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Nucleoside phosphamide compound and preparation method and application of nucleoside phosphamide in medicine

A compound and hydrate technology, applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve the problems of poor drug efficacy and aggravate the burden on the kidneys, and achieve the effect of low toxicity

Active Publication Date: 2017-04-05
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, Sofosbuvir and its metabolites are mainly eliminated through the kidneys, which will increase the burden on the kidneys for patients with severe kidney damage
Moreover, the metabolic mechanism of the prodrug modified compound based on sofosbuvir is the same as that of sofosbuvir, and there are also defects similar to sofosbuvir
[0008] In addition, Sofosbuvir is less effective for patients with genotype 3 infection, and the course of treatment is 24 weeks

Method used

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  • Nucleoside phosphamide compound and preparation method and application of nucleoside phosphamide in medicine
  • Nucleoside phosphamide compound and preparation method and application of nucleoside phosphamide in medicine
  • Nucleoside phosphamide compound and preparation method and application of nucleoside phosphamide in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0297] (S)-Isopropyl(((((2R,3R,4R,5R)-5-(2,4-dicarbonyl-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro -3-Hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(2,3-dihydrobenzofuran-6-oxyl)phosphoryl)amino)propionate (K1) and its isomers body preparation

[0298]

[0299] Preparation of intermediate compound (S)-isopropyl-2-(((pentafluorophenoxy)(2,3-dihydrobenzofuran-6-oxyl)phosphoryl)amino)propionate

[0300] Dissolve phosphorus oxychloride (1.53g, 10mmol) in dichloromethane (10mL), cool to -60°C, slowly add 6-hydroxy-2,3-dihydrobenzofuran (1.36g, 10mmol) and tris Ethylamine (1.01 g, 10 mmol) in dichloromethane (10 mL). After the dropwise addition was completed, the cooling bath was removed, and the mixture was raised to 25°C and stirred for 2 hours. The reaction system was further cooled to -60°C, L-alanine isopropyl ester hydrochloride (1.51 g, 9 mmol) was added, and then a dichloromethane solution (5 mL) of triethylamine (2.53 g, 25 mmol) was added dropwise. After the dropwise ad...

Embodiment 2

[0321] (S)-Isopropyl-2-((S)-((((2R,3R,4R,5R)-5-(2,4-dicarbonyl-3,4-dihydropyrimidine-1(2H) -yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(benzofuran-6-oxyl)phosphoryl)amino)propionate (K2-b) and (S)-Isopropyl-2-((R)-((((2R,3R,4R,5R)-5-(2,4-dicarbonyl-3,4-dihydropyrimidine-1(2H) -yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(benzofuran-6-oxyl)phosphoryl)amino)propionate (K2-a) preparation

[0322] Except that 6-hydroxybenzofuran was used instead of 6-hydroxy-2,3-dihydrobenzofuran, and the dosage of 6-hydroxybenzofuran was 0.134g, other operations were performed in the same manner as in Example 1 to obtain the title compound . Among them, K2-b is 25 mg, and K2-a is 8 mg.

[0323]

[0324] Its structure is characterized as follows:

[0325] ESI-MS: m / z 570.2 (M + +H)

[0326] 1 H NMR (DMSO-d 6 ,400MHz)δ11.54(s,1H),7.99(s,1H),7.64-7.51(m,3H),7.15(d,J=8.0Hz,1H),6.96(s,1H),6.14-5.90 (m,3H),5.54(d,J=8.0Hz,1H),4.83(m,1H),4.39-3.83(m,5H),1.28-...

Embodiment 3

[0334] (S)-Isopropyl-2-((S)-((((2R,3R,4R,5R)-5-(2,4-dicarbonyl-3,4-dihydropyrimidine-1(2H) -yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(benzo[b][1,4]dioxane-5-oxyl)phosphoryl) Amino)propionate (K3-b) and (S)-isopropyl-2-((R)-((((2R,3R,4R,5R)-5-(2,4-dicarbonyl-3 ,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(benzo[b][1,4]diox Preparation of hexylcyclo-5-oxy)phosphoryl)amino)propionate (K3-a).

[0335] Except using 2,3-dihydro-5-hydroxy-benzo[b][1,4]dioxane instead of 6-hydroxy-2,3-dihydrobenzofuran, making 2,3-dihydro- Except that the amount of 5-hydroxy-benzo[b][1,4]dioxane was 0.137 g, the same operations as in Example 1 were performed to obtain the title compound. Among them, K3-b is 15 mg, and K3-a is 8 mg.

[0336]

[0337] Its structure is characterized as follows:

[0338] ESI-MS: m / z 588.3 (M + +H)

[0339] 1 H NMR (DMSO-d 6 ,400MHz)δ11.52(s,1H),7.58(s,1H),6.86(m,2H),6.74-6.70(m,1H),6.08-6.05(m,1H),5.9...

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Abstract

The invention provides a nucleoside phosphamide compound shown as a formula (I), and an application of the compound as an antiviral drug. The compound can inhibit replication of RNA virus, and can be used as an inhibitor for hepatitis c virus (HCV)NS5B polymerase. The compound has inhibiting effect for NS5B polymerase and has little toxicity on hepatic cells.

Description

technical field [0001] The invention relates to nucleoside phosphoramide compounds and the use of the compounds as antiviral drugs. More specifically, it relates to nucleoside phosphoramide compounds that can inhibit the replication of RNA viruses and can be used as inhibitors of hepatitis C virus (HCV) NS5B polymerase. Background technique [0002] Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus belonging to the Flaviviridae family of the Hepacivirus genus. According to the different genes encoding NS5B ribonucleic acid-dependent ribonucleic acid polymerase, hepatitis C virus is divided into 6 genotypes and 50 subtypes. The global distribution of different genotypes is not the same. In North America and Europe, genotypes 1, 2, and 3 are found, with genotype 1 being the majority. There are almost only patients with genotype 4 and 5 infection in Africa. The common genotypes in China are 1b and 2a, of which 1b is the main one, and genotype 6 is mainl...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/00A61K31/7072A61P31/14
Inventor 刘钢郁楠吴勇勇唐祖建郑小洲陈强强邓汉文段小凡宋帅杨龙李筛黄海涛张毅涛赵明亮邓华钟维李栋宏曾宏郭先芬宋宏梅陶莉华王利春王晶翼其他发明人请求不公开姓名
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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