Antiviral nucleoside phosphoramidate and pharmaceutical composition and applications thereof

A technology of nucleoside phosphoramidate and nucleoside derivatives, which is applied in the field of nucleoside phosphoramidate derivatives and their drug combinations, which can solve the problems of rapid drug resistance of hepatitis C, low cure rate, and long treatment course

Active Publication Date: 2017-03-29
南京甘宁生物科技有限公司
View PDF8 Cites 12 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Hepatitis C virus has the characteristics of multiple genotypes and rapid mutation. Single-drug treatment of hepa...

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Antiviral nucleoside phosphoramidate and pharmaceutical composition and applications thereof
  • Antiviral nucleoside phosphoramidate and pharmaceutical composition and applications thereof
  • Antiviral nucleoside phosphoramidate and pharmaceutical composition and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Isopropyl[(S)‐(pentafluorophenoxy)(phenoxy)phosphoryl]-L-alaninate (3) and isopropyl[(R)‐(pentafluorophenoxy)( Phenoxy)phosphoryl]-D-alanine ester (6)

[0088]

[0089] Add phenyl dichlorophosphate (5.7 g, 25.7 mmol) and L-alanine isopropyl hydrochloride (4.32 g, 25.7 mmol) into the reaction flask, cool to -70°C within 1.5 hours A solution of triethylamine (7.2 ml, 51.7 mmol) in dichloromethane (22 ml) was added dropwise. After the addition was complete, it was raised to room temperature, and after stirring overnight, the reaction mixture was cooled to 0° C., and pentafluorophenol was dissolved within 40 minutes. (4.73 g, 25.7 mmol) and triethylamine (3.6 ml, 25.7 mmol) in dichloromethane (30 mL) were added dropwise to the above solution, stirred at 0° C. for 1 hour, warmed to room temperature, and stirred overnight, Remove the solid triethylamine hydrochloride by filtration, wash the solid filter cake with dichloromethane (3X10mL), concentrate the filtrate under re...

Embodiment 2

[0093]

[0094] 2.1. N-(tert-butoxycarbonyl)-D-alanine (8a)

[0095] Suspend 4.5g (50mmol) D‐alanine, 3.8g (55mmol), potassium hydroxide and 13.0g (55mmol), di-tert-butyl carbonate in a mixed solvent of water (200mL) and THF (20mL), room temperature Stir overnight to obtain N-Boc-D-alanine white solid 9.6g, which can be directly used in the next step of esterification without purification.

[0096] 2.2. N-(tert-butoxycarbonyl)-D-alanine-deuterated isopropyl ester-d 6 (9a)

[0097] The aforementioned N‐Boc‐D‐alanine 8a (2.18g, 11.5mmol) was dissolved in 40 mL of dry dichloromethane, followed by the addition of hexadeuterioisopropanol‐d 6 (Refer to CN 102010384 and prepare by reduction of deuterated acetone, 15mmol). After cooling the reaction solution to 5°C, EDC (3.31g, 17.2mmol) and DMAP (140mg, 1.15mmol) were added, followed by stirring at room temperature overnight. 300 mL of ethyl acetate was added to dilute the reaction solution, the organic phase was washed with s...

Embodiment 3

[0104] Using the same method as 11a, deuterated alanine esters 9b, 9c and pentafluorophenol were reacted with phenoxyphosphoryl dichloride to prepare deuterated (pentafluorophenoxy)(phenoxy)phosphoryl in one step )-alanine isopropyl ester 11b and 11c:

[0105]

[0106] Compound 11b is identical to 11c NMR spectrum:

[0107] 1 H NMR (400MHz, CDCl 3 )δ(ppm):7.40–7.35(m,2H),7.33–7.20(m,3H),3.95(brs,1H),3.65–3.60(m,1H),1.43(s,6H),1.41(d ,J=7.0Hz,3H). 31 P NMR (162MHz, CDCl 3 )δ‐1.99.

[0108] Compound 11b' is identical to 11c' NMR spectrum:

[0109] 1 H NMR (400MHz, CDCl 3 )δ(ppm):7.42–7.34(m,2H),7.32–7.19(m,3H),3.89(brs,1H),3.66–3.61(m,1H),1.45(s,6H),1.42(d ,J=7.0Hz,3H). 31 P NMR (162MHz, CDCl 3 )δ‐1.63.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention provides an antiviral nucleoside phosphoramidate and a pharmaceutical composition and applications thereof. The nucleoside phosphoramidate compound is prepared by connecting nucleoside with phosphate through phosphorus-oxygen bonds. The structural formulas of the nucleoside phosphoramidate compound are represented by a, a1, a2, b, b1, and b2. The invention also discloses stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, or crystals of the nucleoside phosphoramidate compound. The anti-hepatitis C activity of the provided novel nucleoside phosphoramidate is obviously better than that of sofosbuvir used in clinic. On the saccharide ring, the fluorine atoms are replaced by chlorine atoms, and the cytotoxicity of measure cell lines is prominently reduced. By systematically modifying and optimizing the basic groups, saccharide rings, and prodrugs, the anti-hepatitis C activity of partial synthesized compounds is 2 to 10 times higher than that of sofosbuvir. At the same time, the key parts of metabolism are optimized, the metabolism stability and chemical stability of synthesized compounds in plasma are better, compared with those of sofosbuvir.

Description

technical field [0001] The invention relates to a nucleoside phosphoramidate derivative and its pharmaceutical combination and use. Background technique [0002] Hepatitis C virus (HCV) has 3-4 million new patients every year. The World Health Organization estimates that there are more than 200 million infected people in the world, and more than 10 million patients in China. HCV belongs to the Flaviviridae Hepatovirus virus . Long-term hepatitis C virus infection ranges from inflammation to severe liver cirrhosis and liver cancer. And in the decompensated stage of hepatitis C cirrhosis, various complications may appear, such as ascites, abdominal infection, upper gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome, liver failure and other manifestations. The initial treatment for HCV infection was interferon and a combination of interferon and ribavirin, to which only 50% of patients responded, and interferon had significant side effects, such as influe...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07H19/10A61K31/7072A61P31/14A61P1/16C07B59/00
CPCC07B59/00C07B2200/05C07H19/10Y02A50/30
Inventor 杨学聪赵蕾刘江黄新全
Owner 南京甘宁生物科技有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap