DE10216333A1 - New diarylacetic acid quaternized azabicycloheptyl esters, are anticholinergic agents useful e.g. for treating asthma, chronic obstructive pulmonary disease, arrhythmia or menstrual disorders - Google Patents

Abstract

Di(hetero)arylacetic acid (or tricyclic analog) quaternized 1-azabicyclo-(2.2.1)-hept-4-yl esters (I) are new. Also new are corresponding non-quaternized intermediates (IV). Quaternized azabicycloheptyl esters of formula (I), including their optical isomers, enantiomer mixtures, racemates and acid addition salts, are new. X- = monovalent anion, preferably chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate; A, B (preferably the same) = O, S, NH, CH2, CH=CH or N(alkyl); R = H, OH, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, CF3, CHF2, alkoxyalkyl, alkylcarbonyloxy, haloalkylcarbonyloxy, (3-6C) cycloalkylalkyl, OCOF3 or halo; R1 = 1-5C alkyl (optionally substituted by 3-6C cycloalkyl, OH or halo); or R1 + R2 = 3-5C alkylene; R2, R3, R2', R3', Rx, R' = H, alkyl, alkoxy, OH, CF3, CHF2, CN, NO2 or halo; or Rx + Rx' = direct bond, O, S, NH, CH2, CH2CH2, N(alkyl), CH(alkyl) or C(alkyl)2; alkyl moieties have 1-4C unless specified otherwise. Independent claims are included for: (1) new non-quaternized intermediates of formula (IV) (optionally in acid addition salt form); and (2) the use of tropanol compounds of formula (II) (or their acid addiiton salts) in the preparation of (IV).

Description

The present invention relates to new compounds of general formula 1

wherein X ^- and the radicals A, B, R, R ¹ , R ² , R ² ', R ³ , R ³ ', R ^x and R ^x ', which may have the meanings given in the claims and in the description, process for their manufacture and their use as medicines.

Description of the invention

The present invention relates to compounds of general formula 1

wherein
X ^- a single negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate ;
A and B the same or different, preferably the same, -O-, -S-, -NH-, -CH ₂ -, -CH = CH-, or -N (C ₁ -C ₄ alkyl) -;
R is hydrogen, hydroxy, -C ₁ -C ₄ alkyl, -C ₁ -C ₄ alkyloxy, -C ₁ -C ₄ alkylene halogen, -OC ₁ -C ₄ alkylene halogen, -C ₁ -C ₄ -alkylene-OH, -CF ₃ , CHF ₂ , -C ₁ -C ₄ -alkylene-C ₁ -C ₄ -alkyloxy, -O-COC ₁ -C ₄ -alkyl, -O-COC ₁ -C ₄ - Alkylene-halogen, -C ₁ -C ₄ -alkylene-C ₃ -C ₆ -cycloalkyl, -O-COCF ₃ or halogen;
R ^{1 is} hydrogen, -C ₁ -C ₅ alkyl, which may optionally be substituted by -C ₃ -C ₆ cycloalkyl, hydroxy or halogen,
R ² , R ³ , R ² 'and R ³ ', the same or different, hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ or halogen;
R ^x and R ^x 'are identical or different hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ or halogen or
R ^x and R ^x 'together form a single bond or a bridging group selected from the bridges -O-, -S-, -NH-, -CH ₂ -, -CH ₂ -CH ₂ -, -N (C ₁ -C ₄ -Alkyl) -, -CH (C ₁ -C ₄ -alkyl) - and -C (C ₁ -C ₄ -alkyl) ₂ -, mean.

Preferred compounds of general formula 1 are those in which
X ^- a single negatively charged anion selected from the group chloride, bromide, methyl sulfate, 4-toluenesulfonate and methanesulfonate, preferably bromide;
A and B are the same or different, preferably the same, -O-, -S-, -NH- or -CH = CH-;
R is hydrogen, hydroxy, -C ₁ -C ₄ alkyl, -C ₁ -C ₄ alkyloxy, -CF ₃ , -CHF ₂ , fluorine, chlorine or bromine;
R ^{1 is} hydrogen, C ₁ -C ₄ alkyl, which may optionally be substituted by hydroxy, fluorine, chlorine or bromine;
R ² , R ³ , R ² 'and R ³ ', the same or different, hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ , Fluorine, chlorine or bromine;
R ^x and R ^x 'are the same or different hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ , fluorine, chlorine or bromine or
R ^x and R ^x 'together represent a single bond or a bridging group selected from the bridges -O-, -S-, -NH- and -CH ₂ -.

Compounds of general formula 1 are particularly preferred, wherein
X ^- a single negatively charged anion selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide;
A and B are the same or different, preferably the same, -S- or -CH = CH-;
R is hydrogen, hydroxy, methyl, ethyl, methyloxy, ethyloxy, -CF ₃ , or fluorine;
R ^{1 is} hydrogen, methyl, ethyl, -CH ₂ F or -CH ₂ -CH ₂ F, preferably methyl or ethyl;
R ² , R ³ , R ² 'and R ³ ', identical or different, are hydrogen, methyl, methyloxy, -CF ₃ or fluorine;
R ^x and R ^x 'the same or different hydrogen, methyl, methyloxy, -CF ₃ or fluorine or
R ^x and R ^x 'together represent a single bond or the bridging group -O-.

Of particular importance according to the invention are compounds of general formula 1 , in which
X ^- a single negatively charged anion selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide;
A and B are the same or different, preferably the same, -S- or -CH = CH-;
R is hydrogen, hydroxy or methyl, preferably hydroxy;
R ^{1 is} methyl or ethyl;
R ² , R ³ , R ² 'and R ³ ', the same or different, hydrogen, -CF ₃ or fluorine, preferably hydrogen;
R ^x and R ^x 'are the same or different hydrogen, -CF ₃ or fluorine, preferably hydrogen or
R ^x and R ^x 'together represent a single bond or the bridging group -O-, preferably a single bond.

According to the invention, preference is furthermore given to compounds of the general formula 1 in which
X ^- bromide;
A and B are the same or different, preferably the same, -S- or -CH = CH-;
R is hydrogen, hydroxy or methyl, preferably hydroxy;
R ^{1 is} methyl;
R ² , R ³ , R ² 'and R ³ ', the same or different, hydrogen or fluorine, preferably hydrogen;
R ^x and R ^x ', the same or different, are hydrogen or fluorine, preferably hydrogen or
R ^x and R ^x 'together represent a single bond or the bridging group -O-, preferably a single bond.

The invention relates to the respective compounds of formula 1, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and, if appropriate, in the form of their pharmacologically tolerated acid addition salts.

In the compounds of general formula 1 , the radicals R ² , R ³ , R ² 'and R ³ ', if they are not hydrogen, can each be arranged ortho, meta or para with respect to the linkage to the "-CR" group. If none of the radicals R ² , R ³ , R ² 'and R ³ ' is hydrogen, R ² and R ² 'are preferably in the para position and R ³ and R ³ ' are preferably in the ortho or meta position, particularly preferred linked in meta position. If one of the radicals R ² and R ³ and one of the radicals R ² 'and R ³ ' is hydrogen, the other radical is preferably linked in the meta or para position, particularly preferably in the para position. If none of the radicals R ² , R ³ , R ² 'and R ³ ' is hydrogen, the compounds of the general formula 1 in which the radicals R ² , R ³ , R ² 'and R ³ ' have the same meaning are particularly preferred according to the invention ,

Of particular importance according to the invention are the compounds of general formula 1 in which A is -CH = CH- and B is -CH = CH-. These compounds correspond to the general formula 1 ' .

wherein X ^- and the radicals R, R ¹ , R ² , R ² ', R ³ , R ³ ', R ^x and R ^x ', may have the meanings given above.

Of particular importance according to the invention are the compounds of general formula 1 in which A is -S- and B is -S-. These compounds correspond to the general formula 1 ' .

wherein X ^- and the radicals R, R ¹ , R ² , R ² ', R ³ , R ³ ', R ^x and R ^x ', may have the meanings given above.

• - 4-(2-Hydroxy-2,2-diphenylacetoxy)-1-methyl-1-azabicyclo[2.2.1]heptan- bromid;
• - 4-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-methyl-1-azabicyclo[2.2.1]heptan- bromid;
• - 4-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-methyl-1- azabicyclo[2.2.1]heptan-bromid;
• - 4-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-methyl-1-azabicyclo[2.2.1]heptan- bromid;

The following compounds are of particular importance according to the invention:

• - 4- (2-hydroxy-2,2-diphenylacetoxy) -1-methyl-1-azabicyclo [2.2.1] heptane bromide;
• - 4- (9-Hydroxy-9H-fluorene-9-carbonyloxy) -1-methyl-1-azabicyclo [2.2.1] heptane bromide;
• - 4- (9-Hydroxy-9H-xanthene-9-carbonyloxy) -1-methyl-1-azabicyclo [2.2.1] heptane bromide;
• - 4- (2-Hydroxy-2,2-dithien-2-ylacetoxy) -1-methyl-1-azabicyclo [2.2.1] heptane bromide;

Unless otherwise stated, the alkyl groups are branched and denotes unbranched alkyl groups with 1 to 4 carbon atoms. For example are called: methyl, ethyl, propyl or butyl. To designate the groups Abbreviations may also be methyl, ethyl, propyl or butyl Me, Et, Prop or Bu used. Unless otherwise stated, the Definitions Propyl and butyl all possible isomeric forms of the respective radicals. For example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec. butyl and tert-butyl etc.

Unless otherwise stated, the cycloalkyl groups are alicyclic groups understood with 3 to 6 carbon atoms. These are the groups Cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. According to the invention Cyclopropyl is of particular importance in the context of the present invention.

Unless otherwise stated, the alkylene groups are branched and denotes unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene or butylene.

Unless otherwise stated, branched alkylene-halogen groups are used and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms referred to, the one, two or three times, preferably twice by a halogen are substituted. Accordingly, as alkylene OH groups, if not otherwise stated, branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms, the single, double or triple, preferably single are substituted by a hydroxy.

Unless otherwise stated, the alkyloxy groups are branched and denotes unbranched alkyl groups with 1 to 4 carbon atoms, which have a Oxygen atom are linked. Examples include: methylox, ethyloxy, Propyloxy or butyloxy. To designate the groups methyloxy, ethyloxy, Propyloxy or butyloxy may also contain the abbreviations MeO-, EtO-, PropO- or BuO- used. Unless otherwise stated, the Definitions propyloxy and butyloxy all conceivable isomeric forms of the respective Residues. For example, propyloxy includes n-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy, sec-butyloxy and tert-butyloxy etc. Within the scope of the present invention, instead of the term alkyloxy, the Name alkoxy used. To designate the groups methyloxy, ethyloxy, Accordingly, propyloxy or butyloxy may also reach Expressions methoxy, ethoxy, propoxy or butoxy are used.

Unless otherwise stated, branched alkylene-alkyloxy groups and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms referred to, the single, double or triple, preferably simply by one Alkyloxy group are substituted.

Unless otherwise stated, -O-CO-alkyl groups are branched and unbranched alkyl groups with 1 to 4 carbon atoms which are linked via an ester group. The alkyl groups are bonded directly to the carbonyl carbon of the ester group. The term -O-CO-alkyl-halogen group is to be understood in an analogous manner. The group -O-CO-CF ₃ stands for trifluoroacetate.

Halogen in the context of the present invention is fluorine, chlorine, bromine or Iodine. Unless otherwise stated, fluorine and bromine are preferred Halogens. The group CO denotes a carbonyl group.

As explained below, the compounds according to the invention can be prepared in part analogously to procedures already known in the prior art (Scheme 1). The carboxylic acid derivatives of the formula 3 are known in the prior art or can be obtained by synthetic methods known in the prior art. If only appropriately substituted carboxylic acids are known in the prior art, the compounds of the formula 3 can also be obtained directly from these by acid- or base-catalyzed esterification with the corresponding alcohols or by halogenation with the corresponding halogenation reagents.

Scheme 1

Starting from the compound of the formula 2 , the esters of the general formula 4 can be accessed by reaction with the carboxylic acid derivatives of the formula 3 in which R 'is, for example, chlorine or a C ₁ -C ₄ -alkyloxy radical. In the case of R 'equal to C ₁ -C ₄ alkyloxy, this reaction can be carried out, for example, in a sodium melt at elevated temperature, preferably at about 50-150 ° C, particularly preferably at about 90-100 ° C at low pressure, preferably at below 500 mbar, particularly preferably under 75 mbar. Alternatively, instead of the derivatives 3 in which R 'is C ₁ -C ₄ alkyloxy, the corresponding acid chlorides (R is Cl) can also be used.

The compounds of formula 4 obtained in this way can be converted into the target compounds of formula 1 by reaction with the compounds R ¹ -X, in which R ¹ and X can have the meanings mentioned above. This synthesis step can also be carried out analogously to the synthesis examples disclosed in WO 92/16528.

Alternatively, the compounds of formula 4 in which R is halogen are also accessible in the manner shown in Scheme 2.

Scheme 2

For this purpose, the compounds of the formula 4 in which R is hydroxy are converted into the compounds 4 in which R is halogen using suitable halogenating reagents. The implementation of the halogenation reactions to be carried out according to scheme 2 is sufficiently known in the prior art.

As can be seen in Scheme 1, the intermediates of general formula 4 are of central importance. Accordingly, a further aspect of the present invention targets the intermediates of formula 4

wherein the radicals A, B, R, R ² , R ² ', R ³ , R ³ ', R ^x and R ^x 'can have the meanings given above, optionally in the form of their acid addition salts. Among acid addition salts, salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate toluate and hydrochloronate, and preference is given to hydrobenzoate toluate and hydrocarbonate, Hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate understood.

As in the compounds of the general formula 1 , the radicals R ² , R ³ , R ² 'and R ³ ' in the compounds of the general formula 4 can, if they are not hydrogen, in each case ortho, meta or para with respect to the linkage to the " -CR "group. If none of the radicals R ² , R ³ , R ² 'and R ³ ' is hydrogen, R ² and R ² 'are preferably in the para position and R ³ and R ³ ' are preferably in the ortho or meta position, particularly preferred linked in meta position. If one of the radicals R ² and R ³ and one of the radicals R ² 'and R ³ ' is hydrogen, the other radical is preferably linked in the meta or para position, particularly preferably in the para position. If none of the radicals R ² , R ³ , R ² 'and R ³ ' is hydrogen, the compounds of the general formula 4 in which the radicals R ² , R ³ , R ² 'and R ³ ' have the same meaning are particularly preferred according to the invention ,

As can be seen from Scheme 1, the compound of formula 2 serves as starting products for the preparation of the compounds of formula 1 . Methods for their production are known in the prior art. Accordingly, another aspect of the present invention aims to use the compound of formula 2

optionally in the form of your acid addition salts, for the preparation of the compounds of general formula 4 . The present invention further relates to the use of the compound of the formula 2, optionally in the form of its acid addition salts, as a starting material for the preparation of the compounds of the general formula 1 .

Under acid addition salts, salts are selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate and Understand methanesulfonate.

The synthesis examples described below serve the further Illustration of the present invention. However, they are only exemplary To understand procedures for further explanation of the invention, without the same towards the object described below by way of example restrict.

The representation of the compound of formula 2

can be carried out using synthetic methods known from the literature, as described, for example, in WO 93/15080 or EP-A-188255. Example 1 4- (2-Hydroxy-2,2-diphenylacetoxy) -1-methyl-1-azabicyclo [2.2.1] heptane bromide

1.1 .: methyl benzilate 3a

90 g (0.394 mol) of benzilic acid are dissolved in 900 ml of acetonitrile, and 109.6 g (0.72 mol) of DBU are added dropwise at 5 ° C. After addition of 204.4 g (1.44 mol) of methyl iodide, the mixture is stirred for 24 hours at room temperature (about 20-23 ° C.). The solution is evaporated to the residue, the residue is taken up in diethyl ether and extracted with water. The organic phase is washed with 5% aqueous sodium carbonate solution and water, dried and the solvent is distilled off. The product is purified by recrystallization from cyclohexane. Yield: 77.19 g of white crystals (= 81% of theory)
Mp: 74 ° -76 ° C.

1.2 .: 4- (2-hydroxy-2,2-diphenylacetoxy) -1-azabicyclo [2.2.1] heptane 4a

0.35 g (0.0031 mol) of base 2 and 2.0 g (0.0083 mol) of methyl benzilate 3a are placed in 20 ml of toluene, and 0.5 g (0.010 mol) of sodium hydride are added. The mixture is stirred for 5 hours at 120 ° C. and a toluene / methanol mixture is distilled off. After cooling, 10 ml of water are added, the organic phase is separated off and extracted with 1 N hydrochloric acid. The resulting water phase is made alkaline and extracted with dichloromethane. The organic phase is then dried and evaporated to dryness. The residue is crystallized with diethyl ether. Yield: 0.079 g (= 8% of theory).

1.3: 4- (2-Hydroxy-2,2-diphenylacetoxy) -1-methyl-1-azabicyclo [2.2.1] heptane bromide

0.079 g (0.00024 mol) 4a are placed in 5 ml dichloromethane and added with 0.5 ml 50% methyl bromide solution in acetonitrile. The mixture is stirred for 24 hours at room temperature, then the solvent is distilled off under reduced pressure. The cleaning is carried out by crystallization from acetone.
Yield: 0.085 g (= 83% of theory). Example 2 4- (9-Hydroxy-9H-fluorene-9-carbonyloxy) -1-methyl-1-azabicyclo [2.2.1] heptane bromide

2.1 .: Methyl 9-hydroxy-fluorene-9-carboxylate 3b

50.4 g (0.223 mol) of 9-hydroxy-9-fluorenecarboxylic acid are dissolved in 500 ml of methanol dissolved, with 5 ml (0.089 mol) conc. Sulfuric acid added and under 1 hour Reflux cooked. After cooling, 100 ml of sodium bicarbonate solution (about pH 8) added, and the methanol largely under reduced pressure distilled off. The remaining residue is mixed with dichloromethane and water extracted, the organic phase dried and evaporated to dryness.

The purification is carried out by recrystallization from ethyl acetate. Yield: 50.0 g (= 93% of theory Th.)

2.2: 4- (9-Hydroxy-9H-fluorene-9-carbonyloxy) -1-azabicyclo [2.2.1] heptane 4b

0.6 g (0.004 mol) 2 are dissolved in 5 ml of methanol, 0.241 g (0.005 mol) of sodium hydride are added and the solvent is distilled off under reduced pressure. The residue is mixed with 20 ml of toluene, 1.6 g (0.006 mol) of 3b and 0.024 g (0.0005 mol) of sodium hydride are added. The mixture is stirred at 140 ° C. for 2 hours and methanol is distilled off. After cooling, it is washed with water and the organic phase is extracted with 1 N hydrochloric acid. The resulting water phase is made alkaline and extracted with dichloromethane. The organic phase is then dried and the solvent is distilled off under reduced pressure. The residue is crystallized from ethyl acetate.
Yield: 0.32 g (= 20% of theory); Mp: 178 ° -179 ° C.

2.3: 4- (9-Hydroxy-9H-fluorene-9-carbonyloxy) -1-methyl-1-azabicyclo [2.2.1] heptane bromide

0.3 g (0.0009 mol) 4b are dissolved in 10 ml dichloromethane and 1 ml (0.0052 mol) 50% methyl bromide solution in acetonitrile is added. The mixture is stirred for 24 hours at room temperature, then the solvent is distilled off under reduced pressure. Yield: 0.14 g (= 39% of theory). Example 3 4- (9-Hydroxy-9H-xanthene-9-carbonyloxy) -1-methyl-1-azabicyclo [2.2.1] heptane bromide

3.1 .: methyl 9-hydroxy-xanthene-9-carboxylate 3c a) Xanthene-9-carboxylic acid methyl ester

A sodium ethylate solution is generated from 21.75 g (0.95 mol) sodium and 1500 ml ethanol. 214 g (0.95 mol) of xanthene-9-carboxylic acid are added to this solution in portions and the suspension obtained is stirred at room temperature for 1 hour. The solid is then separated off, washed with 1500 ml of diethyl ether, the crystals isolated are suspended in 1500 ml of dimethylformamide and 126.73 ml (2.0 mol) of methyl iodide are added with stirring. The resulting solution is left to stand at room temperature for 24 hours, then diluted with water to a total volume of 6 l, crystallized, filtered off with suction, washed with water and dried. Yield: 167 g of white crystals 7 (= 74% of theory)
Mp: 82 ° C.

b) 9-Hydroxy-xanthene-9-carboxylic acid methyl ester 3c

48.05 g (0.2 mol) of xanthene-9-carboxylic acid methyl ester are dissolved in 1200 ml of tetrahydrofuran, and 23.63 g (0.2 mol) of potassium tert-butoxide are added at 0 ° C. Oxygen is then passed in for 2 hours at -10 ° to -5 ° C, then acidified with 2 N aqueous hydrochloric acid and the major part of the solvent is removed by distillation. The remaining residue is extracted with ethyl acetate and water, the organic phase is extracted with aqueous Na ₂ S ₂ O ₅ solution, washed with water, dried and the solvent is distilled off. The product is purified by crystallization from diisopropyl ether and cyclohexane. Yield: 11.10 g of white crystals (= 22% of theory)

3.2: 4- (9-Hydroxy-9H-xanthene-9-carbonyloxy) -1-azabicyclo [2.2.1] heptane 4c

0.75 g (0.005 mol) 2 are dissolved in 20 ml of methanol, 0.21 g (0.0053 mol) of sodium hydride are added and the mixture is evaporated in vacuo. The residue is mixed with 20 ml of toluene, 1.7 g (0.0066 mol) 3c and 0.02 g (0.0005 mol) sodium hydride. The mixture is stirred at 140 ° C. for 2 hours and methanol is distilled off. After cooling, it is washed with water and the organic phase is extracted with 1 N hydrochloric acid. The resulting water phase is made alkaline and extracted with dichloromethane. The organic phase is then dried and the solvent is distilled off under reduced pressure. The residue is crystallized from ethyl acetate. Yield: 0.25 g (= 15% of theory).

3.3: 4- (9-hydroxy-9H-xanthene-9-carbonyloxy) -1-methyl-1-azabicyclo [2.2.1] heptane bromide

0.20 g (0.0006 mol) 4c are dissolved in 5 ml acetonitrile and 0.5 ml (0.0026 mol) 50% methyl bromide solution in acetonitrile is added. The mixture is stirred for 24 hours at room temperature, then the solvent is distilled off under reduced pressure. The residue is crystallized from acetone.
Yield: 0.22 g (= 86% of theory). Example 4 4- (2-Hydroxy-2,2-dithien-2-ylacetoxy) -1-methyl-1-azabicyclo [2.2.1] heptane bromide

4.1: 4- (2-Hydroxy-2,2-dithien-2-ylacetoxy) -1-azabicyclo [2.2.1] heptane 4d

0.60 g (0.0053 mol) 2 are dissolved in 20 ml of methanol, 0.21 g (0.0053 mol) of sodium hydride are added and the solvent is distilled off under reduced pressure. The residue is mixed with 20 ml of toluene, 1.6 g (0.0063 mol) of di- (2-thienyl) glycolic acid methyl ester 3d and 0.01 g (0.0003 mol) of sodium hydride. The mixture is stirred at 140 ° C. for 2 hours and methanol is distilled off. After cooling, it is washed with water and the organic phase is extracted with 1 N hydrochloric acid. The resulting water phase is made alkaline and extracted with dichloromethane. The organic phase is then dried and the solvent is distilled off under reduced pressure. The residue is crystallized from ethyl acetate.
Yield: 0.26 g (= 15% of theory); Mp: 107 ° -108 ° C

4.3: 4- (2-Hydroxy-2,2-dithien-2-ylacetoxy) -1-methyl-1-azabicyclo [2.2.1] heptane bromide

0.20 g (0.0006 mol) 4d are dissolved in 5 ml acetonitrile and 0.5 ml (0.0026 mol) 50% methyl bromide solution in acetonitrile is added. The mixture is stirred for 24 hours at room temperature, then the solvent is distilled off under reduced pressure. The residue is crystallized from acetone.
Yield: 0.20 g (= 78% of theory); Mp .: 118 ° -119 ° C.

As was found, the compounds of formula 1 according to the invention are antagonists of the M3 receptor (muscarinic receptor subtype 3). The compounds according to the invention have Ki values of less than 100 nM with regard to the affinity for the M3 receptor. These values were determined in accordance with the procedure described below.

chemicals

3H-NMS was developed by Amersham, Braunschweig, with a specific Radioactivity of 3071 GBq / mmol (83 Ci / mmol) related. All other raegantias were obtained from Serva, Heidelberg and from Merck, Darmstadt.

cell membranes

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

Receptor binding studies

The binding assay was carried out in a final volume of 1 ml and settled together from 100 µl of labeled substance in different concentrations, 100 µl Radioligand (3H-N-methylscopolamine 2 nmol / L (3H-NMS), 200 µl Membrane preparation and 600 µl HEPES buffer (20 mmol / L HEPES, 10 mmol / L MgCl2, 100 mmol / L NaCl, adjusted to pH 7.4 with 1 mol / L NaOH).

We determined the nonspecific binding by 10 µmol / L atropine.

The incubation of 45 min. was carried out at 37 ° C. in 96-well microtiter plates (Beckman, Polystyrene, No. 267001) as a double determination. The incubation ended Filtration using Inotech cell harvester (type IH 110) via Whatman G-7 filter. The filters were washed with 3 ml of ice-cold HEPES buffer and before the measurement dried.

Determination of radioactivity

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

evaluation

We calculated the Ki values using implicit equations, which were derived directly from the law of mass action, using the model for the 1 receptor 2 ligand reaction (SysFit - Software, SCHITTKOWSKI). Literature BONNER TI, New subtypes of muscarinic acetylcholine receptors Trends Pharmacol. Sci. 10, Suppl .: 11-15 (1989); SCHITTKOWSKI K Parameter estimation in systems of nonlinear equations Numer Math. 68: 129-142 (1994).

The compounds of formula 1 according to the invention are characterized by a wide range of possible uses in the therapeutic field.

To be emphasized according to the invention are those possible uses for which the compounds of formula 1 according to the invention can preferably be used due to their pharmaceutical activity as an anticholinergic.

These are, for example, the therapy of asthma or COPD (chronic obstructive pulmonary disease = chronic obstructive pulmonary disease). The compounds of general formula 1 can also be used to treat vagal sinus bradycardia and to treat cardiac arrhythmias. In general, the compounds according to the invention can also be used for the treatment of spasms, for example in the gastrointestinal tract, with therapeutic benefits. They can also be used in the treatment of spasms in urinary passages and, for example, in menstrual cramps.

Of the indication areas listed above by way of example, the therapy of asthma and COPD by means of the compounds of formula 1 according to the invention is of particular importance.

The compounds of general formula 1 can be used alone or in combination with other active compounds of formula 1 according to the invention. If appropriate, the compounds of the general formula 1 can also be used in combination with other pharmacologically active compounds. These are, in particular, betamimetics, antiallergics, PAF antagonists, leukotriene antagonists and corticosteroids, and combinations of active substances thereof.

Examples of betamimetics which can be used according to the invention in combination with the compounds of formula 1 include compounds which are selected from the group consisting of bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, Procaterol, reproterol, salmeterol, sulfonterol, terbutaline, tolubuterol, 4-hydroxy-7- [2 - {[2 - {[3- (2-phenylethoxy) propyl] sulfonyl} ethyl] -amino} ethyl] -2 (3H) - benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [3- (4-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-N, N -dimethylaminophenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl ] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2 - [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [ 2H-5-Hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1,2,4-triazol-3-yl] - 2-methyl-2-butylamino} ethanol, 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazin-3- (4H) -one, 1- (4-amino-3 -chloro-5-trifluoromethylphenyl) -2-tert-butylamino) ethanol and 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol, optionally in the form of their racemates Enantiomers, their diastereomers, and optionally their pharmacologically acceptable acid addition salts and hydrates. Such betamimetics are particularly preferably used in combination with the compounds of formula 1 according to the invention which are selected from the group consisting of fenoterol, 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-N, N -dimethylaminophenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2 - [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3 - (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1,2,4-triazol-3-yl] -2-methyl-2-butylamino} ethanol, optionally in the form of their racemates, their enantiomers, their diastereomers, and, if appropriate, their pharmacologically acceptable acid addition salts and hydrates. Of the abovementioned betamimetics, the compounds formoterol and salmeterol, in the form of their racemates, their enantiomers, their diastereomers, and, if appropriate, their pharmacologically acceptable acid addition salts and hydrates, are of particular importance.

According to the invention, the acid addition salts of the betamimetics are preferred selected from the group consisting of hydrochloride, hydrobromide, sulfate, Phosphate, fumarate methanesulfonate and xinafoate. Those are particularly preferred Salts in the case of salmeterol selected from hydrochloride, sulfate and xinafoate, of which the sulfates and xinafoates are particularly preferred. According to the invention Salmeterol xS H2SO4 and salmeterol xinafoate are of outstanding importance. In the case of formoterol, the salts are particularly preferably selected from Hydrochloride, sulfate and fumarate, of which the hydrochloride and fumarate are particularly preferred. According to the invention is of outstanding importance Formoterol fumarate.

In the context of the present invention, corticosteroids, which can optionally be used in combination with the compounds of formula 1 , are understood to mean compounds which are selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide , GW 215864, KSR 592, ST-126 and Dexametasone. In the context of the present invention, the corticosteroids are preferably selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexametasone, here the budesonide, fluticasone, mometasone and ciclesonide, in particular the budesonasone and one Importance. If appropriate, only the term steroids is used in the context of the present patent application instead of the term corticosteroids. Reference to steroids in the context of the present invention includes reference to salts or derivatives which can be formed by the steroids. Examples of possible salts or derivatives are: sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. If necessary, the corticosteroids can also be present in the form of their hydrates.

In the context of the present invention, dopamine agonists, which can optionally be used in combination with the compounds of formula 1 , are understood to mean compounds which are selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole , Roxindol, Ropinirol, Talipexol, Tergurid and Viozan. In the context of the present invention, preference is given to using dopamine agonists as combination partners with the compounds of the formula 1 which are selected from the group consisting of pramipexole, talipexole and viozan, pramipexole being of particular importance. In the context of the present invention, a reference to the above-mentioned dopamine agonists includes a reference to their pharmacologically acceptable acid addition salts which may exist and, if appropriate, their hydrates. The physiologically tolerable acid addition salts which can be formed by the above-mentioned dopamine agonists are understood to mean, for example, pharmaceutically tolerable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and are maleic acid.

Examples of antiallergics which can be used according to the invention as a combination with the compounds of formula 1 are epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, Doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozin. Preferred antiallergics which can be used in the context of the present invention in combination with the compounds of the formula 1 according to the invention are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratidine and mizolastine, where epinastine and Desloratidine are particularly preferred. In the context of the present invention, a reference to the abovementioned antiallergics includes a reference to their pharmacologically acceptable acid addition salts which may exist.

Examples of PAF-antagonists which may occur according to the invention with the compounds of Formula 1 as a combination for use may be mentioned 4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholinyl) -3-propanone-1 -yl] -6H-thieno- [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine, 6- (2-chlorophenyl) -8,9-dihydro -1-methyl-8 - [(4-morpholinyl) carbonyl] -4H, 7H-cyclopenta- [4,5] thieno- [3,2-f] [1,2,4] triazolo [4,3 -a] [1,4] diazepine.

If the compounds of formula 1 are used in combination with other active ingredients, the combination of steroids or betamimetics is particularly preferred from the compound classes mentioned above. The combination with beta mimetics, especially with long-acting beta mimetics, is of particular importance. The combination of the compounds of formula 1 according to the invention with salmeterol or formoterol is to be regarded as particularly preferred, the combination with formoterol being highly preferred.

Suitable forms of application for the application of the compounds of formula 1 are, for example, tablets, capsules, suppositories, solutions etc. According to the invention, the inhalative application of the compounds according to the invention is particularly important (in particular in the treatment of asthma or COPD). The proportion of the pharmaceutically active compound (s) should in each case be in the range from 0.05 to 90% by weight, preferably 0.1 to 50% by weight, of the total composition. Corresponding tablets can be obtained, for example, by mixing the active ingredient (s) with known auxiliaries, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or agents to achieve the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Correspondingly, coated tablets can be coated analogously to the tablets manufactured cores with agents commonly used in dragee coatings, for example Kollidon or shellac, gum arabic, talc, titanium dioxide or Sugar. To achieve a deposit effect or to avoid it of incompatibilities, the core can also consist of several layers. Likewise, the coated tablet case can also be used to achieve a deposit effect consist of several layers, the ones mentioned above for the tablets Excipients can be used.

Juices of the active substances or combinations of active substances according to the invention can also have a sweetener such as saccharin, cyclamate, glycerin or Sugar as well as a taste-improving agent, e.g. B. flavorings such as vanillin or orange extract. You can also use suspension aids or Thickening agents such as sodium carboxymethyl cellulose, wetting agents, for example Condensation products of fatty alcohols with ethylene oxide, or protective substances such as p-hydroxybenzoates.

Solutions are made in the usual way, e.g. B. with the addition of isotonants, Preservatives, such as p-hydroxybenzoates, or stabilizers, such as Alkali salts of ethylenediaminetetraacetic acid, optionally using of emulsifiers and / or dispersants, for example in the Use of water as a diluent, optionally organic Solvents can be used as solubilizers or auxiliary solvents, manufactured and bottled in injection bottles or ampoules or infusion bottles.

The one or more active ingredients or combinations of active ingredients Containing capsules can be made, for example, by the Active ingredients mixed with inert carriers such as milk sugar or sorbitol and in Encapsulated gelatin capsules.

Suitable suppositories can be mixed for this, for example provided carriers, such as neutral greases or polyethylene glycol or its derivatives.

Examples of auxiliaries are water, pharmaceutically acceptable ones organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils Of origin (e.g. peanut or sesame oil), mono- or polyfunctional alcohols (e.g. Ethanol or glycerin), carriers such as. B. natural stone powder (e.g. kaolins, Clays, talc, chalk) synthetic rock flour (e.g. highly disperse Silica and silicates), sugar (e.g. cane, milk and glucose) Emulsifiers (e.g. lignin, liquor from Sufite, methyl cellulose, starch and Polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

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

In the case of oral use, the tablets can of course besides that mentioned carriers also additives such. As sodium citrate, calcium carbonate and Dicalcium phosphate together with various additives, such as starch, preferably contain potato starch, gelatin and the like. Can continue Lubricants such as magnesium stearate, sodium lauryl sulfate and talc for tabletting can also be used. In the case of aqueous suspensions, the active ingredients can be added the above-mentioned excipients with various flavor enhancers or Dyes are added.

The dosage of the compounds according to the invention is of course strongly dependent on the type of application and the disease to be treated. When administered by inhalation, the compounds of formula 1 are highly effective even at doses in the µg range. The compounds of formula 1 can also be used sensibly above the µg range. The dosage can then be in the gram range, for example. In particular in the case of non-inhalation administration, the compounds according to the invention can be administered at higher doses (for example, but not in a limiting manner in the range from 1 to 1000 mg).

The following formulation examples illustrate the present invention without, however, restricting its scope: Pharmaceutical formulation examples

The finely ground active ingredient, milk sugar and part of the corn starch are mixed together. The mixture is sieved, whereupon it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the rest of the corn starch and the magnesium stearate are sieved and mixed together. The mixture is compressed into tablets of a suitable shape and size.

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

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

The suspension is filled into a conventional aerosol container with a metering valve. 50 µl of suspension are preferably dispensed per actuation. If desired, the active ingredient can also be dosed in higher amounts (for example 0.02% by weight).

This solution can be prepared in the usual way.

The inhalable powder is prepared in the usual way by mixing the individual components.

The inhalable powder is produced in the usual manner by Mixing the individual components.

Claims (13)

1. Compounds of the general formula 1

wherein
X ^- a single negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate ;
A and B are the same or different, -O-, -S-, -NH-, -CH ₂ -, -CH = CH-, or -N (C ₁ -C ₄ alkyl) -;
R is hydrogen, hydroxy, -C ₁ -C ₄ -alkyl, -C ₁ -C ₄ -alkyloxy, -C ₁ -C ₄ -alkylene-halogen, -OC ₁ -C ₄ -alkylene-halogen, -C ₁ -C ₄ -alkylene-OH, -CF ₃ , CHF ₂ , -C ₁ -C ₄ -alkylene-C ₁ -C ₄ -alkyloxy, -O-COC ₁ -C ₄ -alkyl, -O-COC ₁ -C ₄ - Alkylene-halogen, C ₁ -C ₄ alkylene-C ₃ -C ₆ cycloalkyl, -O-COCF ₃ or halogen;
R ^{1 is} hydrogen, -C ₁ -C ₅ alkyl, which may optionally be substituted by -C ₃ -C ₆ cycloalkyl, hydroxy or halogen,
R ² , R ³ , R ² 'and R ³ ', the same or different, hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ or halogen;
R ^x and R ^x 'are identical or different hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ or halogen or
R ^x and R ^x 'together form a single bond or a bridging group selected from the bridges -O-, -S-, -NH-, -CH ₂ -, -CH ₂ -CH ₂ -, -N (C ₁ -C ₄ -Alkyl) -, -CH (C ₁ -C ₄ -alkyl) - and -C (C ₁ -C ₄ -alkyl) ₂ -, mean. 2. Compounds of general formula 1 according to claim 1, wherein
X ^- a single negatively charged anion selected from the group consisting of chloride, bromide, methyl sulfate, 4-toluenesulfonate and methanesulfonate;
A and B are the same or different, -O-, -S-, -NH- or -CH = CH-;
R is hydrogen, hydroxy, -C ₁ -C ₄ alkyl, -C ₁ -C ₄ alkyloxy, -CF ₃ , -CHF ₂ , fluorine, chlorine or bromine;
R ^{1 is} hydrogen, C ₁ -C ₄ alkyl, which may optionally be substituted by hydroxy, fluorine, chlorine or bromine;
R ² , R ³ , R ² 'and R ³ ', identical or different, hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ , Fluorine, chlorine or bromine;
R ^x and R ^x 'are the same or different hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ , fluorine, chlorine or bromine or
R ^x and R ^x 'together represent a single bond or a bridging group selected from the bridges -O-, -S-, -NH- and -CH ₂ -. 3. Compounds of general formula 1 according to claim 1 or 2, wherein
X ^- a single negatively charged anion selected from the group consisting of chloride, bromide and methanesulfonate;
A and B are the same or different, -S- or -CH = CH-;
R is hydrogen, hydroxy, methyl, ethyl, methyloxy, ethyloxy, -CF ₃ , or fluorine;
R ^{1 is} hydrogen, methyl, ethyl, -CH ₂ F or -CH ₂ -CH ₂ F;
R ² , R ³ , R ² 'and R ³ ', identical or different, are hydrogen, methyl, methyloxy, -CF ₃ or fluorine;
R ^x and R ^x 'the same or different hydrogen, methyl, methyloxy, -CF ₃ or fluorine or
R ^x and R ^x 'together represent a single bond or the bridging group -O-. 4. Compounds of general formula 1 according to claim 1, 2 or 3, wherein
X ^- a single negatively charged anion selected from the group consisting of chloride, bromide and methanesulfonate;
A and B are the same or different, -S- or -CH = CH-;
R is hydrogen, hydroxy or methyl;
R ^{1 is} methyl or ethyl;
R ² , R ³ , R ² 'and R ³ ', the same or different, are hydrogen, -CF ₃ or fluorine;
R ^x and R ^x 'are identical or different hydrogen, -CF ₃ or fluorine or R ^x and R ^x ' together represent a single bond or the bridging group -O-. 5. Compounds of general formula 1 according to one of claims 1 to 4, wherein
X ^- bromide;
A and B are the same or different -S- or -CH = CH-;
R is hydrogen, hydroxy or methyl;
R ^{1 is} methyl;
R ² , R ³ , R ² 'and R ³ ', the same or different, are hydrogen or fluorine;
R ^x and R ^{x are the} same or different hydrogen or fluorine or
R ^x and R ^x 'together represent a single bond or the bridging group -O-, preferably a single bond. 6. Compounds of general formula 1 according to one of claims 1 to 5, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and optionally in the form of their pharmacologically acceptable acid addition salts. 7. Use of a compound of general formula 1 according to one of claims 1 to 6 as a medicament. 8. Use of a compound of general formula 1 according to one of claims 1 to 6 for the manufacture of a medicament for the treatment of diseases in which anticholinergics can have a therapeutic benefit. 9. Use of a compound of general formula 1 according to one of claims 1 to 6 for the manufacture of a medicament for the treatment of asthma, COPD, vagal sinus bradycardia, cardiac arrhythmias, spasms in the gastrointestinal tract, spasms in urinary tract and menstrual disorders. 10. Pharmaceutical preparations containing as active ingredient one or more compounds of general formula 1 according to one of claims 1 to 6 or their physiologically tolerable salts, optionally in combination with customary auxiliaries and / or carriers. 11. Pharmaceutical preparations according to claim 10, characterized in that, in addition to one or more of the compounds of formula 1, they further contain at least one further active ingredient which is selected from the group of betamimetics, antiallergics, PAF antagonists, leukotriene antagonists and steroids. 12. Intermediates of general formula 4

wherein the radicals A, B, R, R ² , R ² ', R ³ , R ³ ', R ^x and R ^x 'can have the meanings given in claims 1 to 5, optionally in the form of their acid addition salts. 13. Use of the compound of formula 2

optionally in the form of their acid addition salts, for the preparation of the compounds of general formula 4 according to claim 12.