CN100408093C - 血管紧张素转化酶抑制剂在制备预防或降低充血性心衰的药物中的用途 - Google Patents

血管紧张素转化酶抑制剂在制备预防或降低充血性心衰的药物中的用途 Download PDF

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CN100408093C
CN100408093C CNB008110700A CN00811070A CN100408093C CN 100408093 C CN100408093 C CN 100408093C CN B008110700 A CNB008110700 A CN B008110700A CN 00811070 A CN00811070 A CN 00811070A CN 100408093 C CN100408093 C CN 100408093C
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B·肖勒肯斯
N·本德
B·兰古恩瓦拉
G·达格奈斯
H·杰斯坦恩
A·勒琼格仁
S·尤索夫
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Abstract

本发明涉及肾素-血管紧张素***(RAS)抑制剂或其可药用衍生物、特别是雷米普利或雷米普利拉在生产用于预防中风、糖尿病和/或充血性心衰(CHF)的药物中的用途。本发明还涉及预防和/或治疗中风、糖尿病和/或CHF的方法，该方法包括，向需要所述预防和/或治疗的患者施用治疗有效量的RAS抑制剂或其可药用衍生物、特别是雷米普利或雷米普利拉。

Description

血管紧张素转化酶抑制剂在制备预防或降低充血性心衰的药物中的用途
发明领域
本发明涉及肾素-血管紧张素***(RAS)抑制剂或其可药用衍生物在生产用于预防中风、糖尿病和/或充血性心衰(CHF)的药物中的用途。本发明还涉及预防和/或治疗中风、糖尿病和/或CHF的方法，该方法包括，向需要所述预防和/或治疗的患者施用治疗有效量的RAS抑制剂或其可药用衍生物。
发明背景
可以干扰RAS的化合物是本领域已知的，这些化合物可用于治疗心血管疾病、特别是高血压和心衰。主要可以通过抑制合成血管紧张素的酶或者通过阻断效应物部位的相应受体来干扰RAS。目前可以采用的是血管紧张素转化酶(ACE)抑制剂和血管紧张素II的1型受体(AT II)拮抗剂。
ACE抑制剂是可以抑制血管紧张素I转化成有活性的血管紧张素II以及有活性的扩血管缓激肽分解的化合物。这两种机制均可以引起血管扩张。这些化合物记载于，例如，EP 158927、EP 317878、US 4,743,450和US 4,857,520。
雷米普利(公开于EP-A-079022)是一种长效ACE抑制剂。其活性代谢物是游离的二元酸雷米普利拉，其在给药雷米普利后在体内产生。已知向高血压患者施用雷米普利可以降低外周动脉阻力，从而使血压降低而不会引起心率的代偿性增加。该药物目前用于治疗高血压和CHF。此外，已证实雷米普利可以降低有充血性心衰临床征兆的患者从急性心肌梗塞中抢救过来后的死亡率。有人提出，雷米普利与许多其它ACE抑制剂相比具有附加的优点，因为它对组织中的ACE有显著的抑制作用，从而可以对心脏、肾和血管产生器管保护作用。
可以干扰RAS的化合物包括ACE抑制剂和AT II拮抗剂，这些化合物在目前用于治疗各种心血管疾病，特别是对表现出高血压的患者进行治疗。所述化合物很少用于预防心血管疾病，而这些化合物在预防中风、糖尿病和/或CHF中的应用到目前为止还是未知的。
发明概述
本发明涉及RAS抑制剂或其可药用衍生物在生产用于预防中风、特别是在显示正常或低血压的患者中预防中风的药物中的用途。
本发明还涉及RAS抑制剂或其可药用衍生物在生产用于预防糖尿病的药物中的用途。
本发明还涉及RAS抑制剂或其可药用衍生物在生产用于在没有先前存在的CHF、即，没有CHF的征兆或症状的患者中预防CHF发生的药物中的用途。
本发明的另一方面涉及预防中风、糖尿病和/或CHF的方法，该方法包括，向需要所述预防的患者施用治疗有效量的RAS抑制剂或其可药用衍生物。
本发明的另一方面还涉及用于预防中风、糖尿病和/或CHF的药物制剂，所述药物制剂含有治疗有效量的RAS抑制剂或其可药用衍生物。
另一方面，本发明还涉及RAS抑制剂或其可药用衍生物在预防中风、糖尿病和/或CHF中的用途，包括向需要所述预防的患者施用RAS抑制剂或其可药用衍生物。
发明详述
我们惊奇地发现，可以用RAS抑制剂、特别是干扰血管紧张素II合成的ACE抑制剂来预防心血管和代谢疾病例如中风、糖尿病和CHF。本发明的特别令人惊奇之处在于，具有本质上维持的心脏功能和/或显示正常或低血压的患者可以从RAS抑制剂的预防作用中明显获益。本发明描述了通过施用RAS抑制剂来预防中风、糖尿病和/或CHF等疾病的新方法。
显示正常或低血压的患者称为血压正常的患者。对不同患者组群定义血压值的准则的例子包括不同的年龄，包括由WHO和JNC(USA)颁布的准则。在本发明中，正常或低血压的适当定义可以参见JNC VI，该文献引入本文作为参考。
在本发明中，“中风”包括致命的和非致命的。
在本发明中，“糖尿病”包括I型糖尿病、也称为胰岛素依赖型糖尿病(IDMM)和II型糖尿病、也称为非胰岛素依赖型糖尿病(NIDDM)。
在本发明中，“肾素-血管紧张素***(RAS)抑制剂或其可药用衍生物”包括其本身或在给药时可以通过减少血管紧张素II的合成或阻断其在受体上的作用来阻断血管紧张素II对脉管***的负面影响的任何化合物。
在本发明中，“血管紧张素转化酶(ACE)抑制剂或其可药用衍生物”包括其本身或在给药时可以干扰血管紧张素II合成的任何化合物。
当本发明所用的RAS抑制剂有多个不对称碳原子时，这些碳原子可以以多种立体化学形式存在。本发明包括异构体混合物以及单个的立体异构体。本发明还包括几何异构体、旋转异构体、对映体、消旋体和非对映体。
如果可以的话，可将RAS抑制剂以中性的形式(例如羧酸)使用，或以盐的形式使用，优选可药用盐，例如所述化合物的钠、钾、铵、钙或镁盐。如果可以的话，可将上述化合物以可水解的酯的形式使用。
在本发明中，RAS抑制剂包括其所有的前药，无论其在体外是否有活性。因此，尽管该保护了的衍生物本身可能没有药理学活性，但也可将其通过例如胃肠外或口服给药，然后在体内代谢形成RAS的药理学活性的抑制剂。优选的例子是雷米普利(它可以代谢成雷米普利拉)以及坎地沙坦cilexetil(它可以代谢成坎地沙坦)。
RAS的抑制剂包括ACE抑制剂、AT II拮抗剂，也称为血管紧张素受体阻断剂(ARB)、肾素拮抗剂以及血管肽酶抑制剂(VPI)。
短语“血管肽酶抑制剂”包括所谓的NEP/ACE抑制剂(也称为选择性或双重作用的中性内肽酶抑制剂)，其具有中性内肽酶(NEP)抑制活性和血管紧张素转化酶(ACE)抑制活性。
短语“肾素拮抗剂”包括肾素抑制剂。
在本发明中，RAS抑制剂可以显示长的作用持续时间、中等作用持续时间或短的作用持续时间。
可用于预防中风、糖尿病和/或CHF的ACE抑制剂或其可药用衍生物(包括活性代谢物)包括但不仅限于如下化合物：阿拉普利、阿曲普利(alatriopril)、阿替普利钙(altiopril calcium)、安可维宁(ancovenin)、贝那普利、盐酸贝那普利、贝那普利拉、苯甲酰卡托普利、卡托普利、卡托普利-半胱氨酸、卡托普利-谷光甘肽、塞拉普利(ceranapril)、塞拉诺利(ceranopril)、塞罗普利、西拉普利、西拉普利拉、地拉普利、地拉普利二酸、依那普利、依那普利拉、恩那普利(enapril)、表卡托普利、foroxymithine、福芬普利(fosfenopril)、福森普利、福森普利钠、福辛普利、福辛普利钠、福辛普利拉、福辛普利酸、格来普利(glycopril)、hemorphin-4、伊拉普利(idrapril)、咪达普利、吲哚普利、吲哚普利拉、赖本普利(libenzapril)、赖诺普利、lyciumin A、lyciumin B、米安普利(mixanpril)、莫昔普利、莫昔普利拉、莫维普利、muracein A、muracein B、muracein C、喷托普利、培哚普利、培哚普利拉、匹伐普利(pivalopril)、匹伏普利、喹那普利、盐酸喹那普利、喹那普利拉、雷米普利、雷米普利拉、螺普利、盐酸螺普利、螺普利拉、spiropril、盐酸spiropril、替莫普利、盐酸替莫普利、替普罗肽、群多普利、群多普利拉、乌替普利、扎普利、扎普利拉、佐芬普利和佐芬普利拉。
优选的用于本发明的ACE抑制剂是雷米普利、雷米普利拉、赖诺普利、依那普利和依那普利拉。更优选的用于本发明的ACE抑制剂是雷米普利和雷米普利拉。关于雷米普利和雷米普利拉的资料可以参见Merck Index.，第12版，1996，1394-1395页。
可用于预防中风、糖尿病和/或CHF的AT II拮抗剂或其可药用衍生物(包括活性代谢物)包括但不仅限于在如下欧洲专利申请公开号中描述的化合物：253310，323841，324377，399731，400974，401030，403158，403159，407102，407342，409332，411507，411766，412594，412848，415886，419048，420237，424317，425211，425921，426021，427463，429257，430300，430709，432737，434038，434249，435827，437103，438869，442473，443568，443983，445811，446062，449699，450566，453210，454511，454831，456442，456442，456510，459136，461039，461040，465323，465368，467207，467715，468372，468470，470543，475206，475898，479479，480204，480659，481448，481614，483683，485929，487252，487745，488532，490587，490820，492105，497121，497150，497516，498721，498722，498723，499414，499415，499416，500297，500409，501269，501892，502314，502575，502725，503162，503785，503838，504888，505098，505111，505893，505954，507594，508393，508445，508723，510812，510813，511767，511791，512675，512676，512870，513533，513979，514192，514193，514197，514198，514216，514217，515265，515357，515535，515546，515548，516392，517357，517812，518033，518931，520423，520723，520724，521768，522038，523141，526001，527534，和528762.
其它AT II拮抗剂包括国际专利申请公开号
WO 91/00277，WO 91/00281，WO 91/11909，WO 91/11999，WO 91/12001，WO 91/12002，WO 91/13063，91/15209，WO 91/15479，WO 91/16313，WO91/17148，WO 91/18888，WO 91/19697，WO 91/19715，WO 92/00067，WO92/00068，WO 92/00977，WO 92/02510，WO 92/04335，WO 92/04343，WO92/05161，WO 92/06081，WO 92/07834，WO 92/07852，WO 92/09278，WO92/09600，WO 92/10189，WO 92/11255，WO 92/14714，WO 92/16523，WO92/16552，WO 92/17469，WO 92/18092，WO 92/19211，WO 92/20651，WO92/20660，WO 92/20687，WO 92/21666，WO 92/22533，WO 93/00341，WO93/01177，WO 93/03018，WO 93/03033
和WO 93/03040中公开的那些。上述欧洲和国际专利申请的内容引入本文作为参考。
优选的用于本发明的AT II拮抗剂或其可药用衍生物包括但不仅限于具有如下属名的化合物：坎地沙坦(candesartan)、坎地沙坦cilexetil、洛沙坦、缬沙坦、依贝沙坦、他索沙坦、替米沙坦和依普沙坦。
特别优选的用于本发明的AT II拮抗剂或其可药用衍生物是坎地沙坦和坎地沙坦cilexetil。坎地沙坦和坎地沙坦cilexetil记载于Takeda化学品公司的欧洲专利459136B1、US 5,196,444和US5,703,110中。坎地沙坦cilexetil目前由AstraZeneca和Takeda生产并以商标名例如Atacand
Figure C0081107000071
、Amias
Figure C0081107000072
和Blopress
Figure C0081107000073
在世界范围内销售。
可用于预防中风、糖尿病和/或CHF的NEP/ACE-抑制剂或其可药用衍生物(包括活性代谢物)包括但不仅限于5,508,272、5,362,727、5,366,973、5,225,401、4,722,810、5,223,516、5,552,397、4,749,688、5,504,080、5,612,359、5,525,723、5,430,145和5,679,671，以及欧洲专利申请0481522、0534263、0534396、0534492和0671172中公开的化合物。
优选的用于本发明的NEP/ACE抑制剂是在上述美国专利和欧洲专利申请中指定为优选的那些化合物，这些美国专利和欧洲专利申请引入本文作为参考。特别优选的NEP/ACE抑制剂是omapatrilat(公开于美国专利5,508,272)或MDL 100240(公开于美国专利5,430,145)。
可用于预防中风、糖尿病和/或CHF的肾素-抑制剂或其可药用衍生物(包括活性代谢物)包括但不仅限于如下化合物：enalkrein；RO42-5892；A 65317；CP 80794；ES 1005；ES 8891；SQ 34017；CGP29287；CGP 38560；SR 43845；U-71038；A 62198和A 64662。
药物制剂
一方面，本发明涉及含有RAS抑制剂或其可药用衍生物或前药、包括代谢物作为活性成分用于预防中风、糖尿病和/或充血型心衰(CHF)的药物制剂。
对于临床应用，可将RAS抑制剂配制成用于口服、静脉内、皮下、气管、支气管、鼻内、肺、经皮、颊部、直肠、胃肠外或其它给药方式的药物制剂。药物制剂可以含有抑制剂与可药用辅剂、稀释剂和/或载体。
在制备本发明的药物制剂时，可将活性成分与固体、粉状的成分例如乳糖、蔗糖、山梨醇、甘露醇、淀粉、支链淀粉、纤维素衍生物、明胶或其它适宜的成分以及崩解剂和润滑剂例如硬脂酸镁、硬脂酸钙、硬脂基富马酸钠和聚乙二醇蜡混合。然后可将该混合物加工成颗粒剂或压制成片剂。
可将活性成分预先与其它非活性成分混合，然后再混合形成制剂。
软明胶胶囊可以用含有本发明活性成分、植物油、脂肪或其它适用于软明胶胶囊的赋形剂的混合物的胶囊制备。硬明胶胶囊可以含有活性成分的颗粒。硬明胶胶囊还可以含有活性成分与固体粉状成分例如乳糖、蔗糖、山梨醇、甘露醇、土豆淀粉、玉米淀粉、支链淀粉、纤维素衍生物或明胶的混合物。
用于直肠给药的剂量单位可以制成(i)栓剂的形式，其含有与中性脂肪基质混合的活性物质；(ii)明胶直肠胶囊的形式，其含有活性物质与植物油、石蜡油或其它适用于明胶直肠胶囊的载体的混合物；(iii)预先制好的微型灌肠剂的形式；或(iv)用于在临给药前在适宜的溶剂中重建的干粉微型灌肠制剂的形式。
液体制剂可以制成糖浆或混悬剂的形式，例如含有活性成分的溶液或混悬剂，其余的物质包括，例如糖或糖醇以及乙醇、水、甘油、丙二醇和聚乙二醇的混合物。如需要，所述液体制剂可以含有着色剂、矫味剂、防腐剂、糖精和羧甲基纤维素或其它增稠剂。液体制剂还可以制成用于在使用前用适宜的溶剂重建的干粉的形式。
用于胃肠外给药的溶液可以制成本发明制剂在可药用溶剂中的溶液的形式。这些溶液还可以含有稳定剂、防腐剂和/或缓冲剂。用于胃肠外给药的溶液还可以制成用于在使用前用适宜的溶剂重建的干粉制剂的形式。
活性成分的总量可以占制剂的约0.1％(w/w)至约95％(w/w)，例如0.5％至50％(w/w)，优选1％至25％(w/w)。
药物制剂可以含有约0.1mg至约1000mg活性成分，优选1mg至100mg活性成分。
活性成分的给药剂量取决于所涉及的适应症、患者的年龄、体重和性别，并且可以由医生来确定。适宜的剂量可以是约0.01mg/kg至约20mg/kg，优选0.1mg/kg至10mg/kg。
活性成分的典型的每日剂量可以在宽的范围内变化，并且取决于各种因素，例如所涉及的适应症、给药途径、患者的年龄、体重和性别，并且可以由医生来确定。通常，给药剂量、特别是口服和胃肠外给药的剂量可以从约0.1至约100mg/天活性成分、优选1至50mg/天活性成分。
以下实施例是用来说明的，并不以任何方式限定本发明的范围。
实施例
设计了大规模的临床试验以检验ACE抑制剂雷米普利与安慰剂相比在减少心血管事件中的效果。
研究用6年的时间在19个国家的267个中心进行，共有9,541名参加者，这些参加者由于以前的局部缺血性心脏病、中风、外周动脉疾病的病史而有心血管事件的高危险性或是患有糖尿病的个体。
参与研究的患者的收缩期血压平均值为138mm Hg，因此这些患者在研究开始时是血压正常的患者。在用雷米普利或安慰剂治疗一个月后，收缩期血压分别下降了5.48mm Hg和1.59mm Hg。
研究的主要目标是心肌梗死(MI)、中风和心血管(CV)死亡(死亡率)。
研究在早期停止是因为在服用雷米普利的患者中可以非常明显地减少心血管死亡、心脏发作和中风。除以上益处外，还可以使对血管重建术(例如冠状动脉旁路移植术、气囊血管成形术等)的需求和糖尿病并发症降低四分之一至五分之一。
在雷米普利组，发生中风的患者数量减少了32％，这很令人惊讶，因为这些患者在参加研究时血压是正常的。
在雷米普利组，发生CHF的患者数量减少了21％，这很出人意料，因为这些患者在研究开始时并没有CHF的征兆或症状。
同样令人惊奇的是，在雷米普利组，发生糖尿病的患者数量减少了36％。
缩写
ACE＝血管紧张素转化酶
AT II＝血管紧张素II的1型受体
CHF＝充血性心衰
IDMM＝胰岛素依赖型糖尿病
JNC＝***家委员会
MI＝心肌梗死
NIDDM＝非胰岛素依赖型糖尿病
WHO＝世界卫生组织

Claims (4)

1. 血管紧张素转化酶抑制剂或其可药用盐在生产用于在没有先前存在的CHF并具有本质上维持的心脏功能的患者中预防或降低出现充血性心衰(CHF)危险的药物中的用途，其中所述患者是糖尿病患者或者由于以前的局部缺血性心脏病、中风或外周动脉疾病的病史而有心血管事件的高危险性，以及所述患者显示正常或低血压。
2. 根据权利要求1的用途，其中的血管紧张素转化酶抑制剂或其可药用盐选自阿拉普利、阿曲普利、阿替普利钙、安可维宁、贝那普利、盐酸贝那普利、贝那普利拉、苯甲酰卡托普利、卡托普利、卡托普利-半胱氨酸、卡托普利-谷光甘肽、塞拉普利、塞拉诺利、塞罗普利、西拉普利、西拉普利拉、地拉普利、地拉普利-二酸、依那普利、依那普利拉、恩那普利、表卡托普利、foroxymithine、福芬普利、福森普利、福森普利钠、福辛普利、福辛普利钠、福辛普利拉、福辛普利酸、格来普利、hemorphin-4、伊拉普利、咪达普利、吲哚普利、吲哚普利拉、赖本普利、赖诺普利、lyciumin A、lyciumin B、米安普利、莫昔普利、莫昔普利拉、莫维普利、muracein A、muracein B、muracein C、喷托普利、培哚普利、培哚普利拉、匹伐普利、匹伏普利、喹那普利、盐酸喹那普利、喹那普利拉、雷米普利、雷米普利拉、螺普利、盐酸螺普利、螺普利拉、spiropril、盐酸spiropril、替莫普利、盐酸替莫普利、替普罗肽、群多普利、群多普利拉、乌替普利、扎普利、扎普利拉、佐芬普利和佐芬普利拉。
3. 根据权利要求2的用途，其中的血管紧张素转化酶抑制剂选自雷米普利、雷米普利拉、赖诺普利、依那普利和依那普利拉。
4. 根据权利要求3的用途，其中的血管紧张素转化酶是雷米普利或雷米普利拉.
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