CN102264703A - 作为β2肾上腺素受体促效剂的5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羟乙基)-8-羟基喹啉-2(1H)-酮的甲磺酸盐 - Google Patents
作为β2肾上腺素受体促效剂的5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羟乙基)-8-羟基喹啉-2(1H)-酮的甲磺酸盐 Download PDFInfo
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- CN102264703A CN102264703A CN2009801520867A CN200980152086A CN102264703A CN 102264703 A CN102264703 A CN 102264703A CN 2009801520867 A CN2009801520867 A CN 2009801520867A CN 200980152086 A CN200980152086 A CN 200980152086A CN 102264703 A CN102264703 A CN 102264703A
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- 239000000556 agonist Substances 0.000 title 1
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- 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 title 1
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 16
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
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- HJPRDDKCXVCFOH-UHFFFAOYSA-N 1,3-dibutyl-7-(2-oxopropyl)purine-2,6-dione Chemical compound O=C1N(CCCC)C(=O)N(CCCC)C2=C1N(CC(C)=O)C=N2 HJPRDDKCXVCFOH-UHFFFAOYSA-N 0.000 claims description 3
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- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及一种5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羟乙基)-8-羟基喹啉-2(1H)-酮的甲磺酸盐以及其医药学上可接受的溶剂合物:
Description
【技术领域】
本发明涉及一种5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羟乙基)-8-羟基喹啉-2(1H)-酮的新颖水溶性甲磺酸盐(mesylate)、其对映异构体以及溶剂合物。本发明还涉及一种包含所述盐的医药组合物、使用其治疗易由β2肾上腺素受体活性而改善的呼吸道疾病的方法、以及适用于制备所述盐的方法以及中间物。
【背景技术】
β2肾上腺素受体促效剂在用于治疗肺病或呼吸道病症时适合于通过吸入而直接施用于呼吸道。已开发用于通过吸入而施用治疗剂的若干种类型的医药吸入装置,其包括干粉吸入器(dry powder inhaler;DPI)、定剂量吸入器(metered-dose inhaler;MDI)以及喷雾吸入器(nebuliser inhaler)。
液体调配物(尤其是水性调配物)易于施用,因为其在正常呼吸期间经由吹嘴(mouth-piece)或面罩吸入。其尤其适合于最通常需要所述治疗以及使用其它装置有困难的年轻人以及老年人。
已经公开的专利申请WO 2006/122788 A1要求保护且记载了5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羟乙基)-8-羟基喹啉-2(1H)-酮。
尽管5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羟乙基)-8-羟基喹啉-2(1H)-酮已显示出足够的药理性质,但已证明难以获得其可溶于水、特别是在水溶液中时非常稳定的盐形式。
迄今为止,尚未报导具有所需性质的5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羟基-乙基)-8-羟基喹啉-2(1H)-酮的水溶性盐。
因此,需要该化合物的稳定水溶性盐,其可用于制备水溶液,尤其适合于诸如儿童以及老年患者等某些患者。
【发明内容】
现已发现,5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羟乙基)-8-羟基喹啉-2(1H)-酮的甲磺酸盐可以粉末形式获得,其极易溶解且在水性调配物中具有极高的稳定性,因此提供适合于储存以及商业分配的足够存放期。
本发明提供一种5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羟乙基)-8-羟基喹啉-2(1H)-酮的甲磺酸盐以及其医药学上可接受的溶剂合物。
本发明还提供一种医药组合物,其包含本发明的盐以及医药学上可接受的载剂。本发明进一步提供包含本发明的盐以及一或多种其它治疗剂的组合以及包含所述组合的医药组合物。
本发明还提供一种治疗哺乳动物的易由β2肾上腺素受体活性而改善的肺部疾病或病状(诸如哮喘或慢性阻塞性肺病)的方法,其包括向所述哺乳动物施用治疗有效量的本发明的盐。本发明进一步提供一种治疗方法,其包括施用治疗有效量的本发明的盐与一或多种其它治疗剂的组合。
本发明进一步提供本文所述的适用于制备本发明的盐的合成方法以及中间物。
本发明还提供一种如本文所述用于治疗哺乳动物的易由β2肾上腺素受体活性而改善的肺部疾病或病状(诸如哮喘或慢性阻塞性肺病)的本发明的盐。本发明还提供一种治疗这些疾病的方法以及本发明的盐用于制造供治疗这些疾病的调配物或药剂的用途。
【附图简单说明】
图1示出5-(-2-(6-(2,2-二氟-2-苯基乙氧基)己胺基)-1(R)-羟乙基)-8-羟基喹啉-2(1H)-酮甲磺酸盐的DSC图。
【发明详述】
当描述本发明的盐、组合物以及方法时,除非另有指示,否则以下术语具有以下含义。
术语“治疗有效量”是指当向需要治疗的患者施用时足以实现治疗的量。
如本文中所使用,术语“治疗”是指对人类患者的疾病或医学病状的治疗,其包括:
(a)防止所述疾病或医学病状发生,即对患者进行预防性处理;
(b)改善疾病或医学病状,即使得患者的疾病或医学病状消退;
(c)抑制疾病或医学病状,即减缓患者的疾病或医学病状的发展;或
(d)减轻患者的疾病或医学病状的症状。
短语“与β2肾上腺素受体活性相关的肺部疾病或病状”包括现在已确认或将来发现与β2肾上腺素受体活性相关的所有肺病病况及/或病状。所述疾病状况包括(但不限于)哮喘以及慢性阻塞性肺病(包括慢性支气管炎以及肺气肿)。
术语“溶剂合物”是指由一个或多个溶质分子(即本发明的盐或其医药学上可接受的盐)与一个或多个溶剂分子所形成的复合物或聚集体。所述溶剂合物通常是具有基本上固定的溶质与溶剂的摩尔比的结晶固体。代表性溶剂包括(例如)水、乙醇、异丙醇等。当溶剂是水时,所形成的溶剂合物是水合物。
应了解术语“或其溶剂合物或立体异构体”意欲包括溶剂合物以及立体异构体的所有变更形式,诸如式(I)的盐的立体异构体的溶剂合物。
本发明的盐含有手性中心。因此,本发明包含外消旋混合物、对映异构体以及富集任一种对映异构体的混合物。如所述以及要求保护的本发明的范围涵盖盐的外消旋形式以及单独的对映异构体以及对映异构体富集混合物。
以下盐备受关注:
(R,S)5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羟乙基)-8-羟基喹啉-2(1H)-酮甲磺酸盐、
5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1(R)-羟乙基)-8-羟基喹啉-2(1H)-酮甲磺酸盐,
以及其医药学上可接受的溶剂合物。
最优选地,所述盐是式(I)的5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1(R)-羟基-乙基)-8-羟基喹啉-2(1H)-酮甲磺酸盐以及其医药学上可接受的溶剂合物:
本发明还涵盖医药组合物,其包含治疗有效量的如上文所定义的盐以及医药学上可接受的载剂。
在本发明的一个实施例中,所述医药组合物进一步包含治疗有效量的一种或多种其它治疗剂。
本发明的一个实施例还为所述医药组合物经调配用于经口施用或静脉内施用。
如上文所定义的本发明的盐还可与一或多种其它治疗剂、尤其是一种或多种由以下化合物所构成的组中选出的药物组合:皮质类固醇(corticosteroid)、抗胆碱剂(anticholinergic agent)以及PDE4抑制剂。本发明还涉及一种包含本发明的盐以及一种或多种其它治疗剂、尤其是一种或多种由以下化合物所构成的组中选出的药物的组合:皮质类固醇、抗胆碱剂以及PDE4抑制剂。
本发明还涉及一种用于治疗易由β2肾上腺素受体而改善的肺病(诸如哮喘或慢性阻塞性肺病)的式(I)的盐。
本发明还涉及一种治疗哺乳动物的易由β2肾上腺素受体而改善的疾病或病状的方法,所述方法包括向所述哺乳动物施用治疗有效量的包含本发明的β2肾上腺素受体促效剂的医药组合物。尤其相关的是适用于治疗疾病或病状的方法,所述疾病或病状为肺病,优选为哮喘或慢性阻塞性肺病。
本发明还涉及式(I)的盐用于制造供治疗哺乳动物的肺部疾病或病状的药剂的用途。所述哺乳动物优选为人类。尤其相关的肺部疾病或病状为哮喘或慢性阻塞性肺病。
通用合成过程
本发明的盐可使用本文所述的方法以及过程或使用类似方法以及过程来制备。应了解当给定典型或优选处理条件(即反应温度、时间、反应物的摩尔比、溶剂、压力等)时,除非另有说明,否则还可使用其它处理条件。最佳反应条件可随所使用的特定反应物或溶剂而变化,但所述条件可由本领域技术人员通过常规优化方法来确定。
提供制备本发明的盐的方法作为本发明的其它实施例且由以下过程来说明。
本发明的盐可由5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羟乙基)-8-羟基喹啉-2(1H)-酮以及由甲磺酸(例如,可购自Aldrich)合成。
适合于该反应的惰性稀释剂包括(但不限于)丙酮、乙酸乙酯、二甲基甲酰胺、氯仿、甲醇、乙醇、异丙醇、2-丁醇等,以及其混合物,其可任选地含有水。举例而言,可使游离碱与溶解于2-丁醇中的甲磺酸接触。
在以上任一反应完成后,可通过诸如沉淀、浓缩、离心等任一常规手段将盐与反应混合物分离。
应了解当给定具体的处理条件(即反应温度、时间、反应物的摩尔比、溶剂、压力等)时,除非另有说明,否则还可使用其它处理条件。
本发明的水溶性甲磺酸盐通常每摩尔当量游离碱含有介于约0.85摩尔当量与1.15摩尔当量之间的甲磺酸,更通常为每摩尔当量游离碱含有约1摩尔当量甲磺酸。
本发明的方法中所述的摩尔比可容易地通过本领域技术人员可用的多种方法来确定。举例而言,所述摩尔比可容易地通过1H NMR来确定。或者,元素分析以及高效液相色谱(HPLC)方法可用于确定摩尔比。
为制备本发明的甲磺酸盐,通常将游离碱溶解于溶剂(诸如丙酮、乙酸乙酯、二甲基甲酰胺、氯仿、甲醇、乙醇、异丙醇、2-丁醇以及其混合物,尤其是2-丁醇)中,以形成0.20-0.25M溶液,接着将其加热至约60℃-70℃。接着将0.45-0.50M甲磺酸于足够溶剂中的溶液逐滴添加至经加热的溶液中。接着将混合物于70℃-75℃下搅拌60分钟且接着冷却至20℃/25℃并平稳地搅拌过夜。通过过滤分离所形成的沈淀物,用适当的溶剂洗涤且(例如)于50℃下真空干燥。
实例
总则。试剂、起始物质以及溶剂购自商业供货商且按原样使用。
用于制备5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]-胺基}-1(R)-羟乙基)-8-羟基喹啉-2(1H)-酮甲磺酸盐的尤其良好的溶剂是2-丁醇。所述反应包括将11.4克(24.8毫摩尔)游离碱溶解于104毫升2-丁醇中,以形成0.24M溶液,将其加热至约75℃。接着在30分钟内将2.37克(24.6毫摩尔)甲磺酸于52毫升2-丁醇中的溶液逐滴添加至经加热的溶液中。一旦完成所述添加,则将混合物于70℃-75℃下搅拌1小时且接着冷却至室温并于该温度下平稳地搅拌过夜。通过过滤分离所形成的沉淀物,用2-丁醇(15毫升)洗涤且于50℃下真空干燥。接着获得根据HPLC纯度为97.5%的10.93克(产率:79%)的白色固体。
使用DSC-821 Mettler-Toledo第5117423874号获得差示扫描热量(differential scanning calorimetry;DSC)分析。将样品称量至铝盘中,将铝盖置于样品上且用黄铜棒压缩。于30℃下平衡样品且以10℃/分钟加热至300℃。使用铟以及锌标准物校准仪器。
图1示出5-(-2-(6-(2,2-二氟-2-苯基乙氧基)己基-胺基)-1(R)-羟乙基)-8-羟基喹啉-2(1H)-酮甲磺酸盐的DSC图。样品表现出于约62℃时起始的宽且小的吸热峰,以及对应于盐的熔化或分解的于183.04℃时起始的特征性高吸热峰。这表示样品未转化成任何其它多晶型物且未经历任何分解,由此证实其高稳定性。
水溶性测试:
测定室温下5-(-2-(6-(2,2-二氟-2-苯基乙氧基)己基-胺基)-1(R)-羟乙基)-8-羟基喹啉-2(1H)-酮的不同盐于水中的溶解性,以及反丁烯二酸福莫特罗(formoterol fumarate)以及羟萘甲酸沙美特罗(salmeterol xinafoate)的溶解性。结果示于以下表1中。
由所述表格可见,本发明的甲磺酸盐呈现高于相应硫酸氢盐或萘二磺酸盐的溶解性。此外,与反丁烯二酸福莫特罗以及羟萘甲酸沙美特罗(其为两种市售的长效β2促效剂)相比,本发明的甲磺酸盐表现出更高的溶解性。
稳定性测试:
在加速条件下评价本发明的甲磺酸盐的稳定性。将约5毫克本发明的甲磺酸盐引入各个10毫升琥珀色玻璃小瓶中。将这些小瓶在30天内储存于40℃下且分别在15天以及30天内储存于80℃下。在强制应力条件后,将样品溶解于5毫升适当的溶剂中。利用HPLC分析且通过计算相对面积来测定杂质增加。结果报导于表2中。
表2:
数据 | HPLC杂质(面积%) |
于80℃下15天的稳定性 | 3.10% |
于80℃下30天的稳定性 | 3.8% |
于40℃下30天的稳定性 | 2.4% |
于80℃下的15天稳定性表示等同于30℃下1年以上。于80℃下的30天稳定性表示等同于40℃下1年以上。在所有强制条件下所观察到的杂质百分比均小于5%,由此表明不存在盐的任何显著降解。
医药组合物
本发明的医药组合物包含治疗有效量的5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羟乙基)-8-羟基喹啉-2(1H)-酮的甲磺酸盐或其对映异构体或医药学上可接受的溶剂合物,以及医药学上可接受的载剂。
医药调配物可简便地以单位剂型提供,且可通过药剂学领域中熟知的任一方法来制备。所有方法均包括使活性成份与载剂结合的步骤。一般而言,通过均匀且紧密地使活性成份与液体载剂或细粉状固体载剂或这两者结合且接着(必要时)使产物成型为所需调配物来制备所述调配物。
用于通过吸入局部递送至肺的干粉组合物可(例如)提供于(例如)明胶的胶囊以及药筒(cartridge)或(例如)层压铝箔的泡罩(blister)中,以用于吸入器或吹入器中。调配物一般包含本发明的盐以及合适的粉末状基质(载剂物质)(诸如乳糖或淀粉)的吸入用粉末状混合物。优选使用乳糖。所述粉末状基质可包含其它组份,诸如防腐剂、稳定剂、吸收增强剂或空气动力调节剂。
各胶囊或药筒一般可含有介于0.1微克与150微克之间的各治疗活性成份。或者,活性成份可在无赋形剂的情况下提供。
调配物的包装可适合于单位剂量或多剂量递送。在多剂量递送的情况下,调配物可预先计量或在使用时计量。因此,干粉吸入器分为三组:(a)单次剂量、(b)多单位剂量以及(c)多剂量装置。
对于第一类型的吸入器,单次剂量已由制造商称量至小容器中,其主要是硬明胶胶囊。胶囊必须自独立盒子或容器取得且插入吸入器的接收区中。接着,胶囊必须用针或切刀(cutting blade)打开或穿孔,以允许在吸入期间一部分吸入空气流穿过胶囊以带走粉末或借助于离心力通过这些开孔由胶囊排出粉末。吸入后,空胶囊必须再次由吸入器移除。插入以及移除胶囊通常需要拆开吸入器,此操作对于一些患者可能是困难及麻烦的。
与使用硬明胶胶囊来吸入粉末有关的其它缺点是(a)防止由周围空气吸收水分的能力弱、(b)与在胶囊预先暴露于极端相对湿度(其会引起断裂或凹痕(indenture))后打开或穿孔相关的问题以及(c)可能吸入胶囊片段。此外,对于多种胶囊吸入器,已报导不完全排出(例如Nielsen等人,1997)。
如WO 92/03175中所述,一些胶囊吸入器具有仓匣(magazine),可由所述仓匣将各个胶囊转移至接收室,在所述接收室中进行穿孔以及排空。其它胶囊吸入器具有这样的旋转仓匣,其带有可与空气导管相对应以排出剂量的胶囊室(例如WO91/02558以及GB 2242134)。其包括多单位剂量型吸入器以及泡罩式吸入器,其在盘状物或带状物上供应有限量的单位剂量。
与胶囊吸入器相比,泡罩式吸入器提供对药剂的较好防潮保护。通过在覆盖物以及泡罩箔上穿孔或通过剥开覆盖箔来获得粉末。当使用泡罩带状物替代盘状物时,可增加剂量数目,但患者更换空带状物是不方便的。因此,具有所并入的剂量系统的所述装置通常是抛弃式的,其包括用于传送带状物且打开泡罩袋的技术。
多剂量吸入器不含有预测量的粉末调配物。其由相对大的容器以及必须由患者操作的剂量测量组件(dose measuring principle)组成。所述容器带有通过体积排送(volumetric displacement)而单独地与粉末主体分离的多个剂量。存在多种剂量测量组件,包括可旋转膜(例如EP0069715)或盘状物(例如GB 2041763;EP 0424790;DE 4239402以及EP 0674533)、可旋转圆筒体(例如EP 0166294;GB 2165159以及WO 92/09322)以及可旋转锥台(例如WO 92/00771),全部均具有必须填充来自容器的粉末的空腔。其它多剂量装置具有测量活塞,其具有局部或圆周凹槽以将一定体积的粉末由容器排送至递送室或空气导管中(例如EP 0505321、WO 92/04068以及WO 92/04928);或测量滑块,诸如Genuiar装置(以前称为NovolizerSD2FL),其在以下专利申请中有所描述:WO97/000703、第WO03/000325号以及WO03/061742。
本发明的优选实施例为在适合于气溶胶施用的装置或系统(诸如喷雾器或加压定剂量吸入器(pressurized metered dose inhaler;MDI))中使用包含本发明的盐的液体调配物。所述气溶胶可经由气体推进剂、电动叶轮或借助于所谓雾化器来产生,由此可在高压下喷射药理活性物质以致产生可吸入粒子的薄雾。合适的雾化器可为(例如)在(例如)WO 91/14468以及WO 97/12687中所述的Respimat在喷雾器的情况下,可使用专用喷嘴来喷射溶液,诸如在(例如)WO 94/07607中所述的喷嘴。喷雾器通常使用压缩空气、超音波或振动筛(vibrating mesh)来形成液滴的薄雾且还可具有通过冲击将较大液滴从薄雾中移除的挡板。各种喷雾器可用于该目的,诸如超音波喷雾器、喷射喷雾器以及呼吸引动式喷雾器(breath-actuatednebuliser)。
本发明的组合物可任选地包含治疗有效量的一种或多种已知适用于治疗呼吸道病症的其它治疗剂,诸如PDE4抑制剂、皮质类固醇及/或抗胆碱剂。
当然,实现治疗作用所需的各活性剂的量将随特定活性剂、施用途径、所治疗的个体以及所治疗的特定病症或疾病而变化。
活性成份可每日施用1至6次,这足以表现出所需活性。活性成份优选每日施用一次或两次,最优选为每日一次。
可与β2促效剂组合的合适PDE4抑制剂的实例为马来酸氢苯芬群(benafentrine dimaleate)、依他唑酯(etazolate)、登布茶碱(denbufylline)、咯利普兰(rolipram)、西潘茶碱(cipamfylline)、扎达维林(zardaverine)、阿罗茶碱(arofylline)、非明司特(filaminast)、泰鲁司特(tipelukast)、托非司特(tofimilast)、吡拉米司特(piclamilast)、托拉芬群(tolafentrine)、美索普兰(mesopram)、盐酸屈他维林(drotaverine hydrochloride)、利瑞司特(lirimilast)、罗氟司特(roflumilast)、西洛司特(cilomilast)、奥格司特(oglemilast)、阿普司特(apremilast)、替托司特(tetomilast)、非明司特(filaminast)、(R)-(+)-4-[2-(3-环戊基氧基-4-甲氧基苯基)-2-苯乙基]吡啶(CDP-840)、N-(3,5-二氯-4-吡啶基)-2-[1-(4-氟苯甲基)-5-羟基-1H-吲哚-3-基]-2-侧氧基乙酰胺(GSK-842470)、9-(2-氟苯甲基)-N6-甲基-2-(三氟甲基)腺嘌呤(NCS-613)、N-(3,5-二氯-4-吡啶基)-8-甲氧基喹啉-5-甲酰胺(D-4418)、3-[3-(环戊基氧基)-4-甲氧基苯甲基]-6-(乙基胺基)-8-异丙基-3H-嘌呤盐酸盐(V-11294A)、6-[3-(N,N-二甲基胺甲酰基)苯基磺酰基]-4-(3-甲氧基苯基胺基)-8-甲基喹啉-3-甲酰胺盐酸盐(GSK-256066)、4-[6,7-二乙氧基-2,3-双(羟基甲基)萘-1-基]-1-(2-甲氧基乙基)吡啶-2(1H)-酮(T-440)、(-)-反-2-[3′-[3-(N-环丙基胺甲酰基)-4-侧氧基-1,4-二氢-1,8-萘啶-1-基]-3-氟联苯-4-基]环丙烷甲酸(MK-0873)、CDC-801、UK-500001、BLX-914、2-甲氧羰基-4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)环己1-酮、顺[4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)环己-1-醇、CDC-801、5(S)-[3-(环戊基氧基)-4-甲氧基苯基]-3(S)-(3-甲基苯甲基)哌啶-2-酮(IPL-455903)、ONO-6126(Eur Respir J 2003,22(增刊45):摘要2557)以及PCT专利申请第WO03/097613号、第WO2004/058729号、第WO 2005/049581号、第WO 2005/123693号以及第WO 2005/123692号中所要求保护的盐。
可与β2促效剂组合的合适皮质类固醇以及糖皮质激素(glucocorticoid)的实例为泼尼龙(prednisolone)、甲泼尼龙(methylprednisolone)、地塞米松(dexamethasone)、地塞米松磷酸钠(dexamethasone cipecilate)、萘非可特(naflocort)、地夫可特(deflazacort)、乙酸卤泼尼松(halopredone acetate)、布地奈德(budesonide)、二丙酸倍氯米松(beclomethasone dipropionate)、氢皮质酮(hydrocortisone)、曲安奈德(triamcinolone acetonide)、氟轻松(fluocinolone acetonide)、醋酸氟轻松(fluocinonide)、特戊酸氯可托龙(clocortolone pivalate)、醋丙甲泼尼龙(methylprednisolone aceponate)、棕榈酸地塞米松(dexamethasonepalmitoate)、替泼尼旦(tipredane)、醋丙氢皮质酮(hydrocortisoneaceponate)、泼尼卡酯(prednicarbate)、二丙酸阿氯米松(alclometasonedipropionate)、卤米松(halometasone)、磺庚甲泼尼龙(methylprednisolonesuleptanate)、糠酸莫美他松(mometasone furoate)、利美索龙(rimexolone)、法呢酸泼尼龙(prednisolone farnesylate)、环索奈德(ciclesonide)、丙酸布替可特(butixocort propionate)、RPR-106541、丙酸地泼罗酮(deprodonepropionate)、丙酸氟替卡松(fluticasone propionate)、糠酸氟替卡松(fluticasone furoate)、丙酸卤倍他索(halobetasol propionate)、氯替泼诺(loteprednol etabonate)、丁酸丙酸倍他米松(betamethasone butyratepropionate)、氟尼缩松(flunisolide)、泼尼松(prednisone)、地塞米松磷酸钠(dexamethasone sodium phosphate)、曲安西龙(triamcinolone)、17-戊酸倍他米松(betamethasone 17-valerate)、倍他米松(betamethasone)、二丙酸倍他米松(betamethasone dipropionate)、21-氯-11β-羟基-17α-[2-(甲基硫基)乙酰氧基]-4-孕甾烯-3,20-二酮、去异丁酰基环索奈德(Desisobutyrylciclesonide)、乙酸氢皮质酮(hydrocortisone acetate)、氢皮质酮丁二酸钠(hydrocortisone sodium succinate)、NS-126、泼尼龙磷酸钠(prednisolone sodium phosphate)以及丙酸丁酸氢皮质酮(hydrocortisoneprobutate)、泼尼龙间磺酸基苯甲酸钠(Prednisolone sodiummetasulfobenzoate)以及丙酸氯倍他索(clobetasol propionate)。
可与β2促效剂组合的合适M3拮抗剂(抗胆碱剂)的实例为噻托铵(tiotropium)盐、氧托铵(oxitropium)盐、氟托铵(flutropium)盐、异丙托铵(ipratropium)盐、格隆铵(glycopyrronium)盐、曲司铵(trospium)盐、扎非那新(zamifenacin)、瑞伐托酯(revatropate)、艾帕托酯(espatropate)、NPC-14695、BEA-2108、3-[2-羟基-2,2-双(2-噻吩基)乙酰氧基]-1-(3-苯氧基丙基)-1-氮鎓双环[2.2.2]辛烷盐(尤其是阿地铵(aclidinium)盐,更优选为溴化阿地铵)、1-(2-苯乙基)-3-(9H-吨-9-基羰氧基)-1-氮鎓双环[2.2.2]辛烷盐、2-侧氧基-1,2,3,4-四氢喹唑啉-3-甲酸内-8-甲基-8-氮杂双环[3.2.1]辛-3-基酯盐(DAU-5884)、3-(4-苯甲基哌嗪-1-基)-1-环丁基-1-羟基-1-苯基丙-2-酮(NPC-14695)、N-[1-(6-胺基吡啶-2-基甲基)哌啶-4-基]-2(R)-[3,3-二氟-1(R)-环戊基]-2-羟基-2-苯基乙酰胺(J-104135)、2(R)-环戊基-2-羟基-N-[1-[4(S)-甲基己基]哌啶-4-基]-2-苯基乙酰胺(J-106366)、2(R)-环戊基-2-羟基-N-[1-(4-甲基-3-戊烯基)-4-哌啶基]-2-苯基乙酰胺(J-104129)、1-[4-(2-胺基乙基)哌啶-1-基]-2(R)-[3,3-二氟环戊-1(R)-基]-2-羟基-2-苯基乙-1-酮(Banyu-280634)、N-[N-[2-[N-[1-(环己基甲基)哌啶-3(R)-基甲基]胺甲酰基]乙基]胺甲酰基甲基]-3,3,3-三苯基丙酰胺(Banyu CPTP)、2(R)-环戊基-2-羟基-2-苯基乙酸4-(3-氮杂双环[3.1.0]己-3-基)-2-丁炔酯(Ranbaxy 364057)、碘化3(R)-[4,4-双(4-氟苯基)-2-侧氧基咪唑啶-1-基]-1-甲基-1-[2-侧氧基-2-(3-噻吩基)乙基]吡咯啶鎓、三氟乙酸N-[1-(3-羟基苯甲基)-1-甲基哌啶鎓-3(S)-基]-N-[N-[4-(异丙氧基羰基)苯基]胺甲酰基]-L-酪胺酰胺、UCB-101333、默克公司(Merck)的OrM3、7-内-(2-羟基-2,2-二苯基乙酰氧基)-9,9-二甲基-3-氧杂-9-氮鎓三环[3.3.1.0(2,4)]壬烷盐、碘化3(R)-[4,4-双(4-氟苯基)-2-侧氧基咪唑啶-1-基]-1-甲基-1-(2-苯乙基)吡咯啶鎓、来自Novartis的溴化反-4-[2-[羟基-2,2-(二噻吩-2-基)乙酰氧基]-1-甲基-1-(2-苯氧基乙基)哌啶鎓(412682)、7-(2,2-二苯基丙酰氧基)-7,9,9-三甲基-3-氧杂-9-氮鎓三环[3.3.1.0*2,4*]壬烷盐、7-羟基-7,9,9-三甲基-3-氧杂-9-氮鎓三环[3.3.1.0*2,4*]壬烷9-甲基-9H-茀-9-甲酸酯盐,其全部均可任选地呈其外消旋体、其对映异构体、其非对映异构体以及其混合物的形式,且可任选地呈其药理兼容性酸加成盐的形式。在所述盐中,氯化物、溴化物、碘化物以及甲磺酸盐为优选的。
本发明的尤其优选医药组合物包含式(I)的盐以及治疗有效量的一种或多种由以下化合物所构成的组中选出的其它治疗剂:糠酸莫美他松、环索奈德、布地奈德、丙酸氟替卡松、糠酸氟替卡松、噻托铵盐、格隆铵盐、3-[2-羟基-2,2-双(2-噻吩基)乙酰氧基]-1-(3-苯氧基丙基)-1-氮鎓双环[2.2.2]辛烷盐(尤其是阿地铵盐,优选为阿地溴铵)、1-(2-苯乙基)-3-(9H-吨-9-基羰氧基)-1-氮鎓双环[2.2.2]辛烷盐、咯利普兰、罗氟司特、西洛司特以及PCT专利申请第WO03/097613号、第WO2004/058729号、第WO2005/049581号、第WO 2005/123693号以及第WO 2005/123692号中所要求保护的化合物。
本发明的尤其优选医药组合物包含式(I)的盐以及治疗有效量的一种或多种由以下化合物所构成的组中选出的其它治疗剂:糠酸莫美他松、环索奈德、布地奈德、丙酸氟替卡松、糠酸氟替卡松、噻托铵盐、格隆铵盐、3-[2-羟基-2,2-双(2-噻吩基)乙酰氧基]-1-(3-苯氧基丙基)-1-氮鎓双环[2.2.2]辛烷盐(尤其是阿地铵盐,优选为阿地溴铵)、1-(2-苯乙基)-3-(9H-吨-9-基羰氧基)-1-氮鎓双环[2.2.2]辛烷盐、咯利普兰、罗氟司特以及西洛司特。
因此,在本发明的一个方面中,组合物包含式(I)的盐以及皮质类固醇。尤其优选的皮质类固醇为由糠酸莫美他松、环索奈德、布地奈德、糠酸氟替卡松以及丙酸氟替卡松所构成的组中选出的皮质类固醇。
在本发明的另一方面中,组合物包含式(I)的盐以及抗胆碱剂。尤其优选的抗胆碱剂为由噻托铵盐、格隆铵盐、3-[2-羟基-2,2-双(2-噻吩基)乙酰氧基]-1-(3-苯氧基丙基)-1-氮鎓双环[2.2.2]辛烷盐以及1-(2-苯乙基)-3-(9H-吨-9-基羰氧基)-1-氮鎓双环[2.2.2]辛烷盐所构成的组中选出的抗胆碱剂。组合物可进一步包含由糠酸莫美他松、环索奈德、布地奈德、糠酸氟替卡松以及丙酸氟替卡松所构成的组中选出的皮质类固醇。
在本发明的另一方面中,组合物包含式(I)的盐以及PDE4抑制剂。尤其优选的PDE4抑制剂为由咯利普兰、罗氟司特、西洛司特以及PCT专利申请第WO03/097613号、第WO2004/058729号、第WO 2005/049581号、第WO 2005/123693号以及第WO 2005/123692号中所要求保护的化合物所构成的组中选出的PDE4抑制剂。组合物可进一步包含由糠酸莫美他松、环索奈德、布地奈德、糠酸氟替卡松以及丙酸氟替卡松所构成的组中选出的皮质类固醇。除本发明的盐以及PDE4抑制剂外,组合物可进一步包含由噻托铵盐、格隆铵盐、3-[2-羟基-2,2-双(2-噻吩基)乙酰氧基]-1-(3-苯氧基丙基)-1-氮鎓双环[2.2.2]辛烷盐以及1-(2-苯乙基)-3-(9H-吨-9-基羰氧基)-1-氮鎓双环[2.2.2]辛烷盐所构成的组中选出的抗胆碱剂。
在本发明的一个尤其优选实施例中,组合物包含式(I)的盐以及治疗有效量的3-[2-羟基-2,2-双(2-噻吩基)乙酰氧基]-1-(3-苯氧基丙基)-1-氮鎓双环[2.2.2]辛烷盐。组合物还可任选地包含皮质类固醇及/或PDE4抑制剂。
在本发明的另一尤其优选实施例中,组合物包含式(I)的盐以及治疗有效量的糠酸莫美他松。组合物还可任选地包含抗胆碱剂及/或PDE4抑制剂。
在本发明的又一个实施例中,组合物包含式(I)的盐、皮质类固醇、抗胆碱剂以及PDE4抑制剂。
本发明的式(I)的盐以及组合可用于治疗使用支气管扩张剂(bronchodilating agent)预期具有有益作用的呼吸道疾病,例如哮喘、急性或慢性支气管炎、肺气肿或慢性阻塞性肺病(Chronic Obstructive PulmonaryDisease;COPD)。
组合中的活性化合物以及盐(即本发明的β2促效剂以及PDE4抑制剂、皮质类固醇或糖皮质激素及/或抗胆碱剂)可在同一医药组合物中共同施用或在旨在用于通过相同或不同途径分开、同时、伴随或依序施用的不同组合物中施用。
预期所有活性剂均将同时或以时间上极接近的方式施用。或者,一种或两种活性剂可在早上服用而其它活性剂在一天中稍晚的时候服用。或在另一方案中,一种或两种活性剂可每日服用两次而其它活性剂每日服用一次,其与每日两次给药中的一次同时进行,或分开进行。优选至少两种且更优选所有活性剂同时服用。优选至少两种且更优选所有活性剂以混合物形式施用。
本发明的活性物质组合物优选以借助于吸入器(尤其是喷雾器以及定剂量吸入器)递送的吸入用组合物的形式施用;然而,任何其它形式的局部、肠胃外施用或经口施用均有可能。本文中,施用吸入型组合物体现出优选的施用形式,在阻塞性肺病的疗法或哮喘治疗中尤其是如此。
活性化合物调配物一般含有合适的载剂,其可为用于MDI施用的推进剂或用于经由喷雾器施用的水。调配物可包含其它组份,诸如防腐剂(例如苯扎氯铵、山梨酸钾、苯甲醇);pH值稳定剂(例如酸性剂、碱性剂、缓冲剂系统);等渗稳定剂(例如氯化钠);表面活性剂以及湿润剂(例如聚山梨醇酯、脱水山梨糖醇酯);及/或吸收增强剂(例如壳聚糖、透明质酸、表面活性剂)。调配物还可含有添加剂以改善其它活性化合物在与本发明的盐混合时的溶解性。溶解性增强剂可包括诸如环糊精、脂质体或共溶剂(诸如乙醇、甘油以及丙二醇)等组份。
其它适用于本发明的活性盐调配物的载剂可见于Remington:TheScience and Practice of Pharmacy,第20版,Lippincott Williams & Wilkins,Philadelphia,Pa.,2000中。以下非限制性实例示出了本发明的代表性医药组合物。
本发明进一步涵盖一种治疗哺乳动物的与β2肾上腺素受体活性相关的肺部疾病或病状(诸如哮喘或慢性阻塞性肺病)的方法,所述方法包括向所述哺乳动物施用治疗有效量的如上文所述的医药组合物。所述哺乳动物优选为人类。
特别是,治疗肺部疾病或病状的方法包括向哺乳动物(优选为人类)施用治疗有效量的式(I)的化合物的甲磺酸盐以及治疗有效量的一种或多种其它治疗剂(诸如皮质类固醇、抗胆碱剂或PDE4抑制剂)。
调配物实例1(用于喷雾器的调配物)。
调配物实例2(用于喷雾器的调配物)。
调配物实例3(用于MDI的调配物)。
调配物实例4(用于MDI的调配物)。
Claims (15)
1.一种5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羟乙基)-8-羟基喹啉-2(1H)-酮的甲磺酸盐以及其医药学上可接受的溶剂合物。
2.一种如权利要求1所述的盐,其由以下物质所构成的组中选出:(R,S)5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羟基-乙基)-8-羟基喹啉-2(1H)-酮甲磺酸盐、
5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1(R)-羟基-乙基)-8-羟基喹啉-2(1H)-酮甲磺酸盐、
以及其医药学上可接受的溶剂合物。
3.一种医药组合物,其包含治疗有效量的如权利要求1或2中任一项所述的盐以及医药学上可接受的载剂。
4.如权利要求3所述的医药组合物,其中所述组合物被调配为通过吸入施用。
5.如权利要求3或4所述的医药组合物,其中所述组合物还包含治疗有效量的一种或多种其它治疗剂。
6.如权利要求5所述的医药组合物,其中所述其它治疗剂是皮质类固醇、抗胆碱剂及/或PDE4抑制剂。
7.如权利要求5或6所述的医药组合物,其中所述其它治疗剂是由以下化合物所构成的组中选出的皮质类固醇:泼尼龙、甲泼尼龙、地塞米松、地塞米松磷酸钠、萘非可特、地夫可特、乙酸卤泼尼松、布地奈德、二丙酸倍氯米松、氢皮质酮、曲安奈德、氟轻松、醋酸氟轻松、特戊酸氯可托龙、醋丙甲泼尼龙、棕榈酸地塞米松、替泼尼旦、醋丙氢皮质酮、泼尼卡酯、二丙酸阿氯米松、卤米松、磺庚甲泼尼龙、糠酸莫美他松、利美索龙、法呢酸泼尼龙、环索奈德、丙酸布替可特、RPR-106541、丙酸地泼罗酮、丙酸氟替卡松、糠酸氟替卡松、丙酸卤倍他索、氯替泼诺、丁酸丙酸倍他米松、氟尼缩松、泼尼松、地塞米松磷酸钠、曲安西龙、17-戊酸倍他米松、倍他米松、二丙酸倍他米松、21-氯-11β-羟基-17α-[2-(甲基硫基)乙酰氧基]-4-孕甾烯-3,20-二酮、去异丁酰基环索奈德、去异丁酰基环索奈德、乙酸氢皮质酮、氢皮质酮丁二酸钠、NS-126、泼尼龙磷酸钠、丙酸丁酸氢皮质酮、泼尼龙间磺酸基苯甲酸钠以及丙酸氯倍他索。
8.如权利要求5或6所述的医药组合物,其中所述其它治疗剂是由以下化合物所构成的组中选出的抗胆碱剂:噻托铵盐、氧托铵盐、氟托铵盐、异丙托铵盐、格隆铵盐、曲司铵盐、扎非那新、瑞伐托酯、艾帕托酯、NPC-14695、BEA-2108、3-[2-羟基-2,2-双(2-噻吩基)乙酰氧基]-1-(3-苯氧基丙基)-1-氮鎓双环[2.2.2]辛烷盐、1-(2-苯乙基)-3-(9H-吨-9-基羰氧基)-1-氮鎓双环[2.2.2]辛烷盐、2-侧氧基-1,2,3,4-四氢喹唑啉-3-甲酸内-8-甲基-8-氮杂双环[3.2.1]辛-3-基酯盐(DAU-5884)、3-(4-苯甲基哌嗪-1-基)-1-环丁基-1-羟基-1-苯基丙-2-酮(NPC-14695)、N-[1-(6-胺基吡啶-2-基甲基)哌啶-4-基]-2(R)-[3,3-二氟-1(R)-环戊基]-2-羟基-2-苯基乙酰胺(J-104135)、2(R)-环戊基-2-羟基-N-[1-[4(S)-甲基己基]哌啶-4-基]-2-苯基乙酰胺(J-106366)、2(R)-环戊基-2-羟基-N-[1-(4-甲基-3-戊烯基)-4-哌啶基]-2-苯基乙酰胺(J-104129)、1-[4-(2-胺基乙基)哌啶-1-基]-2(R)-[3,3-二氟环戊-1(R)-基]-2-羟基-2-苯基乙-1-酮(Banyu-280634)、N-[N-[2-[N-[1-(环己基甲基)哌啶-3(R)-基甲基]胺甲酰基]乙基]胺甲酰基甲基]-3,3,3-三苯基丙酰胺(Banyu CPTP)、2(R)-环戊基-2-羟基-2-苯基乙酸4-(3-氮杂双环[3.1.0]己-3-基)-2-丁炔酯(Ranbaxy 364057)、碘化3(R)-[4,4-双(4-氟苯基)-2-侧氧基咪唑啶-1-基]-1-甲基-1-[2-侧氧基-2-(3-噻吩基)乙基]吡咯啶鎓、三氟乙酸N-[1-(3-羟基苯甲基)-1-甲基哌啶鎓-3(S)-基]-N-[N-[4-(异丙氧基羰基)苯基]胺甲酰基]-L-酪胺酰胺、UCB-101333、默克公司的OrM3、7-内-(2-羟基-2,2-二苯基乙酰氧基)-9,9-二甲基-3-氧杂-9-氮鎓三环[3.3.1.0(2,4)]壬烷盐、碘化3(R)-[4,4-双(4-氟苯基)-2-侧氧基咪唑啶-1-基]-1-甲基-1-(2-苯乙基)吡咯啶鎓、来自Novartis的溴化反-4-[2-[羟基-2,2-(二噻吩-2-基)乙酰氧基]-1-甲基-1-(2-苯氧基乙基)哌啶鎓(412682)、7-(2,2-二苯基丙酰氧基)-7,9,9-三甲基-3-氧杂-9-氮鎓三环[3.3.1.0*2,4*]壬烷盐、7-羟基-7,9,9-三甲基-3-氧杂-9-氮鎓三环[3.3.1.0*2,4*]壬烷9-甲基-9H-茀-9-甲酸酯盐,其全部均可任选地呈其外消旋体、其对映异构体、其非对映异构体以及其混合物的形式,且可任选地呈其药理兼容性酸加成盐的形式。
9.如权利要求5或6所述的医药组合物,其中所述其它治疗剂是由以下化合物所构成的组中选出的PDE4抑制剂:马来酸氢苯芬群、依他唑酯、登布茶碱、咯利普兰、西潘茶碱、扎达维林、阿罗茶碱、非明司特、泰鲁司特、托非司特、吡拉米司特、托拉芬群、美索普兰、盐酸屈他维林、利瑞司特、罗氟司特、西洛司特、奥格司特、阿普司特、替托司特、非明司特、(R)-(+)-4-[2-(3-环戊基氧基-4-甲氧基苯基)-2-苯乙基]吡啶(CDP-840)、N-(3,5-二氯-4-吡啶基)-2-[1-(4-氟苯甲基)-5-羟基-1H-吲哚-3-基]-2-侧氧基乙酰胺(GSK-842470)、9-(2-氟苯甲基)-N6-甲基-2-(三氟甲基)腺嘌呤(NCS-613)、N-(3,5-二氯-4-吡啶基)-8-甲氧基喹啉-5-甲酰胺(D-4418)、N-[9-甲基-4-侧氧基-1-苯基-3,4,6,7-四氢吡咯并[3,2,1-jk][1,4]苯并二氮呼-3(R)-基]吡啶-4-甲酰胺、3-[3-(环戊基氧基)-4-甲氧基苯甲基]-6-(乙基胺基)-8-异丙基-3H-嘌呤盐酸盐(V-11294A)、6-[3-(N,N-二甲基胺甲酰基)苯基磺酰基]-4-(3-甲氧基苯基胺基)-8-甲基喹啉-3-甲酰胺盐酸盐(GSK-256066)、4-[6,7-二乙氧基-2,3-双(羟基甲基)萘-1-基]-1-(2-甲氧基乙基)吡啶-2(1H)-酮(T-440)、(-)-反-2-[3′-[3-(N-环丙基胺甲酰基)-4-侧氧基-1,4-二氢-1,8-萘啶-1-基]-3-氟联苯-4-基]环丙烷甲酸(MK-0873)、CDC-801、UK-500001、BLX-914,、2-甲氧羰基-4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)-环己1-酮、顺[4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)-环己-1-醇、CDC-801、5(S)-[3-(环戊基氧基)-4-甲氧基苯基]-3(S)-(3-甲基苯甲基)哌啶-2-酮(IPL-455903)、ONO-6126(Eur Respir J 2003,22(增刊45):摘要2557)以及PCT专利申请第WO03/097613号、第WO2004/058729号、第WO 2005/049581号、第WO 2005/123693号以及第WO 2005/123692号中所要求保护的化合物。
10.如权利要求5至9中任一项所述的医药组合物,其中所述其它治疗剂由以下化合物所构成的组中选出:糠酸莫美他松、环索奈德、布地奈德、丙酸氟替卡松、糠酸氟替卡松、噻托铵盐、格隆铵盐、3-[2-羟基-2,2-双(2-噻吩基)乙酰氧基]-1-(3-苯氧基丙基)-1-氮鎓双环[2.2.2]辛烷盐、1-(2-苯乙基)-3-(9H-吨-9-基羰氧基)-1-氮鎓双环[2.2.2]辛烷盐、咯利普兰、罗氟司特以及西洛司特。
11.一种组合,其包含如权利要求1或2中任一项所述的盐以及一种或多种如权利要求5至10中任一项所述的其它治疗剂。
12.用于治疗与β2肾上腺素受体活性相关的病理学病状或疾病的如权利要求1或2中任一项所述的盐、如权利要求3至10中任一项所述的医药组合物或如权利要求11所述的组合。
13.如权利要求12所述的盐,其中所述病理学病状或疾病是哮喘或慢性阻塞性肺病。
14.一种如权利要求1或2中任一项所述的盐、如权利要求3至10中任一项所述的医药组合物或如权利要求11所述的组合用于制造供治疗如权利要求12或13所述的病理学病状或疾病的药剂的用途。
15.一种治疗罹患如权利要求12或13所述的病理学病状或疾病的个体的方法,其包括向所述个体施用有效量的如权利要求1或2中任一项所述的盐、如权利要求3至10中任一项所述的医药组合物或如权利要求11所述的组合。
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Publication number | Priority date | Publication date | Assignee | Title |
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CN103864670A (zh) * | 2014-03-17 | 2014-06-18 | 苏州明锐医药科技有限公司 | 阿普司特的制备方法 |
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