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Arenobufagin derivatives, preparation method thereof, composition containing the derivatives and application of the derivatives

A technology of sandbuad toxin and its derivatives, which is applied in the direction of drug combination, steroids, and pharmaceutical formulations, and can solve problems such as unsatisfactory physical and chemical properties, low solubility, and high toxicity of sandbuad toxin

Active Publication Date: 2019-11-22
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, sabugain has high toxicity, narrow therapeutic window, low solubility, and unsatisfactory physical and chemical properties. Therefore, a new type of bufoadin analogue was designed and synthesized, and anti-tumor structure-activity relationship research was carried out, and a new one with high activity, Sabubuad toxin derivatives with low toxicity and good physical and chemical properties are of great significance

Method used

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  • Arenobufagin derivatives, preparation method thereof, composition containing the derivatives and application of the derivatives
  • Arenobufagin derivatives, preparation method thereof, composition containing the derivatives and application of the derivatives
  • Arenobufagin derivatives, preparation method thereof, composition containing the derivatives and application of the derivatives

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0055] Preparation Example 1 Sabubuadin-3-N-(2-methylaminoethyl) carbamate (compound 1)

[0056]

[0057] In a 50mL round-bottomed flask, dissolve p-nitrophenyl chloroformate (1.206g, 6mmol) in 10mL of anhydrous dichloromethane, add dry pyridine (0.67mL), a white precipitate appears immediately, and add sand dropwise under nitrogen protection. A dichloromethane solution (10 mL) of bufotoxin (2 mmol) was stirred at room temperature for 6 hours, washed twice with water after the reaction was completed, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to silica gel column chromatography (v:v= 90:10, petroleum ether / acetone) to obtain Intermediate A. In a 10mL round-bottomed flask, dissolve Intermediate A in 3mL of dichloromethane, add triethylamine (35μL), add N-methylethylenediamine (6mmol), stir at room temperature for 2 hours, and use Wash once with saturated sodium carbonate solution, and repeatedly wash with water until the solution ...

preparation Embodiment 2

[0058] Preparation Example 2 Sabubuadin-3-N-(2-ethylaminoethyl) carbamate (compound 2)

[0059]

[0060] The reaction operation is as in the preparation of compound 1, the raw material is N-ethylethylenediamine instead of N-methylethylenediamine; silica gel column chromatography eluent: petroleum ether / acetone / ammonia water (v:v:v=50:50 :0.5), the productive rate is 63%. 1 H NMR (400MHz, CDCl 3 )δ7.71(dd, J=9.8,2.6Hz,1H),7.39(d,J=2.6Hz,1H),6.29(d,J=9.8Hz,1H),4.97(s,1H),4.32( dd,J=11.3,2.4Hz,1H),4.10(dd,J=9.6,7.4Hz,1H),3.82(d,J=3.1Hz,1H),3.38–3.20(m,2H),2.93–2.82 (m,2H),2.81–2.74(m,2H),2.41(d,J=13.3Hz,1H),2.15–1.29(m,15H),1.25(t,J=7.1Hz,3H),1.18( s,3H),0.92(s,3H); ESI-MS(m / z)531.3[M+1] + .

preparation Embodiment 3

[0061] Preparation Example 3 Sabubuadin-3-N-(2-dimethylaminoethyl) carbamate (compound 3)

[0062]

[0063] The reaction operation is the same as the preparation of compound 1, the raw material is N,N-dimethylethylenediamine instead of N-methylethylenediamine; silica gel column chromatography eluent: petroleum ether / acetone / ammonia water (v:v:v= 50:50:0.5), the yield was 61%. 1 H NMR (400MHz, CDCl 3 )δ7.71(dd, J=9.8,2.6Hz,1H),7.39(d,J=2.6Hz,1H),6.29(d,J=9.8Hz,1H),4.97(s,1H),4.32( d,J=11.1Hz,1H), 4.11(d,J=9.3,2.2Hz,1H),3.36–3.21(m,2H),2.50–2.44(m,2H),2.40(d,J=16.3Hz ,1H),2.29(s,6H),2.25–1.21(m,15H)1.18(s,3H),0.92(s,3H); ESI-MS(m / z)531.3[M+1] + .

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Abstract

The invention relates to arenobufagin derivatives with structures shown as a general formula I or pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical compositioncontaining the derivatives and application of the derivatives. The arenobufagin derivatives have relatively strong inhibitory activity on tumor cell strains with KRAS mutation, and can be used for preparing medicines for treating malignant tumors with KRAS mutation.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular, the present invention relates to a new class of sabugain derivatives, a preparation method thereof, a pharmaceutical composition comprising the derivatives, and uses thereof. The sabugain derivatives have strong inhibitory activity on KRAS mutated tumor cell lines, and can be used to prepare KRAS mutated malignant tumor drugs. Background technique [0002] Cancer, or malignancy, is a major cause of morbidity and mortality worldwide. According to the World Health Organization (WHO), there were 14 million new cancer cases and 8.2 million cancer deaths in the world in 2012. In my country, there are 3.07 million newly diagnosed cancer cases, accounting for 21.8% of the global total, and about 2.2 million cancer deaths, accounting for 26.9% of the global cancer deaths. At present, the number of new cancer cases in the world is still increasing year by year. Therefore, cance...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00C07J43/00A61K31/585A61P35/00
CPCC07J41/0033C07J43/003A61P35/00
Inventor 果德安吴婉莹栗世铀雷敏侯晋军金青浩周阳王贞
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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