SK287138B6 - Novel anticholinergic agents that can be used as medicaments and method for the production thereof - Google Patents

Abstract

Anticholinergic agents of general formula 1, wherein A, X- and R1, R2, R3, R4, R5, R6 and R7 have the meaning given in the description and claims. The process for preparing these compounds, pharmaceutical preparations containing these compounds and the use these compounds to treatment of asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the urinary tract and menstrual disorders, are described.

Description

Technical field

The invention relates to anticholinergic agents, a process for their preparation and their use as a medicament for the treatment of asthma or COPD.

BACKGROUND OF THE INVENTION

Anticholinergic drugs can be used with therapeutic effect in many diseases. For example, asthma treatment or COPD (chronic obstructive pulmonary disease) should be mentioned. For the treatment of these diseases, WO 92/16528 suggested the use of anticholinergic drugs having the basic structure of scopine, tropenol or even tropin.

The object of WO 92/16528 is to provide anticholinergically active compounds having a long-lasting effect. To solve this problem, WO 92/16528 describes, inter alia, scopine, tropenol or tropine benzylic esters.

For the treatment of chronic diseases, it is often necessary to prepare a drug with a longer duration of action. As a general rule, this is to ensure that the concentration of the active substance in the body is required over a longer period to achieve a therapeutic effect, without having to administer the drug repeatedly too often. Moreover, the application of the active ingredient over a longer period of time greatly contributes to the well-being of the patient. Particularly desirable is the preparation of a medicament which can be administered with a therapeutic effect once a day (single administration). Administration once a day has the advantage that the patient can get used to the drug regularly at a certain time of day.

In order to be able to administer the product once daily, specific requirements should be imposed on the active substance to be administered. First, after administration, the desired effect should appear relatively quickly, and ideally should preferably have a constant effect over a subsequent extended period of time. On the other hand, the duration of action of the drug over approximately one day should not be substantially exceeded. Ideally, the active ingredient has an effect profile such that the manufacture of a daily applied drug containing the active ingredient in therapeutically effective doses can be controlled in a targeted manner.

It has been found that the scopine, tropenol or even tropine benzylic acid esters described in WO 92/16528 do not meet these increased requirements. Due to the extremely long duration of action, which greatly exceeds the indicated time of approximately 1 day, they are not usable once daily.

It is therefore an object of the present invention to provide novel anticholinergic agents which, based on the effect profile, enable the preparation of a once-daily medicament. It is a further object of the present invention to provide compounds having a relatively rapid onset of action. It is a further object of the invention to provide compounds which, after a rapid onset of action, have constant activity over a longer period of time. It is a further object of the present invention to provide compounds whose duration of action does not substantially exceed about one day at therapeutically useful doses. Finally, it is an object of the invention to provide compounds having an effect profile that provides good control of the therapeutic effect (i.e., a full therapeutic effect without side effect due to the accumulation of the substance in the body).

Surprisingly, it has been found that the above-mentioned tasks can be solved by compounds of formula (1) in which the radical R ^{7 is} not hydroxy.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula (1):

(1) in which

SK 287138 Β6

A represents a divalent radical selected from the group consisting of \ / cc h ₂ h ₂ \ / c = c HH

X is simply a negatively charged anion,

R ¹ and R ² are C 1 -C ₄ -alkyl, which may be substituted by hydroxy or halogen;

R ³ , R ⁴ , R ⁵ and R ⁶ , the same or different, represent hydrogen, C 1 -C ₄ -alkyl, C 1 -C ₄ -alkyloxy, hydroxy, CF ₃ , CN, NO ₂ or halogen;

R ⁷ is hydrogen, C _r C ₄ -alkyl, C _r C ₄ alkyloxy, C _r C ₄ -alkylene-halogen, halogen-C _r C ₄ alkyloxy, C _r C ₄ -alkylene-OH, CF _3, - C ₁ -C ₄ -alkylene-C ₁ -C ₄ alkyloxy, -O-CO-C _r C ₄ alkyl, -0-CO-C _r C _{4-alkyl-halogen,} -O-COCF ₃ or halogen, wherein when A means \ /

^H 2 C ^H 2

R ¹ and R ² is methyl, and

R ^3, R ^4, R ^5, and R ⁶ is hydrogen,

R ⁷ cannot be hydrogen either.

Preferred are compounds of formula (1) wherein

A is a divalent radical selected from the group consisting of .alpha.-c-c

H, H, \ / c = c

H H

H

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

R ¹ and R ^2, identical or different, is a radical selected from the group consisting of methyl, ethyl, n-propyl or isopropyl, which may be optionally substituted by hydroxy or fluorine, preferably unsubstituted methyl ^1;

R ³ , R ⁴ , R ⁵ and R ⁶ , the same or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluoro, chloro, bromo, CN, CF ₃ or NO ₂ ;

R ⁷ is hydrogen, methyl, ethyl, methyloxy, ethyloxy, -CH ₂ -F, -CH ₂ -CH ₂ -F, -O-CH ₂ -F, -O-CH ₂ -CH ₂ -F, -CH ₂ -OH, -CH ₂ -CH ₂ -OH, CF ₃ , -CH ₂ -OMe, -CH ₂ -CH ₂ -OMe, -CH ₂ -OEt, -CH ₂ -CH ₂ -OEt, -O-COMe, -O-COEt, -O-COCF ₃ , fluoro, chloro or bromo.

Particularly preferred are compounds of formula (1) wherein

A is a divalent radical selected from the group consisting of

X 'is a single negatively charged anion selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide;

R ¹ and R ² , the same or different, represent a radical selected from the group consisting of methyl and ethyl, which may be optionally substituted by hydroxy or fluorine, preferably unsubstituted methyl;

R ³ , R ⁴ , R ⁵ and R ⁶ , the same or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluoro, chloro or bromo;

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

SK 287138 Β6

According to the invention, the preferred compounds of formula (1) wherein A is a divalent radical which is selected from among \ / C = CH ₂ H ₂

X is bromide;

R ¹ and R ² , the same or different, represent a radical selected from the group consisting of methyl and ethyl, which may be optionally substituted by hydroxy or fluorine, preferably unsubstituted methyl;

R ³ , R ⁴ , R ⁵ and R ⁶ , the same or different, represent hydrogen, methyl, methyloxy, chloro or fluoro;

R ⁷ is hydrogen, methyl or fluoro.

Particularly important according to the invention are compounds of formula (1) wherein

A represents a divalent radical selected from the group consisting of

X is bromide;

R ¹ and R ² , the same or different, denote methyl or ethyl, preferably methyl;

R ³ , R ⁴ , R ⁵ and R ⁶ , the same or different, are hydrogen or fluorine, preferably hydrogen; R 1 represents hydrogen, methyl or fluorine, preferably methyl or fluorine, particularly preferably methyl.

Further, the invention provides compounds of formula (1) optionally in the form of individual optical isomers, mixtures of individual enantiomers, or racemates.

In the compounds of formula (1), the radicals R ³ , R ⁴ , R ⁵ and R ⁶ , if they are not hydrogen, can be attached to the -CR ⁷ group in the ortho, meta or para position. If neither of the radicals R ³ , R ⁴ , R ⁵ and R ⁶ is hydrogen, R ³ and R ⁵ are preferably attached in the para position, and R ⁴ and R ^{6 are} preferably in the ortho or meta position, the meta position is particularly preferred. When one of R ³ and R ⁴ and one of R ⁵ and R ^s is hydrogen, the other radical is preferably in the meta or para position, particularly preferably is attached in the para position. If none of the radicals R ³ , R ⁴ , R ⁵ and R ⁶ is hydrogen, according to the invention those compounds of the general formula (1) in which R ³ , R ⁴ , R ⁵ and R ⁶ have the same meaning are particularly preferred.

Of particular interest according to the invention are compounds of formula (1) wherein the ester substituent on the nitrogen ring is α-substituted. These compounds correspond to the general formula (1-a).

According to the invention, the following compounds have a special meaning:

2,2-diphenylpropionic acid tropenol ester metobromide;

2,2-diphenylpropionic acid scopine ester metobromide;

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

- 2-fluoro-2,2-diphenylacetic acid tropenol ester metobromide.

Alkyl groups, unless otherwise indicated, are branched and unbranched alkyl groups having 1 to 4 carbon atoms. By way of example, methyl, ethyl, propyl or butyl are mentioned. Optionally, the abbreviations Me, Et, Prop or Bu are also used to denote methyl, ethyl, propyl or butyl groups. Unless otherwise described, it will define4

Propyl and butyl include all possible isomeric forms of the residues. For example, propyl includes n-propyl and isopropyl, butyl includes isobutyl, sec-butyl and tert-butyl, and the like.

Alkyl groups, unless otherwise indicated, are branched and unbranched bivalent alkyl bridges of 1 to 4 carbon atoms. By way of example, methylene, ethylene, propylene or butylene are mentioned.

Alkylenehalo groups, unless otherwise indicated, are branched and unbranched bivalent alkyl bridges having from 1 to 4 carbon atoms, which are mono-, di- or triple, preferably monosubstituted by halogen. Accordingly, unless otherwise noted, alkylene-OH groups are branched and unbranched divalent alkyl bridges having from 1 to 4 carbon atoms, which are mono-, di- or triple, preferably simply substituted by hydroxy.

Alkyloxy groups, unless otherwise indicated, are branched and unbranched alkyl groups having 1 to 4 carbon atoms attached through an oxygen atom. Examples which may be mentioned are methyloxy, ethyloxy, propyloxy or butyloxy. Optionally, the abbreviations MeO-, EtO-, PropO- or BuO- are also used to denote methyloxy, ethyloxy, propyloxy or butyloxy groups. Unless otherwise indicated, the definitions of propyloxy and butyloxy include all possible isomeric forms of the residues. For example, propyloxy includes n-propyloxy and isopropyloxy, butyloxy includes isobutyloxy, n-butyloxy and tert-butyloxy, etc. In the present invention, the alkyloxy designation is optionally used instead of the alkyloxy designation. The terms methoxy, ethoxy, propoxy or butoxy are optionally used to denote methyloxy, ethyloxy, propyloxy or even butyloxy groups accordingly.

Alkylenealkoxy groups, unless otherwise indicated, are branched and unbranched bivalent alkyl bridges having from 1 to 4 carbon atoms, which are mono-, di- or triple, preferably simply substituted by alkyloxy.

-O-CO-alkyl groups, unless otherwise indicated, are branched and unbranched alkyl groups having 1 to 4 carbon atoms attached through an ester group. The alkyl groups are bonded directly to the carbon of the carbonyl of the ester group. By analogy is meant the designation -O-CO-alkylhalo. The group -O-CO-CF ₃ represents trifluoroacetate.

Within the scope of the invention, halogen means fluorine, chlorine, bromine or iodine. Unless stated otherwise, preferred halogens are fluorine and bromine. The group CO represents a carbonyl group.

The preparation of the compounds according to the invention can be carried out, as mentioned, in part analogously to the preparation methods known from the prior art (Scheme 1). The carboxylic acid derivatives of formula (3) are known in the art or can be obtained by synthesis methods known in the art. If only substituted carboxylic acids are known in the art, the compounds of formula (3) can also be obtained directly from them by esterification catalyzed by acid or base with the corresponding alcohols or by halogenation with the corresponding halogenating reagents.

Scheme 1

Starting from compounds of formula (2), esters of formula (4) are obtained by reaction with carboxylic acid derivatives of formula (3) wherein R is, for example, chlorine or a C 1 -C ₄ -alkyloxy radical. R is the same as C _r C ₄ -alkyloxy, then the reaction can be carried out, for example, the sodium in the melt at elevated temperature, preferably about 50 to 150, particularly preferably about 90 to 100 ° C at low pressure, preferably below 50 kPa (500 mbar), particularly preferably below 7.5 kPa (75 mbar). Alternatively, instead of derivative 3, wherein R is C _r C ₄ -alkyloxy, to use the corresponding acid chlorides (R equal to C).

The compounds of formula (4) thus obtained can be converted to the target compounds of formula (1) by reaction with compounds R ² -X, in which R ² and X may have the meaning defined above. This synthesis step can also be carried out analogously to the synthesis examples given in WO 92/16528.

Alternatively, with the methods of synthesis of compounds of formula (4) shown in Scheme 1, derivatives 4 wherein the nitrogen cycle is a scopine derivative can be obtained by oxidizing (epoxidizing) the compounds of formula (4) wherein the nitrogen cycle is a tropenyl moiety. According to the invention this can be carried out as described later. Compound 4 wherein A is -CH = CH- is suspended in a polar organic solvent, preferably a solvent selected from the group consisting of N -methyl-2-pyrrolidone (NMP), dimethylacetamide and dimethylformamide, preferably dimethylformamide, and it is subsequently heated to about 30 to 90 ° C, preferably to 40 to 70 ° C. A suitable oxidizing agent is then added and stirred at constant temperature for 2 to 8 hours, preferably 3 to 6 hours. The oxidising agent is preferably used in a mixture with vanádiumpentoxid _{H2O 2j} particularly preferably complexed H ₂ 0 ₂ in combination with urea vanádiumpentoxidom. The processing is carried out in the usual manner. The purification of the products can be performed according to the ability to crystallize either by crystallization or by chromatography.

Alternatively, compounds of formula (4) wherein R ⁷ is halogen may also be obtained by the methods outlined in Scheme 2.

Scheme 2

R

fT

('4) (R ⁷ is halogen)

The benzylic acid esters of formula (5) are converted to compounds 4 in which R ⁷ is halogen using suitable halogenating agents. The carrying out of the halogenation reactions according to Scheme 2 is well known in the art.

The benzylic acid esters of formula (5) can be obtained analogously to methods known in the art (see for example WO 92/16528).

As can be seen in Scheme 1, the intermediates of formula (4) are of central importance. Accordingly, the invention further provides intermediates of formula (4)

which

A represents a bivalent radical selected from the group consisting of

c = c H H

R ¹ represents a C 1 -C ₄ -alkyl group which may be substituted by a hydroxy group or a halogen;

R ^3, R ^4, R ⁵ and R ^6, identical or different, represent hydrogen, a C _r C _4, C _r C ₄ alkyloxy, hydroxy, CF _3, CN, NO ₂ or halogen;

R ⁷ is hydrogen, C _r C ₄ -alkyl, C [-C ₄ alkyloxy, C _r C ₄ -alkylénhalogén, halogen-C _r C ₄ alkyloxy, C _r C ₄ -alkylene-OH, CF _3, C ₁ -C ₄ -alkylene-C ₄ alkyloxy, -O- COC ₁ -C ₄ -alkyl, -O-CO-C] _-C4 -alkylhalogén, -O-COCF ₃ or halogen, with the proviso that when A is \ /

C — C h ₂ h ₂

R ¹ and R ² is methyl, and

R ^3, R ^4, R ^5, and R ⁶ is hydrogen,

R ⁷ cannot be n-propyl.

Preferred are compounds of formula (1) wherein

A represents a divalent radical which is selected from the group consisting of \ Z c-c

H ₂ H, C / C = C

HH ^a

R ¹ , the same or different, means a radical selected from the group consisting of methyl, ethyl, n-propyl and isopropyl, which may be optionally substituted by hydroxy or fluorine, preferably unsubstituted methyl;

R ³ , R ⁴ , R ⁵ and R ⁶ , the same or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluoro, chloro, bromo, CN, CF ₃ or NO ₂ ;

R ⁷ is hydrogen, methyl, ethyl, methyloxy, ethyloxy, -CH ₂ -F, -CH ₂ -CH ₂ -F, -O-CH ₂ -F, -O-CH ₂ -CH ₂ -F, -CH ₂ -OH, -CH ₂ -CH ₂ -OH, CF ₃ , -CH ₂ -OMe, -CH ₂ -CH ₂ -OMe, -CH ₂ -OEt, -CH ₂ -CH ₂ -OEt, -O-COMe, -O-COEt, -O-COCF ₃ , -O-COCF 3, fluoro, chloro or bromo.

Particularly preferred are compounds of formula (1) wherein

A is a divalent radical chosen from among \ / cc h ₂ h ₂

R ¹ , the same or different, represents a radical which is methyl or ethyl, which may be substituted by hydroxy or fluorine, preferably unsubstituted methyl;

R ³ , R ⁴ , R ⁵ and R ⁶ , the same or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluoro, chloro or bromo;

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

According to the invention, compounds of general formula (1) are preferred wherein:

A represents a divalent radical selected from the group consisting of \ Z

C-C

H, H, \ / c = c

H H

R ¹ , the same or different, means a radical which is methyl or ethyl, preferably methyl;

R ³ , R ⁴ , R ⁵ and R ⁶ , the same or different, represent hydrogen, methyl, methyloxy, chloro or fluoro; R ⁷ is hydrogen, methyl or fluoro.

According to the invention, compounds of formula (1) wherein:

A represents a divalent radical selected from the group consisting of

R ¹ , the same or different, represents methyl or ethyl, preferably methyl;

R ³ , R ⁴ , R ⁵ and R ⁶ , the same or different, are hydrogen or fluorine, preferably hydrogen;

R ⁷ represents hydrogen, methyl or fluorine, preferably methyl or fluorine, particularly preferably methyl.

As in the compounds of formula (1) as well as in the intermediates of formula (4), the radicals R ³ , R ⁴ , R ⁵ and R ⁶ , if they do not represent hydrogen, may be ortho, meta relative to the -C-OH group. or para. If neither of the radicals R ³ , R ⁴ , R ⁵ and R ⁶ is hydrogen, R ³ and R 'are preferably attached in the para position, and R ⁴ and R ^{6 are} preferably in the ortho or meta position, the meta position is particularly preferred. When one of the radicals R ³ and R ⁴ and one of the radicals R ⁵ and R ⁶ is hydrogen, the other radical is preferably in the meta or para position, particularly preferably in the para position. If none of the radicals R ³ , R ⁴ , R ⁵ and R ⁶ is hydrogen, according to the invention those intermediates of formula (4) in which R ³ , R ⁴ , R 'and R ⁶ have the same meaning are particularly preferred.

The synthetic examples described illustrate the invention. It is to be understood, however, that they are merely exemplary of the method of further illustrating the invention without limiting the invention to the subject matter described later.

The compounds of formula (1) have been found to possess a variety of therapeutic applications. Emphasis should be placed on those applications in which the compounds of formula (1) according to the invention can advantageously be used as anticholinergic agents on account of their pharmaceutical activity. For example, asthma treatment or COPD (chronic obstructive pulmonary disease). The compounds of formula (1) may further be used for the treatment of vagally-related sinus bradycardia and for the treatment of rhythmic heart disorders. In general, the compounds of the invention may further be used for the treatment of spasms, for example in the gastrointestinal tract with therapeutic effect. They can further be used for the treatment of urinary spasms, as well as, for example, for the treatment of menstrual disorders.

Among the indicated indication areas, by way of example, the treatment of asthma and COPD by the compounds of formula (1) of the invention is of particular importance.

The compounds of formula (1) may be used alone or in combination with other active compounds of formula (1) according to the invention. The compounds of formula (1) may optionally also be used in combination with other pharmacologically active active ingredients. These are in particular beta-mimetics, anti-allergic agents, PAF-antagonists, leukotriene antagonists and corticosteroids, as well as combinations of their active substances.

Examples of beta-mimetics that can be used in combination with the compounds of formula (1) of the invention include compounds selected from the group consisting of bambuterol, bitolterol, carbuterol, clenbuterol, phenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol , procaterol, reproterol, salmeterol, sulfonterol, terbutaline, tolubuterol, 4-hydroxy-7- [2 - {[2 - {[3- (2-phenylethoxy) propyl] sulfonyl} ethyl] amino} ethyl] -2 (377) -benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [3- (4-methoxybenzylamino) -4] -hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4/7-1,4-4- benzoxazin-8-yl] -2- [3- ^(4-N, A-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol, l- [277-5-hydroxy-3-oxo-477-l, 4-Benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2S-5-hydroxy-3-oxo-4 / 7-1, 4-Benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-477-1] , 4-benzoxazin-8-yl] - 2- {4- [3- (4-Methoxy-phenyl) -1,2,4-triazol-3-yl] -2-methyl-2-butylamino} -ethanol, 5-hydroxy-8- (1-hydroxy-2) -isopropylaminobutyl-2H-1,4-benzoxazin-3- (477) -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 racemates, enantiomers, diastereomers, as well as optionally pharmacologically acceptable acid addition salts and hydrates. Particularly preferred as beta-mimetics for use are those active compounds in combination with the compounds of formula (1) of the invention selected from the group consisting of phenoterol, formoterol, salmeterol, 1- [3- (4-methoxybenzylamino)] -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [27H-5-hydroxy-3-oxo-4 / 7-1,4-benzoxazine- 8-yl] -2- [3- ^(4-N, 7V-dimethylamino-phenyl) -2-methyl-2-propylamino] ethanol, l- [27/5-hydroxy-3-oxo-477-l, 4 -benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [277-5-hydroxy-3-oxo-4H-1,4-benzoxazine- 8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [277-5-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, optionally in the form of racemates, enantiomers, diastereomers , as well as in the form of optionally pharmacologically acceptable acid addition salts and hydrates. Of these beta-mimetics, of particular interest are formoterol and salmeterol optionally in the form of racemates, enantiomers, diastereomers, as well as optionally in the form of pharmacologically acceptable acid addition salts and hydrates.

According to the invention, acid addition salts of beta-mimetics selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate and xinafoate are preferred. Salmeterol salts are particularly preferred, which may be hydrochloride, sulfate and xinafoate, of which sulfates and xinafoates are particularly preferred. Particularly preferred according to the invention are salts for formoterol, which may be hydrochloride, sulfate and fumarate, of which hydrochloride and fumarate are particularly preferred. According to the invention, formoterol fumarate is particularly preferred.

SK 287138 Β6

Within the scope of the invention, corticosteroids, which may optionally be used in combination with compounds of formula (1), are compounds selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rileponide, GW 215864, KSR 592, ST-126 and dexamethasone. Within the scope of the invention, corticosteroids are selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexamethasone, with budesonide, fluticasone, mometasone and ciclesonide being particularly preferred, and budesonide being particularly preferred. Optionally, the steroid designation is used in the patent application instead of the corticosteroid designation. Referring to steroids includes within the scope of the invention reference to salts or derivatives that can be formed from steroids. Possible salts or derivatives include, for example, sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalate or furoates. Corticosteroids may optionally be present in the form of hydrates.

For the purposes of the invention, dopamine agonists which may optionally be used in combination with compounds of formula (1) are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozan. Preferably, dopamine agonists are used in combination with compounds of formula (1) selected from the group consisting of pramipexole, talipexole and viozane, with pramipexole being particularly preferred. Optionally existing pharmacologically acceptable acid addition salts and optionally hydrates are also contemplated for the dopamine agonists of the invention. Among the physiologically acceptable acid addition salts that said dopamine agonists can form are pharmaceutically acceptable salts selected from hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, filmaric, succinic, lactic, citric, tartaric and maleic salts.

Examples of antiallergic agents which can be used according to the invention in combination with the compounds of formula (1) include epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipine, cexchl, phenol doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozin. Preferred antiallergic agents which can be used in combination with the compounds of formula (1) of the invention are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratidine and mizolastine, particularly epinastine and desloratidine are preferred. Within the scope of the invention, the existing pharmacologically acceptable acid addition salts are optionally also suitable for the said antiallergic agents.

Examples of PAF antagonists which can be used in combination with the compounds of formula (1) according to the invention include 4- (2-chlorophenyl) -9-methyl-2- [3- (4-morpholinyl) -3-propanone-1]. -yl] -6 H -thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine, 6- (2-chlorophenyl) -8,9 -dihydro-1-methyl-8 - [(4-morpholinyl) carbonyl] -4,7,7,7-cyclopenta- [4,5] -thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine.

When the compounds of formula (1) are used in combination with other active substances, among the groups of compounds mentioned above, a combination with steroids or beta-mimetics is particularly preferred. Combination with beta-mimetics, particularly slow-acting beta-mimetics, is particularly advantageous. Particularly preferred is the combination of the compounds of formula (1) of the invention with salmeterol or formoterol, the combination with formoterol being most preferred.

Suitable forms of application for administration of the compounds of formula (1) are, for example, tablets, capsules, suppositories, solutions, etc. Inhalation of the compounds of the invention is particularly preferred (especially in the treatment of asthma or COPD). The proportion of the pharmaceutical active compound (s) should always be in the range 0.05 to 90% by weight, preferably 0.1 to 50% by weight of the total composition. The corresponding tablets may consist, for example, of mixtures of the active substance or substances with known excipients, for example with known diluents such as calcium carbonate, calcium phosphate or milk sugar, hardeners such as corn starch or alginic acid, binders such as starch or gelatin, with lubricants such as magnesium stearate or talc, and / or with a depot effect such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also consist of multiple layers.

Accordingly, dragees may be prepared by coating the cores, analogously to tablets, with the usual coating compositions, for example collidone, shellac, acacia, talc, titanium dioxide or sugar. To achieve a depot effect or to prevent incompatibility, the core may also consist of multiple layers. Similarly, to achieve a depot effect, the dragee casing may consist of several layers, the excipients mentioned in the tablets being used.

The active substance juices or active compound combinations according to the invention may additionally contain a sweetening agent, for example saccharin, cyclamate, glycerin or sugar, as well as a flavoring agent, for example a flavoring agent such as vanillin or an orange extract. They may additionally contain suspending aids or thickening agents such as sodium carboxymethylcellulose, crosslinking agents such as condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions are prepared in a conventional manner, for example with the addition of isotonic agents, preservatives such as µ-hydroxybenzoates, or stabilizers, such as the alkali salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants, for example using water as a diluent. optionally using organic solvents as co-solvents, and dispensed into vials or ampoules, or infusion bottles.

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

Suitable suppositories may be prepared, for example, by mixing suitable carriers, such as neutral fats or polyethylene glycol, or derivatives thereof. Excipients include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), oils of vegetable origin (e.g. peanut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerin), carriers such as natural mineral flours (e.g. kaolins, clays, talc, chalk), synthetic mineral flours (e.g. high disperse silicic acid and silicates), sugar (e.g. cane, lactic and grape sugar), emulsifiers (e.g. lignin, sufitablaugen, methylcellulose, starch and methylcellulose), starch and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

Administration is carried out in the usual manner, in the case of asthma or COPD, preferably by inhalation.

For oral use, tablets may of course also contain, in addition to the aforementioned carriers, excipients such as sodium citrate, calcium carbonate and dicalcium phosphate together with various other ingredients such as starch, preferably potato starch, gelatin and the like. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may also be used for tabletting. In the case of aqueous suspensions, in addition to the excipients mentioned above, the active substances may be mixed with various flavoring or coloring agents.

The dosage of the compounds of the invention is, of course, highly dependent on the route of administration and the disease being treated. When administered by inhalation, the compounds of formula (1) exhibit high activity even in the microgram dose range. Even above the microgram region, the compounds of formula (1) can be effectively used. For example, the dosage may also be in the gram range. In particular, for non-inhalation administration, the compounds of the invention may be used in larger dosages (for example, but not limited to, in the range of 1 to 1000 mg).

DETAILED DESCRIPTION OF THE INVENTION

Example 1

2,2-Diphenylpropionic acid scopine ester metobromide

1.1. - 2,2-Diphenylpropionic acid chloride 3a

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

1.2. - 2,2-Diphenylpropionic acid scopine ester 4a

The residue obtained from step 1.1 is dissolved in 100 ml of dichloromethane and treated dropwise with a solution containing 51.45 g (0.33 mol) of scopine in 200 ml of dichloromethane at 40 ° C. The resulting suspension is stirred for 24 h at 40 ° C, then the precipitate formed is suction filtered and the filtrate is extracted first with water, then with an acidic aqueous hydrochloric acid solution. the pH of the combined aqueous phases with sodium carbonate adjusted to an alkaline value, extracted with dichloromethane, the organic phase is dried over Na ₂ SO _4, concentrated to dryness and the residue is precipitated hydrochloride. Purification is accomplished by crystallization from acetonitrile.

SK 287138 Β6

Yield: 20.85 g (= 47% of theory)

DC: Rf value: 0.24 (eluent: buta / butanol / formic acid / water 75: 15: 10); mp: 203-204 ° C.

1.3 - 2,2-Diphenylpropionic acid scopine ester methobromide

11.98 g (0.33 mol) of 4a, 210 ml of acetonitrile, 70 ml of dichloromethane and 20.16 g (0.1 mol) of 46.92% bromomethane in acetonitrile are mixed at 20 ° C and allowed to stand for 3 hours. days. The solution was concentrated to dryness and the residue was crystallized from isopropanol.

Yield: 11.34 g (= 75% of theory), m.p. 208-209 ° C.

C ₂₄ H ₂₈ NO ₃ xBr (458.4);

Elemental analysis: calculated: C (62.89) H (6.16) N (3.06) found: C (62.85) H (6.12) N (3.07)

Example 2

2-Fluoro-2,2-diphenylacetic acid scopine ester metobromide

2.1. - Scopine ester of benzylic acid 5a

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

2.2 - 2-Fluoro-2,2-diphenylacetic acid scopine ester 4b

The dimethylaminosulfur trifluoride (2.66 g, 0.02 mol) was cooled to 0 ° C in dichloromethane (10 ml) and a solution containing benzylic acid scopine ester 5a (5.48 g, 0.015 mol) in dichloromethane (100 ml) was added dropwise. Then stir for 30 min. at 0 ° C and 30 min. at 20 ° C. While cooling, the solution is mixed with water, NaHCO ₃ 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 Na ₂ SO ₄ and concentrated to dryness.

The hydrochloride precipitated from the residue and crystallized from acetonitrile.

Yield: 6.90 g (= 85% of theory)

Melting point: 227-230 ° C.

2.3 2-Fluoro-2,2-diphenylacetic acid scopine ester methobromide

2.88 g (0.0078 mol) of benzylic acid scopine ester free base are converted in analogy to Step 1.3. Purification is accomplished by crystallization from isopropanol. Yield: 2.62 g (= 73% of theory).

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

Example 3

2,2-Diphenylpropionic acid tropenol ester metobromide

3.1. - 2,2-Diphenylpropionic acid methyl ester 3b

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

2.3 - 2,2-Diphenylpropionic acid tropenol 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 are heated in the form of a melt at 75 mbar for 4 h on a boiling water bath with occasional drowsiness. After cooling, the sodium residues were dissolved with acetonitrile, the solution was concentrated to dryness and the residue was extracted with dichloromethane / water. The organic phase was washed with water, dried over _MgSO4 and concentrated to dryness.

4c is precipitated from the residue as the hydrochloride, which is crystallized from acetone. Yield: 5.13 g (= 67% of theory);

DC: Rf value: 0.28 (eluent: sec-butanol / formic acid / water 75: 15: 10); mp: 134-135 ° C.

3.3 - 2,2-Diphenylpropionic acid tropenol ester metobromide

2.20 g (0.006 mol) of 4c was converted in analogy to Example 1, step 1.3. The crystals formed are filtered off with suction, washed with dichloromethane, dried and then crystallized from methanol / diethyl ether.

Yield: 1.84 g (= 66% of theory)

DC: R f value: 0.11 (eluent analogous to step 1.2); mp 222-223 ° C. C ₂₄ H ₂₈ NO ₂ xBr (442.4);

Elemental analysis: calculated: C (65.16) H (6.38) N (3.17) found: C (65.45) H (6.29) N (3.16)

Example 4

2-Fluoro-2,2-bis (3,4-difluorophenyl) acetic acid tropenol ester metobromide

4.1. - 3,3 ', 4,4'-Tetrafluorobenzylic acid ethyl ester 3c

The Grignard reagent is prepared from 2.24 g (0.092 mol) magnesium shavings, several grains of iodine and 17.80 g (0.092 mol) 1-bromo-3,4-difluorobenzene in 100 ml THF at 50 ° C. Stirring is continued for one hour after the halide addition is complete. The Grignard reagent thus obtained was 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 was stirred at 5 ° C for 2 hours. The white suspension was poured on to ice-processing / sulfuric acid, extracted with ethyl acetate, the organic phase washed with water, dried over _MgSO4 and concentrated to dryness. Purification of the crude product was carried out by column chromatography (eluent: toluene).

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

2.4 3.3'.4.4'-Tetrafluorobenzylic acid tropenol ester 5b

4.27 g (0.013 mol) of 3,3'4,4'-tetrafluorobenzylic acid ethyl ester 3c, 1.81 g (0.013 mol) of tropenol and 0.03 g of sodium are heated in the form of a melt at 75 mbar for 4 h. boiling water bath with occasional need. After cooling, the sodium residues were dissolved in acetonitrile, the solution was concentrated to dryness, and the residue was extracted with dichloromethane / water. The organic phase was washed with water, dried over _MgSO4 and concentrated to dryness. The remaining residue is mixed with diethyl ether / petroleum ether 1: 9, filtered off with suction and washed. Yield: 2.50 g (= 46% of theory);

DC: Rf value: 0.29 (eluent: sec-butanol / formic acid / water 75: 15: 10); mp: 147-148 ° C.

3.4 2-Fluoro-2,2-bis (3,4-difluorophenyl) acetic acid tropenol ester 4d

2.66 g (0.012 mol) of bis- (2-methoxyethyl) -aminosulfurtrifluoride in 10 ml of dichloromethane are added dropwise over 20 min. at 15-20 ° C with a solution containing 0.01 mol of 5b in 65 ml of dichloromethane. Stir for 20 h at room temperature, cool to 0 ° C and carefully mix with 80 ml of water with vigorous stirring. The pH is then carefully adjusted to 8 using NaHCO ₃ solution, the organic phase is separated, the aqueous phase is again extracted with dichloromethane, the combined organic phases are washed with water, dried over MgSO ₄ and concentrated to dryness. The hydrochloride precipitated and crystallized from acetonitrile / diethyl ether.

Yield: 2.60 g of white crystals (= 57% of theory). Mp 233 ° C.

4.4 - 2-Fluoro-2,2-bis (3,4-difluorophenyl) acetic acid tropenol ester metobromide

2.20 g (0.0052 mol) of 4d was converted in analogy to Example 1, step 1.3. The crystals formed are filtered off with suction, washed with dichloromethane, dried and then crystallized from methanol / diethyl ether.

Yield: 1.95 g (= 72% of theory)

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

C ₂₃ H ₂₁ F _with NO ₂ xBr (518.3);

Elemental analysis: calculated: C (53.30) H (4.08) N (2.70) found: C (53.22) H (4.19) N 2.69)

Example 5

2,2-Diphenylpropionic acid scopine ester ethyl bromide

br

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

Yield: 1.38 g (= 58% of theory); mp: 208-209 ° C ₂₅ H ₃₀ NO ₃ xBr (472.42);

Elemental analysis: calculated: C (63.56) H (6.40) N (2.96) found: C (63.49) H (6.24) N (2.88)

Example 6

2-Fluoro-2,2-bis (3,4-difluorophenyl) acetic acid scopine ester metobromide

SK 287138 Β6

6.1. - Scopinester of 3,3 ', 4,4'-tetrafluorobenzylic acid 5c

3.61 g (0.011 mol) of ethyl tetrafluorobenzyl ester 3c, 1.71 g (0.011 mol) of scopine and 0.03 g of sodium are heated as melt at 75 mbar for 4 hours in a boiling water bath occasionally by shaking. After cooling, the sodium residues were dissolved in acetonitrile, the solution was concentrated to dryness and the residue was extracted with dichloromethane / water. The organic phase was washed with water, dried over _MgSO4 and concentrated to dryness. The remaining residue is mixed with diethyl ether / petroleum ether 1: 9, filtered off with suction and washed. Yield: 1.75 g (= 36% of theory).

Melting point: 178-179 ° C.

2.6 2-Fluoro-2,2-bis (3,4-difluorophenyl) acetic acid scopine ester 4e

0.6 ml (0.0033 mol) of bis- (2-methoxyethyl) -aminosulfurtrifluoride was converted with 1.2 g (0.0028 mol) of 5c analogously to Example 4, step 4.3.

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

3.6 - 2-Fluoro-2,2-bis (3,4-difluorophenyl) acetic acid scopine ester methobromide

1.15 g (0.0026 mol) of 4e and 1.5 g (0.0079 mol) of a 50% methyl bromide solution were converted in analogy to Example 1, step 1.3. The crystals formed are filtered off with suction, washed with dichloromethane, dried and crystallized from acetone.

Yield: 0.88 g (= 63% of theory)

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

C ₂₃ H ₂₁ F ₅ NO ₃ xBr (535.33).

Example 7

2-Fluoro-2,2-bis (fluorophenyl) acetic acid tropenol ester metobromide

7.1. : 4,4'-Difluorobenzylic acid methyl ester 3d

7.1.1. 4,4'-Difluorobenzylic acid

To a solution containing 49.99 g (1.25 mol) of NaOH pellets in 300 ml of water, a solution containing 24.62 g (0.1 mol) of 4,4'-difluorobenzyl in 250 ml of dioxane is added dropwise at approximately 100 ° C. and stirred for 2 hours. The dioxane is largely distilled off and the remaining aqueous solution is extracted with dichloromethane. During acidification of the aqueous solution with sulfuric acid, a precipitate precipitates, which is suctioned off, washed and dried. The filtrate is extracted with dichloromethane, the organic phase is dried over Na ₂ SO ₄ and concentrated to dryness. Yield: 25.01 g (= 95% of theory); mp: 133-136 ° C.

7.1.2. 4,4'-Difluorobenzylic acid methyl ester

To a freshly prepared sodium methanol solution containing 2.17 g (0.095 mol) of sodium and 200 ml of ethanol at 20 ° C was added 25.0 g (0.095 mol) of 4,4'-difluorobenzylic acid and stirred for 3 hours. The solution was concentrated to dryness, the residue was dissolved in DMF, treated dropwise with 22.57 g (0.16 mol) of methyl iodide at 20 ° C and stirred for 24 hours. Stirring and purification are performed analogously to compound 3b. Yield: 21.06 g of 11 (= 80% of theory).

2.7 - 4,4'-Difluorobenzylic acid tropenol ester 5d

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

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

Mp .: 233-235 ° C.

7.3. 2-Fluoro-2,2-bis (4-fluorophenyl) -acetic acid tropenol ester 4 f

2.94 g (0.013 mol) of bis- (2-methoxyethyl) -aminosulfur trifluoride were converted with 3.85 g (0.01 mol) of 5d analogously to Example 4, step 4.3 in 100 ml of dichloromethane. The product is crystallized from acetonitrile as the hydrochloride. Yield: 2.93 g (= 69% of theory).

4.7 - 2-Fluoro-2,2-bis (4-fluorophenyl) acetic acid tropenol ester metobromide

2.6 g (0.0067 mol) of 4f and 1.9 g (0.0079 mol) of a 50% methyl bromide solution were converted analogously to Example 1, step 1.3. The crystals formed are filtered off with suction, washed with dichloromethane, dried and then crystallized from methanol / diethyl ether.

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

DC: Rf value: 0.55 (eluent: according to Example 1, step 1.2); Melting point: 230-231 ° C.

C ₂₃ H ₂₃ F ₃ NO ₂ xBr (482.34);

Elemental analysis: calculated: C (57.27) H (4.81) N (2.90) found: C (57.15) H (4.84) N (2.96)

Example 8

2-Fluoro-2,2-bis (4-fluorophenyl) acetic acid scopine ester metobromide

8.1. - 4,4'-Difluorobenzylic acid scopine ester 5e

4.22 g (0.01 mol) of 4,4'-difluorobenzylic acid tropenol ester 5d is suspended in 80 ml of DMF. At about internal temperature 40 ° C was added a solution of 2.57 g (0.0273 mole) of H ₂ O ₂ -urea in 20 ml of water and 0.2 g (0.0011 mol) of vanadium pentoxide and stirred for 4.5 h at 60 ° C. After cooling to 20 ° C, the precipitate formed is filtered off with suction, the pH of the filtrate is adjusted to 3 with 4N hydrochloric acid and mixed with Na ₂ S ₂ O ₅ dissolved in water. The green solution thus obtained is concentrated to dryness and the residue is extracted with dichloromethane / water. The acidic aqueous phase is made basic with Na ₂ CO ₃ , the dichloromethane is extracted and the organic phase is dried over Na ₂ SO ₄ and concentrated. 0.5 ml of acetyl chloride is then added at about 15 ° C and stirred for 1.5 h. Extraction with 0, lN hydrochloric acid, the aqueous phase is rendered alkaline, extracted with dichloromethane, the organic phase is dried over Na ₂ SO ₄ and concentrated to dryness. The hydrochloride precipitated from the residue and crystallized from methanol / diethyl ether. Yield: 3.61 g of white crystals (= 78% of theoretical).

Melting point: 243-244 ° C.

2.8 - 2-Fluoro-2,2-bis (4-fluorophenyl) acetic acid scopine ester 4g

1.48 g (0.0067 mol) of bis- (2-methoxyethyl) -aminosulfurtrifluoride was converted with 2.0 g (0.005 mol) of 5e analogously to Example 4, step 4.3 in 80 ml of dichloromethane. The product is crystallized as the hydrochloride from ethanol.

Yield: 2.07 g (= 94% of theory); mp 238-239 ° C.

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

1.6 g (0.004 mol) of 4g and 1.14 g (0.0079 mol) of a 50% methyl bromide solution were converted in analogy to Example 1, step 1.3. The crystals formed are filtered off with suction, washed with dichloromethane, dried and then crystallized from acetonitrile.

Yield: 1.65 g of white crystals (= 61% of theoretical) DC: Rf value: 0.25 (eluent: according to Example 1, step 1.2);

Melting point: 213-214 ° C.

C ₂₃ H ₂₃ F ₃ NO ₃ XBR (498.34);

Elemental analysis: calculated: C (55.43) H (4.65) N (2.81) found: C (54.46) H (4.67) N (2.80)

Example 9

2-Fluoro-2,2-diphenylacetic acid tropenol ester metobromide

9.1. - Benzylic acid tropenol ester 5f

Tropenol ester of benzylic acid as well as a process for its preparation is known from WO 92/16528.

9.2 - 2-Fluoro-2,2-diphenylacetic acid tropenol ester 4h

15.86 ml (0.086 mol) of bis- (2-methoxyethyl) -aminosulfurtrifluoride were converted with 25 g (0.072 mol) of 5f analogously to Example 4, step 4.3 in 480 ml of chloroform. The product is crystallized from acetone as the hydrochloride.

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 metobromide

11.12 g (0.032 mol) of 4h and 18.23 g (0.096 mol) of a 50% methyl bromide solution were converted in analogy to Example 1, step 1.3. The resulting crystals are crystallized from acetonitrile.

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

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

Mp .: 238-239 ° C.

C ₂₃ H ₂₅ FNO ₂ xBr (446.36);

Elemental analysis: calculated: C (61.89) H (5.65) N (3.14) found: C (62.04) H (5.62) N (3.17)

Example 10

2-Fluoro-2,2- (3-chlorophenyl) acetic acid tropenol ester metobromide

1.10 : 3,3'-Dichlorobenzylic acid methyl ester 3e

10.1.1. - 3,3'-Dichlorobenzyl

At room temperature, 50.0 g (0.356 mol) of 3-chlorobenzaldehyde and 4.54 g (0.018 mol) of 3-ethyl-5- (2-hydroxyethyl) -4-methylthiazolium bromide are added to 100 ml of ethanol. 10.7 g (0.11 mol) of triethylamine are then added dropwise. The solution was refluxed for 3 h and concentrated to dryness. The residue was taken up in ethyl acetate and extracted with water, sodium pyrosulfite in water and Na ₂ CO _{3 solution} . After drying over _MgSO4, concentration to dryness. The product obtained is crystallized from isopropanol and petroleum ether. Yield: 13.2 g of white crystals (= 13% of theory); mp 69-70 ° C.

13.0 g of the acyloin thus obtained are dissolved in 460 ml of acetonitrile at room temperature, 0.0867 g of vanadium (V) -oxytrichloride are added and oxygen is introduced. After 1.5 h, the solution was concentrated to dryness, extracted with ethyl acetate and water, as well as Na ₂ CO ₂ solution, dried over MgSO ₄ and concentrated to dryness. The remaining residue is extracted with petroleum ether / ethyl acetate 95: 5.

Yield: 12.59 g of yellow crystals (= 97% of theoretical); mp 116-117 ° C.

10.1.2. - 3,3'-Dichlorobenzylic acid

51.45 g (1.286 mol) of sodium hydroxide in 1000 ml of water are mixed dropwise in a boiling water bath with a solution containing 28.5 g (0.102 mol) of 3,3'-dichlorobenzyl in 700 ml of dioxane and then stirred for 1 hour . After cooling, the dioxane is concentrated, the residue is diluted with water and extracted with diethyl ether. The organic phase was acidified, extracted with dichloromethane, dried over _MgSO4, concentrated to dryness. Yield: 32.7 g (= 71% of theory).

10.1.3. - 3,3'-Dichlorobenzylic acid methyl ester

A solution of sodium ethanol is prepared from 100 ml of ethanol and 1.97 g (0.0855 mol) of sodium, to which 26.6 g (0.0855 mol) of 3,3'-dichlorobenzylic acid in 50 ml of ethanol are added dropwise. The solution was stirred for 4 h at room temperature. After distilling off the solvent, the residue was dissolved in 150 ml of DMF and methyl iodide (24.27 g, 0.171 mol) was added dropwise and stirred for an additional 24 hours. While 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, then the organic phases are washed with Na ₂ CO _{3 solution} and water is required to neutralize the pH. Drying bilge ₂ SO ₄ concentrated to dryness.

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

2.10 - 3,3'-Dichlorobenzylic acid tropenol ester 5g

22.9 g (0.074 mol) of 3,3'-dichlorobenzylic acid methyl ester 3e, 15.37 g (0.11 mol) of tropenol and 0.17 g of sodium are heated in the form of a melt at 75 mbar for 4 h. ) on a boiling water bath with occasional drowsiness. After cooling, the sodium residues were dissolved in acetonitrile, the solution was concentrated to dryness and the residue was extracted with dichloromethane / water. The organic phase was washed with water, dried over _MgSO4 and concentrated to dryness. The product crystallizes as the hydrochloride from acetonitrile.

Yield: 16.83 g of white crystals (= 50% of theoretical); Melting point: 184-185 ° C.

10.3. 2-Fluoro-2,2-bis (3-chlorophenyl) acetic acid tropenol ester 4i

1.48 g (0.0067 mol) of bis- (2-methoxyethyl) -aminosulfurtrifluoride in 10 ml of dichloromethane were added dropwise over 20 min. at 15-20 ° C with a solution containing 2.09 g of 5g in 65 ml of dichloromethane. Stir for 20 h at room temperature, cool to 0 ° C and carefully mix with 80 ml of water with vigorous stirring. The pH of the solution is then carefully adjusted to 8 with aqueous NaHCO ₃ , the organic phase is separated, the aqueous phase is back extracted with dichloromethane, the combined organic phases are washed with water, dried over MgSO ₄ and concentrated to dryness. The hydrochloride precipitated and crystallized from acetonitrile / diethyl ether. Yield: 1.20 g of white crystals (= 53% of theory) Melting point: 136-137 ° C.

4.10 - 2-Fluoro-2,2-bis (3-chlorophenyl) acetic acid tropenol ester metobromide

1.0 g (0.002 mol) of 4h was converted in analogy to Example 1, step 1.3. The crystals formed are filtered off with suction, washed with dichloromethane, dried and then crystallized from methanol / diethyl ether. Yield: 0.82 g of white crystals (= 80% of theoretical).

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

C ₂₃ H ₂₃ Cl ₂ FNO ₂ xBr (515.25).

The following pharmaceutical examples illustrate the invention without limiting its scope:

Examples of pharmaceutical compositions

A)

tablets in one tablet Active Ingredient Milk Sugar Maize starch Polyvinylpyrrolidone Magnesium stearate 100 mg 140 mg 240 mg 15 mg 5 mg 500 mg

The finely divided active ingredient, milk sugar and part of the corn starch are mixed. The mixture is sieved, moistened with a solution of polyvinylpyrrolidone in water, mixed, granulated in the wet state and dried. The granulate, the corn starch residue and the magnesium stearate are sieved and mixed. The mixture is compressed into tablets of suitable shape and size.

B)

Tablets in one tablet

Active substance Milk sugar Corn starch Microcrystalline cellulose Polyvinylpyrrolidone Sodiumcarboxmethy starch Magnesium stearate 80 mg 55 mg 190 mg 35 mg 15 mg 23 mg 2 mg 400 mg

The finely divided active ingredient, a portion of corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed, the mixture is sieved and mixed with the corn starch residue and water and processed to a granulate which is dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added thereto, mixed and compressed into tablets of suitable size.

C)

Solution in ampoules

Active substance Sodium chloride Water for injections 50 mg 50 mg 5 ml

The active ingredient is dissolved in water at its own pH or optionally at a pH of 5.5 to 6.5 and mixed with sodium chloride as an isotonizing agent. The solution obtained is pyrogen-free filtered and the filtrate is aseptically filled into ampoules which are then sterilized and sealed. The ampoules contain 5 mg, 25 mg and 50 mg of active ingredient.

D)

Dosing aerosol

Active substance sorbitan Monofluorotrichloromethane and difluorodichloromethane 2: 3 0,005 0.1 ad 100

The suspension is dispensed into a conventional aerosol container with a metering valve. Preferably, 50 μΐ of the suspension is released in one application. The active ingredient can also be dosed higher if desired (e.g. 0.02% by weight).

E)

Solutions (mg / 100 ml)

Active substance F ormoterol fumarate Benzalkonium chloride EDTA HCI 333.3 mg 333.3 mg 10.0 mg 50.0 mg ad pH 3.4

This solution may be prepared in a conventional manner.

F)

Inhalation powder

Active Substance Formoterol fumarate Lactose monohydrate 6 Pg 6PG ad 25 mg

The preparation of the powder for inhalation is carried out in a conventional manner by mixing the individual components.

G)

Inhalation powder

Active Substance Lactose monohydrate 10 µg and 5 mg

The preparation of the powder for inhalation is carried out in a conventional manner by mixing the individual components.

Claims (10)

PATENT CLAIMS A compound of the general formula (1) in which A is a divalent radical selected from the group consisting of c = c H H H X is a single negatively charged anion selected from the group consisting of chloride, bromide, methyl sulfate, 4-toluenesulfonate, and methanesulfonate; R ¹ and R ² , the same or different, denote a radical selected from the group consisting of methyl, ethyl, n-propyl and isopropyl, which may be substituted by hydroxy or fluorine; SK 287138 Β6 R ³ , R ⁴ , R ⁵ and R ⁶ , the same or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluoro, chloro, bromo, CN, CF ₃ or NO ₂ ; R ⁷ is methyl, ethyl, methyloxy, ethyloxy, -CH ₂ -F, -CH ₂ -CH ₂ -F, -O-CH ₂ -F, -O-CH ₂ -CH ₂ -F, -CH ₂ -OH , -CH ₂ -CH ₂ -OH, CF ₃ , -CH ₂ -OMe, -CH ₂ -CH ₂ -OMe, -CH ₂ -OEt, -CH ₂ -CH ₂ -OEt, -O-COMe, Ό- COEf 1 -O-COCF ₃ , fluorine, chlorine or bromine, which may be in the form of individual optical isomers, mixtures of individual enantiomers or racemates. A compound of formula (1) according to claim 1, wherein A is a divalent radical selected from the group consisting of C — C ...... Ttj H H Hq H a X 'is a single negatively charged anion selected from the group consisting of chloride, bromide and methanesulfonate; R ¹ and R ² , the same or different, represent a radical selected from the group consisting of methyl and ethyl, which may be optionally substituted by hydroxy or fluoro; R ³ , R ⁴ , R ⁵ and R ⁶ , the same or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluoro, chloro or bromo; R ⁷ represents methyl, ethyl, methyloxy, ethyloxy, CF ₃ or fluoro, which may be in the form of individual optical isomers, mixtures of individual enantiomers or racemates. A compound of formula (1) according to any one of claims 1 or 2, wherein A is a divalent radical selected from the group consisting of \ / C —p H X is bromide; R ¹ and R ² , the same or different, denote methyl or ethyl; R ³ , R ⁴ , R ⁵ and R ⁶ , the same or different, denote hydrogen, methyl, methyloxy, chloro or fluoro; R ⁷ represents methyl or fluorine, which may be in the form of individual optical isomers, mixtures of individual enantiomers or racemates. A compound of formula (1) according to any one of claims 1 to 3, wherein A is a divalent radical selected from the group consisting of c = cHH X 'is bromide; R ¹ and R ² , the same or different, denote methyl or ethyl; R ³ , R ⁴ , R ⁵ and R ⁶ , the same or different, denote hydrogen or fluorine; R ⁷ represents methyl or fluorine, which may be in the form of individual optical isomers, mixtures of individual enantiomers or racemates. Use of a compound of formula (1) according to any one of claims 1 to 4 as a medicament. Use of a compound of general formula (1) according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of asthma, COPD, vaginal-mediated sinus bradycardia, rhythmic heart disorders, gastrointestinal tract spasms, urinary tract spasms and menstrual disorders. Use of a compound of formula (1) according to claim 6 in the manufacture of a medicament for the treatment of asthma or COPD. Pharmaceutical preparation, characterized in that it contains, as active principle, one or more compounds of the general formula (1) according to any one of claims 1 to 4, or physiologically acceptable salts thereof, optionally in combination with customary auxiliaries and / or carriers. Pharmaceutical preparation according to claim 8, characterized in that, in addition to one or more compounds of the general formula (1), they contain at least one further active substance selected from the group of beta-mimetics, antiallergic agents, PAF antagonists, leukotriene antagonists and steroids . A process for preparing an anticholinergic compound of general formula (1) (1), wherein A, X and the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the meanings given in claims 1 to 4, characterized in that, in a first step, a compound of formula (3) (3) is reacted in which the radicals R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined in claims 1 to 4, and R represents chlorine or C _r -C ₄ -alkyloxy, with a compound of formula (2) (2) wherein a and R ¹ are defined as in claims 1 to 4, to form a compound of formula (4) wherein A and R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the meanings given in claims 1 to 4, and this compound is then reacted with Compound R ² -X, wherein R ² and X may have the meanings set forth in the claims, quaternizes to the compound of formula (1).