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Anti-enterovirus 71 (EV 71) caprolactam aldehyde compound and preparation method and purpose thereof

A technology of caprolactam aldehyde 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: 2013-06-05
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 (EV 71) caprolactam aldehyde compound and preparation method and purpose thereof
  • Anti-enterovirus 71 (EV 71) caprolactam aldehyde compound and preparation method and purpose thereof
  • Anti-enterovirus 71 (EV 71) caprolactam aldehyde compound and preparation method and purpose thereof

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[0096] The present invention is illustrated in more detail by the following non-limiting examples, but the present invention is not limited to the following examples. Temperatures are provided in degrees Celsius in the following examples. Unless otherwise stated, solution percentages express a weight-to-volume relationship, and solution ratios express a volume-to-volume relationship. The structures of the compounds in the examples were determined by one or more of the following methods: nuclear magnetic resonance spectrometer, high-resolution mass spectrometry, and thin-layer chromatography. If the given structural formula representing the compound does not match its chemical name, the structural formula shall prevail.

[0097] NMR spectrum ( 1 H NMR and 13 C NMR) was measured with a Bruker 400 spectrometer at a field strength of 400 MHz. Chemical shifts are expressed in parts per million (ppm, δ) relative to the internal standard tetramethylsilane. 1 The multiplicity of ...

Embodiment 1

[0100] Example 1 Preparation of N-Boc-L-(+)-dimethyl glutamate (1-2)

[0101]

[0102] 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

[0103] Example 2 Preparation of 2-tert-butoxycarbonylamino-4-cyanoethyl-glutaric acid dimethyl ester (1-3)

[0104]

[0105] At -78°C, lithium bis(trimethylsilyl)amide (78.5mL 1.0)M THF solution, 78.5mmol) was slowly added dropwise to N-Boc-L-(+)-glutamic acid Dimethyl 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 o...

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Abstract

A structure general formula of a caprolactam aldehyde enterovirus 71 (EV 71) 3C protease inhibitor is as shown in chemical combination A, all variables in the structure are defined in an instruction book, and the compound effectively restrains or blocks the copy of the enterovirus 71. The invention relates to a compound with the structure as shown in formula (A), various types of optical isomers of the compound with the structure as shown in formula (A), drug active metabolites, officinal salt, solvate and discovery and application when the compound with the structure as shown in formula (A), the various kinds of optical isomers of the compound with the structure as shown in formula (A), the drug active metabolites and the officinal salt are used for preparing antiviral drugs for curing hand-foot-mouth virus infection diseases. The invention further relates to an intermediate and a synthetic method of preparing the compound with the structure as shown in formula (A).

Description

technical field [0001] The present invention relates to compounds of formula (A) for treating enterovirus 71 (EV71) infection, pharmaceutical compositions, synthesis methods, preparation methods of such compounds and compounds used in these synthesis. Specifically, the present invention provides a class of caprolactam aldehyde 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 discasc, HFMD), also known as exanthematous vesicular stomatitis, is a common infectious disease caused by enterovirus, and has been reported 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. Most patients have mild sympt...

Claims

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Application Information

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IPC IPC(8): C07D211/76C07D401/12A61K31/45A61K31/454A61P31/12A61P31/16A61P9/00
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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