CN106749188B - 一种n-(苄基哌啶基)-阿魏酰胺-o-烷基胺类化合物、制备方法及其用途 - Google Patents
一种n-(苄基哌啶基)-阿魏酰胺-o-烷基胺类化合物、制备方法及其用途 Download PDFInfo
- Publication number
- CN106749188B CN106749188B CN201710058531.XA CN201710058531A CN106749188B CN 106749188 B CN106749188 B CN 106749188B CN 201710058531 A CN201710058531 A CN 201710058531A CN 106749188 B CN106749188 B CN 106749188B
- Authority
- CN
- China
- Prior art keywords
- benzyl piepridine
- alkyl amine
- acid
- piepridine base
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种N‑(苄基哌啶基)‑阿魏酰胺‑O‑烷基胺类化合物、制备方法及其用途,其制备方法包括以下步骤:第一步:以阿魏酸和苄基哌啶类化合物为起始原料,在溶剂和缩合剂作用下缩合,得中间体化合物;第二步:中间体化合物在溶剂和碱性条件下与二溴烷烃反应,得溴化合物中间体;第三步:溴化合物中间体在溶剂和碱性条件下与仲胺反应得N‑(苄基哌啶基)‑阿魏酰胺‑O‑烷基胺类化合物。该类化合物为选择性丁酰胆碱酯酶抑制剂、且能够抑制Aβ聚集,还具有抗氧化作用和神经细胞保护作用,进一步在体内实验中展现出较好的治疗阿尔茨海默病的作用,且毒性较低,具备很好的临床应用前景。
Description
技术领域
本发明属于药物化学领域,尤其是涉及一种N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物、制备方法及其用途。
背景技术
阿尔茨海默氏症(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,随着全球人口的急速老龄化,老年人群的健康问题已经成为当前迫切需要解决的社会重大问题。阿尔茨海默症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 diseaseInternational,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。
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。中国专利公开号CN 101053567 A公开了一种乙酰胆碱酷酶抑制剂、其制备方法和其应用,该发明提供一种以化合物茴香醛-石杉碱甲缩醛亚胺或香兰素-石杉碱甲缩醛亚胺或肉桂醛-石杉碱甲缩醛亚胺为活性化合物的乙酞胆碱酷酶抑制剂,它们的制备方法,以及它们在制备抗乙酞胆碱酷酶抑制剂药物中、在制备治疗早老性疾呆症药物中、和制备抗中老年记忆和认知能力减退疾病药物中的应用。中国专利公开号CN 1273135 C公开了一种N-甲基-D-天冬氨酸(NMDA)受体拮抗剂(1S,2S)-1-(4-羟基苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的稳定药物组合物,该药物组合物的制备方法以及该药物组合物的用途,用于治疗中风,脊髓损伤,脑外伤,多发性梗塞性痴呆,CNS退行性疾病,如阿尔茨海默氏疾病等。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具有新型作用机制的AD治疗药物。
AD属多种因素引起的疾病,发病机理复杂,至今还未完全阐明其发病机制,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、tau-蛋白过度磷酸化导致的神经纤维缠结、氧化应激产生大量的活性氧(ROS)和自由基以及神经验证反应等多种因素在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。基于上述结果,研究人员提出了“多靶点导向药物”(Multitarget-directedLigands,MTDLs)策略来研发抗神经退行性疾病药物。所谓“多靶点导向药物”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,此类药也称为“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、低毒副作用的抗阿尔茨海默病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。到目前为止,多靶点抑制剂吸引了更多科研工作者的关注。尽管多靶点的优势是清晰的,但多个靶点功能如何在同一个分子中组合,及如何选择最合适治疗靶点仍然是一个关键点。
最近研究表明,随着AD的进程的发展,乙酰胆碱酯酶(AChE)水平逐渐减低,而丁酰胆碱酯酶(BuChE)活性增加到了正常值的165%。在AD的中重度阶段,BuChE取代AChE来水解乙酰胆碱(ACh),BuChE的抑制可能在AD治疗中是更有效的。另外,根据β-淀粉样蛋白级联假说,脑内低聚物Aβ的产生和聚集引发了致病的发生,最终导致了神经元丢失和痴呆,Aβ能够进入线粒体诱导氧化应激,同时氧化应激存在于AD患者脑内,并通过自由基的产生促进Aβ毒性,进一步恶化AD进程(Proc.Natl.Acad.Sci.U.S.A.2005,102,17213-17218.J.Med.Chem.59(2016)7683-7689.)。因此,发现具有选择性抑制丁酰胆碱酯酶、Aβ聚集和具有抗氧化活性的神经保护剂可能为AD,尤其是中重度AD带来曙光。
发明内容
有鉴于此,本发明的目的是针对现有技术的不足,提供一种N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物、制备方法及其用途,该类化合物能够选择性抑制丁酰胆碱酯酶、抑制Aβ聚集,还具有抗氧化和神经细胞保护作用,进一步在体内实验中展现出较好的治疗阿尔茨海默病的作用,且毒性较低,具备很好的临床应用前景。
为达到上述目的,本发明采用以下技术方案:
一种N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物,该类化合物的化学通式如(I)所示:
式中:n表示2-12;
X表示H、甲氧基、C1~C12烷基、卤素、二甲氨基,取代基可在苯环的任意可能位置;
NR1R2表示1,2,3,4-四氢异喹啉、苄基哌啶、苄基哌嗪、苄基甲基胺、1-(2-吡啶基)哌嗪、1-(2-嘧啶基)哌嗪。
本发明还提供一种N-(苄基哌啶基)-阿魏酰胺-O-烷基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N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物与盐酸、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反应所生成的盐。
本发明还提供了一种N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物的制备方法,包括以下步骤:
第一步:以阿魏酸和苄基哌啶类化合物为起始原料,在溶剂和缩合剂作用下缩合,得中间体化合物;
第二步:中间体化合物在溶剂和碱性条件下与二溴烷烃反应,得溴化合物中间体;
第三步:溴化合物中间体在溶剂和碱性条件下与仲胺反应得N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物;
其化学反应方程式如下所示:
进一步的,所述第一步中缩合剂为EDCI和HOBT、DCC和DMAP或卡特缩合剂中的一种。
进一步的,所述第二步和第三步中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、有机叔胺类或者季胺碱类;
所述第一步、第二步和第三步中的溶剂为乙醚、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烷烃中一种或几种。
进一步的,所述第一步阿魏酸、苄基哌啶类化合物和缩合剂的摩尔投料比为1.0:1.0~10.0:1.0~10.0,优摩尔投料比为1:1.5:1.5;反应温度为0~150℃,优选反应温度为65℃;反应时间为1~120小时,优选反应时间为6~10小时。
进一步的,所述第二步中间体化合物、二溴烷烃和碱的摩尔投料比为1.0:1.0~10.0:1.0~10.0,优摩尔投料比为1:1.5:1.5;反应温度为0~150℃,优选反应温度为65℃;反应时间为1~120小时,优选反应时间为6~10小时。
进一步的,所述第三步溴化合物中间体、仲胺和碱的摩尔投料比为1.0:1.0~10.0:1.0~10.0,优选摩尔投料比为1:1.5:1.5;反应温度为0~150℃,优选反应温度为65℃;反应时间为1~120小时,优选反应时间为6~10小时。
本发明的的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物或其药学上可接受的盐在制备治疗和/或预防阿尔茨海默病药物中的用途。
进一步的,所述N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物或其药学上可接受的盐在药物中总比重为5%-99.5%。
利用上述方法所得的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物分子中含有氨基,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学上可接受的盐。本发明所公开的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物或其或其药学上可接受的盐可与多种药学上可接受的载体或赋形剂制备成药物,用于治疗治疗和/或预防阿尔茨海默病,其中“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。药物中理想的成分比例是N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物或其药学上可接受的盐作为活性成分总重量比为5%-99.5%,其余部分为占总重量比95%以下。
本发明的有益效果是:
本发明公开了一种N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物,该化学物经生物活性试验验证:
1、对乙酰胆碱酯酶和丁酰胆碱酯酶均具有显著的抑制活性,且对丁酰胆碱酯酶的抑制活性高于对乙酰胆碱酯酶的抑制活性,说明该类化合物能够选择性抑制丁酰胆碱酯酶;
2、对Aβ1-42自身聚集具有显著的抑制活性,其抑制率为36.3%-99.5%,阳性药姜黄素的抑制率为46.8%;而广泛使用的抗AD药多奈哌齐在25.0μM浓度下对Aβ1-42自身聚集的抑制率小于5%;
3、对自身诱导的Aβ1-42聚集具有显著的解聚作用,解聚率为35%~95%,姜黄素在相同浓度下的解聚率为57.2%;
4、抗氧化活性为Trolox的0.4-1.0倍,具有强抗氧化活性;
5、对H2O2诱导的PC12细胞损伤由显著的神经保护;
6、急性毒性试验表明具有较低的毒性;
7、对东莨菪碱所致小鼠记忆再现功能障碍均具有明显改善作用。
因此,可用于制备治疗和/或预防阿尔茨海默病药物,具有良好的临床应用前景。
另外本发明还提供了N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物的制备方法,还对制备工艺进行优化,目的产物的得率为25-90%。
附图说明
图1为N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物(I-15)对过氧化氢诱导PC12细胞的神经保护作用测定。
图2为N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物(I-15)对东莨菪碱所致小鼠记忆再现功能障碍模型评价。
具体实施方式
下面结合具体实施例和附图对本发明作进一步描述。
实施例1
一种N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物的制备方法,其化学反应方程式如下:
包括以下步骤,具体X、n以及NR1R2见表1所示,具体参数见表2:
第一步:将阿魏酸1(150mg,0.772mmol)、EDCI(3.54g,0.926mmol)、HOBT(178mg,0.926mmol)和二氯甲烷加入反应瓶中,搅拌均匀后加入苄基哌啶类化合物2(0.926mmol),加毕,室温搅拌过夜,TLC监测;反应结束后,减压蒸除溶剂,残余物中加入水(40mL),用二氯甲烷(40mL×2)萃取,有机层合并后用饱和氯化钠水溶液(40mL)洗涤,无水硫酸钠干燥,过滤,滤液减压蒸除溶剂,残余物以硅胶柱层析纯化(洗脱剂:石油醚/丙酮=20/1v/v),得中间体化合物3,其中阿魏酸1:苄基哌啶类化合物2:缩合剂的摩尔投料比为1:1.2:2.4;
第二步:将中间体化合物3(1mmol)、二溴烷烃4(2.2mmol)和乙腈(10mL)加入反应瓶中,在碳酸钾(1.2mmol)条件下,升温至65℃反应,TLC监测反应,反应结束后,减压蒸干溶剂,经常规处理后,所得粗品经硅胶柱层析纯化(洗脱剂:二氯甲烷/丙酮=50/1v/v),得溴化合物中间体5,其中中间体化合物:二溴烷烃:碱的摩尔投料比为1:2.2:1.2。
第三步:将溴化合物中间体5(1mmol)、仲胺NR1R2(1.2mmol)和乙腈(10mL)加入反应瓶中,在碳酸钾(1.2mmol)条件下,升温至65℃反应,TLC监测反应,反应结束后,减压蒸干溶剂,经常规处理后,所得粗品经硅胶柱层析纯化(洗脱剂:二氯甲烷/丙酮=30/1v/v),得相应的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物(I),其中溴化合物中间体:仲胺:碱性的摩尔投料比为1:1.2:1.2。
实施例2-90
实施例2-90均按照实施例1的方法制备表1中的目标产物其化学结构均经1H NMR、13C NMR和ESI-MS确证。
表1本发明实施例1-90的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物
本发明制备的表1中的部分目标化合物N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物的1HNMR、13C NMR和ESI-MS数据如下:
目标化合物I-8的制备,操作过程同实施例1,得淡黄色油状物,59.2%收率.1HNMR(400MHz,CDCl3)δ7.60(d,J=15.6Hz,1H,C=CH),7.33-7.17(m,8H,8×Ar-H),7.13(d,J=7.6Hz,2H,2×Ar-H),7.07(d,J=8.0Hz,1H,Ar-H),7.03(s,1H,Ar-H),6.86(d,J=8.4Hz,1H,Ar-H),6.76(d,J=15.2Hz,1H,C=CH),4.69(t,J=6.0Hz,1H,1/2phCH2),4.08(t,J=6.0Hz,3H,1/2phCH2+OCH2),3.86(s,3H,OCH3),3.50(s,2H,phCH2),3.03-2.99(m,1H,1/2NCH2),2.68-2.65(m,1H,1/2NCH2)2.57-2.49(m,12H,6×NCH2),2.05-1.98(m,2H,CH2),1.80-1.76(m,1H,CH),1.72(d,J=13.6Hz,2H,CH2),1.24-1.16(m,2H,CH2).13C NMR(100MHz,CDCl3)165.52,149.99,149.51,142.34,139.94,138.05,129.20(2C),129.09(2C),128.49,128.30(2C),128.21(2C),127.05,126.05,121.73,115.38,112.88,110.61,67.36,63.00,56.08,54.96,53.16(2C),52.99(2C),42.95,38.28,26.57.MS(ESI)m/z:568.4[M+H]+。
目标化合物I-9的制备,操作过程同实施例1,得淡黄色油状物,65.7%收率.1HNMR(400MHz,CDCl3)δ7.61(d,J=15.6Hz,1H,C=CH),7.31(t,J=8.4Hz,2H,2×Ar-H),7.22(t,J=7.2Hz,1H,Ar-H)),7.17-7.02(m,8H,8×Ar-H),6.90(d,J=8.4Hz,1H,Ar-H),6.77(d,J=15.6Hz,1H,Ar-H),4.73-4.70(m,1H,1/2phCH2),4.17(t,J=6.0Hz,2H,OCH2),4.13-4.07(m,1H,1/2phCH2),3.91(s,3H,OCH3),3.69(s,2H,phCH2),3.07-3.02(m,1H,1/2NCH2),2.93(t,J=5.2Hz,1H,phCH2),2.79(t,J=5.2Hz,2H,NCH2),2.74(t,J=6.8Hz,2H,NCH2),2.67-2.60(m,1H,1/2NCH2),2.59-2.52(m,2H,NCH2),2.20-2.13(m,2H,CH2),1.84-1.78(m,1H,CH),1.75(d,J=6.8Hz,2H,CH2),1.27-1.18(m,2H,CH2).13C NMR(100MHz,CDCl3)165.60,150.01,149.50,142.37,139.98,134.56,134.23,129.11(2C),128.66,128.52,128.32(2C),126.59,126.20,126.07,125.67,121.65,115.38,112.91,110.66,67.38,56.11,54.70,50.89,42.98,38.34,29.01,26.84.MS(ESI)m/z:525.3[M+H]+。
目标化合物I-10的制备,操作过程同实施例1,得淡黄色油状物,55.6%收率.1HNMR(400MHz,CDCl3)δ8.14(d,J=2.0Hz,1H,Ar-H),7.57(d,J=15.2Hz,1H,C=CH),7.41(t,J=7.6Hz,1H,Ar-H),7.24(t,J=7.2Hz,2H,2×Ar-H),7.15(t,J=7.2Hz,1H,Ar-H),7.09(d,J=7.2Hz,2H,2×Ar-H),7.05(d,J=8.8Hz,1H,Ar-H),7.01(s,1H,Ar-H),6.85(d,J=8.0Hz,1H,Ar-H),6.74(d,J=15.2Hz,1H,C=CH),6.60-6.55(m,2H,2×Ar-H),4.67-4.64(m,1H,1/2phCH2),4.08(t,J=6.4Hz,2H,OCH2),4.06-4.01(m,1H,1/2phCH2),3.84(s,3H,OCH3),3.53-3.50(m,4H,2×NCH2),3.01-2.96(m,1H,1/2NCH2),2.57-2.51(m,8H,4×NCH2),2.50-2.46(m,1H,1/2NCH2),2.06-1.98(m,2H,CH2),1.76-1.72(m,1H,CH),1.68(d,J=13.6Hz,2H,CH2),1.21-1.10(m,2H,CH2).13C NMR(100MHz,CDCl3)165.52,159.46,149.94,149.51,147.90,142.29,139.93,137.43,129.08(2C),128.53,128.28(2C),126.03,121.68,115.42,113.28,112.89,110.60,107.07,67.26,56.06,54.99,52.97(2C),45.11(2C),42.93,38.27(2C),26.48.MS(ESI)m/z:555.3[M+H]+。
目标化合物I-11的制备,操作过程同实施例1,得淡黄色油状物,60.5%收率.1HNMR(400MHz,CDCl3)δ8.24(d,J=1.2Hz,2H,2×Ar-H),7.56(d,J=15.2Hz,1H,C=CH),7.23(t,J=6.8Hz,2H,2×Ar-H),7.14(t,J=6.8Hz,1H,Ar-H),7.08(d,J=7.2Hz,2H,2×Ar-H),7.04(d,J=8.8Hz,2H,2×Ar-H),7.00(s,1H,Ar-H),6.84(d,J=7.6Hz,1H,Ar-H),6.73(d,J=15.2Hz,1H,C=CH),6.43-6.38(m,1H,Ar-H),4.65-4.62(m,1H,1/2phCH2),4.08(t,J=6.4Hz,2H,OCH2),4.05-4.02(m,1H,1/2phCH2),3.83(s,3H,OCH3),3.81-3.78(m,4H,2×NCH2),2.98-2.94(m,1H,1/2NCH2),2.59-2.55(m,1H,1/2NCH2),2.54-2.45(m,8H,4×NCH2),2.03-2.00(m,2H,CH2),1.75-1.71(m,1H,CH),1.67(d,J=13.6Hz,2H,CH2),1.18-1.10(m,2H,CH2).13C NMR(100MHz,CDCl3)165.49,161.60,157.66(2C),149.91,149.49,142.29,139.91,129.06(2C),128.52,128.26(2C),126.01,121.65,115.39,112.86,110.59,109.85,67.21,56.04,55.00(2C),53.01(2C),43.57(2C),42.91,38.25,26.45.MS(ESI)m/z:556.3[M+H]+。
目标化合物I-14的制备,操作过程同实施例1,得淡黄色油状物,66.5%收率.1HNMR(400MHz,CDCl3)δ7.59(d,J=15.2Hz,1H,C=CH),7.31-7.16(m,10H,10×Ar-H),7.12(d,J=7.6Hz,2H,2×Ar-H),7.06(d,J=8.0Hz,1H,Ar-H),7.02(s,1H,Ar-H),6.83(d,J=8.0Hz,1H,Ar-H),6.75(d,J=15.2Hz,1H,C=CH),4.70-4.64(m,1H,1/2phCH2),4.12-4.06(m,1H,1/2phCH2),4.03(t,J=6.0Hz,2H,OCH2),3.86(s,3H,OCH3),3.50(s,2H,phCH2),3.03-2.98(m,1H,1/2NCH2),2.66-2.38(m,13H,1/2NCH2+6×NCH2),1.87-1.81(m,2H,CH2),1.78-1.76(m,1H,CH),1.74-1.64(m,4H,2×CH2),1.23-1.16(m,2H,CH2).13C NMR(100MHz,CDCl3)165.55,149.99,149.49,142.35,139.94,137.95,129.22(2C),129.09(2C),128.42,128.29(2C),128.22(2C),127.08,126.05,121.72,115.33,112.69,110.52,68.73,62.98,58.06,56.06,53.07(2C),52.85(2C),42.96,38.30,27.09,23.23.MS(ESI)m/z:582.4[M+H]+。
目标化合物I-15的制备,操作过程同实施例1,得淡黄色油状物,53.5%收率.1HNMR(400MHz,CDCl3)δ7.61(d,J=15.2Hz,1H,C=CH),7.30(t,J=6.8Hz,2H,2×Ar-H),7.21(t,J=7.6Hz,1H,Ar-H)),7.16-7.01(m,8H,8×Ar-H),6.87(d,J=8.0Hz,1H,Ar-H),6.76(d,J=15.2Hz,1H,C=CH),4.76-4.64(m,1H,1/2phCH2),4.09(t,J=6.0Hz,3H,1/2phCH2+OCH2),3.89(s,3H,OCH3),3.67(s,2H,phCH2),3.05-3.00(m,1H,1/2NCH2),2.92(t,J=5.2Hz,2H,phCH2),2.77(t,J=5.6Hz,2H,NCH2),2.64-2.54(m,5H,1/2NCH2+2×NCH2),1.95-1.89(m,2H,NCH2),1.84-1.77(m,3H,CH+CH2),1.74(d,J=13.6Hz,2H,CH2),1.25-1.18(m,2H,CH2).13C NMR(100MHz,CDCl3)165.60,150.02,149.51,142.38,139.97,134.50,134.19,129.11(2C),128.65,128.43,128.31(2C),126.59,126.19,126.06,125.66,121.68,115.33,112.77,110.60,68.77,57.72,56.10,56.00,50.79,42.97,38.33,28.91,27.05,23.53.MS(ESI)m/z:539.3[M+H]+。
目标化合物I-16的制备,操作过程同实施例1,得淡黄色油状物,60.6%收率.1HNMR(400MHz,CDCl3)δ8.17-8.15(m,1H,Ar-H),7.58(d,J=15.6Hz,1H,C=CH),7.44(t,J=7.2Hz,1H,Ar-H),7.26(t,J=7.2Hz,2H,2×Ar-H),7.18(t,J=7.2Hz,1H,Ar-H),7.11(d,J=6.8Hz,2H,2×Ar-H),7.06(d,J=8.0Hz,1H,Ar-H),7.02(s,1H,Ar-H),6.84(d,J=8.0Hz,1H,Ar-H),6.75(d,J=15.2Hz,1H,C=CH),6.62-6.56(m,2H,2×Ar-H),4.69-4.64(m,1H,1/2phCH2),4.05(t,J=6.0Hz,1H,1/2phCH2+OCH2),3.86(s,3H,OCH3),3.56-3.52(m,4H,2×NCH2),3.02-2.98(m,1H,phCH2),2.56-2.50(m,7H,1/2phCH2+3×NCH2),2.45(t,J=5.6Hz,2H,NCH2),1.90-1.85(m,2H,CH2),1.83-1.80(m,1H,CH),1.73-1.67(m,4H,2×CH2),1.21-1.14(m,2H,CH2).13C NMR(100MHz,CDCl3)165.55,159.50,149.97,149.48,147.91,142.33,139.94,137.43,129.08(2C),128.44,128.28(2C),126.03,121.68,115.34,113.27,112.68,110.52,107.06,68.74,58.17,56.06,52.97(2C),45.14(2C),42.94,38.92,27.09,23.27.MS(ESI)m/z:569.3[M+H]+。
目标化合物I-17的制备,操作过程同实施例1,得淡黄色油状物,67.5%收率.1HNMR(400MHz,CDCl3)δ8.26(d,J=3.6Hz,2H,2×Ar-H),7.56(d,J=15.2Hz,1H,C=CH),7.25(t,J=7.2Hz,2H,2×Ar-H),7.16(t,J=7.2Hz,1H,Ar-H),7.10(d,J=7.2Hz,2H,2×Ar-H),7.05(d,J=8.4Hz,1H,Ar-H),7.01(s,1H,Ar-H),6.82(d,J=8.0Hz,1H,Ar-H),6.73(d,J=15.2Hz,1H,C=CH),6.43(t,J=3.6Hz,1H,Ar-H),4.71-4.62(m,1H,1/2phCH2),4.12-4.08(m,1H,1/2phCH2),4.04(t,J=5.2Hz,2H,OCH2),3.85(s,3H,OCH3),3.83-3.78(m,4H,2×NCH2),3.04-2.92(m,1H,1/2NCH2),2.63-2.55(m,1H,1/2NCH2),2.55-2.40(m,8H,4×NCH2),1.91-1.82(m,2H,CH2),1.81-1.78(m,1H,CH),1.74-1.64(m,4H,2×CH2),1.20-1.12(m,2H,CH2).13C NMR(100MHz,CDCl3)165.53,161.60,157.67(2C),149.95,149.46,142.33,139.92,129.06(2C),128.43,128.27(2C),126.02,121.67,115.32,112.65,110.50,109.85,68.70,58.15,56.03,52.98(2C),43.54(2C),42.93,38.28,27.04,23.20.MS(ESI)m/z:570.3[M+H]+。
目标化合物I-20的制备,操作过程同实施例1,得淡黄色油状物,63.7%收率.1HNMR(400MHz,CDCl3)δ7.59(d,J=15.2Hz,1H,C=CH),7.30-7.22(m,7H,7×Ar-H),7.17(t,J=8.0Hz,1H,Ar-H),7.11(d,J=7.2Hz,2H,2×Ar-H),7.05(t,J=8.0Hz,1H,Ar-H),6.81(d,J=8.4Hz,1H,Ar-H),6.77(d,J=15.2Hz,1H,C=CH),4.70-4.63(m,1H,1/2phCH2),4.12-4.03(m,1H,1/2phCH2),3.99(t,J=6.0Hz,2H,OCH2),3.85(s,3H,OCH3),3.51(s,2H,phCH2),3.06-2.93(m,1H,1/2NCH2),2.68-2.48(m,10H,5×NCH2),2.44(t,J=6.8Hz,2H,NCH2),2.41-2.36(m,1H,1/2NCH2),1.84(t,J=6.4Hz,2H,CH2),1.81-1.75(m,1H,CH),1.70(d,J=13.2Hz,2H,CH2),1.61(t,J=6.4Hz,2H,CH2),1.50-1.42(m,2H,CH2),1.22-1.14(m,2H,CH2).13C NMR(100MHz,CDCl3)165.47,149.98,149.44,142.28,139.89,137.67,129.18(2C),129.06(2C),128.37,128.25(2C),127.14,126.01,121.72,115.35,112.65,110.52,68.72,62.74,58.13,56.04,52.86(2C),52.30(2C),42.90(2C),38.22,29.65,28.88,25.95,23.90.MS(ESI)m/z:596.4[M+H]+。
目标化合物I-21的制备,操作过程同实施例1,得淡黄色油状物,59.3%收率.1HNMR(400MHz,CDCl3)δ7.48(d,J=15.6Hz,1H,C=CH),7.17(t,J=7.2Hz,2H,2×Ar-H),7.08(t,J=7.2Hz,1H,Ar-H)),7.04-6.88(m,8H,8×Ar-H),6.73(d,J=8.4Hz,1H,Ar-H),6.66(d,J=15.6Hz,1H,C=CH),4.68-4.56(m,1H,1/2phCH2),4.05-3.95(m,1H,1/2phCH2),3.92(t,J=6.4Hz,2H,OCH2),3.76(s,3H,OCH3),3.65(s,2H,phCH2),2.98-2.88(m,1H,1/2NCH2),2.85(t,J=4.8Hz,2H,NCH2),2.76(t,J=5.6Hz,2H,NCH2),2.54(t,J=7.2Hz,2H,NCH2),2.47-2.40(m,2H,NCH2),1.80-1.74(m,2H,CH2),1.72-1.68(m,1H,CH),1.66-1.55(m,4H,2×CH2),1.48-1.41(m,2H,CH2),1.12-1.05(m,2H,CH2).13C NMR(100MHz,CDCl3)165.54,150.01,149.46,142.32,139.93,133.55,133.14,129.08(2C),128.65,128.38,128.28(2C),126.62,126.52,126.03,125.92,121.73,115.36,112.70,110.56,68.77,57.50,56.08,55.29,50.49,42.92,38.25,29.67,28.90,28.08,26.20,23.90.MS(ESI)m/z:553.3[M+H]+。
目标化合物I-22的制备,操作过程同实施例1,得淡黄色油状物,63.5%收率.1HNMR(400MHz,CDCl3)δ8.17(d,J=2.8Hz,1H,Ar-H),7.60(d,J=15.2Hz,1H,C=CH),7.43(t,J=7.2Hz,1H,Ar-H),7.26(t,J=7.2Hz,2H,2×Ar-H),7.18(t,J=7.2Hz,1H,Ar-H),7.11(d,J=7.2Hz,H,Ar-H),7.07(d,J=8.4Hz,1H,Ar-H),7.04(s,1H,Ar-H),6.83(d,J=8.0Hz,1H,Ar-H),6.77(d,J=15.2Hz,1H,C=CH),6.63-6.55(m,2H,2×Ar-H),4.71-4.66(m,1H,1/2phCH2),4.13-4.04(m,1H,1/2phCH2),4.02(t,J=5.6Hz,2H,OCH2),3.86(s,3H,OCH3),3.54-3.51(m,4H,2×NCH2),3.03-2.95(m,1H,1/2NCH2),2.68-2.59(m,1H,CH),2.56-2.50(m,6H,3×NCH2),2.38(t,J=7.2Hz,2H,NCH2),1.89-1.82(m,2H,CH2),1.80-1.74(m,1H,CH),1.70(d,J=13.2Hz,2H,CH2),1.63-1.55(m,2H,CH2),1.52-1.46(m,2H,CH2),1.22-1.15(m,2H,CH2).13C NMR(100MHz,CDCl3)165.46,159.47,150.02,149.44,147.84,142.33,139.88,137.38,129.05(2C),128.34,128.25(2C),126.00,121.75,115.28,113.18,112.60,110.48,107.02,68.78,58.48,56.01,53.02(2C),45.12(2C),42.89,38.20,28.99,26.52,23.98.MS(ESI)m/z:583.4[M+H]+。
目标化合物I-23的制备,操作过程同实施例1,得淡黄色油状物,54.8%收率.1HNMR(400MHz,CDCl3)δ8.29(s,2H,2×Ar-H),7.58(d,J=15.2Hz,1H,C=CH),7.27(t,J=6.4Hz,2H,2×Ar-H),7.18(t,J=6.4Hz,1H,Ar-H),7.11(t,J=6.8Hz,2H,2×Ar-H),7.07(d,J=8.0Hz,1H,Ar-H),7.04(s,1H,Ar-H),6.83(d,J=7.6Hz,1H,Ar-H),6.78(d,J=15.2Hz,1H,C=CH),6.48(s,1H,Ar-H),4.72-4.64(m,1H,1/2phCH2),4.16-4.02(m,1H,1/2phCH2),4.02(t,J=6.4Hz,2H,OCH2),3.95-3.92(m,4H,2×NCH2),3.84(s,3H,OCH3),3.05-2.98(m,1H,1/2NCH2),2.70-2.61(m,5H,1/2NCH2+2×NCH2),2.54-2.50(m,4H,2×NCH2),1.88-1.85(m,2H,CH2),1.80-1.76(m,1H,CH),1.76-1.64(m,4H,2×CH2),1.53-1.48(m,2H,CH2),1.22-1.16(m,2H,CH2).13C NMR(100MHz,CDCl3)165.46,161.40,157.66(2C),149.93,149.40,142.26,139.85,129.02(2C),128.34,128.22(2C),125.97,121.70,115.32,112.63,110.48,110.12,68.67,58.14,56.00,52.65(2C),42.89(2C),38.17,32.75,31.82,29.60,28.80,25.70,23.85.MS(ESI)m/z:584.4[M+H]+。
目标化合物I-26的制备,操作过程同实施例1,得淡黄色油状物,58.9%收率.1HNMR(400MHz,CDCl3)δ7.59(d,J=15.2Hz,1H,C=CH),7.30-7.15(m,8H,8×Ar-H),7.12(d,J=7.2Hz,2H,2×Ar-H),7.06(d,J=8.0Hz,1H,Ar-H),7.02(s,1H,Ar-H),6.82(d,J=8.4Hz,1H,Ar-H),6.75(d,J=15.2Hz,1H,C=CH),4.73-4.63(m,1H,1/2phCH2),4.13-4.04(m,1H,1/2phCH2),4.00(t,J=6.4Hz,2H,OCH2),3.86(s,3H,OCH3),3.49(s,2H,phCH2),3.04-2.94(m,1H,1/2NCH2),2.68-2.38(m,11H,1/2NCH2+5×NCH2),2.34(t,J=6.4Hz,2H,NCH2),1.85-1.78(m,2H,CH2),1.77-1.76(m,1H,CH),1.71(d,J=13.6Hz,2H,CH2),1.54-1.43(m,4H,2×CH2),1.38-1.31(m,2H,CH2),1.21-1.14(m,2H,CH2).13C NMR(100MHz,CDCl3)165.53,150.08,149.48,142.37,139.93,138.03,129.20(2C),129.08(2C),128.35,128.28(2C),128.19,127.03,126.04,121.73,115.29,112.66,110.55,68.87,63.01,58.56,56.08,53.17(2C),52.90(2C),42.95,38.28,29.05,27.32,26.66,25.90.MS(ESI)m/z:610.4[M+H]+。
目标化合物I-27的制备,操作过程同实施例1,得淡黄色油状物,61.3%收率.1HNMR(400MHz,CDCl3)δ7.62(d,J=15.2Hz,1H,C=CH),7.28(t,J=7.2Hz,2H,2×Ar-H),7.20(t,J=7.2Hz,1H,Ar-H)),7.14-7.03(m,7H,7×Ar-H),7.01(d,J=5.6Hz,1H,Ar-H),6.84(d,J=8.4Hz,1H,Ar-H),6.77(d,J=15.2Hz,1H,C=CH),4.76-4.64(m,1H,1/2phCH2),4.14-4.06(m,1H,1/2phCH2),4.03(t,J=6.4Hz,2H,OCH2),3.88(s,3H,OCH3),3.63(s,2H,phCH2),3.06-2.96(m,1H,1/2NCH2),2.90(t,J=5.2Hz,2H,phCH2),2.73(t,J=5.2Hz,2H,NCH2),2.65-2.57(m,1H,1/2NCH2),2.55-2.48(m,4H,2×NCH2),1.89-1.83(m,2H,CH2),1.83-1.77(m,1H,CH),1.72(d,J=13.6Hz,2H,CH2),1.66-1.60(m,2H,CH2),1.55-1.46(m,2H,CH2),1.45-1.40(m,2H,CH2),1.28-1.16(m,2H,CH2).13C NMR(100MHz,CDCl3)165.56,150.12,149.51,142.38,139.96,134.72,134.27,129.10(2C),128.63,128.37,128.30(2C),126.59,126.11,126.05,125.60,121.77,115.32,112.70,110.58,68.92,58.31,56.14,56.11,50.93,42.96,38.30,29.10,29.02(2C),27.34,27.03,25.96.MS(ESI)m/z:567.4[M+H]+。
目标化合物I-28的制备,操作过程同实施例1,得淡黄色油状物,64.8%收率.1HNMR(400MHz,CDCl3)δ8.13(s,1H,Ar-H),7.56(d,J=15.2Hz,1H,C=CH),7.40(t,J=8.0Hz,1H,Ar-H),7.23(t,J=6.8Hz,2H,2×Ar-H),7.14(t,J=7.2Hz,1H,Ar-H),7.08(d,J=6.4Hz,2H,2×Ar-H),7.03(d,J=8.4Hz,1H,Ar-H),7.00(s,1H,Ar-H),6.80(d,J=8.0Hz,1H,Ar-H),6.73(d,J=15.2Hz,1H,C=CH),6.59-6.53(m,2H,2×Ar-H),4.68-4.59(m,1H,1/2phCH2),4.07-4.00(m,1H,1/2phCH2),3.98(t,J=6.0Hz,2H,OCH2),3.83(s,3H,OCH3),3.54-3.48(m,4H,2×NCH2),3.06-2.94(m,1H,1/2NCH2),2.62-2.53(m,1H,1/2NCH2),2.52-2.46(m,6H,3×NCH2),2.33(t,J=7.2Hz,2H,NCH2),1.84-1.78(m,2H,CH2),1.76-1.68(m,1H,CH),1.66(d,J=13.2Hz,2H,CH2),1.53-1.40(m,4H,2×CH2),1.38-1.31(m,2H,CH2),1.22-1.10(m,2H,CH2).13C NMR(100MHz,CDCl3)165.48,159.48,150.05,149.46,147.85(2C),142.33,139.89,137.36,129.05(2C),128.32,128.24(2C),125.99,121.75,115.27,113.17,112.63,110.49,107.01,68.83,58.62,56.04,53.03(2C),45.12(2C),42.90,38.21,29.04,27.27,26.67,25.88.MS(ESI)m/z:597.4[M+H]+。
目标化合物I-29的制备,操作过程同实施例1,得淡黄色油状物,67.3%收率.1HNMR(400MHz,CDCl3)δ8.23(d,J=3.6Hz,2H,2×Ar-H),7.55(d,J=15.2Hz,1H,C=CH),7.22(t,J=7.2Hz,2H,2×Ar-H),7.13(t,J=7.2Hz,1H,Ar-H),7.07(d,J=7.2Hz,2H,2×Ar-H),7.02(d,J=8.4Hz,1H,Ar-H),6.99(s,H,Ar-H),6.79(d,J=8.4Hz,1H,Ar-H),6.72(d,J=15.2Hz,1H,C=CH),6.39(t,J=4.4Hz,1H,Ar-H),4.68-4.59(m,1H,1/2phCH2),4.06-3.99(m,1H,1/2phCH2),3.97(t,J=6.0Hz,2H,OCH2),3.82(s,3H,OCH3),3.80-3.75(m,4H,2×NCH2),3.00-2.91(m,1H,1/2NCH2),2.62-2.53(m,1H,1/2NCH2),2.50-2.41(m,6H,3×NCH2),2.32(t,J=6.8Hz,2H,NCH2),1.82-1.76(m,2H,CH2),1.74-1.71(m,1H,CH),1.66(d,J=13.2Hz,2H,CH2),1.54-1.41(m,4H,2×CH2),1.38-1.30(m,2H,CH2),1.28-1.11(m,2H,CH2).13C NMR(100MHz,CDCl3)165.49,161.61,157.62(2C),150.04,149.45,142.33,139.88,129.04(2C),128.32,128.24(2C),125.99,121.72,115.25,112.61,110.49,109.76,68.83,58.63,56.04,53.07(2C),43.60(2C),42.91,38.24,29.04,27.27,26.66,25.88.MS(ESI)m/z:598.4[M+H]+。
实施例91-95
实施例91-95采用与实施例1相同的方法制备表1中的化合物I-1,不同之处在于:制备方法中采用的参数不同,具体如表2所示,其中,表2中第一步中的摩尔比为阿魏酸、苄基哌啶类化合物和缩合剂的摩尔投料比,第二步中的摩尔比为中间体化合物、二溴烷烃和碱的摩尔投料比,第三步中的摩尔比为溴化合物中间体、仲胺和碱的摩尔投料比。
表2实施例1以及实施例91-95参数数据
由表2可以看出,采用不同的参数制备表1中的化合物I-1,产品的得率为25-90%,实施例91中的参数制备的目标产物的得率最高,说明本发明实施例91中的参数最优。
实施例96
一种N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物的药学上可接受的盐,其制备方法包括以下步骤:将实施例1中制备的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物(I)2.5mmol和丙酮50mL,搅拌均匀后加入10.0mmol草酸,升温回流搅拌反应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N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物(I)的盐,其化学结构经1H NMR和ESI-MS确证。
N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物生物活性测试
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1.0mmol/L碘化硫代乙酰胆碱或硫代丁酰胆碱(均购自Sigma公司)30μL,pH=8.0的PBS缓冲液40μL,待测化合物溶液20μL(DMSO含量小于1%)和10μL电鳗乙酰胆碱酯酶(eeAChE)或丁酰胆碱酯酶(equine serum BuChE,eqBuChE)(0.045U,均购自Sigma公司),加毕混匀后,37℃孵育15min,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。测定结果如表3所示。
由表3可以看出,本发明实施例中所公开的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物(I)对丁酰胆碱酯酶均具有显著抑制活性,其IC50为0.01~10μM。并且N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物(I)对丁酰胆碱酯酶的抑制活性显著高于对乙酰胆碱酯酶的抑制活性,说明本发明所公开的化合物对丁酰胆碱酯酶具有选择性抑制作用。
2、N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物(I)对Aβ1-42自身聚集的抑制活性
依照参照文献(Sang,Z.P.et al.Eur.J.Med.Chem.2015,94,348-366)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2.5mM储备液,使用前用pH7.4的PBS缓冲液稀释至相应浓度,分别取20μL的Aβ1-42溶液+20μL的待测化合物溶液、20μLAβ1-42溶液+20μLPBS缓冲液(含2%DMSO)、20μLPBS缓冲液(含2%DMSO)+20μL PBS缓冲液(含25%DMSO)于黑色96孔板中,化合物和Aβ1-42的最终浓度均为25μM。37℃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Varioskan Flash Multimode Reader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录为IFi,Aβ1-42+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Aβ1-42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;以姜黄素为阳性对照。测定结果见表3所示。
由表3可知,本发明实施例中所公开的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物(I)对Aβ1-42自身聚集均具有显著抑制活性,其抑制率为36.3%-99.5%,阳性药姜黄素的抑制率为46.8%;而广泛使用的抗AD药多奈哌齐在25.0μM浓度下对Aβ1-42自身聚集的抑制率小于5%。
3、N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物(I)对Aβ1-42自身聚集的解聚活性
试剂及前期准备:在室温条件下将Aβ1-42三氟乙酸盐(1mg)溶于1ml六氟异丙醇(HFIP)中,超声5min后,室温孵育24h,室温减压除掉溶剂,用DMSO再次溶解,配成200μM的Aβ1-42储备液,于-80℃储存,使用前用50mM的PBS缓冲液(pH=7.4)稀释至50μM;待测化合物用DMSO溶解配成2.5mM储备液,使用前用50mM的PBS缓冲液(pH=7.4)稀释至50μM。
实验方法:取20μL PBS缓冲液(含2%DMSO)+20μLPBS缓冲液(含25%DMSO)(空白组)、20μL的Aβ1-42溶液+20μL PBS缓冲液(含2%DMSO)(对照组)、20μL的Aβ1-42溶液(测试组)于黑色96孔板中。37℃孵育24h,向测试组中加入20μL的待测化合物溶液,化合物和Aβ1-42的最终浓度均为25μM。37℃再孵育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Varioskan Flash Multimode Reader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录为IFi,Aβ1-42+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Aβ1-42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。以姜黄素为阳性对照。测试结果见表3。
由表3可知,公开的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物(I)在25.0μM浓度下对自身诱导的Aβ1-42聚集具有显著的解聚作用,解聚率为35%~95%,姜黄素在相同浓度下的解聚率为57.2%。
4、抗氧化活性测定(ORAC-FL法)
试剂与仪器:6-羟基-2,5,7,8-四甲基色烷-2-羧酸(trolox,购自梯希爱(上海)化成工业发展有限公司)用75mM的PBS缓冲液(pH7.4)配成10-80μmol/L的溶液;荧光素(fluorescein,购自梯希爱(上海)化成工业发展有限公司)用75mM的PBS缓冲液(pH7.4)配成250nmol/L的溶液;2,2’-偶氮二异丁基脒二盐酸盐(AAPH,购自韶远化学科技(上海)有限公司)在使用前用75mM的PBS缓冲液(pH7.4)配成40mmol/L的溶液;酶标仪为VarioskanFlash Multimode Reader(Thermo Scientific)。
测定实验方法:向黑色96孔板中加入50或10μmol/L的化合物溶液20μL和荧光素溶液120μL,混匀,37℃孵育15min,加入AAPH溶液60μL,使每孔总体积为200μL,混匀,立即置于Varioskan Flash Multimode Reader仪器中,在485nm激发波长和535nm发射波长下每分钟测定一次荧光值,连续测定90min,通过仪器自动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,计算公式为:[(AUC Sample-AUC blank)/(AUC Trolox-AUC blank)]×[(concentration ofTrolox/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。测定结果见表3。
由表3中的测定结果表明,本实施例中所公开的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物(I)的抗氧化活性为Trolox的0.4-1.0倍,说明该类化合物具有强抗氧化活性。
5、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5mg/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490nm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。测定结果如图1所示,表明本发明所公开的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物具有显著的神经保护作用。
6、N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物(I)的急性毒性试验
试验材料:实验动物为SPF级昆明种小鼠,由四川省中医药科学院提供,生产合格证号SCXK(川)2008-19。动物饲养于四川省中医药科学院药理毒理研究所SPF屏障系统中。室内温度20~22℃,相对湿度40%-70%左右,照明12小时明亮,12小时黑暗,自由饮水。全营养颗粒饲料由四川省中医药科学院实验动物中心提供。
实验方法:动物随机分组:取SPF级18~22g的小鼠40只,雌雄各半,适应性喂养两天后,按体重随机分为4组。禁食不禁水15h后,分别灌胃化合物(I)1000mg/kg、500mg/kg、250mg/kg、100mg/kg四个剂量组,取给药体积为0.4mL/10g,各组给药一次,连续14天观察并记录各动物的死亡情况,采用Bliss统计软件进行分析。发现各组小鼠未出现毛竖起、行动迟缓、闭眼和呼吸加速以及死亡现象。测定结果表明SPF级昆明种小鼠经N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物(I)处理后,未出现急毒和死亡率,也未出现毛竖起、行动迟缓、闭眼和呼吸加速等现象,表明了N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物(I)是无毒的,且最大耐受量为1000mg/kg。
7、动物实验-跳台被动回避实验
试剂与仪器:多奈哌齐购自Eisai China Inc.;东莨菪碱购自J&K Scientific;18-22g的昆明鼠购自四川中医药科学院实验动物中心(合格证号:SCXK-Sichuan 2008-19);动物饲养于四川省中医药科学院药理毒理研究所SPF屏障系统中。饲养环境12h光照/12h黑暗交替,环境温度控制于20-22℃,湿度控制于50-60%;全营养颗粒饲料由四川省中医药科学院实验动物中心提供;小鼠跳台仪(型号ZXC-5Q)由山东省医学科学院设备维修供应站生产。
实验方法:60只小鼠,18~22g,雌雄各半,按体重随机分为6个组,即空白对照组、模型对照组、多奈哌齐组(0.5、5mg·kg-1)、化合物(I)高剂量组(21.3mg·kg-1)、化合物(I)中剂量组(7.1mg·kg-1)、化合物(I)低剂量组(2.4mg·kg-1)。每组小鼠按给药剂量分上下午给药,连续给药3次,末次给药后50min进行造模,除空白对照组以外其他各组腹腔注射东莨菪碱3mg·kg-1,连续给药24天。造模后20min进行跳台法训练,将动物放入反应箱内适应3min,然后立即通以36V交流电,训练5min,并记录每次小鼠受到电击的次数(错误次数),并由此作为学习成绩。24h后进行测试,每只小鼠测定5min,记录受到电击的动物数及第一次跳下平台的潜伏期以及5min内的错误次数,结果进行统计学分析,所有数据均用均值±标准误差(Stand error,S.E.)表示。采用SPSS11.5软件分析,方差齐的选择单因素方差分析(One-wayANOVA)。计量资料比较采用单因素方差分析,各组均数的比较采用t检验。实验结果见图2。
实验结果表明:本发明N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物对东莨菪碱所致小鼠记忆再现功能障碍均具有明显改善作用。
表3部分N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物的生物活性筛选结果
最后说明的是,以上实施例仅用以说明本发明的技术方案而非限制,本领域普通技术人员对本发明的技术方案所做的其他修改或者等同替换,只要不脱离本发明技术方案的精神和范围,均应涵盖在本发明的权利要求范围当中。
Claims (10)
1.一种N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物,其特征在于:该类化合物的化学通式如(I)所示:
式中:n表示2-12;
X表示H、甲氧基、C1~C12烷基、卤素、二甲氨基,取代基可在苯环的任意可能位置;
NR1R2表示1,2,3,4-四氢异喹啉、苄基哌啶、苄基哌嗪、苄基甲基胺、1-(2-吡啶基)哌嗪、1-(2-嘧啶基)哌嗪。
2.一种如权利要求1所述的N-(苄基哌啶基)-阿魏酰胺-O-烷基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N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物与盐酸、氢溴酸、硝酸、硫酸、磷酸、C1-6脂肪羧酸、苯甲酸、水杨酸、柠檬酸、C1-6烷基磺酸、樟脑磺酸、苯磺酸或对甲苯磺酸反应所生成的盐。
3.一种如权利要求1所述的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物的制备方法,其特征在于:包括以下步骤:
第一步:以阿魏酸和苄基哌啶类化合物为起始原料,在溶剂和缩合剂作用下缩合,得中间体化合物;
第二步:中间体化合物在溶剂和碱性条件下与二溴烷烃反应,得溴化合物中间体;
第三步:溴化合物中间体在溶剂和碱性条件下与仲胺反应得N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物。
4.根据权利要求3所述的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物的制备方法,其特征在于:所述第一步中缩合剂为EDCI和HOBT、DCC和DMAP或卡特缩合剂中的一种。
5.根据权利要求3所述的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物的制备方法,其特征在于:
所述第二步和第三步中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、有机叔胺类或者季胺碱类;
所述第一步、第二步和第三步中的溶剂为乙醚、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烷烃中一种或几种。
6.根据权利要求3所述的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物的制备方法,其特征在于:所述第一步阿魏酸、苄基哌啶类化合物和缩合剂的摩尔投料比为1.0:1.0~10.0:1.0~10.0,反应温度为0~150℃,反应时间为1~120小时。
7.根据权利要求3所述的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物的制备方法,其特征在于:所述第二步中间体化合物、二溴烷烃和碱的摩尔投料比为1.0:1.0~10.0:1.0~10.0,反应温度为0~150℃,反应时间为1~120小时。
8.根据权利要求3所述的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物的制备方法,其特征在于:所述第三步溴化合物中间体、仲胺和碱的摩尔投料比为1.0:1.0~10.0:1.0~10.0,反应温度为0~150℃,反应时间为1~120小时。
9.一种如权利要求1或权利要求2所述的N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物或其药学上可接受的盐在制备治疗和/或预防阿尔茨海默病药物中的用途。
10.根据权利要求9所述的用途,其特征在于:所述N-(苄基哌啶基)-阿魏酰胺-O-烷基胺类化合物或其药学上可接受的盐在药物中总比重为5%-99.5%。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710058531.XA CN106749188B (zh) | 2017-01-23 | 2017-01-23 | 一种n-(苄基哌啶基)-阿魏酰胺-o-烷基胺类化合物、制备方法及其用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710058531.XA CN106749188B (zh) | 2017-01-23 | 2017-01-23 | 一种n-(苄基哌啶基)-阿魏酰胺-o-烷基胺类化合物、制备方法及其用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106749188A CN106749188A (zh) | 2017-05-31 |
CN106749188B true CN106749188B (zh) | 2019-06-18 |
Family
ID=58943183
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710058531.XA Expired - Fee Related CN106749188B (zh) | 2017-01-23 | 2017-01-23 | 一种n-(苄基哌啶基)-阿魏酰胺-o-烷基胺类化合物、制备方法及其用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106749188B (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108276332B (zh) * | 2018-01-29 | 2021-04-23 | 南阳师范学院 | 一种双阿魏酰胺孪药类化合物及其制备方法和用途 |
CN109761883B (zh) * | 2019-01-28 | 2020-11-03 | 南阳师范学院 | 一种4-氨基甲酸酯-肉桂酰胺-4-苄基哌啶类化合物及其制备方法和用途 |
CN116023305A (zh) * | 2022-12-28 | 2023-04-28 | 南阳市中心医院 | 一种咖啡酸-多巴胺-卡巴拉汀杂合化合物、制备方法和应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101723900A (zh) * | 2004-05-26 | 2010-06-09 | 卫材R&D管理有限公司 | 肉桂酰胺类化合物 |
KR20130099676A (ko) * | 2012-02-29 | 2013-09-06 | 이화여자대학교 산학협력단 | 알콕시페닐프로펜온 유도체 또는 이의 약학적으로 허용가능한 염 및 이를 유효성분으로 함유하는 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물 |
CN105801448A (zh) * | 2016-04-01 | 2016-07-27 | 南阳师范学院 | 一种4-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 |
-
2017
- 2017-01-23 CN CN201710058531.XA patent/CN106749188B/zh not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101723900A (zh) * | 2004-05-26 | 2010-06-09 | 卫材R&D管理有限公司 | 肉桂酰胺类化合物 |
KR20130099676A (ko) * | 2012-02-29 | 2013-09-06 | 이화여자대학교 산학협력단 | 알콕시페닐프로펜온 유도체 또는 이의 약학적으로 허용가능한 염 및 이를 유효성분으로 함유하는 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물 |
CN105801448A (zh) * | 2016-04-01 | 2016-07-27 | 南阳师范学院 | 一种4-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 |
Non-Patent Citations (3)
Title |
---|
4-胺烷氧基-3-甲氧基肉桂酸酰胺衍生物的合成及表征;潘万里,王柯人,柳文敏,桑志培;《河南省化学会2016年学术年会论文摘要集》;20160831;327 * |
Donepezil: An Important Prototype to the Design of New Drug Candidates for Alzheimer"s Disease;Simoes M, Viegas F, Moreira M;《Mini Reviews in Medicinal Chemistry》;20141231;第14卷(第1期);2-19 * |
Synthesis and evaluation of donepezil–ferulic acid hybrids as multi-target-directed ligands against Alzheimer"s disease;Xu, Wei; Wang, Xiao-Bing; Wang, Zhi-Min; 等;《Medchemcomm》;20161231;第7卷(第5期);990-998 * |
Also Published As
Publication number | Publication date |
---|---|
CN106749188A (zh) | 2017-05-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Viayna et al. | Dual inhibitors of β-amyloid aggregation and acetylcholinesterase as multi-target anti-Alzheimer drug candidates | |
CN106749188B (zh) | 一种n-(苄基哌啶基)-阿魏酰胺-o-烷基胺类化合物、制备方法及其用途 | |
CN103087024B (zh) | 一类黄酮烷基胺类化合物、其制备方法和用途 | |
CN105503840B (zh) | 一种含三氮唑基的他克林-香豆素衍生物及其应用 | |
CN103113340A (zh) | 一类金雀异黄酮烷基胺类化合物、其制备方法和用途 | |
CN106831574B (zh) | N-(1,2,3,4-四氢异喹啉基)-阿魏酰胺-o-烷基胺类化合物和应用 | |
CN105777614A (zh) | 一种阿魏酸环胺烷基酰胺类化合物及其制备方法和用途 | |
CN109761945A (zh) | 一种柚皮素-o-烷基胺类化合物、制备方法和应用 | |
CN108218744A (zh) | 一种咖啡多巴酰胺氨基甲酸酯类化合物、其制备方法及应用 | |
CN103073440B (zh) | 一类二苯乙烯氧烷基胺类化合物、其制备方法和用途 | |
CN106748969B (zh) | 一种n-(4-苄基哌啶基)-阿魏酰胺化合物、制备方法及其用途 | |
Yang et al. | Development of naringenin-O-alkylamine derivatives as multifunctional agents for the treatment of Alzheimer’s disease | |
CN109265362A (zh) | 一类2,5-二羟基对苯二甲酰胺类化合物、其制备方法和用途 | |
CN106831573B (zh) | (n-1,2,3,4-四氢异喹啉基)-阿魏酰胺化合物、制备方法及其应用 | |
CN108586411A (zh) | 一种柚皮素氨基甲酸酯类化合物、其制备方法及应用 | |
CN105837497B (zh) | 4-氨基甲酸酯-3-甲氧基肉桂酸环胺烷基酰胺类化合物、制备方法及其用途 | |
CN106831714B (zh) | 一种四氢异喹啉化合物及其制备方法和用途 | |
CN104860847B (zh) | 利凡斯的明和咖啡酸、阿魏酸的二聚体,其制备方法及其药物组合物 | |
CN106798743B (zh) | (n-异丙基哌嗪基)-2-羟基苯甲酰胺化合物在制备治疗神经退行性疾病药物中的用途 | |
CN106581013B (zh) | 一种水杨酸类化合物在制备神经退行性疾病药物中的用途 | |
CN108586335A (zh) | 2-羟基苯甲酰胺-1,2,3,4-四氢异喹啉-o-氨基甲酸酯化合物及其制备方法 | |
CN105646289B (zh) | 一种4-氨基甲酸酯-3-甲氧基肉桂酸胺烷基酰胺类化合物及其制备方法和用途 | |
AU2019218153B2 (en) | Therapeutic drug for neurodegenerative disease and application thereof | |
CN114380883B (zh) | 胺烷氧基雷公藤红素衍生物及制备方法和用途 | |
CN106632191B (zh) | 高异黄酮曼尼希碱类化合物、其制备方法和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190618 Termination date: 20220123 |
|
CF01 | Termination of patent right due to non-payment of annual fee |