WO2021227436A1 - 一种抗真菌化合物、合成方法及其应用 - Google Patents

一种抗真菌化合物、合成方法及其应用 Download PDF

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WO2021227436A1
WO2021227436A1 PCT/CN2020/130777 CN2020130777W WO2021227436A1 WO 2021227436 A1 WO2021227436 A1 WO 2021227436A1 CN 2020130777 W CN2020130777 W CN 2020130777W WO 2021227436 A1 WO2021227436 A1 WO 2021227436A1
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antifungal
amino acid
ester
antifungal compound
leucine
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French (fr)
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裴泽军
孙欣
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无锡市第二人民医院
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups

Definitions

  • 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.
  • Fungal infection is one of the main clinical infectious diseases, which can be divided into superficial mycoses and invasive mycoses. Among them, the incidence and mortality of invasive fungal diseases have been increasing year by year in recent decades. Especially in some special patient populations, such as: organ transplant patients, severely ill patients in ICU, and blood diseases and other immunocompromised patients, the incidence rate is as high as about 29%, and the case fatality rate is as high as 49%.
  • polyenes mainly polyenes, pyrroles, echinocandins and 5-fluorocytosine (5-FC).
  • Polyenes are the earliest antifungal drugs used in clinical practice, mainly amphotericin B and its analogs. By acting on the unique sterol combination on the fungal cell membrane, it damages the permeability of the fungal cell membrane and inhibits the growth of the fungus.
  • the advantages of this class of drugs are broad antifungal spectrum and strong activity, but the disadvantage is high toxicity, such as hepatotoxicity, nephrotoxicity and infusion-related toxicity.
  • Pyrroles include imidazoles and triazoles.
  • the ergosterol acting on the fungal cell membrane affects the stability of the cell membrane, causing the fungal cell to rupture and die.
  • the main representatives of imidazoles are ketoconazole, clotrimazole, miconazole, etc., which are suitable for the treatment of superficial fungal infections.
  • the main representatives of triazoles are fluconazole, voriconazole, itraconazole, etc., which can be used to treat deep fungal infections.
  • Such drugs have certain effects on liver and kidney function and some other adverse reactions.
  • the mechanism of action of 5-fluorocytosine is to interfere with the synthesis of nucleic acid and protein of fungal cells, which is prone to fungal drug resistance and is generally not used alone.
  • Echinocandins are relatively new and potent antifungal drugs. They destroy fungal cell walls through non-competitive inhibitor 1,3- ⁇ -D-glucan synthetase and cause fungi to dissolve and die. They have high-efficiency and low-toxicity clinical features. Effect. Its representative drugs include caspofungin, micafungin and so on.
  • the present invention provides an antifungal compound, which has good antifungal effects and can be used to prepare antifungal agents.
  • the technical solution of the present invention is:
  • 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:
  • R 1 is one of a C5-C17 alkane group or a C5-C17 alkene group; the R 2 is an amino acid side chain group.
  • the R 1 is one of a linear alkane group with a total carbon number of C5-C17 or a side-chain alkane group with a total carbon number of C5-C17.
  • R 1 is one of linear alkene groups with a total carbon number of C5-C17 or side-chain alkene groups with a total carbon number of C5-C17.
  • a preparation method of an antifungal compound that is, the preparation method of the amino acid carbon ester, is obtained by refluxing the amino acid and carbon alcohol as raw materials, and the specific steps are as follows:
  • Step 1 Dissolve the amino acid in toluene to form an amino acid toluene solution, and the concentration of the amino acid in toluene is 0.5 mol/L;
  • Step 2 Add carbon alcohol and p-toluenesulfonic acid to the amino acid toluene solution for reflux reaction, and azeotropic separation of water to obtain amino acid carbon ester.
  • the added amount of carbon alcohol is consistent with the molar amount of amino acid and the added amount of p-toluenesulfonic acid
  • the molar amounts of amino acids are the same, and the reflux reaction adopts a slow heating method to raise the temperature to the reflux temperature.
  • the step 2 adopts thin-layer chromatography for reaction monitoring.
  • Step a vacuum concentrating the reaction mixture after azeotropic separation of water, and filtering to obtain a residue;
  • step b the residue is extracted with ethyl acetate, and then washed with sodium carbonate aqueous solution and brine successively, and the organic layer is dried with sodium sulfate, and concentrated in vacuo to obtain a crude product.
  • the mass concentration of sodium carbonate in the sodium carbonate aqueous solution is 5%;
  • step c the crude product is chromatographed on silica gel to obtain the product, and the MeOH:DCM in the silica gel is 1:50-1:5.
  • an antifungal compound the application of the antifungal compound as an antifungal agent, that is, the application of an amino acid carbon ester or a pharmaceutically acceptable salt thereof as an antifungal agent.
  • An application of an antifungal compound the application of the antifungal compound in the preparation of an antifungal drug, that is, the application of an amino acid carbon ester or a pharmaceutically acceptable salt thereof in the preparation of an antifungal drug.
  • An antifungal composition comprising an antifungal compound as an active ingredient, and one or more pharmaceutically acceptable excipients, specifically an amino acid carbon ester or a pharmaceutically acceptable salt thereof as the active ingredient, and one One or more pharmaceutically acceptable excipients.
  • the present invention has the following advantages:
  • the antifungal compound of the present invention has a good antifungal effect and can be used to prepare an antifungal agent.
  • the present invention adopts a slow heating method to cooperate with the reflux reaction, which effectively controls the progress of the reaction, has good reaction efficiency and reaction stability, and effectively reduces side reactions.
  • the present invention uses thin-layer chromatography to track the progress of the reaction, which can effectively control the progress of the reaction and effectively ensure the high efficiency of the reaction.
  • Figure 1 is an infrared spectrum of leucine lauryl ester in Example 1 of the present invention.
  • Example 2 is a mass spectrum chart of leucine lauryl ester in Example 1 of the present invention.
  • Figure 3 is a nuclear magnetic spectrum of leucine lauryl ester in Example 1 of the present invention.
  • Fig. 4 is a nuclear magnetic spectrum chart 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.
  • An antifungal compound is leucine dodecyl ester
  • the structural formula of the leucine dodecyl ester is as follows:
  • the preparation method of the leucine lauryl ester is as follows:
  • Figure 1 is the infrared spectrum of leucine dodecyl ester
  • Figure 2 is the mass spectrum of leucine dodecyl ester
  • Figure 3 is the NMR spectrum of leucine dodecyl ester. It can be verified from 1 to 3 that the product is leucine dodecyl ester.
  • the leucine lauryl ester of this example was tested for antifungal by a half-dilution experiment, and caspofungin was used as a control, and the caspofungin was a commercially available drug.
  • the detection concentration is as follows:
  • Drug name Detection concentration ( ⁇ g/mL) This embodiment 100,50,25,12.5,6.25,3.125,1.56,0.78,0.39,0.195
  • Caspofungin 100,50,25,12.5,6.25,3.125,1.56,0.78,0.39,0.195
  • the experimental strains used Aspergillus fumigatus, spore silk, cryptococcus, and Rhizopus; the positive control bacteria: nearly smooth, Kerou.
  • the product of this example (MIC): the lowest drug concentration that inhibits the growth rate of fungi by 100% compared with the positive control well.
  • Caspofungin The lowest drug concentration that inhibits bacterial growth by 50% compared with the positive control well. Compared with the positive control wells, the growth of filamentous bacteria is restricted, and the minimum drug concentration for colony shrinkage is the minimum effective concentration (MEC).
  • leucine lauryl ester in certain fungi is significantly better than that of caspofungin. Therefore, leucine lauryl ester has good antifungal properties. Antibacterial effect.
  • the leucine dodecyl ester formed by amino acids and dodecanol has an amphoteric lipid formed by the combination of amide bonds.
  • This structure is the main component of the cell membrane and also an important component of the signal molecule. It participates in a variety of cellular processes and plays an important role, such as endocytosis, cell signal transduction, cell heat stress response and cell apoptosis, etc. It also plays an important role in the pathogenesis of fungal cells, and has a good Anti-fungal effect.
  • An antifungal compound is stearyl leucine
  • the preparation method of stearyl leucine is as follows:
  • Figure 4 is the NMR spectrum of octadecyl leucine. It can be simply analyzed from Figure 4 that the product is octadecyl leucine.
  • Example 2 The same experiment as the antifungal test in Example 1 was used to carry out the antifungal experiment of leucine octadecyl ester, and the results showed that the leucine octadecyl ester had good effects on antifungal and drug resistance.
  • An antifungal compound is leucine hexaalkyl ester
  • the preparation method of the leucine hexaalkyl ester is as follows:
  • Figure 5 is the NMR spectrum of leucine hexaalkyl ester. It can be simply analyzed by Figure 5 that the product is leucine hexaalkyl ester.
  • the antifungal experiment of leucine hexaalkyl ester was carried out using the same experiment as the antifungal detection in Example 1, and the results showed that the leucine hexaalkyl ester had good antifungal effects.
  • An antifungal compound wherein the antifungal compound is an iso-octadecyl leucine ester, and the preparation method of the iso-octadecyl leucine ester is as follows:
  • An antifungal compound is 3-methylpentyl leucine ester, and the preparation method of the 3-methylpentyl leucine ester is as follows:
  • An antifungal compound is 3-methyl-4-n-decylleucine ester, and the preparation method of the 3-methylpentylleucine ester is as follows:
  • An antifungal compound is 9-octadecene-1-leucine ester, and the preparation method of the 9-octadecene-1-amino acid ester is as follows:
  • the antifungal test of 9-octadecen-1-leucine ester was carried out using the same experiment as the antifungal test in Example 1. The results showed that 9-octadecen-1-leucine ester was uniform in antifungal aspects. Has a good effect.
  • An antifungal compound is 3-hexene-1-leucine ester, and the preparation method of the 3-hexene-1-leucine ester is as follows:
  • An antifungal compound is 11-hexadecene-1-leucine ester
  • the preparation method of the 11-hexadecene-1-leucine ester is as follows:
  • An antifungal compound is 6-methyl-3-heptene-2-leucine ester, and the preparation method of the 6-methyl-3-heptene-2-leucine ester as follows:
  • the antifungal test of 6-methyl-3-heptene-2-leucine ester was carried out using the same test as the antifungal test in Example 1. The result showed that: 6-methyl-3-heptene-2-liang
  • the amino acid esters have good antifungal effects.
  • An antifungal compound is valine dodecyl ester
  • the preparation method of the valine dodecyl ester is as follows:
  • valine dodecyl ester had good antifungal effects.
  • An antifungal compound is 6-heptene-3-glutamate
  • the preparation method of the 6-heptene-3-glutamate is as follows:
  • the antifungal test of 6-heptene-3-glutamate was carried out using the same experiment as the antifungal test in Example 1. The results showed that 6-heptene-3-glutamate has good antifungal properties. Effect.
  • An antifungal compound is pentyl threonine ester
  • the preparation method of the pentyl threonine ester is as follows:
  • the antifungal test of pentyl threonine ester was carried out using the same experiment as the antifungal test in Example 1, and the results showed that the pentyl threonine ester had good antifungal effects.
  • An antifungal compound is 3-hexadecylserine, and the preparation method of the 3-hexadecylserine is as follows:
  • An antifungal compound is 4-pentene-1-arginine ester
  • the preparation method of the 4-pentene-1-arginine ester is as follows:
  • An antifungal compound is 2,6-dimethylheptene-5-serine ester
  • the preparation method of the 2,6-dimethylheptene-5-serine ester is as follows:
  • An antifungal compound is undecenyl alanine ester
  • the preparation method of the undecenyl alanine ester is as follows:
  • the antifungal experiment of undecenyl alanine ester was carried out using the same experiment as the antifungal detection in Example 1, and the results showed that undecenyl alanine ester had good antifungal effects.

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Abstract

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（I）。其中，R1为C5-C17烷烃基或C5-C17烯烃基中的一种；所述R2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。

Description

一种抗真菌化合物、合成方法及其应用 技术领域
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。
背景技术
真菌感染是临床主要的感染性疾病之一，其分为浅表性真菌病和侵袭性真菌病。其中侵袭性真菌病近几十年来发病率与病死率均呈逐年上升趋势。尤其在一些特殊的患者人群中，如：器官移植患者、ICU重症患者和血液病等免疫功能低下患者,其发病率高达约29％，病死率更高达49％。
目前，临床可选用治疗真菌感染的药物种类并不多，主要有多烯类、吡咯类、棘白菌素类和5-氟胞嘧啶(5-FC)等。多烯类是最早应用于临床的抗真菌药物，主要是两性霉素B及类似物，通过作用于真菌细胞膜上特有的甾醇结合，损伤真菌细胞膜的通透性而抑制真菌生长。该类药物优点是抗真菌谱广，活性强，缺点是毒性大，如肝毒性、肾毒性及输液相关毒性等。吡咯类包括咪唑类与三唑类，通过作用于真菌细胞膜上的麦角甾醇影响细胞膜的稳定性，使真菌细胞破裂而死亡。咪唑类主要代表药物有酮康唑、克霉唑、咪康唑等，适用于治疗浅表性真菌感染。三唑类主要代表药物有氟康唑、伏立康唑、伊曲康唑等，可用于治疗深部真菌感染。该类药物对肝肾功能有一定的影响并有其他一些不良反应。5-氟胞嘧啶的作用机制是干扰真菌细胞的核酸、蛋白质合成，易出现真菌耐药，一般不单独使用。棘白菌素类是相对较新的强效抗真菌药，通过非竞争性抑制剂1，3-β-D-葡聚糖合成酶破坏真菌细胞壁而使真菌溶解死亡，具有高效低毒的临床效果。其代表药物有卡泊芬净、米卡芬净等。
近几十年来抗真菌药物的研发进展缓慢，较新的棘白菌素类卡泊芬净于1970年发现并于2000年开始应用于临床后，近20年来未见有新型抗真菌药物研发并成功应用。由于临床抗真菌药物可选种类和数量的不足，致真菌耐药情况亦越趋严重，甚至已经多次出现有“超级真菌”对卡泊芬净、米卡芬净等抗真菌最后防线药物都出现耐药的现象，严重威胁着患者生命健康安全。因此，尽快寻 找更多更好的新型抗真菌药物，有效克服真菌耐药问题是当前科技工作者迫切需要解决的重要任务。
发明内容
针对现有技术中的问题，本发明提供一种抗真菌化合物，具有良好的抗真菌效果，可制备抗真菌剂。
为实现以上技术目的，本发明的技术方案是：
一种抗真菌化合物，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。
所述氨基酸碳酯具有如下结构式：
Figure PCTCN2020130777-appb-000001
其中，R 1为C5-C17烷烃基或C5-C17烯烃基中的一种；所述R 2为氨基酸侧链基团。
进一步的，所述R 1为总碳数是C5-C17的直链烷烃基或总碳数是C5-C17的带侧链烷烃基中的一种。
进一步的，所述R 1为总碳数是C5-C17的直链烯烃基或总碳数是C5-C17的带侧链烯烃基中的一种。
一种抗真菌化合物的制备方法，即所述氨基酸碳酯的制备方法，以氨基酸和碳醇为原料，回流反应得到，具体步骤如下：
步骤1，将氨基酸溶解在甲苯中形成氨基酸甲苯液，所述氨基酸在甲苯中的浓度为0.5mol/L；
步骤2，将碳醇和对甲苯磺酸加入至氨基酸甲苯液中回流反应，水共沸分离，得到氨基酸碳酯，所述碳醇的加入量是氨基酸摩尔量一致，对甲苯磺酸的加入量与氨基酸摩尔量一致，所述回流反应采用缓慢升温的方式将温度提升至回流温度。
所述步骤2采用薄层色谱法进行反应监测。
进一步的，所述氨基酸碳酯的提纯步骤如下：
步骤a，将水共沸分离后的反应混合物真空浓缩，过滤得到残渣；
步骤b，采用乙酸乙酯提取残渣，然后依次采用碳酸钠水溶液和盐水洗涤，并利用硫酸钠干燥有机层，真空浓缩得到粗品，所述碳酸钠水溶液中的碳酸钠的质量浓度为5％，；
步骤c，采用硅胶层析粗品，得到产品，所述硅胶中的MeOH:DCM＝1:50-1:5。
一种抗真菌化合物的应用，所述抗真菌化合物作为抗真菌剂的应用，即氨基酸碳酯或其药物学上可接受的盐作为抗真菌剂的应用。
一种抗真菌化合物的应用，所述抗真菌化合物在制备抗真菌药物方面的应用，即氨基酸碳酯或其药物学上可接受的盐在制备抗真菌药物方面的应用。
一种抗真菌组合物，包括有效成分为抗真菌化合物，以及一种或多种药学上可接受的辅料，具体的是以氨基酸碳酯或其药物学上可接受的盐为活性成分，配合一种或多种药学上可接受的辅料。
从以上描述可以看出，本发明具备以下优点：
1.本发明的抗真菌化合物具有良好的抗真菌效果，可制备抗真菌剂。
2.本发明采用缓慢升温的方式配合回流反应，有效的控制反应的进行，具有不错的反应效率与反应稳定性，有效的降低了副反应。
3.本发明利用薄层色谱跟踪反应进度，能够有效的控制反应进行，有效的保证反应高效性。
附图说明
图1是本发明实施例1中的亮氨酸十二烷基酯的红外谱图；
图2是本发明实施例1中的亮氨酸十二烷基酯的质谱谱图；
图3是本发明实施例1中的亮氨酸十二烷基酯的核磁谱图；
图4是本发明实施例2中的亮氨酸十八烷基酯的核磁谱图；
图5是本发明实施例3中的亮氨酸十八烷基酯的核磁谱图。
具体实施方式
结合图1至图3，详细说明本发明的一个具体实施例，但不对本发明的权利要求做任何限定。
亮氨酸：
实施例1
一种抗真菌化合物，所述抗真菌化合物为亮氨酸十二烷基酯，所述亮氨酸十二烷基酯的结构式如下：
Figure PCTCN2020130777-appb-000002
所述亮氨酸十二烷基酯的制备方法如下：
将十二醇(16.8g，0.1mol)和对甲苯磺酸(20.9g，0.1mol)添加到DL-亮氨酸(13.1g，0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml)提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:50)得到黄色的油状亮氨酸十二烷基酯(10g，33％)。
图1是亮氨酸十二烷基酯的红外谱图，图2是亮氨酸十二烷基酯的质谱谱图，图3是亮氨酸十二烷基酯的核磁谱图，经图1至图3可以验证，产物为亮氨酸十二烷基酯。
1.抗真菌药敏检测试验
本实施例的亮氨酸十二烷基酯采用对半稀释实验的方式进行抗真菌检测，以卡泊芬净为对照，所述卡泊芬净为市售药物。
检测浓度如下：
药物名称 检测浓度(μg/mL)
本实施例 100,50,25,12.5,6.25,3.125,1.56,0.78,0.39,0.195
卡泊芬净 100,50,25,12.5,6.25,3.125,1.56,0.78,0.39,0.195
实验菌株采用烟曲霉、孢子丝、隐球菌、根霉；阳性对照菌：近平滑、克柔。
Figure PCTCN2020130777-appb-000003
Figure PCTCN2020130777-appb-000004
其中：
本实施例产品(MIC):与阳性对照孔相比抑制真菌生长率达100％的最低药物浓度。
卡泊芬净(MIC/MEC):与阳性对照孔相比抑制菌生长达50％的最低药物浓度。丝状菌与阳性对照孔相比生长受限，菌落皱缩的最低药物浓度为最低有效浓度(MEC)。
经上述数据，可以明确得出，亮氨酸十二烷基酯在某些真菌的抗真菌效果明显优于卡泊芬净，因此，亮氨酸十二烷基酯在抗真菌方面具有良好的抑菌效果。
在本实施例中，氨基酸与十二烷醇形成的亮氨酸十二烷基酯具有通过酰胺键相结合生成的两性脂，该结构是细胞膜的主要构成组份，也是信号分子的重要构成，其参与多种细胞过程并发挥着重要作用，如细胞内吞作用，细胞信号转导，细胞热应激反应和细胞凋亡等，在真菌细胞的发病机理中也起着重要作用，具有良好的抗真菌效果。
实施例2
一种抗真菌化合物，所述抗真菌化合物为亮氨酸十八烷基酯，所述亮氨酸十八烷基酯的制备方法如下：
将十八醇(0.1mol)和对甲苯磺酸(0.1mol)添加到亮氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml)提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:5)得到亮氨酸十八烷基酯(39％)。
图4是亮氨酸十八烷基酯的核磁谱图，通过图4可以简单分析，产物为亮氨酸十八烷基酯。
采用与实施例1中抗真菌检测相同的实验进行亮氨酸十八烷基的抗真菌实验，结果表明：亮氨酸十八烷基酯在抗真菌及其耐药方面均具有不错的效果。
Figure PCTCN2020130777-appb-000005
实施例3
一种抗真菌化合物，所述抗真菌化合物为亮氨酸六烷酯，所述亮氨酸六烷酯的制备方法如下：
将己醇(0.1mol)和对甲苯磺酸(0.1mol)添加到亮氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml)提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:20)得到亮氨酸六烷酯(36％)。
图5是亮氨酸六烷酯的核磁谱图，通过图5可以简单分析，产物为亮氨酸六烷酯。
采用与实施例1中抗真菌检测相同的实验进行亮氨酸六烷酯的抗真菌实验，结果表明：亮氨酸六烷酯在抗真菌方面均具有不错的效果。
Figure PCTCN2020130777-appb-000006
实施例4
一种抗真菌化合物，所述抗真菌化合物为异构十八烷基亮氨酸酯，所述异构十八烷基亮氨酸酯的制备方法如下：
将异构十八醇(0.1mol)和对甲苯磺酸(0.1mol)添加到亮氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml) 提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:10)得到异构十八烷基亮氨酸酯(36％)。
采用与实施例1中抗真菌检测相同的实验进行异构十八烷基亮氨酸酯的抗真菌实验，结果表明：异构十八烷基亮氨酸酯在抗真菌及其耐药方面均具有不错的效果。
实施例5
一种抗真菌化合物，所述抗真菌化合物为3-甲基戊烷基亮氨酸酯，所述3-甲基戊烷基亮氨酸酯的制备方法如下：
将3-甲基-1-戊醇(0.1mol)和对甲苯磺酸(0.1mol)添加到亮氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml)提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:10)得到3-甲基戊烷基亮氨酸酯(37％)。
采用与实施例1中抗真菌检测相同的实验进行3-甲基戊烷基亮氨酸酯的抗真菌实验，结果表明：3-甲基戊烷基亮氨酸酯在抗真菌方面均具有不错的效果。
实施例6
一种抗真菌化合物，所述抗真菌化合物为3-甲基-4-正癸烷基亮氨酸酯，所述3-甲基戊烷基亮氨酸酯的制备方法如下：
将3-甲基-4-正癸醇(0.1mol)和对甲苯磺酸(0.1mol)添加到亮氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml)提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:10)得到3-甲基-4-正癸烷基亮氨酸酯(37％)。
采用与实施例1中抗真菌检测相同的实验进行3-甲基-4-正癸烷基亮氨酸酯的抗真菌实验，结果表明：3-甲基-4-正癸烷基亮氨酸酯在抗真菌方面均具有不错的效果。
实施例7
一种抗真菌化合物，所述抗真菌化合物为9-十八烯-1-亮氨酸酯，所述9-十八烯-1-氨基酸酯的制备方法如下：
将9-十八烯-1-醇(0.1mol)和对甲苯磺酸(0.1mol)添加到亮氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml)提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:5)得到9-十八烯-1-亮氨酸酯(35％)。
采用与实施例1中抗真菌检测相同的实验进行9-十八烯-1-亮氨酸酯的抗真菌实验，结果表明：9-十八烯-1-亮氨酸酯在抗真菌方面均具有不错的效果。
实施例8
一种抗真菌化合物，所述抗真菌化合物为3-己烯-1-亮氨酸酯，所述3-己烯-1-亮氨酸酯的制备方法如下：
将3-己烯-1-醇(0.1mol)和对甲苯磺酸(0.1mol)添加到亮氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml)提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:10)得到3-己烯-1-亮氨酸酯(38％)。
采用与实施例1中抗真菌检测相同的实验进行3-己烯-1-亮氨酸酯的抗真菌实验，结果表明：3-己烯-1-亮氨酸酯在抗真菌方面均具有不错的效果。
实施例9
一种抗真菌化合物，所述抗真菌化合物为11-十六碳烯-1-亮氨酸酯，所述11-十六碳烯-1-亮氨酸酯的制备方法如下：
将11-十六碳烯醇(0.1mol)和对甲苯磺酸(0.1mol)添加到亮氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml)提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:40)得到11-十六碳烯-1-亮氨酸酯(34％)。
采用与实施例1中抗真菌检测相同的实验进行11-十六碳烯-1-亮氨酸酯的抗真菌实验，结果表明：11-十六碳烯-1-亮氨酸酯在抗真菌方面均具有不错的效果。
实施例10
一种抗真菌化合物，所述抗真菌化合物为6-甲基-3-庚烯-2-亮氨酸酯，所述6-甲基-3-庚烯-2-亮氨酸酯的制备方法如下：
将6-甲基-3-庚烯-2-醇(0.1mol)和对甲苯磺酸(0.1mol)添加到谷氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml)提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:10)得到6-甲基-3-庚烯-2-亮氨酸酯(37％)。
采用与实施例1中抗真菌检测相同的实验进行6-甲基-3-庚烯-2-亮氨酸酯的抗真菌实验，结果表明：6-甲基-3-庚烯-2-亮氨酸酯在抗真菌方面均具有不错的效果。
其他氨基酸：
实施例11
一种抗真菌化合物，所述抗真菌化合物为缬氨酸十二烷酯，所述缬氨酸十二烷酯的制备方法如下：
将十二醇(0.1mol)和对甲苯磺酸(0.1mol)添加到缬氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml)提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:5)得到缬氨酸十二烷酯(38％)。
采用与实施例1中抗真菌检测相同的实验进行缬氨酸十二烷酯的抗真菌实验，结果表明：缬氨酸十二烷酯在抗真菌方面均具有不错的效果。
Figure PCTCN2020130777-appb-000007
实施例12
一种抗真菌化合物，所述抗真菌化合物为6-庚烯-3-谷氨酸酯，所述6-庚烯-3-谷氨酸酯的制备方法如下：
将6-庚烯-3-醇(0.1mol)和对甲苯磺酸(0.1mol)添加到谷氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml)提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:10)得到6-庚烯-3-谷氨酸酯(38％)。
采用与实施例1中抗真菌检测相同的实验进行6-庚烯-3-谷氨酸酯的抗真菌实验，结果表明：6-庚烯-3-谷氨酸酯在抗真菌方面均具有不错的效果。
实施例13
一种抗真菌化合物，所述抗真菌化合物为戊烷基苏氨酸酯，所述戊烷基苏氨酸酯的制备方法如下：
将正戊醇(0.1mol)和对甲苯磺酸(0.1mol)添加到苏氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml)提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:10)得到戊烷基苏氨酸酯(37％)。
采用与实施例1中抗真菌检测相同的实验进行戊烷基苏氨酸酯的抗真菌实验，结果表明：戊烷基苏氨酸酯在抗真菌方面均具有不错的效果。
实施例14
一种抗真菌化合物，所述抗真菌化合物为3-十六烷基丝氨酸，所述3-十六烷基丝氨酸的制备方法如下：
将3-十六碳醇(0.1mol)和对甲苯磺酸(0.1mol)添加到丝氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml)提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:40)得到3-十六烷基丝氨酸(38％)。
采用与实施例1中抗真菌检测相同的实验进行3-十六烷基丝氨酸的抗真菌实验，结果表明：3-十六烷基丝氨酸在抗真菌方面均具有不错的效果。
实施例15
一种抗真菌化合物，所述抗真菌化合物为4-戊烯-1-精氨酸酯，所述4-戊烯-1-精氨酸酯的制备方法如下：
将4-戊烯-1-醇(0.1mol)和对甲苯磺酸(0.1mol)添加到精氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml) 提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:40)得到4-戊烯-1-精氨酸酯(34％)。
采用与实施例1中抗真菌检测相同的实验进行4-戊烯-1-精氨酸酯的抗真菌实验，结果表明：4-戊烯-1-精氨酸酯在抗真菌方面均具有不错的效果。
实施例16
一种抗真菌化合物，所述抗真菌化合物为2,6-二甲基庚烯-5-丝氨酸酯，所述2,6-二甲基庚烯-5-丝氨酸酯的制备方法如下：
将2,6-二甲基-5-庚烯醇(0.1mol)和对甲苯磺酸(0.1mol)添加到苏丝氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml)提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:15)得到2,6-二甲基庚烯-5-丝氨酸酯(39％)。
采用与实施例1中抗真菌检测相同的实验进行2,6-二甲基庚烯-5-丝氨酸酯的抗真菌实验，结果表明：2,6-二甲基庚烯-5-丝氨酸酯在抗真菌方面均具有不错的效果。
实施例17
一种抗真菌化合物，所述抗真菌化合物为十一碳烯基丙氨酸酯，所述十一碳烯基丙氨酸酯的制备方法如下：
将十一碳烯醇(0.1mol)和对甲苯磺酸(0.1mol)添加到丙氨酸(0.1mol)的甲苯(200mL)溶液中，缓慢升温至回流温度，水共沸分离，用薄层色谱法对反应物进行监测。反应混合物在真空下浓缩，所得残渣用乙酸乙酯(200ml)提取，用5％Na 2CO 3水溶液(3×50ml)洗涤，然后用盐水溶液洗涤。在Na 2SO 4上干燥有机层，在真空下浓缩得到粗品，硅胶层析(MeOH:DCM＝1:10)得到十一碳烯基丙氨酸酯(37％)。
采用与实施例1中抗真菌检测相同的实验进行十一碳烯基丙氨酸酯的抗真菌实验，结果表明：十一碳烯基丙氨酸酯在抗真菌方面均具有不错的效果。
可以理解的是，以上关于本发明的具体描述，仅用于说明本发明而并非受限于本发明实施例所描述的技术方案。本领域的普通技术人员应当理解，仍然可以对本发明进行修改或等同替换，以达到相同的技术效果；只要满足使用需要，都在本发明的保护范围之内。

Claims (7)

  1. 一种抗真菌化合物，其特征在于：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。
  2. 根据权利要求1所述的抗真菌化合物，其特征在于：所述氨基酸碳酯具有如下结构式：
    Figure PCTCN2020130777-appb-100001
    其中，R 1为C5-C17烷烃基或C5-C17烯烃基中的一种；所述R 2为氨基酸侧链基团。
  3. 一种抗真菌化合物的制备方法，其特征在于：以氨基酸和碳醇为原料，回流反应得到氨基酸碳酯；其制备方法的具体步骤如下：
    步骤1，将氨基酸溶解在甲苯中形成氨基酸甲苯液，所述氨基酸在甲苯中的浓度为0.5mol/L；
    步骤2，将碳醇和对甲苯磺酸加入至氨基酸甲苯液中回流反应，水共沸分离，得到氨基酸碳酯，所述碳醇的加入量是氨基酸摩尔量一致，对甲苯磺酸的加入量与氨基酸摩尔量一致，所述回流反应采用缓慢升温的方式将温度提升至回流温度；采用薄层色谱法进行反应监测。
  4. 根据权利要求3所述的抗真菌化合物的制备方法，其特征在于：所述氨基酸碳酯的提纯步骤如下：
    步骤a，将水共沸分离后的反应混合物真空浓缩，过滤得到残渣；
    步骤b，采用乙酸乙酯提取残渣，然后依次采用碳酸钠水溶液和盐水洗涤，并利用硫酸钠干燥有机层，真空浓缩得到粗品，所述碳酸钠水溶液中的碳酸钠的质量浓度为5％，；
    步骤c，采用硅胶层析粗品，得到产品，所述硅胶中的MeOH:DCM＝1:50-1:5。
  5. 一种如权利要求2-4任意一项所述的抗真菌化合物的应用，所述抗真菌化合物作为抗真菌剂的应用，即氨基酸碳酯或其药物学上可接受的盐作为抗真菌剂的应用。
  6. 一种如权利要求2-4任意一项所述的抗真菌化合物的应用，所述抗真菌化合物在制备抗真菌药物方面的应用，即氨基酸碳酯或其药物学上可接受的盐在制备抗真菌药物方面的应用。
  7. 一种如权利要求2-4任意一项所述的抗真菌化合物的应用，一种抗真菌组合物，包括有效成分为抗真菌化合物，以及一种或多种药学上可接受的辅料。
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