CN103619836A - 抗菌剂/抗菌佐剂化合物及其方法 - Google Patents
抗菌剂/抗菌佐剂化合物及其方法 Download PDFInfo
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- CN103619836A CN103619836A CN201280021139.3A CN201280021139A CN103619836A CN 103619836 A CN103619836 A CN 103619836A CN 201280021139 A CN201280021139 A CN 201280021139A CN 103619836 A CN103619836 A CN 103619836A
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- phenyl
- methyl
- thiophene
- propyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 157
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 239000000463 material Substances 0.000 claims description 37
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- 238000011282 treatment Methods 0.000 claims description 30
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Abstract
除了别的以外,一般来说,抗微生物化合物和/或佐剂化合物通过公式Ia,及其前体药物和其中医药上可接受的盐来提供,(Ia)中E和R1-11有在文中所述的含义。其他公式和使用方法也被提供。
Description
相关申请的相互参照
本发明要求2011年3月提交的U.S.临时申请序列号61/448,682的权益,在此它的内容被整体引用作为参考。
背景技术
感染是一种外来生物对宿主生物体的入侵,通常会对宿主生物体的正常功能产生不利。在治疗人类和其他动物的感染和感染性炎症疾病(如感染性休克)时,医生往往采用有抗菌作用的化学物质,无论是抗病毒、抗细菌、抗真菌或这类的物质。
不幸的是,许多病原体已经能抵抗当前抗生素的治疗。因此抗生素抗性日益成为重要的临床问题,要求效果更好的抗生素。特别有价值的是新的抗菌佐剂化合物,而不一定是抗菌剂本身,这能提高抗菌效力,有效性和/或者抗菌剂的活动范围当它们联合起来或者作为组合疗法时。因此对新的抗菌剂和抗菌佐剂化合物有需求。
发明概述
本发明的化合物作用于抗菌感染方面。在某些情况下,所述化合物它们本身是抗菌剂。在某些情况下,所述化合物(“抗菌佐剂”)与抗菌剂结合,当合理组合时,会有积极的作用,可以减少抗菌活性所需的抗生素剂量。在某些情况下,这些物质既是抗菌剂又是抗菌佐剂。
一般情况下,在一个方面,通式Ia所示化合物被提供:
其中E是-CH2-、或者当噻吩直接连到苯环上时它不存在;R1,R2,R9,R10和R11各自独立地为氢、甲基、乙基、丙基、环丙基、丁基、环丁基、戊基、己基、异丙基、异丁基、新戊基、甲氧基或乙氧基;此外,R1和R2可以连接形成一个苯环或者苯并呋喃环;此外,R9和R10可以连接形成一个苯环或者苯并呋喃环;R3和R8各自独立地为氢、甲基、乙基、丙基、异丙基、氯、氟、叔丁基、甲磺酰基、甲氧基或乙氧基;R4和R7各自独立地为氢、氯、甲酯、乙酯、甲基、乙基、丙基、环丙基、丁基、环丁基、异丙基、异丁基、甲氧基或乙氧基;R5和R6各自独立地为氢、环戊基、环丙基、呋喃、噻吩、三氟甲基、三氟甲基醚、甲巯基、甲醛、氯、氟、溴、苯基、甲基、乙基、异丙基、丙基、丁基、环丁基、异丁基、新戊基、戊基、甲氧基或乙氧基。
一般来说,在本发明的一个方面,提供了一种微生物感染的治疗方法,所述方法包括将有效量的本发明所述的抗菌剂化合物施药给需要它的病人。
一般来说,在本发明的另一个方面,提供了一种微生物感染的治疗方法,所述方法包括将一种有效量的本发明所述抗菌佐剂化合物和一种有效量的抗菌化合物施药给需要它的病人。
其它通式的化合物也都在下面提供了详细描述。
附图说明
图1描述了以噻吩或噻唑为核心的化合物和本发明的相关化合物代码,以及它们各自对MRSA的最低抑制浓度,具体操作程序在实施例9。
(“MRSA_MIC”以μΜ计算)
图2描述了以苯基为核心的化合物和本发明的相关化合物代码。
具体实施方式
定义
除非另有定义,本发明中所用的术语参考以下定义,详述如下。
术语“酰基”在这里指一个文中所定义的烷基通过一个文中所定义的羰基连接到母分子基团上。
酰基的典型实例包括但不局限于:乙酰基,1-氧代丙基,2,2-二甲基-1-氧代丙基,1-氧代丁基和1-氧代戊基。
术语“酰氧基”在这里指一个文中所定义的酰基官能团通过一个氧原子连接到母分子基团上,酰氧基的典型实例包括但不局限于:乙酰氧基,丙酰氧基和异丁酰氧基。
术语“给药”或“给予”化合物应该理解为将本发明的化合物在一个合理的量情况下以一种可以引入个体身体内的方式应用于个体,这种合理的量可以有效地用来预防、治疗或诊断。这些形式可能包括比如口服剂型,注射剂型,透皮吸收制剂,吸入剂型和直肠剂型。
术语“烯基”在这里指一种包含2到20(如2到10、或2到6)个碳原子的直链、支化的和/或者环状烃基,并且包括至少一个碳-碳双键。代表性的烯基官能团包括乙烯基、烯丙基、1-丁烯基、2-丁烯基、异丁烯基、1-戊烯基、2-戊烯基、3-甲基-1-丁烯基、2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基、1-已烯基、2-已烯基、3-已烯基、1-庚烯基、2-庚烯基、3-庚烯基、1-辛烯基、2-辛烯基、3-辛烯基、1-壬烯基、2-壬烯基、3-壬烯基、1-癸烯基、2-癸烯基和3-癸烯基。
术语“烷氧基”在这里指一个文中所定义的烷基通过一个氧原子连接到母体分子基团上,烷氧基的典型实例包括但不局限于:甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基和已氧基。
术语“烷氧基烷氧基”在这里指一个文中定义的烷氧基通过另一个文中定义的烷氧基连接到母体分子基团上,烷氧基烷氧基的典型实例包括但不局限于:叔丁氧基甲氧基、2-乙氧基乙氧基、2-甲氧基乙氧基和甲氧基甲氧基。
术语“烷氧基烷基”在这里指一个文中所定义的烷氧基通过一个文中所定义的烷基连接到母体分子基团上,烷氧基烷基的典型实例包括但不局限于:叔丁氧基甲基、2-乙氧基乙基、2-甲氧基乙基和甲氧基甲基。
术语“烷氧羰基”在这里指一个文中所定义的烷氧基通过一个文中所定义的羰基连接到母体分子基团上,烷氧羰基的典型实例包括但不局限于:甲氧羰基、乙氧羰基和叔丁氧羰基。
术语“烷氧亚胺基”在这里指一个文中所定义的烷氧基通过一个文中所定义的亚胺基连接到母体分子基团上,烷氧亚胺基的典型实例包括但不局限于:乙氧(亚胺)甲基和甲氧(亚胺)甲基。
术语“烷氧磺酰基”在这里指一个文中所定义的烷氧基通过一个文中所定义的磺酰基连接到母体分子基团上,烷氧磺酰基的典型实例包括但不局限于:甲氧磺酰基,乙氧磺酰基和丙氧磺酰基。
术语“烷基”在这里指一种直链或支化的链烃,包含1到20个碳原子,优选为1到10个碳原子,更优选为1,2,3,4,5或6个碳原子。烷基的典型实例包括但不局限于:甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正已基、3-甲基已基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基和正癸基。
术语“烷基氨基”在这里指一个文中所定义的烷基通过一个NH基团连接到母体分子基团上,烷基氨基的典型实例包括但不局限于:甲基氨基、乙基氨基、异丙基氨基和丁基氨基。
术语“烷基羰基”在这里指一个文中所定义的烷基通过一个文中所定义的羰基官能团连接到母体分子基团上,烷基羰基的典型实例包括但不局限于:甲基羰基,乙基羰基,异丙基羰基,正丙基羰基和类似的。
术语“烷基磺酰基”在这里指一个文中所定义的烷基通过一个文中所定义的磺酰基连接到母体分子基团上,烷基磺酰基的典型实例包括但不局限于:甲基磺酰基和乙基磺酰基。
术语“炔基”在这里指一种包含2到10个碳原子,并且优选为包含2,3,4或5个碳原子的直链,或支化的链烃基团,并且包括至少一个碳-碳三键。炔基的典型实例包括但不局限于:乙炔基、1-丙炔基、2-丙炔基、3-丁炔基,2-戊炔基和1-丁炔基。
术语“酰氨基”在这里指一个氨基、烷基氨基或者二烷基氨基通过一个文中所定义的羰基连接到母体分子基团上,酰氨基的典型实例包括但不局限于:氨甲酰基、甲氨基甲酰基、二甲氨基甲酰基和甲基乙基氨甲酰基。
术语“氨基”在这里指—NH2基团。
术语“芳基”在这里指一种单环烃芳环结构,芳基的典型实例包括但不局限于苯基。
术语“芳香基烷基”在这里指一个文中所定义的芳香基团通过一个文中所定义的烷基连接到母体分子基团上,芳香基烷基的典型实例包括但不局限于:苄基、2-苯基乙基和3-苯基丙基。
术语“羰基”在这里指—C(=O)—基团。
术语“羧基”在这里指—COOH基团;它能被保护,作为酯基:—COO—烷基。
术语“氰基”在这里指—CN基团。
术语“腈苯基”在这里指一个—CN基团通过苯基连接到母体分子基团上,包括但不局限于:4-氰基苯基、3-氰基苯基和2-氰基苯基。
术语“环烷基”在这里指包含有3到8个碳原子的饱和环状烃基。环烷基的实例包括环丙基、环丁基、环戊基、环已基、环庚基和环辛基。
术语“环烷基羰基”在这里指一个文中所定义的环烷基通过一个文中所定义的羰基官能团连接到母体分子基团上,环烷基羰基的典型实例包括但不局限于:环丙基羰基、环戊基羰基、环已基羰基和环庚基羰基。
术语“二烷基氨基”在这里指两个独立的文中所定义的烷基基团通过一个氮原子连接到母体分子基团上,二烷基氨基的典型实例包括但不局限于:二甲基氨基、二乙基氨基、甲基乙基氨基和甲基丁基氨基。
术语“氟”在这里指—F。
术语“氟代烷氧基”在这里指至少一个文中所定义的氟代烷基通过一个文中所定义的氧原子连接到母体分子基团上,氟代烷氧基的典型实例包括但不局限于:三氟甲氧基(CF3O-)和二氟甲氧基(CHF2O-)。
术语“氟代烷基”在这里指至少一个文中所定义的氟原子通过一个文中所定义的烷基连接到母体分子基团上,氟代烷基的典型实例包括但不局限于:氟代甲基、二氟代甲基、三氟代甲基、五氟代乙基和2,2,2-三氟乙基。
术语“醛基”在这里指—C(O)H基团。
术语“卤”或“卤素”在这里指Cl、Br、I、或F。
术语“卤代烷氧基”在这里指至少一个文中所定义的卤素通过一个文中所定义的烷氧基连接到母体分子基团上,卤代烷氧基的典型实例包括但不局限于:2-氟代乙氧基、三氟代甲氧基和五氟代乙氧基。
术语“卤代烷基”在这里指至少一个文中所定义的卤素通过一个烷基连接到母体分子基团上,卤代烷基的典型实例包括但不局限于:氯甲基、2-氟乙基、三氟甲基、五氟乙基和2-氯-3-氟戊基。
术语“杂芳基”在这里指含有一个或多个独立地选自氮、氧、或硫的杂原子的芳环或它们的互变异构体,如进一步地所描述,这些环可以是单环也可以是双环。杂芳基环通过一个碳原子或氮原子连接到母体分子基团上。
术语“单环杂芳基”或“5或6元杂环芳基”在这里指含有1、2、3、或4个独立选自氮、氧或硫原子的5或6元芳环或者它们的互变异构体,这些环的例子包括但不局限于:其中一个碳原子被氧或原子取代的环;一个,二个或三个氮原子通过合理的排列方式提供芳环;或者其中二个碳原子被一个氧或硫和一个氮原子取代的环。这些环的包括但不局限于,其中一到四个环碳原子被氮取代的6元芳环;环中包含有一个硫、氧或氮原子的五元芳环;包括一到四个氮原子的五元环;以及包含有一个氧原子或硫原子和一到三个氮原子的五元环。5或6元杂环芳基的典型实施例包括但不局限于:呋喃基、咪唑基、异恶唑基、异噻唑基、恶唑基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、四唑基、[1,2,3]噻二唑基、[1,2,3]恶二唑基、噻唑基、噻吩基、[1,2,3]三嗪基、[1,2,4]三嗪基、[1,3,5]三嗪基、[1,2,3]三唑基和[1,2,4]三唑基。
术语“二环杂芳基”或“8到12元二环杂芳基”在这里指至少包括3个双键并且环中有一个或多个独立选自氧、硫和氮杂原子的8,9,10,11或12元二环芳基。二环杂芳基的典型实例包括:吲哚基、苯并噻吩基、苯并呋喃基、吲唑基、苯并咪唑基、苯并噻唑基、苯并恶唑基、苯并异噻唑基、苯并异恶唑基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、酞嗪基、蝶啶基、嘌呤基、萘啶基、噌啉基、噻吩[2,3-d]咪唑基、噻吩[3,2-b]吡啶基和吡咯并嘧啶基。
术语“杂状环”和“杂环”在这里指4到12元的单环或双环,它们包含一个、两个、三个、四个或五个独立选自氮、氧和硫的杂原子,并且也包含至少一个连在其它四个原子上的碳原子、或含有一个桥氧基取代和连有两个其它原子的碳原子。4和5元环可能有零或一个双键。6元环可能有零、一个或两个双键。7和8元环可能有零、一个、两个或三个双键。本发明中的非芳香性杂环能通过一个碳原子或一个氮原子连接。非芳香性杂环可以出现在互变异构体的形式中。含氮的芳香杂环的典型实例包括但不局限于:氮杂环庚基、氮杂啶基、吖丙啶基、氮杂环辛基、二氢哒嗪基、二氢吡啶基、二氢嘧啶基、吗啉基、哌嗪基、哌啶基、吡咯烷基、吡咯啉基、二氢噻唑基、二氢吡啶基和硫代吗啉基。不含氮的非芳香杂环的典型实例包括但不局限于:二氧六环基、二噻烷基、四氢呋喃基、二氢吡喃基、四氢吡喃基和[1,3]二氧六环基。
术语“羟基”在这里指—OH基团。
术语“羟烷基”在这里指至少一个文中所定义的羟基通过一个文中所定义烷基连接到母体分子基团上,羟烷基的典型实例包括但不局限于:羟甲基、2-羟乙基、2-甲基-2羟乙基、3-羟丙基、2,3-二羟戊基和2-乙基-4-羟庚基。
术语“羟基保护基团”指一个取代基,用来保护羟基可以避免合成过程中不需要的反应,羟基保护基团的具体例子包括但不局限于:甲氧甲基、苄氧甲基、2-甲氧乙氧甲基、2-(三甲基硅烷基)乙氧甲基、苄基、三苯基甲基、2,2,2-三氯乙基、叔丁基、三甲基硅烷基、叔丁基二甲基硅烷基、叔丁基二苯基硅烷基、亚甲基缩醛、缩丙酮苯亚甲基乙缩醛、环原酸酯、甲氧亚甲基、环状碳酸酯和环状硼酸酯。羟基保护基团在碱的条件下,如三乙胺,和含有羟基的物质通过反应连接到羟基上,反应物选自卤代烷、三氟甲磺酸烷基酯、卤代三烷基硅烷基、三烷基硅烷三氟甲烷磺酸酯、芳基二烷基硅烷三氟甲烷磺酸酯或者烷基氯甲酸酯、CH2I2、或二卤代硼酸酯,比如碘甲烷、苄基碘、三乙基硅烷三氟甲烷磺酸酯、乙酰氯、苄基氯或碳酸二甲酯。保护基团也可以和含有羟基的酸和烷基乙缩醛通过反应连接到羟基上。
术语“亚氨基”在这里指—C(=NH)—基团。
术语“巯基”在这里指—SH基团。
术语“硝基”在这里指—NO2基团。
术语“氮原子保护基团”在这里指那些在合成过程中可以保护氮原子避免发生不希望的反应的基团。氮原子保护基团包括氨甲酸酯类、酰胺、N-苄基衍生物和亚胺衍生物。优选的氮原子保护基团是乙酰基、苯甲酰基、苄基、苯氧羰基(Cbz)、甲酰基、苯磺酰基、新戊酰基、叔丁氧羰基(Boc)、叔丁基乙酰基、三氟乙酰基和三苯甲基。氮原子保护基团在碱——如三乙基胺——存在的条件下,和含有氨基的物质通过反应连接到一级或二级胺基团上,并且试剂选自卤代烷,三氟甲磺酸烷基酯,比如以(烷基-O)2C=O、二烷基酸酐为代表的二烷基酸酐,比如(芳基-O)2C=O为代表的二芳基酸酐,卤代酰基,烷基氯甲酸酯或烷基磺酰卤,芳基磺酰卤,或卤代-CON(烷基)2,比如乙酰氯、苯甲酰氯,溴化苄、氯甲酸苄酯、氟化甲酰、苯磺酰氯、新戊酰氯、(叔丁基-O-C=O)2O、三氟乙酸酐和三苯基氯甲烷。
术语“氧代”在这里指(=O)。
除非另有说明,术语“药物前体”包含医药上可接受的酯、碳酸盐、硫代碳酸盐、N-酰基衍生物、N-酰氧基烷基衍生物、叔胺的四价衍生物、N-曼尼烯碱、希夫碱、氨基酸复合物、磷酸酯、金属盐和磺酸。药物前体的例子包括含有生物可水解基团(如生物可水解的氨基化合物、生物可水解的氨基甲酸酯、生物可水解的碳酸盐、生物可水解的酯、生物可水解的磷酸盐或生物可水解的酰脲类似物)的物质。药物前体类物质可通过本领域的常规技术来设计和生产,比如参见”Design and Application of Prodrugs”,Bundgaard,A.Ed.,Elseview,1985;Bundgaard,hours.,”Design and Application of Prodrugs,”A Textbook of DrugDesign and Development,Krosgaard-Larsen and hours.Bundgaard,Ed.,1991,Chapter 5,p.113-191;和Bundgaard,hours.,Advanced Drug Delivery Review,1992,8,1-38。
除非另有说明,术语“保护基团”和“保护性基团”,用在这里指分子的一部分在参与化学反应时,在这种反应条件下不反应的化学部分,并且能够去除以提供在其它反应条件时可以反应的部分。保护基团是本领域所熟知的,比如参见:Greene,T.W.and Wuts,P.G.M.,Protective Groups in Organic Synthesis(3rded.,John Wiley&Sons:1999);Larock,R.C,Comprehensive OrganicTransformations(2nd ed.,John Wiley&Sons:1999)。一些实例包括苄基、二苯甲基、三苯甲基、Cbz、Boc、Fmoc、甲氧羰基、乙氧羰基和邻苯二甲酰亚胺。例如保护基团包括氮原子保护基团和羟基保护基团。
术语“磺酰基”在这里指—S(O)2—基团。
术语“硫代烷氧基”在这里指一个文中所定义的烷基通过一个硫原子连接到母体分子基团上,硫代烷氧基的典型实例包括但不局限于:甲硫基、乙硫基和丙硫基。
本发明的某些物质可能存在立体异构体,其中不对称或手性中心是存在的。这些立体异构体是“R”型或“S”型取决于手性碳原子上取代基的构象。术语“R”型或“S”型在这里是指IUPAC 1974 Recommendations for Section E,Fundamental Stereochemistry,in Pure Appl.Chem.,1976,45:13-30所定义的。本发明包括各种立体异构体和它们的混合物,并且这些都是明确包含在本发明的范围之内的。立体异构体包括对映异构体和非对映异构体,以及对映异构体或非对映异构体的混合物。本发明中的部分立体异构体可以通过含有不对称或手性中心的商业可用原料合成制备,也可以通过本领域技术人员从外消旋混合物分离制备得到。这些分离方法可以被举例证明,通过(1)将对映异构体混合物和手性助剂粘结在一起,然后用重结晶或色谱分析法分离剩余的非对映异构体混合物并且从助剂中选择性释放可选的光学纯物质,就像文献Furniss,Hannaford,Smith,and Tatchell,″Vogel′s Textbook of Practical Organic Chemistry″,5thedition(1989),Longman Scientific&Technical,Essex CM202JE,England中所描述的,这里引用文献作为非对映异构体分离和纯化的方法,或者(2)直接在手性色谱柱上分离对映异构体混合物,或者(3)分步重结晶方法。
本发明中的某些物质可能存在顺式或反式异构体,其中一个环上的取代基可能以一种相对于彼此都位于环的同一边(顺式)的方式连接,或者相对于彼此位于环的两侧(反式)的方式。本领域技术人员所熟知的方法可能包括通过重结晶或色谱分析法分离。应该理解,本发明中的物质可能具有互变异构的形式,也可能具有几何异构体的形式,并且这些也都在本发明的范围之内。
应该注意的是形成一个更大的化合物的一部分的化学部分可以是根据它以单分子形式存在时命名的,也可能是根据它的自由基来命名。比如,术语“吡啶”和“吡啶基”当用来指一个基团连接到其它官能团上时,是一个意思。因此,比如,这两个描述“XOH,其中X是吡啶基”和“XOH,其中X是吡啶”是同一个意思,并且包括吡啶-2-醇,吡啶-3-醇和吡啶-4醇这些物质。
同样应该注意的是,含有一个或多个手性中心、并且这些手性中心的立体化学结构不确定的化合物的名称,包括纯立体异构体和它们的混合物。而且,结构图中任何原子上未连接的空位都被假定为连有足够的氢原子来填充空位。此外,如果化学价允许的话,用一个实线和一个虚线描述的化学键都包含单键和双键(比如芳环)。
术语“医药学上可接受的赋形剂”在这里指无毒的惰性固体、半固体或液体的填充剂、稀释剂、灌封材料或任何形式的配方辅剂。可以作为医药上可接受的载体的材料的例子有:糖,比如乳糖,葡萄糖和蔗糖;淀粉,比如玉米淀粉和马铃薯淀粉;纤维素和它的衍生物,比如羧甲基纤维素钠,乙基纤维素和醋酸纤维素;粉末状黄芪胶;麦芽;凝胶;滑石粉;可可油和栓剂蜡;油,比如花生油,棉花籽油,红花籽油,芝麻油,橄榄油,玉米油和豆油;甘油醇,比如丙二醇;酯,比如油酸乙酯,月桂酸乙酯,琼脂;缓冲剂,比如氢氧化镁和氢氧化铝;藻酸;不含热量的水;生理盐水;林格氏溶液;乙醇和磷酸盐缓冲液,以及其它无毒兼容的润滑剂,比如十二烷基硫酸钠和硬酯酸镁;以及着色剂,释放剂,涂层剂,脱硫,调味和香化剂,根据配方领域熟练技术人员的判断,防腐剂和抗氧化剂也可以出现在组成成分中。
除非特别说明,否则一个化合物的“治疗有效量”指的是一种数量,它足以治疗一种疾病或症状,或者一种或多种与疾病和症状相关的病症。在一些实施例中,“治疗”是通过与未经处理的对比例比较后得出的。
术语“研究对象”旨在包括可能发生的疾病的活的有机体。研究对象的实施例包括人类,猴子,牛,绵羊,山羊,狗,猫,小鼠,大鼠和它们的转基因物种。
至少在某种程度上,本发明是基于设计用来抑制酰基来源蛋白质(ACP)合成酶(AcpS)的物质,这种酶主要是用来将apo-ACP转化为holo-ACP。AcpS不仅存在于革兰氏阳性和阴性细菌中,而且也存在于耐酸性细菌比如结核杆菌,以及原生动物比如恶性疟原虫体内。因此AcpS抑制剂会在许多微生物的生存能力方面产生不良影响,AcpS抑制剂会在微生物细胞功能的维护方面产生有害的影响,比如,包括增加细胞膜的孔隙和造成这种膜上外排泵的功能紊乱。本发明中化合物的活性示范范围包括含有耐甲氧西林金黄色葡萄球菌的革兰氏阳性菌,通过选择对革兰氏阴性杆菌比如铜绿假单胞菌,鲍曼不动杆菌和嗜麦芽窄食单孢菌等等有抵抗保留活性的化合物。本发明中,比如对于铜绿假单胞菌,具有较低或无抗菌效能的物质,当和抗菌化合物——比如说阿奇霉素,红霉素或氨苄青霉素——一起使用,或者和本发明中所述的抗菌化合物一起使用时,它们可能具有抗菌佐剂(“佐剂”或“前抗生素”)的效果。虽然本发明中所述化合物的效用并不取决于它们成为AcpS抑制剂,但是至少在某种程度上,实现这一目的的设计效果取决于本发明中这些化合物的发现。
按照实施例,提供一种化合物,或药物前体或其医药上可接受的盐,根据其中一个通式I给出,或具有通式I所示的一种结构:
其中,
E是-CH2-、或者当噻吩直接连到苯环上时它不存在;
R1,R2,R9,R10和R11如果存在,则各独立选自氢、甲基、乙基、丙基、环丙基、丁基、环丁基、戊基、己基、异丙基、异丁基、新戊基、甲氧基和乙氧基组成的组;
此外,R1和R2可以连接形成一个苯基或者苯并呋喃环;
此外,R9和R10可以连接形成一个苯基或者苯并呋喃环;
R3和R8各自独立选自氢、甲基、乙基、丙基、异丙基、氯、氟、叔丁基、甲磺酰基、甲氧基和乙氧基组成的组;
R4和R7各自独立选自氢、氯、甲酯、乙酯、甲基、乙基、丙基、环丙基、丁基、环丁基、异丙基、异丁基、甲氧基和乙氧基组成的组;
R5和R6各自独立选自氢、环戊基、环丙基、呋喃、噻吩、三氟甲基、三氟甲基醚、甲巯基、甲醛、氯、氟、溴、苯基、甲基、乙基、异丙基、丙基、丁基、环丁基、异丁基、新戊基、戊基、甲氧基和乙氧基组成的组。
在一些实施例中,R1和R2各自独立选自这氢和甲基组成的组,或者当所在的环为萘环时形成苯环;R9和R10各自独立选自氢和甲基组成的组,或者当所在的环为萘环时形成苯环;R11为氢;R3和R8各自独立选自氢、甲基、氯、氟、异丙基、叔丁基、甲氧基和甲磺酰基组成的组;R4和R7各自独立选自氢、甲基、氯和乙酯组成的组;R5和R6各自独立选自甲基、乙基、苯基、氢、氯、异丙基、环戊基、溴、环丙基、三氟甲基、三氟甲基醚、甲巯基、甲醛、呋喃和噻吩组成的组。在一些实施例中,E是不存在的。在一些实施例中,R1、R2、R4、R7、R9和R10都是氢。在一些实施例中,R3和R8都是氯;R5和R6选自氢、甲基和异丙基组成的组。在一个优选的实施例中,所述化合物是DNM0488。在一个优选的实施例中,所述化合物是DNM0548。在一个优选的实施例中,所述化合物是DNM0606。在一个优选的实施例中,所述化合物是DNM0631。(这些化合物的结构式已在图1中列出)在一个优选的实施例中,所述化合物选自于包括图1列出的各种物质。
按照实施例,提供一种化合物,或药物前体或医药上可接受的盐,其中一个通式Ⅱ结构如下:
其中,
R1,R2,R3,R5和R12各自独立选自氢、甲基、乙基、丙基、环丙基、丁基、环丁基、戊基、己基、异丙基、异丁基、新戊基、甲氧基和乙氧基组成的组;
R4和R13各自独立选自氢、甲基、乙基、丙基、环丙基、丁基、环丁基、戊基、己基、异丙基、异丁基、新戊基、甲氧基、乙氧基和二烷基胺组成的组;
此外,R4和R5可以形成一个苯环;
此外,R12和R13可以形成一个苯环;
R6和R11各自独立选自氢、氯、氟、羟基、苯基醚、甲基、乙基、丙基、异丙基、叔丁基、甲氧基和乙氧基组成的组;
R7和R10各自独立选自氢、氯、甲基、乙基、丙基、异丙基、叔丁基、甲氧基和乙氧基组成的组;
R8和R9各自独立选自氢、卤素、甲基、乙基、丙基、异丙基、叔丁基、甲氧基、乙氧基、任意位置可选地被甲基取代的萘基以及任意位置可选地被氯、溴、羧酸和烷基取代的苯基组成的组。
在一些实施例中,R6和R11各自独立选自氢、氯、氟、羟基、苯基醚和烷基组成的组;R7和R10各自独立选自氢、氯和烷基组成的组;R8和R9各自独立选自氢、卤素、甲基、异丙基、任意位置可选地被甲基取代的萘基和任意位置可选地被氯、溴、羧酸和烷基取代的苯基组成的组。在一些实施例中,所述化合物如通式Ila所示。在一些实施例中,所述化合物如通式Ilb所示。在一个优选的实施例中,所述化合物选自于包括图2列出的各种物质组成的组。
在一个本发明优选的实施例中,所述化合物选自于以下物质,包括5-(4,5-二(4-氯-2-甲苯基)噻吩-2-基)-1H-四唑(DNM0488),5-(4,5-二(4-甲基萘-1-基)噻吩-2-基)-1H-四唑(DNM0486),5-(4,5-二(4-氯苯基)噻吩-2-基)-1H-四唑(DNM0487),5-(4,5-二(联二苯基-2-基)噻吩-2-基)-1H-四唑(DNM0489),5-(4,5-二(3-氯-4-甲苯基)噻吩-2-基)-1H-四唑(DNM0504),5-(4,5-二(5-氯-2-甲苯基)噻吩-2-基)-1H-四唑(DNM0508),5-(4,5-二(3,4-二甲基苯基)噻吩-2-基)-1H-四唑(DNM0509),5-(4,5-二(4-异丙基苯基)噻吩-2-基)-1H-四唑(DNM0512),5-(4,5-二(2-甲基苯基)噻吩-2-基)-1H-四唑(DNM0531),5-(4,5-二(2-异丙基苯基)噻吩-2-基)-1H-四唑(DNM0534),5-(4,5-二(2-苯氧基苯基)噻吩-2-基)-1H-四唑(DNM0536),5-(4,5-二(4-氟萘基-1-基)噻吩-2-基)-1H-四唑(DNM0537),5-(4,5-二(2-氯苯基)噻吩-2-基)-1H-四唑(DNM0538),5-(4,5-二(2-乙基苯基)噻吩-2-基)-1H-四唑(DNM0541),5-(4,5-二(二苯并[b,d]呋喃-4-基)噻吩-2-基)-1H-四唑(DNM0542),5-(4,5-二(苯并呋喃-2-基)噻吩-2-基)-1H-四唑(DNM0543),5-(4,5-二(2-甲氧基苯基)噻吩-2-基)-1H-四唑(DNM0544),5-(4,5-二(2,3-二甲氧基苯基)噻吩-2-基)-1H-四唑(DNM0545),5-(4,5-二(4-叔丁基苯基)噻吩-2-基)-1H-四唑(DNM0546),5-(4,5-二(4-氯-2异丙基苯基)噻吩-2-基)-1H-四唑(DNM0548),5-(4,5-二(2-(三氟甲基)苯基)噻吩-2-基)-1H-四唑(DNM0549),5-(4,5-二(2-(三氟甲氧基)苯基)噻吩-2-基)-1H-四唑(DNM0550),5-(4,5-二(2,4-二甲氧基苯基)噻吩-2-基)-1H-四唑(DNM0552),5-(4,5-二(2,6-二甲氧基苯基)噻吩-2-基)-1H-四唑(DNM0553),(2,2’-(5-(1H-四唑-5-基)噻吩-2,3-二基)二(2,1-亚苯基))二甲醇(DNM0555),2,2’-(5-(1H-四唑-5-基)-噻吩-2,3-二基)二苯甲醛(DNM0556),5-(4,5-二(呋喃-3-基)噻吩-2-基)-1H-四唑(DNM0557),5-(4,5-二(噻吩-3-基)噻吩-2-基)-1H-四唑(DNM0558),5-(4,5-二(2-(噻吩-3-基)苯基)噻吩-2-基)-1H-四唑(DNM0559),5-(4,5-二(2-(呋喃-3-基)苯基)噻吩-2-基)-1H-四唑(DNM0560),5-(4,5-二(2-氯-4-甲苯基)噻吩-2-基)-1H-四唑(DNM0563),5-(4,5-二(4-甲氧基-3,5-二甲基苯基)噻吩-2-基)-1H-四唑(DNM0564),5-(4,5-二(3-氯-4-甲氧基苯基)噻吩-2-基)-1H-四唑(DNM0565),3,3’-(5-(1H-四唑-5-基)噻吩-2,3-二基)二苯甲酸二乙酯(DNM0593),1,1’-(3,3’-(5-(1H-四唑-5-基)噻吩-2,3-二基)二(3,1-亚苯基))二丁基-1-酮(DNM0599),5,5’-(5-(1H-四唑-5-基)噻吩-2,3-二基)二(3-羟基苯甲酸乙酯),5-(4,5-二(3-丁苯基)噻吩-2-基)-1H-四唑(DNM0608),5-(4,5-二(3-(环戊基甲基)苯基)噻吩-2-基)-1H-四唑(DNM0612),5-(4-(4-氯-2-甲苯基)-5-(4-甲基萘-1-基)噻吩-2-基)-1H-四唑(DNM0576),5-(4-(4-氯苯基)-5-(4-甲基萘-1-基)噻吩-2-基)-1H-四唑(DNM0572),5-(4-(5-氯苯基)-4-(4-甲基萘-1-基)噻吩-2-基)-1H-四唑(DNM0575),5-(4-(4-氟苯基)-5-(4-(甲磺酰)苯基)噻吩-2-基)-1H-四唑(DNM0592),3-(2-(4-甲基萘-1-基)-5-(1H-四唑-5-基)噻吩-3-基)苯甲酸乙酯(DNM0596),3-(2-(4-氯-2-甲苯基)-5-)1H-四唑-5-基)噻吩-3-基)苯甲酸乙酯(DNM0597),4,5-二(4-氯-2-甲苯基)-2-(1H-四唑-5-基)噻唑(DNM0574),4,5-二(5-氯-2-甲苯基)-2-(1H-四唑-5-基)噻唑(DNM0567),4,5-二(3-氯-4-甲苯基)-2-(1H-四唑-5-基)噻唑(DNM0568),4,5-二(4-甲基萘-1-基)-2-(1H-四唑-5-基)噻唑(DNM0569),4,5-二(4-氯苯基)-2-(1H-四唑-5-基)噻唑(DNM0573),4,5-二(4-氟萘-1-基)-2-(1H-四唑-5-基)噻唑(DNM0578),4,5-二(4-联苯基)-2-(1H-四唑-5-基)噻唑(DNM0581),4,5-二(4-叔丁基苯基)-2-(1H-四唑-5-基)噻唑(DNM0582),4,5-二(3,4-二甲基苯基)-2-(1H-四唑-5-基)噻唑(DNM0583),4,5-二(4-氯-2-异丙基苯基)-2-(1H-四唑-5-基)噻唑(DNM0584),5-(5-(4-氯苯基)-4-(4-甲基萘-1-基)苯硫基-2-基)-1H-四唑(DNM0577),5-(5-(4-氯苯基)-4-(4-氯苯基)苯硫基)-1H-四唑(DNM0579),5-(5-(4-氯苯基)-4-(4-氯-2-异丙基苯基)苯硫基)-1H-四唑(DNM0580),5-(5-(4-氯苯基)-4-(4-氟萘-1-基)噻吩-2-基)-1H-四唑(DNM0587),5-(4-联二苯基-2-基)-5-(4-氯苯基)噻吩-2-基)-1H-四唑(DNM0588),3-(2-(4-氯苯基)-5-(1H-四唑-5-基)噻吩-3-基)苯甲酸乙酯(DNM0595),1-(3-(2-(4-氯苯基)-5-(1H-四唑-5-基)噻吩-3-基)苯基)丁基-1-酮(DNM0600),5-(4-(3-丁苯基)-5-(4-氯苯基)噻吩-2-基)-1H-四唑(DNM0606),3-(2-(4-氯苯基)-5-(1H-四唑-5-基)噻吩-3-基)-5-羟基苯甲酸乙酯(DNM0609),5-(5-(4-氯苯基)-4-(3-(环戊基甲基)苯基)噻吩-2-基)-1H-四唑(DNM0610),3-(2-(4-氯苯基)-5-(1H-四唑-5-基)噻吩-3-基)苯酚(DNM0613),5-(5-(4-氯苯基)-4-(3-甲氧基苯基)噻吩-2-基)-1H-四唑(DNM0615),5-(5-(4-氯苯基)-4-(3-丁氧基苯基)噻吩-2-基)-1H-四唑(DNM0616),5-(5-(4-氯苯基)-4-(3-乙氧基苯基)噻吩-2-基)-1H-四唑(DNM0617),5-(5-(4-氯苯基)-4-(3-丙氧基苯基)噻吩-2-基)-1H-四唑(DNM0618),5-(3,5-二(4-甲基萘-1-基)苯基)-2H-四唑(DNM0461),5-(2,5-二(4-甲基萘-1-基)苯基)-1H-四唑(DNM0446),5-(2,5-二(4-氯-2-甲苯基)苯基)-1H-四唑(DNM0447),5-(3,5-二(4-氯苯)苯基)-2H-四唑(DNM0470),5-(4’-氯-5-(4-甲基萘-1-基)联二苯基-3-基)-1H-四唑(DNM0480),5-(3,5-二(4-氟基萘-1-基)苯基)-2H-四唑(DNM0539),4,5-二(4-氯-2-异丙基苯基)噻吩-2-羧酸(DNM0566),4,5-二(4-联二苯基)噻吩-2-羧酸(DNM0497),4,5-二(4-氯苯基)噻吩-2-羧酸(DNM0498),4,5-二(5-氯-2-甲苯基)噻吩-2-羧酸(DNM0501),4,5-二(3-氯苯基)噻吩-2-羧酸(DNM0502),4,5-二(2,4-二甲基苯基)噻吩-2-羧酸(DNM0503),4,5-二(4-氯-2-甲基苯基)噻吩-2-羧酸(DNM0561),5-(4,5-二(4-氯-2-异丙基苯基)3-甲基噻吩-2-基)-1H-四唑(DNM0631),5-(4,5-二(4-氯-2-甲基苯基)3-甲基噻吩-2-基)-1H-四唑(DNM0614),5-(4,5-二(4-甲萘基-1-基)3-甲基噻吩-2-基)-1H-四唑(DNM0620),5-(4,5-二(3-丁基苯基)3-甲基噻吩-2-基)-1H-四唑(DNM0627),和5-(4,5-二(4-氟萘基-1-基)3-甲基噻吩-2-基)-1H-四唑(DNM0628)。
根据本发明的一个实施例,提供一种微生物感染的治疗方法,所述方法包括将有效量的所述抗菌化合物施药给需要它的病人。比如这样的病人可能指人类或其它被病原菌感染的哺乳动物。在一些实施例中,微生物感染主要是由革兰氏阳性细菌引起的。在一些实施例中,微生物感染主要是由肠球菌引起的。在一些实施例中,微生物感染主要是由葡萄球菌引起的。在一些实施例中,微生物感染主要是由芽孢杆菌引起的。在一些实施例中,微生物感染主要是由表皮葡萄球菌、金黄色酿脓葡萄球菌(包括抗甲氧西林的金黄色酿脓葡萄球菌[MRSA])、肠球菌(包括抗万古霉素的肠球菌[VRE])、链球菌或芽孢杆菌引起的。所谓微生物感染主要是由一种特定的细菌或它的特种所“引起的”,意味着这种特定的细菌属或物种被认为主要影响微生物感染的病理学、流行病学或症状表现,但是不排除其它细菌物种的存在(比如良性的外来细菌)。在一些实施例中,微生物感染是皮肤和皮肤结构感染,包括溃疡、伤口感染、糖尿病足感染、骨髓炎、肺炎、炭疽病感染、脓胞病或后天的外伤性病变、肠胃炎、脑膜炎、肺炎、淋病、消化性溃疡、医院感染或血液感染等等。在一些实施例中,所述的抗菌剂被用作药用化合物,比如当治疗人类时,或者用作兽医化合物当用来治疗动物,家禽,牲畜类以及水产养殖和农业应用。
根据本发明的一个实施例,提供一种微生物感染的治疗方法,所述方法包括将有效量的文中所述抗菌佐剂化合物和一种有效量的抗菌化合物施药给需要它的病人。比如这样的病人可能指人类或其它被病原菌感染的哺乳动物。在一些实施例中,所述抗菌佐剂化合物是DNM0487。在一些实施例中,所述抗菌佐剂化合物是DNM0488。在一些实施例中,所述抗菌佐剂化合物是DNM0548。在一些实施例中,在一定程度上所述抗菌佐剂化合物本身也是抗菌剂。不仅本发明中的化合物相互间的组合是可以的,而且本发明中的化合物和已知的抗菌化合物间的组合也是可以的。在一些实施例中,微生物感染是皮肤和皮肤结构感染,包括溃疡、伤口感染、糖尿病足感染、骨髓炎、肺炎、脓胞病或后天的外伤性病变、肠胃炎、脑膜炎、肺炎、败血病、尿路感染、淋病、消化性溃疡、医院感染、血液感染、布鲁氏菌病、弯曲杆菌病、猫抓热、霍乱、军团杆菌病、细螺旋体病、莱姆病、类鼻疽、脑膜炎、百日咳、瘟疫、沙门氏菌病、痢疾、梅毒、免热病、伤寒或尿道发炎感染。一个有效量的一种或多种上述的抗菌剂可以被用在医药的制备上,所述医药可以用来治疗疾病、失调或由病原菌导致的症状,所述病原菌选自以下但并不局限于埃希氏菌、沙门氏菌、假单胞菌、奈瑟氏菌、军团杆菌、嗜血杆菌、弯曲杆菌、螺杆菌和志贺氏杆菌。
在本发明的另一个实施例中,提供一种治疗微生物感染的医药的制备方法,包括混合所述抗菌化合物和一种合适的赋形剂。
在其它实施例中,提供一种用来治疗微生物感染的所述抗菌化合物的使用。
在本发明另外的实施例中,提供一种治疗微生物感染的医药的制备方法,包括混合一种所述抗菌佐剂化合物和一种合适的抗菌剂。
在其它实施例中,提供一种用来治疗微生物感染的所述抗菌佐剂化合物的使用。在其它实施例中,所述抗菌佐剂化合物的使用或和抗菌剂一起给药。
根据一个实施例,提供一种医药成分,包括本发明中所述的化合物和医药上可接受的赋形剂。
微生物感染可能主要是由一种或多种革兰氏阳性细菌引起的。
微生物感染可能包括葡萄球菌感染。
微生物感染可能包括肠球菌感染。
微生物感染可能包括芽孢杆菌感染。
微生物感染主要是由细菌造成的,所述细菌选自金黄色酿脓葡萄球菌,表皮葡萄球菌,乳酸球菌,肠球菌,蜡样芽孢杆菌和链球菌。
或者,微生物感染主要是由革兰氏阴性细菌引起的。
微生物感染可以是多种微生物的。
微生物感染可能主要是由绿脓杆菌引起的。
所述抗菌佐剂化合物可以选自以下物质,包括DNM0487,DNM0488,和DNM0548。
值得注意的是抗菌剂或抗菌佐剂化合物可以通过多种方式进行给药,比如外敷,口服,静脉注射,肌肉注射,皮下注射,腹腔注射,鼻内注射或使用本领域内已知的系统性血管输液和下面讨论的。本发明中的化合物可以被用来,例如,治疗革兰氏阴性细菌如大肠杆菌引起的感染,或革兰氏阳性细菌如金黄色葡萄球菌引起的感染。在一些实施例中,这些化合物对抗生素耐药菌株比如耐甲氧西林金黄色葡萄球菌(MRSA)有抗菌效果。在一些实施例中,这些化合物对分支杆菌肺结核有抗菌效果。
抗菌剂或抗菌佐剂化合物可以使用的浓度包括大约1nM到大约50mM;或大约10nM到大约50mM;或大约100nM到大约50mM;或1μM到大约50mM;或10μM到50mM或100μM到50mM。就像本领域技术人员所熟知的,这可能就是“有效量”,也就是说,给药一个足够的剂量以致于预想范围内的浓度可以到达所需的位置。在一些抗菌剂的实施例中,有效量至少部分是以这些化合物用来抑菌或针对病原体有抑菌效果所需的最小抑制浓度来确定的。在一些抗菌佐剂的实施例中,有效量至少部分是以一个适宜的最小浓度来确定的,针对病原体,该适宜的最小浓度可以和一种已知的抗生素一起产生所需的辅助效果。在一些实施例中,有效量将被校准为了产生一个超过10倍最低抑菌浓度,或超过5倍最低抑菌浓度,或超过3倍最低抑菌浓度,或在主体遭受感染时的最低抑菌浓度的血清水平。在一些实施例中,有效量将被校准为了产生一个超过10倍MIC,或超过5倍MIC,或超过3倍MIC,或MIC浓度。
本发明其中一种物质的有效量可以以纯的形式使用或者,这样的形式存在于医药上可接受的盐的形式。
或者,化合物可以作为医药成分,这些医药成分包含有与一种或多种医药上可接受的载体结合的物质。然而,应该理解的是这些化合物的总剂量和本发明的组分是由主治医师在医学判断范围内所决定的。对任何特定的病人来说,具体的有效剂量水平是由许多因素决定的,包括由治疗导致的失调和失调的严重性;所使用的具体化合物的活性;所使用的具体成分;年龄,体重,总体健康状况,性别和病人的饮食;给药时间,给药途径和所使用的具体物质的排泄率;治疗周期;风险/收益比率;药物联合使用或所使用的具体化合物的一致性;以及医学领域内所熟知的类似因素。比如,本领域技术人员可以先以低于所需治疗效果的量作为化合物的起始剂量,然后再渐渐增加剂量直到实现想要的效果。
本发明中用于给药人类或低等动物的所述物质的总剂量的范围可从约0.0003到约30mg/kg。对于用来口服的,更优选的剂量是在约0.0003到约1mg/kg的范围内。如果需要,每日有效剂量可以分成多个剂量为了给药;因此,单剂量成分可能包含这样的数量或它的约数来确定每日剂量。对于口服给药,本发明中的成分最好是以含有约1.0,约5.0,约10.0,约15.0,约25.0,约50.0,约100.0,约250.0或约500mg活性成分的片剂形式。
为得到最好的结果,根据本领域大量已知的微生物学方法可以确定一种特定的物质是抗菌剂还是针对病原体的抗菌佐剂(并且在这样的抗菌佐剂中,至于正在使用的抗菌化合物),比如包括在实施例中所使用的方法。在本领域可以很好理解,针对至少一种的病原体,每种“抗菌”化合物有抗菌效果,并且在单个或多个有效量的情况下,抗菌物质它们的活动范围和能力会变化。而且,针对至少一种病原体,每种结合至少一类抗菌剂的“抗菌佐剂”化合物,并且在单个或多个有效量的抗菌剂和佐剂条件下,抗菌佐剂化合物它们的活动范围,能力和/或与特定抗菌剂的兼容性会变化。对本领域技术人员而言显而易见的是,由于许多因素,每日总剂量会变化,这些因素包括但不局限于体重,年龄和个体或病人的状况。
在一些实施例中,结合一种或多种已知的抗生素,一种或多种抗菌剂可能被一起给药。在一些实施例中,结合一种或多种抗菌剂,一种或多种抗菌佐剂化合物可能被一起给药,在这种情况下,抗菌剂的总有效量可能会比原本被要求在没有抗菌佐剂时少,比如约少8倍,或约少16倍,或约少32倍,或约少64倍,或约少125倍,或约少250倍。在一些实施例中,抗菌佐剂化合物它们本身并不是抗菌剂。在一些实施例中,抗菌佐剂化合物它们本身就是抗菌剂。在一些实施例中,在一个单剂型中,一种或多种抗菌佐剂化合物可能结合一种或多种抗菌剂。在一些实施例中,抗菌化合物是本发明中所述的抗菌化合物。在一些实施例中,抗菌化合物是已知的抗菌化合物,比如说:阿美西林,氮脒青霉素,丁胺卡那霉素,阿莫西林,安福霉素,两性霉素B,氨比西林,阿扎胞苷,重氮比氨酸,阿奇霉素,阿洛西林,氨曲南,青蒿素,别嘌呤醇,阿米卡星,氨基糖苷类,两性霉素B,氨比西林,安沙霉素类,氨茴环霉素,抗真菌剂,阿奇霉素,巴氨西林,杆菌肽,苄基青霉烯酰聚赖氨酸,博来霉素,布雷菲德菌素A,布康唑,杀念菌素,卷曲霉素,羧苄青霉素,头孢克罗,头孢羟氨苄,头孢羟唑,头孢唑啉,头孢地尼,头孢吡肟,头孢克肟,头孢甲肟,头孢美唑,头孢地秦,头孢尼西,头孢哌酮,头孢雷特,头孢噻肟,头孢替坦,头孢替安,头孢西丁,头孢匹胺,头孢泊肟,头孢罗齐,头孢磺啶,头孢他定,头孢布烯,头孢唑肟,头孢曲松,头孢呋肟,头孢乙腈,头孢氨苄,头孢苷酸,头孢噻啶,头孢菌素,头孢匹林,头孢拉啶,氯霉素,西司他丁,肉桂霉素,环丙沙星,克拉霉素,克拉维酸,克林霉素,克清诺,氯唑西林,粘杆菌素,粘菌素,环已西林,环丝氨酸,环孢霉素,环(Leu-Pro),喜树碱,噻肟,头孢氨苄,头孢菌素,查耳霉素,教酒菌素,氯四环环素类抗生素,氯丝菌素,突变霉素(chrymutasins),金黄霉素M,金黄霉素V,氯莫环索,放线菌素,达巴万星,达福普丁,达托霉素,道诺霉素,地美环索,地托比星,双氯西林,二氢链霉素,地红霉素,阿霉素,多西环素,椭圆玫瑰树碱,庆大霉素,表阿霉素,红霉素,缬氨霉素,菲律宾菌素,氟康唑,制霉色基素,梭链孢酸,氟氯西林,磷霉素,硫酸庆大霉素,链霉菌素(gilvocarin),灰黄霉素,灰绿霉素,胍哌四环素,吉米沙星,短杆菌肽,海他西林,去甲氧正定霉素,亚胺培南,依色加南,伊佛霉素,艾洛斯胺(ilosamides),伊曲康唑,卡那霉素,天冬霉素,利奈唑酮,氯碳头孢,兰卡霉素,洁霉素,蛙皮素,甲氯环素,美洛培南,美他环素,美洛西林,二甲胺四环素,丝裂霉素,默诺霉素,拉氧头孢,莫西沙星,霉酚酸,大环内酯类,甲氧西林,米托蒽醌,萘夫西林,游霉素,新霉素,奈替米星,尼菲霉素,呋喃咀啶,新生霉素,萘啶酸,诺氟沙星,制霉菌素,氧氟沙星,醋竹桃霉素,土霉素,巴龙霉素,青霉胺,非奈西林,哌拉西林,曾卡霉素,曾那霉素,培西洛星,青霉素,杀虫剂,磷霉素,游霉素,平板霉素,聚烯,多粘菌素B,多粘菌素E,奎奴曾丁,喹诺酮,近灰霉素,利血平,利福霉素,瑞斯西丁素A和B,利福布汀,利福平,利福霉素,氢吡四环素,西索米星,螺旋霉素,安体舒通,乙酰磺胺钠,磺酰胺,奇霉素,链霉素,链脲菌素,舒巴坦,舒他西林,他克莫司,三唑巴坦,替考拉宁,泰利霉素,土霉素,四环素,甲砜霉素,硫藤黄素,妥布霉素,短杆菌素,替卡西林,替加环素,妥布霉素,醋竹桃霉素,衣霉素,红霉素,万古霉素,阿糖腺苷,紫霉素,维及霉素和渥漫青霉素;上述列表中复合名称的存在意思是指在本领域已知的抗生素家族中一种或多种成员,其中物质或多种物质应该被一起给药或结合本发明中的物质,这取决于许多因素,包括但不必须局限于药剂或在缺乏抗菌佐剂化合物的药剂的功效,化合物的作用机制,导致或加重病情的病原体的身份,和/或在治疗中病的严重程度。
药物成分可以制作成以固体或液体形式的口服药,以肠外静脉,皮下,肌肉内,腹腔,动脉内或皮内注射,或用于阴道,鼻子,外用或直肠给药。本发明中适用于口服给药的药物成分可以以离散剂型的形式存在,比如,片剂,咀嚼片,囊片,胶囊,液体和糖浆。这些剂型包含预定数量的活性成分,并且它们可以由本领域技术人员根据众所周知的制药方法制备。通常参考:Remington’sPharmaceutical Sciences,18th ed,Mack Publish,Easton Pa.(1990)。
静脉剂型可以通过不同的途径对病人给药,包括皮下注射、静脉内注射(包括快速浓注)、肌肉注射和动脉注射。因为它们的给药通常避开病人预防感染的自然防御功能,在对病人给药前,静脉剂型是被专门消毒或灭菌的。静脉剂型的例子包括准备注射的溶液,用于注射的可以溶解或悬浮在医药上可接受的载体上的干燥产品,准备注射的悬浮液、和乳剂。用于注射剂的药物组分包括医药上可接受的水溶液或非水溶液,分散体,悬浮液或乳剂和用于构成无菌注射液或分散体的无菌粉沫。可溶性水溶液和非水溶性的载体,稀释剂,溶剂或媒介的例子包括水、乙醇、多元醇(丙二醇,聚乙二醇,丙三醇以及这类的和它们合适的混合物)、植物油(比如说橄榄油)和有机酯注射剂(比如油酸乙酯)或它们合适的混合物。成分中适度的流动性可以被维持,例如,通过使用比如卵磷脂的涂层、通过维持对于分散体来说所需要的粒度、和表面活性剂的使用。这些组合物也可能包含佐剂,比如防腐剂、润湿剂、乳化剂和分散剂。防止微生物的感染可能是通过不同的抗菌剂和抗真菌剂来实现的,比如:苯甲酸脂类、三氯叔丁醇、苯酚、山梨酸等。包括等渗剂可能也是所期望的,例如糖、氯化钠等。可注射药物剂型的长时间吸收可能通过使用延迟吸收试剂来实现,例如,铝单硬脂酸酯和明胶。
在一些实施例中,为了延长药物的效果,通常需要放缓从皮下或肌肉注射的药物的吸收速度。这可能伴随着一种液体悬浮的结晶或水溶性较差的无定形材料。药物的吸收速率取决于它的溶解速率,这反过来可能取决于晶体的大小和晶格形式。或者,肠道外给药物的延迟吸收可以通过溶解或将药物悬浮在油性媒介中。除了活性化合物,悬浮液可能包含悬浮剂,例如:乙氧基植物醇、聚氧乙烯山梨醇和山梨醇酐酯、微晶纤维素、金属氢化铝、硅皂土、琼脂、黄芪胶、和它们的混合物。如果需要,为了更有效的分布,本发明中的物质可以归纳为缓释药物或靶向运载系统比如聚合物基质、脂质体和微球。他们可能是消毒过的,例如,通过含有细菌的过滤器过滤或通过整合以无菌固体形式的消毒剂,它们可以在使用前立即溶解在无菌水或一些其它形式的无菌注射介质中。
药性持久的可注射制剂可以用生物可降解的聚合物——比如聚交酯-聚乙交酯——通过形成微胶囊基质的药物来制备。根据药物和聚合物的比例以及所使用的特定聚合物的性质,药物释放的速度可以得到控制。其它生物可降解聚合物的例子包括聚(原酸酯)和聚(酸酐)。药性持久的注射剂型也可以通过在药物外包裹脂质体或能与生物组织兼容的微乳胶来制备。注射剂型可以是消毒过的,例如,通过一个含有细菌的过滤器过滤或通过整合以无菌固体形式的消毒剂,它们可以在使用前立即溶解在无菌水或一些其它形式的无菌注射介质中。
可注射制剂,例如,无菌注射溶液或油质悬浮液可以根据本领域已知的技术按配方制造,通过使用合适的分散剂或润湿剂和悬浮剂。无菌注射制剂也可以是一种无菌注射溶液,悬浮液或乳浊液溶解在无毒的,肠道外用药可接受的稀释剂或溶剂比如1,3-丁二醇溶液。在可接受的媒介和溶剂中,可以使用的是水、林格氏溶液、U.S.P.和生理盐溶液。另外,无菌的非挥发性油通常用作溶剂或悬浮介质。为了这个目的,可以使用任何温和的非挥发性油包括合成的单或双甘酯。此外,脂肪酸——比如油酸——可以用于注射剂的制备。
用于口服给药的固体制剂包括胶囊、片剂、丸剂、粉末和颗粒剂。在这样的固体制剂中,的一种或多种本发明化合物和至少一种惰性的医药上可接受的载体——比如柠檬酸钠或磷酸氢钙,和/或a)填料或填充剂如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和水杨酸,b)粘结剂如羧甲酸纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯树胶,c)保湿剂比如甘油,d)崩解剂如琼脂、碳酸钙、土豆或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠,e)溶液阻燃剂如石蜡溶液,f)吸收促进剂如季铵化合物,g)润湿剂如十六醇和单硬脂酸甘油酯;h)吸附剂如高岭土和膨润土,i)润滑油如滑石、硬脂酸、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,和它们的混合物进行混合。就胶囊、片剂和丸剂而言,所述制剂剂型还可能包括缓冲剂。
类型相似的固体组合物也可以作为在用乳糖或牛奶糖以及高的分子量的聚乙二醇的软、硬明胶胶囊中的填料。如药片、糖衣、胶囊、颗粒剂和丸的固体剂型可以通过包衣和制壳进行制备,如肠溶包衣等其它医药合成领域众所周知的方式。它们可以选择性地包含乳浊剂,也可以仅包含一个可以让它们释放的活性成分的组份,或优选地,在肠道中的某一部分以延迟方式。可用于延迟释放活性试剂的示例材料有聚合物和蜡。
局部给药的制剂形式可以包括粉末剂、喷雾剂、膏剂和吸入剂。本发明的化合物可以无菌条件下与药学上可接受的载体和所需的任何防腐剂、所需的缓冲液或抛射剂进行混合。眼科制剂、眼药膏、粉剂及溶液也在本发明范围内被考虑。含有本发明的化合物的水的液体组合物也被考虑。
用于口服给药的液体剂型包括药学上可接受的乳剂、微乳剂、溶液、悬浮液、糖浆和酏剂。除了活性化合物之外,液体制剂型可以含有本领域中常用惰性稀释剂,诸如,例如:水或其他溶剂、增溶剂和乳化剂如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3丁二醇、二甲基甲酰胺、油(特别是:棉籽油,花生油,玉米油,胚芽油,橄榄油,蓖麻油,芝麻油),甘油,四氢糠醇,聚乙二醇和失水山梨醇脂肪酸酯,和它们的混合物。
除了惰性稀释剂,该口服组合物还可以包括佐剂,如润湿剂、乳化剂和悬浮剂、甜味剂、香精和芳香剂。本发明化合物的局部或透皮给药的剂型,包括药膏、贴剂、霜剂、乳液、凝胶剂、粉剂、喷雾剂、吸入剂或补片。本发明所需的化合物,在无菌条件下与药学上可接受的载体和所需的任何防腐剂或所需的缓冲液进行混合。眼用制剂,滴耳剂,眼药膏,粉剂和溶液也可以考虑作为本发明的范围内。除了本发明的活性化合物,膏剂、贴剂、霜剂和凝胶剂可能包含动物和植物脂肪、油、蜡、石蜡、黄蓍胶、淀粉、纤维素衍生物、聚乙二醇、有机硅、膨润土、硅酸、滑石和氧化锌、或它们的混合物。
除了本发明的化合物,粉剂和喷雾剂可以包含乳糖、滑石、硅酸、氢氧化铝、钙硅酸盐和聚酰胺粉,或这些物质的混合物。喷雾可以另外包含常规抛射剂,如氯氟代烃。
本发明的化合物也可以在脂质体的形式给药。如本领域中已知的,脂质体是通常来自磷脂和其他脂类物质。脂质体是由单-或多层状水合液晶分散在含水介质形成的。任何无毒的生理上可接受的和代谢能形成脂质体的酯可用作脂质体。除了本发明的化合物,本发明脂质体形式的组合物可以包含稳定剂、防腐剂等。优选的脂质体为天然的和合成的磷脂和卵磷脂(卵磷脂),其单独或一起使用。形成脂质体的方法是本领域已知的,例如,参见Prescott,Ed.,Methods in CellBiology,Volume XIV,Academic Press,New York,N.Y.,(1976),p33et seq。
在一些实施例中,在一种或一种以上的抗菌剂或抗菌佐剂以上讨论的浓度或剂量与医药学或制药学上可接受的载体、赋形剂或稀释剂相结合,或者非生物降解的,或者可生物降解的。典型例子的载体包括、但决不限于诸如:聚(乙烯-乙酸乙烯酯),乳酸和乙醇酸的共聚物,聚(乳酸),明胶,胶原蛋白,多糖,聚(D,L-丙交酯),聚(苹果酸),聚(己内酯),纤维素,清蛋白、淀粉,酪蛋白,右旋糖酐,聚酯,乙醇,甲基丙烯酸酯,聚氨酯,聚乙烯,乙烯基聚合物,甘醇,及其混合物等。标准的赋形剂包括明胶,酪蛋白,磷脂,阿拉伯胶,胆固醇,黄芪胶,硬脂酸,苯扎氯铵,硬脂酸钙,硬脂酸甘油酯,鲸蜡醇,聚西托醇乳化蜡,脱水山梨糖醇酯,聚氧乙烯烷基醚,聚氧乙烯蓖麻油衍生物,山梨糖醇酐脂肪酸聚氧乙烯酯,聚乙二醇,硬脂酸聚氧乙烯酯,胶体二氧化硅,磷酸盐,十二烷基硫酸钠,羧甲基纤维素钙,羧甲基纤维素钠,甲基纤维素,羟乙基纤维素,羟丙基纤维素,邻苯二甲酸羟丙基甲基纤维素酯,非晶纤维素,硅酸铝镁,三乙醇胺,聚乙烯醇,聚乙烯吡咯烷酮,糖和淀粉。
对于本领域技术人员显而易见的是,本领域已知的特定的载体和载体组合可以从预期用途的视角,根据其性质和在释放特性进行选择。具体而言,载体可以是pH-敏感,热敏感,热胶凝,安排用于缓释或快速崩解。在一些实施例中,为了多重效果,不同类的载体可用于组合使用,例如,一个快速崩解载体,附加一个缓释载体。
在其它实施例中,上述浓度或剂量的一种或一种以上的抗菌剂或抗菌佐剂,可以制成胶囊以进行药物传递。具体而言,该化合物可以封装在可生物降解微球、微胶囊、纳米微粒、或纳米微球中。药物传递物质可以包括,例如:透明质酸、聚乙二醇、聚(乳酸)、明胶、聚(E-己内酯),或聚(乳酸-乙醇酸聚合物)。多种组合也可以被使用,例如,明胶微球可以涂有聚合物的聚(乳酸-乙醇酸)。对于本领域技术人员显而易见的是,这些和其他适用的药物传递物质,可以根据本领域已知的研究成果制备,并用于制备化合物的药物传递。
值得注意的是,上述药物可结合本领域内已知的渗透促进剂,提高药物传递。渗透促进剂的例子包括,但不限于,美国专利3,472,931、3,527,864、3,896,238、3,903,256、3,952,099、4,046,886、4,130,643、4,130,667、4,299,826、4,335,115、4,343,798、4,379,454、4,405,616、4,746,515、4,788,062、4,820,720、4,863,738、4,863,970以及5,378,730;英国专利1,011,949;Idson,1975,J.Pharm.Sci.64:901-924中描述的化合物。
“药学上可接受的盐”包括保留了所需的上一代抗菌剂或抗菌佐剂化合物的生物活性、且没有发任何不受欢迎的毒理效应的盐。这样的例子是酸盐,诸如盐酸、氢溴酸、硫酸、磷酸、硝酸等;乙酸、草酸、酒石酸、琥珀酸、苹果酸、苯甲酸、双羟萘酸、褐藻酸、甲基磺酸、萘磺酸等。还包括的阳离子的盐,如钠、钾、锂、锌、铜、钡、铋、钙盐等;或有机阳离子盐,如三烷基铵。上述盐的组合也是有用的。应当理解的是,以无盐的形式公开的化合物和药学上可接受的盐的形式类似化合物是本发明的化合物。此外,前体药物,例如公开的化合物的酯,是本发明的化合物。制备和使用的本发明所述化合物的酸加成盐、羧酸盐、氨基酸加成盐、以及两性离子盐也可以被认为是药学上可接受的,如果他们在合理的医疗判断范围,适用于对人类和低等动物组织的接触,且无异常毒性、刺激性、过敏性反应等,以及在一个相称的合理利益/风险比范围内,并且所期望的使用是有效的。这样的盐也可以包括各种本发明化合物的溶剂化物和水合物。
在一些实施例中,所述抗菌化合物作为药物化合物,例如,用于治疗人类,或兽医的化合物,例如,用于治疗动物,家禽,家畜等,以及在水产养殖和农业上的应用。
尽管上述已经描述了在本发明的多种实施例,但应当认识到的以及应当理解的是,本发明仍可进行改进,在其中,而附加的权利要求覆盖所有这些可能落在本发明精神和范围内改进。
本发明的特定实施例将用实例进行阐明。
实例1
DNM0488和类似物的合成
4,5-二溴噻吩-2-甲酰胺
噻吩-2-氰(3.27g,30mmol)溶解在H2SO4(10mL)和TFA(20mL)的混合物中。NBS(11.75g,66mmol)在20分钟逐步地添加。添加完成后,将反应混合物进一步搅拌4小时,然后倒入200g碎冰。一种白色固体的形成,进行收集,水洗,与五氧化二磷一起真空下干燥,获得8.50g(99%)产品。
4,5-二溴噻吩-2-腈
烘箱干燥的圆底烧瓶中,在氩气气氛下,加入4,5-二溴噻吩-2-甲酰胺(4.28g,15mmol)和20mL DMF。溶液在冰水浴中冷却,之后氰尿酰氯(1.81g,9.8mmol)一次性加入。在0℃搅拌1小时后,将反应混合物加热到室温,进一步搅拌3小时,加入100mL水。一种白色固体的形成,通过吸滤收集,水洗,与五氧化二磷一起在真空下干燥,得到3.70g(92%)产品。
4,5-二(4-氯-2-甲基苯基)噻吩-2-腈
在圆底烧瓶中装有4,5-二溴噻吩-2-腈(534mg,2mmol)、4-氯-2-甲基苯硼酸(818mg,4.80mmol)和Pd(PPh3)4(136mg,0.10mmol)。在脱气,二氧六环(10mL)和碳酸钠水溶液(5mL,2M,10mmol)被加入。将反应混合物加热到90℃,通过TLC监测反应的进展。反应完成后,加入50mL水,并将反应混合物用乙酸乙酯提取。有机相用无水硫酸钠干燥,然后浓缩。残留物由快速色谱法(正己烷∶二氯甲烷=2∶1)纯化。0.60g(84%)的产品以清澈的油的形式获得。
5-(4,5–二(4-氯-2-甲酚)噻吩-2-基)-1H-四唑(DNM0488)
圆底烧瓶中装有4,5-二(4-氯-2-甲苯基)噻吩-2-腈(600mg,1.67mmol)、溴化锌(945mg,4.20mmol)和叠氮化钠(273mg,4.20mmol)。脱气后,DMF(5mL)被添加。将反应混合物加热到110℃,在此温度下搅拌直到反应完成。反应冷却至rt,30mL的0.1 N HCl水溶液被加入。将反应混合物用乙酸乙酯提取。有机相用无水硫酸钠干燥,然后浓缩。残留物由快速色谱法(正己烷∶乙酸乙酯∶醋酸=30∶10∶1)纯化。603mg(90%)产品以白色固体形式获得,1H NMR(DMSO,500MHz)δ7.82(s,1H),7.36(d,J=2.04Hz,1H),7.34(d,J=1.94Hz,1H),7.31(d,J=8.25Hz,1H),7,28(dd,J1=8.26Hz,J2=1.99Hz,1H),7.17(dd,J1=8.20Hz,J2=2.05Hz,1H),7.02(d,J=8.28Hz,1H),2.17(s,3H),2.03(s,3H);13CNMR(DMSO,125MHz)δ140.58,139.14,139.12,138.19,133.59,133.39,132.94,132.47,131.71,131.17,130.57,130.17,130.1 1,126.00,125.80,19.69,19.57.
下列化合物也采用类似的方法制备:
5-(4,5-二(4-甲基萘-1-基)噻吩-2-基)-1H-四唑(DNM0486)1HNMR(DMSO,500MHz)δ8.00(d,J=8.49Hz,1H),7.98-7.90(m,3H),7.88(d,J=8.49Hz,1H),7.57-7.50(m,2H),7.50-7.42(m,2H),7.33(t,J=7.47Hz,1H),7.29(d,J=7.36Hz,1H),7.19(d,J=7.22Hz,1H),7.13(d,J=7.22Hz,1H),2.57(s,3H),2.52(s,3H);l3C NMR(DMSO,125MHz)δ141.36,135.65,134.20,132.18,132.13,131.98,131.68,131.30,130.95,129.21,127.85,127.50,126.30,126.22,126.12,125.95,125.89,125.81,125.75,124.55,124.50,19.07,18.97.
5-(4,5–二(4-氯苯基)噻吩-2-基)-四唑(DNM0487)1H NMR(DMSO,500MHz)δ7.90(s,1H),7.50-7.45(m,4H),7.38-7.31(m,4H);13C NMR(DMSO,125MHz)δ140.14,137.85,133.55,133.45,132.63,131.58,131.15,130.74,130.54,129.19,128.94,124.74.
5-(4,5-二(联二苯-2-基)噻吩-2-基)-四唑(DNM0489)1H NMR(DMSO,500MHz)δ7.48(s,1H),7.35(td,J1=7.55Hz,J2=1.00Hz,1H),7.30(td,J=7.55Hz,J2=1.00Hz,1H),7.21-7.03(m,10H),6.72-6.65(m,2H),6.65-6.58(m,3H),6.55(d,J=7.45Hz,1H);13C NMR(DMSO,125MHz)δ141.91,140.83,140.46,140.19,139.33,132.94,132.02,131.21,130.32,130.23,130.20,129.88,128.63,128.46,128.45,127.95,127.88,127.70,127.45,127.34,126.61,126.34.
5-(4,5-二(3-氯-4-甲苯基)噻吩-2-基)-1H-四唑(DNM0504)1H NMR(DMSO,500MHz)δ7.89(s,1H),7.41(d,J=1.70Hz,1H),7.39(d,J=1.75Hz,1H),7.37(d,J=8.05Hz,1H),7.35(d,J=8.00Hz,1H),7.18(dd,J1=7.85Hz,J2=1.80Hz,1H),7.12(dd,J1=7.83Hz,J2=1.73Hz,1H),2.34(s,6H);13C NMR(DMSO,125MHz)δ139.77,137.40,136.19,135.06,134.02,133.71,133.55,131.80,131.68,131.60,131.54,128.79,128.69,127.71,127.43,19.38,19.32.
5-(4,5-二(5-氯-2-甲苯基)噻吩-2-基)-1H-四唑(DNM0508)1H NMR(DMSO,500MHz)δ7.84(s,1H),7.41(d,J=2.25Hz,1H),7.36(dd,J1=8.23Hz,J2=2.28Hz,1H),7.31-7.23(m,3H),7.11(s,1H),2.13(s,3H),2.01(s,3H);13CNMR(DMSO,125MHz)δ140.36,139.01,136.27,135.74,134.71,133.43,132.26,132.23,131.07,130.59,130.15,130.01,129.56,128.95,19.26,19.16.
5-(4,5-二(3,4-二甲苯基)噻吩-2-基)-1H-四唑(DNM0509)1H NMR(DMSO,500MHz)δ7.84(s,1H),7.21(s,1H),7.19(s,1H),7.12-7.06(m,2H),6.98(dd,J1=8.28Hz,J2=1.63Hz,1H),6.94(dd,J1=7.67Hz,J2=1.48Hz,1H),2.22(s,6H),2.20(s,3H),2.19(s,3H);13C NMR(DMSO,125MHz)δ141.17,138.26,136.90,136.80,136.57,135.65,132.51,131.95,130.14,129.86,129.68,129.65,129.54,126.21,126.06,19.41,19.33,19.14,19.11.
5-(4,5-二(4-异丙苯基)噻吩-2-基)-1H-四唑(DNM0512)1H NMR(DMSO,500MHz)δ7.84(s,1H),7.30-7.23(m,8H),2.90(sep,J=6.88Hz,1H),1.24-1.18(m,12H);13C NMR(DMSO,125MHz)5148.87,147.77,141.11,138.25,132.48,132.01,130.15,128.75,128.55,126.93,126.67,33.11,33.08,23.76,23.65.
5-(4,5-二(2-甲基苯基)噻吩-2-基)-1H-四唑(DNM0531)1H NMR(DMSO,500MHz)δ7.81(s,1H),7.33-7.16(m,6H),7.02(t,J=7.35Hz,1H),7.02(t,J=7.44Hz,1H),2.16(s,3H),2.02(s,3H);13C NMR(DMSO,125MHz)δ141.77,140.03,136.57,135.51,134.73,131.87,131.48,131.26,130.42,130.39,130.10,128.93,127.89,125.89,125.72,19.91,19.75.
5-(4,5-二(2-异丙苯基)噻吩-2-基)-1H-四唑(DNM0534)1H NMR(CDCl3,500MHz)δ7.75(s,1H),7.29-7.19(m,5H),7.14-7.08(m,1H),7.07-7.00(m,2H),3.10-2.95(m,2H),1.04(s,6H),0.95(d,J=6.80Hz,6H);13C NMR(CDC13,125MHz)δ148.48,147.51,140.43,132.28,131.09,129.46,128.43,126.23,126.15,125.72,125.66,30.36,10.15,24.46.
5-(4,5-二(2-苯氧基苯基)噻吩-2-基)-1H-四唑(DNM0536)1H NMR(DMSO,500MHz)δ7.91(s,1H),7.39-7.22(m,8H),7.16-7.05(m,4H),6.79(d,J=7.90Hz,1H),6.75(d,J=7.65Hz,1H),6.66-6.61(m,4H);13C NMR(DMSO,125MHz)δ155.83,155.76,154.04,153.87,138.02,136.48,131.75,131.63,131.33,130.42,129.91,129.86,129.50,126.43,124.08,123.68,123.64,123.46,123.24,118.95,118.70,118.37,117.81.
5-(4,5-二(4-氟萘-1-基)噻吩-2-基)-1H-四唑(DNM0537)1H NMR(DMSO,500MHz)δ8.05-7.95(m,4H),7.85(d,J=8.50Hz,1H),7.66-7.56(m,3H),7.53(t,J=7.53Hz,1H),7.40(t,J=7.55Hz,1H),7.34-7.26(m,2H),7.15(dd,J1=10.55Hz,J2=8.00Hz,1H);13C NMR(DMSO,125MHz)δ159.20,158.48,157.19,156.48,140.42,139.24,132.83,132.79,132.44,132.40,132.00,129.91,129.84,128.92,128.89,127.97,127.90,127.80,127.75,127.02,126.85,125.89,125.85,125.53,125.51,125.41,125.39,122.86,122.75,122.73,122.62,120.25,120.23,120.21,120.19,109.42,109.28,109.26,109.12.
5-(4,5-二(2-氯苯基)噻吩-2-基)-1H-四唑(DNM0538)1H NMR(CDCI3,500MHz)δ8.07(s,1H),7.36(d,J=8.05Hz,1H),7.31(d,J=7.91Hz,1H),7.29-7.22(m,2H),7.18(dt,J1=1.06Hz,J2=7.50Hz,1H),7.15-7.09(m,1H),7.08-7.01(m,2H);13C NMR(CDC13,125MHz)δ142.02,139.64,134.55,134.27,133.64,133.21,132.59,132.11,131.78,130.56,130.40,130.23,129.57,127.08,126.97,124.30.
5-(4,5-二(2-乙基苯基)噻吩-2-基)-1H-四唑(DNM0541)1H NMR(DMSO,500MHz)δ7.77(s,1H),7.33-7.20(m,5H),7.17(t,J=7.43Hz,1H),7.08(dt,J/=1.10Hz,J?=7.33Hz,1H),7.03(d,J=7.50Hz,1H),2.50(q,J=7.50Hz,2H),2.43(q,J=7.50Hz,2H),1.06(t,J=7.50Hz,3H),0.96(t,J=7.50Hz,3H);13CNMR(DMSO,125MHz)δ142.74,141.68,141.58,139.90,134.00,131.53,131.48,130.97,130.33,129.16,128.69,128.45,128.11,125.71,125.56,123.74,25.51,25.38,15.09,15.01.
5-(4,5-二(二苯并[b,d]呋喃-4-基)噻吩-2-基)-1H-四唑(DNM0542)1H NMR(DMSO,500MHz)δ8.26(s,1H),8.15-8.07(m,3H),8.04(dd,J1=7.63Hz,J2=0.98Hz,1H),7.50-7.40(m,4H),7.40-7.34(m,2H),7.34-7.22(m,4H);13CNMR(DMSO,125MHz)δ155.30,155.22,152.65,152.36,137.03,135.52,131.54,128.15,127.93,127.75,127.68,124.22,124.05,123.36,123.34,123.20,123.16,123.12,121.82,121.36,121.28,120.90,119.86,117.22,111.38,111.25.
5-(4,5-二(苯并呋喃-2-基)噻吩-2-基)-1H-四唑(DNM0543)1H NMR(DMSO,500MHz)δ8.23(s,1H),7.74(d,J=7.75Hz,2H),7.67(t,J=7.28Hz,2H),7.49(s,1H),7.45-7.37(m,3H),7.33(dt,J1=2.20Hz,J2=7Λ0Hz,2H);13C NMR(DMSO,125MHz)δ154.12,153.91,149.67,147.67,130.34,130.05,128.48,128.36,128.21,125.92,125.38,123.75,123.53,121.93,121.68,111.27,111.26,107.06,106.01.
5-(4,5-二(2-甲氧苯基)噻吩-2-基)-1H-四唑(DNM0544)1H NMR(DMSO,500MHz)δ7.82(s,1H),7.35-7.28(m,2H),7.10(dd,J1=7.55Hz,J2=1.50Hz,1H),7.04(d,J=8.35Hz,2H),6.98(dd,J1=7.50Hz,J2=1.35Hz,1H),6.90-6.80(m,2H),3.62(s,3H),3.59(s,3H);13C NMR(DMSO,125MHz)δ156.29,156.25,138.75,137.01,131.72,130.91,130.30,130.09,129.16,124.59,121.73,120.37,120.29,111.85,111.60,55.28,55.22.
5-(4,5-二(2,3-二甲氧基苯基)噻吩-2-基)-1H-四唑(DNM0545)1H NMR(DMSO,500MHz)δ7.82(s,1H),7.03(dt,J1=1.20Hz,J2=8.00Hz,2H),6.98(d,J=7.70Hz,1H),6.94(d,J=8.00Hz,1H),6.67(dd,J1=7.75Hz,J2=1.40Hz,1H),6.63(dd,J1=7.58Hz,J2=1.58Hz,1H),3.82(s,6H),3.63(s,3H),3.57(s,3H);13C NMR(DMSO,125MHz)δ152.73,146.13,146.07,138.01,136.68,131.51,129.53,126.64,123.88,122.59,122.43,113.24,112.63,60.12,59.96,55.72,55.67.
5-(4,5-二(4-叔丁基苯基)噻吩-2-基)-1H-四唑(DNM0546)1H NMR(DMSO,500MHz)δ7.84(s,1H),7.53-7.37(m,4H),7.30(d,J=8.41Hz,2H),7.27(d,J=8.41Hz,2H),1.29(s,9H),1.28(s,9H);13C NMR(DMSO,125MHz)δ151.15,150.07,141.08,132.17,132.12,129.84,128.46,128.28,125.80,125.53,34.46,34.37,31.09,30.99.
5-(4,5-二(4-氯-2-异丙基苯基)噻吩-2-基)-1H-四唑(DNM0548)1H NMR(DMSO,500MHz)δ7.75(s,1H),7.43-7.39(m,2H),7.31-7.26(m,2H),7.30(dd,J1=2.24Hz,J2=8.30Hz,1H),7.06(d,J=8.30Hz,1H),2.97-2.82(m,2H),1.04(宽,6H),0.95(d,J=6.80Hz,6H);13C NMR(DMSO,125MHz)δ150.00,149.20,140.39,138.88,134.47,133.44,133.30,132.20,131.71,131.19,128.76,126.16,126.04,125.97,125.76,29.95,29.77,23.54(宽).
5-(4,5-二(2-(三氟甲基)苯基)噻吩-2-基)-1H-四唑(DNM0549)1H NMR(DMSO,500MHz)δ7.88-7.78(m,3H),7.66-7.58(m,2H),7.56-7.49(m,2H),7.41(宽,1H),7.23-7.15(m,1H);13C NMR(DMSO,125MHz)δ
5-(4,5-二(2-(三氟甲氧基)苯基)噻吩-2-基)-1H-四唑(DNM0550)1H NMR(DMSO,500MHz)δ7.90(s,1H),7.57-7.51(m,1H),7.51-7.46(m,1H),7.45-7.34(m,5H),7.32(dd,J1=7.50Hz,J2=1.70Hz,1H);13C NMR(DMSO,125MHz)δ145.44,136.94,135.8,132.48,131.7,131.17,130.98,130.22,127.82,127.62,127.4,125.37,120.88,120.54,118.85,118.81.
5-(4,5-二(2,4-二甲氧基苯基)噻吩-2-基)-1H-四唑(DNM0552)1H NMR(DMSO,500MHz)δ7.75(s,1H),6.99(d,J=8.45Hz,1H),6.87(d,J=8.45Hz,1H),6.64-6.58(m,2H),6.46(dd,J1=8.50Hz,J2=2.25Hz,1H),6.43(dd,J1=8.50Hz,J2=2.25Hz,1H),3.764(s,3H),3.756(s,3H),3.66(s,3H),3.65(s,3H);13C NMR(DMSO,125MHz)δ160.84,160.13,157.52,157.46,138.46,136.36,131.91,131.62,130.91,117.24,114.29,105.25,104.89,98.82,98.79,55,49,55.40,55.29,55.19.
5-(4,5-二(2,6-二甲氧基苯基)噻吩-2-基)-1H-四唑(DNM0553)1H NMR(DMSO,500MHz)δ7.68(s,1H),7.22(t,J=8.38Hz,1H),7.16(d,J=8.33Hz,1H),6.57(d,J=8.40Hz,2H),6.55(d,J=8.35Hz,1H),3.49(s,6H),3.47(s,6H);13C NMR(DMSO,125MHz)δ157.67,157.29,134.19,132.23,130.01,128.89,113.22,110.53,103.80,103.73,55.26,55.10.
(2,2′-(5-(1H-四唑-5-基)噻吩-2,3-二基)二(2,1-亚苯基))二甲醇(DNM0555)1H NMR(DMSO,500MHz)δ7.85(s,1H),7.51(d,J=7.60Hz,1H),7.48(d,J=7.70Hz,1H),7.37(dt,J1=1.47Hz,J2=7.45Hz,1H),7.33-7.21(m,3H),7.13(dt,J1=1.00Hz,J2=7.49Hz,1H),7.02(dd,J1=1.00Hz,J2=7.60Hz,1H),4.36(s,2H),4.23(s,2H);13C NMR(DMSO,125MHz)δ141.19,140.84,140.12,139.48,133.01,131.45,131.19,130.04,129.89,128.87,127.85,127.65,127.26,126.65,126.59,60.71,60.44.
2,2′-(5-(1H-四唑-5-基)噻吩-2,3-二基)二苯甲醛(DNM0556)1H NMR(DMSO,500MHz)69.91(s,1H)S9.80(s,1H),7.93(s,1H),7.75(d,J=7.80Hz,2H),7.59(dt,J1=1.35Hz,J2=7.55Hz,1H),7.49-7.41(m,3H),7.34(t,J=7.53Hz,1H),7.18(d,J=7.50Hz,1H);13C NMR(CDC13,125MHz)6192.30,191.20,153.22,140.91,139.47,137.51,134.79,134.72,134.66,134.40,134.04,133.00,132.44,132.21,130.28,129.89,129.76,129.32,126.53.
5-(4,5-二(呋喃-3-基)噻吩-2-基)-1H-四唑(DNM0557)1H NMR(DMSO,500MHz)δ8.03(dd,J1=0.93Hz,J2=1.38Hz,1H),7.93(dd,J1=0.90Hz,J2=1.30Hz,1H),7.87(s,H),7.83(t,J=1.60Hz,1H),7.77(t,J=1.70Hz,1H),6.63(dd,J1=0.83Hz,J2=1.83Hz,1H),6.59(dd,J1=0.80Hz,J2=1.80Hz,1H);13C NMR(DMSO,125MHz)δ144.46,143.86,141.52,140.76,131.73,130.93,130.30,119.66,117.66,110.91,110.38.
5-(4,5-二(噻吩-3-基)噻吩-2-基)-1H-四唑(DNM0558)1H NMR(DMSO,500MHz)δ7.89(s,1H),7.68(dd,J1=1.33Hz,J2=2.88Hz,1H),7.65(dd,J1=2.95Hz,J2=4.95Hz,1H),7.61(dd,J1=2.95Hz,J2=4.90Hz,1H),7.59(dd,J1=1.28Hz,J2=2.88Hz,1H),7.03(dd,J1=1.18Hz,J2=4.93Hz,1H);13C NMR(DMSO,125MHz)δ135.88,135.23,133.66,132.73,131.40,127.61,127.59,127.52,126.80,125.14,123.88.
5-(4,5-二(2-(噻吩-3-基)苯基)噻吩-2-基)-1H-四唑(DNM0559)1H NMR(DMSO,500MHz)δ7.65(s,1H),7.40-7.35(m,2H),7.32(dt,J1=1.15Hz,J2=7.51Hz,1H),7.29-7.23(m,3H),7.16-7.00(m,2H),6.90(dd,J1=1.23Hz,J2=2.88Hz,1H),6.85(dd,J1=1.23Hz,J2=2.88Hz,1H),6.73(d,J=7.65Hz,1H),6.64(d,J=7.65Hz,1H),6.58(dd,J1=1.20Hz,J2=4.95Hz,1H),6.53(dd,J1=1.20Hz,J2=4.95Hz,1H);13C NMR(DMSO,125MHz)δ142.01,140.99,140.62,139.74,135.76,135.02,132.86,131.72,130.96,130.16,129.91,129.73,129.37,128.68,127.94,127.81,127.73,127.16,127.06,125.56,125.39,123.16,122.78.
5-(4,5-二(2-(呋喃-3-基)苯基)噻吩-2-基)-1H-四唑(DNM0560)1H NMR(DMSO,500MHz)δ7.61(s,1H),7.59-7.56(m,2H),7.38-7.31(m,3H),7.30-7.25(m,2H),7.25-7.22(m,1H),7.19-7.14(m,1H),7.12(dt,J1=1.30Hz,J2=7.58Hz,1H),6.96(d,J=7.54Hz,1H),6.85(dd,J1=0.95Hz,J2=7.66Hz,1H),6.20(dd,J1=0.83Hz,J2=1.78Hz,1H),6.12(dd,J1=0.80Hz,J2=1.75Hz,1H);13C NMR(DMSO,125MHz)δ142.01,140.99,140.62,139.74,135.76,135.02,132.86,131.72,130.96,130.16,129.91,129.73,129.37,128.68,127.94,127.81,127.73,127.16,127.06,125.56,125.39,123.16,122.78.
5-(4,5-二(2-氯-4-甲苯基)噻吩-2-基)-1H-四唑(DNM0563)1H NMR(DMSO,500MHz)δ7.85(s,1H),7.36-7.32(m,2H),7.29(d,J=7.80Hz,1H),7.06(d,J=7.74Hz,1H),7.09-7.02(m,2H),2.30(s,3H),2.28(s,3H);13C NMR(DMSO,125MHz)δ141.00,139.73,138.42,132.59,132.54,131.88,131.38,131.08,130.57,130.19,130.03,128.06,127.87,127.82,20.39,10.37.
5-(4,5-二(4-甲氧基-3,5-二甲苯基)噻吩-2-基)-1H-四唑(DNM0564)1H NMR(DMSO,500MHz)δ7.83(s,1H),7.03(s,2H),6.99(s,2H),3.67(s,6H),2.172(s,6H),2.166(s,6H);13C NMR(DMSO,125MHz)δ156.89,156.12,140.69,137.89,131.78,130.86,130.45,130.27,129.19,128.99,127.91,59.43,59.42,15.78,15.74.
5-(4,5-二(3-氯-4-甲氧苯基)噻吩-2-基)-1H-四唑(DNM0565)1H NMR(DMSO,500MHz)δ7.87(s,1H),7.41(d,J=2.05Hz,1H),7.39(d,J=2.00Hz,1H),7.30(dd,J1=2.15Hz,J2=8.65Hz,1H),7.22(dd,J,=2.08Hz,J2=8.58Hz,1H),7.20(d,J=8.70Hz,1H),7.17(d,J=8.65Hz,1H),3.89(s,3H),3.88(s,3H);13C NMR(DMSO,125MHz)δ172.03,154.75,154.03,139.42,136.95,131.63,130.00,129.84,129.19,128.70,127.88,125.48,121.39,121.18,113.24,113.01,56.29,56.18.
3,3′-(5-(1H-四唑-5-基)噻吩-2,3-二基)二苯甲酸二乙酯(DNM0593)1H NMR(DMSO,500MHz)δ8.17(s,1H),8.14(s,1H),8.06(s,1H),8.03(d,J=7.75Hz,1H),7.98(d,J=7.75Hz,1H),7.48(d,J=7.90Hz,1H),7.44-7.37(m,3H),7.34(t,J=7.75Hz,1H),4.44-4.35(m,4H),1.42-1.35(m,6H);!3C NMR(CDC13,125MHz)δ167.33,166.35,142.50,138.70,135.47,133.75,133.73,133.17,132.49,131.28,131.27,130.90,130.44,130.20,129.85,129.20,128.99,128.97,124.48,61.88,61.64,14.39.
1,1′-(3,3′-(5-(1H-四唑-5-基)噻吩-2,3-二基)二(3,1-亚苯基))二丁基-1-酮(DNM0599)1H NMR(CDCI3,500MHz)δ8.13(s,1H),8.08(s,1H),7.98-7.89(m,3H),7.54(d,J=7.80Hz,1H),7.46(t,J=7.60Hz,1H),7.40(t,J=7.70Hz,1H),2.94(t,J=7.28Hz,2H),2.85(t,J=7.30Hz,2H),1.80-1.67(m,4H),0.99(t,J=7.35Hz,3H),0.98(t,J=7.35Hz,3H);13C NMR(CDC13,125MHz)δ200.52,139.04,137.96,137.80,136.06,134.09,134.00,133.71,132.47,129.80,129.51,129.44,129.04,128.58,128.04,41.20,41.06,18.23,18.18,14.28.
5,5′-(5-(1H-四唑-5-基)噻吩-2,3-二基)二(3-羟苯酸乙酯)(DNM0607)1HNMR(DMSO,500MHz)δ10.12(s,1H),9.99(s,1H),7.87(s,1H),7.43-7.29(m,4H),6.97(s,1H),6.93(s,1H),4.35-4.17(m,4H),1.33-1.20(m,6H);13CNMR(DMSO,125MHz)δ165.34,165.07,157.89,157.75,139.98,138.09,136.36,133.97,131.78,131.60,131.02,120.17,120.10,120.01,115.86,115.11,60.91,60.81,14.07,14.00.
5-(4,5-二(3-丁基苯基)噻吩-2-基)-1H-四唑(DNM0608)1H NMR(CDCI3,500MHz)δ7.44(s,1H),6.91-6.56(m,8H),8.06(s,1H),2.31-2.05(m,4H),1.29-1.16(m,4H),1.16-1.00(m,4H),0.81-0.67(m,6H);13C NMR(CDC13,125MHz)δ142.80,142.62,139.91,138.91,136.26,134.07,129.86,129.58,129.54,128.54,127.63,127.02,126.88,126.61,35.70,35.68,33.79,33.68,22.66,22.63,14.33.
5-(4,5-二(3-(环戊基甲基)苯基)噻吩-2-基)-1H-四唑(DNM0612)1H NMR(CDC13,500MHz)δ8.00(s,1H),7.24-7.17(m,2H),7.17-7.09(m,4H),7.09-7.04(m,2H),2.54-2.48(m,4H),2.00-1.87(m,2H),1.69-1.54(m,8H),1.54-1.41(m,4H),1.17-1.00(m,4H);13C NMR(CDCI3,125MHz)δ152.84,144.09,143.03,142.82,139.94,135.22,133.02,132.94,129.97,129.77,129.12,128.70,128.57,128.14,126.76,126.41,122.42,42.08,41.99,32.56,25.06.
实例2
DNM0576和类似物的合成
4-溴-5-(4-甲基萘-1-基)噻吩-2-腈
圆底烧瓶中装有4,5-二溴噻吩-2-腈(536mg,2mmol)、4-甲基萘-1-基硼酸(409mg,2.20mmol)、Pd2(dba)3(18.3mg,0.020mmol)和KF(383mg,6.60)。脱气后,二氧六环(5mL)和P(Bu-t)3(0.24mL,0.2M,0.048mmol)被加入。反应混合物在rt条件下搅拌直到反应完成。加入30mL水,并将反应混合物用乙酸乙酯提取。有机相用无水硫酸钠干燥,然后浓缩。残留物由快速色谱法(正己烷∶CH2Cl2=3∶1)纯化。0.58g(88%)产品以白色固体形式获得。
4-(4-氯-2-甲苯基)-5-(4-甲基萘-1-基)噻吩-2-腈
圆底烧瓶内装有4-溴-5-(-甲基萘-1-基)噻吩-2-腈(203mg,0.62mmol)、4-氯-2-甲苯基硼酸(119mg,0.70mmol)、Pd2(dba)3(9.2mg,0.010mmol)和KF(126mg,2.17)进行激烈反应。脱气后,二氧六环(2mL)和P(Bu-t)3(0.15ml,0.2M,0.03mmol)被加入。反应混合物在rt条件下搅拌直到反应完成。加入水20mL,并将反应混合物用乙酸乙酯提取。有机相用无水硫酸钠干燥,然后浓缩。残留物由快速色谱法(正己烷∶CH2Cl2=3∶1)纯化。0.21g(90.6%)产品以白色固体形式获得。
5-(4-(4-氯-2-甲苯基)-5(4-甲基萘-1-基)噻吩-2-基)-1H-四唑(DNM0576)
圆底烧瓶内装入4-(4-氯-2-甲苯基)-5-(4-甲基萘-1-基)噻吩-2-腈(209mg,0.56mmol)、溴化锌(338mg,1.50mmol)和叠氮化钠(97.5mg,1.50mmol)。脱气后,DMF(3mL)被添加。将反应混合物加热到110℃并在此温度下搅拌直到反应完成。反应冷却至rt,加入30mL 0.1N HCl水溶液。将反应混合物用乙酸乙酯提取。有机相用无水硫酸钠干燥,然后浓缩。残留物由快速色谱法(正己烷∶乙酸乙酯∶醋酸=30∶10∶1)纯化。196mg(84%)产品以白色固体形式获得。1H NMR(DMSO,500MHz)δ8.03(d,J=8.40Hz,1H),7.88(s,1H),7.80(d,J=8.05Hz,1H),7.55(t,J=7.68Hz,1H),7.48(t,J=7.65Hz,1H),7.45(d,J=7.19Hz,1H),7.37(d,J=7.30Hz,1H),7.23(d,J=1.95Hz,1H),7.09(d,J=8.25Hz,1H),7.04(dd,J1=8.25Hz,J2=2.06Hz,1H),2.65(s,3H),2.17(s,3H);13C NMR(DMSO,125MHz)δ172.05,141.01,139.65,138.35,135.93,133.73,132.18,132.10,131.64,131.31,131.26,129.80,129.23,127.62,126.45,126.26,126.02,125.53,125.51,124.67,21.08,19.82.
下列化合物也采用类似的方法制备:
5-(4-(4-氯苯基)-5-(4-甲基萘-1-基)噻吩-2-基)-1H-四唑(DNM0572)1HNMR(CDC13,500MHz)δ8.09(d,J=8.39Hz,1H),7.84(s,1H),7.82(d,J=8.46Hz,1H),7.56(t,J=7.32Hz,1H),7.44(t,J=7.84Hz,1H),7.31(d,J=7.25Hz,1H),7.23(d,J=7.24Hz,1H)57.17-7.09(m,4H),2.76(s,3H);13CNMR(CDCl3,125MHz)δ152.64,142.65,138.24,135.00,134.09,133.65,133.08,132.16,131.91,131.87,129.76,128.93,127.95,126.54,126.37,126.30,126.11,124.78,124.46,19.80.
5-(4-(5-氯苯基)-4-(4-甲基萘-1-基)噻吩-2-基)-1H-四唑(DNM0575)1H NMR(DMSO,500MHz)δ68.11(s,1H),8.09(d,J=8.44Hz,1H),7.65(d,J=8.11Hz,1H),7.58-7.53(m,2H),7.49-7.42(m,2H),7.28-7.20(m,4H),2.72(s,3H);13C NMR(DMSO,125MHz)δ139.74,139.15,136.18,133.66,132.29,132.15,131.14,130.40,129.40,129.23,128.61,127.69,126.69,126.36,126.28,125.47,124.77,19.23.
5-(4-(4-氟代苯基)-5-(4-(甲磺酰基)苯基)噻吩-2-基)-1H-四唑(DNM0592)1H NMR(DMSO,500MHz)δ7.96(s,1H),7.94(d,J=8.45Hz,2H),7.57(d,J=8.45Hz,2H),7.45-7.38(m,2H),7.28(t,J=8.80Hz,2H),3.27(s,3H);13CNMR(DMSO,125MHz)δ163.32,161.36,141.61,139.83,139.71,137.14,131.45,131.38,131.32,129.58,129.42,128.44,128.42,127.46,124.88,116.37,116.19,43.36.
3-(2-(4-甲基萘-1-基)-5-(1H-四唑-5-基)噻吩-3-基)苯甲酸乙酯(DNM0596)1H NMR(CDC13,500MHz)δ8.00(d,J=8.40Hz,1H),7.96(t,J=1.64Hz,1H),7.87(s,1H),7.83(dt,J1=7.85Hz,J2=1-35Hz,1H),7.73(d,J=8.36Hz,1H),7.35(t,J=7.60Hz,1H),7.28(d,J=7.79Hz,1H),7.22(d,J=7.74Hz,1H),7.17(d,J=7.10Hz,1H),7.14(t,J=7.85Hz,1H),4.24(q,J=7.07Hz,2H),2.68(s,3H),1.24(t,J=7.15Hz,3H);13C NMR(CDCl3,125MHz)δ166.77,143.43,138.88,135.13,134.17,133.51,133.05,132.84,132.03,131.41,130.72,129.59,129.31,128.91,127.95,126.46,126.36,126.14,124.71,123.55,61.60,19.76,14.21.
3-(2-(4-氯-2-甲苯基)-5-(1H-四唑-5-基)噻吩-3-基)苯甲酸乙酯(DNM0597)1H NMR(CDCI3,500MHz)δ8.01-7.95(m,2H),7.78(s,1H),7.41-7.33(m,2H),7.23(s,1H),7.19(dd,J1=8.22Hz,J2=1.50Hz,1H),7.14(d,J=8.22Hz,1H),4.38(q,J=7.15Hz,2H),2.04(s,3H),1.40(t,J=7.14Hz,3H);13C NMR(CDC13,125MHz)δ166.58,142.77,138.62,138.53,134.15,133.77,133.52,132.76,132.50,131.59,131.14,130.70,129.59,129.35,129.24,126.57,124.34,61.74,20.16,14.39.
实例3
DNM0574及其类似物的合成
4,5-二溴噻唑
2,4,5-三溴噻唑(3.12g,9.67mmol)在无水THF(25ml)的溶液被加入,i-PrMgCl(4.84mL,在THF中浓度为2M,9.67mmol)在冰浴温度和氩环境下加入。完成加入后,反应在冰盐浴温度搅拌1小时,然后用甲醇(2mL)终止反应。反应通过一个典型的工艺完成,并且对粗产物通过快速色谱法(30%的DCM在正己烷中)进行分离纯化,获得1.45g的产品。
4,5-二(4-氯-2-甲苯基)噻唑
圆底烧瓶内装入4,5-溴噻唑(160mg,0.66mmol)、4-氯-2-甲苯基硼酸(269mg,1.58mmol)和Pd(PPh3)4(38.1mg,0.033mmol)。脱气后,二氧六环(5mL)和碳酸钠水溶液(3mL,2M,6mmol)被加入。将反应混合物加热到90℃,反应过程用TLC监控。反应完成后,50mL水加入,并将反应混合物用乙酸乙酯提取。有机相用无水硫酸钠干燥,然后浓缩。残留物经快速色谱提纯,获得170mg清澈油状产品。
2-溴-4,5-二(4-氯-2-甲苯基)噻唑
4,5–二(4-氯-2-甲苯基)噻唑(170mg,0.51mmol),NBS(100mg,0.56mmol)和NaOAc(82mg,1mmol)在AcOH(5mL)和DCM(3mL)的溶液,在rt条件下搅拌过夜,然后用水(25mL)终止反应,用乙酸乙酯提取。有机相用无水硫酸钠干燥,然后浓缩。残留物经快速色谱法提纯,获得196mg的产品。
4,5-二(4-氯-2-甲苯基)噻唑-2-腈
圆底烧瓶内装入2-溴-4,5-二(4-氯-2-甲苯基)噻唑(196mg,0.47mmol)和CuCN(84.2mg,0.94mmol)进行反应。脱气后,加入3ml的DMF。将反应混合物加热到150℃反应过夜。后冷却到室温,反应被25mL水终止,用乙酸乙酯萃取。有机相用无水硫酸钠干燥,然后浓缩。残渣经闪光色谱提纯,获得150mg的产品。
4,5-二(4-氯-2-甲苯基)-2-(1H-四唑-5-基)噻唑(DNM0574)
在圆底烧瓶内与4,5-二(4-氯-2-甲苯基)噻唑-2-腈(150mg,0.42mmol)、溴化锌(189mg,0.84mmol)和叠氮化钠(45.5mg,0.84mmol)进行反应。脱气后,DMF(3mL)被添加。将反应混合物加热到150℃过夜。冷却至rt,反应用30mL的0.1N HCl水溶液冷却,用乙酸乙酯萃取。有机相用无水硫酸钠干燥,然后浓缩。残留物通过快速色谱法(正己烷∶乙酸乙酯∶醋酸=30∶10∶1)纯化,得到一个120mg的白色的固体产品。1H NMR(DMSO,500MHz)δ7.93(d,J=8.41Hz,1H),7.57(d,J=1.90Hz,1H),7.49-7.44(m,2H),7.33-7.28(m,2H),2.63(s,3H),2.18(s,3H);13C NMR(DMSO,125MHz)δ166.07,153.61,139.50,138.74,134.92,133.48,132.53,131.87,131.42,130.27,129.98,126.64,125.67,21.13,19.51.
下列化合物也采用类似的方法制备:
4,5-二(5-氯-2-甲苯基)-2-(1H-四唑-5-基)噻唑(DNM0567)1H NMR(DMSO,500MHz)δ7.95(d,J=2.17Hz,1H),7.54(dd,J1=8.25Hz,J2=1.80Hz,1H),7.48(d,J=8.25Hz,1H),7.45(dd,J1=8.23Hz,J2=2.33Hz,1H),7.41-7.36(m,2H),2.61(s,3H),2.11(s,3H);13C NMR(DMSO,125MHz)δ165.31,152.99,135.93,135.54,135.31,133.72,133.07,132.04,130.99,130.09,129.94,129.64,128.79,128.72,20.82,19.03.
4,5-二(3-氯-4-甲苯基)-2-(1H-四唑-5-基)噻唑(DNM0S68)1H NMR(DMSO,500MHz)δ8.09(d,J=1.30Hz,1H),7.92(dd,J1=7.93Hz,J2=1.38Hz,1H),7.79(d,J=1.20Hz,1H),7.57-7.50(m,2H),7.43(d,J=7.95Hz,1H),2.42(s,3H),2.39(s,3H);13C NMR(DMSO,125MHz)δ166.30,153.18,138.95,136.51,134.29,133.22,132.68,132.20,131.49,131.20,129.01,127.53,126.22,125.36,19.68,19.50.
4,5-二(4-甲基萘-1-基)-2-(1H-四唑-5-基)噻唑(DNM0569)1H NMR(DMSO,500MHz)δ9.99(d,J=7.91Hz,1H),8.16(t,J=9.52Hz,2H),8.04(d,J=7.35Hz,1H),7.86(d,J=8.41Hz,1H),7.47-7.49(m,6H),7.47(d,J=7.30Hz,1H),2.764(s,3H),2.761(s,3H);13C NMR(DMSO,125MHz)δ167.71,154.55,138.21,135.74,132.61,132.41,131.55,129.79,129.58,129.06,128.26,127.48,127.41,126.69,126.34,126.23,126.13,126.04,125.93,125.83,124.78,124.59,19.52,19.23.
4,5-二(4-氯苯基)-2-(1H-四唑-5-基)噻唑(DNM0573)1H NMR(DMSO,500MHz)δ8.10(d,J=8.43Hz,2H),7.74(d,J=8.44Hz,2H),7.64(d,J=7.50Hz,2H),53(d,J=8.50Hz,2H);13C NMR(DMSO,125MHz)δ166.61,153.57,135.94,133.87,132.11,130.85,130.74,129.52,128.50,128.29.
4,5-二(4-氟萘-1-基)-2-(1H-四唑-5-基)噻唑(DNM0578)1H NMR(DMSO,500MHz)δ9.02-8.95(m,1H),8.24-8.16(m,3H)57.88(d,J=8.49Hz,1H),7.79-7.73(m,1H),7.73-7.67(m,2H),7.62(t,J=7.80Hz,1H),7.58(dd,J1=8.21Hz,J2=10.14Hz,1H),7.47(dd,J1=7.96Hz,J2=10.54Hz,1H);13CNMR(DMSO,125MHz)δ166.76,160.47,159.60,158.43,157.59,153.30,132.99,132.96,131.08,130.07,129.99,129.08,128.99,128.92,127.82,127.58,126.92,125.63,123.39,123.26,123.23,123.10,120.54,120.49,120.35,120.30,109.92,109.75,109.55,109.40.
4,5-二(4-联苯)-2-(1H四唑-5-基)噻唑(DNM0581)1H NMR(DMSO,500MHz)68.17(d,J=8.32Hz,2H),7.89(d,J=8.32Hz,2H),7.84-7.72(m,8H),7.56-7.47(m,4H),7.47-7.38(m,2H);13C NMR(DMSO,125MHz)δ167.64,154.70,142.75,140.67,139.37,138.93,132.38,131.10,129.43,129.12,129.05,128.23,127.84,127.60,127.17,126.79,126.70,126.68.
4,5-二(4-叔丁基苯基)-2-(1H-四唑-5-基)噻唑(DNM0582)1H NMR(DMSO,500MHz)δ7.99(d,J=8.25Hz,2H),7.60(d,J=8.25Hz,4H),7.48(d,J=8.30Hz,2H),1.34(s,9H),1.32(s,9H);13C NMR(DMSO,125MHz)δ167.93,155.03,154.21,151.65,130.58,129.56,128.52,126.35,126.27,125.27,34.77,34.51,31.02,30.87.
4,5-二(3,4-二甲苯基)-2-(1H-四唑-5-基)噻唑(DNM0583)1H NMR(DMSO,500MHz)δ7.85(s,1H),7.79(dd,J1=1.65,J2=7.80Hz,1H),7.47(s,1H),7.34(d,J=7.95Hz,1H),7.29(d,J=7.70Hz,1H),7.19(d,J=7.85Hz,1H),2.34(s,3H),2.31(s,3H),2.28(s,3H),2.25(s,3H);13C NMR(DMSO,125MHz)δ168.65,155.73,140.64,138.00,137.85,136.73,131.33,130.85,130.32,130.17,129.93,127.70,126.54,124.49,19.91,19.87,19.75,19.71.
4,5-二(4-氯-2-异丙苯基)-2-(1H-四唑-5-基)噻唑(DNM0584)1H NMR(DMSO,500MHz)δ7.73(d,J=8.35Hz,1H),7.62(d,J=2.20Hz,1H),7.52(d,J=2.10Hz,1H),7.47(dd,J1=2.18,J2=8.33Hz,1H),7.30(dd,J1=2.13,J2=8.23Hz,1H),7.25(d,J=8.20Hz,1H),3.77(sep,J=6.85Hz,1H),2.93(sep,J=6.83Hz,1H),1.21(d,J=6.85Hz,6H),1.11(d,J=6.80Hz,6H);13C NMR(DMSO,125MHz)δ166.64,154.25,150.51,150.06,136.15,134.62,132.72,132.50,131.94,129.84,127.13,126.93,126.22,126.16,30.57,29.36,23.72,23.59.
实例4
DNM0577和类似物的合成
4,5-二碘噻吩-2-甲酰胺
噻吩-2-腈(5.39g,49.39mmol)溶解在H2SO4(10mL)和TFA(30niL)的混合物中。NIS(23.34g,103.74mmol)在30分钟内逐步地添加。添加完成后,将反应混合物进一步搅拌4h,然后倒入300g碎冰。一种白色固体的形成,进行收集,水洗,与五氧化二磷一起真空下干燥,获得17.8g(95%)产品。
4,5-二碘噻吩-2-腈
在氩气气氛下,烘箱干燥的圆底烧瓶内装入4,5-二碘噻吩-2-甲酰胺(5.68g,15mmol)和20mL DMF。将溶液在冰水浴中冷却,之后将氰尿酰氯(1.81g,9.8mmol)加入。0℃搅拌1小时后,将反应混合物加热到室温,搅拌进一步3h。100mL水加入。一种白色固体形成,并通过抽吸过滤收集,水洗,与五氧化二磷一起真空下干燥,获得4.87g(90%)产品。
(5-(4-氯苯基)(羟基)甲基)-4-碘噻吩-2-腈
在烘箱干燥的圆底烧瓶内加入4,5-二碘噻吩-2-腈(1.80g,5mmol)。脱气后,无水THF(15mL)通过注射器添加。后冷却到-78℃,滴加i-PpMgCl(3mL,2.0,6mmol)。在完成加入后,反应继续在-78℃搅拌30分钟。4-氯苯甲醛(0.98g,7mmol)溶在5mL THF的溶液被加入。搅拌10分钟后,在-78℃搅拌1小时,将反应混合物加热到室温。50mLNH4Cl饱和水溶液加入。将反应混合物用乙酸乙酯提取。有机相用无水硫酸钠干燥,然后浓缩。残留物由快速色谱法(正己烷∶乙酸乙酯∶二氯甲烷=30∶3∶10)纯化。获得1.39g(74%)白色固体产品。
5-(4-氯苄基)-4-碘噻吩-2-腈
圆底烧瓶内装入5-((4-氯苯基)(羟基)甲基)-4-碘噻吩-2-腈(1.67g,4.45mmol)。脱气后,二氯甲烷(8mL)、TFA(4mL)和三乙基硅烷(1.1mL,6.9mmol)通过注射器依次加入。反应是在rt条件下进一步搅拌直到完成,然后浓缩。残留物由快速色谱法(正己烷∶二氯甲烷=2∶1)纯化。获得1.36g(85%)白色固体的产品。
5-(4-氯苄基)-4-(4-甲基萘-1-基)噻吩-2-腈
圆底烧瓶内装有5-(4-氯苄基)-4-碘噻吩-2-腈(180mg,0.50mmol)、4-甲基萘-1-基硼酸(102mg,0.55mmol)、Pd2(dab)3(9.2mg,0.010mmol)和KF(126mg,2.17)。脱气后,二氧六环(2mL)和P(Bu-t)3(0.15mL,0.2m,0.03mmol)被加入。反应混合物在室温搅拌直到完成。20mL水加入,并将反应混合物用乙酸乙酯提取。有机相用无水硫酸钠干燥,然后浓缩。残留物由快速色谱法(5%乙酸乙酯在己烷中)纯化。获得0.17g(91%)白色固体产品。
5-(5-(4-氯苄基)-4-(4-甲基萘-1-基)噻吩-2-基)-1H-四唑(DNM0577)
在圆底烧瓶内装有5-(4-氯苄基)-4-(4-甲基萘-1-基)噻吩-2-腈(170mg,0.45mmol)、溴化锌(338mg,1.50mmol)和叠氮化钠(97.5mg,1.50mmol)进行反应。脱气后,DMF(3mL)被添加。将反应混合物加热到110℃和在此温度下搅拌直到完成。反应冷却至室温,30mL 0.1N HCl水溶液中加入。将反应混合物用乙酸乙酯提取。有机相用无水硫酸钠干燥,然后浓缩。残留物由快速色谱法(正己烷∶乙酸乙酯∶醋酸=30∶10∶1)纯化。获得161mg(85%)白色固体状的产品。1H NMR(CDC13,500MHz)δ8.05(d,J=8.46Hz,1H),7.73(s,1H),7.63(d,J=8.36Hz,1H),7.53(t,J=7.58Hz,1H),7.42(t,J=7.53Hz,1H),7.33(d,J=7.11Hz,1H),7.23(d,J=7.08Hz,1H),7.14(d,J=8.25Hz,2H),6.92(d,J=8.14Hz,2H),3.86(ABq,2H,ΔδΛΒ=0.06,JAB=15.90Hz),2.70(s,3H);13C NMR(CDCl3,125MHz)δ152.61,145.54,139.59,137.96,135.22,132.97,132.76,132.69,132.27,131.09,130.05,128.81,127.55,126.33,126.25,126.20,126.16,124.75,122.29,34.24,19.77.
下列化合物也采用类似的方法制备:
5-(5-(4-氯苯基)-4-(4-氯苯基)噻吩)-1H-四唑(DNM0579)1H NMR(DMSO,500MHz)δ7.80(s,1H),7.57(d,J=8.70Hz,2H),7.53(d,J=8.70Hz,2H),7.40(d,J=8.34Hz,2H),7.26(d,J=8.34Hz,2H),4.30(s,2H);13C NMR(DMSO,125MHz)δ143.21,138.47,138.38,133.64,132.51,131.51,130.65,130.49,130.24,128.89,128.65,122.97,32.99.
5-(5-(4-氯苯基)-4-(4-氯-2-异丙苯基)噻吩)-1H-四唑(DNM0580)1H NMR(CDC13,500MHz)δ7.66(s,1H),7.31(d,J=2.05Hz,1H),7.19(d,J=8.35Hz,2H),7.16(dd,J1=8.12Hz,J2=2.10Hz,1H),6.99(d,J=8.20Hz,1H),7.23(d,J=78.35Hz,2H),3.89(ABq,2H,ΔδΑΒ=0.04,JAB=14.13Hz),2.76(sep,J=6.85Hz,1H),1.10-0.97(m,6H);13C NMR(CDC13,125MHz)δ152.60,149.93,144.93,139.52,137.57,134.85,132.95,131.97,131.93,131.70,130.02,129.01,126.41,126.15,122.28,30.02,30.85,24.57,23.42.
5-(5-(4-氯苯基)-4-(4-氟化萘-1-基)噻吩-2-基)-1H-四唑(DNM0587)1H NMR(DMSO,500MHz)δ8.17(d,J=8.25Hz,1H),7.75-7.69(m,2H),7.69-7.62(m,2H)57.53-7.42(m,2H),7.30-7.25(m,2H),7.11-7.06(m,2H),4.10-3.91(m,2H);13C NMR(CDC13,125MHz)δ158.86,156.86,144.75,138.33,137.42,132.85,132.81,131.60,131.28,130.30,128.78,128.75,128.41,127.93,127.85,127.78,126.99,125.40,125.38,123.10,122.97,120.43,120.39,109.53,109.37,33.01,21.07.
5-(4-(联苯-2-基)-5-(4-氯苯基)噻吩-2-基)-1H-四唑(DNM0588)1H NMR(DMSO,500MHz)δ7.58-7.52(m,1H),7.52-7.46(m,3H),7.43(d,J=7.60Hz,2H),7.33-7.24(m,5H),7.20-7.13(m,2H),6.89(d,J=8.33Hz,2H),3.73(s,2H);13C NMR(DMSO,125MHz)δ143.34,140.80,140.48,139.40,138.13,133.20,131.66,131.37,130.76,130,42,130.30,129.03,128.69,128.42,128.23,127.71,127.03,122.21,33.01.
3-(2-(4-氯苯基)-5-(1H-四唑-5-基)噻吩-3-基)苯甲酸乙酯(DNM0595)1HNMR(DMSO,500MHz)δ8.09-7.93(m,2H),7.87(s,1H),7.80(d,J=7.24Hz,1H),7.66(t,J=7.71Hz,1H),7.40(d,J=7.86Hz,2H),7.26(d,J=7.86Hz,2H),4.52-4.14(m,4H),1.31(t,J=7.07Hz,3H);13C NMR(DMSO,125MHz)δ165.42,143.15,138.63,138.45,135.17,133.07,131.49,130.65,130.48,130.40,129.46,128.79,128.64,128.37,123.12,60.94,32.96,14.11.
1-(3-(2-(4-氯苯基)-5-(1H-四唑-5-基)噻吩-3-基)苯基)丁基-1-酮(DNM0600)1H NMR(DMSO,500MHz)δ8.00-7.97(m,2H),7.88(s,H),7.77(d,J=7.70Hz,1H),7.65(t,J=7.95Hz,1H),7.39(d,J=8.40Hz,2H),7.26(d,J=8.40Hz,2H),4.32(s,2H),2.98(t,J=7.15Hz,2H),1.63(sex,J=7.30Hz,1H),0.93(t,J=7.35Hz,3H);13C NMR(DMSO,125MHz)δ199.80,142.91,138.94,138.55,137.20,135.19,132.80,131.50,130.68,130.42,129.40,128.66,127.75,127.08,123.27,39.85,32.99,17.17,13.61.
5-(4-(3-丁基苯基)-5-(4-氯苯基)噻吩-2-基)-1H-四唑(DNM0606)1H NMR(DMSO,500MHz)δ7.81(s,1H),7.42-7.34(m,3H),7.32-7.26(m,2H),7.26-7.21(m,3H),4.30(s,2H),2.62(t,J=7.65Hz,2H),1.56(qi,J=7.55Hz,2H),1.31(sex,J=7.54Hz,2H),0.90(t,J=7.37Hz,3H);13C NMR(DMSO,125MHz)δ142.95,139.99,138.72,134.71,131.41,130.87,130.39,128.77,128.59,128.58,128.34,127.76,125.68,122.74,34.73,33.04,21.75,13.79.
3-(2-(4-氯苯基)-5-(1H-四唑-5-基)噻吩-3-基)-5-羟基苯酸乙酯(DNM0609)1H NMR(DMSO,500MHz)δ10.12(s,1H),7.81(s,1H),7.45(s,1H),7.43-7.38(m,3H,7.27(d,J=8.35Hz,2H),7.14(s,1H),4.34-4.25(m,4H),1.30(t,J=7.10Hz,3H);13C NMR(DMSO,125MHz)δ165.41,157.89,150.98,142.84,138.79,138.53,136.37,131.64,131.47,130.45,130.38,128.64,123.18,119.84,119.74,114.99,60.87,32.99,14.11.
5-(5-(4-氯苯基)-4-(3-(环戊基甲基)苯基)噻吩-2-基)-1H-四唑(DNM0610)1HNMR(DMSO,500MHz)δ7.81(s,1H),7.41-7.43(m,3H),7.30(d,J=7.70Hz,1H),7.26(s,1H),7.25-7.19(m,3H),4.30(s,2H),2.61(d,J=7.45Hz,2H),2.10-2.01(m,1H),1.67-1.54(m,4H),1.54-1.41(m,2H),1.21-1.09(m,2H);13C NMR(DMSO,125MHz)δ150.80,142.42,142.22,140.05,138.70,134.61,131.41,130.92,130.34,128.70,128.67,128.58,128.11,125.68,122.65,41.32,41.17,33.01,31.90,24.48.
3-(2-(4-氯苯基)-5-(1H-四唑-5-基)噻吩-3-基)苯酚(DNM0613)1H NMR(DMSO,500MHz)δ9.65(s,1H),7.65(s,1H),7.40(d,J=8.35Hz,2H),7.29(t,J=7.88Hz,1H),7.26(d,J=8.40Hz,2H),6.91(d,J=7.90Hz,1H),6.87(s,1H),6.82(dd,J1=1.79Hz,J2=8.10Hz,1H),4.29(s,2H);13C NMR(DMSO,125MHz)δ157.66,142.45,39.94,138.72,136.01,131.46,130.76,130.44,129.94,128.64,119.11,115.20,114.78,33.07.
5-(5-(4-氯苯基)-4-(3-甲氧基苯基)噻吩-2-基)-1H-四唑(DNM0615)1H NMR(DMSO,500MHz)δ7.84(s,1H),7.47-7.40(m,3H),7.29(d,J=8.45Hz,2H),7.09(d,J=7.80Hz,1H),7.06-7.04(m,1H),7.02(dd,J1=2.00Hz,J2=8.20Hz,1H),4.34(s,2H),3.81(s,3H);13C NMR(DMSO,125MHz)δ159.49,142.69,139.68,138.70,136.13,131.45,130.87,130.44,129.99,128.65,120.68,113.83,113.50,55.14,33.06.
5-(5-(4-氯苯基)-4-(3-丁氧基苯基)噻吩-2-基)-1H-四唑(DNM0616)1H NMR(DMSO,500MHz)δ7.81(s,1H),7.44-7.36(m,3H),7.26(d,J=8.35Hz,2H),7.05(d,J=7.60Hz,1H),6.99-6.95(m,2H),4.31(s,2H),3.95(t,J=6.50Hz,2H),1.69(pen,J=6.96Hz,2H),1.43(sex,J=7.50Hz,2H),0.94(t,J=7.40Hz,2H);13C NMR(DMSO,125MHz)δ158.90,150.96,142.40,139.75,138.74,136.10,131.43,130.85,130.39,129.96,128.63,122.80,120.51,114.13,67.14,33.04,30.73,18.72,13.72.
5-(5-(4-氯苯基)-4-(3-乙氧基苯基)噻吩-2-基)-1H-四唑(DNM0617)1H NMR(DMSO,500MHz)δ7.81(s,1H),7.44-7.37(m,3H),7.26(d,J=8.40Hz,2H),7.05(d,J=7.65Hz,1H),7.01-6.95(m,2H),4.31(s,2H),4.04(q,J=7.00Hz,2H),1.33(t,J=7.00Hz,3H);13C NMR(DMSO,125MHz)δ158.74,142.67,139.70,138.71,136.11,131.44,130.89,130.43,130.01,128.63,120.54,114.20,114.01,63.05,33.05,14.63.
5-(5-(4-氯苯基)-4-(3-丙氧基苯基)噻吩-2-基)-1H-四唑(DNM0618)1H NMR(DMSO,500MHz)δ7.82(s,1H),7.43-7.36(m,3H),7.26(d,J=8.40Hz,2H),7.05(d,J=7.65Hz,1H),7.00-6.95(m,2H),4.31(s,2H),3.91(t,J=6.60Hz,2H),1.73(sex,7.06,2H),0.98(t,J=7.40Hz,3H);13C NMR(DMSO,125MHz)δ158.88,142.50,139.74,138.73,136.09,131.43,130.91,130.39,129.97,128.63,122.72,120.51,114.14,68.92,33.04,22.02,10.37.
实例5
DNM0461及其类似物的合成
5-(3,5-二溴苯)-1H-四唑
圆底烧瓶内装入3,5-二溴苯腈(15.65g,60mmol)、叠氮化钠(7.80g,120mmol)和溴化锌(27g,120mmol)。脱气后,DMF(100mL)被添加。将反应混合物加热到120℃并在此温度下搅拌直到反应完成。反应冷却至室温然后置于冰水浴。300mL 1N HCl水溶液被加入。白色沉淀物形成,吸滤收集,水洗,与五氧化二磷一起真空下干燥,得到17.32g(95%)产品。
2-二苯甲基-5-(3,5-二溴苯基)-2H-四唑
由5-(3,5-二溴苯-1H)-四唑(6.08g,20mmol),二苯基甲醇(3.68g,20mmol)和TsOH·H2O(0.38g,2mmol)溶解在甲苯(50mL)中的悬浮液被加热到100℃,直到得到清澈溶液。溶液冷却至室温,过滤。滤液进行浓缩,残留物经乙醚和己烷重结晶,得8g(85%)白色固体产品。
2-二苯甲基-5-(3,5-二(4-甲基萘-1-基)苯基)-2H-四唑
一个圆底烧瓶装填2-二苯甲基-5-(3,5-二溴苯)-2H--四唑(282mg,0.60mmol),4-甲基萘-1-基硼酸(251mg,1.32mmol)和Pd(PPh3)4(35mg,0.03mmol)。脱气后,二氧六环(5mL)和碳酸钠水溶液(3mL,2M,6mmol)被加入。将反应混合物加热到90℃直到反应完成。加入水30mL,并将反应混合物用乙酸乙酯提取。有机相用无水硫酸钠干燥,然后浓缩。残留物经快速色谱法(正己烷∶CH2Cl2=2∶1)纯化,得到0.32g(90%)白色固体产品。
5-(3,5-二(4-甲基萘-1-基)苯基)-2H-四唑(DNM0461)
2-二苯甲基-5-(3,5-二(4-甲基萘-1-基)苯基)-2H-四唑(0.32g,0.54mmol)溶解在二氯甲烷(2mL)。苯甲醚(0.3mL,2.76mmol)和TFA(1mL)被依次添加。反应搅拌过夜,然后浓缩。残留物由快速色谱法(正己烷∶乙酸乙酯∶醋酸=30∶10∶1)纯化,获得0.22g(95.5%)白色固体产品。1H NMR(DMSO,500MHz)δ8.24(d,J=1.55Hz,2H),8.25(d,J=8.1Hz,2H),8.03(d,J=8.20Hz,2H),7.72(s,1H),7.65(t,J=7.58Hz,2H),7.60(t,J=7.44Hz,2H),7.56(d,J=7.15Hz,2H),7.51(d,J=7.29Hz,2H),2.74(s,6H);13C NMR(DMSO,125MHz)δ141.58,136.38,134.51,133.81,132.43,130.72,127.15,127.03,126.51,126.32,126.11,125.61,124.76.19.21.
下列化合物也采用类似的方法制备:
5-(2,5-二(4-甲基萘-1-基)苯基)-1H-四唑(DNM0446)1H NMR(DMSO,500MHz)δ8.16(d,J=8.45Hz,1H),8.06(d,J=8.41Hz,2H),7.97(s,1H),7.80(dd,J1=7.84Hz,J2=1.80Hz,1H),7.69-7.49(m,7H),7.42(t,J=7.56Hz,1H),7.39(d,J=7.09Hz,1H),7.28(d,J=7.09Hz,1H),2.73(s,3H),2.70(s,3H);13CNMR(DMSO,125MHz)δ139.96,138.93,136.37,135.51,134.38,133.98,132.46,132.21,132.06,132.03,131.37,130.98,130.80,127.11,127.00,126.43,126.34,126.10,126.04,125.89,125.76,125.73,124.73,124.45,19.23,19.14.
5-(2,5-二(4-氯-2-甲苯基)苯基)-1H-四唑(DNM0447)1H NMR(DMSO,500MHz)δ7.79(s,1H),7.65(d,J=7.16Hz,1H),7.51-7.43(m,2H),7.38(s,2H),7.33(s,1H),7.22(d,J=8.09Hz,1H),7.05(d,J=8.14Hz,1H),2.33(s,3H),1.97(s,3H);13C NMR(DMSO,125MHz)δ139.71,138.72,132.58,138.20,138.13,137.59,132.41,132.10,131.39,131.20,131.08,130.96,130.10,130.05,129.00,126.06,125.39,20.05,19.56.
5-(3,5-二(4-氯苯基)苯基)-2H-四唑(DNM0470)1H NMR(DMSO,500MHz)δ8.34(d,J=1.69Hz,2H),8.16(d,J=1.69Hz,2H),7.95-7.91(m,4H),7.65-7.61(m,4H);13C NMR(DMSO,125MHz)δ140.76,137.76,133.22,129.07,128.94,127.58,124.42.
5-(4′-氯-5-(4-甲基萘-1-基)联苯-3-基)-1H-四唑(DNM0480)11H NMR(DMSO,500MHz)δ8.42(t,J=1.60Hz,1H),8.16(d,J=7.98Hz,1H),8.14(t,J=1.58Hz,1H),7.95(t,J=1.62Hz,1H),7.92(d,J=7.90Hz,1H),7.90(d,J=8.70Hz,2H),7.67-7.63(m,1H),7.61(d,J=8.70Hz,2H),7.59-7.55(m,1H),7.54-7.50(m,2H),2.76(s,3H);13C NMR(DMSO,125MHz)δ143.14,141.32,138.28,137.09,134.98,134.46,133.04,131.81,131.53,129.36,128.72,128.11,127.06,126.37,126.31,126.26,126.08,125.13,124.79,19.84.
5-(3,5-二(4-氟萘-1-基)苯基)-2H-四唑(DNM0539)11H NMR(DMSO,500MHz)δ8.26(d,J=1.55Hz,2H),8.19(dd,J1-8.15Hz,J2=1.87Hz,2H),8.05(d,J=7.87Hz,2H),7.77(t,J=1.55Hz,1H),7.75-7.65(m,6H),7.49(dd,J1=10.60Hz,J2=7.95Hz,2H);13C NMR(DMSO,125MHz)δ158.81,156.81,140.71,134.46,134.42,133.80,132.00,131.97,128.67,127.55,127.48,127.46,126.96,125.44,125.42,123.15,123.02,120.46,120.42,109.60,109.44.
实例6
DNM0566及其类似物的合成
4,5-二溴噻吩-2-羧酸乙酯
搅拌条件下,向溶解在12mL硫酸和40mL的TFA里的噻吩-2-羧酸乙酯(12.62g,80.8mmol)中,在2-3小时内被逐步添加NBS(32.00g,177.8mmol)中。然后在室温下搅拌过夜,将反应混合物倒入冰上。白色沉淀物形成,由吸滤收集,并在甲醇重结晶纯化。获得23.38g(92%)白色固体状的产品,熔点:47.0-48.0(lit.mp48.0-49.0℃,Bull.Chem.Soc.Jpn.1991,64(8),2566-8)。
4,5-二(4-氯-2-异丙基苯基)噻吩-2-羧酸乙酯
在圆底烧瓶内装入4,5-二溴噻吩-2-羧酸乙酯(235.5mg,0.75mmol),4-氯-2-异丙基苯基硼酸(327.5mg,1.65mmol)和Pd(PPh3)4(43mg,0.0375mmol)。脱气后,二氧六环(5mL)和碳酸钠水溶液(3mL,2M,6mmol)被加入。将反应混合物加热到90℃直到反应完成。后冷却到室温,反应混合物用30mL的水稀释,用乙酸乙酯提取。有机相用无水硫酸钠干燥,然后浓缩。残留物由快速色谱法(正己烷∶CH2Cl2=2∶1)纯化,获得0.28g(81%)白色固体状的产品。
4,5-二(4-氯-2-异丙基苯基)噻吩-2-羧酸(DNM0566)
搅拌条件下,向溶在THF(3mL)和MeOH(3mL)里的4,5-二(4-氯-2-异丙基苯基)噻吩-2-羧酸乙酯(280mg,0.61mmol)中,加如氢氧化锂(72mg,3mmol)的水(2mL)溶液。反应在室温下搅拌直到完成,然后浓缩。残留物被重新溶解在20mL的水中,并用和1N HCl水溶液酸化到pH值为2。白色沉淀用乙酸乙酯提取。有机相用无水硫酸钠干燥,然后浓缩。残留物经在乙酸乙酯和正己烷混合溶剂下重结晶,得到0.24g(91%)白色固体状产品。1H NMR(CDC13,500MHz)δ7.78(s,1H),7.23(d,J=2.15Hz,1H),7.22(d,J=1.88Hz,1H),7.13-7.07(m,2H),7.03(dd,J1=8.23Hz,J2=2.20Hz,1H),6.89(d,J=8.26Hz,1H),2.95(m,2H),1.04(d,J=4.94Hz,6H),0.98(d,J=6.95Hz,6H);13C NMR(CDC13,125MHz)δ167.13,149.87,149.06,146.58,139.45,137.21,135.53,134.39,132.79,131.84,131.57,131.14,129.01,126.43,126.28,125.86,125.77,30.27,30.23,23.93.
下列化合物也采用类似的方法制备:
4,5-二(4-联苯)噻吩-2-羧酸(DNM0497)1H NMR(CDC13,500MHz)δ13.34(s,1H),7.86(s,1H),7.72-7.65(m,8H),7.50-7.32(m,10H);13C NMR(CDC13,125MHz)δ162.69,143.94,140.16,139.30,139.09,139.00,138.17,135.56,134.08,133.00,131.98,129.46,129.38,129.02,128.98,127.87,127.63,127.12,126.86,126.61,126.53.
4,5-二(4-氯代苯基)噻吩-2-羧酸(DNM0498)1H NMR(CDC13,500MHz)δ13.39(s,1H),7.81(s,1H),7.46(d,J=8.40Hz,2H),7.42(d,J=8.40Hz,2H),7.32(d,J=8.50Hz,2H),7.29(d,J=8.42Hz,2H);13C NMR(CDC13,125MHz)δ162.53,143.06,137.68,135.30,133.60,133.47,133.44,132.47,131.46,130.74,130.64,129.13,128.78.
4,5-二(5-氯-2-甲苯基)噻吩-2-羧酸(DNM0501)1H NMR(CDC13,500MHz)δ13.38(s,1H),7.77(s,1H),7.36(d,J=2.20Hz,1H),7.34(dd,J1=2.20Hz,J2=8.15Hz,1H),7.26-7.22(m,3H),7.05(s,1H),2.01(s,3H),1.96(s,3H);13CNMR(CDCI3,125MHz)δ162.63,143.31,138.84,136.36,135.58,134.85,134.75,133.77,133.76,132.18,132.08,130.47,130.07,129.86,129.60,128.88,127.74,19.22,19.09.
4,5-二(3-氯代苯基)噻吩-2-羧酸(DNM0502)1H NMR(CDC13,500MHz)δ13.34(s,1H),7.85(s,1H),7.47(d,J=8.10Hz,1H),7.44-7.34(m,5H),7.26(d,J=7.65Hz,1H),7.20(d,J=7.45Hz,1H);13C NMR(CDCI3,125MHz)δ162.50,142.92,137.70,136.57,135.23,134.51,133.77,133.50,133.31,130.87,130.48,128.75,128.56,128.53,127.85,127.69,127.63.
4,5-二(2,4-二甲基苯基)噻吩-2-羧酸(DNM0503)1H NMR(CDC13,500MHz)δ13.19(s,1H),7.66(s,1H),7.12(d,J=8.25Hz,1H),7.03-6.95(m,3H),6.87-6.81(m,2H),2.24(s,3H),2.22(s,3H),2.07(s,3H),1.93(s,3H);13CNMR(CDCI3,125MHz)δ162.82,144.83,139.77,138.16,136.78,136.10,135.28,135.22,132.49,132.04,130.98,130.91,130.02,129.43,126.45,126.27,20.66,20.61,19.78,19.64.
4,5-二(4-氯-2-甲苯基)噻吩-2-羧酸(DNM0561)1H NMR(CDC13,500MHz)δ7.81(s,1H),7.17(d,J=2.02Hz,1H),7.14(s,1H),7.13-7.11(m,2H),7.03(dd,J1=8.24Hz,J2=2.02Hz,1H),6.87(d,J=8.24Hz,1H),2.12(s,3H),2.03(s,3H);13C NMR(CDCI3,125MHz)δ167.74,147.16,140.15,139.20,138.26,137.56,135.29,134.06,133.61,132.85,131.97,131.74,131.13,131.03,130.88,126.50,126.43,20.61,20.59.
实例7
DNM0631及其类似物的合成
2-溴-3-甲基噻吩
在rt条件下,NBS(8.90g,50mmol)分批添加到搅拌中的3-甲基噻吩(4.90g,50mmol)醋酸(20mL)的溶液。添加完成后,反应在常温下搅拌直到反应完成。将反应混合物倒入冰水,然后用正己烷和乙醚的3:1的混合溶剂提取。有机层用1N NaOH水溶液和盐水清洗。在用无水硫酸钠干燥后,将有机相真空浓缩,获得2-溴-3-甲基噻吩(8.20g,92.7%),该物质无需进一步纯化,可直接在下一步使用。
3-甲基噻吩-2-腈
用圆底烧瓶装入2-溴-3-甲基噻吩(8.20g,46.3mmol)和CuCN(8.29g,92.6mmol)。脱气后,加入50mL DMF。将反应混合物加热到150℃过夜。冷却到室温后,反应用250mL水终止,用乙酸乙酯萃取。有机相用无水硫酸钠干燥,然后浓缩。残留物通过一个又短又款的硅柱,该柱用己烷洗脱,获得5.07g产品。
4,5-二溴-3-甲基噻吩-2-腈
常温下,溴(4.25mL,82.6mmol)被滴加到搅拌的3-甲基噻吩-2-腈(5.07g,41.2mmol)溶于DMF(20mL)的溶液中。滴加完成后,该反应被加热到60℃直到完成。冷却到常温,将反应混合物倒入冰水。形成浅黄色固体,通过抽吸过滤收集,真空下与五氧化二磷一起进行干燥,获得9.84g的4,5-二溴-3-甲基噻吩-2-腈。
4,5-二(4-氯-2-异丙苯基)-3-甲基噻吩-2-腈
圆底烧瓶内装有4,5-二溴-3-甲基噻吩-2-腈(140.5mg,0.50mmol),2-(4-氯-2-异丙基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(308.7mg,1.10mmol)和Pd(PPh3)4(29mg,0.025mmol)。脱气后,二氧六环(5mL)和碳酸钠水溶液(3mL,2M,6mmol)被加入。将反应混合物加热到95℃直到反应完成。后冷却到室温,反应混合物用30mL水稀释,用乙酸乙酯提取。有机相用无水硫酸钠干燥,然后浓缩。残留物由快速色谱法纯化(正己烷:CH2Cl2=4:1),获得190.5mg(89%)白色固体状的产品。
5-(4,5-二(4-氯-2-异丙基苯基)-3-甲基噻吩-2-基)-1H-四唑(DNM0631)
圆底烧瓶内装入4,5-二(4-氯-2-异丙苯基)-3-甲基噻吩-2-腈(1 0.5mg,0.44mmol),溴化锌(338mg,1.50mmol)和叠氮化钠(97.5mg,1.50mmol)。脱气后,DMF(3mL)被添加。将反应混合物加热到130℃并在此温度下搅拌直到完成。反应冷却至室温,30mL0.1 NHCl水溶液被加入。将反应混合物用乙酸乙酯提取。有机相通过无水硫酸钠干燥,然后浓缩。残留物由快速色谱法(正己烷∶乙酸乙酯∶醋酸=30∶10∶1)纯化。获得188.7mg(90%)白色固体状产品。1H NMR(CDC13,500MHz)δ7.25-7.22(m,2H),7.18(dd,J1=8.18Hz,J2=2.13Hz,1H),7.09-7.06(m,2H),7.02(d,J=8.20Hz,1H),3.04(sep,J=6.75Hz,1H),2.74(sep,J=6.80Hz,1H),2.37(s,3H),1.12(d,J=6.80Hz,3H)51.05(d,J=6.80Hz,6H),0.90(d,J=6.80Hz,3H);13C NMR(CDC13,125MHz)δ150.32,149.87,141.11,140.81,140.72,135.33,134.47,132.72,132.02,131.51,129.01,126.30,126.20,125.84,125.52,30.35,30.10,24.76,23.60,23.13,15.78.
下列化合物也采用类似的方法制备:
5-(4,5-二(4-氯-2-甲苯基)-3-甲基噻吩-2-基)-1H-四唑(DNM0614)1H NMR(CDC13,500MHz)δ7.15(s,1H),7.11(s,1H),7.08(d,J=8.20Hz,1H),7.05-7.01(m,2H),6.93(d,J=8.30Hz,1H),2.31(s,3H),2.17(s,3H),2.04(s,3H);13C NMR(CDCI3,125MHz)δ141.47,140.34,139.95,139.41,139.16,134.57,133.83,133.81,132.76,132.20,131.43,130.52,130.42,126.20,126.00,20.81,20.03,15.56.
5-(4,5-二(4-甲基萘-1-基)-3-甲基噻吩-2-基)-1H-四唑(DNM0620)1H NMR(CDC13,500MHz)δ8.04(d,J=8.30Hz,1H),7.91(d,J=8.30Hz,1H),7.86(d,J=8.40Hz,1H),7.77(dd,J1=8.30Hz,J2=1.10Hz,1H),7.48-7.37(m,3H),7.32(t,J=7.65Hz,1H),7.18(d,J=7.20Hz,1H),7.06-7.00(m,3H),2.55(s,3H),2.54(s,3H),2.28(s,3H);13C NMR(CDC13,125MHz)δ142.29,141.77,141.39,135.21,134.23,132.73,132.52,132.44,132.35,131.52,128.93,128.72,127.94,126.61,126.30,126.07,125.82,125.74,125.70,125.64,125.52,124.44,124.10,119.63,19.49,19.42,15.54.
5-(4,5-二(3-丁基苯基)-3-甲基噻吩-2-基)-1H-四唑(DNM0627)1H NMR(CDC13,500MHz)δ7.30(t,J=7.53Hz,1H),7.17(d,J=7.70Hz,1H),7.15(t,J=7.60Hz,1H),7.10-6.97(m,5H),2.59(t,J=7.58Hz,2H),2.48(s,3H),2.46(t,J=7.75Hz,2H),1.57-1.49(m,2H),1.45-1.37(m,2H),1.33-1.18(m,4H),0.90(t,J=7.35Hz,3H),0.89(t,J=7.30Hz,3H);13C NMR(CDC13,125MHz)δ143.22,143.19,142.95,141.28,141.17,135.74,133.10,130.46,129.16,128.47,128.30,128.15,127.67,127.45,126.23,125.52,35.42,35.36,33.56,33.26,30.31,22.15,22.07,15.64,13.92,.
5-(4,5-二(4-氟萘-1-基)-3-甲基噻吩-2-基)-1H-四唑(DNM0628)1H NMR(CDC13,500MHz)δ8.10-8.06(m,1H),8.03(d,J=8.30Hz,1H),7.96(d,J=8.50Hz,1H),7.76-7.71(m,1H),7.56-7.44(m,3H),7.39(t,J=7.50Hz,1H),7.22(dd,J1=5.40Hz,J2=7.80Hz,1H),7.08(dd,J,=5.38Hz,J2=7.83Hz,1H),6.95-6.87(m,2H),2.34(s,3H);13C NMR(CDCI3,125MHz)δ159.96,159.45,157.93,157.44,141.79,141.44,133.85,133.81,133.52,133.49,128.95,128.89,128.71,128.67,128.08,128.02,127.36,127.24,126.30,126.20,125.67,125.53,125.39,123.72,123.59,123.56,123.43,121.05,121.01,120.70,120.66,109.03,108.87,108.77,108.61,15.53.
实例8
Acps抑制的测试
材料
[3H]乙酰辅酶A([3H]Acetyl-CoA)作为1体积的Perkin Elmer NET290放射性标记的原液(例如0.1mCi/ml,3.7Ci/mmol在醋酸钠,pH 4.5-5.0=27μΜ)与1.2体积的1mM未标记的乙酰辅酶A(Sigma)混合。制备三氯乙酸,作为10%w/v溶液。制备牛血清白蛋白作为25mg/ml水溶液。制备DTT作为50mM水溶液。
工序
1.一个标准的反应包含以下,总量为10μl:
2.试管在室温下培养。[3H]乙酰辅酶A被最后添加从而开始反应。为停止反应,2μl被移除到一个1.5-ml微量离心管,离心管包括了800μl冷10%TCA。多达四个时间点对每一个反应进行收集,例如在5分钟,10分钟,30分钟,60分钟。
3.25μl的25mg/ml BSA被添加到每个试管,混合孵育在冰上10分钟,然后在12000g离心5分钟以形成小球。用P1000除去上清液。
4.每个颗粒用800μl的冷的10%TCA清洗两次,然后每次清洗后在12000g离心分离5分钟。上清液丢弃。每个颗粒是悬浮在50μL甲酸中。悬浮液被转移到一个闪烁瓶和放射性在2mL的液体闪烁鸡尾酒中测量。在闪烁计数中的随机(随机)误差与在计数期间累计的平方根(不是每分钟衰变数)成比例;即10%对100,3.3%对1000,1%对10000,等。提供的放射性计数(dpm)是以千计,测定提供了有用的资料。根据工作基板的空白减计数,结果以%活性被记录。小于约40%的A%活性意味着该浓度下的实验化合物对AcpS酶的抑制作用
就结论来说,参照实例后的表格。
实例9
最小抑菌浓度(MIC)测定
化合物的敏感性通过国家临床实验室标准委员会(NCCLS)的M7-A6培养基稀释法进行测定。阳离子调整Mueller-Hinton培养基(Ca2+,25μg/ml;Mg2+,12.5μg/ml)微量稀释板用于制备含有在合理范围内的抗菌双倍稀释浓度。二甲基亚砜(DMSO)对照组被纳入面板用来模拟在高浓度时用于溶解一些化合物的二甲基亚砜的量。每一个最后的面板以及体积为100μl,含有5×105CFU(菌落形成单位)/mL有关细菌的细菌接种量。微量稀释板被进行如下研究,在环境空气中处于35℃,16至20小时孵育。MIC(最低抑菌浓度)被定义为抗菌药物抑制可见生长的最低浓度。
下面的表格和图1,表明实施例例8和实施例例9可用的实验结果,表明AcpS对耐甲氧西林金黄色葡萄球菌(MRSA)的抗菌作用和大肠杆菌D22的抑制和抗菌作用:
实例10
测定复合MIC,用于评估在铜绿假单胞菌中抗生素佐剂潜力
一般依据实例9程序,氨苄青霉素、红霉素和阿奇霉素的MIC,通过对抗铜绿假单胞菌来测定。与此同时,制备同样的溶液。每个这些分别添加0.5μl给定的本发明化合物的储备溶液,再稀释以产生最终浓度为125μΜ、60μΜ、和/或30μΜ,以测定佐剂活性。如果混合物产生了一个与单独的抗菌剂相比,较低的最低抑制浓度,则化合物被确定为抗菌佐剂。结果如下,说明了抗菌佐剂效果:
·DNM0487,对于红霉素,在125μΜ(独立的MIC>2mM)产生高达60倍的更低的MIC。
·DNM0487,对于氨苄青霉素,在125μΜ产生高达60倍的更低的MIC。
·DNM0488,对于氨苄青霉素,在125μΜ产生高达60倍的更低的MIC。
·DNM0501,对于红霉素,在60μΜ产生高达60倍的更低的MIC。
·DNM0501,对于氨苄青霉素,在60μΜ产生高达250倍更低的MIC。
·DNM0537,对于红霉素,在60μΜ产生高达60倍的更低的MIC。
·DNM0537,对于红霉素,在30μΜ产生高达7倍的更低的MIC。
·DNM0537,对于氨苄青霉素,在30μΜ产生高达250倍的更低的MIC。
·DNM0548,对于红霉素,在125μΜ产生高达125倍的更低的MIC。
·DNM0548,对于氨苄青霉素,在125μΜ产生高达125倍的更低的MIC。
实例11
选定的化合物对一组挑战病原体的MIC的测试
每一种菌株的接种的制备通过选择培养板上5-10个不同的菌落,并使它们在适合的培养基中悬浮,视情况,根据临床和实验室标准协会(CLSI)的指导方针M07-A8、M24-A或者M11-A7。接种物被重新悬浮,通过在旋涡混合器强力摇晃15秒。然后浊度被调整到麦克法兰标准0.5(1-5×106CFU/mL)。接种物在适当的介质被进一步稀释,用于最低抑制浓度,在每个2-8×105CFU/mL的井中给一个最后的接种。最低抑制浓度根据和合适的临床和实验室标准协会(CLSI)的指导在合适的培养基中测试。
在浓度为1.28g/L的二甲基亚砜中制备了各化合物原液。原液被进一步稀释在适当的媒介中,制备化验中128mg/升顶起始浓度。100μL的合适媒体,按临床和实验室标准协会(CLSI)指南,被分配到2-12列的每个井。200μL的每个化合物溶液(在256mg/L)被分配到栏1各井。100μL等份用移液管从列1井中移出,用多道移液管(变异系数±2%)从而稀释2倍,分配到列2。重复该过程,一直到列10。最后来自列10的100μL稀释药物然后被丢弃。行11作为阳性对照(无化合物,但微生物被添加),行12作为阴性对照(无化合物,无位生物被添加)。
在合适介质中的合适接种悬浮液100μL,按CLSI指南,被添加到合适的井中。这导致了一个井含有20μl最终体积(由100μL稀化合物或稀释剂,和100μL接种体或单独的培养基)。所有板在黑暗好氧或厌氧条件下30-37℃孵育24-48小时,根据适当的临床和实验室标准协会(CLSI)指南。板被直接观察24-48小时后期接种。100%的抑制端点确定下来(CLSI解释终点根据目视检查)。
MIC50、MlC80、和100%抑制结果的报告在下面的表中,以μg/mL计量,指示每个化合物与一个给定的物种和菌株进行了对抗测试:
这些结果表明,本发明的化合物是有效的抗菌剂对多种抗生素耐药菌株,而且在许多情况下(特别是相对于VRE)比万古霉素更有效。
实例12
测量对肺炎链球菌A组的MIC
通常来说按照例9的步骤,但是使用Todd Hewitt培养基(牛心消化液)而不是Mueller-Hinton培养基,最初测定本发明化合物对肺炎链球菌群A组的MIC,如下:
上述7种化合物在Todd Hewitt培养基或CASO培养基(酪蛋白,大豆)中的MIC重复测试结果表明,这些化合物的MIC范围为125nM和8μΜ之间,平均MIC为1.6μΜ。这些结果表明,本发明的化合物对链球菌具有有效的抗菌作用。
Claims (30)
1.一种化合物,或其药物前体或医药上可接受的盐,如通式(I)中的一个所示:
其中,
E是-CH2-或者当噻吩直接连到苯环上时它不存在;
R1,R2,R9,R10和R11如果存在,则各独立选自氢、甲基、乙基、丙基、环丙基、丁基、环丁基、戊基、己基、异丙基、异丁基、新戊基、甲氧基和乙氧基组成的组;
此外,R1和R2可以连接形成一个苯基或者苯并呋喃环;
此外,R9和R10可以连接形成一个苯基或者苯并呋喃环;
R3和R8各自独立选自氢、甲基、乙基、丙基、异丙基、氯、氟、叔丁基、甲磺酰基、甲氧基和乙氧基组成的组;
R4和R7各自独立选自氢、氯、甲酯、乙酯、甲基、乙基、丙基、环丙基、丁基、环丁基、异丙基、异丁基、甲氧基和乙氧基组成的组;
R5和R6各自独立选自氢、环戊基、环丙基、呋喃、噻吩、三氟甲基、三氟甲基醚、甲巯基、甲醛、氯、氟、溴、苯基、甲基、乙基、异丙基、丙基、丁基、环丁基、异丁基、新戊基、戊基、甲氧基和乙氧基组成的组。
2.如权利要求1所述的化合物,其中,所述化合物根据通式(Ia)所示;
R1和R2各自独立选自氢和甲基组成的组,或者当所在的环为萘环时形成苯环;
R9和R10各自独立选自氢和甲基组成的组,或者当所在的环为萘环时形成苯环;
R11为氢;
R3和R8各自独立选自氢、甲基、氯、氟、异丙基、叔丁基、甲氧基和甲磺酰基组成的组;
R4和R7各自独立选自氢、甲基、氯和乙酯组成的组;
R5和R6各自独立选自甲基、乙基、苯基、氢、氯、异丙基、环戊基、溴、环丙基、三氟甲基、三氟甲基醚、甲巯基、甲醛、呋喃和噻吩组成的组。
3.根据权利要求2所示的化合物,其中E不存在。
4.根据权利要求3所示的化合物,其中R1、R2、R4、R7、R9和R10都是氢。
5.根据权利要求4所示的化合物,其中R3和R8都是氯;R5和R6选自氢、甲基和异丙基组成的组。
6.5-(4,5-二(4-氯-2-甲苯基)噻吩-2-基)-1H-四唑或其药物前体或药学上可接受的盐。
7.5-(4,5-二(4-氯-2-异丙基苯基)噻吩-2-基)-1H-四唑或其药物前体或药学上可接受的盐。
8.5-(4-(3-丁基苯基)-5-(4-氯苄基)噻吩-2-基)-1H-四唑或其药物前体或药学上可接受的盐。
9.5-(4,5-二(4-氯-2-异丙基苯基)3-甲基噻吩-2-基)-1H-四唑或其药物前体或药学上可接受的盐。
10.根据权利要求1所示的化合物,其中,所述化合物选自于图1列出的各种物质或其药物前体或医药上可接受的盐组成的组。
11.一种化合物,或其药物前体或医药上可接受的盐,如通式(II)中的一个所示:
其中,
R1,R2,R3,R5和R12各自独立选自氢、甲基、乙基、丙基、环丙基、丁基、环丁基、戊基、己基、异丙基、异丁基、新戊基、甲氧基和乙氧基组成的组;
R4和R13各自独立选自氢、甲基、乙基、丙基、环丙基、丁基、环丁基、戊基、己基、异丙基、异丁基、新戊基、甲氧基、乙氧基和二烷基胺组成的组;
此外,R4和R5可以形成一个苯环;
此外,R12和R13可以形成一个苯环;
R6和R11各自独立选自氢、氯、氟、羟基、苯基醚、甲基、乙基、丙基、异丙基、叔丁基、甲氧基和乙氧基组成的组;
R7和R10各自独立选自氢、氯、甲基、乙基、丙基、异丙基、叔丁基、甲氧基和乙氧基组成的组;
R8和R9各自独立选自氢、卤素、甲基、乙基、丙基、异丙基、叔丁基、甲氧基、乙氧基、任意位置被甲基取代的萘基以及任意位置被氯、溴、羧酸和烷基取代的苯基组成的组。
12.根据权利要求9所述的化合物,其中,
R6和R11各自独立选自氢、氯、氟、羟基、苯基醚和烷基组成的组;
R7和R10各自独立选自氢、氯和烷基组成的组;
R8和R9各自独立选自氢、卤素、甲基、异丙基、任意位置被甲基取代的萘基以及任意位置被氯、溴、羧酸和烷基取代的苯基组成的组。
13.根据权利要求10所述的化合物,其中,所述化合物如通式IIa所示。
14.根据权利要求10所述的化合物,其中,所述化合物如通式IIb所示。
15.根据权利要求1所述的化合物,其中,所述化合物选自于图2列出的各种物质组成的组。
16.一种治疗微生物感染的方法,包括将有效量的前述权利要求中任意一项所述化合物施药给需要它的病人。
17.根据权利要求16所述的治疗方法,其中,所述微生物感染主要是由革兰氏-阳性细菌引起的。
18.根据权利要求17所述的治疗方法,其中,所述微生物感染包括葡萄球菌的感染。
19.根据权利要求17所述的治疗方法,其中,所述微生物感染包括肠球菌的感染。
20.根据权利要求17所述的治疗方法,其中,所述微生物感染包括芽孢杆菌的感染。
21.根据权利要求17所述的治疗方法,其中,所述微生物感染主要是由选自于金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、肠球菌、蜡样芽胞杆菌和链球菌所组成的组中的一种细菌物种造成的。
22.一种治疗微生物感染的方法,包括将有效量的上述任意一项权利要求所述的抗菌佐剂化合物和一种有效量的抗菌化合物施药给需要它的病人。
23.根据权利要求22所述的治疗方法,其中,所述微生物感染主要是由革兰氏-阴性细菌引起的。
24.根据权利要求22所述的治疗方法,其中,所述微生物感染主要是由革兰氏-阳性细菌引起的。
25.根据权利要求22所述的治疗方法,其中,所述微生物感染是多种微生物感染。
26.根据权利要求22所述的治疗方法,其中,所述微生物感染主要是由绿脓杆菌引起的。
27.根据权利要求22所述的治疗方法,其中,所述抗菌佐剂化合物是如权利要求1所述的物质。
28.根据权利要求27所述的治疗方法,其中,所述抗菌佐剂化合物选自DNM0487、DNM0488和DNM0548组成的组。
29.根据权利要求28所述的治疗方法,其中,所述抗菌化合物选自氨苄青霉素、红霉素和阿奇霉素所组成的组。
30.一种药物组合物,包括权利要求1-15中任意一项所述的化合物和一种医药上可接受的赋形剂。
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CN112280812A (zh) * | 2020-09-30 | 2021-01-29 | 浙江工业大学 | 一种提高金黄霉素a的发酵产量和金黄霉素a与b之间比例的方法 |
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WO2012116452A1 (en) | 2012-09-07 |
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