CN104326957A - 氨基苯乙酮缩氨基硫脲衍生物及其应用 - Google Patents
氨基苯乙酮缩氨基硫脲衍生物及其应用 Download PDFInfo
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- CN104326957A CN104326957A CN201410535321.1A CN201410535321A CN104326957A CN 104326957 A CN104326957 A CN 104326957A CN 201410535321 A CN201410535321 A CN 201410535321A CN 104326957 A CN104326957 A CN 104326957A
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- Prior art keywords
- dmso
- compound
- nmr
- thiosemicarbazone
- aminoacetophenone
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
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Abstract
本发明公开了式I所示的氨基苯乙酮缩氨基硫脲衍生物及其应用：其中，结构单元
Description
技术领域：
本发明涉及化妆品、药品、食物化学和农业用杀虫剂领域，具体涉及一种氨基苯乙酮缩氨基硫脲衍生物及其应用。
背景技术：
酪氨酸酶，又称酚氧化酶，多酚氧化酶，是一个多功能的含铜酶，广泛存在于微生物、动植物及其人体中。这种酶利用分子氧催化氧化单酚为二酚(单酚酶活性)，之后催化氧化二酚为相应的醌。醌再经过一系列的酶催化或无酶催化过程，得到混合黑色素。
酪氨酸酶与很多生物过程有关，如与人的衰老、人体的色素沉着性疾病密切相关。最近研究表明，酪氨酸酶的高度表达，导致大量的黑色素沉着，而大量黑色素的沉着也与恶性黑色素瘤的发病密切相关，酪氨酸酶抑制剂有可能应用于恶性黑色素瘤的治疗；酪氨酸酶抑制剂可以用来治疗常见的黑色素沉着皮肤病如雀斑、老年斑，本专利所涉及的化合物实体即可以口服，也可以应用在化妆品中，通过皮肤吸收，来抑制酪氨酸酶，起到治疗皮肤病或美白作用；同时该类物质可能在人类大脑的黑质的形成中发挥重要作用，并控制多巴胺的神经毒性，它促使神经退行性疾病-帕金森病的发生。
昆虫表皮的酪氨酸酶可以催化表皮产生黑色素，强化节肢动物的外壳细胞壁，防止紫外线侵害。酪氨酸酶对昆虫的发育和防御功能方面起到促进作用，还在昆虫的黑色素生成，伤口愈合，抵抗寄生虫和皮肤角质化等生理过程中发挥重要作用。所以酪氨酸酶抑制剂的研究开发，可以作为农药应用于农业种植方面。
酪氨酸酶能够促使水果和蔬菜的颜色发生褐变，酪氨酸酶抑制剂也可用于水果和蔬菜的保鲜。
鉴于酪氨酸酶广泛的应用功能，近年来酪氨酸酶抑制剂在药学、化妆品和农业方面得到了越来越多的重视和研究。遗憾的是，大部分化合物或提取物由于活性差或者安全性不够原因无法应用于生产和生活，寻找低毒、高效的酪氨酸酶抑制剂仍然是本领域的重要研究方向。王振、Ramón Garcóa-Domenech等报道了酪氨酸酶抑制剂的合成方法和活性研究，(参见文献：王振等，取代苯甲醛缩氨基硫脲(脲、硝基胍)类化合物的合成及其对小菜蛾酪氨酸酶的抑制活性.《农药学学报》.2010,第12卷(第3期),第264-268页；Ramón Garcóa-Domenech等，Application of molecular topology to the prediction of the phenoloxidase inhibition by a groupof benzaldehyde thiosemicarbazone and their derivatives,《Afinidad LXV》,538,Noviembre-Diciembre，2008,第430-436页。)我们课题组也报道过酪氨酸酶抑制剂的合成方法和活性研究，如申请号：201210454499.4，申请号：201210328248.1，申请号：201210345460.9。
发明内容：
本发明的目的是提供一种新的高活性酪氨酸酶抑制剂及其作为酪氨酸酶抑制剂的应用。
本发明是通过以下技术方案予以实现的：
式I所示的氨基苯乙酮缩氨基硫脲衍生物：
其中，结构单元中，氨基连接在苯环的3-位或4-位，R选自C1～C6的烷基或卤代烷基或烷氧基、芳烃基或取代的芳烃基团。
所述的氨基苯乙酮缩氨基硫脲衍生物的具体结构说明如表1所示：
表1.式I所示的氨基苯乙酮缩氨基硫脲衍生物的化学结构
本发明还提供了式I所示的氨基苯乙酮缩氨基硫脲衍生物的制备方法，其合成路线如下：
本发明还保护所述的酰胺基苯乙酮缩氨基硫脲衍生物制备作为酪氨酸酶抑制剂药物的应用，用于制备美白化妆品、食品保鲜剂、抗黑色素瘤、治疗帕金森综合症及生物杀虫剂。
本发明还提供一种药物组合物，包含至少一种所述的式I化合物作为活性成分，单独或结合一种或几种药学上可接受的、惰性的、无毒的赋形剂或载体。
本发明还保护所述组合物制备作为酪氨酸酶抑制剂药物的应用，用于制备美白化妆品、食品保鲜剂、抗黑色素瘤药物、治疗帕金森综合症药物及生物杀虫剂。
本发明所涉及的化合物活性骨架结构含有氨基苯乙酮，结构新颖、制备简单，对酪氨酸酶的抑制活性强，具有很明显的应用前景。
具体实施方式：
以下是对本发明的进一步说明，而不是对本发明的限制。
实施例1：4’-乙酰氨基苯乙酮缩氨基硫脲(化合物1)的合成：
步骤一、4-氨基苯乙酮经羧酸酰胺化反应得到酰胺化苯乙酮(本步为现有技术)：50mL圆底烧瓶中加入对氨基苯乙酮(0.02mol)、羧酸(0.08mol)和1-2粒沸石，将溶液缓慢加热，使反应物保持微沸约15min。然后逐渐升高温度到100-105℃，约经过45min。当温度计的读数下降时，停止加热。不断搅拌下，将反应物趁热慢慢倒入盛有100ml冷水的烧杯中，继续搅拌，充分冷却，析出酰胺化苯乙酮粗产物。抽滤，用5～10ml冷水洗涤粗产品。再用20mL热水洗涤3次，干燥后用少量乙醇重结晶，得到产物酰胺化苯乙酮。
步骤二、步骤一得到的酰胺化苯乙酮与氨基硫脲发生缩合得到目标产物(化合物1)：将上述酰胺化的氨基苯乙酮(5mmol)溶于50mL无水乙醇中，加入粉碎的氨基硫脲(5mmol)，加入几滴乙酸作为催化剂，于50-80℃搅拌3-8小时。过滤产生的固体沉淀物，投入10mL乙醇中，超声洗涤。过滤除去溶剂后，再用10mL乙醇超声洗涤。重复洗涤3次后，得到的产物干燥后得到淡黄色固体纯物质。产率88％，m.p.228–229℃。1H NMR(300MHz,DMSO-d6):δ10.17(s,1H),10.07(s,1H),8.26(s,1H),7.88(d,J＝8.1Hz,3H),7.60(d,J＝7.3Hz,2H),2.26(s,3H),2.06(s,3H).13C NMR(75MHz,DMSO-d6):δ178.6,168.4,147.5,140.2,132.0,127.1,118.2,24.0,13.6.ESI-MS(m/z)251.2[M+1]+.元素分析：C11H14N4OS:C,52.78；H,5.64；N,22.38；found:C,52.73；H,5.59；N,22.50.
实施例2:4’-三氟乙酰氨基苯乙酮缩氨基硫脲(化合物2)的合成
合成方法参考实施例1，得到的目标产物(化合物2)为无色固体，产率92％.1H NMR(300MHz,DMSO-d6):δ11.37(s,1H),10.26(s,1H),8.33(s,1H),8.02(d,J＝8.7Hz,3H),7.72(d,J＝8.7Hz,2H),2.31(s,3H).13C NMR(75MHz,DMSO-d6):δ178.8,154.7,154.2,146.9,137.1,134.6,127.3,120.4,13.7.ESI-MS(m/z)305.1[M+1]+。
实施例3:4’-三氯乙酰氨基苯乙酮缩氨基硫脲(化合物3)的合成
合成方法参考实施例1，得到的目标产物(化合物3)为淡黄色固体，产率80％.1H NMR(300MHz,DMSO-d6):δ10.95(s,1H),10.23(s,1H),8.30(s,1H),8.00(d,J＝8.8Hz,3H),7.70(d,J＝8.8Hz,2H),2.29(s,3H).13C NMR(75MHz,DMSO-d6):δ178.8,159.6,147.0,138.0,134.3,127.2,120.6,92.9,13.7.ESI-MS(m/z)353.2[M+1]+。
实施例4:4’-丙酰氨基苯乙酮缩氨基硫脲(化合物4)的合成
合成方法参考实施例1，得到的目标产物(化合物4)为淡黄色固体，产率86％，m.p.221–222℃.1H NMR(300MHz,DMSO-d6):δ10.16(s,1H),9.99(s,1H),8.25(s,1H),7.88(d,J＝8.8Hz,3H),7.61(d,J＝8.8Hz,2H),2.40–2.28(m,2H),2.26(s,3H),1.08(t,J＝7.5Hz,3H).13CNMR(75MHz,DMSO-d6):δ178.6,172.1,147.5,140.3,131.9,127.2,118.3,29.5,13.7,9.5.ESI-MS(m/z)265.2[M+1]+。
实施例5:4’-丁酰氨基苯乙酮缩氨基硫脲(化合物5)的合成
合成方法参考实施例1，得到的目标产物(化合物5)为淡黄色固体，产率82％，mp:217–218℃。1H NMR(300MHz,DMSO)δ10.16(s,1H),10.00(s,1H),8.25(s,1H),7.88(d,J＝8.8Hz,3H),7.62(d,J＝8.9Hz,2H),2.30(t,J＝7.4Hz,2H),2.26(s,3H),1.69–1.54(m,2H),0.92(t,J＝7.4Hz,3H).13C NMR(75MHz,DMSO)δ178.6,171.3,147.5,140.3,132.0,127.11,118.3,18.4,13.7,13.6.ESI-MS(m/z)279.2[M+1]+。
实施例6:4’-异丁酰氨基苯乙酮缩氨基硫脲(化合物6)的合成
合成方法参考实施例1，得到的目标产物(化合物6)为浅黄色固体，产率88％。1H NMR(300MHz,DMSO-d6):δ10.16(s,1H),9.96(s,1H),8.25(s,1H),7.89(d,J＝8.8Hz,3H),7.63(d,J＝8.8Hz,2H),2.60(m,1H),2.26(s,3H),1.10(d,J＝6.8Hz,6H).13C NMR(75MHz,DMSO-d6):δ178.6,175.3,147.5140.4,131.9,127.1,118.4,35.0,19.4,13.7.ESI-MS(m/z)279.2[M+1]+。
实施例74’-戊酰氨基苯乙酮缩氨基硫脲(化合物7)的合成
合成方法参考实施例1，得到的目标产物(化合物7)为淡黄色固体，产率87％，mp:213–214℃。1H NMR(300MHz,DMSO-d6):δ10.18(s,1H),10.01(s,1H),8.27(s,1H),7.89(d,J＝8.8Hz,3H),7.62(d,J＝8.8Hz,2H),2.33(t,J＝7.4Hz,2H),2.27(s,3H),1.65–1.52(m,2H),1.40–1.25(m,2H),0.90(t,J＝7.3Hz,3H).13C NMR(75MHz,DMSO-d6):δ178.6,171.4,147.5,140.3,132.0,127.1,118.3,36.1,27.1,21.8,13.7.ESI-MS(m/z)293.3[M+1]+。元素分析：C14H20N4OS:C,57.51；H,6.89；N,19.16；found:C,57.25；H,6.77；N,19.52.
实施例8:4’-己酰氨基苯乙酮缩氨基硫脲(化合物8)的合成
合成方法参考实施例1，得到的目标产物(化合物8)为淡黄色固体，产率81％，mp:178–179℃。1H NMR(300MHz,DMSO-d6):δ10.17(s,1H),10.00(s,1H),8.26(s,1H),7.88(d,J＝8.8Hz,3H),7.62(d,J＝8.8Hz,2H),2.31(t,J＝7.4Hz,2H),2.26(s,3H),1.66–1.53(m,2H),1.36–1.23(m,4H),0.88(t,J＝6.9Hz,3H).13C NMR(75MHz,DMSO-d6):δδ178.6,171.4,147.5,140.3,132.0,127.1,118.3,36.4,30.9,24.7,21.9,13.8,13.7.ESI-MS(m/z)307.3[M+1]+。
实施例9:4’-庚酰氨基苯乙酮缩氨基硫脲(化合物9)的合成
合成方法参考实施例1，得到的目标产物(化合物9)为无色固体，产率83％，mp:187–188℃。1H NMR(300MHz,DMSO-d6):δ10.16(s,1H),10.00(s,1H),8.25(s,1H),7.88(d,J＝8.8Hz,3H),7.61(d,J＝8.7Hz,2H),2.31(t,J＝7.4Hz,2H),2.26(s,3H),1.57(d,J＝6.9Hz,2H),1.27(s,6H),0.85(d,J＝6.6Hz,3H).13C NMR(75MHz,DMSO-d6):δ178.6,171.4,147.5,140.3,132.0,127.1,118.336.42,31.0,28.31,25.0,22.0,13.9,13.7.ESI-MS(m/z)321.3[M+1]+。
实施例10:4’-(甲氧基甲酰氨基)苯乙酮缩氨基硫脲(化合物10)的合成
合成方法参考实施例1，得到的目标产物(化合物10)为淡黄色固体，产率71％，m.p.217–218℃。ESI-MS(m/z)267.3[M+1]+,1H NMR(300MHz,DMSO)δ10.10(s,1H),9.76(s,1H),8.20(s,1H),7.84(d,J＝7.8Hz,3H),7.45(d,J＝8.1Hz,2H),3.66(s,3H),2.24(s,3H).13C NMR(75MHz,DMSO)δ178.6,153.8,147.6,140.1,131.5,127.3,117.4,51.7,13.7.
实施例11:4’-苯甲酰氨基苯乙酮缩氨基硫脲(化合物11)的合成
合成方法参考实施例1，得到的目标产物(化合物11)为无色固体，产率82％。1H NMR(300MHz,DMSO-d6):δ10.38(s,1H),10.20(s,1H),8.29(s,1H),8.03–7.90(m,5H),7.83(d,J＝8.9Hz,2H),7.68–7.49(m,3H),2.30(s,3H).13C NMR(75MHz,DMSO-d6):δ178.7,165.6,147.4,140.2,134.8,132.6,131.7,128.4,127.7,127.1,119.5,13.7.ESI-MS(m/z)313.2[M+1]+。
实施例12:4’-(4-氟苯甲酰氨基)苯乙酮缩氨基硫脲(化合物12)的合成
合成方法参考实施例1，得到的目标产物(化合物12)为无色固体，产率87％，m.p.201–202℃。1H NMR(300MHz,DMSO)δ10.34(s,1H),10.15(s,1H),8.24(s,1H),8.10–7.97(m,2H),7.93(d,J＝8.6Hz,3H),7.79(d,J＝8.2Hz,2H),7.36(t,J＝8.4Hz,2H),2.29(s,3H).13C NMR(75MHz,DMSO)δ178.7,164.5,147.4,140.0,132.7,131.2,130.5,127.1,119.6,115.5,115.2,13.7.ESI-MS(m/z)331.4[M+1]+。
实施例13:4’-(4-甲氧基苯甲酰氨基)苯乙酮缩氨基硫脲(化合物13)的合成
合成方法参考实施例1，得到的目标产物(化合物13)为白色固体，产率87％mp:202-203℃,1H NMR(300MHz,DMSO)δ10.15(d,J＝7.7Hz,2H),8.23(s,1H),7.93(t,J＝8.7Hz,5H),7.79(d,J＝7.9Hz,2H),7.05(d,J＝7.4Hz,3H),3.83(s,3H),2.53(s,1H),2.28(s,3H).13C NMR(75MHz,DMSO)δ178.7,164.9,162.9,147.5,140.4,132.4,129.8,127.0,126.5,119.5,113.6,55.4,13.7.ESI-MS(m/z)343.4[M+1]+。
实施例14:4’-苯乙酰氨基苯乙酮缩氨基硫脲(化合物14)的合成
合成方法参考实施例1，得到的目标产物(化合物14)为无色固体，产率87％，m.p.131–134℃。1H NMR(300MHz,DMSO-d6):δ10.32(s,1H),10.17(s,1H),8.25(s,1H),7.90(d,J＝8.8Hz,3H),7.62(d,J＝8.8Hz,2H),7.34(d,J＝4.4Hz,4H),7.29–7.23(m,1H),3.66(s,2H),2.26(s,3H).13C NMR(75MHz,DMSO-d6):δ178.61,169.2,147.5,140.1,135.8,132.2,129.1,128.3,127.2,126.5,118.4,43.3,13.7.ESI-MS(m/z)327.3[M+1]+。
实施例15:3’-乙酰氨基苯乙酮缩氨基硫脲(化合物15)的合成
合成方法参考实施例1，得到的目标产物(化合物15)为棕色固体，产率88％，m.p.204–205℃。1H NMR(300MHz,DMSO)δ10.35(s,1H),9.99(s,1H),8.41(s,1H),7.95(s,1H),7.78(s,1H),7.73(d,J＝8.0Hz,1H),7.63(d,J＝8.0Hz,1H),7.33(t,J＝8.0Hz,1H),2.31(s,3H),2.08(s,3H).13C NMR(75MHz,DMSO)δ178.9,168.4,147.7,139.2,138.1,128.6,121.3,120.0,117.1,24.0,14.1.ESI-MS(m/z)251.2[M+1]+。
实施例16:3’-三氟乙酰氨基苯乙酮缩氨基硫脲(化合物16)的合成
合成方法参考实施例1，得到的目标产物(化合物16)为无色固体，产率93％，m.p.204–205℃。1H NMR(300MHz,DMSO-d6):δ11.27(s,1H),10.38(s,1H),8.43(s,1H),8.07(s,1H),7.82(d,J＝8.0Hz,2H),7.75(d,J＝8.0Hz,1H),7.44(t,J＝8.0Hz,1H),2.31(s,3H).13C NMR(75MHz,DMSO-d6):δ179.0,154.8,154.3,146.9,138.5,136.2,128.9,123.9,121.8,119.3,14.0.ESI-MS(m/z)305.2[M+1]+。
实施例17:3’-异丁酰氨基苯乙酮缩氨基硫脲(化合物17)的合成
合成方法参考实施例1，得到的目标产物(化合物17)为无色固体，产率85％，m.p.198–199℃。1H NMR(300MHz,DMSO-d6):δ10.34(s,1H),9.86(s,1H),8.41(s,1H),7.99(s,1H),7.75(d,J＝6.0Hz,2H),7.63(d,J＝7.9Hz,1H),7.32(t,J＝8.0Hz,1H),2.68–2.54(m,1H),2.30(s,3H),1.12(d,J＝6.8Hz,6H).13C NMR(75MHz,DMSO-d6):δ179.0,175.3,147.7,139.4,138.1,128.6,121.3,119.9,117.1,35.0,19.5,14.1.ESI-MS(m/z)279.2[M+1]+。元素分析：C13H18N4OS:C,56.09；H,6.52；N,20.13；found:C,55.86；H,6.40；N,20.39.
实施例18:3’-戊酰氨基苯乙酮缩氨基硫脲(化合物18)的合成
合成方法参考实施例1，得到的目标产物(化合物18)为无色固体，产率88％，m.p.198–199℃。1H NMR(300MHz,DMSO-d6):δ10.32(s,1H),9.90(s,1H),8.39(s,1H),7.94(s,1H),7.72(d,J＝7.5Hz,2H),7.61(d,J＝7.7Hz,1H),7.30(t,J＝7.9Hz,1H),2.40–2.20(m,5H),1.64–1.48(m,2H),1.38–1.23(m,2H),0.89(t,J＝7.3Hz,3H).13C NMR(75MHz,DMSO-d6):δ179.0,171.4,147.7,139.3,138.1,128.6,121.3,119.9,117.0,36.1,27.2,21.8,14.1,13.7.ESI-MS(m/z)293.4[M+1]+。
实施例19:3’-特戊酰氨基苯乙酮缩氨基硫脲(化合物19)的合成
合成方法参考实施例1，得到的目标产物(化合物19)为无色固体，产率84％，m.p.220–221℃。1H NMR(300MHz,DMSO-d6):δ10.31(s,1H),9.21(s,1H),8.40(s,1H),8.01(s,1H),7.80(d,J＝7.8Hz,2H),7.64(d,J＝7.8Hz,1H),7.31(t,J＝8.0Hz,1H),2.30(s,3H),1.24(s,9H).13CNMR(75MHz,DMSO-d6):δ178.9,176.5,147.8,139.3,137.9,128.3,121.4,120.9,118.2,27.2,14.1.ESI-MS(m/z)293.2[M+1]+。元素分析：C14H20N4OS:C,57.51；H,6.89；N,19.16；found:C,57.59；H,6.74；N,19.42.
实施例20:3’-己酰氨基苯乙酮缩氨基硫脲(化合物20)的合成
合成方法参考实施例1，得到的目标产物(化合物20)为无色固体，产率83％，m.p.189–190℃。1H NMR(300MHz,DMSO-d6):δ10.34(s,1H),9.90(s,1H),8.40(s,1H),7.95(s,1H),7.74(d,J＝6.6Hz,2H),7.62(d,J＝8.0Hz,1H),7.31(t,J＝8.0Hz,1H),2.37–2.25(m,5H),1.67–1.54(m,2H),1.39–1.20(m,4H),0.88(t,J＝6.8Hz,3H).13C NMR(75MHz,DMSO-d6):δ179.0,171.3,147.7,139.3,138.1,128.6,121.2,119.8,117.0,36.4,30.9,24.7,21.9,14.1,13.8.ESI-MS(m/z)307.3[M+1]+。元素分析：C,58.79；H,7.24；N,18.28；found:C,58.74；H,7.15；N,18.48.
实施例21:3’-庚氨基苯乙酮缩氨基硫脲(化合物21)的合成
合成方法参考实施例1，得到的目标产物(化合物21)为无色固体，产率85％，m.p.127–1128℃。1H NMR(300MHz,DMSO-d6):δ10.33(s,1H),9.90(s,1H),8.40(s,1H),7.94(s,1H),7.73(d,J＝6.7Hz,2H),7.62(d,J＝8.0Hz,1H),7.30(t,J＝8.0Hz,1H),2.36–2.25(m,5H),1.64–1.54(m,2H),1.35–1.23(m,6H),0.87(t,J＝6.6Hz,3H).13C NMR(75MHz,DMSO-d6):δ179.0,171.3,147.7,139.3,138.1,128.6,121.2,119.8,117.0,36.4,31.0,28.3,25.0,22.0,14.1,13.9.ESI-MS(m/z)321.3[M+1]+。
实施例22:3’-苯甲酰氨基苯乙酮缩氨基硫脲(化合物22)的合成
合成方法参考实施例1，得到的目标产物(化合物22)为无色固体，产率84％，m.p.127–1128℃。1H NMR(300MHz,DMSO)δ10.37(s,1H),10.27(s,1H),8.43(s,1H),8.18(s,1H),7.96(t,J＝9.5Hz,3H),7.81(s,1H),7.70(d,J＝7.7Hz,1H),7.56(d,J＝7.9Hz,3H),7.38(t,J＝8.0Hz,1H),2.33(s,3H).13C NMR(75MHz,DMSO)δ179.0,165.6,147.6,139.1,138.1,134.8,131.6,128.6,128.4,127.6,122.0,121.2,118.5,14.1.ESI-MS(m/z)313.2[M+1]+。元素分析：C16H16N4OS:C,61.52；H,5.16；N,17.93；found:C,61.20；H,5.05；N,18.12.
实施例23:3’-(4-甲氧基苯甲酰氨基)苯乙酮缩氨基硫脲(化合物23)的合成
合成方法参考实施例1，得到的目标产物(化合物23)为无色固体，产率88％,mp:203–204℃,1H NMR(300MHz,DMSO)δ10.34(s,1H),10.10(s,1H),8.41(s,1H),8.14(s,1H),7.98(d,J＝8.5Hz,2H),7.91(d,J＝7.6Hz,1H),7.79(s,1H),7.68(d,J＝7.8Hz,1H),7.36(t,J＝7.9Hz,1H),7.14–7.03(m,2H),3.85(s,3H),2.32(s,3H).13C NMR(75MHz,DMSO)δ179.0,164.9,161.9,147.6,139.3,138.0,129.5,128.5,126.8,121.7,121.1,118.4,113.6,55.4,14.1.ESI-MS m/z＝343.4[M+1]+.
实施例24:3’-苯乙氨基苯乙酮缩氨基硫脲(化合物24)的合成
合成方法参考实施例1，得到的目标产物(化合物24)为无色固体，产率87％，m.p.131–134℃。1H NMR(300MHz,DMSO)δ10.34(s,1H),10.23(s,1H),8.39(s,1H),7.96(s,1H),7.73(d,J＝9.1Hz,2H),7.64(d,J＝7.6Hz,1H),7.39–7.21(m,5H),3.66(s,2H),2.28(s,3H).13C NMR(75MHz,DMSO)δ179.0,169.2,147.7,139.2,138.2,135.8,129.1,128.7,128.3,126.5,121.5,119.9,117.1,43.3,14.1.ESI-MS(m/z)327.3[M+1]+。
实施例25:氨基苯乙酮缩氨基硫脲衍生物的体外酪氨酸酶抑制活性测试
体外酪氨酸酶抑制活性测试方法见V.J.Hearing,Methods in Enzymology,Vol.142,Academic Press,New York,1987,154.
具体的测试方法如下：
在1.5mL的离心管中分别加入10μL含不同浓度的抑制剂(用DMSO溶剂配制)，DMSO的终浓度为2％，890μL磷酸缓冲溶液(PBS，pH＝6.8)以及5μL的0.5mg/mL酪氨酸酶的磷酸缓冲溶液(Ph＝6.8)，在25℃恒温水浴中保温10分钟，然后加入40μL L-DOPA(1.50mg/mL)溶液迅速充分混匀后，立即在25℃恒温条件下测定波长为475nm的光密度值(OD值)，由其随时间的增长直线的斜率计算出酶的活力(消光系数ε＝3600M-1cm-1)，测试时间为1min，并用对照扣除缓冲溶液对本试验的影响。
IC50的计算方法：以不加入抑制剂的酶活力(光密度值)为100％，以加入抑制剂后酶的相对活力对抑制剂浓度作图，得到抑制剂的浓度-酶活力曲线，酶相对剩余活力为50％时，对应的抑制剂浓度即为抑制剂的IC50值。
由上述方法测定获得目标产物的IC50值(μmol/L)，列于表2.
表2氨基苯乙酮缩氨基硫脲衍生物的酪氨酸酶抑制活性
通过表中所列数据，可以得出：
1、本专利所涉及的化合物与4-氨基硫脲缩甲醛基苯甲(氨基酸)酰胺化合物(专利号：201210454499.4)、(氨基硫脲缩甲醛基)苯氧乙酸衍生物(申请号：201210328248.1)和亚甲基缩氨基硫脲基取代苯氧羧酸衍生物(申请号：201210345460.9)相比，表现出较高的酪氨酸酶抑制活性；
2、结构式为的取代酰氨基在苯环的4-位的氨基苯乙酮缩氨基硫脲衍生物的酪氨酸酶抑制活性较在苯环的3-位的酪氨酸酶抑制活性好，从结构上分析，其原因如下：根据酪氨酸酶的晶体结构分析可知，酪氨酸酶含有二个铜离子，是酶的活性位点，处于酶的内部。并且酶存在一个狭长的通道，酪氨酸酶抑制剂可以通过这个通道嵌入进酶中与酶结合。我们所合成的酶抑制剂进入酶并与二个铜离子结合的位点是氨基硫脲端。对于4-位的氨基苯乙酮缩氨基硫脲衍生物与3-位的氨基苯乙酮缩氨基硫脲衍生物相比，前者分子接近线型，后者接近三角型，所以前者的氨基硫脲端部分比后者的氨基硫脲端部分更容易通过酶的狭长通道嵌入酶中，前者也就更容易与酶的活性中心结合，抑制作用更好。
Claims (5)
1.式I所示的氨基苯乙酮缩氨基硫脲衍生物：
其中，结构单元中，氨基连接在苯环的3-位或4-位，R选自C1～C6的烷基或卤代烷基或烷氧基、芳烃基或取代的芳烃基团。
2.一种式I所示的氨基苯乙酮缩氨基硫脲衍生物的制备方法，其特征在于，合成路线如下：
3.权利要求1或2所述的氨基苯乙酮缩氨基硫脲衍生物制备作为酪氨酸酶抑制剂药物的应用。
4.药物组合物，包含至少一种权利要求1所述的式I化合物作为活性成分，单独或结合一种或几种药学上可接受的、惰性的、无毒的赋形剂或载体。
5.权利要求4所述的药物组合物制备作为酪氨酸酶抑制剂药物的应用。
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Inventor after: Wang Gang Inventor after: Zeng Chengzhu Inventor before: Song Senchuan Inventor before: You Ao Inventor before: Zhou Jie Inventor before: Zhu Guoxun Inventor before: Pan Wenlong Inventor before: Song Huacan |
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Effective date of registration: 20161128 Address after: Yuexiu District Guangzhou City, Guangdong province 510070 martyrs Road No. 100 building No. 34 compound side Building Room 201 Patentee after: GUANGZHOU ANALYSIS TESTING CENTER KELI TECHNOLOGY DEVELOPMENT CO. Address before: Guangzhou City, Guangdong province 510070 martyrs Road No. 100 building 34 Patentee before: CHINA NATIONAL ANALYTICAL CENTER, GUANGZHOU |
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| C41 | Transfer of patent application or patent right or utility model | ||
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Inventor after: Song Senchuan Inventor after: You Ao Inventor after: Zhou Jie Inventor after: Zhu Guoxun Inventor after: Pan Wenlong Inventor after: Song Huacan Inventor before: Wang Gang Inventor before: Zeng Chengzhu |
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Effective date of registration: 20170113 Address after: Yuexiu District Guangzhou City, Guangdong province 510070 martyrs Road No. 100 building 34 Patentee after: CHINA NATIONAL ANALYTICAL CENTER, GUANGZHOU Address before: Yuexiu District Guangzhou City, Guangdong province 510070 martyrs Road No. 100 building No. 34 compound side Building Room 201 Patentee before: GUANGZHOU ANALYSIS TESTING CENTER KELI TECHNOLOGY DEVELOPMENT CO. |
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Address after: 510070 Guangzhou City, Guangzhou, Guangdong, No. 34 Patentee after: Institute of testing and analysis, Guangdong Academy of Sciences (Guangzhou analysis and testing center, China) Address before: 510070 Guangzhou City, Guangzhou, Guangdong, No. 34 Patentee before: GUANGDONG INSTITUTE OF ANALYSIS (CHINA NATIONAL ANALYTICAL CENTER, GUANGZHOU) |
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Address after: 510070 Guangzhou City, Guangzhou, Guangdong, No. 34 Patentee after: GUANGDONG INSTITUTE OF ANALYSIS (CHINA NATIONAL ANALYTICAL CENTER, GUANGZHOU) Address before: 510070 building 34, 100 Xianlie Middle Road, Yuexiu District, Guangzhou City, Guangdong Province Patentee before: CHINA NATIONAL ANALYTICAL CENTER, GUANGZHOU |