CN1599609A - 选择性PDE4抑制剂与肾上腺素能β2受体激动剂的组合 - Google Patents
选择性PDE4抑制剂与肾上腺素能β2受体激动剂的组合 Download PDFInfo
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- CN1599609A CN1599609A CNA028243935A CN02824393A CN1599609A CN 1599609 A CN1599609 A CN 1599609A CN A028243935 A CNA028243935 A CN A028243935A CN 02824393 A CN02824393 A CN 02824393A CN 1599609 A CN1599609 A CN 1599609A
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- pyridine
- ethyl
- pyrazolo
- triazol
- dihydro
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Abstract
本发明涉及在阻塞性气道或其他炎性疾病治疗中借助吸入途径同时、先后或单独给药的如本文所定义的选择性PDE4抑制剂与肾上腺素能β2受体激动剂的组合。
Description
本发明涉及可吸入的选择性PDE4抑制剂与肾上腺素能β2受体激动剂的组合、药物组合物(包括给药装置)和这样一种组合的用途。
选择性PDE4抑制剂与肾上腺素能β2受体激动剂的组合可用于治疗阻塞性气道与其他炎性疾病,特别是阻塞性气道疾病气喘、慢性阻塞性肺疾病(COPD)和其他因支气管反射增高、炎症、支气管反应性过高与支气管痉挛而恶化的阻塞性气道疾病。该组合尤其可用于治疗COPD。
可以用本发明治疗的特定疾病的实例包括呼吸疾病气喘、急性呼吸窘迫综合征、慢性肺炎性疾病、支气管炎、慢性支气管炎、慢性阻塞性肺(气道)疾病与尘肺病和免疫系统疾病,例如变应性鼻炎和慢性鼻窦炎。
3’,5’-环核苷酸磷酸二酯酶(PDEs)包含一大类分为至少十一个不同家族的酶,它们在结构上、生物化学上和药理学上不同于彼此。每一家族内的酶普遍称为同功酶或同工酶。在这一类中包括总计十五种以上基因产物,进一步的多样性来自于这些基因产物的分化剪接和翻译后加工。本发明主要涉及第四家族PDEs的四种基因产物,也就是PDE4A、PDE4B、PDE4C和PDE4D。这些酶统称为PDE4同工酶家族的同工型或亚型(PDE4s)。
PDE4s是以第二信使环核苷酸,腺苷3’,5’-环一磷酸(cAMP)的选择性、高亲合性水解降解作用和对咯利普兰抑制作用的敏感性为特征的。近年来已经发现了一些选择性PDE4s抑制剂,在多种疾病模型中已经显示了来自该抑制作用的有益药理效果:例如参见Torphy et al.,Environ.Health Perspect.102 Suppl.10,79-84,1994;Duplantieret al.,J.Med.Chem.39 120-125,1996;Schneider et al.,Pharmacol.Biochem.Behav.50 211-217,1995;Banner and Page,Br.J.Pharmacol.114 93-98,1995;Barnette et al.,J.Pharmacol.Exp.Ther.273 674-679,1995;Wright et al.“Differential in vivo andin vitro bronchorelaxant activities of CP-80633,a selectivephosphodiesterase 4 inhibitor”,Can.J.Physiol.Pharmacol.751001-1008,1997;Manabe et al.“Anti-inflammatory andbronchodilator properties of KF19514,a phosphodiesterase 4 and1 inhibitor”,Eur.J.Pharmacol.332 97-107,1997;Ukita etal.,“Novel,potent,and selective phosphodiesterase-4inhibitors as antiasthmatic agents:synthesis and biologicalactivities of a series of 1-pyridylnaphthalene derivatives”,J.Med.Chem.42 1088-1099,1999。
肾上腺素能β受体存在于交感神经系统中。有至少两种类型。肾上腺素能β1受体见于心脏,在经由激动剂肾上腺素和去甲肾上腺素的作用调节心率中扮演重要角色。肾上腺素能β2受体存在于肺中一些细胞类型上(例如气道平滑肌细胞、上皮细胞和多种炎性细胞),肾上腺素能β2受体激动剂是有效的支气管扩张剂,导致气道平滑肌的松弛。拟交感的胺类在以部分可逆性气道狭窄为特征的慢性气道疾病治疗中具有悠久的使用历史,例如COPD和气喘,首先是以静脉内肾上腺素的形式用作支气管扩张剂。后来,使用可吸入的β-肾上腺素能药物,例如异丙肾上腺素,它们对β2之于β1受体是相对无选择性的,因而在有效的支气管扩张剂量下导致心动过速。最近,已经使用可吸入的β-肾上腺素能药物,例如沙丁胺醇,它们对β2受体更有选择性,但是是短效的。可吸入的β-肾上腺素能药物福莫特罗、N-[2-羟基-5-(1-羟基-2-((2-(4-甲氧基苯基)-1-甲基乙基)氨基)乙基)苯基]甲酰胺和沙美特罗既是β2受体选择性的,也是长效的。
现已惊人地发现,特定的选择性PDE4抑制剂与肾上腺素能β2受体激动剂的组合在阻塞性气道与其他炎性疾病的治疗中提供显著优于两种单独药物和其他已知组合的益处。该组合的优点是通过最适于疾病病理学的机理,也就是肾上腺素能β2受体激动作用,提供对气道口径的最佳控制,以及对不适当炎症的有效抑制。按照这种方式,通过纠正不适当的气道神经反射,控制疾病的症状,这些反射引起咳嗽、粘液产生和呼吸困难。经由吸入途径给以肾上腺素能β2受体激动剂与选择性PDE4抑制剂的组合,每一种类的益处都获得释放,而没有所不希望的外周效应。进而,本发明的特定组合产生意外的协同性,功效大于两种药物单独使用的最大耐受剂量。
本发明因此提供下列(a)与(b)的吸入组合:
(a)式(I)选择性PDE4抑制剂
或者其药学上可接受的盐或溶剂化物,其中:
R1是H、(C1-C6)烷基、(C1-C6)烷氧基、(C2-C4)链烯基、苯基、-N(CH3)2、(C3-C6)环烷基、(C3-C6)环烷基(C1-C3)烷基或(C1-C6)酰基,其中该烷基、苯基或链烯基可以被至多两个-OH、(C1-C3)烷基或-CF3基团或者至多三个卤素取代;
R2和R3各自独立地选自由H、(C1-C14)烷基、(C1-C7)烷氧基(C1-C7)烷基、(C2-C14)链烯基、(C3-C7)环烷基、(C3-C7)环烷基(C1-C2)烷基、饱和或不饱和的(C4-C7)杂环(CH2)n基团组成的组,其中n是0、1或2,含有一个或两个氧、硫、磺酰基、氮和NR4作为杂原子,其中R4是H或(C1-C4)烷基;或者式(II)基团:
其中a是整数1至5;b和c是0或1;R5是H、-OH、(C1-C5)烷基、(C2-C5)链烯基、(C1-C5)烷氧基、(C3-C6)环烷氧基、卤素、-CF3、-CO2R6、-CONR6R7、-NR6R7、-NO2或-SO2NR6R7,其中R6和R7各自独立地是H或(C1-C4)烷基;Z是-O-、-S-、-SO2-、-CO-或-N(R8)-,其中R8是H或(C1-C4)烷基;Y是(C1-C5)亚烷基或(C2-C6)亚烯基,可选地被至多两个(C1-C7)烷基或(C3-C7)环烷基取代;其中每个烷基、链烯基、环烷基、烷氧基烷基或杂环基团可以被1至14个、优选1至5个(C1-C2)烷基、CF3或卤代基团取代;
R9和R10各自独立地选自由H、(C1-C6)烷基、(C1-C6)烷氧基、(C6-C10)芳基和(C6-C10)芳氧基组成的组;
和(b)肾上腺素能β2受体激动剂。
进而,本发明提供用作药剂的如上所定义的式(I)选择性PDE4抑制剂与肾上腺素能β2受体激动剂的吸入组合。
进而,本发明提供用于在阻塞性气道或其他炎性疾病治疗中同时、先后或单独给药的如上所定义的式(I)选择性PDE4抑制剂与肾上腺素能β2受体激动剂的吸入组合。
进而,本发明提供药物组合物,包含如上所定义的式(I)选择性PDE4抑制剂、肾上腺素能β2受体激动剂和药学上可接受的赋形剂、稀释剂或载体,用于在阻塞性气道或其他炎性疾病治疗中借助吸入途径给药。
进而,本发明提供如上所定义的式(I)选择性PDE4抑制剂或肾上腺素能β2受体激动剂在药剂制造中的用途,该药剂用于在阻塞性气道或其他炎性疾病治疗中借助吸入途径同时、先后或单独给以这两种药物。
进而,本发明提供治疗阻塞性气道或其他炎性疾病的方法,包含借助吸入途径对需要这类治疗的哺乳动物同时、先后或单独给以有效量的如上所定义的式(I)选择性PDE4抑制剂和肾上腺素能β2受体激动剂。
进而,本发明提供吸入装置,用于在阻塞性气道或其他炎性疾病治疗中同时、先后或单独给以如上所定义的式(I)选择性PDE4抑制剂和肾上腺素能β2受体激动剂。
选择性PDE4抑制剂对PDE4同工酶的亲合性大于所有其他已知的PDE同工酶。优选地,根据本发明的选择性PDE4抑制剂对PDE4同工酶的亲合性比它对其他PDE同工酶的亲合性大至少100倍。
优选的式(I)化合物包括这些,其中R1是甲基、乙基或异丙基,和其中R3是(C1-C6)烷基、(C2-C6)链烯基、(C3-C7)环烷基、(C3-C7)环烷基(C1-C6)烷基或苯基,可选地被1或2个基团取代,取代基选自H、-OH、(C1-C5)烷基、(C2-C5)链烯基、(C1-C5)烷氧基、卤素、三氟甲基、-CO2R6、-CONR6R7、-NR6R7、-NO2或-SO2NR6R7,其中R6和R7各自独立地是H或(C1-C4)烷基。
优选的个别式(I)化合物包括:
9-环戊基-5,6-二氢-7-乙基-3-苯基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(呋喃-2-基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-吡啶基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(4-吡啶基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(3-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
3-苄基-9-环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-丙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
3,9-二环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(1-甲基环己-1-基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
3-(叔丁基)-9-环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-甲基苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-甲氧基苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(噻吩-2-基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
3-(2-氯苯基)-9-环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-碘苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-三氟甲基苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;和
5,6-二氢-7-乙基-9-(4-氟苯基)-3-(1-甲基环己-1-基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
和其药学上可接受的盐和溶剂化物。
特别优选的式(I)化合物包括9-环戊基-5,6-二氢-7-乙基-3-(2-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶和9-环戊基-5,6-二氢-7-乙基-3-(叔丁基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶和其药学上可接受的盐和溶剂化物。
式(I)化合物的合成如WO-A-96/39408所述。
优选地,用在根据本发明的组合中的肾上腺素能β2受体激动剂是选择性肾上腺素能β2受体激动剂,也就是说对肾上腺素能β2受体的亲合性大于所有其他已知的肾上腺素能β受体。优选地,这样一种选择性肾上腺素能β2受体激动剂对肾上腺素能β2受体的亲合性比它对其他肾上腺素能β受体的亲合性大至少100倍。
优选用在本发明中的肾上腺素能β2受体激动剂包括沙美特罗、福莫特罗和其药学上可接受的盐和溶剂化物。
特别优选的组合包括:
9-环戊基-5,6-二氢-7-乙基-3-(2-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶或其药学上可接受的盐或溶剂化物与沙美特罗或其药学上可接受的盐或溶剂化物;
9-环戊基-5,6-二氢-7-乙基-3-(2-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶或其药学上可接受的盐或溶剂化物与福莫特罗或其药学上可接受的盐或溶剂化物;
9-环戊基-5,6-二氢-7-乙基-3-(叔丁基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶或其药学上可接受的盐或溶剂化物与沙美特罗或其药学上可接受的盐或溶剂化物;
9-环戊基-5,6-二氢-7-乙基-3-(叔丁基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶或其药学上可接受的盐或溶剂化物与福莫特罗或其药学上可接受的盐或溶剂化物。
按照本发明所使用的选择性PDE4抑制剂或肾上腺素能β2受体激动剂可以可选地采用药学上可接受的盐或溶剂化物的形式。这样一种盐可以是酸加成盐或碱盐。
适合的酸加成盐是从生成无毒性盐的酸生成的,实例有盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、磷酸氢盐、乙酸盐、马来酸盐、富马酸盐、乳酸盐、酒石酸盐、枸橼酸盐、葡萄糖酸盐、琥珀酸盐、糖质酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对-甲苯磺酸盐和扑酸盐。
适合的碱盐是从生成无毒性盐的碱生成的,实例有钠、钾、铝、钙、镁、锌和二乙醇胺的盐。
关于适合的盐的评述,参见Berge et al.,J.Pharm.Sci.,66,1-19,1977。
按照本发明所使用的选择性PDE4抑制剂和肾上腺素能β2受体激动剂或其盐的药学上可接受的溶剂化物包括其水合物。
本发明的选择性PDE4抑制剂和肾上腺素能β2受体激动剂可以存在一种或多种多晶型。
本发明的选择性PDE4抑制剂和肾上腺素能β2受体激动剂(以下称为“本发明化合物”)可以含有一个或多个不对称的碳原子,因此存在两种或多种立体异构型(例如,R,R′福莫特罗是一项优选实施方案)。当这样一种化合物含有链烯基或亚烯基时,还可以存在顺式/反式(或Z/E)异构。本发明包括本发明化合物的这些个别立体异构体,酌情和其个别的互变异构型,及其混合物。
非对映异构体或顺反式异构体的分离可以通过常规技术实现,例如本发明化合物或其适合的盐或衍生物的立体异构体混合物的分布结晶、色谱或H.P.L.C.。本发明化合物的个别对映体还可以从对应的光学纯中间体制备,或者通过拆分制备,例如使用适合的手性载体进行对应的外消旋物的H.P.L.C.,或者通过非对映异构盐的分布结晶加以制备,该盐是通过对应的外消旋物与适合的旋光活性酸或碱的反应而生成的,视情况而定。
本发明还包括本发明化合物或其药学上可接受的盐的所有适合的同位素变例。本发明化合物或其药学上可接受的盐的同位素变例被定义为其中至少一个原子被原子数相同但原子质量不同于自然界常见的原子质量的原子所代替。可以结合在本发明化合物及其药学上可接受的盐中的同位素实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素,分别例如2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F、36Cl。本发明化合物及其药学上可接受的盐的某些同位素变例——例如其中结合有3H或14C等放射性同位素的那些——可用于药物和/或底物组织分布研究。氚、即3H和碳-14、即14C同位素是特别优选的,因为它们容易制备和检测。进而,被氘、即2H等同位素取代因代谢稳定性更高可以提供某些治疗上的优点,例如体内半衰期增加或剂量需求减少,因此在有些情况下可能是优选的。
可以用本发明组合治疗的疾病类型包括但不限于气喘、慢性或急性支气管收缩、慢性支气管炎、小气道阻塞、肺气肿、慢性阻塞性肺疾病(COPD)、具有慢性支气管炎、肺气肿或与之有关的呼吸困难的COPD、和以不可逆的进行性气道阻塞为特征的COPD。
气喘
可用本发明治疗剂组合治疗的最重要的呼吸疾病之一是气喘,这是一种慢性的、日益普遍的世界范围病症,是以间歇性可逆的气道阻塞、气道反应性过高和炎症为特征的。气喘的原因尚有待确定,但是气喘的最普遍的病理表现是气道的炎症,这即使在轻微气喘患者的气道中也可能是显著的。这种炎症驱使反射性气道事件,导致血浆蛋白外渗、呼吸困难和支气管收缩。基于支气管的活组织检查和灌洗研究,已经清楚地显示了气喘牵涉肥大细胞、嗜曙红细胞和T淋巴细胞浸润到患者气道中。特应性气喘患者中的支气管泡灌洗(BAL)显示有白介素(IL)-3、IL-4、IL-5和粒细胞/巨噬细胞-集落刺激因子(GM-CSF)的活化,这提示了T辅助细胞2(Th-2)样T细胞群的存在。
本发明的治疗剂组合可用于治疗特应性与非特应性气喘。术语“特应性”表示对针对普通环境抗原的I型(即时)过敏反应的形成的遗传素因。最普遍的临床表现是变应性鼻炎,而支气管气喘、特应性皮炎和食物过敏不太常见。因此,本文所用的表达方式“特应性气喘”打算与“变应性气喘”是同义的,也就是支气管气喘在敏感患者中的变应性表现。本文所用的术语“非特应性气喘”打算表示所有其他的气喘,尤其是本质性或“真正的”气喘,它是由各种因素激起的,包括激烈运动、刺激性粒子、心理压力等。
慢性阻塞性肺疾病(COPD)
本发明的治疗剂组合进一步可用于治疗COPD或COAD,包括慢性支气管炎、肺气肿或与之有关的呼吸困难。COPD是以不完全可逆的、进行性气道阻塞为特征的。慢性支气管炎与大软骨气道中粘膜下层粘液分泌腺体的增生和肥大有关。杯状细胞增生、粘膜与粘膜下层炎性细胞浸润、水肿、纤维变性、粘液栓塞和增加了的平滑肌都见于末端与呼吸细支气管。已知小气道是主要的气道阻塞部位。肺气肿是以肺泡壁的破坏和肺弹性的丧失为特征的。也已经认定大量危险因素与COPD的发病率有关。吸烟与COPD之间的联系已得到充分的确定。其他危险因素包括暴露于煤灰和各种遗传因素。参见Sandford et al.,“Genetic risk factorsfor chronic obstructive pulmonary disease”,Eur.Respir.J.101380-1391,1997。COPD的发病率正在增加,已成为工业化国家人口的沉重经济负担。COPD本身在临床上也存在广泛的差异,从没有能力丧失的简单慢性支气管炎到严重的能力丧失状态伴有慢性呼吸衰竭患者。
COPD是以气道炎症为特征的,这也是气喘的情况,但是见于患者支气管泡灌洗液和痰中的炎性细胞是嗜中性白细胞和巨噬细胞,而非嗜曙红细胞。升高了的炎性介质水平也见于COPD患者,包括IL-8、LTB4和TNF-α,已经发现这类患者的支气管的表面上皮和上皮下膜被T淋巴细胞和巨噬细胞所浸润。利用β-激动剂和抗胆碱能支气管扩张剂可以提供COPD患者的症状缓解,但是疾病的进展仍然没有改变。已经使用茶碱治疗COPD,但是没有取得多大的成功,部分原因是有产生所不希望的后果的倾向。类固醇也没有能够成为令人满意的COPD治疗剂,因为它们作为抗炎剂而言是相对无效的。
因此,本发明治疗剂组合治疗COPD及其有关的和所包括的阻塞性气道疾病的用途代表了本领域的显著进步。关于利用本发明治疗剂组合达到所需治疗目的的方式,本发明不限于任何特定的作用方式或任何假设。
支气管炎和支气管扩张
按照上述为本发明治疗剂组合所具有的特定的和不同的抑制活性,它们可用于治疗任何类型、病因或发病机理的支气管炎,例如包括急性支气管炎,它具有短暂的但是严重的病程,是由着凉、吸入刺激性物质或急性感染所导致的;卡他性支气管炎,它是急性支气管炎的一种形式,伴有大量粘液脓性排出物;慢性支气管炎,它是支气管炎的一种长期延续方式,伴有或多或少的在静止阶段后复发的趋势,是由急性支气管炎的反复发作或慢性全身病引起的,是以咳嗽的发作、少痰或多痰和肺组织的继发改变为特征的;干性支气管炎,它是以粘痰的少量分泌为特征的;传染性气喘性支气管炎,它以气喘患者支气管痉挛症状形成继发呼吸道感染而著称的综合征;增生性支气管炎,它是与排痰性咳嗽有关的支气管炎。
利用本领域已知的大量不同模型可以证明本发明治疗剂组合治疗特应性气喘或非特应性气喘、COPD或其他慢性炎性气道疾病的用效力,这些模型包括如下所述模型。
支气管扩张活性——cAMP不仅牵涉在平滑肌松弛中,而且对气道平滑肌增生发挥总体抑制影响,二者都可能来自本发明的PDE4组分升高cAMP。气道平滑肌肥大和增生可以受到cAMP的调制,这些病状是慢性气喘的常见形态特征。
体外支气管解痉活性——在下列试验程序中证明本发明治疗剂组合导致豚鼠气管平滑肌松弛的能力。将豚鼠(350-500g)用硫喷妥钠(100mg/kg i.p.)处死。切开气管,切除长2-3cm的切片。沿下一软骨板的横断面横切气管,得到深3-5mm的组织环。近侧和远侧的环弃去。将各环垂直固定在不锈钢支架上,其中一个固定在器官浴的底部,另一个连接于等距传感器。将环浸在37℃ Krebs溶液浴中(μM组成:NaHCO325;NaCl 113;KCl 4.7;MgSO4·7H2O 1.2;KH2PO4 1.2;CaCl2 2.5;葡萄糖11.7),用O2/CO2(95∶5,v/v)通气。用电场刺激以这种方式制备的环,使其收缩。为了确认解痉活性,将本发明的供试治疗剂组合溶于生理盐水,按5min间隔加入到器官浴中,数量递增,得到累积的浓度-效果曲线。
在上述试验模型中,本发明的治疗剂组合通常在0.001至1.0μM的浓度范围下抑制了电场刺激的豚鼠气管环制备物的收缩。
臭氧诱发的支气管反应性过高模型——通过测定对豚鼠肺响应活性的影响,证明了本发明治疗剂组合预防气道对有害刺激的响应性增加、已知也称支气管反应性过高的能力。按照Yeadon et al.,1992,Pulm.Pharmacology,5,101-112的方法预处理和准备成年豚鼠(300-600g)。在基础状态下和在各种导致肺力学改变的干预之后监测气道对各种刺激的响应性。在攻击之前不同时间,将供试物i.t.给药或者借助气雾剂给药。对照动物的臭氧预处理导致肺响应性的3-100x增加,而本发明的治疗剂组合以剂量相关性方式阻滞了这种增加。
在上述试验模型中,本发明的治疗剂组合通常在0.001至0.3mg/kgi.t.的剂量范围下表现出抗炎活性。
人支气管松弛——在除去之后3天内得到在癌症手术期间切开的人肺样本。切除小支气管(内径≈2-5mm),切成小段,置于装有胎牛血清(FCS)的2ml液氮贮存安瓿内,FCS含有1.8M二甲基亚砜(DMSO)和0.1M蔗糖作为低温保护剂。将安瓿置于聚苯乙烯盒子内(11×11×22cm),在保持在-70℃的冰箱内缓慢冷冻,平均冷却速率为0.6℃/min。3-15小时后,将安瓿转移至液氮(-196℃)中,贮存备用。在使用前,使组织暴露于-70℃达30-60min,然后将安瓿置于37℃水浴中,在2.5min内融化。然后,将支气管小段置于含有37℃ Krebs-Henseleit溶液(μM:NaCl118,KCl 4.7,MgSO4 1.2,CaCl2 1.2,KH2PO4 1.2,NaHCO3 25,葡萄糖11,EDTA 0.03)的盘子中清洗,切成环,悬浮在10ml器官浴中,在约1g的预负载下记录等径张力。施加电场刺激,诱发张力进一步增加,已知这会诱导气道样本神经的活化,经由乙酰胆碱和其他天然介质的释放产生张力。通过累积的加入生成浓度-响应曲线,在前一浓度已经产生最大效果时加入后一浓度。在浓度-响应曲线结束时加入罂粟碱(300μM),诱导支气管环的完全松弛。这种效果被视为100%松弛。
在上述试验模型中,本发明的治疗剂组合通常在0.001至1.0μM的浓度范围下产生人支气管环制备物的浓度相关性松弛,优选的实施方式是在5.0nM至500nM的浓度范围下有活性。
辣椒碱诱导的支气管收缩的抑制——将在实验之前自由饮水进食的雄性Dunkin-Hartley豚鼠(400-800g)用苯巴比妥钠(100mg/kg i.p.[腹膜内])麻醉。根据直肠温度计,利用加热垫使动物维持在37℃,经由气管插管(约8ml/kg,1Hz)通以空气与氧的混合物(45∶55 v/v)。利用与符合呼吸泵的差示压力传感器连接的呼吸速度描记器监测气管处的换气。利用差示压力传感器,经由胸内插管直接监测胸腔内的压力变化,以便能够测量和显示气管与胸腔之间的压力差异。利用数字电子呼吸分析仪,从气流和跨肺压力的这些测量结果计算每一呼吸周期的气道耐受性(R1 cmH2O/l/s)和顺应性(Cddyn)。利用压力传感器从颈动脉记录血压和心率。
当基础耐受性和顺应性都稳定时,利用辣椒碱的静脉内大丸剂诱导支气管痉挛的急性发作。将辣椒碱溶于100%乙醇,用磷酸盐缓冲盐水稀释。当对辣椒碱的响应稳定时给以本发明的供试治疗剂组合,这是在2-3次这样的给药后计算得到的,间隔10min。在气管内或十二指肠内滴注或者静脉内大丸剂注射之后,历经1-8小时评估支气管痉挛的逆转。支气管解痉活性表示为辣椒碱输注后最初的、最大耐受性(RD)的抑制%。ED50值代表导致辣椒碱诱导的耐受性增加降低50%的剂量。作用的持续时间被定义为支气管痉挛被减少50%或以上的时间,按分钟计。对血压(BP)和心率(HR)的影响是以ED20值表示的,也就是在给药后5min测量的减少BP或HR达20%的剂量。
在上述试验模型中,本发明的治疗剂组合通常在0.001至0.1mg/kgi.t.[气管内]的剂量范围下表现出支气管扩张活性。进而,i.t.给药的组合对支气管痉挛表现出至少为加合性的抑制效果,每种组分单独能够抑制50%以上所观察到的对照响应。
LPS诱导的肺嗜中性白细胞增多——肺内嗜中性白细胞的募集和活化被视为COPD和严重气喘的重要病理特征。所以,动物中这些终点之一或之二的抑制提供了本发明实用性的支持性证据。
将雄性Wistar-Albino大鼠(150-250g)或雄性Dunkin-Hartley豚鼠(400-600g)用单独或联合的供试物预处理,在简单的全身麻醉下吸入或者气管内(i.t.)滴注。化合物给药1-24小时后,动物受到细菌脂多糖(LPS)吸入气雾剂的攻击,足以在随后的1-24小时内诱导明显的肺嗜中性白细胞增多。计数支气管洗液中的细胞或者测定肺洗液或组织中的嗜中性白细胞产物,评估嗜中性白细胞增多。在这种试验系统中,本发明的治疗剂通常在0.0001至0.1mg/kg i.t.的剂量范围下表现出抗炎活性。意外的是,i.t.给药的组合对炎症发挥至少为加合性的效果,尽管两种组分之一本身都不发挥显著的抗炎效果。进而,在如本发明那样联合使用时,利用更低的剂量能够观察到高剂量组分之一的等价抗炎效果,从而减少了所不希望的全身效果。
变应性豚鼠测定法——利用Dunkin-Hartley豚鼠(400-600g体重)评价本发明治疗剂组合对呼吸困难和支气管痉挛症状(即呼吸困难或吃力,肺耐受性增加)和炎症症状(即肺嗜中性白细胞增多和嗜曙红细胞增多)的治疗影响的实验。
用在本试验中的结晶与冻干的V级卵清蛋白(EA)、氢氧化铝和马来酸美吡拉敏是商业上可得到的。攻击和随后的呼吸结果读取是在透明塑料盒中进行的,内部尺寸为10×6×4英寸。盒盖和盒体是可以分开的。在使用时将二者用夹子紧紧夹在一起,用软橡胶垫圈维持盒子空间之间的气密密封。通过盒子空间的头端中心,经由气密密封插入雾化器,盒子的每个末端也具有出口。将呼吸速度描记器插入盒子的一个末端,与体积压力传感器连接,然后通过适当的连接器与轨道描记器(dynograph)连接。在雾化抗原的同时,出口是打开的,呼吸速度描记器与盒子空间是分离的。然后关闭出口,在记录呼吸方式期间连接呼吸速度描记器与盒子空间。在攻击时,将2ml 3%抗原的盐水溶液置于每支雾化器内,利用空气生成气雾剂,空气来自小型隔膜泵,在10psi下操作,流速8l/min。
皮下和i.p.注射含有1mg EA和200mg氢氧化铝的1ml盐水悬液,使豚鼠敏感化。在致敏后12与24天之间使用它们。为了消除响应中的组胺因素,在气雾剂攻击之前30min将豚鼠用2mg/kg美吡拉敏i.p.预处理。然后使豚鼠暴露于3% EA的盐水气雾剂达精确的1min,然后记录呼吸曲线达30min。随后,历经1-48小时测定死亡后的肺部炎症。从呼吸记录结果测量连续的呼吸困难持续时间。
本发明的供试治疗剂组合一般是在攻击之前0.5-4小时i.t.给药或借助气雾剂给药的。将化合物的组合溶于盐水或生物相容性溶剂。与载体处理的对照组相比,在它们减少呼吸困难和支气管痉挛症状的幅度和持续时间和/或肺部炎症的幅度的能力的基础上测定化合物的活性。在一系列剂量下评价本发明治疗剂组合的试验,推导出ED50,它被定义为抑制症状持续时间达50%的剂量(mg/kg)。
抗炎活性——借助对嗜曙红细胞或嗜中性白细胞活化的抑制作用,证明本发明治疗剂组合的抗炎活性。在本测定法中,从嗜曙红细胞数在0.06与0.47×109L-1之间的非特应性志愿者采集血样(50ml)。将静脉血收集到含有5ml柠檬酸三钠(3.8%,pH7.4)的离心管内。
在50ml离心管内,将抗凝处理后的血液用磷酸盐缓冲盐水(PBS,既不含钙也不含镁)稀释(1∶1,v∶v),在15ml等渗Percoll(密度1.082-1.085g/ml,pH7.4)上分层。离心(30min,1000×g,20℃)后,小心地抽吸血浆/Percoll界面上的单核细胞,弃去。
将嗜中性白细胞/嗜曙红细胞/红细胞吐弃块(体积约5ml)轻轻地重新悬浮在35ml等渗氯化铵溶液中(NH4Cl,155mM;KHC03,10mM;EDTA,0.1mM;0-4℃)。15min后,将细胞在含有胎牛血清(2%,FCS)的PBS中洗涤两次(10min,400×g,4℃)。
利用磁细胞分离系统分离嗜曙红细胞和嗜中性白细胞。这种系统能够根据表面标记分离悬液中的细胞,包含一个永磁体,其中放置包括可磁化钢基质的柱子。使用前,将柱子用PBS/FCS平衡1小时,然后经由20ml注射器用冰冷的PBS/FCS逆向冲洗。21G皮下针头连接于柱子底部,使1-2ml冰冷的缓冲液从针头中流出。
粒细胞的离心之后,抽吸上清液,将细胞用100μl磁粒(抗-CD16单克隆抗体,与超顺磁粒子缀合)轻轻地重新悬浮。将嗜曙红细胞/嗜中性白细胞/抗-CD16磁粒混合物在冰上培育40min,然后用冰冷的PBS/FCS稀释至5ml。向柱子顶部缓慢引入细胞悬液,打开龙头,使细胞缓慢移动到钢基质。然后将柱子用PBS/FCS(35ml)洗涤,后者是被小心地加入到柱子顶部的,以避免扰乱已被捕集在钢基质内的磁标记嗜中性白细胞。在50ml离心管内收集未标记的嗜曙红细胞,洗涤(10min,400×g,4℃)。将所得吐弃块重新悬浮在5ml Hank氏平衡盐溶液(HBSS)中,以便能够在使用前评估细胞数和纯度。从磁体上取下分离柱,洗脱嗜中性白细胞部分。然后将柱子用PBS(50ml)和乙醇(绝对)洗涤,贮存在4℃下。
利用微量细胞计数器计数全体细胞。向样本加入一滴溶原溶液,30秒后重新计数,以评估红细胞的污染。在Shandon Cytospin 2细胞自旋仪上制备细胞自旋血涂片(100μl样本,3min,500rpm)。将这些制备物染色,利用光学显微镜测定差示细胞数,检查至少500个细胞。借助台盼蓝的排除评估细胞活力。
将嗜曙红细胞或嗜中性白细胞稀释在HBSS中,吸移至96孔微量滴定板(MTP),每孔1-10×103个细胞。每孔含有200μl样本,其中包含:100μl细胞悬液;50μl HBSS;10μl硝酸双-N-甲基吖啶;20μl活化刺激物;和20μl供试化合物。
将样本与供试化合物或载体培育10min,然后加入活化刺激物fMLP(1-10μM)或C5a(1-100nM)的二甲基亚砜溶液,然后稀释在缓冲液中,以便所用最高溶剂浓度为1%(100μM供试化合物)。搅拌MTPs,促进细胞与介质的混合,将MTP置于发光计中。历经20min同时测量每孔的总化学发光和瞬时曲线,结果以任意单位表示,或者以在没有供试化合物的存在下fMLP诱导化学发光的百分率表示。将结果带入Hill方程,自动计算IC50值。
在上述试验方法中,本发明的治疗剂组合通常在0.0001μM至0.5μM的浓度范围下是有活性的,优选的实施方式是在0.1nM至100nM的浓度范围下是有活性的。
借助对血浆外渗至大鼠气道内的抑制作用,另外证明了本发明的治疗剂组合的抗炎活性。在这种测定法中,取气管组织,测定血浆渗漏的程度。这种测定法同样涉及气道的其他慢性炎性疾病,包括但不限于COPD,因此该节没有赘述。
将Wistar白化病大鼠(150-200g)或Dunkin-Hartley豚鼠(450-600g)用戊巴比通钠麻醉,安装静脉和动脉插管。将与血浆蛋白质结合的伊凡斯蓝染剂i.v.给药(30mg/kg)。10min后,将供试物i.t.给药,10min后,将辣椒碱i.v.给药(3μg/kg)。30min后,除去气管组织,用甲酰胺提取过夜,在620nm下读取吸光度。在有些实验中,给药的顺序是相反的,以便在伊凡斯蓝和炎性刺激物之前将化合物给药。
在上述试验模型中,本发明的治疗剂组合通常在0.001至0.1mg/kgi.t.的剂量范围下表现出抗炎活性。
从上文可以看到,本发明的治疗剂组合可用于治疗炎性或阻塞性气道疾病或者其他牵涉气道阻塞的病症。确切而言它们可用于治疗支气管气喘。
鉴于它们的抗炎活性和它们对气道反应性过高的影响,本发明的治疗剂组合可用于治疗阻塞性或炎性气道疾病,确切为预防性处置。因而,通过长时间连续的规律性给药,本发明的化合物组合可用于提供防止继发于阻塞性或炎性气道疾病的支气管收缩或其他症状发作的预先保护作用。本发明的化合物组合也可用于控制、改善或逆转这类疾病的基础状态。
考虑到它们的支气管扩张活性,本发明的治疗剂组合可用作支气管扩张剂,例如治疗慢性或急性支气管收缩,和用于阻塞性或炎性气道疾病的对症治疗。
本发明适用的阻塞性或炎性气道疾病包括气喘;尘肺病;慢性嗜曙红细胞性肺炎;慢性阻塞性气道或肺疾病(COAD或COPD);和成人呼吸窘迫综合征(ARDS),以及气道反应性过高因其他药物疗法而恶化,例如阿司匹林或β-激动剂疗法。
本发明的选择性PDE4抑制剂和肾上腺素能β2受体激动剂可以被单独或联合给药,但是一般将是与适合的药物赋形剂、稀释剂或载体混合给药的。
本发明的选择性PDE4抑制剂和肾上腺素能β2受体激动剂优选地通过吸入给药,适宜以干粉吸入剂形式(单独或作为混合物,例如与乳糖的混合物)从干粉吸入器中或以气雾剂的形式从加压容器、泵、喷雾器、雾化器(atomiser)(优选为利用电子水力学产生微细烟雾的atomiser)或雾化器(nebuliser)中释放出来,释放利用或者不用适合的推进剂,例如二氯二氟甲烷、三氯氟代甲烷、二氯四氟乙烷、氟代烷烃,例如1,1,1,2-四氟乙烷(HFA 134ATM)或1,1,1,2,3,3,3-七氟丙烷(HFA227EATM),二氧化碳、另外的全氟代烃,例如PerflubronTM或其他适合的气体。在加压气雾剂的情况下,借助计量释放的阀门可以确定剂量单位。加压容器、泵、喷雾器、atomiser或nebuliser可以含有活性化合物的溶液或悬液,例如使用乙醇(可选为含水乙醇)或适合于分散、增溶或延时释放的试剂与推进剂的混合物作为溶剂,其中可以另外含有润滑剂,例如脱水山梨醇三油酸酯。用在吸入器或吹入器中的胶囊、泡眼和药筒(例如由明胶或HPMC制成)可以被配制成含有本发明化合物与适合的粉末基质和性能改进剂的粉末混合物,前者例如乳糖或淀粉,后者例如L-亮氨酸、甘露糖醇或硬脂酸镁。
在用在吸入用干粉制剂或混悬制剂之前,本发明化合物将被微粉化为适合于吸入释放的大小(通常认为小于5微米)。微粉化可以借助多种方法实现,例如螺旋喷射研磨、流体床喷射研磨或使用超临界流体结晶。
适合用在利用电子水力学产生微细烟雾的atomiser中的溶液制剂每启动体积可以含有1μg至10mg本发明化合物,启动体积可以从1至100μl不等。典型的制剂可以包含本发明化合物、丙二醇、无菌水、乙醇和氯化钠。可用另外的溶剂代替丙二醇,例如甘油或聚乙二醇。
气雾剂或干粉制剂优选地是这样安排的,每计量剂量或“每揿”含有1至4000μg本发明化合物,用于释放给患者。总的每日气雾剂剂量将在1μg至20mg的范围内,每天可以给药一次,或者更通常为分次给药。
所用的选择性PDE4抑制剂:肾上腺素能β2受体激动剂的优选重量比(w/w)将取决于所检查的特定组合。这是由于个别化合物的效力差异。无论如何,医师将决定每种化合物最适合于任何个别患者的实际剂量,它将因特定患者的年龄、体重和反应而异。
不言而喻,本文关于治疗的所有提法包括治愈、减轻和预防性处置。
试验数据-弹性蛋白酶从离体人嗜中性白细胞中释放的抑制作用
将来自男女健康志愿者的静脉血(90ml)收集在10ml 3.8%(w/v)枸橼酸钠中,将8ml等分试样分配在15ml聚丙烯离心试管内,每支含有4ml 6%葡聚糖(平均分子量148,000)的Hanks平衡盐溶液(HBSS)。轻轻颠倒试管使葡聚糖/血液混合,在室温下放置45分钟,以便红细胞沉降。在50ml聚丙烯离心试管内,将来自白细胞富集性上清液的16ml等分试样覆盖在10ml Ficoll-Hypaque垫上,在21℃下将试管在400g下离心35min。除去血浆、单核细胞层和Ficoll,留下粒细胞富集性吐弃块。将吐弃块首先重新悬浮在10ml冰冷的蒸馏水中达45秒,以溶解污染性红细胞,继之以向每支试管加入10ml冰冷的双重浓缩磷酸盐缓冲盐水(PBS)溶液,以恢复摩尔渗透压浓度。在4℃下将悬液在200g下重新离心10min,生成嗜中性白细胞吐弃块。除去上清液,利用Pasteur吸移管将吐弃块轻轻地重新悬浮在总体积10ml的冰冷HBSS中。利用Beckman Coulter Ac.T5血液学分析仪,对所得嗜中性白细胞悬液进行微分白细胞计数,将细胞贮存在冰上直至测定。在测定前不久,取出嗜中性白细胞悬液的等分试样,在含有2U/ml腺苷脱氨酶的冰冷HBSS中稀释至4×106嗜中性白细胞/ml。
在96孔聚苯乙烯微量滴定板中使用160μl测定体积实现fMLP诱导弹性蛋白酶释放的抑制作用。通过测量合成底物MeOSuc-Ala-Ala-Pro-Val-ρNA的裂解速率,测定弹性蛋白酶的释放。就弹性蛋白酶释放的测量而言,测定孔含有8μl 100μg/ml细胞松弛素B(10% DMSO/90% HBSS中)、8μl供试化合物(稀释在HBSS中)、40μl嗜中性白细胞悬液和96μl 156μM MeOSuc-Ala-Ala-Pro-Val-ρNA(HBSS中)。将测定板在37℃下培育10分钟,然后加入8μl 2μM fMLP(HBSS中),在37℃下在λ=405nm下测量底物裂解的速率达3分钟。加入8μlHBSS代替fMLP,测定基础弹性蛋白酶释放。下表1数据为IC50值,也就是达到fMLP-诱导弹性蛋白酶释放的50%抑制作用所需的活性药物浓度(nM)。在联合实验的情况下,向测定中加入1000nM 9-环戊基-5,6-二氢-7-乙基-3-(2-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶(C),然后从福莫特罗(F)或沙美特罗(S)生成浓度响应曲线。
表1-弹性蛋白酶释放的抑制作用(IC50值,nM)
F | S | C | F+C | S+C |
>1000 | >1000 | >1000 | 0.4 | 1.0 |
β2激动剂(福莫特罗或沙美特罗)与PDE4抑制剂(9-环戊基-5,6-二氢-7-乙基-3-(2-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶)的联合应用已证明产生对促炎性嗜中性白细胞功能的协同抑制作用。采用这些药理试剂的个别治疗达到了对fMLP-诱导弹性蛋白酶从离体人嗜中性白细胞中释放的弱抑制作用(μM),它们的联合应用戏剧性地增强了这种抑制作用至非常强大(nM)。
Claims (17)
1、下列(a)与(b)的吸入组合:
(a)式(I)选择性PDE4抑制剂
或者其药学上可接受的盐或溶剂化物,其中:
R1是H、(C1-C6)烷基、(C1-C6)烷氧基、(C2-C4)链烯基、苯基、-N(CH3)2、(C3-C6)环烷基、(C3-C6)环烷基(C1-C3)烷基或(C1-C6)酰基,其中该烷基、苯基或链烯基可以被至多两个-OH、(C1-C3)烷基或-CF3基团或者至多三个卤素取代;
R2和R3各自独立地选自由H、(C1-C14)烷基、(C1-C7)烷氧基(C1-C7)烷基、(C2-C14)烯基、(C3-C7)环烷基、(C3-C7)环烷基(C1-C2)烷基、饱和或不饱和的(C4-C7)杂环(CH2)n基团组成的组,其中n是0、1或2,含有一个或两个氧、硫、磺酰基、氮和NR4作为杂原子,其中R4是H或(C1-C4)烷基;或者式(II)基团:
其中a是整数1至5;b和c是0或1;R5是H、-OH、(C1-C5)烷基、(C2-C5)链烯基、(C1-C5)烷氧基、(C3-C6)环烷氧基、卤素、-CF3、-CO2R6、-CONR6R7、-NR6R7、-NO2或-SO2NR6R7,其中R6和R7各自独立地是H或(C1-C4)烷基;Z是-O-、-S-、-SO2-、-CO-或-N(R8)-,其中R8是H或(C1-C4)烷基;Y是(C1-C5)亚烷基或(C2-C6)亚烯基,可选地被至多两个(C1-C7)烷基或(C3-C7)环烷基取代;其中每个烷基、链烯基、环烷基、烷氧基烷基或杂环基团可以被1至14个、优选1至5个(C1-C2)烷基、CF3或卤代基团取代;
R9和R10各自独立地选自由H、(C1-C6)烷基、(C1-C6)烷氧基、(C6-C10)芳基和(C6-C10)芳氧基组成的组;
和(b)肾上腺素能β2受体激动剂。
2、如权利要求1所要求保护的组合,其中R1是甲基、乙基或异丙基。
3、如权利要求1或权利要求2所要求保护的组合,其中R3是(C1-C6)烷基、(C2-C6)链烯基、(C3-C7)环烷基、(C3-C7)环烷基(C1-C6)烷基或苯基,可选地被1或2个基团取代,取代基选自H、-OH、(C1-C5)烷基、(C2-C5)链烯基、(C1-C5)烷氧基、卤素、三氟甲基、-CO2R6、-CONR6R7、-NR6R7、-NO2或-SO2NR6R7,其中R6和R7各自独立地是H或(C1-C4)烷基。
4、如在先权利要求任意一项所要求保护的组合,其中式(I)选择性PDE4抑制剂选自:
9-环戊基-5,6-二氢-7-乙基-3-苯基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(呋喃-2-基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-吡啶基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(4-吡啶基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(3-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
3-苄基-9-环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-丙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
3,9-二环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(1-甲基环己-1-基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
3-(叔丁基)-9-环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-甲基苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-甲氧基苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(噻吩-2-基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
3-(2-氯苯基)-9-环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-碘苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-三氟甲基苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;和
5,6-二氢-7-乙基-9-(4-氟苯基)-3-(1-甲基环己-1-基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶;
和其药学上可接受的盐和溶剂化物。
5、如权利要求4所要求保护的组合,其中式(I)选择性PDE4抑制剂选自9-环戊基-5,6-二氢-7-乙基-3-(2-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶和9-环戊基-5,6-二氢-7-乙基-3-(叔丁基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶和其药学上可接受的盐和溶剂化物。
6、如在先权利要求任意一项所要求保护的组合,其中该肾上腺素能β2受体激动剂选自沙美特罗、福莫特罗和其药学上可接受的盐和溶剂化物。
7、如权利要求1所要求保护的组合,其中:
式(I)选择性PDE4抑制剂是9-环戊基-5,6-二氢-7-乙基-3-(2-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶或其药学上可接受的盐或溶剂化物,且肾上腺素能β2受体激动剂是沙美特罗或其药学上可接受的盐或溶剂化物;
式(I)选择性PDE4抑制剂是9-环戊基-5,6-二氢-7-乙基-3-(2-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶或其药学上可接受的盐或溶剂化物,且肾上腺素能β2受体激动剂是福莫特罗或其药学上可接受的盐或溶剂化物;
式(I)选择性PDE4抑制剂是9-环戊基-5,6-二氢-7-乙基-3-(叔丁基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶或其药学上可接受的盐或溶剂化物,且肾上腺素能β2受体激动剂是沙美特罗或其药学上可接受的盐或溶剂化物;
式(I)选择性PDE4抑制剂是9-环戊基-5,6-二氢-7-乙基-3-(叔丁基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]吡啶或其药学上可接受的盐或溶剂化物,肾上腺素能β2受体激动剂是福莫特罗或其药学上可接受的盐或溶剂化物。
8、用作药剂的如任意在先权利要求所要求保护的组合。
9、用于在阻塞性气道或其他炎性疾病治疗中同时、先后或单独给药的如权利要求1至7任意一项所要求保护的组合。
10、药物组合物,包含如权利要求1所定义的式(I)选择性PDE4抑制剂、肾上腺素能β2受体激动剂和药学上可接受的赋形剂、稀释剂或载体,用于在阻塞性气道或其他炎性疾病治疗中借助吸入途径给药。
11、如权利要求10所定义的药物组合物,其中式(I)选择性PDE4抑制剂和肾上腺素能β2受体激动剂是如权利要求2至7任意一项所定义的。
12、如权利要求1所定义的式(I)选择性PDE4抑制剂或肾上腺素能β2受体激动剂在药剂制造中的用途,该药剂用于在阻塞性气道或其他炎性疾病治疗中借助吸入途径同时、先后或单独给以这两种药物。
13、权利要求12的用途,其中式(I)选择性PDE4抑制剂和肾上腺素能β2受体激动剂是如权利要求2至7任意一项所定义的。
14、治疗阻塞性气道或其他炎性疾病的方法,包含借助吸入途径对需要这类治疗的哺乳动物同时、先后或单独给以有效量的如权利要求1所定义的式(I)选择性PDE4抑制剂和肾上腺素能β2受体激动剂。
15、如权利要求14所要求保护的方法,其中式(I)选择性PDE4抑制剂和肾上腺素能β2受体激动剂是如权利要求2至7任意一项所定义的。
16、吸入装置,用于在阻塞性气道或其他炎性疾病治疗中同时、先后或单独给以如权利要求1所定义的式(I)选择性PDE4抑制剂和肾上腺素能β2受体激动剂。
17、如权利要求16所要求保护的吸入装置,其中式(I)选择性PDE4抑制剂和肾上腺素能β2受体激动剂是如权利要求2至7任意一项所定义的。
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