Nitrogen-containing heterocyclic compound as well as preparation method, pharmaceutical composition and application thereof

A technology of nitrogen heterocyclic compounds and compounds, which is applied in the field of nitrogen-containing heterocyclic compounds and their preparation, and can solve the problems of drug resistance and the like

Pending Publication Date: 2021-09-24
SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

Although protein kinases have become important targets in the development of anticancer drugs, similar to other anticancer therapies, anticancer targeted kinase therapy can also produce drug resistance

Method used

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  • Nitrogen-containing heterocyclic compound as well as preparation method, pharmaceutical composition and application thereof
  • Nitrogen-containing heterocyclic compound as well as preparation method, pharmaceutical composition and application thereof
  • Nitrogen-containing heterocyclic compound as well as preparation method, pharmaceutical composition and application thereof

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preparation example Construction

[0096] The present invention also provides a method for preparing a nitrogen-containing heterocyclic compound in an embodiment, which is a method for preparing the nitrogen-containing heterocyclic compound in the above embodiment, comprising the following steps:

[0097] Step S110: compound A, R 1 B(OH) 2 , palladium catalyst and basic reagent reaction, preparation compound B.

[0098] Wherein, the structural formula of compound A is The structural formula of compound B is Y and Z are each independently selected from one of -CH and -N.

[0099] In one embodiment, the palladium catalyst is PdCl 2 (dppf) is (1,1'-bis(diphenylphosphino)ferrocene palladium chloride). The alkaline reagent is sodium carbonate.

[0100] Specifically, compound A, R 1 B(OH) 2 In the step of reacting the palladium catalyst and the alkaline reagent, a degassed aqueous solution of dioxane is also added as a solvent.

[0101] Further, in step S110, the reaction temperature is 80°C-100°C, and the r...

Embodiment 1

[0144] The structural formula of the nitrogen-containing heterocyclic compound of the present embodiment is: The preparation process is as follows:

[0145] (1)

[0146] Weigh compound 1 (2g, 6.19mmol) and dissolve it in DMF, cool in an ice bath to 0°C, add NaH (0.5g, 12.39mmol) slowly, stir for 10 minutes, add SEMCl (2mL, 10.53mmol) dropwise, and stir at room temperature reaction. After the reaction was completed, water was added to quench the reaction, extracted with ethyl acetate (EA), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 2 g of a light yellow solid with a yield of 71.4%, which was Compound 2 . The structural characterization of compound 2 is shown below: LC-MS: m / z 454[M+H] + . 1 H NMR (400MHz, CDCl 3 )δ8.62(d, J=2Hz, 1H), 7.99(d, J=2Hz, 1H), 5.83(S, 2H), 3.66(t, J=7.2Hz, 2H), 0.95(t, J= 7.2Hz,2H),-0.03(s,9H). 13 C NMR (100MHz, CDCl 3 )δ151.3, 149.5, 132.5, 122.1, 113...

Embodiment 2

[0154] The structural formula of the nitrogen-containing heterocyclic compound of the present embodiment is: The preparation process is as follows:

[0155] (1)

[0156] Compound 6 (100mg, 0.192mmol) was dissolved in DMF (3mL), and K 2 CO 3 (79mg, 0.576mmol), the temperature was raised to 80°C and compound 8 (72mg, 0.576mmol) was added in portions, and reacted overnight. After the reaction was completed, water was added to quench the reaction, EA was extracted, filtered, and the crude product obtained after concentration was compound 9, which was directly used in the next reaction. The structure of the crude product was characterized as follows: LC-MS: m / z 565 [M+H] + .

[0157] (2)

[0158] Compound 9 was dissolved in ethanol (6 mL), added with 2N HCl (6 mL), and reacted overnight at 80°C. After the reaction, it was concentrated under reduced pressure, separated and purified in liquid phase, and freeze-dried to obtain the yellow target compound 10, which is the ni...

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Abstract

The invention relates to a nitrogen-containing heterocyclic compound as well as a preparation method, a pharmaceutical composition and application thereof. The structural formula of the nitrogen-containing heterocyclic compound is shown in the specification, wherein Y and Z are respectively and independently selected from one of -CH and -N; the R1 and R2 are respectively and independently selected from one of a substituted aryl group, an unsubstituted aryl group, a substituted heteroaryl group and an unsubstituted heteroaryl group. On one hand, the nitrogen-containing heterocyclic compound is combined with a colchicine binding site of microtubule protein, so that microtubule depolymerization is promoted, and tumor cell proliferation is inhibited; on the other hand, the activity of kinase is inhibited by combining with an ATP binding site of protein kinase, so that proliferation and survival of tumor cells are inhibited at the same time through multiple channels. Compared with drugs such as paclitaxel aiming at tubulin, the compound has the advantages of better water solubility, simpler structure, easiness in synthesis and good drug resistance.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a nitrogen-containing heterocyclic compound and its preparation method, pharmaceutical composition and application. Background technique [0002] Malignant tumors (cancer) have become one of the major public health problems that seriously threaten the health of the Chinese population. According to the latest statistics, the death rate of malignant tumors accounts for 23.91% of all residents' deaths, and the mortality rate of malignant tumors has averaged It shows a continuous upward trend, and the annual medical expenses caused by malignant tumors exceed 220 billion, and the prevention and control situation is severe. Although the research and development of anti-tumor drugs has achieved certain success, the survival rate of cancer patients has been improved to a certain extent, and the quality of life of patients has also been improved to a certain extent, but there are still many defec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/04C07D519/00A61K31/437A61K31/444A61K31/4985A61K31/5025A61K31/496A61K31/5377A61P35/00A61P35/02
CPCC07D471/04C07D487/04C07D519/00A61P35/00A61P35/02
Inventor 徐晶宁澄清陶阿晓
Owner SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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