Uridine bisphenylpropionate-based phosphoramidate compound, its pharmaceutical composition, its preparation method and application

A technology based on phosphoramidate and bisphenylpropionate, applied in the field of medicine, can solve the problems of large dosage, low bioavailability, and long-term safety of virus drug resistance, and achieve the effect of inhibiting infection

Active Publication Date: 2022-03-25
FOSHAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] However, due to the low bioavailability of sofosbuvir in the body, a larger dosage is required, and hepatitis C patients need to receive long-term treatment, and the resulting viral drug resistance and long-term safety issues cannot be ignored. Therefore, the development of new bioavailable Drugs for the treatment of HCV infection with high toxicity, longer half-life and high efficacy are still an urgent clinical need

Method used

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  • Uridine bisphenylpropionate-based phosphoramidate compound, its pharmaceutical composition, its preparation method and application
  • Uridine bisphenylpropionate-based phosphoramidate compound, its pharmaceutical composition, its preparation method and application
  • Uridine bisphenylpropionate-based phosphoramidate compound, its pharmaceutical composition, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] N-[(Pentafluorophenoxy)(((S)-1-(isopropoxycarbonyl)-2-phenylethyl)amino)phosphoryl]-L-phenylalanine isopropyl ester (FP370370 )Synthesis.

[0040]

[0041] Phosphorus oxychloride (5g, 3.04ml, 32.6mmol) was added to the reaction flask, 200mL of acetonitrile was added, cooled to -70°C, HA370 (14.331g, 58.8mmol) was slowly added, cooled to -70°C, and triethyl was added dropwise. 60 mL of acetonitrile solution of amine (7.3g, 10ml, 72mmol) was added, warmed to 0°C, and reacted for 3 hours. A solution of pentafluorophenol (5.4g, 29.4mmol) and triethylamine (7.3g, 10ml, 72mmol) in acetonitrile 60 mL of the solution was added dropwise to the above solution, stirred at 0°C for 1 hour, raised to room temperature, and stirred overnight, then 100 mL of dichloromethane and 100 mL of water were added, the organic phase was separated, dried with anhydrous sodium sulfate, and then reduced in pressure. Concentrated and the residue was separated on a silica gel column (0-30% ethyl a...

Embodiment 2

[0044] N-[(Pentafluorophenoxy)(((S)-1-(ethoxycarbonyl)-2-phenylethyl)amino)phosphoryl]-L-phenylalanine ethyl ester (FP371371) synthesis.

[0045]

[0046] FP371371 was synthesized by a similar synthesis method in Example 1.

[0047] H NMR data of FP371371: 1H NMR (400MHz, CDCl 3 )δ(ppm): 1.17-1.36(6H, m, 2×CH 3 ), 3.75-3.94 (8H, m, 2×CH 2 , 2×NH and 2×NCH), 4.12-4.40(4H, m, 2×COOCH 2 ), 7.05-7.38 (10H, m, hydrogen on two benzene rings).

[0048] LCMS-ESI + (m / z): 615.5 (M+H).

Embodiment 3

[0050] N-[(Pentafluorophenoxy)(((S)-1-(isobutoxycarbonyl)-2-phenylethyl)amino)phosphoryl]-L-phenylalanine isobutyl ester (FP372372 )Synthesis.

[0051]

[0052] FP372372 was synthesized by the similar synthesis method of Example 1.

[0053] H NMR data of FP372372: 1 H NMR (400MHz, CDCl 3 )δ(ppm): 0.86-1.15 (12H, m, 4×CH 3 ), 2.34-2.50 (2H, m, 2×CH), 3.76-3.95 (8H, m, 2×CH) 2 , 2×NH and 2×NCH), 4.04-4.39 (4H, m, 2×COOCH) 2 ), 7.07-7.38 (10H, m, hydrogen on two benzene rings). LCMS-ESI + (m / z): 671.6 (M+H).

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Abstract

The invention belongs to the technical field of medicine, and discloses a uridine bisphenylpropionate phosphoramidate compound, a pharmaceutical composition thereof, a preparation method and an application thereof, especially an application for treating hepatitis C. The test proves that the uridine diphenylpropionate-based phosphoramidate compound of the present invention has the activity of inhibiting the replication of HCV virus. Sofosbuvir has the advantages of high in vitro activity and large development coefficient, and can be used for the development of drugs for the treatment of hepatitis C.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to a uridylic acid bisphenylpropionate phosphoramidate compound, a pharmaceutical composition thereof, a preparation method and application thereof, and is suitable for treating Flaviviridae virus infection, especially for treating hepatitis C. Background technique [0002] The pathogenesis of hepatitis C is still not very clear. When HCV replicates in hepatocytes, it causes changes in the structure and function of hepatocytes or interferes with hepatocyte protein synthesis, which can cause degeneration and necrosis of hepatocytes, indicating that HCV directly damages the liver and plays a role in the pathogenesis. [0003] Since the HCV genome is similar in structure and phenotypic characteristics to human flaviviruses and pestiviruses, it is classified as HCV of the Flaviviridae family. Viruses in the Flaviviridae family include at least three different genera: pestiviruses, which c...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/00A61P31/14A61K31/7072
CPCC07H19/10C07H1/00A61P31/14
Inventor 刘洪海
Owner FOSHAN UNIVERSITY
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