CN110818706B - 一种四稠环喹喔啉类衍生物及其制备方法 - Google Patents
一种四稠环喹喔啉类衍生物及其制备方法 Download PDFInfo
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Abstract
本发明针对现有喹喔啉类化合物结构单一的问题,提供了一种全新型的结构多样的四稠环喹喔啉类衍生物及其制备方法,其结构通式如(I)所示,
Description
技术领域
本发明涉及一种四稠环喹喔啉类衍生物及其制备方法,特别是涉及一种5,12-二氢喹啉[2,3-b]喹喔啉类化合物及其制备方法。
背景技术
含有多元稠环骨架的分子广泛存在于天然产物和合成化合物中,并且拥有显著的生物学和药理学活性。例如,在天然产物中,含有吲哚并喹啉骨架的生物碱cryptolepine具有很好的抗疟疾活性;含有吡啶并咔唑骨架的生物碱ellipticine是天然的DNA拓扑异构酶II抑制剂,具有抗肿瘤活性以及细胞毒活性;含有吡喃并吖啶酮骨架的山油柑碱及其结构改造物具有广谱的抗肿瘤活性。此外,四元稠环骨架也备受药物化学家以及工业界的关注。如WO2010143664、CN104230960中所述,人们合成一系列含有苯并咔唑酮、苯并噻吩并吲哚母核的化合物,并测定其对于间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)的抑制活性;WO2006047017中,合成用作类固醇性激素受体调节剂的新的含杂原子的四环衍生物。
一些稠合的N-杂芳烃含有喹喔啉结构片段,该片段本身具有广泛的生物活性。迄今为止,大量喹喔啉衍生物被用于药物或植物检疫。除药用外,喹喔啉衍生物也广泛应用于染料、有机半导体、有机敏化剂等研究中。在光伏领域出现了很多含有喹喔啉结构片段的共轭聚合物,这些聚合物具有较好的光电转换效率。然而,当前合成稠合喹喔啉衍生物的方法存在许多缺点,如使用金属催化剂,反应时间长,反应步骤多。因此,开发一种无过氧化物、无金属催化剂的方法来合成稠合四环喹喔啉衍生物成为一种新的思路。
发明内容
本发明针对现有喹喔啉类化合物结构单一的问题,提供了一种全新型的结构多样的四稠环喹喔啉类衍生物。在现有文献中,未发现本发明所述四稠环喹喔啉类衍生物的报道。进一步,本发明还提供所述四稠环喹喔啉类衍生物的制备方法及其应用。
一种四稠环喹喔啉类衍生物,其结构通式如(I)所示:
式中,
A1、A2、A3、A4全部为C;
或者A1、A2、A3、A4中的任一个或两个为N,其余为C,并且A1、A2、A3或A4为N时,则不具有相对应的R9、R8、R7或R6取代基;
或者A1、A2、A3、A4中的任一个为O,其余为C,并且A1、A2、A3或A4为O时,则不具有相对应的R9、R8、R7或R6取代基,
R5选自直链或支链C1-C8烷基,优选直链或支链C1-C6烷基,如甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基等等。
R10和R11相同或不同,选自下列的基团:直链或支链C1-C8烷基,优选直链或支链C1-C6烷基,如甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基等等;或者R10和R11与它们共同连接的碳原子一起形成具有4-6个环成员的单环,其中包括但不限于环丁基、环戊基和环己基;
R1、R2、R3、R4、R6、R7、R8和R9,相同或不同,彼此互相独立,选自下列基团:
氢原子、卤素、硝基、腈基、羟基、羧基、氨基、C1-8烷基胺基、二(C1-8烷基)胺基、取代或未取代芳基胺基、二(取代或未取代芳基)胺基、C1-8烷氧基、-O-取代或未取代芳基、-C(=O)O-C1-8烷基、-OC(=O)-C1-8烷基、-C(=O)O-取代或未取代芳基、-OC(=O)-C1-8取代或未取代芳基、-C(=O)O-(卤代C1-8烷基)、-OC(=O)-(卤代C1-8烷基)、磺酸基及其盐,
所述芳基优选苯基;
Cl-8直链或支链烷基、C2-8直链或支链烯基、C2-8直链或支链炔基、卤代C1-8烷基、卤代C2-8烯基、卤代C2-8炔基,优选Cl-6直链或支链烷基、C2-6直链或支链烯基、C2-6直链或支链炔基、卤代C1-6烷基、卤代C2-6烯基、卤代C2-6炔基;
取代或未取代的苯基、取代或未取代的C5-C6杂芳基,其中杂原子可以是S、O、N中的一种或几种,
式-NRaRb、-C(=O)NRaRb的基团,其中:Ra和Rb与载有它们的氮原子一起形成具有5-6个环成员,其中包括但不限于吡咯烷基、异恶唑烷基、恶唑烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、六氢哒嗪基、六氢嘧啶基、哌嗪基、氮杂环庚烷基、氧氮杂环庚烷基和二氮杂环庚烷基。
本发明一个优选的方案R1、R2、R3、R4、R6、R7、R8和R9,相同或不同,彼此互相独立,选自下列基团:氢原子、F、Cl、Br、硝基、腈基、羟基、羧基、氨基、甲氧基、-C(=O)O-CH3、甲基、乙基或丙基。
本发明一个优选的方案,所述化合物结构中:
A1、A2、A3、A4全部为C;
或者A1为N,A2、A3、A4为C,并且不具有R9取代基;
或者A2为N,A1、A3、A4为C,并且不具有R8取代基;
或者A3为N,A1、A2、A4为C,并且不具有R7取代基;
或者A4为N,A1、A2、A3为C,并且不具有R6取代基;
或者A2和A4为N,A1和A3为C,并且不具有R8和R6取代基;
或者A1和A3为N,A2和A4为C,并且不具有R9和R7取代基;
或者A1、A2、A3、A4中的任一个为O,其余为C,并且A1、A2、A3或A4为O时,则不具有相对应的R9、R8、R7或R6取代基。
本发明另一目的在于提供本发明所述的四稠环喹喔啉类衍生物的制备方法,将化合物(Ⅴ)与化合物(Ⅵ)在催化剂催化下反应得到化合物(Ⅰ),
其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、A1、A2、A3和A4如上述式(Ⅰ)定义。
上述反应所选溶剂选自乙腈、DMF、THF、DMA、DMSO、甲苯中的一种或几种。
优选反应温度为0℃~200℃,所用的催化剂为I2、CuO、叔丁基过氧化氢(TBHP)、N-碘代丁二酰亚胺(NIS)、四丁基碘化铵(Bu4NI)、KI和双三氟乙酰碘苯(PIFA)中的一种或几种。
上述反应中的化合物(Ⅴ)可参考刘海东和吉民等人的方法(TetrahedronLetters,2015,56(18):2332-2335.)制备。化合物(Ⅵ)可商业购买。
化合物(Ⅴ)的制备包括如下步骤:
(a)将化合物(Ⅱ)和化合物Ⅲ反应得到化合物(Ⅳ),
(b)化合物(Ⅳ)与R5I反应得到化合物(Ⅴ),R5选自直链或支链C1-C8烷基,
上述制备方法中,优选步骤(a)反应体系使用羧酸溶剂,如醋酸;步骤(b)所选溶剂选自二氯甲烷、三氯甲烷、乙腈、DMF、THF、甲苯中的一种或几种。
本发明一个具体的制备方法如下:
(a)参照刘海东和吉民等人的方法(Tetrahedron Letters,2015,56(18):2332-2335.),将化合物(Ⅱ)、化合物(Ⅲ)加入到反应瓶中,加入溶剂,加热并搅拌。当反应完成时,将反应液置于冰浴中冷却至0-5℃。向反应液中加入水,加入乙酸乙酯萃取3次。将合并的有机层分别用饱和NaHCO3溶液和饱和食盐水洗涤,加入无水Na2SO4干燥。将溶剂旋干,得到粗产物,经油泵拉干后,得到化合物(Ⅳ),不需纯化直接用于下一步。
(b)将上述粗品(Ⅳ)置于圆底烧瓶中,加入溶剂和R5I,加热并搅拌。反应瓶中有大量固体析出,将反应瓶置于冰浴中冷却至5℃,过滤。将所得固体(Ⅴ)在真空下干燥。
(c)将化合物(Ⅴ)、化合物(Ⅵ)和催化剂溶于反应溶剂中,加热搅拌。反应完成后,反应冷却至室温,并用饱和Na2S2O3溶液淬灭,然后用乙酸乙酯萃取。将合并的有机层用饱和食盐水洗涤,加入无水Na2SO4干燥。柱层析分离产品(Ⅰ)。
其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、A1、A2、A3和A4如上述式(Ⅰ)定义。
上述具体反应条件可参见实施例。
本发明所述四稠环喹喔啉类衍生物在体外和体内均具有细胞毒活性,可作为抗肿瘤药物。本发明的化合物可以治疗的癌症类型包括但不限于腺癌和癌症、肉瘤、神经胶质瘤和白血病。
本发明的另一目的在于提高一种药用组合物,所述药用组合物含有作为活性成分的至少一种本发明所述结构(Ⅰ)的四稠环喹喔啉类衍生物,可进一步含有一种或多种药学上可接受的惰性、无毒的赋形剂或载体。
具体实施方式
下面结合具体实施例对本发明作进一步阐述。这些实施例仅是处于解释说明的目的,而不是限制本发明的范围和实质。
所使用的原料是已知的产物或根据已知的方法制备的产物。各种制备方法用于合成本发明化合物制备中所使用的中间体。
在实施例和制备中所述的化合物的结构是根据常规的分光光度技术、红外、核磁共振、质谱分析方法测定的。
本发明的化合物的制备可以用如下化学反应通式表示:
以下为具体实施例。
实施例1:5,12,12-三甲基-8-硝基-5,12-二氢喹啉[2,3-b]喹喔啉(3aa-1)和5,12,12-三甲基-9-硝基-5,12-二氢喹啉[2,3-b]喹喔啉(3aa-2)
步骤A:2,3,3-三甲基-3H-吲哚
向装有回流冷凝器的三颈圆底烧瓶中加入苯肼盐酸盐(20mmol)、醋酸30毫升。然后将3-甲基-2-丁酮(30mmol)加入到反应瓶中,加热至90℃并搅拌12小时。当反应完成时(通过TLC监测),将反应液置于冰浴中冷却至0-5℃。向反应液中加入水,加入乙酸乙酯萃取3次。将合并的有机层分别用饱和NaHCO3溶液和饱和食盐水洗涤,加入无水Na2SO4干燥。将溶剂旋干,得到粗产物,经油泵拉干后,不需纯化直接用于下一步。
步骤B:1,2,3,3-四甲基-3H-吲哚-1-碘化物
将上述粗品吲哚(20mmol)置于圆底烧瓶中,加入无水四氢呋喃(40mL),加入碘甲烷(40mmol),加热至40℃并搅拌12小时。反应瓶中有大量固体析出,将反应瓶置于冰浴中冷却至5℃,过滤,滤饼用冷的四氢呋喃(10mL)洗涤。将所得固体真空下干燥。
步骤C:5,12,12-三甲基-8-硝基-5,12-二氢喹啉[2,3-b]喹喔啉(3aa-1)和5,12,12-三甲基-9-硝基-5,12-二氢喹啉[2,3-b]喹喔啉(3aa-2)
将1,2,3,3-四甲基-3H-吲哚-1-碘化物(1.0mmol)、4-硝基邻苯二胺(1.2mmol)和催化剂(3mmol)溶于反应溶剂中(3mL)中,150℃下搅拌10h。在反应完成后(通过TLC监测),将混合物冷却至室温并用饱和Na2S2O3溶液淬灭,然后用乙酸乙酯(3×20ml)萃取。将合并的有机层用饱和食盐水洗涤,加入无水Na2SO4干燥。柱层析分离产品(洗脱剂EA:PE=1:100洗脱出目标化合物)。得黄色固体3aa-1 99mg,收率31%;黄色固体3aa-2 128mg,收率40%。
结构测定:
3aa-1
MP:178-180℃.
1H NMR(300MHz,CDCl3)δ=8.69(d,J=2.4Hz,1H),8.19(dd,J=9.0,2.5Hz,1H),8.02(d,J=9.0Hz,1H),7.51(d,J=7.6Hz,1H),7.34(t,J=7.5Hz,1H),7.12-7.17(m,2H),3.75(s,3H),1.72(s,6H).13C NMR(75MHz,CDCl3)δ=157.2,150.3,149.5,144.2,142.7,140.8,133.9,132.2,130.4,128.2,125.6,125.4,121.3,116.5,43.7,33.7,31.1.
IRν(KBr,cm-1):3086,3042,2971,2927,2865,1612,1591,1557,1528,1477,1439,1405,1344,1150,1074,889,808,744.
HRMS(ESI+)calcd for C18H16N4O2[M+H]+321.1346.Found 321.1353.
3aa-2
MP:174-176℃.
1H NMR(500MHz,CDCl3)δ=8.83(d,J=2.4Hz,1H),8.35(dd,J=9.1,2.5Hz,1H),7.84(d,J=9.1Hz,1H),7.52(d,J=7.6Hz,1H),7.34(t,J=7.7Hz,1H),7.13-7.19(m,2H),3.77(s,3H),1.73(s,6H).13C NMR(75MHz,CDCl3)δ=156.2,149.7,147.3,146.8,140.5,139.7,134.3,130.4,130.0,128.3,127.6,126.0,125.7,116.7,43.5,33.8,31.3.
IRν(KBr,cm-1):3069,2979,2919,2868,1617,1560,1518,1490,1447,1401,1367,1332,1281,1151,1074,903,834,746.
HRMS(ESI+)calcd for C18H16N4O2[M+H]+321.1346.Found 321.1358。
实施例2:5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3ab)
根据实施例1的方法,采用邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,94mg,34%yield.
MP:85-86℃.
1H NMR(300MHz,CDCl3)δ=7.94(d,J=8.2Hz,1H),7.81(d,J=8.3Hz,1H),7.57(t,J=7.5Hz,1H),7.49-7.51(m,1H),7.44(t,J=7.3Hz,1H),7.30(t,J=7.4Hz,1H),7.07-7.12(m,2H),3.73(s,3H),1.72(s,6H).13C NMR(75MHz,CDCl3)δ=149.7,144.9,139.6,138.1,137.8,130.7,128.1,127.5,126.5,125.7,124.4,124.2,121.1,112.4,39.6,29.9,27.4.
IRν(KBr,cm-1):3068,2961,2921,2858,1599,1556,1478,1433,1394,1361,1129,1099,745.
HRMS(ESI+)calcd for C18H17N3[M+H]+276.1495.Found 276.1524。
实施例3:8-溴-5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉和9-溴-5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3ac,混合物)
根据实施例1的方法,采用4-溴邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,188mg,53%yield.
MP:77-78℃.
1H NMR(300MHz,CDCl3)δ=8.12(d,J=2Hz,1H),7.98(d,J=2.1Hz,1H),7.78(d,J=8.7Hz,1H),7.60-7.68(m,2H),7.44-7.55(m,3H),7.28-7.33(m,2H),7.08-7.13(m,4H),3.70(m,6H),1.70(s,12H).13C NMR(75MHz,CDCl3)δ=142.1,139.0,136.9,135.0,134.1,133.5,132.4,131.6,131.1,130.6,130.2,128.1,125.4,125.1,125.0,120.7,116.2,116.2,43.3,33.6,31.0.
IRν(KBr,cm-1):3062,2970,2925,2866,1597,1560,1451,1380,1357,1285,1144,1050,936,873,822,747.
HRMS(ESI+)calcd for C18H16BrN3[M+H]+354.0600.Found 354.0630。
实施例4:8-氯-5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉和9-氯-5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3ad,混合物)
根据实施例1的方法,采用4-氯邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,161mg,52%yield.
MP:84-86℃.
1H NMR(500MHz,CDCl3)δ=8.00(d,J=2.0Hz,1H),7.90(d,J=8.7Hz,0.5H),7.85(d,J=1.8Hz,0.5H),7.78(d,J=8.8Hz,1H),7.58(d,J=2.1Hz,0.5H),7.56(s,1H),7.54(s,1H),7.43(dd,J=8.7,1.8Hz,0.5H),7.35-7.38(m,1.5H),7.14–7.18(m,3H),3.76(s,4.5H),1.75(s,9H).13CNMR(100MHz,CDCl3)δ=151.8,151.0,146.3,146.0,141.2,139.2,139.1,138.8,137.3,134.7,131.5,130.4,129.8,129.6,127.8,127.6,125.9,125.8,125.5,122.5,122.4,113.6,113.6,40.7,40.7,31.0,28.4,28.4.·
IRν(KBr,cm-1):3059,2967,2923,2865,1599,1557,1463,1398,1354,1283,1147,1063,869,821,743.
HRMS(ESI+)calcd for C18H16ClN3[M+H]+310.1106.Found 310.1107。
实施例5:8-氟-5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉和9-氟-5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3ae,混合物)
根据实施例1的方法,采用4-氟邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,71mg,24%yield.
MP:86-107℃.
1H NMR(500MHz,CDCl3)δ=7.96(dd,J=9.0,6.0Hz,0.7H),7.84(dd,J=9.1,5.7Hz,1H),7.65(dd,J=9.4,2.8Hz,1H),7.56(s,0.7H),7.54(s,1H),7.48(dd,J=9.0,2.7Hz,0.7H),7.42(dd,J=8.6,2.8Hz,1H),7.35–7.38(m,1.7H),7.22-7.26(m,0.7H),7.12–7.18(m,3.4H),3.77(s,2.1H),3.76(s,3H),1.76(s,10.2H).13C NMR(100MHz,CDCl3)δ=164.1,161.6,161.3,158.8,151.7,150.0,139.0,138.8,137.5,131.8,131.5,130.3,130.2,128.2,128.1,127.6,125.4,122.4,122.2,118.8,118.5,114.8,114.5,113.6,113.4,112.6,112.4,110.7,110.5,40.7,40.5,30.9,28.5,28.3.
IRν(KBr,cm-1):3038,2972,2928,2865,1614,1558,1474,1440,1403,1365,1231,1168,1112,851,818,785,742.
HRMS(ESI+)calcd for C18H16FN3[M+H]+294.1401.Found 294.1403。
实施例6:5,12,12-三甲基-8-(三氟甲基)-5,12-二氢喹啉[2,3-b]喹喔啉和5,12,12-三甲基-9-(三氟甲基)-5,12-二氢喹啉[2,3-b]喹喔啉(3af,混合物)
根据实施例1的方法,采用4-三氟甲基邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,230mg,67%yield.
MP:88-89℃.
1H NMR(300MHz,CDCl3)δ=8.25(s,1H),8.12(s,1H),8.03(d,J=8.6Hz,1H),7.90(d,J=8.7Hz,1H),7.74(dd,J=8.7,1.9Hz,1H),7.61(dd,J=8.6,1.8Hz,1H),7.49-7.52(m,2H),7.29-7.35(m,2H),7.11-7.16(m,4H),3.73-3.75(m,6H),1.72(s,12H).13C NMR(75MHz,CDCl3)δ=152.6,146.3,146.0,141.8,139.5,139.4,138.0,137.9,137.2,131.1,131.0,128.9,127.2,127.2,126.9,125.9,125.9,125.1,125.0,124.5,124.5,124.0,124.0,122.3,122.2,120.4,120.3,113.3,113.2,40.4,40.3,30.6,30.5,28.0,27.9.
IRν(KBr,cm-1):3040,2973,2930,2873,1595,1562,1478,1436,1399,1373,1310,1218,1172,1124,1053,896,831,744.
HRMS(ESI+)calcd for C19H16F3N3[M+H]+344.1369.Found 344.1380。
实施例7:5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉-8-羧酸甲酯和5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉甲基-9-羧酸盐(3ag,混合物)
根据实施例1的方法,采用3,4-二氨基苯甲酸甲酯代替4-硝基邻苯二胺制备该产物。
Yellow solid,243mg,73%yield.
MP:116-117℃.
1H NMR(300MHz,CDCl3)δ=8.65(d,J=1.6Hz,1H),8.52(d,J=1.5Hz,1H),8.17(dd,J=8.7,1.8Hz,1H),8.04(dd,J=8.5,1.6Hz,1H),7.95(d,J=8.6Hz,1H),7.79(d,J=8.7Hz,1H),7.48-7.51(m,2H),7.28-7.33(m,2H),7.08–7.14(m,4H),3.98(s,3H),3.96(s,3H),3.73(s,3H),3.72(s,3H),1.72(s,12H).13C NMR(75MHz,CDCl3)δ=169.5,155.6,154.5,149.3,149.0,146.2,143.7,142.6,141.3,141.0,140.5,134.4,134.1,133.8,133.1,131.9,131.8,131.2,130.2,129.3,129.1,128.2,128.1,127.6,125.4,125.1,116.4,116.2,54.9,54.8,43.5,43.3,33.6,33.6,31.2,31.0.
IRν(KBr,cm-1):3035,2951,2862,1723,1597,1560,1472,1437,1401,1363,1293,1208,1144,1088,979,902,843,802,741.
HRMS(ESI+)calcd for C20H19N3O2[M+H]+334.1550.Found 334.1541。
实施例8:5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉-8-甲腈(3ah-1)和5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉-9-甲腈(3ah-2)
根据实施例1的方法,采用3,4-二氨基苯甲腈代替4-硝基邻苯二胺制备该产物。
Yellow solid,87mg,29%yield.
MP:204-205℃.
1H NMR(300MHz,CDCl3)δ=8.14(d,J=1.5Hz,1H),7.98(d,J=8.4Hz,1H),7.58(dd,J=8.5,1.6Hz,1H),7.50(d,J=7.6Hz,1H),7.33(t,J=7.1Hz,1H),7.11-7.16(m,2H),3.73(s,3H),1.72(s,6H).13C NMR(75MHz,CDCl3)δ=153.5,146.2,140.0,139.8,137.8,131.6,130.8,129.3,127.3,125.8,125.0,122.4,118.3,113.3,111.8,40.5,30.6,27.9.
IRν(KBr,cm-1):3045,2976,2928,2866,2224,1596,1555,1477,1433,1403,1369,1296,1136,886,836,743.
HRMS(ESI+)calcd for C19H16N4[M+H]+301.1448.Found 301.1467.
3ah-2
Yellow solid,108mg,36%yield.
MP:169-170℃.
1H NMR(300MHz,CDCl3)δ=8.27(s,1H),7.83(d,J=8.6Hz,1H),7.71(d,J=8.5Hz,1H),7.51(d,J=7.7Hz,1H),7.33(t,J=7.6Hz,1H),7.12-7.18(m,2H),3.75(s,3H),1.71(s,6H).13C NMR(75MHz,CDCl3)δ=152.6,146.4,142.8,137.5,137.4,133.6,131.1,130.1,127.3,127.3,125.1,122.7,118.5,113.5,107.3,40.4,30.6,28.1.
IRν(KBr,cm-1):3040,2958,2925,2862,2219,1592,1558,1500,1443,1401,1353,1284,1132,889,836,747.
HRMS(ESI+)calcd for C19H16N4[M+H]+301.1448.Found 301.1463。
实施例9:8,9-二氟-5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3ai)
根据实施例1的方法,采用4,5-二氟邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,100mg,32%yield.
MP:161-163℃.
1H NMR(300MHz,CDCl3)δ=7.68(dd,J=10.7,8.5Hz,1H),7.48-7.56(m,2H),7.31(t,J=7.6Hz,1H),7.08-7.13(m,2H),3.69(s,3H),1.69(s,6H).13C NMR(75MHz,CDCl3)δ=154.9,152.3,152.1,149.0,140.1,133.0,129.0,126.9,123.9,116.1,115.8,115.0,114.0,113.8,42.0,32.4,29.8.IRν(KBr,cm-1):3079,3041,2975,2931,2872,1561,1480,1440,1401,1236,1188,856,747.
HRMS(ESI+)calcd for C18H15F2N3[M+H]+312.1307.Found 312.1331。
实施例10:8,9-二氯-5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3aj)
根据实施例1的方法,采用4,5-二氯邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,248mg,72%yield.
MP:128-129℃.
1H NMR(300MHz,CDCl3)δ=8.04(s,1H),7.90(s,1H),7.49(d,J=7.5Hz,1H),7.31(t,J=7.7Hz,1H),7.09-7.14(m,2H),3.69(s,3H),1.69(s,6H).13C NMR(75MHz,CDCl3)δ=153.6,147.7,141.2,139.9,139.0,134.6,132.9,130.6,130.2,129.1,128.8,126.9,124.1,115.1,42.2,32.4,29.9.IRν(KBr,cm-1):3057,2975,2927,2867,1597,1555,1446,1390,1351,1207,1145,872,742.
HRMS(ESI+)calcd for C18H15Cl2N3[M+H]+344.0716.Found 344.0743。
实施例11:8,9-二溴-5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3ak)
根据实施例1的方法,采用4,5-二溴邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,299mg,69%yield.
MP:136-137℃.
1H NMR(300MHz,CDCl3)δ=8.22(s,1H),8.13(s,1H),7.49(d,J=7.3Hz,1H),7.32(t,J=7.5Hz,1H),7.09-7.15(m,2H),3.70(s,3H),1.69(s,6H).13C NMR(75MHz,CDCl3)δ=153.8,147.7,141.8,139.9,139.7,134.0,132.9,132.2,129.1,126.9,126.6,124.2,121.7,115.2,42.3,32.5,29.9.IRν(KBr,cm-1):3056,2973,2922,2863,1592,1557,1479,1436,1395,1343,1285,1144,876,744.
HRMS(ESI+)calcd for C18H15Br2N3[M+H]+433.9685.Found 433.9728。
实施例12:5,8,9,12,12-五甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3al)
根据实施例1的方法,采用4,5-二甲基邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,185mg,61%yield.
MP:138-140℃.
1H NMR(300MHz,CDCl3)δ=7.71(s,1H),7.59(s,1H),7.49(d,J=8.0Hz,1H),7.26-7.32(m,1H),7.05-7.10(m,2H),3.70(s,3H),2.42-2.43(m,6H),1.70(s,6H).13C NMR(75MHz,CDCl3)δ=151.0,147.0,140.8,140.6,140.7,139.0,136.4,133.3,129.4,128.8,127.7,126.8,123.3,114.7,41.9,32.3,29.8,21.6,21.2.
IRν(KBr,cm-1):3038,2968,2923,2870,1596,1560,1441,1380,1353,1287,1230,1188,1139,1048,1005,874,748.
HRMS(ESI+)calcd for C20H21N3[M+H]+304.1808.Found 304.1873。
实施例13:5,8,10,10-四甲基-2,3,5,10-四氢吡嗪[2,3-b]喹啉(3bm)
根据实施例1的方法,采用4-甲基苯肼盐酸盐代替苯肼盐酸盐,乙二胺代替4-硝基邻苯二胺制备该产物。
Brown oil,128mg,53%yield.
1H NMR(400MHz,CDCl3)δ=7.16(s,1H),7.08(d,J=8.2Hz,1H),6.84(d,J=8.2Hz,1H),3.46-3.52(m,2H),3.42-3.44(m,2H),3.40(s,3H),2.34(s,3H),1.48(s,6H).13C NMR(100MHz,CDCl3)δ=161.8,147.1,136.9,131.0,128.1,125.2,113.8,68.0,47.5,43.6,41.0,30.0,25.0,20.8.IRν(KBr,cm-1):3033,2935,2840,1651,1591,1504,1461,1420,1374,1327,1281,1244,1163,810.
HRMS(ESI+)calcd for C15H19N3[M+H]+242.1652.Found 242.1693。
实施例14:8,9-二氯-2,5,12,12-四甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3bj)
根据实施例1的方法,采用4-甲基苯肼盐酸盐代替苯肼盐酸盐,4,5-二氯邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,233mg,65%yield.
MP:179-180℃.
1H NMR(500MHz,CDCl3)δ=8.08(s,1H),7.94(s,1H),7.34(s,1H),7.16(d,J=8.2Hz,1H),7.04(d,J=8.2Hz,1H),3.72(s,3H),2.42(s,3H),1.73(s,6H).13C NMR(100MHz,CDCl3)δ=152.3,146.3,139.9,137.5,136.1,133.1,132.1,131.3,129.2,128.5,128.1,127.3,126.2,113.6,40.8,31.0,28.5,20.9.
IRν(KBr,cm-1):3072,3027,2973,2923,2859,1594,1556,1447,1406,1351,1210,1143,885,858,797.
HRMS(ESI+)calcd for C19H17Cl2N3[M+H]+358.0872.Found 358.0874。
实施例15:8,9-二溴-2,5,12,12-四甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3bk)
根据实施例1的方法,采用4-甲基苯肼盐酸盐代替苯肼盐酸盐,4,5-二溴邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,273mg,61%yield.
MP:179-180℃.
1H NMR(500MHz,CDCl3)δ=8.26(s,1H),8.14(s,1H),7.34(s,1H),7.16(d,J=8.2Hz,1H),7.04(d,J=8.3Hz,1H),3.72(s,3H),2.42(s,3H),1.72(s,6H).13C NMR(100MHz,CDCl3)δ=152.4,146.3,140.4,138.1,136.0,132.5,132.1,131.3,130.7,128.1,126.2,125.1,120.0,113.7,40.8,31.0,28.5,20.9.
IRν(KBr,cm-1):3063,3024,2974,2921,2858,1589,1552,1477,1442,1405,1348,1302,1139,885,795.
HRMS(ESI+)calcd for C19H17Br2N3[M+H]+447.9842.Found 447.9843。
实施例16:2,5,8,9,12,12-六甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3bl)
根据实施例1的方法,采用4-甲基苯肼盐酸盐代替苯肼盐酸盐,4,5-二甲基邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,152mg,48%yield.
MP:149-150℃.
1H NMR(500MHz,CDCl3)δ=7.76(s,1H),7.64(s,1H),7.35(s,1H),7.15(d,J=8.2Hz,1H),7.02(d,J=8.1Hz,1H),3.73(s,3H),2.47-2.48(m,6H),2.42(s,3H),1.74(s,6H).13C NMR(100MHz,CDCl3)δ=149.6,145.7,139.2,139.1,137.5,137.0,134.8,131.7,131.2,128.0,127.9,126.2,126.1,113.2,40.4,30.9,28.3,20.8,20.2,19.8.
IRν(KBr,cm-1):3029,2965,2915,2864,1625,1559,1469,1439,1380,1347,1283,1227,1135,876,811.
HRMS(ESI+)calcd for C21H23N3[M+H]+318.1965.Found 318.1971。
实施例17:2,8,9-三氯-5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3cj)
根据实施例1的方法,采用4-氯苯肼盐酸盐代替苯肼盐酸盐,4,5-二氯邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,261mg,69%yield.
MP:188-189℃.
1H NMR(500MHz,CDCl3)δ=8.09(s,1H),7.95(s,1H),7.48(s,1H),7.31(s,1H),7.06(d,J=8.7Hz,1H),3.72(s,3H),1.72(s,6H).13C NMR(100MHz,CDCl3)δ=151.3,145.9,139.7,137.6,137.2,133.4,133.2,129.2,129.1,128.0,127.5,127.4,125.7,114.9,40.9,31.2,28.4.
IRν(KBr,cm-1):3075,2924,2856,1591,1554,1447,1390,1348,1205,1147,884,866,796,742.HRMS(ESI+)calcd for C18H14Cl3N3[M+H]+380.0297.Found 380.0300。
实施例18:8,9-二溴-2-氯-5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3ck)
根据实施例1的方法,采用4-氯苯肼盐酸盐代替苯肼盐酸盐,4,5-二溴邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,295mg,63%yield.
MP:189-190℃.
1H NMR(500MHz,CDCl3)δ=8.15(s,1H),8.03(s,1H),7.36(d,J=2.1Hz,1H),7.19(s,1H),6.94(d,J=8.7Hz,1H),3.60(s,3H),1.60(s,6H).13C NMR(100MHz,CDCl3)δ=151.5,145.9,140.3,138.3,137.2,133.2,132.5,130.8,128.0,127.5,125.7,125.4,120.7,114.9,40.9,31.2,28.4.IRν(KBr,cm-1):3064,2975,2923,2856,1589,1553,1474,1442,1408,1347,1145,875,796,732.HRMS(ESI+)calcd for C18H14Br2ClN3[M+H]+467.9295.Found 467.9295。
实施例19:2-氯-5,8,9,12,12-五甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3cl)
根据实施例1的方法,采用4-氯苯肼盐酸盐代替苯肼盐酸盐,4,5-二甲基邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,242mg,64%yield.
MP:180-182℃.
1H NMR(500MHz,CDCl3)δ=7.64(s,1H),7.52(s,1H),7.36(d,J=2.1Hz,1H),7.15-7.18(m,1H),6.89(d,J=8.7Hz,1H),3.60(s,3H),2.34-2.36(m,6H),1.60(s,6H).13C NMR(100MHz,CDCl3)δ=148.6,145.2,139.4,139.1,138.1,137.6,135.3,133.6,128.0,127.2,127.1,126.3,125.5,114.5,40.6,31.0,28.2,20.3,19.9.
IRν(KBr,cm-1):3040,2969,2918,2860,1590,1554,1475,1400,1354,1224,1138,862,799.
HRMS(ESI+)calcd for C20H20ClN3[M+H]+338.1419.Found 338.1425。
实施例20:8,9-二氯-2-甲氧基-5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3dj)
根据实施例1的方法,采用4-甲氧基苯肼盐酸盐代替苯肼盐酸盐,4,5-二氯邻苯二胺代替4-硝基邻苯二胺制备该产物。
Orange solid,187mg,50%yield.
MP:187-188℃.
1H NMR(500MHz,CDCl3)δ=7.94(s,1H),7.80(s,1H),7.00(d,J=2.8Hz,1H),6.94(d,J=8.8Hz,1H),6.77(dd,J=8.9,2.8Hz,1H),3.77(s,3H),3.59(s,3H),1.60(s,6H).13CNMR(100MHz,CDCl3)δ=155.6,151.8,146.3,139.9,137.4,133.1,133.0,132.3,129.2,128.4,127.2,114.4,112.4,111.7,55.7,41.0,31.1,28.3.
IRν(KBr,cm-1):3061,2982,2928,2858,2824,1623,1591,1555,1483,1447,1405,1273,1238,1141,1059,863,788.
HRMS(ESI+)calcd for C19H17Cl2N3O[M+H]+374.0821.Found 374.0824。
实施例21:8,9-二溴-2-甲氧基-5,12,12-三甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3dk)
根据实施例1的方法,采用4-甲氧基苯肼盐酸盐代替苯肼盐酸盐,4,5-二溴邻苯二胺代替4-硝基邻苯二胺制备该产物。
Orange solid,153mg,33%yield.
MP:193-194℃.
1H NMR(500MHz,CDCl3)δ=8.25(s,1H),8.13(s,1H),7.12(d,J=2.8Hz,1H),7.07(d,J=8.9Hz,1H),6.90(dd,J=8.8,2.8Hz,1H),3.89(s,3H),3.71(s,3H),1.72(s,6H).13CNMR(100MHz,CDCl3)δ=155.6,152.0,146.3,140.5,138.1,133.0,132.5,132.3,130.6,125.1,119.9,114.5,112.4,111.7,55.7,41.0,31.1,28.3.
IRν(KBr,cm-1):3054,2982,2928,2858,2824,1623,1589,1552,1481,1442,1402,1272,1139,1059,863,785.
HRMS(ESI+)calcd for C19H17Br2N3O[M+H]+463.9791.Found 463.9784。
实施例22:2-甲氧基-5,8,9,12,12-五甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3dl)
根据实施例1的方法,采用4-甲氧基苯肼盐酸盐代替苯肼盐酸盐,4,5-二甲基邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,137mg,41%yield.
MP:130-131℃.
1H NMR(500MHz,CDCl3)δ=7.75(s,1H),7.63(s,1H),7.14(d,J=2.7Hz,1H),7.04(d,J=8.8Hz,1H),6.89(dd,J=8.8,2.7Hz,1H),3.89(s,3H),3.72(s,3H),2.46-2.48(m,6H),1.74(s,6H).13C NMR(100MHz,CDCl3)δ=155.1,149.2,145.7,139.2,139.1,137.4,134.7,133.4,128.0,126.1,113.9,112.2,111.5,55.7,40.7,31.0,28.1,20.2,19.8.
IRν(KBr,cm-1):3039,2966,2915,2871,2829,1620,1588,1555,1481,1420,1391,1355,1292,1225,1179,1136,1032,868,787.
HRMS(ESI+)calcd for C21H23N3O[M+H]+334.1914.Found 334.1916。
实施例23:8,9-二氯-4,5,12,12-四甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3ej)
根据实施例1的方法,采用2-甲基苯肼盐酸盐代替苯肼盐酸盐,4,5-二氯邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,244mg,68%yield.
MP:151-152℃.
1H NMR(500MHz,CDCl3)δ=8.11(s,1H),8.00(s,1H),7.39(d,J=7.5Hz,1H),7.18(d,J=7.3Hz,1H),7.13(t,J=7.5Hz,1H),3.82(s,3H),2.56(s,3H),1.68(s,6H).13C NMR(100MHz,CDCl3)δ=154.1,150.2,139.7,138.9,137.8,136.0,133.0,131.7,129.3,128.9,127.4,126.9,123.8,122.7,41.1,39.2,27.1,21.7.
IRν(KBr,cm-1):3078,2963,2922,2860,1603,1558,1484,1449,1397,1343,1154,876,748.
HRMS(ESI+)calcd for C19H17Cl2N3[M+H]+358.0872.Found 358.0873。
实施例24:8,9-二溴-4,5,12,12-四甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3ek)
根据实施例1的方法,采用2-甲基苯肼盐酸盐代替苯肼盐酸盐,4,5-二溴邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,291mg,65%yield.
MP:119-120℃.
1H NMR(500MHz,CDCl3)δ=8.29(s,1H),8.19(s,1H),7.39(d,J=7.5Hz,1H),7.18(d,J=6.9Hz,1H),7.13(t,J=7.5Hz,1H),3.82(s,3H),2.56(s,3H),1.68(s,6H).13C NMR(101MHz,CDCl3)δ=154.3,150.2,140.3,138.9,138.5,136.0,132.7,131.7,130.8,126.9,125.0,123.8,122.7,120.5,41.2,39.2,27.1,21.8.
IRν(KBr,cm-1):3073,2961,2919,2860,1594,1556,1446,1394,1341,1150,1094,873,744.
HRMS(ESI+)calcd for C19H17Br2N3[M+H]+447.9842.Found 447.9841。
实施例25:4,5,8,9,12,12-六甲基-5,12-二氢喹啉[2,3-b]喹喔啉(3el)
根据实施例1的方法,采用2-甲基苯肼盐酸盐代替苯肼盐酸盐,4,5-二甲基邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,187mg,59%yield.
MP:58-59℃.
1H NMR(500MHz,CDCl3)δ=7.78(s,1H),7.68(s,1H),7.39(d,J=7.6Hz,1H),7.16(d,J=7.3Hz,1H),7.09(t,J=7.5Hz,1H),3.83(s,3H),2.56(s,3H),2.47-2.49(m,6H),1.69(s,6H),1.66(s,1.5H).13C NMR(100MHz,CDCl3)δ=151.8,151.0,149.6,149.2,139.8,139.7,139.3,139.1,139.0,137.8,136.6,135.2,131.5,131.4,129.3,128.1,128.1,126.9,126.3,126.2,123.2,122.6,40.8,40.7,39.2,39.2,27.2,27.2,21.6,21.2,20.2,19.9.
IRν(KBr,cm-1):3035,2964,2921,2861,1631,1556,1454,1392,1352,1227,1137,1096,867,744.
HRMS(ESI+)calcd for C21H23N3[M+H]+318.1964.Found 318.1965。
实施例26:8',9'-二氯-5'-甲基-5'H-螺[环己烷-1,12'-喹啉[2,3-b]喹喔啉](3fj)
根据实施例1的方法,采用环己基甲酮代替3-甲基-2-丁酮,4,5-二氯邻苯二胺代替4-硝基邻苯二胺制备该产物。
Yellow solid,231mg,60%yield.
MP:66-68℃.
1H NMR(500MHz,CDCl3)δ=8.14(s,1H),7.99(s,1H),7.67(dd,J=7.7,1.1Hz,1H),7.37(t,J=7.1Hz,1H),7.17-7.22(m,2H),3.73(s,3H),2.34-2.37(m,2H),1.98-2.07(m,2H),1.88-1.93(m,2H),1.67-1.69(m,4H).13C NMR(100MHz,CDCl3)δ=151.8,146.5,139.5,139.1,137.4,133.0,131.7,129.3,128.7,127.4,127.3,125.3,122.7,113.9,43.4,33.5,31.2,26.1,25.6,22.9.
IRν(KBr,cm-1):3068,2924,2853,1597,1559,1475,1440,1397,1344,1139,875,745.
HRMS(ESI+)calcd for C21H19Cl2N3[M+H]+384.1034.Found 384.1032。
实施例27:5',8',9'-三甲基-5'H-螺[环己烷-1,12'-喹啉[2,3-b]喹喔啉](3fl)
根据实施例1的方法,采用环己基甲酮代替3-甲基-2-丁酮,4,5-二甲基邻苯二胺代替4-硝基邻苯二胺制备该产物。
Light yellow solid,165mg,48%yield.
MP:146-148℃.
1H NMR(500MHz,CDCl3)δ=7.81(s,1H),7.66-7.67(m,2H),7.34(t,J=7.6Hz,1H),7.15-7.18(m,2H),3.73(s,3H),2.49(s,3H),2.48(s,3H),2.38-2.40(m,2H),1.95-2.05(m,4H),1.67-1.68(m,4H).13C NMR(100MHz,CDCl3)δ=149.3,145.9,140.4,138.9,138.5,137.4,134.8,132.1,128.2,127.0,126.3,125.1,121.9,113.5,43.10,33.4,31.1,26.3,23.0,20.2,19.8.
IRν(KBr,cm-1):3035,2925,2855,1593,1560,1478,1443,1396,1349,1315,1134,873,745.
HRMS(ESI+)calcd for C23H25N3[M+H]+344.2127.Found 344.2122。
实施例28:6,11,11-三甲基-6,11-二氢吡啶并[3',4':5,6]吡嗪并[2,3-b]喹啉(3an)
根据实施例1的方法,采用3,4-二胺基吡啶代替4-硝基邻苯二胺制备该产物。
Yellow solid,174mg,63%yield.
MP:110-112℃.
1H NMR(500MHz,CDCl3)δ=9.28(s,1H),8.63(d,J=5.7Hz,1H),7.65(d,J=5.7Hz,1H),7.56(dd,J=7.7,1.2Hz,1H),7.40-7.36(m,1H),7.21(d,J=7.5Hz,1H),7.19(d,J=7.8Hz,1H),3.80(s,3H),1.77(s,6H).13C NMR(100MHz,CDCl3)δ=152.9,152.4,148.2,147.3,144.5,138.0,134.8,131.7,127.7,125.6,123.3,119.7,114.1,40.9,31.3,28.6.
IRν(KBr,cm-1):3068,3037,2976,2930,2866,1592,1555,1465,1430,1401,1369,1291,1140,813,746.
HRMS(ESI+)calcd for C17H16N4[M+H]+277.1448.Found 277.1453。
实施例29:6,11,11-三甲基-6,11-二氢吡啶并[2',3':5,6]吡嗪并[2,3-b]喹啉(3ao)
根据实施例1的方法,2,3-二胺基吡啶代替4-硝基邻苯二胺制备该产物。
Brown oil,130mg,47%yield.
1H NMR(500MHz,CDCl3)δ=8.92(s,1H),8.30(dd,J=8.1,1.4Hz,1H),7.54-7.56(m,1H),7.42-7.45(m,1H),7.37(t,J=7.2Hz,1H),7.17-7.19(m,2H),3.85(s,3H),1.76(s,6H).13C NMR(125MHz,CDCl3)δ=152.4,150.4,148.0,138.3,137.1,133.2,131.6,128.8,127.7,125.5,122.9,120.8,114.0,40.9,31.4,28.5.
IRν(KBr,cm-1):3039,2963,2927,2863,1597,1553,1480,1441,1380,1288,1150,1125,790,750.
HRMS(ESI+)calcd for C17H16N4[M+H]+277.1448.Found 277.1455。
实施例30:本发明所述四稠环喹喔啉类衍生物的体外细胞毒性研究
药用组合物:注射溶液
实施例1-29化合物 l0mg
注射制剂用蒸馏水 25m1
细胞株:MCF-7细胞、Hela细胞、A549细胞,所试药品编号为:3aa-3fl和顺铂。
测试方法(改良的MTT法):
实验组:取处于对数生长期的人乳腺癌细胞MCF-7、人宫颈癌细胞Hela、人肺腺癌细胞A549制成细胞悬浮液,将细胞浓度调整为2×104个/mL,每孔90μL加入96孔培养板,将细胞在温度37℃,5%CO2的湿式培养箱中培养,待贴壁后给予加药刺激。每孔分别加入10μL不同浓度的药品(化合物3aa-3ao),每种药品均设3个浓度:10μM、1μM、0.1μM,每组均设4个复孔。细胞加药后在培养箱中孵育48h之后,加入MTT(5mg/mL,Sigma),10μL/孔,在培养箱中继续培养。4h后吸弃培养液,每孔加入100μL DMSO,室温震荡l0min,用酶标仪(VERSAmax,美国)在570nm波长下测定各孔的OD值。
空白组:将实验组中的细胞悬浮液用等体积的细胞培养液代替,其他条件保持不变。
阳性对照组:将实验组中的药品用相同浓度的顺铂代替,其他条件保持不变。
阴性对照组:将实验组中的药品用等体积的PBS代替,其他条件保持不变。
数据处理:
细胞存活率(%)=[OD加药组-OD空白组]/[OD阴性对照组-OD空白组];细胞抑制率(%)=100%-细胞存活率(%)。其中,加药组为实验组或阳性对照组。在测试浓度范围内通过软件计算其IC50值。
结果表明本发明所述四稠环喹喔啉类衍生物对肿瘤细胞具有很好的细胞毒活性,可用于抗肿瘤药物的制备。
Claims (7)
1.一种四稠环喹喔啉类衍生物,其结构通式如下:
式中,
A1、A2、A3、A4全部为C;
或者A1、A2、A3、A4中的任一个为N,其余为C,并且A1、A2、A3或A4为N时,则不具有相对应的R9、R8、R7或R6取代基;
R5选自直链或支链C1-C8烷基,
R10和R11相同或不同,选自下列的基团:直链或支链C1-C8烷基;或者R10和R11与它们共同连接的碳原子一起形成环丁基、环戊基或环己基;
R1、R2、R3、R4、R6、R7、R8和R9,相同或不同,彼此互相独立,选自下列基团:
氢原子、卤素、硝基、腈基、羟基、羧基、氨基、C1-8烷基胺基、二(C1-8烷基)胺基、C1-8烷氧基、-C(=O)O-C1-8烷基、-OC(=O)-C1-8烷基、-C(=O)O-(卤代C1-8烷基)、-OC(=O)-(卤代C1-8烷基),Cl-8直链或支链烷基、卤代C1-8烷基。
2.根据权利要求1所述的四稠环喹喔啉类衍生物,其特征在于所述R5选自直链或支链C1-C6烷基,
R10和R11相同或不同,选自下列的基团:直链或支链C1-C6烷基;或者R10和R11与它们共同连接的碳原子一起形成环丁基、环戊基或环己基;
R1、R2、R3、R4、R6、R7、R8和R9,相同或不同,彼此互相独立,选自下列基团:
氢原子、卤素、硝基、腈基、羟基、羧基、氨基、C1-6烷基胺基、二(C1-6烷基)胺基、C1-6烷氧基、-C(=O)O-C1-6烷基、-OC(=O)-C1-6烷基、-C(=O)O-(卤代C1-6烷基)、-OC(=O)-(卤代C1-6烷基),Cl-6直链或支链烷基、卤代C1-6烷基。
3.根据权利要求2所述的四稠环喹喔啉类衍生物,其特征在于:R1、R2、R3、R4、R6、R7、R8和R9,相同或不同,彼此互相独立,选自下列基团:
氢原子、F、Cl、Br、硝基、腈基、羟基、羧基、氨基、甲氧基、-C(=O)O-CH3、甲基、乙基、丙基。
5.如权利要求4所述的制备方法,其特征在于反应溶剂选自乙腈、DMF、THF、DMA、DMSO、甲苯中的一种或几种。
6.权利要求1-3任一项所述的四稠环喹喔啉类衍生物在制备抗肿瘤药物中的应用。
7.一种药用组合物,其特征在于含有至少一种如权利要求1-3中任一项所述四稠环喹喔啉类衍生物。
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