CN105732479B - 一种4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物、制备方法及其用途 - Google Patents
一种4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物、制备方法及其用途 Download PDFInfo
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- CN105732479B CN105732479B CN201610202885.2A CN201610202885A CN105732479B CN 105732479 B CN105732479 B CN 105732479B CN 201610202885 A CN201610202885 A CN 201610202885A CN 105732479 B CN105732479 B CN 105732479B
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Abstract
本发明涉及一种4‑环胺烷氧基‑3‑甲氧基肉桂酸苯酰胺类化合物、制备方法及其用途,该化合物的化学结构通式如(I)所示:式中:m表示1‑12;R1表示C1~C12烷基、苄基、取代苄基;X表示C1~C12烷基、苄基或取代苄基、苯环上被1‑4个选自下组的基团所取代的苯基:F、Cl、Br、I、C1‑4烷基、C1‑4烷氧基、三氟甲基、三氟甲氧基、硝基、氰基,取代基可在苯环的任意可能位置。本发明的化合物对乙酰胆碱酯酶均具有显著抑制作用,其IC50为0.01μM~5μM,对乙酰胆碱酯酶的抑制活性大大高于对丁酰胆碱酯酶的抑制活性,说明本发明所公开的化合物对乙酰胆碱酯酶具有一定的选择性抑制作用。
Description
技术领域
本发明涉及一种治疗和/或预防神经退行性相关疾病药物,具体涉及一种4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物、制备方法及其用途。
背景技术
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,其主要临床表现包括:认知能力、记忆力和社会生活能力的减退以及情感、性格的改变,是一种慢性进行性疾病。在中国、日本等亚洲国家血管性痴呆是老年期痴呆的第一位原因;随着世界人口向老龄化的不断推进,脑血管病日益增多,血管性痴呆发病率有逐渐上升的趋势,严重影响老年人的工作和生活质量,并给社会和家庭带来沉重的经济和精神负担。因此,VD已成为当今老年医学与精神医学领域中一个重要的研究热点。血管性痴呆由于发病机制复杂,尚无能够阻断疾病发展的药物,目前临床治疗以改善脑部血液循环和脑代谢,加强脑部营养为主。
近年来,国内外研究表明,在VD患者表现认知功能损伤的同时也经常伴有胆碱能系统的异常。VD患者海马区ChAT阳性神经元及纤维密度降低,脑内不同部位的ChAT活性下降,在VD患者脑脊液中的ACh浓度明显低于正常水平,并且其浓度降低的程度与痴呆的严重程度呈正相关;而脑缺血可以导致脑内乙酰胆碱酯酶活性上升;同时也发现乙酰胆碱酯酶抑制剂如:HuperzineA和Revastigmine可以保护缺血造成的神经元损伤,且可以促进脑缺血后神经损伤和脑功能的恢复。这表明乙酰胆碱酯酶抑制剂也可用于血管性痴呆的治疗。
阿尔茨海默症(Alzheimer’s disease, AD)是老年人中发病率和致死率最高的疾病之一。阿尔茨海默症国际协会(Alzheimer’s disease International, ADI)发布的《2015全球阿尔茨海默症报告》指出,2015年全球已有超过4600万人患上痴呆症,据预测,到2050年,全球将有1.315亿人口受到痴呆的困扰,其中中国痴呆症患者的发病率已达到6.61%。随着人均生存年龄的延长,本病已发展为社会和医疗保健系统的主要负担,并且为社会、患者及家属带来了沉重的精神和经济压力。因而,研究开发新型老年痴呆治疗药物意义重大。从市场需求来看,阿尔茨海默症国际协会预测,到2050年老年痴呆症治疗药物的全球销售额将达6000亿美元;在我国,随着老年痴呆症发病率的迅速上升,这类药物的市场也快速膨胀。
AD是一种慢性的、以进行性记忆和认知功能损害为特征的多病因、多环节参与的复杂神经退行性疾病,其主要病理学特征为β-淀粉样肽(β-amyloid peptide, Aβ)大量沉积形成的老年斑(Senile plaque, SP)、tau蛋白过度磷酸化形成的神经纤维缠结(Neurofibrillary tangle, NFT),并伴随神经元的凋亡和神经突触的退化等。近年来,许多研究者致力于从分子和细胞水平来揭示AD的发病机理,提出了多种假说,如:胆碱能神经元损伤、淀粉样蛋白的沉积、tau蛋白过度磷酸化、炎症、自由基氧化、金属离子失调等,因此,针对这些发病机制来发展的新型治疗途径和手段,将有希望缓解和改善AD患者的病情。目前临床上有效治疗AD的药物主要有两类:(1)基于神经递质乙酰胆碱不足导致认知功能失调的胆碱能假说,采用乙酰胆碱酯酶抑制剂来提高病人脑内乙酰胆碱水平,如:Tacrine、Donepezil、Ravastigmine、Galantamine;(2)采用N-甲基-D-天冬氨酸(NMDA)受体抑制剂减少谷氨酸盐对神经细胞的损伤,如:Memantine Hydrochloride。但这些药物存在作用靶点单一、毒副作用较多、对AD患者的长期疗效欠佳等问题。因此,研究开发具有新型化学结构、新型作用机制、多作用靶点、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。
发明内容
本发明提供了一种4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物、制备方法及其用途,开发了一种治疗和/或预防神经退行性相关疾病的药物,包括但不限于血管性痴呆、阿尔茨海默氏病、帕金森症、亨廷顿症、HIV相关痴呆症、多发性硬化症、进行性脊髓侧索硬化症、神经性疼痛、青光眼等神经退行性疾病。
为解决上述技术问题,本发明采用的技术方案为:
一种4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物,该化合物的化学结构通式如(I)所示:该化合物的化学结构通式如(I)所示:
,
式中:m表示1-12;
R1表示C1~C12烷基、苄基、取代苄基;
X表示C1~C12烷基、苄基或取代苄基、苯环上被1-4个选自下组的基团所取代的苯基:F、Cl、Br、I、C1-4烷基、C1-4烷氧基、三氟甲基、三氟甲氧基、硝基、氰基,取代基可在苯环的任意可能位置。
进一步,本发明的一种优选方案为:R1表示苄基、2-甲氧基苄基、3-甲氧基苄基、4-甲氧基苄基、2-三氟甲氧基苄基、3-三氟甲氧基苄基、2-甲基苄基、4-甲基苄基、2-三氟甲基苄基、3-三氟甲基苄基、甲基或乙基。
本发明也提供了一种4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的药学上可接受的盐,所述的药学上可接受的盐为4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物与盐酸、氢溴酸、硝酸、硫酸、磷酸、C1-6脂肪羧酸、草酸、苯甲酸、水杨酸、马来酸、富马酸、琥珀酸、酒石酸、柠檬酸、C1-6烷基磺酸、樟脑磺酸、苯磺酸或对甲苯磺酸的反应所生成的盐。
本发明的一种4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的制备方法,包括如下步骤:
第一步、以阿魏酸为起始原料,在第一溶剂和缩合剂条件下与取代苯胺反应,得到相应的阿魏酸苯酰胺类化合物;
第二步、阿魏酸苯酰胺类化合物在第二溶剂和第一碱性条件下与1-取代-4-氯烷基哌啶反应,生成4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物,其化学反应方程式如下:
。
进一步,本发明的一种优选方案为:所述的第一步中:第一溶剂为:四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、C3-8脂肪酮、苯、甲苯、乙腈或C1-8烷烃,优选溶剂为丙酮、四氢呋喃、甲苯、二氯甲烷或氯仿;
缩合剂为:二环己基碳二亚胺、4-二甲氨基吡啶、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和1-羟基苯并三唑中的一种或一种以上的混合物;
阿魏酸:取代苯胺:缩合剂的摩尔投料比为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25~150℃,优选反应温度为25~100℃;
反应时间为1~72小时,优选反应时间为1~24小时。
进一步,本发明的一种优选方案为:所述的第二步中,第一碱性条件所用碱为: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、三乙烯二胺和四丁基氢氧化铵一种或者一种以上的混合物,优选碱为:氢氧化钾、氢氧化钠、碳酸钾、三乙胺、吡啶和甲醇钠中一种或者一种以上的混合物;
第二溶剂为乙醚、四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、氯仿、C3-8脂肪酮、苯、甲苯、乙腈和C5-8烷烃中一种或者一种以上的混合物,优选溶剂为N,N-二甲基甲酰胺、丙酮、乙腈、四氢呋喃和甲苯中一种或者一种以上的混合物;
阿魏酸酯类化合物:1-取代-4-氯烷基哌啶: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1.0:1.0~5.0:1.0~5.0;
反应温度为25~150℃,优选反应温度为25~100℃;
反应时间为1~72小时,优选反应时间为2~24小时。
本发明的一种4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的药学上可接受的盐的制备方法,包括以下步骤:
4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物和丙酮搅拌均匀后加入酸,升温回流搅拌反应15-30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-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的药学上可接受的盐。
本发明的4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的药学上可接受的盐用于制备治疗和/或预防神经退行性相关疾病的药物中的用途。
进一步,本发明的一种优选方案为:所述的4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的药学上可接受的盐在药物中占总重量比10%~99.5%。
本发明的1-取代-4-卤烷基哌啶可用本领域常见的技术值得,包括但不局限于以下文献中所公开的方法: Rodriguez-Franco M.I. et. al. Bioorg. Med. Chem.,2005, 13, 6795-6802. Bolea I. et. al.J. Med. Chem. 2011, 54, 8251-8270。
本发明也公开了一种药物组合物包括治疗有效量的4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的药学上可接受的盐,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合而成的产品;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-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物或其药学上可接受的盐作为活性成分占总重量比10%~99.5%,其余部分为占总重量比90%以下。
本发明的有益效果:
本发明的化合物对乙酰胆碱酯酶均具有显著抑制作用,其IC50为0.005μM~5μM,对乙酰胆碱酯酶的抑制活性大大高于对丁酰胆碱酯酶的抑制活性,说明本发明所公开的化合物对乙酰胆碱酯酶具有一定的选择性抑制作用。
本发明的化合物对过氧化氢诱导的PC12细胞损伤均有显著的保护作用,且在10- 5mol/L浓度下的抗氧化活性均强于阿魏酸。
本发明的化合物对Aβ 1-42自身诱导的聚集均具有显著抑制作用,其IC50为0.05μM~20μM。
本发明所公开的化合物对东莨菪碱致小鼠获得记忆障碍具有剂量依赖性的改善作用,与模型组比较均具有统计学差异(p < 0.01)。
本发明所公开的化合物对乙醇所致小鼠记忆再现功能障碍均具有明显改善作用,与模型组相比均有统计学差异(p < 0.01)。
具体实施方式
下面将结合本发明具体实施例,对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1-15
一种4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的制备方法,包括以下步骤:
第一步、在反应瓶中加入阿魏酸、第一溶剂、缩合剂和和2-甲基苯胺,搅拌反应,反应进程用TLC跟踪;反应结束后,减压蒸除溶剂,残余物中加入二氯甲烷,依次用饱和碳酸钠水溶液和饱和氯化钠水溶液洗涤,有机层经无水硫酸钠干燥后过滤,减压蒸除溶剂,残余物经柱层析纯化(洗脱液:二氯甲烷:甲醇 = 30:1 v/v),得相应的阿魏酸苯酰胺类化合物;
第二步、将上述阿魏酸苯酰胺类化合物溶于第二溶剂中,加入第一碱性条件所用碱和1-(2’-甲氧基)苄基-4-氯乙基哌啶,升温回流搅拌反应,反应进程用TLC跟踪,反应结束后,趁热过滤,少量丙酮洗涤滤饼,滤液减压蒸除溶剂,残余物经柱层析纯化(洗脱液:二氯甲烷:甲醇 = 30:1 v/v),得相应的4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物,其化学结构均经1H-NMR,13C-NMR和ESI-MS确证。
实施例1-15的具体工艺条件见表1-3 。
表1 第一步工艺条件和结果
由表1可知工艺条件对产物的收率具有严重的影响,选择合适的工艺条件对产物收率具有重要的意思。由表1可知第一溶剂采用二氯甲烷:甲苯的体积比2:1,二环己基碳二亚胺:4-二甲氨基吡啶为2:1,摩尔投料比为1:3,反应温度为70℃,反应时间为6h的条件下,收率较好,为83.8%。当第一溶剂采用二氯甲烷:甲苯的体积比2:1,缩合剂采用二环己基碳二亚胺:4-二甲氨基吡啶:氯化锌为2:1:0.05,摩尔投料比为1:3,反应温度为70℃,反应时间为6h的条件下,收率最高,为87.8%。
表2第二步工艺条件和结果
由表2可知工艺条件对产物的收率具有严重的影响,选择合适的工艺条件对产物收率具有重要的影响。由表2可知第二溶剂采用二氯甲烷:甲苯:氯仿=2:1:2,第一碱性条件所用碱为氢氧化钠:碳酸钾:吡啶:甲醇钠为1:2:3:1,摩尔投料比为1:3:2,反应温度为70℃,反应时间为6h的条件下,收率为:97.8%,收率最高,并且改变上述任何一个条件都会对收率产生巨大影响。
实施例16
具体工艺条件与实施例7相同,不同之处再与考察不同取代基,具体取代基见表3,所得4-胺烷氧基-3-甲氧基肉桂酸酯类化合物,其化学结构均经1H-NMR,13C-NMR和ESI-MS确证。
表3 不同取代基实验
。
实施例17
一种4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的药学上可接受的盐的制备方法,包括以下步骤:
分别取表3 中的4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物和丙酮搅拌均匀后加入酸,升温回流搅拌反应15-30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-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的药学上可接受的盐,其化学结构经1HNR和ESI-MS确证。
实施例18
采用实施例7所制备的产物进行生物活性筛选实验
(1)乙酰胆碱酯酶和丁酰胆碱酯酶抑制活性
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10 μL 乙酰胆碱酯酶(大鼠脑皮层 5%匀浆上清液,pH 7.4 的磷酸缓冲液作匀浆介质),加毕混匀后,37 ℃孵育15 min,向各孔中加入质量分数为 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405 nm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化合物对乙酰胆碱酯酶均具有显著抑制作用,其IC50为0.005μM~5μM,而阳性对照药物——Rivastigmine对乙酰胆碱酯酶抑制的IC50为6.3μM;测定结果还表明,本项目实施例中所公开的化合物对乙酰胆碱酯酶的抑制活性大大高于对丁酰胆碱酯酶的抑制活性,说明本发明所公开的化合物对乙酰胆碱酯酶具有一定的选择性抑制作用。
(2)化合物对H2O2诱导的PC12细胞损伤的保护作用筛选
PC12细胞用含10%小牛血清的DMEM培养液,以1×105个/mL密度接种于96孔培养板上,接种体积为100mL/孔,随后放入含5%CO2的37℃恒温培养箱内培养。培养24小时后,给药组中加相应浓度的化合物(终浓度为10-5mol/L,10-6mol/L)10mL/孔,预孵育2小时(对照组与损伤组分别加10μL/孔PBS,使其体积保持相等)。PC12细胞孵育2小时后,在给药组与损伤组中分别加入100μΜH2O2损伤剂10μL/孔(对照组加10μL/孔PBS),30分钟后,将各组的培养液均换成无小牛血清的RPMI1640培养液继续放入恒温培养箱内培养24小时,培养液体积认为100μL/孔。继续培养24小时后,各组加入5 mg/mL,MTT 100μL/孔,进行活细胞染色。待3小时后,各组中加入100%DMSO终止液100μL/孔,充分溶解混匀。在490 nm的波长下测定各组的OD值,测试结果重复3次,用Duncan’s test 方法统计,各组数值表示为均数±S.E.M.,以对照组为100%,给药组及损伤组值以对照组的百分比表示。测定结果表明,本发明实施例中所公开化合物对过氧化氢诱导的PC12细胞损伤均有显著的保护作用,且在10-5mol/L浓度下的抗氧化活性均强于阿魏酸。
(3)化合物抑制Aβ聚集活性测定
取20 μL的Aβ 1-42溶液+20 μL的待测化合物溶液、20 μL的Aβ 1-42溶液+20 μL PBS缓冲液(含2%DMSO)、20 μL PBS缓冲液(含2%DMSO)+20 μL PBS缓冲液(含25%DMSO)于黑色96孔板中,化合物和Aβ 1-42的最终浓度均为25 μM。37°C孵育24 h,然后加入160 μL含有5 μM硫黄素T的50 mM的甘氨酸-NaOH缓冲液(pH = 8.5),振摇5 s后立即用Varioskan FlashMultimode Reader(Thermo Scientific)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录为IFi,Aβ 1-42+PBS缓冲液的荧光值记录为IFc,只含有PBS缓冲液的荧光值记录为IF0,由化合物抑制Aβ 1-42自身聚集的抑制率计算公式为:100-(IFi-IF0)/(IFc-IF0)*100。每个化合物每个浓度测定两个复孔。测定结果表明,本发明实施例中所公开的化合物对Aβ 1-42自身诱导的聚集均具有显著抑制作用,其IC50为0.05μM~20μM,抑制率65-90%,而阳性对照药物——姜黄素和阿魏酸在25μM浓度下对Aβ 1-42自身诱导聚集的抑制率分别为56.2%和28.3%。
(4)血脑屏障透过能力评价(PAMPA-BBB)
将猪脑磷脂(PBL,购自Avanti Polar Lipids, Inc.)溶在十二烷(Sigma)中(20mg/mL),取4 μL滴加在受体孔的亲脂性滤膜上以模拟生物膜。在受体孔中加入350 μL PBS/EtOH(70:30)缓冲液,在供体孔中加入200 μL样品液(化合物溶解在DMSO中得到5 mg/mL储备液,再用50倍PBS/EtOH(70:30)缓冲液稀释至最终浓度为100 mg/mL。放置96孔滤板于PVDF接收板(Millipore)上,使磷脂膜能刚好接触到供体液,如此形成三明治结构-底部是待测物的供体液,中间是人工磷脂膜,待测药物分子从供体孔中扩散,穿过磷脂膜,进入到上层受体孔中。25 °C静止18 h,孵育完毕后,轻轻移走供体板,分别吸取受体液和供体液,用Varioskan Flash Multimode Reader酶标仪测定浓度,每个样品四孔,独立测试三次,测试10个波长(250-450 nm)下的OD值,依据公式得出有效透过率(P e)。PAMPA有效渗透率P e(cm·s−1) 计算如下:
P e = −V d V a/[(V d + V a)At]ln(1 − drugacceptor/drugequilibrium)
其中,V d是供体孔的体积,V a是受体孔的体积,A是人工磷脂膜的面积,t表示渗透时间,drug acceptor是供体孔液体的吸光度,drug equilibrium是理论平衡吸光度,结果以均值±标准误差(Stand error, S.E.)表示。测试结果表明,在该实验条件下本发明所公开的化合物均具有良好的血脑屏障透过能力,且强于阿魏酸。
(5)化合物对东莨菪碱所致小鼠记忆获得障碍的影响
SPF级ICR雄性小鼠,25-30g,随机分为:正常组、模型组、受试药高、低剂量组(5.0、2.5mg/kg),每组10只动物。一次性灌胃给予受试药物,空白组和模型组给予溶媒0.5%CMC-Na,给药体积均为0.1ml/10g;药后45min,正常组小鼠腹腔注射生理盐水,其余各组动物均注射东莨菪碱(5 mg/kg),给药体积均为0.1 ml/10g;造模30min后,将小鼠放入非电刺激Y迷宫进行行为学测试。测试时将小鼠放于一臂末端,让其在迷宫内自由穿行8min,记录其进入各臂的次数和交替次数,按照以下公式计算交替率:交替率%=[交替次数/(总进入次数-2)] ×100,结果以均数±标准差表示,组间差异采用单因素方差分析。测定结果表明,在该实验条件下,本发明所公开的化合物对东莨菪碱致小鼠获得记忆障碍具有剂量依赖性的改善作用,与模型组比较均具有统计学差异(p < 0.01)。
行为实验完毕立即将小鼠断头取脑,用预冷生理盐水冲洗,在冰盒上迅速分离出脑海马组织,称取海马组织重量,加9倍4 °C生理盐水制成10%的匀浆,3500 r.min-1,4 °C离心15 min,-20 °C储存上清液待测,通过考马斯亮蓝测定总蛋白浓度。按照试剂盒规定的方法在412 nm的波长下测定AChE含量,AChE活力表示为U/mg。ChAT的活力通过ChAT催化的ACh合成反应来测定。操作方法同样根据试剂盒的说明,在412 nm波长下测定,ChAT的活力用U/mg来表示。测定结果表明,在该实验条件下,本发明所公开的化合物能够增强乙酰胆碱转移酶(ChAT)的活力,与空白组比较均具有统计学差异(p < 0.01)。
(6)化合物对乙醇所致小鼠记忆再现障碍的影响
SPF级ICR雄性小鼠,25-30g,随机分为:正常组、模型组、受试药高、低剂量组(5.0、2.5mg/kg)、卡巴拉汀组(3mg/kg),每组10只动物。每天灌胃给受试药物,空白组和模型组给予溶媒0.5%CMC-Na,给药体积均为0.1 ml/10g,连续给药32天;在给药1~24天期间,每日药后30min,模型组和各给药组灌胃0.1 ml/10g乙醇(15% w/v),连续给药24天,撤掉乙醇进入乙醇洗净期,药物继续给予;于给药的31、32天进行动物跳台实验,药后45min进行训练或测试实验,训练时让小鼠置于跳台仪中,轻放于平台上通电,当动物从台上调下时以双足同时接触铜栅为触电,视为错误反应,小鼠受到电击后的正常回避反应为逃避到平台上,记录小鼠逃避至平台上的潜伏期,并记录5min内触电次数,以此作为学习成绩。24小时后进行测试,记录小鼠第一次跳下受电击的时间(潜伏期)及其5min内受电击的次数(错误次数),以此作为记忆再现功能评价指标。测试结果以均数±标准差表示,组间差异采用单因素方差分析。测试结果表明,在该实验条件下本发明所公开的化合物对乙醇所致小鼠记忆再现功能障碍均具有明显改善作用,与模型组相比均有统计学差异(p < 0.01)。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.一种4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物,其特征在于:该化合物的化学结构通式如(I)所示:
,
式中:m表示1-12;
R1表示C1~C12烷基、苄基、2-甲氧基苄基、3-甲氧基苄基、4-甲氧基苄基、2-三氟甲氧基苄基、3-三氟甲氧基苄基、2-甲基苄基、4-甲基苄基、2-三氟甲基苄基、3-三氟甲基苄基;
X表示C1~C12烷基、苄基或取代苄基、苯环上被1-4个选自下组的基团所取代:F、Cl、Br、I、C1-4烷基、C1-4烷氧基、三氟甲基、三氟甲氧基、硝基、氰基,取代基可在苯环的任意可能位置。
2.一种如权利要求1所述的4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的药学上可接受的盐,其特征在于:所述的药学上可接受的盐为4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物与盐酸、氢溴酸、硝酸、硫酸、磷酸、C1-6脂肪羧酸、草酸、苯甲酸、水杨酸、马来酸、富马酸、琥珀酸、酒石酸、柠檬酸、C1-6烷基磺酸、樟脑磺酸、苯磺酸或对甲苯磺酸的反应所生成的盐。
3.一种制备如权利要求1所述4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的方法,其特征在于:包括如下步骤:
第一步、以阿魏酸为起始原料,在第一溶剂和缩合剂条件下与取代苯胺反应,得到相应的阿魏酸苯酰胺类化合物,其中,第一溶剂为:四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、C3-8脂肪酮、苯、甲苯、乙腈或C1-8烷烃,缩合剂为:二环己基碳二亚胺、4-二甲氨基吡啶、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和1-羟基苯并三唑中的一种或一种以上的混合物;阿魏酸:取代苯胺的摩尔投料比为1.0:1.0~10.0,反应温度为25~150℃,反应时间为1~72小时;
第二步、阿魏酸苯酰胺类化合物在第二溶剂和第一碱性条件下与1-取代-4-氯烷基哌啶反应,生成4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物,其中,第一碱性条件所用碱为: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、三乙烯二胺和四丁基氢氧化铵一种或者一种以上的混合物,第二溶剂为乙醚、四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、氯仿、C3-8脂肪酮、苯、甲苯、乙腈和C5-8烷烃中一种或者一种以上的混合物,阿魏酸苯酰胺类化合物:1-取代-4-氯烷基哌啶:碱的摩尔投料比为1.0:1.0~10.0:1.0~10.0,反应温度为25~150℃,反应时间为1~72小时。
4.根据权利要求3所述的4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的制备方法,其特征在于:所述第一步中,第一溶剂为:丙酮、四氢呋喃、甲苯、二氯甲烷或氯仿,阿魏酸:取代苯胺的摩尔投料比为1.0:1.0~5.0,反应温度为25~100℃,反应时间为1~24小时。
5.根据权利要求3所述的4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的制备方法,其特征在于:所述的第二步中,第一碱性条件所用碱为:氢氧化钾、氢氧化钠、碳酸钾、三乙胺、吡啶和甲醇钠中一种或者一种以上的混合物,第二溶剂为N,N-二甲基甲酰胺、丙酮、乙腈、四氢呋喃和甲苯中一种或者一种以上的混合物,阿魏酸苯酰胺类化合物:1-取代-4-氯烷基哌啶:碱的摩尔投料比为1.0:1.0~5.0:1.0~5.0,反应温度为25~100℃,反应时间为2~24小时。
6.一种如权利要求2所述的4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的药学上可接受的盐的制备方法,其特征在于,包括以下步骤:
4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物和丙酮搅拌均匀后加入酸,升温回流搅拌反应15-30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-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的药学上可接受的盐。
7.权利要求6所制备的4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的药学上可接受的盐用于制备治疗和/或预防神经退行性相关疾病的药物中的用途。
8.根据权利要求7所述的用途,其特征在于:所述的4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物的药学上可接受的盐在药物中占总重量比10%~99.5%。
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