CN117986195A - 一种新型杂环化合物及其制备方法和用途 - Google Patents

一种新型杂环化合物及其制备方法和用途 Download PDF

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CN117986195A
CN117986195A CN202410034758.0A CN202410034758A CN117986195A CN 117986195 A CN117986195 A CN 117986195A CN 202410034758 A CN202410034758 A CN 202410034758A CN 117986195 A CN117986195 A CN 117986195A
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刘江
袁尧
赵行
王开超
宋绍涓
陈谦明
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Sichuan University
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Abstract

本发明提供了一种新型杂环化合物及其制备方法和用途，属于化药领域。该杂环化合物的结构如式I所示。本发明提供的化合物能够有效抑制鳞状细胞癌的增殖，为制备预防和/或治疗鳞状细胞癌的药物提供了一种新的选择。

Description

一种新型杂环化合物及其制备方法和用途
技术领域
本发明属于化药领域，具体涉及一种新型杂环化合物及其制备方法和用途。
背景技术
口腔颌面部恶性肿瘤是头颈部常见的恶性肿瘤，其中约90％以上为口腔鳞状细胞癌(oral squamouscell carcinoma，OSCC)，是全球第八大恶性肿瘤。OSCC通常发现和确诊时间较晚，具有早期转移和术后复发率高、预后不佳等特点，导致OSCC死亡率居高不下。90％的早期OSCC患者采用手术治疗可以治愈，但是在确诊患者中，早期病例却不足10％。对于晚期OSCC，一般先采用化疗，肿瘤缩小后可考虑结合手术治疗。
铂类化疗药物是治疗口腔鳞状细胞癌的一线化疗药物。然而化疗耐药极大地限制了铂类化疗药物的临床应用，开发出能够有效治疗口腔鳞状细胞癌的新药具有重要意义。
发明内容
本发明的目的在于提供一种新型杂环化合物及其制备方法和用途。
本发明提供了式I所示化合物、其药学上可接受的盐、其立体异构体：
其中，A环选自氮杂稠环或5～6元不饱和氮杂环；
b选自0～6的整数；
R0各自独立地选自＝O、＝S、氢、氨基、卤素、C1-6烷基、C1-6烷氧基、羟基、羧基、氰基、烷胺基、杂环取代烷基、芳香环取代烷基；
m选自1-3的整数，n选自0-5的整数，R7、R8、R9、R10各自独立地选自氢、氨基、卤素、C1-6烷基、C1-6烷氧基、卤素、羟基、羧基。
进一步地，所述化合物的结构如式II所示：
其中，表示-或
R1为无、氢或R2为氢或且R1为无或氢时，R2不为氢；
n选自0-3的整数，R7、R8、R9、R10各自独立地选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、卤素、羟基、羧基；
R3选自＝O、＝S、氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基；
R4选自＝O、＝S、氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基；
且R3和R4中至少一个为＝O或＝S；
R5选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基、氰基、烷胺基、杂环取代烷基、芳香环取代烷基；
R6选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基。
进一步地，所述化合物的结构如式II-x所示：
其中，R5选自氢、氨基、卤素、C1-2烷基、C1-2烷氧基、羟基、羧基、氰基、烷胺基、杂环取代烷基、芳香环取代烷基；
R1为氢或R2为氢或且R1和R2不同时为氢；n选自0-3的整数，R7、R8、R9、R10各自独立地选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、卤素、羟基、羧基。
进一步地，所述化合物的结构如式II-a或式II-b所示：
其中，R1为氢或R2为氢或且R1和R2不同时为氢；n选自0-3的整数，R7、R8、R9、R10各自独立地选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、卤素、羟基、羧基。
进一步地，所述化合物的结构如式II-c或式II-d所示：
其中，R1为R2为n选自0-3的整数，R7、R8、R9、R10各自独立地选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、卤素、羟基、羧基；
R4选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基。
进一步地，所述化合物的结构如式III-a或式III-b所示：
其中，表示-或
R14为无、氢或R15为氢或且R14为无或氢时，R15不为氢；
n选自0-3的整数，R7、R8、R9、R10各自独立地选自氢、C1-4烷基、C1-4烷氧基、卤素、羟基、羧基；
R11选自＝O、＝S、氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基；
R12选自＝O、＝S、氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基；
R13选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基。
进一步地，所述化合物的结构如式III-c或式III-d所示：
其中，R14为n选自0-3的整数，R7、R8、R9、R10各自独立地选自氢、C1-4烷基、C1-4烷氧基、卤素、羟基、羧基；
R11选自＝O、＝S、氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基；R12选自＝O、＝S、氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基。进一步地，所述化合物为以下化合物之一：
本发明还提供了一种抗肿瘤的药物组合物，它是以上述化合物为活性成分，加上药学上可接受的辅料制备而成的制剂。
本发明还提供了上述化合物在制备抗肿瘤的药物中的用途。
进一步地，所述肿瘤为鳞状细胞癌。
进一步地，所述鳞状细胞癌为头颈部鳞状细胞癌。
进一步地，所述头颈部鳞状细胞癌为口腔鳞状细胞癌。
进一步地，所述口腔鳞状细胞癌为舌鳞状细胞癌。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀Ca～b烷基表示任何含“a”至“b”个碳原子的烷基。例如，C1～6烷基是指包含1～6个碳原子的直链或支链的烷基。
“5～6元不饱和氮杂环”指环原子数为5或6的、含氮的且不饱和的环状烃取代基。
“杂稠环”指多环的杂环基，且该多环的杂环基中有两个环共用两个相邻的碳原子或杂原子。
“氮杂稠环”指环原子含氮的杂稠环。例如：
卤素指氟、氯、溴或碘。
实验结果表明，本发明提供的化合物能够有效抑制鳞状细胞癌的增殖，为制备预防和/或治疗鳞状细胞癌的药物提供了一种新的选择。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1：化合物6a、6b、6c对鳞状细胞癌细胞的增殖抑制能力，以及化合物6a对鳞状细胞癌细胞的IC50值。
图2：化合物8a、8b、8c对鳞状细胞癌细胞的增殖抑制能力，以及化合物8a对鳞状细胞癌细胞的IC50值。
图3：化合物10a、10b、10c对鳞状细胞癌细胞的增殖抑制能力，以及化合物10a对鳞状细胞癌细胞的IC50值。
图4：化合物12a、12b、12c对鳞状细胞癌细胞的增殖抑制能力，以及化合物12a对鳞状细胞癌细胞的IC50值。
图5：化合物14a、14b、14c对鳞状细胞癌细胞的增殖抑制能力，以及化合物14a对鳞状细胞癌细胞的IC50值。
图6：化合物16a、16b、16c对鳞状细胞癌细胞的增殖抑制能力，以及化合物16a对鳞状细胞癌细胞的IC50值。
图7：化合物18a、18b、18c对鳞状细胞癌细胞的增殖抑制能力，以及化合物18a对鳞状细胞癌细胞的IC50值。
图8：化合物20a、20b、20c对鳞状细胞癌细胞的增殖抑制能力，以及化合物20a对鳞状细胞癌细胞的IC50值。
图9：化合物22、24、26对鳞状细胞癌细胞的增殖抑制能力，以及化合物22、24对鳞状细胞癌细胞的IC50值。
具体实施方式
本发明所用原料与设备均为已知产品，通过购买市售产品所得。
实施例1：制备化合物6a、6b、6c
1.制备化合物4
1-溴金刚烷1(1mmol)溶解于10mL 1,4-二氧六环与水的混合溶液中，充入氩气并置于室温搅拌，随后加入过量4-硝基苯硼酸频哪醇酯2(2mmol)、醋酸钾(3mmol)以及催化剂量[1,1'-双(二苯基膦)二茂铁]二氯化钯(0.04mmol)，氩气保护下加热回流反应，通过TLC监测直至反应结束。然后，撤去氩气保护，加水淬灭反应，用二氯甲烷萃取水相3次，合并有机相，用无水硫酸钠干燥，通过减压旋蒸除去有机溶剂，所得到化合物3粗产物不经进一步提纯直接用于下一步反应。
将上一步反应所得到的化合物3(1mmol)溶于10mL无水四氢呋喃中，加入催化剂量钯碳(0.05mmol)以及过量氟化钾(2mmol)和聚甲基氢硅氧烷(4mmol)，氩气保护下室温搅拌反应，通过TLC监测直至化合物3消耗完毕。然后，将过量丙烯酰氯(2mmol)加入到反应液中，继续通过TLC监测直至反应结束。然后，撤去氩气保护，加水淬灭反应，用乙酸乙酯萃取水相3次，合并有机相，用无水硫酸钠干燥，减压旋蒸除去有机溶剂，通过快速柱层析分离纯化得到化合物4，两步反应总收率为50％。
化合物4分析数据：1H NMR(DMSO-d6,600MHz)δ10.05(s,1H),7.60-7.56(m,2H),7.31-7.27(m,2H),6.42(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝17.0,2.0Hz,1H),5.72(dd,J＝10.1,2.0Hz,1H),2.04(p,J＝3.4Hz,3H),1.83(d,J＝3.1Hz,6H),1.76-1.69(m,6H).LRMS calcd forC19H23NO[M+Na]+304.17,found 304.17.
2.制备化合物6a、6b、6c
将等量胸腺嘧啶5和1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)，过量化合物4溶于N,N-二甲基甲酰胺(DMF)中，加热回流反应，通过TLC监测直至反应结束，加水淬灭反应，用二氯甲烷萃取水相3次，合并有机相，用无水硫酸钠干燥，减压旋蒸除去有机溶剂，通过快速柱层析分离纯化依次得到化合物6a、6b、6c，总收率85％～95％。
化合物6a分析数据：1H NMR(DMSO-d6,600MHz)δ9.90(s,1H),9.86(s,1H),7.57(d,J＝1.2Hz,1H),7.48-7.45(m,4H),7.27-7.24(m,4H),4.10(t,J＝7.6Hz,2H),3.96(t,J＝6.7Hz,2H),2.69(t,J＝6.7Hz,2H),2.54(t,J＝7.7Hz,2H),2.05-1.99(m,6H),1.81(d,J＝3.2Hz,12H),1.78(s,3H),1.75-1.67(m,12H).LRMS calcd forC43H52N4O4[M+Na]+711.39,found 711.39.
化合物6b分析数据：1H NMR(DMSO-d6,600MHz)δ11.24(s,1H),9.92(s,1H),7.47(d,J＝1.2Hz,1H),7.47-7.44(m,2H),7.28-7.24(m,2H),3.90(t,J＝6.7Hz,2H),2.67(t,J＝6.7Hz,2H),2.03(dt,J＝6.4,3.2Hz,3H),1.82(d,J＝3.2Hz,6H),1.75-1.68(m,9H).LRMScalcd forC24H29N3O3[M+K]+446.18,found 446.18.
化合物6c分析数据：1H NMR(DMSO-d6,600MHz)δ10.91(s,1H),9.86(s,1H),7.49-7.43(m,2H),7.31(s,1H),7.28-7.23(m,2H),4.06(t,J＝7.7Hz,2H),2.54(t,J＝7.7Hz,2H),2.04(dt,J＝6.4,3.4Hz,3H),1.83(d,J＝3.3Hz,6H),1.78(d,J＝1.2Hz,3H),1.75-1.69(m,6H).LRMS calcd forC24H29N3O3[M-H]-406.21,found 406.21.
实施例2：制备化合物8a、8b、8c
将等量尿嘧啶7和1,8-二氮杂双环[5.4.0]十一碳-7-烯，过量化合物4溶于N,N-二甲基甲酰胺中，加热回流反应，通过TLC监测直至反应结束，加水淬灭反应，用二氯甲烷萃取水相3次，合并有机相，用无水硫酸钠干燥，减压旋蒸除去有机溶剂，通过快速柱层析分离纯化依次得到化合物8a、8b、8c，总收率85％～95％。
化合物8a分析数据：1H NMR(DMSO-d6,600MHz)δ9.92(s,1H),9.87(s,1H),7.66(d,J＝7.9Hz,1H),7.48-7.45(m,4H),7.28-7.21(m,4H),5.66(d,J＝7.9Hz,1H),4.08(t,J＝7.5Hz,2H),3.99(t,J＝6.6Hz,2H),2.70(t,J＝6.6Hz,2H),2.54(t,J＝7.6Hz,2H),2.05-2.00(m,6H),1.81(d,J＝3.1Hz,12H),1.74-1.67(m,12H).LRMS calcd forC42H50N4O4[M+Na]+697.37,found 697.37.
化合物8b分析数据：1H NMR(DMSO-d6,600MHz)δ11.25(s,1H),9.94(s,1H),7.58(d,J＝7.9Hz,1H),7.47-7.44(m,2H),7.28-7.23(m,2H),5.50(d,J＝7.9Hz,1H),3.93(t,J＝6.5Hz,2H),2.68(t,J＝6.6Hz,2H),2.03(p,J＝3.3Hz,3H),1.81(d,J＝3.3Hz,6H),1.74-1.68(m,6H).LRMS calcd forC23H27N3O3[M+Na]+416.20,found 416.19.
化合物8c分析数据：1H NMR(DMSO-d6,600MHz)δ11.12(d,J＝5.3Hz,1H),9.87(s,1H),7.48-7.45(m,2H),7.44-7.41(m,1H),7.27-7.23(m,2H),5.59(d,J＝7.5Hz,1H),4.08-4.00(m,2H),2.57-2.52(m,2H),2.04(p,J＝3.3Hz,3H),1.83(d,J＝3.3Hz,6H),1.72(q,J＝3.8Hz,6H).LRMS calcd forC23H27N3O3[M+Na]+416.20,found 416.20.
实施例3：制备化合物10a、10b、10c
将等量5-乙基尿嘧啶9和1,8-二氮杂双环[5.4.0]十一碳-7-烯，过量化合物4溶于N,N-二甲基甲酰胺中，加热回流反应，通过TLC监测直至反应结束，加水淬灭反应，用二氯甲烷萃取水相3次，合并有机相，用无水硫酸钠干燥，减压旋蒸除去有机溶剂，通过快速柱层分离纯化得到化合物10a、10b、10c，总收率70％～75％。
化合物10a分析数据：1H NMR(600MHz,DMSO-d6)δ9.88(s,1H),9.80(s,1H),7.57-7.51(m,4H),7.41(d,J＝1.3Hz,1H),7.32-7.26(m,4H),4.03(td,J＝9.0,7.0Hz,4H),2.83-2.71(m,4H),2.37(q,J＝5.9Hz,2H),2.11(m,6H),1.92(d,J＝4.0Hz,12H),1.77(t,J＝4.1Hz,12H),1.08(t,J＝s,3H).LRMS calcd for C44H54N4O4[M+H]+703.42,found 703.43.
化合物10b分析数据：1H NMR(600MHz,DMSO-d6)δ11.32(s,1H),9.95(s,1H),7.48-7.45(m,2H),7.42(s,1H),7.23-7.18(m,3H),4.09(t,J＝7.6Hz,1H),3.95(t,J＝6.7Hz,1H),2.69(t,J＝6.8Hz,1H),2.47(t,J＝7.8Hz,1H),2.08(s,3H),1.87(t,J＝3.7Hz,6H),1.75(s,6H),1.03-1.01(m,1H),0.98(td,J＝7.5,1.6Hz,2H).LRMS calcd for C25H31N3O3[M+H]+422.24,found 422.38.
化合物10c分析数据：1H NMR(600MHz,DMSO-d6)δ11.23(s,1H),9.93(s,1H),7.49-7.44(m,2H),7.40(s,1H),7.28-7.22(m,3H),4.07(t,J＝7.6Hz,1H),3.93(t,J＝6.7Hz,1H),2.67(t,J＝6.8Hz,1H),2.55(t,J＝7.8Hz,1H),2.05(s,3H),1.83(t,J＝3.7Hz,6H),1.73(s,6H),1.05-1.00(m,1H),0.96(td,J＝7.5,1.6Hz,2H).LRMS calcd for C25H31N3O3[M+H]+422.24,found 422.35.
实施例4：制备化合物12a、12b、12c
将等量5-氰基尿嘧啶11和1,8-二氮杂双环[5.4.0]十一碳-7-烯，过量化合物4溶于N,N-二甲基甲酰胺中，加热回流反应，通过TLC监测直至反应结束，加水淬灭反应，用二氯甲烷萃取水相3次，合并有机相，用无水硫酸钠干燥，减压旋蒸除去有机溶剂，通过快速柱层分离纯化得到化合物12a、12b、12c，总收率70％～80％。
化合物12a分析数据：1H NMR(600MHz,DMSO-d6)δ9.84(s,1H),9.82(s,1H),7.62(d,J＝1.3Hz H),7.57-7.51(m,4H),7.32-7.26(m,4H),4.11-4.02(m,4H),2.83-2.70(m,4H),2.11-2.08(m,6H),1.92(d,J＝3.8Hz,12H),1.77-1.70(m,12H).LRMS calcd for C43H49N5O4[M+H]+700.39,found 700.37.
化合物12b分析数据：1H NMR(600MHz,DMSO-d6)δ9.90(s,1H),8.49(s,1H),7.56-7.37(m,2H),7.33-7.16(m,2H),4.05(t,J＝7.4Hz,2H),2.56(t,J＝7.4Hz,2H),2.04(p,J＝3.3Hz,3H),1.83(d,J＝3.0Hz,6H),1.73-1.71(m,6H).LRMS calcd for C24H26N4O3[M+H]+419.21,found 419.24.
化合物12c分析数据：1H NMR(600MHz,DMSO-d6)δ9.89(s,1H),8.51(s,1H),7.54-7.39(m,2H),7.35-7.12(m,2H),4.08(t,J＝6.9Hz,2H),2.58(t,J＝7.4Hz,2H),2.08(p,J＝3.3Hz,3H),1.89(d,J＝3.0Hz,6H),1.75-1.73(m,6H).LRMS calcd for C24H26N4O3[M+H]+419.21,found 419.22.
实施例5：制备化合物14a、14b、14c
将等量5-甲氧基尿嘧啶13和1,8-二氮杂双环[5.4.0]十一碳-7-烯、过量化合物4溶于N,N-二甲基甲酰胺中，加热回流反应，通过TLC监测直至反应结束，加水淬灭反应，用二氯甲烷萃取水相3次，合并有机相，用无水硫酸钠干燥，减压旋蒸除去有机溶剂，通过快速柱层分离纯化得到化合物14a、14b、14c，总收率65％～75％。
化合物14a分析数据：1H NMR(600MHz,DMSO-d6)δ11.40(s,2H),7.55-7.47(m,4H),7.32(s,1H),7.30-7.26(m,4H),3.94(t,J＝6.8Hz,4H),3.58(s,3H),2.70(t,J＝6.0Hz,4H),2.10-1.96(m,6H),1.85(d,J＝3.8Hz,12H),1.79-1.67(m,12H).LRMS calcd forC43H52N4O5[M+H]+705.40,found 705.41.化合物14b分析数据：1H NMR(600MHz,DMSO-d6)δ10.77(d,J＝6.0Hz,1H),9.89(s,1H),7.51-7.41(m,2H),7.31-7.21(m,2H),7.14-6.98(m,1H),4.06(t,J＝7.6Hz,2H),3.61(d,J＝1.7Hz,3H),2.55(t,J＝7.6Hz,2H),2.05(s,3H),1.83(d,J＝3.0Hz,6H),1.73(d,J＝4.3Hz,6H).LRMS calcd for C24H29N3O4[M+H]+424.22,found 424.34.
化合物14c分析数据：1H NMR(600MHz,DMSO-d6)δ11.43(s,1H),9.95(s,1H),7.56-7.44(m,2H),7.29(s,1H),7.29-7.24(m,2H),3.92(t,J＝6.8Hz,2H),3.55(s,3H),2.68(t,J＝6.8Hz,2H),2.09-1.99(m,3H),1.83(d,J＝3.0Hz,6H),1.78-1.66(m,6H).LRMS calcdfor C24H29N3O4[M+H]+424.22,found424.36.
实施例6：制备化合物16a、16b、16c
将等量5-氯尿嘧啶15和1,8-二氮杂双环[5.4.0]十一碳-7-烯，过量化合物4溶于N,N-二甲基甲酰胺中，加热回流反应，通过TLC监测直至反应结束，加水淬灭反应，用二氯甲烷萃取水相3次，合并有机相，用无水硫酸钠干燥，减压旋蒸除去有机溶剂，通过快速柱层分离纯化得到化合物16a、,16b、16c，总收率70％～75％。
化合物16a分析数据：1H NMR(600MHz,DMSO-d6)δ11.48(s,2H),7.92(s,1H),7.50(d,J＝6.8Hz,4H),7.24(d,J＝8.8Hz,4H),4.12(t,J＝8.5Hz,4H),2.59(t,J＝5.5Hz,4H),2.07-2.03(m,6H),1.84(d,J＝4.0Hz,12H),1.75-1.66(m,12H).LRMS calcd forC42H49ClN4O4[M+H]+709.35,found 709.37.
化合物16b分析数据：1H NMR(600MHz,DMSO-d6)δ11.56(s,1H),9.91(s,1H),7.92(s,1H),7.47(d,J＝8.6Hz,2H),7.26(d,J＝8.6Hz,2H),4.09(t,J＝7.5Hz,2H),2.56(t,J＝7.5Hz,2H),2.06-2.02(m,3H),1.83(d,J＝3.0Hz,6H),1.73(d,J＝3.8Hz,6H).LRMS calcdfor C23H26ClN3O3[M+H]+428.17,found 428.16.
化合物16c分析数据：1H NMR(600MHz,DMSO-d6)δ11.52(s,1H),9.94(s,1H),7.94(s,1H),7.50(d,J＝7.2Hz,2H),7.29(d,J＝8.0Hz,2H),4.05(t,J＝7.1Hz,2H),2.59(t,J＝6.5Hz,2H),2.09-2.01(m,3H),1.85(d,J＝2.8Hz,6H),1.75(d,J＝3.9Hz,6H).LRMS calcdfor C23H26ClN3O3[M+H]+428.17,found 428.19.
实施例7：制备化合物16a、16b、16c
将等量5-溴尿嘧啶17和1,8-二氮杂双环[5.4.0]十一碳-7-烯，过量化合物4溶于N,N-二甲基甲酰胺中，加热回流反应，通过TLC监测直至反应结束，加水淬灭反应，用二氯甲烷萃取水相3次，合并有机相，用无水硫酸钠干燥，减压旋蒸除去有机溶剂，通过快速柱层分离纯化得到化合物18a、18b、18c，总收率70％～80％。
化合物18a分析数据：1H NMR(600MHz,DMSO-d6)δ11.50(s,2H),7.98(s,1H),7.49(d,J＝2.8Hz,4H),7.48(s,4H),4.11(t,J＝5.2Hz,4H),2.58(t,J＝5.8Hz,4H),2.04(s,6H),1.84(d,J＝3.2Hz,12H),1.75(s,12H).LRMS calcd for C23H26BrN3O3[M+H]+753.30,found 753.32.
化合物18b分析数据：1H NMR(600MHz,DMSO-d6)δ11.60(s,1H),9.93(s,1H),7.99(s,1H),7.47(d,J＝2.1Hz,2H),7.45(s,2H),4.09(t,J＝7.4Hz,2H),2.56(t,J＝7.5Hz,2H),2.04(s,3H),1.83(d,J＝2.9Hz,6H),1.72(s,6H).LRMS calcd for C23H26BrN3O3[M+H]+472.12,found 472.16.
化合物18c分析数据：1H NMR(600MHz,DMSO-d6)δ11.58(s,1H),9.91(s,1H),7.97(s,1H),7.48(d,J＝2.4Hz,2H),7.44(s,2H),4.07(t,J＝6.3Hz,2H),2.59(t,J＝6.0Hz,2H),2.06(s,3H),1.86(d,J＝2.0Hz,6H),1.75(s,6H).LRMS calcd for C23H26BrN3O3[M+H]+472.12,found 472.14.
实施例8：制备化合物20a、20b、20c
将等量5-碘尿嘧啶19和1,8-二氮杂双环[5.4.0]十一碳-7-烯，过量化合物4溶于N,N-二甲基甲酰胺中，加热回流反应，通过TLC监测直至反应结束，加水淬灭反应，用二氯甲烷萃取水相3次，合并有机相，用无水硫酸钠干燥，减压旋蒸除去有机溶剂，通过快速柱层分离纯化得到化合物20a、20b、20c，总收率70％～75％。
化合物20a分析数据：1H NMR(600MHz,DMSO-d6)δ9.90(d,J＝39.5Hz,2H),7.66(d,J＝7.9Hz,1H),7.51-7.43(m,4H),7.28-7.22(m,4H),4.09(t,J＝7.6Hz,2H),4.00(t,J＝6.6Hz,2H),2.71(t,J＝6.6Hz,2H),2.55(t,J＝7.7Hz,2H),2.03(d,J＝4.3Hz,6H),1.85-1.79(m,12H),1.71(q,J＝11.8Hz,12H).LRMS calcd for C42H49IN4O4[M+H]+801.29,found801.28.
化合物20b分析数据：1H NMR(600MHz,DMSO-d6)δ11.25(d,J＝2.3Hz,1H),9.94(s,1H),7.58(d,J＝7.8Hz,1H),7.49-7.43(m,2H),7.29-7.21(m,2H),3.93(t,J＝6.5Hz,2H),2.69(t,J＝6.6Hz,2H),2.05-2.00(m,3H),1.82(d,J＝3.1Hz,6H),1.74-1.69(m,6H).LRMScalcd for C23H26IN3O3[M+Na]+542.09,found 542.06.
化合物20c分析数据：1H NMR(600MHz,DMSO-d6)δ11.12(d,J＝5.4Hz,1H),9.87(s,1H),7.48-7.44(m,2H),7.42(dd,J＝7.5,5.8Hz,1H),7.25(d,J＝8.6Hz,2H),4.08-3.98(m,2H),2.57-2.51(m,2H),2.03(s,3H),1.82(d,J＝2.2Hz,6H),1.74-1.68(m,6H).LRMS calcdfor C23H26IN3O3[M+Na]+542.09,found 542.07.
实施例9：制备化合物22
将等量腺嘌呤21和1,8-二氮杂双环[5.4.0]十一碳-7-烯，过量化合物4溶于N,N-二甲基甲酰胺中，加热回流反应，通过TLC监测直至反应结束，加水淬灭反应，用二氯甲烷萃取水相3次，合并有机相，用无水硫酸钠干燥，减压旋蒸除去有机溶剂，通过快速柱层分离纯化得到化合物22，总收率65％～70％。
化合物22分析数据：1H NMR(DMSO-d6,600MHz)δ9.91(s,1H),8.16(s,1H),8.05(s,1H),7.48-7.22(m,2H),7.17(s,2H),4.43(t,J＝6.7Hz,2H),2.92(t,J＝6.7Hz,2H),2.03(q,J＝3.2Hz,3H),1.82(d,J＝3.0Hz,6H),1.73-1.69(m,6H).LRMS calcd for C24H28N6O[M+H]+417.24,found 417.27.
实施例10：制备化合物24
将等量胞嘧啶23和1,8-二氮杂双环[5.4.0]十一碳-7-烯，过量化合物4溶于N,N-二甲基甲酰胺中，加热回流反应，通过TLC监测直至反应结束，加水淬灭反应，用二氯甲烷萃取水相3次，合并有机相，用无水硫酸钠干燥，减压旋蒸除去有机溶剂，通过快速柱层分离纯化得到化合物24，总收率70％～75％。
化合物24分析数据：1H NMR(600MHz,DMSO-d6)δ9.90(d,J＝19.1Hz,1H),7.48(d,J＝8.4Hz,2H),7.25(dd,J＝8.8,3.2Hz,2H),4.10(t,J＝7.5Hz,1H),4.01(t,J＝6.5Hz,1H),2.72(t,J＝6.5Hz,1H),2.56(t,J＝7.6Hz,1H),2.03(s,3H),1.81(d,J＝3.0Hz,6H),1.71(d,J＝3.7Hz,6H).LRMS calcd for C23H28N4O2[M+Na]+415.21,found 415.20.
实施例11：制备化合物26
将等量鸟嘌呤25和1,8-二氮杂双环[5.4.0]十一碳-7-烯，过量化合物4溶于N,N-二甲基甲酰胺中，加热回流反应，通过TLC监测直至反应结束，加水淬灭反应，用二氯甲烷萃取水相3次，合并有机相，用无水硫酸钠干燥，减压旋蒸除去有机溶剂，通过快速柱层分离纯化得到化合物26，总收率65％～70％。
化合物26分析数据：1H NMR(600MHz,DMSO-d6)δ9.62(d,J＝1.1Hz,2H),7.87(s,1H),7.56-7.49(m,2H),7.30-7.24(m,2H),6.04(d,J＝7.1Hz,1H),5.48(d,J＝7.1Hz,1H),4.39(t,J＝9.9Hz,2H),2.88-2.80(m,2H),2.18-2.04(m,3H),1.93(d,J＝8.0Hz,6H),1.78(t,J＝8.1Hz,6H).LRMS calcd for C24H28N6O2[M+H]+433.24,found 433.26.
以下通过实验例证明本发明的有益效果。
实验例1：化合物对鳞状细胞癌细胞的增殖抑制作用
1.实验方法
鳞状细胞癌细胞系：HSC-3，HSC-4。
以上2种肿瘤细胞系均在37度5％CO2的标准化培养箱中进行培养；取对数生长期的细胞进行消化，计数，以96孔板每孔3000个细胞的数量进行种板，于细胞培养箱中贴壁培养过夜；化合物用DMSO以10mM的浓度配置储存液，处理细胞之前依次稀释(0，1.25，2.5，5，10uM)，对照组按照最高浓度的DMSO含量添加；于细胞培养箱中连续培养48小时，用CCK8细胞增殖试剂盒进行测定，以此检测各个化合物对肿瘤细胞增殖能力的影响。同时，针对代表性化合物的实验结果进行分析，计算其IC50值，从而评估化合物对肿瘤细胞增殖影响。
2.实验结果
如图1-9所示，本发明化合物对鳞状细胞癌细胞的增殖有明显的抑制作用。其中，化合物6a对两种鳞状细胞癌细胞的IC50值分别为：6.202uM，9.834uM(图1)；化合物8a对两种鳞状细胞癌细胞的IC50值分别为：4.848uM，9.868uM(图2)；化合物10a对鳞状细胞癌细胞的IC50值为：6.183uM(图3)；化合物12a对鳞状细胞癌细胞的IC50值为：9.543uM(图4)；化合物14a对鳞状细胞癌细胞的IC50值为：6.178uM(图5)；化合物16a对鳞状细胞癌细胞的IC50值为：9.664uM(图6)；化合物18a对鳞状细胞癌细胞的IC50值为：4.848uM(图7)；化合物20a对鳞状细胞癌细胞的IC50值为：4.861uM(图8)；化合物22、24对鳞状细胞癌细胞的IC50值分别为：2.133uM、1.475uM(图9)。
上述实验结果表明，本发明提供的化合物能够有效抑制鳞状细胞癌细胞的增殖，可以用于制备治疗鳞状细胞癌的药物。

Claims (14)

1.式I所示化合物、其药学上可接受的盐、其立体异构体：
其中，A环选自氮杂稠环或5～6元不饱和氮杂环；
b选自0～6的整数；
R0各自独立地选自＝O、＝S、氢、氨基、卤素、C1-6烷基、C1-6烷氧基、羟基、羧基、氰基、烷胺基、杂环取代烷基、芳香环取代烷基；
m选自1-3的整数，n选自0-5的整数，R7、R8、R9、R10各自独立地选自氢、氨基、卤素、C1-6烷基、C1-6烷氧基、卤素、羟基、羧基。
2.根据权利要求1所述的化合物、其药学上可接受的盐、其立体异构体，其特征在于：所述化合物的结构如式II所示：
其中，表示-或＝；
R1为无、氢或R2为氢或且R1为无或氢时，R2不为氢；
n选自0-3的整数，R7、R8、R9、R10各自独立地选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、卤素、羟基、羧基；
R3选自＝O、＝S、氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基；
R4选自＝O、＝S、氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基；
且R3和R4中至少一个为＝O或＝S；
R5选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基、氰基、烷胺基、杂环取代烷基、芳香环取代烷基；
R6选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基。
3.根据权利要求2所述的化合物、其药学上可接受的盐、其立体异构体，其特征在于：所述化合物的结构如式II-x所示：
其中，R5选自氢、氨基、卤素、C1-2烷基、C1-2烷氧基、羟基、羧基、氰基、烷胺基、杂环取代烷基、芳香环取代烷基；
R1为氢或R2为氢或且R1和R2不同时为氢；n选自0-3的整数，R7、R8、R9、R10各自独立地选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、卤素、羟基、羧基。
4.根据权利要求3所述的化合物、其药学上可接受的盐、其立体异构体，其特征在于：所述化合物的结构如式II-a或式II-b所示：
其中，R1为氢或R2为氢或且R1和R2不同时为氢；n选自0-3的整数，R7、R8、R9、R10各自独立地选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、卤素、羟基、羧基。
5.根据权利要求2所述的化合物、其药学上可接受的盐、其立体异构体，其特征在于：所述化合物的结构如式II-c或式II-d所示：
其中，R1为R2为n选自0-3的整数，R7、R8、R9、R10各自独立地选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、卤素、羟基、羧基；
R4选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基。
6.根据权利要求1所述的化合物、其药学上可接受的盐、其立体异构体，其特征在于：所述化合物的结构如式III-a或式III-b所示：
其中，表示-或＝；
R14为无、氢或R15为氢或且R14为无或氢时，R15不为氢；
n选自0-3的整数，R7、R8、R9、R10各自独立地选自氢、C1-4烷基、C1-4烷氧基、卤素、羟基、羧基；
R11选自＝O、＝S、氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基；
R12选自＝O、＝S、氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基；
R13选自氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基。
7.根据权利要求1所述的化合物、其药学上可接受的盐、其立体异构体，其特征在于：所述化合物的结构如式III-c或式III-d所示：
其中，R14为n选自0-3的整数，R7、R8、R9、R10各自独立地选自氢、C1-4烷基、C1-4烷氧基、卤素、羟基、羧基；
R11选自＝O、＝S、氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基；
R12选自＝O、＝S、氢、氨基、卤素、C1-4烷基、C1-4烷氧基、羟基、羧基。
8.根据权利要求1所述的化合物、其药学上可接受的盐、其立体异构体，其特征在于：所述化合物为以下化合物之一：
9.一种抗肿瘤的药物组合物，其特征在于：它是以权利要求1-8任一项所述化合物为活性成分，加上药学上可接受的辅料制备而成的制剂。
10.权利要求1-8任一项所述化合物在制备抗肿瘤的药物中的用途。
11.根据权利要求10所述的用途，其特征在于：所述肿瘤为鳞状细胞癌。
12.根据权利要求11所述的用途，其特征在于：所述鳞状细胞癌为头颈部鳞状细胞癌。
13.根据权利要求12所述的用途，其特征在于：所述头颈部鳞状细胞癌为口腔鳞状细胞癌。
14.根据权利要求13所述的用途，其特征在于：所述口腔鳞状细胞癌为舌鳞状细胞癌。
CN202410034758.0A 2023-01-10 2024-01-09 一种新型杂环化合物及其制备方法和用途 Pending CN117986195A (zh)

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