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Anti-enteroviral 71(EV71) 4-iminooxazolidine-2-ketone compound as well as preparation method and application of anti-enteroviral 71(EV71) 4-iminooxazolidine-2-ketone compound

A technology of iminooxazolidine and EV71, which is applied in the fields of antiviral agents, resistance to vector-borne diseases, organic chemistry, etc., and can solve problems such as the inability to continue normal transcription and replication of viruses

Active Publication Date: 2017-12-12
NANKAI UNIV
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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-enteroviral 71(EV71) 4-iminooxazolidine-2-ketone compound as well as preparation method and application of anti-enteroviral 71(EV71) 4-iminooxazolidine-2-ketone compound
  • Anti-enteroviral 71(EV71) 4-iminooxazolidine-2-ketone compound as well as preparation method and application of anti-enteroviral 71(EV71) 4-iminooxazolidine-2-ketone compound
  • Anti-enteroviral 71(EV71) 4-iminooxazolidine-2-ketone compound as well as preparation method and application of anti-enteroviral 71(EV71) 4-iminooxazolidine-2-ketone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1 Preparation of N-Boc-L-(+)-dimethyl glutamate (1-2)

[0084]

[0085] 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

[0086] Example 2 Preparation of 2-tert-butoxycarbonylamino-4-cyanoethyl-glutaric acid dimethyl ester (1-3)

[0087]

[0088] 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

[0089] Example 3 Preparation of 2-tert-butoxycarbonylamino-3-(2-carbonyl-3-piperidinane)-propionic acid methyl ester (1-4)

[0090]

[0091] To a solution of dimethyl 2-tert-butoxycarbonylamino-4-cyanoethyl-glutaric acid (1-4) (5 g, 15.9 mmol) in methanol (80 mL) was added cobalt chloride hydrate (4 g, 14.6 mmol ), 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-piperidinan...

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PUM

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Abstract

The invention discloses a 4-iminooxazolidine-2-ketone enterovirus 71(EV71) 3C protease inhibitor of which the structural general formula is shown as a compound (M), each variable in the structure is defined as the specification, and the compounds are used for effectively inhibiting or stopping the replication of enterovirus 71. The invention relates to discovery and application of a compound with a structure shown as the formula (M) as well as various optical isomers of the compound, a pharmaceutically active metabolite, a medicinal salt, a solvate and a prodrug of the compound in preparation of antiviral drugs for treating hand-foot-mouth virus infection diseases and also relates to an intermediate for preparing the compound with the structure shown as the formula (M) and a synthesis method.

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 4-iminooxazolidin-2-one compounds, pharmaceutical compositions containing such compounds and methods for treating EV71 infection with such compounds. Background of the invention [0002] Hand-foot-mouth disease (Hand-Foot-Mouth disease, HFMD) is a common global infectious disease caused by enterovirus, and it has been reported in most regions and countries in the world. Hand, foot and mouth disease is mainly transmitted through the fecal-oral route and the respiratory tract. It is highly contagious and can easily lead to epidemics or outbreaks. The disease mainly occurs in infants and young children under the age of 6, and most patients have mild symptoms, with fever and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14A61K31/454A61P31/14
CPCC07D413/14Y02A50/30
Inventor 尚鲁庆马玉莹罗程翟洋洋王亚鑫尹正
Owner NANKAI UNIV
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