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Derivatives of oseltamivir, and method and medical application thereof

A pharmaceutical and drug technology, applied in the field of oseltamivir derivatives and infectious disease drugs caused by influenza virus, can solve problems such as side effects, virus drug resistance central nervous system, and clinical application limitations

Inactive Publication Date: 2012-09-12
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At the beginning of the new year in 2009, after the deaths of humans infected with swine flu (later corrected by WHO and renamed as the new H1N1 influenza A virus variant) in Mexico, as of May 20, within a short period of 3 to 4 months In China, it has swept more than 40 countries in North America and Europe, and spread to South America, Australia, the Middle East, Asia and other countries and regions. More than 11,000 people have been diagnosed with influenza A cases, and more than 80 cases have died. The epidemic is still ongoing. The spread has not yet been effectively controlled
One drug is an influenza virus M2 protein inhibitor, including amantadine and rimantadine, this drug is only effective against influenza A virus, and viral drug resistance will soon appear with severe central nervous system side effects, Therefore, the clinical application is greatly limited
According to reports, the resistance of influenza viruses to M2 protein inhibitors has increased from 1.9% in 2002 to 91% in 2006, so it is not recommended to use alkylamine drugs in the treatment of influenza at present

Method used

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  • Derivatives of oseltamivir, and method and medical application thereof
  • Derivatives of oseltamivir, and method and medical application thereof
  • Derivatives of oseltamivir, and method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] 2-Chloro-N-(4-chloro-2-methylphenyl)acetamide (II)

[0092] Add CH to o-methyl-p-chloroaniline (1.42g, 10mmol) 2 Cl 2 Dissolve, add triethylamine 2ml, dropwise add the CH of chloroacetyl chloride (0.93g, 12mmol) in system 2 Cl 2 Solution, the system produces a lot of white smoke, and the purple clear solution turns dark green. After the dropwise addition was completed, the ice bath was removed, and the mixture was stirred at room temperature for 1 hour. Add 20ml CH 2 Cl 2 Diluted, saturated NH 4 Wash twice with Cl, CH 2 Cl 2 Anhydrous Na 2 SO 4 Dry for 1 h, spin dry CH 2 Cl 2 , added PE to wash, and suction filtered to obtain 1.41 g of a gray product, with a yield of 64.68%. m.p.132-133℃

Embodiment 2

[0094] (3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-2-methylanilino)-2-oxoethylamino)-3-(1-ethylpropoxy )-1-cyclohexene-1-carboxylic acid ethyl ester (III)

[0095] Add oseltamivir 3.1g (10mmol), 2-chloro-N-(4-chloro-2-methylphenyl)acetamide 2.4g (12mmol), KI0.17 (1mmol) DMF in 100ml single-necked bottle 20mL, react at 45-55℃ for about 14h. After the reaction was detected by TLC, the reaction solution was poured into water, and the system precipitated a fine powdery solid, extracted 3 times with 70 mL of ethyl acetate, and the organic layer was combined, and anhydrous NaSO 4 dry. Silica gel column chromatography (ethyl acetate:methanol=10:1) yielded 1.68 g of a brown oily product as a solid, with a yield of 34%.

[0096] IR(KBr)v max (cm -1 ) 3588, 3568, 3448, 2360, 2342, 1685, 1654, 1647, 1637, 1629, 1618, 1384, 669;

[0097] 1 H NMR (CDCl 3 )0.86-0.91 (6H, m), 1.27-1.32 (4H, t, J=15.0Hz), 1.43-1.62 (4H, m), 1.93 (3H, s), 2.18 (3H, s), 2.17 (3H , s), 2.27(2H, s), 2.41-2...

Embodiment 3

[0100] (3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-2-methylanilino)-2-oxoethylamino)-3-(1-ethylpropoxy )-1-cyclohexene-1-carboxylic acid (I-1)

[0101] Add (3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-2-methylanilino)-2-oxoethylamino)-3-(1 -Ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester 1.4g (2.8mmol), then add 20mLTHF to dissolve, add 1mol / L LiOH15mL, stir at room temperature for 4h. After the reaction was detected by TLC, THF was removed by rotary evaporation. Concentrated hydrochloric acid was added dropwise under ice bath conditions to adjust the pH to 3-4. A khaki solid precipitated out of the system. Suction filtration and drying of the filter cake yielded 1.12 g of the product, with a yield of 85%. m.p.186-190°C.

[0102] IR(KBr)v max (cm -1 )3650, 3415, 2965, 2360, 2342, 1685, 1654, 1647, 1637, 1545, 1484, 1384, 669;

[0103] 1 H NMR (DMSO-d 6 )0.79-0.83 (6H, m), 1.15 (1H, s), 1.29 (3H, s), 1.35-1.43 (4H, m), 1.78 (1H, s), 2.18 (3H, s), 1.91 (2H , s), ...

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Abstract

The invention relates to the field of medical chemistry, in particular to derivatives of oseltamivir (I). R1, R2, L and X are explained in the specifications. The invention also discloses a method for preparing the derivatives of oseltamivir and the purpose of the derivatives for treating infectious diseases, particularly the infectious diseases caused by influenza viruses. The oseltamivir is shown in the description.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of oseltamivir derivatives, their preparation method and their use in treating infectious diseases, especially infectious diseases caused by influenza virus. Background technique [0002] Influenza (commonly referred to as flu) is an acute respiratory infectious disease caused by influenza virus, which ranks first among infectious diseases in affecting human health and causing economic losses. Worldwide, 20% of children and 5% of adults are infected with influenza A (A) or type B (B) every year. Influenza has a high mortality rate, which seriously endangers human health and life, and also causes huge economic losses to humans. It has not only attracted widespread attention all over the world, but also is a viral infectious disease that our country focuses on prevention and control. [0003] At the beginning of the new year in 2009, after the deaths of humans infected ...

Claims

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Application Information

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IPC IPC(8): C07C233/52C07D277/46C07D213/75C07D277/72C07D263/58C07D233/56C07D295/15C07D295/24A61K31/196A61K31/426A61K31/4402A61K31/428A61K31/423A61K31/4164A61K31/4453A61K31/45A61K31/5375A61P31/16
Inventor 尤启冬黄坤杜冠华刘艾林李超
Owner CHINA PHARM UNIV
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