CN115210231A - 新型单环内酰胺类化合物、其制备方法及其作为抗菌药的用途 - Google Patents
新型单环内酰胺类化合物、其制备方法及其作为抗菌药的用途 Download PDFInfo
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- CN115210231A CN115210231A CN202080097627.7A CN202080097627A CN115210231A CN 115210231 A CN115210231 A CN 115210231A CN 202080097627 A CN202080097627 A CN 202080097627A CN 115210231 A CN115210231 A CN 115210231A
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- amino
- phenoxy
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- oxo
- oxoethylidene
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Classifications
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
本发明提供式(I)所示新的单环内酰胺类化合物及其制备方法,以及其作为抗生素用于治疗细菌感染的用途。
Description
技术领域
本发明属于药学领域,涉及新型单环内酰胺类化合物、其制备方法以及其作为治疗药物的用途。更确切地说,本发明涉及脒取代的单环内酰胺类化合物及其作为抗生素用于治疗细菌感染。
背景技术
抗生素用于治疗细菌感染是20世纪最伟大的医学成就之一。然而,在过去几十年中,细菌对多种抗生素的耐药(多重耐药性)开始在全球范围出现,威胁抗生素的疗效。因院内感染无法得到有效治疗而死亡的患者人数持续增加,而对于多重耐药的革兰氏阴性病原体(包括肠杆菌科和非发酵菌)引起的感染,可供选择的治疗药物特别有限。制药行业中正在研发的可有效应对多重耐药的抗生素药物种类也极少,导致细菌的耐药性问题日趋严峻。因此,急需研发新的抗生素以应对日趋严峻的多重耐药细菌的挑战。
β-内酰胺类抗生素是治疗严重细菌感染使用最广泛的抗生素,包括头孢菌素类、碳青霉烯类、青霉素类和单环内酰类。犹如在其它抗生素类别中所观察到的那样,细菌对β-内酰胺类抗生素的耐药性业已出现。对大多数革兰氏阴性细菌而言,这种耐药性主要是由β-内酰胺酶(水解β-内酰胺类抗生素的酶)所致。已有超过1000种的β-内酰胺酶和其他耐药机制严重危及此类抗生素的使用效果。特别是超广谱β-内酰胺酶(ESBL)和碳青霉烯酶的出现,使得细菌的耐药性更为严峻。因此,迫切需要研发新型β-内酰胺类抗生素,以填补因细菌耐药性导致的无抗生素可用的空缺。
氨曲南是迄今唯一的FDA批准的单环内酰类抗生素,在全球范围内广泛用于治疗革兰氏阴性细菌引起的感染。虽然,氨曲南对铜绿假单胞菌(Pseudomonas aeruginosa)和不动杆菌(Acinetobacter)的抗菌活性不甚理想。然而,由于单环内酰类抗生素本身具有抗金属内酰胺酶(metallo-lactamases)水解的特点,已有一些公司开始研发新型单环内酰类抗生素,用于治疗革兰氏阴性细菌引起的感染。Basilea(WO 2007065288)、NAEJA(WO2002022613)、Squibb&Sons(US 5290929、EP 531976、EP 484881)披露了具有能够螯合铁的结构特征(siderophore)的单环内酰类抗生素。辉瑞公司(Pfizer)重新研究了在单环内酰的N1位拥有磺酰氨基羰基活性基团的单环β-内酰胺类抗生素(WO 2010070523)。
最近,美国专利申请US 2014/0275007公开了含有oxamazin基团的单环内酰类抗生素及其用途,另一美国专利申请US 2015/0266867还公开了用作抗菌药的新型单环内酰类抗生素。国际专利申请WO 2013/110643公开了新型单环内酰类抗生素的衍生物及其作为抗菌药的用途。另外,国际专利申请WO 2017/106064公开了具有二芳基的单环内酰类抗生素的衍生物及其作为抗菌药的用途,以及国际专利申请WO 2017/155765公开了具有双环芳基的单环内酰类抗生素的衍生物及其作为抗菌药的用途。
本发明的目的旨在应对日趋严重的多重耐药菌的挑战,满足医疗用药需求。本发明公开的化合物可作为抗生素单独使用,也可与合适的β-内酰胺酶抑制剂联合使用。
发明内容
本发明涉及新型的脒取代的单环内酰类化合物,可单独使用或与β-内酰胺酶抑制剂(例如克拉维酸、他唑巴坦、舒巴坦)和属于内酰胺酶抑制剂的其它β-内酰胺酶抑制剂,二氮杂双环辛烷抑制剂(如阿维巴坦等)、过渡状态类似物抑制剂和/或金属-β-内酰胺酶抑制剂联合使用,用于治疗人或动物的细菌感染。
本发明提供了(A)通式(I)的新化合物;(B)式(I)化合物的药学可接受的盐;(C)式(I)化合物及其药学可接受的盐的溶剂化物;以及(D)(A)、(B)和(C)所述化合物的氘代化化合物(即(i)经氘代化后的式(I)化合物,(ii)经氘代化后的式(I)化合物的药学可接受的盐,(iii)经氘代化后的式(I)化合物及药学可接受的盐的溶剂化物):
其中
M表示氢或药学可接受的成盐阳离子,
R1和R2相互独立地表示氢或甲基,
W表示键或O,
X表示CR4或N,
R4表示卤素,
R3表示氢、氨基、羟基、C1-C6烷基(优选C1-C4烷基)或4-元、5-元或6-元含氮杂环,
其中烷基可被选自以下的取代基取代:羟基、氨基、羧基、羰氧基、单C1-C6烷基氨基或双C1-C6烷基氨基(优选双C1-C4烷基氨基)、-NH-CH(=NH)、-NH-C(=NH)(NH2)、5-或6-元含氮杂芳基、或5-或6-元含氮杂环基,
以及上述化合物的盐,或上述化合物及其盐的溶剂化物。
所述“氘代化后的化合物”指对本发明化合物中的一个或多个氢原子被氘替代或被转化为氘而获得的化合物。
本发明化合物是指式(I)化合物及其盐、所述化合物及其盐的溶剂化物,以及式(I)所涵盖并在本发明中作为示例性实施方案所提及的化合物及其盐、所述示例性化合物及其盐的溶剂化物,包括式(I)所涵盖但尚未成盐、尚未溶剂化的化合物。
根据其结构,本发明化合物可以立体异构形式(对映体、非对映体)存在。因此,本发明还包括对映体或非对映体及相应的混合物。单一立体异构组分可通过已知方式从此类对映体和/或非对映体混合物中分离获得。
如果本发明的化合物可以互变异构形式出现,则本发明涵盖所有互变异构形式。
用于本发明目的的盐优选是本发明化合物的生理学可接受的盐。然也涵盖其本身不适合药学应用的盐,但可用于例如本发明化合物的分离或纯化的盐。
式(I)化合物的药学可接受的盐包括与无机碱形成的盐,如铵盐,碱金属盐特别是钠盐或钾盐,碱土金属盐特别是镁盐或钙盐;也包括与有机碱形成的盐,特别是苄胺盐、辛胺盐、乙醇胺盐、二乙醇胺盐、环己胺盐、二乙胺盐、三乙胺盐、乙二胺盐、普鲁卡因盐、吗啉盐、吡咯啉盐、哌啶盐、N-乙基哌啶盐、N-甲基吗啉盐、哌嗪盐,或与碱性氨基酸形成的盐、特别是与赖氨酸、精氨酸、组氨酸或鸟氨酸形成的盐。
式(I)化合物的药学可接受的盐的实例还包括与无机酸形成的盐,如盐酸盐、氢溴酸盐、硫酸盐、磷酸盐或膦酸盐;也包括有机酸形成的盐,特别是醋酸盐、甲酸盐、丙酸盐、乳酸盐、柠檬酸盐、富马酸盐、马来酸盐、苯甲酸盐、酒石酸盐、苹果酸盐、甲烷磺酸盐、乙烷磺酸盐、苯磺酸盐或甲苯磺酸盐;或与酸性氨基酸特别是与天冬氨酸或谷氨酸形成的盐。
用于本发明目的的溶剂化物是指本发明化合物以固态或液态通过与溶剂分子配位形成络合物。本发明的水合物是指本发明化合物与水发生配位形成的一种特殊形式的溶剂化物。
在本发明的下述文本阐述中,除另有规定外,取代基具体定义以下:
所述烷基指直链或支链C1-C6烷基,优选C1-C4烷基,特别是甲基、乙基、丙基、丁基、异丙基、异丁基和叔丁基。
所述杂芳基指具有5-8个环原子、优选具有5-6个环原子且具有最多4个有杂原子、优选具有最多2个杂原子的环状杂芳族基团,所述杂原子选自N、O、S,其中N也可形成N-氧化物。优选具有5-6个原子的单环杂芳基,具有最多2个选自N、O、S的杂原子,杂芳基特别是指苯并噻吩、呋喃、苯并呋喃、吡咯、噻吩、吡啶、吡嗪、嘧啶、哒嗪、吲哚、异吲哚、嘌呤、喹啉、吡唑、咪唑、噻唑、噻二唑、噁唑、异噁唑或异喹啉。所述杂芳基同时还包括本领域技术人员已知或可在文献中轻易找到用于本发明目的的许多其它合适的杂芳基。
所述杂环基是指具有4-10个环原子、优选具有5-6个环原子且具有最多3个杂原子、优选具有最多2个杂原子的饱和或部分不饱和杂环基,所述杂原子选自N、O、S、SO和SO2,其中N也可形成N-氧化物。优选具有最多2个选自N、O和S的杂原子的具有5-6个原子的饱和单杂环基,特别是指吡咯啉、吡咯烷、咪唑烷、噻唑烷、咪唑啉、四氢呋喃、四氢噻吩、哌啶、吡喃、四氢吡喃、硫吡喃、四氢硫吡喃、吗啉、硫吗啉、哌嗪、哒嗪。所述杂环基烷同时还包括本领域技术人员已知或可在文献中轻易找到用于本发明目的的许多其它合适的杂环烷基。
所述卤素指氟、氯、溴或碘,优选氟或氯。
所述羧基指羧酸基团,即-COOH基团。
所述羰基氧是指通过氧连接的羰基。
本发明涉及如下的式(I)化合物,
其中
M代表氢或药学可接受的成盐阳离子,
R1和R2均表示甲基,
W表示O,
X表示CR4,
R4表示卤素,
R3表示乙基氨、氮杂环丁烷基、吡咯烷基或哌啶基,
及其盐、所述化合物及其盐的溶剂化物。
本发明涉及如下式(I)化合物,
其中
M是氢或药学可接受的成盐阳离子,
R1和R2均表示甲基,
W表示O,
X表示N,
R3表示氨基乙基、氮杂环丁烷基、吡咯烷基或哌啶基,
及其盐、所述化合物及其盐的溶剂化物。
本发明特别包括、但并不仅限于具有以下结构的式(I)化合物:
及其盐、所述化合物及其盐的溶剂化物。
本发明还涉及式(I)化合物的制备方法。本发明化合物式(I)可通过在酸性条件下对式(II)化合物脱去保护基来制备,
其中P1和P2独立地表示保护基团,R1、R2、R3、W和X如上文所定义。
酸性条件可能涉及使用三氟乙酸、甲酸、乙酸或盐酸,在0℃至室温的条件下处理式(II)化合物数分钟至数小时,优选在30℃-60℃的温度下使用90%甲酸或三氟乙酸反应30分钟-60分钟。
式(II)化合物可通过使式(III)化合物与式(IV)化合物反应合成,
其中P1和P2独立地表示保护基团,R3和X如上文所定义,
其中R1、R2和W如上文所定义。
通常在含有偶联剂并在适当情况下添加碱的惰性溶剂中进行反应,在适-20℃至80℃的温度范围内,反应时间1到24小时,优选在20℃至30℃的温度下反应过夜。惰性溶剂为例如N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基吡咯烷-2-酮(NMP)、二氯甲烷(DCM)、四氢呋喃(THF)、1,4-二氧六环、乙腈以及上述溶剂的混合物。优选溶剂为N,N-二甲基甲酰胺(DMF)。
合适的偶联剂为包括1,2-噁唑鎓化合物,如2-乙基-5-苯基-1,2-噁唑鎓-3-硫酸盐,2-叔丁基-5-甲基-异噁唑鎓高氯酸盐;或羰基化合物,如羰基二咪唑(CDI);或酰基胺化合物,如2-乙氧基-1-乙氧羰基-1,2-二氢喹啉,丙膦酸酐,异丁基氯甲酸酯,双-(2-氧代-3-噁唑烷基)-磷酰氯,O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐(HBTU),2-(2-氧代-1-(2H)-吡啶基)-1,1,3,3-四甲基脲鎓四氟硼酸盐(TPTU),O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐(HATU),1-羟基苯并三唑(HOBt),苯并三唑-1-基氧基三(二甲氨基)磷鎓六氟磷酸盐(BOP),苯并三唑-1-基-氧基三(吡咯烷基)-磷鎓六氟磷酸盐(PyBOP);或碳二亚胺类,如N,N′-二乙基-碳二亚胺、N,N'-二丙基-碳二亚胺、N,N'-二异丙基-碳二亚胺、N,N'-二环己基碳二亚胺(DCC)、N-(3-二甲氨基异丙基)-N'-乙基碳二亚胺盐酸盐(EDC)、N-环己基碳二亚胺-N'-丙氧基甲基-聚苯乙烯(PS-碳二亚胺)或N-羟基丁二酰亚胺;以及上述偶联剂的混合物,可以添加或不添加碱。在特定情况下,可同时使用无机碱和有机碱。可供使用的合适的碱如碳酸盐和碳酸氢盐、三乙胺、二异丙基乙胺、N-甲基吗啉、N-甲基哌啶或4-二甲氨基吡啶。优选使用碳二亚胺和1-羟基苯并三唑(HOBt)的混合物进行反应,可以添加或不添加作为碱的碳酸氢钠。
式(III)化合物可通过将式(V)化合物与式(VI)化合物反应制备,
其中P1表示保护基团,X如上文所定义,
其中P2表示保护基团,R3如上文所定义。
反应通常在质子溶剂或至少含有一种质子溶剂的溶剂混合物中进行,温度范围为0℃到100℃,反应时间为1到24小时。合适的质子溶剂有甲醇、乙醇、异丙醇。可用于形成混合物的合适的溶剂为二氯甲烷、三氯甲烷、四氢呋喃、1,4-二氧六环、乙腈和N,N-二甲基甲酰胺。反应优选在作为混合溶剂的无水乙醇和氯仿的混合物中在20℃至30℃下进行过夜。
式(IV)化合物可根据国际专利申请WO2013110643A1制备,
其中R1、R2和W如上文所定义。
式(V)的化合物可根据文献(Bioorg.Med.Chem.,2007,38(21),6716-6732;国际专利(US20120264727A1)或者由本领域技术人员对文献工艺做适当调整后制备,
其中P1表示保护剂,X如上文所定义。
本发明化合物显示了一系列意料之外的有价值的药理作用。
因此,本发明化合物适合用作治疗和/或预防人类和动物疾病的药物。
本发明涉及的化合物特别是在抗菌效果方面具有非常明显的优势。
本发明涉及的化合物尤其适合用于治疗和/或预防由细菌引起的疾病,特别是由革兰氏阴性细菌引起的疾病。
本发明涉及的化合物尤其适合用于治疗和/或预防疾病,特别是下述疾病。
本发明还涉及所述化合物用于制备药物的用途,所述药物用于治疗和/或预防疾病,所述疾病尤其是细菌感染,特别是下述疾病。
本发明还涉及使用治疗有效剂量的本发明化合物治疗和/或预防疾病的方法,所述疾病尤其是细菌感染,特别是下述疾病。
本发明的化合物表现出针对革兰氏阴性菌和选择性的革兰氏阳性菌的抗菌谱且低毒性。本发明化合物尤其适合作为人药和兽药,用于预防和治疗由以下病原体或由以下病原体的混合物引起的局部和全身感染:
需氧革兰氏阳性菌:包括但不限于链球菌(Streptococcus)属(肺炎链球菌(S.pneumoniae)、化脓链球菌(S.pyogenes)、无乳链球菌(S.agalactiae)、C组链球菌(Streptococcus group C)和G组链球菌(Streptococcus group G),葡萄球菌(Staphylococcus)属(金黄色葡萄球菌(S.aureus)以及芽孢杆菌(Bacillus)属和李斯特菌(Listeria monocytogenes)。
需氧革兰阴性菌:肠杆菌科(Enterobacteriaceae),包括但不限于大肠埃希菌(Escherichia)属(大肠杆菌(E.coli)),克雷伯菌(Klebsiella)属(克雷伯肺炎杆菌(K.pneumoniae)、产酸克雷伯菌(K.oxytoca)),柠檬酸杆菌(Citrobacter)属(弗氏柠檬酸杆菌(C.freundii)、异型柠檬酸杆菌(C.diversus)),摩根氏摩根氏菌(Morganellamorgannii),阿尔维哈夫尼亚菌(Hafnia alvei),沙雷氏菌(Serratia)属(粘质沙雷氏菌(S.marcescens))、肠杆菌(Enterobacter)属(阴沟肠杆菌(E.cloacae)、产气肠杆菌(E.aerogenes)),变形杆菌(Proteus)属奇异变形杆菌(P.mirabilis)、寻常变形杆菌(P.vulgaris)、潘氏变形杆菌(P.penneri)),普罗威登斯菌(Providencia)属(斯氏普罗威登斯菌(P.stuartii)、雷氏普罗威登斯菌(P.rettgeri)),耶尔森菌(Yersinia)属(小肠结肠炎耶尔森菌(Y.enterocolitica)、假结核耶尔森菌(Y.pseudotuberculosis)),沙门氏菌(Salmonella)属,志贺氏菌(Shigella)属;以及非发酵菌,包括但不限于假单胞菌(Pseudomonas)属(铜绿假单胞菌(P.aeruginosa)),伯克霍尔德菌(Burkholderia)属(洋葱伯克霍尔德菌(B.cepacia)),嗜麦芽窄食单胞菌(Stenotrophomonas maltophilia),和不动杆菌(Acinetobacter)属(鲍曼不动杆菌属(A.baumannii))、不动杆菌属基因种13TU(Acinetobacter gen.sp.13TU)、不动杆菌属属基因种3(Acinetobacter gen.sp.3)),以及博德杆菌(Bordetella)属(支气管败血性博德杆菌(B.bronchiseptica)),卡他莫拉菌(Moraxella catarrhalis)和嗜肺军团菌(Legionella pneumophila);此外,气单胞菌(Aeromonas)属、嗜血杆菌(Haemophilus)属(流感嗜血杆菌(H.influenzae),奈瑟菌(Neisseria)属(淋病奈瑟菌(N.gonorrhoeae)、脑膜炎奈瑟菌(N.meningitidis))以及产碱杆菌(Alcaligenes)属(包括木糖氧化产碱杆菌(A.xylosoxidans)),幽门螺杆菌(Helicobacter pylori),弧菌(Vibro)属(霍乱弧菌(V.cholerae)),空肠弯曲菌(Campylobacter jejuni)、巴氏杆菌(Pasteurella)属(多杀性巴氏杆菌(P.multocida))。
此外,抗菌谱还包括严格厌氧细菌,包括但不限于消化链球菌(Peptostreptococcus)属(厌氧消化链球菌(P.anaerobius)),拟杆菌(Bacteroides)属(脆弱拟杆菌(B.fragilis),普氏杆菌(Prevotella)属,布鲁氏菌(Brucella)属(流产布鲁氏菌(B.abortus)),梭菌(Clostridium)属(产气荚膜梭菌(Clostridium perfringens))和卟啉单胞菌(Porphyromonas spp)属。
本发明上述所列病原体仅为示例性的,而非仅限定于上述所列病原体。由所述病原体引起且可根据本发明的化合物进行预防、改善或治愈的疾病的实例所示如下:
呼吸道感染,如下呼吸道感染、囊性纤维化患者的肺部感染、慢性支气管炎急性加重、社区获得性肺炎(CAP)、医院获得性肺炎(包括呼吸机相关肺炎(VAP))、上呼吸道疾病、弥漫性泛细支气管炎、扁桃体炎、咽炎、急性鼻窦炎和中耳炎包括乳突炎;尿道和生殖道感染:例如膀胱炎、尿道炎、肾盂肾炎、子宫内膜炎、前列腺炎、输卵管炎和附睾炎;眼部感染,如结膜炎、角膜溃疡、虹膜睫状体炎和放射状角膜切开术患者的术后感染;血液感染如败血症;皮肤和软组织感染:例如感染性皮炎、感染性伤口、感染性烧伤、蜂窝组织炎、毛囊炎和脓疱病;骨和关节感染如骨髓炎和化脓性关节炎,胃肠道感染,如痢疾、肠炎、结肠炎、坏死性小肠结肠炎和肛门直肠感染;腹腔内感染,如伤寒、感染性腹泻、腹膜炎伴阑尾炎、盆腔炎和腹腔内脓肿;口腔感染如牙科手术后的感染;其它感染,如类鼻疽病(meliodosis)、感染性心内膜炎、肝脓肿、胆囊炎、胆管炎、乳腺炎以及脑膜炎和神经系统感染。
除人感染的疾病外,还可用于治疗细菌感染的动物,如马、灵长类动物、猪、反刍动物(绵羊、牛、山羊)、狗、猫、家禽(如鸡、火鸡、鹌鹑、鸽子、观赏鸟)以及生产性和观赏性鱼类、两栖动物和爬行动物。
本发明化合物具有系统性和/或局部性疗效作用。为此,可选择适合的途径给药,如经肠外、经肺、经鼻、经舌下、经舌、经口、经直肠、经皮、透皮、经结膜、经耳或作为植入物或支架等途径。
本发明化合物可以合适的药物方式以满足上述给药途径要求。
肠外给药可通过吸收途径(如肌肉内、皮下、皮内、经皮或腹腔内)或非吸收途径(如静脉、动脉、心内、椎管内或腰椎内注射)进行。适用于肠外施药的给药方式尤其包括采取溶液、悬浮液、乳剂、无菌粉末或冻干剂形式的注射用和输注用制剂。
适用于其它给药途径还包括:吸入给药形式(尤其是粉末吸入器、雾化器)、溶液、滴鼻剂、喷雾剂;用于舌、舌下或口腔使用的片剂、薄膜/糯米纸囊剂或胶囊,栓剂,耳或眼用制剂,阴道胶囊,水悬浮液(洗液、摇动混合物),软膏,乳膏,亲脂性悬浮液,透皮治疗系统(例如贴片),糊剂,乳剂,泡沫,粉剂,支架或植入物等。
可通过与药学可接受的惰性且无毒赋形剂混合将本发明化合物转化为满足上述给药途径的稳定给药形式。本发明所述赋形剂尤其包括载体(如微晶纤维素、乳糖、甘露醇)、乳化剂和分散剂或润湿剂(如十二烷基硫酸钠、聚氧山梨醇酐油酸酯)、溶剂(如液体聚乙二醇)、粘合剂(例如聚乙烯基吡咯烷酮),合成和天然聚合物(如白蛋白)、色素(如无机颜料氧化铁等)、稳定剂(如抗氧化剂抗坏血酸等)以及气味矫正剂和/或调味剂。
本发明还涉及包含至少一种本发明化合物的药物,本发明化合物通常是与一种或多种惰性且无毒的、药学可接受的赋形剂一起使用,以及涉及用于上述目的的用途。
本发明进一步涉及包含至少一种本发明化合物与至少一种β-内酰胺酶抑制剂联合形成的药物,以及涉及用于上述目的的用途。
与本发明联合的活性化合物包括β-内酰胺酶抑制剂类化合物。
适合与本发明化合物联合使用的β-内酰胺酶抑制剂包括克拉维酸(Clavulanicacid)、他唑巴坦(Tazobactam)、舒巴坦(Sulbactam)、阿维巴坦(Avibactam)、雷巴坦(Relebactam)、瓦博巴坦(Vaborbactam)。
本发明化合物的最小给药量为治疗有效剂量。所述“治疗有效剂量”指用于人或动物以防止细菌感染的发生、缓解症状、停止感染导致的进一步恶化和/或消除细菌感染的化合物量。
通常,本发明化合物对成人疗程内的有效给药单次剂量约50mg至约3000mg式(I)化合物;在一个实施方式中,有效单次剂量约为100mg至2000mg,在另一实施方式中,有效单次剂量为约500mg至约1200mg。通常情况,每天给药1至4次,也可每天给药3次。在特定情况下,可能需要使用超出这些限值的剂量。
然而,在特定的情况下,必要时可偏离上述用药量,特别是因体重、施用途径、个体对活性成分的反应差异,制剂类型以及施用时间或间隔的差异,这些差异均会导致偏离上述用药量。在某些情况下,实际用药量低于上述最低剂量,而在其它情况下,实际用药量必须高于上述最高剂量。在较大剂量的给药情况下,建议在一天内以单剂量多次给药为宜。
除非另有说明,以下试验和实施例中的百分比数据为重量百分比,份数以重量计。溶剂比、稀释比和浓度数据均基于体积计算。“w/v”表示“重量/体积”,例如“10%w/v”表示:100ml溶液或悬浮液含有10g物质。
实施例
本发明术语缩写
NMR:核磁共振
δ:以ppm为单位的化学位移
br s:NMR中的宽单峰
CDCl3:氘代氯仿
Hz:赫兹
MHz:兆赫
J:NMR中的耦合常数
d:NMR中的二重峰
dd:NMR中的双二重峰
q:NMR中的四重峰
s:NMR中的单峰
t:NMR中的三重峰
m:NMR中的多重峰
TMS:四甲基硅烷
DCM:二氯甲烷
DMF:N,N-二甲基甲酰胺
DMSO:二甲基亚砜
EtOAc:乙酸乙酯
t-BuOH:叔丁醇
TFA:三氟乙酸
THF:四氢呋喃
PE:石油醚
DCC:N,N'-二环己基碳二亚胺
HOBt:1-羟基苯并三唑
TMEAD:四甲基乙二胺
TLC:薄层层析法
MS:质谱
ES-:电喷雾电离质谱中的负离子模式
ES+:电喷雾电离质谱中的正离子模式
HPLC:高效液相色谱
L:升
M:摩尔浓度
mg:毫克
min:分钟
mL:毫升
mmol:毫摩尔
mol:摩尔
g:克
h:小时
N:当量
分析方法
1H NMR(400MHz)和19F NMR(376MHz)核磁谱均采用Bruker AVANCE NEO 400核磁共振仪获得。NMR数据以内标的四甲基硅烷(TMS)为标准。所用氘代试剂为含有0.05%TMS内标物的CDCl3、CD3OD、含有0.03%TMS的D2O或DMSO-d6。
制备液相色谱采用Agilent 1260 Infinity II系统,制备柱选用Agilent 10Perp-C18 250×21.2mm,在22℃使用乙腈/0.1%三氟乙酸水溶液梯度洗脱,或乙腈/0.1%甲酸水溶液梯度。
质谱(MS)采用ES-或ES+电离模式,经Agilent 1260 Infinity II系统测定获得。
柱层析硅胶采购自青岛科技,粒径230目-400目。
通常情况,商业溶剂和试剂直接使用,无需进一步纯化。所有合成产物在表征以及随后的合成步骤中使用之前均经过干燥。
通用中间体片段合成
1.β-内酰胺砌块的合成
1.1(3S)-3-氨基-4,4-二甲基-1-(磺氧基)氮杂环丁烷-2-酮(1_1)
化合物1_1根据文献WO2013110643A1合成。
1H NMR(400MHz,DMSO-d6):δ1.42(s,3H),1.43(s,3H),4.15(s,1H),8.80(br.s,2H)。
1.2(3S,4S)-3-氨基-4-甲基-2-氧代氮杂环丁烷-1-磺酸(1_2)
化合物1_2根据文献David M.Floyd,Alan W.Fritz,Josip Pluscec,EugeneR.Weaver,Christopher M.Cimarusti J.Org.Chem.,1982,47(26),5160–5167合成。
1H NMR(400MHz,DMSO-d6):δ1.39(d,J=6.2Hz,3H),3.75-3.81(m,1H),4.00(d,J=4.0Hz,1H),8.66(br.s,3H)。
2.氨基噻唑和氨基噻二唑砌块的合成
2.1 2-(2-((叔丁氧羰基)氨基)-5-氯噻唑-4-基)-2-氧代乙酸(2_1)
化合物2_1根据文献Bioorg.Med.Chem.,2007,38(21),6716-6732合成。
1H NMR(400MHz,DMSO-d6):δ1.47(s,9H),12.1(s,1H),(COOH没有显示)。
2.2{5-[(叔丁氧羰基)氨基]-1,2,4-噻二唑-3-基}-氧代乙酸(2_2)
化合物2_2根据文献US20120264727A1合成。
1H NMR(400MHz,DMSO-d6)δ1.51(s,9H),12.81(s,1H),(COOH没有显示)。
3.含有脒侧链片段的合成
3.1(S)-4-(4-(2-(氨基氧基)-3-(二苯甲氧基)-3-氧代丙氧基)苯甲脒基)哌啶-1-羧酸叔丁基酯(3_1_8)
步骤1:(R)-3-(4-氰基苯氧基)-2-羟基丙酸甲酯(3_1_2)
将Co(III)-催化剂(7.0g,8.4mmol,依据参考文献制备:J.Am.Chem.Soc.1999,121,6086-6087)和分子筛(10g)在50mL甲基叔丁基醚中中的混合物,用(R)-环氧乙烷-2-羧酸甲酯(45.0g,441mmol)和4-羟基苯甲腈3_1_1(26.3g,220mmol)处理,将反应液在室温下搅拌两天后用硅藻土层过滤,滤液浓缩。深棕色浓缩液用硅胶柱层析纯化,得到棕色油状化合物3_1_2(79.0g,357mmol,81%)。
1H NMR(400MHz,DMSO-d6):δ3.68(s,3H),4.26(m,2H),4.49(m,1H),5.96(s,1H),7.11(d,J=8.9Hz,2H),7.77(d,J=9.0Hz,2H)。
步骤2:(R)-2-羟基-3-(4-甲氧基碳亚胺基-苯氧基)-丙酸甲酯盐酸盐(3_1_3)
将化合物3_1_2(36.6g,165mmol)溶于160mL无水甲醇中,反应器密封冷却至0℃,向反应体系中通入无水氯化氢气体直至饱和,将反应液搅拌下恢复至室温后,继续搅拌18小时,得到悬浊液。过滤悬浊液所得固体用乙醚洗涤后得到目标化合物3_1_3(29g);将母液浓缩再次得到悬浊液后,再用乙醚洗涤又得到目标化合物(9.89g),总共得到淡绿色固体目标化合物3_1_3(38.9g,81.5%)。
1H NMR(400MHz,DMSO-d6):δ3.66(s,3H),4.24(s,3H),4.27-4.31(m,2H),4.48(t,J=4.4Hz,1H),7.16(d,J=9.1Hz,2H),8.09(d,J=9.1Hz,2H)。
步骤3:(R)-4-(4-(2-羟基-3-甲氧基-3-氧代丙氧基)苯甲脒基)哌啶-1-羧酸叔丁酯(3_1_4)
将化合物3_1_3(1.0g,3.45mmol)溶于3mL无水甲醇中,在0℃下加入三乙胺(0.38g,3.8mmol)和4-氨基哌啶-1-羧酸叔丁酯(0.69g,3.45mmol),并在室温下搅拌反应过夜,将反应液浓缩后用硅胶柱层析纯化,得到白色固态化合物3_1_4(1.0g,69%)。
1H NMR(400MHz,DMSO-d6):δ1.38(s,9H),1.54-1.43(m,2H),1.82-1.93(m,2H),2.60-2.90(m,2H),3.64(s,3H),3.90-4.00(m,3H),4.12-4.28(m,2H),4.44-4.50(m,1H),5.98(s,1H),7.22(d,J=8.8Hz,2H),7.69(d,J=8.8Hz,2H)。
步骤4:(R)-3-(4-(N-(1-(叔丁氧羰基)哌啶-4-基)甲脒基)苯氧基)-2-羟基丙酸(3_1_5)
将化合物3_1_4(1.0g,2.37mmol)溶于2mL四氢呋喃中,在0℃下加入氢氧化钠水溶液(0.2g,4.74mmol,1mL水),室温下搅拌5小时,浓缩除去四氢呋喃,用1N盐酸中和反应液至pH为5,然后将反应液冷冻干燥得到白色固体粗产物3_1_5(0.97g,含NaCl盐),无需进一步纯化,直接进行下一步反应。
1H NMR(400MHz,DMSO-d6):δ1.41(s,9H),1.49(br s,2H),1.92(br s,2H),2.84(brs,2H),3.86(br s,1H),4.00(br s,4H),4.26(d,J=9.8Hz,1H),7.12(s,2H),7.74(s,2H)。
步骤5:(R)-4-(4-(3-(二苯甲氧基)-2-羟基-3-氧代丙氧基)苯甲脒基)哌啶-1-羧酸叔丁酯(3_1_6)
将化合物3_1_5(0.97g,2.37mmol)溶于2mL甲醇中,缓慢加入溶于1.5mL二氯甲烷的二苯基重氮甲烷(0.42g,3.56mmol),将反应液在室温下搅拌过夜后浓缩,剩余物用硅胶柱层析纯化,得到白色固体化合物3_1_6(1.1g,两步反应产率80%)。
1H NMR(400MHz,DMSO-d6):δ1.39(s,9H),1.42-1.52(m,2H),1.87-1.92(m,2H),2.82(br s,2H),3.90-4.00(m,3H),4.30-4.42(m,2H),4.62-4.65(m,1H),6.48(d,J=7.6Hz,1H),6.84(s,1H),7.09(d,J=8.8Hz,2H),7.22-7.41(m,10H),7.69(d,J=8.8Hz,2H),9.10(br s,1H),9.38(br s,1H)。LC-MS:[M+H]+=574.1。
步骤6:(S)-4-(4-(3-(二苯甲氧基)-2-((1,3-二氧代异吲哚-2-基)氧基)-3-氧代丙氧基)苯甲脒基)哌啶-1-羧酸叔丁酯(3_1_7)
将化合物3_1_6(1.2g,2.1mmol)、N-羟基邻苯二甲酰亚胺(1.03g,6.3mmol)和三苯基磷(1.7g,6.3mmol)溶于5mL无水四氢呋喃中,然后在0℃下逐滴加入偶氮二甲酸二乙酯溶液(1.09g,6.3mmol),将反应液在室温下搅拌过夜,旋蒸除去四氢呋喃,浓缩物用硅胶柱层析纯化,得到白色固体化合物3_1_7(1.0g,66.7%)。
1H NMR(400MHz,DMSO-d6):1.42(s,9H),1.44-1.53(m,2H),1.92-1.96(m,2H),2.82(br s,2H),3.92-4.16(m,3H),4.68(br s,2H),5.48(br s,1H),6.98(s,1H),7.11(d,J=8.6Hz,2H),7.26-7.48(m,10H),7.75(d,J=8.6Hz,2H),7.86(s,4H),9.24(br s,1H),9.40(br s,1H)。LC-MS:[M+H]+=719.1。
步骤7:(S)-4-(4-(2-(氨基氧基)-3-(二苯甲氧基)-3-氧代丙氧基)苯甲脒基)哌啶-1-羧酸叔丁酯(3_1_8)
将化合物3_1_7(0.33g,0.45mmol)溶于5mL无水乙醇中,然后在0℃下加入水合肼(23μL,0.52mmol),将反应液在室温下搅拌3.5小时,过滤后用乙醇洗涤(5mL,两次),将滤液浓缩,浓缩物加入10mL二氯甲烷搅拌得到悬浊液。该悬浊液过滤,并用二氯甲烷洗涤(3mL,两次),滤液浓缩得到淡黄色泡沫状化合物3_1_8(0.26g,定量反应),无需进一步纯化,直接进行下一步反应。
1H NMR(400MHz,DMSO-d6):δ1.42(s,9H),1.42-1.54(m,2H),1.87-1.97(m,2H),2.72-2.94(m,2H),3.82-4.06(m,3H),4.30-4.49(m,2H),4.60-4.68(m,1H),6.91(s,1H),7.10(d,J=8.8Hz,2H),7.25-7.47(m,10H),7.71(d,J=8.8Hz,2H),9.15(br s,4H)。LC-MS:[M+H]+=561.2。
按照上述3.1详述的合成方法,在合成步骤3用不同的胺替代4-氨基哌啶-1-羧酸叔丁酯即可分别获得下列目标化合物3_2_8至3_6_8。
3.2(R)-3-(4-((S)-2-(氨基氧基)-3-(二苯甲氧基)-3-氧代丙氧基)苯甲脒基)哌啶-1-羧酸叔丁酯(3_2_8)
1H NMR(400MHz,DMSO-d6):δ1.38(s,9H),1.43-1.49(m,1H),1.52-1.60(m,1H),1.72-1.82(m,1H),1.96-2.03(m,1H),2.91-3.04(m,1H),3.33-3.39(m,3H),3.75-3.82(m,1H),4.36-4.47(m,2H),4.62-4.65(m,1H),6.45(s,2H),6.90(s,1H),7.07(d,J=8.9Hz,2H),7.23-7.32(m,4H),7.33-7.40(m,4H),7.42-7.45(m,2H),7.69(d,J=8.9Hz,2H)。LC-MS:[M+H]+=589.3。
3.3(S)-3-(4-((S)-2-(氨基氧基)-3-(二苯甲氧基)-3-氧代丙氧基)苯甲脒基)哌啶-1-羧酸叔丁酯(3_3_8)
1H NMR(400MHz,DMSO-d6):δ1.39(s,9H),1.43-1.49(m,1H),1.51-1.61(m,1H),1.74-1.82(m,1H),1.96-2.04(m,1H),2.92-3.04(m,1H),3.40-3.47(m,3H),3.74-3.83(m,1H),4.37-4.44(m,2H),4.64(t,J=3.9Hz,1H),6.46(s,2H),6.90(s,1H),7.09(d,J=8.7Hz,2H),7.22-7.32(m,4H),7.33-7.40(m,4H),7.41-7.47(m,2H),7.69(d,J=8.7Hz,2H)。LC-MS:[M+H]+=589.3。
3.4(S)-3-(4-(2-(氨基氧基)-3-(二苯甲氧基)-3-氧代丙氧基)苯甲脒基)氮杂环丁烷-1-羧酸叔丁酯(3_4_8)
1H NMR(400MHz,DMSO-d6):δ1.39(s,9H),3.41-3.46(m,3H),3.85-3.92(m,2H),4.18-4.26(m,1H),4.34-4.38(m,2H),4.01-4.45(m,1H),4.61-4.64(m,1H),6.44(s,2H),6.90(s,1H),7.04(d,J=8.8Hz,2H),7.22-7.31(m,4H),7.33-7.40(m,4H),7.41-7.45(m,2H),7.75(d,J=8.8Hz,2H)。LC-MS:[M+H]+=561.2。
3.5(R)-3-(4-((S)-2-(氨基氧基)-3-(二苯甲氧基)-3-氧代丙氧基)苯甲脒基)吡咯烷-1-羧酸叔丁酯(3_5_8)
1H NMR(400MHz,DMSO-d6):δ1.34(s,9H),1.80-1.99(m,1H),2.11-2.18(m,1H),3.33-3.39(m,3H),3.52-3.61(m,1H),4.27-4.39(m,3H),4.54-4.60(m,1H),6.38(s,2H),6.82(s,1H),7.02(d,J=7.8Hz,2H),7.17-7.24(m,4H),7.26-7.33(m,4H),7.34-7.38(m,2H),7.63(d,J=7.8Hz,2H)。LC-MS:[M+H]+=575.3。
3.6(S)-3-(4-((S)-2-(氨基氧基)-3-(二苯甲氧基)-3-氧代丙氧基)苯甲脒基)吡咯烷-1-羧酸叔丁酯(3_6_8)
1H NMR(400MHz,DMSO-d6):δ1.41(s,9H),1.97-2.07(m,1H),2.17-2.27(m,1H),3.40-3.47(m,3H),3.60-3.68(m,1H),4.35-4.47(m,3H),4.62-4.65(m,1H),6.45(s,2H),6.90(s,1H),7.07(d,J=8.8Hz,2H),7.22-7.32(m,4H),7.33-7.40(m,4H),7.41-7.46(m,2H),7.73(d,J=8.8Hz,2H)。LC-MS:[M+H]+=575.3。
4.最终目标化合物的合成
实施例1
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(哌啶-4-基)甲脒基)苯氧基)丙酸
步骤1:(S,Z)-2-(((1-(二苯甲氧基)-3-(4-(N-(1-(叔丁氧羰基)哌啶-4-基)甲脒基)苯氧基)-1-氧代丙烷-2-基)氧基)亚氨基)-2-(2-((叔丁氧羰基)氨基)-5-氯噻唑-4-基)乙酸(4_1_1)
将化合物3_1_8(0.294g,0.50mmol)溶于乙醇(3mL)和氯仿(3mL)溶液中,然后加入化合物2_1(0.151g,0.490mmol)。所得混合物在室温下搅拌18小时,之后减压浓缩。浓缩物经硅胶柱层析纯化(10-20%MeOH的CH2Cl2洗脱),得到淡黄色固体目标化合物4_1_1(0.31g,71%)。
1H NMR(400MHz,DMSO-d6):δ1.42(s,9H),1.46(s,9H),1.54-1.43(m,2H),1.86-1.96(m,2H),2.71-2.91(m,2H),3.84-4.03(m,3H),4.43-4.57(m,2H),5.05-5.12(m,1H),6.87(s,1H),7.09(d,J=8.8Hz,2H),7.20-7.30(m,6H),7.41-7.50(m,4H),7.68(d,J=8.8Hz,2H),9.20(s,1H),9.38(s,1H),9.47(s,1H),11.9(s,1H)。LC-MS:[M+H]+=877.1,[M+H+2]+=879.1。
步骤2:4-(4-((S)-3-(二苯甲氧基)-2-((((Z)-1-(2-((叔丁氧基羰基)氨基)-5-氯噻唑-4-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-氧代丙氧基)苯甲脒基)哌啶-1-羧酸叔丁酯(4_1_2)
将化合物4_1_1(0.305g,0.350mmol)溶解于无水DMF(3.5mL)中,然后添加二环己基碳二亚胺(DCC,110mg,0.52mmol)和1-羟基苯并三唑(HOBt,70.0mg,0.52mmol)。将所得反应液在室温下搅45分钟,然后添加1_1(110mg,0.52mmol)和NaHCO3(88.0mg,1.05mmol),并在室温下继续搅拌过夜。反应混合物减压浓缩。浓缩物通过硅胶柱层析纯化(用含5%-10%MeOH的CH2Cl2洗脱),得到淡黄色固态目标化合物4_1_2(0.32g,86%)。
1H NMR(400MHz,DMSO-d6):δ1.11(s,3H),1.37(s,3H),1.41(s,9H),1.46(s,9H),1.44-1.51(m,2H),1.87-1.97(m,2H),2.72-2.89(m,2H),3.78-3.88(m,1H),3.94-4.04(m,2H),4.45-4.52(m,1H),4.57(d,J=7.8Hz,1H),4.58-4.65(m,1H),5.33-5.38(m,1H),6.92(s,1H),7.07(d,J=8.8Hz,2H),7.17-7.50(m,10H),7.70(d,J=8.8Hz,2H),8.98(s,1H),9.30(s,1H),9.38(d,J=7.8Hz,1H),9.63(d,J=7.8Hz,1H),12.1(s,1H)。LC-MS:[M-H]-=1066.8,[M+2-H]-=1068.8。
步骤3:(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(哌啶-4-基)甲脒基)苯氧基)丙酸(实施例1)
将化合物4_1_2(0.32g,0.30mmol)溶于4mL无水二氯甲烷中,然后在0℃下加入3mL三氟乙酸,将反应液在0℃下搅拌1小时,再将反应液升至室温搅拌2小时,之后减压浓缩,将浓缩物溶于20mL水中,用石油醚/乙酸乙酯(2:1,40mL)洗涤。将水层经冷冻干燥得到淡黄色粉末状的粗产物(0.28g),将其进一步通过制备液相色谱系统(采用Agilent 10 C18 250×21.2mm色谱柱)纯化,目标组分再经冷冻干燥即可得到白色固体最终目标化合物实施例1(16mg,7.6%)。
1H NMR(400MHz,DMSO-d6):δ1.29(s,3H),1.42(s,3H),1.71-1.87(m,2H),1.98-2.12(m,2H),2.81-2.96(m,3H),3.80-3.91(m,2H),4.37-4.53(m,2H),4.69(d,J=8.8Hz,1H),4.73(d,J=7.8Hz,1H),7.20(d,J=8.2Hz,2H),7.36(br s,2H),7.69(d,J=8.2Hz,2H),8.99(br s,1H),9.45(br s 1H),9.63(br s,1H),11.6(d,J=6.84Hz,1H)。LC-MS:[M-H]-=701.1,[M+2-H]-=703.2。
依据实施例1的合成路径,选取不同胺(BB3:3_2_8至3_6_8)、不同的酮酸(BB2:2_1至2_2)和不同的3-氨基氮杂环丁烷-2-酮(BB1:1_1至1_2)即可成功合成最终目标化合物(从实施例2到实施例12,包括实施例1在内共12个目标化合物,表1)。为方便阅读,表1中列举了最终化合物的结构以及相应片段砌块(BB1:1_x、BB2:2_x和BB3:3_x_8)。
表1.最终化合物结构以及合成使用的相应砌块片段
实施例2
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(哌啶-4-基)甲脒基)苯氧基)丙酸
1H NMR(400MHz,DMSO-d6):δ1.23(s,3H),1.41(s,3H),1.71-1.85(m,2H),2.01-2.09(m,2H),2.81-2.93(m,3H),3.79-3.88(m,2H),4.36-4.50(m,2H),4.67(d,J=8.4Hz,1H),4.76(d,J=6.9Hz,1H),7.21(d,J=7.1Hz,2H),7.70(d,J=7.1Hz,2H),8.14(br s,1H),8.17(br s,1H),8.99(br s,1H),9.43(br s,1H),9.67(br s,1H),11.02(br s,1H)。LC-MS:[M-H]-=667.9。
实施例3
S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((R)-哌啶-3-基)甲脒基)苯氧基)丙酸
1H NMR(400MHz,DMSO-d6):δ1.27(s,3H),1.41(s,3H),1.62-1.74(m,2H),1.87-2.02(m,2H),2.82-2.92(m,2H),3.04-3.12(m,2H),3.82-3.93(m,1H),4.18-4.26(m,1H),4.39-4.46(m,1H),4.69(d,J=8.7Hz,1H),4.74(d,J=5.5Hz,1H),7.08(d,J=8.2Hz,2H),7.36(br s,2H),7.62(d,J=8.2Hz,2H),9.29(br s,2H),10.63(br s 1H)。LC-MS:[M-H]-=700.9,[M+2-H]-=702.8。
实施例4
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((R)-哌啶-3-基)甲脒基)苯氧基)丙酸
1H NMR(400MHz,DMSO-d6):δ1.21(s,3H),1.40(s,3H),1.69-1.79(m,2H),1.94-2.04(m,2H),2.87-3.01(m,2H),3.11-3.19(m,2H),3.84-3.92(m,1H),4.16-4.23(m,1H),4.4 1-4.47(m,1H),4.66(d,J=8.1Hz,1H),4.78-4.82(m,1H),7.02(d,J=8.6Hz,2H),7.59(d,J=8.6Hz,2H),8.14(br s,2H),9.02(br s,1H),9.23(br s,1H),11.04(br s,1H)。LC-MS:[M-H]-=667.9。
实施例5
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((S)-吡咯烷-3-基)甲脒基)苯氧基)丙酸
1H NMR(400MHz,DMSO-d6):δ1.27(s,3H),1.42(s,3H),2.14-2.27(m,2H),3.25-3.45(m,3H),3.57-3.64(m,1H),4.16(d,J=9.7Hz,1H),4.40(t,J=9.7Hz,1H),4.45-3.51(m,1H),4.63(d,J=8.4Hz,1H),4.77(d,J=8.7Hz,1H),7.09(d,J=8.3Hz,2H),7.36(br s,2H),7.75(d,J=8.3Hz,2H),9.04(br s,2H),10.35(br s,1H)。LC-MS:[M-H]-=686.9,[M+2-H]-=688.9。
实施例6
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((S)-吡咯烷-3-基)甲脒基)苯氧基)丙酸
1H NMR(400MHz,DMSO-d6):δ1.19(s,3H),1.40(s,3H),2.04-2.23(m,2H),3.37-3.42(m,3H),3.57-3.63(m,1H),4.19-4.26(m,1H),4.30-4.44(m,2H),4.63(d,J=8.4Hz,1H),4.76(d,J=7.8Hz,1H),7.11(d,J=7.8Hz,2H),7.74(d,J=7.8Hz,2H),8.23(br s,2H),10.35(d,J=8.4Hz,1H)。LC-MS:[M-H]-=654.0。
实施例7
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(氮杂环丁烷-3-基)甲脒基)苯氧基)丙酸
1H NMR(400MHz,DMSO-d6):δ1.15(s,3H),1.37(s,3H),4.01-4.09(m,2H),4.16-4.26(m,2H),4.29-4.39(m,2H),4.55-4.64(m,2H),4.78-4.86(m,1H),7.04(d,J=8.6Hz,2H),7.77(d,J=8.6Hz,2H),8.14(br s,2H),10.20(m,1H)。LC-MS:[M-H]-=640.7。
实施例8
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(氮杂环丁烷-3-基)甲脒基)苯氧基)丙酸
1H NMR(400MHz,DMSO-d6):δ1.29(s,3H),1.42(s,3H),4.12-4.17(m,1H),4.19-4.30(m,2H),4.34-4.41(m,2H),4.43-4.47(m,1H),4.61(d,J=8.3Hz,1H),4.63-4.65(m,1H),4.78-4.85(m,1H),7.21(d,J=8.8Hz,2H),7.33(br s,2H),7.69(d,J=8.8Hz,2H),8.38(br s,4H),11.6(d,J=8.3Hz,1H)。LC-MS:[M-H]-=673.1,[M+2-H]-=675.1。
实施例9
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((2S,3S)-2-甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((S)-哌啶-3-基)甲脒基)苯氧基)丙酸
1H NMR(400MHz,DMSO-d6):δ1.35(d,J=6.4Hz,3H),1.42-1.49(m,1H),1.63-1.71(m,1H),1.79-1.87(m,1H),1.95-2.02(m,1H),2.86-2.95(m,1H),2.98-3.08(m,3H),3.60-3.65(m,1H),3.91-3.97(m,1H),4.13-4.19(m,1H),4.30(t,J=8.6Hz,1H),4.42(dd,J=7.9,2.6Hz,1H),4.72(d,J=7.4Hz,1H),6.65(br s,1H),7.14(d,J=8.7Hz,2H),7.19(brs,2H),7.72(d,J=8.7Hz,2H)。LC-MS:[M-H]-=671.1,[M+2-H]-=673.1。
实施例10
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((R)-吡咯烷-3-基)甲脒基)苯氧基)丙酸
1H NMR(400MHz,DMSO-d6):δ1.27(s,3H),1.41(s,3H),2.00-2.09(m,1H),2.17-2.26(m,1H),3.07-3.15(m,1H),3.21-3.36(m,3H),4.22-4.27(m,1H),4.36-4.44(m,2H),4.65(t,J=8.6Hz,1H),4.72(d,J=8.5Hz,1H),7.13(d,J=8.5Hz,2H),7.35(br s,2H),7.74(d,J=8.5Hz,2H),8.30(br s,3H),10.35(d,J=8.6Hz,1H)。LC-MS:[M-H]-=687.1,[M-H+2]-=689.1。
实施例11
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((S)-哌啶-3-基)甲脒基)苯氧基)丙酸
1H NMR(400MHz,DMSO-d6):δ1.26(s,3H),1.41(s,3H),1.54-1.79(m,3H),1.92-2.02(m,1H),2.73-2.81(m,1H),2.87-2.98(m,3H),3.84-3.91(m,1H),4.10-4.16(m,1H),4.35(t,J=9.5Hz,1H),4.67(d,J=8.8Hz,1H),4.70(d,J=8.5Hz,1H),7.13(d,J=8.5Hz,2H),7.33(br s,2H),7.72(d,J=8.5Hz,2H),9.21(br s,3H),11.08(br s,1H)。LC-MS:[M-H]-=701.1,[M+2-H]-=703.1。
实施例12
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((R)-吡咯烷-3-基)甲脒基)苯氧基)丙酸
1H NMR(400MHz,DMSO-d6):δ1.26(s,3H),1.43(s,3H),1.98-2.03(m,1H),2.07-2.15(m,1H),3.27-3.34(m,1H),3.35-3.45(m,2H),3.46-3.54(m,1H),4.16-4.21(m,1H),4.40-4.45(m,2H),4.69(d,J=8.7Hz,1H),4.72(t,J=4.9Hz,1H),7.18(d,J=8.7Hz,2H),7.72(d,J=8.7Hz,2H),8.12(br s,2H),8.41(br s,5H),11.25(br s,1H)。LC-MS:[M-H]-=654.2。
生物活性评价
本发明化合物对选择的不同供试细菌的抗菌活性可通过如下多种方法进行测定,包括测定体外最低抑菌浓度(MIC)或用小鼠感染模型测定体内疗效。
最低抑菌浓度(MIC)测定
本发明所述化合物的最低抑菌浓度(MIC,单位为μg/mL)根据临床实验室和标准化研究所的指导原则(“Methods for Dilution Antimicrobial Susceptibility Tests forBacteria that Grow Aerobically”,Approved standard,7th ed.,Clinical andLaboratory Standards Institute Document(CLSI)Document M7-A8,Wayne,Pa.,USA,2009(对有氧生长细菌的稀释抗微生物敏感性测定方法,认可标准,第7版,临床实验室标准化研究所文档M7-A8,Wayne,Pa.,美国,2009)测定。使用微量肉汤稀释法(brothmicrodilution method)测定本发明所述化合物的最低抑菌浓度,以氨曲南(AZT)和头孢他啶(CAZ)分别作为对照抗生素。首先,将对照抗生素、本发明化合物分别溶解在DMSO中,然后用微生物培养基(Mueller-Hinton Broth II)以连续两倍稀释的方式进行稀释处理,最终浓度范围为0.063μg/mL-64μg/mL,并确保每个浓度处理的培养基其DMSO的最终浓度均小于0.5%。其次,用96微孔平板法(96-well microtitre)将供试细菌分别添加到上述经连续两倍稀释法得到的不同浓度梯度处理的培养基中,每个微孔培养基的最终细菌菌落密度约为5×105CFU/mL单位。最后,微孔平板在37℃下培养18小时至24小时后,用目测方法确定抑制细菌生长的MIC,即为本发明化合物和对照抗生素抑制细菌生长的最低浓度。当本发明化合物与β-内酰胺酶抑制剂组合一起使用时,用同样的方法可测定其协同抗菌活性:即本发明化合物在上述相同浓度梯度处理条件下(但β-内酰胺酶抑制剂需维持恒定浓度的4mg/L),测定MIC即为协同抗菌活性。
本发明化合物的MIC测定时,其供试验细菌菌株包括但不限于大肠杆菌(E.coliclinical isolate,临床分离株)、大肠杆菌8739(E.coli8739)、克雷伯肺炎杆菌(K.pneumoniae clinical isolate,临床分离株)、克雷伯肺炎杆菌700603(K.pneumoniae700603)、阴沟肠杆菌(E.cloacae clinical isolate,临床分离株)、阴沟肠杆菌700323(E.cloacae 700323)、鲍曼不动杆菌(A.baumannii clinical isolate,临床分离株)、鲍曼不动杆菌19606(A.baumannii 19606)、铜绿假单胞菌(P.aeruginosa clinical isolate,临床分离株)、铜绿假单胞菌9027(P.aeruginosa 9027)。
表2.抗菌活性测定结果
AZT:氨曲南;CAZ:头孢他啶
菌株1 | 大肠杆菌(临床分离株) |
菌株2 | 大肠杆菌8739 |
菌株3 | 克雷伯肺炎杆菌(临床分离株) |
菌株4 | 克雷伯肺炎杆菌700603 |
菌株5 | 阴沟肠杆菌(临床分离株) |
菌株6 | 阴沟肠杆菌700323 |
菌株7 | 鲍曼不动杆菌(临床分离株) |
菌株8 | 鲍曼不动杆菌19606 |
菌株9 | 铜绿假单胞菌(临床分离株) |
菌株10 | 铜绿假单胞菌9027 |
Claims (14)
2.根据权利要求1所述的化合物,其特征在于:
M表示氢或药学可接受的成盐阳离子,
R1和R2表示甲基,
W表示O,
X表示CR4,
R4表示卤素,
R3表示氨乙基、氮杂环丁烷基、吡咯烷基或哌啶基,
及所述化合物的盐、所述化合物及其盐的溶剂化物、或任何此种化合物的氘代化合物。
3.根据权利要求1或2所述的化合物,其特征在于:
M表示氢或药学可接受的成盐阳离子,
R1和R2表示甲基,
W表示O,
X表示N,
R3表示氨乙基、氮杂环丁烷基、吡咯烷基或哌啶基,
及所述化合物的盐、所述化合物及其盐的溶剂化物、或任何此种化合物的氘代化合物。
5.根据权利要求1所述的式(I)化合物,其选自:
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((S)-2,2-二甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(2-氨乙基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((S)-2,2-二甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(2-氨乙基)甲脒基)苯氧基)丙酸,
((S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((2S,3S)-2-甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(2-氨乙基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(哌啶-4-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((R)-哌啶-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((S)-哌啶-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(氮杂环丁烷-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((R)-吡咯烷-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((S)-吡咯烷-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(哌啶-4-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((R)-哌啶-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((S)-哌啶-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(氮杂环丁烷-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((R)-吡咯烷-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((S)-2,2-二甲基-4-氧代-1-(磺氧基)氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((S)-吡咯烷-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((2S,3S)-2-甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(哌啶-4-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((2S,3S)-2-甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((R)-哌啶-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((2S,3S)-2-甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((S)-哌啶-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((2S,3S)-2-甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(氮杂环丁烷-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((2S,3S)-2-甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((R)-吡咯烷-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(2-氨基-5-氯噻唑-4-基)-2-(((2S,3S)-2-甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((S)-吡咯烷-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((2S,3S)-2-甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(哌啶-4-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((2S,3S)-2-甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((R)-哌啶-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((2S,3S)-2-甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((S)-哌啶-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((2S,3S)-2-甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-(氮杂环丁烷-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((2S,3S)-2-甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((R)-吡咯烷-3-基)甲脒基)苯氧基)丙酸,
(S)-2-((((Z)-1-(5-氨基-1,2,4-噻二唑-3-基)-2-(((2S,3S)-2-甲基-4-氧代-1-磺基氮杂环丁烷-3-基)氨基)-2-氧代亚乙基)氨基)氧基)-3-(4-(N-((S)-吡咯烷-3-基)甲脒基)苯氧基)丙酸;
或任何此种化合物的氘代化合物。
6.根据权利要求1至5中任一项所述的化合物,其用于治疗和/或预防疾病的方法中,所述疾病特别是细菌感染,尤其是革兰氏阴性菌感染。
7.根据权利要求1至5中任一项所述的化合物用于治疗和/或预防疾病的用途,所述疾病特别是细菌感染,尤其是革兰氏阴性菌感染。
8.根据权利要求1至5中任一项所述的化合物在制备用于治疗和/或预防疾病的药物中的用途,所述疾病特别是细菌感染,尤其是革兰氏阴性菌感染。
9.一种药物,其包括至少一种根据权利要求1至5中任一项所述的化合物与至少一种其它活性化合物的组合。
10.根据权利要求9所述的药物,其中所述其它活性化合物是β-内酰胺酶抑制剂,优先选自克拉维酸、他唑巴坦、舒巴坦、阿维巴坦、雷巴坦、瓦博巴坦。
11.一种药物,其包括至少一种根据权利要求1至5的任一项所述的化合物与至少一种惰性无毒的药学可接受的赋形剂的组合。
12.根据权利要求9至11中任一项所述的药物,其用于治疗和/或预防细菌感染的方法中。
13.用于控制人和动物的细菌感染的方法,所述方法包括施用抗菌有效剂量的至少一种根据权利要求1至5中任一项所述的化合物或根据权利要求9至11中任一项所述的药物。
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