Preparation method and application of coumarin-hydrazide semi-sandwich type iridium and ruthenium complex

Abstract

The invention discloses a preparation method and application of a coumarin-hydrazide-based semi-sandwich type iridium and ruthenium complex, the structural formula of the complex is as shown in formula (I), the complex takes a coumarin-hydrazide derivative as an NO bidentate ligand, and an oxygen coordination atom in the ligand is derived from hydroxyl of a coumarin mother nucleus; iridium or ruthenium is used as a metal center, benzene is used as a unique solvent, alkali does not need to be added additionally under the protection of nitrogen, and the ligand can be prepared through a coordination reaction of the ligand and a metal dimer. The complex shows good anti-cancer activity, the drug effect of the complex is close to that of cis-platinum, and the complex has the potential value of becoming a novel anti-cancer drug.

Description

Technical Field

[0001] This invention relates to metal complexes, specifically a method for preparing and applying a coumarin-hydrazide semi-sandwich type iridium and ruthenium complex, belonging to the field of chemical pharmaceuticals. Background Technology

[0002] Chemotherapy is a core treatment for malignant tumors. While it can exert a clear tumor-suppressing effect, its lack of specific mechanism of action and tendency to induce severe systemic toxicity significantly limit its clinical application value. Traditional platinum-based antitumor drugs (such as cisplatin and carboplatin) are widely used clinically due to their broad-spectrum antitumor activity, but they suffer from prominent drawbacks such as strong drug resistance, insufficient targeting, and significant toxicity to normal tissues and cells, becoming a core bottleneck restricting treatment efficacy and patients' quality of life. Against this backdrop, the development of novel metal complex anticancer drugs that combine high antitumor activity, low toxicity, and excellent targeting has become a current research focus in the field of medicinal chemistry.

[0003] Coumarin derivatives naturally possess diverse biological activities such as antitumor and anti-inflammatory effects, and their molecular structures can be easily modified through chemical modification to achieve precise regulation of physicochemical properties and biological functions, making them high-quality active ligands for constructing novel antitumor metal complexes. The organic fusion with metal centers provides an effective pathway to overcome the application limitations of traditional metal anticancer drugs. Currently, research on the antitumor effects of coumarin-based metal complexes has achieved phased results. In existing studies, some research groups have developed coumarin-modified fluorescent cycloiridium (III) complexes, and some products have shown better half-maximal inhibitory concentrations (IC50) against lung cancer A549 cells than the first-line clinical drug cisplatin, providing a visual research tool for in-depth analysis of their antitumor mechanisms (e.g., Formula A, CN111646966A); Meanwhile, N... ^ The O chelate coordination mode can form a stable coordination ring with the metal center, effectively ensuring the structural stability and targeting of the complex in the organism (e.g., Formula B, CN118978551 B).

[0004] However, coumarin-based metal complexes with a half-sandwich spatial configuration are extremely rare in existing reports (e.g., iridium ring configuration in Formula A). These complexes use iridium / ruthenium as the metal center, aromatic ring ligands (such as cyclopentane or benzene) as the facet, and monodentate / bidentate auxiliary ligands as the legs, exhibiting both structural stability and tunable properties. Even when a half-sandwich structure is involved, the ligand framework is mostly limited to aryl-based salicylaldimine systems (e.g., Formula C, Dalton Trans. 2020. 50, 11447-11458); based on this, a series of N... ^The O-chelated semi-sandwich iridium and ruthenium complex, with oxygen coordinating atoms in the ligands derived from the hydroxyl groups of the coumarin core, combines the functions of coumarin and hydrazide in a single coordination environment. Its synthetic route and reaction conditions are simple; furthermore, by controlling the types of substituents in the coumarin core and the electronic configuration of the metal center, the antitumor activity and targeting of the complex can be optimized, and its anticancer activity is close to that of cisplatin. This indicates that the coumarin-hydrazide-N... ^ O-chelated semi-sandwich-type complexes show promise as a potential new type of anticancer drug. Summary of the Invention

[0005] In this invention, the coumarin-hydrazide skeleton is in the form of N ^ The O-chelation mode is introduced into semi-sandwich-type metal complexes to form structurally stable organometallic compounds with well-defined configurations. By introducing a series of ligands with different substituents and different metal centers, it is hoped to obtain a series of novel semi-sandwich-type complexes with good antitumor effects. These novel semi-sandwich-type complexes exhibit excellent antitumor effects.

[0006] Contains N ^ The synthetic molecular structure of the O-bidentate coumarin-hydrazide complex is shown in formula (Ⅰ): ; In the formula, R1 is methyl, ethyl, phenyl, or benzyl; R2 is... or One of them; M is one of Ir and Ru.

[0007] The N-containing compounds described in this invention ^ A coumarin-hydrazide complex with bidentate coordination, wherein in formula (I), R1 is methyl and R2 is... M is Ir, and the specific structural formula is shown in Formula 1; in Formula (Ⅰ), R1 is ethyl, and R2 is... M is Ir, and the specific structural formula is shown in Formula 2; in Formula (I), R1 is phenyl, and R2 is... M is Ir, and the specific structural formula is shown in Formula 3; in Formula (I), R1 is benzyl, and R2 is M is Ir, and the specific structural formula is shown in Formula 4; in Formula (I), R1 is methyl, and R2 is... M is Ru, and the specific structural formula is shown in Formula 5; in Formula (I), R1 is ethyl, and R2 is... M is Ru, and the specific structural formula is shown in Formula 6; in Formula (I), R1 is phenyl, and R2 is... M is Ru, and the specific structural formula is shown in Formula 7; in Formula (I), R1 is benzyl, and R2 is... M is Ru, and the specific structural formula is shown in Equation 8; .

[0008] The present invention contains N ^ The preparation method of the O-didentate coumarin-hydrazide complex includes the following steps: Under nitrogen protection, the dimer shown in formula (III) and the coumarin-hydrazide-type ligand shown in formula (II) are reacted with benzene as the sole solvent, and the protons of the hydroxyl groups on the coumarin skeleton can be removed without the addition of additional alkali. The reaction can be completed at room temperature for 24 hours to obtain the N-didentate coumarin-hydrazide-type ligand shown in formula (I). ^ O-didentate coumarin-hydrazide complex; the specific synthetic route is as follows: .

[0009] When the complex is 1, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 26.0 mg of ligand (formula (II) R1 = methyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator. The remaining solid was dissolved in a small amount of dichloromethane and then an excess of the undesirable solvent n-hexane was added. A precipitate was formed. The precipitate was filtered through a sand core and washed with n-hexane. Then it was recrystallized and dried under vacuum to obtain yellow solid 1.

[0010] When the complex is 2, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. , M=Ir), 27.4 mg of ligand (formula (Ⅱ) R1=ethyl) and 30 mL of benzene, reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then an excess of the undesirable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sand core and washed with n-hexane, then recrystallized and dried under vacuum to obtain yellow solid 2.

[0011] When the complex is 3, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 32.2 mg of ligand (formula (II) R1 = phenyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator. The remaining solid was dissolved in a small amount of dichloromethane and then an excess of the undesirable solvent n-hexane was added. A precipitate was formed. The precipitate was filtered through a sand core and washed with n-hexane. Then it was recrystallized and dried under vacuum to obtain a yellow solid 3.

[0012] When the complex is 4, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 33.6 mg of ligand (formula (II) R1 = benzyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then an excess of the undesirable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sand core and washed with n-hexane, then recrystallized and dried under vacuum to obtain a yellow solid 4.

[0013] When the complex is 5, it is prepared by the following method: Under nitrogen protection, 25.0 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 26.0 mg of ligand (formula (II) R1 = methyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then an excess of the undesirable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sand core and washed with n-hexane, then recrystallized and dried under vacuum to obtain a yellowish-brown solid 5.

[0014] When the complex is 6, it is prepared by the following method: Under nitrogen protection, 25.0 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. , M=Ru), 27.4 mg of ligand (formula (II) R1=ethyl) and 30 mL of benzene, reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then an excess of the undesirable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sand core and washed with n-hexane, then recrystallized and dried under vacuum to obtain a yellowish-brown solid 6.

[0015] When the complex is 7, it is prepared by the following method: Under nitrogen protection, 25.0 mg of iridium dimer (formula (III) R2=, M=Ru), 32.2 mg of ligand (formula (II) R1=phenyl) and 30 mL of benzene were added to a 100 mL Schlenk flask and reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then excess unsuitable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sintered glass core and washed with n-hexane, then recrystallized and dried under vacuum to obtain a yellowish-brown solid 7.

[0016] When the complex is 8, it is prepared by the following method: Under nitrogen protection, 25.0 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 33.6 mg of ligand (formula (II) R1 = benzyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then an excess of the undesirable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sand core and washed with n-hexane, then recrystallized and dried under vacuum to obtain a yellowish-brown solid 8.

[0017] Beneficial effects (1) This invention provides an N ^ A method for preparing coumarin-hydrazide complexes with O-didentate coordination was developed, yielding a series of novel semi-sandwich-type complexes with good antitumor effects.

[0018] (2) The synthesis of the complex of the present invention is to react the ligand and the dimer with benzene as solvent under the reaction conditions to obtain a novel semi-sandwich type complex (Ⅰ) in which the coumarin skeleton participates in chelation.

[0019] (3) The N-containing material prepared by this invention ^ The O-didentate coumarin-hydrazide complex exhibits excellent antitumor effects, approaching or even exceeding the anticancer activity of commercial cisplatin, making it a very promising anticancer drug. Attached Figure Description

[0020] Figure 1 The 1H NMR spectrum of complex 1 of this invention; Figure 2 Mass spectrometry of complex 1 of the present invention; Figure 3 The single-crystal structure of complex 1 prepared in this invention (hydrogen atoms have been omitted in the figure for clarity). Figure 4 The 1H NMR spectrum of complex 2 of this invention; Figure 5 Mass spectrometry of complex 2 of the present invention; Figure 6 The 1H NMR spectrum of complex 3 of this invention; Figure 7 Mass spectrometry of complex 3 of the present invention; Figure 8 The 1H NMR spectrum of complex 4 of this invention; Figure 9 Mass spectrometry of complex 4 of the present invention; Figure 10 The single-crystal structure of complex 4 prepared in this invention (hydrogen atoms have been omitted in the figure for clarity). Figure 11 The 1H NMR spectrum of complex 5 of this invention; Figure 12 Mass spectrometry of complex 5 of the present invention; Figure 13 The 1H NMR spectrum of complex 6 of this invention; Figure 14 Mass spectrometry of complex 6 of the present invention; Figure 15 The 1H NMR spectrum of complex 7 of this invention; Figure 16 Mass spectrometry of complex 7 of the present invention; Figure 17 The 1H NMR spectrum of complex 8 of this invention; Figure 18 This is the mass spectrometry of coordination compound 8 of the present invention. Detailed Implementation

[0021] The present invention is further illustrated by the following examples of representative compounds, but these descriptions do not limit the invention.

[0022] The starting compounds used in the synthesis of these compounds are commercial products or can be prepared from known synthetic methods. Methods for preparing all organic compounds are readily available in the literature and are fundamental and obvious to synthetic chemists. Therefore, the following descriptions of synthetic methods can be considered detailed and specific.

[0023] Example 1 When the complex is 1, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 26.0 mg of ligand (formula (II) R1 = methyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then excess unsuitable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sintered glass core and washed with n-hexane, then recrystallized and dried under vacuum to obtain 49.2 mg of yellow solid 1, with a yield of 79.1%.

[0024] Nuclear magnetic resonance characterization 1 H NMR (400 MHz, DMSO- d6) δ 8.03 (d, J = 5.5 Hz, 1H, NH), 7.68 (dd, J = 14.2, 7.4 Hz, 1H, aryl-H), 7.33 (dt, J = 13.6, 6.4 Hz, 3H, aryl-H), 2.31 (s, 3H, C-CH3), 2.10 (s, O=C-CH3), 1.45 (s, 15H, Cp) -C H 3). Mass spectrometry: C 23 H 26 The theoretical value of IrN₂O₄ is 586.6710, and the actual measured value is 586.6717, [M-Cl] + . Elemental analysis: Theoretical value C 23 H 26 ClIrN2O4: C, 44.40; H, 4.21; N, 4.50, actually measured: C, 44.44; H, 4.26; N, 4.58. Example 2 When the complex is 2, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 27.4 mg of ligand (formula (II) R1 = ethyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then excess unsuitable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sintered glass core and washed with n-hexane, then recrystallized and dried under vacuum to obtain 51.6 mg of yellow solid 2, with a yield of 81.1%.

[0025] Nuclear magnetic resonance characterization 1 H NMR (400 MHz, DMSO- d 6) δ 8.01 (s, 1H, NH), 7.82 (s, 1H, aryl-H), 7.69-7.64 (m, 1H, aryl-H), 7.15 (d, J = 6.1 Hz, 2H, aryl-H), 3.07 (s, 2H, C) H 2-CH3), 2.78 (s, 3H, C-CH3), 2.11 (s, 3H, CH2-C H 3), 1.58 (s, 15H, Cp -C H 3). Mass spectrometry: C 24 H 28 The theoretical value for IrN₂O₄ is 600.6866, while the actual measured value is 600.6867. [M-Cl] + . Elemental analysis: Theoretical value C 24 H 28 ClIrN2O4: C, 45.31; H, 4.44; N, 4.40, actually measured: C, 45.38; H, 4.49; N, 4.34. Example 3 When the complex is 3, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 33.2 mg of ligand (Formula (II) R1 = phenyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then excess unsuitable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sand core and washed with n-hexane, then recrystallized and dried under vacuum to obtain 55.4 mg of yellow solid 3, with a yield of 81.0%.

[0026] Nuclear magnetic resonance characterization 1 H NMR (400 MHz, DMSO- d 6) δ 8.09 (s, 1H, NH), 7.83 (d, J = 5.0Hz, 2H, aryl-H), 7.46-7.34 (m, 5H, aryl-H), 7.17 (d, J = 6.0 Hz, 2H, aryl-H), 2.88 (s, 3H, C-CH3), 1.46 (s, 15H, Cp) -C H 3). Mass spectrometry: C 28 H 28 The theoretical value of IrN₂O₄ is 648.6867, and the actual measured value is 648.6869, [M-Cl] + . Elemental analysis: Theoretical value C 28 H 28 ClIrN2O4:C, 49.15;H, 4.13;N, 4.09, Actual measured:C, 49.19;H, 4.20;N, 4.15. Example 4 When the complex is 4, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 33.6 mg of ligand (formula (II) R1 = benzyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then excess unsuitable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sand core and washed with n-hexane, then recrystallized and dried under vacuum to obtain 52.9 mg of yellow solid 4, with a yield of 75.8%.

[0027] Nuclear magnetic resonance characterization 1 H NMR (400 MHz, DMSO- d 6) δ 9.80 (s, 1H, NH), 8.03 (d, J = 6.3Hz, 1H, aryl-H), 7.78 (d, J = 5.8 Hz, 1H, aryl-H), 7.69 – 7.64 (m, 1H, aryl-H), 7.36 (dddd, J = 17.5, 14.9, 9.8, 4.1 Hz, 4H, aryl-H), 7.13 (dd, J = 8.6, 6.3 Hz, 2H, aryl-H), 2.77 (s, 3H, C-CH3), 2.27 (m, J = 6.0, 3.5 Hz, aryl-C H 2), 1.74 (s, 15H, Cp) -C H 3). Mass spectrometry: C 29 H 30 The theoretical value of IrN₂O₄ is 662.7023, and the actual measured value is 662.7030. [M-Cl] + . Elemental analysis: Theoretical value C 29 H 30 ClIrN2O4: C, 49.89; H, 4.33; N, 4.01, actually measured: C, 49.93; H, 4.37; N, 4.06. Example 5 When the complex is 5, it is prepared by the following method: Under nitrogen protection, 25.0 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 26.0 mg of ligand (formula (II) R1 = methyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then excess unsuitable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sand core and washed with n-hexane, then recrystallized and dried under vacuum to obtain 42.3 mg of yellowish-brown solid 5, with a yield of 79.2%.

[0028] Nuclear magnetic resonance characterization 1 H NMR (400 MHz, DMSO- d 6) δ 7.39 (s, 1H, NH), 7.32 (d, J = 4.9 Hz, 1H, aryl-H), 7.27 (s, 1H, aryl-H), 7.20 (d, J = 4.9 Hz, 1H, aryl-H), 7.16 (d, J = 4.8 Hz, 1H, aryl-H), 5.82 (d, J = 4.9 Hz, 2H, arene- H ), 5.77(d, J = 4.8 Hz, 2H, arene - H ), 3.17 (s, 3H, C-CH3), 2.86-2.80 (m, 1H, C H (CH3)2), 2.09 (s, 3H, arene-C H 3), 1.24 (s, 3H, O=C-CH3), 1.19 (d, J = 5.5 Hz,6H, CH(C H 3)2). Mass spectrometry: C 23 H 25 The theoretical value of N₂O₄Ru is 495.1882, and the actual measured value is 495.1864, [M-Cl] + . Elemental analysis: Theoretical value C 23 H 25 ClN2O4Ru: C, 52.89; H, 5.18; N, 5.14, actual measured: C, 52.93; H, 5.12; N, 5.19. Example 6 When the complex is 6, it is prepared by the following method: Under nitrogen protection, 25.0 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 27.4 mg of ligand (Formula (II) R1 = ethyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then excess unsuitable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sand core and washed with n-hexane, then recrystallized and dried under vacuum to obtain 42.4 mg of yellowish-brown solid 6, with a yield of 77.8%.

[0029] Nuclear magnetic resonance characterization 1 H NMR (400 MHz, DMSO- d 6) δ 7.63 (s, 1H, NH), 7.39 (d, J = 4.8Hz, 1H, aryl-H), 7.19 (d, J = 4.7 Hz, 1H, aryl-H), 7.12-7.06 (m, 1H, aryl-H), 6.97 (d, J = 4.8 Hz, 1H, aryl-H), 5.74 (d, J = 4.8 Hz, 1H, arene - H ), 5.53 (d, J =4.7 Hz, 1H, arene - H ), 5.46-5.42 (m,1H, arene - H ), 5.32 (d, J = 4.8 Hz, 1H, arene - H ), 3.10 (d, J = 5.1 Hz, 3H, C-CH3), 2.76-2.72 (m, 2H, C H 2-CH3), 2.54 (s, 3H, CH2-C H 3), 2.25 (d, J = 5.1 Hz, 3H, arene-C H 3), 2.10 (dd, J = 15.1, 9.1 Hz, 1H,C H (CH3)2), 1.36 (dd, J = 25.5, 5.1 Hz, 6H, CH(C H 3)2). Mass spectrometry: C 24 H 27 The theoretical value of N₂O₄Ru is 509.2038, and the actual measured value is 509.2039, [M-Cl]+ . Elemental analysis: Theoretical value C 24 H 27 ClN2O4Ru: C, 53.71; H, 5.41; N, 5.01, actually measured: C, 53.76; H, 5.46; N, 5.07. Example 7 When the complex is 7, it is prepared by the following method: Under nitrogen protection, 25.0 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 32.2 mg of ligand (Formula (II) R1 = phenyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then excess unsuitable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sand core and washed with n-hexane, then recrystallized and dried under vacuum to obtain 43.8 mg of yellowish-brown solid 7, with a yield of 73.9%.

[0030] Nuclear magnetic resonance characterization 1 H NMR (400 MHz, DMSO- d 6) δ 7.95-7.93 (s, 1H, NH), 7.82 (s, 1H, aryl-H), 7.73 (s, 1H, aryl-H), 7.60 (dd, J = 6.3, 1.2 Hz, 3H, aryl-H), 7.53 (dd, J = 6.3, 1.2 Hz, 3H, aryl-H), 7.40 (s, 1H, aryl-H), 5.58 (d, J = 4.7 Hz, 1H, arene - H ), 5.49 (d, J = 4.7 Hz, 1H, arene - H ), 5.44 (d, J = 4.7 Hz, 1H, arene - H ), 5.36 (d, J = 4.7 Hz, 1H, arene - H ), 2.14 (s, 3H, C-CH3), 2.06 – 1.99(m, 1H,C H (CH3)2), 1.63 (s, 3H, arene-C H 3), 1.24 (s, 6H, CH(CH 3)2). Mass spectrometry: C 28 H 27 The theoretical value of N₂O₄Ru is 557.1014, and the actual measured value is 557.1018, [M-Cl] + . Elemental analysis: Theoretical value C 28 H 27 ClN2O3Ru: C, 57.38; H, 4.98; N, 4.61, Actual measured: C, 57.32; H, 4.92; N, 4.66. Example 8 When the complex is 8, it is prepared by the following method: Under nitrogen protection, 25.0 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 33.6 mg of ligand (formula (II) R1 = benzyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then excess unsuitable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sand core and washed with n-hexane, then recrystallized and dried under vacuum to obtain 45.1 mg of yellowish-brown solid 8, with a yield of 74.3%.

[0031] Nuclear magnetic resonance characterization 1 H NMR (500 MHz, DMSO- d 6) δ 7.40 (s, 1H, NH), 7.39-7.36 (m, 1H, aryl-H), 7.34-7.26 (m, 4H, aryl-H), 7.10 (dd, J = 14.0, 6.5 Hz, 4H, aryl-H), 5.82 (d, J = 5.0 Hz, 2H, arene - H ), 5.78 (d, J = 5.0 Hz, 2H, arene - H ), 2.94(s, 2H, aryl-C) H 2), 2.26 (s, 3H, C-CH3), 2.10 (s, 3H, arene-C H 3), 2.00 (m, J = 2.8 Hz, 1H, C H (CH3)2), 1.24 (s, 6H, CH(C H 3) 2) . Mass spectrometry: C29 H 29 The theoretical value of N₂O₄Ru is 571.2195, and the actual measured value is 571.2200. [M-Cl] + . Elemental analysis: Theoretical value C 29 H 29 ClN2O4Ru: C, 58.01; H, 5.19; N, 4.51, Actual measured: C, 58.06; H, 5.13; N, 4.56. Example 9 Experiment on the inhibitory activity of complexes 1-8 with anticancer activity on the proliferation of tumor cell lines: (1) Preparation of the test compound: Dissolve the solid ligand and complex in DMSO to prepare a stock solution of a certain concentration. Dilute the stock solution further with cell culture medium until the working concentration is reached, and culture for 24 h.

[0032] (2) Cell growth inhibition assay (MTT method): 1) Take 5000 human cervical cancer cells (HeLa) and human non-small cell lung cancer cells (A549) respectively, prepare cell suspensions, and seed them in 96-well culture plates; 2) Pre-culture cells in drug-free medium, incubate at 5% CO2 and 310 K for 24 hours, add the prepared test compound, and incubate for 24 hours; 3) Add 15 μL of 5 mg / mL MTT solution to each well and continue culturing for 4 hours to form purple crystalline formazan; 4) Terminate the culture, carefully aspirate the culture medium from the wells, add 100 μL of DMSO to each well to fully dissolve the formazan precipitate, mix with a shaker, and then measure the optical density of each well at a wavelength of 570 nm using a microplate reader. 5) Each experiment was repeated three times, IC 50 =mean ± SEM. The inhibition rates of complexes 1-8 and commercial cisplatin on the growth of cancer cells HeLa and A549 are shown in Table 1.

[0033] Table 1 Table 1 shows that all complexes exhibited good anticancer activity against A549 and HeLa cells, with activity approaching that of commercially available cisplatin. A comparison of the anticancer activities of complexes 1-8 revealed that the type of metal center significantly influenced their anticancer activity. Complexes 1-4 and 5-8 showed significant differences in activity, with the ruthenium-based complex exhibiting superior anticancer activity. Furthermore, structural modification of the ligand substituent R1 had a prominent regulatory effect on activity, with aryl-substituted complexes (3-4, 7-8) showing better anticancer activity than alkyl-substituted complexes (1-2, 5-6). These findings provide practical theoretical reference for the design and development of novel metal complex-based antitumor drugs.

[0034] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. Contains N ^ The coumarin-hydrazide complex with O-didentate coordination is characterized by... The structural formula is shown in equation (Ⅰ): ； In the formula, R1 is methyl, ethyl, phenyl, or benzyl; R2 is... or One of them; M is one of Ir and Ru.

2. The N-containing [material] according to claim 1 ^ The coumarin-hydrazide complex with O-didentate coordination is characterized by... In formula (Ⅰ), R1 is methyl, and R2 is... M is Ir, and the specific structural formula is shown in Formula 1; in Formula (Ⅰ), R1 is ethyl, and R2 is... M is Ir, and the specific structural formula is shown in Formula 2; in Formula (I), R1 is phenyl, and R2 is... M is Ir, and the specific structural formula is shown in Formula 3; in Formula (I), R1 is benzyl, and R2 is M is Ir, and the specific structural formula is shown in Formula 4; in Formula (I), R1 is methyl, and R2 is... M is Ru, and the specific structural formula is shown in Formula 5; in Formula (I), R1 is ethyl, and R2 is... M is Ru, and the specific structural formula is shown in Formula 6; in Formula (I), R1 is phenyl, and R2 is... M is Ru, and the specific structural formula is shown in Formula 7; in Formula (I), R1 is benzyl, and R2 is... M is Ru, and the specific structural formula is shown in Equation 8; 。 3. A nitrogen-containing compound as described in claim 1 or 2 ^ A method for preparing a coumarin-hydrazide complex with O-type bidentate coordination, characterized in that... Includes the following steps: Under nitrogen protection, the dimer shown in formula (III) and the coumarin-hydrazide-type ligand shown in formula (II) are reacted with benzene as the sole solvent. The protons of the hydroxyl groups on the coumarin backbone do not require additional alkali. The reaction can be completed in 24 hours at room temperature, yielding the N-containing ligand shown in formula (I). ^ The specific synthetic route for the O-bidentate coumarin-hydrazide complex is as follows: 。 4. The preparation method according to claim 3, characterized in that, When the complex is 1, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 26.0 mg of ligand (formula (II) R1 = methyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator. The remaining solid was dissolved in a small amount of dichloromethane and then an excess of the unsuitable solvent n-hexane was added. A precipitate was formed. The precipitate was filtered through a sand core and washed with n-hexane. Then it was recrystallized and dried under vacuum to obtain yellow solid 1. When the complex is 2, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 27.4 mg of ligand (formula (Ⅱ) R1 = ethyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator. The remaining solid was dissolved in a small amount of dichloromethane and then an excess of the undesirable solvent n-hexane was added. A precipitate was formed. The precipitate was filtered through a sand core and washed with n-hexane. Then it was recrystallized and dried under vacuum to obtain yellow solid 2. When the complex is 3, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 32.2 mg of ligand (formula (Ⅱ) R1 = phenyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator. The remaining solid was dissolved in a small amount of dichloromethane and then an excess of the undesirable solvent n-hexane was added. A precipitate was formed. The precipitate was filtered through a sand core and washed with n-hexane. Then it was recrystallized and dried under vacuum to obtain a yellow solid 3. When the complex is 4, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 33.6 mg of ligand (formula (II) R1 = benzyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator. The remaining solid was dissolved in a small amount of dichloromethane and then an excess of the undesirable solvent n-hexane was added. A precipitate was formed. The precipitate was filtered through a sand core and washed with n-hexane. Then it was recrystallized and dried under vacuum to obtain yellow solid 4. When the complex is 5, it is prepared by the following method: Under nitrogen protection, 25.0 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 26.0 mg of ligand (formula (II) R1 = methyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then an excess of the undesirable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sand core and washed with n-hexane, then recrystallized and dried under vacuum to obtain a yellowish-brown solid 5. When the complex is 6, it is prepared by the following method: Under nitrogen protection, 25.0 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 27.4 mg of ligand (Formula (II) R1 = ethyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator. The remaining solid was dissolved in a small amount of dichloromethane and then an excess of the undesirable solvent n-hexane was added. A precipitate was formed. The precipitate was filtered through a sand core and washed with n-hexane. Then it was recrystallized and dried under vacuum to obtain a yellowish-brown solid 6. When the complex is 7, it is prepared by the following method: Under nitrogen protection, 25.0 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 32.2 mg of ligand (formula (II) R1 = phenyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator. The remaining solid was dissolved in a small amount of dichloromethane and then an excess of the undesirable solvent n-hexane was added. A precipitate was formed. The precipitate was filtered through a sand core and washed with n-hexane. Then it was recrystallized and dried under vacuum to obtain a yellowish-brown solid 7. When the complex is 8, it is prepared by the following method: Under nitrogen protection, 25.0 mg of iridium dimer (formula (Ⅲ) R2=) was added to a 100 mL Schlenk flask. 33.6 mg of ligand (formula (II) R1 = benzyl) and 30 mL of benzene were reacted at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator, the remaining solid was dissolved in a small amount of dichloromethane, and then an excess of the undesirable solvent n-hexane was added, resulting in a precipitate. The precipitate was filtered through a sand core and washed with n-hexane, then recrystallized and dried under vacuum to obtain a yellowish-brown solid 8.

5. A nitrogen-containing compound according to any one of claims 1-2 ^ O-divalent coumarin-aziridine-iridium and ruthenium complexes or N-containing compounds prepared by the preparation method according to any one of claims 3-4 ^ Application of O-didentate coumarin-iridium hydrazide and ruthenium complexes in the preparation of anticancer drugs.

6. The application according to claim 5, characterized in that, The cancer is either lung cancer or cervical cancer.

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