CN104496922B - 腈基苯二烯四氮唑类化合物、其制备方法和用途 - Google Patents
腈基苯二烯四氮唑类化合物、其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及与血栓性疾病相关的药物领域。具体而言，本发明涉及一类含腈基苯二烯四氮唑结构的PAR-1拮抗剂、其制备方法和用途。其中，R1选自H、C1-C3的烷基、C3-C5的环烷基。
Description
技术领域
本发明涉及与血栓疾病相关的药物领域。具体而言，本发明涉及对血栓性疾病有治疗作用的一类含腈基苯二烯四氮唑结构的PAR-1拮抗剂及其制备方法，含有它们的药物组合物以及在治疗血栓性疾病上的用途。
背景技术
蛋白酶激活受体1(ProteaseActivatedAcceptor-1，PAR-1)是最近发现的抗血小板类抗血栓药物的新靶点。蛋白酶激活受体1又叫凝血酶受体，凝血酶被凝血连锁激活后通过PAR-1受体作用于血小板从而激活血小板，引起血小板聚集从而引起血栓和凝血。PAR-1引起的血栓中富含血小板成分，是动脉血栓的主要成因。PAR-1拮抗剂能阻断凝血酶激活血小板，从而阻断动脉血栓形成，可以用于治疗急性冠状动脉疾病(AcuteCoronarySyndrome)。已经有几个PAR-1抑制剂处于临床研究(ChackalamannilS.,ThrombinReceptor(ProteaseActivatedReceptor-1)AntagonistsasPotentAntithromboticAgentswithStrongAntiplateletEffects,J.Med.Chem.,2006,49(18),5389-5403)。
传统的用于防治血栓性疾病的药物分为三类。第一类是抗凝血类，分为直接凝血酶抑制剂和间接凝血酶抑制剂，该类药物通过作用于凝血连锁的不同环节来抑制血栓形成，具有抑制各种血栓形成的作用，如维生素K拮抗剂和Xa因子抑制剂等；第二类是抗血小板类，如COX-1抑制剂和ADP受体拮抗剂等，该类药物主要用于防治动脉血栓；第三类是纤维蛋白溶解剂，主要用于溶解血液中形成的纤维蛋白。
抗血小板药物多是传统的动脉血栓防治药物，如氯吡格雷和阿司匹林等。这些药物的缺点是出血风险比较大。而作为新发现的抗血小板类抗血栓药物的PAR-1拮抗剂，则具有较小的出血风险，因此这类化合物可以作为治疗动脉血栓的很有前景的药物。
本发明公开了一类含腈基苯二烯四氮唑结构的PAR-1拮抗剂，它们可以用于制备抗动脉血栓疾病的药物。
发明内容
本发明的一个目的是提供一种具有良好抗血栓形成活性的具有通式I的化合物及其药学上可以接受的盐。
本发明的另一个目的是提供制备具有通式I的化合物及其药学上可以接受的盐的方法。
本发明的再一个目的是提供含有通式I的化合物及其药学上可以接受的盐作为有效成分，以及一种或多种药学上可接受的载体、赋形剂或稀释剂的药用组合物，及其在治疗动脉血栓方面的应用。
现结合本发明的目的对本发明内容进行具体描述。
本发明具有通式I的化合物具有下述结构式：
其中，R1选自H、C1-C3的烷基、C3-C5的环烷基。
优选以下具有通式I的化合物，
本发明所述通式I化合物通过以下方法合成：
化合物II参照文献方法合成(CN200780022348.9)，化合物II使用LiBH4还原为III；化合物III使用卤化试剂转化为IV；IV和V在碱的存在下反应得到I；其中所述卤化试剂选自SOCl2、PCl3、PCl5、PBr3等，X选自Cl和Br。；其中R1的定义如前所示。
本发明所述式I化合物的药学上可接受的盐，包括但是不限于与各种无机酸如盐酸、硫酸、硝酸、磷酸、氢溴酸等形成的盐，也包括与各种有机酸如乙酸、琥珀酸、马来酸、苹果酸以及各种氨基酸等形成的盐。
本发明所述通式I化合物具有PAR-1的拮抗作用，可作为有效成分用于制备抗血栓方面的治疗药物。本发明所述通式I化合物的活性是通过体外模型验证。
本发明的通式I化合物在相当宽的剂量范围内是有效的。例如每天服用的剂量约在1mg-500mg/人范围内，分为一次或数次给药。实际服用本发明通式I化合物的剂量可由医生根据有关的情况来决定。这些情况包括：被治疗者的身体状态、给药途径、年龄、体重、对药物的个体反应，症状的严重程度等。
具体实施方式
下面结合实施例对本发明作进一步的说明。需要说明的是，下述实施例仅是用于说明，而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1
取一只100mL圆底烧瓶，加入2.27g(10mmol)化合物II-1，以20mL干燥的THF溶解，冰水浴冷却下搅拌，分批加入0.44g(20mmol)LiBH4后，继续在室温下搅拌过夜。TLC显示反应完成。反应混合物倾倒入冰水中，搅拌，用浓盐酸调节pH＝3，用50mL×3的二氯甲烷萃取，合并萃取有机相，用饱和食盐水洗涤，无水硫酸钠干燥，在旋转蒸发仪上蒸去溶剂，得到的残余物柱层析纯化，得到产物III-1，白色固体，ESI-MS,m/z＝186([M+H]+)。
取一只100mL的圆底烧瓶，加入1.48g(8mmol)化合物III-1和10mL二氯甲烷，冰水浴冷却下搅拌，慢慢加入5.41g(20mmol)PPBr3。加完后，反应混合物室温下搅拌1小时，TLC显示反应完成。反应混合物倾倒入冰水中，搅拌，用50mL×3的二氯甲烷萃取，合并萃取有机相，用饱和食盐水洗涤，无水硫酸钠干燥，在旋转蒸发仪上蒸去溶剂，得到的残余物柱层析纯化，得到产物IV-1，黄白色固体，ESI-MS,m/z＝248、250([M+H]+)。
取一只50mL的圆底烧瓶，加入化合物1.24g(5mmol)IV-1和0.80g(5mmol)化合物V-1，以10mL干燥的DMF溶解，搅拌，再加入2.07g(15mmol)K2CO3，而后升温至100℃，N2气氛下搅拌过夜。TLC显示反应完成。反应混合物倾倒入冰水中，搅拌，用50mL×3的二氯甲烷萃取，合并萃取有机相，用饱和食盐水洗涤，无水硫酸钠干燥，在旋转蒸发仪上蒸去溶剂，得到的残余物柱层析纯化，得到产物I-1，白色固体，ESI-MS,m/z＝328([M+H]+)。
实施例2
取一只100mL圆底烧瓶，加入2.27g(10mmol)化合物II，以20mL干燥的THF溶解，冰水浴冷却下搅拌，分批加入0.44g(20mmol)LiBH4后，继续在室温下搅拌过夜。TLC显示反应完成。反应混合物倾倒入冰水中，搅拌，用浓盐酸调节pH＝3，用50mL×3的二氯甲烷萃取，合并萃取有机相，用饱和食盐水洗涤，无水硫酸钠干燥，在旋转蒸发仪上蒸去溶剂，得到的残余物柱层析纯化，得到产物III，白色固体，ESI-MS,m/z＝186([M+H]+)。
取一只100mL的圆底烧瓶，加入1.48g(8mmol)化合物III和10mL二氯甲烷，冰水浴冷却下搅拌，慢慢加入5.41g(20mmol)PPBr3。加完后，反应混合物室温下搅拌1小时，TLC显示反应完成。反应混合物倾倒入冰水中，搅拌，用50mL×3的二氯甲烷萃取，合并萃取有机相，用饱和食盐水洗涤，无水硫酸钠干燥，在旋转蒸发仪上蒸去溶剂，得到的残余物柱层析纯化，得到产物IV，白色固体，ESI-MS,m/z＝248、250([M+H]+)。
取一只50mL的圆底烧瓶，加入化合物1.24g(5mmol)IV和0.87g(5mmol)化合物V-2，以10mL干燥的DMF溶解，搅拌，再加入2.07g(15mmol)K2CO3，而后升温至100℃，N2气氛下搅拌过夜。TLC显示反应完成。反应混合物倾倒入冰水中，搅拌，用50mL×3的二氯甲烷萃取，合并萃取有机相，用饱和食盐水洗涤，无水硫酸钠干燥，在旋转蒸发仪上蒸去溶剂，得到的残余物柱层析纯化，得到产物I-2，白色固体，ESI-MS,m/z＝342([M+H]+)。
实施例3-8
按照实施例1的方法，合成了具有通式I的下列化合物。
实施例9体外血小板聚集抑制试验
在96孔板中，在TRAP(凝血酶受体活化肽)诱导的血小板聚集中进行物质的药理学试验。注射器中预先加入3.13％的柠檬酸钠溶液，然后抽入20mL健康志愿者的血液，在1500g下离心20分钟，将富含血小板的血浆(PRP)分离出来并以1μLPGE1溶液(500μg/mL的乙醇溶液)/mLPRP的量进行处理。在室温下孵育5分钟后，将其在1200g下离心20分钟以除去白细胞。将不含白细胞的PRP以5mL/份分批转移到15mL的PP管中，并在3600g下离心使血小板沉淀。而后，滗出上层血浆，将得自5mLPRP的血小板沉淀重新混悬于1mLTyrode(120mMNaCl，2.6mMKCl，12mMNaHCO3，0.39mMNaH2PO4，10mMHEPES，0.35％BSA，5.5mM葡萄糖，pH＝7.4)中，并用Tyrode调节至3×105/μL的血小板计数。将13mL这种细胞混悬液用866μL的10mMCaCl2溶液处理，以每孔120μL的量将其吸至96孔板中，在96孔板的孔中已经提前加入了15μL待测试物质。在室温下黑暗中孵育30分钟，加入15μLTRAP溶液(70-100μM)作为激动剂，在SpectraMax中37℃下振荡20分钟，在650nm下纪录动力学，计算阴性对照(tyrode/DMSO)和阳性对照(15μL激动剂/DMSO)的曲线下面积，并将差异定为100％。将待测试化合物以系列稀释物的形式吸移，一式两份地进行测定，同样测定各物质浓度的AUC，计算与对照相比的AUC抑制％。通过该抑制％按照4参数方程借助非线性回归分析计算IC50值。下表给出了结果。
| 化合物 | 血小板凝聚的抑制IC50(μM) |
| I-1 | 1.17 |
| I-2 | 0.22 |
| I-3 | 0.46 |
| I-4 | 0.61 |
| I-5 | 0.29 |
| I-6 | 0.85 |
| I-7 | 1.30 |
| I-8 | 1.51 |
从上表可以看出，本发明的化合物在血小板凝聚试验中均表现出较好的抑制作用。
Claims (4)
1.具有通式I结构的化合物及其药学上可以接受的盐，
其中，R1选自H、C1-C3的烷基、C3-C5的环烷基。
2.权利要求1所定义的通式I化合物，选自下列化合物，
3.合成权利要求1-2任一项所定义的通式I的化合物的方法：
化合物II使用LiBH4还原为III；化合物III使用卤化试剂转化为IV；IV和V在碱的存在下反应得到I；其中X选自Cl和Br；R1的定义如权利要求1-2任一所示。
4.权利要求1-2任一项所定义的通式I化合物及其药学上可以接受的盐在制备治疗血栓性药物方面的应用。
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