CN106243089B - 4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基)嘧啶类化合物及其制备方法和用途 - Google Patents

4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基)嘧啶类化合物及其制备方法和用途 Download PDF

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CN106243089B
CN106243089B CN201610616997.2A CN201610616997A CN106243089B CN 106243089 B CN106243089 B CN 106243089B CN 201610616997 A CN201610616997 A CN 201610616997A CN 106243089 B CN106243089 B CN 106243089B
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benzimidazolyl
radicals
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phenyl
methylpyrimidine
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CN106243089A (zh
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刘宏民
张秋荣
张孝松
曹钦波
崔飞
宋攀攀
王超杰
孟祥川
田亚楠
王雁
张岚清
王巍
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Zhengzhou University
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Abstract

本发明属于药物化学领域，公开了具有抗肿瘤活性的4位含查尔酮结构单元的6‑取代‑2‑(苯并咪唑‑2‑亚甲硫基)嘧啶类化合物及其制备方法和用途。其具有通式Ⅰ结构，其中：R1为甲基、苯基；R2为3,4,5‑三甲氧基苯基、4‑溴苯基、4‑氟苯基、3‑氟苯基、3‑硝基苯基、3‑溴苯基、3,5‑二氟苯基、2‑氟‑4‑溴苯基、3‑溴‑4‑氟苯基、3‑羟基苯基、2‑噻吩基、2‑呋喃基、3,5‑二氟苯基、3,5‑二氯苯基。初步的体外抗肿瘤活性评价发现该系列化合物对多种肿瘤细胞具有明显的抑制和杀伤作用。开发成为新药后可作为活性成分应用于临床预防和癌症治疗。

Description

4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基) 嘧啶类化合物及其制备方法和用途
技术领域
本发明属于药物化学领域，涉及2,4,6-三取代嘧啶类衍生物，具体涉及抗肿瘤活性的4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基)嘧啶类化合物及其制备方法和用途。
背景技术
大量的文献报道了嘧啶类衍生物的生物活性及其药理活性。嘧啶类药物广泛地应用在抗肿瘤、抗炎、抗菌以及抗病毒等多个方面，因此在药物分子设计方面得到了广泛的应用，并且已有多种优秀的抗肿瘤药物成功上市，其抗肿瘤药物的优秀代表为：5-氟尿嘧啶(5-FU)，目前仍然是临床上治疗实体瘤以及消化道肿瘤的重要药物。查尔酮类化合物因为可以通过结合秋水仙碱结合位点而抑制微管蛋白聚合的抗有丝分裂性质而被广泛了解关注。由于查尔酮化合物是由烯酮连接的两个芳环构成，其结构的特殊性导致其具有柔性，从而能与不同的生物受体结合，也正是基于这个原因以及其本身的生物活性，无数的科研工作者将之应用于各类药物的研究中，得到了意想不到的成效，尤其在抗肿瘤、抗疟疾、抗HIV、抗菌、提供食用等等方面得到了较为令人惊喜的研究成果与进展。因此依据药物分子合成设计拼合原理，合成一系列的4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基)嘧啶类化合物，期望得到生物活性良好的化合物，目前未见相关文献报道。
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4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基)嘧啶类化合物，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和其在制备抗肿瘤药物中的应用。
为实现本发明目的，本发明所述4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基)嘧啶类化合物结构通式如下：
通式Ⅰ中：R1为甲基、苯基；R2为3，4,5-三甲氧基苯基、4-溴苯基、4-氟苯基、3-氟苯基、3-硝基苯基、3-溴苯基、3,5-二氟苯基、2-氟-4-溴苯基、3-溴-4-氟苯基、3-羟基苯基、2-噻吩基、2-呋喃基、3,5-二氟苯基、3,5-二氯苯基。
优选如下化合物之一：
N-(3,4,5-三甲氧基苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺
N-(4-溴苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺
N-(4-氟苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺
N-(3-氟苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺
N-(3-硝基苯乙烯基苯乙酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺
N-(3-溴苯乙烯基苯乙酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺
N-(3,5-二氟苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺
N-(2-氟-4-溴苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺
N-(3-溴-4-氟苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺
N-(3-羟基苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺
N-(噻吩-2-苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺
N-(呋喃-2-苯乙烯基苯乙酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺
N-(3,5-二氟苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-苯基嘧啶-4-胺
N-(3,5-二氯苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-苯基嘧啶-4-胺
制备路线：
制备方法：
1)、将乙酰乙酸乙酯或苯甲酰乙酸乙酯和硫脲在氢氧化钾的乙醇溶液中回流发生环合反应得到6-取代-2巯基嘧啶；乙酰乙酸乙酯或苯甲酰乙酸乙酯和硫脲摩尔比为：1:1.0-:1.5。
2)、将6-取代-2巯基嘧啶和2-氯亚甲基苯并咪唑在水和二氧六环的混合溶液中加热，以氢氧化钾催化发生取代反应生成2位苯并咪唑取代的6-取代-2-硫脲嘧啶；6-取代-2巯基嘧啶和2-氯亚甲基苯并咪唑摩尔比为：1:1.0-1.3。
3)、将2位苯并咪唑取代的6-取代-2-硫脲嘧啶与三氯氧磷加热反应，使4位的羟基氯代生成2位苯并咪唑取代的4-氯-6-取代-2-硫脲嘧啶；2位苯并咪唑取代的6-取代-2-硫脲嘧啶与三氯氧磷摩尔比为：1:15-20。
4)、将对氨基苯乙酮与取代苯甲醛、2-噻吩甲醛、2-呋喃甲醛在氢氧化钾的乙醇溶液中发生克莱森-施密特缩合反应得到关键中间体查尔酮4-氨基苯乙烯基苯乙酮、4-氨基噻吩-2-乙烯基苯乙酮、4-氨基呋喃-2-乙烯基苯乙酮；
5)、将2位苯并咪唑取代的4-氯-6-取代-2-硫脲嘧啶与上述4)中取代的氨基类查尔酮加热反应得到4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基)嘧啶类化合物。2位苯并咪唑取代的4-氯-6-取代-2-硫脲嘧啶与取代的氨基类查尔酮摩尔比为：1:0.8-1.2。
本发明所述4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基)嘧啶类化合物对胃癌细胞(MGC-803)、人肝癌细胞(Hepg2)、人食管癌细胞(EC109)、人乳腺癌细胞(MDA-MB-231)有很好的抑制作用。其中有些化合物对胃癌细胞(MGC-803)、人肝癌细胞(Hepg2)、人食管癌细胞(EC109)、人乳腺癌细胞(MDA-MB-231)的IC50值小于10(μmol/L)，与临床上已使用的抗肿瘤药物5-氟尿嘧啶做对照，优于其活性。因此，本发明提供的此类4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基)嘧啶类化合物为开发新型抗肿瘤药物和药物的联合用药开辟了另一有效途径，此类化合物如能开发成为新药将有良好的市场应用前景。而且本发明所述方法反应路线短，简单可行，收率较高，达64％以上。
具体实施方式
下面结合具体实施例，进一步阐述本发明。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Bruker DPX-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1
N-(3,4,5-三甲氧基苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺的制备
将氢氧化钾(3.656g，0.653mol)加入装有60mL乙醇的150mL烧瓶中，50℃超声溶解均匀后，加入压成粉状的硫脲(4.506g，0.592mol)在70℃加热搅拌呈透明状后，滴加乙酰乙酸乙酯(7.5mL，0.592mol)，升温85℃回流5h后，趁热抽滤，滤饼用约70mL水溶解，稀盐酸溶液调pH至6，过程中发热加少许冰块降温，析出沉淀后，抽滤用水洗涤后，真空干燥得产物6-甲基-2巯基嘧啶，白色固体(6.445g，收率78.25％)。
在室温条件下，取对氨基苯乙酮(0.324g，0.0024mol)溶于4mL乙醇中，加入氢氧化钾(0.200g，0.0036mol)慢慢升温75℃加热搅拌，待完全溶解后，逐滴滴加4mL甲醇溶解或稀释的3,4,5-三甲氧基苯甲醛(0.002mol)，回流5h后停止反应，冷却至室温后抽滤，甲醇洗滤饼后，然后真空干燥得3,4,5-三甲氧基苯乙烯基-4-氨基苯乙酮，黄色固体粉末。
将氢氧化钾(0.685g，0.012mol)溶解于10mL水中，再加入6-甲基-2巯基嘧啶(1.415g，0.01mol)超声溶解后，加入2mL二氧六环，搅拌加热至60℃。然后将2-氯亚甲基苯并咪唑(0.011mol)于60℃左右温水下超声溶解于8mL二氧六环中，缓慢滴加至上述反应体系中，用1.5mL二氧六环清洗烧瓶和滴管，加完后加热65℃反应2h，然后趁热抽滤，滤饼用少量二氧六环洗涤，最后真空干燥得2位苯并咪唑取代的6-甲基-2-硫脲嘧啶，黄色固体(2.528g，91.93％)。
分别取三氯氧磷(10mL，0.107mol)和三氯化磷(1mL，0.011mol)在冰浴条件下，混合搅拌10min混合完全均匀后，加入2位苯并咪唑取代的6-甲基-2-硫脲嘧啶(1.567g，0.006mol)，然后缓慢升温至100℃，2h后有大量粉红色固体生成，滴入数滴水，至所有固体溶解，反应液澄清继续回流反应5h后停止反应，待体系稍冷后，倒入剧烈搅拌的冰水中，待三氯氧磷完全反应后，用氨水调pH至8后继续搅拌20min，过程中始终保持有冰，抽滤，滤饼用蒸馏水洗至中性，得到2位苯并咪唑取代的4-氯-6-甲基-2-硫脲嘧啶，白色固体(1.626g，收率96.50％)。
将2位苯并咪唑取代的4-氯-6-甲基-2-硫脲嘧啶(0.174g，0.60mmol)和3,4,5-三甲氧基苯乙烯基-4-氨基苯乙酮(0.157g，0.50mmol)分别溶解于8mL、2mL无水乙醇中，升温至90℃，将后者缓慢滴加入加热搅拌的前者体系中，薄层色谱法监测反应，待反应结束后停止反应，冷却至室温后抽滤，滤饼用分析纯的无水乙醇洗，经真空干燥得产物N-(3,4,5-三甲氧基苯乙烯基苯乙酮)-2-(苯并咪唑-2-亚甲硫基)6-甲基嘧啶-4-胺(0.157g，收率64.4％)。
产物为黄色粉末状固体。m.p.183-184℃；1H NMR(400MHz,DMSO-d6,δ,ppm):10.36(s,1H，NH,benzimidazole,D2O exchangeable),8.18(d,J＝8.6Hz,2H,ethylene linkageH),7.97(d,J＝15.5Hz,1H，phenyl H),7.71(dd,J＝10.9,8.1Hz,5H，phenyl H andbenzimidazole H),7.49(dd,J＝6.0,3.0Hz,2H，phenyl H and benzimidazole H),7.28(s,2H,phenyl H and benzimidazole H),6.55(s,1H,pyrimidine H),4.93(s,2H,CH2-S),3.90(s,6H,CH3O-),3.72(s,3H,CH3O-),2.24(s,3H,CH3-).13C NMR(101MHz,DMSO-d6,δ,ppm):187.65,166.92,164.63,160.41,153.61,151.58,144.23,144.02,143.80,143.46,140.11,132.27,131.26,130.89,130.39,126.16,121.64,119.58,114.21,107.01,103.17,60.61,56.73,26.54,22.98；HR-MS(ESI)Calcd for C31H29N5O4S[M+H]+:568.2018,found:568.2016。
实施例2
N-(4-溴苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺的制备
用4-溴苯甲醛替代3,4,5-三甲氧基苯甲醛，制备方法同实施例1。
产物为黄色粉末状固体。m.p.180-181℃；1H NMR(400MHz,DMSO-d6,δ,ppm):10.60(s,1H，NH,benzimidazole),8.12(d,J＝8.7Hz,2H，ethylene linkage H),8.02(d,J＝15.6Hz,1H，phenyl H),7.91(d,J＝8.5Hz,2H，phenyl H),7.79–7.65(m,6H，phenyl H andbenzimidazole H),7.48(dd,J＝6.1,3.2Hz,2H，phenyl H and benzimidazole H),6.62(s,1H，pyrimidine H),4.96(s,2H，CH2-S),2.26(s,3H,CH3-)；13C NMR(101MHz,DMSO-d6,δ,ppm):187.66,166.18,164.03,163.57,162.90,161.25,160.31,151.03,143.29,142.45,134.58,132.57,132.34,131.28,131.20,130.27,126.17,124.33,123.23,120.23,114.21,103.03,56.48,26.54,21.93,19.03；HR-MS(ESI)Calcd for C28H22BrN5OS[M+H]+:556.0806,found:556.0803。
实施例3
N-(4-氟苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺的制备
用4-氟苯甲醛替代3,4,5-三甲氧基苯甲醛，制备方法同实施例1。
产物为黄色粉末状固体。m.p.171-172℃；1H NMR(400MHz,DMSO-d6,δ,ppm):10.62(s,1H，NH,benzimidazole),8.12(d,J＝8.8Hz,2H，ethylene linkage H),8.06–7.92(m,3H，phenyl H),7.77–7.66(m,5H，phenyl H),7.48(dd,J＝6.1,3.2Hz,2H，phenyl H andbenzimidazole H),7.33(t,J＝8.8Hz,2H，phenyl H and benzimidazole H),6.61(d,J＝5.7Hz,1H，pyrimidine H),4.96(s,2H，CH2-S),2.26(s,3H,CH3-)；13C NMR(101MHz,DMSO-d6,δ,ppm):187.69,166.26,165.07,162.59,160.33,151.09,143.28,142.60,132.62,131.98,131.95,131.76,131.68,131.21,130.23,126.16,122.34,120.17,116.51,116.29,114.89,114.21,103.03,55.86,26.53,22.03；HR-MS(ESI)Calcd for C28H22FN5OS[M+H]+:496.1607,found:496.1605。
实施例4
N-(3-氟苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺的制备
用3-氟苯甲醛替代3,4,5-三甲氧基苯甲醛，制备方法同实施例1。
产物为黄色粉末状固体。m.p.161-162℃；1H NMR(400MHz,DMSO-d6,δ,ppm):10.65(s,1H，NH,benzimidazole),8.12(d,J＝8.7Hz,2H，ethylene linkage H),8.04–7.91(m,3H，phenyl H),7.78–7.64(m,5H，phenyl H),7.48(t,J＝4.7Hz,5H，phenyl H andbenzimidazole H),6.63(s,1H，pyrimidine H),4.97(s,2H，CH2-S),2.27(s,3H,CH3-)；13CNMR(101MHz,DMSO-d6,δ,ppm):187.49,166.58,160.37,151.31,143.83,141.06,134.54,133.76,132.56,132.09,131.24,130.42,129.31,128.74,126.17,125.82,125.33,119.95,114.23,103.16,26.52,22.48；HR-MS(ESI)Calcd for C28H22FN5OS[M+H]+:496.1607,found:496.1608。
实施例5
N-(3-硝基苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺的制备
用3-硝基苯甲醛替代3,4,5-三甲氧基苯甲醛，制备方法同实施例1。
产物为黄色粉末状固体。m.p.170-171℃；1H NMR(400MHz,DMSO-d6,δ,ppm):10.65(s,1H，NH,benzimidazole),8.79(s,1H，ethylene linkage H),8.41(d,J＝7.8Hz,1H，ethylene linkage H),8.29(dd,J＝8.2,1.5Hz,1H，phenyl H),8.18(dd,J＝12.2,9.0Hz,3H，phenyl H),7.90–7.67(m,6H，phenyl H and benzimidazole H),7.49(dd,J＝6.2,3.2Hz,2H，benzimidazole H),6.63(s,1H，pyrimidine H),4.96(s,2H，CH2-S),2.26(s,3H,CH3-)；13C NMR(101MHz,DMSO-d6,δ,ppm):187.58,166.65,160.38,151.43,148.90,143.94,141.23,137.20,135.42,132.07,131.25,130.84,130.51,126.19,125.22,125.05,123.55,119.87,114.25,103.12,26.49,22.62；HR-MS(ESI)Calcd for C28H22N6O3S[M+H]+:523.1552,found:523.1551。
实施例6
N-(3-溴苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺的制备
用3-溴苯甲醛替代3,4,5-三甲氧基苯甲醛，制备方法同实施例1。
产物为黄色粉末状固体。m.p.169-170℃；1H NMR(400MHz,DMSO-d6,δ,ppm):10.58(s,1H，NH,benzimidazole),8.24(s,1H，ethylene linkage H),8.14(d,J＝8.8Hz,2H，phenyl H),8.05(d,J＝15.6Hz,1H，ethylene linkage H),7.91(d,J＝7.8Hz,1H，phenylH),7.79–7.58(m,6H，phenyl H and benzimidazole H),7.55–7.41(m,3H，phenyl H andbenzimidazole H),6.61(s,1H，pyrimidine H),4.94(d,J＝7.9Hz,2H，CH2-S),2.26(s,3H,CH3-)；13C NMR(101MHz,DMSO-d6,δ,ppm):187.59,166.64,160.38,151.44,143.83,142.01,137.82,133.41,132.19,131.43,131.32,131.24,130.43,128.65,126.19,123.95,122.89,119.86,114.24,103.13,26.50,22.62；HR-MS(ESI)Calcd for C28H22BrN5OS[M+H]+:556.0806,found:556.0806。
实施例7
N-(3,5-二氟苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺的制备
用3,5-二氟苯甲醛替代3,4,5-三甲氧基苯甲醛，制备方法同实施例1。
产物为黄色粉末状固体。m.p.182-183℃；1H NMR(400MHz,DMSO-d6,δ,ppm):10.73(s,1H，NH,benzimidazole),8.14(dd,J＝14.4,12.3Hz,3H，ethylene linkage H andphenyl H),7.95–7.66(m,7H，phenyl H and benzimidazole H),7.48(dd,J＝6.2,3.2Hz,2H,phenyl H),7.41–7.30(m,1H,phenyl H),6.64(s,1H，pyrimidine H),4.97(s,2H,CH2-S),2.27(s,3H,CH3-)；13C NMR(101MHz,DMSO-d6,δ,ppm):187.54,166.47,164.42,164.29,161.98,161.84,160.34,151.25,143.78,141.12,139.13,132.12,131.21,130.47,129.17,128.91,126.16,125.17,119.98,114.21,112.38,112.12,105.90,103.12,26.52,22.35；HR-MS(ESI)Calcd for C28H21F2N5OS[M+H]+:514.1513,found:514.1509。
实施例8
N-(2-氟-4-溴苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺的制备
用2-氟-4-溴苯甲醛替代3,4,5-三甲氧基苯甲醛，制备方法同实施例1。
产物为黄色粉末状固体。m.p.171-172℃；δ10.86(d,J＝11.3Hz,1H，NH,benzimidazole),8.06(dd,J＝31.4,12.2Hz,2H，ethylene linkage H),7.91(d,J＝8.4Hz,1H，phenyl H),7.82(d,J＝8.6Hz,1H，phenyl H),7.74–7.65(m,4H，phenyl H andbenzimidazole H),7.56(d,J＝8.6Hz,1H，phenyl H),7.48(ddd,J＝12.8,6.1,3.1Hz,2H，phenyl H and benzimidazole H),6.66(d,J＝6.1Hz,1H，pyrimidine H),4.97(d,J＝9.5Hz,2H,CH2-S),2.28(s,3H,CH3-).13C NMR(100MHz,DMSO-d6,δ,ppm):168.4,165.8,162.2,161.2,153.7,144.3,136.2,131.3,130.7,130.1,129.4,126.9,126.1,123.8,119.3,115.9,114.2,100.2,60.8,27.1,14.7；HR-MS(ESI)Calcd for C28H21BrFN5OS[M+H]+:574.0712,found:574.0713.
实施例9
N-(3-溴-4-氟苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺的制备
用3-溴-4-氟苯甲醛替代3,4,5-三甲氧基苯甲醛，制备方法同实施例1。
产物为黄色粉末状固体。m.p.179-180℃；1H NMR(400MHz,DMSO-d6,δ,ppm):11.01(s,1H，NH,benzimidazole),8.42(d,J＝6.7Hz,1H，phenyl H),8.13(d,J＝8.6Hz,2H，ethylene linkage H),8.02(dd,J＝15.5,11.0Hz,2H，phenyl H),7.75–7.66(m,5H,phenylH and benzimidazole H),7.51–7.44(m,3H,phenyl H and benzimidazole H),6.70(d,J＝5.0Hz,1H，pyrimidine H),5.00(s,2H,CH2-S),2.51(d,J＝1.5Hz,3H,CH3-)；13C NMR(100MHz,DMSO-d6,δ,ppm):187.03,166.02,163.20,160.41,159.87,157.93,150.81,143.20,140.61,133.33,131.78,130.73,130.61,129.89,129.28,125.68,123.18,119.45,117.24,117.01,113.73,108.96,108.75,102.59,26.45,25.99,21.95；HR-MS(ESI)Calcdfor C28H21BrFN5OS[M+H]+:574.0712,found:574.0711.
实施例10
N-(3-羟基苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺的制备
用3-羟基苯甲醛替代3,4,5-三甲氧基苯甲醛，制备方法同实施例1。
产物为黄色粉末状固体。m.p.194-195℃；1H NMR(400MHz,DMSO-d6,δ,ppm):10.80(s,1H，NH,benzimidazole),7.86(d,J＝8.6Hz,2H，ethylene linkage H),7.62(s,1H,phenyl H),7.51(dd,J＝6.1,3.2Hz,3H,phenyl H),7.44(dd,J＝12.2,5.3Hz,3H,phenylH),7.29–7.25(m,2H,benzimidazole H),7.16(d,J＝7.7Hz,1H,phenyl H),7.08(dd,J＝9.7,5.0Hz,2H,benzimidazole H),6.73(dd,J＝7.9,2.0Hz,1H,phenyl H),6.51(s,1H,pyrimidine H),4.80(s,2H,CH2-S),2.32(d,J＝1.7Hz,3H,CH3-)；13C NMR(100MHz,DMSO-d6,δ,ppm):187.31,165.96,163.02,159.88,157.80,150.83,143.62,142.92,135.99,132.09,130.73,129.84,129.68,129.28,125.70,121.72,119.67,119.57,117.73,115.31,113.74,102.55,55.98,26.01,21.84,18.52；HR-MS(ESI)Calcd for C28H23N5O2S[M+H]+:494.1650,found:494.1650.
实施例11
N-(噻吩-2-乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺的制备
用2-噻吩甲醛替代3,4,5-三甲氧基苯甲醛，制备方法同实施例1。
产物为黄色粉末状固体。m.p.190-191℃；1H NMR(400MHz,DMSO-d6,δ,ppm):10.73(s,1H，NH,benzimidazole),8.02(d,J＝8.8Hz,2H，ethylene linkage H),7.90(d,J＝15.3Hz,1H,phenyl H),7.81(d,J＝5.0Hz,1H,phenyl H),7.73(dd,J＝6.0,3.2Hz,3H,phenyl H),7.64(d,J＝8.8Hz,2H,benzimidazole H),7.59(d,J＝15.3Hz,1H,phenyl H),7.49(dd,J＝6.1,3.2Hz,2H,benzimidazole H),6.65(s,1H，pyrimidine H),4.97(s,2H,CH2-S),2.27(s,3H,CH3-)；13C NMR(100MHz,DMSO-d6,δ,ppm):189.50,166.56,160.37,151.81,151.34,143.88,143.46,132.98,132.55,131.23,130.19,129.52,127.40,126.17,121.46,119.95,114.22,103.08,33.90,26.53,24.11,20.31；HR-MS(ESI)Calcd forC26H21N5OS2[M+H]+:484.1266,found:484.1266.
实施例12
N-(呋喃-2-乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺的制备
用2-呋喃甲醛替代3,4,5-三甲氧基苯甲醛，制备方法同实施例1。
产物为黄色粉末状固体。m.p.186-187℃；1H NMR(400MHz,DMSO-d6,δ,ppm):1H NMR(400MHz,DMSO)δ10.68(s,1H，NH,benzimidazole),7.97(dd,J＝5.2,3.5Hz,3H,funan Hand ethylene linkage H),7.73(dd,J＝6.2,3.2Hz,2H,funan H),7.63(d,J＝8.8Hz,2H,benzimidazole H),7.56(s,2H,benzimidazole H),7.50(dd,J＝6.2,3.2Hz,2H,phenylH),7.14(d,J＝3.3Hz,1H,phenyl H),6.72(dd,J＝3.4,1.8Hz,1H,phenyl H),6.63(s,1H，pyrimidine H),4.96(s,2H,CH2-S),2.27(s,3H,CH3-).13C NMR(100MHz,DMSO-d6,δ,ppm):186.69,165.99,159.89,151.26,150.84,146.09,142.93,131.98,130.76,129.88,129.45,125.73,119.58,118.65,116.69,113.76,113.10,102.55,26.01,21.83.；HR-MS(ESI)Calcdfor C26H21N5O2S[M+H]+:468.1494,found:468.1494.
实施例13
N-(3,5-二氟苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-苯基嘧啶-4-胺的制备
用苯甲酰乙酸乙酯替代乙酰乙酸乙酯，3,5-二氟苯甲醛替代3,4,5-三甲氧基苯甲醛，制备方法同实施例1。
产物为黄色粉末状固体。m.p.222-223℃；1H NMR(400MHz,DMSO-d6,δ,ppm):10.68(s,1H，NH,benzimidazole),8.22(d,J＝8.8Hz,2H,ethylene linkage H),8.12(d,J＝15.6Hz,1H,phenyl H),7.88–7.82(m,4H,phenyl H),7.78–7.68(m,5H,phenyl H),7.51–7.44(m,5H,phenyl H and benzimidazole H),7.35(dd,J＝10.3,8.1Hz,1H,phenyl H),7.24(s,1H,pyrimidine H),5.03(s,2H,CH2-S)；13C NMR(101MHz,DMSO-d6,δ,ppm):186.89,167.79,163.87,161.65,161.42,161.29,160.52,151.75,144.23,140.39,138.62,135.65,131.21,130.97,130.74,130.10,128.81,126.36,125.42,124.64,118.62,113.73,112.72,111.76,111.50,105.31,99.90,26.40；HR-MS(ESI)Calcd for C33H23F2N5O2S[M+H]+:576.1669,found:576.1669。
实施例14
N-(3,5-二氯苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-苯基嘧啶-4-胺的制备
用3,5-二氯苯甲醛替代3,5-二氟苯甲醛，制备方法同实施例13。
产物为黄色粉末状固体。m.p.253-254℃；1H NMR(400MHz,DMSO-d6,δ,ppm):10.72(s,1H，NH,benzimidazole),8.22(d,J＝8.8Hz,2H,ethylene linkage H),8.15(d,J＝15.6Hz,1H,phenyl H),8.08(d,J＝1.6Hz,2H,phenyl H),7.88–7.82(m,5H,phenyl H),7.73(dd,J＝6.2,3.2Hz,2H,benzimidazole H),7.70(s,1H,phenyl H),7.68–7.66(m,1H,phenyl H),7.49–7.45(m,5H,phenyl H and benzimidazole H),7.25(s,1H,pyrimidineH),5.03(s,2H,CH2-S)；13C NMR(101MHz,DMSO-d6,δ,ppm):191.45,186.89,167.83,161.72,160.58,151.84,144.31,139.96,138.80,138.59,135.71,134.60,133.78,131.19,131.04,130.80,130.20,129.22,128.86,127.56,127.17,126.43,125.54,124.88,118.68,113.80,99.98,26.44；HR-MS(ESI)Calcd for C33H23Cl2N5OS[M+H]+:608.1078,found:608.1077。
应用例1
体外抗肿瘤活性测试：以CCK-8法采用四种细胞系，分别为胃癌细胞(MGC-803)、人肝癌细胞(Hepg2)、人食管癌细胞(EC109)、人乳腺癌细胞(MDA-MB-231)。
收集对数期细胞，调整细胞悬液浓度，每孔加入100μl，铺板调整待测细胞密度，(边缘孔用PBS填充)。体积百分5％CO2下37℃孵育24h，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药物，一般设9个浓度，每孔200μl，设3个复孔。体积百分5％CO2下37℃孵育72h，倒置显微镜下观察。每孔加入5μLCCK-8进行染色，继续培养72h。终止培养，置摇床上低速振荡10min，使结晶物充分溶解。在酶联免疫检测仪OD450nm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。
体外抗肿瘤活性测试表

Claims (4)

1.4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基)嘧啶类化合物，其特征在于：其具有通式Ⅰ所述结构：
通式Ⅰ
通式Ⅰ中：R1为甲基、苯基；R2为3,4,5-三甲氧基苯基、4-溴苯基、4-氟苯基、3-氟苯基、3-硝基苯基、3-溴苯基、3,5-二氟苯基、2-氟-4-溴苯基、3-溴-4-氟苯基、3-羟基苯基、2-噻吩基、2-呋喃基、3,5-二氟苯基、3,5-二氯苯基。
2.如权利要求1所述的4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基)嘧啶类化合物，其特征在于：该化合物是以下化合物之一：
N-(3,4,5-三甲氧基苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺，
N-(4-溴苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺，
N-(4-氟苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺，
N-(3-氟苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺，
N-(3-硝基苯乙烯基苯乙酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺，
N-(3-溴苯乙烯基苯乙酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺，
N-(3,5-二氟苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺，
N-(2-氟-4-溴苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺，
N-(3-溴-4-氟苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺，
N-(3-羟基苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺，
N-(噻吩-2-乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺，
N-(呋喃-2-乙烯基苯乙酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺，
N-(3,5-二氟苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-苯基嘧啶-4-胺，
N-(3,5-二氯苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-苯基嘧啶-4-胺。
3.如权利要求1-2 其中之一所述的4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基)嘧啶类化合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细胞、人肝癌细胞、人食管癌或乳腺癌细胞的药物。
4.制备如权利要求1所述的4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基)嘧啶类化合物的方法，其特征在于：通过如下方法实现：
R1、R2如权利要求1所述；
1)、将乙酰乙酸乙酯或苯甲酰乙酸乙酯和硫脲在氢氧化钾的乙醇溶液中回流发生环合反应得到化合物1；
2)、将化合物1和2-氯亚甲基苯并咪唑在水和二氧六环的混合溶液中加热，以氢氧化钾催化发生取代反应生成化合物2；
3)、将化合物2与三氯氧磷加热反应，得到化合物3；
4）、将对氨基苯乙酮与取代苯甲醛、2-噻吩甲醛、2-呋喃甲醛在氢氧化钾的乙醇溶液中发生克莱森-施密特缩合反应得到关键中间体查尔酮4-氨基苯乙烯基苯乙酮、4-氨基噻吩-2-乙烯基苯乙酮、4-氨基呋喃-2-乙烯基苯乙酮；
5）、将化合物3与上述4)中取代的氨基类查尔酮加热反应得到4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基)嘧啶类化合物。
CN201610616997.2A 2016-07-28 2016-07-28 4位含查尔酮结构单元的6-取代-2-(苯并咪唑-2-亚甲硫基)嘧啶类化合物及其制备方法和用途 Expired - Fee Related CN106243089B (zh)

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