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Uridine mixed phosphoramidate compound, pharmaceutical composition and application thereof

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

Active Publication Date: 2022-04-26
FOSHAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 mixed phosphoramidate compound, pharmaceutical composition and application thereof
  • Uridine mixed phosphoramidate compound, pharmaceutical composition and application thereof
  • Uridine mixed phosphoramidate compound, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] (R)-N-[(pentafluorophenoxy)(((S)-1-(n-butoxycarbonyl)-2-phenylethyl)amino)phosphoryl]-D-phenylalanine Amyl ester (FP374S373R-1) and (S)-N-[(pentafluorophenoxy)(((S)-1-(n-butoxycarbonyl)-2-phenylethyl)amino)phosphoryl] - Synthesis of D-Phenylalanine Neopentyl Ester (FP374S373R-2).

[0042]

[0043] Add phosphorus oxychloride (5g, 3.04ml, 32.6mmol) into the reaction flask, add acetonitrile 200mL, cool to -70°C, slowly add D-phenylalanine neopentyl hydrochloride (D-HA373) dropwise ( 8.86g, 32.6mmol) and triethylamine (3.3g, 4.53ml, 32.6mmol) in acetonitrile (60mL) solution, the dropwise addition was completed, slowly warmed to room temperature, and reacted overnight. The above mixed solution was cooled to 0°C, L-phenylalanine n-butyl ester hydrochloride (L-HA374) (7.57g, 29.4mmol) was added, cooled to -70°C, triethylamine (7.3g, 10ml, 72mmol) of acetonitrile solution 60mL, after the addition, the temperature was raised to 0°C, and the reaction was carried out for 3 ho...

Embodiment 2

[0051] (R)-N-[(pentafluorophenoxy)(((R)-1-(neopentyloxycarbonyl)-2-phenylethyl)amino)phosphoryl]-D-phenylalanine tert Butyl ester (FP373R378R-1) and (S)-N-[(pentafluorophenoxy)(((R)-1-(neopentyloxycarbonyl)-2-phenylethyl)amino)phosphoryl] -Synthesis of tert-butyl D-phenylalanine (FP373R378R-2).

[0052]

[0053] FP373R378R-1 and FP373R378R-2 were synthesized by a method similar to Example 1.

[0054] H NMR spectrum data of FP373R378R-1: 1 H NMR (400MHz, CDCl 3 )δ (ppm): 0.80-1.21 (18H, m, 6×CH 3 ), 3.70-3.97 (8H, m, 2×CH 2 , 2×NH and 2×NCH), 4.04-4.35 (2H, m, COOCH 2 ), 7.02-7.37 (10H, m, hydrogen on two benzene rings).

[0055] 31 P NMR (162MHz, CDCl 3 )δ-2.03;

[0056] LCMS-ESI + (m / z): 685.6 (M+H).

[0057] H NMR data of FP373R378R-2: 1 H NMR (400MHz, CDCl 3 )δ (ppm): 0.82-1.24 (18H, m, 6×CH 3 ), 3.72-3.98 (8H, m, 2×CH 2 , 2×NH and 2×NCH), 4.06-4.37 (2H, m, COOCH 2 ), 7.04-7.39 (10H, m, hydrogen on two benzene rings).

[0058] 31 P NMR (162MHz, CDCl 3 ...

Embodiment 3

[0061] (R)-N-[(pentafluorophenoxy)(((S)-1-(n-butyloxycarbonyl)ethyl)amino)phosphoryl]-L-phenylalanine n-butyl ester ( FP34S374S-1) and (S)-N-[(pentafluorophenoxy)(((S)-1-(n-butyloxycarbonyl)ethyl)amino)phosphoryl]-L-phenylalanine Synthesis of n-butyl ester (FP34S374S-2).

[0062]

[0063] FP34S374S-1 and

[0064] FP34S374S-2.

[0065] FP34S374S-1 1 H NMR (400MHz, CDCl 3 )δ (ppm): 0.82-1.14 (6H, m, 2×CH 3 ), 1.19-1.42 (7H, m, CH 3 , 2 x CH 2 ), 1.53-1.70 (4H, m, 2×CH 2 ), 3.90-4.08 (6H, m, CH 2 , 2×NH and 2×NCH), 4.19-4.39 (4H, m, 2×COOCH 2 ), 7.01-7.37 (5H, m, hydrogen on the benzene ring).

[0066] 31 P NMR (162MHz, CDCl 3 )δ-1.83;

[0067] LCMS-ESI + (m / z): 595.5 (M+H).

[0068] FP34S374S-2 1 H NMR (400MHz, CDCl 3 )δ (ppm): 0.85-1.16 (6H, m, 2×CH 3 ), 1.19-1.44 (7H, m, CH 3 , 2 x CH 2 ), 1.54-1.72 (4H, m, 2×CH 2 ), 3.94-4.11 (6H, m, CH 2 , 2×NH and 2×NCH), 4.21-4.40 (4H, m, 2×COOCH 2 ), 7.05-7.39 (5H, m, hydrogen on the benzene ring).

[0069] 31 ...

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Abstract

The invention belongs to the technical field of medicine, and discloses a uridine acid mixed phosphoramidate compound, a pharmaceutical composition and application thereof, especially the application for treating hepatitis C. Tests have proved that the uridylic acid mixed phosphoramidate compound of the present invention has the activity of inhibiting the replication of HCV virus, and the uridylic acid mixed phosphoramidate compound has a higher in vitro activity than the current hepatitis C drug Sofosbuvir, and a development coefficient It has great advantages and can be used in the development of drugs for treating hepatitis C.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a uridylic acid mixed phosphoramidate compound, a pharmaceutical composition thereof and an application thereof, and is suitable for treating Flaviviridae virus infection, especially hepatitis C. Background technique [0002] Because the HCV genome is similar to human flaviviruses and pestiviruses in structure and phenotypic characteristics, it is classified as Flaviviridae HCV. The viruses of the Flaviviridae family include at least three distinct genera: pestiviruses, which cause disease in cattle and pigs; and flaviviruses, which are the primary cause of diseases such as dengue fever and yellow fever and the genus hepaciviruses, the only member of which is HCV. The Flavivirus genus includes more than 68 members, grouped based on serological relatedness. Clinical symptoms vary and include fever, encephalitis, and hemorrhagic fever. Flaviviruses of global concern for associati...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/10C07H1/00A61K31/7072A61P31/14
CPCC07H19/10C07H1/00A61P31/14
Inventor 刘洪海
Owner FOSHAN UNIVERSITY