CN118165004A - 一种Type-II型GSK-3β抑制剂及其制备方法与应用 - Google Patents
一种Type-II型GSK-3β抑制剂及其制备方法与应用 Download PDFInfo
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- CN118165004A CN118165004A CN202410287022.4A CN202410287022A CN118165004A CN 118165004 A CN118165004 A CN 118165004A CN 202410287022 A CN202410287022 A CN 202410287022A CN 118165004 A CN118165004 A CN 118165004A
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- compound
- phenyl
- isobutyramide
- pyrazol
- ureido
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Abstract
本发明公开了一种Type‑II型GSK‑3β抑制剂及其制备方法与应用,属于药物化学技术领域。本发明提供的用作Type‑II型GSK‑3β抑制剂的化合物具有具有式(I)所示结构或其药学上可接受的盐,具有良好的GSK‑3β抑制活性,对于增强药物的特异性、有效性、减少毒副作用和防止耐药性等都有很重要的意义,可用于制备治疗糖尿病、阿尔茨海默症、肿瘤、骨质疏松以及精神障碍等疾病的药物。
Description
技术领域
本发明涉及药物化学技术领域,尤其涉及一种Type-II型GSK-3β抑制剂及其制备方法与应用。
背景技术
本发明背景技术中公开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。
糖原合酶激酶-3(glycogen synthase kinase-3,GSK-3)是一种多功能的丝氨酸/苏氨酸蛋白激酶,在蛋白质合成、信号传递、细胞增殖、细胞分化、神经功能、肿瘤形成及胚胎发育等众多细胞进程中均扮演重要的角色。GSK-3能够使多种底物发生磷酸化,并参与胰岛素、Wnt及Hedgehog等多个信号通路的调控。
GSK-3抑制剂在信号通路中能有效地抑制病理情况下GSK-3活性的异常增高,达到治疗的目的。GSK-3的抑制剂将作为一种潜在的药物,有望用于治疗糖尿病、阿尔海默茨症、肿瘤、骨质疏松、以及精神障碍等疾病。目前的GSK-3抑制剂的设计主要以GSK-3β的晶体结构为基础。
抑制剂直接与蛋白激酶活性构象或者非活性构象结合,区分其结构为活性构象还是非活性构象,一般可通过其活性loop起始的保守的DFG残基的朝向进行判断:DFG中苯丙氨酸向里与C-螺旋和N端相互作用的DFG-in构象为活性构象,DFG的苯丙氨酸朝外占据ATP结合口袋的构象为DFG-out非活性构象。基于这种DFG朝向的区别,与之结合的抑制剂也被分为不同的类型,与DFG-in结合的抑制剂被称为Type-I型抑制剂,与DFG-out构象结合的抑制剂被称为Type-II型抑制剂。目前报道的GSK-3β抑制剂主要是Type-I型,而Type-I型ATP竞争性激酶抑制剂(DFG-in)共通的一个缺点是激酶选择性差、易产生耐药性和脱靶毒性,而基于DFG-out非活性构象的II型激酶抑制剂有望解决这些问题,但目前的II型激酶抑制剂种类很少报道,因此有必要研究开发新型GSK-3β抑制剂。
发明内容
有鉴于此,本发明以GSK-3β晶体结构为基础,保留Asp200氨基酸残基,去除氨基酸序列中201-205号氨基酸残基(FGSAK),通过计算机模拟,构建GSK-3βDFG-out构象模型。以此模型为基础,以噻吩并吡唑-3-胺为核心骨架,在噻吩并吡唑-3-胺的5-位引入苯环,通过脲基与Glu97、Asp200的三重氢键作用,锁定DFG-out构象,诱导DFG-out疏水空腔的形成,设计合成了一系列Type-II型GSK-3β抑制剂的化合物,该类化合物具有良好的GSK-3β抑制活性,有望用于糖尿病、阿尔茨海默症、肿瘤、骨质疏松以及精神障碍等疾病的治疗。
第一方面,本发明提供了一种化合物,具有式(I)所示结构或其药学上可接受的盐:
其中,R1、R2、R3、R4、R5各自独立地选自氢、氯、氟、甲基、甲氧基、三氟甲氧基或氰基。
本发明所述的“药学上可接受的盐”是指本发明的化合物的有机酸盐和无机酸盐。所述药学上可接受的能与之成盐的酸包括但不限于盐酸、硫酸、磷酸、氢溴酸、硝酸、苯磺酸、对甲基苯磺酸、柠檬酸、L-脯氨酸、丁酸、羟乙酸、乙酸、已酸、壬酸、丙酸、苹果酸、天门冬氨酸、丙二酸、琥珀酸、酒石酸、乙二磺酸、甲磺酸、富马酸、苯甲酸、乳酸、丁二磺酸、已二酸、α-酮戊二酸、乳糖酸、马来酸、1,5-萘二磺酸、水杨酸、乙酰水杨酸、2-萘磺酸、苯乙酸、烟酸、1-羟基-2-萘甲酸、樟脑酸、2-羟基乙磺酸、扁桃酸、苦味酸、肉桂酸或草酸等。
进一步的,R1为氢,R5为氢,R2、R3、R4各自独立地选自氢、氯、氟、甲基、甲氧基、三氟甲氧基或氰基。
进一步的,R2为氢,R3、R4各自独立地选自氢、氯、氟、甲基、甲氧基、三氟甲氧基或氰基。
优选的,所述化合物选自:
N-(5-(3-(3-苯基脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-1);
N-(5-(3-(3-(2-氯苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-2);
N-(5-(3-(3-(3-氯苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-3);
N-(5-(3-(3-(4-氯苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-4);
N-(5-(3-(3-(3-氟苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-5);
N-(5-(3-(3-(4-氟苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-6);
N-(5-(3-(3-(2-甲基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-7);
N-(5-(3-(3-(4-甲基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-8);
N-(5-(3-(3-(3-三氟甲氧基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-9);
N-(5-(3-(3-(4-三氟甲氧基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-10);
N-(5-(3-(3-(4-甲氧基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-11);
N-(5-(3-(3-(4-氰基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-12);
N-(5-(3-(3-(3,4-二氟苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-13);
N-(5-(3-(3-(4-氯-3-氟苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-14)。
第二方面,本发明提供了上述化合物的制备方法,包括以下步骤:
将式(II)所示化合物与3-硝基苯硼酸经Suzuki偶联反应,合成式(III)所示化合物;
将式(III)所示化合物经FeCl3和水合肼还原,合成式(IV)所示化合物;
将式(IV)所示化合物与苯基异氰酸酯或取代的苯基异氰酸酯反应,合成式(I)所示化合物;
第三方面,本发明提供了一种药物组合物,包括上述化合物或其药学上可接受的盐或上述制备方法制备的化合物或其药学上可接受的盐。
第四方面,本发明提供了一种药物制剂,包括上述化合物或其药学上可接受的盐或上述制备方法制备的化合物或其药学上可接受的盐。
本发明所述药物组合物和药物制剂还包括至少一种药学上可接受的辅料和/或载体。
本发明所述药学上可接受的辅料是指药物组合物或药物制剂中除有效成分之外的成分,其对受试者无毒。本领域常用的辅料比如缓冲剂、稳定剂、防腐剂或赋型剂,常用的赋形剂例如粘合剂、填充剂、润湿剂、崩解剂等。作为示例,本发明的所述药物制剂中可选用的赋形剂包括但不限于:磷酸钙、硬脂酸镁、滑石粉、糊精、淀粉、凝胶纤维素、甲基纤维素、羧甲基纤维素钠盐和聚乙烯吡咯烷酮。
本发明所述药学上可接受的载体可以是药学上可接受的溶剂、悬浮剂、囊泡、纳米材料等,用于将本发明上述第一方面所述的化合物递送至动物或人体内。载体可以是液体或固体,并按照计划的给药方式进行选择。蛋白和脂质体也是药物载体。
本领域技术人员可采用公知的技术将本发明的化合物配制成药物组合物或药物制剂。比如将本发明上述第一方面中披露的任意化合物(至少一种化合物)与药用辅料混合,然后如果需要,使所得混合物形成所需的形状。
第五方面,本发明提供了上述化合物或上述制备方法制备的化合物或上述药物组合物或上述药物制剂在制备Type-II型GSK-3β抑制剂药物或试剂中的应用。
第六方面,本发明提供了上述化合物或上述制备方法制备的化合物或上述药物组合物或上述药物制剂在制备预防或治疗与GSK-3活性异常表达相关疾病的药物中的应用。
优选的,所述与GSK-3活性异常表达相关疾病包括糖尿病、阿尔茨海默症、骨质疏松或精神障碍疾病。
与现有技术相比,本发明取得了以下有益效果:
本发明提供了具有式(I)所示结构的化合物或其药学上可接受的盐,其结构新颖,可用作Type-II型GSK-3抑制剂,具有良好的GSK-3β抑制活性,对于增强药物的特异性、有效性,减少毒副作用和防止耐药性等都有很重要的意义,有望用于糖尿病、阿尔茨海默症、肿瘤、骨质疏松以及精神障碍等疾病的治疗。
具体实施方式
应该指出,以下详细说明都是示例性的,旨在对本发明提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。本发明所使用的试剂或原料均可通过常规途径购买获得,如无特殊说明,本发明所使用的试剂或原料均按照本领域常规方式使用或者按照产品说明书使用。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明提供了式(I)所示化合物的制备方法,反应路线如下所示:
下面结合具体实施例对本发明技术方案做进一步阐述。
以下实施例中,下面的缩写具有如下所示的意义:
DMF表示N,N-二甲基甲酰胺;
DMSO表示二甲基亚砜;
FAM表示羧基荧光素;
ATP表示腺嘌呤核苷三磷酸;
1H NMR表示核磁共振氢谱;
MS(ESI)表示电喷雾质谱。
实施例1N-(5-(3-硝基苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物2)的制备
将N-(5-溴-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物1,1.22g,4.24mmol)溶于DMF(10mL)、乙醇(10mL)和水(3mL)中,氮气保护下,加入3-硝基苯硼酸(0.78g,4.66mmol)、Pd(dppf)Cl2(155mg,0.21mmol)和醋酸钾(1.25g,12.7mmol)于115℃搅拌反应12h。加入水(20mL),用乙酸乙酯(50mL×5)萃取。合并有机相,用饱和食盐水洗,无水硫酸钠干燥。过滤、减压浓缩,经硅胶柱层析(乙酸乙酯100%),得N-(5-(3-硝基苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物2),土黄色固体872mg,收率62.5%,熔点:>240℃。1H NMR(400MHz,DMSO-d6)δ12.61(s,1H),10.78(s,1H),8.44(s,1H),8.16(d,J=6.9Hz,2H),7.79-7.62(m,2H),2.75-2.64(m,1H),1.11(d,J=5.7Hz,6H);MS(ESI):calcd.for C15H15N4O3S[M+H]+:331.1,found:331.3。
实施例2N-(5-(3-氨基苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物3)的制备
将实施例1得到的化合物2(0.82g,2.64mmol)溶于15mL甲醇中,加入FeCl3·6H2O(0.135g,0.79mmol),活性炭(0.317g,26.4mmol),于70℃搅拌反应30min后,向反应液中滴加80%水合肼(1.65g,26.4mmol),维持70℃搅拌反应9h。将反应液冷却至室温,用硅藻土过滤。将滤液浓缩后,经硅胶柱层析(石油醚:乙酸乙酯=2:1),得N-(5-(3-氨基苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物3),白色固体465mg,收率58.7%,熔点:210-211℃。1HNMR(400MHz,DMSO-d6)δ12.35(s,1H),10.66(s,1H),7.18(s,1H),7.06(t,J=7.8Hz,1H),6.92-6.83(m,2H),6.54(dd,J=8.0,1.1Hz,1H),5.20(s,2H),2.73-2.63(m,1H),1.11(d,J=6.8Hz,6H);MS(ESI):calcd.for C15H17N4OS[M+H]+:301.1,found:301.6。
实施例3化合物I-1的制备
冰浴条件下,将苯胺(33mg,0.26mmol)缓慢滴加到三光气(39mg,0.13mmol)的1,4-二氧六环溶液(1mL)中,于100℃搅拌反应2h,得到苯基异氰酸酯的1,4-二氧六环溶液,冷却至室温备用。将化合物3(60mg,0.2mmol)溶于1,4-二氧六环(1mL)中,加入三乙胺(53mg,0.52mmol),缓慢滴加上述苯基异氰酸酯的1,4-二氧六环溶液,室温搅拌反应12h。加水(5mL),用乙酸乙酯萃取。有机相用饱和食盐水洗,无水硫酸钠干燥。过滤、减压浓缩,经硅胶柱层析(石油醚:乙酸乙酯=2:1),得N-(5-(3-(3-苯基脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物I-1),白色固体30mg,收率35.8%。熔点:155-157℃。1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),10.72(s,1H),8.87(s,1H),8.78(s,1H),7.99(s,1H),7.49(d,J=7.6Hz,2H),7.38-7.25(m,6H),6.98(t,J=7.2Hz,1H),2.72-2.64(m,1H),1.12(d,J=6.4Hz,6H);HRMS(ESI)calcd.for C22H22N5O2S[M+H]+:420.1489,found:420.1503。
实施例4化合物I-2的制备
冰浴条件下,将2-氯苯胺(33mg,0.26mmol)缓慢滴加到三光气(39mg,0.13mmol)1,4-二氧六环溶液(1mL)中,于100℃搅拌反应2h,得到2-氯苯基异氰酸酯的1,4-二氧六环溶液,冷却至室温备用。将化合物3(60mg,0.2mmol)溶于1,4-二氧六环(1mL)中,加入三乙胺(53mg,0.52mmol),缓慢滴加上述2-氯苯基异氰酸酯的1,4-二氧六环溶液,室温搅拌反应16h。加水(5mL),用乙酸乙酯萃取。有机相用饱和食盐水洗,无水硫酸钠干燥。过滤、减压浓缩,经硅胶柱层析(石油醚:乙酸乙酯=2:1),得将化合物3(60mg,0.2mmol)、三乙胺(53mg,0.52mmol)、2-氯苯基异氰酸酯的1,4-二氧六环溶液,室温搅拌反应16h,经硅胶柱层析(石油醚:乙酸乙酯=1:2),得N-(5-(3-(3-(2-氯苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物I-2),白色固体30mg,收率33.1%。熔点:144-146℃。1H NMR(400MHz,DMSO-d6)δ12.45(s,1H),10.72(s,1H),9.59(s,1H),8.35(s,1H),8.23(d,J=7.9Hz,1H),8.01(s,1H),7.53-7.27(m,6H),7.04(t,J=7.2Hz,1H),2.74-2.64(m,1H),1.12(d,J=6.6Hz,6H);HRMS(ESI)calcd.for C22H21ClN5O2S[M+H]+:454.1099,found:454.1103。
实施例5化合物I-3的制备
冰浴条件下,将3-氯苯胺(33mg,0.26mmol)缓慢滴加到三光气(39mg,0.13mmol)1,4-二氧六环溶液(1mL)中,于100℃搅拌反应2h,得到3-氯苯基异氰酸酯的1,4-二氧六环溶液,冷却至室温备用。将化合物3(60mg,0.2mmol)溶于1,4-二氧六环(1mL)中,加入三乙胺(53mg,0.52mmol),缓慢滴加上述3-氯苯基异氰酸酯的1,4-二氧六环溶液,室温搅拌反应16h。加水(5mL),用乙酸乙酯萃取。有机相用饱和食盐水洗,无水硫酸钠干燥。过滤、减压浓缩,经硅胶柱层析(石油醚:乙酸乙酯=2:1),得N-(5-(3-(3-(3-氯苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物I-3),白色固体28mg,收率30.9%.熔点:164-166℃。1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),10.72(s,1H),8.94(s,1H),8.90(s,1H),7.96(s,1H),7.73(s,1H),7.40-7.26(m,6H),7.06-6.99(m,1H),2.74-2.65(m,1H),1.12(d,J=6.7Hz,6H);HRMS(ESI)calcd.for C22H21ClN5O2S[M+H]+:454.1099,found:454.1100。
实施例6化合物I-4的制备
冰浴条件下,将4-氯苯胺(33mg,0.26mmol)缓慢滴加到三光气(39mg,0.13mmol)1,4-二氧六环溶液(1mL)中,于100℃搅拌反应2h,得到4-氯苯基异氰酸酯的1,4-二氧六环溶液,冷却至室温备用。将化合物3(60mg,0.2mmol)溶于1,4-二氧六环(1mL)中,加入三乙胺(53mg,0.52mmol),缓慢滴加上述4-氯苯基异氰酸酯的1,4-二氧六环溶液,室温搅拌反应16h。加水(5mL),用乙酸乙酯萃取。有机相用饱和食盐水洗,无水硫酸钠干燥。过滤、减压浓缩,经硅胶柱层析(石油醚:乙酸乙酯=2:1),得N-(5-(3-(3-(4-氯苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物I-4),白色固体25mg,收率27.6%.熔点:172-174℃。1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),10.72(s,1H),8.88(s,1H),8.86(s,1H),7.99(s,1H),7.53(d,J=8.7Hz,2H),7.38-7.26(m,6H),2.72-2.64(m,1H),1.11(d,J=6.7Hz,6H);HRMS(ESI)calcd.for C22H21ClN5O2S[M+H]+:454.1099,found:454.1098。
实施例7化合物I-5的制备
冰浴条件下,将3-氟苯胺(29mg,0.26mmol)缓慢滴加到三光气(39mg,0.13mmol)1,4-二氧六环溶液(1mL)中,于100℃搅拌反应2h,得到3-氟苯基异氰酸酯的1,4-二氧六环溶液,冷却至室温备用。将化合物3(60mg,0.2mmol)溶于1,4-二氧六环(1mL)中,加入三乙胺(53mg,0.52mmol),缓慢滴加上述3-氟苯基异氰酸酯的1,4-二氧六环溶液,室温搅拌反应16h。加水(5mL),用乙酸乙酯萃取。有机相用饱和食盐水洗,无水硫酸钠干燥。过滤、减压浓缩,经硅胶柱层析(石油醚:乙酸乙酯=2:1),得N-(5-(3-(3-(3-氟苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物I-5),白色固体30mg,收率34.3%。熔点:177-179℃。1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),10.71(s,1H),9.02(s,1H),8.94(s,1H),7.96(s,1H),7.51(d,J=11.9Hz,1H),7.41-7.28(m,5H),7.17(d,J=8.2Hz,1H),6.79(td,J=8.4,2.0Hz,1H),2.74-2.63(m,1H),1.12(d,J=6.8Hz,6H);HRMS(ESI)calcd.forC22H21FN5O2S[M+H]+:438.1395,found:438.1399。
实施例8化合物I-6的制备
冰浴条件下,将4-氟苯胺(29mg,0.26mmol)缓慢滴加到三光气(39mg,0.13mmol)1,4-二氧六环溶液(1mL)中,于100℃搅拌反应2h,得到4-氟苯基异氰酸酯的1,4-二氧六环溶液,冷却至室温备用。将化合物3(60mg,0.2mmol)溶于1,4-二氧六环(1mL)中,加入三乙胺(53mg,0.52mmol),缓慢滴加上述4-氟苯基异氰酸酯的1,4-二氧六环溶液,室温搅拌反应16h。加水(5mL),用乙酸乙酯萃取。有机相用饱和食盐水洗,无水硫酸钠干燥。过滤、减压浓缩,经硅胶柱层析(石油醚:乙酸乙酯=2:1),得N-(5-(3-(3-(4-氟苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物I-6),白色固体33mg,收率37.8%。熔点:157-159℃。1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),10.71(s,1H),8.82(s,1H),8.77(s,1H),7.98(s,1H),7.54-7.47(m,2H),7.38-7.27(m,4H),7.12(t,J=8.8Hz,2H),2.73-2.65(m,1H),1.11(d,J=6.8Hz,6H);HRMS(ESI)calcd.for C22H21FN5O2S[M+H]+:438.1395,found:438.1398。
实施例9化合物I-7的制备
冰浴条件下,将2-甲基苯胺(28mg,0.26mmol)缓慢滴加到三光气(39mg,0.13mmol)1,4-二氧六环溶液(1mL)中,于100℃搅拌反应2h,得到2-甲基苯基异氰酸酯的1,4-二氧六环溶液,冷却至室温备用。将化合物3(60mg,0.2mmol)溶于1,4-二氧六环(1mL)中,加入三乙胺(53mg,0.52mmol),缓慢滴加上述2-甲基苯基异氰酸酯的1,4-二氧六环溶液,室温搅拌反应16h。加水(5mL),用乙酸乙酯萃取。有机相用饱和食盐水洗,无水硫酸钠干燥。过滤、减压浓缩,经硅胶柱层析(石油醚:乙酸乙酯=2:1),得N-(5-(3-(3-(2-甲基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物I-7),白色固体22mg,收率22.8%。熔点:138-140℃。1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),10.71(s,1H),9.20(s,1H),7.98(s,2H),7.88(d,J=8.0Hz,1H),7.40-7.29(m,4H),7.20-7.12(m,2H),6.96(t,J=7.3Hz,1H),2.73-2.64(m,1H),2.26(s,3H),1.11(d,J=6.8Hz,6H);HRMS(ESI)calcd.for C23H24N5O2S[M+H]+:434.1645,found:434.1649。
实施例10化合物I-8的制备
冰浴条件下,将4-甲基苯胺(28mg,0.26mmol)缓慢滴加到三光气(39mg,0.13mmol)1,4-二氧六环溶液(1mL)中,于100℃搅拌反应2h,得到4-甲基苯基异氰酸酯的1,4-二氧六环溶液,冷却至室温备用。将化合物3(60mg,0.2mmol)溶于1,4-二氧六环(1mL)中,加入三乙胺(53mg,0.52mmol),缓慢滴加上述4-甲基苯基异氰酸酯的1,4-二氧六环溶液,室温搅拌反应16h。加水(5mL),用乙酸乙酯萃取。有机相用饱和食盐水洗,无水硫酸钠干燥。过滤、减压浓缩,经硅胶柱层析(石油醚:乙酸乙酯=2:1),得N-(5-(3-(3-(4-甲基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物I-8),白色固体24mg,收率31.3%。熔点:166-168℃。1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),10.69(s,1H),8.78(s,1H),8.62(s,1H),7.98(s,1H),7.40-7.26(m,6H),7.09(d,J=8.2Hz,2H),2.74-2.65(m,1H),2.25(s,3H),1.12(d,J=6.8Hz,6H);HRMS(ESI)calcd.for C23H24N5O2S[M+H]+:434.1645,found:434.1662。
实施例11化合物I-9的制备
冰浴条件下,将3-三氟甲氧基苯胺(46mg,0.26mmol)缓慢滴加到三光气(39mg,0.13mmol)1,4-二氧六环溶液(1mL)中,于100℃搅拌反应2h,得到3-三氟甲氧基苯基异氰酸酯的1,4-二氧六环溶液,冷却至室温备用。将化合物3(60mg,0.2mmol)溶于1,4-二氧六环(1mL)中,加入三乙胺(53mg,0.52mmol),缓慢滴加上述3-三氟甲氧基苯基异氰酸酯的1,4-二氧六环溶液,室温搅拌反应16h。加水(5mL),用乙酸乙酯萃取。有机相用饱和食盐水洗,无水硫酸钠干燥。过滤、减压浓缩,经硅胶柱层析(石油醚:乙酸乙酯=2:1),得N-(5-(3-(3-(3-三氟甲氧基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物I-9),白色固体33mg,收率32.7%。熔点:183-185℃。1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),10.71(s,1H),9.06(s,1H),8.91(s,1H),7.95(s,1H),7.69(s,1H),7.48-7.28(m,6H),7.04-6.88(m,1H),2.76-2.64(m,1H),1.12(d,J=6.8Hz,6H);HRMS(ESI)calcd.for C23H21F3N5O3S[M+H]+:504.1312,found:504.1313。
实施例12化合物I-10的制备
冰浴条件下,将4-三氟甲氧基苯胺(46mg,0.26mmol)缓慢滴加到三光气(39mg,0.13mmol)1,4-二氧六环溶液(1mL)中,于100℃搅拌反应2h,得到4-三氟甲氧基苯基异氰酸酯的1,4-二氧六环溶液,冷却至室温备用。将化合物3(60mg,0.2mmol)溶于1,4-二氧六环(1mL)中,加入三乙胺(53mg,0.52mmol),缓慢滴加上述4-三氟甲氧基苯基异氰酸酯的1,4-二氧六环溶液,室温搅拌反应16h。加水(5mL),用乙酸乙酯萃取。有机相用饱和食盐水洗,无水硫酸钠干燥。过滤、减压浓缩,经硅胶柱层析(石油醚:乙酸乙酯=2:1),得N-(5-(3-(3-(4-三氟甲氧基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物I-10),白色固体35mg,收率34.7%。熔点:200-202℃。1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),10.72(s,1H),8.99(s,1H),8.92(s,1H),8.00(s,1H),7.61(d,J=8.5Hz,2H),7.40-7.22(m,6H),2.74-2.63(m,1H),1.12(d,J=6.5Hz,6H);HRMS(ESI)calcd.for C23H21F3N5O3S[M+H]+:504.1312,found:504.1312。
实施例13化合物I-11的制备
冰浴条件下,将4-甲氧基苯胺(32mg,0.26mmol)缓慢滴加到三光气(39mg,0.13mmol)1,4-二氧六环溶液(1mL)中,于100℃搅拌反应2h,得到4-甲氧基苯基异氰酸酯的1,4-二氧六环溶液,冷却至室温备用。将化合物3(60mg,0.2mmol)溶于1,4-二氧六环(1mL)中,加入三乙胺(53mg,0.52mmol),缓慢滴加上述4-甲氧基苯基异氰酸酯的1,4-二氧六环溶液,室温搅拌反应16h。加水(5mL),用乙酸乙酯萃取。有机相用饱和食盐水洗,无水硫酸钠干燥。过滤、减压浓缩,经硅胶柱层析(石油醚:乙酸乙酯=2:1),得N-(5-(3-(3-(4-甲氧基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物I-11),白色固体35mg,收率39.0%。熔点:179-181℃。1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),10.71(s,1H),8.73(s,1H),8.53(s,1H),7.97(s,1H),7.45-7.26(m,6H),6.88(d,J=8.0Hz,2H),3.72(s,3H),2.74-2.62(m,1H),1.11(d,J=6.1Hz,6H);HRMS(ESI)calcd.for C23H24N5O3S[M+H]+:450.1594,found:450.1599。
实施例14化合物I-12的制备
冰浴条件下,将4-氰基苯胺(30mg,0.26mmol)缓慢滴加到三光气(39mg,0.13mmol)1,4-二氧六环溶液(1mL)中,于100℃搅拌反应2h,得到4-氰基苯基异氰酸酯的1,4-二氧六环溶液,冷却至室温备用。将化合物3(60mg,0.2mmol)溶于1,4-二氧六环(1mL)中,加入三乙胺(53mg,0.52mmol),缓慢滴加上述4氰基苯基异氰酸酯的1,4-二氧六环溶液,室温搅拌反应16h。加水(5mL),用乙酸乙酯萃取。有机相用饱和食盐水洗,无水硫酸钠干燥。过滤、减压浓缩,经硅胶柱层析(石油醚:乙酸乙酯=2:1),得N-(5-(3-(3-(4-氰基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物I-12),白色固体30mg,收率33.8%。熔点:216-218℃。1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),10.71(s,1H),9.46(s,1H),9.19(s,1H),7.99(s,1H),7.79-7.65(m,4H),7.45-7.26(m,4H),2.73-2.65(m,1H),1.11(d,J=6.8Hz,6H);HRMS(ESI)calcd.for C23H21N6O2S[M+H]+:445.1441,found:445.1442。
实施例15化合物I-13的制备
冰浴条件下,将3,4-二氟苯胺(34mg,0.26mmol)缓慢滴加到三光气(39mg,0.13mmol)1,4-二氧六环溶液(1mL)中,于100℃搅拌反应2h,得到3,4-二氟苯基异氰酸酯的1,4-二氧六环溶液,冷却至室温备用。将化合物3(60mg,0.2mmol)溶于1,4-二氧六环(1mL)中,加入三乙胺(53mg,0.52mmol),缓慢滴加上述3,4-二氟苯基异氰酸酯的1,4-二氧六环溶液,室温搅拌反应16h。加水(5mL),用乙酸乙酯萃取。有机相用饱和食盐水洗,无水硫酸钠干燥。过滤、减压浓缩,经硅胶柱层析(石油醚:乙酸乙酯=2:1),得N-(5-(3-(3-(3,4-二氟苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物I-13),白色固体25mg,收率27.5%。熔点:125-127℃。1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),10.71(s,1H),8.97(s,1H),8.91(s,1H),7.96(s,1H),7.77-7.60(m,1H),7.45-7.12(m,6H),2.78-2.60(m,1H),1.11(d,J=5.6Hz,6H);HRMS(ESI)calcd.for C22H20F2N5O2S[M+H]+:456.1300,found:456.1304。
实施例16化合物I-14的制备
冰浴条件下,将4-氯-3-氟苯胺(38mg,0.26mmol)缓慢滴加到三光气(39mg,0.13mmol)1,4-二氧六环溶液(1mL)中,于100℃搅拌反应2h,得到4-氯-3-氟苯基异氰酸酯的1,4-二氧六环溶液,冷却至室温备用。将化合物3(60mg,0.2mmol)溶于1,4-二氧六环(1mL)中,加入三乙胺(53mg,0.52mmol),缓慢滴加上述4-氯-3-氟苯基异氰酸酯的1,4-二氧六环溶液,室温搅拌反应16h。加水(5mL),用乙酸乙酯萃取。有机相用饱和食盐水洗,无水硫酸钠干燥。过滤、减压浓缩,经硅胶柱层析(石油醚:乙酸乙酯=2:1),得N-(5-(3-(3-(4-氯-3-氟苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(化合物I-14),白色固体28mg,收率29.7%。熔点:137-139℃。1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),10.71(s,1H),8.96(s,1H),8.93(s,1H),7.96(s,1H),7.82(d,J=5.2Hz,1H),7.44-7.23(m,6H),2.74-2.63(m,1H),1.11(d,J=6.2Hz,6H);HRMS(ESI)calcd.for C22H20ClFN5O2S[M+H]+:472.1005,found:472.1001。
试验例:GSK-3抑制活性实验
1、实验方法:
使用384孔板进行GSK-3β激酶抑制实验。首先将GSK-3β准备液和实施例3~16中所制备的化合物或DMSO置于反应孔中室温条件下孵育10min,加入含有FAM标记的P15peptide和ATP的缓冲液,28℃条件下孵育后,加入终止液,进行Caliper检测。SP01-SP14IC50的初始检测浓度是1μM,三倍稀释。
以Type-II型GSK-3β抑制剂Sorafenib为阳性对照。
抑制率=(阴性对照组读数-实验组读数)/(阴性对照组读数-空白组读数)×100%。XLfit软件用于计算IC50(样品对GSK-3β激酶抑制率达到50%的浓度)。
结果如表1所示。
2、实验结果:
表1本发明化合物对GSK-3β抑制活性
a IC50值±标准偏差(SD);b Sorafenib作阳性药
作为基于DFG-out构象设计的一种Type-II型GSK-3β抑制剂,本发明的化合物表现出优异的GSK-3β抑制活性。与阳性对照药Sorafenib相比,本发明的化合物的GSK-3β抑制活性显著提高,尤其是化合物I-1是目前报道的活性最高的Type-II型GSK-3β抑制剂。
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,对于本领域的技术人员来说,本发明可以有各种更改和变化。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)
1.一种化合物,其特征在于,具有式(I)所示结构或其药学上可接受的盐:
其中,R1、R2、R3、R4、R5各自独立地选自氢、氯、氟、甲基、甲氧基、三氟甲氧基或氰基。
2.如权利要求1所述的化合物,其特征在于,R1为氢,R5为氢,R2、R3、R4各自独立地选自氢、氯、氟、甲基、甲氧基、三氟甲氧基或氰基。
3.如权利要求2所述的化合物,其特征在于,R2为氢,R3、R4各自独立地选自氢、氯、氟、甲基、甲氧基、三氟甲氧基或氰基。
4.如权利要求1所述的化合物,其特征在于,所述化合物选自:
N-(5-(3-(3-苯基脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-1);
N-(5-(3-(3-(2-氯苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-2);
N-(5-(3-(3-(3-氯苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-3);
N-(5-(3-(3-(4-氯苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-4);
N-(5-(3-(3-(3-氟苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-5);
N-(5-(3-(3-(4-氟苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-6);
N-(5-(3-(3-(2-甲基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-7);
N-(5-(3-(3-(4-甲基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-8);
N-(5-(3-(3-(3-三氟甲氧基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-9);
N-(5-(3-(3-(4-三氟甲氧基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-10);
N-(5-(3-(3-(4-甲氧基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-11);
N-(5-(3-(3-(4-氰基苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-12);
N-(5-(3-(3-(3,4-二氟苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-13);
N-(5-(3-(3-(4-氯-3-氟苯基)脲基)苯基)-1H-噻吩[3,2-c]吡唑-3-基)异丁酰胺(I-14)。
5.如权利要求1~4任一项所述的化合物的制备方法,其特征在于,包括以下步骤:
将式(II)所示化合物与3-硝基苯硼酸经Suzuki偶联反应,合成式(III)所示化合物;
将式(III)所示化合物经FeCl3和水合肼还原,合成式(IV)所示化合物;
将式(IV)所示化合物与苯基异氰酸酯或取代的苯基异氰酸酯反应,合成式(I)所示化合物;
6.一种药物组合物,其特征在于,包括权利要求1~4任一项所述的化合物或其药学上可接受的盐或权利要求5所述的制备方法制备的化合物或其药学上可接受的盐。
7.一种药物制剂,其特征在于,包括权利要求1~4任一项所述的化合物或其药学上可接受的盐或权利要求5所述的制备方法制备的化合物或其药学上可接受的盐。
8.如权利要求1~4任一项所述的化合物或权利要求5所述的制备方法制备的化合物或权利要求6所述的上述药物组合物或权利要求7所述的药物制剂在制备Type-II型GSK-3β抑制剂药物或试剂中的应用。
9.如权利要求1~4任一项所述的化合物或权利要求5所述的制备方法制备的化合物或权利要求6所述的上述药物组合物或权利要求7所述的药物制剂在制备预防或治疗与GSK-3活性异常表达相关疾病的药物中的应用。
10.如权利要求9所述的应用,其特征在于,所述与GSK-3活性异常表达相关疾病包括糖尿病、阿尔茨海默症、骨质疏松或精神障碍疾病。
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