CN116925021A - 去氢木香烃内酯烷基化衍生物及其盐、药物组合物及其用途 - Google Patents
去氢木香烃内酯烷基化衍生物及其盐、药物组合物及其用途 Download PDFInfo
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Abstract
本发明涉及一种去氢木香烃内酯烷基化衍生物及其盐及其在制备治疗癌症的药物和在制备治疗癌症的辅助药物中的用途，其中癌症为白血病。
Description
技术领域
本发明涉及去氢木香烃内酯烷基化衍生物及其盐以其为有效成分的治疗癌症或辅助治疗癌症的药物组合物，以及该药物化合物或组合物在制备抗癌或辅助抗癌药物中的应用，属于药物化学领域。
背景技术
从天然产物中寻找抗癌活性化合物已经成为抗癌药物研发的热点。许多抗癌药物都是来源于天然产物。例如，从植物红豆杉树皮里分离出的紫杉醇，已经被广泛应用于乳腺癌、卵巢癌和肺癌的治疗。其主要作用机制是特异性抑制微管蛋白的正常功能，干扰细胞的分裂和增殖。另一个著名的例子是长春新碱(Vincristine, Oncovin,VCR)。长春新碱是夹竹桃科植物长春花中提取出的生物碱，主要应用于淋巴瘤、肺癌、神经母细胞瘤乳腺癌头颈部肿瘤的治疗。其主要机制是作用于细胞有丝分裂期的微管蛋白，抑制微管蛋白聚合，感染纺锤体微管的形成，使有丝分裂期细胞停止于中期，干扰蛋白质代谢及抑制核糖核苷酸聚合酶的活性，抑制细胞膜类脂质合成和氨基酸在细胞膜上的转运。这些成功的案例为基于天然产物的抗肿瘤药物开发提供了支持。
倍半萜化合物广泛分布于植物、微生物、海洋生物以及某些昆虫中，具有多种多样的基本骨架和复杂的立体结构。倍半萜内酯是菊科植物的特征成分，通常具有对其活性至关重要的α-亚甲基-γ- 内酯环结构。倍半萜内酯具有广泛的生物活性，包括抗炎、抗病毒、抗肿瘤和抗增殖等特性。中药木香具有行气止痛，健脾消食、抑菌，治疗乳腺增生等功效。其主要提取成分为木香烃内酯和去氢木香烃内酯。其中，去氢木香烃内酯不仅具有抗炎、抗病毒、抗氧化等多方面的药理活性还具有对肝癌、乳腺癌、肺癌、白血病、卵巢癌等多种人类癌细胞具有细胞毒活性。一些研究证实了去氢木香烃内酯主要通过抗增殖、抑制转移和侵袭、过度诱导细胞凋亡、甚至逆转了多药耐药性。研究认为其分子中的α-亚甲基-γ-内酯环结构对其生理功能起着至关重要的作用。因此，去氢木香烃内酯可能是一种潜在的癌症治疗药物，有望被开发研究。
过渡金属催化的α-重氮苯乙酸酯插入各种羟基键代表了典型的烷基化策略，并已广泛用于这些碳氧键的构建。许多综述和文章对其进行了详细的报道(Chem.Rev.1994,94,1091-1160；Acc.Chem. Res.2012,45,1365-1377；Chem.Soc.Rev.2013,42,4918-4931；Chem.Rev.2015,115,9981-10080)。和其他方法相比，过渡金属催化的α-重氮苯乙酸酯插入各种羟基键反应具有反应选择性好、反应活性高、产率高等优点。Rudi Fasan课题组报道了C9位和C14位具有羟基的小白菊内酯类似物的卡宾插入反应并合成了一系列小白菊内酯烷基化产物。与母体分子相比，它们的抗癌活性显著提高(2- 14倍)。上述研究有望改善天然产物小白菊内酯的抗癌活性方面的潜力。
发明内容
1、一种如下式(I)的去氢木香烃内酯烷基化衍生物及其盐，
式(I)中的R1为芳基、取代基苯基、烷基、以及酯键；其中取代基苯基上的取代基为甲基、甲氧基、卤素、三氟甲基；R2为芳基、烷基。
2、本发明提供了化合物1(去氢木香烃内酯烯丙位氧化产物) 的制备，具体步骤包括：将去氢木香烃内酯(1mmol)溶于适量二氯甲烷(5mL)中，加入SeO2(0.2mmol)，在室温下搅拌，然后用少量二氯甲烷将TBHP(叔丁基过氧化氢)(2mmol)稀释后逐滴滴加，5分钟加完。30min后监测反应结束。用饱和硫代硫酸钠(10 mL)淬灭反应，二氯甲烷萃取三遍。用无水硫酸钠干燥有机相，过滤，减压浓缩；柱层析纯化得到化合物1。
3、如权利要求1所述的方法，具体步骤包括：将化合物1(0.20 mmol)和四聚醋酸铑催化剂(1mol％)加入到史莱克管中，加入干燥的二氯甲烷(2mL)，室温下搅拌，缓慢滴加重氮化合物(0.30～0.40 mmol)的无水CH2Cl2(0.5mL)溶液，室温下搅拌约10分钟，直到原料完全消耗。反应结束后，减压浓缩，硅胶柱层析纯化得到化合物3a-3f。
4、本发明还提供了式3a-3f化合物在制备治疗癌症的药物中的用途，其中癌症为白血病。
5、本发明还提供了式3a-3f化合物在制备治疗癌症的辅助药物中的用途，其中制剂可以为片剂、注射剂或胶囊剂。
附图说明
图1是化合物3a的氢谱图；
图2是化合物3a的碳谱图；
图3是化合物3a的高分辨质谱图；
图4是化合物3b的氢谱图；
图5是化合物3b的碳谱图；
图6是化合物3b的高分辨质谱图；
图7是化合物3c的氢谱图；
图8是化合物3c的碳谱图；
图9是化合物3c的高分辨质谱图；
图10是化合物3d的氢谱图；
图11是化合物3d的碳谱图；
图12是化合物3d的高分辨质谱图；
图13是化合物3e的氢谱图；
图14是化合物3e的碳谱图；
图15是化合物3f的氢谱图；
图16是化合物3f的碳谱图；
具体实施方式
为进一步阐述本发明采取的技术手段和技术效果，以下结合具体实施例对本发明进行详细说明。下面结合具体实施例对本发明做进一步说明，但并不限定本发明。本发明中用到的有机试剂、和溶剂均为商业购买。
实施例1：化合物1的合成
将去氢木香烃内酯(1mmol)溶于适量二氯甲烷(5mL)中，加入SeO2(0.2mmol)，在室温下搅拌，然后用少量二氯甲烷将 TBHP(叔丁基过氧化氢)(2mmol)稀释后逐滴滴加，5分钟加完。 30min后监测反应结束。用饱和硫代硫酸钠(10mL)淬灭反应，二氯甲烷(3*15mL)后处理反应。用无水硫酸钠干燥有机相，过滤，减压浓缩。然后柱层析分离得到纯品。用石油醚：乙酸乙酯＝15:1的洗脱剂回收未反应的原料，用石油醚：乙酸乙酯＝3:1的洗脱剂得到化合物1。1H NMR(400MHz,CDCl3):δ＝6.22(s,1H),5.50(s,2H),5.35 (s,1H),4.92(s,1H),4.78(s,1H),4.69(t,J＝6.0Hz,1H),3.90(t,J＝8.6 Hz,1H),3.09(t,J＝11.3Hz,2H),2.86(t,J＝7.6Hz,1H),2.58–2.48(m, 1H),2.27–2.16(m,2H),1.90–1.84(m,2H),1.46–1.33(m,1H),1.24-1.22 (m,1H).13C NMR(100MHz,CDCl3):δ＝170.1,154.1,148.5,139.4, 120.5,113.2,113.1,84.9,74.5,49.5,45.5,44.1,39.8,36.7,30.9.
将向史朗克管中加入化合物1(49.2mg，0.20mmol)，四聚醋酸铑催化剂(1mol％)，通入氮气，然后加入干燥的CH2Cl2(0.5mL)，室温下搅拌，缓慢滴加重氮化合物2(0.30～0.40mmol)的无水 CH2Cl2(0.5mL)溶液，室温下搅拌约10分钟，直到原料完全消耗。反应结束后，减压浓缩，硅胶柱层析纯化得到化合物3。
实施例2
3a,黄色油状物，产率：66.0％。1H NMR(400MHz,CDCl3):δ＝ 6.22(d,J＝3.5Hz,1H),5.52(dd,J＝10.3,2.6Hz,2H),5.30(d,J＝3.3 Hz,1H),4.91(s,1H),4.68(d,J＝16.1Hz,2H),4.36(dd,J＝5.6,1.9Hz, 1H),3.99–3.90(m,1H),3.80(d,J＝14.2Hz,6H),3.27–3.17(m,1H), 3.09(t,J＝9.8Hz,1H),2.89-2.87(m,1H),2.55-2.50(m,1H),2.30–2.05 (m,4H),1.46–1.34(m,1H).13C NMR(100MHz,CDCl3):δ＝170.1, 167.3,167.1,148.3,148.2,139.1,120.6,115.5,112.9,84.4,83.8,75.9, 52.9,52.9,48.2,45.4,44.4,37.1,36.8,31.3.HRMS(ESI):m/z[M+H]+ calcd for Chemical Formula:C20H25O7:377.1600；found:377.1597.
实施例3
3b,黄色油状物，产率：63.0％。1H NMR(400MHz,CDCl3):δ＝ 6.21(d,J＝3.5Hz,1H),5.50(dd,J＝7.4,2.6Hz,2H),5.30(d,J＝2.4 Hz,1H),4.91(d,J＝10.3Hz,2H),4.69(s,1H),4.61(s,1H),4.27–4.22 (m,4H),3.93(dd,J＝9.7,9.2Hz,1H),3.26–3.17(m,1H),3.09(t,J＝ 9.8Hz,1H),2.92–2.83(m,1H),2.54–2.48(m,1H),2.27–2.14(m,2H), 2.12–1.99(m,2H),1.44–1.34(m,1H),1.28–1.26(m,6H)..13C NMR (100MHz,CDCl3):δ＝170.1,166.9,166.7,148.3,148.2,139.1,120.5, 115.5,112.9,84.4,83.5,76.1,61.9,48.2,45.4,44.3,37.1,36.7,31.3, 14.0,13.9,13.9.HRMS(ESI):m/z[M+H]+calcd forChemical Formula:C22H29O7:405.1913；found:405.1909.
实施例4
3c,黄色油状物，(R,S异构体)产率：82％。1H NMR(400 MHz,CDCl3):δ＝7.4–7.42(m,4H),7.40–7.30(m,6H),6.23(dd,J＝ 5.7,3.5Hz,2H),5.59–5.39(m,4H),5.28(dd,J＝9.8,2.0Hz,2H),5.06 (d,J＝19.0Hz,2H),4.89(d,J＝6.3Hz,2H),4.67(d,J＝14.5Hz,2H),4.43–4.35(m,1H),4.22(d,J＝3.5Hz,1H),4.02–3.86(m,2H),3.71(d, J＝22.8Hz,6H),3.24–2.96(m,4H),2.92–2.80(m,2H),2.55-2.50(m, 2H),2.28-2.20(m,2H),2.18–1.98(m,6H),1.45–1.33(m,2H).13C NMR (100MHz,CDCl3):δ＝171.6,171.4,170.2,170.2,149.0,148.9,148.5, 148.4,139.2,139.2,136.5,136.4,128.7,128.6,127.4,127.3,120.5,114.7,114.4,112.9,112.7,84.6,84.6,81.3,81.2,77.9,77.5,52.2,52.2, 48.5,48.4,45.4,44.4,44.3,37.2,37.2,36.9,31.3,31.2.HRMS(ESI): m/z[M+H]+calcd forChemical Formula:C24H27O5:395.1858；found: 395.1854.
实施例5
3d,黄色油状物，(R,S异构体)产率：30％。1H NMR(400 MHz,CDCl3):7.47–7.43(m,4H),7.39–7.29(m,6H),6.22(dd,J＝4.7, 3.5Hz,2H),5.56–5.46(m,4H),5.30(d,J＝2.4Hz,2H),5.03(d,J＝ 20.6Hz,2H),4.89(d,J＝6.6Hz,2H),4.67(d,J＝14.3Hz,2H),4.51– 4.30(m,2H),4.24–4.09(m,4H),3.98-3.92(m,2H),3.23–2.99(m,4H), 2.93–2.79(m,4H),2.55–2.49(m,2H),2.28–2.20(m,2H),2.18–2.00(m, 6H),1.44–1.33(m,2H),1.25–1.18(m,6H).13C NMR(100MHz,CDCl3): δ＝171.2,171.0,170.2,149.2,148.9,148.5,148.4,139.3,139.2,136.6, 136.6,128.6,128.5,128.5,127.4,127.2,120.4,114.6,114.5,112.8, 112.8,84.6,81.3,81.2,78.0,77.5,61.1,48.5,48.4,45.5,44.4,44.3,37.3, 37.2,36.9,36.9,31.3,31.3,14.1,14.0.HRMS(ESI):m/z[M+H]+calcd forChemical Formula:C25H29O5:409.2015；found:409.2012.
实施例6
3e,黄色油状物，(R,S异构体)产率：63％。1H NMR(400 MHz,CDCl3):δ＝7.54–7.45(m,4H),7.36–7.29(m,4H),6.23(dd,J＝4.9,3.5Hz,2H),5.57–5.42(m,4H),5.31–5.23(m,2H),5.01(d,J＝18.7 Hz,2H),4.90(d,J＝5.8Hz,2H),4.67(d,J＝13.5Hz,2H),4.38(t,J＝4.5Hz,1H),4.20(dd,J＝5.8,2.3Hz,1H),3.98-3.91(m,2H),3.70(d,J ＝22.5Hz,6H),3.21-2.97(m,4H),2.93–2.80(m,2H),2.53-2.50(m, 2H),2.29–2.20(m,2H),2.17–1.97(m,6H),1.45–1.33(m,2H).13C NMR (100MHz,CDCl3):δ＝171.3,170.1,148.9,148.7,148.7,148.4,148.3, 139.2,139.1,135.6,131.8,131.7,129.0,128.9,122.7,120.6,120.5,114.8,114.5,112.9,112.8,84.5,84.5,81.6,52.4,52.3,48.5,45.5,45.4, 44.3,44.3,37.2,37.1,36.9,36.9,31.3.HRMS(ESI):m/z[M+H]+calcd for Chemical Formula:C25H28BrO5:487.1120；found:487.1122.
实施例7
3f,黄色油状物，(R,S异构体)产率：25％。1H NMR(400MHz, CDCl3):δ＝7.42–7.38(m,2H),7.35–7.30(m,2H),6.22(t,J＝3.8Hz, 1H),5.57–5.47(m,2H),5.29-5.26(m,1H),5.00(d,J＝20.1Hz,1H), 4.90(d,J＝6.1Hz,1H),4.67(d,J＝13.0Hz,1H),4.47–4.31(m,1H), 4.22–4.14(m,2H),3.98–3.90(m,1H),3.26–3.13(m,1H),3.02–2.97(m, 1H),2.90–2.80(m,1H),2.55-2.50(m,1H),2.29–2.19(m,1H),2.16–2.03 (m,3H),1.44–1.34(m,1H),1.22(dd,J＝8.6,5.5Hz,3H).13C NMR (100MHz,CDCl3):δ＝170.8,170.6,170.1,149.1,148.8,148.4,148.4, 139.3,139.2,135.2,135.2,134.4,134.4,128.8,128.7,128.6,120.5, 120.4,114.7,114.6,112.9,112.8,84.5,81.6,81.5,76.8,61.3,48.5,48.4,45.5,44.4,44.3,37.3,37.1,36.9,36.9,31.3,14.1,13.9.HRMS(ESI): m/z[M+H]+calcdfor Chemical Formula:C25H28ClO5:443.1625；found: 443.1628.
实施例8：
去氢木香烃内酯烷基化衍生物的药理作用：
将KG-1a白血病细胞配成4.5×104个/mL细胞悬液，加入96孔细胞培养板内，每孔100μL，培养24小时后，分别加入不同浓度的化合物，每一测试浓度设6个复孔，置37℃、5％CO2饱和湿度条件下培养72小时，每孔加入10μLCCK-8，37℃孵育1-4小时后，用酶联检测仪450nm波长测得吸光度(A)值，计算出本化合物对测试癌细胞的抑制作用。
表1实施例1-7的化合物对KG1a(高表达CD34+的急性髓系白血病细胞株)癌细胞的抑制活性(IC50，μM)
| Compound | IC50，μM |
| 3a | 9.78 |
| 3b | 33.97 |
| 3c | 16.77 |
| 3d | 35.29 |
| 3e | 23.56 |
| 3f | 18.29 |
| 1 | 11.12 |
实施例9：注射液
实施例1-实施例7制备的化合物用少量的DMSO溶解后，按照常规加注射用水，精滤，灌封灭菌制成注射液。
实施例10：片剂
实施例1-实施例7制备的化合物与赋形剂按照重量比为5:1的比例加入赋形剂，制粒压片，得片剂。
实施例11：胶囊剂
实施例1-实施例7制备的化合物与赋形剂按照重量比为5:1的比例加入赋形剂，制成胶囊。
本发明的化合物、用途和方法已经通过具体实施例进行了描述。所有类似的替换和改动都被视为包括在本发明范围之内。
Claims (4)
1.一种如下式(I)的去氢木香烃内酯烷基化衍生物及其盐，
式(I)中的R1为芳基、取代基苯基、烷基、以及酯键；其中取代基苯基上的取代基为甲基、甲氧基、卤素、三氟甲基；R2为芳基、烷基。
2.如权利要求1所述的结构，其特征在于具体制备步骤包括：将化合物1(0.20mmol)和四聚醋酸铑催化剂(1mol％)加入到史莱克管中，加入干燥的二氯甲烷(2mL)，室温下搅拌，缓慢滴加重氮化合物(0.30～0.40mmol)的无水CH2Cl2(0.5mL)溶液，室温下搅拌约10分钟，直到原料完全消耗；反应结束后，减压浓缩，硅胶柱层析纯化得到化合物3a-3f。
3.本发明还提供了式3a-3f化合物在制备治疗癌症的药物中的用途，其中癌症为白血病。
4.本发明还提供了式3a-3f化合物在制备治疗癌症的辅助药物中的用途，其中制剂可以为片剂、注射剂或胶囊剂。
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