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WO2018058534A1 - 一种具有2-氨基苯巯醇侧链的截短侧耳素衍生物及其制备方法和用途 - Google Patents

一种具有2-氨基苯巯醇侧链的截短侧耳素衍生物及其制备方法和用途 Download PDF

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WO2018058534A1
WO2018058534A1 PCT/CN2016/101097 CN2016101097W WO2018058534A1 WO 2018058534 A1 WO2018058534 A1 WO 2018058534A1 CN 2016101097 W CN2016101097 W CN 2016101097W WO 2018058534 A1 WO2018058534 A1 WO 2018058534A1
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hydrogen atom
acid
side chain
pleuromutilin
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French (fr)
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汤有志
刘雅红
张昭圣
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South China Agricultural University
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South China Agricultural University
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Priority to US16/236,370 priority patent/US10421715B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/63—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
    • C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings
    • C07C2603/82—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings having three condensed rings with in total fourteen carbon atoms and having a having a [5.4.3.0(1,8)] ring structure, e.g. pleuromutiline

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a pleuromutilin derivative having a 2-aminophenylnonanol side chain, a preparation method thereof and use thereof.
  • Methicillin-resistant Staphylococcus aureus is a pathogen with a wide range of epidemics, high virulence, high morbidity and mortality. Once infected, it can cause fever, poor mental and local infection symptoms. The most common are lung infections, such as skin, urinary tract, maternal reproductive tract infections, severe sepsis, prolonged hospital stay, such as treatment is not timely, Can endanger the lives of patients. A 2003 survey in the Netherlands showed that about 39% of slaughter pigs contained ST398 MRSA, and 27% of the breeders carried pig-derived MRSA. The animal source MRSA ST398 can cause human infection in contact with animals. MRSA is resistant to all ⁇ -lactam antibiotics, and most of them are resistant to macrolides, aminoglycosides, fluoroquinolones and other antibacterial drugs, resulting in difficulty in infection treatment and high mortality.
  • Pleuromutilin (Formula 1) is produced by the higher fungi Pleurotus mutiliz (Fr.) Sacc. and Pleurotus Passeckeranius Pilat, a tricyclic diterpene compound having a conjugated (5-6-8) tricyclic ring. This class of compounds interacts with the ribosome 50S subunit to inhibit bacterial protein synthesis. It has strong antibacterial activity against resistant Gram-positive bacteria, drug-resistant mycoplasma and some Gram-negative bacteria. The pleuromutilin is different from the common nuclear structure of clinical antibacterial drugs, and it is not easy to produce cross-resistance with other structural antibacterials. Through the modification of the side chain of the pleuromutilin C14, two pleuromutilin veterinary antibacterial agents such as Tiamulin and Valnemulin have been introduced into the market.
  • Rumblemulin was approved by the US FDA in 2007 as the first person to use pleuromutilin. Mainly used for the treatment of pustular dermatitis caused by Staphylococcus aureus and Streptococcus pyogenes infection.
  • Rita Miaolin has good antibacterial activity against many common antibiotics such as oxacillin, erythromycin and mupirocin. They also found that rituximab and traditional antibacterial drugs More than, it is less likely to cause resistance to Staphylococcus aureus.
  • pleuromutilin Because the mechanism of action of pleuromutilin is different from that of the currently widely used antibiotics, resistant bacteria against pleuromutilin are still rare. Compared with dozens of drugs based on penicillin, cephalosporin, and serotonin, which have been successfully developed based on the same mother nucleus, only three antibacterial agents have been successfully developed based on pleuromutilin, and the present invention will provide a novel structure. A novel pleuromutilin compound with strong antibacterial activity.
  • Another object of the present invention is to provide a process for producing the above-described pleuromutilin derivative having a 2-aminophenylnonanol side chain.
  • Still another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient a pleuromutilin derivative of the above 2-aminophenylnonanol side chain;
  • Still another object of the present invention is to provide a pleuromutilin derivative of the above 2-aminophenylnonanol side chain in the preparation of a medicament for treating infectious diseases, particularly mycoplasma, or resistant Staphylococcus aureus, or multidrug resistant bacteria Use in drugs that cause infectious diseases.
  • a pleuromutilin derivative having a 2-aminophenylnonanol side chain the pleuromutilin derivative being a compound having the structure shown in Formula 2 and Formula 3, and a pharmaceutically acceptable salt thereof:
  • R 1 is a hydrogen atom, a hydroxyl group, an amino group, a decyl group, a methylol group, an amine methyl group, a nitro group, a halogen, a trihalomethyl group, a methyl group, a natural amino acid acylamino group, and an alkyl group having 1 to 6 carbon atoms.
  • R 2 is a hydrogen atom, a hydroxyl group, an amino group, a mercapto group, hydroxymethyl, aminomethyl, nitro, halo, trihalomethyl, methyl, natural amino acids and amido carbon atoms, an alkoxy group having 1 to 6 One of them;
  • R 3 is a hydrogen atom, a hydroxyl group, an amino group, a decyl group, a methylol group, an amine methyl group, a nitro group, a halogen, a trihalomethyl group, a methyl group, a natural amino acid acylamino group, and an alkoxy group having 1 to 6 carbon atoms. One of them.
  • R 1 is hydrogen, hydroxy, amino, hydroxymethyl, amine methyl, fluoro, trifluoromethyl, nitro, trifluoromethyl, methoxy, ethoxy, prolylamino and guanidine
  • R 1 is hydrogen, hydroxy, amino, hydroxymethyl, amine methyl, fluoro, trifluoromethyl, nitro, trifluoromethyl, methoxy, ethoxy, prolylamino and guanidine
  • R 2 is hydrogen, hydroxy, amino, hydroxymethyl, amine methyl, fluoro, trifluoromethyl, nitro, trifluoromethyl, methoxy, ethoxy, prolylamino and prolylamino a kind
  • R 3 is hydrogen, hydroxy, amino, hydroxymethyl, amine methyl, fluoro, trifluoromethyl, nitro, trifluoromethyl, methoxy, ethoxy, prolylamino and prolylamino One kind.
  • halogen means fluoro, chloro, bromo, iodo.
  • R 1 is a methyl group
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom
  • R 1 is a hydrogen atom
  • R 2 is a methyl group
  • R 3 is a hydrogen atom
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom
  • R 3 is a methyl group
  • R 1 is a fluorine atom
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom
  • R 1 is a hydrogen atom
  • R 2 is a fluorine atom
  • R 3 is a hydrogen atom
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom
  • R 3 is a fluorine atom
  • R 1 is a chlorine atom
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom
  • R 1 is a hydrogen atom
  • R 2 is a chlorine atom
  • R 3 is a hydrogen atom
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom
  • R 3 is a chlorine atom
  • R 1 is a methoxy group
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom
  • R 1 is a hydrogen atom
  • R 2 is a methylhydro group
  • R 3 is a hydrogen atom
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom
  • R 3 is a methoxy group.
  • the pharmaceutically acceptable salt is a compound having a structure as shown in Formula 2 and Formula 3, and hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, amber a salt formed from acid, citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid.
  • the pharmaceutically acceptable salt structural formula of a part of representative compounds of the compounds of Formula 2 and Formula 3 of the present invention is shown in Table 2:
  • the preparation method of the above-mentioned pleuromutilin derivative having 2-aminophenylnonanol side chain comprises the following steps:
  • intermediate II having the structure shown in formula 3;
  • the reaction in the step (1) is carried out by using pyridine as a solvent at 0 ° C for 3 hours; the molar ratio of the p-toluenesulfonyl chloride to pleuromutilin is 1.1:1.
  • the reaction in the step (2) is to use an aprotic solvent as a solvent, and the intermediate I is first dissolved in an aprotic solvent, the solvent is used in an amount of 30 times the mass of the intermediate I, and then anhydrous sodium iodide is added, and the mixture is heated to reflux.
  • the reaction in the step (3) is carried out by using an aprotic solvent as a solvent, adding a substituted benzoic acid, and performing a condensation reaction with the intermediate II at 0-70 ° C for 1-36 hours under the catalysis of a condensing agent and a base, and heating and stirring the reaction, that is,
  • the target product is purified by recrystallization or column chromatography; wherein the aprotic solvent is dichloromethane, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, pyridine;
  • the condensing agent is methyl chloroformate, ethyl chloroformate, tert-butyl chloroformate, carbonyl diimidazole (CDI), sulfonyl chloride, Boc anhydride, N,N-dicyclohexylcarbodiimide (DCC), 6 -Chlorobenzotriazole-1,1,3,3-tetra
  • the synthetic route is as follows:
  • a pharmaceutical composition comprising the above-described pleuromutilin derivative having a 2-aminophenylnonanol side chain as an active ingredient.
  • pleuromutilin derivative having a 2-aminophenylnonanol side chain for the preparation of a medicament for treating an infectious disease, characterized in that the infectious disease is human or animal mycoplasma, or resistant to Staphylococcus aureus Or infectious diseases caused by multi-drug resistant bacteria infection.
  • the pleuromutilin compound provided by the present invention is a new type of compound reported for the first time.
  • the inventors have conducted extensive and in-depth research, synthesized a large number of compounds and carried out extensive biological activity screening, and found for the first time that the compounds of Formula 2 and Formula 3 have good in vitro antibacterial activity, and are particularly suitable as novel antibacterial drugs for animals or humans. Systemic systemic infection.
  • Pleurotus 5.4 g (14.27 mmol) was dissolved in 30 ml of pyridine, and ice-cooled to about 0 ° C, and 8.6 g (45.11 mmol) of p-toluenesulfonyl chloride was added. After stirring for 3 hours in an ice bath, 50 ml of ice water was added to quench the reaction. The reaction solution was poured into a separatory funnel, and then layered with 50 ml of chloroform, and the aqueous phase was separated.
  • the organic phase was washed twice with 100 ml of a sulfuric acid solution having a concentration of 2 mol/L, and the organic phase was washed twice with 50 ml of a saturated sodium hydrogencarbonate solution. Finally, the organic phase was washed twice with 100 ml of deionized water and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness, and 10 ml of isopropanol was added to the residual solid and dissolved by heating. After cooling, a large amount of white powder was precipitated, filtered under reduced pressure, and the filtrate was washed with isopropyl alcohol, and the remaining liquid of the product white powder was naturally evaporated to dryness. A white powder, Intermediate I, was obtained in a yield of 88.84%.
  • the reaction solution was poured into a separatory funnel, and extracted with 30 ml of chloroform to obtain an organic phase.
  • the obtained organic phase is evaporated to dryness, and the mixture is re-dissolved in dichloromethane, and 100 g of 100-200 mesh silica gel is added and mixed well. After the solvent is evaporated, the crude product-silica gel mixture is purified by column chromatography (200-300).
  • the minimum inhibitory concentration (MIC) of the series of compounds obtained by the present invention was determined by the agar double dilution method.
  • the experimental control drug was selected from the group consisting of valnemulin and the valenicillin as the pleuromutilin, which is currently used in the antibiotics.
  • the bacterial solution was inoculated into a petri dish containing different concentrations of the drug using a multi-point inoculator, and the inoculum amount was 10 6 CFU/ml. After incubating at 37 ° C for 24 hours, the results were observed, and the concentration of the compound in the petri dish was determined as the minimum inhibitory concentration (MIC) of the compound.
  • the strains used in the experiment were Escherichia coli ATCC25922, Staphylococcus aureus ATCC29213, methicillin-resistant Staphylococcus aureus ATCC43300, and Mycoplasma gallisepticum S6.
  • the stock solution was diluted in a petri dish by a dilution method, and each culture dish contained 1 ml of the drug solution, and diluted to 20 ml with melted MH agar, so that the final concentration of the test compound in the series culture dishes was 64, 32, 16 respectively. , 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625 ⁇ g/ml.

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Abstract

本发明属于药物化学领域，公开了一种具有2-氨基苯巯醇侧链的截短侧耳素类化合物及其制备方法和用途。该化合物具有如式（2）及式（3）所示的结构。其中，R1、R2、R3各自独立地选自氢原子、羟基、氨基、巯基、羟甲基、胺甲基、硝基、卤素、三卤代甲基、甲基、天然氨基酸酰氨基和C1～6烷氧基中。本发明具有2-氨基苯巯醇侧链的截短侧耳素类化合物具有良好的抑制耐药金黄色葡萄球菌和支原体活性，特别适合作为新型抗菌药物用于防治人或动物支原体或耐药金葡或多药耐药菌引起的感染性疾病。

Description

一种具有2-氨基苯巯醇侧链的截短侧耳素衍生物及其制备方法和用途 技术领域
本发明属于药物化学领域，特别涉及一种具有2-氨基苯巯醇侧链的截短侧耳素衍生物及其制备方法和用途。
背景技术
耐甲氧西林金黄色葡萄球菌(MRSA)是一种流行范围广、致病力强、发病率和死亡率高的病原菌。人体一旦感染，可引起发热，精神差，局部感染症状，最常见的是肺部感染，其他如皮肤、泌尿道、产妇生殖道感染，重者为败血症，延长患者住院时间，如治疗不及时，可危及患者的生命。2003年荷兰的一篇调查显示屠宰猪中约39％含有ST398型MRSA，27％的饲养人员携带猪源MRSA。动物源MRSA ST398可以引起与动物接触的人类感染。MRSA对所有β内酰胺类抗生素耐药，并对大环内酯类、氨基糖苷类、氟喹诺酮类等抗菌药物多数耐药，导致该菌所致感染治疗困难，病死率高。
截短侧耳素(式1)由高等真菌Pleurotusmutiliz(Fr.)Sacc.和Pleurotus Passeckeranius Pilat产生，具有骈合(5-6-8)三环的一种三环二萜化合物。该类化合物与核糖体50S亚基相互作用抑制细菌蛋白质合成。对耐药革兰氏阳性菌、耐药性支原体及部分革兰氏阴性菌均有很强的抗菌活性。截短侧耳素类化合物具有异于临床常见抗菌药母核结构，与其它结构类抗菌药之间不易产生交叉耐药性。通过对截短侧耳素C14侧链的改造，目前已有泰妙菌素(Tiamulin)和沃尼妙林(Valnemulin)两个截短侧耳素类兽用抗菌药进入市场。
瑞他妙林(retapamulin)作为第一个人用截短侧耳素类抗菌药物于2007年通过美国FDA审批上市。主要用于金黄色葡萄球菌和酿脓链球菌感染引起的脓疱性皮炎的治疗。瑞他妙林对临床常见抗菌药如苯唑西林、红霉素、莫匹罗星等在内的多种耐药菌均具有良好的抗菌活性，他们还发现瑞他妙林与传统抗菌药相比，更不易引起金黄色葡萄球菌的耐药性。
由于截短侧耳素类化合物的作用机制与目前临床广泛应用的抗生素不同，故针对截短侧耳素类抗菌药的耐药菌尚不多见。与以青霉素、头孢菌素、沙星类抗菌药，基于同一母核开发成功的药物动辄数十种相比，基于截短侧耳素仅成功开发三种抗菌药，本发明将提供一类结构新颖、抗菌活性强的新型截短侧耳素类化合物。
Figure PCTCN2016101097-appb-000001
发明内容
为了解决上述现有技术中存在的不足之处，本发明的首要目的在于提供一种具有2-氨基苯巯醇侧链的截短侧耳素衍生物。
本发明的另一目的在于提供上述具有2-氨基苯巯醇侧链的截短侧耳素衍生物的制备方法。
本发明的再一个目的在于提供一种药物组合物，其包含上述2-氨基苯巯醇侧链的截短侧耳素衍生物作为活性成分；
本发明的又一个目的在于提供上述2-氨基苯巯醇侧链的截短侧耳素衍生物在制备治疗感染性疾病特别是经支原体、或耐药金黄色葡萄球菌、或多药耐药菌感引起的感染性疾病的药物中的用途。
本发明的目的通过下述技术方案来实现：
一种具有2-氨基苯巯醇侧链的截短侧耳素衍生物，该截短侧耳素衍生物是具有如式2和式3所示结构的化合物及其可药用盐：
Figure PCTCN2016101097-appb-000002
其中，R1为氢原子、羟基、氨基、巯基、羟甲基、胺甲基、硝基、卤素、三卤代甲基、甲基、天然氨基酸酰氨基和碳原子数为1～6的烷氧基中的一种；
R2为氢原子、羟基、氨基、巯基、羟甲基、胺甲基、硝基、卤素、三卤代甲基、甲基、天然氨基酸酰氨基和碳原子数为1～6的烷氧基中的一种；
R3为氢原子、羟基、氨基、巯基、羟甲基、胺甲基、硝基、卤素、三卤代甲基、甲基、天然氨基酸酰氨基和碳原子数为1～6的烷氧基中的一种。
优选的，R1为氢、羟基、氨基、羟甲基、胺甲基、氟、三氟甲基、硝基、三氟甲基、甲氧基、乙氧基、脯氨酰氨基和缬氨酰氨基中的一种；
R2为氢、羟基、氨基、羟甲基、胺甲基、氟、三氟甲基、硝基、三氟甲基、甲氧基、乙氧基、脯氨酰氨基和缬氨酰氨基中的一种；
R3为氢、羟基、氨基、羟甲基、胺甲基、氟、三氟甲基、硝基、三氟甲基、甲氧基、乙氧基、脯氨酰氨基和缬氨酰氨基中的一种。
术语“卤素”表示氟、氯、溴、碘。
更加优选的，所述R1为甲基，R2为氢原子，R3为氢原子；
或R1为氢原子，R2为甲基，R3为氢原子；
或R1为氢原子，R2为氢原子，R3为甲基；
或R1为氟原子，R2为氢原子，R3为氢原子；
或R1为氢原子，R2为氟原子，R3为氢原子；
或R1为氢原子，R2为氢原子，R3为氟原子；
或R1为氯原子，R2为氢原子，R3为氢原子；
或R1为氢原子，R2为氯原子，R3为氢原子；
或R1为氢原子，R2为氢原子，R3为氯原子；
或R1为甲氧基，R2为氢原子，R3为氢原子；
或R1为氢原子，R2为甲氢基，R3为氢原子；
或R1为氢原子，R2为氢原子，R3为甲氧基。
上述优选方式也可以如表1所示：
表1本发明代表性化合物1-12结构式
Figure PCTCN2016101097-appb-000003
Figure PCTCN2016101097-appb-000004
所述可药用盐是具有如式2和式3所示结构的化合物，与盐酸、氢溴酸、硫酸、硝酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、琥珀酸、柠檬酸、苹果酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、谷氨酸或天冬氨酸形成的盐。
优选地，本发明的通式2和式3所示的化合物中部分具有代表性的化合物的可药用盐结构式如表2所示：
表2部分化合物的可药用盐
Figure PCTCN2016101097-appb-000005
Figure PCTCN2016101097-appb-000006
上述具有2-氨基苯巯醇侧链的截短侧耳素衍生物的制备方法，包括以下操作步骤：
(1)将截短侧耳素与对甲苯磺酰氯反应，获取如式4所示结构的中间体Ⅰ；
Figure PCTCN2016101097-appb-000007
(2)将中间体Ⅰ作为原料，通过与碘化钠反应进一步活化，再与2-氨基苯硫醇在碱性条件下反应，获得如式3所示结构的中间体Ⅱ；
(3)将中间体Ⅱ作为原料，与各取代苯甲酸反应，得到如式2所示结构的具有2-氨基苯巯醇侧链的截短侧耳素类化合物。
步骤(1)所述反应是采用吡啶作为溶剂，在0℃条件下反应3小时；所述对甲苯磺酰氯与截短侧耳素摩尔比为1.1：1。
步骤(2)所述反应是采用非质子性溶剂作为溶剂，先将中间体Ⅰ溶于非质子性溶剂中，溶剂用量为中间体Ⅰ质量的30倍，再加入无水碘化钠，加热回流1小时，其中中间体Ⅰ与无水碘化钠摩尔比为1：1.1；所述反应之前，先将2-氨基苯硫醇和碱溶于水中，再与活化所得产物一起加热回流2小时，其中中间体 Ⅰ与2-氨基苯硫醇摩尔比为1：1.1，2-氨基苯硫醇与碱摩尔比为1：2；所述碱为氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾或碳酸铯；所述非质子性溶剂为N,N-二甲基甲酰胺。
步骤(3)所述反应采用非质子溶剂作为溶剂，加入取代苯甲酸，在缩合剂及碱的催化下，与中间体Ⅱ在0-70℃进行缩合反应1-36小时，加热搅拌反应，即得目标产物，重结晶或柱层析纯化；其中，所述非质子溶剂为二氯甲烷、乙酸乙酯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、吡啶；所述缩合剂为氯甲酸甲酯、氯甲酸乙酯、氯甲酸叔丁酯、羰基二咪唑(CDI)、磺酰氯、Boc酸酐、N，N-二环己基碳二亚胺(DCC)、6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(HCTU)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDC)、1-羟基－苯并三氮唑(HOBt)或1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(PyBOP)、草酰氯或二氯亚砜；所述碱为吡啶、三乙胺、吗啉、N-甲基吗啉或N,N-二异丙基乙胺(DIEA)。
合成路线如下式所示：
Figure PCTCN2016101097-appb-000008
一种药物组合物，药物组合物包含了上述具有2-氨基苯巯醇侧链的截短侧耳素衍生物作为活性成分。
上述具有2-氨基苯巯醇侧链的截短侧耳素衍生物在制备治疗感染性疾病药物中的用途，其特征在于：所述感染性疾病为人或动物经支原体、或耐药金黄色葡萄球菌、或多药耐药菌感染引起的感染性疾病。
本发明相对现有技术，具有如下的优点及有益效果：本发明提供的截短侧耳素类化合物是首次报道的新类型化合物。本发明人经过广泛而深入的研究，合成了大量化合物并进行了广泛的生物活性筛选，首次发现通式2和式3化合物具有良好的体外抗菌活性，特别适合作为新型抗菌药物用于动物或人全身系统感染。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限 于此。
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限于此。下述实施例1-12所得化合物的编号如权利要求书中所示。
中间体Ⅰ制备实施例：
截短侧耳素5.4g(14.27mmol)溶于30ml吡啶，冰浴至0℃左右，加入对甲苯磺酰氯8.6g(45.11mmol)。冰浴搅拌反应3h后加入50ml冰水淬灭反应。将反应液倒入分液漏斗，先加50ml氯仿分层，出去水相，后用浓度为2mol/L的硫酸溶液100ml洗涤有机相2次，再用饱和碳酸氢钠溶液50ml洗涤有机相2次，最后用去离子水100ml洗涤有机相2次并用无水硫酸钠干燥。旋转蒸发干有机相，往残余固体中加入10ml异丙醇并加热溶解，冷却后析出大量白色粉末，减压抽滤，滤出物用异丙醇洗涤，产物白色粉末剩余液体自然挥发至干燥，得白色粉末即中间体Ⅰ，产率88.84％。
中间体Ⅱ(式3化合物，化合物13)制备实施例：
中间体Ⅰ1g(1.88mmol)溶于35ml乙酸乙酯，加入无水碘化钠0.31g(2.07mmol)，70℃左右加热搅拌反应1h。取2-氨基苯硫醇0.25g(2.04mmol)置于10ml水中，往水溶液中加入氢氧化钠0.08g(2.04mmol)，将上述水溶液加入反应体系中，70℃左右加热搅拌反应2h。将反应液倒入分液漏斗中，加30ml氯仿萃取，取有机相。所得有机相旋转蒸干得混合物经二氯甲烷复溶，加入100-200目硅胶1g充分混合，待溶剂挥发完后，将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200～300目硅胶粉为固定相，石油醚：乙酸乙酯＝1：2为流动相)，得到如式3所示结构的产物中间体Ⅱ的纯品。产率81.22％。
实施例1：22-O-[2-(2-甲基苯甲酰胺基)苯基]硫乙酰基妙林(化合物1)合成
中间体Ⅱ0.82g(1.88mmol)溶于35ml乙酸乙酯，加入2-甲基苯甲酸(2.07mmol)，草酰氯2.07mmol，70℃左右加热搅拌反应1h，即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶，加入100-200目硅胶1g充分混合，待溶剂挥发完后，将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200～300目硅胶粉为固定相，石油醚：乙酸乙酯＝1：1为流动相)，得到产物22-O-[2-(2-甲基苯甲酰胺基)苯基]硫乙酰基妙林(化合物1)的纯品。产率86.55％。HR-MS(ESI):Cal:604.3091；Found:604.3117。
实施例2：22-O-[2-(3-甲基苯甲酰胺基)苯基]硫乙酰基妙林(化合物2)合成
中间体Ⅱ0.82g(1.88mmol)溶于35ml二氯甲烷，加入3-甲基苯甲酸(2.07mmol)，氯甲酸叔丁酯2.07mmol，70℃左右加热搅拌反应1h，即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶，加入100-200目硅胶1g充分混合，待溶剂挥发完后，将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200～300目硅胶粉为固定相，石油醚：乙酸乙酯＝1：1为流动相)，得到产物22-O-[2-(3-甲基苯甲酰胺基)苯基]硫乙酰基妙林(化合物2)的纯品。产率85.75％。HR-MS(ESI):Cal:604.3091；Found:604.3110。
实施例3：22-O-[2-(4-甲基苯甲酰胺基)苯基]硫乙酰基妙林(化合物3)合成
中间体Ⅱ0.82g(1.88mmol)溶于35ml二氯甲烷，加入4-甲基苯甲酸(2.07mmol)，二氯亚砜2.07mmol，70℃左右加热搅拌反应1h，即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶，加入100-200目硅胶1g充分混 合，待溶剂挥发完后，将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200～300目硅胶粉为固定相，石油醚：乙酸乙酯＝1：1为流动相)，得到产物22-O-[2-(4-甲基苯甲酰胺基)乙基]硫乙酰基妙林(化合物3)的纯品。产率83.09％。HR-MS(ESI):Cal:604.3091；Found:604.3110。
实施例4：22-O-[2-(2-氟苯甲酰胺基)苯基]硫乙酰基妙林(化合物4)合成
中间体Ⅱ0.82g(1.88mmol)溶于35ml N,N-二甲基甲酰胺，加入2-氟苯甲酸2.06mmol，1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐2.06mmol，N,N-二异丙基乙胺6mmol，70℃左右加热搅拌反应1h，即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶，加入100-200目硅胶1g充分混合，待溶剂挥发完后，将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200～300目硅胶粉为固定相，石油醚：乙酸乙酯＝1：1为流动相)，得到产物22-O-[2-(2-氟苯甲酰胺基)苯基]硫乙酰基妙林(化合物4)的纯品。产率91.47％。HR-MS(ESI):Cal:608.2840；Found:608.2867。
实施例5：22-O-[2-(3-氟苯甲酰胺基)苯基]硫乙酰基妙林(化合物5)合成
中间体Ⅱ0.82g(1.88mmol)溶于35ml乙酸乙酯，加入3-氟苯甲酸(2.06mmol)，6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯2.06mmol，三乙胺6mmol，70℃左右加热搅拌反应1h，即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶，加入100-200目硅胶1g充分混合，待溶剂挥发完后，将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200～300目硅胶粉为固定相，石油醚：乙酸乙酯＝1：1为流动相)，得到产物22-O-[2-(3-氟苯甲酰胺基)苯基]硫乙酰基 妙林(化合物5)的纯品。产率87.39％。HR-MS(ESI):Cal:608.2840；Found:608.2856。
实施例6：22-O-[2-(4-氟苯甲酰胺基)苯基]硫乙酰基妙林(化合物6)合成
中间体Ⅱ0.82g(1.88mmol)溶于35ml二氯甲烷，加入4-氟苯甲酸(2.06mmol)，羰基二咪唑2.06mmol，室温搅拌反应1h，即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶，加入100-200目硅胶1g充分混合，待溶剂挥发完后，将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200～300目硅胶粉为固定相，石油醚：乙酸乙酯＝1：1为流动相)，得到产物22-O-[2-(4-氟苯甲酰胺基)苯基]硫乙酰基妙林(化合物6)的纯品。产率84.91％。HR-MS(ESI):Cal:608.2840；Found:608.2836。
实施例7：22-O-[2-(2-氯苯甲酰胺基)苯基]硫乙酰基妙林(化合物7)合成
中间体Ⅱ0.82g(1.88mmol)溶于35ml乙酸乙酯，加入2-氯苯甲酸2.06mmol，1-(3-二甲基氨基丙基)-3-乙基碳二亚胺2.06mmol，50℃加热搅拌反应1h，即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶，加入100-200目硅胶1g充分混合，待溶剂挥发完后，将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200～300目硅胶粉为固定相，石油醚：乙酸乙酯＝1：1为流动相)，得到产物22-O-[2-(2-氯苯甲酰胺基)苯基]硫乙酰基妙林(化合物7)的纯品。产率87.86％。HR-MS(ESI):Cal:624.2545；Found:624.2575。
实施例8：22-O-[2-(3-氯苯甲酰胺基)苯基]硫乙酰基妙林(化合物8)合成
中间体Ⅱ0.82g(1.88mmol)溶于35ml N,N-二甲基甲酰胺，加入3-氯苯甲酸2.06mmol，N，N-二环己基碳二亚胺2.06mmol，25℃加热搅拌反应1h，即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶，加入100-200目硅胶1g充分混合，待溶剂挥发完后，将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200～300目硅胶粉为固定相，石油醚：乙酸乙酯＝1：1为流动相)，得到产物22-O-[2-(3-氯苯甲酰胺基)苯基]硫乙酰基妙林(化合物8)的纯品。产率85.04％。HR-MS(ESI):Cal:624.2545；Found:624.2562。
实施例9：22-O-[2-(4-氯苯甲酰胺基)苯基]硫乙酰基妙林(化合物9)合成
中间体Ⅱ0.82g(1.88mmol)溶于35ml N,N-二甲基乙酰胺，加入4-氯苯甲酸2.06mmol，羰基二咪唑2.06mmol，30℃左右加热搅拌反应1h，即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶，加入100-200目硅胶1g充分混合，待溶剂挥发完后，将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200～300目硅胶粉为固定相，石油醚：乙酸乙酯＝1：1为流动相)，得到产物22-O-[2-(4-氯苯甲酰胺基)苯基]硫乙酰基妙林(化合物9)的纯品。产率89.66％。HR-MS(ESI):Cal:624.2545；Found:624.2540。
实施例10：22-O-[2-(2-甲氧基苯甲酰胺基)苯基]硫乙酰基妙林(化合物10)合成
中间体Ⅱ0.82g(1.88mmol)溶于35ml乙酸乙酯，加入2-甲氧基苯甲酸2.05mmol，氯甲酸甲酯2.05mmol，吗啉2.5mmol，25℃搅拌反应1h，即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶，加入100-200目硅胶1g充分混 合，待溶剂挥发完后，将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200～300目硅胶粉为固定相，石油醚：乙酸乙酯＝1：1为流动相)，得到产物22-O-[2-(2-甲氧基苯甲酰胺基)苯基]硫乙酰基妙林(化合物10)的纯品。产率92.24％。HR-MS(ESI):Cal:620.3040；Found:620.3037。
实施例11：22-O-[2-(3-甲氧基苯甲酰胺基)苯基]硫乙酰基妙林(化合物11)合成
中间体Ⅱ0.82g(1.88mmol)溶于35ml N,N-二甲基甲酰胺，加入3-甲氧基苯甲酸2.05mmol，O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸2.05mmol，N-甲基吗啉6mmol，0℃搅拌反应3h，即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶，加入100-200目硅胶1g充分混合，待溶剂挥发完后，将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200～300目硅胶粉为固定相，石油醚：乙酸乙酯＝1：1为流动相)，得到产物22-O-[2-(3-甲氧基苯甲酰胺基)苯基]硫乙酰基妙林(化合物11)的纯品。产率94.82％。HR-MS(ESI):Cal:620.3040；Found:620.3062。
实施例12：22-O-[2-(4-甲氧基苯甲酰胺基)苯基]硫乙酰基妙林(化合物12)合成
中间体Ⅱ0.82g(1.88mmol)溶于35ml乙酸乙酯，加入4-甲氧基苯甲酸2.05mmol，氯甲酸乙酯2.05mmol，70℃加热搅拌反应36h，即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶，加入100-200目硅胶1g充分混合，待溶剂挥发完后，将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200～300目硅 胶粉为固定相，石油醚：乙酸乙酯＝1：1为流动相)，得到产物22-O-[2-(4-甲氧基苯甲酰胺基)苯基]硫乙酰基妙林(化合物12)的纯品。产率87.07％。HR-MS(ESI):Cal:620.3040；Found:620.3067。
实验实施例：体外抑菌实验
实验方法
采用琼脂二倍稀释法测定本发明所得的系列化合物的最小抑菌浓度(MIC)，实验对照药物选用沃尼妙林，沃尼妙林为截短侧耳素类抗生素，是该类抗生素中目前应用广泛的兽用抗生素。使用多点接种器将菌液接种在含不同浓度药物的培养皿中，接种菌量为106CFU/ml。37℃孵育24小时后观察结果，以不长菌的培养皿中的化合物浓度作为该化合物的最小抑菌浓度(MIC)。
实验中所用的菌株为大肠杆菌ATCC25922、金黄色葡萄球菌ATCC29213、耐甲氧西林金黄色葡萄球菌ATCC43300、鸡毒支原体S6。
精密称取25.6mg所合成的目标化合物，置于10mL的容量瓶中，先用少量N，N-二甲基甲酰胺溶解后，再用N，N-二甲基甲酰胺定容至10mL，配成2560μg/mL的储备液。另分别精密称取25.6mg截短侧耳素、泰妙菌素、沃尼妙林、瑞他妙林，置于10ml容量瓶中，N，N-二甲基甲酰胺稀释并定容至10mL，配成2560μg/mL的对照储备液。
将储备液以倍比稀释法稀释在培养皿中，每个培养皿含药液1ml，以融化的MH琼脂稀释至20ml，使系列培养皿中受试化合物的终浓度分别为64，32，16，8，4，2，1，0.5，0.25，0.125，0.0625μg/ml。
下表3为MIC结果。
表3体外抑菌数据
Figure PCTCN2016101097-appb-000009
全部目标化合物对金黄色葡萄球菌表现出较好的抗菌活性，多数化合物对金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌抗菌活性接近或优于临床上广泛使用的泰妙菌素(tiamulin)，化合物13对金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌抗菌活性明显优于目前临床上广泛使用的沃尼妙林(valnemulin)及瑞他妙林(retapamulin)。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 一种具有2-氨基苯巯醇侧链的截短侧耳素衍生物，其特征在于：该截短侧耳素衍生物是具有如式2和式3所示结构的化合物及其可药用盐：
    Figure PCTCN2016101097-appb-100001
    其中，R1为氢原子、羟基、氨基、巯基、羟甲基、胺甲基、硝基、卤素、三卤代甲基、甲基、天然氨基酸酰氨基和碳原子数为1～6的烷氧基中的一种；
    R2为氢原子、羟基、氨基、巯基、羟甲基、胺甲基、硝基、卤素、三卤代甲基、甲基、天然氨基酸酰氨基和碳原子数为1～6的烷氧基中的一种；
    R3为氢原子、羟基、氨基、巯基、羟甲基、胺甲基、硝基、卤素、三卤代甲基、甲基、天然氨基酸酰氨基和碳原子数为1～6的烷氧基中的一种。
  2. 根据权利要求1所述的一种具有2-氨基苯巯醇侧链的截短侧耳素衍生物，其特征在于：R1为氢、羟基、氨基、羟甲基、胺甲基、氟、三氟甲基、硝基、三氟甲基、甲氧基、乙氧基、脯氨酰氨基和缬氨酰氨基中的一种；
    R2为氢、羟基、氨基、羟甲基、胺甲基、氟、三氟甲基、硝基、三氟甲基、 甲氧基、乙氧基、脯氨酰氨基和缬氨酰氨基中的一种；
    R3为氢、羟基、氨基、羟甲基、胺甲基、氟、三氟甲基、硝基、三氟甲基、甲氧基、乙氧基、脯氨酰氨基和缬氨酰氨基中的一种。
  3. 根据权利要求1所述的一种具有2-氨基苯巯醇侧链的截短侧耳素衍生物，其特征在于：
    所述R1为甲基，R2为氢原子，R3为氢原子；
    或R1为氢原子，R2为甲基，R3为氢原子；
    或R1为氢原子，R2为氢原子，R3为甲基；
    或R1为氟原子，R2为氢原子，R3为氢原子；
    或R1为氢原子，R2为氟原子，R3为氢原子；
    或R1为氢原子，R2为氢原子，R3为氟原子；
    或R1为氯原子，R2为氢原子，R3为氢原子；
    或R1为氢原子，R2为氯原子，R3为氢原子；
    或R1为氢原子，R2为氢原子，R3为氯原子；
    或R1为甲氧基，R2为氢原子，R3为氢原子；
    或R1为氢原子，R2为甲氢基，R3为氢原子；
    或R1为氢原子，R2为氢原子，R3为甲氧基。
  4. 根据权利要求1所述的一种具有2-氨基苯巯醇侧链的截短侧耳素衍生物，其特征在于：所述可药用盐是具有如式2和式3所示结构的化合物，与盐酸、氢溴酸、硫酸、硝酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、琥珀酸、柠檬酸、苹果酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、谷氨酸或天冬氨酸形成的盐。
  5. 根据权利要求1-4任一项所述的一种具有2-氨基苯巯醇侧链的截短侧耳素衍生物的制备方法，其特征在于包括以下操作步骤：
    (1)将截短侧耳素与对甲苯磺酰氯反应，获取如式4所示结构的中间体Ⅰ；
    Figure PCTCN2016101097-appb-100002
    (2)将中间体Ⅰ作为原料，通过与碘化钠反应进一步活化，再与2-氨基苯硫醇在碱性条件下反应，获得如式3所示结构的中间体Ⅱ；
    (3)将中间体Ⅱ作为原料，与各取代苯甲酸反应，得到如式2所示结构的具有2-氨基苯巯醇侧链的截短侧耳素类化合物。
  6. 根据权利要求5所述的制备方法，其特征在于：步骤(1)所述反应是采用吡啶作为溶剂，在0℃条件下反应3小时；所述对甲苯磺酰氯与截短侧耳素摩尔比为1.1：1。
  7. 根据权利要求5所述的制备方法，其特征在于：步骤(2)所述反应是采用非质子性溶剂作为溶剂，先将中间体Ⅰ溶于非质子性溶剂中，溶剂用量为中间体Ⅰ质量的30倍，再加入无水碘化钠，加热回流1小时，其中中间体Ⅰ与无水碘化钠摩尔比为1：1.1；所述反应之前，先将2-氨基苯硫醇和碱溶于水中，再与活化所得产物一起加热回流2小时，其中中间体Ⅰ与2-氨基苯硫醇摩尔比为1：1.1，2-氨基苯硫醇与碱摩尔比为1：2；所述碱为氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾或碳酸铯；所述非质子性溶剂为N,N-二甲基甲酰胺。
  8. 根据权利要求5所述的制备方法，其特征在于：步骤(3)所述反应采用非质子溶剂作为溶剂，加入取代苯甲酸，在缩合剂及碱的催化下，与中间体Ⅱ在0-70℃进行缩合反应1-36小时，加热搅拌反应，即得目标产物，重结晶或柱层 析纯化；其中，所述非质子溶剂为二氯甲烷、乙酸乙酯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、吡啶；所述缩合剂为氯甲酸甲酯、氯甲酸乙酯、氯甲酸叔丁酯、羰基二咪唑、磺酰氯、Boc酸酐、N，N-二环己基碳二亚胺、6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺、1-羟基－苯并三氮唑或1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐、草酰氯或二氯亚砜；所述碱为吡啶、三乙胺、吗啉、N-甲基吗啉或N,N-二异丙基乙胺。
  9. 一种药物组合物，其特征在于：该药物组合物包含了权利要求1-4任一项所述的具有2-氨基苯巯醇侧链的截短侧耳素衍生物作为活性成分。
  10. 根据权利要求1-4任一项所述的一种具有2-氨基苯巯醇侧链的截短侧耳素衍生物在制备治疗感染性疾病药物中的用途，其特征在于：所述感染性疾病为人或动物经支原体或耐药金黄色葡萄球菌、或多药耐药菌感染引起的感染性疾病。
PCT/CN2016/101097 2016-09-30 2016-09-30 一种具有2-氨基苯巯醇侧链的截短侧耳素衍生物及其制备方法和用途 Ceased WO2018058534A1 (zh)

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