CN1202865C - 增效组合物 - Google Patents

增效组合物 Download PDF

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CN1202865C
CN1202865C CNB008118493A CN00811849A CN1202865C CN 1202865 C CN1202865 C CN 1202865C CN B008118493 A CNB008118493 A CN B008118493A CN 00811849 A CN00811849 A CN 00811849A CN 1202865 C CN1202865 C CN 1202865C
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pde inhibitor
adrenoceptor agonists
inhibitor
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R·伯伊梅
D·邦舒
A·哈策尔曼
C·舒德特
C·韦马
U·基利恩
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Abstract

本发明涉及组合施用PDE抑制剂和β2肾上腺素受体激动剂以治疗呼吸道疾病。

Description

增效组合物
本发明的应用领域
本发明涉及用于治疗的一些已知活性化合物的组合物。
在本发明的组合物中使用的物质是属于PDE抑制剂的已知活性化合物和属于β2肾上腺素受体激动剂的活性化合物。现有技术中还未曾提到在本发明意义上的它们在治疗中的组合使用。
发明的描述
本发明的目的是制备满足以下条件的可利用的呼吸道治疗剂：
良好的消炎作用
显著的支气管松驰和扩张作用
至少就PDE抑制剂而言，良好的口服有效性
最小的副作用
对于长期治疗的良好适用性
对支气管反应过度有良好的影响
现已发现，可以作为呼吸道治疗剂使用的PDE抑制剂与β2肾上腺素受体激动剂的组合使用，出色地满足了上述条件。
因此，本发明涉及可以作为呼吸道治疗剂使用的PDE抑制剂和一种β2肾上腺素受体激动剂在治疗呼吸道疾病中的组合使用。
就本发明而言，可以作为呼吸道治疗剂使用的PDE抑制剂是通过抑制磷酸二酯酶减慢环腺苷酸(cAMP)或环乌苷酸(cGMP)的破坏的那些化合物，它们能造成cAMP或cGMP的胞内浓度的相对增高。
本发明意义内的可能的PDE抑制剂主要是被认为属于PDE4抑制剂的物质和被称作混合型PDE3/4抑制剂的物质。例如，可以提到在以下专利申请和专利中描述或提出要求的那些PDE抑制剂：DE1545687，DE2028869，DE2123328，DE2315801，DE2402908，DE2413935，DE3900233，EP0103497，EP0139464，EP0158380，EP0163965，EP0335386，EP0389282，EP0428302，EP0435811，EP0459505，EP0470805，EP0490823，EP0506194，EP0511865，EP0527117，EP0557016，EP0626939，EP0664289，EP0671389，EP0685474，EP0685475，EP0685479，EP0736532，EP0738715，EP0748805，EP0763534，EP0816357，EP0819688，EP0819689，EP0832886，EP0834508，EP0848000，JP92234389，JP94329652，JP95010875，JP98072415，JP98147585，US5703098，US5739144，WO9117991，WO9200968，WO9212961，WO9307146，WO9315044，WO9315045，WO9318024，WO9319068，WO9319720，WO9319747，WO9319749，WO9319751，WO9325517，WO9402465，WO9412461，WO9420455，WO9422852，WO9427947，WO9501338，WO9501980，WO9503794，WO9504045，WO9504046，WO9505386，WO9508534，WO9509623，WO9509624，WO9509627，WO9509836，WO9514667，WO9514680，WO9514681，WO9517392，WO9517399，WO9519362，WO9520578，WO9522520，WO9524381，WO9527692，WO9535281，WO9535283，WO9535284，WO9600218，WO9601825，WO9606843，WO9611690，WO9611917，WO9612720，WO9631486，WO9631487，WO9635683，WO9636595，WO9636596，WO9636611，WO9636625，WO9636638，WO9638150，WO9639408，WO9640636，WO9703967，WO9704779，WO9705105，WO9708143，WO9709345，WO9712895，WO9718208，WO9719078，WO9720833，WO9722585，WO9722586，WO9723457，WO9723460，WO9723461，WO9724117，WO9724355，WO9725312，WO9728131，WO9730999，WO9731000，WO9732853，WO9735854，WO9736905，WO9743288，WO9744036，WO9744322，WO9747604，WO9748697，WO9804534，WO9805327，WO9806692，WO9806704，WO9807715，WO9808828，WO9808830，WO9808841，WO9808844，WO9809946，WO9809961，WO9811113，WO9814448，WO9818796，WO9821208，WO9822453，WO9845268，WO9855481，WO9856756，WO9905111，WO9905112，WO9505113，WO9906404和WO9918095.
应该强调的是在以下专利申请或专利中提出要求的那些PDE抑制剂：EP0393500，EP0510562，EP0553174，WO9501338，WO9603399，WO9636625，WO9636626，WO9735854，WO9821208，WO9831674，WO9840382，WO9855481，WO9905111，WO9905112，WO9905113，WO9931071和WO9931090.
本发明优选具有良好的口服有效性的物质。
以下几页通过其化学式列出典型的PDE抑制剂：
Figure C0081184900051
Figure C0081184900071
Figure C0081184900091
Figure C0081184900101
Figure C0081184900121
BYK-33043
(Pumafentrin)
Figure C0081184900151
Roflumilast
Figure C0081184900161
以上化学式中未标出氢原子。因此-O是-OH，-N是NH2。甲基，例如氧原子上的甲基，用线表示。
选自以上化合物的应该强调说明的PDE抑制剂是以下活性化合物：arofyline，atizoram，AWD-12-281，BAY-19-8004，苯芬群，BYK-33043，CC-3052，CDP-840，CI-1018，cipamfylline，CP-220629，CP-293121，D-22888，D-4396，D-4418，旦布茶碱，filaminast，GW-3600，异丁地特，KF-17625，KS-506-G，拉普茶碱，NA-0226A，NA-23063A，0RG-20241，0RG-30029，PDB-093，己酮可可碱，piclamilast，roflumilast，环戊苯吡酮，RPR-117658，RPR-122818，RPR-132294，RPR-132703，RS-17597，RS-25344-000，SB-207499，SB-210667，SB-211572，SB-211600，SB-212066，SB-212179，SDZ-ISQ-844，SDZ-MNS-949，SKF-107806，SQ-20006，T-2585，T-440，
替贝拉特，tolafentrine，UCB-29646，V-11294A，YM-58997，YM-976和扎达维林。
上述PDE抑制剂中优选的化合物是arofylline，cipamfylline，D-4418，filaminast，异丁地特，拉普茶碱，ORG-20241，piclamilast，环戊苯吡酮，SB-207499，替贝拉特和V-11294A。特别优选的化合物是BYK-33043，尤其是roflumilast。
特别应该提到的β2肾上腺素受体激动剂是选择性作用的物质，它们对心脏仅有轻微的作用，因此也用于治疗，特别是呼吸道疾病的口服治疗。可以提到的β2肾上腺素受体激动剂的实例有：AR-C68397AA，溴噁特罗，CHF-1035，HOKU-81，三丁喘宁，KUL-1248，甲磺喘宁，meluadrine，TA-2005，噻拉米特，舒喘灵，左旋舒喘灵，氯丁喘胺，特布他林，脲喘宁，吡布特罗，利浦特罗，克喘素，酚丙喘宁，异丙喘宁，间羟异丙肾上腺素，异丙肾上腺素，福莫特罗，沙美特罗，哌喘啶，丙卡特罗，班布特罗，比托特罗和马布特罗。优选容易口服的β2肾上腺素受体激动剂，例如克喘素，间羟异丙肾上腺素，舒喘灵，特布他林，氯丁喘胺，班布特罗和利浦特罗。特别优选的是所谓的长效β2肾上腺素受体激动剂，例如沙美特罗。
PDE抑制剂和β2肾上腺素受体激动剂可以原样存在或者以化学上键合的形式存在。当然，所说的活性化合物也可以例如以其药理上可容许的盐和/或溶剂化物(例如水合物)和/或以N-氧化物等形式存在。合适的药理上容许的盐特别是与酸形成的水溶性或水不溶性盐，酸的实例包括：盐酸、氢溴酸、磷酸、硝酸、硫酸、乙酸、柠檬酸、D-葡糖酸、苯甲酸、2-(4-羟基苯甲酰)苯甲酸、丁酸、磺基水杨酸、马来酸、月桂酸、苹果酸、富马酸、琥珀酸、草酸、酒石酸、双羟萘酸、硬脂酸、甲苯磺酸、甲磺酸或1-羟基-2-萘甲酸。根据是一元酸还是多元酸，以及所要求的是何种盐，在制备盐时使用等摩尔定量比例的酸或是不同比例的酸。另外，所述的活性化合物也可以以纯对映体形式或任何混合比例的对映体混合物的形式存在。
可以提到的呼吸道疾病特别包括变态反应原和炎症诱发的支气管病(支气管炎、阻塞性支气管炎、痉挛性支气管炎、过敏性支气管炎、过敏性哮喘、支气管哮喘、慢性阻塞性肺病(COPD))，它们可以在长期治疗的意义上利用本发明的组合物治疗(需要时适当调节各个组分的剂量以适应当时的需要，例如与季节有关的变化需要)。
在本发明的含义内，“组合使用”或“组合”应理解为各个组分可以以已知的和惯用的方式，同时服用(以组合药物的形式)、大体上同时服用(各自分离的包装单元)或顺序服用(直接依次服用，或以相当长时间间隔交替服用)。
在本发明的含义内，“使用”优先指口服两种活性化合物。如果只有PDE抑制剂是口服用药，则对于β2肾上腺素受体激动剂，“使用”特别意味着以吸入的形式局部给药。为此，β2肾上腺素受体激动剂优选以气溶胶的形式用药，该固体、液体或混合组合物的气溶胶颗粒的直径为0.5-10μm，最好为2-6μm。
气溶胶的生成可用例如压力驱动的喷雾器或超声雾化器进行，但最好是利用推进剂驱动的计量式气溶胶装置或无推进剂地施用吸入式胶囊中的微粒化活性化合物。
活性化合物以大约为各自常用剂量的量用药考虑到各自的作用会彼此正面影响和增效，与标准量相比，在活性化合物组合用药时，很可能可以减少各自的剂量。通常，β2肾上腺素受体激动剂(根据效力)在吸入式给药时剂量为每天0.002-2.0mg。
根据使用的吸入器系统，除了活性化合物之外，给药方式中还含有所需的赋形剂，例如，推进剂(如计量式气溶胶装置中的氟利根)、表面活性物质、乳化剂、稳定剂、防腐剂、矫味剂、填料(如粉末吸入器中的乳糖)，或者，适当时的其它活性化合物。
对于吸入给药，已经有许多种采用尽可能适合患者的吸入技术的装置可以用来产生和施用最佳粒度的气溶胶。除了使用适配器(垫圈、扩张器)和梨形容器(例如Nebulator、Volumatic)以及发出喷射烟雾的自动装置(Autohaler)之外，对于计量式气溶胶装置，特别是在粉末吸入器的情形，可以利用许多种现成的技术方法(例如Diskhaler、Rotadisk、Turbohaler或欧洲专利申请EP 0 505 321中描述的吸入器)实现活性化合物的最佳施用。
在β2肾上腺素受体激动剂与PDE抑制剂以优选的用药形式一起口服时，β2肾上腺素受体激动剂以例如0.05-60mg的日剂量用药。对于PDE抑制剂，在口服的情形，剂量可以随活性化合物的不同而在很宽的范围内变化，作为界限，可以由每公斤体重1-2000μg/kg的剂量开始。在服用优选的PDE抑制剂roflumilast的情形，剂量范围为每公斤体重2-20μg。
要口服的PDE抑制剂在适当时与β2肾上腺素受体激动剂一起，按照本领域技术人员熟悉的已知方法，配制成药物。使用药理活性化合物作为药物，优选与合适的药物赋形剂或载体相组合，制成片剂、包衣片剂、胶囊、乳剂、混悬剂或溶液剂等形式，活性化合物的含量宜为0.1-95％，通过适宜选择赋形剂和载体，有可能得到准确适合活性化合物和/或所要求的作用开始时间的药物施用形式(例如，持续释放型或肠溶型)。在本发明的以组合方式口服两种活性化合物的含义内，特别值得指出的是，口服型式(例如片剂或胶囊)中一部分β2肾上腺素受体激动剂和PDE抑制剂以非持续释放的形式存在，而另一部分(最好是较大部分)β2肾上腺素受体拮抗剂以持续释放的形式存在。
本领域技术人员基于其专门知识熟悉何种赋形剂或载体适合所要求的药物制剂。除了溶剂、成凝胶剂、片剂赋形剂和其它活性化合物载体之外，还可以使用例如抗氧化剂、分散剂、乳化剂、消泡剂、矫味剂、防腐剂、增溶剂、着色剂或渗透促进剂及络合剂(例如环糊精)。
                       药理学
模型
在卵白蛋白敏化/激发的挪威褐鼠中的晚期炎性呼吸道反应。
在卵白蛋白(OVA)敏化和OVA-激发的挪威褐鼠中测定Roflumilast、Pumafentrine(BYK-33043)和沙美特罗的消炎活性。在开始敏化后的第1、14、21和28天通过同时腹膜内注射百日咳博尔德杆菌(Bordetella Pertussis)悬浮液和皮下注射OVA/AHG悬浮液进行敏化，使有意识的褐色挪威鼠吸入气溶胶化的OVA溶液1小时(～20ml/小时)进行激发。使用未激发、只敏化的动物作为基线对照。在OVA激发前1小时气管内(i.t.)施用干粉状的药物(与乳糖充分混合)或安慰剂对照物(乳糖)。48小时后，将OVA激发或未激发的动物麻醉，每只动物用3×4mL BAL缓冲液进行支气管肺泡灌洗(BAL)。测定BAL流体中的总细胞数和嗜曙红细胞数，以及无细胞的BAL流体中的蛋白质浓度。计算药物引发的相对变化并利用JonckheereTerpstra试验法作统计分析。
结果
化合物   PDE3/4IC50[μmol]    剂量[μmol/kg]  施药途径   N                          浸润/积累的抑制％[中值/平均值  ±标准偏差]
总细胞数   EOS    蛋白质
Roflumilast ＞10/0.0007     0.3   it   8 -25-37.6±26.7  -15-22±25.7   -8-22.3±25.5
Pumafentrine   0.028/0.007     3   it   8 -19-39.1±30.5  -26-28.5±30.1   1723.5±10.6
沙美特罗     3   it   8 196.3±17.9  3931±14.8   4437.5±16.2
沙美特罗/Roflumilast     3/0.3   it   8 5034.5±21.1  67**61.1±7.9**   59**50.8±13.6**
沙美特罗/Pumafentrine     3/3   it   8 56*58.1±12.3*  85**83±3.7**   75**67.1±11.1**
p＜0.05， ** p＜0.01相对于未处理的、OVA激发的对照组
总结
分别以0.3μmol/kg和3μmol/kg的剂量气管内施用PDE抑制剂Roflumilast(PDE4抑制剂)和Pumafentrine(PDE 3/4抑制剂)对于细胞浸润和蛋白质积累未显示任何显著作用。得到的负值(趋势：发炎扩大)处在模型的生物变异性范围之内，因此，这些数据未必有意义。
相反，以3μmol/kg的剂量气管内施用长效β2-肾上腺素受体激动剂沙美特罗对于流入肺泡空间内的总细胞数及嗜曙红细胞数以及BAL流体内的蛋白质含量显示出抑制作用。然而，数据未达到显著性。
将PDE抑制剂Roflumilast或Pumafentrine与沙美特罗一起施用，与单独服用每一种化合物相比，产生了协同作用，即，与β2激动剂组合的两种PDE抑制剂都显示出BAL流体内嗜曙红细胞的显著抑制和蛋白质浓度的降低。PDE3/4抑制剂Pumafentrine和沙美特罗的组合在测得的所有参数方面都更有效(差别不显著)，另外，在抑制流入肺泡空间内的细胞总数方面表现出显著作用。

Claims (5)

1.一种口服给药的含有PDE抑制剂的药物，其中所述PDE抑制剂属于PDE4或PDE3/4抑制剂，它与β2肾上腺素受体激动剂以固定的组合物或自由的组合物的形式组合，其中PDE抑制剂是roflumilast、其药理上容许的盐和/或N-氧化物。
2.权利要求1的药物，该药物是固定的口服组合物。
3.权利要求1或2的药物，其中的β2肾上腺素受体激动剂是沙美特罗或其药理上容许的盐。
4.权利要求1或2的药物，其中β2肾上腺素受体激动剂是克喘素、间羟异丙肾上腺素、舒喘灵、特布他林、氯丁喘胺、班布特罗或利浦特罗，或它们的药理上容许的盐。
5.roflumilast用于生产与β2肾上腺素受体激动剂联合用药用于治疗呼吸道疾病的口服药物的用途。
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SK287231B6 (sk) 2010-04-07
DK1212089T3 (da) 2006-07-24
NO20020815D0 (no) 2002-02-19
BR0013478A (pt) 2002-04-30
AU6701600A (en) 2001-03-19
EA200200208A1 (ru) 2002-08-29
BRPI0013478B8 (pt) 2016-12-27
ES2260043T3 (es) 2006-11-01
JP5038568B2 (ja) 2012-10-03
KR20020020275A (ko) 2002-03-14
DE60043318D1 (de) 2010-01-14
IL147688A (en) 2007-09-20
NZ517166A (en) 2004-01-30
EP1212089A2 (en) 2002-06-12
ATE447952T1 (de) 2009-11-15
CN1370081A (zh) 2002-09-18
CA2381802A1 (en) 2001-03-01
NO328340B1 (no) 2010-02-01
HRP20020158B1 (en) 2007-08-31
US20040034087A1 (en) 2004-02-19
SI1212089T1 (sl) 2006-08-31
DE60026855D1 (de) 2006-05-11
WO2001013953A2 (en) 2001-03-01
EA006685B1 (ru) 2006-02-24
US7056936B2 (en) 2006-06-06
DE60026855T2 (de) 2006-12-07
HK1047244A1 (en) 2003-02-14

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