CN114478451A - 6-(羟基苄氧基)苯酞曼尼希碱类化合物、其制备方法和用途 - Google Patents
6-(羟基苄氧基)苯酞曼尼希碱类化合物、其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一类6‑(羟基苄氧基)苯酞曼尼希碱类化合物（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、额颞叶痴呆、Prion病、路易体痴呆、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、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6-(羟基苄氧基)苯酞曼尼希碱类化合物（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、额颞叶痴呆、Prion病、路易体痴呆、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、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
神经退行性疾病是指由慢性进行性中枢神经组织退行性变性而产生的疾病总称，包括阿尔茨海默氏病（Alzheimer’s disease, AD）、帕金森氏病（Parkinson’s disease,PD）、亨廷顿氏病（Huntington disease, HD）、肌萎缩侧索硬化症（Amyotrophic lateralsclerosis, ALS）和多发性硬化症（Multiple sclerosis, MS）等，其发病机制与氧化应激、神经炎症及相应的损伤密切相关。氧化应激是由活性氧（Reactive oxygen species, ROS）自由基介导的，包括超氧阴离子、过氧化氢和羟基自由基等。在正常生理条件下，ROS生成水平与机体抗氧化能力处于动态平衡状态，当ROS的产生超过细胞抗氧化能力则会发生氧化应激（Oxidative stress），而大脑对氧化应激尤为敏感，从而诱发多种神经系统疾病。另有研究发现，血管性痴呆、HIV相关痴呆病、神经性疼痛、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也与机体的氧化应激和神经炎症密切相关。
血管性痴呆（Vascular Dementia, VD）是由各种类型的脑血管疾病（包括缺血性脑血管病、出血性脑血管疾病、急性和慢性缺氧性脑血管疾病等）所致的智能及认知功能障碍的临床综合征。血管性痴呆由于发病机制复杂，目前尚无能够阻滞疾病发展的药物，临床治疗以改善脑部血液循环、脑代谢以及加强脑部营养为主。
阿尔茨海默症（老年痴呆症, AD）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。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。据估计，目前全球有超过5000万人患痴呆症，其治疗护理费用总额在2018年已超过1万亿美元，到2050年患病人数将会增加到1.52亿。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、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。
目前，人体内已经鉴定并表征了两种单胺氧化酶（Monoamine oxidases），包括MAO-A和MAO-B两种亚型，它们主要负责5-羟色胺、多巴胺、去甲肾上腺素和苯乙胺等生物胺和单胺类神经递质的氧化脱氨，以调节其在大脑和周围组织中的浓度和代谢。MAO-B主要分布于神经胶质类细胞的线粒体外膜中，并以黄素腺嘌呤二核苷酸（FAD）为辅酶因子，是脑内对多巴胺进行氧化脱氨的主要酶类。近年研究发现，MAO-B在AD或PD患者大脑中的表达量异常增加，该酶不仅可破坏胆碱能神经元，促进Aβ斑块和神经纤维缠结的产生，同时使脑内多巴胺含量显著下降；此外，在MAO-B催化脱氨的同时还会产生H2O2，而生成的H2O2可与内源性Cu2+、Fe2+等离子通过芬顿反应（Fenton reaction）产生羟基自由基，而羟基自由基又可损害脂质、蛋白质和核酸，从而使线粒体功能紊乱，最终导致大脑神经元细胞死亡。因此，抑制MAO-B的脱氨作用既可以提高脑内多巴胺的含量，还可以通过减少自由基、活性氧的产生达到抗氧化应激和神经保护的作用；另有研究发现，抑制MAO-B还可提高脑内苯乙胺含量，通过苯乙胺又可刺激多巴胺的释放和抑制多巴胺的重摄取。因此，发现MAO-B的选择性抑制剂对治疗和/或预防神经系统相关疾病具有重要意义。
近年来，随着对神经退行性疾病致病机理的不断阐明，发现神经退行性疾病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，构成了该类疾病发生和发展过程中复杂的网络调控系统。显然，研发可同时作用于神经退行性疾病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”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。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是当前的重要方向。
发明内容
本发明目的在于公开一类6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）及其药学上可接受的盐。
本发明另一目的在于公开该类6-(羟基苄氧基)苯酞曼尼希碱类化合物（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6-(羟基苄氧基)苯酞曼尼希碱类化合物（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6-(羟基苄氧基)苯酞曼尼希碱类化合物（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、额颞叶痴呆、Prion病、路易体痴呆、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、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。
本发明所公开的6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）的化学结构通式为：
式中：A表示O、S或NR4，R4表示H、C1~C6烷基；R1表示H、C1~C12烷基、C2~C12烯基、苯甲基、苯乙基，其中烯基中的烯键在R1的任意可能位置，但苯酞母核的3-位为饱和碳；R2和R3各自独立地表示C1~C12烷基、苄基、取代苄基，NR2R3还表示四氢吡咯基、吗啉基、哌啶基、4-位被C1~C12烷基所取代的哌啶基、4-位被苄基取代的哌啶基、4-硫代哌啶基、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；分子中的OH和-CH2NR2R3在相应苯环的任意可能位置；所述“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、三氟甲基、三氟甲氧基、二甲氨基或氰基，这些取代基在苄基的苯环上任意可能的位置。
本发明所公开的6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）可通过以下方法制备得到，其反应式如下：
式中：A、R1、R2和R3的定义与化学结构通式（I）相同，分子中的OH和-CH2NR2R3在相应苯环的任意可能位置。
对于上述合成路线，其具体制备方法描述如下：
以相应的6-(羟基苄氧基)苯酞类化合物（2）为起始原料，在溶剂中与甲醛类化合物、胺类化合物（HNR2R3）经Mannich反应，即得到6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）；其中，反应所用溶剂为：C1-8脂肪醇、乙酸乙酯、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、氯仿、1,4-二氧六环、苯、甲苯、乙腈或C5-8烷烃，优选溶剂为：甲醇、乙醇、异丙醇、N,N-二甲基甲酰胺、四氢呋喃、二氯甲烷或甲苯；甲醛类化合物为：甲醛、三聚甲醛或多聚甲醛；化合物（2）：甲醛类化合物：胺类化合物（HNR2R3）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1.0：1.0~5.0：1.0~5.0；反应温度为0~120℃，优选反应温度为室温~100℃；反应时间为1~72小时，优选反应时间为2~48小时。
按照上述方法所得之6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）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。
本发明所公开的药物组合物包括治疗有效量的一种或多种6-(羟基苄氧基)苯酞曼尼希碱类化合物（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，6-(羟基苄氧基)苯酞曼尼希碱类化合物（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6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）及其药学上可接受的盐进行了如下的生物活性筛选：
（1）6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）对胆碱酯酶的抑制活性
向96孔板中依次加入1.0mmol/L碘化硫代乙酰胆碱或碘化硫代丁酰胆碱30μL、pH7.4的PBS缓冲液40μL、待测化合物溶液20μL（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）溶液30μL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6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）对乙酰胆碱酯酶均具有显著抑制作用，其IC50为12.5nM~18.0µM（例如：实施例化合物1-1-3为0.64µM, 化合物1-1-6为0.89µM, 化合物1-1-7为0.087µM），且该类化合物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50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。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15.5 µM，对丁酰胆碱酯酶抑制的IC50为3.8 µM；并且本发明实施例中所使用的6-(羟基苄氧基)苯酞类化合物（2）（A和R1的定义与化学结构通式（I）相同）对乙酰胆碱酯酶的抑制活性均较弱（其IC50值均大于80µM），表明6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）分子中的-CH2NR2R3取代基在抑制乙酰胆碱酯酶活性中发挥关键作用。进一步构效关系研究发现，在6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）的-CH2NR2R3取代基中，当R2=R3=H时所表示的化合物对乙酰胆碱酯酶的抑制活性也均较弱（其IC50值均大于65µM）。
（2）6-(羟基苄氧基)苯酞曼尼希碱类化合物（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℃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 MultimodeReader (Thermo Scientific)仪中，在485 nm激发波长和535 nm发射波长下连续测定90min。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-AUC blank)/(AUC Trolox-AUC blank)]×[(concentration of Trolox/concentrationof sample)]，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6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）的抗氧化活性为Trolox的0.77～3.2倍，说明该类化合物具有较强抗氧化活性。
（3）6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）与金属离子络合作用的测定
用甲醇溶解CuCl2·2H2O、ZnCl2、FeSO4、AlCl3及待测化合物，配成75μmol/L的溶液，向96孔板中加入100μL待测化合物溶液和100μL金属离子溶液，混匀，室温静置30 min，在Varioskan Flash Multimode Reader仪上记录混合物在200-600 nm范围内的紫外吸收曲线，并以100μL待测化合物溶液和100μL甲醇混合液为对照，观察金属离子与待测化合物混合液的最大吸收峰的红移现象及最大吸收峰的强度。测定结果表明，本发明实施例中所公开的6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）对上述金属离子均表现出络合作用；而本发明实施例中所使用的6-(羟基苄氧基)苯酞类化合物（2）（A和R1的定义与化学结构通式（I）相同）与上述金属离子几乎无络合作用（待测化合物与金属离子混合液的最大吸收峰强度无明显变化，最大吸收峰也无红移现象）。该研究表明，6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）分子中的-CH2NR2R3取代基对化合物的金属离子络合作用有显著影响。
（4）6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）对单胺氧化酶B的抑制活性
用100 mM的pH 7.4磷酸钾缓冲液将重组人MAO-B配成75 μg/mL样品液。向黑色96孔板中加入待测化合物溶液20 μL，单胺氧化酶80 μL，混匀，37°C于避光处孵育15 min，加入200 μM Amplex Red试剂，2U/mL辣根过氧化物酶，2 mM苯甲胺引发反应，37°C孵育20min，在多功能酶标仪上，以固定激发波长545 nm，测590 nm处荧光发射强度，以磷酸钾缓冲液代替MAO-B为空白；化合物抑制单胺氧化酶的抑制率计算公式为：100-(IFi)/(IFc)*100，式中，IFi和IFc分别为存在抑制剂和无抑制剂下的荧光强度与空白荧光强度的差。每个化合物每次测定3个复孔，每组实验独立重复三次。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6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）对MAO-B均具有显著抑制作用，其IC50为0.08µM ~13.5µM（例如：实施例化合物1-1-6为0.94µM, 化合物1-1-7为0.30µM, 化合物1-1-8为1.42µM）；进一步构效关系研究发现，将6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）分子中苯酞母核6-位的“O”用“NH”替换，所得相应化合物的MAO-B抑制均大幅降低，IC50值均大于50 µM。
（5）6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）对神经炎症的抑制活性
（a）化合物和脂多糖（LPS）对BV-2细胞活性的影响
取对数生长期的BV-2细胞配成细胞悬液接种于96孔板，置37℃，5%CO2细胞培养箱内培养24h待细胞贴壁后换为无血清的新鲜培养液90μL，分别加入各浓度待测化合物10μL预孵育30 min，每个浓度3个平行孔，同时设空白对照组；然后加或不加LPS，置37℃，5%CO2细胞培养箱内继续培养24h，加入MTT溶液，37℃孵育4h，弃去上清液，每孔加入200μLDMSO溶液，轻微振荡10min后，用酶标仪在490nm处测定OD值，计算各受试样品不同浓度所测得OD值的均值，并按下列公司计算细胞存活率：细胞存活率（%）= 给药组OD均值/对照组OD均值×100%。测试结果表明，本发明实施例中所公开的所有6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）以及本发明实施例中所使用的6-(羟基苄氧基)苯酞类化合物（2）（A和R1的定义与化学结构通式（I）相同）在不超过30μM浓度下均未显示出细胞毒性（抑制率小于<15%）。
（b）6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）对LPS诱导的BV-2细胞释放NO的影响
取对数生长期的BV-2细胞配成细胞悬液接种于96孔板，置37℃，5%CO2细胞培养箱内培养24 h待细胞贴壁后换为无血清的新鲜培养液90 μL，分别加入各浓度待测化合物10μL预孵育30 min，每个浓度3个平行孔，同时设空白对照组；然后加入LPS刺激，置37℃，5%CO2细胞培养箱内继续培养24 h，取不同处理组细胞培养上清液，加入等体积的Griess试剂I和等体积的Griess试剂II，室温避光反应10 min，在540 nm处测定吸光度以检测细胞上清液中NO水平（具体操作按照NO检测试剂盒说明书进行）。测试结果表明，本发明实施例中所公开的所有6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）在0.5 μM至25 μM浓度范围内均显示出较强的抑制LPS诱导的BV-2细胞NO生成作用（在10.0 μM浓度下的抑制率均超过40.0%），并具有明显的量效关系，表明本发明实施例中所公开的6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）具有显著的抗神经炎症活性。进一步研究发现，本发明实施例中所使用的6-(羟基苄氧基)苯酞类化合物（2）（A和R1的定义与化学结构通式（I）相同）的抗神经炎症活性较6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）稍弱（在10.0 μM浓度下的抑制率为17.5%～32.6%）。
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 6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）的制备通法
将2.0 mmol相应的6-(羟基苄氧基)苯酞类化合物（2）溶于20 ml甲醇中，加入多聚甲醛4.0 mmol和相应的胺类化合物（HNR2R3）3.0 mmol，升温回流搅拌反应2-48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40 ml乙酸乙酯，用20 ml饱和食盐水洗涤，有机层经无水硫酸钠干燥后过滤，减压蒸除溶剂，残余物经硅胶柱层析纯化，得相应的6-(羟基苄氧基)苯酞曼尼希碱类化合物（I），收率32.6%-66.5%，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96.5%。采用上述通法制备得到的目标物结构如下：
；
部分化合物的1H-NMR数据如下：
1H NMR (CDCl3): 7.36(s, 1H), 7.33-7.31 (m, 2H), 7.00 (d, J = 7.6 Hz,1H), 6.93 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.41 (dd, J = 7.2, 4.0 Hz, 1H),5.04 (s, 2H), 3.70 (s, 2H), 2.37 (s, 6H), 2.02-1.97 (m, 1H), 1.78-1.71 (m,1H), 1.45-1.33 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H);
1H NMR (CDCl3): 7.37 (d, J = 1.2 Hz, 1H), 7.31-7.30 (m, 2H), 7.01 (d,J = 7.6 Hz, 1H), 6.90 (s, 1H), 6.83 (d, J = 7.6 Hz, 1H), 5.41 (dd, J = 7.6,4.4 Hz, 1H), 5.04 (s, 2H), 3.85 (s, 2H), 2.67 (brs, 4H), 2.04-1.96 (m, 1H),1.88-1.85 (m, 4H), 1.77-1.69 (m, 1H), 1.48-1.34 (m, 4H), 0.91 (t, J = 7.2 Hz,3H);
1H NMR (CDCl3): 7.37 (s, 1H), 7.33-7.23 (m, 2H), 6.99 (d, J = 7.2 Hz,1H), 6.90 (s, 1H), 6.83 (d, J = 7.2 Hz, 1H), 5.42 (dd, J = 7.6, 4.0 Hz, 1H),5.04 (s, 2H), 3.70 (s, 2H), 2.89-1.98 (brs, 4H), 2.03-1.96 (m, 1H), 1.77-1.70(m, 5H), 1.67-1.64 (m, 6H), 0.88 (t, J = 7.0 Hz, 3H);
1H NMR (CDCl3): 7.36 (s, 1H), 7.33-7.28 (m, 2H), 7.00 (d, J = 7.6 Hz,1H), 6.90 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.41 (dd, J = 7.6, 4.4 Hz, 1H),5.05 (s, 2H), 3.73 (s, 2H), 2.60 (brs, 8H), 2.32 (s, 3H), 2.03-1.96 (m, 1H),1.78-1.69 (m, 1H), 1.50-1.34 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H);
1H NMR (CDCl3): 7.37-7.28 (m, 8H), 7.01 (d, J = 7.6 Hz, 1H), 6.90 (s,1H), 6.84 (d, J = 7.6 Hz, 1H), 5.40 (dd, J = 7.6, 4.4 Hz, 1H), 5.04 (s, 2H),3.78 (s, 2H), 3.65 (s, 2H), 2.60 (q, J = 7.2 Hz, 2H), 2.04-1.95 (m, 1H),1.78-1.70 (m, 1H), 1.50-1.34 (m, 4H), 1.51 (t, J = 7.2 Hz, 3H), 0.90 (t, J =6.8 Hz, 3H);
1H NMR (CDCl3): 9.38 (brs, 1H), 7.46 (s, 1H), 7.34-7.28 (m, 3H), 6.96(d, J = 7.2 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 5.40 (dd, J = 8.0, 3.6 Hz,1H), 5.17 (s, 2H), 3.70 (s, 2H), 2.62-2.42 (m, 4H), 2.01-1.96 (m, 1H), 1.77-1.71 (m, 1H), 1.67-1.64 (m, 4H), 1.48-1.33 (m, 6H), 0.90 (t, J = 6.4 Hz, 3H);
1H NMR (CDCl3): 7.46 (d, J = 1.6 Hz, 1H), 7.34 (dd, J = 8.4, 2Hz, 1H),7.30 (s, 1H), 7.29-7.28 (m, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.78 (t, J = 7.6Hz, 1H), 5.40 (dd, J = 7.6, 4.0 Hz, 1H), 5.18 (s, 2H), 3.81 (s, 2H), 2.65 (q,J = 7.2 Hz, 4H), 2.03-1.95 (m, 1H), 1.77-1.68 (m, 1H), 1.47-1.33 (m, 4H),1.13 (t, J = 7.2 Hz, 6H), 0.90 (t, J = 7.2 Hz, 3H)。
实施例2 6-(羟基苄氧基)苯酞曼尼希碱类化合物（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6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）1.0 mmol和甲醇30 ml，搅拌均匀后加入2.0 mmol相应的酸，室温搅拌反应25分钟后减压蒸除溶剂，残余物经重结晶，即得6-(羟基苄氧基)苯酞曼尼希碱类化合物的盐，其化学结构经1H NMR和ESI-MS确证。
Claims (6)
1.一类6-(羟基苄氧基)苯酞曼尼希碱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：A表示O、S或NR4，R4表示H、C1~C6烷基；R1表示H、C1~C12烷基、C2~C12烯基、苯甲基、苯乙基，其中烯基中的烯键在R1的任意可能位置，但苯酞母核的3-位为饱和碳；R2和R3各自独立地表示C1~C12烷基、苄基、取代苄基，NR2R3还表示四氢吡咯基、吗啉基、哌啶基、4-位被C1~C12烷基所取代的哌啶基、4-位被苄基取代的哌啶基、4-硫代哌啶基、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；分子中的OH和-CH2NR2R3在相应苯环的任意可能位置；所述“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、三氟甲基、三氟甲氧基、二甲氨基或氰基，这些取代基在苄基的苯环上任意可能的位置。
2.如权利要求1所述的6-(羟基苄氧基)苯酞曼尼希碱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6-(羟基苄氧基)苯酞曼尼希碱类化合物与盐酸、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6-(羟基苄氧基)苯酞曼尼希碱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：以相应的6-(羟基苄氧基)苯酞类化合物（2）为起始原料，在溶剂中与甲醛类化合物、HNR2R3经Mannich反应，即得相应的6-(羟基苄氧基)苯酞曼尼希碱类化合物（I）；再与酸通过常规的成盐方法即可制得其药物学上可接受的盐；
式中：A、R1、R2和R3的定义与化学结构通式（I）相同，分子中的OH和-CH2NR2R3在相应苯环的任意可能位置。
4.如权利要求3所述6-(羟基苄氧基)苯酞曼尼希碱类化合物或其药学上可接受的盐的制备方法，其特征在于反应所用溶剂为：C1-8脂肪醇、乙酸乙酯、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、氯仿、1,4-二氧六环、苯、甲苯、乙腈或C5-8烷烃；甲醛类化合物为：甲醛、三聚甲醛或多聚甲醛；化合物（2）：甲醛类化合物：HNR2R3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1~72小时。
5.一类药物组合物，其特征在于包含如权利要求1-2任一项所述的6-(羟基苄氧基)苯酞曼尼希碱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。
6.如权利要求1-2任一项所述的6-(羟基苄氧基)苯酞曼尼希碱类化合物或其药学上可接受的盐在制备治疗和/或预防神经系统相关疾病药物中的用途，这类神经系统相关疾病为：血管性痴呆、阿尔茨海默氏病、额颞叶痴呆、Prion病、路易体痴呆、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、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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