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Novel cyclic phospholipids used for treating HCV infection

A therapeutic agent, a technology of phosphorus dioxide, applied in the field of novel cyclophosphate, to achieve the effects of improving pharmacokinetic properties, reducing toxicity and improving safety

Active Publication Date: 2017-03-22
GINKGO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It can be inferred that Hepdirect cyclophosphate, which is based on the nucleoside part of sofosbuvir and uses the following compound 1 as the prodrug precursor, may have the risk of cancer

Method used

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  • Novel cyclic phospholipids used for treating HCV infection
  • Novel cyclic phospholipids used for treating HCV infection
  • Novel cyclic phospholipids used for treating HCV infection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1. Preparation of 1-((2R,3R,4R,5R)-5-(((4-(benzo[d][1,3]dioxa-5-position)-2-oxidation-1 ,3,2-dioxaphosphorinane-2-position)oxy)methyl)-3-fluoro-4-hydroxy-3-methyltetrahydrofuran-2-position)pyrimidine-2,4(1H,3H )-diketone (5)

[0065]

[0066] Compound 5 was prepared according to the following process:

[0067]

[0068] Compound 1 (17.000g, 0.103mol) was dissolved in toluene (150ml), N 2 Under protection, sodium hydrogen (8.284g, 0.207mol, 2eq) was added in batches in an ice bath. After the addition was completed, the stirring reaction was continued for 30 min, and then the compound dimethyl carbonate (27.834 g, 0.309 mol, 3.0 eq) was slowly added dropwise. After the drop, the temperature was raised to reflux for 3 hours. TLC monitored the completion of the reaction. The reaction solution was poured into saturated ammonium chloride solution, extracted with ethyl acetate (150ml*3), the organic phase was separated, and washed 2-3 times with saturated brine...

Embodiment 2

[0072] Example 2. Preparation of cis 1-((2R,3R,4R,5R)-5-(((4-(benzo[d][1,3]dioxa-5-position)-2-oxidation- 1,3,2-Dioxaphosphorinane-2-position)oxy)methyl)-3-fluoro-4-hydroxy-3-methyltetrahydrofuran-2-position)pyrimidine-2,4(1H, 3H)-Diketone (6)

[0073]

[0074] Compound 6 was prepared according to the following process:

[0075]

[0076] Compound 4 (3.140g, 0.016mol) was dissolved in anhydrous THF (50ml), N 2 Triethylamine (6.464 g, 0.064 mol) was added in an ice bath under protection. A THF solution (10 ml) of 4-nitrophenyl phosphate dichloride (4.300 g, 0.0168 mol) was then added. After the dropwise addition, the mixture was raised to room temperature and stirred for 1 hour, then refluxed and stirred for 2 hours. Cool to 30°C, add sodium 4-nitrophenolate (7.728g, 0.048mol) and continue to reflux for 2 hours, then overnight at room temperature. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the filtrate was spin-dried ...

Embodiment 3

[0078] Example 3. Preparation of cis 1-((2R,3R,4R,5R)-5-((((2R,4S)-4-(benzo[d][1,3]dioxa-5-position )-2-oxidation-1,3,2-dioxaphosphorinane-2-position)oxy)methyl)-3-fluoro-4-hydroxyl-3-methyltetrahydrofuran-2-position)pyrimidine- 2,4(1H,3H)-Diketone (7)

[0079]

[0080] Compound 7 was prepared according to the following scheme:

[0081]

[0082] Triethylamine (2.659g, 0.026mol) was slowly added dropwise into HCOOH (3.981g, 0.089mol), and the temperature was controlled below 40°C. After the addition, compound 2 (15.000g, 0.068mol) was dissolved in DMF ( 50ml), nitrogen bubbling to remove oxygen in the system, then add catalyst (s,s)-Ts-DPEN-RuCl-(p-cymene) (0.042g, 0.068mmol), heat to 60°C, react for 19h, TLC shows the reaction up about 1 / 3. Add catalyst (0.042g, 0.068mmol), then react for 5 hours, pour the reaction solution into water, extract 3 times with ethyl acetate (100ml), combine the ethyl acetate layer, wash 2 times with water, and wash with saturated brine (1...

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PUM

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Abstract

The invention relates to novel cyclic phospholipids, pharmaceutically acceptable salts or esters thereof and a medicine composition used for treating HCV infection. Chlorine in a phenyl ring of a Hepdirect cyclic phospholipid prodrug is replaced by a specific ring, thus effectively reducing toxicity, eliminating potential cancer risks and basically maintaining or even improving drug metabolism characteristics and in-vivo activity. Compared with a Hepdirect cyclic phospholipid, the novel cyclic phospholipids, the salts or esters and the composition are ideal clinical treating agents.

Description

technical field [0001] The present invention relates to a novel cyclophosphate suitable for treating HCV infection. Background technique [0002] Hepatitis C virus (HCV) infection is a serious health problem and infection with HCV can lead to chronic liver diseases such as cirrhosis and liver cancer. HCV infects a large number of people, and it is estimated that it accounts for 2-15% of the world's population. The U.S. Centers for Disease Control estimates that there are 4.5 million infected people in the U.S. alone. According to the statistics of the World Health Organization, there are more than 200 million infected people in the world, and at least 3-4 million new infected people are added every year. Among infected people, about 20% of the patients can clear the HCV virus automatically, but the remaining HCV virus in the body of the remaining patients will accompany them throughout their lives. 10-20% of chronically infected individuals eventually develop cirrhosis or...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/11C07H1/00A61K31/7072A61P1/16A61P31/14
CPCC07H1/00C07H19/11
Inventor 李本陈力翟培彬
Owner GINKGO PHARMA
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