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Glycopeptide antifungal compound, and preparation method and application thereof

An antifungal and compound technology, applied in the field of pharmaceutical compounds, can solve the problems of acetate deliquescence, nervous system toxicity, and unseen problems, and achieve the effects of improving antifungal activity, enhancing interaction, and strong inhibitory activity

Inactive Publication Date: 2012-11-07
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But it still has the following defects: first, the potential toxicity of caspofungin to the nervous system is mainly due to its good fat solubility, which causes it to easily pass through the blood-brain barrier; secondly, caspofungin has poor water solubility, usually It needs to be made into acetate before it can be made into a medicine; again, the acetate of this medicine is very easy to deliquescence and has poor stability, which limits the diversification of its dosage forms. At present, the dosage form of this medicine is only one kind of freeze-dried powder
However, there have been no reports of similar

Method used

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  • Glycopeptide antifungal compound, and preparation method and application thereof
  • Glycopeptide antifungal compound, and preparation method and application thereof
  • Glycopeptide antifungal compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 High resolution mass spectrum and proton nuclear magnetic spectrum data of compound 1a-f of the present invention

[0034] See Table 1 and Table 2 for high-resolution mass spectrometry and proton nuclear magnetic spectrum data of compounds 1a-f of the present invention.

[0035] Table 1 High-resolution mass spectrum table of compound 1a-f of the present invention

[0036] Compound No. n R HR-Q-TOF-MS + 1a 3

1642.8437 1b 3

1642.8458 1c 3

1582.8227 1d 3

1610.8553 1e 3

1966.9497 1f 3

1966.9497

[0037] Table 2 The proton nuclear magnetic spectrum data table of compound 1a-f of the present invention

[0038]

Embodiment 2

[0039] Embodiment 2 The preparation of compound 1a-f of the present invention

[0040] The preparation of compound 1a-f of the present invention can be roughly divided into two steps:

[0041] a) Preparation of the key intermediate glycosyl activated ester 7a-f, the reaction scheme is as follows:

[0042]

[0043] b) Preparation of target compounds 1a-f, the reaction scheme is as follows:

[0044]

[0045] The specific preparation method of compound 1a-f of the present invention is as follows:

[0046] 1. Preparation of intermediate acetyl glucoside (3a-f)

[0047] (1) Preparation of 1,2,3,4,6-penta- O -Acetyl- β -D-Glucopyranoside (3a)

[0048] Will β -D-Glucopyranose 2a (40 g, 222 mmol) and sodium acetate (30 g, 330 mmol) were placed in a 500 mL three-necked flask, and acetic anhydride (350 mL, 3.71 mol) was added. The reaction mixture was mechanically stirred, refluxed at 170 °C for 6 h, and then cooled at room temperature. The mixture was poured into ice-water...

Embodiment 3

[0138] Embodiment 3 Pharmacological experiments of compounds of the present invention

[0139] (1) Experimental method: The micro liquid base dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI) CLSI-M27A3 and M38-A2 documents was adopted.

[0140] (1) Experimental strains

[0141] In this experiment, the following 6 kinds of 7 common human pathogenic standard fungal strains were selected as the screening objects:

[0142] Two ATCC standard strains:

[0143] Candida albicans ( Candida albicans ) SC5314

[0144] Cryptococcus neoformans ( Cryptococcus neoformans ) 32609

[0145] Five clinical strains:

[0146] Candida glabrata ( Candida Krusei )537

[0147] Candida parapsilosis ( Candida parapsilosis ) 22019

[0148] Trichophyton rubrum ( Trichophyton rubrum ) Cmccftla

[0149] Microsporum gypsum ( Microsporum gypseum ) Cmccfmza

[0150] Candida albicans ( Candida albicans ) Y0109

[0151] (2) Test method

[0152] ...

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Abstract

The invention provides a glycopeptide antifungal compound and a pharmaceutically acceptable salt thereof, a preparation method and application thereof, and a pharmaceutical composition containing the active component. The glycopeptide antifungal compound has a general structural formula shown as below; n equals to 1, 2 or 3; and R represents monosaccharide or disaccharide, wherein the monosaccharide is glucose, galactose, xylose, rhamnose, mannose, ribose, glucosamine or acetyl glucosamine, and the disaccharide is maltose or lactose. Compared with existing clinical antifungal drugs, the compound provided by the invention has advantages of high efficiency, low toxicity and broad antibacterial spectrum, etc.; therefore, the compound can be applied to preparation of antifungal drugs. The preparation method provided by the invention successfully introduce different glycosyls onto primary amino group of Caspofungin, and has advantages of simple process and high yield.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical compounds, in particular to a glycopeptide antifungal compound and its preparation method and application. Background technique [0002] In recent years, due to the increase in the number of patients with cancer radiotherapy, chemotherapy, organ transplantation and interventional therapy, the widespread use of broad-spectrum antibiotics, corticosteroids and immunosuppressants in clinical practice, and the prevalence of AIDS, the number of clinical deep fungal infection cases has increased sharply. Nearly 300,000 patients with systemic fungal infections are diagnosed in the world every year. Among AIDS patients, 60% of the direct causes of death are systemic fungal infections (Markus, R. Mucosal and systemic fungal infections in patients with AIDS: Prophylaxis and treatment. Drugs , 2004, 64, 1163-1180.). Fungal diseases seriously threaten human life and health. Among the drugs for the tr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K9/00A61K38/14A61P31/10C07K1/107
Inventor 吴秋业胡宏岗郭俊香郭忠武李任武田云桃崔洪黄生军李文娟
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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