CN103848815B - 含脲基片段的4-取代-6-苯基嘧啶衍生物及其制备方法和用途 - Google Patents

含脲基片段的4-取代-6-苯基嘧啶衍生物及其制备方法和用途 Download PDF

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CN103848815B
CN103848815B CN201410091332.5A CN201410091332A CN103848815B CN 103848815 B CN103848815 B CN 103848815B CN 201410091332 A CN201410091332 A CN 201410091332A CN 103848815 B CN103848815 B CN 103848815B
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刘宏民
张秋荣
邵坤鹏
章旭耀
张孝松
顾一飞
陈鹏举
薛登启
贺鹏
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Zhengzhou University
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Abstract

本发明属于药物化学合成技术领域，公开了具有抗肿瘤活性的含脲基片段的4-取代-6-苯基嘧啶衍生物、其合成方法及其用途。本发明以苯甲酰乙酸乙酯为原料经环合、取代、氯代和氨解等反应制备了一系列的含脲基片段的4-取代-6-苯基嘧啶衍生物。本发明化合物具有通式Ⅰ结构，X为N、CH；R为Cl、4<i>-</i>CH3-C6H5-NH2、4<i>-</i>CH3O-C6H5-NH2。体外抗肿瘤活性实验证明，该类化合物对多种肿瘤细胞具有明显的抑制和杀伤作用，对此进一步优化有望获得抗肿瘤的一类新药。

Description

含脲基片段的4-取代-6-苯基嘧啶衍生物及其制备方法和用途
技术领域
本发明属于药物化学合成领域，涉及嘧啶类衍生物，具体涉及具有抗肿瘤活性的含脲基片段的4-取代-6-苯基嘧啶衍生物及其制备方法和用途。
背景技术
肿瘤是严重危害人类健康而又难以克服的疾病，目前已经上市的抗肿瘤药物有很多，嘧啶类化合物具有非常广泛的生物活性，例如抗病毒、抗菌、抗炎以及抗肿瘤等。但已开发的这些药物目前还是因诸多因素难以满足患者需求。因此，新型抗肿瘤药物的研发显得尤为重要。将嘧啶和尿素类化合物结合到一起研究的报道较少，因此本发明所述含脲基片段的4-取代-6-苯基嘧啶衍生物具有非常重要的研究价值，有利于我国自主知识产权药物的开发。
发明内容
为开发利用现有的临床药物资源，本发明目的在于提供一类含脲基片段的4-取代氨基-6-苯基嘧啶衍生物，从而为寻找新的抗肿瘤活性化合物开辟一条新途径；本发明另一目的在于提供其制备方法；又一目的在于提供其在制备抗肿瘤药物中的应用。
本发明所述含脲基片段的4-取代-6-苯基嘧啶衍生物结构通式如下：
通式Ⅰ中X为N、CH；R为Cl、4-CH3-C6H5-NH2、4-CH3O-C6H5-NH2。
本发明所述含脲基片段的4-取代-6-苯基嘧啶衍生物的制备方法，包含如下合成步骤：a.将6-苯基-2-硫脲嘧啶分别和含脲基片段的中间体在丙酮和碳酸钾或氢氧化钾的水溶液中发生取代反应生成4位为羟基的含脲基片段的嘧啶衍生物；b.4位为羟基的含脲基片段的嘧啶衍生物与二氯亚砜反应，生成4位为氯的含脲基片段的嘧啶衍生物；c.将4位为氯的含脲基片段的嘧啶衍生物与苯胺类化合物反应生成4位为芳氨基取代的含脲基片段的4-取代-6-苯基嘧啶衍生物。所述的苯胺类化合物为：对甲基苯胺或对甲氧基苯胺。
合成路线如下：
本发明所述含脲基结构单元的4-取代-6-苯基嘧啶衍生物对胃癌细胞(MGC-803)、食管鳞癌细胞(EC-109)和乳腺癌（MCF-7）有一定的抑制作用。其中有些化合物的IC50值小于2μM，与临床上已使用的抗肿瘤药物5-氟尿嘧啶做对照，优于后者。因此，本发明提供的此类含脲基片段的4-取代-6-苯基嘧啶衍生物为开发新型抗肿瘤药物和联合用药开辟了新途径。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应当理解，这些实施例仅用于说明本发明而不用于限制本发明要求保护的范围。
合成化合物表征使用的仪器：NMR谱使用瑞典BrukerDPX-400型超导核磁共振仪测定，TMS为内标；高分辨质谱使用Waters-Micromass公司Q-Tof质谱仪测定。
实施例12-((4-氯-6-苯基嘧啶-2-基)硫)-N-(吡啶基-2-氨基甲酰基)乙酰胺
50℃条件下，将6-苯基-2-硫脲嘧啶（2.04g，10.0mmol）溶于30ml氢氧化钾（0.4g，10.0mmol）的水溶液中，然后将2-氯-N-(吡啶基-2-氨基甲酰基)乙酰胺(2.13g，10.0mmol)的丙酮溶液（20ml）滴加至上反应液，滴加完毕后继续反应半小时，抽滤，滤饼水洗和丙酮各洗三次（3×10ml），得纯品2-((4-羟基-6-苯基嘧啶-2-基)硫)-N-(吡啶基-2-氨基甲酰基)乙酰胺。
0℃条件下，将10ml二氯亚砜缓慢加到上述合成的2-((4-羟基-6-苯基嘧啶-2-基)硫)-N-(吡啶基-2-氨基甲酰基)乙酰胺(1.91g，5.0mmol)中，加完后缓慢升温至90℃，继续反应1小时，然后停止反应，待反应液冷却至室温后，将反应液慢慢倒入冰水中搅拌，得到的固体抽滤，滤饼水洗至中性得纯品。
白色固体粉末，收率91.2%；1HNMR(400MHz,DMSO-d6,δ,ppm):11.36(s,1H),10.70(s,1H),8.27(d,J=4.6Hz,1H),8.22(d,J=7.4Hz,2H),8.02(s,1H),7.98(d,J=8.3Hz,1H),7.82(t,J=7.8Hz,1H),7.57(t,J=7.3Hz,1H),7.49(t,J=7.5Hz,2H),7.12(dd,J=6.8,5.4Hz,1H),4.30(s,2H).13CNMR(100MHz,DMSO-d6,δ,ppm):171.17(s),165.64(s),161.65(s),151.22(s),150.79(s),148.55(s),139.09(s),134.85(s),132.57(s),129.43(s),127.99(s),120.13(s),113.55(s),113.18(s),36.15(s).CalcdforC18H14ClN5O2S[M+H]+:400.0635,found:400.0632.。
实施例22-((4-((4-甲基苯基)氨基)-6-苯基嘧啶-2-基)硫)-N-(吡啶基-2-氨基甲酰基)乙酰胺
将上述合成的2-((4-氯-6-苯基嘧啶-2-基)硫)-N-(吡啶基-2-氨基甲酰基)乙酰胺(120.02mg，0.3mmol)和对甲基苯胺(38.57mg,0.36mmol)加入到5ml冰醋酸中，然后升温至90℃，TLC检测反应完成后，停止反应。趁热抽滤，滤饼用冰醋酸洗（3×10ml）制得。
白色固体粉末，收率70.3%；1HNMR(400MHz,DMSO-d6,δ,ppm):11.28(s,1H),10.77(s,1H),9.83(s,1H),8.28(d,J=4.8Hz,1H),8.00(dd,J=7.7,1.7Hz,3H),7.83(t,J=7.8Hz,1H),7.66(d,J=8.0Hz,2H),7.48(dd,J=12.5,6.8Hz,3H),7.36(t,J=7.9Hz,2H),7.16–7.10(m,1H),7.05(t,J=7.4Hz,1H),6.99(s,1H),4.20(s,2H).13CNMR(100MHz,DMSO-d6,δ,ppm):171.70(s),169.56(s),161.58(s),161.20(s),151.17(s),150.89(s),148.30(s),139.87(s),139.36(s),136.81(s),131.01(s),129.29(d,J=2.4Hz),126.94(s),123.24(s),120.45(s),120.13(s),113.66(s),99.07(s),35.89(s).HR-MS(ESI)CalcdforC24H20N6O2S[M+H]+:457.1447,found:457.1450.。
实施例32-((4-((4-甲氧基苯基)氨基)-6-苯基嘧啶-2-基)硫)-N-(吡啶基-2-氨基甲酰基)乙酰胺
以实施例2的方法将对甲基苯胺换成对甲氧基苯胺制得。
白色固体粉末，收率84.5%；1HNMR(400MHz,DMSO-d6,δ,ppm):11.25(s,1H),10.77(s,1H),9.68(s,1H),8.28(d,J=4.5Hz,1H),7.98(t,J=7.3Hz,3H),7.83(t,J=7.8Hz,1H),7.52(d,J=8.6Hz,2H),7.47(t,J=6.3Hz,3H),7.16–7.10(m,1H),6.94(d,J=8.9Hz,2H),6.89(s,1H),4.18(s,2H),3.73(s,3H).13CNMR(100MHz,DMSO-d6,δ,ppm):171.66(s),169.48(s),161.24(s),155.76(s),151.18(s),150.90(s),148.32(s),139.33(s),136.80(s),132.61(s),130.93(s),129.25(s),126.93(s),122.55(s),120.12(s),114.53(s),113.65(s),98.45(s),55.61(s),35.88(s).HR-MS(ESI)CalcdforC25H22N6O3S[M+H]+:487.1552,found:487.1551.。
实施例42-((4-氯-6-苯基嘧啶-2-基)硫)-N-(苯氨羰基)乙酰胺
以实施例1的方法，将2-氯-N-(吡啶基-2-氨基甲酰基)乙酰胺换成2-氯-N-(苯基-2-氨基甲酰基)乙酰胺制得。
白色固体粉末，收率92.1%；1HNMR(400MHz,DMSO-d6,δ,ppm):11.17(s,1H),10.32(s,1H),8.23(d,J=7.5Hz,2H),8.03(s,1H),7.58(t,J=7.3Hz,1H),7.50(t,J=7.4Hz,4H),7.31(t,J=7.9Hz,2H),7.08(t,J=7.4Hz,1H),4.27(s,2H).13CNMR(100MHz,DMSO-d6,δ,ppm):171.27(s),170.97(s),165.66(s),161.66(s),151.01(s),137.94(s),134.86(s),132.61(s),129.44(d,J=7.3Hz),128.04(s),124.19(s),120.13(s),113.20(s),35.99(s).HR-MS(ESI)CalcdforC19H15ClN4O2S[M+H]+:399.0682,found:399.0673.。
实施例52-((4-苯基-6-(对甲苯胺基)嘧啶)-2-基)硫)-N-(苯氨羰基)乙酰胺
以实施例2的方法，将实施例4合成的2-((4-氯-6-苯基嘧啶-2-基)硫)-N-(苯氨羰基)乙酰胺和对甲基苯胺反应制得。
白色固体粉末，收率79.7%；1HNMR(400MHz,DMSO-d6,δ,ppm):11.05(s,1H),10.38(s,1H),9.70(s,1H),8.01(t,J=10.6Hz,2H),7.49(dd,J=15.4,7.2Hz,7H),7.32(t,J=7.7Hz,2H),7.16(d,J=8.0Hz,2H),7.08(t,J=7.3Hz,1H),6.93(s,1H),4.16(s,2H),2.26(s,3H).13CNMR(100MHz,DMSO-d6,δ,ppm):171.63(s),169.67(s),161.64(s),161.23(s),151.13(s),138.03(s),137.21(s),136.97(s),132.35(s),130.94(s),129.77(s),129.35(d,J=13.0Hz),126.94(s),124.14(s),120.73(s),120.08(s),98.65(s),35.72(s),20.93(s).HR-MS(ESI)CalcdforC26H23N5O2S[M+H]+:470.1651,found:470.1649.。
实施例62-((4-苯基-6-(对甲氧苯胺基)嘧啶)-2-基)硫)-N-(苯氨羰基)乙酰胺
以实施例5的方法，将对甲基苯胺换成对甲氧基苯胺制得。
白色固体粉末，收率65.7%；1HNMR(400MHz,DMSO-d6,δ,ppm):11.04(s,1H),10.40(s,1H),9.82(s,1H),7.97(d,J=6.1Hz,2H),7.57–7.45(m,7H),7.32(t,J=7.5Hz,2H),7.08(t,J=7.1Hz,1H),6.94(d,J=8.6Hz,2H),6.91(s,1H),4.17(s,2H),3.73(s,3H).13CNMR(100MHz,DMSO-d6,δ,ppm):13CNMR(101MHz,DMSO)δ170.72(s),168.69(s),160.59(s),159.00(s),156.12(s),151.06(s),138.11(s),135.02(s),131.97(s),131.40(s),129.42(s),127.30(s),124.10(s),122.73(s),119.97(s),114.50(s),99.56(s),55.59(s),35.99(s).HR-MS(ESI)CalcdforC26H23N5O3S[M+H]+:486.1600,found:486.1602.。
应用实例
体外抗肿瘤活性测试：以MTT法采用三种细胞系，分别为胃癌细胞(MGC-803)、食管鳞癌细胞(EC-109)、乳腺癌（MCF-7）。
收集对数期细胞，调整细胞悬液浓度，每孔加入200μl，铺板使待测细胞调整密度至6000个/孔，（边缘孔用PBS填充）。5%CO2下37℃孵育24小时，至细胞单层铺满孔底（96孔平地板），加入浓度梯度本发明合成的化合物，一般设9个浓度，每孔200μl，设3个复孔。5%CO2下37℃孵育72h，倒置显微镜下观察，每孔加入20μlMTT溶液（5mg/ml，即0.5%MTT），继续培养4h。终止培养，小心吸去孔内培养液，每孔加入150μl二甲基亚砜，置摇床上低速振荡10min，使化合物充分溶解。在酶联免疫检测仪OD490nm处测量各孔的吸光值。用SPSS软件对实验结果进行统计并计算IC50值（μM），结果如下表。
表1体外抗肿瘤活性的实验数据

Claims (2)

1.含脲基片段的4-取代-6-苯基嘧啶衍生物,其特征在于，其为如下化合物：
或。
2.如权利要求1所述的含脲基片段的4-取代-6-苯基嘧啶衍生物在药物制备中的应用，其特征在于，作为活性成分用于制备抗胃癌、食管癌或乳腺癌的药物。
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