CA2501055A1

CA2501055A1 - Novel betamimetics with extended duration of action, method for production and use thereof as medicaments

Info

Publication number: CA2501055A1
Application number: CA002501055A
Authority: CA
Inventors: Thierry Bouyssou; Frank Buettner; Ingo Konetzki; Sabine Pestel; Andreas Schnapp; Hermann Schollenberger; Kurt Schromm; Claudia Heine
Original assignee: Individual
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2002-10-04
Filing date: 2003-09-25
Publication date: 2004-04-22
Also published as: AU2003270262A1; EP1551792A1; DE10246374A1; WO2004033412A1; JP2006502207A

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

81900pct.211 NOVEL BETAMIMETICS WITH EXTENDED DURATION OF ACTION, METHOD FOR PRODUCTION AND USE THEREOF AS MEDICAMENTS
The present invention relates to compounds of general formula 1 OR' OH
H
HO ~ ~ N\ ~Rs /~,RZ
Ho wherein the groups R', R2 and R3 may have the meanings given in the claims and in the specification, processes for preparing them and their use as pharmaceutical compositions, particularly for the treatment of inflammatory and obstructive respiratory complaints.
BACKGROUND TO THE INVENTION
Betamimetics (f3-adrenergic substances) are known from the prior art. They may be used to good effect in a variety of therapeutic fields.
For drug treatment of diseases it is often desirable to prepare medicaments with a longer duration of activity. As a rule, this ensures that the concentration of the active substance in the body needed to achieve the therapeutic effect is guaranteed for a longer period without the need to re-administer the drug at frequent intervals. Moreover, giving an active substance at longer time intervals contributes to the well-being of the patient to a high degree.
Another major advantage of drugs with a longer duration of activity is apparent in the case of diseases or illnesses the symptoms of which only appear in the second half of the night. A single application of a drug with a longer duration of activity before going to sleep would make things much simpler for the patient and represent an improvement in the quality of life. It is particularly desirable to prepare a pharmaceutical composition which can be used therapeutically by administration once a day (single dose). The use of a drug once a day has the advantage that the patient can become accustomed relatively quickly to regularly taking the drug at certain times of the day.

The aim of the present invention is therefore to provide betamimetics which are characterised by a longer duration of activity and can thus be used to prepare pharmaceutical compositions with a longer duration of activity. A
particular aim of the invention is to prepare betamimetics which, by virtue of their long-lasting effect, can be used to prepare a drug for administration once a day. A further objective of the invention is to prepare new betamimetics which, by virtue of their long-lasting effect, can be used to prepare a drug for administration once a day for the treatment of inflammatory or obstructive respiratory complaints.
In addition to the above objectives, the present invention also sets out to provide betamimetics which are not only exceptionally potent but are also characterised by a high degree of selectivity with respect to the X32-adreno-receptor.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly it has been found that the abovementioned problems are solved by compounds of general formula 1.
Accordingly, the present invention relates to compounds of general formula 1 OR' OH
H
HO I ~ N~R3 ,R2 HO

wherein R' denotes C~-C4-alkyl;
R2 denotes C~-C4-alkyl;
R3 denotes C~-C4-alkyl or phenyl, which may optionally be mono- or polysubstituted, or R2 and R3 together denote a double-bonded group selected from -CH2-CH2-and -CH2-CH2-CH2-.

Preferred are compounds of formula 1, wherein R' denotes C,-C4-alkyl;
R2 denotes C~-C4-alkyl;
R3 denotes C~-C4-alkyl or phenyl, which may optionally be mono-, di-, tri-or tetrasubstituted by one or more groups selected from C~-C3-alkyl, CF3, methoxy, ethoxy, hydroxy, fluorine, chlorine, bromine, -OCF3, -CHF2, -NHCOCH3 and -NHS02CH3, or R2 and R3 together denote a double-bonded group selected from -CH2-CH2-and -C H2-C H2-C Hz-.
Also preferred are compounds of general formula 1, wherein R' denotes C,-C4-alkyl, preferably methyl;
R2 denotes C~-C4-alkyl;
R3 denotes C~-C4-alkyl or phenyl, which may optionally be mono-, di-, tri-or tetrasubstituted by one or more groups selected from methyl, ethyl, CF3, methoxy, ethoxy and hydroxy, or R2 and R3 together denote a double-bonded group selected from -CH2-CH2-and -CHZ-CH2-CH2-.
Also preferred are compounds of general formula 1, wherein R~ denotes C~-C4-alkyl, preferably methyl;
R2 denotes C~-C4-alkyl, preferably methyl;
R3 denotes C~-C4-alkyl, preferably methyl, or phenyl, which may optionally be mono-, di-, tri- or tetrasubstituted by one or more groups selected from methyl, CF3, methoxy and hydroxy, or R2 and R3 together denote the double-bonded group -CH2-CH2-.
Preferred compounds of general formula 1 according to the invention are those wherein R' denotes methyl or ethyl, preferably methyl;
R2 denotes methyl;
R3 denotes methyl, ethyl or phenyl, which may optionally be mono-, di-, tri-or tetrasubstituted by one or more groups selected from methyl, CF3, methoxy and hydroxy, or R2 and R3 together denote the double-bonded group -CH2-CH2-.

Particularly preferred are compounds of general formula 1 wherein R' denotes methyl;
R2 denotes methyl;
R3 denotes methyl or phenyl, which may optionally be mono-, di- or trisubstituted by one or more groups selected from methyl, ethyl and hydroxy, or R2 and R3 together denote the double-bonded group -CH2-CH2-.
Also preferred according to the invention are compounds of general formula 1, wherein R' denotes methyl;
R2 denotes methyl;
R3 denotes methyl or phenyl, or R2 and R3 together denote the double-bonded group -CH2-CH2-.
Of exceptional importance according to the invention are for example the following compounds of formula1:
~ 4-[2-(1,1-dimethyl-propylamino)-1-hydroxy-ethyl]-3-methoxy-benzene-1,2-diol;
~ 4-[1-hydroxy-2-(1-methyl-cyclopentylamino)-ethyl]-3-methoxy-benzene-1,2-diol;
~ 4-{2-[1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethylamino]-1-hydroxy-ethyl}-3-methoxy-benzene-1,2-diol;
~ 4-{2-[1,1-dimethyl-2-phenyl)-ethylamino]-1-hydroxy-ethyl}-3-methoxy-benzene-1,2-diol;
~ 4-{2-[1,1-dimethyl-2-(2,3,5,6-tetra-methyl-phenyl)-ethylamino]-1-hydroxy-ethyl}-3-methoxy-benzene-1,2-diol;
~ 4-[2-(1,1-dimethyl-2-o-tolyl-ethylamino)-1-hydroxy-ethyl]-3-methoxy-benzene-1,2-diol.
The invention relates to the 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 may optionally occur in the form of their individual optical isomers, mixtures of the individual enantiomers or racemates and may 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.
By acid addition salts are meant the salts formed with pharmacologically acceptable acids selected from among hydrochloric acid, hydrobromic acid, hydriodic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, nitric acid, malefic acid, acetic acid, benzoic acid, citric acid, fumaric acid, tartaric acid; oxalic acid, succinic acid and p-toluenesulphonic acid, preferably hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid and methanesulphonic acid.
Unless otherwise stated, the alkyl groups are straight-chained or branched alkyl groups having 1 to 4 carbon atoms. The following are mentioned by way of example: methyl, ethyl, propyl or butyl. In some cases the abbreviations Me, Et, Prop or Bu are used to denote the groups methyl, ethyl, propyl or butyl. Unless otherwise stated, the definitions propyl and butyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec.butyl and tert.-butyl, etc.
Of the abovementioned acid addition salts, the salts of hydrochloric acid, methanesulphonic acid, benzoic acid and acetic acid are particularly preferred according to the invention.
The compounds according to the invention may be prepared analogously to the methods already known in the art. Suitable methods of preparation are known for example from US 3657244, to the contents of which reference is made hereby.
The examples of synthesis described below serve to illustrate the present invention more fully. They are intended only as examples of procedure to illustrate the invention without restricting it to the subject matter described hereinafter.

4-[2-(1,1-dimethyl-propylamino)-1-hydroxy-ethyl]-3-methoxy-benzene-1,2-diol OMe OH
H
HO / I N\
HO
a) 2-(1,1-dimethyl-propylamino)-1-(4-methoxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-ethanone:
42.5 g of a bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone (obtainable according to US 3657244) are refluxed with 30 g of 1,1-dimethylpropylamine in 150 ml of ethanol for 3 hours with stirring. The solvent is distilled off under reduced pressure and the residue is combined with diethyl ether and extracted twice with water. After the solvent has been distilled off under reduced pressure the residue remaining is dissolved in ethyl acetate and acidified with ethereal hydrochloric acid. The precipitated crystals are suction filtered and washed with ethyl acetate and diethyl ether.
Yield: 26 g (56 %, hydrochloride); melting point = 174-176 °C.
b) 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1,1-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 refluxed with 50 ml of 15% methanolic hydrochloric acid for 2 hours with stirring. The solvent is distilled off under reduced pressure and the residue is dissolved in acetonitrile and combined with ethyl acetate. The precipitated crystals are suction filtered and washed with acetonitrile and diethyl ether.
Yield: 15 g (92%) of the compound as the hydrochloride.
For further purification the free base may be released from the hydrochloride under the usual conditions, then suspended in methanol, combined with an equimolar amount of benzoic acid and heated. The crystals thus obtained are suction filtered and washed with diethyl ether.
Melting point = 151-154 °C (benzoate).

c) 4-[2-(1,1-dimethyl-propylamino)-1-hydroxy-ethyl]-3-methoxy-benzene-1,2-diol:
6.5 g of 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1,1-dimethyl-propylamino)-ethanone are hydrogenated with 0.1 g of platinum oxide as catalyst in 125 ml of methanol. The catalyst is suction filtered and the solvent is distilled off under reduced pressure. The residue is dissolved in ethyl acetate, the precipitated crystals are suction filtered and washed with ethyl acetate and diethyl ether.
Yield: 5.5 g (85 %; benzoate); melting point = 172-174 °C.

4-[1-hydroxy-2-(1-methyl-cyclopentylamino)-ethyl]-3-methoxy-benzene-1,2-diol OMe OH
H
HO / I N\
H O ~/~~~//)\
a) 1-methyl-cyclopentylamine:
66.5 g of sodium cyanide are dissolved in 150 ml glacial acetic acid. A
solution of 300 ml of sulphuric acid and 150 ml of glacial acetic acid is added dropwise at 5-10°C to the sodium cyanide solution. 126 g of 1-methyl-cyclopentanol are added to this mixture. The mixture obtained is left to stand overnight. Then 210 ml of water and, while cooling with ice, 770 g of sodium hydroxide solution in 1.5 litres of water are added thereto.
The mixture is refluxed for 4 hours and the amine is isolated by steam distillation. The distillate is acidified with conc. hydrochloric acid, extracted with diethyl ether and then made alkaline with 50% sodium hydroxide solution. The residue is fractionally distilled (BP 760 mm= 114-115 °C).
Yield: 45 g (36 %).
b) 1-(4-methoxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-2-(1-methyl-cyclopentylamino)-ethanone:
35 g of a-bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone are refluxed for 1 hour with 45 g of 1-methyl-cyclopentylamine in 150 ml of ethanol. The solvent is distilled off under reduced pressure, the residue is dissolved in diethyl ether, extracted with water and the solvent is distilled off under reduced pressure. The residue remaining is dissolved in g acetonitrile, acidified with hydrochloric acid and the crystals obtained are isolated.
Yield: 19 g (48%; hydrochloride); melting point = 173 °C
(decomposition).
c) 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1-methyl-cyclopentyl-amino)-ethanone:
19 g of 1-(4-methoxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-2-(1-methyl-cyclopentylamino)-ethanone are refluxed in 190 ml of 15% methanolic hydrochloric acid far 2 hours with stirring. The solvent is distilled off under reduced pressure and the residue remaining is dissolved in acetonitrile.
The precipitated crystals are washed with diethyl ether.
Yield: 11 g (88%; hydrochloride); melting point = 187-189 °C
(decomposition).
d) 4-[1-hydroxy-2-(1-methyl-cyclopentylamino)-ethyl]-3-methoxy-benzene-1,2-diol:
g of 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1-methyl-cyclopentyl-amino)-ethanone-hydrochloride are hydrogenated with 0.2 g of Pt02 in 200 ml methanol. The catalyst is suction filtered and the solvent is distilled off under reduced pressure. The residue remaining is dissolved in ethanol and combined with 5 g of sodium benzoate. The title compound is isolated in the form of its benzoate.
Yield: 4.5 g (70.5%; benzoate); melting point = 179-180 °C.

4-f2-[1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethylamino]-1-hydroxy-ethyl}-3-methoxy-benzene-1,2-diol OMe OH
H
HO / N
HO
a) 2-Chloromethyl-1,3,5-trimethyl-benzene:
400 g of mesitylene are combined with 130 g of paraformaldehyde and 2 litres of hydrochloric acid are piped in at 60-70°C within 7 hours.
Then the mixture is extracted with benzene and the org. phase is then washed with 2N sodium hydroxide solution. The residue is fractionally distilled.
Yield: 204 g (36 %); by ~5 = 130-140 °C.

b) (2,4,6-trimethyl-phenyl)-acetonitrile:
66 g of sodium cyanide are refluxed in 100 ml water and 140 ml of ethanol with stirring, until a clear solution is formed. 136 g of 2-chloromethyl-1,3,5-trimethyl-benzene are slowly added dropwise to this solution and the mixture is refluxed for 3 hours with stirring. It is diluted with 1 litre of water and extracted three times with 200 ml of 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%); by ,5 = 145-153 °C.
c) (2,4,6-trimethyl-phenyl)-acetic acid:
155 g (2,4,6-trimethyl-phenyl)-acetonitrile are added to a solution of 1.1 litre of water and 915 ml of conc. sulphuric acid heated to 50°C. The mixture is refluxed for 6 hours with stirring. Then the reaction mixture is poured onto 3 kg of ice. The solid is suction filtered and washed with water.
Yield: 131 g (86%); melting point = 163-166 °C.
d) methyl (2,4,6-trimethyl-phenyl)-acetate:
173 g (2,4,6-trimethyl-phenyl)-acetic acid are refluxed in 131 ml of conc.
hydrochloric acid and 1.1 I of methanol for 3 hours with stirring. The solvent is distilled off under reduced pressure and the aqueous phase extracted twice with diethyl ether . The combined organic phases are extracted twice with a saturated aqueous sodium hydrogen carbonate solution and dried with sodium sulphate and the solvent is distilled off under reduced pressure. The residue is fractionally distilled.
Yield: 116 g (57 %); by ~5 = 140 °C.
e) 2-methyl-1-(2,4,6-trimethyl-phenyl)-propan-2-ol:
97 g (79 %) of the title compound are prepared from 38 g of magnesium and 222 g of methyl iodide in 1.2 I of diethyl ether and 116 g of methyl (2,4,6-trimethyl-phenyl)-acetate under standard conditions in a Grignard reaction. by ~5 = 140 °C.
f) N-[1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethyl]-formamide:
90 ml of glacial acetic acid and 33 g of potassium cyanide are combined while cooling with ice. 90 ml of sulphuric acid and 90 ml of glacial acetic IU
acid are then added dropwise at 20°C. 65 g of 2-methyl-1-(2,4,6-trimethyl-phenyl)-propan-2-of are slowly added to the solution at constant temperature. After the addition has ended the mixture is stirred for a further hour. The mixture is poured onto ice water, neutralised 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 %); by o.~ = 155 °C.
g) 1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethylamine:
61 g of N-[1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethyl]-formamide are refluxed with 35 g of potassium hydroxide in 155 ml ethyleneglycol for 9 hours with stirring and after the reaction has ended the mixture is poured onto 1 kg of ice. 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 %); by ~5 = 135-140 °C.
h) 2-[1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethylamino]-1-(4-methoxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-ethanone:
42.5 g of a-bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone are refluxed with 22 g of 1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethylamine and 17 g of potassium carbonate in 150 ml of ethanol and 50 ml of acetonitrile for 3 hours with stirring. The solids are filtered off and the solvent is distilled off under reduced pressure. The residue is dissolved in a little acetonitrile and combined with ethereal hydrochloric acid. The crystals precipitated are suction filtered and washed with acetonitrile and ethyl acetate.
Yield: 25 g (44 %; hydrochloride); melting point = 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-(1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethylamino]-1-(4-methoxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-ethanone-hydrochloride are refluxed with 170 ml of 15% methanolic hydrochloric acid for 90 min with stirring. The solvent is largely distilled off under reduced pressure. The residue remaining crystallises out. The crystals are filtered off and washed with diethyl ether.
Yield: 10 g (80%; hydrochloride) melting point = 199-201 °C.

j) 4-{2-[1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethylamino]-1-hydroxy-ethyl}-3-methoxy-benzene-1,2-diol:
9 g of 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-[1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethylamino]-ethanone-hydrochloride are hydrogenated with 0.4 g of platinum(IV)oxide in 125 ml of methanol. 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 precipitated crystals are suction filtered and washed with diethyl ether and ethyl acetate.
Yield: 6 g (67 %, hydrochloride); melting point = 98-105 °C.

4-[2-(1,1-dimethyl-2-phenyl-ethylamino)-1-hydroxy-ethyl]-3-methoxy-benzene-1,2-diol OMe OH
H
HO / N
HO
a) 2-(1,1-dimethyl-phenylethylamino)-1-(4-methoxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-ethanone:
45 g of a-bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone are refluxed with 39 g of 1,1-dimethyl-2-phenylethylamine in 200 ml of ethanol for 3 hours. The reaction mixture is acidified with conc. hydrochloric acid and combined with water. The precipitated crystals are suction filtered and washed successively with water, toluene and ethyl acetate.
Yield: 34 g (61 %, hydrochloride); melting point = 167-170°C.
b) 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1,1-dimethyl-2-phenylethylamino)-ethanone:
34 g of the HCI salt of 2-(1,1-dimethyl-2-phenylethylamino)-1-(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. Then the solvent is distilled off under reduced pressure and the residue is dissolved in ethyl acetate.
The solid precipitated is suction filtered and washed with ethyl acetate and diethyl ether.
Yield: 18 g (77%, hydrochloride); melting point 192-196°C.

c) 4-{2-[1,1-dimethyl-2-phenyl-ethylaminoJ-1-hydroxy-ethyl-3-methoxy-benzene-1,2-diol:
g of 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1,1-dimethyl-2-phenylethylamino)-ethanone hydrochloride are hydrogenated with 0.5 g of Pt02 in 200 ml methanol. The catalyst is suction filtered and the solvent is distilled off under reduced pressure. The residue remaining is dissolved in 200 ml acetonitrile, combined with 5 g of sodium benzoate and refluxed for min. After the excess sodium benzoate has been filtered off the product which crystallises out of the filtrate is filtered off and washed with acetonitrile and diethyl ether.
Yield: 64.5% (benzoate); melting point 149-150°C.

4-~2-[1,1-dimethyl-2-(2,3,5,6-tetra-methyl-phenyl)-ethylamino]-1-hydroxy-ethyl}-3-methoxy-benzene-1,2-diol OMe OH
H
HO / N
HO
a) 2-[1,1-dimethyl-2-(2,3,5,6-tetramethyl-phenyl)-ethylamine]-1-(4-methoxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-ethanone:
28.5 g of a-bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone, 11 g of 1,1-dimethyl-2-(2,3,5,6-tetramethyl-phenyl)-ethylamine and 8 g of sodium carbonate are refluxed for 3 hours in a solution of 100 ml of ethanol and 10 ml of acetonitrile. Then the inorganic salts are filtered off and the solvent is distilled off. The residue is dissolved in ethyl acetate, acidified with ethereal hydrochloric acid and combined with diethyl ether.
The solid precipitated is filtered off, washed with diethyl ether and then boiled in water. The product is obtained after filtering and drying.
Yield 11 g (hydrochloride); melting point 194-198°C.
b) Preparation of 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-[1,1-dimethyl-2-(2, 3, 5,6-tetramethyl-phenyl)-ethylamine]-ethanone:
11 g of 2-[1,1-dimethyl-2-(2,3,5,6-tetramethyl-phenyl)-ethylamine]-1-(4-methoxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-ethanone-hydrochloride are refluxed for 1.5 hours in 110 ml of 15% methanolic hydrochloric acid. The crude product is suction filtered, washed with acetonitrile and then precipitated from methanol/diethyl ether.
Yield: 7 g (hydrochloride); melting point 213-215°
(decomposition).
c) Preparation of 4-{2-[1,1-dimethyl-2-(2,3,5,6-tetra-methyl-phenyl)-ethylamino]-1-hydroxy-ethyl-3-methoxy-benzene-1,2-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 are hydrogenated with 0.2 g of platinum(IV)oxide in 100 ml of methanol. Then the catalyst is filtered off and the solvent is distilled off. The residue is dissolved in 20 ml water and combined with 1 N hydrochloric acid. The crystals precipitated on cooling are filtered off, washed with ice water and after drying recrystallised from ethyl acetate.
Yield: 5 g; melting point 165-168°C.

4-[2-(1,1-dimethyl-2-o-tolyl-ethylamino)-1-hydroxy-ethyl]-3-methoxy-benzene-1,2-diol OMe OH
H
HO / N
HO
a) Preparation of 2-(1,1-dimethyl-2-o-tolyl-ethylamine)-1-(4-methoxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-ethanone:
26 g of a-bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone, 10 g of 1,1-dimethyl-2-o-tolyl-ethylamine and 9.5 g of sodium carbonate are refluxed for 3 hours in acetonitrile. 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, whereupon the starting amine is precipitated and suction filtered. After the addition of diethyl ether to the filtrate the product crystallises out.
Yield 10 g (30%; hydrochloride); melting point 180-184°C.
b) Preparation of 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1,1-dimethyl-2-o-tolyl-ethylamine)-ethanone:
g of 2-(1,1-dimethyl-2-o-tolyl-ethylamine)-1-(4-methoxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-ethanone-hydrochloride are refluxed in 100 ml of 15% methanolic hydrochloric acid for 1.5 hours. The reaction mixture is evaporated down and the residue is recrystallised from ethyl acetate. The solid obtained after filtration is washed with diethyl ether.
Yield 6 g (85%; hydrochloride); melting point 198-201 °
(decomposition).
c) Preparation of 4-[2-(1,1-dimethyl-2-o-tolyl-ethylamino)-1-hydroxy-ethyl]-3-methoxy-benzene-1,2-diol:
4 g of 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1,1-dimethyl-2-o-tolyl-ethylamine)- ethanone-hydrochloride are hydrogenated with 0.2 g of platinum(IV)oxide in 50 ml of methanol under normal conditions. Then the catalyst is filtered off and the solvent is distilled off. The residue is combined with 100 ml of acetonitrile and 3 g of sodium benzoate. It is refluxed for 20 minutes and the inorganic matter is filtered off. The product which crystallises out of the filtrate is suction filtered and recrystallised from acetonitrile.
Yield 2.4 g (benzoate); melting point 114°C.
It has been found that the compounds of general formula 1 are characterised by their versatility of use in the therapeutic field. Particular mention should be made of those applications for which the compounds of formula 1 according to the invention are preferably used by virtue of their pharmaceutical effectiveness as betamimetics.
These include for example the treatment of asthma, COPD (chronic obstructive pulmonary disease), the inhibition of premature labour in midwifery (tocolysis), the restoration of sinus rhythm in the heart in atrio-ventricular block, as well as the elimination of bradycardic heart rhythm disorders (antiarrhythmic), the treatment of cardiovascular shock (vasodilatation and increasing the cardiac output) as well as the treatment of itching and irritations of the skin.
The compounds of general formula 1 may be used on their own or in conjunction with other active substances of formula 1. The compounds of general formula 1 may also be used in combination with other pharmacologically active substances. These may be, in particular, anticholinergics, antiallergics, PAF antagonists, PDE-IV inhibitors, leukotriene antagonists, p38 kinase inhibitors, EGFR kinase inhibitors and corticosteroids as well as combinations of active substances thereof.

IS
Examples of preferred anticholinergics which may be used in conjunction with the compounds of formula 1 are compounds selected from among the tiotropium salts, ipratropium salts, oxitropium salts, salts of the compounds known from WO 02/32899 tropenol N-methyl-2,2-diphenylpropionate, scopine N-methyl-2,2-diphenylpropionate, scopine N-methyl-2-fluoro-2,2-diphenylacetate and tropenol N-methyl-2-fluoro-2,2-diphenylacetate as well as salts of the compounds known from WO 02/32899 tropenol N-methyl-3,3',4,4'-tetrafluorobenzilate, scopine N-methyl-3,3',4,4'-tetrafluorobenzilate;
scopine N-methyl-4,4'-dichlorobenzilate, scopine N-methyl- 4,4'-difluorobenzilate, tropenol N-methyl-3,3'-difluorobenzilate, scopine N-methyl- 3,3'-difluorobenzilate and tropenol N-ethyl-4,4'-difluorobenzilate, optionally in the form of their hydrates and solvates. By salts are meant those compounds which contain, in addition to the abovementioned cations, as counter-ion, an anion with a single negative charge selected from among the chloride, bromide and methanesulphonate.
Particularly preferably the active substances within the scope of the present invention are the bromides or methanesulphonates of the abovementioned structures.
Of exceptional interest within the scope of the present invention are, for example, the anticholinergics tiotropium bromide, ipratropium bromide, oxitropium bromide, tropenol 2,2-diphenylpropionate-methobromide, scopine 2,2-diphenylpropionate-methobromide, scopine 2-fluoro-2,2-diphenylacetate-methobromide, tropenol 2-fluoro-2,2-diphenylacetate-methobromide, tropenol 3,3',4,4'-tetrafluorobenzilate-methobromide, scopine 3,3',4,4'-tetra-fluorobenzilate-methobromide; scopine 4,4'-dichlorobenzilate-methobromide, scopine 4,4'-difluorobenzilate-methobromide, tropenol 3,3'-difluorobenzilate-methobromide, scopine 3,3'-difluorobenzilate-methobromide and tropenol 4,4'-difluorobenzilate-ethylbromide, while tiotropium bromide, ipratropium bromide, tropenol 2,2-diphenylpropionate -methobromide, scopine 2,2-diphenylpropionate-methobromide, scopine 2-fluoro-2,2-diphenylacetate-methobromide and tropenol 2-fluoro-2,2-diphenylacetate-methobromide are particularly important.
Drug combinations which contain tiotropium bromide as another active substance in addition to the compounds of formula 1 according to the invention are particularly preferred according to the invention. This combination is particularly important for the treatment of asthma or COPD, particularly COPD. Of outstanding importance are particularly those combinations which contain tiotropium bromide in the form of its crystalline monohydrate known from WO 02/30928 or in the form of its crystalline anhydrate known from WO 03/000265.
Within the scope of the present invention, the corticosteroids which may optionally be used in conjunction with the compounds of formula 1 may be compounds selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW 215864, KSR 592, ST-126 and dexamethasone. Preferably, within the scope of the present invention, the corticosteroids are selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexamethasone, while budesonide, fluticasone, mometasone and ciclesonide are important and budesonide and fluticasone are particularly important. In some cases, within the scope of the present patent application, the term steroids is used on its own instead of the word corticosteroids. Any reference to steroids within the scope of the present invention includes a reference to salts or derivatives which may be formed from the steroids.
Examples of possible salts or derivatives include: sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. In some cases the corticosteroids may also occur in the form of their hydrates.
Examples of PDE-IV inhibitors which may be used according to the invention as a combination with the compound of formula 1 include compounds selected from among 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 among enprofylline, roflumilast, ariflo, 215370 and AWD-12-281, while AWD-12-281 is particularly preferred as the combination partner with the compound of formula 1 according to the invention. Any reference to the abovementioned PDE-IV
inhibitors also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts thereof which may exist. By the physiologically acceptable acid addition salts which may be formed by the abovementioned PDE-IV inhibitors are meant, according to the invention, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or malefic acid. According to the invention, the salts selected from among the acetate, hydrochloride, hydrobromide, sulphate, phosphate and methanesulphonate are preferred in this context.
Within the scope of the present invention, the term dopamine agonists, which may optionally be used in conjunction with the compounds of formula 1, denotes compounds selected from among bromocriptine, cabergolin, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid and viozan. It is preferable within the scope of the present invention to use, as combination partners with the compounds of formula 1, dopamine agonists selected from among pramipexol, talipexol and viozan, pramipexol being of particular importance. Any reference to the abovementioned dopamine agonists also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts and hydrates thereof which may exist. By the physiologically acceptable acid addition salts thereof which may be formed by the abovementioned dopamine agonists are meant, for example, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and malefic acid.
Examples of antiallergic agents which may be used according to the invention as a combination with the compounds of formula 1 include epinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadine, mizolastin, ketotifen, emedastin, dimetinden, clemastine, bamipin, cexchloropheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastin, desloratidine and meclizine.
Preferred antiallergic agents which may be used within the scope of the present invention in combination with the compounds of formula 1 according to the invention are selected from among epinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadine, ebastin, desloratidine and mizolastin, Ig epinastin and desloratidine being particularly prE~ferred. Any reference to the abovementioned antiallergic agents also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts thereof which may exist.
Examples of PAF antagonists which may be used according to the invention as a combination with the compounds of formula 1 include 4-(2-chlorophenyl)-9-methyl-2-[3-(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f] [1,2,4]triazolo[4.3-a][1,4]diazepine and 6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4.5]thieno-[3,2-f)[1,2,4]triazolo[4,3-a][1,4]diazepine.
Examples of EGFR kinase inhibitors which may be used as a combination with the compounds of formula 1 according to the invention include, in particular, 4-[(3-chloro-4-fluoro-phenyl)amino)-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)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-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-E~-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N-[(ethoxycarbonyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-fi-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline and 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline. Any reference to the above~mentioned EGFR kinase inhibitors also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts thereof which may exist. By the physiologically or pharmacologically acceptable acid addition salts thereof which may be formed by the EGFR kinase inhibitors are meant, according to the invention, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or malefic acid. The salts of the EGFR
kinase inhibitors selected from among the salts of acetic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and methanesulphonic acid are preferred according to the invention.

Particularly preferred examples of p38 kinase inhibitors which may be used as a combination with the compounds of formula 1 according to the invention include 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea; 1-[5-tent-butyl-2-p-tolyl-2H-pyrazol-3-ylj-3-[4-(2-(1-oxothiomorpholin-4-yl)ethoxy)naphthalen-1-ylj-urea; 1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalen-1-yl]-urea; 1-[5-terf-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea or 1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea. Any reference to the abovementioned p38 kinase inhibitors also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts thereof which may exist. By the physiologically or pharmacologically acceptable acid addition salts thereof which may be formed by the p38 kinase inhibitors are meant, according to the invention, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and malefic acid.
If the compounds of formula 1 are used in conjunction with other active substances, the combination with steroids, PDE IV inhibitors or anticholinergics is particularly preferred, of the categories of compounds mentioned above. The combination with anticholinergics is of particular importance.
Suitable preparations for administering the compounds of formula 1 include for example tablets, capsules, suppositories and solutions, etc.
Administration of the compounds according to the invention by inhalation is of particular importance according to the invention (particularly for treating asthma or COPD). The content of the pharmaceutically active compounds) should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-% of the composition as a whole. Suitable tablets may be obtained, for example, by mixing the active substances) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying 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 analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Solutions are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates or stabilisers such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and/or dispersants, while if water is used as diluent, for example, organic solvents may optionally be used as solubilisers or dissolving aids, and the solutions may be transferred into injection vials or ampoules or infusion bottles.
Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose 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.
Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g.
highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
For oral use the tablets may obviously contain, in addition to the carriers specified, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additional substances such as starch, preferably potato starch, gelatine and the like. Lubricants such as magnesium stearate, sodium laurylsulphate and talc may also be used to produce the tablets. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the abovementioned excipients.
In the preferred use of the compounds of formula 1 for the treatment of asthma or COPD it is particularly preferred according to the invention to use preparations or pharmaceutical formulations which are suitable for inhalation.
Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable solutions Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile ready-to-use inhalable solutions. The formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification The inhalable powders which may be used according to the invention may contain 1 either on their own or in admixture with suitable physiologically acceptable excipients.
If the active substances 1 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention:
monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
Within the scope of the inhalable powders according to the invention the excipients have a maximum average particle size of up to 250 Nm, preferably between 10 and 150 pm, most preferably between 15 and 80 pm. In some cases it may seem appropriate to add finer excipient fractions with an average particle size of 1 to 9 pm to the excipient mentioned above. These finer excipients are also selected from the group of possible excipients listed hereinbefore. Finally, in order to prepare the inhalable powders according to the invention, micronised active substance 1, preferably with an average particle size of 0.5 to 10 Vim, more preferably from 1 to 5 Vim, is added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronising and finally mixing the ingredients together are known from the prior art. The inhalable powders according to the invention may be administered using inhalers known from the prior art.
The inhalation aerosols containing propellant gas according to the invention may contain the compounds 1 dissolved in the propellant gas or in dispersed form. The compounds 1 may be contained in separate formulations or in a common formulation, in which the compounds 1 are either both dissolved, both dispersed or in each case only one component is dissolved and the other is dispersed. The propellant gases which may be used to prepare the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.
The propellant-driven inhalation aerosols may also contain other ingredients such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH
adjusters. All these ingredients are known in the art.

The propellant-driven inhalation aerosols according to the invention mentioned above may be administered using inhalers known in the art (MDIs = metered dose inhalers).
Moreover, the active substances 1 according to the invention may be administered in the form of propellant-free inhalable solutions and suspensions. The solvent used may be an aqueous or alcoholic, preferably an ethanolic solution. The solvent may be water on its own or a mixture of water and ethanol. The relative proportion of ethanol compared with water is not limited but the maximum is preferably up to 70 percent by volume, more particularly up to 60 percent by volume and most preferably up to 30 percent by volume. The remainder of the volume is made up of water. The solutions or suspensions containing 1 are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, malefic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.
If desired, the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as stabiliser or complexing agent is unnecessary in these formulations. Other embodiments may contain this compound or these compounds. In a preferred embodiment the content based on sodium edetate is less than 100 mg/100m1, preferably less than 50mg/100m1, more preferably less than 20mg/100m1. Generally, inhalable solutions in which the content of sodium edetate is from 0 to 10mg/100m1 are preferred.
Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols - particularly isopropyl alcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the physiologically suitable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
The preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins and provitamins occurring in the human body.
Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium 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, more preferably between 5 and 20 mg/100 ml.
Preferred formulations contain, in addition to the solvent water and the active substance 1, only benzalkonium chloride and sodium edetate. In another preferred embodiment, no sodium edetate is present.
The dosage of the compounds according to the invention is naturally highly dependent on the method of administration and the complaint which is being treated. When administered by inhalation the compounds of formula 1 are characterised by a high potency even at doses in the Ng range. The compounds of for mula 1 may also be used effectively above the pg range.
The dosage may then be in the gram range, for example.
Particularly when administered by routes other than by inhalation the compounds according to the invention may be administered in higher doses (for example, but not restrictively, in the range from 1 to 1000 mg).
The following examples of formulations illustrate the present invention without restricting its scope:
EXAMPLES OF PHARMACEUTICAL FORMULATIONS
A) TABLETS
per tablet active substance 100 ma lactose 140 mg maize starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 ma The finely ground active substance, lactose and some of the maize starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The granules, the remaining maize starch and the magnesium stearate are screened and mixed together. The mixture is pressed into tablets of suitable shape and size.
B) TABLETS
per tablet active substance 80 ma lactose 55 mg maize starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg 400 ma The finely ground active substance, some of the maize starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining maize starch and water to form granules which are dried and screened. To these are added the sodium carboxymethyl starch and the magnesium stearate, they are mixed together and the mixture is pressed into tablets of suitable size.
C) AMPOULE SOLUTION
active substance 50 ma sodium chloride 50 mg water for ini. 5 ml The active substance is dissolved in water at its own pH or optionally at pH

5.5 to 6.5 and sodium chloride is added to make the solution isotonic. The resulting solution is filtered to remove pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and heat-sealed. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.
D) METERED-DOSE AEROSOL
active substance 0.005 sorbitan trioleate 0.1 monofluorotrichloromethane and ad 100 TG 134a : TG227 2:1 The suspension is transferred into a conventional aerosol container with metering valve. Preferably 50 pl suspension are released on each actuation.
The active substance may also be released in higher doses if desired (e.g. 0.02 wt.-%).
E) SOLUTIONS
(in mg/100m1) active substance 333.3 mg tiotropium bromide 333.3 mg benzalkonium chloride10.0 mg EDTA 50.0 mg HCI (1 n) ad pH 3.4 This solution may be prepared in the conventional manner.
F) INHALABLE POWDER
active substance 6 Ng tiotropium bromide 6 pg lactose monohydrate ad 25 ma The inhalable powder is prepared in the conventional manner by mixing the individual ingredients.

Claims

CLAIMS:

1. A compound of general formula 1 wherein:
R1 is C1-C4-alkyl;
R2 is C1-C4-alkyl; and R3 is unsubstituted, monosubstituted or polysubstituted C1-C4-alkyl; or R2 and R3 together form a group selected from -CH2-CH2- and -CH2-CH2-CH2;
or an optical isomer, enantiomer, racemate or acid addition salt thereof.

2. The compound, isomer, enantiomer, racemate or salt of claim 1, wherein R3 is monosubstituted with a group, disubstituted with two groups, trisubstituted with three groups or tetrasubstituted with four groups independently selected from C1-C3-alkyl, CF3, methoxy, ethoxy, hydroxy, fluorine, chlorine, bromine, -OCF3, -CHF2, -NHCOCH3 and -NHSO2CH3.

3. The compound, isomer, enantiomer, racemate or salt of claim 1, wherein R3 is monosubstituted with a group, disubstituted with two groups, trisubstituted with three groups, or tetrasubstituted with four groups independently selected from methyl, ethyl, CF3, methoxy, ethoxy and hydroxy.

4. The compound, isomer, enantiomer, racemate or salt of claim 1, wherein R3 is monosubstituted with a group, disubstituted with two groups, trisubstituted with three groups or tetrasubstituted with four groups independently selected from methyl, CF3, methoxy and hydroxy.

5. The compound, isomer, enantiomer, racemate or salt of claim 1, wherein R3 is monosubstituted with a group, disubstituted with two groups, trisubstituted with three groups or tetrasubstituted with four groups independently selected from methyl, ethyl and hydroxy.

6. The compound, isomer, enantiomer, racemate or salt of any one of claims 1 to 5, wherein R1 is methyl.

7. The compound, isomer, enantiomer, racemate or salt of any one of claims 1 to 6, wherein R2 is methyl.

8. The compound, isomer, enantiomer, racemate or salt of any one of claims 1 to 7, wherein R3 is methyl or phenyl.

9. The compound, isomer, enantiomer, racemate or salt of claim 1, wherein R2 and R3 together form -CH2-CH2-.

10. The compound, isomer, enantiomer, racemate or salt of claim 9, wherein R1 is methyl.

11. The compound, isomer, enantiomer, racemate or salt of any one of claims 1 to 10 for treatment of a disease for which a betamimetic provides a therapeutic benefit.

12. The compound, isomer, enantiomer, racemate or salt of any one of claims 1 to 11 for treatment of asthma, chronic obstructive pulmonary disease, premature labour in midwifery, tocolysis, atrio-ventricular block, a bradycardiac heart rhythm disorder, antiarrhythmic, cardiovascular shock, vasodilation and an increase of cardiac output, skin irritation and skin itching.

13. A use of the compound, isomer, enantiomer, racemate or salt of any one of claims 1 to 10 for treatment of a disease for which a betamimetic provides a therapeutic benefit.

14. A use of the compound, isomer, enantiomer, racemate or salt of any one of claims 1 to 11 for treatment of asthma, chronic obstructive pulmonary disease, premature labour in midwifery, tocolysis, atrio-ventricular block, a bradycardiac heart rhythm disorder, antiarrhythmic, cardiovascular shock, vasodilation and an increase of cardiac output, skin irritation and skin itching.

15. A use of the compound, isomer, enantiomer, racemate or salt of any one of claims 1 to 10 in manufacture of a medicament for treatment of a disease for which a betamimetic provides a therapeutic benefit.

16. A use of the compound, isomer, enantiomer, racemate or salt of any one of claims 1 to 11 in manufacture of a medicament for treatment of asthma, chronic obstructive pulmonary disease, premature labour in midwifery, tocolysis, atrio-ventricular block, a bradycardiac heart rhythm disorder, antiarrhythmic, cardiovascular shock, vasodilation and an increase of cardiac output, skin irritation and skin itching.

17. A pharmaceutical composition comprising a compound, isomer, enantiomer, racemate or salt of any one of claims 1 to 11 and a pharmaceutically acceptable carrier, diluent or excipient.

18. A pharmaceutical composition according to claim 17 for treatment of a disease for which a betamimetic provides a therapeutic benefit.

19. A pharmaceutical composition according to claim 17 for treatment of asthma, chronic obstructive pulmonary disease, premature labour in midwifery, tocolysis, atrio-ventricular block, a bradycardiac heart rhythm disorder, antiarrhythmic, cardiovascular shock, vasodilation and an increase of cardiac output, skin irritation and skin itching.

20. A pharmaceutical composition according to any one of claims 17 to 19 further comprising one or more of an anticholinergic, an antiallergic, a PAF antagonist, a PDE IV
inhibitor, a leukotriene antagonist, a p38 kinase inhibitor, an EGFR kinase inhibitor and a corticosteroid.

21. A pharmaceutical composition according to any one of claims 17 to 19 further comprising tiotropium bromide.