CN111039983A - 一种抗菌药物的制备方法及其用途 - Google Patents
一种抗菌药物的制备方法及其用途 Download PDFInfo
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- CN111039983A CN111039983A CN201911333310.4A CN201911333310A CN111039983A CN 111039983 A CN111039983 A CN 111039983A CN 201911333310 A CN201911333310 A CN 201911333310A CN 111039983 A CN111039983 A CN 111039983A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6539—Five-membered rings
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- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4021—Esters of aromatic acids (P-C aromatic linkage)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
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- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
- C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/653—Five-membered rings
- C07F9/65324—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
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- C07F9/6539—Five-membered rings
- C07F9/6541—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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- 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
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- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种具有式通式I的具有抗菌作用的亚磷酸酯类化合物,该类化合物的制备方法、在抗菌药物上的应用及含有该类化合物的药物组合物。所合成的10个化合物结构新颖,抑菌活性与阳性对照克林霉素和环丙沙星相当甚至优于阳性药,且抗菌谱较广,特别是化合物5和10,有望进一步开发成为抗菌活性药物。
Description
技术领域
本发明涉及一种亚磷酸酯类化合物,尤其是一种亚磷酸酯类抗菌化合物;本发明还涉及该抗菌化合物在制备抗菌药物上的应用。
背景技术
人类与病原微生物的斗争从未停止,由于鼠疫、肺结核、疟疾、以及近年来出现的获得性免疫缺陷综合症(HIV)等重大疾病的广泛传播,明显增加了人类病原菌感染的发病率与死亡率。直到1942年青霉素的出现,以及后来多种抗生素发展,才使得人与病原菌斗争的天平向人类倾斜。
随后,在19世纪50、60年代,大量新型抗生素快速进入市场,用于治疗细菌感染。抗生素的抗菌作用机制主要有以下几种:(1)干扰细菌细胞壁的合成,导致细菌破裂死亡;(2)干扰蛋白质合成;(3)干扰核酸合成;(4)抑制代谢通路。由于抗生素在抗感染方面的优异作用,使其成为药品中的“神药”。然而,随着抗生素的广泛使用乃至滥用,由抗生素引发的系列问题也逐渐暴露出来,尤其耐药菌的出现,引起了全社会的高度关注。抗生素的耐药性研究早在其临床试验时就已开始,只是在当时未引起人们的重视。1940年,Abraham等鉴定了一种由细菌产生的酶,该酶能催化青霉素伊内酰胺环水解开环失活。1945年,F1eming根据其实验研究结果,在接受《纽约时报》采访时强调:青霉素的不当使用可能导致金色葡萄球菌的“变种”产生耐药,这可能会引发宿主或与宿主接触的人发生更为严重的感染。不幸的是,Fleming的警告变成了现实,在青霉素广泛使用的第一年内就有大量的金黄色葡萄球菌株对青霉素产生耐药;几年后,超过半数的金黄色葡萄球菌对青霉素不再敏感。细菌对抗生素的耐药机制主要有以下几种:(1)细菌产生一种酶,在抗生素未起效前就使其失活;(2)细菌产生一种药泵将抗生素在未到达靶位前就泵出细胞外;(3)细菌通过基因突变使其细胞壁不具有抗生素的结合位点;(4)细菌通过下调膜孔蛋白基因改变细胞膜,限制抗生素进入细胞并达到作用靶标。
然而至19世纪60年代之后,进入市场的抗菌药物几乎都是对已有抗生素结构的改进,这也使得从事抗生素基础研究科学家急剧减少,同时促使细菌有时间适应环境并发展其耐药性。目前,耐药菌已遍布世界的每一个角落,这严重威胁到人类社会的健康与安全。对于耐药菌问题,尽管大量科学家不断开发新型抗生素,但细菌总能以更为聪明的方式产生耐药,而且现在开发新型抗生素的难度越来越大。基于此,开发具有新型抗菌机制的抗菌药物是解决抗生素耐药的重要途径。
发明内容
鉴于以上所述现有技术的缺点,本发明的目的在于提供一种具有抗菌作用的亚磷酸酯衍生物,所述衍生物选自具有式I的结构:
其中取代基R1选自取代或非取代的苯基、芳香杂环基团。
优选地,所述取代基R1选自下列基团:
优选地,所述衍生物选自下列结构:
本发明还提供一种药物组合物,其特征在于由有效剂量的上述化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合制成适于使用的任何剂型。
优选地,所述的药物组合物剂型选自片剂、胶囊、丸剂、注射剂、粉针剂、漱口制剂。
优选地,所述控释制剂的包材选自:聚乳酸羟基乙酸、聚乙二醇、聚酸酐、聚酰胺、聚酯、聚烯、聚醚、聚磷腈或聚糖中的一种或多种的天然或合成的高聚物,或是天然或合成的磷脂、类脂或其组合。
本发明还提供上述化合物或药用组合物在制备治疗或预防细菌引起的疾病药物中的应用。
进一步地,本发明还提供上述化合物或药用组合物在制备治疗或预防细菌引起的疾病药物中的应用,其特征在于所述细菌选自金黄色葡萄球菌、大肠杆菌、志贺氏痢疾杆状细菌。
如上所述,本发明的具有抗菌作用的亚磷酸酯衍生物,具有以下有益效果:(1)本发明首次设计并合成了全新的具有抗菌作用的亚磷酸酯类化合物,并进行了核磁共振氢谱和质谱的结构确认;(2)本发明所合成的化合物抑菌活性与阳性对照克林霉素和环丙沙星相当甚至优于阳性药,且抗菌谱较广,有望进一步开发成为抗菌药物。
具体实施方式
以下由特定的具体实施例说明本发明的实施方式,熟悉此技术的人士可由本说明书所揭露的内容轻易地了解本发明的其他优点及功效。
实施例1
中间体4-甲氧甲酰苯基亚磷酸二甲酯的合成
向搅拌的对溴苯甲酸甲酯(2.13g,10mmol)和无水氯化镍(190mg,1.5mmol)的甲醇溶液中,缓慢滴加亚磷酸三甲酯(3.72g,30mmol),150℃下回流3h。冷却至室温后,乙酸乙酯萃取,有机相用用饱和NaHCO3溶液和饱和NaCl溶液依次洗涤,无水Na2SO4干燥过滤浓缩得目标化合物,无色油状液体,2.00g,收率82.1%。
1H NMR(400MHz,DMSO-d6):6(ppm):8.12-8.09(dd,2H,J1=8.4Hz,J2=4.0Hz,ArH),7.90-7.85(dd,2H,J1=21.2Hz,J2=12.8Hz,ArH),3.86(s,3H,-OCH3),3.71-3.69(s,6H,2-OCH3)
无水氯化镍的制备:向NiCl6-H20(1.0eq)加入氯化亚砜(10eq),回流2h。旋蒸除去未反应的氯化亚砜,油泵抽干即得。
实施例2
4-羧基苯基亚磷酸二甲酯的合成
将4-甲氧甲酰基苯基亚磷酸甲酯(7.48mmol)溶于30ml甲醇中,加入LiOH的水溶液(1.57g in 30ml H2O),40℃下搅拌4h,旋蒸除去甲醇,用乙酸乙酯萃取。弃去乙酸乙酯层,水层用2N盐酸调pH至3,用乙酸乙酯萃取。有机相干燥过滤浓缩后得目标化合物,白色固体,收率72.2%。
1H NMR(400MHz,DMSO-d6):δ(ppm):12.90(brs,1H,-COOH),8.11-8.08(dd,2H,J1=8.0Hz,J2=3.6Hz,ArH),7.87-7.77(dd,2H,J1=12.8Hz,J2=8.4Hz,ArH),3.71-3.68(s,6H,2-OCH3).
实施例3
N-(2-氨基苯基)-2-氯-5-硝基苯甲酰胺
将2-氯-5-硝基苯甲酸(5.04g,25mmol)溶于25ml无水二氯甲烷中,加入10滴DMF,冰浴搅拌下缓慢滴加草酰氯(2.25ml,26.25mmol),搅拌15min后。移去冰浴,室温下搅拌2h。旋蒸除去溶剂和未反应的草酰氯,得到2-氯-5-硝基苯甲酰氯,将粗制的2-氯-5-硝基苯甲酰氯溶于60ml无水四氢呋喃中,缓慢加至冰浴下含有5ml三乙胺的邻苯二胺(2.65g,24.5mmol)的20ml干燥的THF溶液中,室温反应12h。反应液抽滤,除去生成的三乙胺盐,石油醚洗涤,滤液旋干后用乙酸乙酯/水萃取,有机相用饱和NaHCO3和NaCl溶液依次洗涤,无水Na2SO4干燥,浓缩后重结晶得目标化合物,黄色粉末,3.948g,收率54%。
1H NMR(300MHz,DMSO-d6):δ(ppm):9.90(s,1H,-NH),8.61-8.60(d,1H,J=2.4Hz,ArH),8.34-8.30(dd,1H,J1=8.4Hz,J2=2.4Hz,ArH),7.89-7.86(d,1H,J=9.0Hz,ArH),7.28-7.25(d,1H,J=7.5Hz,ArH),7.02-6.97(t,1H,J=7.5Hz,ArH),6.79-6.76(d,1H,J=8.1Hz,ArH),6.62-6.57(t,1H,J=7.5Hz,ArH),5.32(s,2H,-NH2).
实施例4
2-(2-氯-5-硝基苯基)-1H-苯并咪唑
将N-(2-氨基苯基)-2-氯-5-硝基苯甲酰胺(3.948g,13.5mmol)溶于100ml冰醋酸,搅拌回流2h,冷却至室温,将反应瓶置于冰浴中,析出固体。抽滤,水洗得目标化合物,黄色粉末3.01g,收率81.4%。
1H NMR(300MHz,DMSO-d6):δ(ppm):12.97(s,1H,NH),8.76-8.75(d,1H,J=3.0Hz,ArH),8.36-8.32(dd,1H,J1=8.7Hz,J2=2.7Hz,ArH),7.98-7.95(d,1H,J=9.0Hz,ArH),7.74-7.63(m,2H,ArH),7.28(m,2H,ArH).
实施例5
2-(2-氯-5-氨基苯基)-1-异丙基-苯并咪唑
将2-(2-氯-5-氨基苯基)-1H-苯并咪唑(2.73g,10mmol,1.0eq)和NaH(含量30%,2.4g,30mmol,3.0eq)溶于干燥的THF,加入溴代异丙烷(3.69g,30mmol,3.0eq),60℃下搅拌48h,旋蒸除去溶剂,用乙酸乙酯和水萃取,有机相干燥过滤浓缩,重结晶得目标化合物,黄色固体,2.05g,收率65%。
1H NMR(400MHz,DMSO-d6):δ(ppm):8.49-8.48(d,1H,J=2.4Hz,ArH),8.46-8.43(m,1H,ArH),8.02-8.00(d,1H,J=8.8Hz,ArH),7.87-7.86(d,1H,J=7.6Hz,ArH),7.74-7.72(d,1H,J=7.2Hz,ArH),7.36-7.27(m,2H,ArH),4.34-4.27(m,1H,-CH-),1.62-1.51(m,6H,2-CH3).
实施例6
2-(2-氯-5-氨基苯基)-1H-苯并咪唑
将2-(2-氯-5-硝基苯基)-1H-苯并咪唑(3.005g,10.98mmol)溶于40ml乙醇,加入锌粉(3.57g,55mmol)和5ml浓盐酸,搅拌回流10h。冷却至室温,硅藻土过滤,滤液干燥浓缩后柱层析得目标化合物,黄色粉末2.405g,收率89.9%。
实施例7
目标化合物的合成
最终的目标化合物最后一步均是成酰胺,合成通法为:
将羧酸(1.0eq)、相应的芳香胺(1.0eq)、HATU(1.5eq)和DMAP(2.0eq)溶于干燥的DMF中,室温下搅拌过夜。向反应体系中加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤后浓缩,硅胶柱层析,得目标化合物。
化合物1
棕黄色固体收率:33.1%,熔点:275-276℃
1H NMR(400MHz,DMSO-d6):δ(ppm):10.73-10.69(d,1H,-NH),9.92(s,1H,-NHCO),8.16-8.07(m,3H,ArH),7.92-7.84(m,3H,ArH),7.77-7.65(m,2H,ArH),7.56-7.54(m,1H,ArH),7.35-7.33(m,1H,ArH),7.28-7.24(m,1H,ArH),3.72(s,3H,-OCH3),3.68(s,3H,-OCH3).ESI(m/z):456.0975[M+H]+
化合物2
棕黄色固体收率:34.1%,熔点:206-207℃
1H NMR(400MHz,DMSO-d6):δ(ppm):10.81(s,1H,NHCO),8.75(s,1H,ArH),8.16-8.06(m,3H,ArH),7.93-7.85(m,4H,ArH),7.74-7.72(d,1H,J=8.0Hz,ArH),7.53-7.45(m,2H,ArH),3.89(s,3H,-OCH3),3.73(s,3H,-OCH3).ESI(m/z):457.0710[M+H]+
化合物3
棕黄色固体收率:26.3%,熔点:254-255℃
1H NMR(400MHz,DMSO-d6):δ(ppm):10.76(s,1H,-NHCO),8.12-8.09(dd,2H,J1=8.0Hz,J2=3.6Hz,ArH),8.03-8.02(m,2H,ArH),7.91-7.83(m,3H,ArH),7.72-7.69(m,2H,ArH),7.31-7.25(m,2H,ArH),4.36-4.29(m,1H,-CH-),3.69(s,3H,-OCH3),3.66(s,3H,-OCH3),1.66-1.47(m,6H,2-CH3).ESI(m/z):498.1507[M+H]+
化合物4
棕黄色固体收率:24.1%,熔点:259-260℃
1H NMR(400MHz,DMSO-d6):δ(ppm):10.74(s,1H,-NH),8.12-8.00(m,4H,ArH),7.91-7.86(dd,2H,J1=12.0Hz,J2=20.0Hz,ArH),7.75-7.73(m,1H,ArH),7.69-7.67(d,1H,J=8.0Hz,ArH),7.53-7.51(m,1H,ArH),7.28-7.20(m,5H,ArH),6.99-6.89(m,2H,ArH),5.39(s,2H,-CH2-),3.71-3.68(d,6H,J=12.0Hz,2CH3).ESI(m/z):546.1406[M+H]+
化合物5
棕黄色固体收率:33.6%,熔点:212-213℃
1H NMR(400MHz,DMSO-d6):δ(ppm):12.75(s,1H,-NHCO),10.71(s,1H,-NHCO),8.12-8.08(m,3H,ArH),7.95-7.87(m,3H,ArH),7.60-7.55(m,2H,ArH),7.34-7.4(d,1H,J=3.6Hz,ArH),3.72(s,3H,-OCH3),3.69(s,3H,-OCH3).ESI(m/z):466.0385[M+H]+
化合物6
棕黄色固体收率:32.3%,熔点:208-209℃
1H NMR(400MHz,DMSO-d6):(ppm):10.69(s,1H,-NH),10.55(s,1H,-NH),8.12-8.10(m,2H,ArH),8.02-8.01(d,1H,J=4.0Hz,ArH),7.95-7.86(m,3H,ArH),7.73-7.70(m,2H,ArH),7.59-7.56(d,1H,J=12.0Hz,ArH),7.38-7.31(m,2H,ArH),7.14-7.07(m,1H,ArH),3.71(s,3H,-OCH3),3.69(s,3H,-OCH3).ESI(m/z):459.0851[M+H]+
化合物7
棕黄色固体收率:44.1%,熔点:186-187℃
1H NMR(400MHz,DMSO-d6):δ(ppm):11.04(s,1H,-NH),10.68(s,1H,-NH),8.37-8.36(d,1H,J=4.0Hz,ArH),8.19-8.17(d,1H,J=8.0Hz,ArH),8.12-8.09(dd,2H,J1=8.0Hz,J2=8.0Hz,ArH),8.04-8.03(d,1H,J=4.0Hz,ArH),7.93-7.84(m,4H,ArH),7.55-7.53(d,1H,J=12.0Hz,ArH),7.21-7.17(m,1H,ArH),1.33(s,3H,-OCH3),1.18(s,3H,-OCH3).ESI(m/z):460.0881[M+H]+
化合物8
棕黄色固体收率:45.3%,熔点:210-211℃
1H NMR(400MHz,DMSO-d6):δ(ppm):11.26(s,1H,-NH),10.68(s,1H,-NH),8.43(m,1H,ArH),8.24-8.22(d 1H,J=8.0Hz,ArH),8.13-8.10(m,2H,ArH),8.04(s,1H,ArH),8.00-7.97(m,1H,ArH),7.92-7.86(m,3H,ArH),7.56-7.54(d,1H,J=8.0Hz,ArH),3.72(s,3H,-OCH3),3.69(s,3H,-OCH3).ESI(m/z):494.0426[M+H]+
化合物9
棕黄色固体收率:47.1%,熔点:270-271℃
1H NMR(400MHz,DMSO-d6):(ppm):12.90(s,1H,-NH),10.80(s,1H,-NH),8.16-8.12(m,3H,ArH),7.99-7.96(m,1H,ArH),7.92-7.86(m,2H,ArH),7.71-7.68(d,1H,J=8.8Hz,ArH),7.64-7.60(m,2H,ArH),7.08-7.06(m,1H,ArH),3.84(s,3H,-OCH3),3.72(s,3H,-OCH3),3.69(s,3H,-OCH3).ESI(m/z):546.0615[M+H]+
化合物10
棕黄色固体收率:41.8%,熔点:238-239℃
1H NMR(300MHz,DMSO-d6):δ(ppm):8.02-8.01(m,2H,ArH),7.94(s,1H,ArH),7.89-7.82(m,3H,ArH),7.48-7.45(d,1H,J=8.7Hz,ArH),7.06(s,1H,ArH),3.75-3.72(d,3H,J=12Hz,2-OCH3),2.37(s,3H,CH3).ESI(m/z):480.0551[M+H]+
实施例8
药物筛选实验
试验方法:MIC的测定根据CLSI指导原则(Clinical and Laboratory StandardsInstitute guidelines),用肉汤微稀释法进行。
受试菌株:大肠杆菌、金葡菌、志贺菌、放线菌、韦荣氏球菌。
用菌株培养液将上述10个化合物稀释,通过十倍比稀释法,将上述化合物稀释成不同的浓度梯度,并添加到加了菌液的培养孔中,每孔100ul,设置三个重复孔,结果取3个数的平均值。同时设置阳性对照组。药敏实验重复两次,并调整加药浓度以获得确定的MIC值,实验结果如表1所示。
表1所合成的化合物与阳性药抑菌活性结果(mg/L)
从表1可以看出,所合成的化合物抑菌活性与阳性对照克林霉素和环丙沙星相当甚至优于阳性药,且抗菌谱较广,特别是化合物5和10,有望进一步开发成为抗菌药物。
实施例仅例示性说明本发明的原理及其功效,而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下,对上述实施例进行修饰或改变。因此,举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变,仍应由本发明的权利要求所涵盖。
Claims (8)
4.一种药物组合物,其特征在于由有效剂量的如权利要求1-3任一项所述的化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合制成适于使用的任何剂型。
5.根据权利要求4所述的药物组合物,其特征在于所述的药物组合物剂型选自片剂、胶囊、丸剂、注射剂、粉针剂、漱口制剂。
6.根据权利要求5所述的药物组合物,其特征在于所述控释制剂的包材选自:聚乳酸羟基乙酸、聚乙二醇、聚酸酐、聚酰胺、聚酯、聚烯、聚醚、聚磷腈或聚糖中的一种或多种的天然或合成的高聚物,或是天然或合成的磷脂、类脂或其组合。
7.权利要求1-6任一项所述的化合物或药用组合物在制备治疗或预防细菌引起的疾病药物中的应用。
8.根据权利要求7所述的化合物或药用组合物在制备治疗或预防细菌引起的疾病药物中的应用,其特征在于所述细菌选自金黄色葡萄球菌、大肠杆菌、志贺氏痢疾杆状细菌。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4326344A1 (de) * | 1993-08-05 | 1995-02-09 | Thomae Gmbh Dr K | Carbonamide, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
CN104370738A (zh) * | 2014-10-23 | 2015-02-25 | 暨南大学 | 木豆素结构类似物及其在制备抗菌药物中的应用 |
CN107573394A (zh) * | 2017-09-30 | 2018-01-12 | 中国科学院南海海洋研究所 | 脱氯台勾霉素类化合物及其制备方法和在制备抗菌药物中的应用 |
CN108295075A (zh) * | 2018-04-09 | 2018-07-20 | 青岛市市立医院 | 一种用于防治牙周炎的药物及其制备方法 |
WO2019072112A1 (zh) * | 2017-10-12 | 2019-04-18 | 中国科学院上海药物研究所 | 一类二聚吲哚生物碱类化合物、其制备方法及其在制备抗菌药物中的应用 |
CN109820854A (zh) * | 2019-03-27 | 2019-05-31 | 中国科学院化学研究所 | 一种超分子光响应药物及其制备方法与调控方法 |
-
2019
- 2019-12-19 CN CN201911333310.4A patent/CN111039983B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4326344A1 (de) * | 1993-08-05 | 1995-02-09 | Thomae Gmbh Dr K | Carbonamide, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
CN104370738A (zh) * | 2014-10-23 | 2015-02-25 | 暨南大学 | 木豆素结构类似物及其在制备抗菌药物中的应用 |
CN107573394A (zh) * | 2017-09-30 | 2018-01-12 | 中国科学院南海海洋研究所 | 脱氯台勾霉素类化合物及其制备方法和在制备抗菌药物中的应用 |
WO2019072112A1 (zh) * | 2017-10-12 | 2019-04-18 | 中国科学院上海药物研究所 | 一类二聚吲哚生物碱类化合物、其制备方法及其在制备抗菌药物中的应用 |
CN108295075A (zh) * | 2018-04-09 | 2018-07-20 | 青岛市市立医院 | 一种用于防治牙周炎的药物及其制备方法 |
CN109820854A (zh) * | 2019-03-27 | 2019-05-31 | 中国科学院化学研究所 | 一种超分子光响应药物及其制备方法与调控方法 |
Non-Patent Citations (1)
Title |
---|
胡德禹 等: "噻唑类杀菌剂的合成及生物活性研究进展", 《合成化学》 * |
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