CN107737126A - 香豆素‑二硫代氨基甲酸酯衍生物在制药中的应用 - Google Patents
香豆素‑二硫代氨基甲酸酯衍生物在制药中的应用 Download PDFInfo
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Abstract
本发明公开了一类香豆素‑二硫代氨基甲酸酯衍生物在制药中的应用，其中涉及的衍生物按下述步骤合成：1)以浓硫酸为催化剂取间苯二酚和乙酰乙酸乙酯置于第一有机溶剂中反应，得到中间体2；2)取中间体2和二溴烷烃置于第二有机溶剂中，在pH≥8的条件下反应，得到中间体3；3)取中间体3、二硫化碳和仲胺置于第三有机溶剂中，在pH≥8的条件下反应，得到相应的目标化合物。申请人的实验表明，香豆素‑二硫代氨基甲酸酯衍生物表现出良好的选择性乙酰胆碱酯酶抑制活性、抗Aβ1‑42自身聚集活性和血脑屏障通透性，部分化合物对神经细胞的毒性低，且能够透过血脑屏障并表现出理想的低毒或无毒，在治疗AD等疾病方面具有良好应用前景。
Description
技术领域
本发明涉及医药技术领域，具体涉及香豆素-二硫代氨基甲酸酯衍生物在制药中的应用。
背景技术
阿尔茨海默症(Alzheimer's disease,AD)，又称老年性痴呆，是一种在老年人中常见的神经退行性疾病。随着老龄化社会的到来，老年痴呆问题越来越严峻。目前治疗AD的药物主要依赖乙酰胆碱酯酶(AChE)抑制剂(多奈哌齐、加兰他敏、卡巴拉汀)和N-甲基-D-天冬氨酸(NMDA)受体拮抗剂(美金刚)。虽然这些药物能缓解AD症状，但不能从根本上改善疾病状态或终止疾病的进程。
阿尔茨海默病具有复杂的致病机制。尽管阿尔茨海默病的发病机制不完全清楚，但已经确定多种相互作用的因素与该病的发生和发展相关。例如乙酰胆碱(ACh)功能下降、淀粉样蛋白(Aβ)沉淀、金属离子和氧化应激等一些因素在AD的发病过程中扮演了重要的角色。因此，AD被认为是多种因素导致的疾病。目前以胆碱能损伤假说和Aβ-异常沉积学说的影响力最大。在AD病理过程中，发现基底前脑区的胆碱能神经元丢失、乙酰胆碱转移酶和乙酰胆碱酯酶活性下降，引起乙酰胆碱的运输、合成、释放、摄取的减少，最终导致学习和记忆力衰退，这被认为是阿尔茨海默病的重要病因，这一假说已经被尸检证实。此外，β-淀粉样蛋白(为39-43个氨基酸)是通过β-分泌酶和γ-分泌酶裂解淀粉样前体蛋白(APP)产生。在患者的大脑中发现了两种常见的β-淀粉样蛋白，它们分别是Aβ1-40和Aβ1-42。其中Aβ1-42是老年斑的主要组成部分，它比Aβ1-40的毒性更大。β-淀粉样蛋白聚集主要是通过Aβ间的疏水力相互作用，Aβ通过疏水键和氢键的相互作用，不断形成β-淀粉样蛋白的低聚物，最后形成纤维状聚合物。最近研究表明，低分子量的Aβ低聚物可能与阿尔茨海默病的致病机制相关性最大。此外，患者大脑中存在过量的金属离子(如Cu,Zn,Fe),金属离子与Aβ相互作用促进其聚集、增加ROS的产生，这些能够导致氧化应激、神经细胞死亡和认知障碍。
越来越多的数据表明，阿尔茨海默病的发病机制是一种潜在的相互联系的复杂性网络，包括生理学的、生物化学的、化学介质等同时参与的通路。科学家们根据这些数据，提出了多种因素的AD致病假说，Melchiorre课题组根据这种假说提出作用于多个靶点药物分子的设计概念(MTDLs)。因此，寻找同时作用于多个靶标的单一药物分子成为治疗阿尔茨海默病的新趋势。
胆碱酯酶不但是治疗阿尔茨海默病的药物靶点，而且也是脑血管痴呆、青光眼或重症肌无力疾病的药物作用靶，其抑制剂成为目前这些疾病主要治疗药物。血管性痴呆(vascular dementia,VaD)是各种脑血管疾病引起的获得智能性损害和认知障碍的慢性综合症，是仅次于AD病的第二位常见痴呆。VaD患者的认知程度也和乙酰胆碱(ACh)的水平降低和乙酰胆碱酯酶(AChE)的活性相对增高有关，VaD患者脑中乙酰胆碱(Ach)的水平降低的程度与痴呆程度一致。青光眼是由于眼内房水流入与流出失调导致眼内压升高而引起的疾病，故降低眼内压是目前治疗青光眼的主要手段。可逆的胆碱酯酶抑制剂具有缩瞳、兴奋孔扩约肌和睫状肌、调节痉挛等作用，从而降低眼内压达到治疗青光眼的目的。重症肌无力疾病是一种损伤全身神经肌肉接头的自身免疫性疾病，临床表现为神经肌肉接头传递阻滞，导致眼肌、吞咽肌、呼吸肌以及四肢骨骼肌无力。目前普遍认为乙酰胆碱受体抗体(AchRab)是重症肌无力疾病发病的主要因素之一，重症肌无力疾病人的乙酰胆碱受体与乙酰胆碱受体抗体(AchRab)结合，使乙酰胆碱受体退化并阻碍受体再生，使得乙酰胆碱受体数量减少，所形成的终板电位不能诱发肌细胞产生动作电位，以致肌肉不能收缩，从而导致重症肌无力疾病。由此可见，乙酰胆碱酯酶抑制剂可以通过抑制乙酰胆碱酯酶(AChE)来提高乙酰胆碱(Ach)的水平，从而在改善VaD患者痴呆程度，降低眼内压用于治疗青光眼，以及通过延长和增强了乙酰胆碱与乙酰胆碱受体的相互作用的能力，达到升高微小终板电位，增加神经肌肉传导的安全系数来达到治疗和缓解重症肌无力疾病的作用。故乙酰胆碱酯酶抑制剂还有望发展成为脑血管痴呆、青光眼或重症肌无力疾病的潜力候选选药物。
香豆素类化合物广泛分布于自然界中，是中药中一种重要的活性成分，具有抗菌，抗病毒、抗炎、神经保护，抗癌等多种生物活性，有着良好的开发前景。但目前尚未发现有香豆素-二硫代氨基甲酸酯衍生物及其合成方法以及将其应用于治疗AD等病症方面的相关报道。
发明内容
本发明要解决的技术问题是提供一系列结构新颖的香豆素-二硫代氨基甲酸酯衍生物在制药中的应用。
本发明涉及香豆素-二硫代氨基甲酸酯衍生物在制药中的多种应用，其中所述的香豆素-二硫代氨基甲酸酯衍生物为具有下述式(I)所示结构的化合物或其药学上可接受的盐：
其中：
R1表示H、CH3、OCH3、F、Cl或Br；
R2表示H、CH3、OCH3、F、Cl或Br；
R3表示
n＝2-8。
为方便描述，在本申请说明书的以下内容中出现的“香豆素-二硫代氨基甲酸酯衍生物”可以理解为上述对R1、R2、R3和n进行限定的式(I)所示结构的化合物的简称。
本发明的第一个目的在于提供香豆素-二硫代氨基甲酸酯衍生物或其药学上可接受的盐在制备乙酰胆碱酯酶抑制剂药物或保健品中的应用。
本发明的第二个目的在于提供香豆素-二硫代氨基甲酸酯衍生物或其药学上可接受的盐在制备抗Aβ聚集的药物或保健品中的应用。
本发明的第三个目的在于提供香豆素-二硫代氨基甲酸酯衍生物或其药学上可接受的盐在制备治疗阿尔茨海默病、脑血管痴呆、青光眼或重症肌无力的药物或保健品中的应用。
本发明的第四个目的在于提供一种乙酰胆碱酯酶抑制剂药物或保健品，该药物或保健品含有治疗上有效剂量的香豆素-二硫代氨基甲酸酯衍生物或其药学上可接受的盐。
上述乙酰胆碱酯酶抑制剂药物或保健品的剂型可以是药学上可接受的任意剂型，具体可以是颗粒剂、片剂、丸剂、胶囊或注射剂等常规剂型。
本发明的第五个目的在于提供一种抗Aβ聚集的药物或保健品，该药物或保健品含有治疗上有效剂量的香豆素-二硫代氨基甲酸酯衍生物或其药学上可接受的盐。
上述抗Aβ聚集的药物或保健品的剂型可以是药学上可接受的任意剂型，具体可以是颗粒剂、片剂、丸剂、胶囊或注射剂等常规剂型。
本发明的第六个目的在于提供一种治疗阿尔茨海默病、脑血管痴呆、青光眼或重症肌无力的药物或保健品，该药物或保健品含有治疗上有效剂量的香豆素-二硫代氨基甲酸酯衍生物或其药学上可接受的盐。
上述治疗阿尔茨海默病、脑血管痴呆、青光眼或重症肌无力的药物或保健品的剂型可以是药学上可接受的任意剂型，具体可以是颗粒剂、片剂、丸剂、胶囊或注射剂等常规剂型。
本发明中涉及的涉及香豆素-二硫代氨基甲酸酯衍生物优选为下述化合物：
本发明中涉及的香豆素-二硫代氨基甲酸酯衍生物的药学上可接受的盐，具体可以是上述式(I)所示结构化合物的盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、富马酸盐、水杨酸盐、苯磺酸盐、丙酮酸盐、乙酸盐、杏仁酸盐、碱性金属阳离子盐或铵阳离子盐。优选是其碱性金属阳离子盐。
本发明中涉及的涉及香豆素-二硫代氨基甲酸酯衍生物可以自行设计路线进行合成，具体也可以按下述方法进行合成：
1)取间苯二酚和乙酰乙酸乙酯置于第一有机溶剂中，以浓硫酸为催化剂，于加热或不加热条件下反应，所得反应液倒入冷水中，有固体析出，分离，得到中间体2；
2)取中间体2和二溴烷烃置于第二有机溶剂中，调节体系的pH≥8，于加热或不加热条件下反应，得到中间体3；
3)取中间体3、二硫化碳和仲胺置于第三有机溶剂中，调节体系的pH≥8，于加热或不加热条件下反应，得到相应的目标化合物粗品；
其中：
所述的二溴烷烃为Br(CH2)nBr，n＝2-8；
所述的仲胺为HR3，其中R3表示
上述合成方法的步骤1)中，所述的第一有机溶剂可以是选自二氧六环、甲醇和乙醇中的一种或两种以上的组合。所述第一有机溶剂的用量可以根据需要进行确定，通常情况下，以1mmol的间二苯酚为基准计算，第一有机溶剂的用量一般为1-10mL。对于参加反应的各原料的溶解，可以分别用第一有机溶剂溶解后再混合在一起反应，也可以先混合后再用第一有机溶剂溶解。
上述合成方法的步骤1)中，浓硫酸的用量通常为按每1g间苯二酚用2-7ml的浓硫酸计算。优选是在冰浴条件下加入浓硫酸。
上述合成方法的步骤1)中，当反应在不加热的条件下进行时，所得产物的产率较低，因此，优选反应在加热条件下进行，进一步优选反应在50℃至第一有机溶剂的沸点温度范围内进行，更优选反应在60℃至第一有机溶剂的沸点温度范围内进行。反应是否完全可采用薄层层析跟踪检测。
上述步骤1)制得是中间体2的粗产物，为了提高其纯度，可对其进行纯化操作后再用于步骤2)中。具体可将中间体2的粗产物进行重结晶以获得纯化后的中间体2，其中，用于重结晶的溶剂的选择与第一有机溶剂的选择相同。
上述合成方法的步骤2)中，所述的第二有机溶剂可以是选自丙酮、二甲基甲酰胺、乙腈和四氢呋喃中的一种或两种以上的组合。所述第二有机溶剂的用量可以根据需要进行确定，通常情况下，以1mmol的中间体2为基准计算，第二有机溶剂的用量一般为3-9ml。对于参加反应的各原料的溶解，可以分别用第二有机溶剂溶解后再混合在一起反应，也可以先混合后再用第二有机溶剂溶解。
上述合成方法的步骤2)中，反应在加热条件下进行比在不加热条件下进行可以获得更高的产率，因此，优选反应在加热条件下进行，进一步优选反应在50℃至第二有机溶剂的沸点温度范围内进行，更优选反应在60℃至第二有机溶剂的沸点温度范围内进行。反应是否完全可采用薄层层析跟踪检测。
上述步骤2)制得是中间体3的粗产物，为了提高其纯度，可对其进行纯化操作后再用于步骤3)中。具体可将中间体3的粗产物用硅胶柱层析以获得纯化后的中间体3，其中，在用硅胶柱层析时，通常用由体积比为5-30：1的石油醚和乙酸乙酯组成的洗脱剂洗脱，收集洗脱液，洗脱液减压蒸除溶剂，得到纯化后的中间体3。所述组成洗脱剂的石油醚和乙酸乙酯的体积比优选为10-20：1。
上述合成方法的步骤3)中，所述的第三有机溶剂为二甲基甲酰胺，或者是二甲基甲酰胺和水的组合物，优选二甲基甲酰胺和水的体积比为5-15：1，更优选为10：1。所述第三有机溶剂的用量可以根据需要进行确定，通常情况下，以1mmol的中间体3为基准计算，第三有机溶剂的用量一般为3-9ml。对于参加反应的各原料的溶解，可以分别用第三有机溶剂溶解后再混合在一起反应，也可以先混合后再用第三有机溶剂溶解。
上述合成方法的步骤3)中，反应在加热条件下进行比在不加热条件下进行可以获得更高的产率，因此，优选反应在加热条件下进行，进一步优选反应在50℃至第三有机溶剂的沸点温度范围内进行，更优选反应在60℃至第三有机溶剂的沸点温度范围内进行。反应是否完全可采用薄层层析跟踪检测。在反应完成后，向所得反应物中加水，然后用萃取剂(如乙酸乙酯、二氯甲烷、氯仿或甲苯等)进行萃取，收集有机相，水洗之后用无水硫酸钠干燥，即得到目标产物粗品。
上述合成方法的步骤2)和3)中，采用碱性物质(如三乙胺、碳酸钠、碳酸钾、碳酸氢钠等)调节体系的pH≥8，优选是调节体系的pH＝9-11。在这两个步骤中，优选是采用三乙胺、碳酸钠、碳酸钾、碳酸氢钠等弱碱性物质来调节体系的pH值。
由上述方法制得的是目标化合物的粗品，可采用现有常规的纯化方法对其进行纯化以提高目标化合物的纯度。通常采用硅胶柱层析来进行纯化，在将制得的目标化合物粗品上硅胶柱层析时，通常用由体积比为5-20：1的石油醚和乙酸乙酯组成的洗脱剂洗脱，收集洗脱液，洗脱液减压蒸除溶剂，得到纯化后的目标化合物。所述组成洗脱剂的石油醚和乙酸乙酯的体积比优选为8-15：1。
与现有技术相比，本发明提供了一系列结构新颖的香豆素-二硫代氨基甲酸酯衍生物及其药学上可接受的盐在制备中的应用，申请人的实验表明，本发明所述香豆素-二硫代氨基甲酸酯衍生物表现出良好的选择性乙酰胆碱酯酶抑制活性、抗Aβ1-42自身聚集活性和血脑屏障通透性，部分化合物对神经细胞的毒性低，更难得的是该类化合物能够透过血脑屏障并表现出理想的低毒或无毒，在治疗阿尔茨海默病和脑血管痴呆等疾病方面具有良好应用前景。需要特别指出的是，目前双位点的乙酰胆碱酯酶抑制剂，作用于CAS位点的基团的结构片段通常是他克林,各种伯胺,仲胺,叔胺和季胺,各种胺形成的正电中心与CAS位点结合而产生活性作用；而本申请中的二硫代氨基甲酸酯，从结构特点上看，跟各种伯胺,仲胺,叔胺和季胺有很大差别，二硫代氨基甲酸酯不能形成正点中心，但将它和香豆素相连接后，竟能起到很好的抑制乙酰胆碱酯酶的作用。
附图说明
图1为本发明所述目标化合物14抑制乙酰胆碱酯酶的动力学研究中的双倒数曲线；
图2为本发明所述目标化合物14血脑屏障通透性相关参数曲线。
具体实施方式
下面结合具体实施例对本发明作进一步的详述,以更好地理解本发明的内容,但本发明并不限于以下实施例。
本发明中涉及的目标化合物的合成路线如下：
其中，(a)乙酰乙酸乙酯，浓硫酸，第一有机溶剂；(b)二溴烷烃，碱性物质，第二有机溶剂；(c)二硫化碳，仲胺，碱性物质，第三有机溶剂；
R1表示H、CH3、OCH3、F、Cl或Br；
R2表示H、CH3、OCH3、F、Cl或Br；
R3表示
n＝2-8。
下述各实施例中合成的目标化合物1-17中，其中目标化合物1-12，n＝2，R3＝A-L(如下所示)；目标化合物13-17，n＝3，4，5，6，R3＝D；
对应的目标化合物1-17中的R1、R2、R3和n的具体选择如下述表1所示：
表1：
实施例1：中间体2(7-羟基-4-甲基香豆素)的制备
量取15ml二氧六环(也可以是甲醇或乙醇)，向其中加入间二苯酚(10mmol,1.1g),在冰浴的条件下,滴加4ml的浓硫酸,浓硫酸滴完后,往溶液中加入乙酰乙酸乙酯(10mmol,1.3g),搅拌并加热到60℃,反应4h,反应结束后,将反应液倒入冷水中,析出固体，抽滤，收集滤渣，并将其置于甲醇中重结晶，得到白色针状固体结晶,收率为91％。1H NMR(600MHz,acetone-d6)δ7.61(1H,d,J＝9.0Hz),6.85(1H,dd,J＝9.0,2.5Hz),6.75(1H,d,J＝2.5Hz),6.09(1H,s),2.40(3H,s).ESI-MS m/z:175.0[M-H]-。
实施例2：中间体3a-f的制备的通用方法
在丙酮(也可以是DMF、乙腈或四氢呋喃)中边搅拌边加入5.0mmol中间体2，二溴烷烃50mmol(该原料大大过量,提高反应的选择性)，然后加入无水K2CO3(1.4g,10mmol)调节体系的9-11，室温条件下反应4h后，冷却后抽滤，收集滤渣，滤渣经硅胶柱纯化(石油醚：乙酸乙酯＝15：1，体积比)，最后得到白色固体3a-f。
实施例3：中间体7-(8-溴乙氧基)-4-甲基香豆素(3a)的收率、核磁数据及质谱数据
收率86％；1H NMR(600MHz,CDCl3)δ7.53(d,J＝8.8Hz,1H),6.91(dd,J＝8.8,2.5Hz,1H),6.83(d,J＝2.5Hz,1H),6.17(s,1H),4.37(t,J＝6.1Hz,2H),3.70(t,J＝6.1Hz,2H),2.40(s,3H)；ESI-MS m/z:283.1[M+H]+.
实施例4：中间体7-(8-溴丙氧基)-4-甲基香豆素(3b)的收率、核磁数据及质谱数据
收率92％；1H NMR(600MHz,CDCl3)δ7.51(d,J＝8.8Hz,1H),6.88(d,J＝8.8Hz,1H),6.84(d,J＝1.0Hz,1H),6.15(s,1H),4.19(t,J＝5.8Hz,2H),3.63(t,J＝6.3Hz,2H),2.40(s,3H),2.37(p,J＝6.0Hz,2H)；ESI-MS m/z:297.1[M+H]+.
实施例5：中间体7-(8-溴丁氧基)-4-甲基香豆素(3c)的收率、核磁数据及质谱数据
收率87％；1H NMR(600MHz,CDCl3)δ7.52–7.48(m,1H),6.86(dd,J＝8.8,2.5Hz,1H),6.80(d,J＝2.5Hz,1H),6.14(d,J＝1.2Hz,1H),4.07(t,J＝6.1Hz,2H),3.51(t,J＝6.6Hz,2H),2.40(s,3H),2.16–2.05(m,2H),2.03–1.95(m,2H)；ESI-MS m/z:311.1[M+H]+.
实施例6：中间体7-((8-溴戊基)氧)-4-甲基香豆素(3d)的收率、核磁数据及质谱数据
收率90％；1H NMR(600MHz,CDCl3)δ7.48(d,J＝8.8Hz,1H),6.84(dd,J＝8.8,2.5Hz,1H),6.79(d,J＝2.5Hz,1H),6.12(s,1H),4.04(t,J＝6.1Hz,2H),3.45(t,J＝6.1Hz,2H),2.41(s,3H),1.94(br s,2H),1.85(br s,2H),1.66(br s,2H)；ESI-MS m/z:325.2[M+H]+.
实施例7：中间体7-((8-溴已基)氧)-4-甲基香豆素(3e)的收率、核磁数据及质谱数据
收率82％；1H NMR(600MHz,CDCl3)δ7.50(d,J＝8.8Hz,1H),6.86(d,J＝8.8,2.0Hz,1H),6.81(d,J＝2.0Hz,1H),6.14(s,1H),4.03(t,J＝6.3Hz,2H),3.45(t,J＝7.2Hz,2H),2.41(s,3H),1.92(br s,2H),1.85(br s,2H),1.54(br s,4H)；ESI-MS m/z:339.1[M+H]+.
实施例8：中间体7-((8-溴辛基)氧)-4-甲基香豆素(3f)的收率、核磁数据及质谱数据
收率85％；1H NMR(600MHz,CDCl3)δ7.49(d,J＝8.8Hz,1H),6.86(d,J＝9.8Hz,1H),6.80(d,J＝2.5Hz,1H),6.13(s,1H),4.02(t,J＝5.8Hz,2H),3.42(t,J＝6.3Hz,2H),2.41(s,3H),1.87(br s,2H),1.82(br s,2H),1.48(br s,4H),1.38(br s,4H)；ESI-MS m/z:367.2[M+H]+.
实施例9：化合物1-17的通用制备方法
取99mg,1.3mmol的CS2滴加到含有仲胺(1.3mmol)和三乙胺(262mg,2.6mmol)的10ml的DMF中，搅拌5min(体系的pH＝9-11)，向其中缓慢加入含有中间体3a-f(1.3mmol)的3ml DMF溶液，在常温下反应12-24小时。反应结束后，向反应液中加入30ml的水，用乙酸乙酯萃取三次(20mL*3)，合并乙酸乙酯层，分别用20mL的水再洗三次，然后用无水硫酸钠干燥，放置30min,滤掉无水硫酸钠，得到相应的目标化合物粗品，目标化合物粗品用硅胶柱进行纯化(石油醚：乙酸乙酯＝10：1，体积比)，得到目标化合物1-17。
实施例10：目标化合物1的收率、核磁数据和质谱数据
收率：85％；黄色固体；1H NMR(600MHz,CDCl3)δ7.52(d,J＝8.8Hz,1H),6.93(dd,J＝8.8,2.4Hz,1H),6.88(d,J＝2.4Hz,1H),6.16(s,1H),4.33(t,J＝6.3Hz,2H),3.78(t,J＝6.3Hz,3H),3.60(s,3H),3.43(s,3H),2.42(s,3H).13C NMR(151MHz,CDCl3)δ196.06,161.59,161.37,155.28,152.46,125.30,113.54,112.33,112.17,102.06,66.92,45.68,41.48,35.92,18.64.HRMS:calcd for C15H18NO3S2[M+H]+324.0723,found 324.0760.
实施例11：目标化合物2的收率、核磁数据和质谱数据
收率：82％；白色固体；1H NMR(600MHz,CDCl3)δ7.54(d,J＝8.8Hz,1H),6.91(dd,J＝8.8,2.4Hz,1H),6.84(d,J＝2.4Hz,1H),6.18(s,1H),4.07(t,J＝6.0Hz,2H),3.84–3.74(m,4H),3.70(t,J＝6.1Hz,2H),2.43(s,3H),1.38–1.21(m,6H).13C NMR(151MHz,CDCl3)δ194.37,161.59,161.02,155.21,152.46,125.76,113.85,112.34,112.14,102.08,67.05,49.87,46.89,35.92,18.70,12.53,12.56.HRMS:calcd for C15H18NO3S2[M+H]+352.1036,found 352.1053.
实施例12：目标化合物3的收率、核磁数据和质谱数据
收率：87％；黄色固体；1H NMR(600MHz,CDCl3)δ7.51(d,J＝9.0Hz,1H),6.93(dd,J＝9.0,2.4Hz,1H),6.86(d,J＝2.4Hz,1H),6.14(s,1H),4.31(t,J＝6.6Hz,2H),3.95(t,J＝6.6Hz,2H),3.77(t,J＝6.6Hz,2H),3.69(t,J＝7.2Hz,2H),2.40(s,3H),2.10–2.09(m,2H),2.01–1.99(m,2H).13C NMR(151MHz,CDCl3)δ191.56,161.57,161.29,155.20,152.47,125.58,113.86,112.32,112.14,102.07,67.07,55.31,50.73,34.88,26.08,24.30,18.69.HRMS:calcd for C17H20NO3S2[M+H]+350.0879,found 350.0904.
实施例13：目标化合物4的收率、核磁数据和质谱数据
收率84％；白色固体；1H NMR(600MHz,CDCl3)δ7.53(d,J＝8.8Hz,1H),6.93(dd,J＝8.8,2.5Hz,1H),6.88(d,J＝2.5Hz,1H),6.16(s,1H),4.33(t,J＝6.3Hz,2H),3.93(br s,2H),3.81-3.79(m,2H),3.71-3.68(m,2H),2.42(s,3H),1.74(br s,6H).13C NMR(151MHz,CDCl3)δ194.36,161.61,161.02,155.21,152.46,125.75,113.85,112.56,112.13,102.06,67.11,53.36,51.44,35.47,28.47,24.22,18.69.HRMS:calcd for C18H22NO3S2[M+H]+364.1036,found 364.1062.
实施例14：目标化合物5的收率、核磁数据和质谱数据
收率：81％,白色固体；1H NMR(600MHz,CDCl3)δ7.51(d,J＝8.4Hz,1H),6.91(dd,J＝9.0,1.8,1H),6.88(d,J＝1.8Hz 1H),6.14(s,1H),4.37(br s,2H),4.32(t,J＝6.2Hz,2H),3.98(br s,2H),3.81(t,J＝6.6Hz,2H),3.78(br s,4H)2.40(s,3H).13C NMR(151MHz,CDCl3)δ196.37,161.47,161.23,155.20,152.43,125.61,113.92,112.32,112.20,101.99,66.83,66.35,66.10,51.61,50.49,35.38,18.69.HRMS:calcd for C17H20NO4S2[M+H]+366.0828,found 366.0865.
实施例15：目标化合物6的收率、核磁数据和质谱数据
收率：83％；黄色固体；1H NMR(600MHz,CDCl3)δ7.52(d,J＝8.8Hz,1H),6.93(dd,J＝8.8,2.4Hz,1H),6.88(d,J＝2.4Hz,1H),6.16(s,1H),4.62(s,1H),4.35(t,J＝6.3Hz,2H),4.25–4.21(m,2H),4.14–4.08(m,1H),3.80(m,2H),3.79(t,J＝5.4Hz,2H),2.42(s,3H),1.79–1.62(m,4H).13C NMR(151MHz,CDCl3)δ194.95,161.61,161.32,155.19,152.51,125.59,113.88,112.43,112.14,102.03,67.02,66.06,48.74,46.98,35.77,18.69.HRMS:calcd for C18H22NO4S2[M+H]+380.0985,found 380.1024.
实施例16：目标化合物7的收率、核磁数据和质谱数据
收率：82％；白色固体；1H NMR(600MHz,CDCl3)δ7.51(d,J＝8.4Hz,1H),6.90(dd,J＝8.4,2.4Hz,1H),6.87(d,J＝2.4Hz,1H),6.14(s,1H),4.35(t,J＝6.6Hz,2H),4.32(br s,2H),4.16(br s,2H),4.06(br s,2H),3.96(br s,2H),3.76(t,J＝6.6Hz,2H),2.40(s,3H).13C NMR(151MHz,CDCl3)δ198.18,161.97,161.77,155.43,152.97,125.90,114.16,112.94,112.36,102.16,66.85,61.00,59.47,58.04,36.24,19.00.HRMS:calcd forC17H22NO5S2[M+H]+384.0934,found 384.0940.
实施例17：目标化合物8的收率、核磁数据和质谱数据
收率：80％；白色固体；1H NMR(600MHz,CDCl3)δ7.52(d,J＝9.0Hz,1H),6.93(dd,J＝9.0,2.4Hz,1H),6.88(d,J＝2.4Hz,1H),6.13(s,1H),4.35(t,J＝6.3Hz,2H),4.23(br s,4H),3.93(br,4H),3.74(t,J＝6.5Hz,2H),2.40(s,3H),1.99(s,3H).13C NMR(151MHz,CDCl3)δ194.55,161.46,161.20,155.17,152.48,125.64,113.96,112.45,112.21,101.88,66.83,53.95,50.89,49.58,45.45,35.52,18.78.HRMS:calcd for C18H23N2O3S2[M+H]+379.1145,found 379.1170.
实施例18：目标化合物9的收率、核磁数据和质谱数据
收率：88％；黄色固体；1H NMR(600MHz,CDCl3)δ7.52(d,J＝8.8Hz,1H),6.93(dd,J＝8.8,2.5Hz,1H),6.88(d,J＝2.5Hz,1H),6.16(s,1H),4.40(br s,2H),4.33(t,J＝6.3Hz,2H),4.02(br s,2H),3.81(t,J＝6.3Hz,2H),2.81(s,1H),2.66(s,4H),2.42(s,3H),1.10(s,3H),1.09(s,3H).13C NMR(151MHz,CDCl3)δ195.37,161.53,161.26,155.21,152.45,125.60,113.89,112.33,112.17,102.04,66.97,54.60,51.62,50.14,42.97,35.45,18.69,18.34.HRMS:calcd for C20H27N2O3S2[M+H]+407.1458,found 407.1456.
实施例19：目标化合物10的收率、核磁数据和质谱数据
收率76％；黄色固体；1H NMR(600MHz,CDCl3)δ7.52(d,J＝8.8Hz,1H),6.93(dd,J＝8.8,2.5Hz,1H),6.88(d,J＝2.5Hz,1H),6.16(s,1H),4.33(t,J＝6.7Hz,2H),4.03–3.87(m,4H),3.81(t,J＝6.3Hz,2H),2.74(br s,4H),2.41(s,3H),2.06(m,1H),0.50(br s,4H).13CNMR(151MHz,CDCl3)δ195.32,161.58,160.97,155.03,152.35,125.60,113.89,112.33,112.18,102.04,66.90,52.56,39.93,35.54,18.65,6.00.HRMS:calcd for C20H25N2O4S2[M+H]+405.1301,found 405.1302.
实施例20：目标化合物11的收率、核磁数据和质谱数据
收率：89％；黄色油状物；1H NMR(600MHz,CDCl3)δ7.54(d,J＝9.0Hz,1H),6.95(dd,J＝9.0Hz,J＝2.4Hz,1H),6.89(d,J＝2.4Hz,1H),6.17(s,1H),4.34(t,J＝6.6Hz,2H),3.82(br s,2H),3.25(br s,3H),2.70(br s,1H),2.57(br s,4H),2.43(s,3H),2.00(br s,3H),1.65(br s,6H),1.49(br s,2H).13C NMR(151MHz,CDCl3)δ194.86,161.56,161.30,155.20,152.49,125.60,113.87,112.35,112.15,102.04,67.01,61.97,60.63,50.28,35.69,29.71,26.11,25.66,24.53,22.09,18.69.HRMS:calcd for C23H31N2O3S2[M+H]+447.1771,found 447.1766.
实施例21：目标化合物12的收率、核磁数据和质谱数据
收率：86％；白色固体；1H NMR(600MHz,CDCl3)δ8.37(d,J＝8.4Hz,2H),7.53(d,J＝8.4Hz,1H),6.94(d,J＝8.4Hz,1H),6.89(d,J＝2.4Hz,1H),6.61(d,J＝3.8Hz,1H),6.16(s,1H),4.43(br s,2H),4.36(br s,2H),4.26-4.22(m,2H),4.09(br s,2H),4.00(br s,2H),3.85(t,J＝6.3Hz,2H),2.42(s,3H).13C NMR(151MHz,CDCl3)δ196.26,161.50,161.24,157.83,155.21,152.43,125.60,113.91,112.33,112.19,110.76,102.01,68.86,42.97,38.73,35.50,29.80,28.93,18.68.HRMS:calcd for C21H23N4O3S2[M+H]+443.1206,found443.1153.
实施例22：目标化合物13的收率、核磁数据和质谱数据
收率：89％；白色固体；1H NMR(600MHz,CDCl3)δ7.54(d,J＝9.0Hz,1H),6.90(dd,J＝9.0,2.4Hz,1H),6.86(d,J＝2.4Hz,1H),6.17(s,1H),4.32(br s,2H),4.16(t,J＝6.0Hz,2H),3.92(br s,2H),3.54(t,J＝6.6Hz,2H),2.42(s,3H),2.30-2.26(m,2H),1.76-1.69(brs,6H).13C NMR(151MHz,CDCl3)δ195.12,161.93,155.29,152.48,125.61,113.82,112.44,111.97,101.60,67.95,53.10,51.27,38.68,28.90,24.26,23.00,18.59.HRMS:calcd forC19H24NO3S2[M+H]+378.1187,found 378.1209.
实施例23：目标化合物14的收率、核磁数据和质谱数据
收率：83％；白色固体；1H NMR(600MHz,CDCl3)δ7.49(d,J＝9.0Hz,1H),6.87(dd,J＝9.0,2.4Hz,1H),6.81(d,J＝2.4Hz,1H),6.13(s,1H),4.30(br s,2H),4.06(t,J＝6.6Hz,2H),3.90(br s,2H),3.40(t,J＝7.2Hz,2H),2.40(s,3H),1.97-1.92(m,4H),1.72-1.69(m,6H).13C NMR(151MHz,CDCl3)δ195.55,162.06,161.37,155.29,152.57,125.50,113.52,112.64,111.90,101.43,67.99,52.97,51.27,36.63,28.24,25.56,24.33,18.69.HRMS:calcd for C20H26NO3S2[M+H]+392.1349,found 392.1346.
实施例24：目标化合物15的收率、核磁数据和质谱数据
收率：80％；白色固体；1H NMR(600MHz,CDCl3)δ7.51(d,J＝8.8Hz,1H),6.87(dd,J＝8.8,2.5Hz,1H),6.82(d,J＝2.5Hz,1H),6.15(s,1H),4.32(s,2H),4.05(t,J＝6.4Hz,2H),3.92(br s,2H),3.36(t,J＝6.4Hz,2H),2.42(s,3H),1.92–1.86(m,2H),1.84-1.79(m,2H),1.77–1.58(m,8H).13C NMR(151MHz,CDCl3)δ195.80,162.16,161.39,155.31,152.59,125.50,113.47,112.64,111.87,101.41,68.31,52.79,51.32,36.91,28.57,28.56,25.40,24.34,18.69.HRMS:calcd for C21H28NO3S2[M+H]+406.1505,found 406.1491.
实施例25：目标化合物16的收率、核磁数据和质谱数据
收率：87％；白色固体；1H NMR(600MHz,CDCl3)δ7.50(d,J＝9.0Hz,1H),6.86(dd,J＝8.8,2.4Hz,1H),6.80(d,J＝2.4Hz,1H),6.13(s,1H),4.30(br s,2H),4.03(t,J＝6.6Hz,2H),3.90(br s,2H),3.32(t,J＝7.2Hz,2H),2.40(s,3H),1.85–1.81(m,2H),1.77–1.68(m,8H),1.53–1.51(m,4H).13C NMR(151MHz,CDCl3)δ196.31,162.56,161.75,155.68,152.95,125.84,113.80,113.05,112.20,101.73,68.81,53.18,51.59,37.42,29.21,29.04,29.03,25.95,24.71,19.05.HRMS:calcd for C22H30NO3S2[M+H]+420.1662,found 420.1638.
实施例26：目标化合物17的收率、核磁数据和质谱数据
收率：86％；白色固体；1H NMR(600MHz,CDCl3)δ7.51(d,J＝8.8Hz,1H),6.87(dd,J＝8.8,2.5Hz,1H),6.83(d,J＝2.5Hz,1H),6.15(s,1H),4.32(br s,2H),4.03(t,J＝6.5Hz,2H),3.91(br s,2H),3.35–3.29(m,2H),2.42(s,3H),1.87–1.80(m,2H),1.75-1.72(m,2H),1.54–1.25(m,14H).13C NMR(151MHz,CDCl3)δ196.09,162.25,161.42,155.33,152.60,125.47,113.42,112.71,111.85,101.37,68.55,52.74,51.22,37.24,30.37,29.16,29.07,28.96,28.93,28.68,25.89,24.35,23.75,18.69.HRMS:calcd for C24H33NO3S2[M+H]+448.1975,found 448.1901.
实验例1：对按本发明所述方法合成得到的目标化合物1-17对胆碱酯酶的抑制活性实验
实验方法：按照文献报道的方法测试胆碱酯酶活性。乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BuChE)抑制活性测试方法为Ellman法。将化合物溶解于DMSO中，依次用缓冲液A稀释至所需浓度，控制所配置溶液中的DMSO含量低于1％。往96空白中依次加入，160微升1.5毫摩尔DTNB,50微升AChE(0.22U/mL,用缓冲液B制得)和10微升不同浓度抑制剂。37度下孵化6分钟，然后快速加入30微升碘化乙酰胆碱(15mM)。在405纳米下测定0,60,120和180秒的吸光度变化。丁酰胆碱酯酶的测定方法同乙酰胆碱酯酶类似，将所用的乙酰胆碱酯酶换为丁酰胆碱酯酶(0.12U/mL,用缓冲液B制得)同时替换底物碘化乙酰胆碱为硫代碘化丁酰胆碱(15mM)。抑制率的计算为:[1-(实验组吸光度变化/空白组吸光度变化)]*100％。选择化合物的五至七个浓度测定酶的抑制率(0.001-100μM)并以该化合物摩尔浓度的负对数与酶抑制率进行线性回归,求得50％抑制时的摩尔浓度即为该化合物的IC50值.每个实验重复三次，实验结果表达为平均值±SEM。实验结果如下述表2所示：
表2：
a人源乙酰胆碱酯酶50％的抑制浓度或者在10μM浓度下的抑制率(三次重复试验求平均值±SD).
b在10μM浓度下药物对丁酰胆碱酯酶的抑制率(三次重复试验求平均值±SD).
c‘n.a.’表示没活性,化合物定义为’没活性’表示药物在10μM浓度下,对酶的抑制率低于5％.
由表2可知，本发明化合物对乙酰胆碱酯酶具有显著抑制作用，活性数值介于微摩尔和纳摩尔之间，特别是化合物14对乙酰胆碱酯酶的抑制活性为27nM,和阳性对照药多奈哌齐23nM的活性相当，化合物14作为选择性乙酰胆碱酯酶的选择性比阳性对照药多奈哌齐好，化合物3,4,13,14,15,16(0.89μM，0.47μM，0.29μM，0.027μM，0.21μM，0.61μM)的活性强于或类似于阳性对照药他克林(0.57μM)的活性。说明本发明的化合物是活性好的选择性乙酰胆碱酯酶抑制剂。需要特别指出的是，7-羟基-4-甲基香豆素是这类化合物的母核结构，但是并未检测出它对乙酰胆碱酯酶和丁酰胆碱酯酶的抑制活性。
实验例2：目标化合物14抑制乙酰胆碱酯酶的动力学研究
为了研究化合物同乙酰胆碱酯酶的作用模式，用Ellman法对化合物14进行酶动力学研究。化合物14的三个不同浓度选作动力学研究分别为50.0,25.0和12.5nM。往96空板中依次加入，160微升1.5毫摩尔的DTNB,50微升AChE(0.22U/mL,用缓冲液B制得)和10微升50nM的化合物14。37度下孵化6分钟，然后快速加入30微升不同浓度的碘化乙酰胆碱(终浓度为0.05-0.5mM)。在405纳米下测定0,60,120和180秒的吸光度变化。以浓度的倒数为X轴和吸光度变化速率为Y轴作图，做出第一条双倒数曲线。依此方法，加入25.0nM,12.5nM和0nM浓度的化合物14，做出第二、三、四双倒数曲线(如图1所示)，以双倒数曲线的的交点判断化合物同酶的作用模式。以每个双倒数曲线的斜率为X轴，以双倒数曲线相对应的抑制剂浓度为Y轴作图，回归线在X轴的上的交点即为化合物14的Ki值。
实验例3：目标化合物抗Aβ1-42聚集作用研究
实验方法：将1mg Aβ1-42用HFIP溶解后，分装为10份，在通风橱中隔夜挥干，使其解聚，保存在-30℃待用。在准备实验之前，取其中一份加DMSO配成悬浮液，再加入磷酸缓冲液稀释至25μM，超声使其溶解，控制DMSO含量不高于10％。化合物用DMSO配制为浓度200μM。往黑色96孔板中依次加入，1μL测试化合物和9μL Aβ1-42磷酸盐溶液，加入完毕后，轻拍使之混匀，用盖板膜将96空板盖好，防止溶液挥发，于室温下，黑暗处静置46-48小时。静置结束后，加入200μL用甘氨酸-氢氧化钠缓冲液制备的50mM硫代硫磺素T，于激发光波长446nm和吸收光波长为490nm下测定荧光吸收。其抑制率计算公式为：100-(IFi/IFo*100)，IFi代表抑制剂存在下的荧光吸收；IFo代表无抑制存在下的荧光吸收。每个实验重复三次，结果表达为平均值±SD，结果如表3所示。
表3：
d药物浓度在25μM浓度下，对Aβ1-42自身聚集的抑制率。
表3表明，用硫代硫磺素T法测定化合物的抗Aβ1-42聚集活性，已知Aβ1-42聚集抑制剂姜黄素做为阳性对照药。发明的化合物表现出中等到较强的抑制Aβ1-42聚集活性(10.02％-43.53％，25μM),(阳性对照药姜黄素：39.62％，25μM)。化合物11、14、15(43.53％、40.19％、40.03％，25μM)都表现出较强的抑制Aβ1-42自身聚集的活性，均比阳性对照药的活性稍强。化合物3,4,8,9，10,13,16的活性接近于阳性对照药。
实验例4：目标化合物14对SH-SY5Y神经细胞的毒性
细胞培养和存活率实验：SH-SY5Y细胞植于盛有1:1混合的Eagle’s minimumessential medium(EMEM)和ham’s F-12培养基的25mL培养瓶中，并辅以10％的胎牛血清，100U/mL青霉素和100μg/mL链霉素，置于37℃下，5％二氧化碳培养箱中培养。然后将细胞以10,000每孔的密度分植于96孔板中生长。当细胞融合达到要求后，将细胞置于无血清培养基中，加入化合物培养24小时。培养结束后,加入20μL MTT 37℃下培养4小时，结束后加入200μL DMSO溶解甲瓒结晶，570nM下测定其吸光度。
化合物14浓度为12.5,25,50μM的情况下，神经细胞SH-SY5Y的存活率分别为：12.5μM：99.2±1.4％；25μM:101.1±10.3％；50μM:90.1±2.4％。当化合物的浓度增加到100μM时，化合物14的存活率为80.3±1.5％。实验结果表明，化合物14对神经细胞SH-SY5Y的毒性较低。
实验例5：目标化合物14对血脑屏障的通透性
采用体外人工膜实验方法(PAMPA-BBB)对化合物14进行血脑屏障通透性进行测试。10个对比药物的渗透参数如表4所示：
表4：用人工膜实验的方法验证10种药物的渗透系数Pe(×106cm/s).
a数值来源文献.
b三次独立实验取平均值,表示为平均值±SD,用PBS:EtOH(70:30)配比的溶剂.
根据实验和已知的数值绘制相关参数曲线(如图2所示)，并计算Pe公式，Pe(exp.)＝1.2653Pe(bibl.)+0.7955(R2＝0.9483)。根据参数判断化合物血脑屏障的通透性如下：
‘CNS+’(高的血脑屏障通透性):Pe(10-6cm/s)>5.86
‘CNS-’(低的血脑屏障通透性):Pe(10-6cm/s)<3.33
‘CNS+/-’(血脑屏障通透不确定性):3.33<Pe(10-6cm/s)<5.86
测定化合物14的Pe值为9.21×10-6cm/s，这表明化合物14能通透血脑屏障。
通过动物急性毒实验，验证化合物14的急性毒，化合物14的半数致死量为LD50:2000mg/kg,化合物14并未表现出急性毒。
上述试验表明，香豆素-二硫代氨基甲酸酯衍生物在体外实验中显示出良好的选择性乙酰胆碱酯酶抑制活性，抗Aβ1-42自身聚集活性，血脑屏障通透性，并通过体内、外检测化合物14的毒性，表现出理想的低毒或者无毒。
Claims (9)
1.具有下述式(I)所示结构的化合物或其药学上可接受的盐在制备乙酰胆碱酯酶抑制剂药物或保健品中的应用；
其中：
R1表示H、CH3、OCH3、F、Cl或Br；
R2表示H、CH3、OCH3、F、Cl或Br；
R3表示
n＝2-8。
2.具有下述式(I)所示结构的化合物或其药学上可接受的盐在制备抗Aβ聚集的药物或保健品中的应用；
其中：
R1表示H、CH3、OCH3、F、Cl或Br；
R2表示H、CH3、OCH3、F、Cl或Br；
R3表示
n＝2-8。
3.具有下述式(I)所示结构的化合物或其药学上可接受的盐在制备治疗阿尔茨海默病、脑血管痴呆、青光眼或重症肌无力的药物或保健品中的应用；
其中：
R1表示H、CH3、OCH3、F、Cl或Br；
R2表示H、CH3、OCH3、F、Cl或Br；
R3表示
n＝2-8。
4.一种乙酰胆碱酯酶抑制剂药物或保健品，含有治疗上有效剂量的下述式(I)所示结构的化合物或其药学上可接受的盐：
其中：
R1表示H、CH3、OCH3、F、Cl或Br；
R2表示H、CH3、OCH3、F、Cl或Br；
R3表示
n＝2-8。
5.根据权利要求4所述的药物或保健品，其特征在于：所述药物或保健品的剂型为药学上可接受的剂型。
6.一种抗Aβ聚集的药物或保健品，含有治疗上有效剂量的下述式(I)所示结构的化合物或其药学上可接受的盐：
其中：
R1表示H、CH3、OCH3、F、Cl或Br；
R2表示H、CH3、OCH3、F、Cl或Br；
R3表示
n＝2-8。
7.根据权利要求6所述的药物或保健品，其特征在于：所述药物或保健品的剂型为药学上可接受的剂型。
8.一种治疗阿尔茨海默病、脑血管痴呆、青光眼或重症肌无力的药物或保健品，含有治疗上有效剂量的下述式(I)所示结构的化合物或其药学上可接受的盐：
其中：
R1表示H、CH3、OCH3、F、Cl或Br；
R2表示H、CH3、OCH3、F、Cl或Br；
R3表示
n＝2-8。
9.根据权利要求8所述的药物或保健品，其特征在于：所述药物或保健品的剂型为药学上可接受的剂型。
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-
2017
- 2017-10-17 CN CN201710968604.9A patent/CN107737126B/zh active Active
Non-Patent Citations (4)
| Title |
|---|
| MAI A. ABD-EL-FATTAH等: "Pyrrolidine dithiocarbamate protects against scopolamine-induced cognitive impairment in rats", 《EUROPEAN JOURNAL OF PHARMACOLOGY》 * |
| RAMA PATHI TRIPATHI等: "Syntheses and spermicidal activities of dithiocarbamates", 《ACTA PHARM.》 * |
| SAI-SAI XIE等: "Design, synthesis and evaluation of novel tacrineecoumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer’s disease", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 苗艳: "新型香豆素衍生物的合成与抗增殖活性研究", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》 * |
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