BG107688A - Novel anticholinergic agents that can be used as medicaments and method for the production thereof - Google Patents

Abstract

The invention relates to novel anticholinergic agents of general formula wherein A, X- and radicals R1, R2, R3, R4, R5, R6 and R7 can have the meanings as cited in the claims and in the description. The invention also relates to the use of these agents as medicaments 11 claims

Description

The invention relates to novel anticholinergic agents used as medicaments and to a method for their preparation. Anticholinergic agents presented are of formula 1:

• · · · in which A, X and the radicals R _b R ₂ ,

and R ₇ have the meanings defined in the claims and in the description. A method is given for obtaining them as well as using them as medicines. BACKGROUND OF THE INVENTION

Anticholinergic agents can be successfully used in the treatment of many diseases. In this regard, the treatment of asthma or chronic obstructive pulmonary disease (COPD) may be exemplified. For the treatment of these diseases, the anticholinergic agents proposed in WO 92/16528 having the basic structure of scopin, tropenol or tropin are used.

The object of WO 92/16528 is to provide anticholinergically active compounds characterized by long-lasting action. In order to achieve this, WO 92/16528, among other things, have created benzyl acid esters with scopin, with tropenol or also with tropin.

For the treatment of chronic diseases, it is often desirable to prepare drugs with a longer duration of action. Thus, it is generally ensured that the necessary concentration of the active ingredient to achieve a therapeutic effect is available for a longer time in the body without the need for too frequent administration of the drug. Taking the active ingredient at greater intervals contributes significantly to patient comfort. It is especially desirable to provide a medicament that may be therapeutically useful at a single dose (single dose). A single daily intake has the advantage that the patient can get used to the regular administration of the drug relatively quickly at a fixed time of the day relatively quickly.

In order for a medicinal product to be administered once a day, special ingredients are placed on the active ingredient contained therein.

Kwania. First, after the administration of the drug, the desired effect should be reached relatively quickly and ideally a constant action over a longer period of time should be achieved. On the other hand, the duration of action of the medicinal product should not exceed more than one day. Ideally, the active ingredient exhibits such a profile of action that the preparation of a once-daily drug containing the therapeutically active doses of the active ingredient allows its targeted regulation.

The gasoline esters of skopin, tropenol or tropin proposed in WO 92/16528 were found not to satisfy these higher requirements. Due to the excessively long action, which exceeds the significantly mentioned above period by about one day, they are not therapeutically applicable for a single daily intake.

It is an object of the present invention to provide novel anticholinergic agents which, based on their activity profile, allow the preparation of a once daily medicament.

It is another object of the invention to provide compounds characterized by a relatively rapid initial action.

It is another object of the invention to provide compounds which, after rapid initial action, subsequently exhibit the maximum possible continuous action over a longer period of time.

It is another object of the invention to provide compounds whose duration of action does not significantly exceed one day at therapeutically acceptable dosages.

Finally, it is an object of the invention to provide compounds with an action profile that allows for good regulation of the therapeutic effect (i.e., complete therapeutic action without side effects from the accumulation of a substance in the body).

TECHNICAL SUMMARY OF THE INVENTION * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

It has surprisingly been found that the aforementioned objectives of the invention can be achieved by the compounds of general formula 1, in which the radical R ₇ does not mean a hydroxyl group.

In connection with the foregoing, the present invention relates to compounds of general formula 1:

wherein:

means a divalent radical selected from the group consisting of

X '

Rt and R ₂

Vz> R5 and r ₇ wherein, of:

\ / s — p

H ₂ n ₂ denotes a monovalent negatively charged anion;

denote C ₁ -C ₄ -alkyl which may be optionally substituted by hydroxy or halogen;

R ₆ are the same or different and represent hydrogen, C ₁ -C ₄ -alkyl,

C ₁ -C ₄ -alkyloxy, hydroxy, CF ₃ , CN, NO ₂ or halogen;

represents hydrogen, C _d C ₄ -alkyl, C ₁ -C ₄ alkyloxy, C _d C ₄ -alkilenhalogen, halogen-C _d C ₄ alkyloxy, C _d C ₄ -alkylene-OH, CF _3, C _D C ₄ alkylene-C ₁ -C ₄ -alkyloxy, -O-COC ₂ C ₄ -alkyl, -O-COC ₂ C ₄ -alkyl halogen, -O-COCF ₃ or halogen, 1 / c-c in case A represents ⁿ 2 ⁿ 2, ····

Rt and R ₂ are methyl and

R ₃ , R ₄ , R ₅ and R ₆ are hydrogen,

R ₇ cannot, in fact, be hydrogen.

Preferred are compounds of general formula I wherein:

means a divalent radical selected from the group consisting of:

\ / s — s n ₂ n ₂ \ /

C = C and nn

X 'means a monovalent negatively charged anion selected from the group chloride, bromide, methylsulfate, 4-toluenesulfonate and methanesulfonate, preferably bromide;

R 1 and R ₂ are the same or different and represent 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 are the same or different and represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF ₃ or

R ₇ represents hydrogen, methyl, ethyl, methoxy, ethoxy, -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-SOMe, - O-COEt, -O-COCF3, -O-COCF ₃ , fluorine, chlorine or bromine.

Particularly preferred are the compounds of general formula 1, in which:

A means a divalent radical selected from the group consisting of:

\ / s-s n ₂ n ₂ \ /

С— С ин н

• · · · · · ·

X represents a monovalent negatively charged anion selected from the group chloride, bromide and methanesulfonate, preferably bromide;

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

R ₃ , R ₄ , R ₅ and R ₆ are the same or different and represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine;

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

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

A means a divalent radical selected from the group consisting of:

\ / s — С н ₂ н ₂ \ / C = C and N N N O N X ' means bromide;

R 1 and R ₂ are the same or different and represent a radical selected from methyl and ethyl, preferably methyl;

R ₃ , R ₄ , R ₅ and R ₆ are the same or different and represent hydrogen, methyl, methyloxy, chlorine or fluorine;

R? means hydrogen, methyl, or fluorine.

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

A means a divalent radical selected from the group consisting of:

\ /

C = C and

N N

X 'means bromide;

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

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

R ₇ represents hydrogen, methyl or fluorine, preferably methyl or fluorine and methyl is particularly preferred.

The subject of the invention are the corresponding compounds of formula I, optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates.

In the compounds of general formula I, the radicals R ₃ , R ₄ , R ₅ and R ₆ , if not hydrogen, may be in the ortho-, methyl or para-position of the '- CR ₇ ' group, respectively. In case none of the radicals R ₃ , R ₄ , R ₅ and R ₆ means hydrogen, it is preferable that R ₃ and R ₅ be in the para-position and R ₄ and R ₆ respectively in the ortho- or meta location, the meta position is especially preferred. If one of the radicals R ₃ and R ₄ and one of the radicals R ₅ and R ₆ denotes hydrogen, it is preferable that the other be in the meta or para position, especially the para position. If none of the radicals R ₃ , R ₄ , R ₅ and R ₆ is hydrogen, the compounds of the invention of general formula 1 are preferred, in which the radicals R ₃ , R ₄ , R ₅ and R ₆ have one and also meaning.

Of particular importance are the compounds of the invention of general formula 1 in which the ester substituent of the bicyclic nitrogen compound is in the α-configuration. These compounds correspond to the general formula I-a:

• · · · 9 · · ♦ ··

1 ° C

Of particular importance are the following compounds of the invention:

- 2,2-diphenylpropionic acid tropenol ester methobromide;

- 2,2-diphenylpropionic acid copin ester methobromide;

- 2-fluoro-2,2-diphenylpropionic acid metopromide copin ester;

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

Unbranched and unbranched alkyl groups of 1 to 4 carbon atoms are indicated as alkyl groups, unless specifically indicated. Methyl, ethyl, propyl or butyl may be mentioned as examples. Alternatively, the abbreviations Me, Et, Prop and Vi may be used to refer to the groups methyl, ethyl, propyl or butyl. Unless otherwise stated, the definitions of propyl and butyl cover all possible isomeric forms of the corresponding radicals. For example, propyl includes n-propyl and isopropyl, butyl includes isobutyl, t-butyl and t-butyl, etc.

Unbranched and unbranched bivalent alkyl bridges having 1 to 4 carbon atoms are indicated as alkylene groups, unless specifically indicated. Methylene, ethylene, propylene or butylene may be mentioned as examples.

Unbranched and unbranched bivalent alkyl bridges having 1 to 4 carbon atoms, which are substituted by one, two or three, are preferably referred to as alkylene halogen groups, unless otherwise indicated. .. · · ·. '::.

. '·' * · ·::. : ·::. s ........

reading, with a halogen atom. Accordingly, branched or unbranched divalent alkyl bridges of 1 to 4 carbon atoms substituted with one, two or three, preferably one hydroxyl group, are indicated as alkylene-OH groups, unless otherwise indicated.

Unbranched and unbranched alkyl groups of 1 to 4 carbon atoms to which an oxygen atom is attached are referred to as alkyloxy groups, unless otherwise indicated. Methyloxy, ethyloxy, propyloxy or butyloxy may be mentioned as examples. Alternatively, the abbreviations MeO-, EtO-, PrO- or VI- may be used to refer to the methyloxy, ethyloxy, propyloxy or butyloxy groups. Unless specifically described, the definitions of propyloxy and butyloxy cover all possible isomers of the corresponding radicals. For example, propyloxy includes n-propyloxy and isopropyloxy; butyloxy includes isobutyloxy, t-butyloxy and t-butyloxy, etc. Optionally, the term alkoxy may also be used in place of the alkyloxy designation within the present invention. The methoxy, ethoxy, propoxy or butoxy groups may optionally be used to refer to the methyloxy, ethyloxy, propyloxy or butyloxy groups.

As the alkylene-alkyloxy groups, unless specifically mentioned, are indicated branched or branched divalent alkyl bridges of 1 to 4 carbon atoms which are substituted by one, two or three, preferably one alkyloxy group.

As -O-CO-alkyl groups are indicated, unless specifically mentioned, branched and unbranched alkyl groups of 1 to 4 carbon atoms which are linked to an ester group. In addition, the alkyl groups are directly bonded to the carbonyl carbon atom of the ester group. Similarly, the term -O-CO-alkylhalogen group is to be understood. The -OCO-CF _{3 group} represents trifluoroacetate.

In the present invention, halogen means fluorine, io., · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Chlorine, bromine or iodine. Unless otherwise stated, 'fluorine and bromine' are the preferred halogens. The group CO means a carbonyl group.

The preparation of the compounds according to the invention, as explained below, may be performed in part analogous to methods already known in the art (Scheme 1). The carboxyl derivatives of formula 3 are known to those skilled in the art or can be prepared by methods of synthesis known in the art. If suitably substituted carboxylic acids are present, the compounds of formula 3 may be prepared directly from them by acid-catalyzed or esterification bases with appropriate alkali-

Scheme 1:

Starting from the compounds of formula 2, it is possible to reach the esters of general formula 4 by reaction with the carboxyl derivatives of formula 3, in which R, for example, may be chlorine or a C 1 -C 4 alkoxy radical. In the case where R is C ₂ -C ₄ -alkoxy, this reaction may be carried out, for example, in molten sodium at elevated temperature, preferably at about 50-150 ° C, especially preferably at about 90-100 ° C. , under reduced pressure, preferably less than 500 mbar and particularly preferably less than 75 mbar. Alternatively, the corresponding acid chlorides (R = Cl) may be used instead of derivatives 3 in which R is C 1 -C 4 alkoxy.

The compounds of the formula 4 thus obtained can be converted to a compound of formula (4). The compounds of formula I are returned to the desired compounds by reaction with the compounds R ₂ -X in which R ₂ and X have the meanings given above. Also, carrying out this synthesis step can be accomplished by a method analogous to the synthesis examples described in WO 92/16528.

Alternatively to the synthetic method presented in Scheme 1 for the preparation of the compounds of formula 4, the derivatives 4 in which the nitrogen-containing bicyclic compound is a scopic derivative can be prepared by oxidizing (epoxidating) compounds of formula 4 in which the nitrogen bicyclic compound is a tropenyl radical. For this purpose, the following method according to the invention is approached. Compound 4, in which A is -CH = CH-, is suspended in a polar organic solvent, preferably in a solvent selected from the group Nmethyl-2-pyrrolidone (ΝΜΡ = ΝΜΠ), dimethylacetamide and dimethylformamide, preferably dimethylformamide, and then it is heated to a temperature of about 30-90 ° C, preferably 40-70 ° C. A suitable oxidant is then added and the mixture is stirred at constant temperature for 2 to 8 hours, preferably 3 to 6 hours. Preferably vanadium petoxide in admixture with H ₂ O ₂ may be used as the oxidant, particularly the use of the H ₂ O ₂ urea complex in combination with vanadium petoxide. The subsequent treatment is carried out by known methods. Purification of the products can be carried out depending on their tendency to crystallize, by crystallization or by chromatography.

Alternatives to these compounds are the compounds of formula 4 in which R _? means halogen and obtained by the methods presented in Scheme 2.

• · · · · · · · · ·

To this end, the benzyl esters of formula 5 are converted to the compounds 4 in which R ₇ is halogen using suitable halogenating agents. The halogenation reactions presented in Scheme 2 are performed by well-known methods of chemical practice.

Benzyl esters of formula 5 are prepared by or analogously to methods known in the art (see, e.g., WO 92/16528).

As shown in Scheme 1, intermediates of general formula 4 play a central role. In this connection, another object of the present invention is the intermediates of formula 4:

wherein:

A means a divalent radical selected from the group consisting of:

• · • · · «• · · · · · \ / s — s n ₂ n ₂ \ /

C = C and nn

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

R _3, R _4, R ₅ and R ₆ are identical or different and denote hydrogen, C ₁ -C ₄ -alkyl, C _d C ₄ -alkyloxy, hydroxy, CF _3, CN, NO ₂ or halogen;

R ₇ represents hydrogen, C 1 -C 4 alkyl, C ₂ -C ₄ -alkyloxy, C 1 -C 4 -alkidenhalogen, halogen-C 1 -C 4 alkyloxy, C ₂ -C ₄ -alkylene-OH, CF ₃ , -C 1 -C ₄ -alkylene-C ₂ -C ₄ -alkyloxy, -O-COC ₂ C ₄ -alkyl, -O-COC ₄ -C ₆ -alkyl halogen, -O-COCF ₃ or halogen, wherein, N / C is-c in case A is ⁿ 2 ⁿ 2,

R 1 stands for methyl and

R ₃ , R ₄ , R ₅ and R ₆ are hydrogen,

R ₇ cannot be n-propyl.

Preferred are compounds of general formula I wherein:

means a divalent radical selected from the group consisting of:

\ / s-s n ₂ n ₂ \ /

C = C and nn

R1 represents a radical selected from the group consisting of methyl, ethyl, n-propyl and isopropyl, which may optionally be substituted with hydroxy or fluorine, preferably unsubstituted methyl;

R ₃ , R ₄ , R ₅ and R ₆ are the same or different and represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF ₃ or

NO ₂ ;

• · · · · · · · · · · ·

Ry denotes 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, -0COEt, -O-COCF3, -O-COCF3, fluorine, chlorine or bromine.

Particularly preferred are the compounds of general formula 1, in which:

A represents a divalent radical selected from the group consisting of

by:

\ / s-c

H ₂ H ₂ \ /

With C and n

means a radical selected from methyl and ethyl, which may be optionally substituted by hydroxy or fluorine, preferably unsubstituted methyl;

R ₃ , R ₄ , R ₅ and R ₆ are the same or different and represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine;

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

Preferred compounds of the invention are general compounds

formula 1 in which:

A represents a divalent radical selected from the group consisting of

by: \ / with— p H ₂ n ₂

\ /

C = C and

N N

R! means a radical selected from methyl and ethyl, preferably methyl;

R ₃ , R ₄ , R ₅ and R ₆ are the same or different and represent hydrogen, methyl, methyloxy, chlorine or fluorine;

R ₇ represents hydrogen, methyl, or fluorine.

• · · · · · · · · ·

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

A means a divalent radical selected from the group consisting of:

\ /

C-C and

N N

R1 stands for methyl or ethyl, preferably methyl;

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

R ₇ represents hydrogen, methyl or fluorine, preferably methyl or fluorine and methyl is particularly preferred.

In the compounds of general formula I as well as in the intermediates of formula 4, the radicals R ₃ , R ₄ , R ₅ and R ₆ , if not hydrogen, may be in the ortho-, meta- or para- position relative to the group "-C-OH". In case none of the radicals R ₃ , R ₄ , R ₅ and R ₆ means hydrogen, it is preferable that R ₃ and R ₅ be in the position and R ₄ and R ₆ respectively in the ortho- or meta-position , the meta position is particularly preferred. In the case where one of the radicals R ₃ and R ₄ and one of the radicals R ₅ and R ₆ denote hydrogen, it is preferable that the other be in the meta or para position, particularly preferably the position. In the case that none of the radicals R ₃ , R ₄ , R ₅ and R ₆ represents hydrogen, the intermediates of the invention of the general formula 4 are preferred, wherein the radicals R ₃ , R ₄ , R ₅ and R ₆ have one and the same meaning.

The following synthesis examples serve to further illustrate the present invention. They should, however, only be understood as exemplary methods for further elucidation of the invention, without serving to limit the object of the invention described.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

EXAMPLES OF THE INVENTION '..........

Example 1: 2.2-diphenylpropionic acid metopromide Skopin ester

2.2-Diphenylpropionic acid chloride For:

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

1.2 .: 2.2-diphenylpropionic acid Skopin ester 4a:

Obtained in step 1.1. the residue was dissolved in 100 ml of dichloromethane and at 40 ° C, a solution of 51.45 g (0.33 mol) of scopin in 200 ml of dichloromethane was added dropwise. The resulting slurry was stirred for 24 hours at 40 ° C, after which the resulting precipitate was removed by filtration in vacuo, and the filtrate was first extracted with water and then with aqueous hydrochloric acid. The combined aqueous phases were basified with aqueous sodium carbonate solution, extracted with dichloromethane, the organic phase was dried over Na ₂ SO ₄ , evaporated to dryness and the hydrochloride was separated from the residue. Purification is performed by recrystallization from acetonitrile.

Yield: 20.85 g (= 47% of theta).

TLC (thin layer chromatography): Rf: 0.24 (eluent: wt-butanol / formic

1 / ·· ·· ······ · ···· ···· ·· · · · · · · · · · · · · · · · · water 75:15:10).

M.p .: 203-204 ° C.

1.3 .: 2.2-diphenylpropionic acid Skopin ester methobromide:

11.98 g (0.033 mol) of 4a, 210 ml of acetonitrile, 70 ml of dichloromethane and

20.16 g (0.1 mol) of a 46.92% solution of bromomethane in acetonitrile were stirred at 20 ° C and the resulting mixture stood for 3 days. The solution was evaporated to dryness and the residue was recrystallized from isopropanol.

Yield: 11.34 g (75% of theory); mp: 208-209 ° C.

C24H ₂₈ NO ₃ x Br (458.4)

Elemental analysis: calculated: C (62.89); H (6.16); N (3.06) measured: C (62.85); H (6.12); N (3.07).

Example 2: 2-Fluoro-2,2-diphenylacetic acid metopromide Skopin ester

2.1: Petrol Acid 5A Skopin ester:

The preparation of the skopin gasoline ester is well known in the art. It is described in WO 92/16528.

2.2: 2-Fluoro-2.2-diphenyloxy acid 4b Skopin ester:

2.66 g (0.02 mole) of dimethylaminosulfur trifluoride in 10 ml of dichloromethane was cooled to 0 ° C and a solution of 5.48 g (0.015 mole) of benzoic acid Skopin ester 5a in 100 ml of dichloromethane was added dropwise. The mixture was then stirred for 30 minutes at 0 ° C and 30 minutes at

20 ° C. On cooling, the solution is mixed with water, NaHCO ₃ (up to pH 7-8) is added and the organic phase is separated. The aqueous phase was extracted with dichloromethane, the combined organic phases were washed with water, dried over Na ₂ SO ₄ and evaporated to dryness. Hydrochloride was recovered from the residue, which was crystallized from acetonitrile.

Yield: 6.90 g (85%).

Mp: 227-230 ° C.

2.3: 2-Fluoro-2.2-diphenyloic acid methobromide Skopin ester:

2.88 g (0.0078 moles) of the free base of benzyl acid scopic ester was treated analogously to the method described in step 1.3. Purification is carried out by recrystallization from isopropanol. Yield: 2.62 g (73% of theory).

TLC: Rf: 0.31 (eluent: same as in step 1.2); mp: 130-134 ° C.

Example 3: Tropenol ester of 2,2-diphenylpropionic acid methobromide

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

In a suspension of 50.8 g (0.225 mol) of 2,2-propionic acid and 200 ml of acetonitrile, 37.60 g (0.247 mol) of DBU (1,8diazabicyclo [5.4.0] undec-7-ene) were added dropwise at 20 ° C. . 70.10 g (0.494 mol) of methyl iodide were added dropwise over 30 minutes to the resulting solution. The mixture was then stirred overnight at 20 ° C. The solvent was evaporated, the residue was extracted with diethyl ether / water, the organic phase was washed with water, dried over Na ₂ SO ₄ and evaporated to dryness. Yield: 48.29 g of viscous residue 3b (89% of theory).

• · · · · · • «· · · ·

3.2: 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 melted at 75 mbar pressure for 4 hours in a boiling water bath with shaking from from time to time. After cooling, the sodium residues were dissolved in acetonitrile, the solution was evaporated to dryness and the residue was extracted with dichloromethane / water. The organic phase was washed with water, dried over MgSO ₄ and evaporated to dryness. From the residue was separated 4c in the form of hydrochloride which was crystallized from acetone.

Yield: 5.13 g (67% of theory);

TLC: Rf: 0.28 (eluent: sec-butanol / formic acid / water 75:15:10);

Mp: 134-135 ° C.

3.3: 2.2-diphenylpropionic acid tropophenic ester methobromide:

2.20 g (0.006 mol) of 4c were treated analogously to Example 1, step 1.3. The crystals obtained are separated by filtration in vacuo, washed with dichloromethane, dried and finally recrystallized from methanol / diethyl ether.

Yield: 1.84 g (66% of theory);

TLC: Rf: 0.11 (eluent same as step 1.2); mp: 222-223 ° C. Elemental analysis: calculated: C (65.16); H (6.38); N (3.17) measured: C (65.45); H (6.29); N (3.16).

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

4.1. : 3.3 ', 4,4'-tetrafluorobenzyl acid 3c ethyl ester 3c:

The Grignard reagent was obtained from 2.24 g (0.092 mol) of magnesium chips, several crystals of iodine and 17.80 g (0.092 mol) of 1-bromo-3,4-difluoro benzene in 100 ml of THF (tetrahydrofuran) at 50 ° C. After the addition of the halide is complete, the mixture is stirred for another hour. The Grignard reagent thus obtained is added dropwise to 18.81 g (0.088 mol) of 3,4-difluorophenylglyoxyl acid ethyl ester in 80 ml of THF at

10-15 ° C and the resulting mixture was stirred for 2 hours at 5 ° C. To complete the treatment, the white suspension was poured onto ice / sulfuric acid, extracted with ethyl acetate, the organic phase was washed with water, dried over MgSO ₄ and evaporated to dryness. Purification of the crude product is carried out by column chromatography (eluent: toluene).

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

4.2. : Tropenol ester for 3,3'.4.4'-tetrafluoro-benzyl acid 5b:

4.27 g (0.013 mol) of 3,3 ', 4,4'-tetrafluorobenzyl acid 3c ethyl ester, 1.81 g (0.013 mol) of tropenol and 0.03 g of sodium were melted at 75 mbar for 4 hours in a boiling water bath with shaking from time to time. After cooling, the sodium residues were dissolved in acetonitrile, the solution was evaporated to dryness and the residue was extracted with dichloromethane / water. The organic phase was washed with water, dried over MgSO ₄ and evaporated to dryness. The residue was taken up in diethyl ether / petroleum ether 1: 9, filtered under reduced pressure and washed. Yield: 2.50 g (46% of theory);

TLC: Rf: 0.29 (eluent: sec-butanol / formic acid / water 75:15:10);

M.p .: 147-148 ° C.

4.3: 2-Fluoro-2.2-bis (3.4-difluorophenyl) acetic acid tropenol ester 4d:

2.66 g (0.012 mol) of bis- (2-methoxyethyl) aminosulfur trifluoride were pre-placed in 10 ml of dichloromethane, and a solution of 0.01 mol of 0.01 mol was added dropwise over 20 minutes at 15-20 ° C. 5b in 65 ml of dichloromethane. The mixture was stirred for 20 hours at room temperature, cooled to 0 ° C and gently mixed with 80 ml of water with vigorous stirring. Then, carefully, with aqueous NaHCO ₃ solution, it was adjusted to pH 8; The organic phase was separated, the aqueous phases were re-extracted with dichloromethane, the combined organic phases were washed with water, dried over MgSO ₄ and evaporated to dryness. The hydrochloride was separated and recrystallized 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 tropophenol ester methobromide:

2.20 g (0.0052 mol) of 4d were treated analogously to Example 1, step

1.3. The crystals obtained are separated by filtration in vacuo, washed with dichloromethane, dried and finally recrystallized from methanol / diethyl ether.

Yield: 1.95 g (72% of theory)

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

C ₂₃ H ₂₁ F ₅ NO ₂ x Br (518.3);

Elemental analysis: calculated: C (53.30); H (4.08); N (2.70) measured: C (53.22); H (4.19); N (2.69).

• · ·· t 4 • * 4 4 4 4 • 4 4 4 · 4 · 4 44 • 44 4 4 · · e ·

4 4 4 4 4 4 4 4 4 · • · 4 4 4 4 44 ··· • 444 44 4 4 · * ·· · ·

Example 5: 2.2-diphenylpropionic acid ethyl ester of bromine

1.81 g (0.005 mol) of 4a, 35 ml of acetonitrile and 1.64 g (0.015 mol) of ethyl W bromide were stirred at 20 C and the mixture stood for 3 days. The solution was evaporated to dryness and the residue was recrystallized from ethanol.

Yield: 1.38 g (58% of theory) mp: 208 - 209 ° C;

TLC: Rf: 0.33 (eluent: same as in step 1.2); mp: 210-211 ° C; C ₂₅ H ₃₀ NO ₃ xBr (472.42);

Elemental analysis: calculated: C (63.56); H (6.40); N (2.96) measured: C (63.49); H (6.24); N (2.88).

Example 6: 2-Fluoro-2.2-bis (3.4-difluorophenyl) acetic acid Skopin ester

6.1 .: 3.3 ', 4,4'-Tetrafluorobenzyl acid 5c Skopin ester:

3.61 g (0.011 mol) of 3,3 ', 4,4'-tetrafluorobenzyl acid 3c ethyl ester, 1.71 g (0.011 mol) of scopin and 0.03 g of sodium are melted at 75 mbar pressure for 4 hours in boiling water ·· ···· • · · ·

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Shaking a bathroom from time to time. After cooling, the sodium residues were dissolved in acetonitrile, the solution was evaporated to dryness and the residue was extracted with dichloromethane / water. The organic phase was washed with water, dried over MgSO ₄ and evaporated to dryness. The residue was taken up in diethyl ether / petroleum ether 1: 9, filtered under reduced pressure and washed. Yield: 1.75 g (36% of theory); mp: 178-179 ° C.

6.2: 2-fluoro-2,2-bis (3.4-difluorophenyl) -one 4-epe capine ester

0.6 ml (0303Zmola) of bis- (2-methoxyethyl) aminosulfur trifluoride was reacted with 1.2 g (0.0028 mol) of 5c by the method of Example 4, step 4.3.

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

6.3: 2-Fluoro-2.2-bis (3.4-difluorophenyl) acetic acid Skopin ester methobromide

1.15 g (0.0026 mol) of 4e and 1.15 g (0.0079) of 50% methyl bromide solution were reacted according to the method of Example 1, step 1.3. The resulting crystals were filtered off under vacuum, washed with dichloromethane, dried and finally recrystallized from acetone.

Yield: 0.88 g (63% of theory);

TLC: Rf: 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 NO3 x Br (535.33).

Example 7: Tropenol ester of 2-fluoro-2.2-bis (4-fluorophenyl) acetic acid

· · · • · • • • •

7.1. : 4.4′-difluorobenzyl acid 3d methyl ester:

7.1.1. : 4,4'-difluorobenzyl acid:

To a solution of 49.99 g (1.25 mol) of NaOH flakes in 300 ml of water, at a solution of 100 ° C was added dropwise a solution of 24.62 g (0.1 mol) of 4,4'-difluorobenzyl in 250 ml of dioxane and the resulting mixture was stirred. 2:00. Most of the dioxane is distilled off and the residual aqueous solution is extracted with dichloromethane. Upon acidification of the aqueous solution with sulfuric acid, a precipitate precipitates, which is filtered off under vacuum, washed and dried, the filtrate is extracted with dichloromethane, the organic phase is dried over Na ₂ SO ₄ and evaporated to dryness.

Yield: 25.01 g (95% of theory); mp: 133-136 ° C.

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

To a freshly prepared solution of sodium methanolate of 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'-difluorobenzyl acid and the resulting mixture was stirred for 3 hours. The solution was evaporated to dryness, the residue dissolved in dimethylformamide (DMF), mixed at 20 ° C, dropwise, with 22.57 g (0.16 mol) of methyl iodide and stirred for 24 hours. Finishing and purification are the same as D for compound 3b. Yield: 21.06 g 11 (80% of theory).

Th »

7.2. : Tropenol ester of 4.4′-difluorobenzyl acid 5d

11.13 g (0.04 mol) of 4,4'-difluorobenzyl acid 3d ester and 5.57 g (0.04 mol) of tropenol were reacted by a method analogous to that of Example 3, step 3.2. The product was recrystallized from acetonitrile. Yield: 10.43 g (62% of theory);

M.P. : 233-235 ° C.

7.3. : Tropenol ester of 2-fluoro-2.2-bis (4-fluorophenyl) acetic acid 4f

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

Yield: 2.93 g (69% of theory).

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

2.6 g (0.0067 mol) of 4f and 1.9 g (0.0079 mol) of 50% methyl bromide were reacted according to a method analogous to that in Example 1, step 1.3. The crystals obtained were separated by filtration under reduced pressure, washed with dichloromethane, dried and finally recrystallized from methanol / diethyl ether.

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

TLC: Rf: 0.55 (eluent: same as in Example 1, step 1.2);

Mp: 230-231 ° C;

C ₂₃ H ₂ 3F ₃ NO ₂ x Br (482.34);

Elemental analysis: calculated: C (57.27); H (4.81); N (2.90) measured: C (57.15); H (4.84); N (2.96).

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

8.1: 4.4′-Difluorobenzyl acid 5e Skopin ester:

4.22 g (0.01 mol) of 4,4'-difluorobenzyl acid tropenol ester

5d was suspended in 80 ml of DMF (dimethylformamide). At a solution temperature of about 40 ° C, a solution of 2.57 g (0.0273 mol) of H ₂ O ₂ urea in 20 ml of water was added thereto, as was 0.2 g (0.0011 mol) of vanadium (\ /) oxide, after • · • · · Which the mixture was stirred for 4.5 hours at 60 ° C. · · · · · · · · · · · · · · · · · · · · · · · · · · After cooling to 20 ° C, the resulting precipitate was removed by filtration in vacuo, the filtrate was brought to pH 3 with 4N hydrochloric acid and mixed with Na ₂ S ₂ O ₅ dissolved in water.

The green solution thus obtained is evaporated to dryness and the residue is extracted with dichloromethane / water. The acidic aqueous phase was basified with Na ₂ CO ₃ , extracted with dichloromethane and the organic phase dried over Na ₂ SO ₄ and concentrated.

0.5 ml of acetyl chloride was then added at about 15 ° C and stirred for 1.5 hours. After extraction with 0.1 N hydrochloric acid, the aqueous phase was basified, extracted with dichloromethane, the organic phase was dried over Na ₂ SO ₄ and evaporated to dryness. The residue gives the hydrochloride which is recrystallized from methanol / dichloromethane.

Yield: 3.61 g of white crystals (78% otor.);

M.p .: 243-244 ° C.

8.2 2-Fluoro-2,2-bis (4-fluorophenyl) acetic acid Skopin ester 4g:

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

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

8.3 2-Fluoro-2.2-bis (4-fluorophenyl) acetic acid Skopin ester methobromide

1.6 g (0.004 mol) of 4 g and 1.14 g (0.0079 mol) of a 50% methyl bromide solution were reacted in a manner analogous to that of Example 1, step 1.3. The resulting crystals were separated by filtration under reduced pressure, washed with dichloromethane, dried and finally recrystallized from acetonitrile.

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

TLC: Rf: 0.25 (eluent: same as in Example 1, step 1.2);

· · · • · · · · • • • •

Mp: 213-214 ° C;

· · · · · · · · · · · ·

C ₂ 3H ₂ 3F ₃ NO3 x Br (498.34);

Elemental analysis: calculated: C (55.34); H (4.65); N (2.81) measured: C (54.46); H (4.67); N (2.80).

Example 9: 2-Fluoro-2.2-diphenylacetic acid tropenol ester methobromide

9.1 Benzyl acid tropenol ester 5f

The benzenic acid tropenol ester and the process for its preparation are known from WO 92/16528.

9.2: 2-Fluoro-2.2-diphenyloic acid tropenol ester 4h:

15.86 ml (0.086 mol) of bis- (2-methoxyethyl) aminosulfur trifluoride were reacted with 25 g (0.072 mol) of 5f by a method analogous to that of Example 4, step 4.3 in 480 ml of chloroform. The product, in the form of hydrochloride, was recrystallized from acetone.

Yield: 18.6 g white crystals (67% otor.);

Mp: 181-182 ° C.

9.3: 2-Fluoro-2.2-diphenyloic acid tropophenol ester methobromide

11.2 g (0.032 mol) of 4h and 18.23 g (0.096 mol) of a 50% methyl bromide solution were reacted in a manner analogous to that of Example 1, step 1.3. The crystals obtained were recrystallized from acetonitrile.

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

TLC: Rf: 0.4 (eluent: same as in Example 4, step 4.4); mp: 238-239 ° C;

• · · · · · · · ·

C ₂₃ H ₂₅ FNO ₂ x Br (446.36);

Elemental analysis: calculated: C (61.89); H (5.65); N (3.14) measured: C (62.04); H (5.62); N (3.17).

Example 10: Tropenol ester of 2-fluoro-2.2- (3-chlorophenyl) acetic acid

10.1 .: 3.3′-Dichlorobenzylate Ze methyl ester:

1.1.1: 3,3'-dichlorobenzyl:

50.0 g (0.356 mol) of 3-chlorobenzaldehyde and 4.54 g (0.018 mol) of 3-ethyl-5- (2-hydroxyethyl) -4methylthiazol bromide are charged into 100 ml of ethanol at room temperature. Then 10.7 g (0.11 mol) of triethylamine are added dropwise. The mixture was refluxed for 3 hours and evaporated to dryness. The residue was taken up in ethyl acetate and extracted with water, with sodium w pyrosulfite in water and with a solution of Na ₂ CO ₃ . After drying over MgSO ₄ , the solution was evaporated to dryness. The product obtained was recrystallized from isopropanol and petroleum ether.

Yield: 13.2 gb crystals (13% otor.); mp: 69-70 ° C.

13.0 g of the thus obtained acyloin were dissolved in 460 ml of acetonitrile at room temperature, 0.0867 g of vanadium (1) oxytrichloride was added and oxygen was passed. After 1.5 hours, the solution was evaporated to dryness, extracted with ethyl acetate and water, and with a solution of Na ₂ CO ₃ , dried over

MgSO ₄ and evaporated to dryness. The resulting residue was triturated with petroleum ether / ethyl acetate 95: 5.

• · · · · · · · · ·

Yield: 12.59 g of yellow crystals (97% of theory); mp: 116-LU ° C

10.1.2: 3,3'-Dichlorobenzyl acid

51.45 g (1.286 mol) of sodium hydroxide in 1000 ml of water were stirred vigorously in a boiling water bath and a solution of 28.5 g (0.102 mol) of 3,3'-dichlorobenzyl in 700 ml of dioxane was added dropwise thereto. the resulting mixture was stirred for 1 hour. After cooling, the dioxane was evaporated, the residue was diluted with water and extracted with diethyl ether. The organic phase was acidified, extracted with dichloromethane, dried over MgSO ₄ and evaporated to dryness.

Yield: 32.7 g (71% of theory).

Y.1.S .: 3,3'-Dichlorobenzyl acid methyl ester

A solution of sodium ethanolate is added from 100 ml of ethanol and 1.97 g (0.0855 mol) of sodium, which is added dropwise to a solution of 26.6 g (0.855 mol) of 3,3'-dichlorobenzyl acid in 50 ml of ethanol and the mixture is then stirred. 4 hours at room temperature. After distilling off the solvent, the residue was dissolved in 150 ml of DMF and 24.27 g (0.171 mol) of methyl iodide were added dropwise thereafter and the mixture was stirred for another 24 hours. Under ice-cooling, 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 a solution of Na ₂ CO ₃ and the neutral medium is stirred. with water. After drying on Na ₂ SO ₄ , the solution is evaporated to dryness. Yield: 22.91 g of a yellow oil (82% of theory).

10.2 .: Tropenol ester of 3.3′-dichlorobenzyl acid 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 were heated as a melt at 75 mbar pressure for 4 hours in a boiling water bath with shaking over time on time. After cooling, the residues of sodium were dissolved with acetonitrile, the solution was evaporated to dryness and the residue was extracted with dichloromethane / water. The organic phase was washed with water, dried over MgSO ₄ and evaporated to dryness. The product, 'Hydrochloride Ah hydrochloride, was recrystallized from acetonitrile.

Yield: 16.83 gb (50% of theory); mp: 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) aminosulfur trifluoride were dissolved in 10 ml of dichloromethane and a solution of 2.09 g of 5 g in 65 ml was added dropwise over 20 minutes at 15-20 ° C. dichloromethane. The mixture was stirred for 20 hours at room temperature, cooled to 0 ° C and mixed gently, with vigorous stirring, with 80 ml of water. Finally, it was adjusted to pH 8 by carefully mixing with aqueous NaHCO ₃ , the organic phase was separated, the aqueous phases were re-extracted with dichloromethane, the combined organic phases were washed with water, dried over MgSO ₄ and evaporated to dryness. Hydrochloride is recovered which is crystallized from acetonitrile / diethyl ether.

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

mp: 136-137 ° C.

10.4: 2-Fluoro-2.2-bis (3-chlorophenyl) acetic acid troprophenyl ester methobromide g (0.002 mol) of 4h was treated in a manner analogous to that of Example 1, step 1.3. The crystals obtained are separated by filtration in vacuo, washed with dichloromethane, dried and finally recrystallized from methanol / diethyl ether.

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

TLC: Rf: 0.14 (eluent: n-butanol / water / formic acid (conc.) / Acetone / dichloromethane 36: 15: 15: 15: 5); mp .: 180-18GS;

C ₂₃ H ₂₃ CI ₂ FNO ₂ x Br (515.25).

As has been found, the compounds of the general Formula 1 are distinguished by a variety of therapeutic applications. Of particular importance are those possibilities in which the compounds of the invention having form31 are used.

mulas 1, based on their pharmaceutical action, are preferred as anticholinergic agents. These applications include, for example, treatment of asthma or COPD (chronic obstructive pulmonary disease). The compounds of general formula I can further be used to treat oscillatory sinus bradycardia and to treat heart rhythm disorders. In general, the compounds of the invention can also be used to treat spasms, for example in the gastrointestinal tract. In addition, they can also be used to treat urinary spasms and menstrual complaints.

Of the indications mentioned above, asthma and

COPD with the compounds of the invention of formula 1 is of particular importance.

The compounds of general formula 1 may be used alone or in combination with other active ingredients of the invention of formula 1. Optionally, the compounds of formula 1 may be combined with other pharmacologically active ingredients. In this case, particular consideration is given to betamimetics, anti-allergic agents, platelet aggregation antagonists, leukotriene and corticosteroid antagonists, and combinations thereof.

As an example of betamimetics which according to the invention can be used in combination with the compounds of formula 1, the compounds selected from the group consisting of: bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pyrbuterol, procatherol, reproterol, salmeterol, sulfonterol, terbutalin, tolubuterol, 4-hydroxy-7- [2 - {[2 - {[3- (2-phenylethoxy) propyl] sulfonyl} ethyl] amino} ethyl] -2 (3H ) -benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [3- (4-methoxybone) cinchonidine) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butil32 • · 4 4 4 4 • · 4 · • · 4 4 4 4 ···· 44

4444 44 4 444

444 444444

444 4 444 44

44 44444444 amino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] '- N - [3- (4-N, N-dimethylaminophenyl) -2-methyl- 2-propylamino] ethanol, 1- [2H-5-hydroxy-30X0-4H-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-1,4benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1,2,4-triazol-3-yl] -2-methyl-2-butylamino} ethanol, 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-

1,4-benzoxazin-3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl-2-tert-butylamino) ethanol and 1- (4-ethoxycarbonylamino-3-cyano-5 -fluorophenyl) -2- (tert-butylamino) ethanol, optionally in the form of their racemates, enantiomers, diastereomers, and optionally in the form of their pharmaceutically acceptable acid addition salts and hydrates. Particularly preferred as betamimetics are those active ingredients in combination with compounds of the invention of formula I, which are 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- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3 - (4-1,1,1-N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2 - [3- (4-methoxyphenyl) -2methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-yl] -2- [3- (4- n-butyloxyphenyl) -2-meth yl-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-yl] -2-methyl-2-butylamino} ethanol, optionally in the form of their racemates, enantiomers, diastereomers, and optionally in the form of their pharmaceutically acceptable acid addition salts and hydrates. Of the betamimetics listed above, compounds of formoterol and salmeterol, optionally in the form of their racemates, enantiomers, diastereomers, and optionally in the form of their pharmaceutically acceptable acid addition salts and hydrates, are of particular importance.

According to the invention, the acid addition salts of betamimetics selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate and xinafoate are preferred. Salts are particularly preferred in the case of salmeterol, selected as hydrochloride, sulfate and xinafoate, of which sulfates and xinafoates are particularly preferred. According to the invention, salmeterol x 4H ₂ SO ₄ and salmeterol xinafoate are extremely important. Particularly preferred are the salts in the case of formoterol selected from hydrochloride, sulfate and fumarate, of which hydrochloride and fumarate are particularly preferred. According to the invention, formoterol fumarate is of utmost importance.

In the context of the present invention, corticosteroids, which may be used in combination with the compounds of formula 1, are understood to mean compounds selected from the group consisting of: flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasadone, rofleponide, GW 215864, KSR 592, ST-126 and dexamethasone. Preferred within the present invention are corticosteroids selected from the group consisting of: flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, and dexamethasone, wherein, in this case, budesonide, cyzezonide, and fluticasone are of particular importance. In the context of the present invention, the term steroids may optionally be used instead of the term corticosteroids. A reference to steroids includes, within the present invention, a reference to salts or derivatives which may be derived from steroids. Possible salts or derivatives include: sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or fluorates. Corticostero34 • The ides may also be in the form of their hydrates. "

In the context of the present invention, dopamine agonists, which may be used in combination with the compounds of formula 1, are understood to mean compounds selected from the group consisting of: bromocriptine, cabergoline, alpha-dihydroergocriptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, turguride and viazane. Within the scope of the present invention, dopamine agonists are preferred which can be used in combination with the compounds of formula I selected from the group consisting of: pramipexole, talipexole and vosan, with pramipexole being of particular importance. Reference to the above-mentioned dopamine agonists includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts thereof, respectively. hydrates. By physiologically acceptable acid addition salts obtainable from the dopamine agonists mentioned above, it is to be understood, for example, pharmaceutically acceptable salts selected from salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic, lactic, citric, tartaric and maleic acid.

W ·

As an example of anti-allergic agents which, according to the invention, can be used in combination with the compounds of formula 1, may be named: epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastin, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozin. Preferred anti-allergic agents that can be used in the present invention in combination with the compounds of the invention of formula 1 are selected from the group consisting of: epinastine, cetirizine, azelastine, fexofenadine, levocabastine, ··· ··· · · Loratadine, ebastine, desloratidine, and misolastine, with epinastine and desloratidine being particularly preferred. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · A reference to the aforementioned anti-allergic agents includes within the scope of the present invention a reference to any pharmaceutically acceptable acid addition salts which may exist.

Examples of platelet aggregation factor antagonists which according to the invention may be combined with the compounds of formula 1 are the following: 4- (2-chlorophenyl) -9-methyl2- [3- (4-morpholinyl) ) -3-propanon-1-yl] -6H-thieno- [3,2-L [1,2,4] triazolo [4,3-a] [1,4] diazepine, 6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8 - [(4-morpholinyl) carbonyl] -4H, 7H-cyclopenta- [4,5] thieno- [3,24] [1,2,4] triazolo [4 , 3-a] [1,4] diazepine.

When the compounds of formula I are used in combination with other active ingredients, the combination of steroids or betamimetics is of particular importance in the abovementioned classes of compounds. The combination with betamimetics, especially those with depot action, is crucial. Particularly preferred is the combination of the compounds of the invention of formula 1 with salmeterol or formoterol, with the combination with formoterol being most preferred.

Suitable forms for administering the compounds of formula 1 are e.g. tablets, capsules, suppositories, solutions and more. According to the invention, administration by inhalation of the compounds of the invention is of particular importance (especially in the treatment of asthma and COPD). The amount of pharmaceutically active compound (s) should be in the range of 0.05 to 90% by weight, preferably from 0.1 to 50% by weight. of the total weight of the composition. Suitable tablets may be prepared, for example, by mixing one or more active ingredients with known excipients, e.g. with inert diluents such as calcium carbonate, calcium phosphate or milk sugar, fillers such as maize starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents to achieve depot-action, such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may be coated with several layers.

Respectively, dragees can be obtained by applying to the nuclei obtained in a manner analogous to tablets by the traditional methods substances used to prepare dragees, e.g. colidone or shellac, arabic gum, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the cores can be coated with several layers. Similarly, to achieve a depot effect, the coating of the dragee may consist of several layers for the use of the aforementioned tablet preparation aids.

Liquids containing the active ingredients of the invention or respectively. the combination of active ingredients may additionally contain another sweetener such as saccharin, cyclamate, glycerin or sugar, as well as flavor enhancers, e.g. flavoring agents such as vanillin or orange extract. In addition, they may contain auxiliary suspending agents or thickeners such as sodium carboxymethylcellulose, cross-linking agents, e.g. condensation products of fatty alcohols with ethylene oxide or preservatives such as pihydroxybenzoate.

The solutions may be prepared by conventional methods, for example, by the addition of isotonic agents, preservatives, such as n-hydroxybenzoates, or stabilizers, such as alkali salts of EDTA, optionally using emulsifiers and / or dispersing agents, e.g. when using water as a diluent, organic solvents may also be used as solubilizing agents, respectively. as auxiliary solvents. The solutions thus obtained may then be filled with ampoules, vials or infusion bottles.

• · · · <· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Capsules containing one or more active ingredients, respectively.

a combination of active ingredients can be prepared by pre-mixing the active ingredients with inert carriers such as milk sugar or sorbitol, after which the mixture is loaded into gelatin capsules.

Suitable suppositories may be obtained, for example, by mixing with carriers designed for this purpose, such as neutral fats or polyethylene glycol, respectively. with their derivatives.

Water, pharmaceutically acceptable organic solvents such as paraffins (eg petroleum fractions), vegetable oils (eg peanut or sesame oil), mono- or polyvalent alcohols (eg ethanol or glycerol), carriers, may be mentioned as adjuvants, such as natural mineral powders (eg kaolin, clays, talc, chalk), synthetic mineral powders (eg highly dispersed silicic acid and silicates), sugars (eg crude, lactic and grape sugar), emulsifiers (eg lignin, sulphite) alkalis, methylcellulose, starch and polyvinyl irolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The administration of medicines by the conventional route of asthma or COPD is preferably by inhalation.

W · '

In the case of oral administration, the tablets may, of course, contain, in addition to said carriers, additives, e.g. sodium citrate, calcium carbonate and dicalcium phosphate, together with various other additives such as starches, preferably potato starch, gelatin and the like. In addition, they may contain tabletting lubricants such as magnesium stearate, sodium lauryl sulfate and talc. In the case of aqueous suspensions, the active ingredients may be mixed in addition to the excipients mentioned above and with various flavor enhancers or colorants.

The dosage of the compounds according to the invention is highly dependent on the route of administration and the disease to be treated. When administered by inhalation, the compounds of formula 1 exhibit enhanced action even at doses in the order of micrograms. Also in the interval above the micrograms the compounds of formula 1 can be successfully administered. In these cases, the dosages may for example be in the gram area. Particularly for non-inhaled administration, the compounds of the invention may be used at high doses (e.g., but not limited to, in the range of 1 to 100 mg).

The following recipe examples illustrate the present invention without limiting it to their scope.

Pharmaceutical Formulation Examples

For a tablet

A) Tablets

Active ingredient 100 mg milk sugar 140 mg cornstarch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg Z W · 500 mg The fine-grained are mixed active ingredient, milk sugar and one

part of the corn starch. The mixture was screened, then moistened with a solution of polyvinylpyrrolidone in water, mixed, granulated in a wet and dried. The granulate, maize starch residue and magnesium stearate are sieved and mixed. Tablets of suitable shape and size are compressed from the mixture.

B) Tablets For tablet active ingredient milk sugar mg mg ·· ·· • 4 ·· ·· / ···· 4

4 4 4 4 4 4 4 4 «corn starch microcrystalline cellulose polyvinylpyrrolidone

190 mg mg mg • 4 4 «4 4 4 4 4 44

4 4 4 4 4 444

4444 4 4 44 4444 sodium carboxymethyl 23 mg magnesium stearate mg

400 mg

The finely divided active ingredient, one part of corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone is mixed; the mixture is sieved and granulated with the remainder of the corn starch and water, after which the granulate is dried and sieved. Sodium carboxymethylcellulose and magnesium stearate are added thereto, mixed and compressed into tablets of suitable sizes.

IN) Ampoule solution Active ingredient 50 mg sodium chloride 50 mg water for injections 5 ml

The active ingredient is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and mixed with sodium chloride to form an isotonic solution. The resulting solution was filtered pyrogen-free and the filtrate was filled with aseptic ampoules, which were then sterilized and soldered. The ampoules contain 5 mg, 25 mg and 50 mg of active ingredient.

D) Aerosol with active ingredient dosage 0.005 sorbitan trioleate 0.1 monofluorotrichloromethane and difluorodichloromethane 2: 3 to 100 · · · · · · · · · · · · · · · · · · · ·

The suspension is loaded into its traditional container with a metering valve. With one valve action, about 50 µl (microlitre) of suspension is released. If desired, the active ingredient may be at a higher dosage (e.g., 0.02% by weight).

Solution (mg / 100 ml) Active ingredient 333.3 mg formotepolfumarate 333.3 mg benzalkonium chloride 10.0 mg eating 50.0 mg HCI (1N) to pH 3.4

This solution is prepared by conventional methods.

E) Inhalation powder active ingredient formoterol fumarate lactose monohydrate mcg (micrograms) mcg up to 25 mg

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

Inhalation powder active ingredient lactose monohydrate mcg to 5 mg

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

Claims (11)

1. Compounds of general formula 1: wherein: means a divalent radical selected from the group consisting of: X ' Rt and R ₂ R3, R _4> R5 and r ₇ \ / c with n ₂ n ₂ \ / c = c n n n o H represents a monovalent negatively charged anion; denote C ₁ -C ₄ -alkyl, which may optionally be substituted with hydroxy or halogen; R ₆ is the same or different and denotes hydrogen, C 1 -C 4 alkyl, C ₁ -C ₄ -alkyloxy, hydroxy, CF ₃ , CN, NO ₂ or halogen; means hydrogen, C 1 -C 4 alkyl, C ₁ -C ₄ alkyloxy, C ₁ -C ₄ -alkylene halogen, halogen-C ₂ -C ₄ alkyloxy, C ₁ -C ₄ -alkylene-OH, CF ₃ , -C ₁ -C ₄ alkyleneC ₂ C ₄ -alkyloxy, -O-COC ₁ -C ₄ -alkyl, -O-COC ₂ C ₄ -alkyl halogen, -O-COCF ₃ or halogen, optionally in the form of separate optical isomers, mixtures of separate enantiomers or racemates, wherein, \ / s-C in case A is ⁿ 2 ⁿ 2, R! and R ₂ is methyl and R ₃ , R ₄ , R ₅ and R ₆ are hydrogen. R ₇ cannot be hydrogen. Compounds of general formula 1 according to claim 1, wherein: A denotes a divalent radical selected from the group consisting of: \ / \ / yWv C-C. C = C and \ 'H ₂ n ₂ n n n o n X ' means a monovalent negatively charged anion selected from the group chloride, bromide, methylsulfate, 4-toluenesulfonate and methanesulfonate; R! and R ₂ are the same or different and mean a radical selected from the group consisting of methyl, ethyl, n-propyl and isopropyl, which may be optionally substituted by hydroxy or fluorine; R ₃ , R ₄ , R ₅ and R ₆ are the same or different and represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF ₃ or NO ₂ ; R ₇ represents 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 , fluorine , chlorine or bromine, optionally in the form of separate optical isomers, mixtures of individual enantiomers or racemates. Compounds of general formula 1 according to one of claims 1 or 2, in which: by: \ / s-s n ₂ n ₂ \ / C = C and N N A denotes a divalent radical selected from the group consisting of · · χ · Rt and R ₂ ······ ···· · is a monovalent negatively charged anion, 'selected from the group *' chloride, bromide and methanesulfonate; are the same or different and mean a radical selected from methyl and ethyl, which may be optionally substituted by hydroxy or fluorine; r ₇ R ₃ , R ₄ , R ₅ and R ₆ are the same or different and represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine; means hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF ₃ or fluorine, optionally in the form of separate optical isomers, mixtures of individual enantiomers or racemates. Compounds of general formula I according to one of claims 1, 2 or 3, in which: means a divalent radical selected from the group consisting of: \ / s — s n ₂ n ₂ X ' R 1 and R ₂ denote bromide; are the same or different and denote a radical selected from methyl and ethyl; R ₃ , R ₄ , R ₅ and R ₆ are the same or different and represent hydrogen, methyl, methyloxy, chlorine or fluorine; R ₇ represents hydrogen, methyl or fluorine, optionally in the form of separate optical isomers, mixtures of individual enantiomers or racemates. Compounds of general formula I according to any one of claims 1 to 4, in which: means a divalent radical selected from the group consisting of: \ / c = c n n • · ··· · ··· X 'stands for bromide; R 1 and R ₂ are the same or different and denote methyl or ethyl; R ₃ , R ₄ , R ₅ and R ₆ are the same or different and denote hydrogen or fluorine; R ₇ represents hydrogen, methyl or fluorine, optionally in the form of separate optical isomers, mixtures of individual enantiomers or racemates. Use of a compound of general formula I according to any one of claims 1 to 5 as a medicament. Use of a compound of general formula I according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of diseases in which anticholinergic agents may be useful for the therapy. Use of a compound of general formula I as claimed in any one of claims 1 to 5 for the preparation of a medicament for the treatment of asthma, COPD, oscillatory sinus bradycardia, disorders of the heart rhythm, gastrointestinal spasms, urinary spasms and for menstrual complaints. Pharmaceutical compositions characterized in that they contain as active ingredient one or more of the compounds of the general formula I according to one of claims 1 to 5 or their physiologically acceptable salts, optionally in combination with traditional auxiliary materials and / or carriers . 10. Pharmaceutical compositions according to claim 9, characterized in that they contain, in addition to one or more of the compounds of formula 1, at least one other active ingredient selected from the group of betamimetics, anti-allergic agents, antagonists of the factor of platelet aggregation, leukotriene antagonists and steroids. • · · · · · · · · · 11) Process for the preparation of a compound of general formula 1: in which A, X 'and the radicals R _b R ₂ , R ₃ , R ₄ . Ρθ ^and R7 have the meanings defined in claims 1 to 5, characterized in that in a first step, a compound of general formula 3: wherein the radicals R ₃ , R ₄ , R ₅ , R ₆ and R ₇ have the meanings defined in claims 1 to 5 and R represents chlorine or C 1 -C 4 alkyloxy, reacted with a compound of formula 2: in which A and R have the meanings given in claims 1 to 5, resulting in a compound of formula 4: • · in which A and the radicals R _1; R ₃ , R ₄ , R ₅ , R ₆ and R ₇ have the meanings defined in claims 1 to 5, and finally this compound is reacted with a compound of formula R ₂ -X in which R ₂ and X can have the meanings, as defined in claims 1 to 5 and yields the compound of formula I. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Patent claims deposited in 'MB'. EPLS. ·· Patent Claims