CA2552871A1 - Novel, sustained-action beta-2-agonists and their use as medicaments - Google Patents

Abstract

The invention relates to the use of compounds of formula (I), in which the groups R1, R2, R3, R4 and n can be defined as cited in the claims and the description, for producing a medicament for the treatment of inflammatory and obstructive respiratory tract diseases. The invention also relates to novel compounds of formula (I) per se.

Description

86613pct NOVEL, SUSTAINED-ACTION BETA-2-AGONISTS AND THEIR USE AS
MEDICAMENTS
The present invention relates to the use of compounds of formula 1 R' OH N=
R3SOZNH ~ N %~N~N
Me ~(M~e~ ~'' ~Rz wherein the groups R1, R2, R3, R4 and n may have the meanings given in the claims and in Io the specification, for preparing a pharmaceutical composition for the treatment of inflammatory and obstructive respiratory complaints, and new compounds of formula 1 per se.
is Background to the invention Betamimetics (13-adrenergic substances) are known from the prior art.
For the 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 zo 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 wellbeing of the patient to a high degree.
zs 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.
3o 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 (32-adreno-receptor.
DESCRIPTION OF THE INVENTION
io Surprisingly it has been found that the above-mentioned objectives are achieved by compounds of formula 1. Accordingly, the present invention relates to the use of compounds of formula 1 R' OH H N=
R3SOZNH ~ N %~N~N
v Me ~(M~e~ ~'' R2 wherein R1 denotes hydrogen, -C1_6-alkyl, -C1_6-haloalkyl, -OH, -O-C1_6-alkyl, halogen or a group selected from among aryl or a heterocycle, while aryl or the heterocycle are if possible each optionally substituted by 1, 2, 3, 4 or 5 Zo identical or different groups Rs;
RZ denotes hydrogen, -C~_6-alkyl, -C1_6-haloalkyl; preferably methyl;
R3 denotes -C~_6-alkyl; preferably methyl;
R4 denotes -OH, -NH2, halogen; preferably -OH;
Rs denotes halogen, -CN, -N02, -C1_6-alkyl, -C3_6-cycloalkyl, -C1_6-haloalkyl, zs -COR6, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6SOZR7, -SR6, -SORE, -SOZR6 or -SOZNR6R7, or two Rs joined together denote a group selected from -CZ_6-alkylene, -C2_6-alkenylene and -O-C1_6-alkylene-O-;
R6 and R7 denotes hydrogen, -C1_6-alkyl, -C3_6-cycloalkyl;
n denotes 0, l, 2 or 3; preferably 1;
30 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, for preparing a pharmaceutical composition for the treatment of inflammatory and obstructive respiratory complaints.

WO 200s/077361 3 PCT/EP2005/001232 It is preferable to use compounds of formula 1 as stated above wherein R1, R2, R3 and n are as hereinbefore defined and R4 denotes -OH
optionally in the form of the individual optical isomers, mixtures of the individual s enantiomers or racemates, in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
It is particularly preferable to use compounds of formula 1 as stated above wherein RZ, R3, R4 and n are as hereinbefore defined and io Rl denotes hydrogen, -C1_6-alkyl, -C1_6-haloalkyl, -OH, -O-C1_6-alkyl, halogen or aryl, if possible optionally substituted by l, 2, 3, 4 or 5 identical or different groups Rs;
Rs denotes halogen, -CN, -N02, -C1_6-alkyl, -C3_6-cycloalkyl, -C1_6-haloalkyl, -CORE, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6SOZR7, -SR6, is -SORE, -S02R6 or -SO2NR6R7, or two Rs joined together denote a group selected from -CZ_6-alkylene, -CZ_6-alkenylene and -O-C1_6-alkylene-O-;
R6 and R7 denote hydrogen, -C1_6-alkyl, -C3_6-cycloalkyl;
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 Zo salts with pharmacologically acceptable acids.
It is particularly preferable to use compounds of formula 1 as stated above wherein Rl denotes hydrogen, -C1_6-alkyl, -O-C1_6-alkyl, aryl, if possible optionally substituted by 1, 2, 3, 4 or 5 identical or different groups Rs;
Zs RZ denotes hydrogen, -CI_6-alkyl; preferably methyl;
R3 denotes methyl;
R4 denotes -OH;
Rs denotes halogen, -CN, -N02, -C,_6-alkyl, -C3_6-cycloalkyl, -C1_6-haloalkyl, -CORE, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6S02R7, -SR6, 30 -SORE, -SOZR6 or -SOZNR6R7, or two Rs joined together denote a group selected from -CZ_6-alkylene, -CZ_6-alkenylene and -O-C1_6-alkylene-O-;
R6 and R7 denote hydrogen, -C1_6-alkyl, -C3_6-cycloalkyl;
n denotes 0, 1, 2 or 3; preferably 1;
optionally in the form of the individual optical isomers, mixtures of the individual 3s enantiomers or racemates, in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
It is particularly preferable to use compounds of formula 1 as stated above wherein Rl denotes hydrogen, aryl, if possible optionally substituted by 1, 2, 3, 4 or ao identical or different groups Rs;

R2 denotes hydrogen, -C1_6-alkyl; preferably methyl;
R3 denotes methyl;
R4 denotes -OH;
Rs denotes halogen, -CN, -N02, -Ct_6-alkyl, -C3_6-cycloalkyl, -C1_6-haloalkyl, s -CORE, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6SOZR7, -SR6, -SORE, -SOZR6 or -SOZNR6R7, or two Rs joined together denote a group selected from -C2_6-alkylene, -CZ_6-alkenylene and -O-C1_6-alkylene-O-;
R6 and R7 denotes hydrogen, -C1_6-alkyl, -C3_6-cycloalkyl;
n denotes 0, 1, 2 or 3; preferably 1;
to 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.
is It is particularly preferable to use compounds of formula 1 as stated above wherein Rt denotes hydrogen, phenyl, optionally substituted by 1, 2, 3, 4 or 5 identical or different groups Rs;
RZ denotes hydrogen, ethyl, methyl; preferably methyl or ethyl;
R3 denotes methyl;
ao R4 denotes OH;
Rs denotes halogen, -CN, -N02, -C1_6-alkyl, -C3_6-cycloalkyl, -C1_6-haloalkyl, -CORE, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6SOZR~, -SR6, -SORE, -SOZR6 or -SOZNR6R7, or two Rs joined together denote a group selected from -CZ_6-alkylene, -CZ_6-alkenylene and -O-C1_6-alkylene-O-;
is R6 and R' denote hydrogen, -C1_6-alkyl, -C3_6-cycloalkyl;
n denotes 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.
It is particularly preferable to use the compounds of general formula 1 as detailed above for preparing a pharmaceutical composition for the treatment of respiratory complaints selected from among obstructive pulmonary diseases of various origins, pulmonary emphysema of various origins, restrictive pulmonary diseases, interstitial pulmonary 3s diseases, cystic fibrosis, bronchitis of various origins, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary oedema.
The compounds are preferably used for preparing a pharmaceutical composition for the treatment of obstructive pulmonary diseases selected from among bronchial asthma, paediatric asthma, severe asthma, acute asthma attacks, chronic bronchitis and COPD
(chronic obstructive pulmonary disease), while it is particularly preferable according to the invention to use them for preparing a pharmaceutical composition for the treatment of bronchial asthma (optionally also referred to only as asthma within the scope of the present invention) and COPD.
It is also preferable to use the compounds as detailed above for preparing a pharmaceutical composition for the treatment of pulmonary emphysema which has its origins in COPD or al-proteinase inhibitor deficiency.
~o It is also preferable to use the compounds as detailed above for preparing a pharmaceutical composition for the treatment of restrictive pulmonary diseases selected from among allergic alveolitis, restrictive pulmonary diseases triggered by work-related noxious substances, such as asbestosis or silicosis, and restriction caused by lung tumours, such as 1s for example lymphangiosis carcinomatosa, bronchoalveolar carcinoma and lymphomas.
It is also preferable to use the compounds as detailed above for preparing a pharmaceutical composition for the treatment of interstitial pulmonary diseases selected from among pneumonia caused by infections, such as for example infection by viruses, bacteria, fungi, zo protozoa, helminths or other pathogens, pneumonitis caused by various factors, such as for example aspiration and left heart insufficiency, radiation-induced pneumonitis or f brosis, collagenoses, such as for example lupus erythematodes, systemic sclerodermy or sarcoidosis, granulomatoses, such as for example Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF) 2s It is also preferable to use the compounds detailed above for preparing a pharmaceutical composition for the treatment of cystic fibrosis or mucoviscidosis.
It is also preferable to use the drug combinations according to the invention for preparing a 3o pharmaceutical composition for the treatment of bronchitis, such as for example bronchitis caused by bacterial or viral infection, allergic bronchitis and toxic bronchitis.
It is also preferable to use the compounds detailed above for preparing a pharmaceutical composition for the treatment of bronchiectasis.

It is also preferable to use the compounds detailed above for preparing a pharmaceutical composition for the treatment of ARDS (adult respiratory distress syndrome).
It is also preferable to use the compounds detailed above for preparing a pharmaceutical composition for the treatment of pulmonary oedema, for example toxic pulmonary oedema after aspiration or inhalation of toxic substances and foreign substances.
It is particularly preferable to use the compounds detailed above for preparing a pharmaceutical composition for the treatment of asthma or COPD. Also of particular io importance is the above-mentioned use of the drug combinations according to the invention for preparing a pharmaceutical composition for once-a-day treatment of inflammatory and obstructive respiratory complaints, particularly for the once-a-day treatment of asthma or COPD.
is The invention also relates to new compounds of formula 1 per se. In particular the present invention relates to new compounds of formula 1 wherein R', R2 and n may have the meanings given above and wherein R3 methyl and R4 denote OH, 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 zo acceptable acids.
Preferred are compounds of formula 1 wherein R1 and n may have the meanings given above and wherein RZ denotes methyl or ethyl;
zs R3 denotes methyl and R4 denotes OH, 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.
Also preferred are compounds of formula 1 wherein R1 may have the meanings given above and wherein R2 denotes methyl or ethyl;
R3 denotes methyl;
3s R4 denotes OH and n denotes 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.

Preferred according to the invention are compounds of formula 1 wherein R1 denotes hydrogen, phenyl, optionally substituted by l, 2 or 3 identical or different groups RS;
s RZ denotes methyl or ethyl, preferably methyl;
R3 denotes methyl;
R4 denotes OH;
RS denotes halogen, -CI_6-alkyl, -C3_6-cycloalkyl, -C1_6-haloalkyl, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6SOZR7 or two RS joined ~o together denote a group selected from -C2_6-alkylene, -CZ_6-alkenylene and -O-C 1 _6-alkylene-O-;
R6 and R' denote hydrogen, -C1_6-alkyl, -C3_6-cycloalkyl;
n denotes 1;
optionally in the form of the individual optical isomers, mixtures of the individual is enantiomers or racemates, in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
Also preferred are compounds of formula 1 wherein Rl denotes hydrogen, phenyl, optionally substituted by 1, 2 or 3 identical or Zo different groups R5;
RZ denotes ethyl or methyl; preferably methyl;
R3 denotes methyl;
R4 denotes OH;
RS denotes halogen, -CI_6-alkyl, -CI_6-haloalkyl, -COOR6, -CONR6R7, -OR6, 2s -NR6R7 or two RS joined together represent -O-C1_6-alkylene-O-;
R6 and R7 denote hydrogen, -C1_6-alkyl;
n denotes l;
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 3o salts with pharmacologically acceptable acids.
Particularly preferred are compounds of formula 1 wherein Rl denotes phenyl, optionally substituted by l, 2 or 3 identical or different groups R5;

3s Rz denotes methyl, ethyl; preferably methyl;

R3 denotes methyl;

R4 denotes OH;

RS denotes chlorine, bromine, fluorine, methyl, ethyl, -CF3, -COOH, -COOMe, -OH, -OMe;
ao n denotes 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.
s Particularly preferred compounds of formula 1 are selected from the group consisting of:
~ N-[5-(2-{3-[5-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino } -1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulphonamide, ~ N-[5-(2-{1,1-dimethyl-3-[5-methyl-3-(4-trifluoromethyl-phenyl)-[1,2,4]triazol-1-yl]-propylamino } -1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulphonamide, io ~ N-(5-{2-[1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4]triazol-1-yl)-propylamino]-1-hydroxy-ethyl } -2-hydroxy-phenyl)-methane sulphonamide, ~ N-[5-(2-{3-[3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl)-1,1-dimethyl-propylamino)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulphonamide, methyl3-(1-{3-[2-hydroxy-2-(4-hydroxy-3-methanesulphonylamino-phenyl)-is ethylamino]-3-methyl-butyl}-S-methyl-1H-[1,2,4]triazol-3-yl)-benzoate, ~ N-[5-(2-{3-[3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-l,l-dimethyl-propylamino } -1-hydroxy-ethyl)-2-hydroxy-phenyl] -methane sulphonamide, ~ N-[2-hydroxy-5-(1-hydroxy-2-{3-[3-(2-methoxy-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-phenyl]-methanesulphonamide, ao ~ N-[2-hydroxy-5-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-phenyl]-methanesulphonamide, ~ N-(5-{2-[3-(3-benzo[1,3]dioxol-5-yl-5-methyl-[1,2,4]triazol-1-yl)-1,1-dimethyl-propyl amino]-1-hydroxy-ethyl } -2-hydroxy-phenyl)-methanesulphonamide, ~ N-[2-hydroxy-5-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimet Zs hyl-propylamino}-ethyl)-phenyl]-methanesulphonamide and ~ N-{5-[2-[1,1-dimethyl-3-[1,2,4]triazol-1-yl-propylamino)-1-hydroxy-ethyl]-2-hydroxy-phenyl}-methanesulphonamide, optionally in the form of the individual optical isomers, mixtures of the individual 3o enantiomers or racemates, in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
The compounds of formula 1 may optionally be used in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates. They are particularly 3s preferably used in the form of the enantiomerically pure compounds, while the compounds of formula 1, wherein the asymmetric carbon centre "-CH(OH)-" benzylic to the phenyl ring is in the R-configuration. The particularly preferred R-enantiomers of the compounds of general formula 1 may be represented by general formula R-1, R' OH H N=
R3SOZNH ~ * N %~N~N
/ v Me ~M~e~ ~'' Rz wherein the groups Rl, Rz, R3, R4 and n may have the meanings given above.
By acid addition salts with pharmacologically acceptable acids are meant, for example, the salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro p-toluenesulphonate, preferably the hydrochloride, io hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.
Halogen within the scope of the present invention denotes fluorine, chlorine, bromine or iodine. Unless stated otherwise, fluorine and bromine are the preferred halogens, while is fluorine is generally preferred.
Unless otherwise stated, the alkyl groups (alkyl) are straight-chained or branched alkyl groups having 1 to 6, preferably 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 zo 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.
zs Examples of alkylene groups (alkylene), unless otherwise stated, are branched and unbranched alkylene groups with 1 to 6, preferably 1 to 4 carbon atoms. The following are mentioned by way of example: methylene, ethylene, propylene or butylene.
Unless stated otherwise, the definitions propylene and butylene include all the possible isomeric forms of the groups in question.
Examples of alkenylene groups (alkenylene), unless otherwise stated, are branched and unbranched alkenylene groups with 1 to 6, preferably 1 to 4 carbon atoms. The following are mentioned by way of example: ethenylene, propenylene or butenylene.

Examples of cycloalkyl groups (cycloalkyl), unless otherwise stated, are cyclic alkyl groups with 3 to 6. The following are mentioned by way of example:
cyclopropyl, cyclobutanyl, cyclopentyl or cyclohexyl.
s Examples of alkyloxy groups (O-alkyl) , unless otherwise stated, are branched and unbranched alkyl groups with 1 to 6, preferably 1 to 4 carbon atoms, linked via an oxygen atom. The following are mentioned by way of example: methyloxy, ethyloxy, propyloxy or butyloxy. In some cases the abbreviations -OMe, -OEt, -Oprop or -OBu are used to denote the groups methyloxy, ethyloxy, propyloxy or butyloxy . Unless stated otherwise, io the definitions propyloxy and butyloxy include all the possible isomeric forms of the groups in question. Thus, for example, propyloxy includes n-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy, sec-butyloxy and tert-butyloxy etc. In some cases within the scope of the present invention the term alkoxy may be used instead of the term alkyloxy. The groups methyloxy, ethyloxy, propyloxy or also butyloxy may is optionally also be referred to as methoxy, ethoxy, propoxy or butoxy.
Examples of halogenoalkylene (haloalkyl) groups, unless otherwise stated, are branched and unbranched alkyl groups with 1 to 6 carbon atoms, wherein one or more hydrogen atoms are replaced by halogen atoms, preferably by fluorine . The following are 2o mentioned, for example: CHF2, CF3, CH2CF3, CF2CF3.
Suitable aryl groups, unless otherwise stated, are aromatic ring systems with 6 to 10 carbon atoms. Preferred aryl groups are phenyl and naphthyl, while phenyl is particularly preferred according to the invention.
Examples of heterocyclic groups (heterocycles) , unless otherwise stated, are aromatic or non-aromatic ring systems with 2 to 5 carbon atoms and 1, 2 or 3 atoms selected from among O, S or N, preferably N. Particularly preferred heterocycles are piperidine, piperazine, morpholine, pyrolidine, pyrrole, imidazole, triazole, pyridine, pyrimidine, 3o thiophene, tetrahydrofuran or furan.
The compounds according to the invention may be prepared analogously to methods already known in the art. Suitable methods of preparation are known for example from EP
43 940 or from WO 01/83462, to which reference is hereby made in its entirety.
The examples of synthesis described below serve to illustrate new compounds according to the invention in more detail. However, they are intended only as examples of procedures to illustrate the invention without restricting it to the subject matter described in an exemplifying capacity hereinafter.

Intermediate product 1: 1.1-dimethvl-3-(5-methvl-3-n-tolvl-f 1.2.41triazol-1-propylamine Me, ~~--N
/ Me Me Me a) 4-methyl-benzoic acid-(1-imino-ethyl)-hydrazide 1.65 g (72 mmol) sodium are dissolved in 80 mL ethanol. 8.89 g (72 mmol) ethylacetimidate hydrochloride in 160 mL ethanol are added at ambient temperature and the precipitated sodium chloride is filtered off. The filtrate is combined with 6.00 g (40 mmol) 4-methyl-benzoic acid hydrazide and stirred overnight. The reaction mixture is evaporated down and cooled. The precipitated solid is filtered off and washed with cold io ethanol and diethyl ether (5.7 g white solid). A further 1.2 g of solid are obtained from the filtrate after distillation of the solvent and recrystallisation from ethanol.
Yield: 6.93 g (91 %); mass spectroscopy [M+H]+ = 192.
b) 5-methyl-3-p-tolyl-[ 1,2,4]triazole is 7.58 g (40 mmol) 4-methyl-benzoic acid-(1-imino-ethyl)-hydrazide are heated to 180°C for 30 minutes with stirring. After cooling the solid is dissolved in chloroform.
The precipitate formed on cooling is suction filtered and recrystallised from chloroform.
Yield: 4.82 g (70%); mass spectroscopy [M+H]+ = 174.
20 ~ tert-butyl [1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4~triazol-1-yl)-propyll-carbamate 1.35 g (34 mmol, 60%) sodium hydride are added at 0°C to a solution of 4.87 g (28 mmol) 5-methyl-3-p-tolyl-[1,2,4]triazole in 40 mL DMPU. The reaction mixture is heated to ambient temperature and then stirred for one hour. 9.35 g (42 mmol) tert-butyl (3-chloro-1,1-dimethyl-propyl)-carbaminate and 1.87 g (5 mmol) tetrabutylammonium iodide are 2s added and the mixture is stirred overnight at ambient temperature and then for another 2 hours at 80°C. It is combined with water and ethyl acetate, the aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are washed with water and sodium chloride solution, dried with sodium sulphate and evaporated down.
The residue is purified by column chromatography (silica gel; petroleum ether/ethyl acetate =
30 1:1). oil.
Yield: 2.97 g (30%); mass spectroscopy [M+H]+ = 359.

_d) 1 1-dimethyl-3-(5-methyl-3-p-tolyl-[1 2 4]triazol-1-yll-nropylamine A total of 11 mL trifluoroacetic acid are added dropwise to a solution of 2.97 g (8.3 mmol) tert-butyl [1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4]triazol-1-yl)-propyl]-carbamate in 80 mL dichloromethane and the mixture is stirred overnight at ambient temperature. The solvent is distilled off and the residue is combined with diethyl ether and stirred. The precipitated solid is filtered off and washed.
Yield: 2.11 g (68%, trifluoroacetate); mass spectroscopy [M+H]+ = 259.
Intermediate product 2~ 3-[3-(4-fluoro-phenyl)-5-methyl-[1 2 4]triazol-1-yll-1,1-dimethyl-Io propylamine Me, ~~--N
HZN N~ ~
N \ / F
Me Me a) 4-fluoro-benzoic acid-(1-imino-ethyl)-hydrazide Prepared from 7.2 g (58 mmol) ethylacetimidate hydrochloride and 5.00 g (32 mmol) 4-is fluoro-benzoic acid hydrazide analogously to the method described for intermediate product 1, Step a).
Yield: 5.78 g (91 %); mass spectroscopy [M+H]+ = 196.
,b, 3-(4-fluoro~henyl)-5-methyl-[1,2,41triazole Zo The product is prepared analogously to the method described for intermediate product 1 b) from 5.77 g (30 mmol) 4-fluoro-benzoic acid-(1-imino-ethyl)-hydrazide.
Yield: 4.11 g (78%); mass spectroscopy [M+H]+ = 178.
c) tert-butyl {3-f3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-~]-1,1-dimethyl-propyl}-zs carbamate 5.88 g (33 mmol) 3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazole are dissolved in 40 mL
DMPU and reacted with 11.04 g (50 mmol) tert-butyl (3-chloro-1,1-dimethyl-propyl)-carbamate, 1.59 g (40 mmol, 60%) sodium hydride and 2.21 g (6 mmol) tetrabutylammonium iodide as described for intermediate product 1 c).
3o Yield: 4.22 g (35%); mass spectroscopy [M+H]+ = 363.

WO 200s/077361 13 PCT/EP2005/001232 d) 3-[3-(4-fluoro=phenyl)-5-methyl-[1 2 4]triazol-1-yll-1 1-dimethyl-propylamine Obtained by reacting 4.22 g (11.6 mmol) tert-butyl {3-[3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propyl}-carbamate in 100 mL dichloromethane and 15 mL trifluoroacetic acid. White solid.
Yield: 4.43 g (trifluoroacetate); mass spectroscopy [M+H]+ = 263.
Intermediate~roduct 3~ 3-[3-(3 5-difluoro-phen~)-5-methyl-f 1,2,41triazol-1-yll-1,1-dimethyl-propylamine Me ~N F
hizN~~N~N \
Me 'M '~e F
io a) 3 5-difluoro-benzoic acid-(1-imino-ethyl)-hydrazide The compound is obtained analogously to the method described for intermediate product 1 a) from 4.91 g (40 mmol) ethylacetimidate hydrochloride and 3.80 g (22 mmol) 3,5 difluoro-benzoic acid hydrazide.
Yield: 4.49 g (95%); mass spectroscopy [M+H]+ = 214.
is b) 3-(3 5-difluoro-phen~)-5-methyl-f 1,2,41triazole Prepared from 4.61 g (22 mmol) 3,5-difluoro-benzoic acid-(1-imino-ethyl)-hydrazide.
Yield: 3.81 g (91 %); mass spectroscopy [M+H]+ = 196.
zo c) tert-butyl 13-f3-(3,5-difluoro-phenyl)-5-methyl-f 1,2,41triazol-1-yll-1,1-dimethyl-propYl 1-carbamate 3.74 g (19 mmol) 3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazole in 25 mL
DMPU are reacted with 0.92 g (23 mmol, 60%) sodium hydride, 6.37 g (29 mmol) tent-butyl (3-chloro-1,1-dimethyl-propyl)-carbamate and 1.27 g (3.5 mmol) tetrabutylammonium iodide zs analogously to Example 1 c). Oil.
Yield: 2.62 g (36%); mass spectroscopy [M+H]+ = 381.
d) 3-f3-(3 5-difluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yll-1,1-dimethyl-uropylamine 2.62 g (6.9 mmol) tert-butyl {3-[3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4] triazol-1-yl]-l,l-3o dimethyl-propyl}-carbamate in 65 mL dichloromethane are reacted with 9 mL
trifluoroacetic acid in the manner described for intermediate product 1d).
White solid.
Yield: 2.11 g (trifluoroacetate); mass spectroscopy [M+H]+ = 281.

Intermediate product 4: 3-f5-ethyl-3-(4-methoxv-phenyl)-f 1,2,41triazol-1-vll-1,1-dimethvl-propylamine Me -N
HzN /~~N~N ~ / OMe Me 7~M ''e a) 4-method-benzoic acid-(I-imino-propyl)-hydrazide Prepared from 4.90 g (45 mmol) propioamidine hydrochloride and 5. 00 g (30 mmol) 4-methoxy-benzoic acid hydrazide analogously to the method described for intermediate product 1 a). After the ethanol has been distilled off 10.0 g crude product are obtained io which is reacted without any further purification.
b) 5-ethyl-3-(4-methoxy-phen~)-[1,2,4]triazole 9.99 g (60%, approx. 28 mmol) 4-methoxy-benzoic acid-(1-imino-propyl)-hydrazide are heated to 1 SO°C for two hours. After cooling the melt is purified by chromatography on a is silica gel column (petroleum ether/ethyl acetate = 3/7). Light yellow solid.
Yield: 4.56 g (75% over two steps); mass spectroscopy [M+H]+ = 204.
c tent-butyl ( 3-f 5-ethyl-3-(4-methox~phenyl)-[ 1,2,4]triazol-1-yl]-1,1-dimethyl-propyl-carbamate 20 4.30 g (21.2 mmol) S-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazole are dissolved in 30 mL
DMPU and cooled to 0°C . Under a protective gas atmosphere 1.02 g (24 mmol, 60%) sodium hydride are then added batchwise and the reaction mixture is slowly heated to ambient temperature and then stirred for one hour. 6.10 g (27.5 mmol) tent-butyl (3-chloro-1,1-dimethyl-propyl)-carbamate and 1.41 g (3.8 mmol) tetrabutylammonium iodide are zs added. The mixture is stirred overnight and the reaction is then stopped by the addition of water and ethyl acetate. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried with sodium sulphate and evaporated down. The oil remaining is purified by chromatography on a silica gel column (petroleum ether/ethyl acetate = 3:7).
3o Yield: 6.82 g (83%); mass spectroscopy [M+H]+ = 389.

d) 3-[5-ethyl-3-(4-methoxy=phenyl)-f 1 2 4]triazol-1-yl]-1 1-dimethyl-propylamine A total of 20 mL trifluoroacetic acid are added dropwise to a solution of 6.81 g (17.5 mmol) tert-butyl {3-[5-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propyl-carbamate in 150 mL dichloromethane. After three hour's stirring at ambient temperature the solution is evaporated down and the oil remaining is combined with diethyl ether. The precipitated white solid is filtered off, washed with diethyl ether and dried.
Yield: 7.86 g (trifluoroacetate); mass spectroscopy [M+H]+ = 289.
io Intermediate product 5' methyl 3-f 1-(3-amino-3-methyl-butyl)-5-methyl-1H-f 1,2,41triazol-3-yll-benzoate Me O
1=N _ OMe Me Me a) methyl 3-jN'-benzyloxycarbonyl-hydrazinocarbonyl)-benzoate is 10.80 g (54.4 mmol) methyl 3-chlorocarbonyl-benzoate in 100 mL diethyl ether are added dropwise to a solution of 9.04 g (54.4 mmol) benzyl hydrazinecarboxylate in 100 mL
diethyl ether, 100 mL dichloromethane and 4.83 mL pyridine while being cooled with an ice bath. The reaction mixture is stirred overnight at ambient temperature and then combined with water. The precipitated solid is filtered off and washed with diethyl ether.
2o White solid.
Yield: 14.1 g (79%); mass spectroscopy [M-H]+ = 327.
b methyl3-hydrazinocarbonyl-benzoate 14.6 g (44.5 mmol) methyl 3-[N'-benzyloxycarbonyl-hydrazinocarbonyl)-benzoate are is dissolved in 75 mL methanol and hydrogenated in the presence of palladium on charcoal (10%) at ambient temperature and 3 bar hydrogen pressure. The catalyst is filtered off and the filtrate is freed from solvent. White solid.
Yield: 7.98 g (92%); mass spectroscopy [M+H]+ = 195.
3o c methyl3-[N'-(1-imino-ethyl)-hydrazinocarbonyl]-benzoate Prepared analogously to the method described for intermediate product 1 a) from methyl 3-hydrazinocarbonyl-benzoate and ethylacetimidate hydrochloride. White solid.
Yield: 8.60 g (90%); mass spectroscopy [M+H]+ = 236.

d) methyl 3-(5-metal-1H-[1,24]triazol-3-yl)-benzoate 8.10 g (34.4 mmol) methyl 3-[N'-(1-imino-ethyl)-hydrazinocarbonyl]-benzoate are heated to 180°C for 30 minutes. 80 mL chloroform are added to the solid obtained after cooling.
The suspension is filtered and the product is dried. White solid.
Yield: 4.03 g (SS%); mass spectroscopy [M+H]+ = 218.
e) methyl 3-[1-(3-tent-butox cad rbonylamino-3-methyl-butyl)-5-methyl-1H-[1,2,4~triazol-3-yl-benzoate 6.00 g (27.6 mmol) methyl 3-(S-methyl-1H-[1,24]triazol-3-yl)-benzoate and 9.19 g (41.4 io mmol) tert-butyl (3-chloro-1,1-dimethyl-propyl)-carbamate are reacted and worked up in the manner described for intermediate product lc). Yellow oil.
Yield: 5.96 g (54%); mass spectroscopy [M+H]+ = 403.
fl methyl 3-[1-(3-amino-3-methyl)-5-methyl-1H-[1,2,4]triazol-3-yl]-benzoate is Obtained from methyl 3-[1-(3-tert-butoxycarbonylamino-3-methyl-butyl)-5-methyl-1H-[1,2,4]triazol-3-yl-benzoate analogously to the method described for intermediate product 1 d).
Yield: 5.36 g (68%, di-trifluoroacetate); mass spectroscopy [M+H]+ = 303.
zo The following intermediate products may also be obtained analogously using the methods of synthesis described.
Intermediate product 6: 3-(5-methyl-3-(2-methoxv-nhenvll-f 1,2.41triazol-1-vll-1.1 dimethyl-propylamine Me, Me0 ~I-N
Fi2N~~N~N
zs Me~M ~'e Intermediate product 7: 3-(5-methyl-3-(4-methoxv-phenyl)-f 1,2,41triazol-1-vll-1.1 dimethyl-propylamine Me~
N
i HZN~~N~N ~ / OMe Me ~M ''e Intermediate product 8: 3-fS-methyl-3-(3-benzo~1.31dioxol-S-vl)-f 1.2.41triazol-1-vll-1.1-dimethyl-pr ropylamine Me, ~~--N O
HN N N
\ /
Me Me Intermediate product 9: 2-f3-(4-methoxv-phenyl)-f1.2,41triazol-1-vll-1.1-dimeth ethylamine Me Me ~N
i HZN~N~N ~ ~ OMe Intermediate product 10: 1,1,-dimethyl-3-(jl 2,4]triazol-1-yl)-~ropylamine io N
HZN N
~ N
Me Me General method 1 (AAV 1 ):
1 mmol of N-[2-benzyloxy-S-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide ~s and 1 mmol of amine (or intermediate product) are stirred for 30 minutes in S mL
tetrahydrofuran at ambient temperature. The mixture is cooled to 0°C
and l .S mL of a 2 molar solution of lithium borohydride in tetrahydrofuran are added dropwise under an argon atmosphere. The mixture is stirred for 1 S min at 0°C, combined with 10 mL
dichloromethane and 3 mL water, stirred for a further hour at ambient temperature and Zo then filtered through kieselguhr, eluting with dichloromethane. The eluate is freed from solvent and the residue, if necessary, is purified by chromatography. The benzyl ether thus obtained is dissolved in methanol and hydrogenated with palladium on charcoal (10%) as catalyst at 2.S bar and ambient temperature. Then the catalyst is separated off and the crude product is purified by chromatography (reverse phase, acetonitrile/water gradient with is 0.1 % trifluoroacetic acid).

Example 1: N~jS-(2- 3-[5-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-pro~ylamino~ 1-hydrox~-ethyl)-2-hydroxy-phenyl]-methanesulphonamide Me OH -N
MeSOzNH ~ N N~ i N \ / OMe Me Me HO
Prepared according to AAV 1 from N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 3-[S-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine.
Yield: 255 mg (40% over 2 steps, trifluoroacetate); mass spectroscopy: [M+H]+
= 518.
to Example 2: N-[5-(2-{1,1-dimethyl-3-[5-methyl-3-(4-trifluoromethyl-phen'rl~-~1,2,4]triazol-1-yll-propylamino],-1-hydroxY ethyl)-2-hydroxy phe~lL
methanesu~honamide Me OH ~N
MeSO2NH ~ N N~ ~
N ~ /~
Me~ ~CF3 HO
is Obtained according to AAV 1 by reacting N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 1,1-dimethyl-3-[5-methyl-3-(4-trifluoromethyl-phenyl)-[1,2,4]triazol-1-yl]-propylamine. White solid.
2o Yield: 78 mg (12% over 2 steps, trifluoroacetate); mass spectroscopy:
[M+H]+ = 541.
Example 3: N-(~2-[1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4~]triazol-1-yl)-propylaminol-1-hydrox -Y ethyl}-2-hydroxy-phenyl)-methanesu~honamide Me OH ~N
MeSO2NH ~ N N~ ~
N
Me~ ~Me 2s H~

Obtained according to AAV 1 from N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4]triazol-1-yl)-propylamine. White solid.
Yield: 7 mg (1% over 2 steps, trifluoroacetate); mass spectroscopy: [M+H]+ =
488.
Example 4: N-[5-(2-~3-f3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl)-1,1-dimethyl=
propylamino)-1-h day-ethyl)-2-hydroxy-phenyll-methanesulphonamide Me OH ~N
MeSOzNH ~ N N~ i N ~ / F
Me Me HO
Prepared from N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 3-[3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine according to AAV 1. White solid. Yield: 155 mg (26% over 2 steps, trifluoroacetate); mass spectroscopy: [M+H]+ = 492.
is Example 5: 3-(1-f 3-[2-hydroxy-2-(4-hydroxy-3-methanesulphonylamino-phenyl)-ethylamino]-3-methyl-butyll-5-methyl-1H-[1,2,4]triazol-3-~)-benzoate meth Me O
OH ~=N OMe MeSO2NH ~ N~~N~ i '' N
/ Me Me HO
Prepared according to AAV 1 from N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and methyl 3-[1-(3-amino-3-methyl-butyl)-5-methyl-[1,2,4]triazol-3-yl]-benzoate. White solid.
Yield: 36 mg (7% over 2 steps, trifluoroacetate); mass spectroscopy: [M+H]+ =
532.

Example 6: N-[5-(2-f 3-(3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4~triazol-1 yl]-1,1-dimethyl-propylamino> -~hydroxy-ethyl~2-hydroxy-phenyll-methanesulphonamide Me OH ~N F
MeSO2NH ~ N~~N~ ~
N
Me Me HO F
Prepared according to AAV 1 from N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 3-[3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine. White solid.
Yield: 20 mg (3% over 2 steps, trifluoroacetate); mass spectroscopy: [M+H]+ =
510.
io Example 7: N [2-hydrox~(1-h droxy-~3-[3-(2-methoxyphen~)-S-methyl-(1 2 4]triazol-1-yll-1 1-dimethyl-propylamino}-eth 1)-phenyl]'-methanesulphonamide Me Me0 OH H ~N
MeSO2NH ~ N~N,N~
'' Me Me HO
~s 347 mg (1 mmol) 3-[3-(2-methoxy-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-l,l-dimethyl-propylamine hydrochloride are combined with sodium hydroxide solution and stirred for 2 hours at ambient temperature. The solution is added to kieselguhr and eluted with dichloromethane. The eluate is evaporated down and the residue is taken up in 5 mL THF.
2o 379 mg (1 mmol) N [2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide are added and the mixture is stirred for 30 min at ambient temperature. After cooling to 0°C 1.5 mL of a 2 molar solution of lithium borohydride in THF are added dropwise and the mixture is stirred for 30 minutes at ambient temperature.
The reaction mixture is combined with 10 mL dichloromethane and 3 mL water, stirred for 2s one hour and then filtered through kieselguhr with dichloromethane as eluant. The solvent is distilled off and the residue is taken up in 5 mL methanol. Then it is hydrogenated with 100 mg palladium on charcoal at 2.5 bar. The catalyst is separated off and the filtrate is evaporated down. For further purification the residue is chromatographed (RP, acetonitrile:water gradient with 0.1 % trifluoroacetate).
3o Yield: 323 mg (52%, trifluoroacetate); mass spectrometry: [M+H]+ = 504.

WO 200s/077361 21 PCT/EP2005/001232 Example 8: N f 2-h~droxy-5-( 1-hydroxy-~ 3-[3-(4-methoxy-phenyl)-5-methyl-[1 2 4]triazol-1-yll-1 1-dimethyl-propylamino}-ethyl)-phenyl]-methanesulphonamide Me OH H ~=N
MeSO2NH ~ N N, ~
N ~ / OMe Me Me HO
379 mg (1 mmol) of N [2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 274 mg (1 mmol) of 3-[3-(4-methoxy-phenyl)-S-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine are suspended in S mL ethanol and heated to 70°C. The solution formed is stirred for one hour at 70°C and then cooled to ambient io temperature. After the addition of 113 mg (3 mmol) sodium borohydride the mixture is stirred for 3 hours at ambient temperature, combined with 0.7 mL saturated potassium carbonate solution and stirred for a further 30 minutes. It is filtered through aluminium oxide (basic), washed repeatedly with methylene chloride/methanol 15:1, evaporated down and chromatographed (silica gel; dichloromethane with 0-10% methanol:ammonia =
9:1).
is The benzyl compound thus obtained is dissolved in 10 mL methanol and hydrogenated with palladium on charcoal at 2.5 bar hydrogen pressure. Then it is filtered and the filtrate is evaporated down.
Yield: 339 mg (67%); mass spectrometry: [M+H]+ = 504.
2o Example 9: N (~2-[3-(3-benzo[1,3]dioxol-5-yl-5-meths[1,2,4]triazol-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl ~-2-hydroxy-phenyl)-methanesulphonamide Me OH H ~=N \ O
MeSO2NH ~ N~N,Ni~O
Me~Me '~ /
HO
as Analogously to the method described for Example 7, 379 mg (1 mmol) N [2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 288 mg (1 mmol) 3-(3-benzo[1,3]dioxol-5-yl-5-methyl-[1,2,4]triazol-1-yl)-l,l-dimethyl-propylamine are reacted with one another. The subsequent debenzylation yields the target compound.
Yield: 371 mg (72%); mass spectrometry: [M+H]+ = 518.

Example 10: N [2-hydroxy-5-(1-hydroxy-2~3-[3-(4-methoxy-phenyl)-[1,2,41riazol-1-yl]-1, I-dimethyl-propylamino)-ethyl)-phenyl],-methanesulphonamide OH H
MeSOZNH ~ N\ ~ ,N
N
Me Me ~N \ ~ OMe HO
The target compound is obtained by reacting 379 mg (1 mmol) N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 246 mg (1 mmol) 2-[3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-ethylamine in the manner described for Example 7 followed by debenzylation.
to Yield: 305 mg (64%); mass spectrometry: [M+H)+ = 476.
Example 11: N- 5-[2-[1,1-dimethyl-3-[1,2,4]triazol-1-y~ropylamino)-1-hydroxy-ethyll-2-hydroxy-phenyl ) -m ethanesu~honami de OH H ~=N
MeSOZNH ~ N~N,N
Me~M ''e is HO
The target compound is prepared analogously to the methods described for Example 7 from 379 mg (1 mmol) N [2-benzyloxy-S-[2-ethoxy-2-hydroxy-acetyl)-phenyl)-methanesulphonamide and 154 mg (1 mmol) 1,1-dimethyl-3-[1,2,4)triazol-1-yl-zo propylamine. Colourless solid.
Yield: 225 mg (59%); mass spectrometry: [M+H]+ = 384.
As has been found, the compounds of formula 1 are characterised by their range of uses in the therapeutic field. Particular mention should be made of those applications for which the zs compounds of formula 1 according to the invention may preferably be used on the basis of their pharmaceutical activity as betamimetics.
These include, for example, the treatment of inflammatory and obstructive respiratory complaints, selected from among obstructive pulmonary diseases of various origins, pulmonary emphysema of various origins, restrictive pulmonary diseases, interstitial 3o pulmonary diseases, cystic fibrosis, bronchitis of various origins, bronchiectasis, ARDS
(adult respiratory distress syndrome) and all forms of pulmonary oedema.
The compounds of formula 1 are preferably used for preparing a pharmaceutical composition for the treatment of obstructive pulmonary diseases selected from among bronchial asthma, paediatric asthma, severe asthma, acute asthma attacks, chronic bronchitis and COPD (chronic obstructive pulmonary disease), while it is particularly preferable according to the invention to use them for preparing a pharmaceutical composition for the treatment of bronchial asthma and COPD.
It is also preferable to use the compounds of formula 1 for preparing a pharmaceutical composition for the treatment of pulmonary emphysema which has its origins in COPD or a,l-proteinase inhibitor deficiency.
io It is also preferable to use the compounds of formula 1 for preparing a pharmaceutical composition for the treatment of restrictive pulmonary diseases selected from among allergic alveolitis, restrictive pulmonary diseases triggered by work-related noxious substances, such as asbestosis or silicosis, and restriction caused by lung tumours, such as ~s for example lymphangiosis carcinomatosa, bronchoalveolar carcinoma and lymphomas.
It is also preferable to use the compounds of formula 1 for preparing a pharmaceutical composition for the treatment of interstitial pulmonary diseases selected from among pneumonia caused by infections, such as for example infection by viruses, bacteria, fungi, zo protozoa, helminths or other pathogens, pneumonitis caused by various factors, such as for example aspiration and left heart insufficiency, radiation-induced pneumonitis or fibrosis, collagenoses, such as for example lupus erythematodes, systemic sclerodermy or sarcoidosis, granulomatoses, such as for example Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).
2s It is also preferable to use the compounds of formula 1 for preparing a pharmaceutical composition for the treatment of cystic fibrosis or mucoviscidosis.
It is also preferable to use the compounds of formula 1 for preparing a pharmaceutical 3o composition for the treatment of bronchitis, such as for example bronchitis caused by bacterial or viral infection, allergic bronchitis and toxic bronchitis.
It is also preferable to use the compounds of formula 1 for preparing a pharmaceutical composition for the treatment of bronchiectasis.
3s It is also preferable to use the compounds of formula 1 for preparing a pharmaceutical composition for the treatment of ARDS (adult respiratory distress syndrome).
It is also preferable to use the compounds of formula 1 for preparing a pharmaceutical composition for the treatment of pulmonary oedema, for example toxic pulmonary oedema after aspiration or inhalation of toxic substances and foreign substances.
It is particularly preferable to use the compounds of formula 1 for preparing a pharmaceutical composition for the treatment of asthma or COPD. Also of particular io importance is the above-mentioned use for preparing a pharmaceutical composition for once-a-day treatment of inflammatory and obstructive respiratory complaints, particularly for the once-a-day treatment of asthma or COPD.
Suitable preparations for administering the compounds of formula 1 include for example is tablets, capsules, suppositories, solutions, powders, etc. 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 Zo 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.
zs 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 of layers to achieve delayed release, possibly using the 3o excipients mentioned above for the tablets.
Syrups or elixirs containing the active substances or combinations of active substances 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 3s 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.
io 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 is 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 zo 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).
is 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 3o 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
3s according to the invention it is particularly preferred to use preparations or pharmaceutical WO 200s/077361 26 PCT/EP2005/001232 formulations which are suitable for inhalation. Inhalable preparations include inhalable powders, propellant-containing metered-dose 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 its own or in admixture with suitable physiologically acceptable excipients.
io 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, ~s 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 zo maximum average particle size of up to 250 Vim, preferably between 10 and 150 Vim, most preferably between 15 and 80 Vim. In some cases it may seem appropriate to add finer excipient fractions with an average particle size of I to 9 ~m to the excipients 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, Zs micronised active substance 1, preferably with an average particle size of 0.5 to 10 ~,m, 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 lastly 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 3o 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.
s 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 fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-mentioned propellant gases may be used on their own or mixed together. Particularly preferred io propellant gases are 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 is 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).
zo 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 zs 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 3o 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, 3s 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 may be omitted 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 I00 mg/100m1, preferably less than SOmg/100m1, more preferably less than 20mg/100m1. Generally, inhalable solutions in ~o which the content of sodium edetate is from 0 to l0mg/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, is 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 20 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 is 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.
3o 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.
s 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 io by inhalation the compounds of formula 1 are characterised by a high potency even at doses in the ~g range. The compounds of formula 1 may also be used effectively above the ~g range. The dosage may then be in the milligram range, for example.
In another aspect the present invention relates to the above-mentioned pharmaceutical ~5 formulations as such, which are characterised in that they contain a compound of formula 1, particularly preferably the above-mentioned pharmaceutical formulations administered by inhalation.
The following examples of formulations illustrate the present invention without restricting zo its scope:
A) Tablets per tablet active substance of formula 1 100 mg is lactose 140 mg maize starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 30 500 mg The finely ground active substance, lactose and some of the corn 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 corn starch and the ~
~ ~ CA 02552871 2006-07-06 magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.
s B) Tablets per tablet active substance of formula 80 mg lactose 55 mg maize starch 190 mg microcrystalline cellulose 35 mg io polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg is The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened.
The sodium carboxymethyl starch and the magnesium stearate are added and mixed in and zo the mixture is compressed to form tablets of a suitable size.
C) Ampoule solution active substance of formula 1 50 mg sodium chloride 50 mg Zs water for inj. 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 it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are 3o then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.
D) Metered-dose aerosol active substance of formula 1 0.005 3s sorbitolan trioleate 0.1 monofluorotrichloromethane and TG134a : TG227 2:1 ad 100 The suspension is transferred into a conventional aerosol container with a metering valve. Preferably, 50 ~l of suspension are delivered per spray. The active substance may also be metered in higher doses if desired (e.g. 0.02 % by weight).
F) Powder for inhalation active substance of formula 1 12 ~g lactose monohydrate ad 10 mg The powder for inhalation is produced in the usual way by mixing the individual io ingredients together.

Claims (17)

1. Use of compounds of formula 1 wherein R1 denotes hydrogen, -C1-6-alkyl, -C1-6-haloalkyl, -OH, -O-C1-6-alkyl, halogen or a group selected from among aryl or a heterocycle, while aryl or the heterocycle, if possible each optionally substituted by 1, 2, 3, 4 or 5 are identical or different groups R5;
   R2 denotes hydrogen, -C1-6-alkyl, -C1-6-haloalkyl;
   R3 denotes -C1-6-alkyl;
   R4 denotes -OH, -NH2, halogen;
   R5 denotes halogen, -CN, -NO2, -C1-6-alkyl, -C3-6-cycloalkyl, -C1-6-haloalkyl, -COR6, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6SO2R7, -SR6, -SOR6, -SO2R6 or -SO2NR6R7, or two R5 joined together denote a group selected from -C2-6-alkylene, -C2-6-alkenylene and -O-C1-6-alkylene-O-;
   R6 and R7 denote hydrogen, -C1-6-alkyl, -C3-6-cycloalkyl;
   n denotes 0, 1, 2 or 3;
   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 for preparing a pharmaceutical composition for the treatment of inflammatory and obstructive respiratory complaints
2. 2. Use according to claim 1, wherein in the compounds of formula 1 R1, R2, R3 and n may be defined as in claim 1 and wherein R4 denotes -OH.
3. 3. Use of compounds of formula 1 according to one of claims 1 or 2, wherein R2, R3, R4 and n are as hereinbefore defined and R1 denotes hydrogen, -C1-6-alkyl, -C1-6-haloalkyl, -OH, -O-C1-6-alkyl, halogen or aryl, if possible optionally substituted by 1, 2, 3, 4 or 5 identical or different groups R5;
   R5 denotes halogen, -CN, -NO2, -C1-6-alkyl, -C3-6-cycloalkyl, -C1-6-haloalkyl, -COR6, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6SO2R7, -SR6, -SOR6, -SO2R6 or -SO2NR6R7, or two R5 joined together denote a group selected from -C2-6-alkylene, -C2-6-alkenylene and -O-C1-6-alkylene-O-;
   R6 and R7 denote hydrogen, -C1-6-alkyl, -C3-6-cycloalkyl;
   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.
4. 4. Use of compounds of formula 1 according to one of claims 1-3, wherein R1 denotes hydrogen, -C1-6-alkyl, -O-C1-6-alkyl, aryl, if possible optionally substituted by 1, 2, 3, 4 or 5 identical or different groups R5;
   R2 denotes hydrogen, -C1-6-alkyl;
   R3 denotes methyl;
   R4 denotes -OH;
   R5 denotes halogen, -CN, -NO2, -C1-6-alkyl, -C3-6-cycloalkyl, -C1-6-haloalkyl, -COR6, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6SO2R7, -SR6, -SOR6, -SO2R6 or -SO2NR6R7, or two R5 joined together represent a group selected from -C2-6-alkylene, -C2-6-alkenylene and -O-C1-6-alkylene-O-;
   R6 and R7 denote hydrogen, -C1-6-alkyl, -C3-6-cycloalkyl;
   n denotes 0, 1, 2 or 3;
   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.
5. 5. Use of compounds of formula 1 according to one of claims 1-4, wherein R1 denotes hydrogen, aryl, if possible optionally substituted by 1, 2, 3, 4 or 5 identical or different groups R5;
   R2 denotes hydrogen, -C1-6-alkyl;
   R3 denotes methyl;
   R4 denotes -OH;
   R5 denotes halogen, -CN, -NO2, -C1-6-alkyl, -C3-6-cycloalkyl, -C1-6-haloalkyl, -COR6, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6SO2R7, -SR6, -SOR6, -SO2R6 or -SO2NR6R7, or two R5 joined together represent a group selected from -C2-6-alkylene, -C2-6-alkenylene and -O-C1-6-alkylene-O-;
   R6 and R7 denote hydrogen, -C1-6-alkyl, -C3-6-cycloalkyl;
   n denotes 0, 1, 2 or 3;
   
   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.
6. 6. Use according to one of claims 1 to 5, characterised in that the compounds of formula 1 are used in the form of their R-enantiomers.
7. 7. Compounds of formula 1 wherein R1, R2 and n may have the meanings given in claims 1 to 5 and wherein R3 denotes methyl;
   R4 denotes OH, 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.
8. 8. Compounds of formula 1 according to claim 7, wherein R2 denotes methyl or ethyl, 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.
9. 9. Compounds of formula 1 according to claim 7 or 8, wherein n = 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.
10. 10. Compounds of formula 1 according to one of claims 7 - 9, wherein R1 denotes hydrogen, phenyl, optionally substituted by 1, 2 or 3 identical or different groups R5;
    R2 denotes methyl or ethyl;
    R3 denotes methyl;
    R4 denotes OH;
    R5 denotes halogen, -C1-6-alkyl, -C3-6-cycloalkyl, -C1-6-haloalkyl, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6SO2R7 or two R5 joined together denote a group selected from -C2-6-alkylene, -C2-6-alkenylene and -O-C1-6-alkylene-O-;
    R6 and R7 denote hydrogen, -C1-6-alkyl, -C3-6-cycloalkyl;
    n denotes 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.
11. 11. Compounds of formula 1 according to one of claims 7-10, wherein R1 denotes hydrogen, phenyl, optionally substituted by 1, 2 or 3 identical or different groups R5;
    R2 denotes methyl or ethyl;
    R3 denotes methyl;
    R4 denotes OH;
    R5 denotes halogen, -C1-6-alkyl, -C1-6-haloalkyl, -COOR6, -CONR6R7, -OR6, -NR6R7 or two R5 joined together represent -O-C1-6-alkylene-O-;
    R6 and R7 denote hydrogen, -C1-6-alkyl;
    n denotes 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.
12. 12. Compounds of formula 1, wherein the groups R1, R2, R3, R4 and n are defined as in claims 7-11, characterised in that they are in the form of the R-enantiomers of formula R-1
13. 13. Use of the compounds of formula 1 according to one of claims 7 to 12 as pharmaceutical compositions.
14. 14. Use of the compounds of formula 1 according to one of claims 7 - 12 for preparing a pharmaceutical composition for the treatment of diseases in which therapeutically effective doses of a betamimetic may develop a therapeutic benefit.
15. 15. Pharmaceutical formulations, characterised in that they contain one or more compounds of formula 1 according to one of claims 7 to 12.
16. 16. Pharmaceutical formulation capable of being administered by inhalation, characterised in that it contains a compound of formula 1 according to one of claims 1 to 12.
17. 17. Pharmaceutical formulation capable of being administered by inhalation according to claim 16, characterised in that it is selected from among the inhalable powders, propellant-containing metered-dose aerosols and propellant-free inhalable solutions.