CN109912694B - Rgdf修饰的七环醛,其合成,抗栓活性和应用 - Google Patents
Rgdf修饰的七环醛,其合成,抗栓活性和应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-亚乙基-Arg-Gly-Asp-Phe)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮,涉及它的制备方法,涉及它的抗动脉血栓活性,因而本发明涉及它在制备抗动脉血栓药物中的应用。本发明属于生物医药领域。
背景技术
血栓形成是缺血性心脏病,缺血性中风和静脉血栓的共同病理。在全球范围内,缺血性心脏病和缺血性中风导致的死亡人数占全部因病死亡人数的1/4。而静脉血栓则是不发达国家,中等发达国家和高度发达国家主要的疾病负担。血栓可以使得一系列相关的疾病恶化,例如极少出现的生物材料管的堵塞性血栓可以为反复换管,或接受溶栓治疗或长期接受抗凝治疗的患者带来难以预料的后果,可以引起接受经皮冠状动脉内介入治疗后患者再栓塞,可以伴随肝素诱导的血小板减少症状,以及弯曲的冠状动脉血栓可以引起急性冠状综合症。此外,血栓形成是相关疾病的合并症,例如大块的脑静脉血栓是患有癫痫病的早期怀孕妇女的合并症,以及支架血栓是经皮冠状动脉内介入治疗患者的严重合并症。可见,发明新型抗血栓药物具有临床重要性。
β-咔啉是抑制血栓的重要药效团。然而β-咔啉,例如3S-1,2,3,4-四氢-β-咔啉-3-羧酸要得到抗动脉血栓目的,不仅需要静脉注射,而且剂量需要5μmol/kg。从3S-1,2,3,4-四氢-β-咔啉-3-羧酸抗动脉血栓的角度看,既期待将静脉注射改变为口服,又期待降低剂量。发明人假设,两个β-咔啉药效团融合,例如两个(1R,3S)-1-羰甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸分子间缩合为(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-羰甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮应有强的口服抗血栓活性。发明人进一步假设,往这种新型七环醛的醛基连接Arg-Gly-Asp-Phe应有更强的口服抗血栓活性。根据这个假设,发明人提出了本发明。
发明内容
本发明的第一个内容是提供下式的(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-亚乙基-Arg-Gly-Asp-Phe)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮。
本发明的第二个内容是提供(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-亚乙基-Arg-Gly-Asp-Phe]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮的制备方法,该方法包括:
1)将L-色氨酸苄酯在三氟醋酸的催化下与1,1,3,3-四甲氧基丙烷进行Pictet-Spengler缩合,得到(1R,3S)-1-(二甲氧基亚乙基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯(1);
2)在甲醇中(1R,3S)-1-(二甲氧基亚乙基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯在Pd/C催化下氢解脱苄得到(1R,3S)-1-(二甲氧基亚乙基)-2,3,4,9-四氢-β-咔啉-3-羧酸(2);
3)在苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTu)存在下,(1R,3S)-1-(二甲氧基亚乙基)-2,3,4,9-四氢-β-咔啉-3-羧酸在无水DMF(N,N-二甲基甲酰胺)中分子间缩合为(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-二甲氧基亚乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(3);
4)采用冰醋酸为溶剂,浓盐酸和水为催化剂(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-二甲氧基亚乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(3)转化为(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-羰甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(4);
5)采用二环己基碳二亚胺为缩合剂,1-羟基苯并***为催化剂的液相缩合的方法合成HCl·Arg(NO2)-Gly-Asp(OBzl)-Phe-OBzl;
6)用氰基硼氢化钠为还原剂将HCl·Arg(NO2)-Gly-Asp(OBzl)-Phe-OBzl连接到(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-羰甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(4)的醛基上,合成(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{[1R-亚乙基-Arg(NO2)-Gly-Asp(OBzl)-Phe-OBzl]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(5);
7)在三氟醋酸和三氟甲磺酸的混合溶剂中(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{[1R-亚乙基-Arg(NO2)-Gly-Asp(OBzl)-Phe-OBzl]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(5)脱除硝基和苄酯得到(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-亚乙基-Arg-Gly-Asp-Phe)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(6)。
本发明的第三个内容是评价(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-亚乙基-Arg-Gly-Asp-Phe]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮的抗动脉血栓作用。
附图说明
图1.(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-亚乙基-Arg-Gly-Asp-Phe)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮的合成路线.(i)二氯甲烷,三氟醋酸;(ii)CH3OH,Pd/C,H2;(iii)HBTu,NMM,无水DMF;(iv)H2O,冰醋酸,浓盐酸;(v)DCC,HOBt,NMM,THF;(vi)氯化氢的乙酸乙酯溶液(4M);(vii)CH3OH,NaOH溶液(2M);(viii)二氯甲烷,NaCNBH3,无水MgSO4;(ix)三氟醋酸,三氟甲磺酸。
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(1R,3S)-1-(二甲氧基亚乙基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯(1)
冰浴下180mL二氯甲烷,10mL1,1,3,3-四甲氧基丙烷和10mL三氟醋酸的混合溶液搅拌40min。之后,后加入10.25g(34.86mmol)L-Trp-OBzl。反应混合物室温搅拌14h,TLC(石油醚/乙酸乙酯=1:1)显示L-Trp-OBzl消失。反应液分别用饱和NaHCO3水溶液洗(40mL×3),饱和NaCl水溶液洗(40mL×3),分离的二氯甲烷用无水NaSO4干燥12h,过滤,滤液减压浓缩,残留物用硅胶柱层析进行纯化(石油醚/乙酸乙酯=3:1),得5.12g(37%)标题化合物,为棕红色油状物。ESI-MS(m/e):393[M+H]-。
实施例2制备(1R,3S)-1-(二甲氧基亚乙基)-2,3,4,9-四氢-β-咔啉-3-羧酸(2)
向5.12g(13.00mmol)(1R,3S)-1-(二甲氧基亚乙基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯与100mL甲醇的溶液中加入500mg Pd/C,充入氢气并室温搅拌18h,TLC(石油醚/乙酸乙酯=1:1)显示1消失,终止反应。滤除Pd/C,滤液减压浓缩至干,得3.63g(92%)标题化合物,为亮黄色油状物。ESI-MS(m/e):303[M-H]-。
实施例3制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-二甲氧基亚乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(3)
冰浴搅拌下向6.12g(20.13mmol)(1R,3S)-1-(2,2-二甲氧基亚乙基)-2,3,4,9-四氢-β-咔啉-3-羧酸(2)与100mL无水DMF的溶液中加入3.00g(22.22mmol)HBTu。然后用N-甲基吗啉将反应液的pH调至8-9,反应24h后点TLC(石油醚/乙酸乙酯=1:1)显示2消失,终止反应。反应液减压浓缩,残留物用150mL乙酸乙酯溶解。之后,分别用饱和NaHCO3水溶液洗(30mL×3),饱和NaCl水溶液洗(30mL×3),5%KHSO4水溶液洗(30mL×3),饱和NaCl水溶液洗(30mL×3),饱和NaHCO3水溶液洗(30mL×3),饱和NaCl水溶液洗(30mL×3)。乙酸乙酯层用无水硫酸钠干燥12h,过滤,滤液减压浓缩。得到的深黄色固体用硅胶柱层析分离(石油醚/乙酸乙酯=2:1),得1.14g(10%)标题化合物,为黄色固体。ESI-MS(m/e):573[M+H]+;1HNMR(300MHz,DMSO-d6)δ/ppm=11.08(s,2H),7.39(d,J=7.5Hz,2H),7.34(d,J=8.1Hz,2H),7.08(t,J=7.2Hz,2H),6.97(t,J=7.2Hz,2H),5.93(dd,J1=3.6Hz,J2=9.0Hz,2H),4.62(dd,J1=3.3Hz,J2=11.4Hz,2H),4.53(t,J=4.8Hz,2H),3.34(s,6H),3.26(s,6H),3.20(m,2H),2.79(m,2H),2.24(m,4H)。
实施例4制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-羰甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(4)
冰浴与搅拌下向380mg(0.66mmol)(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-二甲氧基亚乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(3)和9mL冰醋酸的溶液中加入6mL水和3mL浓盐酸,搅拌2h,TLC显示(石油醚/乙酸乙酯=1:1)3消失,终止反应。冰浴下,用NaOH水溶液(2M)调节反应液pH值到7。得到的溶液用乙酸乙酯萃取(50mL×3),合并的乙酸乙酯层分别用饱和NaHCO3水溶液洗(30mL×3),饱和NaCl水溶液洗(30mL×3),乙酸乙酯相用无水硫酸钠进行干燥12h,滤去硫酸钠,滤液减压浓缩得到288mg(90%)标题化合物,为黄色固体。ESI-MS(m/e):481[M+H]+;1H-NMR(300MHz,DMSO-d6)δ/ppm=10.95(s,2H),9.79(m,2H),7.42(d,J=8.1Hz,2H),7.38(d,J=7.5Hz,2H),7.10(t,J=6.9Hz,2H),6.99(t,J=6.9Hz,2H),6.22(dd,J1=3.6Hz,J2=9.0Hz,2H),4.67(dd,J1=3.3Hz,J2=11.4Hz,2H),3.26(m,2H),3.11(m,4H),2.84(m,2H)。
实施例5制备Boc-Arg(NO2)-Gly-OBzl
冰浴下向3.19g(10.00mmol)Boc-Arg(NO2)与150mL无水四氢呋喃的溶液中加入1.35g(10.00mmol)HOBt,搅拌5min后加入2.27g(11.00mmol)DCC,冰浴下搅拌30min,得到反应液A。冰浴下,将3.50g(12.00mmol)HCl·Gly-OBzl加入反应液A中,用N-甲基吗啉调节pH值到9。反应混合物室温搅拌反20h,TLC(二氯甲烷/甲醇=20:1)显示Boc-Arg(NO2)消失。滤除反应液中的不溶物,滤液减压浓缩,残留物用150mL乙酸乙酯溶解,滤去不溶的无色固体,滤液分别用饱和NaHCO3水溶液洗(30mL×3),饱和NaCl水溶液洗(30mL×3),5%KHSO4水溶液洗(30mL×3),饱和NaCl水溶液洗(30mL×3),饱和NaHCO3水溶液洗(30mL×3),饱和NaCl水溶液洗(30mL×3),得到的乙酸乙酯相用无水硫酸钠干燥12h,滤去硫酸钠,滤液减压浓缩,得到黄色糖浆,加入30mL二氯甲烷溶解,置于4℃静置12h;析出白色固体,减压过滤,得到4.32g(93%)标题化合物,为无色固体。ESI-MS(m/e):467[M+H]+。
实施例6制备Boc-Arg(NO2)-Gly
冰浴下向4.32g(9.25mmol)Boc-Arg(NO2)-Gly-OBzl与30mL甲醇的溶液中滴加2MNaOH溶液,调节溶液pH值为13-14。反应混合物冰浴搅拌反1h,TLC(二氯甲烷/甲醇,20/1,v/v,含2滴/乙酸)显示Boc-Arg(NO2)-Gly-OBzl消失。于冰浴下滴加饱和KHSO4溶液,调节溶液的pH为7,减压旋除甲醇。残留物于冰浴下滴加饱和KHSO4溶液,调节溶液的pH为2-3,用乙酸乙酯萃取(50mL×3),合并乙酸乙酯层,用饱和NaCl水溶液洗(30mL×3),得到的乙酸乙酯相用无水硫酸钠干燥12h,滤去硫酸钠,滤液减压浓缩,3.21g(92%)标题化合物,为无色糖浆。
实施例7制备Boc-Asp(OBzl)-Phe-OBzl
按照实施例5的方法从3.23g(10.00mmol)Boc-Asp(OBzl)和3.50g(12.00mmol)HCl·Phe-OBzl得到5.14g(92%)标题化合物,为黄色糖浆。ESI-MS(m/e):561[M+H]+。
实施例8制备HCl·Asp(OBzl)-Phe-OBzl
将5.14g(9.18mmol)Boc-Asp(OBzl)-Phe-OBzl用20mL无水乙酸乙酯溶解,然后于冰浴下向溶液中加入50mL氯化氢的乙酸乙酯溶液(4M),室温搅拌6h,TLC(二氯甲烷/甲醇,20/1,v/v,含2滴/乙酸)显示Boc-Asp(OBzl)-Phe-OBzl消失。将反应液减压浓缩,残留物用无水乙酸乙酯复溶后再减压浓缩,再用无水乙酸乙酯复溶。该操作至少重复3次。最后残留物用无水***洗,得到4.25g(93%)标题化合物,为黄色固体。
实施例9制备Boc-Arg(NO2)-Gly-Asp(OBzl)-Phe-OBzl
按照实施例5的方法从2.50g(6.65mmol)Boc-Arg(NO2)-Gly和3.96g(7.98mmol)HCl·Asp(OBzl)-Phe-OBzl得到3.29g(61%)标题化合物,为无色粉末。ESI-MS(m/e):819[M+H]+。
实施例10制备HCl·Arg(NO2)-Gly-Asp(OBzl)-Phe-OBzl
按照实施例8的方法从1.18g(1.44mmol)Boc-Arg(NO2)-Gly-Asp(OBzl)-Phe-OBzl得到1.04g(96%)标题化合物,为无色固体。
实施例11制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{[1R-亚乙基-Arg(NO2)-Gly-Asp(OBzl)-Phe-OBzl]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(5)
将220mg(0.46mmol)(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-羰甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(4)溶于15mL二氯甲烷,冰浴下以三乙胺调节pH值到9。将1.04g(1.38mmol)HCl·Arg(NO2)-Gly-Asp(OBzl)-Phe-OBzl用15mL二氯甲烷溶解,冰浴下以三乙胺调节pH值到9,于冰浴下滴加到化合物4的二氯甲烷溶液中,加100mgMgSO4。反应混合物冰浴搅拌1h后,每隔1h加入36mg NaCNBH3,共加入144mg NaCNBH3。之后,在室温搅拌24hTLC(二氯甲烷/甲醇=7:1)显示化合物4消失,终止反应。反应液分别用饱和NaHCO3水溶液洗(7mL×3),饱和NaCl水溶液洗(7mL×3),得到的二氯甲烷相用无水硫酸钠干燥12h后,滤去硫酸钠,滤液减压浓缩,得到的黄色固体用硅胶柱层析纯化(二氯甲烷/甲醇=20:1),得到156mg(18%)标题化合物,为淡黄色固体。ESI-MS(m/e):1886[M+H]+;1H-NMR(300MHz,DMSO-d6)δ/ppm=10.99(s,2H),8.60(m,2H),8.47(d,J=7.5Hz,2H),8.37(d,J=8.1Hz,2H),8.26(m,2H),7.39~7.15(m,34H),7.07(t,J=7.8Hz,2H),6.96(t,J=7.5Hz,2H),5.94(m,2H),5.04(m,8H),4.76(dd,J1=8.1Hz,J2=13.5Hz,2H),4.57(dd,J1=3.3Hz,J2=11.1Hz,2H),4.49(dd,J1=7.8Hz,J2=15.0Hz,2H),3.80(m,4H),3.25(m,2H),3.17(m,8H),3.01(m,6H),2.81~2.55(m,10H),2.27(m,2H),2.07(m,4H),1.63(m,8H)。
实施例12制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{[1R-亚乙基-Arg-Gly-Asp-Phe]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(6)
冰浴下将100mg(0.05mmol)(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{[1R-亚乙基-Arg(NO2)-Gly-Asp(OBzl)-Phe-OBzl]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(5)用3mL三氟乙酸溶解。之后,加入1mL三氟甲磺酸,冰浴下搅拌30min,TLC(二氯甲烷/甲醇=7:1)显示化合物5消失。冰浴下往反应混合物中加50mL无水***,搅拌10min,静置,倾去上清液。残留物再加50mL无水***,搅拌10min,静置,倾去上清液。该操作至少重复3次。得到的黄黑色固体用1.5mL 5%醋酸溶解,溶液用Sephadex纯化,得到31mg(41%)标题化合物,为淡黄色固体。ESI-MS(m/e):1435[M+H]+;1H-NMR(300MHz,DMSO-d6)δ/ppm=12.68(s,4H),10.75(s,2H),9.17(m,2H),8.92(m,2H),8.47(d,J=7.5Hz,2H),8.25(m,2H),7.42(m,8H),7.19(m,10H),7.14(m,2H),7.01(t,J=7.2Hz,2H),5.77(m,2H),4.68(dd,J1=8.7Hz,J2=12.9Hz,2H),4.56(dd,J1=3.6Hz,J2=10.8Hz,2H),4.40(dd,J1=8.1Hz,J2=13.5Hz,2H),3.94(m,4H),3.25(m,2H),3.14(m,8H),3.01(m,6H),2.91~2.68(m,8H),2.49(m,2H),2.38(m,2H),2.28(m,2H),1.78(m,4H),1.55(m,4H)。
实施例13评价(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-亚乙基-Arg-Gly-Asp-Phe)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(6)的抗动脉血栓作用
实验材料:阿司匹林(Aspirin,CAS:50-78-2,货号:298969,百灵威科技有限公司)、乌拉坦(CAS:51-79-6,货号:30191228,国药集团化学试剂有限公司)、肝素钠(CAS:9041-08-1,货号:542858,百灵威科技有限公司)、生理盐水(石家庄四药有限公司)、无水***(北京化学试剂公司)、硅油(北京化学试剂公司)、二水合柠檬酸三钠(CMCNa,货号:20170713,北京化工厂)。
实验动物:SD品系大鼠,雄性,200±20g,购自北京维通利华实验动物技术有限公司。
实验方法:实验采用颈总动脉-颈外静脉体外循环旁路丝线法。
分组及剂量:(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-亚乙基-Arg-Gly-Asp-Phe)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(简称化合物6)的剂量为0.1μmol/kg,阳性对照阿司匹林的剂量为167μmol/kg,阴性对照为0.5%CMCNa。
试剂的剂型:麻醉剂为乌拉坦的生理盐水溶液(20%),抗凝剂为肝素钠的生理盐水溶液(42mg/100mL),化合物6为0.5%CMCNa的悬浮液,阿司匹林为0.5%CMCNa的悬浮液。
旁路插管:右颈静脉和左颈动脉的旁路插管由内径为1.0mm,外径为2.0mm,长10.0cm的聚乙烯管构成。它们的一端均加热拉成为斜口的细管,以便***右颈静脉和左颈动脉。它们构成旁路插管的两端。旁路插管的中段由内径为3.5mm,长为8.0cm的聚乙烯管构成。
血栓负载线:长为6.0cm,重为4.0±0.1mg的表面毛糙丝线。
旁路插管组装:三段聚乙烯管内壁均用硅油的***溶液(1%)硅烷化,完全晾干后,将丝线于颈动脉插管方向置于中段聚乙烯管中,利用封口膜将三段聚乙烯管组装并固定,插管前需在管中充满肝素。
实验操作:按照0.1μmol/kg的剂量将化合物6的CMCNa的悬浮液以0.3mL/100g体重给大鼠灌胃,按照167μmol/kg的剂量将阿司匹林的CMCNa的悬浮液以0.3mL/100g体重给大鼠灌胃,以及将CMCNa以0.3mL/100g体重给大鼠灌胃。30min后腹腔注射20%的乌拉坦溶液进行麻醉(0.7mL/100g)。仰卧位将大鼠固定于板上,剪开颈部皮肤,分离右颈总动脉及左颈外静脉,分别将右颈总动脉和左颈外静脉的远心端用手术线进行结扎,于暴露的左颈外静脉剪一V字型小口,将上面制好的旁路插管的静脉端斜口***左颈外静脉开口的近心端,插管处用手术线将血管与聚乙烯管固定。按照0.1mL/100g体重的剂量通过旁路插管准确注入肝素钠水溶液,注射器不撤离聚乙烯管。用动脉夹夹住右颈总动脉近心端,在暴露的动脉上剪一V字型小口,将聚乙烯管的尖端从注射器取下,将管***右颈总动脉的近心端,用手术线将动脉血管与聚乙烯管固定,松开动脉夹,建立体外循环旁路。维持大鼠体温及旁路插管中血流通畅,体外循环15min后先将静脉端插管剪断观察血液循环是否顺畅,从插管的动脉端取出血栓线,在滤纸上吸去丝线上的血后称量并记录血栓重,代表抗动脉血栓活性。数据采用t检验进行统计。实验数据见表1。
表1的数据表明,在0.1μmol/kg口服剂量下(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-亚乙基-Arg-Gly-Asp-Phe]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(简称化合物6)可显著性抑制大鼠形成动脉血栓。这个有效剂量是静脉注射3S-1,2,3,4-四氢-β-咔啉-3-羧酸抗血栓的有效剂量5μmol/kg的1/50。本发明的化合物6不仅将3S-1,2,3,4-四氢-β-咔啉-3-羧酸的静脉注射改变为口服,而且降低了剂量。可见,本发明有意想不到的技术效果。
表1化合物6的抗动脉血栓活性
化合物 | 剂量 | 血栓重(均值±SD mg) |
0.5%CMCNa | 3mL/kg | 29.29±4.94 |
阿司匹林 | 167μmol/kg | 18.98±4.24<sup>a</sup> |
化合物6 | 0.1μmol/kg | 21.10±3.34<sup>a</sup> |
a)与0.5%CMCNa比P<0.01;n=8。
Claims (3)
2.权利要求1的Arg-Gly-Asp-Phe修饰七环醛的制备方法,该方法包括:
1)将L-色氨酸苄酯在三氟醋酸的催化下与1,1,3,3-四甲氧基丙烷进行Pictet-Spengler缩合,得到(1R,3S)-1-(二甲氧基亚乙基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯(1);
2)在甲醇中(1R,3S)-1-(二甲氧基亚乙基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯在Pd/C催化下氢解脱苄得到(1R,3S)-1-(二甲氧基亚乙基)-2,3,4,9-四氢-β-咔啉-3-羧酸(2);
3)在苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTu)存在下,(1R,3S)-1-(二甲氧基亚乙基)-2,3,4,9-四氢-β-咔啉-3-羧酸在无水DMF(N,N-二甲基甲酰胺)中分子间缩合为(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-二甲氧基亚乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(3);
4)采用冰醋酸为溶剂,浓盐酸和水为催化剂(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-二甲氧基亚乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(3)转化为(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-羰甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(4);
5)采用二环己基碳二亚胺为缩合剂,1-羟基苯并***为催化剂的液相缩合的方法合成HCl·Arg(NO2)-Gly-Asp(OBzl)-Phe-OBzl;
6)用氰基硼氢化钠为还原剂将HCl·Arg(NO2)-Gly-Asp(OBzl)-Phe-OBzl连接到(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-羰甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(4)的醛基上,合成(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{[1R-亚乙基-Arg(NO2)-Gly-Asp(OBzl)-Phe-OBzl]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(5);
7)在三氟醋酸和三氟甲磺酸的混合溶剂中(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{[1R-亚乙基-Arg(NO2)-Gly-Asp(OBzl)-Phe-OBzl]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(5)脱除硝基和苄酯得到(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R-亚乙基-Arg-Gly-Asp-Phe)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(6)。
3.权利要求1的Arg-Gly-Asp-Phe修饰七环醛在制备抗动脉血栓药物中的应用。
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