CN102250204A - Rgd序列肽基甲基姜黄素类化合物及其合成方法和应用 - Google Patents
Rgd序列肽基甲基姜黄素类化合物及其合成方法和应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及一类1-(3,4-二甲氧基苯基)-7-(4-氧乙酰RGD序列肽基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮,涉及它们的制备方法,涉及它们在体外血小板聚集模型上的抗血小板聚集作用、在大鼠颈动静脉旁路插管丝线法模型上的抗血栓作用和应用。本发明属于生物医药领域。
背景技术
1,7-二-(4-羟基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(姜黄素)是从中药姜黄里提取出来的一种物质,是姜黄发挥作用的主要成分,具有多种药理活性。从1985年开始,就有研究者不断研究姜黄素抗血栓的药理活性。RGD序列(RGD=Arg-Gly-Asp)是血液里纤维蛋白α链和γ链里的一个序列,能特异性被血小板表面膜糖蛋白受体Ⅱb和Ⅲa(GPIIb/Ⅲa)识别,在血栓形成中发挥重要作用。在体内,RGD序列肽可以竞争性的抑制纤维蛋白和血小板的结合,发挥抗栓的作用。姜黄素水溶性极差,由此带来生物利用度不高,易被降解的缺陷,不能很好发挥药效。
本发明人认为,将姜黄素结构中一侧的羟基修改为甲氧基可得到甲基姜黄素,即1-(3,4-二甲氧基苯基)-7-(4-羟基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮,能增强姜黄素的脂溶性,能很好地和脂溶性细胞膜结合,增强跨膜能力。本发明人还认为,将具有抗栓活性的含RGD序列肽和甲基姜黄素的羟基相连接可得到1-(3,4-二甲氧基苯基)-7-(4-氧乙酰RGD序列肽基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮,可改善姜黄素的水溶性,增强生物利用度,提高药效。根据这些认识,发明人提出了本发明。
发明内容
本发明的目的在于是提供一类具有如通式5a-h所示结构的化合物:
其中,R’为C端保护且侧链全保护的RGD序列肽基,所述RGD序列肽选自Arg-Gly-Asp,Arg-Gly-Asp-Val,Arg-Gly-Asp-Val-Arg-Gly-Asp-Val,Arg-Gly-Asp-Phe,Arg-Gly-Asp-Phe-Arg-Gly-Asp-Phe,Arg-Gly-Asp-Ser,Arg-Gly-Asp-Ser-Arg-Gly-Asp-Ser或Asp(Arg-Gly-Asp-Val)-Arg-Gly-Asp-Val。
所述C端保护是指用苄氧基(OBzl)等常用保护基团对多肽的C端进行保护,所述侧链全保护是指用苄氧基(OBzl)、苄基(Bzl)、对甲苯磺酰基(Tos)等常用保护基团对多肽侧链进行保护,所述保护基团可以是不同的种类,只要能在后续的步骤中很好的脱除且不带来副产物即可。
在本发明优选的实施方式中,所述R’选自Arg(Tos)-Gly-Asp(OBzl)-OBzl,Arg(Tos)-Gly-Asp(OBzl)-Val-OBzl,Arg(Tos)-Gly-Asp(OBzl)-Val-Arg(Tos)-Gly-Asp(OBzl)-Val-OBzl,Arg(Tos)-Gly-Asp(OBzl)-Phe-OBzl,Arg(Tos)-Gly-Asp(OBzl)-Phe-Arg(Tos)-Gly-Asp(OBzl)-Phe-OBzl,Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-(OBzl),Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-(OBzl)或Asp(Arg(Tos)-Gly-Asp(OBzl)-Val)-Arg(Tos)-Gly-Asp(OBzl)-Val-(OBzl)。
本发明还提供一类1-(3,4-二甲氧基苯基)-7-(4-氧乙酰RGD序列肽基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮化合物,具有如通式6a-h所示结构:
其中,R为RGD序列肽基,选自Arg-Gly-Asp,Arg-Gly-Asp-Val,
Arg-Gly-Asp-Val-Arg-Gly-Asp-Val,Arg-Gly-Asp-Phe,
Arg-Gly-Asp-Phe-Arg-Gly-Asp-Phe,Arg-Gly-Asp-Ser,Arg-Gly-Asp-Ser-Arg-Gly-Asp-Ser或Asp(Arg-Gly-Asp-Val)-Arg-Gly-Asp-Val。
本发明的又一目的在于提供所述通式5a-h或通式6a-h所示结构的化合物的制备方法,该方法包括:
1)制备6-(3,4-二-甲氧苯基)-5,6-己烯-2,4-二酮;
2)制备3-甲氧基-4-氧乙酰乙酯基苯甲醛;
3)以步骤1)和步骤2)的产物为原料进行反应,制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰乙酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮;
4)将1-(3,4-二甲氧基苯基)-7-(4-氧乙酰乙酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二 酮皂化,得到1-(3,4-二甲氧基苯基)-7-(4-氧乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮;
5)将1-(3,4-二甲氧基苯基)-7-(4-氧乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮和C端保护且侧链全保护的RGD序列肽缩合,制备通式5a-h所示化合物;
6)在三氟乙酸和三氟甲磺酸的条件下,脱除肽基侧链的保护基,制备通式6a-h所示的1-(3,4-二甲氧基苯基)-7-(4-氧乙酰RGD序列肽基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮。
其中,所述步骤5)的C端保护且侧链全保护的RGD序列肽基,所述C端保护是指用苄氧基(OBzl)等常用保护基团对多肽的C端进行保护,所述侧链全保护是指用苄氧基(OBzl)、苄基(Bzl)、对甲苯磺酰基(Tos)等常用保护基团对多肽侧链进行保护;所述RGD序列肽选自Arg-Gly-Asp,Arg-Gly-Asp-Val,
Arg-Gly-Asp-Val-Arg-Gly-Asp-Val,Arg-Gly-Asp-Phe,
Arg-Gly-Asp-Phe-Arg-Gly-Asp-Phe,Arg-Gly-Asp-Ser,Arg-Gly-Asp-Ser-Arg-Gly-Asp-Ser或Asp(Arg-Gly-Asp-Val)-Arg-Gly-Asp-Val。
所述C端保护且侧链全保护的RGD序列肽基是按照现有液相合成技术将各氨基酸的保护中间体逐步接肽缩合而成的,所述液相合成技术及所述保护、缩合、脱保护的过程是本领域的常规并公知的技术。
在本发明优选的实施方式中,所述C端保护且侧链全保护的RGD序列肽基选自
Arg(Tos)-Gly-Asp(OBzl)-OBzl,Arg(Tos)-Gly-Asp(OBzl)-Val-OBzl,
Arg(Tos)-Gly-Asp(OBzl)-Val-Arg(Tos)-Gly-Asp(OBzl)-Val-OBzl,
Arg(Tos)-Gly-Asp(OBzl)-Phe-OBzl,
Arg(Tos)-Gly-Asp(OBzl)-Phe-Arg(Tos)-Gly-Asp(OBzl)-Phe-OBzl,
Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-(OBzl),
Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-(OBzl)或
Asp(Arg(Tos)-Gly-Asp(OBzl)-Val)-Arg(Tos)-Gly-Asp(OBzl)-Val-(OBzl)。
本发明的另一目的是通过评价所述1-(3,4-二甲氧基苯基)-7-(4-氧乙酰RGD序列肽基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮化合物体外抑制血小板聚集的活性,及它们的体内抗血栓活性,提供该类化合物在制备抗血栓药物中的应用。
附图说明
图1为本发明提供的1-(3,4-二甲氧基苯基)-7-(4-氧乙酰RGD序列肽基-3-甲氧基苯 基)-1,6-庚二烯-3,5-二酮类化合物的合成路线图;i)B2O3,乙酰丙酮,(nBuo)3B,nBu-NH2,1N HCl;ii)无水K2CO3,BrCH2CO2C2H5;iii)B2O3,(nBuo)3B,nBu-NH2,1N HCl;iv)4NNaOH,2N HCl;v)二环己基羰二亚胺(DCC),N-羟基苯并三唑(HOBt),N-甲基吗啉(NMM),RGD序列肽基(侧链全保护盐酸盐);vi)三氟乙酸(TFA),三氟甲磺酸(TFMSA)。
具体实施方式
为了进一步阐述本发明,下面给出一系列实施例。这些实施例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。
实施例1制备6-(3,4-二-甲氧苯基)-5,6-己烯-2,4-二酮(1)
250ml三颈瓶中加入31ml(0.3mol)乙酰丙酮,14.5g(0.21mol)三氧化二硼,乙酸乙酯70ml,70℃反应一小时,反应变为白色悬浊液,然后加入29.5ml(0.11mol)硼酸三正丁酯,和16.6g(0.1mol)3,4-二甲氧基苯甲醛,85反应半小时后,溶液变浅黄色悬浊液,升温至100℃,恒压漏斗滴加乙酸乙酯稀释的10.88ml(0.11mol)正丁胺,反应一小时后反应变红色,降温至50℃,加入稀释至200ml 1N的盐酸,半小时后停止反应,分出水层,加40ml乙酸乙酯萃取三次后合并乙酸乙酯,加无水硫酸钠干燥,过滤出硫酸钠后减压除去溶剂,剩余物硅胶柱层析后得到8.6g(34.6%)目标化合物,为淡黄色固体。Mp 85℃;ESI-MS(m/e)249[M+H]+;IR(KBr):2920,2845,1641,1593,1512,1421,1348,1265,1236,1157,1139,1020,974,931,852,817,785,613,538,470. 1H-NMR(300MHz,CDCl3):δ/ppm=15.48(s,1H),7.54(d,J=15.9Hz,1H),7.10(d,J=7.8Hz,1H),7.04(s,1H),6.86(d,J=8.1Hz,1H),6.34(d,J=15.9Hz,1H),5.64(s,1H),3.91(s,6H),2.15(s,3H).13C-NMR(125MHz,CDCl3):δ/ppm=197.08,193.05,177.78,150.89,149.22,145.19,139.84,128.06,126.93,123.74,123.62,122.35,120.60,111.13,109.84,109.66,100.76,56.48,55.96,55.89,26.85.
实施例2制备3-甲氧基-4-氧乙酰乙酯基苯甲醛(2)
250ml茄瓶内加入7.6g(50mmol)香草醛,无水THF溶解后加入9.66g(70mmol)无水碳酸钾,开始反应,30min后,反应体系变为白色浑浊液,滴加5.93ml(55mmol)溴乙酸乙酯,开始反应。48h后,薄层层析监测,原料消失,过滤,滤除不溶物,除去溶剂后加入200ml乙酸乙酯溶解,饱和碳酸氢钠水溶液萃洗三次后加入无水硫酸钠干燥,除去溶剂后得到11.316g(95.1%)目标化合物,为无色固体。Mp 84℃;ESI-MS(m/e)239[M+H]+;IR(KBr):3082,2987,2962,2937,2831,1901,1749,1676,1589, 1508,1465,1425,1402,1292,1261,1197,1139,1066,1031,867,833,736,646,594. 1H-NMR(300MHz,CDCl3):δ/ppm=9.83(d,J=4.2Hz,1H),7.41(m,3H),6.85(d,J=7.8Hz,1H),4.75(s,2H)4.24(m,2H),3.93(d,J=4.5Hz,3H),1.26(m,3H).13C-NMR(75MHz,CDCl3):δ/ppm=190.79,168.00,152.49,149.91,131.09,126.07,112.32,109.83,65.88,61.58,56.04,14.11.
实施例3制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰乙酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(3)
250ml三颈瓶中加入1.097g(4.42mmol)6-(3,4-二甲氧基苯基)-5,6-己烯-2,4-二酮,0.213g(3.09mmol)三氧化二硼,70ml乙酸乙酯,70℃反应一小时,反应变为淡黄色悬浊液,然后加入1.43ml(5.3mmol)硼酸三正丁酯,和1.158g(4.87mmol)3-甲氧基-4-氧乙酰乙酯基苯甲醛,85℃反应半小时后,溶液变红色悬浊液,升温至100℃,恒压漏斗滴加乙酸乙酯稀释的0.53ml(5.3mmol)正丁胺,反应一小时后溶液变红色,降温至50℃,加入1N的盐酸10ml,半小时后停止反应,分出水层,加10ml乙酸乙酯萃取三次后合并乙酸乙酯,加无水硫酸钠干燥,过滤出硫酸钠后减压除去溶剂,剩余物硅胶柱层析后得到目标化合物0.435g(21.0%)为淡黄色固体。Mp 82℃;ESI-MS(m/e):469[M+H]+;IR(KBr):2935,2839,1755,1625,1585,1512,1463,1419,1263,1199,1138,1026,970,848,808.1H-NMR(300MHz,CDCl3)δ/ppm=16.03(s,1H),7.63(d,J=15.9Hz,1H)7.60(d,J=15.9Hz,1H),7.13(m,4H),6.89(d,J=8.4Hz,1H),6.80(d,J=8.4Hz,1H),6.52(d,J=15.9Hz,1H),4.75(s,2H),5.84(s,1H),3.95(d,9H),3.82(s,3H).13C-NMR(75MHz,CDCl3):δ/ppm=183.57,182.87,168.52,151.09,149.71,149.24,149.11,140.55,140.00,129.50,128.03,122.67,122.02,113.64,111.15,110.74,109.78,101.37,66.20,61.46,55.99,55.91,29.27
实施例4制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(4)
100ml茄瓶内,加入468mg(1mmol)1-(3,4-二甲氧基苯基)-7-(4-氧乙酰乙酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮,加入丙酮溶解后,溶液呈黄色透明,然后滴加4N的氢氧化钠水溶液1ml,溶液逐渐变红,最后变为红黑色,5min后,有黄色固体析出,10min后,薄层层析监测原料消失,滴加2N HCl水溶液,调节pH值到中性,减压除去丙酮,剩余物过滤,用自来水洗涤沉淀,得到目标化合物424mg(96.4%)为橙色固体粉末。Mp 94℃ESI-MS(m/e):439[M-H]-,879[2M-H]-;IR(KBr):3508,3361,2939,2835,1734,1624,1585,1510,1423,1263,1232,1134,1068,1022,966,842,808, 671.1H-NMR(300MHz,DMSO-d6):δ/ppm=7.59(d,J=15.9Hz,1H),7.58(d,J=15.9Hz,1H),7.39-7.35(m,2H),7.29-7.23(m,2H),7.02(d,J=8.4Hz,1H),6.90(d,J=8.4Hz,1H),6.85(d,J=15.9Hz,2H),6.118(s,1H),4.75(s,2H),3.85(s,3H),3.83(s,3H),3.81(s,3H).13C-NMR(75MHz,DMSO-d6):δ/ppm=206.87,183.84,183.51,170.33,151.49,149.78,149.57,149.53,140.96,140.66,128.70,128.05,123.41,122.95,122.87,122.56,113.44,112.22,111.58,111.01,101.47,65.38,56.49,56.19,56.09,31.13
实施例5制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg(Tos)-Gly-Asp(OBzl)-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(5a)
100ml茄瓶内加入213mg(0.48mmol)1-(3,4-二甲氧基苯基)-7-(4-氧乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮,无水THF溶解后,加入86mg(0.63mmol)HOBt,再滴加入130mg(0.63mmol)DCC的THF溶液,15min后,加入415.6mg(0.58mmol)HCl·Arg(Tos)-Gly-Asp(OBzl)-OBzl的无水THF溶液,滴入前用NMM调节THF溶液的pH值到9,开始反应;12h后,薄层层析监测反应结束,减压除去溶剂,剩余物氯仿甲醇层析柱纯化后得到目标化合物310mg(58.6%),为黄色固体粉末。Mp 95℃;[α]D 25=34(c=0.13,氯仿);ESI-MS(m/e):1104[M+H]+;IR(KBr):3325,3062,2931,2374,2324,1735,1672,1633,1585,1546,1510,1460,1419,1263,1134,1028,966,808,754,698,555.1H-NMR(300MHz,DMSO-d6):δ/ppm=8.47-8.41(m,2H),8.13(d,J=7.5Hz,1H),7.65-7.63(m,3H),7.56(d,J=3Hz,1H),7.38-7.22(m,15H),7.01(d,J=8.4Hz,1H),6.95(d,J=8.4Hz,1H),6.87(d,J=4.8Hz,1H),6.82(d,J=4.8Hz,1H),6.58(s,1H),5.09(s,2H),5.07(s,2H),4.81-4.76(m,1H),4.67(s,2H),4.38-4.36(m,1H),3.85-3.73(m,10H),3.59-3.55(m,6H),3.05(s,2H),2.94-2.75(m,2H),2.18(s,3H),1.75-1.69(m,2H),1.55-1.41(m,3H).13C-NMR(125MHz,DMSO-d6):δ/ppm=171.73,170.76,170.21,169.19,169.11,167.90,157.01,156.96,151.50,149.84,149.81,149.55,141.53,140.92,140.47,136.26,136.13,129.50,129.28,128.87,128.51,128.50,128.39,128.16,128.07,126.03,123.39,123.12,122.90,122.59,114.66,112.23,111.61,111.02,111.56,79.68,79.42,79.15,68.26,67.49,66.82,66.38,56.27,56.10,55.37,55.33,52.24,49.10,49.00,46.31,42.05,41.94,36.26,31.11,30.04,25.59,21.45,21.30
实施例6制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg(Tos)-Gly-Asp(OBzl)-Val-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(5b)
按照实施例5的方法,从350mg(0.8mmol)1-(3,4-二甲氧基苯基)-7-(4-氧乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮和717.6mg(0.88mmol) HCl·Arg(Tos)-Gly-Asp(OBzl)-Val-OBzl,得到目标化合物525mg(54.6%),为黄色粉末。Mp 88℃;[α]D 25=-8.0(c=0.12,氯仿);ESI-MS(m/e):1202[M+H]+;IR(KBr):3334,2935,1737,1668,1625,1583,1546,1512,1456,1263,1136,1026,812,700,555.1H-NMR(300MHz,DMSO-d6):δ/ppm=8.38(s,1H),8.32-8.27(m,2H),8.18(d,J=8.1Hz,1H),8.11(d,J=7.8Hz,1H),7.65-7.62(m,3H),7.55(d,J=3.6Hz,1H),7.38-7.32(m,11H),7.26(d,J=8.1Hz,1H),7.21(s,1H),7.01(d,J=8.4Hz,1H),6.95(d,J=8.7Hz,1H),6.87(d,J=4.5Hz,1H),6.76(d,J=4.5Hz,lH),6.58(s,1H),5.11-5.02(m,4H),4.78-4.73(m,1H),4.60(s,2H),4.17(t,J=7.5Hz,J=6.6Hz,1H),3.84-3.81(m,7H),3.76-3.72(m,3H),3.04(s,2H),2.77-2.70(m,1H),2.60-2.52(m,1H),2.31(s,3H),2.12-2.00(m,1H),1.67(s,1H),1.54-1.40(m,3H),1.23-1.03(m,3H),0.83(d,J=6.6Hz,6H).13C-NMR(125MHz,DMSO-d6):δ/ppm=171.87,171.78,171.50,171.05,170.25,169.09,151.48,149.79,149.53,149.47,141.54,140.93,140.47,136.45,136.26,129.51,129.25,129.17,128.86,128.57,128.50,128.34,128.05,126.03,123.41,123.11,122.93,122.58,114.61,112.22,112.12,111.56,110.98,79.63,68.24,66.42,66.19,65.37,58.14,58.04,56.26,56.21,56.10,55.21,52.23,49.49,42.23,42.13,36.60,30.24,30.03,29.79,21.31,19.34,18.56,15.63.
实施例7制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg(Tos)-Gly-Asp(OBzl)-Val-Arg(Tos)-Gly-Asp(OBzl)-Val-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(5c)
按照实施例5的方法,从230mg(0.53mmol),1-(3,4-二甲氧基苯基)-7-(4-氧乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮和685mg(0.46mmol)
HCl·Arg(Tos)-Gly-Asp(OBzl)-Val-Arg(Tos)-Gly-Asp(OBzl)-Val-OBzl,得到395mg(45.8%)目标化合物,为黄色固体粉末。Mp 138℃;[α]D 25=20.7(c=0.12,氯仿);ESI-MS(m/e):1875[M+H]+;IR(KBr):3313,3064,2962,2935,2372,2320,1737,16311581,1543,1512,1454,1263,1165,1134,1082,1026,966,813,698,678,553.1H-NMR(300MHz,DMSO-d6):δ/ppm=8.38(s,1H),8.30-8.23(M,2h),8.17-7.99(M,4h),7.78(d,J=8.1Hz,1H),7.65-7.56(m,6H),7.39-7.22(m,23H),7.01(d,J=8.4Hz,1H),6.96(d,J=8.4Hz,1H),6.87(d,J=5.1Hz,1H),6.81(d,J=4.2Hz,1H),6.58(s,2H),6.13(s,1H),5.16-5.03(m,6H),4.79-4.75(m,2H),4.62(s,2H),4.39-4.37(m,1H),4.25-4.17(m,1H),4.25-3.99(m,4H),3.85-3.57(m,13H),3.05(s,4H),2.88-2.63(m,4H),2.32(s,6H),2.09-1.99(m,4H),1.67-1.43(m,8H),1.23-1.04(m,2H),0.85-0.79(m,12H).13C-NMR(125MHz,DMSO-d6):δ/ppm=172.04,171.51,171.22,170.61, 170.52,170.25,169.17,169.06,156.97,151.47,149.80,149.56,149.52,141.55,140.96,140.50,136.44,136.26,129.51,129.23,128.85,128.57,128.51,128.43,128.32,128.07,128.04,126.03,123.43,123.11,122.94,122.58,112.18,110.93,66.43,66.19,60.24,58.14,58.04,56.28,56.24,56.11,56.08,49.68,49.45,42.23,36.65,36.41,31.14,30.87,30.24,21.31,19.67,19.34,18.56,18.36,14.54.
实施例8制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg(Tos)-Gly-Asp(OBzl)-Phe-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(5d)
按照实施例5的方法,从474mg(1.08mmol)1-(3,4-二甲氧基苯基)-7-(4-氧乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮和1.124g(1.3mmol)
HCl·Arg(Tos)-Gly-Asp(OBzl)-Phe-OBzl,得到713mg(52.8%)目标化合物,为黄色固体粉末。Mp 94℃;[α]D 25=-100(c=0.12,氯仿);ESI-MS(m/e):1250[M+H]+;IR(KBr):3332,2935,1739,1666,1625,1585,1544,1512,1452,1261,1166,1134,1026,968,810,746,700,621,553.1H-NMR(300MHz,DMSO-d6):δ/ppm=8.42(d,J=7.5Hz,1H),8.36-8.31(m,1H),8.24(d,J=8.1Hz,1H),8.12(d,J=7.5Hz,1H),7.65-7.59(m,3H),7.56-7.55(d,J=3.9Hz,1H),7.37-7.19(m,20H),7.01(d,J=8.4Hz,1H),6.94(d,J=8.4Hz,1H),6.87(d,J=4.2Hz,1H),6.81(d,J=3.9Hz,1H),6.57(s,1H),5.11-4.99(m,4H),4.73-4.71(m,1H),4.59(s,2H),4.48(q,J=7.5Hz,J=13.8Hz,J=6.3Hz),4.38(m,1H),3.84-3.81(m,8H),3.76-3.63(m,3H)3.57(t,J=4.5Hz,4H),3.02-2.89(m,4H),2.73-2.67(m,1H),2.17(s,3H),1.75-1.37(m,4H),1.23-1.13(m,1H). 13C-NMR(125MHz,DMSO-d6):δ/ppm=171.80,171.42,170.73,170.21,168.90,167.87,156.93,151.48,149.78,149.53,141.54,140.92,140.46,137.31,136.45,136.09,129.55,129.51,129.25,128.85,128.82,128.76,128.68,128.49,128.44,128.33,128.05,127.06,126.03,123.41,123.11,122.91,122.58,114.60,112.22,111.56,110.98,79.63,68.23,66.54,66.42,66.19,60.23,56.26,56.10,55.41,54.36,54.27,52.20,49.36,46.39,42.15,40.58,36.93,36.69,30.05,21.31,14.55.
实施例9制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg(Tos)-Gly-Asp(OBzl)-Phe-Arg(Tos)-Gly-Asp(OBzl)-Phe-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(5e)
按照实施例5的方法,从141mg(0.32mmol),1-(3,4-二甲氧基苯基)-7-(4-氧乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮和455mg(0.29mmol)
HCl·Arg(Tos)-Gly-Asp(OBzl)-Phe-Arg(Tos)-Gly-Asp(OBzl)-Phe-OBzl,得到344mg(60.2%)目标化合物,为黄色固体粉末。Mp 132℃;[α]D 25=19.3(c=0.12,氯仿);ESI-MS (m/e):1970[M+H]+;IR(KBr):3311,3062,3032,2935,2372,2320,1737,1633,1546,1512,1454,1417,1263,1166,1134,1082,1026,972,813,744,700.1H-NMR(300MHz,DMSO-d6):δ/ppm=8.40(d,J=4.5Hz,1H)8.33-8.32(m,1H),8.22-8.21(d,J=4.8Hz,1H),8.10-8.07(t,J=4.5Hz,J=3.0Hz,2H),8.01(d,J=4.2Hz,2H),7.65-7.57(m,5H),7.39-7.29(m,13H),7.27-7.13(m,17H),7.02(d,J=5.1Hz,1H),6.96(d,J=5.1Hz,1H),6.85(d,J=3.9Hz,1H),6.83(d,J=3.9Hz,1H),6.58(s,2H),6.13(s,1H),5.09-5.01(m,6H),4.75-4.69(m,2H),4.61(s,2H),4.52(m,2H),4.41(m,J=3.6Hz,1H),4.27(m,J=3.6Hz,1H),3.86-3.82(m,7H),3.77-3.67(m,4H),3.58-3.56(m,6H),3.06-2.96(m,6H),2.84-2.71(m,3H),2.17(s,5H),1.68-1.66(m,2H),1.53-1.42(m,6H).13C-NMR(125MHz,DMSO-d6):δ/ppm=183.95,171.99,171.86,171.42,171.19,170.81,170.53,170.45,170.20,169.04,168.94,167.91,157.10,151.51,149.82,149.55,142.14,141.51,141.01,140.56,137.99,137.31,136.45,136.10,129.69,129.55,129.49,129.24,128.84,128.81,128.74,128.49128.42,128.32,128.06,127.04,126.70,126.03,123.42,123.11,122.95,122.58,114.60,112.24,111.62,111.04,101.52,68.27,6652,66.48,66.21,66.18,56.27,56.11,55.47,54.44,54.36,52.82,52.29,49.66,49.47,46.46,42.26,37.62,36.99,36.81,36.58,30.08,29.67,21.51,21.31.
实施例10制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(5f)
按照实施例5的方法,从652mg(1.48mmol),1-(3,4-二甲氧基苯基)-7-(4-氧乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮和1.458g(1.63mmol)
HCl·Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-(OBzl),得到653mg(34.4%)目标化合物,为黄色固体粉末。Mp 101℃;[α]D 25=16.3(c=0.11,氯仿);ESI-MS(m/e):1281[M+H]+;IR(KBr):3419,3302,2935,2862,1735,1633,1583,1546,1512,1454,1419,1263,1165,1134,1026,968,810,740,578.1H-NMR(300MHz,DMSO-d6):δ/ppm=8.46(d,J=7.8Hz,1H),8.35-8.32(m,1H),8.25(d,J=8.1Hz,1H),8.06(d,J=8.1Hz,1H),7.65-7.61(m,2H),7.56(d,J=3.9Hz,1H),7.38-7.22(m,16H),7.02(d,J=8.7Hz,1H),6.96(d,J=8.4Hz,1H),6.87(d,J=4.8Hz,1H),6.82(d,J=4.5Hz,1H),6.49(s,1H),6.13(s,1H),5.17-5.03(m,4H),4.85-4.78(m,1H),4.60-4.56(m,2H),4.53-4.42(q,J=12Hz,J=21.6Hz,J=9.6Hz,1H),4.40-4.35(m,1H),3.85-3.82(m,7H),3.72-3.61(m,3H),3.63(t,J=4.5Hz,4H),3.04(s,2H),2.80-2.52(m,2H),2.16(s,3H),2.09(s,1H),1.76-1.68(m,1H),1.56-1.39(m,3H),1.24-1.16(m,1H).13C-NMR(125MHz,DMSO-d6): δ/ppm=171.83,171.07,170.22,170.18,169.05,167.89,157.09,151.50,149.81,149.54,141.50,141.01,140.57,138.28,136.47,136.23,129.50,129.23,128.81,128.68,128.44,128.33,128.16,127.98,126.03,123.44,123.11,122.96,122.58,114.58,112.23,111.60,111.02,101.52,79.65,72.75,69.48,68.24,67.74,67.66,66.61,66.38,66.18,56.27,56.11,55.38,53.12,52.30,49.49,46.34,42.25,40.63,36.85,31.15,30.13,25.75,21.31,20.46.
实施例11制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(5g)
按照实施例5的方法,从242mg(0.55mmol),1-(3,4-二甲氧基苯基)-7-(4-氧乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮和815mg(0.5mmol)
HCl·Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-(OBzl),得到461mg(45.4%)目标化合物,为黄色固体粉末。Mp 131℃;[α]D 25=-136.3(c=0.12,氯仿);ESI-MS(m/e):2031[M+H]+;IR(KBr):3319,3064,2931,2372,1737,1633,1581,1546,1512,1417,1261,1134,1026,813,740,700,555.1H-NMR(300MHz,DMSO-d6):δ/ppm=8.46(d,J=7.5Hz,1H),8.34-8.30(m,1H),8.29-8.17(m,2H),8.13-8.04(m,3H),7.66(d,J=8.1Hz,5H),7.53(d,J=3.9Hz,1H),7.35-7.26(m,33H),7.03-6.89(d,J=8.4Hz,2H),6.86(d,J=4.8Hz,1H),6.83(d,J=4.5Hz,1H),6.57(m,2H),6.13(s,1H),5.17-5.01(m,6H),4.84-4.77(m,2H),4.59-4.56(m,3H),3.87-3.81(m,6H),3.79-3.52(m,10H),3.17(s,1H),3.03(s,4H),2.78-2.62(m,2H),2.67-2.54(m,2H),2.32(s,3H),2.30(s,3H),1.87(s,1H),1.68(s,2H),1.58-1.46(m,6H),1.23-1.76(m,1H).13C-NMR(125MHz,DMSO-d6):δ/ppm=171.85,171.77,171.01,170.51,170.20,170.18,170.04,168.91,156.95,151.45,149.76,149.49,141.57,138.50,138.45,138.25,136.43,136.21,129.52,128.85,128.82,128.69,128.68,128.51,128.47,128.45,128.34,128.17,127.99,127.90,127.10,126.88,126.04,122.86,122.15,114.45,110.86,79.62,72.73,72.62,72.55,70.19,69.97,69.42,66.62,62.24,66.18,56.22,56.07,53.11,53.02,52.71,49.30,42.06,36.82,29.61,22.81,21.32.
实施例12制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Asp[Arg(Tos)-Gly-Asp(OBzl)-Val]-Arg(Tos)-Gly-Asp(OBzl)-Val-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(5h)
按照实施例5的方法,从230mg(0.53mmol)1-(3,4-二甲氧基苯基)-7-(4-氧乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮和800mg(0.48mmol)
HCl·Asp(Arg(Tos)-Gly-Asp(OBzl)-Val)-Arg(Tos)-Gly-Asp(OBzl)-Val-(OBzl),得到456 mg(45.7%)目标化合物,为黄色固体粉末。Mp 164℃;[α]D 25=-22.3(c=0.11,氯仿);ESI-MS(m/e):2080[M+H]+;IR(KBr):3321.,3064,3035,2964,2935,2875,2372,1737,1660,1629,1583,1546,1512,1454,1263,1166,1134,1082,1026,968,813,748,698,555.1H-NMR(300MHz,DMSO-d6):δ/ppm=8.20-8.11(m,8H)7.66-7.57(m,6H),7.35-7.25(m,28H),7.03-6.95(m,J=7.8Hz,3H),6.84(m,J=15.3Hz,3H),6.59(s,2H),6.14(s,1H),5.16-5.09(m,8H),4.79-4.70(m,3H),4.58(s,2H),4.20(s,4H),3.85-3.83(m,8H),3.73(s,4H),3.04(s,4H),2.80-2.75(m,3H),2.64(s,3H),2.31(s,6H),2.08-1.99(m,4H),1.69(s,2H),1.46(s,6H),1.19-1.07(m,2H),0.85(s,12H). 13C-NMR(125MHz,DMSO-d6):δ/ppm=172.24,172.18,171.50,171.09,171.02,170.28,170.19,169.28,169.20,168.05,156.99,151.48,149.82,149.79,149.52,141.56,140.96,140.53,136.45,136.26,129.51,129.24,128.86,128.85,128.57,128.50,128.44,128.34,128.05,126.04,123.44,123.10,122.95,122.55,114.63,112.18,111.55,110.93,68.25,66.43,66.19,60.24,58.15,58.05,56.25,56.08,49.54,49.45,42.26,36.62,31.13,30.25,29.67,21.31,21.21,19.34,18.57,14.54.
实施例13制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg-Gly-Asp基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6a)
冰浴冷却下,将135mg(0.122mmol)1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg(Tos)-Gly-Asp(OBzl)-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮至于100ml茄瓶内,先加入5.2ml TFA,然后加入1.3ml TFMSA,茄瓶上加盖干燥管,开始反应,1h后停止反应,往反应体系内加入乙醚,可看到溶液变为紫黑色浑浊,有固体析出,静置,倾出上清,再加入乙醚,静置后倾出,反复操作四次后减压除去溶剂,得到紫黑色固体,加少量蒸馏水溶解,并用氨水调节pH值为中性,葡聚糖凝胶(sephadex)除盐后,冷冻干燥,得到92mg(98.4%)目标化合物,为暗黄色固体。Mp 137℃;[α]D 25=85.2(c=0.12,水)ESI-MS(m/e):767[M-H]-;IR(KBr):3402,3348,2929,2370,1660,1595,1510,1408,1259,1149,1028.1H-NMR(300MHz,DMSO-d6):δ/ppm=10.37(s,1H),9.19(s,1H),8.74(s,1H),8.39-8.04(m,2H),7.78-7.38(m,7H),7.15-6.60(m,5H),4.61-4.43(m,2H),4.21-3.56(m,14H),3.14-3.03(m,3H),2.29(m,3H),1.94(s,1H),1.66-1.46(m,3H)1.23-1.13(s,2H).13C-NMR(75MHz,DMSO-d6):δ/ppm=174.91,171.91,168.94,168.32,157.67,149.77,148,75,147.21,144.61,138.90,138.19,134.31,130.57,129.06,127.71,126.07,122.13,119.70,115.05,112.11,109.24,104.58,69.13,67.69,65.19,60.72,60.08,56.25,56.10,52.03,49.91,49.00,30.79,24.93,21.42, 14.50.
实施例14制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg-Gly-Asp-Val基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6b)
按照实施例13的方法,从138mg(O.115mmol)1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg(Tos)-Gly-Asp(OBzl)-Val-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮得到91mg(91.4%)目标化合物,为暗黄色固体。Mp 171℃;[α]D 25=102.8(c=0.12,水)ESI-MS(m/e):781[M-H]-;IR(KBr):3354,2931,2372,2318,1653,1571,1421,1263,1149,1026,659,619.1H-NMR(300MHz,DMSO-d6):δ/ppm=10.33-10.25(m,1H),9.04-8.93(m,2H),7.93-7.65(m,3H),7.40-6.88(m,12H),4.93-4.35(m,6H),4.06-3.56(m,42H),3.18(s,1H),2.93(s,1H),2.27(m,2H),2.09(s,3H),1.84(s,4H),1.53(s,2H),1.23-1.16(m,1H).13C-NMR(75MHz,DMSO-d6):δ/ppm=176.34,174.64,171.60,171.39,169.86,168.47,157.94,151.74,149.69,146.96,145.25,138.88,130.57,129.05,127.70,124.06,114.83,112.10,69.72,60.88,59.13,57.45,56.15,51.93,50.24,48.53,45.80,42.82,37.85,31.46,31.11,30.82,28.02,23.07,21.40,19.85,19.18,18.27,18.13,14.44.
实施例15制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg-Gly-Asp-Val-Arg-Gly-Asp-Val基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6c)
按照实施例13的方法,从236mg(0.126mmol)1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg(Tos)-Gly-Asp(OBzl)-Val-Arg(Tos)-Gly-Asp(OBzl)-Val-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮得到138mg(88.5%)目标化合物,为暗黄色固体。Mp 147℃;[α]D 25=100.6(c=0.12,水)ESI-MS(m/e):1294[M-H]-;IR(KBr):3338,2966,2372,2322,1660,1512,1398,1263,1151,1026.1H-NMR(300MHz,DMSO-d6):δ/ppm=10.21-10.01(m,3H),9.06-8.83(m,3H),8.48(s,1H),8.36-8.25(m,1H),8.17-8.01(m,2H),7.93-7.62(m,3H),7.36-6.86(m,16H),4.62-3.45(m,26H),3.16-2.96(m,5H),2.61-2.57(m,1H),2.28(s,3H),2.05(s,3H),1.69-1.50(m,5H),1.20-1.15(m,1H),0.83-0.78(m,12H).13C-NMR(75MHz,DMSO-d6):δ/ppm=176.19,175.99,175.82,174.34,172.75,172.39,171.67,171.39,170.63,169.07,168.87,168.35,158.06,157.84,149.88,149.50,149.22,148.66,146.32,144.61,138.89,138.47,130.57,128.95,127.69,126.49,68.99,68.35,60.81,60.59,58.77,57.61,57.34,56.33,56.27,56.12,52.11,50.99,50.29,42.71,38.27,31.27,30.67,29.91,25.31,24.79,21.42,19.68,19.52,19.20,18.38,18.30,17.87,14.45.62.
实施例16制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg-Gly-Asp-Phe基-3-甲氧基 苯基)-1,6-庚二烯-3,5-二酮(6d)
按照实施例13的方法,从215mg(0.172mmol)1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg(Tos)-Gly-Asp(OBzl)-Phe-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮得到145mg(92.1%)目标化合物,为暗黄色固体。Mp 136℃;[α]D 25=102.3(c=0.11,水)ESI-MS(m/e):914[M-H]-;IR(KBr):3356,2935,1660,1595,1510,1261,1149,1026.1H-NMR(500MHz,DMSO-d6):δ/ppm=9.02-8.46(m,1H),8.32-7.98(m,1H),7.78-7.52(m,2H),7.37-6.59(m,16H),6.32(s,1H),4.62-4.52(m,2H),4.42-4.38(m,2H),4.15-4.10(m,2H),3.92-3,72(m,8H),3.62-3.44(m,8H),3.22-2.90(m,5H),2.33(s,2H),1.95(s,1H),1.68-1.49(m,2H),1.31-1.06(m,1H).13C-NMR(125MHz,DMSO-d6):δ/ppm=172.21,170.58,168.80,168.33,157.86,154.15,148.89,146.34,144.64,139.16,138.95,135.82,130.58,130.24,130.01,129.84,129.48,129.03,128.68,128.21,127.71,126.91,126.18,124.61,120.54,115.10,112.39,107.63,105.94,60.88,60.58,58.40,56.12,52.23,50.63,46.18,42.83,38.19,30.62,27.50,24.60,21.44,17.66,14.49,14.27.
实施例17制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg-Gly-Asp-Phe-Arg-Gly-Asp-Phe基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6e)
按照实施例13的方法,从173mg(0.088mmol)1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg(Tos)-Gly-Asp(OBzl)-Phe-Arg(Tos)-Gly-Asp(OBzl)-Phe-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮得到116mg(95.3%)目标化合物,为暗黄色固体。Mp 165℃;[α]D 25=106.7(c=0.11,水)ESI-MS(m/e):1390[M-H]-;IR(KBr):3342,2937,2372,2318,1660,1512,1400,1261,1149,1029,704.1H-NMR(500MHz,DMSO-d6):δ/ppm=8.84-8.62(m,1H),8.29-7.99(m,1H),7.78-7.51(m,2H),7.37-6.36(m,22H),6.30(d,J=10Hz,1H),4.62-4.40(m,3H),4.18-3.37(m,12H),3.62-3.22(m,16H),3.18-2.92(m,9H),2.33-2.22(m,4H),2.08(s,3H),1.96-1.47(m,6H),1.30-0.86(m,2H).13C-NMR(125MHz,DMSO-d6):δ/ppm=206.93,176.13,175.28,174.20,172.22,171.35,170.65,168.85,168.41,168.03,157.83,149.90,149.44,148.66,144.64,138.94,137.48,130.57,130.20,129.98,129.81,129.48,129.02,128.68,128.50,128.26,127.71,126.93,126.26,121.51,119.04,115.34,114.49,112.25,68.82,68.12,60.90,60.59,56.33,56.16,55.34,54.24,52.11,50.58,50.07,42.86,41.12,38.11,31.12,30.60,24.65,21.42,19.29,18.98,14.48,14.27.
实施例18制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg-Gly-Asp-Ser基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6f)
按照实施例13的方法,从156mg(0.181mmol)1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮得到98mg(94.2%)目标化合物,为暗黄色固体。Mp 141℃;[α]D 25=103.7(c=0.13,水)ESI-MS(m/e):854[M-H]-;IR(KBr):3209,3064,2935,2839,1660,1597,1512,1417,1251,1138,1029,806,574.1H-NMR(300MHz,DMSO-d6):δ/ppm=10.14(s,1H),8.66(m,1H),8.32(s,1H),7.48(d,J=4.2Hz,2H),7.32(m,9H),6.82(m,4H),4.51(m,5H)3.88(m,5H),3.62(m,7H),3.53(m,4H),3.15(d,J=11.4Hz,2H),2.98(s,2H),2.29(m,2H),1.98(s,1H),1.71(s,1H),1.48(s,2H).13C-NMR(125MHz,DMSO-d6):δ/ppm=175.21,173.32,172.54,171.00,168.94,167.89,164.82,158.41,158.05,157.82,149.76,146.27,138.04,136.97,130.57,130.19,129.09,128.89,128.50,127.89,127.71,126.33,125.97,121.53,126.65,114.23,114.12,68.05,62.70,56.25,55.67,55.45,52.37,50.34,45.46,43.02,37.95,30.76,24.87,21.45,21.24
实施例19制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg-Gly-Asp-Ser-Arg-Gly-Asp-Ser基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6g)
按照实施例13的方法,从200mg(0.099mmol)1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮得114mg(91.2%)目标化合物,为暗黄色固体。Mp 108℃;[α]D 25=101.1(c=0.12,水)ESI-MS(m/e):1270[M-H]-;IR(KBr):3338,3219,2935,2374,1656,1512,1400,1255,1138,1029.1H-NMR(300MHz,DMSO-d6):δ/ppm=9.889(m,3H),8.76-8.25(m,10H),7.88-7.48(m,4H),7.38-7.07(m,4H),4.91-4.38(m,12H),4.13-3.32(m,32H),3.10(s,4H),2.35-2.29(m,1H),2.12-1.87(m,1H),1.69-1.52(m,5H).13C-NMR(75MHz,DMSO-d6):δ/ppm=176.10,175.70,173.95,172.96,172.46,171.28,170.86,168.97,168.79,168.22,159.26,157.77,149.77,128.96,128.55,125.96,123.72,122.01,119.62,114.77,114.18,112.10,110.73,73.48,69.72,69.44,62.90,61.71,56.28,56.04,55.45,52.27,50.29,42.79,30.65,29.32,24.98,23.00.
实施例20制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Asp(Arg-Gly-Asp-Val)-Arg-Gly-Asp-Val基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6h)
按照实施例13的方法,从246mg(0.118mmol)1-(3,4-二甲氧基苯基)-7-(4-氧乙酰-Asp[Arg(Tos)-Gly-Asp(OBzl)-Val]-Arg(Tos)-Gly-Asp(OBzl)-Val-OBzl基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮得158mg(95.1%)目标化合物,为暗黄色固体。Mp 126℃;[α]D 25=98.6(c=0.11,水)ESI-MS(m/e):1408[M-H]-;IR(KBr):3350,3280,3215,3059, 2962,2873,1658,1512,1400,1261,1215,1149,1028.1H-NMR(300MHz,DMSO-d6):δ/ppm=10.10(s,1H),8.70-8.28(m,5H),7.77-7.60(m,3H),7.28-6.51(m,17),4.74-4.03(m,7H),3.91-3.34(m,22H),3.13-2.96(m,6H),2.80-2.57(m,2H),3.50(s,3H),2.00(d,J=5.7Hz,2H),1.58(m,5H),1.32-1.06(m,2H),0.788(s,12H).13C-NMR(75MHz,DMSO-d6):δ/ppm=175.98,174.93,172.79,171.73,171.46,170.71,170.16,169.58,168.96,157.88,148.91,144.58,138.91,130.55,130.22,129.06,127.68,126.30,69.04,64.94,60.83,60.51,59.11,57.59,56.20,53.15,50.91,50.36,42.93,38.54,31.39,30.67,30.17,24.94,21.40,19.79,19.26,18.79,18.28,14.45.
实验例11-(3,4-二甲氧基苯基)-7-(4-氧乙酰RGD序列肽基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮体外抗血小板聚集活性
抗血小板聚集活性采用比浊法测定,具体方法为:取健康新鲜猪血,加3.8%枸橼酸钠按1∶9的比例抗凝,1000rpm离心10min后取上清,得富血小板血浆(PRP),剩余血浆继续3500rpm离心10min,得贫血小板血浆(PPP),以贫血小板血浆为参比,放入血小板聚集仪的PPP槽中,取240μl PRP加入聚集管中,37℃孵育5min后,放入仪器上标记有PRP的槽中,在聚集管中加入转子,然后加入5μl空白溶液或者待测化合物溶液,然后加入5μl诱导剂,开始测试。每个样品重复测三次,用以下公式,抑制率%=(空白聚集率-化合物聚集率)/空白聚集率,求得化合物抗血小板聚集的抑制率,根据化合物不同浓度下的抑制率,求得化合物抑制血小板聚集的IC50值。
本试验中,所用的诱导剂总共有四种,它们诱导聚集的浓度如表1所示
表1血小板聚集诱导剂及浓度
诱导剂 | ADP | 花生四烯酸钠 | 凝血酶 | PAF |
浓度 | 2×10-6M | 0.15mg/ml | 1U/ml | 2*10-7M |
以ADP为诱导剂时6a-h的抗聚集活性如表2所示。
表2100μM 6a-h抑制ADP诱导的血小板聚集百分率
化合物 | 6a | 6b | 6c | 6d | 6e | 6f | 6g | 6h |
%抑制率 | 12.73 | 44.55 | 40.91 | 12.73 | 48.18 | 23.64 | 17.27 | 21.82 |
[0090] 以PAF为诱导剂时6a-h的抗聚集活性如表3所示。
表3100μM 6a-h抑制PAF诱导的血小板聚集百分率
化合物 | 6a | 6b | 6c | 6d | 6e | 6f | 6g | 6h |
%抑制率 | 17.16 | 20.15 | 38.81 | 19.40 | 43.28 | 16.42 | 23.13 | 21.64 |
以花生四烯酸钠为诱导剂时6a-h的抗聚集活性如表4所示。
表4100μM 6a-h抑制花生四烯酸钠诱导的血小板聚集百分率
化合物 | 6a | 6b | 6c | 6d | 6e | 6f | 6g | 6h |
%抑制率 | 23.90 | 82.27 | 73.40 | 62.32 | 77.09 | 18.72 | 34.98 | 71.92 |
对其中活性较好的6b-e,h测试定了IC50值,如表5。
表56a-h抑制花生四烯酸钠诱导的血小板聚集的IC50值
化合物 | 6b | 6c | 6d | 6e | 6h |
IC50(μM) | 49.92 | 39.11 | 107.238 | 57.26 | 60.2 |
以凝血酶为诱导剂时6a-h的抗血小板聚集的IC50值如表6所示。
表66a-h抑制凝血酶诱诱导的血小板聚集的IC50值
化合物 | 6a | 6b | 6c | 6d | 6e | 6f | 6g | 6h |
IC50(μM) | 48.3 | 13.51 | 6.84 | 34.18 | 13.91 | 27.82 | 18.47 | 18.02 |
实验例21-(3,4-二甲氧基苯基)-7-(4-氧乙酰RGD序列肽基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮体内抗血栓活性
6a-h的体内抗血栓活性是通过大鼠颈动静脉旁路插管模型评价的,具体方法为:雄性SD大鼠,180±10g,灌胃给1nmol/kg 6a-h后腹腔注射20%乌拉坦麻醉,分离出右颈总动脉和左颈外静脉,在聚乙烯管的中段放入事先称重的6cm长的丝线,以肝素生理盐水(50IU/kg)充满聚乙烯管,将一端插入左颈外静脉,另一端插入右颈总动脉。血液从右颈总动脉经聚乙烯管流向左颈外静脉,15min后中断血流,取出丝线称重,总重量减去丝线原重量即为血栓湿重,统计各组的血栓湿重的均值和标准差 和空白组进行比较,得出结论。6a-h的体内抗栓活性用血栓湿重表示,结果如表7所示。
表7口服1mol/kg 6a-h大鼠的血栓湿重a
化合物 | 血栓湿重 | 化合物 | 血栓湿重 |
生理盐水 | 35.37±1.77 | 阿司匹林 | 17.64±0.6 |
6a | 21.34±1.89b | 6b | 24.75±1.48b |
6c | 23.98±1.30b | 6d | 28.28±2.48b |
6e | 23.42±1.14b | 6f | 26.24±1.70b |
6g | 23.21±1.72b | 6h | 26.57±1.60b |
a)n=10,阿司匹林为阳性对照,生理盐水为阴性对照,血栓湿重用均值±SD mg表示,6a-h剂量为1nmol/kg,阿司匹林的给药剂量为30mg/kg,相当于167μmol/kg;
b)与生理盐水组相比p<0.01。
Claims (8)
2.根据权利要求1所述的化合物,其中所述C端保护是指用苄氧基(OBzl)等常用保护基团对多肽的C端进行保护,所述侧链全保护是指用苄氧基(OBzl)、苄基(Bzl)、对甲苯磺酰基(Tos)等常用保护基团对多肽侧链进行保护。
3.根据权利要求1所述的化合物,所述R’选自Arg(Tos)-Gly-Asp(OBzl)-OBzl,Arg(Tos)-Gly-Asp(OBzl)-Val-OBzl,Arg(Tos)-Gly-Asp(OBzl)-Val-Arg(Tos)-Gly-Asp(OBzl)-Val-OBzl,Arg(Tos)-Gly-Asp(OBzl)-Phe-OBzl,Arg(Tos)-Gly-Asp(OBzl)-Phe-Arg(Tos)-Gly-Asp(OBzl)-Phe-OBzl,Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-(OBzl),Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-(OBzl)或Asp(Arg(Tos)-Gly-Asp(OBzl)-Val)-Arg(Tos)-Gly-Asp(OBzl)-Val-(OBzl)。
5.一种制备权利要求1或4所述的化合物的制备方法,该方法包括:
1)制备6-(3,4-二-甲氧苯基)-5,6-己烯-2,4-二酮;
2)制备3-甲氧基-4-氧乙酰乙酯基苯甲醛;
3)以步骤1)和步骤2)的产物为原料进行反应,制备1-(3,4-二甲氧基苯基)-7-(4-氧乙酰乙酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮;
4)将1-(3,4-二甲氧基苯基)-7-(4-氧乙酰乙酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮皂化,得到1-(3,4-二甲氧基苯基)-7-(4-氧乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮;
5)将1-(3,4-二甲氧基苯基)-7-(4-氧乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮和C端保护且侧链全保护的RGD序列肽缩合,制备权利要求1所述的通式5a-h所示化合物;
6)在三氟乙酸和三氟甲磺酸的条件下,脱除肽基侧链的保护基,制备权利要求4所述的通式6a-h所示的1-(3,4-二甲氧基苯基)-7-(4-氧乙酰RGD序列肽基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮。
6.根据权利要求1所述的方法,其中,所述步骤5)的C端保护且侧链全保护的RGD序列肽基,所述C端保护是指用苄氧基(OBzl)等常用保护基团对多肽的C端进行保护,所述侧链全保护是指用苄氧基(OBzl)、苄基(Bzl)、对甲苯磺酰基(Tos)等常用保护基团对多肽侧链进行保护,所述RGD序列肽选自Arg-Gly-Asp,Arg-Gly-Asp-Val,Arg-Gly-Asp-Val-Arg-Gly-Asp-Val,Arg-Gly-Asp-Phe,Arg-Gly-Asp-Phe-Arg-Gly-Asp-Phe,Arg-Gly-Asp-Ser,Arg-Gly-Asp-Ser-Arg-Gly-Asp-Ser或Asp(Arg-Gly-Asp-Val)-Arg-Gly-Asp-Val。
7.根据权利要求6所述的方法,其中,所述C端保护且侧链全保护的RGD序列肽基选自Arg(Tos)-Gly-Asp(OBzl)-OBzl,Arg(Tos)-Gly-Asp(OBzD-Val-OBzl,Arg(Tos)-Gly-Asp(OBzl)-Val-Arg(Tos)-Gly-Asp(OBzl)-Val-OBzl,Arg(Tos)-Gly-Asp(OBzl)-Phe-OBzl,Arg(Tos)-Gly-Asp(OBzl)-Phe-Arg(Tos)-Gly-Asp(OBzl)-Phe-OBzl,Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-(OBzl),Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-Arg(Tos)-Gly-Asp(OBzl)-Ser(Bzl)-(OBzl)或Asp(Arg(Tos)-Gly-Asp(OBzl)-Val)-Arg(Tos)-Gly-Asp(OBzl)-Val-(OBzl)。
8.权利要求4所述的1-(3,4-二甲氧基苯基)-7-(4-氧乙酰RGD序列肽基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮化合物在制备抗血栓药物中的应用。
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