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Oseltamivir derivative as well as preparation method and application thereof

A technology of oseltamivir and derivatives, which is applied in the field of disease drugs, oseltamivir derivatives and their preparation, can solve the problems of decreased effectiveness of NA inhibitors, limited clinical application and the like, and achieves highly selective effects

Inactive Publication Date: 2014-07-16
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In recent years, influenza viruses resistant to oseltamivir and zanamivir have emerged continuously, such as H5N1, H1N1, H3N2 and other virus strains. The mutation of important amino acids in the NA active site reduces the effectiveness of NA inhibitors. Clinical application is also limited to some extent

Method used

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  • Oseltamivir derivative as well as preparation method and application thereof
  • Oseltamivir derivative as well as preparation method and application thereof
  • Oseltamivir derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] (3R,4R,5S)-4-Acetamido-5-(([1,1'-biphenyl]-4-ylmethyl)amino)-3-(1-ethylpropoxy)-1 -Ethyl cyclohexene-1-carboxylate (II-10)

[0075] Add oseltamivir phosphate (0.82g, 2.0mmol) and 25.0mL absolute ethanol into a 50mL round bottom flask, add p-phenylbenzaldehyde (0.4g, 2.2mmol) under stirring conditions, stir at room temperature for 5 minutes, add Sodium cyanoborohydride (0.25g, 4.0mmol), react at room temperature. After four hours, filter through celite. Silica gel column chromatography gave 0.64 g of a white solid, with a yield of 67%. 1 H NMR (CDCl 3 ,300MHz)δ7.53-7.60(m,4H),7.30-7.46(m,5H),6.80(s,1H),5.50(d,1H,J=7.2Hz),4.18-4.26(m,3H) ,3.93-3.98(m,1H),3.72-3.82(m,2H),3.33-3.41(m,1H),3.15-3.24(m,1H),2.80(dd,1H,J=17.7,5.1Hz) ,2.22-2.35(m,1H),2.01(s,3H),1.46-1.56(m,4H),1.30(t,3H,J=7.2Hz),0.90(t,6H,J=7.5Hz). 13 C NMR (CDCl 3 ,75MHz)δ170.65,166.52,140.92,139.95,139.29,137.19,129.38,128.75,128.57,127.35,127.17,127.03,81.77,74.53,60.88,55.81,53.60,50.25,30.41,26.15,25....

Embodiment 2

[0080](3R,4R,5S)-4-Acetamido-5-((2-thienylmethyl)amino)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid tris Fluoroacetate (A1)

[0081] The experimental operation is the same as in Example 1, the product II-1 obtained by the reaction of oseltamivir phosphate (0.82g, 2.0mmol), thiophene 2-carbaldehyde (0.25g, 2.2mmol) and sodium cyanoborohydride (0.25g, 4.0mmol) , a white solid was obtained after Boc protection, hydrolysis and de-Boc, the total yield was 27%, mp=86~88℃. 1 H NMR (DMSO-d 6 ,300MHz)δ7.80(d,1H,J=9.0Hz),7.37(dd,1H,J=4.5,1.8Hz),6.93-6.97(m,2H),6.59(s,1H),3.94-4.01 (m,2H),3.85-3.91(m,1H),3.66-3.76(m,1H),3.31-3.38(m,1H),2.71-2.80(m,1H),2.64(dd,1H,J= 17.4,4.8Hz),2.01-2.11(m,1H),1.91(s,3H),1.85(s,3H),1.33-1.49(m,4H),0.83(t,3H,J=7.5Hz), 0.79(t,3H,J=7.5Hz). 13 C NMR (DMSO-d 6 ,75MHz)δ177.22,174.83,172.84,150.35,142.52,134.61,131.77,129.74,129.56,86.06,80.58,59.59,59.17,49.78,35.63,30.85,30.39,28.23,26.27,14.65,14.17.HRMS calculated for calcd for C 19 h 29 N 2...

Embodiment 3

[0083] (3R,4R,5S)-4-Acetamido-5-(benzylamino)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid trifluoroacetate (A2 )

[0084] The experimental operation was the same as in Example 1, the product II-2 obtained by the reaction of oseltamivir phosphate (0.82g, 2.0mmol), benzaldehyde (0.23g, 2.2mmol) and sodium cyanoborohydride (0.25g, 4.0mmol) was tested by Boc protection, hydrolysis and de-Boc yielded a white solid with a total yield of 52%, mp=80-82°C. 1 H NMR (CD 3 OD,300MHz)δ7.45-7.51(m,5H),6.90(s,1H),4.40-4.45(m,2H),4.18-4.30(m,3H),3.57-3.67(m,1H),3.42 -3.50(m,1H),3.05(dd,1H,J=17.4Hz,5.7Hz),2.62-2.73(m,1H),2.06(s,3H),1.49-1.60(m,4H),0.93( t,3H,J=7.2Hz),0.91(t,3H,J=7.2Hz). 13 C NMR (CD 3 OD,75MHz)δ173.02,166.58,136.78,130.25,129.01,128.85,128.48,126.69,81.86,74.00,54.32,50.94,25.25,25.21,24.71,21.41,7.88,7.63. 21 h 31 N 2 o 4 [M+H] + :375.2284,found:m / z375.2280.

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Abstract

The invention relates to an oseltamivir derivative as well as a preparation method and application thereof. The compound has the structure shown in a formula I. The invention provides an efficient influenza virus neuraminidase inhibitor with high selectivity, which is used for preparing drugs for preventing or curing flu, particularly the diseases caused by N1 influenza virus. The invention also relates to a drug composition comprising the compound shown in the formula I.

Description

technical field [0001] The invention relates to oseltamivir derivatives and a preparation method and application thereof, especially for preparing medicines for preventing or treating diseases caused by N1 influenza virus, and belongs to the field of chemical technology. Background technique [0002] Influenza (abbreviated as influenza) is an acute respiratory infection caused by influenza virus, and is a highly contagious and fast-spreading disease. According to the different epitopes of viral nucleoprotein and matrix protein, influenza virus can be divided into three subtypes, A (A), B (B), and C (C). It is easy to mutate, and it is the most harmful to human beings. This type of influenza virus can be divided into multiple types according to the antigenicity of the two proteins on the surface of the virus - neuraminidase (Neuraminidase, NA, N1-N9) and hemagglutinin (Hemagglutinin, HA, H1-H16). subtype. According to statistics, 250,000 to 500,000 people die from influenz...

Claims

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Application Information

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IPC IPC(8): C07D333/20C07C233/52C07C231/12C07D307/42A61K31/381A61K31/196A61K31/341A61K31/215A61P31/16
CPCC07C231/12C07C233/52C07D307/42C07D333/20
Inventor 徐文方谢元超张颖杰
Owner SHANDONG UNIV
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