EP1551792A1

EP1551792A1 - Novel beta mimetics with extended duration of action, method for production and use thereof as medicaments

Info

Publication number: EP1551792A1
Application number: EP03750623A
Authority: EP
Inventors: Thierry Bouyssou; Frank Buettner; Ingo Konetzki; Sabine Pestel; Andreas Schnapp; Hermann Schollenberger; Kurt Schromm; Claudia Heine
Original assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2002-10-04
Filing date: 2003-09-25
Publication date: 2005-07-13
Also published as: AU2003270262A1; JP2006502207A; CA2501055A1; DE10246374A1; WO2004033412A1

Abstract

The invention relates to compounds of general formula (I), where the groups R1, R2 and R3 can have the meanings given in the claims and the description, method for production and use thereof as medicaments, in particular for the treatment of inflammatory and obstructive bronchial diseases.

Description

NEW BETAMIMETICS WITH EXTENDED EFFECTIVENESS. METHOD FOR THE PRODUCTION AND USE THEREOF

DRUG

The present invention relates to compounds of general formula 1

wherein the radicals R ¹ , R ² and R ³ can have the meanings given in the claims and in the description, processes for their preparation and their use as medicaments, in particular for the treatment of inflammatory and obstructive respiratory diseases.

BACKGROUND OF THE INVENTION

Betamimetics (β-adrenergic substances) are known from the prior art. They can be used in a variety of therapeutic areas.

For drug therapy of diseases, it is often desirable

To provide medicines with a longer duration of action. This can generally ensure that the concentration of the active ingredient in the organism required to achieve the therapeutic effect is given over a longer period of time without having to repeat the drug too often. The application of an active ingredient at longer intervals contributes to

To a large extent, contribute to the well-being of the patient. Another great advantage of drugs with a longer duration of action is shown in diseases whose symptoms only show up in the second half of the night. Here, a single application of a drug with a longer duration of action before going to bed would mean a significant relief for the patient and an increase in the quality of life.

It is particularly desirable to provide a drug that can be used therapeutically by applying it once per day (single dose). An application once a day has the advantage that the patient is relatively quick can get used to the regular use of the drug at certain times of the day.

It is therefore an object of the present invention to provide betamimetics which are characterized by a longer duration of action and can therefore be used for the production of medicaments with a longer activity. It is a particular object of the present invention to provide betamimetics which, owing to their long effectiveness, can be used to produce a medicament which can be applied once a day. Another object of the present invention is to provide new beta mimetics which, owing to their long effectiveness, can be used to produce a medicament which can be applied once a day for the treatment of inflammatory or obstructive respiratory diseases.

In addition to the above-mentioned objects, it is also an object of the present invention to provide those betamimetics which are not only extremely potent but are also characterized by a high degree of selectivity towards the β ₂ -adreno-receptor.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, it has been found that the above-mentioned objects are achieved by compounds of the general formula 1.

Accordingly, the present invention relates to compounds of general formula 1

wherein

R ¹ -C ₄ alkyl; R ² QG _t alkyl;

R ³ C 1 -C 4 -alkyl or phenyl, which can optionally be mono- or polysubstituted, or R ² and R ³ together form a divalent group selected from -CH ₂ -CH ₂ - and -CH ₂ -CH ₂ -CH ₂ - mean. Compounds of formula 1 are preferred in which R ^{1 is} C ¹ -C 4 -alkyl; R ² CC ₄ alkyl;

R ³ -C 1 -alkyl or phenyl, which may optionally be mono-, di-, tri- or tetrasubstituted by one or more radicals selected from -C ₃ -alkyl,

CF ₃ , methoxy, ethoxy, hydroxy, fluorine, chlorine, bromine, -OCF ₃ , -CHF ₂ , -NHCOCH ₃ and -NHSO ₂ CH ₃ , or R ² and R ³ together form a divalent group selected from -CH ₂ -CH ₂ - and -CH ₂ -CH ₂ -CH ₂ - mean.

Also preferred are compounds of general formula 1, in which R ^{1 is} C ¹ -C ₄ -alkyl, preferably methyl; R ² CC ₄ alkyl;

R ³ -C ₄ alkyl or phenyl, which may optionally be mono-, di-, tri- or tetra-substituted by one or more radicals selected from methyl, ethyl, CF ₃ , methoxy, ethoxy and hydroxy, or R ² and R ³ together represent a double-bonded group selected from -CH ₂ -CH ₂ - and -CH ₂ -CH ₂ -CH ₂ -.

Also preferred are compounds of general formula 1, wherein R ¹ - alkyl, preferably methyl; R ² QQ-alkyl, preferably methyl;

R ³ -C-alkyl, preferably methyl, or phenyl, which may optionally be substituted once, twice, three or four times by one or more radicals selected from methyl, CF ₃ , methoxy and hydroxy, or R ² and R. ³ together represent the double-bonded group -CH ₂ -CH ₂ -.

According to the invention, preference is given to compounds of the general formula 1 in which R ^{1 is} methyl or ethyl, preferably methyl; R ² methyl; R ^{3 is} methyl, ethyl or phenyl, which may optionally be mono-, di-, tri- or tetrasubstituted by one or more radicals selected from methyl, CF ₃ , methoxy and hydroxy, or R ² and R ³ together form the divalent group - CH ₂ -CH ₂ - mean.

Compounds of the general formula 1 in which R ^{1 is} methyl are particularly preferred; R ² methyl;

R ^{3 is} methyl or phenyl, which may optionally be mono-, di- or trisubstituted by one or more radicals selected from methyl, ethyl and hydroxy, or R ² and R ³ together denote the -CH -CH ₂ - group.

According to the invention, preference is also given to compounds of the general formula 1 in which R ^{1 is} methyl; R ² methyl; R ^{3 is} methyl or phenyl, or

R ² and RR ³³ together mean the double-bond group -CH ₂ -CH ₂ .

The following compounds of formula 1 are of outstanding importance according to the invention:

4- [2- (l, l-dimethyl-propylamino) -l-hydroxyethyl] -3-methoxy-benzene-1,2-diol;

• 4- [1-hydroxy-2- (1-methylcyclopentylamino) ethyl] -3-methoxy-benzene-1, 2-diol;

• 4- {2- [l, l-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethylamino] -l-hydroxyethyl} -3-methoxy-benzene-1,2-diol;

• 4- {2- [1,1-dimethyl-2-ρhenyl) ethylamino] - 1-hydroxyethyl} -3-methoxy-benzene-1,2-diol;

4- {2- [l, l-dimethyl-2- (2,3,5,6-tetra-methyl-ρhenyl) -ethylamino] -l-hydroxy-ethyl} -3-methoxy-benzene-1,2 diol; • 4- [2- (l, l-dimethyl-2-o-tolyl-ethylamino) -l-hydroxy-ethyl] -3-methoxy-benzene-l, 2-diol;

The invention relates to the respective compounds of formula 1, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.

The compounds of general formula 1 according to the invention can optionally be present in the form of their individual optical isomers, mixtures of the individual enantiomers or racemates and can be separated into the pure forms using methods known from the literature. If the compounds are used in enantiomerically pure form, the R enantiomers are preferred.

Acid addition salts are understood to mean salts which are formed with pharmacologically acceptable acids selected from the group consisting of hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, methanesulfonic acid, nitric acid, maleic acid, acetic acid, benzoic acid, citric acid, fumaric acid, tartaric acid; Oxalic acid, succinic acid and toluenesulfonic acid, preferably hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, fumaric acid and methanesulfonic acid.

Unless otherwise stated, the alkyl groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl or butyl. The abbreviations Me, Et, Pr or Bu may also be used to denote the groups methyl, ethyl, propyl or butyl. Unless otherwise described, the definitions propyl and butyl encompass all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec. Butyl and tert-butyl, etc.

Of the above acid addition salts, the salts are the

Hydrochloric acid, methanesulfonic acid, benzoic acid and acetic acid are particularly preferred according to the invention.

The compounds according to the invention can be prepared analogously to procedures already known in the prior art. Suitable manufacturing processes are known for example from US 3657244, to which reference is made here in full.

The synthesis examples described below serve to further illustrate the present invention. However, they are only to be understood as exemplary procedures for further explaining the invention, without restricting it to the subject matter described below by way of example.

EXAMPLE 1 4- [2- (1,1-Dimethyl-propylammo) -1-hydroxyethyl] -3-methoxy-benzene-1,2-diol

a) 2- (l, l-Dimethyl-propylamino) -l- (4-methoxy-2,2-diphenyl-benzo [l, 3] dioxol-5-yl) - ethanone:

42.5 g of bromo-2-methoxy-3,4-diphenylmethylene dioxyacetophenone (obtainable according to US 3657244) are stirred under reflux with 30 g of 1,1-dimethylpropylamine in 150 ml of ethanol for 3 hours. The solvent is distilled off under reduced pressure and the residue is mixed with diethyl ether and extracted twice with water. After the solvent has been distilled off under reduced pressure, the remaining residue is dissolved in ethyl acetate and acidified with ethereal hydrochloric acid. The crystals which precipitate are filtered off with suction and washed with ethyl acetate and diethyl ether. Yield: 26 g (56%, hydrochloride); Mp = 174-176 ° C.

b) 1 - (3, 4-Dihydroxy-2-methoxyphenyl) -2- (l, 1-dimethyl-propylamino) -ethanone:

25 g of 2- (1,1-dimethyl-propylamino) -1- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxol-5-yl) -ethanone are mixed with 50 mL 15% methanolic hydrochloric acid Stirred under reflux for 2 hours. The solvent is distilled off under reduced pressure and the residue is dissolved in acetonitrile and mixed with ethyl acetate. The failing

J crystals are suctioned off and washed with acetonitrile and diethyl ether. Yield: 15 g (92%) of the compound as the hydrochloride. For further purification, the free base can be released from the hydrochloride according to usual conditions Slurried methanol, mixed with the equimolar amount of benzoic acid and heated. The crystals thus obtained are filtered off with suction and washed with diethyl ether. Mp = 151-154 ° C (benzoate).

c) 4- [2- (1,1-dimethyl-propylamino) -1-hydroxy-ethyl] -3-methoxy-benzene-1,2-diol:

6.5 g of l- (3,4-dihydroxy-2-methoxy-phenyl) -2- (l, l-dimethyl-propylamino) -ethanone are hydrogenated with 0.1 g of platinum oxide as a catalyst in 125 ml of methanol. The catalyst is suctioned off and the solvent is distilled off under reduced pressure. The residue is dissolved in ethyl acetate, the crystals which precipitate are filtered off with suction and washed with ethyl acetate and diethyl ether.

Yield: 5.5 g (85%; benzoate); Mp = 172-174 ° C.

EXAMPLE 2 4- [l-Hydroxy-2- (l-methyl-cyclopentiamino) -ethyl] -3-methoxy-benzene-1,2-dioI

a) 1-methyl-cyclopentylamine:

66.5 g sodium cyanide are dissolved in 150 mL glacial acetic acid. A solution of 300 mL sulfuric acid and 150 mL glacial acetic acid is added dropwise to the sodium cyanide solution at 5-10 ° C. 126 g of 1-methyl-cyclopentanol become this

Given mixture. The mixture obtained is left to stand overnight. Then 210 mL water and 770 g sodium hydroxide solution in 1.5 L water are added while cooling with ice. The mixture is heated to reflux for 4 hours and the amine is isolated using steam distillation. The distillate is concentrated. Acidified hydrochloric acid, extracted with diethyl ether and then made alkaline with 50% sodium hydroxide solution. The residue is fractionally distilled (K _p 760 mm = 114-115 ° C). Yield: 45 g (36%).

b) l- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxol-5-yl) -2- (l-methyl-cyclopentylamino) - ethanone:

35 g of bromine-2-methoxy-3,4-diphenylmethylene dioxyacetophenone are refluxed with 45 g of 1-methyl-cyclopentylamine in 150 ml of ethanol for 1 hour. The solvent is distilled off under reduced pressure, the residue is dissolved in diethyl ether with Water is extracted and the solvent is distilled off under reduced pressure. The remaining residue is dissolved in acetonitrile, acidified with hydrochloric acid and the crystals obtained are isolated. Yield: 19 g (48%; hydrochloride); Mp = 173 ° C (decomposition).

c) 1 - (3, 4-Dihydroxy-2-methoxyphenyl) -2- (1 -methyl-cyclopentylamino) -ethanone: 19 g l- (4-methoxy-2,2-diphenyl-benzo [l , 3] dioxol-5-yl) -2- (l-methyl-cyclopentylamino) -ethanone are stirred under reflux in 190 ml of 15% methanolic hydrochloric acid for 2 hours. The solvent is distilled off under reduced pressure and the remaining residue is dissolved in acetonitrile. The precipitated crystals are washed with diethyl ether. Yield: 11 g (88%; hydrochloride); Mp = 187-189 ° C (decomposition).

d) 4- [l-Hydroxy-2- (l-methyl-cyclopentylamino) -ethyl] -3-methoxy-benzene-l, 2-diol: 5 g of l- (3,4-dihydroxy-2-methoxy-phenyl ) -2- (l-methyl-cyclopentylamino) ethanone hydrochloride are hydrogenated with 0.2 g PtO ₂ in 200 mL methanol. The catalyst is suctioned off and the solvent is distilled off under reduced pressure. The remaining residue is dissolved in ethanol and 5 g of sodium benzoate are added. The title compound is isolated in the form of its benzoate. Yield: 4.5 g (70.5%; benzoate); Mp = 179-180 ° C.

EXAMPLE 3

4- {2- [l, l-DimethyI-2- (2,4,6-trimethyl-phenyl) -ethyIamino] -l-hydroxy-ethyI} -3-methoxy-benzene-l, 2-diol

a) 2-chloromethyl-l, 3,5-trimethyl-benzene:

400 g mesitylene are combined with 130 g paraformaldehyde and 2 L hydrochloric acid are introduced at 60-70 ° C within 7 hours. Then it is extracted with benzene and the org. Phase then washed with 2N sodium hydroxide solution. The residue is fractionally distilled. Yield: 204 g (36%); Bp ₁₅ = 130-140 ° C. b) (2,4,6-trimethylphenyl) acetonitrile:

66 g of sodium cyanide are stirred under reflux in 100 mL water and 140 mL ethanol until a clear solution is obtained. 136 g of 2-chloromethyl-1,3,5-trimethyl-benzene are slowly added dropwise to this solution and the mixture is stirred for 3 hours under reflux. It is diluted with 1 L water and extracted three times with 200 mL benzene. The combined organic phases are washed with water and the solvent is distilled off under reduced pressure. The residue is fractionally distilled. Yield: 92 g (72%); Bp ₁₅ = 145-153 ° C.

c) (2,4,6-trimethylphenyl) acetic acid:

To a solution of 1.1 L water and 915 mL conc. Heated to 50 ° C. 155 g of (2,4,6-trimethylphenyl) acetonitrile are added to sulfuric acid. The mixture is stirred under reflux for 6 hours. The reaction mixture is then poured onto 3 kg of ice. The solid is filtered off and washed with water.

Yield: 131 g (86%); Mp = 163-166 ° C.

d) (2,4,6-Trimethyl-phenyl) -acetic acid methyl ester:

173 g (2,4,6-trimethylphenyl) acetic acid are concentrated in 131 mL. Hydrochloric acid and 1.1 L methanol stirred for 3 hours under reflux. The solvent is distilled off under reduced pressure and the aqueous phase is extracted twice with diethyl ether. The combined organic phases are extracted twice with a saturated aqueous sodium bicarbonate solution, dried with sodium sulfate and the solvent is distilled off under reduced pressure. The residue is fractionally distilled.

Yield: 116 g (57%); Bp ₁₅ = 140 ° C.

e) 2-methyl-1- (2,4,6-trimethylphenyl) propan-2-ol:

38 g of magnesium and 222 g of methyl iodide in 1.2 L of diethyl ether and 116 g of (2,4,6-trimethyl-phenyl) -acetic acid methyl ester are converted into one under standard conditions

Grignard reaction 97 g (79%) of the title compound prepared. Bp ₁₅ = 140 ° C.

f) N- [1,1-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethyl] -formamide:

90 mL glacial acetic acid and 33 g potassium cyanide are combined with ice cooling. 90 mL sulfuric acid and 90 mL glacial acetic acid are then added dropwise at 20 ° C. 65 g of 2-methyl-1- (2,4,6-trimethyl-phenyl) propan-2-ol are slowly added to the solution at a constant temperature. After the addition has ended, the mixture is stirred for a further hour. The mixture is poured onto ice water, neutralized with sodium carbonate solution and extracted with diethyl ether. The solvent is distilled off under reduced pressure and the residue is fractionally distilled.

Yield: 55 g (74%); Kp ₀ , ι = 155 ° C.

g) l, l-dimethyl-2- (2,4,6-trimethylphenyl) ethylamine:

61 g of N- [l, l-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethyl] -formamide are stirred with 35 g of potassium hydroxide in 155 ml of ethylene glycol under reflux for 9 hours and, after the reaction has ended, to 1 kg Given ice cream. The aqueous phase is extracted three times with diethyl ether and the solvent is distilled off under reduced pressure. The residue is fractionally distilled. Yield: 48 g (89%); Bp ₁₅ = 135-140 ° C.

h) 2- [l, l-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethylamino] -l- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxol-5 yl) ethanone:

42.5 g -Brom-2-methoxy-3,4-diphenylmethylene dioxyacetophenone are mixed with 22 gl, l-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethylamine and 17 g potassium carbonate in 150 mL ethanol and 50 mL of acetonitrile was stirred under reflux for 3 hours. The solids are filtered off and the solvent is distilled off under reduced pressure. The

The residue is dissolved in a little acetonitrile and mixed with ethereal hydrochloric acid. The crystals which precipitate are filtered off with suction and washed with acetonitrile and ethyl acetate. Yield: 25 g (44%; hydrochloride); Mp = 240-250 ° C.

i) 1 - (3,4-Dihydroxy-2-methoxy-phenyl) -2- [1,1-dimethyl-2- (2,4,6-trimethyl-phenyl) ethylamino] ethanone:

17 g of 2- [l, l-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethylamino] -l- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxol-5 -yl) -ethanone hydrochloride are stirred with 170 mL 15% methanolic hydrochloric acid under reflux for 90 min. Most of the solvent is distilled off under reduced pressure. The remaining residue crystallizes out. The crystals are filtered off and washed with diethyl ether. Yield: 10 g (80%; hydrochloride) mp = 199-201 ° C. j) 4- {2- [l, l-dimethyl-2- (2,4,6-trimethyl-ρhenyl) -ethylamino] -l-hydroxy-ethyl} -3-methoxy-benzene-1, 2-diol:

9 g of l- (3,4-dihydroxy-2-methoxy-ρhenyl) -2- [l, l-dimethyl-2- (2,4,6-trimethyl-phenyl) ethylamino] ethanone hydrochloride are added with 0 , 4 g of platinum (IN) oxide in 125 mL of methanol are hydrogenated. The catalyst is filtered off and the solvent is distilled off under reduced pressure. The residue is dissolved in 50 ml of ethyl acetate and the crystals which precipitate are filtered off with suction and washed with diethyl ether and ethyl acetate. Yield: 6 g (67%, hydrochloride); = 98-105 ° C.

EXAMPLE 4 4- [2- (l, l-Dimethyl-2-phenyl-ethylamino) -l-hydroxy-ethyl] -3-methoxy-benzene-l, 2-diol

a) 2- (l, l-Dimethyl-phenylethylamino) -l- (4-methoxy-2,2-diphenyl-benzo [1,3, dioxol-5-yl) -ethanone:

45 g of α-bromo-2-methoxy-3,4-diphenylmethylene dioxyacetophenone are refluxed with 39 g of l, l-dimethyl-2-phenylethylamine in 200 ml of ethanol for 3 hours. The reaction mixture was concentrated with. Acidified hydrochloric acid and mixed with water. The crystals which precipitate are filtered off with suction and washed successively with water, toluene and ethyl acetate. Yield: 34 g (61%, hydrochloride); Mp = 167-170 ° C.

b) 1- (3,4-Dihydroxy-2-methoxy-phenyl) -2- (1,1-dimethyl-2-phenylethylamino) -ethanone: 34 g of the HCl salt of 2- (1,1-dimethyl- 2-phenylethylamino) -l- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxol-5-yl) -ethanone are refluxed in 340 ml of 15% methanolic hydrochloric acid for 2 hours. The solvent was then distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The solid which precipitates is filtered off with suction and washed with ethyl acetate and diethyl ether. Yield: 18 g (77%, hydrochloride); Mp 192-196 ° C.

c) 4- {2- [1, 1-dimethyl-2-phenyl-ethylamino] - 1-hydroxy-ethyl} -3-methoxy-benzene-1, 2-diol: 10 g of l- (3,4-dihydroxy-2-methoxy-phenyl) -2- (l, l-dimethyl-2-phenylethylamino) - ethanone hydrochloride are hydrogenated with 0.5 g of PtO ₂ in 200 mL of methanol. The catalyst is suctioned off and the solvent is distilled off under reduced pressure. The remaining residue is dissolved in 200 ml of acetonitrile, mixed with 5 g of sodium benzoate and refluxed for 15 minutes. After the excess sodium benzoate has been filtered off, the product which has crystallized out of the filtrate is filtered off and washed with acetonitrile and diethyl ether. Yield: 64.5% (benzoate); 149-150 ° C.

EXAMPLE 5

4- {2- [1,1-dimethyl-2- (2,3,5,6-tetra-methyl-phenyl) -ethylamino] -1-hydroxyethyl} -3-methoxy-benzene-1,2 diol

a) 2- [l, l-Dimethyl-2- (2,3,5,6-tetramethyl-ρhenyl) -ethylamine] -l- (4-methoxy-2,2-diphenyl-benzo [1, 3] dioxole -5-yl) ethanone:

28.5 g of α-bromo-2-methoxy-3,4-diphenylmethylene dioxyacetophenone, 11 g of 1,1-dimethyl-2- (2,3,5,6-tetramethylphenyl) ethylamine, and 8 g of sodium carbonate are added in 3 hours a solution of 100 mL ethanol and 10 mL acetonitrile refluxed.

The inorganic salts are then filtered off and the solvent is distilled off. The residue is dissolved in ethyl acetate, acidified with ethereal hydrochloric acid and mixed with diethyl ether. The solid which precipitates out is filtered off, washed with diethyl ether and then boiled in water. The product is obtained after filtration and drying.

Yield 11 g (hydrochloride); 194-198 ° C.

b) Preparation of l- (3,4-dihydroxy-2-methoxy-ρhenyl) -2- [l, l-dimethyl-2- (2,3,5,6-tetramethylphenyl) ethylamine] ethanone: 11 g of 2- [l, l-dimethyl-2- (2,3,5,6-tetramethyl-phenyl) -ethylamine] -l- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxol -5-yl) -ethanone hydrochloride is allowed to reflux for 1.5 hours in 110 mL of 15% methanolic hydrochloric acid. The raw product is suctioned off with Washed acetonitrile and then precipitated from methanol / diethyl ether. Yield: 7 g (hydrochloride); Mp 213-215 ° (decomposition).

c) Preparation of 4- {2- [l, l-dimethyl-2- (2,3,5,6-tetra-methyl-phenyl) -ethylamino] -l-hydroxy-ethyl} -3-methoxy-benzene- l, 2-diol:

7 g of 1 - (3,4-dihydroxy-2-methoxy-phenyl) -2- [1,1-dimethyl-2- (2,3, 5, 6-tetramethyl-phenyl) -ethylamine] -ethanone hydrochloride hydrogenated with 0.2 g platinum (IV) oxide in 100 mL methanol. The catalyst is then removed by filtration and the solvent is distilled off. The residue is dissolved in 20 ml of water and 1N hydrochloric acid is added. The crystals which precipitate on cooling are filtered off with

Washed ice water and recrystallized in ethyl acetate after drying. Yield: 5 g; M.p. 165-168 ° C.

EXAMPLE 6 4- [2- (l, l-DimethyI-2-o-tolyl-ethylamino) -l-hydroxy-ethyl] -3-methoxy-benzene-l, 2-diol

a) Preparation of 2- (l, l-dimethyl-2-σ-tolyl-ethylamine) -l- (4-methoxy-2,2-diphenyl-benzo [l, 3] dioxol-5-yl) -ethanone:

26 g of α-bromo-2-methoxy-3,4-diphenylmethylene dioxyacetophenone, 10 g of 1,1-dimethyl-2-o-tolylethylamine and 9.5 g of sodium carbonate are refluxed in acetonitrile for 3 hours. The inorganic salts are filtered off and the solvent is distilled off. The residue is dissolved in ethyl acetate and acidified with ethereal hydrochloric acid, the starting amine precipitating and being filtered off with suction. After adding

The product crystallizes from diethyl ether to the filtrate. Yield 10 g (30%; hydrochloride); Mp 180-184 ° C.

b) Preparation of l- (3,4-dihydroxy-2-methoxyphenyl) -2- (l, l-dimethyl-2-o-tolylethylamine) ethanone:

10 g of 2- (l, l-dimethyl-2-o-tolyl-ethylamine) -l- (4-methoxy-2,2-diphenylbenzo [1,3, dioxol-5-yl) -ethanone hydrochloride boiled in 100 mL 15% methanolic hydrochloric acid under reflux for 1.5 hours. The The reaction mixture is concentrated and the residue is recrystallized from ethyl acetate. The solid present after filtration is washed with diethyl ether. Yield 6 g (85%; hydrochloride); Mp 198-201 ° (decomposition).

c) Preparation of 4- [2- (l, l-dimethyl-2-o-tolyl-ethylamino) -l-hydroxy-ethyl] -3-methoxy-benzene-1, 2-diol:

4 g of l- (3,4-dihydroxy-2-methoxy-phenyl) -2- (l, l-dimethyl-2-σ-tolyl-ethylamine) - ethanone hydrochloride are mixed with 0.2 g of platinum (IV) oxide in 50 mL of methanol hydrogenated under normal conditions. The catalyst is then removed by filtration and the solvent is distilled off. The residue is mixed with 100 ml

Acetonitrile and 3 g of sodium benzoate were added. The mixture is stirred for 20 minutes under reflux and the inorganic constituent is filtered off. The product which crystallizes out of the filtrate is filtered off with suction and recrystallized in acetonitrile. Yield 2.4 g (benzoate); Mp 114 ° C.

As has been found, the compounds of general formula 1 are distinguished by a wide range of possible uses in the therapeutic field. To be emphasized are those possible uses for which the compounds of formula 1 according to the invention can preferably be used as beta-mimetics due to their pharmaceutical activity.

These include, for example, the treatment of asthma, COPD (chronic obstructive pulmonary disease), the inhibition of premature contractions in obstetrics (tocolysis), the restoration of the sinus rhythm in the heart in the case of atrio-ventricular block, and the elimination of bradycal arrhythmias (antiarrhythmic) Therapy of circulatory shock (vasodilation and increase in cardiac output) and the treatment of itching and inflammation of the skin.

The compounds of general formula 1 can be used alone or in combination with other active compounds of formula 1 according to the invention. If appropriate, the compounds of the general formula 1 can also be used in combination with other pharmacologically active compounds. These are in particular anticholinergics, antiallergics, PAF antagonists, PDE IV inhibitors, leukotriene antagonists, p38 kinase inhibitors, EGFR kinase inhibitors and corticosteroids, and combinations of active substances thereof. Examples of preferred anticholinergics that can be used in combination with the compounds of formula 1 include compounds selected from the group consisting of tiotropium salts, ipratropium salts, oxitropium salts, salts of the compounds N-methyl-2 known from WO 02/32899 , 2-Diphenylpropionsäuretropenolester, N-methyl-2,2-Diphenylpropionsäurescopinester, N-Methyl-2-Fluor-2,2-Diphenylessigsäurescopinester and N-Methyl-2-fluoro-2,2-Diphenylacetic Acid Tropenolester as well as salts of the from WO 02 / 32899 known compounds N-methyl-3,3 ', 4,4'-tetraf uorbenzilsäuretropenolester, N-methyl-3, 3', 4,4'-tetrafluorobenzilsäurescopinester;N-methyl-4,4'-dichlorobenzic acid copinate ester, N-methyl-4,4'-difluorobenzic acid copine ester, N-methyl-3, 3'-difluorobenzic acid tropenol ester, N-methyl-3,3'-difluorobenzic acid copine ester and

N-ethyl-4,4'-difluorobenzilic acid tropenol esters, optionally in the form of their hydrates and solvates. Salts are understood to mean those compounds which, in addition to the cations mentioned above, contain a single negatively charged anion selected from the group consisting of chloride, bromide and methanesulfonate as counterion. The bromides or methanesulfonates of the abovementioned structures are particularly preferred as active ingredients in the context of the present invention. Of outstanding interest in the context of the present invention are, for example, the anticholinergics tiotropium bromide, ipratropium bromide, oxitropium bromide, 2,2-diphenylpropionic acid, tropenol ester methobromide, 2,2-diphenylpropionic acid copinate methobromide, 2-fluoro-2,2-diphenylacetic acid scopinester, scopinester Fluoro-2,2-diphenylacetic acid tropenol ester methobromide, 3,3 ', 4,4'-tetrafluorobenzic acid tropenol ester methobromide, 3,3', 4,4'-tetrafluorobenzic acid copinate methobromide; 4,4'-dichlorobenzilic acid copinesate methobromide, 4,4'-difluorobenzilic acid copinate methobromide, 3, 3 '-difluorobenzic acid tropenol ester methobromide, 3,3'-difluorobenzic acid copinate methobromide and 4,4'-difluorobenzic acid copropesterium methobromide the ipratropium bromide, the 2,2-diphenylpropionic acid tropenol ester methobromide, the 2,2-diphenylpropionic acid copinate methobromide, the 2-fluoro-2,2-diphenylacetic acid scopine ester methobromide and the 2-fluoro-2,2-diphenylacetic acid tropenol ester methobromide of particular importance. Pharmaceutical combinations which, in addition to the compounds of formula 1 according to the invention, contain tiotropium bromide as a further active ingredient are particularly preferred according to the invention. This combination is of particular importance in the treatment of asthma or COPD, especially COPD. Of particular importance here are those combinations which contain the tiotropium bromide in the form of its crystalline monohydrate known from WO 02/30928 or in the form of its crystalline anhydride known from WO 03/000265:

In the context of the present invention, corticosteroids, which can optionally be used in combination with the compounds of formula 1,

Compounds understood which are selected from the group consisting of Flunisolide, Beclomethasone, Triamcinolone, Budesonid, Fluticasone, Mometasone, Ciclesonide, Rofleponide, GW 215864, KSR 592, ST-126 and Dexametasone. In the context of the present invention, the corticosteroids are preferably selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexametasone, with here the budesonide, fluticasone, mometasone and ciclesonide, in particular the budesonasone and one Importance. If appropriate, only the term steroids is used in the context of the present patent application instead of the term corticosteroids. A reference to steroids concludes in the context of the present

Invention a reference to salts or derivatives that can be formed by the steroids. Examples of possible salts or derivatives are: sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. If necessary, the corticosteroids can also be present in the form of their hydrates.

As an example of PDE-IV inhibitors which can be used according to the invention as a combination with the compound of formula 1, there may be mentioned compounds which are selected from the group consisting of Enprofylline, Roflumilast, Ariflo, Bay-198004, CP-325,366, BY343, D-4396 (Sch-351591), V-11294A, Z-15370 and AWD-12-281. Preferred PDE-IV inhibitors are selected from the group consisting of Enprofylline, Roflumilast, Ariflo, Z15370 and AWD-12- 281, with AWD-12-281 being particularly preferred as a combination partner with the compound of the formula I_ according to the invention. A reference to the aforementioned PDE-IV inhibitors includes a reference to the present invention optionally existing pharmacologically acceptable acid addition salts. According to the invention, the physiologically tolerable acid addition salts which can be formed by the abovementioned PDE-IV inhibitors are understood as pharmaceutically tolerable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, JM-lactic acid , Citric acid, tartaric acid or maleic acid. According to the invention, the salts selected from the group consisting of acetate, hydrochloride, hydrobromide, sulfate, phosphate and methanesulfonate are preferred in this context.

In the context of the present invention, dopamine agonists, which can optionally be used in combination with the compounds of formula 1, are understood to mean compounds which are selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole , Roxindol, Ropinirol, Talipexol, Tergurid and Viozan. In the context of the present invention, preference is given to using dopamine agonists as combination partners with the compounds of the formula 1 which are selected from the group consisting of pramipexole, talipexole and viozan, pramipexole being of particular importance. In the context of the present invention, a reference to the above-mentioned dopamine agonists includes a reference to their optionally existing pharmacologically acceptable acid addition salts and, if appropriate, their hydrates. The physiologically tolerable acid addition salts which can be formed by the above-mentioned dopamine agonists are understood to mean, for example, pharmaceutically tolerable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and are maleic acid.

Examples of antiallergics which can be used according to the invention as a combination with the compounds of formula 1 are epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, Doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozin. Preferred antiallergics which are used in the context of the present invention in combination with the compounds of the formula 1 according to the invention are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratidine and mizolastine, with epinastine and desloratidine being particularly preferred. In the context of the present invention, a reference to the abovementioned antiallergics includes a reference to their pharmacologically acceptable acid addition salts which may exist.

4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholinyl) -3-propanone-1 may be mentioned as an example of PAF antagonists which can be used in combination with the compounds of formula 1 according to the invention -yl] -6H-thieno- [3,2-f] [1,2,4] triazolo [4,3-a] [1,4,] diazepine,

6- (2-chloro-henyl) -8,9-dihydro-l-methyl-8 - [(4-morpholinyl) carbonyl] -4H, 7H-cyclopenta- [4,5] thieno- [3,2- f] [l, 2,4] triazolo [4,3-a] [l, 4] diazepine.

4 - [(3-chloro-4-fluorophenyl) amino] -7- [4 may be mentioned as a particularly preferred example of EGFR kinase inhibitors which can be used in combination with the compounds of the formula 1 according to the invention - ((R) -6-methyl-2-oxo-morpholin-4-yl) - butyloxy] -6 - [(vinylcarbonyl) amino] -quinazoline; 4 - [(3-Chloro-4-fluorophenyl) amino] -7- [4- ((S) -6-methyl-2-oxo-morpholin-4-yl) butyloxy] -6 - [(vinylcarbonyl ) amino] -quinazoline, 4- [(3-chloro-4-fluoro-phenyl) amino] -7- (2- {4 - [(S) - (2-oxo-tetrahydrofuran-5-yl) carbonyl] - piperazin-l-yl} ethoxy) -6 - [(vinylcarbonyl) amino] -quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2 - ((S) -6- methyl-2-oxo-morpholin-4-yl) ethoxy] ~ 6- [(vinylcarbonyl) amino] -quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4- {N - [2- (ethoxycarbonyl) ethyl] -N - [(ethoxycarbonyl) methyl] amino} -l-oxo-2-buten-l-yl) amino] -7-cyclopropylmethoxy-quinazoline, 4 - [(R) - (l-phenyl-ethyl) amino] -6- {[4- (morpholin-4-yl) - l-oxo-2-buten-l-yl] amino} -7-cyclopropylmethoxy-quinazoline and 4- [(3rd -Chlor-4-fluorophenyl) amino] -6- [3 - (morpholin-4-yl) propyloxy] -7-methoxy-quinazoline. A reference to the above-mentioned EGFR-JKinase inhibitors in the context of the present invention includes a reference to their pharmacologically acceptable acid addition salts which may exist.

Under the physiological or pharmacologically acceptable acid addition salts which can be formed by the EGFR kinase inhibitors are understood according to the invention to be pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or Are maleic acid. According to the invention, the salts of the EGFR kinase inhibitors are preferably selected from the salts of acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.

As an example of p38 kinase inhibitors which can be used in combination with the compounds of formula 1 according to the invention, l- [5-tert-butyl-2-> -tolyl-2H-pyrazole-3- yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] urea; 1 - [5-tert-Butyl-2 - /? - tolyl-2H-pyrazol-3 -yl] -3 - [4- (2- (1 - oxothiomorpholin-4-yl) ethoxy) naphthalen-1 -yl] -urea; 1 - [5-tert-butyl-2- (2-methylpyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2-pyridin-4-yl-ethoxy) naphthalene-l- yl] - urea; l- [5-tert-butyl-2- (2-methoxypyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalene-1 - yl] urea or 1 - [5-tert-butyl-2-methyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalene-l-yl] - urea. A reference to the above-mentioned p38 kinase inhibitors in the context of the present invention includes a reference to their pharmacologically acceptable acid addition salts which may exist. According to the invention, the physiologically or pharmacologically acceptable acid addition salts which can be formed by the p38 kinase inhibitors are understood to be pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, J are lactic acid, citric acid, tartaric acid or maleic acid.

If the compounds of formula 1 are used in combination with other active substances, the combination of steroids, PDE IV inhibitors or anticholinergics is particularly preferred from the compound classes mentioned above. The combination with anticholinergics is of particular importance.

Suitable forms of application for the application of the compounds of formula 1 are, for example, tablets, capsules, suppositories, solutions etc. According to the invention is of particular importance (in particular in the treatment of

Asthma or COPD) the inhalative application of the compounds according to the invention.

The proportion of the pharmaceutically active compound (s) should each be in the range of

0.05 to 90 wt .-%, preferably 0.1 to 50 wt .-% of the total composition.

Corresponding tablets can be mixed, for example, by mixing the active ingredient (s) with known auxiliaries, for example inert diluents, such as Calcium carbonate, calcium phosphate or milk sugar, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or agents for achieving the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Correspondingly, coated tablets can be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core can also consist of several layers to achieve a deposit effect or to avoid incompatibilities. Likewise, the coated tablet shell can also consist of several layers in order to achieve a depot effect, it being possible to use the auxiliaries mentioned above for the tablets. Juices of the active substances or combinations of active substances according to the invention can additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. They can also contain suspending agents or thickening agents, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

Solutions are usually, e.g. with the addition of isotonants, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants, where, for example, when using water as a diluent, organic solvents can optionally be used as solubilizers or auxiliary solvents , manufactured and filled into injection bottles or ampoules or infusion bottles.

The capsules containing one or more active ingredients or combinations of active ingredients can be produced, for example, by mixing the active ingredients with inert carriers, such as milk sugar or sorbitol, and encapsulating them in gelatin capsules. Suitable suppositories can be produced, for example, by mixing them with carrier agents such as neutral fats or polyethylene glycol or its derivatives. Examples of auxiliaries are water, pharmaceutically acceptable organic solvents, such as paraffins (for example petroleum fractions), oils of vegetable origin (for example peanut or sesame oil), monofunctional or polyfunctional alcohols (for example ethanol or glycerol), carriers such as natural rock meal (for example kaolins, clays, Talc, chalk) synthetic rock flour (e.g. highly disperse silica and silicates), sugar (e.g. cane, milk and dextrose) emulsifiers (e.g. lignin, sufite liquor, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl) mentioned.

In the case of oral use, the tablets can of course also contain additives, such as e.g. Contain sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions, in addition to the auxiliaries mentioned above, the active ingredients can be mixed with various flavor enhancers or colorants.

In the preferred application according to the invention of the compounds of formula 1 for the therapy of asthma or COPD, administration forms or pharmaceutical formulations which can be administered by inhalation are particularly preferably used. Inhalable dosage forms are inhalable powders, metered-dose aerosols containing propellant gas, or propellant-free inhalation solutions. In the context of the present invention, the term propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions. The dosage forms which can be used in the context of the present invention are described in detail in the following part of the description.

Inhalable powders which can be used according to the invention can contain 1 either alone or in a mixture with suitable physiologically acceptable auxiliaries.

If the active ingredients 1 are contained in a mixture with physiologically acceptable auxiliaries, the following physiologically acceptable auxiliaries can be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo- and polysaccharides ( e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, Xylitol), salts (eg sodium chloride, calcium carbonate) or mixtures of these auxiliaries with one another. Mono- or disaccharides are preferably used, the use of lactose or glucose being preferred, in particular, but not exclusively, in the form of their hydrates. Lactose, most preferably lactose monohydrate, is used as an auxiliary as particularly preferred in the sense of the invention. In the context of the inhalable powders according to the invention, the auxiliaries have a maximum average particle size of up to 250 μm, preferably between 10 and 150 μm, particularly preferably between 15 and 80 / xm. If appropriate, it may seem sensible to add finer excipient fractions with an average particle size of 1 to 9 μm to the excipients mentioned above. The latter finer excipients are also selected from the group of excipients that can be used. Finally, to produce the inhalable powder according to the invention, micronized active ingredient 1, preferably with an average particle size of 0.5 to 10 μm, particularly preferably from 1 to 5 μm, is admixed with the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronizing and by finally mixing the constituents are known from the prior art. The inhalable powders according to the invention can be applied using inhalers known from the prior art.

Inhalation aerosols containing propellant gas according to the invention may contain 1 dissolved in the propellant gas or in dispersed form. Here, 1 can be contained in separate dosage forms or in a common dosage form, where 1 can either be both dissolved, both dispersed or in each case only one component dissolved and the other dispersed. The propellant gases which can be used to produce the inhalation aerosols are known from the prior art. Suitable propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-mentioned propellant gases can be used alone or in mixtures thereof. Particularly preferred propellants are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.

The inhalation aerosols containing blowing gases can furthermore contain further constituents such as cosolvents, stabilizers, surfactants, antioxidants, Contains lubricants and agents for adjusting the pH. All of these components are known in the art.

The aforementioned inhalation aerosols containing propellant gas can be administered using inhalers known in the art (MDIs = metered dose inhalers).

Furthermore, the active compounds 1 according to the invention can be applied in the form of propellant-free inhalation solutions and inhalation suspensions. Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic, solutions. The solvent can only be water or it is a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70 percent by volume, in particular up to 60 percent by volume and particularly preferably up to 30 percent by volume. The remaining volume percentages are filled up with water. The solutions or suspensions containing 1 are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. Acids selected from inorganic or organic acids can be used to adjust this pH. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others. Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active ingredients. Ascorbic acid, fumaric acid and citric acid are preferred among the organic acids. If appropriate, mixtures of the acids mentioned can also be used, in particular in cases of acids which, in addition to their acidifying properties, also have other properties, e.g. as flavors, antioxidants or complexing agents, such as citric acid or ascorbic acid. According to the invention, hydrochloric acid is particularly preferably used to adjust the pH.

In these formulations, the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as a stabilizer or complexing agent may optionally be dispensed with. Other embodiments include this connection (s). In such a preferred embodiment, the content, based on sodium edetate, is particularly below 100 mg / 100 ml, preferably below 50 mg / 100 ml preferably below 20 mg / 100ml. Inhalation solutions in which the sodium edetate content is 0 to 10 mg / 100 ml are generally preferred.

Co-solvents and / or other auxiliaries can be added to the propellant-free inhalation solutions. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. In this context, additives and additives are understood to mean any pharmacologically acceptable substance which is not an active substance, but which can be formulated together with the active substance (s) in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation. These substances preferably have no or no significant or at least no undesirable pharmacological effect in the context of the desired therapy. The JJffilfs and additives include e.g. surfactants such as Soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives which ensure or extend the useful life of the finished pharmaceutical formulation, flavors, vitamins and / or other additives known in the prior art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.

The preferred auxiliary substances include antioxidants, such as, for example, ascorbic acid, unless already used for adjusting the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human organism. Preservatives can be used to protect the formulation from contamination with germs. Suitable preservatives are those known from the prior art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. The preservatives mentioned above are preferably present in concentrations of up to 50 mg / 100 ml, particularly preferably between 5 and 20 mg / 100 ml.

In addition to the solvent water and the active ingredient 1, preferred formulations only contain benzalkonium chloride and sodium edetate. In another preferred embodiment, sodium edetate is dispensed with. The dosage of the compounds according to the invention is of course strongly dependent on the type of application and the disease to be treated. When administered by inhalation, the compounds of formula 1 are highly effective even at doses in the μg range. Even above the μg range, the compounds of formula 1 can be used expediently. The dosage can then be in the gram range, for example. In particular in the case of non-inhalation administration, the compounds according to the invention can be administered with a higher dosage (for example, but not in a limiting manner in the range from 1 to 1000 mg).

The following formulation examples illustrate the present invention without, however, restricting its scope:

PHARMACEUTICAL FORMULATION EXAMPLES

A) TABLETS

per tablet

Active ingredient 100 mg

Milk sugar 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg

500 mg

The finely ground active ingredient, milk sugar and part of the corn starch are mixed together. The mixture is sieved, whereupon it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the rest of the corn starch and the magnesium stearate are sieved and mixed together. The mixture is compressed into tablets of a suitable shape and size. B) TABLETS

per tablet

Active ingredient 80 mg

Milk sugar 55 mg

Corn starch 190 mg

Microcrystalline cellulose 35 mg

Polyvinyl pyrrolidone 15 mg

Sodium carboxymethyl starch 23 mg

Magnesium stearate 2 mg

400 mg

The finely ground active ingredient, part of the corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the rest of the corn starch and water to form a granulate which is dried and sieved. The sodium carboxymethyl starch and the magnesium stearate are added, the mixture is mixed and compressed into tablets of a suitable size.

C) AMPOULE SOLUTION

Active ingredient 50 mg

Sodium chloride 50 mg aqua per inj. 5 ml

The active ingredient is dissolved in water at its own pH or, if appropriate, at pH 5.5 to 6.5, and sodium chloride is added as an isotonic agent. The solution obtained is filtered pyrogen-free and the filtrate is filled into ampoules under aseptic conditions, which are then sterilized and melted. The ampoules contain 5 mg, 25 mg and 50 mg of active ingredient. D) DOSING AEROSOL

Active ingredient 0.005

S orbitantrioleate 0.1

Monofluorotrichloromethane and ad 100

TG134a: TG227 2: l

The suspension is filled into a conventional aerosol container with a metering valve. 50 μl of suspension are preferably dispensed per actuation. If desired, the active ingredient can also be dosed at a higher level (e.g. 0.02% by weight).

E) SOLUTIONS

(in mg / lOOml)

Active ingredient 333.3 mg

Tiotropium bromide 333.3 mg

Benzalkonium chloride 10.0 mg

EDTA 50.0 mg

HC1 (In) ad pH 3.4

This solution can be prepared in the usual way.

F) F HALATION POWDER

Active ingredient 6 μg

Tiotropium bromide 6 μg

Lactose monohydrate ad 25 mg

The inhalable powder is produced in the usual way by mixing the individual components.

Claims

1) Compounds of the general formula 1

wherein

R ¹ CC ₄ alkyl; R ² CC ₄ alkyl;

R ³ -CC ₄ alkyl or phenyl, which may optionally be substituted one or more times, or R ² and R ³ together form a divalent group selected from -CH ₂ -CH ₂ - and

-CH -CH ₂ -CH ₂ - mean.

2) Compounds of formula 1 according to claim 1, wherein R ¹ -C-C ₄ alkyl;

R ² -C ₄ alkyl;

R ³ CrC ₄ alkyl or phenyl, which may optionally be mono-, di-, tri- or tetra-substituted by one or more radicals selected from Ci

C ₃ alkyl, CF ₃ , methoxy, ethoxy, hydroxy, fluorine, chlorine, bromine, -OCF ₃ , -CHF ₂ , -NHCOCH ₃ and -NHSO ₂ CH ₃ , or R ² and R ³ together selected from a divalent group -CH -CH ₂ - and -CH ₂ -CH ₂ -CH ₂ - mean.

3) Compounds of general formula 1 according to claim 1 or 2, wherein R ¹ -C ¹ -C ₄ alkyl, preferably methyl; R ² -C ₄ alkyl;

R ³ -CC ₄ alkyl or phenyl, which may optionally be substituted once, twice, three or four times by one or more radicals selected from methyl, ethyl, CF ₃ , methoxy, ethoxy and hydroxy, or R and R together form a double-bonded group selected from -CH -CH ₂ - and

-CH ₂ -CH ₂ -CH ₂ - mean.

4) Compounds of general formula 1 according to one of claims 1 to 3, wherein

R ¹ Ci-alkyl, preferably methyl; R ² -C ₄ alkyl, preferably methyl;

R ^{3 is} C ₁ -C ₄ alkyl, preferably methyl, or phenyl, which may optionally be mono-, di-, tri- or tetra-substituted by one or more radicals selected from methyl, CF ₃ , methoxy and hydroxy, or R ² and R ³ together represent the divalent group -CH ₂ -CH ₂ -.

5) Compounds of general formula 1 according to one of claims 1 to 4, wherein

R ^{1 is} methyl or ethyl, preferably methyl;

R ² methyl;

R ^{3 is} methyl, ethyl or phenyl, which may optionally be mono-, di-, tri- or tetra-substituted by one or more radicals selected from methyl, CF, methoxy and hydroxy, or

R and R together represent the divalent group -CH ₂ -CH ₂ -.

6) Compounds of general formula 1 according to one of claims 1 to 5, wherein

R ^{1 is} methyl; R ² methyl; R ^{3 is} methyl or phenyl, which may optionally be mono-, di- or trisubstituted by one or more radicals selected from methyl, ethyl and hydroxyl, or R ² and R ³ together denote the -CH -CH - group. 7) Compounds of general formula 1 according to one of claims 1 to 6, wherein

R ^{1 is} methyl; R ² methyl; R ^{3 is} methyl or phenyl, or R ² and R ³ together represent the divalent group -CH ₂ -CH -.

8) Compounds of formula 1 according to one of claims 1 to 7 in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.

9) Use of a compound of general formula 1 according to one of claims 1 to 8 as a medicament.

10) Use of a compound of general formula 1 according to one of claims 1 to 8 for the manufacture of a medicament for the treatment of

Diseases in which betamimetics can have therapeutic benefits.

11) Use of a compound of general formula 1 according to one of claims 1 to 8 for the manufacture of a medicament for the treatment of

Asthma, COPD, premature contractions in obstetrics (tocolysis), atrioventricular block and bradycal arrhythmia (antiarrhythmic), circulatory shocks (vasodilation and increase in cardiac output) and itching and inflammation of the skin.

12) Pharmaceutical preparations containing as active ingredient one or more compounds of general formula 1 according to one of claims 1 to 8, optionally in combination with customary auxiliaries and / or carriers. 13) Pharmaceutical preparations according to claim 12, characterized in that, in addition to one or more of the compounds of formula 1, they further contain at least one further active ingredient which is selected from the group of anticholinergics, antiallergics, PAF antagonists, PDE IV inhibitors, s leukotriene Antagonists, p38 kinase inhibitors, EGFR kinase inhibitors and

Corticosteroids, and combinations of active ingredients thereof.

14) Pharmaceutical preparations according to claim 13, characterized in that they also contain 0 tiotropium bromide as active ingredient in addition to one or more of the compounds of formula 1.