CN106317194B - 环组氨酰-karpak,其合成,血栓相关活性及应用 - Google Patents
环组氨酰-karpak,其合成,血栓相关活性及应用 Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明公开了下式环组氨酰‑KARPAK(6s)‑4,5,6,7‑四氢‑3H‑咪唑[4,5‑c]并吡啶‑6‑甲酰‑Lys‑Ala‑Arg‑Pro‑Ala‑Lys,公开了它的制备方法,公开了它治疗中风大鼠的作用,因而本发明公开了它在制备缺治疗血性中风药物中的应用。
Description
技术领域
本发明涉及下式(6s)-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-Lys-Ala-Arg- Pro-Ala-Lys,涉及它的制备方法,涉及它治疗缺血性中风的作用,因而本发明涉及它在制备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
缺血性中风是一类较常见且危害严重的脑血管疾病,特点是发病率高、病死率高、致残率高和复发率高。目前临床治疗缺血性中风面临没有有效药物的现实,尤其中风面4h以上的患者非死即残。发明对中风面4h以上的患者有效的药物是临床的重要需求。发明人曾经公开式II的咪唑啉化合物在中风面24h的大鼠缺血性中风模型上,显示优秀疗效。即连续静脉注射6天式II的咪唑啉化合物,每天1次,首次剂量为5 μmol/kg,后5次的剂量为2μmol/kg具有优秀疗效。式中aa1和aa2可为同时存在,aa1存在但aa2不存在,或同时不存在;当aa1和aa2同时存在时,aa1为R(Arg),且aa2为G (Gly),A(Ala)或Q(Gin);当aa1存在但aa2不存在时,aa1为R(Arg);aa3可为S(Ser),V (Val)或F(Phe)。由于式II的取代咪唑啉结构单元比较复杂需要简化。
发明人在经过3年实验研究,发现用4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰基代替式II的取代咪唑啉结构单元可以获得结构简单和疗效好意想不到的双重技术效果。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(6s)-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰 -Lys-Ala-Arg-Pro-Ala-Lys。
本发明的第二个内容是提供上式(6s)-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰 -Lys-Ala-Arg-Pro-Ala-Lys的合成方法,该方法包括:
(1)在二环己基碳二亚胺(DCC)存在下Boc-Pro在无水THF中与和N-羟基琥珀酰亚胺 (HOSu)缩合为Boc-Pro-OSu,在NaHCO3存在下Boc-Pro-OSu与Ala反应生成 Boc-Pro-Ala;
(2)在DCC和HOBt存在下Boc-Pro-Ala在无水THF中与Lys(Z)-OBzl缩合为Boc-Pro-Ala-Lys(Z)-OBzl;
(3)在氯化氢-乙酸乙酯溶液中Boc-Pro-Ala-Lys(Z)-OBzl脱去Boc保护基生成Pro-Ala-Lys(Z)-OBzl;
(4)在DCC和HOBt存在下Boc-Arg(NO2)在无水THF中与Pro-Ala-Lys(Z)-OBzl缩合为Boc-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl;
(5)在氯化氢-乙酸乙酯溶液中Boc-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl脱去Boc保护基生成Arg(NO2)-Pro-Ala-Lys(Z)-OBzl;
(6)在DCC和HOBt存在下Boc-Ala在无水THF中与Arg(NO2)-Pro-Ala-Lys(Z)-OBzl缩合为Boc-Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl.
(7)在氯化氢-乙酸乙酯溶液中Boc-Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl脱去Boc保护基生成Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl;
(8)在稀硫酸存在下,甲醛与L-组氨酸在60℃下反应,生成(6s)-4,5,6,7-四氢-3H-咪唑 [4,5-c]并吡啶-6-羧酸;
(9)在DCC和HOBt存在下(6s)-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-羧酸在无水四氢呋喃中与Lys(Boc)-OBzl缩合为(6s)-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑并 [4,5-c]吡啶-6-甲酰-L-Lys(Boc)-OBzl。
(10)在Pd/C存在下(6s)-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酰-L-Lys(Boc)-OBzl在甲醇溶液中脱去OBzl生成(6s)-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酰-L-Lys(Boc);
(11)在DCC和HOBt存在下(6s)-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酰-L-Lys(Boc)在无水四氢呋喃中与HCl·Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl缩合为 (6s)-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酰-L-Lys(Boc)-Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl。
(12)将步骤(11)所制备的化合物脱去保护基,得到上式所示的化合物。
其中所述HOBt是N-羟基苯并三氮唑的缩略术语,DCC是二环己基羰二亚胺的缩略术语,Boc为叔丁氧羰基的缩略术语,Pd/C为钯/碳。
本发明的第三个内容是评价上式(6s)-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰 -Lys-Ala-Arg-Pro-Ala-Lys治疗缺血性中风的活性。
附图说明
图1(6s)-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-Lys-Ala-Arg-Pro-Ala-Lys的合成路线.(i)H2SO4,HCHO,60℃;(ii)1N NaOH,(Boc)2O;(iii)DCC,HOBt,NMM;(iv)H2,Pd/C;(v)HOSu,DCC;(vi)TFA/TFSA;(vii)4N氯化氢-乙酸乙酯溶液。
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-咪唑并[4,5-c]吡啶-6-羧酸(1)
将10g(64.5mmol)L-His用80mL蒸馏水和20mL甲醛混合溶液溶解,然后往里滴加1mL浓H2SO4,60℃微波反应5小时,冷却到室温,往反应化合物中冰浴下滴加浓氨水调pH至7,有大量沉淀析出。过滤,得10.5g(97%)标题化合物,为无色固体。ESI-MS(m/z)167[M+H]+。
实施例2制备(6s)-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-羧酸(2)
冰浴下将1.67g(10mmol)(6s)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-羧酸溶于5ml 2N氢氧化钠水溶液。往该反应液中加5.23g(24mmol)(Boc)2O与10mL二氧六环的溶液。室温搅拌,TLC(CH2Cl2∶MeOH=15∶1)监控反应原料点消失。反应完成后,过滤,滤液减压浓缩除去二氧六环。残留的水层用饱和KHSO4水溶液酸化至pH值至 2,用乙酸乙酯萃取三次,合并乙酸乙酯层,并用少量水反洗,乙酸乙酯层用无水Na2SO4干燥,过滤,减压浓缩得到的淡黄色固体用乙酸乙酯浸泡磨洗,过滤,得1.55g(42%) 标题化合物,为无色固体。ESI-MS(m/z)367[M+H]+。
实施例3制备(6s)-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-Lys(Boc)-OBzl(3)
冰浴和搅拌下3.67g(10.0mmol)(6s)-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑并[4,5-c] 吡啶-6-羧酸,1.48g(11.0mmol)HOBt和2.47g(12.0mmol)DCC加50ml无水THF 溶解,反应液活化30分钟。然后将3.91g(10.5mmol)Tos·Lys(Boc)-OBzl与50mL 无水THF并用1.0mLNMM调节pH至9的悬浮液滴加到活化的反应液中。撤去冰浴,室温搅拌12小时,滤除二环己基脲(DCU)。滤液减压浓缩至干,残留物用乙酸乙酯溶解,再滤除DCU。滤液层依次用饱和NaHCO3溶液洗3次,饱和NaCl溶液洗3 次,饱和KHSO4溶液洗3次,饱和NaCl溶液洗3次,饱和NaHCO3溶液洗3次,饱和NaCl溶液洗3次,乙酸乙酯层用无水Na2SO4干燥,过滤、滤液减压浓缩,残留物经柱层析(石油醚/丙酮体系8∶1-2∶1)纯化得3.97g(58%)标题化合物,为无色固体,ESI-MS(m/z)686[M+H]+。
实施例4制备(6s)-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-L-Lys(Boc) (4)
称取200mg(0.29mmol)(6s)-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6- 甲酰-L-Lys(Boc)-OBzl于50mL茄形瓶中,用10mL甲醇溶解后,加入20mg Pd/C,先用真空水泵抽走反应瓶中的空气,然后通入氢气,如此反复三次,最后保持通氢气状态反应12小时,利用TLC(石油醚∶丙酮=3∶1)监测至原料斑点消失后,减压过滤,将滤液减压浓缩至干得160mg(92%)标题化合物,为无色固体,ESI/MS(m/e):596 [M+H]+。
实施例5制备HCl·Pro-Ala-Lys(Z)-OBzl
5-1)制备Boc-Pro-Ala
冰浴下向1.075g(5.0mmol)Boc-Pro和20mL无水THF的溶液中加0.637g(5 mmol)N-羟基琥珀酰亚胺(HOSu),并使完全溶解。往该溶液中加少量无水THF与1.236 g(6.0mmol)二环己基羰二亚胺(DCC)的溶液。室温搅拌7小时,TLC(二氯甲烷∶甲醇=10∶1)监测Boc-Pro消失。滤除DCU,滤液减压浓缩除去THF。残留物先用乙酸乙酯溶解,然后依次用饱和NaHCO3水溶及饱和NaCl水溶液洗。乙酸乙酯层减压浓缩至干,残留物加入适量THF溶解。往该溶液中加已溶于少量水的0.489g(5.5mmol)Ala 溶液。得到的反应液用NaHCO3固体调pH到9,室温反应12小时,减压浓缩除去THF,残留物加5mL水溶解,用饱和KHSO4水溶液调pH到2,用乙酸乙酯少量多次萃取,合并的乙酸乙酯层用饱和NaCl水溶液洗至中性,用无水硫酸钠干燥。过滤,滤液减压浓缩得1.41g(98%)标题化合物,为无色固体。ESI-MS(m/e):285[M-H]-。
5-2)制备Boc-Pro-Ala-Lys(Z)-OBzl
采用实施例3的方法从1.43g(5.0mmol)Boc-Pro-Ala和2.71g(5.0mmol) Lys(Z)-OBzl得3.09g(97%)标题化合物,为米黄色固体。ESI-MS(m/e):639[M+H]+。
5-3)制备HCl·Pro-Ala-Lys(Z)-OBzl
将0.638g(1mmol)Boc-Pro-Ala-Lys(Z)-OBzl溶于10mL乙酸乙酯。冰浴下向得到的溶液中加15mL浓度为4N的氯化氢-乙酸乙酯溶液,TLC(二氯甲烷∶甲醇=1∶1) 显示Boc-Pro-Ala-Lys(Z)-OBzl消失。反应混合液在室温下减压浓缩,残留物再用乙酸乙酯溶解并室温减压浓缩,如此反复3次,除净游离氯化氢。残留物用无水乙醚析晶,得0.516g(90%)标题化合物,直接用于下步反应。ESI-MS(m/e):539[M+H]+。
实施例6制备HCl·Arg(NO2)-Pro-Ala-Lys(Z)-OBzl
采用实施例3的方法从798mg(2.5mmol)Boc-Arg(NO2)和1.322g(2.3mmol) HCl·Pro-Ala-Lys(Z)-OBzl得1.642g(78%)Boc-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl,为无色固体。ESI-MS(m/z)864[M+Na]+。
采用实施例5-3的方法从2.099g(2.5mmol)Boc-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl得 1.9g(98%)标题化合物,为无色固体。直接用于下步反应。ESI-MS(m/z)742[M+H]+。
实施例7制备Boc-Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl
采用实施例3的方法从817mg(4.32mmol)Boc-Ala和3.36g(4.32mmol) HCl·Arg(NO2)-Pro-Ala-Lys(Z)-OBzl得3.27g(83%)标题化合物,为无色固体。 ESI-MS(m/e)911[M+H]+。
实施例8制备HCl·Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl
采用实施例5-3的方法从2.241g(2.46mmol)Boc-Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl得2.04g(98%)标题化合物,为无色固体。直接用于下步反应。 ESI-MS(m/e)811[M+H]+。
实施例9制备3,5-二-Boc-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-酰基 -Lys(Boc)-Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl(5)
采用实施例3的方法从1.46g(2.46mmol)(6s)-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑 [4,5-c]并吡啶-6-甲酰-L-Lys(Boc)和2.083g(2.46mmol)HCl·Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl得1.02g(30%)标题化合物,为无色固体产物。ESI-MS(m/e):1388[M+H]+;1H-NMR(300MHz,DMSO-d6):δ/ppm=8.18(m,1H),8.07(s,1H),8.01-7.95(m,4H), 7.35-7.20(m,9H),5.10(s,2H),5.00(s,2H),4.79(m,1H),4.45-4.18(m,6H),3.59-3.51 (m,2H),3.15(s,2H),2.98-2.92(m,3H),2.86-2.84(m,2H),1.99-1.81(m,3H),1.72-1.62 (m,3H),1.57(s,9H),1.44(s,9H),1.36(s,9H),1.30-1.10(m,11H).
实施例10制备4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-酰基-Lys-Ala-Arg-Pro-Ala- Lys(6)
冰浴下向60mg(0.043mmol)3,5-二-Boc-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-酰基 -Lys(Boc)-Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl中加3mL TFA和1mL TFMSA,搅拌30 min后TLC(CH2Cl2∶MeOH=1∶1)显示原料点消失,停止反应。反应物用无水乙醚反复洗涤,减压浓缩至干,残留物用水溶解,用氨水调pH值至8。得到的溶液先用Sephadex G10除盐,然后用制备柱T3Prep OBDTM 5μm 30×150mm纯化。相应的馏分冻干得9mg(25%)标题化合物,为无色固体。ESI-MS(m/e):820[M+H]+;1H-NMR(500 MHz,DMSO-d6):(δ/ppm=8.654(s,1H),8.576(s,1H),8.153(m,1H),8.042(m,1H), 8.007(m,1H),7.962(m,1H),7.771(m,3H),7.703(m,2H),7.644(m,1H),4.430(m,1H), 4.348-4.331(m,2H),4.325-4.235(m,5H),4.128(m,1H),3.602(m,1H),3.504(m,1H), 3.313(m,1H),3.090-3.052(m,2H),2.800-2.720(m,5H),1.999(m,1H),1.865-1.821(m, 3H),1.720-1.683(m,3H),1.583-1.484(m,9H),1.374-1.301(m,4H),1.204-1.176(m, 6H)。
实验例1评价化合物6对缺血性中风大鼠的治疗作用
评价方法
SD雄性大鼠(280-300g)用10%水合氯醛(400mg/kg)腹腔注射麻醉,从颈部正中略偏右部竖直开约2cm长切口,沿胸锁乳突肌内侧缘分离出右颈总动脉、颈外动脉和颈内动脉。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,在颈外动脉剪一小口,结扎颈外动脉远心端,松开颈总动脉近心端的动脉夹,取10μL血,取血之后再用无创动脉夹夹闭颈总动脉近心端。将取得的10μL血装入1mLEP管中,先在常温下放置30分钟使血液凝固,然后转移至-20℃冰箱中放置1小时,使血液凝块结实。 1小时后取出血液凝块,加入1mL生理盐水用钢铲把血液凝块捣成大小比较均一的细小血栓,然后把细小血栓混悬液转移至1mL注射器内备用。松开大鼠颈内动脉夹的同时,将上述1mL注射器内的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。然后分离大鼠颈总静脉,注入治疗药物,结扎静脉,伤口处滴加3滴青霉素(40mg/10mL),缝合伤口,等待动物苏醒。供试化合物的剂量为1nmol/kg(溶于生理盐水)。大鼠苏醒24小时后按Zealonga方法(Wen Wang,Jingdong Xu,Lei Li,Peichang Wang,Xunming Ji,Houxi Ai,Li Zhang,Lin Li, Neuroprotective effect ofmorroniside on focal cerebral ischemia in rats.Brain Research Bu lletin,2010,83,196-201)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。将以上各组评分结果进行统计学比较,并作t检验。
大鼠苏醒24小时Zealonga方法评定神经功能缺损程度后,用乌拉坦麻醉后迅速断头取脑,将脑组织置于-20℃冰箱2小时后,从前额极开始行约2mm冠状连续切片,共6片,然后置于2%TTC溶液中37℃避光孵育30min,并观察脑切片的颜色变化,正常组织被TTC染成红色,而缺血组织呈白色。然后用数码相机照相,经SPSS 统计软件处理,计算冠状切片中梗死体积和正常组织的面积,统计各组的梗死体积百分比值,并做t检验。
大鼠苏醒后24小时,按Zealonga方法评定神经功能缺损程度,评分结果列入表 1,大鼠脑梗死体积百分比如下表2。结果表明1nmol/kg化合物6能有效地保护中风大鼠的脑神经。因为不像已经公开的化合物需要5μmol/kg剂量,化合物6的剂量为1 nmol/kg。这样一来,1次剂量降低了5000倍。获得了意想不到的技术效果。
表1 1nmol/kg化合物6治疗大鼠苏醒24h后评分
n=10;a:与生理盐水比较p<0.01。
表2 1nmol/kg化合物6治疗大鼠大脑梗死体积百分比
n=10;a:与生理盐水组比,p<0.01,与t-PA比,p>0.05。
Claims (3)
1.下式4,5,6,7-四氢-3H-咪唑并吡啶-6-甲酰-Lys-Ala-Arg-Pro-Ala-Lys,
2.权利要求1的4,5,6,7-四氢-3H-咪唑并吡啶-6-甲酰-Lys-Ala-Arg-Pro-Ala-Lys的制备方法,该方法包括:
(1)在稀硫酸存在下,甲醛与L-组氨酸在60℃下反应,生成6s-4,5,6,7-四氢-3H-咪唑并吡啶-6-羧酸;
(2)在DCC和HOBt存在下6s-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑并吡啶-6-羧酸在无水四氢呋喃中与Lys(Boc)-OBzl缩合为6s-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑并吡啶-6-甲酰-Lys(Boc)-OBzl;
(3)在Pd/C存在下6s-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑并吡啶-6-甲酰-Lys(Boc)-OBzl在甲醇溶液中脱去OBzl生成6s-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑并吡啶-6-甲酰-Lys(Boc);
(4)在二环己基碳二亚胺存在下Boc-Pro在无水THF中与和N-羟基琥珀酰亚胺缩合为Boc-Pro-OSu,在NaHCO3存在下Boc-Pro-OSu与Ala反应生成Boc-Pro-Ala;
(5)在DCC和HOBt存在下Boc-Pro-Ala在无水THF中与Lys(Z)-OBzl缩合为Boc-Pro-Ala-Lys(Z)-OBzl;
(6)在氯化氢-乙酸乙酯溶液中Boc-Pro-Ala-Lys(Z)-OBzl脱去Boc保护基生成Pro-Ala-Lys(Z)-OBzl;
(7)在DCC和HOBt存在下Boc-Arg(NO2)在无水THF中与Pro-Ala-Lys(Z)-OBzl缩合为Boc-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl;
(8)在氯化氢-乙酸乙酯溶液中Boc-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl脱去Boc保护基生成Arg(NO2)-Pro-Ala-Lys(Z)-OBzl;
(9)在DCC和HOBt存在下Boc-Ala在无水THF中与Arg(NO2)-Pro-Ala-Lys(Z)-OBzl缩合为Boc-Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl;
(10)在氯化氢-乙酸乙酯溶液中Boc-Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl 脱去Boc保护基生成Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl ;
(11)在DCC和HOBt存在下6s-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑并吡啶-6-甲酰-Lys(Boc)在无水四氢呋喃中与Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl 缩合为6s-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑并吡啶-6-甲酰-Lys(Boc)-Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl ;
(12)将6s-3,5-二-Boc-4,5,6,7-四氢-3H-咪唑并吡啶-6-甲酰-Lys(Boc)-Ala-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl 脱去保护基,得到4,5,6,7-四氢-3H-咪唑并吡啶-6-甲酰-Lys-Ala-Arg-Pro-Ala-Lys。
3.权利要求1的4,5,6,7-四氢-3H-咪唑并吡啶-6-甲酰-Lys-Ala-Arg-Pro-Ala-Lys在制备治疗缺血性中风药物中的应用。
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CN102796167A (zh) * | 2011-05-26 | 2012-11-28 | 首都医科大学 | (S)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酰-L-脯氨酰-L-丙氨酰-L-氨基酸及其制备方法和应用 |
CN102887941A (zh) * | 2012-09-05 | 2013-01-23 | 永光制药有限公司 | Pak/咪唑啉/rgd三元缀合物及其制备方法和用途 |
CN103665107A (zh) * | 2012-09-05 | 2014-03-26 | 永光制药有限公司 | 同时具溶血栓、清除自由基和血栓靶向功能的新颖化合物及其制备方法和用途 |
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CN102887941A (zh) * | 2012-09-05 | 2013-01-23 | 永光制药有限公司 | Pak/咪唑啉/rgd三元缀合物及其制备方法和用途 |
CN103665107A (zh) * | 2012-09-05 | 2014-03-26 | 永光制药有限公司 | 同时具溶血栓、清除自由基和血栓靶向功能的新颖化合物及其制备方法和用途 |
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