An antitumor matrine hydrazine thiazole derivative, preparation method and application thereof

Abstract

The application discloses an anti-tumor matrine hydrazine thiazole derivative and a preparation method and application thereof, NaH is added into a reaction container one, then a DMF solution is added, and then aminothiourea is added into the reaction container one to stir the solution; sophoridine is added into the stirred solution to perform a reflux reaction, after the reaction is completed, a quenching reaction is performed, and then extraction, concentration drying and column chromatography separation are performed to obtain an aminothiourea matrine intermediate; the obtained aminothiourea matrine intermediate is added into a reaction container two, and an ethanol dissolving solvent is added to dissolve; the dissolved solution is added with alpha-bromo R base ethanone to perform a reaction, after the reaction is completed, concentration drying and column chromatography separation are performed to obtain the anti-tumor matrine hydrazine thiazole derivative. The anti-tumor matrine hydrazine thiazole derivative has strong anti-tumor activity, and the preparation method is simple and the reaction condition is easy to control.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of drug synthesis, and particularly relates to an anti-tumor matrine hydrazine thiazole derivative and a preparation method and application thereof. BACKGROUND

[0002] Matrine alkaloids are extracted from the traditional Chinese medicine Sophora flavescens, and have been attracting attention in the past few decades. Matrine-type alkaloids belong to quinolinoridin analogs, which are composed of matrine, bisophoramine, sophocarpine, sophoridine, oxymatrine, sophoramine, and sophoranol. Matrine-type alkaloids have many biological activities and therapeutic properties. For example, matrine exhibits a variety of effective effects, including anti-inflammatory, antiviral, antitumor, antiparasitic, antimicrobial, immunosuppressive, neuroprotective, and cardioprotective effects; on the other hand, matrine is also used to prepare surface imprinting materials for molecular selective recognition. Sophoridine, as another chemical component of the traditional Chinese medicine compound Sophora flavescens injection, also exhibits similar biological activities to matrine. Matrine, oxymatrine, and sophoridine, as the main active ingredients, have been widely used in China for the treatment of acute and chronic liver disease, vaginitis, chronic cervicitis, and arrhythmia. SUMMARY

[0003] The present application provides an anti-tumor matrine hydrazine thiazole derivative.

[0004] The technical scheme adopted by the present application to achieve the above-mentioned purpose is as follows:

[0005] An anti-tumor matrine hydrazine thiazole derivative, which has the following structural formula:

[0006]

[0007] R is one of the following groups:

[0008]

[0009] It is another object of the present application to provide a preparation method of the anti-tumor matrine hydrazine thiazole derivative.

[0010] Step S1, NaH is added to a reaction container one, then a DMF solution is added, and then aminothiourea is added to the reaction container one to stir the solution.

[0011] Step S2, sophocarpine is added to the solution of step S1 to perform a reflux reaction, after the reaction is completed, a quenching reaction is performed, and then extraction, concentration and drying, and column chromatography separation are performed to obtain an aminothiourea matrine intermediate.

[0012] Step S3, the aminothiourea sophoridine intermediate obtained in step S2 is added into reaction container two, dissolved in ethanol as the dissolving solvent. The solution after dissolution is added with α-bromo R group ketone for reaction. After the reaction is completed, it is concentrated and dried, and column chromatography is used for separation to obtain the anti-tumor sophoridine hydrazine thiazole derivative 5.

[0013] Preferably, after the reaction is quenched in step S2, the aqueous phase is extracted with ethyl acetate, and the organic phases are combined and concentrated and dried.

[0014] Preferably, acetic acid is used for quenching the reaction in step S2.

[0015] Preferably, the reaction process is monitored by TLC plate.

[0016] Preferably, the molar ratio of sophoridine to aminothiourea is 1:1-1.2 in mmol:mmol.

[0017] Preferably, the molar ratio of thiourea sophoridine to α-bromoacetophenone is 1:1.1-1.3 in mmol:mmol.

[0018] Preferably, the solution after dissolution in step S3 is added with α-bromo R group ketone for reaction to obtain the anti-tumor sophoridine hydrazine thiazole derivative 5, which includes:

[0019] The anti-tumor sophoridine-C13 position hydrazine thiazole derivative 5-2 is synthesized by reacting the thiourea sophoridine intermediate 3 with α-bromo-4-phenylacetophenone.

[0020] The anti-tumor sophoridine-C13 position hydrazine thiazole derivative 5-7 is synthesized by reacting the thiourea sophoridine intermediate 3 with α-bromo-4-nitroacetophenone.

[0021] The anti-tumor sophoridine-C13 position hydrazine thiazole derivative 5-8 is synthesized by reacting the thiourea sophoridine intermediate 3 with α-bromo-4-bromoacetophenone.

[0022] The anti-tumor sophoridine-C13 position hydrazine thiazole derivative 5-11 is synthesized by reacting the thiourea sophoridine intermediate 3 with α-bromo-4-fluoroacetophenone.

[0023] The anti-tumor sophoridine-C13 position hydrazine thiazole derivative 5-13 is synthesized by reacting the thiourea sophoridine intermediate 3 with α-bromo-4-cyanoacetophenone.

[0024] The anti-tumor sophoridine-C13 position hydrazine thiazole derivative 5-15 is synthesized by reacting the thiourea sophoridine intermediate 3 with α-bromo-2,4-dichloroacetophenone.

[0025] The hydrazine-thiazole derivatives of anti-tumor matrine at C13 position are synthesized by reacting the intermediate 3 of matrine with α-bromo-2,4-difluoroacetophenone.

[0026] The hydrazine-thiazole derivatives of anti-tumor matrine at C13 position are synthesized by reacting the intermediate 3 of matrine with α-bromo-4-trifluoromethoxyacetophenone.

[0027] The hydrazine-thiazole derivatives of anti-tumor matrine at C13 position are synthesized by reacting the intermediate 3 of matrine with α-bromo-4-methylsulfonylacetophenone.

[0028] Still another object of the present application is to provide the use of the hydrazine-thiazole derivatives of anti-tumor matrine in the preparation of tumor inhibitors.

[0029] Preferably, the tumor inhibitors are lung cancer cell inhibitors, cervical cancer cell inhibitors, and colon cancer cell inhibitors.

[0030] Compared with the prior art, the present application has the following beneficial effects:

[0031] The hydrazine-thiazole derivatives of anti-tumor matrine of the present application retain the structure of matrine while forming the hydrazine-thiazole structure of matrine derivatives, thereby enhancing the anti-tumor activity of matrine derivatives. The molecular structures of the hydrazine-thiazole derivatives of anti-tumor matrine are novel, and all are new compounds. The hydrazine-thiazole derivatives of anti-tumor matrine have distinct chemical structural characteristics, and the preparation method is not only simple, but also has controllable reaction conditions. The product can be obtained by column chromatography. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 The figure is a schematic diagram of the preparation method of the matrine derivatives in the embodiments of the present application.

[0033] Figure 2 The figure is the nuclear magnetic resonance hydrogen spectrum of the compound 5-2 in the embodiments of the present application.

[0034] Figure 3 The figure is the nuclear magnetic resonance carbon spectrum of the compound 5-2 in the embodiments of the present application.

[0035] Figure 4 The figure is the nuclear magnetic resonance hydrogen spectrum of the compound 5-7 in the embodiments of the present application.

[0036] Figure 5 The figure is the nuclear magnetic resonance carbon spectrum of the compound 5-7 in the embodiments of the present application.

[0037] Figure 6 The figure is the nuclear magnetic resonance hydrogen spectrum of the compound 5-8 in the embodiments of the present application.

[0038] Figure 7 The figure is the nuclear magnetic resonance carbon spectrum of the compound 5-8 in the embodiments of the present application.

[0039] Figure 8 NMR spectrum of the hydrogen of the compound 5-11 of the embodiment of the present application.

[0040] Figure 9 NMR spectrum of the carbon of the compound 5-11 of the embodiment of the present application.

[0041] Figure 10 NMR spectrum of the fluorine of the compound 5-11 of the embodiment of the present application.

[0042] Figure 11 NMR spectrum of the hydrogen of the compound 5-13 of the embodiment of the present application.

[0043] Figure 12 NMR spectrum of the carbon of the compound 5-13 of the embodiment of the present application.

[0044] Figure 13 NMR spectrum of the hydrogen of the compound 5-15 of the embodiment of the present application.

[0045] Figure 14 NMR spectrum of the carbon of the compound 5-15 of the embodiment of the present application.

[0046] Figure 15 NMR spectrum of the hydrogen of the compound 5-16 of the embodiment of the present application.

[0047] Figure 16 NMR spectrum of the carbon of the compound 5-16 of the embodiment of the present application.

[0048] Figure 17 NMR spectrum of the fluorine of the compound 5-16 of the embodiment of the present application.

[0049] Figure 18 NMR spectrum of the hydrogen of the compound 5-17 of the embodiment of the present application.

[0050] Figure 19 NMR spectrum of the carbon of the compound 5-17 of the embodiment of the present application.

[0051] Figure 20 NMR spectrum of the fluorine of the compound 5-17 of the embodiment of the present application.

[0052] Figure 21 NMR spectrum of the hydrogen of the compound 5-18 of the embodiment of the present application.

[0053] Figure 22 NMR spectrum of the carbon of the compound 5-18 of the embodiment of the present application. DETAILED DESCRIPTION

[0054] The present application will be further clarified by the following examples, which should not be construed as limiting the scope of the application. Various modifications of the application in addition to those described herein will become apparent to those skilled in the art from the disclosure herein. Such modifications are also intended to fall within the scope of the appended claims.

[0055] Example 1

[0056] A kind of anti-tumor matrine hydrazine thiazole derivative, its structural formula is:

[0057]

[0058] Wherein, R is one of the following groups:

[0059]

[0060] Example 2

[0061] The present embodiment provides a preparation method of an anti-tumor matrine hydrazine thiazole derivative, to prepare the anti-tumor matrine hydrazine thiazole derivative in example 1, comprising the following steps:

[0062] Step S1, NaH is added to reaction container one, then DMF solution is added, and then aminothiourea is added to the solution in reaction container one. Specifically, 60% pure NaH (300 mg) is first added to a 5 reaction bottle containing 10 mL of DMF solution, and then aminothiourea (1.0 g) is added to the above system, and stirred at 0°C for 10 min.

[0063] Step S2, sophoridine is added to the solution of step S1 to carry out reflux reaction, after the reaction is completed, quenching reaction is carried out, and then extraction, concentration and drying are carried out, and column chromatography separation is carried out to obtain aminothiourea matrine intermediate, and the reaction process is as shown in Figure 1

[0064] Specifically, sophoridine (2.5 g) is added to the solution of step S1 to carry out reflux reaction, and the reflux reaction is carried out for 12 h. The molar ratio of sophoridine to aminothiourea is 1:1.1 in mmol:mmol. In another embodiment, the molar ratio of sophoridine to aminothiourea is 1:1 in mmol:mmol. In another embodiment, the molar ratio of sophoridine to aminothiourea is 1:1.2 in mmol:mmol. The reaction is detected by TLC plate until the reaction is completed, and then an appropriate amount of acetic acid is added to quench the reaction. After the reaction, the aqueous phase is extracted with ethyl acetate three times, the organic phase is combined, concentrated and dried, and the crude product is purified by column chromatography (dichloromethane:methanol=10:1-8:1) to obtain 1.3 g of aminothiourea matrine, with a yield of 40%.

[0065] ​Step S3, adding the amino-thiosemicarbazide sophoridine intermediate obtained in step S2 into a reaction container two, dissolving with ethanol as the dissolving solvent; adding α-bromo R-ethyl ketone into the dissolved solution to react, after the reaction is completed, concentrating and drying, column chromatography separation to obtain the anti-tumor sophoridine hydrazine-thiazole derivative 5, the reaction process is shown in Figure 1 .

[0066] Specifically, first, the amino-thiosemicarbazide sophoridine is dissolved in ethanol, second, α-bromo phenyl ethyl ketone is added to react, after the reaction is completed, the reaction liquid is concentrated and dried, column chromatography separation (dichloromethane:methanol = 30:1~10:1) to obtain the sophoridine derivative 5. The molar ratio of the thiosemicarbazide sophoridine and the α-bromo phenyl ethyl ketone is 1:1.2 in mmol:mmol. In another embodiment, the molar ratio of the thiosemicarbazide sophoridine and the α-bromo phenyl ethyl ketone is 1:1.1 in mmol:mmol. In another embodiment, the molar ratio of the thiosemicarbazide sophoridine and the α-bromo phenyl ethyl ketone is 1:1.3 in mmol:mmol.

[0067] In this embodiment, first, the sophocarpine and the amino-thiosemicarbazide are used as the starting substrates, N,N-dimethylformamide is used as the solvent to synthesize the amino-thiosemicarbazide sophoridine, then the amino-thiosemicarbazide sophoridine and the α-bromo R-ethyl ketone are used as the reactants, ethanol is used as the solvent to synthesize a series of anti-fungal sophoridine derivatives. While the structure of the sophoridine is completely retained, the anti-fungal sophoridine derivative with the hydrazine-thiazole structure is formed, and the anti-fungal sophoridine derivative is enhanced in the bacteriostatic activity.

[0068] Example 3

[0069] The difference between this embodiment and example 2 is that the anti-tumor sophoridine-C13 hydrazine-thiazole derivative 5-2 is synthesized by the reaction of the thiosemicarbazide sophoridine intermediate 3 and the α-bromo-4-phenyl phenyl ethyl ketone.

[0070] The amino-thiosemicarbazide sophoridine intermediate 3 is added into a round bottom flask, dissolved with ethanol as the solvent, then the α-bromo-4-phenyl phenyl ethyl ketone is added, the molar ratio of the amino-thiosemicarbazide sophoridine intermediate 3 and the α-bromo-4-phenyl phenyl ethyl ketone is 0.3:0.36 in mmol:mmol, the reaction is carried out at room temperature, the reaction is monitored by TLC plate until the reaction is completed, the reaction time is 1h. The reaction liquid is concentrated and dried, column chromatography separation (dichloromethane:methanol = 30:1~10:1) to obtain the product anti-tumor sophoridine-C13 hydrazine-thiazole derivative 5-2:

[0071]

[0072] As shown in Figure 2 , 3 , the anti-tumor sophoridine-C13 hydrazine-thiazole derivative 5-2 spectrum data analysis:

[0073] White solid, R f : 0.60 (DCM:MeOH = 10:1), 114.9 mg (74.6% yield)

[0074] 1 H NMR (400 MHz, CDC13) δ 7.82 (dd, J = 8.3, 2.1 Hz, 2H), 7.62 (dd, J = 6.4, 4.0 Hz, 4H), 7.48 - 7.42 (m, 2H), 7.39 - 7.33 (m, 1H), 6.81 (d, J = 2.1 Hz, 1H), 4.47 - 4.19 (m, 2H), 4.11 - 3.98 (m, 1H), 3.30 - 3.22 (m, 1H), 3.13 (t, J = 12.7 Hz, 1H), 2.87 (s, 2H), 2.54 - 2.36 (m, 2H), 2.18 (s, 1H), 2.05 - 1.89 (m, 3H), 1.8 - 1.61 (m, 5H), 1.55 - 1.40 (m, 4H), 1.38 - 1.28 (m, 3H).

[0075] 13 C NMR (101 MHz, CDC13) δ 174.9, 167.2, 150.8, 140.5, 140.2, 134.1, 128.8 (2C), 127.4, 127.2 (2C), 126.9 (2C), 126.3 (2C), 103.3, 63.8, 57.1 (2C), 51.4, 50.1, 42.5, 41.6, 36.1, 35.4, 29.2, 27.5, 26.2, 20.9, 20.4.

[0076] Example 4

[0077] The difference between this example and Example 2 is that the anti-tumor matrine hydrazine thiazole derivatives 5-7 at C13 position are synthesized by reacting the thiourea matrine intermediate 3 with a-bromo-4-nitroacetophenone.

[0078]

[0079] As shown in Figure 4 , 5 , the anti-tumor matrine hydrazine thiazole derivatives 5-7 spectrum data analysis:

[0080] Yellow solid, R f : 0.60 (DCM:MeOH = 10:1), 115.7 mg (80% yield)

[0081] 1H NMR (400 MHz, Chloroform-d) δ 8.24 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 8.8 Hz, 2H), 7.04 (s, 1H), 6.93 (s, 1H), 4.42 (dd, J = 12.9, 4.3 Hz, 1H), 4.34 (s, 1H), 4.18 - 4.05 (m, 1H), 3.47 (s, 1H), 3.18 (t, J = 12.7 Hz, 1 H), 2.92 - 2.78 (m, 2H), 2.62 - 2.48 (m, 2H), 2.20 - 2.09 (m, 2H), 2.04 - 1.95 (m, 2H), 1.88 (d, J = 13.1 Hz, 1H), 1.80 - 1.67 (m, 4H), 1.59 - 1.41 (m, 6H).

[0082] 13 C NMR (151 MHz, CDCI3) δ 174.2, 166.7, 149.6, 147.8, 139.6, 126.3 (2C), 124.1 (2C), 108.2, 63.7, 57.2 (2C), 51.8, 50.2, 43.0, 41.4, 36.1, 35.3, 29.5, 27.7, 26.7, 25.1, 22.1, 20.7.

[0083] Example 5

[0084] The difference between this example and Example 2 is that the anti-tumor matrine hydrazine thiazole derivatives 5-8 at C13 position were synthesized by reacting the thiourea matrine intermediate 3 with a-bromo-4-bromoacetophenone.

[0085]

[0086] As shown in Figure 6 , 7 , the anti-tumor matrine hydrazine thiazole derivatives 5-8 spectrum data analysis:

[0087] White solid, R f : 0.60 (DCM:MeOH = 10:1), 120.5 mg (78% yield)

[0088] 1H NMR (400MHz, CDCl3) δ7.63(d,J=8.3Hz,2H),7.49(d,J=8.2Hz,2H),6.79(s, 1H),4.45(dd,J=13.0,4.5Hz,2H),4.20-4.10(m,1H),3.38(d,J=6.1Hz,1H), 3.18(t,J=12.9Hz,1H),3.10-2.97(m,2H),2.56-2.43(m,2H),2.39(s,1H), 2.20-2.02(m,3H),1.92-1.77(m,3H),1.76-1.63(m,3H),1.60-1.41(m,5H).

[0089] 13 C NMR (101MHz, CDCl3) δ174.5,167.3,150.1,133.9,132.0,131.7,127.8,127.5,121.4,1 03.9,64.1,56.9(2C),51.2,49.8,42.3,41.2,36.1,35.0,29.3,26.9,25.9,20.4,19.9.

[0090] Example 6

[0091] The difference between this embodiment and Example 2 is that the antitumor matrine-C13 hydrazine derivative 5-11 is synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-fluoroacetophenone.

[0092]

[0093] like Figures 8-10 As shown, the spectral data analysis of matrine-C13 hydrazine-thiazole derivative 5-11 is as follows:

[0094] White solid, R f :0.60(DCM:MeOH=10:1),107.9mg(79%yield)

[0095] 1H NMR (400 MHz, CDCI3) δ 7.76-7.68 (m, 2H), 7.06 (t, J = 8.7 Hz, 2H), 6.70 (s, 1H), 4.52-4.25 (m, 2H), 4.12 (s, 1H), 3.37-3.29 (m, 1H), 3.18 (t, J = 12.8 Hz, 1H), 2.97 (s, 2H), 2.56-2.40 (m, 2H), 2.38-2.20 (m, 1H), 2.14-1.95 (m, 3H), 1.92-1.62 (m, 6H), 1.59-1.39 (m, 5H).

[0096] 13 C NMR (151 MHz, CDCI3) δ 174.6, 167.2, 163.2, 161.6, 150.2, 131.3, 131.3, 127.6, 127.6, 115.5, 115.4, 102.8, 64.0, 57.1, 51.4, 50.0, 42.5, 41.4, 36.1, 35.3, 29.3, 27.3, 26.1, 20.8, 20.4.

[0097] 19 F NMR (377 MHz, CDCI3) δ -114.3.

[0098] Example 7

[0099] The difference between this example and Example 2 is that the antitumor matrine hydrazine thiazole derivative 5-13 at C13 position is synthesized by reacting the thiourea matrine intermediate 3 with α-bromo-4-nitroacetophenone;

[0100] As shown in Figure 11 , 12 , the antitumor matrine hydrazine thiazole derivative 5-13 spectrum data analysis:

[0101] White solid, R f : 0.60 (DCM:MeOH = 10:1), 108.9 mg (78.5% yield)

[0102] 1H NMR (400 MHz, CDC13) δ 7.84 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H), 6.95 (s, 1H), 4.40 (dd, J = 12.8, 4.5 Hz, 2H), 4.16 - 4.04 (m, 1H), 3.51 - 3.37 (m, 1H), 3.15 (t, J = 12.7 Hz, 1H), 2.91 - 2.80 (m, 2H), 2.59 - 2.45 (m, 2H), 2.18 (s, 1H), 2.13 - 1.93 (m, 4H), 1.86 (d, J = 13.1 Hz, 1H), 1.79 - 1.65 (m, 4H), 1.58 - 1.40 (m, 5H).

[0103] 13 C NMR (101 MHz, CDC13) δ 174.6, 167.1, 149.5, 139.0, 132.4 (2C), 126.2 (2C), 119.1, 110.6, 106.5, 63.7, 57.1 (2C), 51.5, 50.0, 42.8, 41.6, 36.0, 35.4, 29.4, 27.6, 26.4, 21.0, 20.5.

[0104] Example 8

[0105] The difference between this example and Example 2 is that the anti-tumor matrine hydrazine thiazole derivative 5-15 at C13 position is synthesized by reacting the thiourea matrine intermediate 3 with a-bromo-2,4-dichloroacetophenone.

[0106]

[0107] As shown in Figure 13 , 14 , the spectral data of matrine hydrazine thiazole derivative 5-15 at C13 position is analyzed:

[0108] White solid, R f : 0.60 (DCM:MeOH = 10:1), 129.7 mg (85.6% yield)

[0109] 1H NMR (400 MHz, CDC13) δ 7.71 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.02 (s, 1H), 4.52 - 4.22 (m, 2H), 4.12 (d, J = 11.7 Hz, 1H), 3.26 - 3.12 (m, 2H), 3.03 - 2.80 (m, 2H), 2.51 - 2.36 (m, 2H), 2.26 (s, 1H), 2.13 - 1.89 (m, 4H), 1.88 - 1.60 (m, 6H), 1.56 (d, J = 13.7 Hz, 1H), 1.51 - 1.37 (m, 4H).

[0110] 13 C NMR (151 MHz, CDC13) δ 174.0, 167.2, 146.2, 133.5, 132.5, 132.3, 131.8, 130.1, 127.1, 108.7, 63.9, 57.1 (2C), 51.4, 50.1, 42.5, 41.5, 36.0, 35.3, 29.3, 27.4, 26.2, 20.8, 19.4.

[0111] Example 9

[0112] The difference between this example and Example 2 is that the anti-tumor matrine hydrazine thiazole derivative 5-16 at C13 position is synthesized by reacting the thiourea matrine intermediate 3 with a-bromo-2,4-difluoroacetophenone.

[0113]

[0114] As shown in Figures 15-17 , the spectral data of matrine hydrazine thiazole derivative 5-16 at C13 position is analyzed:

[0115] White solid, R f : 0.60 (DCM:MeOH = 10:1), 110.6 mg (77.9% yield)

[0116] 1H NMR (400 MHz, CDC13) δ 7.96 (q, J = 8.1 Hz, 1H), 7.01 (s, 1H), 6.96 6.82 (m, 2H), 4.39 (dd, J = 12.7, 4.6 Hz, 1H), 4.28 (s, 1H), 4.14 - 4.02 (m, 1H), 3.38 (s, 1H), 3.14 (t, J = 12.8 Hz, 1H), 2.81 (t, J = 9.8 Hz, 2H), 2.60 - 2.40 (m, 2H), 2.11 (s, 1H), 2.07 - 1.93 (m, 3H), 1.82 (d, J = 13.5 Hz, 1H), 1.77 - 1.64 (m, 4H), 1.59 - 1.48 (m, 2H), 1.50 - 1.36 (m, 5H).

[0117] 13 C NMR (151 MHz, CDC13) δ 172.8, 166.9, 161.1, 161.0, 151.4, 144.1, 130.4, 119.7, 119.3, 111.4, 111.3, 107.9, 107.8, 104.4, 104.2, 104.1, 63.7, 57.2, 51.6, 50.2, 42.8, 41.7, 36.3, 35.5, 29.3, 27.7, 26.5, 21.1, 20.7.

[0118] 19 F NMR (377 MHz, CDC13) δ -110.1, -110.1, -111.2, -111.2.

[0119] Example 10

[0120] The difference between this example and Example 2 is that the anti-tumor matrine hydrazine thiazole derivative 5-17 at C13 position is synthesized by reacting the thiourea matrine intermediate 3 with a-bromo-4-trifluoromethoxy acetophenone.

[0121]

[0122] As shown in Figures 18-20 , the spectral data of matrine hydrazine thiazole derivative 5-17 at C13 position is analyzed:

[0123] White solid, R f : 0.60 (DCM:MeOH = 10:1), 135.6 mg (86.7% yield)

[0124] 1H NMR (600 MHz, CDC13) δ 7.78 (d, J = 8.4 Hz, 2H), 7.43 (s, 1H), 7.22 (d, J = 8.3 Hz, 2H), 6.79 (s, 1H), 4.38 (dd, J = 12.7, 4.3 Hz, 1H), 4.25 (d, J = 3.3 Hz, 1H), 4.13 - 3.99 (m, 1H), 3.34 (s, 1H), 3.14 (t, J = 12.6 Hz, 1H), 2.88 - 2.74 (m, 2H), 2.56 - 2.41 (m, 2H), 2.10 (s, 1H), 2.02 - 1.92 (m, 3H), 1.81 (d, J = 13.6 Hz, 1H), 1.77 - 1.63 (m, 4H), 1.58 - 1.49 (m, 2H), 1.48 - 1.34 (m, 4H).

[0125] 13 C NMR (151 MHz, CDC13) δ 174.4, 166.9, 150.0, 148.6, 133.9, 127.2 (2C), 121.0 (2C), 103.9, 63.7, 57.2 (2C), 51.6, 50.1, 42.8, 41.7, 36.1, 35.5, 29.3, 27.7, 26.5, 21.2, 20.7.

[0126] 19 F NMR (377 MHz, CDC13) δ -57.8.

[0127] Example 11

[0128] The difference between this example and Example 2 is that the anti-tumor matrine hydrazine thiazole derivative 5-18 at C13 position is synthesized by reacting the thiourea matrine intermediate 3 with a-bromo-4-methanesulfonyl acetophenone.

[0129]

[0130] As shown in Figure 21 , 22 , the anti-tumor matrine hydrazine thiazole derivative 5-18 spectrum data analysis:

[0131] White solid, R f : 0.60 (DCM:MeOH = 10:1), 108.2 mg (70% yield)

[0132] 1H NMR (600 MHz, CDCI3) δ 7.94-7.87 (m, 4H), 6.95 (s, 1H), 4.65-4.34 (m, 2H), 4.11 (s, 1H), 3.45-3.37 (m, 1H), 3.15 (t, J = 12.7 Hz, 1H), 3.07 (s, 3H), 2.89 (s, 2H), 2.56-2.43 (m, 2H), 2.30-2.15 (m, 1H), 2.11-2.00 (m, 3H), 1.86 (d, J = 13.8 Hz, 1H), 1.81-1.59 (m, 5H), 1.57-1.39 (m, 5H).

[0133] 13 C NMR (151 MHz, CDCI3) δ 175.0, 167.2, 149.3, 140.0, 138.8, 127.7 (2C), 126.5 (2C), 106.6, 63.8, 57.1 (2C), 51.5, 50.0, 44.6, 42.7, 41.5, 36.0, 35.3, 29.4, 27.5, 26.1, 21.5, 20.4.

[0134] Example 12

[0135] The present example provides an application of the anti-tumor matrine hydrazine thiazole derivative in the preparation of a tumor inhibitor. The tumor inhibitor is a lung cancer cell inhibitor, a cervical cancer cell inhibitor, and a colon cancer cell inhibitor.

[0136] The test of the in vitro anti-tumor activity of the anti-tumor matrine hydrazine thiazole derivative is as follows:

[0137] Cell lines: human lung cancer cells (A549), cervical cancer cells (Hela), human colon cancer cells (HCT-116)

[0138] Method: MTT method

[0139] The specific process is as follows:

[0140] (1) Cell culture and drug treatment. Take the tumor cells with strong growth vigor, trypsin digestion, centrifugation, add fresh culture medium, resuspend the cells and dilute the count, inoculate the cells into 96-well plates at a density of 5000 per hole, place in a 37℃, 5% CO2 incubator overnight, observe the cell morphology on the 2nd day, discard the old culture medium, add the sample to be tested to the experimental group, set 5 sample concentration gradients, dilute the sample to a final concentration of 200, 100, 50, 25, 12.5 μmol / L, set 5 replicate holes for each concentration, 250 μL per hole, add fresh culture medium to the negative control group and the blank group, place in the incubator and culture for 48 h, screen out the approximate concentration of 50% inhibition rate, according to this concentration, test 3-4 concentrations with a spacing of 10 ug / mL, and the method is as above.

[0141] (2) MTT detection: add 20 μL of pre-prepared MTT solution to each hole, place in the incubator and incubate for 4 h, aspirate the liquid in the hole after incubation, add 200 μL of dimethyl sulfoxide to each hole, shake thoroughly for 10 min, detect the absorbance value at 490 nm with an enzyme-labeled instrument, record the data, calculate the inhibition rate according to the formula, and obtain the IC 50 value by software Origin fitting.

[0142] (3) Calculation: cell inhibition rate = [(control-background)-(dose-background)] / (control-background)*100%

[0143] The determination results are shown in the table:

[0144] Table 1 in vitro anti-tumor activity IC 50 of hydrazine thiazole derivatives of matrine-C13 number

[0145]

[0146]

[0147] The in vitro anti-tumor activity results of the experimental group compounds, the parent matrine, are shown in Table 1 above, and the in vitro anti-tumor activity of compounds 5-2, 5-7, 5-8, 5-11 and 5-16 is significantly improved relative to the parent matrine, among which compound 5-8 has good inhibition effect on human lung cancer cells (A549) and human colon cancer cells (HCT-116) with IC 50 values of 21.9 ug / mL and 85.9 ug / mL respectively; the best compound 5-16 for cervical cancer cells (Hela) has an IC 50 value of 39.6 ug / mL, which shows that matrine derivatives have potential anti-tumor activity and can be developed as anti-tumor drugs.

[0148] The anti-tumor matrine derivative has excellent growth inhibition effect on tumor cells, and has great potential to be developed into an anti-tumor drug. The preparation process is simple and convenient, and the obtained product has good stability. The matrine derivative synthesized in the application has excellent activity and high medicinal value, and opens up a new way for designing new anti-tumor drugs based on natural products, and provides valuable reference and guidance.

[0149] The above only describes the preferred embodiments of the present application, and it should be pointed out that for ordinary skilled persons in the art, some improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. An antitumor matrine hydrazine thiazole derivative, characterized in that, The structural formula is: R is one of the following groups: 。 2. A method for preparing the antitumor matrine hydrazine-thiazole derivative as described in claim 1, characterized in that: The method comprises the following steps: Step S1, NaH is added into a reaction container one, then a DMF solution is added, and then aminothiourea is added into the reaction container one to stir the solution; Step S2, sophoridine is added into the solution of step S1 to perform a reflux reaction, after the reaction is completed, a quenching reaction is performed, then extraction, concentration, drying and column chromatography separation are performed to obtain aminothiourea sophoridine intermediate 3; Step S3, the aminothiourea sophoridine intermediate 3 obtained in step S2 is added into a reaction container two, and ethanol is added to dissolve; after the solution is dissolved, α-bromo R group ketone 4 is added to perform a reaction, after the reaction is completed, concentration, drying and column chromatography separation are performed to obtain the anti-tumor sophoridine hydrazine thiazole derivative. 。 3. The method of claim 2, wherein: In step S2, after the quenching reaction, the water phase is extracted with ethyl acetate, and the organic phases are combined and concentrated and dried.

4. The method of claim 3, wherein: In step S2, acetic acid is used to perform the quenching reaction.

5. The method of claim 4, wherein: In the reaction process, the reaction process is monitored by using a TLC plate.

6. The method of claim 5, wherein: The molar ratio of sophoridine and aminothiourea is 1:1-1.2 in mmol:mmol.

7. The method of claim 6, wherein: The molar ratio of aminothiourea sophoridine intermediate 3 and α-bromo R group ketone 4 is 1:1.1-1.3 in mmol:mmol.

8. The anti-tumor sophoridine hydrazine thiazole derivative of claim 1 is used to prepare a tumor inhibitor; the tumor inhibitor is a lung cancer cell inhibitor, a cervical cancer cell inhibitor and a colon cancer cell inhibitor.

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