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Fatty acid prodrug of nucleoside-like broad-spectrum antiviral drug as well as preparation method and application of fatty acid prodrug

A long-chain fatty acid, prodrug technology, applied in antiviral agents, preparation of sugar derivatives, chemical instruments and methods, etc., can solve problems such as poor oral bioavailability, improve metabolic stability, and improve biofilm permeability The effect of stability and broad application prospects

Active Publication Date: 2022-07-29
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In in vitro models, NHC can effectively inhibit the replication of MERS-CoV, SARS-CoV and SARS-CoV-2 (including remdesivir-resistant strains), and also has significant inhibitory effects on Venezuelan equine encephalitis virus and murine hepatitis virus , no apparent cytotoxicity, poor oral bioavailability in cynomolgus monkeys

Method used

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  • Fatty acid prodrug of nucleoside-like broad-spectrum antiviral drug as well as preparation method and application of fatty acid prodrug
  • Fatty acid prodrug of nucleoside-like broad-spectrum antiviral drug as well as preparation method and application of fatty acid prodrug
  • Fatty acid prodrug of nucleoside-like broad-spectrum antiviral drug as well as preparation method and application of fatty acid prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Preparation of Lauroyl Prodrug (Compound 19)

[0045]

[0046] In a 100ml reaction flask, N4-hydroxycytidine isopropyl ester (2.64g, 8mmol) was added, dichloromethane (30ml), triethylamine (3.36ml, 24mmol) were added, and lauroyl chloride was added at low temperature (0-10°C). (1.67ml, 7.2mmol) was slowly added dropwise to the reaction system, and then the reaction was naturally heated for 2-24h. After the reaction was completed, water was added to quench, and the organic phase was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by column chromatography (DCM:MeOH(v / v)=50:1) to obtain solid product. Yield 57%.

[0047] 1 H NMR (600MHz, chloroform-d) δ9.02(s, 1H), 7.08(d, J=8.3Hz, 1H), 5.87– 5.70 (m, 2H), 4.36–4.17 (m, 5H), 2.58 ( p, J=7.0Hz, 1H), 2.48 (t, J=7.6Hz, 2H), 1.69 (q, J=7.5Hz, 2H), 1.24-1.29 (m, 16H), 1.18 (d, J=7.0 Hz,6H),0.88(t, J=7....

Embodiment 2

[0050] Example 2: Preparation of Myristoyl Prodrug (Compound 20)

[0051]

[0052] Compound 20 was prepared as in Example 1 except that lauroyl chloride was replaced with myristoyl chloride. Finally a solid product is obtained. Yield 52%. 1 H NMR (600MHz, chloroform-d) δ9.02(s, 1H), 7.08(d, J=8.3Hz, 1H), 5.87-5.70(m, 2H), 4.36-4.17(m, 5H), 2.58( p, J=7.0Hz, 1H), 2.48 (t, J=7.6Hz, 2H), 1.69 (q, J=7.5Hz, 2H), 1.24-1.29 (m, 20H), 1.18 (d, J=7.0 Hz,6H),0.88(t,J=7.0Hz,3H).MS(ESI):m / z=540.30(M+H) + . 1 H NMR spectrum as Figure 9 shown.

Embodiment 3

[0053] Example 3: Preparation of Palmitoyl Prodrug (Compound 21)

[0054]

[0055] Compound 21 was prepared in the same manner as in Example 1, except that lauroyl chloride was replaced by palmitoyl chloride. Finally a solid product is obtained. Yield 55%.

[0056] 1 H NMR (600MHz, chloroform-d) δ9.02 (s, 1H), 7.08 (d, J=8.3 Hz, 1H), 5.87–5.70 (m, 2H), 4.36–4.17 (m, 5H), 2.58 ( p, J=7.0Hz, 1H), 2.48 (t, J=7.6Hz, 2H), 1.69 (q, J=7.5Hz, 2H), 1.24-1.29 (m, 24H), 1.18 (d, J=7.0 Hz,6H),0.88(t,J=7.0Hz,3H).MS(ESI):m / z=568.34(M+H) + . 1 H NMR spectrum as Figure 10 shown.

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Abstract

The invention discloses a long-chain fatty acid prodrug of N4-hydroxy isopropyl cytidine. The prodrug is freely selected from one of a lauroyl prodrug, a myristoyl prodrug and a palmitoyl prodrug represented by the following structural formula. According to the three prodrugs disclosed by the invention, long-chain alkyl is introduced to hydroxylamine in N4-hydroxy isopropyl cytidine molecules, so that the biological membrane permeability is greatly improved. Moreover, the invention finds that the too long carbon chain easily causes cytotoxicity, and the too short carbon chain cannot achieve the effect of improving the biological homopermeable membrane. In addition, the N4-hydroxycytidine isopropyl ester hydroxylamine structure is easy to oxidize and inactivate in vivo, and the design of a hydroxylamine ester prodrug is beneficial to improving the metabolic stability. Therefore, the compound disclosed by the invention is better in antiviral effect and has a wide application prospect.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular, relates to a fatty acid prodrug of a nucleoside-like broad-spectrum antiviral drug N4-hydroxycytidine isopropyl ester. Background technique [0002] Monabiravir (Molnupiravir), generic N4-hydroxycytidine isopropyl ester (EIDD-2801), chemical name is 1((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxyl Methyl)tetrahydrofuran-2-yl)-4-(hydroxyamino)-pyrimidin-2(1H)one, CAS No: 2349386-89-4, is the isopropyl nucleoside analog N4-hydroxycytidine (NHC) Ester prodrugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome virus (SARS-CoV) and influenza A viruses etc. have broad-spectrum antiviral activity. In in vitro models, NHC can effectively inhibit the replication of MERS-CoV, SARS-CoV and SARS-CoV-2 (including remdesivir-resistant strains), and also has significant inhibitory effects on Venez...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/067C07H1/00A61P31/12A61P31/16
CPCC07H19/067C07H1/00A61P31/12A61P31/16Y02P20/55
Inventor 何新华周涛李爱玲邹晓翠李展张学敏
Owner ACADEMY OF MILITARY MEDICAL SCI
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