CN101917990B - 药物组合物、2-亚氨基吡咯烷衍生物用于制造药物组合物的用途和心脏病治疗用或改善用试剂盒 - Google Patents
药物组合物、2-亚氨基吡咯烷衍生物用于制造药物组合物的用途和心脏病治疗用或改善用试剂盒 Download PDFInfo
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Abstract
本发明的实施方式是含有至少1种指定的2-亚氨基吡咯烷衍生物与至少1种其它化合物(B)的药物组合物;以及含有至少1种指定的2-亚氨基吡咯烷衍生物的、用于与至少1种其它化合物(B)组合使用的药物组合物。由此,提供能够有效地治疗或改善心脏病等疾病的药物组合物。
Description
技术领域
本发明涉及药物组合物、2-亚氨基吡咯烷衍生物用于制造药物组合物的用途和心脏病治疗用或改善用试剂盒等。
背景技术
心脏病包括急性冠心病综合征、粥样斑血栓症、再狭窄、高血压、稳定型心绞痛、心律失常、心力衰竭(心不全)、ST段抬高心肌梗死等。作为用于治疗这些心脏病的靶标物质,可以列举出作为凝血因子的一种的凝血酶。此外,作为血小板膜糖蛋白质的GP(Glycoprotein,糖蛋白)IIb/IIIa的受体也可以作为用于治疗心脏病的靶标。而且,凝血酶受体已知存在于血小板、血管平滑肌细胞、内皮细胞和成纤维细胞等细胞。凝血酶受体也可以作为治疗心脏病的靶标。
发明内容
发明所要解决的问题
在这种状况下,需要能够有效地治疗或改善心脏病等疾病的药物组合物。
解决问题的方法
本发明人等为解决上述问题进行了深入研究,结果发现:通过组合使用至少一种指定的2-亚氨基吡咯烷衍生物和至少一种其它化合物(B),能够有效地治疗或改善心脏病等;从而完成了本发明。
即,本发明如下。
(1)含有选自下述式(I)~(VII)中的至少一种化合物或其药学可接受的盐和选自下述B组中的至少一种其它化合物(B)的药物组合物。
根据本发明的某些实施方式,组合物是心脏病治疗用或改善用药物组合物。
(2)选自式(I)~(VII)中的至少一种化合物或其药学可接受的盐在制造与选自下述B组中的至少一种其它化合物(B)组合使用的心脏病治疗用或改善用药物组合物中的用途。
(3)心脏病治疗用或改善用试剂盒,其包含含有选自下述式(I)~(VII)中的至少一种化合物或其药学可接受的盐的药物组合物和含有选自下述B组中的至少一种其它化合物(B)的药物组合物。
(4)心脏病治疗或改善方法,该方法中同时或分别对患者施用有效量的选自下述式(I)~(VII)中的至少一种化合物或其药学可接受的盐和选自下述B组中的至少一种其它化合物(B)。
[化学式1]
(B组)
环氧合酶抑制剂、血栓素A2生物合成抑制剂、血栓素受体拮抗药、腺苷二磷酸受体拮抗药、GPIIb/IIIa拮抗药、PGE1或PGI2衍生物、血小板凝集抑制剂、5-羟色胺受体拮抗药、凝血酶抑制剂、肝素、低分子肝素、Xa抑制剂、VIIa抑制剂、K+通道抑制剂、维生素K拮抗剂、血管紧张素拮抗药、血管紧张素转化酶抑制剂、内皮缩血管肽拮抗药、磷酸二酯酶抑制剂、钙拮抗剂、β-受体阻滞剂、亚硝酸药、血栓溶解剂、HMGCoA还原酶抑制剂、贝特(fibrate)类药物、烟酸类药物、胆汁酸吸附剂、胆固醇吸收抑制剂、PPARγ激动药、PPARα激动药、PPARβ激动药、中性内肽酶抑制剂和利尿药。
在本发明中,作为选自式(I)~(VII)中的至少一种化合物或其药学可接受的盐,可以列举出例如式(I)所示的化合物的氢溴酸盐。
此外,在本发明的一个实施方式中,作为心脏病,可以列举出例如选自急性冠心病综合征、粥样斑血栓症、再狭窄、高血压、稳定型心绞痛、心律失常、心力衰竭、ST段抬高心肌梗死和脑梗死中的至少一种疾病。
在本发明中,作为上述化合物(B),可以示例出作为环氧合酶抑制剂的阿司匹林或作为腺苷二磷酸受体拮抗药的氯吡格雷。
发明效果
本发明提供能够有效地治疗或改善疾病的药物组合物。根据本发明的优选实施方式,能够有效地治疗或改善心脏病。
附图说明
图1为图表,显示了在豚鼠光增感血栓模型中,施用实施例1化合物或阿司匹林以及两化合物组合使用的抗血栓作用。
发明的具体实施方式
以下,对本发明进行具体说明。以下的实施方式仅是用于说明本发明的示例,并不意味本发明受这些实施方式的限定。在不脱离其要旨的范围内,本发明可以以各种方式实施。
而且,本说明书中引用的文献、公开公报、专利公报以及其它专利文献均并入本说明书作为参考。此外,本说明书包含作为本申请优先权基础的日本专利申请2008-4318号以及美国临时申请61/020,426号的说明书或附图所记载的内容。
根据本发明的某些实施方式,提供含有至少一种2-亚氨基吡咯烷衍生物和至少一种其它化合物(B)的药物组合物。此外,根据本发明的其它实施方式,提供含有至少一种2-亚氨基吡咯烷衍生物、且用于与至少一种其它化合物(B)组合使用的药物组合物。药物组合物优选为心脏病治疗用或改善用药物组合物。
(1)2-亚氨基吡咯烷衍生物
本发明的药物组合物中包含的2-亚氨基吡咯烷衍生物是选自式(I)~(VII)中的至少1种(例如1种)化合物或其药学可接受的盐。
[化学式2]
本发明中使用的2-亚氨基吡咯烷衍生物优选为式(I)的化合物或其药学可接受的盐,更优选为式(I)的化合物的氢溴酸盐。
在本发明中,对于药学可接受的盐没有特殊限制,只要对心脏病等疾病具有治疗作用或改善作用、且在药学可接受即可。具体地,可以列举出例如氢卤酸盐(例如氢氟酸盐、盐酸盐、氢溴酸盐和氢碘酸盐)、无机酸盐(例如硫酸盐、硝酸盐、高氯酸盐、磷酸盐、碳酸盐和碳酸氢盐)、有机羧酸盐(例如乙酸盐、草酸盐、马来酸盐、酒石酸盐、富马酸盐和柠檬酸盐)、有机磺酸盐(例如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐、苯磺酸盐、甲苯磺酸盐和樟脑磺酸盐)、氨基酸盐(例如天冬氨酸盐和谷氨酸盐)、季铵盐、碱金属盐(例如钠盐和钾盐)以及碱土金属盐(例如镁盐和钙盐)。
此外,当2-亚氨基吡咯烷衍生物存在几何异构体和非对映体等光学异构体时,只要针对心脏病等疾病有治疗作用或改善作用,则这些异构体也包括在本发明的化合物或其药理学可接受的盐之中。
而且,2-亚氨基吡咯烷衍生物可以是无水物,也可以形成水合物等溶剂合物。溶剂合物可以是水合物,也可以是非水合物,优选水合物。溶剂可以使用水、醇(例如甲醇、乙醇、正丙醇)、二甲基甲酰胺等。只要对心脏病等疾病有治疗作用或改善作用,则这些溶剂合物也包括在本发明的化合物或其药理学可接受的盐之中。
这里,本发明的药物组合物中包含的2-亚氨基吡咯烷衍生物(优选式(I)的化合物的氢溴酸盐)是作为凝血酶受体之一的蛋白酶活化受体(PAR1)的拮抗药。由于PAR1拮抗药具有选自抗血栓活性、抗血小板凝集活性、抗粥样斑性动脉硬化活性、抗再狭窄活性中的至少一种活性,因而2-亚氨基吡咯烷衍生物(优选式(I)的化合物的氢溴酸盐)可用于治疗或改善选自急性冠心病综合征(例如非ST段抬高心肌梗死和不稳定心绞痛)、粥样斑血栓症(例如外周动脉阻塞)、再狭窄、高血压、稳定型心绞痛、劳累型心绞痛、静息时心绞痛、心律失常、心力衰竭、ST段抬高心肌梗死、血栓性脑卒中、血栓栓塞性脑卒中、静脉血栓栓塞症、深部静脉血栓症、肺栓塞、粥样斑性动脉硬化症、外周性血管性疾病、炎症性疾病、大脑缺血、脑梗死、其它阻塞性血管疾病、弥散性血管内凝血综合征、类风湿(リウマチ)、哮喘、肾小球肾炎、骨质疏松症和神经疾病等中的至少一种疾病。
(2)2-亚氨基吡咯烷衍生物的制造方法
本发明中使用的2-亚氨基吡咯烷衍生物、即选自式(I)~(VII)中的至少1种(例如1种)化合物或其药学可接受的盐可以采用例如国际公开02/085855号小册子、国际公开04/078721号小册子等记载的方法来制造。更具体地,这些化合物或其药学可接受的盐可以采用例如国际公开02/085855号小册子说明书40页24行~139页15行、170页6行~177页12行(实施例7)、177页13行~183页1行(实施例8)、190页21行~193页2行(实施例11)、200页11行~203页1行(实施例14)、203页2行~205页17行(实施例15)、316页7行~317页3行(实施例112)和325页3行~13行(实施例125)等记载的方法或基于此的方法来制造。或者,这些化合物或其药学可接受的盐可以采用国际公开04/078721号小册子说明书全文记载的方法或基于此的方法来制造。
而且,在后述的实施例1中,以制造式(I)的化合物的氢溴酸盐和盐酸盐的情况为例,对2-亚氨基吡咯烷衍生物的制造方法进行了说明。式(II)~(VII)的化合物或其药学可接受的盐可以采用例如基于实施例1的方法的方法来制造。
(3)药物组合物
如前述,本发明的药物组合物含有至少一种(例如一种)2-亚氨基吡咯烷衍生物。在本发明中,指定的2-亚氨基吡咯烷衍生物是选自式(I)~(VII)中的至少一种化合物或其药学可接受的盐。
本发明的药物组合物可以用于心脏病治疗用途或改善用途。“治疗”或“改善”一般是指获得所希望的药理学效果和/或生理学效果。就效果而言,完全或部分地防止疾病和/或症状称为予防;部分或完全治愈疾病和/或疾病引起的不良影响称为治疗。在本说明书中,“治疗”或“改善”是指患者哺乳动物、特别是人的疾病的任意治疗或改善,也包含上述的一般性治疗的含义。“治疗或改善”包含例如以下(a)~(c)的事项中的至少一个:
(a)在能够持有疾病或症状的素因、但尚未诊断为持有的患者中,予防疾病或症状的发生;
(b)抑制疾病症状,即阻止或延迟其进展;
(c)缓解疾病症状,即引发疾病或症状的减退、消失或症状进展的逆转。
在本发明中,2-亚氨基吡咯烷衍生物是选自式(I)~(VII)中的至少一种化合物或其药学可接受的盐,优选是式(I)的化合物或其药学可接受的盐,更优选是式(I)的化合物的氢溴酸盐。
在本发明的药物组合物中,选自式(I)~(VII)中的至少一种化合物或其药学可接受的盐可以直接使用,也可以配合公知的药学可接受的载体等来制剂化。作为这样的药学可接受的载体,可以列举出例如:赋形剂、粘合剂、崩解剂、滑润剂、着色剂、矫味矫臭剂、稳定化剂、乳化剂、吸收促进剂、表面活性剂、pH调整剂、防腐剂和抗氧化剂等。
此外,对于本发明的药物组合物的施用方式没有特殊限定,可以基于上述剂型口服或非口服施用。作为非口服施用的方式,可以列举出例如:静脉内注射、点滴静脉注射、皮下注射、皮内注射或腹腔内注射等。作为制剂化的剂型,可以列举出:用于口服施用方式的片剂、散剂、细粒剂、颗粒剂、胶囊剂、糖浆剂等,以及用于非口服施用方式的栓剂、注射剂、软膏剂、罨剂等。
在制备用于口服施用方式的口服用制剂时,可以在向该有效成分中加入赋形剂、进而视需要加入粘合剂、崩解剂、滑润剂、着色剂、矫味矫臭剂等后,采用常规方法制成片剂、包衣片剂、颗粒剂、细粒剂、散剂、胶囊剂等。
作为赋形剂,可以使用例如乳糖、玉米淀粉、白糖、葡萄糖、山梨糖醇、结晶纤维素、二氧化硅等;作为粘合剂,可以使用例如聚乙烯醇、乙基纤维素、甲基纤维素、阿拉伯胶、羟基丙基纤维素、羟基丙基甲基纤维素等;作为滑润剂,可以使用例如硬脂酸镁、滑石、二氧化硅等;作为着色剂,可以使用允许在医药品中添加的着色剂;作为矫味矫臭剂,可以使用可可粉、薄荷脑、芳香酸、薄荷油、龙脑、桂皮粉等。不言自明的是,这些片剂、颗粒剂可以视需要用糖衣、明胶衣及其它适宜包衣。
在本发明中,注射剂可以视需要在主药中添加非水性稀释剂(例如丙二醇、聚乙二醇等二醇,齐墩果油等植物油,乙醇等醇类等)、悬浮剂、助溶剂、稳定化剂、等渗化剂、防腐剂、pH调整剂、缓冲剂等来制备。注射剂的无菌化可以通过利用滤器进行过滤灭菌、配合杀菌剂等来进行。此外,注射剂可以以即用即配的方式来制造。即,可以这样使用:通过冻干法等制成无菌的固体组合物,在使用前溶解于无菌的注射用蒸馏水或其它溶剂中。当以贴膏剂(貼布剤)的形式通过经皮吸收施用时,优选选择不形成盐的所谓游离体。注射剂可以采用常规方法制成点滴静脉注射剂或者静脉、皮下、肌肉内注射剂。
作为悬浮剂,可以列举出例如甲基纤维素、聚山梨酯80、羟基乙基纤维素、阿拉伯胶、黄蓍胶粉、羧甲基纤维素钠、聚氧乙烯失水山梨糖醇单月桂酸酯等。
作为助溶剂,可以列举出例如聚氧乙烯氢化蓖麻油、聚山梨酯80、烟酰胺、聚氧乙烯失水山梨糖醇单月桂酸酯、聚乙二醇、蓖麻油脂肪酸乙酯等。
此外,作为稳定化剂,可以列举出例如亚硫酸钠、偏亚硫酸钠等;作为防腐剂,可以列举出例如对氧苯甲酸甲酯、对氧苯甲酸乙酯、山梨酸、苯酚、甲酚、氯甲酚等。
口服施用情况下的式(I)~(VII)的化合物或其药学可接受的盐的有效施用量因症状程度、患者年龄、性别、体重、敏感性差异、施用方法、施用时期、施用间隔、施用期间、制剂性质、调剂、种类、有效成分种类等而异,本领域技术人员可以适宜地设定。例如,成人(体重60kg)可以每日口服施用0.001~10,000mg,优选0.1~1,000mg、更优选1~1,000mg。
对非口服施用例如注射剂而言,式(I)~(VII)的化合物或其药学可接受的盐的有效施用量因症状程度、患者年龄、性别、体重、敏感性差异、施用方法、施用时期、施用间隔、施用期间、制剂性质、调剂、种类、有效成分种类等而异,本领域技术人员可以适宜地设定,可以将以适当浓度溶解或悬浮在生理食盐水或市售的注射用蒸馏水等药学可接受的载体中而得的剂型适宜施用于需要处置的患者。例如,对注射剂而言,成人(体重60kg)可以每日施用0.001~10,000mg,优选0.01~1,000mg,更优选0.1~1,000mg。
(4)2-亚氨基吡咯烷衍生物与其它化合物(B)的组合使用
本发明中,为了治疗或改善心脏病等疾病,将至少一种其它化合物(B)与至少一种(例如一种)所述2-亚氨基吡咯烷衍生物组合使用。组合使用是指将至少一种其它化合物(B)与所述2-亚氨基吡咯烷衍生物相组合,包括将上述化合物(B)与2-亚氨基吡咯烷衍生物同时或相继施用的方式以及作为混合物(配合剂)的方式这两种方式。即,“组合使用”并非仅仅包括化合物(B)与2-亚氨基吡咯烷衍生物的施用时期完全相同的情况,只要某施用方式中包含在1个施用计划(schedule)中施用化合物(B)与2-亚氨基吡咯烷衍生物的方式,则这种施用方式即为“组合使用”。
为了组合使用,其它化合物(B)可以包含在所述含有2-亚氨基吡咯烷衍生物的药物组合物中,也可以包含在与上述含有2-亚氨基吡咯烷衍生物的药物组合物不同的药物组合物中。
其它化合物(B)优选为具有选自抗血栓、抗血小板凝集、抗粥样斑性动脉硬化、抗再狭窄和抗凝血等中的至少一种作用的药物。
其它化合物(B)优选为选自以下的B组中的至少一种治疗药。
(B组)
环氧合酶抑制剂、血栓素A2生物合成抑制剂、血栓素受体拮抗药、腺苷二磷酸(ADP)受体拮抗药、GPIIb/IIIa拮抗药、PGE1或PGI2衍生物、血小板凝集抑制剂、5-羟色胺受体拮抗药、凝血酶抑制剂、肝素、低分子肝素、Xa抑制剂、VIIa抑制剂、K+通道抑制剂、维生素K拮抗剂、血管紧张素拮抗药、血管紧张素转化酶(ACE)抑制剂、内皮缩血管肽拮抗药、磷酸二酯酶抑制剂、钙拮抗剂、β-受体阻滞剂、亚硝酸药、血栓溶解剂、HMGCoA还原酶抑制剂、贝特类药物、烟酸类药物、胆汁酸吸附剂、胆固醇吸收抑制剂、PPARγ激动药、PPARα激动药、PPARβ激动药、中性内肽酶抑制剂以及利尿药。
作为上述化合物(B)的具体例子,可以列举出以下的化合物。
(1)环氧合酶抑制剂:阿司匹林、美洛昔康(Meloxicam)、罗非昔布(Rofecoxib)和塞来昔布(Celecoxib)等
(2)血栓素A2生物合成抑制剂:奥扎格雷(Ozagrel)等
(3)血栓素受体拮抗药:塞曲司特(Seratrodast)、吡考米特(Picotamide)和雷马曲班(Ramatroban)等
(4)腺苷二磷酸受体拮抗药:氯吡格雷(Clopidogrel)、普拉格雷(Prasugrel)、AZD-6140、坎格雷洛(Cangrelor)和噻氯匹定(Ticlopidine)等
(5)GPIIb/IIIa拮抗药:阿昔单抗(Abciximab)、依替巴肽(Eptifibatide)和替罗非班(Tirofiban)等
(6)PGE1或PGI2衍生物:利马前列素(Limaprost)和贝前列素(Beraprost)等
(7)血小板凝集抑制剂:西洛他唑(Cilostazol)和双嘧达莫(Dipyridamole)等
(8)5-羟色胺受体拮抗药:盐酸沙格雷酯(Sarpogrelate)等
(9)凝血酶抑制剂:阿加曲班(Argatroban)、比伐卢定(Bivalirudin)和达比加群(Dabigatran)等
(10)肝素、低分子肝素:未分级肝素和依诺肝素(Enoxaparin)等
(11)Xa抑制剂:磺达肝素(Fondaparinux)、利伐沙班(Rivaroxaban)和阿哌沙班(Apixaban)等
(12)VIIa抑制剂:rNAPc2、PCI-27483等
(13)K+通道抑制剂:苄普地尔(Bepridil)、索他洛尔(Sotalol)等
(14)维生素K拮抗剂:华法林(Warfarin)等
(15)血管紧张素拮抗药:维沙坦(Valsartan)、泰米沙坦(Telmisartan)、坎地沙坦(Candesartran)、厄贝沙坦(Irbesartran)、Iosartan和依普罗沙坦(Eprosartan)等
(16)血管紧张素转化酶抑制剂:卡托普利(Captopril)、依那普利(Enalapril)、依那普利拉(Enaliprilat)、螺普利(Spirapril)、喹那普利(Quinapril)、培哚普利(Perindopril)、雷米普利(Ramipril)、福辛普利(Fosinopril)、群多普利(Trandolapril)、赖诺普利(Lisinopril)、莫西普利(Moexipril)和贝那普利(Benazepril)等
(17)内皮缩血管肽拮抗药:替唑生坦(Tezosentan)等
(18)磷酸二酯酶抑制剂:米力农(Milrinone)和依诺昔酮(Enoximone)等
(19)钙拮抗剂:氨氯地平(Amrodipine)等
(20)β-受体阻滞剂:阿替洛尔(Atenolol)和普萘洛尔(Propranolol)等
(21)亚硝酸药:硝酸甘油和硝酸异山梨醇酯等
(22)血栓溶解剂:尿激酶、链激酶和组织纤溶酶原活化因子等
(23)HMGCoA还原酶抑制剂:阿托伐他汀(Atorvastatin)、氟伐他汀(Fluvastatin)和普伐他汀(Pravastatin)等
(24)贝特类药物:吉非贝齐(Gemfibrozil)、非诺贝特(Fenofibrate)和贝特(Fibrate)等
(25)烟酸类药物:烟酸等
(26)胆汁酸吸附剂:考来烯胺(Cholestyramine)和考来替泊(Cholestipol)等
(27)胆固醇吸收抑制药:依泽替米贝(Ezetimibe)等
(28)PPARγ激动药:吡格列酮(Pioglitazone)等
(29)PPARα激动药:LY518674、WY14643等
(30)PPARβ/δ激动药:GW501516、L165041等
(31)中性内肽酶抑制剂:坎沙曲(Candoxatril)和依卡曲尔(Ecadotril)等
(32)利尿药:氯噻嗪、氢氯噻嗪、依他尼酸(Ethacrynic acid)、呋塞米和阿米洛利等
用于与所述2-亚氨基吡咯烷衍生物组合使用的其它化合物(B)优选为环氧合酶抑制剂、血栓素A2生物合成抑制剂、血栓素受体拮抗药、腺苷二磷酸(ADP)受体拮抗药、GPIIb/IIIa拮抗药、PGE1或PGI2衍生物、磷酸二酯酶抑制剂或血小板凝集抑制剂。更优选的其它化合物(B)是阿司匹林、氯吡格雷。
其它化合物(B)可以口服或非口服施用,可以采用与所述药物组合物的制剂化方法相同的方法来制剂化。
对于其它化合物(B)的有效施用量没有特殊限制,只要是显示药效的用量即可,优选为各化合物(B)在单剂中的处方用量或其以下。具体地,其它化合物(B)的施用量为成人(体重60kg)每日例如0.015~4000mg、优选50~400mg,相对于所述2-亚氨基吡咯烷衍生物为例如约0.0001~100倍(重量比)、优选约0.1~10倍(重量比)。
更具体地,在将所述2-亚氨基吡咯烷衍生物与阿司匹林相组合的情况下,并非限定,可以使2-亚氨基吡咯烷衍生物的施用量是成人(体重60kg)每日例如1~1000mg、优选10~600mg、更优选50~400mg,且阿司匹林的施用量是成人(体重60kg)每日例如10~1000mg、优选50~600mg、更优选80~350mg,而且,阿司匹林的施用量相对于2-亚氨基吡咯烷衍生物的施用量为例如约0.1~10倍(重量比)、优选约0.2~2倍(重量比)。
此外,在将所述2-亚氨基吡咯烷衍生物与氯吡格雷相组合的情况下,并非限定,可以使2-亚氨基吡咯烷衍生物的施用量是成人(体重60kg)每日例如1~1000mg、优选10~600mg、更优选50~400mg,且氯吡格雷的施用量是成人(体重60kg)每日例如10~1000mg、优选50~600mg、更优选75~300mg,而且,氯吡格雷的施用量相对于2-亚氨基吡咯烷衍生物的施用量是例如约0.1~10倍(重量比)、优选约0.2~2倍(重量比)。
为了迅速发挥药物的最大效果,也可以在首次施用时以高于维持用量的用量作为导入用量来施用2-亚氨基吡咯烷衍生物和其它化合物(B)中的一个或两者。
本发明中,通过组合使用至少一种指定的2-亚氨基吡咯烷衍生物和至少一种其它化合物(B),能够治疗或改善例如选自急性冠心病综合征(例如非ST段抬高心肌梗死和不稳定心绞痛)、粥样斑血栓症(例如外周动脉阻塞)、再狭窄、高血压、稳定型心绞痛、劳累型心绞痛、静息时心绞痛、心律失常、心力衰竭、ST段抬高心肌梗死、血栓性脑卒中、血栓栓塞性脑卒中、静脉血栓栓塞症、深部静脉血栓症、肺栓塞、粥样斑性动脉硬化症、外周性血管性疾病、炎症性疾病、大脑缺血、脑梗死、其它阻塞性血管疾病、弥散性血管内凝血综合征、类风湿、哮喘、肾小球肾炎、骨质疏松症和神经疾病等中的至少一种疾病。优选地,本发明中能够治疗或改善心脏病。在本发明中,作为能够治疗或改善的心脏病,可以列举出例如:选自急性冠心病综合征、粥样斑血栓症、再狭窄、高血压、稳定型心绞痛、心律失常、心力衰竭、ST段抬高心肌梗死和脑梗死中的至少一种疾病。
在本发明中,与组合使用所述本发明的2-亚氨基吡咯烷衍生物以外的化合物与其它化合物(B)的情况相比较,组合使用所述本发明的2-亚氨基吡咯烷衍生物与其它化合物(B)的情况下,能够更有效地治疗或改善这些疾病。
(5)治疗方法和改善方法
本发明提供一种心脏病等疾病的治疗或改善方法,其中,将有效量的至少一种(例如一种)指定的2-亚氨基吡咯烷衍生物和至少一种其它化合物(B)施用于患者。在本发明的方法中,指定的2-亚氨基吡咯烷衍生物是所述式(I)~(VII)的化合物等,优选式(I)的化合物等,更优选式(I)的化合物的氢溴酸盐。这里,式(I)~(VII)的化合物等中也包含式(I)~(VII)的化合物的药学可接受的盐。此外,关于其它化合物(B),可以参照所述2-亚氨基吡咯烷衍生物与其它化合物(B)的组合使用中的记载。在本发明的方法中,对式(I)~(VII)的化合物和化合物(B)的施用途径和施用方法没有特殊限制,可以参照上述药物组合物的记载。
(6)试剂盒
本发明包括心脏病等疾病治疗用或改善用试剂盒,其中包含含有至少一种指定的2-亚氨基吡咯烷衍生物的药物组合物和含有至少一种其它化合物(B)的药物组合物。本发明的试剂盒中,指定的2-亚氨基吡咯烷衍生物是式(I)~(VII)的化合物等,优选式(I)的化合物等,更优选式(I)的化合物的氢溴酸盐。本发明的试剂盒中,关于其它化合物(B),可以参照所述2-亚氨基吡咯烷衍生物与其它化合物(B)的组合使用中的记载。
试剂盒中视需要还可以包含附件和使用说明书等。
(7)用途
本发明包括至少一种指定的2-亚氨基吡咯烷衍生物在制造用于与至少一种(例如一种)其它化合物(B)组合使用的心脏病等疾病治疗用或改善用药物组合物中的用途。在本发明的用途中,指定的2-亚氨基吡咯烷衍生物是式(I)~(VII)的化合物等,优选式(I)所表示的化合物等,更优选式(I)的化合物的氢溴酸盐。在本发明的用途中,关于其它化合物(B),可以参照所述2-亚氨基吡咯烷衍生物与其它化合物(B)的组合使用中的记载。
而且,本发明包括用于与至少一种其它化合物(B)组合使用、且用于治疗或改善心脏病等疾病的、选自式(I)~(VII)中的至少一种化合物或其药学可接受的盐。
以下,通过实施例对本发明进行具体说明,但本发明并不受本实施例的限定。
实施例1
(1)式(I)的化合物的氢溴酸盐的制造
1-(3-叔丁基-4-甲氧基-5-吗啉代-苯基)-2-(5,6-二乙氧基-7-氟-1-亚氨基
-1,3-二氢-异吲哚-2-基)-乙酮(エタノン)氢溴酸盐
[0049]
[化学式3]
[0050]
(步骤A-1)
1-溴-3,4-二乙氧基-2-氟苯
[0051]
[化学式4]
冰冷却条件下,向1,2-二乙氧基-3-氟苯(150.00g,814mmoL)的乙腈(900mL)溶液中滴加N-溴琥珀酰亚胺(NBS)(153.72g,864mmoL)的乙腈(1.5L)溶液后,室温搅拌过夜。蒸馏除去溶剂后,向残渣中加入乙酸乙酯,然后进行水洗。将所得水层用乙酸乙酯再抽提,并与此前的有机层混合。按水、饱和食盐水、水的顺序洗涤有机层,用无水硫酸镁进行干燥。浓缩溶液得到油状物,向其中加入己烷,滤去析出的晶体。再次浓缩溶液得到油状物,进行减压蒸馏,得到标题化合物205.65g(收率:96%)。
b.p℃:110~111℃/2mmHg
1H-NMR(CDCl3)δ:1.35(3H,t,J=6.8Hz),1.42(3H,t,J=6.8Hz),4.03(2H,q,J=6.8Hz),4.11(2H,q,J=6.8Hz),6.57(1H,dd,J=2.0,9.3Hz),7.15(1H,dd,J=7.3,8.8Hz).
MS m/z:262(M+)
(步骤A-2)
3,4-二乙氧基-2-氟氰苯
[化学式5]
室温下,向1-溴-3,4-二乙氧基-2-氟苯(12.0g,45.6mmoL)的N,N-二甲基甲酰胺(DMF)(60mL)溶液中加入氰化铜(I)(6.8g,68.3mmoL),然后,于155℃搅拌3小时。将反应液冰冷后,加入乙酸乙酯、28%氨水,分离出有机层,用水、饱和食盐水进行洗涤,并用无水硫酸镁进行干燥。过滤后蒸馏除去溶剂,将残渣用二氧化硅凝胶色谱(正己烷、乙酸乙酯)进行纯化,得到了标题化合物9.0g(收率:94.3%)。
1H-NMR(CDCl3)δ:1.35(3H,t,J=6.8Hz),1.49(3H,t,J=6.8Hz),4.14(2H,q,J=6.8Hz),4.15(2H,q,J=6.8Hz),6.70(1H,dd,J=1.5,8.8Hz),7.24(1H,dd,J=6.4,8.8Hz).
MS m/z:209(M+)
(步骤A-3)
3,4-二乙氧基-2-氟-6-甲酰基氰苯
[化学式6]
氮气气流下向反应罐中投入THF(18.7Kg)后再投入正庚烷(13.7kg),再投入2,2,6,6-四甲基哌啶(TMP)(7.50kg,53.1mol),进行搅拌。使体系为封闭体系,在氮微正压(窒素微陽圧)条件下冷却至-15℃并搅拌过夜。在内温-10℃以下的条件下,滴加将内温调整为-42.3℃的15%正丁基锂-己烷溶液(22.4kg,50.2mol)。将滴加配管内用正庚烷(0.68kg)冲洗。然后将内温冷却至-86.9℃,滴加3,4-二乙氧基-2-氟氰苯(7.00kg,33.5mol)的THF(10.68kg)溶液。将滴加配管用THF(1.8kg)冲洗。约1小时后,滴加N,N-二甲基甲酰胺(4.89kg,66.9mol)的THF(4.49kg)溶液。DMF-THF溶液滴加结束33分钟后,滴加正庚烷(34.5Kg)。搅拌1小时后,滴加乙酸(10.5kg,175.0mol)的THF(2.99kg)溶液,并使外部浴为10℃。55分钟后,滴加水(50.4L),再加入正庚烷(17.2kg)。使外部浴为10℃,14.7小时搅拌。取出反应液,分成两个一半量进行离心分离。将所得晶体用正庚烷(5L)、水5L以及正庚烷(5L)进行洗涤,得到粗品4.85kg,于冰箱中保存。对于另一半浆料,也像首次那样进行处理,得到粗品5.25kg(湿体合计:10.10kg)。
将湿体投入反应罐,加入水(40L)和正庚烷(80L),于25℃搅拌18.7小时。取出反应液,用正庚烷(5L)与水(10L)的混合液冲洗反应罐壁。将反应液与冲洗液合并后,进行离心分离。将所得晶体用正庚烷(5L)、水(5L)以及正庚烷(5L)洗涤,以湿体的形式得到标题化合物10.30kg。
将湿体投入锥形干燥器后,于50℃减压干燥20小时,再于55℃减压干燥4小时,以微绿白色粉末状晶体的形式得到了标题化合物5.98kg(收率:75.3%)。
1H-NMR(CDCl3)δ:1.39(3H,t,J=6.8Hz),1.49(3H,t,J=6.8Hz),4.20(2H,q,J=6.8Hz),4.28(2H,q,J=6.8Hz),7.32(1H,d,J=1.5Hz),10.19(1H,s)
MS m/z:238[(M+H)+]
(步骤A-4)
3,4-二乙氧基-2-氟-6-羟基甲基氰苯
[化学式7]
在氮气气体氛围下,向反应罐中投入3,4-二乙氧基-2-氟-6-甲酰基氰苯(5.90kg,24.87mol)和乙酸乙酯(59.0L),搅拌下加入三乙酰氧基硼氢化钠(NaB(OAc)3H)(11.70kg)。搅拌30分钟后,将内温加热至40℃,搅拌2小时。使反应液冷却,在内温15℃的条件下缓慢滴加水(2L),使过量的三乙酰氧基硼氢化钠分解。然后再加入水(27.5L)。使外部浴为40℃来溶解不溶物,再次进行冷却并分液。分液后,将所得有机层用碳酸氢钠水洗涤2次,然后用食盐水进行洗涤。将所得有机层于外部浴10℃进行冷却,放置过夜。
使外部浴为50℃,减压浓缩至液体量约为14L。将外部浴调整为10℃,投入正庚烷(59L),搅拌2.8小时。对析出的晶体进行过滤后,将晶体用正庚烷(5.9L)进行洗涤,得到了湿体形式的标题化合物5.66kg。将该湿体用锥形干燥器于50℃减压干燥18.3小时,以微黄白色粉末状晶体的形式得到了标题化合物5.17kg(收率:87%)。
1H-NMR(CDCl3)δ:1.36(3H,t,J=6.8Hz),1.48(3H,t,J=6.8Hz),4.12(2H,q,J=6.8Hz),4.17(2H,q,J=6.8Hz),4.82(2H,s),5.53(1H,s),6.95(1H,s).
MS m/z:240(M+H)+
(步骤A-5)
甲磺酸2-氰基-4,5-二乙氧基-3-氟苄基酯
[化学式8]
向反应罐中投入3,4-二乙氧基-2-氟-6-(羟基甲基)氰苯(4.50kg,18.81mol)和1,2-二甲氧基乙烷(45L)后,进行搅拌。冷却反应液,并使体系内为氮气体氛围。在内温8.4℃的条件下,加入三乙基胺(2.47kg,24.45mol)。然后再滴加甲磺酰氯(2.59kg,22.61mol),并保持内温不超过20℃。搅拌34分钟后,向体系内通入氮气流,并停止冷却。向反应液中加入甲苯(45L)和0.5N盐酸(9L)并进行分液。将所得有机层用水(18L)、10%碳酸氢钠水溶液(18L)、10%食盐水(18L)、水(18L)进行洗涤,并对有机层进行减压浓缩。向浓缩液中投入甲苯(45L)后,再次进行减压浓缩,将浓缩液冷却后,加入甲苯(40L)进行稀释,从反应罐将稀释液平均取出到两个容器中。将反应罐壁用甲苯(5L)进行冲洗。将该冲洗液两等分,并与上述稀释液混合,从而得到了甲磺酸2-氰基-4,5-二乙氧基-3-氟苄基酯的甲苯溶液。将其分别称为A溶液和B溶液,称量溶液重量(A溶液:32.16Kg,B溶液:32.24kg)后,取溶液的一部分作为样品,用HPLC进行了定量。
甲磺酸2-氰基-4,5-二乙氧基-3-氟苄基酯的甲苯溶液
性状:褐色甲苯溶液、定量值:5.79kg(A溶液2.92kg,B溶液2.87kg)、收率:96.9%、HPLC纯度:A溶液98.8%,B溶液98.6%
1H-NMR(400MHz,CDCl3)δ:1.38(3H,t,J=6.8Hz),1.50(3H,t,J=6.8Hz),3.13(3H,s),4.17(4H,q,J=6.8Hz),5.28(2H,s),6.89(1H,d,J=1.0Hz).
MS m/z:317(M+)
(步骤A-6)
5,6-二乙氧基-7-氟-3H-异吲哚-1-基胺
向反应罐中投入上述步骤中得到的甲磺酸2-氰基-4,5-二乙氧基-3-氟苄基酯的甲苯A溶液[32.16kg(以甲磺酸2-氰基-4,5-二乙氧基-3-氟苄基酯计为2.92kg),9.20mol]和甲苯(170L),室温下进行搅拌。将反应液冷却至20℃以下,停止搅拌后,将体系内置换为氨气。搅拌后,再次将氨气加压至0.86MPa。将反应液在这种条件下搅拌过夜后,放出氨气。向反应液中加入水(35L)后,再加入2N盐酸(35L)并进行分液。向所得有机层中加入1N盐酸(23.4L)并进行分液。将所得水层与此前的水层混合,澄清过滤。用水(10L)冲洗后,移送至反应罐。注水(15L)进行清洗(洗い込み),冷却反应液。滴加5N氢氧化钠水溶液(7.18L),以外部浴30℃的条件对反应液进行加热,搅拌约4小时。将反应液冷却,在反应液温17.4℃的条件下滴加5N氢氧化钠水溶液(12.82L)后,将反应液搅拌过夜。将析出的晶体过滤后,将晶体用水(30L)、叔丁基甲基醚(6L)进行洗涤,得到了湿体2.29kg。将湿体用锥形干燥器于40℃进行减压干燥,以微黄白色粉末状晶体的形式得到了标题化合物(1.85kg)。
性状:微黄白色粉末状结、产量:1.85kg、收率:84%、HPLC纯度:97.5%、水分含量:0.22%
1H-NMR(400MHz,DMSO-d6)δ:1.24(3H,t,J=7.0Hz),1.34(3H,t,J=7.0Hz),4.01(2H,q,J=7.0Hz),4.17(2H,q,J=7.0Hz),4.38(2H,s),6.04(2H,bs),7.04(1H,s).
MS m/z:239(M+H)+
(步骤B-1)
1-(3-叔丁基-4-羟基苯基)乙酮
[化学式9]
将氯化铝(44.4g,333mmol)冷却至-45℃,加入甲苯(1.25L)。加入2-叔丁基苯酚(50.0g,333mmol),搅拌2小时。再滴加乙酰氯(26.1g,333mmol),搅拌2.5小时。将反应液滴加到冰冷水(250mL)中后,室温搅拌。过滤取出晶体后,减压干燥(50℃),以白色晶体的形式得到了标题化合物48.7g(收率:76.1%,HPLC纯度:99.8%)。
1H-NMR(400MHz,CDCl3)δ:1.43(9H,s),2.57(3H,s),6.17(1H,s),6.76(1H,d,J=8.0Hz),7.73(1H,dd,J=2.4,8.0Hz),7.96(1H,d,J=2.4Hz).
MS m/z:193[(M+H)+]
(步骤B-2)
1-(5-溴-3-叔丁基-4-羟基苯基)乙酮
[化学式10]
将1-(3-叔丁基-4-羟基苯基)乙酮(690.9g,3.75mol)溶解在乙腈(6.05L)中,冰冷搅拌下滴加N-溴琥珀酰亚胺(701.28g,3.94mol)的乙腈(5L)溶液。升温至室温后,将溶剂浓缩至约3L,加入正庚烷(5L)和水(5L)进行抽提和分液。将水层进一步用正庚烷(2L)进行抽提和分液,将有机层混合后,用5%硫代硫酸钠水溶液(1L)和水(2L)进行洗涤,进行减压浓缩(35℃),以微褐色油状物的形式得到了标题化合物977.0g(产量:99.1%,HPLC纯度:95.8%)。
1H-NMR(400MHz,CDCl3)δ:1.42(9H,s),2.55(3H,s),6.26(1H,s),7.88(1H,d,J=2.0Hz),7.99(1H,d,J=2.0Hz).
MS m/z:271[(M+H)+]
(步骤B-3)
2-溴-6-叔丁基-4-(1,1-二甲氧基乙基)苯甲醚
[化学式11]
在氮气气体氛围下,在1-(5-溴-3-叔丁基-4-羟基苯基)乙酮(678g,2.50mol)中加入甲醇(678mL)、原甲酸三甲酯(796g,7.50mol)和(±)-10-樟脑磺酸[(±)-CSA](11.6g,0.050mol,2mol%),并进行搅拌。搅拌2.7小时后,加入N,N-二甲基甲酰胺(1.7L),并进行冰冷。进而,加入碘甲烷(700g),再加入碳酸钾(518g),室温下进行搅拌。搅拌5.5小时后,加入水(4750mL)和正庚烷(4750mL),并进行分液。将有机层用水(2370mL)洗涤后,加入硫酸钠(120.2g)并进行搅拌,然后进行抽滤。此时,用正庚烷(250mL)进行清洗(洗い込み)。蒸馏除去滤液中的溶剂(50℃),以褐色油状物的形式得到了标题化合物808g(收率:98%,HPLC纯度:96.8%)。
1H-NMR(400MHz,DMSO-d6)δ:1.35(9H,s),1.43(3H,s),3.07(6H,s),3.86(3H,s),7.32(1H,d,J=2.0Hz),7.47(1H,d,J=2.0Hz).
MS m/z:330(M+)
(步骤B-4)
4-[3-叔丁基-5-(1,1-二甲氧基乙基)-2-甲氧基苯基]吗啉
[化学式12]
氮气气体氛围下,于室温将2-溴-6-叔丁基-4-(1,1-二甲氧基乙基)苯甲醚(650g,1.962mol)、乙酸钯(4.4g,19.6mmol,1mol%)和(±)-BINAP(18.3g,29.4mmol,1.5mol%)用1,2-二甲氧基乙烷(1.96L)溶解,加入吗啉(205g,2.36mol)和叔丁氧基钠(264g,2.75mol)。
85℃搅拌2小时后,冰冷搅拌下使温度为30℃以下。过滤出不溶物后,将滤滓(滤さい)用1,2-二甲氧基乙烷(1L)洗涤。减压蒸馏除去溶剂后,加入甲醇(600mL)、N,N-二甲基甲酰胺(1.2L)和正庚烷(6L)进行抽提和分液。再将N,N-二甲基甲酰胺层用正庚烷(3L)抽提两次,分液后混合正庚烷层,用甲醇(200mL)和水(1.8L)进行洗涤。向所得正庚烷层中加入硫氰尿酸(TMT)(13g),室温搅拌15小时后,使用硅藻土进行过滤。将滤滓用正庚烷(500mL)进行洗涤,将滤液用87%N,N-二甲基甲酰胺水(1.3L)和水(1.3L)洗涤后,进行减压浓缩(50℃),以褐色油状物的形式得到了标题化合物618g(收率:93.3%,HPLC纯度:99.5%)。
1H-NMR(400MHz,CDCl3)δ:1.37(9H,s),1.52(3H,s),3.07(4H,t,J=4.4Hz),3.18(6H,s),3.88(4H,t,J=4.4Hz),3.94(3H,s),6.97(1H,d,J=2.4Hz),7.10(1H,d,J=2.4Hz).
MS m/z:337(M+)
(步骤B-5)
2-溴-1-(3-叔丁基-4-甲氧基-5-吗啉代苯基)乙酮
[化学式13]
将4-[5-(1,1-二甲氧基乙基)-3-叔丁基-2-甲氧基苯基]吗啉(600g,1.78mol)溶解在四氢呋喃(2.67L)和甲醇(0.89L)的混合溶剂中,氮气气体氛围下,于7℃投入三溴化苯基三甲基铵(716g,1.87mol)。搅拌1小时后,向反应液中加入5%硫代硫酸钠水溶液(660mL)。再投入水(4.68L),搅拌1小时后,过滤取出晶体,以皮肤黄色晶体的形式得到了标题化合物的粗晶体。
于7℃将标题化合物的粗晶体在正庚烷(1980mL)和2-丙醇(660mL)的混合溶剂中进行悬浮搅拌。搅拌13小时,过滤取出晶体,用10%2-丙醇/正庚烷溶液(660mL)和正庚烷(660mL)洗涤后,进行减压干燥(50℃),以淡黄白色晶体的形式得到了标题化合物566.2g(收率:86.0%,HPLC纯度:99.0%)。
4-[5-(2-溴-1,1-二甲氧基乙基)-3-叔丁基-2-甲氧基苯基]吗啉
1H-NMR(400MHz,CDCl3)δ:1.37(9H,s),3.07(4H,t,J=4.4Hz),3.24(6H,s),3.57(2H,s),3.88(4H,t,J=4.4Hz),3.94(3H,s),6.98(1H,d,J=2.4Hz),7.08(1H,d,J=2.4Hz).
2-溴-1-(3-叔丁基-4-甲氧基-5-吗啉代苯基)乙酮
1H-NMR(400MHz,CDCl3)δ:1.40(9H,s),3.09(4H,t,J=4.4Hz),3.90(4H,t,J=4.4Hz),3.99(3H,s),4.41(2H,s),7.52(1H,d,J=2.0Hz),7.69(1H,d,J=2.0Hz).
MS m/z:369(M+)
(步骤B-6:最终步骤)
1-(3-叔丁基-4-甲氧基-5-吗啉代苯基)-2-(5,6-二乙氧基-7-氟-1-亚氨基
-1,3-二氢-2H-异吲哚-2-基)乙酮氢溴酸盐
[化学式14]
将2-溴-1-(3-叔丁基-4-甲氧基-5-吗啉代苯基)乙酮(550g,1.485mol)溶解在四氢呋喃(3L)中,进行澄清过滤后,在外温6℃的条件下进行搅拌,同时分三次滴加5,6-二乙氧基-7-氟-3H-异吲哚-1-基胺(300g,1.254mol)的四氢呋喃(4.5L)溶液(共三次,每次100g/1.5L)。滴加结束后,有晶体析出。搅拌18小时后,过滤取出析出的晶体。用冰冷条件下冷却的四氢呋喃(1.2L)进行洗涤,以湿晶体的形式得到了标题化合物696.5g。
于50℃将该湿晶体(693.5g)溶解在50%四氢呋喃/水(5L)中后,进行澄清过滤,用50%四氢呋喃/水(0.5L)进行洗涤。冰冷搅拌下,向滤液中加入水(2.5L),并加入晶种(1.52g)后,滴加水(7.5L)。于8℃搅拌15小时后,过滤取出晶体,用水(2L)洗涤后,通风干燥26小时(60℃),以白色晶体的形式得到标题化合物622.1g(收率:81.5%,HPLC纯度:99.6%)。
(步骤B-6其它方法(1):最终步骤)
于室温将5,6-二乙氧基-4-氟-1H-3-异吲哚胺(20g)、2-溴-1-[3-(叔丁基)-4-甲氧基-5-吗啉代苯基]-1-乙酮(34.2g)溶解在二甲基甲酰胺(300ml)中,搅拌48小时。减压蒸馏除去溶剂后,向残渣中加入乙酸乙酯(500ml),使之结晶化。对所得晶体进行过滤后,用乙酸乙酯进行洗涤,以白色晶体的形式得到了目的化合物(40g)。
1H-NMR(DMSO-d6)δ(ppm)
1.29(3H,t,J=6.8Hz)1.36(9H,s)1.39(3H,t,J=6.8Hz))2.95~3.12(4H,m)3.75~3.84(4H,m)3.94(3H,s)4.12(2H,q)4.20(2H,q,J=6.8Hz)4.78(2H,s)5.46(2H,s)7.33(1H,s)7.49(1H,s)7.59(1H,s)
MS:m/e(ESI)528.2(MH+)
(步骤B-6其它方法(2):最终步骤)
1-(3-叔丁基4-甲氧基-5-吗啉代-苯基)-2-(5,6-二乙氧基-7-氟-1-亚氨基
-1,3-二氢-异吲哚-2-基)-乙酮;盐酸盐
[化学式15]
于室温将5,6-二乙氧基-4-氟-1H-3-异吲哚胺(3.2g)、2-溴-1-[3-(叔丁基)-4-甲氧基-5-吗啉代苯基]-1-乙酮(4.8g)溶解在二甲基甲酰胺(15ml)中,搅拌48小时。减压蒸馏除去溶剂后,向残渣中加入乙酸乙酯50ml,使之结晶化。对所得晶体进行过滤后,用乙酸乙酯进行洗涤,以白色晶体的形式得到了目的化合物(2.56g)。
1H-NMR(DMSO-d6)δ(ppm)
1.29(3H,t,J=6.8Hz)1.36(9H,s)1.39(3H,t,J=6.8Hz))2.95~3.04(4H,m)3.77~3.85(4H,m)3.94(3H,s)4.11(2H,q)4.20(2H,q,J=6.8Hz)4.77(2H,s)5.46(2H,s)7.32(1H,s)7.49(1H,s)7.59(1H,s)
实施例2
按以下规程对式(I)~(VII)的化合物等的活性进行了确定。
(1)针对式(I)~(VII)的化合物等的体外测试规程
(a)血小板膜的制备
从1星期内未服用药物的健康正常人采血,添加作为抗凝血剂的3.8%柠檬酸(比例为9份血液1份抗凝血剂)。通过在室温下以100g离心10分钟,得到富血小板血浆(PRP:platelet rich plasma)。将对PRP进行离心而得到的血小板悬浮于pH7.5的5mMTris-HCl、5mM EDTA中,用Dounce匀浆器进行匀浆,以40,000g离心60分钟,得到了血小板膜。将所得血小板膜悬浮在下述溶液中,并于-80℃保存,所述溶液是在含10mM MgCl2和1mMEGTA(乙二醇四乙酸酯)的pH7.5的50mM Tris-HCl缓冲液(缓冲液1)中添加DMSO(二甲基亚砜)并使其浓度为1%而得到的。
(b)凝血酶受体放射性配体结合测定
凝血酶受体拮抗药活性采用Ahn等的凝血酶受体放射性配体结合测定法(Ahn等,Mol.Pharmacol.,51卷,p.350-356(1997))的改进方法来进行评价。向缓冲液1(pH7.5的50mM Tris-HCl、10mM MgCl2、1mM EGTA)中添加终浓度分别为0.1%和20%的牛白蛋白和DMSO,以此为受试化合物的制备液。将用该制备液稀释成各种浓度的受试化合物溶液(20μl)添加在96孔的多孔筛选平板上。然后,添加用缓冲液1稀释成25nM的[3H]Ala-(4-fluoro)Phe-Arg-(cyclohexyl)Ala-(homo)Arg-Tyr-NH2(highaffinityTRAP)([3H]Ala-(4-氟)Phe-Arg-(环己基)Ala-(高)Arg-Tyr-NH2(高亲和力TRAP))80μl。进而,添加预先制备好的血小板膜溶液(0.4mg/ml)100μl并进行混合后,于37℃温育1小时。对反应液进行抽滤后,用200μl的缓冲液1洗涤3次。然后,添加液体闪烁剂30μl,使用Top Counter(Packard)测定平板的放射活性。用受试物质存在时的放射活性与非特异性结合量的差值除以特异性结合(不存在化合物时的结合与非特异性结合量的差值),来求出结合率,计算出IC50值。而且,特异性结合是添加10μM的高亲和力TRAP而得到的值。
(2)食蟹猴的先体外后体内(ex vivo)条件血小板凝集
(a)药物施用和血液采取
在清醒情况下,对食蟹猴单独或者混合口服施用所述选自式(I)~(VII)中的至少一种化合物或其药学可接受的盐和所述选自B组中的至少一种其它化合物(B)。当静脉内持续施用所述选自B组中的至少一种其它化合物(B)时,在导入氯胺酮进行麻醉后,用麻醉气体(组成:笑气2L/min、氧1L/min、异氟烷0.5%)进行吸入麻醉。使用留置针在上臂静脉插入用于注入测试物质的导管。使用输液泵花费一定时间例如90分钟将药物施用到静脉内。采血在口服施用受试物质前以及两受试物质施用结束后进行。采血是使用装有作为抗凝固剂的3.8%柠檬酸溶液200μL的注射器从上臂静脉或隐静脉采集1.8mL。
(b)PRP凝集
将采集到的血液移入Eppendorf管,于室温6400rpm离心5秒,分离出上清作为PRP。对于分离后的血液再以10,000rpm离心5分钟,分离出贫血小板血浆(PPP:platelet poor plasma)。使用PPP对PRP的血小板浓度进行稀释,将其制备成3×105/μL。PRP凝集按Born等的浊度法进行。将PRP(225μl)加入测定通道,加温至37℃后,添加凝血酶受体活化肽(TRAP)25μL,基于6分钟时间的浊度变化记录凝集曲线。对该凝集曲线下的面积值进行评价,作为凝集强度。
(3)体外血小板凝集规程
从1星期内未服用药物的健康正常人采血,添加作为抗凝血剂的3.8%柠檬酸(比例为9份血液1份抗凝血剂)。通过室温下以100g离心10分钟,获得PRP。对于除去了PRP的血液,再以1000g离心10分钟,获得PPP。使用多项目自动血球计数装置(K4500,SYSMEX)测定血小板数,用PPP稀释PRP,使其为约30万/μl。将所述选自式(I)~(VII)中的化合物稀释成各种浓度而得到的溶液与PRP于37℃预温育60分钟。在预温育处理后的PRP(175μl)中添加所述B组化合物(B)的各种浓度的溶液(25μl),添加作为纤维蛋白聚集抑制剂的GPRP-NH2(终浓度1mM)25μl。使用聚集测量计(MCMEDICAL)测定血小板凝集能力,于37℃保温3分钟后,添加25μl的凝血酶溶液(1U/ml),考察6分钟的凝集反应,通过比较凝集曲线的曲线下面积来评价抑制作用。在使用凝血酶以外的凝集引发剂的情况下,不添加GPRP-NH2,并将PRP的容量变更为200μl。
实施例3
[实施例3-1]
将所述选自式(I)~(VII)中的至少一种化合物或其药学可接受的盐和所述选自B组的至少一种其它化合物(B)单独或混合口服施用于雄性Hartree系豚鼠。作为媒介,使用了0.5%甲基纤维素溶液或含二甲基亚砜、Tween20的水溶液(可以反复施用)。
口服施用后一定时间,腹腔内施用戊巴比妥酸钠进行麻醉。麻醉下露出颈静脉,用聚乙烯管实施套管插入术,用于施用玫瑰红。露出大腿动脉,安装血流测定用探针。对探针的上游部位照射绿色光(波长540nm、500,000勒克斯),照射5分钟后,花费约1分钟的时间施用溶解在生理食盐水中的5mg/mL的玫瑰红溶液(5mg/kg)。测定至血流完全停止经过的时间。
通过这些实验数据,对化合物单独和组合使用的抗血栓作用进行评价。
[实施例3-2]
将上述式(I)的化合物的氢溴酸盐(以下称为实施例1化合物)以及阿司匹林分别用DMSO溶解,使其分别为200mg/ml和1000mg/ml。使用这些DMSO溶液、Tween20和蒸馏水,制备了4种施用溶液,它们均为DMSO和Tween20的浓度分别为5%和2%的水溶液,这4种施用溶液分别是:不存在化合物的载体(Vehicle)、单独实施例1化合物6mg/ml、单独阿司匹林50mg/ml以及实施例1化合物6mg/ml和阿司匹林20mg/ml的混合溶液。以5ml/kg的比例口服施用于雄性Hartree系豚鼠,在经过约80分钟的时间点上,腹腔内施用戊巴比妥酸钠进行了麻醉。麻醉下露出颈静脉,用聚乙烯管实施套管插入术,用于施用玫瑰红。露出大腿动脉,安装血流测定用探针。化合物施用后约115分钟,对探针的上游部位照射绿色光(波长540nm、500,000勒克斯),照射5分钟后,花费约1分钟的时间施用溶解在生理食盐水中的5mg/mL的玫瑰红溶液(5mg/kg)。通过测定从开始施用玫瑰红溶液至血流完全停止的血流时间,对抗血栓作用进行了评价。
<结果>
如图1所示,施用了载体的对照组的血流时间为6.72分钟,与此相对,实施例1化合物30mg/kg和阿司匹林100mg/kg的血流时间分别延长至10.77分钟和11.30分钟。进而,两者组合使用的组的血流时间延长至24.19分钟。
该结果显示:通过组合施用选自通式(I)~(VII)中的至少一种化合物与阿司匹林等指定的化合物(B),能够获得良好的抗血栓作用。因此,从该结果来看,可知:通过将两化合物组合施用于患者,能够治疗或改善心脏病等疾病。
工业实用性
根据本发明,提供含有至少一种2-亚氨基吡咯烷衍生物和至少一种其它化合物(B)的药物组合物。所述药物组合物对例如心脏病的治疗或改善是有用的。
Claims (6)
2.根据权利要求1所述的组合物,其中,所述式(I)的化合物或其药学可接受的盐是式(I)化合物的氢溴酸盐。
3.根据权利要求1或2所述的组合物,其中,所述组合物是心脏病治疗用或改善用药物组合物。
4.根据权利要求3所述的组合物,其中,所述心脏病是选自急性冠心病综合征、粥样斑血栓症、再狭窄、高血压、稳定型心绞痛、心律失常、心力衰竭、ST段抬高心肌梗死和脑梗死中的至少一种疾病。
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PCT/JP2009/050184 WO2009088063A1 (ja) | 2008-01-11 | 2009-01-09 | 医薬組成物、医薬組成物製造のための2-イミノピロリジン誘導体の使用および心疾患の治療用または改善用キット |
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CN101917990A CN101917990A (zh) | 2010-12-15 |
CN101917990B true CN101917990B (zh) | 2012-11-28 |
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US (1) | US8658620B2 (zh) |
EP (1) | EP2241315B1 (zh) |
JP (1) | JP5571389B2 (zh) |
KR (1) | KR20100119862A (zh) |
CN (1) | CN101917990B (zh) |
AU (1) | AU2009203368A1 (zh) |
BR (1) | BRPI0906395A2 (zh) |
CA (1) | CA2711612A1 (zh) |
IL (1) | IL206464A0 (zh) |
MX (1) | MX2010007527A (zh) |
WO (1) | WO2009088063A1 (zh) |
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US20100056519A1 (en) * | 2008-07-15 | 2010-03-04 | Serebruany Victor L | Composition and method for reducing platelet activation and for the treatment of thrombotic events |
US8673890B2 (en) | 2009-10-29 | 2014-03-18 | Janssen Pharmaceutica Nv | 2,3-dihydro-1H-isoindol-1-imine derivatives useful as thrombin PAR-1 receptor antagonist |
JPWO2012014889A1 (ja) * | 2010-07-29 | 2013-09-12 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | フタロニトリル誘導体の製造方法 |
CN113929736B (zh) * | 2020-06-29 | 2024-01-26 | 首都医科大学 | Gly-Pro-Arg-Pro-氧乙氨羰基华法林,其合成,活性和应用 |
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CN1503784A (zh) * | 2001-04-19 | 2004-06-09 | ������������ʽ���� | 2-亚氨基吡咯烷衍生物 |
WO2007075964A2 (en) * | 2005-12-22 | 2007-07-05 | Schering Corporation | Thrombin receptor antagonists as prophylaxis to complications from cardiopulmonary surgery |
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US6245782B1 (en) * | 1999-05-17 | 2001-06-12 | Heartdrug Research L.L.C. | Methods of inhibiting platelet activation with selective serotonin reuptake inhibitors |
JP4549970B2 (ja) | 2003-02-19 | 2010-09-22 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 環状ベンズアミジン誘導体の製造方法 |
EP1721610B1 (en) | 2004-03-04 | 2009-05-13 | Eisai R&D Management Co., Ltd. | Composition containing benzamidine derivative and method for stabilizing benzamidine derivative |
WO2006051648A1 (ja) * | 2004-11-09 | 2006-05-18 | Eisai R & D Management Co., Ltd. | トロンビン受容体アンタゴニストを有効成分とするくも膜下出血に伴う血管攣縮の治療剤 |
TW200812619A (en) * | 2006-04-06 | 2008-03-16 | Schering Corp | TRA combination therapies |
US20100056519A1 (en) * | 2008-07-15 | 2010-03-04 | Serebruany Victor L | Composition and method for reducing platelet activation and for the treatment of thrombotic events |
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- 2009-01-09 AU AU2009203368A patent/AU2009203368A1/en not_active Abandoned
- 2009-01-09 KR KR1020107017487A patent/KR20100119862A/ko not_active Application Discontinuation
- 2009-01-09 CN CN2009801018349A patent/CN101917990B/zh not_active Expired - Fee Related
- 2009-01-09 JP JP2009548960A patent/JP5571389B2/ja not_active Expired - Fee Related
- 2009-01-09 EP EP09701323.9A patent/EP2241315B1/en active Active
- 2009-01-09 MX MX2010007527A patent/MX2010007527A/es unknown
- 2009-01-09 BR BRPI0906395A patent/BRPI0906395A2/pt not_active IP Right Cessation
- 2009-01-09 CA CA2711612A patent/CA2711612A1/en not_active Abandoned
- 2009-01-09 WO PCT/JP2009/050184 patent/WO2009088063A1/ja active Application Filing
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CN1503784A (zh) * | 2001-04-19 | 2004-06-09 | ������������ʽ���� | 2-亚氨基吡咯烷衍生物 |
WO2007075964A2 (en) * | 2005-12-22 | 2007-07-05 | Schering Corporation | Thrombin receptor antagonists as prophylaxis to complications from cardiopulmonary surgery |
Also Published As
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EP2241315B1 (en) | 2013-12-11 |
US8658620B2 (en) | 2014-02-25 |
BRPI0906395A2 (pt) | 2016-11-01 |
CA2711612A1 (en) | 2009-07-16 |
MX2010007527A (es) | 2010-10-05 |
KR20100119862A (ko) | 2010-11-11 |
JPWO2009088063A1 (ja) | 2011-05-26 |
US20100286087A1 (en) | 2010-11-11 |
EP2241315A4 (en) | 2012-03-28 |
EP2241315A1 (en) | 2010-10-20 |
AU2009203368A1 (en) | 2009-07-16 |
WO2009088063A1 (ja) | 2009-07-16 |
JP5571389B2 (ja) | 2014-08-13 |
IL206464A0 (en) | 2010-12-30 |
CN101917990A (zh) | 2010-12-15 |
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