NZ613917B2 - 9-[4-(3-chlor-2-fluor-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diazaspiro[5.5]undecan-5-one dimaleate, use thereof as a drug, and production thereof - Google Patents

Abstract

Disclosed is crystalline 9-[4-(3-chloro-2-fluorophenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diazaspiro[5.5]undecan-5-one dimaleate of formula (I) optionally in the form of the tautomers thereof, wherein reflections in the X-ray powder diagram occur at dhkl values of 7.11, 5.77, 4.69, 4.36, 4.15, 3.85 and 3.61 Å, and has corresponding values 2theta of 12.43, 15.33, 18.92, 20.37, 21.38, 23.06 and 24.67. Also disclosed is a process for the stereoselective preparation of the crystalline compound of formula (I) starting from 1,4-cyclohexanedione-mono-ethyleneketal. Also disclosed is a process for the chlorination of tert-butyl (trans)-9-(4-hydroxy-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate or tert-butyl (trans)-9-(4-oxo-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate with a reactant selected from among N-chlorosuccinimide/triphenylphosphane oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, carbon tetrachloride/triphenylphosphane, dichlorotriphenylphosphorane and P,P-dichlorophenylphosphine oxide, to form tert-butyl (trans)-9-(4-chloro-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate. Further disclosed are intermediates such as tert-butyl (trans)-9-(3-benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate and (trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecan-5-one hydrochloride. 3.85 and 3.61 Å, and has corresponding values 2theta of 12.43, 15.33, 18.92, 20.37, 21.38, 23.06 and 24.67. Also disclosed is a process for the stereoselective preparation of the crystalline compound of formula (I) starting from 1,4-cyclohexanedione-mono-ethyleneketal. Also disclosed is a process for the chlorination of tert-butyl (trans)-9-(4-hydroxy-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate or tert-butyl (trans)-9-(4-oxo-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate with a reactant selected from among N-chlorosuccinimide/triphenylphosphane oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, carbon tetrachloride/triphenylphosphane, dichlorotriphenylphosphorane and P,P-dichlorophenylphosphine oxide, to form tert-butyl (trans)-9-(4-chloro-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate. Further disclosed are intermediates such as tert-butyl (trans)-9-(3-benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate and (trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecan-5-one hydrochloride.

Description

-[4-(3-chlorfluor-phenylamino)methoxy-quinazolinyloxy]-1,4-diazaspiro [5.5]undecanone dimaleate, use thereof as a drug, and production thereof The present invention relates to the compound of formula (I), Cl NH O O F O O N OH OH OH OH N OMe NH O O (I), which has valuable pharmacological ties, particularly an inhibiting effect on signal transduction mediated by tyrosine s, processes for stereoselectively preparing this compound, particularly ceutical formulations suitable for inhalation and their use for the treatment of diseases, particularly tumoral diseases, benign prostatic hyperplasia and diseases of the lungs and airways.

BACKGROUND TO THE INVENTION Quinazoline derivatives are known from the prior art as active substances for example for the ent of tumoral diseases and also diseases of the lungs and airways. Processes for ing quinazoline tives are described in WO03082290 and WO07068552.

WO2009098061 discloses the base (compound (II)) of the dimaleate salt according to the invention und (I)).

The aim of the present invention is to provide of 9-[4-(3-chlorofluoro-a salt phenylamino)methoxy-quinazolinyloxy]-1,4-diaza-spiro[5.5]undecanone which by virtue of its pharmaceutical efficacy as a tyrosine-kinase inhibitoris le for use in the therapeutic field, i.e. for the treatment of pathophysiological processes that are caused by the hyperfunction of tyrosine-kinases. (9797753_1):KZA The compound prepared in the present invention is supposed to meet the requirements for physical and chemical stability and other properties, such as for example crystalline stability, the absence of polymorphism and low hygroscopicity, particularly with regard to the absence of polymorphism, that are imposed on an active substance of a medicament.

A further aim of the present invention is to provide a stereoselective process for preparing the nd according to the invention.

DESCRIPTION OF THE DRAWINGS Figure 1: X-ray powder diagram of compound (I) Figure 2: DSC/TG schemes of compound (I) Figure 3: Sorption isotherms of compound (I): a.) kinetic plot, b.) isothermic plot Y OF THE INVENTION A first aspect of the invention es for a crystalline compound of formula (I) Cl NH O O F O O N OH OH OH OH N OMe NH O O (I), optionally in the form of the tautomers thereof, wherein reflections in the X-ray powder diagram occur at dhkl values of 7.11, 5.77, 4.69, 4.36, 4.15, 3.85 and 3.61 Å.

A second aspect of the invention es for a crystalline nd according tothe first aspect of the invention for use as a ment.

A third aspect of the ion provides foruse of a crystalline compound according to the first aspect of the invention for the manufacture of the a medicament for the treatment of inflammatory or allergic diseases of the airways. (9797753_1):KZA A fourth aspect of the invention provides for a process for the stereoselective preparation of the compound of formula (I) according to the first aspect of the invention, optionally in the form of the tautomers thereof: Cl NH O O F O O N OH OH OH OH N OMe HN O O (I), wherein the process comprises reaction steps (A) to (M), n (A) is the reaction of 1,4-cyclohexanedione-mono-ethyleneketal with ethylenediamine and chloroform to form a compound of formula (1) (1), (B) is the reaction of a nd of formula (1) to form the compound of formula (2) O O x HCl HN (2), (C) is the reaction of a compound of formula (2) with bases selected from among NaOtBu, KOtBu and NaOEt , , K2CO3, Li2CO3 and Na2CO3 to form the compound of formula (3) O O (D) is the reaction of a compound of formula (3) with the protective group t di-tert-butyldicarbonate in combination with (4-(dimethylamino)-pyridine (DMAP) to form the compound of formula (4) O O O N O (10257817_1):KZA (E) is the reduction of a compound of formula (4) with NaBH4 or LiBH4 to form the compound of formula (5) HO O O N O (F) is the reaction of a compound of formula (5) with trifluoroacetic anhydride to form a compound of formula (6) HO O O N O O N F F (6) (G) is the on of a compound of formula (6) with a compound of formula (13) and with a reagent selected from among triphenylphosphine/ diisopropyl azodicarboxylate, triphenylphosphine/ diethyl arboxylate and tributylphosphine/ azodicarbonyl)dipiperidine to form a compound of formula (7) N O (13) O O O N O N O O N F F (7) (H) is the reaction of a compound of formula (7) in the presence of Pd/C or Pd(OH)2 to form a compound of formula (8a) or its tautomeric form (8b), O O O N O N O O N F F (8a) (10257817_1):KZA O O O N O N O O N F F (8b) (I) is the chlorination of the compound of formula (8a) or (8b) with a nt selected from among N-chlorosuccinimide/triphenylphosphane oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, carbon tetrachloride/triphenylphosphane, dichlorotriphenylphosphorane and P,P-dichlorophenylphosphine oxide, to form a nd of formula (9) O O O N O N O O N (9) F F (J) + (K) is the reaction of the compound of formula (9) with 3-chlorofluoroaniline and the cleaving of a protective group to form a compound of formula (11) or (11A) Cl NH F O O N O O N F F (11) Cl NH F O O N O O N F F x HCl (11A) (10257817_1):KZA or instead of steps (J+K) optionally steps (N+O) may be used, wherein (N+O) is the cleaving of a protective group of the compound of formula (9) to form the compound of formula (12) and subsequent reaction with 3-chlorofluoroaniline to form the compound of formula (11) or (11A) O O N O O N F F (12), (L) is the cleaving of another protective group with a reagent selected from among ethanolamine, ammonia and Ba(OH) to form the compound of a (II) Cl NH F O O N OMe (II) (M) is the reaction of the compound of formula (II) with two equivalents of maleic acid to form a compound of formula (I), ally in the form of the tautomers thereof, Cl NH O O F O O N OH OH OH OH N OMe HN O O (I), wherein process steps (A) to (M) take place successively in the sequence specified and Step (M) is ed by crystallization and isolation of the compound of a (I).

A fifth aspect of the invention es for a process for the stereoselective preparation of a compound of formula (I), wherein the process consists of process steps as defined the fourth aspect of the invention (I), (J), (K), (L), and (M) or of s steps (I), (N), (O), (L) and (M), wherein the process steps (I) to (M) in each case take place successively in the sequence specified. (10257817_1):KZA A sixth aspect of the invention provides for a process for the stereoselective preparation of a compound of formula (II), wherein the process consists of process steps as defined in the fourth aspect of the invention (I), (J), (K) and (L), or of s steps (I), (N), (O) and (L), wherein the process steps (I) to (L) in each case take place successively in the sequence specified.

A h aspect of the invention provides for a s for the chlorination of a compound of Formula (8a) or (8b) O O O N O N O O N F F (8a) O O O N O N O O N F F (8b) with a reactant selected from among N-chlorosuccinimide/triphenylphosphane oxalyl chloride, thionyl chloride, phosphorus oride, phosphorus pentachloride, carbon tetrachloride/triphenylphosphane, dichlorotriphenylphosphorane and P,P-dichlorophenylphosphine oxide, to form a compound of formula (9) O O O N O N O O N (9) F F . (10257817_1):KZA An eighth aspect of the invention provides for an intermediate of formula (7) O O O N O N O O N F F (7) optionally in the form of the tautomers f.

A ninth aspect of the invention provides for an intermediate of formula (8a) or (8b), O O O N O N O O N F F (8a) O O O N O N O O N F F (8b) optionally in the form of the tautomers thereof.

A tenth aspect of the invention provides for an ediate of formula (9), O O O N O N O O N (9) F F optionally in the form of the tautomers thereof. (10257817_1):KZA An th aspect of the ion provides for an ediate of formula (11) or (11A), Cl NH F O O N O O N F F (11) Cl NH F O O N O O N F F x HCl (11A) optionally in the form of the tautomers thereof.

DETAILED DESCRIPTION OF THE INVENTION The present invention solves the above-mentioned problems by providing the compound of formula (I) that is suitable in particular for oral administration, which is highly crystalline, has low hygroscopicity and low polymorphism, the pharmaceutical formulation thereof and the method of synthesis described hereinafter. By crystalline stability is meant, within the scope of the present invention, that X-ray powder diagrams of the compound of formula (I) have sharp reflections with high intensity up to the upper 2 Θ range, preferably up to 20 – 40 ° 2 Θ.

By low hygroscopicity is meant, within the scope of the present invention, that in sorption experiments on the nd of formula (I) a water uptake of less than 1 % is ed in the humidity range of 10 – 90 % investigated.

By low polymorphism is meant, within the scope of the t invention, that after recrystallisation from different solvents of the nd of formula (I) a maximum of other crystal modifications, preferably a maximum of 3 other crystal modifications, particularly preferably no other crystal modifications are obtained. (10257817_1):KZA The invention relates to a compound of a (I) optionally in the form of the ers, es or hydrates thereof.

A crystalline compound of formula (I) is preferred wherein reflections occur in the X-ray powder diagram with dhk. values of 7.11, 5.77, 4.69, 4.36, 4.15, 3.85 and 3.61 A.

The ion further relates to the mentioned compound for use as a medicament, preferably for the treatment of inflammatory or allergic diseases of the ainNays, particularly preferably for the treatment of chronic obstructive bronchitis (COPD) and/or chronic bron- chitis.

It is also preferable to use the compound of formula (I), the disease in question being one that is selected from among acute bronchitis, bronchitis caused by ial or viral infec- tion or fungi or helminths, allergic bronchitis, toxic bronchitis, asthma (intrinsic or allergic), paediatric asthma, iectasis, allergic alveolitis, allergic or non-allergic rhinitis, chronic sinusitis, cystic fibrosis or mucoviscidosis, alpha—1-antitrypsin deficiency, cough, pulmonary emphysema, interstitial lung diseases, alveolitis, hyperreactive airways, nasal polyps, pulmonary oedema, pneumonitis of different origins, e.g. radiation-induced or caused by aspiration or infectious pneumonitis, collagenoses such as lupus erythema- todes, systemic scleroderma, sarcoidosis and Boeck’s disease, and for treating complica- tions in asthma and COPD triggered by viral, bacterial or other causes, for treating viral or bacterial infections of the s or lungs.

It is also red to use the compound of formula (I) in cases of inflammatory or allergic complaints in which autoimmune reactions are involved.

It is also preferred to use the compounds of formula (I) in cases of a disease in the form of benign or malignant tumours.

The invention further s to a process for the stereoselective preparation of the com- pound of formula (I), optionally in the form of the tautomers, solvates or hydrates thereof: (I), the process comprising reaction steps (A) to (M), wherein (A) denotes the reaction of 1,4-cyclohexanedione-mono--ethyleneketal to form a compound of formula (1) (1), (B) is the reaction of a compound of formula (1) to form the compound of for- mula (2) (C) is the on of a compound of a (2) to form the compound of for- mula (3) (D) is the reaction of a compound of formula (3) with a protective group reagent to form the compound of formula (4) 0weO O (4), (E) is the reduction of a compound of formula (4) to form the compound of for- mula (5) H0,“@N0 JOL0% (F) is the reaction of a compound of formula (5) to form a compound of a (G) is the reaction of a compound of formula (6) with a nd of formula (13) to form a compound of formula (7) cnfimOH (13) jofinio+ l EINQ F F (7) (H) is the reaction of a compound of formula (7) to form a compound of formula (8a) or its tautomeric form (8b), F F (8a) F F (8b) (I) is the chlorination of the compound of formula (8a) or (8b) to form a com- pound of formula (9) F F (J) + (K) are the reaction of the compound of formula (9) with 3-chloro—2—fluoraniline and the cleaving of a protective group to form a compound of a (11) or (11A) l o N F F x HCI (11A) (L) is the cleaving of another protective group to form the compound of formula (II) (M) is the reaction of the compound of formula (II) with maleic acid to form a compound of formula (I), optionally in the form of the tautomers, solvates or hy- drates thereof, while process steps (A) to (M) take place successively in the sequence ted.

The invention further relates to a process for the stereoselective preparation of the com- pound of formula (I), optionally in the form of the tautomers, es or hydrates thereof, comprising process steps (A) to (M), wherein process steps (J+K) are replaced by steps (N+O), where (N+O) is the cleaving of a protective group of the compound of formula (9) to form the compound of a (12) and subsequent reaction with 3-chlorofluoraniline to form the compound of formula (11) or (11A) In a preferred process for the stereoselective ation of a compound of formula (I), the process consists of s steps (I), (J), (K), (L), and (M) or of process steps (I),(N), (O), (L) and (M), while process steps (I) to (M) in each case take place suc- cessively in the order indicated. r preferred process for the stereoselective preparation of a compound of formula (II) is characterised in that the process consists of process steps (I), (J), (K) and (L), or of process steps (I),(N), (O) and (L), while process steps (I) to (L) in each case take place successively in the order indicated.

Particularly preferred is process step (G).

Also particularly preferred is process step (I).

The invention r relates to the intermediate of formula (6), optionally in the form of the tautomers, solvates or hydrates thereof.

The invention further relates to the intermediate of formula (7), optionally in the form of the tautomers, solvates or hydrates thereof.

The invention further relates to the intermediate of formula (8), optionally in the form of the tautomers, solvates or hydrates thereof.

The invention further relates to the intermediate of formula (9), optionally in the form of the tautomers, solvates or hydrates thereof.

The invention further relates to the intermediate of formula (11) or (11A), ally in the form of the tautomers, es or hydrates thereof.

The invention further s to a pharmaceutical composition containing a compound of formula (I). An orally administered pharmaceutical ition containing a compound of formula (I) is preferred.

In another aspect the ion relates to medicament ations which contain, in ad- dition to a compound of a (I) according to claim 1, as a further active sub- stance, one or more compounds selected from among the categories of the be- tics, anticholinergics, corticosteroids, PDE4—inhibitors, LTD4-receptor an- tagonists, LTB4-receptor antagonists, inhibitors of MAP kinases, bradykinin recep— tor antagonists, endothelin receptor antagonists, CXCR1 and/ or CXCR2 receptor antagonists, and antitussives, or double or triple combinations f.

In process steps A, C to L and N alternative reagents may be used, which are selected from among the reagents listed below: 10 2012/051298 In process step A: in addition to ethylenediamlne and chloroform : ably benzyltriethylammonium chloride /NaOH, tetrabutylammonium de/ KOH, benzyltriethylammonium chloride /KOH,_tetrabutylammonium chloride/ NaOH, particularly preferably benzyltriethylammonium de/ NaOH; preferably alkoxide bases selected from among NaO‘Bu, KO‘Bu and NaOEt , car- bonate bases selected from among Cs2C03, K2C03, Li2C03 and Na2C03, particu- larly preferably sodium methoxide; in addition to di-tert—butyldicarbonate and DMAP (4-(dimethylamino)—pyridine): preferably K2C03,Cs2CO3, Li2C03 and Na2C03, particularly preferably K2C03; preferably NaBH4 and LiBH4, particularly preferably NaBH4; in on to oroacetic anhydride: as base preferably trlethylamine, Hijnig base, N-methylmorpholine and N,N- laniline, particularly preferably triethylamine; in addition to 3-benzylhydroxymethoxy—3H—quinazolinone: preferably triphenylphosphine/ diisopropyl azodicarboxylate, triphenylphosphine/ diethyl azodicarboxylate, tributylphosphine/ 1,1'-(azodicarbonyl)dipiperldine, par- ticularly preferably triphenylphosphlne/ diisopropyl azodicarboxylate; sts, preferably selected from among Pd/C and Pd(OH)2 , particularly prefera- bly Pd/C; preferably N-chlorosuccinimide/triphenylphosphane (in combination), oxalyl chlo- ride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, carbon tetrachloride/triphenylphosphane, dichlorotriphenylphosphorane and P,P-dichloro- phenylphosphine oxide, ularly ably N-chlorosuccinimide/ triphenylphos— phane (in combination); J+K: in addition to 3-chlorofluooraniline: preferably HCl, methanesulphonic acid, ethanesulphonic acid, p-toluenesulphonic acid and HBr, particularly preferably HCI; preferably ethanolamine, ammonia and Ba(OH)2, particularly preferably ethanola— mine; |+N: preferably N-chlorosuccinimide/triphenylphosphane (in combination), HCl, oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, car- bon hloride/trlphenylphosphane, dichlorotriphenylphosphorane, P,P-dichloro- phenylphosphine oxide, methanesulphonic acid, ethanesulphonic acid, p- toluenesulphonic acid and HBr, particularly preferably N- chIorosuccinimide/triphenylphosphane (in combination) and HCI.

The use of the following ts selected from the group specified in each case is pre- ferred in the process steps described above: In process step A: CH2CI2, CHCI3, THF (tetrahydrofuran) and dioxane; B: HOAc, dioxane, H20 and aqueous solutions of the ing solvents selected from among EtOH, THF, iPrOH, MeOH, NMP (N-methyIpyrrolidone) and DMF (dimethylfor- mamide); C: ACN (CH3CN), EtOH, MeOH, iPrOH, H20, THF and NMP; D: ACN, EtOH and NMP; E: H20, MeOH, EtOH, THF and e; F: Me-THF, THF, toluene, CH2CI2 and dioxane; G: THF, NMP, dioxane, DMF and CH2CIZ; H: iPrOH, dioxane, EtOH, MeOH, THF and NMP; I: dioxane/ACN and THF/dioxane; J: ACN, e, THF and EtOH; K: ACN, dioxane, THF and EtOH; L: EtOH, MeOH, iPrOH and dioxane; M: EtOH, MeOH and H20; N: dioxane/ACN and THF/dioxane O: EtOH, n-PrOH, dioxane and NMP The s steps described above are preferably carried out in the following temperature ranges: In process step: A: preferably -15 to 40°C, particularly preferably 0 to 20°C; B: preferably 0 to 100°C, particularly preferably 75 to 100°C; C: preferably 0 to 65°C, particularly preferably 15 to 30°C; D: preferably 10 to 80°C, particularly preferably 15 to 35°C; E: preferably 0 to 40°C, particularly preferably 0 to 15°C; F: ably —10 to 60°C, particularly ably 0 to 35°C; G: preferably 10 to 65°C, particularly preferably 45 to 60°C; H: preferably 20 to 85°C, ularly preferably 70 to 85°C; I: preferably 20 to 100°C, particularly preferably 70 to 95°C; J: preferably 20 to 100°C, particularly preferably 50 to 85°C; K: ably 20 to 100°C, particularly preferably 50 to 85°C; L: preferably 50 to 80°C, particularly preferably 70 to 80°C; M: ably 0 to 75°C, particularly preferably 0 to 70°C.

N: preferably 20 to 100°C, particularly preferably 50 to 85°C; 0: preferably 50 to 100°C, particularly ably 70 to 80°C; Preferably, protective groups selected from among benzyl, Cbz, trifluoracetyl and Boc, particularly trifluoracetyl and Boc, are used.

The abbreviation Boc used in the above formulae denotes tertiary butyl carbamate and Cbz denotes benzyloxycarbonyl.

Scheme 1 illustrates the synthesis according to the invention. All the compounds are shown in the form of their bases.

Scheme 1 (part 1 of 2) sis of compound (I) H0,“ 0 j: o o o N ‘— WNJLo/k _ 0% o QQ F3: (6) F F o \N o/ (13) (EARN”O U» AO O O H N o WO 04206 14 Scheme 1 (part 2 of 2) (10) II: F (9) F F IO ,1) N o 5 I :i'k) (11) ii The following Examples serve to illustrate the processes carried out by way of example for preparing the compound of formula (I). These Examples are to be understood as being an illustration of the invention, t limiting it to their t-matter.

Example 1 1 xa-9,12-diaza-dispiro[4.2.5.2]pentadecanone Process step A .1 kg of 50% sodium hydroxide solution are added dropwise at 5°C to a e of 437 g benzyltriethylammonium de and 2700 ml ethylenediamine in 19.2 L dichloro- methane. Then a solution of 6000 g of 1,4-cyclohexanedione-mono-ethyleneketal and 6100 g chloroform in 4.8 L dichloromethane within the next 4.5 h is added dropwise at 5- 15°C. The dropping funnel is rinsed with 3 L dichloromethane. After 15 h, 18 L water and 39 L dichloromethane are added at 15-25°C. The phases are separated and the aqueous phase is extracted with 20 L dichloromethane. The combined organic phases are concen- trated by distillation. After 72 L t have been distilled off, 48 L isopropanol are added to the suspension and then a further 30 L solvent are distilled off. After cooling to 3°C the precipitate is filtered off and washed twice with 7.5 L cold isopropanol. After drying at 50°C in vacuo, 6144 g of product is obtained.

Mass spectrum (ESP): m/z = 227 [M+H]+ Example 2 1,4-diaza-spiro[5.5]undecane;5,9-dione Omm,0 Process step B 14.5 kg of 4M HCI in dioxane are added dropwise within 15 min to 6085 g oxa-9,12- diaza-dispiro[4.2.5.2]pentadecanone in 25 kg acetic acid at 80-100°C. The dropping funnel is rinsed with 3 kg acetic acid. After 140 min the sion is cooled to 20°C.

After 2h the precipitate is filtered off and washed twice with 12 L dioxane. After drying at 60°C in vacuo, 5333 g of product is obtained as the hydrochloride.

Mass spectrum (ESP): m/z = 183 [M+H]+ Process step C 5200 g of 1,4—diaza-spiro[5.5]undecane-5,9-dione hydrochoride in 52 L acetonitrile are combined with 4370 ml 30% sodium methoxide solution in methanol at RT within 3h. The dropping funnel is rinsed with 1 L methanol. 250 g sodium carbonate are added and the mixture is stirred for 16 h. 30 L solvent are distilled off and after the addition of 20 L ace- ile the suspension is filtered. The filter cake is washed with 10 L acetonitrile. 22 L solvent are distilled off from the filtrate and the residue that ns the product is further d directly in the next step.

Example 3 tert-butyl oxo-1,4—diaza-spiro[5.5]undecanecarboxylate Process step D 6573 g potassium carbonate and 145 g 4—(dimethylamino)—pyridine are added to the resi- due from the previous mixture which contains the 1,4-diaza-spiro[5.5]undecane-5,9—dione.

Then within 30 min 6487 g di-tert—butyldicarbonate in 8 L acetonitrile is added se.

The dropping funnel is rinsed with 2 L acetonitrile. After 100 min the mixture is added to L water at 10°C. it is rinsed with 2 L water, 5 L acetonitrile and 16 L toluene. After phase tion the organic phase is combined with 10 L toluene. 55 L solvent are dis- tilled off. After the addition of 30 L methylcyclohexane and 10 L toluene the mixture is in- oculated with product and the suspension is stirred for 14 h at 20-30°C. 20 L methylcyclo- hexane are added and the mixture is cooled to -5°C. After 2.5h the precipitate is filtered off and washed with 10 L methylcyciohexane. After drying at 50°C in vacuo, 5160 g of product is obtained.

Mass spectrum (ESF): m/z = 283 [M+H]+ Example 4 tert—butyl (cis)-9—hydroxyoxo-1,4-diaza-spiro[5.5]undecane-4—carboxylate Process step E 201 g sodium borohydride in 5 L water are added dropwise at 3°C within 17 min to a mix- ture of 5000 g of tert-butyl 5,9-dioxo-1,4-diaza-spiro[5.5]undecane-4—carboxylate in 35 L water. The ng funnel is rinsed with 1.4 L water. After 15 min, 30 L methyl- tetrahydrofuran are added. After the addition of 10 L of sat. potassium carbonate solution the phases are separated and the aqueous phase is extracted with 20 L methyl- tetrahydrofuran. The combined organic phases are washed with 1 L sat. saline solution.

The organic phase is separated off and d with 27.5 L -tetrahydrofuran. 55 L solvent are distilled off. Then 15 L methyl-tetrahydrofuran are added and 15 L solvent are distilled off. Then 20 L methyl-tetrahydrofuran are added and 20 L solvent are distilled off.

Then 20 L methyl-tetrahydrofuran are added and 20 L solvent are led off. The e which contains the product is further reacted directly in the next step.

Mass spectrum (ESF): m/z = 285 [M+H]+ Example 5 tert-butyl (cis)—9—hydroxy—5-oxo(2,2,2-trifluoro-acetyl)—1 ,4-diaza-spiro[5.5]undecane carboxylate Ho,, 0 JOL N OJ? 0 N\/I; F F (6) s step F 11.1 L triethylamine are added to the organic phase from the previous mixture. Then 5170 ml trifluoroacetic anhydride are added dropwise within 30 min at 3-25°C. After 15 min 12.4 L ol are added. After 1h, 30 L solvent are distilled off in vacuo. Then 15.3 L methanol are added and 8 L of solvent are distilled off in vacuo. 12.4 L methanol are added and 35 L water are added se at 1-10°C within 50 min. After 1h at 2°C the precipitate is centrifuged off and washed with 10 L of a 2:1 mixture of water and methanol and then again washed with 10 L water. After drying at 55°C in the circulating air dryer 5299 g of product is obtained as a cis/trans mixture.

This crude product is suspended in 70 L toluene. Then 500 ml solvent are distilled off and then 10 L toluene are added. The solution is 'and at 52°C it is inoculated with prod- uct. After 3h at 1°C the precipitate is centrifuged off and washed with 8 L cold toluene.

After drying at 55°C in vacuo 4398 g of product is obtained, which still contains . 4% trans product.

Mass spectrum (ESP): m/z = 381 [M+H]+ Example 6 tert-butyl (trans)(3-benzyl-7—methoxy—4—oxo-3,4-dihyd ro-quinazolinyloxy)oxo—1 - (2,2,2—trifluoro—acetyl)-1 ,4-diaza-spiro[5.5]undecane—4-carboxylate l oiwd F F (7) Process step G 2471 ml diisopropyl azodicarboxylate is added dropwise, within 100 min, to a mixture of 3500 g tert-butyl (cis)—9—hydroxy-5—oxo—1-(2,2,2-trifluoro—acetyl)—1 ,4-diaza- .5]undecane—4—carboxylate, 2362 g 3-benzylhydroxy-7—methoxy-3H—quinazolin-4— one and 3292 g triphenylphosphine in 45 L tetrahydrofuran at 50-55°C. The dropping fun- nel is rinsed with 4 L tetrahydrofuran and 30 L solvent are distilled off in vacuo. Then, dur- ing the continuous addition of 60 L ethanol, a further 30 L solvent are led off at normal pressure. It is inoculated with product and left to cool slowly to RT. After 19 h the i- tate is filtered off and washed with 15 L ethanol. After drying at 50°C in vacuo, 4710 g of product is obtained.

Mass spectrum (ESP): m/z = 645 [M+H]+ Example 7 tert-butyl (trans)(4—hydroxymethoxy-quinazolin-6—yloxy)—5-oxo(2,2,2-trifluoro- acetyl)—1,4-diaza—spiro[5.5]undecane—4-carboxylate 0H 0 o o o o o o N/ HN N oU/HJLA $(Z UAMV— N o '01”F ”IV—F (8a) F F F F (8b) Process step H 470 g palladium (10%) on al are added to a mixture of 47009 tert-butyl (trans)—9—(3— benzylmethoxy—4—oxo-3,4-dihydro—quinazolinyloxy)oxo(2,2,2-trifluoro-acetyl)- 1,4-diaza-spiro[5.5]undecane—4-carboxylate in 33 L isopropanol and 33 L dioxane. After 4 h hydrogenation at 80°C the mixture is filtered at 60°C and washed with a mixture of 10 L isopropanol and 10 L dioxane. 58 L t are distilled off from the filtrate in vacuo and 32 L tert-butylmethylether are added. After 2 h at 0-5°C the precipitate is filtered off and washed with 15 L tert-butylmethylether. After drying at 50°C in vacuo 4153 g of product is obtained.

Mass spectrum (ESP): m/z = 555 [M+H]+ Example 8 tert-butyl (trans)—9-(4-chloromethoxy-quinazolinyloxy)—5-oxo—1-(2,2,2-trifluoro-acetyl)- 1 ,4-diaza-spiro[5.5]undecanecarboxylate (9) Process step I 1590 g N-chlorosuccinimide in 20 L acetonitrile are added to a mixture of 5500 g tert-butyl (trans)—9-(4-hydroxymethoxy-quinazolinyloxy)—5-oxo—1-(2,2,2—trifluoro—acetyl)-1 ,4- diaza-spiro[5.5]undecane—4-carboxylate and 3122 g triphenylphosphine in 24 L dioxane at 60°C within one minute. The ng funnel is rinsed with 4 L acetonitrile and the mixture is heated to 80-90°C for 30 min. The mixture containing the product is used directly in the next step.

Example 9 utyl (trans)—9-[4-(3-chloro—2-fluoro-phenylamino)methoxy-quinazolin-6—yloxy]— 5- oxo(2,2,2—trifluoro—acetyl)—1 ,4-diaza-spiro[5.5]undecanecarboxylate (10) (trans)—9-[4-(3-chlorofluoro-phenylamino)—7—methoxy—quinazolinyloxy]-1—(2,2,2— trifluoro—acetyl)—1,4-diaza-spiro[5.5]undecanone hydrochloride Process step J+K After 20 min at 50-60°C 1733 g 3-chloro—2—fluoranilin are added to the mixture. The drop- ping funnel is rinsed with 2 L acetonitriie. Then 7.8 kg 4 M hydrochloric acid in dioxane are added and the mixture is stirred for 45 min at 55-80°C. After cooling to 1°C the precipitate is filtered off and washed with 10 L ethanol. The precipitate is suspended in 40 L l and ed with 290 g 3-chloro—2—fluoroaniline. The suspension is stirred for 45 min at C and then for 13 h at RT. The precipitate is filtered off and washed with 10 L etha- nol. After drying at 60°C in vacuo 4853 g of product is obtained as the hydrochloride.

Mass spectrum (ESP): m/z = 582 [M+H]+ Process step 0 A e of 3.42 g (trans)—9-(4-ch|oromethoxy-quinazolinyloxy)—1-(2,2,2-trif|uoro- )-1,4-diaza—spiro[5.5]undecan-5—one and 1.25 g 3-chIorofluoroaniline in 40 ml of ethanol is heated to 80°C for 2 h. After the suspension has been cooled to 20°C and stirred for 16 h the precipitate is ed off and washed with 10 mL ethanol and 10 mL tert-butylmethylether. After drying at 100°C in vacuo, 3.28 g of product is obtained.

Mass spectrum (ESP): m/z = 582 [M+H]+ Example 10 (trans)[4-(3-chIoro—2-fluoro-phenylamino)—7—methoxy-quinazoiin-6—yloxy]-1 ,4—diaza- spiro[5.5]undecanone Process step L A mixture of 4700 g (trans)—9—[4—(3-ch|orof|uoro-pheny|amino)methoxy—quinazolin yioxy](2,2,2-trifluoro-acetyl)—1,4-diaza-spiro[5.5]undecanone and 5150 g ethanola— mine in 47 L ethanol is heated to 75-80°C for 17 h. After the suspension has been cooled to 20°C the precipitate is filtered off and washed with 15 L ethanol. After drying at 60°C in vacuo, 3776 g of product is obtained as the mono—ethanol solvate.

Mass spectrum (ESP): m/z = 486 [M+H]+ 1H NMR (400 MHz, DMSO): 9.60 (1H, s); 8.37 (1H, s); 7.82 (1H, s); 7.44-7.55 (2H, m), 7.37 (1H, s); 7.28 (1H, t); 7.22 (1H, s); 4.63-4.69 (1H, m); 4.33 (1H, t); 3.96 (3H, s); 3.41- 3.49 (2H, m); 3.11-3.16 (2H, m); 2.82-2.87 (2H, m); 2.30 (1H, s); 2.14-2.23 (2H, m); 1.34- 1.97 (4H, m); 1.44-1.51 (2H, m); 1.06 (3H, t).

Example 11 (trans)[4—(3-chlorofluoro-phenylamino)methoxy-quinazolinyloxy]-1 ,4-diaza- spiro[5.5]undecanone dimaleic acid compound (I) Process step M A solution of 1680 g maleic acid in 7 L ethanol and 7 L water is added at 77°C to 3500 g (trans)—9-[4-(3-chlorofluoro-phenylamino)methoxy-quinazolin-6—yloxy]-1 ,4-diaza- .5]undecanone thanol solvate in 18 L of ethanol. The ng funnel is rinsed with 3 L ethanol. The solution is inoculated with product at 66°C and after 5 min 35 L ethanol are added dropwise to the suspension. The suspension is cooled to 20° and stirred for 1 h at this ature. Then it is cooled to 1°C and stirred for 16 h at this tem- perature. The precipitate is filtered off and washed twice with 10 L ethanol. After drying at 60°C in vacuo, 4362 g of product is ed.

Mass spectrum (ESl+): m/z = 486 [M+H]+ 1H NMR (400 MHz, DMSO): 8.50 (1H, s); 8.24 (1H, s); 7.93 (1H, s); 7.50—7.57 (2H, m), 7.29-7.35 (1H, m); 7.27 (1H, s); 6.15 (4H, s); 4.65-4.71 (1H, m); 3.98 (3H, s); 3.45-3.51 (2H, m); 3.39-3.44 (2H, m); 2.38—2.48 (2H, m); 2.06-2.15 (2H, m); 1.83-2.02 (4H, m).

Example 1 2 (trans)—9-(4-chIoromethoxy-quinazolinyloxy)(2,2,2-trifluoro—acetyl)-1 ,4-diaza- spiro[5.5]undecanone (12) Process step I+N 19.6 g N-chlorosuccinimide in 240 mL acetonitrile are added at 60°C within two s to a mixture of 60 g tert-butyl (trans)—9-(4-hydroxymethoxy-quinazolinyloxy)—5-oxo —trifluoro-acetyl)—1,4-diaza-spiro[5.5]undecanecarboxylate and 37.5 g triphenyl- phosphine in 300 mL dioxane. The e is heated to 80-90°C for 100 min. After 20 min at 50-60°C, 84 mL of 4 M hydrochloric acid in dioxane are added to the mixture and the mixture is stirred for 3 h at 50-85°C. After stirring for 17 h at ambient temperature the mix- ture is cooled to 5°C and the precipitate is filtered off. The filter cake is washed with a 1:1 mixture of dioxane/acetonitrile and with tert-butylmethylether. After drying at 50°C 40 g of product is obtained.

Mass spectrum (ESP): m/z = 473 [M+H]+ Collection of data The following equipment and test ions are used to collect the data appended hereto.

X-ray powder diffractometer STOE Stadi P X-ray powder diffractometer with a location-sensitive detector in transmis- sion mode with a curved germanium (111) primary monochromator; wavelength used: Cqu with 7» = 1.540598 A; ion of the X—ray tube: 40 kV, 40 mA; 2 9 range: 3-40°.

Thermoanalysis eguipment A DSC 822 made by r Toledo is used. The following measuring parameters used: heating rate: 10 K/min; type of crucible: perforated aluminium crucible; atmosphere: N2, 80 m|/min flux; typical weights: 3-10 mg.

A TGA/SDTA 851 made by Mettler Toledo which is coupled to a Nicolet FT-lR 4700 spec- trometer (for analysing the volatile fractions) is used. The following measuring parameters are used: heating rate: 10 K/min; type of crucible: open aluminium oxide le; atmos- phere: N2, 20 ml/min flux; typical s: 15-25 mg.

The melting point of compound (I) can be inferred from the DSC/TG schemes in Figure 2 1O appended hereto.

Eguipment for water sorption tests A DVS-1 made by Surface Measurement Systems (= SMS) is used to test the hygroscopic characteristics: the following humidity profiles are used: 10 — 90 % r.h. in 1O % steps, re- cording both a sorption and a desorption profile, l s: 10 — 20 mg The corresponding ms (kinetic and isothermic plot) of the different forms are shown in Figures 3a) and b).

Biological Test The biological properties of compound (I) are igated as follows, for example: The inhibition of the EGF-R—mediated signal transmission can be demonstrated e.g. with cells which express human EGF—R and whose survival and proliferation depend on stimu- lation by EGF or TGF-alpha. A murine haematopoietic cell line is genetically modified so as to express functional human EGF-R. The proliferation of this cell line can therefore be stimulated by EGF.

The test is carried out as follows: The cells are cultivated in RPMl/1640 medium. The proliferation is ated with 20 ng/ml of human EGF (Promega). To investigate the inhibitory activity of the compounds according to the invention these compounds are dissolved in 100% dimethylsulphoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration being 1%. The cultures are incubated for 48 hours at 37°C.

In order to determine the inhibitory activity of nd (I) according to the invention the relative cell number is measured in OD. units using the Cell Titer 96TM AQueous Non- Radioactive Cell Proliferation Assay (Promega). The relative cell number is calculated as a percentage of the control and the concentration of active substance which inhibits the proliferation of the cells by 50% (IC50) is derived therefrom. 1O Table 2 Compound tion of the EGFR-dependent proliferation lcso [NM] Indications As has been found, the compound of formula (I) is characterised by its versatility in the therapeutic field. Particular mention should be made of the possible applications for which the nd of formula (I) according to the invention is preferably used on the basis of its ceutical efficacy as a ne inhibitor.

The compound of general formula (I) according to the invention thus inhibits signal trans- n by tyrosine kinases, as trated by the example of the human EGF receptor, and is therefore useful for treating pathophysiological processes caused by unction of tyrosine kinases. These are e.g. benign or malignant tumours, particularly tumours of lial and neuroepithelial origin, metastasisation and the abnormal eration of vas— cular endothelial cells (neoangiogenesis).

The compound (I) according to the invention is also useful for preventing and treating dis- eases of the airways and lungs which are accompanied by increased or altered production of mucus caused by stimulation of tyrosine kinases, e.g. in inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, a1—antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.

The compound (I) is also suitable for treating diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found e.g. in chronic inflammatory changes such as cholecystitis, Crohn’s disease, tive colitis, and ulcers in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Ménétrier’s disease, secreting adenomas and protein loss syndrome.

In addition, the compound (I) may be used to treat other diseases caused by abnormal function of tyrosine kinases, such as e.g. epidermal roliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory ses, diseases of the immune system, hyperproliferation of haematopoietic cells, the treatment of nasal , etc.

Combinations The compound of formula (I) may be used on its own or in combination with other active substances. These combinations may be administered either simultaneously or sequen- tially. ally the compound of formula (I) may also be used in combination with W, wherein W denotes a pharmacologically active substance and is selected (for example) from among betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4- receptor (CysLT1, CysLT2, ) antagonists, LTB4-receptor (BLT1, BLT2) antago- nists, tors of MAP kinases such as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, bradykinin (BK1, BK2) receptor nists, endothelin receptor antago- nists, CXCR1 and/ or CXCR2 receptor antagonists, and anti-tussive substances.

In addition, double or triple combinations Of W may be combined with the nds of formula (I). Examples of combinations of W with the compound of formula (I) might be: o W denotes a betamimetic, ed with an olinergic, corticosteroid, PDE4- or, EGFR-inhibitor or LTD4-receptor antagonist, o W denotes an anticholinergic, combined with a metic, corticosteroid, PDE4- inhibitor, EGFR-inhibitor or LTD4—receptor antagonist, o W denotes a corticosteroid, combined with a PDE4-inhibitor, EGFR-inhibitor or LTD4- receptor antagonist o W denotes a PDE4-inhibitor, combined with an EGFR—inhibitor or LTD4—receptor an- tagonist o W denotes an EGFR—inhibitor, combined with an anticholinergic.

Examples of betamimetics which may be used here preferably include compounds which are selected from among arformoterol, carmoterol, formoterol, indacaterol, salmeterol, al- l, bambuterol, erol, erol, carbuterol, clenbuterol, fenoterol, hexoprenalin, ibuterol, isoetharin, isoprenalin, levosalbutamol, mabuterol, meluadrin, metaproterenol, milveterol, orciprenalin, pirbuterol, procaterol, reproterol, rol, ritodrin, salmefamol, soterenol, sulphonterol, terbutalin, id, tolubuterol, zinterol and 6—hydroxy-8—{1-hydroxy[2-(4-methoxy-phenyl)—1 ,1 -dimethyl-ethylamino]-ethyI}-4H- benzo[1 ,4]oxazin-3—one, 8—{2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethy|amino]hydroxy- ethyl}—6-hydroxy-4H-benzo[1 ,4]oxazinone, 8—{2-[2-(3,5-difluoro-phenyl)-1 ,1 -dimethyl- mino]hydroxy-ethy|}hydroxy-4H-benzo[1 ,4]oxazinone, 8—{2-[2-(4-ethoxy- pheny|)-1 ,1 -dimethyl-ethylamino]-1 -hyd roxy-ethyl}-6—hydroxy-4H-benzo[1 ,4]oxazinone, 8—{2-[2-(4—fluoro-phenyl)-1 ,1 -dimethyl-ethylamino]-1—hydroxy-ethy|}hydroxy—4H- benzo[1 ,4]oxazinone, N-(5-{2-[3—(4,4-diethyIoxo-4H-benzo[d][1 ,3]oxazinyl)-1 ,1- dimethyl-propylamino]—1-hydroxy-ethyI}hydroxy-phenyl)-methanesuIphonamide, N-(5- {2-[3—(4,4-diethyl—6—fluorooxo-4H-benzo[d][1,3]oxaziny|)-1,1-dimethyI-propylamino]-1— hydroxy-ethy|}hydroxy-phenyl)—methanesuIphonamide, N-(5-{2—[3-(4,4-diethyI—6- methoxyoxo-4H-benzo[d][1 ,3]oxazinyl)-1 ,1-dimethyI-propylamino]hydroxy-ethyl}- 2-hydroxy-pheny|)-methanesu|phonamide, N-(5-{2-[1,1-dimethyI(2-oxo-4,4-dipropyI-4H- benzo[d][1 ,3]oxaziny|)-propylamino]hydroxy-ethy|}hydroxy-phenyl)- methanesulphonamide, 8-{2-[1,1-dimethyl(2-oxo-2,3-dihydro-benzimidazol-1—yl)— amino]—1-hydroxy-ethyI}hydroxy-4H-benzo[1 ,4]oxazinone, 8—{2-[1 ,1 -dimethyl- 3-(6—methyloxo-2,3-dihydro-benzimidazoIy|)-propylamino]hydroxy-ethyl}-6— hydroxy-4H-benzo[1 ,4]oxazinone, 8—{2-[1 ,1 hyl(2-oxotrifluoromethyl-2,3- dihydro-benzimidazoIyl)-propylamino]hydroxy-ethyl}hydroxy-4H-benzo[1 ,4]oxazin- 3-one, 8-{2-[1 ,1 —dimethyl(3-methyloxo-2,3-dihyd ro-benzimidazol-1 ropy|amino]- 1-hydroxy-ethyl}—6—hydroxy-4H-benzo[1 ,4]oxazinone, N-[2-hydroxy((1R)—1-hydroxy- 2-{2-[4-(2-hydroxy—2-phenyl—ethylamino)-phenyl]-ethylamino}-ethyl)—phenyl]-formamide, 8- hydroxy—5-((1 R)—1-hydroxy{2-[4-(6—methoxy-biphenyIylamino)-phenyl]-ethylamino}- ethy|)-1H-quinolinone, 8—hydroxy[(1R)—1-hydroxy(6—phenethylamino-hexylamino)- ethyl]-1H-quinolinone, 5-[(1R)(2-{4-[4-(2-aminomethy|-propoxy)—pheny|amino]- }-ethy|amino)hydroxy-ethyI]hydroxy—1 H-quinolinone, [3-(4-{6-[(2R)-2— hydroxy(4-hydroxyhydroxymethyl-phenyl)-ethylamino]—hexy|oxy}—butyl)methyl- ]-urea, 4-((1 R){6-[2-(2,6-dichIoro-benzyloxy)—ethoxy]-hexylamino}hydroxy- ethy|)—2-hydroxymethyI-phenol, 3-(4-{6-[(2R)hydroxy(4-hydroxyhydroxymethyl- phenyI)—ethylamino]-hexyloxy}-buty|)-benzenesuIphonamide, 3-(3-{7-[(2R)hydroxy(4- hydroxyhydroxymethyI-phenyl)—ethy|amino]-heptyloxy}-propy|)-benzenesu|phonamide, 4-((1 R){6-[4-(3-cyclopentanesulphonyI-phenyl)-butoxy]-hexylamino}hydroxy—ethyl) hydroxymethyI-phenol, NadamantanyI{3-[(2R)—2-({(2R)—2-hydroxy[4-hydroxy—3- (hydroxymethyl)phenyl]ethy|}amino)propy|]phenyl}acetamide, (1 R){2-[6-(2,2-difluoro—2- phenyI-ethoxy)—hexy|amino]hydroxy-ethyI}hydroxy-1 H-quinolin-Z-one, (R,S)(2-{[6- (2,2-difluoro-4—phenylbutoxy)hexyl]amino}hydroxy—ethyI)—2-(hydroxymethyl)phenol, (R,S)—4-(2-{[6-(2,2-difluoro-2—phenylethoxy)hexyl]aminc}-1—hydroxy—ethyI)—2- (hydroxymethyl)pheno|, (R,S)—4—(2-{[4,4—difluoro(4-phenylbutoxy)hexyl]amino}-1 - hydroxy—ethyI) (hydroxymethy|)pheno|, (R,S)—4-(2-{[6-(4,4-diquoro phenylbutoxy)hexyl]amino}hydroxy-ethyl)(hydroxymethyl)phenol, (R,S)—5-(2-{[6-(2,2- difluorophenylethoxy)hexyl]amino}hydroxy-ethyl)—8— hydroxyquinolin-2(1 H)-one, [2-({6-[2,2-difluoro(3-methylphenyl)ethoxy]hexy|}amino)—1-hydroxyethyI] (hydroxymethyl)phenol, 4—(1R)—2-{[6-(2,2-difluorophenylethoxy)hexyl]amino} hydroxyethyl)-2—(hydroxymethyl)phenol, (R,S)—2-(hydroxymethyl)—4-(1-hydroxy{[4,4,5|5- tetrafluoro—6-(3-phenylpropoxy)hexyl]amino}ethyl)phenol, (R,S)-[5-(2-{[6-(2,2-difluoro—2- phenylethoxy)hexyl]amino}hydroxy—ethyI) hydroxyphenyl]formamide, (R,S)—4-[2-({6- [2-(3-bromophenyl)—2,2-difluoroethoxy]hexyl}amino)-1—hydroxyethy|]- 2- (hydroxymethyl)phenol, (R, S)—N-[3-(1,1-difluoro{[6-({2—hydroxy[4-hydroxy xymethyl)phenyl]ethyl}amino)hexy|]oxy}ethy|)phenyI]-urea, 3-[3-(1 ,1—difluoro{[6- ({2-hydroxy—2-[4—hydroxy(hydroxymethyl) phenyl]ethyl}- amino)hexyl]oxy}ethyl)phenyl]imidazolidin-2,4—dione, (R,S)—4—[2-({6-[2,2-difluoro—2-(3- methoxyphenyl)ethoxy]hexy|}amino)—1-hydroxyethyI](hydroxymethyl)phenol, 5-((1 R) ,2-difluorophenylethoxy)hexyl]amino}hydroxyethyl)—8- hydroxyquinolin-2(1H)- one, 4-((1 R)—2-{[4,4-difluoro—6—(4-phenylbutoxy)hexyl]amino}hydroxy—ethyl)—2- (hydroxymethyl)phenol, (R,S)—4—(2-{[6-(3,3-difIuorophenylpropoxy)hexyl]amino}-1 - hydroxy-ethyl)—2-(hydroxymethyl)phenol, (R,S)—(2-{[6—(2,2-difluorophenylethoxy)—4,4- rohexy|]amino}hydroxyethy|)(hydroxymethyl)phenol, (R,S)—4—(2-{[6-(2,2- difluorophenylpropoxy)hexyl]amino}hydroxy ethyI)-2— (hydroxymethyl)phenol, 3-[2-(3- chloro-phenyl)—ethoxy]—N-(2-diethylamino—ethyl)-N-{2-[2-(4-hydroxy—2-oxo—2,3-dihyd ro- benzothiazol-7—yl)—ethylamino]-ethy|}-propionamide, N-(2-diethylamino-ethyl)-N-{2-[2—(4— hydroxy-2—oxo-2,3-dihydro-benzothiazolyI)-ethylamino]-ethyl}(2-naphthalenyl- ethoxy)—propionamide 7-[2-(2-{3-[2-(2-chloro—phenyl)-ethylamino]-propylsulphanyl}—ethylamino)hydroxy-ethyl]- 4-hydroxy-3H-benzothiazole-2—one, optionally in the form of the racemates, enantiomers, diastereomers and ally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.

Preferably, according to the invention, the acid addition salts of the betamimetics are se- lected from among hydrochloride, hydrobromide, dide, hydrosulphate, hydrophos— phate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, artrate, alate, hydrosuccinate, hydrobenzoate and hydro-p- toluenesulphonate.

Examples of anticholinergics which may be used here preferably include compounds which are selected from among: tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the e salt, ipratropium salts, preferably the bromide salt, aclidinium salts, preferably the bromide salt, yr- ronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine, (3R)phenethy|(9H-xanthencarbonyloxy)—1-azoniabicyclo[2,2,2]octane- salts. In the above-mentioned salts the cations are the pharmacologically active constitu- ents. As X' anions the mentioned salts may preferably contain chloride, e, iodide, sulphate, phosphate, methanesulphonate, e, maleate, acetate, e, fu- marate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions. Of all the salts the chlorides, bromides, iodides and methanesulphonates are particularly preferred.

Other specified compounds are: tropenol 2,2—diphenylpropionate methobromide, scopine 2,2-diphenylpropionate romide, scopine 2—fluoro-2,2-diphenylacetate methobromide, ol 2-fluoro-2,2—diphenylacetate methobromide, tropenol 3,3',4,4'- tetrafluorobenzilate methobromide, scopine 3,3',4,4'-tetrafluorobenzilate methobromide, tropenol 4,4'-difluorobenzilate methobromide, scopine 4,4'-difluorobenzilate methobro- mide, tropenol 3,3'—difluorobenzilate methobromide, scopine 3,3'— difluorobenzilate methobromide; tropenol 9-hydroxy—fluorene-Q-carboxylate methobromide, tropenol 9- fluoro-fluorene-Q—carboxylate methobromide, scopine oxy-fluorene carbokylate methobromide, scopine 9—fluoro-fluorene—9—carboxylate methobromide; tropenol 9-methyl- ne—9— carboxylate methobromide, scopine 9—methyl—fluorene—9— carboxylate metho- bromide, cyclopropyltropine benzilate romide, cyclopropyltropine 2,2- diphenylpropionate methobromide, cyclopropyltropine 9—hydroxy-xanthenecarboxylate methobromide, cyclopropyltropine 9-methyl-fluorene—9-carboxylate methobromide, cyclo- propyltropine 9-methyl-xanthene-9—carboxylate romide, cyclopropyltropine 9- hydroxy-fluorenecarboxylate methobromide, cyclopropyltropine methyl 4,4'- difluorobenzilate romide, tropenol oxy—xanthenecarboxylate methobro- mide, scopine 9-hydroxy-xanthene—9-carboxylate methobromide, tropenol 9—methyl— ne—9—carboxylate -methobromide, e 9-methyl-xanthene—9-carboxylate - methobromide, tropenol l-xanthene—9-carboxylate methobromide, tropenol 9- romethyI-xanthenecarboxylate methobromide, scopine 9-hydroxymethyl- xanthene—9—carboxylate methobromide. The above-mentioned compounds may also be used as salts within the scope of the present invention, while instead of the methobro- mide, the metho-X salts may be used wherein X may have the meanings given hereinbe- fore for X'.

Compounds which may be used as osteroids are preferably those selected from among: ethasone, betamethasone, budesonide, butixocort, ciclesonide, de- ort, dexamethasone, etiprednol, flunisolide, fluticasone, |oteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone, tipredane and pregna-1,4-diene— 3.20-dione, 6-fluorohydroxy-16,17-[(1—methylethylidene)bis(oxy)][[4- [(nitrooxy)methy|]benzoyl]oxy]-, (6-alpha,11—beta,16-alpha)— (9Cl) (NCX-1024), 16,17- butylidenedioxy-6,9-dif|uoro-1 1-hydroxy(methylthio)androst-4—enone (RPR- 106541 ), (S)—fluoromethyl 6,9-difluoro[(2-furanylcarbonyl)oxy]-1 1-hydroxymethyl- 3-oxo—androsta—1,4-diene—17-carbothionate, (S)-(2-oxo-tetrahydro-furan-3S-yl) 6,9- difluoro—1 1-hydroxymethyloxo—1 7—propionyloxy—androsta-1 ,4-dien-1 7-carbothionate, cyanomethyl 6-alpha,9-alpha-difluoro-1 1-beta-hydroxy-16alpha-methyloxo—17alpha— (2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-and rosta-1 ,4-diene-1 7beta-carboxylate, optionally in the form of the racemates, enantiomers or reomers thereof and option- ally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof.

Any nce to steroids includes a reference to any salts or derivatives, hydrates or sol— vates thereof which may exist. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as for example sodium or potassium salts, sulphobenzo- ates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.

PDE4-inhibitors which may be used are preferably compounds selected from among en- profyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, ntrin, lirimilast, apre- , arofyllin, atizoram, oglemilast, tetomilast, and -[(N-(2,5-dichloro—3—pyridinyl)-carboxamide]methoxy—quinoline (D-4418), N-(3,5- dichiorooxidopyridinyl)-carboxamide]methoxy(trif|uoromethyl)—quinoline (D— 4396 (Sch-351591)), -dichIoropyrid-4—y|)-[1-(4-f|uorobenzy|)-5,-hydroxy-indo| y|]g|yoxy|ic acid amide (AWD281 (GW-842470)), 9-[(2-f|uorophenyl)methyI]-N-methyl- 2—(trifluoromethyl)—9H-purinamine (NOS-613), 4-[(2R)[3-(cyc|opentyloxy)—4- methoxyphenyl]phenylethyi]-pyridine (GDP-840), N-[(3R)-3,4,6,7-tetrahydromethyI oxopheny|pyrrolo[3,2,1-jk][1,4]benzodiazepinyI]pyridinecarboxamide (PD- 168787), 4-[6,7-diethoxy-2,3—bis(hydroxymethy|)—1-naphthaienyl]—1-(2-methoxyethyl)- 2(1H)—pyridinone (T-440), 6,7-diethoxy—2,3-bis(hydroxymethyI)naphthalenyl] pyridiny|]—4-(3-pyridinyI)-1(2H)-phthalazinone (T-2585), (3-(3-cyclopenyioxy ybenzyl)ethy|aminoisopropyi-3H—purine (V-1 1294A), beta-[3—(cyciopentyloxy)— oxyphenyl]—1,3-dihydro-1,3-dioxo-2H—isoindole-2—propanamide (CDC-801), imi- dazo[1,5—a]pyrido[3,2-e]pyrazin-6(5H)—one, 9-ethylmethoxy-7—methylpropyl- (D- 22888), 5-[3-(cyclopentyloxy)—4-methoxyphenyl]—3-[(3-methy|phenyl)methyl], (3S,58)—2- piperidinone (HT-0712), 4-[1-[3,4-bis(dif!uoromethoxy)phenyl]—2-(3-methyl-1—oxido—4- pyridinyl)ethyi]—alpha,alpha—bis(trif|uoromethyl)-benzenemethano| (L-826141), N-(3,5- dichlorooxo-pyridinyI)difluoromethoxy—3-cyclopropylmethoxybenzamide, (-)p- ,10bS*)—9-ethoxy-1,2,3,4,4a,10b-hexahydro-8—methoxy—2- methylbenzo[s][1,6]naphthyridin-6—yI]-N,N-diisopropylbenzamide, (R)-(+)(4- bromobenzyi)[(3-cyciopentyloxy)—4-methoxyphenyI]pyrrolidone, 3-(cyclopentyloxy methoxyphenyl)(4-N'-[Ncyano-S-methyI-isothioureido]benzyl)—2-pyrrolidone, cis[4- cyano(3-cyclopentyloxymethoxyphenyl)cyclohexanecarboxy|ic acid], 2- ethoxy—4-cyano(3-cyclopropylmethoxy-4—d ifluoromethoxyphenyl)cyclohexan-1 - one, cis[4-cyano(3-cyclopropylmethoxydifluoromethoxyphenyl)cyclohexano|], (R)- (+)-ethyl[4-(3-cyclopentyloxy—4-methoxyphenyl)pyrrolidinylidene]acetate, (S)-(-)—ethy|[4- (3-cyclopentyloxy—4-methoxyphenyl)pyrroiidinylidene]acetate, 9-cyclopentyI-5,6- dihydroethyl(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4—triazolo[4,3-a]pyridine, 9- cyclopentyl-5,6-dihyd roethyI-3—(tert-butyl)-9H-pyrazo|o[3,4-c]-1 ,2,4—triazo|o[4,3- a]pyridine, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention the preferred acid addition salts are ed from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydro- methanesulphonate, hydronitrate, hydromaleate, cetate, hydrocitrate, hydrofu- , hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p- toluenesulphonate.

LTB4-receptor antagonists used here are preferably compounds selected from among for example ant (=ethyl [[4-[[3-[[4-[1-(4—hydroxypheny|) methylethyl]phenoxy]methy|]phenyl]methoxy]pheny|]iminomethyl]-carbamate), optionally in the form of the tes, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates, prodrugs or hy- drates thereof. According to the invention the red acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydro- fumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p- toluenesulphonate.

LTD4-receptor antagonists used here are preferably compounds selected from among montelukast, pranlukast, zafirlukast, and (E)—8-[2—[4-[4-(4- fluorophenyl)butoxy]phenyl]ethenyI]—2-(1 H-tetrazoI—5-yl)-4Hbenzopyranone (MEN- 91507), cetyl[3-(4—acetyIhydroxy—2-propylphenylthio)propoxy] propylphenoxy]butyric acid (MN-001), )—(3-(2-(6,7-difluoro quinolinyl)ethenyl)phenyl)—3-(2-(2-hydroxypropyl)phenyl)thio)methy|cyc|opropaneacetic acid, 1-(((1 ( -(2—(2,3-dichlorothieno[3,2-b]pyridinyl )-( E)-ethenyl)phenyl)(2-(1 - hydroxy-1—methylethyl)pheny|)propyl)thio)methy|) cyclopropaneacetic acid, -(4-tert- butyl—2-thiazolyl)—5-benzofurany|]oxymethyl]phenyl]acetic acid optionally in the form of the tes, enantiomers, diastereomers thereof and optionally in the form of the pharma- cologically acceptable acid addition salts, solvates or es thereof. According to the invention the preferred acid addition salts are selected from among hloride, hydro- bromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydroni- trate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrox- alate, hydrosuccinate, hydrobenzoate and p-toluenesulphonate.

By salts or derivatives which the LTD4—receptor antagonists are optionally capable of forming are meant, for example: alkali metal salts, such as for example sodium or potas- sium salts, alkaline earth metal salts, sulphobenzoates, phosphates, otinates, ace- tates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.

MAP Kinase inhibitors used are preferably compounds selected from among: bentamapimod (AS-602801), doramapimod 796), 5-carbamoylindole (SD-169), 6- [(aminocarbonyl)(2,6-dif|uoropheny|)amino](2,4-difluorophenyl)pyridinecarboxamide (VX—702), a|pha-[2-[[2-(3-pyridiny|)ethyl]amino]pyrimidiny|]benzothiazoleacetonitrile (AS-601245), 9,12—epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4—i][1.6]benzodiazocine— -carboxylic acid (CEP-1347), 4-[3-(4-chlorophenyl)—5-(1-methyl-4—piperidinyl)-1 H- pyrazoley|]-pyrimidine (SC-409), optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates thereof.

Bradykinin receptor antagonists that may be used are preferably compounds selected from among icatibant and 1-piperazinepentanaminium, delta-amino[[4—[[[2,4-dichloro [[(2,4-dimethyl-8—quinoliny|)oxy]methyl]pheny|]su|phonyl]amino]tetrahydro-2H-pyran bony|]-N,N,N-trimethyl-£-oxo, chloride, hloride (1 :1 :1), (deltaS)- (MEN-16132), optionally in the form of the racemates, omers and diastereomers thereof and op- ly in the form of the cologically acceptable acid on salts, prodrugs, sol- vates or hydrates thereof.

Endothelin antagonists that may be used are preferably compounds ed from among actelion-1, ambrisentan, sitaxsentan, N-(2-acetyl-4,6-dimethylphenyl)—3-[[(4-ch|oro methylisoxazolyl)amino]sulphonyl]thiophenecarboxamide (TBC-3214) and bosentan, ally in the form of the racemates, enantiomers and diastereomers thereof and op- tionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, sol- vates or hydrates thereof.

Antitussive substances that may be used are preferably compounds selected from among hydrocodone, caramiphen, carbetapentane and dextramethorphan, optionally in the form of the tes, enantiomers and diastereomers thereof and optionally in the form of the pharmacologically acceptable acid on salts, prodrugs, solvates or hydrates thereof.

Substances of preferred CXCR1 and /or CXCR2 receptor antagonists that may be used are preferably compounds such as e.g. 3-[[3-[(dimethylamino)carbony|] hydroxyphenyl]amino]—4—[[(R)(5-methylfurany|)propy|]amino]cyc|obutene-1,2-dione 1O (SCH-527123), optionally in the form of the racemates, enantiomers and diastereomers thereof and op- tionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, sol- vates or hydrates thereof. it is preferable, according to the invention, to use the acid addition salts of the above— mentioned metics, anticholinergics, corticosteroids, PDE4 inhibitors, LTB4(BLT1, BLT2) receptor nists, LTD4 (CysLT1, CysLT2, CysLT3) or antagonists, in- hibitors of MAP kinases such as for example p38, ERK1, ERK2, JNK‘l, JNK2, JNK3 or SAP, bradykinin receptor antagonists, endothelin receptor antagonists, antitussive sub- stances, CXCR1 and / or CXCR2 receptor antagonists also ed from among hydro- chloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesul- e, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotar- trate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

Pharmaceutical compositions The compound according to the invention may be administered by oral, transdermal, inha- lative, eral or sublingual route. The compound according to the invention is present as an active ingredient in conventional preparations, for example in itions consist- ing ially of an inert pharmaceutical carrier and an effective dose of the active sub- stance, such as for example tablets, coated tablets, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal systems etc. An effective dose of the compound according to the invention for oral administration is between 0.1 and 5000, ably n 1 and 500, particularly preferably between 5-300 mg/dose, when administered by intravenous, subcutaneous or uscular route between 0.001 and 50, preferably between 0.1 and 10 mg/dose. For Inhalation, according to the invention suitable solutions are those that contain 0.01 to 1.0, preferably 0.1 to 0.5 % of active sub- stance. For inhalative administration the use of powders, ethanolic or aqueous solutions is red. It is also possible to use the compound according to the invention as an infu- sion solution, preferably in a physiological saline solution or nutrient solution.

The compound according to the invention may be used on its own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances. Suitable formulations include, for example, tablets, capsules, suppositories, solutions, syrups, emulsions or dispersible powders.

Corresponding s may be obtained for example by mixing the active substance(s) with known excipients, for e inert diluents, such as calcium carbonate, calcium phosphate or lactose, egrants such as maize starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delay- ing release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores produced ously to the tablets with substances normally used for tablet coatings, for example collidone shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed e or pre- vent atibilities the core may also t of a number of . Similarly the tablet coating may consist of a number of layers to achieve delayed e, possibly using the excipients mentioned above for the tablets.

Syrups containing the active substances or ations thereof according to the inven- tion may additionally contain a sweetener such as saccharine, cyclamate, glycerol sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange t. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cel— lulose, wetting agents such as, for e, condensation ts of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions for injection are prepared in the usual way, e.g. with the addition of preserva- tives such as oxybenzoates, or stabilisers such as alkali metal salts of ethylenedia- mine tetraacetic acid, and transferred into injection vials or ampoules.

Capsules containing one or more active substances or combinations of active substances may for e be ed by mixing the active substances with inert carriers such as e or sorbitol and packing them into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.

For pharmaceutical use the compound according to the invention is generally used for warm-blooded vertebrates, particularly , in doses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg. For administration it may be ated for example with one or more tional inert carriers and/or diluents, e.g. with corn starch, lactose, glu- cose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tar- taric acid, water, water/ethanol, water/glycerol, sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.

The Examples which follow rate the present invention without restricting its scope: WO 04206 38 2012/051298 Examples of pharmaceutical ations A) Coated tablets containing 75 mg of active substance Composition: 1 tablet core contains: active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mg 230.0 mg Preparation: The active substance is mixed with m phosphate, corn starch, polyvinyl—pyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium te.

Blanks 13 mm in diameter are produced in a tablet-making machine and these are then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate. This granulate is compressed in a tablet-making machine to form tablets of the desired shape.

Weight of core: 230 mg die: 9 mm, convex The tablet cores thus produced are coated with a film consisting essentially of hydroxypro- pylmethylcellulose. The finished film-coated tablets are polished with beeswax.

Weight of coated : 245 mg.

B) Tablets containing 100 mg of active substance Composition: 1 tablet contains: active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate g.0_mg Method of Preparation: The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist ition has been ed (2.0 mm mesh size) and dried in a rack-type drier at 50°C it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets.

Weight of tablet: 220 mg Diameter: 10 mm, biplanar, ed on both sides and notched on one side.

C) Tablets containing 150 mg of active substance Composition: 1 tablet contains: active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate M 300.0 mg Preparation: The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 45°C, are passed through the same screen again and mixed with the specified amount of magnesium te. Tablets are pressed from the mixture.

Weight of tablet: 300 mg die: 10 mm, flat D) Hard gelatine capsules containing 150 mg of active substance Composition: 1 capsule contains: active substance 150.0 mg corn starch (dried) approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium te 3.0 mg approx. 420.0 mg Preparation: The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and neously mixed using a le apparatus. The finished mix- ture is packed into size 1 hard gelatine capsules.

Capsule filling: approx. 320 mg Capsule shell: size 1 hard gelatine capsule.

E) Suggositories containing 150 mg of active substance Composition: 1 suppository contains: active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 0 mg Preparation: After the suppository mass has been melted the active substance is homogeneously dis- tributed therein and the melt is poured into d moulds.

F) Suspension containing 50 mg of active nce Composition: 100 ml of suspension contain: active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 9 methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 9 glucose 10.00 g glycerol 5.00 g 70% ol solution 20.00 g flavouring 0.30 g dist. water ad 100 ml Preparation: The distilled water is heated to 70°C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stir- ring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, the sorbitol on and the flavouring have been added and dissolved, the suspension is evacuated with ng to eliminate air. ml of suspension contain 50 mg of active substance.

G) Ampoules containing 10 mg active substance Composition: active substance 10.0 mg 0.01 N hydrochloric acid q.s. -distilled water ad 2.0 ml Preparation: The active nce is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.

H) Ampoules containing 50 mg of active substance ition: active substance 50.0 mg 0.01 N hydrochloric acid q.s. double-distilled water ad 10.0 ml Preparation: The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.

Appendix Table 1: X-ray reflections to 30o 2 Ɵ inclusive intensities ardised) of Compound (1) (9797753_1):KZA 53_1):KZA

Claims (12)

We Claim:

1. lline compound of formula (I) Cl NH O O F O O N OH OH OH OH N OMe NH O O (I), optionally in the form of the tautomers thereof, 5 wherein reflections in the X-ray powder diagram occur at dhkl values of 7.11, 5.77, 4.69, 4.36, 4.15, 3.85 and 3.61 Å.

2. Crystalline compound according to claim 1 for use as a medicament.

3. Use of a crystalline compound according to claim 1 for the manufacture of the a ment for the ent of inflammatory or allergic diseases of the airways. 10

4. Process for the stereoselective preparation of the compound of formula(I) ing to claim 1, optionally in the form of the tautomers thereof: Cl NH O O F O O N OH OH OH OH N OMe NH O O (I), wherein the process comprises reaction steps (A) to (M), wherein (A) is the reaction of 1,4-cyclohexanedione-mono-ethyleneketal with 15 ethylenediamine and chloroform to form a compound of formula (1) (1), (9797753_1):KZA (B) is the reaction of a compound of formula (1) to form the compound of formula (2) O O x HCl HN (2), 5 (C) is the on of a compound of formula (2) with bases selected from among NaOtBu, KOtBu and NaOEt , , K2CO3, Li2CO3 and Na2CO3 to form the compound of formula (3) O O (D) is the reaction of a compound of formula (3) with the protective group reagent 10 di-tert-butyldicarbonate in ation with (4-(dimethylamino)-pyridine (DMAP) to form the compound of formula (4) O O O N O (E) is the reduction of a compound of formula (4) with NaBH4 or LiBH4 to form the 15 compound of formula (5) HO O O N O (F) is the reaction of a compound of formula (5) with trifluoroacetic anhydride to form a compound of formula (6) HO O O N O O N F F 20 (6) (10257817_1):KZA (G) is the reaction of a compound of formula (6) with a compound of formula (13) and with a reagent selected from among triphenylphosphine/ diisopropyl azodicarboxylate, triphenylphosphine/ diethyl azodicarboxylate and tributylphosphine/ azodicarbonyl)dipiperidine to form a compound of formula (7) N O 5 (13) O O O N O N O O N F F (7) (H) is the reaction of a nd of formula (7) in the presence of Pd/C or Pd(OH)2 to form a compound of formula (8a) or its tautomeric form (8b), O O O N O N O O N F F (8a) O O O N O N O O N F F 10 (8b) (10257817_1):KZA (I) is the chlorination of the compound of formula (8a) or (8b) with a reactant selected from among rosuccinimide/triphenylphosphane oxalyl chloride, l chloride, phosphorus oxychloride, phosphorus pentachloride, carbon tetrachloride/triphenylphosphane, dichlorotriphenylphosphorane and P,P-dichloro- 5 phenylphosphine oxide, to form a compound of formula (9) O O O N O N O O N (9) F F (J) + (K) is the reaction of the compound of formula (9) with 3-chlorofluoroaniline and the cleaving of a protective group to form a nd of formula (11) or (11A) Cl NH F O O N O O N F F 10 (11) Cl NH F O O N O O N F F x HCl (11A) or instead of steps (J+K) optionally steps (N+O) may be used, wherein (10257817_1):KZA (N+O) is the cleaving of a protective group of the compound of formula (9) to form the compound of formula (12) and subsequent reaction with 3-chlorofluoroaniline to form the compound of formula (11) or (11A) O O N O O N F F (12), 5 (L) is the ng of another protective group with a reagent selected from among ethanolamine, ammonia and Ba(OH) to form the compound of formula (II) Cl NH F O O N OMe (II) (M) is the reaction of the compound of formula (II) with two equivalents of maleic acid to form a compound of formula (I), optionally in the form of the tautomers thereof, Cl NH O O F O O N OH OH OH OH N OMe HN O O 10 (I), n process steps (A) to (M) take place successively in the sequence specified and Step (M) is followed by crystallization and isolation of the nd of Formula (I). (10257817_1):KZA

5. Process according to claim 4, wherein s steps (J+K) are replaced by steps (N+O), wherein (N+O) is the cleaving of a protective group of the compound of formula (9) to form the compound of formula (12) and subsequent reaction with 3-chlorofluoroaniline to form 5 the compound of formula (11) or (11A) according to claim 4 O O N O O N F F (12).

6. s for the selective preparation of a compound of formula (I), wherein the process consists of process steps as d in claim 4 (I), (J), (K), (L), and (M) or of process steps (I), (N), (O), (L) and (M), wherein the process steps (I) to (M) in 10 each case take place successively in the sequence specified.

7. Process for the stereoselective ation of a compound of formula (II), wherein the process consists of process steps as defined in claim 4 (I), (J), (K) and (L), or of process steps (I),(N), (O) and (L), wherein the process steps (I) to (L) in each case take place successively in the sequence specified. 15 8. Process for the chlorination of a compound of Formula (8a) or (8b) O O O N O N O O N F F (8a) O O O N O N O O N F F (8b) (10257817_1):KZA with a nt selected from among N-chlorosuccinimide/triphenylphosphane oxalyl chloride, thionyl chloride, phosphorus oxychloride, orus pentachloride, carbon tetrachloride/triphenylphosphane, dichlorotriphenylphosphorane and P,P-dichlorophenylphosphine oxide, to form a compound of formula (9) O O O N O N O O N (9) F F

5 .

9. Intermediate of formula (7) O O O N O N O O N F F (7) optionally in the form of the tautomers thereof.

10. Intermediate of formula (8a) or (8b), O O O N O N O O N F F 10 (8a) O O O N O N O O N F F (8b) optionally in the form of the tautomers thereof. (10257817_1):KZA

11. Intermediate of formula (9), O O O N O N O O N (9) F F optionally in the form of the tautomers thereof.

12. Intermediate of formula (11) or (11A), Cl NH F O O N O O N F F 5 (11) Cl NH F O O N O O N F F x HCl (11A) optionally in the form of the tautomers thereof. Boehringer Ingelheim International GmbH By the Attorneys for the Applicant 10 N & FERGUSON Per: (10257817_1):KZA