CN104250246B - 一种蒽醌并噻唑化合物、其制备方法及其用途 - Google Patents
一种蒽醌并噻唑化合物、其制备方法及其用途 Download PDFInfo
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Abstract
本发明涉及一种以5,7‑二羟基蒽醌[2,1‑d]噻唑为母核的化合物,其具有以下通式,还涉及其制备方法以及其在制备抗肿瘤药物中的用途。本发明以传统天然产物大黄酸为起始原料,通过温和的反应条件合成了一系列抗肿瘤活性较高的化合物。本发明的优选化合物的体外抗肿瘤活性较大黄酸强30倍以上。
Description
技术领域
本发明涉及一种以5,7-二羟基蒽醌[2,1-d]噻唑为母核的化合物,还涉及其制备方法以及其在制备抗肿瘤药物中的用途。
背景技术
恶性肿瘤是当前严重影响人类健康、威胁人类生命的主要疾病之一。拓扑异构酶抑制剂是目前临床上应用最多的五大类抗肿瘤药物之一,由于对消化系统肿瘤、肺癌等多种实体瘤疗效确切,已成为恶性肿瘤药物治疗的临床一线药物。拓扑异构酶抑制剂分为两类:拓扑异构酶Ⅰ抑制剂,主要是喜树碱及其衍生物;拓扑异构酶Ⅱ抑制剂分为嵌入型与非嵌入型。嵌入型拓扑异构酶Ⅱ抑制剂结构各不相同,通常有平面芳香结构,可以嵌入DNA碱基对之间,妨碍正常的DNA功能,主要有放线菌素D及阿霉素类。非嵌入型拓扑异构酶Ⅱ抑制剂包括表鬼臼毒素类和一些异黄酮类。
目前常用的拓扑异构酶Ⅱ抑制剂包括依托泊苷(etoposide)、替尼泊苷(teniposide)、多柔比星(doxorubicin)、表柔比星(epirubicin)、米托蒽醌(mitoxantrone)等。长期的临床药物应用确证了拓扑异构酶Ⅱ作为抗癌靶点的有效性。但现有药物的毒副作用往往限制其使用。多柔比星是临床广泛应用的拓扑异构酶Ⅱ抑制剂,对多种肿瘤均有很好的治疗效果,但它除了抑制拓扑异构酶Ⅱ的作用外,还产生羟基自由基;由于心肌对羟基自由基的损伤作用非常敏感,因此多柔比星易对心脏产生累积性损伤而致命,严重限制了它的应用。米托蒽醌抗肿瘤活性高于环磷酰胺、长春新碱和氟尿嘧啶,对乳腺癌有明显疗效,对恶性淋巴瘤疗效也较好。但米托蒽醌存在充血性心力衰竭和继发性白血病的危险。因此临床上迫切需要更加安全、有效的拓扑异构酶抑制性抗肿瘤药物。
大黄酸是一种含有蒽醌母核的传统中药,由于其良好的生物活性得到长久的应用,主要用于治疗便秘、消化系统及血液系统疾病。研究发现,大黄酸具有一定的抗肿瘤活性。将大黄酸与多柔比星联合作用于肿瘤细胞,能明显提高肿瘤细胞抑制率。但是其抗肿瘤活性较低(IC50:80-100μM),严重妨碍了其进一步的临床开发。为了提高大黄酸的抗肿瘤活性,我们对其进行结构改造,设计合成了一系列新型2位取代的5,7-二羟基蒽醌[2,1-d]噻唑化合物,获得了一类新型的抗肿瘤化合物。
发明人从提高抗肿瘤活性、降低毒副作用、改善理化性质的角度出发,首先对大黄酸3位羧基进行改造,设计合成了一类2-取代5,7-二羟基蒽醌[2,1-d]噻唑化合物。本发明所设计合成的2位取代的5,7-二羟基蒽醌[2,1-d]噻唑化合物比大黄酸增加了一个杂环,增加了水溶性基团,提高了溶解性。实验证明本发明所设计合成的化合物在体外肿瘤细胞生长抑制实验中表现出很强的抑制能力,为全新结构的抗肿瘤化合物。
发明内容
本发明的目的是提供一种新型的2位取代的5,7-二羟基蒽醌[2,1-d]噻唑化合物,其具有通式(Ⅰ)所示的结构。
其中,
R1、R2选自以下基团:未取代或者由羟基取代的C1~C10直链或支链烷基,或者R1、R2和与它们相连的氮原子一起形成含有1~3个N、O或S原子的5~7元杂环,该杂环可以在碳或氮原子上被取代基R3取代;优选地,R1、R2选自未取代或者由羟基取代的C1~C6直链或支链烷基,或者R1、R2和与它们相连的氮原子一起形成含有1~3个N、O或S原子的5~7元杂环,该杂环可以在碳或氮原子上被取代基R3取代;更优选地,R1、R2和与它们相连的氮原子一起形成
其中,R3为羟基、未取代或由R4取代的C1~C10直链或支链烷基、C1~C10烷氧基羰基、羰基、未取代或由C1~C10烷基取代的氨基、C3~C8环烷基;优选地,R3为未取代或由R4取代的C1~C6直链或支链烷基、未取代或由C1~C6烷基取代的氨基、C3~C6环烷基;更优选地,R3为未取代或由R4取代的乙基;
其中,R4为羟基、未取代或由C1~C10烷基取代的氨基、含有1~3个N、O或S原子的5~7元杂环,R4中的该杂环可以被C1~C10直链或支链烷基取代;优选地,R4为羟基、未取代或由C1~C6烷基取代的氨基、含有1~2个N或O原子的5~6元杂环,R4中的该杂环可以被C1~C6直链或支链烷基取代。
优选地,本发明的化合物为以下化合物:
对上述的化合物8p进行结构修饰,得到了更优选的化合物15a-k,其结构如下所示:
本发明的另一目的是提供该类化合物的制备方法,该方法包括以下步骤:
所述通式8a-8s化合物的制备方法包括如下步骤:
a、将大黄酸1在碱作用下,以无水二甲基甲酰胺(DMF)做溶剂与碘甲烷反应得化合物2,其中碱为氢化钠、氢氧化钠、氢氧化钾或碳酸钠;
b、化合物2在碱水溶液中水解,生成化合物3,其中碱为氢氧化钠或氢氧化钾;
c、化合物3在三乙胺做碱的条件下与叠氮磷酸二苯酯反应生成化合物4;
d、化合物4在二氧六环溶液中回流,并用氢氧化钠水溶液回流,得到柯提斯重排后的化合物5;
e、化合物5在银盐催化作用下发生碘卤代反应得化合物6,其中银盐为硫酸银、醋酸银和碘化银;
f、化合物6在二甲基甲酰胺(DMF)作溶剂,碳酸钾催化下与胺NR1R2H及二硫化碳反应得到一系列产物7;
g、中间体7与三氯化铝、硫醇或者三溴化硼反应,脱甲基得一系列最终产物8;
从化合物的体外肿瘤细胞增殖抑制实验结果分析(见下表1),化合物8p的效果最好。考虑到化合物的溶解度,以及进一步提高其生物活性,我们对化合物8p进行结构修饰,获得系列化合物15a-k。
即,优选地,通过以下步骤制备化合物13以得到上述步骤f中的部分试剂,然后,通过上述的步骤f、g,制得不同的化合物15。其中,R4的定义与前述的化合物中的定义相同:
a、将化合物9溶于四氢呋喃(THF)溶液与二碳酸二叔丁酯((Boc)2O)反应得化合物10;
b、化合物10在二甲氨基吡啶(DMAP)催化下,以三乙胺作碱,在无水四氢呋喃(THF)溶液中与甲基磺酰氯反应,生成化合物11;
c、化合物11在碘化钠催化条件下与取代胺反应生成化合物12;
d、化合物12在二氯甲烷溶液中与三氟乙酸反应得到化合物13;
e、化合物13与6在二甲基甲酰胺(DMF)作溶剂,碳酸钾催化下与胺及二硫化碳反应得到一系列产物14a-k;
f、中间体14a-k与三溴化硼反应,脱甲基得一系列最终产物15a-k;
本发明的另一目的是提供一种包含所述化合物的药物组合物,其包括治疗有效量的通式1的化合物即药学上可接受的载体。
本发明的另一目的是提供一种抗肿瘤的方法,其包括向患者施用治疗有效量的上述化合物或组合物。
本发明的再一目的是提供所述化合物作为抗肿瘤的试剂的用途。
本发明的再一目的是提供所述化合物在制备抗肿瘤药物中的用途。
本发明的再一目的是提供所述药物组合物在制备抗肿瘤药物中的用途。
上述的肿瘤包括:肺癌和宫颈癌。
本发明以传统天然产物大黄酸为起始原料,通过温和的反应条件合成了一系列抗肿瘤活性较高的化合物。
具体实施方式
下面结合实施例对本发明作进一步阐述,但这些实施例不应理解为对本发明的限制。所有实施例中,1H NMR由BrucherAM-400型和GEMINI-300型核磁共振仪记录,化学位移以δ(ppm)表示;TLC所用薄层层析板为GF254(青岛海洋化工厂生产),分离用硅胶为200-300目。除了本发明制备的化合物以外,大黄酸购自南京泽朗科技有限公司,取代胺(NR1R2H)购自韶远化学科技(上海)有限公司与上海毕得医药科技有限公司,其他原材料和试剂均是购买于国药试剂有限公司。
实施例1
化合物2的制备
将化合物1(10g,35mmol)溶于无水二甲基甲酰胺(DMF),冰浴;加入氢化钠(9g,225mmol;60%),氮气保护;待无气泡产生,加入碘甲烷(18mL,290mmol),慢慢升至室温搅拌过夜。TLC检测原料反应完全后,加水淬灭;用二氯甲烷反复萃取至水层无明显产物残留,回收溶剂,粗产品以二氯甲烷甲醇重结晶得黄色化合物2(8.9g)。
1H NMR(400MHz,CDCl3):d=8.46(d,1H,J=1.6Hz),7.94(d,1H,J=1.2Hz),7.87–7.85(dd,1H,J=0.8,7.6Hz),7.67(t,1H,J=8.0Hz),7.32(d,1H,J=8.4Hz),4.07(s,3H),4.02(s,3H),4.00(s,3H)。
化合物3的制备
称取化合物2(8.9g,27mmol)溶于45mL乙醇溶液,加入90毫升氢氧化钠乙醇水(1:1,0.46M)溶液。50℃搅拌1h,溶液颜色由黄变为深红色。冷却反应液,冰浴下加入盐酸溶液(1M),生成大量黄色固体,过滤得化合物3。
1H NMR(400MHz,DMSO-d6):d=8.17(d,1H,J=1.6Hz),7.89(d,1H,J=1.2Hz),7.76–7.69(m,2H),7.54(d,1H,J=8.0Hz),3.99(s,3H),3.93(s,3H)。
化合物4的制备
将化合物3(8.9g,28mmol)溶于100mL无水二甲基甲酰胺(DMF),加入三乙胺(4.1mL,57mmol);冰浴滴加叠氮磷酸二苯酯(DPPA),慢慢升至室温搅拌1.5h。加水稀释有沉淀产生,过滤得化合物4(9g)。
1H NMR(400MHz,CDCl3):d=8.43(d,1H,J=1.6Hz),7.90(d,1H,J=1.2Hz),7.86–7.84(dd,1H,J=0.8,7.6Hz),7.67(t,1H,J=8.0Hz),7.33(d,1H,J=8.0Hz),4.07(s,3H),4.02(s,3H)。
化合物5的制备
将叠氮化合物4溶于200mL无水二氧六环,氮气保护下回流0.5h;TLC检测,待化合物4消失后,加入350mL氢氧化钠溶液(1M),回流4h后冷却至室温。过滤得滤液,滤渣用丙酮冲洗,合并有机相;回收溶剂,得深红色化合物5(4g)。
1H NMR(400MHz,CDCl3):d=7.78(d,1H,J=7.6Hz),7.55(t,1H,J=8.0Hz),7.25(m,1H),7.03(d,1H,J=2.0Hz),6.44(d,1H,J=2.0Hz),3.96(s,3H),3.91(s,3H)。
化合物6的制备
称取化合物5(3g,10.6mmol)溶于100mL乙二醇,加入碘(1.56g,6.1mmol)和硫酸银(3.3g,10.6mmol),室温搅拌2.5h;TLC检测,待原料反应完全后加饱和硫代硫酸钠溶液淬灭;以二氯甲烷反复萃取,合并萃取液以硫酸钠固体干燥,回收溶剂得粗产品,柱层析(石油醚/乙酸乙酯=3:1)得化合物6(3.35g)。
1H NMR(300MHz,CDCl3)δ7.69(dd,J=7.7,1.0Hz,1H),7.60–7.54(m,1H),7.22(d,J=8.6Hz,1H),6.57(s,1H),3.97(s,3H),3.92(s,3H).LC/MS m/z:410.2(M+H+)。
化合物7a-s的制备
称取化合物6(0.5mmol)溶于20mL二甲基甲酰胺(DMF),然后加入二硫化碳(0.6mmol)、胺(0.75mmol)及碳酸钾(1.5mmol);115℃搅拌6h,TLC检测反应。待原料反应完全后,冷却至室温;加水稀释,然后用二氯甲烷萃取;有机溶剂中加入无水硫酸镁固体干燥,回收溶剂后得红色粗品,柱层析得化合物7a-s,各产物表征如下:
5,7-二甲氧基-2-(哌啶-1-基)蒽醌[2,1-d]噻唑6,11-二酮(7a)
1H NMR(300MHz,CDCl3)δ7.86(d,J=7.7Hz,1H),7.62(t,J=8.1Hz,1H),7.38(s,1H),7.31(d,J=8.2Hz,1H),4.02(s,3H),4.01(s,3H),3.83–3.62(m,4H),1.78–1.70(m,6H).13CNMR(126MHz,CDCl3)δ183.93,181.69,175.11,160.12,159.74,158.86,134.00,133.49,126.89,124.20,121.96,118.97,118.63,117.56,107.23,56.69,56.58.LC/MS m/z:409.2(M+H+)。产率70%,红色固体。
5,7-二甲氧基-2-(吡咯烷-1-基)蒽醌[2,1-d]噻唑6,11-二酮(7b)
1H NMR(400MHz,CDCl3)δ7.88(dd,J=7.7,1.1Hz,1H),7.63(dd,J=8.3,7.7Hz,1H),7.46(s,1H),7.32(d,J=8.4,1H),4.03(s,3H),4.02(s,3H),3.84–3.55(m,4H),2.15(d,J=6.2Hz,4H).13C NMR(126MHz,CDCl3)δ183.94,181.67,172.05,160.14,159.75,159.01,134.03,133.46,126.92,124.19,122.07,118.96,118.62,117.32,107.28,56.67,56.57,49.63,25.65.LC/MS m/z:395.2(M+H+)。产率66%,红色固体。
2-(氮杂环庚烷-1-基)-5,7-二甲氧基蒽醌[2,1-d]噻唑-6,11-二酮(7c)
1H NMR(300MHz,CDCl3)δ7.87(dd,J=7.7,1.1Hz,1H),7.65–7.59(m,1H),7.41(s,1H),7.32(dd,J=8.5,1.0Hz,1H),4.03(s,3H),4.01(s,3H),3.93–3.62(m,4H),1.99–1.84(m,4H),1.65(dt,J=5.6,2.6Hz,4H).13CNMR(126MHz,CDCl3)δ184.03,181.65,174.93,160.10,159.72,159.12,134.01,133.40,126.86,124.22,122.08,118.92,118.60,117.30,107.17,56.65,56.53,29.65,27.73,27.35.LC/MS m/z:423.2(M+H+)。产率68%,红色固体。
5,7-二甲氧基-2-(4-甲基哌啶-1-基)蒽醌[2,1-d]噻唑6,11-二酮(7d)
1H NMR(300MHz,CDCl3)δ7.83(d,J=7.7Hz,1H),7.59(t,J=8.0Hz,1H),7.37(s,1H),7.29(d,J=8.4Hz,1H),4.01(s,2H),3.99(s,3H),3.80–3.66(m,4H),2.81–2.69(m,4H),2.67–2.53(m,1H),0.48(d,J=12.4Hz,3H).13C NMR(126MHz,CDCl3)δ183.97,181.70,175.13,160.12,159.75,159.04,134.02,133.49,126.92,124.23,122.11,118.98,118.64,117.59,107.29,57.60,56.70,56.60,33.60,30.80,21.70.LC/MS m/z:423.2(M+H+)。产率70%,红色固体。
2-(2-(2-羟乙基)哌啶-1-基)-5,7-二甲氧基蒽醌[2,1-d]噻唑-6,11-二酮(7e)
1H NMR(300MHz,CDCl3)δ7.86(d,J=7.7Hz,1H),7.66–7.59(m,1H),7.33(d,J=7.2Hz,1H),7.32(s,1H),4.02(s,3H),4.01(s,3H),3.83–3.61(m,2H),3.48–3.30(m,2H),2.22–2.05(m,1H),1.98–1.81(m,2H),1.81–1.66(m,6H).13C NMR(126MHz,DMSO)δ183.49,180.31,174.60,159.65,159.37,158.93,134.32,133.70,126.71,124.02,121.33,119.81,118.64,117.35,107.65,58.30,56.85,56.75,28.09,25.50,18.99.LC/MS m/z:453.2(M+H+)。产率75%,红色固体。
2-(3-羟基哌啶-1-基)-5,7-二甲氧基蒽醌[2,1-d]噻唑-6,11-二酮(7f)
1H NMR(400MHz,CDCl3)δ7.86(d,J=7.8Hz,1H),7.62(t,J=8.1Hz,1H),7.38(s,1H),7.32(d,J=8.4Hz,1H),4.03(s,3H),4.01(s,3H),3.82(d,J=11.8Hz,1H),3.60(dd,J=12.5,6.9Hz,2H),2.07–1.93(m,3H),1.79–1.65(m,4H).13C NMR(126MHz,CD3OD)δ183.79,182.17,175.69,160.16,159.73,158.64,133.91,133.80,126.84,123.69,121.89,118.98,118.77,117.41,106.95,65.31,56.38,56.27,56.19,55.79,32.09,22.35.LC/MS m/z:425.1(M+H+)。产率79%,红色固体。
2-(二异丙基氨基)-5,7-二甲氧基蒽醌[2,1-d]噻唑6,11-二酮(7g)
1H NMR(400MHz,CDCl3)δ7.87(d,J=7.7Hz,1H),7.62(t,J=8.0Hz,1H),7.38(s,1H),7.31(d,J=8.4Hz,1H),4.14(dt,J=13.9,6.8Hz,2H),4.05(s,3H),4.01(s,3H),1.49(s,6H),1.47(s,6H).13C NMR(126MHz,CDCl3)δ184.11,181.79,172.80,160.05,159.75,159.27,134.11,133.40,126.70,124.33,121.60,118.97,118.59,117.11,107.24,56.69,56.58,56.54,20.31.LC/MS m/z:426.2.0(M+H+)。产率64%,红色固体。
2-(二乙基氨基)-5,7-二甲氧基蒽醌[2,1-d]噻唑6,11-二酮(7h)
1H NMR(300MHz,CDCl3)δ7.87(d,J=7.6Hz,1H),7.62(t,J=8.0Hz,1H),7.41(s,1H),7.32(d,J=8.7Hz,1H),4.04(s,3H),4.01(s,3H),3.68(q,J=7.1,6.4Hz,4H),1.35(t,J=7.0Hz,6H).13C NMR(126MHz,CDCl3)δ184.03,181.75,174.28,160.12,159.76,159.20,134.03,133.56,126.87,124.22,122.18,119.00,118.70,117.33,107.22,56.76,56.67,29.73,13.03.LC/MS m/z:397.2(M+H+)。产率80%,红色固体。
5,7-二甲氧基-2-吗啉基蒽醌[2,1-d]噻唑-6,11-二酮(7i)
1H NMR(300MHz,CDCl3)δ7.87(d,J=7.7Hz,1H),7.63(t,J=8.0Hz,1H),7.42(s,1H),7.32(d,J=8.4Hz,1H),4.04(s,3H),4.02(s,3H),3.90–3.83(m,4H),3.81–3.74(m,4H).13CNMR(126MHz,CDCl3)δ183.76,181.64,175.53,160.06,159.76,158.29,133.91,133.60,127.04,124.07,121.55,118.97,118.68,118.10,107.83,66.22,56.71,56.58,48.32.LC/MS m/z:411.2(M+H+)。产率76%,红色固体。
2-(4-(二甲基氨基)哌啶-1-基)-5,7-二甲氧基蒽醌[2,1-d]噻唑-6,11-二酮(7j)
1H NMR(300MHz,CDCl3)δ7.86(d,J=7.7Hz,1H),7.62(t,J=8.1Hz,1H),7.39(s,1H),7.31(d,J=8.3Hz,1H),4.02(s,3H),4.01(s,3H),3.31–3.21(m,2H),3.03–3.00(m,1H),2.58–2.44(m,2H),2.32(s,6H),1.76–1.50(m,4H).13C NMR(126MHz,CD3OD)δ179.88,178.11,171.05,156.17,155.76,154.68,129.87,123.01,119.85,118.03,115.05,114.78,113.74,103.40,57.75,52.55,52.41,43.66,36.89,23.20.LC/MS m/z:452.2(M+H+)。产率45%,红色固体。
2-(4-环丙基哌嗪-1-基)-5,7-二甲氧基蒽醌[2,1-d]噻唑-6,11-二酮(7k)
1H NMR(400MHz,CDCl3)δ7.86(d,J=7.7Hz,1H),7.62(t,J=8.0Hz,1H),7.40(s,1H),7.32(d,J=8.4Hz,1H),4.03(s,3H),4.01(s,3H),3.78–3.71(m,4H),2.82–2.74(m,4H),1.74–1.70(m,1H),0.54–0.46(m,4H).13C NMR(126MHz,CDCl3)δ183.87,181.64,175.25,160.09,159.75,158.69,133.97,133.53,126.98,124.17,121.90,118.97,118.66,117.84,107.55,56.71,56.59,52.55,38.38,6.09.LC/MS m/z:450.2(M+H+)。产率52%,红色固体。
4-(5,7-二甲氧基-6,11-二酮蒽醌[2,1-d]噻唑-2-基)哌嗪-1-甲酸乙酯(7l)
1H NMR(300MHz,CDCl3)δ7.83(d,J=7.7Hz,1H),7.61(t,J=8.0Hz,1H),7.35(s,1H),7.33(d,1H),4.21(q,J=7.1Hz,2H),4.03(s,3H),4.01(s,3H),3.79–3.70(m,4H),3.70–3.62(m,4H),1.31(t,J=7.1Hz,3H).13CNMR(126MHz,CDCl3)δ183.65,181.53,175.18,160.01,159.73,158.23,155.29,133.86,133.58,126.97,124.01,121.57,118.93,118.66,118.03,107.78,61.91,56.67,56.54,14.67.LC/MS m/z:482.2(M+H+)。产率89%,红色固体。
2-(4-异丙基哌嗪-1-基)-5,7-二甲氧基蒽醌[2,1-d]噻唑-6,11-二酮(7m)
1H NMR(300MHz,CDCl3)δ7.87(dd,J=7.7,1.0Hz,1H),7.66–7.60(m,1H),7.40(s,1H),7.34–7.29(m,1H),4.03(s,3H),4.01(s,3H),3.84–3.77(m,4H),2.81(dt,J=13.4,6.5Hz,1H),2.73–2.66(m,4H),1.10(s,3H),1.08(s,3H).13C NMR(126MHz,MeOD)δ183.82,182.15,175.33,160.14,159.73,158.58,133.82,126.94,123.76,121.85,119.01,118.76,117.63,107.34,56.46,56.32,54.76,47.91,18.06.LC/MS m/z:452.2(M+H+)。产率82%,红色固体。
2-(4-乙基哌嗪-1-基)-5,7-二甲氧基蒽醌[2,1-d]噻唑-6,11-二酮(7n)
1H NMR(300MHz,CDCl3)δ7.86(dd,J=7.7,1.0Hz,1H),7.66–7.58(m,1H),7.40(s,1H),7.31(dd,J=8.4,0.9Hz,1H),4.03(s,3H),4.01(s,3H),3.85–3.76(m,4H),2.66–2.57(m,4H),2.51(q,J=7.2Hz,2H),1.14(t,J=7.2Hz,3H).13C NMR(126MHz,CDCl3)δ183.87,181.64,175.22,160.09,159.76,158.65,133.97,133.51,127.00,124.17,121.87,118.96,118.65,117.89,107.60,56.70,56.58,52.29,52.05,48.28,11.97.LC/MS m/z:438.2(M+H+)。产率68%,红色固体。
5,7-二甲氧基-2-(4-甲基哌嗪-1-基)蒽醌[2,1-d]噻唑6,11-二酮(7o)
1H NMR(300MHz,CDCl3)δ7.83(dd,J=7.7,1.0Hz,1H),7.64–7.56(m,1H),7.37(s,1H),7.29(dd,J=8.5,1.0Hz,1H),4.01(s,3H),3.99(s,3H),3.81–3.74(m,4H),2.59–2.52(m,4H),2.47(s,3H).13C NMR(126MHz,CDCl3)δ183.84,181.63,175.25,160.08,159.75,158.61,133.96,133.53,127.00,124.16,121.85,118.97,118.66,117.92,107.62,56.71,56.59,54.34,54.26,46.14.LC/MS m/z:424.2(M+H+)。产率89%,红色固体。
2-(4-(2-羟乙基)哌嗪-1-基)-5,7-二甲氧基蒽醌[2,1-d]噻唑-6,11-二酮(7p)
1H NMR(300MHz,CDCl3)δ7.87(d,J=7.7Hz,1H),7.63(t,J=8.0Hz,1H),7.41(s,1H),7.33(d,J=8.5Hz,1H),4.42–4.26(m,1H),4.04(s,3H),4.02(s,3H),3.85–3.78(m,4H),3.68(dt,J=10.9,5.4Hz,4H),2.74–2.68(m,4H).13C NMR(126MHz,CDCl3)δ183.91,181.69,175.24,160.12,159.79,158.56,133.97,133.59,127.08,124.17,121.81,119.00,118.71,118.05,107.73,59.38,59.00,56.74,56.61,52.28,52.23.LC/MS m/z:454.2(M+H+)。产率75%,红色固体。
4-(5,7-二甲氧基-6,11-二氧代-6,11-二氢蒽醌并[2,1-d]噻唑-2-基)-1,4-二氮杂环庚烷-1-甲醛(7q)
1H NMR(300MHz,CDCl3)δ8.10(d,J=23.9Hz,1H),7.86(d,J=7.6Hz,1H),7.63(t,J=8.0Hz,1H),7.41(s,1H),7.33(d,J=8.3Hz,1H),4.04(s,3H),4.02(s,3H),3.87–3.76(m,2H),3.76–3.65(m,2H),3.66–3.55(m,2H),3.55–3.43(m,2H),2.18–2.07(m,2H).13C NMR(126MHz,CDCl3)δ188.39,186.17,178.71,167.17,164.63,164.37,163.43,138.54,131.69,128.70,126.59,123.61,122.60,122.49,112.51,61.45,61.32,51.58,47.31,34.34,30.29,27.36.LC/MS m/z:452.2(M+H+)。产率52%,红色固体。
2-((2,3-二羟基丙基)(甲基)氨基)-5,7-二甲氧基蒽醌[2,1-d]噻唑6,11-二酮(7r)
1H NMR(300MHz,CDCl3)δ7.80–7.75(dd,J=7.7,1.0Hz,1H),7.61–7.54(m,1H),7.30–7.27(m,1H),7.25(s,1H),3.95(s,3H),3.93(s,3H),3.78–3.69(m,2H),3.52(d,J=4.4Hz,2H),3.32–3.30(m,1H),3.28(s,3H).13CNMR(126MHz,CD3OD)δ179.80,177.95,172.42,156.21,155.80,153.85,129.89,129.83,123.03,119.77,117.72,115.05,114.81,113.59,103.05,66.22,59.04,52.57,52.43,25.69.LC/MS m/z:429.2(M+H+)。产率67%,红色固体。
2-((2-羟乙基)(甲基)氨基)-5,7-二甲氧基蒽醌[2,1-d]噻唑6,11-二酮(7s)
1H NMR(400MHz,CDCl3)δ7.86(dd,J=7.7,1.0Hz,1H),7.72–7.65(m,1H),7.47(s,1H),7.40(dd,J=8.3,1.0Hz,1H),4.04(s,3H),4.02(s,3H),3.92(t,J=5.4Hz,2H),3.81(d,J=5.2Hz,1H),3.38(s,3H),3.36(dt,J=3.2,1.6Hz,2H).13C NMR(126MHz,CDCl3)δ187.74,186.23,179.82,164.10,163.68,162.60,137.91,137.76,130.80,127.59,126.04,122.95,122.75,121.16,110.83,63.42,60.27,60.16.LC/MS m/z:399.2(M+H+)。产率64%,红色固体。
化合物8a-i的制备
将化合物7a-i(0.073mmol)溶于20mL无水二氯甲烷,加入三氯化铝(0.73mmol)与乙硫醇(0.73mmol);35℃搅拌10h,TLC检测反应;待原料消失后冰浴搅拌,加入饱和碳酸钠溶液淬灭;用二氯甲烷反复萃取,合并有机相后浓缩至30mL,调节pH至2-3,静置分层收集下层有机相;回收溶剂得红色粗产品,硅胶柱层析(二氯甲烷/甲醇)得最终产物8a-i,其中,R1和R2的定义与相应产物中的相同,各产物表征如下:
5,7-二羟基-2-(哌啶-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(8a)
1H NMR(300MHz,CDCl3)δ12.42(s,1H),12.39(s,1H),7.82(d,1H),7.64(t,J=7.9Hz,1H),7.29(d,J=0.7Hz,1H),7.18(s,1H),3.87–3.68(m,4H),1.81–1.72(m,6H).13CNMR(126MHz,CDCl3)δ189.94,181.78,175.48,163.43,162.75,162.32,136.17,132.76,126.34,124.95,124.75,119.67,116.28,110.67,109.74,29.72,25.63,24.12.HRMS(EI):m/z[M]+calcd for C20H16N2O4S:380.0831,found:380.0829.
5,7-二羟基-2-(吡咯烷-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(8b)
1H NMR(300MHz,CDCl3)δ12.42(s,1H),12.37(s,1H),7.82(d,J=7.8Hz,1H),7.64(t,J=7.8Hz,1H),7.31(d,J=9.3Hz,1H),7.17(s,1H),3.89–3.55(m,4H),2.19–2.15(m,4H).13C NMR(126MHz,CDCl3)δ190.13,181.93,172.68,163.44,162.66,162.39,136.23,132.85,126.47,125.17,124.86,119.73,116.32,110.86,109.71,29.72,22.72.HRMS(EI):m/z[M]+calcd for C19H14N2O4S:366.0674,found:366.0667.
2-(氮杂环庚烷-1-基)-5,7-二羟基蒽醌[2,1-d]噻唑-6,11-二酮(8c)
1H NMR(300MHz,CDCl3)δ12.40(s,1H),12.34(s,1H),7.78(dd,J=7.5,1.0Hz,1H),7.61(t,J=7.9Hz,1H),7.25–7.21(m,1H),7.15(s,1H),4.04–3.80(m,4H),1.94–1.88(m,4H),1.67–1.62(m,4H).13C NMR(126MHz,CDCl3)δ189.92,181.83,175.59,163.40,162.72,162.32,136.14,132.78,126.48,124.96,124.75,119.65,116.30,110.62,109.60,52.51,29.72,27.30.HRMS(EI):m/z[M]+calcd for C21H18N2O4S:394.0987,found:394.0981.
5,7-二羟基-2-(4-甲基哌啶-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(8d)
1H NMR(300MHz,CDCl3)δ12.42(s,1H),12.39(s,1H),7.81(d,J=6.8Hz,1H),7.67–7.60(m,1H),7.29(d,J=1.2Hz,1H),7.18(s,1H),3.39–3.09(m,4H),1.92–1.70(m,5H),1.02(d,J=7.1Hz,3H).13C NMR(126MHz,CDCl3)δ190.00,181.84,175.46,163.44,162.78,162.35,136.19,132.78,126.39,124.99,124.78,119.69,116.30,110.72,109.79,33.70,30.78,29.72,21.63.HRMS(EI):m/z[M]+calcd for C21H18N2O4S:394.0987,found:394.0981.
5,7-二羟基-2-(2-(2-羟乙基)哌啶-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(8e)
1H NMR(300MHz,DMSO-d6)δ12.10(s,1H),12.09(s,1H),7.68(t,J=7.9Hz,1H),7.53(d,J=7.3Hz,1H),7.25(d,J=8.0Hz,1H),6.87(s,1H),4.73–4.51(m,2H),3.48(q,J=6.4Hz,3H),2.04–1.68(m,8H).13C NMR(126MHz,DMSO)δ189.28,181.02,175.34,162.80,162.52,161.71,137.02,132.47,124.85,124.75,119.52,116.09,109.62,109.33,35.58,32.61,25.58,24.21,22.57,18.91,14.43.HRMS(EI):m/z[M]+calcd for C22H20N2O5S:424.1039,found:424.1101.
5,7-二羟基-2-(3-羟基哌啶-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(8f)
1H NMR(400MHz,DMSO-d6)δ12.10(s,2H),7.69(t,J=7.8Hz,1H),7.54(d,J=7.0Hz,1H),7.27(d,J=8.0Hz,1H),6.87(s,1H),5.14(s,1H),4.20–3.43(m,5H),2.05–1.75(m,4H).13C NMR(126MHz,DMSO)δ189.35,180.96,175.28,162.78,162.46,161.71,137.07,132.47,125.73,124.92,124.77,119.59,116.10,109.76,109.43,65.10,35.57,31.75,25.57,22.57.HRMS(EI):m/z[M]+calcd for C20H16N2O5S:396.0780,found:396.0773.
2-(二异丙基氨基)-5,7-二羟基蒽醌[2,1-d]噻唑-6,11-二酮(8g)
1H NMR(400MHz,CDCl3)δ12.46(s,1H),12.40(s,1H),7.80(dd,J=7.5,1.0Hz,1H),7.62(t,J=7.9Hz,1H),7.26(dd,J=8.3,0.9Hz,1H),7.17(s,1H),4.20–4.05(m,2H),1.50(s,6H),1.49(s,6H).13C NMR(101MHz,CDCl3)δ189.81,181.92,173.40,163.38,162.86,162.26,136.02,132.80,125.85,124.71,124.63,119.56,116.36,110.52,109.39,29.70,20.35.HRMS(EI):m/z[M]+calcd for C21H20N2O4S:396.1144,found:396.1142.
2-(二乙基氨基)-5,7-二羟基蒽醌[2,1-d]噻唑-6,11-二酮(8h)
1H NMR(300MHz,CDCl3)δ12.39(s,1H),12.34(s,1H),7.77(d,J=7.4Hz,1H),7.61(t,J=8.0Hz,1H),7.24(d,J=1.0Hz,1H),7.16(s,1H),3.69(m,4H),1.36(t,J=7.2Hz,6H).13CNMR(126MHz,CDCl3)δ189.89,181.80,174.89,163.37,162.77,162.31,136.14,132.74,126.50,124.91,124.75,119.63,116.27,110.63,109.59,29.72,13.08.HRMS(EI):m/z[M]+calcd for C19H16N2O4S:368.0831,found:368.0825.
5,7-二羟基-2-吗啉基蒽醌[2,1-d]噻唑-6,11-二酮(8i)
1H NMR(300MHz,CDCl3)δ12.37(s,1H),12.34(s,1H),7.82(dd,J=7.5,1.1Hz,1H),7.68–7.62(m,1H),7.30(dd,J=8.5,1.1Hz,1H),7.24(s,1H),3.76–3.71(m,4H),3.65–3.56(m,4H).13C NMR(126MHz,CDCl3)δ186.81,182.27,175.38,163.31,163.12,162.97,135.25,134.77,124.54,123.83,121.02,120.06,118.52,112.25,111.68,66.43,52.02.HRMS(EI):m/z[M]+calcd for C19H14N2O5S:382.0623,found:382.0616.
化合物8j-s的制备
将化合物7j-s(0.073mmol)溶于20mL无水二氯甲烷,加入三溴化硼(0.73mmol);-5℃搅拌3h后慢慢升至室温,TLC检测反应;待原料消失后冰浴搅拌,加入饱和碳酸氢钠溶液淬灭;用二氯甲烷反复萃取,合并有机相。硫酸钠固体干燥,回收溶剂得红色粗产品,硅胶柱层析(二氯甲烷/甲醇)得最终产物8j-s,其中,R1和R2的定义与相应产物中的相同,各产物表征如下:
2-(4-(二甲基氨基)哌啶-1-基)-5,7-二羟基蒽醌[2,1-d]噻唑-6,11-二酮(8j)
1H NMR(300MHz,CDCl3)δ12.36(s,1H),12.34(s,1H),7.76(d,J=7.7Hz,1H),7.62(t,J=8.1Hz,1H),7.39(s,1H),7.31(d,J=8.3Hz,1H),3.31–3.21(m,2H),3.03–3.00(m,1H),2.58–2.44(m,2H),2.32(s,6H),1.76–1.50(m,4H).13C NMR(126MHz,DMSO)δ189.67,181.16,174.99,162.63,162.05,161.74,137.29,132.58,125.61,125.15,119.72,116.17,115.67,110.41,109.94,61.87,36.29,29.49,25.98.HRMS(EI):m/z[M]+calcd for C22H21N3O4S:423.1253,found:423.1250.
2-(4-环丙基哌嗪-1-基)-5,7-二羟基蒽醌[2,1-d]噻唑-6,11-二酮(8k)
1H NMR(300MHz,CDCl3)δ12.38(s,1H),12.35(s,1H),7.80(dd,J=7.5,1.1Hz,1H),7.68–7.59(m,1H),7.29(d,J=1.2Hz,1H),7.19(s,1H),3.92–3.71(m,4H),2.85–2.73(m,4H),1.77–1.66(m,1H),0.59–0.42(m,4H).13C NMR(126MHz,CDCl3)δ190.03,181.60,175.58,163.30,162.33,136.23,132.67,126.04,125.00,124.80,119.70,116.19,111.06,109.92,77.29,52.57,38.34,6.12.HRMS(EI):m/z[M]+calcd for C22H19N3O4S:421.1096,found:421.1089.
4-(5,7-二羟基-6,11-二氧代-6,11-二氢蒽醌并[2,1-d]噻唑-2-基)哌嗪-1-甲酸乙酯(8l)
1H NMR(400MHz,CDCl3)δ12.32(s,1H),12.29(s,1H),7.78(dd,J=7.5,1.0Hz,1H),7.66–7.60(m,1H),7.28(d,J=1.0Hz,1H),7.18(s,1H),4.21(q,J=7.1Hz,2H),3.84–3.76(m,4H),3.70–3.65(m,4H),1.31(t,J=7.1Hz,3H).13C NMR(126MHz,CDCl3)δ190.24,181.56,175.67,163.22,162.39,161.89,155.27,136.40,132.62,125.63,125.19,124.94,119.80,116.12,111.56,110.24,62.03,29.72,14.69.HRMS(EI):m/z[M]+calcd for C22H19N3O6S:453.0995,found:453.0988.
5,7-二羟基-2-(4-异丙基哌嗪-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(8m)
1H NMR(300MHz,CDCl3)δ12.33(s,1H),12.27(s,1H),7.74(d,J=7.5Hz,1H),7.59(t,J=7.9Hz,1H),7.23(d,J=8.4Hz,1H),7.10(s,1H),3.91–3.69(m,4H),2.81(dt,J=12.8,6.4Hz,1H),2.73–2.63(m,4H),1.09(s,3H),1.07(s,3H).13C NMR(126MHz,DMSO)δ189.13,180.66,174.61,162.15,161.67,161.20,136.67,132.07,129.51,124.94,124.50,119.14,115.67,109.71,109.27,53.92,47.53,47.34,17.88,17.85.HRMS(EI):m/z[M]+calcd forC22H21N3O4S:423.1253,found:423.1256.
2-(4-乙基哌嗪-1-基)-5,7-二羟基蒽醌[2,1-d]噻唑-6,11-二酮(8n)
1H NMR(300MHz,CDCl3)δ12.34(s,1H),12.29(s,1H),7.76(d,J=7.4Hz,1H),7.60(t,J=7.8Hz,1H),7.23(d,1H),7.13(s,1H),3.89–3.70(m,4H),2.65–2.56(m,4H),2.46(q,J=14.3,7.0Hz,2H),1.14(t,J=14.2Hz,3H).13C NMR(101MHz,CDCl3)δ190.02,181.56,175.53,163.27,162.31,136.23,132.65,126.00,124.99,124.80,119.69,116.16,111.08,109.92,52.26,52.07,47.40.HRMS(EI):m/z[M]+calcd for C21H19N3O4S:409.1096,found:409.1087.
2-(4-甲基哌嗪-1-基)-5,7-二羟基蒽醌[2,1-d]噻唑-6,11-二酮(8o)
1H NMR(300MHz,CDCl3)δ12.35(s,1H),12.31(s,1H),7.77(dd,J=7.5,1.1Hz,1H),7.65–7.58(m,1H),7.26(dd,J=8.4,1.2Hz,1H),7.16(s,1H),3.89–3.75(m,4H),2.62–2.53(m,4H),2.37(s,3H).13C NMR(126MHz,CDCl3)δ190.14,181.67,175.62,163.31,162.37,162.31,136.28,132.70,126.00,125.09,124.86,119.74,116.20,111.19,110.02,54.28,46.08.HRMS(EI):m/z[M]+calcd for C21H17N3O4S:395.0940,found:395.0942.
5,7-二羟基-2-(4-(2-羟乙基)哌嗪-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(8p)
1H NMR(300MHz,CDCl3)δ12.38(s,1H),12.35(s,1H),7.82(d,J=7.5Hz,1H),7.69–7.60(m,1H),7.30(d,J=1.6Hz,1H),7.22(s,1H),3.90–3.78(m,4H),3.73–3.66(m,2H),2.74–2.67(m,4H),2.67–2.62(m,2H).13CNMR(126MHz,DMSO)δ189.48,180.92,175.18,162.65,162.12,161.71,137.13,132.45,125.48,124.97,124.89,119.63,116.06,110.19,109.65,60.23,58.87,52.69.HRMS(EI):m/z[M]+calcd for C21H19N3O5S:425.1045,found:425.1039.
4-(5,7-二羟基-6,11-二氧代-6,11-二氢蒽醌并[2,1-d]噻唑-2-基)-1,4-二氮杂环庚烷-1-甲醛(8q)
1H NMR(300MHz,DMSO-d6)δ12.19(s,1H),12.18(s,1H),8.06(s,1H),7.78(t,J=7.9Hz,1H),7.69(dd,J=7.4,1.2Hz,1H),7.37(dd,J=8.3,1.0Hz,1H),7.14(d,J=3.1Hz,1H),4.11–3.85(m,4H),3.82–3.63(m,4H),2.04–1.95(m,2H).13C NMR(126MHz,CD3OD)δ190.39,181.75,177.86,163.31,163.26,163.22,162.92,136.46,131.82,129.80,128.39,124.87,119.75,115.07,111.10,110.17,42.01,38.94,35.51,31.79,29.55.HRMS(EI):m/z[M]+calcd for C21H17N3O5S:423.0889,found:423.0876.
2-((2,3-二羟基丙基)(甲基)氨基)-5,7-二羟基蒽醌[2,1-d]噻唑-6,11-二酮(8r)
1H NMR(300MHz,CDCl3)δ12.29(s,1H),12.25(s,1H),7.78(d,J=7.4Hz,1H),7.64(t,J=7.8Hz,1H),7.34–7.27(m,1H),7.16(s,1H),4.10–3.91(m,2H),3.72–3.52(m,3H),2.01(s,3H).13C NMR(126MHz,DMSO)δ189.43,181.07,175.94,162.73,162.07,161.72,137.07,131.86,124.91,119.58,117.10,116.16,113.13,109.72,109.38,69.75,64.23,49.05.HRMS(EI):m/z[M]+calcd for C19H16N2O6S:400.0729,found:400.0674.
5,7-二羟基-2-((2-羟乙基)(甲基)氨基)蒽醌[2,1-d]噻唑-6,11-二酮(8s)
1H NMR(300MHz,DMSO-d6)δ12.13(s,2H),7.71(t,J=7.9Hz,1H),7.59(d,J=7.4Hz,1H),7.29(d,J=8.2Hz,1H),6.97(s,1H),3.80–3.63(m,4H),3.25(s,3H).13C NMR(101MHz,DMSO)δ189.38,180.93,175.76,162.73,162.40,161.72,137.04,132.51,124.89,124.76,119.56,116.10,109.73,109.33,58.58,58.49,14.41.HRMS(EI):m/z[M]+calcd forC18H14N2O5S:370.0623,found:370.0611.
我们对上述化合物8a~8s进行了体外肿瘤细胞增殖抑制实验,其结果见表1,根据该结果分析得出,化合物8p的效果最好。考虑到化合物的溶解度,以及进一步提高其生物活性,我们对化合物8p进行结构修饰,进一步获得了系列化合物15a-j。实验如下:
实施例2
化合物10的制备
称取化合物9(13.0g,100mmol)溶于100mL无水四氢呋喃(THF)溶液,加入二碳酸二叔丁酯((Boc)2O)(21.8g,100mmol),室温搅拌1h;TLC检测,碘缸显色;原料消失后回收溶剂得化合物10(23g)。
1H NMR(400MHz,CDCl3):δ1.40(s,9H),2.40(t,J=4.8Hz,4H),2.50(t,J=5.2,2H),3.38(t,J=4.8Hz,4H),3.58(t,J=5.2Hz,2H).LC/MS m/z:231.2(M+H+)。
化合物11的制备
称取化合物10(8.7g,37.8mmol)溶于无水四氢呋喃(THF)溶液,然后加入二甲氨基吡啶DMAP(0.23g,1.9mmol)及三乙胺(4.9g,49.1mmol);冰浴下滴加甲基磺酰氯(5.2g,45.3mmol),滴加完毕后慢慢升至室温搅拌5h;TLC检测,碘缸显色;待原料消失后加入少量冰水淬灭,回收溶剂得粗品,硅胶柱层析(石油醚/乙酸乙酯)得化合物11(3.9g)。
1H NMR(400MHz,CDCl3)δ3.57(t,J=6.9Hz,2H),3.47-3.39(m,4H),2.72(t,J=6.9Hz,2H),2.48-2.41(m,4H),1.44(s,9H).LC/MS m/z:249.1(M+H+)。
化合物12的制备
将化合物11(248.0mg,1.0mmol)和碘化钠(180.0mg,1.2mmol)加入到甲醇(10.0mL)中搅拌,随后加入取代胺(2.1mmol)并升温到40℃反应3~6小时,TLC监测显示原料反应完全,浓缩,柱层析得化合物12,其中R4的定义与相应产物中的相同。
化合物13的制备
将化合物12溶于二氯甲烷中,随后加入三氟乙酸,室温下搅拌2-6小时,TLC检测反应,原料消失后,回收溶剂得化合物13的三氟乙酸盐,其中R4的定义与相应产物中的相同。
化合物14的制备
称取化合物6(0.5mmol)溶于20mL二甲基甲酰胺(DMF),然后加入二硫化碳(0.6mmol)、化合物13(0.75mmol)及碳酸钾(1.5mmol);115℃搅拌6h,TLC检测反应。待原料反应完全后,冷却至室温;加水稀释,然后用二氯甲烷萃取;加入硫酸镁固体干燥,回收溶剂后得红色粗品,柱层析得化合物14,其中R4的定义与相应产物中的相同。
化合物15的制备
将化合物14(0.073mmol)溶于20mL无水二氯甲烷,-5℃滴加三溴化硼(0.73mmol),氮气保护,搅拌3h后慢慢升至室温过夜;TLC检测反应,待原料消失后冰浴搅拌,加入饱和碳酸氢钠溶液淬灭;用二氯甲烷反复萃取,合并有机相。硫酸钠固体干燥,回收溶剂得红色粗产品,硅胶柱层析(二氯甲烷/甲醇)得最终产物15,其中R4的定义与相应产物中的相同。
化合物12-15的图谱数据如下所示,部分中间产物直接进入下一阶段反应因而未进行表征:
4-(2-(吡咯烷-1-基)乙基)哌嗪-1-甲酸叔丁酯(12a)
1H NMR(300MHz,CDCl3)δ3.56–3.37(m,8H),3.27(t,J=5.9Hz,2H),2.90(t,J=5.9Hz,2H),2.52–2.45(m,4H),2.22–2.14(m,4H),1.43(s,9H).LC/MS m/z:284.3(M+H+)。
4-(2-(4-甲基哌啶-1-基)乙基)哌嗪-1-甲酸叔丁酯(12c)
1H NMR(300MHz,CDCl3)δ3.67(d,J=12.1Hz,2H),3.48–3.37(m,4H),3.16(t,J=5.9Hz,2H),3.03–2.87(m,4H),2.54–2.43(m,4H),2.05–1.67(m,5H),1.44(s,9H),1.03(d,J=6.4Hz,3H).LC/MS m/z:312.3(M+H+)。
4-(2-(二丁基氨基)乙基)哌嗪-1-甲酸叔丁酯(12e)
1H NMR(400MHz,CDCl3)δ3.32–3.19(m,4H),2.81–2.74(m,6H),2.72–2.64(m,2H),2.39–2.27(m,4H),1.27–1.19(m,17H),0.76(t,J=5.8Hz,6H).LC/MS m/z:341.5(M+H+)。
4-(2-(二乙基氨基)乙基)哌嗪-1-甲酸叔丁酯(12f)
1H NMR(400MHz,CDCl3)δ3.41–3.35(m,4H),3.28(q,J=7.2Hz,4H),3.20(t,J=5.9Hz,2H),2.79(t,J=5.9Hz,2H),2.46–2.39(m,4H),1.36(t,J=7.4Hz,6H),1.33(s,9H).LC/MS m/z:286.3(M+H+)。
4-(2-(4-乙基哌嗪-1-基)乙基)哌嗪-1-甲酸叔丁酯(12i)
1H NMR(400MHz,CDCl3)δ3.61–3.54(m,4H),3.38–3.29(m,6H),3.15–2.95(m,8H),2.45(q,J=7.1Hz,4H),1.43(s,9H),1.11(t,J=7.2Hz,3H).LC/MS m/z:327.3(M+H+)。
4-(2-(4-甲基哌嗪-1-基)乙基)哌嗪-1-甲酸叔丁酯(12j)
1H NMR(300MHz,CDCl3)δ3.56–3.49(m,2H),3.34–3.25(m,6H),3.20(m,2H),3.05(m,2H),2.93–2.84(m,6H),2.82–2.76(m,2H),2.41(s,3H),1.42(s,9H).LC/MS m/z:313.3(M+H+)。
4-(2-(4-异丙基-1-基)乙基)哌嗪-1-甲酸叔丁酯(12k)
1H NMR(400MHz,CDCl3)δ3.53–3.38(m,5H),3.36–2.98(m,8H),2.78–2.70(m,2H),2.69–2.60(m,2H),2.55–2.45(m,4H),1.55–1.35(m,15H).LC/MS m/z:341.4(M+H+)。
5,7-二甲氧基-2-(4-(2-(吡咯烷-1-基)乙基)哌嗪-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(14a)
1H NMR(300MHz,CDCl3)δ7.85(d,J=7.5Hz,1H),7.62(t,J=7.8Hz,1H),7.38(s,1H),7.31(d,J=8.7Hz,1H),4.03(s,3H),4.01(s,3H),3.86–3.75(m,4H),2.73–2.61(m,12H),1.87–1.80(m,4H).13C NMR(126MHz,CDCl3)δ183.81,181.61,175.16,160.06,159.74,158.61,133.94,133.54,126.97,124.13,121.85,118.96,118.67,117.86,107.59,56.71,56.60,54.66,53.42,52.82,48.22,23.38.LC/MS m/z:507.3(M+H+)。产率50%,深红色固体。
5,7-二甲氧基-2-(4-(2-(哌啶-1-基)乙基)哌嗪-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(14b)
1H NMR(300MHz,CDCl3)δ7.82(d,J=7.6Hz,1H),7.58(t,J=8.0Hz,1H),7.35(s,1H),7.28(d,J=9.0Hz,1H),4.00(s,3H),3.98(s,3H),3.80–3.70(m,4H),2.65–2.60(m,4H),2.55–2.51(m,4H),2.47–2.42(m,4H),1.62–1.54(m,6H).13C NMR(126MHz,CDCl3)δ183.84,181.61,175.18,160.07,159.74,158.63,133.95,133.51,126.97,124.15,121.85,118.95,118.65,117.86,107.58,56.69,56.61,56.58,55.85,55.38,55.08,55.05,52.92,52.87,25.86,24.24.LC/MS m/z:521.3(M+H+)。产率39%,深红色固体。
5,7-二甲氧基-2-(4-(2-(4-甲基哌啶-1-基)乙基)哌嗪-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(14c)
1H NMR(300MHz,CDCl3)δ7.83(d,J=6.5Hz,1H),7.69–7.54(m,1H),7.36(s,1H),7.30(d,J=7.7Hz,1H),4.01(s,3H),3.99(s,3H),3.86–3.72(m,4H),3.24–2.98(m,4H),2.78–2.56(m,12H),1.26–1.17(m,1H),0.95–0.91(m,3H).13C NMR(126MHz,CDCl3)δ183.84,181.63,175.18,160.07,159.76,158.59,133.96,133.59,127.01,124.15,121.86,119.01,118.71,117.91,107.64,56.76,56.66,55.58,55.00,54.39,52.84,48.28,33.14,30.22,21.61.LC/MS m/z:535.3(M+H+)。产率40%,深红色固体。
5,7-二甲氧基-2-(4-(2-吗啉基乙基)哌嗪-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(14d)
1H NMR(300MHz,CDCl3)δ7.85(dd,J=7.7,1.1Hz,1H),7.66–7.57(m,1H),7.39(s,1H),7.31(dd,J=8.5,1.0Hz,1H),4.02(s,3H),4.01(s,3H),3.85–3.75(m,4H),3.75–3.68(m,4H),2.73–2.62(m,4H),2.59(dd,J=5.8,3.2Hz,4H),2.55–2.45(m,4H).13C NMR(126MHz,CDCl3)δ183.77,181.52,175.08,159.99,159.67,158.50,133.86,133.43,126.91,124.06,121.73,118.86,118.58,117.84,107.54,66.69,56.60,56.48,56.16,55.29,54.02,52.77,48.11.LC/MS m/z:523.2(M+H+)。产率64%,深红色固体。
2-(4-(2-(二丁基氨基)乙基)哌嗪-1-基)-5,7-二甲氧基蒽醌[2,1-d]噻唑-6,11-二酮(14e)
1H NMR(300MHz,CDCl3)δ7.86(d,J=7.1Hz,1H),7.63(t,J=8.7Hz,1H),7.40(s,1H),7.32(d,J=8.1Hz,1H),4.03(s,3H),4.02(s,3H),3.86–3.74(m,4H),2.76–2.64(m,8H),1.64–1.48(m,4H),1.41–1.23(m,8H),0.98–0.91(m,6H).13C NMR(126MHz,CDCl3)δ183.86,181.67,175.20,160.09,159.77,158.56,133.96,133.59,127.04,124.16,121.84,119.00,118.70,117.99,107.69,56.75,56.63,53.66,52.80,48.22,29.71,20.49,13.95.LC/MSm/z:565.3(M+H+)。产25%,深红色固体。
2-(4-(2-(二乙基氨基)乙基)哌嗪-1-基)-5,7-二甲氧基蒽醌[2,1-d]噻唑-6,11-二酮(14f)
1H NMR(300MHz,CDCl3)δ7.84(d,J=7.2Hz,1H),7.60(t,J=7.7Hz,1H),7.37(s,1H),7.30(d,J=8.1Hz,1H),4.01(s,3H),4.00(s,3H),3.86–3.68(m,4H),2.66–2.51(m,12H),1.05(t,J=6.9Hz,6H).13C NMR(126MHz,CDCl3)δ183.88,181.66,175.22,160.09,159.77,158.63,133.98,133.58,127.02,124.18,121.88,118.70,117.92,107.63,77.02,56.76,56.65,56.22,52.94,50.08,48.30,47.47,11.40.LC/MS m/z:509.3(M+H+)。产率64%,深红色固体。
2-(4-(2-(二甲基氨基)乙基)哌嗪-1-基)-5,7-二甲氧基蒽醌[2,1-d]噻唑-6,11-二酮(14g)
1H NMR(300MHz,CDCl3)δ7.85(d,J=7.0Hz,1H),7.68–7.55(m,1H),7.39(s,1H),7.31(d,J=8.5Hz,1H),4.02(s,3H),4.01(s,3H),3.88–3.72(m,4H),2.71–2.60(m,4H),2.59–2.48(m,4H),2.30(s,6H).13C NMR(126MHz,CDCl3)δ183.86,181.63,175.20,160.08,159.76,158.65,133.97,133.56,126.99,124.17,121.88,118.99,118.69,117.88,107.60,58.33,56.75,56.64,56.48,52.89,48.24,45.94.LC/MS m/z:481.3(M+H+)。产率55%,深红色固体。
2-(4-(2-(二异丙基氨基)乙基)哌嗪-1-基)-5,7-二甲氧基蒽醌[2,1-d]噻唑-6,11-二酮(14h)
1H NMR(300MHz,CDCl3)δ7.84(d,J=7.7Hz,1H),7.60(t,J=8.0Hz,1H),7.38(s,1H),7.30(d,J=8.4Hz,1H),4.01(s,3H),4.00(s,3H),3.84–3.68(m,4H),3.23–2.92(m,2H),2.74–2.32(m,8H),1.27–0.84(m,12H).13C NMR(126MHz,CDCl3)δ183.88,181.66,175.23,160.09,159.76,158.62,133.97,133.54,127.01,124.17,121.87,118.98,118.67,117.92,107.63,56.71,56.59,52.94,48.25,20.67.LC/MS m/z:537.3(M+H+)。产率20%,深红色固体。
2-(4-(2-(4-乙基哌嗪-1-基)乙基)哌嗪-1-基)-5,7-二甲氧基蒽醌[2,1-d]噻唑-6,11-二酮(14i)
1H NMR(300MHz,CDCl3)δ7.84(d,J=7.7Hz,1H),7.60(t,J=8.0Hz,1H),7.38(s,1H),7.30(d,J=8.5Hz,1H),4.01(s,3H),4.00(s,3H),3.81–3.70(m,4H),2.68–2.61(m,6H),2.61–2.52(m,8H),2.46(q,J=7.1Hz,4H),1.10(t,J=7.2Hz,3H).13C NMR(126MHz,CDCl3)δ183.88,181.66,175.19,160.09,159.76,158.62,133.96,133.54,127.01,124.17,121.85,118.97,118.67,117.92,107.62,56.71,56.59,55.69,55.65,53.06,52.84,52.45,52.27,48.26,11.55.LC/MS m/z:550.3(M+H+)。产率32%,深红色固体。
2-(4-(2-(4-甲基哌嗪-1-基)乙基)哌嗪-1-基)-5,7-二甲氧基蒽醌[2,1-d]噻唑-6,11-二酮(14j)
1H NMR(300MHz,CDCl3)δ7.83(d,J=7.6Hz,1H),7.60(t,J=8.0Hz,1H),7.36(s,1H),7.29(d,J=8.3Hz,1H),4.00(s,3H),3.99(s,3H),3.81–3.71(m,4H),2.66–2.61(m,4H),2.60–2.51(m,10H),2.29(s,3H).13CNMR(126MHz,CDCl3)δ183.85,181.63,175.18,160.08,159.75,158.60,133.95,133.54,126.99,124.15,121.84,118.96,118.67,117.90,107.61,56.70,56.58,55.67,54.81,53.20,52.87,45.73.LC/MS m/z:536.3(M+H+)。产率31%,深红色固体。
2-(4-(2-(4-异丙基-1-基)乙基)哌嗪-1-基)-5,7-二甲氧基蒽醌[2,1-d]噻唑-6,11-二酮(14k)
1H NMR(300MHz,CDCl3)δ7.83(d,J=7.7Hz,1H),7.60(t,J=7.2Hz,1H),7.37(s,1H),7.29(d,J=8.6Hz,1H),4.01(s,3H),3.99(s,3H),3.82–3.70(m,4H),2.68–2.51(m,17H),1.07(d,J=6.3Hz,6H).13C NMR(126MHz,CDCl3)δ183.88,181.65,175.19,160.09,159.76,158.63,133.96,133.54,127.01,124.17,121.85,118.98,118.68,117.92,107.62,76.85,56.72,56.60,55.77,55.68,54.94,53.49,53.37,52.88,18.39.LC/MS m/z:564.3(M+H+)。产率45%,深红色固体。
5,7-二羟基-2-(4-(2-(吡咯烷-1-基)乙基)哌嗪-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(15a)
1H NMR(300MHz,CDCl3)δ12.34(s,2H),7.78(dd,J=7.5,1.1Hz,1H),7.66–7.58(dd,J=8.3,7.5Hz,1H),7.29–7.26(dd,J=7.5,1.2Hz,1H),7.16(s,1H),3.89–3.76(m,4H),2.73–2.63(m,10H),1.90–1.80(m,4H).13CNMR(126MHz,CDCl3)δ190.13,181.66,175.55,163.31,162.36,162.29,136.29,132.69,126.00,125.09,124.86,119.74,116.19,111.16,110.01,54.59,53.25,52.77,29.72,23.38.产率26%,深红色固体。
5,7-二羟基-2-(4-(2-(哌啶-1-基)乙基)哌嗪-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(15b)
1H NMR(300MHz,CDCl3)δ12.35(s,2H),7.79(dd,J=7.5,1.1Hz,1H),7.63(dd,J=8.3,7.6Hz,1H),7.28(dd,J=4.6,1.0Hz,1H),7.18(s,1H),3.89–3.75(m,4H),2.68–2.65(m,4H),2.62–2.53(m,4H),2.53–2.40(m,4H),1.66–1.59(m,4H),1.52–1.44(m,2H).13C NMR(126MHz,CDCl3)δ190.15,181.72,175.56,163.34,162.38,162.35,136.29,132.73,126.04,125.11,124.86,119.74,116.22,111.15,110.02,56.37,55.53,55.03,52.87,29.72,25.61,24.09.产率31%,深红色固体。
5,7-二羟基-2-(4-(2-(4-甲基哌啶-1-基)乙基)哌嗪-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(15c)
1H NMR(500MHz,CDCl3)δ12.34(s,2H),7.79(d,J=7.3Hz,1H),7.63(t,J=7.9Hz,1H),7.28(d,J=8.7Hz,1H),7.16(s,1H),3.92–3.75(m,4H),3.15–2.88(m,4H),2.71–2.65(m,6H),2.63–2.59(m,2H),2.13–1.92(m,4H),1.63–1.55(m,1H),0.96(d,J=6.2Hz,3H).13CNMR(126MHz,CDCl3)δ190.07,181.61,175.53,163.29,162.34,162.30,136.25,132.67,126.00,125.03,124.82,119.71,116.18,111.10,109.96,55.98,55.63,54.46,52.85,29.71,21.79,14.15.产率34%,深红色固体。
5,7-二羟基-2-(4-(2-吗啉基乙基)哌嗪-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(15d)
1H NMR(300MHz,CDCl3)δ12.35(s,2H),7.79(d,J=7.5Hz,1H),7.62(t,J=7.9Hz,1H),7.27(d,J=5.9Hz,1H),7.17(s,1H),3.88–3.78(m,4H),3.76–3.70(m,4H),2.71–2.64(m,4H),2.62–2.55(m,4H),2.54–2.48(m,4H).13C NMR(126MHz,CDCl3)δ190.12,181.68,175.52,163.30,162.36,162.29,136.27,132.68,125.97,125.08,124.85,119.72,116.19,111.15,110.00,66.88,56.32,55.38,54.11,52.87.产率20%,深红色固体。
2-(4-(2-(二丁基氨基)乙基)哌嗪-1-基)-5,7-二羟基蒽醌[2,1-d]噻唑-6,11-二酮(15e)
1H NMR(300MHz,CDCl3)δ12.36(s,2H),7.80(dd,J=7.5,1.1Hz,1H),7.63(dd,J=8.3,7.6Hz,1H),7.29–7.26(dd,J=7.2,1.1Hz,1H),7.18(s,1H),3.89–3.77(m,4H),2.69–2.64(m,6H),2.63–2.58(m,2H),2.56–2.49(m,4H),1.51–1.36(m,8H),0.87(t,J=5.9Hz,6H).13C NMR(126MHz,CDCl3)δ190.17,181.73,175.58,163.33,162.39,162.33,136.31,132.73,126.02,125.13,124.88,119.75,116.22,111.18,110.05,54.15,54.09,54.07,52.89,33.85,20.63,14.04.产率57%,深红色固体。
2-(4-(2-(二乙基氨基)乙基)哌嗪-1-基)-5,7-二羟基蒽醌[2,1-d]噻唑-6,11-二酮(15f)
1H NMR(300MHz,CDCl3)δ12.34(s,2H),7.80(dd,J=7.4,1.0Hz,1H),7.63(dd,J=8.4,7.7Hz,1H),7.30–7.26(dd,J=7.5,1.1Hz,1H),7.19(s,1H),3.89–3.79(m,4H),2.72–2.68(m,4H),2.05–1.96(m,8H),0.90–0.88(m,6H).13C NMR(126MHz,CDCl3)δ190.21,181.71,175.58,163.31,162.40,162.22,136.35,132.71,125.95,125.17,124.91,119.78,116.20,111.28,110.11,52.72,49.14,47.22,14.15.产率17%,深红色固体。
2-(4-(2-(二甲基氨基)乙基)哌嗪-1-基)-5,7-二羟基蒽醌[2,1-d]噻唑-6,11-二酮(15g)
1H NMR(300MHz,CDCl3)δ12.36(s,2H),7.80(dd,J=8.7,1.5Hz,1H),7.63(dd,J=8.3,7.6Hz,1H),7.27(dd,J=6.7,1.1Hz,1H),7.18(s,1H),3.92–3.73(m,4H),2.70–2.62(m,4H),2.61–2.55(m,2H),2.55–2.49(m,2H),2.31(s,6H).13C NMR(126MHz,CDCl3)δ190.15,181.74,175.55,163.34,162.38,162.36,136.29,132.73,126.05,125.12,124.87,119.75,116.23,111.15,110.02,56.58,56.12,52.86,45.74.产率35%,深红色固体。
2-(4-(2-(二异丙基氨基)乙基)哌嗪-1-基)-5,7-二羟基蒽醌[2,1-d]噻唑-6,11-二酮(15h)
1H NMR(300MHz,CDCl3)δ12.34(s,2H),7.81–7.76(d,J=7.4Hz,1H),7.62(t,J=7.9Hz,1H),7.27(d,J=7.5Hz,1H),7.17(s,1H),3.88–3.74(m,4H),2.71–2.66(m,4H),2.08–1.88(m,4H),1.63–1.48(m,2H),1.29–1.26(m,12H).13C NMR(126MHz,CDCl3)δ190.14,181.68,175.59,163.31,162.37,162.28,136.29,132.71,126.00,125.11,124.86,119.74,116.20,111.18,110.03,52.92,14.15.产率61%,深红色固体。
2-(4-(2-(4-乙基哌嗪-1-基)乙基)哌嗪-1-基)-5,7-二羟基蒽醌[2,1-d]噻唑-6,11-二酮(15i)
1H NMR(300MHz,CDCl3)δ12.34(s,2H),7.79(dd,J=7.5,1.2Hz,1H),7.63(dd,J=8.3,7.5Hz,1H),7.29–7.26(dd,J=7.6,1.1Hz,1H),7.18(s,1H),3.89–3.70(m,4H),2.69–2.64(m,4H),2.64–2.51(m,12H),2.47(q,J=7.1Hz,2H),1.12(t,J=7.2Hz,3H).13C NMR(126MHz,CDCl3)δ190.16,181.74,175.55,163.34,162.38,162.34,136.30,132.73,126.02,125.12,124.88,119.75,116.22,111.17,110.03,55.78,55.66,53.32,52.89,52.60,52.31,14.15.产率71%,深红色固体。
5,7-二羟基-2-(4-(2-(4-甲基哌嗪-1-基)乙基)哌嗪-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(15j)
1H NMR(300MHz,CDCl3)δ12.34(s,2H),7.79(dd,J=7.5,1.1Hz,1H),7.63(dd,J=8.3,7.6Hz,1H),7.29–7.26(dd,J=7.8,1.1Hz,1H),7.18(s,1H),3.88–3.74(m,4H),2.68–2.64(m,4H),2.62–2.39(m,12H),2.32(s,3H).13C NMR(126MHz,CDCl3)δ190.16,181.74,175.56,163.34,162.39,162.34,136.30,132.73,126.02,125.13,124.88,119.75,116.22,111.17,110.03,55.75,55.64,54.93,53.35,52.88,45.87.产率49%,深红色固体。
5,7-二羟基-2-(4-(2-(4-异丙基-1-基)乙基)哌嗪-1-基)蒽醌[2,1-d]噻唑-6,11-二酮(15k)
1H NMR(300MHz,CDCl3)δ12.37(s,2H),7.78(dd,J=7.5,1.1Hz,1H),7.62(dd,J=8.3,7.6Hz,1H),7.27(dd,J=8.3,1.1Hz,1H),7.16(s,1H),3.87–3.75(m,4H),2.66(dt,J=7.5,3.8Hz,13H),2.60(s,4H),1.14(d,J=6.5Hz,6H).13C NMR(126MHz,CDCl3)δ190.13,181.68,175.54,163.32,162.37,162.31,136.29,132.70,126.00,125.10,124.86,119.74,116.20,111.16,110.01,55.65,55.51,55.25,52.86,48.35,18.19.产率45%,深红色固体。
实验实施例
体外抑制肿瘤细胞生长活性测定
筛选方法:磺酰罗丹明B蛋白染色法
细胞株:人肺癌A549和人宫颈癌HeLa
作用时间:72h
采用磺酰罗丹明B蛋白染色法(sulforhodamine B,SRB)对所有化合物进行抗肿瘤活性的初步研究。
SRB是一种蛋白结合染料,可与生物大分子中的碱性氨基酸结合,其在515nm的光密度(OD)读数与细胞数成良好的线性关系,故可以用作细胞数的定量。人肺癌细胞A-549用含有10%小牛血清的RPMI-1640培养,测定时将对数生长期的细胞配成细胞悬液,接种于96孔培养板上。实验组每孔加入10μL不同浓度的化合物,对照组加等体积含量最高浓度溶剂(DMSO)的RPMI-1640培养液,在37℃,5%二氧化碳条件下培养72h后,用三氯乙酸固定,每孔加入100μL SRB液,洗去未结合的SRB,用自动分光光度平板读数计测定OD值。以不加药物的肿瘤细胞对照组为空白对照,计算药物对该肿瘤细胞的生长抑制率。
抑制率=[(空白对照组-给药组)/空白对照组]×100%
结果如下:
表1 8a-s癌细胞的抑制活性。
表2 15a-k癌细胞的抑制活性。
15a | 70.3 | 81.1 |
15b | 46.4 | 86.9 |
15c | 38.2 | 82.1 |
15d | >100.0 | >100.0 |
15e | 57.1 | >100.0 |
15f | >100.0 | >100.0 |
15g | 32.8 | >100.0 |
15h | >100.0 | >100.0 |
15i | 23.4 | 71.3 |
15j | 24.2 | 80.1 |
15k | 54.0 | >100.0 |
用磺酰罗丹明B蛋白染色法(SRB法)法检测了化合物抑制肿瘤细胞增殖作用。结果表明,受试化合物均具有不同程度的抑制人肺癌A549细胞和人宫颈癌HeLa细胞增殖生长活性(表1);其中,化合物8p在细胞水平表现出了优异的癌细胞抑制活性,对A549和和HeLa细胞增殖生长抑制的IC50分别为3.5μM和4.1μM;8a-8s对2种细胞作用程度没有明显差异,15a-15k对两种细胞株作用有一定的差异性;其中化合物8p体外抗肿瘤活性较大黄酸强30倍以上。
Claims (10)
1.一种2位取代的5,7-二羟基蒽醌[2,1-d]噻唑化合物,其具有以下通式(I)所示的结构。
通式(I)
其中,
R1、R2选自以下基团:未取代或者由羟基取代的C1~C10直链或支链烷基,或者R1、R2和与它们相连的氮原子一起形成含有1~3个N、O或S原子的5~7元杂环,该杂环未被取代或者在碳或氮原子上被取代基R3取代;
其中,R3为羟基、未取代或由R4取代的C1~C10直链或支链烷基、C1~C10烷氧基羰基、羰基、未取代或由C1~C10烷基取代的氨基、C3~C8环烷基;
其中,R4为羟基、未取代或由C1~C10烷基取代的氨基、含有1~3个N、O或S原子的5~7元杂环,所述R4中的该杂环未被取代或者被C1~C10直链或支链烷基取代。
2.根据权利要求1所述的化合物,其中
R1、R2选自未取代或者由羟基取代的C1~C6直链或支链烷基,或者R1、R2和与它们相连的氮原子一起形成含有1~3个N、O或S原子的5~7元杂环,该杂环未被取代或者在碳或氮原子上被取代基R3取代;
其中,R3为未取代或由R4取代的C1~C6直链或支链烷基、未取代或由C1~C6烷基取代的氨基、C3~C6环烷基;
其中,R4为羟基、未取代或由C1~C6烷基取代的氨基、含有1~2个N或O原子的5~6元杂环,所述R4中的该杂环未被取代或者被C1~C6直链或支链烷基取代。
3.根据权利要求1所述的化合物,其中
R1、R2和与它们相连的氮原子一起形成
R3为未取代或由R4取代的乙基,
其中,R4为羟基、未取代或由C1~C10烷基取代的氨基、含有1~3个N、O或S原子的5~7元杂环,所述R4中的该杂环未被取代或者被C1~C10直链或支链烷基取代。
4.根据权利要求1所述的化合物,其中
所述化合物为以下化合物:
5.根据权利要求1所述的化合物,其中,所述化合物为以下化合物:
6.根据权利要求1所述的化合物的制备方法,该方法包括以下步骤:
a、将大黄酸1在碱作用下,以无水二甲基甲酰胺(DMF)做溶剂与碘甲烷反应得化合物2,其中所述碱为氢化钠、氢氧化钠、氢氧化钾或碳酸钠;
b、化合物2在碱水溶液中水解,生成化合物3,其中所述碱为氢氧化钠或氢氧化钾;
c、化合物3在三乙胺为碱的条件下与叠氮磷酸二苯酯反应生成化合物4;
d、化合物4在二氧六环溶液中回流,并用氢氧化钠水溶液回流,得到柯提斯重排后的化合物5;
e、化合物5在银盐催化作用下发生碘卤代反应得化合物6,其中银盐为硫酸银、醋酸银和碘化银;
f、化合物6在二甲基甲酰胺(DMF)作溶剂,碳酸钾催化下与胺NR1R2H及二硫化碳反应得到一系列产物7;
g、中间体7与三氯化铝、硫醇或者三溴化硼反应,脱甲基得一系列最终产物8;
其中,所述R1和R2与权利要求1中所述的化合物的R1和R2的定义相同。
7.根据权利要求6所述的方法,其中,通过以下步骤制备化合物13以得到上述步骤f中的部分试剂,然后,通过与上述的步骤f、g相类似的步骤e’、f’,制得不同的化合物15,其中,R4的定义与前述的化合物中的定义相同:
a’、将化合物9溶于四氢呋喃(THF)溶液与二碳酸二叔丁酯((Boc)2O)反应得化合物10;
b’、化合物10在二甲氨基吡啶(DMAP)催化下,以三乙胺作碱,在无水四氢呋喃(THF)溶液中与甲基磺酰氯反应,生成化合物11;
c’、化合物11在碘化钠催化条件下与取代胺反应生成化合物12;
d’、化合物12在二氯甲烷溶液中与三氟乙酸反应得到化合物13;
e’、化合物13与6在二甲基甲酰胺(DMF)作溶剂,碳酸钾催化下与胺及二硫化碳反应得到一系列产物14;
f’、中间体14与三溴化硼反应,脱甲基得一系列最终产物15。
8.一种药物组合物,其包括治疗有效量的如权利要求1中所述的通式(I)的化合物及药学上可接受的载体。
9.根据权利要求1所述的化合物或根据权利要求8所述的药物组合物在制备抗肿瘤药物中的用途。
10.根据权利要求9所述的用途,其中,所述的肿瘤包括:人肺癌A549和人宫颈癌HeLa。
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