CN115819414B - 含n-酰基芳腙类衍生物及其制备方法和用途 - Google Patents
含n-酰基芳腙类衍生物及其制备方法和用途 Download PDFInfo
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- CN115819414B CN115819414B CN202211621792.5A CN202211621792A CN115819414B CN 115819414 B CN115819414 B CN 115819414B CN 202211621792 A CN202211621792 A CN 202211621792A CN 115819414 B CN115819414 B CN 115819414B
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- acid
- nitrophenyl
- methylene
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Abstract
含N‑酰基芳腙类衍生物及其制备方法和用途,属于药物化学领域,涉及通式I所示的N‑酰基芳基腙类衍生物或其药学上可接受的盐,其中取代基R、R’和X具有在说明书中给出的含义。本发明还涉及通式I的化合物具有抑制RyRs和AchE的作用,并且还涉及该类化合物或其药学上可接受的盐在制备治疗/或预防神经退行性疾病的用途,特别是制备治疗和/或预防阿尔兹海默症的药物中的用途。
Description
技术领域
本发明属于药物化学领域,具体涉及一种新颖的N-酰基芳基腙类衍生物及其药学上可接受的盐,以及其制备方法和含有所述化合物的药物组合物在制备治疗神经退行性疾病,特别是在治疗阿尔兹海默症药物中的应用。
背景技术
钙通道是各种电压门控通道蛋白的成员,钙通道是跨膜的,多亚单位蛋白质,使得Ca2+离子从细胞外流体受控进入细胞。动物领域内的可兴奋细胞和至少一些细菌、真菌和植物细胞具有一种或多种类型的钙通道。几乎所有的动物“可兴奋”细胞,如中枢神经系统(CNS)的神经元,周围神经细胞和肌肉细胞,包括骨架肌肉,心脏肌肉,以及静脉和动脉平滑肌的那些细胞具有电压依赖性钙通道。
多种类型的钙通道已在来自各种组织,包括骨骼肌肉、心脏肌肉、肺、平滑肌和大脑的哺乳动物细胞中被确认。该家族的大多数是L-型钙通道,其功能受到常见类型的钙通道阻断剂(二氢吡啶如硝苯地平,苯基烷基胺如维拉帕米,和苯并硫氮杂卓如硫氮卓酮)的抑制。其他种类的血浆膜钙通道称作T、N、P、Q和R。
“T-型”(或低压激活)钙通道是因为其开口的持续时间(T=短暂)短于L-型钙通道的较长的(L=长效)开口而被命名。L、N、P和Q-型通道在更正性的电势下激活(高电压激活)和具有多种多样的动力学和电压依赖性能。有三种亚型的T-型钙通道,已从包括鼠在内的各种暖血动物被分子,药理和电生理确认。这些亚型称作α1G、α1H和α1I。这些通道的分子性能显示,氨基酸序列60-70%是相同的。这些各个亚型的电生理表征已显示出在其电压依赖性活化、失活、减活和稳定态失活水平和其对各种离子如钡的选择性上的差异。药理学上,这些亚型还具有不同的对离子镍阻断的敏感性。这些通道亚型由于其在其组装过程中经历各种剪切事件的能力而表现为各种形式。
亚型钙通道涉及与各种疾病和病症有关的病理,包括癫痫症、原发性震颤、疼痛、神经病疼痛、精神分裂症、阿尔茨海默症、帕金森氏疾病、抑郁、焦虑、睡眠病症、睡眠障碍、精神病、心脏节律不齐、高血压、疼痛、癌症、糖尿病、不育症和性功能障碍。用于治疗这些疾病和病症的已知的治疗方法存在许多问题,如镇痛药物的使用易产生依赖性、耐药性,阿尔茨海默症目前上市药物只能改善患者短期内的症状,尚无法阻止疾病的进展。因此,非常需要一种用于治疗这些疾病和病症的方法。
阿尔兹海默病(AD)起病隐匿,是以进行性认知功能障碍和行为损害为特征的中枢神经系统退行性疾病。《2015年世界阿尔兹海默报告》中指出,全球约有4680万阿尔兹海默病患者,平均每3秒钟就有1例新发患者,预计2050年全球患者将突破1亿3150万人。我国目前阿尔兹海默病患者已经超过800万。阿尔兹海默病在65岁以上的年龄段的人群中患病率为5%;超过85岁患病率增加至25%,95岁以上的老人则高达60%。由于人口老龄化,AD患者给家庭和社会带来巨大的精神负担和经济负担。
关于AD的发病机制有两大假说。一是以Aβ淀粉样蛋白聚集形成的淀粉样斑(又称老年斑)以及由此引发的神经炎症、胶质细胞活化、突触传递功能障碍、突触与神经元丢失的β淀粉样蛋白瀑布假说:另外是tau蛋白学说,tau过度磷酸化导致神经原纤维缠结,破坏神经元和突触的正常功能、引起神经元死亡。
目前,针对阿尔兹海默病,临床使用的药物主要有乙酰胆碱酯酶抑制剂和谷氨酸NMDA受体抑制剂。迄今为止,阿尔兹海默病患者没有特异性的有效药物阻止疾病的发展。因此,研发针对AD的病理过程、减少Aβ淀粉样蛋白的产生、以及由此神经炎症引起的神经损伤,延缓、阻止病变的发展,有极大的应用前景和社会价值。一些临床研究报告了多种药物联合乙酰胆碱酯酶(AChE)抑制剂治疗AD的强大益处。然而,目前针对Ca2+和AChE的双重抑制抑制剂的相关文献报道较少,且没有批准上市的Ca2+/AChE小分子抑制剂。本发明人在相关文献和连续性研究的基础上,设计并合成了一系列N-酰基芳腙类衍生物,经体外对Ca2+/AChE抑制活性测试及体内药理学研究,结果表明该系列化合物具有不错的生物学活性,可作为阿尔兹海默症的候选药物。
发明内容
本发明的首要目的在于提供一种式I所示的含N-酰基芳腙类衍生物或其药学上可接受的盐;
其中,
R为3-10元饱和或部分饱和的环烷基,3-10元饱和或部分饱和的杂环基(C0-C4)烷基、5-10元杂芳基(C0-C4)烷基、苯氨基、5-10元杂芳基氨基或苄氨基,所述杂环基和杂芳基含有1-4个选自N、O和S的杂原子,所述杂环基任选被0-2个氧代,所述苯基、环烷基、杂环基和杂芳基任选被0-3个R1取代;
R’为H或(C1-C6)烷基;
X为羰基或磺酰基;
或R’和X与共同连接的氮原子一起形成5-10元饱和或部分饱和的杂环基或5-10元杂芳基,所述杂环基和杂芳基含有1-4个选自N、O、S的杂原子,所述杂环基和杂芳基任选被0-3个R1取代;
R1为0-3个选自卤素、三氟甲基、三氟甲氧基、甲磺酰基、(C1-C6)烷基、(C1-C6)烷氧基、硝基。
本发明优选如下通式Ⅰ所示的化合物或其药学上可接受的盐:
R为环丙基、5-10元饱和或部分饱和的杂环基亚甲基、5-10元杂芳基亚甲基、苯基氨基、5-10元杂芳基氨基或苄氨基,所述杂环基和杂芳基含有1-4个选自N、O、S的杂原子,所述杂环基任选被0-2个氧代,所述苯基、杂环基和杂芳基任选被0-2个R1取代;
R’为H或甲基;
X为羰基或磺酰基;
或R’和X与共同连接的氮原子一起形成5-10元饱和或部分饱和的杂环基或5-10元杂芳基,所述杂环基和杂芳基含有1-4个N原子,所述杂环基和杂芳基任选被0-2个R1取代;
R1为0-3个选自卤素、三氟甲基、三氟甲氧基、甲磺酰基、(C1-C6)烷基、(C1-C6)烷氧基、硝基。
本发明特别优选如下通式Ⅰ所示的化合物或其药学上可接受的盐:
R为5-10元饱和或部分饱和的杂环基亚甲基、5-10元杂芳基亚甲基、苯氨基、5-10元杂芳基氨基或苄氨基,所述杂环基和杂芳基含有1-4个选自N、O、S的杂原子,所述苯基、杂环基和杂芳基任选被0-2个R1取代;
R’为H或甲基;
X为羰基或磺酰基;
或R’和X与共同连接的氮原子一起形成结构式
R1为0-2个选自F、Cl、Br、三氟甲基、三氟甲氧基、甲磺酰基、甲基、甲氧基、硝基。
本发明最终优选通式I化合物或其药学上可接受的盐为如下所示化合物中任一种:
按照本发明所属领域的一些通常方法,本发明中通式I所示的N-酰基芳基腙类衍生物可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐,与下列酸加成的盐是特别优选的:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
此外,本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式I的衍生物,它们自身可能具有较弱的活性甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明中“卤素”是指氟、氯、溴或碘代;“烷基”是指直链或支链的烷基;“环烷基”是指取代或未取代的环烷基;“芳基”是指无取代基或连有取代基的苯基;“杂芳基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系,环状体系是芳香性的,如咪唑基、吡啶基、吡唑基、(1,2,3)-和(1,2,4)-三唑基、呋喃基、噻吩基、吡咯基、噻唑基、苯并噻唑基、噁唑基、异噁唑基、萘基、喹啉基、异喹啉基、苯并咪唑基、苯并噁唑基;“饱和或部分饱和的杂环基”是指含有一个或多个选自N、O、S的杂原子的单环或多环的环状体系,如吡咯烷基、吗啉基、哌嗪基、哌啶基、吡唑烷基、咪唑烷基、邻苯二甲酰亚氨基和噻唑啉基。
一种药物组合物,包含通式I所示的含N-酰基芳腙类衍生物或其在药学上可接受的盐或药学上可接受的载体或赋形剂。
用于本发明药物组合物的载体是药学领域中可得到的常见类型,包括:口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂;注射制剂用的防腐剂、加溶剂、稳定剂;局部制剂用的基质、稀释剂、润滑剂、防腐剂。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的,可将其配制成肠衣片剂。
本发明的有益效果:
本发明的研究在AD治疗领域属于全新的作用靶点,动物实验表明其抗AD的作用不依赖于大脑内Aβ的减少,而是通过抑制Ca2+释放,从而减少神经元的过度兴奋,减少由其产生的神经细胞损伤。因此,本项目的研究成果在AD治疗靶点及药物研发中具有重要意义。
附图说明
图1实施例3制备的化合物处理的小鼠海马横切片(300mm)CA1层的场兴奋性突触后电位(fEPSP)。
具体实施方式
下面结合实施例进一步阐述本发明的内容,但本发明的内容并不仅仅局限于以下实施例。下文提及的合成路线A、路线B、路线C描述了本发明的通式I衍生物的制备,实施例中所用原料均为市售原料,本发明提及的全部中间体化合物及最终化合物都是通过路线A、路线B、路线C中描述的方法或类似的方法制备的,且已经过相关结构确证。
路线A:化合物I-i的合成
按照本发明通式Ⅰ化合物,在本合成路线中,R1为化合物I-i对应位置的相应基团;选自卤素、三氟甲基、三氟甲氧基、(C1-C6)烷基、(C1-C6)烷氧基、氢、酰基、硝基取代的(C5-C6)芳香环。
以对硝基苯胺(A)为起始原料在20%盐酸及NaNO2条件下生成中间体重氮盐(B),之后与2-呋喃甲醛(C)得到中间体5-(4-硝基苯基)呋喃-2-甲醛(D);室温下,不同类型的芳基磺酰氯与80%水合肼反应得到不同类型的芳基磺酰肼(E);之后中间体(D)再与不同芳香环的磺酰肼中间体E在醋酸催化下得到通式I的化合物I-i。
路线B:化合物I-ii的合成
按照本发明通式Ⅰ化合物,在本合成路线中,R2为化合物I-ii对应位置的相应基团;选自卤素、三氟甲基、三氟甲氧基、(C1-C6)烷基、(C1-C6)烷氧基、氢、酰基、硝基取代的(C5-C6)芳香环。
按路线A中的合成方法制备关键中间体5-(4-硝基苯基)呋喃-2-甲醛(D);不同类型的芳基甲酸与乙醇酯化得到不同类型的芳基甲酸酯(F);芳基甲酸酯(F)与80%水合肼反应得到不同类型的芳基碳酰肼(G);之后中间体(D)再与不同芳香环的碳酰肼中间体G在醋酸催化下得到通式I的化合物I-ii。
路线C:化合物I-iii的合成
按照本发明通式Ⅰ化合物,在本合成路线中,R3为化合物I-iii对应位置的相应基团;选自卤素、三氟甲基、三氟甲氧基、(C1-C6)烷基、(C1-C6)烷氧基、氢、酰基、硝基取代的(C5-C6)芳香环。
按路线A中的合成方法制备关键中间体5-(4-硝基苯基)呋喃-2-甲醛(D);不同类型的邻芳基二甲酸(H)与水合肼反应得到不同类型的N-氨基邻芳基二甲酰亚胺(J),之后中间体D与中间体J在醋酸催化下得到通式I的化合物I-iii。
以下实验所用试剂均为分析纯或化学纯;化合物熔点均采用济南海能仪器股份有限公司制造的MP420/430全自动熔点仪测定,温度未经校正;质谱采用Agilent 1100型四级杆液相色谱联用仪测定;核磁共振氢谱用Bruker ARX-400MHz型核磁共振分析仪测定。
实施例1
N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)噻吩-2-磺酰肼的制备
步骤1:1-氯-2-(4-硝基苯基)重氮盐(B)的合成
将对硝基苯胺(2.54g,20mmol)悬浮在0℃的10mL 20%盐酸溶液中,加入亚硝酸钠的冷水溶液(1.7g,23mmol),在0-5℃下搅拌1h,得到4-硝基苯基重氮盐(B)。直接用重氮盐B的反应液进行下一步反应。
步骤2:5-(4-硝基苯基)呋喃-2-甲醛(D)的合成
在搅拌下将1-氯-2-(4-硝基苯基)重氮盐(B)滴加到呋喃甲醛(C)(0.1mol,9.6g)和CuCl2·2H2O(0.058mol,1g)的丙酮(40mL)溶液中,温度为20-30℃。混合物搅拌直至不再放出氮气,用水(200mL)稀释,过滤得到5-(4-硝基苯基)呋喃-2-甲醛(D),用DMF(17.7g,81.7%)重结晶。Mp:202.7-204.1℃,MS(ESI)m/z(%):218.26[M+H]+;1H NMR(400MHz,DMSO-d6)δ(ppm):9.69(s,1H,CHO),8.35(d,J=8.9Hz,2H,Ph-H),8.13(d,J=8.9Hz,2H,Ph-H),7.72(d,J=3.8Hz,1H,furan-H),7.59(d,J=3.8Hz,1H,furan-H)。
步骤3:磺酰肼中间体(E)的合成
将2-噻吩磺酰氯(1.2μmol)和80%水合肼(1.5μmol)加入四氢呋喃(10mL)中。室温下剧烈搅拌,反应3h,加入纯净水,搅拌析出白色固体,抽滤得到中间体(E)噻吩-2-磺酰肼,收率67.2%。
步骤4:N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)噻吩-2-磺酰肼(I-i)的合成
冰醋酸催化下,将关键中间体D(1.5mmol)和磺酰肼中间体E(1.5mmol)在EtOH(10mL)中于室温搅拌2h,用EtOH(5mL)过滤洗涤沉淀,减压干燥,得到N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)噻吩-2-磺酰肼(化合物1)的淡黄色固体,收率81.4%。
Mp:219.3-220.7℃;MS(ESI)m/z(%):378.25[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):11.82(s,1H,NNHCO),8.32(d,J=8.5Hz,2H,Ph-H),8.06–7.96(m,3H,Ph-H,thiophene-H),7.88(s,1H,CH=N),7.71(d,J=2.0Hz,0H),7.42(d,J=2.8Hz,1H,furan-H),7.22(t,J=3.6Hz,1H,thiophene-H),7.07(d,J=2.9Hz,1H,furan-H).
实施例2
5-氯-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)噻吩-2-磺酰肼的制备
以对硝基苯胺为原料,按照实施例1中的步骤2的合成方法制备关键中间体D;按照实施例1中的步骤3的合成方法制备磺酰肼中间体E;再按照实施例1中步骤4的合成方法制备得到5-氯-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)噻吩-2-磺酰肼,红色固体,收率71.3%。
Mp:210.4-212.1℃;MS(ESI)m/z(%):412.01[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):11.96(s,1H,NNHCO),8.31(d,J=8.9Hz,2H,Ph-H),8.00(d,J=8.9Hz,2H,Ph-H),7.91(s,1H,CH=N),7.61(d,J=4.1Hz,1H,thiophene-H),7.43(d,J=3.6Hz,1H,furan-H),7.29(d,J=4.1Hz,1H,thiophene-H),7.10(d,J=3.7Hz,1H,furan-H).
实施例3
N'-((5-(4-硝基苯)呋喃-2-基)亚甲基)苯磺酰肼的制备
以对硝基苯胺为原料,按照实施例1中的步骤2的合成方法制备关键中间体D;按照实施例1中的步骤3的合成方法制备磺酰肼中间体E;再按照实施例1中步骤4的合成方法制备得到N'-((5-(4-硝基苯)呋喃-2-基)亚甲基)苯磺酰肼,黄色固体,收率72.6%。
Mp:217.3-218.7℃;MS(ESI)m/z(%):370.02[M-H]-;1H NMR(600MHz,DMSO-d6)δ(ppm):11.75(s,1H,NNHSO),8.31(d,J=9.0Hz,2H,Ph-H),7.98(d,J=9.0Hz,2H,Ph-H),7.91-7.89(m,2H,Ph-H),7.87(s,1H,CH=N),7.70–7.62(m,3H,Ph-H),7.41(d,J=3.7Hz,1H,furan-H),7.03(d,J=3.7Hz,1H,furan-H).13C NMR(151MHz,DMSO-d6)δ152.27,150.08,146.34,138.95,136.43,135.06,133.19,129.34(2C),127.12(2C),124.59(2C),124.52(2C),116.12,112.22.
实施例4
4-甲基-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼的制备
以对硝基苯胺为原料,按照实施例1中的步骤2的合成方法制备关键中间体D;按照实施例1中的步骤3的合成方法制备磺酰肼中间体E;再按照实施例1中步骤4的合成方法制备得到4-甲基-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼,红色固体,收率73.7%。
Mp:218.0-219.1℃;MS(ESI)m/z(%):408.07[M+Na]+;1H NMR(600MHz,DMSO-d6)δ(ppm):11.65(s,1H,NNHSO),8.31(d,J=8.9Hz,2H,Ph-H),7.98(d,J=8.8Hz,2H,Ph-H),7.85(s,1H,CH=N),7.78(d,J=8.3Hz,2H,Ph-H),7.44(d,J=8.2Hz,2H,Ph-H),7.41(d,J=3.6Hz,1H,furan-H),7.02(d,J=3.6Hz,1H,furan-H),2.37(s,3H,PhCH3).
实施例5
4-溴-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼的制备
以对硝基苯胺为原料,按照实施例1中的步骤2的合成方法制备关键中间体D;按照实施例1中的步骤3的合成方法制备磺酰肼中间体E;再按照实施例1中步骤4的合成方法制备得到4-溴-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼,红色固体,收率83.6%。
Mp:216.1-217.5℃;MS(ESI)m/z(%):448.23[M-H]-;1H NMR(600MHz,DMSO-d6)δ(ppm):11.82(s,1H,NNHSO),8.31(d,J=9.0Hz,2H,Ph-H),7.98(d,J=9.0Hz,2H,Ph-H),7.88(s,1H,CH=N),7.88(d,J=8.7Hz,2H,Ph-H),7.82(d,J=8.7Hz,2H,Ph-H),7.42(d,J=3.7Hz,1H,furan-H),7.05(d,J=3.7Hz,1H,furan-H).
实施例6
2,4-二氯-N'-(5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼的制备
以对硝基苯胺为原料,按照实施例1中的步骤2的合成方法制备关键中间体D;按照实施例1中的步骤3的合成方法制备磺酰肼中间体E;再按照实施例1中步骤4的合成方法制备得到2,4-二氯-N'-(5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼,黄色固体,收率80.0%。
Mp:218.5-219.6℃;MS(ESI)m/z(%):438.08[M-H]-;1H NMR(600MHz,DMSO-d6)δ(ppm):12.34(s,1H,NNHSO),8.28(d,J=9.0Hz,2H,Ph-H),8.09(d,J=8.6Hz,1H,Ph-H),7.99(s,1H,CH=N),7.93(d,J=9.0Hz,2H,Ph-H),7.91(d,J=2.1Hz,1H,Ph-H),7.71(dd,J=8.6,2.1Hz,1H,Ph-H),7.40(d,J=3.7Hz,1H,furan-H),7.04(d,J=3.7Hz,1H,furan-H).
实施例7
4-(乙酰氨基)-,2-[[5-(4-硝基苯基)-2-呋喃基]亚甲基]酰肼的制备
以对硝基苯胺为原料,按照实施例1中的步骤2的合成方法制备关键中间体D;按照实施例1中的步骤3的合成方法制备磺酰肼中间体E;再按照实施例1中步骤4的合成方法制备得到4-(乙酰氨基)-,2-[[5-(4-硝基苯基)-2-呋喃基]亚甲基]酰肼,黄色固体,收率79.0%。
Mp:215.3-217.0℃;MS(ESI)m/z(%):427.18[M-H]-;1H NMR(600MHz,DMSO-d6)δ(ppm):11.60(s,1H,NNHSO),10.34(s,1H,Ph-NH),8.31(d,J=8.9Hz,2H,Ph-H),7.98(d,J=8.9Hz,2H,Ph-H),7.85(s,1H,CH=N),7.83(d,J=9.0Hz,2H,Ph-H),7.79(d,J=9.0Hz,2H,Ph-H),7.41(d,J=3.7Hz,1H,furan-H),7.02(d,J=3.7Hz,1H,furan-H),2.06(s,3H,COCH3).
实施例8
4-硝基-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼的制备
以对硝基苯胺为原料,按照实施例1中的步骤2的合成方法制备关键中间体D;按照实施例1中的步骤3的合成方法制备磺酰肼中间体E;再按照实施例1中步骤4的合成方法制备得到4-硝基-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼,红色固体,收率79.3%。
Mp:219.1-220.4℃;MS(ESI)m/z(%):438.41[M+Na]+;1H NMR(600MHz,DMSO-d6)δ(ppm):12.07(s,1H,NNHSO),8.46(d,J=8.9Hz,2H,Ph-H),8.31(d,J=8.8Hz,2H,Ph-H),8.16(d,J=8.9Hz,2H,Ph-H),7.99(d,J=8.8Hz,2H,Ph-H),7.90(s,1H CH=N),7.42(d,J=3.6Hz,1H,furan-H),7.08(d,J=3.7Hz,1H,furan-H).
实施例9
4-(叔丁基)-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼的制备
以对硝基苯胺为原料,按照实施例1中的步骤2的合成方法制备关键中间体D;按照实施例1中的步骤3的合成方法制备磺酰肼中间体E;再按照实施例1中步骤4的合成方法制备得到4-(叔丁基)-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼,黄色固体,收率86.3%。
Mp:214.4-216.2℃;MS(ESI)m/z(%):428.01[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):11.74(s,1H,SONHN),8.29(d,J=8.9Hz,2H,Ph-H),7.96(d,J=8.9Hz,2H,Ph-H),7.87(s,1H,CH=N),7.82(d,J=8.6Hz,2H,Ph-H),7.65(d,J=8.6Hz,2H,Ph-H),7.39(d,J=3.6Hz,1H,furan-H),7.02(d,J=3.7Hz,1H,furan-H),1.27(s,9H,CH3).13C NMR(151MHz,DMSO-d6)δ156.15,152.24,150.13,146.33,136.29,136.21,135.06,126.98(2C),126.19(2C),124.59(2C),124.51(2C),116.07,112.25,34.91,30.71(3C).
实施例10
N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)环丙基-磺酰肼的制备
以对硝基苯胺为原料,按照实施例1中的步骤2的合成方法制备关键中间体D;按照实施例1中的步骤3的合成方法制备磺酰肼中间体E;再按照实施例1中步骤4的合成方法制备得到N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)环丙基-磺酰肼,黄色固体,收率75.2%。
Mp:212.1-213.5℃;MS(ESI)m/z(%):336.06[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):11.36(s,1H,NNHSO),8.31(d,J=9.0Hz,2H,Ph-H),8.01(d,J=9.0Hz,2H,Ph-H),7.93(s,1H,CH=N),7.45(d,J=3.7Hz,1H,furan-H),7.08(d,J=3.7Hz,1H,furan-H),2.73(tt,J=7.8,4.9Hz,1H,cyclopropane-H),1.17–1.00(m,1H,cyclopropane-H).
实施例11
5-溴-N'-((5-(4-硝基苯基)呋喃-4-基)亚甲基)-1H-咪唑-4-碳酰肼的制备
步骤1:1-氯-2-(4-硝基苯基)重氮盐(B)的合成
将对硝基苯胺(2.54g,20mmol)悬浮在0℃的10mL 20%盐酸溶液中,加入亚硝酸钠的冷水溶液(1.7g,23mmol),在0-5℃下搅拌1h,得到4-硝基苯基重氮盐(B)。直接用重氮盐B的反应液进行下一步反应。
步骤2:5-(4-硝基苯基)呋喃-2-甲醛(D)的合成
在搅拌下将1-氯-2-(4-硝基苯基)重氮盐(B)滴加到呋喃甲醛(C)(0.1mol,9.6g)和CuCl2·2H2O(0.058mol,1g)的丙酮(40mL)溶液中,温度为20-30℃。混合物搅拌直至不再放出氮气,用水(200mL)稀释,过滤得到5-(4-硝基苯基)呋喃-2-甲醛(D),用DMF(17.7g,81.7%)重结晶。Mp:202.7-204.1℃,MS(ESI)m/z(%):218.26[M+H]+;1H NMR(400MHz,DMSO-d6)δ(ppm):9.69(s,1H,CHO),8.35(d,J=8.9Hz,2H,Ph-H),8.13(d,J=8.9Hz,2H,Ph-H),7.72(d,J=3.8Hz,1H,furan-H),7.59(d,J=3.8Hz,1H,furan-H)。
步骤3:芳基甲酸乙酯(F)的合成
浓硫酸条件下,将2-溴-1H-咪唑-5-羧酸和无水乙醇混合,回流下剧烈搅拌,反应8h,加水稀释混合物,二氯甲烷提取,减压浓缩,干燥得到中间体(F),收率81.8%。
步骤4:芳基碳酰肼中间体(G)的合成
将2-溴-1H-咪唑-5-甲酸乙酯(1.1μmol)和80%水合肼(1.3μmol)加入四氢呋喃(10mL)中。回流下剧烈搅拌,反应8h,加入纯净水,搅拌析出灰白色固体,抽滤后干燥得到2-溴-1H-咪唑-5-甲酰肼(G),收率76.4.%。
步骤5:5-溴-N'-((5-(4-硝基苯基)呋喃-4-基)亚甲基)-1H-咪唑-4-碳酰肼(I-ii)的合成
冰醋酸催化下,将关键中间体D(1.5mmol)和2-溴-1H-咪唑-5-甲酰肼(中间体G)(1.5mmol)在EtOH(10mL)中于室温搅拌2h,用EtOH(5mL)过滤洗涤沉淀,减压干燥,得到5-溴-N'-((5-(4-硝基苯基)呋喃-4-基)亚甲基)-1H-咪唑-4-碳酰肼(I-ii)的淡黄色固体,收率76.1%。
Mp:241.3-243.2℃;MS(ESI)m/z(%):404.13[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):13.79(s,1H,imidazole-NH),12.31(s,1H,NNHCO),8.24(s,1H,CH=N),8.32(d,J=8.9Hz,2H,Ph-H),8.05(d,J=8.9Hz,2H,Ph-H),7.64(s,1H,N=CHN),7.49(d,J=3.6Hz,1H,furan-H),7.14(d,J=3.6Hz,1H,furan-H).
实施例12
5-溴-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)-1H-咪唑-2-碳酰肼的制备
以对硝基苯胺为原料,按照实施例11中的步骤2的合成方法制备关键中间体D;按照实施例11中的步骤4的合成方法制备碳酰肼中间体G;再按照实施例11中步骤5的合成方法制备得到5-溴-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)-1H-咪唑-2-碳酰肼,黄色固体,收率86.1%。
Mp:243.6-245.1℃;MS(ESI)m/z(%):404.16[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):13.79(s,1H,imidazole-NH),12.31(s,1H,NNHCO),8.53(s,1H,CH=N),8.32(d,J=8.9Hz,2H,Ph-H),8.05(d,J=8.9Hz,2H,Ph-H),7.59(s,1H,NCH=C),7.49(d,J=3.6Hz,1H,furan-H),7.14(d,J=3.6Hz,1H,furan-H).
实施例13
2-溴-4-甲基-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)-1H-咪唑-5-碳酰肼的制备
以对硝基苯胺为原料,按照实施例11中的步骤2的合成方法制备关键中间体D;按照实施例11中的步骤4的合成方法制备碳酰肼中间体G;再按照实施例11中步骤5的合成方法制备得到2-溴-4-甲基-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)-1H-咪唑-5-碳酰肼,黄色固体,收率72.3%。
Mp:240.1-242.3℃;MS(ESI)m/z(%):440.21[M+Na]+;1H NMR(600MHz,DMSO-d6)δ(ppm):13.39(s,1H,imidazole-NH),11.81(s,1H,NNHCO),8.48(s,1H,CH=N),8.39(d,J=8.9Hz,2H,Ph-H),8.34(d,J=8.9Hz,2H,Ph-H),7.61(d,J=3.8Hz,1H,furan-H),7.21(d,J=3.8Hz,1H,furan-H),2.52(s,3H,imidazole-CH3).
实施例14
N'-((5-(4-硝基苯)呋喃-2-基)亚甲基)-1H-1,2,4-三唑-3-甲酰肼的制备
以对硝基苯胺为原料,按照实施例11中的步骤2的合成方法制备关键中间体D;按照实施例11中的步骤4的合成方法制备碳酰肼中间体G;再按照实施例11中步骤5的合成方法制备得到N'-((5-(4-硝基苯)呋喃-2-基)亚甲基)-1H-1,2,4-三唑-3-甲酰肼,黄色固体,收率81.1%。
Mp:246.1-248.1℃;MS(ESI)m/z(%):325.31[M-H]-;1H NMR(600MHz,DMSO-d6)δ(ppm):14.84(s,1H,triazole-H),12.28(s,1H,NNHCO),8.65(s,1H,triazole-H),8.53(s,1H,CH=N),8.33(d,J=9.0Hz,2H,Ph-H),8.05(d,J=9.0Hz,2H,Ph-H),7.49(d,J=3.7Hz,1H,furan-H),7.16(d,J=3.7Hz,1H,furan-H).
实施例15
N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)-1H-1,2,4-三唑-1-碳酰肼的制备
以对硝基苯胺为原料,按照实施例11中的步骤2的合成方法制备关键中间体D;按照实施例11中的步骤4的合成方法制备碳酰肼中间体G;再按照实施例11中步骤5的合成方法制备得到N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)-1H-1,2,4-三唑-1-碳酰肼,黄色固体,收率65.1%。
Mp:250.1-254.2℃;MS(ESI)m/z(%):359.11[M+Na]+.
实施例16
N'-((5-(4-硝基苯)呋喃-2-基)亚甲基)噻吩-2-碳酰肼的制备
以对硝基苯胺为原料,按照实施例11中的步骤2的合成方法制备关键中间体D;按照实施例11中的步骤4的合成方法制备碳酰肼中间体G;再按照实施例11中步骤5的合成方法制备得到N'-((5-(4-硝基苯)呋喃-2-基)亚甲基)噻吩-2-碳酰肼,黄色固体,收率71.8%。
Mp:240.8-243.0℃;MS(ESI)m/z(%):342.21[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):11.98(s,1H,NNHCO),8.40(s,1H,CH=N),8.32(d,J=8.9Hz,2H,Ph-H),8.12-7.96(m,3H,Ph-H,furan-H),7.91(s,1H,furan-H),7.47(d,J=3.5Hz,1H,furan-H),7.25(s,1H,furan-H),7.14(d,J=3.7Hz,1H,furan-H).
实施例17
N'-((5-(4-硝基苯)呋喃-2-基)亚甲基)呋喃-2-碳酰肼的制备
以对硝基苯胺为原料,按照实施例11中的步骤2的合成方法制备关键中间体D;按照实施例11中的步骤4的合成方法制备碳酰肼中间体G;再按照实施例11中步骤5的合成方法制备得到N'-((5-(4-硝基苯)呋喃-2-基)亚甲基)呋喃-2-碳酰肼,黄色固体,收率78.1%。
Mp:239.6-241.5℃;MS(ESI)m/z(%):326.33[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):11.98(s,1H,NNHCO),8.42(s,1H,CH=N),8.33(d,J=8.9Hz,2H,Ph-H),8.04(d,J=8.9Hz,2H,Ph-H),7.97(s,1H,furan-H),7.49(d,J=3.6Hz,1H,furan-H),7.32(s,1H,furan-H),7.15(d,J=3.7Hz,1H,furan-H),6.73(s,1H,furan-H).13C NMR(151MHz,DMSO-d6)δ154.51,152.84,151.29,146.87,146.67,146.36,137.34,135.53,125.00(2C),124.93(2C),116.76,115.67,112.87,112.60.
实施例18
N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)-1H-吡咯-2-甲酰肼的制备
以对硝基苯胺为原料,按照实施例11中的步骤2的合成方法制备关键中间体D;按照实施例11中的步骤4的合成方法制备碳酰肼中间体G;再按照实施例11中步骤5的合成方法制备得到N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)-1H-吡咯-2-甲酰肼,黄色固体,收率79.2%。
Mp:238.1-240.2℃;MS(ESI)m/z(%):325.09[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):11.77(s,1H,pyrrole-NH),11.57(s,1H,CONHN),8.35(s,1H,CH=N),8.32(d,J=8.7Hz,2H,Ph-H),8.02(d,J=8.8Hz,2H,Ph-H),7.47(d,J=3.6Hz,1H,furan-H),7.10(d,J=3.6Hz,1H,furan-H),7.05–6.96(m,2H,pyrrole-H),6.20(s,1H,pyrrole-H).
实施例19
5-氯-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)噻吩-2-碳酰肼的制备
以对硝基苯胺为原料,按照实施例11中的步骤2的合成方法制备关键中间体D;按照实施例11中的步骤4的合成方法制备碳酰肼中间体G;再按照实施例11中步骤5的合成方法制备得到5-氯-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)噻吩-2-碳酰肼,白色固体,收率80.2%。
Mp:243.1-245.0℃;MS(ESI)m/z(%):376.02[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):12.18(s,1H,NNHCO),8.29(d,J=8.7Hz,2H,Ph-H),8.07(d,J=8.7Hz,2H,Ph-H),7.99(s,1H,CH=N),7.90(d,J=4.0Hz,1H,Thiophene-H),7.48(d,J=3.5Hz,1H,furan-H),7.29(d,J=4.1Hz,1H,Thiophene-H),7.15(d,J=3.5Hz,1H,furan-H).
实施例20
N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)烟酰肼的制备
以对硝基苯胺为原料,按照实施例11中的步骤2的合成方法制备关键中间体D;按照实施例11中的步骤4的合成方法制备碳酰肼中间体G;再按照实施例11中步骤5的合成方法制备得到N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)烟酰肼,黄色固体,收率68.2%。
Mp:233.1-234.4℃;MS(ESI)m/z(%):337.23[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):12.12(s,1H,NNHCO),9.08(d,J=1.6Hz,1H,pyridine-H),8.79(dd,J=4.7,1.3Hz,1H,pyridine-H),8.41(s,1H,CH=N),8.33(d,J=8.8Hz,2H,Ph-H),8.30–8.25(m,1H,pyridine),8.05(d,J=8.8Hz,2H,Ph-H),7.60(dd,J=7.5,5.0Hz,1H,pyridine,),7.50(d,J=3.6Hz,1H,furan-H),7.20(d,J=3.6Hz,1H,furan-H).
实施例21
5-甲基-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)吡嗪-2-甲酰肼的制备
以对硝基苯胺为原料,按照实施例11中的步骤2的合成方法制备关键中间体D;按照实施例11中的步骤4的合成方法制备碳酰肼中间体G;再按照实施例11中步骤5的合成方法制备得到5-甲基-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)吡嗪-2-甲酰肼,红色固体,收率75.4%。
Mp:230.7-232.9℃;MS(ESI)m/z(%):308.22[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):10.62(s,1H,NNHCO),8.29(d,J=9.0Hz,2H,Ph-H),7.99(d,J=9.0Hz,2H,Ph-H),7.83(s,1H,CH=N),7.42(d,J=3.6Hz,1H,furan-H),7.28–7.25(m,2H,Ph-H),7.10(dd,J=8.4,0.9Hz,2H,Ph-H),6.88(d,J=3.6Hz,1H,furan-H),6.81(t,J=7.7Hz,1H).
实施例22
2-(((5-(4-硝基苯基)呋喃-2-基)亚甲基)氨基)异吲哚-1,3-二酮的制备
步骤1:1-氯-2-(4-硝基苯基)重氮盐(B)的合成
将对硝基苯胺(2.54g,20mmol)悬浮在0℃的10mL 20%盐酸溶液中,加入亚硝酸钠的冷水溶液(1.7g,23mmol),在0-5℃下搅拌1h,得到4-硝基苯基重氮盐(B)。直接用重氮盐B的反应液进行下一步反应。
步骤2:5-(4-硝基苯基)呋喃-2-甲醛(D)的合成
在搅拌下将1-氯-2-(4-硝基苯基)重氮盐(B)滴加到呋喃甲醛(C)(0.2mol,19.2g)和CuCl2·2H2O(0.116mol,2g)的丙酮(60mL)溶液中,温度为20-30℃。混合物搅拌直至不再放出氮气,用水(300mL)稀释,过滤得到5-(4-硝基苯基)呋喃-2-甲醛(D),用DMF(35.4g,81.8%)重结晶。Mp:202.7-204.1℃,MS(ESI)m/z(%):218.26[M+H]+;1H NMR(400MHz,DMSO-d6)δ(ppm):9.69(s,1H,CHO),8.35(d,J=8.9Hz,2H,Ph-H),8.13(d,J=8.9Hz,2H,Ph-H),7.72(d,J=3.8Hz,1H,furan-H),7.59(d,J=3.8Hz,1H,furan-H)。
步骤3:N-氨基邻芳基二甲酰亚胺中间体(J)的合成
将邻苯二甲酸(1.1μmol)和80%水合肼(1.3μmol)加入四氢呋喃(10mL)中。回流下剧烈搅拌,反应6h,加入纯净水,搅拌析出白色固体,抽滤后干燥得到N-氨基邻苯二甲酰亚胺(J),收率77.1%。
步骤4:2-(((5-(4-硝基苯基)呋喃-2-基)亚甲基)氨基)异吲哚-1,3-二酮(I-iii)的合成
冰醋酸催化下,将关键中间体D(1.5mmol)和N-氨基邻苯二甲酰亚胺(中间体J)(1.5mmol)在EtOH(10mL)中于室温搅拌2h,用EtOH(5mL)过滤洗涤沉淀,减压干燥,得到2-(((5-(4-硝基苯基)呋喃-2-基)亚甲基)氨基)异吲哚-1,3-二酮的黄色固体,收率68.1%。
Mp:220.1-221.8℃;MS(ESI)m/z(%):360.31[M-H]-;1H NMR(600MHz,DMSO-d6)δ(ppm):9.23(s,1H,CH=N),8.36(d,J=9.0Hz,2H,Ph-H),8.11(d,J=9.0Hz,2H,Ph-H),7.96(td,J=5.2,2.0Hz,2H,Ph-H),7.91(td,J=5.2,2.0Hz,2H,Ph-H),7.58(d,J=3.7Hz,1H,furan-H),7.46(d,J=3.7Hz,1H,furan-H).
实施例23
N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)-4-苯氧基苯甲酰肼的制备
以对硝基苯胺为原料,按照实施例11中的步骤2的合成方法制备关键中间体D;按照实施例11中的步骤4的合成方法制备碳酰肼中间体G;再按照实施例11中步骤5的合成方法制备得到N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)-4-苯氧基苯甲酰肼,黄色固体,60.1%。
MS(ESI)m/z(%):428.12[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):11.92(s,1H,NNHCO),8.43(s,1H,CH=N),8.32(d,J=8.6Hz,2H,Ph-H),8.04(d,J=8.6Hz,2H,Ph-H),7.97(d,J=8.5Hz,2H,Ph-H),7.49(d,J=3.5Hz,1H,furan-H),7.46(d,J=8.5Hz,2H,Ph-H),7.16(d,J=2.7Hz,1H,furan-H),7.12(d,,J=1.9Hz,2H,Ph-H),7.11(d,J=1.9Hz,2H,Ph-H).
实施例24
2,4,6-三甲基-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼的制备
以对硝基苯胺为原料,按照实施例1中的步骤2的合成方法制备关键中间体D;按照实施例1中的步骤3的合成方法制备磺酰肼中间体E;再按照实施例1中步骤4的合成方法制备得到2,4,6-三甲基-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼,黄色固体,收率77.1%。
MS(ESI)m/z(%):412.33[M-H]-;1H NMR(600MHz,DMSO-d6)δ(ppm):11.78(s,1H,NNHCO),8.32(d,J=9.0Hz,2H,Ph-H),7.92(d,J=9.0Hz,2H,Ph-H),7.83(s,1H,CH=N),7.39(d,J=3.6Hz,1H,furan-H),7.07(s,2H,Ph-H),6.95(d,J=3.6Hz,1H,furan-H),2.69(s,6H,PhCH3),2.24(s,3H,PhCH3).
实施例25
5-溴-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)烟酰肼的制备
以对硝基苯胺为原料,按照实施例11中的步骤2的合成方法制备关键中间体D;按照实施例11中的步骤4的合成方法制备碳酰肼中间体G;再按照实施例11中步骤5的合成方法制备得到5-溴-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)烟酰肼,黄色固体,收率63.9%。
MS(ESI)m/z(%):415.20[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):11.50(s,1HNNHCO),8.30(d,J=8.8Hz,2H,Ph-H),8.01(d,J=8.8Hz,2H,Ph-H),7.96(s,1H,CH=N),7.61(t,J=7.9Hz,1H,Ph-H),7.44(d,J=8.2Hz,1H,furan-H),7.21(d,J=8.2Hz,1H,furan-H),6.99(t,J=5.9Hz,2H,Ph-H).
实施例26
4-氟-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼的制备
以对硝基苯胺为原料,按照实施例1中的步骤2的合成方法制备关键中间体D;按照实施例1中的步骤3的合成方法制备磺酰肼中间体E;再按照实施例1中步骤4的合成方法制备得到4-氟-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼,黄色固体,收率80.1%。
MS(ESI)m/z(%):388.10[M-H]-;1H NMR(600MHz,DMSO-d6)δ(ppm):11.75(s,1H,NNHCO),8.32(d,J=8.8Hz,2H,Ph-H),7.98(d,J=8.8Hz,2H,Ph-H),7.97–7.95(m,2H,Ph-H),7.88(s,1H,CH=N),7.50(t,J=8.8Hz,2H,Ph-H),7.41(d,J=3.6Hz,1H,furan-H),7.05(d,J=3.6Hz,1H,furan-H).
生物实验例1
本发明化合物的体外Ca2+抑制(SOICR)、乙酰胆碱酯酶(AChE)抑制活性测试测试物:本发明中通式I的化合物(实施例1-22),稀释浓度:0.1μM、3μM、5μM、10μM。
对照药:已公开化合物Dantrolene、Donepezil
SOICR抑制活性测试方法:
细胞经1mg/ml四环素诱导后,在载玻片上培养20~24h,然后在KRH缓冲液(125mM磷酸二氢钠1.2mM葡萄糖、1.2mM氯化镁和25mM HEPES,pH 7.35~7.45)中负载荧光钙指示剂(Fura-2AM,5mM),室温保存20min。将盖玻片安装在灌注室内,向KRH溶液中注入不同浓度的CaCl2,使钙浓度从0.1、0.5逐渐增加到1mM。然后用含1mM CaCl2的KRH溶液持续灌流细胞,使受试化合物(0.1μM、3μM、10μM)的浓度逐渐增加,每次8min。在每个实验结束时应用咖啡因(10MM),以验证细胞中确实存在功能正常的RyR1通道。
实验结束后,用显微镜捕捉延迟图像(0.25帧/s),选择加入咖啡因后有钙振荡信号和钙振荡峰的细胞进行统计。记录不同浓度时间范围内无钙振荡信号的细胞数,按以下公式计算:
抑制率=无钙振荡信号的细胞数/总细胞数*100%
AChE抑制活性测试方法:
在96孔板上分光光度法测定AChE抑制活性。目标化合物很好地溶解在DMSO溶液中。将60μM Ellman试剂添加到250μL DMSO的最终体积中,同时添加100μM抑制剂、0.05MpH8磷酸盐缓冲液和0.25U/mL的AChE。孵育30min后,通过向上述溶液中加入1.5mM乙酰硫代胆碱碘开始反应。该测定在三个单独的测定中重复进行,并在412nm波长下记录10min的吸光度。通过对比小鼠与对照组的酶反应速率,计算抑制百分比。
以dantrolene和donepezil为阳性对照药,对目标化合物进行Ca2+和AChE抑制率测试,结果见表2。
表2
如表2实验结果所示,本发明的化合物在体外对Ca2+和乙酰胆碱酯酶具有良好的双重抑制活性,部分化合物优于阳性对照药,这为阿尔兹海默症的治疗方案提供了一个新的方向。说明本发明化合物在治疗阿尔兹海默疾病方面具有较好的临床应用潜力。
生物实验例2
本发明化合物的体内海马突触强度测试
长时程增强作用(Long-term potentiation,LTP)是发生在两个神经元的信号传导中的一种长期增强,是神经元间学习和记忆存储的机制之一。为研究化合物是否促进突触活动,本发明测试了化合物3对急性海马脑切片中LTP的影响。
测试对象:本发明中通式I的化合物(实施例3)
测试方法:
选择了5至6个月大的无特定病原体级(SPF)家族性阿尔茨海默病(FAD)小鼠,有雄性和雌性。麻醉后迅速将动物全脑放于4℃的人工脑脊液(ACSF,无菌)中。然后,在4℃的供氧条件下,用振动切片机沿垂直于海马长轴的方向将海马切成约300毫米的片状。在26°C培养1h后,让海马切片在记录室中再恢复10min。在CA3亚区刺激Schaffer侧支纤维,以记录来自DMSO和化合物处理小鼠的横向海马切片(300毫米)CA1层的场兴奋性突触后电位(fEPSPs)。我们使用一系列的刺激强度(0-200μA)来评估基础突触传递,并绘制了fEPSP与电流输入的斜率,以比较fEPSP的输入/输出(I/O)曲线的斜率。收集基线至少20min,或直到fEPSP斜率的差异小于10%。用强直的高频刺激(HFS)诱导长期电位(LTP)。在强直刺激后至少60min记录突触反应,并使用诱发的fEPSP的斜率量化为基线的百分比。使用MultiClamp700B和Dididata 1440A来记录LTP(Molecular Devices,LLC.,San Jose,CA,USA.)。数据分析和记录使用pCLAMP 10.6软件包(Molecular Devices,LLC,San Jose,CA,USA;RRID:SCR_011323)进行。
通过在CA3亚区刺激Schaffer侧支纤维,以记录经DMSO和化合物3处理的小鼠海马横切片(300mm)CA1层的场兴奋性突触后电位(fEPSP)。结果见图1。
与DMSO组相比,5–6个月大的FAD小鼠经化合物3处理后显示出海马LTP增强(即高频刺激后fEPSP斜率的增强水平,HFS),这表明化合物3可以显著增强海马中的突触强度,即有利于动物学习和记忆行为的建立。进一步证明本发明化合物在治疗阿尔兹海默疾病方面的临床应用潜力。
Claims (5)
1.一种含N-酰基芳腙类衍生物或其药学上可接受的盐,其特征在于,其为如下所示化合物中任一种:
(1)N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)噻吩-2-磺酰肼
(2)5-氯-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)噻吩-2-磺酰肼
(3)N'-((5-(4-硝基苯)呋喃-2-基)亚甲基)苯磺酰肼
(5)4-溴-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼
(6)2,4-二氯-N'-(5-(4-硝基苯基)呋喃-2-基)亚甲基)苯磺酰肼
(14)N'-((5-(4-硝基苯)呋喃-2-基)亚甲基)-1H-1,2,4-三唑-3-甲酰肼
(15)N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)-1H-1,2,4-三唑-1-碳酰肼
(19)5-氯-N'-((5-(4-硝基苯基)呋喃-2-基)亚甲基)噻吩-2-碳酰肼。
2.根据权利要求1所述的含N-酰基芳腙类衍生物或其药学上可接受的盐,其特征在于,药用加成盐为无机酸或有机酸加成盐,所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸或苯甲酸。
3.一种药物组合物,其特征在于,包含权利要求1所述的含N-酰基芳腙类衍生物或其在药学上可接受的盐或药学上可接受的载体或赋形剂。
4.权利要求1所述的含N-酰基芳腙类衍生物或其在药学上可接受的盐或权利要求3所述的药物组合物在制备治疗和/或预防神经退行性疾病药物中的应用。
5.权利要求1所述的含N-酰基芳腙类衍生物或其在药学上可接受的盐或权利要求3所述的药物组合物在制备治疗和/或预防阿尔兹海默症的药物中的应用。
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Bolognino, Isabella等.Synthesis and Biological Evaluation of Dantrolene-Like Hydrazide and Hydrazone Analogues as Multitarget Agents for Neurodegenerative Diseases.ChemMedChem.2021,第16卷(第18期),2807-2816,第3页表1化合物1-2,第8页制备方法。其中化合物1即本申请实施例16. * |
Dai, Baozhu等.Design, synthesis, and biological activity of novel semicarbazones as potent Ryanodine receptor1 inhibitors of Alzheimer's disease.Bioorganic & Medicinal Chemistry.2020,第29卷115891,第4页12acd,第5页表1-2,第3页流程1-5,12d即本申请实施例13. * |
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Weaver, G. W..Product class 8: 1,3,4-oxadiazoles.Science of Synthesis.2004,第13卷219-251,第22页表格中反应物66的第5行即本申请实施例17. * |
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