WO2005074932A1

WO2005074932A1 - The use of (s) - pantoprazole magnesium for the treatment of airway disorders

Info

Publication number: WO2005074932A1
Application number: PCT/EP2005/050338
Authority: WO
Inventors: Reinhard Huber; Bernhard Kohl; Wolfgang Kromer; Wolfgang-Alexander Simon
Original assignee: Altana Pharma Ag
Priority date: 2004-01-28
Filing date: 2005-01-27
Publication date: 2005-08-18

Abstract

The invention relates to the use of (S)-pantoprazole magnesium and its hydrates in the treatment of airway disorders and to the combination of (S)-pantoprazole magnesium and its hydrates and airway therapeutics for the treatment of airway disorders.

Description

THE USE OF ( S) -PANTOPRAZOLE MAGNESIUM FOR THE TREATMENT OF AIRWAY DISORDERS

Technical field

The invention relates to a new medicinal use and to the combination of new and certain known active compounds for therapeutic purposes.

Technical background

In U. S. Patent 5,888,535, according to the abstract of said patent "methods and compositions are disclosed utilizing optically pure (-)-pantoprazole for the treatment of ulcers in humans while substantially reducing the concomitant liability of adverse effects associated with the racemic mixture of panto- prazole." - In U. S. Patent 6,410,569 the dihydrate of the magnesium salt of pantoprazole is disclosed. - Furthermore, compounds are known from the prior art which can be used for treating airway disorders and which are herein below referred to as airway therapeutics.

Prior art

In International Patent Application WO 03/075926 the use of Proton Pump Inhibitors (PPI) in the treatment of airway diseases is disclosed. In International Patent Application WO 03/094968 the combined use of Proton Pump Inhibitors (PPI) and airway therapeutics in the treatment of airway diseases is disclosed. In International Patent Application WO 96/22978, substituted phenyl compounds are described which are said to be useful as endothelin antagonists. The combination of these compounds with compounds of a variety of other substance classes, inter alia with proton pump inhibitors, is mentioned. However, no particular utility of these combinations is given. In International Patent Application WO 98/16228 the combined use of a H⁺,K^*-ATPase inhibitor and of a glucocorticoid in the treatment of asthma is described. International Patent Application WO 99/04816 relates to the combined use of a proton pump inhibitor and of an antibacterial active substance. International Patent Application WO 00/10529 relates to certain oral liquid mucoadhesive compositions, which may contain various pharmaceutically active classes compounds, and mixtures thereof. International Patent Application WO 00/69438 describes inter alia the use of an NK-1 antagonist and a proton pump inhibitor in the preparation of a pharmaceutical composition for use in the treatment of asthma conditions. T. O. Kiljander et al. (CHEST 1999; 116: 1257-1264) concluded after an 8-week double-blind, placebo-controlled crossover study with omeprazole as sole medication that there was a reduction in nocturnal asthma symptoms. W. J. Pan et al. (Aliment. Pharmacol. Ther.2000; 14: 345-352) found a lack of pharmacokinetic interaction between lansoprazole or pantoprazole and theophyllin, without studying any effects of these combinations on asthma symptoms. J. Cuppoletti et al. (Clinical and Experimental Pharmacology and Physiology (2000) 27, 896-900) describe the activation of human CIC-2 CI^" channels and the resulting implications for cystic fibrosis. D. Stancic-Rokotov et al. describe the beneficial effect of e. g. omepra- zole on HCI-induced lung lesions in rats. - In Chinese patent application 1369491 the potassium, sodium, magnesium, calcium and zinc salts of S(-)-pantoprazole and R(+)-pantoprazole are described.

Description of the invention

Surprisingly, it has now been found that (S)-pantoprazole magnesium and its hydrates, whose original field of use is the treatment of gastric and intestinal disorders, is , alone or in combination with airway therapeutics, particularly suitable for the treatment of airway disorders.

The invention thus relates in a first aspect to the use of (S)-pantoprazole magnesium and its hydrates in the treatment of airway disorders.

In a second aspect, the invention provides the combined use of (S)-pantoprazole magnesium and its hydrates and airway therapeutics for treating airway disorders.

Within the scope of this invention, "(S)-pantoprazole magnesium and its hydrates" is understood to include:

- (S)-pantoprazole magnesium [which is the same as (-)-pantoprazole magnesium]

- (S)-pantoprazole magnesium hydrates [(-)-pantoprazole magnesium hydrates]

- (S)-pantoprazole magnesium [(-)-pantoprazole magnesium] being substantially free of (R)- pantoprazole magnesium [(+)-pantoprazole magnesium]

- (S)-pantoprazole magnesium hydrates [(-)-pantoprazole magnesium hydrates] being substantially free of (R)-pantoprazole magnesium hydrates [(+)-pantoprazole magnesium hydrates].

"Substantially free" in the context of the invention means that (S)-pantoprazole magnesium and its hydrates contains less than 10 % by weight of (R)-pantoprazole magnesium and its hydrates. Preferably, "substantially free" means that (S)-pantoprazole magnesium and its hydrates contains less than 5 % by weight of (R)-pantoprazole magnesium and its hydrates. In the most preferred embodiment, "substantially free" means that (S)-pantoprazole magnesium and its hydrates contains less than 1 % by weight of (R)-pantoprazole magnesium and its hydrates.

Among the (S)-pantoprazole magnesium hydrates, the dihydrate [(S)-pantoprazole magnesium di- hydrate] has to be mentioned particularly.

Airway disorders to be treated which may be mentioned in particular are pulmonary abnormalities such as bronchitis (including COPD), asthma (particularly night-time asthma attacks), pneumonitis and pulmonary fibrosis.

The invention relates in a further aspect to the use of (S)-pantoprazole magnesium and its hydrates for the treatment of patients who are suffering from an airway disorder. The invention further relates to a method for the treatment of airway disorders which consists in administering to a patient who needs such a treatment an effective amount of (S)-pantoprazole magnesium or its hydrate.

The invention further relates to the use of (S)-pantoprazole magnesium and its hydrates for the production of medicaments for the treatment of airway disorders.

The invention further relates to a pharmaceutical preparation for the treatment of airway disorders which contains (S)-pantoprazole magnesium and/or its hydrate as active compound.

The invention further relates to a ready-to-use medicament, comprising (S)-pantoprazole magnesium and/or its hydrate as active compound, which contains a reference to the fact that this ready-to-use medicament can be employed for the treatment of airway disorders.

Airway therapeutics which are suitable for the combined use with (S)-pantoprazole magnesium and its hydrates for the purpose of the invention are active compounds from different classes of active compounds [with the exception of glucocorticoids in general, except ciclesonide, and with the exception of tachykinine NK-i antagonists], such as, for example, the following:

- β₂-adrenoceptor agonists (in particular selectively acting substances having only slight cardiac action which, as a result, are also suitable for use in the therapy of airway disorders), such as, for example, 4-hydroxy-7-[2-[2-[3-(2-phenylethoxy)propoxy]ethylamino]ethyl]benzothiazol-2(3H)-one (AR- C68164AA),

3-[2-(4-hydroxy-2-oxo-2,3-dihydrobenzothiazol-7-yl)ethylamino]-N-[2-[2-(4-methylphenyl)ethoxy]ethyl]- propanesulphonamide (AR-C89855AA),

5-[2-[N-(dimethylaminocarbonyl)-N-(1 ,1 -dimethylethyl)amino]-1 -hydroxyethyl]-1 ,3-benzenediol (BAM- BUTEROL),

4-methylbenzoic acid 4-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-1,2-phenylene ester (Bl- TOLTEROL),

3-bromo-α-[(tert-butylamino)methyl]-5-isoxazolemethanol (BROXATEROL), [5-[2-[(1 , 1 -dimethylethyl)amino]-1 -hydroxyethyl]-2-hydroxyphenyl]urea (CARBUTEROL), 4-[2-(6-phenethylaminohexylamino)ethyl]benzene-1,2-diol (DOPEXAMINE), N-(3,3-diphenylpropyl)-α-methylcyclohexaneethylamine (DROPRENILAMINE), (+/-)-2'-hydroxy-5'-[(RS)-1-hydroxy-2-[[(RS)-p-methoxy-α-methylphenethyl]amino]ethyl]formanilide (FORMOTEROL),

(R)-α [(tert-butylamino)methyl]-4-hydroxy-m-xylene-α,α'-diol (LEVOSALBUTAMOL), 4-amino-3-chloro-α-[[(1 , 1 -dimethylethyl)amino]methyl]-5-(trifluoromethyl)benzenemethanol (MA- BUTEROL),

(-)-(R)-2-(tert-butylamino)-1-(2-chloro-4-hydroxyphenyl)ethanol (MELUADRINE), (+/-)-5,6-diisobutyryloxy-2-(methylamino)-1_!2,3,4-tetrahydronaphthalene (NOLOMIROLE), (RS)-{6-[2-(tert-butylamino)-1-hydroxyethyl]-3-hydroxy-2-pyridyl}methanol (PIRBUTEROL), 7-[3-[[2-(3,5-dihydroxyphenyl)-2-hydroxyethyl]amino]propyl]-3,7-dihydro-1,3-dimethyl-1H-purine-2,6- dione (REPROTEROL), α(1 )-[[(1 ,1 -dimethylethyl)amino]methyl]-4-hydroxy-1 ,3-benzenedimethanol (SALBUTAMOL),

(+/-)-N-[2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]-N-[6-(4-phenylbutoxy)hexyl]amine

(SALMETEROL),

4-hydroxy-7-[2-[2-[3-(2-phenylethoxy)propylsulphonyl]ethylamino]ethyl]benzothiazol-2(3H)-one (SIBE-

NADET),

[R-(R*_lR*)]-8-hydroxy-5-[1-hydroxy-2-[2-(4-methoxyphenyl)-1-methylethylamino]ethyl]-2(1H)-quinoline

(TA-2005),

5-[2-[(1 ,1-dimethylethyl)amino]-1-hydroxyethyl]-1 ,3-benzenediol (TERBUTALINE),

5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl-2-benzothiazolinone (TIARA IDE) and α-[(tert-butylamino)methyl]-o-chlorobenzyl alcohol (TULOBUTEROL);

- muscarinic receptor antagonists, such as, for example, endo-8-(2-fluoroethyl)-3-[(hydroxydiphenylacetyl)oxy]-8-methyl-8-azoniabicyclo[3.2.1]octane bromide (FLUTROPIUM BROMIDE),

3-(3-hydroxy-2-phenylpropanoyloxy)-8-isopropyl-8-methyl-8-azoniabicyclo[3.2.1]octane bromide (IP- RATROPIUM BROMIDE),

(8r)-6β-7β-epoxy-8-ethyl-3-α-hydroxy-1-αH-5-αH-tropanium bromide (OXITROPIUM BROMIDE), (R)-3-quinuclidinyl (S)-β-hydroxy-α-[2-(R)-methylsulphinyl]ethyl]hydratrapate (REVATROPATE) and [7(S)-(1 α_J2β,4β,5 α,7β)]-7-[2-hydroxy-2,2-di(2-thienyl)acetoxy]-9,9-dimethyl-3-oxa-9-azoniatri- cyclo[3.3.1.0(2,4)]nonane bromide (TIOTROPIUM BROMIDE);

- theophylline-like bronchodilators, such as, for example,

3,7-dihydro-1 ,3-dimethyl-1 H-purine-2,6-dione/1 ,2-ethanediamine (AMINOPHYLLINE),

3,7-dihydro-1 ,3-dimethyl-7-[(5-methyl-1 ,2,4-oxadiazol-3-yl)methyl]-1 H-purine-2,6-dione (CHINOIN-

170),

7-(2,3-dihydroxypropyl)-1 ,2,3,6-tetrahydro-l ,3-dimethylpurine-2,6-dione (DIPROPHYLLINE),

7-(1 ,3-dioxolan-2-ylmethyl)-3,7-dihydro-1 ,3-dimethyl-1 H-purine-2,6-dione (DOXOFYLLINE),

[R-(R*,S*)]-3-[(2-hydroxy-1 -methyl-2-phenylethyl)amino]-1 -(3-methoxyphenyl)-1 -propanone (OXY-

FEDRINE),

3,7-dimethyl-1-hexyl-1 H,3H-purine-2,6-dione (PENTIFYLLINE),

3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione (PENTOXIFYLLINE),

3,7-dihydro-3-methyl-1-(5-oxohexyl)-7-propyl-1H-purine-2,6-dione (PROPENTOFYLLINE),

3,7-dihydro-7-(2-hydroxypropyl)-1 ,3-dimethyl-1 H-purine-2,6-dione (PROXYPHYLLINE) and

3,7-dihydro-1 ,3-dimethyl-1 H-purine-2,6-dione (THEOPHYLLINE);

- PDE3/4- and PDE4 inhibitors, such as, for example, the compounds mentioned as examples in the following patent applications and patents:

EP 0163965, EP 0389282, EP 0393500, EP 0435811, EP 0482302, EP 0499216, EP 0506194, EP 0510562, EP 0528922, EP 0553174, EP 0731099, WO 9319749, WO 9500516, WO 9501338, WO 9600218, WO 9603399, WO 9611690, WO 9636625, WO 9636626, WO 9723457, WO 9728131, WO 9735854, WO 9740032, WO 9743288, WO 9809946, WO 9807715, WO 9808841, WO 9821207, WO 9821208, WO 9821209, WO 9822453, WO 9831674, WO 9840382, WO 9855481, WO 9905111, WO

9905112, WO 9905113, WO 9931071, WO 9931090, WO 9947505, WO 9957115, WO 9957118, WO

9964414, WO 0001695, WO 0012501, WO 0042017, WO 0042018, WO 0042019, WO 0042020, WO

0042034, WO 0119818, WO 0130766, WO 0130777 and WO0151470, in particular the compounds

(Z)-3-(3,5-dichloro-4-pyridyl)-2-[4-(2-indanyloxy-5-methoxy-2-pyridyl]propenenitrile,

N-[9-amino-4-oxo-1 -phenyl-3,4,6,7-tetrahydropyrrolo[3,2, 1 -jk][1 ,4]benzodiazepin-3(R)-yl]pyridine-3- carboxamide (CI-1044),

3-(benzyloxy)-1-(4-fluorobenzyl)-N-[3-(methylsulphonyl)phenyl]-1H-indole-2-carboxamide,

(1 S-exo)-5-[3-(bicyclo[2.2.1 ]hept-2-yloxy)-4-methoxyphenyl]tetrahydro-2(1 H)-pyrimidinone

(ATIZORAM),

N-(3,5-dichloro-4-pyridinyl)-2-[1 -(4-fluorobenzyl)-5-hydroxy-1 H-indol-3-yl]-2-oxoacetamide (AWD-12-

281), β-[3-(cyclopentyloxy)-4-methoxyphenyl]-1 ,3-dihydro-1 ,3-dioxo-2H-isoindole-2-propanamide (CDC-801 ),

N-[9-methyl-4-oxo-1 -phenyl-3,4,6,7-tetrahydropyrrolo[3,2, 1 -jk][1 ,4]benzodiazepin-3(R)-yl]pyridine-4- carboxamide (CI-1018), cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid (CILOMILAST),

8-amino-1 ,3-bis(cydopropylmethyl)xanthine (CIPAMFYLLINE),

N-(2,5-dichloro-3-pyridinyl)-8-methoxy-5-quinoli necarboxamide (D-4418),

5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-iminothiazolidin-4-one (DARBUFELONE),

2-methyl-1 -[2-(1 -methylethyl)pyrazolo[1 ,5-a]pyridin-3-yl]-1 -propanone (IBUDI LAST),

2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzofuran-6-yl methanesulphonate (LIRIMILAST),

(-)-(R)-5-(4-methoxy-3-propoxyphenyl)-5-methyloxazolidin-2-one (MESOPRAM),

(-)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)- benzo[c][1 ,6]naphthyridine (PUMAFENTRINE),

3-(cycIopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)benzamide (ROFLUMILAST), the N-oxide of ROFLUMILAST,

(RS)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidinone (ROLIPRAM),

5,6-diethoxybenzo[b]thiophene-2-carboxylic acid (TIBENELAST),

2,3,6,7-tetrahydro-2-(mesitylimino)-9, 10-dimethoxy-3-methyl-4H-pyrimido[6, 1 -a]isoquinolin-4-one

(TREQUINSIN) and

3-[[3-(cyclopentyloxy)-4-methoxyphenyl]methyl]-N-ethyl-8-(1-methylethyl)-3H-purine-6-amine (V-

11294 A);

- prostaglandin D₂ antagonists, such as, for example,

(1R,2R,3S,5S)-7-[2-(5-hydroxybenzothiophen-3-ylcarboxamido)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]- 5(Z)-heptenoic acid (S-5751);

- adenosine A₃ antagonists, such as, for example,

3-ethyl 5-(3-methylbenzyl) 2-methyl-6-phenyl-4-(phenylethynyl)-1,4-dihydropyridine-3,5-dicarboxylate

(MRS-1328), propyl 6-ethyl-5-(ethylsulphanylcarbonyl)-2-phenyl-4-propyl-pyridine-3-carboxylate (MRS-1523), ethyl 6-ethyl-5-(ethylsulphanylcarbonyl)-2-phenyl-4-propylpyridine-3-carboxylate (MRS-1476), propyl 2-(3-chlorophenyl)-4,6-diethyl-5-(propylsulphanylcarbonyl)-pyridine-3-carboxylate (MRS-1505), ethyl 4-ethyl-5-(ethylsulp anylcarbonyl)-2-phenyl-6-propylpyridine-3-carboxylate (MRS-1486) and cis-3-(5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin^-ylamino)cyclopentanol (CDS-90910);

- bradykinin B2 antagonists, such as, for example,

D-arginyl-L-arginyl-L-prolyl-L-(4-hydroxy)prolyl-glycyl-L-(2-thienyl)alanyl-L-seryl-D-(1,2,3,4- tetrahydroisoquinolin-3-ylcarbonyl)-(N-cyclohexyl)glycyl-L-arginine (CP-0597), (E)-N-[N-[3-(3-bromo-2-methylimidazo[1,2-a]pyridin-8-yloxymethyl)-2,4-dichlorophenyl]-N- methylcarbamoylmethyl]-4-(N,N-dimethylcarbamoyl)cinnamamide (FR-167344), 3-(6-acetamido-3-pyridyl)-N-[N-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]-N- methylcarbamoylmethyl]-2(E)-propenamide (F R-173657),

D-arginyl-arginyl-prolyl-[4(R)-hydroxy]prolyl-glycyl-(2-thienyl)alanyl-seryl-[1,2,3,4-tetrahydroisoquinolin- 3(R)-ylcarbonyl]-[(3aS,7aS)-octahydroindol-2(S)-ylcarbonyl]-arginine (ICATIBANT), 1-[4-(aminoiminomethyl)benzoyl]-4-[[(2S)-1-[[2,4-dichloro-3-[[(2,4-dimethyl-8-quinolinyl)oxy]methyl]- phenyl]sulphonyl]-2-pyrrolidinyl]carbonyl]piperazine (LF-16.0335) and D-arginyl-L-arginyl-L-prolyI-L-(trans-4-hydroxy)prolyl-glycyl-L-phenylalanyl- L-seryl-D-(trans-4- propoxy)prolyl-L-[(2α,3β,7β)octahydroindol- 2-ylcarbonyl]-L-arginine (NPC-17731 );

- leukotriene LTB antagonists, such as, for example,

N-(ethoxycarbonyl)-4-[3-[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxymethyl]benzyloxy]benzene- carboximidamide (AMELUBANT),

2-[3-[3-(5-ethyl-4'-fluoro-2-hydroxybiphenyl-4-yloxy)propoxy]-2-propylphenoxy]benzoic acid (LY- 293111) and 4-[5-(4-amidinophenoxy)pentyloxy]-N,N-diisopropyl-3-methoxybenzamide (MOXILUBANT);

- cysteinyl-leukotriene_ϊ receptor antagonists, such as, for example,

9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (AS-35),

(+)-4(S)-(4-carboxyphenylthio)-7-[4-(4-phenoxybutoxy)phenyl]-5(Z)-heptenoic acid (BAY-X-7195), (E)-4-[3-[2-(4-cyclobutylthiazol-2-yl)vinyl]phenylamino]-2,2-diethyl-4-oxobutanoic acid (CINALUKAST), 6-(2-cyclohexylethyl)-[1 ,3,4]thiadiazolo[3,2-a]1 ,2,3-triazolo[4,5-d]pyrimidin-9(1 H)-one (DS-4574), 7-[(1R,2S)-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-1-hydroxy-1-(3-trifluoromethylphenyl)deca- 3(E),5(Z)-dien-2-ylthio]-4-oxo-4H-1-benzopyran-2-carboxylic acid (IRALUKAST), 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyric acid (KCA- 757),

4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulphonyl]-gamma-oxobenzenebutyricacid (L-648051) (E)-2,2-diethyl-3'-[2-[2-(4-isopropyl)thiazolyl)ethenyl]succinanilinic acid (MCI-826),

2-[1 -[1 (R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1 -hydroxy-1 -methylethyl)phenyl]propyl- sulphanylmethyl]cyclopropyl]acetic acid (MONTELUKAST),

8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5-yl)-4H-1-benzopyran-4-one (PRANLUKAST), 2(S)-hydroxy-3(R)-(2-carboxyethylthio)-3-[2-(8-phenyloctyl)-phenyl]propionic acid (POBILUKAST), 5-[2-[4-(quinolin-2-yl)methoxyphenoxymethyl]benzyl]tetrazole (RG-12525), 5-[3-[3-(2-quinolinylmethoxy)phenoxy]propyl]-1 H-tetrazole (RG-7152), 1,1,1-trifluoro-N-[3-(2-quinolinylmethoxy)phenyl]methanesulphonamide (RITOLUKAST) (1 S,2R)-5-[3-[2-(2-carboxyethylthio)-1 -hydroxypentadeca-3(E),5(Z)-dienyl]phenyl]-1 H-tetrazole (SU-

LUKAST),

2'-hydroxy-3'-propyl-4'-[4-(1H-tetrazol-5-yl)butoxy]acetophenone (TOMELUKAST),

5-[3-[2-(7-chloroquinolin-2yl)vinyl]phenyl]-8-(dimethylcarbamoyl)-4,6-dithiaoctanoic acid (VERLU-

KAST),

[[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazol-2-yl]thio]acetic acid (YM-638),

4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-yl-methyl)-3-methoxy-N-o-tolylsulphonylbenzamide

(ZAFIRLUKAST) and

1(R)-3-methoxy-4-[1-methyl-5-[N-(2-methyl-4,4,4-trifluorobutyl)carbamoyl]indol-3-ylmethyl]-N-(2- methylphenylsulphonyl)benzamide (ZD-3523);

- leukotriene synthesis inhibitors, such as, for example,

(+)-N-[3-[5-(4-fluorophenoxy)-2-furyl]-1 (R)-methyl-2-propynyl]-N-hydroxyurea (ABT-175), (R)-N-[3-[5-(4-fluorobenzyl)thien-2-yl]-1-methyl-2-propynyl]-N-hydroxyurea (ATRELEUTON), (R)-2-cyclopentyl-2-[4-(quinolin-2-ylmethoxy)phenyl]acetic acid (BAY-X-1005), (-)-2(R)-cycloheptyl-2-[4-(2-quinolylmethoxy)phenyl]-N-(methylsulphonyl)acetamide (BAY-Y-1015), N-(3-phenoxycinnamyl)acetohydroxamic acid (BWA-4C),

(2S,5S)-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)tetrahydrofuran (CMI-977), (+/-)-4-(p-fluorobenzyl)-2-(hexahydro-1-phenethyl-1 H-azepin-4-yl)-1 (2H)-phthalazinone (FLEZE- LASTINE),

1-[[5'-(3"-methoxy-4"-ethoxycarbonyloxyphenyl)-2',4'-pentadienoyl]aminoethyl]-4-diphenylmethoxy- piperidine (LINETASTINE),

3-[1-(4-chlorobenzyl)-3-(tert-butylthio)-5-isopropylindol-2-yl]-2,2-dimethylpropionic acid (MK-886), (S)-N-[2-cyclohexyl-1(S)-(2-pyridyl)ethyl]-5-methylbenzoxazole-2-amine (ONTAZOLAST), [4R-[4α(1 E,3S*),5β]-1 ,4,5,6-tetrahydro-5-hydroxy-4-(3-hydroxy-1 -octenyl)-1 -phenylcyclopen- ta[b]pyrrole-2-pentanoic acid (PIRIPROST),

4-hydroxy-1 -phenyl-3-(1 -pyrrolidinyl)-1 ,8-naphthyriden-2(1 H)-one (PIRODOMAST),

N-[3-(6-methyl-3-pyridyl)acryloxy]-4-(4-diphenylmethyl-1-piperazinyl)butylamine (TAGORIZINE),

4,4-bis[4-(quinolin-2-ylmethoxy)phenyl]pentanoic acid (VML-530),

6-[3-fluoro-5-(4-methoxytetrahydropyran-4-yl)phenoxymethyl]-1 -methylquinolin-2(1 H)-one (ZD-2138) and

(+/-)-1 -(1 -benzo[b]thien-2-ylethyl)-1 -hydroxyurea (ZILEUTON);

- lipoxygenase inhibitors, such as, for example,

N-[3-[5-(4-fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]-N-hydroxyurea (A-78773), 1-(6-phenoxy-2H-1-benzopyran-3-ylmethyl)-1-hydroxyurea (CGS-23885), 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (DOCEBENONE), 4-[[(6-hydroxy-4,5,7-trimethyl-2-benzothiazolyl)amino]methyl]benzenesulphonamide (E-6080), N-[2-[4-(diphenylmethoxy)piperidin-1-yl]ethyl]-3-hydroxy-5-(3-pyridylmethoxy)naphthalene-2- carboxamide (NC-2000),

2-[3-(1-hydroxyhexyl)phenoxymethyl)quinoline (REV-5901A), [2-[3,5-bis(tert-butyl)-4-hydroxyphenylthio]-1 -methylpropoxy]acetic acid (SC-45662), 4-hydroxy-7-(4-hydroxy-3,5-dimethoxycinnamoylamino)-1-methyl-3-octyloxy-2(1H)-quinoline (TA-270), 3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)pyrazol-3-yl]-N-hydroxy-N-methylpropionamide (TEPOXA- LIN),

S-(+)-α-methyl-6-(2-quinolinylmethoxy)-2-naphthaleneacetic acid (WY-50295) and

(2S,4R)-5-[4-(4-hydroxy-2-methyltetrahydropyran-4-yl)-thien-2-ylsulphanyl]-1-methyl-2,3-dihydro-1H- indol-2-one (ZD-4407);

- inhibitors of mediator release, such as, for example,

N,N'-(2-chloro-5-cyano-m-phenylene)bis[glycolamide] diacetat (ACREOZAST),

1-[4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone (AHR-

5333B),

8-hexyloxy-3-(1 H-tetrazol-5-yl)-2H-chromen-2-one (AL-136),

2-amino-7-isopropyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid (AMLEXANOX),

4-(1 H-tetrazol-5-yl)-N-[4-(1 H-tetrazol-5-yl)phenyl]benzamide (ANDOLAST),

2-ethoxyethyl -[4-(3-methylisoxazol-5-yl)thiazol-2-yl]oxamate (ASOBAMAST),

3-[3-(methylcarbamoyloxy)propyl]-1 -propylquinoxalin-2(1 H)-one (BAMAQUIMAST),

4'-tert-butylphenyl trans-4-guanidinomethylcyclohexanecarboxylate (BATEBULAST),

6-butyryl-1-ethyl-4-hydroxy-7-methyl-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid (CGP-25875),

5-methoxy-3-isopropoxy-1-phenyl-N-(1 H-tetrazol 5-yl)-1H-indole-2-carboxamide (CI-949),

3-isopropoxy-5-methoxy-N-(1 H -tetrazol-5-yl)benzo[b]thiophene-2-carboxamide (CI-959), diethyl 1,3-bis[2-(ethoxycarbonyl)-4-oxo-4H-benzo[b]pyran-5-yloxy]-2-propyl-L-lysinate (CROMOGLI-

CATE LISETIL),

5,5'-(2-hydroxytrimethylenedioxy)bis(4-oxo-4H-1-benzopyran-2-carboxylic acid) (CROMOGLYCINIC

ACID),

11 -oxo-11 H-pyrido[2, 1 -b]quinazoline-2-carboxylic acid (DOQUALAST),

1-[2-[(2,6-dimethyl-3-nitro-4-pyridyl)amino]ethyl]-4-(diphenylmethyl)piperazine (ELBANIZINE),

6-(1-pyrrolidinyl)-N-(1 H-tetrazol-5-yl)pyrazine-2-carboxamide (HSR-6071 ),

2-(ethoxymethyl)pteridin-4(3H)-one (LCB-2183),

1 ,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidine-carboxylic acid (MAR-99),

4,6-dioxo-1-ethyl-10-propyl-4H,6H-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid (NEDOCROMIL),

3-(5-methylfurfuryl)-2-(4-piperidylamino)-3H-imidazo[4,5-b]pyridine (NOBERASTINE),

1-[3-[4-(diphenylmethyl)-1-piperazinyl]propyl]-2-benzimidazolinone (OXATOMIDE),

9-methyl-3-(1 H-tetrazol-5-yl)-4H-pyrido[1 ,2-a]pyrimidin^-one (PEMIROLAST),

7-[3-[4-[(4-chlorophenyl)methyl]-1-piperazinyl]propoxy]-3,4-dimethyl-2H-1-benzopyran-2-one (PICU-

MAST),

9-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-2,4-bis(pyrrolidin-1-yl)-9H-pyrimido[4,5-b]indole (PNU-142731A)

2-carbomethoxy-5-chloro-1 ,3-oxazolo[4,5-h]quinoline (QUAZOLAST),

4-oxo-1-phenoxy-N-1H-tetrazol-5-yl-4H-quinolizine-3-carboxamide (QUINOTOLAST), isoamyl 5,6-dihydro-7,8-dimethyI-4,5-dioxo-4H-pyrano[3,2-c]quinoline-2-carboxylate (REPIRINAST),

[2-[4-(3-ethoxy-2-hydroxopropoxy)phenylcarbamoyl]ethyl]dimethylsulphonium p-toluenesulphonate

(SUPLATAST TOSILATE),

6-methyl-N-(1 H-tetrazol-5-yl)-2-pyridine (TA-5707), butyl N-[3-(1H-tetrazol-5-yl)phenyl]oxamate (TAZANOLAST), ethyl 4-methoxyphenyl-4-thiazolyl-2-oxamat (TIOXAMAST) and N-acetylaspartyl-glutamic acid magnesium salt (ZY-15106);

- tachykinin NK₂ antagonists, such as, for example,

(S)-N-[4-(4-acetamido-4-phenylpiperidin-1-yl)-2-(3,4-di-chlorophenyl)-butyl]-N-methylbenzamide (SAREDUTANT);

- thromboxan A₂ antagonists, such as, for example,

4-[2-(4-chlorobenzenesulfonylamino)ethyl]benzeneacetic acid (DALTROBAN), 3-(1 H-imidazol-1-ylmethyl)-2-methyl-1 H-indol-1-propionic acid (DAZMEGREL), (+)-(Z)-7-[3-endo-(phenylsulfonylamino)bicyclo[2.2.1]hept-2-exo-yl]-heptenoic acid (DOMITROBAN), 7-[2α,4α-(dimethylmethano)-6-β-(2-cyclopentyl-2β-hydroxyacetamido)-1α-cyclohexyl]-5(Z)-heptenoic acid (ONO-3708) and

3-(4-tert-butylthiazol-2-ylrnethoxy)-N-[5-[3-(4-chlorophenylsulfonyl)propyl]-2-(1H-tetrazol-5- ylmethoxy)phenyl]benzamide (YM-158);

- thromboxan synthase inhibitors, such as, for example, 2-(1-imidazolylmethyl)-4,5-dihydrobenzo[b]thiophen-6-carboxylic acid (MITRODAST),

1 -[3-[4-(diphenylmethyl)piperazin-1 -yl]propyl]-3-(imidazol-1 -ylmethyl)-indol-6-carboxylic acid (KY-234), (E)-3-[4-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic acid (OZAGREL) and 4-[α-hydroxy-5-(1 -imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid (Y-20811 );

- α₄βr(VLA-4) antagonists, such as, for example,

3-(1,3-benzodioxol-5-yl)-3-[N-[2-(4-hydroxyphenyl)acet-yl]-D,L-leucyl-amino]propionic add (BIO-1006), N-[[4-[[[(2-methylphenyl)amino]carbonyl]amino]phenyl]-acetyl]-L-leucyl-L-a-aspartyl-L-valyl-L-proline (BIO-1211),

N-[5,5-dimethyl-3-(4-methylphenylsulfonyl)thiazolidin-4(R)-ylcarbonyl]- 4-0-[3-(dimethylamino)propyl]- L-tyrosine (CT-747),

N-(4-methylphenylsulfonyl)-L-prolyl-L-phenylalanine (CT-757),

N-(4-methylphenylsulfonyl)-L-prolyl-4-(4-piperidinyl-carboxamido)-L-phenylalanine (CT-767), N-[3-acetyl-4(S)-thiazolidinylcarbonyl]-L-[4-0-(2,6-dichlorobenzyl)]-tyrosine (CT-5219), 1-methyl-4-[N-methyl-N-(2-phenylacetyl)-L-leucyl-L-aspartyl-L-phenylalanyl]-piperazine (CY-9701), 3-[N-(3,4-dimethoxybenzyl)-N-[2-[2-[3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl]acet- amido]acetyl]amino]-propionic acid (IVL-745),

3(R)-[1-[2-[4-[3-(2-methylphenyl)ureido]phenyl]acetyl]-pyrrolidin-2(S)-ylcarboxamido]butyric acid (O- MEPUPA-V),

3(S)-(1,3-benzodioxol-5-yl)-3-[3-[2-(benzylsulfanyl)-1(S)-(phenylsulfanyl-methyl)ethyl]ureido]-propionic acid (TBC-3342),

3(S)-(1,3-benzodioxol-5-yl)-3-[N3-[1(S)-[N,N-bis(2-thienylmethyl)-carbamoyl]pentyl]ureido]propionic acid (TBC-3486),

N-[3(R)-carboxy-2,2,3-trirnethylcyclopent-1(S)-ylcarbonyl]-4-(2,6-dichlorobenzamido)-L-phenylalanine (TR-9109),

2(S)-(2,6-dichlorobenzamido)-3-(2',6*-dimethoxybiphenyl-4-yl)-propionic acid (TR-14035) and 3-[4-(4-carbamoylpiperidin-1-ylcarbonyloxy)phenyl]-2(S)-[4-methyl-2(S)-[2-(2-methylphenoxy)acet- amido]pentanamido]-propionic acid; - VCAM inhibitors, such as, for example,

4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxamide (A-249377), 4-(4-bromophenoxy)-N-methylthieno[2,3-c]pyridine-2-carboxamide (A-277232), N-methyl-4-[4-(trifluoromethyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide (A-277249), 1-[2-[2,3-dichloro-4-[trans-2-[N-[3-(2-oxopyrrolidin-1-yl)propyl]carbamoyl]cyclopropyl]phenylsulfanyl]- phenyl]-piperidin-3-carboxylic acid (A-324920),

5(R)-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-1 ,5-dimethylimidazolidine-2,4-dione (BIRT-377) and N-(phenylsulfonyl)-4(S)-phenyl-L-prolyl-4-(2,6-dimethoxyphenyl)-L-phenylalanine (TR-14531 ), and

- chimase inhibitors, such as, for example,

3-carboxyphenylmethyl (6R,7R)-7-methoxy-7-[(2-methoxybenzoyl)amino]-3-[[(1-methyl-1H-tetrazol-5- yl)thio]methyl]-8-oxo-5-oxa-1 -azabicyclo[4.2.0]oct-2-en-2-carboxylate (B-135),

4-carboxyphenylmethyl (6R,7R)-7-methoxy-7-[(2-methoxybenzoyl)amino]-3-[[(1-methyl-1H-tetrazol-5- yl)thio]methyl]-8-oxo-5-oxa-1 -azabicyclo[4.2.0]oct-2-en-2-carboxylate (B-136),

3-methylphenylmethyl (6R,7R)-7-methoxy-7-[(2-methoxybenzoyl)amino]-8-oxo-3-[[[1-[2-oxo-2-(2- propenyloxy)ethyl]-1H-tetrazol-5-yl]thio]methyl]-5-oxa-1-azabicydo[4.2.0]oct-2-ene-2-carboxylate (B-

146),

3-methyIbenzyl (6R,7R)-3-[1-(carboxymethyl)tetrazol-5-ylsulfanylmethyl]-7-methoxy-7-(2- methoxybenzamido)-1-oxa-3-cephem-4-carboxylate (B-152) and

3-methylbenzyl (6R,7R)-3-[1-(carboxymethyl)tetrazol-5-ylsulfanylmethyl]-7-methoxy-7-(2- ethoxybenzamido)-1 -oxa-3-cephem-4-carboxylate (B-153).

The airway therapeutics can be present as such or in chemically bonded form. It is understood hereby that the active compounds mentioned can also be present, for example, in the form of their pharmacologically acceptable salts and/or as solvates (e.g. hydrates), and/or in the form of their N-oxides etc. Suitable pharmacologically acceptable salts here are in particular water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxy- benzoyl)benzoic acid, butyric acid, sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonic acid, methanesulphonic acid or 1-hydroxy-2-naphthoic acid, the acids being employed in salt preparation - depending on whether it is a mono- or polybasic acid and depending on which salt is desired - in an equimolar quantitative ratio or one differing there from. Furthermore, the active compounds mentioned can also be present as pure enantiomers or as enantiomer mixtures in any mixing ratio.

Airway therapeutics to be emphasized as being suitable for combined application with (S)-pantoprazole magnesium and its hydrates in the meaning of the invention are in particular

- from the class of the β₂-adrenoceptor agonists the active compounds

BAMBUTEROL, BITOLTEROL, BROXATEROL, CARBUTEROL, DOPEXAMINE, DROPRENILAMINE, FORMOTEROL, R.R-FORMOTEROL, LEVOSALBUTAMOL, MABUTEROL, PIRBUTEROL, REPRO- TEROL, SALBUTAMOL, SALMETEROL, TERBUTALINE, TIARAMIDE and TULOBUTEROL;

- from the class of the muscarinic receptor antagonists the active compounds FLUTROPIUM BROMIDE, IPRATROPIU BROMIDE, OXITROPIUM BROMIDE and TIOTROPIUM BROMIDE;

- from the class of the theophylline-like bronchodilators the active compounds AMINOPHYLLINE, DIPROPHYLLINE, DOXOFYLLINE, OXYFEDRINE, PENTIFYLLINE, PENTOXI- FYLLINE, PROPENTOFYLLINE and PROXYPHYLLINE;

- from the class of the PDE3/4- and PDE4 inhibitors the active compounds (Z)-3-(3,5-dichloro-4-pyridyl)-2-[4-(2-indanyloxy-5-methoxy-2-pyridyl]propenenitrile, N-[9-amino-4-oxo-1 -phenyl-3,4,6,7-tetrahydropyrrolo[3,2, 1 -jk][1 ,4]benzodiazepin-3(R)-yl]pyridine-3- carboxamide (CI-1044),

N-(3,5-dichloro-4-pyridinyl)-2-[1 -(4-fluorobenzyl)-5-hydroxy-1 H-indol-3-yl]-2-oxoacetamide (AWD-12- 281), cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid (CILOMILAST), 8-amino-1 ,3-bis(cyclopropylmethyl)xanthine (CIPAMFYLLINE), 2-methyl-1 -[2-(1 -methylethyl)pyrazolo[1 ,5-a]pyridin-3-yl]-1 -propanone (IBUDI LAST), 2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzofuran-6-yl methanesulphonate (LIRIMILAST), (-)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)- benzo[c][1 ,6]naphthyridine (PUMAFENTRINE),

3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)benzamide (ROFLUMILAST), the N-oxide of ROFLUMILAST, and

3-[[3-(cyclopentyloxy)-4-methoxyphenyl]methyl]-N-ethyl-8-(1-methylethyl)-3H-purine-6-amine (V- 11294A);

- from the class of the cysteinyl-leukotrienei receptor antagonists the active compounds

2-[1 -[1 (R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1 -hydroxy-1 -methylethyl)phenyl]propyl- sulphanylmethyl]-cydopropyl]acetic acid (MONTELUKAST),

8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5-yl)-4H-1 -benzopyran-4-one (PRANLUKAST) and 4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-yl-methyl)-3-methoxy-N-o-tolylsulphonylbenzamide (ZAFIRLUKAST),

- from the class of the leukotriene synthesis inhibitors the active compound (+/-)-1-(1-benzo[b]thien-2-ylethyl)-1-hydroxyurea (ZILEUTON);

- from the class of the lipoxygenase inhibitors the active compound

3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)pyrazol-3-yl]-N-hydroxy-N-methylpropionamide (TEPOXA- LIN),

- from the class of the inhibitors of mediator release the active compounds 2-amino-7-isopropyl-5-oxo-5H-[1 ]benzopyrano[2,3-b]pyridine-3-carboxylic acid (AMLEXANOX), 5,5'-(2-hydroxytrimethylenedioxy)bis(4-oxo-4H-1-benzopyran-2-carboxylic acid) (CROMOGLYCINIC ACID), 4,6-dioxo-1-ethyl-10-propyl-4H,6H-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid (NEDOCROMIL),

1 -[3-[4-(diphenylmethyl)-1 -piperazinyl]propyl]-2-benzimidazolinone (OXATOMIDE), 9-methyl-3-(1 H-tetrazol-5-yl)-4H-pyrido[1 ,2-a]pyrimidin^-one (PEMIROLAST), isoamyl 5,6-dihydro-7,8-dimethyl-4,5-dioxo-4H-pyrano[3,2-c]quinoline-2-carboxylate (REPIRINAST), [2-[4-(3-ethoxy-2-hydroxopropoxy)phenylcarbamoyl]ethyl]dimethylsulphonium p-toluenesulphonate

(SUPLATASTTOSILATE) and butyl N-[3-(1H-tetrazol-5-yl)phenyl]oxamate (TAZANOLAST),

- from the class of the thromboxane A₂ antagonists the active compound (+)-(Z)-7-[3-endo-(phenylsulphonylamino)bicyclo[2.2.1]hept-2-exo-yl]heptenoic acid (DOMITROBAN),

- and from the class of the thromboxane synthase inhibitors the active compound (E)-3-[4-(1 H-imidazol-1-ylmethyl)phenyl]-2-propenoic add (OZAGREL).

The invention provides especially the combined use of (S)-pantoprazole magnesium and its hydrates and airway therapeutics from the class of the PDE3/4- and PDE4 inhibitors for the treatment of airway disorders.

The invention furthermore provides the combined use of (S)-pantoprazole magnesium and its hydrates and ciclesonide for the treatment of airway disorders.

The invention provides particularly especially the combined use of (S)-pantoprazole magnesium and its hydrates and an airway therapeutic from the class of the PDE3/4- and PDE4 inhibitors selected from the group consisting of (Z)-3-(3,5-dichloro-4-pyridyl)-2-[4-(2-indanyloxy-5-methoxy-2- pyridyrjpropenenitrile, N-[9-amino-4-oxo-1 -phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1 -jk][1 ,4]benzodiaze- pine-3(R)-yl]pyridine-3-carboxamide (CI-1044), N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5- hydroxy-1 H-indol-3-yl]-2-oxoacetamide (AWD-12-281 ), cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxy- phenyl)cyclohexane-1-carboxylic acid (CILOMILAST), 8-amino-1,3-bis(cyclopropylmethyl)xanthine (CIPAMFYLLINE), 2-methyl-1-[2-(1-methylethyl)pyrazolo[1,5-a]pyridin-3-yl]-1-propanone (IBUDILAST), 2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzofuran-6-yl methanesulphonate (LIRIMILAST), (-)-cis-9- ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)benzo[c]- [1 ,6]naphthyridine (PUMAFENTRINE), 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(difluoro- methoxy)benzamide (ROFLUMILAST), ROFLUMILAST-N-OXIDE and 3-[[3-(cyclopentyloxy)-4- methoxyphenyl]methyl]-N-ethyl-8-(1-methylethyl)-3H-purine-6-amine (V-11294A) for the treatment of airway disorders.

The invention preferably provides the combined use of (S)-pantoprazole magnesium and its hydrates and an airway therapeutic from the class of the PDE3/4- and PDE4 inhibitors selected from the group consisting of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid (CILOMILAST), 2-methyl-1-[2-(1-methylethyl)pyrazolo[1 ,5-a]pyridin-3-yl]-1-propanone (IBUDILAST), (- )-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphe- nyl)benzo[c][1,6]naphthyridine (PUMAFENTRINE), 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)- 4-(difluoromethoxy)benzamide (ROFLUMILAST) and ROFLUMILAST-N-OXIDE for the treatment of airway disorders. The invention particularly preferable provides the combined use of (S)-pantoprazole magnesium and its hydrates and 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)benzamide (ROFLUMILAST) for the treatment of airway disorders.

The invention furthermore particularly preferable provides the combined use of (S)-pantoprazole magnesium and its hydrates and ciclesonide for the treatment of airway disorders.

Airway disorders which may be mentioned are in particular allergen- and inflammation-induced pulmonary abnormalities and bronchial disorders (for example bronchitis, obstructive bronchitis including COPD, spastic bronchitis, allergic bronchitis, allergic asthma, bronchial asthma, in particular night-time asthma attacks, pneumonitis and pulmonary fibrosis), which can be treated by the combination according to the invention also in the context of a long-term therapy (if desired with appropriate adjustment of the dose of the individual components to the needs at the time, for example needs subject to seasonally related variations).

"Combined use" or "combination" within the meaning of the present invention is to be understood as meaning that the individual components can be administered simultaneously (in the form of a combination medicament), more or less simultaneously (from separate pack units) or in succession (one directly after the other directly or else alternatively within a relatively large time span) in a manner which is known per se and customary.

Within the meaning of the present invention, "use" is preferably understood as meaning the oral administration of both active compounds. However, it is also conceivable to administer (S)-pantoprazole magnesium and its hydrates parenterally (for example intravenously) and/or to administer the airway therapeutic parenterally or topically (in particular by inhalation). For administration by inhalation, the airway therapeutic is preferably administered in the form of an aerosol, the aerosol particles of solid, liquid or mixed composition having a diameter of 0.5 to 10 μm, advantageously of 2 to 6 μm.

Aerosol generation can be carried out, for example, by pressure-operated jet atomizers or ultrasonic atomizers, but advantageously by propellant-operated metered aerosols or propellant-free administration of micronized active compounds from inhalation capsules.

Depending on the inhaler system used, in addition to the active compounds the administration forms also contain the required excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavourings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of apparatuses are available with which aerosols of optimum particle size can be generated and administered, using an inhalation technique which is as appropriate as possible for the patient. In addition to the use of adaptors (spacers, expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), and automatic devices emitting a puff of spray (Autohaler®), for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhaler described in European Patent Application EP 0 505321 ), using which an optimal administration of active compound can be achieved.

The active compounds are dosed in an order of magnitude customary for the individual dosage, where it may be possible, on account of the individual actions, which are mutually positively influencing and reinforcing, to reduce the respective dosages on the combined administration of the active compounds compared with the norm, or where - if the dosage of the individual components is the customary dosage - a surprisingly better and longer-lasting activity is obtained.

(S)-Pantoprazole magnesium and its hydrates is usually administered in a dose of from 5 to 100, advantageously from 10 to 60, in particular from 20 to 40 mg, administered once or, if required, twice a day. In the case of the airway therapeutics, the dose customary for the person skilled in the art is administered, which, depending on the class of active compound, may vary within a very broad range. Thus, for example, the β₂ adrenoceptor agonist is - depending on the active compound - in the case of administration by inhalation usually administered in a dosage of, for example, 0.002 to 2.0 mg per day. For the PDE inhibitors, it is possible in the case of oral administration to vary the doses - depending on the active compound - within a wide range, it being possible, as a framework, to start from a dose of 1 - 2000 μg/kg of body weight. In the case of the administration of the preferred PDE inhibitor roflumilast, the dosage is in the range from 2 - 20 μg/kg of body weight.

The (S)-pantoprazole magnesium and its hydrates and the airway therapeutics to be administered orally are formulated - if appropriate jointly - to give medicaments according to processes known per se and familiar to the person skilled in the art. The pharmacologically active compounds are employed as medicaments, preferably in combination with suitable pharmaceutical excipients or vehicles, in the form of tablets, coated tablets, capsules, emulsions, suspensions or solutions, the active compound content advantageously being between 0.1 and 95% and, by the appropriate choice of the excipients and vehicles, it being possible to achieve a pharmaceutical administration form precisely tailored to the active compound(s) and/or to the desired onset of action (e.g. a sustained-release form or an enteric form). The person skilled in the art is familiar on the basis of his/her expert knowledge with which excipients or vehicles are suitable for the desired pharmaceutical formulations. In addition to solvents, gel-forming agents, tablet excipients and other active compound carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavour corrigents, preservatives, solubilizers, colorants or permeation promoters and complexing agents (e.g. cyclodextrins), where for all dosage forms the generally known sensitivity of (S)-pantoprazole magnesium and its hydrates - in particular to acids - has to be taken into account.

In a further aspect, the invention provides the use of (S)-pantoprazole magnesium and its hydrates in combination with an airway therapeutic for treating patients suffering from an airway disorder. The invention further provides a method for treating airway disorders which comprises administering to a patient in need of such a treatment an effective amount of (S)-pantoprazole magnesium or its hydrate together with an airway therapeutic.

The invention further provides the use of (S)-pantoprazole magnesium and its hydrates and airway therapeutics for preparing combination medicaments for treating airway disorders.

The invention further provides a pharmaceutical preparation for treating airway disorders, which preparation comprises, as active compounds, (S)-pantoprazole magnesium or its hydrate and an airway therapeutic.

The invention further provides a ready-to-use medicament, comprising, as active compounds, (S)- pantoprazole magnesium or its hydrate and an airway therapeutic, which contains a reference to the fact that these active compounds are to be taken for the treatment of an airway disorder more or less simultaneously or in succession (one directly after the other or else within a relatively large time span).

The invention further provides a ready-to-use medicament, comprising, as active compound, (S)- pantoprazole magnesium or its hydrate, which contains a reference to the fact that this compound is to be taken for the treatment of an airway disorder more or less simultaneously or in succession (one directly after the other or else within a relatively large time span) with an airway therapeutic.

The invention further provides to a ready-to-use medicament, comprising, as active compound, an airway therapeutic, which contains a reference to the fact that this airway therapeutic is to be taken for the treatment of an airway disorder more or less simultaneously or in succession (one directly after the other or else within a relatively large time span) with (S)-pantoprazole magnesium or its hydrate.

In case of a combined use of (S)-pantoprazole magnesium or its hydrate and an airway therapeutic, it is to be understood that, when used herein, 'medicament' or 'pharmaceutical composition' shall be taken to refer to a composition comprising both the airway therapeutic and (S)-pantoprazole magnesium or its hydrate in a fixed combination (fixed unit dosage form), or a medicament pack comprising the two active ingredients as discrete separate dosage forms. In case of a medicament pack comprising the two active ingredients in oral dosage form, the active ingredients are preferably packed into blister cards which are suited for improving compliance.

Each blister card preferably contains the medicaments to be taken on one day of treatment. If the medicaments are to be taken at different times of day, the medicaments can be disposed in different sections on the blister card according to the different ranges of times of day at which the medicaments are to be taken (for example morning and evening or morning, midday and evening). The blister cavities for the medicaments to be taken together at a particular time of day are accommodated in the respective range of times of day. The various times of day are, of course, also put on the blister in a clearly visible way. It is also possible, of course, for example to indicate a period in which the medicaments are to be taken, for example stating the times.

The daily sections may represent one line of the blister card, and the times of day are then identified in chronological sequence in this column.

Medicaments which must be taken together at a particular time of day are placed together at the appropriate time on the blister card, preferably a narrow distance apart, allowing them to be pushed out of the blister easily, and having the effect that removal of the dosage form from the blister is not forgotten.

Examples

1. Magnesium (-)-bis{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1 H- benzimidazolide} dihydrate

At 20-25°C, 20.2 g (52.7 mmol) of (-)-pantoprazole {(-)-[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyri- dinyl)methylsulphinyl]-1H-benzimidazole} were suspended in 200 ml of purified water. A solution of (55.2 mmol) sodium hydroxide in 10 ml of water was added, and the mixture was stirred at 20-30°C for 30 min. With addition of a filter aid (1g Hyflo-Super-Cel), the turbid solution was filtered. 6.32 g (31.2 mmol) of magnesium dichloride hexahydrate in 150 ml of water were then added drop by drop with stirring over a period of 30 min. After a further 30 min., the precipitated solid was filtered off with suction using a suction filter, stirred with water (2 x 50 ml) and again filtered off with suction. Drying under reduced pressure at 50-60°C gave, in a yield of 17.36 g (80%), a hydrate of magnesium (-)-bis{[5- (difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1 H-benzimidazolide} having a water content of 4.5-4.7 % as a colourless to beige powder (m. p. 158-161 °C, with decomposition).

Specific rotation: α_D ^20° = -114° (c = 0.5, measured in methanol)

For recrystallisation, 1.88 g of the hydrate were, at 55°C, dissolved in 6 ml of methanol, and 20 ml of water were added with stirring. A colourless to beige solid crystallized out. This gave the title compound of m. p. 160-163°C (with decomposition) having a water content of 4.3-4.4 %.

Alternatively, the title compound can also be prepared from organic-aqueous solvent mixtures. To this end, (-)-pantoprazole sodium, or (-)-pantoprazole together with one equivalent of aqueous, for example 2N, sodium hydroxide solution, is dissolved in an organic solvent, for example warm acetone. 0.5 to 0.55 equivalents of a magnesium salt (for example magnesium chloride hexahydrate), dissolved in water, are added drop by drop, and the mixture is cooled with stirring. The precipitated solid is filtered off, washed with the solvent mixture in question and dried at 50°C under reduced pressure until the weight remains constant. This gives the title compound as a colourless to beige powder.

2. Magnesium (-)-bis{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H- benzimidazolide} dihydrate

A. (-)-Pantoprazole-Na

36 g of (-)-pantoprazole were suspended in 180 ml of methyl isobutyl ketone (MIBK) and 18 ml of 2-propanol and heated to an internal temperature of 45°C. The suspension was stirred at this temperature for 15 min. At 50°C, 11 g of 30% (w/w) aqueous sodium hydroxide solution were slowly added drop by drop to this suspension. A clear to slightly turbid solution resulted. This solution was stirred for a bit longer and then filtered to give a clear solution. The clear filtrate was slowly cooled to room temperature. Between 45°C and 30°C, crystallization, which could be accelerated by seeding with (-)-pantoprazole sodium, began. The resulting suspension was stirred at an internal temperature of < 20°C for another 2 h. The suspension was then filtered, and the crystals were washed with 40 ml of MIBK.

Drying was carried out in a vacuum drying cabinet at < 50 mbar and 40-45°C. [It is also possible to dispense with drying and to use the moist product (having an MIBK content of 10-20 %) directly for step B]. The white-beige crystalline product obtained after drying was hygroscopic. The water content was from 2 to 12 %. The absorption and release of water were reversible. Yield: 34 g = 90 % of theory (based on anhydrous product). Specific rotation: αo^20" = - 95 (c = 0.5, measured in methanol, sodium salt having a water content of 12%). m. p.: 145-165°C (decomposition, sodium salt having a water content of 2 %); 102-109°C (decomposition, sodium salt having a water content of 12 %).

B. (-)-Pantoprazole-Mg

30 g of (-)-pantoprazole sodium salt (calculated anhydrous substance) were suspended in 260 ml of water. The suspension was heated to 35-40°C and stirred at 35-40°C for another 10 min. This gave a clear solution. The clear solution was cooled to 22-27°C. 14.3 g of magnesium chloride hexahydrate were dissolved in 100 ml of water, and at room temperature and with stirring, the solution was slowly added dropwise to the (-)-pantoprazole sodium salt solution. The resulting suspension was then stirred at room temperature for another 4 h. The suspension was, under pressure, filtered through a Nutsche filter, and the product was, a little at a time, washed twice with 300 ml of water. Drying in a vacuum drying cabinet at < 50 mbar and 40-45°C gave 27.5 g (90 %) of the title compound of m. p. 160-163°C. Water content 4.3-4.4 %; specific rotation: α ²⁰ = -129 (c= 0.5, measured in methanol).

Recrystallisation of (-)-pantoprazole-Mg

For recrystallisation, 6.0 g of the (-)-pantoprazole-Mg-di hydrate were, at 55°C, dissolved in 18 ml of methanol. After 15 min, 90 ml of water were added with stirring to the orange-brown-solution. A colourless to beige solid crystallised out. The resulting suspension was then stirred at 20-25°C for another 1 hour. The solid was filtered off, washed with 10 ml of water and dried under vacuum for 20 hours at 50°C. The yield for the title compound was 88 % (5.26 g) with the following data:

M.P.: 161-165°C (with decomposition)

Specific rotation: α_D ^20° = -130° (c = 0.5, measured in methanol)

Claims

1. Use of (S)-pantoprazole magnesium and its hydrates in the treatment of airway disorders.

2. Method for the treatment of airway disorders consisting in that an effective amount of (S)- pantoprazole magnesium or its hydrate is administered to a patient who needs such a treatment.

3. Pharmaceutical preparation intended for the treatment of airway disorders, comprising (S)- pantoprazole magnesium or its hydrate as active compound.

4. Airway disorder as mentioned in any of Claims 1 to 3, characterized in that it is bronchitis, COPD, asthma, pneumonitis or pulmonary fibrosis.

5. Medicament for treating airway disorders, comprising (S)-pantoprazole magnesium or its hydrate and an airway therapeutic in fixed or free combination.

6. Method for treating airway disorders which comprises administering to a patient in need of such a treatment an effective amount of (S)-pantoprazole magnesium or its hydrate together with an airway therapeutic.

7. Use of (S)-pantoprazole magnesium and its hydrates in combination with an airway therapeutic for treating patients suffering from an airway disorder.

8. Pharmaceutical preparation for treating airway disorders, which preparation comprises, as active compounds, (S)-pantoprazole magnesium or its hydrate and an airway therapeutic.

9. Ready-to-use medicament, comprising, as active compounds, (S)-pantoprazole magnesium or its hydrate and an airway therapeutic, which contains a reference to the fact that these active compounds are to be taken for the treatment of an airway disorder more or less simultaneously or in succession (one directly after the other or else within a relatively large time span).

10. Composition, method, use or preparation according to any of Claims 5 to 9, characterized in that the airway therapeutic is selected from the group consisting of cis-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-1-carboxylic acid (CILOMILAST), 2-methyl-1-[2-(1-methylethyl)pyrazolo- [1 ,5-a]pyridin-3-yl]-1-propanone (IBUDILAST), (-)-cis-9-ethoxy-8-methoxy-2-methyl-1 ,2,3,4,4a, 10b- hexahydro-6-(4-diisopropylaminocarbonylphenyl)benzo[c][1 ,6]naphthyridine (PUMAFENTRINE), 3- (cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)benzamide (ROFLUMILAST) and ROFLUMILAST-N-OXIDE and their salts.