CN112724109A - 倍半萜内酯氮甲基哌嗪衍生物及其盐,及其在药物制备中的用途 - Google Patents
倍半萜内酯氮甲基哌嗪衍生物及其盐,及其在药物制备中的用途 Download PDFInfo
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- CN112724109A CN112724109A CN201911031855.XA CN201911031855A CN112724109A CN 112724109 A CN112724109 A CN 112724109A CN 201911031855 A CN201911031855 A CN 201911031855A CN 112724109 A CN112724109 A CN 112724109A
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Abstract
Description
技术领域
本发明属于药物技术领域,具体地说,本发明涉及倍半萜内酯氮甲基哌嗪衍生物及其药学上可接受的盐,以及它们在药物制备中的用途。
背景技术
倍半萜内酯是菊科植物的特征化合物和主要药效成分,具有显著的生物学和药理学活性,如抗癌、抗炎和抗痢疾作用等,是当今学者研究的热点问题之一。例如:小白菊内酯(Parthenolide,PTL)是倍半萜内酯化合物,从中药野生甘菊中提取,原本用来治疗发热、偏头痛、炎症、类风湿性关节炎等疾病。近几年发现,小白菊内酯在多种肿瘤体内外实验中发挥强抗癌活性作用,如乳腺癌、结肠直肠癌、肝癌、肺癌等,并且对正常细胞具有较低的毒副作用。而含笑内酯同样具有抗乳腺癌、抗脑胶质瘤、抗风湿性关节炎等作用。一系列的药理研究表明该类化合物的关键药效团是α、β-不饱和羰基(酯)结构。但是由于常见的倍半萜内酯类化合物具有水溶性较差,生物利用率低,半衰期短等缺点。
本专利针对倍半萜内酯类化合物的上述缺点,通过和氮甲基哌嗪迈克尔加成反应、成盐反应得到一系列倍半萜类衍生物。该类衍生物具有缓释对应倍半萜内酯化合物的特点。
发明内容
本发明提供了一种如式(I)、(II)、(III)、(IV)所示的倍半萜内酯氮甲基哌嗪衍生物及其药学上可接受的盐,
所述的药学上可接受的盐是与无机酸或有机酸形成的盐,包括氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、磷酸、硝酸、亚磷酸、亚硫酸、碳酸、硼酸、磷钼酸、亚硒酸、甲基磺酸、取代甲基磺酸、苯基磺酸、取代苯基磺酸、富马酸、柠檬酸、马来酸、酒石酸、草酸、D-苹果酸、L-苹果酸、DL-苹果酸、L-乳酸、D-乳酸、DL-乳酸、甲酸、取代甲酸、乙酸、丙酸、丁酸、戊酸、油酸、月桂酸、对甲基苯磺酸、1-萘磺酸、2-萘磺酸、酞酸、丙二酸、丁二酸、乙醇酸、硫醇酸、甘氨酸、肌氨酸、磺酸、烟酸、甲基吡啶酸、异烟酸、二氯乙酸、苯甲酸、取代苯甲酸。其中,与富马酸形成的盐如式(V)、(VI)、(VII)、(VIII)所示:
所述式(I)、(II)、(III)、(IV)及其盐可缓慢释放相应的倍半萜内酯。
所述式(I)、(II)、(III)、(IV)化合物及其盐在制备治疗癌症的药物中的用途,其中癌症优选为白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴癌、胰腺癌、直肠结肠癌、子官颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤。
所述式(I)、(II)、(III)、(IV)化合物及其盐在制备治疗癌症的辅助药物中的用途,其中癌症优选为白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴癌、胰腺癌、直肠结肠癌、子官颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤。
一种用于治疗癌症的药物组合物,所述药物组合物含有有效量的式(I)、(II)、(III)、(IV)化合物及其盐和药学上可接受的载体或其他抗癌药物,其中癌症优选白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴癌、胰腺癌、直肠结肠癌、子官颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤。
附图说明
图1式(I)化合物及其富马酸盐(V)制备
图2式(II)化合物及其富马酸盐(VI)的制备
图3式(III)化合物及其富马酸盐(VII)的制备
图4式(IV)化合物及其富马酸盐(VIII)的制备
图5式(I)化合物在HEPES溶液中释放趋势图
图6 DMA.MCL在HEPES溶液中释放趋势图
具体实施方式
本发明提供了一种如式(I)、(II)、(III)、(IV)所示的倍半萜内酯氮甲基哌嗪衍生物及其药学上可接受的盐,
所述的药学上可接受的盐是与无机酸或有机酸形成的盐,包括氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、磷酸、硝酸、亚磷酸、亚硫酸、碳酸、硼酸、磷钼酸、亚硒酸、甲基磺酸、取代甲基磺酸、苯基磺酸、取代苯基磺酸、富马酸、柠檬酸、马来酸、酒石酸、草酸、D-苹果酸、L-苹果酸、DL-苹果酸、L-乳酸、D-乳酸、DL-乳酸、甲酸、取代甲酸、乙酸、丙酸、丁酸、戊酸、油酸、月桂酸、对甲基苯磺酸、1-萘磺酸、2-萘磺酸、酞酸、丙二酸、丁二酸、乙醇酸、硫醇酸、甘氨酸、肌氨酸、磺酸、烟酸、甲基吡啶酸、异烟酸、二氯乙酸、苯甲酸、取代苯甲酸。其中,与富马酸形成的盐如式(V)、(VI)、(VII)、(VIII)所示:
所述式(I)、(II)、(III)、(IV)及其盐可缓慢释放相应的倍半萜内酯。
所述式(I)、(II)、(III)、(IV)化合物及其盐在制备治疗癌症的药物中的用途,其中癌症优选为白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴癌、胰腺癌、直肠结肠癌、子官颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤。
所述式(I)、(II)、(III)、(IV)化合物及其盐在制备治疗癌症的辅助药物中的用途,其中癌症优选为白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴癌、胰腺癌、直肠结肠癌、子官颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤。
一种用于治疗癌症的药物组合物,所述药物组合物含有有效量的式(I)、(II)、(III)、(IV)化合物及其盐和药学上可接受的载体或其他抗癌药物,其中癌症优选白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴癌、胰腺癌、直肠结肠癌、子官颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤
为了理解本发明,下面以实施例进一步说明本发明,但不限制本发明。
实施例1:式(I)化合物及其富马酸盐(V)制备
室温下,将含笑内酯(Micheliolide,MCL)(124mg,0.5mmol)和碳酸钾(2.1g,15mmol)依次加入反应瓶中,随后加入5毫升二氯甲烷作为溶剂,室温下加入氮甲基哌嗪(751mg,7.5mmol)。室温搅拌2小时后,TLC监测反应完成。砂芯漏斗过滤反应液,少量二氯甲烷(2毫升)洗涤滤饼,得到滤液。向滤液中加入5毫升饱和氯化钠,分液,收集有机相,无水硫酸钠干燥,过滤,浓缩得到粗品。柱层析分离(二氯甲烷:甲醇=10:1)得到白色迈克尔加成产物(产率:65%)。1H NMR(400MHz,DMSO-d6):δ=4.25(s,1H),3.72(t,J=10.2Hz,1H),2.63-2.46(m,4H),2.4-2.15(m,7H),2.10-1.97(m,7H),1.95-1.84(m,2H),1.60-1.50(m,5H),1.25-1.07(m,5H).13C NMR(100MHz,CDCl3)δ=177.50,133.12,130.76,82.54,79.53,57.53,56.73,54.99,54.74,51.72,45.76,43.21,40.36,34.90,29.58,26.66,23.60,22.62.HRMS(ESI):m/z[M+H]+calcd for C20H33N2O3:349.2491;found:?.室温下,将迈克尔加成产物(55mg,0.16mmol)溶于丙酮(2mL)中,然后加入富马酸(18.6mg,0.16mmol)。室温搅拌2个小时以后有白色固体析出。砂芯漏斗抽滤,乙酸乙酯洗涤滤饼得到化合物(I)(产率:57%)。1H NMR(400MHz,D2O):δ=1H NMR(400MHz,D2O)δ6.71(s,2H),4.11(t,J=10.3Hz,2H),3.41(s,3H),3.16-2.99(m,4H),2.99-2.89(m,4H),2.85-2.77(m,1H),2.70(d,J=10.2Hz,1H),2.43(dd,J=16.4,8.1Hz,1H),2.30-2.09(m,6H),1.98-1.95(m,1H),1.84-1.74(m,1H),1.71(s,3H),1.42–1.38(m,1H),1.31(s,3H).;13C NMR(100MHz,DMSO-d6)δ=177.43,167.09,162.41,134.66,133.14,130.77,82.61,79.55,57.51,56.03,53.57,51.42,44.05,43.48,40.37,35.88,34.90,29.60,26.62,23.63,22.64..HRMS(ESI):m/z[M+H]+calcd for C20H33N2O3:349.2491;found:349.2494.
实施例2:式(II)化合物及其富马酸盐(VI)的制备
室温下,将小白菊内酯(Parthenolide,PTL)(124mg,0.5mmol)和碳酸钾(2.1g,15mmol)依次加入反应瓶中,随后加入5毫升二氯甲烷作为溶剂,室温下加入氮甲基哌嗪(751mg,7.5mmol)。室温搅拌2小时后,TLC监测反应完成。砂芯漏斗过滤反应液,少量二氯甲烷(2毫升)洗涤滤饼,得到滤液。向滤液中加入5毫升饱和氯化钠,分液,收集有机相,无水硫酸钠干燥,过滤,浓缩得到粗品。柱层析分离(二氯甲烷:甲醇=10:1)得到白色迈克尔加成产物(产率:71%)。1H NMR(400MHz,DMSO-d6):δ=5.17(d,J=10.1Hz,1H),3.92(t,J=9.1Hz,1H),2.75(d,J=9.1Hz,1H),2.65-2.53(m,3H),2.50-2.45(m,1H),2.45-2.14(m,9H),2.13-2.07(m,4H),2.05-1.89(m,4H),1.64-1.53(m,4H),1.19-1.04(m,4H).13C NMR(100MHz,DMSO-d6)δ=176.91,134.65,124.27,81.66,65.70,61.19,56.51,54.87,53.24,47.59,45.81,44.99,40.67,36.22,28.99,23.71,16.93,16.83.HRMS(ESI):m/z[M+H]+calcd for C20H33N2O3:349.2491;found:?.室温下,将迈克尔加成产物(53mg,0.15mmol)溶于丙酮(2mL)中,然后加入富马酸(18mg,0.15mmol)。室温搅拌2个小时以后有白色固体析出。砂芯漏斗抽滤,乙酸乙酯洗涤滤饼得到化合物(II)(产率:84%)。1H NMR(400MHz,DMSO-d6):δ=6.57(s,3H),5.21(d,J=10.3Hz,1H),3.97(t,J=9.1Hz,1H),2.97-2.76(m,4H),2.75-2.46(m,9H),2.42-2.28(m,1H),2.26-2.12(m,2H),2.10-1.86(m,5H),1.68-1.59(s,3H),1.20(s,2H),1.11(td,J=12.7,5.8Hz,1H);13C NMR(100MHz,DMSO-d6)δ=176.83,166.89,134.54,124.41,81.73,65.65,61.28,55.46,53.33,51.29,47.20,45.37,43.44,40.64,36.28,30.80,28.91,23.75,16.95,16.81.HRMS(ESI):m/z[M+Na]+calcd forC20H32N2NaO3:371.2311;found:371.2315.
实施例3:式(III)化合物及其富马酸盐(VII)的制备
室温下,将土木香内酯(Alantolactone)(0.5mmol)溶于2毫升二氯甲烷。然后分批次加入间氯过氧苯甲酸(m-CPBA,100mg,0.58mmol)。TLC检测反应完成后,加入饱和硫代硫酸钠溶液5毫升,然后用10毫升二氯甲烷萃取水相三遍。收集有机相,无水硫酸钠干燥,过滤,浓缩得到粗品。使用硅胶柱层析法过滤粗品(洗脱剂=石油醚/乙酸乙酯,比例:5:2)得到环氧化产物(产率88%).
室温下,将环氧化产物(124mg,0.5mmol)和碳酸钾(2.1g,15mmol)依次加入反应瓶中,随后加入5毫升二氯甲烷作为溶剂,室温下加入氮甲基哌嗪(751mg,7.5mmol)。室温搅拌2小时后,TLC监测反应完成。砂芯漏斗过滤反应液,少量二氯甲烷(2毫升)洗涤滤饼,得到滤液。向滤液中加入5毫升饱和氯化钠,分液,收集有机相,无水硫酸钠干燥,过滤,浓缩得到粗品。柱层析分离(二氯甲烷:甲醇=10:1)得到迈克尔加成产物(产率:62%)。1H NMR(400MHz,CDCl3):δ=4.62-4.57(m,1H),3.34(s,1H),3.21-3.15(m,2H),2.87-2.80(m,1H),2.78-2.65(m,3H),2.53-2.35(m,6H),2.30(s,3H),1.88-1.79(m,3H),1.59(dd,J=14.8,2.7Hz,1H),1.51-1.49(m,2H),1.44-1.41(m,2H),1.39-1.34(m,1H),1.19(s,3H),1.12(d,J=7.8Hz,3H);13C NMR(100MHz,CDCl3)δ=176.92,75.88,68.10,57.23,55.13,54.96,45.95,39.61,38.82,37.84,37.73,35.91,32.06,29.60,24.09,17.73,16.48.HRMS(ESI):m/z[M+H]+calcd for C20H33N2O3:349.2491;found:349.2495.
室温下,将迈克尔加成产物(173mg,0.5mmol)溶于丙酮(7mL)中,然后加入富马酸(58mg,0.5mmol)。室温搅拌2个小时以后有白色固体析出。砂芯漏斗抽滤,乙酸乙酯洗涤滤饼得到化合物(III)(产率56%)。1H NMR(400MHz,DMSO-d6):δ=6.58(s,2H),4.63-4.52(m,1H),3.46(d,J=4.9Hz,1H),3.17(s,1H),3.08(dd,J=10.1,8.0Hz,1H),2.95-2.70(m,6H),2.68-2.56(m,3H),2.54-2.48(m,2H),2.09(s,1H),1.82-1.62(m,3H),1.50-1.40(m,4H),1.32-1.20(m,2H),1.13-1.00(m,6H);13C NMR(100MHz,DMSO-d6)δ=176.57,166.72,134.39,75.03,67.28,56.59,54.20,53.24,43.58,38.81,38.48,37.49,37.32,35.21,31.60,30.68,29.34,23.72,17.49,16.13.HRMS(ESI):m/z[M+H]+calcd for C20H33N2O3:349.2491;found:349.2491.
实施例4:式(IV)化合物及其富马酸盐(VIII)的制备
在0℃下,将SeO2(38.17mg,0.344mmol)溶解在CH2Cl2(4mL)中,加入TBHP(0.172mL),30分钟后,将异土木香内酯(isoalantolactone)(232.15mg,1mmol)溶解在CH2Cl2(3mL)中缓慢的加入到上述体系中,反应体系在室温下搅拌24小时,TLC监测反应完之后,加入饱和硫代硫酸钠水溶液,用CH2Cl2萃取三次,有机相用无水硫酸镁干燥,减压浓缩,过硅胶色谱柱(石油醚/乙酸乙酯=5:1至2:1)得烯丙位氧化产物(产率50%)。1H NMR(400MHz,MeOD):δ=5.96(s,1H),5.60(s,1H),4.88(s,1H),4.51-4.44(m,2H),4.15(s,1H),3.08-2.97(m,1H),2.36(dd,J=12.5,1.5Hz,1H),2.04(dd,J=15.6,1.4Hz,1H),1.69-1.59(m,4H),1.53(dd,J=15.7,4.7Hz,1H),1.27-1.14(m,2H),0.70(s,3H).
室温下,将烯丙位氧化产物(125.3mg,0.5mmol)溶于CH2Cl2(2mL)中,分批加入m-CPBA(114.7mg,0.66mmol),反应体系在室温下搅拌2h,反应混合物用饱和硫代硫酸钠溶液淬灭,收集的有机相用饱和碳酸氢钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩得粗品。柱层析分离(石油醚/乙酸乙酯=1:1)得到环氧化产物(产率72%)。1H NMR(400MHz,CDCl3):δ=6.11(s,1H),5.56(s,1H),4.50(td,J=4.8,1.4Hz,1H),3.42(t,J=2.8Hz,1H),2.98-2.89(m,1H),2.80(d,J=4.0Hz,1H),2.64(d,J=4.0Hz,1H),2.37(s,1H),2.27(dd,J=13.2,2.4Hz,1H),2.20(dd,J=15.7,1.4Hz,1H),1.88-1.81(m,2H),1.74-1.64(m,1H),1.60-1.51(m,2H),1.40-1.33(m,1H),1.02-0.96(m,4H).
室温下,将环氧化产物(230mg,0.87mmol)和碳酸钾(3.6g,26mmol)依次加入反应瓶中,随后加入5毫升二氯甲烷作为溶剂,室温下加入氮甲基哌嗪(1.4mL,13mmol)。室温搅拌2小时后,TLC监测反应完成。砂芯漏斗过滤反应液,少量二氯甲烷(2毫升)洗涤滤饼,得到滤液。向滤液中加入5毫升饱和氯化钠,分液,收集有机相,无水硫酸钠干燥,过滤,浓缩得到粗品。柱层析分离(二氯甲烷:甲醇=10:1)得到迈克尔加成产物(产率:65%)。1H NMR(400MHz,CDCl3):δ=4.46(d,J=1.5Hz,1H),3.41(t,J=2.8Hz,1H),2.97-2.87(m,1H),2.80(d,J=4.1Hz,1H),2.73-2.69(m,1H),2.64-2.39(m,12H),2.28(s,4H),2.24-2.14(m,2H),1.84-1.83(m,1H),1.71-1.63(m,1H),1.56-1.51(m,2H),1.38-1.32(m,1H),0.95(s,3H),0.70(q,J=12.8Hz,1H).13C NMR(100MHz,CDCl3)δ=177.56,77.84,72.58,61.26,54.87,52.99,52.76,49.80,45.87,45.36,41.60,39.32,37.34,34.92,34.38,26.94,18.02,16.12.HRMS(ESI):m/z[M+H]+calcd for C20H33N2O4:365.2440;found:365.2441.
室温下,将迈克尔加成产物(233mg,mmol)溶于丙酮(8mL)中,然后加入富马酸(73mg,0.64mmol)。室温搅拌2个小时以后有白色固体析出。砂芯漏斗抽滤,乙酸乙酯洗涤滤饼得到化合物(IV)(产率:56%)。1H NMR(400MHz,DMSO-d6):δ=6.57(s,2H),4.48(s,1H),3.16-3.12(m,1H),2.77-2.47(m,13H),2.09(s,4H),1.98-1.94(m,1H),1.78-1.70(m,1H),1.63-1.53(m,2H),1.49(dd,J=15.4,4.0Hz,1H),1.34-1.16(m,3H),0.84(s,3H),0.76-0.57(m,1H);13C NMR(100MHz,DMSO-d6)δ=177.80,167.27,134.91,77.95,71.54,61.34,53.72,52.79,48.45,44.51,44.10,41.78,38.86,37.25,35.18,34.72,31.16,28.15,18.40,15.90.HRMS(ESI):m/z[M+H]+calcd for C20H33N2O4:365.2440;found:365.2443.
实施例5:式(I)化合物与DMA.MCL释放MCL比较试验
式(I)化合物在HEPES溶液中的释放试验:
溶液配制:
HEPES缓冲溶液(浓度:10mmol/L):称取4-(2-羟乙基)哌嗪-1-乙磺酸(HEPES)237.9mg,加入新鲜的纯水,定容至100ml。用1mol/L的氢氧化钠溶液调至pH=7.4,即得。
式(V)化合物溶液:称取式(V)化合物24.40mg,置50ml量瓶中,用流动相A溶解并稀释至刻度,摇匀,即得。
试验步骤:
准确量取式(I)化合物溶液20μl,至PE管中,加入HEPES缓冲溶液980μl,混匀,立即放入37℃水浴中,分别于0、0.5、1、2、4、6、8、24小时时取样,测定。
实验仪器:
METTLER TOLEDO NewClassicMS电子天平;Waters高效液相色谱仪:AllianceWaters e2695 Separations Module、2998 PDA Detector检测器、Waters Empowers 3色谱工作站。
色谱条件:
梯度:
进样量:20μl。
试验结果:
式(I)化合物在HEPES溶液中释放趋势图见说明书附图图5。
DMA.MCL在HEPES溶液中的释放试验:
溶液配制:
HEPES缓冲溶液(浓度:10mmol/L):
称取4-(2-羟乙基)哌嗪-1-乙磺酸(HEPES)237.9mg,加入新鲜的纯水,定容至100ml。用1mol/L的氢氧化钠溶液调至pH=7.4,即得。
ACT001溶液:
称取ACT001(批号:20170901)21.88mg,置50ml量瓶中,用流动相A溶解并稀释至刻度,摇匀,即得。
试验步骤:准确量取ACT001溶液20μl,至PE管中,加入HEPES缓冲溶液980μl,混匀,立即放入37℃水浴中,分别于0、0.5、1、2、4、6、8、24小时时取样,测定。
实验仪器:METTLER TOLEDO NewClassic MS电子天平;Waters高效液相色谱仪:Alliance Waters e2695 Separations Module、2998 PDA Detector检测器、WatersEmpowers 3色谱工作站。
色谱条件:
梯度:
进样量:20μl。
试验结果:
DMA.MCL在HEPES溶液中释放趋势图见说明书附图图6。
本发明提供的(I)化合物释放MCL比DMA.MCL释放MCL的速度更慢。
实施例6:生物活性评价
细胞按常规方法进行复苏,传代:从液氮中取出冻存管,37℃水浴使冻存液融化,600~800r/min离心5min,弃上清液,U118MG的培养液为DMEM,用完全培养基重悬细胞,37℃、5%CO2环境下培养。
待细胞铺满培养皿底部70~80%时,吸弃培养液,用PBS缓冲液5~10ml清洗后加入0.25%胰酶1~2ml(能够铺满瓶底即可)消化,在培养箱中放置一段时间直至细胞变圆,立即加入完全培养基终止消化,合并消化细胞悬液,1000rpm/min离心5min,弃去上清,用完全培养基重悬细胞,轻轻吹散细胞,计数,定容到3000个cell/孔,每孔95μL,接种到96孔板中。
接种细胞后隔天加药,每个板分为空白组、阴性对照组和10个药物组,每个组6个复孔,每孔加药10μL,孵育72h,药物终浓度详见excel。孵育到相应时间,向每孔加入10μLCCK-8溶液(注意不要在孔中生成气泡,它们会影响OD值的读数),培养箱内孵育1-4h,酶标仪测定在450nm处的OD值,计算IC50。数据用EXCEL软件处理求解不同浓度下的抑制率,SPSS拟合IC50值。
抑制率%={1-(药物孔OD值-空白孔OD值)/(对照孔OD值-空白孔OD值)}*100%
实验结果:
本发明的用途和方法已经通过具体的实施例进行了描述。本领域技术人员可以借鉴本发明的内容适当改变原料、工艺条件等环节来实现相应的其它目的,其相关改变都没有脱离本发明的内容,所有类似的替换和改动对于本领域技术人员来说是显而易见的,都被视为包括在本发明的范围之内。
Claims (6)
2.根据权利要求1所述的药学上可接受的盐是与无机酸或有机酸形成的盐,包括氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、磷酸、硝酸、亚磷酸、亚硫酸、碳酸、硼酸、磷钼酸、亚硒酸、甲基磺酸、取代甲基磺酸、苯基磺酸、取代苯基磺酸、富马酸、柠檬酸、马来酸、酒石酸、草酸、D-苹果酸、L-苹果酸、DL-苹果酸、L-乳酸、D-乳酸、DL-乳酸、甲酸、取代甲酸、乙酸、丙酸、丁酸、戊酸、油酸、月桂酸、对甲基苯磺酸、1-萘磺酸、2-萘磺酸、酞酸、丙二酸、丁二酸、乙醇酸、硫醇酸、甘氨酸、肌氨酸、磺酸、烟酸、甲基吡啶酸、异烟酸、二氯乙酸、苯甲酸、取代苯甲酸。
3.根据权利要求1所述的化合物可缓慢释放相应的倍半萜内酯。
4.根据权利要求1所述的化合物在制备治疗癌症的药物中的用途,其中癌症优选为白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴癌、胰腺癌、直肠结肠癌、子官颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤。
5.根据权利要求1所述的化合物在制备治疗癌症的辅助药物中的用途,其中癌症优选为白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴癌、胰腺癌、直肠结肠癌、子官颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤。
6.一种用于治疗癌症的药物组合物,所述药物组合物含有有效量的权利要求1所述的化合物和药学上可接受的载体或其他抗癌药物,其中癌症优选白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴癌、胰腺癌、直肠结肠癌、子官颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤。
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CN114773356A (zh) * | 2022-05-16 | 2022-07-22 | 天津济坤医药科技有限公司 | 一种倍半萜衍生物、其药物组合物及其制备方法和用途 |
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CN114736214B (zh) * | 2022-05-16 | 2024-04-09 | 天津济坤医药科技有限公司 | 一种倍半萜衍生物、其药物组合物及其制备方法和用途 |
CN116925094A (zh) * | 2023-06-14 | 2023-10-24 | 深圳市第二人民医院(深圳市转化医学研究院) | 松香烷内酯型二萜化合物对映体的制备方法和应用 |
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