CN114957296A - 一类新型阿尔茨海默病检测探针及其生物应用 - Google Patents
一类新型阿尔茨海默病检测探针及其生物应用 Download PDFInfo
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Abstract
本发明提供了一类新型阿尔茨海默病检测探针及其生物应用,具体地,本发明提供了一种如下式(I)所示的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、水合物或溶剂合物。本发明的化合物可以用于治疗或预防与乙酰胆碱酯酶相关的神经***疾病,或作为诊断与乙酰胆碱酯酶相关的神经***疾病的影像探针使用。
Description
技术领域
本发明属于生物分子检测、成像和诊疗一体化领域,具体涉及一种基于靶向Aβ和AChE的新型阿尔茨海默病检测探针及其生物应用。
背景技术
阿尔茨海默病(Alzheimer's Disease,AD)是一种复杂的中枢神经***退行性疾病,其临床上主要表现为认知障碍、迷失方向、记忆力逐渐减退,最终丧失思考能力、运动能力,以及生活不能自理等。在老年人的死亡原因中,AD已经成为继心血管、肿瘤和脑卒中之后的第四号杀手。据估计,目前全世界有超过3500万人罹患此病且该数字预计在2030年翻一番,到2050年会翻两番,达到1.15亿,AD的治疗和护理也已经成为了社会的重大经济负担。
AD患者的主要病理学特征是β-淀粉样蛋白(Aβ)聚集成老年斑,细胞内Tau蛋白异常聚集形成神经元纤维缠结(NFT)和神经元死亡。近年来,针对AD的发病机制,主要集中在Aβ毒性假说、胆碱能神经元假说和Tau蛋白假说等方面,其中Aβ毒性假说占主导地位,表现为Aβ的神经毒性聚集形成淀粉样纤维,此外,与一些蛋白质包括载脂蛋白E(apoE)、乙酰胆碱酯酶(AChE)、α1-抗凝乳蛋白酶和硫酸肝素蛋白多糖相关。其中,AChE在哺乳动物中枢神经***胆碱能传递中起关键作用,也可能参与非胆碱能机制。有研究报道,AD患者大脑中大部分皮层AChE活力主要与老年斑的淀粉样蛋白核心有关,而不是周围发现的神经炎成分。AChE直接促进Aβ肽聚集形成淀粉样蛋白纤维以及与小Aβ肽片段形成复合物,与AD患者脑中的Aβ沉积物的共定位点一致。
生物标志物是一种可用于正常生理或病理过程客观测定和评价的指示因子,是实现AD早期诊断、病程监测、干预治疗和疗效判断的重要依据等。随着基因组学、成像技术的发展,人们在AD的诊断技术和生物标志物方面也取得了较大的进展。过去的数十年中,人们逐步建立起了一系列的体液标志物(如脑脊液、血液、尿液等)和神经影像探针(如脑结构影像、功能影像和分子影像等)。尤其是正电子成像术(PET)、单光子发射断层扫描(SPECT)等神经影像技术的发展使得体内检测正常衰老和早期AD导致的大脑区域变化成为可能。在与正电子发射器如18F和11C联用下,PET对轻度早期脑部变化和病程进展都能敏感检测。18F-氟代脱氧葡萄糖(FDG—PET)影像探针已被用于脑部葡萄糖代谢的成像,用于无症状AD病程追踪和预防治疗的检测。至今为止,已有3个Aβ影像探针被FDA批准用于AD的诊断,如Florbetapir(18F AV-45)、18F-Flutemetamol、Florbetaben(18F-BAY94-9172)。此外,一些Tau蛋白PET影像探针也取得了较大的发展,如18F-THK523、18F-THK5117、18F-THK5105、18F-THK5351、18F-AV1451(T807)和11C-PBB3等,这些探针为理解Tau蛋白在AD发病早期的角色提供了很有价值的信息。尽管这些探针在一定程度上清晰的反应AD的病程进展,且呈现出良好的诊断价值并被纳入了新的AD诊断标准,开始用于临床AD病人的诊断,但是仍有各自的不足,如在很多非痴呆的病人出现假阳性现象。因此,非常有必要开发新颖、灵敏度更高的诊断探针或诊疗一体化探针,用于AD的诊断和治疗。
发明内容
本发明基于Aβ肽和AChE生物学特征,设了一类新颖的靶向Aβ和AChE的AD检测探针分子,寻找具备高效、高选择性Aβ结合能力,又具有抑制的胆碱酯酶双靶点小分子探针,使不同靶点间产生协同或互补作用,发挥联动效果,实现AD的诊断或诊疗一体化。
本发明的第一方面,提供了一种如下式I所示的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、水合物或溶剂合物,
其中,
Ar选自下组:取代或未取代的苯基、或取代或未取代的5-7元芳杂环;其中,所述5-7元芳杂环含有1-3个选自氧、硫和氮的杂原子;
X可为CH或N;且当X为CH时,所述的连接桥可以位于X上(此时CH上的H被连接桥替代);
连接桥(Linker)可选自如下结构片段:
其中,Y选自下组:-(CH2)n-、-Ph(CH2)n-、-O-、-Ph(CH2)n-、-NR-、-S-;
p选自下组:1、2、3、4、5或6;
p2选自下组:0、1、2或3;
R选自下组:H、取代或未取代的C1-C4烷基;
其中:
m为0、1、2或3;
n选自下组:0、1、2或3;
X选自下组:(CH2)p、CO或SO2,其中p为0、1、2或3;优选为(CH2)p或CO,p优选1或2;
R1选自下组:卤素、C1-C6直链或支链烃基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1-C4烷氧基、巯基、C2-C6酰基、磺酰基、氨基磺酰基和C2-C6磺酰基;
R3选自下组:取代或未取代的C3-C10环烷基、取代或未取代的C3-C10环烯基、取代或未取代3-12元杂环基、取代或未取代的C6-C12芳基;所述R1中的取代基为选自卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C6-C10芳基和3-12元杂环基中的相同或不同的1、2、3、4或5个取代基;或者在所述C6-C12芳基上两个相邻的取代基与其相邻的芳环上的碳原子共同构成C3-C7环烷基、C3-C7环烯基或者3-7元杂环基;各个杂环基各自独立地含有1~4个选自氧、硫和氮中的杂原子;
R4为一个或多个选自下组的基团:氢、卤素、C1-C6烷基、用卤素取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基;
R5和R6各自独立地选自下组:氢、羧基、C1-C4烷氧基羰基和C1-C4烷基;或R5和R6共同形成C1-C4亚烷基;
其中,所述的取代指基团上的一个或多个(优选为1~5个)氢原子被选自下组的取代基所替代:卤素、C1-C6直链或支链烷基、C1-C6直链或支链烯基、C1-C6直链或支链炔基、氰基、硝基、NH2、C1-C6胺基(包括直链或支链烃基单取代或双取代的胺基)、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1-C6烷氧基、巯基、C2-C6酰基、磺酰基、氨基磺酰基和C2-C6磺酰基、C5-C10芳香基。
R1、R2选自下组:卤素、C1-C6直链或支链烃基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1-C4烷氧基、巯基、C1-C4酰基、磺酰基、氨基磺酰基和C1-C4取代的磺酰基;
m和n各自独立地选自下组:0、1、2或3;
且所述的取代指基团上的一个或多个(优选为1~5个)氢原子被选自下组的取代基所替代:卤素、C1-C6直链或支链烷基、C1-C6直链或支链烯基、C1-C6直链或支链炔基、氰基、硝基、NH2、C1-C6胺基(包括直链或支链烃基单取代或双取代的胺基)、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1-C6烷氧基、巯基、C2-C6酰基、磺酰基、氨基磺酰基和C2-C6磺酰基、C5-C10芳香基。
在另一优选例中,所述的R1、R2各自独立地为卤素。
在另一优选例中,所述的R1、R2各自独立地为F。
在另一优选例中,所述的Ar选自下组:取代或未取代的苯基、或取代或未取代的5-7元芳杂环;其中,所述5-7元芳杂环含有1-3个选自氧、硫和氮的杂原子,且所述的取代指基团上的一个或多个(优选为1~5个)氢原子被选自下组的取代基所替代:卤素、C1-C4直链或支链烷基、C1-C4直链或支链烯基、C1-C4直链或支链炔基、氰基、硝基、NH2、C1-C4胺基(包括直链或支链烃基单取代或双取代的胺基)、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1-C4烷氧基、巯基、C2-C4酰基、磺酰基、氨基磺酰基和C2-C4磺酰基、C5-C10芳香基。
在另一优选例中,所述的连接桥选自下组:
在另一优选例中,所述的式I化合物选自下组:
本发明的第二方面,提供了一种如本发明第一方面所述的式I化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、水合物或溶剂合物的制备方法,其特征在于,所述的式I化合物具有式I-1所示的结构,且所述的化合物采用如下方法制备:
在惰性溶剂中,用式I-a化合物和式I-b化合物反应,得到式I-1化合物;
或
所述的式I化合物具有式I-2所示的结构,且所述的化合物采用如下方法制备:
在惰性溶剂中,用式I-c化合物和式I-d化合物反应,得到式I-2化合物。
本发明的第三方面,提供了一种药物组合物,其含有治疗有效量的如本发明第一方面所述的式I化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、水合物或溶剂合物,以及一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
本发明的第四方面,提供了一种如本发明第一方面所述的式I化合物,或其对映异构体、非对映异构体、外消旋体或其混合物的用途,其用于制备治疗或预防与乙酰胆碱酯酶相关的神经***疾病的药物组合物,或用于制备诊断与乙酰胆碱酯酶相关的神经***疾病的影像探针。
在另一优选例中,所述与乙酰胆碱酯酶相关的神经***疾病选自下组:老年性痴呆、阿尔茨海默病、帕金森综合症、癫痫、或精神***症。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1为Cy系列化合物对APP/PS1转基因小鼠脑片荧光成像作用图。A:皮层;B:海马。
具体实施方式
本发明人经过长期而深入的研究,设了一类新颖的靶向Aβ和AChE的AD检测探针分子,该类探针分子同时具备高选择性Aβ结合能力和胆碱酯酶抑制活性,因此可实现AD的诊断或诊疗一体化。基于上述发现,发明人完成了本发明。
术语
如本文所用,术语“烷基”包括直链或支链的烷基。例如C1-C8烷基表示具有1-8个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用,术语“烯基”包括直链或支链的烯基。例如C2-C6烯基指具有2-6个碳原子的直链或支链的烯基,例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用,术语“炔基”包括直链或支链的炔基。例如C2-C6炔基是指具有2-6个碳原子的直链或支链的炔基,例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用,术语“C3-C8环烷基”指具有3-8个碳原子的环烷基。其可以是单环,例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式,例如桥环或螺环形式。
如本文所用,术语“C1-C6烷胺基”是指被C1-C6烷基所取代的胺基,可以是单取代或双取代的;例如,甲胺基、乙胺基、丙胺基、异丙胺基、丁胺基、异丁胺基、叔丁胺基、二甲胺基、二乙胺基、二丙胺基、二异丙胺基、二丁胺基、二异丁胺基、二叔丁胺基等。
如本文所用,术语“C1-C6烷氧基”是指具有1-6个碳原子的直链或支链的烷氧基;例如,甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用,术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂环烷基”是指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环,也可以是双环形式,例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用,术语“C6-C10芳基”是指具有6-10个碳原子的芳基,例如,苯基或萘基等类似基团。
如本文所用,术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环,也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-***基以及(1,2,4)-***基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
本发明所述的基团除非特别说明是“取代的或未取代的”,否则本发明的基团均可被选自下组的取代基所取代:卤素、腈基、硝基、羟基、氨基、C1-C6烷基-胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤代C1-C6烷氧基、烯丙基、苄基、C6-C12芳基、C1-C6烷氧基-C1-C6烷基、C1-C6烷氧基-羰基、苯氧羰基、C2-C6炔基-羰基、C2-C6烯基-羰基、C3-C6环烷基-羰基、C1-C6烷基-磺酰基等。
如本文所用,“卤素”或“卤原子”指F、Cl、Br、和I。更佳地,卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体)):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体等。因此,本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用,术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒,从而互相转化。比如,质子互变异构体(即质子移变)包括通过质子迁移进行互变,如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用,术语“水合物”是指本发明化合物与水进行配位形成的配合物。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、具体实施方式与其他化学合成方法的结合所形成的实施方式、以及本领域技术人员所熟知的等同替换方式,优选的实施方式包括但不限于本申请的实施例。
新型阿尔茨海默病检测探针
本发明的新型阿尔茨海默病检测探针可为具有如下通式(I)的化合物或其盐,所述化合物包括其对映异构体、非对映异构体、外消旋体或其混合物,
其中,Ar可为苯基、取代苯基、或5-7元芳杂环,其中所述取代苯基可为包括1~5个取代基,该取代基选自卤素、C1-C6直链或支链烃基、氰基、硝基、氨基、C1-C6直链或支链烃基单取代或双取代的氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1-C4烷氧基、巯基、C1-C4酰基、磺酰基、氨基磺酰基和C1-C4取代的磺酰基;所述5-7元芳杂环含有1-3个选自氧、硫和氮的杂原子,并至少含有一个选自卤素、C1-C6直链或支链烃基、氰基、硝基、氨基、C1-C6直链或支链烃基单取代或双取代的氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1-C4烷氧基、巯基、C1-C4酰基和C5-C10芳香基的取代基;
X可为C或N;
连接桥(Linker)可选自如下结构片段:
其中,Y可选自-(CH2)n-、-Ph(CH2)n-、C1-C6直链或支链亚烷基、苯亚烷基;
其中,R1、R2可选自卤素、C1-C6直链或支链烃基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1-C4烷氧基、巯基、C1-C4酰基、磺酰基、氨基磺酰基和C1-C4取代的磺酰基;
上述m、n可为0-3的整数。
在本发明更优选的实施方案中,本发明的通式I的化合物优选为如下具体化合物:
式I化合物的制备方法
本发明提供了一种通式(I)表示的化合物探针的制备方法,该制备方法按照如下方案进行。
方案一:
步骤a:将2-溴-5-醛基吡啶、1-叔丁氧基羰基哌嗪和K2CO3加入到无水DMSO中,加热搅拌反应过夜的化合物F-2;所述的加热条件可60~100度。
步骤b:将乙酰丙酮加入到无水甲苯中,再将BF3*Et2O溶液缓慢加入到上述溶液中,40-80℃反应2h,得化合物F-4。
步骤c:将F-4溶于乙腈中,再将冰醋酸,四氢异喹啉和对二甲氨基苯甲醛加入上述体系。40-80℃反应过夜,得化合物F-5。
步骤d和e:将F-5溶于乙腈中,再将冰醋酸,四氢异喹啉和F-2加入上述体系。40-80℃反应过夜,得化合物F-6。
步骤f:将3-氟-4-甲基苯乙酸甲酯溶于无水四氯化碳中,再将N-溴代丁二酰亚胺和偶氮二异丁腈加入上述体系,回流反应2h,得化合物F-8。
步骤g:将F-9于50%TFA/DCM体系中,室温反应,将反应液旋干后,得化合物F-10。
步骤h:将F-10溶于DMF中,再将K2CO3和F-8加入上述体系,反应8h,得化合物F-8。
步骤i:将F-11溶于KOH水溶液中反应,得化合物F-12。
步骤j:将F-12溶于THF中,再将F-6,缩合剂加入上述体系。室温反应得目标化合物。
方案二:
将方案一的中间体F-2替换为本方案的F-13,其他合成方法同方案一。
方案三:
将方案一的中间体F-12替换为本方案的F-16,其他合成方法同方案一。
药物组合物和施用方法
由于本发明化合物具有优异的乙酰胆碱酯酶的抑制活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)治疗与乙酰胆碱酯酶相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有1-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他药学上可接受的治疗剂联合给药。
联合给药时,所述药物组合物还包括与一种或多种(2种,3种,4种,或更多种)其他药学上可接受的治疗剂。该其他药学上可接受的治疗剂中的一种或多种(2种,3种,4种,或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗细胞因子和/或干扰素介导的疾病。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选1~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
检测探针成像方法
如本文所述,本发明的检测探针化合物对于Aβ和AChE均具有较好的靶向作用,因此可以用于无症状AD病程追踪和预防治疗的检测。因此,本发明还提供了早期检测和诊断阿尔茨海默氏症的较好的工具。
本发明还提供了体外或体内检测β-淀粉样蛋白沉积物的方法,其包括以下步骤:
i)将如式I所示的阿尔茨海默检测探针施用到检测对象;
ii)使本发明的如式I所示的阿尔茨海默检测探针与在所述检测对象中的β-淀粉样蛋白结合,得到待测样本;
iii)对所述的待测样本进行染色,然后检测所述样本中的荧光信号;
iv)产生表示所述荧光信号的位置和/或量的图像;和
v)确定所述β-淀粉样蛋白沉积物在所述受试者体内的分布和程度。
本发明的检测探针可以采用常规的施用方法进行,优选经肠胃外进行。在所述施用步骤之后且在所述检测步骤之前,使本发明的检测探针与β-淀粉样蛋白结合。例如,当受试者为完整的哺乳动物时,本发明的检测探针将动态地穿过哺乳动物身体,与其中的各种组织接触。本发明的检测探针一旦接触到β-淀粉样蛋白,其就将与β-淀粉样蛋白结合。
本发明的检测方法优选地包括借助于例如具有摄影功能的荧光显微镜的对由样本中释放的荧光信号进行检测和成像,该检测步骤还可理解为获取信号数据。
本发明的“检测对象”可为任何人类或动物受试者。优选本发明的受试者为哺乳动物。最优选所述受试者为完整的哺乳动物身体体内。在一个特别优选的实施方案中,本发明的检测对象为人类。
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。除非另外说明,否则百分比和份数按重量计算。
下述实施例所使用的实验方法如无特殊说明,均为常规方法:下述实施例所用的试剂、生物材料,如无特殊说明,均可从商业途径得到。
实施例1.Cy-3化合物的制备
(1)F-2的合成
将2-溴-5-醛基吡啶(50.0mg,0.27mmol),1-叔丁氧基羰基哌嗪(75.1mg,0.40mmol)和K2CO3(74.3mg,0.54mmol)加入到2.0ml无水DMSO中,80℃反应过夜,反应液旋干后,用乙酸乙酯和水体系萃取,有机层再分别用水和饱和NaCl洗涤,无水Na2SO4干燥,浓缩后得黄色固体61.4mg,收率78.5%。ESI-MS:[M+H]+=292.15;[M+Na]+=314.15。
(2)F-4的合成
将乙酰丙酮(1.0g,9.98mmol)加入到2.5ml无水甲苯中,再将BF3*Et2O溶液缓慢加入到上述溶液中,60℃反应2h,将反应液倒入冰水中,再用乙酸乙酯萃取,有机层再分别用水和饱和NaCl洗涤,无水Na2SO4干燥,浓缩后得淡黄色固体1.0g,收率71%。
(3)F-5的合成
将F-4(150.0mg,1.0mmol)溶于2.0ml乙腈中,再将冰醋酸(0.1ml),四氢异喹啉(0.02ml)和对二甲氨基苯甲醛(149.9mg,1.00mmol)加入上述体系。60℃反应过夜,蒸干溶剂后,将反应粗物用flash柱色谱仪分离(PE:EA=5:1),得到红褐色固体59mg,收率21%。ESI-MS:[M+Na]+=302.10;[M+K]+=318.10。
(4)F-6的合成
将F-5(30.0mg,0.11mmol)溶于1.0ml乙腈中,再将冰醋酸(20ul),四氢异喹啉(4.0ul)和F-2(31.3mg,0.11mmol)加入上述体系。60℃反应过夜,蒸干溶剂后,将反应粗物用flash柱色谱仪分离(PE:EA:DCM=4:1:1),得到深蓝色固体16.8mg,收率21%。ESI-MS:[M+H]+=553.35;[M+Na]+=575.40。
(5)F-8的合成
将3-氟-4-甲基苯乙酸甲酯(100.0mg,0.55mmol)溶于15ml无水四氯化碳中,再将N-溴代丁二酰亚胺(107.0mg,0.60mmol)和偶氮二异丁腈(2.7mg,0.016mmol)加入上述体系,回流反应2h,反应粗物用flash柱色谱仪分离(PE:EA=40:1,含1%乙酸),得到黄色固体51mg,收率33%。
(6)F-10的合成
将F-9(155mg,0.38mmol)于50%TFA/DCM体系中,室温反应30min,将反应液旋干后,得淡黄色固体110mg,收率94.3%。ESI-MS:[M+H]+=307.16。
(7)F-11合成
将F-10(110mg,0.38mmol)溶于2.0ml DMF中,再将K2CO3(265mg,1.9mmol)和F-8(150mg,0.57mmol)加入上述体系,30℃反应8h,蒸干溶剂后,用乙酸乙酯和水体系萃取,有机层再分别用水和饱和NaCl洗涤,无水Na2SO4干燥,浓缩后得黄色固体161mg,收率87.3%。
(8)F-12的合成
将F-11(161mg,0.38mmol)溶于1N/KOH中,45℃反应6h,将反应液倒入冰水中,用1MHCl盐酸调至pH 6.5,再用DCM萃取,有机层分别用水和饱和NaCl洗涤,无水Na2SO4干燥,浓缩后得到淡黄色固体147mg,收率81.8%。
(9)Cy-3的合成
将F-12(100.7mg,0.21mmol)溶于无水10.0ml THF中,再将F-6(98.5mg,0.18mmol),HBTU(80.7mg,0.21mmol)及DIPEA(44ul,0.26mmol)加入上述体系。室温反应2h后,将反应液蒸干,反应粗物用C18制备液相分离,得到深蓝色粉末Cy-3共计41.7mg,收率25.9%。ESI-MS:[M+H]+=908;[M+Na]+=930。1H-NMR(CDCl3,400MHz):δ(ppm)8.25(s,1H),7.96(d,1H,J=14.7Hz),7.95(d,1H,J=11.0Hz),7.59(d,1H,J=15.5Hz),7.49(d,2H,J=8.8Hz),7.45-7.50(m,1H),7.13(s,1H),7.11(d,2H,J=9.7Hz),6.96(d,1H,J=9.4Hz),6.84(s,1H),6.67(d,2H,J=8.8Hz),6.59(d,1H,J=15.6Hz),6.43(d,1H,J=15.0Hz),5.95(s,1H),3.94(s,3H),3.87(s,3H),3.71-3.78(m,10H),3.55(d,2H,J=9.2Hz),3.27-3.33(m,1H),3.07(s,6H),3.12(m,2H),2.77-2.82(m,2H),2.37-2.47(m,1H),2.07-2.26(m,4H),1.66-1.69(m,1H).
采用与上述方法类似的合成方法,换用相应底物,得到如下表所示的各个化合物:
实施例2Cy系列化合物对体外乙酰胆碱酯酶的抑制作用
用Ellman比色法测定胆碱酯酶活性[8]。用小鼠皮层匀浆作为AChE酶原,小鼠皮层匀浆在进行酶活力测定前加入0.1mM丁酰胆碱酯酶的选择性抑制剂——四异丙基焦磷酰胺(iso-OMPA),以排除丁酰胆碱酯酶的影响。酶活性测定程序如下:250μl总酶反应混合液内含50μl磷酸钠缓冲液(0.1M,pH 7.4),30μl硫代乙酰胆碱的碘化物(2mM,AChE的底物),109μl水,1μl化合物,50μl 3%(w/v)的5,5'-二硫代-二(2-硝基苯)以及10μl酶原,在室温孵育20分钟。20分钟后加入1ml 3%(w/v)的十二烷基磺酸钠终止反应,在分光光度计450nm处测定有色产物的比色值。全酶活力以不加抑制剂时的酶活力的百分率来表示,计算公式:抑制率%=(全酶酶活OD值–受试化合物OD值)/全酶酶活OD值×100%。结果显示Cy-1和Cy-4的IC50值分别为0.131nM和1.86nM,均为纳摩尔级,表明Cy-1和Cy-4对小鼠皮层乙酰胆碱酯酶具有较好抑制作用。
实施例3Cy系列化合物对APP/PS1转基因小鼠脑片荧光成像作用
将12月龄APP/PS1小鼠用水合氯醛麻醉后,用生理盐水心脏灌流后取出全脑,放于4%多聚甲醛中固定一周后进行石蜡切片,切片包括皮层和海马两个区域。染色前,石蜡切片经二甲苯脱蜡、酒精梯度复水、蒸馏水和PBS前处理后,用ThS(阳性染色剂)进行避光染色时间20分钟,染色完毕用50%酒精洗涤除去多余染料,用PBS漂洗3次。再用荧光化合物避光染色30分钟,染色完毕用PBS漂洗3次,最后加入防淬灭剂后封片,晾干。次日用莱卡正置荧光显微镜观察化合物特异性识别Aβ斑块作用。结果显示,Cy-1、Cy-2、Cy-3和Cy-4在APP/PS1小鼠脑片中均具有较好荧光信号,且与老年斑具有共定位作用(图1)。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种如下式I所示的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、水合物或溶剂合物,
其中,
Ar选自下组:取代或未取代的苯基、或取代或未取代的5-7元芳杂环;其中,所述5-7元芳杂环含有1-3个选自氧、硫和氮的杂原子;
X可为CH或N;且当X为CH时,所述的连接桥可以位于X上;
连接桥(Linker)选自如下结构片段:
其中,Y选自下组:-(CH2)n-、-Ph(CH2)n-、-O-、-Ph(CH2)n-、-NR-、-S-;
p选自下组:1、2、3、4、5或6;
p2选自下组:0、1、2或3;
R选自下组:H、取代或未取代的C1-C4烷基;
其中:
m为0、1、2或3;
n选自下组:0、1、2或3;
X选自下组:(CH2)p、CO或SO2,其中p为0、1、2或3;优选为(CH2)p或CO,p优选1或2;
R1选自下组:卤素、C1-C6直链或支链烃基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1-C4烷氧基、巯基、C2-C6酰基、磺酰基、氨基磺酰基和C2-C6磺酰基;
R3选自下组:取代或未取代的C3-C10环烷基、取代或未取代的C3-C10环烯基、取代或未取代3-12元杂环基、取代或未取代的C6-C12芳基;所述R1中的取代基为选自卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C6-C10芳基和3-12元杂环基中的相同或不同的1、2、3、4或5个取代基;或者在所述C6-C12芳基上两个相邻的取代基与其相邻的芳环上的碳原子共同构成C3-C7环烷基、C3-C7环烯基或者3-7元杂环基;各个杂环基各自独立地含有1~4个选自氧、硫和氮中的杂原子;
R4为一个或多个选自下组的基团:氢、卤素、C1-C6烷基、用卤素取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基;
R5和R6各自独立地选自下组:氢、羧基、C1-C4烷氧基羰基和C1-C4烷基;或R5和R6共同形成C1-C4亚烷基;
其中,所述的取代指基团上的一个或多个(优选为1~5个)氢原子被选自下组的取代基所替代:卤素、C1-C6直链或支链烷基、C1-C6直链或支链烯基、C1-C6直链或支链炔基、氰基、硝基、NH2、C1-C6胺基(包括直链或支链烃基单取代或双取代的胺基)、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1-C6烷氧基、巯基、C2-C6酰基、磺酰基、氨基磺酰基和C2-C6磺酰基、C5-C10芳香基。
R1、R2选自下组:卤素、C1-C6直链或支链烃基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1-C4烷氧基、巯基、C1-C4酰基、磺酰基、氨基磺酰基和C1-C4取代的磺酰基;
m和n各自独立地选自下组:0、1、2或3;
且所述的取代指基团上的一个或多个(优选为1~5个)氢原子被选自下组的取代基所替代:卤素、C1-C6直链或支链烷基、C1-C6直链或支链烯基、C1-C6直链或支链炔基、氰基、硝基、NH2、C1-C6胺基(包括直链或支链烃基单取代或双取代的胺基)、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1-C6烷氧基、巯基、C2-C6酰基、磺酰基、氨基磺酰基和C2-C6磺酰基、C5-C10芳香基。
4.如权利要求1所述的式I化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、水合物或溶剂合物,其特征在于,所述的Ar选自下组:取代或未取代的苯基、或取代或未取代的5-7元芳杂环;其中,所述5-7元芳杂环含有1-3个选自氧、硫和氮的杂原子,且所述的取代指基团上的一个或多个(优选为1~5个)氢原子被选自下组的取代基所替代:卤素、C1-C4直链或支链烷基、C1-C4直链或支链烯基、C1-C4直链或支链炔基、氰基、硝基、NH2、C1-C4胺基(包括直链或支链烃基单取代或双取代的胺基)、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1-C4烷氧基、巯基、C2-C4酰基、磺酰基、氨基磺酰基和C2-C4磺酰基、C5-C10芳香基。
8.一种药物组合物,其含有治疗有效量的如权利要求1所述的式I化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、水合物或溶剂合物,以及一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
9.如权利要求1所述的式I化合物,或其对映异构体、非对映异构体、外消旋体或其混合物的用途,其特征在于,用于制备治疗或预防与乙酰胆碱酯酶相关的神经***疾病的药物组合物,或用于制备诊断与乙酰胆碱酯酶相关的神经***疾病的影像探针。
10.如权利要求9所述的用途,其特征在于,所述与乙酰胆碱酯酶相关的神经***疾病选自下组:老年性痴呆、阿尔茨海默病、帕金森综合症、癫痫、或精神***症。
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