Abstract:
The present invention relates to new anticholinergics of general formula 1:                            
     wherein A, X −  and the groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  may have the meanings given in the claims and in the specification, processes for preparing them and their use as pharamaceutical compositions.

Description:
RELATED APPLICATIONS 
     Benefit of U.S. Provisional Application Ser. No. 60/252,777, filed on Nov. 22, 2000 is hereby claimed, and said Provisional Application is herein incorporated by reference. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to new anticholinergics of general formula 1:                           
     wherein A, X −  and the groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  may have the meanings given in the claims and specification, processes for preparing them as well as their use as medicaments. 
     BACKGROUND OF THE INVENTION 
     Anticholinergics may be used to therapeutic effect in a wide range of illnesses. Special mention should be made, for example, of the treatment of asthma or COPD (chronic obstructive pulmonary disease). For treating these complaints, WO 92/16528 proposes anticholinergics which have a scopine, tropenol or tropine basic structure. 
     The underlying objective of WO 92/16528 is the preparation of anticholinergically effective compounds which are characterised by their long-lasting activity. To achieve this aim WO 92/16528 discloses, inter alia, benzilic acid esters of scopine, tropenol or tropine. 
     For treating chronic diseases it is often desirable to prepare medicaments with a longer duration of activity. As a rule, this ensures that the concentration of the active substance in the body needed to achieve the therapeutic effect is guaranteed for a longer period without the need to re-administer the drug at frequent intervals. Moreover, giving an active substance at longer time intervals contributes to the wellbeing of the patient to a high degree. It is particularly desirable to prepare a pharmaceutical composition which can be used therapeutically by administration once a day (single dose). The use of a drug once a day has the advantage that the patient can become accustomed relatively quickly to regularly taking the drug at certain times of the day. 
     In order to be used as a medicament taken once a day, the active substance to be given must meet particular requirements. First of all, the onset of the desired activity should take place relatively quickly after administration of the drug and ideally should have as constant an effect as possible over a subsequent fairly long period of time. On the other hand, the duration of activity of the drug should not substantially exceed a period of about one day. Ideally, an active substance has an activity profile such that the preparation of a drug for administration once a day, which contains the active substance in therapeutically beneficial doses, can be deliberately controlled. 
     It has been found that the benzilic acid esters of scopine, tropenol and tropine disclosed in WO 92/16528 do not meet these stringent requirements. Because of their extremely long period of activity, which significantly exceeds the above-mentioned period of about one day, they cannot be used therapeutically for administration in a single dose per day. 
     The aim of the present invention is therefore to provide new anticholinergics which, by virtue of their activity profile, make it possible to prepare a drug for administration once a day. A further objective of the invention is to prepare compounds characterised by a relative rapid onset of activity. The invention further sets out to provide compounds which, after a rapid onset of activity, have as constant an activity as possible over a subsequent lengthy period of time. A further aim of the invention is to provide compounds whose duration of activity does not substantially exceed a period of about one day in therapeutically beneficial doses. Finally, the invention sets out to provide compounds which have an activity profile which ensures good control of the therapeutic effect (i.e. total therapeutic effect without side effects caused by a build-up of the substance in the body). 
     DETAILED DESCRIPTION OF THE INVENTION 
     Surprisingly, it has been found that the above objectives are achieved by means of compounds of general formula 1 wherein the group R 7  does not denote hydroxy. 
     Accordingly the present invention relates to compounds of general formula 1:                           
     wherein 
     A denotes a double-bonded group selected from among:                           
     X −  denotes anion with a single negative charge, 
     R 1  and R 2  denote C 1 -C 4 -alkyl, which may optionally be substituted by hydroxy or halogen; 
     R 3 , R 4 , R 5  and R 6 , which may be identical or different, denote hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy, hydroxy, CF3, CN, NO2 or halogen; 
     R7 denotes hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy, C 1 -C 4 -alkylene-halogen, halogen-C 1 -C 4 -alkyloxy, C 1 -C 4 -alkylene-OH, CF3, —C 1 -C 4 -alkylene-C 1 -C 4 -alkyloxy, —O—COC 1 -C 4 -alkyl, —O—COC 1 -C 4 -alkyl-halogen, —O—COCF 3  or halogen, while                           
     if A denotes 
     R 1  and R 2  denote methyl and 
     R 3 , R 4 , R 5  and R 6  denote hydrogen, 
     R 7  cannot also be hydrogen. 
     Preferred compounds of general formula 1 are those wherein 
     A denotes a double-bonded group selected from among:                           
     X −  denotes an anion with a single negative charge selected from among chloride, bromide, methylsulphate, 4-toluenesulphonate and methanesulphonate, preferably bromide, 
     R 1  and R 2  which may be identical or different denote a group selected from among methyl, ethyl, n-propyl and iso-propyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl; 
     R 3 , R 4 , R 5  and R 6 , which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF 3  or NO 2 ; 
     R7 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, —O—COEt, —O—COCF 3 , —O—COCF 3 , fluorine, chlorine or bromine. 
     Particularly preferred are compounds of general formula 1, wherein 
     A denotes a double-bonded group selected from among:                           
     X −  denotes an anion with a single negative charge selected from among chloride, bromide and methanesulphonate, preferably bromide; 
     Rand R 2  which may be identical or different denote a group selected from methyl and ethyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl; 
     R 3 , R 4 , R 5  and R 6 , which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine; 
     R 7  denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF 3 , or fluorine. 
     Preferred compounds of general formula 1 according to the invention are those wherein 
     A denotes a double-bonded group selected from among:                           
     X −  denotes bromide; 
     R 1  and R 2  which may be identical or different denote a group selected from methyl and ethyl, preferably methyl; 
     R 3 , R 4 , R 5  and R 6 , which may be identical or different, denote hydrogen, methyl, methyloxy, chlorine or fluorine; 
     R 7  denotes hydrogen, methyl or fluorine. 
     Of particular importance according to the invention are compounds of general formula 1, wherein 
     A denotes a double-bonded group selected from among:                           
     X −  denotes bromide; 
     R 1  and R 2  which may be identical or different denote methyl or ethyl, preferably methyl; 
     R 3 , R 4 , R 5  and R 6 , which may be identical or different, denote hydrogen or fluorine, preferably hydrogen; 
     R 7  denotes hydrogen, methyl or fluorine, preferably methyl or fluorine, most preferably methyl. 
     The invention relates to the compounds of formula 1, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof. 
     In the compounds of general formula 1 the groups R 3 , R 4 , R 5  and R 6 , provided that they do not denote hydrogen, may each be in the ortho, meta or para position relative to the bond to the “—C—R 7 ” group. Provided that none of the groups R 3 , R 4 , R 5  and R 6  denotes hydrogen, R 3  and R 5  are preferably linked in the para-position and R 4  and R 6  are preferably linked in the ortho- or meta-position, most preferably in the meta-position. If one of the groups R 3  and R 4  and one of the groups R 5  and R 6  denotes hydrogen, the other group in each case is preferably linked in the meta- or para-position, most preferably in the para-position. If none of the groups R 3 , R 4 , R 5  and R 6  denotes hydrogen, according to the invention the compounds of general formula 1 wherein the groups R 3 , R 4 , R 5  and R 6  have the same meaning are particularly preferred. 
     Of particular importance according to the invention are the compounds of general formula 1 wherein the ester-substituent on the nitrogen-bicyclic group is in the -configuration. These compounds correspond to general formula 1-:                           
     According to the invention, the following compounds are of particular importance: 
     tropenol 2,2-diphenylpropionate-methobromide; 
     scopine 2,2-diphenylpropionate-methobromide; 
     scopine 2-fluoro-2,2-diphenylacetate-methobromide; 
     tropenol 2-fluoro-2,2-diphenylacetate-methobromide; 
     Unless otherwise stated, the alkyl groups are straight-chained or branched alkyl groups having 1 to 4 carbon atoms. The following are mentioned by way of example: methyl, ethyl, propyl or butyl. In some cases the abbreviations Me, Et, Prop or Bu are used to denote the groups methyl, ethyl, propyl or butyl. Unless otherwise stated, the definitions propyl and butyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec.butyl and tert.-butyl, etc. 
     Unless otherwise stated, the alkylene groups are branched and unbranched double-bonded alkyl bridges having 1 to 4 carbon atoms. The following are mentioned by way of example: methylene, ethylene, propylene or butylene. 
     Unless otherwise stated, the alkylene-halogen groups are branched and unbranched double-bonded alkyl bridges having 1 to 4 carbon atoms which are mono-, di- or trisubstituted, preferably monosubstituted, by a halogen. Accordingly, unless otherwise stated, the alkylene-OH groups are branched and unbranched double-bonded alkyl bridges having 1 to 4 carbon atoms which are mono-, di- or trisubstituted, preferably monosubstituted, by a hydroxy. 
     Unless otherwise stated, the term alkyloxy groups denotes branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an oxygen atom. Examples of these include: methyloxy, ethyloxy, propyloxy or butyloxy. The abbreviations MeO—, EtO—, PropO— or BuO— are used in some cases to denote the groups methyloxy, ethyloxy, propyloxy or butyloxy. Unless otherwise stated, the definitions propyloxy and butyloxy include all possible isomeric forms of the groups in question. Thus, for example, propyloxy includes n-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy, sec.butyloxy and tert.-butyloxy, etc. In some cases, within the scope of the present invention, the term alkoxy is used instead of the term alkyloxy. Accordingly, the terms methoxy, ethoxy, propoxy or butoxy may also be used to denote the groups methyloxy, ethyloxy, propyloxy or butyloxy 
     Unless otherwise stated, the term alkylene-alkyloxy groups denotes branched and unbranched double-bonded alkyl bridges having 1 to 4 carbon atoms which are mono-, di- or trisubstituted, preferably monosubstituted, by an alkyloxy group. 
     Unless otherwise stated, the term —O—CO-alkyl groups denotes branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an ester group. The alkyl groups are linked directly to the carbonyl carbon of the ester group. The term —O—CO-alkyl-halogen group should be understood in the same way. The group —O—CO—CF 3  denotes trifluoroacetate. 
     Halogen within the scope of the present invention denotes fluorine, chlorine, bromine or iodine. Unless stated otherwise, fluorine and bromine are the preferred halogens. The group CO denotes a carbonyl group. 
     The compounds according to the invention may partly be prepared, as illustrated below, analogously to procedures which are already known from the prior art (Diagram 1). The carboxylic acid derivatives of formula 3 are known in the art or may be obtained using methods of synthesis known in the art. If only suitably substituted carboxylic acids are known in the art, the compounds of formula 3 may also be obtained directly from them by acid- or base-catalysed esterification with the corresponding alcohols or by halogenation with the corresponding halogenation reagents.                           
     Diagram 1 
     Starting from the compounds of formula 2 the esters of general formula 4 may be obtained by reacting the carboxylic acid derivatives of formula 3, wherein R may denote chlorine or a C 1 -C 4 -alkyloxy group, for example. When R denotes C 1 -C 4 -alkyloxy this reaction may be carried out, for example, in a sodium melt at elevated temperature, preferably at about 50-150° C., most preferably at about 90-100° C. at low pressure, preferably below 500 mbar, most preferably below 75 mbar. Alternatively, instead of the derivatives 3 wherein R denotes C 1 -C 4 -alkyloxy, the corresponding acid chlorides (R equals Cl) may be used. 
     The compounds of formula 4 thus obtained may be converted into the target compounds of formula 1 by reacting the compounds R 2 —X, wherein R2 and X may be as hereinbefore defined. This synthesis step may also be carried out analogously to the examples of synthesis disclosed in WO 92/16528. 
     Alternatively to the procedure illustrated in Diagram 1 for synthesising the compounds of formula 4, the derivatives 4 in which the nitrogen bicyclic group is a scopine derivative may be obtained by oxidation (epoxidation) of compounds of formula 4 wherein the nitrogen-bicyclic group is a tropenyl group. This may be done as follows, according to the invention. 
     Compound 4, wherein A denotes —CH═CH—, is suspended in a polar organic solvent, preferably in a solvent selected from among N-methyl-2-pyrrolidone (NMP), dimethylacetamide and dimethylformamide, preferably dimethylformamide, and then heated to a temperature of about 30-90° C., preferably 40-70° C. Then a suitable oxidising agent is added and the mixture is stirred at constant temperature for 2 to 8 hours, preferably 3 to 6 hours. The preferred oxidising agent is vanadium pentoxide mixed with H 2 O 2 , most preferably H 2 O 2 -urea complex combined with vanadium pentoxide. The mixture is worked up in the usual way. The products may be purified by crystallisation or chromatography, depending on their crystallisation tendencies. 
     Alternatively, the compounds of formula 4 wherein R 7  denotes halogen may also be obtained by the method shown in Diagram 2.                           
     Diagram 2 
     For this, the benzilic acid esters of formula 5 [verb missing (are converted?)], using suitable halogenating reagents, into the compounds 4 wherein R 7  denotes halogen. The reaction of halogenation to be carried out according to Diagram 2 is already sufficiently well known in the art. 
     The benzilic acid esters of formula 5 may be obtained in accordance with or analogously to methods known in the art (see e.g. WO 92/16528). 
     As shown in Diagram 1, the intermediate products of general formula 4 are of crucial importance. Accordingly, in another aspect, the present invention relates to the intermediates of formula 4:                           
     wherein 
     A denotes a double-bonded group selected from among:                           
     R 1  denotes C 1 -C 4 -alkyl, which may optionally be substituted by hydroxy or halogen; 
     R 3 , R 4 , R 5  and R 6 , which may be identical or different, denote hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy, hydroxy, CF3, CN, NO2 or halogen; 
     R 7  denotes hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy, C 1 -C 4 -alkylene-halogen, halogen-C 1 -C 4 -alkyloxy, C 1 -C 4 -alkylene-OH, CF3, —C 1 -C 4 -alkylene-C 1 C 4 -alkyloxy, —O—COC 1 -C 4 -alkyl, —O—COC 1 -C 4 -alkyl-halogen, —O—COCF3 or halogen, while                           
     if A denotes 
     R 1  denotes methyl and 
     R 3 , R 4 , R 5  and R 6  denote hydrogen, 
     R 7  cannot be n-propyl. 
     Preferred are compounds of general formula 4, wherein 
     A denotes a double-bonded group selected from among:                           
     R 1  denotes a group selected from among methyl, ethyl, n-propyl and iso-propyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl; 
     R 3 , R 4 , R 5  and R 6 , which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF3 or NO2; 
     R 7  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, CF3, —CH 2 —OMe, —CH 2 —CH 2 —OMe, —CH 2 —OEt, —CH 2 —CH 2 —OEt, —O—COMe, —O—COEt, —O—COCF3, —O—COCF3, fluorine, chlorine or bromine. 
     Particularly preferred are compounds of general formula 4, wherein 
     A denotes a double-bonded group selected from among:                           
     R 1  denotes a group selected from methyl and ethyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl; 
     R 3 , R 4 , R 5  and R 6 , which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine; 
     R 7  denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF 3 , or fluorine. 
     Preferred compounds of general formula 4 according to the invention are those wherein 
     A denotes a double-bonded group selected from among:                           
     R 1  denotes a group selected from methyl and ethyl, preferably methyl; 
     R 3 , R 4 , R 5  and R 6 , which may be identical or different, denote hydrogen, methyl, methyloxy, chlorine or fluorine; 
     R 7  denotes hydrogen, methyl or fluorine. 
     Of particular importance according to the invention are compounds of general formula 4 wherein 
     A denotes a double-bonded group selected from among:                           
     R 1  denotes methyl or ethyl, preferably methyl; 
     R 3 , R 4 , R 5  and R 6 , which may be identical or different, denote hydrogen or fluorine, preferably hydrogen; 
     R 7  denotes hydrogen, methyl or fluorine, preferably methyl or fluorine, most preferably methyl. 
     As in the compounds of general formula 1, in the intermediates of formula 4, the groups R 3 , R 4 , R 5  and R 6 , provided that they do not denote hydrogen, may each be in the ortho, meta or para position relative to the bond to the “—C—R 7 ” group. Provided that none of the groups R 3 , R 4 , R 5  and R 6  denotes hydrogen, R 3  and R 5  are preferably linked in the para-position and R 4  and R 6  are preferably linked in the ortho- or meta-position, most preferably in the meta-position. If one of the groups R 3  and R 4  and one of the groups R 5  and R 6  denotes hydrogen, the other group in each case is preferably linked in the meta- or para-position, most preferably in the para-position. If none of the groups R 3 , R 4 , R 5  and R 6  denotes hydrogen, according to the invention the intermediates of general formula 1 wherein the groups R 3 , R 4 , R 5  and R 6  have the same meaning are particularly preferred. 
     The examples of synthesis described hereinafter serve to illustrate the present invention still further. However, they are intended only as examples of procedures as an illustration of the invention without restricting the invention to the subject-matter described by way of example. 
    
    
     EXAMPLE 1 
     Scopine 2,2-diphenylpropionate-methobromide 
     
       
                 
         
             
             
         
      
     
     1.1.: 2,2-diphenylpropionic Acid Chloride 3a 
     52.08 g (0.33 mol) of oxalyl chloride are slowly added dropwise to a suspension of 25.0 g (0.11 mol) of 2,2-diphenylpropionic acid, 100 ml of dichloromethane and 4 drops of dimethylformamide at 20° C. The mixture is stirred for 1 h at 20° C. and 0.5 h at 50° C. The solvent is distilled off and the residue remaining is used in the next step without any further purification. 
     1.2.: Scopine 2,2-diphenylpropionate 4a 
     The residue obtained in step 1.1. is dissolved in 100 ml dichloromethane and at 40° C. a solution of 51.45 g (0.33 mol) of scopine in 200 ml dichloromethane is added dropwise. The resulting suspension is stirred for 24 h at 40° C., then the precipitate formed is suction filtered and the filtrate is acidically extracted first with water, then with aqueous hydrochloric acid. The combined aqueous phases are made alkaline with aqueous sodium carbonate solution, extracted with dichloromethane, the organic phase is dried over Na 2 SO 4 , evaporated to dryness and the hydrochloride is precipitated from the residue. The product is purified by recrystallisation from acetonitrile. 
     Yield: 20.85 g (=47% of theory) 
     TLC: Rf value: 0.24 (eluant: sec. butanol/formic acid/water 75:15:10); 
     Melting point: 203-204° C. 
     1.3: Scopine 2,2-diphenylpropionate-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 46.92% bromomethane in acetonitrile are combined at 20° C. and left to stand for 3 days. The solution is evaporated to dryness and the residue recrystallised from isopropanol. 
     Yield: 11.34 g (=75% of theory); Melting point: 208-209° C. C 24 H 28 NO 3 xBr (458.4); 
     Elemental analysis: calculated: C, (62.89); H, (6.16); N, (3.06). found: C, (62.85); H, (6.12); N, (3.07). 
     EXAMPLE 2 
     Scopine 2-fluoro-2,2-diphenylacetate-methobromide 
     
       
                 
         
             
             
         
      
     
     2.1: Scopine Benzilate 5a 
     The preparation of scopine benzilate is known in the art. It is described in WO 92/16528. 
     2.2: Scopine 2-fluoro-2,2-diphenylacetate 4b 
     2.66 g (0.02 mol) of dimethylaminosulphur trifluoride are cooled to 0° C. in 10 ml of dichloromethane and a solution of 5.48 g (0.015 mol) of scopine benzilate 5a in 100 ml of dichloromethane is added dropwise. Then the mixture is stirred for a further 30 min at 0° C. and 30 min at 20° C. While cooling the solution is combined with water, NaHCO 3  is added (to pH 7-8) and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, the combined organic phases are washed with water, dried over Na 2 SO 4  and evaporated to dryness. 
     The hydrochloride is precipitated from the residue and recrystallised from acetonitrile. 
     Yield: 6.90 g (=85% of theory) 
     Melting point: 227-230° C. 
     2.3: Scopine 2-fluoro-2,2-diphenylacetate-methobromide 
     2.88 g (0.0078 mol) of the free base of scopine benzil are reacted analogously to the procedure in step 1.3. The product is purified by recrystallisation from isopropanol. Yield: 2.62 g (=73% of theory) 
     TLC: Rf value: 0.31 (eluant as in step 1.2); Melting point: 130-134° C. 
     EXAMPLE 3 
     Tropenol 2,2-diphenylpropionate-methobromide 
     
       
                 
         
             
             
         
      
     
     3.1.: Methyl 2,2-diphenylpropionate 3b 
     37.60 g (0.247 mol) of DBU are added dropwise to a suspension of 50.8 g (0.225 mol) of 2,2-diphenylpropionic acid and 200 ml of acetonitrile at 20° C. 70.10 g (0.494 mol) of methyliodide are added dropwise to the resulting solution within 30 min. Then the mixture is stirred overnight at 20° C. The solvent is evaporated down, the residue is extracted with diethylether/water, the organic phase is washed with water, dried over Na 2 SO 4  and evaporated to dryness. Yield: 48.29 g of viscous residue 32 (=89% of theory). 
     3.2: Tropenol 2,2-diphenylpropionate 4c 
     4.80 g (0.02 mol) of methyl 2,2-diphenylpropionate 3b, 2.78 g (0.02 mol) of tropenol and 0.046 g of sodium are heated as a melt at 75 mbar for 4 h over a bath of boiling water, shaking from time to time. After cooling the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness and the residue extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO 4  and evaporated to dryness. 
     From the residue, 4c is precipitated as the hydrochloride and this is recrystallised from acetone. 
     Yield: 5.13 g (=67% of theory); 
     TLC: Rf value: 0.28 (eluant: sec. butanol/formic acid/water 75:15:10); 
     Melting point: 134-135° C. 
     3.3: Tropenol 2,2-diphenylpropionate-methobromide 
     2.20 g (0.006 mol) of 4c are reacted analogously to Example 1, step 1.3. The crystals formed are suction filtered, washed with dichloromethane, dried and then recrystallised from methanol/diethylether. 
     Yield: 1.84 g (=66% of theory) 
     TLC: Rf value: 0.11 (eluant as in step 1.2); Melting point: 222-223° C. C 24 H 28 NO 2 xBr (442.4); 
     Elemental analysis: calculated: C, (65.16); H, (6.38); N, (3.17). found.: C, (65.45); H, (6.29); N, (3.16). 
     EXAMPLE 4 
     Tropenol 2-fluoro-2,2-bis(3,4-difluorophenyl)acetate-methobromide 
     
       
                 
         
             
             
         
      
     
     4.1.: Ethyl 3,3′,4,4′-tetrafluorobenzilate 3c 
     The Grignard reagent is prepared from 2.24 g (0.092 mol) of magnesium chips, a few granules of iodine and 17.80 g (0.092 mol) of 1-bromo-3,4-difluoro-benzene in 100 ml of THF at 50° C. After the halide has all been added, the mixture is stirred for another hour. The Grignard reagent thus obtained is added dropwise to 18.81 g (0.088 mol) of ethyl 3,4-difluorophenylglyoxylate in 80 ml of THF at 10°-15° C. and the mixture obtained is stirred for 2 hours at 5° C. 
     The white suspension is poured onto ice/sulphuric acid for working up, extracted with ethyl acetate, the organic phase is washed with water, dried over MgSO 4  and evaporated to dryness. The crude product is purified by column chromatography (eluant: toluene). 
     Yield: 10.80 g of oil 1 (=38% of theory) 
     4.2.: Tropenol 3,3′,4,4′-tetrafluorobenzilate 5b 
     4.27 g (0.013 mol) of ethyl 3,3′,4,4′-tetrafluorobenzilate 3c, 1.81 g (0.013 mol) of tropenol and 0.03 g sodium are heated as a melt at 75 mbar for 4 h over a bath of boiling water, shaking from time to time. After cooling the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness and the residue extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO 4  and evaporated to dryness. 
     The residue remaining is mixed with diethylether/petroleum ether 1:9, suction filtered and washed. Yield: 2.50 g (=46% of theory); 
     TLC: Rf value: 0.29 (eluant: sec. butanol/formic acid/water 75:15:10); 
     Melting point: 147°-148° C. 
     4.3: Tropenol 2-fluoro-2,2-bis(3,4-difluorophenyl)acetate 4d 
     2.66 g (0.012 mol) of bis-(2-methoxyethyl)-aminosulphur trifluoride were placed in 10 ml of dichloromethane and within 20 minutes a solution of 0.01 mol of 5b in 65 ml of dichloromethane was added dropwise at 15°-20° C. 
     The mixture is stirred for 20 h at ambient temperature, cooled to 0° C. and carefully mixed with 80 ml of water with thorough stirring. The mixture is then carefully adjusted to pH 8 with aqueous NaHCO 3  solution, the organic phase is separated off, the aqueous phase is extracted again with dichloromethane, the combined organic phases are washed with water, dried over MgSO 4  and evaporated to dryness. The hydrochloride is precipitated and recrystallised from acetonitrile/diethylether. 
     Yield: 2.60 g of white crystals (=57% of theory) 
     Melting point: 233° C. 
     4.4: Tropenol 2-fluoro-2,2-bis(3,4-difluorophenyl)acetate-methobromide 
     2.20 g (0.0052 mol) of 4d are reacted analogously to Example 1, step 1.3. The crystals formed are suction filtered, washed with dichloromethane, dried and then recrystallised from methanol/diethylether. 
     Yield: 1.95 g (=72% of theory) 
     TLC: Rf value: 0.17 (eluant: n-butanol/water/formic acid(conc.)/acetone/dichloromethane 36:15:15:15:5); Melting point: 247° C. 
     C 23 H 21 F 5 NO 2 xBr (518.3); 
     Elemental analysis: calculated: C, (53.30); H, (4.08); N, (2.70). found.: C, (53.22); H, (4.19); N, (2.69). 
     EXAMPLE 5 
     Scopine 2,2-diphenylpropionate-ethylbromide 
     
       
                 
         
             
             
         
      
     
     1.81 g (0.005 mol) of 4a, 35 ml of acetonitrile and 1.64 g (0.015 mol) of ethylbromide are combined at 20° C. and left to stand for 3 days. The solution is evaporated to dryness and the residue recrystallised from ethanol. 
     Yield: 1.38 g (=58% of theory); Melting point: 208-209° C. 
     TLC: Rf value: 0.33 (eluant as in step 1.2); Melting point: 210-211° C. C 25 H30NO 3 xBr (472.42); 
     Elemental analysis: calculated: C, (63.56); H, (6.40); N. (2.96). found.: C, (63.49); H, (6.24); N, (2.88). 
     EXAMPLE 6 
     Scopine 2-fluoro-2,2-bis(3,4-difluorophenyl)acetate-methobromide 
     
       
                 
         
             
             
         
      
     
     6.1.: Scopine 3,3′,4,4′-tetrafluorobenzilate 5c 
     3.61 g (0.011 mol) of ethyl 3,3′,4,4′-tetrafluorobenzilate 3c, 1.71 g (0.011 mol) of scopine and 0.03 g sodium are heated as a melt at 75 mbar over a bath of boiling water for 4 h, shaking from time to time. After cooling the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness and the residue extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO 4  and evaporated to dryness. 
     The residue remaining is combined with diethylether/petroleum ether 1:9, suction filtered and washed. Yield: 1.75 g (=36% of theory); 
     Melting point: 178-179° C. 
     6.2: Scopine 2-fluoro-2,2-bis(3,4-difluorophenyl)acetate 4e 
     0.6 ml (0.0033 mol) of bis-(2-methoxyethyl)-aminosulphur trifluoride are reacted with 1.2 g (0.0028 mol) of 5c analogously to Example 4, step 4.3. 
     Yield: 1.15 g of colourless oil (=95% of theory) 
     6.3: Scopine 2-fluoro-2,2-bis(3,4-difluorophenyl)acetate-methobromide 
     1.15 g (0.0026 mol) of 4e and 1.5 g (0.0079 mol) of 50% methyl bromide solution are reacted analogously to Example 1, step 1.3. The crystals formed are suction filtered, washed with dichloromethane, dried and then recrystallised from acetone. 
     Yield: 0.88 g (=63% of theory) 
     TLC: Rf value: 0.27 (eluant: n-butanol/water/formic acid(conc.)/acetone/dichloromethane 36:15:15:15:5); Melting point: 212° C. 
     C 23 H 21 F 5 NO 3 xBr (535.33); 
     EXAMPLE 7 
     Tropenol 2-fluoro-2,2-bis(4-fluorophenyl)acetate-methobromide 
     
       
                 
         
             
             
         
      
     
     7.1.: Methyl 4,4′-difluorobenzilate 3d 
     I.3.1.: 4,4′-difluorobenzilic acid: 
     At about 100° C. a solution of 24.62 g (0.1 mol) of 4,4′-difluorobenzil in 250 ml of dioxane is added dropwise to a solution of 49.99 g (1.25 mol) of NaOH flakes in 300 ml of water and stirred for 2 h. The dioxane is largely distilled off and the aqueous solution remaining is extracted with dichloromethane. When the aqueous solution is acidified with sulphuric acid, a precipitate is formed which is suction filtered, 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); melting point:133°-136° C. 
     7.1.2.: Methyl 4,4′-difluorobenzilate 
     25.0 g (0.095 mol) of 4,4′-difluorobenzilic acid are added to freshly prepared sodium ethoxide solution containing 2.17 g (0.095 mol) of sodium and 200 ml of ethanol at 20° C. and stirred for 3 h. The solution is evaporated to dryness, the residue is dissolved in DMF, 22.57 g (0.16 mol) of methyl iodide are added dropwise at 20° C. and the mixture is stirred for 24 h. It is worked up and purified analogously to compound 3b. Yield: 21.06 g of 11 (=80% of theory) 
     7.2.: Tropenol 4,4′-difluorobenzilate 5d 
     11.13 g (0.04 mol) of methyl 4,4′-difluorobenzilate 3d and 5.57 g (0.04 mol) of tropenol are reacted with 0.09 g sodium analogously to Example 3, step 3.2. The product is recrystallised from acetonitrile. 
     Yield: 10.43 g (=62% of theory); 
     Melting point: 233-235° C. 
     7.3: Tropenol 2-fluoro-2,2-bis(4-fluorophenyl)-acetate 4f 
     2.94 g (0.013 mol) of bis-(2-methoxyethyl)-aminosulphur trifluoride are reacted with 3.85 g (0.01 mol) of 5d analogously to Example 4, step 4.3 in 100 ml of dichloromethane. The product is recrystallised from acetonitrile in the form of its hydrochloride. 
     Yield: 2.93 g (=69% of theory) 
     7.4: Tropenol 2-fluoro-2,2-bis(4-fluorophenyl)-acetate-methobromide 
     2.6 g (0.0067 mol) of 4f and 1.9 g (0.0079 mol) of 50% methylbromide solution are reacted analogously to Example 1, step 1.3. The crystals formed are suction filtered, washed with dichloromethane, dried and then recrystallised from methanol/diethylether. 
     Yield: 2.82 g of white crystals (=87% of theory) 
     TLC: Rf value: 0.55 (eluant: according to Example 1, step 1.2); 
     Melting point: 230-231° C. 
     C 23 H 23 F 3 NO 2 xBr (482.34); 
     Elemental analysis: calculated: C, (57.27); H, (4.81); N, (2.90). found: C, (57.15); H, (4.84); N, (2.96). 
     EXAMPLE 8 
     Scopine 2-fluoro-2,2-bis(4-fluorophenyl)acetate-methobromide 
     
       
                 
         
             
             
         
      
     
     8.1: Scopine 4,4′-difluorobenzilate 5e 
     4.22 g (0.01 mol) of tropenol 4,4′-difluorobenzilate 5d are suspended in 80 ml of DMF. At an internal 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, together with 0.2 g (0.0011 mol) of vanadium-(V)-oxide is added and the resulting mixture is stirred for 4.5 h at 60° C. After cooling to 20° C. the precipitate formed is suction filtered, the filtrate is adjusted to pH3 with 4 N hydrochloric acid and combined with Na 2 S 2 O 5  dissolved in water. The resulting green solution is evaporated to dryness, the residue is extracted with dichloromethane/water. The acidic aqueous phase is made basic with Na 2 CO 3 , extracted with dichloromethane and the organic phase is dried over Na 2 SO 4  and concentrated. 
     Then 0.5 ml of acetylchloride is added at about 15° C. and stirred for 1.5 h. After extraction with 0.1 N hydrochloric acid, the aqueous phase is made basic, extracted with dichloromethane, the organic phase is dried over Na 2 SO 4  and evaporated to dryness. The hydrochloride is precipitated from the residue and recrystallised from methanol/diethylether. 
     Yield: 3.61 g of white crystals (=78% of theory); 
     Melting point: 243-244° C. 
     8.2: Scopine 2-fluoro-2,2-bis(4-fluorophenyl)-acetate 4g 
     1.48 g (0.0067 mol) of bis-(2-methoxyethyl)-aminosulphur trifluoride are reacted with 2.0 g (0.005 mol) of 5e analogously to Example 4, step 4.3 in 80 ml of dichloromethane. The product is recrystallised from ethanol in the form of its hydrochloride. 
     Yield: 2.07 g (=94% of theory); Melting point: 238-239° C. 
     8.3: Scopine 2-fluoro-2,2-bis(4-fluorophenyl)-acetate-methobromide 
     1.6 g (0.004 mol) of 4g and 1.14 g (0.0079 mol) of 50% methylbromide solution are reacted analogously to Example 1, step 1.3. The crystals formed are suction filtered, washed with dichloromethane, dried and then recrystallised from acetonitrile. 
     Yield: 1.65 g of white crystals (=61% of theory) 
     TLC: Rf value: 0.25 (eluant: according to Example 1, step 1.2); 
     Melting point: 213-214° C. 
     C 23 H 23 F 3 NO 3 xBr (498.34); 
     Elemental analysis: calculated: C, (55.43); H, (4.65); N, (2.81). found.: C, (54.46); H, (4.67); N, (2.80). 
     EXAMPLE 9 
     Tropenol 2-fluoro-2,2-diphenylacetate-methobromide 
     
       
                 
         
             
             
         
      
     
     9.1.: Tropenol Benzilate 5f 
     Tropenol benzilate and processes for preparing it are known from WO 92/16528. 
     9.2: Tropenol 2-fluoro-2,2-diphenylacetate 4h 
     15.86 ml (0.086 mol) of bis-(2-methoxyethyl)-aminosulphur trifluoride are reacted with 25 g (0.072 mol) of 5f analogously to Example 4, step 4.3 in 480 ml of chloroform. The product is recrystallised from acetone in the form of its hydrochloride. Yield: 18.6 g of white crystals (=67% of theory); 
     Melting point: 181-182° C; 
     9.3: Tropenol 2-fluoro-2,2-diphenyl-acetate-methobromide 
     11.12 g (0.032 mol) of 4h and 18.23 g (0.096 mol) of 50% methylbromide solution are reacted analogously to Example 1, step 1.3. The crystals formed are recrystallised from acetonitrile. 
     Yield: 11.91 g of white crystals (=83% of theory) 
     TLC: Rf value: 0.4 (eluant: according to Example 4, step 4.4); 
     Melting point: 238-239° C. 
     C 23 H 25 FNO 2 xBr (446.36); 
     Elemental analysis: calculated: C, (61.89); H, (5.65); N, (3.14). found.: C, (62.04); H, (5.62); N, (3.17). 
     EXAMPLE 10 
     Tropenol 2-fluoro-2,2-(3-chlorophenyl)acetate-methobromide 
     
       
                 
         
             
             
         
      
     
     10.1.: Methyl 3,3′-dichlorobenzilate 3e 
     10.1.1.: 3,3′-dichlorobenzil: 
     100 ml of ethanol are used at ambient temperature and 50.0 g (0.356 mol) of 3-chlorobenzaldehyde and 4.54 g (0.018 mol) of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide are added. Then 10.7 g (0.11 mol) of triethylamine are added dropwise. The mixture is refluxed for 3 hours and evaporated to dryness. The residue is taken up in ethyl acetate and extracted with water, sodium pyrosulphite in water and Na 2 CO 3  solution. After drying over MgSO4 it is evaporated to dryness. The product obtained is recrystallised from isopropanol and petroleum ether. 
     Yield: 13.2 g of white crystals (=13% of theory); melting point: 69-70° C. 
     13.0 g of the acyloin thus obtained are dissolved in 460 ml acetonitrile at RT, 0.0867 g of vanadium-(V)-oxytrichloride are added and oxygen is piped in. After 1.5 h the solution is evaporated to dryness, extracted with ethyl acetate and water, as well as Na 2 CO 3  solution, dried over MgSO4 and evaporated to dryness. The residue remaining is stirred with petroleum ether/ethyl acetate 95:5. 
     Yield: 12.59 g of yellow crystals (=97% of theory); melting point: 116-117° C. 
     10.1.2.: 3,3′-dichlorobenzilic acid 
     51.45 g (1.286 mol) of sodium hydroxide in 1000 ml water are placed in a bath of boiling water with thorough stirring and a solution of 28.5 g (0.102 mol) of 3,3′-dichlorobenzil in 700 ml dioxane is added dropwise and then stirred for another 1 h. After cooling the dioxane is evaporated down, the residue is diluted with water and extracted with diethylether. The organic phase is acidified, extracted with dichloromethane, dried over MgSO4, evaporated to dryness. 
     Yield: 32.7 g (=71% of theory). 
     10.1.3.: Methyl 3,3′-dichlorobenzilate 
     From 100 ml of ethanol and 1.97 g (0.0855 mol) of sodium, a sodium ethoxide solution is prepared to which 26.6 g (0.0855 mol) of 3,3′-dichlorobenzilic acid in 50 ml of ethanol are added dropwise. The mixture is then stirred for 4 h at ambient temperature. After the solvent has been distilled off the residue is dissolved in 150 ml DMF and 24.27 g (0.171 mol) of methyl iodide are added dropwise, then stirred for another 24 h. While cooling with ice, 300 ml of water and 200 ml of diethylether are added dropwise, the phases are separated, the aqueous phase is extracted with diethylether, then the organic phases are washed with Na 2 CO 3  solution and shaken with water till neutral. After drying over Na 2 SO 4  the mixture is evaporated to dryness. Yield: 22.91 g of yellow oil (=82% of theory). 
     10.2.: Tropenol 3,3′-dichlorobenzilate 5g 
     22.9 g (0.074 mol) of methyl 3,3′-dichlorobenzilate 3e, 15.37 g (0.11 mol) of tropenol and 0.17 g of sodium are heated for 4 h as a melt over a bath of boiling water at 75 mbar with occasional shaking. After cooling the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness and the residue is extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO 4  and evaporated to dryness. The product is recrystallised from acetonitrile in the form of its hydrochloride. Yield: 16.83 g of white crystals (=50% of theory); melting point: 184-185° C. 
     10.3: Tropenol 2-fluoro-2,2-bis(3-chlorophenyl)acetate 4i 
     1.48 g (0.0067 mol) of bis-(2-methoxyethyl)-aminosulphur trifluoride are used in 10 ml of dichloromethane and within 20 minutes at 15°-20° C. a solution of 2.09 g of 5g in 65 ml of dichloromethane is added dropwise. 
     The mixture is stirred for 20 h at ambient temperature, cooled to 0° C. and carefully combined with 80 ml of water with thorough stirring. The mixture is then carefully adjusted to pH 8 with aqueous NaHCO 3  solution, the organic phase is separated off, the aqueous phase is again extracted with dichloromethane, the combined organic phases are washed with water, dried over MgSO 4  and evaporated to dryness. The hydrochloride is precipitated and recrystallised from acetonitrile/diethylether. 
     Yield: 1.20 g of white crystals (=53% of theory) 
     Melting point: 136-137° C. 
     10.4: Tropenol 2-fluoro-2,2-bis(3-chlorophenyl)acetate-methobromide 
     1.0 g (0.002 mol) of 4h are reacted analogously to Example 1, step 1.3. The crystals formed are suction filtered, washed with dichloromethane, dried and then recrystallised from methanol/diethylether. 
     Yield: 0.82 g of white crystals (=80% of theory) 
     TLC: Rf value: 0.14 (eluant: n-butanol/water/formic acid(conc.)/acetone/dichloromethane 36:15:15:15:5); Melting point: 180-181° C. 
     C 23 H 23 Cl 2 FNO 2 xBr (515.25). 
     As has been found, the compounds of general formula 1 are characterised by their versatility in therapeutic use. Particular mention should be made of those applications for which the compounds of formula 1 according to the invention are preferably used on the basis of their pharmaceutical activity as anticholinergic agents. These include, for example, the treatment of asthma or COPD (chronic obstructive pulmonary disease). The compounds of general formula 1 may also be used to treat vagally induced sinus bradycardia and to treat heart rhythm disorders. In general, the compounds according to the invention may also be used to treat spasms, e.g. in the gastrointestinal tract, with therapeutic benefit. They may also be used in the treatment of spasms in the urinary tract and in menstrual disorders, for example. Of the ranges of indications mentioned above, the treatment of asthma and COPD using the compounds of formula 1 according to the invention is of particular importance. 
     The compounds of general formula 1 may be used on their own or combined with other active substances of formula 1 according to the invention. 
     The compounds of general formula 1 may optionally also be combined with other pharmacologically active substances. These include, in particular, betamimetics, antiallergic agents, PAF-antagonists, leukotriene-antagonists and corticosteroids and combinations of these active substances. 
     Examples of betamimetics which may be used in conjunction with the compounds of formula 1 according to the invention include compounds selected from among bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulphonterol, terbutaline, tulobuterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-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)-on, 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol and 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol, optionally in the form of their racemates, their enantiomers, their diastereomers, as well as optionally their pharmacologically acceptable acid addition salts and hydrates. It is particularly preferable to use, as betamimetics, active substances of this kind, combined with the compounds of formula 1 according to the invention, selected from among fenoterol, formoterol, salmeterol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1benzimidazolyl)-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, as well as optionally their pharmacologically acceptable acid addition salts and hydrates. Of the betamimetics mentioned above, the compounds formoterol and salmeterol, optionally in the form of their racemates, their enantiomers, their diastereomers, as well as optionally their pharmacologically acceptable acid addition salts and hydrates, are particularly important. 
     The acid addition salts of the betamimetics selected from among the hydrochloride, hydrobromide, sulphate, phosphate, fumarate, methanesulphonate and xinafoate are preferred according to the invention. In the case of salmeterol, the salts selected from among the hydrochloride, sulphate and xinafoate are particularly preferred, especially the sulphates and xinafoates. Of outstanding importance according to the invention are salmeterol×½ H 2 SO 4  and salmeterol xinafoate. In the case of formoterol, the salts selected from among the hydrochloride, sulphate and fumarate are particularly preferred, especially the hydrochloride and fumarate. Of outstanding importance according to the invention is formoterol fumarate. 
     Within the scope of the present invention, the term corticosteroids, which may optionally be used in conjunction with the compounds of formula 1, denotes compounds selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW 215864, KSR 592, ST-126 and dexamethasone. The preferred corticosteroids within the scope of the present invention are those selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexamethasone, while budesonide, fluticasone, mometasone and ciclesonide, especially budesonide and fluticasone, are of particular importance. The term steroids may be used on its own, within the scope of the present patent application, instead of the term corticosteroids. Any reference to steroids within the scope of the present invention also includes a reference to salts or derivatives which may be formed from the steroids. Examples of possible salts or derivatives include: sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. The corticosteroids may optionally also be in the form of their hydrates. 
     Within the scope of the present invention, the term dopamine agonists, which may optionally be used in conjunction with the compounds of formula 1, denotes compounds selected from among bromocriptine, cabergolin, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid and viozan. It is preferable within the scope of the present invention to use, as combination partners with the compounds of formula 1, dopamine agonists selected from among pramipexol, talipexol and viozan, pramipexol being of particular importance. Any reference to the abovementioned dopamine agonists also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts and hydrates thereof which may exist. By the physiologically acceptable acid addition salts thereof which may be formed by the abovementioned dopamine agonists are meant, for example, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid. 
     Examples of antiallergic agents which may be used according to the invention as a combination with the compounds of formula 1 include epinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadine, mizolastin, ketotifen, emedastin, dimetinden, clemastine, bamipin, cexchloropheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastin, desloratidine and meclizine. Preferred antiallergic agents which may be used within the scope of the present invention in combination with the compounds of formula 1 according to the invention are selected from among epinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadine, ebastin, desloratidine and mizolastin, epinastin and desloratidine being particularly preferred. Any reference to the abovementioned antiallergic agents also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts thereof which may exist. 
     The following are examples of PAF antagonists which may be used in conjunction with the compounds of formula 1 according to the invention: 
     4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-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 conjunction with other active substances, the combination with steroids or betamimetics is particularly preferred of all the categories of compounds mentioned above. Combinations with betamimetics, particularly betamimetics having a long-lasting activity, is of particular importance. The combination of the compounds of formula 1 according to the invention with salmeterol or formoterol is particularly preferred, whilst the combination with formoterol is most preferred. 
     Suitable preparations for administering the compounds of formula 1 include tablets, capsules, suppositories, solutions, etc. Of particular importance according to the invention (particularly when treating asthma or COPD) is the administration of the compounds according to the invention by inhalation. The proportion of pharmaceutically active compound or compounds should be in the range from 0.05 to 90% by weight, preferably 0.1 to 50% by weight of the total composition. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, 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 gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers. 
     Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets. 
     Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates. 
     Solutions are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, optionally organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles. 
     Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules. Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof. Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate). 
     The preparations are administered by the usual methods, preferably by inhalation in the treatment of asthma or COPD. For oral administration the tablets may, of course, contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above. 
     The dosage of the compounds according to the invention is naturally greatly dependent on the route of administration and the complaint to be treated. When administered by inhalation the compounds of formula 1 are characterised by high efficacy even at doses in the μg range. The compounds of formula 1 can also be used effectively above the μg range. The dosage may then be in the gram range, for example. Particularly when administered by a method other than inhalation, the compounds according to the invention may be given in higher doses (in the range from 1 to 1000 mg, for example, although this does not imply any limitation). 
     The examples of formulations which follow illustrate the present invention without restricting its scope: 
     Examples of Pharmaceutical Formulations 
     A) 
     
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                 Tablets 
                 per tablet 
               
               
                   
                   
               
             
             
               
                   
                 active substance 
                 100 mg 
               
               
                   
                 lactose 
                 140 mg 
               
               
                   
                 corn starch 
                 240 mg 
               
               
                   
                 polyvinylpyrrolidone 
                  15 mg 
               
               
                   
                 magnesium stearate 
                  5 mg 
               
               
                   
                   
                 500 mg 
               
               
                   
                   
               
             
          
         
       
     
     The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size. 
     B) 
     
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                 Tablets 
                 per tablet 
               
               
                   
                   
               
             
             
               
                   
                 active substance 
                 80 mg 
               
               
                   
                 lactose 
                 55 mg 
               
               
                   
                 corn starch 
                 190 mg  
               
               
                   
                 microcrystalline cellulose 
                 35 mg 
               
               
                   
                 polyvinylpyrrolidone 
                 15 mg 
               
               
                   
                 sodium-carboxymethyl starch 
                 23 mg 
               
               
                   
                 magnesium stearate 
                  2 mg 
               
               
                   
                   
                 400 mg  
               
               
                   
                   
               
             
          
         
       
     
     The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodium carboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size. 
     C) 
     
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 Ampoule solution 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 active substance 
                 50 mg 
               
               
                   
                 sodium chloride 
                 50 mg 
               
               
                   
                 water for inj. 
                  5 ml 
               
               
                   
                   
               
             
          
         
       
     
     The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance. 
     D) 
     
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 Metering aerosol 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Active substance 
                 0.005 
               
               
                   
                 Sorbitan trioleate 
                 0.1 
               
               
                   
                 Monofluorotrichloromethane and 
                 2:3 ad 100 
               
               
                   
                 difluorodichioromethane 
               
               
                   
                   
               
             
          
         
       
     
     The suspension is transferred into a conventional aerosol container with a metering valve. Preferably, 50 μl of suspension are delivered per spray. The active substance may also be metered in higher doses if desired (e.g. 0.02% by weight). 
     E) 
     
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 Solutions (in mg/100 ml) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Active substance 
                 333.3 mg 
               
               
                   
                 Formoterol fumarate 
                 333.3 mg 
               
               
                   
                 Benzalkonium chloride 
                  10.0 mg 
               
               
                   
                 EDTA 
                  50.0 mg 
               
               
                   
                 HCl(ln) 
                 ad pH 3.4 
               
               
                   
                   
               
             
          
         
       
     
     This solution may be prepared in the usual manner. 
     F) 
     
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 Powder for inhalation 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Active substance 
                 6 μg 
               
               
                   
                 Formoterol fumarate 
                 6 μg 
               
               
                   
                 Lactose monohydrate 
                 ad 25 mg 
               
               
                   
                   
               
             
          
         
       
     
     The powder for inhalation is produced in the usual way by mixing the individual ingredients together. 
     G) 
     
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 Powder for inhalation 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Active substance 
                 10 μg 
               
               
                   
                 Lactose monohydrate 
                 ad 5 mg 
               
               
                   
                   
               
             
          
         
       
     
     The powder for inhalation is produced in the usual way by mixing the individual ingredients together.