WO2017084231A1 - 系列含氟咔唑类化合物及其制备方法和应用 - Google Patents

系列含氟咔唑类化合物及其制备方法和应用 Download PDF

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WO2017084231A1
WO2017084231A1 PCT/CN2016/077646 CN2016077646W WO2017084231A1 WO 2017084231 A1 WO2017084231 A1 WO 2017084231A1 CN 2016077646 W CN2016077646 W CN 2016077646W WO 2017084231 A1 WO2017084231 A1 WO 2017084231A1
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fluorine
listed below
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containing carbazole
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曹昌盛
周生亮
史延慧
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江苏师范大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • 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 field of organic chemistry, medicinal chemistry and pharmaceutical intermediates, and particularly relates to a series of fluorine-containing carbazole compounds and a preparation method and application thereof.
  • MRSA Methicillin-resistant Staphylococcus aureus
  • VRE Vancomycin-resistant Enterococcus spp.
  • Mycobacterium tuberculosis etc.
  • the new antibiotics currently on the market or in the clinical development stage are basically structural modifications of existing antibiotics.
  • the mother nucleus of these new drugs is the same or similar to the original drugs, and the corresponding drug-resistant bacteria often appear soon, sometimes a drug is still In the research and development stage, the corresponding drug resistance genes and drug resistant strains have been produced. People have been working hard to develop new structures of antibiotics from multiple sources, but in the past 40 years, there have been almost no new broad-spectrum antibiotics on the market.
  • a substantial portion of these known fluorochemicals are structurally symmetric carbazoles, i.e., containing the same number and number of fluorine atoms on the benzene ring on either side of the carbazole structure, due to the symmetry of such symmetrical carbazoles.
  • Asymmetric carbazole is easier to synthesize.
  • the invention provides a series of fluorine-containing carbazole compounds, a preparation method and application thereof, and a series of fluorine-substituted oxazole compounds of the invention are mostly asymmetric carbazoles, and in vitro bacteriostatic experiments show that some compounds of the invention have the inhibition of wild type The activity of strains such as Escherichia coli, Staphylococcus aureus and Bacillus subtilis. More importantly, some of the compounds of the present invention have biological activities for inhibiting "E. coli” such as Escherichia coli and Klebsiella pneumoniae carrying NDM-1 resistance genes and MRSA.
  • the preliminary toxicological experiments showed that the selected compound II d with good antibacterial activity had an LD 50 of >1000 mg/Kg, and the compound LD 50 had an LD 50 of 595 mg/Kg.
  • the invention provides a lead compound for developing a new structure of antibacterial drugs, in particular, a drug for inhibiting "super bacteria" carrying NDM-1 drug resistance genes, which has simple synthesis method, low production cost, high development value and application prospect. .
  • R 0 is any of the groups listed below:
  • R 1 to R 8 are any one of the groups listed below, and at least one of the substituents R 1 to R 4 is an F atom:
  • Formula 2 is further divided into two cases:
  • R 1-2 and R are any of the groups listed below:
  • R m is any of the groups listed below:
  • R 0 is any of the groups listed below:
  • R m is any of the groups listed below:
  • Formula 3 is further divided into two cases:
  • R m is any of the groups listed below:
  • R 0 is any of the groups listed below:
  • R m is any of the groups listed below:
  • R R 1 to R 8 ;
  • R m R 1 to R 8 ;
  • m 1-4;
  • R 0 is any of the groups listed below:
  • the series of fluorine-containing carbazole compounds and pharmaceutically acceptable salts, esters, amides or prodrugs thereof preferably, have four fluorine atoms on the right benzene ring, and their structural formula is formula 5 As shown,
  • R m is any of the groups listed below:
  • the structural formula is as shown in the formula 6, wherein the benzene ring on the right side
  • the 1st and 4th positions are methyl and fluorine substituents, respectively, and the 2 and 3 positions are unsubstituted or have other substituents.
  • R 0 is any of the groups listed below:
  • R m is any of the groups listed below:
  • the structural formula 3 As a compound of the structural formula 3 containing only two fluorine atoms, the structural formula is as shown in the formula 7. Wherein the 2 and 4 positions of the benzene ring on the right side are two fluorine substituents, respectively.
  • R 0 is any of the groups listed below:
  • R m is any of the groups listed below:
  • R R 1 to R 8 ;
  • R m R 1 to R 8 ;
  • m 1-4;
  • R 0 is any of the groups listed below:
  • the invention also relates to a method for preparing the above-mentioned fluorine-containing carbazole compound, the steps are as follows:
  • the solvent was spin-dried and separated by column chromatography.
  • the developing solvent was a mixed solvent of petroleum ether and diethyl ether at 30-60 ° C, and the volume ratio was 10:1.
  • the corresponding pure product is obtained, and the reaction equation is shown in Formula 9.
  • the invention further relates to the use of a series of fluorine-containing carbazole compounds of the above general structure for the preparation of a medicament for inhibiting microorganisms.
  • the types of microorganisms inhibited by such compounds include, but are not limited to, E. coli carrying NDM-1 resistance genes, and "super bacteria" strains such as Klebsiella pneumoniae and MRSA, and wild-type Escherichia coli and Staphylococcus aureus. And strains such as Bacillus subtilis.
  • the present invention provides novel fluorine-containing carbazole compounds and methods for their synthesis and use.
  • Some of the compounds of the present invention have activity against strains such as wild-type Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. More importantly, some of the compounds of the present invention have the activity of inhibiting "super bacteria” such as Escherichia coli and Klebsiella pneumoniae carrying NDM-1 gene and MRSA, and have better antibacterial activity and low toxicity, and have been further developed.
  • the potential of new structural antibiotics provides a lead compound for the synthesis of new structural antibiotics and can also be applied to the synthesis of pharmaceutical intermediates.
  • the compound of the invention has simple synthesis method, low production cost, high development value and application prospect.
  • Example 8 Antibacterial Activity There are four kinds of carbazoles having a fluorine atom bonded to the right side of the benzene ring, and their structures and codes are as shown in Formula 10.
  • I a-I d are all new compounds.
  • the synthesis of carbazoles I c and I d is given in each of Examples 1-2, and the synthesis of I a and I b can be carried out in the same manner, and their synthesis steps and characterization data are not specifically given here.
  • the preparation of the main raw materials used in the above synthesis method i.e., substituted fluorine-containing diphenylamine
  • N,N-dimethyl-3-(2,4,7-trifluoro-9H-indazol-9-yl)-1-propanamine (0.306 g, 1 mmol) obtained above was dissolved in 6 mL of 0.2 M hydrochloric acid. The mixture was stirred for 1 h, then dried with EtOAc EtOAc.
  • Example 8 Antibacterial Activity Experiments There were 15 kinds of carbazoles and hydrochlorides having two fluorine atoms attached to the right benzene ring, and their structures and codes are as shown in Formula 11. All II a-II o are new compounds. The synthesis methods of carbazole II a, II b, II d and II n are respectively given in Examples 3-6, and the synthesis of II c, II e-II m and II o can be carried out by the same method, which is not specifically given here. Their synthesis steps and characterization data. The preparation of the main raw materials used in the above synthesis method (i.e., substituted fluorine-containing diphenylamine) can be referred to the literature X.Kong, H. Zhang, Y. Xiao, C. Cao, Y. Shi, G. Pang, RSC Adv. , 2015, 5, 7035–7048.
  • the preparation of the main raw materials used in the above synthesis method i.e., substitute
  • Example 8 Antibacterial Activity Experiments There were 7 kinds of carbazoles having three fluorine atoms attached to the right benzene ring, and their structures and codes are as shown in Formula 12. All III a-III g are new compounds.
  • the synthesis method of carbazole III a is given in Example 7, and the synthesis of III b-III g can be carried out in the same manner, and their synthesis steps and characterization data are not specifically given here.
  • the preparation of the main raw materials used in the above synthesis method i.e., substituted fluorine-containing diphenylamine
  • Antibacterial experiment Add 1 ⁇ L of each test compound solution (or antibiotic solution) to each well of a sterile 96-well plate, add 1 ⁇ L of DMSO to one of the wells as a control, and then add 100 ⁇ L to each well.
  • the diluted bacterial solution was mixed and incubated at 37 ° C for 18 to 20 hours.
  • the minimum drug concentration that completely inhibits bacterial growth in the pores is the minimum inhibitory concentration (MIC).
  • MIC minimum inhibitory concentration
  • test compound has no bacteriostatic action within the test concentration range (0.1 ⁇ g/mL - 100 ⁇ g/mL).
  • the MIC range for the 18H4 strain is 25-100 ⁇ g/mL, which is superior to or equivalent to all four existing antibiotics.
  • the tested compounds In the in vitro bacteriostatic test of three wild-type bacteria, the tested compounds have good antibacterial activity against strains 1F7 and 1F8, and the antibacterial activities of compounds II g and III g are better than that of meropenem and tega. Cyclin and streptomycin, slightly lower than ampicillin. Some of the compounds also have an inhibitory effect on the 1F9 strain.
  • mice mice, weighing 18 to 22 g, each half.
  • the intragastric concentrations were: 200mg/kg, 300mg/kg, 400mg/kg, 500mg/kg, 700mg/kg, 800mg/kg, 1000mg/kg, 1600mg/kg; find the minimum dose of 100% death and 0% death
  • the maximum dose which is the upper and lower doses (D m and D n ).
  • 1 group number Take 36 mice, randomly divided into 6 groups, 6 in each group, each half.

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Abstract

本发明公开了系列含氟咔唑类化合物及其制备方法和应用，属于有机化学、药物化学及药物中间体领域。本发明通过催化C-C键偶联反应得到系列含氟咔唑类化合物，其结构通式为式1所示。式1体外实验表明，本发明的部分化合物具有抑制携带NDM-1耐药基因的大肠杆菌和肺炎克雷伯菌、耐甲氧西林金黄色葡萄球菌(MRSA)等"超级细菌"菌株的活性。本发明为研制全新结构的抗菌药物提供了先导化合物，其合成方法简单，生产成本低，具有较高的开发价值和应用前景。

Description

系列含氟咔唑类化合物及其制备方法和应用 技术领域
本发明属于有机化学、药物化学及药物中间体领域，具体涉及系列含氟咔唑类化合物及其制备方法和应用。
背景技术
细菌耐药性在世界范围内日趋严重和复杂，具有多重耐药基因的“超级细菌”不断涌现，给细菌感染性疾病的治疗带来了巨大挑战。继耐甲氧西林金黄色葡萄球菌(Methicillin-resistant Staphylococcus aureus,简写为MRSA)、耐万古霉素肠球菌(Vancomycin-resistant Enterococcus spp.，简写为VRE)、多重耐药结核杆菌(Mycobacterium tuberculosis)等多重耐药菌出现后，2010年8月世界著名医学杂志《The Lancet Infectious Diseases》(《柳叶刀-传染病》)报道了一种携带“新德里金属-β-内酰胺酶-1”(New Delhi metallo-β-lactamase-1，简写为NDM-1)耐药基因的新型“超级细菌”，该“超级细菌”能够耐受除多粘菌素(colistin)和替加环素(tigecycline)外所有的抗生素，而多粘菌素具有较大的毒副作用，替加环素的适应症很有限，18岁以下患者不适用。该耐药基因可通过质粒在异种细菌之间传递，从而使其快速传播和蔓延。此类细菌相继在世界多国被发现，包括印度、巴基斯坦、英国、美国、加拿大和澳大利亚等国家，我国也于2010年10月宣布检测出携带NDM-1耐药基因的菌株。携带NDM-1耐药基因的“超级细菌”的出现和报道引起了人们极大的震动和关注，研发新型抗生素迫在眉睫。
目前上市的或处于临床研发阶段的新抗生素基本上都是对现有抗生素进行结构修饰，这些新药的母核和原有药物相同或相似，相应的耐药菌往往很快出现，有时一个药物尚在研发阶段，相应的耐药基因及耐药菌株就已经产生。人们也一直从多个途径努力研发全新结构的抗生素，但近四十年来，世界范围内几乎没有全新结构的广谱抗生素上市。
目前，含氟咔唑类的化合物不是很多，其中在咔唑结构一侧的苯环上含一个氟原子的化合物大约有2000种，一侧苯环上含二个氟原子的化合物大约有100种，一侧苯环上含三个氟原子的化合物还未见报道，一侧苯环上含四个氟原子的化合物大约有20种。这些已知的含氟化合物中有相当一部分是结构对称的咔唑，即在咔唑结构两侧的苯环上含有在位置和数目上相同的氟原子，这是由于这类对称的咔唑相对于不对称的咔唑在合成上更容易一些。
发明内容
本发明提供了系列含氟咔唑类化合物及其制备方法和应用，本发明的系列氟取代咔唑类化合物多数是不对称咔唑，体外抑菌实验表明，本发明的部分化合物具有抑制野生型大肠杆菌(Escherichia coli)、金黄色葡萄球菌和枯草芽孢杆菌(Bacillus subtilis)等菌株的活性。更重要地，本发明的部分化合物具有抑制携带NDM-1耐药基因的大肠杆菌和肺炎克雷伯菌(Klebsiella pneumoniae)以及MRSA等“超级细菌”的生物活性。初步毒理实验表明，选测的具有较好抑菌活性的化合物II d的LD50>1000mg/Kg，化合物II l的LD50为595mg/Kg。本发明为研制全新结构的抗菌药物，特别是抑制携带NDM-1耐药基因的“超级细菌”的药物提供了先导化合物，其合成方法简单，生产成本低，具有较高的开发价值和应用前景。
本发明的目的是通过以下技术方案实现的：
一系列含氟咔唑类化合物及其在药学上可接受的盐、酯、酰胺或前药，其结构通式为式1所示，
Figure PCTCN2016077646-appb-000001
式1
R0为下述所列基团中的任意一种：
Figure PCTCN2016077646-appb-000002
R1～R8为下述所列基团中的任意一种，R1～R4取代基至少有一个为F原子：
Figure PCTCN2016077646-appb-000003
所述的一系列含氟咔唑类化合物及其在药学上可接受的盐、酯、酰胺或前药，优选地，其右侧苯环上只含一个氟原子，它们的结构通式为式2所示，
Figure PCTCN2016077646-appb-000004
式2
通式2进一步分为两种情况：
情况一，式2中R≠CH3；R0＝H；m＝1-4；
R1-2和R为下述所列基团的任意一种：
Figure PCTCN2016077646-appb-000005
Rm为下述所列基团的任意一种：
Figure PCTCN2016077646-appb-000006
情况二，式2中R＝CH3且右侧苯环的C4上连有F取代基；
R1-2＝R1～R8；m＝1-4；
R0为下述所列基团的任意一种：
Figure PCTCN2016077646-appb-000007
Rm为下述所列基团的任意一种：
Figure PCTCN2016077646-appb-000008
所述的一系列含氟咔唑类化合物及其在药学上可接受的盐、酯、酰胺或前药，优选地，其右侧苯环上只含二个氟原子，它们的结构通式为式3所示，
Figure PCTCN2016077646-appb-000009
式3
通式3进一步分为两种情况：
情况一，式3中右侧苯环上的两个F取代基没有同时连接在C2和C4位置上；
R0＝H；R1-2＝R1～R8；m＝1-4；
Rm为下述所列基团的任意一种：
Figure PCTCN2016077646-appb-000010
情况二，式3中右侧苯环上的两个F取代基分别连接在C2和C4位置上；
R1-2＝R1～R8；m＝1-4；
R0为下述所列基团的任意一种：
Figure PCTCN2016077646-appb-000011
Rm为下述所列基团的任意一种：
Figure PCTCN2016077646-appb-000012
所述的一系列含氟咔唑类化合物及其在药学上可接受的盐、酯、酰胺或前药，优选地，其右侧苯环上只含三个氟原子它们的结构通式为式4所示，
Figure PCTCN2016077646-appb-000013
式4
其中R＝R1～R8；Rm＝R1～R8；m＝1-4；
R0为下述所列基团的任意一种：
Figure PCTCN2016077646-appb-000014
所述一系列含氟咔唑类化合物及其在药学上可接受的盐、酯、酰胺或前药，优选地，其右侧苯环上含四个氟原子，它们的结构通式为式5所示，
Figure PCTCN2016077646-appb-000015
式5
其中R0＝H；R1-2＝R1～R8；m＝1-4；
Rm为下述所列基团的任意一种：
Figure PCTCN2016077646-appb-000016
作为只含一个氟原子的结构通式2的一类化合物，结构式如通式6，式中右侧苯环的 1位和4位分别为甲基和氟取代基，2位和3位无取代或有其他取代基，
Figure PCTCN2016077646-appb-000017
式6
其中R1-2＝R1～R8；m＝1-4；
R0为下述所列基团的任意一种：
Figure PCTCN2016077646-appb-000018
Rm为下述所列基团的任意一种：
Figure PCTCN2016077646-appb-000019
具体合成的四种化合物的结构如式10。
作为只含有二个氟原子的结构通式3的一类化合物，结构式如通式7。式中右侧苯环的2位和4位分别为二个氟取代基，
Figure PCTCN2016077646-appb-000020
式7
其中R1-2＝R1～R8；m＝1-4；
R0为下述所列基团的任意一种：
Figure PCTCN2016077646-appb-000021
Rm为下述所列基团的任意一种：
Figure PCTCN2016077646-appb-000022
具体合成的15种化合物的结构如式11。
作为只含三个氟原子的结构通式4的一类化合物，结构式如通式8。式中右侧苯环的1位、3位和4位为三个氟取代基，
Figure PCTCN2016077646-appb-000023
其中m＝1-4；Rmor R＝R1～R8。
式8
其中R＝R1～R8；Rm＝R1～R8；m＝1-4；
R0为下述所列基团的任意一种：
Figure PCTCN2016077646-appb-000024
具体合成的7种化合物的结构如式12。
本发明还涉及一种制备上述含氟咔唑类化合物的方法，步骤如下：
称取1mmol的二芳基胺，2.5mmol的叔丁醇钠，0.5mol％的醋酸钯，20mol％的碘化亚铜 加入到含有搅拌子的4mL平底小瓶中，旋紧附有聚四氟乙烯垫的带孔瓶盖。用注射器加入0.8mL二氧六环作为溶剂，将小瓶放置在加热盘的孔中，加热到120℃保持10h。后将小瓶从加热盘的孔中取出，冷却至室温，用水淬灭反应。用二氯甲烷萃取产物，无水硫酸钠干燥溶液。旋干溶剂，用柱层析方法分离，展开剂为30-60℃的石油醚与乙醚的混合溶剂，体积比为10:1。得到相应的纯产物，反应方程式见式9。
Figure PCTCN2016077646-appb-000025
式9含氟咔唑类化合物的通用合成方法
本发明还涉及一系列上述通式结构的含氟咔唑类化合物在制备抑制微生物药物中的应用。所述被此类化合物抑制的微生物的种类包括但不限于携带NDM-1耐药基因的大肠杆菌和肺炎克雷伯菌及MRSA等“超级细菌”菌株，以及野生型大肠杆菌、金黄色葡萄球菌和枯草芽孢杆菌等菌株。
本发明工作得到了国家自然科学基金项目(NSFC 31300067,21071121,21172188和21571087)、江苏省高校自然科学研究重大项目(15KJA150004，15KJA180002)的资助。
有益效果
本发明提供了含氟咔唑类新化合物及其合成方法和应用。本发明的部分化合物具有抑制野生型大肠杆菌、金黄色葡萄球菌、枯草芽孢杆菌等菌株的活性。更重要地，本发明的部分化合物具有抑制携带NDM-1基因的大肠杆菌和肺炎克雷伯菌及MRSA等“超级细菌”的活性，其抑菌活性较好、毒性较低，具有进一步开发成全新结构抗生素的潜质，为全新结构抗生素的合成提供了先导化合物，也可应用于药物中间体的合成。本发明的化合物合成方法简单，生产成本低，具有较高的开发价值和应用前景。
具体实施方式
下面结合具体实施例来进一步详细描述本发明，但这些实施例仅是范例性的，本发明的保护范围并不限于下述实施例。本领域的普通技术人员很容易根据本文说明对本发明做出各种替换、修改或改变，这些替换、修改或改变均在本发明的保护范围内。
实施例1：式2中6-乙基-4-氟-1-甲基-9H-咔唑(I c)的合成
化学反应式：
Figure PCTCN2016077646-appb-000026
实验过程：称取0.3082g(1mmol)的2-溴-4-乙基-N-(5-氟-2-甲基苯基)苯胺，0.2403g(2.5mmol)的叔丁醇钠，1.123mg(0.5mol％)的醋酸钯，38.09mg(20mol％)的碘化亚铜加入到含有搅拌子的4mL平底小瓶中，旋紧附有聚四氟乙烯垫的带孔瓶盖。用注射器加入0.8mL二氧六环作为溶剂，将小瓶放置在加热盘的孔中，加热到120℃保持10h。后将小瓶从加热盘的孔中取出，冷却至室温，用水淬灭反应。用二氯甲烷萃取产物，无水硫酸钠干燥溶液。旋干溶剂，柱层析(展开剂为混合溶剂,30-60℃石油醚:乙醚＝10:1)，得到相应纯的产物。产率88％。
产物的表征数据：MP 127.1-130.1℃.1H NMR(400MHz,CDCl3):δ＝8.03(s,1H),7.92(br,1H),7.39-7.26(m,2H),7.10(dd,J1＝7.2Hz,J2＝5.2Hz,1H),6.82(dd,J1＝10.4Hz,J2＝8.4Hz,1H),2.85(q,J＝7.6Hz,2H),2.50(s,3H),1.36(J＝7.6Hz,3H).13C NMR(100MHz,CDCl3):δ＝157.2(d,J＝244.1Hz),140.9(d,J＝10.5Hz),137.4,136.4,126.5(d,J＝7.9Hz),126.3,121.8(d,J＝3.3Hz),121.6(d,J＝2.1Hz),115.3(d,J＝3.7Hz),111.2(d,J＝20.8Hz),110.4,104.9(d,J＝18.9Hz),29.1,16.7,16.4.19F NMR(376MHz,CDCl3):δ＝-123.6.Anal.Calc.for C15H14FN(227.28g/mol):C,79.27；H,6.21；N,6.16；Found:C,79.01；H,6.18；N,6.19％。
实施例2：式2中4-氟-1-甲基-7-(三氟甲基)-9H-咔唑(I d)的合成
化学反应式：
Figure PCTCN2016077646-appb-000027
实验过程：称取0.3481g(1mmol)的2-溴-N-(5-氟-2-甲基苯基)-5-(三氟甲基)苯胺，0.2403g(2.5mmol)的叔丁醇钠，1.123mg(0.5mol％)的醋酸钯，38.09mg(20mol％)的碘化亚铜加入到含有搅拌子的4mL平底小瓶中，旋紧附有聚四氟乙烯垫的带孔瓶盖。用注射器加入0.8mL二氧六环作为溶剂，将小瓶放置在加热盘的孔中，加热到120℃保持10h。后将小瓶从加热盘的孔中取出，冷却至室温，用水淬灭反应。用二氯甲烷萃取产物，无水硫酸钠干燥溶液。旋干溶剂，柱层析(展开剂为混合溶剂,30-60℃的石油醚:乙醚＝10:1(v:v))，得 到相应的纯产物0.2325mg。产率87％。
产物的表征数据：MP 161.5-163.0℃.1H NMR(400MHz,CDCl3):δ＝8.26(d,J＝8.0Hz,1H),8.19(br,1H),7.72(s,1H),7.51(d,J＝8.0Hz,1H),7.20(m,1H),6.87(dd,J＝10.0Hz,J＝8.0Hz,1H),2.54(s,3H).13C NMR(100MHz,CDCl3):δ＝157.3(d,J＝246.1Hz),141.3(d,J＝9.6Hz),138.1,128.1(d,J＝8.0Hz),127.8(d,J＝31.7Hz),124.8(q,J＝270.3Hz),124.0,123.3(d,J＝3.4Hz),117.0(q,J＝3.6Hz),115.8(d,J＝4.0Hz),110.7(d,J＝20.8Hz),107.9(q,J＝4.4Hz),105.8(d,J＝18.6Hz),16.3.19F NMR(376MHz,CDCl3):δ＝-61.1,-122.5。
实施例8抑菌活性实验所用到的右侧苯环连有一个氟原子的咔唑有4种，它们的结构及代号如式10。I a-I d均为新化合物。实施例1-2分别给出了咔唑I c、I d的合成方法，I a和I b的合成可用相同的方法，这里就不具体给出它们的合成步骤和表征数据了。上述合成方法中所使用的主要原料(即取代的含氟二苯胺)的制备可参考文献X.Kong,H.Zhang,Y.Xiao,C.Cao,Y.Shi,G.Pang,RSC Adv.,2015,5,7035–7048。
Figure PCTCN2016077646-appb-000028
式10
实施例3：式3中2,4-二氟-7-甲基-9H-咔唑(II a)的合成
化学反应式：
Figure PCTCN2016077646-appb-000029
实验过程：称取0.2981g(1mmol)的2-溴-N-(3,5-二氟苯基)-5-甲基苯胺，0.2403g(2.5mmol)的叔丁醇钠，1.123mg(0.5mol％)的醋酸钯，38.09mg(20mol％)的碘化亚铜加入到含有搅拌子的4mL平底小瓶中，旋紧附有聚四氟乙烯垫的带孔瓶盖。用注射器加入0.8mL二氧六环作为溶剂，将小瓶放置在加热盘的孔中，加热到120℃保持10h。后将小瓶从加热盘的孔中取出，冷却至室温，用水淬灭反应。用二氯甲烷萃取产物，无水硫酸钠干燥溶液。旋干溶剂，柱层析(展开剂为混合溶剂,30-60℃的石油醚:乙醚＝10:1(v:v))，得到相应的纯产物197.7mg。产率91％。
产物的表征数据：MP 133.6-134.0℃.1H NMR(400MHz,CDCl3):δ＝8.01(br,1H),7.98(d,J＝8.0Hz,1H),7.17(s,1H),7.08(d,J＝8.0Hz,1H),6.86(dd,J1＝9.2Hz,J2＝2.0Hz,1H),6.66(td,J1＝10.0Hz,J2＝2.0Hz,1H),2.50(s,3H).13C NMR(100MHz,CDCl3):δ＝161.5(dd,J1＝241.0Hz,J2＝6.0Hz),157.9(dd,J1＝249.0Hz,J2＝7.5Hz),141.2(dd,J1＝15.0Hz,J2＝13.0Hz),139.9(d,J＝2.0Hz),136.2(s),122.2,122.1,118.6,110.7,108.6(dd,J1＝21.0Hz,J2＝2.0Hz),95.3(dd,J1＝28.0Hz,J2＝23.0Hz),93.6(dd,J1＝27.0Hz,J2＝4.0Hz),22.2.19F{1H}NMR(376MHz,CDCl3):δ＝-113.8(d,J＝3.8Hz),-116.4(d,J＝7.5Hz).HRMS(ESI):m/z[M+H]+calc for C12H6F5N 260.0499,found 260.0501.Anal.Calc.for C35H38Cl4N6Pd2(897.37g/mol):C,46.85；H,4.27；N,9.37.Found:C,46.27；H,3.79；N,9.89％。
实施例4：式3中2,4-二氟-9H-咔唑(II b)的合成
化学反应式：
Figure PCTCN2016077646-appb-000030
实验过程：称取0.2841g(1mmol)的N-(2-溴苯基)-3,5-二氟苯胺，0.2403g(2.5mmol)的叔丁醇钠，1.123mg(0.5mol％)的醋酸钯，38.09mg(20mol％)的碘化亚铜加入到含有搅拌子的4mL平底小瓶中，旋紧附有聚四氟乙烯垫的带孔瓶盖。用注射器加入0.8mL二氧六环作为溶剂，将小瓶放置在加热盘的孔中，加热到120℃保持10h。后将小瓶从加热盘的孔中取出，冷却至室温，用水淬灭反应。用二氯甲烷萃取产物，无水硫酸钠干燥溶液。旋干溶剂，柱层析(展开剂为混合溶剂,30-60℃的石油醚:乙醚＝10:1(v:v))，得到相应的纯产物195.1mg。产率96％。
产物的表征数据：MP 110.1-111.2℃.1H NMR(400MHz,CDCl3):δ＝8.14(br,1H),8.11(d,J＝8.0Hz,1H),7.43-7.37(m,2H),7.29-7.24(m,1H),6.89(dd,J1＝8.8Hz,J2＝2.0Hz,1H),6.68(td,J1＝10.0Hz,J2＝2.0Hz,1H).13C NMR(100MHz,CDCl3):δ＝161.8(dd,J1＝241.0Hz,J2＝12.0Hz),158.2(dd,J1＝249.0Hz,J2＝16.0Hz),141.2(dd,J1＝14.0Hz,J2＝13.0Hz m),139.4(d,J＝2.0Hz),126.0(s),122.6(d,J＝3.0Hz),120.8(s),120.7(m),110.6(s),108.7(dd,J1＝20.0Hz,J2＝2.0Hz),95.5(dd,J1＝28.0Hz,J2＝23.0Hz),93.7(dd,J1＝27.0Hz,J2＝4.0Hz).19F{1H}NMR(376MHz,CDCl3):δ＝-112.9(d,J＝3.8Hz),-115.9(d,J＝7.5Hz).Anal.Calc.for C12H7F2N(203.18g/mol):C,70.93；H,3.47；N,6.89；Found:C,71.34；H,3.43；N,6.82％。
实施例5：式3中2,4,7-三氟-9H-咔唑(II d)的合成
化学反应式：
Figure PCTCN2016077646-appb-000031
实验过程：称取0.3021g(1mmol)的2-溴-N-(3,5-二氟苯基)-5-氟苯胺，0.2403g(2.5mmol)的叔丁醇钠，1.123mg(0.5mol％)的醋酸钯，38.09mg(20mol％)的碘化亚铜加入到含有搅拌子的4mL平底小瓶中，旋紧附有聚四氟乙烯垫的带孔瓶盖。用注射器加入0.8mL二氧六环作为溶剂，将小瓶放置在加热盘的孔中，加热到120℃保持10h。后将小瓶从加热盘的孔中取出，冷却至室温，用水淬灭反应。用二氯甲烷萃取产物，无水硫酸钠干燥溶液。旋干溶剂，柱层析(展开剂为混合溶剂,30-60℃的石油醚:乙醚＝10:1(v:v))，得到相应的纯产物192.4mg。产率87％。
产物的表征数据：MP 111.5-112.8℃.1H NMR(400MHz,CDCl3):δ＝8.16(br,1H),7.79(dd,J1＝8.8Hz,J2＝2.4Hz,1H),7.34(dd,J1＝8.8Hz,J2＝4.0Hz,1H),7.16(td,J1＝9.2Hz,J2＝2.4Hz,1H),6.92(dd,J1＝9.2Hz,J2＝2.0Hz,1H),6.70(td,J1＝10.0Hz,J2＝2.0Hz,1H).13C NMR(100MHz,CDCl3):δ＝161.8(d,J＝241.0Hz),161.5(dd,J1＝213.9Hz,J2＝12.2Hz),157.7(dd,J＝248.7Hz,J＝15.0Hz),141.6(m),140.0(dd,J＝125.0Hz,J＝1.6Hz),123.4(dd,J1＝10.3Hz,J2＝3.0Hz),117.0,108.8(d,J＝23.9Hz),97.6(d,J＝26.7Hz),95.8(dd,J1＝28.0Hz,J2＝23.2Hz),93.8(dd,J1＝26.6Hz,J2＝4.2Hz).19F{1H}NMR(376MHz,CDCl3):δ＝-113.2(d,J＝6.4Hz),-115.1,-116.6(d,J＝6.4Hz).Anal.Calc.for C12H6F3N(221.18g/mol):C,65.16；H,2.73；N,6.33；Found:C,64.87；H,2.71；N,6.42％。
实施例6：式3中，N,N-二甲基-3-(2,4,7-三氟-9H-咔唑-9-基)-1-丙胺盐酸盐(II n)的合成
化学反应式：
Figure PCTCN2016077646-appb-000032
称0.2212g(1mmol)的2,4,7-三氟-9H-咔唑溶于10mL DMF中，再加入0.14g(3.47mmol)的NaH(60％in oil)，搅拌10min。于此体系中再加入3-氯-1-(N,N-二甲基)丙胺盐酸盐(0.16g,1.01mmol)，升温到50℃，再反应2.5h。然后将反应液倒入冰水中，用DCM萃取，无水 硫酸钠干燥，旋干得到液体0.306g，产率100％。
Figure PCTCN2016077646-appb-000033
将上面得到的N,N-二甲基-3-(2,4,7-三氟-9H-咔唑-9-基)-1-丙胺(0.306g,1mmol)溶于6mL 0.2M的盐酸甲醇溶液中，搅拌1h后旋干，加入乙醚洗涤，得到白色固体0.308g,产率为90％。
产物的表征数据：MP 217.8-219.6℃,1H NMR(400MHz,DMSO):δ＝7.75(dd,J1＝8.8Hz,J2＝2.4Hz,1H),7.68(dd,J1＝8.8Hz,J2＝4.0Hz,1H),7.45-7.34(m,2H),7.02(m,1H),4.40(t,J＝6.8Hz,2H),2.17(t,J＝6.8Hz,2H),2.13(s,6H),1.88(m,2H).13C NMR(100MHz,DMSO):δ＝162.6,162.5,158.4,158.3,158.1,156.0,155.8,142.8(dd,J1＝15.0Hz,J2＝12.5Hz),136.8,119.2(d,J＝10.7Hz),113.5(d,J＝25.0Hz),110.8(d,J＝9.3Hz),107.1(dd,J1＝23.8Hz,J2＝2.3Hz),55.6,44.9,40.8,26.1.19F NMR(376MHz,DMSO):δ＝-111.4(d,J＝6.8Hz),-116.4(d,J＝6.8Hz),-123.4.Anal.Calc.for C17H18ClF3N2(342.79g/mol):C,59.57；H,5.29；N,8.17；Found:C,59.89；H,5.32；N,8.20％。
实施例8抑菌活性实验所用到的右侧苯环上连有二个氟原子的咔唑及其盐酸盐有15种，它们的结构及代号如式11。所有的II a-II o均为新化合物。实施例3-6分别给出了咔唑II a、II b、II d、II n的合成方法，II c、II e-II m和II o的合成可用相同的方法，这里就不具体给出它们的合成步骤和表征数据了。上述合成方法中所使用的主要原料(即取代的含氟二苯胺)的制备可参考文献X.Kong,H.Zhang,Y.Xiao,C.Cao,Y.Shi,G.Pang,RSC Adv.,2015,5,7035–7048。
Figure PCTCN2016077646-appb-000034
式11
实施例7：式4中1,3,4-三氟-6-甲基-9H-咔唑(III a)的合成
化学反应式：
Figure PCTCN2016077646-appb-000035
实验过程：称取0.3161g(1mmol)的N-(2-溴-4-甲基苯基)-2,4,5-三氟苯胺，0.2403g(2.5mmol)的叔丁醇钠，1.123mg(0.5mol％)的醋酸钯，38.09mg(20mol％)的碘化亚铜加入到含有搅拌子的4mL平底小瓶中，旋紧附有聚四氟乙烯垫的带孔瓶盖。用注射器加入0.8mL二氧六环作为溶剂，将小瓶放置在加热盘的孔中，加热到120℃保持10h。后将小瓶从加热盘的孔中取出，冷却至室温，用水淬灭反应。用二氯甲烷萃取产物，无水硫酸钠干燥溶液。旋干溶剂，柱层析(展开剂为混合溶剂,30-60℃的石油醚:乙醚＝10:1(v:v))，得到相应的纯产物0.2046mg。产率87％。
产物的表征数据：MP 140.5-141.7℃.1H NMR(400MHz,CDCl3):δ＝7.98(br,1H),7.94(s,1H),7.31(d,J＝1.2Hz,2H),7.00(td,J＝10.4Hz,J＝6.0Hz,1H),2.53(s,3H).13C NMR(100MHz,CDCl3):δ＝143.1(ddd,J1＝240.1Hz,J2＝10.7Hz,J3＝2.9Hz),142.6(ddd,J1＝236.8Hz,J2＝13.0Hz,J3＝10.2Hz),141.9(ddd,J1＝244.2Hz,J2＝14.3Hz,J3＝4.1Hz), 137.9,130.2,128.9,124.8(dd,J1＝15.2Hz,J2＝9.0Hz),122.8(d,J＝3.1Hz),121.2(m),114.8(m),110.8,101.3(dd,J1＝24.2Hz,J2＝23.1Hz),21.4.19F NMR(376MHz,CDCl3):δ＝-137.5(dd,J1＝19.2Hz,J2＝1.5Hz),-148.8(dd,J1＝21.1Hz,J2＝1.9Hz),-150.8(t,J＝20.7Hz)。
实施例8抑菌活性实验所用到的右侧苯环上连有三个氟原子的咔唑有7种，它们的结构及代号如式12。所有的III a-III g均为新化合物。实施例7给出了咔唑III a的合成方法，III b-III g的合成可用相同的方法，这里就不具体给出它们的合成步骤和表征数据了。上述合成方法中所使用的主要原料(即取代的含氟二苯胺)的制备可参考文献X.Kong,H.Zhang,Y.Xiao,C.Cao,Y.Shi,G.Pang,RSC Adv.,2015,5,7035–7048。
Figure PCTCN2016077646-appb-000036
式12
实施例8：体外抑菌活性的实验
一、实验方法(微量肉汤二倍稀释法)
1)菌种：涉及的实验细菌菌种信息如表1所示
表1体外抑菌实验涉及细菌的相关信息
2)
Figure PCTCN2016077646-appb-000037
3)菌种的活化：将各菌种从-80℃冰箱中取出，分别划线接种于Luria-Bertani(LB)平板上(其中培养18H2、18H4和18H5菌株的LB平板中含终浓度为100μg/mL的氨苄青霉素)，置平板于37℃培养箱中过夜培养。
4)菌液的配制：从上述各LB平板上分别挑取单菌落至含LB液体培养基的试管中，其中接种18H2、18H4和18H5菌株的培养液含终浓度为100μg/mL的氨苄青霉素。将上述各试管置于摇床上，于37℃下振荡培养，每隔一段时间取出少量菌液用酶标仪测定其在波长600nm处的光密度(optical density,OD600)值，当菌液OD600值为1时取出菌液，用LB培养液稀释5,000倍，备用。
5)化合物溶液的制备：将各待测化合物用二甲基亚砜(DMSO)溶解，配成10mg/mL的溶液，然后分别依次2倍稀释，配成系列梯度溶液，最低浓度至0.01mg/mL。另取四种现有抗生素分别配制成与上述化合物相同的系列浓度梯度溶液，这四种抗生素包括美罗培南(meropenem)、替加环素(tigecycline)、链霉素(straptomycin)和氨苄青霉素(ampicillin)。配制溶液的过程中，所用的移液器吸头及塑料小管均在灭菌后使用。
6)抑菌实验：在无菌96-孔板的各孔中分别加入1μL各待测化合物溶液(或抗生素溶液)，向其中一个孔中加入1μL DMSO作为对照，然后再向各孔中加入100μL稀释后的菌液，混匀后于37℃恒温培养18～20h。以在小孔内完全抑制细菌生长的最低药物浓度为最低抑菌浓度(minimum inhibitory concentration,MIC)。上述实验重复3次，根据实验结果确定各化合物的MIC。
二、实验结果：
部分化合物对测试细菌的MIC见表2。
表2化合物对四种耐药菌及三种野生型细菌的最低抑菌浓度(μg/mL)
Figure PCTCN2016077646-appb-000038
注：1.各细菌菌种编号对应的菌种见表1。
2.“-”表示所测化合物在测试浓度范围内(0.1μg/mL–100μg/mL)无抑菌作用。
3.化合物编号对应的化合物结构见式7、式8和式9。
从表2可以看出，在对四种耐药菌的体外抑菌实验中，本实验所测的化合物表现出不同程度的作用。1)对18H2菌株的MIC范围在12.5-100μg/mL，其抑菌活性优于链霉素(测试浓度范围内无作用)和氨苄青霉素(测试浓度范围内无作用)，优于或相当于美罗 培南(MIC＝100μg/mL)、弱于替加环素(MIC<3.125μg/mL)。2)对18H4菌株的MIC范围在25-100μg/mL，优于或相当于所有四种现有抗生素。3)对18H5菌株的MIC范围在12.5-100μg/mL，其抑菌活性优于氨苄青霉素(测试浓度范围内无作用)，优于或相当于链霉素(MIC＝100μg/mL)，弱于美罗培南(MIC＝6.25μg/mL)和替加环素(MIC<3.125μg/mL)。4)对18H8菌株的MIC范围在3.125-50μg/mL，其抑菌活性优于氨苄青霉素(测试浓度范围内无抑制作用)，部分化合物的抑菌活性优于替加环素(MIC＝12.5μg/mL)，与链霉素相当(MIC＝3.125μg/mL)，弱于美罗培南(MIC＝0.78μg/mL)。
在对三种野生型细菌的体外抑菌实验中，所测的化合物对菌株1F7和1F8均有较好的抑菌作用，其中化合物II g和III g的抑菌活性优于美罗培南、替加环素和链霉素，稍低于氨苄青霉素。部分化合物对1F9菌株也具有抑制作用。
从表2中可看出，部分化合物有较广谱的抑菌作用，如化合物II b、II d、II e(分子结构见实施例6后面的式11)。由此可见，本发明提供的部分化合物具有进一步开发成全新结构抗生素的潜质，具有较高的开发价值和应用前景。
实施例9：急性毒性的测试
一、实验方法：采用加权机率单位法(Bliss法)测试化合物LD50
实验动物：小白鼠，体重18～22g，♀♂各半。
实验药品：化合物II d，II l。
给药方式：灌胃。
1.预实验：探索剂量范围
灌胃浓度分别为：200mg/kg,300mg/kg,400mg/kg,500mg/kg,700mg/kg,800mg/kg,1000mg/kg,1600mg/kg；找出100％死亡的最小剂量及0％死亡的最大剂量，此即上下限剂量(Dm和Dn)。
2.正式实验：
1)确定组数、计算各组剂量：
按公式求公比r:
Figure PCTCN2016077646-appb-000039
按公比求各组剂量：D1,D2,…,Dm，其中D1＝Dn＝最小剂量，
D2＝D1·r,…,Dn＝Dn-1·r,Dm＝最大剂量。
2)给药：
①分组编号：取小白鼠36只，随机分成6组，每组6只，♀♂各半。
②给药：灌胃给药。
③观察记录：记录小白鼠给药后的反应，死亡时间，统计死亡数。
二、实验结果：
1.化合物II d的LD50>1000mg/Kg
化合物II l的LD50＝595mg/Kg

Claims (10)

  1. 一系列含氟咔唑类化合物及其在药学上可接受的盐、酯、酰胺或前药，其特征在于，其结构通式如式1所示，
    Figure PCTCN2016077646-appb-100001
    式1
    R0为下述所列基团中的任意一种：
    Figure PCTCN2016077646-appb-100002
    R1～R8为下述所列基团中的任意一种，R1～R4取代基至少有一个为F原子：
    H,F,Cl,Br,I,OTf,OTs,OH,Y,OY,CH2CH3,CF3,COOH,NO2,NH2,NHY,NY2,CONH2,CONHY,CONHNH2,
    Figure PCTCN2016077646-appb-100003
    Figure PCTCN2016077646-appb-100004
  2. 权利要求1所述的一系列含氟咔唑类化合物及其在药学上可接受的盐、酯、酰胺或前药，其特征在于，结构通式如式2所示，其右侧苯环上只含一个氟原子，
    Figure PCTCN2016077646-appb-100005
    式2
    式2中m＝1-4；
    当R≠CH3；R0＝H时，R1-2和R为下述所列基团的任意一种：
    H,Cl,Br,I,OTf,OTs,OH,Y,OY,CH2CH3,CF3,COOH,NO2,NH2,NHY,NY2,CONH2,CONHY,
    Figure PCTCN2016077646-appb-100006
    CONHNH2(Y＝CnH2n+1)；
    Rm为下述所列基团的任意一种：
    OTf,OTs,CF3,NY2,
    Figure PCTCN2016077646-appb-100007
    (Y＝CnH2n+1)；
    当R＝CH3且右侧苯环的C4上连有F取代基时，R1-2＝R1～R8；R0为下述所列基团的任意一种：
    Figure PCTCN2016077646-appb-100008
    Rm为下述所列基团的任意一种：
    F,Cl,Br,I,OTf,OTs,OH,Y,OY,CH2CH3,CF3,COOH,NO2,NH2,NHY,NY2,CONH2,CONHY,CONHNH2,
    Figure PCTCN2016077646-appb-100009
    Figure PCTCN2016077646-appb-100010
  3. 权利要求1所述的一系列含氟咔唑类化合物及其在药学上可接受的盐、酯、酰胺或前药，其特征在于，结构通式如式3所示，其右侧苯环上只含二个氟原子，
    Figure PCTCN2016077646-appb-100011
    式3
    式3中m＝1-4；
    当右侧苯环上的两个F取代基没有同时连接在C2和C4位置上时，R0＝H；R1-2＝R1～R8；
    Rm为下述所列基团的任意一种：
    Cl,Br,I,OTf,OTs,Y,OY,CH2CH3,CF3,COOH,NO2,NH2,NHY,NY2,CONH2,CONHY,
    Figure PCTCN2016077646-appb-100012
    当右侧苯环上的两个F取代基分别连接在C2和C4位置上时，R1-2＝R1～R8；R0为下述所列基团的任意一种：
    Figure PCTCN2016077646-appb-100013
    Rm为下述所列基团的任意一种：
    H,Cl,Br,I,OTf,OTs,OH,Y,OY,CH2CH3,CF3,COOH,NO2,NH2,NHY,NY2,CONH2,CONHY,CONHNH2,
    Figure PCTCN2016077646-appb-100014
    Figure PCTCN2016077646-appb-100015
  4. 权利要求1所述的一系列含氟咔唑类化合物及其在药学上可接受的盐、酯、酰胺或前 药，其特征在于，结构通式如式4所示，其右侧苯环上只含三个氟原子，
    Figure PCTCN2016077646-appb-100016
    式4
    其中R＝R1～R8；Rm＝R1～R8；m＝1-4；
    R0为下述所列基团的任意一种：
    Figure PCTCN2016077646-appb-100017
  5. 权利要求1所述一系列含氟咔唑类化合物及其在药学上可接受的盐、酯、酰胺或前药，其特征在于，结构通式如式5所示，其右侧苯环上含四个氟原子，
    Figure PCTCN2016077646-appb-100018
    式5
    其中R0＝H；m＝1-4；
    Rm为下述所列基团的任意一种：
    Cl,Br,I,OTf,OTs,OH,Y,OY,CH2CH3,CF3,COOH,NO2,NH2,NHY,NY2,CONH2,CONHY,
    Figure PCTCN2016077646-appb-100019
    CONHNH2(Y＝CnH2n+1)。
  6. 权利要求1中式1所示通式结构的含氟咔唑类化合物的制备方法，其特征在于：将二芳基胺、叔丁醇钠、醋酸钯和碘化亚铜加入到反应容器中，以二氧六环作为溶剂，加热到120℃保持10h，冷却至室温，用水淬灭反应，用二氯甲烷萃取产物，无水硫酸钠干燥溶液， 旋干溶剂，柱层析分离，得到相应的纯产物，其中二芳基胺、叔丁醇钠、醋酸钯和碘化亚铜的摩尔比为1:2.5:0.005:0.2。
  7. 根据权利要求6所述的含氟咔唑类化合物的制备方法，其特征在于，所述柱层析分离的展开剂为30-60℃的石油醚和乙醚的混合溶剂，石油醚和乙醚的体积比为10:1。
  8. 权利要求1中式1所示通式结构的含氟咔唑类化合物在制备用于抑制微生物的生物活性的药物中的应用。
  9. 根据权利要求8所述的应用，其特征在于，所述被此类化合物抑制的微生物的种类包括但不限于携带NDM-1基因的大肠杆菌和肺炎克雷伯菌、耐甲氧西林金黄色葡萄球菌，以及野生型大肠杆菌、金黄色葡萄球菌和枯草芽孢杆菌等菌株。
  10. 应用权利要求1所述的式1所示通式结构的含氟咔唑类化合物的形式，包括前导物、原料及其制剂。
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