L-nucleoside compounds and application thereof

A technology of nucleosides and compounds, applied in the field of medicinal chemistry, can solve problems such as difficulty in controlling the epidemic

Inactive Publication Date: 2016-06-08
GUANGZHOU HENOVCOM BIOSCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For RNA viruses such as Ebola virus, there is still no marketed drug, which makes the epidemic difficult to control

Method used

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  • L-nucleoside compounds and application thereof
  • L-nucleoside compounds and application thereof
  • L-nucleoside compounds and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Preparation of L-3-deoxynucleoside compounds.

[0073] Prepare according to the following reaction scheme:

[0074]

[0075] (1) Preparation of 1,2-O-isopropylidene-α-L-xylofuranose (compound 1)

[0076] Take a 500mL three-necked flask, add L-xylose (20g, 133mmol) and acetone (300mL), cool down to 0°C, add 20mL of concentrated sulfuric acid dropwise under stirring, stir at 0°C for 6h, the reaction solution is clear, cool down to -10°C , add 1M (i.e. 1mol / L) NaOH solution to adjust the pH to neutral, evaporate acetone, add saturated brine, EA (ethyl acetate) for extraction, dry, and spin dry to obtain a colorless oily liquid, which is a monoacetonide protected Mixture of xylose (compound 1) and diacetonylidene-protected xylose. The mixture was dissolved in 100 mL of methanol, 50 mL of water and 40 g of 732-type cation exchange resin were added, stirred at room temperature for one day, filtered, and the filtrate was spin-dried to obtain 24.77 g of a light yellow oily...

Embodiment 2

[0101] Preparation of L-2-methyl-2-fluoronucleoside compounds.

[0102] Prepare according to the following reaction scheme:

[0103]

[0104] (1) (2E)-3-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-methyl-2-propenoic acid ethyl ester (compound 10) preparation of

[0105] Ph 3 PC(Me)CO 2 Et (152g, 419.85mmol, 2.2 equivalents) was dissolved in 500mL redistilled DCM, cooled to -40°C, and compound 9 ((S)-(-)-2,2-dimethyl- 1,3-dioxolane-4-carbaldehyde) in DCM (50 g, 190.84 mmol, 100 mL), raised to room temperature, and stirred for 17 h. The reaction solution was spin-dried, added EA, stirred for 1 h, and filtered. The filtrate was spin-dried again, added tert-butyl methyl ether, stirred overnight, filtered, and spin-dried to obtain 81.86 g of an oily liquid. A small amount was passed through the column (PE:EA=10:1) to determine the structure and content, and the calculated yield was 90.07%.

[0106] Characterization data of compound 10: 1 HNMR (400MHz, Chloroform-d): δ6.69(d, ...

Embodiment 3

[0136] Preparation of 3-beta-methyluracil compounds.

[0137] Prepare according to the following reaction scheme:

[0138]

[0139] (1) Preparation of compound 23

[0140] Suspend L-ribose (10 g) in 100 mL of anhydrous methanol, add 0.8 mL of acetyl chloride, heat to reflux for 2 h, and spin dry to obtain crude compound 21.

[0141] The crude compound 21 was dissolved in 100 mL of dry pyridine, a catalytic amount of DMAP was added, the temperature was lowered to 0°C, and benzoyl chloride (24 mL, 206.7 mmol, 3.1 equivalents) was slowly added dropwise. After the dropwise addition, it was raised to room temperature and reacted overnight. Spin the reaction solution to dryness, add DCM, saturated NaHCO 3 solution, stirred for 10 min and then separated, the aqueous phase was extracted with DCM, the combined organic phase was washed with 1N dilute hydrochloric acid, saturated NaHCO 3 solution, washed with saturated brine, dried, and spin-dried to obtain the crude compound 22. ...

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Abstract

The invention discloses L-nucleoside compounds having the structure characteristic represented by the formula (I) or pharmaceutically acceptable salts thereof, and belongs to the technical field of pharmaceutical chemistry. The compounds can inhibit the activity of RNA viral polymerase, so the compounds can be used as potential drugs for prevention and treatment of infection of RNA viruses such as HCV, influenza virus, HRV (rhinovirus), RSV, Ebola virus, dengue virus, intestinal virus and the like.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to an L-nucleoside compound and its application. Background technique [0002] Outbreaks of viral epidemics happen from time to time. As early as 1997, H5N1 bird flu broke out in Hong Kong, causing 18 infections and 6 deaths. Subsequently, the virus ravaged Asia many times, especially in 2005. Other subtypes of influenza virus have also caused considerable impact around the world, including H1N1 in 2009 and H7N9 in 2013. Recently, the Ebola epidemic with a very high mortality rate broke out in West Africa, and the dengue fever epidemic broke out in Guangzhou, infecting tens of thousands of people. The pathogens causing the above-mentioned outbreaks all belong to RNA viruses, which shows that the harm of RNA viruses to human health is becoming more and more serious. [0003] And, in addition to causing acute infectious diseases, RNA viruses can also cause chronic dise...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/207C07H19/10C07H19/056C07H1/00A61K31/708A61K31/7076A61K31/7072A61K31/7068A61K31/7056A61P31/14A61P31/16
CPCY02A50/30
Inventor 张健存周溢谦张菊福顾自强张袁超
Owner GUANGZHOU HENOVCOM BIOSCI CO LTD
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