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Application of nucleoside compound to preparation of medicament for treating enterovirus 71 (EV71) infectious disease

A technology for infectious diseases and enteroviruses, applied in antiviral agents, drug combinations, respiratory diseases, etc., can solve problems such as death, lack of specific and effective therapeutic drugs, and treatment without favorable effects

Inactive Publication Date: 2014-09-03
NANKAI UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the specific mechanism of EV71 virus persistence and hand, foot and mouth disease has not been elucidated, and there is still a lack of specific and effective therapeutic drugs in clinical practice, and only traditional Chinese medicine or other antiviral drugs can be used for treatment. The treatment did not produce a beneficial effect, and clinical deaths continued

Method used

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  • Application of nucleoside compound to preparation of medicament for treating enterovirus 71 (EV71) infectious disease
  • Application of nucleoside compound to preparation of medicament for treating enterovirus 71 (EV71) infectious disease
  • Application of nucleoside compound to preparation of medicament for treating enterovirus 71 (EV71) infectious disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Example 1. Synthesis of (2R, 3S, 4R)-1-O-methyl-2-ketone-3-(2,4-dichlorobenzyloxy)-4-(2,4-dichlorobenzyloxymethyl base) tetrahydrofuran (1-5).

[0103]

[0104] Synthesize according to step I-4 of scheme I and obtain compound (2R, 3S, 4R)-1-O-methyl-2-ketone-3-(2,4-dichlorobenzyloxy)-4-(2,4 -Dichlorobenzyloxymethyl)tetrahydrofuran (1-5), white solid. ESI-MS m / z: 481.2 (M+H); 1 H-NMR (300MHz, MeOD) δ7.31(m, 6H), 4.95(1H, d, J=12.0Hz), 4.83(1H, s), 4.65(1H, d, J=12.0Hz), 4.57( 1H, d, J = 12.0Hz), 4.48 (1H, d, J = 12.0Hz), 4.30 (1H, m), 4.14 (1H, m), 3.80 (1H, dd, J = 12.0, 4.0Hz), 3.62 (1H, dd, J = 12.0, 4.0 Hz), 3.47 (3H, s).

Embodiment 2

[0106] Synthesis of (2R, 3R, 4R, 5R)-1-(4-chloro-pyrrolo[2,3-d]pyrimidine)-7-(2-ethynyl-2,3-dihydroxy-4-hydroxymethyl ) Tetrahydrofuran (IX)

[0107]

[0108] At 0°C, (2R,3R,4R)-1-O-methyl-2-ketone-3-(2,4-dichlorobenzyloxy)-4-(2,4-dichlorobenzyl Oxymethyl) tetrahydrofuran (1-5) (6.6 g, 13.7 mmol) was dissolved in dry THF (50 mL), which was then added dropwise to the Grignard reagent MgBr in THF (0.5M, 137.5mL) solution, keep constant temperature for 3h, add saturated NH 4Cl solution (50mL) was used to stop the reaction, extracted with ethyl acetate (60mL×3), the organic phase was washed with dilute hydrochloric acid (1.0M) and saturated brine, dried, and the solvent was evaporated, and the residue was separated by column chromatography The compound (2R, 3R, 4R)-1-O-methyl-2-ethynyl-2-hydroxyl-3-(2,4-dichlorobenzyloxy)-4-(2,4-dichlorobenzyloxy) was obtained Oxymethyl) tetrahydrofuran (1-6).

[0109] The compound (2R, 3R, 4R)-1-O-methyl-2-ethynyl-2-hydroxyl-3-(2,4-dichlo...

Embodiment 3

[0111] Example 3. Synthesis of (2R, 3R, 4R, 5R)-1-(4-amino-pyrrole[2,3-d]pyrimidine)-7-(2-ethynyl-2,3-dihydroxy-4 -Hydroxymethyl)tetrahydrofuran (VIII)

[0112]

[0113] The compound (2R, 3R, 4R, 5R)-1-(4-chloro-pyrrole[2,3-d]pyrimidine)-7-(2-ethynyl-2-hydroxyl-4-hydroxymethyl-2 , 3-dihydroxy)tetrahydrofuran (IX) (96mg, 0.31mmol) mixed with ammonia water (10mL), heated to reflux, reacted for 2h, TLC monitored the end of the reaction, rotary evaporated the solvent, and the residue was separated by column chromatography to obtain Compound (2R, 3R, 4R, 5R)-1-(4-amino-pyrrolo[2,3-d]pyrimidine)-7-(2-ethynyl-2-hydroxyl-4-hydroxymethyl-2, 3-Dihydroxy)tetrahydrofuran (VIII) (75 mg, 80% yield), pale yellow solid. ESI-MS m / z: 291.2 (M+H); 1 H-NMR (300MHz, MeOD) δ8.07(1H, s), 7.48(1H, d, J=3.9), 6.58(1H, d, J=3.6), 6.29(1H, s), 4.49(1H, d, J=8.4), 4.08-3.96 (2H, m), 3.90-3.75 (1H, m), 2.52 (1H, s). 13 C NMR (75 MHz, DMSO-d6): δ 157.4, 151.6, 150.1, 121.6, 102.4, 99.6, 89.6, 82.1,...

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Abstract

The invention relates to an application of a nucleoside compound (I) to preparation of a medicament for treating an enterovirus 71 (EV71) infectious disease, and further relates to applications of various optical isomers, pharmaceutically-acceptable salts, solvates and prodrugs thereof to preparation of medicaments for treating the enterovirus 71 (EV71) infectious disease. The invention further relates to a medicinal composition containing the nucleoside compound shown as a formula (I) and an application thereof to preparation of a medicament for treating the enterovirus 71 (EV71) infectious disease.

Description

technical field [0001] The invention relates to a compound and a pharmaceutical composition for treating enterovirus 71 (EV71) infection, as well as a synthesis method and a preparation method of the compound. Specifically, the present invention provides a class of nucleoside compounds, a pharmaceutical composition containing such compounds and a method for treating EV71 infection with such compounds. Background of the invention [0002] Hand-foot-mouth disease (Hand-Foot-Mouth disease, HFMD), also known as exanthematous vesicular stomatitis, is a common global infectious disease caused by enterovirus, and there are reports of the prevalence of this disease in most countries and regions of the world. The disease is mainly transmitted through the fecal-oral route and the respiratory tract, which is highly contagious and can easily lead to epidemics or outbreaks. Hand, foot and mouth disease mainly occurs in infants and young children, and most patients have mild symptoms, ma...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/7076A61K31/7068A61K31/7064A61P31/14A61P25/00A61P9/00A61P11/00
Inventor 尚鲁庆娄智勇王亚鑫杨诚尹正饶子和
Owner NANKAI UNIV