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2'-deoxy-2'-fluoro-2'-methylnucleoside derivative as well as preparation method and application of derivative in pharmaceuticals

A technology of methyl nucleoside derivatives and derivatives is applied in the field of preparing anti-hepatitis C virus drugs, 2'-deoxy-2'-fluoro-2'-methyl nucleoside derivatives, and can solve the problem of dosage large, drug resistance, recurrent virus infection and other problems

Active Publication Date: 2015-03-25
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the drug still has some deficiencies: First, although the virus polymerase is not easy to mutate, a type of S282T mutation still appears in the virus under drug induction; The degree of drug sensitivity is reduced by more than 10 times; in phase II clinical trials, it was also found that continuous single administration increased the number of S282T mutant viruses in the patient's body, resulting in drug resistance; treatment, the resulting viral resistance and long-term safety issues cannot be ignored; finally, in some clinical trials, patients who received this treatment still had relapsed viral infections (Jules Levin, et al. EASL 47 th , 2012)

Method used

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  • 2'-deoxy-2'-fluoro-2'-methylnucleoside derivative as well as preparation method and application of derivative in pharmaceuticals
  • 2'-deoxy-2'-fluoro-2'-methylnucleoside derivative as well as preparation method and application of derivative in pharmaceuticals
  • 2'-deoxy-2'-fluoro-2'-methylnucleoside derivative as well as preparation method and application of derivative in pharmaceuticals

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] (S)-2-(((S)-(((2R, 3R, 4R, 5R)-5-(4-methylamino-2-oxopyrimidin-1(2H)-yl)-4-fluoro -3-Hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoic acid isopropyl ester (I-1)

[0084]

[0085] Step A

[0086] 3',5'-di-O-benzoyl-2'-deoxy-2'-fluoro-2'-methyluridine (II-1) (50 mg) was suspended in acetonitrile (4 ml), and three Ethylamine (30 mg) and 4-dimethylaminopyridine (40 mg) were stirred in an ice bath for 30 minutes, 2,4,6-triisopropylbenzenesulfonyl chloride (90 mg) was added, moved to room temperature and stirred for 24 hours, and methyl The tetrahydrofuran solution (2ml) of the amine was stirred overnight at room temperature; after concentrating part of the reaction solution, the residue was poured into water (20ml), and the aqueous phase was extracted with ethyl acetate (20ml x 3), and the organic phase was washed with saturated brine, without Dry over sodium sulfate, evaporate the organic phase to get the crude product, and get N4-methy...

Embodiment 2

[0092] (S)-2-(((S)-(((2R,3R,4R,5R)-5-(4-isopropylamino-2-oxopyrimidin-1(2H)-yl)-4- Fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoic acid isopropyl ester (I-2)

[0093]

[0094] The preparation method refers to Example 1, replacing methylamine with isopropylamine to obtain compound I-2; 1 H NMR (300MHz, CD 3 OD) δ7.55(d, J=7.5Hz, 1H), 7.41(t, J=7.8Hz, 2H), 7.29(d, J=7.7Hz, 2H), 7.24(t, J=7.5Hz, 1H ), 6.25(br d, J=18.9Hz, 1H), 5.82(d, J=7.5Hz, 1H), 5.06-4.90(m, 1H), 4.65-4.44(m, 1H), 4.47-4.28(m , 1H), 4.12(br d, J=8.6Hz, 1H), 4.01-3.55(m, 4H), 1.36(d, J=5.2Hz, 3H), 1.31(d, J=21.5Hz, 3H), 1.29-1.07(m, 12H).

Embodiment 3

[0096] (S)-2-(((S)-(((2R,3R,4R,5R)-5-(4-n-butylamino-2-oxopyrimidin-1(2H)-yl)-4- Fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoic acid isopropyl ester (I-3)

[0097]

[0098] The preparation method refers to Example 1, and methylamine is replaced by n-butylamine to obtain compound I-3; 1 H NMR (300MHz, CD 3 OD) δ7.53(d, J=7.5Hz, 1H), 7.39(t, J=7.6Hz, 2H), 7.28(d, J=7.8Hz, 2H), 7.21(t, J=7.2Hz, 1H ), 6.24(br d, J=17.7Hz, 1H), 5.81(d, J=7.5Hz, 1H), 5.04-4.89(m, 1H), 4.66-4.49(m, 1H), 4.47-4.31(m , 1H), 4.11(br d, J=8.4Hz, 1H), 4.00-3.79(m, 2H), 3.38(t, J=6.9Hz, 2H), 1.67-1.50(m, 2H), 1.50-1.40 (m, 2H), 1.36(d, J=5.2Hz, 3H), 1.31(d, J=21.5Hz, 3H), 1.22(d, J=6.2Hz, 6H), 0.96(t, J=7.2Hz , 3H). 13 C NMR (75MHz, CD 3 OD) δ172.89 (d, J=5.4Hz), 163.76, 157.02, 150.74, 138.55 (br s), 129.42, 124.79, 119.93 (d, J=4.8Hz), 100.14 (d, J=181.3Hz), 96.22, 89.85(br s), 79.29(br s), 71.88(d, J=18.1Hz), 68.72, 64.48(br s), 50.23, 39.98, 30.63, ...

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Abstract

The invention discloses a 2'-deoxy-2'-fluoro-2'-methylnucleoside derivative as well as a preparation method and application of the derivative in pharmaceuticals. The compound represented by the formula I has a better inhibiting effect on wild-type and S282T mutant-type HCV and low cytotoxicity and can be used in preparation of anti-hepatitis C virus drugs. The invention also provides a preparation method of the compound represented by the formula I.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to 2'-deoxy-2'-fluoro-2'-methyl nucleoside derivatives and their preparation methods and their use in pharmacy, especially to 2'-deoxy-2'-fluoro -Application of 2'-methyl nucleoside derivatives in the preparation of anti-hepatitis C virus drugs. [0002] This patent application requires Chinese patent application (application number 201310432002.3, application date: September 23, 2013, invention name: 2'-deoxy-2'-fluoro-2'-methyl nucleoside derivatives and their preparation methods and use in pharmaceuticals) priority. Background technique [0003] Chronic hepatitis C is a serious liver disease caused by the hepatitis C virus (HCV). After HCV infects the body, the lipid metabolism in the liver tissue is disordered and accompanied by chronic inflammation, resulting in liver damage, fatty liver and possibly liver cirrhosis or hepatocellular carcinoma. About a quarter of c...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/00A61K31/7068A61P31/14
CPCC07H1/00C07H19/10
Inventor 孙宏斌甄乐
Owner CHINA PHARM UNIV
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