CN118164913A - 茚并哌啶类衍生物及其制备方法和应用 - Google Patents
茚并哌啶类衍生物及其制备方法和应用 Download PDFInfo
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- CN118164913A CN118164913A CN202410328083.0A CN202410328083A CN118164913A CN 118164913 A CN118164913 A CN 118164913A CN 202410328083 A CN202410328083 A CN 202410328083A CN 118164913 A CN118164913 A CN 118164913A
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- halogen
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- alkyl
- phenyl
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- UAOQXXSUJPFVBK-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1h-indeno[2,1-b]pyridine Chemical class C12=CC=CC=C2CC2=C1CCCN2 UAOQXXSUJPFVBK-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 20
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Abstract
本发明公开了一类茚并哌啶类衍生物及其制备方法和在制备抗肿瘤药物中的应用。制备方法包括：茚类化合物、甲醛以及伯胺类化合物和/或其盐发生三组分Mannich反应，得到茚并哌啶类衍生物。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类茚并哌啶类衍生物及其制备方法和应用。
背景技术
茚并哌啶环化合物是天然产物与药物化学中的一种优势骨架，该类化合物往往具有重要的生物活性或药用价值，包括镇痛、麻醉、抑郁、过敏抗菌、抗病毒、抗炎、心血管保护等多种药理活性，并且在神经保护、肌肉松弛和免疫调节等方面具有潜在的应用价值。例如，Phenindamine是由罗氏原研的一种茚并哌啶环类化合物，属于组胺受体家族拮抗剂，主要通过阻断H1受体来发挥作用，被FDA批准用于超敏反应，治疗各种过敏反应引起的症状，如荨麻疹、皮肤瘙痒症等。此外，它还可能配合其他药物用于治疗震颤麻痹和伤风感冒等症状，且在一段时间内稳定地发挥治疗作用，无需频繁给药。CRIS148是一类抗锥虫活性的新型先导化合物，其体内实验结果表明，它在10μg/mL浓度下显示出超过70％的表皮内生鞭毛体抑制作用，并且表现出较低的细胞毒性。同时，该类化合物也可以作为mGluR2(代谢型受体-2亚型)的正性变构调节剂，用于治疗或者预防与谷氨酸功能障碍相关的神经病证和精神病症，以及其中涉及代谢受体mGluR2亚型的疾病。除此之外，该类茚并哌啶环化合物结构还在PDE5(5型磷酸二酯酶)抑制剂和Alpha-2C(肾上腺素能受体)抑制剂中得到应用，相关的化合物在体外实验中显示出抗肿瘤特性和调节神经传递和心血管功能的作用。
目前已经有许多研究团队对茚并哌啶类化合物的合成方法进行了设计和探讨。Castagnoli及其同事利用Arecoline与苯基溴化镁发生加成反应得到相应的酯，通过水解反应将酯水解成哌啶羧酸，所得的哌啶羧酸发生分子内环化形成三环酮中间体，在LiAlH4的条件下将三环酮中间体还原形成醇，该醇通过消除脱水和碱促进的异构化反应后得到最终茚并哌啶类化合物。Plati课题组利用苯乙酮、甲醛以及一级胺盐酸盐等基础原料通过Mannich反应(也称为曼尼希反应或胺甲基化反应)形成中间体哌啶衍生物，而后通过Dieckmann缩合反应进行环化得到三环中间体，该中间体在酸催化下还原形成茚并哌啶类结构。
多组分反应是一种有机合成方法，它能够将三种或多种起始原料通过一步法反应转化为单一的复杂产物。其中，Mannich反应是最为经典的多组分反应之一，是指具有活泼氢的化合物与不可烯醇化羰基化合物和一级或二级胺(氨)同时缩合，生成胺烷基化衍生物(通常称为席夫碱)的有机化学反应。它是有机合成的经典工具之一，在复杂天然产物及小分子药物的设计与合成中占据重要地位。
发明内容
本发明提供了一类具有抗肿瘤活性的茚并哌啶类衍生物，可通过易得的烷基茚类化合物经过两次Mannich反应环化得到，并仍保持天然氨基酸的手性，这在之前从未被报道过。
第一方面，本发明提供了具有式(I)所示结构的茚并哌啶类衍生物：
R0为氢、酯基、酰胺基、卤素、被一个或多个取代基取代或未取代的苯基、被一个或多个取代基取代或未取代的C1～C6烷基，所述苯基上的取代基分别独立选自C1～C6烷基、卤素、羟基、C1～C4烷氧基、酯基、叔胺基、酰胺基，所述C1～C6烷基上的取代基分别独立选自苯基、卤素、羟基、C1～C4烷氧基、酯基、叔胺基、酰胺基；
R1为H、C1～C6烷基、C1～C6烷氧基、苄氧基、C1～C6烷硫基、C1～C6烃胺基、羟基、卤素、酯基、酰胺基、硼酸酯基、被一个或多个取代基取代或未取代的苯基中的一个或者多个，所述苯基上的取代基分别独立选自C1～C6烷基、C1～C6烷氧基、苄氧基、C1～C6烷硫基、C1～C6烃胺基、羟基、卤素、酯基、酰胺基、硼酸酯基；
R4为被一个或多个取代基取代或未取代的C1～C6链烷基、被一个或多个取代基取代或未取代的C3～C6环烷基、所述C1～C6链烷基上的取代基分别独立选自C1～C4烷氧羰基、C1～C4烷氧基、噻吩基、C3～C6环烷基、呋喃基、苯基、羟基苯基、萘基、卤素、硝基苯基、炔基、C1～C4烷基磺酰基、烯基、酯基、酰胺基，所述C3～C6环烷基上的取代基分别独立选自C1～C4烷氧羰基、C1～C4烷氧基、噻吩基、C1～C6链烷基、呋喃基、苯基、羟基苯基、萘基、卤素、硝基苯基、炔基、C1～C4烷基磺酰基、烯基、酯基、酰胺基。
进一步的，所述的茚并哌啶类衍生物可选自以下任一化合物：
第二方面，本发明提供了一种茚并哌啶类衍生物的制备方法，包括：具有式(II)所示结构的茚类化合物、甲醛以及具有式(III)所示结构的伯胺类化合物和/或其盐发生三组分Mannich反应，得到具有式(IV)所示结构的茚并哌啶类衍生物；
R4-NH2(III)；
R1为H、C1～C6烷基、C1～C6烷氧基、苄氧基、C1～C6烷硫基、C1～C6烃胺基、羟基、卤素、酯基、酰胺基、硼酸酯基、被一个或多个取代基取代或未取代的苯基中的一个或者多个，所述苯基上的取代基分别独立选自C1～C6烷基、C1～C6烷氧基、苄氧基、C1～C6烷硫基、C1～C6烃胺基、羟基、卤素、酯基、酰胺基、硼酸酯基；
R2、R3分别独立选自氢、酯基、酰胺基、卤素、被一个或多个取代基取代或未取代的苯基、被一个或多个取代基取代或未取代的C1～C6烷基，所述苯基上的取代基分别独立选自C1～C6烷基、卤素、羟基、C1～C4烷氧基、酯基、叔胺基、酰胺基，所述C1～C6烷基上的取代基分别独立选自苯基、卤素、羟基、C1～C4烷氧基、酯基、叔胺基、酰胺基；
R4为被一个或多个取代基取代或未取代的C1～C6链烷基、被一个或多个取代基取代或未取代的C3～C6环烷基、所述C1～C6链烷基上的取代基分别独立选自C1～C4烷氧羰基、C1～C4烷氧基、噻吩基、C3～C6环烷基、呋喃基、苯基、羟基苯基、萘基、卤素、硝基苯基、炔基、C1～C4烷基磺酰基、烯基、酯基、酰胺基，所述C3～C6环烷基上的取代基分别独立选自C1～C4烷氧羰基、C1～C4烷氧基、噻吩基、C1～C6链烷基、呋喃基、苯基、羟基苯基、萘基、卤素、硝基苯基、炔基、C1～C4烷基磺酰基、烯基、酯基、酰胺基。
本发明设计茚并哌啶类衍生物的制备方法，通过一锅法高效快速地合成茚并哌啶类衍生物，其可包括如下过程：茚类化合物、甲醛以及伯胺类化合物和/或其盐发生三组分Mannich反应，反应完成后，可经后处理得到所述的茚并哌啶类衍生物。该制备方法通过两次Mannich反应，在温和的条件下实现了茚并哌啶类衍生物的快速合成，反应高效简洁快速，收率较高，对有机合成和药物化学具有深远意义。
第二方面所述的制备方法，所述具有式(IV)所示结构的茚并哌啶类衍生物可选自以下任一化合物：
第二方面所述的制备方法，所述茚类化合物、甲醛以及所述伯胺类化合物和/或其盐的摩尔比可为1:2～8:1～4，甲醛以及所述伯胺类化合物和/或其盐这两种组分过量可保证反应比较彻底。
第二方面所述的制备方法，所述反应可在溶剂中进行。进一步的，所述溶剂可包括乙腈、乙酸、乙醇、甲醇、丙酮、二氧六环、四氢呋喃、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺中的至少一种。
第二方面所述的制备方法，所述反应的温度可为60～80℃，优选80℃。反应温度过高会导致产物分解，反应温度过低会导致反应转化率过低。
第二方面所述的制备方法，所述反应的时间可以通过薄层层析(TLC)进行监测，一般进行1～24小时后，反应比较彻底。
第二方面所述的制备方法，所述伯胺类化合物的盐可包括盐酸盐、硫酸盐、氢溴酸盐中的至少一种。
第三方面，本发明提供了第一方面所述的茚并哌啶类衍生物或根据第二方面所述的制备方法制备得到的茚并哌啶类衍生物在制备抗肿瘤药物中的应用。所述肿瘤可为白血病、肺癌或乳腺癌。
第四方面，本发明提供了一种抗肿瘤药物组合物，包括有效量的第一方面所述的茚并哌啶类衍生物和/或根据第二方面所述的制备方法制备得到的茚并哌啶类衍生物，以及药学上可接受的辅料。所述肿瘤可为白血病、肺癌或乳腺癌。
本发明与现有技术相比，有益效果有：本发明提供了一类具有抗肿瘤活性的茚并哌啶类衍生物，以及一条快速合成茚并哌啶类衍生物的方法，在有机合成和药物化学领域具有很大的应用潜力。
附图说明
图1为实施例2所制得的产物的1H NMR谱图。
图2为实施例2所制得的产物的13C NMR谱图。
图3为实施例3所制得的产物的1H NMR谱图。
图4为实施例3所制得的产物的13C NMR谱图。
具体实施方式
下面结合附图及具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的操作方法，通常按照常规条件，或按照制造厂商所建议的条件。
实施例1：合成化合物(IIa)
在100mL两口瓶中加入茚酮(10mmol)，氩气置换三次后，加入20mL干燥的四氢呋喃溶解。在0℃下缓慢加入甲基氯化镁(30mmol)，滴加完毕后将反应转移到室温反应3-4小时。TLC检测反应转化完全后，反应液用饱和氯化铵水溶液淬灭，加入乙酸乙酯萃取三次，合并所得有机相，饱和食盐水洗，无水硫酸钠干燥，旋干得到粗品。另取单口瓶加入上述粗品(10mmol)和对甲苯磺酸(0.5mmol)，加入20mL甲醇溶解，并且在80℃下反应3小时。待反应完后，加入水，乙酸乙酯萃取三次，合并所得有机相，饱和食盐水洗，无水硫酸钠干燥，加入硅胶，经过柱层析分离(洗脱剂为石油醚)得到产物3-甲基茚(即化合物(IIa))910mg。收率70％。
实施例2：合成化合物(1a)
在干燥的反应管中加入3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和甘氨酸甲酯盐酸盐(0.4mmol)，加入1mL乙腈和1mL醋酸，80℃反应过夜。待反应完全后，加入碳酸氢钠饱和水溶液中和，乙酸乙酯萃取三次，合并所得有机相，饱和食盐水洗，无水硫酸钠干燥，加入硅胶，经过柱层析分离(洗脱剂为石油醚：乙酸乙酯＝10:1)可得产物36mg，收率为75％。
反应式如下：
产物的物理性质和谱图(图1、图2)数据如下：淡黄色液体，1H NMR(400MHz,Chloroform-d)δ7.40(d,J＝7.2Hz,1H),7.23(m,2H),7.14(m,1H),3.76(s,3H),3.59(s,2H),3.49(s,2H),3.28(s,2H),2.93(t,J＝5.6Hz,2H),2.63(t,J＝5.6Hz,2H).13C NMR(100MHz,Chloroform-d)δ171.1,144.9,142.6,138.1,134.7,126.2,124.2,123.6,117.9,58.7,52.8,51.9,49.9,38.7,22.9。
实施例3：合成化合物(1b)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和L-丙氨酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1b，得到产物35mg，收率为68％。
产物的谱图(图3、图4)数据如下：1H NMR(400MHz,Chloroform-d)δ7.38(d,J＝7.2Hz,1H),7.22(m,2H),7.13(m,1H),3.74(s,3H),3.61(s,2H),3.56(t,J＝7.2Hz,1H),3.27(s,2H),3.01–2.93(m,1H),2.89–2.78(m,1H),2.62–2.54(m,2H),1.43(d,J＝7.2Hz,3H).13C NMR(100MHz,Chloroform-d)δ173.8,145.0,142.7,138.7,134.9,126.2,124.1,123.5,117.8,62.2,51.6,49.5,46.6,38.8,23.6,15.1。
实施例4：合成化合物(1c)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和L-缬氨酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1c，得到产物38mg，收率为67％。
产物1H NMR(400MHz,Chloroform-d)δ7.38(d,J＝7.2Hz,1H),7.25–7.17(m,2H),7.12(m,1H),3.71(s,3H),3.53(s,2H),3.26(s,2H),2.99(dd,J＝11.2,6.0Hz,2H),2.75–2.62(m,1H),2.58–2.50(m,2H),2.20(m,1H),1.02(d,J＝6.8Hz,3H),0.92(d,J＝6.8Hz,3H).13C NMR(100MHz,Chloroform-d)δ172.5,145.2,142.7,139.3,134.9,126.2,124.0,123.5,117.8,74.1,50.8,50.1,46.0,38.8,27.2,23.8,19.9,19.5。
实施例5：合成化合物(1d)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和L-亮氨酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1d，得到产物41mg，收率为69％。
产物1H NMR(400MHz,Chloroform-d)δ7.38(d,J＝7.2Hz,1H),7.21(m,2H),7.12(m,1H),3.72(s,3H),3.60(s,2H),3.53–3.46(m,1H),3.26(s,2H),2.99(m,1H),2.81(m,1H),2.63–2.43(m,2H),1.81–1.70(m,1H),1.70–1.58(m,2H),0.95(d,J＝6.4Hz,3H),0.93(d,J＝6.4Hz,3H).13CNMR(100MHz,Chloroform-d)δ173.2,145.1,142.7,139.1,134.9,126.2,124.0,123.5,117.8,65.3,51.2,49.7,46.4,38.8,38.6,25.2,23.8,22.8,22.6。
实施例6：合成化合物(1e)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和L-异亮氨酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1e，得到产物42mg，收率为70％。
产物1H NMR(400MHz,Chloroform-d)δ7.38(d,J＝7.2Hz,1H),7.22(m,2H),7.12(m,1H),3.71(s,3H),3.53(s,2H),3.26(s,2H),2.99(dd,J＝11.2,5.6Hz,2H),2.77–2.61(m,1H),2.54(m,2H),2.19(m,1H),1.65(m,2H),1.02(d,J＝6.4Hz,3H),0.92(d,J＝6.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ172.5,145.2,142.7,134.9,126.2,123.9,123.5,117.7,100.0,77.4,74.1,50.8,50.1,46.0,38.8,27.2,23.8,19.9,19.4。
实施例7：合成化合物(1f)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和O-(叔丁基)-L-丝氨酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1f，得到产物48mg，收率为73％。
产物1H NMR(400MHz,Chloroform-d)δ7.38(d,J＝7.2Hz,1H),7.25–7.16(m,2H),7.12(m,1H),3.85(t,J＝8.4Hz,1H),3.74(s,3H),3.70(dd,J＝8.4,5.2Hz,1H),3.66(t,J＝2.4Hz,1H),3.64–3.56(m,2H),3.25(s,2H),3.04–2.86(m,2H),2.63–2.48(m,2H),1.19(s,9H).13C NMR(100MHz,Chloroform-d)δ171.7,145.1,142.6,138.8,134.9,126.2,124.1,123.5,117.8,73.4,67.7,61.1,51.4,50.6,47.5,38.8,27.5,23.6。
实施例8：合成化合物(1g)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和(S)-2-氨基丁酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1g，得到产物50mg，收率为80％。
产物1H NMR(400MHz,Chloroform-d)δ7.38(d,J＝7.2Hz,1H),7.26–7.17(m,2H),7.13(m,1H),4.00(dd,J＝8.8,6.4Hz,1H),3.78–3.71(m,4H),3.69(s,3H),3.56–3.46(m,1H),3.26(s,2H),3.07–2.90(m,2H),2.83–2.69(m,2H),2.58–2.48(m,2H).13C NMR(100MHz,Chloroform-d)δ171.9,171.5,144.9,142.6,138.6,134.8,126.2,124.2,123.5,117.8,63.2,51.9,51.7,49.9,46.7,38.7,34.4,23.8。
实施例9：合成化合物(1h)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和L-谷氨酸二甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1h，得到产物48mg，收率为71％。
产物1H NMR(400MHz,Chloroform-d)δ7.39(d,J＝7.2Hz,1H),7.22(m,2H),7.13(m,1H),3.73(s,3H),3.69–3.59(m,4H),3.54–3.42(m,2H),3.26(s,2H),3.09–2.97(m,1H),2.85–2.70(m,1H),2.59–2.48(m,2H),2.44(t,J＝7.2Hz,2H),2.26–2.01(m,2H).13C NMR(100MHz,Chloroform-d)δ173.7,172.4,145.1,142.7,138.9,134.9,126.2,124.1,123.5,117.8,66.1,51.6,51.3,49.6,46.5,38.7,30.8,24.4,23.7。
实施例10：合成化合物(1i)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和L-苯丙氨酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1i，得到产物42mg，收率为63％。
产物1H NMR(400MHz,Chloroform-d)δ7.39(d,J＝7.2Hz,1H),7.32–7.17(m,7H),7.13(m,1H),3.73–3.64(m,3H),3.62(s,3H),3.27(s,2H),3.21(dd,J＝13.2,9.6Hz,1H),3.12–3.01(m,2H),2.87(m,1H),2.65–2.52(m,2H).13C NMR(100MHz,Chloroform-d)δ172.0,145.0,142.7,138.7,138.1,134.9,129.2,128.5,126.6,126.2,124.1,123.6,117.8,69.3,51.3,49.9,46.8,38.8,36.1,23.8。
实施例11：合成化合物(1j)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和L-酪氨酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1j，得到产物45mg，收率为65％。
产物1H NMR(400MHz,Chloroform-d)δ7.39(m,1H),7.25–7.18(m,2H),7.14(m,1H),7.10–7.02(m,2H),6.75–6.68(m,2H),3.65(dd,J＝8.8,3.6Hz,2H),3.62(s,3H),3.28(s,2H),3.14(dd,J＝13.2,10.0Hz,1H),3.09–2.94(m,3H),2.88(m,1H),2.65–2.52(m,2H).13C NMR(100MHz,Chloroform-d)δ172.1,154.4,144.9,142.7,138.6,134.9,130.4,129.9,126.2,124.2,123.5,117.8,115.4,69.6,60.5,51.3,49.9,46.9,38.8,35.2,23.7,21.1。
实施例12：合成化合物(1k)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和甲胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1k，得到产物34mg，收率为91％。
产物1H NMR(400MHz,Chloroform-d)δ7.40(d,J＝7.2Hz,1H),7.27–7.19(m,2H),7.14(m,1H),3.41(s,2H),3.29(s,2H),2.78(t,J＝5.6Hz,2H),2.66–2.59(t,J＝5.6Hz,2H),2.52(s,3H).13C NMR(100MHz,Chloroform-d)δ144.9,142.7,138.2,134.6,126.3,124.2,123.6,117.9,55.2,52.0,45.6,38.7,22.9。
实施例13：合成化合物(1l)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和乙胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1l，得到产物35mg，收率为89％。
产物1H NMR(400MHz,Chloroform-d)δ7.41(d,J＝7.2Hz,1H),7.28–7.21(m,2H),7.20–7.14(m,1H),3.62(s,2H),3.31(s,2H),2.98(t,J＝5.6Hz,2H),2.82(q,J＝7.2Hz,2H),2.74–2.68(t,J＝5.6Hz,2H),1.30(t,J＝6.8Hz,3H).13C NMR(100MHz,Chloroform-d)δ144.4,142.6,134.9,133.6,126.4,124.6,123.6,118.1,52.1,51.3,49.3,38.8,21.9,11.6。
实施例14：合成化合物(1m)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和环丁胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1m，得到产物33mg，收率为73％。
产物1H NMR(400MHz,Chloroform-d)δ7.42(d,J＝7.2Hz,1H),7.26(m,2H),7.17(m,1H),3.32(m,4H),3.00(p,J＝8.0Hz,1H),2.68(m,2H),2.62(m,2H),2.21–2.12(m,2H),2.12–1.96(m,2H),1.88–1.67(m,2H).13C NMR(100MHz,Chloroform-d)δ145.1,142.7,134.9,126.2,124.1,123.5,117.9,59.8,49.7,46.1,38.8,29.8,27.7,22.8,14.6。
实施例15：合成化合物(1n)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和环己胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1n，得到产物34mg，收率为69％。
产物1H NMR(400MHz,Chloroform-d)δ7.38(d,J＝7.2Hz,1H),7.22(dd,J＝15.6,7.2Hz,2H),7.12(td,J＝7.2,1.2Hz,1H),3.56(s,2H),3.27(s,2H),2.87(t,J＝5.6Hz,2H),2.57(dq,J＝6.0,2.8Hz,2H),2.53–2.47(m,1H),2.03–1.55(m,8H),1.43–1.19(m,2H).13CNMR(100MHz,Chloroform-d)δ145.2,142.7,135.1,126.1,123.9,123.4,117.7,63.2,49.0,46.0,38.9,29.7,29.0,26.4,26.0,23.7。
实施例16：合成化合物(1o)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和氯乙胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1o，得到产物36mg，收率为77％。
产物1H NMR(400MHz,Chloroform-d)δ7.44(d,J＝7.6Hz,1H),7.26(m,2H),7.18(m,1H),3.74(t,J＝7.2Hz,2H),3.56(s,2H),3.32(s,2H),3.00(t,J＝7.2Hz,2H),2.91(t,J＝5.6Hz,2H),2.65(t,J＝5.6Hz,2H).13C NMR(100MHz,Chloroform-d)δ144.8,142.6,135.0,130.9,126.3,124.3,123.6,117.9,68.2,59.3,53.4,50.2,41.3,38.8。
实施例17：合成化合物(1p)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和氯丙胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1p，得到产物36mg，收率为72％。
产物1H NMR(400MHz,Chloroform-d)δ7.40(d,J＝7.2Hz,1H),7.27–7.17(m,2H),7.14(m,1H),3.66(t,J＝6.4Hz,2H),3.44(s,2H),3.28(s,2H),2.80(t,J＝5.6Hz,2H),2.76–2.68(m,2H),2.64–2.54(m,2H),2.17–2.01(m,2H).13C NMR(100MHz,Chloroform-d)δ144.9,142.7,135.0,128.0,126.3,124.3,123.6,117.9,55.1,53.5,50.2,43.3,38.8,30.3,29.8。
实施例18：合成化合物(1q)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和苯基甲胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1q，得到产物39mg，收率为73％。
产物1H NMR(400MHz,Chloroform-d)δ7.44–7.26(m,5H),7.31–7.26(m,1H),7.21(m,2H),7.13(m,1H),3.73(s,2H),3.40(s,2H),3.24(s,2H),2.79(t,J＝5.6Hz,2H),2.58(t,J＝5.6Hz,2H).13C NMR(100MHz,Chloroform-d)δ145.1,142.8,138.9,138.4,135.0,129.3,128.4,127.2,126.2,124.1,123.5,117.9,62.7,53.5,49.9,38.8,23.1。
实施例19：合成化合物(1r)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和(4-硝基苯基)甲胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1r，得到产物40mg，收率为65％。
产物1H NMR(400MHz,Chloroform-d)δ8.24–8.18(m,2H),7.59(d,J＝8.8Hz,2H),7.40(m,1H),7.26(d,J＝2.8Hz,1H),7.23(m,1H),7.15(m,1H),3.82(s,2H),3.42(s,2H),3.26(s,2H),2.80(t,J＝5.6Hz,2H),2.60(t,J＝5.6Hz,2H).13C NMR(100MHz,Chloroform-d)δ147.3,146.6,144.9,142.6,138.3,135.0,129.6,126.3,124.3,123.7,123.6,117.9,61.7,53.6,50.1,38.8,23.0。
实施例20：合成化合物(1s)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和炔丙胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1s，得到产物30mg，收率为70％。
产物1H NMR(400MHz,Chloroform-d)δ7.44(d,J＝7.2Hz,1H),7.29–7.23(m,2H),7.18(m,1H),3.59(d,J＝2.4Hz,4H),3.33(s,2H),2.92(t,J＝5.6Hz,2H),2.67(t,J＝5.6Hz,2H),2.33(t,J＝2.4Hz,1H).13C NMR(100MHz,Chloroform-d)δ144.9,142.7,138.5,134.5,126.2,124.2,123.6,117.9,73.4,51.7,48.9,46.5,38.8,23.2。
实施例21：合成化合物(1t)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和2-(甲磺酰基)乙烷-1-胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1t，得到产物39mg，收率为70％。
产物1H NMR(400MHz,Chloroform-d)δ7.41(d,J＝7.2Hz,1H),7.31–7.26(m,1H),7.22(d,J＝7.2Hz,1H),7.16(m,1H),3.48(s,2H),3.29(s,2H),3.25(t,J＝6.4Hz,2H),3.11(t,J＝6.4Hz,2H),3.04(s,3H),2.84(t,J＝5.6Hz,2H),2.59(t,J＝5.6Hz,2H).13C NMR(100MHz,Chloroform-d)δ144.6,142.6,137.9,134.9,126.4,124.5,123.7,117.9,53.3,52.7,51.4,49.9,42.6,38.8,23.0。
实施例22：合成化合物(1u)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和2-苯基乙烷-1-胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1u，得到产物36mg，收率为65％。
产物1H NMR(400MHz,Chloroform-d)δ7.39(m,1H),7.30–7.27(m,2H),7.26–7.23(m,2H),7.17(m,4H),3.40(s,2H),3.34(d,J＝2.4Hz,2H),2.81(dd,J＝9.6,6.4Hz,2H),2.62(dd,J＝9.6,6.4Hz,2H),2.30(m,2H),2.09(t,J＝2.0Hz,2H).13C NMR(100MHz,Chloroform-d)δ146.9,143.1,140.6,139.5,128.8,128.4,126.2,126.1,125.9,124.4,123.4,118.6,59.4,55.5,42.6,40.4,34.0,10.5。
实施例23：合成化合物(1v)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和2-(噻吩-2-基)乙烷-1-胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1v，得到产物35mg，收率为62％。
产物1H NMR(400MHz,Chloroform-d)δ7.40(d,J＝7.2Hz,1H),7.30–7.27(m,1H),7.25–7.20(m,1H),7.14(m,2H),6.94(dd,J＝5.2,3.2Hz,1H),6.88–6.85(m,1H),3.51(s,2H),3.29(s,2H),3.15(dd,J＝9.2,6.8Hz,2H),2.95–2.83(m,4H),2.63(m,2H).13C NMR(100MHz,Chloroform-d)δ145.1,142.7,138.7,135.0,126.7,126.2,124.7,124.4,124.1,123.6,123.5,117.9,59.8,53.4,50.2,38.8,28.3,23.2。
实施例24：合成化合物(1w)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和环丙基甲胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1w，得到产物30mg，收率为67％。
产物1H NMR(400MHz,Chloroform-d)δ7.39(d,J＝7.2Hz,1H),7.24–7.19(m,2H),7.14(m,1H),3.54(s,2H),3.29(s,2H),2.90(t,J＝5.6Hz,2H),2.63(t,J＝5.6Hz,2H),2.51(d,J＝6.8Hz,2H),1.08–0.96(m,1H),0.59(q,J＝4.8Hz,2H),0.20(q,J＝4.8Hz,2H).13CNMR(100MHz,Chloroform-d)δ144.9,142.7,138.3,134.9,126.2,124.2,123.5,117.9,63.0,53.1,50.1,38.9,22.8,8.7,4.2。
实施例25：合成化合物(1x)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和环戊基-1,3-二烯-1-基乙胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1x，得到产物35mg，收率为70％。
产物1H NMR(400MHz,Chloroform-d)δ7.40(dd,J＝2.0,0.8Hz,1H),7.37(d,J＝7.2Hz,1H),7.21(dd,J＝16.4,7.2Hz,2H),7.12(m,1H),6.34(dd,J＝3.2,2.0Hz,1H),6.27(d,J＝3.2Hz,1H),3.77(s,2H),3.43(s,2H),3.25(s,2H),2.83(t,J＝5.6Hz,2H),2.59(t,J＝5.6Hz,2H).13C NMR(100MHz,Chloroform-d)δ152.0,145.1,142.7,142.3,138.6,134.9,126.2,124.1,123.5,117.8,110.1,108.7,54.2,52.8,49.7,38.8,22.9。
实施例26：合成化合物(1y)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和1-氨基环丙烷-1-甲酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1y，得到产物23mg，收率为40％。
产物1H NMR(400MHz,Chloroform-d)δ7.38(d,J＝7.2Hz,1H),7.21(dd,J＝19.2,7.6Hz,2H),7.11(t,J＝7.2Hz,1H),4.15(q,J＝6.8Hz,2H),3.87(s,2H),3.27(s,3H),2.48(s,2H),1.37(d,J＝3.6Hz,2H),1.26(t,J＝6.8Hz,4H),1.08(s,2H).13C NMR(100MHz,Chloroform-d)δ174.4,145.4,142.7,139.6,134.9,126.1,123.9,123.6,123.5,117.7,60.4,49.1,47.1,45.5,38.7,24.2,19.2,14.4。
实施例27：合成化合物(1z)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和(R)-1-苯基乙烷-1-胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1z，得到产物42mg，收率为76％。
产物1H NMR(400MHz,Chloroform-d)δ7.41–7.30(m,4H),7.29–7.16(m,4H),7.11(m,1H),3.65–3.53(m,2H),3.32(m,1H),3.24(s,2H),2.90–2.78(m,1H),2.68–2.56(m,1H),2.55–2.43(m,2H),1.49(d,J＝6.8Hz,3H).13C NMR(100MHz,Chloroform-d)δ145.1,144.2,142.8,139.1,135.2,128.4,127.7,127.1,126.2,124.0,123.5,117.8,64.5,51.0,47.5,38.9,23.3,20.3。
实施例28：合成化合物(1aa)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和(R)-1-(萘-1-基)乙烷-1-胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1aa，得到产物49mg，收率为75％。
产物1H NMR(400MHz,Chloroform-d)δ8.48–8.39(m,1H),7.91–7.85(m,1H),7.77(d,J＝8.0Hz,1H),7.71(d,J＝7.2Hz,1H),7.51–7.44(m,3H),7.37(d,J＝7.2Hz,1H),7.28–7.21(m,1H),7.18(d,J＝7.2Hz,1H),7.12(m,1H),4.36(q,J＝6.8Hz,1H),3.70(d,J＝16.4Hz,1H),3.38(m,1H),3.24(s,2H),2.97–2.86(m,1H),2.78–2.63(m,1H),2.61–2.51(m,1H),2.49–2.38(m,1H),1.59(d,J＝6.8Hz,3H).13C NMR(100MHz,Chloroform-d)δ145.2,142.8,135.3,134.1,131.7,128.9,127.4,126.2,125.7,125.7,125.4,124.6,124.0,123.9,123.5,117.8,51.3,48.0,38.9,23.4,19.9。
实施例29：合成化合物(1ab)
以3-甲基茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和1-(2,6-二甲基苯氧基)丙-2-胺盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1ab，得到产物42mg，收率为61％。
产物1H NMR(400MHz,Chloroform-d)δ7.39(d,J＝7.2Hz,1H),7.25–7.19(m,2H),7.13(m,1H),7.02(s,1H),7.00(s,1H),6.92(dd,J＝8.0,6.8Hz,1H),3.99(dd,J＝9.2,5.2Hz,1H),3.77(dd,J＝9.2,6.4Hz,1H),3.68(s,2H),3.38–3.21(m,3H),2.97(m,2H),2.71–2.47(m,2H),2.31(s,6H),1.35(d,J＝6.8Hz,3H).13C NMR(100MHz,Chloroform-d)δ155.9,142.7,139.4,139.3,135.2,130.9,128.9,126.2,124.0,123.9,123.5,117.8,73.9,58.9,49.8,45.9,38.9,23.8,16.5,12.9。
实施例30：合成化合物(1ac)
在干燥的反应管中加入1w(0.2mmol,1equiv.)、4-叠氮硝基苯(0.22mmol,1.1equiv.)、三乙胺(0.4mmol,2equiv.)和碘化亚铜(0.01mmol.0.05equiv.)。加入2mL二氯甲烷溶解，室温反应2小时。待反应完全后，旋干溶剂，加入硅胶，经过柱层析分离得到1ac，得到产物49mg，收率为66％(两步收率)。
产物1H NMR(400MHz,Chloroform-d)δ8.45–8.37(m,2H),8.15(s,1H),8.02–7.94(m,2H),7.39(d,J＝7.2Hz,1H),7.25–7.19(m,2H),7.14(m,1H),4.01(s,2H),3.55(s,2H),3.27(s,2H),2.92(t,J＝5.6Hz,2H),2.62(t,J＝5.6Hz,2H).13C NMR(100MHz,Chloroform-d)δ147.2,146.9,144.8,142.7,141.3,138.2,134.9,126.3,125.6,124.3,123.6,120.7,120.4,117.9,53.3,52.8,50.1,38.8,23.1。
实施例31：合成化合物(1ad)
以3,6-二甲基-1H-茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和甘氨酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1ad，得到产物44mg，收率为85％。
产物1H NMR(400MHz,Chloroform-d)δ7.23–7.19(m,1H),7.12–7.08(m,1H),7.08–7.05(m,1H),3.76(s,3H),3.56(s,2H),3.47(s,2H),3.23(s,2H),2.92(t,J＝5.6Hz,2H),2.60(t,J＝5.6Hz,2H),2.37(s,3H).13CNMR(100MHz,Chloroform-d)δ171.1,142.9,142.3,136.9,134.5,133.8,126.8,124.6,117.5,58.7,52.8,51.8,49.9,38.6,22.9,21.5。
实施例32：合成化合物(1ae)
以6-甲氧基-3-甲基-1H-茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和甘氨酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1ae，得到产物49mg，收率为89％。
产物1H NMR(400MHz,Chloroform-d)δ7.09(d,J＝8.4Hz,1H),7.03–6.98(m,1H),6.87–6.73(m,1H),3.81(s,3H),3.75(s,3H),3.54(s,2H),3.46(s,2H),3.24(s,2H),2.90(t,J＝5.6Hz,2H),2.64–2.52(t,J＝5.6Hz,2H).13C NMR(100MHz,Chloroform-d)δ171.1,157.5,144.5,138.2,135.8,134.2,118.0,111.3,110.7,58.8,55.6,52.8,51.8,49.9,38.8,22.9。
实施例33：合成化合物(1af)
以6-(苄氧基)-3-甲基-1H-茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和甘氨酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1af，得到产物56mg，收率为80％。
产物1H NMR(400MHz,Chloroform-d)δ7.47–7.29(m,6H),7.08(s,1H),6.88(dd,J＝8.0,2.4Hz,1H),5.07(s,2H),3.75(s,3H),3.53(s,2H),3.46(s,2H),3.23(s,2H),2.90(t,J＝5.6Hz,2H),2.58(t,J＝5.6Hz,2H).13CNMR(100MHz,Chloroform-d)δ171.2,156.8,144.5,138.5,137.4,136.0,134.2,128.6,127.9,127.5,118.0,112.4,111.7,70.5,58.8,52.8,51.8,49.9,38.8,22.9。
实施例34：合成化合物(1ag)
以3,5-二甲基-1H-茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和甘氨酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1ag，得到产物41mg，收率为79％。
产物1H NMR(400MHz,Chloroform-d)δ7.28(s,1H),7.03(d,J＝1.6Hz,1H),6.96(d,J＝7.6Hz,1H),3.76(s,3H),3.57(s,2H),3.48(s,2H),3.23(s,2H),2.92(t,J＝5.6Hz,2H),2.60(t,J＝5.6Hz,2H),2.38(s,3H).13CNMR(100MHz,Chloroform-d)δ173.9,145.2,138.3,136.9,135.8,124.9,123.2,118.9,118.7,58.7,52.9,51.8,49.9,38.4,29.7,21.6。
实施例35：合成化合物(1ah)
以3-甲基-5-苯基-1H-茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和甘氨酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1ah，得到产物31mg，收率为49％。
产物1H NMR(400MHz,Chloroform-d)δ7.62(d,J＝7.6Hz,2H),7.50–7.40(m,4H),7.39–7.30(m,2H),3.77(s,3H),3.60(s,2H),3.48(s,2H),3.32(s,2H),2.94(t,J＝5.6Hz,2H),2.71–2.60(t,J＝5.6Hz,2H).13C NMR(100MHz,Chloroform-d)δ171.1,145.7,141.9,141.8,139.7,138.9,134.7,128.7,127.3,126.9,123.7,123.4,116.8,52.9,51.8,49.9,38.5,29.8,22.9。
实施例36：合成化合物(1ai)
以5,6-二甲氧基-3-甲基-1H-茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和甘氨酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1ai，得到产物53mg，收率为87％。
产物1H NMR(400MHz,Chloroform-d)δ7.02(s,1H),6.77(s,1H),3.91(s,3H),3.89(s,3H),3.76(s,3H),3.55(s,2H),3.46(s,2H),3.21(s,2H),2.91(t,J＝5.6Hz,2H),2.63–2.55(t,J＝5.6Hz,2H).13C NMR(100MHz,Chloroform-d)δ171.2,148.3,146.7,137.9,136.8,134.9,134.3,108.4,102.1,58.8,56.4,56.2,52.9,51.8,49.9,38.6,23.1。
实施例37：合成化合物(1aj)
以3-乙基-1H-茚(0.2mmol)、甲醛水溶液(37％,5equiv.)和甘氨酸甲酯盐酸盐(0.4mmol)为原料，参考1a的合成方法制备1aj，得到产物30mg，收率为59％。
产物1H NMR(400MHz,Chloroform-d)δ7.39(d,J＝7.2Hz,1H),7.28–7.21(m,2H),7.13(m,1H),3.75(s,3H),3.63–3.55(m,1H),3.52–3.48(m,1H),3.47–3.43(m,2H),3.34–3.19(m,2H),2.95–2.85(m,2H),2.67–2.52(m,1H),1.34(d,J＝6.8Hz,3H).13C NMR(100MHz,Chloroform-d)δ171.2,144.5,143.0,139.3,137.9,126.1,123.9,123.7,118.8,58.8,57.7,53.1,51.7,38.7,29.0,17.9。
生物实验实施例1：抗肿瘤活性评价
本发明的式(I)具有重要的抗肿瘤细胞增殖的生物活性，选取人白血病细胞株MV4-11、人肺癌细胞A549、人乳腺癌细胞MDA-MB-231，利用MTT检测了上述化合物对以上肿瘤细胞的体外抑制活性实验。
收集处于对数生长期的细胞，以3×103个/孔的密度接种于96孔板中，置于37℃、5％CO2的细胞培养箱中培养24h。次日，吸弃孔内旧培养基，用RPMI-1640培养基稀释经二甲基亚砜DMSO溶解的待测化合物到相应浓度并加入到96孔板中，每孔100μL，每个浓度设3个复孔，每块板同时设置正常细胞组(只含细胞和1640培养基)和空白对照组(不含细胞只含培养基)。给药后将96孔板置于37℃、5％CO2的细胞培养箱中孵育。72小时候，每孔加20μL的MTT(噻唑蓝)溶液(5mg/mL)，再次孵育1.5h。随后，去掉孔板中的培养基，每孔加入150μLDMSO，置于水平振荡仪上中速振荡5min，使用酶标仪检测562nm波长下的吸光度。利用相应的计算公式计算抑制率并统计化合物对个细胞的半数抑制浓度，各数据重复三次，并计算平均值，结果见表1。
表1
表1中：+表示＞10μM，++表示≥1μM至≤10μM，+++表示＞0.1μM至＜1μM，-表示没有抑制活性。
实验结论，以上述部分化合物为代表的本发明所述的茚并哌啶类衍生物对人白血病细胞株MV4-11、人肺癌细胞A549以及人乳腺癌细胞MDA-MB-231表现出明显的体外抑制作用，有可能发展成为新的具有抗肿瘤作用的药物。
此外应理解，在阅读了本发明的上述描述内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.具有式(I)所示结构的茚并哌啶类衍生物：
R0为氢、酯基、酰胺基、卤素、被一个或多个取代基取代或未取代的苯基、被一个或多个取代基取代或未取代的C1～C6烷基，所述苯基上的取代基分别独立选自C1～C6烷基、卤素、羟基、C1～C4烷氧基、酯基、叔胺基、酰胺基，所述C1～C6烷基上的取代基分别独立选自苯基、卤素、羟基、C1～C4烷氧基、酯基、叔胺基、酰胺基；
R1为H、C1～C6烷基、C1～C6烷氧基、苄氧基、C1～C6烷硫基、C1～C6烃胺基、羟基、卤素、酯基、酰胺基、硼酸酯基、被一个或多个取代基取代或未取代的苯基中的一个或者多个，所述苯基上的取代基分别独立选自C1～C6烷基、C1～C6烷氧基、苄氧基、C1～C6烷硫基、C1～C6烃胺基、羟基、卤素、酯基、酰胺基、硼酸酯基；
R4为被一个或多个取代基取代或未取代的C1～C6链烷基、被一个或多个取代基取代或未取代的C3～C6环烷基、所述C1～C6链烷基上的取代基分别独立选自C1～C4烷氧羰基、C1～C4烷氧基、噻吩基、C3～C6环烷基、呋喃基、苯基、羟基苯基、萘基、卤素、硝基苯基、炔基、C1～C4烷基磺酰基、烯基、酯基、酰胺基，所述C3～C6环烷基上的取代基分别独立选自C1～C4烷氧羰基、C1～C4烷氧基、噻吩基、C1～C6链烷基、呋喃基、苯基、羟基苯基、萘基、卤素、硝基苯基、炔基、C1～C4烷基磺酰基、烯基、酯基、酰胺基。
2.根据权利要求1所述的茚并哌啶类衍生物，其特征在于，选自以下任一化合物：
3.一种茚并哌啶类衍生物的制备方法，其特征在于，包括：具有式(II)所示结构的茚类化合物、甲醛以及具有式(III)所示结构的伯胺类化合物和/或其盐发生三组分Mannich反应，得到具有式(IV)所示结构的茚并哌啶类衍生物；
R1为H、C1～C6烷基、C1～C6烷氧基、苄氧基、C1～C6烷硫基、C1～C6烃胺基、羟基、卤素、酯基、酰胺基、硼酸酯基、被一个或多个取代基取代或未取代的苯基中的一个或者多个，所述苯基上的取代基分别独立选自C1～C6烷基、C1～C6烷氧基、苄氧基、C1～C6烷硫基、C1～C6烃胺基、羟基、卤素、酯基、酰胺基、硼酸酯基；
R2、R3分别独立选自氢、酯基、酰胺基、卤素、被一个或多个取代基取代或未取代的苯基、被一个或多个取代基取代或未取代的C1～C6烷基，所述苯基上的取代基分别独立选自C1～C6烷基、卤素、羟基、C1～C4烷氧基、酯基、叔胺基、酰胺基，所述C1～C6烷基上的取代基分别独立选自苯基、卤素、羟基、C1～C4烷氧基、酯基、叔胺基、酰胺基；
R4为被一个或多个取代基取代或未取代的C1～C6链烷基、被一个或多个取代基取代或未取代的C3～C6环烷基、所述C1～C6链烷基上的取代基分别独立选自C1～C4烷氧羰基、C1～C4烷氧基、噻吩基、C3～C6环烷基、呋喃基、苯基、羟基苯基、萘基、卤素、硝基苯基、炔基、C1～C4烷基磺酰基、烯基、酯基、酰胺基，所述C3～C6环烷基上的取代基分别独立选自C1～C4烷氧羰基、C1～C4烷氧基、噻吩基、C1～C6链烷基、呋喃基、苯基、羟基苯基、萘基、卤素、硝基苯基、炔基、C1～C4烷基磺酰基、烯基、酯基、酰胺基。
4.根据权利要求3所述的制备方法，其特征在于，所述具有式(IV)所示结构的茚并哌啶类衍生物选自以下任一化合物：
5.根据权利要求3或4所述的制备方法，其特征在于，所述茚类化合物、甲醛以及所述伯胺类化合物和/或其盐的摩尔比为1:2～8:1～4。
6.根据权利要求3或4所述的制备方法，其特征在于，所述反应在溶剂中进行，所述溶剂包括乙腈、乙酸、乙醇、甲醇、丙酮、二氧六环、四氢呋喃、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺中的至少一种。
7.根据权利要求3或4所述的制备方法，其特征在于，所述反应的温度为60～80℃，时间为1～24小时。
8.根据权利要求3或4所述的制备方法，其特征在于，所述伯胺类化合物的盐包括盐酸盐、硫酸盐、氢溴酸盐中的至少一种。
9.根据权利要求1或2所述的茚并哌啶类衍生物或根据权利要求3～8任一项所述的制备方法制备得到的茚并哌啶类衍生物在制备抗肿瘤药物中的应用，其特征在于，所述肿瘤为白血病、肺癌或乳腺癌。
10.一种抗肿瘤药物组合物，其特征在于，包括有效量的权利要求1或2所述的茚并哌啶类衍生物和/或根据权利要求3～8任一项所述的制备方法制备得到的茚并哌啶类衍生物，以及药学上可接受的辅料。
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