CN101735222A - 吡咯并氮杂卓酮类化合物及其作为蛋白酪氨酸磷酸酯酶1b抑制剂的应用 - Google Patents
吡咯并氮杂卓酮类化合物及其作为蛋白酪氨酸磷酸酯酶1b抑制剂的应用 Download PDFInfo
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- CN101735222A CN101735222A CN200910261418A CN200910261418A CN101735222A CN 101735222 A CN101735222 A CN 101735222A CN 200910261418 A CN200910261418 A CN 200910261418A CN 200910261418 A CN200910261418 A CN 200910261418A CN 101735222 A CN101735222 A CN 101735222A
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- compound
- phenyl
- azatropylidene
- perhydroazepinone
- diketone
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 14
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Abstract
本发明公开了一种吡咯并氮杂卓酮类化合物及其作为蛋白酪氨酸磷酸酯酶1B抑制剂的应用,旨在提供一类具有蛋白酪氨酸磷酸酯酶1B抑制活性的吡咯并氮杂卓酮类化合物及其在制备治疗II型糖尿病和肥胖症的药物中的应用。它具有式(I)其中n代表0或1;R1代表H,C1-C6烷基,苄基或C(O)R4,其中R4代表C1-C4烷基,苯基或被羧基、羧酸酯、醛基、羟基、或烷氧基取代的苯基;R2代表OH,O,或N-NHR5其中R5代表苯环或被N、O、S原子取代的五元或六元芳香基;R3代表H、乙酰基,卤素,苯基或取代苯基。本发明可以用于制备治疗II型糖尿病和肥胖症的药物。
Description
技术领域
本发明涉及一类蛋白酪氨酸磷酸酯酶1B抑制剂(PTP1B Inhibitors),具体涉及一类新型的吡咯并氮杂卓酮类化合物及其作为蛋白酪氨酸磷酸酯酶1B抑制剂的应用。
背景技术
糖尿病是一种由于体内胰岛素缺乏或胰岛素敏感性降低,而引起糖、蛋白、脂肪、水、电解质等一系列代谢紊乱的疾病,其基本特征是长期高血糖。由于糖尿病严重危害着人们的健康,现已成为继肿瘤、心脑血管病之后严重威胁人类健康的第三大杀手,因此对糖尿病的防治研究已经成为各国医药学界的重要课题。
根据患者体内胰岛素是绝对缺乏还是相对缺乏,糖尿病主要分为I型糖尿病和II型糖尿病,即胰岛素依赖型糖尿病和非胰岛素依赖型糖尿病。I型糖尿病患者体内胰腺产生胰岛素的细胞已经损坏,从而失去了正常产生胰岛素的功能,属于胰岛素的绝对缺乏。II型糖尿病患者发病原因与分泌胰岛素的能力没有关系,而在于体内对胰岛素产生了抵抗,即正常浓度的胰岛素的生理效应低于正常,胰岛素促进血液中游离的葡萄糖被骨骼肌肉吸收的能力和抑制肝释放葡萄糖的能力降低,属于胰岛素的相对缺乏。其中II型糖尿病所占的比例在90%以上。
对II型糖尿病发病机制复杂,目前一线的临床治疗药物存在多种缺陷,不能根本上治愈糖尿病患者。随着研究的深入,以胰岛素信号转导通路中酶或受体为靶标,筛选发展药物成为寻找新药的关键途径。最新研究表明,蛋白酪氨酸磷酸酯酶(PTPase)在胰岛素作用的信号途径中起到重要的负调节作用,其中PTP1B的作用尤为明显。通过抑制PTP1B在细胞中的表达,可以提高胰岛素信号通路的敏感性;同时小鼠模型试验表明,PTP1B基因敲除的小鼠健康良好,表现出良好的抵抗肥胖和糖尿病的能力(Echebly M.,et al;Science,283,1544-1548)。从而说明,PTP1B是一个新颖的治疗糖尿病和肥胖症的有效分子靶点。
近年来,PTP1B抑制剂的研究已经取得了很大的进展。但由于PTP1B与PTP家族其他酶(如SHP、VHR、LAR、CD45等)在结构上都具有同源性,特别是TCPTP同源性达到80%,因此大多数已报道的抑制剂的选择性都不高;而一些选择性高的抑制剂大多为多肽类磷酸化合物,但由于其强的电负性,细胞膜通透性较差,不易达到分子靶标。所以到目前尚未有PTP1B抑制剂进入III期临床研究。因此,找寻一种具有高活性和高选择性的PTP1B抑制剂成为目前的一个研究热点。
本发明是在国家863基金资助下,为设计合成一类新型的具有自主知识产权的PTP1B抑制剂而进行的研究。
发明内容
本发明的一个目的是提供了一类具有蛋白酪氨酸磷酸酯酶1B抑制活性的如式(I)结构所示的吡咯并氮杂卓酮类化合物或者其药用盐。
为解决上述技术问题,本发明采用的技术方案为:
如式(I)表示的吡咯并氮杂卓酮类化合物或者其药用盐
(I)
其中n代表0或1;R1代表H,C1-C6烷基,苄基或C(O)R4,其中R4代表C1-C4烷基,苯基或被羧基、羧酸酯、醛基、羟基、或烷氧基取代的苯基;R2代表OH,O,或N-NHR5,当R2代表OH时,其与相应的C单键连接,当R2代表O或者N-NHR5时候,其与相应的C双键连接,其中R5代表苯环或被N、O、S原子取代的五元或六元芳香基;R3代表H、乙酰基,卤素,苯基或取代苯基。
优选为:当R3代表取代苯基时,具有如下结构式(II)所示的结构:
(II)
其中,R6代表C4-C6烷氧基,或被N、O、S原子取代的五元或六元饱和烷烃基。
优选为:所述吡咯并氮杂卓酮类化合物或其药用盐选自以下化合物:
4-(1-苄基-4,8-二酮-1,4,5,6,7,8-六氢吡咯[2,3-c]氮杂卓-7-羰基)苯甲酸甲酯、
4-(1-苄基-4,8-二酮-1,4,5,6,7,8-六氢吡咯[2,3-c]氮杂卓-7-羰基)苯甲醛、
7-苯甲酰基-1-苯基-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮、
4-(4,8-二酮-1-苯基-1,4,5,6,7,8-六氢吡咯[2,3-c]氮杂卓-7-羰基)苯甲醛、
7-乙酰基-1-苯基-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮、
(E)-1-((4’-甲氧联苯基-4-取代)甲基)-4-(2-吡啶-2-取代)腙-4,5,6,7-四氢吡咯[2,3-c]氮杂卓-8(1H)-酮、
1-((4’-丁氧联苯基-4-取代)甲基)-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮、
1-((4’-吗啡啉联苯基-4-取代)甲基)-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮、
1-((4’-(4-甲基哌啶-1-取代)联苯基-4-取代)甲基)-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮。
本发明的另外一个目的是提供了吡咯并氮杂卓酮类化合物或者其药用盐作为蛋白酪氨酸磷酸酯酶1B抑制剂的应用。
本发明的再一个目的是提供了吡咯并氮杂卓酮类化合物或者其药用盐在制备治疗II型糖尿病和肥胖症的药物中的应用。
本发明的式(I)所示的化合物能够以可药用盐的形式使用,尤其是酸的加成盐,采用可药用的游离酸来制备,如氢氯酸,硫酸,柠檬酸,酒石酸等。
一种治疗II型糖尿病或肥胖症的药物组合物,其含有有效量的作为活性成份的上述吡咯并氮杂卓酮类化合物或其药用盐和可药用的载体。
本发明的化合物的制备可通过以下基本方法和原则制备,其所用的原料都可从市场上购买,本领域的技术人员可以根据本发明制备到本发明所述的任一种化合物。
步骤一:根据化学方程式
以乙腈做溶剂,三乙胺做碱,三氯乙酰吡咯与β-氨基丙酸乙酯盐酸盐在室温下发生偶合反应,生产化合物2;然后化合物2在2N NaOH溶液中室温水解得到化合物3;在加热条件下,化合物3在PPA和P2O5作用下关环得到化合物4.
步骤二:根据化学方程式
以乙腈做溶剂,碳酸钾做碱,在回流的条件下,化合物4与苄溴偶合得到化合物5;而以二氯甲烷做溶剂,醋酸铜做催化剂,化合物4与苯硼酸在室温条件可以偶联得到化合物6;化合物5和化合物6在三乙胺做碱,室温下与酰氯反应可以得到相应的化合物7和化合物8。
步骤三:根据化学方程式
化合物9和化合物10在Pd(PPh3)4催化下偶联得到化合物11;随后,NBS溴代得到化合物12;在回流条件下,化合物12和化合物4偶联得到化合物13;化合物13在醇中,浓盐酸催化下与肼脱水成腙得到化合物14.
步骤四:根据化学方程式
化合物4和4-溴苄溴反应得到化合物15;化合物15在Pd(dppf)Cl2·CH2Cl2催化下与联硼酸频那醇酯反应得到化合物16;化合物16又在同样的催化剂下与溴代物偶联得到化合物17。
本发明所述的吡咯并氮杂卓酮类化合物及其药用盐对蛋白酪氨酸磷酸酯酶1B具有较好的抑制作用,可用于制备治疗II型糖尿病和肥胖症的药物中。为临床治疗II型糖尿病或肥胖症提供了更多的药物选择。
本发明所提供的制备方法具有简单,易操作,成本低等优点。
具体实施方式
下列实施例进一步解释了本发明的化合物及其中间体的合成方法,但并不限制本发明的范围。
一、仪器与药品
NMR由美国VARIAN公司生产的Mercury-Plus 300M仪器测定,溶剂峰做内标;质谱由DSQ台式质谱仪(EI源)和日本岛津公司生产的LCMS-2010A(ESI源)测定;化学试剂购自广州东征,粤申化学品公司,Alfar-Aser公司,百灵威化学,阿拉丁化学试剂公司;柱层析用硅胶购自青岛海洋化工厂。
实施例一:6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮的合成(化合物4)
在含有8.5g(40mmol)三氯乙酰吡咯的100mL无水乙腈溶液中,加入7.38gβ-丙氨酸甲酯盐酸盐(48mmol)和7.2mL(52mmol)三乙胺。混合溶液在室温下搅拌12小时左右,至原料转化完全,停止搅拌,减压转旋蒸发除掉溶剂,再用乙酸乙酯溶解,用水,1N HCl溶液,饱和食盐水分别洗涤,有机相用无水Na2SO4干燥,抽滤除去Na2SO4,减压旋蒸除去溶剂,得化合物2(7.70g,产率92%)。
往化合物2(7.7g,36.7mmol)中加入37mL 2N的NaOH溶液(约73.4mmol),混合液在室温下搅拌15小时,至反应物转化完全,冰浴下用6N的HCl溶液(约8mL)将混合液调至pH=3,析出大量灰白色固体,抽滤,洗涤,滤饼真空40℃下烘干,称量,得化合物3(6.28g,产率94%)。
9.80g P2O5与103.2g PPA在120℃条件下搅拌50分钟左右,至溶液澄清。将温度降至105℃,加入化合物3(6.28g,34.6mmol),搅拌1个小时左右,把混合液倾倒进碎冰中(约200mL),搅拌1个小时,抽滤,固体烘干,得2.319g褐色固体。滤液用用乙酸乙酯萃取,合并有机层用饱和食盐水洗涤两次,用无水Na2SO4干燥,抽滤除去Na2SO4,减压旋蒸除去乙酸乙酯,得淡黄色固体1.243g。合并固体得化合物4(3.56g,产率65%)。
1H NMR(300MHz,DMSO-d6):δ12.14(br s,1H),8.31(m,1H),6.96(m,1H),6.52(m,1H),3.34(m,2H),2.68(m,2H);EI-MS:m/z=164[M]+.
实施例二:1-苄基-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮的合成(化合物5)
将化合物4(1mmol,164mg)溶于20ml无水乙腈中,在向其中加入溴苄(1.5mmol,256mg)和无水碳酸钾(2mmol,276mg)。回流反应12h至原料点消失。减压蒸发溶剂,加入乙酸乙酯和水,分出有机相,水层用乙酸乙酯抽提2次,合并有机相,用饱和食盐水洗涤。干燥,浓缩,粗产品柱层析(二氯甲烷∶乙酸乙酯=1∶1),得化合物5(220mg,产率87%)。
1H NMR(300MHz,CDCl3):δ7.23-7.34(m,6H),6.52(d,J=2.7Hz,1H),6.73(d,J=2.7Hz,1H),5.60(s,2H),3.40-3.46(m,2H),2.75-2.79(m,2H);EI-MS:m/z=254[M]+.
实施例三:1-苯基-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮的合成(化合物6)
在带有CaCl2干燥管的100mL圆底烧瓶中依次加入化合物4(1.00g,6.10m mol)、苯硼酸(1.49g,12.20m mol)、一水乙酸铜(1.83g,9.20m mol),50mL无水二氯甲烷和吡啶(1.00mL,12.20m mol),在室温下搅拌5小时。停止反应,减压蒸出二氯甲烷,剩余物中加入水和乙酸乙酯,过滤除去不溶物,水相用乙酸乙酯萃取2次,合并有机相。用饱和食盐水洗涤有机相2~3次,无水Na2SO4干燥,抽滤,浓缩,粗产品柱层析(二氯甲烷∶乙酸乙酯=3∶1),得到白色固体6(1.5g,产率90%)。
1H NMR(300MHz,CDCl3):δ7.47~7.27(m,5H),6.97(d,J=3Hz,1H),6.84(d,J=3Hz,1H),3.55(m,2H),2.82(m,2H);EI-MS:m/z=240[M]+.
实施例四:4-(1-苄基-4,8-二羰基-1,4,5,6,7,8-六氢吡咯[2,3-c]氮杂卓-7-羰基)苯甲酸甲酯的合成
将对苯二甲酸单甲酯(3mmol)溶于CH2Cl2中,加入SOCl2(1ml),和催化量的DMF。40℃下反应3h。减压浓缩掉溶剂和SOCl2,得4-氯羰基苯甲酸甲酯。
将化合物5(1mmol)溶于CH2Cl2中,加入2ml三乙胺。将上述酰氯溶于5ml二氯甲烷,然后滴入。加完后,室温搅拌5h。反应完毕后,向反应液中加水和CH2Cl2。分出有机相,用饱和食盐水洗涤,有机相用无水Na2SO4干燥。浓缩得132mg白色固体,产率32%。
1H NMR(300MHz,CDCl3):δ7.99(d,J=8.1Hz,2H),7.48(d,J=8.1Hz,2H),7.28-7.31(m,3H),7.00-7.02(m,3H),6.80(d,J=2.7Hz,1H),5.49(s,2H),4.34(t,J=5.4Hz,2H),3.93(s,3H),2.94(t,J=5.4Hz,2H);EI-MS:m/z=416[M]+.
实施例五:4-(1-苄基-4,8-二羰基-1,4,5,6,7,8-六氢吡咯[2,3-c]氮杂卓-7-羰基)苯甲醛的合成
将4-甲酰基苯甲酸(3mmol)溶于CH2C12中,加入SOCl2(1ml),和催化量的DMF。40℃下反应3h。减压浓缩掉溶剂和SOCl2。得甲酰基苯甲酰氯。
将化合物5(1mmol)溶于CH2Cl2中,加入1ml三乙胺。将上述酰氯溶于5ml二氯甲烷,然后滴入。加完后,室温搅拌5h。反应完毕后,向反应液中加水和CH2Cl2。分出有机相,用饱和食盐水洗涤,有机相用无水Na2SO4干燥。浓缩得148mg白色固体,产率38%。
1H NMR(300MHz,CDCl3)δ:10.03(s,1H),7.83(d,J=7.6Hz,2H),7.57(d,J=7.6Hz,2H),7.22-7.36(m,3H),6.94-7.06(m,3H),6.81(s,1H),5.48(s,2H),4.36(s,2H),2.95(s,2H);EI-MS:m/z=386[M]+.
实施例六:7-苯甲酰基-1-苯基-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮的合成
合成方法与实施例四类似,不同之处在于将化合物5换成化合物6,4-氯羰基苯甲酸甲酯换为苯乙酰氯。纯化后得120mg白色固体,产率68%。
1H NMR(300MHz,CDCl3):δ7.23-7.51(m,10H),7.08(d,J=2.7Hz,1H),6.88(d,J=2.7Hz,1H),4.52(m,2H),2.99(m,2H);EI-MS:m/z=344[M]+.
实施例七:4-(4,8-二酮-1-苯基-1,4,5,6,7,8-六氢吡咯[2,3-c]氮杂卓-7-羰基)苯甲醛的合成
合成方法与实施例五类似,不同之处在于将化合物5换成化合物6。纯化后得60mg白色固体,产率54%。
1H NMR(300MHz,CDCl3):δ9.97(s,1H),7.80(d,J=8.1Hz,2H),7.57(d,J=8.1Hz,2H),7.35-7.42(m,3H),7.21-7.24(m,2H),7.10(d,J=3Hz,1H),6.89(d,J=3Hz,1H),4.55(t,J=5.4Hz,2H),3.02(t,J=5.4Hz,2H);EI-MS:m/z=372[M]+.
实施例八:7-乙酰基-1-苯基-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮的合成
合成方法与实施例四类似,不同之处在于将化合物5换成化合物6,4-氯羰基苯甲酸甲酯换为乙酰氯。纯化后得58mg白色固体,产率52%。
1H NMR(300MHz,CDCl3):δ7.46-7.50(m,3H),7.30-7.33(m,2H),7.08(d,J=3Hz,1H),6.81(d,J=3Hz,1H),4.41(t,J=5.4Hz,2H),2.86-2.90(m,2H),2.44(s,3H);EI-MS:m/z=282[M]+.
实施例九:1-((4’-丁氧联苯基-4-取代)甲基)-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮
将1-溴-4-正丁氧基苯(1mmol),4-甲基苯硼酸(1.5mmol)溶于水和丙酮的混合液6.5ml(3.5/3,v/v),然后向其中加入碳酸钠(2mmol)和Pd(OAc)2(0.5mol%)。溶液室温搅拌4h,加水和乙酸乙酯,抽滤,滤饼用乙酸乙酯洗涤,合并有机相,盐水洗,干燥,浓缩,柱层析(乙酸乙酯∶石油醚=1∶10),得白色固体化合物11(204mg,产率85%)。
在10ml微波反应管中加入化合物11(192mg,0.8mmol),NBS(149mg,0.84mmol),BPO(19mg,0.08mmol)和CCl4(2ml),加入搅拌磁子后盖上密封盖,置于单模微波反应器内。80℃下反应20分钟,停止反应,冷却至室温,反应液抽滤,滤液浓缩,得白色固体12,不需纯化,直接投入下步反应。
在一50ml的圆底烧瓶中加入化合物4(98mg,0.6mmol),K2CO3(166mg,1.2mmol),上步粗产物和20ml无水乙腈,加热回流10h,停止反应,浓缩。向剩余物中加入水和乙酸乙酯,水相用乙酸乙酯萃取两次,合并有机相,用无水硫酸钠干燥,干燥完后蒸去溶剂,粗产品柱层析分离(二氯甲烷∶乙酸乙酯=1∶1),得化合物13(140mg,产率58%)。
1H NMR(300MHz,CDCl3):δ7.46-7.51(m,4H),7.19(d,J=8.4Hz,2H),6.95(d,J=8.4Hz,2H),6.91(d,J=2.7Hz,1H),6.78(d,J=2.7Hz,1H),6.37-6.42(m,1H),5.65(s,2H),4.00(t,J=6.6Hz,2H),3.51-3.56(m,2H),2.83-2.87(m,2H),1.75-1.85(m,2H),1.48-1.58(m,2H),1.00(t,J=7.2Hz,3H);EI-MS:m/z=402[M]+.
实施例十:(E)-1-((4,-甲氧联苯基-4-取代)甲基)-4-(2-吡啶-2-取代)腙-4,5,6,7-四氢吡咯[2,3-c]氮杂卓-8(1H)-酮
将1-((4’-甲氧联苯基-4-取代)甲基)-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮(180mg,0.5mmol),2-肼吡啶(81.7mg,0.75mmol)溶于5ml无水乙醇中,加热回流5h后,冷却至室温,析出固体,抽滤,用冰乙醇洗涤,干燥得淡黄色固体(158mg,70%)。
1H NMR(300MHz,CDCl3):δ8.33(s,1H),8.08-8.11(m,1H),7.56-7.62(m,1H),7.46-7.49(m,4H),7.37(d,J=8.4Hz,1H),7.18(d,J=8.1Hz,2H),6.95-6.99(m,3H),6.86(d,J=2.7Hz,1H),6.74-6.78(m,1H),6.70(d,J=2.7Hz,1H),5.58(s,2H),3.83(s,3H),3.40-3.45(m,2H),2.76-2.80(m,2H);EI-MS:m/z=452[M]+.
实施例十一:1-((4’-吗啡啉联苯基-4-取代)甲基)-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮
化合物15(664mg,2mmol)溶解在预先脱氧气的DMF(5ml)中,然后向其中加入联硼酸频那醇酯(558mg,2.20mmol),KOAc(589mg,6mmol),Pd(dppf)Cl2·CH2Cl2(61mg,0.075mmol)。反应混合液在氮气保护下80℃反应6h。冷却到室温,倒入水中,乙酸乙酯萃取,有机相干燥,干燥完后蒸去溶剂,粗产品柱层析分离(乙酸乙酯∶石油醚=2∶1),得化合物16(480mg,产率61%)。
化合物16(0.5mmol),4-(4-溴苯基)吗啡啉(1mmol),2N Na2CO3水溶液(1.5ml)加入到预先脱氧气的DMF(5ml)中,然后向其中加入Pd(dppf)Cl2·CH2Cl2(25mg,0.03mmol)。反应混合液在氮气保护下80℃反应6h。冷却到室温,倒入水中,乙酸乙酯萃取,有机相干燥,干燥完后蒸去溶剂,粗产品柱层析分离(二氯甲烷∶乙酸乙酯=20∶1),得化合物17(73mg,产率35%)。
1H NMR(300MHz,CDCl3):δ7.48-7.52(m,4H),7.19(d,J=8.1Hz,2H),6.97(d,J=9.0Hz,2H),6.90(d,J=3.0Hz,1H),6.78(d,J=3.0Hz,1H),6.15(t,J=6.6Hz,1H),5.65(s,2H),3.89(t,J=4.8Hz,4H),3.50-3.56(m,2H),3.21(t,J=4.8Hz,4H),2.83-2.86(m,2H);ESI-MS:m/z=416[M+H]+
实施例十二:1-((4’-(4-甲基哌啶-1-取代)联苯基-4-取代)甲基)-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮
合成方法与实施例十类似,不同之处在于将4-(4-溴苯基)吗啡啉换成1-(4-溴苯)-4-甲基哌嗪。纯化后得64mg白色固体,产率30%。
1H NMR(300MHz,CDCl3):7.48(t,J=7.5Hz,4H),7.18(d,J=8.4Hz,2H),6.98(d,J=8.7Hz,2H),6.89(d,J=2.7Hz,1H),6.77(d,J=2.4Hz,1H),6.27(t,J=5.1Hz,1H),5.64(s,2H),3.49-3.54(m,2H),3.27(t,J=4.5Hz,4H),2.84(t,J=5.1Hz,2H),2.61(t,J=4.5Hz,4H),2.38(s,3H);ESI-MS:m/z=429[M+H]+.
实施例十三:PTP1B抑制活性实验
实验方法:用于筛选的蛋白酪氨酸磷酸酯酶PTP1B是从大肠杆菌中表达并纯化的GST融合蛋白。采用紫外底物pNPP,观察不同化合物对重组酶的活性的抑制,以初步评价化合物的药用效果。PTP1B水解底物pNPP的磷脂得到的产物在410nm处有很强的光吸收。因此可以直接检测410nm处光吸收的变化以观察酶的活性变化以及化合物对其抑制情况。阳性对照BPV在200uM浓度时的抑制率为98.32%。
按照实施例十三所介绍的方法,测定了本发明的部分式(I)和(II)结构中的吡咯并氮杂卓酮类化合物对PTP1B的抑制活性,测试结果是指抑制剂在100uM浓度时对酶活性的百分抑制率,抑制活性高出50%时,按常规筛出IC50值。结果如下表:
由上述结果可以看出本发明的吡咯并氮杂卓酮类化合物或者其药用盐对蛋白酪氨酸磷酸酯酶PTP1B具有抑制作用,因此可以用于制备治疗II型糖尿病和肥胖症的药物,具有广阔的应用前景。
Claims (7)
3.根据权利要求1所述的吡咯并氮杂卓酮类化合物或者其药用盐,其特征在于所述的吡咯并氮杂卓酮类化合物或者其药用盐选自以下化合物:
4-(1-苄基-4,8-二酮-1,4,5,6,7,8-六氢吡咯[2,3-c]氮杂卓-7-羰基)苯甲酸甲酯、
4-(1-苄基-4,8-二酮-1,4,5,6,7,8-六氢吡咯[2,3-c]氮杂卓-7-羰基)苯甲醛、
7-苯甲酰基-1-苯基-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮、
4-(4,8-二酮-1-苯基-1,4,5,6,7,8-六氢吡咯[2,3-c]氮杂卓-7-羰基)苯甲醛、
7-乙酰基-1-苯基-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮。
4.根据权利要求2所述的吡咯并氮杂卓酮类化合物或者其药用盐,其特征在于所述的吡咯并氮杂卓酮类化合物或者其药用盐选自以下化合物:
(E)-1-((4’-甲氧联苯基-4-取代)甲基)-4-(2-吡啶-2-取代)腙-4,5,6,7-四氢吡咯[2,3-c]氮杂卓-8(1H)-酮、
1-((4’-丁氧联苯基-4-取代)甲基)-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮、
1-((4’-吗啡啉联苯基-4-取代)甲基)-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮、
1-((4’-(4-甲基哌啶-1-取代)联苯基-4-取代)甲基)-6,7-二氢吡咯[2,3-c]氮杂卓-4,8(1H,5H)-二酮。
5.权利要求1所述的吡咯并氮杂卓酮类化合物或者其药用盐作为蛋白酪氨酸磷酸酯酶1B抑制剂的应用。
6.权利要求1所述的吡咯并氮杂卓酮类化合物或者其药用盐在制备治疗II型糖尿病或肥胖症药物中的应用。
7.一种治疗II型糖尿病或肥胖症的药物组合物,其含有有效量的作为活性成份的权利要求1所述的吡咯并氮杂卓酮类化合物或者其药用盐和药用载体。
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CN111285878A (zh) * | 2020-04-03 | 2020-06-16 | 杭州新博思生物医药有限公司 | 二氮杂卓类化合物及制法与其药用盐、前药和用途 |
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CN102276612B (zh) * | 2011-06-21 | 2013-08-28 | 中山大学 | C-2位取代Aldisin衍生物及其药用盐,它们的药物组合物,及其在制备抗肿瘤药物中的应用 |
CN111285878A (zh) * | 2020-04-03 | 2020-06-16 | 杭州新博思生物医药有限公司 | 二氮杂卓类化合物及制法与其药用盐、前药和用途 |
CN111285878B (zh) * | 2020-04-03 | 2022-05-13 | 杭州新博思生物医药有限公司 | 二氮杂卓类化合物及制法与其药用盐、前药和用途 |
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