CN102827049A - （氨基硫脲缩甲醛基）苯氧乙酸衍生物及其应用 - Google Patents
（氨基硫脲缩甲醛基）苯氧乙酸衍生物及其应用 Download PDFInfo
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- CN102827049A CN102827049A CN2012103282481A CN201210328248A CN102827049A CN 102827049 A CN102827049 A CN 102827049A CN 2012103282481 A CN2012103282481 A CN 2012103282481A CN 201210328248 A CN201210328248 A CN 201210328248A CN 102827049 A CN102827049 A CN 102827049A
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Abstract
本发明公开了一种（氨基硫脲缩甲醛基）苯氧乙酸衍生物，及其作为酪氨酸酶抑制剂的应用。所述的（氨基硫脲缩甲醛基）苯氧乙酸衍生物如式I所示：
式I其中，R1选自氢、1-6个碳的烷氧基；R2选自
R3选自1-6个碳的直链烷基。
Description
技术领域
本发明涉及化妆品、食品、药物化学领域，具体涉及（氨基硫脲缩甲醛基）苯氧乙酸衍生物，及其作为酪氨酸酶抑制剂的应用。
技术背景
目前酪氨酸酶（EC 1.14.18.1，Tyrosinase）又称酚氧化酶、多酚氧化酶、儿茶酚氧化酶，是结构复杂的多亚基的含铜氧化还原酶，广泛存在于微生物、动植物及人体中。酪氨酸酶具有独特的双重催化功能，是生物体内黑色素合成的关键酶，与人的衰老、人体的色素沉着性疾病有密切关联。因此，酪氨酸酶抑制剂可以用来治疗目前常见的黑色素沉着皮肤病如雀斑、黄褐斑、老年斑，目前，市场上使用的美白化妆品中添加的增白剂均是酪氨酸酶抑制剂，如熊果苷、维生素C衍生物以及一些天然产物提取物等。酪氨酸酶是果蔬中导致褐变的主要酶类，一些酪氨酸酶抑制剂已经应用于果蔬和其它食品的保鲜，如4-己基间苯二酚用于虾的保鲜。酪氨酸酶的高度表达导致大量的黑色素沉着，最近的研究表明，大量黑色素沉着与恶性黑色素瘤的发病有着密切关联，酪氨酸酶抑制剂有可能应用于恶性黑色素瘤的治疗。酪氨酸酶的活性水平过高和与帕金森综合症及其它神经退行性疾病的发展有关联，因此，酪氨酸酶抑制剂可能应用于治疗帕金森综合症和其它神经退行性疾病。昆虫表皮的酪氨酸酶可以催化产生黑色素，用于保护昆虫免受紫外线的辐射，酪氨酸酶也与昆虫蜕皮过程中的鞣化 作用有关，所以，酪氨酸酶是昆虫赖于生存的一种关键酶，因此，酪氨酸酶抑制剂将在新型生物杀虫剂方面有良好的应用前景。
目前市面常用的酪氨酸酶抑制剂的种类十分有限，主要包括熊果苷，曲酸、维生素C及其衍生物等，熊果苷安全性好，但其抑制活性低，价格高昂，维生素C价格低，安全性好，也存在活性太差而得不到大量使用，而曲酸活性较好，但由于有致癌作用而逐渐停止使用。鉴于酪氨酸酶抑制剂的广泛应用和良好的潜在应用前景，开发高效低毒的酪氨酸酶抑制剂已成为重要的研究方向。
酪氨酸酶抑制剂的活性测试方法见V.J.Hearing,Methods in Enzymology，vol.142,Academic Press,New York,1987,p 154.
发明内容：
本发明的目的是提供一类新的对酪氨酸酶具有高抑制活性的（氨基硫脲缩甲醛基）苯氧乙酸衍生物，及其作为酪氨酸酶抑制剂的应用。
本发明还提供了包括上述（氨基硫脲缩甲醛基）苯氧乙酸衍生物成分的药物组合物。
本发明是通过以下技术方案予以实现的：
式I所示的（氨基硫脲缩甲醛基）苯氧乙酸衍生物：
式I
其中，R1选自：氢、1-6个碳的烷氧基；
R2选自
R3选自1-6个碳的直链烷基。
本发明（氨基硫脲缩甲醛基）苯氧乙酸衍生物的结构优选为式A、式B或式C：
本发明（氨基硫脲缩甲醛基）苯氧乙酸衍生物的具体结构说明如表1-3所示：
表1.式A所示的（氨基硫脲缩甲醛基）苯氧乙酸衍生物具体包含的化合物的结构
表2式B所示（氨基硫脲缩甲醛基）苯氧乙酸衍生物具体包含的化合物的结构
表3式C所示（氨基硫脲缩甲醛基）苯氧乙酸衍生物具体包含的化合物的结构
本发明化合物较优选为如下化合物：化合物5、化合物17和化合物18；
式I所示（氨基硫脲缩甲醛基）苯氧乙酸衍生物合成路线如下：
本发明的（氨基硫脲缩甲醛基）苯氧乙酸衍生物，具有极好的酪氨酸酶抑制活性，可以作为酪氨酸酶抑制剂，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。
所述组合物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。
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-（氨基硫脲缩甲醛基）苯氧乙酸甲酯(化合物1)的制备
对羟基苯甲醛2.44g（20mmol）溶于40mL干燥丙酮，加入5.52g（40mmol）碳酸钾（微波活化）和氯乙酸甲酯3.24g（30mmol），加毕于回流条件下搅拌8小时。TLC跟踪至反应至完全。过滤，旋干溶剂，得到初产物。再用硅胶柱层析分离得中间体，收率83%。
将上述得到的中间体5mmol溶于无水甲醇中，加入5mmol氨基硫脲，于回流条件下搅拌4小时，TLC跟踪至反应至完全。待反应溶液冷却后，过滤，得白色固体产物，即4-（氨基硫脲缩甲醛基）苯氧乙酸甲酯(1)，收率92%。1H-NMR(300MHz,DMSO-d6):δ11.37(s,1H,NH),8.16(s,1H,NH2),8.01(s,1H,NCH),7.96(s,1H,NH2),7.77(d,J=8.7Hz,2H,Ph-H),6.98(d,J=9.0Hz,2H,Ph-H),4.86(s,2H,OCH2),3.71(s,3H,CH3).13C NMR(75MHz,DMSO-d6):δ177.6,168.9,158.8,141.9,128.8,127.4,114.9,114.6,64.5,51.8.
同上述方法制备得到化合物2-24。
化合物2-24的结构由1H-NMR、13C NMR确认，图谱数据如下：
化合物2：
1H-NMR(300MHz,DMSO-d6):δ11.36(s,1H,NH),8.14(s,1H,NH2),8.00(s,1H,NCH),7.94(s,1H,NH2),7.74(d,J=8.7Hz,2H,Ph-H),6.96(d,J=9.0Hz,2H,Ph-H),4.81(s,2H, PhOCH2),4.11-4.18(m,2H,CH2CH3),1.18(t,J=7.2Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ177.6,168.4,158.8,141.9,128.7,127.3,114.6,64.6,60.8,13.9.
化合物3：
1H-NMR(300MHz,DMSO-d6):δ11.35(s,1H,NH),8.13(s,1H,NH2),8.00(s,1H,NCH),7.94(s,1H,NH2),7.75(d,J=8.7Hz,2H,Ph-H),6.96(d,J=8.7Hz,2H,Ph-H),4.94(s,2H,PhOCH2),4.07(t,J=6.6Hz,2H,CH2CH2CH3),1.52-1.64(m,2H,CH2CH2CH3),0.87(t,J=7.5Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ177.6,168.5,158.9,141.9,128.7,127.3,114.6,66.0,64.5,21.4,10.0.
化合物4：
1H-NMR(300MHz,DMSO-d6):δ11.35(s,1H,NH),8.14(s,1H,NH2),8.00(s,1H,NCH),7.94(s,1H,NH2),7.75(d,J=8.7Hz,2H,Ph-H),6.96(d,J=8.7Hz,2H,Ph-H),4.83(s,2H,PhOCH2),4.11(t,J=6.3Hz,2H,CH2CH2CH2CH3),1.49-1.59(m,2H,CH2CH2CH2CH3),1.21-1.34(m,2H,CH2CH2CH2CH3),0.84(t,J=7.5Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ177.6,168.5,158.9,141.9,128.7,127.3,114.6,64.5,64.2,30.0,18.4,13.4.
化合物5：
1H-NMR(300MHz,DMSO-d6):δ11.38(s,1H,NH),8.15(s,1H,NH2),8.03(s,1H,NCH),7.95(s,1H,NH2),7.77(d,J=10.2Hz,2H,Ph-H),6.99(d,J=12.0Hz,2H,Ph-H),4.86(s,2H,PhOCH2),4.11(t,J=6.3Hz,2H,CH2CH2CH2CH2CH3),1.54-1.59(m,2H,CH2CH2CH2CH2CH3),1.23-1.32(m,4H,CH2CH2CH2CH2CH3),0.84(t,J=6.6Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ177.6,168.5,158.9,141.9,128.7,127.3,114.6,64.6,64.5,27.7,27.3,21.6,13.7.
化合物6：
1H-NMR(300MHz,DMSO-d6):δ11.38(s,1H,NH),8.16(s,1H,NH2),8.03(s,1H,NCH),7.94(s,1H,NH2),7.74(d,J=8.7Hz,2H,Ph-H),6.98(d,J=6.9Hz,2H,Ph-H),4.85(s,2H,PhOCH2),4.11(t,J =6.6Hz,2H,CH2CH2CH2CH2CH2CH3),1.53-1.58(m,2H,CH2CH2CH2CH2CH2CH3),1.17-1.27(m,6H,CH2CH2CH2CH2CH2CH3),0.84(t,J=6.6Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ177.6,168.5,158.9,141.9,128.7,127.4,114.6,64.6,64.5,30.7,27.9,24.8,21.9,13.8.
化合物7：
1H-NMR(300MHz,DMSO-d6):δ11.40(s,1H,NH),8.23(s,1H,NH2),8.09(s,1H,NH2),8.02(s,1H,NCH),7.57(s,1H,Ph-H),7.18(d,J=8.4Hz,1H,Ph-H),6.91(d,J=8.4Hz,1H,Ph-H),4.84(s,2H,OCH2),3.87(S,3H,PhOCH3),3.71(S,3H,COOCH3).13C NMR(75MHz,DMSO-d6):δ177.5,168.9,149.1,148.6,142.2,127.7,121.6,112.6,109.0,64.9,55.7,51.7.
化合物8：
1H-NMR(300MHz,DMSO-d6):δ11.38(s,1H,NH),8.21(s,1H,NH2),8.07(s,1H,NH2),8.00(s,1H,NCH),7.56(s,1H,Ph-H),7.17(d,J=8.4Hz,1H,Ph-H),6.90(d,J=8.4Hz,1H,Ph-H),4.82(s,2H,PhOCH2),4.13-4.21(m,2H,CH2CH3),3.86(S,3H,OCH3),1.21(t,J=6.9Hz,3H,CH2CH3).13C NMR(75MHz,DMSO-d6):δ177.5,168.4,149.1,148.6,142.2,127.8,121.6,112.7,109.0,65.0,60.6,55.7,13.9.
化合物9：
1H-NMR(300MHz,DMSO-d6):δ11.35(s,1H,NH),8.19(s,1H,NH2),8.05(s,1H,NH2), 7.97(s,1H,NCH),7.54(s,1H,Ph-H),7.13(d,J=8.4Hz,1H,Ph-H),6.87(d,J=8.4Hz,1H,Ph-H),4.82(s,2H,PhOCH2),4.06(t,J=6.6Hz,2H,CH2CH2CH3),3.84(S,3H,OCH3),1.52-1.64(m,2H,CH2CH2CH3),0.85(t,J=7.2Hz,3H,CH2CH2CH3)..13C NMR(75MHz,DMSO-d6):δ117.5,168.5,149.1,148.6,142.1,127.7,121.6,112.6,109.0,65.9,65.0,55.7,21.4,10.0.
化合物10：
1H-NMR(300MHz,DMSO-d6):δ11.37(s,1H,NH),8.20(s,1H,NH2),8.06(s,1H,NH2),7.98(s,1H,NCH),7.55(s,1H,Ph-H),7.15(d,J=8.4Hz,1H,Ph-H),6.89(d,J=8.4Hz,1H,Ph-H),4.83(s,2H,PhOCH2),4.12(t,J=6.6Hz,2H,CH2CH2CH2CH3),3.85(S,3H,OCH3),1.50-1.60(m,2H,CH2CH2CH2CH3),1.23-1.35(m,2H,CH2CH2CH2CH3),0.86(t,J=7.5Hz,3H,CH2CH2CH2CH3).13C NMR(75MHz,DMSO-d6):δ177.5,168.5,149.1,148.6,142.1,127.8,121.6,112.7,109.0,65.0,64.2,55.7,30.0,18.4,13.4.
化合物11：
1H-NMR(300MHz,DMSO-d6):δ11.38(s,1H,NH),8.21(s,1H,NH2),8.06(s,1H,NH2),7.99(s,1H,NCH),7.56(s,1H,Ph-H),7.15(d,J=8.4Hz,1H,Ph-H),6.89(d,J=8.4Hz,1H,Ph-H),4.83(s,2H,PhOCH2),4.11(t,J=6.9Hz,2H,CH2CH2CH2CH2CH3),3.86(S,3H,OCH3),1.54-1.58(m,2H,CH2CH2CH2CH2CH3),1.22-1.26(m,4H,CH2CH2CH2CH2CH3),0.84(t,J=6.6Hz,3H,CH2CH2CH2CH2CH3).13C NMR(75MHz,DMSO-d6):δ177.5,168.5,149.2,148.6,142.1,127.8,121.6,112.7,109.0,65.0,64.4,55.7,27.7,27.3,21.6,13.7.
化合物12：
1H-NMR(300MHz,DMSO-d6):δ11.37(s,1H,NH),8.20(s,1H,NH2),8.05(s,1H,NH2),7.99(s,1H,NCH),7.56(s,1H,Ph-H),7.14(d,J=8.4Hz,1H,Ph-H),6.89(d,J=8.4Hz,1H,Ph-H),4.83(s,2H,PhOCH2),4.10(t,J=6.6Hz,2H,CH2CH2CH2CH2CH2CH3),3.85(S,3H,OCH3),1.53-1.57(m,2H,CH2CH2CH2CH2CH2CH3),1.22-1.25(m,6H,CH2CH2CH2CH2CH2CH3),0.84(t,J=5.7Hz,3H,CH2CH2CH2CH2CH2CH3).13C NMR(75MHz,DMSO-d6):δ177.5,168.5,149.2,148.6,142.1,127.8,121.6,112.6,109.0,65.0,64.5,55.7,30.8,27.9,24.8,21.9,13.8.
化合物13：
1H-NMR(300MHz,DMSO-d6):δ11.53(s,1H,NH),8.31(s,1H,NH2),8.16(s,1H,NH2),8.08(s,1H,NCH),7.53(s,1H,Ph-H),7.35(br s,1H,Ph-H),7.34(br s,1H,Ph-H),7.00(t,1H,J=8.4Hz,Ph-H),4.88(s,2H,PhOCH2),3.72(s,3H,CH3).13C NMR(75MHz,DMSO-d6):δ177.9,169.0,157.7,141.9,135.5,129.7,121.2,116.5,111.6,64.4,51.7.
化合物14：
1H-NMR(300MHz,DMSO-d6):δ11.53(s,1H,NH),8.47(s,1H,NH2),8.25(s,1H,NH2),8.17(s,1H,NCH),7.53(s,1H,Ph-H),7.33(br s,2H,Ph-H),6.95(br s,1H,Ph-H),4.86(s,2H,PhOCH2),4.11-4.18(m,2H,CH2CH3),1.14(t,J=9.0Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ177.9,168.5,157.8,141.8,135.5,129.7,121.2,116.6,111.5,65.0,60.6,13.9.
化合物15：
1H-NMR(300MHz,DMSO-d6):δ11.47(s,1H,NH),8.26(s,1H,NH2),8.08(s,1H,NH2),8.01(s,1H,NCH),7.47(s,1H,Ph-H),7.28-7.33(m,2H,Ph-H),6.95(t,1H,J=5.7Hz,Ph-H),4.84(s,2H,PhOCH2),4.06(t,J=6.3Hz,2H,CH2CH2CH3),1.53-1.60(m,2H,CH2CH2CH3),0.83 (t,J=7.5Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ179.7,170.4,159.6,143.5,137.3,131.4,122.9,118.3,113.2,67.7,62.2,23.2,11.8.
化合物16：
1H-NMR(300MHz,DMSO-d6):δ11.47(s,1H,NH),8.26(s,1H,NH2),8.08(s,1H,NH2),8.01(s,1H,NCH),7.47(s,1H,Ph-H),7.28-7.33(m,2H,Ph-H),6.95(br s,1H,Ph-H),4.84(s,2H,PhOCH2),4.10(t,J=6.9Hz,2H,CH2CH2CH2CH3),1.48-1.55(m,2H,CH2CH2CH2CH3),1.23-1.30(m,2H,CH2CH2CH2CH3),0.83(t,J=7.2Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ177.9,168.6,157.8,141.7,135.6,129.6,121.2,116.6,111.4,64.5,64.1,30.0,18.4,13.4.
化合物17：
1H-NMR(300MHz,DMSO-d6):δ11.50(s,1H,NH),8.29(s,1H,NH2),8.11(s,1H,NH2),8.04(s,1H,NCH),7.51(s,1H,Ph-H),7.29-7.33(m,2H,Ph-H),6.95-6.99(m,1H,Ph-H),4.87(s,2H,PhOCH2),4.11(t,J=6.9Hz,2H,CH2CH2CH2CH2CH3),1.50-1.59(m,2H,CH2CH2CH2CH2CH3),1.21-1.26(m,4H,CH2CH2CH2CH2CH3),0.83(t,J=6.6Hz,3H,CH3).13CNMR(75MHz,DMSO-d6):δ177.9,168.4,157.8,141.7,137.5,129.6,121.1,116.5,111.4,64.6(2C),27.9,27.7,21.7,13.6.
化合物18：
1H-NMR(300MHz,DMSO-d6):δ11.49(s,1H,NH),8.28(s,1H,NH2),8.09(s,1H,NH2),8.03(s,1H,NCH),7.49(s,1H,Ph-H),7.29-7.35(m,2H,Ph-H),6.97(t,J=6.0Hz,1H,Ph-H),4.86(s,2H,PhOCH2),4.11(t,J=6.6Hz,2H,CH2CH2CH2CH2CH2CH3),1.51-1.58(m,2H,CH2CH2CH2CH2CH2CH3),1.22(br s,6H,CH2CH2CH2CH2CH2CH3),0.84(t,J=6.3Hz,3H,CH3). 13C NMR(75MHz,DMSO-d6):δ175.5,166.2,155.4,139.3,133.2,127.2,118.7,114.1,109.1,62.1,62.0,28.4,25.6,22.5,19.5,11.4.
化合物19：
1H-NMR(300MHz,DMSO-d6):δ11.61(s,1H,NH),8.54(s,1H,NCH),8.24(s,1H,NH2),8.16(d,J=6.3Hz,1H,Ph-H),8.03(s,1H,NH2),7.37(t,J=7.2Hz,1H,Ph-H),6.97-7.05(m,2H,Ph-H),4.91(s,2H,PhOCH2),3.72(s,3H,CH3).13C NMR(75MHz,DMSO-d6):δ175.8,168.9,156.0,137.9,131.0,126.3,122.5,121.3,112.5,64.9,51.8.
化合物20：
1H-NMR(300MHz,DMSO-d6):δ11.55(s,1H,NH),8.48(s,1H,NCH),8.19(s,1H,NH2),8.12(d,J=8.4Hz,1H,Ph-H),7.98(s,1H,NH2),7.32(t,J=6.9Hz,1H,Ph-H),6.93-7.00(m,2H,Ph-H),4.85(s,2H,PhOCH2),4.11-4.18(m,2H,CH2CH3),1.18(t,J=7.2Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ177.8,168.4,156.1,137.8,131.0,126.3,122.6,121.2,112.6,65.0,60.7,13.9.
化合物21：
1H-NMR(300MHz,DMSO-d6):δ11.54(s,1H,NH),8.48(s,1H,NCH),8.18(s,1H,NH2),8.12(d,J=7.8Hz,1H,Ph-H),7.97(s,1H,NH2),7.32(t,J=7.8Hz,1H,Ph-H),6.93-7.00(m,2H,Ph-H),4.88(s,2H,PhOCH2),4.05(t,J=6.6Hz,2H,CH2CH2CH3),1.53-1.60(m,2H,CH2CH2CH3),0.82(t,J=7.2Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ177.8,168.5,156.1,137.8,131.0,126.3,122.6,121.2,112.5,66.0,65.0,21.4,10.0.
化合物22：
1H-NMR(300MHz,DMSO-d6):δ11.54(s,1H,NH),8.48(s,1H,NCH),8.18(s,1H,NH2),8.12(d,J=7.2Hz,1H,Ph-H),7.96(s,1H,NH2),7.32(t,J=7.2Hz,1H,Ph-H),6.93-7.00(m,2H,Ph-H),4.87(s,2H,PhOCH2),4.10(t,J=6.0Hz,2H,CH2CH2CH2CH3),1.50-1.55(m,2H,CH2CH2CH2CH3),1.22-1.29(m,2H,CH2CH2CH2CH3),0.83(t,J=7.2Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ177.8,168.5,156.1,137.8,130.9,126.3,122.7,121.2,112.5,65.0,64.3,30.0,18.4,13.4.
化合物23：
1H-NMR(300MHz,DMSO-d6):δ11.54(s,1H,NH),8.48(s,1H,NCH),8.17(s,1H,NH2),8.12(d,J=7.8Hz,1H,Ph-H),7.94(s,1H,NH2),7.31(t,J=7.8Hz,1H,Ph-H),6.92-7.00(m,2H,Ph-H),4.86(s,2H,PhOCH2),4.08(t,J=6.3Hz,2H,CH2CH2CH2CH2CH3),1.53(br s,2H,CH2CH2CH2CH2CH3),1.20(br s,4H,CH2CH2CH2CH2CH3),0.79(br s,3H,CH3).13C NMR(75MHz,DMSO-d6):δ177.8,168.5,156.1,137.8,130.9,126.3,122.7,121.2,112.5,65.0,64.5,27.7,27.3,21.6,13.7.
化合物24：
1H-NMR(300MHz,DMSO-d6):δ11.54(s,1H,NH),8.49(s,1H,NCH),8.16(s,1H,NH2),8.10(d,J=7.8Hz,1H,Ph-H),7.91(s,1H,NH2),7.29(t,J=8.4Hz,1H,Ph-H),6.90-6.98(m,2H,Ph-H),4.84(s,2H,PhOCH2),4.06(t,J=6.6Hz,2H,CH2CH2CH2CH2CH2CH3),1.46-1.52(m,2H,CH2CH2CH2CH2CH2CH3),1.16(br s,6H,CH2CH2CH2CH2CH2CH3),0.78(t,J=6.3Hz,3H,CH3). 13C NMR(75MHz,DMSO-d6):δ177.9,168.4,156.1,137.8,130.8,126.3,122.7,121.2,112.4,65.0,64.6,31.0,27.9,24.9,21.9,13.7.
实施例2（氨基硫脲缩甲醛基）苯氧乙酸衍生物的体外酪氨酸酶抑制活性测试
测试方法参考文献【V.J.Hearing,Methods in Enzymology,vol.142,Academic Press,New York,1987,154】，具体实施方法为：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)，945μL磷酸缓冲溶液(pH=6.8)以及5μL的0.45mg/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)溶液迅速充分混匀启动反应，在25℃恒温条件下测定波长为475nm的光密度值，由其随时间的增长直线的斜率计算出酶的活性（消光系数ε=3600M-1cm-1）。并用对照扣除缓冲溶液对本试验的影响。
由此方法测得的（氨基硫脲缩甲醛基）苯氧乙酸衍生物的体外酪氨酸酶抑制活性数据如表4所示。
表4.（氨基硫脲缩甲醛基）苯氧乙酸衍生物的体外酪氨酸酶a抑制活性值（IC50）
a:酪氨酸酶（EC 1.14.18.1，Tyrosinase）,来源于蘑菇；
b:IC50，指半数抑制浓度
表4结果表明，与对照物熊果苷相比（本实验测试IC50值为为7300μM，文献值为5300μM-8400μM，【Funayama,M.;Arakawa,H.;Yamamoto,R.;Nishino,T.;Shin,T.;Murao,S.Biosci.Biotech.Biochem.1995,59,143.和Shi,Y;Chen,Q.X.;Wang,Q.;Song,K.K.;Qiu,L.Food Chem.2005,92,707.】，所有化合物均表现出极好的酪氨酸酶抑制活性，其抑制活性提高了2-4个数量级；特别是化合物5、17和18的IC50值分别为0.77μM、0.98μM和0.75μM，达到了nM的水平。
Claims (6)
1.式I所示的（氨基硫脲缩甲醛基）苯氧乙酸衍生物：
式I
其中，R1选自氢、1-6个碳的烷氧基；
R2选自
R3选自1-6个碳的直链烷基。
2.根据权利要求1所述的（氨基硫脲缩甲醛基）苯氧乙酸衍生物，其特征在于，选自如下化合物：
3.根据权利要求1或2所述的（氨基硫脲缩甲醛基）苯氧乙酸衍生物，其特征在于，选自如下化合物：
4.权利要求1或2所述的（氨基硫脲缩甲醛基）苯氧乙酸衍生物作为酪氨酸酶抑制剂的应用。
5.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。
6.权利要求6所述的药物组合物作为酪氨酸酶抑制剂的应用。
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| CN105294527A (zh) * | 2015-11-27 | 2016-02-03 | 中国广州分析测试中心 | 芳基取代苯甲醛或苯乙酮缩氨基硫脲衍生物及其作为酪氨酸酶抑制剂的应用 |
| CN105439926A (zh) * | 2015-11-27 | 2016-03-30 | 中国广州分析测试中心 | 烷基取代苯甲醛或苯乙酮缩氨基硫脲衍生物及其作为酪氨酸酶抑制剂的应用 |
| CN108047105A (zh) * | 2017-12-01 | 2018-05-18 | 广东轻工职业技术学院 | 3-/4-酯基取代苯甲醛缩氨基硫脲衍生物及其制备与应用 |
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