CN102827050A - 亚甲基缩氨基硫脲基取代苯氧羧酸衍生物,其制备方法及其应用 - Google Patents
亚甲基缩氨基硫脲基取代苯氧羧酸衍生物,其制备方法及其应用 Download PDFInfo
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- CN102827050A CN102827050A CN2012103454609A CN201210345460A CN102827050A CN 102827050 A CN102827050 A CN 102827050A CN 2012103454609 A CN2012103454609 A CN 2012103454609A CN 201210345460 A CN201210345460 A CN 201210345460A CN 102827050 A CN102827050 A CN 102827050A
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Abstract
Description
技术领域
本发明涉及化妆品、食品、药物化学领域,具体涉及亚甲基缩氨基硫脲基取代苯氧羧酸衍生物,其制备方法及其作为酪氨酸酶抑制剂的应用。
技术背景
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亚甲基缩氨基硫脲基取代苯氧羧酸衍生物,其制备方法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亚甲基缩氨基硫脲基取代苯氧羧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所示的亚甲基缩氨基硫脲基取代苯氧羧酸衍生物:
其中,R1选自氢或一个羟基或多个羟基或1-6个碳的烷氧基;
n=1-6时,R2选自氢;
或n=0或n=3-6时,R2选自1-6个碳的直链烷基。
本发明亚甲基缩氨基硫脲基取代苯氧羧酸衍生物,包括其羧酸酯及其羧酸化合物,结构优选为式A、式B或式C:
本发明亚甲基缩氨基硫脲基取代苯氧羧酸衍生物的具体结构说明如表1-3所示:
表1.式A所示的亚甲基缩氨基硫脲基取代苯氧羧酸衍生物具体结构
表2式B所示亚甲基缩氨基硫脲基取代苯氧羧酸衍生物具体结构
表3式C所示亚甲基缩氨基硫脲基取代苯氧羧酸衍生物具体结构
本发明化合物较优选为如下化合物:化合物7~9,化合物13、化合物15、化合物18~24和化合物26,它们的结构式如下:
式I所示亚甲基缩氨基硫脲基取代苯氧羧酸衍生物合成路线如下:
所述步骤a中与Br(CH2)nCOOR2和K2CO3的物质的量的比为1:1.5:2,反应温度为回流条件,溶剂为干燥无水丙酮;所述步骤b中氨基硫脲与的物质的量的比值为1:1,反应温度为回流条件,溶剂为干燥无水甲醇;所述步骤c中氢氧化钠的质量分数为15%,反应温度为室温,所述氢氧化钠与步骤b产物的物质的量比为60:1,盐酸的浓度为1N,调节溶液PH为2-3。
本发明的亚甲基缩氨基硫脲基取代苯氧羧酸衍生物,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、亚甲基缩氨基硫脲基-4-苯氧丁酸乙酯(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)和溴丁酸乙酯5.85g(30mmol),加毕,于回流条件下搅拌8小时。TLC跟踪至反应完全。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74%。
将上述得到的中间体5mmol溶于20mL无水甲醇中,加入5mmol氨基硫脲,于回流条件下搅拌4小时,TLC跟踪至反应完全。待反应溶液冷却后,加入40mL乙酸乙酯,产生沉淀,过滤,得白色固体产物,即亚甲基缩氨基硫脲基-4-苯氧丙酸乙酯(化合物1),收率86%。
同上述方法制备得到化合物2-9,22-24,29-31。
实施例2、亚甲基缩氨基硫脲基-4-苯氧丁酸(化合物11)的制备
取化合物1(2mmol),加入15%(W/W)NaOH水溶液32克,常温搅拌4小时,于冰水浴条件下,往反应液中缓慢加入1N稀盐酸,调节溶液PH为2-3,产生固体沉淀,过滤,真空干燥,的白色固体,即为化合物11,产率94%。
同上述方法制备得到化合物10-21,25-28,32-35。
化合物1-35的结构鉴定由1H-NMR、13C NMR确认,图谱数据如下:
化合物1:
1H-NMR(300MHz,DMSO-d6):δ 11.37(s,1H,NH),8.16(s,1H,NH2),8.04(s,1H,NCH),7.95(s,1H,NH2),7.75(d,J=8.7Hz,2H,Ph-H),6.93(d,J=9.0Hz,2H,Ph-H),4.01-4.11(m,4H,OCH2CH2CH2,CH2CH3),2.46(t,J=7.2Hz,2H,OCH2CH2CH2),1.95-2.03(m,2H,OCH2CH2CH2),1.18(t,J=7.2Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ 177.5,172.4,159.8,142.2,128.8,126.6,114.5,66.5,59.8,30.0,24.1,14.0.
化合物2:
1H-NMR(300MHz,DMSO-d6):δ 11.32(s,1H,NH),8.11(s,1H,NH2),8.00(s,1H,NCH),7.90(s,1H,NH2),7.71(d,J=8.7Hz,2H,Ph-H),6.92(d,J=8.4Hz,2H,Ph-H),3.95-4.05(m,4H,OCH2CH2CH2CH2,CH2CH3),2.32(t,J=6.9Hz,2H,OCH2CH2CH2CH2),1.67(br s,4H,OCH2CH2CH2CH2),1.15(t,J=7.2Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ 177.5,172.6,160.0,142.2,128.8,126.5,114.5,67.1,59.6,48.5,33.0,27.9,21.1,14.0.
化合物3:
1H-NMR(300MHz,DMSO-d6):δ 11.34(s,1H,NH),8.12(s,1H,NH2),8.01(s,1H,NCH),7.89(s,1H,NH2),7.70(d,J=8.4Hz,2H,Ph-H),6.90(d,J=8.7Hz,2H,Ph-H),3.97-4.04(m,2H,CH2CH3),3.92(t,J=6.0Hz,2H,OCH2CH2CH2CH2CH2),2.24(t,J=6.9Hz,2H,OCH2CH2CH2CH2CH2),1.63-1.68(m,2H,OCH2CH2CH2CH2CH2),1.51-1.56(m,2H,OCH2CH2CH2CH2CH2),1.34-1.39(m,2H,OCH2CH2CH2CH2CH2),1.13(t,J=7.2Hz,3H,CH3). 13C NMR(75MHz,DMSO-d6):δ 177.5,172.7,160.0,142.2,128.8,126.5,114.4,67.3,59.5,33.3,28.2,24.9,24.1,14.0.
化合物4:
1H-NMR(300MHz,DMSO-d6):δ 11.34(s,1H,NH),8.17(s,1H,NH2),8.02(s,1H,NH2),7.99(s,1H,NCH),7.49(s,1H,Ph-H),7.11(d,J=8.4Hz,1H,Ph-H),6.88(d,J=8.4Hz,1H,Ph-H),3.94-4.02(m,4H,OCH2CH2CH2,CH2CH3),3.80(s,3H,OCH3),2.40(t,J=7.2Hz,2H,OCH2CH2CH2),1.89-1.98(m,2H,OCH2CH2CH2),1.12(t,J=7.2Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ 177.5,172.3,149.6,149.2,142.5,126.9,121.9,112.1,108.6,67.1,59.8,55.6,30.0,24.1,13.9.
化合物5:
1H-NMR(300MHz,DMSO-d6):δ 11.37(s,1H,NH),8.20(s,1H,NH2),8.06(s,1H,NH2),8.02(s,1H,NCH),7.54(s,1H,Ph-H),7.16(d,J=8.4Hz,1H,Ph-H),6.95(d,J=8.1Hz,1H,Ph-H),4.05-4.10(m,2H,CH2CH3),4.00(t,J=6.9Hz,2H,OCH2CH2CH2CH2),3.85(s,3H,OCH3),2.37(t,J=7.2Hz,2H,OCH2CH2CH2CH2),1.67-1.77(m,4H,OCH2CH2CH2CH2),1.19(t,J=7.2Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ 177.4,172.7,149.8,149.2,142.5,126.7,122.0,112.1,108.6,67.7,59.6,55.6,33.0,27.9,21.1,13.9.
化合物6:
1H-NMR(300MHz,DMSO-d6):δ 11.35(s,1H,NH),8.15(s,1H,NH2),8.00(s,1H,NH2),7.97(s,1H,NCH),7.50(s,1H,Ph-H),7.11(d,J=8.4Hz,1H,Ph-H),6.90(d,J=8.4Hz,1H,Ph-H),4.02-4.09(m,2H,CH2CH3),3.94(t,J=6.9Hz,2H,OCH2CH2CH2CH2CH2),3.80(s,3H,OCH3), 2.26(t,J=7.2Hz,2H,OCH2CH2CH2CH2CH2),1.64-1.72(m,2H,OCH2CH2CH2CH2CH2),1.52-1.59(m,2H,OCH2CH2CH2CH2CH2),1.34-1.41(m,2H,OCH2CH2CH2CH2CH2),1.14(t,J=6.9Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ 177.50,172.7,149.9,149.2,142.5,126.7,122.0,112.0,108.6,67.9,59.9,55.6,33.3,28.3,25.0,24.1,13.9.
化合物7:
1H-NMR(300MHz,DMSO-d6):δ 11.28(s,1H,Ph-OH),9.94(s,1H,NH),8.30(s,1H,NCH),8.04(s,1H,NH2),7.85(s,1H,NH2),7.81(d,J=7.2Hz,1H,Ph-H),6.45(d,J=7.5Hz,1H,Ph-H),6.42(s,1H,Ph-H),4.04-4.11(m,2H,CH2CH3),3.97(t,J=6.3Hz,2H,OCH2CH2CH2),2.45(t,J=7.2Hz,2H,OCH2CH2CH2),1.95-2.01(m,2H,OCH2CH2CH2),1.18(t,J=6.6Hz,3H,CH3).13CNMR(75MHz,DMSO-d6):δ 177.1,172.4,161.0,157.7,140.1,128.2,113.2,106.5,101.2,66.4,59.8,30.0,24.1,14.0.
化合物8:
1H-NMR(300MHz,DMSO-d6):δ 11.26(s,1H,Ph-OH),9.87(s,1H,NH),8.29(s,1H,NCH),8.01(s,1H,NH2),7.81(s,1H,NH2),7.73(d,J=9.0Hz,1H,Ph-H),6.41(d,J=7.5Hz,1H,Ph-H),6.38(s,1H,Ph-H),3.96-4.03(m,2H,CH2CH3),3.89(br s,2H,OCH2CH2CH2CH2),2.29(t,J=6.9Hz,2H,OCH2CH2CH2CH2),1.64(br s,4H,OCH2CH2CH2CH2),1.12(t,J=7.2Hz,3H,CH3).13CNMR(75MHz,DMSO-d6):δ 177.0,172.6,161.1,157.8,140.6,128.3,112.9,106.5,101.3,67.0,59.6,33.0,27.8,21.1,13.9.
化合物9:
1H-NMR(300MHz,DMSO-d6):δ 11.28(s,1H,Ph-OH),9.92(s,1H,NH),8.31(s,1H,NCH), 8.03(s,1H,NH2),7.84(s,1H,NH2),7.80(d,J=8.4Hz,1H,Ph-H),6.44(d,J=7.5Hz,1H,Ph-H),6.41(s,1H,Ph-H),4.02-4.09(m,2H,CH2CH3),3.93(t,J=6.3Hz,2H,OCH2CH2CH2CH2CH2),2.30(t,J=7.2Hz,2H,OCH2CH2CH2CH2CH2),1.66-1.73(m,2H,OCH2CH2CH2CH2CH2),1.53-1.61(m,2H,OCH2CH2CH2CH2CH2),1.37-1.45(m,2H,OCH2CH2CH2CH2CH2),1.18(t,J=7.2Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ 177.1,172.7,161.2,157.8,140.3,128.2,113.0,106.6,101.2,67.2,59.6,33.3,28.2,24.9,24.1,14.0.
化合物10:
1H-NMR(300MHz,DMSO-d6):δ 11.33(s,1H,NH),8.11(s,1H,NH2),7.99(s,1H,NCH),7.92(s,1H,NH2),7.73(d,J=8.7Hz,2H,Ph-H),6.93(d,J=8.7Hz,2H,Ph-H),4.72(s,2H,CH2).13CNMR(75MHz,DMSO-d6):δ 177.5,169.9,159.0,142.1,128.7,127.1,114.6,64.4.
化合物11:
1H-NMR(300MHz,DMSO-d6):δ 11.35(s,1H,NH),8.14(s,1H,NH2),8.03(s,1H,NCH),7.94(s,1H,NH2),7.74(d,J=8.7Hz,2H,Ph-H),6.97(d,J=8.7Hz,2H,Ph-H),4.03(t,J=6.6Hz,2H,OCH2CH2CH2),2.41(t,J=7.5Hz,2H,OCH2CH2CH2),1.92-2.01(m,2H,OCH2CH2CH2).13CNMR(75MHz,DMSO-d6):δ 177.5,174.0,159.9,142.3,128.8,126.6,114.5,66.6,30.0,24.1.
化合物12:
1H-NMR(300MHz,DMSO-d6):δ 11.35(s,1H,NH),8.14(s,1H,NH2),8.03(s,1H,NCH),7.94(s,1H,NH2),7.74(d,J=8.7Hz,2H,Ph-H),6.96(d,J=8.7Hz,2H,Ph-H),4.01(t,J=6.0Hz,2H,OCH2CH2CH2CH2),2.30(t,J=7.2Hz,2H,OCH2CH2CH2CH2),1.64-1.77(m,4H,OCH2CH2CH2CH2).13C NMR(75MHz,DMSO-d6):δ 177.5,174.3,160.0,142.2,128.8,126.5, 114.5,67.2,33.2,28.0,21.1.
化合物13:
1H-NMR(300MHz,DMSO-d6):δ 11.32(s,1H,NH),8.11(s,1H,NH2),8.00(s,1H,NCH),7.90(s,1H,NH2),7.71(d,J=8.7Hz,2H,Ph-H),6.92(d,J=8.7Hz,2H,Ph-H),3.95(br s,2H,OCH2CH2CH2CH2CH2),2.25(t,J=6.6Hz,2H,OCH2CH2CH2CH2CH2),1.68(br s,2H,OCH2CH2CH2CH2CH2),1.55(brs,2H,OCH2CH2CH2CH2CH2),1.38(brs,2H,OCH2CH2CH2CH2CH2).13C NMR(75MHz,DMSO-d6):δ 177.5,172.7,160.0,142.2,128.8,126.5,114.5,67.3,33.3,28.3,25.1,24.2.
化合物14:
1H-NMR(300MHz,DMSO-d6):δ 11.34(s,1H,NH),8.17(s,1H,NH2),8.04(s,1H,NH2),7.97(s,1H,NCH),7.54(s,1H,Ph-H),7.12(d,J=8.1Hz,1H,Ph-H),6.85(d,J=8.4Hz,1H,Ph-H),4.71(s,2H,CH2),3.84(s,3H,OCH3).13C NMR(75MHz,DMSO-d6):δ 117.4,169.9,149.1,148.8,142.3,127.4,121.7,112.3,108.9,64.8,55.7.
化合物15:
1H-NMR(300MHz,DMSO-d6):δ 11.33(s,1H,NH),8.17(s,1H,NH2),8.03(s,1H,NH2),7.97(s,1H,NCH),7.52(s,1H,Ph-H),7.12(d,J=7.8Hz,1H,Ph-H),6.96(d,J=7.8Hz,1H,Ph-H),3.98(t,J=7.2Hz,2H,OCH2CH2CH2),3.83(s,3H,OCH3),2.39(t,J=6.9Hz,2H,OCH2CH2CH2),1.95(br s,2H,OCH2CH2CH2).13C NMR(75MHz,DMSO-d6):δ 177.4,174.0,149.7,149.2,142.5,126.9,122.0,112.3,108.7,67.2,55.6,29.9,24.1.
化合物16:
1H-NMR(300MHz,DMSO-d6):δ 11.34(s,1H,NH),8.18(s,1H,NH2),8.04(s,1H,NH2),7.99(s,1H,NCH),7.53(s,1H,Ph-H),7.14(d,J=8.1Hz,1H,Ph-H),6.96(d,J=8.4Hz,1H,Ph-H),3.99(t,J=6.3Hz,2H,OCH2CH2CH2CH2),3.83(s,3H,OCH3),2.30(t,J=6.9Hz,2H,OCH2CH2CH2CH2),1.63-1.77(m,4H,OCH2CH2CH2CH2).13C NMR(75MHz,DMSO-d6):δ177.4,174.3,149.8,149.2,142.5,126.7,122.1,112.1,108.6,67.7,55.6,33.2,28.0,21.1.
化合物17:
1H-NMR(300MHz,DMSO-d6):δ 11.34(s,1H,NH),8.15(s,1H,NH2),8.04(s,1H,NH2),8.02(s,1H,NCH),7.52(s,1H,Ph-H),7.15(d,J=8.4Hz,1H,Ph-H),6.95(d,J=8.1Hz,1H,Ph-H),3.97(t,J=6.9Hz,2H,OCH2CH2CH2CH2CH2),3.83(s,3H,OCH3),2.25(t,J=7.2Hz,2H,OCH2CH2CH2CH2CH2),1.70-1.75(m,2H,OCH2CH2CH2CH2CH2),1.55-1.60(m,2H,OCH2CH2CH2CH2CH2),1.39-1.45(m,2H,OCH2CH2CH2CH2CH2).13C NMR(75MHz,DMSO-d6):δ 177.3,174.4,149.9,149.1,142.6,126.7,122.1,112.1,108.6,68.0,55.6,33.6,28.3,25.1,24.2.
化合物18:
1H-NMR(300MHz,DMSO-d6):δ 11.28(s,1H,Ph-OH),10.06(s,1H,NH),8.28(s,1H,NCH),8.03(s,1H,NH2),7.84(s,1H,NH2),7.82(d,J=6.6Hz,1H,Ph-H),6.42(d,J=5.7Hz,1H,Ph-H),6.40(s,1H,Ph-H),4.66(s,2H,CH2).13C NMR(75MHz,DMSO-d6):δ 177.1,169.9,160.1,157.7,139.6,127.9,113.7,106.4,101.3,64.4.
化合物19:
1H-NMR(300 MHz,DMSO-d6):δ 11.25(s,1H,Ph-OH),10.10(s,1H,NH),8.27(s,1H,NCH), 7.98(s,1H,NH2),7.82(s,1H,NH2),7.78(d,J=8.7Hz,1H,Ph-H),6.45(s,1H,Ph-H),6.42(d,J=7.5Hz,1H,Ph-H),3.93(t,J=6.3Hz,2H,OCH2CH2CH2),2.36(t,J=7.2Hz,2H,OCH2CH2CH2),1.86-1.95(m,2H,OCH2CH2CH2),.13C NMR(75MHz,DMSO-d6):δ 177.0,174.1,161.0,157.8,140.1,128.0,113.1,106.5,101.2,66.5,30.0,24.0.
化合物20:
1H-NMR(300MHz,DMSO-d6):δ 11.28(s,1H,Ph-OH),10.00(s,1H,NH),8.31(s,1H,NCH),8.02(s,1H,NH2),7.85(s,1H,NH2),7.81(d,J=8.4Hz,1H,Ph-H),6.51(s,1H,Ph-H),6.44(d,J=7.5Hz,1H,Ph-H),3.96(t,J=5.4Hz,2H,OCH2CH2CH2CH2),2.30(t,J=7.2Hz,2H,OCH2CH2CH2CH2),1.65-1.72(m,4H,OCH2CH2CH2CH2).13C NMR(75MHz,DMSO-d6):δ177.0,174.3,161.2,157.8,140.3,128.1,113.0,106.6,101.2,67.1,33.2,27.9,21.1.
化合物21:
1H-NMR(300MHz,DMSO-d6):δ 11.20(s,1H,Ph-OH),10.17(s,1H,NH),8.26(s,1H,NCH),7.82(s,1H,NH2),7.75(s,1H,NH2),7.80(d,J=8.4Hz,1H,Ph-H),6.41(s,1H,Ph-H),6.38(d,J=8.4Hz,1H,Ph-H),3.84(t,J=6.0Hz,2H,OCH2CH2CH2CH2CH2),2.17(t,J=7.2Hz,2H,OCH2CH2CH2CH2CH2),1.58-1.63(m,2H,OCH2CH2CH2CH2CH2),1.45-1.50(m,2H,OCH2CH2CH2CH2CH2),1.28-1.35(m,2H,OCH2CH2CH2CH2CH2).13C NMR(75MHz,DMSO-d6):δ 176.7,174.9,161.3,157.8,141.0,128.2,112.7,106.7,101.3,67.3,33.5,28.1,24.9,24.1.
化合物22:
1H-NMR(300 MHz,DMSO-d6):δ 11.49(s,1H,NH),8.29(s,1H,NH2),8.11(s,1H,NH2),8.07(s, 1H,NCH),7.47(s,1H,Ph-H),7.26-7.35(m,2H,Ph-H),6.96(d,J=6.3Hz,1H,Ph-H),4.03-4.12(m,4H,OCH2CH2CH2,CH2CH3),2.48(t,J=7.2Hz,2H,OCH2CH2CH2),1.97-2.03(m,2H,OCH2CH2CH2),1.19(t,J=7.2Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ 177.9,172.4,158.7,142.1,135.5,129.6,120.5,116.5,111.4,66.5,59.8,30.0,24.1,14.0.
化合物23:
1H-NMR(300MHz,DMSO-d6):δ 11.40(s,1H,NH),8.26(s,1H,NH2),8.10(s,1H,NH2),8.06(s,1H,NCH),7.45(s,1H,Ph-H),7.26-7.34(m,2H,Ph-H),6.96(d,J=7.5Hz,1H,Ph-H),4.00-4.09(m,4H,OCH2CH2CH2CH2,CH2CH3),2.37(t,J=6.9Hz,2H,OCH2CH2CH2CH2),1.67(br s,4H,OCH2CH2CH2CH2),1.18(t,J=7.2Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ 177.9,172.6,158.8,142.1,135.5,129.6,120.4,116.4,111.5,67.0,59.6,33.1,28.0,21.1,14.0.
化合物24:
1H-NMR(300MHz,DMSO-d6):δ 11.47(s,1H,NH),8.26(s,1H,NH2),8.10(s,1H,NH2),8.05(s,1H,NCH),7.45(s,1H,Ph-H),7.25-7.33(m,2H,Ph-H),6.95(d,J=7.8Hz,1H,Ph-H),3.98-4.09(m,4H,OCH2CH2CH2CH2CH2,CH2CH3),2.31(t,J=7.2Hz,2H,OCH2CH2CH2CH2CH2),1.70-1.74(m,2H,OCH2CH2CH2CH2CH2),1.55-1.62(m,2H,OCH2CH2CH2CH2CH2),1.40-1.48(m,2H,OCH2CH2CH2CH2CH2),1.18(t,J=6.9Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ177.9,172.7,158.9,142.1,135.5,129.6,120.4,116.4,111.5,67.3,59.6,33.4,28.3.25.0,24.2,14.0.化合物25:
1H-NMR(300MHz,DMSO-d6):δ 11.46(s,1H,NH),8.26(s,1H,NH2),8.10(s,1H,NH2),8.03(s,1H,NCH),7.47(s,1H,Ph-H),7.24-7.33(m,2H,Ph-H),6.96(d,J=6.0Hz,1H,Ph-H),4.77(s,2H, CH2).13C NMR(75MHz,DMSO-d6):δ 177.9,170.1,158.0,141.9,135.5,129.7,121.0,116.6,111.5,64.3.
化合物26:
1H-NMR(300MHz,DMSO-d6):δ 11.40(s,1H,NH),8.17(s,1H,NH2),8.06(s,1H,NH2),8.00(s,1H,NCH),7.43(s,1H,Ph-H),7.25-7.29(m,2H,Ph-H),6.93(d,J=6.0Hz,1H,Ph-H),4.00(br s,2H,OCH2CH2CH2),2.39(br s,2H,OCH2CH2CH2),1.93(br s,2H,OCH2CH2CH2).13C NMR(75MHz,DMSO-d6):δ 177.8,174.2,158.7,142.4,135.4,129.7,120.6,116.5,111.5,66.6,30.0,24.1.
化合物27:
1H-NMR(300MHz,DMSO-d6):δ 11.31(s,1H,NH),8.03(s,1H,NH2),7.98(br s,2H,NH2,NCH),7.33(s,1H,Ph-H),7.22-7.30(m,2H,Ph-H),6.91(d,J=7.5Hz,1H,Ph-H),3.94(t,J=6.0Hz,2H,OCH2CH2CH2CH2),2.25(t,J=7.2Hz,2H,OCH2CH2CH2CH2),1.61-1.67(m,4H,OCH2CH2CH2CH2).13C NMR(75MHz,DMSO-d6):δ 177.6,174.8,158.7,142.9,135.1,129.8,120.3,116.5,111.7,67.1,33.0,27.9,21.1.
化合物28:
1H-NMR(300MHz,DMSO-d6):δ 11.31(s,1H,NH),8.03(s,1H,NH2),7.98(br s,2H,NH2,NCH),7.32(s,1H,Ph-H),7.21-7.29(m,2H,Ph-H),6.88(d,J=7.5Hz,1H,Ph-H),3.90(t,J=6.3Hz,2H,OCH2CH2CH2CH2CH2),2.18(t,J=6.9Hz,2H,OCH2CH2CH2CH2CH2),1.61-1.66(m,2H,OCH2CH2CH2CH2CH2),1.47-1.52(m,2H,OCH2CH2CH2CH2CH2),1.32-1.37(m,2H,OCH2CH2CH2CH2CH2).13C NMR(75MHz,DMSO-d6):δ 177.6,174.9,158.8,142.9,135.1,129.8,120.2,116.4,111.8,67.3,33.5,28.2,25.0,24.1.
化合物29:
1H-NMR(300MHz,DMSO-d6):δ 11.47(s,1H,NH),8.50(s,1H,NCH),8.16(s,1H,NH2),8.06(d,J=7.8Hz,1H,Ph-H),7.92(s,1H,NH2),7.31(t,J=7.2Hz,1H,Ph-H),6.89-6.98(m,2H,Ph-H),3.97-4.06(m,4H,OCH2CH2CH2,CH2CH3),2.52(t,J=7.5Hz,2H,OCH2CH2CH2),1.92-2.00(m,2H,OCH2CH2CH2),1.14(t,J=7.2Hz,3H,CH3).13C NMR(75MHz,DMSO-d6):δ177.7,172.5,156.9,138.3,131.2,125.8,122.2,120.5,112.3,66.8,59.8,29.9,24.2,14.0.
化合物30:
1H-NMR(300MHz,DMSO-d6):δ 11.51(s,1H,NH),8.49(s,1H,NCH),8.15(s,1H,NH2),8.06(d,J=7.8Hz,1H,Ph-H),7.91(s,1H,NH2),7.31(t,J=7.2Hz,1H,Ph-H),6.89-6.97(m,2H,Ph-H),3.96-4.04(m,4H,OCH2CH2CH2CH2,CH2CH3),2.33(br s,2H,OCH2CH2CH2CH2),1.72(br s,4H,OCH2CH2CH2CH2),1.13(t,J=7.2Hz,3H,CH2).13C NMR(75MHz,DMSO-d6):δ177.7,172.6,157.1,138.3,131.1,125.8,122.2,120.4,112.3,67.4,59.6,33.1,28.0,21.0,14.0.
化合物31:
1H-NMR(300MHz,DMSO-d6):δ 11.47(s,1H,NH),8.47(s,1H,NCH),8.15(s,1H,NH2),8.07(d,J=7.8Hz,1H,Ph-H),7.92(s,1H,NH2),7.31(t,J=6.9Hz,1H,Ph-H),6.89-6.99(m,2H,Ph-H),3.94-4.06(m,4H,OCH2CH2CH2CH2CH2,CH2CH3),2.29(t,J=7.2Hz,2H,OCH2CH2CH2CH2CH2),1.68-1.73(m,2H,OCH2CH2CH2CH2CH2),1.54-1.62(m,2H,OCH2CH2CH2CH2CH2),1.42-1.49(m,2H,OCH2CH2CH2CH2CH2),1.14(t,J=7.2Hz,3H,CH3). 13C NMR(75MHz,DMSO-d6):δ 177.7,172.7,157.1,138.2,131.1,125.8,122.3,120.3,112.4,67.6,59.6,33.4,28.3,24.9,24.1,14.0.
化合物32:
1H-NMR(300MHz,DMSO-d6):δ 11.51(s,1H,NH),8.47(s,1H,NCH),8.15(s,1H,NH2),8.09(d,J=7.8Hz,1H,Ph-H),7.96(s,1H,NH2),7.30(t,J=6.9Hz,1H,Ph-H),6.92-6.99(m,2H,Ph-H),4.77(s,2H,CH2).13C NMR(75MHz,DMSO-d6):δ 177.8,170.0,156.2,138.0,131.0,126.3,122.5,121.0,112.4,64.8.
化合物33:
1H-NMR(300MHz,DMSO-d6):δ 11.35(s,1H,NH),8.40(s,1H,NCH),7.87-7.96(m,3H,Ph-H,NH2),7.31(t,J=6.6Hz,1H,Ph-H),6.92-6.97(m,2H,Ph-H),3.99(t,J=6.0Hz,2H,OCH2CH2CH2),2.42(t,J=7.2Hz,2H,OCH2CH2CH2),1.91-1.98(m,2H,OCH2CH2CH2).13CNMR(75MHz,DMSO-d6):δ 177.3,174.8,157.0,139.0,131.6,125.7,121.8,120.7,112.3,67.0,30.2,24.1.
化合物34:
1H-NMR(300MHz,DMSO-d6):δ 11.42(s,1H,NH),8.43(s,1H,NCH),7.97(s,1H,NH2),7.95(br s,1H,Ph-H),7.86(s,1H,NH2),7.31(t,J=7.2Hz,1H,Ph-H),6.89-6.97(m,2H,Ph-H),3.94(t,J=6.9Hz,2H,OCH2CH2CH2CH2),2.26(t,J=6.9Hz,2H,OCH2CH2CH2CH2),1.67(br s,4H,OCH2CH2CH2CH2).13C NMR(75MHz,DMSO-d6):δ 177.4,174.8,157.1,138.9,131.5,125.7,121.9,120.5,112.4,67.5,33.2,27.9,21.0.
化合物35:
1H-NMR(300MHz,DMSO-d6):δ 11.46(s,1H,NH),8.44(s,1H,NCH),8.06(s,1H,NH2),8.01(d,J=6.9Hz,1H,Ph-H),7.89(s,1H,NH2),7.31(t,J=7.8Hz,1H,Ph-H),6.89-6.98(m,2H, Ph-H),3.94(t,J=6.0Hz,4H,OCH2CH2CH2CH2CH2),2.22(t,J=7.5Hz,2H,OCH2CH2CH2CH2CH2),1.64-1.71(m,2H,OCH2CH2CH2CH2CH2),1.49-1.56(m,2H,OCH2CH2CH2CH2CH2),1.39-1.47(m,2H,OCH2CH2CH2CH2CH2).13C NMR(75MHz,DMSO-d6):δ 177.5,174.7,157.2,138.5,131.4,125.8,122.0,120.4,112.4,67.6,33.5,28.3,24.9,24.1.
实施例3、亚甲基缩氨基硫脲基取代苯氧羧酸酯及其羧酸类化合物的体外酪氨酸酶抑制活性测试
测试方法见V.J.Hearing,Methods in Enzymology,vol.142,Academic Press,New York,1987,p 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。
由此方法测得的亚甲基缩氨基硫脲基取代苯氧羧酸酯及其羧酸类化合物的体外酪氨酸酶抑制活性数据如表4所示。
表4.亚甲基缩氨基硫脲基取代苯氧羧酸衍生物的体外酪氨酸酶a抑制活性(IC50值)
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。
通过表中所列数据,可以得出:所有化合物均表现出高度的酪氨酸酶抑制活性,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,见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.),其抑制活性提高了2-5个数量级;3位羟基取代的亚甲基缩氨基硫脲基苯氧羧酸衍生物的酪氨酸酶抑制活性最高,化合物21的活性达到81nM,相当于对照品熊果苷的近十万倍。化合物7~9,化合物13、化合物15、化合物18~24和化合物26活性比化合物21低十倍,相当于对照品熊果苷的近万倍。
Claims (7)
1.式I所示的亚甲基缩氨基硫脲基取代苯氧羧酸衍生物:
其中,R1选自氢或一个羟基或多个羟基或1-6个碳的烷氧基;
n=1-6时,R2选自氢;
或n=0或n=3-6时,R2选自1-6个碳的直链烷基。
2.亚甲基缩氨基硫脲基取代苯氧羧酸衍生物,其特征在于,选自如下化合物:
4.权利要求1或2所述的亚甲基缩氨基硫脲基取代苯氧羧酸衍生物作为酪氨酸酶抑制剂的应用。
6.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。
7.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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