WO2019072112A1 - Series of dimeric indole alkaloid compounds, preparation method therefor and use of same in preparation of antibacterial drugs - Google Patents

Series of dimeric indole alkaloid compounds, preparation method therefor and use of same in preparation of antibacterial drugs Download PDF

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WO2019072112A1
WO2019072112A1 PCT/CN2018/108524 CN2018108524W WO2019072112A1 WO 2019072112 A1 WO2019072112 A1 WO 2019072112A1 CN 2018108524 W CN2018108524 W CN 2018108524W WO 2019072112 A1 WO2019072112 A1 WO 2019072112A1
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compound
hydrogen
dimeric
preparation
pharmaceutically acceptable
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Chinese (zh)
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郭跃伟
蓝乐夫
李序文
陈菲菲
刘进
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中国科学院上海药物研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61P31/04—Antibacterial agents

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  • the invention belongs to the field of organic synthesis and medicinal chemistry.
  • it relates to a class of dimeric indole alkaloids, a process for their preparation and their use in the preparation of antibacterial agents.
  • the results showed that these compounds have strong antibacterial activity, especially for the resistant strains of Staphylococcus aureus and Enterococcus, and can be used as a new lead compound for the development of antibacterial drugs.
  • Staphylococcus aureus is an important pathogen, a Gram-positive bacterium belonging to the genus Staphylococcus. It is the most common pathogen in human purulent infection, can cause local suppurative infection, can also cause pneumonia, pseudomembranous colitis, pericarditis, etc., and even systemic infections such as sepsis and sepsis, and has another name for "felophilic bacteria". In recent years, the US Centers for Disease Control has reported that infections caused by Staphylococcus aureus are second only to E. coli. Staphylococcal enterotoxin is a worldwide health problem.
  • Enterococcus belongs to the genus Enterococcus, which is part of the normal flora of human and animal gut. It is usually found in mixed hyphae that cause infection of the abdominal cavity and pelvic cavity. It is considered that Enterococcus is a harmless bacterium that is harmless to humans. However, recent studies have confirmed the virulence of Enterococcus. Among aerobic gram-positive cocci, it is an important nosocomial infection pathogen after Staphylococcus, and enterococci can cause out-of-hospital infection. Enterococcus can cause not only urinary tract infections, skin and soft tissue infections, but also life-threatening abdominal infections, sepsis, endocarditis and meningitis.
  • Group A streptococci also known as streptococcus pyogenes, is one of the most important pathogens in human bacterial infections.
  • the main infections are acute pharyngitis, acute tonsillitis, pulmonary infection, scarlet fever, skin and soft tissue infections, and systemic infections.
  • This bacterium is also an indirect cause of allergic disease rheumatic fever and acute glomerulonephritis.
  • the serious infection caused by group A streptococci the increase in the incidence of invasive group A streptococcus infections, has also caused people to pay more attention to this type of bacterial infection.
  • a streptococcus group can invade people of any age, but the majority of the cases are children.
  • Staphylococcus epidermidis is a bacterium that breeds on the epidermis of living organisms. It is parasitic on the skin, vagina and other parts of the human body and belongs to the normal flora type. Staphylococcus is a group of Gram-positive cocci, which are often clustered into bunches of grapes. Most are non-pathogenic, and a few can cause disease. Staphylococcus is the most common pyogenic cocci, and is an important source of cross-infection in hospitals.
  • ⁇ -lactams include penicillins, cephalosporins, carbapenems, ⁇ -lactams containing enzyme inhibitors, and monocyclic amides. ; aminoglycosides; tetracyclines; fluoroquinolones; folic acid pathway inhibitors; chloramphenicol; glycopeptides including vancomycin and teicoplanin; macrolides.
  • these antibacterial drugs generally have problems of side effects and drug resistance. For example, the most badly adverse reaction of ⁇ -lactam antibiotics is anaphylactic shock, and the adverse reactions of macrolide antibiotics are gastrointestinal reactions.
  • alkaloids are numerous and complex in structure type. Most alkaloids have various significant physiological activities, and the antibacterial activity of some alkaloids is gradually being discovered. Today, antibiotics are widely used and resistant bacteria are increasing. The role of alkaloids in antibacterial has received wide attention. Domestic and foreign authors not only carry out antibacterial research on natural alkaloid products, but also study the structure-activity relationship and structural modification of natural alkaloids on the basis of this, aiming to enhance the antibacterial activity of alkaloids.
  • the present inventors structurally modified and modified the marine natural product Phidianidine, and carried out activity screening, and found that a class of dimeric alkaloid compounds have strong antibacterial activity, especially for Gram-positive. Strains such as Staphylococcus, Bacillus, Enterococcus and related strains have specific inhibitory effects. And so far, no reports have been made on the synthesis methods and applications of such compounds.
  • the present invention relates to a method for the synthesis of a class of dimeric indole alkaloids, such as structural formula I, and their use in the preparation of antibacterial agents.
  • the purpose of this aspect is to provide a novel structure of dimeric guanidine alkaloids having a therapeutic effect on infections caused by broad-spectrum bacteria and drug-resistant bacteria.
  • a first aspect of the present invention provides a dimeric indole alkaloid compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C1-C12 alkyl, C1-C12 alkoxy;
  • n is an integer from 1 to 12;
  • R 1 , R 3 , and R 4 are all hydrogen, and R 2 is selected from the group consisting of hydrogen, fluorine, chlorine, and bromine;
  • n is an integer from 2-6.
  • the compound of formula (I) is selected from the following specific compounds:
  • R 1 , R 2 , R 3 , and R 4 are all hydrogen, and n is 2;
  • R 1 , R 2 , R 3 , and R 4 are all hydrogen, and n is 6;
  • R 1 , R 3 , R 4 are all hydrogen, R 2 is fluorine, and n is 5;
  • R 1 , R 3 , R 4 are all hydrogen, R 2 is chlorine, and n is 5;
  • R 1 , R 3 and R 4 are all hydrogen, R 2 is bromine, and n is 5.
  • R 1 , R 2 , R 3 , R 4 and n are the same as described above.
  • Step (1) is that the base is triethylamine
  • Step (1) is carried out in the presence of an organic solvent, preferably dichloromethane.
  • the base described in the steps (2) and (3) is sodium hydrogencarbonate.
  • a pharmaceutical composition comprising: a dimeric indole alkaloid compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier are provided.
  • the pharmaceutical composition comprises from 1% by weight to 96% by weight, preferably from 10% by weight to 85% by weight, of the dimeric indolinoid compound or a pharmaceutically acceptable salt thereof, The total weight of the pharmaceutical composition.
  • the pharmaceutically acceptable carrier comprises sugar, starch, cellulose and derivatives thereof, gelatin, talc, solid lubricants, vegetable oils, polyols, emulsifiers, wetting agents, colorants, Flavoring agents, stabilizers, antioxidants, preservatives and pyrogen-free water.
  • a dimeric indole alkaloid compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in the preparation of an antibacterial agent, in particular Preparation of a drug for inhibiting drug-resistant bacteria.
  • the preliminary pharmacological experiment results of each strain showed that the initial inhibitory concentration was between ⁇ 0.125-4 ⁇ g/mL, indicating that it has significant inhibitory effect, and it is expected to be applied in the preparation of antibacterial drugs.
  • a method of an antibacterial agent comprising the steps of:
  • the dimeric alkaloid compound represented by the formula (I) or the pharmaceutical composition is administered to a subject in need of treatment.
  • the subject is a human or non-human mammal such as a cow, a rat, or a mouse.
  • the dimeric alkaloid of the invention has novel structure, simple and convenient operation route, high yield and good safety, and against Staphylococcus aureus, Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis, Bacillus subtilis, pus Streptococcus, and related drug-resistant bacteria have obvious inhibitory effects, and can be used for preparing antibacterial and anti-drug resistant drugs.
  • Example 1 the ethylenediamine in the step (1) was replaced with 1,5-pentanediamine, and the indole acetic acid in the step (4) was replaced with 5-fluoro-indoleacetic acid.
  • Compound 1c was obtained as a pale yellow oil.
  • ethylenediamine in step (1) was replaced with 1,5-pentanediamine, and the indole acetic acid in step (4) was replaced with 5-bromo-indoleacetic acid.
  • Compound 1e was obtained as a pale yellow oil.
  • the medium used in the experiment was TSB medium containing 5% DMSO.
  • the bacteria used were Newman Staphylococcus aureus Newman strain [G+,methicillin sensitive Staphylococcus aureus (MSSA), vancomycin sensitive)], methicillin resistant & vancomycin moderately resistant Mu50 Staphylococcus Staphylococcus Aureus Mu50strain [G+, MRSA (methicillin-resistant S. aureus) & VISA (vancomycin-intermediate S.
  • the dimeric indole alkaloid compound prepared in Example 1-5 was dissolved in DMSO to a stock solution of 5.12 mg/mL. Then, all the samples were diluted to 256 ⁇ g/mL with the culture solution (ie, TSB medium containing 5% DMSO) as a starting concentration, and further subjected to a 1:2 gradient dilution with the culture solution to obtain a concentration ranging from 128 ⁇ g/mL to 0.125. A series of samples at a concentration of ⁇ g/mL, 100 ⁇ L of each concentration sample was placed on a 96-well plate.
  • the culture solution ie, TSB medium containing 5% DMSO
  • DMSO was set in place of the compound of the present invention as a negative control group, and vancomycin and linezolid were set to be treated in the same manner as a positive control group. A blank control group in which no bacteria was added was set, and no bacterial growth was observed in the blank control group.

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Abstract

The present invention falls within in the fields of organic synthesis and pharmaceutical chemistry. In particular, the present invention relates to a series of dimeric indole alkaloid compounds as shown in structural general formula I, preparation methods therefor and the use of same in the preparation of antibacterial drugs. After same undergo in vitro activity screening, the results show that such compounds have strong antibacterial activity, in particular have specific inhibitory effects on gram-positive bacteria, such as strains of staphylococcus, bacillus and enterococcus, and related drug-resistant strains thereof, and can be used as the lead compounds for developing new antibacterial drugs.

Description

一类二聚吲哚生物碱类化合物、其制备方法及其在制备抗菌药物中的应用Dimeric alkaloid compound, preparation method thereof and application thereof in preparing antibacterial medicine 技术领域Technical field
本发明属于有机合成和药物化学药物领域。具体而言，涉及一类二聚吲哚生物碱类化合物、其制备方法及其在制备抗菌药物中的应用。经过体外活性筛选，结果显示此类化合物具有较强的抗菌活性，特别是对于金黄色葡萄球菌和肠球菌的耐药菌株有良好的抑制效果，可作为一类研制新的抗菌药物先导化合物。The invention belongs to the field of organic synthesis and medicinal chemistry. In particular, it relates to a class of dimeric indole alkaloids, a process for their preparation and their use in the preparation of antibacterial agents. After in vitro activity screening, the results showed that these compounds have strong antibacterial activity, especially for the resistant strains of Staphylococcus aureus and Enterococcus, and can be used as a new lead compound for the development of antibacterial drugs.
背景技术Background technique
金黄色葡萄球菌(Staphylococcus aureus)是一种重要的病原菌，革兰氏阳性菌，隶属于葡萄球菌属(Staphylococcus)。它是人类化脓感染中最常见的病原菌，可引起局部化脓感染，也可引起肺炎、伪膜性肠炎、心包炎等，甚至败血症、脓毒症等全身感染，有“嗜肉菌"的别称。近年来，美国疾病控制中心报告，由金黄色葡萄球菌引起的感染占第二位，仅次于大肠杆菌。金黄色葡萄球菌肠毒素是个世界性卫生难题。肠球菌(Enterococcus)属肠球菌属，是人类和动物肠道正常菌群的一部分，通常在引起腹腔和盆腔感染所分离的混合菌丝中发现，既往认为肠球菌是对人类无害的共栖菌，但近年研究已证实了肠球菌的致病力。在需氧革兰阳性球菌中，它是仅次于葡萄球菌的重要院内感染致病菌，肠球菌亦可引起院外感染。肠球菌不仅可引起***、皮肤软组织感染，还可引起危及生命的腹腔感染、败血症、心内膜炎和脑膜炎等。 链球菌群(group A streptococci)又称化脓性链球菌(streptococcus pyogenes)，是人类细菌感染中最重要的病原之一。引起的感染主要有急性咽炎、急性扁桃体炎，也可致肺部感染、猩红热、皮肤软组织感染，并可致全身性感染。该菌也是***反应性疾病风湿热和急性肾小球肾炎的间接原因。近年来由A组链球菌所引起的严重感染，侵袭性A链球菌群(invasive group A streptococcus infections)的发病率的增长，也引起了人们对该类细菌感染更大的关注。A链球菌群可侵袭任何年龄的人，但发病者多为儿童。正常人鼻咽部、皮肤可带菌，并有***、***带菌而引起暴发流行的报告。呼吸道与直接接触均可传播。亦有进食被污染食物曾引起咽峡炎暴发的报道。生活贫困、卫生条件差、居住拥挤、密切接触等均有助于链球菌感染的发生。表皮葡萄球菌是滋生于生物体表皮上的一种细菌。在人体的皮肤，***等部位寄生，属正常菌群类型。葡萄球菌是一群革兰氏阳性球菌，因常堆聚成葡萄串状，故名。多数为非致病菌，少数可导致疾病。葡萄球菌是最常见的化脓性球菌，是医院交叉感染的重要来源。Staphylococcus aureus is an important pathogen, a Gram-positive bacterium belonging to the genus Staphylococcus. It is the most common pathogen in human purulent infection, can cause local suppurative infection, can also cause pneumonia, pseudomembranous colitis, pericarditis, etc., and even systemic infections such as sepsis and sepsis, and has another name for "felophilic bacteria". In recent years, the US Centers for Disease Control has reported that infections caused by Staphylococcus aureus are second only to E. coli. Staphylococcal enterotoxin is a worldwide health problem. Enterococcus belongs to the genus Enterococcus, which is part of the normal flora of human and animal gut. It is usually found in mixed hyphae that cause infection of the abdominal cavity and pelvic cavity. It is considered that Enterococcus is a harmless bacterium that is harmless to humans. However, recent studies have confirmed the virulence of Enterococcus. Among aerobic gram-positive cocci, it is an important nosocomial infection pathogen after Staphylococcus, and enterococci can cause out-of-hospital infection. Enterococcus can cause not only urinary tract infections, skin and soft tissue infections, but also life-threatening abdominal infections, sepsis, endocarditis and meningitis. Group A streptococci, also known as streptococcus pyogenes, is one of the most important pathogens in human bacterial infections. The main infections are acute pharyngitis, acute tonsillitis, pulmonary infection, scarlet fever, skin and soft tissue infections, and systemic infections. This bacterium is also an indirect cause of allergic disease rheumatic fever and acute glomerulonephritis. In recent years, the serious infection caused by group A streptococci, the increase in the incidence of invasive group A streptococcus infections, has also caused people to pay more attention to this type of bacterial infection. A streptococcus group can invade people of any age, but the majority of the cases are children. Normal people have reports of nasopharynx and skin, and there are reports of outbreaks caused by anus and vaginal bacteria. The respiratory tract can be transmitted in direct contact. There have also been reports of outbreaks of angina caused by eating contaminated food. Living poverty, poor sanitation, overcrowding, and close contact all contribute to the development of streptococcal infections. Staphylococcus epidermidis is a bacterium that breeds on the epidermis of living organisms. It is parasitic on the skin, vagina and other parts of the human body and belongs to the normal flora type. Staphylococcus is a group of Gram-positive cocci, which are often clustered into bunches of grapes. Most are non-pathogenic, and a few can cause disease. Staphylococcus is the most common pyogenic cocci, and is an important source of cross-infection in hospitals.
目前临床上常用的抗菌药主要分为八大类，其中β-内酰胺类包括青霉素类、头孢菌素类、碳青霉烯类、含酶抑制剂的β-内酰胺类及单环酰胺类等；氨基糖苷类；四环素类；氟喹诺酮类；叶酸途径抑制剂类；氯霉素；糖肽类包括万古霉素和替考拉宁；大环内酯类。然而，这些抗菌药物一般都存在副作用和耐药性的问题，例如其中的β-内酰胺类抗生素最可怕的不良反应就是过敏性休克，大环内酯类抗生素的不良反应为胃肠道反应、肝功紊乱和过敏反应等，喹诺酮类则会影响生长发育，处于生长发育期的儿童 应该禁用喹诺通类药物。而且，这些药物的自主知识产权都不属于中国，迄今为止，中国也只有一个自主知识产权的抗菌药物-中科院上海药物所研发的盐酸安妥沙星。针对上述现状，迫切需要研发出副作用小、具有良好抗菌活性的并且属于中国自主知识产权的抗菌药物。At present, the commonly used antibacterial drugs in clinical practice are mainly divided into eight categories, among which β-lactams include penicillins, cephalosporins, carbapenems, β-lactams containing enzyme inhibitors, and monocyclic amides. ; aminoglycosides; tetracyclines; fluoroquinolones; folic acid pathway inhibitors; chloramphenicol; glycopeptides including vancomycin and teicoplanin; macrolides. However, these antibacterial drugs generally have problems of side effects and drug resistance. For example, the most terrible adverse reaction of β-lactam antibiotics is anaphylactic shock, and the adverse reactions of macrolide antibiotics are gastrointestinal reactions. In patients with liver dysfunction and allergic reactions, quinolones affect growth and development, and children in growth and development should ban quinolone drugs. Moreover, the independent intellectual property rights of these drugs do not belong to China. So far, China has only one antibacterial drug with independent intellectual property rights - the antibiotics developed by the Shanghai Institute of Traditional Chinese Medicine, and the antibiotics. In view of the above situation, it is urgent to develop antibacterial drugs with small side effects, good antibacterial activity, and belonging to China's independent intellectual property rights.
生物碱作为一类重要的天然产物，其数量众多，结构类型复杂。大多数生物碱具有各种显著的生理活性，其中一些生物碱的抗菌活性也逐渐被发现。在抗生素被广泛使用，耐药菌日趋增加的今天，生物碱在抗菌方面的作用受到了广泛关注。国内外学者不但对天然生物碱产物进行了抗菌研究，而且在此基础上对天然生物碱进行构效关系研究以及结构修饰，旨在增强生物碱类化合物的抗菌活性。As a kind of important natural products, alkaloids are numerous and complex in structure type. Most alkaloids have various significant physiological activities, and the antibacterial activity of some alkaloids is gradually being discovered. Today, antibiotics are widely used and resistant bacteria are increasing. The role of alkaloids in antibacterial has received wide attention. Domestic and foreign scholars not only carry out antibacterial research on natural alkaloid products, but also study the structure-activity relationship and structural modification of natural alkaloids on the basis of this, aiming to enhance the antibacterial activity of alkaloids.
本发明人对海洋天然产物菲地鳃素(Phidianidine)进行结构修饰和改造，并进行活性筛选，发现一类二聚吲哚生物碱类化合物具有较强的抗菌活性，特别是对于革兰氏阳性菌如葡萄球菌、芽孢杆菌、肠球菌等菌株及其相关耐药菌株有特异性的抑制效果。且迄今为止，未见关于这类化合物的合成方法及其应用的报道。本发明涉及一类二聚吲哚生物碱类化合物，如结构式I，的合成方法及其在制备抗菌药物中的应用。The present inventors structurally modified and modified the marine natural product Phidianidine, and carried out activity screening, and found that a class of dimeric alkaloid compounds have strong antibacterial activity, especially for Gram-positive. Strains such as Staphylococcus, Bacillus, Enterococcus and related strains have specific inhibitory effects. And so far, no reports have been made on the synthesis methods and applications of such compounds. The present invention relates to a method for the synthesis of a class of dimeric indole alkaloids, such as structural formula I, and their use in the preparation of antibacterial agents.
发明内容Summary of the invention
本方面的目的在于提供一种新型结构的二聚吲哚生物碱，具有对广谱菌及耐药菌导致的感染的治疗作用。The purpose of this aspect is to provide a novel structure of dimeric guanidine alkaloids having a therapeutic effect on infections caused by broad-spectrum bacteria and drug-resistant bacteria.
本发明的第一方面是提供式(I)所示的二聚吲哚生物碱类化合物或其药学上可接受的盐，A first aspect of the present invention provides a dimeric indole alkaloid compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2018108524-appb-000001
Figure PCTCN2018108524-appb-000001
式中，R 1、R 2、R 3、R 4各自独立地选自氢、氟、氯、溴、C1-C12烷基、C1-C12烷氧基； Wherein R 1 , R 2 , R 3 , R 4 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C1-C12 alkyl, C1-C12 alkoxy;
n为1-12的整数；n is an integer from 1 to 12;
优选地，R 1、R 3、R 4均为氢，R 2选自氢、氟、氯、溴； Preferably, R 1 , R 3 , and R 4 are all hydrogen, and R 2 is selected from the group consisting of hydrogen, fluorine, chlorine, and bromine;
优选地，n为2-6的整数。Preferably, n is an integer from 2-6.
进一步优选地，式(I)所示化合物选自如下具体化合物：Further preferably, the compound of formula (I) is selected from the following specific compounds:
化合物1a：R 1、R 2、R 3、R 4均为氢，n为2； Compound 1a: R 1 , R 2 , R 3 , and R 4 are all hydrogen, and n is 2;
化合物1b：R 1、R 2、R 3、R 4均为氢，n为6； Compound 1b: R 1 , R 2 , R 3 , and R 4 are all hydrogen, and n is 6;
化合物1c：R 1、R 3、R 4均为氢，R 2为氟，n为5； Compound 1c: R 1 , R 3 , R 4 are all hydrogen, R 2 is fluorine, and n is 5;
化合物1d：R 1、R 3、R 4均为氢，R 2为氯，n为5； Compound 1d: R 1 , R 3 , R 4 are all hydrogen, R 2 is chlorine, and n is 5;
化合物1e：R 1、R 3、R 4均为氢，R 2为溴，n为5。 Compound 1e: R 1 , R 3 and R 4 are all hydrogen, R 2 is bromine, and n is 5.
本发明的第二方面，提供所述的二聚吲哚生物碱类化合物的制备方法，可以通过如下步骤实现：In a second aspect of the present invention, there is provided a method for producing the dimeric quinone alkaloid compound, which can be achieved by the following steps:
Figure PCTCN2018108524-appb-000002
Figure PCTCN2018108524-appb-000002
(1)在碱存在的条件下，化合物2与二胺类化合物
Figure PCTCN2018108524-appb-000003
在室温下反应10-12小时得到化合物3； (1) Compound 2 and diamine compounds in the presence of a base
Figure PCTCN2018108524-appb-000003
The reaction is carried out at room temperature for 10-12 hours to obtain a compound 3;
(2)在以水和二氯甲烷为溶剂，在碱存在的条件下，在零摄氏度下向化合物3滴加入溴化氰，然后在室温下反应1-2小时得到化合物4；(2) using water and dichloromethane as a solvent, in the presence of a base, adding cyanogen bromide to compound 3 at zero degrees Celsius, and then reacting at room temperature for 1-2 hours to obtain compound 4;
(3)化合物4在乙醇溶液中，在碱存在的条件下，与盐酸羟胺反应得到化合物5，反应温度室温，反应时间2-4小时；(3) Compound 4 is reacted with hydroxylamine hydrochloride in an ethanol solution in the presence of a base to obtain a compound 5, the reaction temperature is room temperature, and the reaction time is 2-4 hours;
(4)化合物5与有HATU活化的吲哚乙酸(化合物6)在二氯乙烷溶液中在85℃下回流2-3小时，环化得到具有噁二唑环的化合物7；(4) Compound 5 and HATU-activated indoleacetic acid (Compound 6) are refluxed in a solution of dichloroethane at 85 ° C for 2-3 hours, cyclized to give compound 7 having an oxadiazole ring;
(5)化合物7在三氟乙酸的二氯甲烷溶液中反应10-12小时，脱去Boc保护，得化合物1的三氟乙酸盐，通过水解反应等，可以得到化合物1。(5) Compound 7 is reacted in a solution of trifluoroacetic acid in dichloromethane for 10-12 hours, and Boc protection is removed to obtain a trifluoroacetate salt of Compound 1, and Compound 1 can be obtained by a hydrolysis reaction or the like.
其中，R 1、R 2、R 3、R 4、n的定义与前述相同。 Here, the definitions of R 1 , R 2 , R 3 , R 4 and n are the same as described above.
步骤(1)是所述的碱是三乙胺；Step (1) is that the base is triethylamine;
步骤(1)在有机溶剂存在下进行，所述有机溶剂优选为二氯甲烷。Step (1) is carried out in the presence of an organic solvent, preferably dichloromethane.
步骤(2)和(3)中所述的碱是碳酸氢钠。The base described in the steps (2) and (3) is sodium hydrogencarbonate.
本发明的第三方面，提供一种药物组合物，包含：式(I)所示的二聚吲哚生物碱类化合物或其药学上可接受的盐；以及药学上可接受的载体。在另一优选例中，所述药物组合物包含1wt％至96wt％、较佳地为10wt％至85wt％的所述的二聚吲哚生物碱类化合物或其药学上可接受的盐，以所述药物组合物的总重量计。在另一优选例中，所述药学上可以接受的载体包括糖、淀粉、纤维素及其衍生物、明胶、滑石、固体润滑剂、植物油、多元醇、乳化剂、润湿剂、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂和无热原水。According to a third aspect of the present invention, a pharmaceutical composition comprising: a dimeric indole alkaloid compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier are provided. In another preferred embodiment, the pharmaceutical composition comprises from 1% by weight to 96% by weight, preferably from 10% by weight to 85% by weight, of the dimeric indolinoid compound or a pharmaceutically acceptable salt thereof, The total weight of the pharmaceutical composition. In another preferred embodiment, the pharmaceutically acceptable carrier comprises sugar, starch, cellulose and derivatives thereof, gelatin, talc, solid lubricants, vegetable oils, polyols, emulsifiers, wetting agents, colorants, Flavoring agents, stabilizers, antioxidants, preservatives and pyrogen-free water.
本发明的第四方面，提供式(I)所示的二聚吲哚生物碱类化合物或其药学上可接受的盐或所述的药物组合物的用途，用于制备抗菌药物，特别是在制备抑制耐药菌的药物应用中。对各菌株的初步药理实验结果显示其最先抑菌浓度在≤0.125-4μg/mL之间，表明具有显著的抑制效果，有望在制备抗菌药物中得到应用。According to a fourth aspect of the present invention, there is provided a dimeric indole alkaloid compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for use in the preparation of an antibacterial agent, in particular Preparation of a drug for inhibiting drug-resistant bacteria. The preliminary pharmacological experiment results of each strain showed that the initial inhibitory concentration was between ≤0.125-4μg/mL, indicating that it has significant inhibitory effect, and it is expected to be applied in the preparation of antibacterial drugs.
本发明的第五方面，提供一种抗菌药物的方法，包括步骤：According to a fifth aspect of the invention, there is provided a method of an antibacterial agent comprising the steps of:
给需要治疗的对象施用式(I)所示的二聚吲哚生物碱类化合物或所述的药物组合物。所述对象为人或非人哺乳动物，如牛、大鼠、小鼠。本发明的二聚吲哚生物碱，结构新颖，合成路线操作简便，收率高，安全性好，对金黄色葡萄球菌、表面葡萄球菌、屎肠球菌、粪肠球菌、枯草芽孢杆菌、酿脓链球菌、及相关耐药菌具有明显的抑制作用，可用于制备抗菌及抗耐药菌药物。The dimeric alkaloid compound represented by the formula (I) or the pharmaceutical composition is administered to a subject in need of treatment. The subject is a human or non-human mammal such as a cow, a rat, or a mouse. The dimeric alkaloid of the invention has novel structure, simple and convenient operation route, high yield and good safety, and against Staphylococcus aureus, Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis, Bacillus subtilis, pus Streptococcus, and related drug-resistant bacteria have obvious inhibitory effects, and can be used for preparing antibacterial and anti-drug resistant drugs.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从 而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It is to be understood that within the scope of the present invention, the above-described various technical features of the present invention and the technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
具体实施方式：Detailed ways:
以下的实施例是说明本发明的，而不是以任何方式限制本发明。The following examples are illustrative of the invention and are not intended to limit the invention in any way.
实施例1化合物1a的制备：Preparation of Compound 1a of Example 1:
(1)取0.28g乙二胺溶于30ml二氯甲烷，加入0.47g三乙胺，再滴加入1.50g溶于二氯甲烷的化合物2(N,N’-di-Boc-N”-triflylguanidine)。于室温下搅拌反应10-12h.用饱和碳酸氢钠溶液洗涤萃取2次，水和饱和食盐水再分别洗涤萃取一次。有机相用无水硫酸钠干燥，过滤浓缩，残余物经硅胶柱层析(洗脱剂为乙酸乙酯：甲醇：三乙胺(体积比)＝10:1:0.1)的无色油状物。得化合物3a。(1) 0.28 g of ethylenediamine was dissolved in 30 ml of dichloromethane, 0.47 g of triethylamine was added, and 1.50 g of compound 2 (N,N'-di-Boc-N"-triflylguanidine dissolved in dichloromethane was added dropwise. The reaction was stirred at room temperature for 10-12 h. The extract was washed twice with a saturated aqueous solution of sodium bicarbonate, and then extracted twice with water and brine. The organic phase was dried over anhydrous sodium sulfate. Chromatography (eluent: ethyl acetate:methanol: triethylamine (volume ratio) = 10:1:0.1).
(2)化合物3a溶于二氯甲烷，在加入碳酸氢钠水溶液，在零摄氏度下滴加入溶于二氯甲烷的溴化氰，再在室温下反应搅拌1-2h，加水分离萃取得到有机相用无水硫酸钠干燥，过滤浓缩，残余物经硅胶柱层析(洗脱剂为乙酸乙酯：石油醚(体积比)＝1:1)的无色油状物，即化合物4a。(2) Compound 3a is dissolved in dichloromethane, and an aqueous solution of sodium hydrogencarbonate is added thereto, and cyanogen bromide dissolved in dichloromethane is added dropwise at zero degrees Celsius, and the mixture is stirred at room temperature for 1-2 hours, and extracted with water to obtain an organic phase. The mixture was dried over anhydrous sodium sulfate (MgSO4).
(3)化合物4a在乙醇中以碳酸氢钠为碱性条件下与盐酸羟胺反应2-4h，过滤除去固相，过滤浓缩，残余物经硅胶柱层析(洗脱剂为二氯甲烷：甲醇：氨水(体积比)＝5:1:0.1)的白色固体化合物5a。(3) Compound 4a is reacted with hydroxylamine hydrochloride under basic conditions of sodium hydrogencarbonate in ethanol for 2-4 h, the solid phase is removed by filtration, and concentrated by filtration. The residue is purified by silica gel column chromatography. : Ammonia (volume ratio) = 5:1:0.1) of white solid compound 5a.
(4)吲哚乙酸(1eq)溶于二氯甲烷，加入N，N-二异丙基乙胺(1.3eq)和HATU(1eq)搅拌反应0.5h，再滴加入溶于二氯甲烷的化合物6a(1eq)，搅拌反应1h。将二氯甲烷减压旋干，加入二氯乙烷，在85℃下回流2h。减压蒸干，加入饱和碳酸氢钠溶液和二氯甲烷分离萃取，得有机相，无水硫酸钠干燥，过滤浓缩，残余物经硅胶柱层析(洗脱剂为二氯甲烷：***(体积比)＝10:3)的白色固体 化合物7a。(4) Indoleacetic acid (1 eq) was dissolved in dichloromethane, and N,N-diisopropylethylamine (1.3 eq) and HATU (1 eq) were added and stirred for 0.5 h. 6a (1 eq), the reaction was stirred for 1 h. The dichloromethane was evaporated to dryness under reduced pressure, and then dichloromethane was evaporated and refluxed at 85 ° C for 2 h. The organic layer was dried over anhydrous sodium sulfate (MgSO4). Ratio = 10:3) of white solid compound 7a.
(5)化合物7a在三氟乙酸的二氯甲烷溶液中搅拌反应10-12h。得到化合物1a。淡黄色油状。产率：0.25。(5) Compound 7a is stirred and reacted in a solution of trifluoroacetic acid in dichloromethane for 10-12 h. Compound 1a was obtained. Light yellow oily. Yield: 0.25.
1H NMR(400MHz,CD 3OD)δ(ppm):7.54(d,1H,ArH),7.40(t,2H,ArH),7.30(d,1H,ArH),7.24(s,1H,CH),7.14(t,1H,ArH),7.08(t,1H,ArH),7.04(t,1H,ArH),6.96(t,1H,ArH),6.81(s,1H,CH),4.39(s,2H,CH 2),4.23(s,2H,CH 2),3.98(t,2H,CH 2)，3.35(t,2H,CH 2). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.54 (d, 1H, ArH), 7.40 (t, 2H, ArH), 7.30 (d, 1H, ArH), 7.24 (s, 1H, CH) , 7.14 (t, 1H, ArH), 7.08 (t, 1H, ArH), 7.04 (t, 1H, ArH), 6.96 (t, 1H, arH), 6.81 (s, 1H, CH), 4.39 (s, 2H, CH 2 ), 4.23 (s, 2H, CH 2 ), 3.98 (t, 2H, CH 2 ), 3.35 (t, 2H, CH 2 ).
实施例2化合物1b的制备：Preparation of Compound 1b of Example 2:
参照实施例1，将步骤(1)中乙二胺换成1,6-己二胺。得到化合物1b，为淡黄色油状。Referring to Example 1, ethylenediamine in step (1) was replaced with 1,6-hexanediamine. Compound 1b was obtained as a pale yellow oil.
1H NMR(400MHz,CD 3OD)δ(ppm):7.54(d,1H,ArH),7.40(dd,2H,ArH),7.28(d,1H,ArH),7.23(s,1H,CH),7.13(t,1H,ArH),7.07(t,1H,ArH),7.04(t,1H,ArH),7.02(t,1H,ArH),6.94(t,1H,ArH),6.73(s,1H,CH)，4.36(s,2H,CH 2)，4.14(s,2H,CH 2)，3.79(t,2H,CH 2)，3.05(t,2H,CH 2)，1.52(m,2H,CH 2)，1.43(m,2H,CH 2)，1.27-1.21(m,4H,CH 2). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.54 (d, 1H, ArH), 7.40 (dd, 2H, ArH), 7.28 (d, 1H, ArH), 7.23 (s, 1H, CH) , 7.13 (t, 1H, ArH), 7.07 (t, 1H, ArH), 7.04 (t, 1H, ArH), 7.02 (t, 1H, ArH), 6.94 (t, 1H, ArH), 6.73 (s, 1H, CH), 4.36 (s, 2H, CH 2 ), 4.14 (s, 2H, CH 2 ), 3.79 (t, 2H, CH 2 ), 3.05 (t, 2H, CH 2 ), 1.52 (m, 2H) , CH 2 ), 1.43 (m, 2H, CH 2 ), 1.27-1.21 (m, 4H, CH 2 ).
实施例3化合物1c的制备：Preparation of Compound 1c of Example 3:
参照实施例1，将步骤(1)中乙二胺换成1,5-戊二胺，并将步骤(4)中的吲哚乙酸换成5-氟-吲哚乙酸。得到化合物1c，为淡黄色油状。Referring to Example 1, the ethylenediamine in the step (1) was replaced with 1,5-pentanediamine, and the indole acetic acid in the step (4) was replaced with 5-fluoro-indoleacetic acid. Compound 1c was obtained as a pale yellow oil.
1H NMR(400MHz,CD 3OD)δ(ppm):7.34(d,1H,ArH),7.31(s,1H,CH),7.25(d,1H,ArH),7.23(d,1H,ArH),7.10(d,1H,ArH),6.90(dd,1H,ArH),6.84(dd,1H,ArH),6.84(s,1H,CH)，4.35(s,2H,CH 2)，4.12(s,2H,CH 2)，3.82(t,2H,CH 2)，3.03(t,2H,CH 2)，1.58-1.48(m,4H,CH 2)，1.31-1.27(m,2H,CH 2). 1 H NMR (400 MHz, CD 3 OD) δ (ppm): 7.34 (d, 1H, ArH), 7.31 (s, 1H, CH), 7.25 (d, 1H, ArH), 7.23 (d, 1H, ArH) , 7.10 (d, 1H, ArH), 6.90 (dd, 1H, ArH), 6.84 (dd, 1H, ArH), 6.84 (s, 1H, CH), 4.35 (s, 2H, CH 2 ), 4.12 (s , 2H, CH 2 ), 3.82 (t, 2H, CH 2 ), 3.03 (t, 2H, CH 2 ), 1.58-1.48 (m, 4H, CH 2 ), 1.31-1.27 (m, 2H, CH 2 ) .
实施例4化合物1d的制备：Preparation of Compound 1d of Example 4:
参照实施例1，将步骤(1)中乙二胺换成1,5-戊二胺，并将步骤(4)中的吲哚乙酸换成5-氯-吲哚乙酸。得到化合物1d，为淡黄色油状。Referring to Example 1, ethylenediamine in step (1) was replaced with 1,5-pentanediamine, and the indole acetic acid in step (4) was replaced with 5-chloro-indoleacetic acid. Compound 1d was obtained as a pale yellow oil.
1H NMR(400MHz,CD 3OD)δ(ppm):7.56(d,1H,ArH),7.43(d,1H,ArH),7.35(d,1H,ArH),7.30(s,1H,CH),7.26(d,1H,ArH),7.09(dd,1H,ArH),7.03(dd,1H,ArH),6.85(s,1H,CH)，4.35(s,2H,CH 2)，4.13(s,2H,CH 2)，3.82(t,2H,CH 2)，3.02(t,2H,CH 2)，1.58-1.46(m,4H,CH 2)，1.28(m,2H,CH 2). 1 H NMR (400 MHz, CD 3 OD) δ (ppm): 7.56 (d, 1H, ArH), 7.43 (d, 1H, ArH), 7.35 (d, 1H, ArH), 7.30 (s, 1H, CH) , 7.26 (d, 1H, ArH), 7.09 (dd, 1H, ArH), 7.03 (dd, 1H, ArH), 6.85 (s, 1H, CH), 4.35 (s, 2H, CH 2 ), 4.13 (s , 2H, CH 2 ), 3.82 (t, 2H, CH 2 ), 3.02 (t, 2H, CH 2 ), 1.58-1.46 (m, 4H, CH 2 ), 1.28 (m, 2H, CH 2 ).
实施例5化合物1e的制备：Preparation of Compound 1e of Example 5:
参照实施例1，将步骤(1)中乙二胺换成1,5-戊二胺，并将步骤(4)中的吲哚乙酸换成5-溴-吲哚乙酸。得到化合物1e，为淡黄色油状。Referring to Example 1, ethylenediamine in step (1) was replaced with 1,5-pentanediamine, and the indole acetic acid in step (4) was replaced with 5-bromo-indoleacetic acid. Compound 1e was obtained as a pale yellow oil.
1H NMR(400MHz,CD 3OD)δ(ppm):7.73(d,1H,ArH),7.59(d,1H,ArH),7.32(d,1H,ArH),7.30(s,1H,CH),7.23(dd,1H,ArH),7.21(dd,1H,ArH),7.16(dd,1H,ArH),6.84(s,1H,CH)，4.36(s,2H,CH 2)，4.13(s,2H,CH 2)，3.82(t,2H,CH 2)，3.03(t,2H,CH 2)，1.59-1.49(m,4H,CH 2)，1.30(m,2H,CH 2). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.73 (d, 1H, ArH), 7.59 (d, 1H, ArH), 7.32 (d, 1H, ArH), 7.30 (s, 1H, CH) , 7.23 (dd, 1H, ArH), 7.21 (dd, 1H, ArH), 7.16 (dd, 1H, ArH), 6.84 (s, 1H, CH), 4.36 (s, 2H, CH 2 ), 4.13 (s , 2H, CH 2 ), 3.82 (t, 2H, CH 2 ), 3.03 (t, 2H, CH 2 ), 1.59-1.49 (m, 4H, CH 2 ), 1.30 (m, 2H, CH 2 ).
实施例6抗菌生物活性测试方法：Example 6 Test method for antibacterial biological activity:
实验所用培养基为含有5％DMSO的TSB培养基。所使用的细菌为Newman金黄色葡萄球菌Staphylococcus aureus Newman strain[G+,methicillin sensitive Staphylococcus aureus(MSSA),vancomycin sensitive)]、甲氧西林耐药&万古霉素中度耐药的Mu50金黄色葡萄球菌Staphylococcus aureus Mu50strain[G+,MRSA(methicillin-resistant S.aureus)&VISA(vancomycin-intermediate S.aureus)]、甲氧 西林耐药&利奈唑胺耐药的NRS271金黄色葡萄球菌Staphylococcus aureus NRS271strain[G+,MRSA&linezolid-resistant S.aureus.]、万古霉素耐药&替考拉宁耐药的0649屎肠球菌Enterococcus faecium Efm-HS0649[G+,vancomycin&teicoplanin resistant(vanA type)]、万古霉素耐药&替考拉宁敏感的08257屎肠球菌Enterococcus faecium Efm-HS08257[G+,vancomycin-resistant,teicoplanin sensitive(vanM type)]、万古霉素耐药&替考拉宁敏感的vanB粪肠球菌Enterococcus faecalis[G+,vancomycin-resistant,teicoplanin sensitive(vanB type)]。ATCC 12344酿脓链球菌Streptococcus pyogenes ATCC12344(G+,)、CMCC 63501枯草芽孢杆菌Bacillus subtilis CMCC 63501(G+,)、1457表皮葡萄球菌Staphylococcus epidermidis 1457(G+,)、AB1157大肠杆菌Escherichia coli AB1157(G-)。The medium used in the experiment was TSB medium containing 5% DMSO. The bacteria used were Newman Staphylococcus aureus Newman strain [G+,methicillin sensitive Staphylococcus aureus (MSSA), vancomycin sensitive)], methicillin resistant & vancomycin moderately resistant Mu50 Staphylococcus Staphylococcus Aureus Mu50strain [G+, MRSA (methicillin-resistant S. aureus) & VISA (vancomycin-intermediate S. aureus)], methicillin-resistant & linezolid-resistant NRS271 Staphylococcus aureus NRS271strain [G+, MRSA & linezolid- Resistant S.aureus.], vancomycin-resistant & teicoplanin-resistant 0649 Enterococcus faecium Efm-HS0649 [G+, vancomycin & teicoplanin resistant (vanA type)], vancomycin resistance & teicoplanin Sensitive 08,572 Enterococcus faecium Efm-HS08257 [G+, vancomycin-resistant, teicoplanin sensitive (vanM type)], vancomycin-resistant & teicoplanin-sensitive vanB Enterococcus faecalis [G+, vancomycin-resistant , teicoplanin sensitive(vanB type)]. ATCC 12344 Streptococcus pyogenes ATCC12344 (G+,), CMCC 63501 Bacillus subtilis CMCC 63501 (G+,), 1457 Staphylococcus epidermidis 1457 (G+,), AB1157 Escherichia coli AB1157 (G-) .
将实施例1-5所制备的二聚吲哚生物碱类化合物用DMSO溶解成5.12mg/mL的原液。然后用培养液(即含有5％DMSO的TSB培养基)将所有样品稀释至256μg/mL，作为起始浓度，进一步用培养液进行1:2的梯度稀释，得到浓度范围从128μg/mL到0.125μg/mL的一系列浓度的样品，各浓度样品取100μL置于96孔板上。各96孔板上加入5μL细菌悬液大约10 5CFU/well，将这些接种过的板置于37℃环境孵化14h。化合物的MIC值即被定义为，完全抑制细菌生长时的最低化合物浓度。这五个二聚吲哚生物碱类化合物对于各菌株的MIC值如表1。同时设置DMSO替代本发明的化合物作为阴性对照组，设置万古霉素和利奈唑胺使用相同方式处理，作为阳性对照组。设置不加入细菌的空白对照组，空白对照组未发现细菌生长。 The dimeric indole alkaloid compound prepared in Example 1-5 was dissolved in DMSO to a stock solution of 5.12 mg/mL. Then, all the samples were diluted to 256 μg/mL with the culture solution (ie, TSB medium containing 5% DMSO) as a starting concentration, and further subjected to a 1:2 gradient dilution with the culture solution to obtain a concentration ranging from 128 μg/mL to 0.125. A series of samples at a concentration of μg/mL, 100 μL of each concentration sample was placed on a 96-well plate. 5 μL of the bacterial suspension was added to each 96-well plate at approximately 10 5 CFU/well, and the inoculated plates were incubated at 37 ° C for 14 h. The MIC value of a compound is defined as the minimum compound concentration at which the growth of the bacteria is completely inhibited. The MIC values of these five dimeric alkaloid compounds for each strain are shown in Table 1. At the same time, DMSO was set in place of the compound of the present invention as a negative control group, and vancomycin and linezolid were set to be treated in the same manner as a positive control group. A blank control group in which no bacteria was added was set, and no bacterial growth was observed in the blank control group.
表1二聚吲哚生物碱类化合物MIC值(g/ml):Table 1 MIC values of dimeric alkaloids (g/ml):
Figure PCTCN2018108524-appb-000004
Figure PCTCN2018108524-appb-000004
从表1中可以看出，这类二聚吲哚生物碱类化合物对革兰氏阳性菌都具有很好的抑制活性，对Mu50、NRS271、0649/08257、VanB等耐药菌株都有良好的抑制活性，且部分化合物活性优于阳性对照万古霉素和利奈唑胺。其中烷基链的长度对抑制活性有一定的影响。其中以化合物1d的抑制活性最强，MIC值达到≤0.125μg/mL,对耐药菌的抑制MIC值也达到0.5-2μg/mL。总而言之，此类化合物在制备抗菌剂药物时具有非常良好的应用前景。It can be seen from Table 1 that these dimeric alkaloids have good inhibitory activity against Gram-positive bacteria, and have good resistance to Mu50, NRS271, 0649/08257, VanB and other resistant strains. Inhibition activity, and some compounds are better than the positive control vancomycin and linezolid. The length of the alkyl chain has a certain influence on the inhibitory activity. Among them, the inhibitory activity of the compound 1d was the strongest, the MIC value reached ≤0.125 μg/mL, and the MIC value of the resistant bacteria was also 0.5-2 μg/mL. In summary, such compounds have very good application prospects in the preparation of antibacterial agents.

Claims (10)

  1. 一类式(I)所示的二聚吲哚生物碱类化合物或其药学上可接受的盐，a dimeric quinone alkaloid compound of the formula (I) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2018108524-appb-100001
    Figure PCTCN2018108524-appb-100001
    式中，R 1、R 2、R 3、R 4各自独立地选自氢、氟、氯、溴、C1-C12烷基、C1-C12烷氧基； Wherein R 1 , R 2 , R 3 , R 4 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C1-C12 alkyl, C1-C12 alkoxy;
    n为1-12的整数。n is an integer from 1-12.
  2. 如权利要求1所述的二聚吲哚生物碱类化合物或其药学上可接受的盐，其特征在于：R 1、R 3、R 4均为氢，R 2选自氢、氟、氯、溴。 The dimeric alkaloid compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 , R 3 and R 4 are each hydrogen, and R 2 is selected from the group consisting of hydrogen, fluorine and chlorine. bromine.
  3. 如权利要求1所述的二聚吲哚生物碱类化合物或其药学上可接受的盐，其特征在于：n为2-6的整数。The dimeric alkaloid compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein n is an integer of from 2 to 6.
  4. 如权利要求1所述的二聚吲哚生物碱类化合物或其药学上可接受的盐，其特征在于，式(I)所示化合物选自如下具体化合物：The dimeric alkaloid compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of the formula (I) is selected from the following specific compounds:
    化合物1a：R 1、R 2、R 3、R 4均为氢，n为2； Compound 1a: R 1 , R 2 , R 3 , and R 4 are all hydrogen, and n is 2;
    化合物1b：R 1、R 2、R 3、R 4均为氢，n为6； Compound 1b: R 1 , R 2 , R 3 , and R 4 are all hydrogen, and n is 6;
    化合物1c：R 1、R 3、R 4均为氢，R 2为氟，n为5； Compound 1c: R 1 , R 3 , R 4 are all hydrogen, R 2 is fluorine, and n is 5;
    化合物1d：R 1、R 3、R 4均为氢，R 2为氯，n为5； Compound 1d: R 1 , R 3 , R 4 are all hydrogen, R 2 is chlorine, and n is 5;
    化合物1e：R 1、R 3、R 4均为氢，R 2为溴，n为5。 Compound 1e: R 1 , R 3 and R 4 are all hydrogen, R 2 is bromine, and n is 5.
  5. 权利要求1-4中任一项所述的二聚吲哚生物碱类化合物的制备方法，其特征在于，包括如下步骤：The method for preparing a dimeric alkaloid compound according to any one of claims 1 to 4, comprising the steps of:
    Figure PCTCN2018108524-appb-100002
    Figure PCTCN2018108524-appb-100002
    (1)在碱存在的条件下，化合物2与二胺类化合物
    Figure PCTCN2018108524-appb-100003
    在室温下反应10-12小时得到化合物3；     (1) Compound 2 and diamine compounds in the presence of a base
    Figure PCTCN2018108524-appb-100003
    The reaction is carried out at room temperature for 10-12 hours to obtain a compound 3;
    (2)在以水和二氯甲烷为溶剂，在碱存在的条件下，在零摄氏度下向化合物3滴加入溴化氰，然后在室温下反应1-2小时得到化合物4；(2) using water and dichloromethane as a solvent, in the presence of a base, adding cyanogen bromide to compound 3 at zero degrees Celsius, and then reacting at room temperature for 1-2 hours to obtain compound 4;
    (3)化合物4在乙醇溶液中，在碱存在的条件下，与盐酸羟胺反应得到化合物5，反应温度室温，反应时间2-4小时；(3) Compound 4 is reacted with hydroxylamine hydrochloride in an ethanol solution in the presence of a base to obtain a compound 5, the reaction temperature is room temperature, and the reaction time is 2-4 hours;
    (4)化合物5与有HATU活化的吲哚乙酸(化合物6)在二氯乙烷溶液中在85℃下回流2-3小时，环化得到具有噁二唑环的化合物7；(4) Compound 5 and HATU-activated indoleacetic acid (Compound 6) are refluxed in a solution of dichloroethane at 85 ° C for 2-3 hours, cyclized to give compound 7 having an oxadiazole ring;
    (5)化合物7在三氟乙酸的二氯甲烷溶液中反应10-12小时，脱去Boc保护，得化合物1的三氟乙酸盐，通过水解反应等，可以得到化合物1；(5) Compound 7 is reacted in a solution of trifluoroacetic acid in dichloromethane for 10-12 hours, deprotected by Boc to obtain a trifluoroacetate salt of compound 1, and a compound 1 can be obtained by a hydrolysis reaction or the like;
    其中，R 1、R 2、R 3、R 4、n的定义与相应的权利要求中相同。 Wherein R 1 , R 2 , R 3 , R 4 , n are as defined in the corresponding claims.
  6. 如权利要求5所述的制备方法，其特征在于：The preparation method according to claim 5, wherein:
    步骤(1)是所述的碱是三乙胺；Step (1) is that the base is triethylamine;
    步骤(1)在二氯甲烷中进行；Step (1) is carried out in dichloromethane;
    步骤(2)和(3)中所述的碱是碳酸氢钠。The base described in the steps (2) and (3) is sodium hydrogencarbonate.
  7. 一种药物组合物，包含如权利要求1-4中任一项所述的二聚吲哚生物碱类化合物或其药学上可接受的盐，以及药学上可接受的载体。A pharmaceutical composition comprising the dimeric alkaloid compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  8. 权利要求1-4中任一项所述的式(I)所示的二聚吲哚生物碱类化合物或其药学上可接受的盐或权利要求7所述的药物组合物在制备抗菌药物中的用途。The dimeric indole alkaloid compound of the formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7, in the preparation of an antibacterial agent the use of.
  9. 根据权利要求8所述的用途，其特征在于：所述抗菌药物为抑制耐药菌的药物。The use according to claim 8, wherein the antibacterial agent is a drug that inhibits resistant bacteria.
  10. 根据权利要求8所述的用途，其特征在于：所述菌为金黄色葡萄球菌、表面葡萄球菌、屎肠球菌、粪肠球菌、枯草芽孢杆菌、酿脓链球菌、及相关耐药菌。The use according to claim 8, wherein the bacteria are Staphylococcus aureus, Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis, Bacillus subtilis, Streptococcus pyogenes, and related resistant bacteria.
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