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3'-phenyl spirono[indoline-3, 2'-pyrrolidine]-2-ketone derivative and preparation method and application thereof

A derivative, indoline technology, applied in the direction of drug combination, organic chemistry, anti-tumor drugs, etc., can solve the problem of unsatisfactory inhibitory activity, and achieve good value-added activity and good anti-tumor cell value-added activity.

Inactive Publication Date: 2016-06-22
SHAOXING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many anticancer drugs contain spirocycles. The structure-activity relationship studies show that the activity of lactone ring-opening compounds is significantly higher than that of lactone compounds. Among them, the p53-MDM2 binding inhibition of indoline 6-position or benzene ring chlorinated derivatives Activity was not superior to that of the non-chlorinated derivatives

Method used

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  • 3'-phenyl spirono[indoline-3, 2'-pyrrolidine]-2-ketone derivative and preparation method and application thereof
  • 3'-phenyl spirono[indoline-3, 2'-pyrrolidine]-2-ketone derivative and preparation method and application thereof
  • 3'-phenyl spirono[indoline-3, 2'-pyrrolidine]-2-ketone derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] A solution of N-ethylglycine (0.18g, 2.0mmol), 3-acetylcoumarin (0.38g, 2.0mmol) and indolequinone 2-117 (0.29g, 2.0mmol) in methanol (30mL) was refluxed for 15h , after the reaction was completed, cooled to room temperature, suction filtered, recrystallized from the obtained solid methanol to obtain a white solid, the structure of which was:

[0028] The above-mentioned white solid is an intermediate, and its melting point is >250°C.

[0029] Carry out NMR testing on it:

[0030] 1 HNMR (500MHz, DMSO), δ10.35(s, NH, 1H), 7.64(d, J=7.2Hz, Ar-H, 1H), 7.48(td, J=7.7, 1.0Hz, Ar-H, 1H ),7.42(m,Ar-H,1H),7.32(d,J=7.3Hz,Ar-H,1H),7.17(d,J=7.7Hz,Ar-H,1H),7.01(td,J =7.6,0.8Hz,Ar-H,1H),6.90(d,J=7.7Hz,Ar-H,1H),6.41(d,J=6.7Hz,Ar-H,1H),4.12(d,J =10.9Hz, CH, 1H), 4.09(m, CH, 1H), 3.96(t, J=9.1Hz, CH, 1H), 3.68(dd, J=9.1, 4.4Hz, CH, 1H), 2.22( q,J=7.1,CH 2 ,2H),1.19(t,J=7.1,CH 3 ,3H); MS(ESI): 334[M+H] + .

Embodiment 2

[0032] The intermediate (50mg, 0.16mmol) in Example 1 was dissolved in THF (6mL), and N-methylpiperazine (48mg, 0.48mmol) was added to reflux for 30min, and the solvent was recovered, extracted with ethyl acetate / water, and The ethyl acetate layer was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, and the solvent was recovered. The obtained solid was recrystallized in ethyl acetate / petroleum ether to obtain a white solid with the structure

[0033] The above white solid is an intermediate with a melting point of 128-130°C.

[0034] Carry out NMR testing on it:

[0035] 1 HNMR (500MHz, CDCl 3 ), δ7.85(s, OH, 1H), 7.53(d, J=7.5Hz, Ar-H, 1H), 7.25(m, Ar-H, 1H), 7.15(t, J=7.7Hz, Ar -H,1H),7.04(dd,J=13.7,6.6Hz,Ar-H,2H),6.84(d,J=8.0Hz,Ar-H,1H),6.69(dd,J=7.5,4.1Hz ,Ar-H,2H),4.50(d,J=9.6Hz,CH,1H),4.03(td,J=10.1,6.0Hz,CH,1H),3.77(m,CH 2 ×2,4H),3.40(t,J=7.2Hz,3H),2.35(t,J=5.1Hz,CH 3 ,3H),2.31(m,6H),2.16(q,J=7.1,CH 2 ,2H),1.21(t,J=7.1,CH 3 ,3H); MS(...

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Abstract

The invention relates to a 3'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one derivative and its preparation method and application, and belongs to the technical field of heterocyclic compounds. The three components of acetyl coumarin compounds, indolequinone compounds and amino acids are used as the main raw materials. The three components undergo a cyclization reaction to form a spiro ring structure. The spiro ring structure then reacts with the corresponding nitrogen-containing fragment to form a spiro ring. Derivatives, namely 3'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one derivatives. The present invention is applied to the preparation of anti-cancer drugs such as anti-non-small cell lung cancer and colon cancer drugs, and has the advantages of high yield, anti-tumor cell value-proliferating activity and other advantages.

Description

technical field [0001] The invention relates to a 3'-phenylspiro[indoline-3,2'-pyrrolidinyl]-2-one derivative, a preparation method and application thereof, and belongs to the technical field of heterocyclic compounds. Background technique [0002] Spiral compounds are a class of widely used intermediates in organic synthesis, and the spiro structure exists in many important natural product molecules and pharmaceuticals with physiological activity. Many anticancer drugs contain spirocycles. The structure-activity relationship studies show that the activity of lactone ring-opening compounds is significantly higher than that of lactone compounds. Among them, the p53-MDM2 binding inhibition of indoline 6-position or benzene ring chlorinated derivatives The activity was not superior to that of the non-chlorinated derivatives. From the perspective of tumor growth inhibitory activity, the introduction of chlorine atoms helps to improve the activity, and the activity of N-piperidi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/20C07D487/10A61P35/00
CPCC07D491/20C07D487/10
Inventor 胡纯琦
Owner SHAOXING UNIVERSITY
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