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Tenofovir bisphenylpropionate phosphoramidate compound as well as pharmaceutical composition and application thereof

A technology of phosphoramidate and bisphenylpropionate, applied in the field of medicine, can solve the problems of bone and kidney side effects, certain drug resistance, small side effects, etc., and achieve a large biological activity selection coefficient, low toxicity, and high bioavailability. degree of effect

Active Publication Date: 2020-11-10
FOSHAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Advantages of ETV: small side effects; Disadvantages: certain drug resistance, contraindicated for pregnant women;
[0006] Advantages of TDF: good antiviral effect, little drug resistance; Disadvantages: certain nephrotoxicity, long-term application will have certain side effects on bones and kidneys;
[0010] To sum up, although Gilead’s TDF and TAF compound preparations still dominate the market for AIDS / Hepatitis B drugs in the world, our research on TNF-based AIDS / Hepatitis B drugs is still of great significance

Method used

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  • Tenofovir bisphenylpropionate phosphoramidate compound as well as pharmaceutical composition and application thereof
  • Tenofovir bisphenylpropionate phosphoramidate compound as well as pharmaceutical composition and application thereof
  • Tenofovir bisphenylpropionate phosphoramidate compound as well as pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 9-[(R)-2-[[Di[[(S)-(1-n-butoxycarbonyl-2-phenyl)ethyl]amino]phosphinyl]methoxy]propyl]adenine Preparation of (COP374374).

[0033] Take commercially available tenofovir (COP00) 7.2g (25mmol), add in the 250ml flask, then add thionyl chloride 50g, heat up to 55°C, after 10 minutes, continue to heat up to 70°C and stir for 1 hour , distilled thionyl chloride under reduced pressure, added 100ml of dry acetonitrile after the distillation was completed and refluxed at 85°C for 10min, evaporated the acetonitrile to dryness under reduced pressure, cooled down to room temperature, then added 50ml of dry dichloromethane, and continued to stir for 0.5h Add 19.4g (75mmol, 3eq) of L-phenylalanine n-butyl hydrochloride (AH374), stir for another 10min, then add about 20ml of triethylamine dropwise, after the dropwise addition is complete, continue stirring for 0.5h.

[0034] After suction filtration, the filtrate was evaporated to dryness, and then 100ml of ethyl acetate was added. ...

Embodiment 2

[0038] 9-[(R)-2-[[Di[[(S)-(1-n-butoxycarbonyl-2-phenyl)ethyl]amino]phosphinyl]methoxy]propyl]adenine Preparation of Fumarate (FCOP374374).

[0039]

[0040] An equivalent amount of 9-[(R)-2-[[two[[(S)-(1-n-butoxycarbonyl-2-phenyl)ethyl]amino]

[0041]Phosphinyl] methoxyl group] propyl group] adenine (COP374374) and fumaric acid were dissolved in hot acetonitrile, stirred at reflux for 2 hours, cooled and crystallized at room temperature, filtered out the precipitated solid and washed with acetonitrile to obtain a white solid: 9-[(R)-2-[[Di[[(S)-(1-n-butoxycarbonyl-2-phenyl)ethyl]amino]phosphinyl]methoxy]propyl]adenine Fumarate (FCOP374374).

Embodiment 3

[0043] In Vitro Determination of Anti-HBV Viral Activity of Compounds of the Present Invention

[0044] 1. In vitro cell model: HepG 2.2.15 cells

[0045] 2. Dot blot method to determine the anti-hepatitis B virus activity of the compound

[0046] 2.1 HepG 2.2.15 cells (4×10 4 Cells / well) into 96-well plates, cultured overnight at 37°C with 5%.

[0047] 2.2 On the second day, dilute the compound and add different concentrations of the compound to the culture wells. The final concentration of DMSO in the culture medium was 1%. 1 μM entecavir (ETV) was used as 100% Inhibition control; 1% DMSO was used as 0% Inhibition control.

[0048] 2.3 On the fifth day, replace with fresh culture medium containing the compound.

[0049] 2.4 On the eighth day and the ninth day, the culture medium in the culture well was removed, and the cells were harvested for dot hybridization.

[0050] 3. Results: See Table 1.

[0051] Table 1: Cytotoxicity of compounds, extracellular anti-HBV activ...

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Abstract

The invention discloses a tenofovir bisphenylpropionate phosphoramidate compound and salt thereof, and also discloses a preparation method and a pharmaceutical composition containing the tenofovir bisphenylpropionate phosphoramidate compound. Tests prove that the compound has the activity of inhibiting HBV virus replication, and has the advantages of higher activity, higher development coefficientand the like than the existing drug tenofovir disoproxil fumarate (TAF) for treating AIDS. The tests also prove that the compound also has the activity of inhibiting HIV1 virus replication, and can be used for developing medicines for treating AIDS or medicines for treating hepatitis B.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a tenofovir bisphenylpropionate-based phosphoramidate compound, a pharmaceutical composition containing the compound and use thereof. Background technique [0002] Hepatitis B, especially chronic hepatitis B, has become a global public health problem. According to statistics, more than 1 million people worldwide die from HBV infection and related diseases every year. However, there is still a lack of ideal treatment methods and drugs for chronic hepatitis B so far. Therefore, how to effectively prevent and treat hepatitis B is a major problem that will be faced and needs to be solved in the 21st century. [0003] At present, TAF (Valide) and ETV (Entecavir), the first-class drugs for the treatment of hepatitis B in the Chinese market, have gradually shown their respective shortcomings since they were launched. [0004] In the 2018 American Society of Liver Diseases Prevention,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/20A61P31/18
CPCC07F9/65616A61P31/20A61P31/18Y02P20/55
Inventor 刘洪海
Owner FOSHAN UNIVERSITY
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