WO2019072112A1 - Série de composés alcaloïdes d'indole dimère, son procédé de préparation et son utilisation dans la préparation de médicaments antibactériens - Google Patents

Série de composés alcaloïdes d'indole dimère, son procédé de préparation et son utilisation dans la préparation de médicaments antibactériens Download PDF

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Publication number
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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WIPO (PCT)
Prior art keywords
compound
hydrogen
dimeric
preparation
pharmaceutically acceptable
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PCT/CN2018/108524
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English (en)
Chinese (zh)
Inventor
郭跃伟
蓝乐夫
李序文
陈菲菲
刘进
Original Assignee
中国科学院上海药物研究所
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Publication of WO2019072112A1 publication Critical patent/WO2019072112A1/fr

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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

Definitions

  • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte aux domaines de la synthèse organique et de la chimie pharmaceutique. La présente invention concerne particulièrement, une série de composés alcaloïdes d'indole dimère tels que représentés par la formule générale I, leurs procédés de préparation et leur utilisation dans la préparation de médicaments antibactériens. Selon des résultats, les composés fournis par la présente invention ont une forte activité antibactérienne, après avoir été soumis à une activité de criblage in vitro, en particulier, ces composés ont des effets inhibiteurs spécifiques sur des bactéries à Gram positif, tels que des souches de staphylococcus, bacillus et enterococcus, et des souches résistantes aux médicaments associées de celles-ci, et peuvent être utilisés en tant que composés têtes de série pour développer de nouveaux médicaments antibactériens.
PCT/CN2018/108524 2017-10-12 2018-09-29 Série de composés alcaloïdes d'indole dimère, son procédé de préparation et son utilisation dans la préparation de médicaments antibactériens WO2019072112A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710948531.7A CN109651352B (zh) 2017-10-12 2017-10-12 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
CN201710948531.7 2017-10-12

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111039983A (zh) * 2019-12-19 2020-04-21 赵洁 一种抗菌药物的制备方法及其用途
CN111956642A (zh) * 2020-09-17 2020-11-20 福建师范大学 吲哚及其衍生物提高氨基糖苷类抗生素杀菌效率的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004018461A2 (fr) * 2002-08-23 2004-03-04 Pharmacia & Upjohn Company Llc Derives d'acide benzoique antibacteriens
CN102399215A (zh) * 2010-09-19 2012-04-04 中国科学院上海药物研究所 吲哚类生物碱菲地鳃甲素、菲地鳃乙素及其制备方法和用途
WO2013140331A1 (fr) * 2012-03-19 2013-09-26 Consiglio Nazionale Delle Ricerche Nouveaux dérivés de 1,2,4-oxadiazole, leur procédé de préparation et utilisation de ceux-ci comme intermédiaires dans la préparation d'alcaloïdes indoliques

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105272900B (zh) * 2015-01-21 2018-06-19 南通大学 双吲哚类衍生物及其制备方法与应用
CN106749213B (zh) * 2016-11-25 2019-07-02 济南大学 一种具有1,2,4-恶二唑结构的吲哚衍生物及制备方法和在制备抗菌药物中的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004018461A2 (fr) * 2002-08-23 2004-03-04 Pharmacia & Upjohn Company Llc Derives d'acide benzoique antibacteriens
CN102399215A (zh) * 2010-09-19 2012-04-04 中国科学院上海药物研究所 吲哚类生物碱菲地鳃甲素、菲地鳃乙素及其制备方法和用途
WO2013140331A1 (fr) * 2012-03-19 2013-09-26 Consiglio Nazionale Delle Ricerche Nouveaux dérivés de 1,2,4-oxadiazole, leur procédé de préparation et utilisation de ceux-ci comme intermédiaires dans la préparation d'alcaloïdes indoliques

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111039983A (zh) * 2019-12-19 2020-04-21 赵洁 一种抗菌药物的制备方法及其用途
CN111039983B (zh) * 2019-12-19 2022-04-15 赵洁 一种抗菌药物的制备方法及其用途
CN111956642A (zh) * 2020-09-17 2020-11-20 福建师范大学 吲哚及其衍生物提高氨基糖苷类抗生素杀菌效率的方法

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CN109651352B (zh) 2022-02-15

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