CN107286101B - 1-芳醛肟尿嘧啶及其制备方法 - Google Patents
1-芳醛肟尿嘧啶及其制备方法 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及药物领域,具体是一种抑制肿瘤细胞生长活性,具有显著地抑制胸苷磷酸化酶和抗肿瘤活性的1-芳醛肟尿嘧啶及其制备方法。
背景技术
血管生成在肿瘤生长和转移的过程中扮演着十分重要的角色。胸苷磷酸化酶(TP),是一种涉及到胸苷体内平衡和代谢的酶,由于其内皮细胞具有能够刺激内皮细胞迁移的趋向性运动从而被认为是依赖血管生成的。这种酶主要的功能是可以可逆的将胸苷磷酸化为胸腺嘧啶和2-脱氧核糖-1-磷酸盐,并活化5-氟尿嘧啶及前体。胸苷磷酸化酶不仅可以识别胸苷还可以识别脱氧尿苷和嘧啶核苷衍生物。根据基因序列比较,人类的胸苷磷酸化酶相当于血管生成蛋白质,内皮细胞血小板源生长因子。胸苷磷酸化酶和内皮细胞血小板源生长因子这类蛋白质都与胃癌、肾脏癌、子宫癌、平滑肌瘤、乳腺癌、结肠癌和肺癌有着不可分割的联系。
内皮细胞的迁移对于血管生成是十分重要的一步,而胸苷磷酸化酶的催化活性对于内皮细胞的迁移又十分重要,因此这些年来来有很多各种晶体结构的胸苷磷酸化酶及其类似物的阐述。近来,一系列含碱基或不含碱基的胸苷磷酸化酶抑制剂已经被合成和发表,并具有潜在的抗胸苷磷酸化酶活性及抗新生血管生成。在身体上,最有效的胸苷磷酸化酶抑制剂是尿嘧啶类衍生物,预期与胸苷上的位点相结合从而达到抑制的效果。目前最有效的抑制剂是5-氯-6-[1-(2-氨基吡咯)甲基]尿嘧啶磷酸盐(TPI),其IC50达到35nM,表现出了很好的抑制活性。与此同时,一系列无碱基的TP抑制剂已经合成并进行了测试,对其中一些化合物的作用机制进行了预测,它们是通过与TP的变构结合位点相互作用实现抑制作用,这有别于一般的底物位点结合。然而,在临床上长期使用同一种TP抑制剂可能会有毒性耐药性等副作用。为了解决这一问题应该进一步研究新的一系列的TP抑制剂。
胺肟是一类重要的有机物,其具有酰胺基肟的结构,常常被用作原料合成杂环及相关的中间体从而广泛的应用于制药、抗肿瘤剂、抗菌剂、抗炎剂等。胺肟的末端基团和TPI的氨基吡咯具有相似性,因此我们设计了目标分子。除了尿嘧啶单元外,新的胺肟结构有C=N、N-OH、N-H、C=O及不同的取代基,这些都有可能会与活性位点相结合从而实现抑制活性。
发明内容
本发明针对现有技术的不足,提供一种抑制肿瘤细胞生长活性,具有显著地抑制胸苷磷酸化酶和抗肿瘤活性的1-芳醛肟尿嘧啶及其制备方法。
本发明的1-芳醛肟尿嘧啶,其特征在于该化合物具有如下结构I:
其中,R1为甲基或氢,R2为氯、碘、羧基或氢,Ar为烷基苯基、卤代苯基、烷氧基苯基、噻吩基、呋喃基。
所述的1-芳醛肟尿嘧啶,为以下二十四种中的任意一种:
一种1-芳醛肟尿嘧啶的制备方法,其特征在于该制备方法的合成反应式为:
具体制备步骤如下:
(1)将芳香醛溶于甲醇中,常温下搅拌,待芳香醛完全溶解后,将盐酸羟胺和碳酸钾加入甲醇中,反应2-5h,反应完全后,萃取反应液,然后用饱和碳酸氢钠溶液进行洗涤,用无水硫酸钠干燥,减压蒸馏回收甲醇,得到芳香醛肟。
(2)将芳香醛肟溶于N,N-二甲基甲酰胺中,常温下搅拌,待芳香醛肟完全溶解后,加入NCS即氯代丁二酰亚胺,常温搅拌2-6h,反应完全后,萃取,利用饱和氯化钠溶液洗涤,用无水硫酸钠干燥,减压蒸馏除去溶剂,得到邻氯芳香醛肟;
(3)将邻氯芳香醛肟、取代尿嘧啶及碱溶解在有机溶剂1中,常温搅拌2-4h,待反应完全后,萃取、洗涤后,加入3-羧基苯甲醛,常温搅拌6h,析出白色固体,过滤、洗涤后,再用无水硫酸钠干燥,柱层析分离或重结晶,即可得到得1-芳醛肟尿嘧啶。
所述的步骤(3)中,有机溶剂1为甲醇、乙醇、异丙醇、乙酸乙酯、甲苯、四氢呋喃、甲苯、二氯甲烷、氯仿、1,4-二氧六环、N,N-二甲基甲酰胺或二甲基亚砜中的任意两种或两种以上溶剂的混合液。
所述的步骤(3)中,碱为氢氧化锂、氢氧化钠、氢氧化钾、碳酸钾、碳酸铯、磷酸钾、氟化铯、三乙胺中的一种或多种混合物。
本发明的1-芳醛肟尿嘧啶,其特征在于该化合物作为胸苷磷酸化酶的抑制剂,具有抑制胸苷磷酸化酶的活性,用于治疗胃癌、肾脏癌、子宫癌、平滑肌瘤、乳腺癌、结肠癌或肺癌。
本发明的1-芳醛肟尿嘧啶及其制备方法,展示出很高的抑制肿瘤细胞生长活性,具有显著地抑制胸苷磷酸化酶和抗肿瘤活性的作用,制备过程简便,可行性高,便于大规模生产,有利于降低生产成本。
具体实施方式
实施例1:一种1-芳醛肟尿嘧啶,具有如下结构I:
其中,R1为甲基或氢,R2为氯、碘、羧基或氢,Ar为烷基苯基、卤代苯基、烷氧基苯基、噻吩基、呋喃基。
该1-芳醛肟尿嘧啶,其结构式为:
1-芳醛肟尿嘧啶的制备方法,其合成反应式为:
具体制备步骤如下:
(1)将0.02mol芳香醛溶于25mL甲醇中,常温下搅拌,待芳香醛完全溶解后,将0.02mol盐酸羟胺和0.022mol碳酸钾加入甲醇中,反应3h,反应完全后,萃取反应液,然后用饱和碳酸氢钠溶液进行洗涤,用无水硫酸钠干燥,减压蒸馏回收甲醇,得到芳香醛肟。
(2)将0.02mol芳香醛肟溶于25mL N,N-二甲基甲酰胺中,常温下搅拌,待芳香醛肟完全溶解后,加入0.022mol NCS,常温搅拌4h,反应完全后,萃取,利用饱和氯化钠溶液洗涤,用无水硫酸钠干燥,减压蒸馏除去溶剂,得到邻氯芳香醛肟;
(3)将2.4mmol邻氯芳香醛肟、2mmol取代尿嘧啶及2.4mmol氢氧化钠溶解在10mLN,N-二甲基甲酰胺与10mL甲醇的混合溶剂中,常温搅拌2-4h,待反应完全后,萃取、洗涤后,加入3-羧基苯甲醛,常温搅拌6h,析出白色固体,过滤、洗涤后,再用无水硫酸钠干燥,柱层析分离或重结晶,即可得到得1-芳醛肟尿嘧啶。
(Z)-1-(苯基)(肟基)甲基)-6-甲基嘧啶-2,4-(1H,3H)-二酮(化合物1)。
白色固体;M.p.245-246℃;IR(KBr,νmax,cm-1):3451,2918,1731,1658,1459,1367,1085,947,813,693,462;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.35(s,1H,NH),11.48(s,1H,OH),7.63-7.61(m,J=2.0Hz,2H,ArH),7.48-7.46(t,J=7.0Hz,3H,ArH),5.72(s,1H,CH),1.89(s,3H,CH3);13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,152.5,149.8,143.2,132.0,130.7,129.6,125.5,101.5,18.3;HRMS(ESI-TOF,[M+Na]+):m/z calcd for C12H11N3O3,268.0693;found,268.0687。
1、体外抗肿瘤实验:
采用的阳性参照化合物为7-去氮黄嘌呤(7DX)和5-氯-6-[1-(2-氨基吡咯)甲基]尿嘧啶磷酸盐(TPI)。
表1体外细胞水平的胸苷磷酸化酶抑制活性
药理结果显示,这类1-芳醛肟尿嘧啶化合物是一类高活性的肿瘤生长抑制剂,具有很强的抑制胸苷磷酸化酶的活性,尤其化合物4、5、6、7、12的IC50值达到0.12-9.7μM,显示出很高的抑制活性。
2、细胞毒素的实验
采用的参照化合物为环己酰亚胺。
选取对胸苷磷酸化酶具有较好抑制活性的化合物4、5、6、12,在小鼠成纤维细胞系上进行了细胞毒性,生长抑制能力评估。实验发现,所有的活性化合物在50μM的浓度以内都是无毒的。
实施例2:一种1-芳醛肟尿嘧啶,其结构式为
(Z)-1-((2-氟苯基)(肟基)甲基)-6-甲基嘧啶-2,4-(1H,3H)-二酮(化合物2)。
白色固体;M.p.248-249℃;IR(KBr,νmax,cm-1):3440,2919,1695,1432,1302,1179,989,811,512;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.57(s,1H,NH),11.50(s,1H,OH),7.52-7.47(m,J=7.6Hz,3H,ArH),7.46-7.33(m,1H,ArH),5.73(s,1H,CH),1.89(s,3H,CH3);13CNMR(150MHz,DMSO-d6)(δ,ppm):163.4,162.1,152.3,149.8,142.5(d,3JC–F=3Hz),134.6(d,3JC–F=7.5Hz),131.7(d,3JC–F=7.5Hz),121.7(d,3JC–F=1.5Hz),117.6(d,2JC–F=21Hz),112.3(d,2JC–F=24Hz),101.8,18.3;HRMS(ESI-TOF,[M+H]+):m/z calcd for C12H10FN3O3,264.0779;found,264.0776。
实施例3:一种1-芳醛肟尿嘧啶,其结构式为
(Z)-1-((4-氟苯基)(肟基)甲基)-6-甲基嘧啶-2,4-(1H,3H)-二酮(化合物3)。
白色固体;M.p.234-235℃;IR(KBr,νmax,cm-1):3419,2921,1706,1513,1459,1159,841,605,538;1H NMR(500MHz,DMSO-d6)(δ,ppm):12.36(s,1H,NH),11.48(s,1H,OH),7.70-7.67(m,J=8.5Hz,2H,ArH),7.31-7.28((m,J=7Hz,2H,ArH),5.72(s,1H,CH),1.89(s,3H,CH3);13C NMR(125MHz,DMSO-d6)(δ,ppm):163.4,162.7,152.4,149.8,142.5,128.7(d,3JC–F=2.5Hz),128.0(d,3JC–F=8.8Hz),116.7,116.5,101.6,18.3;HRMS(ESI-TOF,[M+H]+):m/z calcd for C12H10FN3O3,264.0779;found,264.0776。
实施例4:一种1-芳醛肟尿嘧啶,其结构式为
(Z)-1-((4-氯苯基)(肟基)甲基)-6-甲基嘧啶-2,4-(1H,3H)-二酮(化合物4)。
白色固体;M.p.249-250℃;IR(KBr,νmax,cm-1):3445,2922,1673,1493,1312,1093,942,836,705,504;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.50(s,1H,NH),11.51(s,1H,OH),7.66-7.64(d,J=8.6Hz,2H,ArH),7.53-7.52(d,J=8.6Hz,2H,ArH),5.73(s,1H,CH),1.89(s,3H,CH3);13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,152.4,149.8,142.5,135.3,131.0,129.6,127.4,101.7,18.3;HRMS(ESI-TOF,[M+H]+):m/z calcd for C12H10ClN3O3,280.0483;found,264.0480。
实施例5:一种1-芳醛肟尿嘧啶,其结构式为
(Z)-1-((肟基)(对甲苯基)甲基)-6-甲基嘧啶-2,4-(1H,3H)-二酮(化合物5)。
白色固体;M.p.256-257℃;IR(KBr,νmax,cm-1):3431,3287,2854,1671,1612,1408,1303,1185,941,823,706,531;1H NMR(500MHz,DMSO-d6)(δ,ppm):12.17(s,1H,NH),11.42(s,1H,OH),7.51-7.49(d,J=8.5Hz,2H,ArH),7.28-7.26(d,J=8Hz,2H,ArH),5.70(s,1H,CH),2.34(s,3H,CH3),1.88(s,3H,CH3);13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,152.6,149.8,143.2,140.5,130.1,129.5,125.5,101.4,21.3,18.3;HRMS(ESI-TOF,[M+Na]+):m/zcalcd for C13H13N3O3,282.0849;found,282.0845。
实施例6:一种1-芳醛肟尿嘧啶,其结构式为
(Z)-1-((4-乙基苯基)(肟基)甲基)-6-甲基嘧啶-2,4-(1H,3H)-二酮(化合物6)。
白色固体;M.p.256-257℃;IR(KBr,νmax,cm-1):3444,3242,2964,1720,1656,1462,1370,1154,1020,950,849,526;1H NMR(500MHz,DMSO-d6)(δ,ppm):12.18(s,1H,NH),11.42(s,1H,OH),7.53-7.52(d,J=8Hz,2H,ArH),7.31-7.29(d,J=8Hz,2H,ArH),5.70(s,1H,CH),2.65-2.64(m,2H,CH2),1.89(s,3H,CH3),1.21-1.18(m,3H,CH3);13C NMR(125MHz,DMSO-d6)(δ,ppm):163.4,152.6,149.8,146.7,143.2,129.6,128.9,125.6,101.4,28.4,18.3,15.8;HRMS(ESI-TOF,[M+H]+):m/z calcd for C14H15N3O3,274.1186;found,274.1182。
实施例7:一种1-芳醛肟尿嘧啶,其结构式为
(Z)-1-((4-溴苯基)(肟基)甲基)-6-甲基嘧啶-2,4-(1H,3H)-二酮(化合物7)。
白色固体;M.p.261-262℃;IR(KBr,νmax,cm-1):3426,1697,1672,1409,1310,1182,999,848,772,511;1H NMR(500MHz,DMSO-d6)(δ,ppm):12.51(s,1H,NH),11.51(s,1H,OH),7.72-7.70(m,J=8.5Hz,2H,ArH),7.63-7.62(d,J=8.5Hz,2H,ArH),5.76(s,1H,CH),1.94(s,3H,CH3);13C NMR(125MHz,DMSO-d6)(δ,ppm):163.4,152.4,149.8,142.6,132.5,131.7,127.6,124.1,101.7,18.3;HRMS(ESI-TOF,[M+H]+):m/z calcd for C12H10BrN3O3,323.9984;found,323.9978。
实施例8:一种1-芳醛肟尿嘧啶,其结构式为
(Z)-1-((肟基)(3-甲氧基苯基)甲基)-6-甲基嘧啶-2,4-(1H,3H)-二酮(化合物8)。
白色固体;M.p.256-257℃;IR(KBr,νmax,cm-1):3427,3200,2922,1717,1659,1459,1385,1310,1236,1018,815,704;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.37(s,1H,NH),11.47(s,1H,OH),7.38-7.37(m,J=8Hz,1H,ArH),7.16-7.14(m,J=2Hz,3H,ArH),5.72-5.71(d,1H,CH),3.80(s,3H,CH3),1.89(s,3H,CH3);13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,160.1,152.5,149.8,143.1,133.5,130.8,118.0,116.4,110.5,101.5,55.7,18.3;HRMS(ESI-TOF,[M+H]+):m/z calcd for C13H13N3O4,276.0984;found,276.0978.
实施例9:一种1-芳醛肟尿嘧啶,其结构式为
(Z)-1-((4-乙基苯基)(肟基)甲基)-6-甲基嘧啶-2,4-(1H,3H)-二酮(化合物9)。
白色固体;M.p.243-244℃;IR(KBr,νmax,cm-1):3436,2920,1730,1669,1608,1450,1367,1181,1033,944,813,523;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.05(s,1H,NH),11.43(s,1H,OH),7.55-7.54(d,J=8.8Hz,2H,ArH),7.01-7.00(d,J=8.8Hz,2H,ArH),5.69(s,1H,CH),3.80(s,3H,CH3),1.88(s,3H,CH3);13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,161.3,152.6,149.8,143.0,127.1,124.5,115.0,101.4,55.8,18.3;HRMS(ESI-TOF,[M+H]+):m/z calcd for C13H13N3O4,276.0984;found,276.0982。
实施例10:一种1-芳醛肟尿嘧啶,其结构式为
(Z)-1-((肟基)(间甲苯基)甲基)-6-甲基嘧啶-2,4-(1H,3H)-二酮(化合物10)。
白色固体;M.p.246-247℃;IR(KBr,νmax,cm-1):3443,2920,1655,1480,1315,1022,923,802,711,507;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.27(s,1H,NH),11.44(s,1H,OH),7.43(s,1H,ArH),7.41-7.40(d,J=7.9Hz,1H,ArH),7.36-7.33(t,J=7.7Hz,1H,ArH),7.30-7.29(d,J=7.5Hz,1H,ArH),5.71(s,1H,CH),2.35(s,3H,CH3),1.89(s,3H,CH3);13CNMR(150MHz,DMSO-d6)(δ,ppm):163.4,152.6,149.8,143.3,138.9,132.1,131.4,129.4,125.8,122.8,101.5,21.4,18.4;HRMS(ESI-TOF,[M+Na]+):m/z calcd for C13H13N3O3,282.0849;found,282.0844。
实施例11:一种1-芳醛肟尿嘧啶,其结构式为
(Z)-1-((3-氟苯基)(肟基)甲基)-6-甲基嘧啶-2,4-(1H,3H)-二酮(化合物11)。
白色固体;M.p.255-256℃;IR(KBr,νmax,cm-1):3439,3155,2766,1712,1616,1432,1296,1082,955,818,745,514;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.49(s,1H,NH),11.41(s,1H,OH),7.45-7.42(m,J=7.7Hz,3H,ArH),7.39-7.38(m,J=7.3Hz,1H,ArH),7.28-7.26(t,J=8Hz,1H,ArH)5.65(s,1H,CH),1.81(s,3H,CH3);13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,162.1,152.3,149.8,142.5,134.7,131.8(d,3JC–F=7.5Hz),121.7,117.6(d,2JC–F=21Hz),112.3(d,2JC–F=24Hz),101.8,18.3;HRMS(ESI-TOF,[M+H]+):m/z calcd forC12H10FN3O3,264.0779;found,264.0776。
实施例12:一种1-芳醛肟尿嘧啶,其结构式为
(Z)-1-((3,4-二氯苯基)(肟基)甲基)-6-甲基嘧啶-2,4-(1H,3H)-二酮(化合物12)。
白色固体;M.p.244-245℃;IR(KBr,νmax,cm-1):3428,2901,1755,1928,1367,1128,1025,892,655,543;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.70(s,1H,NH),11.51(s,1H,OH),7.89(s,1H,ArH),7.74-7.73(d,J=8.5Hz,1H,ArH),7.66-7.65(d,J=8.5Hz,1H,ArH),5.73(s,1H,CH),2.35(s,3H,CH3),1.90(s,3H,CH3);13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,152.2,149.9,141.8,133.3,132.9,132.5,131.8,127.2,125.8,102.0,18.3;HRMS(ESI-TOF,[M+H]+):m/z calcd for C12H9Cl2N3O3,314.0094;found,314.0088。
实施例13:一种1-芳醛肟尿嘧啶,其结构式为
(Z)-1-((肟基)(噻吩基)甲基)-6-甲基嘧啶-2,4-(1H,3H)-二酮(化合物13)。
黄色固体;M.p.234-235℃;IR(KBr,νmax,cm-1):3452,2901,1822,1652,1331,839,524;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.08(s,1H,NH),11.43(s,1H,OH),7.82-7.81(m,1H,CH),7.67-7.65(m,1H,CH),7.42-7.41(m,1H,CH),5.69(s,1H,CH),1.90(s,3H,CH3);13CNMR(150MHz,DMSO-d6)(δ,ppm):163.5,152.3,149.7,140.6,134.7,128.7,126.3,124.9,101.5,18.3。
实施例14:一种1-芳醛肟尿嘧啶,其结构式为
(E)-1-((肟基)(对甲苯基)甲基)-5-碘嘧啶-2,4-(1H,3H)-二酮(化合物14)。
白色固体;M.p.241-242℃;IR(KBr,νmax,cm-1):3438,3189,3049,2892,1720,1652,1408,1283,1140,1018,950,826,605,492;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.14(s,1H,NH),11.90(s,1H,OH),8.10(s,1H,CH),7.51-7.49(d,J=8.2Hz,2H,ArH),7.25-7.24(d,J=8.1Hz,2H,ArH),2.33(s,3H,CH3);13C NMR(150MHz,DMSO-d6)(δ,ppm):161.5,149.1,148.4,143.8,140.4,129.8,128.9,126.0,70.3,21.4;HRMS(ESI-TOF,[M+H]+):m/z calcd forC12H10IN3O3,371.9840;found,371.9838。
实施例15:一种1-芳醛肟尿嘧啶,其结构式为
(E)-1-((4-乙基苯基)(肟基)甲基)-5-碘嘧啶-2,4-(1H,3H)-二酮(化合物15)。
白色固体;M.p.238-240℃;IR(KBr,νmax,cm-1):3417,3187,3047,2965,2881,1720,1651,1603,1411,1285,1140,1014,949,841,606,530;1H NMR(500MHz,DMSO-d6)(δ,ppm):12.15(s,1H,NH),11.92(s,1H,OH),8.10(s,1H,CH),7.54-7.52(d,J=7.5Hz,2H,ArH),7.28-7.27(d,J=7.5Hz,2H,ArH),2.65-2.61(m,2H,CH2),1.19-1.16(t,3H,CH3);13C NMR(125MHz,DMSO-d6)(δ,ppm):161.5,149.2,148.4,146.7,143.8,129.2,128.7,126.1,70.3,28.5,15.9;HRMS(ESI-TOF,[M+Na]+):m/z calcd for C12H11IN3O3,407.9821;found,407.9816。
实施例16:一种1-芳醛肟尿嘧啶,其结构式为
(E)-1-((2-氟苯基)(肟基)甲基)-5-碘嘧啶-2,4-(1H,3H)-二酮(化合物16)。
白色固体;M.p.249-250℃;IR(KBr,νmax,cm-1):3441,3052,2882,1724,1652,1601,1410,1306,1283,1139,1014,948,846,611,542;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.48(s,1H,NH),11.91(s,1H,OH),8.11(s,1H,CH),7.49-7.48(m,J=2.4Hz,3H,ArH),7.33-7.30(m,J=2.4Hz,1H,ArH);13C NMR(150MHz,DMSO-d6)(δ,ppm):163.6,162.0,161.5,149.2,148.1,143.1(d,3JC–F=3Hz),134.3(d,3JC–F=9Hz),131.4(d,3JC–F=9Hz),122.3,117.5(d,2JC–F=22.5Hz),112.9(d,2JC–F=24Hz),70.7;HRMS(ESI-TOF,[M-H]-):m/z calcd forC11H7FIN3O3,373.9438;found,373.9442。
实施例17:一种1-芳醛肟尿嘧啶,其结构式为
(E)-1-((4-氯苯基)(肟基)甲基)-5-碘嘧啶-2,4-(1H,3H)-二酮(化合物17)。
白色固体;M.p.225-226℃;IR(KBr,νmax,cm-1):3440,3190,3048,2924,1727,1651,1601,1410,1307,1287,1095,948,832,770,511;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.41(s,1H,NH),11.94(s,1H,OH),8.11(s,1H,CH),7.66-7.65(d,J=8.6Hz,2H,ArH),7.50-7.49(m,J=1.8Hz,2H,ArH);13C NMR(150MHz,DMSO-d6)(δ,ppm):161.5,149.2,148.2,143.1,135.2,130.7,129.3,127.9,70.7;HRMS(ESI-TOF,[M+H]+):m/z calcd for C11H7ClIN3O3,391.9299;found,391.9294。
实施例18:一种1-芳醛肟尿嘧啶,其结构式为
(E)-1-((4-氟苯基)(肟基)甲基)-5-碘嘧啶-2,4-(1H,3H)-二酮(化合物18)。
白色固体;M.p.242-243℃;IR(KBr,νmax,cm-1):3440,3199,3052,2905,1728,1655,1600,1444,1305,1285,1214,1023,842,794,678,550;1H NMR(500MHz,DMSO-d6)(δ,ppm):12.29(s,1H,NH),11.92(s,1H,OH),8.12(s,1H,CH),7.70-7.68(m,J=8.5Hz,2H,ArH),7.29-7.26(m,J=9Hz,2H,ArH);13C NMR(125MHz,DMSO-d6)(δ,ppm):164.5,162.8,161.5,149.2,148.3,143.1,128.5(t,2JC–F=22.5Hz),115.8(d,2JC–F=17.5Hz),70.5;HRMS(ESI-TOF,[M-H]-):m/z calcd for C11H7FIN3O3,373.9438;found,373.9444。
实施例19:一种1-芳醛肟尿嘧啶,其结构式为
(E)-1-((肟基)(4-甲氧基苯基)甲基)-5-碘嘧啶-2,4-(1H,3H)-二酮(化合物19)。
黄色固体;M.p.245-246℃;IR(KBr,νmax,cm-1):3189,3050,2894,1722,1655,1521,1415,1345,1285,1178,1013,948,836,638,542;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.00(s,1H,NH),11.89(s,1H,OH),8.08(s,1H,CH),7.56-7.54(d,J=8.8Hz,2H,ArH),6.99-6.98(d,J=8.9Hz,2H,ArH),3.79(s,3H,CH3);13C NMR(150MHz,DMSO-d6)(δ,ppm):161.5,161.3,149.1,148.4,143.6,127.7,124.1,114.7,70.2,55.9;HRMS(ESI-TOF,[M+H]+):m/z calcdfor C11H10IN3O4,387.9789;found,387.9787。
实施例20:一种1-芳醛肟尿嘧啶,其结构式为
(E)-1-((肟基)(苯基)甲基)-5-碘嘧啶-2,4-(1H,3H)-二酮(化合物20)。
白色固体;M.p.253-254℃;IR(KBr,νmax,cm-1):3443,3087,3051,2916,1722,1649,1439,1285,1015,949,781,610;1H NMR(500MHz,DMSO-d6)(δ,ppm):12.28(s,1H,NH),11.93(s,1H,OH),8.13(s,1H,CH),7.62-7.61(d,2H,ArH),7.48-7.42(m,2H,ArH);13C NMR(125MHz,DMSO-d6)(δ,ppm):161.5,149.2,148.4,143.8,131.7,130.6,129.3,126.1,70.5;HRMS(ESI-TOF,[M+Na]+):m/z calcd for C11H8IN3O3,379.9308;found,379.9504。
实施例21:一种1-芳醛肟尿嘧啶,其结构式为
(E)-1-((肟基)(3-甲氧基苯基)甲基)-5-碘嘧啶-2,4-(1H,3H)-二酮(化合物21)。
黄色固体;M.p.255-256℃;IR(KBr,νmax,cm-1):3478,3072,2894,1738,1608,1434,1218,1138,1044,940,756,636,549;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.31(s,1H,NH),11.92(s,1H,OH),8.11(s,1H,CH),7.36-7.35(t,1H,ArH),7.16-7.14(m,2H,ArH),7.07-7.05(t,1H,ArH),3.79(s,3H,CH3);13C NMR(150MHz,DMSO-d6)(δ,ppm):161.9,151.7,149.2,148.3,143.7,133.1,130.5,118.6,116.3,111.2,55.8;HRMS(ESI-TOF,[M-H]-):m/zcalcd for C12H10IN3O4,385.9638;found,385.9645。
实施例22:一种1-芳醛肟尿嘧啶,其结构式为
(E)-5-氯-3-((肟基)(对甲苯基)甲基)-4-甲基吡啶-2,6(1H,3H)-二酮(化合物22)。
白色固体;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.32(s,1H,NH),11.05(s,1H,OH),7.60-7.58(d,J=8.2Hz,2H,ArH),7.27-7.26(d,J=8.1Hz,2H,ArH),2.38-2.33(m,3H,CH3),2.20-2.19(d,3H,CH3);13C NMR(150MHz,DMSO-d6)(δ,ppm):159.3,148.9,148.3,143.2,140.7,130.3,130.1,129.0,126.5,125.7,107.6,21.4,16.8.l。
实施例23:一种1-芳醛肟尿嘧啶,其结构式为
(E)-5-((肟基)(对甲苯基)甲基)-2,6-二酮-1,2,5,6-四氢吡啶-3-羧酸(化合物23)。
白色固体;1H NMR(600MHz,DMSO-d6)(δ,ppm):15.12(s,1H,COOH),12.32(s,1H,NH),11.05(s,1H,OH),8.13(s,1H,CH),7.72-7.70(d,2H,ArH),7.26-7.25(d,2H,ArH),2.57(s,3H,CH3)。
实施例24:一种1-芳醛肟尿嘧啶,其结构式为
(E)-5-氟-3-((肟基)(对甲苯基)甲基)吡啶-2,6-(1H,3H)-二酮(化合物24)。
白色固体;1H NMR(600MHz,DMSO-d6)(δ,ppm):11.01(s,1H,NH),10.23(s,1H,OH),7.56(s,1H,CH),7.28-7.27(m,2H,ArH),7.71-7.70(m,2H,ArH),2.57(s,3H,CH3)。
Claims (6)
3.一种1-芳醛肟尿嘧啶的制备方法,其特征在于该制备方法的合成反应式为:
具体制备步骤如下:
(1)将芳香醛溶于甲醇中,常温下搅拌,待芳香醛完全溶解后,将盐酸羟胺和碳酸钾加入甲醇中,反应2-5h,反应完全后,萃取反应液,然后用饱和碳酸氢钠溶液进行洗涤,用无水硫酸钠干燥,减压蒸馏回收甲醇,得到芳香醛肟。
(2)将芳香醛肟溶于N,N-二甲基甲酰胺中,常温下搅拌,待芳香醛肟完全溶解后,加入NCS即氯代丁二酰亚胺,常温搅拌2-6h,反应完全后,萃取,利用饱和氯化钠溶液洗涤,用无水硫酸钠干燥,减压蒸馏除去溶剂,得到邻氯芳香醛肟;
(3)将邻氯芳香醛肟、取代尿嘧啶及碱溶解在有机溶剂1中,常温搅拌2-4h,待反应完全后,萃取、洗涤后,加入3-羧基苯甲醛,常温搅拌6h,析出白色固体,过滤、洗涤后,再用无水硫酸钠干燥,柱层析分离或重结晶,即可得到得1-芳醛肟尿嘧啶。
4.如权利要求3所述的1-芳醛肟尿嘧啶的制备方法,其特征在于所述的步骤(3)中,有机溶剂1为甲醇、乙醇、异丙醇、乙酸乙酯、甲苯、四氢呋喃、二氯甲烷、氯仿、1,4-二氧六环、N,N-二甲基甲酰胺或二甲基亚砜中的任意两种或两种以上溶剂的混合液。
5.如权利要求3所述的1-芳醛肟尿嘧啶的制备方法,其特征在于所述的步骤(3)中,碱为氢氧化锂、氢氧化钠、氢氧化钾、碳酸钾、碳酸铯、磷酸钾、氟化铯、三乙胺中的一种或多种混合物。
6.如权利要求1所述的1-芳醛肟尿嘧啶,其特征在于该化合物作为胸苷磷酸化酶的抑制剂,具有抑制胸苷磷酸化酶的活性,用于治疗胃癌、肾脏癌、子宫癌、平滑肌瘤、乳腺癌、结肠癌或肺癌。
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