Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
  • C07D451/06—Oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/06—Anti-spasmodics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
  • C07D451/06—Oxygen atoms
  • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

Definitions

• the present invention relates to new xanthene carboxylic acid esters of the general formula 1
• X - and the group may have the meanings given in the claims and in the description, processes for their preparation and their use as medicaments.
• A is a divalent radical selected from the group consisting of
• a single negatively charged anion preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate;
• R is hydroxy, methyl, hydroxymethyl, ethyl, -CF3, CHF2 or fluorine;
• R1 and R 2 are the same or different, -Cj-Cs-alkyl, which can optionally be substituted by -C3-C6-cycloalkyl, hydroxy or halogen, or R " 1 and R 2 together form a -C3-C5 ⁇ alkylene bridge;
• R 3 , R 4 , R 3 'and R 4 ' are hydrogen, -C ⁇
• A is a double-bonded residue selected from the group consisting of
• Chloride bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide;
• R is hydroxy, methyl, hydroxymethyl, ethyl or CHF2, preferably, hydroxy, or methyl;
• R 1 and R 2 are the same or different, methyl, ethyl or fluoroethyl;
• R 3 , R 4 , R 3 'and R 4 ', identical or different, are hydrogen, methyl, methyloxy, hydroxy, -CF3, -CHF2 or fluorine.
• R is hydroxy or methyl
• R1 and R 2 are the same or different, methyl or ethyl, preferably methyl;
• R 3 , R 4 R 3 'and R 4 ' are hydrogen, -CF3, -CHF2 or fluorine, preferably hydrogen or fluorine.
• A is a double-bonded residue selected from the group consisting of
• R is hydroxy or methyl, preferably methyl
• R1 and R 2 are the same or different, methyl or ethyl, preferably methyl;
• R 3 , R 4 , R 3 'and R 4 ', identical or different, are hydrogen or fluorine.
• the invention relates to the respective compounds of the formula, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates.
• the radicals R 3 , R 4 , R 3 'and R 4 ' insofar as they are not hydrogen, can each be arranged ortho, meta or para with respect to the link to the "-C- R" group , If none of the radicals R 3 , R 4 , R 3 'and R 4 ' is hydrogen, R 3 and R 3 'are preferably in the para position and R 4 and R 4 ' are preferably in the ortho or meta position, particularly preferred linked in meta position. If one of the radicals R 3 and R 4 and one of the radicals R 3 'and R 4 ' is hydrogen, the other radical is preferably linked in the meta or para position, particularly preferably in the para position.
• radicals R 3 , R 4 , R 3 'and R 4 ' are hydrogen
• the compounds of the general formula in which the radicals R 3 , R 4 , R 3 'and R 4 ' have the same meaning are particularly preferred according to the invention.
• the following compounds are of particular importance according to the invention: 9-hydroxy-xanthene-9-carboxylic acid tropenol ester methobromide; 9-hydroxy-xanthene-9-carboxylic acid copinate methobromide; 9-methyl-xanthene-9-carboxylic acid tropenol ester methobromide; - 9-methyl-xanthene-9-carboxylic acid copinate methobromide; 9-ethyl-xanthene-9-carboxylic acid tropenol ester methobromide; 9-difluoromethyl-xanthene-9-carboxylic acid tropenol ester methobromide; 9-hydroxymethyl-xanthene-9-carboxylic acid copinate methobromide.
• the alkyl groups are branched and unbranched alkyl groups having 1 to 5 carbon atoms. Examples include: methyl, ethyl, propyl or butyl.
• the abbreviations Me, Et, Prop or Bu may also be used to denote the groups methyl, ethyl, propyl or butyl.
• the definitions propyl and butyl encompass all conceivable isomeric forms of the respective radicals.
• propyl includes n-propyl and iso-propyl
• butyl includes iso-butyl, sec. Butyl and tert-butyl, etc.
• alkylene groups are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene or butylene.
• the alkylene-halogen groups are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms, which are mono-, di- or trisubstituted, preferably disubstituted, by a halogen. Accordingly, unless specified otherwise, branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms are designated as alkylene-OH groups, which are mono-, di- or trisubstituted, preferably monosubstituted by a hydroxy.
• alkyloxy groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an oxygen atom. Examples include: methylox, ethyloxy, propyloxy or butyloxy.
• the abbreviations MeO-, EtO-, PropO- or BuO- are also used to denote the groups methyloxy, ethyloxy, propyloxy or butyloxy.
• the definitions propyloxy and butyloxy encompass all conceivable isomeric forms of the respective radicals.
• propyloxy includes n-propyloxy and iso-propyloxy
• butyloxy includes iso-butyloxy, sec.
• alkoxy is also 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.
• alkylene-alkyloxy groups are, unless stated otherwise, branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which are mono-, di- or trisubstituted, preferably monosubstituted, by an alkyloxy group.
• -O-CO-alkyl groups are branched and unbranched alkyl groups with 1 to 4 carbon atoms which are linked via an ester group.
• the alkyl groups are bonded directly to the carbonyl carbon of the ester group.
• the term -O-CO-alkyl-halogen group is to be understood in an analogous manner.
• the group -O-CO-CF3 stands for trifluoroacetate.
• Halogen in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless stated otherwise, fluorine and bromine are preferred halogens.
• the group CO denotes a carbonyl group.
• the compounds according to the invention can be prepared in part analogously to procedures already known in the prior art (Scheme 1).
• the carboxylic acid derivatives of the formula 3 are known in the prior art or can be obtained by synthetic methods known in the prior art. If only appropriately substituted carboxylic acids are known in the prior art, the compounds of the formula 3 can also be obtained directly from these by acid- or base-catalyzed esterification with the corresponding alcohols or by halogenation with the corresponding halogenation reagents.
• the compounds of formula 4 thus obtained can be converted into the target compounds of formula 1 by reaction with the compounds R -X, in which R 2 and X can have the meanings mentioned above. Also the compounds R -X, in which R 2 and X can have the meanings mentioned above. Also the compounds R -X, in which R 2 and X can have the meanings mentioned above. Also the compounds R -X, in which R 2 and X can have the meanings mentioned above. Also the compounds R -X, in which R 2 and X can have the meanings mentioned above. Also the compounds R -X, in which R 2 and X can have the meanings mentioned above. Also the compounds R -X, in which R 2 and X can have the meanings mentioned above. Also the compounds R -X, in which R 2 and X can have the meanings mentioned above. Also the compounds R -X, in which R 2 and X can have the meanings mentioned above. Also the compounds R -X, in which R 2 and X can have the meanings mentioned above. Also the compounds R
• This synthesis step can be carried out analogously to the synthesis examples disclosed in WO 92/16528.
• R ⁇ and R 2 together form an alkylene bridge
• the addition of the reagent R 2 -X is not necessary, as can be seen by the person skilled in the art.
• the compounds of formula 4 have a suitably substituted radical R " ! (For example -C3-C5-alkylene-halogen) according to the definitions given above and the compounds of formula 1 are prepared by intramolecular quaternization of the amine.
• the derivatives 4 in which the nitrogen bicyclus is a scopin derivative can be obtained by oxidation (epoxidation) of compounds of the formula 4 in which the nitrogen bicyclus is a Is tropenyl residue. According to the invention, this can be done as follows.
• the compound 4, in which A stands for -CH CH-, is suspended in a polar organic solvent, preferably in a solvent selected from the group consisting of 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. A suitable oxidizing agent is then added and the mixture is stirred at a constant temperature for 2 to 8 hours, preferably 3 to 6 hours. Vanadium pentoxide mixed with H2O2, particularly preferably H2O2-urea complex in combination with vanadium pentoxide, is preferably used as the oxidizing agent.
• the processing takes place in the usual way. Depending on the tendency to crystallize, the products can be cleaned by crystallization or chromatography.
• salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate toluate and hydrochloride pentahydrate and hydrobenzoate toluate and hydrochloride pentahydrate and hydrobenzoate toluene and hydrobenzonate and hydrobenzonate and hydrobenzonate and hydrobenzoate toluene and hydrobenzonate and hydrobenzoate toluate and hydrobenzonate and hydrobenzonate and hydrobenzoate toluate and hydrobenzonate and hydrobenzonate and hydrobenzoate toluate and hydrobenzonate and hydrobenzonate and hydrobenzoate toluate and hydrobenzonate and hydrobenzonate and hydrobenzoate toluate and hydrochloride preferably. Hydrobromide, hydros
• the compounds of the formula 4 are preferably used in ⁇ -configured form as starting materials. These ⁇ -configured compounds are therefore of particular importance according to the invention and correspond to the general formula 4 ⁇ c.
• a further aspect of the present invention relates to the use of compounds of the general formula 2 for the preparation of the compounds of the general formula 4. Furthermore, the present invention relates to the use of the compounds of the general formula 2 as starting material for the preparation of the compounds of the general formula 1 The present invention relates to the use of the compounds of the general formula 4 as an intermediate in the preparation of the compounds of the general formula 1.
• the reaction mixture is diluted with water to a total volume of 800 ml, extracted with diethyl ether, the organic phase extracted with saturated aqueous Na2CO3 solution, washed with water, dried over MgSO4 and the solvent removed by distillation.
• the acid chloride is prepared from 7.76 g (0.03 mol) of 3b, 0.06 mol of oxalyl chloride and 4 drops of dimethylformamide in 100 ml of dichloromethane. This is added dropwise as a solution in dichloromethane to 8.77 g (0.063 mol) of tropenol in 140 ml of dichloromethane, then stirred at 40 ° C. for 24 hours and cooled. The reaction mixture is extracted with water, dried over MgSO4, filtered off. The filtrate obtained is acidified to pH 2 with ethereal hydrochloric acid, extracted with diethyl ether and the aqueous phase made basic.
• the compounds according to the invention of the formula ⁇ represent antagonists of the M3 receptor (muscarinic receptor subtype 3).
• the compounds according to the invention have Ki values of less than 10nM with regard to the affinity for the M3 receptor. These values were determined according to the procedure described below.
• Cell membranes We use cell membranes from CHO cells (Chinese hamster ovary) that were transfected with the corresponding genes of the human muscarinic receptor subtypes hm1 to hm5 (BONNER). The cell membranes of the desired subtype were thawed, resuspended by hand with a glass homogenizer and diluted with HEPES buffer to a final concentration of 20-30 mg protein / ml.
• the binding assay was carried out in a final volume of 1 ml and was composed of 100 ⁇ l of unlabelled substance in various concentrations,
• radioligand 3H-N-methylscopolamine 2 nmol / L (3H-NMS)
• membrane preparation 200 ⁇ l membrane preparation and 600 ⁇ l HEPES buffer (20 mmol / L HEPES, 10 mmol / L
• the radioactivity of the filter mats was measured simultaneously using a two-dimensional, digital autoradiograph (Berthold, Wildbad, type 3052).
• the compounds of the formula i according to the invention are distinguished by a wide range of possible uses in the therapeutic field. According to the invention, particular mention should be made of those possible uses for which the compounds of the formula 1 according to the invention can preferably be used as an anticholinergic because of their pharmaceutical activity.
• the compounds of general formula 1 can also be used to treat vagal sinus bradycardia and to treat cardiac arrhythmias.
• the compounds according to the invention can also be used for the treatment of spasms, for example in the gastrointestinal tract, with therapeutic benefits. They can also be used in the treatment of spasms in urinary passages and, for example, in menstrual cramps.
• the compounds of the general formula ⁇ can be used alone or in combination with other active compounds of the formula 1 according to the invention. If appropriate, the compounds of the general formula can also be used in combination with other pharmacologically active compounds. These are, in particular, betamimetics, antiallergics, PAF antagonists, PDE IV inhibitors, leukotriene antagonists, p38 kinase inhibitors, EGFR kinase inhibitors and corticosteroids, and combinations of active substances thereof.
• betamimetics which can be used according to the invention as a combination with the compounds of the formula include compounds which are selected from the group consisting of bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol , Reproterol, salmeterol, sulfonterol, terbutaline, tolubuterol, 4-hydroxy-7- [2 - ⁇ [2 - ⁇ [3- (2-phenylethoxy) propyl] sulfonyl ⁇ ethyl] -amino ⁇ ethyl] -2 (3H) - benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylaminojethanol, 1 - [3- (4-methoxybenzylamino)
• Such betamimetics are particularly preferably used in combination with the compounds of formula 1 according to the invention which are selected from the group consisting of fenoterol, formoterol, salmeterol, 1- [3- (4-methoxybenzylamino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylaminojethanol, 1 - [2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl] -2- [3 - (4-N, N-dimethylaminophenyI) -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- [
• the compounds formoterol and salmeterol optionally come in the form of their racemates, their enantiomers, theirs Diastereomers, as well as their pharmacologically acceptable acid addition salts and hydrates, are of particular importance.
• the acid addition salts of the betamimetics are preferred, for example, selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate and xinafoate.
• the salts are particularly preferably selected from hydrochloride, sulfate and xinafoate, of which the xinafoate is particularly preferred.
• the salts are particularly preferably selected from hydrochloride, sulfate and fumarate, of which the hydrochloride and fumarate are particularly preferred. According to the invention, formoterol fumarate is of outstanding importance.
• corticosteroids which can optionally be used in combination with the compounds of formula 1, are understood to mean compounds which are selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide,
• 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 in particular Importance. If necessary, 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 that can be formed by the steroids.
• Examples of possible salts or derivatives are: sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. If appropriate, the corticosteroids can also be present in the form of their hydrates.
• PDE-IV inhibitors which can be used according to the invention as a combination with the compound of formula 1
• 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.
• 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.
• the salts selected from the group consisting of acetate, hydrochloride, hydrobromide, sulfate, phosphate and methanesulfonate are preferred according to the invention.
• dopamine agonists which can optionally be used in combination with the compounds of formula 1, are understood to mean compounds which are selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole , Roxindol, Ropinirol, Talipexol, Tergurid and Viozan.
• dopamine agonists preference is given to using dopamine agonists as combination partners with the compounds of the formula 1 which are selected from the group consisting of pramipexole, talipexole and viozan, pramipexole being of particular importance.
• 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.
• antiallergics which can be used according to the invention as a combination with the compounds of formula 1 are epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, Doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozin.
• Preferred antiallergics which can be used in the context of the present invention in combination with the compounds of the formula 1_ are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, Ebastine, desloratidine and mizolastine, with epinastine and desloratidine being particularly preferred.
• a reference to the above-mentioned antiallergics includes a reference to their pharmacologically acceptable acid addition salts which may exist.
• EGFR kinase inhibitors which can be used in combination with the compounds of the formula according to the invention, 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) butyloxy] -6 - [(vinylcarbonyl) amino] -quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4 - ((S) -6-methyl-2-oxo-morpholin-4-yI) butyloxy] -6- [(vinylcarbonyl) amino] -quinazoline, 4 - [(3-chloro-4- fluorophenyl) amino] -7- (2- ⁇ 4 - [(S) - (2-oxo-tetrahydrofuran-5-yl) carbonyl] piperazin-1-yl ⁇ ethoxy) -6
• a reference to the above-mentioned EGFR kinase inhibitors includes a reference to their pharmacologically acceptable acid addition salts which may exist.
• physiological or pharmacologically acceptable acid addition salts which can be formed by the EGFR kinase inhibitors are understood according to the invention to be 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 or are maleic acid.
• the salts of the EGFR kinase inhibitors are preferably selected from the salts of acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.
• p38 kinase inhibitors which can be used in combination with the compounds of the formula 1 according to the invention, 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl ] -3- [4- (2-morpholin-4-ylethoxy) naphthalen-1-yl] urea; 1 - [5-ferf-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (1 - oxothiomorpholin-4-yl) ethoxy) naphthalen-1 -yl] - urea; 1 - [5-terf-butyl-2- (2-methylpyridin-5-yl
• a reference to the above-mentioned p38 kinase inhibitors in the context of the present invention includes a reference to their pharmacologically acceptable acid addition salts which may exist.
• the physiologically or pharmacologically acceptable acid addition salts which can be formed by the p38 kinase inhibitors are understood to be 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, Are lactic acid, citric acid, tartaric acid or maleic acid.
• the combination of steroids, PDE IV inhibitors or betamimetics is particularly preferred from the compound classes mentioned above.
• the combination with beta mimetics, in particular with long-acting beta mimetics, is of particular importance.
• the combination of the compounds of the formula according to the invention with salmeterol or formoterol is to be regarded as particularly preferred.
• Suitable forms of application for the application of the compounds of formula 1 are, for example, tablets, capsules, suppositories, solutions etc.
• the inhalative application of the compounds according to the invention is particularly important (in particular in the treatment of asthma or COPD).
• the proportion of the pharmaceutically active compound (s) should in each case be in the range from 0.05 to 90% by weight, preferably 0.1 to 50% by weight, of the total composition.
• Corresponding tablets can be mixed, for example, by mixing the active ingredient (s) with known auxiliaries, 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 to achieve the depot effect, such as carboxymethyl cellulose, Cellulose acetate phthalate, or polyvinyl acetate can be obtained.
• auxiliaries 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 to achieve the depot effect, such as carboxymethyl cellulose, Cellulose acetate phthalate, or polyvinyl acetate can be obtained.
• coated tablets can be produced by coating cores produced analogously to the tablets with agents commonly used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
• the core can also consist of several layers in order to achieve a depot effect or to avoid incompatibilities.
• 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 as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. 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.
• a sweetener such as saccharin, cyclamate, glycerol or sugar
• a taste-improving agent e.g.
• Flavorings such as vanillin or orange extract
• 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.
• isotonants 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
• 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.
• inert carriers such as milk sugar or sorbitol
• Suitable suppositories can be produced, for example, by mixing them with carrier agents such as neutral fats or polyethylene glycol or its derivatives.
• carrier agents such as neutral fats or polyethylene glycol or its derivatives.
• 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 Silica and silicates), sugar (e.g. cane, milk and glucose) emulsifiers (e.g.
• lignin e.g. lignin, sufite liquor, methyl cellulose, starch and polyvinylpyrrolidone
• lubricants e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate
• the tablets can of course also contain additives, such as e.g. Contain sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like.
• Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting.
• the active ingredients can be mixed with various flavor enhancers or colorants.
• Inhalable dosage forms include inhalable powders, metered-dose aerosols containing propellants or propellant-free inhalation solutions.
• propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions.
• Inhalable powders which can be used according to the invention can contain 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,
• Mono- or disaccharides are preferably used, the use of lactose or glucose being preferred, particularly 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.
• the auxiliaries have a maximum average particle size of up to 250 ⁇ m, preferably between 10 and 150 ⁇ m, particularly preferably between 15 and 80 ⁇ m. If appropriate, it may appear sensible to add finer excipient fractions with an average particle size of 1 to 9 ⁇ m to the excipients mentioned above. The latter finer excipients are also selected from the group of excipients that can be used.
• micronized active ingredient preferably with an average particle size of 0.5 to 10 ⁇ m, particularly preferably from 1 to 5 ⁇ m, 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 can 1. contain dissolved in the propellant gas or in dispersed form. This can be done in separate
• 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 active compounds according to the invention can be applied in the form of propellant-free inhalation solutions and inhalation suspensions.
• Aqueous or alcoholic, preferably ethanolic, solutions are suitable as solvents for this Consideration.
• 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 volume percent, in particular up to 60 volume percent and particularly preferably up to 30 volume percent.
• the remaining volume percentages are filled up with water.
• the ⁇ -containing solutions or suspensions 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.
• mixtures of the acids mentioned can also be used, in particular in the case of acids which, in addition to their acidifying properties, also have other properties, for example as flavorings, antioxidants or complexing agents, such as, for example, citric acid or ascorbic acid.
• hydrochloric acid is particularly preferably used to adjust the pH.
• 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 this connection (s).
• 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 auxiliaries 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.
• auxiliaries and additives are understood to mean any pharmacologically acceptable substance which is not an active substance but can be formulated together with the active substance (s) in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation.
• These substances preferably do not develop or in the context of the desired therapy, no significant or at least no undesirable pharmacological effects.
• 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 additives known in the prior art.
• the additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
• the preferred auxiliaries 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 in the concentration known from the prior art.
• the preservatives mentioned above are preferably present in concentrations of up to 50 mg / 100 ml, particularly preferably between 5 and 20 mg / 100 ml.
• Preferred formulations contain water and the solvent
• Active substance 1 only benzalkonium chloride and sodium edetate.
• sodium edetate is dispensed with.
• the dosage of the compounds according to the invention is of course highly dependent on the type of application and the disease to be treated.
• the compounds of formula 1 When administered by inhalation, the compounds of formula 1 are highly effective even at doses in the ⁇ g range.
• the compounds of the formula can also be used sensibly above the ⁇ g range.
• the dosage can then be in the gram range, for example.
• the compounds according to the invention can be administered with a higher dosage (for example, but not in a limiting manner in the range from 1 to 1000 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 compressed into tablets of a suitable shape and size.
• the finely ground active ingredient, part of the corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the rest of the corn starch and water to form a granulate which is dried and sieved.
• the sodium carboxymethyl starch and the magnesium stearate are added, and the mixture is mixed and pressed into tablets of a suitable size.
• the suspension is filled into a conventional aerosol container with a metering valve. 50 ⁇ l of suspension are preferably dispensed per actuation. If desired, the active ingredient can also be dosed higher (e.g. 0.02% by weight).
• This solution can be prepared in the usual way.
• the inhalable powder is prepared in the usual way by mixing the individual components.
• the inhalable powder is prepared in the usual way by mixing the individual components.

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• 2002
  • 2002-01-31 DE DE10203753A patent/DE10203753A1/de not_active Withdrawn
• 2003
  • 2003-01-21 WO PCT/EP2003/000532 patent/WO2003064417A1/de not_active Ceased
  • 2003-01-21 AT AT03704440T patent/ATE335738T1/de active
  • 2003-01-21 CA CA2471578A patent/CA2471578C/en not_active Expired - Fee Related
  • 2003-01-21 DE DE50304569T patent/DE50304569D1/de not_active Expired - Lifetime
  • 2003-01-21 JP JP2003564040A patent/JP4554936B2/ja not_active Expired - Lifetime
  • 2003-01-21 EP EP03704440A patent/EP1472249B1/de not_active Expired - Lifetime
  • 2003-01-21 ES ES03704440T patent/ES2269977T3/es not_active Expired - Lifetime

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