PH-responsive amphotericin B derivative as well as preparation method and application thereof

A technology for amphotericin and its derivatives, which is applied in the field of pH-responsive amphotericin B derivatives and its preparation, can solve the problems of high price, high cost, and restrictions on wide application, and achieve high safety, good antibacterial activity, Little hemolysis effect

Active Publication Date: 2021-11-05
SOUTHWEST UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these new drug carriers can change the distribution of AMB in the body and reduce its liver and kidney toxicity, they are expensive and costly, which limits their wide application.

Method used

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  • PH-responsive amphotericin B derivative as well as preparation method and application thereof
  • PH-responsive amphotericin B derivative as well as preparation method and application thereof
  • PH-responsive amphotericin B derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Preparation of pH-responsive amphotericin B derivatives whose structural formula is I-1, the structural formula of I-1 is:

[0046]

[0047] Specifically include the following steps:

[0048] (1) Weigh 20mg of amphotericin B (AMB) and dissolve it in 5ml of anhydrous DMF, add maleic anhydride (MA, 2.0eq.) and stir to make it dissolve completely. 2Reaction was carried out at 30°C for 4 h under protection, and the solvent was removed by rotary evaporation under reduced pressure at 50°C to obtain a solid product;

[0049] (2) Add the solid product prepared in step (1) to methanol (the volume ratio of solid product to methanol is 50:0.2, mg:ml) to dissolve, and pour into 25ml of methyl tert-butyl ether pre-cooled to 4°C Precipitate, collect the precipitate by filtration

[0050] (3) Repeat the precipitation operation with methanol and methyl tert-butyl ether for 3 times on the above-mentioned precipitate, and the precipitate collected by filtration is vacuum-dried, and ...

Embodiment 2

[0052] Preparation of pH-responsive amphotericin B derivatives whose structural formula is I-2, the structural formula of I-2 is:

[0053]

[0054] Specifically include the following steps:

[0055] (1) Weigh 10 mg of amphotericin B (AMB) and dissolve it in 3 ml of anhydrous DMF, add citraconic anhydride (CA, 1.2 eq.), stir to make it dissolve completely, and 2 Reaction was carried out at 25°C for 2 h under protection, and the solvent was removed by rotary evaporation under reduced pressure at 50°C to obtain a solid product;

[0056] (2) Add the solid product prepared in step (1) to methanol (the volume ratio of solid product to methanol is 100:1, mg:ml) to dissolve, pour into 20ml of methyl tert-butyl ether pre-cooled to 4°C Precipitate, collect the precipitate by filtration

[0057] (3) Repeat the precipitation operation with methanol and methyl tert-butyl ether for 3 times on the above-mentioned precipitate, and the precipitate collected by filtration is vacuum-dried, ...

Embodiment 3

[0059] Preparation of pH-responsive amphotericin B derivatives whose structural formula is I-3, the structural formula of I-3 is:

[0060]

[0061] Specifically include the following steps:

[0062] (1) Weigh 50mg of amphotericin B (AMB) and dissolve it in 10ml of anhydrous DMF, add 2,3-dimethylmaleic anhydride (DMMA, 3.0eq.), stir to make it dissolve completely, and 2 Reaction was carried out at 35°C for 20 h under protection, and the solvent was removed by rotary evaporation under reduced pressure at 50°C to obtain a solid product;

[0063] (2) Add the solid product prepared in step (1) to methanol (the volume ratio of solid product to methanol is 50:1, mg:ml) to dissolve, pour into 50ml of methyl tert-butyl ether pre-cooled to 4°C Precipitate in, filter and collect precipitate;

[0064] (3) Repeat the precipitation operation with methanol and methyl tert-butyl ether for 3 times on the above-mentioned precipitate, and the precipitate collected by filtration is vacuum-dr...

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PUM

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Abstract

The invention relates to a pH-responsive amphotericin B derivative as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical chemistry preparation. According to the derivative of the invention, the amphotericin B derivative with a novel structure is obtained by modifying amino on trehalosamine in an amphotericin B molecule, and compared with non-modified amphotericin B, the amphotericin B derivative has the characteristics of low renal toxicity, small hemolysis and high safety. In addition, the invention further provides a preparation method of the derivative, the yield is high as well, and the prepared derivative has a good antifungal effect and has a wide market prospect in the aspect of treating systemic deep fungal infection.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemical preparation, and relates to a pH-responsive amphotericin B derivative, a preparation method and application thereof. Background technique [0002] Amphotericin B (AMB), a polyene macrolide antifungal drug, was first discovered in 1955 from the metabolites of Streptomyces nodosus in Orinoco soil. be found. Clinically, it is mainly used to treat visceral or systemic fungal infections caused by Candida albicans, Cryptococcus neoformans, yeast, Mucormyces and histoplasma. However, the solubility of AMB in water is extremely poor, the oral bioavailability is low, and it will cause serious toxic side effects in the body, especially hemolytic toxicity and renal toxicity. In 1958, in order to improve the water solubility of AMB, formulation researchers introduced amphotericin B deoxycholate injection (Fungizone). However, in clinical use, most patients have various acute adverse reactions su...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/08C07H1/00A61K31/7048A61P31/10
CPCC07H17/08C07H1/00A61P31/10Y02A50/30
Inventor 于洋李翀陈章宝郑廷瑜吴林冲
Owner SOUTHWEST UNIVERSITY
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