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Coelenterazine analog and preparing method and application thereof

An analogue, coelenterazine technology, applied in the field of coelenterazine analogues and its preparation, can solve problems such as the influence of bioluminescent properties

Active Publication Date: 2016-09-28
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In conclusion, modifications to the structure of coelenterazine may affect its bioluminescent properties

Method used

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  • Coelenterazine analog and preparing method and application thereof
  • Coelenterazine analog and preparing method and application thereof
  • Coelenterazine analog and preparing method and application thereof

Examples

Experimental program
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example 1

[0146] [Example 1: 2-(phenylmethyl)-6-(4-fluorophenyl)-8-benzyl-imidazo[1,2-a]pyrazin-3-(7H)-one (B1) Preparation]

[0147] Preparation of intermediate 2-amino-5-bromo-3-phenylmethyl-pyrazine (1-1)

[0148] Under nitrogen protection, zinc powder (235 mg, 3.6 mmol) and iodine particles (12 mg) were mixed, DMF was added, and stirred at room temperature until the color of iodine disappeared. Then benzyl bromide (0.57mg, 3mmol) was added, moved to 80°C under reflux and stirred for about 3 hours. After the reaction solution was allowed to cool to room temperature, 2-amino-3,5-dibromopyrazine (506 mg, 2 mmol) and triphenylphosphine palladium dichloride (70 mg, 0.1 mmol) were added. React at room temperature for 24 hours. The reaction solution was filtered with diatomaceous earth, extracted with ethyl acetate, the ethyl acetate phase was washed with saturated sodium chloride solution, the ethyl acetate phase was dried with anhydrous sodium sulfate, filtered, and purified by 200-30...

example 2

[0155] [Example 2: 2-(phenylmethyl)-6-(3-fluoro-4-aminophenyl)-8-benzyl-imidazo[1,2-a]pyrazine-3-(7H)- Preparation of ketone (B2)]

[0156] Preparation of intermediate 2-amino-5-(4-amino-3-fluoro-phenyl)-3-benzyl-pyrazine

[0157] Under nitrogen protection, the intermediate 2-amino-5-bromo-3-benzyl-pyrazine (200mg, 0.756mmol), bisbenzonitrile palladium dichloride (II) (20mg, 0.050mmol), [1, 4-bis(diphenylphosphino)butane]palladium(II) dichloride (30 mg, 0.050 mmol) was dissolved in 8 mL of toluene, then 3-fluoro-4-amino-phenylboronic acid pinacol ester (240 mg , 1.058mmol) and aqueous potassium carbonate (2M, 0.6mL). Stir at reflux at 109°C for 10 hours. After stopping the reaction, the reaction solution was filtered, the filtrate was concentrated, ethyl acetate and saturated sodium chloride solution were added, and after extraction, the ethyl acetate layer was dried with anhydrous sodium sulfate, filtered, and 200-300 mesh silica gel column chromatography to obtain 133 mg ...

example 3

[0160] [Example 3: 2-(phenylmethyl)-6-(4-hydroxymethylphenyl)-8-benzyl-imidazo[1,2-a]pyrazin-3-(7H)-one ( Preparation of B3)]

[0161] Preparation of intermediate 2-amino-5(4-hydroxymethylphenyl)-3-benzyl-pyrazine

[0162] Under nitrogen protection, the intermediate 2-amino-5-bromo-3-benzyl-pyrazine (100mg, 0.378mmol), bisbenzonitrile palladium dichloride (II) (10mg, 0.026mmol), [1, 4-bis(diphenylphosphino)butane]palladium(II) dichloride (20 mg, 0.033 mmol) was dissolved in 6 mL of toluene, then 4-hydroxymethylphenylboronic acid (85 mg, 0.559 mmol) and sodium carbonate were added Aqueous solution (1M, 0.4 mL). Stir at reflux at 109°C for 10 hours. After stopping the reaction, the reaction solution was filtered, the filtrate was concentrated, ethyl acetate and saturated sodium chloride solution were added, and after extraction, the ethyl acetate layer was dried with anhydrous sodium sulfate, filtered, and 70 mg of a yellow solid was obtained by 200-300 mesh silica gel column...

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Abstract

The invention discloses a coelenterazine analog and a preparing method and application thereof. The coelenterazine analog has the general structure formula (I) shown in the description, wherein R1, R2 and R3 in the formula are different substituents. According to application of the compound as a bioluminescence substrate, the existence and quantity (including the enzyme level, the cell level and the animal level) of coelenterazine luciferase can be detected with bioluminescence, and the in vitro, cell and in vivo distribution imaging of luciferase can be detected; the compound can serve as a report signal to detect the pharmacologic action and the toxic effect of medicine on the enzyme level, the cell level and the animal level under the existence of luciferase.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a class of coelenterazine analogues and their preparation method and application. Background technique [0002] Bioluminescence (bioluminescence) widely exists in nature and refers to the luminescence phenomenon in which chemical energy is converted into light energy based on chemical reactions of life activities in living organisms. Biological extracts can also emit light in in vitro models. It does not depend on the absorption of light by an organism, but is a special type of chemiluminescence in which chemical energy is converted into light energy with almost 100% efficiency. The luciferin and luciferase of different bioluminescent systems are also different, but the mechanism of bioluminescence is roughly the same: luciferin is catalyzed by luciferase to generate an electron intermediate in an excited state, and the electron is excited by Photons are released ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04G01N21/76A61K49/00
CPCA61K49/0021C07D487/04G01N21/763
Inventor 李敏勇杜吕佩姜天宇
Owner SHANDONG UNIV
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