CN110698411B - 一类4-(胺烷基)酞嗪-1-酮类化合物、其制备方法和用途 - Google Patents
一类4-(胺烷基)酞嗪-1-酮类化合物、其制备方法和用途 Download PDFInfo
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- CN110698411B CN110698411B CN201810744293.2A CN201810744293A CN110698411B CN 110698411 B CN110698411 B CN 110698411B CN 201810744293 A CN201810744293 A CN 201810744293A CN 110698411 B CN110698411 B CN 110698411B
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- phthalazin
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Abstract
本发明公开了一类新型的4‑(胺烷基)酞嗪‑1‑酮类化合物（I）及其药学上可接受的盐、其制备方法、药物组合物和在制备治疗和/或预防神经系统相关疾病药物中的用途，包括但不限于血管性痴呆、阿尔茨海默氏病、帕金森氏症、亨廷顿氏症、HIV相关痴呆症、多发性硬化症、肌萎缩侧索硬化症、神经性疼痛、青光眼、缺血性脑卒中、出血性脑卒中、以及脑外伤引起的神经损伤等疾病；
Description
技术领域
本发明属药物化学领域，涉及一类新型的4-(胺烷基)酞嗪-1-酮类化合物（I）、其制备方法、药物组合物和在制备治疗和/或预防神经系统相关疾病药物中的用途，包括但不限于血管性痴呆、阿尔茨海默氏病、帕金森氏症、亨廷顿氏症、HIV相关痴呆症、多发性硬化症、肌萎缩侧索硬化症、神经性疼痛、青光眼、缺血性脑卒中、出血性脑卒中、以及脑外伤引起的神经损伤等疾病。
背景技术
阿尔茨海默症（Alzheimer’s disease，AD，老年痴呆症）是一种以进行性认知障碍和记忆力损害为主的中枢神经系统退行性疾病，其发病率呈逐年上升趋势，成为仅次于心血管病和癌症的高发性疾病，在欧美等发达国家已上升为死亡原因的第四位。据世界卫生组织报告，全球65岁以上老人有10%智力障碍，其中二分之一发生痴呆，八十五岁以上发病率近50%。在我国AD患者人数约600-700万，发病率超过5%。随着全球人口老龄化进程的加快，其发病率呈明显上升趋势，据Alzheimer's Disease International在2013年12月公布的《阿尔茨海默症的全球影响：2013-2050》报告中指出，AD将成为未来几十年全球面临的最大健康挑战，到2030年，患者人数将由2013年的4400万上升到7600万，到2050年，这一数值将达到惊人的1.35亿。由于AD临床表现为记忆能力、定向能力、思维和判断能力减退，以及日常生活能力降低，甚至出现异常精神行为症状等，使患者护理难度较大，给社会和家庭带来沉重负担。目前已批准用于治疗轻/中度AD的药物有乙酰胆碱酯酶（AChE）抑制剂，以及用于重度AD治疗的N-甲基-D-天冬氨酸（NMDA）受体拮抗剂。但临床使用表明，这些药物可通过提高患者体内乙酰胆碱水平或者抑制兴奋性氨基酸的兴奋毒性来缓解AD症状，但不能有效阻止或逆转病程，而且还会引起幻觉、意识混沌、头晕、头痛、恶心、肝脏毒性、食欲不振以及大便频繁等严重毒副作用，因而长期疗效不甚理想。因此，临床上迫切需要研发兼具AD症状改善和病程改变的新型AD治疗药物。
AD属多种因素引起的疾病，发病机理复杂，其发病机制至今还未完全阐明。但研究表明，患者脑内乙酰胆碱水平的下降、β-淀粉样蛋白的过度生成与沉积、脑血管内的血小板聚集、金属离子代谢紊乱、Ca2+平衡失调、tau-蛋白过度磷酸化导致的神经纤维缠结、谷氨酸受体活性过高、氧化应激产生大量活性氧（ROS）和自由基以及神经炎症反应等多种因素在AD的发病过程中扮演重要角色。针对上述发病因素，研究人员采用传统“一药一靶”药物设计策略，发现了大量对某一靶点具有高活性和高选择性的药物，如：胆碱酯酶抑制剂和N-甲基-D-天冬氨酸受体拮抗剂等。但这些药物存在作用靶点单一、临床使用毒副作用较多、对AD患者的长期疗效欠佳等问题。
近年来，随着对AD致病机理的不断阐明，发现AD的发生和发展具有多机制、多因素作用的特点，不同机制之间又相互关联相互影响，构成了AD发生和发展过程中复杂的网络调控系统。显然，研发可同时作用于AD病理过程中多个环节的治疗药物是目前的必然选择。基于上述结果，研究人员提出了“多靶点导向药物”（Multitarget-directed Ligands,MTDLs）策略来研发抗神经退行性疾病药物。所谓“多靶点药物”是指单一化学实体同时作用于疾病网络中的多个靶点，对各靶点的作用可产生协同效应，使总效应大于各单效应之和，此类化合物也称为“Multifunctional”或“Multipotential”药物。多靶点药物与多药联合应用以及复方药物的主要区别在于：可减少服药量、提高治疗效果、避免药物之间的相互作用及由此带来的毒副作用，均一的药代动力学特性，便于使用等。因此，研究开发具有新型化学结构、新型作用机制，且具有多靶点作用、低毒副作用的抗神经退行性疾病治疗药物不仅符合社会老龄化进程的迫切需求，而且具有良好的市场前景。大量临床研究已证实，AChE抑制剂能有效缓解AD患者症状，短期治疗疗效肯定；因此，在设计多靶点抗AD药物时通常需保留化合物的AChE抑制活性（抑制该酶对改善AD患者症状至关重要），并在此基础上增加一个或多个具有药理协同作用的其它靶标或功能，以达到多靶点AD治疗作用【1、黄淑芳等.多靶点阿尔茨海默症治疗药物的研究进展. 中国药物化学杂志 2011, 21(6): 433-434；2、罗稳等. 多靶点小分子抑制剂治疗阿尔茨海默症的研究进展. 中国药物化学杂志2011, 21(6): 442-443】。显然，设计并发现同时具有抑制乙酰胆碱酯酶、抑制β-淀粉样蛋白的过度生成与沉积、抗氧化应激、抗血小板凝聚、以及抗神经炎症反应的多靶点AD治疗药物仍是目前重要的研究方向。
发明内容
本发明目的在于公开一类4-(胺烷基)酞嗪-1-酮类化合物（I）及其药学上可接受的盐；
本发明另一目的在于公开该类4-(胺烷基)酞嗪-1-酮类化合物（I）及其药学上可接受的盐的制备方法；
本发明的又一目的在于公开包含该类4-(胺烷基)酞嗪-1-酮类化合物（I）及其药学上可接受的盐的药物组合物；
本发明再一目的在于公开该类4-(胺烷基)酞嗪-1-酮类化合物（I）及其药学上可接受的盐具有多靶点作用，可用于制备治疗和/或预防神经系统相关疾病药物中的用途，包括但不限于血管性痴呆、阿尔茨海默氏病、帕金森氏症、亨廷顿氏症、HIV相关痴呆症、多发性硬化症、肌萎缩侧索硬化症、神经性疼痛、青光眼、缺血性脑卒中、出血性脑卒中、以及脑外伤引起的神经损伤等疾病。
本发明所提供的4-(胺烷基)酞嗪-1-酮类化合物（I）的化学结构通式为：
式中：R1表示-(CH2)n-NR4R5，n表示1-12，R4表示H、C1~C12烷基；R5表示C1~C12烷基、苄基或取代苄基；NR4R5也表示四氢吡咯基、吗啉基、哌啶基、4-位被C1~C12烷基所取代的哌啶基、4-位被苄基或取代苄基所取代的哌啶基、哌嗪基、4-位被C1~C12烷基所取代的哌嗪基、4-位被苄基或取代苄基所取代的哌嗪基；R1也表示
，m表示0-10，R6表示H、C1~C12烷基、苄基或取代苄基；R2和R3各自独立地表示H、OH、SH、C1~C12烷基、C1~C12烷氧基、CN、卤素、NR7R8或C1~C12烷硫基；R7和R8各自独立地表示H、C1~C12烷基；NR7R8也表示四氢吡咯基、吗啉基或哌啶基；R2和R3在苯环任意可能的位置。上述术语“卤素”是指F、Cl、Br或I；“取代苄基”是指苯环上被1-4个选自下组的基团所取代的苄基：F、Cl、Br、I、C1-4烷基、C1-4烷氧基、NR9R10、三氟甲基、三氟甲氧基、氨基、羟基或氰基，R9和R10各自独立地表示C1~C12烷基，NR9R10也表示四氢吡咯基、吗啉基或哌啶基，这些取代基在苯环的任意可能位置。
本发明所提出的4-(胺烷基)酞嗪-1-酮类化合物（I）可通过以下方法制备得到：
以相应的3-溴苯酞类化合物（1）为起始原料，在适当溶剂中和三苯基膦反应，得相应的3-三苯基膦苯酞盐类化合物（2）；所得化合物2与相应的胺烷基醛类化合物（3）在适当溶剂和碱性条件下经Wittig反应得相应化合物（4）的E/Z构型混合物，该混合物可不经分离纯化，直接与水合肼在适当溶剂中反应，即可制备得到相应的4-(胺烷基)酞嗪-1-酮类化合物（I）；也可将化合物（4）的E/Z构型混合物经硅胶柱层析分离纯化，分别得到相应的E-式或Z-式构型化合物（4），再分别与水合肼在适当溶剂中反应，也可制备得到相应的4-(胺烷基)酞嗪-1-酮类化合物（I）；其反应式如下：
式中：R1、R2和R3的定义与4-(胺烷基)酞嗪-1-酮类化合物（I）的化学结构通式相同。
对于上述合成路线，其具体制备方法描述如下：
步骤A)：3-溴苯酞类化合物（1）和三苯基膦在适当溶剂中反应，得相应的3-三苯基膦苯酞盐类化合物（2）；其中，反应所用溶剂为：C3-8脂肪酮、N,N-二甲基甲酰胺、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、乙醚、苯、甲苯、乙腈、1,4-二氧六环、乙二醇二甲醚或C5-8烷烃，优选溶剂为2-甲基四氢呋喃、乙酸乙酯、乙腈、甲苯或1,4-二氧六环；3-溴苯酞类化合物（1）：三苯基膦的摩尔投料比为1.0：1.0~10.0，优选摩尔投料比为1.0：1.0~5.0；反应温度为40~150℃，优选反应温度为60~120℃；反应时间为1~120小时，优选反应时间为2~72小时。
步骤B)：由步骤A)得到的3-三苯基膦苯酞盐类化合物（2）与相应的胺烷基醛类化合物（3）在适当溶剂和碱性条件下经Wittig反应，得相应化合物（4）的E/Z构型混合物；其中，反应所用溶剂为：C1-8脂肪醇、C3-8脂肪酮、乙醚、四氢呋喃、2-甲基四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、1,4-二氧六环、苯、甲苯、乙腈或C5-8烷烃，优选溶剂为：氯仿、、二氯甲烷、丙酮、乙腈、四氢呋喃或甲苯；反应所用碱为：碱金属氢氧化物、碱土金属氢氧化物、碱金属碳酸盐、碱土金属碳酸盐、碱金属碳酸氢盐、碱土金属碳酸氢盐、C1-8醇的碱金属盐、有机叔胺类或季铵碱类（如：三乙胺、三丁胺、三辛胺、吡啶、N-甲基吗啉、N-甲基哌啶、三乙烯二胺、四丁基氢氧化铵），优选碱为：氢氧化钾、氢氧化钠、碳酸钾、三乙胺、吡啶或甲醇钠；3-三苯基膦苯酞盐类化合物（2）：胺烷基醛类化合物（3）：碱的摩尔投料比为1.0：1.0~10.0：1.0~10.0，优选摩尔投料比为1.0：1.0~3.0：1.0~5.0；反应温度为0~120℃，优选反应温度为室温~100℃；反应时间为20分钟~48小时，优选反应时间为1~24小时。
步骤C)：由步骤B)得到的化合物（4）混合物不经分离纯化，直接与水合肼在适当溶剂中反应，即可制备得到相应的4-(胺烷基)酞嗪-1-酮类化合物（I）；其中，反应所用溶剂为：C1-6脂肪醇、C3-8脂肪酮、C1-6脂肪酸、C1-6脂肪酸与C1-6脂肪醇所形成酯、醚类（如：乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、乙二醇二甲醚等）、苯、甲苯或二甲苯、脂肪烃（如：己烷、庚烷、辛烷等），优选溶剂为：四氢呋喃、甲醇、乙醇或异丙醇；化合物（4）与水合肼的摩尔投料比为1.0：1.0~10.0，优选摩尔投料比为1.0：1.0~3.0；反应温度为室温~150℃，优选为室温~120℃；反应时间为30分钟~48小时，优选为1~24小时。
按照上述方法所得之4-(胺烷基)酞嗪-1-酮类化合物（I）分子的侧链中含有氨基，该氨基呈碱性，可与任何合适的酸通过药学上常规的成盐方法制得其药物学上可接受的盐，所述的酸为：盐酸、氢溴酸、硝酸、硫酸、磷酸、胺基磺酸、C1-6脂肪羧酸（如：甲酸、乙酸、丙酸等）、三氟乙酸、硬脂酸、扑酸、草酸、苯甲酸、苯乙酸、水杨酸、马来酸、富马酸、琥珀酸、酒石酸、柠檬酸、苹果酸、乳酸、羟基马来酸、丙酮酸、谷氨酸、抗坏血酸、硫辛酸、C1-6烷基磺酸（如：甲基磺酸、乙基磺酸等）、樟脑磺酸、萘磺酸、苯磺酸、对甲苯磺酸或1,4-丁二磺酸。
本发明的起始原料——3-溴苯酞类化合物（1）和胺烷基醛类化合物（3）可用本领域常见的技术制得，包括但不局限于以下文献中所公开的方法：1、Guidong Z. et al. WO2011130478A1；2、Sakamoto F. et al.Chem. Pharm. Bull.1983, 31(8), 2698-2707；3、Chunzhi Z. et al.Chinese Journal of Organic Chemistry2014, 34, 1881-1888；4、Sugimoto H. et al. US 5100901；5、Mingyu W. et al.European Journal of Medicinal Chemistry2016, 121, 864-879。
本发明所公开的药物组合物包括治疗有效量的一种或多种4-(胺烷基)酞嗪-1-酮类化合物（I）或其药学上可接受的盐，该药物组合物可进一步含有一种或多种药学上可接受的载体或赋形剂。所述“治疗有效量”是指引起研究者或医生所针对的组织、系统或动物的生物或医药反应的药物或药剂的量；所述“组合物”是指通过将一种以上物质或组份混和而成的产品；所述“药学上可接受的载体”是指药学上可接受的物质、组合物或载体，如：液体或固体填充剂、稀释剂、赋形剂、溶剂或包囊物质，它们携带或转运某种化学物质。本发明所提供的药物组合物其理想的比例是，4-(胺烷基)酞嗪-1-酮类化合物（I）或其药学上可接受的盐作为活性成分占总重量比2%～99.5%。
本发明所公开的4-(胺烷基)酞嗪-1-酮类化合物（I）及其药学上可接受的盐进行了如下的生物活性筛选。
（1）4-(胺烷基)酞嗪-1-酮类化合物（I）对乙酰胆碱酯酶和丁酰胆碱酯酶的抑制活性
向96孔板中依次加入1.0 mmol/L碘化硫代乙酰胆碱或碘化硫代丁酰胆碱（均购自Sigma公司）30 μL、pH7.4的PBS缓冲液40 μL、待测化合物溶液20 μL（DMSO含量小于1%）和10μL乙酰胆碱酯酶（大鼠脑皮层5%匀浆上清液，pH7.4的磷酸缓冲液作匀浆介质）或丁酰胆碱酯酶（大鼠血清25%上清液，pH7.4磷酸缓冲液作匀浆介质）溶液，加毕混匀后，37℃孵育15min，向各孔中加入0.2%的5,5’-二硫代-双(2-硝基苯甲酸)（DTNB, 购自Sigma公司）溶液30 μL显色，用酶标仪测定405nm处各孔的光密度（OD值），与不加待测样品的空白孔比较，计算化合物对酶的抑制率（酶抑制率(%)=(1-样品组OD值/空白组OD值)×100%）；选择化合物的五至六个浓度，测定其酶抑制率，并以该化合物摩尔浓度的负对数与酶的抑制率线性回归，求得50%抑制率时的摩尔浓度即为该化合物的IC50。测定结果表明，本发明实施例中所公开的4-(胺烷基)酞嗪-1-酮类化合物（I）对乙酰胆碱酯酶均具有显著抑制作用，其IC50值为0.11 nM~10.0 µM；并且4-(胺烷基)酞嗪-1-酮类化合物（I）对乙酰胆碱酯酶的抑制活性显著高于对丁酰胆碱酯酶的抑制活性（选择性大于100倍以上），说明本发明所公开的化合物对乙酰胆碱酯酶具有选择性抑制作用，表明该类化合物对外周系统的毒性较小。另外，测定结果还显示，在临床上使用的卡巴拉汀对AChE抑制的IC50为10.5 µM，对丁酰胆碱酯酶抑制的IC50为2.6 µM；如下所示的对照化合物（II）和对照化合物（III）对乙酰胆碱酯酶抑制的IC50均大于150µM，并且对照化合物（IV）（其结构中的R1、R2和R3的定义与4-(胺烷基)酞嗪-1-酮类化合物（I）的化学结构通式相同）对乙酰胆碱酯酶抑制的IC50值均高于具有相同取代基的相应4-(胺烷基)酞嗪-1-酮类化合物（I）2-10倍；
（2）4-(胺烷基)酞嗪-1-酮类化合物（I）的抗氧化活性（ORAC-FL方法）
参照文献（Qiang, X.M. et al.Eur. J Med. Chem.2014, 76, 314-331）所报道的方法进行测定，即：6-羟基-2,5,7,8-四甲基色烷-2-羧酸（Trolox）用pH7.4的PBS缓冲液配成10-80 μmol/L的溶液，荧光素（fluorescein）用pH7.4的PBS缓冲液配成250 nmol/L的溶液，2,2’-偶氮二异丁基脒二盐酸盐（AAPH）使用前用pH7.4的PBS缓冲液配成40 mmol/L的溶液。向96孔板中加入50-10 μmol/L的化合物溶液和荧光素溶液，混匀，37°C孵育15min，加入AAPH溶液，使每孔总体积为200 μL，混匀，立即置于Varioskan Flash Multimode Reader(Thermo Scientific)仪中，在485 nm激发波长和535 nm发射波长下连续测定90 min。计算出荧光衰减曲线下面积AUC，其中以1-8μmol/L的Trolox作为标准，以不加待测样品为空白，化合物的抗氧化活性结果表达为Trolox的当量，其计算公式为：[(AUC Sample-AUCblank)/(AUC Trolox-AUC blank)] ×[(concentration of Trolox/concentration ofsample)]，每个化合物每次测定3个复孔，每组实验独立重复三次。测定结果表明，本发明实施例中所公开的4-(胺烷基)酞嗪-1-酮类化合物（I）的抗氧化活性为Trolox的0.5～4.0倍，说明该类化合物具有较强抗氧化活性。另外，测定结果还显示，4-(胺烷基)酞嗪-1-酮类化合物（I）的抗氧化活性还显著高于具有相同取代基的相应对照化合物（IV）（n=3，p<0.05）。
（3）4-(胺烷基)酞嗪-1-酮类化合物（I）对Aβ 1-42自身聚集的抑制活性
参照文献（Qiang, X.M. et al.Eur. J Med. Chem.2014, 76, 314-331）所报道的方法进行测定，即：预处理后的Aβ 1-42用DMSO配成储备液，使用前用pH7.4的PBS缓冲液稀释至50μM；待测化合物用DMSO配成2.5 mM储备液，使用前用pH7.4的PBS缓冲液稀释至相应浓度，取20μL的Aβ 1-42溶液+20μL的待测化合物溶液、20μL的Aβ 1-42溶液+20μL的PBS缓冲液（含2%DMSO）于96孔板中，37°C孵育24h，然后加入160μL含有5μM硫黄素T的50mM的甘氨酸-NaOH缓冲液（pH=8.5），振摇5s后立即用多功能酶标仪在446 nm激发波长和490 nm发射波长下测定荧光值；Aβ 1-42+待测化合物的荧光值记为IFi，Aβ 1-42+PBS缓冲液的荧光值记为IFc，只含有PBS缓冲液的荧光值记为IF0，化合物抑制Aβ 1-42自身聚集的抑制率为：100-(IFi-IF0)/(IFc-IF0)*100；选择化合物的五至六个浓度，测定其抑制率；每个化合物每个浓度复测三次，以姜黄素为阳性对照。测定结果表明，本发明实施例中所公开的4-(胺烷基)酞嗪-1-酮类化合物（I）对Aβ 1-42自身聚集均具有显著抑制活性，在20.0 µM浓度下对Aβ 1-42自身聚集的抑制率在25.0%～65.0%之间；而临床上广泛使用的抗AD药物：多奈哌齐、卡巴拉汀、盐酸美金刚胺、以及上述对照化合物（II）和对照化合物（III）在25.0 µM浓度下对Aβ 1-42自身聚集的抑制率均小于10%。
（4）4-(胺烷基)酞嗪-1-酮类化合物（I）的抗血小板聚集活性
取雄性家兔3只，用利多卡因局部麻醉，手术分离颈总动脉取血，采取3.8%枸橼酸钠1：9抗凝，以500 r/min离心10分钟，制备富血小板血浆（PRP），剩余部分再以3000 r/min离心，制备贫血小板血浆（PPP），按比浊法进行血小板聚集实验。测定管中加入240 μL的PRP和30 μL不同浓度受试药物，温孵5分钟，分别以30 μL二磷酸腺苷（ADP）（终浓度为10 μmol/L），30 μL凝血酶（终浓度为0.5 U/mL）和30 μL花生四烯酸（AA）（终浓度为1.0 mmol/L）为诱导剂，观察记录5分钟内最大聚集率。用生理盐水（NS）作对照，计算各受试化合物的抑制率（%）。测定结果表明，本发明实施例中所公开的4-(胺烷基)酞嗪-1-酮类化合物（I）在33.0 µM浓度下对ADP诱导、凝血酶诱导和AA诱导的血小板聚集均有显著抑制作用，其抑制率均大于15.0%。而临床上广泛使用的抗AD药物：多奈哌齐、卡巴拉汀、盐酸美金刚胺、以及上述对照化合物（II）、（III）和（IV）在相同浓度下对血小板聚集的抑制率均小于10.0%。
具体实施方式
通过下面的实施例可对本发明进行进一步的描述，然而，本发明的范围并不限于下述实施例。本领域的专业人员能够理解，在不背离本发明的精神和范围的前提下，可以对本发明进行各种变化和修饰。
实施例1 4-(胺烷基)酞嗪-1-酮类化合物（I）的制备通法
将2.0 mmol相应的3-溴化物（1）、2.4 mmol三苯基膦和20 ml甲苯加入反应瓶中，升温回流搅拌反应8～24.0小时（反应进程用TLC跟踪）；反应结束后，将反应液冷至室温，抽滤，滤饼依次以甲苯和石油醚洗涤，干燥，得相应的3-三苯基膦盐类化合物（2），收率60.0%-88.0%，其化学结构均经1H-NMR确证；
将上步制备得到的3-三苯基膦盐类化合物（2）1.0 mmol、胺烷基醛类化合物（3）1.2 mmol和二氯甲烷30 ml加入反应瓶中，搅拌均匀后加入三乙胺1.2 mmol，然后室温搅拌反应6.0～24.0小时（反应进程用TLC跟踪）；反应结束后，减压蒸除溶剂，残余物中加入30mL去离子水，用10%盐酸水溶液调节反应液pH至强酸性，再用饱和碳酸氢钠水溶液调节反应液pH至弱碱性，用120 mL二氯甲烷分三次萃取，有机层合并后用饱和氯化钠水溶液洗涤，经无水硫酸钠干燥后过滤，减压蒸除溶剂，残余物即为相应化合物（4）的E/Z构型混合物，收率80.0%-98.0%，其化学结构均经1H-NMR确证；
将上步制备得到的化合物（4）的E/Z构型混合物0.6 mmol、乙醇15 ml和水合肼1.0mmol加入反应瓶中，升温回流搅拌反应2.0～12.0小时（反应进程用TLC跟踪）；反应结束后，减压蒸除溶剂，残余物经硅胶柱层析纯化（洗脱液：二氯甲烷:甲醇=20～30:1 v/v），得相应的4-(胺烷基)酞嗪-1-酮类化合物（I），收率70.0%-90.0%，其化学结构均经1H-NMR、13C-NMR和ESI-MS确证；所得目标物的纯度经HPLC测定均大于97.0%。
采用上述通法制备得到了如下所示的目标物：
（1）当R1表示-(CH2)n-NR4R5时的目标化合物结构如下：
注：表中R4和R5共用一个单元格时，表示取代基“-NR4R5”；
部分化合物的1H-NMR数据如下：
1H NMR (CDCl3): 10.39 (s, 1H), 7.79 (s, 1H), 7.30-7.26 (m, 5H), 7.04(s, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.66 (s, 2H), 3.15 (t, J = 7.2 Hz, 2H),2.88 (t, J = 7.2 Hz, 2H), 2.43 (s, 3H)；
1H NMR (CDCl3): 11.25 (s, 1H), 7.81 (s, 1H), 7.33-7.23 (m, 2H), 7.16(s, 1H), 6.92-6.85 (m, 2H), 4.05 (s, 3H), 3.95 (s, 3H), 3.82 (s, 3H), 3.74(s, 2H), 3.25 (t, J = 7.6 Hz, 2H), 2.96 (t, J = 7.6 Hz, 2H), 2.46 (s, 3H)；
1H NMR (CDCl3): 10.80 (s, 1H), 7.82 (s, 1H), 7.32-7.24 (m, 5H), 7.08(s, 1H), 4.05 (s, 3H), 4.01 (s, 3H), 3.55 (s, 2H), 2.92 (t, J = 7.2 Hz, 2H),2.50 (t, J = 7.2 Hz, 2H), 2.24 (s, 3H), 1.89-1.81 (m, 2H), 1.75-1.69 (m, 2H)；
1H NMR (CDCl3): 11.00 (s, 1H), 7.83 (s, 1H), 7.33-7.19 (m, 5H), 7.06(s, 1H), 4.05 (s, 3H), 4.00 (s, 3H), 3.62 (s, 2H), 2.89 (t, J = 7.2 Hz, 2H),2.57-2.50 (m, 4H), 1.85-1.77 (m, 2H), 1.69-1.63 (m, 2H), 1.06 (t, J = 7.2 Hz,3H)；
1H NMR (CDCl3): 10.75 (s, 1H), 7.81 (s, 1H), 7.40 (d, J = 7.2 Hz, 1H),7.29 (t, J = 7.2 Hz, 1H), 7.10 (s, 1H), 6.94 (t, J = 7.2 Hz, 1H), 6.88 (d, J= 8.4 Hz, 1H), 4.05 (s, 3H), 4.02 (s, 3H), 3.81 (s, 3H), 3.79 (s, 2H), 2.95(t, J = 7.2 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.39 (s, 3H), 1.86-1.69 (m,4H)；
1H NMR (CDCl3): 10.87 (s, 1H), 7.82-7.75 (m, 2H), 7.29 (t, J = 7.2 Hz,1H), 7.17-7.08 (m, 3H), 4.06 (s, 2H), 4.05 (s, 3H), 4.04 (s, 3H), 2.94 (t, J= 7.2 Hz, 2H), 2.90-2.78 (m, 4H), 2.65 (s, 6H), 1.95-1.78 (m, 4H), 1.32-1.15(m, 3H)；
1H NMR (CDCl3): 10.75 (s, 1H), 7.81 (s, 1H), 7.23 (d, J = 8.4 Hz, 2H),7.08 (s, 1H), 6.66 (d, J = 8.4 Hz, 2H), 4.05 (s, 3H), 4.03 (s, 3H), 3.74 (s,2H), 2.93 (s, 6H), 2.92 (t, J = 7.2 Hz, 2H), 2.80-2.61 (m, 4H), 1.86-1.79 (m,4H), 1.22-1.18 (m, 3H)；
1H NMR (CDCl3): 12.37 (s, 1H), 7.62 (s, 1H), 7.28 (s, 1H), 3.99 (s,3H), 3.94 (s, 3H), 3.12-3.01 (m, 6H), 2.99-2.94 (m, 2H), 1.82-1.72 (m, 4H),1.23-1.19 (m, 6H)；
1H NMR (CDCl3): 11.19 (s, 1H), 7.79 (s, 1H), 7.08 (s, 1H), 4.06 (s,3H), 4.05 (s, 3H), 2.98-2.92 (m, 2H), 2.78-2.67 (m, 6H), 2.00-1.84 (m, 8H),1.71-1.55 (m, 2H)；
1H NMR (CDCl3): 11.15 (s, 1H), 7.81 (s, 1H), 7.08 (s, 1H), 4.05 (s,3H), 4.02 (s, 3H), 2.93 (t, J = 7.6 Hz, 2H), 2.72-2.50 (m, 8H), 2.48 (t, J =7.6 Hz, 2H), 2.34 (s, 3H), 1.86-1.79 (m, 2H), 1.70-1.66 (m, 2H)；
1H NMR (CDCl3): 10.86 (s, 1H), 7.82 (s, 1H), 7.40 (d, J = 7.2 Hz, 1H),7.28 (t, J = 7.2 Hz, 1H), 7.10 (s, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.88 (d, J= 8.0 Hz, 1H), 4.05 (s, 3H), 4.00 (s, 3H), 3.83 (s, 3H), 3.76 (s, 2H), 2.90(t, J = 7.2 Hz, 2H), 2.61-2.55 (m, 2H), 2.37 (s, 3H), 1.86-1.78 (m, 2H),1.77-1.62 (m, 2H), 1.55-1.36 (m, 4H)；
1H NMR (CDCl3): 10.49 (s, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H),7.34 (t, J = 7.2 Hz, 1H), 7.23-7.14 (m, 2H), 7.09 (s, 1H), 4.28 (s, 2H), 4.07(s, 3H), 4.05 (s, 3H), 3.08-2.87 (m, 6H), 2.65 (s, 6H), 1.83-1.45 (m, 4H),1.44-1.28 (m, 7H)。
（2）当R1表示
时的目标化合物结构如下：
部分化合物的1H-NMR数据如下：
1H NMR (CDCl3): 10.23 (s, 1H), 7.82 (s, 1H), 7.31-7.23 (m, 5H), 7.07(s, 1H), 4.05 (s, 3H), 4.03 (s, 3H), 3.49 (s, 2H), 2.89-2.85 (m, 4H), 1.96-1.91 (m, 2H), 1.81-1.76 (m, 2H), 1.69-1.66 (m, 3H), 1.40-1.36 (m, 2H), 1.28-1.25 (m, 2H)。
实施例2 4-(胺烷基)酞嗪-1-酮类化合物（I）与酸成盐制备通法
在反应瓶中加入按照上述实施例1所得之4-(胺烷基)酞嗪-1-酮类化合物（I）3.0mmol和丙酮25 ml，搅拌均匀后加入8.0 mmol相应的酸，升温回流搅拌反应20分钟，反应结束后冷却至室温，减压蒸除溶剂，残余物用丙酮重结晶，过滤析出的固体，即得4-(胺烷基)酞嗪-1-酮类化合物（I）的盐，其化学结构经1H NMR和ESI-MS确证。
Claims (8)
1.一类4-(胺烷基)酞嗪-1-酮类化合物或其药学上可接受的盐，其特征在于该类化合物的化学结构通式如(I)所示：
式中：R1表示-(CH2)n-NR4R5，n表示1、2、3、4、5或6，R4表示甲基或乙基；R5表示甲基、乙基、苄基或取代苄基；NR4R5也表示四氢吡咯基、吗啉基；R1也表示
m表示0、1、2、3、4、5或6，R6表示H、甲基、乙基、苄基或取代苄基；R2和R3各自独立地表示H、OH、甲基、甲氧基、溴、二甲氨基、四氢吡咯基或甲硫基；R2和R3在苯环任意可能的位置；“取代苄基”是指苯环上被1-4个选自下组的基团所取代的苄基：F、Cl、Br、C1-4烷基、C1-4烷氧基、二甲氨基、三氟甲基或三氟甲氧基，这些取代基在苄基的苯环上任意可能位置。
2.如权利要求1所述的4-(胺烷基)酞嗪-1-酮类化合物或其药学上可接受的盐，其特征在于所述的药学上可接受的盐为此类4-(胺烷基)酞嗪-1-酮类化合物与盐酸、氢溴酸、硝酸、硫酸、磷酸、胺基磺酸、C1-6脂肪羧酸、三氟乙酸、硬脂酸、扑酸、草酸、苯甲酸、苯乙酸、水杨酸、马来酸、富马酸、琥珀酸、酒石酸、柠檬酸、苹果酸、乳酸、羟基马来酸、丙酮酸、谷氨酸、抗坏血酸、硫辛酸、C1-6烷基磺酸、樟脑磺酸、萘磺酸、苯磺酸、对甲苯磺酸或1,4-丁二磺酸的盐。
3.如权利要求1-2任一项所述4-(胺烷基)酞嗪-1-酮类化合物或其药学上可接受的盐的制备方法，其特征在于所述化合物可通过以下方法制备得到：
式中：R1、R2和R3的定义与4-(胺烷基)酞嗪-1-酮类化合物(I)的化学结构通式相同；
步骤A)：以相应的3-溴苯酞类化合物(1)为起始原料，在适当溶剂中和三苯基膦反应，得相应的3-三苯基膦苯酞盐类化合物(2)；
步骤B)：由步骤A)得到的3-三苯基膦苯酞盐类化合物(2)与相应的胺烷基醛类化合物(3)在溶剂和碱性条件下经Wittig反应，得相应化合物(4)的E/Z构型混合物；
步骤C)：由步骤B)得到的化合物(4)混合物不经分离纯化，直接与水合肼在适当溶剂中反应，得相应的4-(胺烷基)酞嗪-1-酮类化合物(I)；
利用上述方法所得之4-(胺烷基)酞嗪-1-酮类化合物(I)分子中含有氨基，该氨基呈碱性，可与任何合适的酸通过药学上常规的成盐方法制得其药物学上可接受的盐。
4.如权利要求3所述4-(胺烷基)酞嗪-1-酮类化合物或其药学上可接受的盐的制备方法，其特征在于所述步骤A)中，反应所用溶剂为：C3-8脂肪酮、N,N-二甲基甲酰胺、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、乙醚、苯、甲苯、乙腈、1,4-二氧六环、乙二醇二甲醚或C5-8烷烃；3-溴苯酞类化合物(1)：三苯基膦的摩尔投料比为1.0：1.0～10.0；反应温度为40～150℃；反应时间为1～120小时。
5.如权利要求3所述4-(胺烷基)酞嗪-1-酮类化合物或其药学上可接受的盐的制备方法，其特征在于所述步骤B)中，反应所用溶剂为：C1-8脂肪醇、C3-8脂肪酮、乙醚、四氢呋喃、2-甲基四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、1,4-二氧六环、苯、甲苯、乙腈或C5-8烷烃；反应所用碱为：碱金属氢氧化物、碱土金属氢氧化物、碱金属碳酸盐、碱土金属碳酸盐、碱金属碳酸氢盐、碱土金属碳酸氢盐、C1-8醇的碱金属盐、三乙胺、三丁胺、三辛胺、吡啶、N-甲基吗啉、N-甲基哌啶、三乙烯二胺、四丁基氢氧化铵；3-三苯基膦苯酞盐类化合物(2)：胺烷基醛类化合物(3)：碱的摩尔投料比为1.0：1.0～10.0：1.0～10.0；反应温度为0～120℃；反应时间为20分钟～48小时。
6.如权利要求3所述4-(胺烷基)酞嗪-1-酮类化合物或其药学上可接受的盐的制备方法，其特征在于所述步骤C)中，反应所用溶剂为：C1-6脂肪醇、C3-8脂肪酮、C1-6脂肪酸、C1-6脂肪酸与C1-6脂肪醇所形成酯、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、乙二醇二甲醚、苯、甲苯或二甲苯；化合物(4)与水合肼的摩尔投料比为1.0：1.0～10.0；反应温度为室温～150℃；反应时间为30分钟～48小时。
7.一类药物组合物，其特征在于包含如权利要求1-2任一项所述的4-(胺烷基)酞嗪-1-酮类化合物或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。
8.如权利要求1-2任一项所述的4-(胺烷基)酞嗪-1-酮类化合物或其药学上可接受的盐用于制备通过乙酰胆碱酯酶抑制剂、抗氧化应激、抑制Aβ1-42自身聚集或抗血小板聚集进行治疗和/或预防疾病药物中的用途，这类疾病为：血管性痴呆、阿尔茨海默氏病、帕金森氏症、亨廷顿氏症、HIV相关痴呆症、多发性硬化症、肌萎缩侧索硬化症、神经性疼痛、青光眼、缺血性脑卒中、出血性脑卒中、以及脑外伤引起的神经损伤。
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