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Anti-enterovirus 71 (EV71) valerolactam compounds, preparation method and uses thereof

A valerolactam, EV71 technology, applied in antiviral agents, resistance to vector-borne diseases, organic chemistry, etc., can solve the problem that virus transcription and replication cannot continue normally.

Inactive Publication Date: 2012-12-26
NANKAI UNIV +1
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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) valerolactam compounds, preparation method and uses thereof
  • Anti-enterovirus 71 (EV71) valerolactam compounds, preparation method and uses thereof
  • Anti-enterovirus 71 (EV71) valerolactam compounds, preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Example 1 Preparation of N-Boc-L-(+)-dimethyl glutamate (1-2)

[0113]

[0114] 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 THF (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 produ...

Embodiment 2

[0115] Example 2 Preparation of 2-tert-butoxycarbonylamino-4-cyanomethyl-glutaric acid dimethyl ester (1-3)

[0116]

[0117] 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, bromoacetonitrile (3.4 mL) was slowly added dropwise, and the reaction mixture was stirred at -78° C. for 2 hours. After the reaction was complete, saturated ammonium chloride aqueous solution (50 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 colu...

Embodiment 3

[0118] Example 3 Preparation of 2-tert-butoxycarbonylamino-3-(2-carbonyl-3-pyrrolidine)-propionic acid methyl ester (1-4)

[0119]

[0120] To a solution of dimethyl 2-tert-butoxycarbonylamino-4-cyanomethyl-glutarate (1-4) (5 g, 15.9 mmol) in methanol (80 mL) was added cobalt chloride hydrate (2 g, 7.9 mmol ), and then added sodium borohydride (6 g, 59.5 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 solvent was evaporated under reduced pressure. Water (100 mL) was added and extracted from the aqueous phase with DCM (3 x 100 mL), the combined organic phases were dried over anhydrous sodium sulfate and then concentrated to give the crude product which was purified by flash chromatography (EA) to give 2-tert Butoxycarbonylamino-3-(2-carbonyl-3-pyrr...

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Abstract

The invention relates to valerolactam enterovirus 71 (EV71) 3C protease inhibitors, wherein a structure general formula of the inhibitors is represented by a compound M, various variables in the structure is defined in an instruction, and EV71 replication is effectively inhibited or blocked with the compounds. The present invention relates to discoveries and applications of the compounds containing the structure represented by the formula (M), optical isomers, metabolites with pharmaceutical activities, pharmaceutically acceptable salts, solvates, and prodrugs thereof in preparations of anti-virus drugs for treatment of hand-foot-mouth disease infection. The present invention further relates to an intermediate of the structure compound represented by the formula (M) and a synthesis method thereof.

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 valerolactam compounds, a pharmaceutical composition containing such compounds and a method for treating EV71 infection with such 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 childr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/26C07D403/12A61K31/4015A61K31/404A61P31/14
CPCY02A50/30
Inventor 尚鲁庆徐梦莹娄智勇王亚鑫赵强赵向帅杨诚尹正饶子和
Owner NANKAI UNIV
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