CN115724779A - 酰胺烷二硫化合物、其制备方法和用途 - Google Patents
酰胺烷二硫化合物、其制备方法和用途 Download PDFInfo
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- CN115724779A CN115724779A CN202111022116.1A CN202111022116A CN115724779A CN 115724779 A CN115724779 A CN 115724779A CN 202111022116 A CN202111022116 A CN 202111022116A CN 115724779 A CN115724779 A CN 115724779A
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- acid
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- amidoalkanedisulfide
- disease
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Abstract
本发明公开了一类酰胺烷二硫化合物（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，涉及一类酰胺烷二硫化合物（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。
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酰胺烷二硫化合物（I）及其药学上可接受的盐。
本发明另一目的在于公开该类酰胺烷二硫化合物（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酰胺烷二硫化合物（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酰胺烷二硫化合物（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。
本发明所公开的酰胺烷二硫化合物（I）的化学结构通式为：
式中：
本发明所公开的酰胺烷二硫化合物（I）可通过以下方法制备得到：
以相应的胺烷基二硫化合物（1）和氨基被Boc（叔丁氧羰基）保护的氨基酸类化合物（2）为起始原料，在适当溶剂和缩合剂条件下缩合，得相应的酰胺类中间体（3）；然后在酸性条件下脱除Boc保护基即得到相应的酰胺烷二硫化合物（I）；其反应式如下：
式中：R和n的定义与酰胺烷二硫化合物（I）的化学结构通式相同；R1表示R中的氨基被Boc保护后的取代基。
对于上述合成路线，其具体制备方法描述如下：
步骤A)：胺烷基二硫化合物（1）和氨基被Boc保护的氨基酸类化合物（2）在适当溶剂和缩合剂作用下缩合，得相应的酰胺类中间体（3）；其中，反应所用溶剂为：吡啶、N,N-二甲基甲酰胺、二甲基亚砜、C3-8脂肪酮、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙二醇二甲醚、C1-6脂肪酸与C1-6脂肪醇所形成酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯、乙腈或C5-8烷烃，优选溶剂为：四氢呋喃、二氯甲烷、氯仿或乙腈；所用缩合剂为：碳酰二咪唑（CDI）、氯甲酸C1-8脂肪醇酯类化合物（如：氯甲酸乙酯、氯甲酸叔丁酯、氯甲酸苄酯等）、N-乙氧羰基-2-乙氧基-1,2-二氢喹啉（EEDQ）、碳二亚胺类化合物（如：二环己基碳二亚胺（简称为DCC）、1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐（简称为EDCI））、氰基磷酸二乙酯（DEPC）、2-氯-4,6-二甲氧基-1,3,5-三嗪（简称为CDMT）、氯化4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉盐（简称为DMTMM），优选缩合剂为：CDI、氯甲酸乙酯、DCC、EDCI、DMTMM；化合物（1）：化合物（2）：缩合剂的摩尔投料比为1.0：2.0~8.0：2.0~8.0，优选摩尔投料比为1.0：2.2~6.0：2.2~6.0；缩合反应温度为0~100℃，优选反应温度为室温~60℃；缩合反应时间为1~72小时，优选反应时间为2~48小时。
步骤B)：由步骤A)得到的酰胺类中间体（3）在酸性条件下脱除Boc保护基得相应的酰胺烷二硫化合物（I）；其中，反应所用酸为：盐酸、硫酸、苯磺酸、对甲苯磺酸、樟脑磺酸、C1-6烷基磺酸、磷酸、高氯酸、三氟乙酸、三氟甲磺酸或硝酸，优选酸为盐酸、三氟乙酸、对甲苯磺酸、甲烷磺酸或乙烷磺酸；酰胺类中间体（3）：酸的摩尔投料比为1.0：0.1~10.0，优选摩尔投料比为1.0：0.3~5.0，反应温度为0~100℃，优选反应温度为室温~60℃；反应时间为1~60小时，优选反应时间为2~48小时。
按照上述方法所得之酰胺烷二硫化合物（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酰胺烷二硫化合物（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，酰胺烷二硫化合物（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%。
本发明所公开的酰胺烷二硫化合物（I）及其药学上可接受的盐进行了如下的生物活性筛选：
（1）酰胺烷二硫化合物（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酰胺烷二硫化合物（I）的抗氧化活性为Trolox的0.56～2.0倍，说明该类化合物具有较强抗氧化活性；测试结果还发现，将实施例中的酰胺烷二硫化合物（I）中的S原子用CH2替换，所得相应化合物几乎无抗氧化活性（其抗氧化强度均小于Trolox的0.12倍）。
（2）酰胺烷二硫化合物（I）对Aβ1-42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Aβ1-42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Aβ1-42溶液+20μL的待测化合物溶液、20μL的Aβ1-42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446nm激发波长和490nm发射波长下测定荧光值；Aβ1-42+待测化合物的荧光值记为IFi，Aβ1-42+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Aβ1-42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酰胺烷二硫化合物（I）对Aβ1-42自身聚集均具有显著抑制活性，在20.0 µM浓度下对Aβ1-42自身聚集的抑制率在28.5%～62.0%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、以及所用起始原料胺烷基二硫化合物（1）在20.0 µM浓度下对Aβ1-42自身聚集的抑制率均小于16.0%；测试结果还发现，将实施例中的酰胺烷二硫化合物（I）中的S原子用CH2替换，所得相应化合物对Aβ1-42自身聚集的抑制率均显著降低（其抑制率均小于20%）。
（3）酰胺烷二硫化合物（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酰胺烷二硫化合物（I）、所用起始原料——胺烷基二硫化合物（1）在不超过30μM浓度下均未显示出细胞毒性（抑制率小于<10%）。
（b）酰胺烷基硫醇缩酮类化合物（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酰胺烷二硫化合物（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5.0 μM浓度下的抑制率均超过30.0%），并具有明显的量效关系，表明本发明实施例中所公开的酰胺烷二硫化合物（I）具有显著的抗神经炎症活性。研究还发现，本发明实施例中所用起始原料—胺烷基二硫化合物（1）也具有显著抗神经炎症活性（在5.0 μM浓度下对LPS诱导的BV-2细胞NO生成的抑制率均超过16.0%）。
（4）酰胺烷二硫化合物（I）对NaNO2所致小鼠学习记忆巩固障碍的影响
亚硝酸钠（NaNO2）能将红细胞中的血红蛋白氧化为高铁血红蛋白，且高剂量的NaNO2可使体内还原型小分子（GSH）及还原酶系（SOD、GPx、GR）的含量显著下降，进而引起脂质过氧化和蛋白质羰基化，导致氧化应激，因此NaNO2诱导的小鼠模型常被用于抗氧化应激候选药物的体内活性筛选。
SPF级ICR小鼠，雌雄各半，初始体重为18-22克，随机分为：正常组、模型组、阳性对照组（盐酸多奈哌齐）、受试药高中低剂量组，每组10只。跳台试验前，向各组小鼠分别给予相应的化合物（每天2次，中间间隔12小时，持续4天），正常组和模型组小鼠给予同等体积的生理盐水，受试药高中低剂量组分别给予相应药生理盐水溶液（25.0 mg/kg、10.0 mg/kg、4.0 mg/kg）；在第三天第二次给药后1.0小时，将小鼠置于跳台仪适应3分钟，然后再将其置于圆形平台，通以36V交流电训练5分钟，记录小鼠第一次跳下平台的时间作为训练潜伏期；训练后向除正常组的各组小鼠皮下注射NaNO2生理盐水溶液（90.0 mg/kg）；次日最后一次给药后1小时，再用跳台仪对小鼠进行测试，记录小鼠第一次跳下平台的时间作为测试潜伏期，以及在5分钟内跳下平台被电击的次数作为错误次数。行为学测试结束后将小鼠断头取脑，并在冰层上分离小鼠大脑皮层，然后按测试要求进行匀浆，匀浆上清液用于小鼠大脑皮层丙二醛（MDA）和SOD含量测定。
测定结果表明，所测试的酰胺烷二硫化合物（I）（实施例化合物2-4、2-16、2-18）在高、中、低剂量下对NaNO2致小鼠学习记忆巩固障碍均具有改善作用（延长潜伏期并减少错误次数），与模型组比较均有统计学差异（p<0.001），且活性显著高于相同剂量下的相应胺烷基二硫化合物（1）（p<0.001），也强于相同剂量下的临床用药盐酸多奈哌齐（p<0.01）。另外，测定结果还显示，所测试的酰胺烷二硫化合物（I）在高、中、低剂量下均可不同程度地降低小鼠大脑皮层的MDA含量，并提升SOD活性，具有剂量依赖性，其作用也显著高于相同剂量下的相应胺烷基二硫化合物（1）（p<0.001）；因此本发明实施例中所公开的酰胺烷二硫化合物（I）可缓解由NaNO2引起的小鼠中枢氧化应激。
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 酰胺类中间体（3）的制备通法
在反应瓶中依次加入2.0 mmol胺烷基二硫化合物（1）、5.0 mmol相应的氨基被Boc保护的氨基酸类化合物（2）和30 ml二氯甲烷，室温搅拌均匀后加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐5.0 mmol和三乙胺5.0 mmol，继续室温搅拌反应4~40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70 mL二氯甲烷，依次用30 mL去离子水，30 mL饱和Na2CO3水溶液和30 mL饱和NaCl水溶液洗涤，有机层经无水硫酸钠干燥后过滤，减压蒸除溶剂，残余物即为酰胺类中间体（3），无需纯化即可用于下步反应。
实施例2 酰胺烷二硫化合物（I）的制备通法
将实施例1所得酰胺类中间体（3）（约2.0 mmol）溶于30 ml二氯甲烷中，在冷却下加入6.0 mmol三氟乙酸，室温搅拌反应3～20.0小时（反应进程用TLC跟踪）；反应结束后，加入50 mL去离子水，用饱和Na2CO3水溶液调节反应液pH至碱性，用100 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Na2SO4干燥后过滤，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=15～30/1 v/v），即得相应的目标物（两步总收率：50.3%～84.8%），其结构均经1H-NMR、13C-NMR和ESI-MS确证，化合物纯度经HPLC测定均大于97.0%；采用上述通法制备得到的目标物结构如下：
实施例3 酰胺烷二硫化合物（I）与酸成盐制备通法
在反应瓶中加入按照上述实施例2所得之酰胺烷二硫化合物（I）1.0 mmol和甲醇35 ml，搅拌均匀后加入3.0 mmol相应的酸，室温搅拌反应20分钟后减压蒸除溶剂，残余物经重结晶，即得酰胺烷二硫化合物的盐，其化学结构经1H NMR和ESI-MS确证。
Claims (8)
1.一类酰胺烷二硫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：
2.如权利要求1所述的酰胺烷二硫化合物或其药学上可接受的盐，其特征在于
优选自L-丙氨酸、L-缬氨酸、L-酪氨酸、L-苯丙氨酸或L-γ-谷氨酸的残基。
3.如权利要求1-2所述的酰胺烷二硫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酰胺烷二硫化合物与盐酸、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。
4.如权利要求1-3任一项所述酰胺烷二硫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：R和n的定义与酰胺烷二硫化合物（I）的化学结构通式相同；R1表示R中的氨基被Boc保护后的取代基；
步骤A)：相应的胺烷基二硫化合物（1）和氨基被Boc保护的氨基酸类化合物（2）在溶剂和缩合剂条件下缩合，得相应的酰胺类中间体（3）；
步骤B)：由步骤A)得到的酰胺类中间体（3）在酸性条件下脱除Boc保护基，得相应的酰胺烷二硫化合物（I）；
按照上述方法所得之酰胺烷二硫化合物（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。
5.如权利要求4所述酰胺烷二硫化合物或其药学上可接受的盐的制备方法，其特征在于步骤A)中，反应所用溶剂为：吡啶、N,N-二甲基甲酰胺、二甲基亚砜、C3-8脂肪酮、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙二醇二甲醚、C1-6脂肪酸与C1-6脂肪醇所形成酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯、乙腈或C5-8烷烃；所用缩合剂为：碳酰二咪唑、氯甲酸C1-8脂肪醇酯类化合物、N-乙氧羰基-2-乙氧基-1,2-二氢喹啉、碳二亚胺类化合物、1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐、氰基磷酸二乙酯、2-氯-4,6-二甲氧基-1,3,5-三嗪、氯化4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉盐；化合物（1）：化合物（2）：缩合剂的摩尔投料比为1.0：2.0~8.0：2.0~8.0；缩合反应温度为0~100℃；缩合反应时间为1~72小时。
6.如权利要求4所述酰胺烷二硫化合物或其药学上可接受的盐的制备方法，其特征在于步骤B)中，反应所用酸为：盐酸、硫酸、苯磺酸、对甲苯磺酸、樟脑磺酸、C1-6烷基磺酸、磷酸、高氯酸、三氟乙酸、三氟甲磺酸或硝酸；酰胺类中间体（3）：酸的摩尔投料比为1.0：0.1~10.0，反应温度为0~100℃；反应时间为1~60小时。
7.一类药物组合物，其特征在于包含如权利要求1-3任一项所述的酰胺烷二硫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1-3任一项所述的酰胺烷二硫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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