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Synthesis of amino combretastatin derivative and application of amino combretastatin derivative as oral antitumour drug

An amino and drug technology, applied in the field of medicine, can solve problems such as inconvenient use

Active Publication Date: 2014-11-05
ZHEJIANG DADE PHARMACEUTICAL GROUP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still many inconveniences in its use

Method used

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  • Synthesis of amino combretastatin derivative and application of amino combretastatin derivative as oral antitumour drug
  • Synthesis of amino combretastatin derivative and application of amino combretastatin derivative as oral antitumour drug
  • Synthesis of amino combretastatin derivative and application of amino combretastatin derivative as oral antitumour drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methylpiperidine-4-formyl)amino-4-ethoxyphenyl)ethylene synthesis

[0070]

[0071] Step 1: Synthesis of Trimethoxybenzyltriphenylphosphine Bromide

[0072] Dissolve 4Kg of 3,4,5-trimethoxybenzaldehyde in absolute ethanol, stir, and add 1.4Kg of sodium borohydride in small amounts at a temperature below 35°C. After the addition was complete, the reaction was carried out overnight. After the reaction was complete, ethanol was removed by rotary evaporation. Ethyl acetate (10L×4) was added for extraction, the ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the ethyl acetate was distilled off under reduced pressure to obtain 3200ml of the product.

[0073] Dissolve 3200ml of 3,4,5-trimethoxybenzyl alcohol in 20L of toluene, stir, cool down to -5-0°C, add 1L of phosphorus tribromide dropwise, and control the temperature at -5-0°C. After the dropwise addition was completed, react at low te...

Embodiment 2

[0083] (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methylpiperidine-4-formyl)amino-4-ethoxyphenyl)ethylene lemon Salt preparation

[0084] (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methylpiperidine-4-formyl)amino-4-ethoxyphenyl)ethylene Add 20g into 200ml of acetone, heat to dissolve, add 10g of citric acid, continue to heat and reflux for 3h, filter the precipitate after cooling, and recrystallize with ethanol to obtain the compound shown in the title.

[0085] Utilize different raw materials, by the similar method of embodiment 1, synthesized following various compounds respectively:

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

Embodiment 31

[0092] Example 31 Pharmaceutical preparation formulation

[0093] The invention provides formulations of pharmaceutical compositions for several diseases related to abnormal proliferation of new blood vessels, and the pharmaceutical compositions mainly include oral preparations such as tablets and capsules. Hereinafter, the compounds shown in the present invention are represented by "active compound".

[0094]

[0095]

[0096]

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PUM

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Abstract

Disclosed in the present invention are compounds as shown in formula (I) for inhibiting tumour angiogenesis and pharmaceutically acceptable salts or configurational isomers thereof, wherein substituents R1, R2 and R3 are as defined in the description. Also disclosed in the present invention are the preparation method of compounds as shown by formula (I), a pharmaceutical composition, and the use of these compounds as tubulin inhibitors for inhibiting tumour angiogenesis, especially when used as oral preparations.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a series of Combretastatin A4 derivatives, a preparation method thereof, and an application in preparation of tubulin inhibitors. Background technique [0002] Combretastatins series compounds were originally extracted and isolated from the trunk of Combretum caffrum in South Africa. It has anti-tumor activity, can directly act on endothelial cells, induce the apoptosis of proliferating endothelial cells, thereby inhibiting the formation of neovascularization in tumors, and achieve the purpose of eradicating tumors. Combretastatins series compounds have a cis-1,2-stilbene structure. Among them, combretastatin A-4[CA-4, Comprestatin, cis-1-(3,4,5-trimethoxy)phenyl-2-(3′-hydroxy-4′-methoxy)benzene Vinyl] has the strongest inhibition of microtubule polymerization (Pettit G R, et al. J. Med. Chem (1995) 38 1666-1672). Recently, as a tumor vessel targeting agent, CA-4 has shown exce...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/62C07D401/04C07D409/04C07D213/82C07D213/81C07D213/84A61K31/4468A61K31/4545A61K31/454A61K31/4535A61K31/455A61K31/44A61P35/00A61P35/02A61P29/00A61P19/02A61P27/02A61P17/06A61P37/00A61P27/06A61P31/04A61P31/10A61P31/22A61P33/02A61P1/02A61P31/18A61P15/00
CPCC07D211/62C07D409/04A61K31/454A61K31/4468C07D213/81A61K31/4535A61K31/4545A61K31/455C07D401/04C07D213/82C07D213/84A61P1/02A61P15/00A61P17/06A61P19/02A61P27/02A61P27/06A61P29/00A61P31/04A61P31/10A61P31/18A61P31/22A61P33/02A61P35/00A61P35/02A61P37/00
Inventor 王建平王建国
Owner ZHEJIANG DADE PHARMACEUTICAL GROUP CO LTD
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