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Hepatitis C virus inhibitor and application thereof

A solvate, isopropyl propionate technology, applied in the field of medicinal chemistry, can solve problems such as weight loss and fatigue

Active Publication Date: 2016-02-10
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 application thereof
  • Hepatitis C virus inhibitor and application thereof
  • Hepatitis C virus inhibitor and application thereof

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 14-(pyridin-2-yl)phenol

[0171] Weigh 1.38g of 4-hydroxyphenylboronic acid (10mmol), 1.58g of 2-bromopyridine (10mmol), 0.4g of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl 2 , 0.5mmol) and 9g of cesium carbonate (30mmol) in a 250mL eggplant-shaped bottle, add 50mL of 1,4-dioxane and 5mL of water, and react at 90°C for 1.5h under the protection of argon. After the reaction, add 100mL of ethyl acetate The ester was extracted with 50 mL saturated aqueous sodium chloride solution, the organic phase was collected, washed with saturated aqueous sodium chloride solution (3×50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obt...

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] Preparation of step 14-(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-MSm / 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 3...

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 14-(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-MSm / 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 3...

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Abstract

The invention belongs to the field of medical chemistry, and particularly relates to a compound with the good hepatitis C virus inhibition effect, a preparation method of the compound, a composition comprising the compound and application of the compound or the composition as a medicine for treating hepatitis C virus infectious diseases. The compound has the excellent antiviral activity, meanwhile has the low cytotoxicity, is good in safety, good in plasma protein binding effect and suitable for patent medicine and has the quite good clinical application prospect.

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 Applications(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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