CN115353534B - 一种秋水仙碱衍生物及其制备和其应用 - Google Patents
一种秋水仙碱衍生物及其制备和其应用 Download PDFInfo
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- CN115353534B CN115353534B CN202111660642.0A CN202111660642A CN115353534B CN 115353534 B CN115353534 B CN 115353534B CN 202111660642 A CN202111660642 A CN 202111660642A CN 115353534 B CN115353534 B CN 115353534B
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Abstract
本发明提供了新的式Ⅳ所示结构的化合物或其衍生物,
Description
技术领域
本发明属于医药技术领域,具体涉及一种秋水仙碱衍生物及其制备和其应用。
背景技术
恶性肿瘤是威胁人类生命与健康的严重疾病。全球癌症数据库2020年度报告显示,2020年全球新发癌症病例1929万例,死亡996万例。中国新发癌症病例457万例,死亡300万例,中国新发癌症人数位居全球第一。为此,研究开发防治肿瘤的创新药物以满足临床需求。
秋水仙碱(Colchicum)是从百合科植物秋水仙的种子和鳞茎中提取分离制得的天然生物碱,是人类最早发现的微管蛋白聚合抑制剂,具有抗肿瘤、抗炎等多种生物活性,对多种肿瘤细胞有很强的抑制活性,临床上主要用于治疗痛风、家族性地中海热、白塞氏综合征等疾病。但秋水仙碱的毒性较大,治疗安全窗较窄,临床上未将其用于治疗癌症。为了给全球肿瘤患者提供更多安全、有效的抗肿瘤药物,需对秋水仙碱进行结构修饰,以获得对肿瘤细胞增殖抑制活性好、对正常细胞影响小,具有优异地抗肿瘤选择性和靶向性的创新药物。
发明内容
本发明的目的在于提供式Ⅳ所示结构的化合物或其衍生物,
其中,
当X为CH2时,n选自0~10,
当X为S时,n选自1~2,
当X为O时,n选自1,
R选自葡萄糖、甘露糖、半乳糖、鼠李糖、异鼠李糖、岩藻糖、橄榄霉糖、毛地黄毒糖、加拿大麻糖、阿拉伯糖、果糖、山梨糖、塔格糖、戊酮糖、丁酮糖、阿洛糖、阿卓糖、古洛糖、艾杜糖、核糖、木糖、来苏糖、苏糖、赤藓糖、氨基葡萄糖、氨基甘露糖、柔红霉糖的任一种或其带有苄基、酯基、缩酮、硅基保护基的衍生物,
或者选自
的任一种,
其中,R1~R4各自独立地选自氢、苄基、酯基、缩酮、硅基保护基的任一种。
本发明的优选技术方案中,当X为CH2时,n选自1~5,
R选自的任一种,
其中,R1~R4各自独立地选自氢、苄基、缩酮、三乙基硅基的任一种。
本发明的优选技术方案中,当X为CH2时,n选自1~5,
R选自 的任一种。
本发明的优选技术方案中,当X为S时,n选自1~2,
R选自的任一种,
其中,R1~R4各自独立地选自氢、苄基、缩酮、三乙基硅基的任一种。
本发明的优选技术方案中,当X为S时,n选自1~2,
R选自 的任一种。
本发明的优选技术方案中,当X为O时,n选自1,
R选自的任一种,
其中,R1~R4各自独立地为氢、苄基、缩酮、三乙基硅基的任一种。
本发明的优选技术方案中,当X为O时,n选自1,
R选自 的任一种。
本发明优选的技术方案中,所述衍生物选自式Ⅳ所示结构的化合物的药学上可接受的盐、酯、溶剂化物、立体异构体的任一种或其组合。
本发明优选的技术方案中,所述溶剂化物为水合物,优选结晶水为0~16中的任意实数,更优选为1~10,优选为1~5。
本发明优选的技术方案中,式Ⅳ所示结构的化合物或其衍生物选自下述化合物的任一种,
本发明的另一目的在于提供式Ⅳ所示化合物的制备方法,包括下述步骤:
其中,
当X为CH2时,n为0~10,n优选为1~5;
当X为S时,n为1~2;
当X为O时,n选自1;
R选自葡萄糖、甘露糖、半乳糖、鼠李糖、异鼠李糖、岩藻糖、橄榄霉糖、毛地黄毒糖、加拿大麻糖、阿拉伯糖、果糖、山梨糖、塔格糖、戊酮糖、丁酮糖、阿洛糖、阿卓糖、古洛糖、艾杜糖、核糖、木糖、来苏糖、苏糖、赤藓糖、氨基葡萄糖、氨基甘露糖、柔红霉糖的任一种或其带有苄基、酯基、缩酮、硅基保护基的衍生物,
或者选自
的任一种,
其中,R1~R4各自独立地选自氢、苄基、酯基、缩酮、硅基保护基的任一种。
本发明优选的技术方案中,式Ⅲ化合物先进行酰化反应,再与式Ⅰ化合物反应,制得式Ⅳ化合物。
本发明优选的技术方案中,式Ⅲ化合物与式Ⅰ化合物发生酰胺缩合反应,制得式Ⅳ化合物。
本发明优选的技术方案中,式Ⅲ化合物经活化后,再与式Ⅰ化合物发生反应,制得式Ⅳ化合物,优选活化剂为4-二甲氨基吡啶。
本发明优选的技术方案中,当R基团中羟基带有苄基、酯基、缩酮、硅基保护基时,可进行脱保护获得相应羟基,优选在酸性条件下进行脱保护。
本发明优选的技术方案中,所述式Ⅲ化合物由式Ⅱ化合物与式Ⅴ-1化合物反应制得,
当X为CH2时,n为0~10,n优选为1~5;
当X为S时,n为1~2;
当X为O时,n选自1;
R选自葡萄糖、甘露糖、半乳糖、鼠李糖、异鼠李糖、岩藻糖、橄榄霉糖、毛地黄毒糖、加拿大麻糖、阿拉伯糖、果糖、山梨糖、塔格糖、戊酮糖、丁酮糖、阿洛糖、阿卓糖、古洛糖、艾杜糖、核糖、木糖、来苏糖、苏糖、赤藓糖、氨基葡萄糖、氨基甘露糖、柔红霉糖的任一种或其带有苄基、酯基、缩酮、硅基保护基的衍生物,
或者选自
的任一种,
其中,R1~R4各自独立地选自氢、苄基、酯基、缩酮、硅基保护基的任一种。
本发明优选的技术方案中,所述式Ⅲ化合物由式Ⅱ化合物与式Ⅴ-2化合物反应制得,
其中,
当X为CH2时,n为0~10,n优选为1~5;
当X为S时,n为1~2;
当X为O时,n选自1;
R选自葡萄糖、甘露糖、半乳糖、鼠李糖、异鼠李糖、岩藻糖、橄榄霉糖、毛地黄毒糖、加拿大麻糖、阿拉伯糖、果糖、山梨糖、塔格糖、戊酮糖、丁酮糖、阿洛糖、阿卓糖、古洛糖、艾杜糖、核糖、木糖、来苏糖、苏糖、赤藓糖、氨基葡萄糖、氨基甘露糖、柔红霉糖的任一种或其带有苄基、酯基、缩酮、硅基保护基的衍生物,
或者选自
的任一种,
其中,R1~R4各自独立地选自氢、苄基、酯基、缩酮、硅基保护基的任一种;
R5选自卤素、羟基的任一种。
本发明的另一目的在于提供一种药物组合物,所述组合物由式Ⅳ所示结构的化合物或其衍生物和药学上可接受的载体组成。
本发明的另一目的在于提供式Ⅳ所示结构的化合物或其衍生物用于制备治疗肿瘤疾病的药物中的应用。
本发明优选的技术方案中,所述肿瘤选自肺癌、卵巢癌、结肠癌、直肠癌、黑色素瘤、肾癌、膀胱癌、乳腺癌、肝癌、淋巴瘤、恶性血液病、脑肿瘤、头颈癌、胶质瘤、胃癌、鼻咽癌、喉癌、宫颈癌、子宫体瘤、骨肉瘤、骨癌、胰腺癌、皮肤癌、前列腺癌、子宫癌、肛区癌、睾丸癌、输卵管癌、子宫内膜癌、阴道癌、阴户癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病、儿童实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管发生、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤、表皮状癌、鳞状细胞癌、T细胞淋巴瘤、环境诱发的癌症的任一种或其组合。
与现有技术相比,本发明具有下述有益技术效果:
1、本发明对秋水仙碱的结构改造,优化母体化合物的脂水分配特性并实现对肿瘤细胞葡萄糖转运蛋白的靶向性,本发明的式Ⅳ所示结构的化合物对肿瘤细胞具有优异地选择性增殖抑制活性,具有优异的抗肿瘤作用,并对正常细胞的影响较小,在保障治疗良好有效性的同时,保障了安全性,为患者提供更多的用药选择。
2、本发明所提供的秋水仙碱衍生物制备方法具有操作简便、收率高、绿色环保、成本更优、适合工业化生产等优点。
具体实施方式
以下通过实施例的方式对本发明作出进一步说明,但不应将本发明限制在所述实施例范围之内。基于本发明中的实施例,本领域技术人员在没有付出创造性的前提下,任何对本发明的变换和变型都归属于本发明的保护范围之内。
本发明所用试剂均为市售,核磁共振谱由Bruker AVANCE-600高分辨核磁共振谱仪测定,质谱由Bruker Esqure 2000、Shimadzu GCMS-QP5050A型质谱仪测定。
实施例1
将2,3,4,6-四苄基-D-吡喃葡萄糖(500mg,0.92mmol),丁二酸酐(184mg,1.84mmol),DMAP(11mg,0.092mmol)溶于5mL无水CH2Cl2中,室温搅拌滴加DIEA(0.64mL,3.68mmol),室温搅拌2h。反应完毕,先加饱和NH4Cl溶液,再加1.0M的盐酸调pH=5,CH2Cl2萃取3次(5mL×3);合并有机层,无水硫酸镁干燥,减压浓缩,残留物柱层析(EtOAc:MeOH=8:1),得中间体(III1)480mg。将中间体(109mg,0.17mmol),EDCI(40mg,0.21mmol),HOBt(28mg,0.21mmol)溶于5mL无水CH2Cl2中,室温搅拌30min,随后加入N-去乙酰基秋水仙碱(50mg,0.14mmol),室温搅拌3h。反应结束,加水10mL,CH2Cl2萃取3次(5mL×3),合并有机层,无水硫酸镁干燥,减压浓缩,残留物柱层析,得化合物1,淡黄色固体107mg,总收率78%。M.P.90-92℃。
1H-NMR(600MHz,CDCl3):δ7.45(s,1H),7.29(m,20H),7.11(m,2H),6.79(d,J=10.8Hz,1H),6.52(s,1H),6.35(d,J=3.5Hz,1H),4.91(d,J=10.8Hz,1H),4.83-4.75(m,2H),4.70-4.61(m,2H),4.59-4.55(m,2H),4.47-4.40(m,2H),3.94(s,3H),3.93(s,3H),3.89(s,3H),3.84-3.79(m,2H),3.74-3.68(m,2H),3.62(s,3H),3.60-3.54(m,2H),2.77-2.67(m,1H),2.67-2.55(m,2H),2.54-2.44(m,2H),2.43-2.35(m,1H),2.30-2.21(m,1H),1.86-1.77(m,1H)。
HRMS calcd for C58H61NO13:979.4143,found:979.4121。
实施例2
采用2,3,4,6-四苄基-D-吡喃葡萄糖与戊二酸酐,按照实施例1相同的方法合成中间体(III2),进一步制备化合物2;总收率74%。M.P.85-86℃。
1H-NMR(600MHz,CDCl3):δ7.31-7.24(m,20H),7.15-7.12(m,2H),6.78(d,J=10.8Hz,1H),6.48(s,1H),6.37(d,J=3.5Hz,1H),4.91-4.87(m,1H),4.83-4.80(m,2H),4.76-4.68(m,2H),4.60-4.56(m,2H),4.53-4.46(m,2H),3.96(s,3H),3.92(s,3H),3.88(s,3H),3.73-3.69(m,2H),3.68-3.65(m,2H),3.63(s,3H),2.49-2.39(m,3H),2.36-2.27(m,2H),2.25-2.22(m,2H),2.20-2.17(m,2H),1.93-1.86(m,2H),1.80-1.72(m,1H)。
HRMS calcd for C59H63NO13:993.4299,found:993.4292。
实施例3
采用2,3,4,6-四苄基-D-吡喃葡萄糖与己二酸酐,按照实施例1相同的方法合成中间体(III3),进一步制备化合物3;总收率70%。M.P.71-73℃。
1H-NMR(600MHz,CDCl3):δ7.43(s,1H),δ7.32-7.28(m,20H),7.14-7.12(m,2H),6.83(d,J=10.8Hz,1H),6.52(s,1H),6.36(d,J=3.5Hz,1H),4.93(d,J=10.8Hz,1H),4.83-4.79(m,2H),4.68-4.58(m,4H),4.50-4.45(m,2H),3.97(s,3H),3.93(s,3H),3.89(s,3H),3.64(s,3H),3.47(s,2H),2.52-2.49(m,1H),2.41-2.31(m,3H),2.26-2.17(m,3H),1.86-1.81(m,1H),1.64-1.58(m,4H)。
HRMS calcd for C60H65NO13:1007.4456,found:1007.4451。
实施例4
采用2,3,4,6-四苄基-D-吡喃葡萄糖与硫代羟基乙酸酐,按照实施例1相同的方法合成中间体(III4),进一步制备化合物4;总收率77%。M.P.72-74℃。
1H-NMR(600MHz,CDCl3):δ7.37(s,1H),7.32-7.29(m,14H),7.27-7.25(m,6H),7.14-7.12(m,2H),6.78(d,J=10.8Hz,1H),6.50(s,1H),6.38(d,J=3.5Hz,1H),4.91(d,J=10.8Hz,1H),4.82-4.80(m,2H),4.71-4.66(m,2H),4.60-4.57(m,2H),4.49-4.45(m,2H),3.95(s,3H),3.93(s,3H),3.88(s,3H),3.72-3.69(m,3H),3.62(s,3H),3.45(s,1H),3.39-3.31(m,2H),3.18(s,2H),4.49-2.46(m,1H),2.41-2.36(m,1H),2.21-2.16(m,1H),1.87-1.82(m,1H)。
HRMS calcd for C58H61NO13S:1011.3864,found:1011.3874。
实施例5
采用2,3,4,6-四苄基-D-吡喃葡萄糖与二硫代甘醇酸,按照实施例1相同的方法合成中间体(III5),进一步制备化合物5;总收率57%。M.P.77-79℃。
1H-NMR(600MHz,CDCl3):δ7.53(s,1H),7.26-7.33(m,20H),7.14-7.12(m,2H),6.79(d,J=10.8Hz,1H),6.51(s,1H),6.42(d,J=3.5Hz,1H),5.28(s,1H),4.96-4.91(m,2H),4.85-4.81(m,2H),4.75-4.70(m,2H),4.67-4.63(m,1H),4.59-4.55(m,2H),4.50-4.43(m,2H),3.97(s,3H),3.94(s,3H),3.89(s,3H),3.77-3.74(m,2H),3.73-3.70(m,2H),3.64(s,3H),3.46-3.40(m,2H),3.30-3.21(m,2H),2.51-2.47(m,1H),2.44-2.38(m,1H),2.28-2.20(m,1H),1.91-1.81(m,1H)。
HRMS calcd for C58H61NO13S2:1043.3584,found:1043.3699。
实施例6
将1,3,4,6-四-O-三乙基硅基-2-脱氧-2-氨基-D葡萄糖(100mg,0.16mmol)与丁二酸酐(19mg,0.19mmol)溶于5mL无水CH2Cl2中,室温搅拌2h,随后加入EDCI(31mg,0.16mmol),HoBt(22mg,0.16mmol),室温搅拌30min,再加入N-去乙酰基秋水仙碱(39mg,0.11mmol),室温搅拌3h,加水10mL,CH2Cl2萃取3次(5mL×3),合并有机层,无水硫酸镁干燥,减压浓缩,残留物柱层析(CH2Cl2:MeOH=15:1),得化合物6,淡黄色固体75mg,收率63%。M.P.89-91。
1H-NMR(600MHz,CDCl3):δ7.41(s,1H),7.25(d,J=10.8Hz,1H),6.78(d,J=10.8Hz,1H),6.52(s,1H),6.01(d,J=7.6Hz,1H),5.10(d,J=2.8Hz,1H),4.59-4.55(m,1H),3.97(s,3H),3.93(s,3H),3.89(s,3H),3.85-3.83(m,1H),3.81-3.77(m,2H),3.74-3.72(m,1H),3.64(s,3H),2.66-2.62(m,1H),2.53-2.48(m,2H),2.47-2.39(m,4H),2.24-2.18(m,1H),1.87-1.82(m,2H),0.98-0.94(m,27H),0.90-0.88(m,9H),0.67-0.62(m,12H),0.60-0.56(m,12H)。
HRMS calcd for C54H94N2O12Si4:1074.5884,found:1074.5910。
实施例7
将化合物6(130mg,0.14mmol)与TBAF(0.84mL,0.84mmol)溶于5mL无水THF中,室温搅拌2h。减压蒸除THF,加水10mL,EtOAc萃取3次(5mL×3),合并有机层,无水硫酸镁干燥,减压浓缩,残留物柱层析(CH2Cl2:MeOH=2:1),得化合物7,淡黄色固体67mg,收率77%。M.P.152-154℃。
1H-NMR(600MHz,CDCl3):δ7.41-7.39(m,2H),7.20(d,J=10.8Hz,1H),6.73(s,1H),5.03(d,J=3.5Hz,1H),4.50-4.47(m,1H),3.99(s,3H),3.89(s,3H),3.87(s,3H),3.82-3.77(m,3H),3.70-3.65(m,2H),3.59(s,3H),3.34(s,3H),2.64-2.56(m,3H),2.51-2.48(m,2H),2.36-2.31(m,1H),2.24-2.18(m,1H),1.95-1.90(m,1H),1.68-1.62(m,1H)。
HRMS calcd for C30H38N2O12:618.2425,found:618.2436。
实施例8
采用1,3,4,6-四-O-三乙基硅基-2-脱氧-2-氨基-D葡萄糖与戊二酸酐为原料,按照实施例6相同的方法制备化合物8;收率65%。M.P.80-82℃。
1H-NMR(600MHz,CDCl3):δ7.38(s,1H),7.25(d,J=9.6Hz,1H),6.78(d,J=10.8Hz,1H),6.51(s,1H),6.23(d,J=9.6Hz,1H),5.18(d,J=2.0Hz,1H),4.63-4.59(m,1H),3.97(s,3H),3.94(s,3H),3.89(s,3H),3.83-3.79(m,3H),3.70-3.68(m,1H),3.65(s,3H),2.52-2.48(m,1H),2.45-2.36(m,2H),2.27-2.11(m,5H),1.94-1.84(m,5H),0.98-0.94(m,36H),0.66-0.57(m,24H)。
HRMS calcd for C55H96N2O12Si4:1088.6040,found:1088.6005。
实施例9
采用化合物8为原料,以实施例7相同的方法制备化合物9;收率82%。M.P.139-141℃。
1H-NMR(600MHz,CDCl3):δ7.46-7.41(m,2H),7.21(d,J=10.8Hz,1H),6.92(s,1H),6.74(s,1H),5.10(d,J=3.5Hz,1H),4.00(s,3H),3.89(s,3H),3.87(s,3H),3.82-3.78(m,3H),3.76-3.65(m,3H),3.59(s,3H),2.65-2.62(m,2H),2.37-2.28(m,3H),1.97-1.85(m,4H),1.68-1.63(m,2H)。
HRMS calcd for C31H40N2O12:632.2581,found:632.2604。
实施例10
采用1,3,4,6-四-O-三乙基硅基-2-脱氧-2-氨基-D葡萄糖与己二酸酐为原料,按照实施例6相同的方法制备化合物10;收率60%。M.P.86-88℃。
1H-NMR(600MHz,CDCl3):δ7.39(s,1H),7.28(d,J=10.8Hz,1H),6.85(d,J=6.5Hz,1H),6.80(d,J=10.8Hz,1H),6.52(s,1H),6.01(m,1H),5.15(d,J=2.0Hz,1H),4.63-4.59(m,1H),3.97(s,3H),3.94(s,3H),3.89(s,3H),3.88-3.86(m,1H),3.82-3.77(m,3H),3.65(s,3H),2.53-2.50(m,1H),2.45-2.39(m,1H),2.26-2.20(m,4H),2.19-2.13(m,2H),1.93-1.88(m,2H),0.97-0.94(m,36H),0.66-0.57(m,24H)。
HRMS calcd for C56H98N2O12Si4:1102.6197,found:1102.6147。
实施例11
采用化合物10为原料,以实施例7相同的方法制备化合物11;收率75%。M.P.128-130℃;1H-NMR(600MHz,CDCl3):δ7.42-7.38(m,2H),7.21(d,J=10.8Hz,1H),6.91(s,2H),6.73(s,1H),5.06(d,J=3.5Hz,1H),4.49-4.46(m,1H),4.00(s,3H),3.89(s,3H),3.88(s,3H),3.59(s,3H),2.65-2.62(m,1H),2.37-2.31(m,3H),2.28-2.24(m,4H),2.21(s,3H),1.68-1.61(m,8H);HRMS calcd for C32H42N2O12:646.2738,found:646.2766。
实施例12
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采用1,3,4,6-四-O-三乙基硅基-2-脱氧-2-氨基-D葡萄糖与硫代羟基乙酸酐为原料,以实施例6相同的方法制备化合物12;收率66%。M.P.87-89℃;1H-NMR(600MHz,CDCl3):δ8.18(d,J=6.5Hz,1H),7.41(s,1H),7.27(d,J=10.8Hz,1H),6.98(d,J=8.8Hz,1H),6.79(d,J=10.8Hz,1H),6.52(s,1H),5.22(s,1H),4.60-4.56(m,1H),4.03-4.01(m,1H),3.97(s,3H),3.94(s,3H),3.90(s,3H),3.88-3.82(m,3H),3.73-3.71(m,1H),3.64(s,3H),3.47-3.40(m,1H),3.26-3.15(m,3H),2.52-2.49(m,1H),2.46-2.41(m,1H),2.23-2.17(m,1H),1.98-1.93(m,1H),0.99-0.94(m,36H),0.66-0.57(m,24H);HRMS calcd forC54H94N2O12SSi4:1106.5605,found:1106.5592。
实施例13
采用化合物12为原料,以实施例7相同的方法制备化合物13;收率79%。M.P.145-147℃。
1H-NMR(600MHz,CDCl3):δ7.47-7.41(m,2H),7.20(d,J=10.8Hz,1H),6.92(s,1H),6.75(s,1H),5.02(d,J=3.5Hz,1H),4.50-4.45(m,1H),4.00(s,3H),3.90(s,3H),3.88(s,3H),3.82-3.76(m,3H),3.72-3.65(m,2H),3.60(s,3H),3.36-3.33(m,3H),2.65-2.62(m,1H),2.37-2.32(m,1H),2.28-2.23(m,1H),2.00-1.94(m,1H),1.69-1.63(m,1H)。
HRMS calcd for C30H38N2O12S:650.2145,found:650.2160。
实施例14
采用1,3,4,6-四-O-三乙基硅基-2-脱氧-2-氨基-D葡萄糖与二硫代甘醇酸为原料,以实施例6相同的方法制备化合物14;收率51%。M.P.64-66℃;1H-NMR(600MHz,CDCl3):δ8.34(d,J=6.2Hz,1H),7.60(s,1H),7.23(d,J=10.8Hz,1H),6.74(d,J=10.8Hz,1H),6.49(s,1H),5.21(s,1H),4.67-4.63(m,1H),4.07-4.05(m,1H),3.97(s,3H),3.94(s,3H),3.89(s,3H),3.65(s,3H),3.61-3.53(m,2H),3.51-3.47(m,2H),3.45(s,2H),2.52-2.48(m,1H),2.46-2.41(m,1H),2.29-2.22(m,1H),2.01-1.96(m,1H),0.99-0.94(m,36H),0.67-0.54(m,24H);HRMS calcd for C54H94N2O12S2Si4:1138.5325,found:1138.5456。
实施例15
将化合物14(20mg,0.018mmol)溶于0.5mL三氟乙酸水溶液(TFA:H2O=4:1)中,室温反应3h。反应完毕,EtOAc萃取3次(5mL×3),合并有机层,无水硫酸镁干燥,减压浓缩,残留物柱层析(CH2Cl2:MeOH=8:1),得化合物15,淡黄色油状物11mg,收率90%。1H-NMR(600MHz,MeOD):δ7.53(s,1H),7.39(d,J=10.8Hz,1H),7.18(d,J=10.8Hz,1H),6.71(s,1H),5.31-5.29(m,1H),5.06(d,J=3.5Hz,1H),4.56-4.49(m,1H),4.17(d,J=6.2Hz,1H),3.97(s,3H),3.87(s,3H),3.84(s,3H),3.77-3.74(m,2H),3.71-3.65(m,2H),3.57(s,3H),3.56-3.50(m,2H),3.49-3.45(m,2H),3.18-3.15(m,1H),2.62-2.59(m,1H),2.36-2.31(m,1H),2.26-2.20(m,1H),2.16-2.14(m,1H);HRMS calcd for C30H38N2O12S2:682.1866,found:682.1886。
实施例16
将二丙酮-D葡萄糖(400mg,1.54mmol),丁二酸酐(308mg,3.08mmol),DMAP(38mg,0.308mmol)溶于10mL无水CH2Cl2中,室温搅拌滴加DIEA(1.06mL,6.16mmol),室温搅拌2h。先加饱和NH4Cl溶液,再加1.0M的盐酸调pH=5,CH2Cl2萃取3次(5mL×3),合并有机层,无水硫酸镁干燥,减压浓缩,残留物柱层析(CH2Cl2:MeOH=10:1),得中间体(III6),黄色油状物390mg。将中间体(108mg,0.3mmol),EDCI(58mg,0.3mmol),HOBt(40mg,0.3mmol)溶于5mL无水CH2Cl2中,室温搅拌30min,随后加入N-去乙酰基秋水仙碱(70mg,0.2mmol),室温搅拌3h,加水10mL,CH2Cl2萃取3次(5mL×3),合并有机层,无水硫酸镁干燥,减压浓缩,残留物柱层析(CH2Cl2:MeOH=17:1),得化合物16,淡黄色固体130mg,收率91%。M.P.118-120℃;1H-NMR(600MHz,CDCl3):δ7.86(d,J=6.2Hz,1H),7.50(s,1H),7.29(d,J=10.8Hz,1H),6.85(d,J=10.8Hz,1H),6.51(s,1H),5.71(d,J=3.5Hz,1H),5.14(d,J=2.5Hz,1H),4.62-4.58(m,1H),4.43(d,J=3.5Hz,1H),4.17-4.13(m,2H),4.03-4.00(m,1H),3.97(s,3H),3.96-3.94(m,1H),3.90(s,3H),3.87(s,3H),3.61(s,3H),2.65-2.60(m,2H),2.56-2.47(m,3H),2.38-2.33(m,1H),2.30-2.25(m,1H),1.89-1.84(m,1H),1.45(s,3H),1.34(s,3H),1.23(s,3H),1.21(s,3H);HRMS calcd for C36H45NO13:699.2891,found:699.2895。
实施例17
将化合物16(60mg,0.09mmol)溶于2mL三氟乙酸水溶液中(TFA :H2O=9:1),室温反应3h。反应完毕,EtOAc萃取3次(5mL×3),合并有机层,无水硫酸镁干燥,减压浓缩,残留物柱层析(CH2Cl2:MeOH=6:1),得化合物17,淡黄色固体44mg,收率79%。M.P.111-113℃;1H-NMR(600MHz,CDCl3):δ7.41(s,1H),7.39(s,1H),7.19(d,J=10.8Hz,1H),6.73(s,1H),5.11(d,J=3.5Hz,1H),4.49-4.46(m,1H),3.99(s,3H),3.89(s,3H),3.87(s,3H),3.86-3.84(m,1H),3.79-3.76(m,1H),3.71-3.63(m,2H),3.60(s,3H),3.32-3.28(m,4H),3.14-3.11(m,1H),2.64-2.60(m,1H),2.58-2.54(m,4H),2.36-2.31(m,1H),2.23-2.17(m,1H),1.96-1.91(m,1H);HRMS calcd for C30H37NO13:619.2265,found:619.2285。
实施例18
采用二丙酮-D葡萄糖与戊二酸酐,按照实施例16相同的方法合成中间体(III7),进一步制备化合物18;总收率90%。M.P.110-112℃。
1H-NMR(600MHz,CDCl3):δ7.45(s,1H),7.32(d,J=10.8Hz,1H),7.21(d,J=6.2Hz,1H),6.86(d,J=10.8Hz,1H),6.54(s,1H),5.86(d,J=3.5Hz,1H),5.23(s,1H),4.66-4.62(m,1H),4.48(d,J=3.5Hz,1H),4.17(s,2H),4.00(s,3H),3.94(s,3H),3.90(s,3H),3.66(s,3H),2.54-2.51(m,1H),2.43-2.34(m,3H),2.33-2.25(m,4H),1.93-1.84(m,4H),1.50(s,3H),1.39(s,3H),1.30(s,3H),1.28(s,3H)。
HRMS calcd for C37H47NO13:713.3047,found:713.3060。
实施例19
采用化合物18为原料,以实施例17相同的方法制备化合物19;收率76%。M.P.114-116℃;1H-NMR(600MHz,CDCl3):δ7.33-7.31(m,2H),7.13-7.11(m,1H),6.64(s,1H),5.11(d,J=3.5Hz,1H),4.50-4.48(m,1H),3.91(d,3H),3.80(s,3H),3.78(s,3H),3.76-3.74(m,1H),3.70-3.67(m,1H),3.64-3.57(m,1H),3.50(s,3H),3.42-3.36(m,1H),2.55-2.52(m,1H),2.32-2.30(m,2H),2.27-2.21(m,3H),2.13-2.07(m,1H),1.87-1.80(m,3H);HRMScalcd for C31H39NO13:633.2421,found:633.2429。
实施例20
采用二丙酮-D葡萄糖与己二酸酐,按照实施例16相同的方法合成中间体(III8),进一步制备化合物20;总收率89%。M.P.104-106℃。
1H-NMR(600MHz,CDCl3):δ7.83(d,J=6.2Hz,1H),7.52(s,1H),7.35(d,J=10.8Hz,1H),6.91(d,J=10.8Hz,1H),6.55(s,1H),5.86(d,J=3.5Hz,1H),5.22(s,1H),4.67-4.63(m,1H),4.48(d,J=3.5Hz,1H),4.18-4.17(m,2H),4.01(s,3H),3.94(s,3H),3.91(s,3H),3.66(s,3H),3.45(s,1H),2.54-2.51(m,1H),2.40-2.36(m,1H),2.33-2.31(m,2H),2.29-2.22(m,3H),1.95-1.90(m,1H),1.50(s,3H),1.38(s,3H),1.29(s,3H),1.27(s,3H)。
HRMS calcd for C38H49NO13:727.3204,found:727.3235。
实施例21
采用化合物20为原料,以实施例17相同的方法制备化合物21;收率71%。M.P.85-86℃;1H-NMR(600MHz,CDCl3):δ7.327.30(m,1H),7.29(s,1H),7.11(d,J=10.8Hz,1H),6.64(s,1H),5.04(d,J=3.5Hz,1H),4.39-4.36(m,1H),3.90(s,3H),3.79(s,3H),3.78(s,3H),3.74-3.72(m,1H),3.68-3.66(m,1H),3.61-3.55(m,1H),3.50(s,3H),3.41-3.39(m,1H),3.36-3.31(m,1H),3.28-3.25(m,1H),2.55-2.52(m,1H),2.33-2.31(m,2H),2.25-2.15(m,4H),2.13-2.06(m,1H),1.87-1.82(m,1H);HRMS calcd for C32H41NO13:647.2578,found:647.2590。
实施例22
采用二丙酮-D葡萄糖与硫代羟基乙酸酐,按照实施例16相同的方法合成中间体(III9),进一步制备化合物22;总收率92%。M.P.100-102℃;1H-NMR(600MHz,CDCl3):δ7.39(s,1H),7.29(d,J=10.8Hz,1H),6.83(d,J=10.8Hz,1H),6.54(s,1H),5.91(d,J=3.5Hz,1H),5.29(d,J=2.8Hz,1H),4.65-4.61(m,1H),4.58(d,J=3.5Hz,1H),4.23-4.18(m,2H),4.09-4.07(m,1H),4.01-3.99(m,1H),3.98(s,3H),3.94(s,3H),3.90(s,3H),3.65(s,3H),3.43-3.30(m,4H),2.57-2.53(m,1H),2.47-2.41(m,1H),2.29-2.24(m,1H),1.95-1.90(m,1H),1.52(s,3H),1.38(s,3H),1.31(s,3H);HRMS calcd for C36H45NO13S:731.2612,found:731.2625。
实施例23
采用化合物22为原料,以实施例17相同的方法制备化合物23;收率80%。M.P.99-101℃;1H-NMR(600MHz,CDCl3):δ7.35-7.30(m,2H),7.11(d,J=10.8Hz,1H),6.65(s,1H),5.01(d,J=3.5Hz,1H),4.40-4.35(m,1H),3.90(s,3H),3.80(s,3H),3.78(s,3H),3.76-3.73(m,1H),3.69-3.65(m,1H),3.61-3.54(m,2H),3.50(s,3H),3.31-3.24(m,5H),2.56-2.53(m,1H),2.28-2.23(m,1H),2.16-2.11(m,1H),1.89-1.84(m,1H);HRMS calcd forC30H37NO13S:651.1986,found:651.1999。
实施例24
先将二硫代甘醇酸(200mg,1.1mmol)溶于3mL无水乙酸酐中,30℃磁力搅拌3h,加甲苯(5mL×3)旋干,得黄色油状物;再加入双丙酮葡萄糖(250mg,0.96mmol),DMAP(12mg,0.096mmol),2mL无水CH2Cl2溶解,室温搅拌3h。反应完毕,加水10mL,EtOH萃取3次(5mL×3),合并有机层,无水硫酸镁干燥,减压浓缩,残留物柱层析(Petrol:EtOH:HCOOH=1:1:0.002),得中间体(III10),暗黄色油状物120mg。将中间体(105mg,0.25mmol)用2mL无水CH2Cl2溶解,加入EDCI(47mg,0.25mmol),HOBt(15mg,0.125mmol),-5℃搅拌1h,再加入N-去乙酰基秋水仙碱(88mg,0.25mmol),室温搅拌3h,反应完毕柱层析(CH2Cl2:MeOH=20:1),得化合物24,白色固体102mg,收率53%。M.P.110-112℃;1H-NMR(600MHz,CDCl3):δ7.61(s,1H),7.32(d,J=10.8Hz,1H),6.84(d,J=10.8Hz,1H),6.54(s,1H),5.90(d,J=3.5Hz,1H),5.36-5.34(m,2H),4.73-4.68(m,1H),4.58(d,J=3.5Hz,1H),4.23-4.19(m,2H),4.11-4.09(m,1H),4.04-4.02(m,1H),3.99(s,3H),3.94(s,3H),3.91(s,3H),3.73-3.71(m,1H),3.65(s,3H),3.56-3.44(m,2H),2.57-2.54(m,1H),2.46-2.41(m,1H),2.35-2.26(m,1H),2.23-2.21(m,1H),1.52(s,3H),1.40(s,3H),1.31(s,3H),1.30(s,3H);HRMS calcd forC36H45NO13S2:763.2332,found:763.2427。
实施例25
采用化合物24为原料,以实施例17相同的方法制备化合物25;收率89%。M.P.141-143℃;1H-NMR(600MHz,MeOD):δ7.47(d,J=6.2Hz,1H),7.39(d,J=10.8Hz,1H),7.16(d,J=10.8Hz,1H),6.71(s,1H),5.26-5.22(m,1H),5.12(d,J=3.5Hz,1H),4.56-4.53(m,1H),4.50-4.47(m,1H),3.97(s,3H),3.86(s,3H),3.84(s,3H),3.75-3.67(m,2H),3.64-3.60(m,2H),3.57(s,3H),3.54-3.42(m,4H),2.62-3.59(m,1H),2.34-2.29(m,1H),2.25-2.18(m,1H),1.99-1.94(m,1H);HRMS calcd for C30H37NO13S2:683.1706,found:683.1731。
试验例1本发明化合物的体外抗肿瘤活性研究
试验例1以化合物1-25为例,并采用四氮唑盐(micoculturetetrozolium,MTT)还原法研究本发明化合物的体外抗肿瘤活性。
阳性对照:N-去乙酰基秋水仙碱(N-deacetyl colchicine)。
细胞株:人鼻咽癌细胞株(NPC-TW01 cell line)、人结肠癌细胞株(HCT-116cellline)、人血管内皮细胞株(EC-304cell line)。
作用时间:在37℃下,分别加入受试化合物孵育72小时。
各化合物对三种肿瘤细胞生长的抑制率(30μg/mL)见表1。
表1
研究发现,秋水仙碱对人血管内皮细胞株的抑制率高达89.2%,对正常细胞毒性很大,而本发明的化合物1-25显著降低了秋水仙碱对正常细胞的影响,显著提高了用药安全性。
试验例2动物体内抗肿瘤活性测试
以化合物3、化合物11、化合物15和化合物17为例,研究本发明化合物在小鼠S-180肉瘤模型上研究体内抗肿瘤活性。阳性对照药为氟尿嘧啶(Fluorouracil,5-Fu),NS为空白对照组。
选用18-22克雌性昆明小鼠及生长良好的7-11天的S-180瘤种,将瘤组织制成细胞悬液,接种至小鼠右侧腋部皮下,约1.0-2.0×106细胞/只,接种24小时后随机分笼,腹腔注射给药连续7天。停药后24小时处死动物,称体重、瘤重,计算各组平均瘤重,计算肿瘤抑制率并进行t检验。结果见表2。
肿瘤抑制率=[(空白对照组平均瘤重-治疗组平均瘤重)/(空白对照组平均瘤重)]×100%
表2
试验例3急性毒性实验
以化合物11为例,研究急性毒性反应和死亡情况。选用Wistar大鼠,雌雄各半,体重140.8±5.4g。随机分组,各组按剂量设置分别静脉给药,观察大鼠给药后的即时反应,观察有无毒性反应。研究分为七个剂量组20mg/kg、16mg/kg、12mg/kg、10mg/kg、8mg/kg、6mg/kg、5mg/kg,静脉给药。死亡动物进行解剖观察,存活动物继续观察两周,并记录两周内动物死亡情况。两周后将存活动物进行解剖,观察实质性脏器的病变,具有实质性病变的脏器需作病理检查。根据各组动物的死亡数,计算药物的半数致死量。结果见表3。
表3
化合物11大鼠单次静脉给药急性毒性LD50为10.46mg/kg,未见毒性反应。置信系数a=0.05时,置信区间为:8.66≤LD50≤12.63mg/kg。
以上对本发明具体实施方式的描述并不限制本发明,本领域技术人员可以根据本发明作出各种改变或变形,只要不脱离本发明的精神,均应属于本发明权利要求保护的范围。
Claims (11)
1.一种式Ⅳ所示结构的化合物或其药学上可接受的盐,
其中,X选自CH2、S、O,
X为CH2,n选自1~5,
R选自 的任一种,
其中,R1~R4各自独立地选自氢、苄基、缩酮、三乙基硅基的任一种;
或X为S,n选自1~2,
R选自 的任一种,
其中,R1~R4各自独立地选自氢、苄基、缩酮、三乙基硅基的任一种;
或X为O,n选自1,
R选自 的任一种,
其中,R1~R4各自独立地为氢、苄基、缩酮、三乙基硅基的任一种。
2.如权利要求1所述的化合物或其药学上可接受的盐,X为CH2,n选自1~5,R选自 的任一种。
3.如权利要求1所述的化合物或其药学上可接受的盐,X为S,n选自1~2,R选自 的任一种。
4.如权利要求1所述的化合物或其药学上可接受的盐,X为O,n选自1,
R选自 的任一种。
5.如权利要求1所述的化合物或其药学上可接受的盐,所述化合物选自下述化合物的任一种,
6.一种式Ⅳ所示化合物或其药学上可接受的盐的制备方法,包括下述步骤:
X为CH2,n选自1~5,
R选自的任一种,
其中,R1~R4各自独立地选自氢、苄基、缩酮、三乙基硅基的任一种;
或X为S,n选自1~2,
R选自的任一种,
其中,R1~R4各自独立地选自氢、苄基、缩酮、三乙基硅基的任一种;
或X为O,n选自1,
R选自的任一种,
其中,R1~R4各自独立地为氢、苄基、缩酮、三乙基硅基的任一种。
7.根据权利要求6所述的制备方法,其中,所述式Ⅲ化合物由式Ⅱ化合物与式Ⅴ-1化合物反应制得,
X、n、R定义如权利要求6所述。
8.根据权利要求7所述的制备方法,其中,所述式Ⅲ化合物由式Ⅱ化合物与式Ⅴ-2化合物反应制得,
X、n、R定义如权利要求6所述。
9.一种药物组合物,所述组合物由如权利要求1所述的式Ⅳ化合物或其药学上可接受的盐和药学上可接受的载体组成。
10.一种如权利要求1所述的式Ⅳ化合物或其衍生物用于制备治疗肿瘤疾病的药物中的应用。
11.如权利要求10所述的应用,所述肿瘤选自肺癌、卵巢癌、结肠癌、直肠癌、黑色素瘤、肾癌、膀胱癌、乳腺癌、肝癌、淋巴瘤、恶性血液病、脑肿瘤、头颈癌、胶质瘤、胃癌、鼻咽癌、喉癌、宫颈癌、子宫体瘤、骨肉瘤、骨癌、胰腺癌、皮肤癌、前列腺癌、子宫癌、肛区癌、睾丸癌、输卵管癌、子宫内膜癌、阴道癌、阴户癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病、儿童实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管发生、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤、表皮状癌、鳞状细胞癌、T细胞淋巴瘤、环境诱发的癌症的任一种或其组合。
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