TW201602117A - Palladium pincer complex of normal and abnormal carbene, preparation method for the same and uses thereof - Google Patents

Abstract

Palladium pincer complexes of both normal and abnormal carbene and preparation methods thereof are disclosed. Furthermore, uses of palladium pincer complexes of normal and abnormal carbene and pharmaceutical applications thereof are disclosed. Palladium pincer complex of normal and abnormal carbene are useful catalysts for C-C coupling reaction and therapeutic drugs for inhibiting tumor cell proliferation.

Description

Typical and atypical nitrogen isocyclic carbene palladium metal chelate compound, preparation method and application thereof

The present invention relates to a chelating nitrogen-isocyclic carbene transition metal-substituted compound, a preparation method thereof and use thereof, and particularly a typical and atypical nitrogen-isocyclic carbene palladium metal chelate compound, and a preparation method thereof And its applications.

Cancer has become one of the main threats to human health, and the incidence is increasing. Currently, cancer has become the leading cause of death. Therefore, research on anticancer drugs is one of the most important strategic issues for the development of new drugs. The anti-cancer drugs with high efficiency, low toxicity and high selectivity have become the long-term goals and tasks of drug researchers.

Today cisplatin (cis -platin) has become one of the world's most widely used of three drugs to treat cancer. Although the use of cisplatin is successful, there are also many disadvantages, including serious side effects such as kidney, nerves, and nausea and vomiting, as well as limited range of anticancer activity and drug resistance. Some cancers are naturally resistant to cisplatin, making cisplatin ineffective against most cancers, and some cancers are resistant to cisplatin after the first use of cisplatin. These shortcomings limit the wider use of cisplatin.

Among the noble metal elements, only palladium and platinum wrong compounds have similar or identical structural characteristics. Both palladium and platinum metal ions are bonded to the ligand by dsp ² mixed orbital mode, and all form a planar quadrilateral structure complex. Since the palladium ion is a relatively weak Lewis acid, the complex base of the weak base chelating ligand is selected to form a complex of N, P, and S. In some crystal molecular structures, palladium and platinum wrong compounds have exactly the same molecular spatial configuration, and the bond lengths of the coordination bonds are also very similar. Due to the structural identity of palladium and platinum-missing compounds, they exhibit similar or similar chemical properties. Therefore, after platinum anti-tumor complexes, palladium-discriminated compounds have potency as potential anti-cancer drugs.

It is an object of the present invention to provide a typical and atypical nitrogen isocyclic carbene palladium metal chelate compound which combines a nitrogen isocyclic carbene, a multi-bud ligand and a pyrimidine, and has both efficacy and low toxicity. Palladium metal wrong compound.

Another object of the present invention is to provide a method for preparing a typical and atypical nitrogen-isocyclic carbene metal chelating compound, which solves the solubility of the metal-misc compound in the prior art in a mild, simple and rapid manner. Low, complex structure and method, but the complex preparation of the ligand precursor and the high price of the starting materials are not in line with economic benefits.

A further object of the present invention is to provide a typical and atypical nitrogen Use of a heterocyclic carbene palladium metal chelate compound which is a catalyst for a carbon-carbon coupling reaction. Typical and atypical nitrogen-isocyclic carbene palladium metal chelate compounds, which are neutral, air-stable and strongly capable of providing electrons, and have low toxicity to nitrogen isocyclic carbene ligands. In many catalytic reactions, it exhibits better heat, air and moisture stability than metal phosphorus groups. Therefore, it is more effective than conventional phosphorus bases in palladium-catalyzed carbon-carbon coupling reactions requiring high temperature and oxygen-free conditions. .

Still another object of the present invention is to provide a typical and atypical nitrogen isocyclic carbene palladium metal chelate compound for use in the preparation of a medicament for inhibiting tumor cell proliferation in mammals. Typical and atypical nitrogen-isocyclic carbene palladium metal chelate compounds, which have a functional role in the overall structure containing nitrogen isocyclic carbene, hydrazine and pyridine, which are extremely helpful in anticancer action. Further, the palladium metal compound has good antitumor activity and low toxicity, and can solve the problem that the antitumor drug of the platinum metal compound has serious side effects.

According to one embodiment of the first aspect of the present invention, there is provided a typical nitrogen isocyclic carbene palladium metal chelate compound having a structural formula of the formula (I), wherein R is hydrogen in the formula (I). Methoxy or fluorine:

According to another embodiment of the first aspect of the present invention, there is provided an atypical nitrogen heterocyclic carbene palladium metal chelate compound having a structural formula represented by formula (II), wherein R ¹ in formula (II) Is hydrogen or methyl; R ² is hydrogen, methoxy or fluorine:

According to one embodiment of the second aspect of the present invention, there is provided a process for the preparation of a typical nitrogen isocyclic carbene palladium metal chelate compound comprising the following steps. First, a ligand precursor having a structure of the formula (III), a palladium-containing reagent and a basic catalyst are dissolved in a first organic solvent to carry out a reaction to form an intermediate reaction solution. A drying step is provided to remove the first organic solvent of the intermediate reaction solution to obtain an intermediate solid. Further, an extraction step is provided in which the intermediate solid is subjected to extraction to obtain a compound of the structure represented by the formula (I). Among them, the formula (III) is as follows: In the formula (III), R is hydrogen, methoxy or fluorine.

According to another embodiment of the second aspect of the present invention, there is provided a process for the preparation of an atypical nitrogen isocyclic carbene palladium metal chelate compound comprising the following steps. First, a ligand precursor of the formula (IV), a palladium-containing reagent and a basic catalyst are dissolved in a first organic solvent to form an intermediate reaction solution. A drying step is provided to remove the first organic solvent of the intermediate reaction solution to obtain an intermediate solid. Further, an extraction step is provided for extracting the intermediate solid to obtain a compound of the structure represented by the formula (II). Wherein, formula (IV) is as follows: In the formula (IV), R ¹ is hydrogen or methyl; and R ² is hydrogen, methoxy or fluorine.

According to one embodiment of the third aspect of the present invention, there is provided a use of a typical nitrogen isocyclic carbene palladium metal chelate compound which is a catalyst for a carbon-carbon coupling reaction.

Another embodiment in accordance with a third aspect of the present invention is the use of an atypical nitrogen isocyclic carbene metal chelating compound for use in a carbon-carbon coupling reaction.

According to one embodiment of the fourth aspect of the present invention, there is provided a use of a typical nitrogen isocyclic carbene palladium metal chelate compound for the preparation of a medicament for inhibiting tumor cell proliferation in mammals.

According to another embodiment of the fourth aspect of the present invention, there is provided a method for providing an atypical nitrogen isocyclic carbene palladium metal chelate compound. For the preparation of a drug for inhibiting the proliferation of tumor cells in mammals.

According to one embodiment of the fifth aspect of the present invention, there is provided a pharmaceutical composition for inhibiting tumor cell proliferation in a mammal, comprising an effective amount of a compound having the structure represented by the following formula (I) and a pharmaceutically acceptable Acceptable carrier: In the formula (I), R is hydrogen, methoxy or fluorine.

According to another embodiment of the fifth aspect of the present invention, there is provided a pharmaceutical composition for inhibiting tumor cell proliferation in a mammal, comprising an effective amount of a compound having the structure represented by the following formula (II) and Pharmaceutically acceptable carrier: In the formula (II), R ¹ is hydrogen or methyl; and R ² is hydrogen, methoxy or fluorine.

The above summary is intended to provide a simplified summary of the disclosure The reader has a basic understanding of the disclosure. This Summary is not an extensive overview of the disclosure, and is not intended to be an

In order to make the present invention is known in the above and other objects, features, advantages and embodiments can be more fully understood by reading the accompanying drawings as follows: ¹ H-NMR spectrum of the final product of Example 1 of the embodiment 1A graph.

Figure 1B is a ¹³ C-NMR spectrum of the final product of Example 1.

Figure 2A is a ¹ H-NMR spectrum of the final product of Example 2.

Figure 2B is a ¹³ C-NMR spectrum of the final product of Example 2.

Figure 3A is a ¹ H-NMR spectrum of the final product of Example 3.

Figure 3B is a ¹³ C-NMR spectrum of the final product of Example 3.

Figure 4A is a ¹ H-NMR spectrum of the final product of Example 4.

Figure 4B is a ¹³ C-NMR spectrum of the final product of Example 4.

Figure 5A is a ¹ H-NMR spectrum of the final product of Example 5.

Figure 5B is a ¹³ C-NMR spectrum of the final product of Example 5.

Figure 6A is a ¹ H-NMR spectrum of the final product of Example 6.

Figure 6B is a ¹³ C-NMR spectrum of the final product of Example 6.

Figure 7A is a ¹ H-NMR spectrum of the final product of Example 7.

Figure 7B is a ¹³ C-NMR spectrum of the final product of Example 7.

Figure 8A is a ¹ H-NMR spectrum of the final product of Example 8.

Figure 8B is a ¹³ C-NMR spectrum of the final product of Example 8.

Figure 9A is a ¹ H-NMR spectrum of the final product of Example 9.

Figure 9B is a ¹³ C-NMR spectrum of the final product of Example 9.

A typical nitrogen isocyclic carbene palladium metal chelate compound having a structural formula represented by formula (I) wherein R in the formula (I) is hydrogen, methoxy or fluorine:

The preparation method of the above-mentioned typical nitrogen isocyclic carbene palladium metal chelate compound represented by formula (I) is as follows: First, a ligand precursor of the formula (III), a palladium-containing reagent and a The basic catalyst is dissolved in a first organic solvent to carry out a reaction to form an intermediate reaction solution. A drying step is provided to remove the first organic solvent of the intermediate reaction solution to obtain an intermediate solid. An extraction step is provided to extract the intermediate solids. The extracting step comprises: providing a phase separation step of adding water and a second organic solvent to the intermediate solid to form an aqueous layer and an organic layer, and taking a portion of the organic layer. Further, a water removal step is provided by adding a desiccant to the organic layer for water removal. Finally, a drying step is provided to remove the organic solvent of one of the organic layers to obtain the compound of the structure represented by the formula (I). Formula (III) is as follows wherein R is hydrogen, methoxy or fluoro:

The above-mentioned typical nitrogen isocyclic carbene palladium metal chelate compound represented by the formula (I) is a catalyst which can be used for a carbon-carbon coupling reaction, and a preparation of a medicament for inhibiting proliferation of tumor cells inhibiting mammals.

An atypical nitrogen isocyclic carbene palladium metal chelate compound having a structural formula of formula (II) wherein R ¹ in the formula (II) is hydrogen or methyl; and R ² is hydrogen, methoxy or fluorine:

The aforesaid structure of the atypical nitrogen-isoprene-carbon palladium metal chelate compound represented by formula (II) is as follows: First, a ligand precursor having a structure such as formula (IV), a palladium-containing reagent, and An alkaline catalyst is dissolved in a first organic solvent to carry out a reaction to form an intermediate reaction solution. A drying step is provided to remove the first organic solvent of the intermediate reaction solution to obtain an intermediate solid. An extraction step is provided to extract the intermediate solids. The extracting step comprises: providing a phase separation step of adding water and a second organic solvent to the intermediate solid to form an aqueous layer and an organic layer, and taking a portion of the organic layer. Further, a water removal step is provided by adding a desiccant to the organic layer for water removal. Finally, a drying step is provided to remove an organic solvent of the organic layer to obtain a compound of the structure represented by the formula (II). Formula (IV) is as follows wherein R ¹ is hydrogen or methyl; R ² is hydrogen, methoxy or fluoro:

The atypical nitrogen-isocyclic carbene metal chelating compound represented by the formula (II) is a catalyst which can be used for a carbon-carbon coupling reaction, and a preparation of a medicament for inhibiting proliferation of tumor cells inhibiting mammals.

The "nitrohecyclocarbene" referred to in the present invention is a heterocyclic carbene in which a carbene carbon is sandwiched between two nitrogen atoms, and the carbene is a neutral hydrocarbon having two valence electrons in a two-coordinated position. And the nitrogen isocyclic carbene has a five-heterocyclic six-electron resonance structure due to the inclusion of an unsaturated carbon-carbon bond, which adds extra stability. The nitrogen-isoprene ligand has a strong electron-donating ability, and the nitrogen-isocyclic carbene has neutral and strong properties of providing electron and air stability, and can be widely used in coordination chemistry and transition metal catalysis. , materials and biomedical.

The "chelating compound" referred to in the present invention is a coordination type having two or more buds containing a ligand. Most of the ligands have a strong ability to provide electrons, and their structures are relatively rigid and thermally stable. Chelating compounds are commonly used in stoichiometric and organometallic catalytic reactions. In general, the trilobate compound is more stable than the di- chelating compound, and the ligand used in the present invention is a function containing a nitrogen isocyclic carbene, a hydrazine, and a pyridine. The base is combined with a metal and has a three-bud chelation property.

The term "typical nitrogen isocyclic carbene" as used herein refers to a nitrogen-based heterocyclic carbene based on imidazole, and the ligand is bonded to the metal by carbon at position 2 on the imidazole. "Atypical nitrogen isocyclic carbene" means an imidazole-based nitrogen isocyclic carbene, and the ligand is debonded to the metal by imidazole 4 or 5 carbon. Atypical nitrogen-isoprene compounds have a stronger ability to provide electrons than typical nitrogen-isoprene compounds. Such an ability contributes to the oxidative addition of chemical bonds and generally exhibits better catalytic activity. The chelated form of atypical nitrogen-isocyclic carbene palladium metal-defect compound has a rigid structure and thermal stability, so it can be used in catalytic reactions and biomedical applications, such as anticancer drugs. The metal and nitrogen isocyclic carbon ene bond will have π electron feedback.

The following examples and examples are set forth to illustrate certain aspects of the invention and are in the These examples are not to be considered as limiting the scope of the invention, but are intended to illustrate the materials and methods of the invention.

A typical nitrogen heterocyclic carbene palladium metal chelate compound of the structure represented by the formula (I) and an atypical nitrogen isocyclic carbene palladium metal chelate compound having the structure represented by the formula (II)

Test Example 1-1: Synthesis of a ligand precursor

First, 2-chloro-N-(pyridin-2-ylmethyl)acetamide was synthesized. Potassium carbonate (K ₂ CO ₃ ) was placed in a round bottom two-necked flask, and 9.24 mmol of 2-aminomethylpyridine [2-(aminomethyl)pyridine] was added and mixed with 50 mL of dichloromethane (DCM). Further, 4.62 mmol of 2-chloroacetyl chloride was slowly added at 0 ° C with an isocratic funnel. After reacting for 1 hour at room temperature, filtering and drying with a filter paper, a red liquid product was obtained.

The reaction equation 1 of the aforementioned synthesis reaction is as follows:

Further, a phenylimidazole having a structure represented by the formula (V) wherein R ² is hydrogen, methoxy or fluorine is synthesized. Taking an imidazole starting material of the formula (IV) wherein R ¹ is hydrogen or methyl, and is placed in a Schlenk bottle in a ratio of 1:4 with sodium hydroxide (NaOH) in a molar ratio (Schlenk flask) In the syringe, the chlorobenzene compound was taken out into a flask, and 50 mL of tetrahydrofuran (THF) was added thereto, and the mixture was heated to 80 ° C and refluxed overnight. After the reaction is completed, it is cooled to room temperature, and the tetrahydrofuran is removed by suction, and extracted with dichloromethane and water. The organic layer is taken and added with magnesium sulfate (MgSO ₄ ) to remove water, and after draining, the structure is obtained. (V)-1 to a phenylimidazole represented by the formula (V)-6. The imidazole starting material used in the phenylimidazole represented by the formula (V)-1 to the formula (V)-3 is imidazole, and the formula (V)-4 to the formula (V)-6 are shown. The imidazole starting material used for the phenylimidazole is 2-methyl-imidazole. The chlorobenzene compound comprises benzyl chloride, 4-fluorobenzyl chloride and 3-methoxybenzyl chloride, and the formula (V)-1 to The chlorobenzene compound used in the phenylimidazole shown by (V)-6 and its millimolar number are shown in Table 1.

The reaction equation 2 of the aforementioned synthesis reaction is as follows: The phenylimidazole structures of the synthesized formulas (i) to (vi) are shown in Table 1 below.

The synthesized 2-chloropyridinium amide and the phenylimidazole represented by the formula (V)-1 to (V)-6 are dissolved in the concentration according to the following Table 2, respectively. In 97% by weight of ethanol, it was placed in a Schlenk bottle, heated and refluxed for 5 hours. After the reaction was completed, it was cooled to room temperature, washed with tetrahydrofuran, collected on a glass, and vacuum-dried to obtain a ligand precursor having a structure such as a to f.

The reaction equation 3 of the aforementioned synthesis reaction is as follows:

Test Example 1-2: Synthesis of a typical nitrogen isocyclic carbene palladium metal chelate compound

A method for preparing a typical nitrogen isoprene-carbon palladium metal chelate compound of the formula (I) is as follows: First, a ligand precursor having a structure such as formula (III), a palladium-containing reagent and a basic catalyst are provided. Dimethylacetamide (DMF) was dissolved in a ratio of Table 3 to form an intermediate reaction solution in which the palladium-containing reagent was palladium chloride and the basic catalyst was potassium carbonate. The reaction is carried out in a nitrogen atmosphere at a temperature of 25 ° C to 30 ° C for 12 hours to 16 hours. A drying step is provided to remove the dimethyl acetamide of the intermediate reaction solution to obtain an intermediate solid. An extraction step is provided to extract the intermediate solids. The extracting step comprises: providing a phase separation step of adding water and dichloromethane to the intermediate solid to form an aqueous layer and an organic layer, and taking a portion of the organic layer. Further, a water removal step is provided in which magnesium sulfate is added to the organic layer to remove water. Finally, a drying step is provided to remove the organic layer organic A solvent is used to obtain a compound of the structure represented by the formula (I).

The reaction equation 4 of the aforementioned synthesis reaction is as follows: The typical nitrogen isocyclic carbene palladium metal chelate compound of Examples 1-3 synthesized is shown in Table 3 below.

Please refer to FIGS. 1A to 3B. FIG. 1A is a ¹ H-NMR spectrum of the final product of Example 1, and FIG. 1B is a ¹³ C-NMR spectrum of the final product of Example 1. FIG. ¹ H-NMR spectrum of the final product of Example 2, Figure 2B is a ¹³ C-NMR spectrum of the final product of Example 2; Figure 3A is a ¹ H-NMR spectrum of the final product of Example 3, Figure 3B is a ¹³ C-NMR spectrum of the final product of Example 3. From Fig. 1A to Fig. 3B, it was confirmed that the final product of Examples 1-3 was a typical nitrogen isocyclic carbene palladium metal chelate compound (I).

Test Example 1-3: Synthesis of atypical nitrogen isocyclic carbene palladium metal chelate compound

The preparation method of the atypical nitrogen isocyclic carbene palladium metal chelate compound represented by the formula (II) is as follows: First, a ligand precursor having the structure of the formula (IV), a palladium-containing reagent and an alkali are provided. The catalyst is dissolved in dimethylacetamide (DMF) according to the ratio of Table 4 to form an intermediate reaction solution, wherein the palladium reagent in the examples 4-6 is palladium acetate and the basic catalyst is sodium acetate; The palladium-containing reagent in 7-9 is palladium chloride, which is alkaline. The catalyst is potassium carbonate. The reaction is carried out in a nitrogen atmosphere at a temperature of 25 ° C to 50 ° C for 12 hours to 16 hours. A drying step is provided to remove the dimethyl acetamide of the intermediate reaction solution to obtain an intermediate solid. An extraction step is provided to extract the intermediate solids. The extracting step comprises: providing a phase separation step of adding water and dichloromethane to the intermediate solid to form an aqueous layer and an organic layer, and taking a portion of the organic layer. Further, a water removal step is provided in which magnesium sulfate is added to the organic layer to remove water. Finally, a drying step is provided to remove the organic solvent of the organic layer to obtain the compound of the structure represented by the formula (II).

The reaction equations 5 and 6 of the aforementioned synthesis reaction are as follows: The typical nitrogen isocyclic carbene palladium metal chelate compound of Examples 1-3 synthesized is shown in Table 4 below.

Please refer to FIG. 4A to FIG. 9B, FIG. 4A is a ¹ H-NMR spectrum chart of the final product of Example 4, and FIG. 4B is a ¹³ C-NMR spectrum chart of the final product of Example 4; FIG. 5A is a graph ¹ H-NMR spectrum of the final product of Example 5, Figure 5B is a ¹³ C-NMR spectrum of the final product of Example 5; Figure 6A is a ¹ H-NMR spectrum of the final product of Example 6, Figure 6B is a ¹³ C-NMR spectrum of the final product of Example 6; Figure 7A is a ¹ H-NMR spectrum of the final product of Example 7, and Figure 7B is a ¹³ C- of the final product of Example 7. NMR spectrum; Figure 8A is a ¹ H-NMR spectrum of the final product of Example 8, Figure 8B is a ¹³ C-NMR spectrum of the final product of Example 8, and Figure 9A is the final product of Example 9. ¹ H-NMR spectrum, and FIG. 9B is a ¹³ C-NMR spectrum of the final product of Example 9. From Fig. 4A to Fig. 9B, it was confirmed that the final product of Examples 4-9 was an atypical nitrogen isocyclic carbene palladium metal chelate compound (II).

2. A typical nitrogen-isocyclic carbene palladium metal chelate compound of the structure represented by the formula (I) and an atypical nitrogen-isoprene-palladium metal chelate compound having the structure represented by the formula (II) are applied to the Heck reaction.

Test Example 2: Heck reaction

The following are typical nitrogen-isocyclic carbene palladium metal chelate compoundes having the structure of formula (I) in various embodiments of the present invention, and atypical nitrogen-isocyclic carbene palladium metal chelate compound having the structure of formula (II) As a catalyst for the Heck reaction. The Heck reaction is a coupling reaction of an unsaturated halogenated hydrocarbon with an olefin to form a substituted olefin under the catalysis of a strong base and palladium. The test procedure is as follows: firstly, 1.1 mmol of sodium acetate and 0.5 mol% of typical and atypical nitrogen isocyclic carbene palladium metal chelate compound of the present invention are used as catalysts, and 1 mmol of chlorobenzene is taken out with a micro syringe. The ketone (chloroacetonphenone) and 1.4 mmol of styrene (styrene) were placed in a straight tube with tetrabutylammonium bromide (TBAB) as a solvent, and heated to 140 ° C for 2 hours. After the reaction was completed, it was cooled to room temperature, extracted with ethoxyethane and water, and the organic layer was taken and added with magnesium sulfate to remove water, and then drained after collection. Finally, 1 mmol of 1,3,5-trimethoxybenzene (1,3,5-Trimethoxybenzene) was added as an internal standard, and NMR was measured by a little CDCl ₃ dissolution to obtain a yield. The test results are shown in Table 5 below.

As can be seen from Table 5, the typical nitrogen-isocyclic carbene palladium metal chelating compound and the atypical nitrogen-isoprene metal chelating compound of the present invention have the ability to catalyze the Heck reaction and can be used as a catalyst for the Heck reaction.

3. The typical nitrogen-isocyclic carbene palladium metal chelate compound of the structure represented by formula (I) and the atypical nitrogen-isoprene-palladium metal chelate compound of the structure represented by formula (II) inhibit tumor cell proliferation

Test Example 3-1: Cell line and cell culture

The test examples of the invention include human ovarian cancer cell line TOV21G, human colorectal adenocarcinoma cell line HCT116, human colorectal adenocarcinoma cell line SW620, human lung adenocarcinoma cell line NCI-HI1688, human acute leukemia cell line HL60 and human gastric cancer cells. Strain AGS was the subject.

Test Example 3-2: Analysis of tumor cell survival rate in different tissues

The following uses the typical nitrogen isocyclic carbene palladium metal chelate compound having the structure of the formula (I) in Examples 1-9, and the atypical nitrogen isocyclic carbene palladium metal chelate compound having the structure of the formula (II), The cell growth rate was analyzed by [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide; MTT assay], and the growth inhibition of tumor cells in different tissues was determined, and the tumor cell activity was evaluated. .

The test cells were seeded at a density of 1 × 10 ³ cells/well in a 96-well plate, and the cells were cultured at 37 ° C, 5% CO _{2 for} 24 hours, and then different concentrations of the compounds of Examples 1-9 were added and placed at 37. Incubate for 48 hours at °C, 5% CO ₂ . 5 mg/ml of MTT reagent dissolved in PBS was added to each well, and after reacting at 37 ° C for 4 hours, the MTT reagent was aspirated, and 150 μL of dimethylammonium (DMSO) was further added to dissolve the MTT-formazan to color the solution. The absorbance at a wavelength of 550 nm was measured by an enzyme immunoassay reader. The half-lethal dose (IC50) of the compounds of Examples 1-9 against tumor cells of different tissues was converted according to the results of cell viability analysis. The results of the test are shown in Table 6 below, where N indicates that the cell viability is the same as the untreated negative control group.

As shown in Table 5, the compounds of Examples 1-9 all have a toxic effect on tumor cell lines, while the compounds of Examples 1-3, 5 and 7-8 were tested for the 5 tumors tested. The cells all have a toxic effect.

Among them, the compound of Example 3 had an IC50 of 6.05 μM, 2809 μM, 46.13 μM, 211 μM, 2307 μM, and 23.1 μM for the six cell lines of the five tumor cells tested, respectively, and the ability to kill tumor cells was significantly better.

According to the above test results, a typical nitrogen isocyclic carbene palladium metal chelate compound of the structure represented by the formula (I) and an atypical nitrogen isoprocarbene palladium metal chelate compound of the structure represented by the formula (II) can be used as A pharmaceutical or pharmaceutical composition for inhibiting tumor cell proliferation in mammals. The above agents or pharmaceutical compositions may be prepared according to well-accepted pharmaceutical procedures and may comprise pharmaceutically acceptable coatings which are compatible with the other ingredients of the formulation and which are compatible with the organism. By pharmaceutically acceptable carrier herein is meant a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler. , a diluent, an excipient, a solvent, or an encapsulating material that can be used to carry or transport a target component to another organ or part of the body from one organ or part of the body. Share.

The present invention has been disclosed in the above embodiments, but it is not intended to limit the invention, and the present invention can be modified and modified without departing from the spirit and scope of the invention. The scope is subject to the definition of the scope of the patent application.

Claims (26)

A typical nitrogen isocyclic carbene palladium metal chelate compound having the structure represented by the following formula (I): In the formula (I), R is hydrogen, methoxy or fluorine. A use of a typical nitrogen isocyclic carbene palladium metal chelate compound as claimed in claim 1 for use as a catalyst for a carbon-carbon coupling reaction. The use of a typical nitrogen isocyclic carbene palladium metal chelate compound as claimed in claim 2, wherein the carbon-carbon coupling reaction is a Heck reaction. A use of a typical nitrogen isoprocarbene palladium metal chelate compound as claimed in claim 1 for the preparation of a medicament for inhibiting tumor cell proliferation in a mammal. A use of the typical nitrogen isoproterenol palladium metal chelate compound according to claim 4, wherein the medicament for inhibiting tumor cell proliferation of a mammal comprises a medicament for inhibiting proliferation of colorectal cancer cells, and inhibiting ovarian A drug that proliferates cancer cells, a drug that inhibits proliferation of gastric cancer cells, or a drug that inhibits proliferation of acute leukemia cells. A pharmaceutical composition for inhibiting tumor cell proliferation in a mammal, comprising an effective amount of a compound having the structure of the following formula (I) and a pharmaceutically acceptable carrier: In the formula (I), R is hydrogen, methoxy or fluorine. A method for preparing a typical nitrogen isoprocarbene palladium metal chelate compound according to claim 1, comprising: providing a ligand precursor having a structure such as formula (III), a palladium-containing reagent and a basic catalyst Dissolving in a first organic solvent to form an intermediate reaction solution; providing a drying step of removing the first organic solvent of the intermediate reaction solution to obtain an intermediate solid; and providing an extraction step The intermediate solid is subjected to extraction to obtain a compound of the structure represented by the formula (I); wherein, the formula (III) is as follows: In the formula (III), R is hydrogen, methoxy or fluorine. The method for preparing a typical nitrogen isoprocarbene palladium metal chelate compound according to claim 7, wherein the intermediate reaction solution is formed in a nitrogen atmosphere and reacted at a temperature of 25 ° C to 30 ° C for 12 hours to 16 hours. . A process for the preparation of a typical nitrogen isoprene-carbon palladium metal chelate compound according to claim 7, wherein the palladium-containing reagent is palladium chloride. A process for the preparation of a typical nitrogen isocyclic carbene palladium metal chelate compound according to claim 7, wherein the basic catalyst is potassium carbonate. A process for the preparation of a typical nitrogen isoprene-carbon palladium metal chelate compound according to claim 7, wherein the first organic solvent is dimethylacetamide. The method for preparing a typical nitrogen isoprocarbene palladium metal chelate compound according to claim 7, wherein the extracting step further comprises: providing a phase separation step of adding water and a second organic solvent to the intermediate solid Forming an aqueous layer and an organic layer; taking the organic layer; providing a water removal step, adding a desiccant to the organic layer to remove water; and providing a drying step to remove an organic solvent of the organic layer A compound of the structure represented by the formula (I) is obtained. A process for the preparation of a typical nitrogen isoprocarbene palladium metal chelate compound according to claim 12, wherein the second organic solvent is dichloromethane. An atypical nitrogen isocyclic carbene palladium metal chelate compound having the structure represented by the following formula (II): In the formula (II), R ¹ is hydrogen or methyl; and R ² is hydrogen, methoxy or fluorine. An atypical nitrogen isocyclic carbon ene palladium as claimed in claim 14 It is a chelating compound which is used as a catalyst for a carbon-carbon coupling reaction. The use of the atypical nitrogen-isocyclic carbene metal chelating compound according to claim 15, wherein the carbon-carbon coupling reaction is a Heck reaction. A use of the atypical nitrogen isoproterenol palladium metal chelate compound according to claim 14 for the preparation of a medicament for inhibiting tumor cell proliferation in a mammal. A use of the atypical nitrogen-isocyclic carbene metal chelating compound according to claim 17, wherein the drug for inhibiting tumor cell proliferation of a mammal comprises a drug for inhibiting proliferation of colorectal cancer cells and inhibiting proliferation of lung cancer cells a drug, a drug for inhibiting proliferation of ovarian cancer cells, a drug for inhibiting proliferation of gastric cancer cells, or a drug for inhibiting proliferation of acute leukemia cells A pharmaceutical composition for inhibiting tumor cell proliferation in a mammal, comprising an effective amount of a compound having the structure represented by the following formula (II) and a pharmaceutically acceptable carrier: In the formula (II); in the formula (II), R ¹ is hydrogen or methyl; and R ² is hydrogen, methoxy or fluorine. A method for preparing an atypical nitrogen-isocyclic carbene palladium metal chelate compound according to claim 14, comprising: providing a ligand precursor having a structure such as formula (IV), a palladium-containing reagent and an alkali The catalyst is dissolved in a first organic solvent to form an intermediate reaction solution; a drying step is provided to remove the first organic solvent of the intermediate reaction solution to obtain an intermediate solid; and an extraction step is provided, The intermediate solid is subjected to extraction to obtain a compound of the structure represented by the formula (II); wherein, the formula (IV) is as follows: In the formula (IV), R ¹ is hydrogen or methyl; and R ² is hydrogen, methoxy or fluorine. The method for preparing an atypical nitrogen isoprene-carbon palladium metal chelate compound according to claim 20, wherein the intermediate reaction solution is formed in a nitrogen atmosphere and reacted at a temperature of 25 ° C to 50 ° C for 12 hours to 16 hours. hour. A method for producing an atypical nitrogen-isocyclic carbene metal chelating compound according to claim 20, wherein the palladium-containing reagent is palladium chloride or palladium (II) diacetate. The method for producing an atypical nitrogen isocyclic carbene palladium metal chelate compound according to claim 20, wherein the basic catalyst is potassium carbonate or sodium acetate. The method for producing an atypical nitrogen isocyclic carbene palladium metal chelate compound according to claim 20, wherein the first organic solvent is dimethylacetamide. The method for preparing an atypical nitrogen-isocyclic carbene metal chelating compound according to claim 20, wherein the extracting step further comprises: providing a phase separation step of adding water and a second organic solvent to the intermediate solid Forming an aqueous layer and an organic layer; taking the organic layer; providing a water removal step, adding a desiccant to the organic layer to remove water; and providing a drying step to remove an organic solvent of the organic layer A compound of the structure represented by the formula (II) is obtained. The method for producing an atypical nitrogen isocyclic carbene palladium metal chelate compound according to claim 25, wherein the second organic solvent is dichloromethane.