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

Abstract

The invention discloses a compound which is shown as a formula (I) and used for inhibiting generation of tumour neovascularization as well as officinal salt or a configurational isomer thereof, wherein substituent groups R1, R2 and R3 are defined in the specification. The invention also discloses a preparation method of the compound in the formula (I), a pharmaceutical composition and an application of the compound as a microtubulin inhibitor in the aspect of inhibiting the tumour neovascularization, especially an application as an oral preparation.

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...

Examples

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]

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...

Examples

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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