CN1314811A - 治疗肺病的方法 - Google Patents
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Abstract
本发明涉及通过联合施用磷酸二酯酶4抑制剂与β肾上腺素能支气管扩张剂来治疗肺病例如慢性阻塞性肺病或哮喘。
Description
发明领域
本发明涉及预防或减轻肺病症状发作、或者治疗或减轻肺病严重性的组合物和方法。本发明尤其涉及通过施用PDE4抑制剂和其它影响肺功能的药物活性剂来治疗由磷酸二酯酶4(PDE4)介导的肺病的组合物和方法。
发明背景
由于有多种介质导致肺病发展，这使得鉴定治疗肺病的新治疗剂很困难。因此，消除单一介质的影响看上去似乎不可能对慢性哮喘的所有三种介质都起实质作用。替代“介质途径”的一种方法是调节导致肺病病理生理学的细胞的活性。
这类方法中的一种是提高cAMP(腺苷环3′,5′-一磷酸酯)的水平。已表明环AMP是调节对多种激素、神经递质和药物的生物反应的第二信使[Krebs Endocrinology Proceedings of the 4thInternational Congress Excerpta Medica,17-29,1973]。当适当激动剂结合到特定细胞表面受体上时，腺苷酸环化酶就被激活，从而以加快的速度将Mg2+-ATP转化成cAMP。
环cAMP调节大多数(如果不是全部的话)导致外因性(变应性)哮喘病理生理学的细胞的活性。因此提高cAMP水平将产生有益作用，包括：1)松弛气管平滑肌，2)抑制肥大细胞介质释放，3)抑制嗜中性白细胞脱粒，4)抑制嗜碱细胞脱粒，和5)抑制单核细胞与巨噬细胞活化。因此，激活腺苷酸环化酶或者抑制磷酸二酯酶的化合物能有效地抑制气管平滑肌和多种炎性细胞的不适当活化。导致cAMP失活的主要细胞机制是通过称为环核苷酸磷酸二酯酶(PDEs)的一个或多个家族的同工酶将3′-磷酸二酯键水解。
已表明环核苷酸磷酸二酯酶(PDE)同工酶PDE IV是导致气管平滑肌和炎性细胞中cAMP分解的原因[Torphy，“磷酸二酯酶同工酶：新抗哮喘剂的潜在目标”，New Drugs for Asthma,Barnes,ed.IBCTechnical Services Ltd.,1989]。研究表明，抑制该酶不仅能使气管平滑肌松弛，而且还能抑制肥大细胞、嗜碱细胞和嗜中性白细胞脱粒，以及抑制单核细胞和嗜中性白细胞的活化。此外，当靶细胞的腺苷酸环化酶活性被适当激素或内分泌物提高时(例如在体内)，可显著增强PDE IV抑制剂的有益作用。因此，PDE IV抑制剂能有效地作用于其中***素E2和***环素(腺苷酸环化酶的激活子)水平提高的肺。这类化合物将给支气管哮喘的药物治疗提供独一无二的途径，并且与目前市售的治疗剂相比，其具有显著的治疗优点。
此外，由于许多肺病的病因学牵涉多种介质，所以PDE IV抑制剂可用于联合治疗。本发明提供了治疗肺病、尤其是COPD或哮喘的PDE4抑制剂与吸入长效β激动剂的组合。
发明简述
在第一个方面，本发明涉及通过给患者施用有效量PDE4抑制剂与长效β肾上腺素能支气管扩张剂来治疗肺病的方法，其中所述PDE4抑制剂与长效β肾上腺素能支气管扩张剂是以单一组合方式、单独、或者其中顺序给药是紧接着或间隔长时间的单独且依次的方式给药。
在第二个方面，本发明涉及治疗肺病的组合物，其中包含有效量的PDE4抑制剂、有效量的长效β肾上腺素能支气管扩张剂和可药用赋形剂。
在第三个方面，本发明涉及制备能有效地预防肺病症状或治疗肺病的组合物的方法，所述方法包括将有效量的PDE4抑制剂和长效β肾上腺素能支气管扩张剂与可药用赋形剂混合。
发明详述
本发明联合治疗包括施用PDE4抑制剂和长效β肾上腺素能支气管扩张剂来预防肺病发作或者治疗已有的病症。这些化合物可以在单一剂型中一起施用。或者这些化合物可以在不同剂型中施用。这些化合物可以同时施用。或者这些化合物可以紧接着或者间隔长时间施用，例如一种药物是在早晨施用，另一种药物是在晚上施用。该联合治疗可以以预防为目的使用，或者可以在症状发作已经发生后使用。在某些情况下，可采用本发明联合治疗来阻止肺病的发展，或者阻止功能例如肺功能的下降。
适用于本发明的PDE4抑制剂可以是已知能抑制PDE4酶或者被发现起PDE4抑制剂作用、并且仅是PDE4抑制剂的所有化合物，而不是同时抑制其它PDE家族成员和PDE4的化合物。通常优选使用IC50比例为大约0.1或更大的PDE4拮抗剂，其中所述IC50比例是指对于以高亲和力结合环戊苯吡酮的PDE IV催化形式的IC50除以对于以低亲和力结合环戊苯吡酮的PDE IV催化形式的IC50而获得的比例。
在炎症治疗中使用并且用作支气管扩张剂的PDE抑制剂，例如茶碱和己酮可可碱在所有组织中都不加区别地抑制PDE同工酶。这些化合物表现出副作用，显然这是由于它们在所有组织中非选择性地抑制所有5种PDE同工酶所致。虽然这些化合物可以有效地治疗目标疾病，但是它们会带来不需要的次级作用，如果能避免这些次级作用或者将其降至最小的话，将能提高该方法的治疗一些疾病的整体疗效。例如，对于作为抗抑郁剂开发出的选择性PDE4抑制剂环戊苯吡酮的临床研究表明，其具有治疗精神病的活性，并且产生胃肠道反应例如胃灼热、恶心和呕吐。
据证明，对于抑制剂结合在其上面的人单核细胞重组PDE4(hPDE4)，至少有两种结合形式。对于这些观察结果的一种解释是，hPDE4以两种不同形式存在。一种形式以高亲和力结合环戊苯吡酮和旦布茶碱等类似化合物，另一种形式以低亲和力结合这些化合物。用于本发明的优选PDE4抑制剂是具有有益的治疗比例的这类化合物，即优先抑制cAMP催化活性(这时该酶呈以低亲和力结合环戊苯吡酮的形式)的化合物，由此降低了与抑制以高亲和力结合环戊苯吡酮的该酶形式有关的副作用。换句话说，优选的化合物具有大约0.1或更大的IC50比例，其中所述IC50比例是指对于以高亲和力结合环戊苯吡酮的PDE4催化形式的IC50除以对于以低亲和力结合环戊苯吡酮的PDE4催化形式的IC50而获得的比例。这类化合物的实例是：罂粟碱-1-[(3,4-二甲氧基苯基)甲基]-6,7-二甲氧基异喹啉；曲喹辛-2,3,6,7-四氢-2-(基亚氨基)-9,10-二甲氧基-3-甲基-4H-嘧啶并[6,1-a]异喹啉-4-酮；双嘧达莫-这是2,2′,2″,2-[(4,8-二哌啶基嘧啶并[5,4-d]嘧啶-2,6-二基)二次氮基]四乙醇的俗称；(R)-(+)-1-(4-溴苄基)-4-[(3-环戊基氧基)-4-甲氧基苯基]-2-吡咯烷酮；(R)-(+)-1-(4-溴苄基)-4-[(3-环戊基氧基)-4-甲氧基苯基]-2-吡咯烷酮；3-(环戊基氧基-4-甲氧基苯基)-1-(4-N′-[N2-氰基-S-甲基异硫脲基]苄基)-2-吡咯烷酮；顺-[4-氰基-4-(3-环戊基氧基-4-甲氧基苯基)环己烷-1-甲酸酯]；顺-[4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)环己烷-1-醇]；(R)-(+)-[4-(3-环戊基氧基-4-甲氧基苯基)吡咯烷-2-亚基]乙酸乙酯；(S)-(-)-[4-(3-环戊基氧基-4-甲氧基苯基)吡咯烷-2-亚基]乙酸乙酯。
最优选的是IC50比例大于0.5的PDE4抑制剂,特别是IC50比例大于1.0的化合物。优选的化合物是曲喹辛、双嘧达莫和罂粟碱。化合物例如顺-[氰基-4-(3-环戊基氧基-4-甲氧基苯基)环己烷-1-甲酸酯]、2-甲酯基-4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)环己烷-1-酮、和顺-[4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)环己烷-1-醇]是优先结合低亲和力结合位点、并且IC50比例为0.1或更大的结构的实例。
参考本申请人提交的未结案的美国申请08/456274(申请日为1995年5月31日)及其在1995年1月5日公开的母案PCT申请WO95/00139，该文献公开了用来鉴定高/低IC50比例为0.1或更大的化合物的方法和技术(该比例的定义如上所述)。本申请人提交的未结案的申请USSN 08/456274全文引入本发明以作参考。
上文中列出的没有俗称或商品名的几种具体化合物可通过在下述本申请人提交的未结案的美国专利申请中描述的方法制得：1992年10月30日提交的USSN 862083；1992年10月30日提交的USSN862111；1992年10月30日提交的USSN 862030；和1992年10月30日提交的USSN 862114或它们的后续申请或者要求一篇或多篇这些申请的优先权的美国专利。每一篇这些专利或相关专利都全文引入本发明以作参考。
在本发明中使用的β肾上腺素能支气管扩张剂，实际上是β2-肾上腺素能激动剂应当是长效化合物。所有这类化合物都可用于本发明联合治疗中。长效表示药物对支气管的作用持续大约6小时或更长，在某些情况下高达12小时。例如，一些间苯二酚如奥西那林、特布他林、和非诺特罗可以与PDE4抑制剂联合使用来实施本发明。适用的β肾上腺素能支气管扩张剂的其它实例是两个在结构上相关的化合物，沙丁胺醇{外消旋(∝1--[(叔丁基氨基)甲基]-4-羟基间二甲苯-∝,∝′--二醇)}和福莫特罗{(R*,R*)-(±)-N-[2-羟基-5-[1-羟基-2-[[2-(4-甲氧基苯基)-1-甲基乙基]乙基]苯基]甲酰胺}。
奥西那林是US 3341594的主题，并且可以以商品名Alotec、Alupent、Metaprel或Novasmasol商购获得。特布他林描述在US3938838中，并且可以以商品名Brethine从Novartis商购获得。US4341593中描述了非诺特罗的制备。非诺特罗有数种商品名，包括Airum、Berotec、Dosberotec和Partusisten。沙丁胺醇是以商标Proventil由Schering Corporation销售的。福莫特罗描述在US3994974中，并且可以以商品名Atock和Foradil商购获得。
优选的联合治疗是采用福莫特罗与顺-[氰基-4-(3-环戊基氧基-4-甲氧基苯基)环己烷-1-甲酸酯]的联合治疗。
这些药物-β激动剂一般是作为口或鼻用喷雾剂或气雾剂、或者作为吸入粉剂给药。这些药物通常不***给药或注射给药。PDE4抑制剂可口服给药或吸入给药(经口或鼻内吸入)。本发明涉及在一个递送形式例如将两种药物置于同一吸入器内的吸入器中一起施用两种药物。或者，可将PDE4抑制剂置于药丸中，并用包含β激动剂的吸入器包装所述药丸。制剂是本领域常识。
这两种活性剂可同时给药，或者以非常临近的时间给药。或者，可在早晨施用一种药物，在当天的晚些时候施用另一种药物。或者在另一方案中，一种药物可以每天给药2次，另一种每天给药1次，每天给药1次的药物可以与每天给药2次药物中的一次同时给药或者单独给药。这两种药物优选同时给药。
上述描述和实例是为了举例说明本发明，不是限制本发明。本发明人所要求保护的范围参考权利要求书。
Claims (4)
1．通过给患者施用有效量PDE4抑制剂与长效β肾上腺素能支气管扩张剂来治疗肺病的方法，其中所述PDE4抑制剂与长效β肾上腺素能支气管扩张剂是以组合方式、单独、或者其中顺序给药是紧接着或间隔长时间的单独且顺序的方式给药。
2．权利要求1的方法，其中所述PDE4抑制剂是顺-[4-氰基-4-(3-环戊基氧基-4-甲氧基苯基)环己烷-1-甲酸酯]，并且所述β激动剂是福莫特罗。
3．治疗肺病的组合物，其中包含有效量的PDE4抑制剂、有效量的长效β肾上腺素能支气管扩张剂和可药用赋形剂。
4．制备能有效地预防肺病症状或治疗肺病的组合物的方法，所述方法包括将有效量的PDE4抑制剂和长效β肾上腺素能支气管扩张剂与可药用赋形剂混合。
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- 1999-08-24 CZ CZ2001692A patent/CZ293735B6/cs not_active IP Right Cessation
- 1999-08-25 MA MA25745A patent/MA26302A1/fr unknown
- 1999-08-25 PE PE1999000856A patent/PE20001032A1/es not_active Application Discontinuation
- 1999-09-03 AR ARP990104234A patent/AR022072A1/es not_active Application Discontinuation
-
2001
- 2001-02-21 NO NO20010882A patent/NO20010882D0/no not_active Application Discontinuation
- 2001-08-20 US US09/933,455 patent/US6555583B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| TR200100500T2 (tr) | 2001-06-21 |
| US6555583B2 (en) | 2003-04-29 |
| AU5493999A (en) | 2000-03-21 |
| KR20010072931A (ko) | 2001-07-31 |
| US20010056122A1 (en) | 2001-12-27 |
| CZ293735B6 (cs) | 2004-07-14 |
| DZ2876A1 (fr) | 2003-12-15 |
| EP1107747A1 (en) | 2001-06-20 |
| AU754379B2 (en) | 2002-11-14 |
| MY126544A (en) | 2006-10-31 |
| US6288118B1 (en) | 2001-09-11 |
| WO2000012078A1 (en) | 2000-03-09 |
| NO20010882L (no) | 2001-02-21 |
| NO20010882D0 (no) | 2001-02-21 |
| AR022072A1 (es) | 2002-09-04 |
| NZ527232A (en) | 2005-03-24 |
| MA26302A1 (fr) | 2004-10-01 |
| BR9913152A (pt) | 2001-05-15 |
| HUP0103160A2 (hu) | 2002-01-28 |
| EP1107747A4 (en) | 2003-04-23 |
| CZ2001692A3 (cs) | 2002-02-13 |
| PE20001032A1 (es) | 2000-11-10 |
| PL346271A1 (en) | 2002-01-28 |
| HUP0103160A3 (en) | 2002-11-28 |
| JP2002523452A (ja) | 2002-07-30 |
| CA2341488A1 (en) | 2000-03-09 |
| IL141335A0 (en) | 2002-03-10 |
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| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
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