CN108129370A - 一种腈基二苯基硫代乙酸结构的p2y12受体拮抗剂及其用途 - Google Patents
一种腈基二苯基硫代乙酸结构的p2y12受体拮抗剂及其用途 Download PDFInfo
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Abstract
本发明涉及与心血管疾病相关的药物领域。具体而言,本发明涉及一种含腈基二苯基硫代乙酸结构的P2Y12受体拮抗剂、其制备方法及其在制备治疗心血管疾病尤其是血栓栓塞性疾病药物中的应用。
Description
技术领域
本发明涉及血管疾病治疗的药物领域。具体地讲,本发明涉及对血管疾病尤其是血栓栓塞性疾病具有治疗作用的一种含腈基二苯基硫代乙酸结构的P2Y12受体拮抗剂、其制备方法及其在制药上的用途。
背景技术
与发生血栓形成有关的医学并发症代表一种主要的致死原因。一些与发展血栓形成有关的病理学实例包括急性心肌梗塞、不稳定型心绞痛和慢性稳定型心绞痛、短暂性缺血发作、脑血管意外、周围性血管疾病、先兆子痫和子痫、深部静脉血栓形成、栓塞(脑栓塞、肺栓塞、冠状动脉栓塞、肾栓塞等等)、弥散性血管内凝血或血栓性血小板减少性紫癜。在侵入性外科手术期间和之后仍有发生血栓形成和再狭窄并发症的危险,所述侵入性外科手术如血管成形术、颈动脉内膜切除术、主动脉冠状动脉旁路移植术或支架或血管内假体的安置。
动脉血栓形成可在血管壁损伤或动脉粥样化斑块破裂后发生。血小板在这些血栓形成中发挥着必要的作用。血小板可通过以下物质激活:血流中循环细胞或沿血管壁呈现的损害性内皮细胞所释放的介体,或者在血管损伤期间所暴露的内皮下基质(如胶原)的血栓形成分子。此外,血小板还可在具有高剪切应力的血流条件下如在狭窄血管中所观察到的那样激活。激活后,所述循环血小板粘附并积聚在血管损伤处,形成血栓。在该过程中,血管中所产生的血栓对血流是体积足够大的,从而使其被部分或完全堵塞。
在静脉中,血栓还可在阻塞或血流慢处形成。由于这些静脉血栓的性质,其可产生在血管系统中移动的栓子。这些栓子因而可堵塞更远距离的血管中的血流,所述血管如肺动脉或冠状动脉。
许多研究已经证明5'-二磷酸腺苷(ADP)是血小板激活和聚集的主要介体,在血栓形成的启动和进展中发挥着决定性作用(Maffrand et al.,Thromb.Haemostas.,1988,59,225-230)。ADP通过损害的红细胞和动脉粥样硬化壁的内皮细胞释放到循环中,更具体而言,由以密集颗粒在非常高浓度储存ADP之处的激活血小板所分泌。ADP-诱导的血小板聚集由其与在人血小板的细胞膜表达的两种特异性嘌呤能受体P2Y1和P2Y12的结合所触发。所述P2Y1受体,与经Gαq的PLCβ刺激联合,负责内部钙储存的动员、血小板形状的改变和在ADP上的瞬间聚集。所述P2Y12,与经Gαi2的腺苷酸环化酶的抑制和PI-3激酶的激活联合,负责响应的放大和聚集的稳定化。P2Y1-/-转基因小鼠(Gachet et al.,J.Clin.Invest.,1999,104,1731-1737)和P2Y12-/-小鼠(Conley et al.,Nature,2001,409,202-207)的使用证明了所述两种受体在体内血栓发展中的重要性。在人类中,已经描述P2Y12基因缺陷与出血表型和ADP-诱导的血小板聚集的显著衰退有关。在人类临床实践中使用氯吡格雷已经证明,由拮抗剂阻断P2Y12受体代表着治疗心血管疾病的关键治疗策略。氯吡格雷为噻吩并吡啶家族的前药,其活性代谢物共价结合至P2Y12受体,导致体内血小板活性的不可逆抑制(Savi et al.,Biochem.Biophys.Res.Commun.,2001,283,379-383),该药物在若干临床试验中显示其效能,即降低有危险的患者发生心血管意外的危险。
本发明公开了一种含腈基二苯基硫代乙酸结构的P2Y12受体拮抗剂,这些化合物可用于制备治疗心血管疾病尤其是血栓栓塞性疾病的药物。
发明内容
本发明的一个目的是提供一种具有式I的良好活性的P2Y12受体拮抗剂。
本发明的另一个目的是提供制备具有式I的化合物的方法。
现结合本发明的目的对本发明内容进行具体描述。
本发明具有式I的化合物具有下述结构式:
本发明所述式I化合物可以通过以下路线合成:
化合物II和与三苯基膦反应,得到盐III;化合物III用正丁基锂处理,得到对应的膦叶立德IV,后者与化合物V在加热的情况下反应,得到化合物VI;化合物VI与溴反应,得到二溴代物VII;化合物VII与巯基乙酸在碱性条件下反应,得到化合物I。
本发明所述式I化合物具有P2Y12受体的拮抗作用,可作为有效成分用于制备心血管疾病尤其是血栓栓塞性疾病治疗药物。本发明所述式I化合物的活性是通过体外人血血小板聚集的抑制试验来验证的。
本发明的式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-700mg/人范围内,分为一次或数次给药。实际服用本发明式I化合物的剂量可由医生根据有关的情况来决定。
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化合物I-1的合成
步骤1.化合物III-1的合成
化合物II-1(1.63g,10mmol)和三苯基膦(2.62g,10mmol)溶于30mL氯仿中,搅拌下回流过夜,析出大量晶体。反应混合物冷却,抽滤收集固体,室温下真空干燥,得到化合物III-1,白色结晶性固体,ESI-MS,m/z=345([M-Br]+)。
步骤2.化合物VI-1的合成
化合物III-1(3.40g,8mmol)溶于50mL干燥的THF中,搅拌,在氮气气氛中冷却到-20℃,而后用注射器慢慢滴加1.6M的n-BuLi的正己烷溶液(5mL,8mmol),滴加完毕后,反应混合物在该温度下继续搅拌1小时。用注射器再慢慢滴加二苯甲酮(V-1,1.46g,8mmol)溶于5mL干燥的THF制成的溶液,滴加完毕后,反应混合物在该温度下搅拌半小时,而后升温至室温搅拌1小时,最后再回流下搅拌过夜。反应混合物小心倾倒入300mL冰水中,搅拌,用50mL×3CH2Cl2萃取,合并萃取相,用盐水洗涤,无水硫酸钠干燥。抽滤除去干燥剂,滤液在旋转蒸发仪上蒸干,残余物使用硅胶柱层析纯化,得到化合物VI-1,ESI-MS,m/z=249([M+H]+),白色固体。
步骤3.化合物VII-1的合成
化合物VI-1(0.99g,4mmol)溶于10mL CH2Cl2中,搅拌,慢慢滴加Br2(0.80g,5mmol)和1mL CH2Cl2配制的溶液,滴加完毕后,反应混合物在室温下搅拌过夜,TLC检查发现反应完成。往反应混合物中加入30mL乙醚和20mL正己烷,室温下搅拌1小时,抽滤,收集固体,室温下真空干燥,得到化合物VII-1,ESI-MS,m/z=409([M+H]+)。
步骤4.化合物I-1的合成
将巯基乙酸(0.28g,3mmol)溶于10mL乙醇中,搅拌,慢慢滴加30%的NaOH溶液(1mL),而后加入化合物VII-1(0.82g,2mmol),反应混合物在氮气气氛中回流24小时,TLC检查发现反应完成。反应混合物小心倾倒入200mL冰水中,搅拌,用浓盐酸调节pH=2-3,用50mL×3CH2Cl2萃取,合并萃取相,用盐水洗涤,无水硫酸钠干燥。抽滤除去干燥剂,滤液在旋转蒸发仪上蒸干,残余物使用硅胶柱层析纯化,得到化合物I-1,ESI-MS,m/z=337([M-H]-),白色固体。
实施例2化合物I-2的合成
步骤1.化合物III-2的合成
化合物II-2(1.77g,10mmol)和三苯基膦(2.62g,10mmol)溶于30mL氯仿中,搅拌下回流过夜,析出大量晶体。反应混合物冷却,抽滤收集固体,室温下真空干燥,得到化合物III-2,白色结晶性固体,ESI-MS,m/z=359([M-Br]+)。
步骤2.化合物VI-2的合成
化合物III-2(3.51g,8mmol)溶于50mL干燥的THF中,搅拌,在氮气气氛中冷却到-20℃,而后用注射器慢慢滴加1.6M的n-BuLi的正己烷溶液(5mL,8mmol),滴加完毕后,反应混合物在该温度下继续搅拌1小时。用注射器再慢慢滴加V-2(1.86g,8mmol)溶于5mL干燥的THF制成的溶液,滴加完毕后,反应混合物在该温度下搅拌半小时,而后升温至室温搅拌1小时,最后再回流下搅拌过夜。反应混合物小心倾倒入300mL冰水中,搅拌,用50mL×3CH2Cl2萃取,合并萃取相,用盐水洗涤,无水硫酸钠干燥。抽滤除去干燥剂,滤液在旋转蒸发仪上蒸干,残余物使用硅胶柱层析纯化,得到化合物VI-2,ESI-MS,m/z=313([M+H]+),白色固体。
步骤3.化合物VII-2的合成
化合物VI-2(1.25g,4mmol)溶于10mL CH2Cl2中,搅拌,慢慢滴加Br2(0.80g,5mmol)和1mL CH2Cl2配制的溶液,滴加完毕后,反应混合物在室温下搅拌过夜,TLC检查发现反应完成。往反应混合物中加入30mL乙醚和20mL正己烷,室温下搅拌1小时,抽滤,收集固体,室温下真空干燥,得到化合物VII-2,ESI-MS,m/z=473([M+H]+)。
步骤4.化合物I-2的合成
将巯基乙酸(0.28g,3mmol)溶于10mL乙醇中,搅拌,慢慢滴加30%的NaOH溶液(1mL),而后加入化合物VII-2(0.95g,2mmol),反应混合物在氮气气氛中回流24小时,TLC检查发现反应完成。反应混合物小心倾倒入200mL冰水中,搅拌,用浓盐酸调节pH=2-3,用50mL×3CH2Cl2萃取,合并萃取相,用盐水洗涤,无水硫酸钠干燥。抽滤除去干燥剂,滤液在旋转蒸发仪上蒸干,残余物使用硅胶柱层析纯化,得到化合物I-2,白色固体,ESI-MS,m/z=402([M-H]-)。
实施例3化合物体外对人血血小板的抑制作用
使用含有2mL缓冲的柠檬酸钠的20mL注射器,从健康志愿者采集血液。将血液转移至聚丙烯管中,并在室温离心(100g)5分钟(不使用离心机的制动)。然后收集浮在表面的富血小板血浆(PRP),稀释,并在将其用于聚集测量之前进行血小板计数。
在玻璃管中37℃进行血小板聚集的测量(血小板聚集仪)。将4μL测试化合物(比需要的终浓度浓100倍的DMSO溶液)与392μL新制的PRP混合,并伴随搅拌孵育1分钟。然后向混合物中加入4μL 250μM的ADP溶液。持续搅拌,通过按照G.V.R.Born的方法记录光密度变化(Born,Nature,1962,194,927),监测聚集的测量6至8分钟。使用以高度表示的聚集振幅计算结果,并以抑制百分数表示。本发明化合物的(血小板聚集抑制作用的)IC50如下表所示。
化合物 | IC50(nM) |
化合物I-1 | 761 |
化合物I-2 | 158 |
从上表结果可以看出,本发明的化合物对P2Y12具有很强拮抗作用,可以作为制备治疗心血管疾病尤其是血栓栓塞性疾病的药物。
Claims (3)
1.具有通式I结构的化合物,
2.合成权利要求1化合物的方法:
化合物II和与三苯基膦反应,得到盐III;化合物III用正丁基锂处理,得到对应的膦叶立德IV,后者与化合物V在加热的情况下反应,得到化合物VI;化合物VI与溴反应,得到二溴代物VII;化合物VII与巯基乙酸在碱性条件下反应,得到化合物I。
3.权利要求1化合物在制备治疗血栓栓塞性疾病药物方面的应用。
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