CN108778334A - 用于治疗肾脏疾病的药物 - Google Patents
用于治疗肾脏疾病的药物 Download PDFInfo
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- CN108778334A CN108778334A CN201780019274.7A CN201780019274A CN108778334A CN 108778334 A CN108778334 A CN 108778334A CN 201780019274 A CN201780019274 A CN 201780019274A CN 108778334 A CN108778334 A CN 108778334A
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- pharmaceutical composition
- antagonist
- angiotensin
- receptor
- kidney
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Abstract
提供了用于治疗肾脏疾病的药物组合物。用于治疗肾脏疾病的药物组合物包含盐皮质激素受体拮抗剂。
Description
技术领域
本发明涉及用于治疗肾脏疾病的包含盐皮质激素受体(醛固酮受体:MR)拮抗剂的药物组合物,用MR拮抗剂治疗肾脏疾病的方法,以及用于治疗肾脏疾病的MR受体拮抗剂和具有抗高血压剂的药物的联合使用或组合制剂。
背景技术
随着肾脏疾病的疾病状态的进展,肾功能降低,并且肾脏疾病转变为慢性肾衰竭,这需要通过血液透析进行治疗。特别地,开始血液透析疗法的最常见原因是糖尿病肾病。现在血液透析患者逐年增加,这是目前一个主要的医学问题。在这种情况下,肾脏疾病的治疗目的不仅是避免和延迟透析,而且还要抑制心血管疾病的发作,以保持与健康个体相似的日常生活质量,并确保健康的预期寿命。因此,开发肾脏疾病治疗剂是一个迫切的目标。
近年来,还已知蛋白尿缓解至正常水平导致抑制肾脏疾病的进展和抑制心血管事件。因此,对肾脏疾病治疗剂进行的缓解治疗的期望越来越高。
已知盐皮质激素受体在控制体内电解质平衡和血压方面起重要作用。糖尿病肾病(非专利文献1)和肾小球肾炎(例如IgA肾病或系膜增生性肾小球肾炎)(非专利文献2和3),肾硬化(非专利文献4)等作为涉及盐皮质激素受体的肾脏疾病是已知的。
已知盐皮质激素受体在控制体内电解质平衡和血压方面起重要作用,并且已知具有类固醇结构的MR拮抗剂,例如安体舒通和依普利酮,可用于治疗高血压和心力衰竭。此外,为MR拮抗剂的1-(2-羟乙基)-4-甲基-N-[4-(甲基磺酰基)苯基]-5-[2-(三氟甲基)苯基]-1H-吡咯-3-甲酰胺(下文称为化合物(I))公开于专利文献1和2中。
血管紧张素II受体拮抗剂和钙拮抗剂广泛用作治疗或预防高血压等的药物。
血管紧张素II受体拮抗剂是肾素-血管紧张素系统的抑制剂,其对肾素依赖性高血压特别有效,并且显示出对心血管病症和肾脏病症的保护作用。
钙拮抗剂对于具有体液潴留的高血压(非肾素依赖性高血压)也是有效的,因为除了它们的血管舒张作用之外它们还通过拮抗(抑制)钙通道功能而具有促尿钠排泄作用。
4-(1-羟基-1-甲基乙基)-2-丙基-1-[2'-(1H-四唑-5-基)联苯-4-基甲基]咪唑-5-甲酸(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲酯(下文称为奥美沙坦酯)为血管紧张素II受体拮抗剂,已知其可用作治疗或预防高血压、心脏疾病等的药物(专利文献3)。
奥美沙坦酯可作为Olmetec (R)片剂或Benicar (R)商购获得,其含有5 mg、10mg、20 mg或40 mg奥美沙坦酯作为活性成分,并含有低取代的羟丙基纤维素、羟丙基纤维素、结晶纤维素、乳糖和硬脂酸镁作为添加剂。
(±)-2-[(2-氨基乙氧基)甲基]-4-(2-氯苯基)-1,4-二氢-6-甲基吡啶-3,5-二甲酸3-乙酯5-甲酯(下文称为氨氯地平)是一种已知的化合物,其可用作优异的钙拮抗剂和治疗或预防高血压、心脏疾病等的药物(专利文献4)。
氨氯地平可作为Norvasc (R)片剂商购获得,其含有3.47 mg或6.93 mg苯磺酸氨氯地平(2.5 mg或5 mg氨氯地平)作为活性成分,并含有结晶纤维素、无水磷酸氢钙、羧甲基淀粉钠、硬脂酸镁、羟丙基甲基纤维素、氧化钛、滑石和巴西棕榈蜡作为添加剂。
引用列表
专利文献
专利文献1:国际公开WO 2006/012642 (美国公开US 2008-0234270)
专利文献2:国际公开WO 2008/056907 (美国公开US 2010-0093826)
专利文献3:日本专利第2082519号 (美国专利第5,616,599号)
专利文献4:日本专利第1401088号 (美国专利第4,572,909号)
非专利文献
非专利文献1:Nephron. Experimental Nephrology 2014; 126: 16-24
非专利文献2:Journal of Nephrology 2013; 26: 199-206
非专利文献3:Journal of Translational Medicine 2011; 9:169
非专利文献4:American Journal of Nephrology 2004; 24: 242-9。
发明概述
技术问题
为了开发用于肾脏疾病的优异治疗剂的目的,本发明人进行了勤奋的研究。结果,发明人发现通过含有盐皮质激素受体拮抗剂作为活性成分的药物实现了该目的,从而完成了本发明。
问题的解决方案
本发明人为了解决上述问题进行了勤奋的研究,结果发现特定的MR拮抗剂对涉及盐皮质激素受体的肾脏疾病(特别是糖尿病肾病)具有优异的治疗效果。本发明人还发现,这种药物对于涉及盐皮质激素受体的肾脏疾病(特别是糖尿病肾病)的缓解治疗是有效的。已经基于上述发现完成了本发明。
具体地,本发明包括发明的以下方面:
(1) 药物组合物,其包含盐皮质激素受体拮抗剂或其药学上可接受的盐或其水合物,所述药物组合物用于通过改善涉及盐皮质激素受体激活的肾脏病症来治疗肾脏疾病;
(2) 药物组合物,其包含盐皮质激素受体拮抗剂或其药学上可接受的盐或其水合物,所述药物组合物用于通过改善涉及盐皮质激素受体激活的肾脏病症来治疗肾脏疾病使其处于缓解状态;
(3) 根据上述(1)或(2)的药物组合物,其中所述肾脏疾病为糖尿病肾病、肾小球肾炎或肾硬化;
(4) 根据上述(1)或(2)的药物组合物,其中所述肾脏疾病为糖尿病肾病;
(5) 根据上述(1)-(4)中任一项的药物组合物,其中所述盐皮质激素受体拮抗剂为(S)-1-(2-羟乙基)-4-甲基-N-[4-(甲基磺酰基)苯基]-5-[2-(三氟甲基)苯基]-1H-吡咯-3-甲酰胺;
(5-1) 根据上述(1)-(4)中任一项的药物组合物,其中所述盐皮质激素受体拮抗剂为(S)-1-(2-羟乙基)-4-甲基-N-[4-(甲基磺酰基)苯基]-5-[2-(三氟甲基)苯基]-1H-吡咯-3-甲酰胺、安体舒通或依普利酮;
(6) 根据上述(1)-(5)中任一项的药物组合物,其进一步包含选自血管紧张素II受体拮抗剂和钙拮抗剂的一种或多种组分;
(6-1) 药物组合物,其包含盐皮质激素受体拮抗剂或其药学上可接受的盐或其水合物与含有选自血管紧张素II受体拮抗剂和钙拮抗剂的一种或多种组分的药物的组合;
(7) 根据上述(6)的药物组合物,其中所述选自血管紧张素II受体拮抗剂和钙拮抗剂的一种或多种组分为奥美沙坦酯;
(8) 根据上述(6)的药物组合物,其中所述选自血管紧张素II受体拮抗剂和钙拮抗剂的一种或多种组分为氨氯地平;
(9) 通过改善涉及盐皮质激素受体激活的肾脏病症来治疗肾脏疾病使其处于缓解状态的方法,所述方法包括向哺乳动物施用盐皮质激素受体拮抗剂;和
(10) 根据上述(9)的方法,所述方法包括与盐皮质激素受体拮抗剂同时或分开向哺乳动物施用选自血管紧张素II受体拮抗剂和钙拮抗剂的一种或多种组分。
本发明的有利效果
根据本发明的含有MR拮抗剂作为活性成分的药物可用作肾脏疾病缓解治疗的药物,因为它对肾脏疾病(优选糖尿病肾病)表现出优异的改善作用。上述药物优选是用于哺乳动物的药物,更优选是用于人类的药物。
实施方案描述
本发明的药物的特征在于含有作为活性成分的MR受体拮抗剂,所述MR受体拮抗剂包含选自下列的物质:式(I)表示的化合物和其阻转异构体及其药学上可接受的盐。
作为本发明药物的活性成分的上述式(I)表示的化合物和其阻转异构体及其药学上可接受的盐是已知的,并且可以例如按照诸如描述于国际公开WO 2006/012642 (美国公开US 2008-0234270)、国际公开WO 2008/056907 (美国公开US 2010-0093826)等中的方法制备。化合物(I)或其阻转异构体优选为下列阻转异构体化合物(Ia) (化学名:(S)-1-(2-羟乙基)-4-甲基-N-[4-(甲基磺酰基)苯基]-5-[2-(三氟甲基)苯基]-1H-吡咯-3-甲酰胺)。
[式1]
作为选自化合物(I)及其阻转异构体的物质,也可以使用其水合物或溶剂化物。化合物(I)也可以以纯阻转异构体或任何阻转异构体混合物的形式使用。
在本发明中,“血管紧张素II受体拮抗剂”的实例包括联苯四唑化合物,例如奥美沙坦酯、olmesartan cilexetil、氯沙坦、坎地沙坦酯、缬沙坦或厄贝沙坦;联苯羧酸化合物,例如替米沙坦;依普沙坦或阿齐沙坦;优选联苯四唑化合物;更优选奥美沙坦酯、氯沙坦、坎地沙坦酯、缬沙坦或厄贝沙坦;特别优选奥美沙坦酯、氯沙坦或坎地沙坦酯;并且最优选奥美沙坦酯。
奥美沙坦酯描述于日本未审查专利申请公开第H05-78328号、美国专利第5,616,599号等中,并且其化学名为4-(1-羟基-1-甲基乙基)-2-丙基-1-[2'-(1H-四唑-5-基)联苯-4-基甲基]咪唑-5-甲酸(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲酯。本申请的奥美沙坦酯包括其药理学上可接受的盐。
氯沙坦(DUP-753)描述于日本未审查专利申请公开第S63-23868号、美国专利第5,138,069号等中,并且其化学名为2-丁基-4-氯-1-[2'-(1H-四唑-5-基)联苯-4-基甲基]-1H-咪唑-5-甲醇。本申请的氯沙坦包括其药理学上可接受的盐(例如氯沙坦钾盐)。
坎地沙坦酯描述于日本未审查专利申请公开第H04-364171号、EP-459136、美国专利第5,354,766号等中,并且其化学名为2-乙氧基-1-[2'-(1H-四唑-5-基)联苯-4-基甲基]-1H-苯并咪唑-7-甲酸1-(环己基氧基羰基氧基)乙酯。本申请的坎地沙坦酯包括其药理学上可接受的盐。
缬沙坦(CGP-48933)描述于日本未审查专利申请公开第H04-159718号、EP-433983等中,并且其化学名为(S)-N-戊酰基-N-[2'-(1H-四唑-5-基)联苯-4-基甲基)缬氨酸。本申请的缬沙坦包括其药理学上可接受的酯或药理学上可接受的盐。
厄贝沙坦(SR-47436)描述于日本未审查专利申请公开(PCT申请的译文)第H04-506222号、WO 91-14679等中,并且其化学名为2-N-丁基-4-螺环戊烷-1-[2'-(四唑-5-基)联苯-4-基甲基]-2-咪唑啉-5-酮。本申请的厄贝沙坦包括其药理学上可接受的盐。
依普沙坦(SKB-108566)描述于美国专利第5,185,351号等中,并且其化学名为3-[1-(4-羧基苯基甲基)-2-n-丁基-咪唑-5-基]-2-噻吩基-甲基-2-丙烯酸。本申请的依普沙坦包括其羧酸衍生物,羧酸衍生物的药理学上可接受的酯或其药理学上可接受的盐(例如甲磺酸依普沙坦)。
替米沙坦(BIBR-277)描述于美国专利第5,591,762号等中,并且其化学名为4'-[[4-甲基-6-(1-甲基-2-苯并咪唑基)-2-丙基-1-苯并咪唑基]甲基]-2-联苯甲酸。本申请的替米沙坦包括其羧酸衍生物,羧酸衍生物的药理学上可接受的酯或其药理学上可接受的盐。
阿齐沙坦描述于日本未审查专利申请公开第H05-271228号、美国专利第5,243,054号等中,并且其化学名为2-乙氧基-1{[2'-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)联苯-4-基]甲基}-1H-苯并[d]咪唑-7-甲酸。
当每一上述化合物具有不对称碳时,本发明的每一血管紧张素II受体拮抗剂还包括光学异构体及其异构体的混合物。此外,包括上述化合物的水合物。
在本发明中,“钙拮抗剂”是钙拮抗剂,其包含选自基于1,4-二氢吡啶的化合物及其药理学上可接受的盐的物质。
作为包含基于1,4-二氢吡啶的化合物的钙拮抗剂,已经提议了各种药物并且实际上在临床实践中使用,因此本领域技术人员可以选择显示出本发明效果的合适药物。可以使用的包含基于1,4-二氢吡啶的化合物的钙拮抗剂的实例包括但不限于阿折地平、氨氯地平、贝尼地平、尼群地平、马尼地平、尼卡地平、硝苯地平、尼索地平、西尼地平、乐卡地平、尼古地平、尼莫地平、阿雷地平、依福地平、巴尼地平、非洛地平、氯维地平、拉西地平和尼伐地平。
基于1,4-二氢吡啶的化合物的药理学上可接受的盐的种类没有特别限定,并且可以由本领域技术人员适当选择。药理学上可接受的盐可以是酸加成盐或碱加成盐。药理学上可接受的盐的实例包括但不限于碱金属盐,例如钠盐、钾盐或锂盐,碱土金属盐,例如钙盐或镁盐,和金属盐,例如铝盐、铁盐、锌盐、铜盐、镍盐或钴盐;碱加成盐,例如无机盐,如铵盐或胺盐,例如有机盐,如叔辛胺盐、二苄胺盐、吗啉盐、葡糖胺盐、苯基甘氨酸烷基酯盐、乙二胺盐、N-甲基葡糖胺盐、胍盐、二乙胺盐、三乙胺盐、二环己基胺盐、N,N'-二苄基乙二胺盐、氯普鲁卡因盐、普鲁卡因盐、二乙醇胺盐、N-苄基苯乙胺盐、哌嗪盐、四甲基铵盐、三(羟甲基)氨基甲烷盐;或者无机酸盐,例如氢氟酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、高氯酸盐、硫酸盐或磷酸盐;磺酸盐,例如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐、苯磺酸盐或对甲苯磺酸盐;羧酸盐,例如苯磺酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、草酸盐或马来酸盐;和氨基酸盐,例如谷氨酸盐或天冬氨酸盐。
作为包含基于1,4-二氢吡啶的化合物的钙拮抗剂,可以使用上述化合物的水合物或溶剂化物或其药理学上可接受的盐。包含基于1,4-二氢吡啶的化合物的钙拮抗剂在分子中还可具有一个或多个不对称碳,并且可以使用基于一个或多个不对称碳的纯形式的光学异构体或立体异构体(例如非对映异构体)或立体异构体的任何混合物或外消旋体等,但是(±)-2-氨基-1,4-二氢-6-甲基-4-(3-硝基苯基)-3,5-吡啶二甲酸3-(1-二苯基甲基氮杂环丁烷-3-基)酯5-异丙酯是优选的。
包含基于1,4-二氢吡啶的化合物的钙拮抗剂更优选为氨氯地平,其可以根据日本专利第1401088号(美国专利第4,572,909号)等中描述的方法容易地制备。氨氯地平可以形成药理学上可接受的盐,并且这些盐也包括在本发明中。药理学上可接受的盐可以是酸加成盐或碱加成盐。药理学上可接受的盐的实例包括但不限于苯磺酸盐、盐酸盐、氢溴酸盐、富马酸盐、柠檬酸盐、酒石酸盐、马来酸盐、樟脑磺酸盐(camsylate)、乳酸盐、甲磺酸盐、烟酸盐和葡糖酸盐,并且优选为苯磺酸盐。
在本发明中,短语“包含盐皮质激素受体拮抗剂或其药学上可接受的盐或其水合物与含有一种或多种选自血管紧张素II受体拮抗剂和钙拮抗剂的组分的药物的组合”是指一方面,其中与含有一种或多种选自血管紧张素II受体拮抗剂和钙拮抗剂的组分的制剂同时或分开施用含有盐皮质激素受体拮抗剂或其药学上可接受的盐或其水合物的制剂,或者一方面,其中施用含有盐皮质激素受体拮抗剂或其药学上可接受的盐和一种或多种选自血管紧张素II受体拮抗剂和钙拮抗剂的组分的制剂(下文称为“组合制剂”)。
在本发明中,“同时”施用没有特别限制,只要制剂是在可以在大约相同时间施用的剂型中,但它们优选作为单一组合物施用。
在本发明中,“分开”施用是指在不同时间分别施用。例如,首先施用选自血管紧张素II受体拮抗剂和钙拮抗剂的组分,然后在预定的时间段后施用盐皮质激素受体拮抗剂或其药学上可接受的盐或其水合物,或反之亦然。
为本发明药物组合物的活性成分的MR拮抗剂和血管紧张素II受体拮抗剂、钙拮抗剂或利尿剂各自以单独的单位剂型独立施用,或者它们可以混合以制备物理单一的单位剂型。
当使用本发明的药物组合物作为上述疾病的预防或治疗剂时,为本发明药物组合物的活性成分的MR拮抗剂和血管紧张素II受体拮抗剂、钙拮抗剂或利尿剂各自可以以其本身,或者以剂型如片剂、胶囊剂、颗粒剂、粉剂或糖浆剂(在口服施用的情况下)或注射剂或栓剂(在肠胃外施用的情况下)口服或肠胃外施用,根据公知方法使用适当的药学上可接受的添加剂如赋形剂、润滑剂、粘合剂、崩解剂、乳化剂、稳定剂、调味剂或稀释剂制备所述剂型。然而,由于本发明药物中所含的活性成分是通常口服施用的药物,因此希望口服施用本发明的药物。
当向哺乳动物(例如人、马、牛或猪,优选人)施用时,本发明的药物组合物或组合制剂可全身或局部和口服或肠胃外施用。
可以通过常用的制备各种制剂的方法根据施用方式以所选的合适形式制备本发明的药物组合物或组合制剂。
在本发明中,术语“缓解”和“缓解状态”如健康、劳动和福利部的药品与食品安全局提出的“糖尿病肾病治疗剂临床评价方法指南(草案)(the Guideline on ClinicalEvaluation Method of Therapeutic Agent for Diabetic Nephropathy (draft))”所定义,如下所述。
若连续两次测量晨尿样本,每个测量值对应于:
(i)尿白蛋白值(尿白蛋白/Cr比)<30 mg/g Cr;和
(ii)比先前值减少不少于30%。
“糖尿病肾病”由日本糖尿病学会分为如下第1阶段至第5阶段的疾病阶段。
第1阶段:肾病前阶段
第2阶段:早期肾病阶段
第3阶段:明显肾病阶段
第4阶段:肾衰竭阶段
第5阶段:透析阶段。
在本发明中,“缓解”优选是从第2阶段到第1阶段的缓解。
所用“赋形剂”的实例包括糖衍生物,例如乳糖、蔗糖、葡萄糖、甘露醇或山梨糖醇;淀粉衍生物,例如玉米淀粉、马铃薯淀粉、α-淀粉或糊精;纤维素衍生物,例如结晶纤维素;阿拉伯树胶;葡聚糖;或有机赋形剂,例如支链淀粉;或无机赋形剂,例如硅酸盐衍生物,如轻质无水硅酸、合成硅酸铝、硅酸钙或偏硅酸铝镁;磷酸盐,例如磷酸氢钙;碳酸盐,例如碳酸钙;和硫酸盐,例如硫酸钙。
所用“润滑剂”的实例包括硬脂酸;金属硬脂酸盐,例如硬脂酸钙或硬脂酸镁;滑石;胶体二氧化硅;蜡,例如蜂蜡或鲸蜡;硼酸;己二酸;硫酸盐,例如硫酸钠,乙二醇;富马酸;硬脂酰富马酸钠;苯甲酸钠;D,L-亮氨酸;十二烷基硫酸盐,例如十二烷基硫酸钠或十二烷基硫酸镁;硅酸,例如硅酸酐或硅酸水合物;和上述淀粉衍生物。
所用“粘合剂”的实例包括羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮和聚乙二醇,以及与对赋形剂所述相同的化合物。
所用“崩解剂”的实例包括纤维素衍生物,例如低取代的羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙或内部交联的羧甲基纤维素钠;交联聚乙烯吡咯烷酮;和化学改性的淀粉或纤维素,例如羧甲基淀粉或羧甲基淀粉钠。
所用“乳化剂”的实例包括胶质粘土,例如膨润土或Veegum;金属氢氧化物,例如氢氧化镁或氢氧化铝;阴离子表面活性剂,例如十二烷基硫酸钠或硬脂酸钙;阳离子表面活性剂,例如苯扎氯铵;和非离子表面活性剂,例如聚氧乙烯烷基醚、聚氧乙烯脱水山梨糖醇脂肪酸酯或蔗糖脂肪酸酯。
所用“稳定剂”的实例包括对羟基苯甲酸酯,例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;醇,例如氯丁醇、苯甲醇或苯乙醇;苯扎氯铵;酚,例如苯酚或甲酚;硫柳汞;脱氢乙酸;和山梨酸。
所用“调味剂”的实例包括甜味剂,例如糖精钠或阿斯巴甜;酸化剂,例如柠檬酸、苹果酸或酒石酸;和香料,例如薄荷醇、柠檬味或橙味香料。
所用“稀释剂”的实例包括通常用作稀释剂的那些,例如乳糖、甘露醇、葡萄糖、蔗糖、硫酸钙、磷酸钙、羟丙基纤维素、微晶纤维素、水、乙醇、聚乙二醇、丙二醇、甘油、淀粉、聚乙烯吡咯烷酮、偏硅酸铝镁或其混合物。
(S)-1-(2-羟乙基)-4-甲基-N-[4-(甲基磺酰基)苯基]-5-[2-(三氟甲基)苯基]-1H-吡咯-3-甲酰胺的剂量可以根据各种条件而变化,例如个体药物的活性,患者的症状、年龄和体重等。剂量根据症状、年龄等而变化,但可以每天向成人施用一至三次,在口服施用的情况下,每次的下限为0.1 mg (优选0.5 mg)和每次的上限为20 mg (优选10 mg),并且在肠胃外施用的情况下,每次的下限为0.01 mg (优选0.05 mg)和每次的上限为2 mg (优选1 mg)。
血管紧张素II受体拮抗剂的剂量可根据各种条件而变化,例如个体药物的活性,患者的症状、年龄和体重等。剂量根据症状、年龄等而变化,但根据症状可以每天向成人施用一至三次,在口服施用的情况下,每次的下限为0.1 mg (优选0.5 mg)和每次的上限为100 mg (优选50 mg),并且在肠胃外施用的情况下,每次的下限为0.01 mg (优选0.05 mg)和每次的上限为10 mg (优选5 mg)。
钙拮抗剂的剂量可根据各种条件而变化,例如个体药物的活性,患者的症状、年龄和体重等。
剂量根据患者的症状、年龄等而变化,但根据症状可以每天向成人施用一至三次,在口服施用的情况下,每次的下限为0.1 mg (优选0.5 mg)和每次的上限为100 mg (优选50 mg),并且在肠胃外施用的情况下,每次的下限为0.01 mg (优选0.05 mg)和每次的上限为10 mg (优选5 mg)。
当施用多种药物时,可以根据症状将他们同时或以一定间隔分开施用。
实施例
在下文中,将参考实施例进一步详细描述本发明。然而,这些实施例不旨在限制本发明的范围。
<实施例1> 对肾脏病症的改善作用
通过以下程序制备醋酸脱氧皮质酮(DOCA)/氯化钠负荷的高血压模型。对6周龄雄性WKY大鼠(WKY/Izm, SPF级, 由Funabashi Farm Co., Ltd.生产)进行单侧肾切除术,通过自由喂食从7周龄给予含有4%氯化钠的饮食(含有4% NaCl的FR-2,由Funabashi FarmCo., Ltd.制造),并且每周一次皮下施用DOCA。将DOCA悬浮于0.5%羧甲基纤维素溶液(20mg/mL),并以相当于1 mL/kg的量施用。未施用DOCA的组被指定为DOCA未施用组,并且施用DOCA的组被指定为DOCA施用组。
在11周龄时,解剖DOCA未施用组中的一些动物,将DOCA未施用组中的其他动物指定为正常组(第1组)。同时,也解剖DOCA施用组中的一些动物,DOCA施用组的其他动物被分成以下组(第2至4组)。
第1组:正常组,n = 6只动物
第2组:对照组,n = 6只动物
第3组:化合物(Ia)施用组[化合物(Ia) 3 mg/kg],n = 6只动物
第4组:DOCA施用中断+化合物(Ia)施用组[化合物(Ia) 3 mg/kg],n = 6只动物。
11周后各组的测试药物的给药方案如下。
对于第1组,持续4周口服施用0.5%甲基纤维素溶液。
对于第2组,持续4周口服施用0.5%甲基纤维素溶液和皮下施用(每周一次)DOCA。
对于第3组,持续4周口服施用悬浮在0.5%甲基纤维素溶液中的化合物(Ia) (2mL/kg)和皮下施用(每周一次)DOCA。
对于第4组,仅持续4周口服施用悬浮在0.5%甲基纤维素溶液中的化合物(Ia) (2mL/kg)。
在测试药物等的4周施用结束时(15周龄),解剖所有动物。
在7、11、13和15周龄时,使用代谢笼(2100-R, Watanabe Isolator Systems Co.,Ltd.)进行24小时尿液收集。从尿蛋白浓度(由BiOLiS 24i premium [Tokyo BoekiMedisys Inc.]测量)和尿量计算每日尿蛋白排泄。结果显示在表1中。
[表1]
在11周龄和15周龄解剖时,将肾脏分离并称重,计算肾脏重量/体重。结果显示在表2中。
[表2]
此外,从一部分分离的肾脏制备组织病理学切片,并进行组织病理学评估(肾小球硬化和肾小管病症的评分)。对于肾小球硬化,每个样本随机选择30个肾小球,并在5个阶段(0-4)的基础上量化每个样本的肾小球硬化程度以确定30个值的平均值,将其用作样本得分(Uehara Y等人, Hypertens. Res. 1992; 15, pp17-26)。对于肾小管病症,对于每个皮质和髓质侧,每个样本选择10个视野,在5个阶段(0-4)的基础上量化肾小管病症的程度以确定每10个视野值的平均值,将其用作样本得分(Uehara Y等人, Hypertens. Res. 1992;15, pp17-26)。结果显示在表3中(表中的每个数值代表平均值±标准误差)。
[表3]
已知DOCA充当MR的配体,并且DOCA/氯化钠负荷的高血压模型被广泛用作由MR激活介导的疾病模型。上述结果表明,通过施用化合物(Ia),疾病模型动物对肾脏病症(蛋白尿、肾肥大、肾小球硬化和肾小管病症)表现出优异的改善效果。
第4组的结果表明,通过向疾病模型动物施用化合物(Ia),另外通过中断DOCA施用(= 中断MR激活)进一步抑制MR激活,几乎将肾脏病症改善到正常组水平。由于通过调节化合物(Ia)的剂量可以实现MR激活抑制作用至在中断DOCA施用的情况下施用化合物(Ia)的水平,因此可以通过仅施用化合物(Ia)将肾脏病症改善(缓解)至接近于正常组的状态。
在肾脏疾病中,已知糖尿病肾病、肾小球肾炎(例如IgA肾病和系膜增生性肾小球肾炎)和肾硬化是在疾病状态发作和进展中涉及MR激活的疾病。因此,对于涉及MR激活的这些疾病,应理解化合物(Ia)的施用可改善肾脏病症,甚至对于与MR激活相关的肾脏疾病,其可达到缓解状态。
此外,通过与化合物(Ia)同时或分开施用选自血管紧张素II受体拮抗剂和钙拮抗剂的药物,预期会产生诸如缓解率增加的组合效果。
<实施例2> 化合物(Ia)的临床研究
进行针对具有白蛋白尿的2型糖尿病患者的临床研究,以评价化合物(Ia)的功效、安全性等。
该研究是一项II期随机、双盲对照研究,其中安慰剂对照组被随机分配。每个患者经历4至12周的清洗期,然后进行治疗,包括在12周的治疗期内每天一次施用化合物(Ia)(0.625 mg、1.25 mg、2.5 mg、5 mg)。
预计大约70个设施中的大约400名患者将参加该研究。适合参加的患者如下:
1.患者是2型糖尿病患者;
2.患者在同意时年满20岁以上;
3.尿白蛋白/肌酐比(UACR)为45 mg/g Cr或更高且低于300 mg/g Cr;
4.来自肌酐的肾小球滤过率估值(eGFRcreat)为30 mL/min/1.73 m2或更高;和
5.患者已自治疗开始前至少3个月经历血管紧张素转化酶抑制剂或血管紧张素II受体拮抗剂(血管紧张素转化酶抑制剂或血管紧张素II受体拮抗剂和任选钙拮抗剂)治疗。
在给药结束后大约6周对患者进行随访,并评估UACR相对于基线的变化,UACR的缓解率和eGFR的数值以及安全性。
通过进行上述研究,发现可以向通过用血管紧张素转化酶抑制剂或血管紧张素II受体拮抗剂(血管紧张素转化酶抑制剂或血管紧张素II受体拮抗剂和任选钙拮抗剂)治疗不能获得足够的治疗效果的患者施用化合物(Ia)以实现优异的治疗效果(例如,UACR降低作用)。
<实施例3> 化合物(Ia)的临床研究 (II期)
进行针对具有白蛋白尿的2型糖尿病患者的临床研究,以评价化合物(Ia)的功效和安全性等。该研究是II期随机、安慰剂对照、双盲对照研究。每个患者经历4至12周的清洗期,然后进行治疗,包括在12周的治疗期内每天一次施用安慰剂或化合物(Ia) (0.625 mg、1.25 mg、2.5 mg、5 mg)。
365名符合以下标准的日本患者参加该研究,功效和安全性分析组包括358例。
1.患者是2型糖尿病患者;
2.患者在同意时年满20岁以上;
3.尿白蛋白/肌酐比(UACR)为45 mg/g Cr或更高且低于300 mg/g Cr;
4.用血清肌酐计算的肾小球滤过率估值(eGFRcreat)为30 mL/min/1.73 m2或更高;和
5.患者已自治疗开始前至少3个月经历血管紧张素转化酶抑制剂或血管紧张素II受体拮抗剂(和任选钙拮抗剂)治疗。
在给药结束后大约6周对患者进行随访,并评估UACR相对于基线的变化,UACR的缓解率和eGFR的数值以及安全性。
在下文中,表4显示了在给药结束时UACR相对于基线的下降率(几何平均值)的结果,和表5显示了UACR*1的缓解率的结果。
[表4]
[表5]
*1) 当UACR在11周和12周均小于30 mg/g Cr且相对于观察期的UACR降低30%或更多时,认为2型糖尿病已被缓解,并根据以下等式计算UACR的缓解率。
UACR的缓解率 (%) = (缓解个体的数量÷分析的所有个体的数量) × 100。
根据上述结果,发现可以向通过用血管紧张素转化酶抑制剂或血管紧张素II受体拮抗剂(和任选钙拮抗剂)治疗不能获得足够的治疗效果的患者施用化合物(Ia)以实现优异的治疗效果(例如,UACR降低作用和缓解率增加)。
工业实用性
根据本发明,可以获得用于治疗涉及盐皮质激素受体的肾脏疾病(特别是糖尿病肾病)的药物。
Claims (10)
1.药物组合物,其包含盐皮质激素受体拮抗剂或其药学上可接受的盐或其水合物,所述药物组合物用于通过改善涉及盐皮质激素受体激活的肾脏病症来治疗肾脏疾病。
2.药物组合物,其包含盐皮质激素受体拮抗剂或其药学上可接受的盐或其水合物,所述药物组合物用于通过改善涉及盐皮质激素受体激活的肾脏病症来治疗肾脏疾病使其处于缓解状态。
3.根据权利要求1或2的药物组合物,其中所述肾脏疾病为糖尿病肾病、肾小球肾炎或肾硬化。
4.根据权利要求1或2的药物组合物,其中所述肾脏疾病为糖尿病肾病。
5.根据权利要求1-4中任一项的药物组合物,其中所述盐皮质激素受体拮抗剂为(S)-1-(2-羟乙基)-4-甲基-N-[4-(甲基磺酰基)苯基]-5-[2-(三氟甲基)苯基]-1H-吡咯-3-甲酰胺。
6.根据权利要求1-5中任一项的药物组合物,其进一步包括选自血管紧张素II受体拮抗剂和钙拮抗剂的一种或多种组分。
7.根据权利要求6的药物组合物,其中所述选自血管紧张素II受体拮抗剂和钙拮抗剂的一种或多种组分为奥美沙坦酯。
8.根据权利要求6的药物组合物,其中所述选自血管紧张素II受体拮抗剂和钙拮抗剂的一种或多种组分为氨氯地平。
9.通过改善涉及盐皮质激素受体激活的肾脏病症来治疗肾脏疾病使其处于缓解状态的方法,所述方法包括向哺乳动物施用盐皮质激素受体拮抗剂。
10.根据权利要求9的方法,所述方法包括与盐皮质激素受体拮抗剂同时或分开向哺乳动物施用选自血管紧张素II受体拮抗剂和钙拮抗剂的一种或多种组分。
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ARAT K.等: ""Pharmacological profile of CS-3150, a novel,highly potent and selective nonsteriodal mineralocorticoid receptor antagonist"", 《EUROPEAN JOURNAL OF PHARMACOLOGY》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN110483401A (zh) * | 2019-09-11 | 2019-11-22 | 何琴 | 艾沙利酮药用盐及其制备方法和医药应用 |
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EP3434284A1 (en) | 2019-01-30 |
TW201737909A (zh) | 2017-11-01 |
US20190175551A1 (en) | 2019-06-13 |
EP3434284A4 (en) | 2019-11-13 |
JPWO2017164208A1 (ja) | 2019-02-07 |
CA3015964A1 (en) | 2017-09-28 |
WO2017164208A1 (ja) | 2017-09-28 |
KR20180123021A (ko) | 2018-11-14 |
JP6934859B2 (ja) | 2021-09-15 |
CA3015964C (en) | 2021-08-03 |
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