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N-phenyl-4-phenylbutyramide oxime and its derivatives with anti-hepatitis B virus activity

A phenylbutyramide oxime, anti-hepatitis B technology, applied in antiviral agents, organic chemistry, drug combination, etc., can solve the problems of drug resistance, expensive interferon, synthetic interference, etc., and achieve the effect of low toxicity

Active Publication Date: 2018-06-05
GUANGXI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Interferon is expensive and other problems
Nucleoside analogues have been the focus of antiviral drug research since the 1980s, and have become the first choice for hepatitis B treatment. Lamivudine, entecavir, adefovir dipivoxil, telbivudine, etc. are widely used. This type of drug competes to participate in the synthesis of DNA in HBV, resulting in the interference and termination of HBV DNA synthesis, but long-term use of nucleoside drugs will lead to general drug resistance and drug withdrawal rebound

Method used

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  • N-phenyl-4-phenylbutyramide oxime and its derivatives with anti-hepatitis B virus activity
  • N-phenyl-4-phenylbutyramide oxime and its derivatives with anti-hepatitis B virus activity
  • N-phenyl-4-phenylbutyramide oxime and its derivatives with anti-hepatitis B virus activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The preparation of the first compound of embodiment 1

[0032] (1) Weigh 10mmol of toluene in a 250mL single-necked round bottom flask, add 20mL of dichloromethane, and insert 2dry tube, add 20mmol anhydrous AlCl in batches under ice-bath condition 3 After adding 0.5h, continue to stir in the ice bath for 20min, then stir overnight at room temperature. According to TLC detection, after the raw materials were completely reacted, dilute glacial hydrochloric acid was added to stop the reaction (pH2 O was recrystallized to give 4-oxo-4-(4-methylphenyl)butanoic acid.

[0033] (2) Weigh 10mmol of 4-oxo-4-(4-methylphenyl)butyric acid prepared in step (1) of the example, 10mmol of aniline, and 5% 4-dimethylaminopyridine in a 100mL single-port round bottom flask, add 20mL tetrahydrofuran, loaded with CaCl 2 Stir in an ice bath for 10 minutes, add 11 mmol of dicyclohexylcarbodiimide in batches, complete the addition after 20 minutes, continue to stir in an ice bath for 0.5 h, ...

Embodiment 2

[0041] The preparation of the second compound of embodiment 2

[0042] (1) Same as step (1) of Example 1.

[0043] (2) Same as step (2) of Example 1.

[0044] (3) Weigh 10mmol of the N-phenyl-4-oxo-4-(4-methylphenyl)butyramide prepared in the embodiment step (2), 12mmol of methoxyamine hydrochloride, and 12mmol of pyridine in a 100mL round Add 20mL of dichloromethane to the bottom flask, stir the reaction at 70°C, TLC detects that there is no raw material point after 6h, stop the reaction. The solvent was distilled off under reduced pressure, 20 mL of water was added, extracted with ethyl acetate (3×20 mL), the organic layers were combined, washed with water (3×20 mL), saturated brine (3×20 mL) successively, dried over anhydrous sodium sulfate, and reduced Concentrated under reduced pressure, separated by silica gel column chromatography, the mobile phase is composed of: petroleum ether (boiling point 60-90 ° C): ethyl acetate: dichloromethane volume ratio of 12: 2: 1 solven...

Embodiment 3

[0051] The preparation of the third compound of embodiment 3

[0052] (1) Same as step (1) of Example 1.

[0053] (2) Same as step (2) of Example 1.

[0054] (3) Weigh 10mmol of the N-phenyl-4-oxo-4-(4-methylphenyl)butyramide prepared in the embodiment step (2), 12mmol of benzyloxyamine hydrochloride, and 12mmol of pyridine in a 100mL round Add 20mL of dichloromethane to the bottom flask, stir the reaction at 70°C, TLC detects that there is no raw material point after 6h, stop the reaction. The solvent was distilled off under reduced pressure, 20 mL of water was added, extracted with ethyl acetate (3×20 mL), the organic layers were combined, washed with water (3×20 mL), saturated brine (3×20 mL) successively, dried over anhydrous sodium sulfate, and reduced Concentrated under reduced pressure, separated by silica gel column chromatography, the mobile phase is composed of: petroleum ether (boiling point 60-90 ° C): ethyl acetate: dichloromethane volume ratio of 12: 2: 1 solve...

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Abstract

The invention discloses N-phenyl-4-phenyl butyrylamide oxime with anti-hepatitis B virus activity and a derivative thereof. The structure of the N-phenyl-4-phenyl butyrylamide oxime is represented by the following general formula: shown in the specification. An in-vitro HepG2.2.15 cell activity experiment shows that the N-phenyl-4-phenyl butyrylamide oxime has a certain inhibition effect on HBV surface antigens (HBsAg) and e antigens (HBeAg). Under the same condition, the inhibition rates of positive reference drug Lamivudine to HBsAg and HBeAg are respectively 50.9 percent and 45.2 percent, while the compound disclosed by the invention has the inhibition rates to HBsAg and HBeAg of 91.7 percent and 59.5 percent. The structure of the novel N-phenyl-4-phenyl butyrylamide oxime is different from that of a nucleoside similar drug, so that the N-phenyl-4-phenyl butyrylamide oxime is obvious in inhibition to the HBV activity, low in toxicity and expected to be further developed into a novel anti-hepatitis B virus drug.

Description

technical field [0001] The invention belongs to N-benzamide-oxime compounds, in particular to N-phenyl-4-phenylbutyramide oxime and its derivatives with anti-hepatitis B virus activity. Background technique [0002] Viral hepatitis type B (viral hepatitis type B), referred to as hepatitis B, is a common infectious disease caused by hepatitis B virus (Hepatitis B virus, HBV). advanced features. Hepatitis B is a serious global health problem that causes chronic liver disease and infection, and its patients are at high risk of dying from cirrhosis and liver cancer. About 1 / 2 of the world's population lives in HBV-susceptible areas, about 2 billion people have been proven to have been infected with HBV, 300-400 million people are chronically infected with HBV, and about 780,000 people die of acute or chronic hepatitis B every year. The etiology ranks 10th. China is the country with the largest number of people infected with hepatitis B virus in the world. About 690 million pe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C251/48A61P31/20A61P1/16
CPCC07C251/48
Inventor 韦万兴谭洁周敏
Owner GUANGXI UNIV
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