CN115043820A - Par-1抑制剂及其类似物的制备方法和在血栓性疾病防治中的应用 - Google Patents
Par-1抑制剂及其类似物的制备方法和在血栓性疾病防治中的应用 Download PDFInfo
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- CN115043820A CN115043820A CN202210590220.9A CN202210590220A CN115043820A CN 115043820 A CN115043820 A CN 115043820A CN 202210590220 A CN202210590220 A CN 202210590220A CN 115043820 A CN115043820 A CN 115043820A
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Abstract
本发明属于有机合成和药物化学技术领域,具体涉及PAR‑1抑制剂及其类似物的制备方法和在血栓性疾病防治中的应用。本发明以大宗天然产物穿心莲内酯为原料,进一步优化舒心帕沙的结构,提供一种具有靶点明确、作用机制清晰、结构新颖、安全性好、活性更优的新型PAR‑I抑制剂,其IC50值能够达到纳摩尔级别;本发明同时提供其制备方法和在预防和/或治疗血栓性疾病中的用途,可使其作为治疗血栓性疾病的很有前景的药物,因此具有良好的实际应用之价值。
Description
技术领域
本发明属于有机合成和药物化学技术领域,具体涉及PAR-1抑制剂及其类似物的制备方法和在血栓性疾病防治中的应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
心血管疾病已经成为世界上最主要的死亡原因。在中国,从1990年到2017 年间,中国缺血性心脏病粗死亡率(未标化年龄)上升了155.4%,年龄标化死亡率上升了20.6%。其中,由于血管栓塞引起的心血管疾病的发病率逐年上升,目前已经成为我国重大的公共卫生问题。日益增长的患者数量,使得我们迫切需要预防和治疗心血管疾病的新方法。
研究表明,血小板过度活化在血栓形成和和血栓性疾病的发生和发展过程中起到重要作用。因此抑制血小板的过度活化,减小血小板的黏附、聚集和释放是防治血栓性疾病的重要手段。抗血小板药物是减少血小板聚集和抑制血栓形成的药物。它们广泛用于血栓性脑血管或心血管疾病的一级预防和二级预防。最常见的抗血小板药物是环氧化酶抑制剂(阿司匹林)和腺苷二磷酸(ADP)受体抑制剂氯吡格雷和噻氯匹定。但传统抗血小板药物只要通过抑制TXA2或ADP阻碍血栓的形成,但TXA2和ADP同时参与人体正常的止血过程,这将导致在抑制病理性血栓形成过程的同时影响正常的止血功能,进而大大提高患者发生出血的概率并产生一定的安全风险。
据报道,凝血酶受体(PARs)是G蛋白偶联受体(GPCRs)超家族的一员,在人体内表达,它是心血管疾病治疗的靶点。PAR家族由PAR-1、PAR-2、PAR-3 和PAR-4组成,凝血酶主要在血管内皮和血小板中不可逆地激活PAR-1,PAR-1 作为一种高亲和力受体,在亚纳摩尔凝血酶浓度下介导血小板反应。抑制PAR-1 受体能够阻断由凝血酶介导的血小板聚集和病理性血栓形成的过程,而且不会影响由TXA2和ADP参与的人体正常的止血过程。因此,PAR-1抑制类药物的研究是一个热点。
截至目前,上市的PAR-1类抑制类药物只有硫酸沃拉帕沙(Vorapaxar Sulfate),它由美国默沙东公司研发,于2014年5月获得美国食品药品管理局 (FDA)批准上市,主要用于有心肌梗塞或外周动脉疾病史患者以减少血栓性心血管情况的发生。尽管临床数据表明沃拉帕沙具有良好的抗凝血活性,但其存在结构复杂、合成路线较长、合成工艺冗杂和制备成本昂贵的缺点。而且,长期临床数据显示部分人群会出现一定程度的出血副作用,同时由于该药半衰期较长 (10天),目前没有合适的药物能够抑制和缓解这种出血症。
天然产物由于其具有种类多样、结构复杂、手性明确、构象固定等特点,是研发新药的重要来源。以廉价易得的天然产物作为起始原料或药物前体,对其进行结构改造和修饰,可以迅速构建并大规模制备药物,同时还可有效降低生产成本。二萜类化合物穿心莲内酯是常见的重要活性天然产物,其结构式如下:
其结构中手性中心的构象与沃拉帕沙结构中对应的关键手性中心构象完全一致。因此,以二萜类化合物为前体,在确保其关键手心中心构象保持不变的前提下,对其进行结构修饰与改造,是快速发现新的PAR-1抑制剂类药物的重要途径。前期研究过程中,以穿心莲内酯为原料,通过对其进行结构修饰与改造,发现了新型PAR-1小分子抑制剂舒心帕沙,其结构如下:
该化合物具有结构新颖、作用机制清晰、生物半衰期合理、安全性高和制备成本低等优点;然而,发明人发现,其PAR-1抑制活性在微摩尔级别,尚有进一步优化和提升的空间。
发明内容
针对现有技术中的不足,本发明提供PAR-1抑制剂及其类似物的制备方法和在血栓性疾病防治中的应用。本发明以大宗天然产物穿心莲内酯为原料,进一步优化舒心帕沙的结构,提供一种具有靶点明确、作用机制清晰、结构新颖、安全性好、活性更优的新型PAR-I抑制剂,其IC50值能够达到纳摩尔级别;本发明同时提供其制备方法和在预防和/或治疗血栓性疾病中的用途,可使其作为治疗血栓性疾病的很有前景的药物,因此具有良好的实际应用之价值。
本发明的技术方案如下:
本发明的第一个方面,提供一种化合物,其选自如下式Ⅰ所示化合物,
R1和R2独立地选自:氢原子、卤素原子、羟基、(C1-C4)烷基、(C1-C4) 烷氧基或(C1-C4)羟烷基;或,
R1和R2共同形成一个具有3-7个原子的环或杂环;
所述R3和R4独立地选自:氢原子、羟基、氨基、酮羰基、(C1-C4)烷基、 (C1-C4)羟烷基或(C1-C4)烷氧基;或,
R3独立地选自:-C(O)R6、-C(O)OR6、-CO(O)R6、-COSOR6、-C(O)NR6R7;
R4独立地选自:-O(O)CR8、-OSOR8、-OSO2R8、-NHC(O)OR8、-NHC(O)R8、 -NHCONHR8、-NHC(O)NR8R9、-NHSO2R8;
R5独立地选自:卤素原子、三氟甲氧基或三氟甲基;
进一步的,R6、R7、R8和R9独立选自氢原子、(C1-C6)烷基、氨基、酯基、羧酸基、苯基及苄基。
优选的,所述R1和R2共同形成一个具有4-7个原子的内酯环;R3为氢原子、(C1-C4)羟烷基、甲酸基、甲酸甲酯基、醛基或甲酰胺基;R4为羟基、甲氧基或-NHC(O)OEt;R5为卤素原子或三氟甲基。
进一步优选的,所述R1和R2共同形成五元内酯环。
除非另外指出,术语“(C1-C4)烷氧基”表示基团-O-R,其中R为(C1-C4) 烷基。
术语“(C1-C4)羟烷基”表示被羟基取代的(C1-C4)烷基基团。
术语“环”表示R1和R2间通过共价键相连,并且与六元碳环上的原子共同形成一个环状结构。
术语“杂环”表示由R1、R2构成的环中,包含有一个或多个杂原子,例如:氧原子、氮原子或硫原子等。
关于取代基,本发明所述独立地是指当可能存在多于一个的取代基时,所述取代基可彼此相同或不同的情况。
所述化合物还包括其药学上可接受的盐或酯或溶剂化物、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物或前药。
本发明的第二个方面,提供上述化合物的制备方法,所述制备方法中,合成路线如下:
即可以使式(II)所示的化合物与式(III)所示的化合物反应得到式(I)所示的化合物。
其中,R1、R2、R3、R4和R5具有如前所述的定义。此外,R3和R4还可代表共同形成的4至8元碳环或杂环。
上述式(II)所示的化合物,其合成路线如下:
本发明的第三个方面,提供一种药物组合物,所述药物组合物包括第一方面所述化合物。更具体的,其作为活性成分发挥治疗血栓性疾病的作用,另外,除第一方面所述化合物之外,还可能包括其他具有心血管疾病治疗作用的药物。
以及,一种药物制剂,其包含上述第一方面中所述化合物,和至少一种药学上可接受的辅料和/或载体。
本发明的第四个方面,提供上述第一方面所述化合物或者上述第三方面中所述的药物组合物或药物制剂在制备防治血栓性疾病产品中的应用。
本发明的第五个方面,提供一种血栓性疾病的治疗方法,其包括向受试者施用治疗有效量的本发明第一方面所述的化合物或本发明第三方面所述的药物组合物或药物制剂。
上述一个或多个技术方案的有益效果:
(1)上述技术方案提供的PAR-I抑制剂,作用靶点明确、结构新颖、活性高,其IC50值能够达到纳摩尔级别,安全性高,制备成本低廉、易于工业化批量生产,在作为治疗血栓性疾病的候选药物中具有很好的应用前景;
(2)上述技术方案中的化合物的合成工艺路线中所使用的起始物料为市售的活性天然物质穿心莲内酯。该反应路线中使用的试剂及物料均为常用市售产品,合成过程中也不涉及化合物手性中心的生成和转化。因此,合成该路线可在确保其手性中心构象不变的前提下,通过连续反应,由起始物料快速且高效的制备得到目标产物,具有良好的经济性,适合进行大规模工业化批量生产。。
具体实施方式
需要指出的是,以下详细说明都是例示性的,旨在对本发明提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案,以下将结合具体的实施例详细说明。
本发明的一个典型具体实施方式中,提供一种化合物,其选自如下式Ⅰ所示化合物,
其中,
R1和R2独立地选自:氢原子、卤素原子、羟基、(C1-C4)烷基、(C1-C4) 烷氧基或(C1-C4)羟烷基;或,
R1和R2共同形成一个具有3-7个原子的环或杂环;
所述R3和R4独立地选自:氢原子、羟基、氨基、酮羰基、(C1-C4)烷基、 (C1-C4)羟烷基或(C1-C4)烷氧基;或,
R3独立地选自:-C(O)R6、-C(O)OR6、-CO(O)R6、-COSOR6、-C(O)NR6R7;
R4独立地选自:-O(O)CR8、-OSOR8、-OSO2R8、-NHC(O)OR8、-NHC(O)R8、 -NHCONHR8、-NHC(O)NR8R9、-NHSO2R8;
R5独立地选自:卤素原子、三氟甲氧基或三氟甲基;
进一步的,R6、R7、R8和R9独立选自氢原子、(C1-C6)烷基、氨基、酯基、羧酸基、苯基及苄基。
优选的,所述R1和R2共同形成一个具有4-7个原子的内酯环;R3为氢原子、 (C1-C4)羟烷基、甲酸基、甲酸甲酯基、醛基或甲酰胺基;R4为羟基、甲氧基或-NHC(O)OEt;R5为卤素原子或三氟甲基。
进一步优选的,所述R1和R2共同形成五元内酯环。
除非另外指出,术语“(C1-C4)烷氧基”表示基团-O-R,其中R为(C1-C4) 烷基。
术语“(C1-C4)羟烷基”表示被羟基取代的(C1-C4)烷基基团。
术语“环”表示R1和R2间通过共价键相连,并且与六元碳环上的原子共同形成一个环状结构。
术语“杂环”表示由R1、R2构成的环中,包含有一个或多个杂原子,例如:氧原子、氮原子或硫原子等。
关于取代基,本发明所述独立地是指当可能存在多于一个的取代基时,所述取代基可彼此相同或不同的情况。
所述化合物还包括其药学上可接受的盐或酯或溶剂化物、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物或前药。
根据本领域一般技术人员的理解,所述药学上可接受的盐包括上述化合物的碱金属盐形式(具体实例如钠盐或钾盐),或所述化合物与无机盐如盐酸、硫酸、硝酸或氢溴酸形成的盐,以及与有机酸,例如甲磺酸、甲苯磺酸或三氟乙酸形成的盐。术语“药学可接受的”或者与其可互换使用的“可药用的”,例如在描述“药学可接受的盐”时,表示该盐其不但是受试者生理学上可接受,而且还可指在药学上有使用价值的合成物质,例如在为进行手性拆分时所形成的作为中间体的盐,虽然这种中间体的盐并不能直接给予受试者,但该盐可在为获得本发明终产物中起作用。
本发明的又一具体实施方式中,所述化合物包括:
本发明的又一具体实施方式中,提供上述化合物的制备方法,所述制备方法中,合成路线如下:
即可以使式(II)所示的化合物与式(III)所示的化合物反应得到式(I)所示的化合物。
其中,R1、R2、R3、R4和R5具有如前所述的定义。此外,R3和R4还可代表共同形成的4至8元碳环或杂环。
上述式(II)所示的化合物,其合成路线如下:
具体的,所述式(II)所示化合物,其制备方法包括:以穿心莲内酯为起始原料,经脱水重排反应和环氧化反应得(VII)所示的化合物,再经臭氧裂解得式(VI)化合物;其经一锅法E1消除以及羰基保护得式(V)所示的化合物,再经硼氢化氧化得式(IV)所示化合物,再对羰基位点进行修饰引入R2基团,即制得式(II)所示的化合物。
R1、R2、R3和R4具有如前所述的定义。此外,R3和R4还可代表共同形成的 4至8元碳环或杂环。
本发明的又一具体实施方式中,提供一种药物组合物,所述药物组合物包括第一方面所述化合物。更具体的,其作为活性成分发挥治疗血栓性疾病的作用,另外,除第一方面所述化合物之外,还可能包括其他具有心血管疾病治疗作用的药物。
所述血栓性疾病包括但不限于血栓形成、动脉粥样硬化、再狭窄症、高血压、心绞痛、心脏衰竭、紧急梗死、肾小球炎或周边血管疾病。
所述心血管疾病具体为与血栓形成相关的疾病,其包括血栓形成、动脉粥样硬化、再狭窄症、高血压、心绞痛、心律不整、心脏衰竭、心肌梗死、肾小球炎、血栓形成性中风、血栓栓塞性中风、周边血管疾病、其他心血管疾病以及凝血酶及其受体在其中其病理作用的其他疾病。
以及,一种药物制剂,其包含上述第一方面中所述化合物,和至少一种药学上可接受的辅料和/或载体。
本发明所述辅料是指药物组合物或药物制剂中除有效成分之外的成分,其对受试者无毒。本领域常用的辅料比如缓冲剂、稳定剂、防腐剂或赋型剂,常用的赋形剂例如粘合剂、填充剂、润湿剂、崩解剂等。
作为示例,本发明的所述制剂中可选用的赋形剂包括但不限于:所述赋形剂选自磷酸钙、硬脂酸镁、滑石粉、糊精、淀粉、凝胶纤维素、甲基纤维素、羧甲基纤维素钠盐和聚乙烯吡咯烷酮。
本发明所述药物载体可以是药学上可接受的溶剂、悬浮剂、囊泡、纳米材料等,用于将本发明上述第一方面所述的化合物递送至动物或人体内。载体可以是液体或固体,并按照计划的给药方式进行选择。蛋白和脂质体也是药物载体。
本领域技术人员可采用公知的技术将本发明的化合物配制成药物组合物或制剂。比如将本发明上述第一方面中披露的任意化合物(至少一种化合物)与药用辅料混合,然后如果需要,使所得混合物形成所需的形状。除本发明提到的除外,也可根据已知药物制剂进行药物制剂的制备。以及,除本发明提到的以外,合适的药用辅料是本领域已知的,例如参见2005年版的药用辅料手册(原著第四版),作者(英)R.C.罗(RaymondCRowe)(美)P.J.舍斯基(PaulJSheskey)。
本发明的又一具体实施方式中,提供上述第一方面所述化合物或者上述第三方面中所述的药物组合物或药物制剂在制备防治血栓性疾病产品中的应用。
所述产品具体为药品,所述药品可以治疗或缓解血栓性疾病,如上所示,所述血栓性疾病包括但不限于血栓形成、动脉粥样硬化、再狭窄症、高血压、心绞痛、心脏衰竭、紧急梗死、肾小球炎或周边血管疾病。
本发明所述受试者是指已经是治疗、观察或实验的对象的动物,优选指哺乳动物,最优选指人。
本发明所述治疗有效量是指包括本发明化合物在内的活性化合物或药物制剂的量,该量可引起研究者、兽医、医生或其他医疗人员所追求的组织系统、动物或人的生物学或医学响应,所述响应包括减轻或部分减轻所述治疗疾病、综合征、病症或障碍的症状。
本领域的研究者、兽医、医生或其他医疗人员可根据临床试验或者本领域其他公知的手段获知可使用的治疗有效量的范围。
以下通过实施例对本发明做进一步解释说明,但不构成对本发明的限制。应理解这些实施例仅用于说明本发明而不用于限制本发明的范围。实施例中用到的所有原料除特殊说明外,均为市购获得。
实施例1
新型PAR-1抑制剂(化合物I)的制备方法,具体步骤如下:
(1)化合物3的制备
称0.75kg中间体2加入50L反应釜,加22.5L THF/DMSO混合溶剂(30倍质量体积)室温搅拌溶解;称1.8kg IBX加入反应体系;加料完成后升温至40℃反应6h;TLC监测反应完成后往反应釜中加15L纯水搅拌10min;0-5℃下往反应体系加入0.34kg Na2S2O3(3.0eq)猝灭反应,控制反应体系温度≤25℃;称 0.55kg NaHCO3(3.0eq)分批加入反应体系,控制反应体系温度≤25℃。加料完成后继续搅拌20min;停止搅拌,静止分层,放出上层有机相,下层水相加5L EA,搅拌15min后静置20min分层。弃去水相合并有机相;有机相加5L纯水搅拌15min,静置20min分层后弃去水相,此操作重复两次,有机相转移至物料桶中;称0.4kg无水硫酸钠加入有机相,手动搅拌干燥20min;抽滤,滤饼用200mL EA 洗涤;减压蒸馏至剩余溶剂约100mL(35℃,≤-0.08MP);柱层析,湿法上样,溶剂为PE/EA混合溶剂(PE:EA=1:1);柱层析结束,减压蒸馏(35℃,≤-0.08MP)得到淡黄色固体中间体湿品;湿品中间体二送入鼓风干燥箱干燥 (50℃)4h,得黄色固体0.57kg,收率为76%。
(2)化合物4的制备
称0.55kg中间体3加入30L反应釜,加4.4L t-BuOH和4.4L 2,3-二甲基 -2-丁烯(16倍质量体积),室温搅拌;称0.2kg亚氯酸钠(80%)(1.1eq.)、0.2kg NaH2PO4·2H2O(0.7eq.)加入5L烧杯中,加纯水3.85L溶解配置盐溶液;将盐溶液加入反应体系,室温反应8h;配置1L 3N盐酸溶液,TLC监测反应完成后滴加盐酸溶液至体系pH=2-3停止搅拌,静置20min分层,放出上层有机相,下层水相加5L EA,搅拌15min后静置20min分层。弃去水相合并有机相;有机相加5L纯水搅拌15min,静置20min分层后弃去水相,此操作重复两次,有机相转移至物料桶中;称0.2kg无水硫酸钠加入有机相,手动搅拌干燥20min;抽滤,滤饼用100mL EA洗涤;减压蒸馏(35℃,≤-0.08MP)得到淡黄色固体;黄色固体转移至30L反应釜中,加11L EA室温搅拌溶解;温度升至85℃回流搅拌8h;TLC监测反应完成后(展开剂:PE/EA=1:1,紫外显色),往反应釜中加10L纯水搅拌10min;静置20min分层后弃去水相,有机相转移至物料桶中;称0.15kg无水硫酸钠加入有机相,手动搅拌干燥20min;抽滤,滤饼用100mLEA 洗涤;减压蒸馏(35℃,≤-0.08MP)得到淡黄色油状物;柱层析,湿法上样(30mL CH2Cl2溶解样品),溶剂为PE/EA混合溶剂(PE:EA=1:1);柱层析结束,减压蒸馏(35℃,≤-0.08MP)得到淡黄色固体中间体湿品;湿品中间体二送入鼓风干燥箱干燥(50℃)4h。得淡黄色固体0.57kg,收率为70%。1H NMR(400MHz, CDCl3)δ7.15(s,1H),6.64(dd,J=15.4,10.1Hz,1H),6.17(d,J=15.6Hz,1H), 4.78(s,2H),2.85(d,J=2.7Hz,1H),2.61(d,J=4.2Hz,1H),2.43(td,J=14.5,6.1 Hz,1H),2.37–2.32(m,1H),2.31(d,J=4.2Hz,1H),2.25(d,J=9.9Hz,1H),1.94 (d,J=14.3Hz,1H),1.91–1.86(m,1H),1.86–1.80(m,1H),1.53–1.40(m,3H),1.33(dd,J=17.7,8.3Hz,1H),1.22(s,3H),1.02(d,J=6.5Hz,3H)。
(3)化合物5的制备
称30g中间体4加入圆底烧瓶中,量取550mL甲醇以及50mL吡啶加入烧瓶并在室温下溶解。将体系移至-78℃下搅拌10min,通入氧气,打开臭氧发生器,控制氧气流速为2-4L/min,直至反应溶液呈现淡蓝色,停止通入气体1min 不变色,停止通入氧气。并通入氮气排出体系内剩余臭氧。加入33mL二甲硫醚,在-78℃下搅拌0.5h。将体系移至室温搅拌过夜。减压蒸馏除去挥发物,得到的黄色油状物加入EA 300mL,氯化钠水溶液250mL,通过分液漏斗分液, EA萃取水相,合并有机相,硫酸钠干燥,蒸干,柱分离(PE:EA=5:1)得白色固体8.1g,收率为36%。1H NMR(400MHz,CDCl3)δ9.63–9.59(m,1H),3.03(d, J=1.8Hz,1H),2.76(d,J=2.4Hz,1H),2.59(s,1H),2.46(td,J=14.5,6.3Hz,1H), 2.38–2.27(m,2H),2.12–2.04(m,1H),2.02–1.88(m,2H),1.60(td,J=13.8,4.7 Hz,1H),1.54–1.45(m,1H),1.45–1.40(m,1H),1.36(s,3H),1.36–1.29(m,1H), 1.03(d,J=6.5Hz,3H)。
(4)化合物6的制备
称3.04g中间体5加入干燥的圆底烧瓶中,量取60mL二氯甲烷加入烧瓶并在室温下溶解。取CSA(1.5g,0.5eq.)加入反应瓶,并量取乙二醇(21mL,30 eq.)加入体系,并在室温下搅拌6h。反应完毕,加入60mL饱和碳酸氢钠水溶液淬灭,分离有机层,二氯甲烷(60mL×2)萃取水相。合并有机相,硫酸钠干燥,蒸干,柱分离(PE:EA=2:1)得无色油状物2.7g,收率为67%。1H NMR (400MHz,CDCl3)δ5.48(s,1H),4.92(dd,J=4.5,1.8Hz,1H),4.42(d,J=11.1Hz, 1H),4.18(d,J=11.0Hz,1H),3.98–3.89(m,4H),3.76–3.36(m,4H),2.98(br s,1H),2.31(s,1H),2.19(d,J=17.2Hz,1H),1.71–1.64(m,2H),1.64–1.60(m, 1H),1.60–1.55(m,2H),1.54–1.44(m,2H),0.82(d,J=6.6Hz,1H),0.78(s,1H)。
(5)化合物7的制备
称2.73g中间体6加入干燥的圆底烧瓶中,量取54mL二氯甲烷加入烧瓶并在室温下溶解。在0℃下加入咪唑(1.4g,2.5eq.),随后分批加入TBSCl(2.2g, 1.7eq.),并在室温下搅拌1h。加入60mL饱和碳酸氢钠水溶液淬灭,分离有机层,二氯甲烷(60mL×2)萃取水相。合并有机相,硫酸钠干燥,蒸干,得黄色油状物。不经柱分离直接进行后续反应。
将上述油状物溶解在35mL无水THF中,在0℃下缓慢加入硼烷二甲硫醚络合物(6.7mL,1.7eq.,1M THF solution),并在室温下反应2h。重新降温至0 ℃,缓慢滴加10%氢氧化钠4mL,随后加入30%过氧化氢水溶液1.1mL。在室温在搅拌过夜。加入40mL饱和碳酸氢钠水溶液淬灭,分离有机层,EA(40mL ×2)萃取水相。合并有机相,硫酸钠干燥,蒸干,柱分离(PE:EA=5:1)得无色油状物1.98g,收率为51%。1H NMR(400MHz,CDCl3)δ8.44(br s,1H),4.99(s, 1H),4.02(t,J=8.4Hz,1H),3.99–3.89(m,5H),3.73(t,J=5.2Hz,2H),3.71–3.64(m,2H),3.46(dd,J=10.5,5.3Hz,1H),2.53–2.44(m,1H),2.06(d,J=8.7Hz, 1H),1.85–1.78(m,1H),1.71(dd,J=11.2,6.3Hz,1H),1.67–1.58(m,4H),1.58– 1.54(m,1H),1.53–1.46(m,1H),0.88(s,9H),0.85(s,3H),0.84(d,J=6.8Hz,3H), 0.05(s,6H)。
(6)化合物8的制备
称3.84g中间体7加入干燥的圆底烧瓶中,量取38mL二氯甲烷加入烧瓶并在室温下溶解。取戴斯-马丁氧化剂在0℃下(5.36g,1.5eq.)分批加入反应瓶,并在室温下搅拌2h。反应完毕,加入30mL亚硫酸钠水溶液淬灭及30mL 饱和碳酸氢钠水溶液,分离有机层,二氯甲烷(30mL×2)萃取水相。合并有机相,硫酸钠干燥,蒸干,柱分离(PE:EA=6:1)得无色油状物3.65g,收率为 92%。1H NMR(400MHz,CDCl3)δ5.00(s,1H),4.41(dd,J=8.8,3.2Hz,1H),4.01 –3.92(m,4H),3.90(d,J=8.8Hz,1H),3.73(t,J=5.2Hz,2H),3.64(dt,J=9.9,4.8Hz,1H),3.44(dt,J=10.7,5.5Hz,1H),3.00–2.91(m,1H),2.56–2.49(m,1H), 2.47(d,J=10.9Hz,1H),1.92(q,J=11.7Hz,2H),1.72–1.68(m,2H),1.68–1.66 (m,1H),1.65–1.59(m,1H),1.58–1.51(m,1H),0.88(s,9H),0.83(d,J=6.5Hz, 3H),0.67(s,3H),0.05(s,6H)。
(7)化合物9的制备
称3.65g中间体8加入干燥的圆底烧瓶中,量取36mL无水THF加入烧瓶并在室温下溶解。将反应瓶移至-78℃下并向其中缓慢加入NaHMDS(4.82mL, 1.2eq.),并在该温度下继续搅拌1h。称取PhNTf2(4.3g,1.5eq.)并溶解在36mL 无水THF中,缓慢滴入反应体系。加料完毕,在该温度下搅拌,然后升至室温继续搅拌1h。反应完毕,加入50mL饱和碳酸氢钠水溶液,分离有机层,乙酸乙酯(50mL×2)萃取水相。合并有机相,硫酸钠干燥,蒸干,用短粗柱快速柱分离得黄色油状物直接用于下一步反应。
将上述油状物用36mL甲醇以及9mL DMF溶于干燥圆底烧瓶中,依次加入三苯基膦(211mg,0.1eq.),醋酸钯(90mg,0.05eq.),并使用CO气球鼓气20 min。换气完成,向体系中加入三乙胺(1.62mL,2eq.)。在CO气球压力,40℃条件下搅拌2h。将体系恢复室温,用硅藻土过滤,并使用EA洗涤。蒸除大部分有机溶剂,加入EA 80mL稀释体系,并使用水洗涤(50mL×2),饱和食盐水洗涤。分离有机相,硫酸钠干燥,蒸干,柱分离(PE:EA=9:1)得白色固体2.8g,两步收率为70%。1H NMR(400MHz,CDCl3)δ4.98(d,J=5.8Hz,1H),4.74(s, 2H),4.00–3.91(m,4H),3.85–3.81(m,1H),3.79–3.75(m,2H),3.73(s,3H),3.63 –3.59(m,1H),2.52–2.42(m,2H),1.86–1.79(m,1H),1.78–1.75(m,1H),1.74– 1.70(m,1H),1.70–1.66(m,1H),1.63–1.60(m,1H),1.57–1.50(m,2H),1.52– 1.46(m,1H),0.90(d,J=6.5Hz,3H),0.89(s,9H),0.78(s,3H),0.06(d,J=1.6Hz, 6H)。
(8)化合物10的制备
将2.8g化合物9溶于23mL EA以及4.6mL冰醋酸中,称取840mg二氧化铂加入高压釜。使用氢气排出釜内空气,充入高压氢气,并在室温下搅拌2d。反应完毕,打开反应釜,向体系中加入饱和碳酸氢钠水溶液50mL,分离有机层,并使用EA(30mL×2)萃取水相。合并有机相,硫酸钠干燥,蒸干,柱分离(PE: EA=8:1)得无色油状物2.5g,收率为90%。1H NMR(400MHz,CDCl3)δ4.93(s, 1H),4.00–3.97(m,1H),3.97–3.91(m,4H),3.74(t,J=5.2Hz,2H),3.71–3.67(m, 1H),3.66(s,3H),3.66–3.63(m,1H),3.44(dt,J=10.8,5.6Hz,1H),3.11–3.00(m, 1H),2.82–2.74(m,1H),1.83–1.79(m,3H),1.68–1.62(m,2H),1.60–1.57(m,1H),1.43–1.36(m,1H),1.35–1.25(m,1H),1.19(t,J=11.9Hz,1H),0.89(s,9H), 0.88(s,3H),0.87(d,J=4.9Hz,3H),0.05(s,6H)。
(9)化合物11的制备
将913mg化合物10溶于10.5mL丙酮以及3.5mL水中,向体系中加入 PTSA(174mg,0.5eq.),并在55℃下搅拌3h。反应完毕,将反应容器移至室温,缓慢加入饱和碳酸氢钠水溶液,加入5mL水以及EA 10mL,分离有机层,用 EA(10mL×2)萃取水相。合并有机相,硫酸钠干燥,蒸干,柱分离(PE:EA= 1:1)得白色固体433mg,收率为80%。1H NMR(400MHz,CDCl3)δ5.42(d,J= 2.3Hz,1H),4.12(t,J=9.1Hz,1H),3.74(dd,J=11.1,8.8Hz,1H),3.69(s,3H), 3.22–3.17(m,1H),2.85–2.78(m,1H),2.64–2.55(m,1H),2.50(td,J=14.6,6.1 Hz,1H),2.41–2.37(m,1H),2.36–2.31(m,1H),2.10–2.03(m,1H),1.92–1.85 (m,1H),1.83(d,J=7.2Hz,1H),1.63–1.61(m,1H),1.55–1.51(m,1H),1.19(td, J=12.1,1.8Hz,1H),1.11(s,3H),1.07(d,J=6.5Hz,3H)。
(10)化合物12的制备
将化合物11(329mg,1.0eq.)溶于11mL苯中,向其中加入PTSA(42mg, 0.2eq.)。将体系移至80℃下搅拌0.5h,恢复室温,加入饱和碳酸氢钠水溶液淬灭反应。分离有机层,EA(10mL×2)萃取水相。合并有机相,硫酸钠干燥,蒸干,柱分离(PE:EA=2:1)得白色固体132mg,收率为52%(α-CHO:β-CHO= 4:1)。代表性1H NMR(400MHz,CDCl3)δ10.00–9.98(m,1H),9.89–9.86(m, 0.2H),4.82–4.75(m,1H),4.36(dd,J=11.4,9.9Hz,1H)。
(11)化合物14的制备
将中间体13(286mg,1.8eq.)溶解在6mLTHF中,并在0℃下缓慢滴入正丁基锂(355μL,1.8eq.),在室温下搅拌0.5h。另准备一反应瓶,将化合物12(130mg, 1.0eq.)溶于3mLTHF中,在0℃下缓慢将制备的磷叶立德滴入体系,在室温搅拌0.5h。加入饱和氯化铵水溶液淬灭反应,分离有机层,EA(10mL×2)萃取水相。合并有机相,硫酸钠干燥,蒸干,硅胶柱粗分离(PE:EA=4:1)得白色固体170mg。
(12)化合物15及C7-epi-15的制备
将中间体14(50mg,1.0eq.)溶解在2mL甲醇中,并在-78℃下加入硼氢化钠(26mg,6eq.),在室温下搅拌,并加入水淬灭。使用EA萃取三遍,并用食盐水洗涤。合并有机相,硫酸钠干燥,蒸干,硅胶柱粗分离(PE:EA=1:1)得化合物15(17mg,35%)以及C7-epi-15(12mg,25%),二者均为白色固体。
Data of 15:
1H NMR(400MHz,CDCl3)δ8.72(s,1H),7.78(dd,J=8.0,1.8Hz,1H),7.42(dd,J =13.9,7.8Hz,1H),7.34(d,J=7.7Hz,1H),7.30–7.21(m,2H),7.08(t,J=7.4Hz, 1H),6.97(dd,J=15.5,9.2Hz,1H),6.60(d,J=15.4Hz,1H),3.92–3.84(m,1H), 3.80(d,J=8.7Hz,1H),3.67–3.58(m,2H),3.12–3.05(m,1H),2.29–2.23(m,1H), 2.18–2.11(m,1H),1.99–1.90(m,1H),1.82–1.73(m,1H),1.61–1.55(m,1H), 1.51–1.41(m,2H),1.35–1.29(m,2H),1.51–1.41(m,1H),0.97(d,J=6.3Hz,3H), 0.89–0.86(m,1H),0.77(d,J=7.6Hz,3H).
Data of C7-epi-15:
1H NMR(400MHz,CDCl3)δ8.72(s,1H),7.78(dd,J=8.0,1.8Hz,1H),7.42(dd,J =13.9,7.8Hz,1H),7.34(d,J=7.7Hz,1H),7.30–7.21(m,2H),7.08(t,J=7.4Hz, 1H),6.97(dd,J=15.5,9.2Hz,1H),6.60(d,J=15.4Hz,1H),3.92–3.84(m,1H), 3.80(d,J=8.7Hz,1H),3.67–3.58(m,2H),3.12–3.05(m,1H),2.29–2.23(m,1H), 2.18–2.11(m,1H),1.99–1.90(m,1H),1.82–1.73(m,1H),1.61–1.55(m,1H), 1.51–1.41(m,2H),1.35–1.29(m,2H),1.51–1.41(m,1H),0.97(d,J=6.3Hz,3H), 0.89–0.86(m,1H),0.77(d,J=7.6Hz,3H).
(13)化合物17及18的制备
将中间体14(170mg,1.0eq.)溶解在4.8mL无水甲醇中,加入醋酸铵(270 mg,10eq.),氰基硼氢化钠(108mg,5.0eq.),将体系置于室温下并搅拌过夜。向体系中加入5mL碳酸氢钠水溶液,经加入EA稀释。分离有机层,EA(10mL ×2)萃取水相。合并有机相,硫酸钠干燥,蒸干,柱分离(DCM:MeOH=9:1) 得化合物18(72mg,41%)以及17(47mg,28%),二者均为白色固体。
Data of 18:
1H NMR(400MHz,MeOD)δ8.76(d,J=1.9Hz,1H),8.07(dd,J=8.2,2.3Hz,1H),7.59(d,J=8.2Hz,1H),7.53(t,J=5.1Hz,2H),7.45(d,J=10.0Hz,1H),7.20– 7.14(m,1H),6.82–6.68(m,2H),4.66(dd,J=11.8,9.4Hz,1H),4.48(t,J=8.9Hz, 1H),3.36(s,1H),2.98–2.86(m,1H),2.81(td,J=11.6,4.6Hz,1H),2.75–2.66(m, 1H),2.54–2.46(m,1H),2.13(dd,J=12.4,6.5Hz,1H),1.93–1.86(m,1H),1.82(d, J=13.4Hz,1H),1.67(ddd,J=23.1,11.8,5.2Hz,2H),1.15(s,3H),1.10(d,J=6.3 Hz,3H)。
Data of 17:
1H NMR(400MHz,MeOD)δ8.76(d,J=2.0Hz,1H),8.07(dd,J=8.2,2.3Hz,1H),7.60(d,J=8.2Hz,1H),7.52(t,J=5.1Hz,2H),7.45(d,J=10.0Hz,1H),7.20– 7.13(m,1H),6.75(d,J=7.0Hz,2H),4.67(dd,J=11.8,9.4Hz,1H),4.49(t,J=9.0 Hz,1H),3.44(s,1H),2.94(dd,J=13.4,5.4Hz,1H),2.80–2.68(m,1H),2.59(t,J= 6.8Hz,1H),2.11–1.93(m,3H),1.78(d,J=15.0Hz,1H),1.62(d,J=13.9Hz,1H), 1.43(d,J=11.2Hz,1H),1.36(dd,J=9.4,5.3Hz,1H),1.29(s,1H),1.15(s,3H), 1.09(d,J=6.9Hz,3H)。
(14)化合物19的制备
将化合物17(30mg,1.0eq.)溶解在二氯甲烷(1.0mL),然后加入三乙胺 (0.1mL)。将反应瓶移至0℃下并缓慢滴入氯甲酸乙酯(0.05mL),然后升高至室温并持续搅拌0.5h。向体系中加入饱和碳酸氢钠溶液,分离有机层,二氯甲烷 (2.5mL×2)萃取水相。合并有机相,硫酸钠干燥,蒸干,柱分离(PE:EA=4: 1)得白色固体31mg,收率为90%。1H NMR(400MHz,CDCl3)δ8.77(d,J=2.1 Hz,1H),7.81(dd,J=8.1,2.3Hz,1H),7.48–7.39(m,1H),7.35(d,J=7.8Hz,1H), 7.28(s,1H),7.26–7.24(m,1H),7.09(td,J=8.3,2.0Hz,1H),6.71(dd,J=15.3, 9.9Hz,1H),6.60(d,J=15.3Hz,1H),4.83(s,1H),4.58(dd,J=11.8,9.3Hz,1H),4.45(t,J=9.0Hz,1H),4.15–4.08(m,2H),3.86(s,1H),2.90–2.81(m,1H),2.62 (dt,J=12.8,7.3Hz,1H),2.39(dd,J=9.8,6.7Hz,1H),2.11–2.04(m,1H),1.77(s, 1H),1.69(d,J=13.4Hz,2H),1.60(s,1H),1.31(d,J=12.7Hz,1H),1.26–1.24(m, 3H),1.16(d,J=12.1Hz,1H),1.10(s,3H),1.00(d,J=11.1Hz,1H),0.95(d,J=6.7 Hz,3H).
(15)化合物20的制备
将化合物18(30mg,1.0eq.)溶解在二氯甲烷(1.0mL),然后加入三乙胺 (0.1mL)。将反应瓶移至0℃下并缓慢滴入氯甲酸乙酯16(0.05mL),然后升高至室温并持续搅拌0.5h。向体系中加入饱和碳酸氢钠溶液,分离有机层,二氯甲烷(2.5mL×2)萃取水相。合并有机相,硫酸钠干燥,蒸干,柱分离(PE:EA =4:1)得白色固体31mg,收率为90%。1H NMR(400MHz,CDCl3)δ8.77(s,1H), 7.81(d,J=8.0Hz,1H),7.43(dd,J=14.6,7.2Hz,1H),7.35(d,J=7.7Hz,1H), 7.29(s,1H),7.26(s,1H),7.08(dd,J=12.0,4.7Hz,1H),6.72(dd,J=15.2,9.9Hz, 1H),6.61(d,J=15.3Hz,1H),4.62–4.53(m,1H),4.45(dd,J=17.2,8.6Hz,2H), 4.09(dd,J=13.6,6.6Hz,2H),3.19(d,J=8.0Hz,1H),2.91–2.78(m,1H),2.67– 2.56(m,1H),2.41–2.31(m,1H),2.17(dd,J=13.7,6.4Hz,1H),1.84(s,1H),1.76 (s,1H),1.40(s,1H),1.35(d,J=10.2Hz,1H),1.30(s,1H),1.23(s,1H),1.18–1.11 (m,1H),1.07(s,3H),1.03–0.97(m,1H),1.00(d,J=6.3Hz,3H).
实施例2:化合物的生物活性(PAR-1抑制活性)测定
1.细胞培养
1.1细胞复苏
将HEK293-Gα15-PAR1细胞株(HD Biosciences稳转细胞株)从液氮罐内迅速取出,37℃水浴中不停摇晃,直到全部融化。迅速将细胞悬液加入预热的培养基(90%DMEM+10%FBS+1X Pen/Strep)中,放入离心机,1000转/分钟,离心10分钟。将离心管取出,弃去上清液,向离心管内加入新鲜预热的培养基,重悬细胞,将细胞悬液加入培养皿,37℃,5%CO2培养。
1.2传代
当细胞长满至培养皿80~90%,用0.05%胰酶-EDTA轻轻洗细胞,去除部分消化液后孵育细胞2~3min,用新的培养基终止消化,枪头轻轻吹打细胞并将细胞重悬,通常情况下,每2~3天按1:4至1:8传代。
2.钙离子内流实验
2.1细胞板包被
实验前一天,在干净的384孔细胞板中加入1×Matrigel(Brand:BD,Cat#:356230),在37℃孵育30分钟,然后500转/分倒置离心30秒去除包被液。
2.2铺板
消化收集细胞沉淀,用培养基重悬至3×105细胞/mL,每孔50μL加入包被好的细胞板,后37℃,5%CO2孵育过夜。
2.3缓冲液配制
实验当天,配制新鲜的实验缓冲液和0.5×Calcium 4(Brand:MolecularDevices,Cat#:R8141)上样缓冲液。
2.4化合物的配制
先将30mM的DMSO储存液用DMSO稀释至10mM,后从10mM开始4 倍倍比稀释,共10个浓度。将化合物的10个DMSO浓度梯度按1:20的比例加入到实验缓冲液中,制备成化合物的工作液(终反应浓度的5倍)。后将化合物的工作液按照布局转至384孔化合物板中待用。
阳性对照:将参照化合物SCH79797的40mM DMSO储存液稀释至2mM;
阴性对照:实验缓冲液配制的5%DMSO
2.5PAR-1激动剂haTRAP的配制
用实验缓冲液将激动剂haTRAP的10mM DMSO储存液稀释至18μM(终反应浓度3μM的6倍),后至少以25μl/孔转入384孔化合物板中待用。
2.6染料孵育
取出孵育过夜的细胞板,300转/分倒置离心30秒去除细胞培养基,每孔加入20μL新鲜配制的0.5×Calcium 4上样缓冲液,后37℃,5%CO2孵育1小时。
2.7加入化合物
按照布局从化合物板中转移5μL/孔的化合物工作液至细胞板中,然后再次置于37℃,5%CO2孵育15分钟。
2.8加激动剂读取荧光信号
按FLIPR设置程序从384孔化合物板(FLIPR)转5μl/孔激动剂到细胞板,同时读取细胞板中每孔的荧光信号。
3.数据分析
根据每块细胞板上的阳性对照和阴性对照的荧光信号值计算该细胞板上每孔中化合物的抑制率(%)。阳性对照含有高浓度的参照化合物(400μM的 SCH79797),为100%抑制对照;阴性对照不含任何化合物,只有作为化合物溶剂的DMSO(1%DMSO),为0%抑制对照。将计算所得抑制率和相对应的化合物浓度导入相关软件作图,并按照4-PL剂量效应公式计算出该化合物的IC50值。参照化合物的IC50结果亦是检验每次实验质量的标准之一。
部分化合物的活性筛选结果如表1所示。
表1部分化合物剂量效应结果
舒心帕沙 | Cpd14 | Cpd15 | Cpd17 | Cpd18 | Cpd19 | Cpd20 | |
Slope | 1.47 | 2.01 | 1.98 | 3.26 | 1.28 | 2.68 | 1.26 |
IC<sub>50</sub>(nM) | 518 | 507 | 495 | 1230 | 753 | 832 | 112 |
活性筛选结果表明:化合物20具有显著的体外抗PAR-1活性,其IC50值为 121nM,较先导化合物舒心帕沙(IC50值=518nM)的活性提高了近三倍,具有更加良好的新药开发前景。
以上所述仅为本发明的优选实施例,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
2.如权利要求1所述的化合物,其特征在于,
R1和R2共同形成一个具有3-7个原子的环或杂环;
R3独立地选自:-C(O)R6、-C(O)OR6、-CO(O)R6、-COSOR6、-C(O)NR6R7;
R4独立地选自:-O(O)CR8、-OSOR8、-OSO2R8、-NHC(O)OR8、-NHC(O)R8、-NHCONHR8、-NHC(O)NR8R9、-NHSO2R8;
优选的,R6、R7、R8和R9独立选自氢原子、(C1-C6)烷基、氨基、酯基、羧酸基、苯基及苄基;
优选的,所述R1和R2共同形成一个具有4-7个原子的内酯环;进一步优选的,所述R1和R2共同形成五元内酯环;
R3为氢原子、(C1-C4)羟烷基、甲酸基、甲酸甲酯基、醛基或甲酰胺基;
R4为羟基、甲氧基或-NHC(O)OEt;R5为卤素原子或三氟甲基。
3.如权利要求1所述的化合物,其特征在于,
所述化合物还包括其药学上可接受的盐或酯或溶剂化物、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物或前药。
7.如权利要求6所述的制备方法,其特征在于,所述式(II)所示化合物,其制备方法包括:以穿心莲内酯为起始原料,经脱水重排反应和环氧化反应得(VII)所示的化合物,再经臭氧裂解得式(VI)化合物;其经一锅法E1消除以及羰基保护得式(V)所示的化合物,再经硼氢化氧化得式(IV)所示化合物,再对羰基位点进行修饰引入R2基团,即制得式(II)所示的化合物。
8.一种药物组合物,其特征在于,所述药物组合物包括权利要求1-4任一项所述化合物;其作为活性成分发挥治疗血栓性疾病的作用;优选的,所述药物组合物还包括其他具有心血管疾病治疗作用的药物;
优选的,所述血栓性疾病包括血栓形成、动脉粥样硬化、再狭窄症、高血压、心绞痛、心脏衰竭、紧急梗死、肾小球炎或周边血管疾病;
所述心血管疾病具体为与血栓形成相关的疾病,其包括血栓形成、动脉粥样硬化、再狭窄症、高血压、心绞痛、心律不整、心脏衰竭、心肌梗死、肾小球炎、血栓形成性中风、血栓栓塞性中风、周边血管疾病、其他心血管疾病以及凝血酶及其受体在其中其病理作用的其他疾病。
9.一种药物制剂,其特征在于,其包含权利要求1-4任一项所述化合物,和至少一种药学上可接受的辅料和/或载体。
10.权利要求1-4任一项所述化合物、权利要求8所述所述的药物组合物或权利要求9所述的药物制剂在制备防治血栓性疾病产品中的应用;
优选的,所述产品为药品。
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