阅读说明：本技术 一种抗真菌化合物、合成方法及其应用 (Antifungal compound, synthesis method and application thereof ) 是由 裴泽军 孙欣 于 2020-05-14 设计创作，主要内容包括：本发明属于药物合成技术领域,涉及一种抗真菌化合物,具体涉及一种抗真菌化合物、合成方法及其应用,所述抗真菌化合物为氨基酸碳酯或其药物学上可接受的盐,且所述氨基酸碳酯具有如下结构式：<Image he="307" wi="602" file="DDA0002491259960000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,R<Sub>1</Sub>为C5-C17烷烃基或C5-C17烯烃基中的一种；所述R<Sub>2</Sub>为氨基酸侧链基团；并提供了抗真菌化合物的合成方法和抗真菌领域的应用。(The invention belongs to the technical field of drug synthesis, and relates to an antifungal compound, in particular to an antifungal compound, a synthesis method and an application thereof, wherein the antifungal compound is amino acid carbon ester or pharmaceutically acceptable salt thereof, and the amino acid carbon ester has the following structural formula: wherein R is 1 Is one of C5-C17 alkyl or C5-C17 alkenyl; the R is 2 Is an amino acid side chain group; also provides a synthetic method of the antifungal compound and application in the antifungal field.)

1. An antifungal compound characterized by: the antifungal compound is an amino acid carbon ester or a pharmaceutically acceptable salt thereof.

2. The antifungal compound of claim 1, wherein: the amino acid carbon ester has the following structural formula:

wherein R is₁Is one of C5-C17 alkyl or C5-C17 alkenyl; the R is₂Is an amino acid side chain group.

3. A process for the preparation of an antifungal compound, characterized in that: taking amino acid and carbon alcohol as raw materials, and carrying out reflux reaction to obtain amino acid carbon ester; the preparation method comprises the following specific steps:

step 1, dissolving amino acid in toluene to form amino acid toluene liquid, wherein the concentration of the amino acid in the toluene is 0.5 mol/L;

step 2, adding carbon alcohol and p-toluenesulfonic acid into amino acid toluene liquid for reflux reaction, and performing water azeotropic separation to obtain amino acid carbon ester, wherein the addition amount of the carbon alcohol is consistent with the molar amount of the amino acid, the addition amount of the p-toluenesulfonic acid is consistent with the molar amount of the amino acid, and the reflux reaction is performed by raising the temperature to the reflux temperature in a slow temperature raising manner; the reaction was monitored by thin layer chromatography.

4. A process for the preparation of antifungal compounds as claimed in claim 3, characterized in that: the purification steps of the amino acid carbon ester are as follows:

step a, concentrating a reaction mixture subjected to water azeotropic separation in vacuum, and filtering to obtain a residue;

step b, extracting residues by using ethyl acetate, washing by using a sodium carbonate aqueous solution and saline water in sequence, drying an organic layer by using sodium sulfate, and concentrating in vacuum to obtain a crude product, wherein the mass concentration of sodium carbonate in the sodium carbonate aqueous solution is 5%;

step c, the crude product was chromatographed on silica gel with MeOH in silica gel: DCM ═ 1:50 to 1:5 to give the product.

5. Use of an antifungal compound according to any one of claims 2 to 4 as an antifungal agent, i.e. as an antifungal agent, an amino acid carbon ester or a pharmaceutically acceptable salt thereof.

6. Use of an antifungal compound according to any one of claims 2 to 4 in the preparation of an antifungal medicament, i.e., the use of a carbon ester of an amino acid or a pharmaceutically acceptable salt thereof in the preparation of an antifungal medicament.

7. Use of an antifungal compound according to any one of claims 2 to 4, an antifungal composition comprising as active ingredient an antifungal compound together with one or more pharmaceutically acceptable excipients.

Technical Field

The invention belongs to the technical field of drug synthesis, and relates to an antifungal compound, in particular to an antifungal compound, a synthesis method and application thereof.

Background

Fungal infections are one of the major infectious diseases in the clinic, which are classified into superficial mycoses and invasive mycoses. The incidence and the fatality rate of invasive mycosis both rise year by year in recent decades. Especially in some special patient populations, such as: the incidence rate of organ transplantation patients, ICU severe patients, patients with hypoimmunity such as hematopathy and the like is up to about 29 percent, and the fatality rate is higher up to 49 percent.

At present, the types of drugs which can be clinically selected for treating fungal infection are not many, and mainly comprise polyenes, pyrroles, echinocandins, 5-fluorocytosine (5-FC) and the like. Polyenes are the first antifungal drugs used in clinical applications, mainly amphotericin B and the like, and inhibit fungal growth by acting on the specific sterol binding on fungal cell membranes to impair the permeability of fungal cell membranes. The medicine has the advantages of wide antifungal spectrum, strong activity and great toxicity, such as hepatotoxicity, nephrotoxicity, transfusion related toxicity, etc. The pyrrole comprises imidazole and triazole, and the ergosterol acting on the fungal cell membrane influences the stability of the cell membrane to break the fungal cell and kill the fungal cell. Imidazoles mainly represent ketoconazole, clotrimazole, miconazole and the like, and are suitable for treating superficial fungal infections. Triazoles mainly represent drugs such as fluconazole, voriconazole, itraconazole and the like, and can be used for treating deep fungal infection. The medicine has certain influence on liver and kidney functions and has other adverse reactions. The action mechanism of the 5-fluorocytosine is to interfere nucleic acid and protein synthesis of fungal cells, so that fungal drug resistance is easy to appear, and the 5-fluorocytosine is not used independently. Echinocandins are relatively new powerful antifungal agents, dissolve and die fungi by destroying the cell walls of the fungi through a non-competitive inhibitor 1, 3-beta-D-glucan synthetase, and have high-efficiency and low-toxicity clinical effects. Representative drugs are caspofungin, micafungin, etc.

The development of antifungal drugs has been progressing slowly in recent decades, and after newer echinocandin caspofungin was discovered in 1970 and started to be applied clinically in 2000, no new antifungal drug has been developed and successfully applied in recent 20 years. Due to the shortage of selectable types and quantity of clinical antifungal medicines, the drug resistance of fungi is more serious, and even the phenomenon that the existing 'super fungi' has drug resistance to the last line-defense medicines of the antifungal medicines such as caspofungin, micafungin and the like is repeated for many times, so that the life health and safety of patients are seriously threatened. Therefore, as soon as possible, more and better novel antifungal drugs are searched, and effective overcoming of the problem of fungal drug resistance is an important task urgently needed to be solved by current technologists.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides an antifungal compound which has good antifungal effect and can be used for preparing antifungal agents.

In order to achieve the technical purpose, the technical scheme of the invention is as follows:

an antifungal compound which is an amino acid carbon ester or a pharmaceutically acceptable salt thereof.

The amino acid carbon ester has the following structural formula:

wherein R is¹Is one of C5-C17 alkyl or C5-C17 alkenyl; the R is²Is an amino acid side chain group.

Further, said R₁Is one of straight chain alkyl with total carbon number of C5-C17 or alkyl with side chain with total carbon number of C5-C17.

Further, said R₁Is one of a linear alkylene group having a total carbon number of C5-C17 or a branched alkylene group having a total carbon number of C5-C17.

The preparation method of the antifungal compound, namely the preparation method of the amino acid carbon ester, takes amino acid and carbon alcohol as raw materials, and the antifungal compound is obtained by reflux reaction, and comprises the following specific steps:

step 1, dissolving amino acid in toluene to form amino acid toluene liquid, wherein the concentration of the amino acid in the toluene is 0.5 mol/L;

and 2, adding carbon alcohol and p-toluenesulfonic acid into the amino acid toluene liquid for reflux reaction, performing water azeotropic separation to obtain amino acid carbon ester, wherein the addition amount of the carbon alcohol is consistent with the molar amount of the amino acid, the addition amount of the p-toluenesulfonic acid is consistent with the molar amount of the amino acid, and the reflux reaction is carried out to raise the temperature to the reflux temperature in a slow temperature raising manner.

The step 2 adopts thin layer chromatography for reaction monitoring.

Further, the purification steps of the amino acid carbon ester are as follows:

step a, concentrating a reaction mixture subjected to water azeotropic separation in vacuum, and filtering to obtain a residue;

step b, extracting residues by using ethyl acetate, washing by using a sodium carbonate aqueous solution and saline water in sequence, drying an organic layer by using sodium sulfate, and concentrating in vacuum to obtain a crude product, wherein the mass concentration of sodium carbonate in the sodium carbonate aqueous solution is 5%;

step c, the crude product was chromatographed on silica gel with MeOH in silica gel: DCM ═ 1:50 to 1:5 to give the product.

Use of an antifungal compound, i.e., a carbon ester of an amino acid or a pharmaceutically acceptable salt thereof, as an antifungal agent.

An application of antifungal compound in preparing antifungal medicine, i.e. the application of carbon amino acid ester or its pharmaceutically acceptable salt in preparing antifungal medicine.

An antifungal composition comprises an active ingredient which is an antifungal compound and one or more pharmaceutically acceptable auxiliary materials, and specifically comprises amino acid carbon ester or pharmaceutically acceptable salt thereof which is used as an active ingredient and is matched with one or more pharmaceutically acceptable auxiliary materials.

From the above description, it can be seen that the present invention has the following advantages:

1. the antifungal compound has good antifungal effect and can be used for preparing antifungal agents.

2. The invention adopts a slow temperature rise mode to be matched with the reflux reaction, effectively controls the reaction, has good reaction efficiency and reaction stability and effectively reduces side reaction.

3. The invention utilizes the thin-layer chromatography to track the reaction progress, can effectively control the reaction and effectively ensure the high efficiency of the reaction.

Drawings

FIG. 1 is an IR spectrum of lauryl leucine according to example 1 of the present invention;

FIG. 2 is a mass spectrum of lauryl leucine according to example 1 of the present invention;

FIG. 3 is a nuclear magnetic spectrum of lauryl leucine according to example 1 of the present invention;

FIG. 4 is a nuclear magnetic spectrum of octadecyl leucine in example 2 of the present invention;

FIG. 5 is a nuclear magnetic spectrum of octadecyl leucine in example 3 of the present invention.

Detailed Description

An embodiment of the present invention is described in detail with reference to fig. 1 to 3, but the present invention is not limited in any way by the claims.

Leucine: