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Indole-substituteing imidazoline-2-ketones derivant, preparing method and uses of the same

A technology of imidazoline and derivatives, applied in the field of compound preparation, can solve the problems of unstable cis-stilbene structure, poor water solubility, weak anti-tumor activity and the like

Inactive Publication Date: 2008-02-27
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although CA-4 has cytotoxic activity and anti-tubulin polymerization activity in vitro, as an anti-mitotic agent, CA-4 only shows weak anti-tumor activity in vivo activity studies, mainly due to its poor water solubility, The structure of cis-stilbene is unstable, and it is easy to isomerize into trans configuration

Method used

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  • Indole-substituteing imidazoline-2-ketones derivant, preparing method and uses of the same
  • Indole-substituteing imidazoline-2-ketones derivant, preparing method and uses of the same
  • Indole-substituteing imidazoline-2-ketones derivant, preparing method and uses of the same

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Example 1: Preparation of 1-(1H-indol-5-yl)-5-(4-bromophenyl)-4-imidazolidin-2-one (compound IVa1)

[0026] Add 0.53g (4mmol) of 5-amino-1H-indole and 4mL of anhydrous toluene to the reaction flask, cool in an ice-salt bath, and slowly drop into a solution prepared from 0.79g of solid phosgene and 6mL of anhydrous toluene. After dropping, continue stirring and reacting for 1 hour under the protection of nitrogen, remove the ice-salt bath, react at room temperature for 30 minutes, slowly heat up to reflux, and after 4 hours, the reaction solution becomes clear, add 4-bromo-α-aminophenyl ethyl Ketone hydrochloride 0.38g (2mmol), added anhydrous toluene 10mL, heated to reflux overnight. Cool, recover the solvent under reduced pressure, wash the residue with chloroform 20mL×2, combine the filtrates, wash with saturated NaCl solution, and wash the organic layer with anhydrous NaCl 2 SO 4 After drying, the solvent was recovered under reduced pressure to obtain a brown solid...

Embodiment 2

[0028] Example 2: N,3-bis(1H-indol-5-yl)-4-(2,4-difluorophenyl)-4-imidazolidin-2-one-1-carboxamide (compound IVb1) preparation of

[0029] Add 0.58g (4mmol) of 5-amino-1H-indole and 4mL of anhydrous toluene to the reaction flask, cool in an ice-salt bath, and slowly drop into a solution prepared from 0.79g of solid phosgene and 6mL of anhydrous toluene. After dropping, continue to stir and react for 1 hour under the protection of nitrogen, remove the ice-salt bath, and react at room temperature for 30 minutes, then slowly heat up to reflux. After 4 hours, the reaction solution becomes clear, and 2,4-difluoro-α- Aminoacetophenone hydrochloride 0.38g (2mmol), added anhydrous toluene 10mL, heated to reflux overnight. Cool, filter with suction, wash the filter cake with chloroform 20mL×2, combine the filtrates, wash with saturated NaCl solution, and wash the organic layer with anhydrous NaCl 2 SO 4 After drying, the solvent was recovered under reduced pressure to obtain a tan s...

Embodiment 3

[0031] Embodiment 3: N, the preparation of 3-two (1H-indol-5-yl)-4-(4-chlorophenyl)-4-imidazolidin-2-one-1-formamide (compound IVb2)

[0032] The operation process is the same as in Example 2, except that 2,4-difluoro-α-aminoacetophenone hydrochloride is replaced with 4-chloro-α-aminoacetophenone hydrochloride. A pale yellow solid (compound IVb2) was obtained with a yield of 49.6%. Melting point: 239-241°C.

[0033] 1 H NMR (δ, DMSO-d 6 ): 5.57-5.59 (d, 1H, J = 8.0Hz, indole H), 6.43-6.48 (d, 2H, J = 20Hz, indole H), 6.95-6.97 (d, 1H, J = 8.4Hz, indole H ) 7.15-7.20 (d, 2H, J=8.8Hz, aromatic H), 7.29-7.31 (d, 2H, J=8.8Hz, aromatic H), 7.37-7.39 (d, 2H, J=6.0Hz, indole H ), 7.41-7.45 (m, 3H, indole H×2, imidazolin-2-one H), 7.55 (s, 1H, indole H), 7.83 (s, 1H, indole H), 10.77 (s, 1H, - O=C-N-H-), 11.14(s, 1H, indole N-H), 11.37(s, 1H, indole N-H).

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Abstract

The invention discloses an indole to replace imidazoline-2-ketones derivant, which is characterized by the following: choosing natural product Combretastatin A-4 as lead compound; replacing ethene chain with imidazoline-2-ketone five-membered hetero ring; replacing benzene ring in CA-4 with indole ring; getting a series of imidazoline ketones derivant. This invention can be used to prepare antitumor agent, which possesses the function to inhibit tumor cell propagation and simple preparing method.

Description

technical field [0001] The invention belongs to compound preparation, and mainly relates to the preparation method and application of indole-substituted imidazolin-2-one derivatives. Background technique [0002] In the early 1980s, the group of chemical researchers Pettit isolated a series of Combretastatin compounds from the African plant Combretum caffrum, including diarylethene compounds CombretastatinA-1, A-2, A-3, A-4, A -5, A-6; Dibenzyl compounds Combretastatin B-1, B-2, B-3, B-4; Combretastatin C-1; Macrolide compounds Combretastatin D-1, D-2 and Phenathrene and Dihydrophenathrene. Anti-tumor cell activity experiments in vitro show that these compounds have high activity (ED 50 =0.003~18 μg / mL). Therefore, the simplicity of their structure and their unique activity in anti-tumor, especially drug-resistant tumors, make them attract more and more attention. [0003] Combretastatin A-4, as the compound with the best activity and the simplest structure in the Combret...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D403/14A61K31/4178A61P35/00
Inventor 胡永洲薛娜杨晓春杨波何俏军
Owner ZHEJIANG UNIV
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