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Novel N-phenyl-2-pyrimidinaminederivative and application thereof to preparation of anti-tumor medicine

A technology of anilinopyrimidine and derivatives, which is applied to novel 2-anilinopyrimidine derivatives and its application in the preparation of antitumor drugs, can solve problems such as drug resistance, and achieve improved solubility and antitumor activity. , Good anti-tumor activity

Inactive Publication Date: 2018-04-20
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the curative effect of osimertinib on patients with EGFR-T790M mutation is encouraging, tumor cells have a strong screening ability, and it is still possible for tumor cells to develop drug resistance after adapting to the third-generation EGFR-TKI

Method used

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  • Novel N-phenyl-2-pyrimidinaminederivative and application thereof to preparation of anti-tumor medicine
  • Novel N-phenyl-2-pyrimidinaminederivative and application thereof to preparation of anti-tumor medicine
  • Novel N-phenyl-2-pyrimidinaminederivative and application thereof to preparation of anti-tumor medicine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1: the synthesis of target product 1 (structural formula 1).

[0040] The synthesis of intermediate 13-16 was carried out with reference to the method in the literature (J.Med.Chem.2014, 57, 8249-8267).

[0041] Preparation of Intermediate 17: Dissolve Intermediate 16 (1.0mmol) in N,N-dimethylformamide (DMF) (10mL), add sodium methyl mercaptide (1.5mmol) and triethylamine (1.5mL) dropwise in sequence mmol), reacted at 50°C; after the reaction was monitored by TLC, the reaction system was poured into ice water, resulting in a large amount of precipitation. The resulting precipitate was filtered off, washed three times with water, and dried in vacuo to afford intermediate 17. Yield: 65%.

[0042] Preparation of Intermediate 18: Intermediate 17 (1.0 mmol) was dissolved in CH 2 Cl 2 (10mL), the reaction system was lowered to 0°C, and m-CPBA (1.0mmol) was added in batches; after the reaction was monitored by TLC, saturated sodium bicarbonate solution was added t...

Embodiment 2

[0045] Embodiment 2: the synthesis of target product 2 (structural formula 2)

[0046]

[0047] Intermediate 20 was prepared in the same way as Intermediate 19, yield: 63%.

[0048] The preparation of target product 2 is the same as that of target product 1. Yield: 72%. 1H NMR (400MHz, Chloroform-d) δ9.79(s,1H),9.28(s,1H),9.00(s,1H),8.36(d,J=5.3Hz, 1H),8.12–7.97(m, 1H),7.68(s,1H),7.43–7.34(m,1H),7.23–7.15(m,1H), 6.72(s,1H),6.47–6.36(m,2H),5.72–5.60(m, 1H), 3.95(s, 3H), 3.86(s, 3H), 3.65(t, J=5.0Hz, 2H), 2.93(t, J=5.0Hz, 2H), 2.69(s, 3H).MS: [M+H] + =473.2.

Embodiment 3

[0049] Embodiment 3: the synthesis of target product 3 (structural formula 3).

[0050]

[0051] Intermediate 21 was prepared in the same way as Intermediate 19, yield: 65%.

[0052] The preparation method of the target product 3 is the same as that of the target product 1. Yield: 82%. 1H NMR (400MHz, Chloroform-d) δ9.89(d, J=3.4Hz, 1H), 9.10(d, J=22.6Hz, 2H), 8.38(s, 1H), 8.06(t, J=5.2Hz ,1H),7.76(s,1H),7.40(d,J=8.1Hz,1H),7.22(d,J=4.6Hz,1H),6.76(d,J=3.5Hz,1H),6.52–6.31 (m,2H),5.74(d,J=9.6Hz,1H), 3.99(d,J=3.5Hz,3H),3.89(d,J=3.3Hz,3H),3.58(q,J=4.9Hz ,2H),3.18 (q,J=5.0Hz,2H),2.71(d,J=3.5Hz,3H).MS: [M+H] + =491.2.

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Abstract

The invention discloses a novel N-phenyl-2-pyrimidinaminederivative. A side chain of the novel N-phenyl-2-pyrimidinaminederivative contains a sulfoxide SO functional group, a sulphone SO2 functional group, a hydroxyl functional group, a halogen functional group or a methylmercapto functional group, which replaces a NCH3 group and a N(CH3)2 group in osimertinib. As sulfoxide SO, sulphone SO2, hydroxyl, halogen or methylmercapto is introduced into the side chain, favorable activity is achieved on the solubility, the bioavailability and the antitumor activity of a medicine.

Description

technical field [0001] The present invention relates to the field of medicines, in particular to a novel 2-anilinopyrimidine derivative and its application in the preparation of antitumor drugs, the side chain of which contains sulfoxide SO, sulfone SO 2 , hydroxyl, halogen or methylthio functional groups. Background technique [0002] Malignant tumor, commonly known as cancer, is a major disease that seriously threatens human health and life, and has become the world's leading "killer of life". The National Central Cancer Registry of China (NCCRC) reported that there were 4,300,000 new cancer cases in 2015, including 2,800,000 deaths. According to predictions by experts from the World Health Organization at relevant conferences in Geneva, by 2020, the number of deaths from cancer worldwide may double, and approximately 84 million people will die of cancer in the next 10 years. By 2020, China will also have 5.5 million new cancer cases, of which up to 4 million people will...

Claims

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Application Information

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IPC IPC(8): C07D403/04A61K31/506A61K31/541A61P35/00
CPCC07D403/04
Inventor 黎兴术安佰娇庞延青陈新滋黄玲
Owner SUN YAT SEN UNIV
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