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A kind of indazole piperidine pyrimidine derivative and its preparation method and application

A technology of indazole, piperidine pyrimidine and its derivatives, which is applied in the field of medicine, and can solve problems such as severe toxic and side effects, large toxic and side effects, and drug resistance reducing the curative effect of compounds

Active Publication Date: 2020-08-25
WUHAN INSTITUTE OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Most of the first-generation EGFR inhibitors are quinazoline parent ring structures, which have shown good therapeutic effects in early clinical applications, but drug resistance caused by mutations greatly reduces the efficacy of these compounds
The parent ring of the second-generation EGFR inhibitor still retains the quinazoline structure, which forms a strong covalent interaction with amino acid residues through the introduction of unsaturated bonds, so as to reduce the drug resistance caused by mutation, but the large Most of these compounds have relatively high toxic and side effects
On the basis of retaining unsaturated bonds, the third-generation EGFR inhibitors replaced quinazoline with pyrimidine rings to obtain a new class of inhibitors, which also showed good properties in clinical research, but most of these compounds still exist greater toxic side effects

Method used

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  • A kind of indazole piperidine pyrimidine derivative and its preparation method and application
  • A kind of indazole piperidine pyrimidine derivative and its preparation method and application
  • A kind of indazole piperidine pyrimidine derivative and its preparation method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: the synthesis of intermediate Ⅰ-c1

[0026]

[0027] Weigh Ⅰ-a1 (1mmol) and Ⅰ-b (1mmol) and dissolve in 1,4-dioxane (10mL), add K under stirring at room temperature 2 CO 3 , stirred at room temperature for 4h. Thin-layer chromatographic detection showed that the two raw material points had basically reacted completely, so the stirring was stopped. Pour the reaction solution into 50mL water, extract with ethyl acetate (2×50mL), wash with saturated brine (2×40mL), dry the organic phase over anhydrous sodium sulfate, filter with suction, spin the filtrate to obtain an oily substance, and column chromatography I-c1 was purified with a yield of 35.2%.

Embodiment 2

[0028] Embodiment 2: Synthesis of Intermediate I-c1

[0029] Weigh I-a1 (1 mmol) and I-b (1 mmol) and dissolve in N-methylpyrrolidone (10 mL), add DIEA under stirring at room temperature, and stir at room temperature for 4 h. Thin-layer chromatographic detection showed that the two raw material points had basically reacted completely, so the stirring was stopped. Pour the reaction solution into 50 mL of water, extract with ethyl acetate (2×50 mL), wash with saturated brine (2×50 mL), dry the organic phase over anhydrous sodium sulfate, filter with suction, and spin the filtrate to obtain an oily substance, which is subjected to column chromatography I-c1 was purified with a yield of 42.3%.

Embodiment 3

[0030] Embodiment 3: the synthesis of intermediate I-c2

[0031]

[0032] Weigh I-a2 (1 mmol) and I-b (1 mmol) and dissolve in DCM (10 mL), add sodium bicarbonate with stirring at room temperature, and stir at room temperature for 3 h. Thin-layer chromatographic detection showed that the two raw material points had basically reacted completely, so the stirring was stopped. The reaction solution was poured into 50mL water, extracted with DCM (2×50mL), washed with saturated brine (2×50mL), the organic phase was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was spin-dried to obtain an oil, which was purified by column chromatography to obtain Ⅰ-c2, yield 34.4%.

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PUM

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Abstract

The invention belongs to the technical field of medicine, and specifically relates to an indazole, piperidine and pyrimidine derivative, a preparation method and application thereof. The indazole piperidine pyrimidine derivatives provided by the present invention replace the acrylamide structure forming a covalent bond on the basis of retaining the pyrimidine parent ring of the third-generation EGFR inhibitor, and obtain a class of non-covalent bond inhibitors . The results of the drug activity test show that the compound exhibits excellent in vitro inhibitory effect on human lung cancer H1975 cells. At the same time, most of the compounds are less toxic to normal human cells than lung cancer cells, showing better selectivity and can be used for further development of anticancer drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to an indazole piperidine pyrimidine derivative and a preparation method and application thereof. Background technique [0002] Human cancer cells are often accompanied by overexpression of growth factors and their receptors. The epidermal growth factor receptor family (epidermal growth factor receptor, EGFR) is also known as type I tyrosine kinase receptor or ErbB tyrosine kinase receptor. The receptor family consists of four types of homologous receptors: epidermal growth factor receptor (ErbB1 / EGFr / HER1), ErbB2 (HER2), ErbB3 (HER3), ErbB4 (HER4). [0003] Overexpression of epidermal growth factor receptor exists in more than 80% of non-small cell lung cancer patients, so the receptor protein has become an important research target for anti-small cell lung cancer. EGFR inhibitors can be roughly divided into two categories: 1) non-covalently bonded EGFR inhibitors, su...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14A61P35/00
CPCA61P35/00C07D401/14
Inventor 古双喜王超肖婷朱园园汤佳凡卢文龙徐志强刘根炎高昭
Owner WUHAN INSTITUTE OF TECHNOLOGY
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