CN111518102A - 环基甲酰及环基酮类化合物及其制备方法和药学上的用途 - Google Patents
环基甲酰及环基酮类化合物及其制备方法和药学上的用途 Download PDFInfo
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- CN111518102A CN111518102A CN202010406795.1A CN202010406795A CN111518102A CN 111518102 A CN111518102 A CN 111518102A CN 202010406795 A CN202010406795 A CN 202010406795A CN 111518102 A CN111518102 A CN 111518102A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
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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
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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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
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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Abstract
本发明公开了环基甲酰及环基酮类化合物及其制备方法和药学上的用途。本发明发现(I)所示化合物具有较好抑制寨卡病毒、登革病毒的感染和复制功能，它们可能作为治疗和预防寨卡病毒、登革热病毒引起的疾病的药物，也可能成为治疗和预防其它黄病毒引起的疾病的药物，如黄热病、西尼罗河病毒感染、乙脑病毒感染引起的乙型脑炎、基孔肯雅病病毒感染、丙型肝炎、森林脑炎以及HIV引起的爱滋病等，以及手足口病毒感染引起的疾病等。该类型化合物可以治疗细菌感染引起的疾病，包括炎症性肠病的溃疡性结肠炎和克罗恩病，大肠杆菌引起的疾病，金黄葡萄球菌等引起的疾病，鲍曼不动杆菌引起的疾病。
Description
技术领域
本发明属于药物化学技术领域，具体涉及环基甲酰及环基酮类化合物及其制备方法和药学上的用途。
背景技术
病毒科(Flaviviridae)的寨卡病毒(ZIKV)、登革病毒(DENV)、黄病毒(YFV)、西尼罗河病毒(WNV)、乙型脑炎病毒(JEV)及甲病毒属的基孔肯雅病毒(CHIKV)都是虫媒病毒(arbovirus)，它们在生命周期的许多方面是相似的。这些虫媒病毒的主要载体伊蚊(Aedesmosquito)(包括埃及伊蚊(Aedes aegypti)、白纹伊蚊(Aedes albopictus)和波利尼西亚伊蚊(Aedes polynesiensis))是世界体型最大的蚊子之一，存活在除南极洲之外的世界所有大洲。一般被具传染性的伊蚊(Aedes)叮咬之后3-14天出现登革热样疾病症状(平均4-7天)。
比较特别的是DENV有4个血清型，尽管4个血清型DENV之间有65–70％的相似度，不同血清型DENV再次感染却会引起抗体依赖的增强效应(ADE)，而近年研究发现这种抗体依赖的增强效应也可能会出现在DENV感染后的ZIKV交叉感染，这种ADE效应可能会产生一些不确定性。2015-2016年在巴西ZIKV感染流行，而2016年又在巴西出现DENV疫情，这是否是交叉感染助长了两股疫情，并可能引起病毒的毒力强度增加甚至病毒基因突变？2016-2017年《柳叶刀·传染病》的数份报告称2016年越南和新加坡爆发的ZIKV感染疫情已经发现可能出现基因变异，最早认为由南美洲输入的ZIKV可能是原本已在东南亚传播的ZIKV的变种而非源自南美洲输入。
在全球环境恶化和变暖等诸多因素影响下，登革热和寨卡疫情近年有扩大的趋势，但目前只有1款限定区域的登革疫苗，没有寨卡病毒疫苗和其它疫苗，也没有有效的抗寨卡病毒或抗登革病毒的药物可用于临床治疗登革热疾病，现在临床治疗主要是渐进的支持疗法(intensive supportive therapy)，其中维持体液平衡是主要手段。所以对寨卡病毒、登革病毒等虫媒病毒感染引起的疾病的药物研究显得极为重要和迫切。
其它的虫媒病毒具有和寨卡病毒、登革病毒相似的症状，也存在变异成更高毒性的变异病毒的可能。
发明内容
本部分的目的在于概述本发明的实施例的一些方面以及简要介绍一些较佳实施例。在本部分以及本申请的说明书摘要和发明名称中可能会做些简化或省略以避免使本部分、说明书摘要和发明名称的目的模糊，而这种简化或省略不能用于限制本发明的范围。
鉴于上述的技术缺陷，提出了本发明。本发明提供一类具有相应活性的五元环的并环化合物及其衍生物、立体异构体、顺反异构体、或其药学上可接受的盐。因此，作为本发明其中一个方面，本发明提供环基甲酰及环基酮类化合物及其制备方法和药学上的用途。
为解决上述技术问题，本发明提供了如下技术方案：式(I)所示的化合物、异构体或其药学上可接受的盐；
其中，A环包括任意取代或未取代的非芳香环、非芳香杂环、碳芳香环、或芳香杂环中的一种；X1和/或X2包括空、O、S、S(O)、S(O2)、NR8、C(O)、(C(R9R10))p中的一种，且X1和X2不同时为O、S、S(O)、S(O2)；Y1、Y2可以相同或不同，Y1和/或Y2分别为N、CR11中的一种；m和/或n为0～6的整数，m+n为0～6的整数；p为1～6的整数；当X1或X2中一个为NR8、另一个为空时，Y1为N，R1包括取代或未取代的苯环中的一种或几种，R2与R3和/或R4和/或R5和/或R6和/或R7和/或R8之间未形成环状结构，甲酰基两侧的连接N的R4和/或R5和/或R7是酰基或胺基甲酰基或甲酸酯基或甲酰肼基或六个碳及以下的烷基中的一种或几种时，A环不包括取代或未取代的吡咯环；当X1或X2中一个为空，Y1为N，R2与甲酰基两侧的连接N的R4和/或R5和/或R7之间形成环状结构时，A环不包括吡咯环和4-取代吡咯环；R1～R11是H、CN、CF3、硝基、卤素、任意取代的烷基、任意取代的环烷基、任意取代的杂环基、任意取代的烷氧基、任意取代的烷硫基、任意取代的烷硫单氧基(亚砜)、任意取代的烷硫双氧基(砜)、任意取代的磺酰基、羧酸、羧酸酯、任意取代的酯基、酰胺、任意取代酰胺氨基、任意取代的烯烃基、任意取代的环烯烃基、任意取代芳香烷基、任意取代杂环芳香烷基、任意取代芳香烃基、任意取代杂环芳香烃基、任意取代芳香烯烃基、任意取代杂环芳香烯烃基；所述取代基选自卤素、氰基、硝基、C1～6烷基、C1～6卤代烷基、C1～6烷氧基、C1～6烷硫基或C2～6烯烃基、羧基、羧酸酯、磺酸酯；X1和X2之间可以形成双键；X1和X2之间可以形成4～6元并环；X1和R2之间可以形成4～6元环；X1与R11和/或Y1之间可以形成双键；X1与R11和/或Y1之间可以形成4～6元环；R2和R7之间或R2和R4或R2和R5或R2和R6之间可以形成4～6元环；R2和R3之间可以形成4～6元螺环；相邻取代基之间可以形成双键；相邻取代基之间可以形成环，环可能是碳环或杂环，可能是芳香环或非芳香环；其中，所述相邻取代基包括R3和R7；同碳取代基之间可以形成环，环可能是碳环或杂环或芳香环或非芳香环中的一种或几种；其中，同碳取代基包括R9和R10、R7和R11；非同碳且非相邻碳取代基之间、非同氮且非相邻氮取代基之间可以形成桥环，桥环可能是碳环或杂环；所有元素的同位素取代视为等同；骨架结构中的手性中心可以是R构型或S构型；取代基上的手性基团可能是R构型或S构型。
优选的，本发明所述的化合物、异构体或其药学上可接受的盐，所述化合物如式(II)所示，其中，B环是由A环的任何相邻2个位置连接形成的并环，可以是任意取代或未取代的非芳香环、非芳香杂环、碳芳香环或芳香杂环，
优选的，本发明所述的化合物、异构体或其药学上可接受的盐，所述化合物如式(III)-1、(III)-2所示，
其中，C环是五元环结构，可以是五元碳环或五元杂环；Y3为N、或CR4、或CR5；当X1和X2中有一个为空，Y1、Y2或Y1、Y3为N时，A环不能为吡咯环或4-取代吡咯环；R12、R13是H、CN、CF3、硝基、卤素、任意取代的烷基、任意取代的环烷基、任意取代的杂环基、任意取代的烷氧基、任意取代的烷硫基、任意取代的烷硫单氧基(亚砜)、任意取代的烷硫双氧基(砜)、任意取代的磺酰基、羧酸、羧酸酯、任意取代的酯基、酰胺、任意取代酰胺氨基、任意取代的烯烃基、任意取代的环烯烃基、任意取代芳香烷基、任意取代杂环芳香烷基、任意取代芳香烃基、任意取代杂环芳香烃基、任意取代芳香烯烃基、任意取代杂环芳香烯烃基中取代基的一种或几种；所述取代基选自卤素、氰基、硝基、C1～6烷基、C1～6卤代烷基、C1～6烷氧基、C1～6烷硫基或C2～6烯烃基、羧基、羧酸酯、磺酸酯。
优选的，本发明所述的化合物、异构体或其药学上可接受的盐，所述化合物如式(IV)-1、(IV)-2所示，其中，A环和B环是任意取代或未取代的非芳香环、非芳香杂环、碳芳香环、或芳香杂环；C环是五元环结构，可以是五元碳环或五元杂环；Y3为N、或CR4、或CR5，
优选的，本发明所述的化合物、异构体或其药学上可接受的盐，所述化合物如式(V)所示，
优选的，本发明所述的化合物、异构体或其药学上可接受的盐，所述化合物如式(VI)所示，
优选的，本发明所述的化合物、异构体或其药学上可接受的盐，所述化合物如式(VII)所示，
优选的，本发明所述的化合物、异构体或其药学上可接受的盐，其特征在于：所述的化合物包括，
本发明的第二个目的是提供一种上述化合物在制药方面的用途。所述的化合物、其异构体和/或其盐在制备用于治疗或预防疾病药物中的应用，其为：所述疾病包括与寨卡病毒、登革病毒、黄病毒、西尼罗河病毒、基孔肯雅病毒中的一种或几种的繁殖、复制或感染的有关疾病、丙型肝炎、乙型脑炎、森林脑炎、由HIV引起的爱滋病中的一种或几种。
本发明的第三个目的是提供一种所述的化合物、异构体或其盐在制备用于治疗或预防疾病药物中的应用，其特征在于：所述疾病为细菌引起的疾病。
优选的，本发明所述的化合物、异构体或其盐在制备用于治疗或预防疾病药物中的应用，其特征在于：所述疾病包括鲍曼不动杆菌引起的疾病。
本发明的第四个目的是提供一种药物组合物，所述药物组合物以所述的化合物、异构体或其或其药学上可接受的盐为主要活性成分，辅以药学上可接受的载体组成。
本发明的有益效果是发现了(I)所示化合物具有较好抑制寨卡病毒、登革病毒的感染和复制功能，它们可能作为治疗和预防寨卡病毒、登革热病毒引起的疾病的药物，也可能成为治疗和预防其它黄病毒引起的疾病的药物，如黄热病、西尼罗河病毒感染、乙脑病毒感染引起的乙型脑炎、基孔肯雅病(Chikungunya)病毒感染、丙型肝炎、森林脑炎以及HIV引起的爱滋病等，以及手足口病毒感染引起的疾病等。该类型化合物可以治疗细菌感染引起的疾病，包括炎症性肠病的溃疡性结肠炎和克罗恩病，大肠杆菌引起的疾病，金黄葡萄球菌等引起的疾病，鲍曼不动杆菌等引起的疾病。
具体实施方式
为使本发明的上述目的、特征和优点能够更加明显易懂，下面结合具体实施例对本发明的具体实施方式做详细的说明。在下面的描述中阐述了很多具体细节以便于充分理解本发明，但是本发明还可以采用其他不同于在此描述的其它方式来实施，本领域技术人员可以在不违背本发明内涵的情况下做类似推广，因此本发明不受下面公开的具体实施例的限制。其次，此处所称的“一个实施例”或“实施例”是指可包含于本发明至少一个实现方式中的特定特征、结构或特性。在本说明书中不同地方出现的“在一个实施例中”并非均指同一个实施例，也不是单独的或选择性的与其他实施例互相排斥的实施例。应说明的是，以下实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围当中。
实施例1：本发明化合物的制备方法，包括：
将2.74ml苯肼，7.0g ZDL-5溶于500ml DCM中，加入5.3ml 2,6-二甲基吡啶，最后加入12.3g TBTU，室温搅拌过夜。纯化得到约7g ZDL-17。
将600mg苯甲酰肼，1.39g ZDL-5溶于100ml DCM中，加入0.77ml 2,6-二甲基吡啶，最后加入2.12g TBTU，室温搅拌过夜。纯化得到约1.6g ZDL-27。
将ZDL-5(500mg)溶于50ml DCM中，冰浴下加入CDI(323mg)，搅拌20min，滴加水合肼(0.55ml)，冰浴下搅拌2h。
将850mg ZDL-26溶于100ml DCM中，冰浴下加入0.74ml吡啶，最后加入815mg对硝基苯磺酰氯，室温下搅拌6h。得到约1.2g ZDL-29。将250mg ZDL-29溶于8ml DCM中，加入2mlTFA，室温搅拌2h，蒸干反应体系，真空干燥6h后加入10ml甲苯和82mg对硝基苯甲醛，0.22ml三乙胺，110度反应2h.纯化得到90mg ZDL-39。将150mg ZDL-29溶于4ml DCM中，加入1mlTFA，室温搅拌2h，蒸干反应体系，真空干燥6h后加入10ml甲苯，加入95mg ZAL-2，0.16ml三乙胺，110度反应2h。纯化得到约110mg ZDL-41。
将1.0g 1,2-环戊二甲酰亚胺在氮气保护后溶于50ml无水THF中，然后冰浴充分冷却后小心滴加6.0ml苯基溴化镁，最后室温下搅拌3h。纯化得到560mg ZDL-52粗品。将560mgZDL-52溶于40ml 1,2-二氯乙烷中，加入0.6ml TFA，加入1.2ml三乙基硅烷，50度反应1h。纯化得到400mg ZDL-53。将100mg ZDL-53，19mg碘化亚酮，323mg碳酸铯加入到圆底烧瓶中，N2保护后加入20ml 1,4-二氧六环，再加入80微升碘苯，20微升N,N’-二甲基乙二胺，100度反应8h。纯化得到约ZDL-60。
将200mg ZDL-53，38mg碘化亚酮，647mg碳酸铯加入到圆底烧瓶中，N2保护下加入20ml 1,4-二氧六环，再加入371mg 4-硝基碘苯，40微升N,N’-二甲基乙二胺，100度反应8h。纯化得到120mg ZDL-61。
将1.0g 1,2-环戊二甲酰亚胺在氮气保护后溶于50ml无水THF中，然后冰浴充分冷却后小心滴加6.0ml 4-氯苯基溴化镁，最后室温下搅拌3h。纯化得到1g ZDL-58粗品。
将1.0g ZDL-58溶于40ml 1,2-二氯乙烷中，加入0.9ml TFA，加入1.9ml三乙基硅烷，50度下反应1h。纯化得到500mg ZDL-59。
将200mg ZDL-59，32mg碘化亚酮，552mg碳酸铯加入到圆底烧瓶中，N2保护后加入20ml 1,4-二氧六环，再加入140微升碘苯，40微升N,N’-二甲基乙二胺，100度反应8h。纯化得到约95mg ZDL-62。
将200mg ZDL-59，32mg碘化亚酮，552mg碳酸铯加入到圆底烧瓶中，N2保护后加入20ml 1,4-二氧六环，再加入316mg对硝基碘苯，40微升N,N’-二甲基乙二胺，100度反应8h。纯化得到约70mg ZDL-63。
将7.0g ZDL-5溶于400ml DCM中，冰浴下加入5.3ml N-甲基咪唑，搅拌5min后加入2.06ml MsCl，搅拌30min后加入3.66g对硝基苯肼，室温下搅拌过夜。纯化得到6.5g ZDL-18。
将300mg ZDL-18溶于DCM中，加入2ml TFA，室温搅拌2h后蒸干反应体系，真空干燥6h。将形成的游离碱溶于10ml甲苯中，加入60微升3,4-二甲氧基苯甲醛，0.32ml三乙胺，110度反应2h。纯化得到90mg ZDL-89。
将200mg ZDL-28悬浮在10ml异丙醇中，加入123mg藜芦醛，再加入2滴浓盐酸，85度反应8h后脱去挥发性成分。残留物硅胶柱层析DCM:EA体系过柱子得到150mg ZFD-33A。
12.5g ZXD-10用100mL乙酸溶解，于5℃下搅拌，分五批分别加入0.125eq,0.125eq,0.25eq,0.5eq和0.25eq共1.25eq硼氢化钠。反应共6h后停止，加入200mL水，用碳酸钠固体调节pH至弱碱性，用DCM萃取多次萃取，合并有机相，无水硫酸钠干燥。柱层析分得产物12.5g ZXD-15B，无色液体，收率48.0％，回收未反应ZXD-10。
16.2g ZXD-15B溶解于250mL DCM中，加入21.4g碳酸氢钠固体(3equiv)，然后滴加17.9mL Cbz-Cl(1.5equiv)，加完后反应转移至30℃反应9h后停止。蒸去溶剂后粗品用乙酸乙酯稀释，NaHCO3溶液水洗后干燥。柱层析分得产物25.6g ZXD-47，无色液体，收率92.9％。6g ZXD-47以甲醇和水混合溶剂(36mL:24mL)溶解，加入960mg(1.3equiv)氢氧化钠固体，升至60℃回流反应，2h后显示原料反应完全。蒸去甲醇后加水，以1N HCl调节体系pH至1-2，DCM萃取，无水硫酸钠干燥。浓缩得ZXD-60泡状固体5.65g，收率98.4％。ZXD-60溶于DCM中，于0℃下冷却，然后加入三乙胺(1.5equiv)，在该温度下搅拌5min，之后加入氯甲酸异丁酯(IBCF，1.1equiv)在该温度继续搅拌1h，转化为活性酯中间体后加入苯肼(苯胺或者苄胺)。在0℃搅拌4h后显示中间体全部转化停止。加入DCM稀释，依次用饱和NaHCO3溶液以及brine洗，无水硫酸钠干燥。浓缩后用石油醚与乙酸乙酯混合溶剂搅拌析出产物ZXD-51，白色固体，93.9％收率。
ZXD-51溶于THF中，加入10％钯碳(0.05equiv)，抽真空后插入氢气球，于25℃下反应6h后停止，硅藻土抽滤除去钯碳。母液蒸去后柱层析分离得到产物ZXD-44，白色固体，99.0％收率。
250mg ZXD-44和醛(1.1equiv)溶解于10mL乙腈，氮气保护下加入TFA(1.0equiv)，将反应转移至预热至60℃油浴中回流反应。1.5h后点板有产物生成，原料基本反应完毕，停止反应。冷却至室温后加饱和碳酸氢钠溶液淬灭反应，加入乙酸乙酯稀释，然后NaHCO3溶液水洗与brine洗，无水硫酸钠干燥。浓缩后柱层析分离ZXD-86B，白色固体，收率95.0％。
将6g四氢异喹啉-3-甲酸溶于50ml 1N NaOH中，加入50ml 1，4-二氧六环，冰浴下滴加9ml(Boc)2O，室温反应4h。反应结束后减压蒸馏除去二氧六环，用柠檬酸将体系调至酸性EA萃取，饱和NaCl溶液洗，无水硫酸钠干燥。有机相蒸干后无需纯化，得7.8g 透明油状物ZSD-2。
将3.1g ZSD-2溶于50ml DCM，冰浴下加入1.4g对硝基苯胺、124mg DMAP，分批次加入2.1g DCC，室温过夜。反应结束后抽滤，母液浓缩后EA萃取，饱和NaCl溶液洗，无水硫酸钠干燥。重结晶得产物3.5g ZSD-4。
将250mg ZSD-4溶于3ml DCM，加入1ml三氟醋酸，室温搅30min后反应完全，反应结束后直接蒸干溶剂得到ZSD-5。将ZSD-5溶于甲苯，加0.3ml三乙胺，再加入113mg对羟基苯甲醛，然后110℃回流1h。EA萃取，饱和NaHCO3、NaCl溶液洗，无水硫酸钠干燥。干燥后浓缩溶剂，柱层析进一步分离纯化得到目标产物150mg ZSD-7。
将5g ZSD-2溶于50ml DCM，冰浴下加入1.77ml苯肼、220mg DMAP，分批次加入3.72g DCC，室温过夜。反应结束后抽滤，母液浓缩后EA萃取，饱和NaCl溶液洗，无水硫酸钠干燥。重结晶得产物5.7g ZSD-14。将250mg ZSD-14溶于3ml DCM，加入1ml三氟醋酸，室温搅30min后反应完全。反应结束后直接蒸干溶剂得到ZSD-16备用。将ZSD-16溶于甲苯，加0.3ml三乙胺，再加入104mg对羟基苯甲醛，然后110℃回流1h。EA萃取，饱和NaHCO3、NaCl溶液洗，无水硫酸钠干燥。干燥后浓缩溶剂，柱层析进一步分离纯化得到目标产物161mg ZSD-20。
按上述方法制备如下各具体化合物(EC50是指化合物抗病毒感染活性，其中登革病毒：DENV；寨卡病毒:ZIKV；乌苏土病毒：USUV(usutu virus，属于黄病毒，与寨卡病毒相似)；AB：鲍曼不动杆菌)的抗菌能力，见下表。
表1抗寨卡病毒和抗乌苏土病毒活性(抑制率)
表2抗寨卡病毒活性(EC50)
| 序号 | 化合物编号 | EC<sub>50</sub>(μM) | 序号 | 化合物编号 | EC<sub>50</sub>(μM) |
| 1 | ZXD-142A | 1.56±0.21 | 3 | ZXD-87A | 3.40±0.38 |
| 2 | ZXD-167 | 7.40±0.37 | 4 | ZFD-33A+B | 17.21 |
表3抗登革病毒活性(EC50，μM)
表4抗鲍曼不动杆菌耐药株(EC50，MIC(μg/mL))
表5抗鲍曼不动杆菌耐药株(抑菌圈，直径(mm))
表6化合物结构及其核磁共振氢谱(Z**表示化合物编号)
表7化合物结构及其核磁质谱
Claims (12)
1.式(I)所示的化合物、异构体或其药学上可接受的盐：
其中，A环包括任意取代或未取代的非芳香环、非芳香杂环、碳芳香环、或芳香杂环中的一种；X1和/或X2包括空、O、S、S(O)、S(O2)、NR8、C(O)、(C(R9R10))p中的一种，且X1和X2不同时为O、S、S(O)、S(O2)；Y1、Y2可以相同或不同，Y1和/或Y2分别为N、CR11中的一种；m和/或n为0～6的整数，m+n为0～6的整数；p为1～6的整数；
当X1或X2中一个为NR8、另一个为空时，Y1为N，R1包括取代或未取代的苯环中的一种或几种，R2与R3和/或R4和/或R5和/或R6和/或R7和/或R8之间未形成环状结构，甲酰基两侧的连接N的R4和/或R5和/或R7是酰基或胺基甲酰基或甲酸酯基或甲酰肼基或六个碳及以下的烷基中的一种或几种时，A环不包括取代或未取代的吡咯环；
当X1或X2中一个为空，Y1为N，R2与甲酰基两侧的连接N的R4和/或R5和/或R7之间形成环状结构时，A环不包括吡咯环和4-取代吡咯环；R1～R11是H、CN、CF3、硝基、卤素、任意取代的烷基、任意取代的环烷基、任意取代的杂环基、任意取代的烷氧基、任意取代的烷硫基、任意取代的烷硫单氧基(亚砜)、任意取代的烷硫双氧基(砜)、任意取代的磺酰基、羧酸、羧酸酯、任意取代的酯基、酰胺、任意取代酰胺氨基、任意取代的烯烃基、任意取代的环烯烃基、任意取代芳香烷基、任意取代杂环芳香烷基、任意取代芳香烃基、任意取代杂环芳香烃基、任意取代芳香烯烃基、任意取代杂环芳香烯烃基；所述取代基选自卤素、氰基、硝基、C1～6烷基、C1～6卤代烷基、C1～6烷氧基、C1～6烷硫基或C2～6烯烃基、羧基、羧酸酯、磺酸酯；
X1和X2之间可以形成双键；X1和X2之间可以形成4～6元并环；X1和R2之间可以形成4～6元环；X1与R11和/或Y1之间可以形成双键；X1与R11和/或Y1之间可以形成4～6元环；R2和R7之间或R2和R4或R2和R5或R2和R6之间可以形成4～6元环；R2和R3之间可以形成4～6元螺环；
相邻取代基之间可以形成双键；相邻取代基之间可以形成环，环可能是碳环或杂环，可能是芳香环或非芳香环；其中，所述相邻取代基包括R3和R7；
同碳取代基之间可以形成环，环可能是碳环或杂环或芳香环或非芳香环中的一种或几种；其中，同碳取代基包括R9和R10、R7和R11；非同碳且非相邻碳取代基之间、非同氮且非相邻氮取代基之间可以形成桥环，桥环可能是碳环或杂环；所有元素的同位素取代视为等同；骨架结构中的手性中心可以是R构型或S构型；取代基上的手性基团可能是R构型或S构型。
2.根据权利要求1所述的化合物、异构体或其药学上可接受的盐，所述化合物如式(II)所示，
其中，B环是由A环的任何相邻2个位置连接形成的并环，可以是任意取代或未取代的非芳香环、非芳香杂环、碳芳香环或芳香杂环。
3.根据权利要求1所述的化合物、异构体或其药学上可接受的盐，所述化合物如式(III)-1、(III)-2所示，
其中，C环是五元环结构，可以是五元碳环或五元杂环；Y3为N、或CR4、或CR5；当X1和X2中有一个为空，Y1、Y2或Y1、Y3为N时，A环不能为吡咯环或4-取代吡咯环；
R12、R13是H、CN、CF3、硝基、卤素、任意取代的烷基、任意取代的环烷基、任意取代的杂环基、任意取代的烷氧基、任意取代的烷硫基、任意取代的烷硫单氧基(亚砜)、任意取代的烷硫双氧基(砜)、任意取代的磺酰基、羧酸、羧酸酯、任意取代的酯基、酰胺、任意取代酰胺氨基、任意取代的烯烃基、任意取代的环烯烃基、任意取代芳香烷基、任意取代杂环芳香烷基、任意取代芳香烃基、任意取代杂环芳香烃基、任意取代芳香烯烃基、任意取代杂环芳香烯烃基中取代基的一种或几种；所述取代基选自卤素、氰基、硝基、C1～6烷基、C1～6卤代烷基、C1～6烷氧基、C1～6烷硫基或C2～6烯烃基、羧基、羧酸酯、磺酸酯。
4.根据权利要求1或3所述的化合物、异构体或其药学上可接受的盐，所述化合物如式(IV)-1、(IV)-2所示，其中，A环和B环是任意取代或未取代的非芳香环、非芳香杂环、碳芳香环、或芳香杂环；C环是五元环结构，可以是五元碳环或五元杂环；Y3为N、或CR4、或CR5，
5.根据权利要求1所述的化合物、异构体或其药学上可接受的盐，所述化合物如式(V)所示，
6.根据权利要求1或5所述的化合物、异构体或其药学上可接受的盐，所述化合物如式(VI)所示，
7.根据权利要求1或5所述的化合物、异构体或其药学上可接受的盐，所述化合物如式(VII)所示，
8.根据权利要求1所述的化合物、异构体或其药学上可接受的盐，其特征在于：所述的化合物包括，
9.权利要求1～8中任一项所述的化合物、其异构体和/或其盐在制备用于治疗或预防疾病药物中的应用，其特征在于：所述疾病包括与寨卡病毒、登革病毒、黄病毒、西尼罗河病毒、基孔肯雅病毒中的一种或几种的繁殖、复制或感染的有关疾病、丙型肝炎、乙型脑炎、森林脑炎、由HIV引起的爱滋病中的一种或几种。
10.权利要求1～8中任一项所述的化合物、异构体或其盐在制备用于治疗或预防疾病药物中的应用，其特征在于：所述疾病为细菌引起的疾病。
11.权利要求11所述的化合物、异构体或其盐在制备用于治疗或预防疾病药物中的应用，其特征在于：所述疾病包括鲍曼不动杆菌引起的疾病。
12.一种药物组合物，其特征在于：所述药物组合物以权利要求1～8中任一项所述的化合物、异构体或其或其药学上可接受的盐为主要活性成分，辅以药学上可接受的载体组成。
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| CN115417834A (zh) * | 2020-11-24 | 2022-12-02 | 中国人民解放军海军军医大学 | 一类取代苯甲酰哌嗪类化合物及在制备抗基孔肯雅病毒药物中的应用 |
| CN115417834B (zh) * | 2020-11-24 | 2024-06-11 | 中国人民解放军海军军医大学 | 一类取代苯甲酰哌嗪类化合物及在制备抗基孔肯雅病毒药物中的应用 |
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| CN107814803A (zh) * | 2016-09-12 | 2018-03-20 | 南京工业大学 | 四氢吡咯和二氢咪唑酮的并环化合物及其制备和药学上的用途 |
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| CN115417834A (zh) * | 2020-11-24 | 2022-12-02 | 中国人民解放军海军军医大学 | 一类取代苯甲酰哌嗪类化合物及在制备抗基孔肯雅病毒药物中的应用 |
| CN115417834B (zh) * | 2020-11-24 | 2024-06-11 | 中国人民解放军海军军医大学 | 一类取代苯甲酰哌嗪类化合物及在制备抗基孔肯雅病毒药物中的应用 |
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