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Adipamide D-hydroxyproline derivative and application thereof as nucleic acid vaccine adjuvant

A technology of hydroxyproline and adipoyl bisulfite, applied in the field of medicine, can solve the problems of decreased immune response and the like

Inactive Publication Date: 2013-10-02
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

As a result, the antigen gene expression and induced immune response of the plasmid DNA are also significantly reduced.

Method used

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  • Adipamide D-hydroxyproline derivative and application thereof as nucleic acid vaccine adjuvant
  • Adipamide D-hydroxyproline derivative and application thereof as nucleic acid vaccine adjuvant
  • Adipamide D-hydroxyproline derivative and application thereof as nucleic acid vaccine adjuvant

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1: Preparation of 1-[6-[4R-hydroxy-2R-carboxy-1-pyrrolidinyl]-6-oxohexanoyl]-pyrrolidine-4R-hydroxy-2R-carboxylic acid (1)

[0041]2.9g (20.0mmol) of 4R-hydroxy-cis-D-proline methyl ester hydrochloride was dissolved in 100mL of anhydrous dichloromethane, and 3.5mL of diisopropylethylamine (DIPEA) was added at 0°C. 1.46g (10.0mmol) adipic acid, 3.4g (25.2mmol) N-hydroxybenzotriazole (HOBt) and 4.8g (25.6mmol) 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (EDC·HCl), stirred for 24 hours, recovered the solvent under reduced pressure, added 100mL of ethyl acetate and 50mL of 10% (w / v) citric acid aqueous solution to the oily residue, shaken fully, and separated the acetic acid The ethyl ester layer was washed successively with saturated aqueous sodium carbonate, water, and saturated brine, and anhydrous Na 2 SO 4 Dry, recover the solvent, add 80mL of methanol and 80mL of 0.5mol / L sodium hydroxide aqueous solution, stir for 2h, adjust the pH to 5-6 w...

Embodiment 2

[0044] Example 2: Preparation of 1-[6-[4R-hydroxy-2R-carboxy-1-pyrrolidinyl]-6-oxohexanoyl]-pyrrolidine-4S-hydroxy-2R-carboxylic acid (3)

[0045] 1.45g (10.0mmol) of 4R-hydroxy-cis-D-proline methyl ester hydrochloride was dissolved in 50mL of anhydrous dichloromethane, and 2.0mL of DIPEA and 1.28g (10.0mmol) of adipic anhydride were added at 0°C , stirred for 24 hours, then added 1.45g (10.0mmol) of 4S-hydroxy-trans-D-proline methyl ester hydrochloride, 1.5mL DIPEA1.7g (12.6mmol) HOBt and 2.4g (12.8mmol) EDC·HCl , continue to stir and react for 24 hours, recover the solvent under reduced pressure, add 100mL ethyl acetate and 50mL10% (w / v) citric acid aqueous solution to the oily residue, shake fully, separate the ethyl acetate layer, and successively wash with saturated sodium carbonate water Liquid, water, saturated brine washing, anhydrous Na 2 SO 4 Dry, recover the solvent, add 80mL of methanol and 80mL of 0.5mol / L sodium hydroxide aqueous solution, stir for 2h, adjust t...

Embodiment 3

[0049] Example 3: 1-[6-[4R-azido-2R-carboxy-1-pyrrolidinyl]-6-oxohexanoyl]-pyrrolidine-4S-azido-2R-carboxylic acid (6 ) preparation

[0050] 1.70g (10.0mmol) of 4R-azido-cis-D-proline methyl ester hydrochloride was dissolved in 50mL of anhydrous dichloromethane, and 2.0mL of DIPEA and 1.28g (10.0mmol) of hexyl Diacid anhydride, stirred and reacted for 24h, then added 1.70g (10.0mmol) of 4S-azido-trans-D-proline methyl ester hydrochloride, 1.5mL DIPEA1.7g (12.6mmol) HOBt and 2.4g (12.8 mmol) EDC·HCl, continue to stir and react for 24 hours, recover the solvent under reduced pressure, add 100mL ethyl acetate and 50mL 10% (w / v) citric acid aqueous solution to the oily residue, shake fully, separate the ethyl acetate layer, and successively Wash with saturated sodium carbonate aqueous solution, water, saturated brine, anhydrous Na 2 SO 4 Dry, recover the solvent, add 80mL of methanol and 80mL of 0.5mol / L sodium hydroxide aqueous solution, stir for 2h, adjust the pH to 5-6 with ...

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Abstract

The invention relates to the technical field of medicines, and provides an adipamide D-hydroxyproline derivative and a pharmaceutically acceptable salt thereof. The derivative has the following general structural formula. The invention further provides an application of the adipamide D-hydroxyproline derivative and the pharmaceutically acceptable salt thereof in preparing a nucleic acid vaccine adjuvant.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a class of adipyl di-D-hydroxyproline derivatives and their use as adjuvants in nucleic acid vaccines to improve the immune level of the vaccines. Background technique [0002] As the third generation of new vaccines, nucleic acid vaccines have received extensive attention since their birth in the late 1990s, and have become one of the important directions for the development of modern vaccines. Nucleic acid vaccines have significant advantages over traditional vaccines in terms of research and development efficiency, preparation process, and gene controllability. In particular, they can directly transfect antigen-presenting cells and induce cell The special ability of immunity makes it have great potential in the prevention and treatment of intracellular bacterial infection, viral infection, tumor and other diseases. However, nucleic acid vaccines have suffered a fatal blow in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16A61K39/39A61P37/04
Inventor 孙树汉王越郭瀛军姚建忠
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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