CN105646579B - [2‑(1h)‑喹啉酮‑3‑基]苯氨甲基膦酸酯作为抗癌药物的应用 - Google Patents
[2‑(1h)‑喹啉酮‑3‑基]苯氨甲基膦酸酯作为抗癌药物的应用 Download PDFInfo
- Publication number
- CN105646579B CN105646579B CN201610063646.3A CN201610063646A CN105646579B CN 105646579 B CN105646579 B CN 105646579B CN 201610063646 A CN201610063646 A CN 201610063646A CN 105646579 B CN105646579 B CN 105646579B
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- China
- Prior art keywords
- quinolinone
- bases
- aminomethylphosphoniacid
- alkyl
- phenylaminomethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title claims abstract description 115
- -1 phenylaminomethyl phosphonate ester Chemical class 0.000 title claims abstract description 50
- 239000003814 drug Substances 0.000 title description 9
- 229940079593 drug Drugs 0.000 title description 6
- 238000011275 oncology therapy Methods 0.000 title description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052805 deuterium Inorganic materials 0.000 claims abstract description 18
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 15
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 15
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 15
- 239000000460 chlorine Substances 0.000 claims abstract description 15
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 15
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- 239000011737 fluorine Substances 0.000 claims abstract description 15
- 239000011630 iodine Substances 0.000 claims abstract description 15
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 10
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- 210000004027 cell Anatomy 0.000 description 38
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 22
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了结构式Ⅰ所示的[2‑(1H)‑喹啉酮‑3‑基]苯氨甲基膦酸酯及其在药学上可接受的盐:其中,R选自:C1~C2烷基、C3~C4直链烷基或支链烷基;X1、X2选自:氢、氘、C1~C2烷基;X3、X7选自:氢、氘、C1~C2烷基、氟、氯、溴、碘或硝基;X4、X6选自:氢、氘、三氟甲基、C1~C2烷基、氟、氯、溴、碘;X5选自:氢、氘、三氟甲基、C1~C2烷基、C1~C2烷氧基、氟、氯、溴、碘或硝基。[2‑(1H)‑喹啉酮‑3‑基]苯氨甲基膦酸酯及其药学上可接受的盐以及药物组合物在制备抗癌药中的应用。
Description
技术领域
本发明涉及一类新化合物的制备与应用;具体是[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯及其作为抗癌药物的应用。
背景技术
Chen等[Bioorg.Med.Chem.2013,21:5064–5075]描述了2-(1H)-喹啉酮衍生物诱导细胞凋亡在G2/M期,6,7-亚甲二氧基-4-(2,4-二甲氧基苯基)-2-(1H)-喹啉酮(A1)对MCF-7细胞株具有良好的抑制活性,其IC50值为6.0μM;Raghavana等[Med.Chem.Lett.2015,25:3601–3605]描述了2-(1H)-喹啉酮衍生物的制备和抗肿瘤活性,3-((1E,4Z,6E)-5-羟基-7-(4-羟基-3-甲氧基苯基)-3-氧代-1,4,6-庚三烯-1-基)-1-(丙烯基)-2-(1H)-喹啉酮(A2)对四种细胞株(A549、MCF-7、SKOV3和H460)具有较好的抑制活性,其IC50值分别为21.3μM、15μM、19μM和25.4μM;Asish等[Eur.J.Med.Chem.2013,66:146–152]描述了氨基膦酸酯衍生物作为抗肿瘤药物,二丁基(苯并[d][1,3]二氧杂-5-基(((R)-1-苯乙基)氨基)甲基)膦酸酯(A3)对A549细胞株和Jurkat细胞株具有良好的抑制活性,其IC50值分别为43.4μM和4.0μM;Li等[Molecules.2015,20,14791–14809]描述了氨基膦酸酯衍生物的制备和抗肿瘤活性,其中二乙基-1-(3-(4-甲基-2-氧代色满-7-氧基)丙酰胺)-1-苯乙基-膦酸酯(A4)对HCT-116细胞株具有较好的抑制活性,IC50值为8.68μM。
发明内容
本发明解决的技术问题是提供一类[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯、其制备方法、药物组合物和用途。
为解决本发明的技术问题,本发明提供如下技术方案:
本发明技术方案的第一方面是化学结构式Ⅰ所示的[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯及其在药学上可接受的盐:
其中,R选自:C1~C2烷基、C3~C4直链烷基或支链烷基;X1、X2选自:氢、氘、C1~C2烷基;X3、X7选自:氢、氘、C1~C2烷基、氟、氯、溴、碘或硝基;X4、X6选自:氢、氘、三氟甲基、C1~C2烷基、氟、氯、溴、碘;X5选自:氢、氘、三氟甲基、C1~C2烷基、C1~C2烷氧基、氟、氯、溴、碘或硝基。
进一步的,优选的化合物选自:[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2-甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3-甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-4-甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-4-三氟甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2-硝基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-4-硝基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-4-甲氧基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2-氯苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3-氯苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-4-氯苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2-溴苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3-溴苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2,6-二甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3,4-二甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3,5-二三氟甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2,4-二硝基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2-氯-4-硝基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3-氯-4-氟苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2,3-二氯苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3,5-二氯苯氨甲基膦酸二乙酯。
本发明技术方案的第二方面是提供了第一方面所述的[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯的制备方法,其特征在于它的制备反应如下:
R选自:C1~C2烷基、C3~C4直链烷基或支链烷基;X1、X2选自:氢、氘、C1~C2烷基;X3、X7选自:氢、氘、C1~C2烷基、氟、氯、溴、碘或硝基;X4、X6选自:氢、氘、三氟甲基、C1~C2烷基、氟、氯、溴、碘;X5选自:氢、氘、三氟甲基、C1~C2烷基、C1~C2烷氧基、氟、氯、溴、碘或硝基。
本发明技术方案的第三方面是提供含有第一方面所述化合物及其药学上可接受的盐的药物组合物,该药物组合物含有治疗有效量的本发明的[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯及其药学上可接受的盐,以及任选的含有药用载体。其中所述的药用载体指药学领域常用的药用载体;该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物及其药学上可接受的盐与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂组合,制成适于人或动物使用的任何剂型。本发明化合物及其药学上可接受的盐在其药物组合物中的含量通常为0.1%~95%重量百分比。
本发明化合物及其药学上可接受的盐或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物及其药学上可接受的盐可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物及其药学上可接受的盐制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明化合物及其药学上可接受的盐与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物及其药学上可接受的盐先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物及其药学上可接受的盐片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物及其药学上可接受的盐的胶囊剂。
为将本发明化合物及其药学上可接受的盐制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明技术方案的第四方面是提供本发明第一方面所述[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯及其药学上可接受的盐以及第三方面所述药物组合物在制备抗癌药方面的应用。
有益技术效果:
本发明的[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯是一类新结构类型的具有抗癌活性的化合物。
具体实施方式
以下实施例旨在说明本发明而不是对本发明的进一步限定。
实施例1
[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸二乙酯的制备
(1)3-甲酰基-2-(1H)-喹啉酮的制备
98ml POCl3逐滴加入到7ml N,N-二甲基甲酰胺中,在0~5℃搅拌30min,加入50mmol乙酰苯胺,升温至90℃,反应16h。冷却,反应也倾入500ml冰水中,抽滤,用水洗涤。固体中加入200ml 70%的醋酸溶液,95℃反应4h。冷却反应液,析出絮状固体,过滤,水洗,干燥得3-甲酰基-2-(1H)-喹啉酮,收率73.8%,m.p.303~305℃。
(2)[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应4h,脱溶后用V(石油醚):V(乙酸乙酯)=4:1进行柱层析,得白色固体,收率60%,熔点194~196℃;1H NMR(400MHz,CDCl3)δ:11.53(s,1H,NH),8.06(d,J=3.7Hz,1H),7.53(t,J=7.8Hz,1H),7.48(d,J=7.7Hz,1H),7.36(d,J=8.1Hz,1H),7.19(t,J=7.9Hz,1H),7.11(t,J=7.9Hz,1H),6.74~6.68(m,3H),5.58,5.52(s,1H,NCHP),4.30~4.25(m,2H,OCH2),4.13~3.97(m,2H,OCH2),1.34(t,3H,J=7.1Hz,CH3),1.14(t,3H,J=7.0Hz,CH3);13C NMR(100MHz,CDCl3)δ:163.43,146.26,138.66,138.04,130.53,129.30,128.66,128.17,122.69,119.99,118.47,115.81,113.74,63.89,63.52,48.70(47.16),16.54,16.30。
实施例2
[2-(1H)-喹啉酮-3-基]-2-甲基苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 2-甲基苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应3h,脱溶后用V(石油醚):V(乙酸乙酯)=4:1进行柱层析,得浅黄色固体,收率86.3%,熔点191~193。1H NMR(400MHz,CDCl3)δ:11.59(s,1H,NH),8.01(d,J=3.6Hz,1H),7.54(d,J=7.9Hz,1H),7.49(t,J=7.6Hz,1H),7.40(d,J=7.6Hz,1H),7.20(t,J=7.4Hz,1H),7.05(d,J=7.2Hz,1H),6.97(t,J=7.7Hz,1H),6.65(t,J=7.3Hz,1H),6.58(d,J=8.0Hz,1H),5.56,5.50(s,1H,NCHP),4.86(s,1H,NH),4.32~4.23(m,2H,OCH2),4.15~3.96(m,2H,OCH2),2.30(s,3H,CH3),1.34(t,3H,J=7.0Hz,CH3),1.15(t,3H,J=6.9Hz,CH3);13C NMR(100MHz,CDCl3)δ:163.37,143.92,138.35,138.02,130.58,130.30,128.49,128.17,127.23,123.02,122.78,119.98,118.31,115.89,111.00,63.79,63.53,49.26(47.71),17.66,16.54,16.32。
实施例3
[2-(1H)-喹啉酮-3-基]-3-甲基苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 3-甲基苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应2h,脱溶后用V(石油醚):V(乙酸乙酯)=4:1进行柱层析,得黄色固体,收率77.5%,熔点174~176℃;1H NMR(400MHz,CDCl3)δ:11.37(s,1H,NH),8.04(d,J=3.7Hz,1H),7.53(d,J=7.8Hz,1H),7.47(t,J=7.7Hz,1H),7.34(d,J=8.2Hz,1H),7.18(t,J=7.5Hz,1H),6.99(t,J=7.7Hz,1H),6.58~6.50(m,3H),5.56~5.50(m,1H,NCHP),4.29~4.25(m,2H,OCH2),4.12~3.95(m,2H,OCH2),2.20(s,3H,CH3),1.34(t,3H,J=7.1Hz,CH3),1.13(t,3H,J=7.0Hz,CH3);13C NMR(100MHz,CDCl3)δ:163.40,146.16,139.08,138.53,137.97,130.50,129.19,128.71,128.16,122.70,119.97,119.48,115.82,114.66,110.59,63.83,63.47,48.81(47.28),21.57,16.53,16.29。
实施例4
[2-(1H)-喹啉酮-3-基]-4-甲基苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 4-甲基苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应4h,脱溶后用V(石油醚):V(乙酸乙酯)=4:1进行柱层析,得黄色固体,收率72.5%,熔点181~184℃;1H NMR(400MHz,CDCl3)δ:11.47(s,1H,NH),8.06(d,J=3.3Hz,1H),7.52(d,J=7.9Hz,1H),7.47(t,J=7.7Hz,1H),7.34(d,J=8.2Hz,1H),7.18(t,J=7.5Hz,1H),6.93(d,J=8.2Hz,2H),6.67(d,J=7.8Hz,2H),5.55,5.49(s,1H,NCHP),4.32~4.24(m,2H,OCH2),4.12~3.96(m,2H,OCH2),2.17(s,3H,CH3),1.34(t,3H,J=7.1Hz,CH3),1.14(t,3H,J=7.1Hz,CH3);13C NMR(100MHz,CDCl3)δ:163.37,143.64,138.67,137.99,130.51,129.81,128.60,128.18,127.90,122.68,119.98,115.80,114.02,63.81,63.45,49.12(47.58),20.38,16.48,16.25。
实施例5
[2-(1H)-喹啉酮-3-基]-3-三氟甲基苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 3-三氟甲基苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应2.5h,脱溶后用V(石油醚):V(乙酸乙酯)=4:1进行柱层析,得浅黄色固体,收率79.2%,熔点219~222℃;1H NMR(400MHz,CDCl3)δ:11.91(s,1H,NH),8.10(d,J=3.6Hz,1H),7.53(d,J=8.0Hz,1H),7.45(t,J=8.0Hz,1H),7.36(d,J=8.0Hz,1H),7.22~7.15(m,2H),7.01(s,1H),6.93(d,J=8.0Hz,1H),6.49(dd,J=1.6Hz,J=2.0Hz,1H),5.53~5.47(m,1H,NCHP),4.30~4.22(m,2H,OCH2),4.14~3.98(m,2H,OCH2),1.33(t,J=7.2Hz,3H,CH3),1.17(t,J=6.8Hz,3H,CH3);13C NMR(100MHz,CDCl3)δ:162.98,146.44,139.07,137.73,131.78,131.46,130.95,129.82,128.23,127.77,123.13,119.94,116.16,115.90,114.91,110.56,63.94,63.67,48.68(47.18),16.46,16.26。
实施例6
[2-(1H)-喹啉酮-3-基]-4-三氟甲基苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 4-三氟甲基苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应4h,脱溶后用V(石油醚):V(乙酸乙酯)=4:1进行柱层析,得黄色固体,收率78.0%,熔点219~222℃;1H NMR(400MHz,DMSO-d6)δ:12.03(s,1H,NH),8.09(d,J=3.6Hz,1H),7.61(d,J=7.8Hz,1H),7.54~7.49(m,2H),7.39(d,J=8.8Hz,1H),7.33(d,J=8.1Hz,1H),7.19(t,J=7.4Hz,1H),7.13(t,1H,J=8.0Hz,1H),6.84(d,J=8.7Hz,1H).5.40,5.32(s,1H,NCHP),4.12~3.90(m,4H,2×OCH2),1.21(t,3H,J=7.0Hz,CH3),1.10(t,3H,J=7.0Hz,CH3);13C NMR(100MHz,DMSO-d6)δ:161.37,142.41,138.06,133.61,130.54,128.75,127.75,126.22,122.60,122.16,118.77,118.10,115.10,112.53,62.87,62.61,47.25(45.71),16.22,16.05。Anal.calcd.for C21H22F3N2O4P:C,55.51;H,4.88;N,6.17。Found C,55.53;H,4.89;N,6.18。
实施例7
[2-(1H)-喹啉酮-3-基]-2-硝基苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 2-硝基苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应1.5h,脱溶后用V(石油醚):V(乙酸乙酯)=4:1进行柱层析,得黄色固体,收率75.6%,熔点207~209℃;1H NMR(400MHz,CDCl3)δ:11.27(s,1H,NH),9.05(t,J=8.9Hz,1H,NH),8.20(d,J=7.3Hz,1H),8.03(d,J=3.6Hz,1H),7.59(d,J=7.9Hz,1H),7.53(t,J=7.7Hz,1H),7.36(t,J=7.2Hz,2H),7.24(t,J=7.6Hz,1H),6.87(d,J=8.5Hz,1H),6.71(t,J=7.8Hz,1H),5.74,5.66(s,1H,NCHP,NH),4.29~4.16(m,2H,OCH2),4.22~4.14(m,2H,OCH2),1.36~1.28(m,6H,2×CH2);13C NMR(100MHz,CDCl3)δ:162.98,143.61,139.00,137.87,136.47,133.40,131.19,128.29,127.21,126.90,123.32,119.96,116.98,116.10,114.54,64.08,63.73,48.60(47.06),16.47,16.41。
实施例8
[2-(1H)-喹啉酮-3-基]-4-硝基苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 4-硝基苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应2h,脱溶后用V(石油醚):V(乙酸乙酯)=4:1柱层析,得黄色固体,收率81.4%,熔点221~224℃;1H NMR(400MHz,DMSO-d6)δ:12.11(s,1H,NH),8.12(d,J=3.2Hz,1H,),8.02(d,J=9.2Hz,2H),7.96~7.92(m,1H,NH),7.65(d,J=7.6Hz,1H),7.53(t,J=8.0Hz,1H),7.20(t,J=7.6Hz,1H),6.85(d,J=8.8Hz,2H),5.48,5.42(d,J=9.4Hz,1H,NCHP),4.14~4.09(m,2H,OCH2),4.04~3.93(m,2H,OCH2),1.22(t,J=7.2Hz,3H,CH3),1.11(t,J=7.2Hz,3H,CH3);13C NMR(100MHz,DMSO-d6)δ:160.93,153.18,138.13,138.01,137.21,130.69,128.09,127.85,125.89,122.20,118.72,118.69,115.16,111.94,62.97,62.87,47.31(45.75),16.23,16.06。
实施例9
[2-(1H)-喹啉酮-3-基]-4-甲氧基苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 4-甲氧基苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应2h,脱溶后用V(石油醚):V(乙酸乙酯)=2:1柱层析,得亮黄色固体,收率67.5%,熔点187~189℃;1H NMR(400MHz,CDCl3)δ:11.19(s,1H,NH),8.03(d,J=3.7Hz,1H),7.53(d,J=7.9Hz,1H),7.48(t,J=7.7Hz,1H),7.33(d,J=8.2Hz,1H),7.19(t,J=7.6Hz,1H),6.73~6.64(m,4H),5.49,5.43(s,1H,NCHP),4.32~4.23(m,2H,OCH2),4.12~3.97(m,2H,OCH2),3.66(s,3H,CH3),1.34(t,J=7.1Hz,3H,CH3),1.15(t,J=7.0Hz,3H,CH3);13C NMR(100MHz,DMSO-d6)δ:161.19,151.69,140.86,137.98,137.15,130.28,129.66,127.61,122.04,118.92,115.00,114.45,62.73,62.41,55.13,48.45(46.89),16.28,16.09。
实施例10
[2-(1H)-喹啉酮-3-基]-2-氯苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 2-氯苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应2h,脱溶后用V(石油醚):V(乙酸乙酯)=4:1进行柱层析,得橙色固体,收率91.7%,熔点174~177℃;1H NMR(400MHz,CDCl3)δ:11.68(s,1H),8.04(d,J=3.7Hz,1H),7.58(d,J=7.9Hz,1H),7.49(t,J=7.6Hz,1H),7.37(d,J=8.2Hz,1H),7.21(t,J=7.5Hz,1H),7.02(d,J=8.4Hz,2H),6.66(d,J=8.8Hz,2H),5.55,5.49(s,1H,NCHP),4.31-4.25(m,2H,OCH2),4.16~4.03(m,2H,OCH2),1.35(t,J=7.1Hz,3H,CH3),1.15(t,J=7.1Hz,3H,CH3);13C NMR(100MHz,CDCl3)δ:163.30,142.03,138.67,137.84,130.81,129.30,128.20,127.95,127.75,123.02,120.01,119.93,118.75,115.96,112.44,64.02,63.63,49.03(47.49),16.51,16.33。
实施例11
[2-(1H)-喹啉酮-3-基]-3-氯苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 3-氯苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应2h,脱溶后用V(石油醚):V(乙酸乙酯)=4:1进行柱层析,得黄色固体,收率89.3%,熔点170~172℃;1H NMR(400MHz,CDCl3)δ:12.02(s,1H),8.08(d,J=3.6Hz,1H),7.53(d,J=7.9Hz,1H),7.48(t,J=7.7Hz,1H),7.39(d,J=8.2Hz,1H),7.20(t,J=7.5Hz,1H),7.01(t,J=8.1Hz,1H),6.75(t,J=2.0Hz,1H),6.66(dd,J=7.7,1.4Hz,1H),6.58(dd,J=8.2,2.1Hz,1H),5.50~5.44(m,1H,NCHP),4.32~4.23(m,2H,OCH2),4.10~3.7(m,2H,OCH2),1.34(t,J=7.1Hz,3H,CH3),1.15(t,J=7.1Hz,3H,CH3);13CNMR(100MHz,CDCl3)δ:163.28,147.69,139.02,137.98,134.98,130.73,130.29,128.16,128.08,122.84,119.92,118.31,115.92,113.86,111.69,64.05,63.72,48.57(47.03),16.52,16.29。Anal.calcd.for C20H22ClN2O4P:C,57.08;H,5.27;N,6.66。Found C,57.10;H,5.26;N,6.68。
实施例12
[2-(1H)-喹啉酮-3-基]-4-氯苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 4-氯苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应2h,脱溶后用V(石油醚):V(乙酸乙酯)=4:1进行柱层析,得黄色固体,收率88.1%,熔点192~194℃;1H NMR(400MHz,CDCl3)δ:11.65(s,1H,NH),8.06(d,J=3.6Hz,2H),7.54~7.48(m,2H),7.36(d,J=8.2Hz,1H),7.21(t,J=7.3Hz,1H),7.05(d,J=8.8Hz,1H),6.66(d,J=8.8Hz,2H),5.51,5.45(s,1H,NCHP),4.34~4.21(m,2H,OCH2),4.10~3.99(m,2H,OCH2),1.35(t,J=7.2Hz,3H,CH3),1.15(t,J=7.2Hz,3H,CH3);13C NMR(100MHz,CDCl3)δ:163.21,144.83,138.81,137.94,130.76,129.12,128.19,128.13,123.20,122.90,119.89,115.80,114.97,63.95,63.59,48.90(47.35),16.52,16.29。Anal.calcd.for C20H22ClN2O4P:C,57.08;H,5.27;N,6.66。Found C,57.05;H,5.29;N,6.64。
实施例13
[2-(1H)-喹啉酮-3-基]-2-溴苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 2-溴苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应1.5h,脱溶后用V(石油醚):V(乙酸乙酯)=4:1进行柱层析,得黄色固体,收率84.8%,熔点209~211℃;1H NMR(400MHz,CDCl3)δ:11.62(s,1H,NH),8.02(d,J=3.6Hz,1H),7.58(d,J=8.0Hz,1H),7.46(t,J=8.0Hz,1H),7.43~7.38(m,2H),7.22(t,J=3.6Hz,1H),7.05(t,J=7.6Hz,1H),6.65(d,J=8.0Hz,1H),6.58(t,J=7.6Hz,1H),5.53~5.47(m,1H,NCHP),4.33~4.26(m,2H,OCH2),4.14~4.06(m,2H,OCH2),1.35(t,J=6.8Hz,3H,CH3),1.20(t,J=7.2Hz,3H,CH3);13C NMR(100MHz,CDCl3)δ:163.44,142.94,138.51,138.00,132.54,130.72,128.61,128.24,127.94,122.89,119.94,119.21,115.92,112.52,110.44,63.95,63.54,49.23(47.70),16.56,16.36。
实施例14
[2-(1H)-喹啉酮-3-基]-3-溴苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 3-溴苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应1h,脱溶后用V(石油醚):V(乙酸乙酯)=4:1进行柱层析,得淡黄色固体,收率63%,熔点213~216℃;1H NMR(400MHz,CDCl3)δ:12.14(s,1H,NH),8.10(d,J=3.6Hz,1H),7.52(d,J=8.0Hz,1H),7.45(t,J=8.0Hz,1H),7.38(d,J=8.0Hz,1H),7.18(d,J=8.0Hz,1H),6.97~6.92(m,2H),6.80(dd,J=2.0Hz,J=1.2Hz,1H),6.64(dd,J=1.6Hz,J=2.4Hz,1H),5.5,1,5.45(s,1H,NCHP),4.31~4.23(m,2H,OCH2),4.13~3.97(m,2H,OCH2),1.35(t,J=5.6Hz,3H,CH3),1.17(t,J=3.2Hz,3H,CH3);13C NMR(100MHz,CDCl3)δ:163.17,147.69,139.06,137.88,130.81,130.60,128.15,127.89,123.21,122.94,121.30,119.90,116.80,115.99,112.07,64.02,63.70,48.68(47.13),16.52,16.30。
实施例15
[2-(1H)-喹啉酮-3-基]-2,6-二甲基苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 2,6-二甲基苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应2.5h,脱溶后用V(石油醚):V(乙酸乙酯)=2:1柱层析,得褐色固体,收率68.7%,熔点213~216℃;1H NMR(CDCl3,400MHz)δ:11.46(s,1H,NH),8.11(d,J=3.0Hz,1H),7.61(d,J=7.9Hz,1H),7.50(t,J=7.7Hz,1H),7.34(d,J=8.2Hz,1H),7.23(d,J=7.7Hz,1H),6.93(d,J=7.5Hz,2H),6.76(t,J=7.4Hz,1H),5.25,5.19(s,1H,NCHP),4.18~4.11(m,2H,OCH2),4.05~3.86(m,2H,OCH2),2.33(s,6H,2×CH3),1.24(t,3H,J=6.9Hz,CH3),1.10(t,3H,J=7.0Hz,CH3);13C NMR(100MHz,CDCl3)δ:163.18,144.57,139.09,137.93,130.52,129.94,129.05,128.55,128.01,122.85,121.75,119.93,115.98,63.16,63.11,52.38(51.39),18.84,16.32,16.26。
实施例16
[2-(1H)-喹啉酮-3-基]-3,4-二甲基苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 3,4-二甲基苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应2.5h,脱溶后用V(石油醚):V(乙酸乙酯)=3:1柱层析,得淡黄色固体,收率91.5%,熔点185~188℃;1H NMR(400MHz,CDCl3)δ:12.06(s,1H,NH),8.06(d,J=4.0Hz,1H),7.51(t,J=7.6Hz,1H),7.46(d,J=7.2Hz,1H),7.40(d,J=8.4Hz,1H),7.17(t,J=7.6Hz,1H),6.85(d,J=8.0Hz,1H),6.57(d,J=1.6Hz,1H),6.49(dd,J=2.4Hz,J=2.0Hz,1H),5.57,5.51(s,1H,NCHP),4.32~4.25(m,2H,OCH2),4.10~3.98(m,2H,OCH2),2.1(s,3H,CH3),2.07(s,3H,CH3),1.34(t,J=7.2Hz,3H,CH3),1.12(t,J=7.2Hz,3H,CH3);13C NMR(100MHz,CDCl3)δ:163.44,144.22,138.59,137.99,137.39,130.45,130.34,128.81,128.15,126.52,122.65,120.01,115.84,115.72,110.88,63.92,63.46,48.99(47.45),20.00,18.67,16.55,16.30。
实施例17
[2-(1H)-喹啉酮-3-基]-3,5-二三氟甲基苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 3,5-二三氟甲基苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应4h,脱溶后用V(石油醚):V(乙酸乙酯)=3:1柱层析,得白色固体,收率84.6%,熔点246~248℃;1H NMR(400MHz,DMSO-d6)δ:12.16(s,1H,NH),8.11(d,J=3.3Hz,1H),7.65(d,J=7.8Hz,1H),7.56~7.49(m,2H),7.32(d,J=5.2Hz,3H),7.20(t,J=7.6Hz,1H),7.15(s,1H),5.42~7.53(m,1H,NCHP),4.13(m,2H,OCH2),4.04~3.90(m,2H,OCH2),1.22(t,J=7.0Hz,3H,CH3),1.10(t,J=7.0Hz,3H,CH3);13CNMR(100MHz,DMSO)δ:161.36,148.92,138.41,138.27,131.38,131.07,128.42,128.25,125.13,122.56,119.02,115.44,112.80,109.35,63.20,63.12,47.40(45.85),16.52,16.37。Anal.calcd.for C22H21F6N2O4P:C,50.58;H,4.05;N,5.36。
实施例18
[2-(1H)-喹啉酮-3-基]-2,4-二硝基苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 2,4-二硝基苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应2h,脱溶后用V(石油醚):V(乙酸乙酯)=3:1柱层析,得红色固体,收率57.4%,熔点201~204℃;1H NMR(400MHz,DMSO-d6)δ:12.20(s,1H,NH),9.70(s,1H),8.89(d,J=2.8Hz,1H),8.34(dd,J=9.5,2.4Hz,1H),8.14(d,J=3.2Hz,1H),7.68(t,J=7.8Hz,1H),7.54(t,J=7.7Hz,1H),7.35(d,J=8.1Hz,2H),7.20(t,J=7.3Hz,1H),7.11(d,J=9.6Hz,1H),5.78,5.70(d,1H,NCHP),4.21~4.11(m,2H,OCH2),4.08~3.98(m,2H,OCH2),1.25(t,J=7.0Hz,3H,CH3),1.14(t,J=7.1Hz,3H,CH3);13C NMR(100MHz,DMSO-d6)δ:160.94,146.67,138.44,138.22,136.10,131.11,130.92,130.36,128.16,125.72,123.34,122.29,118.68,115.51,115.13,63.38,63.32,50.54(49.02),16.18,16.09。Anal.calcd.for C20H21N4O8P:C,50.43;H,4.44;N,11.76。
实施例19
[2-(1H)-喹啉酮-3-基]-2-氯-4-硝基苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 2-氯-4-硝基苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应4h,脱溶后用V(石油醚):V(乙酸乙酯)=3:1柱层析,得橙红色固体,收率70.0%,熔点137~139℃;1H NMR(400MHz,DMSO-d6)δ:12.15(s,1H),8.23(d,J=2.6Hz,1H),8.18(d,J=3.2Hz,1H),8.10(dd,J=9.1,2.8Hz,1H),7.71(d,J=7.7Hz,1H),7.54(t,J=7.7Hz,1H),7.36(d,J=8.2Hz,1H),7.22(t,J=7.5Hz,1H),6.96(d,J=9.3Hz,1H),5.63,5.55(d,J=9.0Hz,1H,NCHP),4.16~4.07(m,2H,OCH2),4.05~3.96(m,2H,OCH2),1.22(t,J=7.0Hz,3H,CH3),1.12(t,J=7.0Hz,3H,CH3);13C NMR(100MHz,DMSO-d6)δ:161.29,147.65,138.77,138.12,137.35,130.84,128.07,125.57,125.04,124.75,122.33,117.80,115.15,113.52,110.90,63.08,63.02,50.99(49.46),16.20,16.11。
实施例20
[2-(1H)-喹啉酮-3-基]-3-氯-4-氟苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 3-氯-4氟苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应4h,脱溶后用V(石油醚):V(乙酸乙酯)=1:1柱层析,得浅黄色固体,收率85.2%,熔点157~159℃。1H NMR(400MHz,CDCl3)δ:11.51(s,1H),8.06(d,J=3.6Hz,1H),7.52(dd,J=15.2,7.8Hz,2H),7.36(d,J=8.3Hz,1H),7.21(t,J=7.2Hz,1H),6.87(t,J=8.8Hz,1H),6.79(dd,J=6.0,2.8Hz,1H),6.58~6.54(m,1H),5.46,5.39(s,1H,NCHP),4.32~4.23(m,2H,OCH2),4.11~3.96(m,2H,OCH2),1.34(t,J=7.1Hz,3H,CH3),1.15(t,J=7.0Hz,3H,CH3);13C NMR(100MHz,CDCl3):δ163.20,150.41,143.03,139.15,137.94,130.90,128.19,127.82,122.99,121.08,119.93,116.70,115.97,115.46,112.93,63.91,63.58,49.17,47.62,16.47,16.24。
实施例21
[2-(1H)-喹啉酮-3-基]-2,3-二氯苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 2,3-二氯苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应2.5h,脱溶后用V(石油醚):V(乙酸乙酯)=1:1柱层析,得浅黄色固体,收率70.3%,熔点172~175℃;1H NMR(400MHz,CDCl3)δ:11.77(s,1H),8.02(d,J=3.6Hz,1H),7.59(d,J=7.8Hz,1H),7.52(t,J=7.7Hz,1H),7.40(d,J=8.1Hz,1H),7.23(t,J=7.4Hz,1H),6.93(t,J=8.1Hz,1H),6.80(d,J=7.0Hz,1H),6.59(d,J=7.7Hz,1H),5.74(t,J=8.5Hz,1H,NH),5.57,5.51(d,J=7.8Hz,J=12.7Hz,1H,NCHP),4.32~4.25(m,2H,OCH2),4.16~4.03(m,2H,OCH2),1.35(t,J=7.0Hz,3H,CH3),1.19(t,J=7.0Hz,3H,CH3);13C NMR(100MHz,CDCl3)δ:163.39,143.66,138.61,138.00,133.06,130.86,128.26,127.85,122.99,119.84,119.81,119.38,118.11,115.88,110.29,63.99,63.67,49.32(47.79),16.53,16.34。
实施例22
[2-(1H)-喹啉酮-3-基]-3,5-二氯苯氨甲基膦酸二乙酯的制备
2mmol 3-甲酰基-2-(1H)-喹啉酮、2mmol 3,5-二氯苯胺加入15ml甲苯中,室温下搅拌10min后加入2mmol亚磷酸二乙酯,反应2h,脱溶后用V(石油醚):V(乙酸乙酯)=1:1柱层析,得白色固体,收率84.4%,熔点240~242℃;1H NMR(400MHz,DMSO-d6)δ:12.13(s,1H,NH),8.07(d,J=3.2Hz,1H),7.64(d,J=7.8Hz,1H),7.53(t,J=7.7Hz,1H),7.34(d,J=8.2Hz,1H),7.22(t,J=7.4Hz,1H),6.73(d,J=1.6Hz,2H),6.69(s,1H),5.28,5.20(d,J=9.5Hz,1H,NCHP),4.18~4.09(m,2H,OCH2),4.05~3.86(m,2H,OCH2),1.23(t,J=7.0Hz,3H,CH3),1.10(t,J=7.0Hz,3H,CH3).13C NMR(100MHz,DMSO-d6)δ:161.31,149.81,138.35,137.97,134.64,131.00,128.81,128.16,122.57,119.03,116.24,115.45,111.53,63.24,63.07,47.47(45.92),16.58,16.39。
实施例23
[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯的抗癌活性
1.抗肿瘤活性原理
MTT法又称MTT比色法,是一种用于确定活细胞中线粒体脱氢酶活性的经典方法。MTT分析法以活细胞代谢还原剂噻唑蓝[3-(4,5-二甲基-2-噻唑)-2,5二苯基溴化四氮唑;3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide,MTT]为基础。MTT是一种能接受氢原子的染料。活细胞线粒体中与NADP相关的脱氢酶在细胞内可将黄色的MTT转化为不溶性的蓝紫色甲瓒(formazn),而死细胞则无此功能。用DMSO溶解甲瓒后,在一定波长下用酶标仪测定光密度值,即可定量测出细胞的存活率。根据光密度值的变化观察样品对肿瘤细胞株的抑制作用。
2.抗肿瘤活性实验
试样:实施例化合物
细胞系:人肺腺癌细胞株A549;人宫颈癌细胞株HeLa细胞株;人乳腺癌细胞株MCF-7;人骨肉瘤细胞株U2OS(中南大学湘雅医学院细胞库提供)。
试剂:噻唑蓝(MTT)、RPMI 1640培养基、新生胎牛血清、新生牛血清、双抗(Gibco);胰酶(Gibco);96孔板;二甲亚砜(国药集团)。
仪器:HFsafe-1500型超净台、HF151UV型CO2培养箱(上海力申科学仪器有限公司);XSP-15C型倒置显微镜(上海长方光学仪器有限公司);Multiskan MK3型酶标仪(美国Thermo公司);超纯水制备仪(美国Milli-Q公司)。
实验操作:试样对A549细胞、HeLa细胞、MCF-7细胞和U2OS细胞的测试。试样作用于四种细胞的实验过程相同。每组实验设置空白对照组,试样分为5个浓度梯度(1.0mmol/L、0.3mmol/L、0.1mmol/L、0.03mmol/L和0.01mmol/L),每个浓度设4个复孔,每组实验平行测定三次。设置波长为570nm检测各孔的OD值,并通过OD的变化计算试样对各细胞株的细胞毒活性。
3.抗肿瘤活性评价
1)细胞增殖抑制率计算:
2)IC50值计算
运用SPSS软件进行分析,样品浓度对数值与细胞抑制率线性回归,计算化合物对各细胞株的半数抑制浓度IC50值(均值±标准差)。化合物对A549细胞、HeLa细胞、MCF-7细胞和U2OS细胞株的IC50值如表1~4所示。
表1 [2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯对A549细胞的抑制活性
[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯 | IC50,μM |
[2-(1H)-喹啉酮-3-基]-2-氯苯氨甲基膦酸二乙酯 | 22.7±3.0 |
[2-(1H)-喹啉酮-3-基]-3,4-二甲基苯氨甲基膦酸二乙酯 | 26.4±1.4 |
[2-(1H)-喹啉酮-3-基]-2,4-二硝基苯氨甲基膦酸二乙酯 | 21.6±1.2 |
[2-(1H)-喹啉酮-3-基]-3-氯-4-氟苯氨甲基膦酸二乙酯 | 16.6±0.9 |
表2 [2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯对HeLa细胞的抑制活性
[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯 | IC50,μM |
[2-(1H)-喹啉酮-3-基]-2-甲基苯氨甲基膦酸二乙酯 | 25.5±0.9 |
[2-(1H)-喹啉酮-3-基]-3-溴苯氨甲基膦酸二乙酯 | 19.2±0.4 |
[2-(1H)-喹啉酮-3-基]-2-氯-4-硝基苯氨甲基膦酸二乙酯 | 15.1±1.4 |
[2-(1H)-喹啉酮-3-基]-3-氯-4-氟苯氨甲基膦酸二乙酯 | 2.5±0.6 |
表3 [2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯对MCF-7细胞的抑制活性
[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯 | IC50,μM |
[2-(1H)-喹啉酮-3-基]-4-甲基苯氨甲基膦酸二乙酯 | 28.4±0.4 |
[2-(1H)-喹啉酮-3-基]-3-三氟甲基苯氨甲基膦酸二乙酯 | 29.1±0.6 |
[2-(1H)-喹啉酮-3-基]-4-甲氧基苯氨甲基膦酸二乙酯 | 28.5±1.9 |
[2-(1H)-喹啉酮-3-基]-2-氯苯氨甲基膦酸二乙酯 | 25.5±0.4 |
[2-(1H)-喹啉酮-3-基]-2-溴苯氨甲基膦酸二乙酯 | 26.0±0.5 |
[2-(1H)-喹啉酮-3-基]-3-氯-4-氟苯氨甲基膦酸二乙酯 | 1.0±0.4 |
[2-(1H)-喹啉酮-3-基]-3,5-二氯苯氨甲基膦酸二乙酯 | 27.0±3.4 |
表4 [2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯对U2OS细胞的抑制活性
[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯 | IC50,μM |
[2-(1H)-喹啉酮-3-基]-2,6-二甲基苯氨甲基膦酸二乙酯 | 26.3±1.3 |
[2-(1H)-喹啉酮-3-基]-3-氯-4-氟苯氨甲基膦酸二乙酯 | 26.3±2.0 |
活性测试结果表明,[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯及其在药学上可接受的盐对人肺腺癌细胞A549、人宫颈癌细胞HeLa细胞、人乳腺癌细胞MCF-7和人骨肉瘤细胞具有良好的抑制活性,可用于制备抗癌药物。
Claims (6)
1.一类化学结构式Ⅰ所示的[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯及其在药学上可接受的盐:
其中,R选自:C1~C2烷基、C3~C4直链烷基或支链烷基;X1、X2选自:氢、氘、C1~C2烷基;X3、X7选自:氢、氘、C1~C2烷基、氟、氯、溴、碘或硝基;X4、X6选自:三氟甲基、氟、氯、溴或碘;X5选自:三氟甲基、C1~C2烷氧基、氟、氯、溴或碘。
2.权利要求1所述的[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯,其特征在于,所述的化合物选自:
[2-(1H)-喹啉酮-3-基]-4-三氟甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-4-甲氧基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3-氯苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-4-氯苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3-溴苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3,5-二三氟甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3-氯-4-氟苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2,3-二氯苯氨甲基膦酸二乙酯或[2-(1H)-喹啉酮-3-基]-3,5-二氯苯氨甲基膦酸二乙酯。
3.权利要求1所述的[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯的制备方法,其特征在于它的制备反应如下:
式中,R、X1~X7如权利要求1所述。
4.权利要求1和2任一项所述的[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯及其药学上可接受的盐在制备抗癌药中的应用。
5.一类化学结构式Ⅰ所示的[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯及其在药学上可接受的盐在制备抗癌药中的应用:
其中,R选自:C1~C2烷基、C3~C4直链烷基或支链烷基;X1、X2选自:氢、氘、C1~C2烷基;X3、X7选自:氢、氘、C1~C2烷基、氟、氯、溴、碘或硝基;X4、X6选自:氢、氘、三氟甲基、C1~C2烷基、氟、氯、溴或碘;X5选自:氢、氘、三氟甲基、C1~C2烷基、C1~C2烷氧基、氟、氯、溴、碘或硝基。
6.权利要求5所述的应用,其中式Ⅰ所示的[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸酯选自:
[2-(1H)-喹啉酮-3-基]苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2-甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3-甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-4-甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-4-三氟甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2-硝基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-4-硝基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-4-甲氧基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2-氯苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3-氯苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-4-氯苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2-溴苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3-溴苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2,6-二甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3,4-二甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3,5-二三氟甲基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2,4-二硝基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2-氯-4-硝基苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-3-氯-4-氟苯氨甲基膦酸二乙酯、[2-(1H)-喹啉酮-3-基]-2,3-二氯苯氨甲基膦酸二乙酯或[2-(1H)-喹啉酮-3-基]-3,5-二氯苯氨甲基膦酸二乙酯。
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