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US 2005O165041A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0165041 A1 Hanauer et al. (43) Pub. Date: Jul. 28, 2005 (54) COMBINATION FOR THE TREATMENT OF (86) PCT No.: PCT/EP03/04657 AIRWAY DISORDERS (30) Foreign Application Priority Data (75) Inventors: Guido Hanauer, Konstanz (DE); Wolfgang Kromer, Konstanz (DE); May 7, 2002 (EP)........................................ O2O10306.5 Stefan Postius, Konstanz (DE); O O Wolfgang-Alexander Simon, Konstanz Publication Classification DE (DE) (51) Int. Cl.' ................ A61K 31/4745; A61K 31/4439; Correspondence Address: A61K 31/277 NATH & ASSOCATES PLLC (52) U.S. Cl. ......................... 514/290; 514/338; 514/303; 1030 FIFTEENTH STREET, N.W. 514/522 SIXTH FLOOR WASHINGTON, DC 20005 (US) (57) ABSTRACT (73) Assignee: Altana Pharma AG, Konstanz (DE) (21) Appl. No.: 10/513,594 The invention relates to the combination of proton pump inhibitors and airway therapeutics for the treatment of (22) PCT Filed: May 3, 2003 airway disorders. US 2005/0165041 A1 Jul. 28, 2005 COMBINATION FOR THE TREATMENT OF 0007 Accordingly, in a first aspect, the invention pro AIRWAY DISORDERS vides the combined use of proton pump inhibitors and airway therapeutics for treating airway disorders. TECHNICAL FIELD 0008 Proton pump inhibitors are designated as those 0001. The invention relates to the combination of certain Substances which inhibit gastric acid Secretion by blocking known active compounds for therapeutic purposes. the proton pump, i.e. which bind covalently to H+/K+- ATPase, the enzyme responsible for gastric acid Secretion. 0002) 1. Technical Background This includes in particular active compounds having a 0003) A whole series of compounds are known from the 2-(2-pyridinyl)methylsulphinyl)-1H-benzimidazole skel prior art which inhibit gastric acid Secretion by blocking the eton or a related Skeleton, where these skeletons may be proton pump and which have therefore also been designated Substituted in various forms. According to the invention, the as proton pump inhibitors (PPI). These compounds are term “proton pump inhibitors' includes not only the active Suitable for the treatment of gastric and intestinal disorders compounds as Such, but also their pharmacologically accept and reflux oesophagitis, and Some of them have been able Salts, Solvates (in particular hydrates), etc. approved by health authorities in this respect. Furthermore, 0009 Exemplary proton pump inhibitors which may be compounds are known from the prior art which can be used mentioned are those described and claimed in the following for treating airway disorders and which are herein below patent applications and patents: DE-A-3531487, EP-A-0 referred to as airway therapeutics. The purposive combined 005 129, EP-A-0 124495, EP-A-0 166287, EP-AO 174726, use of PPIs and airway therapeutics in the meaning of the EP-AO 184322, EP-AO 254 588, EP-A-0 261478, EP-A-0 invention described in more detail below for therapeutic 268 956, EP-A-0 434 999 and WO-A-9523149. The com purposes has hitherto not been described in the prior art. pounds 2-2-(N-isobutyl-N-methylamino)benzyl-Sulphinyl 0004 2. Prior art benzimidazole (INN: leminoprazole), 2-(4-methoxy-6,7,8, 9-tetrahydro-5H-cycloheptabpyridin-9-ylsulphinyl)-1H 0005. In International Patent Application WO 96/22978, benzimidazole (INN: nepaprazole), 2-(4-methoxy-3- Substituted phenyl compounds are described which are said methyl-pyridin-2-ylmethylsulphinyl)5-pyrrol-1-y-1H to be useful as endothelin antagonists. The combination of benzimidazole (IY-81149), 5-methoxy-2-(4-methoxy-3,5- these compounds with compounds of a variety of other dimethyl-2-pyridinyl)methylsulphinyl-1-H-inidazo 4,5-b] Substance classes, inter alia with proton pump inhibitors, is pyridine(tenatoprazole), especially 5-methoxy-2-(4- mentioned. However, no particular utility of these combi methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl)-1H nations is given. In International Patent Application WO benzimidazole (INN: omeprazole), 5-methoxy-2-(S)-(4- 98/16228 the combined use of a H, K*-ATPase inhibitor methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl)-1H and of a glucocorticoid in the treatment of asthma is benzimidazole (INN: esomeprazole), 2-3-methyl-4-(2,2,2- described. International Patent Application WO 99/04816 trifluoroethoxy)-2-pyridinyl)methylsulphinyl)-1H relates to the combined use of a proton pump inhibitor and benzimidazole (INN: lansoprazole) and 2-4-(3- of an antibacterial active Substance. International Patent methoxypropoxy)-3-methylpyridin-2-yl)-methylsulphinyl Application WO 00/10529 relates to certain oral liquid 1H-benzimidazole (INN: rabeprazole) and in particular mucoadhesive compositions, which may contain various 5-difluoromethoxy-2-(3,4-dimethoxy-2-pyridinyl)methyl pharmaceutically active classes compounds, and mixtures sulphinyl)-1H-benzimidazole (INN: pantoprazole) and (-)- thereof. International Patent Application WO 00/69438 5-difluoromethoxy-2-(3,4-dimethoxy-2-pyridinyl)methyl describes inter alia the use of an NK-1 antagonist and a proton pump inhibitor in the preparation of a pharmaceutical Sulphinyl)-1H-benzimidazole (-)pantoprazole may be composition for use in the treatment of asthma conditions. T. mentioned by way of example. O. Kiljander et al. (CHEST 1999; 116: 1257-1264) con 0010. The proton pump inhibitors are present as such or cluded after an 8-week double-blind, placebo-controlled in the form of their salts with bases. Examples of salts with croSSOver Study with omeprazole as Sole medication that bases which may be mentioned are Sodium, potassium, there was a reduction in nocturnal asthma Symptoms. W. J. magnesium or calcium Salts. If the proton pump inhibitors or Pan et al. (Aliment. Pharmacol. Ther. 2000; 14: 345-352) their Salts are isolated in crystalline form, the crystals may found a lack of pharmacokinetic interaction between lanSo contain variable amounts of Solvent. Thus, according to the prazole or pantoprazole and theophyllin, without Studying invention, the term “proton pump inhibitor” also includes all any effects of these combinations on asthma Symptoms. J. Solvates, in particular all hydrates, of the proton pump Cuppoletti et al. (Clinical and Experimental Pharmacology inhibitors and their Salts. Pantoprazole-Sodium Sesquihy and Physiology (2000) 27; 896-900 describe the activation drate (=pantoprazole-Sodiumx 1.5 HO), (-)-pantoprazole of human CIC-2 Cl channels and the resulting implications Sodium Sesquihydrate, pantoprazole-magnesium dihydrate, for cystic fibrosis. D. Stancic-Rokotov et al. describe the omeprazole-magnesium, omeprazole-magnesium tetrahy beneficial effect of e.g. omeprazole on HCl-induced lung drate, eSomeprazole-magnesium and eSomeprazole-magne lesions in rats. sium tetrahydrate may be mentioned as particularly pre ferred Salts or hydrates of proton pump inhibitors. DESCRIPTION OF THE INVENTION 0011 Airway therapeutics which are suitable for the 0006 Surprisingly, it has now been found that proton purpose of the invention are active compounds from differ pump inhibitors, whose original field of use is the treatment ent classes of active compounds-with the exception of of gastric and intestinal disorders, are, in combination with glucocorticoides in general, except cicleSonide, and with the airway therapeutics, particularly Suitable for the treatment of exception of tachykinine NK antagonists-, Such as, for airway disorders. example, the following: US 2005/0165041 A1 Jul. 28, 2005 0012 f2-adrenoceptor agonists (in particular selec 0032) 5-2-(1,1-dimethylethyl)amino-1-hydroxy tively acting Substances having only slight cardiac ethyl-1,3-benzenediol (TERBUTALINE), action which, as a result, are also Suitable for use in 0033 5-chloro-3-4-(2-hydroxyethyl)-1-piperaziny the therapy of airway disorders), Such as, for carbonylmethyl-2-benzothiazolinone (TIARA example, MIDE) and C-(tert-butylamino)methyl-o-chlo 0013 4-hydroxy-7-2-2-3(2-phenylethoxy)pro robenzyl alcohol (TULOBUTEROL); poxyethylaminoethylbenzothiazol-2(3H)-one 0034 muscarinic receptor antagonists, Such as, for (AR-C68164AA), example, 0014) 3-2-(4-hydroxy-2-oxo-2,3-dihydroben Zothiazol-7-yl)ethylamino-N-2-2-(4-methylphe 0035) endo-8-(2-fluoroethyl)-3-(hydroxydipheny nyl)ethoxyethyl-propaneSulphonamide (AR lacetyl)oxy-8-methyl-8-azoniabicyclo3.2.1]octane C89855AA), bromide (FLUTROPIUM BROMIDE). 0.015 5-2-N-(dimethylaminocarbonyl)-N-(1,1- 0036 3-(3-hydroxy-2-phenylpropanoyloxy)-8-iso dimethylethyl)amino]-1-hydroxyethyl-1,3-ben propyl-8-methyl-8-azoniabicyclo3.2.1]octane bro Zenediol (BAMBUTEROL), mide (IPRATROPIUM BROMIDE), 0016 4-methylbenzoic acid 4-2-(1,1-dimethyl 0037 (8r)-6B-7B-epoxy-8-ethyl-3-O-hydroxy-1- ethyl)amino-1-hydroxyethyl-1,2-phenylene ester CH-5-OH-tropanium bromide (OXITROPIUM (BITOLTEROL), BROMIDE), 0038) (R)-3-quinuclidinyl (S)-e-hydroxy-C-2-(R)- 0017 3-bromo-O-(tert-butylamino)methyl-5-isox methylsulphinyl)ethylhydratropate (REVATRO azolemethanol (BROXATEROL), PATE) and 0018 5-2-(1,1-dimethylethyl)amino-1-hydroxy 0.039 7(S)-(1C.2B,43,5C,7(3)-7-2-hydroxy-2,2- ethyl-2-hydroxyphenylurea (CARBUTEROL), di(2-thienyl)acetoxy-9,9-dimethyl-3-oxa-9-azoni 0019) 4-2-(6-phenethylaminohexylamino)ethyl atricyclo3.3.1.0(2,4)nonane bromide (TIOTRO benzene-1,2-diol (DOPEXAMINE), PIUM BROMIDE); 0020 N-(3,3-diphenylpropyly)-O-methylcyclohex 0040 theophylline-like bronchodilators, such as, for aneethylamine (DROPRENILAMINE), example, 0021 (+/-)-2'-hydroxy-5'-(RS)-1-hydroxy-2- 0041 3,7-dihydro-1,3-dimethyl-1H-purine-2,6-di (RS)-p-methoxy-C.-methylphenethylaminoethyl
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