EP1562892A1

EP1562892A1 - Novel dihydroxy-methylphenyl derivatives, method for the production and use thereof as medicaments

Info

Publication number: EP1562892A1
Application number: EP03773711A
Authority: EP
Inventors: Thierry Bouyssou; Frank Buettner; Ingo Konetzki; Sabine Pestel; Andreas Schnapp; Hermann Schollenberger; Kurt Schromm; Claudia Heine
Original assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2002-11-15
Filing date: 2003-11-11
Publication date: 2005-08-17
Also published as: AU2003282094A1; JP2006506425A; US7135500B2; WO2004046083A1; US20040138307A1; CA2506109A1; DE10253220A1

Abstract

The invention relates to compounds of general formula (I), where the groups R<1>, R<2>, R<3> and R<4> can have the meanings given in the claims and description, method for production and use thereof as medicament, in particular for the treatment of inflammatory and obstructive airway diseases.

Description

NEW DIHYDROXY-METHYL-PHENYL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS

The present invention relates to compounds of general formula 1

wherein the radicals R ¹ , R ² , R ³ and R ⁴ can have the meanings given in the claims and in the description, processes for their preparation and their use as medicaments, in particular for the treatment of inflammatory and obstructive respiratory diseases.

Background of the Invention Betamimetics (β-adrenergic substances) are known from the prior art. In this regard, reference is made, for example, to the disclosures of US 4647563, US 4581367, US 4378361, US 4341778, US 3969410 and US 3657244. Betamimetics can be used in a variety of therapeutic areas.

For drug therapy of diseases, it is often desirable to provide drugs with a longer duration of action. This can generally ensure that the concentration of the active ingredient in the organism required to achieve the therapeutic effect is given over a longer period of time without having to repeat the drug too often. The application of an active ingredient at longer intervals also contributes greatly to the well-being of the patient. It is particularly desirable to provide a drug that can be used therapeutically by applying it once per day (single dose). Use once a day has the advantage that the patient can get used to taking the medication regularly at certain times of the day relatively quickly. It is therefore an object of the present invention to provide betamimetics which are characterized by a longer duration of action and can therefore be used for the production of medicaments with a longer activity. It is a particular object of the present invention to provide betamimetics which, owing to their long effectiveness, can be used to produce a medicament which can be applied once a day. Another object of the present invention is to provide new beta mimetics which, owing to their long effectiveness, can be used to produce a medicament which can be applied once a day for the treatment of inflammatory or obstructive respiratory diseases.

In addition to the above-mentioned objects, it is also an object of the present invention to provide beta mimetics which are not only extremely potent but are also characterized by a high degree of selectivity towards the β ₂ adrenoceptor.

Detailed Description of the Invention Surprisingly, it has been found that the above objects are achieved by compounds of general formula 1.

Accordingly, the present invention relates to compounds of general formula 1

woπn n 1, 2 or 3; R ¹ -C * -C alkyl;

R ² , R ³ and R ⁴ , the same or different hydrogen, -C-C alkyl, -OH,

-0-C * -C ₄ -alkyl, -C * -C ₄ -alkylene-halogen, -Cι-C ₄ -alkylene-OH, -Cι-C ₄ -alkylene-O-Cι-C -alkyl, -CF ₃ , -CHF ₂ , -NH ₂ , -NH (C * -C ₄ alkyl), -N (-C-C ₄ alkyl) ₂ , halogen, -COOH, -COO-C - C ₄ alkyl, -NHCO-Cι-C ₄ alkyl, -NHSO ₂ -C * -C ₄ alkyl or -S0 ₂ NH ₂ mean. Compounds of formula 1 are preferred in which n is 1 or 2;

R ^{1 is} methyl or ethyl;

R ² , R ³ and R ⁴ , identical or different, hydrogen, methyl, ethyl, -OH, methoxy, ethoxy, -CH ₂ F, -CH ₂ C1, -CH ₂ Br, -CH ₂ CH ₂ F, -CH ₂ CH ₂ C1, -CH ₂ CH ₂ Br,

-CH OH, -CH ₂ CH ₂ OH, -CH ₂ OMethyl, -CH ₂ CH ₂ OMethyl, -CH ₂ OEthyl, -CH CH ₂ OEthyl, -CF ₃ , -CHF ₂ , -NH ₂ , -NHMethyl, - NHEthyl, -N (methyl) ₂ , -N (ethyl) ₂ , fluorine, chlorine, bromine, -COOH, -COOMethyl, -COOEthyl, -NHCO-methyl, -NHCO-ethyl, -NHSO ₂ -methyl or -NHSO ₂ -Ethyl mean.

Compounds of the formula 1 in which n is 1 or 2;

R ^{1 is} methyl or ethyl; R ² , R ³ and R ⁴ , identical or different, hydrogen, methyl, ethyl, -OH, methoxy, ethoxy, -CH ₂ F, -CH ₂ CH ₂ F, -CH ₂ OH, -CH ₂ CH ₂ OH, - CH ₂ OMethyl, -CH ₂ CH ₂ OMethyl, -CH ₂ OEthyl, -CH ₂ CH ₂ OEthyl, -CF ₃ or -CHF ₂ mean.

Of particular importance according to the invention are furthermore compounds of the formula 1 in which n is 1 or 2, preferably 1;

R ^{1 is} methyl or ethyl;

R ² , R ³ and R ⁴ , identical or different, denote hydrogen, methyl, ethyl, -OH, methoxy, ethoxy, -CF ₃ or -CHF ₂ .

Furthermore, compounds of formula 1 in which n is 1 or 2, preferably 1;

R ^{1 is} methyl or ethyl; R ² , R ³ and R ⁴ , identical or different, denote hydrogen, methyl, ethyl, -OH, or -CF ₃ .

Particular preference is given to compounds of the formula 1 in which n is 1 or 2, preferably 1; R ^{1 is} methyl or ethyl; R ² , R ³ and R ⁴ , identical or different, represent hydrogen, methyl or -OH.

Finally, compounds of formula 1 in which n is 1 or 2, preferably 1;

R ^{1 is} methyl or ethyl;

R ^{2 is} hydrogen;

R ³ and R ^{4 are} identical or different and represent hydrogen, methyl or -OH.

In the compounds of general formula 1, the radicals R ² , R ³ and R ^{4 can have} the same or different meanings. In the compounds, the radicals R ² , R ³ and R ⁴ , if they are not hydrogen, can each be arranged ortho, meta or para with respect to the linkage to the benzylic “-CH ₂ ” group.

Of particular interest are compounds of formula 1 in which R ^{1 is} methyl and the radicals R ² , R ³ and R ⁴ can have the meanings mentioned above.

Of particular interest are also compounds of formula 1, in which R ^{1 is} methyl, R ^{2 is} hydroxy and the radicals R ³ and R ⁴ can have the meanings mentioned above.

Of particular interest are compounds of the formula 1 in which n is 1 or 2, preferably 1, R ^{3 is} hydrogen, and the radicals R ² and R ^{4 can have} the meanings given above, but not hydrogen. In these compounds the R ⁴ radical can in each case be arranged ortho, meta or para with respect to the linkage to the benzylic “-CH” group. Those compounds in this group in which the radical R has an ortho configuration are preferred.

The following compounds of formula 1 are of outstanding importance according to the invention:

- 4- {2- [l, l-dimethyl-2- (2,6-dimethyl-4-hydroxyphenyl) ethylamino] -l-hydroxyethyl} -3-methyl-benzene-1,2 diol;

- 4- {2- [l, l-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethylamino] -l-hydroxy-ethyl} -3-methyl-benzene-l, 2-diol. The invention relates to the respective compounds of formula 1, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids. Among acid addition salts with parmacologically unacceptable acids, for example, salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotate and hydratate benzate, p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate.

Of the acid addition salts mentioned above, the salts of hydrochloric acid, methanesulfonic acid, benzoic acid and acetic acid are particularly preferred according to the invention.

For the use according to the invention, the compounds of general formula 1 can optionally be used in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates. If the compounds are used in enantiomerically pure form, the R enantiomers are preferably used. The individual enantiomers of the compounds according to the invention can be obtained from the racemates by methods known in the art (e.g. chromatography on chiral phases etc.).

Unless otherwise stated, the alkyl groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl or butyl. Abbreviations Me, Et, Prop or Bu may also be used to denote the groups methyl, ethyl, propyl or butyl. Unless otherwise described, the definitions propyl and butyl encompass 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.

Unless otherwise stated, alkylene groups are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms. Examples include: methylene, ethylene, n-propylene or n-butylene. Unless otherwise stated, alkyloxy groups (or also -O-alkyl groups) are branched and unbranched alkyl groups with 1 to 4 carbon atoms which are linked via an acidic atom. Examples include: methyloxy, ethyloxy, propyloxy or butyloxy. To designate the groups

The abbreviations MeO-, EtO-, PropO- or BuO- are also used where appropriate, methyloxy, ethyloxy, propyloxy or butyloxy. Unless otherwise described, the definitions propyloxy and butyloxy encompass 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. In the context of the present invention, the term alkoxy may also be used instead of the term alkyloxy. Accordingly, the terms methoxy, ethoxy, propoxy or butoxy are also used to designate the groups methyloxy, ethyloxy, propyloxy or butyloxy.

Halogen in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless stated otherwise, fluorine and bromine are preferred halogens.

The compounds according to the invention can be prepared analogously to procedures already known in the prior art. Suitable manufacturing processes are known, for example, from US 3969410 and US 3657244, to which reference is made here in full.

The synthesis examples described below serve to further illustrate the present invention. However, they are only to be understood as exemplary procedures for further explaining the invention, without restricting the same to the subject matter described below by way of example.

Example 1: 4- {2- | ^" l, l-dimethyl-2- (2,6-dimethyl-4-hydroxy-phenyl) -ethylaminol-l-hydroxy-ethvU-3-methyl-benzene-l, 2-diol

a) 2-ri, l-Dimethyl-2- (2,6-dimethyl-hydroxy-phenyl) -ethylamino1-l- (3,4-dibenzyloxy-2-methyl-phenvD-ethanone

14 g of 2-hydroxy-2-ethoxy-l-oxo-l- (2-methyl-3,5-dibenzyloxyphenyl) ethane and 8.5 g of 1,1-dimethyl-2- (2,6-dimethyl-4-acetyloxy -phenyl) -ethylamine are rested for 3 hours at 50-60 ° C in 150 mL ethanol. After cooling to 10 ° C., 5 g of sodium borohydride are added and the mixture is stirred for one hour. A little acetone is then added and the mixture is stirred for a further 30 minutes. The reaction mixture is mixed with ethyl acetate, washed with water, dried with sodium sulfate and concentrated. The residue is dissolved in ethyl acetate and acidified with ethereal hydrochloric acid. The crystallizing hydrochloride is filtered off and reprecipitated in methanol / water.

Yield: 10 g (50%, hydrochloride); Mp = 214-216 ° C (decomposition).

b) 4- {2-ri, l-dimethyl-2- (2,6-dimethyl-4-hydroxyphenyl) ethylaminol-l-hydroxy-. ethyl) -3-methyl-benzene-l, 2-diol 7 g of 2- [l, l-dimethyl-2- (2,6-dimethyl-hydroxy-phenyl) -ethylamino] -l- (3,4-dibenzyloxy -2-methyl-phenyl) -ethanone hydrochloride in 125 mL methanol are hydrogenated using 2 g palladium on carbon (5%). After the catalyst has been separated off, the solvent is distilled off. The solid which crystallizes out is stirred in acetonitrile, suction filtered and washed. Yield: 3.5 g (hydrochloride); Mp = 182-183 ° C (decomposition).

Example 2: 4-r2- (l, l-dimethyl-2-o-tolyl-ethylamino) -l-hydroxy-ethyl1-3-methyl-benzene-1,2-diol

a) 2- (l, l-Dimethyl-2-o-tolyl-ethylamino) -l- (3,4-dibenzyloxy-2-methyl-phenyl) -ethanone 36.5 g of α-bromo-3,4-dibenzyloxy-2-methyl Acetophenone, 14 gl, l-dimethyl-2-o-tolylethylamine and 15 g sodium carbonate are combined and refluxed in 200 mL acetonitrile for two hours. Then the inorganic salts are filtered off and the filtrate with 100 mL water and 10 mL conc. Hydrochloric acid added. The precipitated product is suctioned off and washed.

Yield: 27 g (58%, hydrochloride); Mp = 190-195 ° C. b) 2- (ll-DimethyI-2-o-tolyl-ethylamino) -l- (3,4-dihydroxy-2-methyl-phenyl) -ethanone 27 g of the above ketone are dissolved in 250 mL methanol and mixed with palladium (II ) hydrogenated chloride at 60 ° C and 5 bar. After the theoretically calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is concentrated. The product which crystallizes out on distilling off the solvent is stirred with ethyl acetate, suction filtered and washed. Yield: 15 g (83%, hydrochloride).

For further purification, the hydrochloride can first be converted into the free base. By treating the free base with conc. Hydrochloric acid in methanol can then optionally be precipitated again as the hydrochloride. Mp = 218-225 ° C (decomposition).

c) 4-ri- (l. l-dimethyl-2-o-tolyl-ethylamino1-l-hvdroxy-ethvn-3-methyl-benzene-1,2-diol

8 g of 2- (l, l-dimethyl-2-o-tolyl-ethylamino) -l- (3,4-dihydroxy-2-methyl-phenyl) -ethanone hydrochloride are placed in 125 ml of methanol and in the presence of 0.3 g

Platinum (IV) oxide is hydrogenated at room temperature and normal pressure. The catalyst is suctioned off and the filtrate is freed from the solvent. The crude product is recrystallized from ethyl acetate, filtered off and washed.

Yield: 6.5 g (hydrochloride), mp = 166-169 ° C.

Example 3: 4- (2-ri.l-dimethyl-2- (2.4.6-trimethyl-phenyl) -ethylaminol-l-hydroxy-ethyl | -

3-methyl-benzene-1,2-diol

350 mg (0.86 mmol) l- (3,4-bis-benzyloxy-2-methylphenyl) -2-ethoxy-2-hydroxyethanone and 198 mg (1.03 mmol) l, l-dimethyl-2- (2nd , 4,6-trimethyl-phenyl) -ethylamine were dissolved in 3 ml of ethanol and heated to 80 ° C. in the presence of a little molecular sieve for 30 minutes. After cooling to room temperature, 33 mg (0.86 mmol) of sodium borohydride were added and the mixture was allowed to stir for 1 hour. The reaction mixture was mixed with ethyl acetate and washed with sodium hydrogen carbonate solution. The organic phase was then freed from the solvent and chromatographies. To split off the benzyl protecting groups, the ethanolamine (364 mg) thus obtained was dissolved in methanol, 150 mg of Pearlmann catalyst were added and the mixture was at room temperature and normal pressure hydrogenated. The reaction mixture was filtered through Celite® and concentrated. Chromatographic purification of the residue with dichloromethane and methanol as the eluent gave the target compound as a beige solid. Yield: 179 mg (29%); Mass spectrometry: [M + H] ⁺ = 391.

As has been found, the compounds of general formula 1 are distinguished by a wide range of possible uses in the therapeutic field. To be emphasized are those possible uses for which the compounds of formula 1 according to the invention can preferably be used as beta-mimetics due to their pharmaceutical activity.

These are, for example, the treatment of inflammatory and obstructive respiratory diseases, preferably the therapy of asthma or COPD (chronic obstructive pulmonary disease), the inhibition of premature contractions in obstetrics (tocolysis), the restoration of the sinus rhythm in the heart with atrioventricular block, and the elimination of bradycal arrhythmias

(Antiarrhythmic), therapy for circulatory shock (vasodilation and increase in cardiac output) and the treatment of itching and inflammation of the skin.

One aspect of the present invention relates to the use of the compounds of general formula 1 as medicaments. Another aspect of the present invention relates to the use of the compounds of general formula 1 for the manufacture of a medicament for the treatment of diseases in which therapeutically effective doses of a beta-mimetic can develop a therapeutic benefit. Particularly preferred is the use of compounds of general formula 1 for the manufacture of a medicament for the treatment of inflammatory and obstructive respiratory diseases, particularly preferably of asthma or COPD, for the inhibition of premature contractions in obstetrics (tocolysis), for the restoration of the sinus rhythm in the heart atrio-ventricular block, for the elimination of bradycal arrhythmias, for the treatment of circulatory shock (vasodilation and increase in cardiac output) and for the treatment of itching and inflammation of the skin. According to the invention, particular preference is given to the use of compounds of the general formula 1 for the production of a medicament for the treatment of inflammatory and obstructive respiratory diseases, particularly preferably for the treatment of asthma or COPD. The above-mentioned use of compounds of general formula 1 for the preparation of a is also of particular importance Medicinal product for the once-daily treatment of inflammatory and obstructive respiratory diseases, particularly preferably for the once-daily treatment of asthma or COPD.

The compounds of general formula 1 can be used on their own or in combination with other active compounds of formula 1 according to the invention. If appropriate, the compounds of the general formula 1 can also be used in combination with other pharmacologically active compounds. These are in particular anticholinergics, possibly other betamimetics, antiallergics, PDE IV inhibitors, PAF antagonists, leukotriene antagonists and steroids, and combinations of active substances thereof.

Examples of anticholinergics include ipratropium bromide, oxitropium bromide and, in particular, tiotropium bromide. Pharmaceutical combinations which, in addition to the compounds of formula 1 according to the invention, contain tiotropium bromide, optionally in the form of one of its solvates or hydrates, as a further active ingredient are particularly preferred according to the invention. Tiotropium bromide is particularly preferably used in the form of its monohydrate, in particular in the form of its crystalline monohydrate. This crystalline monohydrate is described in detail in WO 02/30928.

In the context of the present invention, corticosteroids, which can optionally be used in combination with the compound of formula 1, are understood to mean compounds which are selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide,

Rofleponide and Dexametasone. In the context of the present invention, the corticosteroids are preferably selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexametasone, here the budesonide, fluticasone, mometasone and ciclesonide, in particular the budesonasone and one Importance. If appropriate, only the term steroids is used in the context of the present patent application instead of the term corticosteroids. Reference to steroids in the context of the present invention includes reference to salts or derivatives which can be formed by the steroids. Examples of possible salts or derivatives are: sodium salts, sulfobenzoates, phosphates, Isonicotinate, Acetate, Propionate, Dihydrogenphosphate, Palmitate, Pivalate or Furoate. If necessary, the corticosteroids can also be present in the form of their hydrates.

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

Examples of antiallergics which can be used according to the invention as a combination with the compound of the formula 1 are epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchloφheniramine, pheniramine Doxylamine, Chloφhenoxamine, Dimenhydrinat, Diphenhydramin, Promethazin, Ebastin, Desloratidin and Meclozin. Preferred antiallergics which can be used in the context of the present invention in combination with the compound of formula 1 are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratidine and mizolastine, with epinastine and desloratidine are particularly preferred. In the context of the present invention, a reference to the abovementioned antiallergics includes a reference to their pharmacologically acceptable acid addition salts which may exist. As an example of PDE-IV inhibitors which can be used according to the invention as a combination with the compound of formula 1, there may be mentioned 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, with AWD-12-281 being particularly preferred as a combination partner with the compound of the formula I_ according to the invention. In the context of the present invention, a reference to the PDE-IV inhibitors mentioned above includes a reference to their pharmacologically acceptable acid addition salts which may exist. According to the invention, the physiologically tolerable acid addition salts which can be formed by the abovementioned PDE-IV inhibitors are understood as pharmaceutically tolerable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid , Citric acid, tartaric acid 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 forms of application for applying the compounds of the formula j. are, for example, tablets, capsules, suppositories, solutions, 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% by weight, of the total composition , Corresponding tablets can be made, for example, by mixing the active ingredient (s) with known auxiliary substances, for example inert diluents, such as

Calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents for achieving the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate can be obtained. The tablets can also consist of several layers.

Correspondingly, coated tablets can be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a deposit effect or to avoid incompatibilities the core can also consist of several layers. Likewise, the coated tablet shell can also consist of several layers in order to achieve a depot effect, it being possible to use the auxiliaries mentioned above for the tablets. Juices of the active substances or combinations of active substances according to the invention can additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, and a taste-improving agent, for example flavorings, such as vanillin or orange extract. They can also contain suspending agents or thickening agents, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

Solutions are made in the usual way, e.g. with the addition of isotonants, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants, where, for example, when using water as a diluent, organic solvents can optionally be used as solubilizers or auxiliary solvents , manufactured and filled into injection bottles or ampoules or infusion bottles.

The capsules containing one or more active ingredients or combinations of active ingredients can be produced, for example, by mixing the active ingredients with inert carriers, such as milk sugar or sorbitol, and encapsulating them in gelatin capsules. Suitable suppositories can be produced, for example, by mixing them with carrier agents such as neutral fats or polyethylene glycol or its derivatives.

Examples of auxiliaries are water, pharmaceutically acceptable organic solvents, such as paraffins (for example petroleum fractions), oils of vegetable origin (for example peanut or sesame oil), mono- or polyfunctional alcohols (for example ethanol or glycerol), carriers such as natural rock meal (for example kaolins, Clays, talc, chalk) synthetic rock flour (e.g. highly disperse silicic acid and silicates), sugar (e.g. cane, milk and glucose) emulsifiers (e.g. lignin, Sufitabl eyes, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate). In the case of oral use, the tablets can of course also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like, in addition to the carrier substances mentioned. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions, in addition to the auxiliaries mentioned above, the active ingredients can be mixed with various flavor enhancers or colorants.

In the preferred application according to the invention of the compounds of formula 1 for the therapy of asthma or COPD, administration forms or pharmaceutical formulations which can be administered by inhalation are particularly preferably used. Inhalable dosage forms are inhalable powders, metered-dose aerosols containing propellant gas, or propellant-free inhalation solutions. In the context of the present invention, the term propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions. The dosage forms which can be used in the context of the present invention are described in detail in the following part of the description.

Inhalable powders which can be used according to the invention can contain 1 either alone or in a mixture with suitable physiologically acceptable auxiliaries. If the active ingredients 1 are contained in a mixture with physiologically acceptable auxiliaries, the following physiologically acceptable auxiliaries can be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo- and polysaccharides ( e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these auxiliaries with one another. Mono- or disaccharides are preferably used, the use of lactose or glucose being preferred, in particular, but not exclusively, in the form of their hydrates. Lactose, most preferably lactose monohydrate, is used as an auxiliary as particularly preferred in the sense of the invention. In the context of the inhalable powders according to the invention, the auxiliaries have a maximum average particle size of up to 250 μm, preferably between 10 and 150 μm, particularly preferably between 15 and 80 μm. If necessary, it may seem sensible to add finer excipient fractions to the excipients mentioned above add average particle size of 1 to 9μm. The latter finer excipients are also selected from the group of excipients that can be used. Finally, to produce the inhalable powder according to the invention, micronized active ingredient 1, preferably with an average particle size of 0.5 to 10 μm, particularly preferably 1 to 5 μm, is admixed with the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronizing and by finally mixing the constituents are known from the prior art.

The inhalable powders according to the invention can be applied using inhalers known from the prior art.

Inhalation aerosols containing propellant gas according to the invention may contain 1 dissolved in the propellant gas or in dispersed form. Here, 1 can be contained in separate dosage forms or in a common dosage form, where 1 can either be both dissolved, both dispersed or in each case only one component dissolved and the other dispersed.

The propellant gases which can be used to produce the inhalation aerosols are known from the prior art. Suitable propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-mentioned propellant gases can be used alone or in mixtures thereof. Particularly preferred propellants are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.

The inhalation aerosols containing propellant gas can also contain further constituents such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and agents for adjusting the pH. All of these components are known in the art.

The aforementioned inhalation aerosols containing propellant gas can be administered using inhalers known in the art (MDIs = metered dose inhalers).

The active compounds 1 according to the invention can also be applied in the form of propellant-free inhalation solutions and inhalation suspensions. As a solvent aqueous or alcoholic, preferably ethanolic solutions are suitable for this. The solvent can only be water or it is 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 percent by volume, in particular up to 60 percent by volume and particularly preferably up to 30 percent by volume. The remaining volume percentages are filled up with water. The solutions or suspensions containing 1 are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. Acids selected from inorganic or organic acids can be used to adjust this pH. 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. It is also possible to use the acids which already form an acid addition salt with one of the active ingredients. Ascorbic acid, fumaric acid and citric acid are preferred among the organic acids. If appropriate, mixtures of the acids mentioned can also be used, in particular in cases of acids which, in addition to their acidifying properties, also have other properties, e.g. as flavors, antioxidants or complexing agents, such as citric acid or

Ascorbic acid. According to the invention, hydrochloric acid is particularly preferably used to adjust the pH.

In these formulations, the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as a stabilizer or complexing agent may optionally be dispensed with. Other embodiments include these

Links). In such a preferred embodiment, the content based on sodium edetate is below 100 mg / 100 ml, preferably below 50 mg / 100 ml, particularly preferably below 20 mg / 100 ml. Inhalation solutions in which the sodium edetate content is 0 to 10 mg / 100 ml are generally preferred. Co-solvents and / or other auxiliary substances can be added to the propellant-free inhalation solutions. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. In this context, everyone under auxiliary and additives understood pharmacologically acceptable substance that is not an active ingredient, but can be formulated together with the active ingredient (s) in the pharmacologically suitable solvent in order to improve the qualitative properties of the active ingredient formulation. These substances preferably have no or no significant or at least no undesirable pharmacological effect in the context of the desired therapy. The auxiliaries and additives include, for example, surface-active substances, such as, for example, soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives which guarantee or extend the useful life of the finished pharmaceutical formulation, flavors, vitamins and / or other known in the art

Additives. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.

The preferred auxiliary substances include antioxidants, such as, for example, ascorbic acid, unless already used for adjusting the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human organism.

Preservatives can be used to protect the formulation from contamination with germs. Suitable preservatives are those known from the prior art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate from those known from the prior art

Concentration. The preservatives mentioned above are preferably contained in concentrations of up to 50 mg / 100 ml, particularly preferably between 5 and 20 mg / 100 l. In addition to the solvent water and the active ingredient 1, preferred formulations only contain benzalkonium chloride and sodium edetate.

In another preferred embodiment, sodium edetate is dispensed with.

The dosage of the compounds according to the invention is of course strongly dependent on the type of application and the disease to be treated. When administered by inhalation, the compounds of formula 1 are highly effective even at doses in the μg range. Even above the μg range, the compounds of formula 1 can be used expediently. The dosage can then be in the gram range, for example. Another aspect of the present invention relates to the above-mentioned pharmaceutical formulations as such, which are characterized by a content of a compound of the formula 1, particularly preferably the above-mentioned inhalable pharmaceutical formulations.

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

Pharmaceutical formulation examples

A) tablets per tablet of active ingredient l 80 mg milk sugar 160 mg corn starch 240 mg

Polyvinylpyrrolidone 15 mg magnesium stearate 5 mg

500 mg

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

B) tablets per tablet

Active ingredient 1 100 mg

Milk sugar 55 mg

Corn starch 170 mg

Microcrystalline cellulose 35 mg

Polyvinyl pyrrolidone 15 mg

Sodium carboxymethyl starch 23 mg

Magnesium stearate 2 mg

400 mg

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

C) Ampoule solution

Active ingredient 1 40 mg sodium chloride 50 mg

Aqua per inj. 5 ml

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

D) Dosage aerosol active ingredient 1 0.01

Sorbitan trioleate 0.1 monofluorotrichloromethane and

TG134a: TG227 2: l ad 100 The suspension is filled into a conventional aerosol container with a metering valve. 50 μl of suspension are preferably dispensed per actuation. If desired, the active ingredient can also be dosed in higher amounts (for example 0.02% by weight).

E) solutions (in mg / lOOml)

Active ingredient! 300 mg

Tiotropium bromide 50 mg

Benzalkonium chloride 10.0 mg

EDTA 50.0 mg

HC1 (In) ad pH 3.4

This solution can be prepared in the usual way.

F) Inhalation powder active ingredient! 8 μg

Tiotropium bromide monohydrate 7 μg

Lactose monohydrate ad 25 mg

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

Claims

claims

1) Compounds of the general formula 1

woπn n 1, 2 or 3;

R ¹ -CC ₄ alkyl;

R ² , R ³ and R ⁴ , identical or different, hydrogen, -C * -C ₄ alkyl, -OH,

-0--C-C ₄ -alkyl, -C - C -alkylene-halogen, -C * -C ₄ -alkylene-OH, -Ci- -alkylene-Od- -alkyl, -CF ₃ , -CHF ₂ , -NH ₂ , -NH (-C-C ₄ alkyl), -N (Cι-C-alkyl) ₂ , halogen, -COOH, -COO-C - C ₄ -alkyl, -NHCO-Cι-C ₄ - Alkyl, -NHSO ₂ -CC ₄ -alkyl or -SO ₂ NH ₂ mean.

2) Compounds of the formula! according to claim 1, wherein n is 1 or 2;

R ^{1 is} methyl or ethyl;

R ² , R ³ and R ⁴ , identical or different, hydrogen, methyl, ethyl, -OH, methoxy, ethoxy, -CH ₂ F, -CH ₂ C1, -CH ₂ Br, -CH ₂ CH ₂ F, -CH ₂ CH ₂ C1, -CH ₂ CH ₂ Br, -CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ OMethyl, -CH ₂ CH ₂ OMethyl, -CH ₂ OEthyl, -CH ₂ CH ₂ OEthyl, -CF ₃ , -CHF ₂ , -NH ₂ , -NHMethyl, -NHEthyl, -N (methyl) ₂ ,

-N (ethyl) ₂ , fluorine, chlorine, bromine, -COOH, -COOMethyl, -COOEthyl, -NHCO-methyl, -NHCO-ethyl, -NHSO ₂ -methyl or -NHSO ₂ -ethyl.

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

R 'is methyl or ethyl;

R> 2, R r.3 and R, the same or different hydrogen, methyl, ethyl, -OH, methoxy, ethoxy, -CH ₂ F, -CH ₂ CH ₂ F, -CH ₂ OH, -CH ₂ CH ₂ OH , -CH ₂ OMethyl, -CH ₂ CH ₂ OMethyl, -CH ₂ OEthyl, -CH ₂ CH ₂ OEthyl, -CF ₃ or -CHF ₂ . 4) compounds of the formula! according to one of claims 1 to 3, wherein n is 1 or 2, preferably 1;

R ^{1 is} methyl or ethyl;

R ² , R ³ and R ⁴ , identical or different, denote hydrogen, methyl, ethyl, -OH, methoxy, ethoxy, -CF ₃ or -CHF.

5) compounds of the formula! according to one of claims 1 to 4, wherein n is 1 or 2, preferably 1;

6) Compounds of the formula according to one of claims 1 to 5, wherein n is 1 or 2, preferably 1; R ^{1 is} methyl or ethyl;

R ² , R ³ and R ⁴ , identical or different, represent hydrogen, methyl or -OH.

7) Compounds of formula 1 according to any one of claims 1 to 6, wherein n is 1 or 2, preferably 1; R ^{1 is} methyl or ethyl;

R ^{2 is} hydrogen;

8) Compounds of formula 1 according to any one of claims 1 to 7, in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.

9) Use of the compounds of general formula 1 according to one of claims 1 to 8 as a medicament.

10) Use of the compounds of general formula 1 according to one of claims 1 to 8 for the manufacture of a medicament for the treatment of diseases in which therapeutically effective doses of a beta-mimetic can develop a therapeutic benefit. 11) Pharmaceutical formulations characterized by the content of one or more compounds of formula 1 according to one of claims 1 to 8.