N'-(2-(1H-indole-3-yl)acetyl)arylhydrazide compound and preparation method and application thereof

A technology of acetyl group and aroyl hydrazide, applied in the field of drug preparation, can solve problems such as lack of preventive vaccines

Inactive Publication Date: 2016-07-06
KUNMING UNIV OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There is still no effective preventive vaccine for HCV. In the past 20 years, the main treatment method is the combination of interferon (IFN)-α or polyethylene glycol (PEG) modified long-acting IFN and broad-spectrum antiviral drug ribavirin. This therapy is effective for type II and type III patients, but it is only effective for about 40% of type I patients, and severe adverse reactions such as rash also affect its use

Method used

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  • N'-(2-(1H-indole-3-yl)acetyl)arylhydrazide compound and preparation method and application thereof
  • N'-(2-(1H-indole-3-yl)acetyl)arylhydrazide compound and preparation method and application thereof
  • N'-(2-(1H-indole-3-yl)acetyl)arylhydrazide compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] In this example, the compound of formula I-1 is prepared by the following method, which specifically includes the following steps:

[0067] (1) Add 8.8g (50mmol) of indole acetic acid (50mmol), methanol (60mL), and concentrated sulfuric acid (3mL) to a 500ml round bottom flask, and react at 70°C for 1-3 hours. water (50mL), separate the organic phase, extract the aqueous phase with ethyl acetate (3×20mL), combine the organic phases, wash with saturated sodium bicarbonate solution and water successively, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain indole The crude product of methyl acetate was directly used in the next reaction without further purification.

[0068] (2) Add 9.46g (48mmol) of methyl indole acetate, ethylene glycol methyl ether (40mL), and 5mL of hydrazine hydrate into a 500ml round-bottomed flask, heat and reflux at 115°C for about 20 hours, thin-layer chromatography (TLC) After detecting the disappearance of the r...

Embodiment 2

[0074] In this example, the compounds of formula I-2 to formula I-35 were prepared. The only difference between the preparation method and the preparation of the compound of formula I-1 in Example 1 was that the aroyl chlorides used in step (4) were respectively Other than that, the preparation method is the same as that of the compound of formula I-1 in Example 1.

[0075] The properties, yields and structural characterization results of the prepared compounds of formula I-2 to formula I-35 are as follows:

[0076] N'-(2-(1H-indol-3-yl)acetyl)-2-iodobenzohydrazide (Formula I-2): white solid, yield: 94%, mp: 188.1-189.0°C; 1 H-NMR (500MHz, DMSO-d 6 ), δ(ppm): 3.68(s,2H,CH 2 ),6.92-6.93(s,1H,Ar-H),6.98-7.24(m,4H,Ar-H),7.32-7.35(m,1H,Ar-H),7.43-7.44(m,1H,Ar-H -H),7.53-7.55(m,1H,Ar-H),7.80-7.82(m,1H,Ar-H),10.23(s,1H,NH),10.29(s,1H,NH),10.97( s,1H,indole-NH); m / z418.0[M + -1].

[0077] N'-(2-(1H-indol-3-yl)acetyl)phenylacetylhydrazide (Formula I-3): white solid, yield: ...

Embodiment 3

[0117] In this example, the in vitro anti-HCV activity of the compounds of formula I-1 to formula I-35 was evaluated, and the human liver cancer cell line Huh7.5.1 was used to evaluate the anti-HCV activity at the cellular level in vitro. The method is described as follows:

[0118] MTT method to detect drug cytotoxicity: Huh7.5.1 cells in the logarithmic growth phase were taken, and 9×10 3 Cells / well were spread on a 96-well plate, and after 5 hours of attachment, 2 μL DMSO was added to serially dilute the drug, 5-fold dilution, 5 dilutions, each gradient had three replicate wells, and a blank control (only medium) was set at the same time. , cell control, DMSO control and anti-HCV positive drug Ribavirin (Ribavirin) control, the final volume is 200 μL / well. Place the culture plate at 37°C, 5% CO 2 incubator for cultivation. On the third day, 20 μL of 5 mg / mL MTT solution was added to the experimental wells, at 37 °C, 5% CO 2 Incubate for 4 hours. Discard the supernatant,...

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Abstract

The invention provides a N'-(2-(1H-indole-3-yl)acetyl)arylhydrazide compound and a preparation method and application thereof.The N'-(2-(1H-indole-3-yl)acetyl)arylhydrazide compound has a structure shown as a formula I (please see the formula in the description) and has the obvious inhibiting effect on an HCV virus, the anti-HCV virus treatment index is higher than that of existing clinical drugs including alpha-1b(IFNalpha-1b) interferon and ribavirin, and the N'-(2-(1H-indole-3-yl)acetyl)arylhydrazide compound can serve as an anti-HCV drug candidate; in addition, the preparation method is simple, high in yield and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and relates to an N'-(2-(1H-indol-3-yl)acetyl)aromatic hydrazide compound and its preparation method and application. Background technique [0002] Hepatitis C is caused by hepatitis C virus (hepatitisCvirus, HCV), a liver disease that seriously threatens human health. About 170 million people in the world are infected with HCV, and nearly 60%-80% of them will develop into chronic hepatitis. It further develops into cirrhosis and liver cancer. There is still no effective preventive vaccine for HCV. In the past 20 years, the main treatment method is the combination of interferon (IFN)-α or polyethylene glycol (PEG) modified long-acting IFN and broad-spectrum antiviral drug ribavirin. This therapy is effective for type II and type III patients, but it is only effective for about 40% of type I patients, and severe adverse reactions such as rash also affect its use. In recent years, a ...

Claims

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Application Information

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IPC IPC(8): C07D209/18C07D405/12A61P31/14
CPCC07D209/18C07D405/12
Inventor 夏雪山何严萍冯悦范孟然高凤萍张玉芳李聪
Owner KUNMING UNIV OF SCI & TECH
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