CN101851209B - 咪唑乙基香草酸醚、其制备方法及其医药用途 - Google Patents

咪唑乙基香草酸醚、其制备方法及其医药用途 Download PDF

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CN101851209B
CN101851209B CN2010102034663A CN201010203466A CN101851209B CN 101851209 B CN101851209 B CN 101851209B CN 2010102034663 A CN2010102034663 A CN 2010102034663A CN 201010203466 A CN201010203466 A CN 201010203466A CN 101851209 B CN101851209 B CN 101851209B
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CN101851209A (zh
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何广卫
李家明
吴强
李丰
何勇
赵永海
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Hefei Industrial Pharmaceutical Institute Co ltd
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Abstract

本发明涉及医药领域,具体涉及咪唑乙基香草酸醚(I)化合物、其制备方法、含有该化合物的药用组合物以及其医药用途,本发明的化合物I对由血小板聚集引起的心脑血管疾病具有防治作用,特别是化合物I在不延长出血时间的基础上对ADP诱导的血小板聚集有强大的抑制作用。

Description

咪唑乙基香草酸醚、其制备方法及其医药用途
技术领域
本发明涉及医药领域,具体涉及一个咪唑乙基香草酸醚化合物及其药学上可接受的盐,本发明还公开了它的制备方法、含有该化合物的药用组合物以及其医药用途,特别是作为抗血小板聚集药物的用途。
背景技术
血栓栓塞是导致心脑血管疾病的重要因素之一,以冠状动脉血栓和脑血栓为核心的血栓栓塞性疾病在我国也有很高的发病率和死亡率,因此,防止血栓也就成了心血管疾病领域当今最为热门的研究课题之一。血小板聚集是正常凝血机制中的一个关键环节,血小板的粘附、聚集和释放反应导致血栓形成。抗血小板聚集药物是指可抑制血小板的粘附和聚集功能,阻止血栓形成的药物,因此在治疗血栓栓塞性疾病中发挥重要作用。血栓烷素(TXA2)是花生四烯酸代谢过程中生成的具有很强生理活性的产物。TXA2对血管张力具有调节作用,可使血管、支气管和平滑肌收缩,具有强烈的血小板聚集作用,能促使血小板聚集形成血栓。临床研究结果表明,许多心血管疾病的发生与TXA2的过多生成有关。奥扎格雷和Dazoxiben为高度选择性的TXA2合成酶抑制剂,具有很高的抗血小板聚集作用,能抑制脑血栓形成和脑血管痉挛,临床上主要用于急性脑梗死、冠心病和心绞痛的治疗。
我国中药资源丰富,从传统的活血化淤中药中筛选具有抑制血小板聚集作用的成分作为先导化合物,利用现代药物化学研究原理对先导化合物进行合理药物设计、合成,从中筛选出疗效更好、副作用少、生物利用度高,半衰期较长的治疗血栓栓塞性疾病药物具有重要的理论意义和临床应用价值。
发明内容
本发明公开了一个咪唑乙基香草酸醚化合物,其结构式I如下:
Figure BSA00000164485700011
化学名为:4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯甲酸。
根据本发明,化合物I的药学上可接受的盐也同样具有与化合物I一样的药效。所述的药学上可接受的盐包括结构式I化合物与下列碱金属或碱土金属、碱性氨基酸、或医药上允许的无机酸或有机酸形成的盐。碱金属盐为钠盐、钾盐;碱土金属盐为钙盐、镁盐;碱性氨基酸盐为精氨酸盐;无机酸盐为盐酸、硫酸、磷酸;有机酸盐为马来酸、富马酸、枸橼酸、甲磺酸、对甲苯磺酸、酒石酸。更优选的化合物I的盐酸盐。
本发明的化合物的制备方法如下:
Figure BSA00000164485700021
本发明的化合物可以添加药学上可接受的载体制成常见的药用制剂,如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、针剂,可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明所述的化合物在临床上的给药方式可以采用口服、注射等方式。
本发明的化合物临床所用剂量为0.01mg~1000mg/天,也可根据病情的轻重或剂型的不同偏离此范围。
药理试验证明,本发明的化合物具有预防或治疗血小板聚集引起的心脑血管疾病的功效,特别是能治疗血栓性心、脑的缺血或梗死等疾病。下面是部分药理试验及结果:
一、体内对ADP诱导的家兔血小板最大聚集率的影响
给药剂量及样品配制:
奥扎格雷钠:称取样品奥扎格雷钠75mg,加25ml生理盐水,终浓度12.0mmol/L。
化合物I:与奥扎格雷钠等摩尔浓度,称取I化合物78.6mg,先加入15ml生理盐水,超声溶解,再加入1mol/L的氢氧化钠溶液20-50μl,使溶液完全澄清,再加生理盐水稀释至25ml,终浓度为12.0mmol/L;取上述溶液,再用生理盐水稀释制成8.0mmol/L、4.0mmol/L的溶液分组及给药:
将大耳白家兔,雄性,随机分组,每组10只。分别给予化合物I、奥扎格雷钠和生理盐水,给药体积为2ml/kg。耳缘静脉给药后麻醉,颈动脉插管放血,3.8%的枸橼酸钠1∶9抗凝,以800r/min离心10min,取富血小板血浆(PRP),剩余部分以3000r/min离心10min,取贫血小板血浆(PPP),聚集诱导剂用ADP(终浓度30μmol/L)。每管270μl PRP温育5min,然后加入ADP诱导聚集,用LG-PABER-1型血小板聚集仪检测血小板最大聚集率。
按下列公式计算血小板聚集抑制率:
Figure BSA00000164485700031
将结果进行组间t检验比较。
表1体内对ADP诱导的家兔血小板最大聚集率的影响(n=10,
Figure BSA00000164485700032
)
Figure BSA00000164485700033
*P<0.05,**P<0.01,与空白对照组比较
结果如表1所示,空白对照组的最大聚集率为38.0%,奥扎格雷钠、化合物I高、中、低各剂量组的最大聚集率分别为28.6%、5.9%、15.1%、18.0%,与空白对照组比较,都明显抑制了血小板的聚集。
二、对小鼠凝血、出血时间的影响
给药剂量及样品配制:
奥扎格雷钠:称取样品奥扎格雷钠6mg,加5ml生理盐水,终浓度4.8mmol/L。
化合物I:与奥扎格雷钠等摩尔浓度,称取化合物I 6.3mg,先加入4ml生理盐水,超声溶解,再加入1mol/L的氢氧化钠溶液20-50μl,使溶液完全澄清,再加生理盐水稀释至5ml,终浓度为4.8mmol/L;取上述溶液,再用生理盐水稀释制成3.2mmol/L、1.6mmol/L的溶液试验方法:
采用玻片法检测化合物I对小鼠凝血时间的影响:取健康清洁级ICR小鼠,体重18~22g,分为空白组、奥扎格雷钠组和化合物I高、中、低剂量组,每组20只。每组给予相应的化合物,空白组给予生理盐水,给药体积为0.2ml/10g。尾静脉给药5分钟后,以内径为1mm的玻璃毛细管插入小鼠眼眶内,使血自动流出,弃去第一滴血,再分别滴血于清洁载玻片的两端,血滴直径为5~10mm,立即开始计时,此后每隔10s用干燥针头挑动血液1次,至针头能挑起纤维蛋白丝为止,即为凝血时间,用秒表记录凝血时间。
采用断尾法检测受试药对小鼠出血时间的影响:动物分组、给药剂量及给药方式同凝血时间测定实验。给药后,将其尾部垂直,用毫米尺测量,并在距尾尖5mm处作标记,然后用手术刀片在鼠尾标记处垂直切断,待血液自行溢出开始计时,每隔30s用滤纸吸去血滴1次,直至血液自然停止(滤纸吸时无血为止),即为出血时间,用记录出血时间。
将结果进行组间t检验比较,实验结果见表2。
表2对小鼠凝血时间和出血时间的影响(n=20,
Figure BSA00000164485700041
)
Figure BSA00000164485700042
*P<0.05,**P<0.01,与空白对照组比较
由表2可见,在小鼠的凝血实验中,与空白对照比,奥扎格雷钠显著延长凝血时间(p<0.05),化合物I可极显著延长凝血时间(p<0.01)。小鼠的出血时间,化合物I与空白组比较,无显著性差异,未延长动物的出血时间,且化合物I高、中、低剂量组出血时间均较奥扎格雷组短。
通过综合比较,化合物I能极显著抑制ADP诱导的血小板聚集,能极显著延长凝血时间,具有体内抗凝血的作用,同时对出血时间基本无影响,考虑到出血时间的副作用,化合物I具有在不显著延长出血时间的基础上,具有强大的抗凝血活性,显示出极强的成药性优势。
具体实施方式
实施例1.
4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯甲酸盐酸盐的合成
1.1.4-(2-溴乙氧基)-3-甲氧基苯甲酸甲酯的合成
反应式
反应步骤
将1,2-二溴乙烷(10g,0.05mol)、无水碳酸钾(10g)、丁酮(75mL)加入带有回流冷凝装置的三颈烧瓶中,搅拌并升温至回流,分批加入香草酸甲酯,回流反应6h后,TLC检测,石油醚∶乙酸乙酯=4∶1(V/V)为展开剂,显示反应基本完全,冷却后,过滤除去固体,用少量乙酸乙酯洗涤滤饼,减压回收乙酸乙酯后的淡黄色油状物,经硅胶柱洗脱分离,石油醚∶乙酸乙酯=4∶1(V/V)为洗脱剂,收集产物,减压回收溶剂,得4-(2-溴乙氧基)-3-甲氧基苯甲酸甲酯白色晶体,收率59%,m.p.70.5-70.8℃。
1H-NMR(CDCl3,300MHz)δ:7.66(dd,J=8.4,2.4Hz,1H,ArH),7.58(d,J=2.4Hz,1H,ArH),6.91(d,J=8.4Hz,1H,ArH),4.39(t,J=6.6Hz,2H,BrCH2CH2O),3.69(t,J=6.6Hz,2H,BrCH2CH2O),3.92(s,6H,2×OCH3);13C-NMR(CDCl3,75.5MHz)δ:166.7,151.5,149.2,123.4,113.0,112.8,68.9,56.2,52.1,28.5;IR(KBr,cm-1)υ:3092.1,2946.3,2872.9,2838.6,1743.0,1711.6,1598.2,1516.1,1461.6,1430.9,1387.3,1345.9,1276.2,1222.4,1183.3,1134.7,1007.5,869.1,760.5。
1.2.4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯甲酸甲酯的合成
反应式
Figure BSA00000164485700051
反应步骤
将咪唑(0.9g,13.2mmol)、95%NaH(0.3g,11.9mmol)、无水DMF20mL加入带有回流冷凝装置的100mL三颈烧瓶中,升温至95℃,恒温反应15min后,加入4-(2-溴乙氧基)-3-甲氧基苯甲酸甲酯(2.62g,9.1mmol),反应6小时。TLC检测,石油醚∶乙酸乙酯=4∶1(V/V)为展开剂,检测显示原料基本反应完全,停止反应,冷却至室温,加入50mL水,用乙酸乙酯萃取(50mL×3),合并乙酸乙酯层,并用50mL水洗三次,无水硫酸钠干燥,减压回收溶剂后得淡黄色油状物,经硅胶柱洗脱分离,甲醇∶乙酸乙酯=1∶6(V/V)为洗脱剂,收集产物,减压回收溶剂后得4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯甲酸甲酯白色晶体,收率为55%,m.p.95.8-98.1℃。
1H-NMR(CDCl3,400MHz)δ:7.67(s,1H,2-Hinimidazol),7.62(dd,J=8.4,1.6Hz,1H,ArH),7.56(d,J=1.6Hz,1H,ArH),7.11(s,1H,4-Hinimidazol),7.07(s,1H,5-Hinimidazol),7.11(s,1H,ArH),6.79(d,J=8.4Hz,1H,ArH),4.40(t,J=5.0Hz,2H,OCH2CH2),4.30(t,J=5.0Hz,2H,NCH2CH2),3.90(s,6H,OCH3and COOCH3);13C-NMR(CDCl3,100MHz)δ:166.6,151.4,149.2,137.7,129.5,123.9,123.3,119.6,112.8,112.4,68.4,56.1,52.0,46.4;IR(KBr,cm-1)υ:3429.6,2952.0,1711.9,1659.3,1598.9,1563.6,1461.5,1438.4,1344.3,1273.9,1221.8,1178.2,1105.6,1135.7,1073.0,1032.6,977.5,902.0,875.7,819.8,764.8,733.6,665.8;ESI-Mass(+c)m/z for C14H16N2O4:277.10(M++H)。
1.3.4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯甲酸盐酸盐的合成
反应式
Figure BSA00000164485700061
反应步骤
在圆底烧瓶中依次加入4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯甲酸甲酯白色晶体(1.3g,4.71mmol)、NaOH(0.4g,9.00mmol)、甲醇10mL、水10mL,室温搅拌4h,TLC检测,展开剂CHCl3∶甲醇=2∶1(V/V),检测反应完全,回收有机溶剂后,在冰浴中,用12mol/L盐酸调节pH至2左右,减压回收溶剂至近干,加入20mL无水乙醇,加热,趁热抽滤,冷却析晶,过滤,滤饼用无水乙醇重结晶,干燥,得4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯甲酸白色晶体,收率为86%,m.p.194.9-195.9℃。1H-NMR(D2O,400MHz)δ:8.76(s,1H,2-H in imidazol),7.54(s,1H,4-H in imidazol),7.52(d,J=8.4Hz,1H,ArH),7.43(s,1H,ArH),7.41(s,1H,5-H in imidazol),6.94(d,J=8.4Hz,1H,ArH),4.63(t,J=4.8Hz,2H,OCH2),4.47(t,J=4.8Hz,2H,NCH2),3.77(s,3H,OCH3);13C-NMR(D2O,100MHz)δ:169.9,150.9,148.1,135.1,124.0,123.3,122.2,119.6,112.9,112.7,66.9,55.8,48.6;IR(KBr,cm-1)υ:2937.9,2825.9,2591.1,1690.6,1599.5,1516.3,1461.9,1425.4,1391.8,1268.4,1226.5,1133.2,1040.3,906.3,818.8,759.6;ESI-Mass(+c)m/z for C13H14N2O4:263.12(M++H)。
实施例2.
注射液的制备
将实施例1制得的化合物120mg及5g葡萄糖在80ml注射用水中搅拌溶解,调pH(7.0-9.0),加入针用活性炭常温搅拌15min,脱炭,加注射用水至全量(100ml),滤过,灌装,121℃灭菌12min即可。

Claims (6)

1.结构式I的化合物或其药学上可接受的盐:
Figure FDA00001726459300011
2.权利要求1的化合物或其药学上可接受的盐,其中药学上可接受的盐是结构式I化合物的钠盐、钾盐、钙盐、镁盐、精氨酸盐、盐酸盐、硫酸盐、磷酸盐、马来酸盐、富马酸盐、枸橼酸盐、甲磺酸盐、对甲苯磺酸盐或酒石酸盐。
3.权利要求2的化合物或其药学上可接受的盐,其中药学上可接受的盐是结构式I化合物的盐酸盐。
4.一种药物组合物,其中含有权利要求1的化合物或其药学上可接受的盐及药学上可接受的载体。
5.权利要求1的化合物或其药学上可接受的盐用于制备预防或治疗血小板聚集引起的心脑血管疾病的药物的用途。
6.权利要求5的用途,其中心脑血管疾病是血栓性心、脑的缺血或梗死。
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