EP1429751A1

EP1429751A1 - Salicylic acid salts, methods for the production and use thereof as medicaments

Info

Publication number: EP1429751A1
Application number: EP02764875A
Authority: EP
Inventors: Günter Linz; Rainer Soyka; Andre Steiner
Original assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2001-09-14
Filing date: 2002-09-06
Publication date: 2004-06-23
Also published as: JP4199114B2; JP2005504798A; UY27443A1; PE20030444A1; MXPA04002400A; WO2003024440A1; CA2460440A1

Abstract

The present invention relates to novel, substituted salicylic acid salts of salmeterol as well as to methods for the production and use thereof as medicaments.

Description

Salicylic acid salts, process for their preparation and their use as medicaments

The present invention relates to novel, substituted salicylic salts of salmeterol, processes for their preparation and their use as medicaments.

DETAILED DESCRIPTION OF THE INVENTION It is an object of the present invention to provide salts of salmeterol which are characterized by a high degree of local tolerance, in particular during inhalation application.

This object is achieved by the following substituted salicylic acid salts of the formula. Accordingly, the present invention relates to salts of general formula 1

1 in which R 1 and R 2, identical or different, denote hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halogen, COOH, OH, -COOCι-C 4-alkyl, -CO-C 1 -C 4 -alkyl, -NH 2, -NH (C -C -alkyl), -N (C 1 -C 4 -alkyl) 2, -SO ₂ -OH, -CF 3 or phenyl; R ^{3 is} hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halogen, -CF 3 or phenyl, where the phenyl ring may optionally be mono-, di- or trisubstituted by one, two or three radicals selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halogen or

with the proviso that not all of the radicals R ¹ , R ² and R ^{3 can} simultaneously be hydrogen, if appropriate in the form of their enantiomers, mixtures of the enantiomers or racemates. Preference is given to salts of the formula 1 in which

R ¹ and R ^2, identical or different, denote hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, COOH, OH, -COOMethyl, -CO-methyl, -NH ₂ , -NH ( Methyl), -N (methyl) ₂ , -NH (ethyl), -N (ethyl) 2, -SO 2 -OH, -CF 3 or phenyl;

R ^{3 is} hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, fluorine, chlorine,

Bromine, iodine -CF3 or phenyl, where the phenyl ring may optionally be mono-, di- or trisubstituted by one, two or three radicals selected from the group consisting of methyl, ethyl, propyl, butyl, methoxy, ethoxy, fluorine, chlorine , Bromine, iodine or -CF3, with the proviso that not all of the radicals RR ² and R ^{3 can} simultaneously be hydrogen, mean, if appropriate in the form of their enantiomers, mixtures of the enantiomers or racemates.

Particular preference is given to salts of the formula 1 in which

R ¹ and R ^{2 are} identical or different and are hydrogen, methyl, ethyl, propyl, methoxy, fluorine, chlorine, bromine, iodine, -COOH, OH, -COOMethyl, -CO-methyl, -NH 2, -SO 2 -OH or -CF 3 ; R ^{3 is} hydrogen, methyl, ethyl, methoxy, fluorine, chlorine, -CF 3 or phenyl, where the phenyl ring may optionally be monosubstituted or disubstituted by one or two radicals selected from the group consisting of fluorine, chlorine, bromine or -CF 3, with the proviso that not all of the radicals R ^" 1, R ² and R ^{3 can} simultaneously be hydrogen, mean, if appropriate in the form of their enantiomers, mixtures of the enantiomers or racemates.

Of particular importance according to the invention are compounds of formula 1, wherein

R 1 and R ^{2 are} identical or different and are hydrogen, methyl, propyl, methoxy, chlorine, iodine, -COOH, OH, -COOMethyl, -CO-methyl, -NH 2, or -SO 2 -OH; R ^{3 is} hydrogen or phenyl, where the phenyl ring may optionally be monosubstituted or disubstituted by one or two radicals, preferably a radical selected from the group consisting of

Fluorine, chlorine, bromine or -CF3, with the proviso that not all of the radicals R ¹ , R ² and R ³ simultaneously

Represent hydrogen, optionally in the form of their enantiomers, mixtures of the enantiomers or racemates.

Particular preference is given in accordance with the invention to compounds of the general formula I in which R ¹ and R ^2, identical or different, denote hydrogen, methyl, propyl, methoxy, chlorine, iodine, -COOH, OH, -COOMethyl, -CO-methyl, -NH 2, or Sθ2-OH; R ^{3 is} hydrogen with the proviso that not all of the radicals R ¹ , R ² and R ³ can be hydrogen at the same time, optionally in the form of their enantiomers, mixtures of the enantiomers or racemates.

Of particular importance according to the invention are also compounds of formula 1, wherein R ¹ and R ^{2 are} hydrogen;

R ^{3 is} phenyl, where the phenyl ring may optionally be monosubstituted or disubstituted by one or two radicals, preferably a radical selected from the group consisting of fluorine, chlorine, bromine or -CF 3, preferably fluorine, optionally in the form of their enantiomers, Mixtures of the enantiomers or racemates.

Unless otherwise specified, alkyl groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl or butyl. If appropriate, the abbreviations Me, Et, Prop or Bu are also used to designate the groups methyl, ethyl, propyl or butyl. Unless otherwise stated, the definitions of propyl and butyl include all conceivable 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.

As alkyloxy groups, unless otherwise stated, branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an oxygen atom. For example: methylox, ethyloxy, propyloxy or butyloxy are mentioned. To designate the groups methyloxy, ethyloxy,

Propyloxy or butyloxy are optionally also the abbreviations MeO, EtO, PropO or BuO- used. Unless otherwise stated, the definitions propoxy and butoxy include all conceivable isomeric forms of the respective radicals. For example, propyloxy includes n-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy, sec. Butyloxy and tert-butyloxy, etc. Optionally, the term alkoxy is also used in the present invention instead of the name alkyloxy. Accordingly, the terms methoxy, ethoxy, propoxy or butoxy are also used to designate the groups methyloxy, ethyloxy, propyloxy or butyloxy.

Halogen is in the context of the present invention for fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine and bromine are preferred halogens. The group CO denotes a carbonyl group.

The salts of formula 1 represent novel acid addition salts of the salmeterol known in the art. Salmeterol has a center of chirality. The present invention relates to the salts of formula 1 in racemic or enantiomerically pure form. Here, both the (R) - and the (S) - enantiomer is of particular importance. Furthermore, the present invention relates to the salts of formula 1 in the form of non-racemic mixtures of the two enantiomers.

In the compounds of general formula 1, the radicals RR ² and R _r can, if not hydrogen, ortho, of the link may be arranged for each carboxyl group is meta or para with respect to them. If none of the radicals R ^' ', R ² and R ^{3 is} hydrogen, the radical R ^{3 is} preferably in the meta position and the radicals R ¹ and R ^{2 are} linked in the ortho and / or para position. If one of the radicals R ¹ , R ² and R ^{3 is} hydrogen, at least one of the other radicals is preferably linked in the meta or para position, particularly preferably in the para position. Compounds in which the radical R ³ does not denote hydrogen are of particular importance in accordance with the invention. In these compounds, the radical R ^{3 is} preferably located in the meta position relative to the carboxyl group.

The preparation of the salts 1 according to the invention starting from the free base of salmeterol can be carried out analogously to processes known in the prior art for the formation of acid addition salts starting from secondary amines. It involves the reaction of the free base salmeterol with carboxylic acids of the formula 2

wherein the radicals R ¹ , R ² and R ^{3 may have} the abovementioned meanings, in suitable solvents, preferably organic solvents. For this purpose, the acid 2 is taken up in a suitable solvent, preferably an organic solvent, more preferably a solvent selected from the group consisting of ethyl acetate, methanol, ethanol, isopropanol and diethyl ether or mixtures thereof. Optionally, the abovementioned solvents can also be used in mixtures with tert-butyl methyl ether or cyclohexane. Optionally, the acids 2 taken up in one of the abovementioned solvents are dissolved by heating, preferably with heating to the boiling point of the solvent. Salmeterol, optionally dissolved in one of the abovementioned solvents, is added to this solution. From the resulting solution, the salts 1 are optionally crystallized with cooling and isolated.

As has been found, the compounds of formula 1 are characterized by a variety of possible applications in the therapeutic field. Worthy of mention are those applications for which the salts of the formula 1 according to the invention can be used as betamimetics due to their pharmaceutical activity.

These are, for example, the therapy of bronchial asthma (usually irritation-induced, paroxysmal bronchospasm with mucosal swelling and increased mucus production), the treatment of COPD (chronic obstructive bronchitis), the inhibition of premature onset labor and imminent abortion in obstetrics (tocolytic), the restoration of sinus rhythm in the heart with atrio-ventricular block as well as the rectification bradykarder

Cardiac arrhythmia (antiarrhythmic), the therapy of circulatory shock (vasodilation and cardiac output increase) and the treatment of itching and inflammation of the skin. The salts of the formula 1 are preferably used in the treatment of asthma or COPD.

The salts of the formula can be used alone or in combination with other active ingredients. These are, in particular, anticholinergics, antiallergics, leukotriene antagonists, dopamine agonists, PDEIV inhibitors and corticosteroids, and combinations of active substances thereof.

Examples of anticholinergics include ipratropium bromide, oxitropium bromide and, in particular, tiotropium bromide. Medicament combinations in addition to the compound of the invention of the formula Tiotropiumbromid are included as another active ingredient particularly preferred according to the invention. Of particular importance are those drug combinations which, in addition to the compound of formula 1, contain crystalline tiotropium bromide monohydrate, which can be obtained by the experimental procedure given in the experimental section.

This combination is of particular importance in the treatment of asthma or COPD, especially COPD.

In the context of the present invention, corticosteroids which may optionally be used in combination with the compound of the formula 1 are compounds which are selected from the group consisting of flunisolides, beclomethasones, triamcinolones, budesonide, fluticasones, mometasones, ciclesonides, Rofleponide and Dexametasone. Preferred in the context of the present invention are the corticosteroids selected from the group consisting of flunisolides, beclomethasones, triamcinolones, budesonide, fluticasones, mometasones, ciclesonides and dexametasone, in which case the budesonide, fluticasone, mometasone and ciclesonide, in particular budesonide and fluticasone, have a special Meaning. Optionally, in the context of the present patent application instead of the term corticosteroids only the term steroids is used. Reference to steroids in the context of the present invention includes reference to salts or derivatives that may be formed by the steroids. Examples of possible salts or derivatives are: sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. Optionally, the corticosteroids may also be in the form of their hydrates.

In the context of the present invention, dopamine agonists, which may optionally be used in combination with the compound of formula 1, are compounds which are selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole , Roxindol, Ropinirole, Talipexole, Terguride and Viozan. In the context of the present invention, dopamine agonists are preferably used as combination partners with the compound of the formula selected from the group consisting of pramipexole, talipexole and viozan, with pramipexole being of particular importance. A reference to the aforementioned dopamine agonists in the context of the present invention includes a reference to their optionally existing pharmacologically acceptable acid addition salts and optionally their hydrates. Among the physiological Compatible acid addition salts which can be formed from the aforementioned dopamine agonists are, for example, pharmaceutically acceptable salts which are selected from the salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic, lactic, citric, tartaric and maleic acids ,

As an example of antiallergics, which can be used according to the invention with the compound of formula 1 as a combination, called epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipine, cexchlorpheniramine, pheniramine, Doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozin. Preferred antiallergic agents which can be used in combination with the compound of the formula I in the context of the present invention are selected from the group consisting of epinastin,

Cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratidine and mizolastine with epinastine and desloratidine being particularly preferred. Reference to the aforementioned antiallergic agents in the context of the present invention includes a reference to their optionally existing pharmacologically acceptable acid addition salts.

Examples of PDE-IV inhibitors which can be used in combination with the compound of formula 1 according to the invention are compounds which are selected from the group consisting of enprofylline, roflumilast, Ariflo, Bay-198004, CP-325,366, BY343, D-4396 (Sch-351591), V-11294A and AWD-12-281. Preferred PDE IV inhibitors are selected from the group consisting of Enprofylline, Roflumilast, Ariflo and AWD-12-281. Reference to the aforementioned PDE-IV inhibitors in the context of the present invention includes reference to their optionally existing pharmacologically acceptable acid addition salts. Among the physiologically acceptable acid addition salts which can be formed by the abovementioned PDE-IV inhibitors, according to the invention are pharmaceutically acceptable salts selected from the salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic and lactic acids , Citric acid, tartaric acid or maleic acid. According to the invention, the salts selected from the group consisting of acetate, hydrochloride, hydrobromide, sulfate, phosphate and methanesulfonate are preferred in this context. Suitable application forms for the application of the salts of the formula 1 are, for example, tablets, capsules, suppositories and powders, etc. 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 wt .-% of the total composition. Corresponding tablets can be prepared, 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 gelatin, lubricants such as magnesium stearate or talc, and / or agents to obtain the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Likewise, the dragee wrapper to achieve a depot effect of several layers, wherein the above mentioned in the tablets excipients can be used.

Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, as well as a taste-improving agent, e.g. Flavorings such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

The capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.

Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.

As auxiliaries, for example, water, pharmaceutically acceptable organic solvents such as paraffins (eg petroleum fractions), oils of vegetable origin (eg peanut or sesame oil), mono- or polyfunctional alcohols (eg ethanol or glycerol), excipients such as natural minerals (eg kaolin, Clays, talc, chalk) synthetic minerals (eg fumed silica and silicates), sugars (eg, cane, milk and dextrose), emulsifiers (eg lignin, liquor liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and Sodium lauryl sulfate).

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

In the case of inhalation, the compounds may be used in the form of inhalable powders, propellant-containing inhalable solutions or suspensions or propellant-free inhalable solutions or suspensions.

The usable during the use according to the invention, preferably used for reaching inhalation powder, the salts may contain 1 either alone or in admixture with suitable physiologically acceptable excipients. If the salts 1 are mixed with physiologically acceptable auxiliaries, the following physiologically acceptable excipients can be used to prepare these inhalable powders according to the invention: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligosaccharides and polysaccharides ( eg dextranes), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride, calcium carbonate) or mixtures of these auxiliaries with one another. Preferably, mono- or disaccharides are used, wherein the use of lactose or glucose, in particular, but not exclusively in the form of their hydrates, is preferred. Lactose, most preferably lactose monohydrate, is used as adjuvant for the purposes of the invention.

The propellant-containing inhalation-type inhalable aerosols which can be used in the context of the use according to the invention can dissolve the salts 1 in propellant gas or contain them in dispersed form. The propellant gases which can be used for the preparation of the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The abovementioned propellant gases can be used alone or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG 134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,3,3,3,3-heptafluoropropane) and mixtures thereof. The propellant-containing inhalation aerosols which can be used in the context of the use according to the invention can also contain further constituents, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH-adjusting agents. All of these ingredients are known in the art.

If the inhaled application of the salts 1 according to the invention takes place in the form of propellant-free solutions or suspensions, suitable solvents are aqueous or alcoholic, preferably ethanolic, solutions. The solvent may be water only or it may be a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70% by volume, in particular up to 60% by volume and more preferably up to 30% by volume. The remaining volume percentages are filled up with water. Optionally, the solutions or suspensions containing auf are adjusted to a pH of from 2 to 7, preferably from 2 to 5, with suitable acids. To adjust this pH, acids selected from inorganic or organic acids can be used. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are:

Ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others. Preferred inorganic acids are hydrochloric acid, sulfuric acid. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferable. Optionally, mixtures of said acids may also be employed, particularly in the case of acids which, in addition to their acidification properties, also possess other properties, e.g. as flavorants, antioxidants or complexing agents, such as citric acid or ascorbic acid. Hydrochloric acid is particularly preferably used according to the invention for adjusting the pH.

In the case of oral administration, the tablets may, of course, besides the abovementioned excipients also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various adjuvants such as starch, preferably potato starch, gelatin and the like. Further, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting. In the case of aqueous suspensions, the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes. The dosage of the compounds according to the invention is naturally highly dependent on the mode of administration and the disease to be treated. When administered by inhalation, the salts of the formula are already characterized by high efficacy at doses in the μg range. Even above the μg range, the compounds of the formula can be used meaningfully. The dosage can then also be in the gram range, for example.

The synthesis example described below serves to further illustrate the present invention. However, it is only to be understood as a typical procedure for the further explanation of an exemplary possible access to the compound according to the invention, without limiting the invention to the subject matter described below by way of example.

Svnthesebeispiele:

4-Hydroxy-α ¹ - [[[6- (4-phenylbutoxy) hexyl] amino] methyl] -1,3-benzenedimethanol-5- (2,4-difluorophenyl) salicylate salt 1a:

30 g salmeterol is dissolved by heating to reflux in 300 mL ethyl acetate. 18.3 g of 5- (2,4-difluorophenyl) salicylic acid (diflunisal) are added to this solution. The solution is allowed to cool to room temperature. The suspension is filtered off, the precipitate is washed with ethyl acetate and dried in vacuo at 35.degree. This gives 46 g of the title salt as a colorless solid. Melting point: 104 ° C.

The following compounds were prepared in an analagous manner: 4-hydroxy-α ¹ - [[[6- (4-phenylbutoxy) hexyl] amino] methyl] -1,3,3-benzenedimethanol 3,5-diisopropyl salicylate salt 1b; Melting point: 115 ° C;

4-hydroxy- ¹ - [[[6- (4-phenylbutoxy) hexyl] amino] methyl] -1,3,3-benzenedimethanol 4-chloro-salicylate salt 1c; Melting point: 123 ° C;

4-hydroxy-α ¹ - [[[6- (4-phenylbutoxy) hexyl] amino] methyl] -1,3-benzenedimethanol 3,5-dichloro-salicylate salt 1d; Melting point: 108 ° C;

4-hydroxy-α ¹ - [[[6- (4-phenylbutoxy) hexyl] amino] methyl] -1,3-benzenedimethanol 2,5-dihydroxy terephthalate salt 1e; (Base: acid = 1: 2). Melting point: 102 ° C;

4-hydroxy-α ¹ - [[[6- (4-phenylbutoxy) -hexyl] -amino] -methyl] -1,3-benzenedimethanol-3-methoxysalicylate salt 1f; Melting point: 118 ° C;

4-hydroxy-α ¹ - [[[6- (4-phenylbutoxy) hexyl] amino] methyl] -1,3-benzenedimethanol 4-methoxysalicylate salt g; Melting point: 113 ° C;

4-hydroxy-α ¹ - [[[6- (4-phenylbutoxy) -hexyl] -amino] -methyl] -1,3-benzenedimethanol-5-methoxysalicylate salt 1h; Melting point: 114 ° C;

4-hydroxy-α ¹ - [[[6- (4-phenylbutoxy) -hexyl] -amino] -methyl] -1,3-benzenedimethanol-4-methylsalicylate salt 1]; Melting point: 116 ° C;

4-Hydroxy-α - [[[6- (4-phenylbutoxy) -hexyl] -amino] -methyl] -1,3-benzenedimethanol-5-aminosalicylate salt 1j; Melting point: 146 ° C;

4-hydroxy-α ¹ - [[[6- (4-phenylbutoxy) hexyl] amino] methyl] -1,3-benzenedimethanol 3-chlorosalicylate salt 1k; Melting point: 108 ° C; 4-hydroxy- ¹ - [[[6- (4-phenylbutoxy) -hexyl] -amino] -methyl] -1,3-benzenedimethanol-5-sulfo-salicylate salt 1]; Melting point: 129 ° C;

4-Hydroxy-α - [[[6- (4-phenylbutoxy) -hexyl] -amino] -methyl] -1,3-benzenedimethanol-5-acetylsalicylate salt Im; Melting point: 80 ° C;

4-Hydroxy-α ¹ - [[[6- (4-phenylbutoxy) -hexyl] -amino] -methyl] -1,3-benzenedimethanol 3,5-diiodo-salicylate salt In; Melting point: 133 ° C;

In the abovementioned salts 1_ according to the invention, the base salmeterol and the acid of the formula 2 are present, unless stated otherwise, in the molar ratio of salmeteric acid 1: 1.

The identity of the above compounds was confirmed by 1 H-NMR spectroscopy and ESI mass spectrometry.

The salts of the formula according to the invention can optionally be used in combination with, for example, crystalline tiotropium bromide monohydrate. Insofar as the latter is not yet known in the prior art, its representation is described below. Tiotropium bromide can be obtained as described in European patent application EP 418 716 A1. From this, crystalline tiotropium bromide monohydrate is obtainable according to the procedure described below. 15.0 kg of tiotropium bromide are introduced into 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90 ° C and stirred at a constant temperature until a clear solution is formed. Activated carbon (0.8 kg), moist with water, is slurried in 4.4 kg of water, this mixture is added to the tiotropium bromide-containing solution and rinsed with 4.3 kg of water. The resulting mixture is stirred for at least 15 minutes at 80-90 ° C and then filtered through a heated filter in a pre-heated to 70 ° C jacket temperature apparatus. The filter is rinsed with 8.6 kg of water. The contents of the apparatus are cooled at 3-5 ° C per 20 minutes to a temperature of 20-25 ° C. With cold water cooling, the apparatus is further cooled to 10-15 ° C and the crystallization is completed by at least one hour stirring. The crystals are isolated on a Nutschentrockner, the isolated crystal pulp with 9 L cold water (10-15 ° C) and cold acetone (10-15 ° C). The resulting crystals are dried at 25 ° C for 2 hours in a stream of nitrogen. Yield: 13.4 kg of crystalline tiotropium bromide monohydrate (86% of theory)

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

Pharmaceutical Formulation Examples

A) Tablets per tablet

Active ingredient 5 mg

Lactose 140 mg

Corn starch 240 mg

Polyvinylpyrrolidone 10 mg

Magnesium stearate 5 mg

400 mg

The finely ground active substance, lactose and part 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 remainder of the corn starch and the magnesium stearate are sieved and mixed together. The mixture is compressed into tablets of suitable shape and size.

B) Tablets per tablet

Active substance 10 mg

Lactose 55 mg

Corn starch 190 mg

Microcrystalline cellulose 35 mg

Polyvinylpyrrolidone 15 mg

Natriu m-ca rboxymethyl starch 23 mg

Magnesium stearate 2 mg

330 mg The finely ground active ingredient, a portion of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the remainder of the corn starch and water to a granulate which is dried and sieved. To this is added the sodium carboxymethyl starch and the magnesium stearate, mixed and pressed the mixture into tablets of suitable size.

C) metered dose inhaler

Active ingredient 0.005

Sorbitan trioleate 0.1 monofluorotrichloromethane and

Difluorodichloromethane 2: 3 ad 100

The above-mentioned numerical values are given in% by weight. The suspension is filled in a conventional aerosol container with metering valve. Per actuation preferably 50 ul suspension are delivered. If desired, the active ingredient can also be metered in higher (for example 0.02% by weight).

D) inhalation powder

Active ingredient 110 μg

Lactose monohydrate ad 25 mg

The preparation of the inhalation powder is carried out in the usual manner by mixing the individual components. D) inhalation powder

Active ingredient 50 μg

Tiotropium bromide monohydrate 22.5 μg lactose monohydrate ad 25 mg

The preparation of the inhalation powder is carried out in the usual manner

Mixing the individual ingredients.

Claims

claims

1) Compounds of general formula 1

1 in which

R ¹ and R ^{2 are} identical or different, hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halogen, COOH, OH, -COOC- | -C -alkyl, -CO-C- | -C 4 -alkyl, - NH2, -NH (Cι-C4 alkyl), -N (C ^<| -C4-alkyl) 2, -SO2-OH, -CF3, or phenyl;

R ^{3 is} hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halogen, -CF 3 or

Phenyl wherein the phenyl ring optionally mono-, di- or may be selected trisubstituted by one, two or three radicals from the group consisting of C ^"] -C4 Alkyi, C <| -C4- alkoxy, halogen or -CF 3, with the proviso that not all of the radicals R ¹ , R ² and R ^{3 can} simultaneously be hydrogen, if appropriate in the form of their enantiomers, mixtures of the enantiomers or racemates.

2) Compounds of formula 1 according to claim 1, wherein

R 1 and R ^{2 are} identical or different, are hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, COOH, OH, -COOMethyl, -CO-methyl, -NH 2, -NH (methyl) , -N (methyl) 2,

-NH (ethyl), -N (ethyl) 2, -SO 2 -OH, -CF 3 or phenyl; R ^{3 is} hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, fluorine,

Chlorine, bromine, iodine -CF 3 or phenyl, where the phenyl ring may optionally be mono-, di- or trisubstituted by one, two or three radicals selected from the group consisting of methyl, ethyl, propyl, butyl, methoxy, ethoxy, fluorine , Chlorine, bromine, iodine or -CF3, with the proviso that not all of the radicals R ¹ , R ² and R ^{3 can} simultaneously be hydrogen, mean, if appropriate in the form of their enantiomers, mixtures of the enantiomers or racemates.

3) Compounds of formula 1 according to claim 1 or 2, wherein

R ¹ and R ^{2 are} identical or different and are hydrogen, methyl, ethyl, propyl, methoxy, fluorine, chlorine, bromine, iodine, -COOH, OH, -COOMethyl, -CO-methyl, -NH 2, -SO 2 -OH or -CF 3 ;

R ^{3 is} hydrogen, methyl, ethyl, methoxy, fluorine, chlorine, -CF 3 or

Phenyl, it being possible for the phenyl ring is optionally substituted mono- or disubstituted by one or two radicals selected from the group consisting of fluorine, chlorine, bromine or -CF 3, with the proviso that not all of R 1, R ² and R ³ simultaneously

4) Compounds of formula 1 according to claim 1, 2 or 3, wherein

R ¹ and R ^{2 are} identical or different and are hydrogen, methyl, propyl, methoxy, chlorine, iodine, -COOH, OH, -COOMethyl, -CO-methyl, -H 2, or -SO 2 -OH; R ^{3 is} hydrogen or phenyl, where the phenyl ring may optionally be monosubstituted or disubstituted by one or two

Radicals, preferably a radical selected from the group consisting of fluorine, chlorine, bromine or -CF3, with the proviso that not all of the radicals Rl, R ² and R ^{3 can} simultaneously be hydrogen, mean, if appropriate in the form of their enantiomers, mixtures of the

Enantiomers or racemates. 5) Compounds of formula 1 according to any one of claims 1 to 4, wherein

R ¹ and R ^{2 are} identical or different and are hydrogen, methyl, propyl, methoxy, chlorine, iodine, -COOH, OH, -COOMethyl, -CO-methyl, -NH 2, or R ^{3 is} hydrogen with the proviso that not all of the radicals R ¹ , R ² and R ^{3 can} simultaneously be hydrogen, mean, if appropriate in the form of their enantiomers, mixtures of the enantiomers or racemates.

6) Compounds of formula I according to one of claims 1 to 4, wherein

R ¹ and R ^{2 are} hydrogen;

R ^{3 is} phenyl, where the phenyl ring may optionally be monosubstituted or disubstituted by one or two radicals, preferably a radical selected from the group consisting of fluorine,

Chlorine, bromine or -CF3, mean, if appropriate in the form of their enantiomers, mixtures of the enantiomers or racemates.

7) Medicaments, characterized by a content of a compound of formula 1 according to any one of claims 1 to 6.

8) Use of a compound of formula 1 according to any one of claims 1 to 6 for the manufacture of a medicament with betamimetic activity.

9) Use of a compound of formula 1 according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of asthma or COPD.