CN1297265C - 抗血栓形成药与阿司匹林的新组合及其在制备用于治疗动脉粥样硬化血栓形成性疾病的药物中的用途 - Google Patents
抗血栓形成药与阿司匹林的新组合及其在制备用于治疗动脉粥样硬化血栓形成性疾病的药物中的用途 Download PDFInfo
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Abstract
本发明涉及抗血栓形成药与阿司匹林的新组合以及包含所述组合的药物组合物。
Description
本新发明涉及抗血栓形成药与阿司匹林的新组合以及包含它们的药物组合物。
更具体而言,本发明涉及TP受体拮抗剂与阿司匹林的组合。
血栓烷A2(TXA2)是花生四烯酸的一种不稳定代谢物,其与多种血液循环疾病的发病机制有关。血栓烷A2不仅是强效血小板活化剂,而且是强效血管收缩剂,其具有细胞增殖和促粘着性质。
TXA2与花生四烯酸的其它代谢物如内过氧化物(PGH2)、HETE和异***素(isoprostane)通过称为TP受体的共同受体发挥它们的作用。
近来已进行了大量探索性研究,旨在预防由血栓烷A2产生过多引起的循环疾病。已发现:在所述拮抗剂中,专利说明书EP 648741中所述的那些是强效和选择性的TP受体拮抗剂、经口服途径施用有效且作用持续时间长。
更具体而言,已发现:外消旋形式或旋光纯异构体形式的式(I)的化合物(A)及其可药用盐是强效抗血栓形成药:
通过口服途径施用后,该化合物可选择性抑制由TP受体活化引起的血小板凝集,此外还具有抗动脉粥样硬化性质。
我们现已发现:化合物A与阿司匹林的组合可令人惊讶地使得在抗血栓形成活性方面获得协同作用。
据文献所述,某些抗血小板凝集剂如双嘧达莫与阿司匹林的组合具有相加作用,并且已证明所述组合在预防脑血管事件中非常有益。
其它抗血小板凝集剂与阿司匹林的组合在文献中已有描述。由于如下事实:这些抗凝集剂作用于血小板凝集途径(如嘌呤能途径,ADP),与阿司匹林通过花生四烯酸代谢途径发挥作用不同,所以预计可观察到这些化合物活性的相加作用。
本发明所涉及的组合则完全不同:化合物A与阿司匹林均作用于花生四烯酸代谢途径:前者通过不可逆性抑制将花生四烯酸转化为内过氧化物(PGH2)的环加氧酶发挥作用,而后者通过对抗花生四烯酸的某些代谢物如血栓烷A2、异***素和内过氧化物的活性发挥作用。
已令人惊讶地发现:化合物A与阿司匹林的组合可使得在活性方面获得大的协同作用,其不能由任何文献的教导中预见到。
该协同作用已在用豚鼠进行的动脉血栓形成试验中得到证实。在所述试验过程中显示:在阿司匹林存在下,化合物A的抗血栓形成活性被增强,并且以非常大且完全无法预见的方式增加。
在本发明的组合中,化合物(A)与阿司匹林可以以可药用盐形式存在。
在化合物(A)的加成盐中,可非限制性地提及的是与可药用碱的加成盐,如钠盐、钾盐、叔丁胺盐和二乙胺盐等。
优选使用钠盐。
在阿司匹林的加成盐中,可非限制性地提及的是与可药用酸的加成盐,如乙酸盐、苯甲酸盐、富马酸盐、马来酸盐、柠檬酸盐、酒石酸盐、赖氨酸盐等。
在本发明的组合中,化合物(A)优选具有绝对构型(R)。
本发明还涉及药物组合物,其包含化合物(A)与阿司匹林的组合以及一种或多种适宜的、惰性的、无毒赋形剂,适宜时,化合物(A)和阿司匹林可以是可药用盐形式。
在本发明的药物组合物中,可更具体地提及的是适于经口、经胃肠外或经鼻施用的那些,如片剂或糖锭剂、舌下片、明胶胶囊、锭剂、栓剂、乳膏剂、软膏剂、皮肤凝胶剂等。
剂量可根据病症的性质和严重程度、施用途径以及患者的年龄和体重而变化。
在本发明的组合物中,活性成分的量为化合物(A)1至300mg、阿司匹林100至1000mg。
因此,本发明的组合物可用于治疗与TP受体活化和/或代谢物形成有关的动脉粥样硬化血栓形成性疾病(atherothrombotic illness)以及治疗这些疾病的后果。这些病症包括但不限于稳定型或不稳定型心绞痛、伴有内皮或血管功能障碍的疾病如高血压、糖尿病、心力衰竭、心血管或脑血管***的疾病,或者尤其是与动脉粥样硬化有关的血栓栓塞性疾病。
已对本发明的组合进行了研究,其协同作用已在用豚鼠进行的动脉血栓形成试验中得到证实。
该试验基于最初由Roux等人(Thromb Haemost 71:252-256,1994)所述的模型。用***+甲苄噻嗪(90+12)mg/kg肌肉注射麻醉豚鼠。在气管中***导管并保持动物自发呼吸。在颈静脉中***导管,以便可静脉内施用供试化合物。分离颈总动脉,并安装多普勒探头以便可测量动脉血流量。稳定后,通过用在多普勒探头远端的夹子制造动脉壁损伤。制造损伤后,血流量减少。当流量达到零时,轻微震动动脉,这可以使流量恢复。继续血栓形成方法,再次导致流量减少和停止。相应地,血栓形成现象导致循环流量减少(CFR),在20分钟的一段时间中对其进行观察。该段期间后,将动物用或不用化合物(A)治疗,并再次对CFR观察20分钟。在对照动物中或在通过静脉内途径用阿司匹林(2mg/kg)治疗的动物中进行该试验。
该研究用化合物(A)的(R)异构体的钠盐进行。
结果显示:在未治疗的动物中观察到10±1CFR/20分钟。化合物(A)通过静脉内途径施用可以以剂量依赖方式减轻CFR;自0.3mg/kg剂量即可获得显著效果(5±2CFR/20分钟)。用1mg/kg的剂量可获得几乎完全的抑制作用(2±2CFR/20分钟)。
在用阿司匹林治疗的动物中,观察到8±1CFR/20分钟;该值与在对照动物中获得的值没有差异。
化合物(A)通过静脉内途径施用于已经用阿司匹林治疗的动物可以以剂量依赖方式减轻CFR;在此情况下,自0.01mg/kg剂量即可获得显著效果(5±1CFR/20分钟),并且用0.1mg/kg的剂量可获得几乎完全的抑制作用(2±1CFR/20分钟)。
这些结果首次证明了化合物(A)的强效抗血栓形成活性,其自0.3mg/kg剂量起有效。
此外,在不产生抗血栓形成效果的阿司匹林剂量存在下,化合物(A)的抗血栓形成活性被增强并且增加至少30倍。事实上,自0.01mg/kg剂量即可观察到所述效果,这表明:当两种活性成分同时施用时,存在非常大的协同作用。
Claims (8)
1.用于治疗与血栓烷A2/***素内过氧化物受体活化和/或代谢物形成有关的动脉粥样硬化血栓形成性疾病的式(I)化合物或其可药用盐之一与阿司匹林或其可药用盐之一的组合产品:
2.根据权利要求1的组合产品,其特征在于式(I)化合物是R构型的旋光异构体形式。
3.根据权利要求1或权利要求2的组合产品,其特征在于式(I)化合物是钠盐形式。
5.根据权利要求4的药物组合物,其特征在于式(I)化合物是R构型的旋光异构体形式。
6.根据权利要求4或权利要求5的药物组合物,其特征在于式(I)化合物是钠盐形式。
7.根据权利要求4或权利要求5的药物组合物,其特征在于活性成分的量分别为式(I)化合物1至300mg、阿司匹林10至1000mg。
8.权利要求4至7中任一项的药物组合物在制备药物中的用途,所述药物用于治疗与血栓烷A2/***素内过氧化物受体活化和/或代谢物形成有关的动脉粥样硬化血栓形成性疾病。
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Application Number | Priority Date | Filing Date | Title |
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FR02/04222 | 2002-04-05 | ||
FR0204222A FR2838057B1 (fr) | 2002-04-05 | 2002-04-05 | Nouvelle association d'un antithrombotique et d'aspirine |
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CN1646111A CN1646111A (zh) | 2005-07-27 |
CN1297265C true CN1297265C (zh) | 2007-01-31 |
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US (1) | US7618955B2 (zh) |
EP (1) | EP1496884B1 (zh) |
JP (1) | JP4065853B2 (zh) |
KR (1) | KR100645143B1 (zh) |
CN (1) | CN1297265C (zh) |
AR (1) | AR039253A1 (zh) |
AT (1) | ATE329591T1 (zh) |
AU (1) | AU2003246774B2 (zh) |
BR (1) | BR0309019A (zh) |
CA (1) | CA2480697A1 (zh) |
CY (1) | CY1105106T1 (zh) |
DE (1) | DE60306133T2 (zh) |
DK (1) | DK1496884T3 (zh) |
EA (1) | EA006978B1 (zh) |
ES (1) | ES2264533T3 (zh) |
FR (1) | FR2838057B1 (zh) |
GE (1) | GEP20074101B (zh) |
HK (1) | HK1076034A1 (zh) |
MA (1) | MA27114A1 (zh) |
MX (1) | MXPA04009760A (zh) |
NO (1) | NO20044700L (zh) |
NZ (1) | NZ535430A (zh) |
PL (1) | PL371620A1 (zh) |
PT (1) | PT1496884E (zh) |
UA (1) | UA79457C2 (zh) |
WO (1) | WO2003084525A1 (zh) |
ZA (1) | ZA200407593B (zh) |
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EP1906966A2 (en) * | 2005-07-22 | 2008-04-09 | The Procter and Gamble Company | Compositions for reducing the incidence of drug induced arrhythmia |
MX2009010953A (es) * | 2007-04-13 | 2009-10-29 | Millenium Pharmaceuticals Inc | Terapia anticoagulante en combinacion, con un compuesto que actua como un inhibidor del factor xa. |
JP2009001537A (ja) * | 2007-06-25 | 2009-01-08 | Lab Servier | 血管障害の処置を目的とする医薬の入手における抗アテローム血栓化合物の使用 |
FR2920772B1 (fr) * | 2007-09-11 | 2009-10-23 | Servier Lab | Association entre un anti-atherothrombotique et un inhibiteur de l'enzyme de conversion de l'angiotensine |
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US5472979A (en) * | 1993-10-15 | 1995-12-05 | Adir Et Compagnie | 1,2,3,4-tetrahydronaphthalene compounds |
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US5472979A (en) * | 1993-10-15 | 1995-12-05 | Adir Et Compagnie | 1,2,3,4-tetrahydronaphthalene compounds |
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