DE10246374A1 - New 4-(2-alkylamino-1-hydroxyethyl)-3-alkoxy-benzene-1,2-diol derivatives, are beta-mimetics having a long duration of action, useful e.g. for treating asthma, chronic obstructive pulmonary disease or arrhythmia - Google Patents

New 4-(2-alkylamino-1-hydroxyethyl)-3-alkoxy-benzene-1,2-diol derivatives, are beta-mimetics having a long duration of action, useful e.g. for treating asthma, chronic obstructive pulmonary disease or arrhythmia

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DE10246374A1
DE10246374A1 DE10246374A DE10246374A DE10246374A1 DE 10246374 A1 DE10246374 A1 DE 10246374A1 DE 10246374 A DE10246374 A DE 10246374A DE 10246374 A DE10246374 A DE 10246374A DE 10246374 A1 DE10246374 A1 DE 10246374A1
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methyl
alkyl
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Inventor
Thierry Bouyssou
Frank Büttner
Claudia Heine
Ingo Konetzki
Sabine Pestel
Andreas Schnapp
Hermann Schollenberger
Kurt Schromm
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Boehringer Ingelheim Pharma GmbH and Co KG
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Boehringer Ingelheim Pharma GmbH and Co KG
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Priority claimed from US10/666,068 external-priority patent/US6951888B2/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C07C217/66Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
    • C07C217/70Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/18Sulfonamides
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00Systems containing only non-condensed rings
    • C07C2601/06Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Abstract

4-(2-(Tertiary alkylamino)-1-hydroxyethyl)-3-alkoxy-benzene-1,2-diol derivatives (I) are new. Phenylethanolamine derivatives of formula (I), including individual optically isomers, enantiomer mixtures and racemates, and their acid addition salts are new. R1, R2 = 1-4C alkyl; R3 = 1-4C alkyl or mono- or polysubstituted phenyl; or R2 + R3 = (CH2)2 or (CH2)3.

Description

  • The present invention relates to compounds of general formula 1
    Figure 00010001
    wherein the radicals R 1 , R 2 and R 3 can have the meanings given in the claims and in the description, processes for their preparation and their use as medicaments, in particular for the treatment of inflammatory and obstructive respiratory diseases.
  • Background of the Invention
  • Betamimetics (β-adrenergic substances) are known from the prior art. You can choose from a variety of therapeutic areas of application can be used sensibly.
  • For drug therapy of diseases it is common desirable, Medicines with a longer one Provide duration of action. This can usually ensure be that the concentration required to achieve the therapeutic effect of the active ingredient in the organism a longer one Period is given without too frequent, repeated administration of the Perform drug to have to. The application of an active ingredient at longer intervals contributes to to a high degree to the well-being of the patient. The provision is particularly desirable of a drug that is therapeutically useful due Application per day (single dose) can be used. One once per Day use has the advantage that the patient is relative quickly on the regular intake can get used to the drug at certain times of the day.
  • It is therefore the task of the present Invention to provide beta mimetics by a longer duration of action are marked and thus for the manufacture of medicinal products with longer Effectiveness can be used. It is a particular object of the present invention to betamimetics provide that due to their long effectiveness in manufacturing once a day Applicable drug can be used. Another goal of present invention is the provision of new beta mimetics, which due to their long effectiveness in making one time Every day Applicable drug for the treatment of inflammatory or obstructive airway diseases can be used.
  • In addition to the above-mentioned objects, it is also an object of the present invention to provide those betamimetics which are not only extremely potent but are also characterized by a high degree of selectivity towards the β 2 -adreno-receptor.
  • Detailed description the invention
  • Surprisingly it was found that the aforementioned tasks through connections of the general Formula 1 solved become.
  • Accordingly, the present invention relates to compounds of the general formula 1
    Figure 00020001
    wherein
    R 1 C 1 -C 4 alkyl;
    R 2 C 1 -C 4 alkyl;
    R 3 is C 1 -C 4 alkyl or phenyl, which may optionally be mono- or polysubstituted, or
    R 2 and R 3 together denote a divalent group selected from -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 .
  • Compounds of formula 1 are preferred in which
    R 1 C 1 -C 4 alkyl;
    R 2 C 1 -C 4 alkyl;
    R 3 is C 1 -C 4 alkyl or phenyl, which may optionally be mono-, di-, tri- or tetra-substituted by one or more radicals selected from C 1 -C 3 alkyl, CF 3 , methoxy, ethoxy, hydroxy, Fluorine, chlorine, bromine, -OCF 3 , -CHF 2 , -NHCOCH 3 and -NHSO 2 CH 3 , or
    R 2 and R 3 together denote a divalent group selected from -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 .
  • Also preferred are compounds of general formula 1, wherein
    R 1 is C 1 -C 4 alkyl, preferably methyl;
    R 2 C 1 -C 4 alkyl;
    R 3 is C 1 -C 4 alkyl or phenyl, which may optionally be mono-, di-, tri- or tetra-substituted by one or more radicals selected from methyl, ethyl, CF 3 , methoxy, ethoxy and hydroxy, or
    R 2 and R 3 together denote a divalent group selected from -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 .
  • Also preferred are compounds of general formula 1, wherein
    R 1 is C 1 -C 4 alkyl, preferably methyl;
    R2 C 1 -C 4 alkyl, preferably methyl;
    R 3 is C 1 -C 4 alkyl, preferably methyl, or phenyl, which may optionally be mono-, di-, tri- or tetra-substituted by one or more radicals selected from methyl, CF 3 , methoxy and hydroxy, or
    R 2 and R 3 together mean the divalent group -CH 2 -CH 2 .
  • According to the invention, preference is given to compounds of the general formula 1 in which
    R 1 is methyl or ethyl, preferably methyl;
    R 2 methyl;
    R 3 is methyl, ethyl or phenyl, which may optionally be substituted once, twice, three or four times by one or more radicals selected from methyl, CF 3 , methoxy and hydroxy, or
    R 2 and R 3 together mean the divalent group -CH 2 -CH 2 .
  • Compounds of general formula 1 are particularly preferred
    R 1 is methyl;
    R 2 methyl;
    R 3 is methyl or phenyl, which may optionally be mono-, di-, tri- or tetra-substituted by one or more radicals selected from methyl, ethyl and hydroxy, or
    R 2 and R 3 together mean the divalent group -CH 2 -CH 2 .
  • According to the invention, preference is furthermore given to compounds of the general formula 1 in which
    R 1 is methyl;
    R 2 methyl;
    R 3 is methyl or phenyl, or R 2 and R 3 together mean the divalent group -CH 2 -CH 2 .
  • Of outstanding importance according to the invention are, for example, the following compounds of formula 1:
    • - 4- [2- (1,1-dimethyl-propylamino) -1-hydroxyethyl] -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-timethylphenyl) ethylamino] -1-hydroxyethyl} -3-methoxy-benzene-1,2-diol ;
    • - 4- {2- [1,1-dimethyl-2-phenyl) ethylamino) -1-hydroxyethyl} -3-methoxy-benzene-1,2-diol;
    • - 4- {2- [1,1-Dimethyl-2- (2,3,5,6-tetra-methylphenyl) ethylamino] -1-hydroxyethyl} -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 respective compounds of formula 1 optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids. Under acid addition salts with pharmacologically harmless acids, for example Salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, Hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, Hydroacetate, hydrobenzoate, hydronitrate, hydrofumarate, hydrotartrate, Hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, Hydrofumarate and hydromethanesulfonate understood.
  • As alkyl groups, if not otherwise stated, branched and unbranched alkyl groups with 1 referred to 4 carbon atoms. Examples include: Methyl, ethyl, propyl or butyl. To designate the groups methyl, The abbreviations may also be ethyl, propyl or butyl Me, Et, Prop or Bu used. Unless otherwise stated, the definitions propyl and butyl include all possible isomers Forms of the respective residues. For example, propyl includes n-propyl and isopropyl, butyl iso-butyl, sec.butyl and tert.-butyl etc.
  • Of the above acid addition salts are the salts of hydrochloric acid, methanesulfonic acid, the benzoic acid and acetic acid according to the invention particularly prefers.
  • The compounds according to the invention can be prepared analogously to procedures already known in the prior art. Suitable manufacturing processes are, for example, from US 3657244 known, to which reference is made here in full.
  • The synthesis examples described below serve to further illustrate the present invention. However, they are only examples of how to proceed explanation to understand the invention without exemplifying the following restrict the described subject.
  • Example 1: 4- [2- (1,1-Dimethvl-propylamino) -1-hydroxy-ethyl] -3-methoxv-benzene-1 2-diol
    Figure 00050001
    • a) Preparation of 2- (1,1-dimethyl-propylamino) -1- (4-methoxy-2,2-diphenylbenzo [1,3] dioxol-5-yl) -ethanone 42.5 g of α-bromo-2 -methoxy-3,4-diphenylmethylene dioxyacetophenone (available according to US 3657244 ) are stirred under reflux with 30 g of 1,1-dimethylpropylamine in 150 ml of ethanol for 3 hours. The solvent is distilled off under reduced pressure and the residue is mixed with diethyl ether and extracted twice with water. After the solvent has been distilled off under reduced pressure, the remaining residue is dissolved in ethyl acetate and acidified with ethereal hydrochloric acid. The crystals which precipitate are filtered off with suction and washed with ethyl acetate and diethyl ether. Yield: 26 g (56%, hydrochloride); Mp = 174 - 176 ° C.
    • b) Preparation of 1- (3,4-dihydroxy-2-methoxyphenyl) -2- (1,1-dimethylgrogylamino) ethanone 25 g 2- (1,1-Dimethyl-propylamino) -1- (4-methoxy-2,2-diphenyl-benzo [1,3jdioxol-5-yl) ethanone are mixed with 50 mL 15% methanolic hydrochloric acid 2 hours under reflux touched. The solvent is distilled off under reduced pressure and the residue is dissolved in acetonitrile and mixed with ethyl acetate. The crystals that precipitate are suction filtered and washed with acetonitrile and diethyl ether. Yield: 15 g (92%) of the compound as the hydrochloride. For further cleaning can from the hydrochloride according to usual Conditions the free base is released, which is slurried in methanol with the equimolar amount benzoic acid offset and warmed becomes. The crystals thus obtained are filtered off with suction and with diethyl ether washed. Mp = 151-154 ° C (benzoate).
    • c) Preparation of 4- [2- (1,1-dimethyl-progylamino) -1-hydroxy-ethvl] -3-methoxy-benzene-1,2-diol 6.5 g 1- (3,4-Dihydroxy-2-methoxyphenyl) -2- (1,1-dimethylpropylamino) ethanone are hydrogenated with 0.1 g of platinum oxide in 125 ml of methanol. The catalyst is suctioned off and the solvent distilled off under reduced pressure. The residue is dissolved in ethyl acetate solved, the crystals which precipitate are filtered off and extracted with ethyl acetate and washed with diethyl ether. Yield: 5.5 g (85%; benzoate); Mp. = 172-174 ° C.
  • Example 2: 4- [1-Hvd roxy-2- (1-methyl-cyclopentylamino) -ethvl] -3-methoxy-benzene-1,2-diol
    Figure 00060001
    • a) Preparation of 1-methyl-cyclopentylamine 66.5 g of sodium cyanide are dissolved in 150 mL glacial acetic acid. A solution of 300 mL sulfuric acid and 150 mL glacial acetic acid is at 5-10 ° C added dropwise to the sodium cyanide solution. 126 g of 1-methyl-cyclopentanol are added to this mixture. The mixture obtained is overnight ditched. Subsequently 210 mL of water and 770 g of sodium hydroxide solution are cooled with ice 1.5 L of water added. It is heated to reflux for 4 hours and the amine with Steam distillation isolated. The distillate is concentrated. Acidified hydrochloric acid, with Extracted diethyl ether and then with 50% sodium hydroxide solution made alkaline. The residue is fractionally distilled (bp 760 mm = 114 - 115 ° C). Yield: 45 g (36%).
    • b) Preparation of 1- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxol-5-yl) -2- (1-methyl-cyclopentylamino) ethanone 35 g α-bromo-2-methoxy-3,4-diphenylmethylene dioxyacetophenone with 45 g of 1-methyl-cyclopentylamine refluxed in 150 mL ethanol for 1 hour. The solvent is reduced Pressure distilled off, the residue dissolved in diethyl ether, extracted with water and the solvent distilled off under reduced pressure. The remaining residue is dissolved in acetonitrile, with hydrochloric acid acidified and the crystals obtained were isolated. Yield: 19 g (48%; hydrochloride); Mp = 173 ° C (Decomposition).
    • c) Preparation of 1- (3,4-dihydroxy-2-methoxyphenyl) -2- (1-methyl-cyclopentylaminoethanone 19 g 1- (4-Methoxy-2,2-diphenyl-benzo [1,3] dioxol-5-yl) -2- (1-methyl-cyclopentyl-amino) -ethanone stirred in reflux in 190 mL 15% methanolic hydrochloric acid for 2 hours. The solvent is distilled off under reduced pressure and the remaining Residue in acetonitrile. solved. The precipitated crystals are washed with diethyl ether. Yield: 11 g (88%; hydrochloride); Mp = 187 - 189 ° C (decomposition).
    • d) Preparation of 4- [1-hydroxy-2- (1-methyl-cyclopentylamino) -ethyl] -3-methoxybenzene-1,2-diol 5 g of 1- (3,4-dihydroxy-2-methoxy-phenyl) -2- (1-Methyl-cyclopentyl-amino) -ethanone hydrochloride are hydrogenated with 0.2 g PtO 2 in 200 mL methanol. The catalyst is suctioned off and the solvent is distilled off under reduced pressure. The remaining residue is dissolved in ethanol and 5 g of sodium benzoate are added. The title compound is isolated in the form of its benzoate. Yield: 4.5 g (70.5%; benzoate); Mp = 179-180 ° C.
  • Example 3: 4- {2- [1,1-Dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxyethyl} -3-methoxy-benzene-1,2-diol
    Figure 00080001
    • a) Preparation of 2-chloromethyl-1 3 5-timethyl-benzene 400 g of mesitylene are combined with 130 g of paraformaldehyde and 2 L of hydrochloric acid are introduced at 60-70 ° C. within 7 hours. Then it is extracted with benzene and the org. Phase then washed with 2N sodium hydroxide solution. The residue is fractionally distilled. Yield: 204 g (36%); Bp 15 = 130-140 ° C.
    • b) Preparation of (2,4,6-trimethyl-phenyl) acetonitrile 66 g of sodium cyanide are stirred under reflux in 100 ml of water and 140 ml of ethanol until a clear Solution arises. 136 g of 2-chloromethyl-1,3,5-trimethyl-benzene are slowly added dropwise to this solution and the mixture is stirred for 3 hours under reflux. It is diluted with 1 L water and extracted three times with 200 mL benzene. The combined organic phases are washed with water and the solvent is distilled off under reduced pressure. The residue is fractionally distilled. Yield: 92 g (72%); Bp 15 = 145-153 ° C.
    • c) Preparation of (2,4,6-trimethyl-phenyl) acetic acid To one at 50 ° C heated solution of 1.1 L water and 915 mL conc. 155 g of sulfuric acid (2,4,6-trimethylphenyl) acetonitrile given. The mixture is stirred under reflux for 6 hours. Then the Put the reaction mixture on 3 kg of ice. The solid is suctioned off and washed with water. Yield: 131 g (86% of theory); Mp = 163-166 ° C.
    • d) Preparation of (2,4,6-trimethyl-phenyl) -acetic acid methyl ester 173 g (2,4,6-trimethyl-phenyl) -acetic acid are concentrated in 131 mL. Hydrochloric acid and 1.1 L of methanol were stirred under reflux for 3 hours. The solvent is distilled off under reduced pressure and the aqueous phase is extracted twice with diethyl ether. The combined organic phases are extracted twice with a saturated aqueous sodium bicarbonate solution, dried with sodium sulfate and the solvent is distilled off under reduced pressure. The residue is fractionally distilled. Yield: 116 g (57%); Bp 15 = 140 ° C.
    • e) 2-Methyl-1- (2,4,6-trimethylphenyl) propan-2-ol From 38 g magnesium and 222 g methyl iodide in 1.2 L diethyl ether and 116 g (2,4,6-trimethyl -phenyl) -acetic acid methyl ester 97 g (79%) of the title compound are prepared under standard conditions in a Grignard reaction. Bp 15 = 140 ° C.
    • f) Preparation of N- [1,1-dimethvl-2- (2 4 6-trimethyl-phenyl) -ethyl] -formamide 90 mL glacial acetic acid and 33 g potassium cyanide are combined with ice cooling. 90 mL sulfuric acid and 90 mL glacial acetic acid are then added dropwise at 20 ° C. 65 g of 2-methyl-1- (2,4,6-trimethyl-phenyl) propan-2-ol are slowly added to the solution at a constant temperature. After the addition has ended, the mixture is stirred for a further hour. The mixture is poured onto ice water, neutralized with sodium carbonate solution and extracted with diethyl ether. The solvent is distilled off under reduced pressure and the residue is fractionally distilled. Yield: 55 g (74%); Bp 15 = 155 ° C.
    • g) Preparation of 1,1-Dimethvl-2- (2 4 6-trimethyl-phenyl) -ethylamine 61 gN- [1,1-Dimethyl-2 = (2,4,6-trimethyl-phenyl) -ethyl] - formamide are stirred with 35 g of potassium hydroxide in 155 ml of ethylene glycol under reflux for 9 hours and, after the reaction has ended, added to 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%); Bp 15 = 135-140 ° C.
    • h) Preparation of 2- [1,1-dimethvl-2- (2,4,6-trimethyl-phenyl) -ethlaminol-1- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxole] 5-yl) -ethanone 42.5 g α-bromo-2-methoxy-3,4-diphenylmethylene dioxyacetophenone with 22 g of 1,1-dimethyl-2- (2,4,6-trimethyl-phenyl) ethylamine and 17 g potassium carbonate in 150 mL ethanol and 50 mL acetonitrile 3 Hours under reflux touched. The solids are filtered off and the solvent is reduced Pressure distilled off. The residue is dissolved in a little acetonitrile and with ethereal hydrochloric acid added. The crystals that precipitate are filtered off with acetonitrile and washed with ethyl acetate. Yield: 25 g (44%; hydrochloride); Mp = 240-250 ° C.
    • i) Preparation of 1- (3,4-dihydroxy-2-methoxv-ghenyl) -2- [1 1-dimethyl-2- (2, 4, 6-trimeth 1-phenyl) -ethvlamino] -ethanone 17 g 2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1- (4-methoxy-2,2-diphenylbenzo [1,3] dioxol-5- y1) -ethanone hydrochloride are refluxed with 170 mL 15% methanolic hydrochloric acid for 90 min touched. The solvent is mostly under reduced pressure distilled off. The remaining residue crystallizes out. The crystals are filtered off and washed with diethyl ether. Yield: 10 g (80%; hydrochloride) mp = 199-201 ° C.
    • j) Preparation of 4- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxyethyl} -3-methoxv-benzene-1,2- diol 9 g 1- (3,4-Dihydroxy-2-methoxyphenyl) -2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] ethanone hydrochloride are hydrogenated with 0.4 g of platinum (IV) oxide in 125 ml of methanol. The The catalyst is filtered off and the solvent is reduced Pressure distilled off. The residue is dissolved in 50 mL ethyl acetate and the precipitated crystals are filtered off and with diethyl ether and washed with ethyl acetate. Yield: 6 g (67%, hydrochloride); Mp. = 98-105 ° C.
  • Example 4: 4- [2- (1,1-dimethyl-2-phenylethylamino) -1-hydroxyethyl] -3-methoxybenzene-1,2-diol
    Figure 00100001
    • a) Preparation of 2- (1; 1-dimethyl-phenylethylamino) -1- (4-methoxv-2 2-diphenylbenzof 1,3] dioxol-5-yl) ethanone 45 g of α-bromo-2-methoxy-3,4-diphenylmethylene dioxyacetophenone with 39 g of 1,1-dimethyl-2-phenylethylamine in 200 ml of ethanol 3 hours refluxed. The reaction mixture was concentrated with. Acidified and hydrochloric acid mixed with water. The precipitated crystals are suctioned off and washed successively with water, toluene and ethyl acetate. Yield: 34 g (61%, hydrochloride); Mp = 167-170 ° C.
    • b) Preparation of 1- (3,4-dihydrodroxy-2-methoxyphenyl) -2- (1 1-dimethyl-2-phenyl-ethylamino) -ethanone 34 g of the HCl 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 was the solvent distilled off under reduced pressure and the residue dissolved in ethyl acetate. The failing Solid is suction filtered and washed with ethyl acetate and diethyl ether. Yield: 18 g (77%, hydrochloride); Mp 192-196 ° C.
    • c) Preparation of 4- {2- [1 1-dimethyl-2-phenyl-ethylamino] -1-hydroxy-ethyl} -3-methoxy-benzene-1,2-diol 10 g of 1- (3,4-dihydroxy -2-methoxy-phenyl) -2- (1,1-dimethyl-2-phenylethylamino) ethanone hydrochloride are hydrogenated with 0.5 g PtO 2 in 200 mL methanol. The catalyst is suctioned off and the solvent is distilled off under reduced pressure. The remaining residue is dissolved in 200 ml of acetonitrile, mixed with 5 g of sodium benzoate and refluxed for 15 minutes. After the excess sodium benzoate has been filtered off, the product which has crystallized out of the filtrate is filtered off and washed with acetonitrile and diethyl ether. Yield: 64.5% (benzoate); 149-150 ° C.
  • Example 5: 4- {2- [1,1-dimethyl-2- (2,3 5,6-tetra-methyl-phenyl) -ethylamino] -1-hydroxyethyl} -3-methoxy-benzene-1,2- diol
    Figure 00110001
    • a) Preparation of 2- [1,1-dimethyl-2- (2 3 5 6-tetramethyl-phenyl) -ethylamine] -1- 4-methoxy-2,2-dighenyl-benzo [1,3] dioxol-5-yl) -ethanone 28.5 g α-bromo-2-methoxy-3,4-diphenylmethylene dioxyacetophenone, 11 g of 1,1-dimethyl-2- (2,3,5,6-tetramethylphenyl) ethylamine, and 8 g of sodium carbonate are dissolved in a solution for 3 hours 100 mL ethanol and 10 mL acetonitrile refluxed. Then be the inorganic salts are filtered off and the solvent is distilled off. The residue is dissolved in ethyl acetate, with ethereal hydrochloric acid acidified and mixed with diethyl ether. The solid that precipitates becomes filtered off, washed with diethyl ether and then boiled in water. The product is obtained after filtration and drying. yield 11 g (hydrochloride); 194-198 ° C.
    • b) Preparation of 1- (3,4-dihydroxy-2-methoxyphenyl) -2- [1,1-dimethyl-2- (2nd 3 5 6-tetramethylphenyl) ethylamine] ethanone 11 g 2- [1,1-dimethyl-2- (2,3,5,6-tetramethylphenyl) ethylamine] -1- (4-methoxy-2,2-diphenylbenzo [1,3] dioxole- 5-yl) ethanone hydrochloride one leaves in Reflux 110 mL of 15% methanolic hydrochloric acid for 1.5 hours. The crude product is filtered off, washed with acetonitrile and then precipitated from methanol / diethyl ether. Yield: 7 g (hydrochloride); Mp 213-215 ° (decomposition).
    • c) Preparation of 4- {2- [1 1-dimethvl-2- (2,3,5,6-tetra-methylphenyl) ethylamino] -1-hydroxyethyl} -3-methoxy-benzene-1 , 2-diol 7 g of 1- (3,4-dihydroxy-2-methoxyphenyl) -2- [1,1-dimethyl-2- (2,3,5,6-tetramethylphenyl) ethylamine] ethanone- hydrochloride are hydrogenated with 0.2 g platinum (IV) oxide in 100 mL methanol. Then the kata lysator removed by filtration and the solvent distilled off. The residue is dissolved in 20 ml of water and 1N hydrochloric acid is added. The crystals which precipitate on cooling are filtered off, washed with ice water and, after drying, recrystallized from ethyl acetate. Yield: 5 g; M.p. 165-168 ° C.
  • Example 6: 4- [2- (1,1-Dimethyl-2-o-tolyl-ethylamino-1-hydroxy-ethyl] -3-methoxybenzene-1,2, -diol
    Figure 00120001
    • a) Preparation of 2- (1,1-dimethvl-2-o-tolyl-ethylamine) -1- (4-methoxy-2 2-diphenylbenzo [1,3] dioxol-5-yl) -ethanone 26 g of α-bromo-2-methoxy-3,4-diphenylmethylene dioxyacetophenone, 10 g 1,1-dimethyl-2-o-tolyl-ethylamine and 9.5 g of sodium carbonate is left 3 Reflux for hours in acetonitrile. The inorganic salts are filtered off and the solvent distilled off. The residue is dissolved in ethyl acetate and with ethereal hydrochloric acid acidified the starting amine precipitated and was suctioned off. After adding The product crystallizes from diethyl ether to the filtrate. yield 10 g (30%; hydrochloride); Mp 180-184 ° C.
    • b) Preparation of 1- (3,4-dihydroxy-2-methoxyphenyl) -2- (1 1-dimethyl-2-o-tolylethylamine) ethanone 10 g 2- (1,1-Dimethyl-2-o-tolylethylamine) -1- (4-methoxy-2,2-diphenylbenzo [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 concentrated and the residue is recrystallized from ethyl acetate. The solid present after filtration is washed with diethyl ether washed. Yield 6 g (85%; hydrochloride); Mp 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 1- (3,4-Dihydroxy-2-methoxyphenyl) -2- (1,1-dimethyl-2-o-tolylethylamine) ethanone hydrochloride with 0.2 g platinum (IV) oxide in 50 mL methanol under normal conditions hydrogenated. Subsequently the catalyst is removed by filtration and the solvent distilled off. The residue 100 ml of acetonitrile and 3 g of sodium benzoate are added. you leaves 20 minutes stir under reflux and filtered off the inorganic component. That from the filtrate the product which crystallizes out is filtered off with suction and recrystallized in acetonitrile. Yield 2.4 g (benzoate); Mp 114 ° C.
  • As was found stand out the compounds of general formula 1 through diverse application possibilities in the therapeutic field. Such possible applications should be emphasized for which the compounds of the invention Formula 1 due to its pharmaceutical effectiveness as a beta amimetic can preferably be used. These are, for example the therapy of asthma, COPD (chronic obstructive pulmonary disease), inhibition premature labor pains in obstetrics (tocolysis), restoration the sinus rhythm in the heart with atrio-ventricular block, as well as the remedy bradycal arrhythmia (Antiarrhythmic), therapy of circulatory shock (vascular senescence and increase in cardiac output) and the treatment of itching and inflammation of the skin.
  • The connections of the general Formula 1 can alone or in combination with other active substances according to the invention Formula 1 are used. If necessary, the Compounds of general formula 1 also in combination with others pharmacologically active substances are used. It deals in particular anticholinergics, possibly others Betamimetics, antiallergics, PDE IV inhibitors, PAF antagonists, Leukotriene antagonists and steroids and combinations of active ingredients thereof.
  • As examples of anticholinergics are too call this ipratropium bromide, oxitropium bromide and in particular the tiotropium bromide. Drug combinations in addition to the compounds of the invention Formula 1 contain the tiotropium bromide as another active ingredient are special according to the invention prefers. This combination is of particular importance in the Treatment of asthma or COPD, especially COPD.
  • Suitable forms of application for application of the compounds of formula 1 are, for example, tablets, capsules, suppositories, Solutions, Powder etc. The proportion of pharmaceutically active compounds) should in each case in the range from 0.05 to 90% by weight, preferably 0.1 to 50 % By weight of the total composition.
  • Appropriate tablets can, for example by mixing the active ingredient (s) with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or milk sugar, disintegrants, like cornstarch or alginic acid, Binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or Agents for achieving the depot effect, such as carboxymethyl cellulose, Cellulose acetate phthalate, or polyvinyl acetate can be obtained. The Tablets can also consist of several layers.
  • Coated tablets can be coated accordingly of cores produced analogously to the tablets with usually used in coated tablets Agents, for example kollidon or shellac, gum arabic, Talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities the core also consist of several layers. The same can also the. coated tablet consist of several layers to achieve a deposit effect, using the excipients mentioned above for the tablets can be.
  • juices of the active ingredients according to the invention or combinations of active ingredients can additionally contain a sweetener, such as saccharin, cyclamate, glycerin or sugar as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. she can Moreover Suspending agents or thickeners, such as sodium carboxymethyl cellulose, Wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective substances such as p-hydroxybenzoates.
  • solutions are in more common Manner, e.g. with the addition of isotonants, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants, where, for example, when using water as a diluent optionally organic solvents as a mediator or auxiliary solvents can be used manufactured and in injection bottles or ampoules or infusion bottles bottled.
  • The one or more active ingredients or capsules containing active ingredient combinations, for example be prepared by combining the active ingredients with inert carriers, such as Milk sugar or sorbitol, mix and encapsulate in gelatin capsules.
  • Suitable suppositories can be, for example by mixing with for it provided carriers, such as neutral greases or polyethylene glycol or its derivatives.
  • Examples of auxiliary substances are Water, pharmaceutically acceptable organic solvents, such as paraffins (e.g. petroleum fractions), vegetable oils Origin (e.g. peanut or sesame oil), monofunctional or polyfunctional alcohols (e.g. ethanol or glycerin), excipients such as. natural Rock flours (e.g. kaolins, clays, talc, chalk) synthetic Rock flour (e.g. highly disperse silica and silicates), sugar (e.g. Cane, milk and dextrose) emulsifiers (e.g. lignin, sufite liquor, Methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, Talc, stearic acid and sodium lauryl sulfate).
  • In the case of oral use, the Tablets of course except the carriers mentioned also additives, such as. Sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatin and the like included. Furthermore, lubricants; like magnesium stearate, Sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions can the active ingredients except the above-mentioned excipients with various flavor enhancers or dyes are added.
  • In the preferred according to the invention Application of the compounds of formula 1 for the therapy of asthma or COPD are particularly preferred administration forms that can be administered by inhalation used. Inhalable dosage forms are inhalable powders, MDI containing propellant gas or inhalation solutions free of propellant gas in Consideration. In the context of the present invention are of the term propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions. The Dosage forms that can be used in the context of the present invention are described in detail in the following part of the description.
  • Inhalable powders which can be used according to the invention can contain 1 either alone or in a mixture with suitable physiologically acceptable auxiliaries. If the active ingredients 1 are contained in a mixture with physiologically acceptable auxiliaries, the following physiologically acceptable auxiliaries can be used to prepare these inhalable powders according to the invention:
    Monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligosaccharides and polysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these additives. Mono- or disaccharides are preferably used, the use of lactose or glucose being preferred, in particular, but not exclusively, in the form of their hydrates. Lactose, most preferably lactose monohydrate, is used as an auxiliary as particularly preferred in the sense of the invention.
  • In the context of the inhalable powders according to the invention, the auxiliaries have a maximum average particle size of up to 250 μm, preferably between 10 and 150 μm, particularly preferably between 15 and 80μm. If appropriate, it may appear sensible to add finer excipient tractions with an average particle size of 1 to 9 μm to the excipients mentioned above. The latter finer excipients are also selected from the group of excipients that can be used. Finally, to produce the inhalable powder according to the invention, micronized active ingredient 1, preferably with an average particle size of 0.5 to 10 μm, particularly preferably 1 to 5 μm, is admixed with the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronizing and by finally mixing the constituents are known from the prior art. The inhalable powders according to the invention can be applied using inhalers known from the prior art.
  • Inhalation aerosols containing propellant gas according to the invention can 1 dissolved in the propellant or contained in dispersed form. Here 1 can in separate dosage forms or be contained in a common dosage form, where 1 either solved both both dispersed or only one component dissolved and the other dispersed may be included.
  • For the production of inhalation aerosols usable propellant gases are known from the prior art. suitable Propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-mentioned propellant gases can be used alone or in mixtures the same are used. Particularly preferred propellants are halogenated alkane derivatives selected from TG134a and TG227 and Mixtures of the same.
  • The inhalation aerosols containing propellant gas can also other components such as cosolvents, stabilizers, surface-active Agents (surfactants), antioxidants, lubricants and agents included to adjust the pH. All of these components are known in the art.
  • The above-mentioned propellant gas Inhalation aerosols can using inhalers known in the prior art (MDIs = metered dose inhalers).
  • Furthermore, the application of the active compounds according to the invention 1 in the form of propellant-free inhalation solutions and inhalation suspensions. As a solvent come to this watery or alcoholic, preferably ethanolic solutions. The solvent can only Be water or it is a mixture of water and ethanol. The relative proportion of ethanol compared Water is not limited, but the maximum limit is preferred at up to 70 percent by volume, in particular up to 60 percent by volume and particularly preferred at up to 30 percent by volume. The remaining Volume percentages are filled up by water. The 1 containing solutions or Suspensions are adjusted to a pH of with suitable acids 2 to 7, preferably from 2 to 5. To. Setting this pH value can acids selected from inorganic or organic acids are used. Examples for special suitable inorganic acids are hydrochloric acid, Bromwasserstoftsäure, Nitric acid, Sulfuric acid and / or Phosphoric acid. examples for particularly suitable organic acids are: ascorbic acid, Citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic and other. Preferred inorganic acids are hydrochloric acid, sulfuric acid. It can also the acids can be used with an acid addition salt already with one of the active ingredients form. Among the organic acids are ascorbic acid, fumaric acid and citric acid prefers. If necessary, you can also mixtures of the acids mentioned are used, especially in cases of acids, in addition to their acidifying properties other properties, e.g. as flavors, antioxidants or have complexing agents such as citric acid or Ascorbic acid. According to the invention particularly hydrochloric acid is preferred PH adjustment used.
  • In these formulations, if necessary on the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as Stabilizer or complexing agent can be dispensed with. Other embodiments include this connection (s). In such a preferred embodiment the content based on sodium edetate is less than 100 mg / 100 ml, preferably below 50 mg / 100 ml, particularly preferably below 20 mg / 100 ml. Inhalation solutions are generally preferred in which the content of sodium edetate is 0 to 10 mg / 100 ml.
  • Co-solvents and / or other auxiliaries can be added to the propellant-free inhalation solutions. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. In this context, auxiliaries and additives are understood to mean any pharmacologically acceptable substance which is not an active substance but can be formulated together with the active substance (s) in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation. These substances preferably have no or no significant or at least no undesirable pharmacological effect in the context of the desired therapy. The auxiliaries and additives include, for example, surface-active substances, such as, for example, soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives, which the ver Ensure or extend the duration of use of the finished pharmaceutical formulation, flavorings, vitamins and / or other additives known in the prior art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
  • The preferred auxiliaries include antioxidants, such as ascorbic acid, if not already for used the adjustment of pH, vitamin A, vitamin E, tocopherols and similar Vitamins or provitamins occurring in the human organism.
  • Preservatives can be used to protect the formulation from contamination with germs. As Preservatives are known from the prior art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or Benzoates such as sodium benzoate in the known from the prior art Concentration. The above preservatives are preferably in concentrations of up to 50mg / 100ml, especially preferably contain between 5 and 20 mg / 100ml.
  • Preferred formulations included except the solvent Water and the active ingredient 1 only benzalkonium chloride and sodium edetate.
  • In another preferred embodiment sodium edetate is dispensed with.
  • The dosage of the compounds according to the invention is naturally strong depends on the type of application and the disease to be treated. at The compounds of the formula are distinguished by inhalation 1 already with doses in the μg range by a high effectiveness. Above the μg range, too Use compounds of formula 1 sensibly. The dosage can then, for example, also be in the gram range.
  • The following formulation examples illustrate the present invention without, however, in its Restrict scope:
  • pharmaceutical formulation Examples
    • A) tablets per tablet active substance 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg
      The finely ground active ingredient, milk sugar and part of the corn starch are mixed together. The mixture is sieved, whereupon it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the rest of the corn starch and the magnesium stearate are sieved and mixed together. The mixture is compressed into tablets of a suitable shape and size.
    • B) tablets per tablet active substance 80 mg lactose 55 mg corn starch 190 mg Microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg Sodium carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg
      The finely ground active ingredient, part of the corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the rest of the corn starch and water to form a granulate which is dried and sieved. The sodium carboxymethyl starch and the magnesium stearate are added, and the mixture is mixed and pressed into tablets of a suitable size.
    • C) Amgullenlösung active substance 50 mg sodium chloride 50 mg Aqua per inj. 5 ml
      The active ingredient is dissolved in water at its own pH or, if appropriate, at pH 5.5 to 6.5, and sodium chloride is added as an isotonic agent. The solution obtained is filtered pyrogen-free and the filtrate is filled into ampoules under aseptic conditions, which are then sterilized and sealed. The ampoules contain 5 mg, 25 mg and 50 mg of active ingredient.
    • D) metered dose inhaler Wirkstoft 0.005 trioleate 0.1 Monofluorotrichloromethane and TG 134a: TG227 2: 1 ad 100
      The suspension is filled into a conventional aerosol container with a metering valve. 50 μl of suspension are preferably dispensed per actuation. If desired, the active ingredient can also be dosed in higher amounts (for example 0.02% by weight).
    • e) Solutions (in mg / 100ml) Wirkstoft 333.3 mg tiotropium 333.3 mg benzalkonium chloride 10.0 mg EDTA 50.0 mg HCI (1 n) ad pH 3.4
      This solution can be prepared in the usual way.
    • F) inhalation powder active substance 6 μg tiotropium 6 μg Lactose monohydrate ad 25 mg
  • The manufacture of the inhalation powder takes place in the usual Way by mixing the individual components.

Claims (14)

  1. Compounds of the general formula 1
    Figure 00220001
    R 1 C 1 -C 4 alkyl; R 2 C 1 -C 4 alkyl; R 3 C 1 -C 4 alkyl or phenyl, which can optionally be mono- or polysubstituted, or R 2 and R 3 together form a divalent group selected from -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 mean.
  2. Compounds of formula 1 according to claim 1, wherein R 1 is C 1 -C 4 alkyl; R 2 C 1 -C 4 alkyl; R 3 is C 1 -C 4 alkyl or phenyl, which may optionally be mono-, di-, tri- or tetra-substituted by one or more radicals selected from C 1 -C 3 alkyl, CF 3 , methoxy, ethoxy, hydroxy, Fluorine, chlorine, bromine, -OCF 3 , -CHF 2 , -NHCOCH 3 and -NHS0 2 CH 3 , or R 2 and R 3 together form a divalent group selected from -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 mean.
  3. Compounds of general formula 1 according to claim 1 or 2, wherein R 1 is C 1 -C 4 alkyl, preferably methyl; R 2 C 1 -C 4 alkyl; R 3 is C 1 -C 4 alkyl or phenyl, which may optionally be mono-, di-, tri- or tetra-substituted by one or more radicals selected from methyl, ethyl, CF 3 , methoxy, ethoxy and hydroxy, or R 2 and R 3 together denote a divalent group selected from -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 . wherein
  4. Compounds of general formula 1 according to one of claims 1 to 3, wherein R 1 is C 1 -C 4 alkyl, preferably methyl; R 2 C 1 -C 4 alkyl, preferably methyl; R 3 is C 1 -C 4 alkyl, preferably methyl, or phenyl, which may optionally be mono-, di-, tri- or tetra-substituted by one or more radicals selected from methyl, CF 3 , methoxy and hydroxy, or R 2 and R 3 together denote the divalent group -CH 2 -CH 2 .
  5. Compounds of general formula 1 according to one of claims 1 to 4, wherein R 1 is methyl or ethyl, preferably methyl; R 2 methyl; R 3 is methyl, ethyl or phenyl, which may optionally be mono-, di-, tri- or tetrasubstituted by one or more radicals selected from methyl, CF 3 , methoxy and hydroxy, or R 2 and R 3 together form the divalent group - CH 2 -CH 2 mean.
  6. Serbindungen of the general formula 1 according to any one of claims 1 to 5, wherein R 1 is methyl; R 2 methyl; R 3 is methyl or phenyl, which may optionally be mono-, di-, tri- or tetra-substituted by one or more radicals selected from methyl, ethyl and hydroxy, or R 2 and R 3 together form the divalent group -CH 2 -CH 2 -mean.
  7. Compounds of general formula 1 according to one of claims 1 to 6, wherein R 1 is methyl; R 2 methyl; R 3 is methyl or phenyl, or R 2 and R 3 together mean the divalent group -CH 2 -CH 2 .
  8. Compounds of formula 1 according to any one of claims 1 to 7 in the form of the individual optical isomers, mixtures of the individual Enantiomers or racemates and in the form of the free bases or corresponding acid addition salts with pharmacologically acceptable acids.
  9. Use of a compound of the general formula 1 according to one of claims 1 to 8 as a medicine.
  10. Use of a compound of the general formula 1 according to one of claims 1 to 8 for the manufacture of a medicament for the treatment of diseases, in which betamimetics can have therapeutic benefits.
  11. Use of a compound of the general formula 1 according to one of claims 1 to 8 for the manufacture of a medicament for the treatment of asthma, COPD, premature labor pains in obstetrics (tocolysis), atrio-ventricular block and bradycal arrhythmias (Antiarrhythmic), circulatory shocks (vasodilation and increase of cardiac output) and itching and inflammation of the skin.
  12. Pharmaceutical preparations containing as an active ingredient one or more compounds of general formula 1 according to one of claims 1 to 8 optionally in combination with conventional auxiliaries and / or carriers.
  13. Pharmaceutical preparations according to claim 12, characterized in that this in addition to one or more of the compounds of formula 1, at least contain another active ingredient which is selected from the group of Anticholinergics, betamimetics, antiallergics, PAF antagonists, PDEIV inhibitors, leukotriene antagonists and steroids.
  14. Pharmaceutical preparations according to claim 13, characterized in that this in addition to one or more of the compounds of formula 1 also tiotropium bromide included as an active ingredient.
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