A neutral half-sandwich [N,NH] complex with anticancer activity, its preparation method and application

Abstract

The present invention discloses a novel neutral half-sandwich type [N,NH] complex with anti-cancer activity, its preparation method and application. The structural formula of the complex is shown in formula (I). The ligand reacts with the dimer under reaction conditions, and then a base or a basic solvent B is further added to the reaction system to obtain the neutral half-sandwich type [N,NH] complex I. These complexes exhibit good anti-cancer activity, and their performance is close to or even better than that of commercially available cisplatin, making them very promising anti-cancer drugs.

Description

Technical Field:

[0001] The present invention relates to metal complexes, specifically a neutral half-sandwich type [N,NH] complex with anti-cancer activity, its preparation method and application, belonging to the field of chemical pharmaceuticals. Background Art:

[0002] In recent years, half-sandwich structure iridium, ruthenium and rhodium complexes have not only developed rapidly as catalysts in the field of organic synthesis, but also been used in the research of anti-cancer drugs and achieved various breakthroughs. A variety of complexes have been prepared as anti-cancer complexes, among which the most are cationic complexes and neutral complexes. For example, the Sadler group once reported a half-sandwich type cationic complex (a) with an [N,N] chelating ligand and a half-sandwich type neutral complex (b) with a [C,N] chelating ligand, both of which showed good anti-cancer activity (Inorg. Chem. 2011, 50, 5777–5783). In the cationic half-sandwich type iridium complex (a), the [N,N] chelating ligand is a neutral ligand, the inner sphere of the complex is a cationic metal center, and the outer sphere has an anion PF6 - counterbalancing. In the neutral half-sandwich type iridium complex (b), the [C,N] chelating ligand is an anionic (monovalent) ligand, the complex is neutral, and there is no counterion. Hu Xueyan et al. once reported a half-sandwich type cationic complex (c) with an [N.NH] chelating ligand, and this type of cationic complex has the characteristic of being easily oxidized (Inorg. Chem. 2022, 61, 10051-10065). However, there is no report on the research of the half-sandwich type neutral complex with an [N,NH] chelating ligand in terms of anti-cancer. Based on the half-sandwich type neutral complex with an [N,NH] chelating ligand, due to its unique coordination mode and chelating structure, it is expected to show certain application potential in terms of higher anti-cancer activity, lower toxicity and side effects, and novel anti-cancer mechanisms.

[0003] Summary of the Invention:

[0004] A series of [N,NH2] ligands containing different substituents are introduced in the hope of obtaining a series of novel neutral half-sandwich type [N,NH] complexes with good anti-tumor effects. Such novel neutral half-sandwich type [N,NH] complexes exhibit excellent anti-tumor effects.

[0005]

[0006] The molecular structural formula of the half-sandwich type neutral [N,NH] complex is:

[0007]

[0008] In the formula, R1 and R2 can be hydrogen, C1-C 15 alkyl, halogen or halogenated C1-C 15 alkyl; R3 is One of them, R4 is one of Cl, CH3O, CH3COO, triphenylphosphine; M is one of Ir, Rh, Ru. In the neutral half-sandwich type [N, NH] complex described in the present invention, in the formula (I), R1 is tert-butyl, R2 is hydrogen, and R3 is R4 is CH3COO, M is Ir, and the specific structural formula is as shown in Formula 1; in the formula (I), R1 is methyl, R2 is methyl, and R3 is R4 is CH3COO, M is Ir, and the specific structural formula is as shown in Formula 2; in the formula (I), R1 is tert-butyl, R2 is hydrogen, and R3 is R4 is CH3COO, M is Ru, and the specific structural formula is as shown in Formula 3; in the formula (I), R1 is methyl, R2 is methyl, and R3 is R4 is CH3COO, M is Ru, and the specific structural formula is as shown in Formula 4; in the formula (I), R1 is methyl, R2 is methyl, and R3 is R4 is Cl, M is Ru, and the specific structural formula is as shown in Formula 5;

[0009]

[0010] The preparation method of the neutral half-sandwich type [N, NH] complex described in the present invention includes the following steps: Under nitrogen protection, the dimer shown in formula (III), the [N, NH2] ligand shown in formula (II), and a base or basic solvent B are reacted at room temperature for 8 h in methanol as a solvent to obtain the half-sandwich type neutral complex shown in formula (I); this complex is an 18-electron complex. When B is sodium methoxide or sodium acetate, the purpose is to remove a proton H on the ligand NH2 to make the ligand become an anionic ligand and coordinate with the metal center as a monodentate ligand; when B is triethylamine or potassium tert-butoxide, the purpose is only to remove a proton H on the ligand NH2 to make the ligand become an anionic ligand; the specific synthesis route is:

[0011]

[0012] When the complex is 1, it is prepared by the following method:

[0013] Under nitrogen protection, 40.03 mg of iridium dimer (formula (III) R3 = 25.36 mg of ligand (in formula (II), R2 = H, R1 = tert-butyl), 33 mg of sodium acetate and 10 mL of anhydrous methanol were added to 40.03 mg of iridium dimer (in formula (III), R3 =

[0014] When the complex is 2, it is prepared by the following method:

[0015] Under nitrogen protection, 40.03 mg of iridium dimer (in formula (III), R3 = M = Ir), 23.95 mg of ligand (in formula (II), R1 = R2 = methyl), 33 mg of sodium acetate and 10 mL of anhydrous methanol were added to a 100 mL Schlenk flask and reacted at room temperature for 8 h. After the reaction, the solvent was evaporated to dryness by a rotary evaporator. The remaining solid was dissolved in dichloromethane and the sodium acetate was removed by filtration through a sintered glass filter. The filtrate was evaporated to a small volume by a rotary evaporator, an excess of poor solvent n-hexane was added, a precipitate appeared, the precipitate was filtered through a sintered glass filter and washed with n-hexane, and then dried in vacuo to obtain red solid 2.

[0016] When the complex is 3, it is prepared by the following method:

[0017] Under nitrogen protection, 29.26 mg of ruthenium dimer (in formula (III), R3 = M = Ru), 24.12 mg of ligand (in formula (II), R2 = H, R1 = tert-butyl), 33 mg of sodium acetate and 10 mL of anhydrous methanol were added to a 100 mL Schlenk flask and reacted at room temperature for 8 h. After the reaction, the solvent was evaporated to dryness by a rotary evaporator. The remaining solid was dissolved in dichloromethane and the sodium acetate was removed by filtration through a sintered glass filter. The filtrate was evaporated to a small volume by a rotary evaporator, an excess of poor solvent n-hexane was added, a precipitate appeared, the precipitate was filtered through a sintered glass filter and washed with n-hexane, and then dried in vacuo to obtain reddish-brown solid 3.

[0018] When the complex is 4, it is prepared by the following method:

[0019] Under nitrogen protection, 29.26 mg of ruthenium dimer (in formula (III), R3 = M = Ru), 22.78 mg of ligand (in formula (II), R1 = R2 = methyl), 33 mg of sodium acetate and 10 mL of anhydrous methanol were added to a 100 mL Schlenk flask and reacted at room temperature for 8 h. After the reaction, the solvent was evaporated to dryness by a rotary evaporator. The remaining solid was dissolved in dichloromethane and the sodium acetate was removed by filtration through a sintered glass filter. The filtrate was evaporated to a small volume by a rotary evaporator, an excess of poor solvent n-hexane was added, a precipitate appeared, the precipitate was filtered through a sintered glass filter and washed with n-hexane, and then dried in vacuo to obtain reddish-brown solid 4.

[0020] When the complex is 5, it is prepared by the following method:

[0021] Under nitrogen protection, add 29.26 mg of ruthenium dimer (in formula (Ⅲ), R3 = M = Ru), 22.78 mg of ligand (in formula (Ⅱ), R1 = R2 = methyl), 2 mL of triethylamine and 10 mL of anhydrous methanol into a 100 mL Schlenk flask, react at room temperature for 8 h. After the reaction, rotary evaporate the solvent to dryness, dissolve the remaining solid in dichloromethane, rotary evaporate the filtrate to a small volume, add an excessive amount of poor solvent n-hexane, precipitate appears, filter the precipitate with a sintered filter and wash it with n-hexane, and dry it under vacuum to obtain a reddish-brown solid 5.

[0022] Beneficial effects:

[0023] (1) The present invention provides a preparation method of a neutral half-sandwich type [N,NH] complex, aiming to obtain a series of novel neutral half-sandwich type complexes with good anti-tumor effects.

[0024] (2) The synthesis of this complex is that the ligand, dimer and base or basic solvent B react under reaction conditions to obtain a novel neutral half-sandwich type complex Ⅰ.

[0025] (3) Such neutral half-sandwich type [N,NH] complexes 1-5 show excellent anti-tumor effects, and some of their performances are even better than those of commercial cisplatin, and they are very potential anti-cancer drugs.

[0026] Contents of the attached drawings:

[0027] Figure 1 1H NMR spectrum of complex 1 of the present invention.

[0028] Figure 2 Mass spectrum of complex 1 of the present invention.

[0029] Figure 3 1H NMR spectrum of complex 2 of the present invention.

[0030] Figure 4 Mass spectrum of complex 2 of the present invention.

[0031] Figure 5 1H NMR spectrum of complex 3 of the present invention

[0032] Figure 6 Mass spectrum of complex 3 of the present invention.

[0033] Figure 7 1H NMR spectrum of complex 4 of the present invention.

[0034] Figure 8 Mass spectrum of complex 4 of the present invention.

[0035] Figure 9 1H NMR spectrum of complex 5 of the present invention.

[0036] Figure 10 Mass spectrum of complex 5 of the present invention. Detailed implementation methods:

[0037] The present invention is further illustrated by the following examples of some representative compounds, but these descriptions do not limit the present invention.

[0038] The starting compounds used in the synthesis of the compounds are commercial products or can be prepared from known synthetic methods. The preparation methods of all organic compounds are available in the literature and are basic and obvious to synthetic chemists. Therefore, the following descriptions of the synthesis methods can be considered detailed and specific.

[0039] Example 1

[0040] When the complex is 1, it is prepared by the following method:

[0041] Under nitrogen protection, 40.03 mg of iridium dimer (in formula (Ⅲ), R3 = M = Ir), 25.36 mg of ligand (in formula (Ⅱ), R2 = hydrogen, R1 = tert-butyl), 33 mg of sodium acetate and 10 mL of anhydrous methanol were added to a 100 mL Schlenk flask and reacted at room temperature for 8 h. After the reaction, the solvent was evaporated to dryness by a rotary evaporator. The remaining solid was dissolved in dichloromethane and the sodium acetate was removed by filtration through a sintered glass filter. The filtrate was evaporated to a small volume by a rotary evaporator, and an excess of poor solvent n-hexane was added. A precipitate appeared. The precipitate was filtered through a sintered glass filter and washed with n-hexane, and then dried in vacuo to obtain a red solid 1.

[0042] Characterized by NMR as 1 H NMR (500 MHz, CDCl3) δ 8.89 (s, 1H, CH=N), 8.71 (d, J = 8.6 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 8.2 Hz, 2H), 2.07 (s, 3H, CH3COO), 1.74 (s, 15H, Cp*-CH3), 1.42 (s, 9H, C(CH3)3).

[0043] Mass spectrum: C 29 H 37 IrN2O2 theoretical value 579.23512, actually measured 579.23368, [M-CH3COO] + . Elemental analysis. Theoretical value: C29 H 37 IrN2O2: C, 54.61; H, 5.85; N, 4.39. Actually measured: C, 54.98; H, 5.62; N, 4.17.

[0044] Example 2

[0045] When the complex is 2, it is prepared by the following method:

[0046] Under nitrogen protection, 40.03 mg of iridium dimer (Formula (III), R3 = M = Ir), 23.95 mg of ligand (Formula (II), R1 = R2 = methyl), 33 mg of sodium acetate and 10 mL of anhydrous methanol were added to a 100 mL Schlenk flask and reacted at room temperature for 8 h. After the reaction, the solvent was evaporated to dryness by a rotary evaporator. The remaining solid was dissolved in dichloromethane and the sodium acetate was removed by filtration through a sintered glass filter; the filtrate was evaporated to a small volume by a rotary evaporator, an excess of poor solvent n - hexane was added, a precipitate appeared, the precipitate was filtered through a sintered glass filter and washed with n - hexane, and then dried in vacuo to obtain a red solid 2.

[0047] Characterized by NMR as 1 H NMR (500 MHz, CDCl3) δ 8.84 (s, 1H, CH=N), 8.62 (s, 1H), 7.70 (s, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.30 (s, 1H), 7.09 (s, 2H), 2.45 (s, 3H, CH3), 2.12 (s, 3H, CH3COO), 1.98 (s, 6H, CH3), 1.72 (s, 15H, Cp*-CH3).

[0048] Mass spectrometry: C 28 H 35 The theoretical value of IrN2O2 is 565.21947, and the actually measured value is 565.21745, [M - CH3COO] + . Elemental analysis. Theoretical value: C 28 H 35 IrN2O2: C, 53.91; H, 5.66; N, 4.49. Actually measured: C, 54.18; H, 5.41; N, 4.37.

[0049] Example 3

[0050] When the complex is 3, it is prepared by the following method:

[0051] Under nitrogen protection, 29.26 mg of ruthenium dimer (Formula (III), R3 = M = Ru), 24.12 mg of ligand (in formula (II), R2 = hydrogen, R1 = tert-butyl), 33 mg of sodium acetate, and 10 mL of anhydrous methanol were reacted at room temperature for 8 h. After the reaction, the solvent was evaporated to dryness using a rotary evaporator. The remaining solid was dissolved in dichloromethane, and sodium acetate was removed by filtration through a sintered glass filter. The filtrate was evaporated to a small volume using a rotary evaporator, an excess of poor solvent n-hexane was added, a precipitate appeared, the precipitate was filtered through a sintered glass filter and washed with n-hexane, and then dried under vacuum to obtain a reddish-brown solid 3.

[0052] Characterized by NMR as 1 1H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H, CH=N), 7.99 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.2 Hz, 3H), 7.25 (s, 1H), 6.99 (t, J = 7.2 Hz, 1H), 5.66 (d, J = 5.1 Hz, 2H, arene-H), 5.50 (d, J = 4.9 Hz, 2H, arene-H), 2.44 (m, 1H, CH(CH3)2), 2.08 (s, 3H, CH3COO), 2.05 (s, 3H, arene-CH3), 1.45 (s, 9H, C(CH3)3), 1.09 (d, J = 6.9 Hz, 6H, CH(CH3)2).

[0053] Mass spectrometry: C 29 H 36 The theoretical value of RuN2O2 is 487.16872, and the actually measured value is 487.16767, [M-CH3COO] + . Elemental analysis. Theoretical values: C 29 H 36 RuN2O2: C, 63.83; H, 6.65; N, 5.13. The actually measured values: C, 64.17; H, 6.44; N, 5.02

[0054] Example 4

[0055] Under nitrogen protection, 29.26 mg of ruthenium dimer (in formula (III), R3 = M = Ru), 22.78 mg of ligand (in formula (II), R1 = R2 = methyl), 33 mg of sodium acetate, and 10 mL of anhydrous methanol were reacted at room temperature for 8 h. After the reaction, the solvent was evaporated to dryness using a rotary evaporator. The remaining solid was dissolved in dichloromethane, and sodium acetate was removed by filtration through a sintered glass filter. The filtrate was evaporated to a small volume using a rotary evaporator, an excess of poor solvent n-hexane was added, a precipitate appeared, the precipitate was filtered through a sintered glass filter and washed with n-hexane, and then dried under vacuum to obtain a reddish-brown solid 4.

[0056] Characterized by NMR as 11H NMR (500 MHz, CDCl3) δ 8.47 (s, 1H, CH=N), 8.44 (d, J = 8.6 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 7.1 Hz, 1H), 7.30 (s, 1H), 6.76 (s, 1H), 5.84 (d, J = 5.2 Hz, 2H, arene-H), 5.67 (d, J = 5.1 Hz, 2H, arene-H), 2.49 (s, 3H, Aryl-CH3), 2.16 (s, 3H, CH3COO), 2.03 (s, 6H, Aryl-CH3), 2.01 (s, 3H, arene-CH3), 1.15 (d, J = 6.8 Hz, 6H, CH(CH3)2).

[0057] Mass spectrometry: C 28 H 34 The theoretical value of RuN2O2 is 473.15307, and the actually measured value is 473.15179, [M-CH3COO] + . Elemental analysis. Theoretical values: C 28 H 34 RuN2O2: C, 63.26; H, 6.45; N, 5.27. The actually measured values: C, 63.59; H, 6.17; N, 5.10

[0058] Example 5

[0059] Under nitrogen protection, 29.26 mg of ruthenium dimer (in formula (Ⅲ), R3 = M = Ru), 22.78 mg of ligand (in formula (Ⅱ), R1 = R2 = methyl), 2 mL of triethylamine and 10 mL of anhydrous methanol were added to a 100 mL Schlenk flask, and the reaction was carried out at room temperature for 8 h. After the reaction, the solvent was evaporated to dryness by a rotary evaporator. The remaining solid was dissolved in dichloromethane, and the filtrate was evaporated to a small volume by a rotary evaporator. An excess of poor solvent n-hexane was added, and precipitation occurred. The precipitate was filtered through a sintered filter and washed with n-hexane, and then dried in vacuo to obtain 5 of a reddish-brown solid.

[0060] The NMR characterization is 11H NMR (500 MHz, CDCl3) δ 8.70 (d, J = 8.6 Hz, 1H, CH=N), 8.46 (s, 1H), 7.61 (t, J = 6.9 Hz, 1H), 7.40 (m, 2H), 7.14 (s, 2H), 5.93 (s, 2H, arene-H), 5.70 (s, 2H, arene-H), 2.48 (s, 3H, Aryl-CH3), 2.41 (dt, 1H, CH(CH3)2), 2.02 (s, 6H, Aryl-CH3), 2.00 (s, 3H, arene-CH3), 1.15 (d, J = 6.8 Hz, 6H, CH(CH3)2).

[0061] Mass spectrometry: C 26 H 31 Theoretical value of RuN2Cl is 473.15307, and the actually measured value is 473.15195, [M-Cl] + .

[0062] Elemental analysis. Theoretical values: C 26 H 31 RuN2Cl: C, 61.47; H, 6.15; N, 5.51. Actually measured: C, 61.68; H, 6.08; N, 5.36

[0063] Example 6

[0064] Proliferation inhibition activity experiment of complexes 1-5 with anti-cancer activity against tumor cell lines:

[0065] (1) Preparation of the compound to be tested: Dissolve the solid complex in DMSO to prepare a stock solution with a certain concentration, and further dilute the stock solution with cell culture medium until the working concentration is reached, and culture for 24 h;

[0066] (2) Cell growth inhibition experiment (MTT method):

[0067] 1) Take 5000 human cervical cancer cells (HeLa), human non-small cell lung cancer cells (A549), human liver cancer cells (HepG2) and human lung adenocarcinoma cisplatin-resistant cells (A549 / DDP) respectively, prepare cell suspensions, and inoculate them into 96-well culture plates;

[0068] 2) Pre-culture the cells with drug-free culture medium, incubate at 5% CO2 and 310 K for 24 hours, add the prepared compound to be tested, and culture for 24 h;

[0069] 3) Add 15 μL of 5 mg / mL MTT solution to each well and continue to culture for 4 hours to form purple crystalline formazan;

[0070] 4) Terminate the culture, carefully aspirate the culture medium in the wells, add 100 μL of DMSO to each well to fully dissolve the formazan precipitate, mix well with an oscillator, and then measure the optical density value of each well with an ELISA reader at a wavelength of 570 nm;

[0071] 5) Each experiment was repeated three times, and IC 50 = mean ± SEM. The inhibition rates of complexes 1-5 and commercially available cisplatin on the growth of cancer cells HeLa, A549, and HepG2 are shown in Table 1.

[0072] Table 1

[0073]

[0074] It can be seen from Example 5 that complexes 1-5 all exhibited very good anticancer activities, approaching or superior to the activity of commercially available cisplatin. The anticancer activity of complex 1 is different from that of complex 3, demonstrating that the metal has an impact on the anticancer activity. The anticancer activity of complex 2 is also superior to that of complex 1, proving that with the change of substituents, the anticancer activity also changes accordingly. In addition, human lung adenocarcinoma cisplatin-resistant cells were detected, and the complexes all showed good activities and no cross-resistance with cisplatin. The above conclusions provide a theoretical basis for the preparation of new antitumor drugs.

[0075] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these changes and modifications.

Claims

1. Neutral semi-sandwich [N,NH] complex, characterized in that, The structural formula is as shown in formula (Ⅰ): ； In the formula (I), R1 is tert-butyl, R2 is hydrogen, and R3 is , R4 is CH3COO, M is Ir, and the specific structural formula is as shown in Formula 1; in the formula (I), R1 is methyl, R2 is methyl, and R3 is , R4 is CH3COO, M is Ir, and the specific structural formula is as shown in Formula 2; in the formula (I), R1 is tert-butyl, R2 is hydrogen, and R3 is , R4 is CH3COO, M is Ru, and the specific structural formula is as shown in Formula 3; in the formula (I), R1 is methyl, R2 is methyl, and R3 is , R4 is CH3COO, M is Ru, and the specific structural formula is as shown in Formula 4; in the formula (I), R1 is methyl, R2 is methyl, and R3 is , R4 is Cl, M is Ru, and the specific structural formula is as shown in Formula 5; 。 2. A method for preparing the neutral semi-sandwich type [N,NH] complex according to claim 1, characterized in that, It includes the following steps: Under nitrogen protection, the dimer shown in formula (Ⅲ), the [N,NH2] ligand shown in formula (Ⅱ), a base or basic solvent B are reacted at room temperature for 8 h in methanol as the solvent to obtain the half-sandwich type neutral complex shown in formula (Ⅰ); this complex is an 18-electron complex. When B is sodium methoxide or sodium acetate, one proton H on the ligand NH2 is removed to make the ligand become an anionic ligand and coordinate with the metal center as a monodentate ligand; when B is triethylamine or potassium tert-butoxide, one proton H on the ligand NH2 is removed to make the ligand become an anionic ligand; the specific synthesis route is: 。 Ⅱ Ⅲ Ⅰ 3. The preparation method according to claim 2, wherein When the complex is 1, it is prepared by the following method: Under nitrogen protection, 40.03 mg of the iridium dimer of formula (III), 25.36 mg of the ligand of formula (II), 33 mg of sodium acetate and 10 mL of anhydrous methanol were added to a 100 mL Schlenk flask. In formula (III), R3 = , M = Ir. In formula (II), R2 = hydrogen, R1 = tert-butyl. The reaction was carried out at room temperature for 8 h. After the reaction was completed, the solvent was evaporated to dryness by a rotary evaporator. The remaining solid was dissolved in dichloromethane, and sodium acetate was removed by filtration through a sintered glass filter. The filtrate was evaporated to a small volume by a rotary evaporator, an excess of the poor solvent n-hexane was added, a precipitate appeared, the precipitate was filtered through a sintered glass filter and washed with n-hexane, and then dried under vacuum to obtain a red solid 1; When the complex is 2, it is prepared by the following method: Under nitrogen protection, 40.03 mg of the iridium dimer of formula (III), 23.95 mg of the ligand of formula (II), 33 mg of sodium acetate and 10 mL of anhydrous methanol were added to a 100 mL Schlenk flask, where R3 = in formula (III) , M = Ir, R1 = R2 = methyl in the ligand of formula (II). The reaction was carried out at room temperature for 8 h. After the reaction was completed, the solvent was evaporated to dryness by a rotary evaporator. The remaining solid was dissolved in dichloromethane, and sodium acetate was removed by filtration through a sintered glass filter. The filtrate was evaporated to a small volume by a rotary evaporator, an excess of the poor solvent n-hexane was added, a precipitate appeared, and the precipitate was filtered through a sintered glass filter and washed with n-hexane, and then dried under vacuum to obtain a red solid 2; When the complex is 3, it is prepared by the following method: Under nitrogen protection, 29.26 mg of ruthenium dimer of formula (III), 24.12 mg of ligand of formula (II), 33 mg of sodium acetate and 10 mL of anhydrous methanol were added to a 100 mL Schlenk flask. In formula (III), R3 = , M = Ru. In the ligand of formula (II), R2 = hydrogen and R1 = tert-butyl. The reaction was carried out at room temperature for 8 h. After the reaction, the solvent was evaporated to dryness by a rotary evaporator. The remaining solid was dissolved in dichloromethane and the sodium acetate was removed by filtration through a sintered glass filter. The filtrate was evaporated to a small volume by a rotary evaporator, an excess of poor solvent n-hexane was added, a precipitate appeared, the precipitate was filtered through a sintered glass filter and washed with n-hexane, and then dried in vacuo to obtain 3 as a reddish-brown solid; When the complex is 4, it is prepared by the following method: Under nitrogen protection, 29.26 mg of ruthenium dimer of formula (III), 22.78 mg of ligand of formula (II), 33 mg of sodium acetate and 10 mL of anhydrous methanol were added to a 100 mL Schlenk flask. In formula (III), R3 = , M = Ru. In the ligand of formula (II), R1 = R2 = methyl. The reaction was carried out at room temperature for 8 h. After the reaction was completed, the solvent was evaporated to dryness by a rotary evaporator. The remaining solid was dissolved in dichloromethane, and sodium acetate was removed by filtration through a sintered glass filter; the filtrate was evaporated to a small volume by a rotary evaporator, an excess of poor solvent n-hexane was added, precipitation occurred, the precipitate was filtered through a sintered glass filter and washed with n-hexane, and then dried under vacuum to obtain 4 of a reddish-brown solid; When the complex is 5, it is prepared by the following method: Under nitrogen protection, 29.26 mg of the ruthenium dimer of formula (III), 22.78 mg of the ligand of formula (II), 2 mL of triethylamine and 10 mL of anhydrous methanol were added to a 100 mL Schlenk flask, where R3 = in formula (III) , M = Ru, R1 = R2 = methyl in the ligand of formula (II). The reaction was carried out at room temperature for 8 h. After the reaction, the solvent was evaporated to dryness by a rotary evaporator. The remaining solid was dissolved in dichloromethane. The filtrate was evaporated to a small volume by a rotary evaporator, and an excess of poor solvent n-hexane was added. A precipitate appeared. The precipitate was filtered through a sintered funnel and washed with n-hexane, and then dried in vacuo to obtain 5.0 mg of a reddish-brown solid 4. Use of the neutral half-sandwich type [N,NH] complex according to claim 1 in the preparation of anticancer drugs, wherein the cancers are liver cancer, lung cancer or cervical cancer.

Images