NO328929B1 - New fluorocarboxylic acid esters, processes for their preparation, intermediates, pharmaceutical compositions containing them, their use as pharmaceuticals and their use in the manufacture of medicaments for the treatment of disease - Google Patents

Description

The present invention relates to new fluorene carboxylic acid esters with the general formula 1_

in which X" and the groups A, R, , R^, R3f r3' r4 0g r<4>' ^ e \ the requirements and the meanings mentioned in the description, a method for their preparation and their use as medicine.

Description of the invention

The present invention relates to compounds of the general formula 1

in which

A is a divalent residue selected from the group consisting of

X" a single negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate;

R hydrogen, hydroxy, methyl, ethyl, -CF3, CHF2 or fluorine;

R<1> and R<2> are the same or different, -C-|-C5-alkyl, which may optionally be substituted with -C3-C6-cycloalkyl, hydroxy or halogen, or

R1 and R<2> together form a -C3-C5 alkylene bridge;

R3, R4, R3' and R<4>', the same or different, are hydrogen, -C1-C4-alkyl,

-C-|-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, NO2 or halogen. Compounds of the general formula Ij are preferred. wherein A means a divalent residue selected from the group consisting of

X" a single negatively charged anion selected from the group of chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide;

R means hydroxy, methyl or fluoro;

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

R3, R<4>, R3' and R<4>', the same or different, are hydrogen, methyl, methyloxy, hydroxy,

-CF3, -CHF2 or fluorine.

Particularly preferred are compounds of the general formula 1^ in which A means a divalent residue selected from the group consisting of

X" a single negatively charged anion selected from the group of chloride, bromide and

methanesulfonate, preferably bromide;

R hydroxy, methyl or fluoro, preferably methyl or hydroxy;

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

R3, R4, R3' and R<4>', the same or different, are hydrogen, -CF3, -CHF2 or fluorine,

preferably hydrogen or fluorine.

According to the invention, compounds with the general formula 1 are of particular importance1 in which

A means a divalent residue selected from the group consisting of

X" bromide;

R hydroxy or methyl, preferably methyl;

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

R3, R4, r3' and R4', the same or different, are hydrogen, or fluorine.

Subject matter of the invention are the individual compounds with the formula 1j_, 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<3>' and R<4>', as long as they do not mean hydrogen, can be ortho, meta or para with regard to the attachment to "- C-R" group. If none of the residues R<3>, R<4>, R3' and R<4>' means hydrogen, R3 and r3" are preferably attached in the para position and R4 and R4' are preferably attached in the ortho or meta position, particularly preferred in the meta position. If one of the residues R<3> and R<4> and one of the residues R3' and R<4>' means hydrogen, the other residue is attached preferably in the meta or para position, especially preferred in the para position. Provided that none of the residues R<3>, R<4>, R3' and R<4>' means hydrogen, according to the invention the compounds of the general form M are particularly preferred, in which the residues R<3>, R<4>, R<3>' and R<4>' have the same meaning.

Also of particular importance according to the invention are the compounds with the general formula 1, in which the ester substituent on the nitrogen bicycle is α-configured. These compounds correspond to the general formula l^x

According to the invention, the following compounds are of particular importance: 9-hydroxy-fluorene-9-carboxylic acid tropenol ester methobromide; 9-fluoro-fluorene-9-carboxylic acid tropenol ester -methobromide; 9-Hydroxy-fluorene-9-carboxylic acid scopine ester methobromide; 9-fluoro-fluorene-9-carboxylic acid scopine ester methobromide;

9-methyl-fluorene-9-carboxylic acid tropenol ester methobromide; 9-methyl-fluorene-9-carboxylic acid scopine ester methobromide;

Alkyl groups are, unless otherwise stated, branched and straight-chain alkyl groups with 1 to 5 carbon atoms. Examples include: methyl, ethyl, propyl or butyl. For the designation of the groups methyl, ethyl, propyl or also butyl, the abbreviations Me, Et, prop or Bu are optionally also used. Unless otherwise described, the definitions propyl and butyl include all conceivable isomeric forms of these 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.

As alkylene-halogen groups are defined, unless otherwise stated, branched and straight-chain divalent alkyl bridges with 1 to 4 carbon atoms, which are one, two or three times, preferably twice, substituted with a halogen. Correspondingly, branched and straight-chain divalent alkyl bridges with 1 to 4 carbon atoms, which are one, two or three times, preferably once, substituted with 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 definitions propyloxy and butyloxy include all conceivable isomeric forms of these 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 terms methoxy, ethoxy, propoxy or butoxy are also used accordingly.

Unless otherwise stated, alkylene-alkyloxy groups are defined as branched and straight-chain divalent alkyl bridges with 1 to 4 carbon atoms, which are substituted once, twice 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 to be 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 denotes a carbonyl group.

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

As can be seen from Scheme 1, the compounds of formula 2 serve as starting products for the preparation of the compounds of formula 1. These compounds are known from the prior art.

From the compounds of formula 2, access to the esters of general formula 4 is successful by reaction with the carboxylic acid derivatives of formula 3, in which R' for example stands for chlorine or a C-|-C4-alkyloxy acid residue. In the event that R' is C-|-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 to this, instead of the derivatives 3, in which R' means C-|-C4-alkyloxy, the corresponding acid chlorides can also be used (R is equal to Cl).

The thereby obtained compounds of the formula 4 can be transferred by reaction with the compounds R<2>X, in which R<2> and X can have the aforementioned meanings, into the target compounds of the formula 1_. This synthesis step can also be carried out analogously to the synthesis examples described in WO 92/16528.1 In the case in which R^ and R<2> together form an alkylene bridge, as is clear to the person skilled in the art, the addition of the reagent R<2->X is not necessary. In this case, the compounds with the formula 4 have a suitable substituted residue R^ (for example -C3-C5-alkylene-halogen) corresponding to the aforementioned definitions, and the preparation of the compounds with the formula 1_ takes place by intramolecular quaternization of the amine.

As an alternative to the method for synthesizing the compounds of formula 4 shown in Scheme 1, the derivatives 4, in which the nitrogen bicycle is a Scopin derivative, can be prepared by oxidation (epoxidation) of compounds of formula 4, in which the nitrogen bicycle is a Tropenyl residue. For this, according to the invention, one proceeds 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 40-70X. 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. As oxidizing agent, vanadium pentoxide is preferably used in mixture with H2O2, particularly preferred H2O2-urea complex in combination with vanadium pentoxide. 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 to this, the compounds of formula 4, in which R also means halogen, are available in the manner shown in Scheme 2.

For this, the compounds of the formula 4^ in which R stands for hydroxy are, using suitable halogenation reagents, transferred into the compounds 4 in which R means halogen. Carrying out the halogenation reaction to be carried out according to Scheme 2 is sufficiently known from the state of the art.

As shown in Scheme 1, the intermediates with the general formula 4 are of central importance. Accordingly, a further aspect of the present invention concerns the intermediates of formula 4

in which the residues A, R, R<1>, R<3>, R<3>', R4 and R<4>' can have the aforementioned meanings, optionally in the form of their acid addition salts.

Acid addition salts are understood to mean salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferred hydrochloride, hydrobromide , hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate.

As in the compounds with the general formula 1, also in the compounds with the general formula 4 the residues R<3>, R<4>, R3' and R<4>', as long as they do not mean hydrogen, can be arranged ortho, meta or para relative to the attachment to the "-C-R" group. If none of the residues R<3>, R<4>, r3' and R<4>' means hydrogen, R<3> and r3" are preferably linked in the para position and R<4> and R<4>' preferably in the ortho- or meta-position, particularly preferred in the meta-position. If one of the residues R3 and R<4> and one of the residues r<3>" and R<4>' means hydrogen, the other residue is preferably associated in the meta or para position, particularly preferred in the para position. Provided that none of the residues R<3>, R<4>, r3" and R<4>' means hydrogen, according to the invention the compounds of the general formula 4 are particularly preferred, in which the residues R<3>, R<4>, r3" and R<4>' have the same meaning.

According to the invention, the compounds with the formula 4 in the a-configured form used as starting materials are preferred. According to the invention, these a-configured compounds are consequently of particular importance and correspond to the general formula 4-g.

A further aspect of the present invention relates to the use of compounds of the general formula 2 for the preparation of the compounds of the general formula 4. Furthermore, the present invention relates to the use of the compounds of the general formula 2 as starting materials for the preparation of the compounds of the general formula V Furthermore the present invention relates to the use of the compounds of the general formula 4 as an intermediate in the preparation of the compounds of the general formula V

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

Example 1: 9-Hydroxy-Fluorene-9-Carboxyl-Hydrophenol Ester-Methobromide:

1.1.: 9-Hydroxy-Fluorene-9-Carboxylsvremetvlester 3a:.

50.4 g (0.223 mol) of 9-hydroxy-9-fluorenecarboxylic acid is dissolved in 500 ml of methanol, mixed with 5 ml (0.089 mol) of conc. sulfuric acid and heated for 1 hour under reflux. After cooling, 100 ml of sodium bicarbonate solution (approx. pH 8) is added and the methanol is mainly evaporated. It is extracted with dichloromethane and water, the organic phase is dried and evaporated to dryness. Purification takes place by recrystallization from ethyl acetate.

Yield: 50.0g white crystals (= 93% of theoretical yield).

1. 2: 9- hydroxy- fluorene- 9- carboxylic acid tropenol esters 4a:

13.4 g (0.056 mol) metvleste r 3a, 11.65 g (0.084 mol) tropenol and 0.3 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 evaporated to dryness and the residue extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSCv* and the solvent is distilled off. The product is purified by recrystallization from diethyl ether. ;Yield: 11.40 g of white crystals (= 59% of theoretical yield). ;1. 3: 9-hydroxy-fluorene-9-carboxylic acid tropenol ester methobromide: 1.75 g (0.005 mol) of 4a is taken up in 30 ml of dichloromethane and 15 ml of acetonitrile and mixed with 2.85 g (0.015 mol) of 50% methyl bromide solution in acetonitrile. The reaction mixture is allowed to stand at room temperature for 3 days, during which the product crystallizes. The precipitated crystals are separated and recrystallized from diethyl ether for purification. ;Yield: 1.95 g of white crystals (= 88% of theoretical yield); m.p.: 250°C. ;;Example 2: 9- fluoro- fluorene- 9- carboxyl svretropenoyl ester methobromide : ; 2. 1: 9-fluoro-fluorene-9-carboxylic acid tropenol ester 4b: 1.66 ml (0.009 mol) of bis-(2-methoxyethyl)-aminosulfur trifluoride is placed in 10 ml of dichloromethane and mixed dropwise during 20 minutes at 15°-20 ° C with a solution of 2.4 g (0.007 mol) 4a in 25 ml of 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 carefully adjusted with aqueous NaHCO 3 solution to 8, the organic phase separated, the aqueous phase re-extracted with dichloromethane, the combined organic phases washed with water, dried over MgSCv* and evaporated to dryness. The hydrochloride is precipitated and recrystallized from acetonitrile/diethyl ether. The free base is then released again with the help of 10% water. sodium carbonate solution. Yield: 1.05 g light yellow crystals (= 53% of theoretical yield)

2. 2: 9- fluoro- fluorene- 9- carboxylic acid tropenol ester - methobromide :

1.05 g (0.003 mol) 4b is taken up in 20 ml of acetonitrile and reacted with 1.71 g (0.009 mol) of 50% methyl bromide solution in acetonitrile analogously to step 1.3. For purification, it is recrystallized from acetonitrile.

Yield: 0.80 g of white crystals (= 60% of theoretical yield); m.p.: 252°C.

Example 3: 9-hydroxy-fluorene-9-carboxylic acid scopine ester methobromide:

3. 1: 9- hydroxy- fluorene- 9- carboxyl fluoroscopine ester 4c:

9.0 g (0.026 mol) of tropenol ester 4a are suspended in 90 ml of dimethylformamide and mixed with 0.47 g (0.003 mol) of vanadium (V)-oxide. At 60°C, a solution of 4.89 g (0.052 mol) H 2 O 2 urea in 20 ml of water is added dropwise and stirred for 6 hours at 60°C. After cooling to 20°C, the formed precipitate is filtered off, the filtrate adjusted with 4 N hydrochloric acid to pH 2 and mixed with Na2S2O5 dissolved in water. The resulting 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.

Then 1 ml of acetyl chloride was added at room temperature and it was stirred for 1 hour. After extraction with 1 N hydrochloric acid, the aqueous phase was made basic, extracted with dichloromethane, the organic phase washed with water and dried over MgSO 4 . The solvent was finally removed by distillation. The crude product was purified by recrystallization from diethyl ether. Yield: 2.8 g of white crystals (= 30% of theoretical yield).

3. 2: 9- hydroxy-fluorene- 9- carboxylic acid scopine ester methobromide:

1.3 g (0.004 mol) 4c is taken up in 20 ml chloroform and 20 ml acetonitrile and reacted with 2.279 g (0.012 mol) 50% methyl bromide solution in acetonitrile analogously to step 1.3. For purification, it is recrystallized from acetonitrile.

Yield: 1.25 g light beige crystals (= 68% of theoretical yield); sm.p.: 243-244X.

Example 4: 9-fluoro-fluorene-9-carboxylic acid scopine ester methobromide:

4. 1: 9- fluoro- fluorene- 9- carboxylic acid scopine ester 4d:

0.885 ml (0.005 mol) of bis-(2-methoxyethyl)-aminosulfur trifluoride is placed in 25 ml of dichloromethane and reacted analogously to the procedure according to 2.1 with 1.42 g (0.004 mol) of 4c.

Yield: 1.1 g beige crystals (= 75% of theoretical yield)

4. 2: 9- fluoro- fluorene- 9- carboxyl svrescopine ester - methobromide :

1.1 g (0.003 mol) of 4d is taken up in 30 ml of acetonitrile and reacted with 1.71 g (0.009 mol) of a 50% methyl bromide solution in acetonitrile analogously to step 1.3. For purification, it is recrystallized from isopropanol.

Yield: 0.45 g of white crystals (= 33% of theoretical yield); m.p.: 200-201 °C. Elemental analysis: calculated: C (60.01) H (5.04) N (3.04)

found.: C (59.91) H (5.18) N (3.10).

Example 5: 9-Methyl-fluorene-9-carboxysylretropenoyl ester- methobromide:

5. 1. : 9- Methyl-fluorene- 9- carboxylic acid 3b:.

a) 9-Methyl-fluorene-9-carboxylic acid methyl ester:

From 7.6 g (0.33 mol) of sodium and 300 ml of ethanol, a sodium ethylate solution is prepared,

to which 69.6 g (0.33 mol) of 9-fluorenecarboxylic acid is added portionwise. After the addition is complete, it is stirred for 2.5 hours at room temperature. It is then evaporated to dryness, the residue is slurried in 600 ml of dimethylformamide and 93.96 g (0.662 mol) of methyl iodide is added dropwise. It is stirred for a further 3 hours at a constant temperature. The cloudy solution is stirred under cooling in 500 ml of water and 300 ml of diethyl ether and extracted, the organic phase washed with water and 10% sodium carbonate solution, dried and evaporated to dryness. The residue is purified by means of column chromatography, eluent: cyclohexane / ethyl acetate 96:4.

Yield: 12.61 g of white crystals (= 16% of theoretical yield); m.p.: 108°-109° C.

b) 9-Methyl-fluorene-9-carboxylic acid 3b:

12.6 g (0.053 mol) 9-methyl-fluorene-9-carboxylic acid methyl ester and 53 ml 2 molar

aqueous sodium hydroxide solution is stirred in 120 ml of 1,4-dioxane for 24 hours at room temperature. The dioxane is distilled off, mixed with water to a total volume of 300 ml and extracted with diethyl ether. The aqueous phase is acidified with 3 molar aqueous HCl, crystallized and filtered.

Yield: 11.25 g of white crystals (= 95% of theoretical yield); m.p.: 168°-169° C.

5. 2: 9- methyl- fluorene- 9- carboxyl svretropenoyl esters 4e:

6.73 g (0.03 mol) 3b is slurried in 60 ml of dichloromethane, mixed with 5.0 g of oxalyl chloride and 1 drop of dimethylformamide, then stirred for one hour at room temperature and then the solvent distilled off. The remaining acid chloride is used without further purification in the next step.

4.18 g (0.03 mol) of Tropenol and 4.27 g (0.033 mol) of diisopropylethylamine are slurried in 100 ml of dichloroethane, the acid chloride in 30 ml of dichloroethane is added dropwise at 35-40°C and then stirred for 24 hours at 40°C. The suspension is diluted with dichloromethane and extracted with dilute hydrochloric acid. The organic phase is then washed with water, dried over MgSO 4 and the product transferred with a solution of HCl in diethyl ether into its hydrochloride. The solvent is then removed. For purification, the precipitated hydrochloride is taken up in water and extracted with diethyl ether. The aqueous phase is set basic with 10% water. sodium carbonate solution and extracted with dichloromethane. The organic phase is dried over MgSO 4 and the solvent is distilled off.

Yield: 4.40 g yellow oil (= 42% of theoretical yield);

5. 3: 9- Methyl- fluorene- 9- carboxylic acid tropenol ester- methobromide:

1.8 g (0.005 mol) of the free base 4e is reacted analogously to the procedure under step 1.3. Purification takes place by recrystallization from acetone. Yield: 1.80 g of white crystals (= 82% of theoretical yield); m.p.: 258-259°C;

Example 6: 9-Methyl-fluorene-9-carboxysylsvescopine ester-methobromide:

6. 1: 9- Methyl- fluorene- 9- carboxyl ester 4f:

2.5 g (0.007 mol) Tropenol ester 4e is reacted with 0.13 g (0.001 mol) vanadium-(V)-oxide and 1.43 g (0.015 mol) h^O^-urea analogously to the procedure according to step 3.1. Yield: 1.8 g of white crystals (= 71% of theoretical yield).

6. 2: 9- methyl- fluorene- 9- carboxyl sveroscopine ester methobromide:

1.8 g (0.005 mol) 4f is taken up in 30 ml of acetonitrile and reacted with 2.848 g (0.015 mol) of 50% methyl bromide solution in acetonitrile analogously to step 1.3. Yield: 1.6 g of white crystals (= 70% of theoretical yield); m.p.: 214°C.

It was found that the compounds according to the invention with the formula 1_ are antagonists of the M3 receptor (muscarinic receptor subtype 3). The compounds according to the invention show with respect to affinity for the M3 receptor Ki values of less than 10 nM. These values were determined according to the method described below.

Chemicals

3H-NMS was supplied by the company Amersham, Braunschweig, with a specific radioactivity of 3071 GBq/mmol (83 Ci/mmol). All further reagents were supplied from Serva, Heidelberg and from Merck, Darmstadt.

Cell membranes:

We use cell membranes from CHO cells (Chinese hamster ovary), which were transfected with the corresponding genes from the human muscarinic receptor subtypes hm1 to hm5 (BONNER). The cell membranes of the desired subtype were thawed, resuspended by hand with a glass homogenizer and diluted with HEPES buffer to a final concentration of 20-30 mg protein/ml.

Receptor binding studies:

The binding measurement was carried out in a final volume of 1 ml and was composed of 100 ul unlabeled substance in different concentrations, 100 ul radioligand (3H-N-methylscopolamine 2 nmol/l (3H-NMS), 200 ul membrane preparation and 600 ul HEPES buffer (20 mmol/l HEPES, 10 mmol/l MgCl2, 100 mmol/l NaCl, adjusted with 1 mol/l NaOH at pH 7.4).

We measured the non-specific binding with 10 Mmol/l atropine.

The incubation of 45 min. run at 37°C in 96-well microtiter plates (Beckman, polystyrene, No. 267001) as a duplicate determination. The incubation ended with filtration using an Inotech cell harvester (Type IH 110) through a Whatman G-7 filter. The filter was washed with 3 ml of ice-cold HEPES buffer and dried before the measurement.

Determination of radioactivity:

The radioactivity of the filter mats was measured simultaneously using a two-dimensional digital autoradiograph (Berthold, Wildbad, Typ 3052).

Rating:

We calculated the Ki value using implicit equations, which were directly derived from the law of mass action with the model for 1 receptor 2 ligand reactions (SysFit - Software, SCHITTKOWSKI).

Literature:

BONNER Tl, New subtypes of muscarinic acetylcholine receptors

Trends Pharmacol. Pollock. 10, Suppl.: 11-15 (1989); SCHITTKOWSKI K

Parameter estimation in systems of nonlinear equations Numer Math. 68: 129-142

(1994).

The compounds according to the invention with the formula 1_ distinguished themselves by their versatile application possibilities in the therapeutic area.

According to the invention, such application possibilities must be emphasized, for which the compounds according to the invention with the formula 1_ can preferably be used on the basis of their pharmaceutical effect as an anticholinergic.

This is, for example, therapy for asthma or COPD (chronic obstructive pulmonary disease). The compounds with the general formula 1. can also be used for the treatment of sinus bradycardia due to atrial fibrillation and for the treatment of heart rhythm disorders. 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 in the treatment of spasms in the urinary tract and, for example, in menstrual complaints. Among the indication areas listed above, for example, the therapy of asthma and COPD with the help of the compounds according to the invention with the formula 1_ is of particular importance.

The compounds with the general formula 1 can be used alone or in combination with other active substances with the formula 1_ according to the invention. Optionally, the compounds of the general formula A_ can also be used in combination with further pharmacologically active active substances.

This includes, in particular, betamimetics, antiallergics, PAF antagonists, PDE IV inhibitors, leukotriene antagonists, p38 kinase inhibitors, EGFR kinase inhibitors and corticosteroids, as well as active ingredient combinations thereof.

As examples of betamimetics, which can be used according to the invention together with the compounds of the formula 1_ as a combination, mention is made of compounds which are from the group consisting of bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, Ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulfonterol, 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-propylamino]ethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine -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-tert-butylamino)ethanol and 1 -(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-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. Such active substances are particularly preferably used as betamimetics in combination with the compounds of the formula 1_ according to the invention, 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-be nzoksazi n-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, their solvates and/or their hydrates. Of 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 particularly important.

According to the invention, the acid addition salts of betamimetics are preferred, for example selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate and xinafoate. Particularly preferred are salts in the case of salmeterol selected from hydrochloride, sulfate and xinafoate, of which xinafoate is particularly preferred. 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 very special importance.

Within the scope of the present invention, corticosteroids, which can optionally be used in combination with the compounds of the formula 1_, are understood to mean compounds selected from the group consisting of flunisolide, beclometasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW 215864 , KSR 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 budesonide, fluticasone, mometasone and ciclesonide, especially budesonide and fluticasone are given particular importance. Possibly, within the framework of the present patent application, instead of the term corticosteroids, only the term steroids is also 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, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. Optionally, the corticosteroids can also be present in the form of their hydrates.

As examples of PDE-IV inhibitors, which according to the invention can be used together with the compound of the formula 1_ as a combination, mention is made of compounds selected from the group consisting of enprofylline, roflumilast, ariflo, Bay-198004, CP-325,366, BY343, D -4396 (Sch-351591), V-11294A and AWD-12-281. Preferred PDE-IV inhibitors are selected from the group consisting of enprofylline, roflumilast, ariflo and AWD-12-281, among which AWD-12-281 is particularly preferred as a combination partner with the compound of formula 1 according to the invention. A reference to the aforementioned PDE-IV inhibitors includes within the scope of the present invention a reference to their possibly present pharmacologically acceptable acid addition salts. According to the invention, the physiologically tolerable acid addition salts which can be formed by the aforementioned PDE-IV inhibitors mean pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. According to the invention, in this context the salts selected from the group consisting of acetate, hydrochloride, hydrobromide, sulphate, phosphate and methanesulphonate are preferred.

Within the scope of the present invention, dopamine agonists, which can optionally be used in combination with the compounds of the formula 1_, are understood to mean compounds which are those selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocriptine, lisuride, pergolide, pramipexole, roxyndole, ropinirole , talipexole, terguride and viozan. Within the framework of the present invention, the dopamine agonist is preferably used as a combination partner with the compounds of formula 1, which is selected from the group consisting of pramipexole, talipexole and viozan, among which pramipexole has a particular importance. A reference to the aforementioned dopamine agonists includes within the scope of the present invention a reference to their optionally available pharmacologically acceptable acid addition salts and optionally their hydrates. By the physiologically tolerable acid addition salts, which can be formed from the aforementioned dopamine agonists, is meant, for example, pharmaceutically acceptable salts, which are selected from 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 can be used according to the invention with the compounds of the formula 1_ as a combination, mention is made of epinastin, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipin, cexchlorpheniramine, pheniramine, doxylamine, chlorphenoxamine , dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozine. Preferred antiallergics that can be used within the scope of the present invention in combination with the compounds according to the invention with the formula 1_, are selected from the group consisting of epinastin, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratidine and mizolastine, among which epinastin and desloratidine are particularly preferred. A reference to the aforementioned antiallergic drugs includes within the scope of the present invention a reference to their possibly present pharmacologically acceptable acid addition salts.

As an example of PAF antagonists, which can be used according to the invention together with the compounds with the formula 1_ as a combination are mentioned

4-(2-Chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f] [1,2,4]triaz olo[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.

As an example of EGFR kinase inhibitors, which can be used together with the compounds of the formula 1_ according to the invention as a combination, mention is made of particularly preferred 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-( (R)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]- 7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro -phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)carbonyl]-piperazin-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino ]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-

((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-kinase 4-[(3-chloro-4-fluorophenyl)amino]-6- [(4-{N-[2-(ethoxycarbonyl)-ethyl]-N-[(ethoxycarbonyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-quinazoline, 4 -[(R)-(1-phenyl-ethyl)amino]-6-{[4-(m 7-cyclopropylmethoxy-quinazoline and

4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(morpholin-4-yl)-propyloxy]-7-methoxyquinazoline A reference to the aforementioned EGFR kinase inhibitors includes within the scope of the present invention a reference to their optionally present pharmacologically acceptable acid addition salts.

With the physiological or pharmacologically tolerable acid addition salts, which can be formed by EGFR kinase inhibitors, are understood according to the invention to be 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 or maleic acid . According to the invention, the salts of EGFR kinase inhibitors selected from the salts with acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid are preferred.

As an example of p38 kinase inhibitors that can be used together with compounds of the formula 1_ according to the invention as a combination, mention is made as particularly preferred of 1 -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3 -[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea; 1 -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1 - oxothiomorpholin-4-yl)ethoxy)naphthalin-1-yl]- urea; 1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalene-1 - yl]-urea; 1 -[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1- yl]-urea or 1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]- urea. A reference to the previously mentioned p38-kinase inhibitors includes within the scope of the present invention a reference to their possibly present pharmacologically acceptable acid addition salts. During the physiological or pharmacologically tolerable acid addition salts, which can be formed by the p38-Kinase inhibitors, are understood according to the invention to be 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 or maleic acid .

If the compounds of the formula 1_ are used in combination with other active substances, among the previously mentioned compound classes the combination with steroids, PDE IV inhibitors or betamimetics is particularly preferred. The combination with betamimetics, especially with long-acting betamimetics, has a particular significance. The combination of the compounds according to the invention with the formula 1_ with salmeterol or formoterol is considered particularly preferred.

Suitable application forms for application of the compounds of the 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 the inhalation application of the compounds according to the invention. The proportion of the pharmaceutically active compound should be in the range 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 ingredient or active ingredients with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or milk sugar, disintegrants, such as corn starch or alginic acid, binding agents, such as starch or gelatin, lubricants, such as magnesium stearate or talc , and/or agents for achieving a 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 agents commonly used 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. Likewise, the drag coat for achieving a depot effect can also consist of several layers, under which the above-mentioned excipients for the tablets can be used.

Juices of active substances or combinations of active substances according to the invention can additionally also 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, surfactants, for example condensation products of fatty alcohols with ethylene oxide, or preservatives, such as p-hydroxybenzoate.

Solutions are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali salts of ethylenediaminetetraacetic acid, possibly using emulsifiers and/or dispersants, whereby for example when using water as a diluent, organic solvents may be used as solvent agents or auxiliary solvent, and is filled into injection bottles or ampoules or infusion bottles.

The capsules containing one or more active substances or combinations of active substances can, for example, be prepared by mixing the active substances with inert carriers, such as milk sugar or sorbitol, and encapsulating them in gelatin capsules.

Suitable suppositories can, for example, be prepared by mixing with the carriers specified for this purpose, such as neutral fats or polyethylene glycol or its derivatives.

Excipients include, for example, water, pharmaceutically harmless organic solvents, such as paraffins (e.g. petroleum fractions), oils of plant origin (e.g. peanut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural stone flours (e.g. kaolins, clays, talc, chalk) synthetic stone flours (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane, milk and grape sugar) emulsifiers (e.g. lignin, sulphite sodium hydroxide, methyl cellulose, starch and polyvinylpyrrolidone) and lubricant (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

In case of oral use, the tablets can of course, in addition to the mentioned carriers, 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, the active substances can also be mixed with various flavor enhancers or dyes in addition to the auxiliaries mentioned above.

In the preferred application of the compounds of formula 1 according to the invention for the therapy of asthma or COPD, administration forms that can be administered by inhalation are particularly preferred, respectively. pharmaceutical formulations. Inhalable administration forms include inhalation powders, propellant-containing dosage aerosols or propellant-free inhalation solutions. Within the scope of the present invention, the term propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions. The applicable forms of administration within the scope of the present invention are described in detail in the following part of the description.

Usable inhalation powders may contain either alone or in admixture with suitable physiologically harmless excipients.

If the active substances 1 are contained in a mixture with physiologically acceptable excipients, the following physiologically acceptable excipients can be used for the production of this inhalation powder according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo- and polysaccharides

(e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with each other. Mono- or disaccharides are preferably used, whereby the use of lactose or glucose, especially, but not exclusively in the form of their hydrates, is preferred. As particularly preferred in connection with the invention, lactose, most preferably lactose monohydrate as an auxiliary substance, is used.

Within the scope of the inhalation powder according to the invention, the excipients have a maximum average particle size of up to 250 µm, preferably between 10 and 150 µm, particularly preferably between 15 and 80 µm. If necessary, it may seem appropriate to mix the aforementioned auxiliary substances into finer auxiliary substance fractions with an average particle size of 1 to 9 µm. The latter finer excipients are likewise selected from the aforementioned group of applicable excipients. Finally, for the production of micronized inhalation powder according to the invention, the active substance 1_, preferably with an average particle size of 0.5 to 10 µm, particularly preferably of 1 to 5 µm, is mixed with the excipient mixture. The method for producing the inhalation powder according to the invention by grinding and micronising as well as with subsequent mixing of the components is known from the state of the art.

The inhalation powder according to the invention can be applied using known inhalers from the state of the art.

According to the invention, inhalation aerosols containing propellant gas can contain 1 dissolved in propellant gas or in dispersed form. Below, 1_ can be present in separate administration forms or in a common administration form, whereby both can either be dissolved, both dispersed or only one of the components dissolved and the other contained, dispersed.

The propellant gases that can be used for the production of the inhalation aerosols are known from the state of the 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 aforementioned propellant gases can be used alone or in mixtures thereof. Particularly preferred propellants are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.

The propellant gas-containing inhalation aerosols can also contain additional ingredients such as carbon solvents, stabilizers, surface-active agents (surfactants), antioxidants, lubricants and agents for adjusting the pH value. All these components are known in the state of the art.

The aforementioned propellant-containing inhalation aerosols can be applied using known inhalers (MDIs = metered dose inhalers) from the state of the art.

Furthermore, application of active substances 1_ according to the invention can take place in the form of propellant gas-free inhalation solutions and inhalation suspensions. As a solvent, aqueous or alcoholic, preferably ethanolic solutions come into consideration. The solvent can be exclusively water or there is a mixture of water and ethanol. The relative proportion of ethanol in relation to water is not limited, preferably the maximum limit is nevertheless up to 70 volume percent, in particular up to 60 volume percent and particularly preferably up to 30 volume percent. The remaining volume percentage is filled up with water. The solutions or suspensions containing 1_ are adjusted with suitable acids to a pH value of 2 to 7, preferably of 2 to 5. For setting this pH value, acids selected from inorganic or organic acids can be used. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid. Examples of particularly suitable organic acids are: Ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid and others. Preferred inorganic acids are hydrochloric acid, sulfuric acid. Those acids which already form an acid addition salt with an active ingredient can also be used. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. Optionally, mixtures of the aforementioned acids can also be used, particularly in the case of acids, which in addition to their acid properties also have other properties, e.g. as flavourings, antioxidants or complex formers, such as citric acid or ascorbic acid. According to the invention, hydrochloric acid is used in particular for setting pH values.

In these formulations, the addition of editic acid (EDTA) or one of its known salts, sodium edetate, as a stabilizer or complex former, may be dispensed with. Other forms of administration contain this compound. In such a preferred administration form, the content in relation to sodium edetate is below 100 mg/100 ml, preferably below 50 mg/100 ml, particularly preferably below 20 mg/100 ml. In general, such inhalation solutions are preferred, in which the content of sodium edetate is 0 to 10 mg/100 ml.

The propellant gas-free inhalation solutions can be added to carbon solvents and/or additional excipients. Preferred carbon solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - especially isopropyl alcohol, glycols - especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. In this context, excipients and additives are understood to mean any pharmacologically acceptable substance, which is not an active substance, but together with the active substance(s) can be formulated in the pharmacologically suitable solvent formulated to improve the qualitative properties of the active substance formulation. Preferably, these substances exert no, or in connection with the intended therapy, no appreciable or at least no unwanted pharmacological effect. The auxiliaries and additives include e.g. surfactants, such as soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complex formers, antioxidants and/or preservatives, to give or extend the duration of use of the finished medicinal formulation, flavourings, vitamins and/or other additives known from the state of the art. Additives also include pharmacologically harmless salts such as sodium chloride as isotonic agents.

Antioxidants, such as for example ascorbic acid, if they have not already been used for setting the pH value, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human organism are among the preferred auxiliaries.

Preservatives can be used to protect the formulation against contamination with germs. As preservatives, those known from the prior art are suitable, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the known concentration from the state of the art. The aforementioned preservatives are preferably present in concentrations of up to 50 mg/100 ml, particularly preferably between 5 and 20 mg/100 ml.

Preferred formulations contain, in addition to the solvent water and the active substance 1, only benzalkonium chloride and sodium edetate.

In another preferred form of administration, sodium edetate is dispensed with.

Dosage of the compounds according to the invention is necessarily highly dependent on the form of application and the disease to be treated. In the case of inhalative application, the compounds of the formula 1_ already excel at doses in the µg range at a high degree of effectiveness. Also above the ug range, the compounds with the formula Iseg can be used appropriately. The dosage can then, for example, also be in the gram range. Particularly in the case of non-inhalative application, the compounds according to the invention can be applied at a higher dosage (for example, but not limited to the range of 1 to 1000 mg).

The following formulation examples illustrate the present invention:

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 corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture sieved and treated with the rest of the corn starch 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 at its own pH or possibly at pH 5.5 to 6.5 in water 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 fused. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

D) Dosing aerosol

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

E) Solutions (in mg/ 100ml)

This solution can be prepared in the usual way.

F) I nhalation powder

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

G) I nhalation powder

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

Claims (12)

1) Compounds with the general formula 1_ in which A means a divalent residue selected from the group consisting of X" a single negatively charged anion, R hydroxy, methyl, ethyl, -CF 3 , CHF 2 or fluorine; R<1> and R<2> the same or different, -C-|-C5-alkyl, which may optionally be substituted with -C3-C6-cycloalkyl, hydroxy or halogen, or R<1> and R<2> together a -C3-C5 alkylene bridge; R3, R4, r3' and R<4>', the same or different, hydrogen, -C-|-C4-alkyl, -C1-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, NO2 or halogen. 2) Compounds with the formula 1_ according to claim 1, wherein A means a divalent residue selected from the group consisting of X" a single negatively charged anion selected from the group chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferred bromide; R is hydroxy, methyl or fluoro; R<1> and R<2> the same or different, methyl, ethyl or fluoroethyl; R3, R<4>, r3" and R<4>', the same or different, are hydrogen, methyl, methyloxy, hydroxy, -CF3, -CHF2 or fluorine. 3) Compounds of the general formula 1 according to claim 1 or 2, wherein A means a divalent residue selected from the group consisting of X" a single negatively charged anion selected from the group chloride, bromide and methanesulfonate, preferably bromide; R hydroxy, methyl or fluoro, preferably methyl or hydroxy; R<1> and R<2> the same or different, methyl or ethyl, preferably methyl; R3, R4, R3' and R<4>', the same or different, hydrogen, -CF3, -CHF2 or fluorine, preferably hydrogen or fluorine. 4) Compounds of the general formula 1_ according to claim 1, 2 or 3, in which A means a divalent residue selected from the group consisting of X" bromide; R hydroxy or methyl, preferably methyl; r<1> and R<2> the same or different, methyl or ethyl, preferably methyl; R3, R4, R3' and R<4>', the same or different, hydrogen or fluorine. 5) Compounds according to one of claims 1 to 4, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates. 6) Use of a compound with the general formula 1 according to one of claims 1 to 5 as a medicinal product. 7) Use of a compound of the general formula 1_ according to one of claims 1 to 5 for the preparation of a drug for the treatment of diseases in which anticholinergics can provide a therapeutic benefit. 8) Use of a compound with the general formula 1 according to one of claims 1 to 5 for the preparation of a drug for the treatment of asthma, COPD, sinus bradycardia, heart rhythm disturbances, spasms in the gastrointestinal tract, spasms in the urinary tract and menstrual complaints. 9) Pharmaceutical preparations containing as active ingredient one or more compounds with the general formula i according to one of claims 1 to 5 or their physiologically acceptable salts, possibly in combination with usual auxiliary and/or carrier substances. 10) Pharmaceutical preparations according to claim 9, characterized in that these contain, in addition to one or more of the compounds of the formula 1_, at least one additional active substance, which is selected from the group betamimetics, antiallergics, PAF antagonists, PDE IV inhibitors, leukotriene- antagonists, p38 kinase inhibitors, EGFR kinase inhibitors and corticosteroids. 11) Intermediates with the general formula 4 in which the residues A, R, R^, R<3>, R<3>', r4 Qg r<4>' |<an na ^ e \ claims 1 to 4 mentioned meanings, possibly in the form of their acid addition salts. 12) Use of compounds with the general formula 2 in which the radicals A and R^ can have the meanings mentioned in claims 1 to 4, optionally in the form of their acid addition salts, for the preparation of compounds with the formula 1_ according to one of claims 1 to 5.