CN105237487B - 含川芎嗪基查尔酮芳氧烷酸类化合物、制备方法及其应用 - Google Patents
含川芎嗪基查尔酮芳氧烷酸类化合物、制备方法及其应用 Download PDFInfo
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- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及药物化学领域，具体涉及含川芎嗪基查尔酮芳氧烷酸类化合物(I)及其制备方法，药效学试验证明，本发明的化合物具有治疗高血脂症、动脉粥样硬化的医药用途。
Description
技术领域
本发明涉及药物化学领域，具体涉及含川芎嗪基查尔酮芳氧烷酸类化合物、其制备方法及治疗高血脂症、动脉粥样硬化的医药用途。
背景技术
高脂血症是人体脂代谢异常导致的血中脂质和脂蛋白水平升高，包括总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)水平过高和高密度脂蛋白胆固醇(HDL-C)水平过低，是非酒精性脂肪肝、动脉粥样硬化性心脏病和糖尿病等疾病发生的主要危险因素[参见Ross R.The Pathogenesis of atherosclerosis:a perspective for the1990s[J].Nature,1993,362:801]。随着人民生活水平的不断提高，我国高脂血症的发病率不断上升且呈现年轻化趋势[参见赵文华,张坚,由悦.中国18岁及以上人群血脂异常流行特点研究[J].中华预防医学杂志,2005,39(5):306-310]。目前临床上治疗高脂血症常用的药物主要有贝特类和他汀类药物等，这些药物虽然调血脂效果明显，但价格昂贵且易引起肝损伤。中医学认为高脂血症属“痰浊”、“瘀血”范畴；“痰浊”是人体津液不归正化的病理产物，“瘀血”是人体血运不畅或离经之血着而不去的病理表现。痰浊和瘀血作为病理产物和致病因子，是高脂血症发病的关键环节，所以对高脂血症的治疗以化痰降浊、活血化瘀为主要原则[参见翁晓清,汪亚群.自拟中药方治疗痰瘀互结型高血脂症80例疗效观察[J].中医药临床杂志,2006,18(2):147-148]。基于中医学的思维，如果能设计出一类既具有活血化瘀又具有降血脂作用的化合物将具有重要的临床意义。
发明人前期研究了结构特征一端为碱性基团，一端为酸性基团的川芎嗪芳酸醚类化合物对对二磷酸腺苷(ADP)诱导的血小板聚集具有较好的抑制活性，结构式如下：
该化合物的抑制活性是奥扎格雷的5.7倍，有很好的临床应用价值[参见李家明,赵永海,马逢时,等.川芎嗪芳酸衍生物的合成及抗血小板聚集活性[J].有机化学,2008,28(9):1578-1583]。
发明内容
本发明公开了一类含川芎嗪基查尔酮芳氧烷酸类化合物，结构特征上包含了一端为碱性基团，一端为酸性基团，同时具有芳氧烷酸结构，期望所设计的化合物既具有抗血小板聚集活性又具有降血脂活性，从而为治疗高血脂症及动脉粥样硬化的治疗提供新的选择。
本发明的化合物结构式如下：
其中R代表H或甲基；R1代表H、CH3或C2H5。
优选下列任一化合物：
本发明还包括化合物(I)药学上可接受的盐，其药学上可接受的盐是化合物(I)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、酒石酸盐或醋酸盐。
药效学实验证明，本发明的化合物可用于治疗或预防高血脂症及动脉粥样硬化疾病。
本发明所述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。
化合物(I)可用下列方法制备：
以下通过实验数据说明本发明化合物的有益效果
实验一体外抗血小板聚集实验
将雄性新西兰家兔(体重1.8～2.2kg)用1％盐酸普鲁卡因注射液局部麻醉，颈动脉插管放血，和枸橼酸钠溶液(0.38g枸橼酸钠与10mL生理盐水配制成3.8％的枸橼酸钠溶液)以9∶1混合，以1000r/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)。采用肝微粒体体外温孵方法：微粒体体外反应体系一共1ml，分别取NADP、G-PD、G-PDH、MgCl2以及肝微粒体适量，加入KCl-磷酸盐缓冲液，使反应体系终体积为1ml，反应体系中分别含0.5mmol/L NADP、5.0mmol/L G-6-PD、1.0U/mL G-6-PDH、5.0mmol/L MgCl2、1.0mg/ml肝微粒体。取需要进行孵育的筛选药物加入到微粒体反应体系中，于37℃水浴中温孵振荡60min，放入-20℃冰箱内终止反应。先取300μl PPP加入测试杯中，然后放入测试孔，按“PPP”键进行定标。然后取280μl PRP加入测试杯中，加入10μl不同浓度的药液，在37℃预温槽中预热3min，放入测试孔后，按“开始”键时立即加入诱导剂10μl，以测定最大聚集率，并计算IC50值。按下列公式计算血小板聚集抑制率：血小板聚集抑制率(％)＝[(空白对照组最大聚集率-给药组最大聚集率)/空白对照组最大聚集率]×100％。本发明化合物对AA和ADP诱导的血小板聚集的抑制活性见表1。
表1化合物对AA和ADP诱导的血小板聚集的抑制活性
体外抗血小板聚集实验结果显示，本发明的化合物均表现出一定的抗血小板聚集作用，其中，化合物YA3和YA5对AA和ADP诱导的血小板聚集的抑制作用较强。虽然化合物YA3和YA5的药效作用弱于奥扎格雷和阿司匹林，但对同时具有降脂和活血化瘀作用的药物是有益的。
实验二本发明化合物对高脂血症C57/BL6小鼠血脂的影响
清洁级雄性健康野生型C57/BL6小鼠84只，随机分成7组，每组12只，分别为空白组(喂食普通饲料)、模型组(喂食高脂饲料，HFD)、阳性对照非诺贝特(FNB)45mg/kg剂量组(喂食高脂饲料)、化合物YA345mg/kg、90mg/kg剂量组(喂食高脂饲料)、化合物YA545mg/kg、90mg/kg剂量组(喂食高脂饲料)。各组灌胃给药3周，于末次给药后30min眼球取血，3000r/min离心10min，分离血清，测定小鼠血清中总胆固醇(TC)，甘油三脂(TG)，低密度脂蛋白胆固醇(LDL-C)，高密度脂蛋白胆固醇(HDL-C)的含量，测定方法按照试剂盒说明书进行。数据以平均值±标准差表示，结果用SPSS 17.0软件进行统计分析，用t检验评价实验结果。本发明化合物对高血脂症C57/BL6小鼠血脂水平的影响见表2。
表2本发明化合物YA3和YA5对高血脂症C57/BL6小鼠血脂水平的影响
(n＝12,**P<0.01vs空白组；△P<0.05,△△P<0.01vs模型组)
体内降血脂活性结果显示，化合物YA3、YA5具有较明显的体内降血脂活性，可以明显降低高脂血症C57/BL6小鼠血清总胆固醇和低密度脂蛋白水平，并能升高显高密度脂蛋白水平。鉴于化合物YA3、YA5具有一定的抗抗血小板聚集作用，又具有明显的降血脂活性，呈现出良好的药用前景。
具体实施方式
实施例1
(E)-2-乙基-(4-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰基)苯氧基)乙酸酯的合成(YA1)的制备1.12-羟甲基-3,5,6-三甲基吡嗪的合成
反应步骤
在250mL三颈烧瓶中依次加入川芎嗪(15.0g，0.1mol)，30％H2O2溶液(24mL,0.2mol)，冰醋酸15mL，94℃反应12h，TLC(石油醚-乙酸乙酯1:1)检测反应基本完全后，冷却下，用50％NaOH溶液调节pH＝10，二氯甲烷萃取(3×30mL)，合并有机相，经无水Na2SO4干燥后，减压浓缩，得川芎嗪单氮氧化物白色晶体13.2g，收率78.8％，mp 82.4-84.1℃。
在250mL三颈烧瓶中依次加入川芎嗪单氮氧化物(13.2g,86.8mmol)，乙酸酐(31.2mL,330.4mmol)，130℃反应5h，TLC(石油醚-乙酸乙酯1:1)检测反应基本完全后，蒸除过量乙酸酐，得(3,5,6-三甲基吡嗪-2-基)乙酸甲酯中间体粗品。
往上步反应得到(3,5,6-三甲基吡嗪-2-基)乙酸甲酯中加入20％NaOH溶液80mL，室温反应12h，TLC(石油醚-乙酸乙酯1:1)检测反应基本完全，过滤得滤液，用二氯甲烷萃取(3×50mL)，合并有机相，经无水Na2SO4干燥，浓缩，石油醚重结晶，得2-羟甲基-3,5,6-三甲基吡嗪淡黄色针状结晶9.7g，收率57.8％，mp 75.3-77.2℃。
1.23,5,6-三甲基吡嗪-2-甲醛的合成
反应步骤
在250mL三颈烧瓶中依次加入2-羟甲基-3,5,6-三甲基吡嗪(9.5g，62.5mmol)，MnO2(16.2g，187.5mmol)，无水乙醇100mL，回流12h，TLC(石油醚-乙酸乙酯2:1)检测反应基本完全，冷却，过滤得滤液，减压回收乙醇，得黄色固体，经硅胶柱色谱(石油醚-乙酸乙酯4:1)纯化，得3,5,6-三甲基吡嗪-2-甲醛淡黄色固体8.8g，收率93.9％，mp84.7-86.5℃。
1.3(E)-1-(4-羟基苯基)-3-(3,5,6-三甲基吡嗪-2-基)丙-2-烯-1-酮的合成
反应步骤
在100mL三颈烧瓶中依次加入3,5,6-三甲基吡嗪-2-甲醛(2.0g,13.3mmol)，4-羟基苯乙酮(1.5g,11.0mmol)，无水乙醇10mL，冰浴条件下缓慢滴加入20％KOH溶液8.0mL，冰浴下反应10h，TLC(石油醚-乙酸乙酯2:1)检测反应基本完全，将反应液倒入100mL冰水中，用10％稀盐酸调节pH＝6～7，析出黄色沉淀。过滤，滤饼用无水乙醇重结晶，干燥得黄色晶体1.0g，收率33.8％，mp 129.7-131.5℃。
1.4(E)-2-乙基(4-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰基)苯氧基)乙酯的合成(YA1)
反应步骤
在100mL三颈烧瓶中依次加入(E)-1-(4-羟基苯基)-3-(3,5,6-三甲基吡嗪-2-基)丙-2-烯-1-酮(1.0g,3.7mmol)，ClCH2COOEt(0.6g,4.9mmol)，K2CO3(0.77g,5.6mmol)，KI20mg，DMF 10mL，90℃反应6h，TLC(石油醚-乙酸乙酯2:1)检测反应基本完全。冷却，过滤，滤液加水50mL，乙酸乙酯(3×50mL)萃取，合并有机相，饱和NaCl溶液(2×25mL)洗涤，经无水Na2SO4干燥后，减压浓缩得黄色油状物，经硅胶柱色谱(石油醚-乙酸乙酯5:1)纯化得YA1淡黄色晶体0.9g，收率为68.2％，mp 119.1-120.3℃。1H NMR(400MHz,CDCl3)δ:8.21(d,J＝14.8Hz,1H,＝CH),8.13(d,J＝8.8Hz,2H,PhH),7.99(d,J＝14.8Hz,1H,＝CH),7.01(d,J＝8.8Hz,2H,PhH),4.71(s,2H,CH2),4.32(q,J＝7.2Hz,2H,CH2),2.66(s,3H,CH3),2.57(s,3H,CH3),2.55(s,3H,CH3),1.313(t,J＝7.2Hz,3H,CH3)；13C NMR(CDCl3,100MHz)δ:188.3,168.2,161.6,152.6,149.9,149.6,143.2,137.8,131.8,131.1,126.1,114.4,65.2,61.6,22.1,21.8,20.8,14.2；IR(KBr,cm-1)υ:3067.9,2984.7,2959.1,2933.4,2901.4,1743.1,1652.3,1606.5,1569.0,1375.2,1208.5,970.1,841.9；ESI-Mass for C20H22N2O4:m/z355.07[M+H]+.
实施例2
(E)-2-乙基(3-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰基)苯氧基)乙酯的合成(YA2)
反应步骤：3,5,6-三甲基吡嗪-2-甲醛的合成按实施例1中1.1，1.2方法操作合成，按实施例1中1.3，1.4方法操作得YA2淡黄色晶体，m.p.116.1-116.9℃。1H NMR(300MHz,CDCl3)δ:8.19(d,J＝14.7Hz,1H,＝CH),8.00(d,J＝14.7Hz,1H,＝CH),7.77(d,J＝7.5Hz,1H,PhH),7.62(s,1H,PhH),7.45(t,J＝7.8Hz,1H,PhH),7.18(dd,J＝2.4Hz,8.1Hz,1H,PhH),4.72(s,2H,OCH2CO),4.30(q,J＝7.2Hz,2H,OCH2CH3),2.66(s,3H,CH3),2.57(s,3H,CH3),2.55(s,3H,CH3),1.32(t,J＝7.2Hz,3H,OCH2CH3)；13C NMR(CDCl3,75MHz)δ:189.5,168.5,158.1,152.8,149.9,149.6,142.9,139.3,138.5,129.8,126.1,122.3,120.0,113.9,65.4,61.5,22.1,21.8,20.8,14.2；IR(KBr,cm-1)υ:3067.9,2981.5,2914.2,1742.1,1658.7,1585.7,1482.6,1450.5,1437.5,1398.4,1211.7,1186.2,1085.2,966.9,854.8,775.4,710.7；ESI-Mass for C20H22N2O4:m/z 355.20[M+H]+.
实施例3
(E)-乙基-2-甲基-2-(4-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰基)苯氧基)丙酸酯的合成(YA3)
反应步骤：3,5,6-三甲基吡嗪-2-甲醛的合成按实施例1中1.1，1.2方法操作合成，按实施例1中1.3，1.4方法操作得(E)-乙基-2-甲基-2-(4-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰基)苯氧基)丙酸酯黄色晶体，m.p.122.8-123.3℃。1H NMR(300MHz,CDCl3)δ:8.13(d,J＝14.7Hz,1H,＝CH),8.00(d,J＝8.7Hz,2H,PhH),7.91(d,J＝14.7Hz,1H,＝CH),6.83(d,J＝8.7Hz,2H,PhH),4.16(q,J＝7.2Hz,2H,OCH2CH3),2.58(s,3H,CH3),2.48(s,3H,CH3),2.47(s,3H,CH3),1.60(s,6H,2×CH3),1.15(t,J＝7.2Hz,3H,OCH2CH3)；13C NMR(CDCl3,75MHz)δ:188.4,173.7,159.9,152.6,149.8,149.6,143.2,137.6,131.4,130.6,126.1,117.4,79.3,61.7,25.4,22.0,21.8,20.8,14.0；IR(KBr,cm-1)υ:3045.6,2997.5,2949.5,1731.8,1656.5,1605.6,1588.6,1508.2,1326.9,1277.0,1259.1,1168.2,1139.6,1020.7,838.8；ESI-Mass for C22H26N2O4:m/z 383.22[M+H]+.
实施例4
(E)-乙基-2-甲基-2-(3-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰基)苯氧基)丙酸酯的合成(YA4)反应式
反应步骤：3,5,6-三甲基吡嗪-2-甲醛的合成按实施例1中1.1，1.2方法操作合成，按实施例1中1.3，1.4方法操作得(E)-乙基-2-甲基-2-(3-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰基)苯氧基)丙酸酯黄色晶体，m.p.126.9-127.5℃。1H NMR(300MHz,CDCl3)δ8.15(d,J＝14.9Hz,1H,＝CH),7.97(d,J＝14.9Hz,1H,＝CH),7.74(d,J＝7.7Hz,1H,PhH),7.58(s,1H,PhH),7.45～7.34(m,1H,PhH),7.09(dd,J＝8.1,2.1Hz,1H,PhH),4.28(q,J＝7.1Hz,2H,OCH2CH3),2.65(s,3H,CH3),2.56(s,3H,CH3),2.54(s,3H,CH3),1.65(s,6H,2×CH3),1.26(t,J＝7.2Hz,3H,OCH2CH3).13C NMR(75MHz,CDCl3)δ:189.5,173.8,155.8,152.8,149.9,149.7,143.0,139.1,138.3,129.4,126.1,123.7,122.5,118.9,79.5,61.6,25.3,22.0,21.7,20.8,14.1；IR(KBr,cm-1)υ:2997.5,2981.5,2933.5,1731.2,1664.9,1606.1,1578.5,1397.6,1323.5,1279.8,1167.3,1142.2,861.2,765.1,717.1；ESI-Mass for C22H26N2O4:m/z 383.06[M+H]+.
实施例5
(E)-2-(4-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰基)苯氧基)乙酸的合成(YA5)
反应步骤：(E)-2-乙基(4-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰基)苯氧基)乙酯的合成按实施例1中1.1～1.4方法操作合成得到。在50mL圆底烧瓶中加入(E)-2-乙基(4-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰基)苯氧基)乙酯(0.8g,2.3mmol)，NaOH(0.1g,2.5mmol)，乙醇4mL和水8mL，室温搅拌反应12h，TLC(石油醚-乙酸乙酯1:1)检测反应基本完全。减压浓缩，残余物加水10mL，用1％稀盐酸调节至pH＝5，析出固体，过滤后得滤饼，用无水乙醇重结晶得YA5白色晶体0.6g，收率82.2％，mp 230.9-231.3℃。1H NMR(300MHz,DMSO-d6)δ:13.17(s,1H,COOH),8.11(d,J＝14.7Hz,2H,＝CH),8.07(d,J＝8.7Hz,2H,PhH),,7.87(d,J＝14.7Hz,1H,＝CH),7.11(d,J＝9Hz,2H,PhH),4.83(s,2H,OCH2),2.60(s,3H,CH3),2.53(s,3H,CH3),2.51(s,3H,CH3),；13C NMR(75MHz,DMSO-d6)δ:192.4,175.0,167.1,158.0,154.9,154.5,147.4,142.7,135.9,135.8,130.7,119.9,69.8,26.9,26.6,25.6；IR(KBr,cm-1)υ:2907.5,1751.9,1660.6,1601.5,1572.2,1506.6,1417.8,1312.9,1220.0,1201.6,1175.7,1072.9,841.8；ESI-Mass for C18H18N2O4:m/z 327.25[M+H]+.
实施例6
(E)-2-(3-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰基)苯氧基)乙酸的合成(YA6)
反应步骤：(E)-2-(3-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰基)苯氧基)乙酸的合成按实施例5方法操作合成得YA6白色晶体，mp 234.2-234.8℃。1H NMR(400MHz,DMSO-d6)δ:8.05(d,J＝14.8Hz,1H,＝CH),7.85(d,J＝14.8Hz,1H,＝CH),7.68(d,J＝7.6Hz,1H,PhH),7.53(s,1H,PhH),7.48(t,J＝7.8Hz,1H,PhH),7.27(dd,J＝2.0Hz,8.4Hz,1H,PhH),4.81(s,2H,OCH2),2.58(s,3H,CH3),2.51(s,3H,CH3),2.48(s,3H,CH3)；13C NMR(100MHz,DMSO-d6)δ:188.8,170.0,158.1,153.0,149.8,149.4,142.0,138.6,138.3,130.1,125.5,121.4,119.8,113.3,64.6,21.6,21.4,20.3；IR(KBr,cm-1)υ:3583.6,3068.0,2923.8,2863.0,1746.5,1660.0,1588.7,1436.4,1401.2,1312.2,1280.8,1196.9,1073.6,970.0,790.4；ESI-Mass for C18H18N2O4:m/z 327.14[M+H]+。
Claims (5)
1.通式(I)的化合物或其药学上可接受的盐：
其中R代表H或甲基；R1代表H、CH3或C2H5。
2.权利要求1的化合物或其药学上可接受的盐，是下列任一结构的化合物：
3.权利要求1的化合物或其药学上可接受的盐，其药学上可接受的盐是化合物(I)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、酒石酸盐或醋酸盐。
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治疗高血脂症或动脉粥样硬化疾病的药物的用途。
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