WO2019170046A1 - 一组具有抗耐药性细菌活性的糖肽类化合物、其制备方法和应用 - Google Patents

一组具有抗耐药性细菌活性的糖肽类化合物、其制备方法和应用 Download PDF

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WO2019170046A1
WO2019170046A1 PCT/CN2019/076826 CN2019076826W WO2019170046A1 WO 2019170046 A1 WO2019170046 A1 WO 2019170046A1 CN 2019076826 W CN2019076826 W CN 2019076826W WO 2019170046 A1 WO2019170046 A1 WO 2019170046A1
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benzaldehyde
phenyl
compound
glycopeptide
preparation
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PCT/CN2019/076826
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English (en)
French (fr)
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邵昌
戈梅
阮林高
魏维
夏兴
饶敏
孟庆前
罗敏玉
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上海来益生物药物研究开发中心有限责任公司
浙江医药股份有限公司
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Priority to KR1020207028442A priority Critical patent/KR102571953B1/ko
Priority to EP19764149.1A priority patent/EP3763728A4/en
Priority to US16/978,688 priority patent/US11696937B2/en
Priority to JP2020570620A priority patent/JP7339288B2/ja
Publication of WO2019170046A1 publication Critical patent/WO2019170046A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
    • C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the technical field of medicinal chemical synthesis, and in particular relates to a group of novel glycopeptide compounds which are useful as medicaments for treating infectious diseases.
  • the invention also relates to methods and uses for the preparation of such compounds.
  • Infectious diseases have always been one of the major diseases faced by human beings. In China, the treatment of infectious diseases has always been an important and difficult problem. The situation of bacterial resistance is especially in developed countries and drugs against various resistant drugs. Demand is also higher than in developed countries. In fact, even if the use of antibiotics is well controlled clinically, resistant bacteria will gradually emerge. Therefore, the struggle between humans and bacterial infections is long-lasting and long-lasting. In the context of the dramatic reduction in research and development expenditures against drug-resistant bacteria in developed countries at the end of the last century, the death caused by “super bacteria” has revived social concerns about bacterial infections.
  • Glycopeptide compounds are a class of compounds which have a high inhibitory activity against bacteria including methicillin-resistant Staphylococcus aureus (MRSA), and the representative drug is vancomycin.
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE Vancomycin-resistant Enterococcus
  • MRSA bacteria with reduced activity of vancomycin have appeared.
  • VRE Vancomycin-resistant Enterococcus
  • a number of vancomycin-like compounds and other glycopeptide compounds are known in the art, and are disclosed in, for example, US Pat. No. 6,663,618 B2, US Pat. No. 6,639, 022, US Pat. No.
  • Chinese Invention Patent No. CN101928331A discloses a novel glycopeptide compound having a structure as shown in the structure II compound of the present invention, which is structurally characterized in that both the 4-position and the 6-position amino acid residue of the peptide skeleton are present.
  • Compound II has a completely new structure relative to conventional glycopeptides and has higher antibacterial activity than vancomycin.
  • the research of the present invention is based on the existing research, and continues to optimize the modification of its structure to obtain new compounds with outstanding features.
  • glycopeptide antibiotic compound of the present invention has higher inhibitory activity against drug-resistant strains, especially MRSA or VRE, compared to the second-generation glycopeptide drug oritavancin; further tests have found that the present invention is absolutely Most glycopeptide compounds have higher safety than oritavancin and can be used to treat or prevent various bacterial infections such as skin and soft tissue infections, meningitis, sepsis, pneumonia, arthritis, A drug for diseases such as peritonitis, bronchitis, and empyema.
  • a first object of the present invention is to provide a group of glycopeptide compounds having antibiotic resistant bacterial activity in accordance with the glycopeptide compound of the formula I:
  • R is represented by the following formula: -A-D-E-G;
  • A is a benzene ring
  • D is -O-, or -S-, or -NH-;
  • E is —(CH 2 ) m — wherein m is 1 to 3;
  • G is a structural formula: Wherein L is any one of hydrogen, methyl, halogen, trifluoromethyl or methoxy.
  • R comprises 4-benzyloxyphenyl, 4-phenylethoxyphenyl, 4-phenylpropoxyphenyl, 4-(4'-methylbenzyloxy) Phenyl, 4-(4'-chlorobenzyloxy)phenyl, 4-(4'-methylphenylethoxy)phenyl, 4-(4'-fluorophenylethoxy)phenyl, 4 -(4'-chlorophenylethoxy)phenyl, 4-(4'-bromophenylethoxy)phenyl, 4-(3'-bromophenylethoxy)phenyl, 4-(4'- Trifluoromethylphenoxy)phenyl, 4-(4'-methoxyphenylethoxy)phenyl, 4-(4'-chlorophenylpropoxy)phenyl, 4-phenylmethylthio Phenyl, 4-(4'-chlorobenzylthio)phenyl, 4-(4'-chlorophenylpropoxyphenyl,
  • a second object of the present invention is to provide a pharmaceutical preparation comprising the glycopeptide compound having antibiotic-resistant bacterial activity as described above as an active ingredient.
  • the pharmaceutical preparation is an injection, an oral preparation, an infusion or an external preparation. It can be administered to a patient in need of treatment by intravenous injection, subcutaneous injection or oral administration. When used orally, it can be prepared into a solid preparation such as a tablet, a powder or a capsule, etc.; when it is used for injection, it can be prepared as an injection. When used externally, it can be made into an ointment, a powder or loaded on a carrier.
  • the various dosage forms of the pharmaceutical preparation of the present invention can be prepared by a conventional method in the medical field, wherein the active ingredient glycopeptide compound has a weight percentage of 0.1% to 99.9%, and preferably a weight percentage of 0.5% to 90%. .
  • the general dosage of the above pharmaceutical preparation applied to a patient in need of treatment can be referred to the existing dosage of vancomycin, norvancomycin and oritavancin, for example, 0.1 to 2.0 g/d for an adult, depending on the age of the patient. And changes in the condition.
  • the glycopeptide compound of the present invention can be prepared into a salt by a conventional method, for example, as a hydrochloride.
  • a third object of the present invention is to provide a process for producing the above glycopeptide compound having antibiotic resistance bacterial activity.
  • glycopeptide compound having antibiotic-resistant bacterial activity of the present invention The preparation of the glycopeptide compound is not intended to be limited to such a method, and may of course be carried out by other methods. It will be appreciated that while typical or preferred process conditions (e.g., reaction solvent, reaction temperature, molar ratio, etc.) are given, other process conditions may be employed, unless otherwise specified. The optimum process conditions may vary depending on the particular reactants or solvents employed, but such conditions can be readily determined by one skilled in the art with the aid of customary process conditions.
  • process conditions e.g., reaction solvent, reaction temperature, molar ratio, etc.
  • protecting groups may be necessary or desirable to prevent certain functional groups from undergoing undesired reactions.
  • suitable protecting groups for a particular functional group and suitable conditions for protection and deprotection of such functional groups are well known in the art. If desired, those protecting groups other than those exemplified herein can be used. For example, various protecting groups and their introduction or removal are described in T. W. Greene and G. M. Wuts, Protective Groups in Organic Synthesis, 3rd, Wiley, New York, 1999 and references cited therein.
  • the compound of the formula I can be prepared by the following synthetic route:
  • D is -O- or -S-
  • R is 4-benzyloxyphenyl, 4-phenylethoxyphenyl, 4-phenylpropoxyphenyl, 4 -(4'-methylbenzyloxy)phenyl, 4-(4'-chlorobenzyloxy)phenyl, 4-(4'-methylphenylethoxy)phenyl, 4-(4 '-Fluorophenoxy)phenyl, 4-(4'-chlorophenylethoxy)phenyl, 4-(4'-bromophenylethoxy)phenyl, 4-(3'-bromophenyl) Oxy)phenyl, 4-(4'-trifluoromethylphenylethoxy)phenyl, 4-(4'-methoxyphenylethoxy)phenyl, 4-(4'-chlorophenylpropene When oxy)phenyl, 4-benzylthiophenyl, 4-(4'-chlorobenzylthio)
  • D is -NH-
  • R is 4-benzylaminophenyl, 4-(4'-methylbenzylamino)phenyl, 4-(4'-chloro Benzylamino)phenyl, 4-phenylethylaminophenyl, 4-(4'-chlorophenylethylamino)phenyl, 4-(4'-trifluoromethylphenylethylamino)phenyl, 4-(4'-methoxyphenethylamino)phenyl, 4-phenylpropylaminophenyl and 4-(4'-chlorophenylpropylamino)phenyl, the compound of formula II with aldehyde, borane The tert-butylamine and diethylamine are reacted to obtain a compound of the formula I:
  • the above reaction is carried out by using one or more organic solvents (e.g., DMF, DMSO, methanol, ethanol, etc.), preferably a mixed solvent of DMF and methanol, in an excess of amine (usually about 2 equivalents), such as DIEA.
  • organic solvents e.g., DMF, DMSO, methanol, ethanol, etc.
  • amine usually about 2 equivalents
  • the compound II is mixed with about 0.5 to 2.5 equivalents, preferably 1.3 equivalents, of aldehyde at a temperature of from about 0 ° C to about 100 ° C, preferably 65 ° C, for about 0.5 to about 4 hours, and then the reactant is cooled.
  • an excess of acid (usually about 3 equivalents), such as trifluoroacetic acid, is added to the reaction, followed by the addition of a reducing agent (eg, sodium borohydride, cyanide) Sodium borohydride, sodium triacetoxyborohydride, borane t-butylamine, borane pyridine, etc., preferably borane t-butylamine (usually about 2 equivalents).
  • a reducing agent eg, sodium borohydride, cyanide
  • the reactants are then mixed at about 0 ° C to about 100 ° C, preferably at room temperature until the reaction is substantially complete.
  • a compound of formula I is obtained by conventional separation and purification processes, such as silica gel, ion exchange resins, polymer fillers, C18 preparative liquid phase, solvent precipitation, crystallization, and the like, preferably separated and purified using a polymeric filler.
  • any protecting group present in the product is removed by well-known methods and generally applicable reagents, for example, organic acid, inorganic acid, organic base, inorganic base, catalytic hydrogenation, alkali hydrolysis, etc., preferably organic The base, for example using diethylamine, removes the Fmoc protecting group from the product.
  • a compound of formula I is obtained by conventional separation and purification processes, such as silica gel, ion exchange resins, polymer fillers, C18 preparative liquid phase, solvent precipitation, crystallization, and the like, preferably separated and purified using a polymeric filler.
  • Aldehydes, reagents, and purification devices suitable for the above routes are commercially available.
  • the aldehyde is selected from the group consisting of 4-benzyloxybenzaldehyde, 4-phenylethoxybenzaldehyde, 4-phenylpropoxybenzaldehyde, 4-(4'-methylbenzene Methoxy)benzaldehyde, 4-(4'-chlorobenzyloxy)benzaldehyde, 4-(4'-methylphenylethoxy)benzaldehyde, 4-(4'-fluorophenylethoxy) Benzaldehyde, 4-(4'-chlorophenylethoxy)benzaldehyde, 4-(4'-bromophenylethoxy)benzaldehyde, 4-(3'-bromophenylethoxy)benzaldehyde, 4- (4'-Trifluoromethylphenylethoxy)benzaldehyde, 4-(4'-methoxyphenylethoxy)benzaldehyde, 4-(4'-chlorobenzyloxy)benzal
  • a fourth object of the present invention is to provide the use of the glycopeptide compound as described above for the preparation of a medicament for treating a drug-resistant bacterial infectious disease.
  • the drug resistant bacterium is a Gram positive resistant bacteria.
  • the drug resistant bacterium is methicillin resistant Staphylococcus aureus or vancomycin resistant Enterococcus.
  • glycopeptide antibiotic compound of the present invention has higher inhibitory activity against drug-resistant strains, especially MRSA or VRE, than the second-generation glycopeptide drug oritavancin; further tests have found that the present invention is absolutely Most glycopeptide compounds have higher safety than oritavancin and can be used to treat or prevent various bacterial infections such as skin and soft tissue infections, meningitis, sepsis, pneumonia, arthritis, A drug for diseases such as peritonitis, bronchitis, and empyema.
  • the method for obtaining the starting compound II is described in the patent application file of the Chinese Patent No. CN101928331A, and other materials, materials, devices and the like in the present invention are commercially available.
  • the crude product obtained by the synthesis was purified using a reverse phase polymer filler Uni PS25-300 and Uni PSA 30-300. After the crude product was dissolved in a methanol (or acetonitrile) aqueous solution, it was applied to a glass column packed with a packing at a flow rate of 1 column volume/h. After the completion of the sample, it was pre-washed with a methanol (or acetonitrile) aqueous solution for 1 hour, and then eluted with a TFA-containing methanol (or acetonitrile) aqueous solution at a flow rate of 1.5 column volumes/h. After eluting 1 column volume, the eluate was collected, and the eluate was concentrated and dried to obtain a pure product of each sample.
  • a reverse phase polymer filler Uni PS25-300 and Uni PSA 30-300 After the crude product was dissolved in a methanol (or acetonitrile) aqueous solution, it was applied to
  • the ratio of the eluent refers to the volume percentage
  • the yield refers to the molar yield, unless otherwise specified.
  • the compound 11 was produced in the same manner as in the preparation of the compound 8, and the aldehyde used was replaced with 4-(4'-trifluoromethylphenylethoxy)benzaldehyde. Compound 11 (white solid 0.68 g, yield 61%) was obtained.
  • the compound 13 was produced in the same manner as in the preparation of the compound 12, and the aldehyde used was replaced with 4-(4'-chlorophenylpropoxy)benzaldehyde.
  • Compound 13 (0.31 g of a white solid, yield 56%) was obtained.
  • the compound 23 was produced in the same manner as in the preparation of the compound 21, and the aldehyde used was replaced with 4-(4'-methoxy-N-Fmoc-phenethylamino)benzaldehyde. Compound 23 (0.3 g of a white solid, yield 55%) was obtained.
  • EtOAc EtOAc <RTIgt; After adding diethylamine (1 mL) for 3 h, methyl t-butyl ether (50 mL) was added to the reaction mixture, and the precipitate was collected by suction filtration, and the residue was purified with a reversed polymer filler, using methanol-0.04% TFA aqueous solution (1: 4, v / v) eluted, concentrated and dried to give compound 25 (white solid, 0.36 g, yield: 65%).
  • the methanesulfonic acid, aspartic acid or glutamic acid is substituted for the hydrogen chloride in the above saturated hydrogen chloride methanol solution to obtain the corresponding salt.
  • active ingredient refers to a compound, solvate, tautomer, optical isomer, prodrug, pharmaceutically acceptable salt thereof and the like of the present invention.
  • An intravenous preparation can be prepared as follows:
  • the solution of the above ingredients is usually administered intravenously to the patient at a rate of 1 mL/min.
  • Example 18 Determination of antibacterial activity of a compound
  • the compounds in Table 1 were tested for in vitro antibacterial activity and the minimum inhibitory concentration (MIC) was read.
  • the method of determination was based on the method provided in the Pharmacopoeia of the People's Republic of China (2015 edition).
  • the MRSA detection strain was purchased from ATCC.
  • the VRE detection strain was obtained from the clinical isolate of drug-resistant strain 07-W3-45 from Shanghai Huashan Hospital.
  • the known antibiotic oritavancin (phosphate) was used as a reference drug. 2 is shown.
  • the zebrafish toxicity test of the compounds in Table 1 was also tested. Wild AB zebrafish were randomly selected from six-well plates, and 50, 100, 150, 200, and 250 ng/tail doses of each test sample were intravenously injected, and a normal control group and a solvent control group (phosphoric acid aqueous solution) were set at the same time; During the course, the death of zebrafish was recorded daily and the dead fish were removed; after 72 hours of treatment, the death of zebrafish was counted. The LD 50 of each test article for zebrafish was calculated separately. The results are combined in Table 2.
  • the glycopeptide compound of the present invention has higher inhibitory activity or less toxicity to the drug-resistant strain MRSA or VRE, and is more safe than the second-generation glycopeptide drug oritavancin. Sex.

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Abstract

本发明公开了一组具有抗耐药性细菌活性的糖肽类化合物，符合通式(Ⅰ)所示的糖肽类化合物。本发明还提供了上述糖肽类化合物的制备方法和应用。经测试，相较于二代糖肽类药物奥利万星，本发明的糖肽类抗生素化合物对耐药性菌株尤其是MRSA或VRE具有更高的抑制活性；进一步测试发现，本发明的绝大部分糖肽类化合物具有比奥利万星更高的安全性，可用于制成治疗或预防各种细菌性感染引起的如皮肤和软组织感染、脑膜炎、脓毒症、肺炎、关节炎、腹膜炎、支气管炎、积脓等疾病的药物。

Description

一组具有抗耐药性细菌活性的糖肽类化合物、其制备方法和应用 技术领域
本发明属于药物化学合成技术领域，具体涉及一组新颖的糖肽类化合物，它们可用作治疗感染疾病的药物。本发明还涉及该类化合物的制备方法和应用。
背景技术
感染性疾病一直是人类面临的主要疾病之一，在我国，感染性疾病的治疗始终是一个重要而棘手的问题，细菌耐药的情况尤甚于发达国家、对各种抗耐药菌药物的需求也高于发达国家。事实上，即便临床上很好地控制对抗生素的使用，耐药菌仍会逐渐出现。因此，人类与细菌感染的斗争是长期而持久的。在上世纪末发达国家大幅度削减对抗耐药菌研发支出的背景下，“超级细菌”导致的致死事件重新引起社会对细菌感染问题的担忧。糖肽类化合物是一类对包括甲氧西林耐药金黄色葡萄球菌(MRSA)在内的细菌具有高度抑制活性的化合物，其代表药物是万古霉素。然而，随着临床应用，出现对万古霉素耐药的肠球菌(VRE)、以及万古霉素对其活性降低的MRSA菌。通过对已有糖肽化合物的结构修饰，可以获得一系列新结构化合物，这些新化合物可以对抗耐药菌，并且在安全性等方面具有潜在优势。许多万古霉素类化合物和其它糖肽类化合物为本领域所公知，参考专利例如：US6635618B2、US6392012B1、US5840684、US8420592B2、WO0039156A1、WO0183521A2、WO2011019839A2、EP0435503A1等所公开的，以及参考文献：Bioorg Med Chem Lett,2003,13(23):4165-4168、Curr Med Chem,2001,8(14):1759-1773以及Expert Opin Invest Drugs,2007,16(3):347-357等报道的糖肽类化合物。
在现有报道中，中国发明授权专利CN101928331A公开了一个新型糖肽类化合物，其结构如本发明的结构Ⅱ化合物所示，其结构特征在于肽骨架4-位和6-位氨基酸残基上均具有万古糖胺，化合物Ⅱ相对于常规的糖肽具有全新的结构，并且具有较万古霉素更高的抗菌活性。本发明的研究是在已有研究的基础上，继续优化对其结构的修饰，获得特点突出的新化合物。
发明内容
本发明的发明人以中国专利CN101928331A记载的化合物为原料，对其进行化学改造，获得了一组改进的糖肽类抗生素化合物。经测试，相较于二代糖肽类药物奥利万星，本发明的糖肽类抗生素化合物对耐药性菌株尤其是MRSA或VRE具有更高的抑制活性； 进一步测试发现，本发明的绝大部分糖肽类化合物具有比奥利万星更高的安全性，可用于制成治疗或预防各种细菌性感染引起的如皮肤和软组织感染、脑膜炎、脓毒症、肺炎、关节炎、腹膜炎、支气管炎、积脓等疾病的药物。
本发明的第一个目的在于提供一组具有抗耐药性细菌活性的糖肽类化合物，符合通式Ⅰ所示的糖肽类化合物：
Figure PCTCN2019076826-appb-000001
或其药学可接受的盐，其中：
R用下式表示：—A—D—E—G；其中
A是苯环；
D是—O—，或—S—，或—NH—；
E是—(CH 2) m—，其中m是1至3；
G是结构式：
Figure PCTCN2019076826-appb-000002
其中，L是氢、甲基、卤素、三氟甲基、甲氧基中的任意一种。
根据本发明的优选实施例，R包括4-苯甲氧基苯基、4-苯乙氧基苯基、4-苯丙氧基苯基、4-(4’-甲基苯甲氧基)苯基、4-(4’-氯苯甲氧基)苯基、4-(4’-甲基苯乙氧基)苯基、4-(4’-氟苯乙氧基)苯基、4-(4’-氯苯乙氧基)苯基、4-(4’-溴苯乙氧基)苯基、4-(3’-溴苯乙氧基)苯基、4-(4’-三氟甲基苯乙氧基)苯基、4-(4’-甲氧基苯乙氧基)苯基、4-(4’-氯苯丙氧基)苯基、4-苯甲硫基苯基、4-(4’-氯苯甲硫基)苯基、4-(4’-氯苯乙 硫基)苯基、4-苯甲胺基苯基、4-(4’-甲基苯甲胺基)苯基、4-(4’-氯苯甲胺基)苯基、4-苯乙胺基苯基、4-(4’-氯苯乙胺基)苯基、4-(4’-三氟甲基苯乙胺基)苯基、4-(4’-甲氧基苯乙胺基)苯基、4-苯丙胺基苯基和4-(4’-氯苯丙胺基)苯基。
本发明的第二个目的在于提供一种药物制剂，包括如上所述的具有抗耐药性细菌活性的糖肽类化合物作为活性成分。所述药物制剂为针剂、口服制剂、输液或外用制剂。可以通过静脉注射、皮下注射或口服的形式施加于需要治疗的患者。用于口服时，可将其制备成固体制剂，如片剂、粉剂或胶囊等；用于注射时，可将其制备成注射液。外用时，可做成软膏、散剂或装载于载体上。本发明的药物制剂的各种剂型可以采用医学领域常规的方法进行制备，其中活性成分糖肽类化合物的重量百分含量为0.1％～99.9％，优选的重量百分含量为0.5％～90％。
上述药物制剂施加于需要治疗的患者的一般剂量可以参照万古霉素、去甲万古霉素和奥利万星的现有剂量，例如成人可以为0.1～2.0g/d，具体可根据患者的年龄和病情等变化。本发明的糖肽类化合物可以按常规方法制成盐，例如制成盐酸盐。
本发明的第三个目的在于提供上述具有抗耐药性细菌活性的糖肽类化合物的制备方法。
以下所述为制备本发明的具有抗耐药性细菌活性的糖肽类化合物的代表性方法。所述糖肽类化合物的制备并非意在受限于这类方法，理所当然地，可通过其它方法来进行。将可能领会到的是，尽管给出了典型的或者优选的过程条件(例如反应溶剂、反应温度、投料摩尔比等)，也可以采用其它过程条件，另有规定除外。最佳过程条件可以因所用特定反应物或溶剂而异，但是借助惯用的过程条件，本领域技术人员能够轻易地确定这类条件。
另外，将为本领域技术人员所显而易见的是，常规保护基团可能是必要的或需要的，以防止某些官能团经历不需要的反应。特定官能团的适宜保护基团以及这类官能团保护和去保护的适宜条件的选择是本领域所熟知的。如果需要的话，可以使用除本文所述例证以外的那些保护基团。例如，各种保护基团和它们的引入或脱除在T.W.Greene and G.M.Wuts,Protective Groups in Organic Synthesis,3rd,Wiley,New York,1999和其中引用的参考文献。
本发明中，所述的通式Ⅰ化合物可由下列合成路线制得：
(1)当D为—O—或—S—时，具体而言，当R为4-苯甲氧基苯基、4-苯乙氧基苯基、4-苯丙氧基苯基、4-(4’-甲基苯甲氧基)苯基、4-(4’-氯苯甲氧基)苯基、4-(4’-甲基苯乙氧基)苯基、4-(4’-氟苯乙氧基)苯基、4-(4’-氯苯乙氧基)苯基、4-(4’-溴苯乙氧 基)苯基、4-(3’-溴苯乙氧基)苯基、4-(4’-三氟甲基苯乙氧基)苯基、4-(4’-甲氧基苯乙氧基)苯基、4-(4’-氯苯丙氧基)苯基、4-苯甲硫基苯基、4-(4’-氯苯甲硫基)苯基和4-(4’-氯苯乙硫基)苯基时，将结构式Ⅱ所示的化合物与醛、硼烷叔丁胺反应，获得通式Ⅰ所示的化合物：
Figure PCTCN2019076826-appb-000003
(2)当D为—NH—时，具体而言，当R为4-苯甲胺基苯基、4-(4’-甲基苯甲胺基)苯基、4-(4’-氯苯甲胺基)苯基、4-苯乙胺基苯基、4-(4’-氯苯乙胺基)苯基、4-(4’-三氟甲基苯乙胺基)苯基、4-(4’-甲氧基苯乙胺基)苯基、4-苯丙胺基苯基和4-(4’-氯苯丙胺基)苯基时，将结构式Ⅱ所示的化合物与醛、硼烷叔丁胺和二乙胺反应，获得通式Ⅰ所示的化合物：
Figure PCTCN2019076826-appb-000004
通常，上述反应是这样进行的，用一种或几种有机溶剂(例如DMF、DMSO、甲醇、乙醇等)，优选使用DMF和甲醇混合溶剂，在过量的胺(通常约2当量)，例如DIEA的存在下，在约0℃至约100℃的温度，优选65℃的温度下，使化合物Ⅱ与约0.5至2.5当量，优选1.3当量的醛混合约0.5至约4小时，然后将反应物冷却至约0℃至约40℃，优选冷却至室温，再往反应物中加入过量的酸(通常约3当量)，例如三氟乙酸，接着加入普遍定义中的还原剂(例如硼氢化钠、氰基硼氢化钠、三乙酰氧基硼氢化钠、硼烷叔丁胺、硼 烷吡啶等)，优选使用硼烷叔丁胺(通常约2当量)。然后将反应物在约0℃至约100℃，优选室温下混合直至反应基本完全。一旦反应完成，利用常规分离纯化工艺获得通式Ⅰ化合物，例如硅胶、离子交换树脂、聚合物填料、C18制备液相、溶剂沉淀、结晶法等，优选使用聚合物填料进行分离纯化。
上述反应完全后，利用熟知方法和普遍适用的试剂脱除存在于产物中的任何保护基团，例如使用有机酸、无机酸、有机碱、无机碱、催化氢化、碱水解等手段，优选使用有机碱，例如使用二乙胺脱除产物中的Fmoc保护基。一旦反应完成，利用常规分离纯化工艺获得通式Ⅰ化合物，例如硅胶、离子交换树脂、聚合物填料、C18制备液相、溶剂沉淀、结晶法等，优选使用聚合物填料进行分离纯化。
适合上述路线过程的醛、反应试剂以及纯化装置均是商业上可获得的。
根据本发明的优选实施例，所述的醛选自4-苯甲氧基苯甲醛、4-苯乙氧基苯甲醛、4-苯丙氧基苯甲醛、4-(4’-甲基苯甲氧基)苯甲醛、4-(4’-氯苯甲氧基)苯甲醛、4-(4’-甲基苯乙氧基)苯甲醛、4-(4’-氟苯乙氧基)苯甲醛、4-(4’-氯苯乙氧基)苯甲醛、4-(4’-溴苯乙氧基)苯甲醛、4-(3’-溴苯乙氧基)苯甲醛、4-(4’-三氟甲基苯乙氧基)苯甲醛、4-(4’-甲氧基苯乙氧基)苯甲醛、4-(4’-氯苯丙氧基)苯甲醛、4-苯甲硫基苯甲醛、4-(4’-氯苯甲硫基)苯甲醛、4-(4’-氯苯乙硫基)苯甲醛、4-(N-Fmoc-苯甲胺基)苯甲醛、4-(4’-甲基-N-Fmoc-苯甲胺基)苯甲醛、4-(4’-氯-N-Fmoc-苯甲胺基)苯甲醛、4-(N-Fmoc-苯乙胺基)苯甲醛、4-(4’-氯-N-Fmoc-苯乙胺基)苯甲醛、4-(4’-三氟甲基-N-Fmoc-苯乙胺基)苯甲醛、4-(4’-甲氧基-N-Fmoc-苯乙胺基)苯甲醛、4-(N-Fmoc-苯丙胺基)苯甲醛和4-(4’-氯-N-Fmoc-苯丙胺基)苯甲醛中的任意一种。
本发明的第四个目的在于提供如上所述的糖肽类化合物在制备治疗耐药性细菌感染性疾病药物中的应用。
根据本发明的优选实施例，所述耐药性细菌为革兰氏阳性耐药细菌。
根据本发明的优选实施例，所述耐药性细菌为耐甲氧西林金黄色葡萄球菌或万古霉素耐药肠球菌。
经测试，相较于二代糖肽类药物奥利万星，本发明的糖肽类抗生素化合物对耐药性菌株尤其是MRSA或VRE具有更高的抑制活性；进一步测试发现，本发明的绝大部分糖肽类化合物具有比奥利万星更高的安全性，可用于制成治疗或预防各种细菌性感染引起的如皮肤和软组织感染、脑膜炎、脓毒症、肺炎、关节炎、腹膜炎、支气管炎、积脓等疾病的药物。
具体实施方式
以下结合具体实施例，对本发明做进一步说明。应理解，以下实施例仅用于说明本发明而非用于限制本发明的范围。
本发明中，下列缩写具有以下含义。未定义的缩写具有其普遍接受的含义，除非另外声明，所有室温均指温度20℃～30℃。
DIEA     N,N-二异丙基乙胺
DMF      N,N-二甲基甲酰胺
DMSO     二甲基亚砜
ESI      电喷雾电离质谱
Fmoc     9-芴甲氧羰酰基
H        小时
LD 50     半数致死量
MRSA     甲氧西林耐药金黄色葡萄球菌
MIC      最低抑菌浓度
MS       质谱
TFA      三氟乙酸
VRE      万古霉素耐药肠球菌
本发明中，涉及的出发化合物Ⅱ的获得方法参照中国专利CN101928331A的专利申请文件的记载，本发明中的其它原料、材料及装置等均为商业化并可获得。
以下实施例中，使用反相聚合物填料Uni PS25-300及Uni PSA30-300对合成所得的粗品进行纯化。取粗品溶解于甲醇(或乙腈)水溶液后，上样至装有填料的玻璃层析柱中，上样流速为1倍柱体积/h。上样结束后以甲醇(或乙腈)水溶液预洗1h，再以含有TFA的甲醇(或乙腈)水溶液洗脱，洗脱流速为1.5倍柱体积/h。洗脱1倍柱体积后开始收集洗脱液，将洗脱液浓缩干燥后即得到各样品的纯品。
以下实施例中，洗脱液的比例均指体积百分比，收率均指摩尔收率，另有规定除外。
以下实施例中涉及的各化合物的结构如表1所示。
表1、各化合物的结构
Figure PCTCN2019076826-appb-000005
Figure PCTCN2019076826-appb-000006
实施例一、化合物1的制备
将化合物Ⅱ(0.5g，0.3mmol)用10mLDMF-甲醇(1:1，v/v)搅匀，加入DIEA(0.1mL，0.6mmol)和4-苯甲氧基苯甲醛(0.085g，0.4mmol)，在65℃搅拌2h后冷却至室温，加入TFA(0.07mL，0.9mmol)和硼烷叔丁胺(0.05g，0.6mmol)继续于室温下搅拌2h，往反应液中加入甲基叔丁基醚(50mL)，抽滤收集沉淀，残余物用反相聚合物填料纯化，用甲醇-0.04％TFA水溶液(1:4，v/v)洗脱，浓缩干燥后得到化合物1(白色固体0.28g，收率52％)。
C 87H 100Cl 2N 10O 27分子量计算值：1786.61，实测值：m/z＝1787.60[M+H] +。
实施例二、化合物2的制备
将化合物Ⅱ(0.5g，0.3mmol)用10mL DMF-甲醇(1:1，v/v)搅匀，加入DIEA(0.1mL，0.6mmol)和4-苯乙氧基苯甲醛(0.09g，0.4mmol)，在65℃搅拌2h后冷却至室温，加入TFA(0.07mL，0.9mmol)和硼烷叔丁胺(0.05g，0.6mmol)继续于室温下搅拌2h，往反应液中加入甲基叔丁基醚(50mL)，抽滤收集沉淀，残余物用反相聚合物填料纯化，用甲醇-0.04％TFA水溶液(1:4，v/v)洗脱，浓缩干燥后得到化合物2(白色固体0.31g，收率57％)。
C 88H 102Cl 2N 10O 27分子量计算值：1800.63，实测值：m/z＝1801.63[M+H] +。
实施例三、化合物3的制备
将化合物Ⅱ(1.0g，0.6mmol)用15mL DMF-甲醇(1:1，v/v)搅匀，加入DIEA(0.2mL，1.2mmol)和4-苯丙氧基苯甲醛(0.2g，0.8mmol)，在65℃搅拌2h后冷却至室温，加入TFA(0.14mL，1.8mmol)和硼烷叔丁胺(0.1g，1.2mmol)继续于室温下搅拌2h，然后加入甲基叔丁基醚(70mL)，抽滤收集沉淀，残余物用反相聚合物填料纯化，用甲醇-0.04％TFA水溶液(1:4，v/v)洗脱，浓缩干燥后得到化合物3(白色固体0.65g，收率60％)。
C 89H 104Cl 2N 10O 27分子量计算值：1814.64，实测值：m/z＝1815.64[M+H] +。
实施例四、化合物4的制备
化合物4的制备方法与化合物1的制备方法相同，所用的醛替换成4-(4’-甲基苯甲氧基)苯甲醛。得到化合物4(白色固体0.3g，收率56％)。
C 88H 102Cl 2N 10O 27分子量计算值：1800.63，实测值：m/z＝1801.63[M+H] +。
实施例五、化合物8的制备
将化合物Ⅱ(1.0g，0.6mmol)用15mL DMF-甲醇(1:1，v/v)搅匀，加入DIEA(0.2mL， 1.2mmol)和4-(4’-氯苯乙氧基)苯甲醛(0.21g，0.8mmol)，在65℃搅拌2h后冷却至室温，加入TFA(0.14mL，1.8mmol)和硼烷叔丁胺(0.1g，1.2mmol)继续于室温下搅拌2h，然后加入甲基叔丁基醚(70mL)，抽滤收集沉淀，残余物用反相聚合物填料纯化，用甲醇-0.04％TFA水溶液(1:4，v/v)洗脱，浓缩干燥后得到化合物8(白色固体0.55g，收率50％)。
C 88H 101Cl 3N 10O 27分子量计算值：1834.59，实测值：m/z＝1835.60[M+H] +。
实施例六、化合物10的制备
将化合物Ⅱ(1.0g，0.6mmol)用15mL DMF-甲醇(1:1，v/v)搅匀，加入DIEA(0.2mL，1.2mmol)和4-(3’-溴苯乙氧基)苯甲醛(0.24g，0.8mmol)，在65℃搅拌2h后冷却至室温，加入TFA(0.14mL，1.8mmol)和硼烷叔丁胺(0.1g，1.2mmol)继续于室温下搅拌2h，然后加入甲基叔丁基醚(70mL)，抽滤收集沉淀，残余物用反相聚合物填料纯化，用甲醇-0.04％TFA水溶液(1:4，v/v)洗脱，浓缩干燥后得到化合物10(白色固体0.65g，收率58％)。
C 88H 101BrCl 2N 10O 27分子量计算值：1878.54，实测值：m/z＝1879.54[M+H] +。
实施例七、化合物11的制备
化合物11的制备方法与化合物8的制备方法相同，所用的醛替换成4-(4’-三氟甲基苯乙氧基)苯甲醛。得到化合物11(白色固体0.68g，收率61％)。
C 89H 101Cl 2F 3N 10O 27分子量计算值：1868.62，实测值：m/z＝1869.64[M+H] +。
实施例八、化合物12的制备
将化合物Ⅱ(0.5g，0.3mmol)用10mL DMF-甲醇(1:1，v/v)搅匀，加入DIEA(0.1mL，0.6mmol)和4-(4’-甲氧基苯乙氧基)苯甲醛(0.1g，0.4mmol)，在65℃搅拌2h后冷却至室温，加入TFA(0.07mL，0.9mmol)和硼烷叔丁胺(0.05g，0.6mmol)继续于室温下搅拌2h，往反应液中加入甲基叔丁基醚(50mL)，抽滤收集沉淀，残余物用反相聚合物填料纯化，用甲醇-0.04％TFA水溶液(1:4，v/v)洗脱，浓缩干燥后得到化合物12(白色固体0.22g，收率40％)。
C 89H 104Cl 2N 10O 28分子量计算值：1830.64，实测值：m/z＝1831.64[M+H] +。
实施例九、化合物13的制备
化合物13的制备方法与化合物12的制备方法相同，所用的醛替换成4-(4’-氯苯丙氧基)苯甲醛。得到化合物13(白色固体0.31g，收率56％)。
C 89H 103Cl 3N 10O 27分子量计算值：1848.61，实测值：m/z＝1849.62[M+H] +。
实施例十、化合物16的制备
将化合物Ⅱ(1.0g，0.6mmol)用15mL DMF-甲醇(1:1，v/v)搅匀，加入DIEA(0.2mL，1.2mmol)和4-(4’-氯苯乙硫基)苯甲醛(0.22g，0.8mmol)，在65℃搅拌2h后冷却至室温，加入TFA(0.14mL，1.8mmol)和硼烷叔丁胺(0.1g，1.2mmol)继续于室温下搅拌2h，然后加入甲基叔丁基醚(70mL)，抽滤收集沉淀，残余物用反相聚合物填料纯化，用甲醇-0.04％TFA水溶液(1:4，v/v)洗脱，浓缩干燥后得到化合物16(白色固体0.55g，收率50％)。
C 88H 101Cl 3N 10O 26S分子量计算值：1850.57，实测值：m/z＝1851.57[M+H] +。
实施例十一、化合物18的制备
将化合物Ⅱ(0.5g，0.3mmol)用10mLDMF-甲醇(1:1，v/v)搅匀，加入DIEA(0.1mL，0.6mmol)和4-(4’-甲基-N-Fmoc-苯甲胺基)苯甲醛(0.18g，0.4mmol)，在65℃搅拌2h后冷却至室温，加入TFA(0.07mL，0.9mmol)和硼烷叔丁胺(0.05g，0.6mmol)继续于室温下搅拌2h，然后加入二乙胺(1mL)搅拌3h，往反应液中加入甲基叔丁基醚(50mL)，抽滤收集沉淀，残余物用反相聚合物填料纯化，用甲醇-0.04％TFA水溶液(1:4，v/v)洗脱，浓缩干燥后得到化合物18(白色固体0.24g，收率44％)。
C 88H 103Cl 2N 11O 26分子量计算值：1799.65，实测值：m/z＝1800.65[M+H] +。
实施例十二、化合物20的制备
化合物20的制备方法与化合物18的制备方法相同，所用的醛替换成4-(N-Fmoc-苯乙胺基)苯甲醛。得到化合物20(白色固体0.35g，收率65％)。
C 88H 103Cl 2N 11O 26分子量计算值：1799.65，实测值：m/z＝1800.65[M+H] +。
实施例十三、化合物21的制备
将化合物Ⅱ(0.5g，0.3mmol)用10mLDMF-甲醇(1:1，v/v)搅匀，加入DIEA(0.1mL，0.6mmol)和4-(4’-氯-N-Fmoc-苯乙胺基)苯甲醛(0.19g，0.4mmol)，在65℃搅拌2h后冷却至室温，加入TFA(0.07mL，0.9mmol)和硼烷叔丁胺(0.05g，0.6mmol)继续于室温下搅拌2h，然后加入二乙胺(1mL)搅拌3h，往反应液中加入甲基叔丁基醚(50mL)，抽滤收集沉淀，残余物用反相聚合物填料纯化，用甲醇-0.04％TFA水溶液(1:4，v/v)洗脱，浓缩干燥后得到化合物21(白色固体0.2g，收率36％)。
C 88H 102Cl 3N 11O 26分子量计算值：1833.61，实测值：m/z＝1834.60[M+H] +。
实施例十四、化合物23的制备
化合物23的制备方法与化合物21的制备方法相同，所用的醛替换成4-(4’-甲氧基 -N-Fmoc-苯乙胺基)苯甲醛。得到化合物23(白色固体0.3g，收率55％)。
C 89H 105Cl 2N 11O 27分子量计算值：1829.66，实测值：m/z＝1830.65[M+H] +。
实施例十五、化合物25的制备
将化合物Ⅱ(0.5g，0.3mmol)用10mL DMF-甲醇(1:1，v/v)搅匀，加入DIEA(0.1mL，0.6mmol)和4-(4’-氯-N-Fmoc-苯丙胺基)苯甲醛(0.2g，0.4mmol)，在65℃搅拌2h后冷却至室温，加入TFA(0.07mL，0.9mmol)和硼烷叔丁胺(0.05g，0.6mmol)继续于室温下搅拌2h，然后加入二乙胺(1mL)搅拌3h，往反应液中加入甲基叔丁基醚(50mL)，抽滤收集沉淀，残余物用反相聚合物填料纯化，用甲醇-0.04％TFA水溶液(1:4，v/v)洗脱，浓缩干燥后得到化合物25(白色固体0.36g，收率65％)。
C 89H 104Cl 3N 11O 26分子量计算值：1847.62，实测值：m/z＝1848.63[M+H] +。
实施例十六、成盐实施例
将50mg化合物8加入1mL饱和氯化氢甲醇溶液中，室温搅拌，冻干，得到化合物8的盐酸盐白色固体50mg。
另外，分别用氢溴酸、硫酸、硝酸、磷酸、甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、天冬氨酸或谷氨酸代替上述饱和氯化氢甲醇溶液中的氯化氢，得到相应的盐。
实施例十七、制剂实施例
需要注意的是，本实施例仅用于说明，并非意在限制本发明的范围。术语“活性成分”是指本发明化合物、溶剂合物、其互变异构体、光学异构体、前药、药学上可接受的盐等。
可按如下方式制备静脉内制剂：
活性成分              100mg
等渗盐水              1000mL
上述成分的溶液通常以1mL/分钟的速率静脉内给与患者。
实施例十八、化合物的抑菌活性测定
对表1中的化合物进行体外抑菌活性测定，读取最低抑菌浓度值(MIC)，测定方法参考《中华人民共和国药典》(2015年版)中提供的方法。MRSA检测菌系购自ATCC，VRE检测菌系来源自上海华山医院临床分离耐药菌株07-W3-45，以已知的抗生素奥利万星(磷酸盐)为对照药，对比试验结果如表2所示。
同时检测了表1中化合物的斑马鱼毒性试验。随机选取野生AB系斑马鱼于六孔板中，分别静脉注射各受试样品50、100、150、200和250ng/尾剂量，同时设置正常对照组和 溶剂对照组(磷酸水溶液)；在实验过程中，每天观察记录斑马鱼的死亡情况并移除死鱼；处理72h后，统计斑马鱼的死亡情况。分别计算各供试品对斑马鱼的LD 50。结果合并于表2。
表2、表1中各化合物对MRSA、VRE的MIC(μg/mL)斑马鱼LD 50
Figure PCTCN2019076826-appb-000007
Figure PCTCN2019076826-appb-000008
所有样品以磷酸盐形式进行斑马鱼毒性试验。
由表2可知，相较于二代糖肽类药物奥利万星，本发明的糖肽类化合物对耐药性菌株MRSA或VRE具有更高的抑制活性或更小的毒性、更高的安全性。
以上对本发明的具体实施例进行了详细描述，但其只作为范例，本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言，任何对该发明进行的等同修改和替代也都在本发明的范畴之中。因此，在不脱离本发明的精神和范围下所作的均等变换和修改，都应涵盖在本发明的范围内。

Claims (10)

  1. 一组具有抗耐药性细菌活性的糖肽类化合物，其特征在于，符合通式Ⅰ所示的糖肽类化合物：
    Figure PCTCN2019076826-appb-100001
    或其药学可接受的盐，其中：
    R用下式表示：—A—D—E—G；其中
    A是苯环；
    D是—O—，或—S—，或—NH—；
    E是—(CH 2) m—，其中m是1至3；
    G是结构式：
    Figure PCTCN2019076826-appb-100002
    其中，L是氢、甲基、卤素、三氟甲基、甲氧基中的任意一种。
  2. 根据权利要求1所述的糖肽类化合物，其特征在于，R包括4-苯甲氧基苯基、4-苯乙氧基苯基、4-苯丙氧基苯基、4-(4’-甲基苯甲氧基)苯基、4-(4’-氯苯甲氧基)苯基、4-(4’-甲基苯乙氧基)苯基、4-(4’-氟苯乙氧基)苯基、4-(4’-氯苯乙氧基)苯基、4-(4’-溴苯乙氧基)苯基、4-(3’-溴苯乙氧基)苯基、4-(4’-三氟甲基苯乙氧基)苯基、4-(4’-甲氧基苯乙氧基)苯基、4-(4’-氯苯丙氧基)苯基、4-苯甲硫基苯基、4-(4’-氯苯甲硫基)苯基、4-(4’-氯苯乙硫基)苯基、4-苯甲胺基苯基、4-(4’-甲基苯甲胺基)苯基、4-(4’-氯苯甲胺基)苯基、4-苯乙胺基苯基、4-(4’-氯苯乙胺基)苯基、4-(4’-三氟甲基苯乙胺基)苯基、4-(4’-甲氧 基苯乙胺基)苯基、4-苯丙胺基苯基和4-(4’-氯苯丙胺基)苯基。
  3. 一种药物制剂，其特征在于，包括如权利要求1所述的具有抗耐药性细菌活性的糖肽类化合物作为活性成分。
  4. 根据权利要求3所述的药物制剂，其特征在于，所述制剂为针剂、口服制剂、输液或外用制剂。
  5. 根据权利要求3所述的药物制剂，其特征在于，所述糖肽类化合物的重量百分含量为0.1％～99.9％。
  6. 如权利要求1或2所述的具有抗耐药性细菌活性的糖肽类化合物的制备方法，其特征在于，
    当D为—O—或—S—时，将结构式Ⅱ所示的化合物与醛、硼烷叔丁胺反应，获得通式Ⅰ所示的化合物：
    Figure PCTCN2019076826-appb-100003
    当D为—NH—时，将结构式Ⅱ所示的化合物与醛、硼烷叔丁胺和二乙胺反应，获得通式Ⅰ所示的化合物：
    Figure PCTCN2019076826-appb-100004
  7. 根据权利要求6所述的制备方法，其特征在于，所述的醛选自4-苯甲氧基苯甲醛、4-苯乙氧基苯甲醛、4-苯丙氧基苯甲醛、4-(4’-甲基苯甲氧基)苯甲醛、4-(4’-氯苯甲氧基) 苯甲醛、4-(4’-甲基苯乙氧基)苯甲醛、4-(4’-氟苯乙氧基)苯甲醛、4-(4’-氯苯乙氧基)苯甲醛、4-(4’-溴苯乙氧基)苯甲醛、4-(3’-溴苯乙氧基)苯甲醛、4-(4’-三氟甲基苯乙氧基)苯甲醛、4-(4’-甲氧基苯乙氧基)苯甲醛、4-(4’-氯苯丙氧基)苯甲醛、4-苯甲硫基苯甲醛、4-(4’-氯苯甲硫基)苯甲醛、4-(4’-氯苯乙硫基)苯甲醛、4-(N-Fmoc-苯甲胺基)苯甲醛、4-(4’-甲基-N-Fmoc-苯甲胺基)苯甲醛、4-(4’-氯-N-Fmoc-苯甲胺基)苯甲醛、4-(N-Fmoc-苯乙胺基)苯甲醛、4-(4’-氯-N-Fmoc-苯乙胺基)苯甲醛、4-(4’-三氟甲基-N-Fmoc-苯乙胺基)苯甲醛、4-(4’-甲氧基-N-Fmoc-苯乙胺基)苯甲醛、4-(N-Fmoc-苯丙胺基)苯甲醛和4-(4’-氯-N-Fmoc-苯丙胺基)苯甲醛中的任意一种。
  8. 如权利要求1或2所述的具有抗耐药性细菌活性的糖肽类化合物在制备治疗耐药性细菌感染性疾病药物中的应用。
  9. 根据权利要求8所述的应用，其特征在于，所述耐药性细菌为革兰氏阳性耐药细菌。
  10. 根据权利要求9所述的应用，其特征在于，所述耐药性细菌为耐甲氧西林金黄色葡萄球菌或万古霉素耐药肠球菌。
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