HRP20030278A2 - Novel anticholinergic agents that can be used as medicaments and method for the production thereof - Google Patents

Description

The proposed invention relates to new anticholinergics of general formula 1

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in which A, KS- and the radicals R1, R2, R3, R4, R5, R6 and R7 can have the meanings given in the patent claims and in the description, to the procedures for their preparation as well as to their use as a medicine.

Background of the invention

Anticholinergics can be meaningfully used therapeutically in a large number of diseases. A prominent example is the treatment of asthma or COPD (chronic obstructive pulmonary disease). For the therapy of these diseases, WO 92/16528 proposes anticholinergics that have the basic structure of scopine, tropenol or also tropine.

The task on which 92/16528 is based is the preparation of anticholinergic compounds characterized by long-term action. According to WO 92/16528, esters of benzylic acid and scopine, tropenol or also tropine were used for the solution of this task.

For the treatment of chronic diseases, it is often desirable to prepare a medicine with a long-term effect. As a rule, it can be achieved by this that the concentration of the active substance necessary to achieve a therapeutic effect is present in the organism for a longer period of time, and that the drug does not have to be administered again often, above all. The application of the active substance over longer periods of time also contributes to a high degree to the patient's well-being. It is particularly desirable to provide a drug that can be therapeutically administered once a day (once-a-day administration). Once-a-day administration has the advantage that the patient can relatively quickly learn to take the medicine regularly at a certain time during the day.

In order for the drug to be administered once a day, special requirements are set for the active substance to be administered. First of all, after the administration of the drug, the desired effect must occur relatively quickly and, ideally, it must then have, if possible, a constant effectiveness during the following longer period of time. On the other hand, the duration of the drug's effect must not significantly exceed a period of approximately one day. In the ideal case, the active substance has such an action profile, that the drug preparation, which can be applied once a day and which contains the active substance in a therapeutically meaningful dose, can be managed in a targeted manner.

It was found that the ester of benzylic acid and scopine, tropenol or also tropine, which are described in WO 92/16528, do not fully meet these requirements. Due to their extremely long duration of action, they significantly exceed the above-mentioned time period of approximately one day, and therefore cannot be used therapeutically for once-a-day administration.

Therefore, the task of the proposed invention is to prepare new anticholinergics which, due to their action profile, enable the preparation of a medicine that can be applied once a day. The task of the invention is also to prepare compounds characterized by the fact that their action is established relatively quickly. A further task of the invention is the preparation of compounds which, after a rapid onset of action, preferably have a constant effectiveness over a further longer period of time. Furthermore, the task of the invention is to prepare compounds whose duration of action generally does not exceed the time period of one day at a dosage that can be used therapeutically. Finally, the task of the invention is the preparation of compounds that have such an action profile that a good management of therapeutic effects is possible (that is, a complete therapeutic effect without side effects due to the accumulation of substances in the body).

Description of the invention in detail

It has surprisingly been found that the above-mentioned tasks can be solved with compounds of the general formula 1 in which the residue R7 does not represent a hydroxy group.

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

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where

A represents a divalent residue selected from the group they comprise

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X- is an anion with one negative charge,

R1 and R2 represent C1-C4-alkyl, which can be substituted with hydroxy or with halogen if necessary;

R3, R4, R5 and R6, the same or different, represent hydrogen, C1-C4-alkyl, C1-C4-alkyloxy, hydroxy, CF3, CN, NO2 or halogen;

R7 is hydrogen, C1-C4-alkyl, C1-C4-alkyloxy, C1-C4-alkylene-halogen, C1-C4-alkyloxy-halogen, C1-C4-alkylene-OH, CF3, -C1-C4-alkylene-C1 -C4-alkyloxy, -O-COC1-C4-alkyl, -O-COC1-C4-alkyl-halogen, -O-COCF3 or halogen,

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if A represents

whereby

R1 and R2 can be methyl,

R3, R4, R5 and R6 represent hydrogen, then R7 cannot also be hydrogen.

Preference is given to compounds of the general formula 1, in which A represents a divalent residue selected from the group they comprise

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X- is an anion with one negative charge selected from the group consisting of chloride, bromide, methylsulfate, 4-toluenesulfonate and methanesulfonate;

R1 and R2, the same or different, represent a residue selected from the group consisting of methyl, ethyl, n-propyl and iso-propyl, which may be substituted with hydroxy or fluorine, preferably unsubstituted methyl;

R3, R4, R5 and R6, the same or different, represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF3 or NO2;

R7 is hydrogen, methyl, ethyl, methyloxy, ethyloxy, -CH2-F, -CH2-CH2-F, -O-CH2-F, -O-CH2-CH2-F, -CH2-OH, -CH2-CH2- OH, CF3, -CH2-OMe, -CH2-CH2-OMe, -CH2-OEt, -CH2-CH2-OEt, -O-COMe, -O-COEt, -O-COCF3, -O-COCF3, fluorine, chlorine or bromine.

Particular preference is given to compounds of the general formula 1 in which

A represents a divalent residue selected from the group they comprise

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X- is an anion with one negative charge selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide;

R1 and R2, equal or different, represent a residue selected from methyl and ethyl, which may be substituted with hydroxy or fluorine, preferably unsubstituted methyl;

R3, R4, R5 and R6, the same or different, represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine;

R 7 is hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF 3 , or fluorine.

According to the invention, preference is given to compounds of the general formula 1 in which

A represents a divalent residue selected from the group they comprise

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X- is bromide;

R and R 2 are the same or different and represent a residue selected from methyl and ethyl, preferably methyl;

R3, R4, R5 and R6, the same or different, represent hydrogen, methyl, methyloxy or fluorine;

R is hydrogen, methyl or fluorine.

According to the invention, the compounds of the general formula 1 in which

A represents a divalent residue selected from the group they comprise

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X- is bromide;

R1 and R2, the same or different, represent methyl or ethyl, preferably methyl;

R3, R4, R5 and R6, the same or different, represent hydrogen or fluorine, preferably hydrogen;

R7 is hydrogen, methyl or fluorine, preferably methyl or fluorine, particularly preferably methyl.

The subject of the invention is in any case the compounds of formula 1 in the form of individual optical isomers, mixtures of individual enantiomers or racemates as needed.

In the compounds of the general formula JL, if the radicals R3, R4, R5 and R6 do not represent hydrogen, they are in each case ortho, meta or para according to the position where the "-C-R7-" group is connected. If none of the residues R 3 , R 4 , R 5 and R 6 is hydrogen, R 3 and R 5 are connected preferably in the para position, and R 4 and R 6 are in the ortho or meta position, particularly preferably in the meta position. If one of the residues R3 and R4 and one of the residues R5 and R6 represents hydrogen, in any case the second residue is connected preferably in the meta or in the para position, especially preferably in the para position. If none of the residues R 3 , R 4 , R 5 and R 6 is hydrogen, compounds according to the invention of the general formula 1 are particularly advantageously those in which the radicals R 3 , R , R 5 and R have the same meaning.

Those compounds of the general formula 1, in which the ester substituent on the nitrogen cycle has an α configuration, have a special meaning according to the invention. These compounds correspond to the general formula 1-α

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According to the invention, the following compounds are of special significance:

2,2-diphenylpropionic acid trophenol 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, unless stated otherwise, are branched and unbranched alkyl groups with 1 to 4 carbon atoms. Examples include methyl, ethyl, propyl or butyl. To indicate methyl, ethyl, propyl or also butyl groups, the abbreviations Me, Et, Prop or Bu are also used as necessary. Unless otherwise stated, the definitions of propyl and butyl include all conceivable isomeric forms of the respective residues. So for example propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc.

Alkylene groups, unless stated otherwise, are understood to mean branched and unbranched divalent alkyl bridges with 1 to 4 carbon atoms. Methylene, ethylene, propylene or butylene may be mentioned, for example.

As alkylene-halogen groups, if not stated otherwise, are meant branched and unbranched divalent alkyl bridges with 1 to 4 carbon atoms that are singly, doubly or triply, preferably singly substituted with halogen. Accordingly, alkylene-OH groups, unless otherwise stated, are understood to mean branched and unbranched divalent alkyl bridges with 1 to 4 carbon atoms that are singly, doubly or triply, preferably singly, substituted with hydroxy.

Alkyloxy groups, if not stated otherwise, are understood as branched and unbranched alkyl groups with 1 to 4 carbon atoms that are connected through oxygen atoms. For example, methyloxy, ethyloxy, propyloxy or butyloxy may be mentioned. The abbreviations MeO-, EtO-, PropO- or BuO- are also used to indicate the groups methyloxy, ethyloxy, propyloxy or also butyloxy, if necessary. Unless stated otherwise, the definitions for propyloxy and butyloxy include all conceivable isomeric forms of the respective residues. Thus, for example, propyloxy includes n-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy, sec-butyloxy and tert-butyloxy, etc. If necessary, within the scope of the proposed invention, instead of the name alkyloxy, the name alkoxy is also used. To indicate the groups methyloxy, ethyloxy, propyloxy or also butyloxy, the terms methoxy, ethoxy, propoxy or butoxy are used accordingly, if necessary.

Alkylene-alkyloxy groups, if not stated otherwise, are understood as branched and unbranched divalent alkyl bridges with 1 to 4 carbon atoms, which are singly, doubly or triply, preferably singly substituted with alkyloxy groups.

By -O-CO-alkyl groups, if not stated otherwise, are meant branched and unbranched alkyl groups having up to 4 carbon atoms and which are connected via an ester group. In this case, the alkyl groups are connected directly to the carbonyl carbon of the ester group. Names for the groups -O-CO-alkyl-halogen are understood analogously. The -O-CO-CF3 group is trifluoroacetate.

Halogen in the scope of the proposed invention is fluorine, chlorine, bromine or iodine. If not stated otherwise, halogen is preferably understood to be fluorine and bromine.

The CO group is a carbonyl group.

The preparation of the compounds according to the invention, as explained below, can be partially carried out, analogously to the state of the art, by already known procedures (scheme 1). Carboxylic acid derivatives of formula 3 are known from the state of the art or can be obtained by synthesis known from the state of the art. If only suitably substituted carboxylic acids are known from the prior art, compounds of formula 3 can also be obtained directly from them by catalytic esterification of the acid or base with suitable alcohols or by halogenation with suitable halogenating reagents.

Scheme 1

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Starting from a compound of formula 2, an ester of general formula 4 is obtained by reaction with a carboxylic acid derivative of formula 3, in which R represents, for example, chlorine or a C1-C4-alkyloxy radical. In case R represents C1-C4-alkyl-oxy, this reaction can be carried out, for example, in a sodium melt at an elevated temperature, preferably at approx. 50-150°C, especially favorable at approx. 90-100°C and under lower pressure, preferably under pressure below 500 mbar, especially advantageous under pressure below 75 mbar. Alternatively, instead of derivative 3, where R is C1-C4-alkyloxy, the corresponding acid chloride (R is Cl) can also be used.

Thus obtained compounds of formula 4 can be converted into the target compounds of formula 1 by reaction with compounds R2-X, in which R2 and X have the above-mentioned meanings. This part of the synthesis can also be carried out analogously to the synthesis examples described in WO 92/16528.

As an alternative to the synthesis procedure shown in scheme 1 for the synthesis of compounds of formula 4, derivatives 4 in which the nitrogen cycle represents a derivative group can be obtained by oxidation of compounds of formula 4 in which the nitrogen cycle represents a tropenyl residue. For this purpose, the invention can be handled as follows.

Compound 4, in which A represents -CH=CH-, is suspended in a polar organic solvent, preferably in a solvent selected from the group consisting of N-methyl-2-pyrrolidone (NMP), dimethylacetamide and dimethylformamide, preferably in dimethylformamide, and then it is heated to a temperature of approx. 30-90°C, preferably 40-70°C. A suitable oxidizing agent is then added and stirred at a constant temperature for 2 to 8 hours, preferably 3 to 6 hours. Vanadium pentoxide in a mixture with H2O2 can be used as an oxidizing agent, especially the H2O2-urea complex in combination with vanadium pentoxide. Processing is done in the usual way. Purification of the product can be carried out, depending on the possibility of crystallization, by crystallization or chromatography. Alternatively, compounds of formula 4, wherein R 7 is halogen, can also be prepared by the process shown in Scheme 2.

Scheme 2

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For this purpose, the benzylic acid ester of formula 5 is converted to compound 4, in which R7 is halogen, using a suitable halogenation reagent. The implementation of the halogenation reaction according to scheme 2 is sufficiently known from the state of the art.

Benzyl acid esters of formula 5 can be obtained by a process known from the state (WO 92/16528).

As seen in Scheme 1, the intermediates of formula 4 take on central importance. Accordingly, a further aspect of the proposed invention relates to intermediates of formula 4

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where

A represents a divalent residue selected from the group they comprise

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R 1 is C 1 -C 4 -alkyl, which may be substituted with hydroxy or with halogen if necessary;

R3, R4, R5 and R6, the same or different, represent hydrogen, C1-C4-alkyl, C1-C4-alkyloxy, hydroxy, CF3, CN, NO2 or halogen;

R7 is hydrogen, C1-C4-alkyl, C1-C4-alkyloxy, C1-C4-alkylene-halogen, C1-C4-alkyloxy-halogen, C1-C4-alkylene-OH, CF3, -C1-C4-alkylene-C1 -C4-alkyloxy, -O-COC1-C4-alkyl, -O-COC1-C4-alkyl-halogen, -O-COCF3 or halogen, wherein

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if A represents

R 1 can be methyl, i

R3, R4, R5 and R6 represent hydrogen, then

R7 cannot also be n-propyl.

Preference is given to those compounds of general formula 1, in which

A represents a divalent residue selected from the group they comprise

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R1, the same or different, represent a residue selected from the group consisting of methyl, ethyl, n-propyl and iso-propyl, which may be substituted with hydroxy or fluorine, preferably unsubstituted methyl;

R3, R4, R5 and R6, the same or different, represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF3 or NO2;

R7 is hydrogen, methyl, ethyl, methyloxy, ethyloxy, -CH2-F, -CH2-CH2-F, -O-CH2-F, -O-CH2-CH2-F, -CH2-OH, -CH2-CH2- OH, CF3, -CH2-OMe, -CH2-CH2-OMe, -CH2-OEt, -CH2-CH2-OEt, -O-COMe, -O-COEt, -O-COCF3, -O-COCF3, fluorine, chlorine or bromine.

Particular preference is given to those compounds of general formula 1, in which

A represents a divalent residue selected from the group they comprise

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R1, the same or different, represents a residue selected from methyl and ethyl, which may be substituted by hydroxy or fluorine, preferably unsubstituted methyl;

R3, R4, R5 and R6, the same or different, represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine;

R is hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF3 or fluorine.

According to the invention, special preference is given to those compounds of general formula 1, in which

A represents a divalent residue selected from the group they comprise

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R1, the same or different, represents a residue selected from methyl and ethyl, preferably methyl;

R3, R4, R5 and R6, the same or different, represent hydrogen, methyl, ethyl, methyloxy, chlorine or bromine;

R is hydrogen, methyl or fluorine.

According to the invention, special meaning is given to the compounds of the general formula 1 in which

A represents a divalent residue selected from the group they comprise

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R1, the same or different, represents methyl or ethyl, preferably methyl;

R3, R4, R5 and R6, the same or different, represent hydrogen or fluorine, preferably hydrogen;

R7 is hydrogen, methyl or fluorine, preferably methyl or fluorine, particularly preferably methyl.

As in the compounds of the general formula 1, also in the intermediates of the formula 4, the radicals R3, R4, R5 and R6, if they do not represent hydrogen, can in any case be in the ortho, meta or para position according to the place where the "-C-OH" group is connected -". If none of the residues R 3 , R 4 , R 5 and R 6 represents hydrogen, then R 3 and R 5 are preferably connected in the para position, and R 4 and R 6 are preferably in the ortho or meta position, particularly preferably in the meta position. If one of the residues R3 and R4, and one of the residues R5 and R5 represents hydrogen, in any case the second residue is preferably connected in the meta or para position, especially preferably in the para position. If none of the residues R 3 , R 4 , R 5 and R 4 is hydrogen, according to the invention preference is given to those intermediates of the general formula 4 in which the radicals R 3 , R 4 , R 5 and R 6 have the same meaning.

The synthesis examples described below serve to further illustrate the proposed invention. They should be understood only as examples of procedures for further explanation of the invention which is not limited to the following described examples.

Example 1

2,2-Diphenylpropionic acid scopine ester-methobromide

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1.1: 2,2-diphenylpropionic acid chloride 3a

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

1.2: 2,2-diphenylpropionic acid scopine ester 4a

The residue obtained in step 1.1 is dissolved in 100 ml of dichloromethane and mixed dropwise at 40°C with a solution of 51.45 g (0.33 mol) of scopine in 200 ml of dichloromethane. The resulting suspension is stirred for 24 h at 40°C, then the resulting precipitate is suctioned off and the filtrate is extracted first with water and then, acidly, with aqueous hydrochloric acid. The combined aqueous phases are basified with an aqueous solution of sodium carbonate, extracted with dichloromethane, the organic phase is dried over Na2SO4, completely dried by evaporation and the hydrochloride is precipitated from the residue. Purification is done by recrystallization from acetonitrile. Yield: 20.85 g (= 47% of theoretical).

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

Melting point: 203-204°C.

1.3: 2,2-diphenylpropionic acid ester-methobromide

11.98 g (0.033 mol) of compound 4a, 210 ml of acetonitrile, 70 ml of dichloromethane and 20.16 g (0.1 mol) of 46.92% bromomethane in acetonitrile were mixed at 20°C and allowed to stand. 3 days. The solution is evaporated to dryness and the residue is recrystallized from isopropanol.

Yield: 11.34 g (= 75% of theoretical).

Melting point: 208-209°C.

C24H28NO3-Br (458.4)

Elementary 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-diphenylacetic acid scopine ester-methobromide

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2.1: Benzyl acid scopine ester 5a

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

2.2: 2-fluoro-2,2-diphenylacetic acid scopine ester 4b

2.66 g (0.02 mol) of dimethylaminosulfur trifluoride in 10 ml of dichloromethane is cooled to 0°C and added dropwise to a solution of 5.48 g (0.015 mol) of benzylic acid scopine ester in 100 ml of dichloromethane. It is then stirred for 30 minutes at 0°C and another 30 minutes at 20°C. While cooling, the solution is mixed with water, NaHCO3 is added (up to pH 7-8) and the organic phase is separated. The aqueous phase is extracted with dichloromethane, the combined organic phases are washed with water, dried over Na2SO4 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-diphenylacetic acid scopine ester methobromide

2.88 g (0.0078 mol) of the free base of benzylic acid scopine ester reacts analogously to the procedure described in step 1.3. Cleaning is done by recrystallization from isopropanol.

Yield: 2.62 g (= 73% of theoretical).

DC: Rf value: 0.31 (flow agent analogous to level 1.3).

Melting point: 130-134°C.

Example 3

2,2-diphenylpropionic acid tropenol ester-methobromide

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3.1: 2,2-diphenylpropionic acid methyl ester 3c

37.60 g (0.247 mol) of DBU was added dropwise to a suspension of 50.8 g (0.225 mol) of 2,2-diphenylpropionic acid and 200 ml of acetonitrile at 20°C. 70.10 g (0.494 mol) of methyl iodide was added dropwise to the resulting solution over 30 minutes. It is then stirred overnight at 20°C. The solvent is evaporated, the residue is washed with diethyl ether/water, the organic phase is washed with water, dried over Na2SO4 and evaporated to dryness.

Yield: 48.29 g of viscous residue 32 (= 89% of theory).

3.2: 2,2-diphenylpropionic acid trophenol ester 4c

4.80 g (0.02 mol) of 2,2-diphenylpropionic acid methyl ester 3b, 2.78 g (0.02 mol) of tropenol and 0.046 g of sodium as a melt are heated at 75 mbar for 4 h on a boiling water bath with occasional agitation. When cooled, the sodium residue was dissolved with acetonitrile, the solution was evaporated to dryness and the residue was extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO4 and evaporated to dryness. Compound 4c precipitated from the residue as hydrochloride and it was recrystallized from acetone.

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

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

Melting point: 134-135°C.

3.3: 2,2-diphenylpropionic acid tropenol ester-methobromide

2.20 g (0.006 mol) of compound 4c 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: 1.84 g (= 66% of theoretical).

DC: Rf value 0.11 (flow agent analogous to level 1.3) .

Melting point: 222-223°C. C24H28NO2-Br (442.4)

Elementary 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 tropenol ester methobromide

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4.1: 3,3',4,4'-tetrafluorobenzyl acid ethyl ester 3c

The Grignard reagent is prepared from 2.24 g (0.092 mol) of magnesium shavings, a few grains of iodine and 17.80 g (0.092 mol) of l-bromo-3,4-difluoro-benzene in 100 ml of THF at 50°C. . After adding the halides, the mixture is stirred for another hour. The thus obtained Grignard reagent 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 resulting mixture is stirred for 2 hours at 5°C . For workup, the white suspension is poured onto ice/sulfuric acid, extracted with ethyl acetate, the organic phase is washed with water, dried over MgSO4 and evaporated to dryness. The crude product is purified by column chromatography (eluant: toluene).

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

4.2: 3,3',4,4'-tetrafluorobenzyl acid tropenol ester 5b

4.27 g (0.013 mol) of 3,3',4,4'-tetrafluorobenzyl acid ethyl ester 3c, 1.81 g (0.013 mol) of tropenol and 0.03 g of sodium as a melt are heated at 75 mbar for 4 h on a boiling water bath with occasional shaking. When cooled, the sodium residue was dissolved with acetonitrile, the solution was evaporated to dryness and the residue was extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO4 and evaporated to dryness. The remaining residue is mixed with diethyl ether/petroleum ether 1:9, suction filtered and washed.

Yield: 2.50 g (= 46% of theoretical).

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

Melting point: 147°-148°C.

4.3: 2-fluoro-2,2-bis(3,4-difluorophenyl)acetic acid trophenol ester 4d

2.66 g (0.012 mol) of bis-(2-methoxyethyl)-amino-sulfur trifluoride is placed in 10 ml of dichloromethane and during 20 minutes at 15°-20°C it is mixed drop by drop with a solution of 0.01 mol of the compound 5b in 65 ml of dichloromethane. It is stirred for 20 h at room temperature, cooled to 0°C and carefully mixed with 80 ml of water with good mixing, then carefully adjusted to pH 8 with an aqueous solution of NaHCO3, the organic phase is separated, the aqueous phase is extracted again with dichloromethane , the combined organic phases are washed with water, dried over MgSO4 and evaporated to dryness. The precipitated hydrochloride is recrystallized from acetonitrile/diethyl ether.

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

Melting point: 233°C

4.4: 2-fluoro-2,2-bis(3,4-difluorophenyl)acetic acid tropenol ester methobromide

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

Yield: 1.95 g (= 72% of theoretical)

DC: Rf value: 0.17 (fluent: n-butanol/water/formic acid (conc.)/acetone/dichloromethane 36:15:15:15:5). Melting point: 247°C. C23H21F5NO2-Br (518.3)

Elementary 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-diphenylpropionic acid scopine ester ethyl bromide

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

Yield: 1.38 g (= 58% of theory).

Melting point: 208-209°C. DC: Rf value: 0.33 (flow agent analogous to level 1.2).

Melting point: 210-211°C C25H30NO3-Br (472.42)

Elementary 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 scopine ester methobromide

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6.1.: 3,3',4,4'-tetrafluorobenzyl acid scopine ester 5c 3.61 g (0.011 mol) 3,3',4,4'-tetrafluorobenzyl acid ethyl ester 3c, 1.71 g (0.011 mol) skopina and 0.03 g of sodium as a melt is heated under 75 mbar for 4 h in a boiling water bath with occasional shaking. When cooled, the sodium residue was dissolved with acetonitrile, the solution was evaporated to dryness and the residue was extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO4 and evaporated to dryness. The resulting residue is mixed with diethyl ether/petroleum ether 1:9, suction filtered and washed. Yield: 1.75g (= 36% of theoretical). Melting point: 178-179°C. 6.2: 2-fluoro-2,2-bis(3,4-difluorophenyl)acetic acid scopine ester 4e 0.6 ml (0.0033 mol) of bis-(2-methoxyethyl)aminosulfur trifluoride is reacted with 1.2 g (0 .0028 mol) of compound 5c analogous to example 4, stage 4.3.

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

6.3: 2-fluoro-2, 2-bis (3, 4-difluorophenyl) acetic acid scopine ester methobromide

1.15 g (0.0026 mol) of compound 4e and 1.5 g (0.0079 mol) of a 50% methyl bromide solution are reacted analogously to example 1, step 1.3. The resulting crystal is filtered off, washed with dichloromethane, dried and then recrystallized from acetone.

Yield: 0.88 g (= 63% of theoretical).

DC: Rf value: 0.27 (flow agent: n-butanol/water/formic acid (conc.)/acetone/dichloromethane 36:15:15:15:5) Melting point: 212°C. No. (535.33)

Example 7

2-fluoro 2,2-bis (4-fluorophenyl) acetic acid tropenol ester methobromide

7.1: 4, 4'-difluorobenzyl acid methyl ester 3d

7.1.1: 4, 4'-difluorobenzyl acid

In a solution of 49.99 g (1.25 mol) of NaOH tablets in 300 ml of water at approx. At 100°C, a solution of 24.62 g (0.1 mol) of 4, 4-difluorobenzyl in 250 ml of dioxane was added dropwise and stirred for 2 h. Most of the dioxane is distilled off and the remaining aqueous solution is extracted with dichloromethane. The aqueous solution is acidified with sulfuric acid, during which a precipitate is secreted which is sucked off, washed and dried. The filtrate is extracted with dichloromethane, the organic phase is dried over Na2SO4 and evaporated to dryness.

Yield: 25.01 g (= 95% of theoretical).

Melting point: 133°-136°C.

7.1.2: 4,4'-difluorobenzyl acid methyl ester

25.0 g (0.095 mol) of 4,4'-difluorobenzyl acid was added to a freshly prepared solution of sodium methanolate from 2.17 g (0.095 mol) of sodium and 200 ml of ethanol at 20°C and stirred for 3 h. The solution is evaporated to dryness, the residue is dissolved in DMF, mixed dropwise with 22.57 g (0.16 mol) of methyl iodide at 20°C and stirred for 24 h. Processing and cleaning are carried out analogously to compound 3b.

Yield: 21.06 g 11 (= 80% of theoretical).

7.2: 4,4'-difluorobenzyl acid tropenol ester 5d

11.13 g (0.04 mol) of 4,4'-difluorobenzyl acid methyl ester 3d and 5.57 g (0.04 mol) of trophenol 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).

Melting point: 233-235°C.

7.3: 2-fluoro-2,2-bis(4-fluorophenyl)acetic acid trophenol ester 4f

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

Yield: 2.93 g (= 69% of theoretical).

7.4: 2-fluoro-2,2-bis(4-fluorophenyl)-acetic acid tropenol ester methobromide

2.6 g (0.0067 mol) of compound 4f and 1.9 g (0.0079 mol) of a 50% methyl bromide solution are reacted analogously to example 1, step 1.3. The resulting crystals are filtered 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 (flux: as in example 1, grade 1.2);

melting point: 230-231°C.

C23H23F3NO2-Br (482.34). Elementary 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-fluorophenino-acetic acid scopine ester methobromide

[image]

8.1: 4,4'-difluorobenzyl acid scopine ester 5e

4.22 g (0.01 mol) of 4,4-difluorobenzyl acid tropenol ester 5d was suspended in 80 ml of DMF. At approx. 40°C internal temperature is added to a solution of 2.57 g (0.0273 mol) of H2O2-urea in 20 ml of water, as well as 0.2 g (0.0011 mol) of vanadium (V) oxide and stirred for 4.5 h at 60°C. It is cooled to 20°C and the resulting precipitate is suctioned off, the filtrate is adjusted to pH 3 with 4 N hydrochloric acid and mixed with Na2S2O5 dissolved in water. The thus obtained green solution is evaporated to dryness and the residue is extracted with dichloromethane/water. The acidic aqueous phase is made alkaline with Na2CO3, extracted with dichloromethane and the organic phase is dried over concentrate. Then 0.5 ml of acetyl chloride is added at approx. 15°C and stirred for 1.5 h. After extraction with 0.1 N hydrochloric acid, the aqueous phase is made alkaline, extracted with dichloromethane, the organic phase is dried over Na2SO4 and evaporated to dryness. The hydrochloride is precipitated from the residue, which is recrystallized from methanol/diethyl ether.

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

melting point: 243-244°C.

8.2. 2-Fluoro-2,2-bis(4-fluorophenyl)-acetic acid scopine ester 4a

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

Yield: 2.07 g (= 94% of theoretical);

melting point: 238-239°C.

8.3: 2-fluoro-2,2-bis(4-fluorophenyl)-acetic acid scopine ester methobromide

1.6 g (0.004 mol) of compound 4g and 1.14 g (0.0079 mol) of a 50% methyl bromide solution are reacted analogously to example 1, step 1.3. The resulting crystals are filtered 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 (flux: as in example 1, stage 1.2);

melting point: 213-214°C.

C23H23F3NO2-Br (498.34)

Elementary 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-diphenylacetic acid tropenol ester methobromide

[image]

9.1: Benzyl acid tropenol ester 5f

Benzylic acid tropenol ester as well as the procedure for its preparation are known from WO 92/16528.

9.2: 2-fluoro-2,2-diphenyl-acetic acid trophenol ester 4h

15.86 ml (0.086 mol) of bis-(2-methoxyethyl)amino-sulfur trifluoride is reacted with 25 g (0.072 mol) of compound 5f analogously to Example 4, step 4.3 in 480 ml of chloroform. The product in the form of its hydrochloride is recrystallized from acetone.

Yield: 18.6 g of white crystals (= 67% of theory);

melting point: 181-182°C.

9.3: 2-fluoro-2,2-diphenyl-acetic acid tropenol ester methobromide

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

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

DC: Rf value: 0.4 (flux: as in example 4, stage 4.4).

Melting point: 238-239°C.

C23H25FNO2-Br (446.36)

Elementary analysis:

calculated: 0(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 trophenol ester

[image]

ethobromide

10.1: 3,3'-dichlorobenzyl acid methyl ester 3e

10.1.1: 3,3'-dichlorobenzyl

At room temperature, add 100 ml of ethanol and add 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. Then 10.7 g (0.11 mol) of triethylamine is added dropwise. Boil for 3 hours under reflux and evaporate to dryness. The residue is taken up in ethyl acetate and extracted with water, a solution of sodium pyrosulfite in water and with a solution of Na2CO3. Dry over MgSO4 and evaporate to dryness. The obtained product is recrystallized from isopropanol and petroleum ether.

Yield: 13.2 g of white crystals (= 13% of theory);

melting point: 69-70°C.

13.0 g of acyloin thus obtained is dissolved in 460 ml of acetonitrile at room temperature, 0.0867 g of vanadium(V) oxytrichloride is added and the oxygen supply is turned on. After 1.5 h, the solution is evaporated to dryness, extracted with ethyl acetate and water as well as with Na2CO3 solution, dried over MgSO4 and evaporated to dryness. The resulting residue is mixed with petroleum ether/ethyl acetate 95:5.

Yield: 12.59 g of yellow crystals (= 97% of theory).

Melting point: 116-117°C.

10.1.2: 3,3-dichlorobenzyl acid

51.45 g (1.286 mol) of sodium hydroxide in 1000 ml of water is placed on a boiling water bath with good stirring and a solution of 28.5 g (0.102 mol) of 3,3'-dichloro-benzyl in 700 ml of dioxane is added dropwise, then mixed another l h. When cooled, dioxane is evaporated, the residue is diluted with water and extracted with diethyl ether. The organic phase is acidified, extracted with dichloromethane, dried over MgSO4 and washed to dryness.

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

10.1.3: 3,3'-dichlorobenzyl acid methyl ester

A sodium ethanolate solution is prepared from 100 ml of ethanol and 1.97 g (0.0855 mol) of sodium, into which 26.6 g (0.0855 mol) of 3,3'-dichlorobenzyl acid in 50 ml of ethanol is added dropwise. Then it is stirred for 4 h at room temperature. The solvent is distilled off and the residue is dissolved in 150 ml of DMF and 24.27 g (0.171 mol) of methyl iodide is added dropwise. Then it is mixed for another 24 hours. After cooling with ice, 300 ml of water and 200 ml of diethyl ether are added dropwise, the phases are separated, the aqueous phase is extracted with diethyl ether and then the organic phase is washed with Na2CO3 solution and shaken with water until neutral. After drying over Na2SO4, it is evaporated to dryness.

Yield: 22.91 g of yellow oil (= 82% of theoretical).

10.2: 3,3'-dichlorobenzyl acid tropenol ester 5g

22.9 g (0.074 mol) of 3,3'-dichlorobenzyl acid methyl ester 3e, 15.37 g (0.11 mol) of tropenol and 0.17 g of sodium as a melt are heated for 4 h at 75 mbar 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 MgSO4 and evaporated to dryness. The product as its hydrochloride is recrystallized from acetonitrile.

Yield: 16.83 g of white crystals (= 50% of theory).

Melting point: 184-185°C.

10.3: 3,3-fluoro-2,2-bis(3-chlorophenyl)acetic acid trophenol ester 4i

1.48 g (0.0067 mol) of bis-(2-methoxyethyl)-amino-sulfur trifluoride is placed in 10 ml of dichloromethane and during 20 minutes at 15°-20°C it is mixed drop by drop with the solution from 2.09 g compound 5g in 65 ml of dichloromethane. It is stirred for 20 h at room temperature, cooled to 0°C and carefully mixed with 80 ml of water with good mixing. It is then carefully adjusted to pH 8 with an aqueous NaHCO3 solution, the organic phase is separated, the aqueous phase is extracted again with dichloromethane, the combined organic phases are washed with water, dried over MgSO4 and evaporated to dryness. The precipitated hydrochloride is recrystallized from acetonitrile/diethyl ether.

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

Melting point: 136-137°C.

10.4: 2-fluoro-2,2-bis (3-chlorophenyl)-acetic acid tropenol ester methobromide

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

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

DC: Rf value: 0.14 (eluant: n-butanol/water/formic acid (conc.)/acetone/dichloromethane 36:15:15:15:5). Melting point: 180-181°C.

C23H23Cl2FNO2·Br (515.25).

As found, the compounds of the general formula 1 are characterized by multiple possibilities of application in the therapeutic field. Such application possibilities of the compounds of formula 1 according to the invention are particularly noteworthy, due to which they can be used, primarily due to their pharmaceutical effectiveness, as anticholinergics. This is, for example, the therapy of asthma or COPD (chronic obstructive pulmonary disease). The compounds of general formula 1 can further be used for the treatment of vagally conditioned sinus bradycardia and for the treatment of heart rhythm disorders. In general, the compounds of the invention can be used therapeutically to treat spasms, for example in the gastro-intestinal tract. Furthermore, they can be used in the treatment of spasms in the urinary tract, such as, for example, menstrual complaints.

Of the areas of indications listed above as examples, the therapy of asthma and COPD using the compounds of formula 1 according to the invention is of particular importance.

The compounds of the general formula 1 can be used alone or in combination with other active substances of the formula according to the invention. If necessary, the compounds of general formula 1 can also be used in combination with other pharmacologically active substances. This is particularly the case with betamimetics, anti-allergic agents, PAF antagonists, leukotriene antagonists and steroids, as well as combinations of these active substances.

As an example of betamimetics, which according to the invention can be used in combination with compounds of formula 1, compounds selected from the group consisting of bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, can be mentioned. salmeterol, sulfonterol, terbutaline, tolubuterol,

4-hydroxy-7-[2-{[2-{[3-(2-phenyl-ethoxy}propyl]sulfonyl}ethyl-3-amino}ethyl]-2(3H)-benzo-thiazolone,

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-butylamino]ethanol,

1-[2H-5-hydroxy-3-oxo-4H-1,4-benzox-azin-8-ii]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propyl -amino]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-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3- ii]-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-ethoxycarbonyl-amino-3-cyano-5-fluorophenyl])-2-(tert-butylamino)ethanol,

as appropriate in the form of their racemates, their enantiomers, their diastereomers, and also as appropriate in the form of their pharmacologically unambiguous acid addition salts and hydrates. As betamimetics, in combinations with compounds of formula 1 according to the invention, those selected from the group consisting of fenoterol, formoterol, salmeterol,

1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimid-azolyl)-2-methyl-2-butylamino]ethanol,

1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylamino-phenyl)-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-benz-oxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol- 3-yl]-2-methyl-2-butylamino}ethanol,

as needed in the form of their racemates, their enantiomers, their diastereomers, as well as as needed in the form of their pharmacologically unquestionable acid addition salts and hydrates. Of the above-mentioned betamimetics, the compounds formoterol and salmeterol are of particular importance here, as necessary in the form of their racemates, their enantiomers, their diastereomers, as well as, if necessary, in the form of their pharmacologically unambiguous acid addition salts and hydrates.

According to the invention, preferred acid addition salts of betamimetics are selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate and xinafoate. In the case of salmeterol, particular preference is given to salts selected from the hydrochloride, sulfate, and xinafoate, of which sulfates and xinafoates are particularly preferred. According to the invention salmeterol x 1⁄2H2SO4 and salmeterol xinafoate are given prominent meaning. In the case of formoterol, particular preference is given to salts selected from hydrochloride, sulfate and fumarate, of which hydrochloride and fumarate are particularly preferred. According to the invention, a prominent meaning is given to formoterol fumarate.

In the context of the proposed invention, corticosteroids that can be used in combination with compounds of formula 1, if necessary, are compounds selected from the group consisting of flunisolide, beclomethasone, triamquinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW 215864, KSR 592 , ST-126 and dexamethasone. Within the scope of the proposed invention, preference is given to corticosteroids selected from the group consisting of flunizolid, beclomethasone, triamquinolone, budesonide, fluticasone, mometasone, ciclesonide and dexamethasone, whereby budesonide, fluticasone, mometasone and ciclesonide, especially budesonide and fluticasone, are of particular importance here. If necessary, in the framework of the proposed patent application, instead of the name corticosteroid, only the designation steroid is used. The name steroid within the scope of the proposed invention also refers to salts or derivatives that steroids can form. Possible salts or derivatives include, for example, sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates. If necessary, corticosteroids can also exist in the form of their hydrates.

Within the scope of the proposed invention, dopamine agonists that can be used in combination with compounds of formula 1r, if necessary, mean compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocriptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viocan. In the framework of the proposed invention, as participants in the combination with the compounds of formula 1, preference is given to those dopamine agonists selected from the group consisting of pramipexole, talipexole and viocan, whereby pramipexole is of particular importance. When the above-mentioned dopamine agonists are mentioned within the scope of the proposed invention, their possibly existing pharmacologically tolerable acid addition salts and their hydrates are included as necessary. Physiologically tolerable acid addition salts, which can be formed by the above-mentioned dopamine agonists, are meant, for example, salts selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid acid, citric acid, tartaric acid and maleic acid.

As an example of antiallergic drugs, which according to the invention can be used with the compounds of formula 1 as a combination, epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorphenoxamine can be mentioned. , dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozine. Advantageous antiallergic drugs, which can be used in combination with the compounds of formula 1 according to the invention, are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastin, loratadine, ebastine, desloratidine and mizolastine, whereby epinastine and desloratidine. When the above-mentioned antiallergic agents are mentioned within the framework of the proposed invention, it is understood that their possibly existing pharmacologically tolerable acid addition salts are also included.

As an example of PAF antagonists, which are used as a combination with the compounds of formula 1 according to the invention, the following can be cited:

4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f][1,2,4]tri -azolo[4,3-a][1,4]diazepine,

6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclopenta-[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 above-mentioned classes of compounds, particular preference is given to the combination with steroids or betamimetics. The combination with betamimetics, especially long-acting betamimetics, is particularly significant. The combination of the compounds of formula 1 with salmeterol or formoterol is considered to be particularly advantageous, whereby the combination with formoterol is preferred.

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

According to the invention, a special meaning (especially in the treatment of asthma or COPD) is given to the inhalation application of the compounds according to the invention. The proportion of pharmaceutically effective compound(s) must in any case be in the range of 0.05 to 90 wt. %, preferably 0.1 to 50 wt. % of the total composition. Suitable tablets can be obtained, for example, by mixing one or more active substances with known excipients, for example with inert diluents such as calcium carbonate, calcium phosphate or milk sugar, with solubilizers such as corn starch or alginate acid, with binding agents such as starch or gelatin, with lubricants such as magnesium stearate or talc, and/or with agents for achieving a depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets can also consist of several layers.

Suitable dragees can be produced by coating analogously produced tablet cores with the usual agents used in dragee coatings, such as, for example, collidon or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to prevent incompatibility, cores can also consist of multiple layers. Coats of dragees can also consist of several layers to achieve a depot effect, whereby the excipients mentioned above for tablets can be used.

Juices containing an active substance or a combination of active substances according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerin or sugar, as well as an agent for improving taste, for example aromatic substances such as vanillin or orange extract. In addition to suspending aids or thickening agents, such as sodium carboxymethylcellulose, they may also contain leavening agents, for example condensation products of fatty alcohols and ethylene oxide, or preservatives such as p-hydroxybenzoate.

The solutions are prepared in the usual way, e.g. with the addition of isotonants, preservatives, such as p-hydroxybenzoate, or stabilizers, such as alkaline salts of ethylenediaminetetraacetic acid, if necessary with the use of emulsifiers and/or dispersants, whereby, for example, when using water as diluting agents, and organic solvents as means to improve dissolution, i.e. as auxiliary solvents, can be used as necessary. Ready solutions are filled into vials for injections or ampoules or into infusion bottles.

Capsules containing one or more active substances, or a combination of active substances, can be produced, for example, by mixing the active substances with inert carriers such as milk sugar or sorbitol and filling them into gelatin capsules.

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

Excipients can be mentioned, for example, water, pharmaceutically acceptable organic solvents, such as paraffins (e.g. petroleum fractions), oils of vegetable origin (e.g. peanut or sesame oil), alcohols with one or more alcohol functional groups (e.g. ethanol or glycerin), carriers such as natural stone flour (e.g. kaolin, clay, talc, chalk) synthetic stone flour (e.g. highly dispersed silicic acid and silicates), sugar (e.g. cane sugar, milk sugar, grape sugar ), emulsifiers (such as lignin, sulfite leachates, methylcellulose, starch and polyvinylpyrrolidone) and glidants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The application is carried out in the usual way, in the therapy of asthma or COPD, primarily by inhalation.

In the case of oral administration, apart from the mentioned carriers, the tablets can understandably also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additives such as starch, especially potato starch, gelatin and the like. Furthermore, in addition to the above-mentioned excipients for tableting, sliding agents such as magnesium stearate, sodium lauryl sulfate and talc can also be used. In the case of aqueous suspensions, the active substances, in addition to the auxiliaries mentioned above, can also be mixed with different flavor enhancers or colorants.

The dosage of the compounds according to the invention depends, of course, on the method of application and on the disease being treated. In the case of application by inhalation, the compounds of formula 1 are characterized by high efficiency already at dosages in the microgram range. The compounds of formula 1 can also be meaningfully used in the above μg-region. Then the dosage can be, for example, also in the range of grams. In particular, in the case of non-inhalational application, the compounds according to the invention can also be applied with a higher dosage (for example, but not limited to the range of 1 to 1000 mg).

The following example formulations serve to illustrate the proposed invention without any intention of limiting its scope.

Examples of pharmaceutical formulations

A) Tablets Per tablet

active substance 100 mg

milk sugar 140 mg

corn starch 240 mg

polyvinylpyrrolidone 15 mg

magnesium stearate 5 mg

500 mg

Finely ground active substance, milk sugar and part of corn starch are mixed together. The mixture is sieved, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated 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 a suitable shape and size.

B) Tablets Per tablet

active substance 80 mg

milk sugar 55 mg

corn starch 190 mg

microcrystalline cellulose 35 mg

polyvinylpyrrolidone 15 mg

sodium carboxymethyl starch 23 mg

magnesium stearate 2 mg

400 mg

Finely ground active substance, part of corn starch/milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and with the rest of corn starch and water it is processed into granulate, which is dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added to this, mixed and the mixture is pressed into tablets of suitable size.

C) Solution for ampoules

active substance 50 mg

sodium chloride 50 mg

water for injections 5 ml

The active substance is dissolved in water as needed at a pH value of 5.5 to 6.5 and adjusted with sodium chloride as isotonance. The resulting solution is filtered to remove pyrogens and the filtrate is filled under aseptic conditions into ampoules, which are then sterilized and sealed. Ampoules contain 5 mg, 25 mg and 50 mg of active substance.

D) Aerosol for dosing

active substance 0.005

sorbitan trioleate 0.1

monofluorotrichloromethane and

difluorodichloromethane 2:3 to 100

The suspension is filled in a conventional aerosol container with a dosing valve. With one activation, at least 50 μl of the suspension is released. If desired, more active can also be dosed (eg 0.02 wt. %).

E) Solutions (in mg/100 ml)

active substance 333.3 mg

formoterol fumarate 333.3 mg

benzalkonium chloride 10.0 mg

EDTA 50.0 mg

HCl (In) to pH 3.4

This solution is prepared in the usual way.

F) Inhalation powder

active substance 6 μg

formotero fumarate 6 μg

lactose monohydrate up to 25 mg

The inhalation powder is prepared in the usual way by mixing the individual ingredients.

F) Inhalation powder

active substance 10 μg

lactose monohydrate up to 5 mg

The inhalation powder is prepared in the usual way by mixing the individual ingredients.

Claims (11)

1. Compounds of general formula 1 [image] indicated by that A represents a divalent residue selected from the group they comprise [image] X- is an anion with one negative charge selected from the group consisting of chloride, bromide, methylsulfate, 4-toluenesulfonate and methanesulfonate; R1 and R2, the same or different, represent a residue selected from the group consisting of methyl, ethyl, n-propyl and iso-propyl, which can be substituted with hydroxy or with fluorine if necessary; R3, R4, R5 and R6, the same or different, represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF3 or NO2; R7 is hydrogen, methyl, ethyl, methyloxy, ethyloxy, -CH2-F, -CH2-CH2-F, -O-CH2-F, -O-CH2-CH2-F, -CH2-OH, -CH2-CH2- OH, CF3, -CH2-OMe, -CH2-CH2-OMe, -CH2-OEt, -CH2-CH2-OEt, -O-COMe, -O-COEt, -O-COCF3, -O-COCF3, fluorine, chlorine or bromine, as required in the form of individual optical isomers, mixtures of individual enantiomers or racemates. 2. Compounds of general formula 1 according to claim 1, characterized in that A represents a divalent residue selected from the group they comprise [image] X- is an anion with one negative charge selected from the group consisting of chloride, bromide and methanesulfonate; R1 and R2, the same or different, represent a residue selected from methyl and ethyl, which can be substituted with hydroxy or with fluorine if necessary; R3, R4, R5 and R6, the same or different, represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine; R7 is hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF3, or fluorine, as needed in the form of individual optical isomers, mixtures of individual enantiomers or racemates. 3. Compounds of general formula 1 according to any claim 1 to 2, characterized in that A represents a divalent residue selected from the group they comprise [image] X- is bromide; R 1 and R 2 are the same or different residues selected from methyl or ethyl; R3, R4, R5 and R6, the same or different, represent hydrogen, methyl, methyloxy, chlorine or fluorine; R 7 is methyl or fluoro; as needed in the form of individual optical isomers, mixtures of individual enantiomers or racemates. 4. Compounds of general formula 1 according to any claim 1 to 3, characterized in that A represents a divalent residue selected from the group they comprise [image] X- is bromide; R1 and R1, the same or different, represent methyl or ethyl; R 3 , R 4 , R 5 and R 6 , the same or different, represent hydrogen or fluorine; R7 is methyl or fluorine, as needed in the form of individual optical isomers, mixtures of individual enantiomers or racemates. 5. Use of a compound of general formula 1 according to any one of claims 1 to 4, characterized in that it is used as a medicine. 6. The use of a compound of the general formula 1 according to any one of claims 1 to 4, characterized in that it is used for the preparation of a drug for the treatment of asthma, COPD, vagally conditioned sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the airways for the removal of urine and menstrual problems. 7. Use of the compound of general formula 1 according to claim 6, characterized in that it is used for the preparation of a medicine for the treatment of asthma or COPD. 8. Pharmaceutical preparations, characterized by the fact that they contain as an active substance one or more compounds of the general formula 1, according to any claim 1 to 4 or their physiologically tolerable salts, if necessary in combination with usual auxiliary substances and/or carriers. 9. Pharmaceutical preparations according to claim 8, characterized in that, in addition to one or more compounds of formula 1, they contain at least one other active substance selected from the group consisting of betamimetics, antiallergics, PAF-antagonists, leukotriene antagonists and steroids. 10. Procedure for the preparation of the compound of general formula 1 [image] in which A, X- and the radicals R1, R2, R3, R4, R5, R6 and R7 can have the meanings specified in claims 1 to 4, indicated that in the first stage the compound of the general formula 3 [image] in which the radicals R3, R4, R5, R6 and R7 can have the meanings specified in claims 1 to 5, and R1 is chlorine or C1-C4-alkyloxy, reacts with the compound of formula 2 [image] wherein A and R1 can have the meanings set forth in claims 1 to 5, thereby giving the compound of formula 4 [image] in which A and the radicals R1, R3, R4, R5, R6 and R7 can have the meanings given in claims 1 to 4, and it is then converted with the compound R2-X, where R2 and X can have the meanings given in claims 1 to 4 , quaternizes to the compound of formula 1. 11. Intermediate of general formula 4 [image] indicated by that And the radicals R1, R3, R4, R5, R6 and R7 can have the meanings specified in claims 1 to 4.