CN116514727A - 5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物及其制备方法与应用 - Google Patents
5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物及其制备方法与应用 Download PDFInfo
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- CN116514727A CN116514727A CN202310482227.3A CN202310482227A CN116514727A CN 116514727 A CN116514727 A CN 116514727A CN 202310482227 A CN202310482227 A CN 202310482227A CN 116514727 A CN116514727 A CN 116514727A
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Abstract
本发明涉及化学结构式I所示的5‑氟‑2,4‑二氧代‑3,4‑二氢嘧啶醋酸酯衍生物及其药学上可接受的盐，药物组合物以及其在制备抗肿瘤药物中的应用：
Description
技术领域
本发明涉及一类新化合物、其制备方法与应用，具体是5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物及其制备方法与应用、其制备方法及其作为抗肿瘤药物的应用。
背景技术
酯类化合物的应用非常广泛，在药物、农业、香料、材料、食品等领域都有涉及，如传统中药蟾酥的主要成分是蟾毒内酯类化合物，研究表明蟾毒内酯类化合物对肝癌、非小细胞肺癌、乳腺癌等多种恶性肿瘤具有一定的抑制活性[Oncology Letters, 2012, 4(4):792–798]。
2010年，Qian等[Bioorganic & Medicinal Chemistry, 2010, 18(14): 4991–4996]设计合成了一系列肉桂酸甲硝唑酯衍生物，并对其作为潜在的EGFR和HER-2激酶抑制剂的生物活性进行了评估，其中化合物A1对MCF-7具有一定的抗增殖活性，IC50值为3.76 μM。
2019年，Cheremnykh等[Medicinal Chemistry Research, 2019, 28: 545–558]通过采用一锅多组分的方法，设计合成了一系列具有氨基甲酸酯基的2,4,6-三取代的嘧啶类化合物，使用MTT方法评估了它们对癌细胞系的细胞毒性活性，其中三取代的嘧啶化合物A2对乳腺癌细胞系MDA-MB-231和人类前列腺细胞系DU-145显示出一定的生长抑制活性，GI50值分别为10.08和12.14 μM。
发明内容
本发明解决的技术问题是提供一类5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物、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提供了一类如结构式Ⅰ所示5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物及其药学上可接受的盐：
其中，R选自：2-甲氧基、3-甲氧基、4-甲氧基、2,3-二甲氧基、2,4-二甲氧基、2,5-二甲氧基、2,6-二甲氧基、3,4-二甲氧基、3,5-二甲氧基、2-羟基-3-甲氧基、2-羟基-4-甲氧基、2-羟基-5-甲氧基、2-羟基-6-甲氧基、3-羟基-2-甲氧基、3-羟基-4-甲氧基、3-羟基-5-甲氧基、3-羟基-6-甲氧基、4-羟基-2-甲氧基、4-羟基-3-甲氧基、4-羟基-3,5-二甲氧基、2,3,4-三甲氧基或3,4,5-三甲氧基。
进一步的，优选的化合物选自：2-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、3-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、4-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2,3-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2,4-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2,5-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2,6-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、3,4-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、3,5-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2-羟基-3-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2-羟基-4-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2-羟基-5-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2-羟基-6-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、3-羟基-2-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、3-羟基-4-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、3-羟基-5-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、3-羟基-6-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、4-羟基-2-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、4-羟基-3-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、4-羟基-3,5-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2,3,4-三甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯或3,4,5-三甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯。
本发明技术方案的第二方面是提供了5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物的制备方法，其特征在于它的制备反应如下：
其中，R选自：2-甲氧基、3-甲氧基、4-甲氧基、2,3-二甲氧基、2,4-二甲氧基、2,5-二甲氧基、2,6-二甲氧基、3,4-二甲氧基、3,5-二甲氧基、2-羟基-3-甲氧基、2-羟基-4-甲氧基、2-羟基-5-甲氧基、2-羟基-6-甲氧基、3-羟基-2-甲氧基、3-羟基-4-甲氧基、3-羟基-5-甲氧基、3-羟基-6-甲氧基、4-羟基-2-甲氧基、4-羟基-3-甲氧基、4-羟基-3,5-二甲氧基、2,3,4-三甲氧基或3,4,5-三甲氧基。
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5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物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所述5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物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肿瘤药物方面的应用。
有益技术效果：
本发明的5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物是一类新型的具有抗肿瘤活性的化合物。
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
一种5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物，其分子式如下式：
其中，R选自：2-甲氧基、3-甲氧基、4-甲氧基、2,3-二甲氧基、2,4-二甲氧基、2,5-二甲氧基、2,6-二甲氧基、3,4-二甲氧基、3,5-二甲氧基、2-羟基-3-甲氧基、2-羟基-4-甲氧基、2-羟基-5-甲氧基、2-羟基-6-甲氧基、3-羟基-2-甲氧基、3-羟基-4-甲氧基、3-羟基-5-甲氧基、3-羟基-6-甲氧基、4-羟基-2-甲氧基、4-羟基-3-甲氧基、4-羟基-3,5-二甲氧基、2,3,4-三甲氧基或3,4,5-三甲氧基。
实施例2
2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸的制备
将20.0 mmol氢氧化钾在室温搅拌下溶解于10 mL水溶液中，随后加入5.0 mmol5-氟尿嘧啶，继续搅拌使其溶解后，升温至80℃，缓慢滴加7.5 mmol溴乙酸，保温搅拌反应10 h，TLC跟踪监测反应进程。将反应液冷却至室温，用浓盐酸调节pH至2~3，减压旋转蒸发除去反应液中的水，粗产物用适量的乙醇重结晶，抽滤，干燥得2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸，白色固体，熔点>250℃，收率92%。
实施例3
2,6-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯（M1）的制备
2.0 mmol 2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸、4.0 mmol 2,6-二甲氧基苯酚和4.0 mmol N, N-二环己基碳二亚胺（DCC）溶于30 mL无水二氯甲烷溶液中，室温搅拌反应24 h，TLC跟踪监测反应进程。将反应混合物抽滤，滤饼用适量二氯甲烷洗涤3次，滤液用水萃取3次，有机相通过旋转蒸发浓缩，粗品经硅胶柱色谱法提纯，干燥得2,6-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯（M1），白色固体，熔点173~175℃，收率92%。1H NMR (500 MHz, DMSO-d6) δ：11.86 (s, 1H, NH), 7.92 (d, J =6.6 Hz, 1H, C4HN2), 7.19 (d, J = 8.4 Hz, 1H, C6H3), 6.75 (d, J = 8.4 Hz, 2H,C6H3), 4.78 (s, 2H, COCH2), 3.75 (s, 6H, di-OCH3)。
实施例4
4-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯（M2）的制备
2.0 mmol 2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸、3.0 mmol 4-甲氧基苯酚和3.0 mmol N, N-二环己基碳二亚胺（DCC）溶于30 mL无水二氯甲烷溶液中，室温搅拌反应24 h，TLC跟踪监测反应进程。将反应混合物抽滤，滤饼用适量二氯甲烷洗涤3次，滤液用水萃取3次，有机相通过旋转蒸发浓缩，粗品经硅胶柱色谱法提纯，干燥得4-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯（M2），白色固体，熔点177~179℃，收率83%。1H NMR (500 MHz, DMSO-d6) δ：12.01 (s, 1H, NH), 8.16 (d, J = 6.7 Hz,1H, C4HN2), 7.08 (d, J = 6.9 Hz, 2H, C6H4), 6.98 (d, J = 6.9 Hz, 2H, C6H4),4.74 (s, 2H, COCH2), 3.75 (s, 3H, OCH3)。
实施例5
5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物的抗肿瘤活性
1．抗肿瘤活性实验原理
活细胞的线粒体中的琥珀脱氢酶能使外源性的MTT还原为难溶性的蓝紫色结晶物甲臜（Formazan）并沉积在细胞中，而死细胞无此功能。二甲基亚砜能溶解细胞中的紫色结晶物，用酶联免疫检测仪在490 nm波长处测定其光吸收值，可间接反映细胞数量。在一定细胞数范围内，MTT结晶物形成的量与细胞数成正比。
2．抗肿瘤活性实验方法
细胞系：4T1（鼠源乳腺癌细胞）及TPC-1（人乳头瘤甲状腺癌细胞），南京大学现代工程与应用科学实验室赠予。
试剂：噻唑蓝（MTT）、含抗生素的RPMI 1640 培养液（南京凯基生物科技发展有限公司）、胎牛血清（浙江天杭生物科技有限公司）、胰酶（南京凯基生物科技发展有限公司）、96 孔培养板（无锡耐思生命科技股份有限公司）、二甲基亚砜[Sigma（上海）公司]。
仪器：1300 series A2型生物安全柜（美国 Thermo 公司）、CLM-170B-8-CN型CO2培养箱（ESCO）、BDS400型倒置显微镜（重庆奥特光学仪器有限责任公司）、Multiskan GO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：试样对于4T1（鼠源乳腺癌细胞）及TPC-1（人乳头瘤甲状腺癌细胞）的测试。一次实验过程中，每种试样设置7个浓度梯度（2500 ng/L、1250 ng/L、625 ng/L、312.5ng/L、156 ng/L、78 ng/L和39 ng/L），DMSO溶解药物，孵育72小时，每个浓度四个平行试样，每组实验平行3次，并通过空白组对照得出结论。酶标仪检测各孔OD值，检测波长490 nm。
3．检测样品：化合物2,6-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯
4．抗肿瘤活性评价
分别以4T1（小鼠乳腺癌细胞）、TPC-1（人乳头瘤状甲状腺癌细胞）细胞进行孵育，DMSO溶解药物，孵育72小时，用MTT法检测细胞活性，结果表明化合物2,6-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯对癌细胞的细胞毒性较大，对4T1（小鼠乳腺癌细胞）及TPC-1（人乳头瘤甲状腺癌细胞）的IC50值列入表1。
表1 5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物对4T1和TPC-1细胞的IC50
活性测试结果显示，5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物对乳腺癌4T1细胞和人乳头瘤状甲状腺癌TPC-1细胞具有良好的抑制活性，可用于制备抗肿瘤药物。
Claims (5)
1.一类化学结构式Ⅰ所示5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物及其药学上可接受的盐：
其中，R选自：2-甲氧基、3-甲氧基、4-甲氧基、2,3-二甲氧基、2,4-二甲氧基、2,5-二甲氧基、2,6-二甲氧基、3,4-二甲氧基、3,5-二甲氧基、2-羟基-3-甲氧基、2-羟基-4-甲氧基、2-羟基-5-甲氧基、2-羟基-6-甲氧基、3-羟基-2-甲氧基、3-羟基-4-甲氧基、3-羟基-5-甲氧基、3-羟基-6-甲氧基、4-羟基-2-甲氧基、4-羟基-3-甲氧基、4-羟基-3,5-二甲氧基、2,3,4-三甲氧基或3,4,5-三甲氧基。
2.一类5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物及其药学上可接受的盐，选自下列化合物：
2-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、3-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、4-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2,3-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2,4-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2,5-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2,6-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、3,4-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、3,5-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2-羟基-3-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2-羟基-4-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2-羟基-5-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2-羟基-6-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、3-羟基-2-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、3-羟基-4-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、3-羟基-5-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、3-羟基-6-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、4-羟基-2-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、4-羟基-3-甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、4-羟基-3,5-二甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯、2,3,4-三甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯或3,4,5-三甲氧基苯基-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)醋酸酯。
3.权利要求1所述的5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物的制备方法，其特征在于，它的制备反应如下：
式中，R的定义如权利要求1所述。
4.权利要求1或2所述的5-氟-2,4-二氧代-3,4-二氢嘧啶醋酸酯衍生物及其在药学上可接受的盐在制备抗肿瘤药物方面的应用。
5.一种药物组合物，包括权利要求1或2中至少一种化合物和制药学上可用的载体。
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