NO328207B1 - New anticholinergic agents which may be used as medicaments and methods for their preparation - Google Patents

Description

The present invention relates to new anticholinergic drugs with the general formula 1

in which A, X_ and the residues R<1>, R<2>, R3, R<4>, R<5>, R6 and R<7>, may have the meanings mentioned in the claims and in the description, a method for their manufacture as well as their use as medicine.

Background for the invention

Anticholinergics can be used therapeutically appropriately in several diseases. Here, for example, the therapy of asthma or COPD (chronic obstructive pulmonary disease) must be highlighted. For the therapy of these diseases, WO 92/16528 proposes anticholinergics, which have a scopin, tropenol or also tropin base shell.

The task underlying WO 92/16528 aims at the provision of anticholinergic active compounds, which are characterized by a long sustained action. To solve this problem, WO 92/16528 describes, among other things, benzylic acid esters of scopine, tropenol or also tropine.

For the therapy of chronic diseases, it is often desirable to provide a drug with a longer duration of action. This can usually be achieved by adding the necessary concentration of the active substance in the organism over a longer period of time to achieve a therapeutic effect without having to carry out too often repeated delivery of the drug. The application of an active substance at longer intervals also contributes greatly to the patients' well-being. Particularly desirable is the provision of a drug, which can be therapeutically sensibly used with a single application per day (one-time delivery). Once-a-day application has the advantage that the patient can get used relatively quickly to the regular intake of the drug at certain times of the day.

In order to be used once a day as a medicine, special requirements must be placed on the active substance to be applied. First, the desired onset of action after the drug has been administered should occur relatively quickly, and in the ideal case have as constant an effect as possible over a longer subsequent period of time. On the other hand, the duration of action of the medicine should not significantly exceed a period of approx. one day. In the ideal case, an active ingredient shows such an effect profile that the production of a once-a-day medicinal product, which contains the active ingredient in therapeutically appropriate doses, can be controlled.

It was found that the benzylic acid ester of scopine, tropenol or also tropine described in WO 92/16528 did not satisfy these high requirements. They can, on the basis of their extremely long duration of action, which clearly exceeds the previously mentioned period of approx. a day, not usefully used for once-a-day administration.

It is therefore the task of the present invention to provide new anticholinergics, which, on the basis of their action profile, enable the production of a medicine that can be applied once a day. It is further the task of the invention to provide compounds which are characterized by a relatively rapid onset of action. It is also a task for the invention to provide compounds which, after a rapid onset of action, have a possible constant effect over a subsequent longer period of time. Furthermore, it is the task of the invention to provide compounds whose duration of action does not significantly exceed a period of approx. a day at therapeutically appropriate dosages. Finally, it is a task for the invention to provide compounds that have an action profile, which makes the therapeutic effect easy to control (that is, complete therapeutic effect without the side effect of cumulation of the substance in the organism).

Detailed description of the invention

Surprisingly, it was found that the aforementioned tasks are solved with compounds of the general formula 1, in which the radical R<7> does not mean hydroxy.

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

in which

A means a double-bonded group selected from

X" is an anion with a single negative charge preferably selected from chloride,

bromide, methyl sulfate, 4-toluenesulfonate and methanesulfonate;

R<1> and R<2> which are the same or different are a group selected from methyl, ethyl, n-propyl and iso-propyl which may optionally be substituted with hydroxy

or fluorine;

R3, R<4>, R5 and r6, which are the same or different are hydrogen, methyl, ethyl,

methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CF3, CN, or NO2;

R<7> is methyl, ethyl, methyloxy, ethyloxy, -CH2-F, -CH2-CH2-F, -O-CH2-F,

-0-CH2-CH2-F, -CH2-OH, -CH2-CH2-OH, CF3,

-CH2-OMe, -CH2-CH2-OMe, -CH2-OEt, -CH2-CH2-OEt, -O-CO-Me,

-O-CO-Et, -O-COCF3, fluorine, chlorine or bromine.

Preferred are compounds of the general formula 1,

in which

A means a divalent residue selected from the group consisting of

X" is a single negatively charged anion selected from the group

chloride, bromide and methanesulfonate, preferably bromide,

R<1> and R<2> are the same or different and are a residue selected from the group consisting of methyl,

ethyl, which may optionally be substituted with hydroxy or fluorine,

preferably unsubstituted methyl;

R3, R<4>, R5 and R6 are the same or different and are hydrogen, methyl, ethyl, methyloxy,

ethyloxy, hydroxy, fluorine, chlorine, bromine;

R<7> is methyl, ethyl, methyloxy, ethyloxy or fluoro.

Particularly preferred are compounds of the general formula 1,

in which

A means a divalent residue selected from the group consisting of

X" is bromide;

r<1> and R<2> are the same or different and are a residue selected from methyl and ethyl;

R3, R<4>, R5 and R6 are the same or different and are hydrogen, methyl, methyloxy,

fluorine and chlorine;

R7 is methyl or fluorine.

Preferred according to the invention are compounds of the general formula 1, in which

A means a divalent residue selected from the group consisting of

X ■ is bromide;

R<1> and R<2> are the same or different and are a residue selected from methyl and ethyl, preferably

methyl;

R3, R4, R5 and R<6> are the same or different and are hydrogen, methyl or fluoro;

R7 is methyl or fluorine.

According to the invention, compounds with the general formula 1 are of particular importance, in which

A means a divalent residue selected from the group consisting of

X" is bromide;

R<1> and R<2> are the same or different and are methyl or ethyl, preferably methyl;

R3, R4, R5 and R<6> are the same or different and are hydrogen or fluorine, preferred

hydrogen;

R<7> is hydrogen, methyl or fluorine, preferably methyl.

Subject matter of the invention are the compounds with the formula 1_ possibly in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates.

In the compounds of the general formula 1, the residues R<3>, R<4>, R<5> and R<6>, as long as they do not mean hydrogen, can sit ortho, meta or para with regard to the attachment of "-C-R< 7>" group. Provided that none of the residues R3, R<4>, R5 and R6 means hydrogen, R<3> and R5 are attached preferably in the para position and R<4> and R<6> preferably in the ortho or meta position, especially preferred in meta position. If one of the residues R<3> and R<4> and one of the residues R<5> and R<6> means hydrogen, the other residue is preferably attached in the meta or para position, particularly preferably in the para position. Provided that none of the residues R<3>, R<4>, R5 and R6 means hydrogen, those compounds according to the invention with the general formula 1 are particularly preferred, in which the residues R<3>, R<4>, R<5> and R<6> have the same meaning.

Of particular importance according to the invention are the compounds of the general formula 1, in which the ester substituent on the nitrogen bicycle has oc configuration. These compounds correspond to those with the general formula l^x

According to the invention, the following compounds are of particular importance:

- 2,2-diphenylpropionic acid tropenol ester methobromide; - 2,2-diphenylpropionic acid scopine ester methobromide; - 2-fluoro-2,2-diphenylacetic acid scopine ester methobromide; - 2-fluoro-2,2-diphenylacetic acid tropenol ester methobromide;

Alkyl groups are, unless otherwise stated, branched and straight-chain alkyl groups with 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl or butyl. For designation of the groups methyl, ethyl, propyl or butyl, the abbreviations Me, Et, prop or Bu are also optionally used. Unless otherwise described, the definitions propyl and butyl include all conceivable isomeric forms of the individual residues. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec. butyl and tert.-butyl etc.

Alkylene groups are, unless otherwise stated, branched and straight-chain divalent alkyl bridges with 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene or butylene.

Unless otherwise stated, alkylene-halogen groups are defined as branched and straight-chain divalent alkyl bridges with 1 to 4 carbon atoms, which are substituted one, two or three times, preferably once with a halogen. Correspondingly, branched and straight-chain divalent alkyl bridges with 1 to 4 carbon atoms, which are substituted one, two or three times, preferably once with a hydroxy, are designated as alkylene-OH groups, unless otherwise stated.

Alkyloxy groups are, unless otherwise stated, branched and straight-chain alkyl groups with 1 to 4 carbon atoms, which are linked through an oxygen atom. Examples include: methyloxy, ethyloxy, propyloxy or butyloxy. For designation of the groups methyloxy, ethyloxy, propyloxy or also butyloxy, the abbreviations MeO-, EtO-, propO- or BuO- are possibly also used. Unless otherwise described, the definition propyloxy and butyloxy includes all conceivable isomeric forms of the individual residues. Thus, for example, propyloxy includes n-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy, sec. butyloxy and tert.-butyloxy etc. Possibly, within the scope of the present invention, instead of the term alkyloxy, the term alkoxy is also used. For designation of the groups methyloxy, ethyloxy, propyloxy or also butyloxy, the designations methoxy, ethoxy, propoxy or butoxy are used accordingly.

As alkylene-alkyloxy groups are used, unless otherwise stated, branched and straight-chain divalent alkyl bridges with 1 to 4 carbon atoms, which are substituted one, two or three times, preferably once with an alkyloxy group.

Branched and straight-chain alkyl groups with 1 to 4 carbon atoms, which are linked through an ester group, are referred to as -O-CO-alkyl groups, unless otherwise stated. Underneath, the alkyl groups are directly attached to the carbonyl carbon in the ester group. In an analogous way, the term -O-CO-alkyl-halogen group is understood. The group -O-CO-CF3 stands for trifluoroacetate.

Within the scope of the present invention, halogen stands for fluorine, chlorine, bromine or iodine. Unless otherwise stated, fluorine and bromine apply as preferred halogens. The group CO is referred to as a carbonyl group.

The production of the compounds according to the invention can, as illustrated in the following, take place in part analogously to methods already known in the state of the art (Scheme 1). The carboxylic acid derivatives with the formula 3 are known from the state of the art or can be obtained according to known synthesis methods from the state of the art. If only suitable substituted carboxylic acids are known from the state of the art, the compounds of formula 3 can also be directly obtained from these by acid- or base-catalyzed esterification with the corresponding alcohols or by halogenation with the corresponding halogenation reagents.

Schedule 1:

From the compounds of the formula 2, the esters of the general formula 4 are successfully accessed by reaction with the carboxylic acid derivatives of the formula 3, in which R, for example, stands for chlorine or a C 1 -C 4 -alkyloxy acid residue. If R is equal to C1-C4-alkyloxy, this reaction can for example be carried out in a sodium melt at an elevated temperature, preferably at approx. 50-150°C, particularly preferred at approx. 90-100°C at low pressure, preferably at less than 500 mbar, particularly preferred at less than 75 mbar. Alternatively, instead of the derivatives 3, in which R means C-1-C4-alkyloxy, the corresponding acid chlorides (R equal to Cl) can also be used.

The thereby obtained compounds of formula 4 can be transferred by reaction with the compounds R<2->X, in which R2 and X can have the above-mentioned meanings, to the target compounds of formula 1. The execution of this synthesis step can also be carried out analogously to those in WO 92/16528 described synthesis examples.

As an alternative to the method shown in scheme 1 for the synthesis of the compounds of the formula 4, the derivatives 4, in which the nitrogen bicycle is a scopin derivative, can be obtained by oxidation (epoxidation) of compounds of the formula 4, in which the nitrogen bicycle is a tropenyl residue. According to the invention, this can be done as follows.

The compound 4, in which A stands for -CH=CH-, is suspended in a polar organic solvent, preferably in a solvent selected from the group of N-methyl-2-pyrrolidone (NMP), dimethylacetamide and dimethylformamide, preferably dimethylformamide and then heated to a temperature of approx. 30-90°C, preferably 40-70°C. A suitable oxidizing agent is then added, and it is stirred at a constant temperature for 2 to 8 hours, preferably 3 to 6 hours. Vanadium pentoxide in mixture with H2O2, particularly preferred H2O2-urea complex in combination with vanadium pentoxide is used as an oxidizing agent. Processing takes place in the usual way. Depending on the crystallization tendency, the purification of the products can take place by crystallization or chromatography.

Alternatively, the compounds of formula 4, in which R<7> means halogen, are also available in the manner shown in Scheme 2.

Schedule 2:

For this, the benzylic acid ester of the formula 5 is transferred using suitable halogenating reagents in the compounds 4, in which R<7> means halogen. The implementation of the halogenation reactions to be carried out according to Scheme 2 is sufficiently known in the state of the art.

The benzylic acid ester of the formula 5 is available according to or analogously to the methods known in the state of the art (see e.g. WO 92/16528).

As visible in Scheme 1, the intermediates with the general formula 4 play a central role. Correspondingly, a further aspect of the present invention relates to the intermediate products with formula 4

in which

A means a divalent residue selected from the group consisting of

R<1> is methyl, ethyl, n-propyl and iso-propyl, which may optionally be

substituted with hydroxy or halogen

R3, R4, R5 and R6 are the same or different and are hydrogen, methyl, ethyl,

methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CF3, CN, or NO2;

R<7> is methyl, ethyl, methyloxy, ethyloxy, -CH2-F, -CH2-CH2-F, -0-CH2-F, -0-CH2-CH2-F, -CH2-OH, -CH2-CH2 -OH, CF3, -CH2-OMe, -CH2-CH2-OMe, -CH2-OEt, -CH2-CH2-OEt, -O-CO-Me, -O-CO-Et,

-O-COCF3, fluorine, chlorine or bromine.

Preferred are compounds of the general formula i,

in which

A means a divalent residue selected from the group consisting of

R<1> is a residue selected from the group consisting of methyl, ethyl which may optionally

be substituted with hydroxy or fluorine, preferably unsubstituted methyl;

R3, R<4>, R5 and R6, are the same or different and are hydrogen, methyl, ethyl, methyloxy,

ethyloxy, hydroxy, fluorine, chlorine, bromine;

R<7> is hydrogen, methyl, ethyl, methyloxy, ethyloxy or fluorine.

Particularly preferred are compounds of the general formula 1,

in which

A means a divalent residue selected from the group consisting of

R 1 is a residue selected from methyl and ethyl;

R3, R<4>, R5 and R<6> are the same or different and are hydrogen, methyl, methyloxy,

fluorine or chlorine;

R7 is methyl or fluorine.

According to the invention, preferred compounds are those of the general formula 1, wherein

A means a divalent residue selected from the group consisting of

R<1> is a residue selected from methyl and ethyl, preferably methyl;

R3, R<4>, R5 and R6 are the same or different and are hydrogen, methyl or fluoro;

R7 is methyl or fluorine.

According to the invention, compounds of particular importance are those of the general formula 1, in which

A means a divalent residue selected from the group consisting of

R 1 is methyl or ethyl, preferably methyl;

R3, R4, R<5> and R<6> are the same or different are hydrogen or fluorine, preferred

hydrogen;

R7 is methyl or fluorine, preferably methyl.

As in the compounds with the general formula 1, also in the intermediates with the formula 4 the residues R<3>, R<4>, R<5> and R6, as long as they do not mean hydrogen, can be arranged ortho, meta or para with regard to the attachment to the "-C-OH" group. If none of the residues R<3>, R<4>, R<5> and R<6> means hydrogen, R<3> and R<5> are preferred in the para position and R<4> and R<6> preferably in the ortho or meta position, particularly preferably linked in the meta position. If one of the residues R<3> and R<4> and one of the residues R<5 >and R<6> means hydrogen, the other residue is preferably attached in the meta or para position, particularly preferably in the para position. If none of the residues R<3>, R<4>, R5 and R6 is hydrogen, according to the invention the intermediates with the general formula 4 are particularly preferred, in which the residues R<3>, R<4>, R<5> and R <6> has the same meaning.

The subsequently described synthesis examples serve as further illustration of the present invention.

Example 1: 2. 2- Diphenylpropionylscopine ester methobromide:

1.1.: 2. 2- Pifenvlpropionvrechloride 3a:.

To a suspension of 25.0 g (0.11 mol) of 2,2-diphenylpropionic acid, 100 ml of dichloromethane and 4 drops of dimethylformamide was slowly added dropwise at 20°C 52.08 g (0.33 mol) of oxalyl chloride. It is stirred for 1 h at 20° C. and 0.5 h at 50° C. The solvent is distilled off and the remaining residue used without further purification in the next step.

1. 2. : 2. 2- Diphenylpropionyl scopine ester 4a:

The one from step 1.1. the residue obtained is dissolved in 100 ml of dichloromethane and mixed at 40° C. dropwise with a solution of 51.45 g (0.33 mol) of scopine in 200 ml of dichloromethane. The suspension formed is stirred for 24 h at 40° C., then the precipitate formed is filtered off and the filtrate first extracted with water, then with aqueous hydrochloric acid. The combined aqueous phases are made alkaline with aqueous sodium carbonate solution, extracted with dichloromethane, the organic phase dried over Na 2 SO 4 ) evaporated to dryness and the hydrochloride precipitated from the residue. Purification takes place by recrystallization from acetonitrile.

Yield: 20.85 g (= 47% of theoretical)

DC: Rf value: 0.24 (eluent: sec. butanol/formic acid/water 75:15:10);

M.p.: 203-204°C.

I. 3: 2. 2- Diphenvlpropionvrescopine ester methobromide:

II, 98 g (0.033 mol) 4a , 210 ml of acetonitrile, 70 ml of dichloromethane and 20.16 g (0.1 mol) of 46.92% ig bromomethane in acetonitrile are combined at 20°C and allowed to stand for 3 days. The solution is evaporated to dryness and the residue recrystallized from isopropanol. Yield: 11.34 g (= 75% of theoretical); m.p.: 208-209°C.

C 24 H 28 NO 3 x Br (458.4);

Elemental analysis: calculated: C (62.89) H (6.16) N (3.06)

Found.: C (62.85) H (6.12) N (3.07).

Example 2: 2-Fluoro- 2. 2-diphenvleddicvrescopine ester methobromide:

2. 1: Benzilsvrescopinester 5a:

The production of the benzylic acid scopine ester is known in the art. It is described in WO 92/16528.

2. 2: 2- Fluoro- 2. 2- diphenvleddicvrescopinester 4b:

2.66 g (0.02 mol) of dimethylaminosulfur trifluoride is cooled in 10 ml of dichloromethane to 0°C, and a solution of 5.48 g (0.015 mol) of benzylic acid scopine ester 5a in 100 ml of dichloromethane is added dropwise. It is then stirred for a further 30 min at 0°C and 30 min at 20°C. During cooling, the solution is mixed with water, NaHCO3 added (bis pH 7-8) and the organic phase separated. The aqueous phase is extracted with dichloromethane, the combined organic phases washed with water, dried over Na 2 SO 4 and evaporated to dryness.

The hydrochloride is precipitated from the residue and recrystallized from acetonitrile.

Yield: 6.90 g (= 85% of theoretical)

Melting point: 227°-230° C.

2. 3: 2- fluoro- 2. 2- diphenvleddicvrescopine ester methobromide:

2.88 g (0.0078 mol) of the free base of the benzylic acid scopine ester is reacted analogously to the procedure under step 1.3. The purification is carried out by recrystallization from isopropanol. Yield: 2.62 g (= 73% of theoretical)

DC: Rf value: 0.31 (eluent analogous to step 1.2); m.p.: 130-134°C.

Example 3: 2. 2-diphenylpropionylpropionyl ester methobromide:

3. 1. : 2. 2- diphenvlpropionvremetvlester 3b:.

To the suspension of 50.8 g (0.225 mol) of 2,2-diphenylpropionic acid and 200 ml of acetonitrile, 37.60 g (0.247 mol) of DBU are added dropwise at 20°C. 70.10 g (0.494 mol) methyl iodide is added dropwise to the solution formed over the course of 30 minutes. It is then stirred overnight at 20° C. The solvent is evaporated, the residue extracted with diethyl ether/water, the organic phase washed with water, dried over Na 2 SO 4 and evaporated to dryness. Yield: 48.29 g of viscous residue 32 (= 89% of theory).

3. 2: 2. 2- diphenylpropionylpropionyl ester 4c:

4.80 g (0.02 mol) 2,2-diphenylpropionyl ester 3b. 2.78 g (0.02 mol) of tropenol and 0.046 g of sodium are heated as a melt at 75 mbar for 4 h on a boiling water bath with occasional shaking. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness and the residue is extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO 4 and evaporated to dryness. From the residue, 4c is precipitated as hydrochloride, and this is recrystallized from acetone.

Yield: 5.13 g (= 67% of theoretical);

DC: Rf value: 0.28 (eluent: sec. butanol/formic acid/water 75:15:10);

M.p.: 134-135°C.

3. 3: 2. 2- Diphenylpropionylpropionyl ester methobromide:

2.20 g (0.006 mol) 4c is reacted analogously to Example 1, step 1.3. The formed crystals are filtered off, washed with dichloromethane, dried and then recrystallized from methanol/diethyl ether.

Yield: 1.84 g (=66% of theoretical)

DC: Rf value: 0.11 (eluent analogous to step 1.2); m.p.: 222-223°C. C24H28N02xBr (442.4);

Elemental analysis: calculated: C (65.16) H (6.38) N (3.17)

found.: C (65.45) H (6.29) N(3.16).

Example 4: 2- fluoro- 2. 2- bis( 3. 4- difluorophenyl) acetic acid red phenol ester methobromide

4. 1 . :3. 3'. 4. 4'- tetrafluorobenzylsulfide ester 3c:.

The preparation of the Grignard Reagent takes place from 2.24 g (0.092 mol) magnesium shavings, a few grains of iodine and 17.80 g (0.092 mol) 1-bromo-3,4-difluoro-benzene in 100 ml of THF at 50°C. After the addition of the halide is finished, it is stirred for another hour. The Grignard reagent thus obtained is added dropwise to 18.81 g (0.088 mol) of 3,4-difluorophenylglyoxylic acid ethyl ester in 80 ml of THF at 10°-15° C and the mixture obtained is stirred for 2 hours at 5° C.

The white suspension is completely worked up on ice/sulfuric acid, extracted with ethyl acetate, the organic phase washed with water, dried over MgSO4 and evaporated to dryness, the purification of the crude product is carried out by column chromatography (eluent: toluene).

Yield: 10.80 g of oil 1 (= 38% of theoretical)

4. 2. : 3. 3'. 4. 4'- tetrafluorobenzyl red tropphenol ester 5b:

4.27 g (0.013 mol) 3,3',4,4,-tetrafluorobenzylic acid ethyl ester 3c, 1.81 g (0.013 mol) tropenol and 0.03 g sodium are heated as a melt at 75 mbar for 4 h on a boiling water bath with shaking occasionally. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness and the residue is extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO 4 and evaporated to dryness.

The remaining residue is mixed with diethyl ether/petroleum ether 1:9, filtered off and washed. Yield: 2.50 g (= 46% of theoretical);

DC: Rf value: 0.29 (eluent: sec. butanol/formic acid/water 75:15:10);

M.p.: 147°-148°C.

4. 3: 2- fluoro- 2. 2- bis( 3. 4- difluorophenyl) acetic acid red phenol ester 4d:

2.66 g (0.012 mol) of bis-(2-methoxyethyl)-aminosulfur trifluoride was placed in 10 ml of dichloromethane and during 20 minutes at 15°-20° C mixed dropwise with a solution of 0.01 mol of 5b in 65 ml dichloromethane.

It is stirred for 20 h at room temperature, cooled to 0° C and carefully mixed with 80 ml of water while stirring well. The pH is then adjusted carefully with aqueous NaHCO 3 solution to pH 8, the organic phase is separated, the aqueous phase is extracted again with dichloromethane, the combined organic phases are washed with water, dried over MgSC-4 and evaporated to dryness. The hydrochloride is precipitated and recrystallized from acetonitrile/diethyl ether.

Yield: 2.60 g of white crystals (= 57% of theory)

M.p.: 233° C

4. 4: 2- fluoro- 2. 2- bis( 3. 4- difluorophenyl) acetic acid red phenol ester methobromide:

2.20 g (0.0052 mol) 4d is reacted analogously to Example 1, step 1.3. The formed crystals are sucked off, washed with dichloromethane, dried and then recrystallized from methanol/diethyl ether.

Yield: 1.95 g (=72% of theoretical)

DC: Rf value: 0.17 (eluent: n-butanol/water/formic acid (conc.)/acetone/dichloromethane 36:15:15:15:5); m.p.: 247°C.

C 23 H 2 i F 5 NO 2 x Br (518.3);

Elemental analysis: calculated: C (53.30) H (4.08) N (2.70)

found.: C (53.22) H (4.19) N (2.69).

Example 5: 2. 2- diphenylpropionylscopine ester-ethylbromide:

1.81 g (0.005 mol) 4a , 35 ml of acetonitrile and 1.64 g (0.015 mol) of ethyl bromide are combined at 20°C and allowed to stand for 3 days. The solution is evaporated to dryness and the residue recrystallized from ethanol.

Yield: 1.38 g (= 58% of theoretical); m.p.: 208-209°C.

DC: Rf value: 0.33 (eluent analogous to step 1.2); m.p.: 210-211°C. C 25 H 30 NO 3 x Br (472.42);

Elemental analysis: calculated: C (63.56) H (6.40) N (2.96)

found.: C (63.49) H (6.24) N (2.88).

Example 6: 2-fluoro-2.2-bis(3,4-difluorophenyl)acetic acid ester methobromide:

6. 1. : 3. 3'. 4, 4'- tetrafluorobenzylic acid scopine ester 5c:

3.61 g (0.011 mol) of 3,3',4,4-tetrafluorobenzyl<y>reet<y>ester 3c , 1.71 g (0.011 mol) of scopine and 0.03 g of sodium are heated as a melt at 75 mbar 4 h in a boiling water bath, shaking occasionally. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness and the residue is extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO 4 and evaporated to dryness. The remaining residue is mixed with diethyl ether/petroleum ether 1:9, filtered off and washed. Yield: 1.75 g (= 36% of theoretical);

M.p.: 178-179°C.

6. 2: 2- fluoro- 2. 2- bis( 3. 4- difluorophenyl) acetic acid ester 4e:

0.6 ml (0.0033 mol) bis-(2-methoxyethyl)-aminosulfur trifluoride is reacted with 1.2 g (0.0028 mol) 5c analogously to Example 4, step 4.3.

Yield: 1.15 g colorless oil (= 95% of theory)

6. 3: 2- fluoro- 2. 2- bis( 3. 4- difluorophenyl) acetic vrescopine ester- methobromide:

1.15 g (0.0026 mol) 4e and 1.5 g (0.0079 mol) 50% methyl bromide solution are reacted analogously to Example 1, step 1.3. The formed crystals are sucked off, washed with dichloromethane, dried and then recrystallized from acetone.

Yield: 0.88 g (=63% of theoretical)

DC: Rf value: 0.27 (eluent: n-butanol/water/formic acid (conc.)/acetone/dichloromethane 36:15:15:15:5); m.p.: 212°C.

C 23 H 2 I F 5 NO 3 x Br (535.33);

Example 7: 2-fluoro-2.2-bis(4-fluorophenyl)acetic acid red phenol ester methobromide:

7. 1. : 4, 4'- difluorobenzylsvremetvlester 3d:.

7.1.1. : 4,4'-difluorobenzyl acid:

To a solution of 49.99 g (1.25 mol) NaOH-Pletzchen in 300 ml of water, drip at approx. 100°C a solution of 24.62 g (0.1 mol) 4,4'-difluorobenzyl in 250 ml dioxane and stirred for 2 h. The dioxane is mainly distilled off and the remaining aqueous solution extracted with dichloromethane. When the aqueous solution is acidified with sulfuric acid, a precipitate falls out, which is filtered off, washed and dried. The filtrate is extracted with dichloromethane, the organic phase dried over Na 2 SO 4 and evaporated to dryness. Yield: 25.01 g (= 95% of theoretical); m.p.: 133°-136° C

7.1.2. : 4,4'-difluorobenzyl acid methyl ester:

To a freshly prepared sodium ethanolate solution from 2.17 g (0.095 mol) sodium and 200 ml ethanol, add 25.0 g (0.095 mol) 4,4'-difluorobenzyl acid at 20°C and stir for 3 h. The solution is evaporated to dryness, the remainder dissolved in DMF, at 20° C mixed dropwise with 22.57 g (0.16 mol) methyl iodide and stirred for 24 h. Work-up and purification are carried out analogously to compound 3b. Yield: 21.06 g 11 (= 80% of theoretical)

7. 2. : 4. 4'- difluorobenzyl red phenolic ester 5d:

11.13 g (0.04 mol) of 4,4'-difluorobenzyl acid methyl ester 3d and 5.57 g (0.04 mol) of tropenol are reacted with 0.09 g of sodium analogously to Example 3, step 3.2. The product is recrystallized from acetonitrile.

Yield: 10.43 g (= 62% of theoretical);

M.p.: 233-235°C.

7. 3: 2- fluoro- 2. 2- bis( 4- fluorophenyl)- acetic vretropenoyl ester 4f:

2.94 g (0.013 mol) bis-(2-methoxyethyl)-aminosulfur trifluoride is reacted with 3.85 g (0.01 mol) 5d analogously to Example 4, step 4.3 in 100 ml dichloromethane. The product is recrystallized in the form of its hydrochloride from acetonitrile.

Yield: 2.93 g (= 69% of theoretical)

7. 4: 2- fluoro- 2. 2- bis( 4- fluorophenyl)- acetic vretrophenol ester- methobromide:

2.6 g (0.0067 mol) 4f and 1.9 g (0.0079 mol) 50% methyl bromide solution are reacted analogously to Example 1, step 1.3. The formed crystals are sucked off, washed with dichloromethane, dried and then recrystallized from methanol/diethyl ether.

Yield: 2.82 g of white crystals (=87% of theory)

DC: Rf value: 0.55 (eluent: according to Example 1, step 1.2);

M.p.: 230-231 °C.

C23H23F3N02xBr (482.34);

Elemental analysis: calculated: C (57.27) H (4.81) N (2.90)

found.: C (57.15) H (4.84) N (2.96).

Example 8: 2-fluoro-2.2-bis(4-fluorophenyl)acetic acid ester methobromide:

8. 1: 4. 4'- difluorobenzylscrescopine ester 5e:

4.22 g (0.01 mol) of 4,4'-difluorobenzyl red phenol ester 5d is slurried in 80 ml of DMF. At approx. 40°C internal temperature becomes a solution of 2.57 g (0.0273 mol) H202-urea in 20 ml of water, as well as 0.2 g (0.0011 mol) vanadium (V)-oxide added and stirred 4, 5 h at 60°C. After cooling to 20°C, the formed precipitate is filtered off, the filtrate adjusted to pH 3 with 4 N hydrochloric acid and mixed with Na2S2O5 dissolved in water. The resulting green solution is evaporated to dryness, the residue extracted with dichloromethane/water. The acidic aqueous phase is made basic with Na 2 CO 3 , extracted with dichloromethane, and the organic phase dried over Na 2 SO 4 and concentrated.

This is followed by the addition of 0.5 ml of acetyl chloride at approx. 15°C and stirring for 1.5 h. After extraction with 0.1 N hydrochloric acid, the aqueous phase is made basic, extracted with dichloromethane, the organic phase is dried over Na 2 SO 4 and evaporated to dryness. From the residue, the hydrochloride is precipitated and recrystallized from methanol/diethyl ether.

Yield: 3.61 g of white crystals (= 78% of theory);

M.p.: 243-244°C.

8. 2: 2- fluoro- 2. 2- bis( 4- fluorophenvn- acetic vrescopinester 4q:

1.48 g (0.0067 mol) of bis-(2-methoxyethyl)-aminosulfur trifluoride is reacted with 2.0 g (0.005 mol) of 5e analogously to Example 4, step 4.3 in 80 ml of dichloromethane. The product is recrystallized in the form of its hydrochloride from ethanol.

Yield: 2.07 g (= 94% of theoretical); m.p.: 238-239°C.

8. 3: 2- fluoro- 2. 2- bis( 4- fluorophenyl)- acetic acid ester methobromide

1.6 g (0.004 mol) 4g and 1.14 g (0.0079 mol) 50% methyl bromide solution are reacted analogously to Example 1, step 1.3. The formed crystals are sucked off, washed with dichloromethane, dried and then recrystallized from acetonitrile.

Yield: 1.65 g of white crystals (=61% of theory)

DC: Rf value: 0.25 (eluent: according to Example 1, step 1.2); M.p.: 213-214°C.

C23H23F3N03xBr (498.34);

Elemental analysis: calculated: C (55.43) H (4.65) N (2.81)

found.: C (54.46) H (4.67) N (2.80).

Example 9: 2- fluoro- 2. 2- diphenvled acetic acid propylene ester methobromide:

9. 1. : benzyl red phenol esters 5f:.

The benzylic acid tropenol ester and the method for its production are known from WO 92/16528.

9. 2: 2- fluoro- 2. 2- diphenvleddiacetic acid phenolic esters 4h:

15.86 ml (0.086 mol) of bis-(2-methoxyethyl)-aminosulfur trifluoride is reacted with 25 g (0.072 mol) of 5f analogously to Example 4, step 4.3 in 480 ml of chloroform. The product is recrystallized in the form of its hydrochloride from acetone. Yield: 18.6 g of white crystals (= 67% of theory);

M.p.: 181-182°C;

9. 3: 2- fluoro- 2, 2- diphenyl- acetic acid vretropenolester- methobromide:

11.12 g (0.032 mol) 4h and 18.23 g (0.096 mol) 50% methyl bromide solution are reacted analogously to Example 1, step 1.3. The crystals formed are recrystallized from acetonitrile.

Yield: 11.91 g of white crystals (=83% of theory)

DC: Rf value: 0.4 (eluent: according to Example 4, step 4.4);

M.p.: 238-239°C.

C23H25FN02xBr (446.36);

Elemental analysis: calculated: C (61.89) H (5.65) N (3.14)

found.: C (62.04) H (5.62) N(3.17).

Example 10: 2-Fluoro-2,2-(3-Chlorophenyl) acetic acid red phenol ester methobromide:

10. 1. :3. 3'-dichlorobenzylsvremetvlester 3e:.

10.1.1. : 3,3'-dichlorobenzyl:

100 ml of ethanol is placed at room temperature and 50.0 g (0.356 mol) of 3-chlorobenzaldehyde and 4.54 g (0.018 mol) of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide are added. Then 10.7 g (0.11 mol) of triethylamine are added dropwise. It is boiled for 3 hours under reflux and evaporated to dryness. The residue is taken up in ethyl acetate and extracted with water, sodium pyrosulphite in water and Na 2 CO 3 solution. After drying over MgSO4, it is evaporated to dryness. The product obtained is recrystallized from isopropanol and petroleum ether.

Yield: 13.2 g of white crystals (= 13% of theory); m.p.: 69-70°C.

13.0 g of the acyloin thus obtained is dissolved in 460 ml of acetonitrile at RT, 0.0867 g of vanadium-(V)-oxytrichloride added and oxygen introduced. After 1.5 h, the solution is evaporated to dryness, extracted with ethyl acetate and water, as well as Na2CO3 solution, over dried MgSO4 and evaporated to dryness. The remaining residue is stirred out with petroleum ether/ethyl acetate 95:5.

Yield: 12.59 g of yellow crystals (= 97% of theory); m.p.: 116-117°C.

10.1.2. : 3,3'-dichlorobenzyl acid:

51.45 g (1.286 mol) of sodium hydroxide in 1000 ml of water are placed under good stirring in a boiling water bath and a solution of 28.5 g (0.102 mol) of 3,3'-dichlorobenzyl in 700 ml of dioxane is added dropwise and then stirred for 1 h to.

After cooling, the dioxane is evaporated, the residue diluted with water and extracted with diethyl ether. The organic phase is made acidic, extracted with dichloromethane, dried over MgSO 4 , evaporated to dryness.

Yield: 32.7 g (= 71% of theoretical).

10.1.3.: 3,3'-dichlorobenzyl acid methyl ester:

From 100 ml of ethanol and 1.97 g (0.0855 mol) of sodium, a sodium ethanolate solution is prepared, to which 26.6 g (0.0855 mol) of 3,3'-dichlorobenzyl acid in 50 ml of ethanol is added dropwise. It is then stirred for 4 hours at room temperature. After distilling off the solvent, the residue is dissolved in 150 ml of DMF and 24.27 g (0.171 mol) methyl iodide is added dropwise and then stirred for a further 24 h. Under ice cooling, 300 ml of water and 200 ml of diethyl ether are added dropwise, the phases are separated, the water phase is extracted with diethyl ether, then the organic phase washed with Na 2 CO 3 solution and shaken neutral with water. After drying over Na2S04, it is evaporated to dryness. Yield: 22.91 g yellow oil (= 82% of theoretical).

10. 2. : 3. 3'- Dichlorobenzyl red phenol ester 5a:

22.9 g (0.074 mol) 3,3'-dichlorobenzyl acid methyl ester 3e, 15.37 g (0.11 mol) tropenol and 0.17 g sodium are heated as a melt at 75 mbar for 4 h on a boiling water bath with occasional shaking . After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness and the residue is extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO 4 and evaporated to dryness. The product is recrystallized in the form of its hydrochloride from acetonitrile. Yield: 16.83 g of white crystals (= 50% of theory);

M.p.: 184-185°C.

10. 3: 2- fluoro- 2. 2- bis( 3- chlorophenyl) acetic acid red phenol ester 4i:

1.48 g (0.0067 mol) of bis-(2-methoxyethyl)-aminosulfur trifluoride is placed in 10 ml of dichloromethane and mixed dropwise over 20 minutes at 15°-20°C with a solution of 2.09 g of 5fl in 65 ml dichloromethane.

It is stirred for 20 h at room temperature, cooled to 0° C and carefully mixed with 80 ml

water while stirring well. It is then carefully adjusted with aqueous NaHCO 3 solution to pH 8, the organic phase separated, the aqueous phase re-extracted with dichloromethane, the combined organic phases washed with water, dried over MgSO 4 and evaporated to dryness. The hydrochloride is precipitated and recrystallized from aceto n itri l/di iety I ete r.

Yield: 1.20 g of white crystals (= 53% of theory)

Melting point: 136-137° C

10. 4: 2- fluoro- 2. 2- bis( 3- chlorophenv0acetic acid propylene ester methobromide:

1.0 g (0.002 mol) 4h is reacted analogously to Example 1, step 1.3. The formed crystals are sucked off, washed with dichloromethane, dried and then recrystallized from methanol/diethyl ether.

Yield: 0.82 g of white crystals (=80% of theoretical)

DC: Rf value: 0.14 (eluent: n-butanol/water/formic acid (conc.)/acetone/dichloromethane 36:15:15:15:5); m.p.: 180-181°C.

C23H23Cl2FN02xBr (515.25);

As it was found, the compounds of the general formula 1 are distinguished by many possibilities of application in the therapeutic field. Such application possibilities must be highlighted, for which the compounds according to the invention with formula 1, on the basis of their pharmaceutical effect, can preferably be used as anticholinergics.

This is, for example, therapy for asthma or COPD (chronic obstructive pulmonary disease). The compounds with the general formula 1 can further be used for the treatment of vagally conditioned sinus bradycardia and for the treatment of heart rhythm disturbances. In general, the compounds according to the invention can also be used for the treatment of spasms, for example in the gastrointestinal tract with therapeutic benefit. They can also be used to treat spasms in the ureters as well as, for example, menstrual complaints. Among the indication areas listed above, for example, the therapy of asthma and COPD using the compounds according to the invention with the formula 1 is particularly important. The compounds with the general formula 1 can be used alone or in combination with other active substances according to the invention with the formula 1. Optionally, the compounds with the general formula 1 can also be used in combination with further pharmacologically active active substances.

This includes, in particular, betamimetics, antiallergics, PAF antagonists, leukotriene antagonists and corticosteroids, as well as active ingredient combinations thereof.

Examples of betamimetics, which according to the invention can be used in combination with the compounds of formula 1, are compounds selected from the group consisting of bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, Ibuterol, pirbuterol, procaterol, reproterol, salmeterol , sulfonerol, terbutaline, tolubuterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl)-2-[4-(1 -benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1 -[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2 -[4-(1-benzimidazolyl)-2-methyl-2-butylaminoethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-( 4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3- (4-Methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4- n-butyloxyphenyl)-2-methyl-2-propylaminoethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1 - hydroxy-2 -isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1 -(4-amino-3-chloro-5-trifluoromethylphenyl)-2-fet.-butylamino)ethanol and 1 -( 4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(fetr.-butylamino)ethanol, optionally in the form of their racemates, their enantiomers, their diastereomers, as well as optionally their pharmacologically acceptable acid addition salts and hydrates. Particularly preferred as betamimetics are such active substances in combination with the compounds according to the invention with the formula 1 for use, which are selected from the group consisting of fenoterol, formoterol, salmeterol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]- 2-[4-(1-benzimidazolyl)-2-methyl-2-butylaminoethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3- (4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3 -(4-Methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4 -n-butyloxyphenyl)-2-methyl-2-propylaminoethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4 -methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, optionally in the form of their racemates, their enantiomers, their diastereomers, as well as optionally their pharmacologically acceptable acid addition salts and hydrates. Among the aforementioned betamimetics, the compounds formoterol and salmeterol, possibly in the form of their racemates, their enantiomers, their diastereomers, and possibly their pharmacologically acceptable acid addition salts and hydrates are of particular importance.

According to the invention, the acid addition salts of betamimetics are preferred which are selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate methanesulfonate and xinafoate. In the case of salmeterol, the salts are particularly preferred

hydrochloride, sulfate and xinafoate, of which the sulfates and xinafoates are particularly preferred. According to the invention, salmeterol x Vfe H2SO4 and salmeterol xinafoate are of prominent importance. Particularly preferred are the salts in the case of formoterol chosen from hydrochloride, sulphate and fumarate, of which the hydrochloride and fumarate are particularly preferred. According to the invention, formoterol fumarate is of prominent importance.

Within the scope of the present invention, corticosteroids are understood to mean the compounds which may be used in combination with the compounds of formula 1, which are selected from the group consisting of flunisolide, beclometasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW 215864 , KS R 592, ST-126 and dexamethasone. Preferred within the scope of the present invention are the corticosteroids selected from the group consisting of flunisolide, beclometasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexamethasone, under which here budesonide, fluticasone, mometasone and ciclesonide, especially budesonide and fluticasone have a particular meaning. Possibly, within the scope of the present patent application, instead of the term corticosteroids, only the term steroids is used. A reference to steroids includes within the scope of the present invention a reference to salts or derivatives which can be formed from the steroids. Examples of possible salts or derivatives are: sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. Optionally, the corticosteroids can also be present in the form of their hydrates.

Within the scope of the present invention, dopamine agonists are understood to mean compounds which can possibly be used in combination with the compounds of formula 1, which are selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocriptine, lisuride, pergolide, pramipexole, roxyndole, ropinirole , talipexole, terguride and viozan. Within the scope of the present invention, dopamine agonists are preferably used as combination partners with the compounds of formula 1, which are selected from the group consisting of pramipexole, talipexole and viozan, under which pramipexole is given special importance. A reference to the aforementioned dopamine agonists includes within the scope of the present invention a reference to their possibly existing pharmacologically acceptable acid addition salts and possibly their hydrates. Under the physiologically acceptable acid addition salts, which can be formed from the aforementioned dopamine agonists, is meant, for example, pharmaceutically acceptable salts, which are selected from the salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid .

As examples of antiallergic drugs which according to the invention can be used with the compounds of formula 1 as a combination, epinastin, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipin, cexchlorpheniramine, pheniramine, doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozine. Preferred antiallergic drugs, which within the scope of the present invention can be used in combination with the compounds according to the invention with formula 1, are selected from the group consisting of epinastin, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratidine and mizolastine, among which epinastin and desloratidine is particularly preferred. A reference to the aforementioned antiallergic drugs includes within the scope of the present invention a reference to their possibly existing pharmacologically acceptable acid addition salts.

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

6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f ][1,2,4]triazolo[4,3-a][1,4]diazepine.

If the compounds of formula 1 are used in combination with other active substances, of the previously mentioned compound classes the combination with steroids or betamimetics is particularly preferred. The combination with betamimetics, especially with long-acting betamimetics, takes on special significance. Combination of the compounds according to the invention with formula 1 with salmeterol or formoterol is considered particularly preferred, with the combination with formoterol being most preferred.

Suitable application forms for application of the compounds of formula 1 are, for example, tablets, capsules, suppositories, solutions, etc.

Of particular importance according to the invention (especially in the treatment of asthma or COPD) is application by inhalation of the compounds according to the invention. The proportion of the pharmaceutically active compound(s) should lie in the range from 0.05 to 90% by weight, preferably 0.1 to 50% by weight of the total composition. Similarly, tablets can for example be prepared by mixing the active substance or active substances with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and/or agents for obtaining of depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Similarly, dragees can be produced by coating cores produced analogously to

the tablets with commonly used agents in dragee coatings, for example collidon or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Similarly, the dragee sleeve for achieving a depot effect can also consist of several layers, under which the excipients mentioned above for the tablets can be used.

Juices of the active substances or the active substance combination according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar as well as a taste-enhancing agent, e.g. flavoring substances, such as vanillin or orange extract. They may also contain suspension aids or thickeners, such as sodium carboxymethyl cellulose, a surface-active agent, for example condensation products of fatty alcohols with ethylene oxide, or protective substances 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 the stabilizer, such as alkali salts of ethylenediaminetetraacetic acid, possibly using emulsifiers and/or dispersing agents, whereby, for example, when using water as a diluent, organic solvents may be used as solvents or auxiliary solvent and filled into injection bottles or ampoules or infusion bottles.

The capsules containing one or more active substances, respectively active substance combinations, can for example be prepared by mixing the active substances with inert carriers, such as milk sugar or sorbitol and encapsulating in gelatin capsules. Suitable suppositories can, for example, be prepared by mixing with intended carriers, such as neutral fat or polyethylene glycol or derivatives thereof. Excipients include, for example, water, pharmaceutically acceptable organic solvents, such as paraffins (e.g. petroleum fractions), oils from plants (e.g. peanut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol) , carriers such as e.g. natural stone flour (e.g. kaolins, clay, talc, chalk) synthetic stone flour (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane, milk and grape sugar) emulsifier (e.g. lignin, suffite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

The application takes place in the usual way, in the therapy of asthma or COPD, preferably by inhalation.

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

The dosage of the compounds according to the invention is necessarily highly dependent on the form of application and the disease to be treated. By inhalation application

the compounds with the formula 1 already excel at doses in the µg range by a high effect. The compounds of formula 1 can also be used appropriately above the ug range. The dosage can then, for example, also be in the gram range. Particularly for non-inhalative application, the compounds according to the invention can be applied at a higher dosage (for example, but not limited to the range from 1 to 1000 mg).

The following formulation examples illustrate the present one:

Pharmaceutical formulation examples

The finely ground active ingredient, milk sugar and part of the corn starch are mixed together. The mixture is sieved, after which it is moistened with a solution of polyvinylpyrrolidone in water, crushed, granulated moist and dried. The granulate, the rest of the corn starch and the magnesium stearate are sieved and mixed together. The mixture is pressed into tablets of suitable shape and size.

The finely ground active ingredient, part of the cornstarch, the milk sugar, the microcrystalline cellulose and the polyvinylpyrrolidone are mixed together, the mixture sieved and processed with the rest of the cornstarch and water into a granule, which is dried and sieved. To this is added the sodium carboxymethyl starch and the magnesium stearate, mixed and pressed into tablets of a suitable size.

C) Ampoule solution

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

D) Doserinase aerosol

The suspension is filled in an ordinary aerosol container with a dosing valve. Per activation, preferably 50 µl suspension is released. If desired, the active ingredient can also be dosed higher (e.g. 0.02% by weight).

E) Solutions (in mo/ 100ml)

This solution can be prepared in the usual way.

F) Inhalation powder

The preparation of the inhalation powder takes place in the usual way by mixing the individual components.

G) Inhalation powder

The preparation of the inhalation powder takes place in the usual way by mixing the individual components.

Claims (9)

1) Compounds with the general formula 1 in which A means a double-bonded group selected from X an anion with a single negative charge preferably selected from chloride, bromide, methyl sulfate, 4-toluenesulfonate and methanesulfonate; R<1> and R<2> which are the same or different are a group selected from methyl, ethyl, n- propyl and iso-propyl which may optionally be substituted with hydroxy or fluorine; R 3 , R 4 , R 5 and r 6 , which are the same or different, are hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CF3, CN, or NO2; R<7> methyl, ethyl, methyloxy, ethyloxy, -CH2-F, -CH2-CH2-F, -0-CH2-F, -0-CH2-CH2-F, -CH2-OH, -CH2-CH2- OH, CF3, -CH2-OMe, -CH2-CH2-OMe, -CH2-OEt, -CH2-CH2-OEt, -O-CO-Me, -O-CO-Et, -O-COCF3, fluorine, chlorine or bromine. 2) Compounds with the general formula 1 according to claim 1, in which A means a double-bonded group selected from X" an anion with a single negative charge selected from chloride, bromide, and methanesulfonate; R<1> and R<2> which are the same or different are a group selected from methyl, ethyl, as optional may be substituted with hydroxy or fluorine; R3, R<4>, R5 and R6, which may be the same or different, are hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluoro, chloro, or bromo; R<7> methyl, ethyl, methyloxy, ethyloxy, CF3, or fluorine. 3) Compounds with the general formula 1, according to one of claims 1 or 2, in which A means a double-bonded group selected from X" is bromide; R<1> and R<2> which may be the same or different are a group selected from methyl and ethyl; R 3 , R 4 , R 5 and r 6 , which may be the same or different, are hydrogen, methyl, methyloxy, chlorine or fluorine; R7 methyl or fluorine. 4) Compounds of the general formula 1, according to one of claims 1, 2 or 3, in which A means a double-bonded group selected from X_ bromide; R<1> and R<2> which are the same or different are methyl or ethyl; R3, R<4>, R5 and R6, which are the same or different, are hydrogen, methyl or fluorine; R7 methyl or fluorine. 5) Compound with the general formula 1 according to one of claims 1 to 4 as a medicinal product. 6) Use of a compound of the general formula 1 according to one of claims 1 to 4 for the production of a drug for the treatment of asthma, COPD, ventral sinus bradycardia, heart rhythm disorders, spasms in the digestive tract, spasms in the urinary tract and menstrual disorders. 7) Use of a compound with the general formula 1 according to claim 6 for the production of a medicinal product for the treatment of asthma or COPD. 8) Pharmaceutical preparations containing as active ingredient one or more compounds with the general formula 1 according to one of the claims 1 to 4 or their physiologically acceptable salts, possibly in combination with usual excipients and/or carriers. 9) Process for preparing a compound of the general formula 1 in which A, X - and the residues R<1>, R<2>, R3, R<4>, R<5>, R<6> and R<7>, can have the meanings mentioned in claims 1 to 4, characterized in that in a first step a compound with the general formula 3 is reacted in which the residues R<3>, R<4>, R<5>, r<6> and R<7> can have the meanings mentioned in claims 1 to 4 and R stands for chlorine or C-| -C4-alkyloxy with a compound of the formula 2 in which A and R"! can have the meanings mentioned in claims 1 to 4, to a compound with the formula 4 in which A and the residues R<1>, R3, R<4>, R<5>, R<6> and R<7>, can have the meanings mentioned in claims 1 to 4, and then quaternize these by reaction with a compound R<2->X, in which R<2> and X can have the meanings mentioned in claims 1 to 4 for a compound with the formula \.