CN111848729B - 茶氨酰四氢咪唑并吡啶-6-甲酰天冬酰胺和谷氨酰胺的制备,活性和应用 - Google Patents
茶氨酰四氢咪唑并吡啶-6-甲酰天冬酰胺和谷氨酰胺的制备,活性和应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-AA,涉及它们的制备方法,涉及它们的抗血栓活性,涉及它们的溶血栓活性以及涉及它们对治疗缺血性中风24小时的治疗作用,因而本发明涉及它们在制备抗血栓药物,溶血栓药物以及治疗缺血性中风药物中的应用。本发明属于生物医药领域。
背景技术
缺血性中风是常见的危害严重的脑血管疾病。缺血性中风以发病率高、致残率高、复发率高和死亡率高为特点,是人类最严重的致死性疾病之一。目前,rtPA是临床公认的治疗缺血性中风的唯一有效药物。然而,rtPA治疗缺血性中风存在两个难以逾越的难题。第一个难题是rtPA对中风超过4h的患者没有疗效。第二个难题是连续使用rtPA可引起脑、胸腔及腹腔出血。发明对中风超过4h尤其对中风24h患者有效又无出血副作用的药物是脑血管药物研究的热点与前沿。
发明人曾经公开下式Ⅰ的菠菜素衍生物在10nmol/kg口服剂量下具有抗血栓活性(彭师奇,赵明,史薇薇.氨基酸修饰的菠菜素衍生物及其制备方法和应用,CN 102807600A[P].2011.)。可是,在这个口服剂量下它们既不显示溶栓活性也不显示治疗缺血性中风作用。
发明人曾经公开下式Ⅱ的菠菜素衍生物在1nmol/kg剂量下静脉给药能降低缺血性脑卒中大鼠脑梗死体积的作用(彭师奇,赵明,王玉记,吴建辉,曹烨.环组氨酰-KAK,其合成,血栓相关活性及应用,CN 106317186 A[P].2017.)。可是,在这个静脉注射剂量下它对中风4h以上的病例没有疗效。
在进一步的结构修饰中,发明人发现在上式Ⅰ的菠菜素衍生物的氨基上引入茶氨酰基,用L-天冬酰胺残基和L-谷氨酰胺残基替代AA得到的化合物不仅对中风24h的大鼠仍然有效,而且无出血副作用。按照这个发现,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(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-AA(AA为L-天冬酰胺残基残基和L-谷氨酰胺残基)。
本发明的第二个内容是提供(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰
-AA(AA为L-天冬酰胺残基和L-谷氨酰胺残基)的合成方法,该方法包括:
(1)制备(6S)-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-羧酸;
(2)制备(6S)-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酸甲酯;
(3)制备(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酸甲酯;
(4)制备(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-羧酸;
(5)制备(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-AA-OBzl(AA为L-天冬酰胺残基、L-谷氨酰胺残基);
(6)制备(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-AA-OBzl(AA为L-天冬酰胺残基和L-谷氨酰胺残基);
(7)制备(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-AA(AA为L-天冬酰胺和L-谷氨酰胺残基)。
本发明的第三个内容是评价(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-AA(AA为L-天冬酰胺残基和L-谷氨酰胺残基)的抗血栓活性,溶血栓活性以及治疗缺血性中风的活性。
附图说明
图1(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-AA(AA为L-天冬酰胺残基(7a)和L-谷氨酰胺残基(7b))的合成路线。i)HCHO,H2O,浓H2SO4;ii)CH3OH,SOCl2;iii)无水DMF,Boc-The,HATU,NMM;iv)2N NaOH;v)AA-OBzl,DCC,HOBt,NMM;vi)氯化氢的乙酸乙酯溶液(4M);vii)H2/Pd。
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(6S)-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-羧酸(1)
将10.0g(64.5mmol)L-His与80mL蒸馏水的混合物超声振荡成混悬溶液。0℃与搅拌下向该混悬溶液中缓慢滴加2mL浓硫酸。之后,再加入20mL甲醛水溶液(40%)。反应混合物于60℃反应7h,然后冷却到室温。0℃与搅拌下反应混合物用浓氨水调节pH值至6,放置使产物充分析出。滤出析出的产物,干燥,得7.4g(69%)标题化合物,为无色固体。
实施例2制备(6S)-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酸甲酯(2)
0℃与搅拌下缓慢往120mL甲醇中滴入7.8mL二氯亚砜,活化30分钟,将5.09g(30.4mmol)(6S)-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-羧酸加入其中,室温搅拌72小时后,反应液减压浓缩,残留物用甲醇稀释,再减压浓缩。该操作重复三次。得7.4g(96%)标题化合物,为无色固体。
实施例3制备叔丁氧羰茶氨酸
将3.6g(20.7mmol)茶氨酸用30mL蒸馏水溶解,得到的水溶液用30mL二氧六环稀释,并加5.5g(25.2mmol)(Boc)2O,在0℃与搅拌下反应混合物用2N NaOH调节pH值为9,并用2N NaOH维持反应液pH值为9。室温搅拌96小时后,0℃与搅拌下缓慢滴加饱和KHSO4水溶液调节pH到中性,减压浓缩除去二氧六环。残留物用饱和硫酸氢钾水溶液调pH值为2,再用乙酸乙酯(40mL×3)萃取,合并的乙酸乙酯层用饱和氯化钠水溶液洗3次,用无水硫酸钠干燥12小时,过滤,滤液减压浓缩至干,得到4.8g(85%)标题化合物。
实施例4制备(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酸甲酯(3)
将3.1g(11.3mmol)叔丁氧羰茶氨酸和2.87g(11.3mmol)(6S)-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酸甲酯用无水N,N-二甲基甲酰胺(DMF)溶解,0℃与搅拌下加4.7g(12.4mmol)2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU),然后用N-甲基吗啉(NMM)调pH值为9。室温下搅拌8h,然后减压浓缩除去DMF。残留物用乙酸乙酯溶解,得到的溶液用饱和碳酸氢钠水溶液洗2次,再用饱和氯化钠水溶液洗2次,乙酸乙酯层溶液用无水硫酸钠干燥12小时,过滤,滤液减压浓缩至干,得到的黄色油状物经硅胶柱层析,得到3.6g(73%)标题化合物,为无色固体。ESI-MS(m/z):438[M+H]+。1H NMR(DMSO-d6,300MHz)δ/ppm=11.94(s,1H),7.79(t,J=6.0Hz,1H),7.53(d,J=6.0Hz,1H),7.07(m,1H),5.71(m,1H),4.81(m,1H),4.41(m,1H),3.58(d,J=6.0Hz,3H),3.40-2.84(m,4H),2.22-1.64(m,4H),1.35(d,J=6.0Hz,9H),1.01(m,3H)。
实施例5制备(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-羧酸(4)
将1.2g(2.7mmol)(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酸甲酯用甲醇溶解,0℃与搅拌下加入10mL NaOH甲醇溶液(2M),反应2h后缓慢滴加饱和KHSO4水溶液调节pH到中性,过滤除去析出的盐,滤液减压浓缩,残留物用20mL无水乙醇溶解,过滤除去不溶盐,滤液减压浓缩至干,得到1.12g(93%)标题化合物,为无色固体。ESI-MS(m/z):422[M-H]-。
实施例6制备(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-羧酸(4’)
0℃与搅拌下将0.48g(1.13mmol)(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-羧酸,用6mL氯化氢的乙酸乙酯溶液(4M)溶解,室温反应4h后将反应液减压浓缩,残留物再加入适量无水乙酸乙酯溶解,再抽干。该操作重复三次,得0.15g(33%)标题化合物,为无色粉末。ESI-MS(m/e):324[M+H]+。1H NMR(DMSO-d6,300MHz)δ/ppm=8.46(s,2H),7.84(m,1H),7.55(d,1H),5.10(d,J=15Hz,1H),4.21(m,1H),3.94(m,2H),3.06-2.69(m,4H),2.19-1.91(m,4H),0.97(m,3H)。
实施例7制备(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-L-天冬酰胺苄酯(5a)
将0.62g(1.47mmol)(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-羧酸用20mL无水四氢呋喃溶解,0℃与搅拌下往得到的溶液中依次加入0.24g(1.76mmol)N-羟基苯骈三氮唑(HOBt)和用无水四氢呋喃溶解的0.36g(1.76mmol)N,N-二环己基碳二亚胺(DCC)溶液,充分搅拌30分钟得溶液A;将20mL无水四氢呋喃溶解的0.43g(1.47mmol)HCl·Asn-OBzl加入到反应液A中,用N-甲基吗啉调节pH至9。室温搅拌8小时后减压浓缩,残留物用乙酸乙酯溶解,滤除不溶物。乙酸乙酯层依次用饱和碳酸氢钠水溶液洗3次、饱和氯化钠水溶液洗3次,用无水硫酸钠干燥12小时,过滤,得到的滤液减压浓缩,残留物经硅胶柱层析纯化,得到0.31g(39%)标题化合物,为无色粉末。ESI-MS(m/e):628[M+H]+。1HNMR(DMSO-d6,300MHz)δ/ppm=11.83(s,1H),8.21(m,1H),7.83(m,1H),7.46(m,2H),7.33(m,5H),6.97(m,2H),5.50(m,1H),5.04(m,2H),4.79(m,1H),4.63(m,1H),4.49(m,2H),3.21-2.55(m,6H),2.16(m,2H),1.77(m,2H),1.34(m,9H),1.00(m,3H)。
实施例8制备(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-L-谷氨酰胺苄酯(5b)
采用实施例7的方法从0.97g(2.31mmol)(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-羧酸和0.63g(2.31mmol)HCl·Gln-OBzl得到0.16g(11%)标题化合物,为无色粉末。ESI-MS(m/e):642[M+H]+。1H NMR(DMSO-d6,300MHz)δ/ppm=11.84(s,1H),8.35(m,1H),7.84(m,1H),7.48(m,1H),7.34(m,5H),7.21(m,1H),6.77(m,1H),5.50(m,1H),5.07(m,2H),4.76(m,1H),4.51(m,2H),4.22(m,1H),3.23-2.74(m,4H),2.18-1.63(m,8H),1.34(m,9H),0.98(m,3H)。
实施例9制备(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-L-天冬酰胺苄酯(6a)
0℃与搅拌下将0.21g(0.33mmol)(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-L-天冬酰胺苄酯用2mL氯化氢的乙酸乙酯溶液(4M)溶解,室温反应4h后将反应液减压浓缩,残留物再加入适量无水乙酸乙酯溶解,再抽干。该操作重复三次。得0.20g(93%)标题化合物,为无色粉末。ESI-MS(m/e):528[M+H]+。
实施例10制备(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-L-谷氨酰胺苄酯(6b)
采用实施例9的方法从0.15g(0.23mmol)(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-L-谷氨酰胺苄酯得0.14g(97%)标题化合物,为无色粉末。ESI-MS(m/e):542[M+H]+。
实施例11制备(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-L-天冬酰胺(7a)
将0.07g(0.11mmol)(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-L-天冬酰胺苄酯与加入10mg Pd/C混合,通入氢气并室温搅拌反应4h,之后滤除Pd/C,滤液减压浓缩至干得0.06g(95%)标题化合物,为无色固体。ESI-MS(m/e):438[M+H]+;mp:209-210℃;(c=0.1,CH3OH);IR(cm-1):2979,2928,1723,1649,1539,1440,1382,1345,1201,1146,992,943,877,803;1H NMR(DMSO-d6,300MHz)δ/ppm=14.65(s,1H),8.96(d,J=6Hz,1H),8.74(m,1H),8.47(m,2H),8.06(m,1H),7.48(s,1H),6.91(s,1H),5.51(m,1H),5.12(m,1H),4.61(m,1H),4.43(m,2H),3.39-3.01(m,4H),2.84(m,2H),2.35(m,2H),1.97(m,2H),1.01(m,3H)。
实施例12制备(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-L-谷氨酰胺(7b)
采用实施例11的方法从0.07g(0.11mmol)(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-L-谷氨酰胺苄酯,得0.05g(86%)标题化合物,为无色固体。ESI-MS(m/e):452[M+H]+;mp:187-188℃;(c=0.1,CH3OH);IR(cm-1):2979,2929,1728,1649,1540,1444,1383,1348,1288,1203,1146,987,940,880,798;1H NMR(DMSO-d6,300MHz)δ/ppm=14.66(s,1H),9.01(m,1H),8.71(m,1H),8.49(s,2H),8.07(m,1H),7.41(m,1H),6.84(m,1H),5.51(m,1H),5.12(m,1H),4.64(m,1H),4.18(m,2H),3.37-2.94(m,4H),2.41-1.81(m,8H),1.01(m,3H)。
实验例1评价7a和7b的抗血栓活性
将雄性SD大鼠(200±20g),随机分组,每组10只,饲养1天,停止喂食过夜。灌胃给予化合物4’(剂量1μmol/kg)或化合物7a,b的生理盐水溶液(剂量10nmol/kg)或阿司匹林的生理盐水溶液(剂量167μmol/kg)或生理盐水(剂量3mL/kg)。30min之后,大鼠用20%乌来糖的生理盐水(7mL/kg)溶液麻醉,之后手术。分离大鼠的右颈动脉和左颈静脉,将准确称重的丝线置于旁路插管,管的一端插入左静脉,另一端管插入右侧动脉并注射0.2mL肝素钠抗凝。使得血流从右侧动脉流经旁路插管进入左侧静脉,15min之后取出附有血栓的丝线称量,计算血液循环前后丝线的重量,得到的血栓重以均值±SD mg表示并代表抗血栓活性,作t检验。数据列入表1。结果表明口服10nmol/kg化合物7a,b不仅能有效地抑制血栓形成,而且活性与1μmol/kg化合物4’及167μmol/kg阿司匹林无显著差异,说明本发明的技术效果明显。
表1化合物7a,b的抗血栓活性
n=10,a)与生理盐水相比P<0.01,与化合物4’及阿司匹林相比P>0.05.
实验例2评价化合物7a,b的溶血栓活性
SD大鼠(雄性,200±20g)使用20%乌来糖的生理盐水(7mL/kg)腹腔注射进行麻醉。麻醉大鼠后将其仰卧位固定,分离其右颈总动脉,近心端处夹住动脉夹,将近心端及远心端分别穿入手术线,远心端的手术线结扎,远心端插管,将动脉夹松开,取出1mL动脉血,置于1mL离心管中。往垂直固定的橡胶管(长5mm,内径2.5mm,外径5.0mm,管底用胶塞密封,para膜封紧)内注入0.1mL大鼠动脉血,随后在管内迅速插入一支不锈钢材质的血栓的固定螺栓(血栓固定螺旋用直径为0.2mm的不锈钢丝绕成,螺旋部分长10mm,内含15个螺圈,螺圈的直径为1.0mm,托柄与螺旋相连,长约7.0mm,呈问号型)。
旁路插管由三部分构成,中间段为长60.0mm,内径3.5mm的聚乙烯胶管;两端均为长100.0mm,内径1.0mm,外径2.0mm的相同的聚乙烯管,该管一端拉成尖管,长约10.0mm(用于插入大鼠颈动脉及静脉),外径为1.0mm,其另一端的外部套一段长为7.0mm,外径为3.5mm的聚乙烯管(用于插入中段的聚乙烯胶管内),3段管的内壁均需要硅烷化(1%的硅油乙醚溶液)。将血栓包裹的血栓固定螺旋置于中段聚乙烯胶管内,胶管的另外两端分别与两根聚乙烯的加粗端相套,保证在循环的过程中不会漏血。用注射器通过尖管端将管中注满肝素生理盐水溶液(50IU/kg),排除气泡,备用。
分离大鼠的左颈外静脉,近心端和远心端分别穿入手术线,结扎远心端的血管,在暴露的左颈外静脉上剪一小口,将上述制备好的旁路管道尖管由小口插入左颈外静脉开口处,同时远离旁路管中段(含精确称量的血栓固定螺旋)内血栓固定螺旋。用注射器通过另一端的尖管注入准确量的肝素钠的生理盐水溶液(50IU/kg),此时注射器不要撤离聚乙烯管,用动脉夹夹住注射器与聚乙烯管之间的软管。在右颈总动脉的近心端用动脉夹止血,结扎远心端,在离动脉夹不远处将右颈总动脉剪一小口,从聚乙烯管的尖部拔出注射器,将聚乙烯管的尖部插入动脉斜口的近心端。旁路管道的两端均用4号手术缝线将动静脉固定。
用头皮针将生理盐水(3mL/kg)或尿激酶的生理盐水溶液(剂量为20000IU/kg)或化合物4’(剂量为1000nmol/kg)或化合物7a,b的生理盐水溶液(剂量为10nmol/kg)通过旁路管的中段(含精确称量的血栓固定螺旋),扎入远离血栓固定螺旋的近静脉端,松开动脉夹,使血流通过旁路管道从动脉流向静脉。将注射器中的溶液缓慢注入血液,通过血液循环,按静脉-心脏-动脉的顺序作用于螺旋的血栓上。血液循环1h之后,从旁路管道中取出固定血栓的螺旋,精确称量。计算每只大鼠旁路管道中固定血栓的螺旋血液循环前后血栓的重量差,即血栓减重。对数据(均值±SD mg)作t检验。血栓减重代表溶血栓活性。表2的结果表明,10nmol/kg化合物7a,b不仅能有效地溶解血栓,而且活性与1000nmol/kg化合物4’及20000IU/kg尿激酶无显著差异,说明本发明技术效果明显。
表2化合物7a,b的溶血栓活性
n=10,a)与生理盐水比P<0.05,与化合物4’及尿激酶比P>0.05.
实验例3评价化合物7a,b对缺血性中风24h大鼠的治疗作用
在雄性SD大鼠(体重300±20g)的颈部正中部竖直开约2cm长切口,沿胸锁乳突肌内侧缘分离出右颈总动脉、颈外动脉及颈内动脉。用无创动脉夹分别夹闭颈内动脉开口处和颈总动脉近心端,结扎颈外动脉的远心端,在颈外动脉剪一小口,松开颈总动脉近心端的动脉夹,取10μL血,之后再用无创动脉夹夹闭颈总动脉的近心端。将取得的10μL血放置在1mLEP管中常温放置15分钟使血液凝固,然后转移至-20℃冰箱中放置过夜,使血液凝块结实。大鼠用10%水合氯醛(4mL/kg)腹腔注射麻醉。取出血液凝块,加入1mL生理盐水,用钢铲把血液凝块捣成大小均一的细小血栓块,制备细小血栓的悬液并转移至1mL注射器内。松开颈总动脉近心端的动脉夹,将1mL血栓混悬液缓慢从大鼠颈外动脉向近心端经过颈内动脉注入大鼠的大脑,然后结扎颈外动脉近心端,打开颈内动脉和颈总动脉处得动脉夹,恢复血流。伤口处滴加3滴青霉素(40mg/10mL)的生理盐水溶液,缝合伤口,等待苏醒。大鼠苏醒24小时后按Zealonga方法评定神经功能缺损程度。0分表示无任何神经功能缺失体征、1分表示未损伤侧前肢不能伸展、2分表示向未损伤侧行走、3分表示向未损伤侧转圈成追尾状行走、4分表示意识障碍无自主行走、5分表示死亡。按照得分随机分组。大鼠每天1次经尾静脉注射给予化合物7a,b的生理盐水溶液(剂量10nmol/kg)或生理盐水(剂量3mL/kg),剂量为3mL/kg;连续注射3天,每天评分。根据评分计算出各组的死亡率、显效率以及治愈率(死亡率=(死亡数/总数)×100%;显效率=(最后一天评分低于给药前评分的只数/总数)×100%;治愈率=(最后一天评分为0的只数/总数)×100%)。实验结果列为表3。表3的数据表明,经化合物7a,b治疗的中风大鼠死亡率低于生理盐水,治愈率高于生理盐水,说明本发明技术效果明显。
表3中风24小时大鼠静脉注射7a,b每天1次共治疗3天的神经生物学评分
从上面的数据可以看出,本发明的化合物同时具备抗栓活性,溶栓活性及治疗24h缺血性中风的活性,即一次性口服10nmol/kg化合物7a,b可有效地抑制血栓形成,一次性注射10nmol/kg化合物7a,b可有效地溶解血栓,连续3天每天一次静脉给予10nmol/kg化合物7a,b可有效地恢复缺血性中风24小时大鼠的神经生物学行为,可有效地降低缺血性中风大鼠的死亡率,增加其存活率,不存在出血副作用。与曾经公开的化合物相比,本发明的化合物有突出的技术效果。
Claims (5)
2.制备权利要求所述1的茶氨酰四氢-3H-咪唑并吡啶-6-甲酰AA的方法,该方法包括以下七个步骤:
(1)制备(6S)-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-羧酸;
(2)制备(6S)-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酸甲酯;
(3)制备(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酸甲酯;
(4)制备(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-羧酸;
(5)制备(6S)-5-叔丁氧羰茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-AA-OBzl;
(6)制备(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-AA-OBzl;
(7)制备(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-AA。
3.权利要求1所述的茶氨酰四氢-3H-咪唑并吡啶-6-甲酰AA在制备抗血栓药物中的应用。
4.权利要求1所述的茶氨酰四氢-3H-咪唑并吡啶-6-甲酰AA在制备溶血栓药物中的应用。
5.权利要求1所述的茶氨酰四氢-3H-咪唑并吡啶-6-甲酰AA在制备治疗缺血性中风药物中的应用。
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