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Bicyclol-glutathione conjugate and preparation method and application thereof

A glutathione and bicyclol technology, which is applied in the production of peptides and bulk chemicals, can solve the problems of low oral utilization, poor water solubility of bicyclol, and weak antiviral ability, achieving good water solubility and low cost. Effects of low and significant antiviral capacity

Active Publication Date: 2014-11-19
潍坊英沛生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the water solubility of bicyclol is poor, the oral utilization rate is not high, and the antiviral ability is not strong at the same time, so it is not widely used

Method used

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  • Bicyclol-glutathione conjugate and preparation method and application thereof
  • Bicyclol-glutathione conjugate and preparation method and application thereof
  • Bicyclol-glutathione conjugate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1 Preparation of Bicyclic Alcohol-Glutathione Conjugate.

[0047] (1) Protection of glutathione sulfhydryl group

[0048] Glutathione (5g, 16.27mmol) was added to 50mL DMF, then Mmt-Cl (5.6g, 18.1mmol) was added, and the reaction was stirred at room temperature for 12h. The reaction solution was evaporated to dryness, recrystallized with dichloromethane and petroleum ether, and filtered to obtain 7.1 g of white solid, that is, compound 12. [M-H] - =578.1.

[0049]

[0050] (2) Co-protection of sulfhydryl-protected glutathione α-position carboxyl and amino groups

[0051] Compound 12 (5.95g, 10mmol) was dissolved in 50mL THF, under nitrogen protection, 20mL of 1mol / L Et was added 3 B (20mmol) solution, reacted for 15h. The reaction solution was evaporated to dryness, recrystallized with acetonitrile and dichloromethane, and filtered to obtain (6.50) g ​​of a white solid, namely compound 13.

[0052]

[0053] (3) Esterification reaction

[0054] Weigh...

Embodiment 2

[0060] Example 2 Preparation of Bicyclic Alcohol-Glutathione Conjugate.

[0061] (1) Protection of glutathione sulfhydryl group

[0062] Take 10mmol glutathione and add it to 50mL DMF, then add 12mmol Mob-Cl, and stir at 5°C for 24h. The reaction solution was evaporated to dryness, recrystallized with dichloromethane and petroleum ether, and filtered to obtain a white solid, thiol-protected glutathione.

[0063] (2) Co-protection of glutathione α-position carboxyl and amino groups

[0064] Take 5mmol of thiol-protected glutathione and dissolve it in 50mL THF, under nitrogen protection, add 5mmol of Et 3 B, react at 5°C for 20h. The reaction solution was evaporated to dryness, recrystallized with acetonitrile and dichloromethane, and filtered to obtain a white solid, which was protected glutathione.

[0065] (3) Esterification reaction

[0066] Weigh 3 mmol of protected glutathione and dissolve it in 20 mL of DCM, cool in an ice bath, add 40 mg of 4-dimethylaminopyridine...

Embodiment 3

[0069] Example 3 Preparation of Bicyclic Alcohol-Glutathione Conjugate.

[0070] (1) Protection of glutathione sulfhydryl group

[0071] Take 10mmol glutathione and add it to 50mL DMF, then add 12mmol Tmb-Cl, and stir at 40°C for 2h. The reaction solution was evaporated to dryness, recrystallized with dichloromethane and petroleum ether, and filtered to obtain a white solid, which was sulfhydryl-protected glutathione.

[0072] (2) Co-protection of glutathione α-position carboxyl and amino groups

[0073] Dissolve 5 mmol of sulfhydryl-protected glutathione in 50 mL of THF under nitrogen protection, add 7.5 mmol of 9-boronbicyclo[3.3.1]nonane dimer (25 mmol) solution, and react at 40°C for 10 h. The reaction solution was evaporated to dryness, recrystallized with acetonitrile and dichloromethane, and filtered to obtain a white solid, which was protected glutathione.

[0074] (3) Esterification reaction

[0075] Weigh 3 mmol of protected glutathione and dissolve it in 20 mL o...

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Abstract

The invention discloses a bicyclol-glutathione conjugate and a preparation method thereof. The conjugate has high antiviral activity, good water solubility and high oral utilization rate. The preparation method of the bicyclol-glutathione conjugate includes bonding bicyclol hydroxyl and one carboxyl of glutathione by an ester bond to obtain the bicyclol-glutathione conjugate or sequentially bonding the protected glycine, cysteine and glutamic acid to bicyclol. The preparation method is easy and convenient to operate, low-cost and high-yield. The compound formula is shown as follows.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a bicyclol-glutathione conjugate, a preparation method and application thereof. Background technique [0002] Bicyclic alcohol, the chemical name is 4,4'-dimethoxy-5,6,5',6'-dimethoxy-2-hydroxymethyl-2'- [0003] Methoxycarbonyl biphenyl, its structural formula is: [0004] [0005] Bicyclol has significant effects of protecting the liver, reducing enzymes and anti-HBV activity. It is a new drug with multiple functions and multiple targets. It is mainly used for the treatment of chronic hepatitis B and chronic hepatitis C. Hepatitis, alcoholic hepatitis, drug-induced hepatitis, etc. have a certain effect. The liver-protecting and enzyme-lowering mechanism of bicyclol is mainly through scavenging free radicals, thereby maintaining the integrity of cells, protecting liver cells from damage and releasing transaminases; bicyclol has a protective effect on liver cell mitochondria...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/037
CPCY02P20/55
Inventor 苏贤斌赵兴猛朱佳魏鹏楚遵雷
Owner 潍坊英沛生物医药科技有限公司
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