CN101560175B - 一类硫脲类衍生物及其制备方法与用途 - Google Patents
一类硫脲类衍生物及其制备方法与用途 Download PDFInfo
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- CN101560175B CN101560175B CN200910031329A CN200910031329A CN101560175B CN 101560175 B CN101560175 B CN 101560175B CN 200910031329 A CN200910031329 A CN 200910031329A CN 200910031329 A CN200910031329 A CN 200910031329A CN 101560175 B CN101560175 B CN 101560175B
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- thiourea derivatives
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Abstract
一类硫脲类衍生物,它有如下通式:
Description
技术领域
本发明涉及硫脲类衍生物及其制备方法与在制备抗肿瘤药物中的应用。
背景技术
N-取代硫脲类衍生物是一类用途广泛的化合物,其结构中的非对称单元是许多酶抑制剂和生物模拟肽的常见结构特征,故多数具有生物活性,在农药上应用广泛,其中许多可用作除草剂、杀虫剂和植物生长调节剂等。在医药、生物领域中也具有十分重要的地位,它除了具有广谱的抗菌性之外,对白血病、肿瘤也有很好的药效。因此,取代硫脲类化合物具有很广的应用前景。
自发现硫脲类化合物具有一定的生物活性后,人们就将其作为一种具有开发潜力的生物靶标,开展合理分子设计以及从天然生物活性物质中寻找更高或更广谱的生物活性、更高的选择性、更低的毒性、更长或更短的残效期等,即开发出具有广阔前景且对人类、生态更安全的新型硫脲类化合物。
硫脲类衍生物作为医药的前景十分值得关注。国际上相关领域的最新研究表明硫脲衍生物作为非肽类促生长素抑制素的激动剂具有很高的活性,而后者在许多癌症的发生机制中扮演着重要角色。而且这只是取代硫脲类化合物生物活性的一个方面。因此,对其进行深入研究具有一定的理论和实际价值,尤其是在合成系列新型取代硫脲类衍生物的基础上对它们的生物活性进行系统的研究具有十分重要的意义。
发明内容
本发明的目的在于提供一类新硫脲类衍生物以及它们的制备方法与用途。
本发明的技术方案如下:
一类硫脲类衍生物,其特征是它有如下通式:
式中:R1为:
基团;
R2为:
一种上述的硫脲类衍生物的制法,它由下列步骤组成:
步骤1.于无水乙醇中,加入具有R1结构的醛和具有R2结构的胺,醛与胺的物质的量之比为1∶1.2搅拌加热至60~65℃,反应3h后冷却,减压蒸去多余的溶剂和胺,重结晶得到R1=N-R2,
步骤2.将得到的R1=N-R2溶于无水乙醇,置于冰浴中,缓慢向其中加入等物质的量的NaBH4,加完之后,撤去冰浴,在常温下反应6h,反应结束后,向体系加水,用氯仿萃取水溶液2~3次,之后减压蒸干,得到R1NHR2,
步骤3.将等物质的量的化合物R1NHR2与异硫氰酸苯酯(PhNCS)溶于氯仿,在60℃温度下搅拌回流4h,过滤,将所得固体在乙醇中重结晶得到本发明的硫脲类衍生物。
上述的制法,所述的步骤1中,无水乙醇的用量为每毫摩尔醛加10-15ml。
上述的制法,所述的步骤2中,无水乙醇的用量为每毫摩尔R1=N-R2加10-15ml。
上述的制法,所述的步骤3中,CHCl3的用量为每毫摩尔R1NHR2加10-15ml。
本发明的硫脲类衍生物对人白血病细胞(K562)和人体口腔上表皮癌细胞(KB)有明显的抑制作用,因此本发明的硫脲类衍生物可以应用于制备抗肿瘤药物。
具体实施方式
实施例一:N-苄基-N-(5-氯-2-羟基苄基)-N’-苯基硫脲(化合物1)的制备
于250ml单口圆底烧瓶中加入100ml无水乙醇,选用5-氯水杨醛(10mmol)和苄胺(12mmol)。搅拌反应约3个小时在旋转蒸发仪上减压蒸去多余溶剂和胺,得到黄色油状物。加热条件下用40ml乙醇将其全部溶解,之后冷却重结晶,得到亮黄色固体。将固体转移进250ml单口圆底烧瓶,加100ml无水乙醇将其完全溶解,并将烧瓶置于冰浴中,分批缓慢加入硼氢化钠(320mg,10mmol),撤去冰浴,在常温下搅拌反应约6h。取下烧瓶,向反应体系中加水,转移出至500ml分液漏斗,每次加200ml氯仿萃取2~3次,减压蒸去氯仿后得到2-((苄胺基)甲基)-4-氯酚。将其转移至250ml单口圆底烧瓶中,加100ml氯仿溶解,再向溶液中滴加10mmol异硫氰酸苯酯(PhNCS),加热至60℃搅拌回流4h,有白色固体物质生成。将固体过滤出,在常温下用乙醇清洗3~4次,除去杂质。再以40ml无水乙醇,在加热至65℃左右时将固体完全溶解,冷却至室温,重结晶得到白色颗粒状目标化合物。产率65%。Mp 131-134℃.1H-NMR(300MHz,DMSO-d6,δppm):4.90(s,2H);5.12(s,2H);6.84(d,J=8.6,1H);7.08(s,1H);7.13(d,J=4.1,1H);7.20(m,2H);7.23(d,J=5.2,2H);7.26(t,J=3.7,2H);7.33(m,2H);7.70(d,J=8.1,2H);9.47(s,1H);10.08(s,1H).MS(ESI):382.09([M+H]+).Anal.calc.for C21H19ClN2OS:C 65.87,H 5.00,Cl 9.26,N 7.32,O 4.18,S8.37%;found:C 65.98,H 4.92,Cl 9.36,N 7.25,O 4.08,S 8.29%.
实施例二:N-对氟苄基N-(5-氯-2-羟基苄基)-N’-苯基硫脲(化合物2)的制备
制备方法同实施例一。以对氟苄胺代替苄胺,得到白色颗粒状目标化合物。产率63%。Mp 133-138℃.1H-NMR(300MHz,DMSO-d6,δppm):4.95(s,2H);5.16(s,2H);6.77(d,J=7.2,1H);6.94(s,1H);7.02(d,J=8.3,1H);7.12(d,J=5.1,2H);7.20(m,2H);7.26(t,J=2.4,1H);7.39(d,J=6.2,2H);7.70(d,J=8.1,2H);10.47(s,1H);12.08(s,1H).MS(ESI):400.08([M+H]+).Anal.calc.forC21H18ClFN2OS:C 62.92,H 4.53,Cl 8.84,F4.74,N 6.99,O 3.99,S 8.00%;found:C63.98,H 4.38,Cl 8.76,F4.69,N 6.89,O 3.95,S 8.01%.
实施例三:N-(2-吗啉乙基)-N-(5-氯-2-羟基苄基)-N’-苯基硫脲(化合物3)的制备
制备方法同实施例一。以N-(3-氨基乙基)吗啉代替苄胺,得到黄色粉末状目标化合物。产率57%。Mp 123-126℃.1H-NMR(300MHz,DMSO-d6,δppm):2.36(t,J=2.7,4H);2.39(t,J=2.2,2H);3.55(t,J=6.0,2H);3.65(t,J=2.4,4H);5.16(s,2H);6.77(d,J=8.2,1H);6.81(t,J=6.4,1H);7.13(d,J=5.2,1H);7.20(m,2H);7.26(s,1H);7.70(d,J=5.8,2H);9.29(s,1H);11.52(s,1H).MS(ESI):405.13([M+H]+).Anal.calc.for C20H24ClN3O2S:C,59.17;H,5.96;Cl,8.73;N,10.35;O,7.88;S,7.90%;found:C,60.07;H,5.88;Cl,8.73;N,10.34;O,7.76;S,7.91%.
实施例四:N-(3-吗啉丙基)-N-(5-氯-2-羟基苄基)-N’-苯基硫脲(化合物4)的制备
制备方法同实施例一。以N-(3-氨基丙基)吗啉代替苄胺,得到黄色粉末状目标化合物。产率52%。Mp 120-123℃.1H-NMR(300MHz,DMSO-d6,δppm):1.56(m,2H);2.35(t,J=2.7,4H);2.46(t,J=3.4,2H);3.44(t,J=2.8,2H);3.65(t,J=3.6,4H);5.16(s,2H);6.76(d,J=6.8,1H);6.82(t,J=8.0,1H);7.13(d,J=7.2,1H);7.21(m,2H);7.26(s,1H);7.72(d,J=8.2,2H);8.14(s,1H);10.26(s,1H).MS(ESI):419.14([M+H]+).Anal.calc.for C21H26ClN3O2S:C,60.06;H,6.24;Cl,8.44;N,10.01;O,7.62;S,7.64%;found:C,60.15;H,6.19;Cl,8.42;N,10.11;O,7.56;S,7.61%.
实施例五:N-苄基-N-(5-溴-2-羟基苄基)-N’-苯基硫脲(化合物5)的制备
制备方法同实施例一。以5-溴水杨醛代替5-氯水杨醛,得到淡黄色粉末状目标化合物。产率64%。Mp 141-144℃.1H-NMR(300MHz,DMSO-d6,δppm):4.93(s,2H);5.16(s,2H);6.85(d,J=8.1,1H);7.09(s,1H);7.14(d,J=4.5,1H);7.20(m,2H);7.23(d,J=5.162H);7.25(t,J=3.7,2H);7.33(m,2H);7.72(d,J=7.8,2H);9.52(s,1H);10.20(s,1H).MS(ESI):426.04([M+H]+).Anal.calc.forC21H19BrN2OS:C,59.02;H,4.48;Br,18.70;N,6.56;O,3.74;S,7.50%;found:C,59.14;H,4.42;Br,18.65;N,6.51;O,3.74;S,7.48%.
实施例六:N-对氟苄基-N-(5-溴-2-羟基苄基)-N’-苯基硫脲(化合物6)的制备
制备方法同实施例一。以5-溴水杨醛代替5-氯水杨醛,对氟苄胺代替苄胺,得到淡黄色粉末状目标化合物。产率62%。Mp 152-154℃.1H-NMR(300MHz,DMSO-d6,δppm):4.93(s,2H);5.14(s,2H);6.77(d,J=7.6,1H);6.92(s,1H);7.02(d,J=8.5,1H);7.09(d,J=5.4,2H);7.18(m,2H);7.24(t,J=2.4,1H);7.38(d,J=7.2,2H);7.68(d,J=7.8,2H);10.50(s,1H);12.12(s,1H).MS(ESI):444.03([M+H]+).Anal.calc.for C21H18BrFN2OS:C,56.64;H,4.07;Br,17.94;F,4.27;N,6.29;O,3.59;S,7.20%;found:C,56.86;H,4.02;Br,17.91;F,4.15;N,6.21;O,3.56;S,7.13%.
实施例七:N-(2-吗啉乙基)-N-(5-溴-2-羟基苄基)N’-苯基硫脲(化合物7)的制备
制备方法同实施例一。以5-溴水杨醛代替5-氯水杨醛,N-(3-氨基乙基)吗啉代替苄胺,得到黄色粉末状目标化合物。产率52%。Mp 133-136℃.1H-NMR(300MHz,DMSO-d6,δppm):2.39(t,J=2.7,4H);2.41(t,J=2.2,2H);3.55(t,J=6.0,2H);3.65(t,J=2.4,4H);5.16(s,2H);6.77(d,J=8.2,1H);6.81(t,J=6.4,1H);7.13(d,J=5.2,1H);7.20(m,2H);7.26(s,1H);7.70(d,J=5.8,2H);9.20(s,1H);12.02(s,1H).MS(ESI):449.08([M+H]+).Anal.calc.for C20H24BrN3O2S:C,53.33;H,5.37;Br,17.74;N,9.33;O,7.10;S,7.12%;found:C,53.51;H,5.32;Br,17.68;N,9.30;O,7.10;S,7.07%.
实施例八:N-(3-吗啉丙基)-N-(5-溴-2-羟基苄基)-N’-苯基硫脲(化合物8)的制备
制备方法同实施例一。以5-溴水杨醛代替5-氯水杨醛,N-(3-氨基丙基)吗啉代替苄胺,得到黄色粉末状目标化合物。产率49%。Mp 119-123℃.1H-NMR(300MHz,DMSO-d6,δppm):1.54(m,2H);2.33(t,J=2.7,4H);2.46(t,J=3.4,2H);3.44(t,J=2.8,2H);3.63(t,J=3.6,4H);5.16(s,2H);6.76(d,J=6.8,1H);6.82(t,J=8.0,1H);7.13(d,J=7.2,1H);7.28(m,2H);7.36(s,1H);7.72(d,J=8.2,2H);9.14(s,1H);11.23(s,1H).MS(ESI):463.09([M+H]+).Anal.calc.forC21H26BrN3O2S:C,54.31;H,5.64;Br,17.21;N,9.05;O,6.89;S,6.90%;found:C,54.51;H,5.62;Br,17.15;N,9.05;O,6.84;S,6.82%.
实施例九:N-苄基-N-(3,5-二氯-2-羟基苄基)-N’-苯基硫脲(化合物9)的制备
制备方法同实施例一。以3,5-二氯水杨醛代替5-氯水杨醛,得到白色粉末状目标化合物。产率62%。Mp 149-152℃.1H-NMR(300MHz,DMSO-d6,δppm):5.12(s,2H);5.16(s,2H);6.81(t,J=7.4,1H);7.14(s,1H);7.22(m,8H);7.70(d,J=6.2,2H);9.24(s,1H);12.03(s,1H).MS(ESI):416.05([M+H]+).Anal.calc.forC21H18Cl2N2OS:C,60.43;H,4.35;Cl,16.99;N,6.71;O,3.83;S,7.68%;found:C,60.56;H,4.28;Cl,16.94;N,6.66;O,3.83;S,7.57%.
实施例十:N-对氟苄基-N-(3,5-二氯-2-羟基苄基)-N’-苯基硫脲(化合物10)的制备
制备方法同实施例一。以3,5-二氯水杨醛代替5-氯水杨醛,对氟苄胺代替苄胺,得到白色粉末状目标化合物。产率64%。Mp 151-154℃.1H-NMR(300MHz,DMSO-d6,δppm):5.03(s,2H);5.12(s,2H);6.77(t,J=7.6,1H);7.12(d,J=5.4,2H);7.14(s,1H);7.26(m,5H);7.68(d,J=8.2,2H);10.20(s,1H);12.13(s,1H).MS(ESI):434.04([M+H]+).Anal.calc.for C21H17Cl2FN2OS:C,57.94;H,3.94;Cl,16.29;F,4.36;N,6.43;O,3.68;S,7.37%;found:C,58.12;H,3.86;Cl,16.23;F,4.28;N,6.43;O,3.68;S,7.25%.
实施例十一:N-(2-吗啉乙基)-N-(3,5-二氯-2-羟基苄基)-N’-苯基硫脲(化合物11)的制备
制备方法同实施例一。以3,5-二氯水杨醛代替5-氯水杨醛,N-(3-氨基乙基)吗啉代替苄胺,得到黄色粉末状目标化合物。产率53%。Mp 133-138℃.1H-NMR(300MHz,DMSO-d6,δppm):2.34(t,J=3.7,4H);2.39(t,J=2.1,2H);3.55(t,J=5.8,2H);3.68(t,J=3.4,4H);5.18(s,2H);6.77(d,J=8.8,1H);7.14(s,1H);7.20(m,2H);7.34(s,1H);8.03(d,J=7.8,2H);8.95(s,1H);10.02(s,1H).MS(ESI):439.09([M+H]+).Anal.calc.for C20H23Cl2N3O2S:C,54.55;H,5.26;Cl,16.10;N,9.54;O,7.27;S,7.28%;found:C,54.68;H,5.18;Cl,16.06;N,9.54;O,7.29;S,7.23%.
实施例十二:N-(3-吗啉丙基)-N-(3,5-二氯-2-羟基苄基)-N’-苯基硫脲(化合物12)的制备
制备方法同实施例一。以3,5-二氯水杨醛代替5-氯水杨醛,N-(3-氨基丙基)吗啉代替苄胺,得到黄色粉末状目标化合物。产率55%。Mp 122-127℃.1H-NMR(300MHz,DMSO-d6,δppm):1.56(m,2H);2.37(t,J=3.1,4H);2.46(t,J=3.4,2H);3.44(t,J=2.8,2H);3.63(t,J=3.6,4H);5.16(s,2H);6.76(s,1H);6.82(s,1H);7.13(t,J=7.2,1H);7.28(m,2H);7.36(s,1H);7.72(d,J=8.2,2H);9.14(s,1H);11.23(s,1H).MS(ESI):453.10([M+H]+).Anal.calc.forC21H25Cl2N3O2S:C,55.51;H,5.55;Cl,15.60;N,9.25;O,7.04;S,7.06%;found:C,55.64;H,5.48;Cl,15.54;N,9.23;O,7.02;S,7.06%.
实施例十三:N-苄基-N-(3,5-二溴-2-羟基苄基)-N’-苯基硫脲(化合物13)的制备
制备方法同实施例一。以3,5-二溴水杨醛代替5-氯水杨醛,得到黄色颗粒状目标化合物。产率65%.。Mp 142-147℃.1H-NMR(300MHz,DMSO-d6,δppm):5.14(s,2H);5.16(s,2H);6.78(t,J=7.8,1H);7.15(s,1H);7.26(m,8H);7.83(d,J=7.2,2H);10.34(s,1H);12.13(s,1H).MS(ESI):503.95([M+H]+).Anal.calc.for C21H18Br2N2OS:C,49.82;H,3.58;Br,31.57;N,5.53;O,3.16;S,6.33%;found:C,49.98;H,3.54;Br,31.51;N,5.47;O,3.13;S,6.30%.
实施例十四:N-对氟苄基-N-(3,5-二溴-2-羟基苄基)-N’-苯基硫脲(化合物14)的制备
制备方法同实施例一。以3,5-二溴水杨醛代替5-氯水杨醛,对氟苄胺代替苄胺,得到黄色颗粒状目标化合物。产率64%。Mp 154-156℃.1H-NMR(300MHz,DMSO-d6,δppm):5.13(s,2H);5.16(s,2H);6.87(t,J=8.2,1H);7.14(d,J=5.4,2H);7.17(s,1H);7.31(m,5H);7.72(d,J=8.8,2H);10.19(s,1H);11.73(s,1H).MS(ESI):521.94([M+H]+).Anal.calc.for C21H17Br2FN2OS:C,48.11;H,3.27;Br,30.48;F,3.62;N,5.34;O,3.05;S,6.12%;found:C,48.24;H,3.22;Br,30.44;F,3.60;N,5.31;O,3.02;S,6.08%.
实施例十五:N-(2-吗啉乙基)-N-(3,5-二溴-2-羟基苄基)-N’-苯基硫脲(化合物15)的制备
制备方法同实施例一。以3,5-二溴水杨醛代替5-氯水杨醛,N-(3-氨基乙基)吗啉代替苄胺,得到黄色粉末状目标化合物。产率47%。Mp 143-148℃.1H-NMR(300MHz,DMSO-d6,δppm):2.36(t,J=2.8,4H);2.41(t,J=2.4,2H);3.55(t,J=5.8,2H);3.65(t,J=4.6,4H);5.20(s,2H);6.87(d,J=8.3,1H);7.21(m,2H);7.54(s,1H);7.64(s,1H);8.03(d,J=7.8,2H);8.98(s,1H);10.12(s,1H).MS(ESI):526.99([M+H]+).Anal.calc.for C20H23Br2N3O2S:C,45.38;H,4.38;Br,30.19;N,7.94;O,6.05;S,6.06%;found:C,45.58;H,4.29;Br,30.13;N,7.84;O,6.02;S,6.04%.
实施例十六:N-(3-吗啉丙基)-N-(3,5-二溴-2-羟基苄基)-N’-苯基硫脲(化合物16)的制备
制备方法同实施例一。以3,5-二溴水杨醛代替5-氯水杨醛,N-(3-氨基丙基)吗啉代替苄胺,得到黄色粉末状目标化合物。产率50%。Mp 121-124℃.1H-NMR(300MHz,DMSO-d6,δppm):1.56(m,2H);2.40(t,J=3.4,4H);2.46(t,J=3.4,2H);3.45(t,J=3.8,2H);3.63(t,J=3.6,4H);5.16(s,2H);6.78(t,J=7.9,1H);7.22(m,2H);7.53(s,1H);7.62(s,1H);7.74(d,J=8.2,2H);10.09(s,1H);11.23(s,1H).MS(ESI):541.00([M+H]+).Anal.calc.for C21H25Br2N3O2S:C,46.42;H,4.64;Br,29.41;N,7.73;O,5.89;S,5.90%;found:C,46.54;H,4.58;Br,29.37;N,7.66;O,5.81;S,5.90%.
实施例十七:N-苄基-N-(3-硝基苄基)-N’-苯基硫脲(化合物17)的制备
制备方法同实施例一。以间硝基苯甲醛代替5-氯水杨醛,得到黄色粉末状目标化合物。产率63%。Mp 144-147℃.1H-NMR(300MHz,DMSO-d6,δppm):5.16(s,2H);5.18(s,2H);6.80(t,J=7.9,1H);7.26(m,7H);7.65(m,4H);8.10(m,2H);12.16(s,1H).MS(ESI):377.12([M+H]+).Anal.calc.for C21H19N3O2S:C,66.82;H,5.07;N,11.13;O,8.48;S,8.49%;found:C,66.95;H,5.01;N,11.10;O,8.42;S,8.39%.
实施例十八:N-对氟苄基-N-(3-硝基苄基)-N’-苯基硫脲(化合物18)的制备
制备方法同实施例一。以间硝基苯甲醛代替5-氯水杨醛,对氟苄胺代替苄胺,得到黄色颗粒状目标化合物。产率63%。Mp 144-146℃.1H-NMR(300MHz,DMSO-d6,δppm):5.15(s,2H);5.18(s,2H);6.92(t,J=8.6,1H);7.14(d,J=6.4,2H);7.30(m,4H);7.65(m,4H);8.07(d,J=7.2,1H);8.12(s,1H);11.53(s,1H).MS(ESI):395.11([M+H]+).Anal.calc.for C21H18FN3O2S:C,63.78;H,4.59;F,4.80;N,10.63;O,8.09;S,8.11%;found:C,63.88;H,4.55;F,4.80;N,10.62;O,8.08;S,8.07%.
实施例十九:N-(2-吗啉乙基)-N-(3-硝基苄基)-N’-苯基硫脲(化合物19)的制备
制备方法同实施例一。以间硝基苯甲醛代替5-氯水杨醛,N-(3-氨基乙基)吗啉代替苄胺,得到淡黄色粉末状目标化合物。产率48%。Mp 145-148℃.1H-NMR(300MHz,DMSO-d6,δppm):2.37(t,J=2.9,4H);2.41(t,J=2.4,2H);3.58(t,J=3.8,2H);3.70(t,J=4.1,4H);5.20(s,2H);6.87(d,J=8.3,1H);7.21(m,2H);7.63(m,4H);8.10(m,2H);12.12(s,1H).MS(ESI):400.16([M+H]+).Anal.calc.for C20H24N4O3S:C,59.98;H,6.04;N,13.99;O,11.98;S,8.01%;found:C,60.12;H,6.01;N,13.94;O,11.92;S,8.00%.
实施例二十:N-(3-吗啉丙基)-N-(3-硝基苄基)-N’-苯基硫脲(化合物20)的制备
制备方法同实施例一。以间硝基苯甲醛代替5-氯水杨醛,N-(3-氨基丙基)吗啉代替苄胺,得到淡黄色粉末状目标化合物。产率52%。Mp 131-134℃.1H-NMR(300MHz,DMSO-d6,δppm):1.58(m,2H);2.40(t,J=2.8,4H);2.48(t,J=3.2,2H);3.45(t,J=3.2,2H);3.67(t,J=5.4,4H);5.16(s,2H);6.85(t,J=7.9,1H);7.22(m,2H);7.63(m,4H);8.12(d,J=7.7,1H);8.17(s,1H);11.78(s,1H).MS(ESI):414.17([M+H]+).Anal.calc.for C21H26N4O3S:C,60.85;H,6.32;N,13.52;O,11.58;S,7.74%;found:C,60.98;H,6.30;N,13.52;O,11.54;S,7.71%.
实施例二十一:N-苄基-N-(4-硝基苄基)-N’-苯基硫脲(化合物21)的制备
制备方法同实施例一。以对硝基苯甲醛代替5-氯水杨醛,得到黄色粉末状目标化合物。产率60%。Mp 146-147℃.1H-NMR(300MHz,DMSO-d6,δppm):5.16(s,2H);5.18(s,2H);6.82(t,J=8.3,1H);7.28(m,7H);7.65(d,J=8.2,2H);7.95(d,J=8.1,2H);8.14(d,J=8.7,2H);12.12(s,1H).MS(ESI):377.12([M+H]+).Anal.calc.for C21H19N3O2S:C,66.82;H,5.07;N,11.13;O,8.48;S,8.49%;found:C,66.96;H,5.00;N,11.13;O,8.44;S,8.39%.
实施例二十二:N-对氟苄基-N-(4-硝基苄基)-N’-苯基硫脲(化合物22)的制备
制备方法同实施例一。以对硝基苯甲醛代替5-氯水杨醛,对氟苄胺代替苄胺,得到黄色粉末状目标化合物。产率61%。Mp 143-145℃.1H-NMR(300MHz,DMSO-d6,δppm):5.16(s,2H);5.21(s,2H);7.02(t,J=8.4,1H);7.16(d,J=7.6,2H);7.31(m,4H);7.72(d,J=6.6,2H);7.95(d,J=8.6,2H);8.14(d,J=7.2,2H);12.13(s,1H).MS(ESI):395.11([M+H]+).Anal.calc.for C21H18FN3O2S:C,63.78;H,4.59;F,4.80;N,10.63;O,8.09;S,8.11%;found:C,63.89;H,4.56;F,4.73;N,10.62;O,8.02;S,8.01%.
实施例二十三:N-(2-吗啉乙基)-N-(4-硝基苄基)-N’-苯基硫脲(化合物23)的制备
制备方法同实施例一。以对硝基苯甲醛代替5-氯水杨醛,N-(3-氨基乙基)吗啉代替苄胺,得到黄色粉末状目标化合物。产率51%。Mp 142-148℃.1H-NMR(300MHz,DMSO-d6,δppm):2.34(t,J=2.2,4H);2.38(t,J=2.9,2H);3.58(t,J=3.8,2H);3.66(t,J=4.1,4H);5.18(s,2H);6.82(d,J=8.3,1H);7.25(m,2H);7.70(d,J=7.5,2H);8.01(d,J=8.3,2H);8.21(d,J=8.5,2H);11.82(s,1H).MS(ESI):400.16([M+H]+).Anal.calc.for C20H24N4O3S:C,59.98;H,6.04;N,13.99;O,11.98;S,8.01%;found:C,60.15;H,6.02;N,13.96;O,11.90;S,7.93%.
实施例二十四:N-(3-吗啉丙基)N-(4-硝基苄基)-N’-苯基硫脲(化合物24)的制备
制备方法同实施例一。以对硝基苯甲醛代替5-氯水杨醛,N-(3-氨基丙基)吗啉代替苄胺,得到黄色粉末状目标化合物。产率52%。Mp 121-124℃.1H-NMR(300MHz,DMSO-d6,δppm):1.56(m,2H);2.38(t,J=2.5,4H);2.48(t,J=2.8,2H);3.46(t,J=3.2,2H);3.67(t,J=6.4,4H);5.22(s,2H);7.05(t,J=8.9,1H);7.30(m,2H);7.81(d,J=9.8,2H);8.12(d,J=7.7,2H);8.27(d,J=9.2,2H);12.08(s,1H).MS(ESI):414.17([M+H]+).Anal.calc.for C21H26N4O3S:C,60.85;H,6.32;N,13.52;O,11.58;S,7.74%;found:C,60.92;H,6.31;N,13.45;O,11.52;S,7.71%.
实施例二十五:硫脲类衍生物体外抗肿瘤活性研究
采用MTT[3-(4,5)-双甲基-2-噻唑-(2,5)-苯基溴化四氮唑蓝]法来测定硫脲类衍生物对人体口腔上表皮癌细胞株(KB)和人白血病细胞株(K562)的IC50值。
(1)培养液(每升)的配制:①悬浮细胞:RPMI-1640培养粉一袋(10.4g),新生牛血清100ml,青霉素溶液(20万U/ml)0.5ml,链霉素溶液(20万U/ml)0.5ml,加三蒸水溶解后,用5.6%的NaHCO3溶液调PH值至7.2-7.4,最后定容至1000ml。过滤灭菌。②贴壁细胞:同上,再加入NaHCO3 2.00g,HEPES 2.38g。
(2)D-Hanks缓冲液(每升)的配制:NaCl 8.00g,KCl 0.40g,Na2HPO4·12H2O 0.06g,KH2PO4 0.06g,NaHCO3 0.35g。高压灭菌。
(3)胰蛋白酶液的配制:利用D-Hanks缓冲液配成浓度为0.5%胰蛋白酶液。过滤除菌。
(4)实验药液的配制:将测试样品用少量的三蒸水溶解配成储备液,一般按实验最高浓度的10倍配制储备液。根据化合物溶解性不同,可用三蒸水直接溶解,或用少量DMSO助溶,再加三蒸水溶解。DMSO在培养液中的浓度不宜过大,加药后的每孔细胞悬液中DMSO的终浓度一般不超过0.05%-0.1%。储备液保存于-20℃冰箱中备用。
(5)人白血病细胞K562的培养:为悬浮生长细胞,常规培养于RPMI-1640培养液内(含10%小牛血清、100U/ml链霉素),置于37℃、5%CO2培养箱中培养,每隔3-4天传代一次。传代时将原瓶中培养液转移至离心管中,1000rpm离心5min,弃去原培养液,加入等量新鲜培养液,吹打均匀,移取适量至新鲜培养瓶中,再补充新鲜培养液至原体积(培养液体积约为培养瓶容量的1/10)。
(6)人体口腔上表皮癌细胞KB的培养:为贴壁生长细胞,常规培养于RPMI-1640培养液内(含10%小牛血清、100U/ml链霉素),置37℃、5%CO2培养箱中培养,每隔3-4天传代一次。传代时先弃去原培养液,再用D-Hanks缓冲液洗涤;然后用0.5%胰蛋白酶消化30秒左右,加入少量新鲜培养液终止消化;吹打,使贴壁细胞从培养瓶壁上脱落下来;移取适量至新鲜培养瓶中,再补充新鲜培养液至原体积(培养液体积约为培养瓶容量的1/10)。
(7)细胞孵育:取对数生长期的2种肿瘤细胞,调细胞悬液浓度为1-1.5×105个ml-1。在96孔培养板中每孔加细胞悬液100μl,置37℃,5%CO2培养箱中培养24h。培养24h后,分别按设计加入药液。
(8)加药:将测试药液按照最终浓度的浓度梯度分别加入到各个孔中,每个浓度设6个平行孔。实验分为药物试验组(分别加入不同浓度的测试药)、对照组(只加培养液和细胞,不加测试药)和空白组(只加培养液,不加细胞和测试药)。将加药后的96孔板置于37℃,5%CO2培养箱中培养48h。阳性对照药物的活性按照测试样品的方法测定。
(9)存活细胞的测定:在培养了48h后的96孔板中,每孔加MTT 40μl(用D-Hanks缓冲液配成4mg/ml)。在37℃放置4h后,移去上清液。每孔加150μl DMSO,振荡5min,使formazan结晶溶解。最后,利用自动酶标仪在570nm波长处检测各孔的光密度(OD值)。
抑制率的计算:细胞生长的抑制率按照下列公式计算:
生长抑制率=(1-存活率)×100%=[1-(OD实验-OD空白)/(OD对照-OD空 白)]×100%(OD实验表示测试药物组的平均光密度,OD对照表示对照组的平均光密度,OD空白表示对照组的平均光密度)。
半数抑制浓度(IC50)定义为当50%的肿瘤细胞存活时的药物浓度。根据测定的光密度(OD值),制作细胞生长抑制率的标准曲线,在标准曲线上求得其对应的药物浓度。
测得的IC50见表1所示
表1本发明所列硫脲类化合物的对肿瘤细胞的抑制IC50值(μM)
Claims (6)
2.一种权利要求1所述的硫脲类衍生物的制法,其特征是它由下列步骤组成:
步骤1.于无水乙醇中,加入具有R1结构的醛和具有R2结构的胺,醛与胺的物质的量之比为1∶1.2搅拌加热至60~65℃,反应3h后冷却,减压蒸去多余的溶剂和胺,重结晶得到R1=N-R2,
步骤2.将得到的R1=N-R2溶于无水乙醇,置于冰浴中,缓慢向其中加入等物质的量的NaBH4,加完之后,撤去冰浴,在常温下反应6h,反应结束向体系加水,用氯仿萃取水溶液2~3次,之后减压蒸干,得到R1NHR2,
步骤3.将等物质的量的化合物R1NHR2与异硫氰酸苯酯溶于氯仿,在60℃温度下搅拌回流4h,过滤,将所得固体在乙醇中重结晶得到所述的硫脲类衍生物。
3.根据权利要求2所述的制法,其特征是:步骤1中,所述的无水乙醇的用量为每毫摩尔醛加10-15ml。
4.根据权利要求2所述的制法,其特征是:步骤2中,所述的无水乙醇的用量为每毫摩尔R1=N-R2加10-15ml。
5.根据权利要求2所述的制法,其特征是:步骤3中,所述的CHCl3的用量为每毫摩尔R1NHR2加10-15ml。
6.权利要求1所述的硫脲类衍生物在制备抗肿瘤药物中的应用。
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Citations (4)
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CN1278256A (zh) * | 1997-09-05 | 2000-12-27 | 罗赫诊断器材股份有限公司 | 用作抗肿瘤剂的4-氨基-2(5h)-呋喃酮和4-氨基-2(5h)-噻吩酮的脲基和硫脲基衍生物 |
US20030069284A1 (en) * | 2001-03-02 | 2003-04-10 | Keegan Kathleen S. | Compounds useful for inhibiting Chk1 |
CN101161645A (zh) * | 2007-11-27 | 2008-04-16 | 南京大学 | 尿素类衍生物及其制备方法与用途 |
CN101195597A (zh) * | 2006-12-08 | 2008-06-11 | 中国科学院上海药物研究所 | 1-取代-4,4-二取代氨基硫脲类化合物、其制备方法以及其用途 |
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CN1278256A (zh) * | 1997-09-05 | 2000-12-27 | 罗赫诊断器材股份有限公司 | 用作抗肿瘤剂的4-氨基-2(5h)-呋喃酮和4-氨基-2(5h)-噻吩酮的脲基和硫脲基衍生物 |
US20030069284A1 (en) * | 2001-03-02 | 2003-04-10 | Keegan Kathleen S. | Compounds useful for inhibiting Chk1 |
CN101195597A (zh) * | 2006-12-08 | 2008-06-11 | 中国科学院上海药物研究所 | 1-取代-4,4-二取代氨基硫脲类化合物、其制备方法以及其用途 |
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