CN116199687B - 一种β-咔啉-3位连接1,2,3-三氮唑类化合物及其制备方法、应用 - Google Patents
一种β-咔啉-3位连接1,2,3-三氮唑类化合物及其制备方法、应用 Download PDFInfo
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Abstract
本发明为一种β‑咔啉‑3位连接1,2,3‑三氮唑类化合物及其制备方法、应用。本发明公开了一类新的化合物—β‑咔啉‑3位连接1,2,3‑三氮唑类化合物,及β‑咔啉‑3位连接1,2,3‑三氮唑类化合物在制备抗肿瘤药物中的应用。本发明的β‑咔啉‑3位连接1,2,3‑三氮唑类化合物为一种新的化合物,具有较好的抗肿瘤活性,可应用于抗肿瘤药物中。
Description
技术领域
本发明属于医药化学领域,具体涉及一种β-咔啉-3位连接1,2,3-三氮唑类化合物及其制备方法、应用。
背景技术
β-咔啉衍生物是一种吲哚生物碱,其结构中具有三环吡啶并[3,4-b]吲哚环。β-咔啉类化合物是一类重要的药理活性支架,通过多种机制发挥其抗癌活性。研究发现这类生物碱具有抗焦虑、抗抑郁、抗痉挛、抗惊厥、镇静、止痛等神经药理学活性以及抗肿瘤抗疱疾、抗寄生虫、抗艾滋病等药理学活性,其中有些已被研究证明有高效低毒的药理活性,作为新药开发有较好的应用前景。
三唑类化合物是一种特殊的化合物,由于其在药物开发中的作用而受到世界各地有机化学家的广泛关注。三唑类化合物具有广泛应用,如缓蚀剂、染料、光稳定剂和药物。含有三唑的杂环药效团,已被用于抗病毒、抗癌、抗过敏、和抗炎药物的不同治疗目的。其中,1,2,3-三唑类药物在化学、生物学和材料科学中得到了广泛的应用。
有鉴于此,本发明提出一种新的化合物—β-咔啉-3位连接1,2,3-三氮唑类化合物,对开发出具有优良活性、低毒性、同时又环境友好型的新型抗肿瘤先导物或药物具有重要意义。
发明内容
本发明的目的在于提出一种β-咔啉-3位连接1,2,3-三氮唑类化合物,是一种具体三环吡啶并[3,4-b]吲哚环的三唑类化合物。
为了实现上述目的,所采用的技术方案为:
一种β-咔啉-3位连接1,2,3-三氮唑类化合物,其化学结构通式为:
进一步的,所述的β-咔啉-3位连接1,2,3-三氮唑类化合物的化学结构通式中,R1为氢、苯基、甲基、异丙基中的一种;
R9为氢、甲基、苄基中的一种;
R3为苯基、萘基、2-溴苯基、3-甲基苯基、4-氟苯基、4-硝基苯基、4-碘苯基、4-三氟甲基苯基中的一种。
再进一步的,所述的β-咔啉-3位连接1,2,3-三氮唑类化合物,为下列任一化合物:
1-甲基-3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
3-(4-(2-溴苯基)-1H-1,2,3-三唑)-1-甲基-9H-吡啶并[3,4-b]吲哚,
3-(4-(4-氟苯基)-1H-1,2,3-三唑)-1-甲基-9H-吡啶并[3,4-b]吲哚,
1-甲基-3-(4-(4-硝基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
1-甲基-3-(4-(4-(三氟甲基)苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
1-甲基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
1-甲基-3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
9-苄基-3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
9-苄基-3(4-(4-(三氟甲基)苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
9-苄基-3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
9-苄基-3-(4-(4-碘苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
9-苄基-3-(4-(4-氟苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
9-苄基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
1-苯基-3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
3-(4-(4-氟苯基)-1H-1,2,3-三唑)-1-苯基-9H-吡啶并[3,4-b]吲哚,
1-苯基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
1-异丙基-9-甲基-3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
1-异丙基-9-甲基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
1-异丙基-9-甲基-3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
3-(4-(4-氟苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚。
本发明的另一个目的在于提供上述的β-咔啉-3位连接1,2,3-三氮唑类化合物的制备方法,该制备方法具有较好的收率。
为了实现上述目的,所采用的技术方案为:
上述的β-咔啉-3位连接1,2,3-三氮唑类化合物的制备方法,所述的制备方法的化学反应式为:
进一步的,将相应的3-氨基-β-咔啉、对甲苯磺酰肼(TsNHNH2)、相应的酮类化合物溶解于溶剂二甲基亚砜(DMSO)中后,加入I2,加热搅拌反应;
反应结束后,冷却至室温,加水,用乙酸乙酯(EtOAc)萃取,得提取物;
将所述的提取物洗涤、干燥、去除溶剂、纯化,得所述的β-咔啉-3位连接1,2,3-三氮唑类化合物。
再进一步的,所述的相应的3-氨基-β-咔啉、TsNHNH2、相应的酮类化合物、I2的摩尔比为2.4:3:2:3。
再进一步的,所述的加热搅拌反应的温度为100℃,时间为4-12h。
再进一步的,所述的加水后,用EtOAc萃取3次。
再进一步的,所述的提取物用10%w/w Na2S2O3溶液洗涤,用无水Na2SO4干燥,并在真空下除去溶剂得到粗产物,通过硅胶柱色谱纯化。
本发明还有一个目的在于提供上述的β-咔啉-3位连接1,2,3-三氮唑类化合物在制备抗肿瘤药物中的应用。
与现有技术相比,本发明的有益效果在于:
本发明的β-咔啉-3位连接1,2,3-三氮唑类化合物为一种新的化合物,具有优良活性、低毒性、同时又环境友好,并且具有较好的抗肿瘤活性,可应用于抗肿瘤药物中。
具体实施方式
为了进一步阐述本发明一种β-咔啉-3位连接1,2,3-三氮唑类化合物及其制备方法、应用,达到预期发明目的,以下结合较佳实施例,对依据本发明提出的一种β-咔啉-3位连接1,2,3-三氮唑类化合物及其制备方法、应用,其具体实施方式、结构、特征及其功效,详细说明如后。在下述说明中,不同的“一实施例”或“实施例”指的不一定是同一实施例。此外,一或多个实施例中的特定特征、结构或特点可由任何合适形式组合。
下面将结合具体的实施例,对本发明一种β-咔啉-3位连接1,2,3-三氮唑类化合物及其制备方法、应用做进一步的详细介绍:
实施例1.
β-咔啉-3位连接1,2,3-三氮唑类化合物的制备方法采用以下反应式:
具体操作步骤如下:
合成化合物C8a:
称取相应的3-氨基-β-咔啉化合物(0.6mmol)、TsNHNH2(0.75mmol)、苯乙酮(0.5mmol)于反应管中,加入溶剂DMSO(5mL),搅拌均匀至溶解后中加入I2(0.75mmol)。
将混合物在100℃下,空气中搅拌4-12小时。
反应完成后(通过TLC监测),将反应混合物冷却至室温,向混合物中加入水(30mL),然后用EtOAc(3×50mL)萃取,得提取物。
将提取物用10%w/w Na2S2O3溶液洗涤,用无水Na2SO4干燥,并在真空下除去溶剂得到粗产物,通过硅胶柱色谱纯化(PE:EA=5:1),得到目标产物C8a。
1-甲基-3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8a):棕色固体,收率:56.1%。1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),9.27(s,1H),8.72(s,1H),8.42(d,J=8.0Hz,1H),8.06(d,J=7.6Hz,2H),7.67–7.59(m,2H),7.50(t,J=7.6Hz,2H),7.39(t,J=7.2Hz,1H),7.30(t,J=7.2Hz,1H),2.89(s,3H).13C NMR(100MHz,DMSO-d6)δ147.28,142.09,141.60,140.00,135.00,130.93,129.90,129.40,129.34,128.58,125.96,122.99,121.63,120.25,118.98,112.72,103.48,20.73.HRMS(ESI)m/z calcd for C20H16N5 +(M+H)+326.1400,found 326.1401.
实施例2.
实施例2的操作步骤与实施例1相同,其中,R1为甲基,R9为氢,R3为2-溴苯基,得到的产物为3-(4-(2-溴苯基)-1H-1,2,3-三唑)-1-甲基-9H-吡啶并[3,4-b]吲哚(C8b)。
3-(4-(2-溴苯基)-1H-1,2,3-三唑)-1-甲基-9H-吡啶并[3,4-b]吲哚(C8b):棕色固体,收率:72.6%。1H NMR(400MHz,DMSO-d6)δ11.94(s,1H),9.20(s,1H),8.75(s,1H),8.42(d,J=8.0Hz,1H),8.05(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.70–7.59(m,2H),7.56(t,J=7.6Hz,1H),7.39(d,J=7.6Hz,1H),7.30(t,J=7.6Hz,1H),2.87(s,3H).13C NMR(100MHz,DMSO-d6)δ145.27,142.10,141.74,139.76,135.07,134.09,131.42,131.15,130.60,129.90,129.38,128.56,123.01,121.62,121.45,121.12,120.28,112.74,103.53,20.76.HRMS(ESI)m/z calcd for C20H15BrN5 +(M+H)+404.0505,found404.0505.
实施例3.
实施例3的操作步骤与实施例1相同,其中,R1为甲基,R9为氢,R3为4-氟苯基,得到的产物为3-(4-(4-氟苯基)-1H-1,2,3-三唑)-1-甲基-9H-吡啶并[3,4-b]吲哚。
3-(4-(4-氟苯基)-1H-1,2,3-三唑)-1-甲基-9H-吡啶并[3,4-b]吲哚(C8c):棕色固体,收率:60.1%。1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),9.28(s,1H),8.71(s,1H),8.41(d,J=8.0Hz,1H),8.13–8.09(m,2H),7.67–7.59(m,2H),7.35–7.29(m,3H),5.75(s,1H),2.88(s,3H).13C NMR(100MHz,DMSO-d6)δ161.21(d,J=243.5Hz),146.43,142.09,141.60,139.96,135.01,129.77(d,J=12.9Hz),129.34,127.99(d,J=8.2Hz),126.09,122.99,121.62,120.25,118.93,116.21(d,J=21.4Hz),112.72,103.46,20.72.HRMS(ESI)m/zcalcd for C20H15FN5 +(M+H)+345.1384,found 345.1383.
实施例4.
实施例4的操作步骤与实施例1相同,其中,R1为甲基,R9为氢,R3为4-硝基苯基,得到的产物为1-甲基-3-(4-(4-硝基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚。
1-甲基-3-(4-(4-硝基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8d):黄色固体,收率:54.1%。1H NMR(400MHz,DMSO-d6)δ11.93(s,1H),9.52(s,1H),8.72(s,1H),8.32(s,4H),7.65–7.60(m,2H),7.29(t,J=7.2Hz,1H),2.88(s,3H).13C NMR(100MHz,DMSO-d6)δ147.20,145.37,142.08,141.70,139.66,137.34,135.10,129.84,129.35,126.75,124.77,122.97,121.60,121.01,120.29,112.73,103.57,20.71.HRMS(ESI)m/z calcd forC20H15N6O2 +(M+H)+371.1251,found 371.1250.
实施例5.
实施例5的操作步骤与实施例1相同,其中,R1为甲基,R9为氢,R3为4-(三氟甲基)苯基,得到的产物为1-甲基-3-(4-(4-(三氟甲基)苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8e)。
1-甲基-3-(4-(4-(三氟甲基)苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8e):黄色固体,收率:62.4%。1H NMR(400MHz,DMSO-d6)δ11.93(s,1H),9.52(s,1H),8.73(s,1H),8.43–8.37(m,3H),7.74(d,J=4.8Hz,2H),7.67–7.58(m,2H),7.35–7.25(m,1H),2.89(s,3H).13C NMR(100MHz,DMSO-d6)δ145.90,142.09,141.63,139.84,135.06,132.05,130.57,130.16(q,J=31.1Hz),129.88,129.73,129.34,124.99(q,J=3.9Hz),123.33(q,J=270.6Hz),122.99,122.34(q,J=3.8Hz),121.62,120.26,120.06,112.72,103.49,20.71.HRMS(ESI)m/z calcd for C20H15F3N5 +(M+H)+394.1274,found394.1274.
实施例6.
实施例6的操作步骤与实施例1相同,其中,R1为甲基,R9为氢,R3为间3-甲基苯基,得到的产物为1-甲基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8f)。
1-甲基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8f):黄色固体,收率:57.6%。1H NMR(400MHz,DMSO-d6)δ11.91(s,1H),9.24(s,1H),8.72(s,1H),8.41(d,J=8.0Hz,1H),7.90(s,1H),7.84(d,J=7.6Hz,1H),7.66–7.58(m,2H),7.37(t,J=7.6Hz,1H),7.30(t,J=7.2Hz,1H),7.20(d,J=7.6Hz,1H),2.89(s,3H),2.40(s,3H).13CNMR(100MHz,DMSO-d6)δ147.37,142.09,141.58,140.00,138.58,134.98,130.82,129.90,129.32,129.30,129.22,126.53,123.09,122.99,121.64,120.24,118.86,112.71,103.40,21.53,20.73.HRMS(ESI)m/z calcd for C21H18N5 +(M+H)+340.1557,found340.1557.
实施例7.
实施例7的操作步骤与实施例1相同,其中,R1为甲基,R9为氢,R3为2-萘基,得到的产物为1-甲基-3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8g)。
1-甲基-3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8g):棕色固体,收率:53.7%。1H NMR(400MHz,DMSO-d6)δ11.93(s,1H),9.41(s,1H),8.76(s,1H),8.64(s,1H),8.43(d,J=8.0Hz,1H),8.29–8.19(m,2H),7.96(d,J=8.0Hz,2H),7.56(d,J=6.0Hz,2H),7.34–7.26(m,2H),2.91(s,4H).13C NMR(100MHz,DMSO-d6)δ147.33,142.11,141.63,140.00,135.03,133.70,133.17,130.12,129.93,129.34,129.00,128.57,128.25,128.19,127.07,126.70,124.41,124.31,123.01,120.27,119.32,112.73,103.44,20.75.HRMS(ESI)m/z calcd for C24H18N5 +(M+H)+376.1557,found 376.1555.
实施例8.
实施例8的操作步骤与实施例1相同,其中,R1为氢,R9为苄基,R3为苯基,得到的产物为9-苄基-3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8h)。
9-苄基-3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8h):棕色固体,收率:48.8%。1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),9.11(s,1H),8.98(s,1H),8.54(d,J=8.0Hz,1H),8.06(d,J=7.6Hz,2H),7.68(t,J=7.6Hz,1H),7.50(t,J=7.6Hz,2H),7.45–7.36(m,3H),7.31–7.26(m,5H),5.87(s,2H).13C NMR(100MHz,DMSO-d6)δ147.45,142.65,141.06,137.62,136.78,131.50,130.85,130.76,130.01,129.43,129.23,128.66,128.30,128.08,127.40,125.97,123.40,121.12,120.81,119.12,111.36,105.76,46.66.HRMS(ESI)m/z calcd for C26H20N5 +(M+H)+402.1713,found 402.1716.
实施例9.
实施例9的操作步骤与实施例1相同,其中,R1为氢,R9为苄基,R3为4-(三氟甲基)苯基,得到的产物为9-苄基-3(4-(4-(三氟甲基)苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8i)。
9-苄基-3(4-(4-(三氟甲基)苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8i):棕色固体,收率:51.3%。1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),9.12(s,1H),9.00(s,1H),8.54(d,J=8.0Hz,1H),8.41(s,1H),8.38(t,J=4.4Hz,1H),7.81(d,J=8.4Hz,1H),7.75(d,J=4.4Hz,2H),7.72–7.63(m,1H),7.37(t,J=7.6Hz,1H),7.32–7.23(m,5H),5.88(s,2H).13C NMR(100MHz,DMSO-d6)δ146.07,142.64,140.90,137.61,136.86,131.96,131.56,130.74,130.64,130.18(q,J=31.7Hz),130.03,129.78,129.23,128.08,127.39,125.10(q,J=3.8Hz),123.42,123.30(q,J=276.1Hz),122.30(q,J=3.9Hz),121.12,120.85,120.23,111.38,105.82,46.66.HRMS(ESI)m/z calcd for C27H19F3N5 +(M+H)+470.1587,found 470.1586.
实施例10.
实施例10的操作步骤与实施例1相同,其中,R1为氢,R9为苄基,R3为2-萘基,得到的产物为9-苄基-3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8j)。
9-苄基-3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8j):黄色固体,收率:67.3%。1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.12(s,1H),9.01(s,1H),8.64(s,1H),8.55(d,J=8.0Hz,1H),8.21(d,J=8.4Hz,1H),8.07–7.86(m,4H),7.81(d,J=8.8Hz,1H),7.68(t,J=7.6Hz,1H),7.55(t,J=7.2Hz,2H),7.41–7.24(m,5H),5.88(s,2H).13C NMR(100MHz,DMSO-d6)δ147.49,142.65,141.05,137.62,136.81,133.66,133.19,131.53,130.77,130.11,130.02,129.24,129.04,128.58,128.29,128.20,128.08,127.40,127.09,126.73,124.41,124.32,123.42,121.14,120.83,119.47,111.35,105.74,46.67.HRMS(ESI)m/z calcd for C30H22N5 +(M+H)+452.1869,found 452.1869.
实施例11.
实施例11的操作步骤与实施例1相同,其中,R1为氢,R9为苄基,R3为4-碘苯基,得到的产物为9-苄基-3-(4-(4-碘苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8k)。
9-苄基-3-(4-(4-碘苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8k):黄色固体,收率:60.8%。1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),9.10(s,1H),8.97(s,1H),8.53(d,J=8.0Hz,1H),7.83(d,J=26.8Hz,5H),7.68(t,J=7.6Hz,1H),7.41–7.19(m,6H),5.87(s,2H).13C NMR(100MHz,DMSO-d6)δ146.58,142.64,140.95,138.20,137.61,136.81,131.52,130.74,130.41,130.02,129.23,128.07,128.00,127.39,123.40,121.11,120.83,119.47,111.36,105.79,94.65,46.66.HRMS(ESI)m/z calcd for C26H19IN5 +(M+H)+528.0679,found 528.0679.
实施例12.
实施例12的操作步骤与实施例1相同,其中,R1为氢,R9为苄基,R3为4-氟苯基,得到的产物为9-苄基-3-(4-(4-氟苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8l)。
9-苄基-3-(4-(4-氟苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8l):黄色固体,收率:51.6%。1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),9.10(s,1H),8.97(s,1H),8.53(d,J=8.0Hz,1H),8.11–8.08(m,2H),7.81(d,J=8.4Hz,1H),7.68(t,J=7.6Hz,1H),7.41–7.31(m,3H),7.27(t,J=8.0Hz,5H),5.87(s,2H).13C NMR(100MHz,DMSO-d6)δ161.25(d,J=243.4Hz),146.59,142.64,141.01,137.61,136.79,131.50,130.75,130.02,129.23,128.08,128.00(d,J=8.0Hz),127.44(d,J=4.0Hz),127.40,123.40,121.11,120.82,119.07,116.25(d,J=21.5Hz),111.36,105.73,46.66.HRMS(ESI)m/z calcd for C26H19FN5 +(M+H)+420.1619,found 420.1617.
实施例13.
实施例13的操作步骤与实施例1相同,其中,R1为氢,R9为苄基,R3为3-甲基苯基,得到的产物为9-苄基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8m)。
9-苄基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8m):黄色固体,收率:49.3%。1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),9.09(s,1H),8.97(s,1H),8.52(d,J=8.0Hz,1H),7.89(s,1H),7.86–7.72(m,2H),7.67(t,J=7.6Hz,1H),7.36(d,J=7.2Hz,2H),7.33–7.23(m,5H),7.19(d,J=7.6Hz,1H),5.86(s,2H),2.39(s,3H).13C NMR(100MHz,DMSO-d6)δ147.54,142.63,141.05,138.58,137.61,136.76,131.47,130.74,129.98,129.91,129.31,129.28,129.22,128.07,127.39,126.51,123.38,123.13,121.12,120.79,118.98,111.33,105.68,46.65,21.54.HRMS(ESI)m/z calcd for C27H22N5 +(M+H)+416.1869,found 416.1868.
实施例14.
实施例14的操作步骤与实施例1相同,其中,R1为苯基,R9为氢,R3为苯基,得到的产物为1-苯基-3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8n)。
1-苯基-3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8n):黄色固体,收率:62.5%。1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),9.44(s,1H),8.91(s,1H),8.49(d,J=8.0Hz,1H),8.23(d,J=7.6Hz,2H),8.09(d,J=7.6Hz,2H),7.74–7.57(m,5H),7.51(t,J=7.6Hz,2H),7.39(t,J=7.2Hz,1H),7.33(t,J=7.6Hz,1H).13C NMR(100MHz,DMSO-d6)δ147.42,142.94,140.75,140.49,137.42,133.30,132.57,130.92,129.74,129.66,129.39,129.25,128.63,126.02,122.89,121.43,120.56,119.21,113.20,104.61.HRMS(ESI)m/zcalcd for C25H18N5 +(M+H)+388.1557,found 388.1557.
实施例15.
实施例15的操作步骤与实施例1相同,其中,R1为苯基,R9为氢,R3为4-氟苯基,得到的产物为3-(4-(4-氟苯基)-1H-1,2,3-三唑)-1-苯基-9H-吡啶并[3,4-b]吲哚(C8o)。
3-(4-(4-氟苯基)-1H-1,2,3-三唑)-1-苯基-9H-吡啶并[3,4-b]吲哚(C8o):黄色固体,收率:61.7%。1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),9.44(d,J=2.0Hz,1H),8.90(d,J=2.0Hz,1H),8.48(d,J=8.0Hz,1H),8.23–8.20(m,2H),8.16–8.12(m,2H),7.75–7.65(m,3H),7.65–7.56(m,2H),7.38–7.29(m,3H).13C NMR(100MHz,DMSO-d6)δ161.25(d,J=243.2Hz),146.56,142.94,140.73,140.44,137.41,133.30,132.57,129.74,129.66,129.38,129.24,128.04(d,J=8.1Hz),127.48(d,J=3.0Hz),122.88,121.42,120.55,119.14,116.20(d,J=21.4Hz),113.20,104.57.HRMS(ESI)m/z calcd for C25H17FN5 +(M+H)+406.1462,found 406.1463.
实施例16.
实施例16的操作步骤与实施例1相同,其中,R1为苯基,R9为氢,R3为3-甲基苯基,得到的产物为1-苯基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8p)。
1-苯基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8p):黄色固体,收率:56.3%。1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),9.39(s,1H),8.90(s,1H),8.48(d,J=8.0Hz,1H),8.32–8.17(m,2H),7.92(s,1H),7.88(d,J=7.6Hz,1H),7.75–7.66(m,3H),7.62–7.58(m,2H),7.40–7.30(m,2H),7.20(d,J=7.6Hz,1H),2.40(s,3H).13C NMR(100MHz,DMSO-d6)δ147.50,142.94,140.73,140.50,138.58,137.44,133.28,132.57,130.81,129.71,129.64,129.38,129.27,129.25,126.54,123.16,122.87,121.43,120.54,119.05,113.19,104.55,21.54.HRMS(ESI)m/z calcd for C26H20N5 +(M+H)+402.1713,found402.1712.
实施例17.
实施例17的操作步骤与实施例1相同,其中,R1为异丙基,R9为甲基,R3为苯基,得到的产物为1-异丙基-9-甲基-3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8q)。
1-异丙基-9-甲基-3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8q):黄色固体,收率:55.8%。1H NMR(400MHz,DMSO-d6)δ9.28(d,J=14.4Hz,1H),8.75(s,1H),8.45(d,J=7.6Hz,1H),8.09(d,J=7.6Hz,1H),7.94–7.86(m,1H),7.78(d,J=8.4Hz,1H),7.67(t,J=7.6Hz,1H),7.51(t,J=7.6Hz,1H),7.42–7.35(m,1H),7.32(t,J=7.2Hz,1H),7.20(d,J=7.6Hz,1H),4.20(s,3H),4.13–4.06(m,1H),1.51(d,J=6.8Hz,6H).13C NMR(100MHz,DMSO-d6)δ150.08,147.41,147.33,143.62,139.77,138.57,134.08,131.70,130.89,130.79,129.56,129.36,129.25,126.56,126.06,123.21,122.55,120.96,120.38,118.75,118.61,111.03,102.89,102.86,33.04,31.15,23.17,23.15,21.54.HRMS(ESI)m/z calcdfor C23H22N5 +(M+H)+368.1869,found368.1869.
实施例18.
实施例18的操作步骤与实施例1相同,其中,R1为异丙基,R9为甲基,R3为3-甲基苯基,得到的产物为1-异丙基-9-甲基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8r)。
1-异丙基-9-甲基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8r):黄色固体,收率:47.3%。1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),8.75(s,1H),8.45(d,J=7.6Hz,1H),7.92(s,1H),7.88(d,J=7.6Hz,1H),7.79(d,J=8.4Hz,1H),7.72–7.64(m,1H),7.39(t,J=7.6Hz,1H),7.32(t,J=7.6Hz,1H),7.20(d,J=7.6Hz,1H),4.21(s,3H),4.13–4.07(m,1H),2.41(s,3H),1.51(d,J=6.4Hz,6H).13C NMR(100MHz,DMSO-d6)δ150.09,147.42,143.63,139.78,138.58,134.08,131.70,130.79,129.57,129.26,126.56,123.21,122.56,120.96,120.39,118.62,111.04,102.87,33.04,31.15,23.17,21.54.HRMS(ESI)m/z calcd for C24H24N5 +(M+H)+382.2026,found 382.2026.
实施例19.
实施例19的操作步骤与实施例1相同,其中,R1为异丙基,R9为甲基,R3为2-萘基,得到的产物为1-异丙基-9-甲基-3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8s)。
1-异丙基-9-甲基-3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8s):黄色固体,收率:52.6%。1H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.83(s,1H),8.66–8.49(m,1H),8.48(d,J=7.6Hz,1H),8.09–8.01(m,2H),7.99–7.92(m,1H),7.80(d,J=8.4Hz,1H),7.74–7.68(m,1H),7.66(d,J=7.6Hz,1H),7.64–7.60(m,2H),7.34(t,J=7.2Hz,1H).4.22(s,3H),4.14–4.08(m,1H),1.50(d,J=6.4Hz,6H).13C NMR(100MHz,DMSO-d6)δ150.17,147.01,143.64,139.76,134.15,134.05,131.73,131.00,129.60,129.32,128.92,128.10,127.91,127.25,126.62,126.08,126.05,122.57,121.44,120.99,120.43,111.09,103.12,33.05,31.15,23.12.HRMS(ESI)m/z calcd for C27H24N5 +(M+H)+418.2026,found 418.2026.
实施例20.
实施例20的操作步骤与实施例1相同,其中,R1为氢,R9为氢,R3为苯基,得到的产物为3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8t)。
3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8t):黄色固体,收率:51.3%。1H NMR(400MHz,DMSO-d6)δ11.93(s,1H),9.34(s,1H),8.91(d,J=11.6Hz,2H),8.47(d,J=8.0Hz,1H),8.07(d,J=7.6Hz,2H),7.69–7.62(m,2H),7.51(t,J=7.6Hz,2H),7.39(t,J=7.2Hz,1H),7.32(t,J=7.2Hz,1H).13C NMR(100MHz,DMSO-d6)δ147.42,142.41,140.59,136.46,132.40,130.88,130.75,129.69,129.42,128.63,125.97,123.11,121.17,120.32,119.04,112.80,105.65.HRMS(ESI)m/z calcd for C19H14N5 +(M+H)+312.1244,found312.1242.
实施例21.
实施例21的操作步骤与实施例1相同,其中,R1为氢,R9为氢,R3为4-氟苯基,得到的产物为3-(4-(4-氟苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8u)。
3-(4-(4-氟苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8u):黄色固体,收率:56.8%。1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),9.42(s,1H),8.98(s,1H),8.95(s,1H),8.53(d,J=8.0Hz,1H),8.17(d,J=3.2Hz,1H),7.70(m,2H),7.39(m,4H).13C NMR(100MHz,DMSO-d6)δ161.24(d,J=243.2Hz),146.56,142.41,140.55,136.47,132.38,130.74,129.69,127.98(d,J=8.2Hz),127.45(d,J=3.0Hz),123.10,121.16,120.32,118.99,116.23(d,J=21.6Hz),112.80,105.62.HRMS(ESI)m/z calcd for C19H13FN5 +(M+H)+330.1149,found 330.1147.
实施例22.
实施例22的操作步骤与实施例1相同,其中,R1为氢,R9为氢,R3为3-甲基苯基,得到的产物为3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8v)。
3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8v):黄色固体,收率:57.4%。1H NMR(400MHz,DMSO-d6)δ11.91(s,1H),9.30(s,1H),8.90(d,J=12.8Hz,2H),8.46(d,J=8.0Hz,1H),7.90(s,1H),7.84(d,J=7.6Hz,1H),7.68-7.61(m,2H),7.38(t,J=7.6Hz,1H),7.31(t,J=7.2Hz,1H),7.20(d,J=7.6Hz,1H),2.40(s,3H).13C NMR(100MHz,DMSO-d6)δ147.51,142.41,140.60,138.58,136.45,132.40,130.77,130.75,129.68,129.32,129.27,126.51,123.13,123.11,121.18,120.31,118.95,112.79,105.62,21.55.HRMS(ESI)m/z calcd for C21H16ClN4O2 +(M+H)+326.1400,found 326.1400.
实施例23.
实施例23的操作步骤与实施例1相同,其中,R1为氢,R9为氢,R3为2-萘基,得到的产物为3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8w)。
3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚(C8w):黄色固体,收率:61.3%。1H NMR(400MHz,DMSO-d6)δ11.93(s,1H),9.48(s,1H),8.93(d,J=20.0Hz,2H),8.64(d,J=1.6Hz,1H),8.49(d,J=8.0Hz,1H),8.23–8.20(m,1H),8.04(t,J=7.6Hz,2H),7.97–7.95(m,1H),7.69–7.59(m,2H),7.56–7.52(m,1H),7.32(t,J=7.6Hz,1H).13C NMR(100MHz,DMSO-d6)δ147.46,142.42,140.60,136.48,133.68,133.19,132.44,130.77,129.70,129.03,128.58,128.34,128.20,127.09,126.72,124.40,124.33,123.14,121.19,120.34,119.42,112.81,105.66.HRMS(ESI)m/z calcd for C23H16N5 +(M+H)+362.1400,found362.1399.
实施例1-23合成的化合物C8a-C8w的化学结构式见表1。
表1
实施例24.
体外抗肿瘤活性研究
以A549(肺癌细胞),BGC-823(胃癌细胞),CT-26(结肠癌细胞),Bel-7402(肝癌细胞)和MCF-7(乳腺癌细胞)为对象,采用MTT法测试了目标化合物C8a-C8w对肿瘤细胞株的抑制活性。分别将生长状态良好、处于对数生长期的细胞株以1×104/mL的浓度接种于96孔板,置于37℃的CO2培养箱中培养24h,弃旧液,换新鲜培养液,加入灭菌处理的待测化合物,继续培养48h后,弃去培养液,每孔加20μL含5mg/mL MTT的RPMI1640培养液,继续培养4h,小心除去上清后,每孔加入100μL的DMSO,振荡约10min溶解沉淀,随后用酶标仪检测OD值,波长490nm,按作图法求出每个样品的IC50值。结果如表2所示。
表2化合物C8a-C8w的体外抗肿瘤活性(IC50,μmol·L-1)
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结合表2,该类化合物的构效关系发现:
1)当R1和R9位均无取代基时,R3取代基为苯基、4-氟苯基、3-甲基苯基和2-萘基时,化合物C8t、C8u、C8v和C8v对于所有测试的肿瘤细胞显示出较弱的抑制作用。
2)当R1为甲基取代基,R9位无取代基,R3为苯基、2-溴苯基、4-氟苯基、4-硝基苯基等7种取代基时,化合物C8a-C8g中R3为4-硝基苯基的化合物C8d和R3为4-三氟甲基苯基C8e对于两种肿瘤细胞都显示出优异的抗肿瘤活性,IC50值均低于10μM。
3)当R1无取代基,R9位为苄基取代基,R3为3-甲基苯基、4-碘苯基、4-氟苯基、4-三氟甲基苯基等6种取代基时,化合物C8h-C8m中,部分化合物的IC50值与顺铂相比,都低于顺铂,且化合物C8i、C8l和C8m对于一种以上的肿瘤细胞都表现出非常优异的抗肿瘤活性。
4)当R1为苯基取代基,R9位无取代基,R3为苯基、4-氟苯基和3-甲基苯基时,化合物C8n,C8o和C8p对于所测肿瘤细胞都展现出较弱的抑制活性,IC50值均高于20μM。
5)当R1为异丙基取代基,R9为甲基取代基,R3为苯基、萘基和3-甲基苯基时,化合物C8q,C8r和C8s中,化合物C8q对两种肿瘤细胞(肺癌细胞和肝癌细胞)的IC50值均低于顺铂,其中对所测结肠癌细胞的IC50值低于10μM。
综合上述可知:当R1为甲基取代基,R9位无取代基,R3为4-硝基苯基和4-三氟甲基苯基取代基时,化合物展现出较为优异的抗肿瘤活性;当R1无取代基,R9位为苄基取代基,R3为3-甲基苯基、4-氟苯基、4-三氟甲基苯基取代基时,该类化合物对肿瘤细胞表现出一定的抑制作用;当R1为异丙基取代基,R9为甲基取代基,R3为苯基时,该化合物表现出较好的抗肿瘤活性,可应用于抗肿瘤药物中。
以上所述,仅是本发明实施例的较佳实施例而已,并非对本发明实施例作任何形式上的限制,依据本发明实施例的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明实施例技术方案的范围内。
Claims (8)
1.一种β-咔啉-3位连接1,2,3-三氮唑类化合物,其特征在于,所述的β-咔啉-3位连接1,2,3-三氮唑类化合物的化学结构通式为:
所述的β-咔啉-3位连接1,2,3-三氮唑类化合物的化学结构通式中,R1为氢、苯基、甲基、异丙基中的一种;
R9为氢、甲基、苄基中的一种;
R3为苯基、萘基、2-溴苯基、3-甲基苯基、4-氟苯基、4-硝基苯基、4-碘苯基、4-三氟甲基苯基中的一种。
2.根据权利要求1所述的β-咔啉-3位连接1,2,3-三氮唑类化合物,其特征在于,
所述的β-咔啉-3位连接1,2,3-三氮唑类化合物,为下列任一化合物:
1-甲基-3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
3-(4-(2-溴苯基)-1H-1,2,3-三唑)-1-甲基-9H-吡啶并[3,4-b]吲哚,
3-(4-(4-氟苯基)-1H-1,2,3-三唑)-1-甲基-9H-吡啶并[3,4-b]吲哚,
1-甲基-3-(4-(4-硝基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
1-甲基-3-(4-(4-(三氟甲基)苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,1-甲基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
1-甲基-3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
9-苄基-3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
9-苄基-3(4-(4-(三氟甲基)苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
9-苄基-3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
9-苄基-3-(4-(4-碘苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
9-苄基-3-(4-(4-氟苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
9-苄基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
1-苯基-3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
3-(4-(4-氟苯基)-1H-1,2,3-三唑)-1-苯基-9H-吡啶并[3,4-b]吲哚,
1-苯基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
1-异丙基-9-甲基-3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
1-异丙基-9-甲基-3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
1-异丙基-9-甲基-3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
3-(4-苯基-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
3-(4-(4-氟苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
3-(4-(3-甲基苯基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚,
3-(4-(2-萘基)-1H-1,2,3-三唑)-9H-吡啶并[3,4-b]吲哚。
3.权利要求1所述的β-咔啉-3位连接1,2,3-三氮唑类化合物的制备方法,其特征在于,所述的制备方法包括以下步骤:
将由R1、R9取代的3-氨基-β-咔啉、对甲苯磺酰肼、由R3取代的酮类化合物溶解于溶剂二甲基亚砜中后,加入I2,加热搅拌反应;其中,所述的R1、R3、R9具有权利要求1所述的β-咔啉-3位连接1,2,3-三氮唑类化合物的化学结构通式所述定义;
反应结束后,冷却至室温,加水,用乙酸乙酯萃取,得提取物;
将所述的提取物洗涤、干燥、去除溶剂、纯化,得所述的β-咔啉-3位连接1,2,3-三氮唑类化合物。
4.权利要求3所述的制备方法,其特征在于,
所述的由R1、R9取代的3-氨基-β-咔啉、对甲苯磺酰肼、由R3取代的酮类化合物、I2的摩尔比为2.4:3:2:3;
其中,所述的R1、R3、R9具有权利要求1所述的β-咔啉-3位连接1,2,3-三氮唑类化合物的化学结构通式所述定义。
5.权利要求3所述的制备方法,其特征在于,
所述的加热搅拌反应的温度为100℃,时间为4-12h。
6.权利要求3所述的制备方法,其特征在于,
所述的加水后,用乙酸乙酯萃取3次。
7.权利要求3所述的制备方法,其特征在于,
所述的提取物用10%w/w Na2S2O3溶液洗涤,用无水Na2SO4干燥,并在真空下除去溶剂得到粗产物,通过硅胶柱色谱纯化。
8.权利要求1所述的β-咔啉-3位连接1,2,3-三氮唑类化合物在制备抗肿瘤药物中的应用。
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