Hepatitis C virus inhibitor and its application

A compound, selected technology, applied in the field of medicinal chemistry, can solve the problems of weight loss, fatigue and weakness

Active Publication Date: 2020-11-20
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, only 50% of patients respond to this approach, and interferon has significant side effects, such as influenza-like symptoms, weight loss, and fatigue, while the combination of interferon and ribavirin produces considerable Side effects, including hemolysis, anemia, and fatigue

Method used

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  • Hepatitis C virus inhibitor and its application
  • Hepatitis C virus inhibitor and its application
  • Hepatitis C virus inhibitor and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0168] Example 1 (2S)-2-(((4-(pyridin-2-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3 ,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionate isopropyl

[0169]

[0170] The preparation of step 1 4-(pyridin-2-yl)phenol

[0171] Weigh 1.38g 4-hydroxyphenylboronic acid (10mmol), 1.58g 2-bromopyridine (10mmol), 0.4g [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf )Cl 2 , 0.5mmol) and 9g cesium carbonate (30mmol) in a 250mL eggplant-shaped bottle, add 50mL 1,4-dioxane and 5mL water, react at 90°C for 1.5h under the protection of argon, after the reaction, add 100mL acetic acid Extract with ethyl ester and 50 mL saturated aqueous sodium chloride solution, collect the organic phase, wash with saturated aqueous sodium chloride solution (3×50 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography to obtain the title compound.

[0172] LC-MS...

Embodiment 2

[0179] Example 2 (2S)-2-(((4-(3-fluoropyridin-2-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo Isopropyl (3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionate

[0180]

[0181] Step 1 Preparation of 4-(3-fluoropyridin-2-yl)phenol

[0182] Using 4-hydroxyphenylboronic acid and 2-bromo-3-fluoropyridine as raw materials, the title compound was obtained by the same method as in Step 1 of Example 1.

[0183] LC-MS m / z:[M+H] + =190.

[0184] Step 2 (2S)-2-(((4-(3-fluoropyridin-2-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo -3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl preparation

[0185] 4-(3-fluoropyridin-2-yl)phenol, phosphorus oxychloride, L-alanine isopropyl hydrochloride, pentafluorophenol and (2'R)-2'-deoxy Using -2'-fluoro-2'-methyluridine as the starting material, the target compound was prepared in the same way as in Steps 2 and...

Embodiment 3

[0188] Example 3 (2S)-2-(((4-(2-fluoropyridin-4-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo Isopropyl (3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionate

[0189]

[0190] Preparation of step 1 4-(2-fluoropyridin-4-yl)phenol

[0191] Using 4-hydroxyphenylboronic acid and 2-fluoro-4-bromopyridine as raw materials, the title compound was obtained by the same method as in Step 1 of Example 1.

[0192] LC-MS m / z:[M+H] + =190.

[0193] Step 2 (2S)-2-(((4-(2-fluoropyridin-4-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo -3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl preparation

[0194] 4-(2-fluoropyridin-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl hydrochloride, pentafluorophenol and (2'R)-2'-deoxy Using -2'-fluoro-2'-methyluridine as the starting material, the target compound was prepared in the same way as in Steps 2 and...

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Abstract

The present invention relates to the field of medical chemistry, and particularly to a compound having good hepatitis C virus inhibition effect, a preparation method therefor, a composition containing the compound, and a use of the compound or composition as a medicine for treating hepatitis C virus infected diseases. The compound of the present invention shows excellent anti-virus activity and meanwhile has low cytotoxicity and high safety and plasma protein binding rate, is suitable for medicine making and has a great prospect in clinical application.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a compound with good hepatitis C virus inhibitory effect, a preparation method thereof, a composition containing the compound, and the compound or composition as a drug for treating hepatitis C virus infectious diseases the use of. Background technique [0002] Hepatitis C virus (HCV) infection is a worldwide epidemic disease, the global chronic infection has exceeded 200 million, and the infection rate in China is 3.2%, ranking among the top three in the world. The clinical manifestations of hepatitis C virus infection are diverse, ranging from mild inflammation to severe liver cirrhosis and liver cancer. Chronic hepatitis C can also be complicated by certain extrahepatic manifestations, including rheumatoid arthritis, conjunctival keratitis sicca, lichen planus, glomerulonephritis, mixed cryoglobulinemia, B-cell lymphoma, and delayed Cutaneous porphyria, etc., m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/10A61K31/685A61P31/14
CPCA61K31/7072C07F9/24
Inventor 王勇赵立文张先毕胜高毅平陈宏雁王德忠南阳张仓李玉秀张迪
Owner NANJING SANHOME PHARMACEUTICAL CO LTD
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