CN107304200B - 一种新的喜巴辛类似物及其在医药中的应用 - Google Patents
一种新的喜巴辛类似物及其在医药中的应用 Download PDFInfo
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- CN107304200B CN107304200B CN201710264296.1A CN201710264296A CN107304200B CN 107304200 B CN107304200 B CN 107304200B CN 201710264296 A CN201710264296 A CN 201710264296A CN 107304200 B CN107304200 B CN 107304200B
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- heteroaryl
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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Abstract
本发明涉及一种新的喜巴辛类似物，所述化合物具有式(Ι)结构，以及式(Ι)化合物的立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物和含有它们的药物组合物，以及其用途。
Description
技术领域
本发明涉及有机化学和药物学领域，具体而言，本发明涉及一种新的喜巴辛类似物，所述化合物具有式(Ι)结构，以及式(Ι)化合物的立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物和含有它们的药物组合物，以及其用途。
背景技术
心脑血管事件包括急性冠脉综合征(acute coronary syndrome，ACS)、心肌梗塞、脑血栓等，具有高发病率和高死亡率的特点。世界卫生组织也指出缺血性心脑血管事件是导致死亡的首要因素。目前我国每年有超过300万人死于心脑血管疾病，占全部死亡人数的40.3％。此类疾病的病理原因是由于血小板活化后聚集形成血栓，进而导致机体组织的缺血，因此抗血栓治疗是目前预防心脑血管事件发生的主要方式。
血小板发生黏附后是血小板的活化过程，包括多种自分泌和旁分泌因子的释放，这些因子包括二磷酸腺苷(adenosine diphosphate，ADP)、凝血酶、肾上腺素、血栓烷素A2，它们不仅对血小板的最初反应起信号放大和维持作用，而且使血液循环中的血小板逐渐形成止血栓子。血小板表面结合的多种凝血因子激活促使凝血酶原转化为凝血酶，凝血酶可促进血小板的聚集又可促进纤维蛋白原转化为纤维蛋白，这是促进凝血和止血的主要原因。血小板对凝血酶的反应由血小板表面G蛋白偶联受体，即凝血酶受体介导。进一步研究发现凝血酶受体可被蛋白酶水解所激活，因此凝血酶受体又被称为蛋白酶激活受体(Protease Activated Receptors，PARs)。有4种PARs亚型，广泛分布于组织中，PAR-1，PAR-3，PAR-4可被凝血酶激活，PAR-2则被胰蛋白酶或类胰蛋白酶激活。人类血小板只表达PAR-1和PAR-4两种受体，其中PAR-1在凝血酶介导的血小板激活中起着最主要的作用。鼠类血小板表达PAR-1和PAR-3两种受体。
目前已上市的口服抗血栓药物均通过抑制血小板活化途径发挥作用。环氧化酶抑制剂阿司匹林可以抑制血栓烷素A2的产生。噻吩吡啶类药物(如氯吡格雷)可与血小板表面的ADP受体P2Y12产生不可逆结合，从而抑制ADP的血小板活化作用。ADP和血栓烷素A2引起的血小板活化途径对于常规病理性血栓形成和止血都是关键性步骤，因而联合应用环氧化酶抑制剂和噻吩吡啶类药物在发挥抗栓作用的同时，不可避免地导致出血并发症风险的上升。因此尽管抗血小板治疗在目前临床上已取得了较好的效果，但其所带来的出血风险仍值得关注。
由PAR-1介导的血小板活化途径主要对病理性血栓形成有作用。PAR-1受体抑制剂可阻断凝血酶介导的血小板激活而不影响凝血酶介导的纤维蛋白原裂解，同时PAR-1受体抑制剂也不影响参与血小板黏附、激活或聚集途径的相关因子，如胶原，vWF，ADP和促凝血素(参见Coughlin SR.；J Thromb Haemost.,2005,3:1800-1814)，因此PAR-1受体抑制剂既有抗血栓的作用又有可能不会增加出血风险，是理想的抗血小板药物。另外，凝血酶受体拮抗剂还可与阿司匹林、氯吡格雷等联合用药以增加抗血栓作用。凝血酶受体拮抗剂也有希望开发成抗动脉硬化和抗癌的新药。
自凝血酶受体发现以来，许多制药公司都致力于以凝血酶受体为靶点的新药开发研究。目前已经公开了一系列凝血酶受体拮抗剂的专利申请，如WO03089428公开一类喜巴辛衍生物；WO2002085855公开了一种2-亚氨基吡咯烷类衍生物。Merck公司开发的凝血酶受体拮抗剂SCH530348在Ⅲ期临床试验中显示，SCH530348明显降低了心肌梗塞或脑血栓等心血管疾病的发病率，但同时也发现有出血不良反应，尤其是中风、短暂性脑缺血以及脑出血患者，脑颅内出血几率增加，这使得目前凝血酶受体拮抗剂的适用人群大大减少。研发出血副反应更少，疗效更优的新型凝血酶受体拮抗剂仍具有很大挑战。
本发明设计具有通式(I)所示的化合物，本发明化合物同现有技术中具体公开的化合物具有较大的结构差异，且表现出优异的效果和作用。
发明内容
为了克服现有技术的不足之处，本发明的目的是提供具有式(Ι)结构所示的新的喜巴辛类似物，以及它们的立体异构体、互变异构体、或药学上可接受的盐或溶剂化物，或代谢产物和代谢前体或前药，
一种具有式(Ι)结构的化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物：
其中:
R1选自杂环基、芳基或杂芳基，其中所述的杂环基、芳基或杂芳基可进一步任选的被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；其中所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基可进一步任选的被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
R2选自-C(O)OR3、-CN、-C(O)NR3R4、杂环基、芳基或杂芳基，其中所述的杂环基、芳基或杂芳基可进一步任选的被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；其中所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基可进一步的任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
X选自CH或N；
n选自0、1、2或3，且当n＝0，X＝N时，R2选自杂芳基，其中所述的杂芳基可进一步的任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；其中所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基可进一步的任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
R3和R4各自独立选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的杂环基、芳基或杂芳基可进一步的任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、烷氧基、烷基或环烷基的取代基所取代。
优选的，本发明的式(Ι)结构的化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物：
其中，
R1选自杂环基、芳基或杂芳基，其中所述的杂环基、芳基或杂芳基可进一步的任选被一个或多个选自卤素、羟基、氰基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；其中所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基可进一步的任选被一个或多个选自卤素、羟基、氰基、胺基、-NR3R4、烷氧基、烷基、环烷基的取代基所取代；
R2选自-C(O)OR3、-CN、-C(O)NR3R4、或杂芳基，其中所述的杂芳基可进一步的任选被一个或多个选自卤素、羟基、氰基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；其中所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基可进一步的任选被一个或多个选自卤素、羟基、氰基、胺基、-NR3R4、烷氧基、烷基、环烷基的取代基所取代；
X选自CH或N；
n选自0、1或2，且当n＝0，X＝N时，R2选自杂芳基，其中所述的杂芳基可进一步的任选被一个或多个选自卤素、羟基、氰基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；其中所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基可进一步的任选被一个或多个选自卤素、羟基、氰基、胺基、-NR3R4、烷氧基、烷基、环烷基的取代基所取代；；
R3和R4各自独立选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的杂环基、芳基或杂芳基可进一步的任选被一个或多个选自卤素、羟基、氰基、胺基、烷氧基、烷基或环烷基的取代基所取代。
进一步优选，如式(Ⅱ)结构所述的化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，其特征在于，该化合物优选自：
其中：
R1选自杂环基、芳基或杂芳基，所述的杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
式(Ⅱ-1)结构中，R2选自-C(O)OR3、-CN、-C(O)NR3R4、杂环基、芳基或杂芳基，所述的杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
式(Ⅱ-2)结构中，R2选自杂芳基；所述的杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
R3和R4各自独立选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，所述的杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、烷氧基、烷基或环烷基的取代基所取代。
本发明涉及式(Ⅰ)中任何一项化合物或其立体异构体、互变异构体、前药在药学上可接受的盐或溶剂化物，其中药学上可接受的盐为所述化合物与无机酸/有机酸或无机碱/有机碱形成的常规无毒盐，这些盐可以为单盐、二盐、三盐或者多盐，由所述化合物所含的可成盐官能团所决定。其中如果所述式(Ⅰ)化合物含有碱性官能团，则可与硫酸、盐酸、氢溴酸、磷酸、酒石酸、富马酸、马来酸、柠檬酸、乙酸、甲酸、甲磺酸、对甲苯磺酸、草酸或琥珀酸形成酸加成盐，这些盐可以根据常规化学方法从包含碱性官能团的本发明化合物和相应无机酸/有机酸反应合成；如果所述式(Ⅰ)化合物含有酸性官能团，则可与碱性试剂形成稳定的碱金属盐、碱土金属盐或任选取代的铵盐，所述碱性试剂为例如氢氧化物、碳酸盐、碳酸氢盐、烷氧化物和氨或者有机碱，例如三甲基胺、三乙基胺、乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇或其他碱性氨基酸，例如赖氨酸、鸟氨酸或精氨酸等；这些盐可以根据常规化学方法从包含酸性官能团的本发明化合物和相应无机碱/有机碱反应合成。
本发明还涉及所述化合物在药学上可接受的溶剂化物，包括常规溶剂化物，例如本发明所述化合物在制备过程中由于溶剂存在而形成的溶剂化物，由水或者乙醇的存在形成的溶剂化物可以作为非限制性实例。
本发明的另一方面涉及所述式(Ⅰ)结构中任何一项化合物的异构体，式(Ⅰ)结构所述化合物中存在一个或多个碳碳双键，可能存在顺反异构体，没有特殊说明下本发明包含所有可能存在的顺反异构体或者不同比例异构体组成的混合物；同时式(Ⅰ)结构所述化合物中还存在一个或多个手性中心，没有特殊说明下本发明包含所有理论上可能存在的消旋体、消旋体混合物、对映异构体、非对映异构体及非对应异构体混合物。本发明中所述的化学结构式、化学名称包括所述化合物所有理论上可能存在的异构体。
如果式(Ⅰ)所述化合物以非对映异构体或者对映异构体的混合物形式存在或在所选合成中以其混合物形式得到，则式(Ⅰ)所述化合物可按如下方法分离成光学纯立体异构体：在任选手性的载体物质上进行色谱分离，或如果外消旋化合物能够形成盐，则也可与作为助剂的光学活性碱或者光学活性酸形成的非对映异构体盐进行分级结晶。对于非对映异构体薄层色谱分离或者柱色谱的合适手性固定相的实例为改性硅胶载体(成为Pirkle相)和高分子量烃例如三乙酰基纤维素。为了分离式(Ⅰ)所述化合物中含有酸性基团的外消旋体，与光学活性碱例如(-)-烟碱、(+)-和(-)-苯基乙基胺、奎宁碱、L-赖氨酸、L-精氨酸和D-精氨酸形成具有不同溶解度的非对映异构体盐，溶解度较小的组分以固体形式来分离，纯的对映异构体由以上方法得到的非对映异构体盐来得到。式(Ⅰ)所述化合物中含有碱性基团例如氨基的外消旋体可按上述方法用光学活性酸例如(+)-樟脑-10-磺酸、D-和L-酒石酸、D-和L-乳酸、D-和L-扁桃酸转化成纯的对映异构体。
本发明的另一方面涉及式(Ⅰ)所述化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物的同位素取代物，其中任何一个化合物中可以存在至少一个氢原子被氘原子取代或至少一个碳原子或氟原子被相应的同位素取代。
本发明的另一方面涉及一种药物组合物，其含有式(Ⅰ)中任何一项化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物及可药用的载体。
本发明的另一方面涉及式(Ⅰ)中所述任何一项化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，或药物组合物在制备凝血酶受体拮抗剂的药物中的用途。
本发明的另一方面涉及式(Ⅰ)中所述任何一项化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，或药物组合物在制备凝血酶受体拮抗剂的药物中的用途，其中凝血酶受体拮抗剂是PAR1受体拮抗剂。
本发明的另一方面涉及式(Ⅰ)中所述任何一项化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，或药物组合物在制备血小板凝集抑制剂的药物中的用途。
本发明的另一方面涉及式(Ⅰ)中所述任何一项化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，或药物组合物在制备治疗和/或预防与凝血酶受体有关疾病的药物中的用途，其中所述的与凝血酶受体有关疾病选自动脉和静脉血栓症、急性冠状动脉综合征、再狭窄、稳定型心绞痛、心律紊乱、心肌梗塞、高血压、心衰竭、中风、炎性疾病、肺栓塞症等肺部疾病、胃肠疾病、风湿、哮喘、慢性肝纤维化、肿瘤和皮肤病。
本发明的另一方面涉及式(Ⅰ)中所述任何一项化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，或药物组合物和另外一种心血管类药物的产品，作为组合产品同时、或分别用于心血管疾病治疗，其中所述的另一类心血管类药物是选自阿司匹林、氯吡格雷、噻氯匹啶、阿昔单抗、替罗非班或依替巴肽等抗血小板凝集药物。
发明的详述
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
“卤素”指氟、氯、溴、碘。
“烷基”指饱和的脂肪族烃基团，包括1至20个碳原子的直链和支链基团。优选含有1至12个碳原子的烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2_三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2_二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3_二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4_二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3_二甲基己基、2，4_二甲基己基、2，5_二甲基己基、2，2_二甲基己基、3，3_二甲基己基、4，4_二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2，2-二乙基戊基、正癸基、3，3-二乙基己基、2，2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2_二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基。
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个碳原子，优选包括3至12个碳原子，更优选环烷基环包含3至10个碳原子。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。多环环烷基包括螺环、稠环和桥环的环烷基。
“螺环烷基”指5至20元，单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。
“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个环原子，其中一个或多个环原子选自N、O或S(O)m(其中m是整数0至2)的杂原子，其余环原子为C。优选包括3至12个环原子，其中1～4个是杂原子，更优选环烷基环包含3至10个环原子。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等；多环杂环基包括螺环、稠环和桥环的杂环基。
“螺杂环基”指5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自N、O或S(O)m(其中m是整数0至2)的杂原子，其余环原子为C。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。
“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自N、O或S(O)m(其中m是整数0至2)的杂原子，其余环原子为C。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。
“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自N、O或S(O)m(其中m是整数0至2)的杂原子，其余环原子为C。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基；杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基。
“芳基”指6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环；芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基。
“杂芳基”指包含1至4个杂原子，5至14个环原子的杂芳族体系，其中杂原子包括氧、硫和氮。优选为6至10元，更优选为是5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环；杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基。
“烷氧基”指-O-(烷基)和-O-(未取代的环烷基)，其中烷基的定义如上所述。非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。烷氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自为卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本发明还包括，含有本发明化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物的药物组合物。
本发明的药物组合物，可以是任何可服用的药物形式：如片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂或贴剂。
本发明的药物组合物，优选的是单位剂量的药物制剂形式。
本发明的药物组合物，在制成药剂时，单位剂量的药剂可含有本发明的药物活性物质0.1-1000mg，其余为药学上可接受的载体。药学上可接受的载体以重量计可以是制剂总重量的0.01-99.99％。
本发明的组合物在使用时根据病人的情况确定用法用量，如一日1-3次。一次1-10片等。
优选的，本发明的组合物为口服制剂或注射剂。
其中，所述口服制剂选自胶囊剂、片剂、滴丸、颗粒剂、浓缩丸、口服液和合剂中的一种。
其中，所述注射剂选自注射液、冻干粉针剂和水针剂中的一种。
本发明的药物组合物，其口服给药的制剂可含有常用的赋形剂，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂或湿润剂，必要时可对片剂进行包衣。
适用的填充剂包括纤维素、甘露糖醇、乳糖或其它类似的填充剂。适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮或淀粉衍生物，优选羟基乙酸淀粉钠。适宜的润滑剂为硬脂酸镁。适宜的湿润剂为十二烷基硫酸钠。
本发明的药物组合物可通过混合，填充，压片等常用的方法制备固体口服组合物。进行反复混合可使活性物质分布在整个使用大量填充剂的组合物中。
口服液体制剂的形式可以是水性或油性悬浮液、溶液、乳剂、糖浆剂或酏剂，也可以是一种在使用前可用水或其它适宜的载体复配的干燥产品。这种液体制剂可含有常规的添加剂，诸如悬浮剂，例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪，乳化剂，例如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶；非水性载体(它们可以包括食用油)，例如杏仁油、分馏椰子油、诸如甘油酯的油性酯、丙二醇或乙醇；防腐剂，例如对羟基苯甲酯、对羟基苯甲酸丙酯或山梨酸，并且如果需要，可含有常规的香味剂或着色剂。
对于注射剂，制备的液体单位剂型含有本发明的活性物质和无菌载体。根据载体和浓度，可以将此化合物悬浮或者溶解。溶液的制备通常是通过将活性物质溶解在一种载体中，在将其装入一种适宜的小瓶或安瓿前过滤消毒，然后密封。辅料例如一种局部麻醉剂、防腐剂和缓冲剂也可以溶解在这种载体中。为了提高其稳定性，可在装入小瓶以后将这种组合物冰冻，并在真空下将水除去。
本发明的药物组合物，在制备成药剂时可选择性的加入适合的药物可接受的载体，所述药物可接受的载体选自如下的一种或几种：甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、土温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β－环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本发明的药物剂型不完全局限于此，它可以制备成更多的剂型，如滴丸、缓释制剂等任何可服用的药物形式。
具体实施方式
下面通过具体的实施例进一步说明本发明，下述实施例中给出了代表性化合物的合成及相关结构鉴定数据，其用于说明本发明而不是对本发明的限制，根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
实施例1：N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-氟苯)-2-吡啶基]-乙烯基]十二氢-1-甲基-3-氧代萘并[2,3-c]呋喃-6-基]氨基乙酸(Ι-1)
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]aminoacetic acid(Ι-1)
第一步：
将化合物1a(30g,0.275mol)和吡啶(32g)加入到300mL DCM中，氮气保护下降温至0℃；滴加三氟甲磺酸酐(93g，0.33mol)，反应体系升至室温；1h后反应体系倒入400mL水中，150mL二氯甲烷萃取，有机相用2N的稀盐酸(100mL)洗一次，饱和食盐水洗一次,干燥浓缩得棕色液体化合物1b(62g，收率93％)。
第二步：
将化合物1b(62g，0.257mol)、1c(43.2g，0.308mol)、碳酸钾(106g，0.77mol)、Pd(PPh3)4依次加入到400mL甲苯中，氮气置换3次，将体系温度升至90℃，回流反应6h；体系降至室温后，倒入400mL水中,体系经硅藻土过滤,滤液经水洗一次,饱和食盐水洗一次,干燥浓缩得145g棕色液体；粗品经柱层析纯化(PE:EA＝20：1)，浓缩得棕色液体化合物1d(42g，收率87％)。
第三步：
氮气保护下，将正丁基锂滴加到-40℃的二异丙胺THF(280mL)溶液中，-30℃反应1.5h；将1d(48g，0.256mol)溶于500mL THF中，氮气保护下，降温至-60℃，将上述LDA滴加到该体系中，-60℃保温反应1h；将1e(53g，0.308mol)滴加到体系中，-50℃反应1.5h；将体系倒入1L的饱和氯化铵中，水相用乙酸乙酯(400mL×2)萃取，合并有机相，浓缩干得红棕色液体，经柱层析纯化(DCM:MeOH＝50:1)，得红棕色液体化合物1f(38g，收率79.7％)。
第四步：
N2保护下，0℃，将LHMDS的THF滴加到1f(600mg，1.8mmol)的THF(6mL)溶液中，加毕，保温30min；将Ti(i-OPr)4的THF(1mL)滴加到体系中，反应10min；将1g【合成方法见Bioorganic&Medicinal Chemistry Letters，20，2010，6676】(200mg，0.61mmol)的THF(1.5mL)滴加到体系中，然后恢复至室温反应3h；向体系中加入20mL饱和酒石酸钾钠的水溶液，乙酸乙酯萃取，干燥旋干有机相。后经柱色谱纯化得淡白色固体1h(130mg，收率22％)。
第五步：
室温下将1h(0.8g，1.6mmol)溶于浓盐酸中，升至120℃反应3小时；旋干得化合物1i，并直接投入下一步。
第六步：
室温下，N2保护，将TEA加入到1i(200mg，0.43mmol)的MeOH中，室温反应15min；向体系中加入乙醛酸水溶液(65mg，0.43mmol)，室温反应30min；向体系中加入NaBH3CN(28mg，0.43mmol)，室温反应1h；向体系中加入少量的水-甲醇淬灭，直接浓缩旋干，薄层色谱制备(MeCN:H2O＝5:1)，浓缩得淡黄色固体化合物I-1(50mg，收率24％)。
1H NMR(DMSO,400MHz):δ8.65(1H,s),7.95(1H,d,J＝6.0Hz),7.48(1H,d,J＝8.0Hz),7.40(2H,m),7.33(1H,d,J＝9.6Hz),7.05(1H,s),6.55(2H,d,J＝3.6Hz),4.74(1H,m),3.46(2H,m),3.21(1H,m),2.65(1H,m),2.35(2H,t,J＝1.6Hz),2.03(2H,m),1.85(2H,m),1.30-1.18(12H,m),0.80(2H,m),0.77(2H,m)；
ESI-MS:479.2[M+H]+
实施例2：N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-氟苯)-2-吡啶基]-乙烯基]十二氢-1-甲基-3-氧代萘并[2,3-c]呋喃-6-基]氨基乙腈(Ι-2)
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]aminoacetonitrile(Ι-2)
室温下，将1i(0.39g，0.92mmol)、溴乙腈(0.14g，1.21mmol)、DIPEA(0.36g，2.78mmol)加入到乙腈中，氮气保护下40℃反应5h；反应体系中加入饱和100mL NaHCO3溶液，乙酸乙酯萃取，有机相浓缩干燥得0.185g粗产品；经薄层色谱纯化(DCM:MeOH＝15:1)后得白色固体Ⅰ-2(60mg，收率25％)。
1H NMR(DMSO,400MHz):δ8.78(1H,s),7.82(1H,d,J＝6.4Hz),7.47(1H,m),7.37(1H,m),7.28(4H,m),7.10(1H,m),6.61-6.53(2H,m),4.75(1H,m),3.64(2H,m),2.73(2H,m),2.39(2H,m),2.01-1.91(4H,m),1.61-0.89(12H,m)；
ESI-MS:460.2[M+H]+
实施例3：N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-氟苯)-2-吡啶基]-乙烯基]十二氢-1-甲基-3-氧代萘并[2,3-c]呋喃-6-基]-N-(4-甲基嘧啶基-2)-氨(Ι-3)
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]-N-(4-methylpyrimidin-2-yl)amino(Ι-3)
将1i(150mg，0.36mmol)、3a(92mg，0.71mmol)、DIPEA(1mL)加入至5mL DMSO中，N2保护下，加热至150℃反应10h；反应体系降至室温，加入20mL水析出固体，过滤，滤饼用水洗，得白色固体Ι-3(40mg，收率21.9％)。
1H NMR(DMSO,400MHz):δ8.70(1H,s),8.04(1H,d,J＝4.0Hz),7.74(1H,d,J＝11.2Hz),7.37(1H,m),7.34(1H,m),7.28(1H,m),7.02(1H,m),6.55(2H,m),6.31(1H,d,J＝4.8Hz),4.83(1H,d,J＝7.6Hz),4.68(1H,m),3.82(1H,m),2.67(1H,m),2.53(1H,m),2.31(2H,m),2.22(3H,s),2.02(2H,m),1.88(2H,m),1.37(3H,s),1.24-0.80(8H,m)；
ESI-MS:513.35[M+H]+
实施例4：N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-氟苯)-2-吡啶基]-乙烯基]十二氢-1-甲基-3-氧代萘并[2,3-c]呋喃-6-基]-N–(苯并恶唑基-2)-氨(Ι-4)
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]-N-(benzo[d]oxazol-2-yl)amino(Ι-4)
室温下，将1i(110mg，0.26mmol)、4a(80mg，0.52mmol)、碳酸钾(69mg，0.52mmol)加入至10mL DMF中，N2保护下，加热至100℃反应10h；反应体系降至室温，加入20mL水，乙酸乙酯(20mL×2)萃取，合并有机相，干燥浓缩后经高压制备色谱纯化得到白色固体Ι-4(29mg，收率20.7％)。
1H NMR(DMSO,400MHz):δ8.82(1H,s),7.87(1H,d,J＝2.0Hz),7.48(1H,s),7.47(2H,m),7.46-7.06(6H,m),6.63(2H,m),5.43(1H,d,J＝12.6Hz),4.80(1H,d,J＝12.6Hz),3.85(1H,m),2.76(1H,m),2.44(2H,d,J＝8.0Hz),2.28(2H,m),2.02(3H,m),1.48(3H,s),1.36-1.01(7H,m)；
ESI-MS:538.60[M+H]+
实施例5:N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-(3’-氟-1,1’-联苯基)-4-乙烯基]十二氢-1-甲基-3-氧代萘并[2,3-c]呋喃-6-基]氨基甲酸乙酯(Ι-5)
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[3'-fluoro-(1,1'-biphenyl)-4-yl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]carbamic acidethyl ester(Ι-5)
第一步：
0℃下，将NaH(139mg，2.7mmol)加入到5a(1.78g，2.7mmol)的10mL THF溶液中，继续反应1h；滴加1g(450mg，1.38mmol)的THF(10mL)溶液，升至室温反应2h；体系用饱和NH4Cl水溶液淬灭，乙酸乙酯萃取，有机相干燥浓缩后得化合物5b直接用于下一步。
第二步：
室温下，将5c(0.48g，3.4mmol)、Pd(PPh3)4(140mg，0.7mmol)加入到5b(0.66g，1.3mmol)的甲苯-EtOH-Na2CO3水溶液(10mL-5mL-5mL)的混合液中，N2保护升温到85℃过夜；向体系中加入50mL水，乙酸乙酯萃取，合并有机相，干燥浓缩后经硅胶柱色谱纯化得白色固体Ⅰ-5(100mg，收率15.6％)。
1H NMR(DMSO,400MHz):δ8.65(1H,s),7.54(2H,d,J＝8.0Hz),7.40(4H,m),7.27(1H,d,J＝10.8Hz),7.04(1H,s),6.47(1H,d,J＝16.0Hz),5.95(1H,m),4.72(1H,d,J＝4.0Hz),4.55(1H,m),4.10(2H,m),3.56(1H,m),2.70(1H,m),2.37(2H,m),2.04(2H,m),1.90(2H,m),1.44(3H,s),1.27(6H,m),0.97(2H,m),0.91(2H,m)；
ESI-MS:492.20[M+H]+
实施例6：N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-4-(2-吡啶基)-苯乙烯基]十二氢-1-甲基-3-氧代萘并[2,3-c]呋喃-6-基]氨基甲酸乙酯(Ι-6)
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[4-(pyridin-2-yl)-phenyl]ethenyl]dode cahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]carbamic acidethyl ester(Ι-6)
0℃下，Ar保护，将n-BuLi滴加到6a(590mg，1.9mmol)的THF(6mL)溶液中,并在0℃下反应30min；向体系滴加1g(250mg，0.77mmol)的THF(6mL)溶液，反应1h；饱和NH4Cl水溶液淬灭反应，乙酸乙酯萃取，有机相浓缩干燥后经硅胶柱色谱纯化(PE:EA＝1:2)得白色固体Ⅰ-6(140mg，收率38.2％)。
1H NMR(DMSO,400MHz):δ8.69(1H,s),7.98(2H,d,J＝6.8Hz),7.75(2H,d,J＝8.6Hz),7.44(2H,d,J＝6.8Hz),7.25(1H,d,J＝7.6Hz),6.48(1H,d,J＝7.6Hz),5.97(1H,m),4.73(1H,m),4.5(1H,m),4.10(2H,d,J＝6.0Hz),3.50(1H,m),2.69(1H,m),2.39(2H,m),2.04(2H,m),1.93(2H,m),1.43(3H,s),1.23(6H,m),1.07(2H,m),0.92(2H,m)；
ESI-MS:475.25[M+H]+
生物测试实施例1：钙离子转运抑制实验
下面所述的模型表明本发明所述化合物是PAR-1受体抑制剂。在各种细胞类型中，通过选择性PAR-1激动剂激活PAR-1受体触发细胞内信号通路导致内质网释放钙离子。在表达人类PAR1的KNRK细胞系中，使用钙离子选择性探针通过荧光技术测定通过SFLLR激活的对受体里的钙释放。荧光的发射强度与PAR-1拮抗剂的活性和浓度成正比。该方法可以测定本发明化合物对PAR-1介导的钙离子转运的影响。
一、实验材料：
试剂：HBSS缓冲液，HEPES，probenecid，BSA，Calcium 4dye购自Invitrogen。TFLLR-NH2，SCH-79797等试剂由法国SEREP公司提供。
细胞系：稳定表达人类PAR1的KNRK细胞系。
荧光显微镜：CellLux(PerkinElmer)。
化合物Ⅰ-1～Ⅰ-6：由天士力制药集团股份有限公司研究院提供。
缓冲液与原液配制：
Assay buffer：1×HBSS缓冲液，配制成含20mM HEPES，2.5mM probenecid，0.1％BSA，PH＝7.4(probenecid与BSA需要新鲜配制)的缓冲液；
Loading buffer：1×HBSS缓冲液，配制成含20mM HEPES，2.5mM probenecid，0.1％BSA，PH＝7.4(probenecid与BSA需要新鲜配制)，2μM calcium 4dye的缓冲液；
化合物原液(5×CPD)：首先用100％DMSO溶解化合物，使化合物终浓度为10mM。实验时，将上述原液用assay buffer配制成5倍浓度溶液备用；
6×TFLLR-NH2：用assay buffer将haTRAP稀释成终浓度为30uM备用。
反应终体积：20uL loading buffer，5uL 5×CPD，5uL 6×TFLLR-NH2(haTRAP，终浓度为5uM)。
二、实验步骤：
1、预先用1倍Matrigel处理无菌384孔板，37℃放置15-30min；
2、将上述处理好的无菌384孔板的每孔中加入2×104个稳定表达人类PAR1的KNRK细胞，细胞培养箱中培养24小时；
3、将384孔板中的细胞培养液去除，加入20uL含Calcium 4dye的loading buffer；
4、在培养箱中避光培养60min；
5、然后再培养孔中加入5uL 5倍化合物原液(DMSO的终浓度为1％)，继续培养15min，然后加入5uL 6倍TFLLR-NH2，在荧光显微镜下记录荧光强度100秒。
6、实验结果中抑制剂活性表示为抑制剂在不同浓度下的荧光强度占空白对照haTRAP激发荧光强度的百分比。测试化合物对PAR-1的抑制率按以下公式计算：IR＝(FNC-FTC)/FNC％
FNC:阴性对照组孔的荧光强度
FTC:测试化合物孔的荧光强度
在10μM浓度下，钙信号拮抗作用>60％，本发明的衍生物被鉴定为PAR-1受体拮抗剂。
7、测试化合物的半数抑制浓度IC50可以通过不同浓度下的抑制率计算得出。
三、实验结果：
本发明化合物不同浓度下对PAR-1受体的抑制率如下：
本发明化合物的半数抑制浓度IC50测定如下：
结论：本发明测试化合物对PAR-1介导的钙离子转运具有明显的抑制作用，钙信号拮抗作用IC50在0.18～2.1μM范围内，活性优于或近似于上市药物SCH530348，本发明所述化合物被鉴定为PAR-1受体拮抗剂。
生物测试实施例2：本发明化合物的药代动力学测试
研究本发明实施例Ⅰ-2、Ⅰ-3、Ⅰ-6化合物不同时刻血浆及脑组织中的药物浓度，研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。
1.实验动物
健康成年SD大鼠8只，雌雄各半，平均分成4组。购买于北京维通利华实验动物技术有限公司。
2.给药剂量
本研究为单剂量给药实验。8只SD大鼠雌雄各半，平均分成4组，每组2只，分别为SCH530348组、Ⅰ-2组、Ⅰ-3组、Ⅰ-6组。给药前禁食12h。给药剂量为5mg/kg。
3.药物配制
称取适量药物，加入0.5％羧甲基纤维素钠研磨至样品均匀混悬，样品浓度为2.0mg/ml，临用时配制。
4.采血方案
大鼠给药后0min，5min，15min，25min，40min，1h，2h，4h，8h,12h，24h眼眶取血0.5mL，于4500rpm离心10分钟取血浆。-20℃冰箱保存。
5.样品制备
取血浆样品50ul,加入20ul 1ug/ml的地西泮内标溶液，再加入10uL甲醇，400uL的乙酸乙酯，充分涡旋3min后，17000r/min离心10min,取上清300ul，氮吹吹干后，用100uL的甲醇：水＝1:1复溶，充分涡旋1min后直接进样进行LC-MS分析。
本发明化合物的药代动力学参数如下表：
结论：本发明化合物Ⅰ-2和Ⅰ-6化合物在体内的半衰期和血药浓度均优于已上市药物SCH530348，并且Ⅰ-2和Ⅰ-6化合物在脑组织/血浆中的药物浓度比值要远远小于SCH530348，提示本发明化合物Ⅰ-2和Ⅰ-6穿越血脑屏障能力更弱，脑出血的风险可能会大大减小，具有更好的临床应用前景。
Claims (8)
1.一种化合物或其药学上可接受的盐：
2.根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，所述化合物药学上可接受的盐为所述化合物与无机酸或有机酸或无机碱或有机碱形成的常规无毒盐。
3.一种药物组合物，其特征在于，含有权利要求1-2任何一项所述化合物或其药学上可接受的盐及可药用的载体。
4.权利要求1-2任意一项所述化合物或其药学上可接受的盐或权利要求3药物组合物在制备凝血酶受体拮抗剂的药物中的用途。
5.权利要求1-2任意一项所述化合物或其药学上可接受的盐或权利要求3药物组合物在制备治疗和/或预防与凝血酶受体有关疾病的药物中的用途。
6.根据权利要求4所述的用途，其特征在于，所述凝血酶受体拮抗剂是PAR1受体拮抗剂。
7.根据权利要求5所述的用途，其特征在于，与凝血酶受体有关疾病选自动脉和静脉血栓症、急性冠状动脉综合征、再狭窄、稳定型心绞痛、心律紊乱、心肌梗塞、高血压、心衰竭、中风、肺栓塞症、胃肠疾病、风湿、哮喘、慢性肝纤维化、肿瘤和皮肤病。
8.权利要求1-2任意一项所述化合物或其药学上可接受的盐和另外一种心血管类药物作为组合产品用于制备治疗心血管疾病的药物中的用途，其特征在于，所述的另外一种心血管类药物选自阿司匹林、氯吡格雷、噻氯匹啶、阿昔单抗、替罗非班或依替巴肽。
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| CN1659162A (zh) * | 2002-04-16 | 2005-08-24 | 先灵公司 | 三环凝血酶受体拮抗剂 |
| CN1878552A (zh) * | 2003-11-10 | 2006-12-13 | 先灵公司 | 凝血酶受体拮抗剂的使用方法 |
| CN101384259A (zh) * | 2005-12-22 | 2009-03-11 | 先灵公司 | 作为预防来自心肺外科手术的并发症的凝血酶受体拮抗剂 |
| WO2009124103A2 (en) * | 2008-04-02 | 2009-10-08 | Schering Corporation | Combination therapies comprising par1 antagonists with par4 antagonists |
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| CN1659162A (zh) * | 2002-04-16 | 2005-08-24 | 先灵公司 | 三环凝血酶受体拮抗剂 |
| CN1878552A (zh) * | 2003-11-10 | 2006-12-13 | 先灵公司 | 凝血酶受体拮抗剂的使用方法 |
| CN101384259A (zh) * | 2005-12-22 | 2009-03-11 | 先灵公司 | 作为预防来自心肺外科手术的并发症的凝血酶受体拮抗剂 |
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