.72 (s, 1H), 8.35 (s, 1H), 7.99 (d, J = 6.9 Hz, 1H), 7.91 (s, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.26-7.20 (m, 4H), 7.08 (d, J = 9.0 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.05 (s, 2H), 5.02 (s, 2H), 3.99 (s, 3H), 3.79 (s, 3H), 3.75 (s, 3H), 3.53 (s, 6H). 13C NMR (101MHz, CDCl3) δ169.84, 163.74, 159.24, 154.21, 153.23, 146.34, 139.40, 139.34, 137.99, 137.08, 134.04 , 132.25, 129.82, 129.00, 128.11, 127.29, 126.65, 125.31, 114.02, 105.65, 60.96, 56.80, 56.17, 55.29, 53.38.

[0072] Example 15

[0073] The benzoylhydrazone derivative Q-15, R = naphthyl, has the chemical name ((E)-N-(4-methoxybenzyl)-4-(2-(naphthalen-2-ylmethylene)hydrazine-1-carbonyl)-N-(3,4,5-trimethoxyphenyl)benzamide and the English name (E)-N-(4-methoxybenzyl)-4-(2-(naphthalen-2-ylmethylene)hydrazine-1-carbonyl)-N-(3,4,5-trimethoxyphenyl)benzamide. Its structural formula is as follows:

[0074]

[0075] The preparation method is as described in Example 1. The yield of target compound Q-15 is 80%; mp 101.5-102.5℃.1H NMR (400MHz, CDCl3) δ10.41 (s, 1H), 9.08 (s, 1H), 8.66-8.62 (m, 1H), 7.95 (d, J = 7.6Hz, 1H), 7.86 (t, J = 8.1Hz, 2H), 7.70 (d, J = 6.9Hz, 2H), 7.51-7.4 3 (m, 3H), 7.32 (d, J = 8.0Hz, 2H), 7.22 (d, J = 6.3Hz, 2H), 6.80 (d, J = 8.5Hz, 2H), 6.04(s, 2H), 5.02(s, 2H), 3.77(s, 3H), 3.74(s, 3H), 3.52(s, 6H).13C NMR (101MHz, CDCl3) δ169.77, 163.60, 159.14, 153.19, 148.40, 139.23, 138.09, 137.02, 134.31, 133.72, 130.98, 129 .96, 129.30, 128.74, 128.17, 127.76, 127.19, 126.06, 125.28, 123.90, 113.93, 105.61, 60.96, 56.11, 55.25, 53.36.

[0076] Example 16

[0077] The benzoylhydrazone derivative Q-16, R = methyl, has the chemical name (E)-N-(4-methoxybenzyl)-4-(2-(4-methylbenzylidene)hydrazine-1-carbonyl)-N-(3,4,5-trimethoxyphenyl)benzamide and the English name (E)-N-(4-methoxybenzyl)-4-(2-(4-methylbenzylidene)hydrazine-1-carbonyl)-N-(3,4,5-trimethoxyphenyl)benzamide. Its structural formula is as follows:

[0078]

[0079] The preparation method is as described in Example 1. The yield of target compound Q-16 was 66%; mp 100.5-101.5°C. 1H NMR (500 MHz, CDCl3) δ 9.68 (s, 1H), 8.28 (s, 1H), 7.62 (d, J = 7.8 Hz, 3H), 7.47-7.32 (m, 3H), 7.25-7.22 (m, 2H), 7.19 (d, J = 7.8 Hz, 2H), 6.84 (d, J = 8.3 Hz, 2H), 6.04 (s, 2H), 5.01 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.55 (s, 6H), 2.37 (s, 3H). 13C NMR (101MHz, CDCl3) δ169.79, 163.57, 159.17, 153.19, 149.30, 140.83, 139.12, 138.10, 137.03, 134.40 , 131.00, 129.98, 129.37, 128.10, 127.74, 127.16, 113.95, 105.63, 60.95, 56.13, 55.27, 53.36, 21.51. BRIEF DESCRIPTION OF THE DRAWINGS

[0080] Figure 1 Example 1 Final product 1 H-NMR spectrum; Figure 2 Example 1 Final product 13 C-NMR spectrum;

[0081] Figure 3 Example 2 Final product 1 H-NMR spectrum; Figure 4 Example 2 Final product 13 C-NMR spectrum;

[0082] Figure 5 Example 3 Final product 1 H-NMR spectrum; Figure 6 Example 3 Final product 13 C-NMR spectrum;

[0083] Figure 7 Example 4 Final product 1 H-NMR spectrum; Figure 8 Example 4 Final product 13 C-NMR spectrum;

[0084] Figure 9 Example 5 Final product 1 H-NMR spectrum; Figure 10 Example 5 Final product 13 C-NMR spectrum;

[0085] Figure 11 Example 6 Final product 1 H-NMR spectrum; Figure 12 Example 6 Final product 13 C-NMR spectrum;

[0086] Figure 13 Example 7 Final product 1 H-NMR spectrum; Figure 14 Example 7 Final product 13 C-NMR spectrum;

[0087] Figure 15 Example 8 Final product 1 H-NMR spectrum; Figure 16 Example 8 Final product 13 C-NMR spectrum;

[0088] Figure 17 Example 9 Final product 1 H-NMR spectrum; Figure 18 Example 9 Final product 13 C-NMR spectrum;

[0089] Figure 19 Example 10 Final product 1 H-NMR spectrum; Figure 20 Example 10 Final product 13 C-NMR spectrum;

[0090] Figure 21 Example 11 Final product 1 H-NMR spectrum; Figure 22 Example 11 Final product 13 C-NMR spectrum;

[0091] Figure 23 Example 12 Final product 1 H-NMR spectrum; Figure 24 Example 12 Final product 13 C-NMR spectrum;

[0092] Figure 25 Example 13 Final product 1 H-NMR spectrum; Figure 26 Example 13 Final product 13 C-NMR spectrum;

[0093] Figure 27 Example 14 Final product 1 H-NMR spectrum; Figure 28 Example 14 Final product13 C-NMR spectrum;

[0094] Figure 29 Example 15 Final product 1 H-NMR spectrum; Figure 30 Example 15 Final product 13 C-NMR spectrum;

[0095] Figure 31 Example 16 Final product 1 H-NMR spectrum; Figure 32 Example 16 Final product 13 C-NMR spectrum.

[0096] Example 17: Antitumor activity of the 16 benzoylhydrazone derivatives mentioned above in this patent.

[0097] The present invention tests the antitumor activities of 16 benzoylhydrazone derivatives on three different types of tumor cells using the CCK8 method.

[0098] The specific test method is as follows: U87 (human brain astroglioblastoma cells), SGC-7901 (human gastric cancer cells) and HepG2 (human liver cancer cells) were selected as experimental cell lines. 17 benzoylhydrazone derivatives were dissolved in anhydrous DMSO, and each compound was prepared as a 100mM stock solution. The stock solution was further diluted with DMEM culture medium to prepare working solutions of different concentrations (e.g., 1nM, 5nM, 25nM, 125nM, 625nM, 1μM, 5μM, 10μM, 50μM). At least 3 replicate wells were set up for each concentration of compound to ensure the accuracy of the data. The prepared working solution was added to a 96-well plate with a cell density of 7000 cells per well, and different concentrations of compounds were added to each well. A negative control group was set up (adding the same volume of DMSO solution), and the positive control group could be treated with common anti-tumor drugs (such as colchicine or pentafluorouracil). After 48 hours of compound treatment, the culture medium was replaced with 100 μL DMEM containing 10 μL CCK8 dye and incubated for 2 hours. The absorbance at 450 nm was measured using a microplate reader. The cell inhibition rate was calculated based on the measured absorbance. The inhibition rate was calculated as follows: (negative control group OD - treatment group OD) / (negative control group OD - blank group OD) * 100%. The test results are shown in Table 1.

[0099] The IC50 value refers to the concentration of the compound that reduces cell viability by 50%. Use software (such as GraphPadPrism) to perform nonlinear regression analysis and fit the concentration-survival rate curve. The IC50 value of each compound is obtained by curve fitting. 50 IC values ​​were calculated in U87, SGC-7901, and HepG2 cell lines.50 value, and according to IC 50 The IC values ​​of compound 12 on breast cancer cells were used to determine its anti-tumor activity. 50 The highest was 12.5±0.49 nM. The test results are shown in Table 1.

[0100] Table 1 IC values ​​of compounds 1-17 in three tumor cell lines 50

[0101]

Claims

1. Synthesis and application of a series of derivatives, the structures are shown below:

2. The use of the derivative according to claim 1 in the preparation of anti-tumor drugs, characterized in that The derivatives have broad-spectrum anti-tumor inhibitory activity.

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