CN101222923A - 可溶性鸟苷酸环化酶活化剂和刺激剂用于预防或治疗肾脏疾病的新用途 - Google Patents
可溶性鸟苷酸环化酶活化剂和刺激剂用于预防或治疗肾脏疾病的新用途 Download PDFInfo
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Abstract
本发明涉及一种治疗肾衰竭或肾性高血压的药物生产的用途，尤其是生产通过可溶性鸟苷酸环化酶活性剂或鸟苷酸环化酶治疗，促进急性肾衰竭或肾性高血压的恢复的药物。
Description
技术领域
本发明涉及治疗肾衰竭或肾性高血压药物的制备，尤其是通过使用可溶性鸟苷酸环化酶活化剂或鸟苷酸环化酶刺激剂的治疗，促使急性肾衰竭或肾性高血压恢复的药物的制备。
背景技术
哺乳动物肾脏系统的主要作用是从血流中除去分解代谢的废物，以及维持体内液体和电解质的平衡。因而肾衰竭是危及生命的病症，分解代谢物和其它毒素的增多和/或电解质或液体的严重不平衡的发展，会导致其它主要器官系统的衰竭以及死亡。通常，肾衰竭分为“急性”或“慢性”。如下文所述，对于不采取适当治疗的病人来说，慢性肾衰竭是一种致衰甚至危及生命的疾病。
肾衰竭疾病的特征是功能性肾单位数量的减少，导致氮代谢产物排泄量减少，最终导致无法维持生物体环境的体内平衡。特别地，肾衰竭病症的血液尿素氮和肌苷酸水平持续升高。肾衰竭分为两种主要类型：急性肾衰竭和慢性肾衰竭(后者是缓慢发展且不可逆的)。
急性肾衰竭主要分为以下两种类型：一种是少尿型急性肾衰竭，通常伴随着水、电解质和酸碱失衡并出现少尿或无尿症状；另一种是非少尿型急性肾衰竭，并无尿量减少的现象发生。
根据发病原因，急性肾衰竭也可分为以下三种类型：
1)前肾的急性肾衰竭，它是由于系统的血液动力的改变，如前肾的脱水和休克，出现了肾血流的减少，导致肾小球的过滤速度降低；
2)肾的急性肾衰竭，它是由肾小球和管状疾病如急性管状坏死引起的；
3)后肾的急性肾衰竭，它是由尿道阻塞如结石所引起的。
根据临床表现，在治疗急性肾衰竭过程中，可分为少尿期、利尿期和恢复期三个阶段，找到病因并充分完成对病人的全身控制是重要的。这种治疗包括两种主要形式，保守治疗和透析治疗。依照保守治疗，在少尿期要避免病人过度饮水并且要限制蛋白质的摄入量，而与此同时，要提供充足的卡路里摄入量。在少尿期，或当心脏衰竭出现时，要限制钠的摄入量。相反地，在利尿期，钾的摄入量要增加。
慢性肾衰竭是由于慢性肾脏疾病的发展，发生肾功能逐渐减弱的病症，其中肾功能减弱表现为正常的肾所负责的所有功能出现不全。慢性肾衰竭的病因是所有的肾脏疾病，包括原发性肾病、先天性肾病、肾感染、由任何肾中毒物质以及阻塞性泌尿疾病引起的肾病。正如从被介入透析治疗慢性肾衰竭病人的临床背景所看到的，慢性肾衰竭的主要病因可包括慢性肾小球性肾炎、糖尿病肾病(diabetic nephropathy)、慢性肾盂肾炎、肾硬化和膀胱肾。其中，慢性肾小球性肾炎和糖尿病肾病占了很大的比例。近几年来，随着糖尿病病人的迅速增加，在总的病例中，以糖尿病肾病为病因的比例也显著增加了。
如上所述，肾衰竭可由各种疾病引起。但是，尽管病因不同，所有类型的肾衰竭都具有特别共同的临床表现，如高血压、肺充血和充血性心脏衰竭伴随着尿量减少，神经或精神疾病伴随着高级尿毒症，由于肾脏红细胞生成素产量减少而引起的贫血，电解质不平衡如低钠血症和高钾血症，肠胃疾病，骨代谢不足，以及碳水化合物代谢不足。
早期慢性肾衰竭的适应并不能成功地完全恢复肾小球过滤速度或其它肾功能参数的恢复，事实上，使得余下的肾单位遭受增加损耗的危险。为了在保守阶段治疗慢性肾衰竭，主要采用包括低蛋白，高卡路里的饮食疗法。同时，需要限制钠和水的摄入量，并使用抗高血压试剂控制高血压，因为高血压是肾衰竭恶化的危险因素。然而，这种饮食疗法和上述抗高血压试剂的治疗会产生不能令人满意的效果。因此，因肾功能晚期病症会导致表现尿毒症而不可避免地进行血液透析的病人数量在逐年增多。对于进行透析治疗的肾衰竭病人，由于近几年来血液透析治疗的改进，其延长生命的几率显著提高。然而，病人每周两到三次不可避免地去医院仍然存在问题，可能会导致红血球在产生或成熟时出现缺陷。
本发明的目的是提供一种治疗肾衰竭和/或肾性高血压的药剂，而目前的药物或药剂对于肾衰竭和/或肾性高血压不能获得令人满意的效果。
发明详述
异二聚(heterodimeric)血红素蛋白可溶性鸟苷酸环化酶(sGC)是主要的一氧化氮(NO)细胞内接受体，并用于促进第二信使环鸟苷-3′，5′-单磷酸盐(cGMP)的形成，cGMP通过特定激酶、离子通道和磷酸二酯酶的相互作用依次控制细胞功能的诸多方面。信号传导途径成为主要的归因于NO的生理作用的基础，并对心血管、肠胃、泌尿生殖、神经和免疫系统的调节很重要。因此，异常的sGC-依赖信号可以是很多种病理学的病因学基础，因此能够以可选择方式调节酶活性的药剂具有相当多的治疗学潜能。
人们提倡使用有机硝酸酯(如甘油三硝酸酯，GTN，异山梨醇二硝酸酯)治疗诸如心绞痛和心脏衰竭之类的病症已经近一个世纪，虽然这种化合物的作用机制并不清楚，直到二十世纪七十年代末，它们被发现涉及NO的代谢转化和随后的sGC活化。或许令人惊讶的是，几乎没有注意力集中到识别选择性的sGC-调节化合物，尤其是可能具有更大兴趣治疗剂的酶活化剂。尽管sGC功能障碍有可能对致病原因及不适当的NO生成产生相同的影响，但是sGC异构重整的组织特异性分布有可能提供一种目标药物治疗的方法。
有机硝酸酯(和其它NO-供体或“硝基血管扩张剂”药物)释放内源性配体NO来活化sGC，虽然它们可供临床医生使用，但是这些化合物的使用是有疑问的。首先，NO-供体化合物，尤其是有机硝酸酯受到持续用药后的发展耐药性。这种快速抗药反应潜在的机制仍然不清楚，但是可能会导致化合物代谢活性的减少，过多的过氧化物、内皮缩血管肽或血管紧缩素II水平，或NO受体敏感性/活性的减少。其次，由于NO与其它生物学分子的非特定性相互作用，体内NO-供体的使用存在潜在的问题，由于NO从硝基血管扩张剂的自发释放以及它在生物系统中的自由扩散使得反应难以控制。目前普遍认为NO的有益(生理学)作用主要通过sGC(即cGMP-依赖的)活性调节，NO的有害(病理学)作用主要通过对蛋白(亚硝化，硝化)、脂(如过氧化反应)和核苷酸(如DNA链断裂)的直接(即cGMP-非依赖的)修饰来作用。因此，基于NO疗法的使用者代表着双刃剑。即使剂量滴定率使得这些副作用达到最小，大多数也是不可逆的，并会随时间积累，有可能显示出长期的问题。而且，NO的持续氧化磷酸化抑制作用有可能引发细胞死亡。考虑到这些缺点，能以NO-非依赖的方式活化sGC而不受快速耐受性影响的化合物，在目前治疗心肾疾病方面将带来相当大的进步。
近年来，一些NO-非依赖性可溶鸟苷酸环化酶活性已被确定。根据它们的特征，这些化合物可被分为两组，第一组是包含NO-非依赖性，而血红素-依赖性的可溶鸟苷酸环化酶刺激剂，如式(I)至(III)所示化合物，第二组是式(IV)至(VI)所示的NO-和血红素-非依赖性可溶鸟苷酸环化酶活化剂。当与NO连接时，第一组显示了强大的协同作用，当去除修复的可溶性鸟苷酸环化酶的血红素部分后，则失去效力。相反，式(IV)表示的可溶性鸟苷酸环化酶的活性则通过去除血红素基团而增强，由于该化合物的高度亲和力键的位点包括在酶朊的血红素袋中。通过氧化血红素部分可以强烈促进式(IV)化合物中血红素基团的取代，导致血红素与酶结合的不稳定。
可被提到的可溶性鸟苷酸环化酶刺激剂的实例为下式(I)至(III)所述的化合物：
以及这些化合物的药学可接受的盐。
可被提到的可溶性鸟苷酸环化酶活化剂的实例为下式(IV)至(VI)所述的化合物：
| (IV) | 式(IV)所述化合物，其作为药物活性剂的生产和用途被公开于WO01/19780。 |
以及这些化合物的药学可接受的盐。
本发明涉及向患者施用适量sGC刺激剂或sGC活化剂，用来减少、抑制或防止哺乳动物(包括人)的肾衰竭或肾性高血压症状。可通过肠内用药，如口服或直肠用药；注射用药，如静脉注射或表皮注射。
本文所用术语“肾衰竭”意指肾组织不能完成正常功能的病状或病症。肾衰竭包括慢性和急性肾衰竭或功能障碍。
急性肾衰竭广义的定义为一种肾功能的快速衰退，其足以导致体内氮废物的堆积。这种衰退的原因包括肾血流灌注不足，梗阻性尿路病，以及体内肾病如急性血管球性肾炎。
慢性肾衰竭通常由更为持续性质的肾损伤导致，这种持续性通常导致肾单位群的渐进性的破坏。血管球性肾炎，管状间隙疾病，糖尿病肾病和肾硬化是慢性肾衰竭最常见的致病原因。慢性肾衰竭可被定义为一种由于肾单位的显著并持续的损耗而导致的肾小球过滤速度逐渐、持久、显著减少的疾病。由进一步的肾功能损失引起的临床综合症被称为尿毒症。
肾衰竭的症状包括低于正常的肌苷酸清除率；低于正常的自由水清除率；高于正常的血尿和/或氮和/或钾和/或肌苷酸水平；肾脏酶如γ-谷酰胺合成酶活性的改变；尿渗量或容量的改变；微蛋白尿或大蛋白尿水平的提高；肾小球和小动脉的损伤；管状扩张；高磷酸盐血症；或需要透析。
对肾衰竭的抑制程度可通过本领域公知的方法测量哺乳动物的这些进行参数评估，如通过测量肌苷酸清除率。
肾衰竭可被分为几个阶段，从开始的轻微型，到中度和严重型，进而到通常所说的肾病末期。这些阶段以常规方法鉴别，如通过测定肌苷酸清除率的值，即可明确肾功能不全的不同阶段。
用于向患者施用的sGC活化剂或sGC刺激剂的有效量通常取决于处理条件，施药途径，患者的年龄、体重等情况，成人口服sGC刺激剂或sGC活化剂的用量为约0.1-400mg/天，优选0.2-100mg/天，更优选0.5-20mg/天，根据患者的年龄，体重等情况决定每天服用一次或分为几次服用。
sGC刺激剂或sGC活化剂可通过静脉注射施用，典型的注射速率约为0.01-10μg/kg/min，更典型的约为0.02-5μg/kg/min。对于肾衰竭的静脉注射治疗，推注10-200μg/kg需要以0.2-3μg/kg/min的速度注射。
以本领域公知的手段制成适于治疗肾衰竭和/或肾性高血压的sGC刺激剂或sGC活化剂的剂型。以这种形式将其施于患者或优选与适当的药物赋形剂结合形成片剂，糖衣丸，胶囊，栓剂，乳剂，悬浮液或溶液，其中剂型内活性化合物的含量为约0.5-100％的重量份。选择适当的组合物成分对于本领域技术人员是常规的。很明显，也可以使用适当的载体、溶液、凝胶形成成分、分散液形成成分、抗氧化剂、着色剂、甜味剂、增湿化合物、释放控制成分和其它本领域常用的成分。
sGC刺激剂或sGC活化剂的盐可以通过已知方法制成药学上可接受的盐。
实验方法
1.L-NAME处理的肾素转基因鼠(TGR(mRen2)27)
在内皮细胞中通过NO合成酶经L-精氨酸合成NO，NO合成酶被L-精氨酸类似物如L-NAME所抑制。在不同的鼠种和其它实验动物中，对NO合成酶的急性或慢性抑制会使缺血性肾功能异常恶化，并诱导血压升高。在人体中，由乙酰胆碱和舒缓激肽引起的血管舒张可以通过注射NO合成酶抑制剂而减弱。sGC刺激剂或sGC活化剂对于心血管的影响，是通过测定在高肾素，低NO水平的鼠模型的高血压条件下，该化合物对血液动力和激素参数的长期效果来评价的。在研究中，我们使用了转基因鼠，增加了肾素基因(TGR(mRen2)27)，其代表一种对与NO/sGC系统结合的化合物的心血管影响非常敏感的模型。饮水过程中接受NO合成酶抑制剂L-NAME的年老的肾素转基因鼠(TGR(mRen2)27)的心脏收缩压增加，而经L-NAME和sGC刺激剂或sGC活化剂处理的动物，在观察期间，可阻止血压增加。研究最后，血浆中的肾素活性，醛甾酮，尿素，肌氨酸酐可用于显示sGC刺激剂或sGC活化剂对肾脏的保护效果。死亡率的减少也显示了sGC刺激剂或sGC活化剂在治疗上相关的动物模型方面具有有益效果。
2.5/6肾切除的鼠
肾功能损伤建立好的模型为5/6肾切除的鼠。这些鼠的特点是肾小球超滤，进而发展为肾衰竭，直至肾病末期，且高血压会诱导左心室肥大和心脏的纤维化。作四组分析：一组空白操作对照组，一组5/6肾切除组，一组经sGC刺激剂处理的5/6肾切除组，一组经sGC活化剂处理的5/6肾切除组。将鼠处理约12周。通过管饲法口服给药。通过5/6肾切除术使鼠的肾功能不全。该方法包括全部摘除右肾两周后，对其余肾的三分之一实施上下结扎术。
经第二次手术后，鼠逐渐发展成肾衰竭(GFR减少)并伴有蛋白尿和高血压。心脏特征为尿毒症的高血压性心脏病。由于肾病末期或高血压会诱导末梢器官损伤，因而没有处理死于16-26周的鼠。
将鼠放置于代谢笼中24小时以采集尿液。测定其钠，钾，钙，磷酸盐和蛋白质。通过使用适当的自动分析器的试剂盒测定葡萄糖、Crp(仅血清)、ALAT(仅血清)、ASAT(仅血清)、钾、钠、钙、磷酸盐、尿素和肌苷酸。尿素和血清中的蛋白含量通过Hitachi 717自动分析器的焦酚红钼酸盐(pyrogallolred-molybdate)混合试剂测定。肾小球过滤速度通过内原性肌酐清除率计算。心脏收缩压和心率通过对有意识且轻微受限制鼠的尾动脉(tail-cuff)容积描记法测定。每周测量体重。
血浆肾素活性及尿醛甾酮通过商业可获得的放射性免疫分析法分析。
所有的鼠在研究末期都有抓痕。为进行常规临床化学检测(葡萄糖、尿素、肝酶、C-反应肽、钠、血清-蛋白)和血浆肾素活性的检测，需要取血。测定身体、心脏和肾脏的重量。
通过计算sGC刺激剂和sGC活化剂保护心肾的效果进行心脏和肾脏的组织学评价。
Claims (5)
1.包含有效量的式(I)至(VI)化合物及其盐、水合物、盐的水合物和溶剂化物的药物生产在预防和/或治疗肾衰竭或肾性高血压中的用途，
2.如权利要求1所述的药物生产的用途，用以促进急性肾衰竭的恢复或肾性高血压的恢复。
3.如权利要求1或2所述的用途，其中所述药物为口服使用。
4.如权利要求1或2所述的用途，其中所述药物为预防性使用。
5.治疗肾衰竭或肾性高血压的药物组合物，包括至少一种如权利要求1中的式(I)至(VI)化合物。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104434845A (zh) * | 2014-11-12 | 2015-03-25 | 广东东阳光药业有限公司 | 一种包含利奥西呱的固体药物制剂 |
| CN105979959A (zh) * | 2013-08-09 | 2016-09-28 | 阿德利克斯公司 | 用于抑制磷酸盐转运的化合物和方法 |
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| DE102007015034A1 (de) * | 2007-03-29 | 2008-10-02 | Bayer Healthcare Ag | Lactam-substituierte Dicarbonsäuren und ihre Verwendung |
| US8741910B2 (en) | 2008-11-25 | 2014-06-03 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
| WO2011056511A2 (en) | 2009-10-26 | 2011-05-12 | Auspex Pharmaceuticals, Inc. | 4,6-diaminopyrimidine stimulators of soluble guanylate cyclase |
| DE102009046115A1 (de) * | 2009-10-28 | 2011-09-08 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 3-Phenylpropansäuren und ihre Verwendung |
| EP2549875B1 (en) | 2010-03-25 | 2015-05-13 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
| DE102010021637A1 (de) | 2010-05-26 | 2011-12-01 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 5-Fluor-1H-Pyrazolopyridine und ihre Verwendung |
| SI2576548T1 (sl) * | 2010-05-26 | 2015-11-30 | Adverio Pharma Gmbh | Uporaba sGC stimulatorjev, sGC aktivatorjev, samih in v kombinacijah s PDE5 inhibitorji za zdravljenje sistemske skleroze |
| MX2012013774A (es) | 2010-05-27 | 2012-12-17 | Merck Sharp & Dohme | Activadores de guanilato ciclasa soluble. |
| CA2803688A1 (en) * | 2010-06-25 | 2011-12-29 | Bayer Intellectual Property Gmbh | Use of stimulators and activators of soluble guanylate cyclase for treating sickle-cell anemia and conserving blood substitutes |
| US8569339B2 (en) | 2011-03-10 | 2013-10-29 | Boehringer Ingelheim International Gmbh | Soluble guanylate cyclase activators |
| US8815857B2 (en) | 2011-08-12 | 2014-08-26 | Boehringer Ingelheim International Gmbh | Soluble guanylate cyclase activators |
| NZ703989A (en) | 2012-09-07 | 2017-04-28 | Boehringer Ingelheim Int | Alkoxy pyrazoles as soluble guanylate cyclase activators |
| EP2968808B1 (en) * | 2013-03-14 | 2019-06-05 | Fisher & Paykel Healthcare Limited | Catheter mount with suction port |
| US9687312B2 (en) * | 2014-03-17 | 2017-06-27 | Intuitive Surgical Operations, Inc. | Detection pins to determine presence of surgical instrument and adapter on manipulator |
| CN106459017B (zh) | 2014-07-22 | 2020-07-17 | 勃林格殷格翰国际有限公司 | 作为可溶性鸟苷酸环化酶活化剂的杂环羧酸 |
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| TR200100147T2 (tr) * | 1998-07-08 | 2001-05-21 | Aventis Pharma Deutschland Gmbh | Sülfür ile ikame edilmiş sülfonilaminokarboksilik asit N-arilamidleri |
| DE19834044A1 (de) * | 1998-07-29 | 2000-02-03 | Bayer Ag | Neue substituierte Pyrazolderivate |
| DE19943635A1 (de) * | 1999-09-13 | 2001-03-15 | Bayer Ag | Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften |
| AR031176A1 (es) * | 2000-11-22 | 2003-09-10 | Bayer Ag | Nuevos derivados de pirazolpiridina sustituidos con piridina |
| DE10351903A1 (de) * | 2003-11-06 | 2005-06-09 | Bayer Healthcare Ag | Neue Kombination |
| DE102004012365A1 (de) * | 2004-03-13 | 2005-09-29 | Bayer Healthcare Ag | Substituierte Dihydropyridine |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105979959A (zh) * | 2013-08-09 | 2016-09-28 | 阿德利克斯公司 | 用于抑制磷酸盐转运的化合物和方法 |
| CN105979959B (zh) * | 2013-08-09 | 2021-11-30 | 阿德利克斯公司 | 用于抑制磷酸盐转运的化合物和方法 |
| CN104434845A (zh) * | 2014-11-12 | 2015-03-25 | 广东东阳光药业有限公司 | 一种包含利奥西呱的固体药物制剂 |
| CN104434845B (zh) * | 2014-11-12 | 2017-12-05 | 广东东阳光药业有限公司 | 一种包含利奥西呱的固体药物制剂 |
Also Published As
| Publication number | Publication date |
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| IL188657A0 (en) | 2008-12-29 |
| US20100016305A1 (en) | 2010-01-21 |
| RU2008105481A (ru) | 2009-08-27 |
| EP1906957A1 (en) | 2008-04-09 |
| AU2006272088A1 (en) | 2007-01-25 |
| ZA200800466B (en) | 2009-05-27 |
| CA2615426A1 (en) | 2007-01-25 |
| JP2009501739A (ja) | 2009-01-22 |
| WO2007009607A1 (en) | 2007-01-25 |
| MX2008000779A (es) | 2008-02-21 |
| KR20080030669A (ko) | 2008-04-04 |
| BRPI0614001A2 (pt) | 2011-03-01 |
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