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N4-hydroxycytidine lipid prodrug as well as preparation method and application thereof

A pharmaceutical preparation and drug technology are applied in the field of N4-hydroxycytidine lipid prodrug and its preparation, which can solve the problems of poor oral bioavailability and unfavorable absorption, and achieve good application prospects and high anti-new coronavirus activity. , the effect of short preparation process

Pending Publication Date: 2022-06-03
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

EIDD-1931 contains more polar groups, which is not conducive to absorption and has poor oral bioavailability

Method used

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  • N4-hydroxycytidine lipid prodrug as well as preparation method and application thereof
  • N4-hydroxycytidine lipid prodrug as well as preparation method and application thereof
  • N4-hydroxycytidine lipid prodrug as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0040] The preparation method of the compounds Z1-Z4 is as follows: adding acid chloride to the organic reagent solution of the compound EIDD-1931, stirring overnight, and purifying to obtain the compounds Z1-Z4.

[0041] The above reaction process can be carried out at room temperature, and the purification includes the steps of concentration and chromatography.

[0042] Further, the compound EIDD-1931 was dissolved in pyridine.

[0043] Further, the molar ratio of compound EIDD-1931 to acid chloride is 1:1.0-3.0, and further, the molar ratio is 1:1.0-1.5.

[0044] A third aspect of the present invention provides a pharmaceutical composition comprising the compound of the first aspect. More specifically, it acts as an active ingredient. In addition, in addition to the compound described in the first aspect, it may also include other ingredients with antiviral effects, which will not be specifically limited here.

[0045] And, a pharmaceutical preparation, which comprises th...

Embodiment 1

[0059] Synthesis of the compound of Example 1

[0060] Prepared according to the following synthetic route

[0061]

[0062] (1) Synthesis of compound Z1

[0063]

[0064] EIDD-1931 (200 mg, 0.77 mmol) was dissolved in pyridine (4 mL), cooled in an ice-water bath, dodecyl chloroformate (0.23 mL, 0.85 mmol) was slowly added dropwise, and the mixture was stirred at room temperature overnight. The solution was evaporated to dryness under reduced pressure, and 300 mg of white solid was obtained by silica gel column chromatography (DCM:MeOH=20:1, 10:1), which was compound Z1, and the yield was 77%. 1 H NMR (400MHz, DMSO-d 6 )δ10.81(s, 1H), 7.44(d, J=8.2Hz, 1H), 5.95(d, J=8.2Hz, 1H), 5.75(d, J=5.9Hz, 1H), 5.32(d, J=4.5Hz, 1H), 5.10–5.00 (m, 2H), 4.12 (t, J=6.6Hz, 2H), 4.02–3.91 (m, 2H), 3.81 (q, J=3.2Hz, 2H), 3.62-3.49(m,2H),1.66-1.55(m,2H),1.37-1.17(m,22H),0.85(t,J=6.6Hz,3H).HRMS calcd for C 24 H 41 N 3 O 8 [M+H] + 500.2966, found 500.2970.

[0065] (2) Synthesis o...

Embodiment 2

[0074] Example 2 In vitro antiviral activity test and cytotoxicity of the compound against SARS-CoV-2

[0075] Vero cells (ATCC-CCL81) at 1 × 10 per well 4 The density of individual cells was seeded in 96-well plates in DMEM 10% FCS medium. After 24 hours of growth, the culture medium was removed, and cells were treated with different concentrations of compounds, using about 100 TCID 50 Mock infection or infection with SARS-CoV-2 per well (final volume 200 μL / well of DMEM 2% FCS). On the 5th day after infection, the viral CPE was recorded under the microscope, and the 50% effective concentration (EC) was calculated. 50 ). Meanwhile, the cytotoxic effects of compounds were assessed by assessing MCC (the minimum cytotoxic concentration that results in a microscopically detectable change in cell morphology). The effect of compounds on cell growth was determined by counting the number of cells in mock-infected cultures using a Coulter counter and expressed as the cytostatic ...

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Abstract

The invention belongs to the technical field of biological medicine and nucleoside compound preparation, and particularly relates to an N4-hydroxy cytidine lipid prodrug as well as a preparation method and application thereof. The N4-hydroxy cytidine lipid prodrug is selected from a compound shown in the following formula I, and n is an integer from 0 to 20; x is independently selected from CH2, O, S or NH; r is independently selected from hydrogen, deuterium, fluorine, chlorine, alkenyl, alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl, dichloromethyl, trichloromethyl, hydroxymethyl, alkoxy, azido, cyano, aryl or heterocyclic radical. Tests prove that the prepared compound, namely the N4-hydroxy cytidine lipid prodrug, has higher anti-new coronavirus activity, so that the N4-hydroxy cytidine lipid prodrug can be used for preparing anti-new coronavirus drugs. In addition, compared with the existing nucleotide drugs, the compound provided by the invention has the advantages that the preparation process is shorter, the yield is higher, and the compound is suitable for industrial large-scale production and has a good application prospect.

Description

technical field [0001] The invention belongs to the technical field of biomedicine and nucleoside compound preparation, in particular to an N4-hydroxycytidine lipid prodrug and a preparation method and application thereof. Background technique [0002] The information disclosed in this Background section is only for enhancement of understanding of the general background of the invention and should not necessarily be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art. [0003] The novel coronavirus pneumonia (COVID-19) (corona virus disease 2019) broke out on a large scale around the world, and the World Health Organization (WHO) declared the novel coronavirus pneumonia epidemic as a public health emergency of international concern (PHEIC). The global assessment of the risk of transmission and impact of the new coronavirus has been revised up to the highest level. However, the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/067C07H1/00A61K31/7068A61P31/12A61P31/14
CPCC07H19/067C07H1/00A61P31/12A61P31/14
Inventor 刘超文照慧刘兆鹏
Owner SHANDONG UNIV
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