CN114728953B - β-内酰胺类化合物,及其制备方法以及其作为抗菌素的应用 - Google Patents
β-内酰胺类化合物,及其制备方法以及其作为抗菌素的应用 Download PDFInfo
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- CN114728953B CN114728953B CN202080081727.0A CN202080081727A CN114728953B CN 114728953 B CN114728953 B CN 114728953B CN 202080081727 A CN202080081727 A CN 202080081727A CN 114728953 B CN114728953 B CN 114728953B
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Abstract
本发明提供式(I)所示的β‑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,其中M、X、W、R1、R2和R3在本文中定义。
Description
技术领域
本发明属于药学领域,涉及新型β-内酰胺类化合物、其制备方法以及其作为治疗药物的用途。更具体地说,本发明涉及脒取代的β-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)开始在全世界出现,威胁抗生素的疗效。目前,一方面,因感染而无法得到有效治疗而死亡的患者人数持续增加,而另一方面,对于多重耐药的革兰氏阴性病原体(包括肠杆菌科)引起的感染,可供选择的治疗药物尤其有限,制药行业管线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细菌的挑战。
β-内酰胺类抗生素是治疗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已出现,且日趋严峻。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。据报道β-内酰胺酶已多达1500种以上,严重危及现有抗生素的使用效果。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FDA批准的迄今唯一的单环内酰类抗生素,在全球范围内广泛使用以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)水解的的特点和优势,因此,一些公司正在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。例如研发的具有能够螯合铁的结构的单环内酰类抗生素(WO 2007065288,Basilea)、(WO 2002022613,NAEJA)、(US 5290929、EP 531976、EP 484881,Squibb&Sons)。辉瑞公司重新研究的在单环内酰的N1位拥有磺酰氨基活性基团的单环β-内酰胺类抗生素(WO 2010070523)。
最近,美国专利(US 2014/0275007)公开了含有oxamazin基团的单环内酰类抗生素及其用途,另一项美国专利(US 2015/0266867)还公开了用作抗菌的新型单环内酰类抗生素。国际专利(WO2013/110643)公开了新型脒取代的单环内酰类抗生素的衍生物及其作为抗菌素的用途,国际专利(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素的用途,此外,国际专利(WO2017/155765)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素的用途。
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;所研发的化合物可作为抗生素单独使用,也可与合适的β-内酰胺酶抑制剂配伍一起使用。
发明内容
本发明涉及脒取代的单环内酰类化合物,其结构新颖,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)、或与其它属于内酰胺酶抑制剂(如含有二氮双环辛烷结构的阿维巴坦等)、或金属-β-内酰胺酶抑制剂等配伍一起使用,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)通式(I)化合物的药学上可接受的盐;(C)通式(I)化合物及其盐的药学上可接受的溶剂化物;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)化合物的药学上可接受的盐,(iii)经氘代化后的式(I)化合物及其盐的药学上可接受的溶剂化物:
其中
M表示氢或药学上可接受的成盐阳离子,
R1和R2相互独立地表示氢或C1-C6烷基,
W表示一个键或O,
X独立地表示C1-C6烷基(优选C1-C3烷基,例如,甲基、乙基、正丙基、异丙基)、CF3、CF2、CF,
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,
其中烷基可被羟基、氨基、羧基、羰氧基取代,或被C1-C6单烷基取代的氨基取代,或被C1-C6双烷基取代的氨基取代,或-NH-CH(=NH)、-NH-C(=NH)(NH2)取代,或被5-或6-元含氮杂芳基取代,或被5-或6-元含氮杂环烷基取代。
以及上述化合物及其盐,上述化合物或其盐的溶剂化物,或上述化合物及其盐的氘代化合物。
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取代而获得的化合物。
本发明化合物为式(I)化合物及其盐、化合物及其盐的溶剂化物,式(I)所涵盖并在本发明中作为实施例的化合物及其盐、实施例的化合物及其盐的溶剂化物,以及式(I)所涵盖且本发明中作为实施例的化合物但尚未成盐、且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其各自的混合物。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。
本发明所述的盐首选生理上可接受的盐。然也涵盖其本身不适合药学应用的盐,但可用于本发明化合物的分离或纯化的盐。
式(I)化合物的药学上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,或含有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)化合物的药学上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;或含有酸性氨基酸特别是与天冬氨酸或谷氨酸形成的盐。
本发明的溶剂化物是指本发明化合物在固态或液态中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个原子的环、优选具有5-6个原子的环且具有最多4个、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。优选的是具有5-6个原子的单环杂芳基,所述杂原子选自N、O、S中的最多2个杂原子,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。
所述杂环基指具有4-10个原子的环、优选具有5-6个原子的环且具有最多3个、首选具有最多2个杂原子的饱和或部分不饱和杂环基团,所述杂原子选自N、O、S、SO和SO2,其中N也可形成N-氧化物。选自N、O和S最多2个杂原子的具有5-6个原子的饱和单环杂环基,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基。
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,及O-C=O基团。
本发明涉及式(I)化合物及其盐、式(I)化合物及其盐的溶剂化物,
其中
M代表氢或药学上可接受的成盐阳离子,
R1和R2均表示甲基,
W表示O,
X独立地表示甲基、乙基、CF3、CF2、CF,
R3表示乙基氨、氮杂环丁烷基、吡咯烷基或哌啶基。
本发明涉及式(I)化合物及其盐、式(I)化合物及其盐的溶剂化物,
其中
M是氢或药学上可接受的成盐阳离子,
R1和R2均表示甲基,
W表示O,
X表示甲基,
R3表示乙基氨、氮杂环丁烷基、吡咯烷基或哌啶基。
本发明涉及式(I)化合物及其盐、式(I)化合物及其盐的溶剂化物,
其中
M表示氢或药学上可接受的成盐阳离子,
R1和R2均表示甲基,
W表示O,
X表示CF3,
R3表示乙基氨、氮杂环丁烷基、吡咯烷基或哌啶基。
本发明特别包括具有以下结构的式(I)化合物及其盐、式(I)化合物及其盐的溶剂化物,但并不仅限于下列化合物例:
本发明化合物包括以下化合物,但并不仅限于下列化合物例:
(S)-2-((((Z)-1-(2-氨基-5-(三氟甲基)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-甲基噻唑-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-乙基噻唑-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-(三氟甲基)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-(2-氨基-5-甲基噻唑-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-(2-氨基-5-乙基噻唑-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-(2-氨基-5-(二氟-λ3-甲基)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-(2-氨基-5-(二氟-λ3-甲基)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-(二氟-λ3-甲基)噻唑-4-基)-2-(((2R,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-(氟-λ2-甲基)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-(2-氨基-5-(氟-λ2-甲基)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-(氟-λ2-甲基)噻唑-4-基)-2-(((2R,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-甲基噻唑-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-甲基噻唑-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-甲基噻唑-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-甲基噻唑-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-甲基噻唑-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-甲基噻唑-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-(2-氨基-5-甲基噻唑-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-甲基噻唑-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-甲基噻唑-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-甲基噻唑-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-甲基噻唑-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-甲基噻唑-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-(2-氨基-5-甲基噻唑-4-基)-2-(((2R,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-甲基噻唑-4-基)-2-(((2R,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-甲基噻唑-4-基)-2-(((2R,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-甲基噻唑-4-基)-2-(((2R,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-甲基噻唑-4-基)-2-(((2R,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-(2-氨基-5-甲基噻唑-4-基)-2-(((2R,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-乙基噻唑-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-乙基噻唑-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-乙基噻唑-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-乙基噻唑-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-乙基噻唑-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-乙基噻唑-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-(2-氨基-5-乙基噻唑-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-乙基噻唑-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-乙基噻唑-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-乙基噻唑-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-乙基噻唑-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-乙基噻唑-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-(2-氨基-5-(三氟甲基)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-(三氟甲基)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-(三氟甲基)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-(三氟甲基)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-(三氟甲基)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-(三氟甲基)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-(2-氨基-5-(三氟甲基)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-(三氟甲基)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-(三氟甲基)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-(三氟甲基)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-(三氟甲基)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-(三氟甲基)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-(2-氨基-5-(三氟甲基)噻唑-4-基)-2-(((2R,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-(三氟甲基)噻唑-4-基)-2-(((2R,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-(三氟甲基)噻唑-4-基)-2-(((2R,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-(三氟甲基)噻唑-4-基)-2-(((2R,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-(三氟甲基)噻唑-4-基)-2-(((2R,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-(三氟甲基)噻唑-4-基)-2-(((2R,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-(2-氨基-5-(二氟-λ3-甲基)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-(二氟-λ3-甲基)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-(二氟-λ3-甲基)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-(二氟-λ3-甲基)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-(二氟-λ3-甲基)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-(二氟-λ3-甲基)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-(2-氨基-5-(二氟-λ3-甲基)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-(二氟-λ3-甲基)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-(二氟-λ3-甲基)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-(二氟-λ3-甲基)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-(二氟-λ3-甲基)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-(二氟-λ3-甲基)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-(2-氨基-5-(氟代-λ2-甲基)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-(氟代-λ2-甲基)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-(氟代-λ2-甲基)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-(氟代-λ2-甲基)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-(氟代-λ2-甲基)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-(氟代-λ2-甲基)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-(2-氨基-5-(氟代-λ2-甲基)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-(氟代-λ2-甲基)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-(氟代-λ2-甲基)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-(氟代-λ2-甲基)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-(氟代-λ2-甲基)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-(氟代-λ2-甲基)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。
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0℃-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)化合物可通过将式(III)化合物与式(IV)化合物经缩合反应合成
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。
通常在含有偶联剂的惰性溶剂中进行反应,并在适时于-20℃至80℃的温度范围内添加碱,反应历时1到24小时,首选在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;以及添加或不添加碱的上述偶联剂的混合物。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,碳酸氢钠作为碱可以添加或不添加。
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。可供组合为合适的混合溶剂为二氯甲烷、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。反应首选无水乙醇和氯仿混合作为混合溶剂,在20℃至30℃下过夜进行。
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治疗和/或预防疾病,尤其是细菌感染、特别是下述疾病的药物。
本发明还涉及使用治疗有效量的本发明化合物治疗和/或预防疾病,尤其是细菌感染,特别是下述疾病的方法。
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)属。
本发明上述所列病原体仅为示例性的,但并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、痰、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,还可用于细菌感染的动物疾病治疗,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。
本发明化合物具有周身性和/或局部性疗效作用。为此,可选择适合的途径给药,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/晶片或胶囊,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,牛奶,泡沫,粉剂或植入物等。
本发明化合物可与药学上可接受的惰性且无毒赋形剂混合组配以满足上述给药途径的要求。本发明所述赋形剂包括载体(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,通常是与一种或多种惰性且无毒的、在药学上可接受的赋形剂一起使用,以用于上述目的和用途。
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-内酰胺酶抑制剂经组配形成的药物,以用于上述目的和用途。
与本发明组配的活性化合物包括β-内酰胺酶抑制剂类化合物。
适合与本发明化合物组合使用的β-内酰胺酶抑制剂包括克拉维酸、他唑巴坦、舒巴坦、阿维巴坦、雷巴坦、瓦博巴坦。
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:即在某些情况下,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,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。
具体实施方式
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
DMSO-d6:氘代二甲基亚砜
CD3OD:氘代甲醇
D2O:氘代水
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:常态
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。
质谱引导的制备液相色谱采用Agilent 1260Infinity 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 1260Infinity 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-内酰胺片段(BB-1)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.氨基噻唑砌块(BB-2)的合成
2.1 2-(2-((叔丁氧羰基)氨基)-5-甲基噻唑-4-基)-2-氧代乙酸(2_1)
在0℃下,将Br2(1.1mL,20.8mmol)缓慢加入到化合物2_1_1(3g,20.8mmol)的干燥二氯甲烷溶液中(20mL),将反应液在室温下搅拌过夜,然后用饱和碳酸钠溶液淬灭后,再继续搅拌15分钟,用二氯甲烷萃取,有机层用饱和食盐水洗涤,后用无水硫酸钠干燥,最后旋蒸并用硅胶柱层析纯化,得到油状的目标产物2_1_2(1.95g,65%)。
1H NMR(400MHz,DMSO-d6):δ1.20(t,J=7.1Hz,3H),1.66(d,J=6.7Hz,3H),4.11(q,J=7.1Hz,1H),4.88(q,J=6.7Hz,2H),5.43(s,1H),11.84(s,1H)。
在室温下将化合物2_1_2(1.2g,5.4mmol)加入到8mL甲苯中搅拌,之后加入硫脲(0.82g,10.8mmol),将反应液在室温下过夜反应,再回流3小时。然后将溶剂去除并用二氯甲烷稀释,加入饱和碳酸钠,将反应液强力搅拌15分钟,分离出有机层,加入硫酸钠干燥。滤液浓缩,经二氯甲烷和正己烷重结晶,得到白色结晶化合物2_1_3(1.1g,87%)。
1H NMR(400MHz,DMSO-d6):δ1.17(t,J=7.1Hz,3H),2.12(s,3H),3.83(s,2H),4.05(q,J=7.1Hz,3H),6.69(s,2H)。
在室温下将化合物2_1_3(0.69g,3.45mmol)加入到15mL乙腈中搅拌,之后在室温下加入二碳酸二叔丁酯(1.28g,5.86mmol)和N,N,N',N'-四甲基乙二胺(TMEAD,0.8g,6.89mmol),加热至50℃,反应8小时后,TLC监测反应底物消失,加入乙酸乙酯稀释,用水洗涤三次后再用饱和食盐水洗涤,用无水硫酸钠干燥,将有机相浓缩后用硅胶柱层析纯化,得到黄色固体目标化合物2_1_4(0.46g,66%)。
1H NMR(400MHz,DMSO-d6):δ1.17(t,J=7.1Hz,3H),1.46(s,9H),2.23(s,3H),3.56(s,2H),4.05(q,J=7.1Hz,2H),11.24(s,1H)。
在室温下将化合物2_1_4(4.6g,15.32mmol)加入到1,4-二氧六环(20mL)中搅拌,之后在室温下加入二氧化硒(SeO2,3.4g,30.63mmol),反应液在105℃下回流24小时。然后将反应液通过硅胶层过滤后加压浓缩,剩余物用硅胶柱层析纯化,得到黄色非结晶化合物2_1_5(1.5g,33%)。
1H NMR(400MHz,DMSO-d6):δ1.29(t,J=7.1Hz,3H),1.47(s,9H),2.66(s,3H),4.32(q,J=7.1Hz,2H),11.74(s,1H)。
在0℃下将化合物2_1_5(1.6g,5.09mmol)加入到8mL四氢呋喃和8mL乙醇中搅拌,之后在0℃下加入氢氧化钠水溶液(1N,7.63mL),反应液在0℃下搅拌6小时。然后将反应液浓缩去除有机溶剂,冷却至0℃,用1N盐酸溶液调节pH至4得到沉淀物,经过滤干燥得到白色固体化合物2_1(1.3g,85%)。
1H NMR(400MHz,DMSO-d6):δ1.46(s,9H),2.61(s,3H),11.70(s,1H)。
2.2 2-(2-((叔丁氧羰基)氨基)-5-(三氟甲基)噻唑-4-基)-2-氧代乙酸(2_2)
将化合物2_2_1(10.0g,50mmol)、二碳酸二叔丁基甲酯((Boc)2O,12.0g,55mmol)及N,N,N',N'-四甲基乙二胺(MEDA,6.4g,55mmol)溶于50mL碳酸二甲酯中,加热至40℃反应14小时,之后浓缩并用硅胶柱层析纯化(乙酸乙酯和石油醚洗脱),得到黄色固体化合物2_2_2(4.95g,33%)。
1H NMR(400MHz,CDCl3):δ1.34(t,J=7.2Hz,3H),1.45(s,9H),4.35(q,J=7.2Hz,2H),8.20(s,1H),8.96(br s,1H)。
在室温下将化合物2_2_2(2g,6.66mmol)、N-碘代丁二酰亚胺(NIS,4.5g,20mmol)及过氧化苯甲酰(0.1g,作为催化剂)溶于10mL二甲基甲酰胺中,在80℃下搅拌6小时。之后冷却至室温,加入蒸馏水淬灭,然后加入硫代硫酸钠直至过量的碘被去除,最后用乙酸乙酯萃取,用水和饱和食盐水洗涤,有机相用硫酸镁干燥后浓缩,再用硅胶柱层析纯化(含有1%甲醇的二氯甲烷洗脱),得到油状化合物2_2_3(2.76g,97%)。
1H NMR(400MHz,CDCl3):δ1.31(t,J=7.2Hz,3H),1.45(s,9H),4.33(q,J=7.2Hz,2H),8.17(br s,1H)。
将化合物2_2_3(0.97g,2.28mmol)溶于DMF与六甲基磷酰三胺的混合溶液中(HMPA,8:1,6mL),并置于微波玻璃瓶中,然后加入碘化铜(CuI,0.087g,0.45mmol))和2,2-二氟-2-(氟磺酰)乙酸甲酯(MFDSA,0.87g,4.56mmol)。随后将玻璃瓶密封在100℃下微波反应6分钟,冷却后用乙酸乙酯稀释反应液,用水洗涤,有机相加入无水硫酸镁干燥后减压浓缩,再用二氯甲烷纯化,得到淡黄色固体化合物2_2_4(0.44g,52%)。
1H NMR(400MHz,CDCl3):δ1.31(t,J=7.2Hz,3H),1.46(s,9H),4.32(q,J=7.2Hz,2H),8.12(br s,1H).19F NMR(376MHz,CDCl3):δ-53.4(s,3F)。
将化合物2_2_4(0.138g,0.375mmol)溶解于THF(2.5mL)中,冷却至0℃后滴加1NNaOH溶液(0.94mL),然后在0℃下搅拌1.5小时。在10℃下浓缩,然后添加5mL水,冷却至0℃,用1N HCl酸化至pH~4。将混合物冻干,得到残渣,用含10%MeOH的DCM(3×20mL)提取。浓缩有机相得到白色固体目标化合物2_2(63mg,53%),无需进一步纯化,直接用于下一步反应。
1H NMR(400MHz,DMSO-d6):δ1.48(s,9H),12.30(s,1H).19FNMR(376MHz,DMSO-d6):δ-51.1(s,3F)。
3.含有脒侧链片段(BB-3)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)溶于50mL甲基叔丁基醚中,再加入(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),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,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所需化合物,81%)。
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%)。
1HNMR(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]+=589.2。
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)
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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(Example 1)
(S)-2-((((Z)-1-(2-氨基-5-甲基噻唑-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-甲基噻唑-4-基)乙酸(4_1_1)
将化合物3_1_8(0.24g,0.40mmol)溶于乙醇(3mL)和氯仿(3mL)溶液中,然后加入2-(2-((叔丁氧羰基)氨基)-5-甲基噻唑-4-基)-2-氧代乙酸2_1(0.13g,0.44mmol)。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(5-15%MeOH的CH2Cl2洗脱),得到淡黄色固体目标化合物4_1_1(0.21g,61%)。
1H NMR(400MHz,DMSO-d6):δ1.40(s,9H),1.45(s,9H),1.43-1.53(m,2H),1.86-1.96(m,2H),2.20(s,3H),2.70-2.91(m,2H),3.84-4.04(m,3H),4.40-4.58(m,2H),5.03-5.14(m,1H),6.89(s,1H),7.10(d,J=8.8Hz,2H),7.19-7.32(m,6H),7.40-7.51(m,4H),7.68(d,J=8.8Hz,2H),9.19(s,1H),9.39(s,1H),9.46(s,1H),11.5(s,1H).LC-MS:[M+H]+=857.3。
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-甲基噻唑-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(0.21g,0.24mmol)溶解于无水DMF(2.5mL)中,然后添加二环己基碳二亚胺(DCC,76mg,0.37mmol)和1-羟基苯并三唑(HOBt,50mg,0.37mmol)。将所得反应液在室温下搅45分钟,然后添加(S)-3-氨基-2,2-二甲基-4-氧代氮杂环丁烷-1-基硫酸氢酯1_1(78mg,0.37mmol)和NaHCO3(62mg,0.74mmol),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3%-5%MeOH的CH2Cl2洗脱),得到淡黄色固态目标化合物4_1_2(0.23g,89%)。
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),1.89-1.98(m,2H),2.21(s,3H),2.71-2.90(m,2H),3.77-3.89(m,1H),3.94-4.06(m,2H),4.45-4.51(m,1H),4.58(d,J=8.0Hz,1H),4.58-4.64(m,1H),5.31-5.35(m,1H),6.92(s,1H),7.08(d,J=8.8Hz,2H),7.16-7.49(m,10H),7.70(d,J=8.8Hz,2H),8.99(s,1H),9.32(s,1H),9.40(d,J=8.0Hz,1H),9.55(d,J=8.0Hz,1H),11.7(s,1H).LC-MS:[M-H]-=1047.0。
步骤3:(S)-2-((((Z)-1-(2-氨基-5-甲基噻唑-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(0.23g,0.22mmol)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(0.21g),将其进一步通过制备液相色谱系统(采用Agilent 10C18250×21.2mm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(25mg,16%)。
1H NMR(400MHz,DMSO-d6):δ1.28(s,3H),1.42(s,3H),1.73-1.86(m,2H),1.99-2.10(m,2H),2.24(s,3H),2.79-2.92(m,3H),3.81-3.91(m,2H),4.38-4.44(m,1H),4.47-4.54(m,1H),4.66(d,J=8.6Hz,1H),4.70(d,J=7.8Hz,1H),6.85(br s,2H),7.19(d,J=8.2Hz,2H),7.71(d,J=8.2Hz,2H),11.00(d,J=7.8Hz,1H).LC-MS:[M-H]-=681.0。
实施例2
(S)-2-((((Z)-1-(2-氨基-5-甲基噻唑-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
步骤1:(Z)-2-((((S)-1-(二苯甲氧基)-3-(4-(N-((R)-1-(叔丁氧羰基)哌啶-3-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-甲基噻唑-4-基)乙酸(4_2_1)
将化合物3_2_8(0.24g,0.40mmol)溶于乙醇(3mL)和氯仿(3mL)溶液中,然后加入2-(2-((叔丁氧羰基)氨基)-5-甲基噻唑-4-基)-2-氧代乙酸2_1(0.12g,0.42mmol)。所得混合物在室温下搅拌12小时,之后减压浓缩。浓缩物经硅胶柱层析纯化(5-15%MeOH的CH2Cl2洗脱),得到淡黄色固体目标化合物4_2_1(0.27g,79%)。
1H NMR(400MHz,DMSO-d6):δ1.38(s,9H),1.45(s,9H),1.51-1.61(m,2H),1.72-1.80(m,1H),1.96-2.04(s,1H),2.20(s,3H),2.89-3.05(m,1H),3.33-3.51(m,2H),3.68-3.72(m,1H),3.75-3.83(m,1H),4.44-4.59(m,2H),5.07-5.13(m,1H),6.88(s,1H),7.12(d,J=8.5Hz,2H),7.20-7.30(m,6H),7.42-7.49(m,4H),7.69(d,J=8.5Hz,2H),9.07(s,1H),9.48(br s,2H),11.47(br s,1H).LC-MS:[M+H]+=857.3。
步骤2:(R)-3-(4-((S)-3-(二苯甲氧基)-2-((((Z)-1-(2-((叔丁氧基羰基)氨基)-5-甲基噻唑-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_2_2)
将化合物4_2_1(0.27g,0.35mmol)溶解于无水DMF(3.5mL)中,然后添DCC(97mg,0.47mmol)和HOBt(64mg,0.47mmol)。将所得反应液在室温下搅45分钟,然后添加(S)-3-氨基-2,2-二甲基-4-氧代氮杂环丁烷-1-基硫酸氢酯1_1(99mg,0.47mmol)和NaHCO3(118mg,1.41mmol),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3%-5%MeOH的CH2Cl2洗脱),得到淡黄色固态目标化合物4_2_2(0.30g,91%)。
1H NMR(400MHz,DMSO-d6):δ1.10(s,3H),1.37(s,3H),1.39(s,9H),1.45(s,9H),1.58-1.64(m,1H),1.69-1.81(m,2H),1.98-2.05(s,1H),2.20(s,3H),2.94-3.06(m,1H),3.31-3.33(m,1H),3.73-3.80(s,2H),3.87-3.95(m,1H),4.44-4.49(m,1H),4.58(d,J=7.7Hz,1H),4.60-4.64(m,1H),5.33(t,J=3.3Hz,1H),6.92(s,1H),7.08(d,J=8.8Hz,2H),7.16-7.21(m,3H),7.27-7.36(m,3H),7.38-7.41(m,2H),7.45-7.49(m,2H),7.68(d,J=8.8Hz,2H),9.09(s,1H),9.38(s,1H),9.39(s,1H),9.54(d,J=7.7Hz,1H),11.63(s,1H).LC-MS:[M-H]-=1047.0。
步骤3:((S)-2-((((Z)-1-(2-氨基-5-甲基噻唑-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(实施例2)
将化合物4_2_2(0.30g,0.29mmol)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。将水相经冷冻干燥得到淡黄色粉末状的粗产物(0.21g),将其进一步通过制备液相色谱系统(采用Agilent 10 C18250×21.2mm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2(15mg,8%)。
1H NMR(400MHz,DMSO-d6):δ1.25(s,3H),1.41(s,3H),1.65-1.79(m,2H),1.92-2.03(m,2H),2.25(s,3H),2.93-3.05(m,3H),3.06-3.14(m,1H),3.88-3.96(m,1H),4.09-4.17(m,1H),4.36-4.35(m,1H),4.65(d,J=8.3Hz,1H),4.70-4.75(m,1H),6.86(br s,2H),7.06(d,J=7.7Hz,2H),7.64(d,J=7.7Hz,2H),7.29(br s,3H),10.22(br s,1H).LC-MS:[M-H]-=681.0。
实施例3
(S)-2-((((Z)-1-(2-氨基-5-甲基噻唑-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
步骤1:(Z)-2-((((S)-1-(二苯甲氧基)-3-(4-(N-((S)-1-(叔丁氧羰基)吡咯烷-3-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-甲基噻唑-4-基)乙酸(4_3_1)
将化合物3_6_8(0.20g,0.35mmol)溶于乙醇(3mL)和氯仿(3mL)溶液中,然后加入2-(2-((叔丁氧羰基)氨基)-5-甲基噻唑-4-基)-2-氧代乙酸2_1(0.10g,0.36mmol)。所得混合物在室温下搅拌12小时,之后减压浓缩。浓缩物经硅胶柱层析纯化(含5-15%MeOH的CH2Cl2洗脱),得到淡黄色固体目标化合物4_3_1(0.21g,69%)。
1H NMR(400MHz,DMSO-d6):δ1.40(s,9H),1.45(s,9H),1.97-2.05(m,1H),2.17-2.24(m,4H),3.35-3.44(m,3H),3.59-3.67(m,1H),4.31-4.38(m,1H),4.44-4.56(m,2H),5.08-5.02(m,1H),6.89(s,1H),7.11(d,J=8.8Hz,2H),7.20-7.23(m,3H),7.25-7.30(m,3H),7.41-7.45(m,2H),7.46-7.49(m,2H),7.69(d,J=8.8Hz,2H),9.13(s,1H),9.48(s,1H),9.77(s,1H),11.47(s,1H).LC-MS:[M+H]+=843.3。
步骤2:(S)-3-(4-((S)-3-(二苯甲氧基)-2-((((Z)-1-(2-((叔丁氧基羰基)氨基)-5-甲基噻唑-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)吡咯烷-1-羧酸叔丁酯(4_3_2)
将化合物4_3_1(0.20g,0.24mmol)溶解于无水DMF(2.5mL)中,然后添DCC(76mg,0.37mmol)和HOBt(50mg,0.37mmol)。将所得反应液在室温下搅45分钟,然后添加(S)-3-氨基-2,2-二甲基-4-氧代氮杂环丁烷-1-基硫酸氢酯1_1(78mg,0.37mmol)和NaHCO3(62mg,0.74mmol),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3%-5%MeOH的CH2Cl2洗脱),得到淡黄色固体目标化合物4_3_2(0.20g,81%)。
1H NMR(400MHz,DMSO-d6):δ1.11(s,3H),1.37(s,3H),1.41(s,9H),1.45(s,9H),1.98-2.08(m,1H),2.17-2.25(m,4H),3.35-3.46(m,3H),3.59-3.68(m,1H),4.26-4.34(m,1H),4.44-4.50(m,1H),4.58(d,J=7.9Hz,1H),4.59-4.61(m,1H),5.33(t,J=3.6Hz,1H),6.92(s,1H),7.07(d,J=8.8Hz,2H),7.15-7.21(m,3H),7.26-7.41(m,5H),7.45-7.48(m,2H),7.70(d,J=8.8Hz,2H),9.00(s,1H),9.41(s,1H),9.55(d,J=7.9Hz,1H),9.70(d,J=6.8Hz,1H),11.68(s,1H).LC-MS:[M-H]-=1033.1。
步骤3:(S)-2-((((Z)-1-(2-氨基-5-甲基噻唑-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(实施例3)
将化合物4_3_2(0.20g,0.19mmol)溶于3.5mL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,再将反应液升温至室温搅拌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。将水相经冷冻干燥得到淡黄色粉末状的粗产物(0.21g),将其进一步通过制备液相色谱系统(采用Agilent10C18250×21.2mm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3(25mg,19%)。
1H NMR(400MHz,DMSO-d6):δ1.28(s,3H),1.42(s,3H),2.15(s,3H),2.17-2.29(m,2H),3.37-3.44(m,3H),3.63(d,J=12.2Hz,1H),4.18(d,J=9.5Hz,1H),4.41-4.54(m,2H),4.62(d,J=8.4Hz,1H),4.75(d,J=8.4Hz,1H),6.88(br s,2H),7.10(d,J=8.5Hz,2H),7.76(d,J=8.5Hz,2H),9.40(br s,2H),10.20(d,J=8.4Hz,1H),10.63(br s,2H).LC-MS:[M-H]-=666.9。
实施例4
(S)-2-((((Z)-1-(2-氨基-5-甲基噻唑-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
步骤1:(S,Z)-2-(((1-(二苯甲氧基)-3-(4-(N-(1-(叔丁氧羰基)氮杂环丁烷-3-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-甲基噻唑-4-基)乙酸(4_4_1)
将化合物3_4_8(0.23g,0.40mmol)溶于乙醇(3mL)和氯仿(3mL)溶液中,然后加入2-(2-((叔丁氧羰基)氨基)-5-甲基噻唑-4-基)-2-氧代乙酸2_1(0.12g,0.42mmol)。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(用含有5-15%MeOH的CH2Cl2洗脱),得到淡黄色固态目标化合物4_4_1(0.41g,定量产率)。
1H NMR(400MHz,DMSO-d6):δ1.38(s,9H),1.45(s,9H),2.20(s,3H),3.97-3.04(m,2H),4.10-4.16(m,1H),4.18-4.26(m,2H),4.46-4.61(m,2H),5.12-5.18(m,1H),6.89(s,1H),7.11(d,J=8.0Hz,2H),7.20-7.30(m,6H),7.40-7.49(m,4H),7.75(d,J=8.0Hz,2H),9.13(s,1H),9.51(s,1H),10.13(br s,1H),11.46(s,1H).LC-MS:[M+H]+=829.3。
步骤2:3-(4-((S)-3-(二苯甲氧基)-2-((((Z)-1-(2-((叔丁氧基羰基)氨基)-5-甲基噻唑-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)氮杂环丁烷-1-羧酸叔丁酯(4_4_2)
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将化合物4_4_1(0.41g,上述所得)溶解于无水DMF(3.5mL)中,然后添加DCC(15mg,0.76mmol)和HOBt(0.10g,0.75mmol)。将所得反应液在室温下搅45分钟,然后添加(S)-3-氨基-2,2-二甲基-4-氧代氮杂环丁烷-1-基硫酸氢酯1_1(0.16g,0.75mmol)和NaHCO3(0.13g,1.50mmol),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3%-5%MeOH的CH2Cl2洗脱),得到淡黄色固体目标化合物4_4_2(0.23g,两步总收率56%)。
1H NMR(400MHz,DMSO-d6):δ1.10(s,3H),1.36(s,3H),1.39(s,9H),1.45(s,9H),2.21(s,3H),3.98-4.04(m,2H),4.17-4.25(m,3H),4.45-4.52(m,1H),4.58(d,J=7.8Hz,1H),4.60-4.65(m,1H),5.34(t,J=3.2Hz,1H),6.93(s,1H),7.09(d,J=8.8Hz,2H),7.15-7.21(m,3H),7.28-7.36(m,3H),7.37-7.41(m,2H),7.45-7.49(m,2H),7.76(d,J=8.8Hz,2H),8.92(s,1H),9.46(s,1H),9.55(d,J=7.8Hz,1H),10.05(d,J=5.0Hz,1H),11.70(s,1H).LC-MS:[M-H]-=1047.0。
步骤3:(S)-2-((((Z)-1-(2-氨基-5-甲基噻唑-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(实施例4)
将化合物(0.48g,0.45mmol)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。将水相经冷冻干燥得到淡黄色粉末状的粗产物(0.21g),将其进一步通过制备液相色谱系统(采用Agilent 10C18 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4(34mg,11%)。
1H NMR(400MHz,DMSO-d6):δ1.25(s,3H),1.40(s,3H),2.19(s,3H),4.12-4.18(m,1H),4.19-4.30(m,2H),4.34-4.42(m,2H),4.43-4.49(m,1H),4.60(d,J=8.4Hz,1H),4.63-4.67(m,1H),4.79(d,J=8.0Hz,1H),6.91(br s,2H),7.12(d,J=8.6Hz,2H),7.80(d,J=8.6Hz,2H),10.37(br s,1H).LC-MS:[M-H]-=653.2.
实施例5
(S)-2-((((Z)-1-(2-氨基-5-甲基噻唑-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
步骤1:(Z)-2-((((S)-1-(二苯甲氧基)-3-(4-(N-((S)-1-(叔丁氧羰基)哌啶-3-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-甲基噻唑-4-基)乙酸(4_5_1)
将化合物3_3_8(0.24g,0.40mmol)溶于乙醇(3mL)和氯仿(3mL)溶液中,然后加入2-(2-((叔丁氧羰基)氨基)-5-甲基噻唑-4-基)-2-氧代乙酸2_1(0.12g,0.42mmol)。所得混合物在室温下搅拌12小时,之后减压浓缩。浓缩物经硅胶柱层析纯化(用含有5-15%MeOH的CH2Cl2洗脱),得到淡黄色固体目标化合物4_5_1(0.32g,94%)。
1H NMR(400MHz,DMSO-d6):δ1.39(s,9H),1.45(s,9H),1.52-1.60(m,2H),1.73-1.81(m,1H),1.97-2.04(m,1H),2.21(s,3H),2.91-2.30(m,2H),3.58-3.71(s,1H),3.74-3.82(m,2H),4.47-4.58(m,2H),5.03-5.09(m,1H),6.88(s,1H),7.13(d,J=8.8Hz,2H),7.20-7.24(m,3H),7.25-7.31(m,3H),7.42-7.50(m,4H),7.68(d,J=8.8Hz,2H),9.06(s,1H),9.48(s,2H),11.46(s,1H).LC-MS:[M+Na]+=879.3。
步骤2:(S)-3-(4-((S)-3-(二苯甲氧基)-2-((((Z)-1-(2-((叔丁氧基羰基)氨基)-5-甲基噻唑-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_5_2)
将化合物4_5_1(0.32g,0.38mmol)溶解于无水DMF(3.5mL)中,然后添DCC(11mg,0.57mmol)和HOBt(77mg,0.57mmol)。将所得反应液在室温下搅45分钟,然后添加(S)-3-氨基-2,2-二甲基-4-氧代氮杂环丁烷-1-基硫酸氢酯1_1(120mg,0.57mmol)和NaHCO3(96mg,1.14mmol),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3%-5%MeOH的CH2Cl2洗脱),得到淡黄色固体目标化合物4_5_2(0.20g,51%)。
1H NMR(400MHz,DMSO-d6):δ1.12(s,3H),1.37(s,3H),1.39(s,9H),1.45(s,9H),1.58-1.65(m,2H),1.60-1.79(m,1H),1.94-2.05(m,1H),2.21(s,3H),2.95-2.98(m,1H),3.72-3.81(m,3H),4.45-4.50(m,1H),4.57(d,J=7.7Hz,1H),4.58-4.63(m,1H),5.32(t,J=3.3Hz,1H),6.92(s,1H),7.07(d,J=8.7Hz,2H),7.16-7.21(m,3H),7.27-7.34(m,3H),7.38-7.42(m,4H),7.68(d,J=8.7Hz,2H),9.02(s,1H),9.37(s,1H),9.39(s,1H),9.53(d,J=7.7Hz,1H).LC-MS:[M-H]-=1047.3。
步骤3:(S)-2-((((Z)-1-(2-氨基-5-甲基噻唑-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(实施例5)
将化合物4_5_2(0.20g,0.19mmol)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。将水相经冷冻干燥得到淡黄色粉末状的粗产物(0.21g),经进一步制备液相色谱系统(采用Agilent 10 C18250×21.2mm色谱柱)纯化,目标组分经冷冻干燥即可得到白色固态最终目标化合物实施例5(14mg,10%)。
1H NMR(400MHz,DMSO-d6):δ1.23(s,3H),1.39(s,3H),1.59-1.68(m,1H),1.69-1.76(m,1H),1.77-1.86(m,1H),1.92-1.99(m,1H),2.25(s,3H),2.88-2.94(m,1H),2.96-3.04(m,3H),3.91-3.97(m,1H),3.99-4.10(m,1H),4.34(t,J=8.9Hz,1H),4.62(d,J=8.7Hz,1H),4.71(d,J=7.3Hz,1H),6.64(br s,1H),6.87(br s,2H),7.10(d,J=8.3Hz,2H),7.18(br s,1H),7.73(d,J=8.3Hz,2H).LC-MS:[M-H]-=681.2。
实施例6
(S)-2-((((Z)-1-(2-氨基-5-甲基噻唑-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
步骤1:(Z)-2-((((S)-1-(二苯甲氧基)-3-(4-(N-((R)-1-(叔丁氧羰基)吡咯烷-3-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-甲基噻唑-4-基)乙酸(4_6_1)
将化合物3_5_8(0.23g,0.40mmol)溶于乙醇(3mL)和氯仿(3mL)溶液中,然后加入2-(2-((叔丁氧羰基)氨基)-5-甲基噻唑-4-基)-2-氧代乙酸2_1(0.12g,0.42mmol)。所得混合物在室温下搅拌12小时,之后减压浓缩。浓缩物经硅胶柱层析纯化(用含有5-15%MeOH的CH2Cl2洗脱),得到浅棕色固体目标化合物4_6_1(0.33g,97%)。
1H NMR(400MHz,DMSO-d6):δ1.41(s,9H),1.45(s,9H),1.97-2.05(m,1H),2.17-2.24(m,4H),3.35-3.44(m,3H),3.60-3.66(m,1H),4.10-4.15(m,1H),4.29-4.37(m,1H),4.52-4.61(m,1H),6.91(s,1H),7.12(d,J=8.8Hz,2H),7.21-7.31(m,6H),7.40-7.47(m,4H),7.70(d,J=8.8Hz,2H),9.09(s,1H),9.46(s,1H),9.92(s,1H),11.58(s,1H).LC-MS:[M+H]+=843.3。
步骤2:(R)-3-(4-((S)-3-(二苯甲氧基)-2-((((Z)-1-(2-((叔丁氧基羰基)氨基)-5-甲基噻唑-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)吡咯烷-1-羧酸叔丁酯(4_6_2)
将化合物4_6_1(0.42g,0.40mmol)溶解于无水DMF(3.5mL)中,然后添DCC(0.12g,0.60mmol)和HOBt(0.08g,0.60mmol)。将所得反应液在室温下搅45分钟,然后添加(S)-3-氨基-2,2-二甲基-4-氧代氮杂环丁烷-1-基硫酸氢酯1_1(0.13g,0.60mmol)和NaHCO3(0.10g,1.20mmol),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3%-5%MeOH的CH2Cl2洗脱),得到淡黄色固体目标化合物4_6_2(0.41g,99%)。
1H NMR(400MHz,DMSO-d6):δ1.10(s,3H),1.36(s,3H),1.41(s,9H),1.45(s,9H),1.98-2.06(m,1H),2.18-2.24(m,4H),3.39-3.47(m,3H),3.59-3.67(m,1H),4.27-4.33(m,1H),4.44-4.49(m,1H),4.58(d,J=7.9Hz,1H),4.59-4.63(m,1H),5.33(t,J=3.5Hz,1H),6.92(s,1H),7.07(d,J=8.8Hz,2H),7.15-7.21(m,3H),7.26-7.41(m,5H),7.45-7.48(m,2H),7.70(d,J=8.8Hz,2H),9.01(s,1H),9.42(s,1H),9.55(d,J=7.9Hz,1H),9.70(d,J=6.8Hz,1H),11.68(s,1H).LC-MS:[M-H]-=1033.1。
步骤3:(S)-2-((((Z)-1-(2-氨基-5-甲基噻唑-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(实施例6)
将化合物4_6_2(0.41g,0.40mmol)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。将水相经冷冻干燥得到淡黄色粉末状的粗产物(0.21g)。所得粗产物经进一步制备液相色谱系统(采用Agilent10C18 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6(35mg,13%)。
1H NMR(400MHz,DMSO-d6):δ1.25(s,3H),1.41(s,3H),1.96-2.04(m,1H),2.19(s,3H),2.20-2.25(m,1H),3.25-3.43(m,3H),3.45-3.57(m,1H),4.15-4.21(m,1H),4.35-4.42(m,1H),4.63(d,J=8.6Hz,1H),4.66-4.70(m,1H),5.32(t,J=4.9Hz,1H),6.66(br s,1H),6.87(br s,2H)7.12(d,J=8.6Hz,2H),7.21(br s,2H),7.74(d,J=8.6Hz,2H).LC-MS:[M-H]-=667.1。
实施例7
(S)-2-((((Z)-1-(2-氨基-5-(三氟甲基)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
步骤1:(Z)-2-((((S)-1-(二苯甲氧基)-3-(4-(N-((R)-1-(叔丁氧基羰基)吡咯烷-3-基)甲脒基)苯氧基)-1-氧代丙烷-2-基)氧基)亚氨基)-2-(2-((叔丁氧基羰基)氨基)-5-(三氟甲基)噻唑-4-基)乙酸(4_7_1)
将化合物3_5_8(97mg,0.17mmol)溶于乙醇(3mL)和氯仿(3mL)溶液中,然后加入2-(2-((叔丁氧基羰基)氨基)-5-(三氟甲基)噻唑-4-基)-2-氧代乙酸2_2(60mg,0.17mmol)。所得混合物在室温下搅拌两天,之后减压浓缩。浓缩物经硅胶柱层析纯化(用含有5-15%MeOH的CH2Cl2洗脱),得到淡黄色固体目标化合物4_7_1(30mg,61%)。
1H NMR(400MHz,DMSO-d6):δ1.40(s,9H),1.47(s,9H),1.97-2.05(m,1H),2.17-2.24(m,4H),3.35-3.44(m,3H),3.59-3.66(m,1H),4.28-4.35(m,1H),4.44-4.51(m,1H),4.52-4.57(m,1H),5.08(t,J=4.4Hz,1H),6.84(s,1H),7.11(d,J=8.1Hz,2H),7.21-7.29(m,6H),7.38-7.47(m,4H),7.69(d,J=8.1Hz,2H),9.05(s,1H),9.47(s,1H),9.74(s,1H).19F NMR(376MHz,DMSO-d6)):δ-50.2(s,3F).LC-MS:[M+H]+=897.3。
步骤2:(R)-3-(4-((S)-3-(二苯甲氧基)-2-((((Z)-1-(2-((叔丁氧基羰基)氨基)-5)-(三氟甲基)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)吡咯烷-1-羧酸叔丁酯(4_7_2)
将化合物4_7_1(30mg,0.03mmol)溶解于无水DMF(1mL)中,然后添加DCC(18mg,0.09mmol)和HOBt(12mg,0.09mmol)。将所得反应液在室温下搅拌30分钟,然后添加(S)-3-氨基-2,2-二甲基-4-氧代氮杂环丁烷-1-基硫酸氢酯1_1(18mg,0.09mmol)和NaHCO3(18.5mg,0.22mmol),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3%-5%MeOH的CH2Cl2洗脱),得到淡黄色固体目标化合物4_7_2(0.20g,55%)。
1H NMR(400MHz,DMSO-d6):δ1.10(s,3H),1.36(s,3H),1.41(s,9H),1.47(s,9H),1.98-2.06(m,1H),2.17-2.24(m,1H),3.39-3.47(m,3H),3.59-3.67(m,1H),4.27-4.33(m,1H),4.48-4.53(m,1H),4.60(d,J=7.9Hz,1H),4.62-4.67(m,1H),5.35(t,J=3.5Hz,1H),6.89(s,1H),7.06(d,J=8.6Hz,2H),7.15-7.21(m,3H),7.26-7.46(m,6H),7.70(d,J=8.6Hz,2H),9.00(s,1H),9.42(s,1H),9.70(d,J=7.9Hz,1H),12.48(s,1H).19FNMR(376MHz,DMSO-d6)):δ-51.1(s,3F).LC-MS:[M-H]-=1087.3。
步骤3:(S)-2-((((Z)-1-(2-氨基-5-(三氟甲基)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(实施例7)
将化合物4_7_2(20mg,0.02mmol)溶于4mL无水二氯甲烷中,然后在0℃下加入0.8mL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。将水相经冷冻干燥得到淡黄色粉末状的粗产物(0.21g)。所得粗产物进一步通过制备液相色谱系统(采用Agilent10C18 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7(4mg,30%)。
1H NMR(400MHz,DMSO-d6):δ1.27(s,3H),1.43(s,3H),1.96-2.03(m,2H),3.24-3.35(m,3H),3.49-3.51(m,1H),4.20-4.25(m,1H),4.41-4.47(m,1H),4.65(d,J=8.6Hz,1H),4.78(d,J=8.7Hz,1H),5.23(t,J=5.1Hz,1H),6.71(br s,1H),7.13(d,J=8.4Hz,2H),7.23(br s,1H),7.75(d,J=8.4Hz,2H),7.83(s,1H),7.91(br s,1H).19F NMR(376MHz,DMSO-d6)):δ-49.8(s,3F).LC-MS:[M-H]-=721.1。
实施例8
(S)-2-((((Z)-1-(2-氨基-5-甲基噻唑-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
步骤1:(2S,3S)-3-((Z)-2-((((S)-1-(二苯甲氧基)-3-(4-(N-((R)-1-(叔丁氧基羰基))吡咯烷-3-基)甲脒基)苯氧基)-1-氧代丙烷-2-基)氧基)亚氨基)-2-(2-((叔丁氧基羰基)氨基)-5-甲基噻唑-4-基)乙酰胺)-2-甲基-4-氧代氮杂环丁烷-1-磺酸(4_8_1)
将化合物4_6_1(301mg,0.35mmol)溶解于无水DMF(2.5mL)和DCM(3.5mL)中,然后添加DCC(108mg,0.52mmol)和HOBt(71mg,0.52mmol)。将所得反应液在室温下搅拌45分钟,然后添加(2S,3S)-3-氨基-2-甲基-4-氧代氮杂丁烷-1-磺酸1_2(110mg,0.52mmol)和NaHCO3(89mg,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3%-5%MeOH的CH2Cl2洗脱),得到淡黄色固体目标化合物4_8_1(151mg,43%)。
1H NMR(400MHz,DMSO-d6):δ1.36(d,J=6.5Hz,3H),1.37(s,9H),1.39(s,9H),1.90-2.00(m,1H),2.07-2.17(m,4H),3.39-3.47(m,3H),3.52-3.62(m,1H),4.01-4.07(m,1H),4.20-4.28(m,1H),4.39-4.44(m,1H),4.50(d,J=7.9Hz,1H),4.52-4.56(m,1H),5.29(t,J=3.2Hz,1H),6.85(s,1H),7.00(d,J=8.6Hz,2H),7.09-7.15(m,3H),7.19-7.33(m,5H),7.37-7.42(m,2H),7.63(d,J=8.6Hz,2H),8.93(s,1H),9.34(s,1H),9.57(d,J=7.9Hz,1H),9.62(d,J=6.5Hz,1H),12.06(s,1H).LC-MS:[M-H]-=1003.3。
步骤2:(S)-2-((((Z)-1-(2-氨基-5-甲基噻唑-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(实施例8)
将化合物4_8_1(151mg,0.15mmol)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。将水相经冷冻干燥得到淡黄色粉末状的粗产物(0.21g)。所得粗产物进一步通过制备液相色谱系统(采用Agilent 10C18250×21.2mm色谱柱)纯化,目标组分再经冷冻干燥即可得到白色固态最终目标化合物实施例8(35mg,36%
1H NMR(400MHz,DMSO-d6):δ1.35(d,J=6.4Hz,3H),1.90-2.00(m,1H),2.07-2.17(m,4H),3.39-3.47(m,3H),3.52-3.62(m,1H),4.01-4.08(m,1H),4.20-4.28(m,1H),4.39-4.44(m,1H),4.50(d,J=7.9Hz,1H),4.52-4.56(m,1H),5.29(t,J=3.2Hz,1H),6.66(br s,1H),6.87(br s,2H),7.12(d,J=8.6Hz,2H),7.21(br s,2H),7.74(d,J=8.6Hz,2H).LC-MS:[M-H]-=637.1.
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_1、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片段砌块
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药理学方法
术语缩写
MIC:最低抑菌浓度
CFU:菌落单位
ED100:100%保护剂量
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”(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(CLSI)文档M7-A8,Wayne,Pa.,美国,2009.)】(Approved standard,7th ed.,Clinical and Laboratory Standards InstituteDocument测定。使用微量肉汤稀释法(broth microdilution 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-wellmicrotitre)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后,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),通过MIC即可测定协同抗菌活性。
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.coli 8739)、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
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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 |
小鼠感染模型体内抗菌活性的测定
制剂(Formulations)
本发明化合物在20℃-45℃下,用商用10%甘露醇水溶液经蒸馏水稀释至3%甘露醇水溶液溶解,形成浓度在0.02mg/mL至3mg/mL范围内的澄清施用溶液。
用商用10%甘露醇水溶液用蒸馏水稀释至3%甘露醇水溶液,然后添加固体乙酸钠配置成乙酸钠浓度为2mM-20mM、含有3%甘露醇水溶液。本发明化合物在20℃-45℃下,用乙酸钠浓度为2mM-20mM的含有3%甘露醇水溶液溶解,形成浓度在0.02mg/mL至3mg/mL范围内的澄清施用溶液。
本发明化合物在20℃-25℃下溶解于DMSO中,形成浓度在60mg/mL的澄清储备溶液备用。将此储备溶液在20℃-25℃下用3%甘露醇水溶液稀释,形成浓度在2mg/mL的澄清施用溶液。
本发明化合物在20℃-45℃下,溶解于商用乳酸化林格氏溶液中(Ringer’ssolution)形成浓度在0.02mg/mL至3mg/mL范围内的澄清施用溶液。
本发明化合物在20℃-45℃下,溶解于不含钙和镁的商用Dulbecco磷酸缓冲盐水中(Dulbecco’s Phosphate Buffered Saline),制备成浓度在0.02/mL至3mg/mL范围内的澄清施用溶液。
将D(+)-葡萄糖一水合物溶解在蒸馏水中,形成5%的葡萄糖水溶液。本发明化合物在20℃-45℃下,用此5%的葡萄糖水溶液溶解,配置成浓度在0.02mg/mL至3mg/mL范围内的澄清施用溶液。
将本发明化合物在20℃-45℃下溶解于商用0.9%盐水中,以制备成浓度在0.02mg/mL至3mg/mL范围内的澄清用药溶液。
腹膜炎模型(Peritonitis model)
雌性CD-1小鼠经腹膜内感染5%粘蛋白中的细菌接种物,导致未治疗组(n=10)在实验的前24小时内死亡(每只小鼠约1×104CFU至约5×107CFU,取决于所用菌株的毒力)。使用的菌株包括但不限于野生型大肠杆菌Neumann、野生型铜绿假单胞菌Walther、野生型鲍曼不动杆菌、野生型克雷伯肺炎杆菌。在感染后30分钟、60分钟和120分钟,通过静脉注射本发明的化合物(单独或与β-内酰胺酶抑制剂组合用药)、以及静脉内注射对照抗生素(包括但不限于美罗培南)对小鼠进行治疗。通过5天疗效和致死率观测,测定100%保护剂量(ED100)。
肺部感染模型(Lung infection model)
用异氟醚麻醉雌性BALB/C小鼠,经鼻腔内用32μl的细菌接种物感染(例如,对于铜绿假单胞菌PAO1,每只小鼠约3.5×107CFU)。在感染后30、60和120分钟,通过静脉注射本发明化合物以及对照抗生素(包括但不限于美罗培南)对小鼠进行治疗。24小时后处死动物,包括未经用药治疗的对照组。将肺部无菌取出,匀浆,连续稀释并接种在山羊血琼脂平板上,以确定CFU计数。
尿道感染模型(Urinary tract infection model)
雌性CD-1小鼠从实验前16小时到实验结束,以5%葡萄糖溶液作为唯一的饮用水来源。麻醉的小鼠用含有致病性大肠杆菌菌株的液体25μl体积(0.25%琼脂的0.9%NaCl的菌液)通过尿道感染(每只小鼠约5×106CFU)。在感染后1小时、5小时、23小时和30小时,通过静脉注射本发明的化合物以及对照抗生素(包括但不限于美罗培南)对小鼠进行治疗。在感染后48小时处死小鼠(包括未用药治疗的对照组小鼠)。在无菌条件下将膀胱取出、匀浆、连续稀释并涂在Mueller Hinton琼脂平板上以确定CFU计数。
Claims (10)
1.一种化合物或其盐或氘代化合物,所述化合物选自:
2.根据权利要求1所述的化合物,其中所述化合物为:
或其盐或氘代化合物。
3.根据权利要求1或2所述的化合物在制备用于治疗和/或预防细菌感染的药物中的用途。
4.根据权利要求3所述的用途,其中所述细菌感染是革兰氏阴性菌感染。
5.根据权利要求1或2所述的至少一种一所述的化合物药物与至少一种其它活性化合物组合形成的一种药物。
6.根据权利要求5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。
7.根据权利要求6所述的药物,其中β-内酰胺酶抑制剂选自克拉维酸、他唑巴坦、舒巴坦、阿维巴坦、雷巴坦或瓦博巴坦。
8.根据权利要求1或2所述的至少一种一所述的化合物与至少一种惰性无毒的在药学上可接受的赋形剂组合形成的一种药物。
9.根据权利要求5至8中任一项所述的药物在制备用于治疗和/或预防细菌感染的药物中的用途。
10.有效抗菌剂量的根据权利要求1或2所述的至少一种所述的化合物或根据5至8中任一项所述的至少一种所述药物在制备用于治疗和/或预防细菌感染的人和动物的药物中的用途。
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CN112094247A (zh) * | 2020-08-21 | 2020-12-18 | 宁夏农林科学院农业资源与环境研究所(宁夏土壤与植物营养重点实验室) | 头孢菌素类药物中间体及其合成方法 |
CN112079791A (zh) * | 2020-08-21 | 2020-12-15 | 宁夏农林科学院农业资源与环境研究所(宁夏土壤与植物营养重点实验室) | 单环β-内酰胺类抗生素侧链酸及其酯、其制备方法和应用 |
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- 2020-08-06 CN CN202080081727.0A patent/CN114728953B/zh active Active
- 2020-08-06 EP EP20948108.4A patent/EP4007759A4/en active Pending
- 2020-08-06 US US17/777,272 patent/US20230150996A1/en active Pending
- 2020-08-06 WO PCT/CN2020/107417 patent/WO2022027439A1/en unknown
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WO2019020810A1 (en) * | 2017-07-28 | 2019-01-31 | Aicuris Anti-Infective Cures Gmbh | CRYSTALLINE FORM OF (2S) -2 - [[(Z) - [- 1- (2-AMINO-4-THIAZOLYL) -2 - [[(3S) -2,2-DIMETHYL-4-OXO] -Acid 1- (SULFOOXY) -3-AZETIDINYL] AMINO] -2-OXOETHYLIDENE] AMINO] OXY] -3- [4- [IMINO [(3R) -3-PIPERIDINYLAMINO] METHYL] PHENOXY] -PROPANOIC |
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EP4007759A4 (en) | 2024-04-10 |
EP4007759A1 (en) | 2022-06-08 |
WO2022027439A1 (en) | 2022-02-10 |
US20230150996A1 (en) | 2023-05-18 |
CN114728953A (zh) | 2022-07-08 |
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