CN115073448A - 稠环杂环化合物、或其药学上可接受的盐在制备治疗脑卒中药物中的应用 - Google Patents
稠环杂环化合物、或其药学上可接受的盐在制备治疗脑卒中药物中的应用 Download PDFInfo
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- CN115073448A CN115073448A CN202110267927.1A CN202110267927A CN115073448A CN 115073448 A CN115073448 A CN 115073448A CN 202110267927 A CN202110267927 A CN 202110267927A CN 115073448 A CN115073448 A CN 115073448A
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Abstract
Description
技术领域
本发明实施例涉及化学药物应用领域,特别涉及稠环杂环化合物、或其药学上可接受的盐在制备治疗脑卒中药物中的应用。
背景技术
脑卒中(cerebralapoplexy)是脑血液循环障碍性疾病,具有极高的病死率与致残率。我国心血管病2016报告资料指出,我国脑卒中发病率持续升高,死亡人数逐年增加,根据已有统计,2015年卒中人数高达700万;死亡率也高居各类疾病之首,达到153.63/10万(农村)和128.23/10万(城市)。脑卒中主要分为出血性脑卒中(脑出血或蛛网膜下腔出血)与缺血性脑卒中(脑梗死、脑血栓)两大类,其中,缺血性脑卒中(ischemic stroke)占全部脑卒中的86%。
诱导脑卒中发生的因素主要包括高血压、动脉粥样硬化、心脏病、脑出血、炎症侵犯脑膜与脑血管、血液病、代谢病、各种外伤、脑瘤等,也与环境、劳力过度和情志过激等因素相关。近年来,已有大量科学家深入研究了脑卒中的发病机制,经典的理论包括炎症反应、钙超载、细胞凋亡、谷氨酸兴奋毒性、血液流变学、能量耗竭与酸中毒等。而近年来,氧化应激、线粒体功能紊乱也被认为是导致脑缺血神经元死亡的关键因素。
根据缺血性脑卒中发病高、致死致残率高的特征,国内外在防治该疾病的药物研发方面已经投入了大量的人力物力,进行了长期探索。目前,对该疾病的临床治疗,不同国家也制定了不同的诊治指南,多是根据症状和已经认识的机制进行针对性的药物选择,而在所有的治疗药物中,只有组织型纤溶酶原激活剂(tissue-type plas分钟ogenactivator,tPA)是各国诊治指南中公认的针对脑血栓溶解的药物,而其他药物均没有得到各国的公认。并且,值得注意的是,这些防治手段对该病的发病率、死亡率和致残率并没有产生明显的影响,说明目前依然缺乏有效的防治脑卒中的临床药物。因此,找寻脑缺血损伤过程中的关键分子并研发新型药物,十分迫切。
发明内容
如本文所用的,术语“药学上可接受的盐”是指在制药上可接受的并且具有母体化合物药理学活性的本发明化合物的盐。这类盐包括:与无机酸或与有机酸形成的酸加成的盐,所述的无机酸诸如硝酸,磷酸,碳酸等;所述的有机酸诸如丙酸,己酸,环戊丙酸,乙醇酸,丙酮酸,葡糖酸,硬脂酸,粘康酸等;或在母体化合物上存在的酸性质子被金属离子,例如碱金属离子或碱土金属离子取代时形成的盐;或与有机碱形成的配位化合物,所述的有机碱诸如乙醇胺,二乙醇胺,三乙醇胺,N-甲基葡糖胺等。本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地,优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。除了盐的形式,本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外,前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
如本文所用的,术语“杂芳基”,“杂芳基环”和“杂芳环”可互换使用,指环原子被至少一个独立选自氮、氧或硫的杂原子取代的单环或稠合多环(即共享毗邻环原子对,共享的毗邻环原子对可以是C-C或N-C)基团,其中氮和硫原子可任选地被氧化,氮原子可任选地被季铵化。本文所用术语“五元杂芳基”指的是具有五个环原子的杂芳基,术语“六元杂芳基”指的是具有六个环原子的杂芳基,本文所用的“五元杂芳基”和“六元杂芳基”非限制地包括下述形式:
如本文所用的,术语“杂环基”是单环中至少一个碳原子被杂原子取代的环基,所述杂原子为非碳原子,优选为N、O或S原子。
本发明实施方式的目的在于提供一种稠环杂环化合物、或其药学上可接受的盐在制备治疗脑卒中药物中的应用。
为解决上述技术问题,本发明的实施方式第一方面提供了一种稠环杂环化合物、或其药学上可接受的盐在制备治疗脑卒中药物中的应用,所述稠环杂环化合物具有通式(I)所示结构:
式中,R1为未取代或至少一个氢原子被R1-1取代的杂芳基、未取代或至少一个氢原子被R1-2取代的苯基,其中,R1-1为卤素或C1~6烷基,R1-2为卤素、氰基、硝基、C2~8酯基、C1~6烷基或C1~6烷氧基;
X为碳原子或氮原子。
在一些优选的方案中,所述R1为未取代或至少一个氢原子被R1-1取代的杂芳基,所述未取代或至少一个氢原子被R1-1取代的杂芳基为未取代或至少一个氢原子被R1-1取代的五元杂芳基或未取代或至少一个氢原子被R1-1取代的六元杂芳基;其中,所述R1-1为卤素或C1~6烷基,所述卤素优选为氟、氯、溴或碘,所述C1~6烷基优选为C1~4烷基(例如:甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基);
所述未取代或至少一个氢原子被R1-1取代的五元杂芳基优选为含有至少一个N、O或S原子的未取代或至少一个氢原子被R1-1取代的五元杂芳基,更优选为含有一个O或S原子的未取代或至少一个氢原子被R1-1取代的五元杂芳基,最优选为呋喃基或噻吩基,所述的呋喃基优选为所述的噻吩基优选为(所述的R1-1的个数可为一个或多个,当存在多个R1-1时,所述的R1-1相同或不同);
所述未取代或至少一个氢原子被R1-1取代的六元杂芳基优选为含有至少一个N、O或S原子的的未取代或至少一个氢原子被R1-1取代的六元杂芳基,更优选为未取代或至少一个氢原子被R1-1取代的吡啶基,所述的吡啶基优选为(所述的R1-1的个数可为一个或多个,当存在多个R1-1时,所述的R1-1相同或不同);
或者,所述R1为未取代或至少一个氢原子被R1-2取代的苯基(所述的R1-2的个数可为一个或多个,当存在多个R1-2时,所述的R1-2相同或不同),所述R1-2为卤素、氰基、硝基、C2~8酯基、C1~6烷基、C1~6烷氧基;所述卤素优选为氟、氯、溴或碘;所述C1~6烷基优选为C1~4烷基(例如:甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基);所述C1~6烷氧基优选为C1~4烷氧基(例如:甲氧基或乙氧基)。
在一些优选的方案中,表示单键,R2为羟基、C2~12酰氧基或C1~6烷氧基;所述C2~12酰氧基优选为C2~8酰氧基,所述C2~8酰氧基为其中Re为C1~7烷基(例如:甲基、乙基、丙基、丁基、戊基、己基或庚基);所述C1~6烷氧基优选为C1~4烷氧基(例如:甲氧基、乙氧基或丙氧基);
在一些优选的方案中,R3为羟基、C1~4烷基、C1~6烷氧基、或含有至少一个N、O或S原子的杂环基,其中Ra和Rb分别独立地选自氢、C1~4烷基或C1~4烷氧基;所述C1~4烷基优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;所述C1~6烷氧基优选为C1~4烷氧基(例如:甲氧基、乙氧基或丙氧基);所述中,Ra和Rb分别独立地优选为氢、甲基、乙基、甲氧基或乙氧基(例如: );所述含有至少一个N、O和/或S原子的杂环基优选为含有至少一个N、O和/或S原子的三元杂环基、含有至少一个N、O和/或S原子的四元杂环基、含有至少一个N、O和/或S原子的五元杂环基或含有至少一个N、O和/或S原子的六元杂环基,更优选为含有至少一个N和/或O原子的四元杂环基、含有至少一个N和/或O原子的五元杂环基或含有至少一个N和/或O原子的六元杂环基,进一步优选为含有一个或两个N和/或O原子的四元杂环基、含有一个或两个N和/或O原子的五元杂环基、含有一个或两个N和/或O原子的六元杂环基,最优选为:四至六元环亚胺基(例如:)、含有两个N原子的六元杂环基,优选为其中Rc选自氢或C1~4烷氧基,(例如:)或含有一个N原子和一个氧原子的六元杂环基,(例如:)。
在一些优选的方案中,X为碳原子,所述稠环杂环化合物具有通式(II)所示结构:
式中,R1为未取代或至少一个氢原子被R1-1取代的杂芳基、未取代或至少一个氢原子被R1-2取代的苯基,其中,R1-1为卤素或C1~6烷基,R1-2为卤素、氰基、硝基、C1~6烷基、C1~6烷氧基;
式中,R1为未取代或至少一个氢原子被R1-2取代的苯基,其中,R1-2为卤素、氰基、硝基、C1~6烷基、C1~6烷氧基;优选地,R1为未取代的苯基;
R2为羟基、C2~12酰氧基或C1~6烷氧基;优选地,R2为羟基、C2~8酰氧基或C1~4烷氧基,所述C2~8酰氧基为其中Re为C1~7烷基(例如:甲基、乙基、丙基、丁基、戊基、己基或庚基);所述C1~4烷氧基优选为甲氧基、乙氧基或丙氧基;
R3为羟基、C1~4烷基、C1~6烷氧基或其中Ra和Rb分别独立地选自氢、C1~4烷基或C1~4烷氧基;优选地,R3为羟基、C1~4烷氧基或其中Ra和Rb分别独立地选自氢或C1~4烷基;更优选地,R3为羟基、甲氧基、乙氧基、
式中,R1为未取代或至少一个氢原子被R1-1取代的杂芳基、未取代或被R1-2取代的苯基,其中,R1-1为卤素或C1~6烷基,R1-2为卤素、氰基、硝基、C1~6烷基、C1~6烷氧基;
R3为羟基、C1~4烷基、C1~6烷氧基、含有至少一个N、O和/或S原子的杂环基或其中Ra和Rb分别独立地选自氢、C1~4烷基或C1~4烷氧基;优选地,R3为羟基、C1~4烷氧基、含有至少一个N和/或O原子的四元杂环基、含有至少一个N和/或O原子的五元杂环基、含有至少一个N和/或O原子的六元杂环基或其中Ra和Rb分别独立地选自氢、氢、甲基、乙基、甲氧基或乙氧基;更优选地,R3为羟基、甲氧基、乙氧基、丙氧基、四至六元环亚胺基(例如:)、含有两个N原子的六元杂环基(例如: )或含有一个N原子和一个氧原子的六元杂环基(例如:)。
在一些优选的方案中,所述稠环杂环化合物选自下述任一种结构:
式中,R1为未取代或至少一个氢原子被R1-2取代的苯基,其中,R1-2为卤素、氰基、硝基、C1~6烷基、C1~6烷氧基;优选地,R1为未取代的苯基或至少一个氢原子被卤素或C1~4烷基取代的苯基;更优选地,R1为未取代的苯基;
R2为羟基或C1~6烷氧基;优选为羟基;
R3为羟基、C1~4烷基或C1~6烷氧基;优选为C1~6烷氧基;更优选为C1~4烷氧基(例如:乙氧基)。
式中,R1为未取代或至少一个氢原子被R1-2取代的苯基,其中,R1-2为卤素、氰基、硝基、C1~6烷基、C1~6烷氧基;优选地,R1为未取代的苯基或至少一个氢原子被卤素或C1~4烷基取代的苯基;
R3为羟基、C1~4烷基、C1~6烷氧基、含有至少一个N的杂环基或其中Ra和Rb分别独立地选自氢或C1~4烷基;优选地,R3为羟基、C1~4烷氧基(例如:乙氧基)、五或六元环亚胺基(例如:)或其中Ra和Rb分别独立地选自氢、甲基或乙基(例如:)。
在一些优选的方案中,所述稠环杂环化合物具有下述任一种结构:
在一些优选的方案中,所述脑卒中为缺血性脑卒中。
本发明的实施方式第二方面提供了一种治疗脑卒中的方法,所述方法包括步骤:向脑卒中患者施用有效剂量的上述稠环杂环化合物或其药学上可接受的盐。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明实施方式相对于现有技术而言,至少具有下述优点:
(1)本发明为稠环杂环化合物开辟了新的应用领域,尤其是在制备治疗脑卒中药物应用方面。
(2)本发明中的产品稠环杂环化合物具有显著减少脑梗死面积,增强缺血复灌过程中的自噬功能的作用从而实现脑保护的作用。
(3)本发明中的产品稠环杂环化合物可通过抑制TRPM2通道从而抑制神经元锌离子累积从而起到脑保护作用,因此本发明所述稠环杂环化合物有助于脑损伤后的修复。
附图说明
一个或多个实施例通过与之对应的附图中的图片进行示例性说明,这些示例性说明并不构成对实施例的限定。
图1是根据本发明实施例66中所述稠环杂环化合物II-1、II-19和II-36抑制TRPM2通道电流的电生理代表性电流示意图;
图2是根据本发明实施例67中C57BL/6小鼠进行短暂性大脑中动脉阻塞模型(tMACO)造模后,化合物II-1和阳性对照药(依达拉奉)对小鼠脑组织缺血侧TTC染色结果示意图;
图3是根据本发明实施例68中小鼠脑组织的梗死面积示意图;
图4是根据本发明实施例68中各组模型小鼠缺血再灌注24小时后进行神经运动功能障碍评分结果示意图;
图5是根据本发明实施例68中PI染色和Newport Green染色法监测野生型和TRPM2基因敲除小鼠海马脑片结果示意图;
图6是根据本发明实施例68中OGD后野生型和TRPM2基因敲除小鼠细胞内锌离子的量和神经元细胞死亡数量示意图;
图7是本发明实施例69中tMCAO造模后野生型和TRPM2基因敲除小鼠脑组织缺血侧TTC染色、脑梗死面积、神经运动功能障碍评分测试结果示意图;
图8是本发明实施例69中tMCAO造模中施用自噬抑制剂3-MA的野生型和TRPM2基因敲除小鼠脑组织缺血侧TTC染色、脑梗死面积、神经运动功能障碍评分测试结果示意图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将结合实施例对本发明的各实施方式进行详细的阐述。然而,本领域的普通技术人员可以理解,在本发明各实施方式中,为了使读者更好地理解本申请而提出了许多技术细节。但是,即使没有这些技术细节和基于以下各实施方式的种种变化和修改,也可以实现本申请所要求保护的技术方案。
实施例1:5-苯甲酰亚胺-7-羧酸乙酯(ⅠI-1)的制备。
步骤a:在氮气保护的条件下,将吡咯-2-甲醛(0.95g,10.0mmol)和碳酸钾(1.66g,12.0mmol)溶解在50mL无水乙腈中,然后分批次加入2-溴-1-苯基乙烷-1-酮(2.3g,12.0mmol),完全加入后,升温至60℃反应过夜。薄层色谱监测原料完全反应完全后,冷却至室温,过滤除去碳酸钾,滤液减压蒸馏除去溶剂,所得粗产物经硅胶柱层析纯化得到的产物1-(2-氧代-2-苯基乙基)-1H-吡咯-2-甲醛为白色固体。
步骤b:在氮气保护的条件下,将上一步所得的化合物1-(2-氧代-2-苯基乙基)-1H-吡咯-2-甲醛(852mg,4.0mmol)、丙炔酸乙酯(470mg,4.8mmol)和碳酸钾(662mg,4.8mmol)溶解在25毫升无水N,N-二甲基甲酰胺中,80摄氏度下反应过夜,薄层色谱监测原料反应完全后,冷却至室温,反应液用乙酸乙酯100毫升和50毫升萃取,水相用乙酸乙酯萃取两次(50毫升×2),合并乙酸乙酯相,无水硫酸钠干燥,减压蒸馏除去溶剂,所得粗产物经硅胶柱层析纯化得黄色固体(II-1,63%)。1H NMR(500MHz,CDCl3):δ8.93(m,1H),8.47(d,J=1.5Hz,1H),7.84(dd,J=8.0,1.5Hz,2H),7.78(d,J=1.5Hz,1H),7.66(tt,J=7.5,1.5Hz,1H),7.55(t,J=7.5Hz,2H),7.10(dd,J=4.0,3.0Hz,1H),7.03(dd,J=4.0,1.0Hz,1H),4.38(q,J=7.0Hz,2H),1.40(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C19H17NO3[M+H]+294.1130,检测值294.1132。
实施例2:5-苯甲酰亚胺-7-羧酸丙酯(ⅠI-2)的制备。
根据实施例1的方法,用丙炔酸丙酯(538mg,4.8mmol)代替丙炔酸乙酯,得黄色固体(II-2,54%)。1H NMR(500MHz,CDCl3):δ8.74(m,1H),8.42(d,J=1.0Hz,1H),7.76(dd,J=7.5,2.0Hz,2H),7.64(d,J=2.0Hz,1H),7.53(tt,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,2H),7.08(dd,J=4.0,3.0Hz,1H),7.01(dd,J=4.0,1.0Hz,1H),4.33(q,J=7.0Hz,2H),1.85(m,2H),1.04(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C18H15NO3[M+H]+308.1287,检测值308.1295。
实施例3:1-(5-苯并酰亚胺-7-基)乙烷-1-酮(ⅠI-3)的制备。
根据实施例1的方法,用丙-3-炔-2-酮(326mg,4.8mmol)代替丙炔酸乙酯,得黄色固体(II-3,57%)。(I-39,54%)。δ8.87(m,1H),8.31(m,1H),7.81(dt,J=7.5,2.0Hz,2H),7.76(d,J=2.0Hz,1H),7.64(tt,J=7.0,1.0Hz,1H),7.53(tt,J=7.0,2.0Hz,2H),7.08(dd,J=4.5,3.0Hz,1H),7.05(dd,J=4.5,1.0Hz,1H),2.58(s,3H);HRMS(ESI):m/z预测值C18H15NO3[M+H]+264.1025,检测值264.1030。
实施例4:5-(4-氟苯甲酰)吲哚嗪-7-羧酸甲酯(ⅠI-4)的制备。
步骤a2:在氮气保护的条件下,将吡咯-2-甲醛溶解在无水N,N-二甲基甲酰胺中,反应液冰浴冷却至0摄氏度,然后分批次加入氢化钠(0.29g,12.0mmol),完全加入后0摄氏度下反应30分钟,滴加溶于N,N-二甲基甲酰胺中的2-溴-1-(4-氟苯基)乙烷-1-酮(2.6g,12.0mmol),滴加完后升温至室温反应过夜,薄层色谱监测原料反应完全后,冰浴下向反应液中滴加饱和氯化铵溶液,滴加完全后,反应液用乙酸乙酯和水萃取,水相用乙酸乙酯萃取两次,合并乙酸乙酯相,无水硫酸钠干燥,减压蒸馏除去溶剂,所得粗产物经硅胶柱层析纯化得到的产物为白色固体,直接用于下一步的反应,本方法适用于合成R1为由氟取代苯环、呋喃环、噻吩环和吡啶环的中间体M1
根据实施例2的方法,用2-溴-1-(4-氟苯基)乙烷-1-酮(2.6g,12.0mmol)代替2-溴-1-苯基乙烷-1-酮,丙炔酸甲酯(403mg,4.8mmol)代替丙炔酸乙酯,得黄色固体(II-4,45%)。1H NMR(500MHz,CDCl3):δ8.86(d,J=2.5Hz,1H),8.47(d,J=1.5Hz,1H),7.89(td,J=5.5,2.0Hz,2H),7.71(d,J=1.5Hz,1H),7.24(t,J=7.5Hz,2H),7.10(q,J=7.0Hz,1H,),7.04(dd,J=4.0,1.0Hz,1H),3.92(s,3H);HRMS(ESI):m/z预测值C17H12FNO3[M+H]+298.0897,检测值298.0899。
实施例5:5-(4-氟苯甲酰)吲哚嗪-7-羧酸乙酯(ⅠI-5)的制备。
根据实施例4的方法,用丙炔酸甲酯(346mg,4.8mmol)代替丙炔酸乙酯,得黄色固体(II-5,56%)。1H NMR(500MHz,CDCl3):δ8.86(d,J=2.5Hz,1H),8.47(J=1.5Hz,1H),7.88(td,J=5.5,2.0Hz,2H),7.73(J=1.5Hz,1H),7.24(t,J=8.5Hz,2H),7.10(dd,J=4.5,2.0Hz,1H),7.03(dd,J=4.5,1.5Hz,1H),4.39(q,J=7.0Hz,2H),1.40(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C18H14FNO3[M+H]+312.1036,检测值312.1038。
实施例6:5-(3-氟苯甲酰)吲哚嗪-7-羧酸甲酯(ⅠI-6)的制备。
根据实施例4的方法,用2-溴-1-(3-氟苯基)乙烷-1-酮(2.6g,12.0mmol)代替2-溴-1-(4-氟苯基)乙烷-1-酮,得黄色固体(II-6,61%)。1H NMR(500MHz,CDCl3):δ8.95(d,J=2.0Hz,1H),8.50(d,J=1.5Hz,1H),7.77(d,J=1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.54(m,2H),7.36(tdd,J=8.5,2.5,1.0Hz,1H),7.12(t,J=6.5Hz,1H),7.06(dd,J=5.5Hz,1H),3.93(s,3H);HRMS(ESI):m/z预测值C17H12FNO3[M+H]+298.0897,检测值298.0901。
实施例7:5-(3-氟苯甲酰)吲哚嗪-7-羧酸乙酯(ⅠI-7)的制备。
根据实施例4的方法,用2-溴-1-(3-氟苯基)乙烷-1-酮(2.6g,12.0mmol)代替2-溴-1-(4-氟苯基)乙烷-1-酮,丙炔乙酯(403mg,4.8mmol)代替丙炔酸甲酯,得黄色固体(II-6,58%)。1H NMR(500MHz,CDCl3):δ8.95(d,J=2.5Hz,1H),8.49(d,J=1.5Hz,1H),7.79(d,J=1.5Hz,1H),7.60(dt,J=7.5,1.0Hz,1H),7.54(m,1H),7.36(tdd,J=8.0,2.5Hz,1H),7.12(t,J=7.0Hz,1H),7.06(dd,J=4.5,1.0Hz,1H),4.39(q,J=7.0Hz,2H),1.40(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C17H12FNO3[M+H]+312.1036,检测值312.1039。
实施例8:5-(2-氟苯甲酰)吲哚嗪-7-羧酸甲酯(ⅠI-8)的制备。
根据实施例4的方法,用2-溴-1-(2-氟苯基)乙烷-1-酮(2.6g,12.0mmol)代替2-溴-1-(4-氟苯基)乙烷-1-酮,得黄色固体(II-8,47%)。1H NMR(500MHz,CDCl3):δ9.24(d,J=2.0Hz,1H),8.51(d,J=1.0Hz,1H),7.79(t,J=1.5Hz,1H),7.59(m,2H),7.33(t,J=1.5Hz,1H),7.24(t,J=9.0Hz,1H),7.15(dd,J=4.0,2.5Hz,1H),7.08(d,J=4.0Hz,1H),3.90(s,3H);HRMS(ESI):m/z预测值C17H12FNO3[M+H]+298.0897,检测值298.0898。
实施例9:5-(3-氯苯甲酰)吲哚嗪-7-羧酸乙酯(ⅠI-9)的制备。
根据实施例1的方法,用2-溴-1-(3-氯苯基)乙烷-1-酮(2.8g,12.0mmol)代替2-溴-1-苯基乙烷-1-酮,得黄色固体(II-9,71%)。1H NMR(500MHz,CDCl3):δ8.74(d,J=2.0Hz,1H),8.26(d,J=2.0Hz,1H),7.57(d,J=1.5Hz,1H),7.42(dd,J=7.5,1.5Hz,1H),7.36(m,2H),7.23(dd,J=4.0,3.0Hz,1H),7.12(t,J=7.0Hz,1H),7.03(dd,J=4.5,1.0Hz,1H),4.17(q,J=7.0Hz,2H),1.41(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C17H12ClNO3[M+H]+328.0740,检测值328.0745。
实施例10:5-(3-溴苯甲酰)吲哚嗪-7-羧酸乙酯(ⅠI-10)的制备。
根据实施例1的方法,用2-溴-1-(3-溴苯基)乙烷-1-酮(3.3g,12.0mmol)代替2-溴-1-苯基乙烷-1-酮,得黄色固体(II-10,65%)。1H NMR(500MHz,CDCl3):δ8.72(d,J=1.5Hz,1H),8.24(d,J=2.0Hz,1H),7.56(m,1H),7.41(dd,J=7.0,2.0Hz,1H),7.34(m,2H),7.21(dd,J=4.0,3.0Hz,1H),7.09(t,J=7.0Hz,1H),7.01(dd,J=4.5,1.0Hz,1H),4.18(q,J=7.0Hz,2H),1.40(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C17H12BrNO3[M+H]+372.0235,检测值372.0238。
实施例11:5-(3-甲基苯甲酰)吲哚嗪-7-羧酸乙酯(ⅠI-11)的制备。
根据实施例1的方法,用2-溴-1-(间甲苯基)乙烷-1-酮(2.5g,12.0mmol)代替2-溴-1-苯基乙烷-1-酮,得黄色固体(II-11,74%)。1H NMR(500MHz,CDCl3):δ8.61(m,1H),8.18(d,J=2.0Hz,1H),7.49(m,1H),7.35(m,3H),7.17(dd,J=4.0,3.0Hz,1H),7.08(t,J=7.0Hz,1H),7.02(dd,J=4.5,1.5Hz,1H),4.21(q,J=7.0Hz,2H),1.41(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C18H15NO3[M+H]+308.1287,检测值308.1285。
实施例12:5-(3-甲氧基苯甲酰基)吲哚嗪-7-羧酸乙酯(ⅠI-12)的制备。
根据实施例1的方法,用2-溴-1-(3-甲氧基苯基)乙烷-1-酮(2.7g,12.0mmol)代替2-溴-1-苯基乙烷-1-酮,得黄色固体(II-12,78%)。1H NMR(500MHz,CDCl3):δ8.67(d,J=2.0Hz,1H),8.18(d,J=1.5Hz,1H),7.47(m,1H),7.36(m,2H),7.21(dd,J=4.0,3.0Hz,1H),7.13(t,J=7.0Hz,1H),7.04(dd,J=4.5,1.0Hz,1H),4.20(q,J=7.0Hz,2H),3.64(s,3H),1.41(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C19H17NO4[M+H]+324.1236,检测值324.1238。
实施例13:5-(呋喃-2-羰基)吲哚嗪-7-羧酸甲酯(ⅠI-13)的制备。
根据实施例1的方法,用2-溴-1-(呋喃-2-基)乙烷-1-酮(2.3g,12.0mmol)代替2-溴-1-苯基乙烷-1-酮,丙炔酸甲酯(403mg,4.8mmol)代替丙炔酸乙酯,得黄色固体(II-13,65%)。1H NMR(500MHz,CDCl3):δ8.79(d,J=3.0Hz,1H),8.47(d,J=1.0Hz,1H),8.19(d,J=1.5Hz,1H),7.80(dd,J=1.5,0.5Hz,1H),7.35(dd,J=3.5,0.5Hz,1H),7.07(dd,J=4.5,3.0Hz,1H),7.01(J=4.5,1.0Hz,1H),6.68(dd,J=4.0,2.0Hz,1H),3.97(s,3H);HRMS(ESI):m/z预测值C15H11NO4[M+H]+270.0766,检测值270.0768。
实施例14:5-(呋喃-2-羰基)吲哚嗪-7-羧酸乙酯(ⅠI-14)的制备。
根据实施例1的方法,用2-溴-1-(呋喃-2-基)乙烷-1-酮(2.3g,12.0mmol)代替2-溴-1-苯基乙烷-1-酮,得黄色固体(II-14,57%)。1H NMR(500MHz,CDCl3):δ8.72(d,J=3.0Hz,1H),8.45(d,J=1.0Hz,1H),8.14(d,J=1.5Hz,1H),7.79(dd,J=1.5,0.5Hz,1H),7.42(dd,J=3.5,0.5Hz,1H),7.14(dd,J=4.5,3.0Hz,1H),6.94(J=4.5,1.0Hz,1H),6.65(dd,J=4.0,2.0Hz,1H),4.37(q,J=7.0Hz,2H),1.49(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C16H13NO4[M+H]+284.0923,检测值284.0927。
实施例15:5-(噻吩-2-羰基)吲哚嗪-7-羧酸甲酯(ⅠI-15)的制备。
根据实施例1的方法,用2-溴-1-(噻吩-2-基)乙烷-1-酮(2.4g,12.0mmol)代替2-溴-1-苯基乙烷-1-酮,丙炔酸甲酯(403mg,4.8mmol)代替丙炔酸乙酯,得黄色固体(II-15,78%)。1H NMR(500MHz,CDCl3):δ8.65(m,1H),8.46(d,J=1.5Hz,1H),7.99(d,J=1.5Hz,1H),7.81(dd,J=5.0,1.0Hz,1H),7.78(dd,J=4.0,1.0Hz,1H),7.24(dd,J=5.0,4.0Hz,1H),7.06(dd,J=4.5,3.0Hz,1H),7.00(dd,J=4.5,1.0Hz,1H),3.96(s,3H);HRMS(ESI):m/z预测值C15H11NO3S[M+H]+286.0538,检测值286.0540。
实施例16:5-(噻吩-2-羰基)吲哚嗪-7-羧酸乙酯(ⅠI-16)的制备。
根据实施例1的方法,用2-溴-1-(噻吩-2-基)乙烷-1-酮(2.4g,12.0mmol)代替2-溴-1-苯基乙烷-1-酮,得黄色固体(II-16,76%)。1H NMR(500MHz,CDCl3):δ8.59(m,1H),8.37(d,J=1.5Hz,1H),7.91(d,J=1.5Hz,1H),7.83(dd,J=4.5,1.5Hz,1H),7.75(dd,J=4.0,1.5Hz,1H),7.21(dd,J=4.5,4.0Hz,1H),7.03(dd,J=4.5,3.0Hz,1H),6.97(dd,J=4.5,1.5Hz,1H),4.35(q,J=7.0Hz,2H),1.47(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C16H13NO3S[M+H]+300.0694,检测值300.0697。
实施例17:5-甲基吡啶酰亚胺-7-羧酸甲酯(ⅠI-17)的制备。
根据实施例1的方法,用2-溴-1-(吡啶-2-基)乙烷-1-酮(2.3g,12.0mmol)代替2-溴-1-苯基乙烷-1-酮,丙炔酸甲酯(403mg,4.8mmol)代替丙炔酸乙酯,得黄色固体(II-17,78%)。1H NMR(500MHz,CDCl3):9.13(m,1H),8.82(m,1H),8.56(d,J=1.5Hz,1H),8.23(d,J=1.5Hz,1H),8.04(dt,J=7.5,1.5Hz,1H),7.97(ddd,J=9.0,7.0,1.0Hz,1H),7.54(ddd,J=8.5,7.0,1.0Hz,1H),7.10(dd,J=4.5,2.5Hz,1H),7.03(dd,J=4.5,1.0Hz,1H),4.05(s,3H);HRMS(ESI):m/z预测值C16H12N2O3[M+H]+281.0926,检测值281.0929。
实施例18:5-甲基吡啶酰亚胺-7-羧酸乙酯(ⅠI-18)的制备。
根据实施例1的方法,用2-溴-1-(吡啶-2-基)乙烷-1-酮(2.3g,12.0mmol)代替2-溴-1-苯基乙烷-1-酮,得黄色固体(II-18,76%)。1H NMR(500MHz,CDCl3):δ9.07(m,1H),8.74(m,1H),8.46(d,J=1.5Hz,1H),8.21(d,J=1.5Hz,1H),8.00(dt,J=8.0,1.0Hz,1H),7.93(ddd,J=9.0,7.5,1.5Hz,1H),7.51(ddd,J=8.0,6.5,1.5Hz,1H),7.08(dd,J=4.5,2.5Hz,1H),7.01(dd,J=4.5,1.0Hz,1H),4.36(q,J=7.0Hz,2H),1.36(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C17H14N2O3[M+H]+295.1083,检测值295.1088。
实施例19:5-苯并酰亚胺-7-羧酸(ⅠI-19)的制备。
步骤c:将化合物Ⅱ-1(2.9g,10mmol)溶于30毫升乙醇中,加入10毫升2N氢氧化钠溶液,反应液于80摄氏度下反应过夜,薄层色谱监测原料反应完全后将乙醇减压蒸馏除去,剩余溶液用盐酸溶液调至酸性,有黄色固体析出、过滤,固体水洗、干燥得黄色固体(ⅠI-19,95%)。1H NMR(500MHz,CDCl3):δ12.05(s,1H),8.74(d,J=2.0Hz,1H),8.35(J=2.0Hz,1H),7.57(m,3H),7.35(dd,J=7.5,2.0Hz,1H),7.21(t,J=8.5Hz,2H),7.10(dd,J=4.5,2.5Hz,1H),7.03(dd,J=4.5,1.5Hz,1H);HRMS(ESI):m/z预测值C16H11NO3[M+H]+266.0817,检测值266.1818。
实施例20:5-苯并酰亚胺-7-甲酰胺(ⅠI-20)的制备。
步骤d:将化合物ⅠI-19(275mg,1mmol)、1-羟基苯并三唑(64mg,0.3mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(229mg,1.2mmol)溶解在10毫升无水四氢呋喃中,室温下加入N,N-二异丙基乙胺(168mg,1.3mmol),室温下反应8小时至薄层色谱监测反应完全,然后加入氯化铵(107mg,2mmol),室温下反应2小时。薄层色谱监测原料反应完全后,反应液减压蒸馏除去溶剂,所得粗产物经硅胶柱层析纯化得到的红色固体(II-20,87%)。1HNMR(500MHz,d6-DMSO):δ8.75(s,1H),8.50(s,1H),8.10(s,1H),7.82(d,J=7.0Hz,2H),7.72(t,J=7.5Hz,1H),7.62(m,3H),7.44(s,1H),7.11(t,J=3.5Hz,1H),7.02(d,J=4.0Hz,1H);HRMS(ESI):m/z预测值C16H12N2O2[M+H]+265.0977,检测值265.0979。
实施例21:5-苯甲酰-N-乙基吲哚嗪-7-甲酰胺(ⅠI-21)的制备。
根据实施例20的方法,用乙胺(90mg,2.0mmol)代替氯化铵,得黄色固体(II-21,86%)。1H NMR(500MHz,CDCl3):δ8.82(d,J=2.0Hz,1H),8.01(d,J=1.5Hz,1H),7.81(dd,J=8.0,1.0Hz,2H),7.62(m,2H),7.52(t,J=7.5Hz,2H),7.05(dd,J=4.0,2.5Hz,1H),6.91(dd,J=3.5,1.0Hz,1H),6.01(s,1H),3.47(m,2H),1.24(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C18H16N2O2[M+H]+293.1290,检测值293.1292。
实施例22:5-苯甲酰-N,N-二甲基吲哚嗪-7-甲酰胺(ⅠI-22)的制备。
根据实施例20的方法,用二甲胺(90mg,2mmol)代替氯化铵,得黄色固体(II-22,85%)。1H NMR(500MHz,CDCl3):δ8.82(d,J=2.0Hz,1H),7.82(d,J=1.5Hz,1H),7.79(dd,J=7.0,1.5Hz,2H),7.60(tt,J=7.5,1.0Hz,1H),7.50(t,J=8.0Hz,2H),7.29(d,J=1.5Hz,1H),7.00(dd,J=4.0,2.5Hz,1H),6.86(dd,J=4.5,1.0Hz,1H),3.08(s,6H).HRMS(ESI):m/z预测值C18H16N2O2[M+H]+293.1290,检测值293.1292。
实施例23:5-苯甲酰-N,N-二乙基吲哚嗪-7-甲酰胺(ⅠI-23)的制备。
根据实施例20的方法,用二乙胺(146mg,2mmol)代替氯化铵,得黄色固体(II-23,89%)。1H NMR(500MHz,CDCl3):δ8.81(d,J=3.0Hz,1H),7.79(m,3H),7.61(tt,J=7.5,1.0Hz,1H),7.50(t,J=8.0Hz,2H),7.23(d,J=2.0Hz,1H),7.04(dd,J=4.5,3.0Hz,1H),6.84(dd,J=4.5,1.5Hz,1H),3.43(m,4H),1.19(m,6H);HRMS(ESI):m/z预测值C20H20N2O2[M+H]+321.1603,检测值321.1606。
实施例24:5-苯甲酰-N-乙基-N-甲基吲哚嗪-7-甲酰胺(ⅠI-24)的制备。
根据实施例20的方法,用甲乙胺(118mg,2mmol)代替氯化铵,得黄色固体(II-24,88%)。1NMR(500MHz,CDCl3):δ8.84(d,J=1.5Hz,1H),7.82(m,3H),7.63(t,J=8.0Hz,1H),7.53(t,J=8.0Hz,2H),7.29(m,1H),7.08(dd,J=4.0,3.0Hz,1H),6.88(dd,J=3.5,1.0Hz,1H),3.49(m,2H),3.06(m,3H),1.20(m,6H);HRMS(ESI):m/z预测值C19H18N2O2[M+H]+307.1447,检测值307.1449。
实施例25:5-苯甲酰基-N-甲氧基-N-甲基吲哚嗪-7-甲酰胺(ⅠI-25)的制备。
根据实施例20的方法,用N、O-二甲基羟胺(122mg,2mmol)代替氯化铵,得黄色固体(II-25,85%)。1NMR(500MHz,CDCl3):δ8.82(d,J=1.5Hz,1H),7.79(m,3H),7.58(t,J=8.0Hz,1H),7.49(t,J=8.0Hz,2H),7.27(m,1H),7.05(dd,J=4.5,3.0Hz,1H),6.85(dd,J=4.5,1.5Hz,1H),3.59(s,2H),3.36(s,3H);HRMS(ESI):m/z预测值C18H16N2O3[M+H]+309.1239,检测值209.1243。
实施例26:氮杂环丁烷-1-基(5-苯甲酰亚胺-7-基)甲酮(ⅠI-26)的制备。
根据实施例20的方法,用:氮杂环丁烷(122mg,2mmol)代替氯化铵,得黄色固体(II-26,77%)。1H NMR(500MHz,CDCl3):δ8.91(d,J=2.0Hz,1H),7.93(d,J=2.0Hz,1H),7.87(dd,J=7.5,2.0Hz,2H),7.67(tt,J=7.5,1.0Hz,1H),7.54(t,J=7.5Hz,2H),7.33(d,J=2.0Hz,1H),7.07(dd,J=4.0,2.5Hz,1H),6.92(dd,J=4.5,1.5Hz,1H),4.06(m,4H),3.58(m,2H);HRMS(ESI):m/z预测值C19H16N2O2[M+H]+305.1290,检测值305.1294。
实施例27:(5-苯甲酰亚胺-7-基)(吡咯烷-1-基)甲酮(ⅠI-27)的制备。
根据实施例20的方法,用吡咯烷(142mg,2mmol)代替氯化铵,得黄色固体(II-27,82%)。1H NMR(500MHz,CDCl3):δ8.84(d,J=2.0Hz,1H),7.81(d,J=2.0Hz,1H),7.77(dd,J=8.0,1.5Hz,2H),7.59(t,J=7.5Hz,1H),7.43(t,J=8.0Hz,2H),7.29(d,J=2.0Hz,1H),7.04(dd,J=4.0,2.5Hz,1H),6.87(dd,J=4.5,1.0Hz,1H),3.94(m,4H),2.17(m,4H);HRMS(ESI):m/z预测值C20H18N2O2[M+H]+319.1447,检测值319.1451。
实施例28:(5-苯并酰亚胺-7-基)(哌啶-1-基)甲酮(ⅠI-28)的制备。
根据实施例20的方法,用哌啶(170mg,2mmol)代替氯化铵,得黄色固体(II-28,84%)。δ8.79(d,J=2.0Hz,1H),7.76(d,J=1.5Hz,1H),7.62(dd,J=7.5,2.0Hz,2H),7.54(t,J=7.5Hz,1H),7.40(t,J=7.5Hz,2H),7.25(m,1H),7.01(dd,J=4.0,2.5Hz,1H),6.84(dd,J=4.5,1.5Hz,1H),3.87(m,4H),1.93(m,4H),1.52(m,2H);HRMS(ESI):m/z预测值C21H20N2O2[M+H]+333.1603,检测值333.1608。
实施例29:(5-苯甲酰吲哚嗪-7-基)(哌嗪-1-基)甲酮(ⅠI-29)的制备。
根据实施例20的方法,用哌嗪(172mg,2mmol)代替氯化铵,得黄色固体(II-29,85%)。1NMR(500MHz,CDCl3):δ8.81(d,J=2.0Hz,1H),7.76(m,3H),7.54(t,J=7.5Hz,1H),7.43(t,J=7.5Hz,2H),7.24(d,J=1.5Hz,1H),7.03(dd,J=4.5,3.0Hz,1H),6.82(dd,J=4.5,1.0Hz,1H),4.01(s,1H),3.62(m,4H),3.47(m,4H);HRMS(ESI):m/z预测值C20H19N3O2[M+H]+334.1556,检测值334.1558。
实施例30:(5-苯甲酰亚胺-7-基)(吗啉基)甲酮(ⅠI-30)的制备。
根据实施例20的方法,用吗啉(174mg,2mmol)代替氯化铵,得黄色固体(II-30,81%)。δ8.82(d,J=1.5Hz,1H),7.80(d,J=2.0Hz,1H),7.68(dd,J=7.5,2.0Hz,2H),7.60(t,J=8.0Hz,1H),7.45(t,J=8.0Hz,2H),7.25(d,J=2.0Hz,1H),7.07(dd,J=4.0,2.5Hz,1H),6.91(dd,J=4.5,1.0Hz,1H),4.05(m,4H),3.93(m,4H);HRMS(ESI):m/z预测值C20H18N2O3[M+H]+335.1396,检测值335.1399。
实施例31:(5-苯甲酰亚胺-7-基)(4-甲基哌嗪-1-基)甲酮(ⅠI-31)的制备。
根据实施例20的方法,用4-甲基哌嗪(200mg,2mmol)代替氯化铵,得黄色固体(II-31,85%)。δ8.91(d,J=2.0Hz,1H),7.87(d,J=1.5Hz,1H),7.78(dd,J=8.0,2.0Hz,2H),7.69(t,J=7.5Hz,1H),7.52(t,J=7.5Hz,2H),7.31(m,1H),7.11(dd,J=4.0,2.5Hz,1H),6.93(dd,J=4.5,1.5Hz,1H),3.72(m,4H),2.93(m,4H),2.78(s,3H);HRMS(ESI):m/z预测值C21H21N3O2[M+H]+348.1712,检测值348.1712。
实施例32:N、N-二乙基-5-(2-氟苯甲酰)吲哚嗪-7-甲酰胺(ⅠI-32)的制备。
步骤c:将化合物Ⅱ-8(1.5g,5mmol)溶于15毫升乙醇中,加入5毫升2N氢氧化钠溶液,反应液于80摄氏度下反应过夜,薄层色谱监测原料反应完全后将乙醇减压蒸馏除去,剩余溶液用盐酸溶液调至微酸性,有黄色固体析出、过滤,固体水洗、干燥得黄色固体(1.3g,94%)。
步骤d:上一步黄色固体(283mg,1mmol)、1-羟基苯并三唑(64mg,0.3mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(229mg,1.2mmol)溶解在10毫升无水四氢呋喃中,室温下加入N,N-二异丙基乙胺(168mg,1.3mmol),室温下反应8小时至薄层色谱监测原料反应完全,然后加入二乙胺(146mg,2mmol),室温下反应2小时。薄层色谱监测原料反应完全后,反应液减压蒸馏除去溶剂,所得粗产物经硅胶柱层析纯化得到的红色固体(II-32,87%)。1H NMR(500MHz,CDCl3):δ8.84(m,1H),7.81(d,J=1.5Hz,1H),7.55(dt,J=7.5,1.0Hz,1H),7.49(m,2H),7.30(dddd,J=11.0,7.5,3.0,1.5Hz,1H),7.26(d,J=2.0Hz,1H),7.05(dd,J=4.5,3.0Hz,1H),6.86(dd,J=4.5,1.5Hz,1H),3.45(q,J=7.0Hz,4H),1.12(t,J=7.0Hz,6H);HRMS(ESI):m/z预测值C20H19FN2O2[M+H]+339.1509,检测值339.1510。
实施例33:(5-(2-氟苯甲酰基)吲哚嗪-7-基)(吡咯烷-1-基)甲酮(ⅠI-33)的制备。
根据实施例32的方法,用用吡咯烷(142mg,2mmol)代替二乙胺,得黄色固体(II-33,81%)。1H NMR(500MHz,CDCl3):δ8.87(m,1H),7.83(d,J=2.0Hz,1H),7.57(dt,J=8.0,1.5Hz,1H),7.52(m,2H),7.33(1H,dddd,J=11.5,8.0,3.5,2.0Hz),7.29(1H,d,J=1.5Hz),7.08(1H,dd,J=4.5,2.5Hz),6.89(1H,dd,J=4.5,1.0Hz),3.57(m,4H),1.82(m,4H);HRMS(ESI):m/z预测值C20H17FN2O2[M+H]+337.1352,检测值337.1356。
实施例34:N、N-二乙基-5-吡啶酰亚胺-7-甲酰胺(ⅠI-34)的制备。
根据实施例32的方法,用化合物II-17(1.4g,5mmol)代替化合物II-9,得黄色固体(II-34,89%)。1H NMR(500MHz,CDCl3):9.17(m,1H),8.85(m,1H),8.61(d,J=2.0Hz,1H),8.27(d,J=2.0Hz,1H),8.09(dt,J=8.0,2.0Hz,1H),7.99(ddd,J=8.5,7.5,2.0Hz,1H),7.56(ddd,J=8.5,7.0,1.5Hz,1H),7.13(dd,J=4.5,2.5Hz,1H),7.05(dd,J=4.5,1.5Hz,1H),3.34(m,4H),1.24(m,6H);HRMS(ESI):m/z预测值C19H19N3O2[M+H]+322.1556,检测值322.1557。
实施例35:(5-苯甲酰亚胺-7-基)(4-甲基哌嗪-1-基)甲酮(ⅠI-35)的制备。
根据实施例32的方法,用化合物II-17(1.4g,5mmol)代替化合物II-9,吡咯烷(142mg,2mmol)代替二乙胺得黄色固体(II-35,85%)。1H NMR(500MHz,CDCl3):9.11(m,1H),8.76(m,1H),8.57(m,1H),8.23(d,J=2.0Hz,1H),8.04(dt,J=7.5,2.0Hz,1H),7.94(ddd,J=8.0,7.0,1.5Hz,1H),7.52(ddd,J=8.0,7.0,1.5Hz,1H),7.10(dd,J=4.5,2.5Hz,1H),7.01(dd,J=4.5,1.0Hz,1H),3.49(m,4H)1.74(m,4H);HRMS(ESI):m/z预测值C19H17N3O2[M+H]+320.1399,检测值320.1403。
实施例36:(5-吡啶酰林多嗪-7-基)(哌嗪-1-基)甲酮(ⅠI-36)的制备。
根据实施例32的方法,用化合物II-17代替化合物II-9,哌嗪(172mg,2mmol)代替二乙胺,得黄色固体(II-36,73%)。1H NMR(500MHz,CDCl3):δ9.05(m,1H),8.71(m,1H),8.54(d,J=1.5Hz,1H),8.18(d,J=2.0Hz,1H),7.99(dt,J=7.5,2.0Hz,1H),7.91(ddd,J=8.5,7.0,1.5Hz,1H),7.48(ddd,J=8.5,7.5,1.5Hz,1H),7.07(dd,J=4.5,2.5Hz,1H),6.98(dd,J=4.5,1.5Hz,1H),4.13(s,1H),3.54(m,4H),3.14(m,4H);HRMS(ESI):m/z预测值C19H18N4O2[M+H]+335.1508,检测值335.1510。
实施例37:(5-苯甲酰亚胺-7-基)(哌嗪-1-基)甲酮盐酸盐(ⅠI-37)的制备。
步骤e:将化合物II-29(33mg,0.1mmol)溶于乙醚中,加入盐酸甲醇溶液,室温下反应2小时至薄层色谱监测原料反应完全后,过滤得黄色固体(II-37,98%);1NMR(500MHz,CDCl3):δ10.43(s,2H),9.04(d,J=1.5Hz,1H),7.94(m,3H),7.73(t,J=7.0Hz,1H),7.61(t,J=7.0Hz,2H),7.42(d,J=2.0Hz,1H),7.13(dd,J=4.5,3.0Hz,1H),6.95(dd,J=4.5,1.5Hz,1H),4.43(m,4H),3.76(m,4H);HRMS(ESI):m/z预测值C20H20ClN3O2[M]+334.1556,检测值334.1560。
实施例38:N、N-二乙基-5-吡啶酰亚胺-7-甲酰胺盐酸盐(ⅠI-38)的制备。
根据实施例37的方法,用化合物II-34(36mg,0.1mmol)代替化合物II-29,得黄色固体(II-38,87%)。1H NMR(500MHz,CDCl3):11.54(1H,s),9.31(d,J=2.0Hz,1H),8.95(m,2H),8.46(d,J=2.0Hz,1H),8.19(t,J=8.0Hz,1H),8.13(ddd,J=8.0,7.0,2.0Hz,1H),7.72(ddd,J=8.0,7.5,1.5Hz,1H),7.23(dd,J=4.5,3.0Hz,1H),7.09(dd,J=4.5,1.0Hz,1H),3.54(m,4H),1.37(m,6H);HRMS(ESI):m/z预测值C19H20ClN3O2[M]+322.1556,检测值322.1559。
实施例39:(5-甲基吡啶酰亚胺-7-基)(吡咯烷-1-基)甲酮盐酸盐(ⅠI-39)的制备。
根据实施例37的方法,用化合物II-35(32mg,0.1mmol)代替化合物II-29,得黄色固体(II-39,92%)。1H NMR(500MHz,CDCl3):11.27(1H,s),9.27(m,1H),8.85(m,1H),8.67(m,1H),8.17(m,2H),8.04(ddd,J=8.5,7.0,1.5Hz,1H),7.59(ddd,J=8.0,7.0,1.5Hz,1H),7.19(dd,J=4.5,3.0Hz,1H),7.05(d,J=4.0Hz,1H),3.65(m,4H)1.86(m,4H);HRMS(ESI):m/z预测值C19H18ClN3O2[M]+320.1399,检测值320.1340。
实施例40:(5-吡啶酰林多嗪-7-基)(哌嗪-1-基)甲酮盐酸盐(ⅠI-40)的制备。
根据实施例37的方法,用化合物II-36(36mg,0.1mmol)代替化合物II-29,得黄色固体(II-40,91%)。1H NMR(500MHz,CDCl3):10.94(1H,s),9.16(m,1H),8.87(m,1H),8.62(d,J=2.0Hz,1H),8.26(m,1H),8.05(t,J=8.0Hz,1H),7.98(ddd,J=8.0,7.5,1.5Hz,1H),7.54(ddd,J=8.0,7.5,1.5Hz,1H),7.11(dd,J=4.5,2.5Hz,1H),7.02(dd,J=4.5,1.0Hz,1H),5.34(s,1H),3.78(m,4H),3.47(m,4H);HRMS(ESI):m/z预测值C19H19ClN4O2[M]+335.1508,检测值335.1511。
实施例41:1-(5-(羟基(苯基)甲基)吲哚嗪-7-基)丙-1-酮(ⅠI-41)的制备。
步骤f:在氮气保护的条件下,将化合物II-1(293mg,1mmol)溶于无水甲醇,反应液冰浴至0摄氏度,将硼氢化钠分批次加入反应液中,0摄氏度下反应2小时,薄层色谱监测原料反应完全后,反应液于冰浴下加饱和氯化铵溶液淬灭,减压蒸馏除去溶剂,所得粗产物经硅胶柱层析纯化得白色固体(II-41,97%)。1H NMR(500MHz,CDCl3):δ8.24(d,J=1.5Hz,1H),7.47(dt,J=8.0,1.5Hz,2H),7.37(m,5H),6.83(dd,J=4.0,3.0Hz,1H),6.79(dd,J=4.5,1.5Hz,1H),6.04(d,J=4.0Hz,1H),4.38(q,J=7.0Hz,2H),2.70(d,J=3.0Hz,1H),1.42(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C18H17NO3[M+H]+296.1287,检测值296.1290。
实施例42:5-(羟基(苯基)甲基吲哚嗪-7-羧酸(ⅠI-42)的制备。
根据实施例41的方法,用化合物II-19(265mg,1mmol)代替化合物II-1,得白色固体(II-42,94%)。1H NMR(500MHz,CDCl3):δ12.72(s,1H),8.14(d,J=1.0Hz,1H),7.63(s,1H),7.42(d,J=7.0Hz,2H),7.36(t,J=7.0Hz,2H),7.30(tt,J=7.0,1.0Hz,1H),6.86(dd,J=3.5,2.0Hz,1H),6.82(dd,J=4.0,1.0Hz,1H),6.38(d,J=4.0Hz,1H),6.01(d,J=5.0Hz,1H),3.34(s,1H);HRMS(ESI):m/z预测值C16H13NO3[M+H]+268.0974,检测值268.0979。
实施例43:N-乙基-5-(羟基(苯基)甲基)吲哚嗪-7-甲酰胺(ⅠI-43)的制备。
根据实施例41的方法,用化合物II-21(293mg,1mmol)代替化合物II-1,得白色固体(II-43,95%)。1H NMR(500MHz,CDCl3):δ8.01(d,J=1.5Hz,1H),7.48(dt,J=7.0Hz,2H),7.43(d,J=2.0Hz,1H),7.36(t,J=7.0Hz,2H),7.30(t,J=7.0Hz,1H),7.21(d,J=1.5Hz,1H),6.78(dd,J=4.0,3.0Hz,1H),6.71(dd,J=4.0,0.5Hz,1H),6.04(s,1H),4.66(s,1H),3.44(q,J=7.0Hz,2H),1.26(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C18H18N2O2[M+H]+295.1447,检测值295.1448。
实施例44:5-(羟基(苯基)甲基)-N,N-二甲基吲哚嗪-7-甲酰胺(ⅠI-44)的制备。
根据实施例41的方法,用化合物II-22(293mg,1mmol)代替化合物II-1,得白色固体(II-44,97%)。1H NMR(500MHz,CDCl3):δ7.50(d,J=1.5Hz,1H),7.41(dd,J=7.0,2.0Hz,2H),7.34(m,3H),7.29(d,J=2.0Hz,1H),6.77(m,2H),6.59(dd,J=4.0,1.0Hz,1H),5.97(s,1H),3.36(s,1H),3.06(s,6H);HRMS(ESI):m/z预测值C18H18N2O2[M+H]+295.1447,检测值295.1451。
实施例45:N、N-二乙基-5-(羟基(苯基)甲基)吲哚嗪-7-甲酰胺(ⅠI-45)的制备。
根据实施例41的方法,用化合物II-23(321mg,1mmol)代替化合物II-1,得白色固体(II-45,96%)。1H NMR(500MHz,CDCl3):δ7.44(d,J=1.0Hz,1H),7.40(dd,J=7.5,1.5Hz,2H),7.32(m,3H),7.26(m,1H),6.75(dd,J=4.0,3.0Hz,1H),6.71(s,1H),6.56(dd,J=4.0,1.0Hz,1H),5.95(s,1H),3.57(s,1H),3.42(m,4H)1.16(m,6H);HRMS(ESI):m/z预测值C20H22N2O2[M+H]+323.1760,检测值323.1763。
实施例46:N-乙基-5-(羟基(苯基)甲基)-N-甲基吲哚嗪-7-甲酰胺(ⅠI-46)的制备。
根据实施例41的方法,用化合物II-25(307mg,1mmol)代替化合物II-1,得白色固体(II-46,97%)。1H NMR(500MHz,CDCl3):δ7.51(s,1H),7.44(d,J=7.0Hz,2H),7.34(m,5H),6.78(m,2H),6.62(d,J=4.0Hz,1H),6.00(s,1H),3.46(m,2H),3.05(s,3H),1.20(m,3H);HRMS(ESI):m/z预测值C19H20N2O2[M+H]+309.1603,检测值309.1606。
实施例47:5-(乙酰氧基(苯基)甲基)吲哚嗪-7-羧酸乙酯(ⅠI-47)的制备。
步骤g1:在氮气保护的条件下,将化合物II-41(296mg,1mmol)和三乙胺(122,1.2mmol)溶于无水二氯甲烷中,反应液冷却至0摄氏度后滴加乙酰氯(94mg,1.2mmol),滴加完成后室温下反应8小时,薄层色谱监测原料反应完全后,冰浴下向反应液中滴加2毫升饱和氯化铵溶液,滴加完成后,反应液用二氯甲烷(15毫升)和水(15毫升)萃取,水相用二氯甲烷(15毫升)萃取两次,合并二氯甲烷相,无水硫酸钠干燥,减压蒸馏除去溶剂,所得粗产物经硅胶柱层析纯化得淡黄色固体(II-47,82%);1H NMR(500MHz,CDCl3):δ8.28(d,J=1.0Hz,1H),7.44(m,2H),7.39(m,3H),7.34(d,J=2.5Hz,1H),7.27(d,J=1.0Hz,1H),7.19(s,1H),6.86(dd,J=4.0,3.0Hz,1H),6.83(dd,J=4.5,1.0Hz,1H),4.40(q,J=7.0Hz,2H),2.24(s,3H),1.43(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C20H19NO4[M+H]+338.1392,检测值338.1395。
实施例48:5-(丁酰氧基)(苯基)甲基)吲哚嗪-7-羧酸乙酯(ⅠI-48)的制备。
根据实施例47的方法,用丁酰氯(127mg,1.2mmol)代替乙酰氯,得淡黄色固体(II-48,77%)。1H NMR(500MHz,CDCl3):δ8.28(s,1H),7.39(m,6H),7.27(s,1H),7.21(s,1H),6.86(dd,J=4.0,2.5Hz,1H),6.83(dd,J=3.5,0.5Hz,1H),4.40(m,2H),2.40(t,J=7.5Hz,2H),1.70(m,2H)1.40(t,J=7.0Hz,3H),0.97(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C22H23NO4[M+H]+366.1705,检测值366.1707。
实施例49:5-((辛烷氧基)(苯基)甲基)吲哚嗪-7-羧酸乙酯(ⅠI-49)的制备。
根据实施例47的方法,用辛酰氯(194mg,1.2mmol)代替乙酰氯,得淡黄色固体(II-49,64%)。1H NMR(500MHz,CDCl3):δ8.26(d,J=1.0Hz,1H),7.43(m,2H),7.36(m,3H),7.31(d,J=2.0Hz,1H),7.25(s,1H),7.18(s,1H),6.84(dd,J=4.0,2.5Hz,1H),6.81(dd,J=4.0,1.0Hz,1H),4.37(t,J=7.5Hz,2H),2.37(t,J=7.5Hz,2H),1.64(m,2H)1.38(m,9H),0.87(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C25H29NO4[M+H]+408.2175,检测值408.2177。
实施例50:(7-(二乙基氨甲酰)吲哚氮-5-基)(苯基)乙酸甲酯(ⅠI-50)的制备。
根据实施例47的方法,用化合物II-45(322mg,1mmol)代替化合物II-41,得淡黄色固体(II-50,79%)。1H NMR(500MHz,CDCl3):δ7.46(d,J=1.5Hz,1H),7.42(dd,J=7.0,2.0Hz,2H),7.34(m,3H),7.21(d,J=2.0Hz,1H),6.77(dd,J=4.0,3.0Hz,1H),6.73(s,1H),6.57(dd,J=4.0,1.0Hz,1H),5.96(s,1H),3.41(m,4H),3.07(s,3H),1.19(m,6H);HRMS(ESI):m/z预测值C22H24N2O3[M+H]+365.1865,检测值365.1866。
实施例51:(7-(二乙基氨甲酰)吲哚氮杂-5-基)(苯基)丁酸甲酯(ⅠI-51)的制备。
根据实施例47的方法,用化合物II-45(322mg,1mmol)代替化合物II-41,用丁酰氯(127mg,1.2mmol)代替乙酰氯,得淡黄色固体(II-51,72%)。1H NMR(500MHz,CDCl3):δ7.43(m,1H),7.39(d,J=7.0Hz,2H),7.31(m,3H),7.19(d,J=2.0Hz,1H),6.75(dd,J=4.0,2.5Hz,1H),6.71(s,1H),6.54(dd,J=4.0,1.5Hz,1H),5.93(s,1H),3.41(m,4H),2.40(t,J=7.5Hz,2H),1.70(m,2H),1.21(m,6H),0.97(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C24H28N2O3[M+H]+393.2178,检测值393.2183。
实施例52:(7-(二乙基氨甲酰)吲哚氮-5-基)(苯基)辛酸甲酯(ⅠI-52)的制备。
根据实施例47的方法,用化合物II-45(322mg,1.0mmol)代替化合物II-41,用辛酰氯(194mg,1.2mmol)(127mg,1.2mmol)代替乙酰氯,得淡黄色固体(II-52,72%)。1H NMR(500MHz,CDCl3):δ7.42(d,J=2.0Hz,1H),7.37(dd,J=7.0,1.5Hz,2H),7.28(m,3H),7.18(d,J=2.0Hz,1H),6.72(dd,J=4.0,2.5Hz,1H),6.69(s,1H),6.51(dd,J=4.0,1.0Hz,1H),5.91(s,1H),3.37(m,4H),2.35(t,J=7.5Hz,2H),1.31(m,15H),0.92(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C28H36N2O3[M+H]+449.2804,检测值449.2805。
实施例53:(5-苯甲酰亚胺-7-基)(4-甲基哌嗪-1-基)甲酮(ⅠI-53)的制备。
步骤g2:在氮气保护的条件下,取化合物II-41(30mg,0.1mmol)溶于N,N-二甲基甲酰胺(2毫升)中,反应液冷却至0摄氏度后加入氢化钠(5mg,0.12mmol),0摄氏度下反应30分钟后,滴加碘甲烷(17mg,0.12mmol),滴加完成后,室温下反应8小时,薄层色谱监测原料反应完全后,冰浴下向反应液中滴加2毫升饱和氯化铵溶液,滴加完成后,反应液用5毫升乙酸乙酯和5毫升水萃取,水相用5毫升乙酸乙酯萃取两次,合并乙酸乙酯相,无水硫酸钠干燥,减压蒸馏除去溶剂,所得粗产物经硅胶柱层析纯化得淡黄色固体(II-53,85%)。1H NMR(500MHz,CDCl3):δ8.14(m,1H),7.36(t,J=8.0Hz,2H),7.27(m,5H),6.71(dd,J=4.0,2.5Hz,1H),6.68(dd,J=4.5,1.0Hz,1H),5.68(s,1H),4.35(q,J=7.0Hz,2H),3.31(s,3H),1.41(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C19H19NO3[M+H]+310.1443,检测值310.1447。
实施例54:5-(苯基(丙氧基)甲基吲哚嗪-7-羧酸乙酯。
根据实施例53的方法,用碘丙烷(20mg,0.12mmol)代替碘甲烷(II-54,65%)。δ8.26(d,J=2.0Hz,1H),7.35(t,J=8.0Hz,2H),7.29(d,J=8.0Hz,2H),7.25(m,3H),6.74(dd,J=4.0,2.5Hz,1H),6.63(dd,J=4.5,1.5Hz,1H),5.72(s,1H),4.37(q,J=7.0Hz,2H),3.2(t,J=7.0Hz,2H),1.52(m,2H),1.41(t,J=7.0Hz,3H),0.94(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C21H23NO3[M+H]+338.1756,检测值338.1758。
实施例55:5-苯甲酰咪唑并[1,2-a]吡啶-7-羧酸甲酯(ⅠII-1)的制备。
步骤h:在氮气保护的条件下,将咪唑(680mg,10mmol)和碳酸钾(1.7mg,12mmol)在无水乙腈(30毫升)中,然后分批次加入2-溴-1-苯基乙烷-1-酮(2.4g,12mmol),完全加入后,升温至60摄氏度反应过夜,薄层色谱监测原料完全反应完全后,冷却至室温,过滤除去碳酸钾,滤液减压蒸馏除去溶剂,所得粗产物经硅胶柱层析纯化得到的产物白色固体直接用于下一步的反应;
步骤i:在氮气保护的条件下,将上一步产物2-(1H-咪唑-1-基)-1-苯基乙烷-1-酮(930mg,5mmol)溶解在无水二氯甲烷(30毫升)中,然后加入三氯氧磷(912mg,6mmol),反应液冰浴至0摄氏度,将N,N-二甲基甲酰胺(438mg,6mmol)缓慢加入反应液中,0摄氏度下反应2小时,薄层色谱监测原料完全反应完全后,反应液用50毫升乙酸乙酯和50毫升水萃取,水相用50毫升乙酸乙酯萃取两次,合并乙酸乙酯相,无水硫酸钠干燥,减压蒸馏除去溶剂,所得粗产物经硅胶柱层析纯化得到的产物为白色固体;
步骤j:在氮气保护的条件下,将上一步所得产物1-(2-氧代-2-苯乙基)-1H-咪唑-2-氨基甲醛(428mg,2mmol),丙炔酸甲酯(202mg,2.4mmol)和碳酸钾(331mg,2.4mmol)溶解在无水N,N-二甲基甲酰胺(6毫升)中,80摄氏度下反应过夜,薄层色谱监测原料反应完全后,冷却至室温,反应液用15毫升乙酸乙酯和15毫升水萃取,水相用15毫升乙酸乙酯萃取两次,合并有机相,无水硫酸钠干燥,减压蒸馏除去溶剂,所得粗产物经硅胶柱层析纯化得到黄色固体(III-1,74%)。1H NMR(500MHz,CDCl3):δ8.91(s,1H),8.61(d,J=1.0Hz,1H),7.99(d,J=1.0Hz,1H),7.95(d,J=1.5Hz,1H),7.83(dt,J=7.0,1.5Hz,2H),7.68(tt,J=7.5,1.0Hz,1H),7.56(t,J=7.5Hz,2H),3.95(s,3H);HRMS(ESI):m/z预测值C16H12N2O3[M+H]+282.0926,检测值282.0929。
实施例56:5-(4-氯苯甲酰基)咪唑并[1,2-a]吡啶-7-羧酸甲酯(ⅠII-2)的制备。
根据实施例55的方法,用2-溴-1-(4-氯苯基)乙烷-1-酮(2.8g,12mmol)替代2-溴-1-苯基乙烷-1-酮得黄色固体(III-2,67%)。1H NMR(500MHz,CDCl3):δ8.93(d,J=1.5Hz,1H),8.64(d,J=1.0Hz,1H),8.01(d,J=1.0Hz,1H),7.97(d,J=1.5Hz,1H),7.86(d,J=7.0Hz,2H),7.57(d,J=7.5Hz,2H),3.92(3H,s);HRMS(ESI):m/z预测值C16H11ClN2O3[M+H]+315.0536,检测值315.0538。
实施例57:5-(4-甲基苯甲酰基)咪唑并[1,2-a]吡啶-7-羧酸甲酯(ⅠII-3)的制备。
根据实施例55的方法,用2-溴-1-(对甲苯基)乙烷-1-酮(2.5g,12mmol)替代2-溴-1-苯基乙烷-1-酮得黄色固体(III-3,82%)。1H NMR(500MHz,CDCl3):δ8.87(m,1H),8.54(d,J=1.5Hz,1H),7.94(d,J=1.5Hz,1H),7.91(d,J=1.5Hz,1H),7.79(d,J=7.0Hz,2H),7.51(d,J=7.0Hz,2H),3.96(3H,s);HRMS(ESI):m/z预测值C17H14N2O3[M+H]+295.1083,检测值295.1088。
实施例58:5-苯甲酰咪唑并[1,2-a]吡啶-7-羧酸乙酯(ⅠII-4)的制备。
根据实施例55的方法,用丙炔酸乙酯(235mg,2.4mmol)替代丙炔酸甲酯得黄色固体(III-4,58%)。1H NMR(500MHz,CDCl3):δ8.89(s,1H),8.57(d,J=1.0Hz,1H),7.96(d,J=1.0Hz,1H),7.94(d,J=1.5Hz,1H),7.80(dt,J=7.0,1.5Hz,2H),7.66(tt,J=7.0,1.5Hz,1H),7.54(t,J=7.0Hz,2H),4.17(q,J=7.0Hz,2H),1.41(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C17H14N2O3[M+H]+295.1083,检测值295.1085。
实施例59:5-苯甲酰亚胺偶氮[1,2-a]吡啶-7-羧酸(ⅠII-5)的制备。
步骤k:将化合物ⅡI-4(588mg,2mmol)溶于6毫升乙醇中,加入2N氢氧化钠溶液(2毫升),反应液于80摄氏度下搅拌过夜,薄层色谱监测原料反应完全后将乙醇减压蒸馏除去,剩余溶液用盐酸溶液调至酸性,有黄色固体析出、过滤,固体水洗、干燥得黄色固体(ⅡI-5,94%)。1H NMR(500MHz,CDCl3):δ12.27(1H,s),8.87(s,1H),8.54(s,1H),7.93(d,J=1.5Hz,1H),7.91(d,J=1.5Hz,1H),7.78(dt,J=7.0,1.0Hz,2H),7.63(tt,J=7.0,1.0Hz,1H),7.52(t,J=7.0Hz,2H);HRMS(ESI):m/z预测值C15H10N2O3[M+H]+267.0770,检测值267.0771。
实施例60:5-苯甲酰-N,N-二甲基咪唑[1,2-a]吡啶-7-甲酰胺(ⅠII-6)的制备。
步骤l:将化合物ⅡI-5(53mg,0.2mmol)、1-羟基苯并三唑(13mg,0.06mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(46mg,0.24mmol)溶解在2毫升无水四氢呋喃中,室温下加入N,N-二异丙基乙胺(34mg,0.26mmol),室温下反应8小时至薄层色谱监测ⅡI-5反应完全,然后加入二甲胺(11mg,0.24mmol),室温下反应2小时。薄层色谱监测原料反应完全后,反应液减压蒸馏除去溶剂,所得粗产物经硅胶柱层析纯化得到的黄色固体(III-6,86%)。1H NMR(500MHz,CDCl3):δ8.87(d,J=2.0Hz,1H),8.55(d,J=1.5Hz,1H),7.92(d,J=1.5Hz,1H),7.87(d,J=1.5Hz,1H),7.73(dt,J=7.5,1.5Hz,2H),7.67(tt,J=7.5,1.5Hz,1H),7.50(t,J=7.0Hz,2H),3.27(s,6H);HRMS(ESI):m/z预测值C17H15N3O2[M+H]+294.1243,检测值294.1245。
实施例61:5-苯甲酰基-N-乙基咪唑并[1,2-a]吡啶-7-甲酰胺(ⅠII-7)的制备。
根据实施例60的方法,用乙胺(11mg,0.24mmol)替代二甲胺得黄色固体(III-7,88%)。1H NMR(500MHz,CDCl3):δ8.85(m,1H),8.56(d,J=1.5Hz,1H),7.94(d,J=1.0Hz,1H),7.86(d,J=1.0Hz,1H),7.74(dt,J=7.5,1.5Hz,2H),7.65(tt,J=7.0,1.5Hz,1H),7.50(t,J=7.5Hz,2H),5.85(m,1H),3.47(m,2H),1.24(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C17H15N3O2[M+H]+294.1243,检测值294.1247。
实施例62:5-苯甲酰-N,N-二乙基咪唑[1,2-a]吡啶-7-甲酰胺(ⅠII-8)的制备。
根据实施例60的方法,用二乙胺(18mg,0.24mmol)替代二甲胺得黄色固体(III-8,79%)。1H NMR(500MHz,CDCl3):δ8.86(m,1H),8.54(d,J=1.5Hz,1H),7.91(d,J=1.5Hz,1H),7.89(d,J=1.5Hz,1H),7.74(dt,J=7.0,1.0Hz,2H),7.65(tt,J=7.0,1.0Hz,1H),7.48(t,J=7.0Hz,2H),3.56(m,4H),1.14(m,6H);HRMS(ESI):m/z预测值C19H19N3O2[M+H]+322.1556,检测值322.1557。
实施例63:(5-苯甲酰咪唑并[1,2-a]吡啶-7-基)(吡咯烷-1-基)甲酮(ⅠII-9)的制备。
根据实施例60的方法,用吡咯烷(17mg,0.24mmol)替代二甲胺得黄色固体(III-9,73%)。1H NMR(500MHz,CDCl3):δ8.86(d,J=1.5Hz,1H),8.56(d,J=1.5Hz,1H),7.93(d,J=1.5Hz,1H),7.87(d,J=1.5Hz,1H),7.72(dt,J=7.0,1.0Hz,2H),7.63(tt,J=7.0,1.0Hz,1H),7.50(t,J=7.0Hz,2H),3.63(m,4H),1.43(m,4H);HRMS(ESI):m/z预测值C19H17N3O2[M+H]+320.1399,检测值320.1402。
实施例64:(5-苯甲酰咪唑[1,2-a]吡啶-7-基)(哌啶-1-基)甲酮(ⅠII-10)的制备。
根据实施例60的方法,用哌啶(20mg,0.24mmol)替代二甲胺得黄色固体(III-10,77%)。1H NMR(500MHz,CDCl3):δ8.89(m,1H),8.55(d,J=1.0Hz,1H),7.93(d,J=1.5Hz,1H),7.90(d,J=1.5Hz,1H),7.72(dt,J=7.0,1.0Hz,2H),7.67(tt,J=7.0,1.0Hz,1H),7.50(t,J=7.0Hz,2H),3.74(m,4H),1.95(m,4H),1.47(m,2H);HRMS(ESI):m/z预测值C20H19N3O2[M+H]+334.1556,检测值334.1558。
实施例65:5-(羟基(苯基)甲基咪唑并[1,2-a]吡啶-7-羧酸乙酯(ⅠII-11)的制备。
步骤m:在氮气保护的条件下,将化合物III-4(294mg,1mmol)溶于无水甲醇(4毫升)中,反应液冰浴至0摄氏度,将硼氢化钠(152mg,4mmol)分批次加入反应液中,0摄氏度下反应2小时,薄层色谱监测原料反应完全后,反应液于冰浴下加5毫升饱和氯化铵溶液淬灭,减压蒸馏除去溶剂,所得粗产物经硅胶柱层析纯化得白色固体(III-11,93%)。1H NMR(500MHz,CDCl3):δ8.37(m,1H),7.51(d,J=1.5Hz,1H),7.28(m,2H),7.21(dt,J=7.0,1.5Hz,2H),7.14(tt,J=7.0,1.5Hz,1H),7.03(t,J=7.0Hz,2H),5.83(s,1H),4.52(s,1H),4.15(q,J=7.0Hz,2H),1.40(t,J=7.0Hz,3H);HRMS(ESI):m/z预测值C17H16N2O3[M+H]+297.1239,检测值297.1243。
实施例66:生物学评价
本发明所述稠环杂环化合物对TRPM2通道具有抑制作用,采用全细胞膜片钳技术(Whole-cell patch)测定其药理活性,其相应的步骤如下:
1)细胞准备
稳定表达人源TRPM2通道的的HEK293细胞,用含有10%牛血清,50units/毫升青霉素,50mg/毫升链霉素的DMEM/F-12培养基,于5%CO2及37摄氏度条件下进行孵育。
2)电生理测试
测试前的细胞保存于细胞外液(147mM NaCl,2mM KCl,1mM MgCl2,2mM CaCl2,10mM HEPES,13mM glucose,pH 7.4)。电极充满电极内液(147mM NaCl,0.05mM EGTA,1mMMgCl2,10mM HEPES,0.5mM ADPR,pH=7.3),电阻保持在3~5MΩ。
通过电极向细胞内给予ADPR,测试用于激活TRPM2的ADPR浓度为500μM;待检测到平稳电流,在细胞外液给予相应浓度的稠环杂环化合物II-1灌流,时间至少为60s,记录电流大小的变化,记录方式为电压斜坡模式记录,500ms时间内电压从-100mV变化到+100mV,正常钳制电压为0mV,每5秒为一个TRPM;最后,将细胞外液置换为pH=5.0的溶液,以阻断TRPM2电流,所得电生理电流测试结果见表1,所得电生理电流图见图1。
同样地,在细胞外液中给予相应的浓度的其他的稠环杂环化合物(II-2~II-54,III-1~III-11)按照同样的方法进行电生理测试,所得结果见表1。部分稠环杂环化合物(II-9、II-19和II-36)抑制TRPM2通道电流的电生理代表性电流图见图1。
表1部分稠环杂环化合物对TRPM2抑制的IC50数据
实施例67:本发明所述稠环杂环化合物II-1、II-23和III-1对缺血/再灌注损伤的保护活性研究
1)小鼠短暂性局灶性脑缺血大脑中动脉栓塞(tMCAO)模型制备
22~25g雄性C57BL/6小鼠进行异氟烷吸入式气体麻醉后,将激光多普勒血流仪光纤探头用胶水固定于动物颅骨上,用于监测大脑中动脉(MCA)供血皮层脑血流。仰卧位固定小鼠,颈部正中去毛,75%酒精常规消毒,取颈正中约1.5cm切口,切开颈部皮肤,沿胸锁骨乳突肌内缘分离肌肉和筋膜;钝性分离右侧颈动脉鞘,暴露右侧颈总动脉(CCA)、颈外动脉(ECA)及颈内动脉(ICA);手术范围暴露满意后,用动脉夹暂时夹闭CCA和ICA,在ECA近心端用显微手术剪剪切一小口,将尼龙单丝缝合线由该小口沿ECA插入,顺着ICA方向轻轻推入至颅内约11.5±0.5mm,堵住大脑中动脉起点。根据脑血流仪监测数据血流数据,只选择血流值降至基础值20%的动物。缺血90分钟后,轻轻抽出单丝缝合线,扎紧动脉残端,检查手术创口,彻底止血后,局部洒少量青霉素粉末预防感染,逐层缝合皮下组织及皮肤,完成缺血再灌注损伤模型。手术过程中采用加热板维持动物体温。手术完成后将缝合好的小鼠放入保温保湿箱中,直至小鼠恢复活动。假手术组动物采用相同手术过程,但不进行中动脉堵塞。
2)动物分组及给药方案
清洁级雄性C57BL/6小鼠随机分成5组,分别为假手术组、阳性对照药依达拉奉组(3mg/kg),化合物II-1、II-23和III-1的的3mg/kg剂量组。小鼠建模再灌注3h后分别进行尾静脉注射依达拉奉、II-1、II-23和III-1,假手术组注射等体积生理盐水,II-1、II-23、III-1和依达拉奉均用0.9%生理盐水溶液溶解。在缺血再灌注24h后进行小鼠神经功能评分及TTC染色,结果见图2、3和4。
3)脑梗死面积测定
小鼠缺血再灌注24h后,断头取脑,冠状面均匀切成厚度约2mm的脑片,脑片置于0.25%的2,3,5-氯化三苯基四氮唑(TTC)溶液中,37摄氏度避光孵育30分钟,染色后于4%多聚甲醛中性缓冲液(pH 7.4)固定过夜。微距相机拍摄,Image J图像分析软件计算并统计脑梗死面积,测得结果见图3。梗死面积百分数计算公式为:(左侧未梗面积之和-右侧未梗面积之和)/左侧未梗面积之和×l00%。
4)神经功能检测:根据五级四分法评分标准,对各组小鼠进行死亡率统计以及神经运动功能障碍评分,测得结果见图4。神经功能评分标准为:0分:无神经功能缺损症状;1分:提尾时脑缺血对侧前肢不能完全伸展;2分:实验动物向脑缺血对侧转圈;3分:实验动物爬行时倒向脑缺血对侧;4分:实验动物不能独立行走,意识丧失。
5)活性结果评价
本发明所述稠环杂环化合物II-1、II-23和III-1均可明显减小tMCAO造成的小鼠脑梗死面积,并显著降低tMCAO引起的神经运动功能障碍评分,与等浓度的阳性对照药物依达拉奉具有相似的药理活性。
实施例68:本发明所述稠环杂环化合物II-I对缺血/再灌注损伤的保护活性研究
1)急性海马脑切片
取3~4周(出生后21天到28天)毛色光亮的小鼠作为实验小鼠。实验前,取200mL的切片液于烧杯中,通95%O2/5%CO2混合气体15分钟,放于-80℃冰箱冷冻25分钟。在冰冻切片液的同时,将孵育槽(自制,250mL烧杯)置于34℃的水浴锅中,孵育槽内加约180mL ACSF,持续通混合气。取出冻好的切片液,并持续通氧。此时,将小鼠用乙醚麻醉后,断颈,在冰上操作快速取脑(小于1分钟),立即将脑置于冰冻的切片液中,冷冻5分钟。将脑从切片液中取出,在玻璃皿上(玻璃皿置于冰上)分离出左右两侧海马。分离出的海马置于4%的琼脂糖块上,用滤纸小心吸干周边水分后,用502将带有海马的琼脂块固定在震动切片机(徕卡1200S)的平台上,并立即倒入冰冻的切片液于切片槽内。切片时,刀口的方向垂直于海马的长轴,切片厚度为300μm。切好的海马脑片用滴管转移到孵育槽内,34℃孵育30分钟后,将孵育槽转移到室温。脑片至少在室温中孵育45分钟后,才进行下一步实验,切片液与ACSF一直通95%O2/5%CO2混合气体以维持液体的pH和给脑片供氧。
2)脑片的缺血缺氧实验
随机将孵育好的急性海马脑片随机分成Sham组和OGD组。Sham组脑片和OGD脑片用滴管取出后,分别放置于正常ACSF和OGD-ACSF中60分钟(34℃)。OGD处理结束后放回至的正常ACSF 30分钟(34℃)。用5μg/mL propidium iodide(PI)和20μM Newport green(Invetrogen)+ACSF室温孵育脑片10分钟,ACSF的量为2mL。使用染料孵育槽孵育脑片,同时保证ACSF的通氧并且尽量减小因为机械振动而影响细胞活性,使用PI标记损伤的细胞,Newport Green检测神经元的锌离子的量。将孵育好染料的脑片取出,置于200mL ACSF的孵育槽内去除多余的染料。最后,将脑片置于记录槽内,使用共聚焦显微镜Olympus FV100060X水镜拍摄,记录槽持续灌流ACSF。ACSF需要提前30分钟通入95%O2/5%CO2混合气体,实验中也需一直冲氧;OGD-ACSF实验前30分钟通95%O2/5%CO2混合气体,以排除液体中的O2,OGD时也需持续通入N2。
分别获取野生型小鼠和TRPM2敲除小鼠的海马脑片,采用离体氧糖剥夺复灌(OGD)造模,模拟在体脑缺血损伤,OGD进行30分钟之后,采用PI染色监测小鼠脑片的海马CA1神经元死亡情况,同时采用Newport Green染色法监测神经元胞内锌离子的量。测试结果见图5。根据图5的测试结果,OGD进行30分钟之后,采用PI染色观察到野生型小鼠脑片的海马CA1神经元死亡明显增加,同时锌离子染色结果也显示大量神经元胞内锌离子累积。而在TRPM2敲除小鼠的海马脑片中,我们发现OGD引发的锌离子累积和PI染色增加均受到显著抑制,表明TRPM2缺乏可通过减少神经元锌离子累积从而起到脑保护作用。
上述实验表明,本发明所述稠环杂环化合物对TRPM2通道具有抑制作用,而抑制TRPM2通道可通过减少神经元锌离子累积从而起到脑保护作用,因此本发明所述稠环杂环化合物有助于脑损伤后的修复。
实施例69:TRPM2通道对缺血/再灌注损伤的保护活性研究
1)小鼠短暂性局灶性脑缺血大脑中动脉栓塞(tMCAO)模型制备
22~25g雄性WT小鼠(TRPM2+/+)和TRPM2基因敲除小鼠(TRPM2-/-)小鼠进行异氟烷吸入式气体麻醉后,将激光多普勒血流仪光纤探头用胶水固定于动物颅骨上,用于监测大脑中动脉(MCA)供血皮层脑血流。仰卧位固定小鼠,颈部正中去毛,75%酒精常规消毒,取颈正中约1.5cm切口,切开颈部皮肤,沿胸锁骨乳突肌内缘分离肌肉和筋膜;钝性分离右侧颈动脉鞘,暴露右侧颈总动脉(CCA)、颈外动脉(ECA)及颈内动脉(ICA);手术范围暴露满意后,用动脉夹暂时夹闭CCA和ICA,在ECA近心端用显微手术剪剪切一小口,将尼龙单丝缝合线由该小口沿ECA插入,顺着ICA方向轻轻推入至颅内约11.5±0.5mm,堵住大脑中动脉起点。根据脑血流仪监测数据血流数据,只选择血流值降至基础值20%的动物。缺血90分钟后,轻轻抽出单丝缝合线,扎紧动脉残端,检查手术创口,彻底止血后,局部洒少量青霉素粉末预防感染,逐层缝合皮下组织及皮肤,完成缺血再灌注损伤模型。
2)手术过程中采用加热板维持动物体温
手术完成后将缝合好的小鼠放入保湿箱中,直至小鼠恢复活动。预先配置3-MA在生理盐水中,加热至60~70℃后在再灌注即刻立即进行侧脑室注射10μg 3-MA。假手术组动物采用相同手术过程,仅夹闭颈总动脉,不进行中动脉阻塞。
3)脑梗死面积测定
小鼠缺血再灌注24h后,断头取脑,冠状面均匀切成厚度约2mm的脑片,脑片置于0.25%的2,3,5-氯化三苯基四氮唑(TTC)溶液中,37摄氏度避光孵育30分钟,染色后于4%多聚甲醛中性缓冲液(pH 7.4)固定过夜。微距相机拍摄,Image J图像分析软件计算并统计脑梗死面积,测试结果见图7。梗死面积百分数计算公式为:(左侧未梗面积之和-右侧未梗面积之和)/左侧未梗面积之和×l00%。
4)分别用WT小鼠(TRPM2+/+)和TRPM2基因敲除小鼠(TRPM2-/-)进行短暂性中动脉阻塞模型(tMCAO)造模。结果提示TRPM2水平降低可增强脑缺血复灌过程中的自噬功能,从而起到脑保护作用,这种脑保护作用可被自噬抑制剂3-MA逆转,测试结果见图8,表明TRPM2缺乏可通过增强自噬从而起到保护作用。
本领域的普通技术人员可以理解,上述各实施方式是实现本发明的具体实施例,而在实际应用中,可以在形式上和细节上对其作各种改变,而不偏离本发明的精神和范围。本领域的普通技术人员可以理解,上述各实施方式是实现本发明的具体实施例,而在实际应用中,可以在形式上和细节上对其作各种改变,而不偏离本发明的精神和范围。
Claims (11)
1.一种稠环杂环化合物,或其药学上可接受的盐在制备治疗脑卒中药物中的应用,所述稠环杂环化合物具有通式(I)所示结构:
式中,R1为未取代或至少一个氢原子被R1-1取代的杂芳基、未取代或至少一个氢原子被R1-2取代的苯基,其中,R1-1为卤素或C1~6烷基,R1-2为卤素、氰基、硝基、C2~8酯基、C1~6烷基或C1~6烷氧基;
X为碳原子或氮原子。
2.根据权利要求1所述的应用,其特征在于,所述R1为未取代或至少一个氢原子被R1-1取代的五元杂芳基、未取代或至少一个氢原子被R1-1取代的六元杂芳基,所述R1-1为卤素或C1~4烷基,
或者,所述R1为未取代或至少一个氢原子被R1-2取代的苯基,所述R1-2为卤素、氰基、硝基、C1~4烷基、C1~4烷氧基;
3.根据权利要求1所述的应用,其特征在于,所述R1为含有一个O或S原子的未取代或至少一个氢原子被R1-1取代的五元杂芳基、未取代或至少一个氢原子被R1-1取代的吡啶基,所述R1-1为氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;
或者,所述R1为未取代或至少一个氢原子被R1-2取代的苯基,所述R1-2为氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基或乙氧基;
8.根据权利要求1所述的应用,其特征在于,所述稠环杂环化合物中,X为氮原子。
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