CN112898378A - 二氧六环修饰的四氢咔啉-3-甲酰-The-HGE、其制备、抗血栓活性和应用 - Google Patents
二氧六环修饰的四氢咔啉-3-甲酰-The-HGE、其制备、抗血栓活性和应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu化合物,涉及它的制备方法,涉及它的动脉血栓活性。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
动脉栓塞已成为目前发病率高和死亡率高的疾病之一。动脉血栓形成对暂时性脑缺血发作,急性冠状动脉综合症,心肌梗塞和心房颤动负责。在房颤中有18%-47%病人患有冠状动脉疾病,在伴随冠状动脉疾病的房颤患者中有大约20%接受经皮冠状动脉介入治疗。动脉血栓形成还对人工心脏瓣膜,动静脉瘘和其他手术后的动脉血栓及不稳定型心绞痛负责。例如肝移植手术之后,患者面临肝脏动脉血栓风险。此外,抗磷脂综合症患者也面临动脉血栓风险。虽然肿瘤与静脉血栓的关联比与动脉血栓的关联广泛,但是对特殊恶性肿瘤及肿瘤治疗中动脉血栓包括外周动脉血栓发病的认识正在日益加深。动脉插管及缺血性中风则使得儿童动脉血栓病例日益增加。十多年前就开始警惕***滥用导致的动脉血栓风险。因为病因不同,所以在传统观念下静脉血栓和动脉血栓被看作两种不同的疾病。最近的流行病学研究表明,静脉血栓和动脉血栓之间的关联性难以割断。这种状况可以归结于它们的风险因子相互重叠。这样一来,动脉血栓的预防和治疗便越来越受到重视。
直接口服抗凝是动脉血栓临床治疗的唯一策略。尽管口服抗凝剂对动脉血栓的疗效确切,但是都有出血副作用。例如在有效的口服剂量下,阿司匹林可诱发消化道出血或颅内出血。这种风险大幅度限制了患者的受益面。临床需要疗效可与阿司匹林媲美,又没有阿司匹林样消化道出血或颅内出血风险的药物。针对这个临床需求,国内外研究人员付出了大量心血。可是,一直取得没有实质性进展。
寻找安全有效的抗栓剂是发明人新药物研究的重要兴趣。在过去的3年里发明人发现下式的3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu是安全有效的抗栓剂。根据这个发现,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3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu。
本发明的第二个内容是提供3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu的制备方法,该方法包括:
1)合成(3S)-1,1-二羟甲基-四氢-β-咔啉-3-羧酸苄酯;
2)合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯;
3)合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸;
4)采用二环己基碳二亚胺(DCC)为缩合剂,1-羟基苯并***(HOBt)为催化剂的液相缩合的方法,合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-OBzl;
5)合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The;
6)采用DCC为缩合剂,HOBt为催化剂的液相缩合的方法,合成HCl·His-Gly-Glu(OBzl)-OBzl;
7)采用DCC为缩合剂,HOBt为催化剂的液相缩合的方法,合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu(OBzl)-OBzl;
8)合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu;
本发明的第三个内容是评价3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu的抗动脉血栓活性。
附图说明
图1.3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-EDG的合成路线:i)三氟乙酸,1,3-二羟基丙酮;ii)浓硫酸,丙酮;iii)钯碳(Pd),H2;iv)二环己基碳二亚胺(DCC),1-羟基苯并***(HOBt),N-甲基吗啉(NMM);v)氯化氢的乙酸乙酯溶液(4M)。
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)-1,1-二羟甲基-四氢-β-咔啉-3-羧酸苄酯(1)
往10mL二氯甲烷中加入2g(7.2mmol)L-色氨酸苄酯,充分搅拌使其溶解。冰浴条件下,往溶液中缓慢滴加1mL三氟醋酸。然后再往该溶液中加0.78g(8.6mmol)1,3-二羟基丙酮,室温反应7小时。TLC显示L-色氨酸苄酯消失(二氯甲烷/甲醇:30:1)。冰浴条件下,往溶液中加入50mL饱和NaHCO3溶液,充分搅拌,然后留下二氯甲烷层,再用饱和NaHCO3溶液(30mL×3)洗,再用饱和NaCl溶液(30mL×3)洗,二氯甲烷层用无水硫酸钠干燥12小时。过滤,滤液减压浓缩得到2.03g(77%)标题化合物,为黄色粉末。ESI-MS(m/e):367[M+H]+。
实施例2制备3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(2)
往5mL无水丙酮中加入0.2g(0.55mmol)(3S)-1,1-二羟甲基-四氢-β-咔啉-3-羧酸苄酯(1)。在冰浴条件下,往里加入100μL浓硫酸,之后,室温搅拌3小时。TLC显示化合物1消失(石油醚/乙酸乙酯,4:1)。冰浴条件下,用饱和NaHCO3溶液调节反应液pH值为7,得到的溶液减压浓缩除去丙酮,残留液再加乙酸乙酯萃洗3遍,乙酸乙酯层用饱和NaCl溶液洗至中性。乙酸乙酯层用无水硫酸钠干燥12小时。过滤,滤液减压浓缩得到的棕黄色固体,经柱层层析分离(石油醚/乙酸乙酯,4:1)得到0.08g(35.8%)标题化合物,为白色国体。ESI-MS(m/e):407[M+H]+。
实施例3制备3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸(3)
往10mL甲醇中加入0.20g(0.5mmol)3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(2)和0.02g Pd/C。搅拌并通12h氢气,TLC显示化合物2消失(石油醚/乙酸乙酯,4:1)。过滤除去钯碳(Pd/C),滤液减压浓缩。残留物用***磨洗,得到0.14g(90%)标题化合物,为无色固体。ESI-MS(m/e):317[M+H]+。
实施例4制备3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-OBzl(4)
往20mL四氢呋喃中加入0.19g(0.6mmol)3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸(3),0.15g(0.72mmol)N,N'-二环己基碳二亚胺(DCC)和0.09g(0.72mmol)1-羟基苯并***(HOBt)。冰浴下搅拌30分钟。之后,再向反应液中加入0.20g(0.66mmol)HCl·The-OBzl。之后,向反应液中滴加N-甲基吗啉(NMM)调节反应液的pH值为9。室温搅拌6小时,TLC显示化合物3消失(二氯甲烷/甲醇,30/1)。滤除二环己基脲(DCU),滤液减压浓缩,得到的残留物用30mL乙酸乙酯溶解,溶液再过滤除去DCU。滤液依次用5%NaHCO3水溶液萃洗(15mL×3),饱和NaCl水溶液洗(15mL×3),5%KHSO4水溶液洗(15mL×3),饱和NaCl水溶液洗(15mL×3),5%NaHCO3水溶液洗(15mL×3),饱和NaCl水溶液洗(15mL×3),用无水硫酸钠干燥12小时。过滤,滤液减压浓缩,得到的黄色粉末经硅胶柱层析纯化(石油醚/乙酸乙酯,10/1),得到0.27g(80%)标题化合物,为无色粉末。ESI-MS(m/e):563[M+H]+;1H-NMR(300MHz,DMSO-d6):δ/ppm=10.94(s,1H),8.28(t,J=7.2Hz,1H),7.79(s,1H),7.37(m,6H),7.07(m,1H),7.02(m,1H),5.16(s,1H),5.12(s,1H),4.40(m,1H),4.21(m,1H),3.99(m,1H),3.75(m,1H),3.61(m,2H),3.02(m,2H),2.12(m,2H),1.82(m,2H),1.65(s,3H),1.42(s,3H),1.22(m,2H),1.01(m,3H)。
实施例5制备3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The(5)
往10mL甲醇中加入0.28g(0.5mmol)3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-OBzl(4)和0.02g钯碳(Pd/C)。搅拌并通12h氢气,TLC显示化合物4消失(二氯甲烷/甲醇,30/1)。过滤除去Pd/C,滤液减压浓缩。残留物用***磨洗,得到0.21g(90%)标题化合物,为黄色固体。ESI-MS(m/e):473[M+H]+,1H-NMR(300MHz,DMSO-d6):δ/ppm=10.98(s,1H),8.18(d,J=7.5Hz,1H),7.79(s,1H),7.40(dt,J1=4.8Hz,J2=8.1Hz,2H),7.02(td,J1=8.1Hz,J2=4.8Hz,2H),4.40(m,1H),4.28(m,1H),4.12(m,1H),4.02(m,1H),3.81(m,1H),3.61(m,1H),3.02(m,2H),2.14(m,2H),1.82(m,2H),1.65(s,3H),1.41(s,3H),1.22(m,2H),1.03(m,3H)。
实施例6制备Boc-Gly-Glu(OBzl)-OBzl
采用实施例4的方法,从0.88g(5mmol)Boc-Gly和2.00g(5.5mmol)Hcl·Glu(OBzl)-OBzl得到1.93g(80%)标题化合物,为无色固体。
实施例7制备HCl·Gly-Glu(OBzl)-OBzl
冰浴下将1.45g(3mmol)Boc-Gly-Glu(OBzl)-OBzl用20mL氯化氢的乙酸乙酯溶液(4M)溶解并反应4小时。TLC监测显示反应完全(体系为二氯甲烷/甲醇,30/1)。反应混合物减压浓缩,残留物用无水乙酸乙酯溶解,得到的溶液再减压浓缩。该操作重复3次。得到的白色粉末样物质用无水***充分磨洗,得到1.14g(90%)标题化合物,为无色固体。
实施例8制备Boc-His(Boc)-Gly-Glu(OBzl)-OBzl
采用实施例4的方法从1.77g(5mmol)Boc-His(Boc)和2.52g(6mmol)HCl·Gly-Glu(OBzl)-OBzl得到2.56g(67%)标题化合物,为无色固体。ESI-MS(m/e):722[M+H]+。
实施例9制备HCl·His-Gly-Glu(OBzl)-OBzl
采用实施例7的方法从1.44g(2mmol)Boc-His(Boc)-Gly-Glu(OBzl)-OBzl得到1.03g(92%)标题化合物,为无色固体。
实施例10制备3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu(OBzl)-OBzl(6)
往30mL无水四氢呋喃中加入0.47g(1mmol)3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The(5)、0.25g(1.2mmol)DCC和0.16g(1.2mmol)HOBt,冰浴下,搅拌30分钟。之后,向反应液中加入0.62g(1.1mmol)HCl·His-Gly-Glu(OBzl)-OBzl。滴入N-甲基吗啉(NMM)调节反应液的pH值为9。室温反应8小时。TLC显示化合物5消失(二氯甲烷/甲醇,15/1),滤除二环己基脲(DCU),滤液减压浓缩。残留物用100mL乙酸乙酯溶解,溶液再过滤除去DCU。滤液依次用5%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),5%NaHCO3水溶液洗(30mL×3),饱和NaCl水溶液洗(30mL×3),用无水硫酸钠干燥12小时。过滤,滤液减压浓缩,得到黄色粉末,经硅胶柱层析纯化(二氯甲烷/甲醇,15/1),得到0.71g(70%)标题化合物,为黄色粉末。ESI-MS(m/e):977[M+H]+;1H-NMR(300MHz,DMSO-d6):δ/ppm=10.99(s,1H),8.35(m,1H),8.27(m,1H),8,16(m,1H),7.79(m,1H),7.49(m,2H),7.35(m,12H),7.00(m,2H),5.13(s,2H),5.06(s,2H),4.41(m,2H),4.21(m,1H),4.02(m,1H),3.81(m,1H),3.65(m,2H),3.04(m,3H),2.92(m,2H),2.44(m,2H),2.09(m,2H),1.95(m,2H),1.85(m,2H),1.72(m,2H),1.62(s,3H),1.39(s,3H),1.23(m,2H),0.97(t,J=7.2Hz,3H)。
实施例11制备3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu(7)
往10mL甲醇中加入0.048g(0.05mmol)3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu(OBzl)-OBzl的制备(6)和0.005gPd/C,搅拌并通12h氢气,TLC显示化合物6消失(乙酸乙酯:水:冰醋酸,4:1:1)。过滤除去钯碳(Pd/C),滤液减压浓缩。残留物用***磨洗,得到0.033g(85%)标题化合物,为无色固体。ESI-MS(m/e):795[M-H]-,1H-NMR(300MHz,DMSO-d6):δ/ppm=10.96(s,1H),8.34(m,1H),8.29(m,1H),8,15(m,1H),8.02(m,1H),7.79(m,1H),7.54(s,1H),7.39(m,1H),7.04(m,1H),6.98(m,1H),6.83(s,1H),4.44(m,3H),4.24(m,2H),4.12(m,2H),4.02(m,1H),3.03(m,3H),2.93(m,2H),2.27(m,2H),2.07(m,2H),1.93(m,2H),1.84(m,2H),1.62(s,3H),1.39(s,3H),1.20(m,2H),0.97(t,J=7.2Hz,3H);13C-NMR(125MHz,DMSO-d6):δ/ppm=173.64,171.83,171.80,171.67,169.31,135.22,120.62,119.33,118.23,111.76,109.32,98.15,64.75,53.92,51.57,42.55,33.80,32.24,30.79,29.60,22.97,22.91,15.17。
实施例12评价化合物7的抗动脉血栓活性
1)将聚乙烯管拉成一端为斜口的细管,定长为10.0cm,分别为右颈静脉(管径较粗)及左颈动脉(管径较细)插管;中段聚乙烯管定长为8.0cm,血栓线压在颈动脉插管方向,插管前需在管中充满肝素。
2)将体重200±20g雄性大鼠大鼠在手术前适应环境并禁食一天。随机分为生理盐水(0.3mL/100g,10只大鼠)组,阿司匹林(167μmol/kg,10只大鼠)组,3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu(化合物7)组(0.01μmol/kg,10只大鼠)组。按照规定剂量给大鼠口服药物。给药30min后,大鼠腹腔注射20%乌拉坦溶液麻醉(7mL/kg),2min之后开始手术。手术中将大鼠仰卧位于固定板上,剪开颈部皮肤,分离右颈总动脉及左颈静脉,血管下压线,结扎远心端,在静脉靠远心端处剪一小口,将插管***静脉端,注射肝素,而后取下注射肝素的注射器,系线固定,再用动脉夹夹住动脉近心端,在靠近远心端方向剪一小口,将动脉端结扎,系线固定后松开动脉夹,建立体外循环旁路。循环15分钟后先剪断静脉端观察血液循环是否正常,若正常从动脉端取出血栓线,在纸上沾干浮血后称重,以血栓重表示活性,数据列入表1。表中的血栓重量表明,在167μmol/kg口服剂量下阿司匹林有效地抑制大鼠患动脉血栓症,在0.01μmol/kg口服剂量下化合物7同样有效抑制大鼠患动脉血栓症。这是本发明的突出技术效果。
表1 化合物7的抗动脉血栓活性
a)与生理盐水比P<0.01;n=10。
Claims (3)
2.权利要求1的3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu的合成方法,该方法包括:
2.1.合成3S-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯;
2.2.合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯;
2.3.合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸;
2.4.采用二环己基碳二亚胺为缩合剂,1-羟基苯并***为催化剂液相合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-OBzl;
2.5.合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The;
2.6.采用二环己基碳二亚胺为缩合剂,1-羟基苯并***为催化剂液相合成HCl·His-Gly-Glu(OBzl)-OBzl;
2.7.采用二环己基碳二亚胺为缩合剂,1-羟基苯并***为催化剂的方法合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu(OBzl)-OBzl;
2.8.合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu。
3.权利要求1的3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu在制备抗动脉血栓药物中的应用。
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