CN107056780A - 硫辛酸‑他克林类似基团异二联体及其治疗阿尔兹海默症的应用 - Google Patents
硫辛酸‑他克林类似基团异二联体及其治疗阿尔兹海默症的应用 Download PDFInfo
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- CN107056780A CN107056780A CN201710342864.5A CN201710342864A CN107056780A CN 107056780 A CN107056780 A CN 107056780A CN 201710342864 A CN201710342864 A CN 201710342864A CN 107056780 A CN107056780 A CN 107056780A
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- Prior art keywords
- compound
- tacrine
- disease
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- lipoic acid
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- 208000024827 Alzheimer disease Diseases 0.000 title claims abstract description 8
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- GHAIYFTVRRTBNG-UHFFFAOYSA-N piperazin-1-ylmethanamine Chemical class NCN1CCNCC1 GHAIYFTVRRTBNG-UHFFFAOYSA-N 0.000 description 1
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- 230000002265 prevention Effects 0.000 description 1
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- 230000001681 protective effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及他克林类似基团和一系列硫辛酸‑他克林类似基团异二联体以及其立体异构体,互变异构体,氮氧化物,溶剂化物,药学上可接受的盐或前药。它们既具有选择性螯合铜离子,抑制胆碱酯酶和神经元保护的多靶点作用。本发明还涉及制备这类化合物的方法,以及在治疗和预防阿尔兹海默症的用途。
Description
技术领域
本发明涉及药物化学领域。具体涉及他克林类似基团和硫辛酸-他克林类似基团异二联体及其药物用途。
背景技术
阿尔兹海默症(Alzheimer’s disease,AD)是一种复杂的慢性进行性中枢神经系统退行性疾病,是最常见与年龄相关的神经衰退症。临床上AD经常导致记忆减退、认知功能障碍,并伴随侵略和抑郁等行为,重度AD患者可导致死亡。2016年全球AD报告中显示:目前,全世界约有4700万AD患者,比西班牙的全部人口还多,预计到2050年全球AD患者人数将达到1.31亿人。2016年全球用于AD花费为8180亿美元,预计到2018年花费将达到 1万亿美元。随着全球人口老龄化到来,AD患者的增长速率还将继续增加。AD不仅对老年人身心健康产生严重的影响,还给家庭和社会带来沉重的负担。
AD患者的主要病理特征为神经细胞外老年斑(senile plaques,SP)、神经细胞内的神经纤维缠结(neurofibrillary tangle,NFT),突触和树突棘的丧失以及神经元的丢失。AD的发病机制涉及多通路,多环节的异常,不同机制之间相互作用、相互影响。目前其发病机制还未完全阐明,仅存在多种假说,包括胆碱能假说、淀粉样蛋白级联假说、氧化应激假说、 tau蛋白假说,金属离子假说,以及炎症和线粒体功能障碍假说等。
目前临床上用于治疗AD的药物多为针对某一假说设计单靶点药物,如针对胆碱能假说设计的乙酰胆碱酯酶抑制剂(acetylcholinesterase inhibitors,AChEIs),针对淀粉样蛋白假说设计的抑制β-淀粉样蛋白(β-amyloid,Aβ)聚集的药物和β-分泌酶(β-site APPcleaving enzyme,BACE)抑制剂。此类化合物虽然能够一定程度上缓解AD的发病进程,但不能完全治愈AD。以目前AD研究进展,AD的发病机制短期内难以完全研究清楚,单靶点药物又不能很好的治愈AD,因此多靶点药物研究成为趋势。
胆碱能假说是AD发病假说中重要假说。胆碱能系统在认知功能中起到重要作用,特别是在与大脑学习记忆相关的区域内,如海马和皮质区。“胆碱能假说”认为,认知功能的丧失与海马和皮质区的胆碱能神经系统功能的下降有关。在AD患者脑内大量胆碱能神经元出现损伤,致使释放到突触间隙的乙酰胆碱(acetylcholine,ACh)水平下降,进而影响脑内神经信号的传导,导致认知和记忆功能障碍。通过抑制乙酰胆碱酯酶,可以减少ACh的水解,增加突触间隙中ACh的水平,进而对抗胆碱能神经元损伤和丢失引起的ACh水平下降,增加信号传导能力,从而改善AD患者的认知和记忆功能。目前上市的治疗AD的药物大多数都是根据这一假说开发出来的乙酰胆碱酯酶抑制剂(acetylcholinesterase inhibitors,AChEIs)。
他克林(Tacrine,TA)是1993年被FDA批准的第一个用于临床治疗AD的AChEI。然而,由于该药临床上引起患者体内转氨酶水平升高,很多患者不能耐受,因此TA使用很快受到限制,并于1998年被撤回并退出市场。但是,较强的抑制AChE活性,分子量低(M.W.: 198,低于其它被批准的AChE抑制剂),潜在抑制Aβ毒性以及合成简单的特点,使得TA再次成为研究的热点。因此,怎样对TA进行结构改造或修饰以降低其肝毒性被研究。
老年斑是AD的主要病理特征之一,其主要成分为β-淀粉样蛋白(Aβ)。老年斑的 AD患者死后尸检分析表明,AD患者脑内的铜、铁和锌的含量大约是正常脑中含量的5.7、 2.9和2.8倍。AD患者脑内过量的金属离子能促进氧化应激的产生,导致氧化性损伤。铜离子能抑制兴奋性神经递质受体N-甲基-D-天冬氨酸(N-Methyl-D-aspartic acid,NMDA)的过度激活,能促进Aβ聚集和淀粉样斑块的形成。8-氨基喹啉衍生物Bis(8-aminoquinolines)ligands是一种四配位铜离子螯合剂,通过与Cu螯合产生Cu-Bis(8-aminoquinolines)络合物。它们还可以减少由Cu-Aβ诱导的氧化损伤。其中,PA1637能够高选择性的螯合Cu和对锌离子几乎没有螯合能力,并且它几乎可以完全逆转注射Aβ1-42的小鼠的记忆缺陷。以8-氨基喹啉为基础开发治疗AD的金属离子螯合剂是一种切实可行策略。
氧化应激是指体内活性氧(reactive oxygen species,ROS)的生成超过内源性ROS 清除而引起的组织分子氧化,造成组织氧化性的损伤。氧化应激在AD的发病机理中起着重要的作用。氧化应激可以导致神经元和线粒体功能障碍,并参与AD多个发病假说,共同引发并加重AD。目前,针对氧化应激假说治疗AD的方法是通过抗氧化作用分子清除ROS,来预防和治疗AD。
α-硫辛酸(Alpha Lipoic Acid),也称为硫辛酸(LA),是几乎存在于所有类型的原核和真核细胞中的天然存在的物质,最初于1950年由美国Reed等人从猪肝中分离提取得到。硫辛酸同时存在二硫戊环和终端羧基,因而它能够具有亲水性和疏水性的两亲性特点,在植物和动物中广泛分布在细胞膜和细胞质中。硫辛酸是目前已知唯一的同时在脂溶性和水溶性环境中都能发挥抗氧化性能的物质,被医学界誉为“万能抗氧化剂”。
发明内容
金属离子在AD发生和发展中具有关键作用,金属离子螯合剂特别是铜离子螯合剂是研发AD药物的重要策略之一。8-氨基喹啉是良好的选择性铜离子螯合剂。基于他克林和8-氨基喹啉结构的相似性,我们将他克林和8-氨基喹啉糅合到一个分子中,发明了他克林类似基团PZ008(图1式(I))。他克林类似基团PZ008具有选择性铜离子螯合和抑制乙酰胆碱酯酶的多靶点作用。
硫辛酸具有强大的抗氧化作用,基于氧化应激假说和多靶点治疗AD的策略,我们将硫辛酸和他克林类似基团以连接链连接,发明了硫辛酸-他克林类似基团异二联体(图2式(II))。此类化合物具有抗氧化、神经保护、选择性铜离子螯合以及抑制乙酰胆碱酯酶的多靶点作用。
本发明涉及图1式(I)和图2式(II)中的化合物和其立体异构体,互变异构体,氮氧化物,溶剂化物,代谢产物,药学上可接受的盐和前药,还包括药用载体、辅剂、赋形剂、稀释剂、媒介物,或它们的组合。
其中,图2式(II)中R为H,F,Cl或Br;
n=2-7;Y为C或N。
除非另外指明,本发明的化合物还意欲包括区别仅在于存在一个或多个同位素富集的原子的化合物。例如,具有本结构的除了用氘或氚替换氢,或者用13C或14C-富集的碳原子替换碳原子,或15N-富集的氮以为的化合物属于本发明的范围内。
本发明涉及本发明化合物或药物组合物在制备药物中的用途,所述药物用于治疗和预防阿尔兹海默症的作用。
本发明另一方面涉及式(I)和式(II)所示的化合物的制备、分离和纯化的方法。
生物实验结果表明,本发明提供的化合物是一类具有乙酰胆碱酯酶抑制作用,选择性螯合铜离子作用以及抗氧化和神经保护作用的多靶点小分子化合物。前面所述内容只概述了本发明的某些方面,但并不限于这些方面。这些方面及其他方面的内容将在下面作更加具体完整的描述。
反应路线列举了制备本发明的化合物的方法。
称取3-氨基吡啶-2-羧酸(5g,36mmol)加入100mL烧瓶,加入环己酮(4.2mL,40mmol),氮气保护,冷却至0℃,缓慢加入32mL三氯氧磷,恢复至室温,加热到110℃,反应4h。反应结束后,加入100mL乙酸乙酯稀释反应液,缓慢滴加入500g冰中,再加入 200mL乙酸乙酯,用浓氨水调pH=8-9,分离得有机相,无水硫酸钠干燥,减压蒸除溶剂。粗品用硅胶柱层析纯化,以石油醚∶乙酸乙酯(5∶1-3∶1)为洗脱剂得到橘红色固体1(3.2g, 40%)。
称取1(100mg,0.46mmol)和苯酚(1g,10.6mmol)加入15mL封管中,加入 1mL氨水,关闭封管,升温至140℃,反应16h。TLC检测反应结束后,反应液中加入2mL 水,用二氯甲烷(10mL×3)萃取,得有机相。减压蒸除溶剂,粗品用硅胶柱层析纯化,以乙酸乙酯(100%,氨水1mL/100mL)为洗脱剂得淡黄色固体产物PZ008(30mg,33%)。
称取1(200mg,0.92mmol)加入10mL烧瓶中,加入5mL正戊醇溶解,加入 1,3-丙二胺(0.23mL,2.76mmol),加热至155℃,回流反应18h。TLC检测反应结束后,反应液用乙醚/HCl溶液调pH=2,产生浑浊,用水(5mL×3)萃取,水相用饱和碳酸钠溶液调pH=10,用二氯甲烷(10mL×6),得橙色液体,无水硫酸钠干燥,减压蒸除溶剂,粗品用硅胶柱层析纯化,以乙酸乙酯(100%,氨水1mL/100mL)为洗脱剂得棕色油状产物2a(47 mg,20%)。
称取2a(30mg,0.12mmol)加入10mL烧瓶,加入3mL二氯甲烷溶解,加入 HOBt(20mg,0.15mmol)和三乙胺(50μL,0.36mmol),然后搅拌下加入硫辛酸(24mg, 0.12mmol),然后再缓慢加入EDCI(28mg,0.15mmol),室温反应过夜。TLC检测反应结束后,减压蒸除溶剂,得粗品。粗品用硅胶柱层析纯化,以二氯甲烷∶甲醇(100∶1,氨水1 mL/100mL)为洗脱剂得淡黄色固体PZ010(27mg,50%)。
称取1(200mg,0.92mmol)加入10mL烧瓶中,加入5mL正戊醇溶解,加入4- 氨基哌啶(0.29mL,2.76mmol),加热至155℃,回流反应18h。TLC检测反应结束后,反应液用乙醚/HCl溶液调pH=2,产生浑浊,用水(5mL×3)萃取,水相用饱和碳酸钠溶液调 pH=10,用二氯甲烷(10mL×6),得橙色液体,无水硫酸钠干燥,减压蒸除溶剂,粗品用硅胶柱层析纯化,以二氯甲烷∶甲醇(100∶1,氨水1mL/100mL)为洗脱剂得棕色油状产物2b (65mg,25%)。
称取2b(50mg,0.18mmol)加入10mL烧瓶,加入3mL二氯甲烷溶解,加入 HOBt(30mg,0.22mmol)和三乙胺(75μL,0.54mmol),然后搅拌下加入硫辛酸(37mg, 0.18mmol),然后再缓慢加入EDCI(42mg,0.22mmol),室温反应过夜。TLC检测反应结束后,减压蒸除溶剂,得粗品。粗品用硅胶柱层析纯化,以二氯甲烷∶甲醇(100∶1,氨水1 mL/100mL)为洗脱剂得淡黄色固体PZ013(34mg,41%)。
称取1(200mg,0.92mmol)加入10mL烧瓶中,加入5mL正戊醇溶解,加入 N-氨乙基哌嗪(0.36mL,2.76mmol),加热至155℃,回流反应18h。TLC检测反应结束后,反应液用乙醚/HCl溶液调pH=2,产生浑浊,用水(5mL×3)萃取,水相用饱和碳酸钠溶液调pH=10,用二氯甲烷(10mL×6),得橙色液体,无水硫酸钠干燥,减压蒸除溶剂,粗品用硅胶柱层析纯化,以二氯甲烷∶甲醇(100∶1,氨水1mL/100mL)为洗脱剂得棕色油状产物 2c(89mg,31%)。
称取2c(70mg,0.22mmol)加入10mL烧瓶,加入3mL二氯甲烷溶解,加入 HOBt(36mg,0.27mmol)和三乙胺(92μL,0.66mmol),然后搅拌下加入硫辛酸(46mg, 0.22mmol),然后再缓慢加入EDCI(52mg,0.27mmol),室温反应过夜。TLC检测反应结束后,减压蒸除溶剂,得粗品。粗品用硅胶柱层析纯化,以二氯甲烷∶甲醇(100∶1-80∶1,氨水1mL/100mL)为洗脱剂得淡黄色固体PZ020(52mg,46%)。
称取1(200mg,0.92mmol)加入10mL烧瓶中,加入5mL正戊醇溶解,加入4- 氨甲基哌啶(315mg,2.76mmol),加热至155℃,回流反应18h。TLC检测反应结束后,反应液用乙醚/HCl溶液调pH=2,产生浑浊,用水(5mL×3)萃取,水相用饱和碳酸钠溶液调 pH=10,用二氯甲烷(10mL×6),得橙红色液体,无水硫酸钠干燥,减压蒸除溶剂,粗品用硅胶柱层析纯化,以二氯甲烷∶甲醇(100∶1,氨水1mL/100mL)为洗脱剂得棕色油状产物 2d(76mg,28%)。
称取2d(60mg,0.20mmol)加入10mL烧瓶,加入3mL二氯甲烷溶解,加入 HOBt(32mg,0.24mmol)和三乙胺(84μL,0.6mmol),然后搅拌下加入硫辛酸(41mg, 0.20mmol),然后再缓慢加入EDCI(46mg,0.24mmol),室温反应过夜。TLC检测反应结束后,减压蒸除溶剂,得粗品。粗品用硅胶柱层析纯化,以二氯甲烷∶甲醇(100∶1-70∶1,氨水1mL/100mL)为洗脱剂得淡黄色固体PZ038(48mg,50%)。
称取1(200mg,0.92mmol)加入10mL烧瓶中,加入5mL正戊醇溶解,加入1, 3-二氨基-2-羟基丙烷(248mg,2.76mmol),加热至155℃,回流反应18h。TLC检测反应结束后,反应液用乙醚/HCl溶液调pH=2,产生浑浊,用水(5mL×3)萃取,水相用饱和碳酸钠溶液调pH=10,用二氯甲烷(10mL×6),得橙色液体,无水硫酸钠干燥,减压蒸除溶剂,粗品用硅胶柱层析纯化,以二氯甲烷∶甲醇(100∶1,氨水1mL/100mL)为洗脱剂得棕色油状产物2e(113mg,45%)。
称取2e(100mg,0.37mmol)加入10mL烧瓶,加入3mL二氯甲烷溶解,加入 HOBt(60mg,0.44mmol)和三乙胺(155μL,1.11mmol),然后搅拌下加入硫辛酸(76mg, 0.37mmol),然后再缓慢加入EDCI(84mg,0.44mmol),室温反应过夜。TLC检测反应结束后,减压蒸除溶剂,得粗品。粗品用硅胶柱层析纯化,以二氯甲烷∶甲醇(100∶1,氨水1 mL/100mL)为洗脱剂得淡黄色固体PZ062(85mg,50%)。
提供下列实施例进一步举例说明本发明,它们不应当认为是对本发明范围的限定。
附图说明
图1他克林类似基团结构式(I)
图2硫辛酸-他克林类似基团异二联体结构通式(II)
图3化合物与生物体内常见金属离子的相互作用的紫外-可见光吸收光谱图
图4化合物对谷氨酸诱导HT22细胞死亡的保护作用
实施例
实施例1:化合物PZ008
1H NMR(400MHz,CDCl3)δ8.63(dd,J=4.1,1.5Hz,1H),8.20-8.04(m,1H),7.58-7.37(m,1H),5.41(s,2H)3.14-2.91(m,2H),2.59(d,J=6.3Hz,2H),2.07-1.81(m,4H);
13C NMR(101MHz,CDCl3)δ158.56,146.43,145.49,140.14,134.96,132.68,122.80, 111.09,33.12,22.8,21.82,21.41;
ESI-MS m/z:200.1[M+H]+。
实施例2:化合物PZ010
1H NMR(400MHz,CDCl3)δ8.65(s,1H),8.14(d,J=6.3Hz,1H),7.48(s,1H),6.31(s,1H),6.04(s,1H),3.77(s,2H),3.54(d,J=5.3Hz,1H),3.41(s,2H),3.25-2.95(m,4H),2.86 (d,J=3.5Hz,2H),2.54-2.35(m,1H),2.16(s,3H),1.87(s,7H),1.66(s,4H),1.44(s,2H);
13C NMR(101MHz,CDCl3)δ173.00,160.31,149.34,146.19,141.47,136.15,135.63, 123.62,115.78,56.40,44.18,40.23,38.45,37.14,36.46,34.58,34.29,31.13,28.89,26.45,25.42, 22.96,22.68;
ESI-MS m/z:445.2[M+H]+。
实施例3:化合物PZ013
1H NMR(400MHz,CDCl3)δ8.65(dd,J=4.1,1.6Hz,1H),8.14(dd,J=8.5,1.6Hz,1H),7.48(dd,J=8.5,4.1Hz,1H),6.24(d,J=10.1Hz,1H),4.41(d,J=13.5Hz,1H),4.26-4.06 (m,1H),3.81(d,J=13.4Hz,1H),3.57(dt,J=12.7,6.4Hz,1H),3.20-3.09(m,2H),3.07(t,J= 6.5Hz,2H),2.98-2.87(m,1H),2.80(t,J=5.4Hz,2H),2.50-2.40(m,1H),2.32(q,J=7.8Hz, 2H),2.00(dd,J=10.2,6.4Hz,2H),1.96-1.86(m,6H),1.76-1.61(m,4H),1.56-1.38(m,4H);
13C NMR(101MHz,CDCl3)δ171.11,160.35,148.40,146.70,141.32,136.11,123.75, 116.75,56.45,51.80,44.05,40.25,38.49,34.75,34.24,34.09,33.23,33.04,29.10,26.84,25.04, 22.89,22.72;
ESI-MS m/z:471.2[M+H]+。
实施例4:化合物PZ020
1H NMR(400MHz,CDCl3)δ8.65(dd,J=4.0,1.4Hz,1H),8.16(d,J=8.0Hz,1H),7.47(dd,J=8.5,4.1Hz,1H),6.77(s,1H),3.84(s,2H),3.66(s,2H),3.58(dt,J=12.8,6.5Hz, 1H),3.49(d,J=4.9Hz,2H),3.22-3.09(m,2H),3.06(t,J=6.5Hz,2H),2.86(t,J=6.1Hz,2H),2.71(t,J=6.0Hz,2H),2.45(dd,J=15.4,9.4Hz,4H),2.33(t,J=7.5Hz,2H),1.95-1.86(m, 4H),1.74-1.64(m,6H),1.53-1.46(m,2H);
13C NMR(101MHz,CDCl3)δ170.28,157.89,149.76,145.47,139.11,134.05,133.44, 123.24,113.57,76.34,76.02,75.71,56.32,55.47,51.93,51.44,44.68,42.14,40.69,39.26,37.50, 33.75,31.95,28.68,28.08,24.99,24.00,21.78,21.30;
ESI-MS m/z:500.2[M+H]+。
实施例5:化合物PZ038
1H NMR(400MHz,CDCl3)δ8.64(dd,J=4.1,1.4Hz,1H),8.13(dd,J=8.5,1.4Hz,1H),7.48(dd,J=8.5,4.1Hz,1H),6.58(t,J=6.5Hz,1H),4.64(d,J=13.1Hz,1H),3.85(d,J= 13.5Hz,1H),3.53(ddd,J=29.1,15.1,7.3Hz,3H),3.21-3.09(m,2H),3.06(t,J=6.4Hz,2H), 2.97(t,J=12.4Hz,1H),2.87(t,J=6.2Hz,2H),2.58-2.41(m,2H),2.32(t,J=7.5Hz,2H),1.98 -1.83(m,8H),1.75-1.60(m,4H),1.55-1.42(m,2H),1.29-1.16(m,2H);
13C NMR(101MHz,CDCl3)δ171.04,160.62,149.53,146.43,141.20,136.11,135.60, 123.75,115.65,56.48,52.05,45.58,41.65,40.25,38.50,37.90,34.77,34.31,33.12,30.67,29.68, 29.12,27.13,25.07,23.01,22.70;
ESI-MS m/z:485.2[M+H]+。
实施例6:化合物PZ062
1H NMR(400MHz,DMSO)δ8.66(d,J=3.1Hz,1H),8.05(d,J=8.3Hz,1H),7.88 (s,1H),7.57(dd,J=8.3,3.9Hz,1H),6.68(s,1H),5.23(d,J=4.7Hz,1H),3.78(dd,J=10.6,5.9 Hz,1H),3.71(d,J=4.8Hz,1H),3.66-3.52(m,2H),3.22-3.03(m,4H),2.90(s,2H),2.81(s, 2H),2.38(rd,J=12.3,6.1Hz,1H),2.10(t,J=7.2Hz,2H),1.85(dd,J=16.5,9.6Hz,5H),1.64 (dt,J=13.5,6.7Hz,1H),1.54(dd,J=17.9,8.0Hz,3H),1.34(dd,J=15.0,7.5Hz,2H);
13C NMR(101MHz,DMSO)δ172.95,159.59,149.30,146.36,141.57,136.29,135.32,124.13,114.71,69.78,56.57,49.66,43.15,40.36,38.55,35.65,34.59,34.25,28.80,26.17,25.55, 23.11,22.75;
ESI-MS m/z:461.2[M+H]+。
实施例7:生物学评估
与生物体内常见金属离子的相互作用
化合物与金属离子(铜离子、锌离子)的相互作用通过紫外-可见光分光光度计进行测定研究。实验操作:反应体系总体积1mL,用无水乙醇将化合物和金属离子稀释成所需浓度,其中待测化合物的终浓度为20μM,CuCl2、ZnCl2、FeCl2、FeCl3溶液终浓度为20μM,同时设立单独待测化合物组,单独金属离子组和溶剂对照组。室温孵育30min。
首先在1cm石英比色皿中加入1mL乙醇扫描基线,再扫描无水乙醇为溶剂对照组,依次放入单独金属离子组溶液,待测化合物溶液以及化合物加金属离子组溶液,用紫外-可见分光光度计扫描各实验组在波长200nm到500nm的吸光度,波长间隔1nm。重复三次实验。
实施例8:生物学评估
抑制谷氨酸诱导细胞毒性作用
小鼠海马神经元细胞株HT22,用含10%胎牛血清的DMEM完全培养基,在37℃,饱和湿度,含体积分数为5%CO2、95%空气的二氧化碳培养箱中常规培养。取对数生长期细胞,用0.25%胰酶溶液消化,加入完全培养基使细胞悬浮,显微镜下细胞计数板计数,调整细胞浓度为1×105个/mL,接种96孔细胞培养板,100μL/孔,培养过夜,使细胞贴壁。实验设置待测样品组、空白组及溶剂对照组,弃去96孔细胞培养板中培养基,加入待测样品组溶液,空白组加入不含化合物的完全培养基,溶剂对照组加入同浓度的DMSO。预孵育30min 后,加入5μL 100mM谷氨酸。模型组不加待测化合物,直接加入5μL 100mM谷氨酸。孵育24h后,培养完毕后,避光,每孔加入10μL 5mg/mL MTT储备液,培养2h。弃去96孔细胞培养板中培养基,每孔加入100μL DMSO,振荡使甲瓒完全溶于DMSO,用酶标仪在 570nm波长处测定每孔的吸光度值。采用公式化合物促进细胞的存活率(%)=100%*(A待测化合物-A模型组)/(A模型组-A空白)计算细胞存活率。
实施例9:生物学评估
胆碱酯酶活性抑制
Ellman(Ellman,G.L.;et al.Biochem.Pharmacol.1961.)报道的比色法在37℃评估 AChE抑制活性。实验设待测化合物组,对照组(0.1M pH 8.0PBS代替待测化合物)和空白组(酶稀释液代替酶溶液)。96孔板中每孔分别加入酶溶液[2μL,终浓度分别为0.03U/mL(AChE)和0.05U/mL(BuChE)],DTNB(40μL,终浓度为500μM),pH 8.0PBS(118μL) 和待测化合物(20μL,10×),共200μL。37℃孵育20min,最后加入20μL底物。用酶标仪在412nm波长处测定反应体系0-5min的吸光度(1min/次,共6次)。每个浓度至少设2 个复孔,重复三次实验。
附表1 化合物抑制乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BuChE)的活性
aMean±SD of at least three independent measurements.
bSelectivity for AChE=IC50(BuChE)/IC50(AChE).
cNot available。
Claims (5)
1.一种化合物,其为式(I)和式(II)所示的结构或式(I)和式(II)所示结构的立体异构体,互变异构体,氮氧化物,溶剂化物,代谢产物,药学上可接受的盐或前药。
其中:
式(II)中R为H,F,Cl或Br;
n=2-7;Y为C或N。
2.根据权利要求1所述的化合物,还意欲包括区别仅在于存在一个或多个同位素富集的原子的化合物。例如,具有本结构的除了用氘或氚替换氢,或者用13C或14C-富集的碳原子替换碳原子,或15N-富集的氮以为的化合物属于本发明的范围内。
3.一种药物组合物包含权利要求1和2任一项所述的化合物,和药学上可接受的载体,赋形剂,稀释剂,辅剂,媒介物或它们的组合。
4.根据权利要求3所述的药物组合物,其中进一步地包含附加治疗剂,所述附加治疗剂为用于阿尔兹海默症治疗的药物。
其中所述的附加治疗剂是:多奈哌齐(donepezil),他克林(tacrine),利凡斯的明(rivastigmine),加兰他敏(galantamine),石杉碱甲(huperzine-A),美金刚(memantine)或它们的组合。
5.根据权利要求1和2任意一项所述化合物或权利要求3和4任意一项所述的药物组合物在制备药物中的用途,所述药物用于治疗和预防阿尔兹海默症。
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