CN117756781A - 一种具有抗肿瘤作用的吲哚类组蛋白去乙酰化酶家族抑制剂 - Google Patents
一种具有抗肿瘤作用的吲哚类组蛋白去乙酰化酶家族抑制剂 Download PDFInfo
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Abstract
本发明属于药物化学领域,具体涉及通式Ⅰ所示的吲哚类衍生物及其光学活性体或消旋体,非对映异构体混合物,以及该类化合物作为SIRT2抑制剂,及其在抗胰腺癌转移方面的应用。本发明还涉及以该类化合物及其在药学上可接受的盐为活性成分的药物组合物。本发明还涉及含有至少一种该类化合物或其盐的该类化合物发给药剂型,其剂型选自以下一种或多种:片剂、胶囊、注射剂、栓剂、贴剂、可吸入粉末制剂、混悬剂、乳剂或软膏。
Description
技术领域
本发明属于药物化学技术领域,具体涉及一种具有抗肿瘤作用的吲哚类组蛋白去乙酰化酶家族抑制剂及其制备方法和用途,特别地所述吲哚类组蛋白去乙酰化酶家族抑制剂具有抗胰腺癌转移活性。
背景技术
沉默信息调节因子(SIRT)是从细菌到人类都高度保守的一类去乙酰化酶,它在序列和细胞功能上具有高度同源性,其催化活性依赖烟酰胺腺嘌呤二核苷酸(NAD+),从乙酰化蛋白质中去除乙酰基,产生烟酰胺(NAM)和乙酰酯代谢物。SIRT翻译后在细胞中修饰,具有十分重要的作用,可以进行DNA识别、蛋白与蛋白之间的相互作用、维持蛋白质稳定性等。SIRT属于第三类组蛋白去乙酰化酶家族,在哺乳动物中,SIRT是参与各种肿瘤发生与转移过程中的关键蛋白质之一,与多种癌症相关事件有关。
SIRT2在细胞侵袭和转移的过程中起到重要的调控作用,涉及到上皮-间充质转化(EMT)、淋巴结转移、血管生成等肿瘤转移过程。研究表明,SIRT2可以促进结直肠癌、胃癌、非小细胞肺癌、肾癌等多种肿瘤的转移,而将SIRT2敲除后对结直肠癌、胃癌、肝癌、肾癌、乳腺癌的转移起到抑制作用。因此,结合SIRT2在细胞调控中所起到的作用,开发出新的SIRT2抑制剂对于治疗恶性肿瘤的发生、侵袭和转移具有十分重要的意义。
尽管在许多恶性肿瘤的早期检测和治疗方面都取得了较为重大的进展,但是胰腺癌通常在晚期才会被诊断发现,并且常规治疗效果很差,5年生存率较低,仅有2-9%。手术切除是胰腺癌患者唯一可能治愈的治疗方法。但在这些患者中,只有20%的患者在诊断时可以通过手术来切除肿瘤,其余80%的患者被诊断为局部晚期或转移性疾病,不符合手术条件。所以化疗仍是晚期转移性胰腺癌的一线治疗方法。因此,寻找更有效的靶向药物来抑制胰腺癌的转移一直是研究热点。
研究表明,在胰腺癌细胞中,SIRT2表达升高,抑制LDH-A在K5处的乙酰化,增加了其活性和蛋白质水平,从而加速糖酵解和乳酸的产生,而乳酸已经被证明可以调节微环境,促进癌细胞和基质细胞之间的相互作用,最终导致癌细胞的迁移。除此之外,LDH-A基因是Myc蛋白的直接靶点,而胰腺癌细胞中存在Myc蛋白的表达上调,从而使得LDH-A表达升高。SIRT2可以稳定C-Myc蛋白的表达,并促进Myc过表达的肿瘤细胞的生长。因而,SIRT2抑制剂对于胰腺癌细胞的增殖和转移具有十分重要的作用。
吲哚类化合物已有很多相关文献报道,此类化合物具有多种生物活性。本发明在大量文献调研的基础上,设计并合成了一系列1位、3位和5位被取代的新型吲哚类衍生物,并进行了抗肿瘤活性测试,意外地发现了所述吲哚类衍生物表现出抗胰腺癌转移活性。
发明内容
本发明的目的在于以原有工作为基础,衍生设计和合成一类新型取代吲哚类衍生物,并进行了抗肿瘤活性测试。本发明意外地发现了所述吲哚类衍生物表现出抗胰腺癌转移活性。
为了完成本发明之目的,可采用如下技术方案:
在第一个方面中,本发明提供了具有下述通式(I)的新型吲哚类衍生物或其药学上可接受的盐或其光学活性体:
其中:
R1、R2、R3各自同时为下列基团中的任意一个基团:(1)H原子,(2)羟基,(3)卤原子,(4)氰基,(5)硝基,(6)三卤甲基,(7)C1-6烷基、C3-8环烷基、C2-6链烯基、C2-6链炔基、C1-6烷磺酰氨基、C1-18烷氧羰基、C1-18烷氧磺酰基、C1-6烷氧基、C2-6链烯氧基、C2-6链炔氧基、C1-6烷硫基、C2-6链烯硫基、C2-6链炔硫基、C1-6烷基磺酰基、C2-6链烯基磺酰基、C2-6链炔基磺酰基、C1-6烷基亚磺酰基、C2-6链烯基亚磺酰基、C2-6链炔基亚磺酰基、C3-8环烯基,上述各基团任意被选自H原子、卤原子、羟基、氰基、硝基或氨基中的一种或多种取代基所取代,(8)被各种取代的羰基,其任意被选自H原子、羟基、C1-6烷基、氨基、C1-6烷氨基、C1-6烷氧基、C1-6烷硫基和C3-8环烷基中的一种或多种取代基所取代,(9)被各种取代的氨基,其任意被选自H原子、C1-6烷基、C2-6链烯基、C2-6链炔基、C1-6烷基磺酰基、C2-6链烯基磺酰基、C2-6链炔基磺酰基、C1-6烷基羰基、C2-6链烯基羰基或C2-6链炔基羰基中的一种或多种取代基所取代,(10)被各种取代的苯基、被各种取代的苄基、被各种取代的苄氧基、被各种取代的苯甲酰基、被各种取代的苯磺酰基、被各种取代的吡啶环、被各种取代的吡唑环、被各种取代的吡咯环、被各种取代的嘧啶环、被各种取代的喹啉环、被各种取代的异喹啉环、被各种取代咪唑环、被各种取代的吗啉环、被各种取代的哌嗪环、被各种取代的哒嗪环、被各种取代的吡嗪环、被各种取代的哌啶环、被各种取代的噻吩环、被各种取代的噻唑环、被各种取代的异噻唑环、被各种取代的苯并噻唑环、被各种取代的吡喃环、被各种取代的吲哚环、被各种取代的噁唑环、被各种取代的异噁唑环、被各种取代的三氮唑类环、被各种取代的苯并三唑环、被各种取代的呋喃环,上述各基团任意被选自H、卤素、C1-6烷基、C1-6烷氨基、C3-7环烷基、C1-6烷氧基、C1-6烷磺酰氨基、苄氧羰基、C1-18烷氧羰基、C1-18烷氧磺酰基、三卤甲基、羟基、氰基、硝基和氨基中的一种或多种取代基所取代,(11)相邻的R1与R2之间相连构成亚烷二氧基。
作为可选的方式,在上述化合物或其药学上可接受的盐或其光学活性体中,其中R1、R2各自同时为下列基团中的任意一个基团:(1)H原子,(2)羟基,(3)卤原子,(4)硝基,(5)C1-4烷基,C1-4烷氧基,上述各基团任意被选自氢原子、卤原子、羟基、氰基、硝基和氨基中的一种或多种取代基所取代,(6)被各种取代的苯基,被各种取代的苄氧基,上述各基团任意被选自H、卤素、C1-6烷基、C1-6烷基氨基、C3-7环烷基、C1-4烷氧基、C1-4烷磺酰氨基、苄氧羰基、C1-10烷氧羰基、C1-10烷氧磺酰基、三卤甲基、羟甲基、羟基、氰基、硝基和氨基中的一种或多种取代基所取代。
作为可选的方式,在上述化合物或其药学上可接受的盐或其光学活性体中,其中R1、R2、R3各自同时为下列基团中的任意一个基团:(1)H原子,(2)羟基,(3)氟、氯、溴,(4)硝基,(5)C1-4烷基,C1-4烷氧基,上述各基团任意被选自氢原子、卤原子、羟基、氰基、硝基和氨基中的一种或多种取代基所取代,(6)未取代或取代的苯基、苄氧基、所述取代基选自H、卤素、C1-4烷基、C1-4烷氧基、C1-4烷氧羰基中的一种或多种。
作为可选的方式,在上述化合物或其药学上可接受的盐或其光学活性体中,其中R1、R2、R3各自同时为下列基团中的任意一个基团:乙氧羰基、H原子、羟基、溴原子、氯原子、甲氧基、乙氧基、2-甲基-苯基、4-甲基-苯基、苄氧基或相邻的R1与R2之间相连构成亚烷二氧基。
作为可选的方式,在上述化合物或其药学上可接受的盐或其光学活性体中,所述化合物选自:
在第二个方面中,制备本发明通式(Ⅰ)的吲哚类衍生物或药学上可接受的盐或其光学活性体或消旋体,非对映异构体混合物的合成路线如下:其中R1、R2、R3与上述第一方面所述相同。
利用5-溴吲哚-3-乙酸在NaH的存在下进行取代反应得到中间体A-1,中间体A-1进行酸胺缩合得到中间体A-2,中间体A-2在Pd(PPh3)4、Na2CO3乙醇和水的体系下,进行suzuki偶联反应合成通式Ⅰ中的化合物Z1-1~Z1-6和Z2-1~Z2-7,其中R1、R3与权利要求1所述相同。
试剂和条件:a.NaH,DMF,0℃至r.t.,b.HATU,DIEA,DMF,r.t./EDCI,HOBT,TEA,DMF,r.t.,c.Pd(PPh3)4,Na2CO3,EtOH,水,100℃,回流/Pd(PPh3)4,K2CO3,甲苯,水,110℃,回流。
利用5-溴吲哚-3-乙酸先进行酯化反应得到中间体B-1,随后通过suzuki偶联反应得到中间体B-2,中间体B-2经过水解反应得到中间体B-3,再在NaH的作用下发生取代反应得到中间体B-4,最后进行酸胺缩合反应合成通式Ⅰ中的化合物Z3-1~Z3-12。
试剂和条件:a.MeOH,SOCl2,0℃至r.t.,b.Pd(PPh3)4,K2CO3,甲苯,水,110℃,回流.c.NaOH,CH3OH,HCl.d.NaH,DMF,冰水,r.t.,e.HATU,DIEA,DMF,r.t./EDCI,HOBt,TEA,DMF,r.t..
在第三个方面中,本发明提供了一种药物组合物,所述药物组合物包含上述第一个方面所述的化合物或其药学上可接受的盐或其光学活性体以及药学上可接受的载体。
在第四个方面中,本发明提供了一种药物制剂,所述药物制剂包含上述第三个方面所述的药物组合物,所述药物制剂的剂型选自以下一种或多种:片剂、胶囊、注射剂、栓剂、贴剂、可吸入粉末制剂、混悬剂、乳剂或软膏。
在第五个方面中,本发明提供了上述第一个方面所述的化合物或其药学上可接受的盐或其光学活性体或者第三个方面所述的药物组合物或者第四个方面所述的药物制剂在制备SIRT2抑制剂中的应用。
在第六个方面中,本发明提供了上述第一个方面所述的化合物或其药学上可接受的盐或其光学活性体或者第三个方面所述的药物组合物或者第四个方面所述的药物制剂在制备抗肿瘤药物中的应用。
作为可选的方式,在上述应用中,所述抗肿瘤药物具有抗胰腺癌转移活性。
本发明相对于现有技术,具有以下有益效果:
本发明衍生设计和合成一类新型取代吲哚类衍生物,并进行了抗肿瘤活性测试,意外地发现了所述吲哚类衍生物表现出抗胰腺癌转移活性。本发明为探索能够有效治疗胰腺癌的药物提供了新的思路,具有重要的临床意义。
附图说明
图1:化合物Z1-1~Z1-6细胞存活率定量结果。
图2:化合物Z2-1~Z2-7细胞存活率定量结果。
图3:化合物Z1-1~Z1-6的划痕实验结果。其中,图3A是48h细胞迁移的照片,图3B是化合物Z1-1~Z1-6的迁移率实验结果。
图4:化合物Z2-2~Z2-4、Z1-4和Z2-7的划痕实验结果。
具体实施方式
下面参照具体的实施例对本发明做进一步说明。应当理解,此处所描述的具体实施例仅用于解释本发明,并不用于限定本发明的范围。
实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道购买得到的常规产品。
下面实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为市售产品。
实施例1:2-(1-异丙基-5-(喹啉-8-基)-1H-吲哚-3-基)-N-(4-甲氧基苄基)乙酰胺(Z1-1)
将5-溴吲哚-3-乙酸(1a,10.00g,39.36mmol)溶于100mL无水DMF中,再将NaH(含量60%,7.97g,118.08mmol)在冰浴下分批缓慢加入至溶液中,加毕,移除冰浴,常温下搅拌反应0.5h,再将2-溴丙烷(2a,5.32g,43.3mmol)缓慢滴加至反应液中,继续在常温下搅拌1h后TLC监测反应。待检测反应完毕后,将反应液浓缩至约50mL,加入500mL水,并以1M的盐酸调pH至4~5,析出大量固体,以乙酸乙酯(100mL×3)萃取,合并有机层,用饱和食盐水洗涤(50mL×2)后浓缩,柱层析(DCM:MeOH=20:1)得黄色油状液体9.70g。溶于100mL无水DMF中,冰浴下缓慢加入HATU(7.48g,19.66mmol)和DIEA(12.75g,6.38mmol),加毕后撤去冰浴,室温下反应0.5h,TLC监测原料反应完毕后加4-甲氧基苄胺(4a,2.48g,18.01mmol),常温下反应1h后TLC监测。待监测反应完毕后,将反应液浓缩至约50mL,加入500mL水,并以1M的盐酸调pH至4~5,析出大量固体,以乙酸乙酯(100mL×3)萃取,合并有机层,用饱和食盐水洗涤(50mL×2)后浓缩,柱层析(PE:EA=2:1)得黄色粉末状固体5.22g。室温下,将8-喹啉硼酸(1b,0.50g,2.31mmol)用18mL甲苯溶解,加入上一步得到的中间体(0.8g,1.93mmol),再加入K3PO4(1.23g,5.78mmol)并加入3mL水溶解,搅拌15min后,加入Pd(PPh3)4(0.36g,0.31mmol),氮气保护,在110℃下回流反应6h,TLC监测原料反应完毕后,过滤除去不溶性杂质,浓缩溶剂,加入乙酸乙酯(50mL)并用饱和食盐水洗涤(50mL×2)后浓缩,柱层析(PE:EA=10:1)得黄色油状液体,加入无水乙醚(20mL)打浆,大量固体析出,抽滤后干燥得白色粉末状固体0.19g,收率21.3%。
1H NMR(600MHz,DMSO)δ8.87(dd,J=4.0,1.8Hz,1H),8.42(dd,J=8.3,1.8Hz,1H),8.37(t,J=5.9Hz,1H),7.97(dd,J=8.1,1.4Hz,1H),7.79(d,J=1.3Hz,1H),7.72(dd,J=7.1,1.5Hz,1H),7.69–7.65(m,1H),7.55(dd,J=8.3,4.1Hz,1H),7.53(d,J=8.5Hz,1H),7.45(dd,J=8.5,1.6Hz,1H),7.36(s,1H),7.09(d,J=8.6Hz,2H),6.70–6.63(m,2H),4.80–4.73(m,1H),4.17(d,J=5.9Hz,2H),3.63(s,3H),3.58(s,2H),1.50(s,3H),1.48(s,3H).13C NMR(150MHz,DMSO)δ170.92(s),158.52(s),150.40(s),146.18(s),142.12(s),136.81(s),135.17(s),131.98(s),130.48(d,J=13.4Hz),128.92(d,J=7.4Hz),127.86(s),127.41(s),126.81(s),125.04(s),123.93(s),121.68(s),121.36(s),113.94(s),109.53(s),109.17(s),55.44(s),46.97(s),42.13(s),33.28(s),23.06(s).ESI-HRMS:calcd for C30H29N3O2,[M+H]+,464.2260,found 465.2333.
实施例2:2-(5-([1,1'-联苯]-3-基)-1-异丙基-1H-吲哚-3-基)-N-(4-甲氧基苄基)乙酰胺(Z1-2)
实施例2的化合物制备方法同实施例1,只是在第一步用3-联苯硼酸代替8-喹啉硼酸,得白色固体粉末,收率23.6%。
1H NMR(600MHz,DMSO)δ8.47(t,J=5.9Hz,1H),7.95(d,J=1.2Hz,1H),7.88(s,1H),7.74(d,J=7.3Hz,2H),7.62(d,J=7.6Hz,1H),7.59(d,J=7.7Hz,1H),7.56(d,J=8.6Hz,1H),7.55–7.51(m,2H),7.49(t,J=7.7Hz,2H),7.39(t,J=7.4Hz,1H),7.36(s,1H),7.14(t,J=9.4Hz,2H),6.70(d,J=8.6Hz,2H),4.76(dq,J=13.3,6.6Hz,1H),4.20(d,J=5.9Hz,2H),3.62(s,3H),3.62(s,2H),1.47(s,3H),1.46(s,3H).13C NMR(150MHz,DMSO)δ170.93(s),158.54(s),142.94(s),141.31(s),141.00(s),135.55(s),131.98(s),131.45(s),129.82(s),129.40(s),128.92(s),128.59(s),127.94(s),127.39(s),126.36(s),125.61(s),125.19(s),124.45(s),120.91(s),118.06(s),113.99(s),110.65(s),109.84(s),46.98(s),42.13(s),33.24(s),23.02(s).ESI-HRMS:calcd for C33H32N2O2,[M+H]+,489.2464,found 489.2524.
实施例3:2-(1-异丙基-5-(2-苯氧基苯基)-1H-吲哚-3-基)-N-(4-甲氧基苄基)乙酰胺(Z1-3)
实施例3的化合物制备方法同实施例1,只是在第一步用2-苯氧基苯硼酸代替8-喹啉硼酸,并在最后一步用石油醚代替无水乙醚得白色固体粉末,收率22.8%。
1H NMR(600MHz,DMSO)δ8.37(t,J=5.9Hz,1H),7.72(d,J=1.3Hz,1H),7.46(dd,J=7.6,1.7Hz,1H),7.43(d,J=8.6Hz,1H),7.35(td,J=7.8,1.7Hz,1H),7.32–7.29(m,2H),7.29–7.28(m,1H),7.28–7.26(m,2H),7.15(d,J=8.6Hz,2H),7.00(t,J=7.3Hz,2H),6.90–6.86(m,2H),6.80–6.74(m,2H),4.68(dt,J=13.3,6.6Hz,1H),4.18(d,J=5.9Hz,2H),3.69(s,3H),3.54(s,2H),1.42(s,3H),1.41(s,3H).13C NMR(150MHz,DMSO)δ170.83(s),158.59(s),157.98(s),153.18(s),135.17(d,J=17.8Hz),132.01(d,J=13.7Hz),130.28(s),129.01(s),128.63(s),128.21(s),128.03(s),124.91(s),124.08(s),123.04–122.96(m),122.86(d,J=25.4Hz),120.83(s),120.08(s),117.85(s),114.03(s),109.71(s),109.57(s),55.51(s),46.88(s),42.13(s),33.15(s),23.03(s).ESI-HRMS:calcd for C33H32N2O3,[M+H]+,505.2413,found 505.2485.
实施例4:2-(1-异丙基-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(4-甲氧基苄基)乙酰胺(Z1-4)
实施例4的化合物制备方法同实施例1,只是在第一步用6-喹啉硼酸代替8-喹啉硼酸,得白色固体粉末,收率25.4%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.1,1.4Hz,1H),8.47(t,J=5.9Hz,1H),8.39(dd,J=8.3,1.1Hz,1H),8.20(s,1H),8.08(s,2H),8.03(s,1H),7.61(s,2H),7.55(dd,J=8.2,4.1Hz,1H),7.39(s,1H),7.16(d,J=8.5Hz,2H),6.70(d,J=8.5Hz,2H),4.77(dt,J=13.3,6.6Hz,1H),4.22(d,J=5.9Hz,2H),3.64(s,2H),3.58(s,3H),1.47(d,J=6.6Hz,6H).13C NMR(150MHz,DMSO)δ170.89(s),158.53(s),150.45(s),147.22(s),140.19(s),136.46(s),135.70(s),132.08(s),130.50(s),129.66(d,J=19.1Hz),129.00(s),128.74(d,J=15.1Hz),124.94(s),124.63(s),122.20(s),121.00(s),118.41(s),113.99(s),110.87(s),109.98(s),55.33(s),47.06(s),42.14(s),33.24(s),23.03(s).ESI-HRMS:calcd forC30H29N3O2,[M+H]+,464.2260,found 464.2333.
实施例5:2-(1-异丙基-5-(异喹啉-5-基)-1H-吲哚-3-基)-N-(4-甲氧基苄基)乙酰胺(Z1-5)
实施例5的化合物制备方法同实施例1,只是在第一步用5-异喹啉硼酸代替8-喹啉硼酸,得白色固体粉末,收率26.1%。
1H NMR(600MHz,DMSO)δ9.39(s,1H),8.45(d,J=6.0Hz,1H),8.39(t,J=5.8Hz,1H),8.14(d,J=8.1Hz,1H),7.78–7.75(m,2H),7.72–7.70(m,2H),7.64(d,J=8.4Hz,1H),7.43(s,1H),7.26(dd,J=8.4,1.6Hz,1H),7.07(d,J=8.6Hz,2H),6.65(d,J=8.6Hz,2H),4.83–4.78(m,1H),4.16(d,J=5.9Hz,2H),3.63(s,3H),3.59(s,2H),1.50(s,3H),1.49(s,3H).13C NMR(150MHz,DMSO)δ170.84(s),158.52(s),153.25(s),143.56(s),140.43(s),135.39(s),134.15(s),131.92(s),131.55(s),129.25(d,J=16.4Hz),128.92(s),128.26(s),127.61(s),126.96(s),124.67(s),123.37(s),120.90(s),118.87(s),113.93(s),110.31(s),109.70(s),47.06(s),42.12(s),33.21(s),23.08(s).ESI-HRMS:calcd forC30H29N3O2,[M+H]+,464.2260,found 464.2333.
实施例6:2-(1-异丙基-5-(菲-9-基)-1H-吲哚-3-基)-N-(4-甲氧基苄基)乙酰胺(Z1-6)
实施例6的化合物制备方法同实施例1,只是在第一步用9-菲硼酸代替8-喹啉硼酸,得白色固体粉末,收率20.1%。
1H NMR(600MHz,DMSO)δ8.95(d,J=8.3Hz,1H),8.89(d,J=8.2Hz,1H),8.39(t,J=5.7Hz,1H),8.01(d,J=7.4Hz,1H),7.94(d,J=8.2Hz,1H),7.77(d,J=2.5Hz,2H),7.73–7.66(m,3H),7.63(d,J=8.4Hz,1H),7.58(t,J=7.5Hz,1H),7.43(s,1H),7.28(dd,J=8.3,1.3Hz,1H),7.05(d,J=8.5Hz,2H),6.58(d,J=8.5Hz,2H),4.81(dt,J=13.3,6.6Hz,1H),4.16(d,J=5.8Hz,2H),3.59(s,2H),3.52(s,3H),1.52(s,3H),1.51(s,3H).13C NMR(150MHz,DMSO)δ170.91(s),158.47(s),140.01(s),135.28(s),131.91–131.56(m),130.86(s),130.64(s),129.66(s),128.92(d,J=7.7Hz),128.14(s),127.64(s),127.50(s),127.33–126.97(m),124.52(s),123.67(d,J=18.8Hz),123.25(s),120.72(s),113.90(s),110.03(s),109.57(s),55.32(s),47.09(s),42.15(s),33.22(s),23.09(s).ESI-HRMS:calcd for C35H32N2O2,[M+H]+,513.2464,found 513.2537.
实施例7:N-(4-氰基苄基)-2-(1-异丙基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酰胺(Z2-1)
将5-溴吲哚-3-乙酸(1a,10.00g,39.36mmol)溶于100mL无水DMF中,再将NaH(含量60%,7.97g,118.08mmol)在冰浴下分批缓慢加入至溶液中,加毕,移除冰浴,常温下搅拌反应0.5h,再将2-溴丙烷(2a,5.32g,43.3mmol)缓慢滴加至反应液中,继续在常温下搅拌1h后TLC监测反应。待检测反应完毕后,将反应液浓缩至约50mL,加入500mL水,并以1M的盐酸调pH至4~5,析出大量固体,以乙酸乙酯(100mL×3)萃取,合并有机层,用饱和食盐水洗涤(50mL×2)后浓缩,柱层析(DCM:MeOH=20:1)得黄色油状液体9.70g,将其溶于100mL无水DMF中,冰浴下缓慢加入HATU(0.75g,1.97mmol)和DIEA(1.28g,0.64mmol),加毕后撤去冰浴,室温下反应0.5h,TLC监测原料反应完毕后加4-氰基苄胺(4a,0.24g,1.80mmol),常温下反应1h后TLC监测。待监测反应完毕后,将反应液浓缩至约50mL,加入500mL水,并以1M的盐酸调pH至4~5,析出大量固体,以乙酸乙酯(100mL×3)萃取,合并有机层,用饱和食盐水洗涤(50mL×2)后浓缩,柱层析(PE:EA=2:1)得黄色粉末状固体0.60g。室温下,将6-喹啉硼酸(1b,0.29g,1.76mmol)用18mL甲苯溶解,加入上一步得到的中间体(0.60g,1.47mmol),再加入K3PO4(0.93g,4.41mmol)并加入3mL水溶解,搅拌15min后,加入Pd(PPh3)4(0.27g,0.24mmol),氮气保护,在110℃下回流反应6h,TLC监测原料反应完毕后,过滤除去不溶性杂质,浓缩溶剂,加入乙酸乙酯(50mL)并用饱和食盐水洗涤(50mL×2)后浓缩,柱层析(PE:EA=10:1)得黄色油状液体,加入无水乙醚(20mL)打浆,大量固体析出,抽滤后干燥得白色粉末状固体0.16g,收率23.8%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.1,1.7Hz,1H),8.63(t,J=6.0Hz,1H),8.40(dd,J=8.3,1.5Hz,1H),8.20(s,1H),8.08(s,2H),8.01(s,1H),7.64–7.61(m,4H),7.55(dd,J=8.2,4.2Hz,1H),7.42(s,1H),7.41(s,2H),4.78(dt,J=13.3,6.7Hz,1H),4.36(d,J=6.0Hz,2H),3.69(s,2H),1.48(s,3H),1.47(s,3H).13CNMR(150MHz,DMSO)δ171.38(s),150.48(s),147.21(s),146.14(s),140.20(s),136.45(s),135.70(s),132.56(s),130.56(s),129.74(s),129.53(s),128.73(d,J=17.2Hz),128.50(s),124.95(s),124.63(s),122.23(s),121.05(s),119.20(s),118.44(s),110.93(s),110.10–109.97(m),109.71(s),47.06(s),42.58(s).ESI-HRMS:calcd for C30H26N4O,[M+H]+,459.2107,found 459.2179.
实施例8:2-(1-异丙基-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(吡啶-2-基甲基)乙酰胺(Z2-2)
实施例8的化合物制备方法同实施例7,是在第一步用2-(5-溴-1-异丙基-1H-吲哚-3-基)-N-(吡啶-2-基甲基)乙酰胺代替2-(5-溴-1-异丙基-1H-吲哚-3-基)-N-(4-氰基苄胺)乙酰胺,得白色固体粉末,收率23.2%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.1,1.7Hz,1H),8.59(t,J=5.9Hz,1H),8.41(ddd,J=9.5,6.6,1.0Hz,2H),8.22(d,J=1.8Hz,1H),8.12(dd,J=8.8,2.0Hz,1H),8.10–8.06(m,2H),7.62(d,J=0.9Hz,2H),7.58(td,J=7.7,1.8Hz,1H),7.55(dd,J=8.3,4.2Hz,1H),7.44(s,1H),7.24(d,J=7.8Hz,1H),7.17(dd,J=7.0,5.2Hz,1H),4.78(dt,J=13.3,6.7Hz,1H),4.38(d,J=5.9Hz,2H),3.71(s,2H),1.49(s,3H),1.48(s,3H).13C NMR(150MHz,DMSO)δ171.27(s),159.21(s),150.46(s),149.24(s),147.21(s),140.16(s),136.96(s),136.48(s),135.69(s),130.52(s),129.73(s),129.57(s),128.76(d,J=11.1Hz),124.95(s),124.68(s),122.47(s),122.22(s),121.47(s),121.02(s),118.41(s),110.90(s),109.79(s),46.82(s),44.94(s),33.10–32.97(m),22.92(s).ESI-HRMS:calcd forC28H26N4O,[M+Na]+,457.2107,found 457.2029.
实施例9:2-(1-异丙基-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(吡啶-3-基甲基)乙酰胺(Z2-3)
实施例9的化合物制备方法同实施例7,只是在第三步用2-(5-溴-1-异丙基-1H-吲哚-3-基)-N-(吡啶-3-基甲基)乙酰胺代替2-(5-溴-1-异丙基-1H-吲哚-3-基)-N-(4-氰基苄胺)乙酰胺,得白色固体粉末,收率为18.4%。
1H NMR(600MHz,DMSO)δ8.88(d,J=2.8Hz,1H),8.59(t,J=5.8Hz,1H),8.50(s,1H),8.43–8.40(m,1H),8.39(d,J=4.0Hz,1H),8.20(s,1H),8.08(s,2H),8.01(s,1H),7.63(d,J=7.9Hz,1H),7.62(s,2H),7.55(dd,J=8.2,4.1Hz,1H),7.40(s,1H),7.21(dd,J=7.6,4.8Hz,1H),4.77(dt,J=13.3,6.7Hz,1H),4.32(d,J=5.9Hz,2H),3.67(s,2H),1.48(s,3H),1.47(s,3H).13C NMR(150MHz,DMSO)δ171.29(s),150.46(s),149.20(s),148.46(s),140.31–140.17(m),136.52(s),135.80–135.31(m),130.58(s),129.66(d,J=19.2Hz),128.75(d,J=17.7Hz),124.96(s),124.66(s),123.81(s),122.22(s),121.05(s),33.34(s),23.03(s).ESI-HRMS:calcd for C28H26N4O,[M+H]+,435.2107,found435.2191.
实施例10:2-(1-异丙基-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(4-甲基苄基)乙酰胺(Z2-4)
实施例10的化合物制备方法同实施例7,只是在第一步用22-(5-溴-1-异丙基-1H-吲哚-3-基)-N-(4-甲基苄胺)乙酰胺代替2-(5-溴-1-异丙基-1H-吲哚-3-基)-N-(4-氰基苄胺)乙酰胺,得淡黄色固体粉末,收率为29.6%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.1,1.6Hz,1H),8.50(t,J=5.9Hz,1H),8.38(d,J=8.3Hz,1H),8.19(s,1H),8.08(s,2H),8.02(s,1H),7.61(s,2H),7.55(dd,J=8.2,4.1Hz,1H),7.40(s,1H),7.11(d,J=7.9Hz,2H),6.93(d,J=7.7Hz,2H),4.77(dt,J=13.3,6.6Hz,1H),4.24(d,J=5.9Hz,2H),3.65(s,2H),2.12(s,3H),1.48(s,3H),1.47(s,3H).13CNMR(150MHz,DMSO)δ170.95(s),140.33(s),137.01(s),136.46(s),136.10(s),135.70(s),130.54(s),129.67(d,J=11.9Hz),129.15(s),128.78(s),128.62(s),127.68(s),124.98(s),124.65(s),122.13(s),121.01(s),118.44(s),22.85(s),21.00(s).ESI-HRMS:calcdfor C30H29N3O,[M+Na]+,470.2311,found 470.2220.
实施例11:2-(1-异丙基-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(噻吩-2-基甲基)乙酰胺(Z2-5)
实施例11的化合物制备方法同实施例7,只是在第一步用2-(5-溴-1-异丙基-1H-吲哚-3-基)-N-(噻吩-2-基甲基)乙酰胺代替2-(5-溴-1-异丙基-1H-吲哚-3-基)-N-(4-氰基苄胺)乙酰胺,得淡黄色固体粉末,收率为29.6%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.63(t,J=5.9Hz,1H),8.40(dd,J=8.3,1.6Hz,1H),8.20(s,1H),8.09(d,J=1.2Hz,2H),8.01(d,J=1.0Hz,1H),7.61(d,J=1.1Hz,2H),7.55(dd,J=8.2,4.2Hz,1H),7.39(s,1H),7.30(dd,J=5.1,1.2Hz,1H),6.96–6.94(m,1H),6.88(dd,J=5.1,3.4Hz,1H),4.80–4.74(m,1H),4.46(d,J=5.8Hz,2H),3.64(s,2H),1.48(s,3H),1.47(s,3H).13C NMR(150MHz,DMSO)δ150.44–150.31(m),147.21(s),143.10–142.97(m),140.19(s),136.52(s),130.54(s),129.68(d,J=12.5Hz),128.74(d,J=11.5Hz),127.03(s),125.77(s),125.36–125.23(m),124.96(s),124.60(s),122.21(s),120.95(s),118.37(s),110.86(s),109.77(s),47.02(s),37.54(s),32.88(s),22.86(s).ESI-HRMS:calcd for C27H25N3OS,[M+H]+,440.1718,found 440.1791.
实施例12:(S)-7-溴-10-(N-羟基辛酰胺)-1,5,10,11a-四氢-3H-苯并[e]吡咯并[1,2-][1,4]二氮杂-3,11(2H)-二酮(Z2-6)
实施例12的化合物制备方法同实施例7,只是在第一步用2-(5-溴-1-异丙基-1H-吲哚-3-基)-N-(4-(叔丁基)苄基)乙酰胺代替2-(5-溴-1-异丙基-1H-吲哚-3-基)-N-(4-氰基苄胺)乙酰胺,得白色固体粉末,收率为28.4%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.50(t,J=5.9Hz,1H),8.40(dd,J=8.3,1.3Hz,1H),8.23(d,J=2.0Hz,1H),8.13(dd,J=8.8,2.1Hz,1H),8.10–8.07(m,2H),7.60(d,J=1.4Hz,2H),7.54(d,J=4.0Hz,1H),7.40(s,1H),7.14(d,J=8.3Hz,2H),7.10–7.07(m,2H),4.80–4.75(m,1H),4.24(d,J=5.9Hz,2H),3.65(s,2H),1.48(d,J=6.7Hz,6H),1.09(s,9H).13C NMR(150MHz,DMSO)δ170.96(s),149.44(s),147.24(s),140.26(s),137.12(s),135.64(s),133.72(s),132.87(s),132.50(s),131.99(s),129.27(s),127.39(s),125.27(s),122.20(s),121.01(s),118.47(s),110.88(s),109.96(s),42.42(s),34.41(s),33.25(s),31.45(s),23.04(s).ESI-HRMS:calcd for C33H35N3O,[M+H]+,490.2780,found 490.2853.
实施例13:N-(4-乙氧基苄基)-2-(1-异丙基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酰胺(Z2-7)
实施例13的化合物制备方法同实施例7,只是在第一步用2-(5-溴-1-异丙基-1H-吲哚-3-基)-N-(4-乙氧基苄基)乙酰胺代替2-(5-溴-1-异丙基-1H-吲哚-3-基)-N-(4-氰基苄胺)乙酰胺,得白色固体粉末,收率为31.2%。
1H NMR(600MHz,DMSO)δ8.97–8.78(m,1H),8.47(t,J=5.4Hz,1H),8.39(d,J=8.3Hz,1H),8.20(s,1H),8.08(s,2H),8.04(s,1H),7.61(s,2H),7.56–7.53(m,1H),7.40(s,1H),7.13(d,J=8.1Hz,2H),6.75–6.56(m,2H),4.82–4.71(m,1H),4.21(d,J=5.8Hz,2H),3.76(q,J=6.9Hz,2H),3.65(s,2H),1.48(s,3H),1.46(s,3H),1.21(t,J=6.9Hz,3H).13CNMR(150MHz,DMSO)δ170.89(s),157.77(s),150.56(s),147.23(s),140.18(s),136.40(s),135.71–135.57(m),131.89(s),130.49(s),129.73(s),129.59(s),128.95(s),128.73(d,J=17.9Hz),124.93(s),124.67(s),122.19(s),121.01(s),118.42(s),114.44(s),42.12(s),33.26(s),22.83(s).ESI-HRMS:calcd for C31H31N3O2,[M+Na]+,500.2416,found500.2327.
实施例14:2-(1-异丁基-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(吡啶-2-基甲基)乙酰胺(Z3-1)
将5-溴吲哚-3-乙酸(1a,10.00g,39.36mmol)溶于200mL无水甲醇中,在冰浴条件下,缓慢滴加氯化亚砜(3.2mL,43.3mmol),滴毕,撤去冰浴,室温下反应1h,TLC监测反应完全后,蒸干溶剂,加入碳酸氢钠水溶液调至约pH 8,以乙酸乙酯(100mL×3)萃取,合并有机层后浓缩,得棕色粉末状固体10.09g,收率96.7%。将中间体(10.09g,37.63mmol)加入200mL甲苯溶解,加入6-喹啉硼酸(7.81g,45.16mmol),加入K3PO4(23.96g,112.89mmol),加5mL水,常温下搅拌反应30min后加入Pd(PPh3)4(6.96g,6.02mmol),氮气保护,在110℃下回流反应6h,TLC监测原料反应完毕后,过滤除去不溶性杂质,浓缩溶剂,加入乙酸乙酯(100mL)并用饱和食盐水洗涤(100mL×2)后浓缩,柱层析(PE:EA=10:1)得黄色油状液体,加入无水乙醚(20mL)打浆,大量固体析出,抽滤后干燥得黄色粉末状固体3.37g,收率28.3%。将中间体(3.37g,10.65mmol)溶于100mLNaOH的甲醇溶液中(2mol/L),搅拌反应2h后TLC监测,反应完全后浓缩反应液,加入200mL水溶解,并以1M的盐酸调pH至6~7,析出大量固体后抽滤,得黄色颗粒状固体3.03g,收率94.3%。将中间体(0.25g,0.83mmol)溶于10mL无水DMF中,再将NaH(含量60%,0.10g,2.49mmol)在冰浴下分批缓慢加入至溶液中,加毕,移除冰浴,常温下搅拌反应0.5h,再将溴代异丙烷(1f,0.13g,0.91mmol)缓慢滴加至反应液中,继续在常温下搅拌1h后TLC监测反应。反应完全后,向反应液中加入100mL水,并以1M的盐酸调pH至4~5,以乙酸乙酯(30mL×3)萃取,合并有机层,用饱和食盐水洗涤(20mL×2)后浓缩,柱层析(DCM:MeOH=20:1)得棕色粉末状固体0.23g,收率78.70%。将上一步得到的中间体1g(0.20g,0.56mmol)溶于20mL无水DMF中,冰浴下缓慢加入HATU(0.26g,0.67mmol)和DIEA(0.22g,1.68mmol),加毕后撤去冰浴,室温下反应0.5h,TLC监测原料反应完毕后加2-吡啶苄胺(2c,0.07g,0.62mmol),常温下反应1h后TLC监测。待监测反应完毕后,向反应液中加入200mL水,以乙酸乙酯(50mL×3)萃取,合并有机层,用饱和食盐水洗涤(25mL×2)后浓缩,柱层析(PE:EA=2:1)得黄色粉末状固体0.20g,收率78.93%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.58(t,J=5.9Hz,1H),8.44–8.37(m,2H),8.23(d,J=1.9Hz,1H),8.12(dd,J=8.8,2.0Hz,1H),8.08(d,J=8.8Hz,1H),8.06(d,J=1.2Hz,1H),7.61–7.58(m,2H),7.56(dd,J=5.9,1.8Hz,1H),7.56–7.53(m,1H),7.31(s,1H),7.22(d,J=7.8Hz,1H),7.17(dd,J=7.1,5.1Hz,1H),4.38(d,J=5.9Hz,2H),4.00(d,J=7.3Hz,2H),3.71(s,2H),2.14(dt,J=13.6,6.8Hz,1H),0.89(s,3H),0.88(s,3H).13C NMR(150MHz,DMSO)δ171.28(s),159.13(s),150.45(s),149.22(s),147.19(s),140.14(s),136.96(s),136.53(d,J=12.6Hz),130.42(s),129.66(d,J=15.9Hz),129.15(s),128.79(s),128.63(s),124.99(s),122.47(s),122.21(s),121.40(s),121.10(s),118.34(s),111.07(s),109.36(s),53.30(s),29.30(s),20.41(s).ESI-HRMS:calcd forC29H28N4O,[M+H]+,449.2263,found 449.2355.
实施例15:2-(1-(环丁基甲基)-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(吡啶-2-基甲基)乙酰胺(Z3-2)
实施例15的化合物制备方法同实施例14,只是在第四步用2-(1-(环丁基甲基)-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸代替2-(1-异丁基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸,得白色固体粉末,收率为31.2%。
1H NMR(600MHz,DMSO)δ8.87(dd,J=4.2,1.7Hz,1H),8.58(t,J=5.9Hz,1H),8.44–8.39(m,2H),8.22(d,J=1.9Hz,1H),8.12(dd,J=8.8,2.0Hz,1H),8.08(d,J=8.8Hz,1H),8.05(s,1H),7.62–7.59(m,2H),7.57(dd,J=7.7,5.9Hz,1H),7.56–7.54(m,1H),7.32(s,1H),7.23(d,J=7.8Hz,1H),7.17(dd,J=6.8,5.0Hz,1H),4.38(d,J=5.9Hz,2H),4.20(d,J=7.3Hz,2H),3.70(s,2H),2.81–2.75(m,1H),1.97–1.78(m,6H).13C NMR(150MHz,DMSO)δ171.27(s),159.15(s),150.46(s),149.24(s),147.20(s),140.17(s),136.96(s),136.46(d,J=6.2Hz),130.43(s),129.66(d,J=19.4Hz),128.91–128.56(m),124.98(s),122.47(s),122.22(s),121.44(s),121.10(s),118.31(s),110.91(s),109.43(s),50.96(s),44.77(s),36.15(s),32.94(s),26.05(s),18.19(s).ESI-HRMS:calcd for C30H28N4O,[M+Na]+,483.2263,found 483.2201.
实施例16:2-(1-(环戊基甲基)-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(吡啶-2-基甲基)乙酰胺(Z3-3)
实施例16的化合物制备方法同实施例14,只是在第四步用2-(1-(环戊基甲基)-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸代替2-(1-异丁基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸,得白色固体粉末,收率为24.4%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.58(t,J=5.9Hz,1H),8.41(ddd,J=9.6,6.7,1.0Hz,2H),8.23(d,J=1.9Hz,1H),8.12(dd,J=8.8,2.0Hz,1H),8.09(d,J=8.8Hz,1H),8.06(s,1H),7.60(dd,J=6.7,5.0Hz,2H),7.59–7.56(m,1H),7.55(dd,J=7.1,3.0Hz,1H),7.35(s,1H),7.23(d,J=7.8Hz,1H),7.17(dd,J=7.0,5.2Hz,1H),4.38(d,J=5.9Hz,2H),4.10(d,J=7.5Hz,2H),3.71(s,2H),2.40(dd,J=15.0,7.5Hz,1H),1.71–1.39(m,8H).13C NMR(150MHz,DMSO)δ171.29(s),159.13(s),150.38–150.25(m),149.20(s),147.16(s),140.20(s),136.97(s),136.47(d,J=15.8Hz),130.42(s),129.65(d,J=10.3Hz),128.83(d,J=10.3Hz),128.66(s),124.98(s),122.47(s),122.21(s),121.43(s),121.09(s),118.34(s),110.94(s),109.39(s),50.54(s),44.76(s),41.05(s),32.95(s),30.37(s),24.93(s).ESI-HRMS:calcd for C31H30N4O,[M+Na]+,497.2420,found449.2359.
实施例17:2-(1-(环丙基甲基)-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(吡啶-2-基甲基)乙酰胺(Z3-4)
实施例17的化合物制备方法同实施例14,只是在第四步用2-(1-(环丙基甲基)-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸代替2-(1-异丁基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸,得白色固体粉末,收率为24.4%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.62(t,J=5.9Hz,1H),8.42(ddd,J=9.6,6.7,1.1Hz,2H),8.23(d,J=2.0Hz,1H),8.12(dd,J=8.8,2.1Hz,1H),8.09–8.07(m,2H),7.63(d,J=1.0Hz,2H),7.58(td,J=7.7,1.8Hz,1H),7.55(dd,J=8.2,4.2Hz,1H),7.40(s,1H),7.24(d,J=7.8Hz,1H),7.17(dd,J=7.0,5.2Hz,1H),4.39(d,J=5.9Hz,2H),4.06(d,J=7.0Hz,2H),3.71(s,2H),1.29–1.26(m,1H),0.55–0.52(m,2H),0.43–0.40(m,2H).13C NMR(150MHz,DMSO)δ171.29(s),150.45(s),149.24(s),147.19(s),140.17(s),136.98(s),136.48(s),136.31(s),130.45(s),129.65(d,J=18.6Hz),128.76(d,J=11.4Hz),128.46(s),124.97(s),122.47(s),122.21(s),121.45(s),121.11(s),118.31(s),110.95(s),109.51(s),50.11(s),44.79(s),32.97(s),12.12(s),4.22(s).ESI-HRMS:calcd for C29H26N4O,[M+Na]+,469.2107,found 469.2042.
实施例18:2-(1-乙基-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(吡啶-2-基甲基)乙酰胺(Z3-5)
实施例18的化合物制备方法同实施例14,只是在第四步用2-(1-乙基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸代替2-(1-异丁基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸,得白色固体粉末,收率为25.5%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.60(t,J=5.9Hz,1H),8.44–8.39(m,2H),8.23(d,J=1.9Hz,1H),8.12(dd,J=8.8,2.0Hz,1H),8.09(d,J=8.8Hz,1H),8.07(d,J=1.5Hz,1H),7.63(dd,J=8.5,1.7Hz,1H),7.60–7.57(m,2H),7.55(dd,J=8.2,4.2Hz,1H),7.36(s,1H),7.24(d,J=7.8Hz,1H),7.17(dd,J=7.1,5.2Hz,1H),4.38(d,J=6.0Hz,2H),4.23(q,J=7.2Hz,2H),3.70(s,2H),1.39(t,J=7.2Hz,3H).13C NMR(150MHz,DMSO)δ171.29(s),159.16(s),150.44(s),149.21(s),147.16(s),140.19(s),137.01(s),136.53(s),135.90(s),130.46(s),129.65(d,J=11.9Hz),128.80(s),128.04(s),124.98(s),122.48(s),122.22(s),121.47(s),121.11(s),118.40(s),110.74(s),109.56(s),44.78(s),40.74(s),32.97(s),16.03(s).ESI-HRMS:calcd for C27H24N4O,[M+Na]+,443.1950,found 443.1881.
实施例19:2-(1-丙基-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(吡啶-2-基甲基)乙酰胺(Z3-6)
实施例19的化合物制备方法同实施例14,只是在第四步用2-(1-丙基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸代替2-(1-异丁基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸,得白色固体粉末,收率为28.6%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.58(t,J=5.9Hz,1H),8.41(ddd,J=9.6,6.7,1.1Hz,2H),8.23(d,J=2.0Hz,1H),8.12(dd,J=8.8,2.0Hz,1H),8.08(d,J=8.8Hz,1H),8.07(d,J=1.3Hz,1H),7.61(dt,J=15.1,3.9Hz,2H),7.57(dd,J=7.6,5.8Hz,1H),7.56–7.54(m,1H),7.34(s,1H),7.23(d,J=7.8Hz,1H),7.17(dd,J=7.0,5.3Hz,1H),4.38(d,J=6.0Hz,2H),4.15(t,J=7.0Hz,2H),3.70(s,2H),1.80(dd,J=14.3,7.2Hz,2H),0.88(t,J=7.4Hz,3H).13CNMR(150MHz,DMSO)δ171.28(s),159.15(s),150.46(s),149.26(s),147.20(s),140.18(s),136.96(s),136.48(s),136.29(s),130.43(s),129.86(s),129.66(d,J=18.5Hz),128.75(d,J=11.7Hz),124.98(s),122.47(s),122.22(s),121.43(s),121.10(s),118.36(s),110.87(s),109.37(s),47.49–47.35(m),23.66(s),11.66(s).ESI-HRMS:calcd for C28H26N4O,[M+Na]+,457.2107,found 457.2039.
实施例20:2-(1-丁基-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(吡啶-2-基甲基)乙酰胺(Z3-7)
实施例20的化合物制备方法同实施例14,只是在第四步用2-(1-丁基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸代替2-(1-异丁基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸,得白色固体粉末,收率为75.28%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.59(t,J=5.9Hz,1H),8.44–8.39(m,2H),8.23(d,J=1.9Hz,1H),8.13–8.11(m,1H),8.08(d,J=8.8Hz,1H),8.06(d,J=1.4Hz,1H),7.62(dd,J=8.5,1.7Hz,1H),7.59(d,J=3.2Hz,1H),7.58–7.56(m,1H),7.56–7.54(m,1H),7.33(s,1H),7.23(d,J=7.8Hz,1H),7.17(dd,J=7.4,4.9Hz,1H),4.38(d,J=5.9Hz,2H),4.19(t,J=7.0Hz,2H),3.70(s,2H),1.78–1.73(m,2H),1.31–1.27(m,2H),0.91(t,J=7.4Hz,3H).13CNMR(150MHz,DMSO)δ171.28(s),159.20(s),150.45(s),149.23(s),147.30(s),140.18(s),136.97(s),136.49(s),136.23(s),130.44(s),129.66(d,J=18.1Hz),128.91–128.55(m),124.98(s),122.47(s),122.22(s),121.44(s),121.11(s),118.37(s),110.84(s),109.45(s),45.65(s),44.77(s),32.95(s),32.58(s),20.10(s),14.09(s).ESI-HRMS:calcd for C29H28N4O,[M+H]+,449.2263,found 449.2336.
实施例21:2-(1-(丁-3-烯-1-基)-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(吡啶-2-基甲基)乙酰胺(Z3-8)
实施例21的化合物制备方法同实施例2-(1-(丁-3-烯-1-基)-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸代替2-(1-异丁基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸,收率为77.98%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.57(t,J=5.9Hz,1H),8.42(dd,J=13.3,6.5Hz,2H),8.23(d,J=1.9Hz,1H),8.13–8.11(m,1H),8.08(d,J=8.8Hz,1H),8.06(d,J=1.1Hz,1H),7.63(dd,J=8.6,1.6Hz,1H),7.61–7.59(m,1H),7.58–7.56(m,1H),7.56–7.54(m,1H),7.34(s,1H),7.23(d,J=7.8Hz,1H),7.17(dd,J=7.4,4.9Hz,1H),5.83(ddd,J=17.1,6.8,3.5Hz,1H),5.08(dd,J=17.2,1.7Hz,1H),5.01(dd,J=10.3,1.8Hz,1H),4.38(d,J=6.0Hz,2H),4.26(t,J=7.1Hz,2H),3.70(s,2H),2.57–2.53(m,2H).13C NMR(150MHz,DMSO)δ171.25(s),159.14(s),150.46(s),149.23(s),147.20(s),136.98(s),136.50(s),136.20(s),135.74(s),130.50(s),129.66(d,J=18.1Hz),128.77(d,J=6.8Hz),128.60(s),125.00(s),122.48(s),122.22(s),121.45(s),121.15(s),118.38(s),117.65(s),110.89(s),109.53(s),45.42(s),44.78(s),34.79(s),32.95(s).ESI-HRMS:calcd for C29H26N4O,[M+H]+,447.2107,found 447.2179.
实施例22:2-(1-(2-甲氧基乙基)-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(吡啶-2-基甲基)乙酰胺(Z3-9)
实施例22的化合物制备方法同实施例14,只是在第四步用2-(1-(2-甲氧基乙基)-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸代替2-(1-异丁基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸。得白色固体粉末,收率为71.23%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.62(t,J=5.8Hz,1H),8.44–8.39(m,2H),8.23(d,J=1.9Hz,1H),8.12(dd,J=8.8,2.0Hz,1H),8.09(d,J=8.8Hz,1H),8.07(d,J=0.9Hz,1H),7.62(t,J=4.3Hz,1H),7.60(d,J=4.9Hz,1H),7.58(dd,J=7.7,1.8Hz,1H),7.56–7.54(m,1H),7.33(s,1H),7.25(d,J=7.8Hz,1H),7.17(dd,J=6.9,5.2Hz,1H),4.38(d,J=6.0Hz,2H),4.35(t,J=5.3Hz,2H),3.70(s,2H),3.68(t,J=5.3Hz,2H),3.17(s,3H).13C NMR(150MHz,DMSO)δ171.25(s),150.45(s),149.23(s),147.18(s),140.17(s),137.00(s),136.50(d,J=5.4Hz),130.52(s),129.66(d,J=14.4Hz),129.00(s),128.76(d,J=10.2Hz),124.99(s),122.48(s),122.22(s),121.47(s),121.12(s),118.30(s),110.99(s),109.58(s),71.59(s),49.07(s),44.79(s),32.92(s).ESI-HRMS:calcd for C28H26N4O2,[M+H]+,451.2056,found 451.2129.
实施例23:2-(1-(2-甲氧基乙基)-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(吡啶-2-基甲基)乙酰胺(Z3-10)
实施例23的化合物制备方法同实施例14,只是在第四步用2-(1-(仲丁基)-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸代替2-(1-异丁基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸。得白色固体粉末,收率为73.26%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.59(t,J=5.9Hz,1H),8.42(ddd,J=9.5,6.6,0.9Hz,2H),8.23(d,J=1.9Hz,1H),8.13–8.12(m,1H),8.09(d,J=8.8Hz,1H),8.07(d,J=1.1Hz,1H),7.63(d,J=8.6Hz,1H),7.61(dd,J=8.6,1.6Hz,1H),7.58–7.56(m,1H),7.55(dd,J=7.3,3.2Hz,1H),7.42(s,1H),7.24(d,J=7.8Hz,1H),7.17(dd,J=7.1,5.2Hz,1H),4.56–4.51(m,1H),4.39(d,J=5.9Hz,2H),3.72(s,2H),1.88–1.81(m,2H),1.47(d,J=6.7Hz,3H),0.76(t,J=7.3Hz,3H).13C NMR(150MHz,DMSO)δ159.08(s),150.39(s),149.14(s),147.11(s),140.20–140.07(m),137.01(s),136.57(s),136.35(s),130.41(s),129.64(s),128.81(s),128.51(s),124.98(d,J=9.0Hz),122.53(s),122.22(s),121.48(s),121.02(s),118.35(s),110.93(s),110.01(s),44.59(s),21.20(s),11.23(s).ESI-HRMS:calcd for C29H28N4O,[M+H]+,449.2263,found 449.2336.
实施例24:2-(1-(戊烷-3-基)-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(吡啶-2-基甲基)乙酰胺(Z3-11)
实施例24的化合物制备方法同实施例14是在第四步用2-(1-(戊烷-3-基)-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸代替2-(1-异丁基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸,得白色固体粉末,收率为71.42%。
1H NMR(600MHz,DMSO)δ8.88(dd,J=4.1,1.7Hz,1H),8.55(t,J=5.9Hz,1H),8.41(t,J=7.2Hz,2H),8.22(d,J=1.9Hz,1H),8.12(dd,J=8.8,2.0Hz,1H),8.09(d,J=8.8Hz,1H),8.05(d,J=1.6Hz,1H),7.64(d,J=8.6Hz,1H),7.59(dd,J=8.6,1.7Hz,1H),7.58–7.56(m,1H),7.55(dd,J=4.8,3.3Hz,1H),7.38(s,1H),7.21(d,J=7.8Hz,1H),7.17(dd,J=7.4,4.9Hz,1H),4.39(d,J=5.9Hz,2H),4.31–4.26(m,1H),3.72(s,2H),1.90–1.83(m,4H),0.71(t,J=7.3Hz,6H).13C NMR(151MHz,DMSO)δ171.28(s),159.09(s),150.41(s),149.20(s),147.14(s),140.24(s),137.34(s),136.97(s),136.53(s),130.38(s),129.65(d,J=5.9Hz),128.80(s),128.33(s),125.02(d,J=15.8Hz),122.49(s),122.21(s),121.40(s),121.07(s),118.33(s),110.95(s),110.33–110.20(m),59.20(s),33.29(s),28.52(s),11.16(s).ESI-HRMS:calcd for C30H30N4O,[M+H]+,463.2420,found 464.2492.
实施例25:2-(1-(2-乙氧基乙基)-5-(喹啉-6-基)-1H-吲哚-3-基)-N-(吡啶-2-基甲基)乙酰胺(Z-25)
实施例25的化合物制备方法同实施例14,只是在第四步用2-(1-(2-乙氧基乙基)-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸代替2-(1-异丁基-5-(喹啉-6-基)-1H-吲哚-3-基)乙酸,得白色固体粉末,收率为68.33%。
1H NMR(600MHz,DMSO)δ8.80(dd,J=4.1,1.5Hz,1H),8.54(t,J=5.9Hz,1H),8.34(dd,J=19.6,6.5Hz,2H),8.16(d,J=1.6Hz,1H),8.05(dd,J=8.8,1.9Hz,1H),8.02(d,J=8.9Hz,1H),8.00(s,1H),7.57–7.52(m,2H),7.52–7.49(m,1H),7.47(dd,J=8.2,4.2Hz,1H),7.27(s,1H),7.17(d,J=7.8Hz,1H),7.09(dd,J=7.3,5.0Hz,1H),4.32(d,J=5.9Hz,2H),4.26(t,J=5.4Hz,2H),3.66–3.61(m,4H),3.35(q,J=7.0Hz,2H),0.99(t,J=7.0Hz,3H).13C NMR(150MHz,DMSO)δ171.27(s),159.14(s),150.44(s),149.22(s),147.19(s),140.16(s),136.98(s),136.55(d,J=13.4Hz),130.51(s),129.65(d,J=18.1Hz),129.01(s),128.77(d,J=9.0Hz),124.98(s),122.47(s),122.21(s),121.46(s),121.09(s),118.29(s),111.01(s),109.59(s),69.53(s),65.83(s),46.10(s),44.70(s),32.94(s).ESI-HRMS:calcd for C29H28N4O2,[M+H]+,465.2212,found 465.2285.
实施例26:本发明产物的药理研究
药理测试已经证明本发明所涉及的化合物具有抗胰腺癌转移活性。
(1)MTT细胞毒性实验
采用MTT细胞毒性实验,将以测试化合物在不同浓度下对于BxPC-3细胞毒性的影响。
取对数生长期的BxPC-3细胞,以6×104个/mL的细胞密度接种于96孔板中。待细胞贴壁后,给药孔加100μL无血清培养液配置的不同浓度的含药培养液,对照组加入等量容积含DMSO(0.1%)的无血清培养液。待连续培养48h后,向每孔中加入MTT(15μL)工作液,孵育4h。随后,弃去所有液体,每孔加150μL的DMSO震荡10min,使结晶充分溶解后,于多功能酶标仪波长为492nm的条件下,检测吸光度(OD)值。按照公式计算细胞存活率。
实验结果如表1、表2以及图1、图2所示。
表1.化合物Z1-1~Z1-6对BxPC-3细胞的存活率测试
表2.化合物Z2-1~Z2-7对BxPC-3细胞的存活率测试
(2)划痕实验测试化合物对胰腺癌转移的活性
取对数生长期的BxPC-3细胞制备成细胞悬液,并计数,稀释其细胞浓度为3×105个/mL,混匀后于6孔板的每个孔加入2mL,待单层细胞铺满孔底后,方可进行划痕。使用10μL的枪头划痕,每孔形成3条划痕。划痕后,弃去原培养液,用无菌的PBS洗涤划痕后飘浮的细胞,重复3次。最后向给药孔中加入2mL不含FBS的培养液配制的含药培养液,对照组加入等量容积的含0%的FBS培养液,于培养箱中培养48h。选取0h和48h这两个时间点进行取样和拍照。用ImageJ软件打开细胞划痕照片,在每条划痕处随机划6条直线,测量直线间的距离,并计算平均值,用计算公式计算出相对迁移率。
实验结果如图3(图3A-图3B)、图4所示。
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (10)
1.通式Ⅰ所示的吲哚类化合物或其药学上可接受的盐或其光学活性体,其特征在于:
其中R1、R2、R3各自同时为下列基团中的任意一个基团:(1)H原子,(2)羟基,(3)卤原子,(4)氰基,(5)硝基,(6)三卤甲基,(7)C1-6烷基、C3-8环烷基、C2-6链烯基、C2-6链炔基、C1-6烷磺酰氨基、C1-18烷氧羰基、C1-18烷氧磺酰基、C1-6烷氧基、C2-6链烯氧基、C2-6链炔氧基、C1-6烷硫基、C2-6链烯硫基、C2-6链炔硫基、C1-6烷基磺酰基、C2-6链烯基磺酰基、C2-6链炔基磺酰基、C1-6烷基亚磺酰基、C2-6链烯基亚磺酰基、C2-6链炔基亚磺酰基、C3-8环烯基,上述各基团任意被选自H原子、卤原子、羟基、氰基、硝基或氨基中的一种或多种取代基所取代,(8)被各种取代的羰基,其任意被选自H原子、羟基、C1-6烷基、氨基、C1-6烷氨基、C1-6烷氧基、C1-6烷硫基和C3-8环烷基中的一种或多种取代基所取代,(9)被各种取代的氨基,其任意被选自H原子、C1-6烷基、C2-6链烯基、C2-6链炔基、C1-6烷基磺酰基、C2-6链烯基磺酰基、C2-6链炔基磺酰基、C1-6烷基羰基、C2-6链烯基羰基或C2-6链炔基羰基中的一种或多种取代基所取代,(10)被各种取代的苯基、被各种取代的苄基、被各种取代的苄氧基、被各种取代的苯甲酰基、被各种取代的苯磺酰基、被各种取代的吡啶环、被各种取代的吡唑环、被各种取代的吡咯环、被各种取代的嘧啶环、被各种取代的喹啉环、被各种取代的异喹啉环、被各种取代咪唑环、被各种取代的吗啉环、被各种取代的哌嗪环、被各种取代的哒嗪环、被各种取代的吡嗪环、被各种取代的哌啶环、被各种取代的噻吩环、被各种取代的噻唑环、被各种取代的异噻唑环、被各种取代的苯并噻唑环、被各种取代的吡喃环、被各种取代的吲哚环、被各种取代的噁唑环、被各种取代的异噁唑环、被各种取代的三氮唑类环、被各种取代的苯并三唑环、被各种取代的呋喃环,上述各基团任意被选自H、卤素、C1-6烷基、C1-6烷氨基、C3-7环烷基、C1-6烷氧基、C1-6烷磺酰氨基、苄氧羰基、C1-18烷氧羰基、C1-18烷氧磺酰基、三卤甲基、羟基、氰基、硝基和氨基中的一种或多种取代基所取代。
2.根据权利要求1所述的化合物或其药学上可接受的盐或其光学活性体,其特征在于:其中R1、R2各自同时为下列基团中的任意一个基团:(1)H原子,(2)羟基,(3)卤原子,(4)硝基,(5)C1-4烷基,C1-4烷氧基,上述各基团任意被选自氢原子、卤原子、羟基、氰基、硝基和氨基中的一种或多种取代基所取代,(6)被各种取代的苯基,被各种取代的苄氧基,上述各基团任意被选自H、卤素、C1-6烷基、C1-6烷基氨基、C3-7环烷基、C1-4烷氧基、C1-4烷磺酰氨基、苄氧羰基、C1-10烷氧羰基、C1-10烷氧磺酰基、三卤甲基、羟甲基、羟基、氰基、硝基和氨基中的一种或多种取代基所取代。
3.根据权利要求1或2所述的化合物或其药学上可接受的盐或其光学活性体,其特征在于:其中R1、R2、R3各自同时为下列基团中的任意一个基团:(1)H原子,(2)羟基,(3)氟、氯、溴,(4)硝基,(5)C1-4烷基,C1-4烷氧基,上述各基团任意被选自氢原子、卤原子、羟基、氰基、硝基和氨基中的一种或多种取代基所取代,(6)未取代或取代的苯基、苄氧基、所述取代基选自H、卤素、C1-4烷基、C1-4烷氧基、C1-4烷氧羰基中的一种或多种。
4.根据权利要求1所述的化合物或其药学上可接受的盐或其光学活性体,其特征在于:其中R1、R2、R3各自同时为下列基团中的任意一个基团:乙氧羰基、H原子、羟基、溴原子、氯原子、甲氧基、乙氧基、2-甲基-苯基、4-甲基-苯基、苄氧基或相邻的R1与R2之间相连构成亚烷二氧基。
5.根据权利要求1所述的化合物或其药学上可接受的盐或其光学活性体,其特征在于:所述化合物选自:
6.一种药物组合物,其特征在于:所述药物组合物包含权利要求1-5中任一项所述的化合物或其药学上可接受的盐或其光学活性体以及药学上可接受的载体。
7.一种药物制剂,其特征在于:所述药物制剂包含权利要求6所述的药物组合物,所述药物制剂的剂型选自以下一种或多种:片剂、胶囊、注射剂、栓剂、贴剂、可吸入粉末制剂、混悬剂、乳剂或软膏。
8.权利要求1-5中任一项所述的化合物或其药学上可接受的盐或其光学活性体或者权利要求6所述的药物组合物或者权利要求7所述的药物制剂在制备SIRT2抑制剂中的应用。
9.权利要求1-5中任一项所述的化合物或其药学上可接受的盐或其光学活性体或者权利要求6所述的药物组合物或者权利要求7所述的药物制剂在制备抗肿瘤药物中的应用。
10.根据权利要求9所述的应用,其特在于:所述抗肿瘤药物具有抗胰腺癌转移活性。
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