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Millepachine-CA-4 derivative as well as preparation method and application thereof

A technology of derivatives and preparation steps, applied in the field of medicinal chemistry, can solve the problems of CA-4 instability, easy photolysis, poor water solubility, etc., and achieve the effect of improved anti-tumor activity, less toxic and side effects, and high selectivity

Active Publication Date: 2020-06-05
GUANGDONG HOSPITAL OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The object of the present invention is to provide a Millepachine-CA-4 derivative with good stability, high anti-tumor activity and little side effects, so as to overcome the cardiovascular toxicity of CA-4 at high doses and the instability, Easy photolysis, prone to cis-trans isomerization, poor water solubility, etc.

Method used

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  • Millepachine-CA-4 derivative as well as preparation method and application thereof
  • Millepachine-CA-4 derivative as well as preparation method and application thereof
  • Millepachine-CA-4 derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Embodiment 1. Preparation of compound A-1

[0056]

[0057] (1) Intermediate 3: Preparation of 5-methoxy-2,2-dimethyl-2H-pyran-benzaldehyde.

[0058]

[0059] The commercial raw material 1 (1mmol) was dissolved in 10mL acetonitrile, and DBU (2mmol), 3-chloro-3-methyl-1-butyne (1.5mmol), chlorinated ketone ( 0.1 mmol), after stirring for 8 h, dilute hydrochloric acid was added to adjust the pH=2, and then ethyl acetate was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate, 10:1) to obtain intermediate 2.

[0060] Intermediate 2 (1 mmol) was dissolved in 10 mL of pyridine, reacted at 70°C for 10 hours, and the solvent was removed under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate...

Embodiment 2

[0074] Embodiment 2. Preparation of Compound A-2

[0075]

[0076] Compound A-1 (2 mmol) was dissolved in dry methanol, sodium methoxide (6 mmol) was added under stirring at room temperature, and the reaction was refluxed for 8 hours. After the reaction, the system was cooled to room temperature. Ethyl acetate was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain the target compound A-2. White solid, 73% yield. 1 HNMR (400MHz, Chloroform-d) δ9.24(s,1H),7.57(s,2H),7.27(d,J=7.5Hz,1H),6.85(d,J=7.5,1H),6.66(d ,J=1.9Hz,1H),6.47(d,J=7.5Hz,1H),5.23(d,J=8.8Hz,1H),4.10(d,J=4.9Hz,2H),3.95(s,3H ),3.87(s,3H),2.87(t,J=5.0Hz,1H),1.44(s,6H). 13 C NMR(101MHz,Chloroform-d)δ197.80,171.54,159.04,155.17,152.77,140.60,134.73,127.03,126.10,122.91,117.66,115.30,111.37,108.73,107.61,106.65,77.48,61.00,56.27,55.93,27.87...

Embodiment 3

[0080] Embodiment 3. Preparation of compound A-3

[0081]

[0082] Compound A-1 (2mmol) was dissolved in ethanol (15mL), and 25% NH 3 ·H 2 O (8 mmol), react at room temperature for 3 hours. After the reaction, the system was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain the target compound A-3. White solid, 65% yield. 1 HNMR (400MHz, Chloroform-d) δ9.26(s, 1H), 7.92(s, 2H), 7.59(d, J=7.5Hz, 1H), 7.26(d, J=7.5Hz, 1H), 6.72( d,J=9.5Hz,1H),6.47(d,J=8.6Hz,1H),5.27(d,J=10.8Hz,1H),3.85(s,2H),3.83(s,3H),3.81( s,3H),1.54(s,2H),1.47(s,6H). 13 C NMR(101MHz,Chloroform-d)δ194.7,168.48,159.04,155.45,150.13,140.93,132.53,128.36,127.71,123.34,117.66,116.75,111.37,109.43,106.65,103.37,76.48,56.01,55.56,44.32,27.82 .

[0083] The synthesis method of compound B-3 and C-3 is the same as that of com...

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Abstract

The invention discloses a Millepachine-CA-4 derivative as well as a preparation method and application thereof. The derivative is good in stability, high in anti-tumor activity and small in toxic andside effects, effectively overcomes the defects that CA-4 has cardiovascular toxicity at a high dose and CA-4 is unstable, prone to photolysis, prone to cis-trans isomerization, poor in water solubility and the like, and the derivative can be used for preparing anti-tumor drugs.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a Millepachine-CA-4 derivative, its preparation method and its application in the preparation of anticancer drugs. Background technique [0002] Chemotherapy is the main treatment for malignant tumors, but the low selectivity of chemotherapeutic drugs to normal cells and the resistance of tumor cells to chemotherapeutic drugs are the main reasons that affect the efficacy of chemotherapy and lead to the failure of chemotherapy. Microtubules widely exist in eukaryotic cells, as a key component of the cytoskeleton, its main role is to form the cell spindle, maintain cell shape, cell mitosis and so on. Tubulin is a protein dimer composed of α-tubulin and β-tubulin, so inhibiting the aggregation of tubulin can prevent the formation of spindles and make tumors Cell mitosis cannot proceed normally, thereby blocking the cell cycle and achieving the purpose of inhibiting the growth of ...

Claims

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Application Information

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IPC IPC(8): C07D311/58C07D311/64A61P35/00A61K31/352
CPCA61P35/00C07D311/58C07D311/64
Inventor 严君庞延青黄宪章张乔轩柯培锋韩丽乔林海标王建兵庄俊华
Owner GUANGDONG HOSPITAL OF TRADITIONAL CHINESE MEDICINE
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