2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds and uses thereof

Abstract

The application discloses a 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound and application thereof in preparation of an antitumor drug, and a structure of the 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound is shown as formula I. In vitro tumor cell proliferation inhibition experiments show that the 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound has good tumor cell proliferation inhibition activity on at least one of human lung cancer cells A549, human colon cancer cells HCT116, human liver cancer cells HepG2 and human breast cancer cells MCF-7, and the 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound has good antitumor activity and can be applied to preparation of an antitumor drug.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and relates to a 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound and application thereof in preparation of an antitumor drug. BACKGROUND

[0002] Compounds containing a tetrahydro-1-benzazepine skeleton are common compounds in pharmaceutical chemistry research, and compounds containing such a fused heterocyclic unit have a wide range of biological activities, including promoting growth hormone secretion, anti-proliferative activity, antagonists targeting arginine vasopressin receptors V1A and V2, anti-HIV-1 infection, cyclin-dependent kinase and glycogen synthase kinase 3 (GSK-3) inhibitors, and anti-leishmania and anti-Chagas disease, etc. However, the application of such compounds in the preparation of antitumor drugs has not been reported so far. SUMMARY

[0003] The present application aims to provide a 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound and application thereof in preparation of an antitumor drug.

[0004] According to an aspect of the present application, a 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound is provided, which has a structure as shown in formula I:

[0005]

[0006] wherein R1 is selected from one of H, Br, Cl, -CH3, -COOCH2CH3; A2 is selected from one of .

[0007] In some embodiments, the 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound is selected from one of the following compounds:

[0008]

[0009] The "pharmaceutically acceptable salt of the compound" according to the present application can be: 1) a pharmaceutically acceptable and soluble salt of the compound shown in formula I formed with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, etc., and having the pharmacological activity of the corresponding compound; 2) a pharmaceutically acceptable and soluble salt of the compound formed with an organic acid such as formic acid, methanesulfonic acid, acetic acid, succinic acid, citric acid, tartaric acid, etc., and having the pharmacological activity of the corresponding compound.

[0010] The in vitro tumor cell proliferation inhibition experiment shows that the 2-aryl-2, 3, 4, 5-tetrahydro-1, 4-epoxybenzazepine compound provided by the application has good tumor cell proliferation inhibition activity on at least one of human lung cancer cells A549, human colon cancer cells HCT116, human liver cancer cells HepG2 and human breast cancer cells MCF-7, indicating that the 2-aryl-2, 3, 4, 5-tetrahydro-1, 4-epoxybenzazepine compound provided by the application has good antitumor activity and can be applied to the preparation of antitumor drugs.

[0011] In some embodiments, the tumor can be at least one of lung cancer, colon cancer, liver cancer, breast cancer, oral squamous cell carcinoma, brain glioma, gastric cancer and prostate cancer.

[0012] According to another aspect of the application, a pharmaceutical composition is provided, which comprises at least one compound provided by the application or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable ingredient.

[0013] In some embodiments, the pharmaceutically acceptable ingredient comprises a pharmaceutically active ingredient and / or a pharmaceutically acceptable auxiliary material which has no antagonistic effect on the compound provided by the application or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the pharmaceutically active ingredient is an ingredient with antitumor activity.

[0015] In some embodiments, the pharmaceutically active ingredient can be any one of the antitumor drugs in the prior art which has no antagonistic effect on the compound provided by the application or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the pharmaceutical composition is administered by injection, orally, parenterally, by inhalation spray or transdermally. DETAILED DESCRIPTION

[0017] The application will be further described in detail below with reference to the embodiments. The examples are only for explanation and do not limit the application in any way. Unless otherwise specified, the raw materials and reagents used in the examples are conventional products which can be obtained commercially; the experimental methods not specified in the examples are usually carried out according to the conventional conditions in the art or according to the recommended conditions of the manufacturers.

[0018] The 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound provided by the present application can be synthesized by referring to any one of the methods for synthesizing 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds disclosed in the prior art, such as the multi-step reaction developed by Ayala et al., in which sodium cyanoborohydride is used to directly reduce and aminate the corresponding benzaldehyde to obtain o-propenylaniline, and then starting from the o-propenylaniline, through successive amino-claisen rearrangement, oxidation / intramolecular 1,3-dipolar cycloaddition, the 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound is obtained (see: Gómez-Ayala, S.; Castrillón, J. A.; Palma, A.; Leal, S. M.; Escobar, P. and Bahsas, A., Synthesis, structural elucidation and in vitro antiparasitic activity against Trypanosoma cruzi and Leishmania chagasi parasites of novel tetrahydro-1-benzazepine derivatives. Biorg. Med. Chem. 2010, 18, 4721-4739.).

[0019] The 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound can also be synthesized by the following synthesis method:

[0020] The rhodium catalyst, the additive, the nitrone compound and the allyl precursor compound are added into an organic solvent, and the nitrone compound and the allyl precursor compound are allowed to react under heating under inert gas protection, so as to obtain the 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound.

[0021] The nitrone compound is selected from one of the following compounds:

[0022]

[0023] The allyl precursor compound can be selected from one of propylene methyl carbonate, propylene ethyl carbonate, propylene acetate, propylene glycol diethyl phosphonate.

[0024] The additive can be selected from one or more of silver acetate, sodium acetate, cesium acetate, silver oxide, silver carbonate, and pivalic acid.

[0025] The organic solvent can be selected from one or more of 1,2-dichloroethane, toluene, trifluorotoluene, chlorobenzene, acetonitrile, 1,4-dioxane, 2,2,2-trifluoroethanol, dimethyl sulfoxide, and N,N-dimethylformamide.

[0026] Example 1

[0027]

[0028] The method for preparing 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds having the structure shown in Formula I-1 includes the following steps:

[0029] (1) Preparation of nitrone compound having the structure shown in Formula II-1

[0030] At room temperature, 4-nitrotoluene (10.0 mmol, 1.0 equiv.), benzaldehyde (11.0 mmol, 1.1 equiv.) and ammonium chloride (12.0 mmol, 1.2 equiv.) were dissolved in 40 mL of a mixed solution of ethanol / water (v / v = 1 / 1). Then, it was cooled to 0°C, and after the addition of zinc powder (20.0 mmol, 2.0 equiv.), the reaction system was slowly raised to room temperature, and the stirring reaction was continued for 8 h. After the completion of the reaction, it was filtered, the filtrate was extracted with dichloromethane, the organic phase was dried with sodium sulfate and concentrated, and then purified by silica gel column chromatography to obtain compound II-1.

[0031] (2) Preparation of compound I-1

[0032] [Cp * Rh(CH3CN)3](SbF6)2(8 mg, 0.01 mmol, 5 mol%), AgOAc (50 mg, 0.3 mmol, 1.5 equiv.), compound II-1 (59 mg, 0.3 mmol, 1.5 equiv.), propylene carbonate (26 mg, 0.2 mmol, 1.0 equiv.) and chlorobenzene (2 mL) were added to a test tube. The reaction mixture was stirred at 120°C for 10 h. After cooling to room temperature, the reaction mixture was filtered by washing with dichloromethane, the solvent was removed under reduced pressure, and the reaction mixture was purified by silica gel column chromatography with PE / EA (20:1) as the eluent to obtain compound I-1 in a yield of 65%.

[0033] The spectral data of compound I-1 are as follows:

[0034] 1H NMR (600 MHz, CDC13) δ 7.53 - 7.41 (m, 2H), 7.41 - 7.32 (m, 2H), 7.27 - 7.24 (m, 1H), 6.97 (d, J = 1.2 Hz, 2H), 6.94 (q, J = 1.1 Hz, 1H), 4.98 - 4.90 (m, 1H), 4.63 - 4.53 (m, 1H), 3.38 (dd, J = 16.5, 5.4 Hz, 1H), 2.68 - 2.57 (m, 2H), 2.51 (d, J = 16.5 Hz, 1H), 2.31 (s, 3H);

[0035] 13 C NMR (151 MHz, CDC13) δ 148.2, 143.9, 135.5, 130.3, 128.5, 127.2, 126.9, 126.4, 124.9, 121.8, 75.5, 75.1, 42.5, 34.7, 21.0;

[0036] HRMS (ESI): m / z [M + H] + calcd for C 17 H 18 NO: 252.1383, found: 252.1391.

[0037] Example 2

[0038]

[0039] The preparation method of the 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound of structure as shown in formula I-2 is similar to Example 1, except that the compound I-2 is prepared from the nitrone compound of structure as shown in formula II-2 as the substrate, with a yield of 57%.

[0040] The spectral data of compound I-2 are as follows:

[0041] 1 H NMR (600 MHz, CDC13) δ 7.53 - 7.41 (m, 2H), 7.41 - 7.32 (m, 2H), 7.27 - 7.24 (m, 1H), 6.97 (d, J = 1.2 Hz, 2H), 6.94 (q, J = 1.1 Hz, 1H), 4.98 - 4.90 (m, 1H), 4.63 - 4.53 (m, 1H), 3.38 (dd, J = 16.5, 5.4 Hz, 1H), 2.68 - 2.57 (m, 2H), 2.51 (d, J = 16.5 Hz, 1H), 2.31 (s, 3H);

[0042] 13 C NMR (151 MHz, CDCI3) δ 150.6, 143.7, 129.8, 128.5, 126.9, 126.6, 126.4, 125.9, 125.2, 122.0, 75.4, 75.1, 42.5, 34.7;

[0043] HRMS (ESI): m / z [M+H] + calcd for C 16 H 16 NO: 238.1226, found: 238.1253.

[0044] Example 3

[0045]

[0046] The preparation method of 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds of structure as shown in formula I-3 is similar to Example 1, except that compound I-3 is prepared from nitrone compound of structure as shown in formula II-3 as substrate, with a yield of 66%.

[0047] The spectral data of compound I-3 are as follows:

[0048] 1 H NMR (600 MHz, CDCI3) δ 7.48 - 7.41 (m, 2H), 7.36 (dd, J = 8.5, 7.0 Hz, 2H), 7.29 - 7.26 (m, 1 H), 7.17 - 7.11 (m, 2H), 7.02 (d, J = 8.1 Hz, 1 H), 4.95 (ddd, J = 7.5, 5.3, 2.0 Hz, 1 H), 4.58 (dd, J = 8.5, 2.9 Hz, 1 H), 3.39 (ddd, J = 16.8, 5.5, 1.2 Hz, 1 H), 2.67 - 2.55 (m, 2H), 2.53 (d, J = 16.7 Hz, 1 H);

[0049] 13 C NMR (151 MHz, CDCI3) δ 148.10, 142.34, 130.12, 128.62, 127.50, 126.22, 126.07, 125.76, 125.33, 122.33, 74.35, 73.60, 41.48, 33.56;

[0050] HRMS (ESI): m / z [M+H] + calcd for C 16 H 15ClNO: 272.0837, found: 272.0867.

[0051] Example 4

[0052]

[0053] The preparation method of 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound of structure as shown in formula I-4 is similar to that of Example 1, except that compound I-4 is prepared from nitrone compound of structure as shown in formula II-4 as substrate, with a yield of 61%.

[0054] The spectral data of compound I-4 are as follows:

[0055] 1 H NMR (600 MHz, CDC13) δ 7.51-7.42 (m, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.32-7.24 (m, 3H), 7.06-6.93 (m, 1H), 5.05-4.76 (m, 1H), 4.58 (dd, J = 8.5, 2.9 Hz, 1H), 3.40 (ddd, J = 16.7, 5.4, 1.2 Hz, 1H), 2.73-2.46 (m, 3H);

[0056] 13 C NMR (151 MHz, CDC13) δ 149.6, 143.3, 132.6, 129.7, 128.5, 127.7, 127.1, 126.3, 123.7, 118.9, 75.3, 74.6, 42.5, 34.5;

[0057] HRMS (ESI): m / z [M+H] + calcd for C 16 H 15 BrNO: 316.0332, found: 316.0361.

[0058] Example 5

[0059]

[0060] The preparation method of 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound of structure as shown in formula I-5 is similar to that of Example 1, except that compound I-5 is prepared from nitrone compound of structure as shown in formula II-5 as substrate, with a yield of 63%.

[0061] The spectral data of compound I-5 are as follows:

[0062] 1 H NMR (600 MHz, CDC13) δ 7.89 - 7.83 (m, 2H), 7.51 - 7.44 (m, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.30 - 7.26 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 4.99 (ddd, J = 7.4, 5.3, 1.9 Hz, 1H), 4.64 (dd, J = 8.6, 2.6 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.55 - 3.39 (m, 1H), 2.66 (dddd, J = 12.9, 7.7, 2.8, 1.2 Hz, 1H), 2.63 - 2.55 (m, 2H), 1.39 (dd, J = 7.4, 6.7 Hz, 3H);

[0063] 13 C NMR (151 MHz, CDC13) δ 166.2, 154.6, 143.2, 131.4, 128.5, 128.2, 128.1, 127.1, 126.3, 125.5, 121.9, 75.3, 74.8, 61.0, 42.5, 34.6, 14.3;

[0064] HRMS (ESI): m / z [M + H] calcd for C + calcd for C 19 H 20 NO3: 310.1438, found: 310.1483.

[0065] Example 6

[0066]

[0067] The preparation method of the 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound of structure I-6 is similar to Example 1, except that compound I-6 is prepared from the nitrone compound of structure II-6 as the substrate, with a yield of 70%.

[0068] The spectral data of compound I-6 are as follows:

[0069] 1H NMR (600 MHz, CDCI3) δ 7.42-7.33 (m, 2H), 7.23-7.12 (m, 5H), 7.08 (dd, J = 7.3, 1.3 Hz, 1H), 4.97 (ddd, J = 7.7, 5.4, 2.4 Hz, 1H), 4.60 (dd, J = 8.1, 3.2 Hz, 1H), 3.42 (dd, J = 16.5, 5.3 Hz, 1H), 2.66-2.57 (m, 2H), 2.55 (d, J = 16.5 Hz, 1H), 2.35 (s, 3H);

[0070] 13 C NMR (151 MHz, CDCI3) δ 150.6, 140.8, 136.6, 129.8, 129.1, 126.5, 126.3, 125.9, 125.2, 121.9, 75.3, 75.0, 42.4, 34.7, 21.0;

[0071] HRMS (ESI): m / z [M+H] + calcd for C 17 H 18 NO: 252.1383, found: 252.1358.

[0072] Example 7

[0073]

[0074] The method for preparing 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds of structure I-7 was similar to Example 1, except that compound I-7 was prepared from nitrone compound of structure II-7 as substrate, with a yield of 69%.

[0075] The spectral data of compound I-7 were as follows:

[0076] 1 H NMR (600 MHz, CDCI3) δ 7.42-7.33 (m, 2H), 7.23-7.12 (m, 5H), 7.08 (dd, J = 7.3, 1.3 Hz, 1H), 4.97 (ddd, J = 7.7, 5.4, 2.4 Hz, 1H), 4.60 (dd, J = 8.1, 3.2 Hz, 1H), 3.42 (dd, J = 16.5, 5.3 Hz, 1H), 2.66-2.57 (m, 2H), 2.55 (d, J = 16.5 Hz, 1H), 2.35 (s, 3H);

[0077] 13C NMR (151 MHz, CDCI3) δ 150.1, 147.6, 129.9, 129.1 (q, J = 32.5 Hz), 126.7, 126.7, 126.2, 125.4 (q, J = 3.8 Hz), 125.2, 124.2 (q, J = 271.8 Hz), 121.9, 75.2, 74.7, 42.6, 34.6;

[0078] HRMS (ESI): m / z [M+H] + calcd for C 17 H 15 F3NO: 306.1101, found: 306.1125.

[0079] Example 8

[0080]

[0081] The preparation method of the 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound of structure as shown in formula I-8 is similar to Example 1, except that compound I-8 is prepared from the nitrone compound of structure as shown in formula II-8 as the substrate, with a yield of 61 %.

[0082] The spectrum data of compound I-8 is as follows:

[0083] 1 H NMR (600 MHz, CDCI3) δ 7.43 (d, J = 2.0 Hz, 1 H), 7.31 - 7.23 (m, 2H), 7.22 - 7.13 (m, 2H), 7.13 - 7.03 (m, 3H), 6.99 (dd, J = 7.3, 1.6 Hz, 1 H), 4.89 (td, J = 7.1, 6.4, 2.5 Hz, 1 H), 4.50 (dd, J = 8.1, 3.4 Hz, 1 H), 3.35 (dd, J = 16.6, 5.4 Hz, 1 H), 2.62 - 2.36 (m, 3H);

[0084] 13 C NMR (151 MHz, CDCI3) δ 150.2, 145.7, 134.4, 129.8, 129.7, 127.1, 126.7 126.7, 126.1, 125.2, 124.6, 121.9, 75.1, 74.7, 42.5, 34.6;

[0085] HRMS (ESI): m / z [M+H] + calcd for C 16 H 15ClNO: 272.0837, found: 272.0895.

[0086] Example 9

[0087]

[0088] The preparation method of the 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound of the structure as shown in formula I-9 is similar to that of Example 1, except that the compound I-9 is prepared from the nitroketone compound of the structure as shown in formula II-9, with a yield of 64%.

[0089] The spectrum data of the compound I-9 are as follows:

[0090] 1 H NMR (600 MHz, CDC13) δ 7.66 (t, J = 1.9 Hz, 1H), 7.42-7.35 (m, 2H), 7.22 (t, J = 7.8 Hz, 1H), 7.20-7.12 (m, 3H), 7.07 (dd, J = 7.2, 1.6 Hz, 1H), 4.96 (ddd, J = 7.3, 5.4, 2.4 Hz, 1H), 4.58 (dd, J = 8.1, 3.3 Hz, 1H), 3.42 (dd, J = 16.6, 5.4 Hz, 1H), 2.65-2.47 (m, 3H);

[0091] 13 C NMR (151 MHz, CDC13) δ 150.1, 146.0, 130.0, 129.8, 129.5, 126.7, 126.1, 125.1, 125.1, 122.6, 121.9, 75.1, 74.7, 42.5, 34.6;

[0092] HRMS (ESI): m / z [M+H] + calcd for C 16 H 15 BrNO: 317.2053, found: 317.2073.

[0093] Example 10

[0094]

[0095] The preparation method of the 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound of the structure as shown in formula I-10 is similar to that of Example 1, except that the compound I-10 is prepared from the nitroketone compound of the structure as shown in formula II-10, with a yield of 59%.

[0096] The spectral data of compound I-10 is as follows:

[0097] 1 H NMR (600 MHz, CDC13) δ 7.75 (ddd, J = 7.5, 1.8, 0.7 Hz, 1H), 7.25 (td, J = 7.8, 1.7 Hz, 1H), 7.19 - 7.11 (m, 3H), 7.07 (dt, J = 7.5, 1.1 Hz, 1H), 7.01 (td, J = 7.5, 1.1 Hz, 1H), 6.86 (dd, J = 8.2, 1.1 Hz, 1H), 4.89 (td, J = 7.9, 7.2, 2.0 Hz, 2H), 3.81 (s, 3H), 3.41 (dd, J = 16.5, 5.4 Hz, 1H), 2.71 - 2.33 (m, 3H);

[0098] 13 C NMR (151 MHz, CDC13) δ 155.8, 150.8, 131.9, 129.7, 127.8, 126.7, 126.4, 125.7, 125.4, 122.0, 120.5, 109.9, 74.8, 70.0, 55.2, 42.1, 34.8;

[0099] HRMS (ESI): m / z [M + H] + calcd for C 16 H 14 F2NO: 268.1332, found: 268.1354.

[0100] Example 11

[0101]

[0102] The preparation method of 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds of structure as shown in formula I-11 is similar to Example 1, except that compound I-11 is prepared from nitrone compound of structure as shown in formula II-11 as substrate, with a yield of 37%.

[0103] The spectral data of compound I-11 is as follows:

[0104] 1H NMR (600 MHz, CDC13) δ 7.40 (dd, J = 1.8, 0.9 Hz, 1H), 7.22-7.09 (m, 4H), 6.38-6.30 (m, 2H), 4.99 (ddd, J = 7.5, 5.3, 1.9 Hz, 1H), 4.64 (dd, J = 8.7, 2.6 Hz, 1H), 3.46-3.37 (m, 1H), 2.78 (dddd, J = 12.8, 7.8, 2.7, 1.2 Hz, 1H), 2.54 (d, J = 16.5 Hz, 1H), 2.42 (ddd, J = 12.7, 8.7, 2.0 Hz, 1H);

[0105] 13 C NMR (151 MHz, CDC13) δ 155.2, 149.9, 142.0, 129.8, 126.7, 126.2, 125.1, 122.1, 110.3, 106.4, 74.8, 69.5, 38.6, 34.6;

[0106] HRMS (ESI): m / z [M + H] + calcd for C 14 H 14 NO2: 228.1019, found: 228.1025.

[0107] Example 12

[0108]

[0109] The method for preparing the 2-aryl-2,3,4,5-tetrahydro-l,4-epoxybenzazepine compound of structure I-12 was similar to Example 1, except that compound I-12 was prepared from the nitrone compound of structure II-12 as the substrate, with a yield of 32%.

[0110] The spectral data of compound I-12 are as follows:

[0111] 1 H NMR (600 MHz, CDC13) δ 7.40 (dd, J = 1.8, 0.9 Hz, 1H), 7.22-7.09 (m, 4H), 6.38-6.30 (m, 2H), 4.99 (ddd, J = 7.5, 5.3, 1.9 Hz, 1H), 4.64 (dd, J = 8.7, 2.6 Hz, 1H), 3.46-3.37 (m, 1H), 2.78 (dddd, J = 12.8, 7.8, 2.7, 1.2 Hz, 1H), 2.54 (d, J = 16.5 Hz, 1H), 2.42 (ddd, J = 12.7, 8.7, 2.0 Hz, 1H);

[0112] 13C NMR (151 MHz, CDC13) δ 150.2, 144.8, 129.8, 126.6, 126.6, 126.0, 126.0, 125.1, 122.0, 120.9, 74.9, 71.9, 41.7, 34.7;

[0113] HRMS (ESI): m / z [M+H] + calcd for C 14 H 14 NOS: 244.0791, found: 244.0801.

[0114] Test Example 1

[0115] The growth inhibition experiment of the compounds on colon cancer cell line HCT116, liver cancer cell line HepG2 and breast cancer cell line MCF-7 is the same as that on lung cancer cell line A549.

[0116] 1) The logarithmic growth period of human lung cancer cell A549 was digested with 0.25% trypsin, and then a cell suspension was prepared with DMEM complete culture solution containing 10% (volume percent) fetal bovine serum. The tumor cells were diluted to 1.0 x 10 5 cells / mL, respectively, and inoculated into 96-well culture plates at 100 μL per well. After incubation at 37°C in a 5% CO2 incubator for 24 h, the culture solution in each well was removed.

[0117] 2) Compound I-1 to I-12 were dissolved in DMSO, and diluted with DMEM complete culture medium to 100 μM, with the DMSO content being 1% (volume percent). The control drug paclitaxel was prepared in the same way, and the blank control was DMEM complete culture medium containing 1% DMSO. The drug-containing culture medium was added to the above-mentioned 96-well plates, and incubation was continued for 48 h.

[0118] 3) After 48 h, the culture medium was discarded, and culture medium containing 10% CCK8 reagent was added to each well, and incubation in the incubator was continued for 3 h.

[0119] 4) The optical density value (OD value) at a wavelength of 450 nm was determined on an enzyme marker, and the tumor cell growth inhibition rate was calculated according to the formula.

[0120] Inhibition rate % = 100 x (control group OD value - experimental group OD value) / control group OD value

[0121] The results of the tumor cell proliferation inhibition activity of compounds I-1 to I-12 are shown in Table 1 (Note: I-1 to I-12 are all racemic compounds).

[0122] Table 1 In vitro tumor cell proliferation inhibition activity of compounds I-1 to I-12

[0123]

[0124] It can be seen from the results of Table 1 that the compound provided by the present application has good in-vitro anti-tumor activity. The test results show that the compound provided by the present application has sensitivity to at least one of lung cancer cell line A549, colon cancer cell line HCT116, liver cancer cell line HepG2 and breast cancer cell line MCF-7, wherein when the concentration of the compound is 100 μM, the proliferation inhibition activity of compounds I-1, I-5, I-6, I-9 and I-10 on lung cancer cells A549 is more than 50%, and the inhibition rate of compound I-6 reaches 65.67%; the proliferation inhibition activity of compounds I-2, I-3 and I-5 on colon cancer cells HCT116 is more than 50%, and the inhibition rates are 61.76%, 77.29% and 66.97%, respectively; the proliferation inhibition activity of compounds I-3, I-5, I-9, I-11 and I-12 on liver cancer cells HepG2 is more than 50%, and the inhibition rate of compound I-11 reaches 63.91%; the proliferation inhibition activity of compound I-7 on breast cancer cell line MCF-7 is also more than 50%.

[0125] The above only describes some embodiments of the present application. For those skilled in the art, without departing from the concept of the present application, several modifications and improvements can be made, which are all within the protection scope of the present application.

Claims

1. Use of a compound represented by Formula I or a pharmaceutically acceptable salt thereof in the preparation of an antitumor medicament, wherein R1is selected from one of H, Cl, -CH3, -COOCH2CH3; A2is selected from one of , , , , , , .

2. Use according to claim 1, characterized in that, the compound is selected from one of the following compounds: 。 3. Use according to claim 1 or 2, characterized in that, the tumor is selected from at least one of lung cancer, colon cancer, liver cancer, breast cancer.

Images