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Nucleotide phosphoramidate compound and pharmaceutical composition thereof, preparation method of nucleotide phosphoramidate compound, and application of nucleotide phosphoramidate compound and pharmaceutical composition

A kind of phosphoramidate and compound technology, applied in the field of medicine

Inactive Publication Date: 2021-01-08
FOSHAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the new coronavirus (2019-nCoV) has such a strong transmissibility that measures such as restricting traffic cannot stop the spread of the disease. The possible long-term problems of the new coronavirus (2019-nCoV) cannot be ignored, so On the one hand, speeding up the marketing of new crown inactivated vaccines, and on the other hand, the development of therapeutic drugs with high efficiency and low toxicity to inhibit the infection of new coronavirus (2019-nCoV) is still an urgent clinical need

Method used

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  • Nucleotide phosphoramidate compound and pharmaceutical composition thereof, preparation method of nucleotide phosphoramidate compound, and application of nucleotide phosphoramidate compound and pharmaceutical composition
  • Nucleotide phosphoramidate compound and pharmaceutical composition thereof, preparation method of nucleotide phosphoramidate compound, and application of nucleotide phosphoramidate compound and pharmaceutical composition
  • Nucleotide phosphoramidate compound and pharmaceutical composition thereof, preparation method of nucleotide phosphoramidate compound, and application of nucleotide phosphoramidate compound and pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] (R)-N-[(pentafluorophenoxy)(isopropoxycarbonyloxymethoxy)phosphoryl]-L-phenylalanine isopropyl ester (FP2370-1) and (S)-N -Synthesis of [(pentafluorophenoxy)(isopropoxycarbonyloxymethoxy)phosphoryl]-L-phenylalanine isopropyl ester (FP2370-2).

[0051]

[0052]Add phosphorus oxychloride (5g, 3.04ml, 32.6mmol) to the reaction flask, add acetonitrile 200mL, cool to -70°C, slowly add K2 (7.16g, 32.6mmol) and triethylamine (3.3g, 4.53ml) , 32.6mmol) in acetonitrile (60mL) solution, after the dropwise addition was completed, it was slowly raised to room temperature, and reacted overnight. Cool the above mixed solution to 0°C, add HA370 (4.93g, 29.4mmol), cool to -70°C, add dropwise 60mL of acetonitrile solution of triethylamine (7.3g, 10ml, 72mmol), after the addition is complete, heat up to 0°C , reacted for 3 hours, added dropwise 60 mL of acetonitrile solution of pentafluorophenol (5.4 g, 29.4 mmol) and triethylamine (7.3 g, 10 ml, 72 mmol) into the above solution, sti...

Embodiment 2

[0060] (R)-N-[(pentafluorophenoxy)(isopropoxycarbonyloxymethoxy)phosphoryl]-L-phenylalanine ethyl ester (FP2371-1) and (S)-N- Synthesis of [(pentafluorophenoxy)(isopropoxycarbonyloxymethoxy)phosphoryl]-L-phenylalanine ethyl ester (FP2371-2).

[0061]

[0062] FP2371-1 and FP2371-2 were synthesized in a similar synthesis method as in Example 1.

[0063] H NMR data of FP2371-1: 1 H NMR (400MHz, CDCl 3 )δ (ppm): 1.26-1.40 (9H, m, 3×CH 3 ), 3.77-3.97 (4H, m, CH 2 , NH and NCH), 4.05-4.39 (2H, m, COOCH 2 ), 4.85-4.97 (1H, m, COOCH), 5.55-5.72 (2H, m, OCH 2 O), 7.06-7.38 (5H, m, hydrogen on the benzene ring).

[0064] 31 P NMR (162MHz, CDCl 3 ) δ-1.72.

[0065] H NMR data of FP2371-2: 1 H NMR (400MHz, CDCl 3 )δ (ppm): 1.28-1.42 (9H, m, 3×CH 3 ), 3.90-4.04 (4H, m, CH 2 , NH and NCH), 4.16-4.38 (2H, m, COOCH 2 ), 4.88-5.05 (1H, m, COOCH), 5.55-5.77 (2H, m, OCH 2 O), 7.07-7.36 (5H, m, hydrogen on the benzene ring).

[0066] 31 P NMR (162MHz, CDCl 3 ) δ-1.99.

[00...

Embodiment 3

[0069] (R)-N-[(pentafluorophenoxy)(isopropoxycarbonyloxymethoxy)phosphoryl]-L-phenylalanine isobutyl ester (FP2372-1) and (S)-N -Synthesis of [(pentafluorophenoxy)(isopropoxycarbonyloxymethoxy)phosphoryl]-L-phenylalanine isobutyl ester (FP2372-2).

[0070]

[0071] FP2372-1 and FP2372-2 were synthesized in a similar synthesis method as in Example 1.

[0072] The H NMR data of FP2372-1: 1 H NMR (400MHz, CDCl 3 )δ (ppm): 0.90-1.04 (6H, m, 2×CH 3 ), 1.27-1.37 (6H, m, 2×CH 3 ), 2.33-2.51 (1H, m, CH), 3.75-3.96 (4H, m, CH 2 , NH and NCH), 4.09-4.35 (2H, m, COOCH 2 ), 4.83-4.98 (1H, m, COOCH), 5.56-5.74 (2H, m, OCH 2 O), 7.04-7.35 (5H, m, hydrogen on the benzene ring).

[0073] 31 P NMR (162MHz, CDCl 3 ) δ-1.66.

[0074] H NMR data of FP2372-2: 1 H NMR (400MHz, CDCl 3 )δ (ppm): 0.92-1.06 (6H, m, 2×CH 3 ), 1.29-1.39 (6H, m, 2×CH 3 ), 2.37-2.58 (1H, m, CH), 3.88-3.99 (4H, m, CH 2 , NH and NCH), 4.12-4.33 (2H, m, COOCH 2 ), 4.87-5.03 (1H, m, COOCH), 5.55-5.76 (2H, m,...

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Abstract

The invention belongs to the technical field of medicines, discloses a nucleotide phosphoramidate compound and a pharmaceutical composition thereof, a preparation method of the nucleotide phosphoramidate compound, and application of the nucleotide phosphoramidate compound and the pharmaceutical composition, particularly application to treatment of the corona virus disease. Tests prove that the compound has the activity of inhibiting replication of 2019-nCoV viruses; and meanwhile, the nucleotide phosphoramidate compound has the advantages of being higher in in-vitro activity, larger in development coefficient and the like compared with an existing medicine, namely redexivir, for treating the corona virus diseases, and can be used for developing medicines for treating the corona virus disease.

Description

technical field [0001] The invention belongs to the field of medical technology, and relates to a nucleotide phosphoramidate compound, a pharmaceutical composition thereof, a preparation method and application thereof, and is suitable for treating coronavirus infections of the family Coronaviridae, especially for treating new coronary pneumonia. Background technique [0002] The impact of the coronavirus (2019-nCoV) pandemic on the world is enormous: Xinhua News Agency, Geneva, August 31 (Reporter Liu Qu) The latest data released by the World Health Organization on August 31 shows that the cumulative number of confirmed cases of new crowns worldwide has reached 25,118,689 cases, the number of deaths reached 844,312. [0003] In terms of systematic classification, coronaviruses belong to the order Nidovirales, the family Coronaviridae, and the genus Coronavirus. A total of 7 coronaviruses that can infect humans have been found, namely HCoV-229E, HCoV-OC43, SARS-CoV, HCoV-NL6...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/685A61K45/06A61P31/14
CPCC07F9/6561A61P31/14
Inventor 刘洪海
Owner FOSHAN UNIVERSITY