CN100577171C - 治疗重度心力衰竭的药物 - Google Patents
治疗重度心力衰竭的药物 Download PDFInfo
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- CN100577171C CN100577171C CN200480000735A CN200480000735A CN100577171C CN 100577171 C CN100577171 C CN 100577171C CN 200480000735 A CN200480000735 A CN 200480000735A CN 200480000735 A CN200480000735 A CN 200480000735A CN 100577171 C CN100577171 C CN 100577171C
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- heart failure
- sub
- treatment
- benzo
- aza
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Abstract
治疗重度心力衰竭的方法，其包括给予患者有效量的苯并氮杂化合物(1)或其盐：其中R1是H或卤素，R2是OH或-NR5R6(R5和R6是H或低级烷基)，R3是H、卤素、低级烷基或低级烷氧基，R4是卤素、低级烷基或低级烷氧基，和包含苯并氮杂化合物(1)或其盐的药物组合物及化合物(1)或其盐在制备治疗重度心力衰竭的药物中的应用。
Description
本发明涉及用含有作为活性成分的苯并氮杂
化合物的药物治疗重度心力衰竭的方法和其有效的药物。更具体地，本发明涉及治疗重度心力衰竭的方法，其包括给予需要的患者治疗有效量的苯并氮杂
化合物(1)或其可药用盐：
其中R1是氢原子或卤原子，R2是羟基或式-NR5R6基团，其中R5和R6相同或不同，各是氢原子或低级烷基，R3是氢原子、卤原子、低级烷基或低级烷氧基，R4是卤原子、低级烷基或低级烷氧基。
本发明进一步提供了用于治疗重度心力衰竭的含有上述的苯并氮杂
化合物作为活性成分的药物和上述化合物(1)在制备用于治疗重度心力衰竭的药物中的应用。
背景技术：
众所周知式(1)的苯并氮杂化合物具有加压素拮抗活性，用作血管扩张剂、降血压剂、利尿剂、血小聚集抑制剂等(参见WO 91/05549，美国专利5,258,510，美国专利5,753,677，JP-A-6-80641)，并且进一步地这些化合物也用作催产素拮抗剂(Wo 94/01113)，白内障治疗剂(WO 94/18975，美国专利5,827,862)，脑水肿治疗剂(JP-A-8-157368)，美尼尔病治疗剂(JP-A-10-120592)或抗溃疡剂(JP-A-7-188021)。
尽管从冠状动脉疾病(CAD)(美国心脏协会，heart and strokefacts：1996年统计增刊，第15页)的年龄特异性死亡率降低50％可反映出过去二十年在美国心血管疾病的预防和治疗方面有重大进展，但心力衰竭的流行稳步增长(Massie BM，Shah NB，心力衰竭流行病，Curr.Opin.Cardiol.1996，11：221-226)。这很可能是美国人口老龄化和多数CAD患者长寿的结果。当前大约5百万个体患有慢性充血性心力衰竭，据估计每年会诊断出400,000新的心力衰竭病例(Massie BM，Shah NB，心力衰竭流行病，Curr.Opin.Cardiol.1996，11：221-226)。每年大约20％的患者由于疾病状态的恶化需要住院治疗(″Cardium″，published by Decision Resources(1998))。已经表明大约50％的心力衰竭的患者死于诊断出5年内(Konstam M，Dracut K，Baker D，etal.，心力衰竭：左心室功能障碍患者的评价和护理，AHCRP出版No.94-0612，Rockville(MD)：美国卫生和人类服务部；1994年6月)。
在美国，治疗心力衰竭的花费估计每年超过120亿美元，甚至高达300亿美元，这还不包括工资和生产力损失的花费(Levitz KR，LazenbyHC，Cown CA，etal.，国民卫生支出，1990，Health Care Fin Rev1991，13：29-54；O′Connell JB，Bristow MR，在美国心力衰竭对经济的影响：该是采用不同方式的时候了，J Heart Lung Transplant，1994，13：107-12)。仅住院治疗的花费超过70亿美元(O′Connell JB，Bristow MR，在美国心力衰竭对经济的影响：该是采用不同方式的时候了，J Heart Lung Transplant，1994，13：107-12)。
心力衰竭被定义为以左心室功能和神经激素调节的异常为特征的复杂的临床综合症，它又会导致乏力、体液滞留和寿命缩短。
以临床症状和疾病的发展过程为根据，将心力衰竭分为“急性心力衰竭”和“慢性心力衰竭”或“在急性恶化期的慢性心力衰竭”。
心力衰竭的治疗措施依照状态，即就是它是处于慢性期还是急性期，而完全不同。对于治疗慢性心力衰竭，治疗是缓解残存的心力衰竭症状，并保持稳定的状态使之不至于转为急性恶化期的慢性心力衰竭。另一方面，当患者转为急性恶化期的慢性心力衰竭后，症状可能会迅速恶化，危及生命，因此，从这个观点，需要采取通过暂时控制呼吸和血压并给予强心剂的拯救生命的措施以便于调节和稳定临床症状，从血液动力学观点着，这是通过增加心输出量，降低心血管循环体积并增加肾血流量而实现的。
因为大多数心力衰竭不能由病因疗法治疗，症状随着时间流逝逐渐恶化。即使心脏功能通过临时性对症疗法暂时恢复，随后功能恶化并且不可能永久痊愈。恶化速度依多种状况如基础病因的类型、疾病的严重性、治疗效力和居住环境而改变。此外，即使当患者处于良好的恢复过程中，他们有时候会莫名其妙的突然死亡。心力衰竭的患者预后的生活很差。根据美国Framingham研究的统计，包括患有心脏病的所有患者的数据，自发病来大约四年中显示出50％的存活率(Kannel，WB，et al.，1982，Mckee，PA，et al.，1982)。此外，在纽约心脏协会分类中，患有重度I型疾病的患者显示预后良好，但是患有重度IV型的患者在不到1年的时间里显示出50％的存活率，患有重度II或III型的患者在不到4年的时间里显示出50％的存活率。因此，那些诊断患有重度心力衰竭的患者有很差的预后。(参见世界医疗综合手册，第30卷，1990，Nakayma Shoten)
发明详述
本发明者集中研究寻求治疗急性心力衰竭的方法和新的有效的药物。最终，他们发现式(1)的苯并氮杂
化合物对治疗心力衰竭是有效的，从而完成了本发明。
因此，本发明包括下述多个实施方案：
[1]在第一个实施方案中，本发明提供治疗重度心力衰竭的新方法，其包括给予需要的患者治疗有效量的式(1)苯并氮杂
化合物或其药用盐：
其中R1是氢原子或卤原子，R2是羟基或式-NR5R6基团，其中R5和R6相同或不同，各是氢原子或低级烷基，R3是氢原子、卤原子、低级烷基或低级烷氧基，R4是卤原子、低级烷基或低级烷氧基。
[2]在另一个实施方案中，本发明提供根据上述[1]治疗重度心力衰竭的方法，其中活性化合物(1)的每日剂量小于0.6mg/kg。
[3]在另一个实施方案中，本发明提供根据上述[1]治疗重度心力衰竭的方法，其中活性化合物(1)的每日剂量为从0.1mg/kg至小于0.6mg/kg。
[4]在另一个实施方案中，本发明提供根据上述[1]治疗重度心力衰竭的方法，其中活性化合物(1)的剂量为每天15至45mg/人。
[5]在另一个实施方案中，本发明提供根据上述[1]治疗重度心力衰竭的方法，其中活性化合物(1)是5-二甲氨基-1-[4-(2-甲基苯甲酰氨基)苯甲酰基]-2，3，4，5-四氢-1H-苯并氮杂
[6]在另一个实施方案中，本发明提供根据上述[1]治疗重度心力衰竭的方法，其中活性化合物(1)是5-羟基-7-氯-1-[2-甲基-4-(2-甲基苯甲酰氨基)-苯甲酰基]-2，3，4，5-四氢-1H-苯并氮杂
[7]在另一个实施方案中，本发明提供根据上述[1]治疗重度心力衰竭的方法，其中重度心力衰竭是急性心力衰竭或急性恶化期的慢性心力衰竭。
[8]在另一个实施方案中，本发明提供根据上述[1]治疗重度心力衰竭的方法，其中重度心力衰竭是纽约心脏协会分类III和IV类重度心力衰竭。
[9]在另一实施方案中，本发明提供治疗量度心力衰竭的新药物，其包括作为活性成分的式(1)苯并氮杂
化合物或其药用盐。
[10]在另一实施方案中，本发明提供根据上述[9]的药物，其中活性化合物(1)5-二甲氨基-1-[4-(2-甲基苯甲酰氨基)苯甲酰基]-2，3，4，5-四氢-1H-苯并氮杂
[11]在另一实施方案中，本发明提供根据上述[9]的药物，其中活性化合物(1)是5-羟基-7-氯-1-[2-甲基-4-(2-甲基苯甲酰氨基)苯甲酰基]-2，3，4，5-四氢-1H-苯并氮杂
[12]在另一实施方案中，本发明提供适于治疗重度心力衰竭的药物组合物，其包括作为活性成分的式(1)苯并氮杂
化合物或其药用盐与常规药用载体或稀释剂的混合物。
[13]在另一实施方案中，本发明提供根据上述[12]的药物组合物，其中活性化合物是5-二甲氨基-1-[4-(2-甲基苯甲酰氨基)苯甲酰基]-2，3，4，5-四氢-1H-苯并氮杂
[14]在另一实施方案中，本发明提供根据上述[12]的药物组合物，其中活性化合物(1)是5-羟基-7-氯-1-[2-甲基-4-(2-甲基苯甲酰氨基)苯甲酰基]-2，3，4，5-四氢-1H-苯并氮杂
[15]在另一实施方案中，本发明提供根据上述[12]至[14]中任一项的药物组合物，其中活性化合物(1)或其药用盐的用量占组合物重量的1至70％。
[16]在另一实施方案中，本发明提供式(1)苯并氮杂
化合物或其药用盐在制备适于治疗重度心力衰竭的药物中的应用。
[17]在另一实施方案中，本发明提供根据上述[16]的式(1)苯并氮杂
或其药用盐的应用，其中活性化合物(1)是5-二甲氨基-1-[4-(2-甲基苯甲酰氨基)苯甲酰基]-2，3，4，5-四氢-1H-苯并氮杂
[18]在另一实施方案中，本发明提供根据上述[16]的式(1)苯并氮杂
或其药用盐的应用，其中活性化合物(1)是5-羟基-7-氯-1-[2-甲基-4-(2-甲基苯甲酰氨基)苯甲酰基]-2，3，4，5-四氢-1H-苯并氮杂
[19]在另一实施方案中，本发明提供根据上述[16]至[18]中任一项的式(1)苯并氮杂或其药用盐的应用，其中包含在药物中的活性化合物的每日剂量单元小于0.6mg/kg。
实施本发明的最好方式
适合本发明的治疗重度心力衰竭的方法的药物包括作为活性成分的至少一种上述式(1)苯并氮杂化合物或其药用盐。
在说明书和权利要求书中，上述式(1)中的基团表示下述基团。
″卤原子″表示氟原子、氯原子、溴原子或碘原子。″低级烷基″表示具有1到6个碳原子的直链或支链烷基，如甲基、乙基、丙基、异丙基、丁基、叔丁基、戊基或己基。
″低级烷氧基″表示具有1到6个碳原子的直链或支链烷氧基如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、戊氧基或己氧基。
此外，在说明书和权利要求书中的术语“重度心力衰竭”是指急性心力衰竭和在急性恶化期的慢性心力衰竭，例如在纽约心脏协会分类中III和IV类心力衰竭。纽约心脏协会分类中III和IV类(纽约心脏分类协会标准委员会：心脏和血管疾病，命名法和诊断标准，第6版，P.110，Little，Brown & Co.，Boston(1964))定义如下：III类，有可导致身体行为明显限制的心脏疾病的患者。在休息时他们是舒适的。少于正常的身体行为就导致疲劳、心悸、呼吸困难或心绞痛。IV类，有导致无能力进行任何不带有不适的身体行为的心脏病患者，即使在休息时，心机能不全或心绞痛综合症的症状也会出现。如果从事任何身体活动，不适就会增加。
根据本发明的方法，活性苯并氮杂
化合物(1)在远远小于现有专利(WO91/05549)中先前要求的剂量时是有效的。即，化合物(1)作为例如抗溃疡药使用时，它通常以每天0.6至50mg/kg的剂量给药，例如每天60-90mg/人，但是根据本发明人的研究，发现当化合物(1)以从每天0.1mg/kg到小于0.6mg/kg的剂量给药，优选每天15mg到45mg/人，更优选大约每天30mg/人，对降低体重和增加尿量有效，而没有不良的副作用如尿频等，于是能改善水肿和死亡率，还发现，对于患有低钠血症的患者能增加血清中钠水平。
因而，根据本发明的方法，即使在患有重度心力衰竭且有不良预后的患者中，预后也得到显著的改善，因此，本发明的方法对治疗重度心力衰竭是有用的。
式(1)的苯并氮杂
和制备他们的方法被WO 91/05549，美国专利5,258,510和美国专利5,753,677及日本副本JP-A-6-80641公开。
式(1)的苯并氮杂
易于与药用酸形成药用酸的加成物。药用酸包括无机酸如硫酸、盐酸、磷酸、氢溴酸等，和有机酸如乙酸、对-甲苯磺酸、甲磺酸、草酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、琥珀酸、苯甲酸等。
在式(1)的苯并氮杂
化合物中，具有酸性基团的化合物易于与药用碱性化合物形成盐。碱性化合物包括金属氢氧化物比如氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钙等；碱金属碳酸盐或碳酸氢盐，如碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾等；和碱金属醇化物，如甲醇钠、甲醇钾等。
本发明的活性化合物(1)以常规药物制剂的形式使用。制剂是通过使用常规的稀释剂或载体如填充剂、增稠剂、粘合剂、润湿剂、崩解剂、表面活性剂、润滑剂等制备的。根据预期的应用，药物制剂可选择多种形式，有代表性的形式是片剂、丸剂、粉末剂、溶液、混悬剂、乳化剂、颗粒、胶囊、栓剂、注射剂(溶液、混悬剂等)等。
为了制成片剂，使用的众所周知的药物载体，例如赋形剂(例如乳糖、精制糖、氯化钠、葡萄糖、尿素、淀粉、木糖醇、甘露糖、赤藓醇、山梨醇、碳酸钙、高岭土、晶态纤维素、硅酸等)、粘合剂(例如水、乙醇、丙醇、单糖浆、葡萄糖溶液、淀粉溶液、明胶溶液、羧甲基纤维素、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等)、崩解剂(例如无水淀粉、藻酸钠、琼脂粉、昆布糖粉、碳酸氢钠、碳酸钙、聚氧乙烯脱水山梨醇脂肪酸酯、月桂酰硫酸钠、硬脂酸甘油单酸酯、淀粉、乳糖等)、崩解抑制剂(例如精制糖、硬脂酸甘油酯、可可脂、氢化油等)、吸收促进剂(例如季铵碱、月桂基硫酸钠等)、润湿剂(如甘油、淀粉等)、吸附剂(例如淀粉、乳糖、陶土、膨润土、胶态硅酸盐等)、润滑剂(如纯滑石粉、硬脂酸酯、硼酸粉、聚乙二醇等)等。而且，片剂也可以制成常规包衣片的形式，如糖包衣片、明胶包衣片、肠溶衣片、薄膜包衣片或双层或多层片剂。在丸剂的制备中，可应用常规载体，其包括例如赋形剂(例如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、高岭土、滑石等)、粘合剂(阿拉伯胶粉、黄芪胶粉、明胶、乙醇等)、崩解剂(例如昆布糖、琼脂等)等。在栓剂的制备中，可采用常规的载体，其包括例如聚乙二醇、可可脂、高级醇、高级醇酯、明胶、半合成甘油酯等。胶囊可通过采用常用方式将本发明的化合物和上述的载体的混合物装入硬明胶胶囊、软胶囊或羟丙甲基纤维素胶囊(HMPC胶囊)来制备。在注射剂的制备中，溶液、乳液和混悬液灭菌并优选制成与血液等渗的。在这些溶液乳液和混悬浪的制备中，使用的常规稀释剂有例如水、乙醇、聚乙二醇、丙二醇、乙氧基化异硬脂醇、聚烷氧基异硬脂醇、聚氧乙烯脱水山梨醇脂肪酸酯等。在这些实例中，药物制剂也可与氯化钠、葡萄糖、或甘油以足够能使它们等渗的量混合，也可以与常规的增溶剂、缓冲剂、麻醉剂混合。而且，如果需要，药物制剂可任选地与着色剂、防腐剂、芳香剂、矫味剂、甜味剂和其它的药物混合。
掺入本发明的药物组合物中的活性化合物(1)的量不是固定的，而是选自很宽的范围，但通常，优选占组合物的总重量的1到70％，更优选5％到50％重量。
本发明的药物的合适的给药方法可根据制剂的各种形式、患者的年龄、性别和其它的条件、疾病的严重程度等确定。例如，片剂、丸剂、溶液、混悬液、乳液、颗粒和胶囊是口服给药。注射剂是单独或与常规辅助液(如葡萄糖、氨基酸溶液)一起静脉内给药，如果需要，其也可以单独肌内、皮内、皮下或腹腔途径给药。栓剂是以直肠内途径给药。
本发明活性化合物的剂量可根据用法、患者的年龄、性别和其他情况、疾病的严重程度等选择，但通常小于每天0.6mg/kg，优选每天从0.1mg/kg至小于0.6mg/kg。合适的剂量是每天15mg至45mg/人。
实施例
本发明通过下述的制剂和实验更详细地阐述，但不应解释为对其的限定。
制剂1
5-二甲氨基-1-[4-(2-甲基苯甲酰氨基)-苯甲酰基]-
2，3，4，5-四氢-1H-苯并氮杂
150g
Avicel(商品名，由日本Asahi Chemical 40gIndustry有限公司制造)
玉米淀粉 30g
硬脂酸镁 2g
羟丙基甲基纤维素 10g
聚乙二醇-6000 3g
蓖麻油 40g
乙醇 40g
将本发明的活性化合物、Avicel、玉米淀粉和硬脂酸镁混合并捏制，混合物通过采用常规的用于糖包衣的捣碎机(R10mm)压片。制得的片剂用包含羟丙基甲基纤维素、聚乙二醇-6000、蓖麻油和乙醇的薄膜包衣剂包衣以制得薄膜包衣片。
制剂2
5-羟基-7-氯-[2-甲基-4-(2-甲基苯甲酰氨基)-
苯甲酰基]-2，3，4，5-四氢-1H-苯并氮杂
150g
柠檬酸 1.0g
乳糖 33.5g
磷酸二钙 70.0g
Pullonic F-68 30.0g
月桂基硫酸钠 15.0g
聚乙烯吡咯烷酮 15.0g
聚乙二醇(Carbowax 1500) 4.5g
聚乙二醇(Carbowax 6000) 45.0g
玉米淀粉 30.0g
无水月桂基硫酸钠 3.0g
无水硬脂酸镁 3.0g
乙醇 适量
将本发明的活性化合物、柠檬酸、乳糖、磷酸二钙、Pullonic F-68和月桂基硫酸钠混合。
混合物过60号筛并用包含聚乙烯吡咯烷酮、Carbowax 1500和Carbowax 6000的醇溶液制粒。如果需要，往其中加入乙醇以使粉末混合物制成糊状体。将玉米淀粉加入混合物中，持续搅拌混合物形成均匀的颗粒。制成的颗粒过10号筛，放入盘中，在烤箱中于100℃干燥12到14小时。干燥的颗粒过16号筛，往其中加入干燥的月桂基硫酸钠和干燥的硬脂酸镁，混合物压片形成想要的形状。
用滑石粉喷洒和修饰这样制备的片芯，以保护其免于受潮。向片芯施加内涂层。为了药片口服给药，修饰片芯多次。为了得到圆形和光滑表面的片剂，施加另外的含润滑剂的内涂层和涂层。片剂进一步地用着色包衣材料包衣直到制得想要的有色片。干燥后，将包衣片抛光以获得想要的具有均匀光泽的片剂。
制剂3
5-羟基-7-氯-[2-甲基-4-(2-甲基苯甲酰氨基)-
苯甲酰基]-2，3，4，5-四氢-1H-苯并氮杂
5g
聚乙二醇(分子量：4000) 0.3g
氯化钠 0.9g
聚氧乙烯脱水山梨醇单油酸酯 0.4g
偏亚硫酸氢钠 0.1g
羟基苯甲酸甲酯 0.18g
羟基苯甲酸丙酯 0.02g
注射用蒸馏水 10.0ml
在80℃，将上述羟基苯甲酸酯、偏亚硫酸氢钠和氯化钠在搅拌下溶入上述一半体积的蒸馏水中。将获得的溶液冷却至40℃，再将本发明的活性化合物以及聚乙二醇和聚氧乙烯脱水山梨醇单油酸酯溶入上述溶液中。加入注射用蒸馏水调节至预定的体积，通过用合适的过滤纸过滤灭菌得到注射制剂。
实验
(1)方法；
给予重度心力衰竭的患者(即就是，急性心力衰竭或急性恶化期的慢性心力衰竭的患者，纽约心脏协会III和IV类)30、60或90mg/天的5-羟基-7-氯-1-[2-甲基-4-(2-甲基苯甲酰氨基)苯甲酰基]-2，3，4，5-四氢-1H-苯并-氮杂
60天时间，该时间段为从住院开始至出院(详情在表1中列出)
(2)结果：
结果在表2和7中列出。
根据统计分析，表2中的数据用ANOVA方法分析，表3和表4中的数据用ANCOVA方法分析，表5中的数据用Log-Rank测试分析。
当这个实验中的剂量转换成每千克体重每日剂量时，在30mg治疗组中是0.371±0.096mg/kg(n＝77)，在60mg治疗组中是0.769±0.205mg/kg(n＝83)，在90mg治疗组中是1.149±0.283mg/kg(n＝76)(都是平均±SD)。
如结果中显示的，在30mg治疗组中，总尿输出量增加(表2)，体重减小(表3)。此外，处于基线的低钠血症患者(具有血清钠浓度低于正常(小于136mEq/L)的患者)表现出血清钠浓度增加(表4)。
在同样的实验中，在30mg治疗组中，从住院直到在门诊部治疗结束整个期间的死亡率明显低于对照组，其用开始治疗至死亡的天数来分析(Log-Rank测试)(表5)。
此外，与高剂量治疗组的数据相比，最低剂量30g的治疗组中作为不良感受的尿频发生率低(表6)，而且由于不良感受而中断治疗的比率低(表7)。结果，很明显，通过控制每天剂量小于每千克体重0.6mg，本发明的化合物表现出对重度心力衰竭有良好的治疗效果。
表1.研究一览表
表5用(A)治疗的患者的死亡率
圆括号中的数字表示组中随机化的患者数
用Log-Rank测试进行“死亡(治疗时)时间”分析
表6.用(A)治疗的患者中观察到的不良反应
圆括号中的数字表示组中随机化的患者数
表7用(A)治疗的患者中由于不良反应中断的病例
圆括号中的数字表示组中随机化的患者数
产业实用性：
本发明的治疗重度心力衰竭的方法对于治疗重度心力衰竭，即急性心力衰竭和处于急性恶化期的慢性心力衰竭，十分适用。此外，本发明的方法非常安全，几乎没有副作用。因此，本发明提供通过给予患者苯并氮杂
化合物(1)或其药用盐治疗重度心力衰竭的方法，和含有所述苯并氮杂
化合物(1)或其药用盐的药用组合物及所述活性化合物在制备适于治疗重度心力衰竭的药物中的应用。
Claims (4)
1.活性成分5-羟基-7-氯-1-[2-甲基-4-(2-甲基苯甲酰氨基)苯甲酰基]-2，3，4，5-四氢-1H-苯并氮杂
或其药用盐在制备用于治疗纽约心脏协会分类IV类重度心力衰竭的药物中的应用。
2.根据权利要求1的应用，其中包含在药物中的活性成分或其药用盐的每日剂量单元小于0.6mg/kg。
3.根据权利要求1的应用，其中包含在药物中的活性成分或其药用盐的每日剂量单元为从0.1mg/kg至小于0.6mg/kg。
4.根据权利要求1的应用，其中包含在药物中的活性成分或其药用盐的每日剂量单元为每天15至45mg/人。
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