CN104072436A - 对位取代的四氮唑苯乙酮化合物、其制备方法和用途 - Google Patents
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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，本发明涉及一类对位取代的含四氮唑苯乙酮结构的PAR-1拮抗剂、其制备方法、及含有它们的药物组合物以及它们在制备治疗血栓性疾病药物中的应用。
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四氮唑苯乙酮结构的PAR-1拮抗剂及其制备方法，以及含有它们的药物组合物。
背景技术
蛋白酶激活受体1 (Protease Activated Acceptor-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(Acute Coronary Syndrome)。已经有几个PAR-1抑制剂处于临床研究(Chackalamannil S., Thrombin Receptor (Protease Activated Receptor-1) Antagonists as Potent Antithrombotic Agents with Strong Antiplatelet Effects, 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。
本发明公开了一类四氮唑苯乙酮结构的PAR-1拮抗剂，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：
( I )
其中，
R选自C1-C5的烷基、C3-C5的环烷基和OR1，R1选自C1-C5的烷基和C3-C5的环烷基。
优选以下具有通式I的化合物，其中，
R选自C1-C3的烷基和OR1，R1选自C1-C3的烷基。
进一步，优选以下具有通式I的化合物，
。
更进一步，优选以下具有通式I的化合物，
。
本发明所述通式I化合物通过以下步骤合成：
。
化合物II和化合物III在酸或者碱的催化下反应，得到化合物(I)。
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的。
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1 mg-500 mg/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
。
反应原料：自制，常规方法。
1.76 g (10 mmol)化合物II-1、3.70 g (10 mmol)化合物III-1和4.15 g (30 mmol)固体碳酸钾在20 mL乙腈中搅拌过夜，而后升温回流3小时。
反应混合物稍冷后倾倒到200 mL冰水中，搅拌，用浓盐酸调节pH = 4，50 mL × 3的二氯甲烷萃取，合并有机相，食盐水洗涤，无水硫酸钠干燥，在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到纯品I-1，白色固体，MS, m/z = 488 ([M+Na]+)。
实施例2-5
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6 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20 mL健康志愿者的血液，在1500 g下离心20分钟，将富含血小板的血浆(PRP)分离出来并以1 μL PGE1溶液(500 μg/mL的乙醇溶液)/mL PRP的量进行处理。在室温下孵育5分钟后，将其在1200 g下离心20分钟以除去白细胞。将不含白细胞的PRP以5 mL/份分批转移到15 mL的PP管中，并在3600 g下离心使血小板沉淀。而后，滗出上层血浆，将得自5 mL PRP的血小板沉淀重新混悬于1 mL Tyrode (120 mM NaCl，2.6 mM KCl，12 mM NaHCO3，0.39 mM NaH2PO4，10 mM HEPES，0.35% BSA，5.5 mM葡萄糖，pH = 7.4)中，并用Tyrode调节至3 × 105/μL的血小板计数。将13 mL这种细胞混悬液用866 μL的10 mM CaCl2溶液处理，以每孔120 μL的量将其吸至96孔板中，在96孔板的孔中已经提前加入了15 μL待测试物质。在室温下黑暗中孵育30分钟，加入15 μL TRAP溶液(70-100 μM)作为激动剂，在SpectraMax中37°C 下振荡20分钟，在650 nm下纪录动力学，计算阴性对照(tyrode/DMSO)和阳性对照(15 μL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：
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明显的抑制作用。
Claims (5)
1.具有通式I结构的化合物及其药学上可以接受的盐，
( I )
其中，
R选自C1-C5的烷基、C3-C5的环烷基和OR1，R1选自C1-C5的烷基和C3-C5的环烷基。
2.权利要求1所定义的具有通式I的化合物及其药学上可以接受的盐，
其中，
R选自C1-C3的烷基和OR1，R1选自C1-C3的烷基。
3.权利要求2所定义的通式I化合物，选自下列化合物，
。
4.权利要求3所定义的通式I化合物，选自下列化合物，
。
5.权利要求1-4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用途。
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