Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Aryl-substituted phosphonaminate and application in medical science thereof

A substituent and pharmaceutical technology, applied in the field of phosphoramide derivatives, can solve the problems of poor biofilm penetration ability and poor bioavailability

Active Publication Date: 2015-10-28
SICHUAN HAISCO PHARMA CO LTD
View PDF10 Cites 5 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Tenofovir (tenofovir), the chemical name is [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methylphosphonic acid (PMPA), is a nucleoside Acid reverse transcriptase inhibitors have anti-HBV and HIV; but because they contain phosphate groups, they have relatively large polarity, poor biomembrane penetration ability, and poor bioavailability in vivo.

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
  • Aryl-substituted phosphonaminate and application in medical science thereof
  • Aryl-substituted phosphonaminate and application in medical science thereof
  • Aryl-substituted phosphonaminate and application in medical science thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Example 1: (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino ]propionic acid-2-(2-methoxyethoxy)ethyl ester (compound 1)

[0117] 2-(2-methoxyethoxy)ethyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate

[0118]

[0119] The first step: (2S)-2-(tert-butoxyamino)propionic acid-2-(2-methoxyethoxy)ethyl ester (1B)

[0120] 2-(2-methoxyethoxy)ethyl(2S)-2-(tert-butoxycarbonylamino)propanoate

[0121]

[0122] (2S)-2-(tert-butoxyamino)propionic acid (6.0g, 0.05mol), 2-(2-methoxyethoxy)ethanol (9.5g, 0.05mol) and toluene dichloro (150 mL), then dicyclohexylcarbodiimide (10.3 g, 0.05 mol) and 4-dimethylaminopyridine (6.1 g, 0.05 mol) were added, and the reaction was stirred overnight at room temperature under a nitrogen atmosphere. The temperature was raised to react overnight. The reaction solution was filtered, the filter cake was washed with saturated brine, dried over anhydrous sodiu...

Embodiment 2

[0135] Embodiment 2: the resolution of compound 1

[0136] Take (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoic acid - 2-(2-Methoxyethoxy)ethyl ester (compound 1) (200 mg) was used for resolution.

[0137] Preparation conditions: Instrument: Gilson GX-281; ​​Column: CHIRALPAK AD-H, 20×250mm, 5μm; Mobile phase: A: n-hexane, B: isopropanol; Isocratic elution: A:B=50:50 (v / v); Flow rate: 6mL / min; Wavelength: 260nm; ml; injection: 20 μL / needle.

[0138] After separation, the fractions were concentrated and dried via a rotary evaporator at 40°C to obtain two optical isomers Compound 1-1 (50 mg) and Compound 1-2 (45 mg).

[0139] Compound 1-1

[0140] 1 H NMR (400MHz, CDCl 3 )δ8.32(s,1H),7.97(s,1H),7.34-7.28(m,2H),7.17-7.14(m,3H),5.80(s,2H),4.43(dd,1H),4.26 -4.14(m,3H),4.13-4.05(m,1H),4.05-4.00(m,1H),4.00-3.94(m,1H),3.69–3.61(m,5H),3.57-3.52(m, 2H), 3.44(t, 1H), 3.37(s, 3H), 1.25(d, 3H), 1.21(s, 3H).

[0141] MS M / Z (ESI): 537....

Embodiment 3

[0147] Example 3: (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino ]propionate-2-(2-hydroxyethoxy)ethyl ester (compound 2)

[0148] 2-(2-hydroxyethoxy)ethyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate

[0149]

[0150] The first step: 2-(2-benzyloxyethoxy)ethanol (2B)

[0151] 2-(2-benzyloxyethoxy)ethanol

[0152]

[0153] 2-(2-Methoxyethoxy)ethanol (2A) (21.2 g, 0.2 mol) and cesium carbonate (8.55 g, 0.05 mol) were dissolved in N,N-dimethylformamide (50 mL), Add benzyl bromide (27.7 g, 0.085 mol). Stir at room temperature for 3 days. Water (300mL) was added to the reaction solution, extracted with ethyl acetate (100mL×2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum Ether / ethyl acetate (v / ...

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 relates to an aryl-substituted phosphonaminate and an application of the aryl-substituted phosphonaminate in medical science, in particular to an aryl-substituted phosphonaminate showed in a general formula (I), stereoisomer of the aryl-substituted phosphonaminate or acceptable salt in the medical science, a preparation method of the aryl-substituted phosphonaminate, a pharmaceutical composite containing with the aryl-substituted phosphonaminate, the stereoisomer and the acceptable salt and an application for preparing medicine curing virus-infectious diseases of the pharmaceutical composite.

Description

technical field [0001] The present invention relates to an aryl-substituted phosphoramidite derivative represented by general formula (I), its stereoisomer or pharmaceutically acceptable salt, its preparation method and a pharmaceutical composition containing them and in the preparation of therapeutic Use in medicine in viral infectious diseases. Background technique [0002] Hepatitis B is one of the worldwide diseases, which is caused by hepatitis B virus. One-third of the world's population is infected with HBV to some degree, including 350 million chronic carriers. Hepatitis B has become endemic in some Asian and African countries, especially in China. Hepatitis B virus can cause acute and chronic infection. Acute infection is usually accompanied by liver inflammation, vomiting, jaundice, and very few can cause death, while chronic infection may induce liver cirrhosis and liver cancer. Although HBV infection can be prevented by vaccines, there is still no effective wa...

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): C07F9/6561A61K31/675A61P31/20A61P31/14A61P31/18
Inventor 魏用刚邱关鹏卢泳华祝国智
Owner SICHUAN HAISCO PHARMA CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com