CN109467549A - 喹啉取代查尔酮类化合物、其制备方法及用途 - Google Patents

喹啉取代查尔酮类化合物、其制备方法及用途 Download PDF

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CN109467549A
CN109467549A CN201811494253.3A CN201811494253A CN109467549A CN 109467549 A CN109467549 A CN 109467549A CN 201811494253 A CN201811494253 A CN 201811494253A CN 109467549 A CN109467549 A CN 109467549A
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quinoline
hydrogen
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chalcone compounds
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徐进宜
李文龙
徐盛涛
徐飞杰
帅雯
孙翃昊
朱哲英
姚鸿
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China Pharmaceutical University
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Abstract

本发明公开了一种喹啉取代查尔酮类新化合物、其可药用的盐，及其制备方法；还公开了一种药用组合物，其包含治疗有效量的喹啉取代查尔酮类新化合物和/或其可药用的盐，以及药学上可接收的载体。本发明还公开了一种微管蛋白抑制剂，其包含上述喹啉取代查尔酮类新化合物和/或其可药用的盐。本发明还公开上述喹啉取代查尔酮类新化合物和/或其可药用的盐在制备治疗包括但不限于结肠癌、白血病、肝癌、乳腺癌等疾病的药物中的应用。本申请化合物显示出优异的抗肿瘤活性，其代谢性质更为稳定，具有更好的成药性前景。

Description

喹啉取代查尔酮类化合物、其制备方法及用途
技术领域
本发明涉及药物化学领域，具体涉及一类具有抗肿瘤活性的喹啉取代查尔酮类化合物。本发明还公开了含有所述化合物的药用组合物和所述化合物在制备***以及通过抑制微管蛋白活性来治疗其他疾病或病症的药物中的应用。
背景技术
微管是细胞骨架的主要组成部分，在维持细胞形态、细胞***、信号转导等过程中起着重要作用，因此，微管蛋白是一个非常有前景的新型化疗药物的靶标。微管蛋白抑制剂能阻止肿瘤细胞的过度增殖，是一类重要的抗肿瘤治疗药物。目前，临床上应用的微管抑制剂主要有以紫杉醇为代表的抑制微管蛋白解聚药物及以长春碱类为代表的抑制微管蛋白聚集药物。而这些药物存在毒副作用大、合成难度大、水溶性差、易产生耐药性等缺点。
秋水仙碱结合位点是目前对微管蛋白研究较多的一个位点，作用于该位点的抑制剂通常结构较简单，如秋水仙碱、Combretastatin A-4等。此外，作用于该位点的抑制剂还能破坏肿瘤组织的血管，因此，对作用于秋水仙碱位点的微管蛋白抑制剂的研究已成为当今抗肿瘤研究的热点。
查尔酮类化合物是一类重要的微管蛋白抑制剂。Ducki等人于1998年在《Bioorganic&Medicinal Chemistry Letters》第8期1051-1056页发表了“Potentantimitotic and cell growth inhibitory properties of substituted chalcones”，该文发现了一种查尔酮化合物具有很高的抗肿瘤细胞增殖活性，并证实它具有抗微管蛋白聚集的作用。Xingshu Li等人于2016年在《Journal of Medicinal Chemistry》第 59期5264-5283页发表了“Synthesis,Evaluation,and Mechanism Study of Novel Indole-Chalcone Derivatives Exerting Effective Antitumor Activity ThroughMicrotubule Destabilization in Vitro and in Vivo”，该文发现了一类吲哚查尔酮类化合物，药理实验证明它们能有效地抑制微管蛋白的聚集，并具有较强的体外及体内抗肿瘤活性。
发明内容
发明目的：本发明提供给了一种喹啉取代查尔酮类新化合物、其可药用的盐，及其制备方法；还提供了一种药用组合物，其包含治疗有效量的喹啉取代查尔酮类新化合物和/或其可药用的盐，以及药学上可接收的载体。本发明还提供了一种微管蛋白抑制剂，其包含上述喹啉取代查尔酮类新化合物和/或其可药用的盐。本发明还公开上述喹啉取代查尔酮类新化合物和/或其可药用的盐在制备治疗包括但不限于结肠癌、白血病、肝癌、乳腺癌等疾病的药物中的应用。
技术方案：本发明公开的通式I或II所示的喹啉取代查尔酮类化合物、其可药用的盐：
其中：
R1选自氢、低级烷烃、羟基、甲氧基、卤素、氰基、酯基、酰胺基、羧基、仲氨基、叔氨基、羟甲基或醛基；
R2选自氢、低级烷烃、卤素、甲氧基、氰基、酯基、酰胺基或羧基；
R3选自甲氧基、甲硫基、氰基、低级烷烃、卤素、酯基或不同取代的氨基；
R4选自羟基、氨基、氟、磷酸酯基、磷酸二钠、糖苷、硼酸基、氨基酸酰胺基或(CH2)1- 6OH；
R5选自氢、低级烷烃、甲氧基、羟甲基、芳香或脂肪取代甲酰基；
通式II中，烯基取代的位置可在吲哚3位，4位，5位，6位或7位。
进一步的，R1优选氢、低级烷烃、羟基、甲氧基、卤素、氰基、酯基、酰胺基、羧基、仲氨基、叔氨基、羟甲基或醛基。
R2优选氢或甲基。
R3优选甲氧基或甲硫基。
R4优选羟基、氨基、氟或磷酸二钠。
R5选自氢或低级烷烃。
通式II中，烯基取代的位置优选吲哚3位，4位或5位。
进一步的，本发明的通式I或II的化合物优选为如下1-30的具体化合物：
本发明通式Ⅰ或II的化合物可用下列方法制备得到：
A.反应式解1合成步骤如下：
以靛红为起始原料，与丙酮缩合反应得到2-甲基喹啉-4-甲酸，制备成wenreib 酰胺后与甲基溴化镁反应可得中间体2-甲基-4-乙酰基喹啉；2-甲基喹啉-4-甲酸成酯后经NaBH4还原成醇，再经Dess-Martin试剂氧化成醛，随后与乙基溴化镁反应后，再经Dess-Martin试剂氧化可得中间体2-甲基-4-丙酰基喹啉。
B.反应式解2合成步骤如下：
以靛红为起始原料，与丙二酸在醋酸中缩合可得2-氧代-1,2-二氢喹啉-4-甲酸，然后经三氯氧磷氯代得2-氯喹啉-4-甲酸，再按照A的方法最终得到2-氯-4- 丙酰基喹啉。
C.反应式解3合成步骤如下：
以上路线得到的喹啉酮中间体与不同的醛发生缩合反应可得到目标产物喹啉取代查尔酮类化合物I或II。
有益效果：本发明所述的一种喹啉取代查尔酮类化合物，所述化合物可应用于制备***的药物，还可以用于制备通过抑制微管蛋白活性来治疗其他疾病或病症的药物。并且，本申请化合物显示出优异的抗肿瘤活性，其活性优于CA-4 和顺铂；抑制微管蛋白聚合作用显著好于阳性药CA-4；抑制肿瘤生长的活性高于CA-4和顺铂，并且相比于顺铂组，本申请化合物毒性更小，且相比于经典的 CA-4，其代谢性质更为稳定，具有更好的成药性前景。
具体实施方式
以下通过实施例形式展示具体的实施方式，对本发明内容进行进一步的详细说明，但不应当将此理解为本发明上述主题的范围仅限于以下的实施例，凡是基于本发明上述内容在本领域内所能实现的技术均应属于本发明的内容。
HepG2,KB,HCT-8,MDA-MB-231,K562南京凯基生物科技发展有限公司；
顺铂，CA-4 南京凯基生物科技发展有限公司。
实施例1
(E)-3-(1H-吲哚-5-基)丙基-1-(2-甲基喹啉-4-基)-2-烯基-1-酮
(a)将吲哚-2,3-二酮(10g,68mmol)与85％的KOH水溶液混合于50℃搅拌1h 后，滴入50mL丙酮，继续搅拌15h，旋去丙酮，稀盐酸调pH至3，抽滤，干燥得2-甲基喹啉-4-甲酸11g(白色固体，86.7％)；将2-甲基喹啉-4-甲酸(500mg, 2.7mml)溶于二氯甲烷中，分别加入二甲羟胺盐酸盐(310mg,3.2mmol)，三乙胺(440μL,3.2mmol)，EDCI(1g,5.4mmol)，催化量DMAP，室温搅拌2h 后加水稀释，二氯甲烷萃取(50mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后得N-甲氧基-N,2-二甲基喹啉-4-甲酰胺510mg，产率83.1％； (b)将N-甲氧基-N,2-二甲基喹啉-4-甲酰胺(500mg,2.7mmol)溶于无水THF中，氮气保护，冰浴条件下缓慢滴入3M的甲基溴化镁***溶液(2.2mL,5.9mmol)，室温反应2h后加水稀释，二氯甲烷萃取(50mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 2:1)得2-甲基-4-乙酰基喹啉420mg，产率84％；
(c)2-甲基-4-乙酰基喹啉(75mg,0.4mmol)与吲哚-5-甲醛(71mg,0.48mmol) 溶于乙醇中，加入氢氧化钠颗粒(80mg,2mmol)，室温搅拌1h后加水稀释，二氯甲烷萃取(50mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 2:1)得目标产物85mg，产率67.5％；1H NMR(300MHz,CDCl3) δ8.87(s,1H),8.02(d,J＝8.5Hz,1H),7.96(d,J＝8.4Hz,1H),7.72(s,1H),7.66- 7.56(m,2H),7.43(d,J＝7.4Hz,1H),7.36(m,3H),7.18-7.08(m,2H),6.48(s,1H), 2.70(s,3H)；13C NMR(75MHz,CDCl3)δ194.83,158.00,150.13,147.88,145.41, 137.28,129.46,128.48,127.87,126.23,125.55,125.27,124.83,123.20,122.64, 121.50,119.50,111.41,103.13,76.97,76.54,76.12,24.83；ESI-MS m/z:312.1calcd for C21H16N2O[M+H]+313.1.
实施例2
(E)-3-(1H-吲哚-4-基)丙基-1-(2-甲基喹啉-4-基)-2-烯基-1-酮
按照实施例1(c)的操作，得黄色固体63mg，产率50％；1H NMR(300MHz, CDCl3)δ9.11(s,1H),8.11(dd,J＝8.2,4.6Hz,2H),7.97(d,J＝16.1Hz,1H),7.78- 7.66(m,1H),7.53(d,J＝7.1Hz,1H),7.48(d,J＝3.4Hz,1H),7.44(m,2H),7.38(s, 1H),7.35-7.27(m,1H),7.19(t,J＝7.8Hz,1H),6.74(s,1H),2.81(s,3H)；13C NMR (75MHz,CDCl3)δ194.85,158.04,147.94,146.93,145.16,135.97,129.53,128.51, 126.78,126.33,125.77,125.64,124.84,122.58,121.44,119.69,114.10,100.73, 76.99,76.56,76.14,24.83；ESI-MS m/z:312.1calcd for C21H16N2O[M+H]+313.1.
实施例3
(E)-3-(3-羟基-4-甲氧基苯基)-1-(2-甲基喹啉-4-基)丙基-2-烯基-1-酮
按照实施例1(c)的操作，得黄色固体120mg，产率70.5％；1H NMR(300 MHz,DMSO)δ9.26(s,1H),8.03(d,J＝9.0Hz,2H),7.76(t,J＝7.6Hz,1H),7.65 (s,1H),7.57(t,J＝7.9Hz,1H),7.50(d,J＝16.0Hz,1H),7.33–7.22(m,2H),7.20 (d,J＝6.3Hz,1H),6.97(d,J＝8.4Hz,1H),3.83(s,3H),2.74(s,3H)；13C NMR(75 MHz,DMSO)δ193.80,158.59,150.87,147.82,147.55,146.77,144.27,129.66, 128.80,126.94,126.61,124.96,123.60,122.60,122.37,120.42,114.68,111.91, 55.65,40.34,40.06,39.79,39.51,39.23,38.95,38.68,24.81；ESI-MS m/z:319.1 calcd for C21H17NO3[M+H]+320.1.
实施例4
(E)-1-(3-羟基-4-甲氧基苯基)-3-(2-甲基喹啉-4-基)丙基-2-烯基-1-酮
将2-甲基喹啉-4-甲醛(50mg,0.29mmol)与2-甲氧基-4-乙酰基苯酚(48mg,0.29mmol)溶于无水乙醇中，加入氢氧化钠颗粒(58mg,1.45mmol)，室温搅拌一小时后，有红色固体析出，稀盐酸调pH至中性，抽滤，水洗，干燥得产物75mg，产率75.8％；1H NMR(300MHz,DMSO)δ8.26(d,J＝15.4Hz,1H),8.13(d,J＝8.2 Hz,1H),8.01(d,J＝15.4Hz,1H),7.92(s,1H),7.88(d,J＝8.3Hz,1H),7.67(dd,J ＝15.2,7.9Hz,2H),7.59–7.44(m,2H),6.97(d,J＝8.4Hz,1H),3.79(s,3H),2.62 (s,3H)；ESI-MS m/z:319.1calcd for C21H17NO3[M+H]+320.1.
实施例5
(E)-3-(6-甲氧基-1H-吲哚-3-基)-1-(2-甲基喹啉-4-基)丙基-2-烯基-1-酮
2-甲基-4-乙酰基喹啉(100mg,0.54mmol)与6-甲氧基吲哚-3-甲醛(114mg,0.65mmol)溶于乙醇中，滴入哌啶(87μL,1.08mmol)，90度搅拌24h后加水稀释，二氯甲烷萃取(50mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 2:1)得目标产物124mg，产率67.4％；1H NMR(300 MHz,DMSO)δ8.04(s,1H),8.01(s,2H),7.81(d,J＝15.8Hz,1H),7.75(d,J＝7.2 Hz,1H),7.63-7.52(m,2H),7.41(d,J＝9.1Hz,2H),7.18(d,J＝16.0Hz,1H),6.90 (dd,J＝8.7,2.1Hz,1H),3.83(s,3H),2.75(s,3H)；13C NMR(75MHz,DMSO)δ 187.69,159.12,153.34,148.40,147.82,140.03,136.66,130.74,130.01,129.44,128.48,126.85,124.61,123.63,122.32,119.66,115.45,111.61,56.20,25.27； ESI-MSm/z:342.1calcd for C22H18N2O2[M+H]+343.1.
实施例6
(E)-3-(1H-吲哚-5-基)-2-甲基-1-(2-甲基喹啉-4-基)丙基-2-烯基-1-酮
(a)2-甲基喹啉-4-甲酸(20g,107mml)溶于100mL二氯甲烷中，滴入催化量的 DMF，冰浴条件下缓慢滴入草酰氯(20mL,214mmol)，室温反应2h后加入甲醇 20mL，继续搅拌1h后旋去溶剂，加水稀释后二氯甲烷萃取(50mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得2-甲基喹啉-4-甲酸甲酯18g，产率85.7％；将2-甲基喹啉-4-甲酸甲酯(20g,100mmol)溶于甲醇中，冰浴条件分批加入NaBH4(11g,300mmol)，室温搅拌24h后，将反应液滴入到饱和氯化铵水溶液中，旋去甲醇后二氯甲烷萃(50mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得2-甲基喹啉-4-甲醇15g，产率88.2％；将2-甲基喹啉-4- 甲醇(15g,86.7mmol)溶于50mL DMSO中，加入IBX(26.7g,95.4mmol)，室温反应2h后将反应液倒入水中，乙酸乙酯萃取(50mL×3)，合并有机相，10％ NaOH水溶液洗三次，饱和食盐水洗，无水硫酸钠干燥，浓缩得2-甲基喹啉-4- 甲醛12g，产率80％；将2-甲基喹啉-4-甲醛(5g,29.1mmol)溶于无水THF中，氮气保护下缓慢注入3mol/L的乙基溴化镁的***溶液(12mL,34.8mmol)，室温反应2h后加水稀释，二氯甲烷萃取(50mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 2:1)得无色油状4.3g，产率74.1％；将上一步产物(2g,9.95mmol)溶于二氯甲烷中，加入戴斯马丁试剂(5.1g,11.9mmol) 室温搅拌2h后加水稀释，二氯甲烷萃取(50mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 2:1)得2-甲基-4-丙酰基喹啉1.3g，产率65.1％。
(b)将2-甲基-4-丙酰基喹啉(75mg,0.38mmol)与吲哚-5-甲醛(73mg,0.46mmol)溶于乙醇中，加入氢氧化钠颗粒(76mg,1.9mmol)，室温搅拌2h后加水稀释，二氯甲烷萃取(50mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 4:1)得黄色固体65mg，产率53.3％；1H NMR(300MHz,CDCl3) δ8.98(s,1H),8.09(d,J＝8.4Hz,1H),7.79(d,J＝8.3Hz,1H),7.72(s,1H),7.67(d, J＝7.2Hz,1H),7.46(t,J＝7.2Hz,1H),7.38-7.24(m,3H),7.19(d,J＝7.6Hz,2H), 6.54(s,1H),2.78(s,3H),2.45(s,3H)；13C NMR(75MHz,CDCl3)δ198.53,157.80, 148.99,147.57,146.47,135.92,134.36,129.44,128.41,127.60,126.46,126.03, 125.11,124.89,124.17,123.43,123.37,119.52,110.76,102.84,24.81,12.51； ESI-MS m/z:326.1calcd for C22H18N2O[M+H]+327.1.
实施例7
(E)-2-甲基-3-(1-甲基-1H-吲哚-5-基)-1-(2-甲基喹啉-4-基)丙基-2-烯基-1-酮
参照实施例6的合成方法，1H NMR(300MHz,CDCl3)δ8.38(s,1H),8.16(d, J＝8.4Hz,1H),7.98(d,J＝8.3Hz,1H),7.71-7.69(m,3H),7.34(d,J＝8.3Hz,1H), 7.25(s,1H),7.00(d,J＝7.3Hz,1H),5.94(s,1H),3.74(s,3H),2.68(s,3H),1.98(s, 3H)；13C NMR(75MHz,CDCl3)δ190.51,154.20,148.58,145.12,143.92,135.84, 134.20,128.40,127.41,126.27,126.58,125.09,124.99,124.57,123.33,120.90, 120.48,119.68,111.13,99.22,36.21,25.82,13.79；ESI-MS m/z:340.1calcd for C23H20N2O3[M+H]+341.1.
实施例8
(E)-3-(1H-吲哚-4-基)-2-甲基-1-(2-甲基喹啉-4-基)丙基-2-烯基-1-酮
参照实施例6的合成方法，1H NMR(300MHz,CDCl3)δ8.71(s,1H),8.02(d, J＝8.4Hz,1H),7.78(d,J＝8.3Hz,1H),7.63(t,J＝7.1Hz,1H),7.55(s,1H),7.42(t, J＝7.4Hz,1H),7.29(d,J＝8.0Hz,1H),7.26(s,1H),7.22(d,J＝7.3Hz,1H),7.14 (dd,J＝13.3,5.6Hz,1H),7.08-7.01(m,1H),5.94(s,1H),2.71(s,3H),2.31(s,3H)；13C NMR(75MHz,CDCl3)δ198.58,157.80,147.58,146.13,144.91,136.89,135.29, 129.49,128.49,127.27,126.53,126.08,124.90,124.67,123.37,121.20,120.48, 119.68,112.13,100.22,24.81,12.79；ESI-MS m/z:326.1calcd for C22H18N2O [M+H]+327.1.
实施例9
(E)-3-(6-甲氧基-1H-吲哚-3-基)-2-甲基-1-(2-甲基喹啉-4-基)丙基-2-烯基-1-酮
参照实施例6的合成方法，1H NMR(300MHz,DMSO)δ8.14(s,1H),8.01(s, 2H),7.75(d,J＝7.2Hz,1H),7.63–7.52(m,2H),7.41(d,J＝9.1Hz,2H),7.08(s, 1H),6.92(dd,J＝8.7,2.1Hz,1H),3.83(s,3H),2.75(s,3H),2.30(s,3H)；13C NMR (75MHz,DMSO)δ187.69,159.12,153.34,148.40,147.82,140.03,136.66,130.74, 130.01,129.44,128.48,126.85,124.61,123.63,122.32,119.66,115.45,111.61,56.20, 25.82,13.59；ESI-MS m/z:356.1calcd for C23H20N2O2[M+H]+357.1.
实施例10
(E)-3-(3-氨基-4-甲氧基苯基)-2-甲基-1-(2-甲基喹啉-4-基)丙基-2-烯基-1-酮
参照实施例6的合成方法，1H NMR(300MHz,CDCl3)δ8.00(d,J＝8.5Hz, 1H),7.64(m,2H),7.39(t,J＝7.4Hz,1H),7.17(d,J＝9.8Hz,1H),6.97(s,1H), 6.84–6.56(m,3H),3.79(s,3H),2.70(s,3H),2.28(s,3H)；13C NMR(75MHz, CDCl3)δ198.29,157.71,148.04,147.56,147.05,146.18,135.72,134.76,129.35, 128.50,127.69,125.95,124.78,123.32,121.43,119.44,115.79,109.56,76.93,76.50, 76.08,55.05,29.17,24.83；ESI-MS m/z:332.1calcd for C21H20N2O2[M+H]+333.1.
实施例11
(E)-3-(3-羟基-4-甲氧基苯基)-2-甲基-1-(2-甲基喹啉-4-基)丙基-2-烯基-1-酮
参照实施例6的合成方法，1H NMR(300MHz,CDCl3)δ8.08(d,J＝8.5Hz, 1H),7.76-7.67(m 2H),7.47(t,J＝7.6Hz,1H),7.24(s,1H),7.12-6.99(m,2H), 6.94-6.78(m,2H),3.89(s,3H),2.77(s,3H),2.35(s,3H)；13C NMR(75MHz, CDCl3)δ198.19,157.71,147.54,147.44,146.36,146.11,145.21,135.33,129.44, 128.39,128.07,126.03,124.75,123.30,123.06,119.50,115.76,110.05,76.94,76.52, 76.10,55.45,24.71,12.31；ESI-MS m/z:333.1calcd for C22H18N2O[M+H]+334.1.
实施例12
(E)-3-(3-氟-4-甲氧基苯基)-2-甲基-1-(2-甲基喹啉-4-基)丙基-2-烯基-1-酮
参照实施例6的合成方法，1H NMR(300MHz,CDCl3)δ8.08(d,J＝8.4Hz, 1H),7.76-7.69(m,2H),7.48(t,J＝7.6Hz,1H),7.24(s,1H),7.19(dd,J＝12.3,1.8 Hz,1H),7.09-7.06(m,2H),6.93(t,J＝8.5Hz,1H),3.90(s,3H),2.78(s,3H),2.35 (s,3H)；13C NMR(75MHz,CDCl3)δ198.03,157.72,147.64,145.61,144.67,136.08, 129.43,128.64,127.72,127.64,126.82,126.05,124.61,123.18,119.43,117.16, 116.91,112.58,55.73,24.86,12.30；ESI-MS m/z:335.1calcd for C21H18FNO2 [M+H]+336.1.
实施例13
(E)-3-(4-甲氧基苯基)-2-甲基-1-(2-甲基喹啉-4-基)丙基-2-烯基-1-酮
参照实施例6的合成方法，1H NMR(300MHz,CDCl3)δ8.01(d,J＝8.4Hz, 1H),7.71-7.57(m,2H),7.39(t,J＝7.6Hz,1H),7.26(d,J＝8.8Hz,2H),7.17(s, 1H),7.04(s,1H),6.82(d,J＝8.8Hz,2H),3.74(s,3H),2.71(s,3H),2.29(d,J＝1.0 Hz,3H)；13C NMR(75MHz,CDCl3)δ198.22,160.18,157.72,147.60,146.22, 146.02,134.97,131.65,129.38,128.56,127.28,125.98,124.74,123.29,119.44, 113.60,54.85,24.85,12.34；ESI-MS m/z:317.1calcd for C21H19NO2[M+H]+318.1.
实施例14
(E)-3-(3,4-二甲氧基苯基)-2-甲基-1-(2-甲基喹啉-4-基)丙基-2-烯基-1-酮
参照实施例6的合成方法，1H NMR(300MHz,CDCl3)δ8.01(d,J＝8.4Hz, 1H),7.74-7.55(m,2H),7.39(t,J＝7.6Hz,1H),7.28-7.26(m,2H),7.14(d,J＝ 13.8Hz,1H),7.04(s,1H),6.82(d,J＝8.8Hz,2H),3.74(s,3H),2.71(s,3H),2.29(d, J＝1.0Hz,3H)；13C NMR(75MHz,CDCl3)δ198.70,158.27,150.32,148.76, 148.10,146.95,146.48,135.67,129.95,129.04,127.98,126.54,125.25,124.15, 123.77,119.95,113.22,110.90,55.95,25.42,12.95；ESI-MS m/z:347.1calcd for C22H21NO3[M+H]+348.1.
实施例15
(E)-3-(4-甲硫基苯基)-2-甲基-1-(2-甲基喹啉-4-基)丙基-2-烯基-1-酮
参照实施例6的合成方法，1H NMR(300MHz,CDCl3)δ8.08(d,J＝8.4Hz, 1H),7.79-7.66(m,2H),7.49(dd,J＝11.2,4.0Hz,1H),7.30-7.19(m,5H),7.11(s, 1H),2.78(s,3H),2.48(s,3H),2.36(d,J＝1.0Hz,3H)；13C NMR(75MHz,CDCl3) δ198.72,158.25,148.09,146.29,146.24,141.39,136.77,131.48,130.62,129.97, 129.08,127.61,126.80,126.57,125.59,125.18,123.72,120.00,25.40,15.06,12.99； ESI-MS m/z:333.1calcdfor C21H19NOS[M+H]+334.1.
实施例16
(E)-3-(3-羟基-4-甲氧基苯基)-2-甲基-1-(2-氯喹啉-4-基)丙基-2-烯基-1-酮
a)将吲哚-2,3-二酮(10g,68mmol)与丙二酸(10.6g,102mmol)溶于80mL 冰醋酸中，回流反应12h后，抽滤，滤饼分别用丙酮，***洗，干燥得产物10.2 g，产率79.3％；
b)将上一步产物(10.2g,53.9mmol)溶于20mL三氯氧磷中，回流反应1h后，旋去三氯氧磷，将剩余物倒入冰水中，用饱和碳酸氢钠水溶液调pH至4-5，抽滤，水洗，干燥得2-氯喹啉-4-甲酸9.8g，产率87.5％；
c)2-氯喹啉-4-甲酸(9.8g,47mmol)溶于50mL二氯甲烷中，滴入催化量的 DMF，冰浴条件下缓慢滴入草酰氯(7.9mL,94mmol)，室温反应2h后加入甲醇20mL，继续搅拌1h后旋去溶剂，加水稀释后二氯甲烷萃取(50mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得2-氯喹啉-4-甲酸甲酯8.2g，产率78.2％；将2-甲基喹啉-4-甲酸甲酯(8.2g,37mmol)溶于甲醇中，冰浴条件分批加入NaBH4(4.2g,111mol)，室温搅拌24h后，将反应液滴入到饱和氯化铵水溶液中，旋去甲醇后二氯甲烷萃取(50mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得2-氯喹啉-4-甲醇5g，产率70.4％；将2-甲基喹啉-4-甲醇(5g,25.8mmol)溶于30mL DMSO中，加入IBX(8g,28.4mmol)，室温反应2h后将反应液倒入水中，乙酸乙酯萃取(50mL×3)，合并有机相，10％ NaOH水溶液洗三次，饱和食盐水洗，无水硫酸钠干燥，浓缩后得2-氯喹啉-4- 甲醛4.2g，产率84％；将2-甲基喹啉-4-甲醛(4.2g,22mmol)溶于无水THF中，氮气保护下缓慢注入3mol/L的乙基溴化镁的***溶液(15mL,44mmol)，室温反应2h后加水稀释，二氯甲烷萃取(50mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 2:1)得无色油状3.5g，产率72.9％；将上一步产物(2g,9mmol)溶于二氯甲烷中，加入戴斯马丁试剂(3g,10.8mmol) 室温搅拌2h后加水稀释，二氯甲烷萃取(50mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 2:1)得2-氯-4-丙酰基喹啉1.3g，产率65.0％。
(d)将2-氯-4-丙酰基喹啉(75mg,0.34mmol)溶于5mL乙醇中，分别加入MEM 保护的异香兰素(99mg,0.41mmol)及氢氧化钠颗粒(89mg,1.7mmol)，室温反应2h后加水稀释，二氯甲烷萃取(30mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA5:1)得油状108mg，产率71.5％；将该产物溶于2mL乙醇中，加入2滴浓盐酸，回流搅拌1h后用饱和碳酸氢钠水溶液中和，二氯甲烷萃取(50mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 2:1)得产物55mg，产率63.9％。1H NMR(300MHz, CDCl3)δ8.01(d,J＝8.4Hz,1H),7.78-7.63(m,2H),7.48(t,J＝7.6Hz,1H),7.28 (s,1H),7.00(s,2H),6.86–6.72(m,2H),5.67(s,1H),3.84(s,3H),2.29(s,3H)；13C NMR(75MHz,CDCl3)δ196.88,149.93,149.39,148.15,148.00,147.59,145.54, 135.55,131.07,129.01,128.31,127.74,125.49,124.36,124.01,120.21,116.07, 110.42,56.00,29.70；ESI-MS m/z:353.1calcd for C22H21NO3[M+H]+354.1.
实施例17
(E)-3-(3-羟基-4-甲氧基苯基)-2-甲基-1-(2-(二甲氨基)喹啉-4-基)丙基-2-烯基-1-酮
将2-氯-4-丙酰基喹啉(150mg,0.68mmol)溶于2mL乙醇中，加入33％的二甲胺水溶液(930μL,6.8mmol)，80度封管反应4h后加水稀释，二氯甲烷萃取(30mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析 (PE/EA 20:1)得2-二甲氨基-4-丙酰基喹啉135mg，产率86.5％。按实施例17 (d)的操作，得产物84mg，产率74％；1H NMR(300MHz,DMSO)δ9.16(s,1H), 7.53(d,J＝8.1Hz,1H),7.49-7.36(m,1H),7.32(d,J＝7.9Hz,1H),7.07(d,J＝7.3 Hz,1H),7.02(s,1H),6.96(s,1H),6.90(s,1H),6.82(dd,J＝16.2,8.1Hz,2H),3.69 (s,3H),3.08(s,6H),2.17(s,3H)；13C NMR(75MHz,DMSO)δ198.74,156.79,149.64,148.20,147.51,146.81,146.47,134.80,130.14,128.04,126.84,125.25,123.62,122.32,119.77,117.40,112.34,107.92,56.01,38.13,13.07；ESI-MS m/z:362.1calcd for C22H22N2O3[M+H]+363.1.
实施例18
(E)-3-(3-羟基-4-甲氧基苯基)-2-甲基-1-(2-甲氧基喹啉-4-基)丙基-2-烯基-1-酮
将2-氯-4-丙酰基喹啉(150mg,0.68mmol)溶于2mL甲醇中，加入甲醇钠 (180mg,3.4mmol)，氮气保护，回流搅拌，反应结束后后加水稀释，二氯甲烷萃取(30mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 20:1)得2-二甲氨基-4-丙酰基喹啉130mg，产率88.4％。按实施例 17的操作，得黄色固体47mg；1H NMR(300MHz,CDCl3)δ7.90(d,J＝8.4Hz, 1H),7.68-7.62(m,2H),7.42-7.31(m,1H),7.26(s,1H),7.14(s,1H),7.05(d,J＝1.8Hz,1H),6.91-6.77(m,3H),5.62(s,1H),4.11(s,3H),3.91(s,3H),2.34(s,3H)；13C NMR(75MHz,CDCl3)δ198.29,161.48,148.95,147.78,146.95,146.86,145.47,135.64,130.02,128.59,127.64,125.36,124.68,123.77,122.61,116.10,111.42,110.39,55.95,53.65,12.83；ESI-MS m/z:348.1calcd for C21H19NO4[M+H]+349.1.
实施例19
(E)-3-(3-羟基-4-甲氧基苯基)-2-甲基-1-(2-(吡咯烷-1-基)喹啉-4-基)丙基-2-烯基 -1-酮
按照实施例17的操作，得黄色固体；1H NMR(300MHz,CDCl3)δ7.76(d,J ＝8.5Hz,1H),7.61-7.49(m,2H),7.18(s,1H),7.16–7.07(m,1H),7.05(s,1H), 6.85(q,J＝8.2Hz,2H),6.66(s,1H),3.89(s,3H),3.62(s,4H),2.32(s,3H),2.03(s, 4H)；13C NMR(75MHz,CDCl3)δ199.38,154.69,148.62,147.99,147.51,146.68, 145.65,135.59,129.97,128.67,126.23,125.28,123.65,121.95,119.99,116.25, 110.52,108.61,55.94,47.00,25.53,12.79；ESI-MS m/z:388.2calcd for C24H24N2O3 [M+H]+389.1.
实施例20
(E)-3-(3-羟基-4-甲氧基苯基)-2-甲基-1-(2-***啉基喹啉-4-基)丙基-2-烯基-1-酮
按照实施例17的操作，得黄色固体；1H NMR(300MHz,CDCl3)δ7.76(d,J ＝8.3Hz,1H),7.59-7.53(m,2H),7.22(t,J＝7.5Hz,1H),7.13(s,1H),7.05(s,1H), 6.90(s,1H),6.89–6.80(m,2H),5.68(s,1H),3.91(s,3H),3.85(d,J＝5.1Hz,4H), 3.73(d,J＝5.1Hz,4H),2.34(s,3H)；13C NMR(75MHz,CDCl3)δ199.17,156.49, 148.11,147.97,147.78,146.78,145.49,135.67,130.12,128.65,127.11,125.14, 123.75,123.29,120.70,116.08,110.42,107.50,66.82,55.97,45.48,12.83；ESI-MS m/z:404.2calcd forC24H24N2O4[M+H]+405.2.
实施例21
(E)-3-(3-羟基-4-甲氧基苯基)-2-甲基-1-(2-羟甲基喹啉-4-基)丙基-2-烯基-1-酮
将2-甲基-4-丙酰基喹啉(300mg,1.52mmol)溶于二氯甲烷中，加入75％的间氯过氧苯甲酸(450mg,1.98mmol)，室温反应，反应结束后加饱和的硫代硫酸钠水溶液，二氯甲烷萃取(30mL×3)，合并有机相，饱和NaHCO3水溶液洗，饱和食盐水洗，无水硫酸钠干燥，浓缩得2-甲基-4-丙酰基喹啉N氧化物；将N氧化物溶于醋酐中于100度搅拌，反应结束后，旋掉醋酐，残余物溶于10mL 甲醇中，加入2mL的氨甲醇溶液，反应1h后浓缩后柱层析(PE/EA2:1)得2- 羟甲基-4-丙酰基喹啉200mg，三步产率67.9％。按实施例17的合成方法，得黄色固体；1HNMR(300MHz,CDCl3)δ8.07(d,J＝8.5Hz,1H),7.69(dd,J＝12.7, 8.4Hz,2H),7.51–7.42(m,1H),7.20(d,J＝1.5Hz,1H),6.97(s,2H),6.75(d,J＝ 8.7Hz,2H),4.88(s,2H),4.69(s,1H),3.83(s,3H),2.29(s,3H)；13C NMR(75MHz, CDCl3)δ198.49,158.39,147.89,147.17,147.08,145.54,135.77,130.31,129.04, 128.46,127.19,125.49,124.95,124.02,123.80,116.48,116.09,110.42,64.26,55.98, 29.70；ESI-MS m/z:349.1calcd forC21H19NO4[M+H]+350.1.
实施例22
(E)-4-(3-(3-羟基-4-甲氧基苯基)-2-甲基丙烯酰基)喹啉-2-甲醛
将实施例21的产物(130mg,0.52mmol)溶于DMSO中，加入IBX(100mg, 0.63mmol)，室温搅拌30min，加水稀释，乙酸乙酯萃取(30mL×3)，水洗(30 mL×3)，饱和食盐水洗一次，干燥，浓缩后柱层析(PE/EA 2:1)得产物100mg，产率76.9％；1H NMR(300MHz,CDCl3)δ10.18(s,1H),8.25(d,J＝8.4Hz,1H), 7.90(s,1H),7.86-7.73(m,2H),7.62(dd,J＝11.2,4.1Hz,1H),6.95(s,2H),6.77- 6.72(m,2H),5.71(s,1H),3.82(s,3H),2.30(s,3H)；13C NMR(75MHz,CDCl3)δ 197.83,193.27,151.69,148.23,147.93,147.63,147.40,145.51,135.73,130.92, 130.88,130.06,128.35,127.37,125.71,123.87,116.10,115.47,110.40,55.97,29.70； ESI-MS m/z:347.1calcd for C21H17NO4[M+H]+348.1.
实施例23
(E)-3-(3-羟基-4-甲氧基苯基)-2-甲基-1-(喹啉-4-基)丙基-2-烯基-1-酮
将4-丙酰基喹啉按照实施例6的方法，得白色固体；1H NMR(300MHz, CDCl3)δ8.88(d,J＝4.3Hz,1H),8.11(d,J＝8.5Hz,1H),7.73(d,J＝8.0Hz,1H), 7.66(dd,J＝11.2,4.1Hz,1H),7.47(dd,J＝11.2,4.0Hz,1H),7.28(d,J＝4.3Hz, 1H),7.00-6.90(m,2H),6.82-6.74(m,2H),3.80(s,3H),2.28(s,3H)；13C NMR(75 MHz,CDCl3)δ198.44,149.27,148.30,148.14,147.22,146.51,145.86,135.69, 130.09,129.57,128.40,127.57,125.53,123.62,119.20,116.43,110.61,55.94,29.70, 12.87；ESI-MS m/z:319.1calcdfor C20H17NO3[M+H]+320.1.
实施例24
(E)-3-(3-羟基-4-甲氧基苯基)-1-(2-((4-甲氧基苄基)氨基)喹啉-4-基)-2-甲基丙基-2- 烯基-1-酮
将1-(2-氯喹啉-4-基)丙烷-1-醇(100mg,0.45mmol)于乙醇中，加入对甲氧基苄胺(74mg,0.54mmol)于封管中150℃加热24h，旋干乙醇，柱层析(PE/EA 3:1)得1-(2-((4-甲氧基苯基)氨基)喹啉-4-基)丙烷-1-醇150mg；将该产物(150 mg,0.46mmol)溶于DMSO中，加入IBX(150mg,0.56mmol)，室温搅拌30min，加水稀释，乙酸乙酯萃取(30mL×3)，水洗(30mL×3)，饱和食盐水洗一次，无水硫酸钠干燥，浓缩得2-(4-甲氧苄基氨基)-4-丙酰基喹啉，直接投下一步；将上一步产物按照实施例17的方法，得黄色固体67mg；1H NMR(300MHz, CDCl3)δ7.68(d,J＝8.4Hz,1H),7.51-7.40(m,2H),7.23-7.18(s,2H),7.10(dd,J ＝11.3,3.8Hz,1H),7.05(s,1H),6.93(s,1H),6.77-6.74(m,4H),6.49(s,1H),5.14 (s,1H),4.54(s,2H),3.79(s,3H),3.68(s,3H),2.20(s,3H)；13C NMR(75MHz, CDCl3)δ198.83,158.93,155.68,148.14,147.94,147.77,146.70,145.57,135.53, 130.93,130.12,129.09,128.61,126.47,125.32,123.71,122.81,120.96,116.24, 114.09,110.50,109.59,55.94,55.29,45.40,29.71；ESI-MS m/z:354.1calcd for C28H26N2O4[M+H]+355.2.
实施例25
(E)-3-(3-羟基-4-甲氧基苯基)-2-甲基-1-(2-(甲氨基)喹啉-4-基)丙基-2-烯基-1-酮
按照实施例24的合成方法，1H NMR(300MHz,CDCl3)δ7.75(d,J＝8.9Hz, 1H),7.66-7.60(m,2H),7.18(d,J＝8.2Hz,1H),7.15(s,1H),7.04(d,J＝1.7Hz, 1H),6.89(dd,J＝8.4,1.7Hz,1H),6.83(d,J＝8.4Hz,1H),6.59(s,1H),5.33(s,1H), 3.89(s,3H),3.06(s,3H),2.31(s,3H)；13C NMR(75MHz,CDCl3)δ198.82,156.54, 148.07,147.67,146.84,145.67,135.49,130.26,128.58,125.89,125.36,123.68, 122.73,120.67,116.30,110.55,109.13,55.96,28.78,12.78；ESI-MS m/z:348.1 calcd for C21H20N2O3[M+H]+349.1.
实施例26
(E)-3-(3-羟基-4-甲氧基苯基)-2-甲基-1-(2-(乙氨基)喹啉-4-基)丙基-2-烯基-1-酮
按照实施例24的合成方法，1H NMR(300MHz,CDCl3)δ7.72(d,J＝8.5Hz, 1H),7.64–7.49(m,2H),7.18–7.14(m,2H),7.04(d,J＝1.8Hz,1H),6.90(dd,J＝ 8.5,1.7Hz,1H),6.84(d,J＝8.4Hz,1H),6.58(s,1H),4.90(s,1H),3.89(s,3H), 3.60-3.48(m,2H),2.31(s,3H),1.27(m,3H)；13C NMR(75MHz,CDCl3)δ198.94, 155.95,148.10,147.90,146.74,145.68,135.52,130.12,128.61,126.19,125.32, 123.63,122.62,120.77,116.34,110.57,109.21,55.95,36.67,29.70,14.95；ESI-MS m/z:362.2calcd for C22H22N2O3[M+H]+363.2.
实施例27
(E)-3-(3-羟基-4-甲氧基苯基)-2-甲基-1-(2-(环丙氨基)喹啉-4-基)丙基-2-烯基-1-酮
按照实施例24的合成方法，1H NMR(300MHz,CDCl3)δ7.62(d,J＝8.5Hz, 1H),7.49-7.43(m,2H),7.19-7.12(m,1H),7.10(s,1H),6.95(s,2H),6.90-6.83 (m,1H),6.79(d,J＝8.5Hz,1H),5.47(s,1H),3.84(s,3H),2.62-2.49(m,1H),2.28 (s,3H),1.18(s,4H)；13C NMR(75MHz,CDCl3)δ198.98,157.43,148.16,147.79, 146.86,145.75,135.56,130.27,128.62,125.99,125.40,123.51,122.95,121.10, 116.45,110.60,107.84,55.96,29.70,24.01,12.82；ESI-MS m/z:374.2calcd for C23H22N2O3[M+H]+375.2.
实施例28
(E)-4-(3-(3-羟基-4-甲氧基苯基)-2-甲基丙烯酰基)喹啉-2-甲酸乙酯
将2-氯-4-乙酰基喹啉(500mg,2.25mmol)溶于10mL无水DMF中，氮气保护，分别加入Ph3(PPh3)4(260mg,0.25mmol)，Zn(CN)2(320mg,2.7mmol)， 120℃反应2h后，加水稀释，乙酸乙酯萃取(30mL×3)，水洗(30mL×3)，饱和食盐水洗一次，干燥，浓缩后柱层析(PE/EA30:1)得2-氰基-4-丙酰基喹啉 415mg，产率87％；将2-氰基-4-丙酰基喹啉(75mg,0.36mmol)，MEM保护的异香兰素(105mg,0.43mmol)及氢氧化钠颗粒(72mg,1.8mmol)，室温反应 2h后加水稀释，乙酸乙酯萃取(30mL×3)，饱和食盐水洗一次，干燥，浓缩后柱层析(PE/EA 2:1)得50mg油状产物，按实施例17的操作，得产物46mg，两步收率33％；1H NMR(300MHz,CDCl3)δ8.26(d,J＝8.5Hz,1H),8.04(s,1H), 7.75(d,J＝8.3Hz,1H),7.73–7.64(m,1H),7.54(d,J＝8.1Hz,1H),7.03–6.87(m, 2H),6.82–6.66(m,2H),6.27(s,1H),4.44(q,J＝7.1Hz,2H),3.75(s,3H),2.27(s, 3H),1.36(t,J＝7.1Hz,3H)；13C NMR(75MHz,CDCl3)δ197.92,164.92,148.18, 147.80,147.63,147.57,147.39,145.63,135.56,130.99,130.68,129.43,128.30, 126.51,125.29,123.90,119.05,116.29,110.51,62.47,55.90,29.67,14.29；ESI-MS m/z:391.1calcd for C23H21NO5[M+H]+392.1.
实施例29
(E)-4-(3-(3-羟基-4-甲氧基苯基)-2-甲基丙烯酰基)喹啉-2-酮
将2-氯-4-丙酰基喹啉(100mg,0.46mmol)溶于H2O:AcOH 5:1的混合溶液中，加入甲烷亚磺酸钠(92mg,0.92mmol)，90℃搅拌过夜，反应结束后用饱和碳酸氢钠调至中性，乙酸乙酯萃取(30mL×3)，饱和食盐水洗一次，干燥，浓缩得2-羟基-4-丙酰基喹啉粗品80mg；将该产物用实施例17的方法，得黄色固体80mg，三步产率52.6％；1H NMR(300MHz,CDCl3)δ12.71(s,1H),7.44(s, 2H),7.39(d,J＝8.2Hz,1H),7.23(s,1H),7.12(s,1H),7.02(s,1H),6.84(d,J＝7.8 Hz,1H),6.76(d,J＝8.1Hz,1H),6.62(s,1H),6.13(s,1H),3.81(s,3H),2.24(s,3H)；13C NMR(75MHz,CDCl3)δ197.04,163.73,151.34,148.13,147.27,145.59,138.70, 134.95,131.36,128.37,126.12,124.05,123.28,119.17,118.02,116.77,116.31, 110.52,55.97,29.70；ESI-MS m/z:335.1calcd for C20H17NO4[M+H]+336.1.
实施例30
(E)-2-甲氧基-5-(2-甲基-3-(2-甲基喹啉-4-基)-3-氧代丙基-1-烯基-1-基)苯基磷酸二钠
实施例11(500mg,1.5mmol)溶于二氯甲烷中，分别滴入三氯氧磷(697μL,7.5mmol)及吡啶(605μL,7.5mmol)，室温搅拌15h后，加入饱和碳酸钠水溶液继续搅拌2h，反应液浓缩，C18柱层析过得产物250mg，产率40.5％。1H NMR (300MHz,DMSO-d6)δ9.08(d,J＝8.5Hz,1H),7.86-7.77(m 2H),7.52(t,J＝7.6 Hz,1H),7.25(s,1H),7.12-6.99(m,2H),6.84-6.99(m,2H),3.88(s,3H),2.67(s, 3H),2.25(s,3H)；13C NMR(75MHz,CDCl3)δ199.19,156.72,148.52,147.44, 146.26,145.91,145.01,135.23,139.44,128.39,128.07,126.03,124.75,123.30, 123.06,119.50,115.76,110.05,76.94,76.52,76.10,55.45,24.71,12.31；ESI-MS m/z: 457.1calcd for C21H18NO6PNa2[M-Na]-434.1.
实施例31 片剂
取上述配方，用常规方法制备成片剂。
下面是本发明部分化合物的药理实验结果：
抗增殖实验
1.实验方法
2.细胞消化、计数、制成浓度为5×104个/mL的细胞悬液，96孔板中每孔加入100μl细胞悬液(每孔5×103个细胞)；
3.96孔板置于37℃，5％CO2培养箱中培养24小时；
4.用完全培养基稀释药物至所需浓度，每孔加入100μL相应的含药培养基；
5.96孔板置于37℃，5％CO2培养箱中培养72小时；
6.MTT法：
1)将96孔板进行MTT染色，λ＝490nm，测定OD值。
2)每孔加入20μL MTT(5mg/mL)，在培养箱继续培养4小时；
3)弃去培养基，每孔加入150μL DMSO溶解，摇床10分钟轻轻混匀；λ＝490 nm，酶标仪读出每孔的OD值。
6.计算抑制率。
2.实验结果
表1本发明化合物对5种人类癌细胞株抗增殖活性的IC50值(μM)
结论：从表中可以发现，实施例11对于五种细胞株都显示出最优的抗肿瘤活性，其活性优于阳性对照CA-4和顺铂实施例。
下面是部分化合物的体外抗微管蛋白聚集的实验
1.实验方法
化合物按照相应要求配置成母液，按照倍数稀释成终浓度后用于后续试验。浓度设置为5个，每个浓度生物学重复3次。将2mg/mL微管蛋白(细胞骨架) 的量重新悬浮于PEM缓冲液[80mM PIPES(pH6.9)，0.5mM EGTA，2mM MgCl2和15％甘油]中，然后在冰上与化合物或溶剂DMSO预孵育5分钟。在检测微管蛋白聚合反应之前，加入含有GTP的PEG至终浓度为3mg/mL。通过Berthold LB941微孔板式多功能酶标仪，30分钟后在340nm检测吸光度。通过设置空白对照组，Graphpad计算得出不同化合物的IC50，结果以μM为单位。
2.实验结果
表2本发明部分化合物的体外微管蛋白聚集的药理实验结果：
实施例 抑制微管蛋白聚集IC<sub>50</sub>
3 2.58
7 2.56
10 1.87
11 1.78
12 2.25
17 2.23
18 2.09
21 2.22
23 2.45
25 1.88
26 2.09
27 2.49
30 2.47
CA-4 2.88
结论：从表中可以看出所测化合物都具有较好的抑制微管蛋白聚合作用，好于阳性药CA-4。
下面是部分化合物的体内抗肿瘤实验
1.实验方法
由上海斯莱克实验动物有限责任公司提供，周龄为3周，体重12-16g的雌性Balb/c裸鼠70只。收集培养的肝癌H22细胞，计数、调整使细胞悬液浓度为 1.5×107个/ml，于裸小鼠右侧腋窝皮下每只接种0.1ml。用游标卡尺测量裸鼠移植瘤的直径，接种肿瘤细胞7天后，肿瘤长至50-75mm3时，每组10只将裸鼠随机分为8组。衍生物溶于DMSO，再滴入poloxamer母液，最后加生理盐水至所需剂量。DMSO终浓度为1％，poloxamer终浓度为2％。各组裸鼠给药，模型组腹腔注射等量溶媒，每天注射1次，持续21天；阳性对照组尾静脉注射20 mg/kg顺铂，每天注射1次，持续21天；实验组静脉注射20mg/kg实施例10,11, 18,23,25,30。每天注射1次，持续21天；给药21天结束后处死裸鼠，通过手术剥取瘤块，称重。计算肿瘤生长抑制率(％)，用SPSS 17.0对结果进行分析，组间用t检验进行统计学分析处理，其计算公式如下：
2.实验结果
表3部分实施例的体内抗肿瘤活性
结论：从表中可以看出实施例10、11、18、23、25、30表现出较好的抑制肿瘤生长的活性，且其抑制率均高于阳性对照顺铂组和CA-4组，并且相比于顺铂组，实施例对小鼠的体重影响较好，说明相比于顺铂，实施例中的化合物毒性更小。

Claims (10)

1.一种通式I所示的喹啉取代查尔酮类化合物、其可药用的盐：
其中，R1选自氢、低级烷烃、羟基、甲氧基、卤素、氰基、酯基、酰胺基、羧基、仲氨基、叔氨基、羟甲基或醛基；
R2选自氢、低级烷烃、卤素、甲氧基、氰基、酯基、酰胺基或羧基；
R3选自甲氧基、甲硫基、氰基、低级烷烃、卤素、酯基或不同取代的氨基；
R4选自羟基、氨基、氟、磷酸酯基、磷酸二钠、糖苷、硼酸基、氨基酸酰胺基或(CH2)1-6OH。
2.根据权利要求1所述的喹啉取代查尔酮类化合物、其可药用的盐，其特征在于，R2为氢或甲基。
3.根据权利要求1所述的喹啉取代查尔酮类化合物、其可药用的盐，其特征在于，R3为甲氧基或甲硫基。
4.根据权利要求1所述的喹啉取代查尔酮类化合物、其可药用的盐，其特征在于，R4为羟基、氨基、氟或磷酸二钠。
5.一种通式II所示的喹啉取代查尔酮类化合物、其可药用的盐：
其中，R1选自氢、低级烷烃、羟基、甲氧基、卤素、氰基、酯基、酰胺基、羧基、仲氨基、叔氨基、羟甲基或醛基；
R2选自氢、低级烷烃、卤素、甲氧基、氰基、酯基、酰胺基或羧基；
R5选自氢、低级烷烃、甲氧基、羟甲基、芳香或脂肪取代甲酰基；
烯基取代的位置在吲哚3位、4位、5位、6位或7位。
6.根据权利要求5所述的喹啉取代查尔酮类化合物、其可药用的盐，其特征在于，R2为氢或甲基；R5为氢或低级烷烃。
7.根据权利要求5所述的喹啉取代查尔酮类化合物、其可药用的盐，其特征在于，烯基取代的位置优选吲哚3位，4位，5位。
8.根据权利要求1-7中任一所述的喹啉取代查尔酮类化合物、其可药用的盐，其特征在于，所述喹啉取代查尔酮类化合物选自以下1-30所示的化合物：
9.一种药物组合物，其中含有治疗有效量的权利要求1-7中任一所述的喹啉取代查尔酮类化合物和/或其可要用的盐，及药学上可接受的载体。
10.权利要求1-7中任一所述的喹啉取代查尔酮类化合物和/或其可要用的盐在制备***以及通过抑制微管蛋白活性来治疗其他疾病或病症的药物中的应用。
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