CN113861130A - 联苯磺胺噻二唑类衍生物及其在抗肿瘤药物的应用 - Google Patents

联苯磺胺噻二唑类衍生物及其在抗肿瘤药物的应用 Download PDF

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CN113861130A
CN113861130A CN202111151928.6A CN202111151928A CN113861130A CN 113861130 A CN113861130 A CN 113861130A CN 202111151928 A CN202111151928 A CN 202111151928A CN 113861130 A CN113861130 A CN 113861130A
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杨金飞
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Conservation Xiamen Medical Technology Co ltd
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Abstract

本发明属于药物化学技术领域，尤其涉及联苯磺胺噻二唑类衍生物和制备方法，及其作为PD1/PDL1抑制剂在抗肿瘤药物中的应用。本发明的提供一种通式(I)所示的新型联苯磺胺噻二唑类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药。本发明通过实验显示，本课题组合成的联苯磺胺噻二唑类衍生物具有开发抗肿瘤药物的前景。

Description

联苯磺胺噻二唑类衍生物及其在抗肿瘤药物的应用
技术领域
本发明属于药物化学技术领域，尤其涉及联苯磺胺噻二唑类衍生物和制备方法，及其作为PD1/PD-L1抑制剂在抗肿瘤药物中的应用。
背景技术
尽管我们希望免疫***自动将癌细胞视为“异物”，但是由于肿瘤细胞独特广泛的变异特点，免疫***和肿瘤之间经常达到平衡一肿瘤耐受，免疫检查点失调成为肿瘤耐受的主要原因之一。免疫检查点是一类免疫抑制性分子，可以调节免疫的强度和力度。由程序性细胞死亡蛋白1(PD-1)及其同源配体程序性死亡配体(PDLS)调控的信号通路在抗癌药物的开发中备受关注。PD1配体在肿瘤细胞中的过表达抑制机体免疫***，防止免疫***杀伤肿瘤细胞。肿瘤抗体治疗的基本思路之一是阻断PD1/PD-L1蛋白-蛋白相互作用(PPI)，从而激活T细胞抗肿瘤免疫反应，清除肿瘤细胞。肿瘤抗体治疗的基本思路之一是阻断PD1-PDL蛋白-蛋白相互作用(PPI)，从而激活T细胞抗肿瘤免疫反应，清除肿瘤细胞。肿瘤抗体治疗的基本思路之一是阻断PD1/PD-L1蛋白-蛋白相互作用(PPI)，从而激活T细胞抗肿瘤免疫反应，清除肿瘤细胞。研究发现，进展期黑色素瘤、细胞肺癌(NSCLC)、肾细胞癌(RCC)应用单克隆抗体阻断该通路引起了持久客观的反应，与传统治疗相比，患者生存期显著延长。
综上所述，研究新型的特异性更强的PD1/PD-L1抑制剂，对肿瘤药物患者的临床免疫治疗至关重要。
发明内容
本发明针对现有技术的不足，提供一种联苯磺胺噻二唑类衍生物；以及该衍生物的制备方法和其作为PD1/PD-L1抑制剂在抗肿瘤药物中的应用。
为实现上述目的，本发明采取的技术方案是：本发明的提供一种通式(I)所示的联苯磺胺噻二唑类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药；
Figure BDA0003287466720000021
所述R1、R2或R3选自氢、卤素、C1-C6烷氧基、C1-C6烷基、C1-C6环烷基、烯烃基、炔烃基或芳香基。
优选的，所述R1或R2选自氢、卤素、C1-C6烷氧基或C1-C6烷基。
优选的，所述R3选自C1-C6烷基。
本发明通式(I)所示的联苯磺胺噻二唑类衍生物，选自：
Figure BDA0003287466720000022
本发明所述的“烷基”是指直链或支链的烷基，其中C1-C6基团是指该部分中具有1-6个碳原子，即基团包含1、2、3、4、5或6个碳原子。
本发明所述的“烷氧基”是指烷基醚基烷基，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基等。
本发明所述的“卤素”是指氟、氯、溴或碘。
按照本发明的式I化合物，均可按照路线1的方法进行合成，由相应的起始原料4-取代苯基苯甲醛与甲基或乙基取代的磺胺噻二唑发生还原胺化反应得到目标化合物。合成路线路线1如下。
Figure BDA0003287466720000031
本发明所述的联苯磺胺噻二唑类衍生物可以作为PD1/PD-L1抑制剂，作为肿瘤患者的临床免疫治疗药物。
具体实施方式
下述实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用BrukerARX-400测定，质谱用Agilent 1100LC/MS测定；所用试剂均为分析纯或化学纯。
实施例1。
Figure BDA0003287466720000032
将4-苯基苯甲醛(0.50g,2.74mmol)和磺胺甲噻二唑(0.74g,2.74mmol)溶于1,2-二氯乙烷中，然后分批加入醋酸硼氢化钠(1.74g,8.23mmol)，继续室温反应28h，TLC检测反应完成。加入40mL水，30mL二氯甲烷萃取，饱和食盐水洗涤有机层，Na2SO4干燥过夜。滤除干燥剂，减压蒸除溶剂，残余物经硅胶柱层析纯化，得0.59g，收率49.26％。
1H-NMR(400MHz,DMSO-d6)δ13.65(s,1H),7.74(d,J＝7.3Hz,2H),7.69(d,J＝8.5Hz,2H),7.50–7.46(m,4H),7.43-7.40(m,3H),7.31(s,1H),7.14(d,J＝8.5Hz,2H),4.32(s,2H),2.47(s,3H).ESI-MS m/z:437.1[M+H]+.
实施例2。
Figure BDA0003287466720000041
1H-NMR(400MHz,DMSO-d6)δ13.66(s,1H),7.69(d,J＝8.5Hz,2H),7.47(d,J＝7.8Hz,2H),7.40(d,J＝7.6Hz,2H),7.33–7.30(m,3H),7.16-7.14(m,4H),4.30(s,2H),2.48(s,3H),2.35(s,3H).ESI-MS m/z:451.1[M+H]+.
实施例3。
Figure BDA0003287466720000042
1H-NMR(400MHz,DMSO-d6)δ13.64(s,1H),7.71-7.69(m,3H),7.47(d,J＝7.8Hz,2H),7.43-7.40(m,3H),7.34-7.31(m,3H),7.12(d,J＝8.8Hz,2H),4.34(s,2H),2.48(s,3H),2.34(s,3H).ESI-MS m/z:451.1[M+H]+.
实施例4。
Figure BDA0003287466720000051
1H-NMR(400MHz,DMSO-d6)δ13.68(s,1H),7.66(d,J＝8.0Hz,2H),7.52–7.49(m,4H),7.42(d,J＝8.5Hz,2H),7.31(s,1H),7.14–7.11(m,4H),4.31(s,2H),2.46(s,3H).ESI-MS m/z:455.2[M+H]+.
实施例5。
Figure BDA0003287466720000052
1H-NMR(400MHz,DMSO-d6)δ13.61(s,1H),7.75-7.71(m,2H),7.69(d,J＝8.5Hz,2H),7.49-7.46(m,3H),7.40(d,J＝8.5Hz,2H),7.32-7.28(m,2H),7.11(d,J＝8.0Hz,2H),4.30(s,2H),2.47(s,3H).ESI-MS m/z:455.2[M+H]+.
实施例6。
Figure BDA0003287466720000053
1H-NMR(400MHz,DMSO-d6)δ13.60(s,1H),7.79(d,J＝7.5Hz,1H),7.69(d,J＝8.5Hz,2H),7.50–7.45(m,4H),7.40(t,J＝7.4Hz,1H),7.32(s,1H),7.25(t,J＝7.8Hz,1H),7.18-7.14(m,3H),4.32(s,2H),2.47(s,3H).ESI-MS m/z:455.1[M+H]+.
实施例7。
Figure BDA0003287466720000061
1H-NMR(400MHz,DMSO-d6)δ13.64(s,1H),8.10(d,J＝8.5Hz,2H),7.66–7.61(m,4H),7.46(d,J＝8.0Hz,2H),7.40(d,J＝7.8Hz,2H),7.32(s,1H),7.12(d,J＝8.2Hz,2H),4.32(s,2H),2.48(s,3H).ESI-MS m/z:471.1[M+H]+.
实施例8。
Figure BDA0003287466720000062
1H-NMR(400MHz,DMSO-d6)δ13.64(s,1H),7.76-7.71(m,2H),7.70(d,J＝8.2Hz,2H),7.49-7.44(m,3H),7.40(d,J＝8.5Hz,2H),7.33-7.28(m,2H),7.12(d,J＝8.4Hz,2H),4.31(s,2H),2.82(q,J＝7.1Hz,2H),1.22(t,J＝7.2Hz,3H).ESI-MS m/z:469.1[M+H]+.
实施例9。
Figure BDA0003287466720000063
1H-NMR(400MHz,DMSO-d6)δ13.66(s,1H),7.64(d,J＝8.0Hz,2H),7.53–7.49(m,4H),7.42(d,J＝8.4Hz,2H),7.30(s,1H),7.15–7.10(m,4H),4.30(s,2H),2.81(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H).ESI-MS m/z:469.1[M+H]+.
实施例10。
Figure BDA0003287466720000071
1H-NMR(400MHz,DMSO-d6)δ13.64(s,1H),7.64(d,J＝8.0Hz,2H),7.53–7.46(m,4H),7.40(d,J＝8.5Hz,2H),7.30(s,1H),7.12(d,J＝8.5Hz,2H),6.98(d,J＝8.4Hz,2H),4.30(s,2H),3.81(s,3H),2.82(q,J＝7.0Hz,2H),1.22(t,J＝7.2Hz,3H).ESI-MS m/z:481.1[M+H]+.
实施例11。
Figure BDA0003287466720000072
1H-NMR(400MHz,DMSO-d6)δ13.64(s,1H),7.78(d,J＝7.4Hz,1H),7.68(d,J＝8.2Hz,2H),7.51–7.46(m,4H),7.41(t,J＝8.4Hz,1H),7.34(s,1H),7.23(t,J＝7.4Hz,1H),7.18-7.14(m,3H),4.31(s,2H),2.80(q,J＝7.2Hz,2H),1.20(t,J＝7.4Hz,3H).ESI-MS m/z:469.1[M+H]+.
一、HTRF均相时间分辨荧光技术。
测试原理：Cisbio公司开发的HTRF PD-1/PD-L1 binding assay kit试剂盒，PD-1/PD-L1结合测定旨在测量PD-1和PD-L 1蛋白之间的相互作用。通过使用抗Tag1-Europium(HTRF供体)和抗Tag2-XL665(HTRF受体)来检测Tag1-PD-L1和Tag2-PD-1之间的相互作用。当供体抗体和受体抗体由于PD-L1和PD-1的的紧密结合而接近时，供体抗体的激发引发朝向受体抗体的荧光共振能量转移((FRET)，后者又在665nm处特异性发射。该特定信号与PD-1/PD-L1相互作用的程度成正比。因此阻断PD-1/PD-L 1相互作用的化合物将导致HTRF信号的减弱。
测试方法：按照说明书操作，对本发明所述的化合物测试对PD-1/PD-L1的抑制效果。在384孔板中预设给药组、对照组和阴性对照组，每组三个复孔。依次向每孔中加入4μLTag1-PD-L1工作液、4μL Tag1-PD-1工作液，并吹打均匀；接着向每孔中加入2μL的化合物稀释液，混合均匀室温孵育15min后，向每孔中依次加入Anti-Tag1-Europium和Anti-Tag2-XL665，封膜避光孵育2小时，使用Tecan酶标仪读取荧光值(Ex:320nM；Em:620和665nM)，然后计算抑制率及拟合IC50，见表1。
表1化合物测试对PD-1/PD-L1的抑制活性(IC50)。
实施例 IC<sub>50</sub>(μM)
实施例1 5.6
实施例2 14.6
实施例3 24.9
实施例4 1.9
实施例5 0.26
实施例6 0.37
实施例7 2.7
实施例8 0.46
实施例9 0.68
实施例10 0.84
实施例11 0.95
采用HTRF(均相时间分辨荧光)技术标准操作程序测定本发明所述的一种联苯磺胺噻二唑类衍生物对PD-1/PD-L1的抑制效果，结果显示该化合物对PD-1/PD-L1具有明显的抑制作用。

Claims (5)

1.联苯磺胺噻二唑类衍生物，其特征在于，所述的衍生物结构式如下：
Figure FDA0003287466710000011
其中，所述R1、R2或R3选自氢、卤素、C1-C6烷氧基、C1-C6烷基、C1-C6环烷基、烯烃基、炔烃基或芳香基。
2.如权利要求1所述的联苯磺胺噻二唑类衍生物，其特征在于，所述R1或R2选自氢、卤素、C1-C6烷氧基或C1-C6烷基。
3.如权利要求1所述的联苯磺胺噻二唑类衍生物，其特征在于，所述R3选自C1-C6烷基。
4.如权利要求1所述的联苯磺胺噻二唑类衍生物，其特征在于，所述的衍生物选自：
Figure FDA0003287466710000012
5.如权利要求1-4任一所述的联苯磺胺噻二唑类衍生物作为PD1/PDL1抑制剂，作为肿瘤患者的临床免疫治疗药物。
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009129267A2 (en) * 2008-04-14 2009-10-22 The Board Of Regents Of The University Of Texas System Small molecule inhibitors of the pleckstrin homology domain and methods for using same
CN103664878A (zh) * 2012-09-12 2014-03-26 山东亨利医药科技有限责任公司 杂芳环及其衍生物类酪氨酸激酶抑制剂
WO2015054662A1 (en) * 2013-10-10 2015-04-16 Eastern Virginia Medical School 4-((2-hydroxy-3-methoxybenzyl)amino) benzenesulfonamide derivatives as 12-lipoxygenase inhibitors
WO2016210296A1 (en) * 2015-06-26 2016-12-29 Dana-Farber Cancer Institute, Inc. 4,6-pyrimidinylene derivatives and uses thereof
CN110325531A (zh) * 2016-12-09 2019-10-11 泽农医药公司 苯磺酰胺及其作为治疗剂的用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009129267A2 (en) * 2008-04-14 2009-10-22 The Board Of Regents Of The University Of Texas System Small molecule inhibitors of the pleckstrin homology domain and methods for using same
CN103664878A (zh) * 2012-09-12 2014-03-26 山东亨利医药科技有限责任公司 杂芳环及其衍生物类酪氨酸激酶抑制剂
WO2015054662A1 (en) * 2013-10-10 2015-04-16 Eastern Virginia Medical School 4-((2-hydroxy-3-methoxybenzyl)amino) benzenesulfonamide derivatives as 12-lipoxygenase inhibitors
WO2016210296A1 (en) * 2015-06-26 2016-12-29 Dana-Farber Cancer Institute, Inc. 4,6-pyrimidinylene derivatives and uses thereof
CN110325531A (zh) * 2016-12-09 2019-10-11 泽农医药公司 苯磺酰胺及其作为治疗剂的用途

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Application publication date: 20211231