CN115819268A - 一类c-14酰胺取代的脱氢松香酸衍生物及其制备方法与应用 - Google Patents
一类c-14酰胺取代的脱氢松香酸衍生物及其制备方法与应用 Download PDFInfo
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供一种式Ⅰ所示C‑14酰胺取代的脱氢松香酸衍生物及其制备方法与应用。本发明的脱氢松香酸衍生物,具有较好的抗癌活性,可用于制备抗肿瘤药物,具有很好的开发前景。
Description
技术领域
本发明涉及天然产物和药物化学领域,具体涉及C-14酰胺取代的脱氢松香酸衍生物及其制备方法和其在制备抗肿瘤药物中的应用。
背景技术
癌症是全球第二大死因,随着社会的发展和人类生活水平的提高,因癌症死亡的人数逐年上升。据统计,2020年全球因癌症死亡的人数达1000多万,其死亡人数仅次于心脑血管疾病死亡人数,因此,针对癌症的治疗迫在眉睫。目前,针对肿瘤的治疗主要是手术切除和药物化疗两个方面。尽管有许多化疗药物问世,但是其耐药性和副作用仍然是肿瘤治疗过程中亟待解决的问题。
天然产物结构复杂,它们的多样性、立体化学及良好的生物活性为新抗癌药的合成开发提供了灵感。据报道临床上使用的抗肿瘤药物60%来自天然产物。例如长春新碱、鬼臼毒素、紫杉醇都是临床上常用的天然产物衍生的化疗药物。萜类化合物是天然产物中最大的一类,是药物候选化合物的丰富储存库。近年来,从天然产物中提取的多种萜类化合物已经进行了抗癌药物的研究和开发,它们通过不同的机制抑制癌细胞的增殖和转移。
脱氢松香酸是一种芳香族松香烷二萜类化合物,具有二萜结构和三个手性碳原子,是丰富的天然林业资源歧化松香的主要成分,来源十分广泛,其分子本身具有抗肿瘤活性,但活性微弱(例如它对人乳腺癌MCF7细胞的IC50>50μM,Gu,W.et al.Bioorg.Chem.2020,100,103845)。因此,对脱氢松香酸进行结构改造来获得抗肿瘤活性增强的先导化合物或候选药物,无论是对于抗肿瘤药物研发还是对松香资源的利用都有非常重要的意义。
申请人前期研究的发现在脱氢松香酸的C-14位引入取代的三氮唑基团会显著增强抗肿瘤活性,其中活性最好的分子A对人卵巢癌SKOV-3细胞(IC50=1.2μM)、前列腺癌PC-3细胞(IC50=0.9μM)、人乳腺癌MDA-MB-231细胞(IC50=0.7μM)和MCF7细胞(IC50=0.8μM)具有良好的抑制活性,但分子A的分子量较大,为629.8,且其分子中还有一个Boc(叔丁氧羰基)基团,在酸性条件下易发生脱除,导致其结构稳定性较差。
因此,进一步基于脱氢松香酸开发活性和类药性质更好的抗肿瘤药物具有重要意义。
发明内容
针对现有技术中存在的上述问题,本发明的目的在于提供一种结构新颖的C-14酰胺取代的脱氢松香酸衍生物及其在制备预防和治疗肿瘤药物中的应用。本发明的又一目的在于提供上述C-14酰胺取代的脱氢松香酸衍生物的制备方法。
为了实现上述目的,本发明采用如下技术方案:
第一方面,本发明提供一种式Ⅰ所示C-14酰胺取代的脱氢松香酸衍生物,
其中:
R2选自下列基团之一:苯基、被硝基或氯取代的苯基、吡啶-2-甲基。
进一步,所述取代为一取代、二取代或三取代。
具体地,所述式I所示的C-14酰胺取代的脱氢松香酸衍生物优选为下列之一:
第二方面,本发明还提供一种上述C-14酰胺取代的脱氢松香酸衍生物在制备抗肿瘤药物中的应用。
进一步,所述的肿瘤为人乳腺癌、肝癌、结肠癌或非小细胞肺癌。优选为人乳腺癌或非小细胞肺癌。
进一步,所述的脱氢松香酸类化合物为化合物10或14。
第三方面,本发明所述的式I所示的C-14酰胺取代的脱氢松香酸衍生物按照下列两种方法之一进行制备:
(1)式C中,R1为氯;将式B所示的化合物、式C所示化合物和有机碱A添加于有机溶剂A中,在0-50℃下反应2-12h,所得反应液A经后处理A得到式I所示的的C-14酰胺取代的脱氢松香酸衍生物;式B所示的化合物、式C所示的化合物与有机碱A的物质的量之比为1:0.5~1.5:1~1.5;
(2)式C中,R1为羟基;将式B所示化合物和式C所示化合物和缩合剂以及有机碱B添加于有机溶剂B中,在0-50℃下反应2-12h,所得反应液B经后处理B得到式I所示的目标化合物;式B所示的化合物、式C所示的化合物、有机碱B与缩合剂的物质的量之比为1:0.5~1.5:0.05~2.5:1~3;
式B和式I中:
R2选自下列基团之一:苯基、被硝基或氯取代的苯基、吡啶-2-甲基。
进一步,所述的有机碱A、有机碱B各自独立选自三乙胺、N,N-二异丙基乙胺(DIPEA)、4-二甲氨基吡啶(DMAP)中的一种或两种以上的混合物,优选为三乙胺和4-二甲氨基吡啶(DMAP)。
有机碱A、有机碱B都是有机碱,只是为了方便描述用字母区分,无特殊含义。
进一步,所述的缩合剂选自于苯并三氮唑-N,N,N’,N’-四甲基脲六氟磷酸(HBTU)、2-(7-氮杂苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)、1-羟基苯并三氮唑(HOBT)、1-(乙基)-3(3-二甲基丙胺)碳二亚胺(EDCI)、N,N’-二环己基碳二亚胺(DCC)中的一种或两种以上的混合物。优选为苯并三氮唑-N,N,N’,N’-四甲基脲六氟磷酸(HBTU)和1-(乙基)-3(3-二甲基丙胺)碳二亚胺(EDCI)。
进一步,所述的有机溶剂A、有机溶剂B各自独立选自于二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、乙酸乙酯、乙腈中的一种或两种以上的混合物,优选为二氯甲烷。
有机溶剂A、有机溶剂B都是有机溶剂,只是为了方便描述用字母区分,无特殊含义。
进一步,所述的有机溶剂A或有机溶剂B的体积以化合物B的物质的量计为0.2-2mL/mmol,优选为0.5-1mL/mmol。
本发明所述的后处理A或后处理B为:将反应液A或反应液B用硅胶拌样,经柱层析分离,以体积比为1~15:1的石油醚与乙酸乙酯的混合液为洗脱剂,收集含目标化合物的洗脱液,蒸除溶剂,即得式I所示的的C-14酰胺取代的脱氢松香酸衍生物。
本发明所述的式B所述的底物及化合物24参考以下文献制备:a)HouW.etal.Eur.J.Med.Chem.138(2017):1042-1052.化合物22、23参考以下文献制备:b)WO2010024298A1.
与现有技术相比,本发明的有益效果在于:本发明的脱氢松香酸衍生物,具有较好的抗癌活性,可用于制备抗肿瘤药物,具有很好的开发前景。
具体实施方式
通过以下具体实例进一步举例说明本发明,但应注意本发明的范围并不受这些实施例的任何限制。
除非另有说明,本发明中采用的制备和测试方法以及设备等为本领域中常规的方法和设备。所用试剂均为分析纯或化学纯。
本发明所述的式A所述的底物参考以下文献制备:a)Hou W.etal.Eur.J.Med.Chem.138(2017):1042-1052.
实施例1
称50mg(0.15mmol)化合物B,22mg(0.14mmol)对甲基苯甲酰氯加入试管中,加入2mL二氯甲烷溶解后,再加入15mg(0.15mmol)三乙胺。室温反应8小时后,加硅胶拌样后经硅胶柱色谱(石油醚:乙酸乙酯的体积比为10:1)纯化,收集含目标化合物的洗脱液,减压旋蒸得到白色固体产物1(60mg,收率95%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ7.79(d,J=8.0Hz,2H),7.28(d,J=8.0Hz,2H),7.24(s,1H),7.19–7.14(m,2H),3.61(s,3H),3.13–3.03(m,1H),2.88–2.66(m,2H),2.42(s,3H),2.30(d,J=13.0Hz,1H),2.21(d,J=13.0Hz,1H),1.80–1.66(m,4H),1.64–1.61(m,1H)(s,1H),1.50–1.35(m,2H),1.24(s,3H),1.21(s,3H),1.19(d,J=7.0Hz,3H),1.16(d,J=7.0Hz,3H).13C NMR(151MHz,CDCl3)δ179.00,166.29,147.94,143.23,142.16,132.95,131.90,131.72,129.37,127.15,124.28,123.34,51.91,47.53,44.07,38.06,37.10,36.43,28.45,26.44,25.15,23.72,23.25,21.46,21.21,18.56,16.44.
实施例2.
按照实施例1所述的方法,不同的是将对甲基苯甲酰氯改为对甲氧基苯甲酰氯(23.5mg,0.14mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为8:1)纯化,得到白色固体产物2(36mg,收率55%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ7.91–7.85(d,J=9.0Hz,2H),7.27(s,1H),7.17(d,J=8.0Hz,1H),7.12(s,1H),7.00–6.96(d,J=8.5Hz,2H),3.88(s,3H),3.63(s,3H),3.14–3.04(m,1H),2.87–2.67(m,2H),2.31(d,J=13.0Hz,1H),2.22(d,J=11.5Hz,1H),1.82–1.69(m,4H),1.65–1.62(m,1H),1.37(m,2H),1.25(s,3H),1.22(s,3H),1.21(d,J=7.0Hz,3H),1.18(d,J=7.0Hz,3H).13C NMR(151MHz,CDCl3)δ179.01,165.87,162.38,147.95,143.25,132.97,131.99,128.99,126.81,124.25,123.34,113.92,55.45,51.92,47.54,44.09,38.07,37.11,36.45,29.67,28.45,26.47,23.74,23.26,21.23,18.57,16.45.
实施例3.
按照实施例1所述的方法,不同的是将对甲基苯甲酰氯改为苯乙酰氯(22mg,0.14mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为6:1)纯化,得到白色固体产物3(38mg,收率61%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ7.44–7.37(m,4H),7.36–7.32(m,1H),7.19(d,J=8.5Hz,1H),7.07(d,J=8.5Hz,1H),6.40(s,1H),3.78(s,2H),3.65(s,3H),2.88–2.77(m,1H),2.66–2.48(m,2H),2.28–2.23(d,J=12.0Hz,1H),2.16(d,J=12.5Hz,1H),1.77–1.67(m,4H),1.65–1.62(m,1H),1.41–1.34(m,2H),1.24(s,3H),1.16(s,3H),1.13–1.04(m,6H).13C NMR(151MHz,CDCl3)δ178.98,169.81,147.93,142.76,135.05,132.75,131.62,129.56,129.30,127.69,124.33,123.20,51.92,47.50,44.17,37.98,37.02,36.40,28.31,26.12,25.10,23.47,23.03,22.66,21.18,18.52,16.43.
实施例4.
称取化合物B(60mg,0.18mmol),乙酰氯(17mg,0.22mmol)加入试管中,加入2mL二氯甲烷溶解后,再加入15mg(0.15mmol)三乙胺。室温反应8小时后,加硅胶拌样后经硅胶柱色谱(石油醚:乙酸乙酯的体积比为6:1)纯化,收集含目标化合物的洗脱液,减压旋蒸得到白色固体产物4(50mg,收率%,液相纯度99%)。
1H NMR(500MHz,DMSO-d6)δ8.76(s,1H),7.19(d,J=8.0Hz,1H),7.09(d,J=8.5Hz,1H),3.62(s,3H),3.08–2.98(m,1H),2.77–2.67(m,1H),2.63–2.53(m,1H),2.33(d,J=13.0Hz,1H),2.02(s,3H),2.00(d,J=1.5Hz,1H),1.79–1.64(m,4H),1.63–1.58(m,1H),1.41–1.34(m,2H),1.23(s,3H),1.17(s,3H),1.13(d,J=6.5Hz,1H),1.10(d,J=7.0Hz,1H).13C NMR(126MHz,DMSO)δ177.57,167.98,146.91,142.47,133.08,132.11,122.60,122.25,51.26,46.62,44.05,37.62,36.32,35.93,27.24,25.21,24.36,23.01,22.65,22.03,20.42,17.71,15.89.
实施例5.
按照实施例1所述的方法,不同的是将对甲基苯甲酰氯改为邻氯苯甲酰氯(24.5mg,0.14mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为6:1)纯化,得到白色固体产物5(63mg,收率96%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ7.81(dd,J=7.0,2.0Hz,1H),7.47(dd,J=8.0,1.5Hz,1H),7.44–7.36(m,2H),7.33(s,1H),7.28(t,J=8.5Hz,1H),7.19(d,J=8.5Hz,1H),3.64(s,3H),3.27–3.17(m,1H),2.96–2.74(m,2H),2.32(d,J=12.0Hz,1H),2.24(d,J=12.5Hz,1H),1.87–1.69(m,4H),1.66–1.61(m,1H),1.55–1.41(m,2H),1.26(s,3H),1.255–1.225(m,6H),1.21(d,J=7.0Hz,3H).13C NMR(151MHz,CDCl3)δ178.98,165.32,148.05,143.26,135.13,132.96,131.51,131.32,130.61,130.50,130.36,127.21,124.61,123.38,51.91,47.52,44.01,38.04,37.11,36.42,28.44,26.61,25.15,23.78,23.25,21.25,18.54,16.44.
实施例6.
称50mg(0.15mmol)化合物A,26mg(0.14mmol)邻硝基苯甲酰氯加入试管中,加入2mL二氯甲烷溶解后,再加入15mg(0.15mmol)三乙胺和3.4mg(0.028mmol)DMAP。室温反应8小时后,加硅胶拌样后经硅胶柱色谱(石油醚:乙酸乙酯的体积比为8:1)纯化,收集含目标化合物的洗脱液,减压旋蒸得到白色固体产物6(19mg,收率28%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ8.08(d,J=8.0Hz,1H),7.75–7.71(m,2H),7.66–7.59(m,1H),7.30(d,J=8.5Hz,1H),7.21(d,J=8.5Hz,1H),7.06(s,1H),3.65(s,3H),3.40–3.30(m,1H),3.08–2.77(m,2H),2.32(d,J=12.0Hz,1H),2.23(d,J=12.5Hz,1H),1.88–1.69(m,4H),1.67–1.62(m,1H),1.54–1.45(m,2H),1.27(s,3H),1.26–1.24(m,6H),1.24(d,J=3.0Hz,3H).13C NMR(126MHz,CDCl3)δ179.04,164.96,148.08,146.99,143.69,133.53,133.08,130.73,130.53,128.63,124.82,124.75,123.52,51.93,47.51,44.01,38.05,37.11,36.46,28.10,26.35,25.12,23.92,23.39,21.28,18.53,16.43.
实施例7.
按照实施例1所述的方法,不同的是将对甲基苯甲酰氯改为2-噻吩甲酰氯(20.5mg,0.14mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为8:1)纯化,得到白色固体产物7(43mg,收率70%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ7.66(dd,J=3.5,1.0Hz,1H),7.53(dd,J=5.0,1.0Hz,1H),7.28(s,1H),7.20–7.12(m,2H),7.08(s,1H),3.63(s,3H),3.15–3.04(m,1H),2.87–2.71(m,2H),2.32(d,J=12.0Hz,1H),2.22(d,J=12.5Hz,1H),1.83–1.70(m,4H),1.65–1.62(m,1H),1.51–1.36(m,2H),1.25(s,3H),1.23–1.20(m,6H),1.18(d,J=3.0Hz,3H).13C NMR(126MHz,CDCl3)δ178.98,160.62,148.02,143.38,138.56,133.10,131.38,130.10,128.79,127.82,124.49,123.39,51.94,47.54,44.10,38.08,37.12,36.47,28.50,26.45,25.15,23.71,23.28,21.20,18.57,16.46.
实施例8.
按照实施例1所述的方法,不同的是将对甲基苯甲酰氯改为苯甲酰氯(20mg,0.14mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为8:1)纯化,得到白色固体产物8(93mg,收率99%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ7.91(d,J=7.0Hz,2H),7.57(t,J=7.5Hz,1H),7.50(t,J=8.0Hz,2H),7.28(d,J=8.5Hz,1H),7.18(d,J=9.0Hz,2H),3.63(s,3H),3.15–3.05(m,1H),2.88–2.70(m,2H),2.32(d,J=12.5Hz,1H),2.23(d,J=13.0Hz,1H),1.81–1.70(m,4H),1.66–1.63(m,1H),1.45–1.34(m,2H),1.26(s,3H),1.23(s,3H),1.22(d,J=7.0Hz,3H),1.19(d,J=7.0Hz,3H).13C NMR(151MHz,CDCl3)δ179.00,166.41,148.03,143.23,134.64,132.94,131.76,131.73,128.77,127.13,124.42,123.40,51.93,47.55,44.09,38.08,37.13,36.45,28.49,26.48,25.17,23.74,23.27,21.23,18.57,16.46.
实施例9.
按照实施例4所述的方法,不同的是将乙酰氯改为4-三氟甲基苯甲酰氯(42mg,0.2mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为6:1)纯化,得到白色固体产物9(93mg,收率51%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ8.02(d,J=8.0Hz,2H),7.77(d,J=8.0Hz,2H),7.29(d,J=8.5Hz,1H),7.23(s,1H),7.19(d,J=8.0Hz,1H),3.63(s,3H),1.47–3.01(m,1H),2.87–2.69(m,2H),2.32(d,J=12.5Hz,1H),2.21(d,J=9.5Hz,1H),1.84–1.69(m,4H),1.66–1.63(m,1H),1.47–1.38(m,2H),1.26(s,3H),1.23(s,3H),1.22(d,J=7.0Hz,3H),1.19(d,J=7.0Hz,3H).
实施例10.
按照实施例4所述的方法,不同的是将乙酰氯改为2,4,6-三氯苯甲酰氯(53mg,0.22mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为15:1)纯化,得到白色固体产物10(53mg,收率55%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ7.41(s,2H),7.29(d,J=8.5Hz,1H),7.19(d,J=8.5Hz,1H),6.91(s,1H),3.65(s,3H),3.48–3.38(m,1H),3.15–3.00(m,1H),2.93–2.77(m,1H),2.33–2.29(d,J=12.5Hz,1H),2.23–2.19(d,J=11.5Hz,1H),1.81–1.71(m,4H),1.67–1.64(s,1H),1.48–1.44(m,2H),1.26(s,3H),1.25(s,3H),1.24(d,J=7.0Hz,3H),1.19(d,J=7.0Hz,3H).13C NMR(126MHz,CDCl3)δ178.98,162.42,148.04,143.51,135.88,134.65,133.21,132.93,130.19,128.46,124.88,123.58,51.90,47.50,44.01,43.95,38.11,37.13,36.44,27.95,27.07,25.08,24.10,23.47,21.21,18.60,18.54,16.46.
实施例11.
按照实施例1所述的方法,不同的是将对甲基苯甲酰氯改为4-氟苯甲酰氯(22.19mg,0.14mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为8:1)纯化,得到白色固体产物11(93mg,收率99%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ7.93–7.88(m,2H),7.28(d,J=9.0Hz,1H),7.21(s,1H),7.20–7.10(m,3H),3.62(s,3H),3.12–3.01(m,1H),2.89–2.66(m,2H),2.31(d,J=12.5Hz,1H),2.20(d,J=13.0Hz,1H),1.80–1.70(m,4H),1.66–1.62(m,1H),1.44–1.35(m,2H),1.25(s,3H),1.22(s,3H),1.20(d,J=6.5Hz,3H),1.18(d,J=6.5Hz,3H).13C NMR(150MHz,CDCl3)δ178.99,165.37,164.85(d,J=252.4Hz),148.05,143.21,132.87,131.69,130.68(d,J=3.2Hz),129.50(d,J=8.9Hz),124.47,123.42,115.76(d,J=22.0Hz),51.92,47.52,44.07,38.05,37.12,36.46,28.48,26.45,25.16,23.73,23.26,21.21,18.55,16.44.
实施例12.
按照实施例1所述的方法,不同的是将对甲基苯甲酰氯改为3,4,5-三甲氧基苯甲酰氯(32.3mg,0.14mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为8:1)纯化,得到白色固体产物12(36mg,收率49%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ7.28(d,J=8.5Hz,3H),7.18(d,J=8.5Hz,3H),7.16(s,1H),7.14(s,2H),3.94(s,6H),3.91(s,3H),3.63(s,3H),3.13–3.03(m,1H),2.87–2.69(m,2H),2.32(d,J=12.5Hz,1H),2.22(d,J=12.5Hz,1H),1.81–1.70(m,4H),1.66–1.63(m,1H),1.47–1.36(m,2H),1.26(s,3H),1.24–1.21(m,6H),1.19(d,J=7.0Hz,3H).13CNMR(126MHz,CDCl3)δ178.96,165.95,153.33,147.99,143.05,141.27,132.78,131.77,129.93,124.31,123.35,104.68,60.87,56.37,51.89,47.50,44.10,38.05,37.09,36.46,28.45,26.40,25.13,23.69,23.25,21.19,18.52,16.42.
实施例13.
按照实施例4所述的方法,不同的是将乙酰氯改为呋喃甲酰氯(21.78mg,0.17mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为6:1)纯化,得到白色固体产物13(24mg,收率37%,液相纯度99%)。
1H NMR(500MHz,DMSO-d6)δ9.51(s,1H),7.89(s,1H),7.28(d,J=8.5Hz,1H),7.23(d,J=3.0Hz,1H),7.15(d,J=8.5Hz,1H),6.671(s,1H),3.59(s,3H),3.04–2.94(m,1H),2.92–2.53(m,2H),2.35(d,J=12.5Hz,1H),2.01(d,J=13.0Hz,1H),1.79–1.64(m,4H),1.61–1.55(m,1H),1.35–1.26(m,2H),1.19(s,3H),1.16(s,3H),1.12(d,J=7.0Hz,3H),1.07(d,J=6.5Hz,3H).13C NMR(126MHz,CDCl3)δ178.96,157.05,147.99,147.96,144.09,143.39,133.06,130.78,124.49,123.38,114.88,112.35,51.92,47.55,44.07,38.07,37.12,36.44,28.46,26.46,25.15,23.72,23.30,21.18,18.57,16.46.
实施例14.
称60mg(0.18mmol)化合物B,27.5mg(0.3mmol)对2-吡啶乙酸和DIPEA(69.7mg,0.54mmol)、HATU(103mg,0.27mmol)加入试管中,再加入2mL二氯甲烷。室温反应8小时后,加硅胶拌样后经硅胶柱色谱(石油醚:乙酸乙酯的体积比为10:1)纯化,收集含目标化合物的洗脱液,减压旋蒸得到白色固体产物14(38mg,收率47%,液相纯度99%)。
1H NMR(500MHz,DMSO-d6)δ9.27(s,1H),8.51(d,J=4.0Hz,1H),7.76(t,J=7.5Hz,1H),7.41(d,J=8.0Hz,1H),7.27(t,J=5.0Hz,1H),7.20(d,J=8.0Hz,1H),7.08(d,J=8.0Hz,1H),3.82(s,2H),3.60(s,3H),2.98(s,1H),2.69(m,2H),2.32(d,J=12.5Hz,1H),1.97(d,J=13.0Hz,1H),1.74–1.61(m,4H),1.60–1.55(m,1H),1.28–1.22(m,2H),1.19(s,3H),1.14(s,3H),1.09–0.96(m,6H).13C NMR(126MHz,CDCl3)δ178.99,167.87,155.77,148.95,147.84,142.74,137.39,132.82,132.20,124.15,123.98,123.11,122.19,51.88,47.54,45.12,43.99,38.02,37.06,36.41,29.66,28.36,26.15,25.14,21.21,18.56,16.44,0.99.
实施例15.
按照实施例14所述的方法,不同的是将对2-吡啶乙酸改为对2-吡啶甲酸(24.6mg,0.2mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为6:1)纯化,得到白色固体产物15(79mg,收率100%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ9.33(s,1H),8.63(d,J=4.5Hz,1H),8.29(d,J=7.5Hz,1H),7.90(td,J=8.0,2.0Hz,1H),7.51–7.46(m,1H),7.28(d,J=8.5Hz,1H),7.18(d,J=8.5Hz,1H),3.62(s,3H),3.15–3.04(m,1H),2.87–2.69(m,2H),2.32(d,J=12.0Hz,1H),2.23(d,J=12.5,1H),1.82–1.70(m,4H),1.64–1.60(m,1H),1.43–1.34(m,2H),1.25(s,3H),1.23(s,3H),1.22(d,J=7.0Hz,3H),1.18(d,J=6.5Hz,3H).13C NMR(126MHz,CDCl3)δ178.96,162.92,149.85,148.13,147.86,143.04,137.44,132.81,131.78,126.28,124.07,123.26,122.51,51.88,47.54,44.09,38.07,37.11,36.44,28.50,26.41,25.15,23.70,23.29,21.20,18.57,16.45.
实施例16.
按照实施例4所述的方法,不同的是将乙酰氯改为6-氯烟酰氯(26.15mg,0.2mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为8:1)纯化,得到白色固体产物16(43mg,收率50%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ8.89(d,J=2.5Hz,1H),8.16(dd,J=8.0,2.5Hz,1H),7.41(d,J=6.0Hz,1H),7.40(s,1H),7.29(d,J=8.5Hz,1H),7.19(d,J=8.5Hz,1H),3.61(s,3H),3.08–2.98(m,1H),2.83–2.65(m,2H),2.30(d,J=12.5Hz,1H),2.16(d,J=12.5Hz,1H),1.80–1.70(m,4H),1.64–1.60(m,1H),1.44–1.35(m,2H),1.24(s,3H),1.21(s,3H),1.19(d,J=8.5Hz,3H),1.17(d,J=7.0Hz,3H).13C NMR(126MHz,CDCl3)δ178.96,163.54,154.48,148.20,148.11,143.15,138.18,132.72,131.14,129.01,124.78,124.47,123.52,51.92,47.48,44.08,38.02,37.10,36.46,28.53,26.45,25.13,23.69,23.24,21.15,18.51,16.42.
实施例17.
按照实施例4所述的方法,不同的是将乙酰氯改为2,4,6-三氟苯甲酰氯(42.5mg,0.22mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为6:1)纯化,得到白色固体产物17(45mg,收率51%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ7.29(d,J=8.5Hz,1H),7.18(d,J=8.5Hz,1H),7.00(s,1H),6.80–6.73(m,2H),3.64(s,3H),3.23–3.10(m,1H),2.95–2.70(m,2H),2.30(d,J=12.0Hz,1H),2.22(d,J=12.5Hz,1H),1.86–1.69(m,4H),1.66–1.61(m,1H),1.52–1.42(m,2H),1.26(s,3H),1.25–1.21(m,6H),1.20(d,J=7.0Hz,3H).13C NMR(150MHz,CDCl3)δ178.99,163.42(ddd,J=254.2,15.1,14.6Hz),160.56(ddd,J=253.2,14.9,10.1Hz),158.66,148.13,143.27,132.97,130.75,124.87,123.37,111.36(ddd,J=21.9,21.9,4.5Hz),100.98(m),51.93,47.53,44.02,38.03,37.12,36.44,28.40,26.26,25.15,23.68,23.17,21.24,18.55,16.45.
实施例18.
按照实施例4所述的方法,不同的是将乙酰氯改为2,4-二氟苯甲酰氯(38.7mg,0.22mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为6:1)纯化,得到白色固体产物18(54mg,收率63%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ7.79–7.73(m,1H),7.67–7.61(m,1H),7.28(d,J=8.0Hz,1H),7.23(d,J=8.5Hz,1H),7.20(s,1H),7.18(d,J=8.5Hz,1H),3.63(s,3H),3.09–2.99(m,1H),2.88–2.64(m,2H),2.32(d,J=12.0Hz,1H),2.20(d,J=12.5Hz,1H),1.83–1.69(m,4H),1.67–1.61(m,1H),1.47–1.35(m,2H),1.25(s,3H),1.22(s,3H),1.20(d,J=7.0Hz,3H),1.18(d,J=7.0Hz,3H).13C NMR(150MHz,CDCl3)δ178.98,164.28,152.62(dd,J=254.7,12.7Hz),150.35(dd,J=251.1,13.0Hz),148.11,143.14,132.75,131.51(m),131.38,124.63,123.48(m),123.48,117.59(d,J=17.8Hz),117.12(d,J=18.4Hz),51.93,47.51,44.07,38.03,37.11,36.46,28.51,26.44,25.15,23.72,23.25,21.19,18.54,16.44.
实施例19.
称60mg(0.18mmol)化合物A、40mg(0.22mmol)对3,5-苯甲酸、EDCI(52mg,0.27mmol)、DIPEA(46mg,0.36mmol)、DMAP(1mg,0.009mmol)和HOBT(36.5mg,0.27mmol)加入试管中,再加入2mL DMF。在室温下反应6小时。将反应液用乙酸乙酯和饱和食盐水萃取7次,收集有机相,无水硫酸钠干燥,过滤。所得溶液加硅胶拌样后经硅胶柱色谱(石油醚:乙酸乙酯的体积比为6:1)纯化,得到白色固体产物19(26mg,收率29%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ7.28(s,1H),7.21–7.15(m,2H),7.03(d,J=2.5Hz,2H),6.63(t,J=2.0Hz,2H),3.86(s,6H),3.63(s,3H),3.13–3.03(m,1H),2.86–2.68(m,2H),2.31(d,J=12.5Hz,2H),2.22(d,J=12.5Hz,2H),1.83–1.69(m,4H),1.68–1.63(m,1H),1.45–1.35(m,2H),1.25(s,3H),1.22(s,3H),1.21(d,J=7.0Hz,3H),1.18(d,J=7.0Hz,3H).13C NMR(126MHz,CDCl3)δ178.99,166.20,161.03,148.00,143.16,136.81,132.89,131.67,124.38,123.36,105.15,103.53,55.60,51.92,47.53,44.09,38.06,37.11,36.44,29.66,28.46,26.41,25.14,23.71,23.26,21.19,18.55,16.44.
实施例20.
按照实施例1所述的方法,不同的是将对甲基苯甲酰氯改为对氯苯甲酰氯(24mg,0.14mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为12:1)纯化,得到白色固体产物20(49mg,收率75%,液相纯度99%)。
1H NMR(600MHz,Chloroform-d)δ7.81(d,J=8.4Hz,2H),7.40(s,1H),7.38(d,J=8.4Hz,2H),7.28(d,J=8.4Hz,1H),7.18(d,J=8.4Hz,1H),3.61(s,1H),3.10–3.01(m,1H),2.82–2.66(m,2H),2.34(d,J=12.6Hz,1H),2.18(d,J=12.0Hz,1H),1.80–1.69(m,4H),1.64–1.60(m,1H),1.43–1.28(m,2H),1.24(s,3H),1.21(s,3H),1.19(d,J=7.2Hz,3H),1.17(d,J=6.6Hz,3H).13C NMR(126MHz,CDCl3)δ178.96,165.39,148.04,143.20,137.90,132.84,132.76,131.67,128.91,128.62,124.47,123.41,51.89,47.50,44.07,38.03,37.09,36.45,28.47,26.42,25.15,23.71,23.23,21.18,18.54,16.43.
实施例21.
按照实施例4所述的方法,不同的是将乙酰氯改为3,5-二氯苯甲酰氯(46mg,0.22mmol),经硅胶柱色谱(石油醚:乙酸乙酯的体积比为12:1)纯化,得到白色固体产物21(53mg,收率59%,液相纯度99%)。
1H NMR(600MHz,Chloroform-d)δ7.77(s,2H),7.53(s,1H),7.30(s,1H),7.28(d,J=8.4Hz,1H),7.18(d,J=8.4Hz,1H),3.62(s,3H),3.08–2.96(m,1H),2.81–2.65(m,2H),2.31(d,J=13.2Hz,1H),2.19(d,J=12.6Hz,1H),1.69–1.81(m,4H),1.66–1.62(m,1H),1.44–1.28(m,2H),1.25(s,3H),1.21(s,3H),1.20(d,J=6.6Hz,3H),1.17(d,J=6.6Hz,3H).13C NMR(126MHz,CDCl3)δ179.01,163.95,148.09,143.10,137.43,135.62,132.66,131.54,131.13,125.80,124.69,123.49,77.25,51.94,47.50,44.05,38.02,37.10,36.43,28.50,26.39,25.12,23.70,23.26,21.15,18.52,16.43.
实施例22.
参考文献WO2010024298A1合成,得到白色固体产物22(65mg,收率80%,液相纯度99%)。
1H NMR(400MHz,Chloroform-d)δ7.67(s,1H),7.39–7.45(m,2H),7.39–7.32(m,3H),6.89(s,1H),6.81(s,1H),3.77(s,2H),3.65(s,3H),2.86–2.76(m,2H),2.37–2.49(m,1H),2.34–2.27(m,1H),2.18(dd,J=12.4,0.2Hz,1H),1.85–1.67(m,5H),1.53–1.45(m,1H),1.42–1.35(m,1H),1.26(s,3H),1.19(s,3H),1.00(d,J=6.8Hz,3H),0.96(d,J=6.8Hz,3H).
实施例23.
参考文献WO2010024298A1合成,得到白色固体产物23(64mg,收率71%,液相纯度99%)。
1H NMR(400MHz,Chloroform-d)δ7.76(d,J=8.0Hz,1H),7.70–7.56(m,4H),7.23(s,1H),6.97(s,1H),3.66(s,3H),3.05–2.93(m,1H),2.91–2.86(m,2H),2.33(d,J=12.4,1H),2.24(dd,J=12.4,2.0Hz,1H),1.90–1.66(m,5H),1.60–1.51(m,1H),1.46–1.39(m,1H),1.28(s,3H),1.25(s,3H),1.23(d,J=6.8Hz,3H),1.21(d,J=6.8Hz,3H).
实施例24.
参考文献Hou W.et al.Eur.J.Med.Chem.138(2017):1042-1052.合成,得到白色固体产物24(130mg,收率81%,液相纯度99%)。
1H NMR(500MHz,Chloroform-d)δ6.78(d,J=8.4Hz,1H),6.67(d,J=8.4Hz,1H),3.75(s,2H),3.15(s,3H),2.49(hept,J=6.8Hz,1H),2.31–2.06(m,2H),1.81(dd,J=12.7,3.0Hz,1H),1.75–1.63(m,1H),1.36–1.17(m,5H),1.14(d,J=7.0Hz,1H),1.07–0.87(m,2H)0.76(s,3H),0.71(m,6H),0.68(d,J=6.9Hz,3H).
体外抗肿瘤活性实验
采用MTT法并选取肺癌A549、乳腺癌MCF-7细胞进行体外抗肿瘤活性评价(采用5-氟尿嘧啶和鬼臼毒素作为阳性对照),操作如下:
1、分别在96孔板中接种100μL A549、MCF-7细胞悬液,每孔细胞密度为3000-5000个,设不含细胞的空白对照,将铺好的96孔板放入CO2恒温培养箱中孵育12小时,使细胞贴壁;
2、用移液枪吸走原培养基,向孔板中加入100μL不同浓度的待测化合物(分别是母核、5-氟尿嘧啶和鬼臼毒素),每个浓度设置5个平行副孔。在CO2恒温培养箱中孵育96小时后,吸取原培养液,向每孔中加入100μL的MTT溶液(5mg/mL),在CO2恒温培养箱(37℃,5%CO2)中反应4小时。
3、用酶标仪检测样品于560nM和620nM处的吸光度:
细胞活力(%)=(A加药-A空白)/(A0加药-A空白)×100%
A加药:含有细胞悬液、MTT溶液和待测化合物溶液的孔的吸光度
A空白:不含细胞悬液,含有培养基溶液、MTT溶液和待测化合物溶液的孔的吸光度
A0加药:不含待测化合物溶液,含有细胞悬液、MTT溶液和培养基溶液的孔的吸光度
细胞抑制率(%)=(A0加药-A加药)/(A0加药-A空白)×100%
表1、化合物在五种浓度下对A549细胞的抑制率
表1的结果表明:所测的21个化合物中有3个化合物在50μM时对A549细胞的抑制率大于50%,有3个化合物在25μM和12.5μM时对A549细胞的抑制率大于50%,有1个化合物在6.25μM时对A549细胞的抑制率大于50%。可见,这一类脱氢松香酸衍生物具有良好的抗肿瘤活性,代表所述的化合物具有显著的抗肿瘤活性。
表2、化合物在五种浓度下对MCF-7细胞的抑制率
表2的结果表明:化合物1-21中有6个化合物在50μM时对MCF-7细胞的抑制率大于50%,有5个化合物在25μM和12.5μM时对MCF-7细胞的抑制率大于50%,有2个化合物在6.25μM时对MCF-7细胞的抑制率大于50%。可见,这一类脱氢松香酸衍生物具有良好的抗肿瘤活性,代表所述的化合物具有显著的抗肿瘤活性。然而C-12取代的化合物22、23和已知化合物24在五种浓度下对MCF-7细胞的抑制率均不超过50%。这一结果说明化合物10和14具有一定的抗肿瘤活性。
进一步选取活性较好的化合物10和14测试它们对肺癌细胞A549、肝癌细胞HepG2、乳腺癌细胞MCF-7、结肠癌细胞HCT-116的半数抑制浓度IC50。结果如表3所示:化合物10、14对四种肿瘤细胞的IC50值均小于20μM,其中化合物10对四种肿瘤细胞的IC50均小于5μM,并且二者的抗增殖活性都强于阳性药物5-FU,这些良好的结果进一步说明这类化合物具有显著的抗肿瘤活性。
表3、部分化合物对几种肿瘤细胞的抑制活性
a每个实验采用9个浓度且至少重复三遍
上述实例只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人员能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所做的等效变换或修饰,都应涵盖在本发明的保护范围之内。
Claims (10)
3.如权利要求1所述的式Ⅰ所示C-14酰胺取代的脱氢松香酸衍生物在制备抗肿瘤药物中的应用。
4.如权利要求3所述的应用,其特征在于:所述的肿瘤为人乳腺癌、肝癌、结肠癌或非小细胞肺癌。
5.如权利要求4所述的应用,其特征在于:所述的肿瘤为人乳腺癌或非小细胞肺癌。
7.如权利要求1所述的式I所示的C-14酰胺取代的脱氢松香酸衍生物的制备方法,其特征在于按照下列两种方法之一进行制备:
(1)式C中,R1为氯;将式B所示的化合物、式C所示化合物和有机碱A添加于有机溶剂A中,在0-50℃下反应2-12h,所得反应液A经后处理A得到式I所示的的C-14酰胺取代的脱氢松香酸衍生物;式B所示的化合物、式C所示的化合物与有机碱A的物质的量之比为1:0.5~1.5:1~1.5;
(2)式C中,R1为羟基;将式B所示化合物和式C所示化合物和缩合剂以及有机碱B添加于有机溶剂B中,在0-50℃下反应2-12h,所得反应液B经后处理B得到式I所示的目标化合物;式B所示的化合物、式C所示的化合物、有机碱B与缩合剂的物质的量之比为1:0.5~1.5:0.05~2.5:1~3;
式B和式I中:
R2选自下列基团之一:苯基、被硝基或氯取代的苯基、吡啶-2-甲基。
8.如权利要求7所述的式I所示的C-14酰胺取代的脱氢松香酸衍生物的制备方法,其特征在于:所述的有机碱A、有机碱B各自独立选自三乙胺、N,N-二异丙基乙胺、4-二甲氨基吡啶中的一种或两种以上的混合物。
9.如权利要求7所述的式I所示的C-14酰胺取代的脱氢松香酸衍生物的制备方法,其特征在于:所述的缩合剂选自于苯并三氮唑-N,N,N’,N’-四甲基脲六氟磷酸、2-(7-氮杂苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯、1-羟基苯并三氮唑(HOBT)、1-(乙基)-3(3-二甲基丙胺)碳二亚胺、N,N’-二环己基碳二亚胺中的一种或两种以上的混合物。
10.如权利要求7所述的式I所示的C-14酰胺取代的脱氢松香酸衍生物的制备方法,其特征在于:所述的有机溶剂A、有机溶剂B各自独立选自于二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、乙酸乙酯、乙腈中的一种或两种以上的混合物;所述的有机溶剂A或有机溶剂B的体积以化合物B的物质的量计为0.2-2mL/mmol;
所述的后处理A或后处理B为:将反应液A或反应液B用硅胶拌样,经柱层析分离,以体积比为1~15:1的石油醚与乙酸乙酯的混合液为洗脱剂,收集含目标化合物的洗脱液,蒸除溶剂,即得式I所示的的C-14酰胺取代的脱氢松香酸衍生物。
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