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 in the treatment of 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 , 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 (in particular selec 0032) 5-2-(1,1-dimethylethyl)amino-1-hydroxy tively acting Substances having only slight cardiac ethyl-1,3-benzenediol (), 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 (); 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 (), mide (), 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 (), 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 (), 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 -like , 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 one/1,2-ethanediamine (), formanilide (), 0042 3,7-dihydro-1,3-dimethyl-7-(5-methyl-1,2,4- 0022 (R)-O-(tert-butylamino)methyl)-4-hydroxy oxadiazol-3-yl)methyl)-1H-purine-2,6-dione (CHI m-xylene-C.C.'-diol (), NOIN-170), 0023 4-amino-3-chloro-O-(1,1-dimethylethy 0043 7-(2,3-dihydroxypropyl)-1,2,3,6-tetrahydro l)aminomethyl-5-(trifluoromethyl)benzenemetha 1,3-dimethylpurine-2,6-dione (), nol (MABUTEROL), 0044) 7-(1,3-dioxolan-2-ylmethyl)-3,7-dihydro-1,3- 0024 (-)-(R)-2-(tert-butylamino)-1-(2-chloro-4-hy dimethyl-1H-purine-2,6-dione (), droxyphenyl)ethanol (MELUADRINE), 0.045 R-(R*.S*)-3-(2-hydroxy-1-methyl-2-phe 0025 (+/-)-5,6-diisobutyryloxy-2-(methylamino)- nylethyl)amino-1-(3-methoxyphenyl)-1-propanone 1,2,3,4-tetrahydronaphthalene (NOLOMIROLE), (OXYFEDRINE), 0026 (RS)-6-2-(tert-butylamino)-1-hydroxy 0046 3,7-dimethyl-1-hexyl-1H,3H-purine-2,6-di ethyl)-3-hydroxy-2-pyridylmethanol (PIR one (), BUTEROL), 0027 7-3-2-(3,5-dihydroxyphenyl)-2-hydroxy 0047 3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)- ethylaminopropyl)-3,7-dihydro-1,3-dimethyl-1H 1H-purine-2,6-dione (), purine-2,6-dione (), 0048 3,7-dihydro-3-methyl-1-(5-oxohexyl)-7-pro 0028 C.(1)-(1,1-dimethylethyl)aminomethyl-4- pyl-1H-purine-2,6-dione (), hydroxy-1,3-benzenedimethanol (), 0049 3,7-dihydro-7-(2-hydroxypropyl)-1,3-dim 0029 (+/-)-N-2-hydroxy-2-4-hydroxy-3-(hy ethyl-1H-purine-2,6-dione () droxymethyl)phenylethyl-N-6-(4-phenylbutoxy and )hexyl)amine (), 0050) 3,7-dihydro-1,3-dimethyl-1H-purine-2,6-di 0030) 4-hydroxy-7-2-2-3-(2-phenylethoxy)pro one (THEOPHYLLINE); pylsulphonylethylaminoethylbenzothiazol-2(3H)- 0051 PDE3/4- and PDE4 inhibitors, such as, for one (SIBENADET), example, the compounds mentioned as examples in 0.031) R-(R*,R)-8-hydroxy-5-1-hydroxy-2-2- the following patent applications and patents: (4-methoxyphenyl)-1-methylethylaminoethyl 0052 EP 0163965.EP 038.9282, EP 0393500, EP 2(1H)-quinoline (TA-2005), 0435811, EP0482302, EP04992.16, EP0506194, EP

US 2005/0165041 A1 Jul. 28, 2005

0213 4-carboxyphenylmethyl (6R,7R)-7-methoxy 0225 from the class of the PDE3/4- and PDE4 7-(2-methoxybenzoyl)aminol-3-(1-methyl-1H inhibitors the active compounds tetrazol-5-yl)thiomethyl-8-5-oxa-1-azabicyclo 0226 (Z)-3-(3,5-dichloro-4-pyridyl)-2-4-(2-inda 4.2.0oct-2-en-2-carboxylate (B-136). nyloxy-5-methoxy-2-pyridylpropenenitrile, 0214) 3-methylphenylmethyl (6R,7R-7-methoxy-7- (2-methoxybenzoyl)amino-8-oxo-3-1-2-oxo-2- 0227 N-9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahy (2-propenyloxy)ethyl)1H-tetrazol-5-yl)thiome dropyrrolo3.2,1-jk]1,4)benzodiazepin-3(R)-ylpy thyl-5-oxa-1-azabicyclo4.2.0oct-2-ene-2- ridine-3-carboxamide (C1-1044), carboxylate (B-146). 0228 N-(3,5-dichloro-4-pyridinyl-2-1-4-fluo 0215. 3-methylbenzyl (6R,7R)-3-1-(carboxymeth robenzyl)-5-hydroxy-1H-indol-3-yl)-2-oxoaceta yl)tetrazol-5-ylsulfanylmethyl-7-methoxy-7-(2- methoxybenzamido)-1-Oxa-3-cephem-4-carboxylate mide (AWD-12-281), (B-152) and 0229 cis-4-cyano-4-(3-cyclopentyloxy-4-methoXis-4 4-(3-cvcl loXV-4 h 0216) 3-methylbenzyl(6R,7R-3-1-(carboxymeth yphenyl)cyclohexan-1-carboxylic acid (CILOMI yl)tetrazol-5-ylsulfanylmethyl-7-methoxy-7-(2- LAST), ethoxybenzamido)-1-Oxa-3-cephem-4-carboxylate 0230 8-amino-1,3-bis(cyctopropylmethyl) (B-153). (CIPAMFYLLINE), 0217. The airway therapeutics can be present as such or in chemically bonded form. It is understood hereby that the 0231 2-methyl-1-2-(1-methylethyl)pyrazolo 1.5- active compounds mentioned can also be present for apyridin-3-yl)-1-propanone (), example, in the form of their pharmacologically acceptable 0232 2-(2,4-dichlorophenylcarbonyl)-3-ureidoben Salts and/or as Solvates (e.g. hydrates), and/or in the form of zofuran-6-yl methanesulphonate (LIRIMILAST), their N-oxides etc. Suitable pharmacologically acceptable Salts here are in particular water-Soluble and water-insoluble 0233 (-)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3, acid addition Salts with acids Such as, for example, hydro 4,4a,10b-hexahydro-6-(4-diisopropylaminocarbon chloric acid, hydrobromic acid, phosphoric acid, nitric acid, ylphenyl)-benzoc1,6naphthyridine (PUMAFEN Sulphuric acid, acetic acid, citric acid, D-gluconic acid, TRINE), benzoic acid, 2-(4-hydroxy-benzoyl)benzoic acid, butyric acid, Sulphosalicylic acid, maleic acid, lauric acid, malic 0234) 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4- acid, fumaric acid, Succinic acid, oxalic acid, tartaric acid, pyridyl)-4-(difluoromethoxy)benzamide (ROFLU embonic acid, Stearic acid, toluenesulphonic acid, methane MILAST), the N-oxide of , and Sulphonic acid or 1-hydroxy-2-naphthoic acid, the acids 0235. 3-3-(cyclopentyloxy)-4-methoxyphenyl being employed in Salt preparation-depending on whether methyl-N-ethyl-8-(1-methylethyl)-3H-purine-6- it is a mono- or polybasic acid and depending on which Salt amine (V-11294A); is desired-in an equimolar quantitative ratio or one differ ing there from. Furthermore, the active compounds men 0236 from the class of the cysteinyl-leukotriene, tioned can also be present as pure enantiomers or as enan receptor antagonists the active compounds tiomer mixtures in any mixing ratio. 0237 2-1-1(R)-3-2(E)-(7-chloroquinolin-2- 0218 Airway therapeutics to be emphasized as being yl) vinylphenyl-3-2-(1-hydroxy-1-methyleth Suitable for combined application with a proton pump yl)phenylpropyl-Sulphanylmethyl-cyclopropyl inhibitor in the meaning of the invention are in particular acetic acid (), 0219 from the class of the B-adrenoceptor agonists 0238 8-4-(4-phenylbutoxy)benzamido-2-(tetra the active compounds zol-5-yl)-4H-1-benzopyran-4-one () 0220 BAMBUTEROL, BITOLTEROL, BROX and ATEROL, CARBUTEROL, DOPEXAMINE, DRO PRENILAMINE, FORMOTEROL, LEVOSALB 0239 4-(5-cyclopentyloxycarbonylamino-1-meth UTAMOL, MABUTEROL, , ylindol-3-yl-methyl)-3-methoxy-N-o-tolylsulpho REPROTEROL, SALBUTAMOL, SALMETEROL, nylbenzamide (). TERBUTALINE, TIARAMIDE and 0240 from the class of the leukotriene synthesis TULOBUTEROL: inhibitors the active compound 0221 from the class of the muscarinic receptor antagonists the active compounds 0241 (+/-)-1-(1-benzobthien-2-ylethyl)-1-hy 0222 FLUTROPIUMBROMIDE, IPRATROPIUM droxyurea (); BROMIDE, and 0242 from the class of the lipoxygenase inhibitors ; the active compound 0223 from the class of the theophylline-like bron 0243 3-5-(4-chlorophenyl)-1-(4-methoxyphe chodilators the active compounds nyl)pyrazol-3-yl)-N-hydroxy-N-methylpropiona 0224 AMINOPHYLLINE, DIPROPHYLLINE, mide (TEPOXALIN), DOXOFYLLINE, OXYFEDRINE, PENTIFYL LINE, PENTOXIFYLLINE, PROPENTOFYLLINE 0244 from the class of the inhibitors of mediator and PROXYPHYLLINE; release the active compounds US 2005/0165041 A1 Jul. 28, 2005

0245 2-amino-7-isopropyl-5-oxo-5H-1 benzopy phinyl)-1H-benzimidazole (-)-pantoprazole and an airway rano 2,3-bipyridine-3-carboxylic acid (AMLEX therapeutic from the class of the PDE3/4- and PDE4 inhibi ANOX), tors Selected from the group consisting of (Z)-3-(3,5- dichloro-4-pyridyl)-2-4-(2-indanyloxy-5-methoxy-2-py 0246 5.5'-(2-hydroxytrimethylenedioxy)bis(4-oxo ridylpropenenitrile, N-9-amino-4-oxo-1-phenyl-3,4,6,7- 4H-1-benzopyran-2-carboxylic acid) (CRO tetrahydropyrrolo3.2,1-jk1,4-benzodiazepine-3(R)-yl) MOGLYCINIC ACID), pyridine-3-carboxamide (CI-1044), N-(3,5-dichloro-4- 0247 4,6-dioxo-1-ethyl-10-propyl-4H,6H-pyrano pyridinyl)-2-1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl)- 3.2-gquinoline-2,8-dicarboxylic acid 2-oxoacetamide (AWD-12-281), cis-4-cyano-4-(3- (), cyclopentyloxy-4-methoxyphenyl)cyclohexane-1- carboxylic acid (), 8-amino-1,3- 0248 1-3-4-(diphenylmethyl)-1-piperazinylpro bis(cyclopropylmethyl)-xanthine (CIPAMFYLLINE), pyl)-2-benzimidazolinone (OXATOMIDE), 2-methyl-1-2-(1-methylethyl)pyrazolo 1.5-alpyridin-3-yl)- 0249 9-methyl-3-(1H-tetrazol-5-yl )-4H-pyrido1, 1-propanone (IBUDILAST), 2-(2,4-dichlorophenylcarbo 2-alpyrimidin-4-one (PEMIROLAST), nyl)-3-ureidobenzofuran-6-yl methanesulphonate (LIRIMI LAST), (-)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a, 0250) isoamyl 5,6-dihydro-7,8-dimethyl-4,5-dioxo 10b-hexahydro-6-(4-diisopropylaminocarbonyl 4H-pyrano.3.2-cquinoline-2-carboxylate (REPIRI phenyl)benzoc1,6naphthyridine (PUMAFENTRINE), NAST), 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(dif 0251 2-4-(3-ethoxy-2-hydroxopropoxy)phenyl luoromethoxy)benzamide (ROFLUMILAST), ROFLUMI carbamoylethyldimethylsulphonium p-toluene LAST-N-OXIDE and 3-3-(cyclopentyloxy)-4-methox sulphonate (SUPLATAST TOSILATE) and yphenyl)methyl-N-ethyl-8-(1-methylethyl)-3H-purine-6- amine (V-11294A) for the treatment of airway disorders. 0252 butyl N-3-(1H-tetrazol-5-yl)phenyloxamate 0260 The invention furthermore provides particularly (TAZANOLAST), especially the combined use of a proton pump inhibitor 0253 from the class of the thromboxane A antago selected from the group consisting of 2-2-(N-isobutyl-N- nists the active compound methylamino)benzylsulphinylbenzimidazole(leminopra zole), 2-(4-methoxy-6,7,8,9-tetrahydro-5H-cyloheptabpy 0254 (+)-(Z)-7-3-endo-(phenylsulphonylamino ridin-9-ylsulphinyl)-1H-benzimidazole(nepaprazole), 2-(4- )bicyclo2.2.1]hept-2-exo-ylheptenoic acid methoxy-3-methyl-pyridin-2-ylmethylsulphinyl)5-pyrrol-1- (DOMITROBAN), y-1H-benzimidazole (IY-81149), 5-methoxy-2-(4- 0255 and from the class of the thromboxane syn methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl)-1H thase inhibitors the active compound imidazo 4,5-b]pyridine(tenatoprazole), 5-methoxy-2-(4- methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl)-1H 0256 (E)-3-4-(1H-imidazol-1-ylmethyl)phenyl-2- benzimidazole(omeprazole), 5-methoxy-2-(S)-(4- propenoic acid (OZAGREL). methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl)-1H benzimidazole(esomeprazole), 2-3-methyl-4-(2,2,2- 0257 The invention provides especially the combined trifluoroethoxy)-2-pyridinyl)methylsulphinyl)-1H use of proton pump inhibitors and airway therapeutics from benzimidazole(lansoprazole), 2-4-(3-methoxypropoxy)-3- the class of the PDE3/4- and PDE4 inhibitors for the methylpyridin-2-yl)-methylsulphinyl)-1H treatment of airway disorders. benzimidazole(rabeprazole), 5-difluoromethoxy-2-(3,4- 0258. The invention furthermore provides the combined dimethoxy-2-pyridinyl)methylsulphinyl)-1H use of proton pump inhibitors and cicleSonide for the benzimidazole(pantoprazole) and (-)-5-difluoromethoxy-2- treatment of airway disorders. I(3,4-dimethoxy-2-pyridinyl)methylsulphinyl)-1H 0259. The invention provides particularly especially the benzimidazole (-)-pantoprazole and the airway combined use of a proton pump inhibitor Selected from the therapeutic cicleSonide. group consisting of 2-2-(N-isobutyl-N-methylamino)ben 0261) The invention preferably provides the combined Zylsulphinylbenzimidazole (lemino-prazole), 2-(4-meth use of a proton pump inhibitor Selected from the group oxy-6,7,8,9-tetrahydro-5H-cycloheptabpyridin-9-ylsul consisting of 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-py phinyl)-1H-benzimidazole(nepaprazole), 2-(4-methoxy-3- ridinyl)methylsulphinyl)-1H-benzimidazole(omeprazole), methyl-pyridin-2-ylmethylsulphinyl)5-pyrrol-1-y-1H 5-methoxy-2-(S)-(4-methoxy-3,5-dimethyl-2-pyridinyl benzimidazole (IY-81149), 5-methoxy-2-(4-methoxy-3,5- )methylsulphinyl)-1H-benzimidazole(esomeprazole), 2-3- dimethyl-2-pyridinyl)methylsulphinyl)-1H-imidazo[4,5-b] methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulphi pyridine(tenatoprazole), 5-methoxy-2-(4-methoxy-3,5- nyl)-1H-benzimidazole(lansoprazole), 2-4-(3- dimethyl-2-pyridinyl)methylsulphinyl)-1H-benzimidazole methoxypropoxy)-3-methylpyridin-2-yl)-methylsulphinyl (omeprazole), 5-methoxy-2-(S)-(4-methoxy-3,5-dimethyl 1H-benzimidazole(rabeprazole) and 5-difluoromethoxy-2- 2-pyridinyl)methylsulphinyl)-1H-benzimidazole(esome I(3,4-dimethoxy-2-pyridinyl)methylsulphinyl)-1H prazole), 2-3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl benzimidazole(pantoprazole) and an airway therapeutic )methylsulphinyl)-1H-benzimidazole(lansoprazole), 2-4- from the class of the PDE3/4- and PDE4 inhibitors Selected (3-methoxypropoxy)-3-methylpyridin-2-yl)- from the group consisting of cis-4-cyano-4-(3-cyclopenty methylsulphinyl)-1H-benzimidazole(rabeprazole), loxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid 5-difluoromethoxy-2-(3,4-dimethoxy-2-pyridinyl)methyl (CILOMILAST), 2-methyl-1-2-(1-methylethyl)pyrazolo1, Sulphinyl)-1H-benzimidazole(pantoprazole) and (-)-5-dif 5-alpyridin-3-yl)-1-propanone (IBUDILAST), (-)-cis-9- luoromethoxy-2-(3,4-dimethoxy-2-pyridinyl)methylsul ethoxy-8-methoxy-2-methyl-1,2,3,4,4a, 10b-hexahydro-6- US 2005/0165041 A1 Jul. 28, 2005

(4-diisopropylaminocarbonylphenyl)benzoc1,6 particle Size can be generated and administered, using an naphthyridine (PUMAFENTRINE), inhalation technique which is as appropriate as possible for 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(dif the patient. In addition to the use of adaptors (spacers, luoromethoxy)benzamide (ROFLUMILAST) and ROFLU expanders) and pear-shaped containers (e.g. Nebulator(R), MILAST-N-OXIDE for the treatment of airway disorders. Volumatic(R), and automatic devices emitting a puff of spray 0262 The invention particularly preferable provides the (Autohaler(R), for metered aerosols, in particular in the case combined use of 5-difluoromethoxy-2-(3,4-dimethoxy-2- of powder inhalers, a number of technical Solutions are pyridinyl)methylsulphinyl)-1H-benzimidazole(pantopra available (e.g. Diskhaler(R), Rotadisk(R), Turbohaler(R) or the zole) and 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-py inhaler described in European Patent Application EPO 505 ridyl)-4-(difluoromethoxy)benzamide (ROFLUMILAST) 321), using which an optimal administration of active com for the treatment of airway disorders. pound can be achieved. 0263. The invention furthermore particularly preferable 0270. The active compounds are dosed in an order of provides the combined use of 5-difluoromethoxy-2-(3,4- magnitude customary for the individual dosage, where it dimethoxy-2-pyridinyl)methylsulphinyl)-1H-benzimida may be possible, on account of the individual actions, which Zole(pantoprazole) and ciclesonide for the treatment of are mutually positively influencing and reinforcing, to airway disorders. reduce the respective dosages on the combined administra 0264. Airway disorders which may be mentioned are in tion of the active compounds compared with the norm, or particular allergen- and -induced pulmonary where-if the dosage of the individual components is the abnormalities and bronchial disorders (for example bronchi customary dosage-a Surprisingly better and longer-lasting tis, obstructive bronchitis including COPD, spastic bronchi activity is obtained. tis, allergic bronchitis, allergic asthma, bronchial asthma, in 0271 The proton pump inhibitor is usually administered particular night-time asthma attacks, pneumonitis and pull in a dose of from 5 to 100, advantageously from 10 to 60, monary fibrosis), which can be treated by the combination in particular from 20 to 40 mg, administered once or, if according to the invention also in the context of a long-term required, twice a day. In the case of the airway therapeutics, therapy (if desired with appropriate adjustment of the dose the dose customary for the perSon Skilled in the art is of the individual components to the needs at the time, for administered, which, depending on the class of active com example needs Subject to Seasonally related variations). pound, may vary within a very broad range. Thus, for 0265 “Combined use” or “combination” within the example, the B adrenoceptor is-depending on the meaning of the present invention is to be understood as active compound-in the case of administration by inhala meaning that the individual components can be administered tion usually administered in a dosage of, for example, 0.002 Simultaneously (in the form of a combination medicament), to 2.0 mg per day. For the PDE inhibitors, it is possible in more or less simultaneously (from Separate pack units) or in the case of oral administration to vary the doses-depending Succession (one directly after the other directly or else on the active compound-within a wide range. It being alternatively within a relatively large time span) in a manner possible, as a framework, to start from a dose of 1-2000 which is known per Se and customary. tug/kg of body weight. In the case of the administration of the preferred PDE inhibitor roflumilast, the dosage is in the 0266. Within the meaning of the present invention, “use” range from 2-20 lug/kg of body weight. is preferably understood as meaning the oral administration of both active compounds. However, it is also conceivable 0272. The proton pump inhibitors or airway therapeutics to administer the proton pump inhibitor parenterally (for to be administered orally are formulated-if appropriate example intravenously) and/or to administer the airway jointly-to give medicaments according to processes known therapeutic parenterally or topically (in particular by inha per Se and familiar to the perSon Skilled in the art. The lation). For administration by inhalation, the airway thera pharmacologically active compounds are employed as medi peutic is preferably administered in the form of an aeroSol, caments, preferably in combination with Suitable pharma the aerosol particles of Solid, liquid or mixed composition ceutical excipients or vehicles, in the form of tablets, coated having a diameter of 0.5 to 10 um, advantageously of 2 to tablets, capsules, emulsions, Suspensions or Solutions, the 6 um. active compound content advantageously being between 0.1 and 95% and, by the appropriate choice of the excipients and 0267 Aerosol generation can be carried out, for example, vehicles, it being possible to achieve a pharmaceutical by preSSure-operated jet atomizers or ultraSonic atomizers, administration form precisely tailored to the active com but advantageously by propellant-operated metered aerosols pound(s) and/or to the desired onset of action (e.g. a Sus or propellant-free administration of micronized active com tained-release form or an enteric form). The person skilled pounds from inhalation capsules. in the art is familiar on the basis of his/her expert knowledge 0268 Depending on the inhaler system used, in addition with which excipients or vehicles are suitable for the desired to the active compounds the administration forms also pharmaceutical formulations. In addition to Solvents, gel contain the required excipients, Such as, for example, pro forming agents, tablet eXcipients and other active compound carriers, it is possible to use, for example, antioxidants, pellants (e.g. Frigen in the case of metered aerosols), Sur dispersants, emulsifiers, antifoams, flavour corrigents, pre face-active Substances, emulsifiers, Stabilizers, preserva Servatives, Solubilizers, colourants or permeation promoters tives, flavourings, fillers (e.g. lactose in the case of powder and complexing agents (e.g. cyclodextrins), where for all inhalers) or, if appropriate, further active compounds. dosage forms the generally known Sensitivity of the proton 0269. For the purposes of inhalation, a large number of pump inhibitors-in particular to acids-has to be taken into apparatuses are available with which aerosols of optimum acCOunt. US 2005/0165041 A1 Jul. 28, 2005

0273. In a further aspect, the invention provides the use taken for the treatment of an airway disorder more or leSS of a proton pump inhibitor in combination with an airway Simultaneously or in Succession with an airway therapeutic. therapeutic for treating patients Suffering from an airway 8. A ready-to-use medicament, comprising, as active disorder. compound, an airway therapeutic, which contains a refer 0274 The invention further provides a method for treat ence to the fact that said airway therapeutic is to be taken for ing airway disorders which comprises administering to a the treatment of an airway disorder more or leSS Simulta patient in need of Such a treatment an effective amount of a neously or in Succession with a proton pump inhibitor. proton pump inhibitor together with an airway therapeutic. 9. A pharmaceutical composition according to claim 1, wherein the proton pump inhibitor is Selected from the group 0275. The invention further provides the use of proton consisting of 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-py pump inhibitors and airway therapeutics for preparing com ridinyl)-methylsulphinyl)-1H-benzimidazole(omeprazole), bination medicaments for treating airway disorders. 5-methoxy-2-(S)-(4-methoxy-3,5-dimethyl-2-pyridinyl )methylsulphinyl)-1H-benzimidazole(esomeprazole), 2-3- 0276 The invention further provides a pharmaceutical methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulphi preparation for treating airway disorders, which preparation nyl)-1H-benzimidizole(lansoprazole), 2-4-(3- comprises, as active compounds, a proton pump inhibitor methoxypropoxy)-3-methylpyridin-2-yl)methylsulphinyl and an airway therapeutic. 1H-benzimidazole(rabeprazole), 5-difluoromethoxy-2-(3, 0277. The invention further provides a ready-to-use 4-dimethoxy-2-pyridinyl)-methylsulphinyl)-1H medicament, comprising, as active compounds, a proton benzimidazole(pantoprazole) and the hydrates, Solvates, pump inhibitor and an airway therapeutic, which contains a Salts, hydrates of the Salts and Solvates of the Salts thereof. reference to the fact that these active compounds are to be 10. A pharmaceutical composition according to claim 1, taken for the treatment of an airway disorder more or leSS wherein the airway therapeutic is Selected from the group Simultaneously or in Succession (one directly after the other consisting of cis-4-cyano-4-(3-cyclopentyloxy-4-methox or else within a relatively large time Span). yphenyl)cyclohexan-1-carboxylic acid (CILOMILAST), 0278. The invention further provides a ready-to-use 2-methyl-1-2-(1-methylethyl)pyrazolo-1,5-alpyridin-3- medicament, comprising, as active compound, a proton yl)-1-propanone (IBUDILAST), (-)-cis-9-ethoxy-8-meth pump inhibitor, which contains a reference to the fact that oxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropy this proton pump inhibitor is to be taken for the treatment of lamino-carbonylphenyl)benzoc1,6naphthyridine an airway disorder more or less simultaneously or in Suc (PUMAFENTRINE), 3-(cyclopropylmethoxy)-N-(3,5- cession (one directly after the other or else within a rela dichloro-4-pyridyl)-4-difluoromethoxy)benzamide (ROF tively large time span) with an airway therapeutic. LUMILAST), ROFLUMILAST N-OXIDE and the hydrates, Solvates, Salts, hydrates of the Salts and Solvates of 0279 The invention further provides to a ready-to-use the salts thereof. medicament, comprising, as active compound, an airway 11. A pharmaceutical composition according to claim 1, therapeutic, which contains a reference to the fact that this wherein the airway therapeutic is ciclesonide. airway therapeutic is to be taken for the treatment of an 12. A pharmaceutical composition according to claim 1, airway disorder more or less Simultaneously or in Succession wherein the proton pump inhibitor is 5-difluoromethoxy-2- (one directly after the other or else within a relatively large I(3,4-dimethoxy-2-pyridinyl)methylsulphinyl)-1H-benzimi time span) with a proton pump inhibitor. dazole (pantoprazole) or a hydrate, Solvate, salt, hydrate of 1. A pharmaceutical composition comprising a proton a Salt or Solvate of a Salt thereof, and wherein the airway pump inhibitor and an airway therapeutic in fixed or free therapeutic is selected from the group consisting of cis-4- combination. cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan 2. A pharmaceutical composition according to claim 1 in 1-carboxylic acid (CILOMILAST), 2-methyl-1-2-(1-meth fixed oral combination. ylethyl)pyrazolo-1,5-apyridin-3-yl)-1-propanone 3. A method for treating an airway disorder in a patient (IBUDILAST), (-)-cis-9-ethoxy-8-methoxy-2-methyl-1,2, comprising administering to a patient in need of Such a 3,4,4a, 10b-hexahydro-6-(4-diisopropylamino-carbonylphe treatment an effective amount of a proton pump inhibitor nyl)benzoc1,6naphthyridine (PUMAFENTRINE), together with an airway therapeutic. 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-dif 4. A method according to claim 3, wherein the airway luoromethoxy)benzamide (ROFLUMILAST), ROFLUMI disorder is Selected from the group consisting of bronchitis, LASTN-OXIDE and the hydrates, solvates, salts, hydrates obstructive bronchitis, COPD, spastic bronchitis, allergic of the salts and Solvates of the salts thereof. bronchitis, allergic asthma, bronchial asthma, pneumonitis 13. A pharmaceutical composition according to claim 1, and pulmonary fibrosis. wherein the proton pump inhibitor is 5-difluoromethoxy-2- 5. A pharmaceutical preparation comprising as active I(3,4-dimethoxy-2-pyridinyl)methylsulphinyl)-1H-benzimi compounds, a proton pump inhibitor and an airway thera dazole (pantoprazole) or a hydrate, Solvate, salt, hydrate of peutic. a Salt or Solvate of a Salt thereof, and wherein the airway 6. A ready-to-use medicament, comprising, as active therapeutic is cicleSonide. compounds, a proton pump inhibitor and an airway thera 14. A method according to claim 3, wherein the proton peutic, which contains a reference to the fact that Said active pump inhibitor is Selected from the group consisting of compounds are to be taken for the treatment of an airway 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinyl)meth disorder more or leSS Simultaneously or in Succession. ylsulphinyl)-1H-benzimidazole(omeprazole), 5-methoxy-2- 7. A ready-to-use medicament, comprising, as active (S)-(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulphi compound, a proton pump inhibitor, which contains a ref nyl)-1H-benzimidazole(esomeprazole), 2-3-methyl-4-(2,2, erence to the fact that Said proton pump inhibitor is to be 2-trifluoroethoxy)-2-pyridinyl)methylsulphinyl)-1H US 2005/0165041 A1 Jul. 28, 2005 benzimidizole(lansoprazole), 2-4-(3-methoxypropoxy)-3- dichloro-4-pyridyl)-4-difluoromethoxy)benzamide (ROF methylpyridin-2-yl)methylsulphinyl)-1H LUMILAST), ROFLUMILAST N-OXIDE and the benzimidazole(rabeprazole), 5-difluoromethoxy-2-(3,4- hydrates, Solvates, Salts, hydrates of the Salts and Solvates of dimethoxy-2-pyridinyl)methylsulphinyl)-1H the salts thereof. benzimidazole(pantoprazole) and the hydrates, Solvates, 21. A pharmaceutical preparation according to claim 5, Salts, hydrates of the Salts and Solvates of the Salts thereof. wherein the airway therapeutic is ciclesonide. 15. A method according to claim 3, wherein the airway 22. A pharmaceutical preparation according to claim 5, therapeutic is selected from the group consisting of cis-(4- wherein the proton pump inhibitor is 5-difluoromethoxy-2- cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan I(3,4-dimethoxy-2-pyridinyl)-methylsulphinyl)-1H-benz 1-carboxylic acid (CILOMILAST), 2-methyl-1-2-(1-meth imidazole(pantoprazole) or a hydrate, Solvate, Salt, hydrate ylethyl)pyrazolo-1,5-apyridin-3-yl)-1-propanone of a Salt or Solvate of a Salt thereof, and wherein the airway (IBUDILAST), (-)-cis-9-ethoxy-8-methoxy-2-methyl-1,2, therapeutic is selected from the group consisting of cis-4- 3,4,4a,10b-hexahydro-6-(4-diisopropylamino-carbonylphe cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan nyl)benzoc1,6-naphthyridine (PUMAFENTRINE), 1-carboxylic acid (CILOMILAST), 2-methyl-1-2-(1-meth 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-dif ylethyl)pyrazolo-1,5-apyridin-3-yl)-1-propanone luoromethoxy)benzamide (ROFLUMILAST), ROFLUMI (IBUDILAST), (-)-cis-9-ethoxy-8-methoxy-2-methyl-1,2, LASTN-OXIDE and the hydrates, Solvates, salts, hydrates 3,4,4a, 10b-hexahydro-6-(4-diisopropylamino-carbonylphe of the salts and Solvates of the salts thereof. nyl)benzoc1,6naphthyridine (PUMAFENTRINE), 16. A method according to claim 3, wherein the airway 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-dif therapeutic is cicleSonide. luoromethoxy)benzamide (ROFLUMILAST), ROFLUMI 17. A method according to claim 3, wherein the proton LASTN-OXIDE and the hydrates, solvates, salts, hydrates pump inhibitor is 5-difluoromethoxy-2-(3,4-dimethoxy-2- of the salts and Solvates of the salts thereof. pyridinyl)methylsulphinyl)-1H-benzimidazole(pantopra 23. A pharmaceutical preparation according to claim 5, Zole) or a hydrate, Solvate, Salt, hydrate of a Salt or Solvate wherein the proton pump inhibitor is 5-difluoromethoxy-2- of a Salt thereof, and wherein the airway therapeutic is I(3,4-dimethoxy-2-pyridinyl)-methylsulphinyl)-1H-benz Selected from the group consisting of cis-4-cyano-4-(3- imidazole(pantoprazole) or a hydrate, Solvate, Salt, hydrate cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic of a Salt or Solvate of a Salt thereof, and wherein the airway acid (CILOMILAST), 2-methyl-1-2-(1-methylethyl)pyra therapeutic is cicleSonide. Zolo-1,5-apyridin-3-yl)-1-propanone (IBUDILAST), (-)- 24. A ready-to-use medicament according to claim 6, cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a, 10b-hexahy wherein the proton pump inhibitor is Selected from the group dro-6-(4-diisopropylamino-carbonylphenyl)benzoc1,6 consisting of 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-py naphthyridine (PUMAFENTRINE), ridinyl)methylsulphinyl)-1H-benzimidazole(omeprazole), 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-dif 5-methoxy-2-(S)-(4-methoxy-3,5-dimethyl-2-pyridinyl luoromethoxy)benzamide (ROFLUMILAST), ROFLUMI )methylsulphinyl)-1H-benzimidazole(esomeprazole), 2-3- LASTN-OXIDE and the hydrates, Solvates, salts, hydrates methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulphi of the salts and Solvates of the salts thereof. nyl)-1H-benzimidizole(lansoprazole), 2-4-(3- 18. A method according to claim 3, wherein the proton methoxypropoxy)-3-methylpyridin-2-yl)methylsulphinyl pump inhibitor is 5-difluoromethoxy-2-(3,4-dimethoxy-2- 1H-benzimidazole(rabeprazole), 5-difluoromethoxy-2-(3, pyridinyl)methylsulphinyl)-1H-benzimidazole(pantopra 4-dimethoxy-2-pyridinyl)methylsulphinyl)-1H Zole) or a hydrate, Solvate, Salt, hydrate of a Salt or Solvate benzimidazole(pantoprazole) and the hydrates, Solvates, of a Salt thereof, and wherein the airway therapeutic is Salts, hydrates of the Salts and Solvates of the Salts thereof. cicleSonide. 25. A ready-to-use medicament according to claim 6, 19. A pharmaceutical preparation according to claim 5, wherein the airway therapeutic is Selected from the group wherein the proton pump inhibitor is Selected from the group consisting of cis-4-cyano-4-(3-cyclopentyloxy-4-methox consisting of 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-py yphenyl)cyclohexan-1-carboxylic acid (CILOMILAST), ridinyl)methylsulphinyl)-1H-benzimidazole(omeprazole), 2-methyl-1-2-(1-methylethyl)pyrazolo-1,5-alpyridin-3- 5-methoxy-2-(S)-(4-methoxy-3,5-dimethyl-2-pyridinyl yl)-1-propanone (IBUDILAST), (-)-cis-9-ethoxy-8-meth )methylsulphinyl)-1H-benzimidazole(esomeprazole), 2-3- oxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropy methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulphi lamino-carbonylphenyl)benzoc1,6-naphthyridine nyl)-1H-benzimidizole(lansoprazole), 2-4-(3- (PUMAFENTRINE), 3-(cyclopropylmethoxy)-N-(3,5- methoxypropoxy)-3-methylpyridin-2-yl)methylsulphinyl dichloro-4-pyridyl)-4-difluoromethoxy)benzamide (ROF 1H-benzimidazole(rabeprazole), 5-difluoromethoxy-2-(3, LUMILAST), ROFLUMILAST N-OXIDE and the 4-dimethoxy-2-pyridinyl)methylsulphinyl)-1H hydrates, Solvates, Salts, hydrates of the Salts and Solvates of benzimidazole(pantoprazole) and the hydrates, Solvates, the salts thereof. Salts, hydrates of the Salts and Solvates of the Salts thereof. 26. A ready-to-use medicament according to claim 6, 20. A pharmaceutical preparation according to claim 5, wherein the airway therapeutic is ciclesonide. wherein the airway therapeutic is Selected from the group 27. A ready-to-use medicament according to claim 6, consisting of cis-4-cyano-4-(3-cyclopentyloxy-4-methox wherein the proton pump inhibitor is 5-difluoromethoxy-2- yphenyl)cyclohexan-1-carboxylic acid (CILOMILAST), I(3,4-dimethoxy-2-pyridinyl)-methylsulphinyl)-1H-benz 2-methyl-1-2-(1-methylethyl)pyrazolo-1,5-alpyridin-3- imidazole(pantoprazole) or a hydrate, Solvate, Salt, hydrate yl)-1-propanone (IBUDILAST), (-)-cis-9-ethoxy-8-meth of a Salt or Solvate of a Salt thereof, and wherein the airway oxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropy therapeutic is selected from the group consisting of cis-4- lamino-carbonylphenyl)benzoc1,6-naphthyridine cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan (PUMAFENTRINE), 3-(cyclopropylmethoxy)-N-(3,5- 1-carboxylic acid (CILOMILAST), 2-methyl-1-2-(1-meth US 2005/0165041 A1 Jul. 28, 2005 ylethyl)pyrazolo-1,5-apyridin-3-yl)-1-propanone 33. A ready-to-use medicament according to claim 7, (IBUDILAST), (-)-cis-9-ethoxy-8-methoxy-2-methyl-1,2, wherein the proton pump inhibitor is 5-difluoromethoxy-2- 3,4,4a,10b-hexahydro-6-(4-diisopropylamino-carbonylphe I(3,4-dimethoxy-2-pyridinyl)-methylsulphinyl)-1H-benz nyl)benzoc1,6naphthyridine (PUMAFENTRINE), imidazole(pantoprazole) or a hydrate, Solvate, Salt, hydrate 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-dif of a Salt or Solvate of a Salt thereof, and wherein the airway luoromethoxy)benzamide (ROFLUMILAST), ROFLUMI therapeutic is cicleSonide. LASTN-OXIDE and the hydrates, Solvates, salts, hydrates 34. A ready-to-use medicament according to claim 8, of the salts and Solvates of the salts thereof. wherein the proton pump inhibitor is Selected from the group 28. A ready-to-use medicament according to claim 6, consisting of 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-py wherein the proton pump inhibitor is 5-difluoromethoxy-2- ridinyl)methylsulphinyl)-1H-benzimidazole(omeprazole), I(3,4-dimethoxy-2-pyridinyl)-methylsulphinyl)-1H-benz 5-methoxy-2-(S)-(4-methoxy-3,5-dimethyl-2-pyridinyl imidazole(pantoprazole) or a hydrate, Solvate, Salt, hydrate )methylsulphinyl)-1H-benzimidazole(esomeprazole), 2-3- of a Salt or Solvate of a Salt thereof, and wherein the airway methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulphi therapeutic is cicleSonide. nyl)-1H-benzimidizole(lansoprazole), 2-4-(3- 29. A ready-to-use medicament according to claim 7, methoxypropoxy)-3-methylpyridin-2-yl)methylsulphinyl wherein the proton pump inhibitor is Selected from the group 1H-benzimidazole(rabeprazole), 5-difluoromethoxy-2-(3, consisting of 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-py 4-dimethoxy-2-pyridinyl)methylsulphinyl)-1H ridinyl)methylsulphinyl)-1H-benzimidazole(omeprazole), benzimidazole(pantoprazole) and the hydrates, Solvates, 5-methoxy-2-(S)-(4-methoxy-3,5-dimethyl-2-pyridinyl Salts, hydrates of the Salts and Solvates of the Salts thereof. )methylsulphinyl)-1H-benzimidazole(esomeprazole), 2-3- 35. A ready-to-use medicament according to claim 8, methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulphi wherein the airway therapeutic is Selected from the group nyl)-1H-benzimidizole(lansoprazole), 2-4-(3- consisting of cis-4-cyano-4-(3-cyclopentyloxy-4-methox methoxypropoxy)-3-methylpyridin-2-yl)methylsulphinyl yphenyl)cyclohexan-1-carboxylic acid (CILOMILAST), 1H-benzimidazole (rabeprazole), 5-difluoromethoxy-2-(3, 2-methyl-1-2-(1-methylethyl)pyrazolo-1,5-alpyridin-3- 4-dimethoxy-2-pyridinyl)methylsulphinyl)-1H yl)-1-propanone (IBUDILAST), (-)-cis-9-ethoxy-8-meth benzimidazole pantoprazole) and the hydrates, Solvates, oxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropy Salts, hydrates of the Salts and Solvates of the Salts thereof. lamino-carbonylphenyl)benzoc1,6-naphthyridine 30. A ready-to-use medicament according to claim 7, (PUMAFENTRINE), 3-(cyclopropylmethoxy)-N-(3,5- wherein the airway therapeutic is Selected from the group dichloro-4-pyridyl)-4-difluoromethoxy)benzamide (ROF consisting of cis-4-cyano-4-(3-cyclopentyloxy-4-methox LUMILAST), ROFLUMILAST N-OXIDE and the yphenyl)cyclohexan-1-carboxylic acid (CILOMILAST), hydrates, Solvates, Salts, hydrates of the Salts and Solvates of 2-methyl-1-2-(1-methylethyl)pyrazolo-1,5-alpyridin-3- the salts thereof. yl)-1-propanone (IBUDILAST), (-)-cis-9-ethoxy-8-meth 36. A ready-to-use medicament according to claim 8, oxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropy wherein the airway therapeutic is ciclesonide. lamino-carbonylphenyl)benzoc1,6-naphthyridine 37. A ready-to-use medicament according to claim 8, (PUMAFENTRINE), 3-(cyclopropylmethoxy)-N-(3,5- wherein the proton pump inhibitor is 5-difluoromethoxy-2- dichloro-4-pyridyl)-4-difluoromethoxy)benzamide (ROF I(3,4-dimethoxy-2-pyridinyl)-methylsulphinyl)-1H-benz LUMILAST), ROFLUMILAST N-OXIDE and the imidazole(pantoprazole) or a hydrate, Solvate, Salt, hydrate hydrates, Solvates, Salts, hydrates of the Salts and Solvates of of a Salt or Solvate of a Salt thereof, and wherein the airway the salts thereof. therapeutic is selected from the group consisting of cis-4- 31. A ready-to-use medicament according to claim 7, cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan wherein the airway therapeutic is cicleSonide. 1-carboxylic acid (CILOMILAST), 2-methyl-1-2-(1-meth 32. A ready-to-use medicament according to claim 7, ylethyl)pyrazolo-1,5-apyridin-3-yl)-1-propanone wherein the proton pump inhibitor is 5-difluoromethoxy-2- (IBUDILAST), (-)-cis-9-ethoxy-8-methoxy-2-methyl-1,2, I(3,4-dimethoxy-2-pyridinyl)-methylsulphinyl)-1H-benz 3,4,4a, 10b-hexahydro-6-(4-diisopropylamino-carbonylphe imidazole(pantoprazole) or a hydrate, Solvate, Salt, hydrate nyl)benzoc1,6naphthyridine (PUMAFENTRINE), of a Salt or Solvate of a Salt thereof, and wherein the airway 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-dif therapeutic is selected from the group consisting of cis-4- luoromethoxy)benzamide (ROFLUMILAST), ROFLUMI cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan LASTN-OXIDE and the hydrates, solvates, salts, hydrates 1-carboxylic acid (CILOMILAST), 2-methyl-1-2-(1-meth of the salts and Solvates of the salts thereof. ylethyl)pyrazolo-1,5-apyridin-3-yl)-1-propanone 38. A ready-to-use medicament according to claim 8, (IBUDILAST), (-)-cis-9-ethoxy-8-methoxy-2-methyl-1,2, wherein the proton pump inhibitor is 5-difluoromethoxy-2- 3,4,4a,10b-hexahydro-6-(4-diisopropylamino-carbonylphe I(3,4-dimethoxy-2-pyridinyl)-methylsulphinyl)-1H-benz nyl)benzoc1,6naphthyridine (PUMAFENTRINE), imidazole(pantoprazole) or a hydrate, Solvate, Salt, hydrate 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-dif of a Salt or Solvate of a Salt thereof, and wherein the airway luoromethoxy)benzamide (ROFLUMILAST), ROFLUMI therapeutic is cicleSonide. LASTN-OXIDE and the hydrates, Solvates, salts, hydrates of the salts and Solvates of the salts thereof. k k k k k