Bufalin derivative as well as preparation method, pharmaceutical composition and application thereof

A technology of bufalin and derivatives, applied in the field of medicinal chemistry, can solve the problems of insufficient patient selection, unsatisfactory pharmacological activity and the like

Active Publication Date: 2014-02-12
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

[0013] However, the above-mentioned compounds still provide insufficient choices for patients, or their pharmacological activities are not yet fully satisfactory.

Method used

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  • Bufalin derivative as well as preparation method, pharmaceutical composition and application thereof
  • Bufalin derivative as well as preparation method, pharmaceutical composition and application thereof
  • Bufalin derivative as well as preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 01

[0096] Example 01: Preparation of Compound 2

[0097]

[0098] Under nitrogen protection, compound 1 (bufalin) (5 mmol) was dissolved in dichloromethane (DCM) (10 mL), and Rh(OAc) 2 (30mg, 0.1mol%), then slowly dropwise added a solution of methyl diazoacetate (25mmol) in dichloromethane (10mL), the solution was stirred at room temperature for 2 hours, quenched with anhydrous methanol, and the organic layer was washed with water (2×20mL) Twice, washed once with 20 mL of saturated saline, dried the dichloromethane layer over anhydrous sodium sulfate, removed the solvent under reduced pressure, and separated by column chromatography with petroleum ether / acetone=4:1 as the eluent to obtain Compound 2 in the form of white powder, the yield is 70%. 1 H NMR (400MHz, CDCl 3 )δ7.84(dd,J=9.7,2.4Hz,1H),7.21(s,1H),6.23(d,J=9.7Hz,1H),4.05(s,2H),3.72(s,3H), 3.69(s,1H),2.46-2.42(m,1H),2.23-1.07(m,23H),0.90(s,3H),0.67(s,3H);ESI-MS(m / z)459.3[M +1] + .

Embodiment 02

[0099] Example 02: Preparation of compound 3

[0100]

[0101] Compound 2 (3mmol) was dissolved in pyridine (10mL), and lithium iodide (LiI) (2g) was added, and the reaction solution was refluxed overnight at 110°C. After the reaction was completed, dichloromethane (10mL) was added, and then successively Wash once with 1N hydrochloric acid, water, and saturated saline with 20 mL each, dry the dichloromethane layer over anhydrous sodium sulfate, remove the solvent under reduced pressure, and perform column chromatography with petroleum ether / acetone = 3:2 as the eluent After separation, Compound 1 was obtained as a white powder with a yield of 80%. 1 H NMR (400MHz, CDCl 3 )δ7.84(dd,J=9.7,2.4Hz,1H),7.23(s,1H),6.27(d,J=9.7Hz,1H),4.07(s,2H),3.79(s,1H), 2.48-2.44(m,1H),2.23-1.07(m,23H),0.94(s,3H),0.70(s,3H);ESI-MS(m / z)445.3[M+1] + .

Embodiment 03

[0102] Example 03: Preparation of Compound A01

[0103]

[0104] In a 25 mL round bottom flask, compound 3 (1 mmol) was dissolved in 5 mL of dichloromethane, and 4-dimethylaminopyridine (DMAP) (0.5 mmol), piperazine (3 mmol), and 1-ethyl-( 3-Dimethylaminopropyl) carbodiimide hydrochloride (EDCI-HCl, 3mmol), stirred at room temperature overnight, after the reaction was completed, 20mL of dichloromethane was added, washed twice with water (2×20mL), Wash once with 20 mL of saturated saline, dry the dichloromethane layer over anhydrous sodium sulfate, remove the solvent under reduced pressure, and use petroleum ether / acetone = 2:1 as the eluent to separate by column chromatography to obtain a white powder The compound A01, yield 70%. 1 H NMR (400MHz, CDCl 3 )δ:7.84(dd,J=9.7,2.4Hz,1H),7.20(s,1H),6.23(d,J=9.7Hz,1H),4.10(s,2H),3.69(s,1H), 3.45(t,J=5.1Hz,4H),2.84(t,J=5.1Hz,4H),2.46(m,1H),2.23-1.07(m,23H),0.91(s,3H),0.67(s ,3H);ESI-MS(m / z)513.3[M+1] + .

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Abstract

The invention relates to a bufalin derivative having a structure represented as a general formula I, wherein R is selected from one of the following structure groups as shown in the specification, or pharmaceutically acceptable salt, as well as a preparation method, a pharmaceutical composition and application of the derivative. The bufalin derivative has an activity on inhibiting tumor cell lines, and can be used as a medicine for treating malignant tumors.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular, the invention relates to a new class of bufalin derivatives, a preparation method thereof, a pharmaceutical composition comprising the derivatives, and uses thereof. The bufondulin derivative has inhibitory activity on tumor cell lines and can be used as a drug for treating malignant tumors. Background technique [0002] According to the report of the World Health Organization, due to the aging of the world's population and factors such as the environment, smoking, drinking, and unhealthy diet, cancer patients are increasing day by day. According to statistics, in 2011, 12.4 million people around the world were diagnosed with some type of cancer, and 7.6 million of them will die from it. In my country, there are more than 1.6 million newly discovered cancer patients and more than 1.3 million deaths every year. Today, malignant tumors have become the largest public health proble...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00C07J41/00A61K31/585A61P35/00A61P35/02
Inventor 胡立宏果德安雷敏刘璇马彪
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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