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EP1706389A1 - Derives 3-hydroxymethyl-4-hydroxyphenyle pour le traitement de maladies des voies respiratoires - Google Patents

Derives 3-hydroxymethyl-4-hydroxyphenyle pour le traitement de maladies des voies respiratoires

Info

Publication number
EP1706389A1
EP1706389A1 EP05700676A EP05700676A EP1706389A1 EP 1706389 A1 EP1706389 A1 EP 1706389A1 EP 05700676 A EP05700676 A EP 05700676A EP 05700676 A EP05700676 A EP 05700676A EP 1706389 A1 EP1706389 A1 EP 1706389A1
Authority
EP
European Patent Office
Prior art keywords
methyl
hydrogen
methoxy
compounds
optionally
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP05700676A
Other languages
German (de)
English (en)
Inventor
Thierry Bouyssou
Frank Buettner
Ingo Konetzki
Sabine Pestel
Andreas Schnapp
Hermann Schollenberger
Kurt Schromm
Claudia Heine
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim International GmbH
Publication of EP1706389A1 publication Critical patent/EP1706389A1/fr
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine

Definitions

  • the present invention relates to compounds of general formula 1
  • R 1 , X and Y 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.
  • Betamimetics ( ⁇ -adrenergic substances) are known from the prior art.
  • drugs 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.
  • betamimetics which are characterized by a longer duration of action and thus for the production of medicaments can be used with longer effectiveness. 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.
  • beta mimetics which are not only extremely potent but are also characterized by a high degree of selectivity towards the ⁇ 2 adrenoceptor.
  • Y is nitrogen, oxygen or CR 3 ;
  • R 1 is hydrogen, -Q-alkyl, halogen, OH or -O-C ⁇ -C 4 alkyl;
  • R 2 is hydrogen, C 1 -C 4 -alkyl, halogen, OH or -O-C 1 -C 4 -alkyl, or phenyl, which may optionally be mono-, di- or trisubstituted by one or more radicals selected from the group consisting of from CrGi alkyl, halogen, OH or -OC C 4 alkyl;
  • Y is nitrogen or CR 3 ;
  • R 1 is hydrogen, methyl, ethyl, fluorine, chlorine, bromine, OH or methoxy, preferably hydrogen or methyl;
  • R 2 is methyl, fluorine, chlorine, bromine, OH or methoxy or phenyl, which can optionally be mono- or disubstituted by one or more radicals selected from the group consisting of methyl, fluorine, chlorine, bromine, OH or methoxy;
  • R 3 is hydrogen, methyl, fluorine, chlorine, bromine, OH or methoxy, 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.
  • R 1 is hydrogen, methyl or ethyl
  • R 2 phenyl which can optionally be mono- or disubstituted by one or more radicals selected from the group consisting of methyl, fluorine, chlorine, bromine, OH or methoxy; mean, 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.
  • R 1 is hydrogen, methyl or ethyl
  • R 2 phenyl which can be mono- or disubstituted by methyl, fluorine or methoxy; mean, 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
  • Y is nitrogen or CR 3 ;
  • R 1 is hydrogen or methyl, preferably hydrogen
  • R 2 is methyl, OH or methoxy, or phenyl, which can optionally be simply substituted by a radical selected from the group consisting of methyl, OH or methoxy, preferably methoxy;
  • R 3 is hydrogen, methyl, OH or methoxy, 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.
  • X is nitrogen or CR 2 ;
  • Y is nitrogen or CR 3 , preferably CR 3 ;
  • R 1 is hydrogen
  • R 2 phenyl which can optionally be substituted by OH or methoxy, preferably methoxy;
  • R 3 is hydrogen; mean, 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
  • salts are selected from the group consisting of hydrochloride, Hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethane sulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromate, hydrobromide, hydrobromate, hydrobromide, hydrobromate, hydrobromide, hydrobromate, hydrobromide, hydrobromate, hydrobromide, hydrobromate, hydrobromide, hydrobromate, hydrobromide, hydrobromate, hydrobromide, hydrobromate, hydrobromide, hydrobromate, hydrobromide, hydrobromate, hydrobromide, preferably hydrochloride, hydrobromide,
  • 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 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.
  • alkyloxy groups are branched and unbranched alkyl groups with 1 to 4 carbon atoms which are linked via an oxygen atom. Examples include: methyloxy, ethyloxy, propyloxy or butyloxy.
  • the abbreviations MeO-, EtO-, PropO- or BuO- are also used to denote the groups methyloxy, ethyloxy, propyloxy or butyloxy. Unless otherwise described, 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. Butyloxy and tert-butyloxy, etc.
  • alkoxy may also be used instead of the term alkyloxy.
  • 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 4647563, to which reference is made here in full.
  • Example 1 4-r2- (l, l-Dimethyl-3- [1.2.41triazol-4-yl-propylamino) -l-hydroxyethyl-1-2-hydroxymethylphenol
  • the ethanol is distilled off, the remaining aqueous phase is made alkaline with sodium hydroxide and extracted with ethyl acetate.
  • the organic phases are dried with sodium sulfate and concentrated.
  • the residue is mixed with 80 mL ethanol, acidified with 3.2 g oxalic acid, dissolved in ethanol, and inoculated.
  • the catalyst is then separated off and the filtrate is concentrated.
  • the residue is dissolved in 15 mL acetonitrile, acidified with 0.5 mL glacial acetic acid and inoculated.
  • the precipitated solid is filtered off and washed with acetonitrile and diethyl ether.
  • Example 3 4- (l-Hvdro ⁇ y-2-l3-r3- (4-methoxy-phenyl-imidazole-l-vn-l, l-dimethyl-propylamino ⁇ -ethylV2-h ydroxy eth yl-phenol a) 2-Benzyloxy-5- (l-hydroxy-2- (3-r3- ( 4-methoxyphenyl) imidazol-l-yll-ll-dimethyl-propylaminol-ethvD-benzoic acid methyl ester
  • Precursor 2 3-r3- (4-fluoro-phenyl) -5-methyl-rL2,41triazol-l-yll-l.l-dimethyl-propylamine
  • V-4-c) (3-r5-ethyl-3- (4-methoxy-phenyl) -ri.2.41triazol-l-yll-ll-dimethylpropyl-carbamic acid tert-butyl ester 4.30 g (21.2 mmol) 5 -Ethyl-3- (4-methoxy-phenyl) - [1,2,4] triazole are dissolved in 30 mL DMPU and cooled to 0 ° C.
  • Example 7 4- (2- (3-r3- (3.5-difluorophenyl) -5-methyl-ri.2.41triazol-l-yll-ll-dimethv1-propylamino) -1-hydroxy-ethyl) -2- hydroxymeth yl phenol
  • Example 8 4- (2- ⁇ 3-r3- (4-fluorophenyl) -5-methyl-rL2.41triazol-l-yll-ll-dimethylpropylamino ⁇ - 1-hydroxy-ethyl) -2-h ydroxymeth yl- phenol
  • Example 9 4- (2- ⁇ 3-r5-ethyl-3-f4-metho ⁇ y -phenylVri.2.41triazol-l-vn-ll-dimethyl-propylamino ⁇ - 1 -h vdroxy-ethylV2-h ydroxymeth yl-phenol
  • 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.
  • 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 in the case of an atrioventricular block, and the correction of bradycal arrhythmias (antiarrhythmic), the therapy of circulatory shock (vasodilation and increase in cardiac output) and the treatment of itching and inflammation of the skin.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • tocolysis the restoration of the sinus rhythm in the heart in the case of an atrioventricular block
  • bradycal arrhythmias antiarrhythmic
  • the therapy of circulatory shock vas and increase in cardiac output
  • 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 therapy of circulatory shock (vasodilation and increase in cardiac output) as well as for the treatment of itching and inflammation of the skin.
  • 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
  • Treating asthma or COPD also of particular importance is the use of compounds of general formula 1 mentioned above for the manufacture of a medicament 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.
  • anticholinergics examples include ipratropium bromide,
  • Oxitropium bromide and especially tiotropium bromide are particularly preferred according to the invention.
  • Tiotropium bromide is particularly preferably in the form of its monohydrate, in particular in the form of its crystalline Monohydrate, for use. This crystalline monohydrate is described in detail in WO 02/30928.
  • corticosteroids which can optionally be used in combination with the compound of formula 1,
  • the corticosteroids are preferably selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexametasone, with here the budesonide, fluticasone, mometasone and ciclesonide, in particular the budesonasone and one in particular Importance.
  • steroids in the context of the present patent application instead of the term corticosteroids.
  • Reference to steroids in the context of the present invention includes reference to salts or derivatives which can be formed by the steroids. Examples of possible salts or derivatives are: sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. If necessary, the corticosteroids can also be present in the form of their hydrates.
  • 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.
  • dopamine agonists 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.
  • 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 tolerated acid addition salts which can be formed by the above-mentioned dopamine agonists are understood to mean, for example, pharmaceutically tolerable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, Acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.
  • antiallergics which can be used according to the invention as a combination with the compound of formula 1 include 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 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.
  • a reference to the abovementioned antiallergics includes a reference to their pharmacologically acceptable acid addition salts which may exist.
  • PDE-IN 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), Vl 1294A 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.
  • a reference to the PDE-IV inhibitors mentioned above includes a reference to their pharmacologically acceptable acid addition salts which may exist.
  • the physiologically acceptable acid addition salts which can be formed by the abovementioned PDE-IV 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, 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 in this context.
  • Suitable forms of application for applying the compounds of the formula 1 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 up to 50% by weight of the total composition.
  • Corresponding tablets can be obtained, for example, by mixing the active ingredient (s) with known auxiliaries, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or agents to achieve the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • auxiliaries for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or agents to achieve the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • the tablets
  • 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.
  • the core can also consist of several layers to achieve a deposit 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.
  • Solutions are in the usual way, for example 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 are optionally used as Solvent mediators or auxiliary solvents can be used, 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 carriers, such as neutral fats or polyethylene glycol or its derivatives.
  • auxiliary substances include water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), oils of vegetable origin (e.g. peanut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerin), carriers such as e.g. natural stone flours (e.g. kaolins, clays,
  • paraffins e.g. petroleum fractions
  • oils of vegetable origin e.g. peanut or sesame oil
  • mono- or polyfunctional alcohols e.g. ethanol or glycerin
  • carriers such as e.g. natural stone flours (e.g. kaolins, clays,
  • Talc chalk
  • synthetic rock flour e.g. highly disperse silica and silicates
  • sugar e.g. cane, milk and dextrose
  • emulsifiers 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 inhalation powders containing propellant gas or propellant-free inhalation solutions come into consideration.
  • 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 may contain 1 either alone or in a mixture with suitable physiologically acceptable excipients. 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
  • oligosaccharides and polysaccharides e.g. dextrans
  • polyalcohols e.g. sorbitol, mannitol, xylitol
  • salts e.g. sodium chloride, calcium carbonate
  • 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.
  • 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 seem 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
  • inhalable powders according to the invention are admixed with the auxiliary 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 by means of 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.
  • 1 can be contained in separate dosage forms or in a common dosage form, where 1 can either be both dissolved, both dispersed or only one component dissolved and the other dispersed.
  • the propellant gases which can be used to prepare the inhalation aerosols are 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 1 according to the invention can be applied in the form of propellant-free inhalation solutions and inhalation suspensions.
  • Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic, solutions.
  • 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.
  • inorganic acids examples include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
  • organic acids examples include: 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 and
  • 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, especially in cases of acids which, in addition to their acidifying properties, also have other properties, for example as flavorings, Have 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.
  • Complexing agents can 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.
  • the auxiliaries and additives include e.g. surfactants such as Soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives which ensure 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 ascorbic acid, if not already used for adjusting the pH, vitamin A, vitamin E, tocopherols and similar vitamins or pro vitamins 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, benzalkomum 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 only contain benzalkomum 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. With inhalation
  • the compounds of formula 1 are characterized by a high effectiveness even at doses in the ⁇ g range. Even above the ⁇ g 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 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.
  • Active ingredient 1 50 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.
  • 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 at a higher level (e.g. 0.02% by weight).
  • This solution can be prepared in the usual way.
  • the inhalable powder is produced in the usual way by mixing the individual components.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne l'utilisation de composés correspondant à la formule générale (1), dans laquelle les groupes R<1>, X et Y peuvent correspondre aux définitions données dans les revendications et dans la description, pour la production d'un médicament servant au traitement de la maladie obstructive respiratoire chronique. L'invention concerne également de nouveaux composés correspondant à la formule générale (1) et leur procédé de production.
EP05700676A 2004-01-09 2005-01-04 Derives 3-hydroxymethyl-4-hydroxyphenyle pour le traitement de maladies des voies respiratoires Ceased EP1706389A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004001413A DE102004001413A1 (de) 2004-01-09 2004-01-09 3-Hydroxymethyl-4-Hydroxy-Phenyl-Derivate zur Behandlung von chronisch obstruktiver Lungenerkrankung
PCT/EP2005/000011 WO2005066140A1 (fr) 2004-01-09 2005-01-04 Derives 3-hydroxymethyl-4-hydroxyphenyle pour le traitement de maladies des voies respiratoires

Publications (1)

Publication Number Publication Date
EP1706389A1 true EP1706389A1 (fr) 2006-10-04

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EP05700676A Ceased EP1706389A1 (fr) 2004-01-09 2005-01-04 Derives 3-hydroxymethyl-4-hydroxyphenyle pour le traitement de maladies des voies respiratoires

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US (2) US7511067B2 (fr)
EP (1) EP1706389A1 (fr)
JP (1) JP4785751B2 (fr)
CA (1) CA2541781C (fr)
DE (1) DE102004001413A1 (fr)
WO (1) WO2005066140A1 (fr)

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DE102004003428A1 (de) * 2004-01-23 2005-08-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue langwirksame Beta-2-Agonisten, und deren Verwendung als Arzneimittel
GT200500281A (es) 2004-10-22 2006-04-24 Novartis Ag Compuestos organicos.
GB0424284D0 (en) 2004-11-02 2004-12-01 Novartis Ag Organic compounds
RU2442771C2 (ru) 2005-08-08 2012-02-20 Арджента Дискавери Лтд Производные бицикло[2,2,1]гепт-7-иламина и их применения
GB0516313D0 (en) 2005-08-08 2005-09-14 Argenta Discovery Ltd Azole derivatives and their uses
GB0601951D0 (en) 2006-01-31 2006-03-15 Novartis Ag Organic compounds
AR060607A1 (es) 2006-04-21 2008-07-02 Novartis Ag Derivados de purina,composiciones farmaceuticas que los contienen, metodo de preparacion y usos en enfermedades obstructivas o inflamatorias de las vias respiratorias.
EP2057152A1 (fr) * 2006-08-07 2009-05-13 Boehringer Ingelheim International GmbH Nouveaux agonistes beta énantiomériquement purs, procédés pour leur préparation et leur utilisation comme médicament
JP5584138B2 (ja) 2008-01-11 2014-09-03 ノバルティス アーゲー キナーゼ阻害剤としてのピリミジン類
US8236786B2 (en) 2008-08-07 2012-08-07 Pulmagen Therapeutics (Inflammation) Limited Respiratory disease treatment
WO2010076553A1 (fr) 2008-12-30 2010-07-08 Dr. Reddy's Laboratories Ltd Composés de sulfonamide pour le traitement de troubles respiratoires
WO2010150014A1 (fr) 2009-06-24 2010-12-29 Pulmagen Therapeutics (Inflammation) Limited Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires
GB0918924D0 (en) 2009-10-28 2009-12-16 Vantia Ltd Azaindole derivatives
GB0918923D0 (en) 2009-10-28 2009-12-16 Vantia Ltd Aminothiazole derivatives
GB0918922D0 (en) 2009-10-28 2009-12-16 Vantia Ltd Aminopyridine derivatives
WO2011098746A1 (fr) 2010-02-09 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Sels d'addition acide cristallins de l'énantiomère (5r) de la pioglitazone
GB201002224D0 (en) 2010-02-10 2010-03-31 Argenta Therapeutics Ltd Respiratory disease treatment
GB201002243D0 (en) 2010-02-10 2010-03-31 Argenta Therapeutics Ltd Respiratory disease treatment
WO2012034095A1 (fr) 2010-09-09 2012-03-15 Irm Llc Composés et compositions comme inhibiteurs de trk
UY33597A (es) 2010-09-09 2012-04-30 Irm Llc Compuestos y composiciones como inhibidores de la trk
JP5959541B2 (ja) 2011-02-25 2016-08-02 ノバルティス アーゲー Ｔｒｋ阻害剤としてのピラゾロ［１，５−ａ］ピリジン

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DE2833140A1 (de) * 1978-07-28 1980-02-07 Boehringer Sohn Ingelheim Neue n-substituierte heterocyclen
DK1028111T3 (da) * 1997-10-17 2004-09-20 Yamanouchi Pharma Co Ltd Amidderivater eller salte heraf
US7144908B2 (en) * 2001-03-08 2006-12-05 Glaxo Group Limited Agonists of beta-adrenoceptors

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CA2541781A1 (fr) 2005-07-21
JP2007517821A (ja) 2007-07-05
JP4785751B2 (ja) 2011-10-05
DE102004001413A1 (de) 2005-08-18
CA2541781C (fr) 2012-10-30
US20080132556A1 (en) 2008-06-05
WO2005066140A1 (fr) 2005-07-21
US20050234112A1 (en) 2005-10-20
US7511067B2 (en) 2009-03-31

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