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Application of a pyrimidine amine compound as a cyclin-dependent kinase 4/6 inhibitor

A technology of pyrimidine amines and compounds, applied in the field of medicinal chemistry, can solve problems such as large side effects, low activity, and low therapeutic index

Active Publication Date: 2020-06-05
扬州市三药制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] There are other reports of multiple similar drugs, but the prior art has the defects of low activity, large side effects, and low therapeutic index in varying degrees. In order to overcome the defects in the above-mentioned prior art, the inventor has carried out extensive research. A new class of compounds were designed and synthesized, and their anti-tumor activity was determined. The biological activity test results showed that its biological activity was better than that of Palbociclib

Method used

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  • Application of a pyrimidine amine compound as a cyclin-dependent kinase 4/6 inhibitor
  • Application of a pyrimidine amine compound as a cyclin-dependent kinase 4/6 inhibitor
  • Application of a pyrimidine amine compound as a cyclin-dependent kinase 4/6 inhibitor

Examples

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Embodiment 1

[0058] Example 1: 5-fluoro-4-(1-isopropyl-1H-indol-3-yl)-N-(5-(piperazin-1-yl)pyridin-2-yl)pyrimidine-2- Synthesis of Amine (Compound (1))

[0059]

[0060] Reaction conditions: i) indole, MeMgBr, 1,2-dichloroethane, 0°C → room temperature; ii) NaH, THF, 0 → 35°C, 48h; iii) Pd 2 (dba) 3 , Xantphos, DIPEA, dioxane, 100°C, 48h; iv) hydrogen chloride gas, ethyl acetate, overnight at room temperature.

[0061] The first step: the synthesis of 3-(2-chloro-5-fluoropyrimidin-4-yl)-1H-indole (intermediate 1)

[0062] 1.17g indole (10.0mmoL) was dissolved in 15mL of 1,2-dichloroethane, 7.5ml of methylmagnesium bromide (15mmoL, 2M THF solution) was added, the temperature was lowered to 0°C, and 1.66g of 2 , 4-dichloro-5-fluoropyrimidine (10.0mmoL) dissolved in 15mL of 1,2-dichloroethane solution, kept at 0°C for 1 hour, returned to room temperature for 1 hour, added 30ml of water under continuous stirring , separate out a large amount of solids, filter, use water, 10% citric acid...

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Abstract

The invention relates to application of a pyrilamine compound as a cycle protein dependency kinase 4 / 6 inhibitor. The compound is of a structure shown as formula (I), preferably, wherein R1 and R2 are respectively hydrogen, hydroxyl or alkyl, and X is halogen. More preferably, R1 is hydrogen or hydroxyl, R2 is alkyl, X is fluorine, chlorine or bromine; and particularly preferably, R1 is hydrogen, R2 is methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl or tertiary butyl, and X is fluorine.

Description

technical field [0001] The invention belongs to the category of medicinal chemistry, and specifically relates to the synthesis of a class of pyrimidine amine-containing compounds and their application as cyclin-dependent kinase CDK4 / 6 inhibitors in cancer treatment. Background technique [0002] Cyclin-dependent kinases (CDKs) play a very important regulatory and driving role in the transition of major cell cycle states in eukaryotic cells. There are 1 to 11 classifications of CDKs, among which CDK4 and 6 are important regulatory proteins of the cell division cycle, which can phosphorylate RB1 so that RB1 loses the function of inhibiting cell growth, and can induce cells from the growth phase (G1 phase) to the DNA replication phase ( S1 phase) transformation. The uncontrolled growth of cells is one of the main hallmarks of cancer. Disregulation of CDK4 / CDK6 can lead to uncontrolled growth of cells and lead to various proliferative diseases including cancer. CDK4 / 6 inhibito...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14A61K31/506A61P35/00
CPCC07D401/14
Inventor 朱锡桢邓承军周中祥
Owner 扬州市三药制药有限公司
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