CN111848549A - 芳基肟类化合物及其制备和应用 - Google Patents
芳基肟类化合物及其制备和应用 Download PDFInfo
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- CN111848549A CN111848549A CN201910355220.9A CN201910355220A CN111848549A CN 111848549 A CN111848549 A CN 111848549A CN 201910355220 A CN201910355220 A CN 201910355220A CN 111848549 A CN111848549 A CN 111848549A
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Abstract
本发明涉及一种通式I所示的芳基肟类化合物、其药剂学上可接受的盐、酯或水合物，及其制备和应用：
其中，R1和R2独立地选自氢、C1‑C8烷基、C1‑C8氧烷基、芳基、取代芳基或芳烷基；或者R1和R2与它们连接的N原子形成3‑8元环；或者R1和R2的其中之一、与它们连接的N原子以及与N原子连接的C原子形成3‑8元环；R3和R4独立地选自氢、C1‑C6烷基、芳基或取代芳基；n＝1‑4中的任一整数。本发明的芳基肟类化合物可应用于制备多种治疗中枢神经系统的疾病的药物。
Description
技术领域
本发明涉及药物化学领域，尤其涉及一种芳基肟类化合物及其制备和应用。
背景技术
Sigma受体于1976年被首次提出，并被归类于阿片类受体家族，其特异性激动剂为(+)SKF10047及pentazocine，但之后，由于Sigma受体配体引起的效应不能被阿片类受体拮抗剂(如纳洛酮、纳曲酮等)逆转，因而又将Sigma受体与阿片类受体区别开来。目前认为，Sigma受体与阿片类受体或其他哺乳动物蛋白无同源性，是一个独立的受体家族，存在2种亚型：Sigma-1和Sigma-2受体。尽管这种受体是20年前首次被克隆的，但蛋白质的分子结构及其与药物样小分子相互作用的机制基础直到最近才被慢慢了解。Sigma-1受体是由223个氨基酸组成，主要位于内质网-线粒体接触面的表面，也常被称作“线粒体相关的内质网膜(MAM)。
研究发现Sigma-1受体是多种特异性精神类药物的结合蛋白，作为受体型分子伴侣发挥其生理功能包括：调节离子通道(K+、Ca2+、Na+通道等)和下游受体[肌醇三磷酸(IP3)受体、NMDAR等]，从而调节线粒体功能及神经递质释放等。中枢神经系统中Sigma-1受体的生理功能主要包括改善药物成瘾及运动障碍\保护神经、调节认知等，而外周Sigma-1受体主要分布于淋巴组织，其作用主要是参与调节机体免疫功能。在稳定状态下，Sigma-1受体主要定位于MAM，与另外一个分子伴侣葡萄糖调节蛋白78(GRP78)，又称免疫球蛋白重链结合蛋白(BiP)，形成Ca2+敏感复合物，当ER中Ca2+浓度降低或特异性激动剂作用于Sigma-1受体时，Sigma-1受体与BiP分离并激活，再分布至细胞膜脂质筏，调节离子通道、蛋白激酶和G蛋白偶联受体(GPCR)，进而启动下游多条信号转导通路。
随着Sigma-1受体特异性配体的应用和中枢神经系统尤其是边缘皮质和运动相关区域Sigma-1受体亚型的发现，Sigma-1受体的生理机制得到了广泛挖掘，Sigma-1受体广泛分布于中枢神经系统，通过调节离子通道、神经递质功能及线粒体功能等，在胆碱能、γ-氨基丁酸(GABA)能及多巴胺能等神经系统中起重要调节作用，从而发挥镇痛、记忆障碍改善、抗癫痫、抗抑郁以及神经保护等作用。
起初Sigma-1受体与配体的共晶结构不明，1994年Glennon等人通过对Sigma-1受体小分子配体进行了归纳总结，提出了Sigma-1受体配体的药效团模型，认为Sigma-1受体配体主要由三部分组成，中间是碱性氮原子中心，氮的一侧是一个主要的疏水特征，位于距氮原子
的位置，另一侧是第二疏水特征，位于距离氮原子中心
的距离。
迄今为止，许多上市的神经精神性疾病治疗药物已被报道非选择性作用于Sigma-1受体，其中SA4503、(+)-Pentazocine、(+)-SKD-10047、PER-084、Fluvoxamine、Fluoxetine等可作为Sigma-1受体激动剂；BD-1047、BD-1063、Halpperidol、E-52862、NE-100等可作为Sigma-1拮抗剂。然而，至今尚无选择性作用于Sigma-1受体的药物成功上市，仅有两个候选药物SIRA和Cutamesine进入临床试验。
因此，亟待开发选择性作用于Sigma-1受体的小分子配体，其将对深入认识和治疗癫痫、阿尔兹海默症、帕金森氏症、缺血性中风、神经性疼痛以及药物成瘾等神经精神性疾病有着非常重要的意义。
发明内容
为解决上述技术问题，本发明的目的是提供一种芳基肟类化合物、其药剂学上可接受的盐、酯或水合物及其制备和应用，本发明的芳基肟类化合物可应用于制备多种治疗中枢神经系统的疾病的药物。
本发明的第一个目的是提供一种通式I所示的芳基肟类化合物、其药剂学上可接受的盐、酯或水合物：
R1和R2独立地选自氢、C1-C8烷基、C1-C8氧烷基、C1-C6胺烷基、芳基、取代芳基或芳烷基；或者
R1和R2与它们连接的N原子形成3-8元环；
或者
R1或R2与它们连接的N原子以及与该N原子另一侧连接的C原子形成3-8元环；
R3和R4独立地选自氢、C1-C6烷基、芳基、取代芳基、芳杂环或取代芳杂环；n＝0-4中的任一整数。
优选地，n＝1或2。
进一步地，R1和R2与它们连接的N原子；或R1和R2的其中之一与它们连接的N原子和N原子另一侧连接的C原子形成
吡咯环、取代吡咯环、哌啶环、取代哌啶环、哌嗪环、烷基取代哌嗪环、杂氮环丁环、氮丙啶环、高哌嗪环、烷基或芳基取代高哌嗪环、吗啉环、取代吗啉环、芳基哌嗪环、四氢异喹啉环、取代四氢异喹啉环、四氢喹啉环、取代四氢喹啉环、二氢吲哚环、取代二氢吲哚环。
进一步地，所述药剂学上可接受的盐为式(1)所示的化合物与无机酸或有机酸形成的盐，所述药剂学上可接受的酯为式(1)所示的化合物与酸(羧酸或无机含氧酸)或醇形成的酯，所述药剂学上可接受的水合物为式(1)所示的化合物与水以配位键或共价键形成的含水化合物。
优选地，R4为芳基、芳杂环、取代芳基或取代芳杂环。
优选地，芳基选自C6-C10芳环，非限制性的包括苯基、萘基或连苯环。萘基上的取代位点为1位、2位或3位。
优选地，芳烷基非限制性的包括取代或未取代的苯甲基、取代或未取代的苯乙基或取代或未取代的苯丙基。
优选地，芳杂环为含有1-3个选自N、O和S原子的5-8元芳杂环，非限制性的包括喹啉、异喹啉、吲哚、苯并呋喃环、呋喃环、苯并噻吩环、噻吩环、吡啶环或吡咯环。
优选地，取代芳基取代芳杂环上的取代基为C1-C6烷基、C1-C6烷氧基、C1-C6烷胺基、氰基、硝基、羟基、羧基、烷氧酰基、氨基、酰胺基、酰氧基、酰基、磺酰基、磺酰氨基、脲、硫脲或氨甲酰基、卤素和C1-C6卤烷基中的一种或几种。
优选地，取代芳基为2、3或4-三氟甲基苯基、2、3或4-氯苯基、2、3或4-溴苯基、2、3或4-甲基苯基、2、3或4-甲氧基苯基、2，3-二甲基苯基、2，4-二甲基苯基、3，5二甲基苯基，2，3-二氯苯基、2，4-二氯苯基、3，5二氯苯基，2-氯-4-三氟甲基苯基，3-氯-4-三氟甲基苯基，2-氯-4-甲基苯基，3-氯-4-甲基苯基。
更优选地，本发明的芳基肟类化合物的结构式如下：
本发明的第二个目的是提供一种通式I所示的芳基肟类化合物的制备方法，包括以下步骤：
(1)将式LB-1所示的化合物在盐酸羟胺和醋酸盐的存在下，在有机溶剂中于85-100℃下反应，反应完全后得到式LB-2所示的化合物；
(2)将式LB-2所示的化合物与含有1-5个碳原子的卤代烃在碱和季铵盐的作用下，在有机溶剂中于40-60℃下反应，反应完全后得到式LB-3所示的化合物；
(3)将式LB-3所示的化合物与胺类化合物在碳酸盐的作用下，在有机溶剂中于80-100℃下反应，反应完全后得到通式I所示的芳基肟类化合物；胺类化合物的结构式为
反应路线如下：
(4)将式LB-2所示的化合物与卤代烷胺在强碱作用下，在有机溶剂中于80-100℃下反应，反应完全后得到通式I所示的芳基肟类化合物；卤代烷胺的结构式为
反应路线如下：
其中，R1、R2、R3、R4和n如上文中所定义的；
X为卤素。
进一步地，在步骤(2)中，式LB-2所示的化合物与卤代烃的摩尔比为1:3至1:5。
进一步地，在步骤(3)中，式LB-3所示的化合物与胺类化合物的摩尔比为1:1.2至1:3。
进一步地，在步骤(4)中，式LB-2所示的化合物与卤代烷胺的摩尔比为1:1.5至1:3。
本发明的第三个目的是提供一种药物组合物，包括本发明上述通式I所示的芳基肟类化合物、其药剂学上可接受的盐、酯或水合物。
本发明的第四个目的是公开通式I所示的芳基肟类化合物、其药剂学上可接受的盐、酯或水合物作为Sigma-1配体在制备预防和/或治疗与Sigma-1相关疾病药物中的应用。
进一步地，与Sigma-1相关疾病包括神经精神性疾病。
优选地，神经精神性疾病包括癫痫、抑郁症、阿尔兹海默症、帕金森氏症、缺血性中风、神经性疼痛或药物成瘾等。
借由上述方案，本发明至少具有以下优点：
本发明从氟伏沙明这类芳基肟类化合物出发，利用Sigma-1受体配体药效团模型，通过合理的结构修饰，从而获得一类具有新型芳基肟类骨架的高选择性Sigma-1配体，并因此可应用于制备多种治疗中枢神经系统的疾病的药物。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，并可依照说明书的内容予以实施，以下以本发明的较佳实施例并配合附图详细说明如后。
附图说明
图1是通式I所示的芳基肟类化合物的制备路线图。
具体实施方式
下面结合附图和实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但不用来限制本发明的范围。
本发明以下实施例中，通式I所示的芳基肟类化合物的制备路线如图1所示；具体步骤如下：
(1)称取盐酸羟胺(556mg，8.0mmol)和醋酸钠(1360mg，10mmol)溶于10mL 80％乙醇中，在室温下搅拌30分钟。向其中加入LB-1所示的化合物(5mmol)100℃回流反应1h。反应结束后将溶剂旋干，加入水(15mL)，用二氯甲烷(20mL×2次)萃取，然后将有机相用盐水(15mL)洗涤，干燥，过滤，然后蒸发得到白色固体粗产物，即为LB-2所示的化合物。
路线1：(2)将LB-2(4mmol)溶于20mL二氯甲烷中，加入5N NaOH(5mL)，随后分别加入20mmol的1，2-二溴乙烷(1724μL)或1-溴-3-氯丙烷(1963μL)，CTMAB(584mg，1.6mmol)，在50℃下反应12h。反应结束后加入水(15mL)稀释，用二氯甲烷(20mL×2次)萃取，然后将有机相用盐水(15mL)洗涤，将有机相用无水硫酸钠干燥并减压浓缩，最后通过硅胶柱层析纯化，得到LB-3。
(3)当LB-3中的n＝1时，称取适量的LB-3(0.25mmol)溶于乙腈(10mL)中，加入碳酸钾(69mg，0.5mmol)和对应的胺(0.5mmol)，在85℃条件下回流2h。反应结束后，将溶剂旋干，用水(15mL)稀释，然后用二氯甲烷(15mL×2)萃取，将合并的有机相用无水硫酸钠干燥并减压浓缩，残余物通过硅胶柱纯化得到通式(I)所示的芳基肟类化合物。
当LB-3中的n＝2时，反应体系中还加有碘化钠(75mg，0.5mmol)。
路线2：(4)将LB-2(4mmol)溶于15mlDMF中，加入卤代烷胺(6mmol),碳酸钾(12mmol)，在80℃下反应12h。反应结束后，用水(15mL)稀释，然后用二氯甲烷(15mL×2)萃取，将合并的有机相用无水硫酸钠干燥并减压浓缩，残余物通过硅胶柱纯化得到通式(I)所示的芳基肟类化合物。
以下实施中，化合物A1-A12、C1-C8、D1-D8、E1-E8、B1-B3的结构式如说明书上文所示。
实施例1
利用LB-1(对三氟甲基苯乙酮)按照上述方法的步骤(1)-(2)制备LB-3-1：
硅胶柱层析使用洗脱剂(PE:EA＝40:1)得到黄色油状物，产率为58％。其核磁氢谱如下：1H NMR(400MHz,CDCl3)δ7.76(d,J＝8.1Hz,2H),7.63(d,J＝8.2Hz,2H),4.49(t,J＝6.3Hz,2H),3.63(t,J＝6.3Hz,2H),2.29(s,3H)。
实施例2
利用LB-1(对溴苯乙酮)按照上述方法的步骤(1)-(2)制备LB-3-2：
硅胶柱层析使用洗脱剂(PE:EA＝45:1)得到黄色油状物，产率为52％。其核磁氢谱如下：1H NMR(400MHz,CDCl3)δ7.68–7.41(m,4H),4.46(t,J＝6.3Hz,2H),3.62(t,J＝6.3Hz,2H),2.25(s,3H)。
实施例3
利用LB-1(对甲氧基苯乙酮)按照上述方法的步骤(1)-(2)制备LB-3-3：
硅胶柱层析使用洗脱剂(PE:EA＝40:1)得到淡黄色固体，产率为55％。其核磁氢谱如下：1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.6Hz,2H),6.89(d,J＝8.6Hz,2H),4.43(t,J＝6.3Hz,2H),3.83(s,3H),3.62(t,J＝6.3Hz,2H),2.24(s,3H)。
实施例4
利用LB-1(对甲基苯乙酮)按照上述方法的步骤(1)-(2)制备LB-3-4：
硅胶柱层析使用洗脱剂(PE:EA＝40:1)得到淡黄色油状物，产率为58％。其核磁氢谱如下：1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.0Hz,2H),7.18(d,J＝7.8Hz,2H),4.44(t,J＝6.3Hz,2H),3.64–3.59(t,J＝6.3Hz,2H),2.36(s,3H),2.25(s,3H)。
实施例5
利用LB-1(苯乙酮)按照上述方法的步骤(1)-(2)制备LB-3-5：
硅胶柱层析使用洗脱剂(PE:EA＝45:1)得到淡黄色油状物，产率为60％。其核磁氢谱如下：1H NMR(400MHz,CDCl3)δ7.64(s,2H),7.37(s,3H),4.46(t,J＝5.8Hz,2H),3.62(t,J＝5.8Hz,2H),2.27(s,3H)。
实施例6
利用LB-1(邻三氟甲基苯乙酮)按照上述方法的步骤(1)-(2)制备LB-3-6：
硅胶柱层析使用洗脱剂(PE:EA＝40:1)得到淡黄色油状物，产率为51％。其核磁氢谱如下：1H NMR(400MHz,CDCl3)δ7.70(d,J＝7.6Hz,1H),7.57(t,J＝7.2Hz,1H),7.49(t,J＝7.6Hz,1H),7.35(d,J＝7.5Hz,1H),4.42(t,J＝6.3Hz,2H),3.59(t,J＝6.3Hz,2H),2.23(s,3H)。
实施例7
利用LB-1(间三氟甲基苯乙酮)按照上述方法的步骤(1)-(2)制备LB-3-7：
硅胶柱层析使用洗脱剂(PE:EA＝40:1)得到淡黄色油状物，产率为55％。其核磁氢谱如下：1H NMR(400MHz,DMSO)δ7.83(s,1H),7.75(d,J＝7.8Hz,1H),7.55(d,J＝7.7Hz,1H),7.42(t,J＝7.8Hz,1H),4.41(t,J＝6.3Hz,2H),3.55(t,J＝6.3Hz,2H),2.21(s,3H)。
实施例8
利用LB-1(二苯甲酮)按照上述方法的步骤(1)-(2)制备LB-3-8：
硅胶柱层析使用洗脱剂(PE:EA＝40:1)得到淡黄色油状物，产率为55％。其核磁氢谱如下：1H NMR(400MHz,CDCl3)δ7.47(d,J＝7.5Hz,2H),7.44–7.36(m,5H),7.33(dd,J＝13.3,5.8Hz,2H),4.42(t,J＝6.4Hz,2H),3.62(t,J＝6.4Hz,2H)。
实施例9
利用LB-1(1-萘乙酮)按照上述方法的步骤(1)-(2)制备LB-3-9：
硅胶柱层析使用洗脱剂(PE:EA＝40:1)得到淡黄色固体，产率为50％。其核磁氢谱如下：1H NMR(400MHz,CDCl3)δ8.06(d,J＝7.7Hz,1H),7.90(dd,J＝5.1,2.1Hz,2H),7.59–7.44(m,4H),4.53(t,J＝6.2Hz,2H),3.70(t,J＝6.2Hz,2H),2.44(s,3H)
实施例10
利用LB-1(2-萘乙酮)按照上述方法的步骤(1)-(2)制备LB-3-10：
硅胶柱层析使用洗脱剂(PE:EA＝40:1)得到白色固体，产率为48％。其核磁氢谱如下：1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.98–7.76(m,4H),7.53(dd,J＝6.0,3.2Hz,2H),4.54(t,J＝6.4Hz,2H),3.70(t,J＝6.4Hz,2H),2.41(s,3H)。
实施例11
利用LB-1(对溴苯甲醛)按照上述方法的步骤(1)-(2)制备LB-3-11：
硅胶柱层析使用洗脱剂(PE:EA＝40:1)得到白色固体，产率为52％。其核磁氢谱如下：1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.51(d,J＝7.7Hz,2H),7.45(d,J＝7.7Hz,2H),4.43(t,J＝5.6Hz,2H),3.61(t,J＝5.7Hz,2H)。
实施例1-11中，步骤(2)中的卤代烃选择1，2-二溴乙烷(1724μL)。
实施例12
按照步骤(3)将得到的LB-3-1与哌啶反应，得到化合物A1，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到无色油状物，产率为88％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.68(d,J＝7.8Hz,2H),7.53(d,J＝7.7Hz,2H),4.29(t,J＝5.0Hz,2H),2.65(t,J＝4.9Hz,2H),2.42(s,4H),2.16(s,3H),1.52(s,4H),1.36(s,2H)。13C NMR(101MHz,CDCl3)δ153.19,140.07,130.74(q,JC-F＝32.1),126.26,125.31(q,JC-F＝4.0),124.08(q,JC-F＝271.2),72.65,57.89,55.01,26.01,24.22,12.66。HRMS(CI)calcdfor C16H22F3N2O[M+H]+:315.1684,found 315.1686。
实施例13
按照步骤(3)将得到的LB-3-1与吗啉反应，得到化合物A2，硅胶柱层析使用洗脱剂(PE:EA ＝3:1)得到无色油状物，产率为95％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.68(d,J＝7.8Hz,2H),7.53(d,J＝7.7Hz,2H),4.29(t,J＝5.0Hz,2H),2.65(t,J＝4.9Hz,2H),2.42(s,4H),2.16(s,3H),1.52(s,4H),1.36(s,2H)。13C NMR(101MHz,CDCl3)δ153.40,139.95,130.83(q,JC-F＝32.4),126.27,125.32(q,JC-F＝3.7),124.05(q,JC-F＝270.4),72.36,67.00,57.59,54.08,12.69。HRMS(CI)calcd forC15H20F3N2O2[M+H]+:317.1477,found 317.1480。
实施例14
按照步骤(3)将得到的LB-3-1与吡咯烷反应，得到化合物A3，硅胶柱层析使用洗脱剂(PE:EA ＝3:1)得到无色油状物，产率为90％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.1Hz,2H),7.64(d,J＝8.1Hz,2H),4.41(t,J＝5.9Hz,2H),2.89(t,J＝5.9Hz,2H),2.65(s,4H),2.28(s,3H),1.83(s,4H)。13C NMR(151MHz,CDCl3)δ153.19,140.00,130.69(q,JC-F＝32.4),126.22,125.25(q,JC-F＝3.6),124.02(q,JC-F＝270.5),73.72,54.95,54.80,23.49,12.67。HRMS(CI)calcd forC15H20F3N3O2[M+H]+:301.1528,found 301.1534。
实施例15
按照步骤(3)将得到的LB-3-1与N-苄基甲胺反应，得到化合物A4，硅胶柱层析使用洗脱剂(PE:EA ＝2:1)得到无色油状物，产率为86％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.76(d,J＝8.2Hz,2H),7.63(d,J＝8.2Hz,2H),7.40–7.30(m,4H),7.27(d,J＝9.4Hz,1H),4.39(t,J＝5.7Hz,2H),3.63(s,2H),2.82(t,J＝5.7Hz,2H),2.36(s,3H),2.28(s,3H)。13C NMR(101MHz,CDCl3)δ153.19,140.09,139.03,130.74(q,JC-F＝32.2),129.02,128.23,127.00,126.29,125.28(q,JC-F＝3.7),124.09(q,JC-F＝270.5),72.82,62.68,55.80,42.93,12.70。HRMS(CI)calcd for C21H25F3N3O2[M+H]+:351.1684,found 351.1691。
实施例16
按照步骤(3)将得到的LB-3-1与1-苯基哌嗪反应，得到化合物A5，硅胶柱层析使用洗脱剂(PE:EA ＝1.5:1)得到白色固体，产率为82％，熔点为75.1-76.0℃。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.1Hz,2H),7.62(d,J＝8.1Hz,2H),7.12(d,J＝5.2Hz,3H),7.02(d,J＝5.3Hz,1H),4.47(t,J＝5.8Hz,2H),3.77(s,2H),2.94(dd,J＝11.4,5.6Hz,4H),2.88(d,J＝5.4Hz,2H),2.27(s,3H)。13C NMR(101MHz,CDCl3)δ153.45,151.33,139.97,130.83(q,JC-F＝32.4),129.14,126.30,125.34(q,JC-F＝3.7),124.06(q,JC-F＝270.2),119.74,116.08,72.53,57.18,53.65,49.18,12.76。HRMS(CI)calcd forC21H25F3N3O2[M+H]+:392.1950,found 392.1957。
实施例17
按照步骤(3)将得到的LB-3-1与四氢异喹啉反应，得到化合物A6，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到黄色油状物，产率为85％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.1Hz,2H),7.62(d,J＝8.1Hz,2H),7.12(d,J＝5.2Hz,3H),7.02(d,J＝5.3Hz,1H),4.47(t,J＝5.8Hz,2H),3.77(s,2H),2.94(dd,J＝11.4,5.6Hz,4H),2.88(d,J＝5.4Hz,2H),2.27(s,3H)。13C NMR(101MHz,CDCl3)δ153.40,140.02,134.67,134.14,130.80(q,JC-F＝32.2),128.72,126.60,126.31,126.18,125.64,125.30(q,JC-F＝3.7),124.17(q,JC-F＝270.7),72.79,56.85,56.43,51.40,28.98,12.76。HRMS(CI)calcd forC20H22F3N2O[M+H]+:363.1684,found 363.1671。
实施例18
按照步骤(3)将得到的LB-3-1与1-(苯并呋喃-2-基)-N-甲基甲胺，得到化合物A7，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到黄色油状物，产率为80％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.1Hz,2H),7.62-7.2(d,J＝8.1Hz,2H),7.12(d,J＝5.2Hz,2H),7.02(d,J＝5.3Hz,2H),6.91(s,1H),4.39(t,J＝5.7Hz,2H),3.63(s,2H),2.82(t,J＝5.7Hz,2H),2.36(s,3H),2.28(s,3H)。13C NMR(101MHz,CDCl3)δ154.5,153.19,140.09,139.03,130.74(q,JC-F＝32.2),129.02,128.23,127.00,126.29,125.28(q,JC-F＝3.7),124.09(q,JC-F＝270.5),102.8,72.82,62.68,55.80,42.93,12.70。
实施例19
按照步骤(3)将得到的LB-3-1与N-甲基-1-(四氢呋喃-2-基)甲胺，得到化合物A8，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到黄色油状物，产率为82％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.76(d,J＝8.2Hz,2H),7.63(d,J＝8.2Hz,2H),4.39(t,J＝5.7Hz,2H),3.63(s,2H),3.35-3.13(m,3H),2.82(t,J＝5.7Hz,2H),2.36(s,3H),2.28(s,3H),1.92-1.67(m,4H)。13C NMR(101MHz,CDCl3)δ153.19,140.00,130.69(q,JC-F＝32.4),126.22,125.25(q,JC-F＝3.6),124.02(q,JC-F＝270.5),80.1,72.82,67.5,62.68,55.80,42.93,33.4 25.212.70。
实施例20
按照步骤(3)将得到的LB-3-1与1-([1,1'-联苯]-4-基)-N-甲基甲胺，得到化合物A9，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到黄色油状物，产率为82％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.76(d,J＝8.2Hz,2H),7.63(d,J＝8.2Hz,2H),7.40–7.30(m,8H),7.27(d,J＝9.4Hz,1H),4.39(t,J＝5.7Hz,2H),3.63(s,2H),2.82(t,J＝5.7Hz,2H),2.36(s,3H),2.28(s,3H)。13C NMR(101MHz,CDCl3)δ153.19,140.09,139.03,135.45,133.25,130.74(q,JC-F＝32.2),129.02,128.88,128.23,127.00,126.88,126.29,125.28(q,JC-F＝3.7),124.09(q,JC-F＝270.5),72.82,62.68,55.80,42.93,12.70。
实施例21
按照步骤(4)将得到的LB-2与2-(氯甲基)氮杂环丁烷，得到化合物A10，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到黄色油状物，产率为60％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.1Hz,2H),7.64(d,J＝8.1Hz,2H),3.91-3.54(m,5H),2.29-2.04(m,2H),2.28(s,3H),1.52(m,2H)。13C NMR(151MHz,CDCl3)δ153.19,140.00,130.69(q,JC-F＝32.4),126.22,125.25(q,JC-F＝3.6),124.02(q,JC-F＝270.5),73.72,54.95,54.80,36.5,23.49,12.67。
实施例22
按照步骤(4)将得到的LB-2与2-(氯甲基)吡咯烷，得到化合物A11，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到黄色油状物，产率为50％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.1Hz,2H),7.64(d,J＝8.1Hz,2H),3.65(t,J＝5.9Hz,2H),2.98-2.68(m,3H),2.65(s,3H),1.83-1.55(m,6H)。13C NMR(151MHz,CDCl3)δ153.19,140.00,130.69(q,JC-F＝32.4),126.22,125.25(q,JC-F＝3.6),124.02(q,JC-F＝270.5),73.72,54.95,54.80,36.82,32.45,23.49,12.67。
实施例23
按照步骤(4)将得到的LB-2与1-苄基-2-(氯甲基)吡咯烷，得到化合物A12，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到黄色油状物，产率为53％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.1Hz,2H),7.64(d,J＝8.1Hz,2H),7.33-7.25(m,3H),7.21(d,J＝8.1Hz,2H),3.71(s,2H)3.65(t,J＝5.9Hz,2H),2.98-2.68(m,3H),2.65(s,3H),1.83-1.55(m,6H)。13C NMR(151MHz,CDCl3)δ153.19,140.00,138.33,130.69(q,JC-F＝32.4),128.41,128.00,127.75,126.22,125.25(q,JC-F＝3.6),124.02(q,JC-F＝270.5),73.72,58.32,54.95,54.80,36.82,32.45,23.49,12.67。
实施例24
按照步骤(3)将得到的LB-3-7与吗啉反应，得到化合物C1，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到无色油状物，产率为92％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.89(s,1H),7.81(d,J＝7.7Hz,1H),7.59(d,J＝7.5Hz,1H),7.46(t,J＝7.6Hz,1H),4.36(t,J＝5.6Hz,2H),3.72(s,4H),2.74(t,J＝5.5Hz,2H),2.55(s,4H),2.23(s,3H)。13C NMR(101MHz,CDCl3)δ153.25,137.36,130.84(q,JC-F＝32.1),129.17(d,JC-F＝0.9),128.87,125.56(q,JC-F＝3.8),124.03(q,JC-F＝270.6),122.79(q,JC-F＝3.8),,72.33,66.99,57.61,54.07,12.63。HRMS(CI)calcd for C15H20F3N2O2[M+H]+:317.1477,found 317.1482。
实施例25
按照步骤(3)将得到的LB-3-6与吗啉反应，得到化合物C2，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到无色油状物，产率为90％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.8Hz,1H),7.56(t,J＝7.4Hz,1H),7.47(t,J＝7.5Hz,1H),7.34(d,J＝7.5Hz,1H),4.32(t,J＝5.7Hz,2H),3.79–3.68(m,4H),2.73(t,J＝5.6Hz,2H),2.56(s,4H),2.18(s,3H)。13C NMR(101MHz,CDCl3)δ155.54,136.68,131.81,129.95,128.65,128.31(q,JC-F＝30.6),126.56(q,JC-F＝5.0),123.95(q,JC-F＝272),72.10,67.03,57.48,54.04,17.02,17.00。HRMS(CI)calcd for C15H20F3N2O2[M+H]+:317.1477,found 317.1481。
实施例26
按照步骤(3)将得到的LB-3-4与吗啉反应，得到化合物C3，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到无色油状物，产率为93％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.0Hz,2H),7.17(d,J＝7.9Hz,2H),4.34(t,J＝5.8Hz,2H),3.78–3.69(m,4H),2.75(t,J＝5.8Hz,2H),2.57(s,4H),2.36(s,3H),2.21(s,3H).13C NMR(101MHz,CDCl3)δ154.71,139.07,133.81,129.10,125.93,71.96,67.04,57.68,54.11,21.26,12.85.HRMS(CI)calcd for C21H25F3N3O2[M+H]+:363.1760,found363.1759.
实施例27
按照步骤(3)将得到的LB-3-8与吗啉反应，得到化合物C4，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到无色油状物，产率为88％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.48(d,J＝7.1Hz,2H),7.35(dd,J＝19.5,12.9Hz,8H),4.33(t,J＝5.6Hz,2H),3.67(s,4H),2.71(t,J＝5.5Hz,2H),2.46(s,4H).13C NMR(151MHz,CDCl3)δ156.98,136.36,133.42,129.28,129.20,128.73,128.20,127.97,127.82,72.38,66.98,57.43,53.98.HRMS(CI)calcd for C19H23N2O2[M+H]+:311.1760,found 311.1751.
实施例28
按照步骤(3)将得到的LB-3-3与吗啉反应，得到化合物C5，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到白色固体，产率为92％，熔点74.9-75.7℃。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.6Hz,2H),6.89(d,J＝8.6Hz,2H),4.33(t,J＝5.7Hz,2H),3.83(s,3H),3.73(d,J＝4.0Hz,4H),2.75(t,J＝5.7Hz,2H),2.57(s,4H),2.20(s,3H).13C NMR(101MHz,CDCl3)δ160.38,154.32,129.19,127.36,113.77,71.92,67.05,57.68,55.33,54.11,12.81.HRMS(CI)calcd for C15H23N2O3[M+H]+:279.1709,found279.1707.
实施例29
按照步骤(3)将得到的LB-3-2与吗啉反应，得到化合物C6，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到无色油状物，产率为88％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.50(q,J＝8.6Hz,4H),4.34(t,J＝5.8Hz,2H),3.80–3.69(m,4H),2.75(t,J＝5.8Hz,2H),2.56(s,4H),2.20(s,3H).13C NMR(101MHz,CDCl3)δ155.54,136.68,131.81,129.95,128.65,128.47,128.16,126.63,126.58,126.53,126.48,125.31,122.59,72.10,67.03,57.48,54.04,17.02,17.00.HRMS(CI)calcd for C14H20BrN2O2[M+H]+:327.0708,found 327.0697.
实施例30
按照步骤(3)将得到的LB-3-5与吗啉反应，得到化合物C7，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到无色油状物，产率为92％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.67–7.60(m,2H),7.36(d,J＝3.9Hz,3H),4.35(t,J＝5.8Hz,2H),3.78–3.67(m,4H),2.75(t,J＝5.8Hz,2H),2.56(s,4H),2.23(s,3H).13C NMR(101MHz,CDCl3)δ154.70,136.62,129.07,128.40,126.03,72.07,67.03,57.66,54.11,12.89.HRMS(CI)calcd for C14H21N2O2[M+H]+:249.1603,found 249.1611。
实施例31
按照步骤(3)将得到的LB-3-11与吗啉反应，得到化合物C8，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到无色油状物，产率为90％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.50(d,J＝8.3Hz,2H),7.44(d,J＝8.4Hz,2H),4.31(t,J＝5.6Hz,2H),3.87–3.68(m,4H),2.72(t,J＝5.6Hz,2H),2.54(s,4H).13C NMR(101MHz,CDCl3)δ155.54,136.68,131.81,129.95,128.65,128.47,128.16,126.63,126.58,126.53,126.48,125.31,122.59,72.10,67.03,57.48,54.04,17.02,17.00.HRMS(CI)calcd forC13H18BrN2O2[M+H]+:315.0531,found 315.0537.
实施例32
按照步骤(3)将得到的LB-3-7与哌啶反应，得到化合物D1，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到无色油状物，产率为88％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.83(d,J＝7.8Hz,1H),7.60(d,J＝7.6Hz,1H),7.48(t,J＝7.8Hz,1H),4.38(t,J＝6.0Hz,2H),2.74(t,J＝6.0Hz,2H),2.51(s,4H),2.25(s,3H),1.66–1.59(m,4H),1.45(d,J＝4.6Hz,2H).13C NMR(101MHz,CDCl3)δ153.09,137.47,130.83(q,JC-F＝32.0),129.17,128.84,125.51(q,JC-F＝3.8),124.05(q,JC-F＝271),122.81(q,JC-F＝3.7),72.59,57.88,54.99,25.98,24.20,12.64.HRMS(CI)calcd forC16H22F3N2O[M+H]+:315.1684,found 315.1684。
实施例33
按照步骤(3)将得到的LB-3-7与1-苯基哌嗪反应，得到化合物D2，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到无色油状物，产率为84％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.83(d,J＝7.8Hz,1H),7.61(d,J＝7.7Hz,1H),7.49(t,J＝7.8Hz,1H),7.28–7.22(m,2H),6.94(d,J＝8.1Hz,2H),6.86(t,J＝7.2Hz,1H),4.42(t,J＝5.8Hz,2H),3.28–3.20(m,4H),2.84(t,J＝5.8Hz,2H),2.79–2.72(m,4H),2.26(s,3H).13C NMR(101MHz,CDCl3)δ153.29,151.34,137.38,130.86(q,JC-F＝32.6),129.19,129.11,128.88,125.58(q,JC-F＝3.7),124.03(q,JC-F＝270.7),122.82(q,JC-F＝4.0),119.69,116.06,72.50,57.19,53.63,49.18,12.70.HRMS(CI)calcd for C21H25F3N3O[M+H]+:392.1950,found 392.1947.
实施例34
按照步骤(3)将得到的LB-3-4与哌啶反应，得到化合物D3，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到无色油状物，产率为94％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.0Hz,2H),7.16(d,J＝7.8Hz,2H),4.33(t,J＝6.0Hz,2H),2.73(t,J＝6.0Hz,2H),2.49(s,4H),2.36(s,3H),2.21(s,3H),1.65–1.54(m,4H),1.44(d,J＝4.4Hz,2H).13C NMR(101MHz,CDCl3)δ154.49,138.96,133.93,129.07,125.93,72.20,57.96,54.99,26.03,24.25,21.26,12.82.HRMS(CI)calcd for C16H25N2O[M+H]+:261.1967,found 261.1973.
实施例35
按照步骤(3)将得到的LB-3-4与吡咯烷反应，得到化合物D4，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到无色油状物，产率为92％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.56(d,J＝8.0Hz,2H),7.19(d,J＝7.9Hz,2H),4.37(t,J＝6.0Hz,2H),2.88(t,J＝6.0Hz,2H),2.64(s,4H),2.38(s,3H),2.24(s,3H),1.82(s,4H).13C NMR(101MHz,CDCl3)δ154.51,138.97,133.91,129.07,125.93,73.31,55.05,54.82,23.54,21.25,12.84.HRMS(CI)calcd for C15H25N2O[M+H]+:247.1810,found 247.1810.
实施例36
按照步骤(3)将得到的LB-3-4与N-苄基甲胺反应，得到化合物D5，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到无色油状物，产率为84％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.55(d,J＝8.0Hz,2H),7.42–7.31(m,4H),7.28(d,J＝6.4Hz,1H),7.20(d,J＝7.9Hz,2H),4.38(t,J＝5.8Hz,2H),3.64(s,2H),2.82(t,J＝5.7Hz,2H),2.38(d,J＝13.1Hz,6H),2.25(s,3H).13C NMR(101MHz,CDCl3)δ154.51,139.14,138.95,133.96,129.07,129.06,128.22,126.95,125.97,72.44,62.66,55.91,42.91,21.28,12.87.HRMS(CI)calcd for C19H25N2O[M+H]+:261.1967,found 261.1973.
实施例37
按照步骤(3)将得到的LB-3-8与哌啶反应，得到化合物D6，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到无色油状物，产率为90％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.49(d,J＝6.8Hz,2H),7.41(t,J＝6.2Hz,3H),7.39–7.30(m,5H),4.34(t,J＝6.1Hz,2H),2.70(t,J＝6.1Hz,2H),2.42(s,4H),1.57(dt,J＝10.7,5.4Hz,4H),1.42(d,J＝4.8Hz,2H).13C NMR(101MHz,CDCl3)δ156.72,136.58,133.50,129.34,129.22,128.72,128.22,127.99,127.89,72.69,57.79,54.95,26.06,24.25.HRMS(CI)calcd forC20H25N2O[M+H]+:309.1967,found 309.1963.
实施例38
按照步骤(3)将得到的LB-3-8与N-甲基哌嗪反应，得到化合物D7，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到无色油状物，产率为82％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.48(d,J＝7.0Hz,2H),7.35(dd,J＝20.0,12.1Hz,8H),4.33(t,J＝5.5Hz,2H),2.72(t,J＝5.5Hz,2H),2.47(d,J＝29.7Hz,8H),2.27(s,3H).13CNMR(151MHz,CDCl3)δ153.03,140.06,130.98,130.77,130.55,130.34,126.19,125.25,125.22,124.93,123.13,72.78,54.20,53.23,28.69,23.42,12.49.HRMS(CI)calcd forC20H26N3O[M+H]+:324.2076,found 324.2078.
实施例39
按照步骤(3)将得到的LB-3-8与N-苄基甲胺反应，得到化合物D8，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到无色油状物，产率为80％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.46(d,J＝6.9Hz,2H),7.43–7.29(m,8H),7.29–7.23(m,5H),4.34(t,J＝5.9Hz,2H),3.53(s,2H),2.77(t,J＝5.8Hz,2H),2.24(s,3H).13C NMR(101MHz,CDCl3)δ156.72,136.58,133.50,129.34,129.22,128.72,128.22,127.99,127.89,72.69,57.79,54.95,26.06,24.25.HRMS(CI)calcd for C23H25N2O[M+H]+:345.1967,found 345.1964.
实施例40
按照步骤(3)将得到的LB-3-10与哌啶反应，得到化合物E1，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到黄色固体，产率为87％，熔点为37.2-38.8℃。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.90(d,J＝8.6Hz,1H),7.82(dt,J＝16.6,5.8Hz,3H),7.47(dd,J＝5.9,3.1Hz,2H),4.40(t,J＝5.9Hz,2H),2.77(t,J＝5.9Hz,2H),2.53(s,4H),2.33(s,3H),1.66–1.56(m,4H),1.44(s,2H).13C NMR(151MHz,CDCl3)δ154.47,138.93,133.85,129.02,125.87,72.27,59.09,51.69,48.23,21.21,12.76,11.64,8.63,3.93.HRMS(CI)calcd for C19H25N2O[M+H]+:297.1967,found 297.1962。
实施例41
按照步骤(3)将得到的LB-3-10与N-甲基哌嗪反应，得到化合物E2，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到白色固体，产率为83％，熔点为51.3-53.5℃。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.89(d,J＝8.7Hz,1H),7.85–7.75(m,3H),7.46(dd,J＝6.1,3.2Hz,2H),4.38(t,J＝5.9Hz,2H),2.80(t,J＝5.9Hz,2H),2.55(d,J＝58.6Hz,8H),2.32(s,3H),2.29(s,3H).13C NMR(101MHz,CDCl3)δ154.48,134.00,133.64,133.14,128.45,127.98,127.64,126.52,126.30,125.70,123.49,72.30,57.17,55.14,53.51,46.04,12.66.HRMS(CI)calcd for C19H26N3O[M+H]+:312.2076,found 312.2083.
实施例42
按照步骤(3)将得到的LB-3-10与吗啉反应，得到化合物E3，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到黄色固体，产率为88％，熔点为66.2-67.6℃。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.90(d,J＝8.6Hz,1H),7.82(dt,J＝16.1,5.4Hz,3H),7.47(dd,J＝5.9,3.0Hz,2H),4.40(t,J＝5.7Hz,2H),3.73(d,J＝4.0Hz,4H),2.79(t,J＝5.7Hz,2H),2.58(s,4H),2.33(s,3H).13C NMR(151MHz,CDCl3)δ154.50,133.89,133.61,133.09,128.41,127.95,127.60,126.52,126.29,125.68,123.41,72.08,66.95,57.64,54.06,12.63.HRMS(CI)calcd for C18H23N2O2[M+H]+:299.1760,found 299.1749.
实施例43
按照步骤(3)将得到的LB-3-10与N-苄基甲胺反应，得到化合物E4，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到黄色油状物，产率为82％，熔点为56.9-58.2℃。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.84(ddd,J＝22.9,16.3,9.0Hz,4H),7.47(dd,J＝6.0,3.2Hz,2H),7.35(d,J＝7.3Hz,2H),7.30(t,J＝7.3Hz,2H),7.23(d,J＝6.7Hz,1H),4.40(t,J＝5.7Hz,2H),3.63(s,2H),2.83(t,J＝5.7Hz,2H),2.34(d,J＝3.0Hz,6H).13CNMR(151MHz,CDCl3)δ154.50,133.89,133.61,133.09,128.41,127.95,127.60,126.52,126.29,125.68,123.41,72.08,66.95,57.64,54.06,12.63.HRMS(CI)calcd for C22H25N2O[M+H]+:333.1967,found 333.1961.
实施例44
按照步骤(3)将得到的LB-3-9与哌啶反应，得到化合物E5，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到黄色油状物，产率为88％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ8.08(d,J＝7.8Hz,1H),7.88(t,J＝7.1Hz,2H),7.59–7.42(m,4H),4.45(t,J＝5.7Hz,2H),2.85(t,J＝5.7Hz,2H),2.62(s,4H),2.38(s,3H),1.76–1.64(m,4H),1.50(s,2H).13C NMR(101MHz,CDCl3)δ156.68,135.52,133.89,130.89,129.05,128.47,126.49,125.99,125.41,125.22,71.89,57.88,54.95,25.78,24.08,17.60.HRMS(CI)calcd forC19H25N2O[M+H]+:297.1967,found 297.1971.
实施例45
按照步骤(3)将得到的LB-3-9与吗啉反应，得到化合物E6，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到黄色油状物，产率为92％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ8.03(d,J＝7.6Hz,1H),7.85(t,J＝6.7Hz,2H),7.59–7.37(m,4H),4.38(t,J＝5.4Hz,2H),3.75(s,4H),2.79(t,J＝5.4Hz,2H),2.60(s,4H),2.34(s,3H).13CNMR(101MHz,CDCl3)δ156.71,135.46,133.87,130.86,129.06,128.48,126.49,125.99,125.96,125.33,125.21,71.93,67.04,57.75,54.13,17.59.HRMS(CI)calcd forC18H23N2O2[M+H]+:299.1760,found 299.1764.
实施例46
按照步骤(3)将得到的LB-3-9与N-苄基甲胺反应，得到化合物E7，硅胶柱层析使用洗脱剂(PE:EA＝2:1)得到无色油状物，产率为85％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.56(d,J＝8.0Hz,2H),7.19(d,J＝7.9Hz,2H),4.37(t,J＝6.0Hz,2H),2.88(t,J＝6.0Hz,2H),2.64(s,4H),2.38(s,3H),2.24(s,3H),1.82(s,4H).13C NMR(101MHz,CDCl3)δ156.48,139.14,135.60,133.88,130.91,129.06,129.00,128.44,128.26,126.99,126.47,126.00,125.96,125.44,125.22,72.46,62.77,56.08,42.94,17.58.HRMS(CI)calcd for C22H25N2O[M+H]+:333.1967,found 333.1957.
实施例47
按照步骤(3)将得到的LB-3-9与吡咯烷反应，得到化合物E8，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到黄色油状物，产率为90％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ8.08(d,J＝7.7Hz,1H),7.88(t,J＝7.1Hz,2H),7.59–7.45(m,4H),4.44(t,J＝5.7Hz,2H),2.94(t,J＝5.7Hz,2H),2.71(s,4H),2.40(s,3H),1.86(s,4H).13C NMR(101MHz,CDCl3)δ156.68,135.52,133.89,130.89,129.05,128.47,126.49,125.99,125.41,125.22,71.89,57.88,54.95,25.78,24.08,17.60.HRMS(CI)calcd forC18H23N2O[M+H]+:283.1810,found 283.1802.
实施例48
按照实施例1的方法制备LB-6，不同之处在于，步骤(2)中的卤代烃选择1-溴-3-氯丙烷。LB-6((E)-1-(4-(三氟甲基)苯基)乙-1-酮O-(3-溴丙基)肟)的结构式如下：
硅胶柱层析使用洗脱剂(PE:EA＝40:1)得到黄色油状物，产率为48％。其核磁氢谱结果如下：
1H NMR(400MHz,CDCl3)δ7.74(d,J＝8.1Hz,2H),7.60(d,J＝8.2Hz,2H),4.34(t,J＝5.9Hz,2H),3.66(t,J＝6.5Hz,2H),2.23(s,3H),2.21–2.16(m,2H).
实施例49
按照步骤(3)将实施例42得到的LB-6与哌啶反应，得到化合物B1，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到黄色油状物，产率为67％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.73(d,J＝8.1Hz,2H),7.59(d,J＝8.2Hz,2H),4.23(t,J＝6.4Hz,2H),2.46–2.37(m,5H),2.21(s,3H),1.98–1.88(m,3H),1.58(dd,J＝10.7,5.3Hz,4H),1.42(s,2H).13C NMR(101MHz,CDCl3)δ153.04,140.14,130.70(q,JC-F＝32.3),126.24,125.29(q,JC-F＝3.7),124.09(q,JC-F＝271.7),73.04,56.12,54.61,26.79,25.90,24.39,12.51.HRMS(CI)calcd for C17H24F3N3O[M+H]+:329.1831,found 329.1833.
实施例50
按照步骤(3)将实施例42得到的LB-6与吗啉反应，得到化合物B2，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到无色油状物，产率为63％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.74(d,J＝8.1Hz,2H),7.59(d,J＝8.2Hz,2H),4.25(t,J＝6.4Hz,2H),3.80–3.64(m,4H),2.47(t,J＝7.2Hz,6H),2.22(s,3H),2.01–1.89(m,2H).13CNMR(151MHz,CDCl3)δ153.08,140.02,130.71(q,JC-F＝32.4),126.18,125.25(q,JC-F＝3.6),124.02(q,JC-F＝270.6),72.64,66.90,55.68,53.69,26.38,12.48.HRMS(CI)calcdforC16H21F3N3O2[M+H]+:331.1633,found 331.1640.
实施例51
按照步骤(3)将实施例42得到的LB-6与吡咯烷反应，得到化合物B3，硅胶柱层析使用洗脱剂(PE:EA＝3:1)得到黄色油状物，产率为73％。其核磁氢谱、核磁碳谱和质谱结果如下：
1H NMR(400MHz,CDCl3)δ7.76(d,J＝8.1Hz,2H),7.61(d,J＝8.1Hz,2H),4.28(t,J＝6.3Hz,2H),2.61(dd,J＝16.6,8.3Hz,6H),2.24(s,3H),2.01(dd,J＝14.4,6.9Hz,2H),1.82(s,4H).13C NMR(151MHz,CDCl3)δ153.03,140.06,130.66(q,JC-F＝32.3),126.19,125.24(q,JC-F＝3.8),124.03(q,JC-F＝270.6),72.78,54.20,53.23,28.69,23.42,12.49.HRMS(CI)calcd forC16H21F3N3O[M+H]+:315.1684,found 315.1682。
实施例52
对上述制备的化合物A1-A6、C1-C8、D1-D8、E1-E8、B1-B2进行生物活性测试，方法如下：
用kreb’s溶液将蛋白稀释至200mg/mL。膜蛋白Sigma-1配体的放射性配基为3H(+)-pentazocine。反应体系由100μL膜蛋白、20μL 3H(+)-pentazocine、20μL受试药物和60μL Kreb’s溶液组成。30℃孵育150分钟后，过滤分离游离的放射性配基和与受体结合的放射性配基。用液闪仪检测与受体结合的同位素的活性。用10μM BD1047来确定非特异性结合活性。未加入测试化合物的特异性结合活性定义为100％。
在浓度为10μM时，若化合物对放射性配体与Sigma-1受体结合抑制率低于50％，则认为化合物对Sigma-1受体没有亲和性。对于抑制率高于85％的化合物，进一步测试在浓度为1μM时，化合物对放射性配体与Sigma-1受体结合抑制率，结果见表一。
表一不同化合物的Sigma-1受体亲和力测试结果
挑选对Sigma-1受体具有高亲和力的化合物进行Sigma-2受体结合实验，操作与Sigma-1受体相似：Sigma-2受体标记配基为3H-DTG。在反应体系中加入10μM BD1047，以阻断Sigma-1的结合活性。用10μM氟哌啶醇来确定非特异性结合活性。未加入测试化合物的特异性结合活性定义为100％。
若在浓度为10μM时，化合物对放射性配体与sigma-2受体结合抑制率高于75％，则认为化合物对sigma-2受体亲和性较低，结果见表二。
表二不同化合物的Sigma2亲和力测试结果
由表一和表二可以看出，所有化合物对Sigma-1受体显示了中到高的活性，对Sigma-2受体显示了较低的活性，特别是化合物A3、D1、D4和D5显示了对Sigma-1受体的高亲和力，对Sigma-2受体几乎无活性。说明本发明提供了一类具有全新结构且高选择性的Sigma-1受体配体。这类芳基肟类化合物将用于制备治疗中枢神经系统的疾病的药物，例如精神分裂症，抑郁症，焦虑症、帕金森氏症、药物成瘾以及抗帕金森氏病/精神分裂症药物引起的运动障碍及神经保护等，有着重要意义。
以上所述仅是本发明的优选实施方式，并不用于限制本发明，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。
Claims (9)
1.一种通式I所示的芳基肟类化合物、其药剂学上可接受的盐、酯或水合物：
R1和R2独立地选自氢、C1-C8烷基、环烷基、C1-C8氧烷基、C1-C6胺烷基、芳基、取代芳基或芳烷基；或者
R1和R2与它们连接的N原子形成3-8元环；或者
R1和R2的其中之一与它们连接的N原子以及与该N原子另一侧连接的C原子形成3-8元环；
R3和R4独立地选自氢、C1-C6烷基、芳基、取代芳基、芳杂环或取代芳杂环；
n＝0-4中的任一整数。
2.根据权利要求1所述的芳基肟类化合物、其药剂学上可接受的盐、酯或水合物，其特征在于：所述药剂学上可接受的盐为式(1)所示的化合物与无机酸或有机酸形成的盐，所述药剂学上可接受的酯为式(1)所示的化合物与酸或醇形成的酯，所述药剂学上可接受的水合物为式(1)所示的化合物与水以配位键或共价键形成的含水化合物。
3.根据权利要求1所述的芳基肟类化合物、其药剂学上可接受的盐、酯或水合物，其特征在于：R1和R2与它们连接的N原子；或R1和R2的其中之一与它们连接的N原子和N原子另一侧连接的C原子形成
吡咯环、取代吡咯环、哌啶环、取代哌啶环、哌嗪环、烷基取代哌嗪环、杂氮环丁环、氮丙啶环、高哌嗪环、烷基或芳基取代高哌嗪环、吗啉环、取代吗啉环、芳基哌嗪环、四氢异喹啉环、取代四氢异喹啉环、四氢喹啉环、取代四氢喹啉环、二氢吲哚环或取代二氢吲哚环。
4.根据权利要求1所述的芳基肟类化合物、其药剂学上可接受的盐、酯或水合物，其特征在于：R4为芳基、取代芳基、芳杂环或取代芳杂环。
5.根据权利要求1所述的芳基肟类化合物、其药剂学上可接受的盐、酯或水合物，其特征在于：所述芳基选自C6-C10芳环；所述芳烷基包括取代或未取代的苯甲基、取代或未取代的苯乙基或取代或未取代的苯丙基；所述芳杂环为含有1-3个选自N、O和S原子的5-8元芳杂环。
6.根据权利要求1所述的芳基肟类化合物、其药剂学上可接受的盐、酯或水合物，其特征在于：所述取代芳基或取代芳杂环上的取代基为C1-C6烷基、C1-C6烷氧基、C1-C6烷胺基、氰基、硝基、羟基、羧基、烷氧酰基、氨基、酰胺基、酰氧基、酰基、磺酰基、磺酰氨基、脲、硫脲或氨甲酰基、卤素和C1-C6卤烷基中的一种或几种。
7.一种权利要求1-6中任一项所述的通式I所示的芳基肟类化合物的制备方法，其特征在于，包括以下步骤：
(1)将式LB-1所示的化合物在盐酸羟胺和醋酸盐的存在下，在有机溶剂中于85-100℃下反应，反应完全后得到式LB-2所示的化合物；
(2)将式LB-2所示的化合物与含有1-5个碳原子的卤代烃在碱和季铵盐的作用下，在有机溶剂中于40-60℃下反应，反应完全后得到式LB-3所示的化合物；
(3)将式LB-3所示的化合物与胺类化合物在碳酸盐的作用下，在有机溶剂中于80-100℃下反应，反应完全后得到通式I所示的芳基肟类化合物；所述胺类化合物的结构式为
反应路线如下：
或者
(4)将式LB-2所示的化合物与卤代烷胺在碱作用下，在有机溶剂中于80-100℃下反应，反应完全后得到通式I所示的芳基肟类化合物；所述卤代烷胺的结构式为
反应路线如下：
其中，R1、R2、R3、R4和n如权利要求1-6中任一项所定义的；
X为卤素。
8.根据权利要求7所述的制备方法，其特征在于：在步骤(2)中，式LB-2所示的化合物与卤代烃的摩尔比为1:3至1:5；在步骤(3)中，式LB-3所示的化合物与胺类化合物的摩尔比为1:1.2至1:3；在步骤(4)中，式LB-2所示的化合物与卤代烷胺的摩尔比为1:1.5至1:3。
9.权利要求1-6中任一项所述的通式I所示的芳基肟类化合物、其药剂学上可接受的盐、酯或水合物作为Sigma-1配体在制备预防和/或治疗与Sigma-1相关疾病药物中的应用。
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| CN115594609A (zh) * | 2022-10-09 | 2023-01-13 | 华中药业股份有限公司（Cn） | 一种2-氨基-5-氯二苯甲酮肟的制备方法及应用 |
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