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Bicyclol-carnosine conjugate, and preparation method and application thereof

A technology of bicyclol and conjugates, which is applied in the field of bicyclol-carnosine conjugates and its preparation, can solve the problems of poor antiviral ability, poor water solubility of bicyclol, and low oral utilization, and achieve liver protection and enzyme reduction Antiviral ability, good water solubility, and high oral utilization

Inactive Publication Date: 2015-05-13
NANJING UNIV OF TECH
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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-carnosine conjugate, and preparation method and application thereof
  • Bicyclol-carnosine conjugate, and preparation method and application thereof
  • Bicyclol-carnosine conjugate, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1 Preparation of bicyclol-carnosine conjugate.

[0039] (1) Fully Protected Carnosine

[0040]

[0041]Weigh 4.482g of compound 1 (10mmol) and dissolve it in 50mL of DMF, add 10mL of triethylamine to remove hydrochloride, stir for 10min, add 2.268g of compound 2 (12mmol) under ice cooling, 1.62g of 1-hydroxybenzotriazole (HOBT ) (12mmol), 3.48mL N, N'diisopropylethylamine (DIPEA) (20mmol), after stirring for 10min, add 4.55g benzotriazole-N, N, N', N'-tetramethylurea Hexafluorophosphate (HBTU) (12mmol). Remove the ice bath and react for 4h. Add a large amount of water to the reaction solution and let it stand. After clarification, filter the supernatant, dissolve the solid with ethyl acetate, wash with 1mol / L HCl, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution successively, and dry to obtain a white solid 4.22g, which is the fully protected carnosine 3, the HPLC analysis purity is greater than 80%, and the yiel...

Embodiment 2

[0052] Example 2 Preparation of bicyclol-carnosine conjugate.

[0053] (1) Condensation reaction between bicycloalcohol and protected histidine, the product is deprotected to obtain a bicycloalcohol-histidine conjugate;

[0054] (1.1) Conjugation of protected histidine (Fmoc-His(Trt)-OH) to bicyclic alcohol

[0055]

[0056] Weigh 2.1g of Fmoc-His(Trt)-OH (3.39mmol) and dissolve it in 20mL of dichloromethane (DCM), cool in an ice bath, add 40mg of 4-dimethylaminopyridine (DMAP) (0.328mmol) and 750mg of 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) (3.91mmol), stirred for 10min, added 1.0118g of bicyclic alcohol (2.60mmol), and reacted for 6h. Add 100 mL of dichloromethane (DCM) to the reaction solution, wash with 1 mol / L hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated sodium chloride aqueous solution successively, dry, and gradient elution on a silica gel column, the mobile phase is PE:EA=4: 1-1:1, 1.58 g o...

Embodiment 3

[0071] Example 3 Preparation of bicyclol-carnosine conjugate.

[0072] (1) Condensation reaction between bicycloalcohol and protected glycine, product deprotection, to obtain glycine-bicycloalcohol conjugate;

[0073] (1.1) Conjugation of protected histidine (Fmoc-His(Trt)-OH) to bicyclic alcohol

[0074] The specific embodiment is the same as (1.1) in Example 2

[0075] (1.2) Deshistidine amino Fmoc protecting group

[0076] The specific embodiment is the same as (1.2) in Example 2

[0077] (2) Condensation reaction of histidine-bicyclol conjugate with protected β-alanine to obtain fully protected carnosine-bicyclol conjugate;

[0078] Weigh 5mmol bicyclol-histidine alcohol conjugate, 10mmol protected β-alanine Boc-β-Ala-OH, 1mmol HOBt and dissolve in 18mL DMF, cool in an ice bath, add 0.8mL DIPEA, stir for 5min , add 1mmol HBTU, react at 40°C for 4h, add 50mL ethyl acetate to the reaction liquid, wash with 1mol / L HCl, saturated aqueous sodium chloride solution successive...

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Abstract

The invention discloses a bicyclol-carnosine conjugate, and a preparation method and an application thereof. The structural formula of the compound is shown in the specification. By adoption of the bicyclol-carnosine conjugate, the problem of poor oral bioavailability of bicyclol is solved. The preparation method comprises the following steps of: bonding hydroxyl groups of bicyclol and carboxyl groups of carnosine by ester bonds or bonding protected histidine and beta-alanine to the bicyclol in sequence, and then removing protecting groups to obtain the bicyclol-carnosine conjugate. The bicyclol-carnosine conjugate and pharmeceutically-accepted salts thereof can be used for treating the liver injury and improving the liver function.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a bicyclol-carnosine 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'-methoxycarbonylbiphenyl, its structural formula for: [0003] [0004] 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 mitochondrial damage, an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14A61K31/4178A61P1/16A61P31/12A61P31/20
CPCY02P20/55
Inventor 苏贤斌王园园郭伦迪马晓娟沈冬健
Owner NANJING UNIV OF TECH
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