CN115028678A - 基于vhl配体诱导bcr-abl蛋白降解的双功能分子及其制备方法和应用 - Google Patents
基于vhl配体诱导bcr-abl蛋白降解的双功能分子及其制备方法和应用 Download PDFInfo
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- CN115028678A CN115028678A CN202210804551.8A CN202210804551A CN115028678A CN 115028678 A CN115028678 A CN 115028678A CN 202210804551 A CN202210804551 A CN 202210804551A CN 115028678 A CN115028678 A CN 115028678A
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Abstract
本发明公开了一种基于VHL配体诱导BCR‑ABL蛋白降解的双功能分子及其制备方法和应用,所述的双功能分子的结构如式(I)所示;其中:X为1~10的整数,Y为0~10的整数。该双功能分子具有较好的对肿瘤细胞的增殖抑制活性,可应用于制备治疗、预防及缓解疾病的药物;所述的疾病因BCR‑ABL融合蛋白表达过多而引起。
Description
技术领域
本发明涉及化学合成技术领域,尤其涉及一种基于VHL配体诱导BCR-ABL蛋白降解的双功能分子及其制备方法和应用。
背景技术
慢性粒细胞白血病(CML)是一种以融合基因BCR-ABL为特征的骨髓增生性疾病,该融合基因是由9号染色体上的ABL基因与22号染色体上的BCR基因易位产生的,从而产生了一种具有结构性活性的蛋白酪氨酸激酶BCR-ABL。BCR-ABL的激酶活性激活下游信号通道,从而导致患者CML细胞的不受调控的增殖。当前已有多个BCR-ABL酪氨酸激酶抑制剂作为ATP竞争性抑制剂被批准用于CML的临床治疗。
Imatinib(式1)作为首个酪氨酸激酶抑制剂(TKI)及第一代ABL抑制剂已经取得了显著的临床效果,被用作CML患者的一线治疗药物。尽管Imatinib已成为靶向癌症治疗的典范,但由于不耐受和耐药性,使得Imatinib对40%左右的患者无效,尤其是以T315I突变为代表的BCR-ABL突变,使得患者产生更加严重的耐受性。第二代Nilotinib(式2)、Dasatinib(式3)、Bosutinib(式4)和第三代Ponatinib(式5)ABL抑制剂的问世为部分突变的患者提供了多种治疗选择。
尽管这些靶向小分子抑制剂在临床上取得令人满意的治疗结果,但是,经过一段时间的服药由于BCR-ABL激酶结构域的点突变从而引起相当多的患者产生获得性耐药,严重影响了其进一步的临床使用。另一方面,比如Ponatinib的血管疾病、Dasatinib的肺动脉高压等副作用严重影响了其临床的应用。目前,尚未有靶向T315I突变的新药获批。因此,急需寻找一种不同于传统抑制剂的全新作用机制的策略来实现CML的治疗与药物开发,为CML的治疗与药物研发提供新思路。
蛋白降解靶向嵌合体(Proteolytic targeting chimera,PROTAC)技术是一种化学诱导靶蛋白(Protein of interest,POI)多泛素化,最终通过蛋白酶体系统降解POI的新兴技术,为疾病的治疗提供了新的策略。PROTAC是由靶蛋白配体和E3泛素连接酶配体通过适当的连接链组成的双功能分子,其独特的作用模式具有广泛的应用前景和发展空间。PROTAC技术可用于研究传统手段无法胜任的难治药物靶点,并为解决获得性耐药提供了一种新的途径。PROTAC将成为继小分子抑制剂和单克隆抗体之后的又一重要领域,并预示着生物医药创新的新纪元。
2015年,Crews课题组开发了首个BCR-ABL降解剂,他们以CRBN配体和Dasatinib为基础,构建了PROTAC分子DAS-6-2-2-6-CRBN(式6)以诱导c-ABL降解[ChemicalCommunications,2020,p56]。经过评估,该PROTAC分子DAS-6-2-2-6-CRBN可引起两种类型ABL蛋白的降解(c-ABL,在1μM时大于85%;BCR-ABL,在1μM时大于60%)。同时,研究还发现DAS-6-2-2-6-CRBN对K562细胞的生长有明显的抑制作用,其EC50值为4.4nM。随后,在2017年Naito课题组报道了第二个基于Dasatinib衍生物的PROTAC分子DAS-IAP(式7,其在抑制CML细胞生长和持续的抗增殖作用方面具有良好的活性[Acs Medicinal Chemistry Letters,2017,p1042]。接下来是于2019年报道的基于Imatinib的新颖PROTAC分子GMB-475,它不仅可以降解野生型BCR-ABL还能降解特定突变的BCR-ABL[Cancer Res.2019;79(18):4744],在300nM下对K562和Ba/F3细胞的BCR-ABL1和c-ABL1均有显著降解作用。GMB-475对BaF3(T315I突变)的IC50达1.98μM,活性是Imatinib的20倍,对G250E突变的细胞株的IC50达0.37μM。在降解方面,GMB-475可以完全降解G250E突变蛋白(DC50=310nM)。与Crews课题组开发的DAS-6-2-2-6-CRBN(EC50=8.8nM)具有相当的抗肿瘤细胞增殖活性。2019年,Jiang课题组报道了基于VHL和Dasatinib构建的PROTAC分子SIAIS178(式8),SIAIS178具有良好的选择性,其对BCR-ABL的DC50值为8.5nM,同时对K562细胞表现出良好的抗增殖活性(IC50值为24nM),并且对小鼠K562移植瘤模型具有很强的抗肿瘤活性[Journal of medicinalchemistry,2019,62(20):9281]。2020年,Crews研究团队合成出了与GMB-475相比更具强诱导BCR-ABL降解的能力的GMB-805(式9)(DC50=30nM),其对BCR-ABL驱动的K562细胞具有很强的抗增殖活性,IC50为169nM,在诱导降解的能力上增加了10倍以上,并显示了体内活性[.Chem Commun(Camb).2020;56(50):6890]。
虽然以上研究都得到了降解效果明显、细胞抑制活性优良的降解剂,但是其对于突变型的BCR-ABL的降解效果均不佳,这成为限制其进一步使用的最大缺点,因此开发能够降解野生型和突变型的BCR-ABL降解剂显得格外重要。
当前,已报道的靶向降解BCR-ABL的PROTAC分子均以结合能力较强的完整抑制剂(如伊马替尼、达沙替尼)为弹头,其分子量庞大,虽在细胞活性评价方面表现良好的降解效果,但鲜有文章报道其在动物水平的活性评价,主要原因是基于完整抑制剂的弹头虽结合能力强,但较大的分子量影响某些特定组织的细胞通透性,进而影响其生物利用度,严重阻滞其在动物模型方面的进一步研究,离临床研究更为遥远。目前尚未检索到基于弱结合的弹头实现BCR-ABL融合蛋白降解的相关文献。
发明内容
本发明提供了一种基于VHL配体诱导BCR-ABL蛋白降解的双功能分子,是一类新的基于弱结合的弹头实现BCR-ABL融合蛋白降解的PROTAC化合物。本发明提供的双功能分子化合物分子量小,具有类似的降解性能,且合成方法成本低,反应体系简单安全。
本发明的技术方案如下:
一种如式(I)所示结构的化合物、其立体异构体或其药学上可接受的盐;
其中:X为1~10的整数,Y为0~10的整数。
优选的,X为1~4的整数,Y为1~4的整数。
所述的药学上可接受的盐为盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、磷酸盐、乙酸盐、丙酸盐、丁酸盐、草酸盐、酒石酸盐、甲磺酸盐、对甲苯磺酸盐、富马酸盐、牛磺酸盐、柠檬酸盐、琥珀酸盐,或其混合盐。
本发明还提供了如式(I)所示结构的化合物的制备方法,包括以下步骤:
(1)将化合物1和炔基酸A作为起始原料在缩合剂HATU作用下得到末端炔基中间体B;
(2)将末端炔基中间体B和叠氮化合物C通过点击化学反应得到如式(I)所示结构的化合物;
其中:X为1~10的整数,Y为0~10的整数。
所述制备方法的反应方程式如下所示:
其中:X为1~10的整数,Y为0~10的整数。
本发明还提供了一种药物组合物,其包含治疗有效量的如式(I)所示结构的化合物、其立体异构体或其药学上可接受的盐,以及药学上可接受的赋形剂或载体。
本发明还提供了所述的化合物、其立体异构体或其药学上可接受的盐在制备用于治疗、预防及缓解疾病的药物中的应用;所述的疾病因BCR-ABL融合蛋白表达过多而引起。
在所述的应用中,所述的化合物、其立体异构体或其药学上可接受的盐作为蛋白降解靶向嵌合体化合物。
优选的,所述的疾病为慢性粒细胞白血病。
本发明还提供了所述的药物组合物在制备用于治疗、预防及缓解疾病的药物中的应用;所述的疾病因BCR-ABL融合蛋白表达过多而引起。
与现有技术相比,本发明的有益效果为:
本发明结合PROTAC的降解独特优势(对靶蛋白的结合亲和力要求较低)以及达沙替尼的结构优化历程,以弱结合的2-氨基-N-(2-氯-6-甲基苯基)-噻唑-5-甲酰胺(化合物1)为弹头,以Von Hippel-Lindau(VHL)为E3连接酶配体设计新型的PROTAC分子。本发明所提供的降解BCR-ABL融合蛋白的PROTAC化合物(如式(I)所示结构的化合物)具有较好的对肿瘤细胞的增殖抑制活性,因而,可以在制备治疗、预防及缓解癌症的药物中有所应用,或者作为先导化合物用于设计活性更高的候选分子。并且,本发明提供的降解BCR-ABL融合蛋白的PROTAC化合物的合成方法原料廉价易得、反应条件温和、操作简便、区域选择性高、产率高、有利于工业化生产。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1中间体B-1的合成
称取化合物1(150mg,0.37mmol,1equiv)和DIPEA(363mg,1.87mmol,5equiv)溶于适量无水THF,置于250mL三颈圆底烧瓶,室温反应5min;加入HATU(319mg,1.87mmol,1.5equiv)于室温反应15min;最后,缓慢加入5-己炔酸A-1(69mg,0.41mmol,1.1equiv),N2置换3次,40℃搅拌反应24h,全程无水无氧。LC-MS和TLC(DCM:EA=5:1)跟踪监测原料反应完全后,停止反应,将反应液减压浓缩至干。硅胶柱层析法分离提纯(DCM:EA=15:1),得到50.7mg中间体化合物B-1,纯度约为98.73%,1H NMR(400MHz,DMSO-d6)δ12.47(s,1H),10.04(s,1H),8.29(s,1H),7.41(dd,J=7.4,1.9Hz,1H),2.84(t,J=2.6Hz,1H),2.60(t,J=7.4Hz,2H),2.26–2.20(m,5H),1.80(p,J=7.2Hz,2H);13C NMR(101MHz,DMSO-d6)δ171.77,161.43,159.94,141.06,139.22,133.74,132.82,129.54,128.79,127.51,127.02,84.19,72.33,34.17,23.79,18.75,17.72.
ESI+-MS(m/z):361.07[M+Na]+。
实施例2中间体B-2的合成
称取化合物1(150mg,0.37mmol,1equiv)和DIPEA(363mg,1.87mmol,5equiv)溶于适量无水THF置于250ml三颈圆底烧瓶,室温反应5min;加入HATU(319mg,1.87mmol,1.5equiv)于室温反应15min;最后,缓慢加入4-戊炔酸A-2(60mg,0.41mmol,1.1equiv),N2置换3次,40℃搅拌反应24h,全程无水无氧。LC-MS和TLC(DCM:EA=5:1)跟踪监测原料反应完全后,停止反应,将反应液减压浓缩至干。硅胶柱层析法分离提纯(DCM:EA=28:1),得到40.5mg中间体化合物B-2,纯度约为97%,1H NMR(400MHz,DMSO-d6)δ12.51(s,1H),10.06(s,1H),8.30(s,1H),7.40(d,J=7.5Hz,1H),2.98(d,J=37.0Hz,1H),2.84(t,J=2.6Hz,1H),2.70(t,J=7.2Hz,2H),2.23(s,3H),1.55–0.69(m,1H);13C NMR(101MHz,DMSO-d6)δ170.60(s),161.30(s),159.84(s),141.07(s),139.15(s),133.66(s),132.88(s),129.55(s),128.81(s),127.52(s),127.17(s),83.50(s),72.32(s),34.41(s),18.67(s),14.12(s).
ESI+-MS(m/z):347.05[M+Na]+。
实施例3中间体B-3的合成
称取化合物1(150mg,0.37mmol,1equiv)和DIPEA(363mg,1.87mmol,5equiv)溶于适量无水THF置于250ml三颈圆底烧瓶,室温反应5min;加入HATU(319mg,1.87mmol,1.5equiv)于室温反应15min;最后,缓慢加入3-丁炔酸A-3(69mg,0.41mmol,1.1equiv),N2置换3次,40℃搅拌反应24h,全程无水无氧。LC-MS和TLC(DCM:EA=5:1)跟踪监测原料反应完全后,停止反应,将反应液减压浓缩至干。硅胶柱层析法分离提纯(DCM:EA=30:1),得到42mg中间体化合物B-3,纯度约为99.43%,1H NMR(400MHz,CDCl3)δ9.90(s,1H),9.41(s,1H),7.41–7.35(m,1H),7.25(s,1H),7.24(d,J=1.7Hz,1H),5.87(s,1H),2.79(s,2H),2.36(s,3H),1.47(s,1H);13C NMR(101MHz,CDCl3)δ166.41,162.48,159.35,157.81,138.53,132.00,129.40,128.70,127.46,126.51,123.06,104.09,29.74
ESI+-MS(m/z):333.03[M+Na]+。
实施例4目标产物D-1-1的合成
称取化合物B-1(50mg,0.11mmol,1equiv)溶于适量无水THF置于250ml三颈圆底烧瓶中,缓慢滴加化合物C-1的1mg/5ul无水THF溶液350ul(70mg,0.11mmol,1equiv);滴毕,依次加入抗坏血酸钠(16mg,0.07mmol,0.8equiv)、无水硫酸铜(4.5mg,0.022mmol,0.4equiv);加毕,立即滴加4、5滴的去离子水。N2置换3次,40℃搅拌反应16h,全程无水无氧。LC-MS和TLC(DCM:MeOH=15:1)跟踪监测原料反应完全后,停止反应,将反应液减压浓缩至干。硅胶柱层析法分离提纯(DCM:MeOH=30:1),得到47mg目标产物D-1-1,纯度约为95.04%,1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),10.04(s,1H),8.98(d,J=2.6Hz,1H),8.61(t,J=6.0Hz,1H),8.29(s,1H),7.86(d,J=10.9Hz,1H),7.50–7.35(m,6H),7.31–7.24(m,2H),5.17(d,J=3.3Hz,1H),4.57(d,J=9.6Hz,1H),4.44(dd,J=10.9,6.1Hz,3H),4.38(dd,J=15.8,6.2Hz,2H),4.27–4.22(m,1H),3.94(d,J=16.1Hz,2H),3.79(dt,J=10.6,5.3Hz,2H),3.66–3.52(m,9H),2.65(t,J=7.6Hz,2H),2.44(d,J=4.4Hz,3H),2.23(s,3H),2.06(dd,J=12.2,8.1Hz,1H),1.93(d,J=7.1Hz,2H),1.37(dd,J=16.7,9.2Hz,1H),1.24(t,J=6.7Hz,2H),0.96–0.90(m,9H);13C NMR(101MHz,DMSO-d6)δ172.14(d,J=18.0Hz),169.60(s),169.07(s),161.45(s),159.95(s),151.95(s),148.22(s),146.48(s),141.06(s),139.91(s),139.22(s),133.75(s),132.82(s),132.01(s),131.60(s),130.17(s),129.54(s),129.49–128.64(m),127.93(s),127.51(s),126.99(s),122.82(s),98.61(s),70.92(s),70.12(d,J=13.8Hz),69.30(d,J=9.4Hz),59.21(s),57.06(s),56.15(s),49.69(s),42.12(s),38.40(s),36.21(s),34.77(s),30.47(s),26.63(s),24.87(d,J=4.5Hz),19.13(s),18.74(s),16.40(s),14.04(s),12.94(s).
ESI+-MS(m/z):1006.36[M+Na]+。
实施例5目标产物D-1-2的合成
称取化合物B-1(30mg,0.081mmol,1equiv)和化合物C-2(45mg,0.081mmol,1equiv)溶于适量无水THF置于250ml三颈圆底烧瓶中;加毕,依次加入抗坏血酸钠(9.6mg,0.05mmol,0.8equiv)、无水硫酸铜(2.6mg,0.02mmol,0.4equiv);加毕,立即滴加4、5滴的去离子水。N2置换3次,40℃搅拌反应16h,全程无水无氧。LC-MS和TLC(DCM:MeOH=15:1)跟踪监测原料反应完全后,停止反应,将反应液减压浓缩至干。硅胶柱层析法分离提纯(DCM:MeOH=25:1),得到45mg目标产物D-1-2,纯度约为98.78%,1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),10.04(s,1H),8.98(s,1H),8.60(t,J=5.8Hz,1H),8.29(s,1H),7.91(s,1H),7.44(d,J=9.6Hz,1H),7.40(s,4H),7.27(q,J=7.6Hz,2H),5.16(d,J=3.2Hz,1H),4.62–4.50(m,3H),4.43(dd,J=14.7,6.9Hz,1H),4.40–4.32(m,1H),4.27(dd,J=15.6,5.4Hz,1H),3.99(s,2H),3.89(t,J=4.8Hz,2H),3.65(dt,J=19.6,7.0Hz,2H),2.66(t,J=7.4Hz,2H),2.44(s,3H),2.23(s,3H),2.11–2.01(m,1H),2.00–1.85(m,3H),1.23(s,1H),0.90(d,J=11.2Hz,9H);13C NMR(101MHz,DMSO-d6)δ172.14(d,J=16.7Hz),169.59(s),168.64(s),165.71(s),161.45(s),159.95(s),151.93(s),148.59(s),148.24(s),146.57(s),141.06(s),139.89(s),139.21(s),133.75(s),132.82(s),131.65(s),130.17(s),129.78–128.99(m),128.83(s),128.62(s),127.92(s),127.51(s),127.00(s),122.88(s),100.00(s),69.99–69.74(m),69.74–69.12(m),59.21(s),57.04(s),56.25(s),49.53(s),42.14(s),38.39(s),36.10(s),34.79(s),26.63(s),24.85(d,J=10.3Hz),18.74(s),16.41(s).
ESI+-MS(m/z):918.31[M+Na]+。
实施例6目标产物D-1-3的合成
称取化合物B-1(50mg,0.14mmol,1equiv)溶于适量无水THF置于250ml三颈圆底烧瓶中,缓慢滴加化合物C-3的1mg/5ul无水THF溶液400ul(95mg,0.14mmol,1equiv);滴毕,依次加入抗坏血酸钠(16mg,0.08mmol,0.8equiv)、无水硫酸铜(4.5mg,0.028mmol,0.4equiv);加毕,立即滴加4、5滴的去离子水。N2置换3次,40℃搅拌反应16h,全程无水无氧。LC-MS和TLC(DCM:MeOH=15:1)跟踪监测原料反应完全后,停止反应,将反应液减压浓缩至干。硅胶柱层析法分离提纯(DCM:MeOH=28:1),得到37mg目标产物D-1-3,纯度约为98.64%,1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),10.04(s,1H),8.98(s,1H),8.61(t,J=6.0Hz,1H),8.29(s,1H),7.85(s,1H),7.45–7.39(m,6H),7.27(dd,J=12.6,5.0Hz,2H),5.17(d,J=3.5Hz,1H),4.57(d,J=9.6Hz,1H),4.48–4.35(m,5H),4.28–4.23(m,1H),3.96(s,2H),3.78(t,J=5.3Hz,2H),3.69–3.45(m,16H),2.66(t,J=7.5Hz,2H),2.45(d,J=4.8Hz,3H),2.23(s,3H),1.92(dt,J=8.5,5.8Hz,3H),0.94(s,10H);13C NMR(101MHz,DMSO-d6)δ172.15(d,J=19.1Hz),169.59(s),169.09(s),161.45(s),159.95(s),152.00(s),148.17(s),146.48(s),141.06(s),139.98(s),139.24(s),133.75(s),132.78(s),131.61(s),130.16(s),129.54(s),129.16(s),128.70(d,J=18.0Hz),127.92(s),127.51(s),126.99(s),122.81(s),70.90(s),70.41–69.81(m),69.29(d,J=12.1Hz),59.21(s),57.06(s),56.15(s),49.68(s),42.13(s),38.39(s),36.14(s),34.81(s),26.69(s),24.89(s),18.71(s),16.39(s).
ESI+-MS(m/z):1050.39[M+Na]+。
实施例7目标产物D-1-4的合成
称取化合物B-1(43mg,0.12mmol,1equiv)和化合物C-4(72mg,0.12mmol,1equiv)溶于适量无水THF置于250ml三颈圆底烧瓶中;加毕,依次加入抗坏血酸钠(14.3mg,0.07mmol,0.8equiv)、无水硫酸铜(4mg,0.04mmol,0.4equiv);加毕,立即滴加4、5滴的去离子水。N2置换3次,40℃搅拌反应16h,全程无水无氧。LC-MS和TLC(DCM:MeOH=10:1)跟踪监测原料反应完全后,停止反应,将反应液减压浓缩至干。硅胶柱层析法分离提纯(DCM:MeOH=20:1),得到48mg目标产物D-1-4,纯度约为99.64%,1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),10.04(s,1H),8.98(s,1H),8.60(t,J=5.8Hz,1H),8.29(s,1H),7.88(d,J=15.2Hz,1H),7.47–7.43(m,1H),7.42–7.36(m,5H),7.30–7.24(m,2H),5.17(t,J=4.6Hz,1H),4.59–4.34(m,6H),4.27(dd,J=10.9,4.9Hz,1H),4.00–3.91(m,2H),3.84(dt,J=16.0,5.4Hz,2H),3.66–3.54(m,5H),2.65(t,J=7.5Hz,2H),2.57–2.52(m,2H),2.46–2.42(m,3H),2.23(s,3H),2.10–2.03(m,1H),1.97–1.87(m,3H),1.27–1.23(m,1H),0.92(d,J=7.6Hz,9H);13CNMR(101MHz,DMSO-d6)δ172.14(d,J=14.2Hz),169.64(s),169.05(s),161.46(s),159.95(s),151.93(s),148.22(s),146.51(s),141.06(s),139.88(s),139.22(s),133.75(s),132.82(s),131.60(s),130.37(d,J=38.9Hz),129.54(s),129.16(s),128.81(d,J=3.5Hz),127.92(s),127.51(s),126.99(s),122.88(s),70.76(s),69.96(d,J=18.3Hz),69.38(d,J=6.7Hz),59.21(s),57.09(s),56.17(s),49.62(s),42.14(s),40.60(s),40.29(d,J=21.0Hz),39.97(s),39.76(s),39.55(s),39.35(s),34.78(s),26.65(s),24.85(d,J=5.9Hz),18.74(s).
ESI+-MS(m/z):962.33[M+Na]+。
实施例8目标产物D-2-1的合成
称取化合物B-2(30mg,0.09mmol,1equiv)溶于适量无水THF置于250ml三颈圆底烧瓶中,缓慢滴加化合物C-1的1mg/5ul无水THF溶液295ul(59mg,0.09mmol,1equiv);滴毕,依次加入抗坏血酸钠(11mg,0.054mmol,0.8equiv)、无水硫酸铜(3mg,0.018mmol,0.4equiv);加毕,立即滴加4、5滴的去离子水。N2置换3次,40℃搅拌反应16h,全程无水无氧。LC-MS和TLC(DCM:MeOH=10:1)跟踪监测原料反应完全后,停止反应,将反应液减压浓缩至干。硅胶柱层析法分离提纯(DCM:MeOH=25:1),得到48mg中间体化合物D-2-1,纯度约为99.73%,1HNMR(400MHz,DMSO-d6)δ12.48(s,1H),10.04(s,1H),8.98(s,1H),8.61(t,J=6.0Hz,1H),8.29(s,1H),7.81(s,1H),7.44–7.38(m,6H),7.27(t,J=5.0Hz,2H),5.17(d,J=3.5Hz,1H),4.57(d,J=9.6Hz,1H),4.46–4.21(m,7H),3.75(t,J=5.2Hz,2H),3.66–3.57(m,4H),3.55–3.46(m,7H),2.97(t,J=7.2Hz,2H),2.86(t,J=7.2Hz,2H),2.23(s,3H),2.15–1.92(m,2H),1.23(s,1H),0.98–0.83(m,11H);13C NMR(101MHz,DMSO-d6)δ172.23(s),171.43(s),169.60(s),169.07(s),161.44(s),159.93(s),151.96(s),150.14(s),148.23(s),145.66(s),141.04(s),139.91(s),139.21(s),133.74(s),132.81(s),130.71–130.19(m),129.86(d,J=62.9Hz),129.17(s),128.81(s),127.94(s),127.51(s),127.03(s),122.91(s),99.99(s),70.90(s),70.12(d,J=13.8Hz),69.31(d,J=6.9Hz),59.20(s),57.06(s),56.15(s),55.40(s),49.72(s),42.14(s),38.39(s),36.21(s),34.79(s),26.64(s),20.81(s),18.73(s),16.40(s).
ESI+-MS(m/z):992.34[M+Na]+。
实施例9目标产物D-2-2的合成
称取化合物B-2(30mg,0.09mmol,1equiv)和化合物C-2(50mg,0.09mmol,1equiv)溶于适量无水THF置于250ml三颈圆底烧瓶中;加毕,依次加入抗坏血酸钠(11mg,0.06mmol,0.8equiv)、无水硫酸铜(3mg,0.02mmol,0.4equiv);加毕,立即滴加4、5滴的去离子水。N2置换3次,40℃搅拌反应16h,全程无水无氧。LC-MS和TLC(DCM:MeOH=15:1)跟踪监测原料反应完全后,停止反应,将反应液减压浓缩至干。硅胶柱层析法分离提纯(DCM:MeOH=20:1),得到54mg目标产物D-2-2,纯度约为99.76%,1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),10.04(s,1H),8.98(s,1H),8.60(t,J=5.8Hz,1H),8.29(s,1H),7.88(d,J=15.2Hz,1H),7.47–7.43(m,1H),7.42–7.36(m,5H),7.30–7.24(m,2H),5.17(t,J=4.6Hz,1H),4.59–4.34(m,6H),4.27(dd,J=10.9,4.9Hz,1H),4.00–3.91(m,2H),3.84(dt,J=16.0,5.4Hz,2H),3.66–3.54(m,5H),2.65(t,J=7.5Hz,2H),2.57–2.52(m,2H),2.46–2.42(m,3H),2.23(s,3H),2.10–2.03(m,1H),1.97–1.87(m,3H),1.27–1.23(m,1H),0.92(d,J=7.6Hz,9H);13C NMR(101MHz,DMSO-d6)δ172.23(s),171.45(s),169.61(s),168.64(s),161.46(s),159.94(s),151.95(s),145.78(s),141.04(s),139.88(s),139.21(s),133.74(s),132.82(s),130.17(s),129.54(s),129.18(s),128.79(s),127.90(s),127.51(s),127.07(s),123.00(s),100.00(s),73.55(s),69.63(d,J=10.1Hz),69.36(s),59.25(d,J=5.7Hz),57.04(s),56.26(s),55.69(s),49.55(s),42.15(s),38.38(s),36.13(s),34.73(s),26.65(s),20.81(s),18.74(s),16.41(s).
ESI+-MS(m/z):904.29[M+Na]+。
实施例10目标产物D-2-3的合成
称取化合物B-2(40mg,0.12mmol,1equiv)溶于适量无水THF置于250ml三颈圆底烧瓶中,缓慢滴加化合物C-3的1mg/5ul无水THF溶液400ul(80mg,0.12mmol,1equiv);加毕,依次加入抗坏血酸钠(14.3mg,0.07mmol,0.8equiv)、无水硫酸铜(4mg,0.024mmol,0.4equiv);加毕,立即滴加4、5滴的去离子水。N2置换3次,40℃搅拌反应16h,全程无水无氧。LC-MS和TLC(DCM:MeOH=10:1)跟踪监测原料反应完全后,停止反应,将反应液减压浓缩至干。硅胶柱层析法分离提纯(DCM:MeOH=25:1),得到32mg目标产物D-2-3,纯度约为97.13%,1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),10.04(s,1H),8.98(s,1H),8.60(t,J=5.8Hz,1H),8.29(s,1H),7.88(d,J=15.2Hz,1H),7.47–7.43(m,1H),7.42–7.36(m,5H),7.30–7.24(m,2H),5.17(t,J=4.6Hz,1H),4.59–4.34(m,6H),4.27(dd,J=10.9,4.9Hz,1H),4.00–3.91(m,2H),3.84(dt,J=16.0,5.4Hz,2H),3.66–3.54(m,5H),2.65(t,J=7.5Hz,2H),2.57–2.52(m,2H),2.46–2.42(m,3H),2.23(s,3H),2.10–2.03(m,1H),1.97–1.87(m,3H),1.27–1.23(m,1H),0.92(d,J=7.6Hz,9H);13C NMR(101MHz,DMSO-d6)δ172.25(s),171.42(s),169.60(s),169.07(s),161.42(s),159.93(s),151.95(s),148.22(s),145.67(s),141.04(s),140.06–139.93(m),139.56(d,J=71.2Hz),133.74(s),132.81(s),130.16(s),129.54(s),129.16(s),128.80(s),127.92(s),127.51(s),127.06(s),122.90(s),70.89(s),69.30(d,J=8.7Hz),66.24(s),59.24(s),57.05(s),56.15(s),49.72(s),47.78(s),42.13(s),41.53(s),41.33(s),38.39(s),36.19(s),35.31(s),34.79(s),33.99(s),30.95(s),30.59(s),29.53(s),26.68(d,J=9.2Hz),20.81(s),18.73(s),16.95(s),16.40(s).
ESI+-MS(m/z):1036.27[M+Na]+。
实施例11目标产物D-2-4的合成
称取化合物B-2(40mg,0.12mmo,1equivl)溶于适量无水THF置于250ml三颈圆底烧瓶中,缓慢滴加化合物C-4的1mg/5ul无水THF溶液360ul(72mg,0.12mmol,1equiv);加毕,依次加入抗坏血酸钠(14.3mg,0.07mmol,0.8equiv)、无水硫酸铜(4mg,0.024mmol,0.4equiv);加毕,立即滴加4、5滴的去离子水。N2置换3次,40℃搅拌反应16h,全程无水无氧。LC-MS和TLC(DCM:MeOH=10:1)跟踪监测原料反应完全后,停止反应,将反应液减压浓缩至干。硅胶柱层析法分离提纯(DCM:MeOH=25:1),得到41mg目标产物D-2-3,纯度约为96.58%,1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),10.04(s,1H),8.98(s,1H),8.60(t,J=5.8Hz,1H),8.29(s,1H),7.88(d,J=15.2Hz,1H),7.47–7.43(m,1H),7.42–7.36(m,5H),7.30–7.24(m,2H),5.17(t,J=4.6Hz,1H),4.59–4.34(m,6H),4.27(dd,J=10.9,4.9Hz,1H),4.00–3.91(m,2H),3.84(dt,J=16.0,5.4Hz,2H),3.66–3.54(m,5H),2.65(t,J=7.5Hz,2H),2.57–2.52(m,2H),2.46–2.42(m,3H),2.23(s,3H),2.10–2.03(m,1H),1.97–1.87(m,3H),1.27–1.23(m,1H),0.92(d,J=7.6Hz,9H);13C NMR(101MHz,DMSO-d6)δ172.21(s),171.45(s),170.01(s),169.64(s),169.06(s),168.64(s),161.42(s),159.93(s),151.94(s),148.22(s),145.69(s),141.04(s),139.79(d,J=17.0Hz),139.21(s),133.73(s),132.81(s),131.60(s),130.18(s),129.54(s),128.98(d,J=36.7Hz),128.13–128.07(m),127.72(d,J=42.1Hz),127.06(s),122.97(s),100.00(s),70.76(s),69.97(d,J=19.9Hz),69.39(d,J=8.2Hz),59.21(s),57.09(s),56.18(s),49.66(s),42.15(s),38.41(s),36.25(s),34.79(s),26.65(s),20.82(s),18.74(s),16.40(s).
ESI+-MS(m/z):948.32[M+Na]+。
实施例12盐酸盐的制备(以实施例11的产物为例)
取实施例11的产物100mg,溶于乙酸乙酯中。室温下通入HCl气体至过饱和。降温至0度左右,慢慢析出晶体,为实施例11的产物的盐酸盐。
实施例13肿瘤细胞的增殖抑制活性—MTT法
MTT法又称为MTT比色法,是一种检测细胞存活和生长的方法。其检测原理为活细胞线粒体中的琥珀酸脱氢酶能使得外源性MTT还原为水不溶性的蓝紫色结晶的甲瓒(Formazan),并且能够沉积在细胞内,而死细胞却无此功能。二甲基亚砜(DMSO)能够溶解细胞中的甲瓒,用酶联免疫检测仪在540nm或720nm波长测定其光吸收值,可间接反映活细胞数量。在一定细胞数范围内,MTT结晶形成的量与细胞数成正比。该方法已广泛应用于一些生物活性因子的活性检测、大规模的抗肿瘤药物的筛选、细胞毒性试验以及肿瘤放射敏感性测定等。它的特点是灵敏度高、经济。
实验方法:取对数生长期的肿瘤细胞株,按4000细胞/孔接种于96孔培养液,设置对照组(DMSO)及化合物处理组。化合物浓度最高为50μg/mL,5倍梯度稀释,总共5个浓度,每个浓度三个复孔。化合物作用细胞72小时后,弃去培养液,每孔加入预冷的10%三氯醋酸(TCA)溶液100微升固定细胞,4℃冰箱放置1小时,培养液各孔用去离子水洗涤五遍,去除三氯醋酸溶液,在空气中干燥后,每孔加入1%乙酸配制的SRB溶液(4mg/mL)50微升,室温下放置20分钟,弃去各孔内液体后用1%乙酸洗涤五遍,洗干净未结合的SRB染料后空气干燥,每孔加入pH=10.5的10mM的Tris-base(三羟甲基胺基甲烷)溶液100微升溶解,在平板振荡5分钟,酶标仪515nm波长下测定吸光度OD值。
实施例4~11制备的目标产物在10μM浓度下的抑制率如表1所示:
表1
注:A表示抑制率为80%-100%,B表示抑制率为60%-80%,C表示抑制率为40%-60%,D表示抑制率为20%-40%,E表示抑制率为0%-20%。
由表1可见,本发明提供的化合物具有较好的对肿瘤细胞的增殖抑制活性,因而,可以在制备治疗、预防及缓解癌症的药物中有所应用,或者作为先导化合物用于设计活性更高的候选分子。
以上所述的实施例对本发明的技术方案和有益效果进行了详细说明,应理解的是以上所述仅为本发明的具体实施例,并不用于限制本发明,凡在本发明的原则范围内所做的任何修改、补充和等同替换等,均应包含在本发明的保护范围之内。
Claims (8)
2.根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其特征在于,X为1~4的整数,Y为1~4的整数。
3.根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其特征在于,所述的药学上可接受的盐为盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、磷酸盐、乙酸盐、丙酸盐、丁酸盐、草酸盐、酒石酸盐、甲磺酸盐、对甲苯磺酸盐、富马酸盐、牛磺酸盐、柠檬酸盐、琥珀酸盐,或其混合盐。
5.一种药物组合物,其特征在于,包含治疗有效量的如权利要求1-3任一项所述的化合物、其立体异构体或其药学上可接受的盐,以及药学上可接受的赋形剂或载体。
6.一种如权利要求1-3任一项所述的化合物、其立体异构体或其药学上可接受的盐在制备用于治疗、预防及缓解疾病的药物中的应用;所述的疾病因BCR-ABL融合蛋白表达过多而引起。
7.根据权利要求6所述的应用,其特征在于,所述的疾病为慢性粒细胞白血病。
8.一种如权利要求5所述的药物组合物在制备用于治疗、预防及缓解疾病的药物中的应用;所述的疾病因BCR-ABL融合蛋白表达过多而引起。
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