CN113582911A - 多靶点多奈哌齐-异羟肟酸型化合物及其制备方法和应用 - Google Patents
多靶点多奈哌齐-异羟肟酸型化合物及其制备方法和应用 Download PDFInfo
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- CN113582911A CN113582911A CN202110926473.4A CN202110926473A CN113582911A CN 113582911 A CN113582911 A CN 113582911A CN 202110926473 A CN202110926473 A CN 202110926473A CN 113582911 A CN113582911 A CN 113582911A
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- methyl
- benzylpiperidin
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- aminophenyl
- amino
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- 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
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- 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
- C07D211/28—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 to which a second hetero atom is attached
Abstract
本发明涉及医药化学技术领域,特别涉及一种多靶点多奈哌齐‑异羟肟酸型衍生物制备方法及应用。为了解决现有技术中存在的单一靶点抗AD化合物效果有限,而AD发病机制十分复杂,多靶点抗AD化合物具有提高药效,避免联合用药中产生的药物‑药物不良相互作用,提升病人服药依存性等优点,本发明提出一种多靶点多奈哌齐‑异羟肟酸型化合物(式I)及其制备方法和应用,本发明的化合物能够有效地抑制组蛋白去乙酰化酶(HDACs)和乙酰胆碱酯酶(AChE)的活性,并表现出一定的抑制Aβ蛋白聚积和解聚Aβ蛋白聚积体活性,可用于预防和/或治疗阿尔兹海默病。
Description
技术领域
本发明涉及医药化学技术领域,特别涉及一种多靶点多奈哌齐-异羟肟酸型衍生物制备方法及应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
阿尔茨海默病(Alzheimer’s Disease,AD)是一种不可逆的慢性中枢神经系统退行性疾病,是痴呆病中最常见的类型之一。AD最重要的病理学变化包括细胞外Aβ淀粉样蛋白的沉积形成的老年斑(SP)、细胞内高磷酸化Tau蛋白异常缠绕形成的神经纤维缠结(NFTs)和神经元大量丢失。迄今为止,FDA共批准了5个用于改善AD症状的小分子药物和1个单抗药物Aducanumab,Aducanumab是由渤健生物研发的能特异性识别β-淀粉样蛋白(Aβ)聚集体的人源单克隆抗体。上市的小分子药物中包括4个乙酰胆碱酯酶(AChE)抑制剂:他克林(Tacrine,副作用大,已退市)、多奈哌齐(Donepezil)、加兰他敏(Galantamine)、卡巴拉汀(Rivastigmine)和1个N-甲基-D-天冬氨酸受体(NMDAR)拮抗药:美金刚(Memantine)。另外,由我国自行研制的抗AD天然药物石杉碱甲(Huperzine A,也属于AChE抑制剂)也已上市。这些小分子药物只作用于AD疾病网络中的单一靶点,导致治疗效果不佳,通常只能缓解AD疾病进程而不能逆转病情。
经过近几十年来对AD研究的不断深入,发明人发现AD作为一种复杂性疾病其发生和发展往往是多因素引起的。而已上市的这些药物中全部都是靶向于AD致病网络中的单一靶点。临床表现上,已上市的四种化合物的治疗作用有限,它们仅仅是减轻了某些症状,但不能减慢AD的进展。这种结果也一步说明:AD是因为多种分子在脑内表达异常引起的,而不是由某种单一缺陷造成。在功能上,同时触发与AD发病机制相关的多个途径可能会产生协同作用,提高治疗疗效。想要完成这种构想可以有两种方法:1、联合用药。2、多靶点药物。联合用药采用两种或两种以上药物来达到增效、减毒和克服耐药的目的,但是联合用药却存在药物-药物不良相互作用,配伍禁忌和病人服药依从性差等缺点。多靶点化合物是指将两个或多个针对某一复杂疾病的药效团通过适当的方式连接起来而构成的高效且安全的单一化学实体,可以很好克服联合用药存在的局限性。因此,多靶点药物已经成为治疗复杂疾病如神经退行性疾病、心血管疾病和肿瘤的有效手段。
此外,在人体中共发现18个HDAC家族成员,分为4类:Class I(HDACs 1-3和8),Class II(HDACs 4-7,9和10),Class IV(HDAC11),这三类组蛋白去乙酰化酶为锌离子依赖型的,而Class III HDACs(sirtuins1-7)依赖NAD+发挥活性。
对外,发明人还发现,不同亚型的HDAC在大脑中分布有明显差异,在大鼠脑中,所有I,II和IV类HDAC同工酶均在神经元中表达,在涉及学习和记忆的大脑区域中,例如杏仁核,海马体和皮层区域中I类HDAC的表达高于IIa类HDAC。此外,IIa类HDAC在上述大脑区域中的表达也明显高于IIb类HDAC。HDAC11在这些大脑区域中也大量表达。在I类HDAC中,HDAC2和HDAC3的表达通常比HDAC1和HDAC8更高,不同类酶在认知中发挥不同作用。这意味着,针对特定HDAC研发抗AD药物具有重要的指导意义。
发明内容
为了解决现有技术中存在的单一靶点抗AD化合物效果有限,而AD发病机制十分复杂,多靶点抗AD化合物具有提高药效,避免联合用药中产生的药物-药物不良相互作用,提升病人服药依存性等优点,本发明提出一种多靶点多奈哌齐-异羟肟酸型化合物及其制备方法和应用,本发明的化合物能够有效地抑制组蛋白去乙酰化酶(HDACs)和乙酰胆碱酯酶(AChE)的活性,并表现出一定的抑制Aβ蛋白聚积和解聚Aβ蛋白聚积体活性,可用于预防和/或治疗阿尔兹海默病。
具体地,本发明是通过如下所述的技术方案实现的:
本发明第一方面,提供一种多靶点多奈哌齐-异羟肟酸型化合物,其特征在于,选自通式(I)及其药学上可接受的盐、其立体异构体、同位素标记物、溶剂化物、多晶型物、互变异构体、代谢产物或前药:
本发明第二方面,提供一种靶点多奈哌齐-异羟肟酸型化合物的制备方法。
本发明第三方面,提供一种药物组合物,其包括多靶点多奈哌齐-异羟肟酸型化合物、其药学上可接受的盐、其立体异构体、同位素标记物、溶剂化物、多晶型物、互变异构体、代谢产物或前药以及药学上可接受的载体或赋形剂。
本发明第四方面,提供一种多靶点多奈哌齐-异羟肟酸型化合物、其药学上可接受的盐、其立体异构体、同位素标记物、溶剂化物、多晶型物、互变异构体、代谢产物或前药在制备同时抑制HDACs和AChE的药物中的应用。
本发明第五方面,提供一种靶点多奈哌齐-异羟肟酸型化合物、其药学上可接受的盐、其立体异构体、同位素标记物、溶剂化物、多晶型物、互变异构体、代谢产物或前药在制备HDACs和/或AChE和/或BChE抑制剂药物中的应用。
本发明第六方面,提供一种多靶点多奈哌齐-异羟肟酸型化合物、其药学上可接受的盐、其立体异构体、同位素标记物、溶剂化物、多晶型物、互变异构体、代谢产物或前药在制备预防和/或治疗神经退行性疾病的药物中的应用。
上述一个或多个技术方案具有以下有益效果:
本发明的化合物能够有效地抑制组蛋白去乙酰化酶(HDACs)和乙酰胆碱酯酶(AChE)的活性,其对HDACs的抑制活性IC50最低为22.9nM,对AChE的抑制活性IC50最低为0.49μM,并且能明显抑制Aβ1-42聚积,对Aβ1-42聚积抑制率最大为55.6%。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本公开的示例性实施方式。如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
为了解决现有技术中存在的单一靶点抗AD化合物效果有限,而AD发病机制十分复杂,多靶点抗AD化合物具有提高药效,避免联合用药中产生的药物-药物不良相互作用,提升病人服药依存性等优点,同时由于HDAC种类众多,分布不均匀,无法实现特异性治疗或预防问题,本发明提出一种多靶点多奈哌齐-异羟肟酸型化合物及其制备方法和应用,本发明的化合物能够有效地抑制组蛋白去乙酰化酶(HDACs)和乙酰胆碱酯酶(AChE)的活性,并表现出一定的抑制Aβ蛋白聚积和解聚Aβ蛋白聚积体活性,可用于预防和/或治疗阿尔兹海默病。
具体地,本发明是通过如下所述的技术方案实现的:
本发明第一方面,提供一种多靶点多奈哌齐-异羟肟酸型化合物,其特征在于,选自通式(I)及其药学上可接受的盐、其立体异构体、同位素标记物、溶剂化物、多晶型物、互变异构体、代谢产物或前药:
“药学上可接受的盐”的例子包括无机酸盐,例如盐酸盐、氢溴酸盐、硫酸盐、磷酸盐和硝酸盐;有机酸盐,例如醋酸盐、丙酸盐、草酸盐、琥珀酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、马来酸盐、延胡索酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐和抗坏血酸盐;无机碱盐,例如钠盐、钾盐、钙盐、锌盐、镁盐和铝盐;以及有机碱盐,例如精氨酸盐、苄星盐、胆碱盐、二乙胺盐、二醇胺盐、甘氨酸盐、赖氨酸盐、葡甲胺盐、乙醇胺盐和氨基丁三醇盐。
在本发明一个或多个实施方式中,所述通式(I)中的X选自苯基、烷基取代苯基或醚键取代苯基,R基团选自羟基或氨基取代苯基;
优选地,所述通式(I)中的X选自以下结构片段,
X选自以下结构片段:
其中,X选自以下结构片段:
在本发明一个或多个实施方式中,X基团为非对称基团,分别有a和b两个接入点,如下所示:
在式(W1)或式(W2)所示通式中,根据如上所示的接入点,优选b接入点与-NH-OH相连。
在本发明一个或多个实施方式中,所述化合物选自以下结构:
N1-((1-苄基哌啶-4-基)甲基)-N4-羟基对苯二甲酰胺(A1);
N1-((1-苄基哌啶-4-基)甲基)-N3-羟基对苯二甲酰胺(A2);
4-(3-(((1-苄基哌啶-4-基)甲基)氨基)-3-氧丙基)-N-羟基苯甲酰胺(A3);
N-((1-苄基哌啶-4-基)甲基)-4-(3-(羟基氨基)-3-氧丙基)苯甲酰胺(A4);
N-((1-苄基哌啶-4-基)甲基)-3-(3-(羟基氨基)-3-氧丙基)苯甲酰胺(A5);
N-((1-苄基哌啶-4-基)甲基)-4-(3-(羟基氨基)-3-氧丙基)-2-甲氧基苯甲酰胺(A6);
(E)-4-(3-(((1-苄基哌啶-4-基)甲基)氨基)-3-氧代丙-1-烯-1-基)-N-羟基苯甲酰胺(A7);
(E)-N-((1-苄基哌啶-4-基)甲基)-4-(3-(羟基氨基)-3-氧代丙-1-烯-1-基)苯甲酰胺(A8);
(E)-N-((1-苄基哌啶-4-基)甲基)-3-(3-(羟基氨基)-3-氧代丙-1-烯-1-基)苯甲酰胺(A9);
(E)-N-((1-苄基哌啶-4-基)甲基)-4-(3-(羟基氨基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酰胺(A10);
N1-((1-苄基哌啶-4-基)甲基)-N7-羟基庚二酰胺(A11);
N1-((1-苄基哌啶-4-基)甲基)-N8-羟基辛二酰胺(A12);
N1-((1-苄基哌啶-4-基)甲基)-N9-羟基壬二酰胺(A13);
4-(N-((1-苄基哌啶-4-基)甲基)氨磺酰基)-N-羟基苯甲酰胺(B1);
3-(N-((1-苄基哌啶-4-基)甲基)氨磺酰基)-N-羟基苯甲酰胺(B2);
N1-(2-氨基苯基)-N4-((1-苄基哌啶-4-基)甲基)对苯二甲酰胺(C1);
N1-(2-氨基苯基)-N3-((1-苄基哌啶-4-基)甲基)间苯二甲酰胺(C2);
N-(2-氨基苯基)-4-(3-(((1-苄基哌啶-4-基)甲基)氨基)-3-氧丙基)苯甲酰胺(C3);
4-(3-((2-氨基苯基)氨基)-3-氧丙基)-N-((1-苄基哌啶-4-基)甲基)苯甲酰胺(C4);
3-(3-((2-氨基苯基)氨基)-3-氧丙基)-N-((1-苄基哌啶-4-基)甲基)苯甲酰胺(C5);
4-(3-((2-氨基苯基)氨基)-3-氧丙基)-N-((1-苄基哌啶-4-基)甲基)-2-甲氧基苯甲酰胺(C6);
(E)-N-(2-氨基苯基)-4-(3-(((1-苄基哌啶-4-基)甲基)氨基)-3-氧丙-1-烯-1-基)苯甲酰胺(C7);
(E)-4-(3-((2-氨基苯基)氨基)-3-氧代丙-1-烯-1-基)-N-((1-苄基哌啶-4-基)甲基)苯甲酰胺(C8);
(E)-3-(3-((2-氨基苯基)氨基)-3-氧代丙-1-烯-1-基)-N-((1-苄基哌啶-4-基)甲基)苯甲酰胺(C9);
(E)-4-(3-((2-氨基苯基)氨基)-3-氧代丙-1-烯-1-基)-N-((1-苄基哌啶-4-基)甲基)-2-甲氧基苯甲酰胺(C10);
N1-(2-氨基苯基)-N7-((1-苄基哌啶-4-基)甲基)庚二酰胺(C11);
N1-(2-氨基苯基)-N8-((1-苄基哌啶-4-基)甲基)辛二酰胺(C12);
N1-(2-氨基苯基)-N9-((1-苄基哌啶-4-基)甲基)壬二酰胺(C13);
N-(2-氨基苯基)-4-(N-((1-苄基哌啶-4-基)甲基)氨磺酰基)苯甲酰胺(D1);
N-(2-氨基苯基)-3-(N-((1-苄基哌啶-4-基)甲基)氨磺酰基)苯甲酰胺(D2);
4-((((1-苄基哌啶-4-基)甲基)氨基)甲基)-N-羟基苯甲酰胺(E1)。
本发明第二方面,提供一种靶点多奈哌齐-异羟肟酸型化合物的制备方法。
包括按照以下反应路线进行:
反应路线一:
其中,X如上文所述,R2选自CH3O-或CH3CH2O-;
或反应路线二:
其中,X如上文所述,R2选自CH3O-;
或反应路线三:
其中,X如上文所述,R2选自CH3O-或CH3CH2O-;
或反应路线四:
其中,X如上文所述,R2选自CH3O-;
或反应路线五:
其中,X如上文所述,R2选自CH3O-。
在本发明一些较为具体的一些实施方式中,式(W1)化合物(或者A系列)的合成路线如下:
其中,R2选自CH3O-或CH3CH2O-,X选自以下结构片段:
在一些更为具体的实施方式中,式(W1)化合物的制备方法包括以下步骤:
将中间体4结构中X所示的对应二酸单酯作为反应原料,溶解,再加入中间体3、TEA和TBTU,室温反应,分离提纯得到中间体4。中间体4加入NH2OK甲醇溶液,室温下反应,调pH7-8析出固体,真空干燥得式(W1)化合物,即反应路线中式A所示的目标化合物。
或者:将中间体2冰浴条件下加入LiAlH4,室温反应一段时间,冰浴中搅拌,滴加H2O淬灭反应,搅拌得到中间体3。将中间体4结构中X所示的对应二酸单酯作为反应原料,溶解,再加入中间体3、TEA和TBTU,室温反应,分离提纯得到中间体4。中间体4加入NH2OK甲醇溶液,室温下反应,调pH 7-8析出固体,真空干燥得式(W1)化合物,即反应路线中式A所示的目标化合物。
或者:将1-哌啶-4-甲酰胺溶解,加入K2CO3、苄溴,加热回流,反应一段时间后,过滤除杂,得到中间体2,将中间体2冰浴条件下加入LiAlH4,室温反应一段时间,冰浴中搅拌,滴加H2O淬灭反应,搅拌得到中间体3。将中间体4结构中X所示的对应二酸单酯作为反应原料,溶解,再加入中间体3、TEA和TBTU,室温反应,分离提纯得到中间体4。中间体4加入NH2OK甲醇溶液,室温下反应,调pH 7-8析出固体,真空干燥得式(W1)化合物,即反应路线中式A所示的目标化合物。
所述加热温度为70-90℃,优选为80℃。
更具体包括:
将1-哌啶-4-甲酰胺投入茄型反应瓶,加入适量乙醇溶解,再加入K2CO3做碱,将苄溴滴加至反应瓶中。80℃回流反应,TLC监测反应进程,产物无明显紫外吸收,碘熏显色。6h后反应结束。将反应液冷却至室温,过滤除去K2CO3,滤液用无水硫酸镁干燥30min,过滤,滤液减压蒸除溶剂,真空干燥得到中间体2。将中间体2溶解于无水四氢呋喃中,冰浴下搅拌,待反应液温度降至4℃左右缓慢加入LiAlH4,加毕,撤去冰浴。室温下反应,TLC监测反应进程,30min后反应完成。将反应瓶重新放置于冰浴中搅拌,滴加H2O淬灭反应,加水至不再产生气泡,加毕,室温搅拌30min,过滤,滤液蒸干得到中间体3。中间体3不经纯化直接用于后续反应。将中间体4结构中X所示的对应二酸单酯作为反应原料投入茄型反应瓶中,加入适量DMF溶解,再依次加入中间体3,TEA和TBTU。加毕,室温下搅拌反应,4h后TLC监测反应显示反应完全。停止反应,向反应瓶中加入乙酸乙酯稀释反应液,后转移至分液漏斗分别加入适量乙酸乙酯和水进行萃取。饱和氯化钠洗涤有机相。有机相无水硫酸镁干燥,过滤,滤液减压蒸除挥发性物质。得到粗品,柱层析纯化:2%乙酸乙酯(98%石油醚)至100%乙酸乙酯冲出产物。得到中间体4。将中间体4投入茄形反应瓶,加入NH2OK甲醇溶液,室温下搅拌反应,TLC监测反应进程,30min反应完全。停止反应,减压蒸除挥发物。2N HCl调pH 7-8析出固体黏附于瓶底,弃去上清,瓶内固体用油泵减压蒸除挥发物,真空干燥得式(W1)化合物,即反应路线中式A所示的目标化合物,
在本发明一些较为具体的一些实施方式中,式(W2)化合物(或者B系列)的合成路线如下:
在一些更为具体的实施方式中,式(W2)化合物的制备方法包括以下步骤:
将4-(氯磺酰基)苯甲酸甲酯或3-(氯磺酰基)苯甲酸甲酯与中间体3溶于溶剂中,室温反应,加入环己烷,得到中间体5。中间体5加入NH2OK甲醇溶液,室温反应,调pH 7-8析出固体,真空干燥得式(W2)化合物,即反应路线中式B所示的目标化合物。
或者:将中间体2冰浴条件下加入LiAlH4,室温反应一段时间,冰浴中搅拌,滴加H2O淬灭反应,搅拌得到中间体3。将4-(氯磺酰基)苯甲酸甲酯或3-(氯磺酰基)苯甲酸甲酯与中间体3溶于溶剂中,室温反应,加入环己烷,得到中间体5。中间体5加入NH2OK甲醇溶液,室温反应,调pH 7-8析出固体,真空干燥得式(W2)化合物,即反应路线中式B所示的目标化合物。
或者:将1-哌啶-4-甲酰胺溶解,加入K2CO3、苄溴,加热回流,反应一段时间后,过滤除杂,得到中间体2,将中间体2冰浴条件下加入LiAlH4,室温反应一段时间,冰浴中搅拌,滴加H2O淬灭反应,搅拌得到中间体3。将4-(氯磺酰基)苯甲酸甲酯或3-(氯磺酰基)苯甲酸甲酯与中间体3溶于溶剂中,室温反应,加入环己烷,得到中间体5。中间体5加入NH2OK甲醇溶液,室温反应,调pH 7-8析出固体,真空干燥得式(W2)化合物,即反应路线中式B所示的目标化合物。
更具体包括:
将4-(氯磺酰基)苯甲酸甲酯和3-(氯磺酰基)苯甲酸甲酯分别和中间体3溶于吡啶中。室温下搅拌反应,4h后TLC监测反应显示反应完全。停止反应,向反应瓶中加入适量环己烷,减压蒸除挥发性物质。得到粗品,柱层析纯化:100%乙酸乙酯冲出产物。得到中间体5。将中间体5投入茄形反应瓶,加入NH2OK甲醇溶液,室温下搅拌反应,TLC监测反应进程,30min反应完全。停止反应,减压蒸除挥发物。2N HCl调pH 7-8析出固体黏附于瓶底,弃去上清,瓶内固体用油泵减压蒸除挥发物,真空干燥得式(W2)化合物,即反应路线中式B所示的目标化合物。
在本发明一些较为具体的一些实施方式中,式(W3)化合物(或者C系列)的合成路线如下:
其中,R2选自CH3O-或CH3CH2O-,X选自以下结构片段:
在一些更为具体的实施方式中,式(W3)化合物的制备方法包括以下步骤:
将中间体4与甲醇和LiOH加热回流反应,反应结束后,调pH 5-6析出固体,加入溶剂和TEA,TBTU和邻苯二胺,室温反应,经萃取、干燥获得式(W3)化合物,即反应路线中式C所示的目标化合物。
更具体包括:
中间体3到中间体4方法如本发明中制备式(W1)所示。将中间体4加入圆底烧瓶中,依次加入适量甲醇和LiOH,80℃回流反应,6h后TLC监测反应完全。停止加热,减压蒸除溶剂,向反应瓶中加入少量水,2N HCl调pH 5-6析出固体,过滤得到中间体4的水解产物。干燥后不经过进一步处理,加入适量DMF作溶剂,依次加入TEA,TBTU和邻苯二胺。室温下搅拌反应,4h后,TLC监测反应完全。停止反应,反应液中加入与溶剂等体积的水,乙酸乙酯萃取两次,有机相用饱和食盐水洗涤两次,收集有机相,无水MgSO4干燥,过滤,滤液蒸干,得到淡黄色固体粗品,乙酸乙酯打浆纯化。过滤,滤饼为式(W3)化合物,即反应路线中式C所示的目标化合物。
在本发明一些较为具体的一些实施方式中,式(W4)化合物(或者D系列)的合成路线如下:
在一些更为具体的实施方式中,式(W4)化合物的制备方法包括以下步骤:
将4-(氯磺酰基)苯甲酸甲酯或3-(氯磺酰基)苯甲酸甲酯分别和中间体3溶于溶剂中,室温反应,纯化得到中间体5,将中间体5与甲醇和LiOH加热回流,调pH 5-6析出固体,加入溶剂,依次加入TEA,TBTU和邻苯二胺,室温反应,得到淡黄色固体粗品,乙酸乙酯打浆纯化。过滤,滤饼为式(W4)化合物,即反应路线中式D所示的目标化合物。
更具体包括:
将4-(氯磺酰基)苯甲酸甲酯或3-(氯磺酰基)苯甲酸甲酯分别和中间体3溶于吡啶中。室温下搅拌反应,4h后TLC监测反应显示反应完全。停止反应,向反应瓶中加入适量环己烷,减压蒸除挥发性物质。得到粗品,柱层析纯化:100%乙酸乙酯冲出产物。得到中间体5。将中间体5加入圆底烧瓶中,依次加入适量甲醇和LiOH,80℃回流反应,6h后TLC监测反应完全。停止加热,减压蒸除溶剂,向反应瓶中加入少量水,2N HCl调pH 5-6析出固体,过滤得到中间体5的水解产物。干燥后不经过进一步处理,加入适量DMF作溶剂,依次加入TEA,TBTU和邻苯二胺。室温下搅拌反应,4h后,TLC监测反应完全。停止反应,反应液中加入与溶剂等体积的水,乙酸乙酯萃取两次,有机相用饱和食盐水洗涤两次,收集有机相,无水MgSO4干燥,过滤,滤液蒸干,得到淡黄色固体粗品,乙酸乙酯打浆纯化。过滤,滤饼为式(W4)化合物,即反应路线中式D所示的目标化合物。
在本发明一些较为具体的一些实施方式中,式(W5)化合物(或者E系列)的合成路线如下:
更具体包括:
将中间体3和甲酰基苯甲酸甲酯依次加入圆底烧瓶中,MeOH做溶剂,室温反应1小时后,加入NaBH4,室温反应12h。TLC监测反应,反应完成。减压蒸除反应溶剂,乙酸乙酯萃取,柱层析纯化乙酸乙酯:石油醚=1:15冲出产物,真空干燥得式(W5)化合物,即反应路线中式E所示的目标化合物。
本发明第三方面,提供一种药物组合物,其包括多靶点多奈哌齐-异羟肟酸型化合物、其药学上可接受的盐、其立体异构体、同位素标记物、溶剂化物、多晶型物、互变异构体、代谢产物或前药以及药学上可接受的载体或赋形剂。
优选地,所述载体可以为固体或者液体;
优选地,所述药物组合物可制成口服制剂或肠胃外给药制剂;
优选地,药物组合物可以为片剂、丸剂、胶囊或注射剂;
优选地,所述药物组合物为抑制HDACs和/或AChE和/或BChE活性的药物。
本发明一些实施方式所述的药物组合物通常安全、无毒且为生物学上所需要的,本发明中所述药学上可接受的载体或辅料是无毒且安全的,而且其与本发明所述化合物的组合也是无毒且安全的。本发明所述的药学上可接受的载体和辅料通常为本领域人员所熟知的,或者可由本领域技术人员根据实际情况能够确定的。合适的载体和辅料的实例包括葡萄糖、水、甘油、乙醇、丙二醇、玉米淀粉、明胶、乳糖、蔗糖、海藻酸、微晶纤维素、高岭土、甘露醇、磷酸二钙、氯化钠、交联羧甲基纤维素钠和淀粉羟乙酸钠等等聚山梨酯80、聚乙二醇300、聚乙二醇400、环糊精或其衍生物,比如((2-羟基丙基)-环糊精)和(2-羟基乙基)-环糊精,其又称为HPCD、聚乙二醇化蓖麻油、泊洛沙姆(比如泊洛沙姆407或188);亲水载体、疏水载体,或其组合等。疏水载体包括,例如脂肪乳剂、脂质、聚乙二醇化磷脂、生物相容的聚合物、脂质球、脂质体、小囊泡、聚合物基质、颗粒等等。此外,本领域技术人员会理解的是,稀释剂包括在术语载体和辅料的范围之内。
载体或辅料在药物组合物中的含量可以是1wt%-98wt%,通常大约占到80wt%。为方便起见,局部麻醉剂、防腐剂、缓冲剂等可直接溶于载体中。
本发明一些实施方式所述化合物的药物组合物,可以以选自以下任意方式施与:口服、喷雾吸入、直肠给药、鼻腔给药、阴道给药、局部给药、非肠道给药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内或颅内注射或输入,或借助一种外植的储器用药,其中优选口服、肌注、腹膜内或静脉内用药方式。药物剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混旋剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、填埋剂、贴剂、擦剂等。
本发明第四方面,提供一种多靶点多奈哌齐-异羟肟酸型化合物、其药学上可接受的盐、其立体异构体、同位素标记物、溶剂化物、多晶型物、互变异构体、代谢产物或前药在制备同时抑制HDACs和AChE的药物中的应用。
本发明第五方面,提供一种靶点多奈哌齐-异羟肟酸型化合物、其药学上可接受的盐、其立体异构体、同位素标记物、溶剂化物、多晶型物、互变异构体、代谢产物或前药在制备HDACs和/或AChE和/或BChE抑制剂药物中的应用。
本发明第六方面,提供一种多靶点多奈哌齐-异羟肟酸型化合物、其药学上可接受的盐、其立体异构体、同位素标记物、溶剂化物、多晶型物、互变异构体、代谢产物或前药在制备预防和/或治疗神经退行性疾病的药物中的应用。
优选地,所述神经退行性疾病为阿尔茨海默病;
优选地,所述治疗神经退行性疾病的药物为抑制组蛋白去乙酰化酶和/或乙酰胆碱酯酶活性的药物。
下面结合具体的实施例,对本发明做进一步的详细说明,应该指出,所述具体实施例是对本发明的解释而不是限定。
实施例1:目标化合物A1-A13的合成
中间体4a-4m的合成
中间体甲基4-(((1-苄基哌啶-4-基)甲基)氨基甲酰基)苯甲酸酯(4a)的制备
将对苯二甲酸单甲酯(0.44g,2.45mmol)投入50ml茄型反应瓶中,加入20ml DMF溶解,再依次加入中间体3(0.50g,2.45mmol),TEA(0.74g,7.35mmol),TBTU(0.94g,2.94mmol)。加毕,室温下搅拌反应,4h后TLC监测反应显示反应完全。停止反应,向反应瓶中加入20ml乙酸乙酯稀释反应液,后转移至250ml分液漏斗分别加入适量乙酸乙酯和水进行萃取。饱和氯化钠洗涤有机相。有机相无水硫酸镁干燥,过滤,滤液减压蒸除挥发性物质。得到0.92g红棕色油状物,柱层析纯化:2%乙酸乙酯(98%石油醚)至100%乙酸乙酯冲出产物。减压蒸除挥发物,真空干燥后得中间体4a,得白色固体,收率:70.0%。
中间体3-(((1-苄基哌啶-4-基)甲基)氨基甲酰基)苯甲酸甲酯(4b)的制备
方法同中间体4a,底物中间体3和对苯二甲酸单甲酯,收率:43.2%。
中间体4-(3-(((1-苄基哌啶-4-基)甲基)氨基)-3-氧丙基)苯甲酸甲酯(4c)的制备
方法同中间体4a,底物中间体3和3-(4-(甲氧基羰基)苯基)丙酸,收率:60.9%。
中间体3-(4-(((1-苄基哌啶-4-基)甲基)氨基甲酰基)苯基)丙酸乙酯(4d)的制备
方法同中间体4a,底物中间体3和4-(3-乙氧基-3-氧代丙基)苯甲酸,收率:58.3%。
中间体3-(3-(((1-苄基哌啶-4-基)甲基)氨基甲酰基)苯基)丙酸乙酯(4e)的制备
方法同中间体4a,底物中间体3和3-(3-乙氧基-3-氧代丙基)苯甲酸,收率:33.2%。
中间体3-(4-(((1-苄基哌啶-4-基)甲基)氨基甲酰基)-3-甲氧基苯基)丙酸乙酯(4f)的制备
方法同中间体4a,底物中间体3和4-(3-乙氧基-3-氧代丙基)-2-甲氧基苯甲酸,收率:51.3%。
中间体(E)-4-(3-(((1-苄基哌啶-4-基)甲基)氨基)-3-氧代丙-1-烯-1-基)苯甲酸甲酯(4g)的制备
方法同中间体4a,底物中间体3和(E)-3-(4-(甲氧羰基)苯基)丙烯酸,收率:40.7%。
中间体(E)-3-(4-(((1-苄基哌啶-4-基)甲基)氨基甲酰基)苯基)丙烯酸乙酯(4h)的制备
方法同中间体4a,底物中间体3和(E)-4-(3-乙氧基-3-氧代丙-1-烯-1-基)苯甲酸,收率:32.6%。
中间体(E)-3-(3-(((1-苄基哌啶-4-基)甲基)氨基甲酰基)苯基)丙烯酸乙酯(4i)的制备
方法同中间体4a,底物中间体3和(E)-3-(3-乙氧基-3-氧代丙-1-烯-1-基)苯甲酸,收率:50.2%。
中间体(E)-3-(4-(((1-苄基哌啶-4-基)甲基)氨基甲酰基)-3-甲氧基苯基)丙烯酸乙酯(4j)的制备
方法同中间体4a,底物中间体3和(E)-4-(3-乙氧基-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酸,收率:74.4%。
中间体7-(((1-苄基哌啶-4-基)甲基)氨基)-7-氧庚酸乙酯(4k)的制备
方法同中间体4a,底物中间体3和庚二酸单乙酯,收率:36.5%。
中间体8-(((1-苄基哌啶-4-基)甲基)氨基)-8-氧辛酸甲酯(4l)的制备
方法同中间体4a,底物中间体3和辛二酸单甲酯,收率:49.4%。
中间体9-(((1-苄基哌啶-4-基)甲基)氨基)-9-氧壬酸甲酯(4m)的制备
方法同中间体4a,底物中间体3和壬二酸单甲酯,收率:39.2%。
目标化合物A1-A13的合成
N1-((1-benzylpiperidin-4-yl)methyl)-N4-hydroxyterephthalamide(A1)
N1-((1-苄基哌啶-4-基)甲基)-N4-羟基对苯二甲酰胺(A1)
羟胺钾甲醇溶液的制备:a)将14.18g KOH在冰浴环境下加入到35ml MeOH中,加毕,撤去冰浴,室温下搅拌10min,制得饱和溶液A。b)将11.68g NH2OH·HCl加入到60mlMeOH中,室温搅拌10min,制得饱和溶液B。冰浴环境下,将溶液A倾倒入溶液B中,室温搅拌15min,过滤,收集滤液制得羟胺钾甲醇溶液备用。将中间体4a投入25ml茄形反应瓶,加入8ml NH2OK甲醇溶液,室温下搅拌反应,TLC监测反应进程,30min反应完全。停止反应,减压蒸除挥发物。2N HCl调pH 7-8析出固体黏附于瓶底,弃去上清,瓶内固体用油泵减压蒸除挥发物,真空干燥得目标化合物A1,产率60.0%,Mp:175-177℃,ESI-MS m/z:368.51[M+H+],1HNMR(600MHz,DMSO-d6)δ9.29(d,J=138.5Hz,1H),8.57(t,J=5.8Hz,1H),7.88(d,J=8.0Hz,2H),7.81(d,J=8.2Hz,2H),7.34–7.21(m,5H),3.43(s,2H),3.15(t,J=6.4Hz,2H),2.79(dt,J=11.6,3.6Hz,2H),1.88(td,J=11.6,2.5Hz,2H),1.64(dd,J=13.4,3.5Hz,2H),1.56(ddp,J=11.3,7.7,3.9Hz,1H),1.25–1.14(m,2H).13C NMR(101MHz,DMSO)δ166.12,163.80,139.12,137.28,135.52,133.53,129.18,128.57,127.69,127.24,62.90,53.42,45.34,36.15,30.29.HPLC purity:98.3%.
本实施例中化合物A1-A13,B1-B2,C1-C13,D1-D2和E1纯度采用HPLC测定,实验条件:岛津LC-20AT液相仪,SPD-20A检测器,Inertsil ODS-3 4.6*150mm*5μm色谱柱,60%乙腈和40%的0.1%三氟乙酸做流动性,240nm检测波长(化合物A11-A13检测波长为210nm)
N1-((1-benzylpiperidin-4-yl)methyl)-N3-hydroxyisophthalamide(A2)
N1-((1-苄基哌啶-4-基)甲基)-N3-羟基对苯二甲酰胺(A2)
目标化合物A2的合成同A1的合成方法,以中间体4b为原料,得淡黄色固体,产率52.8%,Mp:158-160℃,ESI-MS m/z:369.13[M+H+],1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),9.17(s,1H),8.57(t,J=5.8Hz,1H),8.22(t,J=1.8Hz,1H),7.93(d,J=7.8Hz,1H),7.85(dt,J=7.7,1.4Hz,1H),7.52(t,J=7.7Hz,1H),7.37–7.19(m,5H),3.43(s,2H),3.16(t,J=6.3Hz,2H),2.79(dt,J=11.7,3.4Hz,2H),1.89(td,J=11.5,2.4Hz,2H),1.65(d,J=12.8Hz,2H),1.61–1.50(m,0H),1.19(qd,J=11.9,3.7Hz,2H).13C NMR(101MHz,DMSO)δ166.36,163.99,139.19,135.30,129.58,129.16,128.72,128.56,127.22,126.31,62.93,53.45,45.36,36.17,30.33.HPLC purity:99.9%
4-(3-(((1-benzylpiperidin-4-yl)methyl)amino)-3-oxopropyl)-N-hydroxybenzamide(A3)
4-(3-(((1-苄基哌啶-4-基)甲基)氨基)-3-氧丙基)-N-羟基苯甲酰胺(A3)
目标化合物A3的合成同A1的合成方法,以中间体4c为原料,得白色固体,产率:21.9%,Mp:166-168℃,ESI-MS m/z:396.28[M+H+],1H NMR(600MHz,DMSO-d6)δ11.15(s,1H),9.07(s,1H),7.82(t,J=5.8Hz,1H),7.67–7.64(m,2H),7.30(d,J=7.3Hz,2H),7.28–7.22(m,5H),3.41(s,2H),2.89(t,J=6.3Hz,2H),2.83(t,J=7.6Hz,2H),2.74(dt,J=11.7,3.3Hz,2H),2.38(t,J=7.6Hz,2H),1.82(td,J=11.7,2.5Hz,2H),1.52–1.46(m,2H),1.33–1.24(m,1H),1.05(qd,J=12.1,3.9Hz,2H).13C NMR(101MHz,DMSO)δ171.54,166.10,139.09,129.21,128.64,128.57,127.25,127.19,62.87,53.38,44.58,37.01,36.11,31.43,30.10.HPLC purity:99.7%.
N-((1-benzylpiperidin-4-yl)methyl)-4-(3-(hydroxyamino)-3-oxopropyl)benz amide(A4)
N-((1-苄基哌啶-4-基)甲基)-4-(3-(羟基氨基)-3-氧丙基)苯甲酰胺(A4)
目标化合物A4的合成同A1的合成方法,以中间体4d为原料,得白色固体,产率38.9%,Mp:150-152℃,ESI-MS m/z:396.49[M+H+],1H NMR(600MHz,DMSO-d6)δ10.38(s,1H),8.74(s,1H),8.40(t,J=5.8Hz,1H),7.75(d,J=7.9Hz,2H),7.27(ddq,J=23.0,14.2,7.4Hz,7H),3.43(s,2H),3.13(t,J=6.3Hz,2H),2.85(t,J=7.6Hz,2H),2.78(d,J=11.1Hz,2H),2.28(q,J=8.9,7.6Hz,2H),1.87(q,J=8.1,4.5Hz,2H),1.66–1.59(m,2H),1.54(ddq,J=11.0,7.5,4.3,3.6Hz,1H),1.27–1.09(m,2H).13C NMR(101MHz,DMSO)δ168.52,166.57,144.75,139.16,132.93,129.17,128.57,128.53,127.70,127.23,62.92,53.45,45.23,36.23,34.01,31.08,30.32.HPLC purity:99.7%.
N-((1-benzylpiperidin-4-yl)methyl)-3-(3-(hydroxyamino)-3-oxopropyl)benz amide(A5)
N-((1-苄基哌啶-4-基)甲基)-3-(3-(羟基氨基)-3-氧丙基)苯甲酰胺(A5)
目标化合物A5的合成同A1的合成方法,以中间体4e为原料,得黄白色固体,产率45.5%,Mp:128-130℃,ESI-MS m/z:396.99[M+H+],1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.72(s,1H),8.42(t,J=5.8Hz,1H),7.75–7.60(m,2H),7.43–7.20(m,6H),3.46(s,2H),3.14(t,J=6.3Hz,2H),2.92–2.76(m,4H),2.29(t,J=7.7Hz,2H),1.92(t,J=11.6Hz,2H),1.60(ddd,J=35.2,10.4,3.6Hz,3H),1.30–1.09(m,2H).13C NMR(101MHz,DMSO)δ168.61,166.84,141.60,135.24,131.35,129.29,128.58,127.60,127.34,125.38,62.76,53.35,45.22,36.10,34.24,31.28,30.18.HPLC purity:99.6%.
N-((1-benzylpiperidin-4-yl)methyl)-4-(3-(hydroxyamino)-3-oxopropyl)-2-methox ybenzamide(A6)
N-((1-苄基哌啶-4-基)甲基)-4-(3-(羟氨基)-3-氧丙基)-2-甲氧基苯甲酰胺(A6)
目标化合物A6的合成同A1的合成方法,以中间体4f为原料,得白色固体,产率63.9%,Mp:130-132℃,ESI-MS m/z:426.44[M+H+],1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.77(s,1H),8.08(t,J=5.9Hz,1H),7.63(d,J=7.8Hz,1H),7.36–7.17(m,5H),6.96(d,J=1.5Hz,1H),6.85(dd,J=7.9,1.4Hz,1H),3.86(s,3H),3.43(s,2H),3.16(t,J=6.3Hz,2H),2.93–2.73(m,4H),2.28(t,J=7.7Hz,2H),1.89(td,J=11.6,2.4Hz,2H),1.70–1.58(m,2H),1.57–1.46(m,1H),1.19(qd,J=12.0,3.8Hz,2H).13C NMR(101MHz,DMSO)δ165.31,157.36,146.26,139.20,130.93,129.14,128.55,127.21,121.47,120.85,112.40,62.91,56.35,53.44,44.99,40.45,40.24,36.26,33.96,31.41,30.22.HPLC purity:99.9%.
(E)-4-(3-(((1-benzylpiperidin-4-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-N-hydroxybenzamide(A7)
(E)-4-(3-(((1-苄基哌啶-4-基)甲基)氨基)-3-氧代丙-1-烯-1-基)-N-羟基苯甲酰胺(A7)
目标化合物A7的合成同A1的合成方法,以中间体4g为原料,得淡黄色固体,产率48.8%,Mp:164-166℃,ESI-MS m/z:394.26[M+H+],1H NMR(600MHz,DMSO-d6)δ11.27(s,1H),9.12(s,1H),8.19(t,J=5.8Hz,1H),7.78(d,J=8.2Hz,2H),7.62(d,J=8.3Hz,2H),7.43(d,J=15.8Hz,1H),7.33–7.21(m,5H),6.73(d,J=15.8Hz,1H),3.43(s,2H),3.08(t,J=6.3Hz,2H),2.79(dt,J=11.8,3.4Hz,2H),1.88(td,J=11.6,2.5Hz,2H),1.65–1.59(m,2H),1.44(ddt,J=11.3,7.8,4.1Hz,1H),1.25–1.12(m,2H).13C NMR(101MHz,DMSO)δ165.22,139.19,137.95,129.16,128.57,127.81,127.23,124.29,62.92,53.43,44.83,36.27,30.21.HPLC purity:99.8%.
(E)-N-((1-benzylpiperidin-4-yl)methyl)-4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzamide(A8)
(E)-N-((1-苄基哌啶-4-基)甲基)-4-(3-(羟基氨基)-3-氧代丙-1-烯-1-基)苯甲酰胺(A8)
目标化合物A8的合成同A1的合成方法,以中间体4h为原料,得白色固体,产率45.82%,Mp:170-172℃,ESI-MS m/z:394.61[M+H+],1H NMR(600MHz,DMSO-d6)δ9.34(s,1H),8.52(t,J=5.8Hz,1H),7.86(d,J=8.1Hz,2H),7.63(d,J=7.9Hz,2H),7.49–7.37(m,1H),7.34–7.20(m,5H),6.55(d,J=15.8Hz,1H),3.43(s,2H),3.15(t,J=6.3Hz,2H),2.79(dt,J=12.2,3.4Hz,2H),1.88(td,J=11.6,2.5Hz,2H),1.68–1.61(m,2H),1.55(dqt,J=10.2,6.4,3.1Hz,1H),1.26–1.14(m,2H).13C NMR(101MHz,DMSO)δ166.17,162.74,139.18,137.89,135.50,133.40,129.16,128.56,128.25,127.68,127.22,121.34,62.92,53.44,45.33,36.20,30.33.HPLC purity:99.5%.
(E)-N-((1-benzylpiperidin-4-yl)methyl)-3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzamide(A9)
(E)-N-((1-苄基哌啶-4-基)甲基)-3-(3-(羟基氨基)-3-氧代丙-1-烯-1-基)苯甲酰胺(A9)
目标化合物A9的合成同A1的合成方法,以中间体4i为原料,得淡黄色固体,产率50.8%,Mp:144-146℃,ESI-MS m/z:394.41[M+H+],1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),9.05(s,1H),8.52(d,J=6.1Hz,1H),8.02(s,1H),7.81(d,J=7.8Hz,1H),7.68(d,J=7.7Hz,1H),7.54–7.42(m,2H),7.37–7.17(m,5H),6.54(dd,J=15.8,2.3Hz,1H),3.48(s,2H),3.22–3.13(m,2H),2.82(d,J=10.9Hz,2H),2.00–1.87(m,2H),1.66(d,J=13.1Hz,2H),1.58(s,1H),1.26–1.18(m,2H).13C NMR(101MHz,DMSO)δ166.39,162.93,138.00,135.78,135.41,130.60,129.36,128.60,127.41,126.37,120.59,62.64,53.28,45.24,40.24,36.03,30.07.HPLC purity:99.9%.
(E)-N-((1-benzylpiperidin-4-yl)methyl)-4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)-2-methoxybenzamide(A10)
(E)-N-((1-苄基哌啶-4-基)甲基)-4-(3-(羟基氨基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酰胺(A10)
目标化合物A10的合成同A1的合成方法,以中间体4j为原料,得淡黄色固体,产率75.1%,Mp:156-158℃,ESI-MS m/z:424.37[M+H+],1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),9.12(s,1H),8.17(t,J=5.9Hz,1H),7.70(d,J=7.9Hz,1H),7.48(d,J=15.8Hz,1H),7.32(d,J=6.0Hz,6H),7.22(dd,J=8.1,1.4Hz,1H),6.56(d,J=15.9Hz,1H),3.91(s,3H),3.49(s,1H),3.17(t,J=6.3Hz,2H),2.91–2.77(m,2H),1.95(s,2H),1.66(d,J=12.8Hz,2H),1.56(s,1H),1.23(s,3H).13C NMR(101MHz,DMSO)δ165.10,162.83,157.54,138.93,137.89,131.23,129.46,128.63,127.52,124.57,121.34,119.64,111.75,62.49,56.46,53.18,44.92,35.97,29.77.HPLC purity:99.9%.
N1-((1-benzylpiperidin-4-yl)methyl)-N7-hydroxyheptanediamide(A11)
N1-((1-苄基哌啶-4-基)甲基)-N7-羟基庚二酰胺(A11)
目标化合物A11的合成同A1的合成方法,以中间体4k为原料,得橙黄色油状物,产率49.7%,ESI-MS m/z:362.57[M+H+],1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.67(s,1H),7.71(t,J=6.0Hz,1H),7.35–7.19(m,5H),3.42(s,2H),2.91(t,J=6.2Hz,2H),2.76(dt,J=11.6,3.5Hz,2H),2.04(t,J=7.5Hz,2H),1.96–1.81(m,4H),1.59–1.55(m,2H),1.47(s,2H),1.36(ddq,J=11.1,7.7,3.9Hz,1H),1.28–1.04(m,6H).13C NMR(101MHz,DMSO)δ172.48,169.46,139.17,129.15,128.55,127.21,62.93,53.43,44.54,36.20,35.73,32.63,30.20,28.75,25.58,25.39.HPLC purity:99.5%.
N1-((1-benzylpiperidin-4-yl)methyl)-N8-hydroxyoctanediamide(A12)
N1-((1-苄基哌啶-4-基)甲基)-N8-羟基辛二酰胺(A12)
目标化合物A12的合成同A1的合成方法,以中间体4l为原料,得橙红色油状物,产率66.6%,ESI-MS m/z:390.63[M+H+],1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.70(s,1H),7.75(t,J=5.8Hz,1H),7.37–7.17(m,5H),3.42(s,2H),2.91(t,J=6.2Hz,2H),2.77(dt,J=11.6,3.5Hz,2H),2.04(t,J=7.4Hz,2H),1.97–1.82(m,4H),1.57(dd,J=13.0,3.5Hz,2H),1.46(p,J=7.3Hz,4H),1.35(ddt,J=11.1,7.6,4.1Hz,1H),1.25–1.05(m,6H).13C NMR(101MHz,DMSO)δ172.84,169.65,131.88,130.62,129.68,129.07,59.25,51.48,48.99,43.75,35.77,32.66,28.84,28.76,26.99,25.69,25.50.HPLC purity:98.8%.
N1-((1-benzylpiperidin-4-yl)methyl)-N9-hydroxynonanediamide(A13)
N1-((1-苄基哌啶-4-基)甲基)-N9-羟基壬二酰胺(A13)
目标化合物A13的合成同A1的合成方法,以中间体4m为原料,得灰绿色油状物,产率40.1%,ESI-MS m/z:390.71[M+H+],1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.63(s,1H),7.71(t,J=5.8Hz,1H),7.29(p,J=7.0,6.5Hz,5H),3.42(s,2H),2.91(t,J=6.2Hz,2H),2.77(dd,J=11.7,3.5Hz,2H),2.04(t,J=7.4Hz,2H),1.96–1.83(m,4H),1.58–1.54(m,2H),1.46(s,2H),1.35(ddt,J=11.1,7.7,3.9Hz,1H),1.28–1.07(m,10H).13C NMR(101MHz,DMSO)δ172.53,169.54,139.16,129.16,128.56,127.23,62.90,53.42,44.51,36.22,35.84,32.71,30.19,29.03,28.96,28.94,25.81,25.55.HPLC purity:99.7%.
实施例2:目标化合物B1-B2的合成
中间体5a-5b的合成
中间体4-(N-((1-苄基哌啶-4-基)甲基)氨磺酰基)苯甲酸甲酯(5a)的制备
将4-(氯磺酰基)苯甲酸甲酯(0.10g,0.43mmol)和中间体3(0.09g,0.43mmol)溶于吡啶中。室温下搅拌反应,4h后TLC监测反应显示反应完全。停止反应,向反应瓶中加入适量环己烷,减压蒸除挥发性物质。得到粗品,柱层析纯化:100%乙酸乙酯冲出产物。得到中间体5a,真空干燥得白色固体,收率:58.8%。
中间体3-(N-((1-苄基哌啶-4-基)甲基)氨磺酰基)苯甲酸甲酯(5b)的制备
方法同中间体5a,底物中间体3和4-(氯磺酰基)苯甲酸甲酯,收率:56.4%。
目标化合物B1-B2的合成
4-(N-((1-benzylpiperidin-4-yl)methyl)sulfamoyl)-N-hydroxybenzamide(B1)
4-(N-((1-苄基哌啶-4-基)甲基)氨磺酰基)-N-羟基苯甲酰胺(B1)
将中间体5a(0.22g,0.54mmol)投入茄形反应瓶,加入NH2OK甲醇溶液,室温下搅拌反应,TLC监测反应进程,30min反应完全。停止反应,减压蒸除挥发物。2N HCl调pH 7-8析出固体黏附于瓶底,弃去上清,瓶内固体用油泵减压蒸除挥发物,真空干燥得目标产物B1,淡黄色固体,产率73.4%,Mp:146-148℃,ESI-MS m/z:404.42[M+H+],1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),9.21(s,1H),7.91(d,J=8.1Hz,2H),7.84(d,J=8.2Hz,2H),7.72(t,J=6.0Hz,1H),7.34–7.19(m,5H),3.42(s,2H),2.75(dd,J=9.5,5.5Hz,2H),2.63(t,J=6.4Hz,2H),1.85(t,J=11.3Hz,2H),1.58(d,J=12.7Hz,2H),1.33(ddt,J=13.3,9.8,5.0Hz,1H),1.06(qd,J=12.0,3.8Hz,2H).13C NMR(101MHz,DMSO)δ163.30,143.32,138.65,136.64,129.30,128.59,128.24,127.37,127.01,62.62,53.10,48.48,36.03,29.71.HPLCpurity:99.5%.
3-(N-((1-benzylpiperidin-4-yl)methyl)sulfamoyl)-N-hydroxybenzamide(B2)
3-(N-((1-苄基哌啶-4-基)甲基)氨磺酰基)-N-羟基苯甲酰胺(B2)
目标化合物B2的合成同B1的合成方法,以中间体5b为原料,得红棕色固体,产率41.5%,Mp:168-170℃,ESI-MS m/z:404.66[M+H+],1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),9.23(s,1H),8.18(s,1H),7.97(d,J=7.7Hz,1H),7.91(d,J=7.8Hz,1H),7.76(t,J=6.0Hz,1H),7.67(t,J=7.8Hz,1H),7.36–7.21(m,5H),3.48(s,2H),2.78(d,J=11.1Hz,2H),2.63(t,J=6.4Hz,2H),1.91(t,J=11.6Hz,2H),1.64–1.55(m,2H),1.34(ddt,J=12.2,8.6,4.3Hz,1H),1.09(tt,J=13.3,6.6Hz,2H).13C NMR(101MHz,DMSO)δ163.16,141.55,138.05,134.15,130.78,129.94,129.50,129.30,128.64,127.56,125.67,62.33,52.94,48.36,35.86,29.44.HPLC purity:99.6%.
实施例3:目标化合物C1-C1的合成
中间体4a-4m的合成同实施例1中所示
N1-(2-aminophenyl)-N4-((1-benzylpiperidin-4-yl)methyl)terephthalamide(C1)
N1-(2-氨基苯基)-N4-((1-苄基哌啶-4-基)甲基)对苯二甲酰胺(C1)
将中间体4a(0.17g,0.46mmol)加入50ml圆底烧瓶中,依次加入10ml甲醇和LiOH(0.05g,2.32mmol),80℃回流进行水解反应,6h后TLC监测反应,水解反应完全。停止加热,减压蒸除溶剂,向反应瓶中加入少量水,2N HCl调pH 5-6析出固体,过滤得到中间体4a的水解产物。干燥后不经过进一步处理,称重后(0.10g,0.28mmol)加入25ml圆底烧瓶中,加入DMF 10ml作溶剂,依次加入TEA(0.087g,0.86mmol),TBTU(0.10g,0.34mmol)和邻苯二胺(0.05g,0.42mmol)。室温下搅拌反应,反应4h后,TLC监测反应完全。停止反应,反应液中加入与溶剂等体积的水,乙酸乙酯萃取两次,有机相用饱和食盐水洗涤两次,收集有机相,无水MgSO4干燥,过滤,滤液蒸干,得到淡黄色固体粗品,乙酸乙酯15ml打浆纯化。过滤,真空干燥得灰白色固体0.06g,产率48.7%,Mp:234-236℃,ESI-MS m/z:443.28[M+H+],1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.62(t,J=5.6Hz,1H),8.05(d,J=8.0Hz,2H),7.95(d,J=8.0Hz,2H),7.38–7.21(m,5H),7.17(d,J=7.7Hz,1H),6.98(t,J=7.4Hz,1H),6.79(dd,J=8.1,1.4Hz,1H),6.60(t,J=7.5Hz,1H),4.93(s,2H),3.44(s,2H),3.18(t,J=6.2Hz,2H),2.80(d,J=11.0Hz,2H),1.90(t,J=10.8Hz,2H),1.66(d,J=13.0Hz,2H),1.58(s,1H),1.20(td,J=12.2,11.4,7.8Hz,2H).13C NMR(101MHz,DMSO)δ166.07,165.20,143.71,139.20,137.43,137.19,129.17,128.57,128.23,127.60,127.28,127.23,127.03,123.62,116.66,116.62,62.93,53.45,45.38,36.15,30.36.HPLC purity:99.8%.
N1-(2-aminophenyl)-N3-((1-benzylpiperidin-4-yl)methyl)isophthalamide(C2)
N1-(2-氨基苯基)-N3-((1-苄基哌啶-4-基)甲基)间苯二甲酰胺(C2)
目标化合物C2的合成同C1的合成方法,以中间体4b为原料,得白色固体,产率62.0%,Mp:196-198℃,ESI-MS m/z:443.75[M+H+],1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.61(t,J=5.8Hz,1H),8.42(t,J=1.9Hz,1H),8.10(d,J=7.8Hz,1H),8.06–7.97(m,1H),7.60(t,J=7.7Hz,1H),7.37–7.20(m,5H),7.21–7.13(m,1H),6.99(td,J=7.6,1.6Hz,1H),6.79(dd,J=8.1,1.4Hz,1H),6.61(td,J=7.6,1.4Hz,1H),4.94(s,2H),3.44(s,2H),3.19(t,J=6.3Hz,2H),2.81(d,J=11.0Hz,2H),1.96–1.84(m,2H),1.73–1.64(m,2H),1.62–1.53(m,1H),1.21(qd,J=11.5,10.5,5.5Hz,2H).13C NMR(101MHz,DMSO)δ166.36,165.54,143.59,139.10,135.32,130.66,130.50,129.19,128.76,128.57,127.25,127.19,127.14,127.04,123.67,116.75,116.64,62.90,53.44,45.39,36.20,30.33.HPLC purity:99.9%.
N-(2-aminophenyl)-4-(3-(((1-benzylpiperidin-4-yl)methyl)amino)-3-oxopro pyl)benzamide(C3)
N-(2-氨基苯基)-4-(3-(((1-苄基哌啶-4-基)甲基)氨基)-3-氧丙基)苯甲酰胺(C3)
目标化合物C3的合成同C1的合成方法,以中间体4c为原料,得白色固体,产率36.4%,Mp:178-180℃,ESI-MS m/z:471.33[M+H+],1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),7.89(d,J=7.9Hz,2H),7.81(t,J=5.8Hz,1H),7.38–7.19(m,7H),7.19–7.12(m,1H),6.97(td,J=7.6,1.5Hz,1H),6.78(dd,J=8.0,1.4Hz,1H),6.60(td,J=7.5,1.4Hz,1H),4.87(s,2H),3.41(s,2H),2.96–2.84(m,4H),2.74(d,J=11.0Hz,2H),2.41(t,J=7.6Hz,2H),1.83(t,J=10.6Hz,2H),1.49(d,J=12.6Hz,2H),1.30(s,1H),1.06(qd,J=12.1,3.7Hz,2H).13C NMR(101MHz,DMSO)δ171.49,165.59,145.53,143.55,132.72,129.20,128.63,128.56,128.23,127.25,127.08,126.86,124.01,116.80,116.70,62.88,53.40,44.61,37.10,36.15,31.52,30.12.HPLC purity:99.7%.
4-(3-((2-aminophenyl)amino)-3-oxopropyl)-N-((1-benzylpiperidin-4-yl)methyl)benzamide(C4)
4-(3-((2-氨基苯基)氨基)-3-氧丙基)-N-((1-苄基哌啶-4-基)甲基)苯甲酰胺(C4)
目标化合物C4的合成同C1的合成方法,以中间体4d为原料,得灰白色固体,产率53.5%,Mp:176-178℃,ESI-MS m/z:471.38[M+H+],1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.37(t,J=5.8Hz,1H),7.77(d,J=8.1Hz,2H),7.36–7.19(m,7H),7.11(dd,J=7.8,1.5Hz,1H),6.88(td,J=7.7,1.6Hz,1H),6.69(dd,J=8.0,1.4Hz,1H),6.52(td,J=7.5,1.4Hz,1H),4.77(s,2H),3.43(s,2H),3.13(t,J=6.3Hz,2H),2.95(t,J=7.6Hz,2H),2.78(d,J=11.0Hz,2H),2.65(t,J=7.7Hz,2H),1.88(t,J=11.5Hz,2H),1.64(d,J=12.9Hz,2H),1.55(s,1H),1.17(p,J=11.3,10.5Hz,2H).13C NMR(101MHz,DMSO)δ170.65,166.62,145.00,142.44,132.93,129.19,128.57,127.75,127.26,126.28,125.85,123.81,116.59,116.28,62.90,53.45,45.25,37.48,36.22,31.37,30.32.HPLC purity:99.7%.
3-(3-((2-aminophenyl)amino)-3-oxopropyl)-N-((1-benzylpiperidin-4-yl)methyl)benzamide(C5)
3-(3-((2-氨基苯基)氨基)-3-氧丙基)-N-((1-苄基哌啶-4-基)甲基)苯甲酰胺(C5)
目标化合物C5的合成同C1的合成方法,以中间体4e为原料,得白色固体,产率67.5%,Mp:148-150℃,ESI-MS m/z:471.98[M+H+],1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.42(t,J=5.8Hz,1H),7.76(t,J=1.8Hz,1H),7.67(dt,J=7.4,1.7Hz,1H),7.41–7.22(m,7H),7.11(dd,J=7.8,1.5Hz,1H),6.88(td,J=7.6,1.5Hz,1H),6.70(dd,J=8.1,1.4Hz,1H),6.51(td,J=7.5,1.4Hz,1H),4.78(s,2H),3.43(s,2H),3.15(t,J=6.3Hz,2H),2.96(t,J=7.7Hz,2H),2.80(s,2H),2.66(dd,J=8.6,6.8Hz,2H),1.88(t,J=11.2Hz,2H),1.64(d,J=12.8Hz,3H),1.22–1.14(m,2H).13C NMR(101MHz,DMSO)δ170.70,166.84,142.44,141.81,139.20,135.28,131.41,129.17,128.64,128.56,127.65,127.23,126.28,125.89,125.34,123.81,62.95,53.47,45.30,37.75,36.24,31.54,30.36.HPLC purity:99.4%.
4-(3-((2-aminophenyl)amino)-3-oxopropyl)-N-((1-benzylpiperidin-4-yl)methyl)-2-methoxybenzamide(C6)
4-(3-((2-氨基苯基)氨基)-3-氧丙基)-N-((1-苄基哌啶-4-基)甲基)-2-甲氧基苯甲酰胺(C6)
目标化合物C6的合成同C1的合成方法,以中间4f为原料,得白色固体,产率45.8%,Mp:152-154℃,ESI-MS m/z:501.81[M+H+],1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.09(t,J=6.0Hz,1H),7.66(d,J=7.8Hz,1H),7.39–7.18(m,5H),7.12(dd,J=7.9,1.5Hz,1H),7.03(d,J=1.5Hz,1H),6.90(ddd,J=17.2,7.7,1.5Hz,2H),6.70(dd,J=8.0,1.4Hz,1H),6.53(td,J=7.5,1.5Hz,1H),4.80(s,2H),3.87(s,3H),3.44(s,2H),3.17(t,J=6.3Hz,2H),2.95(t,J=7.7Hz,2H),2.80(d,J=11.1Hz,2H),2.71–2.63(m,2H),1.89(t,J=11.2Hz,2H),1.63(d,J=12.7Hz,2H),1.52(s,1H),1.23–1.16(m,2H).13C NMR(101MHz,DMSO)δ170.65,165.31,157.39,146.50,142.45,139.20,130.99,129.16,128.57,127.23,126.29,125.83,123.82,121.42,120.90,116.60,116.30,112.40,62.91,56.34,53.45,45.01,37.42,36.26,31.63,30.23.HPLC purity:99.8%.
(E)-N-(2-aminophenyl)-4-(3-(((1-benzylpiperidin-4-yl)methyl)amino)-3-oxoprop-1-en-1-yl)benzamide(C7)
(E)-N-(2-氨基苯基)-4-(3-(((1-苄基哌啶-4-基)甲基)氨基)-3-氧丙-1-烯-1-基)苯甲酰胺(C7)
目标化合物C7的合成同C1的合成方法,以中间体4g为原料,得白色固体,产率76.9%,Mp:246-248℃,ESI-MS m/z:469.37[M+H+],1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.16(t,J=5.9Hz,1H),8.01(d,J=8.1Hz,2H),7.68(d,J=8.2Hz,2H),7.47(d,J=15.9Hz,1H),7.35–7.21(m,5H),7.17(d,J=7.7Hz,1H),6.97(td,J=7.6,1.6Hz,1H),6.80–6.74(m,2H),6.60(td,J=7.6,1.4Hz,1H),4.91(s,2H),3.43(s,2H),3.09(t,J=6.2Hz,2H),2.85–2.75(m,2H),1.95–1.84(m,2H),1.63(d,J=12.5Hz,2H),1.45–1.10(m,3H).13C NMR(101MHz,DMSO)δ165.21,143.65,139.21,138.31,137.95,135.50,129.16,128.86,128.57,127.75,127.24,127.19,127.02,124.56,123.68,116.71,116.59,62.93,53.44,44.85,36.30,30.22.HPLC purity:99.3%.
(E)-4-(3-((2-aminophenyl)amino)-3-oxoprop-1-en-1-yl)-N-((1-benzylpiperidin-4-yl)methyl)benzamide(C8)
(E)-4-(3-((2-氨基苯基)氨基)-3-氧代丙-1-烯-1-基)-N-((1-苄基哌啶-4-基)甲基)苯甲酰胺(C8)
目标化合物C8的合成同C1的合成方法,以中间体4h为原料,得黄色固体,产率35.5%,Mp:186-188℃,ESI-MS m/z:469.39[M+H+],1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),7.89(d,J=7.9Hz,2H),7.81(t,J=5.8Hz,1H),7.39–7.12(m,8H),7.19–7.12(m,1H),6.97(td,J=7.6,1.5Hz,1H),6.78(dd,J=8.0,1.4Hz,1H),6.60(td,J=7.5,1.4Hz,1H),4.87(s,2H),3.41(s,2H),2.94–2.85(m,4H),2.74(d,J=10.9Hz,2H),2.41(t,J=7.6Hz,2H),1.83(t,J=10.6Hz,2H),1.49(d,J=12.6Hz,2H),1.30(s,1H),1.06(qd,J=12.1,3.7Hz,2H).13C NMR(101MHz,DMSO)δ166.37,163.76,141.92,138.80,138.04,135.55,131.81,129.73,129.15,128.36,127.89,126.16,124.99,124.74,124.01,116.64,116.44,60.22,51.82,27.14,21.23,14.56.HPLC purity:98.9%.
(E)-3-(3-((2-aminophenyl)amino)-3-oxoprop-1-en-1-yl)-N-((1-benzylpiperidin-4-yl)methyl)benzamide(C9)
(E)-3-(3-((2-氨基苯基)氨基)-3-氧代丙-1-烯-1-基)-N-((1-苄基哌啶-4-基)甲基)苯甲酰胺(C9)
目标化合物C9的合成同C1的合成方法,以中间体4i为原料,得淡黄色固体,产率38.8%,Mp:206-208℃,ESI-MS m/z:469.21[M+H+],1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.54(t,J=5.8Hz,1H),8.11(s,1H),7.84(d,J=7.8Hz,1H),7.74(d,J=7.7Hz,1H),7.59(d,J=15.7Hz,1H),7.52(t,J=7.7Hz,1H),7.37(d,J=7.8Hz,1H),7.34–7.20(m,5H),6.98(d,J=15.7Hz,1H),6.95–6.86(m,1H),6.75(dd,J=8.0,1.5Hz,1H),6.58(td,J=7.6,1.5Hz,1H),4.96(s,2H),3.44(s,2H),3.18(t,J=6.3Hz,2H),2.80(d,J=10.8Hz,2H),1.90(t,J=11.3Hz,2H),1.71–1.50(m,3H),1.24–1.15(m,2H).13C NMR(101MHz,DMSO)δ166.40,163.81,142.02,139.42,139.19,135.87,135.45,130.84,129.44,129.17,128.63,128.56,127.22,126.56,126.28,125.14,123.95,123.73,116.76,116.49,62.94,53.46,45.38,36.22,30.35.HPLC purity:99.9%.
(E)-4-(3-((2-aminophenyl)amino)-3-oxoprop-1-en-1-yl)-N-((1-benzylpiperidin-4-yl)methyl)-2-methoxybe nzamide(C10)
(E)-4-(3-((2-氨基苯基)氨基)-3-氧代丙-1-烯-1-基)-N-((1-苄基哌啶-4-基)甲基)-2-甲氧基苯甲酰胺(C10)
目标化合物C10的合成同C1的合成方法,以中间体4j为原料,得黄色固体,产率55.9%,Mp:202-204℃,ESI-MS m/z:499.27[M+H+],1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.16(t,J=5.9Hz,1H),7.73(d,J=7.9Hz,1H),7.58(d,J=15.7Hz,1H),7.41–7.18(m,8H),7.03–6.87(m,2H),6.75(dd,J=8.0,1.5Hz,1H),6.58(td,J=7.5,1.4Hz,1H),4.96(s,2H),3.92(s,3H),3.44(s,2H),3.18(t,J=6.4Hz,2H),2.96–2.68(m,2H),1.90(t,J=11.2Hz,2H),1.65(d,J=12.7Hz,2H),1.53(s,1H),1.23(d,J=12.4Hz,2H).13C NMR(101MHz,DMSO)δ165.10,163.74,157.57,142.04,139.28,138.95,131.30,129.18,128.57,127.25,126.30,125.15,124.84,124.50,123.96,119.86,116.78,116.52,111.86,62.90,56.47,53.44,45.07,36.24,30.20.HPLC purity:99.8%.
N1-(2-aminophenyl)-N7-((1-benzylpiperidin-4-yl)methyl)heptanediamide(C11)
N1-(2-氨基苯基)-N7-((1-苄基哌啶-4-基)甲基)庚二酰胺(C11)
目标化合物C11的合成同C1的合成方法,以中间体4k为原料,得黄色固体,产率19.08%,Mp:116-118℃,ESI-MS m/z:437.53[M+H+],1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),7.74(s,1H),7.27(tt,J=13.6,7.0Hz,5H),7.18–7.11(m,1H),6.94–6.82(m,1H),6.76–6.65(m,1H),6.59–6.45(m,1H),4.80(s,2H),3.41(s,2H),2.92(t,J=6.3Hz,2H),2.76(d,J=10.9Hz,2H),2.29(t,J=7.4Hz,2H),2.06(t,J=7.4Hz,2H),1.90–1.80(m,2H),1.54(dt,J=24.8,7.3Hz,7H),1.28(q,J=7.9Hz,2H),1.14–1.06(m,2H).13C NMR(101MHz,DMSO)δ172.51,171.58,142.30,139.14,129.19,128.57,127.25,126.11,125.69,124.08,116.63,116.37,62.89,53.42,44.55,36.19,36.16,35.79,30.19,28.84,25.68,25.57.HPLC purity:98.8%.
N1-(2-aminophenyl)-N8-((1-benzylpiperidin-4-yl)methyl)octanediamide(C12)
N1-(2-氨基苯基)-N8-((1-苄基哌啶-4-基)甲基)辛二酰胺(C12)
目标化合物C12的合成同C1的合成方法,以中间体4l为原料,经过柱层析纯化,DCM:MeOH=50:1冲出产物,真空干燥得黄色固体,产率14.1%,Mp:98-100℃,ESI-MS m/z:451.39[M+H+],1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),7.74(t,J=5.8Hz,1H),7.34–7.20(m,5H),7.14(dd,J=7.9,1.5Hz,1H),6.88(td,J=7.6,1.6Hz,1H),6.71(dd,J=8.0,1.4Hz,1H),6.53(td,J=7.5,1.5Hz,1H),4.80(s,2H),3.41(s,2H),2.91(t,J=6.2Hz,2H),2.82–2.73(m,2H),2.29(t,J=7.4Hz,2H),2.05(t,J=7.4Hz,2H),1.92–1.80(m,2H),1.58(d,J=8.0Hz,4H),1.48(q,J=7.2Hz,1H),1.32–1.10(m,8H).13C NMR(101MHz,DMSO)δ172.51,171.59,142.33,139.19,129.16,128.56,127.22,126.13,125.72,124.08,116.64,116.37,62.91,53.43,44.53,36.23,35.86,30.21,28.98,28.94,25.80,25.72.HPLCpurity:99.0%.
N1-(2-aminophenyl)-N9-((1-benzylpiperidin-4-yl)methyl)nonanediamide(C13)
N1-(2-氨基苯基)-N9-((1-苄基哌啶-4-基)甲基)壬二酰胺(C13)
目标化合物C13的合成同C1的合成方法,以中间体4m为原料,得灰绿色固体,产率11.3%,Mp:88-90℃,ESI-MS m/z:465.39[M+H+],1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),7.74(t,J=5.9Hz,1H),7.28(tt,J=13.3,7.3Hz,5H),7.14(dd,J=7.8,1.5Hz,1H),6.88(td,J=7.6,1.5Hz,1H),6.71(dd,J=7.9,1.4Hz,1H),6.58–6.47(m,1H),4.80(s,2H),3.42(s,2H),2.91(t,J=6.2Hz,2H),2.77(d,J=11.0Hz,2H),2.29(t,J=7.4Hz,2H),2.05(t,J=7.3Hz,2H),1.86(s,2H),1.58–1.32(m,8H),1.30–1.05(m,7H).13C NMR(101MHz,DMSO)δ172.55,171.62,142.31,139.04,129.20,128.57,127.27,126.12,125.69,124.09,116.64,116.38,62.85,53.40,44.51,36.25,36.19,35.87,30.15,29.09,29.06,29.04,25.85,25.76.HPLC purity:99.4%.
实施例4:目标化合物D1-D2的合成
中间体5a-5b的合成同实施例2中所示。
N-(2-aminophenyl)-4-(N-((1-benzylpiperidin-4-yl)methyl)sulfamoyl)benza mide(D1)
N-(2-氨基苯基)-4-(N-((1-苄基哌啶-4-基)甲基)氨磺酰基)苯甲酰胺(D1)
将中间体5a(0.14g,0.34mmol)加入50ml圆底烧瓶中,依次加入10ml甲醇和LiOH(0.04g,1.73mmol),80℃回流进行水解反应,6h后TLC监测反应,水解反应完全。停止加热,减压蒸除溶剂,向反应瓶中加入少量水,2N HCl调pH 5-6析出固体,过滤得到中间体5a的水解产物。干燥后不经过进一步处理,称重后(0.14g,0.36mmol)加入25ml圆底烧瓶中,加入DMF 10ml作溶剂,依次加入TEA(0.11g,1.08mmol),TBTU(0.14g,0.43mmol)和邻苯二胺(0.06g,0.54mmol)。室温下搅拌反应,反应4h后,TLC监测反应完全。停止反应,反应液中加入与溶剂等体积的水,乙酸乙酯萃取两次,有机相用饱和食盐水洗涤两次,收集有机相,无水MgSO4干燥,过滤,滤液蒸干,得到淡黄色固体粗品,乙酸乙酯15ml打浆纯化。过滤,真空干燥得淡黄色固体,产率40.6%,Mp:200-202℃,ESI-MS m/z:479.62[M+H+],1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.15(d,J=8.1Hz,2H),7.89(d,J=8.2Hz,2H),7.74(t,J=5.9Hz,1H),7.37–7.20(m,5H),7.17(d,J=7.8Hz,1H),7.02–6.93(m,1H),6.82–6.75(m,1H),6.60(t,J=7.5Hz,1H),4.94(s,2H),3.42(s,2H),2.75(d,J=10.9Hz,2H),2.64(t,J=6.4Hz,2H),1.85(s,2H),1.60(d,J=12.7Hz,2H),1.37(d,J=13.1Hz,1H),1.15–1.01(m,2H).13CNMR(101MHz,DMSO)δ164.80,143.75,143.40,138.86,138.51,129.26,129.15,128.59,127.33,127.29,127.25,126.87,123.24,116.62,116.50,62.73,53.18,48.56,36.10,29.84.HPLC purity:99.8%.
N-(2-aminophenyl)-3-(N-((1-benzylpiperidin-4-yl)methyl)sulfamoyl)benzamide(D2)
N-(2-氨基苯基)-3-(N-((1-苄基哌啶-4-基)甲基)氨磺酰基)苯甲酰胺(D2)
目标化合物D2的合成同D1的合成方法,以中间体5b为原料,得白色固体,产率52.3%,Mp:122-124℃,ESI-MS m/z:480.23[M+H+],1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.37(d,J=1.9Hz,1H),8.25(d,J=7.8Hz,1H),7.97(d,J=7.8Hz,1H),7.74(t,J=7.8Hz,1H),7.30(s,6H),7.18–7.14(m,1H),6.99(td,J=7.6,1.5Hz,1H),6.79(dd,J=8.1,1.4Hz,1H),6.60(td,J=7.5,1.4Hz,1H),4.96(s,2H),3.40(s,4H),2.65(t,J=6.4Hz,2H),1.83(s,2H),1.60(s,2H),1.35(s,1H),1.08(s,2H).13C NMR(101MHz,DMSO)δ164.59,143.84,141.42,136.03,131.81,129.79,129.50,128.69,127.39,127.26,126.52,123.29,116.63,116.53,53.01,48.35,35.73,34.13,29.60.HPLC purity:99.8%.
实施例5:目标化合物E1的合成
中间体6的合成
中间体4-((((1-苄基哌啶-4-基)甲基)氨基)甲基)苯甲酸甲酯(6)的制备
将原料中间体3(0.90g,4.4mmol)和甲酰基苯甲酸甲酯(0.90g,5.3mmol)依次加入25ml圆底烧瓶中,MeOH做溶剂,室温反应1小时后,加入NaBH4,室温反应12h。TLC监测反应,反应完成。减压蒸除反应溶剂,乙酸乙酯萃取,柱层析纯化(EtOAC:PE=1:15),真空干燥得中间体6,白色固体0.33g,收率:17.7%。
目标化合物E1的合成
4-((((1-benzylpiperidin-4-yl)methyl)amino)methyl)-N-hydroxybenzamide(E1)
4-((((1-苄基哌啶-4-基)甲基)氨基)甲基)-N-羟基苯甲酰胺(E1)
目标化合物E1的合成同A1的合成方法,以中间体6为原料,得黄色固体,产率28.5%,Mp:136-138℃,ESI-MS m/z:354.11[M+H+],1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),8.92(d,J=130.4Hz,1H),7.68(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),7.31–7.21(m,5H),3.70(s,2H),3.42(s,2H),2.77(dd,J=11.7,3.4Hz,2H),2.33(d,J=6.5Hz,2H),1.87(td,J=11.5,2.4Hz,2H),1.67(dd,J=13.3,3.5Hz,2H),1.38(ddd,J=11.2,7.4,4.0Hz,1H),1.11(qd,J=12.0,3.8Hz,2H).13C NMR(101MHz,DMSO)δ166.70,147.65,139.26,129.47,129.15,128.53,128.41,128.31,127.19,63.03,55.33,53.68,53.28,52.42,36.35,30.83.HPLC purity:99.9%.
实施例6:通式(I)所示化合物体外HDACs抑酶活性实验
采用HeLa细胞核提取物(主要含HDAC1和HDAC2)为酶源,对所有的目标化合物进行了初步的HDACs酶抑制活性筛选。HDAC荧光分析方法(两步法),快速、方便检测HDAC活性,操作简单。第一步,HDAC荧光底物(含一个乙酰化的赖氨酸侧链-Boc-Lys(acetyl)-AMC)用含HDAC活性的样本孵育(如Hela细胞核提取液,表达的HDAC8等),使底物去乙酰基化,激活底物。第二步,用胰酶水解Boc-Lys-AMC,产生AMC这一荧光基团(或发色团),在激发波长/发射波长(390nm/460nm)测定荧光强度。
设立空白组、100%对照组、化合物组和阳性药组,每组平行三次:
空白组:60μL的空白HDACs buffer先37℃孵育5min,加入40μL底物后,在37℃下反应30min,然后加入100μL Trypsin solution,并在37℃下再孵育20min,于390nm/460nm测定荧光强度。
100%对照组:50μL的空白HDACs buffer与10μL不同亚型HDAC酶液混合,预先37℃孵育5min,加入40μL底物后,在37℃下反应30min,然后加入100μL Trypsin solution终止上述反应,并在37℃下反应20min,于390nm/460nm测定荧光强度。
化合物组:50μL含有不同浓度化合物的HDACs buffer与10μL不同亚型HDAC酶液混合,预先37℃孵育5min,加入40μL底物后,在37℃下反应30min,然后加入100μL Trypsinsolution终止上述反应,并在37℃下反应20min,于390nm/460nm测定荧光强度。
阳性药组:选用SAHA、PXD101为阳性对照药物,方法同化合物组。
抑制率(%)=[(A1-A0)-(A2-A3)]/(A1-A0)×100%
A0:100%荧光强度。A1:100%荧光强度。A2:化合物荧光强度。A3:空白荧光强度。
根据公式计算抑制率,进一步通过graphpad 8做浓度-抑制率曲线,通过S曲线拟合得出IC50值,结果见表1。
实施例7:通式(X)所示化合物体外乙酰胆碱酯酶(AChE)抑酶活性实验
乙酰胆碱酯酶催化ATCI水解,水解产物可与DTNB络合显黄色,产物吸收波长412nm,酶的活性可通过测定酶催化底物的水解速度来评价。
设立空白组、100%对照组、化合物组和阳性药组,每组平行三次:
向所有孔中加入100μL的缓冲溶液(Tris-HCl pH=8.0 50mM,NaCl 0.1M,MgCl2·6H2O 0.02M)。实验组,加入20μL的稀释好的化合物。标准组和空白组,加入20μL的缓冲溶液。此时每孔有120μL溶液。实验组和标准组,加入20μL的乙酰胆碱酯酶溶液(0.125u/ml)。空白组,加入20μL的缓冲溶液。此时每孔有140μL溶液。加毕后,避光条件下于37℃孵育10min。结束后,向实验组、标准组和空白组分别加入20μL ATCI/BTCI溶液(15mM)和40μLDTNB溶液(1.5mM)。加毕后,避光条件下于37℃孵育5min。结束后,于412nm处测定每孔吸光度。
抑制率(%)=[(A1-A0)-(A2-A3)]/(A1-A0)*100%
A0:100%荧光强度。A1:100%荧光强度。A2:化合物荧光强度。A3:空白荧光强度
根据公式计算抑制率,进一步通过Graphpad Prism 8做浓度-抑制率曲线,通过S曲线拟合得出IC50值,结果见表1。
实施例8:通式(X)所示部分化合物抑制Cu2+诱导的Aβ1-42聚集实验
该实验利用硫黄素T做荧光显色剂,聚集状态的Aβ1-42结构中的β折叠结构可与荧光染料硫黄素T结合从而导致硫黄素T的结构发生改变。当用酶标仪检测时,与聚集状态的Aβ1-42结合的硫黄素T会产生荧光,检测条件为:激发波长/发射波长=450/490nm。实验利用荧光值的大小来测试待测化合物抑制Aβ1-42自身聚集的能力。
在96孔荧光板不同组中分别加入待测化合物,阳性药和Aβ1-42溶液,保持每孔总体积为80μL,具体加入体积和反应时间如下:阳性药组:阳性药氯碘羟喹(40μL 40μM),Cu2+(20μL 40μM)和Aβ1-42溶液(20μL 40μM)。实验组:待测化合物(40μL 40μM),Cu2+(20μL 40μM)和Aβ1-42溶液(20μL 40μM)。阴性组:Cu2+(20μL 40μM),Aβ1-42溶液(20μL 40μM)和40μL HEPES缓冲液。空白组:80μL的HEPES。每个测试浓度下至少设置3个重复孔。加毕,用封口膜将96孔板四周密封,置于37℃恒温摇床振摇24h。振摇结束,每孔加入120μL硫磺素T的甘氨酸-氢氧化钠缓冲液,振摇10min,在激发波长/发射波长=450/490nm处测荧光值。
荧光强度与抑制率计算公式
抑制率=(阴性组荧光值—实验组荧光值)/(阴性组荧光值—空白组荧光值)×100%
根据公式计算抑制率,结果见表2。
通式(I)所示化合物AChE、HDAC活性如表1。
表1通式(I)所示化合物AChE、HDAC活性
表中Donepezil和Tacrine为胆碱酯酶抑制剂的阳性药,SAHA、PXD101为组蛋白去乙酰化酶(HDAC)抑制剂的阳性对照药,nd表示无活性,-表示未测试。
通式(I)所示部分化合物抑制Cu2+诱导的Aβ1-42聚集活性如表2。
表2化合物抑制Cu2+诱导的Aβ1-42聚集活性
表中CQ为氯碘羟喹是Aβ1-42实验的阳性药
体外实验结果显示,本发明所述结构通式(I)所示的化合物具有很好的抑酶活性,大多数化合物都表现出一定的对HDAC的抑制活性,化合物A1,A3,A4,A5,A7,A8,A9,A10,A11,A10,A13,C3和C7对HDAC酶活IC50值都在1μM以下。其中A8和A9的IC50值分别为66.4nM和22.9nM与阳性药SAHA和PXD101相当。而化合物对乙酰胆碱酯酶的活性略有降低,其中C10对对乙酰胆碱酯酶抑制活性最好,IC50值为0.4903μM。
抑制Cu2+诱导的Aβ1-42聚集实验结果显示,A8,A9,A13和C7表现出轻度抑制活性,其抑制率分别为29.2%,21.8%,29.7%和20.3%。A5,A6,A7、A10,C3和C10则有中度抑制活性。抑制率分别为33.8%,30.5%,40.7%,34.2%,39.2%和35.2%。E1抑制活性最好为55.6%,与阳性药CQ接近,综合来说所测试化合物都表现出很好抑制Cu2+诱导的Aβ1-42聚集活性。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。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 (10)
5.根据权利要求1所述多靶点多奈哌齐-异羟肟酸型化合物,其特征在于,所述化合物选自以下结构:
N1-((1-苄基哌啶-4-基)甲基)-N4-羟基对苯二甲酰胺;
N1-((1-苄基哌啶-4-基)甲基)-N3-羟基对苯二甲酰胺;
4-(3-(((1-苄基哌啶-4-基)甲基)氨基)-3-氧丙基)-N-羟基苯甲酰胺;
N-((1-苄基哌啶-4-基)甲基)-4-(3-(羟基氨基)-3-氧丙基)苯甲酰胺;
N-((1-苄基哌啶-4-基)甲基)-3-(3-(羟基氨基)-3-氧丙基)苯甲酰胺;
N-((1-苄基哌啶-4-基)甲基)-4-(3-(羟基氨基)-3-氧丙基)-2-甲氧基苯甲酰胺;
(E)-4-(3-(((1-苄基哌啶-4-基)甲基)氨基)-3-氧代丙-1-烯-1-基)-N-羟基苯甲酰胺;
(E)-N-((1-苄基哌啶-4-基)甲基)-4-(3-(羟基氨基)-3-氧代丙-1-烯-1-基)苯甲酰胺;
(E)-N-((1-苄基哌啶-4-基)甲基)-3-(3-(羟基氨基)-3-氧代丙-1-烯-1-基)苯甲酰胺;
(E)-N-((1-苄基哌啶-4-基)甲基)-4-(3-(羟基氨基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酰胺;
N1-((1-苄基哌啶-4-基)甲基)-N7-羟基庚二酰胺;
N1-((1-苄基哌啶-4-基)甲基)-N8-羟基辛二酰胺;
N1-((1-苄基哌啶-4-基)甲基)-N9-羟基壬二酰胺;
4-(N-((1-苄基哌啶-4-基)甲基)氨磺酰基)-N-羟基苯甲酰胺;
3-(N-((1-苄基哌啶-4-基)甲基)氨磺酰基)-N-羟基苯甲酰胺;
N1-(2-氨基苯基)-N4-((1-苄基哌啶-4-基)甲基)对苯二甲酰胺;
N1-(2-氨基苯基)-N3-((1-苄基哌啶-4-基)甲基)间苯二甲酰胺;
N-(2-氨基苯基)-4-(3-(((1-苄基哌啶-4-基)甲基)氨基)-3-氧丙基)苯甲酰胺;
4-(3-((2-氨基苯基)氨基)-3-氧丙基)-N-((1-苄基哌啶-4-基)甲基)苯甲酰胺;
3-(3-((2-氨基苯基)氨基)-3-氧丙基)-N-((1-苄基哌啶-4-基)甲基)苯甲酰胺;
4-(3-((2-氨基苯基)氨基)-3-氧丙基)-N-((1-苄基哌啶-4-基)甲基)-2-甲氧基苯甲酰胺;
(E)-N-(2-氨基苯基)-4-(3-(((1-苄基哌啶-4-基)甲基)氨基)-3-氧丙-1-烯-1-基)苯甲酰胺;
(E)-4-(3-((2-氨基苯基)氨基)-3-氧代丙-1-烯-1-基)-N-((1-苄基哌啶-4-基)甲基)苯甲酰胺;
(E)-3-(3-((2-氨基苯基)氨基)-3-氧代丙-1-烯-1-基)-N-((1-苄基哌啶-4-基)甲基)苯甲酰胺;
(E)-4-(3-((2-氨基苯基)氨基)-3-氧代丙-1-烯-1-基)-N-((1-苄基哌啶-4-基)甲基)-2-甲氧基苯甲酰胺;
N1-(2-氨基苯基)-N7-((1-苄基哌啶-4-基)甲基)庚二酰胺;
N1-(2-氨基苯基)-N8-((1-苄基哌啶-4-基)甲基)辛二酰胺;
N1-(2-氨基苯基)-N9-((1-苄基哌啶-4-基)甲基)壬二酰胺;
N-(2-氨基苯基)-4-(N-((1-苄基哌啶-4-基)甲基)氨磺酰基)苯甲酰胺;
N-(2-氨基苯基)-3-(N-((1-苄基哌啶-4-基)甲基)氨磺酰基)苯甲酰胺;
4-((((1-苄基哌啶-4-基)甲基)氨基)甲基)-N-羟基苯甲酰胺。
7.一种药物组合物,其包括权利要求1至5中任一项所述多靶点多奈哌齐-异羟肟酸型化合物、其药学上可接受的盐、其立体异构体、同位素标记物、溶剂化物、多晶型物、互变异构体、代谢产物或前药以及药学上可接受的载体或赋形剂;
优选地,所述载体可以为固体或者液体;
优选地,所述药物组合物可制成口服制剂或肠胃外给药制剂;
优选地,药物组合物可以为片剂、丸剂、胶囊或注射剂;
优选地,所述药物组合物为抑制HDACs和/或AChE和/或BChE活性的药物。
8.权利要求1至5中任一项所述多靶点多奈哌齐-异羟肟酸型化合物、其药学上可接受的盐、其立体异构体、同位素标记物、溶剂化物、多晶型物、互变异构体、代谢产物或前药在制备同时抑制HDACs和AChE的药物中的应用。
9.权利要求1至5中任一项所述多靶点多奈哌齐-异羟肟酸型化合物、其药学上可接受的盐、其立体异构体、同位素标记物、溶剂化物、多晶型物、互变异构体、代谢产物或前药在制备HDACs和/或AChE和/或BChE抑制剂药物中的应用。
10.权利要求1至5中任一项所述多靶点多奈哌齐-异羟肟酸型化合物、其药学上可接受的盐、其立体异构体、同位素标记物、溶剂化物、多晶型物、互变异构体、代谢产物或前药在制备预防和/或治疗神经退行性疾病的药物中的应用;
优选地,所述神经退行性疾病为阿尔茨海默病;
优选地,所述治疗神经退行性疾病的药物为抑制组蛋白去乙酰化酶和/或乙酰胆碱酯酶活性的药物。
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CN114262340B (zh) * | 2021-11-29 | 2023-09-26 | 蚌埠中实化学技术有限公司 | 一种氨基苯硼酸的制备方法 |
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