CN100453075C - 抗动脉粥样血栓形成剂与抗血小板凝集剂的新组合产品 - Google Patents

抗动脉粥样血栓形成剂与抗血小板凝集剂的新组合产品 Download PDF

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CN100453075C
CN100453075C CNB2004800283560A CN200480028356A CN100453075C CN 100453075 C CN100453075 C CN 100453075C CN B2004800283560 A CNB2004800283560 A CN B2004800283560A CN 200480028356 A CN200480028356 A CN 200480028356A CN 100453075 C CN100453075 C CN 100453075C
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L·克洛阿雷克-布兰查德
S·科达
L·勒龙
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Abstract

本发明涉及一种抗动脉粥样血栓形成剂与抗血小板凝集剂的新组合产品。

Description

抗动脉粥样血栓形成剂与抗血小板凝集剂的新组合产品
本新发明涉及一种抗动脉粥样血栓形成剂与抗血小板凝集剂的新组合产品，还涉及含有它们的药物组合物。
更具体地讲，本发明涉及一种特异性TP受体拮抗剂和氯吡格雷的组合产品。
血栓烷A2(TXA2)是一种不稳定的花生四烯酸的代谢物，与许多心血管病的发病机制有关。血栓烷A2是一种强的血小板活化剂，且还是一种具有细胞增生和前粘连(pro-adhesive)性质的强血管收缩剂。
TXA2和其它花生四烯酸代谢物，例如内过氧化物(PGGG2-PGH2)、HETEs和异前列腺烷，都通过称之为TP受体(血栓烷-前列腺素-内过氧化物)的共同受体显示作用。
近来人们进行了大量的研究工作，目的在于防止在心血管和神经血管系统中与过量产生血栓烷A2相关的现象。在这样一些拮抗剂中，发现在专利EP 648 741说明书中描述的那些拮抗剂是TP受体的强而有选择性的拮抗剂，通过口服途径给药，它们具有活性并作用时间长。
更特别地讲，申请人已发现呈外消旋形式或光学纯异构体形式的下式(I)化合物(A)及其在药学上可接受盐是强的抗动脉粥样血栓形成剂：
Figure C20048002835600041
化合物(A)是一种特异性TP受体拮抗剂，更特别地讲，是一种血栓烷A2和前列腺素-内过氧化物(PGG2-PGH2)受体的特异性拮抗剂，因此使该化合物具有强的动脉粥样化血栓形成作用。
一般而言，在动脉粥样化斑块破裂后，由于循环血小板与暴露于血流的血管内皮基层的胶原蛋白的相互作用导致血栓形成。这种现象称为动脉粥样化血栓形成。
胶原蛋白存在于血管壁的基层，并且是人和动物体内动脉粥样化病变血栓形成的决定因子。
血小板通过胶原蛋白受体粘附在胶原蛋白纤维上，并且还与血小板粘附、活化和凝集有关。
血小板活化伴随着释放两种主要的激动剂，即ADP和血栓烷A2，它们与相邻血小板上的各自受体(P2Y、TP)结合，使粘附作用和血小板凝集增强。
ADP作为一种循环介质也存在于血液中，而血栓烷A2是一种强的次要介质，它是在活化的血小板中通过环加氧酶1由花生四烯酸生成的。
血栓烷A2不仅促进血栓形成，而且还诱发血管壁机能不良(血管收缩)，促进血管壁增生和炎性浸润。
在目前可采用的抗血小板治疗中，阿司匹林能抑制由血栓烷A2产生血小板，同时氯吡格雷抑制由ADP诱发的血小板凝集。
ADP和血栓烷A2在动脉血栓形成中起到重要的补充作用。
化合物A通过阻断由血栓烷A2和其它TP受体配位体诱发的血小板凝集而起作用，无论其怎样的来源、血小板和血小板外也都如此。
它还通过抑制由血栓烷A2诱发的血管收缩和通过对抗血管壁的内皮机能不良和增生以及炎性而起作用。
申请人现在发现，在人体中，化合物A与氯吡格雷的组合产品具有令人惊奇的抗血栓形成协同作用。
事实上，由于化合物A与氯吡格雷以完全不同的凝集途径作用于血小板，因此，为了获得一种新的治疗方法，将这两种化合物结合起来是特别有利的。
申请人令人惊奇地发现，化合物A与氯吡格雷的组合产品就活性而言具有显著的协同作用，这一点并不能从任何已有的文献中得到启示。这种组合产品对于抗血栓形成作用的改善可通过离体对由胶原蛋白诱发的血小板凝集的抑制进行评价。
该试验表明，在氯吡格雷存在下，化合物A的抗血栓形成活性得到加强，并且以极其显著和完全不可预知的方式增加。此外，该组合产品具有良好的可接受性。
在本发明的组合产品中，化合物A与氯吡格雷可以呈药学上可接受的盐的形式。
在化合物A的加成盐中，可以提到与药学上可接受碱的加成盐，例如钠盐、钾盐、叔丁胺盐和二乙胺盐等，但并不限于此。
优选的盐是钠盐。
在氯吡格雷的加成盐中，优选硫酸氢盐。
在本发明的组合产品中，化合物A优选地具有绝对构型(R)。
本发明还涉及含有化合物A与氯吡格雷或者它们的药学上可接受的盐的组合产品的药物组合物，需要时，该药物组合物还可以含有一种或多种适当的惰性无毒赋形剂。
在本发明的药物组合物中，更具体地可以提到适合于口服、肠胃道外或鼻用药的那些药物组合物，它们是片剂或锭剂、舌下片剂、明胶胶囊、栓剂、霜剂、软膏、皮肤用凝胶等。
采用的剂量可以根据病况的性质与严重程度、用药方式和患者的年龄和体重进行改变。
在本发明的组合物中，活性组分的量是1-300mg化合物A，10-600mg氯吡格雷。
因此，本发明的组合物可以用于治疗涉及TP受体活化的心血管疾病，也用于治疗所述疾病的后果。所述病状包括、但不限于急性冠状动脉综合征、稳定型或非稳定型心绞痛、内皮机能不良、与动脉粥样硬化相关的血管疾病、高血压、糖尿病和心力衰竭，还用于预防和治疗血管、心血管或神经血管系统疾病，特别是与动脉粥样硬化、心房纤颤相关的血栓栓塞疾病以及与心脏病学、神经病学、血管病理学和放射学中的侵入性外科手术(血管成形术、安装支架、分流术、导管等)相关的血栓栓塞疾病。
对胶原蛋白诱发的血小板凝集的抑制作用
使18位志愿者每天口服10mg化合物A与75mg氯吡格雷，连续三天，这些志愿者已用75mg氯吡格雷治疗7天。将化合物A和氯吡格雷组合产品治疗效果与分别服用化合物A与氯吡格雷的效果进行比较。
在试验过程中，使用血小板凝集测量仪测量血小板在富含柠檬酸血小板的血浆(PRPc)上的凝集，计算出离体胶原蛋白(5μg/ml)诱发血小板凝集的抑制百分数。
得到的结果如下：
-服用化合物A本身达到35％抑制，
-服用氯吡格雷本身达到11％抑制，
-服用化合物A与氯吡格雷的组合产品达到62％抑制。
这些结果非常清楚地表明，服用这两种化合物的组合产品对胶原蛋白诱发血小板凝集具有协同作用。由这种组合产品产生的抗聚集作用高于分别服用两种产品的效果之和。在已有文献中从未提及该种作用。
上述结果表明，这种组合产品可以有效治疗需要提高与血管作用相关的抗血栓形成作用的急性或慢性病况(神经血管或心血管疾病的急性治疗或二次预防)。

Claims (12)

1、任选呈光学异构体形式的下式(I)化合物(A)或其一种药学上可接受盐与氯吡格雷或其一种药学上可接受盐的组合产品：
2、根据权利要求1所述的组合产品，其特征在于化合物(A)呈(R)构型的光学异构体形式。
3、根据权利要求1所述的组合产品，其特征在于化合物(A)呈钠盐形式。
4、根据权利要求1、2和3中任一项权利要求所述的组合产品，其特征在于氯吡格雷呈硫酸氢盐形式。
5、药物组合物，该药物组合物含有任选呈光学异构体形式的化合物(A)或其一种药学上可接受盐与氯吡格雷或其一种药学上可接受盐的组合产品作为活性组分，并且还含有一种或多种药学上可接受的惰性赋形剂或载体。
6、根据权利要求5所述的药物组合物，其特征在于化合物(A)呈(R)构型光学异构体形式。
7、根据权利要求5所述的药物组合物，其特征在于化合物(A)呈钠盐形式。
8、根据权利要求5、6和7中任一项权利要求所述的药物组合物，其特征在于氯吡格雷呈硫酸氢盐形式。
9、根据权利要求5-7中任一项权利要求所述的药物组合物，其特征在于活性组分的量分别是1-300mg化合物A，10-600mg氯吡格雷。
10、根据权利要求5-7中任一项权利要求所述的药物组合物，该药物组合物用于治疗涉及TP受体活化的心血管疾病，也用于治疗所述疾病的后果。
11、根据权利要求10所述的药物组合物，该药物组合物用于治疗急性冠状动脉综合征、稳定型或非稳定型心绞痛、内皮机能不良、与动脉粥样硬化相关的血管疾病、高血压、糖尿病和心力衰竭，还用于预防和治疗血管、心血管或神经血管系统疾病和血栓栓塞疾病。
12.根据权利要求11所述的药物组合物，该药物组合物用于预防和治疗与动脉粥样硬化、心房纤颤相关的血栓栓塞疾病以及与心脏病学、神经病学、血管病理学和放射学中的侵入性外科手术相关的血栓栓塞疾病。
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MXPA05014086A (es) * 2005-12-20 2007-06-20 Leopoldo De Jesus Espinosa Abdala Composiciones farmaceuticas que comprenden sustancias antiagregantes plaquetarios combinadas para su uso en el tratamiento y prevencion de eventos vasculares de origen isquemico.
FR2899473B1 (fr) * 2006-04-07 2008-06-13 Servier Lab Utilisation d'un compose anti-atherothrombotique pour l'obtention de medicaments destines au traitement des troubles vasculaires
EP2591783A1 (en) * 2007-04-13 2013-05-15 Millennium Pharmaceuticals, Inc. Combination anticoagulant therapy with a compound that acts as a factor Xa inhibitor
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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EP0648741A1 (fr) * 1993-10-15 1995-04-19 Adir Et Compagnie Dérivés de 1,2,3,4-tétrahydronaphtalène, de chromanne et de thiochrtomanne comme agents antithromotiques
US20030109543A1 (en) * 1998-11-03 2003-06-12 Ogletree Martin L. Novel combination of an ADP-receptor blocking antiplatelet drug and a thromboxane A2 receptor antagonist and a method for inhibiting thrombus formation employing such combination

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EP0648741A1 (fr) * 1993-10-15 1995-04-19 Adir Et Compagnie Dérivés de 1,2,3,4-tétrahydronaphtalène, de chromanne et de thiochrtomanne comme agents antithromotiques
US20030109543A1 (en) * 1998-11-03 2003-06-12 Ogletree Martin L. Novel combination of an ADP-receptor blocking antiplatelet drug and a thromboxane A2 receptor antagonist and a method for inhibiting thrombus formation employing such combination

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CN1859902A (zh) 2006-11-08
AU2004277734B8 (en) 2005-04-14
NO20061944L (no) 2006-05-02
EP1677779A1 (fr) 2006-07-12
MY137953A (en) 2009-04-30
PL1677779T3 (pl) 2009-02-27
WO2005032533A1 (fr) 2005-04-14
JP2007507475A (ja) 2007-03-29
FR2860436B1 (fr) 2006-01-20
DE602004016762D1 (de) 2008-11-06
AU2004277734B2 (en) 2007-05-24
US20100056564A1 (en) 2010-03-04
KR100782246B1 (ko) 2007-12-05
EA200600657A1 (ru) 2006-08-25
HK1093900A1 (en) 2007-03-16
HRP20080546T3 (en) 2009-01-31
EP1677779B1 (fr) 2008-09-24
ES2314457T3 (es) 2009-03-16
UA80220C2 (en) 2007-08-27
FR2860436A1 (fr) 2005-04-08
NZ545988A (en) 2008-11-28
KR20060061399A (ko) 2006-06-07
AU2004277734A1 (en) 2005-04-14
MA28081A1 (fr) 2006-08-01
US20070054934A1 (en) 2007-03-08
EA009418B1 (ru) 2007-12-28
PT1677779E (pt) 2008-10-23
AR046043A1 (es) 2005-11-23
CA2540062A1 (fr) 2005-04-14
ATE409033T1 (de) 2008-10-15
BRPI0415043A (pt) 2006-12-12
CY1108388T1 (el) 2014-02-12
SI1677779T1 (sl) 2009-02-28
DK1677779T3 (da) 2009-01-05
GEP20084546B (en) 2008-11-25
MXPA06003713A (es) 2006-06-14

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