CN110642757A - 具有激动sirt6乙酰化活性的化合物、sirt6激动剂及其应用 - Google Patents

具有激动sirt6乙酰化活性的化合物、sirt6激动剂及其应用 Download PDF

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CN110642757A
CN110642757A CN201910994511.2A CN201910994511A CN110642757A CN 110642757 A CN110642757 A CN 110642757A CN 201910994511 A CN201910994511 A CN 201910994511A CN 110642757 A CN110642757 A CN 110642757A
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张健
赵明珠
魏嘉呈
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Shanghai Jiaotong University School of Medicine
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Abstract

本发明提供一种具有激动SIRT6乙酰化活性的化合物，或其药学上可接受的盐，具有式(I)所示的结构。本发明还提供应用该化合物获得的SIRT6激动剂及该SIRT6激动剂在尤其是制备治疗SIRT6介导的相关疾病的药物中的应用。

Description

具有激动SIRT6乙酰化活性的化合物、SIRT6激动剂及其应用
技术领域
本发明涉及药物化学技术领域，特别涉及一种具有激动SIRT6乙酰化活性的化合物，以及应用该化合物获得的SIRT6激动剂及该SIRT6激动剂在尤其是制备治疗SIRT6介导的相关疾病的药物中的应用。
背景技术
SIRT6属于组蛋白去乙酰化转移酶(Histone deacetylases，HDACs)第III家族，含有7个成员(SIRT1-7)。SIRT6广泛表达于哺乳动物的各种组织，在生物体内，SIRT6主要通过催化细胞内相关蛋白进行去乙酰化和单腺苷二磷酸核糖基化而参与基因组稳定性维持，DNA修复，炎症以及葡萄糖和脂质代谢，并与心脏疾病、糖尿病、肥胖症、癌症、衰老等疾病密切相关。SIRT6活性上调被认为是治疗上述多种疾病的新策略之一，因此对SIRT6小分子激动剂的研究对SIRT6介导相关疾病药物的开发具有重要的意义。
专利CN109384694A公开了一种三苯环双磺酰胺为母核的SIRT6小分子激动剂，然该SIRT6小分子激动剂的乙酰化活性依然有待提高。
因此，需要一种新的SIRT6激动剂，以克服上述现有SIRT6激动剂的缺陷。
发明内容
本发明的目的在于提供一种具有激动SIRT6乙酰化活性的化合物，或其药学上可接受的盐，可显著提高SIRT6去乙酰化活性，进而可以用作SIRT6激动剂，并应用于相关疾病的药物制备中。
为了达到上述目的，本发明提供一种具有激动SIRT6乙酰化活性的化合物，或其药学上可接受的盐，具有式(I)所示的结构：
其中，X1、X2、X3、X4分别独立地表示氢原子或卤素；Y表示氢原子、甲基或卤素；R表示甲酰胺基、氰基或含氮杂环。
在本发明一实施例中，所述卤素为氟、氯、溴或碘。
在本发明一实施例中，所述甲酰胺基为甲酰胺、甲酰脂肪胺或甲酰芳香胺。
在本发明一实施例中，所述含氮杂环为三氮唑、四氮唑、咪唑、吡咯、吡唑、噁唑、异噁唑、噻唑或噻二唑。
在本发明一实施例中，R表示
Figure BDA0002239325020000021
在本发明一实施例中，式(I)所示化合物的药学上可接受的盐具有式(II)或(III)所示的结构：
Figure BDA0002239325020000022
在本发明一较佳实施例中，所述具有激动SIRT6乙酰化活性的化合物，具有式(化合物1)～(化合物29)所示的结构：
Figure BDA0002239325020000023
Figure BDA0002239325020000031
本发明还提供一种SIRT6激动剂，包含上述任意所述的化合物或其药学上可接受的盐。
本发明所述还提供上述任意所述的化合物及其药学上可接受的盐，或SIRT6激动剂，在制备治疗SIRT6介导的相关疾病的药物中的应用。
本发明所述的具有激动SIRT6乙酰化活性的化合物或其药学上可接受的盐，在体外实验中能够明显激动SIRT6的去乙酰化活性，对SIRT6介导的相关疾病药物的开发具有重要的意义。
附图说明
为了更清楚地说明本发明实施例中的技术方案，下面将对实施例描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1：荧光定量方法检测优选化合物在100μM时激活SIRT6去乙酰化活性的倍数。
图2：荧光定量方法检测表明，化合物1浓度依赖性地激活SIRT6去乙酰化活性，其半数最大效应浓度(EC50)为1.5±0.2μM；化合物2浓度依赖性地激活SIRT6去乙酰化活性，其半数最大效应浓度(EC50)为2.3±0.3μM；化合物8浓度依赖性地激活SIRT6去乙酰化活性，其半数最大效应浓度(EC50)为3.3±0.3μM；化合物23浓度依赖性地激活SIRT6去乙酰化活性，其半数最大效应浓度(EC50)为60.1±4.5μM，在400μM时激活SIRT6去乙酰化活性的倍数近40倍。
具体实施方式
下面详细描述本发明的实施方式，所述实施方式的示例在附图中示出，其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施方式是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。
下文的公开提供了许多不同的实施方式或例子用来实现本发明的不同结构。为了简化本发明的公开，下文中对特定例子的部件和设置进行描述。当然，它们仅仅为示例，并且目的不在于限制本发明。此外，本发明可以在不同例子中重复参考数字和/或参考字母，这种重复是为了简化和清楚的目的，其本身不指示所讨论各种实施方式和/或设置之间的关系。此外，本发明提供了的各种特定的工艺和材料的例子，但是本领域普通技术人员可以意识到其他工艺的应用和/或其他材料的使用。
本发明提供结构式为式(I)所示的化合物或其药学上可接受的盐。
其中，X1、X2、X3、X4相同或不同，表示氢原子、卤素，Y表示氢原子、甲基、卤素。所述卤素指氟、氯、溴或碘。R表示甲酰胺基、氰基、含氮杂环。
在本实施例中，式(I)所示的化合物具有式(化合物1)～(化合物29)所示的具体结构。
Figure BDA0002239325020000051
Figure BDA0002239325020000061
实施例1：化合物1～18的合成
在本实施例中，提供上述具有式(化合物1～18)所示结构的化合物。反应路线如下：
Figure BDA0002239325020000062
具体制备方法如下几步。
合成中间体I：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-硝基苯甲酸甲酯
Figure BDA0002239325020000063
室温下，将原料苯胺类化合物(10g，49.0mmol)溶解于20mL吡啶中，加入原料4-硝基-2-甲酸甲酯基苯磺酰氯(16.45g，58.8mmol)，室温反应8小时以上。TLC监测反应完全后，将反应冷却至室温，加入1N的盐酸，调pH至3～4，析出淡黄色沉淀，过滤、干燥即得中间体Int I(18.6g，收率：84.9％)。可直接用于下一步反应。1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.50-8.47(m,2H),7.98-7.96(dd,J＝2.0Hz,J＝8.0Hz,1H),7.36-7.34(d,J＝8.0Hz,1H),7.29-7.27(d,J＝8.0Hz,1H),3.78(s,3H),1.96(s,3H)。
合成中间体II：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-氨基苯甲酸甲酯
Figure BDA0002239325020000064
在室温下，将中间体Int I(18.6g，41.6mmol)用乙酸溶解，加入铁粉(14.0g,250mmol)，然后在50℃反应3小时。将溶剂进行减压蒸馏，加入乙酸乙酯，超声10分钟后抽滤，滤液用饱和碳酸氢钠洗涤3次，再用饱和食盐水洗涤3次后，有机相用无水硫酸钠进行干燥，用柱层析分离纯化得到白色固体，即为中间体Int II(13.9g，收率：80.3％)。1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),7.30-7.20(m,2H),6.73(s,1H),6.64-6.59(m,2H),6.30(s,2H),3.73(s,3H),2.02(s,3H)。
合成中间体III：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)苯甲酸甲酯
室温下，中间体Int II(13.9g,33.32mmol))溶解于30mL吡啶中，0℃下加入原料3,5-二氯苯磺酰氯(16.45g,58.8mmol)l)，反应1小时。升至室温反应6小时。TLC监测反应完全后，0℃下，加入2N的盐酸，调pH至3～4，析出固体，硅胶柱层析纯化得白色中间体Int III(16.5g，收率：79.0％)。1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),9.46(s,1H),8.01(s,1H),7.81(d,J＝2.0Hz,2H),7.60-7.58(d,J＝8.0Hz,1H),7.44-7.40(dd,J＝2.0Hz,J＝8Hz,1H),7.27(d,J＝2.0Hz,1H),7.24-7.22(d,J＝8.0Hz,1H),7.18-7.16(d,J＝8.0Hz,1H),3.74(s,3H),1.82(s,3H)。
合成化合物1～18：
在封管中，将Int III用甲醇溶解，加入5倍当量的胺类化合物，然后将反应温度升高到100℃反应4小时以上。TLC监测反应完全后，将反应冷却至室温，加入2摩尔/毫升的盐酸，调pH至3～4，加入乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗涤3次，有机相用无水硫酸钠干燥。然后用柱层析分离纯化得到式(I)的化合物1～18。
其余化合物均可以通过实施例1记载的相似的方法制备，此处不再赘述。
实例1(化合物1)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),8.78(s,1H),8.35(s,1H),7.97(t,J＝1.9Hz,1H),7.94(s,1H),7.77(d,J＝2.0Hz,2H),7.39(d,J＝8.6Hz,1H),7.28–7.12(m,4H),1.89(s,3H).13C NMR(101MHz,DMSO)δ170.69,156.65(d,J＝244.3Hz),137.24,136.67,136.60,135.59,134.35(d,J＝4.1Hz),133.12,133.04,133.02,130.80,125.60,120.21,118.89,118.55(d,J＝22.9Hz),104.65(d,J＝22.1Hz),17.46.MS(ESI)m/z:609.9(M+H)+。
实例2(化合物2)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-甲基苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),8.85(d,J＝6.3Hz,1H),8.80(s,1H),8.01(dt,J＝6.4,1.9Hz,1H),7.85(d,J＝1.9Hz,2H),7.47(dd,J＝8.9,1.7Hz,1H),7.35(dd,J＝8.6,2.4Hz,1H),7.28(t,J＝2.4Hz,1H),7.21(d,J＝6.7Hz,1H),7.12(dd,J＝9.6,3.1Hz,1H),2.68(s,3H),1.90(s,3H).13C NMR(101MHz,DMSO)δ167.90,156.75(d,J＝244.6Hz),142.22,141.74,137.41,136.91(d,J＝7.9Hz),135.81,133.72,132.83(d,J＝3.1Hz),131.92,131.21,130.90,125.73,119.65,118.73,118.50(d,J＝23.0Hz),104.62(d,J＝22.1Hz),34.68,17.57.MS(ESI)m/z:623.9(M+H)+。
实例3(化合物3)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-二甲基苯甲酰胺
1H NMR(400MHz,DMSO-d6)11.36(s,1H),9.46(s,1H),8.01(s,1H),7.81(d,J＝2.0Hz,2H),7.60-7.58(d,J＝8.0Hz,1H),7.44-7.40(dd,J＝2.0Hz,J＝8Hz,1H),7.27(d,J＝2.0Hz,1H),7.24-7.22(d,J＝8.0Hz,1H),7.18-7.16(d,J＝8.0Hz,1H),2.96(s,3H),2.62(s,3H),1.97(s,3H).13C NMR(101MHz,DMSO)δ169.66,156.55(d,J＝244.2Hz),152.16,148.28,136.96(d,J＝7.7Hz),136.63,134.82,133.19(d,J＝3.1Hz),130.93,130.62,130.14,125.17,124.51,120.11,118.41(d,J＝22.6Hz),117.98,104.50(d,J＝21.9Hz),34.85,34.79,17.62.MS(ESI)m/z:637.9(M+H)+。
实例4(化合物4)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-乙基苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),8.88(d,J＝6.3Hz,1H),8.81(s,1H),8.03(dt,J＝6.4,1.9Hz,1H),7.82(d,J＝1.9Hz,2H),7.45(dd,J＝8.9,1.7Hz,1H),7.33(dd,J＝8.6,2.4Hz,1H),7.27(t,J＝2.4Hz,1H),7.20(d,J＝6.7Hz,1H),7.15(dd,J＝9.6,3.1Hz,1H),3.34–3.26(m,2H),1.88(s,3H),1.15(t,J＝7.2Hz,3H).13C NMR(101MHz,DMSO)δ167.93,156.78(d,J＝244.6Hz),142.24,141.74,137.45,136.97(d,J＝7.9Hz),135.86,133.77,132.80(d,J＝3.1Hz),131.99,131.22,130.91,125.78,119.68,118.77,118.52(d,J＝23.0Hz),104.67(d,J＝22.1Hz),34.65,17.45,14.66.MS(ESI)m/z:637.9(M+H)+。
实例5(化合物5)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-丙基苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ8.48(d,J＝13.7Hz,1H),8.28–8.20(m,1H),7.70(t,J＝2.0Hz,2H),7.54(dt,J＝3.6,1.8Hz,1H),7.34(d,J＝8.5Hz,1H),7.29(s,1H),7.14(dd,J＝6.5,2.5Hz,1H),7.07(dd,J＝8.7,3.4Hz,1H),6.95–6.82(m,2H),3.37(q,J＝6.4Hz,2H),2.04(s,3H),1.64(d,J＝7.2Hz,2H),0.98(q,J＝7.2,6.6Hz,3H).13C NMR(101MHz,CDCl3)δ168.38,157.46(d,J＝248.1Hz),141.37,140.67,136.65,136.50,136.48,136.17(d,J＝7.3Hz),133.80,132.81(d,J＝12.7Hz),131.35,130.89,125.50,119.32,119.12,118.20(d,J＝22.9Hz),105.59(d,J＝22.1Hz),42.35,22.35,17.84,11.45.MS(ESI)m/z:651.9(M+H)+。
实例6(化合物6)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-甲基-N-乙基苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.71(t,J＝1.5Hz,2H),7.53(t,J＝1.9Hz,1H),7.46(dd,J＝8.6,2.6Hz,1H),7.23(dd,J＝14.4,2.3Hz,1H),7.18(dd,J＝6.6,1.4Hz,1H),7.05(ddd,J＝8.6,2.3,1.1Hz,1H),6.87(d,J＝9.0Hz,1H),2.84(s,3H),2.08(s,3H),1.28(q,J＝6.8Hz,3H),1.14(t,J＝7.1Hz,2H).13C NMR(101MHz,CDCl3)δ169.39,157.37(d,J＝249.5Hz),142.42,142.28,137.45,136.97(d,J＝7.9Hz),135.86,133.77,132.80(d,J＝3.1Hz),131.99,131.22,130.91,125.78,119.68,118.77,118.52(d,J＝23.0Hz),104.67(d,J＝22.1Hz),105.42(d,J＝22.1Hz),36.51,32.21,17.79,12.86.MS(ESI)m/z:637.9(M+H)+。
实例7(化合物7)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-N-环丙基-5-((3,5-二氯苯基)磺酰胺基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),8.87(d,J＝4.2Hz,1H),8.80(s,1H),8.05(t,J＝1.8Hz,1H),7.81(d,J＝1.9Hz,2H),7.43(d,J＝8.7Hz,1H),7.30(dd,J＝8.7,2.3Hz,1H),7.21(d,J＝6.8Hz,1H),7.19(d,J＝2.3Hz,1H),7.15(d,J＝9.5Hz,1H),2.82(tq,J＝7.6,3.9Hz,1H),1.87(s,3H),0.73(td,J＝7.1,4.8Hz,2H),0.61–0.50(m,2H).13C NMR(101MHz,DMSO)δ169.26,156.80(d,J＝244.7Hz),142.27,141.75,137.34,137.06(d,J＝7.7Hz),135.86,133.78,132.77(d,J＝3.0Hz),131.84,131.36,130.92,125.78,119.55,118.74,118.52(d,J＝22.7Hz),104.67(d,J＝22.0Hz),23.31,17.45,6.13.MS(ESI)m/z:649.9(M+H)+。
实例8(化合物8)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-N-环丁基-5-((3,5-二氯苯基)磺酰胺基)苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.71(d,J＝1.8Hz,2H),7.54(t,J＝1.8Hz,1H),7.35(d,J＝8.6Hz,1H),7.30(d,J＝2.3Hz,1H),7.15(d,J＝6.5Hz,1H),7.07(dd,J＝8.6,2.3Hz,1H),6.98(d,J＝7.3Hz,1H),6.90–6.85(m,1H),4.47(dt,J＝16.0,8.0Hz,1H),2.43–2.34(m,2H),2.12–1.99(m,2H),2.06(s,3H),1.82–1.75(m,2H).13C NMR(101MHz,CDCl3)δ167.51,157.43(d,J＝247.8Hz),141.74,141.18,136.47,136.41,136.21(d,J＝7.2Hz),133.61,132.64,131.47(d,J＝3.3Hz),130.93,130.89,125.50,119.44,119.25,118.15(d,J＝22.8Hz),105.55(d,J＝22.2Hz),45.85,30.41,17.86,15.45.MS(ESI)m/z:663.9(M+H)+。
实例9(化合物9)：2-(氮杂环丁烷-1-羰基)-N-(5-溴-4-氟-2-甲基苯基)-4-((3,5-二氯苯基)磺酰胺基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),9.06(s,1H),8.05–7.96(m,1H),7.85(d,J＝1.9Hz,2H),7.52(d,J＝8.5Hz,1H),7.37–7.30(m,1H),7.26(d,J＝6.8Hz,1H),7.23(d,J＝6.6Hz,1H),7.17(d,J＝8.8Hz,1H),4.06(t,J＝7.6Hz,2H),3.71(t,J＝7.4Hz,2H),2.25(p,J＝7.4Hz,2H),1.90(s,3H).13C NMR(101MHz,DMSO)δ168.22,156.85(d,J＝244.6Hz),142.25,142.03,137.30(d,J＝7.6Hz),135.79,134.90,133.65,132.47(d,J＝3.0Hz),132.11,131.50,131.09,125.82,120.05,118.54(d,J＝23.0Hz),118.52,104.69(d,J＝22.0Hz),51.26,48.89,17.50,15.63.MS(ESI)m/z:649.9(M+H)+。
实例10(化合物10)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-(3-氧杂环丁烷基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.12(d,J＝7.0Hz,1H),7.75(t,J＝2.0Hz,1H),7.69(t,J＝1.9Hz,2H),7.63–7.55(m,1H),7.28(d,J＝9.7Hz,1H),7.24(d,J＝2.4Hz,1H),7.03(dd,J＝8.4,2.4Hz,1H),4.65(t,J＝6.9Hz,1H),3.47–3.39(m,J＝17.2,7.0Hz,4H),1.91(s,3H).13C NMR(101MHz,DMSO)δ167.38,161.54,155.36(d,J＝240.7Hz),147.67,135.19(d,J＝3.1Hz),134.90,134.67,133.97,133.90,131.03,128.25,127.81,125.35,122.16,121.00,118.11(d,J＝22.5Hz),104.29(d,J＝21.4Hz),61.47,55.75,45.92,17.96.MS(ESI)m/z:665.9(M+H)+。
实例11(化合物11)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-N-环戊基-5-((3,5-二氯苯基)磺酰胺基)苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ8.23(s,1H),8.19(s,1H),7.69(d,J＝1.9Hz,2H),7.55(t,J＝1.8Hz,1H),7.35(d,J＝8.5Hz,1H),7.25(d,J＝2.2Hz,1H),7.14(d,J＝6.5Hz,1H),7.03(dd,J＝8.5,2.1Hz,1H),6.87(d,J＝8.9Hz,1H),6.71(d,J＝7.2Hz,1H),4.30(h,J＝6.5Hz,1H),2.07(s,6H),2.10–2.00(m,2H),1.76–1.70(m,2H),1.67–1.53(m,4H).13C NMR(101MHz,CDCl3)δ168.04,157.46(d,J＝247.8Hz),141.37,140.45,136.84,136.51,136.28(d,J＝7.3Hz),133.82,133.00,131.40(d,J＝3.3Hz),130.95,130.89,125.51,119.26,119.06,118.18(d,J＝22.8Hz),105.57(d,J＝22.1Hz),52.55,32.67,23.87,17.88.MS(ESI)m/z:677.9(M+H)+。
实例12(化合物12)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-4-((3,5-二氯苯基)磺酰胺基)-2-(吡咯烷-1-羰基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.77(s,1H),7.71(d,J＝1.8Hz,2H),7.61(s,1H),7.54(t,J＝1.8Hz,1H),7.50(d,J＝8.5Hz,1H),7.37(s,1H),7.19(d,J＝6.5Hz,1H),7.12(d,J＝8.5Hz,1H),6.86(d,J＝9.0Hz,1H),3.66(t,J＝6.5Hz,2H),3.21(t,J＝6.5Hz,2H),2.07(s,3H),2.03–1.90(m,4H).13C NMR(101MHz,CDCl3)δ168.01,157.45(d,J＝247.7Hz),141.50,140.84,137.31,136.46(d,J＝7.2Hz),136.41,133.62,132.09,131.37(d,J＝3.3Hz),131.06,130.85,125.48,119.55,118.14(d,J＝23.8Hz),118.02,105.52(d,J＝22.1Hz),49.55,46.39,25.83,24.49,17.81.MS(ESI)m/z:663.9(M+H)+。
实例13(化合物13)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-4-((3,5-二氯苯基)磺酰胺基)-2-(哌啶-1-羰基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ7.71(d,J＝1.9Hz,2H),7.55(d,J＝1.8Hz,1H),7.49(d,J＝8.6Hz,1H),7.26(d,J＝2.2Hz,1H),7.18(d,J＝6.6Hz,1H),7.10(dd,J＝8.6,2.3Hz,1H),6.87(d,J＝9.0Hz,1H),3.92–3.86(m,1H),3.64–3.52(m,1H),3.24(dt,J＝8.4,4.1Hz,2H),2.07(s,3H),1.84–1.53(m,6H).13C NMR(101MHz,CDCl3)δ167.90,157.41(d,J＝247.4Hz),141.65,140.65,136.41,136.40(d,J＝7.3Hz),133.60,132.74,131.56(d,J＝3.4Hz),131.02,130.99,125.50,125.45,119.38,118.10(d,J＝23.0Hz),117.82,105.48(d,J＝22.2Hz),48.87,43.32,25.57,25.00,24.34,17.79.MS(ESI)m/z:677.9(M+H)+。
实例14(化合物14)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-4-((3,5-二氯苯基)磺酰胺基)-2-(吗啉-4-羰基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ7.74(t,J＝1.9Hz,1H),7.63(d,J＝1.9Hz,2H),7.21(d,J＝1.3Hz,1H),7.19(s,1H),7.16(d,J＝9.6Hz,1H),6.85(dd,J＝8.8,2.3Hz,1H),6.79(d,J＝2.3Hz,1H),3.84–3.74(m,4H),3.11–3.03(m,4H),2.00(s,3H).13C NMR(101MHz,DMSO)δ168.50,156.55(d,J＝244.3Hz),148.97,148.94,137.10(d,J＝7.9Hz),135.70,134.74,133.23(d,J＝3.0Hz),130.93,130.38,130.15,125.13,124.14,120.44,118.44(d,J＝23.1Hz),117.84,104.47(d,J＝22.1Hz),63.71,43.13,17.67.MS(ESI)m/z:679.9(M+H)+。
实例15(化合物15)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-4-((3,5-二氯苯基)磺酰胺基)-2-(4-甲基哌嗪-1-羰基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ7.84(t,J＝1.9Hz,1H),7.74(d,J＝1.9Hz,2H),7.34(d,J＝8.8Hz,1H),7.19(d,J＝6.8Hz,1H),7.16(d,J＝9.6Hz,1H),7.08(dd,J＝8.7,2.3Hz,1H),7.00(d,J＝2.3Hz,1H),3.88–3.61(m,2H),3.24–3.08(m,2H),2.83(br,2H),2.66–2.56(m,2H),2.49(s,3H),1.95(s,3H).13C NMR(101MHz,DMSO)δ167.66,156.73(d,J＝244.4Hz),146.29,137.46(d,J＝7.3Hz),135.70,135.12,132.81(d,J＝3.0Hz),131.69,131.43,130.51,127.14,125.41,120.19,118.46(d,J＝22.9Hz),117.99,104.53(d,J＝21.9Hz),72.70,60.66,53.07,45.27,44.24,17.60.MS(ESI)m/z:692.9(M+H)+。
实例16(化合物16)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-羟基苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),7.77(d,J＝1.9Hz,1H),7.67(dd,J＝4.5,2.2Hz,2H),7.28(d,J＝8.0Hz,1H),7.24(d,J＝6.7Hz,1H),7.16(d,J＝8.9Hz,1H),7.03(d,J＝7.5Hz,2H),1.98(s,3H).13C NMR(101MHz,DMSO)δ166.02,156.35(d,J＝245.3Hz),136.01(d,J＝5.8Hz),134.97,134.10,133.59,131.14,130.65,129.92,125.18,121.82(d,J＝2.6Hz),119.27,118.53(d,J＝23.1Hz),104.64(d,J＝22.3Hz),17.61.MS(ESI)m/z:625.9(M+H)+。
实例17(化合物17)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-(2-丙炔基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),9.31(q,J＝5.4,4.6Hz,1H),8.76(s,1H),8.03(ddt,J＝9.6,3.8,1.7Hz,1H),7.81(d,J＝1.8Hz,2H),7.44(dd,J＝8.7,2.0Hz,1H),7.33(dd,J＝8.7,2.2Hz,1H),7.26(q,J＝2.2Hz,1H),7.21(d,J＝6.7Hz,1H),7.14(dd,J＝9.7,4.4Hz,1H),4.09(dt,J＝5.2,2.5Hz,2H),3.23(d,J＝2.6Hz,1H),1.86(s,3H).13C NMR(101MHz,DMSO)δ167.69,156.85(d,J＝244.7Hz),142.18,141.66,137.19(d,J＝8.9Hz),136.73,135.86,133.80,132.66(d,J＝3.1Hz),132.12,131.55,131.06,125.77,119.81,119.02,118.50(d,J＝22.4Hz),104.68(d,J＝22.3Hz),80.66,74.13,29.12,17.43.MS(ESI)m/z:647.9(M+H)+。
实例18(化合物18)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-(1,3,4-噻二唑-2-基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),7.92(t,J＝1.9Hz,1H),7.76(d,J＝1.9Hz,2H),7.43(s,1H),7.35(d,J＝8.5Hz,1H),7.17(d,J＝9.6Hz,1H),7.10(d,J＝8.8Hz,1H),7.05(d,J＝6.8Hz,1H),2.04(s,3H).13C NMR(101MHz,DMSO)δ167.95,156.76(d,J＝244.8Hz),142.25,141.74,137.47,136.98(d,J＝7.9Hz),135.87,133.75,132.83(d,J＝3.0Hz),131.97,131.21,130.92,125.75,119.67,118.76,118.54(d,J＝22.0Hz),104.37(d,J＝22.0Hz),17.93.MS(ESI)m/z:693.9(M+H)+。
实施例2：化合物19的合成
在本实施例中，提供上述具有化合物19所示结构的化合物。
实例19(化合物19)：N-(5-溴-4-氟-2-甲基苯基)-2-氰基-4-((3,5-二氯苯基)磺酰胺基)苯磺酰胺
Figure BDA0002239325020000131
制备方法具体如下所列。
在封管中，将化合物1(122mg,0.2mmol)加入到2mL POCl3中，100℃反应4小时以上。TLC监测反应完全后，将反应冷却至室温，反应液加入到水中，加入乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗涤3次，有机相用无水硫酸钠干燥。用硅胶柱层析分离纯化得到化合物19(75mg，收率：63.5％)。1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),8.88(d,J＝6.3Hz,1H),8.81(s,1H),8.03(dt,J＝6.4,1.9Hz,1H),7.82(d,J＝1.9Hz,2H),7.45(dd,J＝8.9,1.7Hz,1H),7.33(dd,J＝8.6,2.4Hz,1H),7.27(t,J＝2.4Hz,1H),7.20(d,J＝6.7Hz,1H),7.15(dd,J＝9.6,3.1Hz,1H),1.98(s,3H).13C NMR(101MHz,DMSO)δ156.88(d,J＝244.7Hz),142.24,141.74,137.45,136.97(d,J＝7.9Hz),135.86,133.77,132.80(d,J＝3.2Hz),131.99,131.22,130.91,125.78,119.68,118.77,118.52(d,J＝23.1Hz),114.37,104.66(d,J＝22.2Hz),17.55.MS(ESI)m/z:591.9(M+H)+。
实施例3：化合物20的合成
在本实施例中，提供上述具有化合物20所示结构的化合物。
实例20(化合物20)：N-(5-溴-4-氟-2-甲基苯基)-4-((3,5-二氯苯基)磺酰胺基)-2-(2H-四唑-5-基)苯磺酰胺
Figure BDA0002239325020000132
制备方法具体如下所列。
化合物19(118mg,0.2mmol)，NaN3(14mg,0.22mmol)，ZnBr2(45mg,0.2mmol)加入到5mL水中。回流反应24小时。反应液冷却至室温加入3N盐酸3mL，乙酸乙酯10mL，继续搅拌1小时。分离乙酸乙酯层，水层用乙酸乙酯萃取2次，合并有机相，用饱和食盐水洗涤3次，无水硫酸钠干燥。然后用柱层析分离纯化得到化合物20(79mg，收率：61.7％)。1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),11.35(s,1H),8.88(d,J＝6.3Hz,1H),8.81(s,1H),8.03(dt,J＝6.4,1.9Hz,1H),7.82(d,J＝1.9Hz,2H),7.45(dd,J＝8.9,1.7Hz,1H),7.33(dd,J＝8.6,2.4Hz,1H),7.27(t,J＝2.4Hz,1H),7.20(d,J＝6.7Hz,1H),7.15(dd,J＝9.6,3.1Hz,1H),1.98(s,3H).13C NMR(101MHz,DMSO)δ156.88(d,J＝244.7Hz),142.24,141.74,137.45,136.97(d,J＝7.9Hz),135.86,133.77,132.80(d,J＝3.2Hz),131.99,131.22,130.91,125.78,119.68,118.77,118.52(d,J＝23.1Hz),114.37,104.66(d,J＝22.2Hz),17.55.MS(ESI)m/z:634.9(M+H)+。
实施例4：化合物21的合成
在本实施例中，提供上述具有化合物21所示结构的化合物。制备方法如下。
Figure BDA0002239325020000141
中间体21-I：2-氨基-N-(5-溴-4-氟-2-甲基苯基)-4-硝基苯磺酰胺
Figure BDA0002239325020000142
在冰浴下，将原料苯胺类化合物(1.0g，5.0mmol)溶解于5mL吡啶中，加入原料4-硝基-2-氨基苯磺酰氯(1.4g，6.0mmol)，室温反应2小时。TLC监测反应完全后，将反应冷却至室温，加入1N的盐酸，调pH至3～4，析出淡黄色沉淀，过滤、干燥即得中间体Int 21-I(1.5g，收率：75.0％)。可直接用于下一步反应。MS(ESI)m/z:403.9(M+H)+。中间体21-II：N-(5-溴-4-氟-2-甲基苯基)-4-硝基-2-(1H-吡咯-1-基)苯磺酰胺
Figure BDA0002239325020000151
在封管中，将中间体Int 21-I(0.45g，1.0mmol)、2,5-二甲氧基四氢呋喃(0.15g，1.2mmol)加入到2mL乙酸中，回流反应3小时。冷却至室温，加入水中，析出类白色固体，即为中间体Int 21-II(0.31g，收率：68.3％)。MS(ESI)m/z:453.9(M+H)+。
中间体21-III：4-氨基-N-(5-溴-4-氟-2-甲基苯基)-2-(1H-吡咯-1-基)苯磺酰胺
Figure BDA0002239325020000152
在室温下，将中间体Int 21-II(0.23g，0.5mmol)用5mL乙酸溶解，加入铁粉(0.23g,5mmol)，然后在50℃反应3小时。将溶剂进行减压蒸馏，加入乙酸乙酯，超声10分钟后抽滤，滤液用饱和碳酸氢钠洗涤3次，再用饱和食盐水洗涤3次后，有机相用无水硫酸钠进行干燥，用柱层析分离纯化的油状物，即为中间体Int 21-III(0.15g，收率：70.7％)。MS(ESI)m/z:424.9(M+H)+。
化合物21：N-(5-溴-4-氟-2-甲基苯基)-4-((3,5-二氯苯基)磺酰胺基)-2-(1H-吡咯-1-基)苯磺酰胺
Figure BDA0002239325020000153
室温下，中间体Int 21-III(0.15g,0.35mmol))溶解于3mL吡啶中，0℃下加入原料3,5-二氯苯磺酰氯(0.10g,0.4mmol)l)，反应1小时。升至室温反应6小时。TLC监测反应完全后，0℃下，加入2N的盐酸，调pH至3～4，析出固体，硅胶柱层析纯化得化合物21(0.14，收率：64.0％)。1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),9.45(s,1H),8.03(s,1H),7.81(d,J＝2.0Hz,2H),7.59(d,J＝8.0Hz,1H),7.43(dd,J＝2.0Hz,J＝8Hz,1H),7.25(d,J＝2.0Hz,1H),7.23(d,J＝8.0Hz,1H),7.20(d,J＝8.2Hz,2H),7.17(d,J＝8.0Hz,1H),6.57(d,J＝8.2Hz,2H),1.85(s,3H).MS(ESI)m/z:631.9(M+H)+。
实施例5：化合物22的合成
在本实施例中，提供上述具有化合物22所示结构的化合物。制备方法如下。
Figure BDA0002239325020000161
中间体22-I：N-(2-N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-硝基苯基)乙酰胺
Figure BDA0002239325020000162
将中间体2-氨基-N-(5-溴-4-氟-2-甲基苯基)-4-硝基苯磺酰胺(404mg，1.0mmol)溶解于5mL二氯甲烷中，加入三乙胺(303mg，3.0mmol)、DMAP(12mg，0.1mmol)。冰浴下，滴加乙酰氯(156mg，2.0mmol)，室温下继续反应3小时。反应液用1N盐酸洗涤、饱和碳酸氢钠洗涤，再用饱和食盐水洗涤，有机相用无水硫酸钠进行干燥，用柱层析分离纯化得中间体Int22-I(220mg，收率：50.0％)。MS(ESI)m/z:445.9(M+H)+。
中间体22-II：N-(5-氨基-2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)苯基)乙酰胺
Figure BDA0002239325020000163
在室温下，将中间体Int 21-II(0.22g，0.5mmol)用5mL乙酸溶解，加入铁粉(0.23g,5mmol)，然后在50℃反应3小时。将溶剂进行减压蒸馏，加入乙酸乙酯，超声10分钟后抽滤，滤液用饱和碳酸氢钠洗涤，再用饱和食盐水洗涤，有机相用无水硫酸钠进行干燥，用柱层析分离纯化得中间体22-Int II(0.13g，收率：62.5％)。MS(ESI)m/z:416.0(M+H)+。
化合物22：N-(2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)苯基)乙酰胺
Figure BDA0002239325020000171
室温下，中间体Int 22-II(125mg,0.3mmol))溶解于3mL吡啶中，0℃下加入原料3,5-二氯苯磺酰氯(88mg,0.36mmol)l)，反应1小时。升至室温反应6小时。TLC监测反应完全后，0℃下，加入2N的盐酸，调pH至3～4，析出固体，硅胶柱层析纯化得化合物22(103mg，收率：55.0％)。1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),8.86(d,J＝6.3Hz,1H),8.80(s,1H),7.79(dt,J＝6.4,1.8Hz,1H),7.81(d,J＝1.8Hz,2H),7.43(dd,J＝8.7,1.7Hz,1H),7.32(dd,J＝8.6,2.4Hz,1H),7.25(t,J＝2.4Hz,1H),7.20(d,J＝6.7Hz,1H),7.15(dd,J＝9.6,3.1Hz,1H),2.02(s,3H),1.88(s,3H).MS(ESI)m/z:623.9(M+H)+。
实施例6：化合物23～27的合成
在本实施例中，提供上述具有化合物23～27所示结构的化合物。制备方法如下。化合物23～27采用如实施例1所述的反应路线合成。
化合物23：2-(N-(2,5-二溴-4-氟苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),8.85(s,1H),8.45(s,1H),7.98(t,J＝1.9Hz,1H),7.95(s,1H),7.79(d,J＝2.0Hz,2H),7.40(d,J＝8.6Hz,1H),7.28(t,J＝2.4Hz,1H),7.22(d,J＝6.8Hz,1H).13C NMR(101MHz,DMSO)δ170.35,156.67(d,J＝244.5Hz),142.25,141.75,137.45,136.98(d,J＝7.8Hz),135.86,133.77,132.82(d,J＝3.2Hz),131.99,131.21,130.90,125.78,119.69,118.78,118.56(d,J＝23.0Hz),104.66(d,J＝22.4Hz).MS(ESI)m/z:673.8(M+H)+。
化合物24：2-(N-(5-溴-2-氯-4-氟苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),8.75(s,1H),8.35(s,1H),7.96(t,J＝1.9Hz,1H),7.94(s,1H),7.77(d,J＝2.0Hz,2H),7.39(d,J＝8.6Hz,1H),7.25(t,J＝2.4Hz,1H),7.20(d,J＝6.7Hz,1H).13C NMR(101MHz,DMSO)δ170.65,156.64(d,J＝244.3Hz),137.22,136.64,136.61,135.56,134.33(d,J＝4.0Hz),133.12,133.04,133.02,130.80,125.60,120.20,118.85,118.51(d,J＝22.6Hz),104.63(d,J＝22.3Hz).MS(ESI)m/z:629.8(M+H)+。
化合物25：2-(N-(2,5-二溴-4-氟苯基)氨磺酰基)-5-((3,5-二氟苯基)磺酰胺基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),8.86(s,1H),8.45(s,1H),7.97(t,J＝1.9Hz,1H),7.98(s,1H),7.79(d,J＝2.0Hz,2H),7.41(d,J＝8.6Hz,1H),7.27(t,J＝2.4Hz,1H),7.24(d,J＝6.8Hz,1H).MS(ESI)m/z:641.9(M+H)+。
化合物26：2-(N-(2,5-二溴-4-氟苯基)氨磺酰基)-5-((3,5-二溴苯基)磺酰胺基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),8.85(s,1H),8.44(s,1H),7.97(t,J＝1.9Hz,1H),7.94(s,1H),7.79(d,J＝2.0Hz,2H),7.42(d,J＝8.6Hz,1H),7.29(t,J＝2.4Hz,1H),7.23(d,J＝6.8Hz,1H).MS(ESI)m/z:761.7(M+H)+。
化合物27：2-(N-(2,5-二溴-4-氟苯基)氨磺酰基)-5-((3-溴-5-氟苯基)磺酰胺基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),8.85(s,1H),8.44(s,1H),7.98(t,J＝1.9Hz,1H),7.94(s,1H),7.79(d,J＝2.0Hz,2H),7.41(d,J＝8.6Hz,1H),7.27(t,J＝2.4Hz,1H),7.21(d,J＝6.8Hz,1H).MS(ESI)m/z:701.8(M+H)+。
实施例7：化合物28的合成
在本实施例中，提供上述具有化合物28所示结构的化合物。制备方法如下。
化合物28：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)苯甲酰胺二钠盐
Figure BDA0002239325020000181
室温下，将化合物1(61mg,0.1mmol)溶解于2mL甲醇中，加入甲醇钠的甲醇溶液(0.02mL,5M)，搅拌30分钟，旋干后得白色固体化合物28(63mg，收率：96.0％)。MS(ESI)m/z:609.9(M+H)+。
实施例8：化合物29的合成
在本实施例中，提供上述具有化合物29所示结构的化合物。制备方法如下。
化合物29：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)苯甲酰胺二钾盐
室温下，将化合物1(61mg,0.1mmol)溶解于2mL甲醇中，加入叔丁醇钾的四氢呋喃(0.1mL,1M)，搅拌30分钟，旋干后得白色固体化合物29(66mg，收率：97.0％)。MS(ESI)m/z:609.9(M+H)+。
实施例9：荧光定量实验检测SIRT6去乙酰化活性及激动剂EC50
采用基于荧光定量的方法来检测SIRT6去乙酰化活性及激动剂EC 50。在乙酰化多肽acetyl-Arg-His-Lys-Lys(ε-acetyl)的C端标记上荧光基团AMC(香豆素)。SIRT6可以对这条多肽(RHKK-Ac-AMC)进行去乙酰化，然后它进一步被胰蛋白酶(Trypsin)剪切，产生游离的AMC，进而对反应进行荧光定量。在50μL的反应体系中含有2.5mM NAD+、75μM RHKK-Ac-AMC、5μM SIRT6、化合物或DMSO以及反应缓冲液(50mM Tris-HCl，pH 8,137mM NaCl,2.7mMKCl,1.0mM MgCl2)。化合物溶解和稀释都使用DMSO。以上反应组分于37℃反应2小时后，加入40mM NAM(烟酰胺)终止去乙酰化反应，并加入6mg/mL的胰蛋白酶于25℃进行30分钟的显色反应。最后通过酶标仪对反应进行荧光定量检测，激发和发射波长分别为360nm和460nm。最后通过GrapHPad Prism 6软件求解三次独立实验中激动剂在多种浓度条件下对SIRT6激活效应的EC50。结果参见图1-图2，说明化合物对于SIRT6具有显著的激动效应。
本发明已由上述相关实施例加以描述，然而上述实施例仅为实施本发明的范例。必需指出的是，已公开的实施例并未限制本发明的范围。相反地，包含于权利要求书的精神及范围的修改及均等设置均包括于本发明的范围内。

Claims (9)

1.一种具有激动SIRT6乙酰化活性的化合物，或其药学上可接受的盐，具有式(I)所示的结构：
Figure FDA0002239325010000011
其中，X1、X2、X3、X4分别独立地表示氢原子或卤素；Y表示氢原子、甲基或卤素；R表示甲酰胺基、氰基或含氮杂环。
2.如权利要求1所述的化合物，其特征在于，所述卤素为氟、氯、溴或碘。
3.如权利要求1所述的化合物，其特征在于，所述甲酰胺基为甲酰胺、甲酰脂肪胺或甲酰芳香胺。
4.如权利要求1所述的化合物，其特征在于，所述含氮杂环为三氮唑、四氮唑、咪唑、吡咯、吡唑、噁唑、异噁唑、噻唑或噻二唑。
5.如权利要求1所述的化合物，其特征在于，R表示
Figure FDA0002239325010000012
6.如权利要求1所述的化合物，其特征在于，式(I)所示化合物的药学上可接受的盐具有式(II)或(III)所示的结构：
Figure FDA0002239325010000013
7.如权利要求1所述的化合物，其特征在于，所述化合物具有式(化合物1)～(化合物29)所示的结构：
Figure FDA0002239325010000014
Figure FDA0002239325010000021
8.一种SIRT6激动剂，包含如权利要求1所述的化合物或其药学上可接受的盐。
9.权利要求1所述的化合物或权利要求7所述的SIRT6激动剂在制备治疗SIRT6介导的相关疾病的药物中的应用。
CN201910994511.2A 2019-10-18 2019-10-18 具有激动sirt6乙酰化活性的化合物、sirt6激动剂及其应用 Pending CN110642757A (zh)

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