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Anti-enterovirus 71 (EV71) caprolactam compounds, and preparation method and application thereof

A technology of caprolactam and EV71, which is applied in the field of formula compounds for the treatment of enterovirus 71 infection, can solve the problem that the virus transcription and replication cannot continue normally

Inactive Publication Date: 2013-06-12
NANKAI UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Among the seven non-structural proteins, 3C protease is considered to mainly perform the function of specific protease and belongs to cysteine ​​protease. Its active center is a catalytic triad composed of Cys147, His40 and Glu71, which is responsible for specifically converting the virus-encoded Each protein of the virus is cut from the polymer to form a protein with independent functions, so once the function of this protein is lost, the further transcription and replication of the virus will not continue normally

Method used

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  • Anti-enterovirus 71 (EV71) caprolactam compounds, and preparation method and application thereof
  • Anti-enterovirus 71 (EV71) caprolactam compounds, and preparation method and application thereof
  • Anti-enterovirus 71 (EV71) caprolactam compounds, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] Example 1 Preparation of N-Boc-L-(+)-dimethyl glutamate (1-2)

[0111]

[0112] At 0°C, slowly add acetyl chloride (5 mL) dropwise into methanol (100 mL), stir for 5 minutes, then add glutamic acid (10 g, 67.9 mmol), continue stirring and heat to reflux, and keep the reflux temperature for 2 hours . The reaction was stopped, the solvent was removed under reduced pressure, and recrystallized from ether. The obtained oil was dissolved in THF (150mL), TEA (28.5mL, 203.7mmol) was added dropwise at 0°C, kept stirring at 0°C for 5 minutes, and dicarbonate dicarbonate dissolved in HF (30mL) was added dropwise. Tert-butyl ester (17.8 g, 81.5 mmol), stirred to room temperature for 2.5 hours. After the reaction, the solvent was distilled off under reduced pressure, water (200 mL) was added to the residue, extracted from the aqueous phase with DCM (2×200 mL), the combined organic phases were dried over anhydrous sodium sulfate, and then concentrated to obtain the crude produc...

Embodiment 2

[0113] Example 2 Preparation of 2-tert-butoxycarbonylamino-4-cyanoethyl-glutaric acid dimethyl ester (1-3)

[0114]

[0115] At -78°C, lithium bis(trimethylsilyl)amide (78.5mL 1.0M solution in THF, 78.5mmol) was slowly added dropwise to N-Boc-L-(+)-dimethylglutamate ester (1-2) (10 g, 36.4 mmol) in anhydrous THF (200 mL), and the resulting solution was stirred at this temperature for 30 minutes. Then, keeping the temperature constant, bromopropionitrile (3.4 mL) was slowly added dropwise, and the reaction mixture was stirred at -78° C. for 2 hours. After the reaction was complete, glacial acetic acid (5 mL) was added to quench the reaction, and stirred to room temperature. First remove the solvent under reduced pressure, then add water (200mL), extract the aqueous phase with DCM (2×200mL), and dry the combined organic phase with anhydrous sodium sulfate, then concentrate, and the obtained crude product is passed through a flash chromatography column (PE :EA=2:1) ​​to obta...

Embodiment 3

[0116] Example 3 Preparation of 2-tert-butoxycarbonylamino-3-(2-carbonyl-3-piperidinane)-propionic acid methyl ester (1-4)

[0117]

[0118] Add cobalt chloride hydrate (4g, 14.6mmol ), and then slowly added sodium borohydride (6 g, 157.9 mmol) in portions to the obtained pink mixture at 0° C., and stirred at room temperature for 18 hours. The reaction was quenched by adding saturated aqueous ammonium chloride (30 mL), and stirred for 10 minutes. The solid impurities were removed by suction filtration, and the volatile solvent was evaporated under reduced pressure. The aqueous phase was extracted with DCM (3×100 mL), the combined organic phases were dried over anhydrous sodium sulfate, and then concentrated, and the resulting crude product was purified by flash chromatography (EA) to give 2-tert-butoxycarbonylamino-3 -(2-Carbonyl-3-piperidinane)-propionic acid methyl ester (2.9 g, yield 60.7%) was a white foamy solid, TLC: R f =0.4(EA); 1 H-NMR (400MHz, CDCl 3 ): δ6.00...

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Abstract

The invention relates to a caprolactam anti-enterovirus 71 (EV71) 3C protease inhibitor with a structural formula shown as compounds (M). Each variable in the structure is defined as the specification. The compounds can effectively inhibit or block replication of enterovirus 71. The invention relates to discovery and application of compounds comprising a structure of formula (M), various optical isomers thereof, metabolites with pharmaceutically activity, pharmaceutically acceptable salts, solvates and prodrugs in preparing antiviral drugs for treating virus infections of hand-foot-and-mouth diseases. The invention also relates to an intermediate and a synthetic method for preparing the compounds having the structure of the formula (M).

Description

technical field [0001] The present invention relates to compounds of formula (M) for treating enterovirus 71 (EV71) infection, pharmaceutical compositions, synthesis methods of such compounds, preparation methods and compounds used in these synthesis. Specifically, the present invention provides a class of caprolactam compounds, a pharmaceutical composition containing the compounds and a method for treating EV71 infection with the compounds. Background of the invention [0002] Hand-foot-mouth disease (Hand-Foot-Mouth disease, HFMD), also known as exanthematous vesicular stomatitis, is a common global infectious disease caused by enterovirus, and there are reports of the prevalence of this disease in most countries and regions of the world. The disease is mainly transmitted through the fecal-oral route and the respiratory tract, which is highly contagious and can easily lead to epidemics or outbreaks. Hand, foot and mouth disease mainly occurs in infants and young children,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/76C07K5/065A61K38/05A61K31/45A61P31/12A61P31/16A61P9/00
CPCY02A50/30
Inventor 尹正尚鲁庆赵向帅娄智勇王亚鑫徐梦莹王朋崔璨璨陈成赵强周红刚杨诚饶子和
Owner NANKAI UNIV
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