CN110577582B - Ldv修饰的七环醛,其合成,抗栓活性和应用 - Google Patents
Ldv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)-[1-乙基-Leu-Asp-Val]-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,涉及它的抗静脉血栓活性,因而本发明涉及它在制备抗静脉血栓药物中的应用。本发明属于生物医药领域。
背景技术
动脉血栓和静脉血栓两种病症已成为当下发病率高和死亡率高的疾病,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。静脉血栓症主要包括深静脉血栓和肺栓塞。深静脉血栓和肺栓塞发病的患者数超过了心肌梗塞和中风发病的总人数,而且比乳腺癌和艾滋病所引起死亡的总人数高。由于静脉血栓症的发病率随年龄增长呈指数态增加,所以这种病症对我国这样的老龄化国家的人民健康的威胁尤其严重。如果把人口基数考虑进去,对我国国计民生的绝对负面影响尤其严重。于是,静脉血栓症的预防及治疗一直是医药领域所关注的重点,发明新型抗静脉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。发明人假设,两个β-咔啉药效团融合,例如两个(R)-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)-[1-羰甲基]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮。这种新型七环醛,应有强的抗静脉血栓活性。发明人进一步假设,往这种新型七环醛的醛基连接Leu-Asp-Val应有更强的抗静脉血栓活性。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)-[1-乙基-Leu-Asp-Val]-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-乙基-Leu-Asp-Val]-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(3S)-1-(2,2-二甲氧基乙基-2-基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯(1);
2)在甲醇中(3S)-1-(2,2-二甲氧基乙基-2-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(3S)-1-(2,2-二甲氧乙基-2-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,(3S)-1-(2,2-二甲氧乙基-2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)-[1-二甲氧乙基-2-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)-[1-二甲氧乙基-2-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)-[1-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-羟基苯并三唑为催化剂的液相缩合的方法合成HCl·Leu-Asp(OBzl)-Val-OBzl;
6)用氰基硼氢化钠为还原剂将HCl·Leu-Asp(OBzl)-Val-OBzl连接到(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-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)-[1-乙基-Leu-Asp(OBzl)-Val-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)-[1-乙基-Leu-Asp(OBzl)-Val-OBzl]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(5)脱苄得到(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-乙基-Leu-Asp-Val]-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-乙基-Leu-Asp-Val]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮的抗静脉血栓作用。
附图说明
图1.(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-亚甲-Leu-Asp-Val]-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)二氯甲烷,NaCNBH3,无水MgSO4;(viii)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(3S)-1-(2,2-二甲氧基乙基-2-基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯(1)
冰浴下180mL二氯甲烷,10mL 1,1,3,3-四甲氧基丙烷和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硫酸钠干燥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(3S)-1-(2,2-二甲氧基乙基-2-基)-2,3,4,9-四氢-β-咔啉-3-羧酸(2)
向5.12g(13.00mmol)(3S)-1-(2,2-二甲氧基乙基-2-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)-[1-二甲氧乙基-2-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)(3S)-1-(2,2-二甲氧基乙基-2-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)-[1-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)-[1-二甲氧乙基-2-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-Asp(OBzl)-Val-OBzl
冰浴下向3.23g(10.00mmol)Boc-Asp(OBzl)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4.55g(12.00mmol)Tos·Val-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=30:1)显示Boc-Asp(OBzl)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4.74g(93%)标题化合物,为黄色糖浆。ESI-MS(m/e):513[M+H]+。
实施例6制备HCl·Asp(OBzl)-Val-OBzl
将4.74g(9.26mmol)Boc-Asp(OBzl)-Val-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(4N),室温搅拌6h,TLC(二氯甲烷/甲醇/乙酸,30/1/2滴,v/v/v)显示Boc-Asp(OBzl)-Val-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。最后残留物用无水乙醚洗,得到3.95g(95%)标题化合物,为黄色固体。
实施例7制备Boc-Leu-Asp(OBzl)-Val-OBzl
按照实施例5的方法从2.24g(9.70mmol)Boc-Leu和3.95g(8.81mmol)HCl·Asp(OBzl)-Val-OBzl得到3.62g(66%)标题化合物,为无色粉末。ESI-MS(m/e):626[M+H]+。
实施例8制备HCl·Leu-Asp(OBzl)-Val-OBzl
按照实施例6的方法从836mg(1.34mmol)Boc-Leu-Asp(OBzl)-Val-OBzl得到703mg(94%)标题化合物,为无色固体。
实施例9制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-乙基-Leu-Asp(OBzl)-Val-OBzl]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(5)
将238mg(0.49mmol)(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-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836mg(1.49mmol)HCl·Leu-Asp(OBzl)-Val-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100mg MgSO4。反应混合物冰浴搅拌1h后,每隔1h加入39mg NaCNBH3,共加入156mg NaCNBH3。之后,在室温搅拌24hTLC(二氯甲烷/甲醇=30:1)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=120:1),得到204mg(27%)标题化合物,为淡黄色固体。ESI-MS(m/e):1499[M+H]+;1H-NMR(300MHz,DMSO-d6)δ/ppm=10.94(s,2H),8.36(d,J=8.1Hz,2H),8.23(d,J=8.4Hz,2H),7.39~7.22(m,24H),7.06(t,J=6.6Hz,2H),6.97(t,J=7.5Hz,2H),5.96(m,2H),5.10(dd,J1=12.3Hz,J2=23.1Hz,4H),4.96(dd,J1=12.6Hz,J2=21.3Hz,4H),4.85(m,2H),4.55(dd,J1=3.9Hz,J2=11.7Hz,2H),4.24(dd,J1=6.0Hz,J2=8.1Hz,2H),3.23(dd,J1=3.9Hz,J2=15.3Hz,2H),3.08(m,2H),2.84~2.65(m,8H),2.05(m,8H),1.74(m,2H),1.34(m,6H),0.85(m,24H)。
实施例10制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-乙基-Leu-Asp-Val]-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(0.07mmol)(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-乙基-Leu-Asp(OBzl)-Val-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=30:1)显示化合物5消失。冰浴下往反应混合物中加50mL无水乙醚,搅拌10min,静置,倾去上清液。残留物再加50mL无水乙醚,搅拌10min,静置,倾去上清液。该操作至少重复3次。得到的土黄色固体用1.5mL5%醋酸溶解,溶液用Sephadex纯化,得到56mg(74%)标题化合物,为土黄色固体。ESI-MS(m/e):1139[M+H]+;1H-NMR(300MHz,DMSO-d6)δ/ppm=12.61(s,4H),10.68(s,2H),9.03(d,J=7.5Hz,2H),8.09(d,J=8.1Hz,2H),7.43(d,J=8.1Hz,4H),7.13(t,J=7.8Hz,2H),7.03(t,J=7.5Hz,2H),5.82(m,2H),4.91(m,2H),4.62(dd,J1=4.2Hz,J2=7.8Hz,2H),4.15(dd,J1=5.7Hz,J2=7.8Hz,2H),3.27(m,2H),3.08(m,2H),2.88~2.58(m,8H),2.27(m,4H),2.06(m,4H),1.67(m,6H),1.54(m,2H),0.88(m,24H)。
实施例11评价(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-乙基-Leu-Asp-Val]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(6)的抗静脉血栓作用
实验材料:华法林钠(CAS:129-06-6,百灵威科技有限公司)、乌拉坦(CAS:51-79-6,货号:30191228,国药集团化学试剂有限公司)、生理盐水(石家庄四药有限公司)、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,250±20g,购自北京维通利华实验动物技术有限公司。
实验方法:实验采用大鼠下腔静脉结扎模型。
分组及剂量:(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-乙基-Leu-Asp-Val]-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,阳性对照华法林钠的剂量为4.87μmol/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%),化合物6为0.5%CMCNa的悬浮液,华法林钠为0.5%CMCNa的悬浮液。
实验操作:大鼠在手术前适应环境并禁食一天,以0.3mL/100g体重的剂量对大鼠进行灌胃给药。给药30min后于手术前2min用20%乌拉坦溶液腹腔给药麻醉。将大鼠固定于大鼠固定板上,腹部备皮且消毒,然后沿腹白线打开腹腔,上至露出肝脏一角,开口大小约4cm长即可。移开腹腔内小肠等器官并用浸润过生理盐水的纱布包裹。钝性分离血管周围结缔组织,暴露下腔静脉及其分支,在左肾静脉下方将腹主动脉和下腔静脉剥离开,然后用生理盐水浸湿的缝合线在下腔静脉与左肾静脉交汇处将下腔静脉结扎,按解剖位置将肠等器官移回腹腔,用缝合线逐层缝合腹腔。
术后将大鼠置于25~28℃的环境中循环4小时,打开腹腔后,逐个将其分支结扎,从下腔静脉与左肾静脉的交汇处的结扎处开始取出2cm下腔静脉,从中取出血栓。血栓称重并利用t检验的方式统计结果。手术以每组四只交替进行。实验数据见表1。
表1的数据表明,在0.1μmol/kg口服剂量下化合物6不仅可显著性抑制大鼠形成静脉血栓,而且活性与4.87μmol/kg华法林钠相当。本发明有意想不到的技术效果。
表1化合物6的抗静脉血栓活性
化合物 | 剂量 | 血栓重(均值±SD mg) |
0.5%CMCNa | 3mL/kg | 21.74±4.51 |
华法林钠 | 4.87μmol/kg | 14.52±5.17 |
化合物6 | 0.1μmol/kg | 13.86±6.42<sup>a</sup> |
a)与0.5%CMCNa比P<0.05,与4.87μmol/kg华法林钠比P>0.05;n=8。
Claims (3)
2.权利要求1所述的Leu-Asp-Val修饰七环醛的制备方法,该方法包括以下步骤:
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(3S)-1-(2,2-二甲氧基乙基-2-基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯;
2)在甲醇中(3S)-1-(2,2-二甲氧基乙基-2-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(3S)-1-(2,2-二甲氧乙基-2-基)-2,3,4,9-四氢-β-咔啉-3-羧酸;
3)在苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯存在下,(3S)-1-(2,2-二甲氧乙基-2基)-2,3,4,9-四氢-β-咔啉-3-羧酸在无水DMF中分子间缩合为(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-二甲氧乙基-2-基]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮;
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)-[1-二甲氧乙基-2-基]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮转化为(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-羰甲基]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮;
5)采用二环己基碳二亚胺为缩合剂,1-羟基苯并三唑为催化剂的液相缩合的方法合成HCl·Leu-Asp(OBzl)-Val-OBzl;
6)用氰基硼氢化钠为还原剂将HCl·Leu-Asp(OBzl)-Val-OBzl连接到(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-羰甲基]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮的醛基上,合成(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-乙基-Leu-Asp(OBzl)-Val-OBzl]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮;
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)-[1-乙基-Leu-Asp(OBzl)-Val-OBzl]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮脱苄得到(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{(1R)-[1-乙基-Leu-Asp-Val]-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮。
3.权利要求1所述的Leu-Asp-Val修饰七环醛在制备抗静脉血栓药物中的应用。
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