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EP1732553A1 - Composes pour traiter des processus de proliferation - Google Patents

Composes pour traiter des processus de proliferation

Info

Publication number
EP1732553A1
EP1732553A1 EP05716229A EP05716229A EP1732553A1 EP 1732553 A1 EP1732553 A1 EP 1732553A1 EP 05716229 A EP05716229 A EP 05716229A EP 05716229 A EP05716229 A EP 05716229A EP 1732553 A1 EP1732553 A1 EP 1732553A1
Authority
EP
European Patent Office
Prior art keywords
group
hydroxy
optionally
methyl
hydrogen
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.)
Withdrawn
Application number
EP05716229A
Other languages
German (de)
English (en)
Inventor
John Edward Park
Nveed Chaudhary
Michael P. Pieper
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
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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 filed Critical Boehringer Ingelheim International GmbH
Publication of EP1732553A1 publication Critical patent/EP1732553A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to the use of anticholinergics for the manufacture of a medicament for the prevention and treatment of proliferative processes.
  • the antimuscarinic anticholinergics 1 are characterized by an anti-proliferative activity.
  • the present invention relates to the use of anticholinergics 1 for the manufacture of a medicament for the prevention and treatment, in particular for the treatment of proliferative processes.
  • the invention relates to the use of anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, in particular for the treatment of diseases associated with proliferative processes.
  • the long-acting anticholinergics I_ used in the context of the present invention are preferably selected from the group consisting of tiotropium salts (1.1). Oxitropium salts (1.2), flutropium salts (1.3), ipratropium salts (1.4), glycopyrronium salts (1.5), trospium salts (1.6) and the compounds of the formulas 1/7 to 1.13.
  • the cations tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium and trospium are the pharmacologically active constituents.
  • An explicit reference to the abovementioned cations is made by the designations 1.1 'to 1.6'.
  • any reference to the abovementioned salts L1 to L6 naturally includes a reference to the corresponding cations tiotropium (1.1 '), oxitropium (1.2'), flutropium (1.3 '), ipratropium (1.4'), glycopyrronium (1.5 '), trospium ( 1.6 ') with a.
  • the salts _____ to L6 are understood to mean those compounds which, in addition to the cations tiotropium (1.1 '), oxitropium (1.2'), flutropium (1.3 '), ipratropium (1.4'), glycopyrronium (1.5 ') and trospium (1.6' ) as counterion (anion) chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate, where chloride, bromide, iodide, sulfate, Methanesulfonate or p-toluenesulfonate are preferred as counterions.
  • the chlorides, bromides, iodide and methanesulfonate are particularly preferred.
  • the chloride is particularly preferred.
  • the methanesulfonates and bromides are of particular importance.
  • Drug combinations which contain tiotropium salts (1.1), oxitropium salts (1.2) or ipratropium salts (1.4) are of particular importance, the particular bromides being particularly important according to the invention.
  • Tiotropium bromide (Ll) is of particular importance.
  • the abovementioned salts can optionally be present in the pharmaceutical combinations according to the invention in the form of their solvates or hydrates, preferably in the form of their hydrates.
  • the pharmaceutical combinations according to the invention preferably contain this in the form of the crystalline tiotropium bromide monohydrate, which is known from WO 02/30928. If the tiotropium bromide is used in anhydrous form in the pharmaceutical combinations according to the invention, the anhydrous crystalline tiotropium bromide which is known from WO 03/000265 is preferably used.
  • the above-mentioned anticholinergics 1 may have chiral carbon centers.
  • the medicaments according to the invention can contain the anticholinergics in the form of their enantiomers, mixtures of the enantiomers or racemates, preferably enantiomerically pure anticholinergics, such as in the case of the salts L4 and L5, being used.
  • compounds of the formula L7 are used as anticholinergics 1,
  • X is a simply negatively charged anion, preferably an anion selected from the group
  • Toluene sulfonate optionally in the form of their racemates, enantiomers or hydrates.
  • X ⁇ is a single negatively charged anion, preferably an anion selected from the group
  • X is a simply negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide, optionally in the form of their racemates, enantiomers or hydrates.
  • the compound of the formula L8 in the form of the free base is 1.8-base
  • A is a double-bonded group selected from the groups ⁇ _ / ⁇ _ / ⁇ _ / CCC - O and -tJ ⁇ 7 ⁇ - H 2 H 2 'HHH ) H' X "one of the single negatively charged anions mentioned above, preferably chloride, bromide or methanesulfonate, 1 9
  • R and R are a group selected from methyl, ethyl, n-propyl and isopropyl, which can be optionally substituted by hydroxyl or fluorine, preferably unsubstituted methyl;
  • R 3 , R 4 , R 5 and R 6 are hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF 3 or NO 2 ;
  • R 7 is hydrogen, methyl, ethyl, methyloxy, ethyloxy, -CH 2 -F, -CH 2 -CH 2 -F, -O-CBfe-F, -O-CH 2 -CH 2 -F, -CH 2 -OH , -CH 2 -CH 2 -OH, CF 3 , -CH 2 -OMe, -CH 2 -CH 2 -OMe, -CH 2 -OEt
  • preferred compounds of the formula L9 are those in which
  • R and R are the same or different, methyl or ethyl, preferably methyl;
  • R 3 , R 4 , R 5 and R 6 are hydrogen, methyl, methyloxy, chlorine or fluorine; R is hydrogen, methyl or fluorine.
  • A is a double-bonded group selected from
  • the following compounds of formula 1.9 are of particular importance: 2,2-Diphenylpropionsauretropenolester methobromide (1.9.1), 2,2-Diphenylpropionsäurescopinester-methobromid (1.9.2), 2-fluoro-2,2-Diphenylessigklarescopinester-methobromide (1.9 .3), 2-fluoro-2,2-diphenylacetic acid tropenol ester methobromide (1.9.4).
  • the compounds of the formula L9 can optionally be present in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or solvates.
  • A, X ", R 1 and R 2 can have the meanings given above and in which R 7 , R 8 , R 9 , R 10 , R 11 and R 12 , identical or different, are hydrogen, methyl, ethyl, methyloxy, ethyloxy , Hydroxy, fluorine, chlorine, bromine, CN, CF 3 or NO 2 , mean, at least one of the groups R 7 , R 8 , R 9 , R 10 , R ⁇ and R 12 cannot be hydrogen.
  • A is a double-bonded group selected from ⁇ _ / " ⁇ and HH H o H
  • R 1 and R 2 are the same or different, methyl or ethyl, preferably methyl;
  • R 7 , R 8 , R 9 , R 10 , R 11 and R 12 identical or different, denote hydrogen, fluorine, chlorine or bromine, preferably fluorine, where at least one of the groups R 7 , R 8 , R 9 , R 10 , R 11 and R 12 cannot be hydrogen.
  • the compounds of formula 1.10 can optionally be present in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or solvates.
  • R ⁇ 5 hydrogen, hydroxy, methyl, ethyl, -CF3, CHF2 or fluorine;
  • R 1 and R are the same or different, C j-C5 ⁇ alkyl, which may optionally be substituted by C3-C (5-cycloalkyl, hydroxy or halogen, or R 1 and R 2 together form a -C3-C5 alkylene bridge;
  • R 13 , R 14 , R 13 ' and R 14' are the same or different, hydrogen, -C j -C ⁇ alkyl- '-Ci -Ci alkyloxy, hydroxy, -CF3, -CHF, CN, NO 2 or halogen, mean.
  • Preferred compounds of the formula 1.11 are those in which
  • X is an anion selected from chloride, bromide and methanesulfonate, preferably bromide;
  • R 1 and R 2 are the same or different, methyl or ethyl, preferably methyl;
  • RR 1133 ,, RR 1144 ,, RR 1133 '' and RR 1144 '' are similar to hydrogen, hydrogen, -CF3, -CHF2 or fluorine, preferably hydrogen or fluorine.
  • Particularly preferred compounds of the formula 1.11 are those in which a two-bound group selected from
  • R 15 is hydroxy or methyl, preferably methyl
  • R and R 2 ' are the same or different, methyl or ethyl, preferably methyl;
  • R 13 , R 14 , R ! and R 14 are the same or different, hydrogen or fluorine.
  • the compounds of formula 1.11 can optionally be present in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or solvates.
  • R 16 is hydrogen, hydroxyl, -C-C4-alkyl, -C ⁇ -C4-alkyloxy, -C ⁇ -C4-alkylene-halogen, -O-Cj-C4-alkylene-halogen, -C ⁇ -C4-alkylene-OH, - CF3, CHF 2 , -C 1 -C 4 alkylene -CC-C 4 -alkyloxy, -O-COC ⁇ -C4-alkyl, -O-COC ⁇ -C4-alkylene-halogen, -C ⁇ -C4-alkylene-C3- C6-cycloalkyl, -O-COCF3 or halogen; R and R are the same or different, -Cj-
  • R 17 , R 18 , R 17 ' and R 18' are hydrogen, -C1-C4-alkyl, -Cj-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, NO 2 or halogen;
  • R x and R x 'the same or different, hydrogen, -C-C4-alkyl, ⁇ -C-C4-alkyloxy, hydroxy, -CF3, -CHF 2 , CN, NO 2 or halogen, or
  • R and R x are a single bond or one of the double-bond groups O, S, NH, CH 2 , CH 2 -CH 2! N (-C 4 alkyl), CH (C 1 -C 4 alkyl) and -C (-C 4 alkyl) mean.
  • R 16 is hydrogen, hydroxy, -Cj ⁇ alkyl, -C 1 -C 4 alkyloxy, -CF3, -CHF 2 , fluorine, chlorine or bromine;
  • R and R are identical or different, C1-C4-alkyl, which may optionally be substituted by hydroxy, fluorine, chlorine or bromine, or R 1 " and R 2" together form a -C3-C4-alkylene bridge;
  • R 17 , R 18 , R 17 ' and R 18' the same or different, hydrogen, -CC 4 alkyl, -C-C 4 alkyloxy, hydroxy, -CF 3 , -CHF 2 , CN, NO 2 , fluorine , Chlorine or bromine;
  • R x and R x ' are the same or different, hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyloxy, hydroxy, -CF3, -CHF2, CN, NO 2 , fluorine, chlorine or bromine, or
  • R x and R x together represent a single bond or a double bond group selected from O, S, NH and CH.
  • Particularly preferred compounds of the formula 1.12 are those in which X "is chloride, bromide or methanesulfonate, preferably bromide;
  • R 16 is hydrogen, hydroxy or methyl; 1 1 9 "
  • R and R are the same or different, methyl or ethyl; 17 1 R 17 '1 fi' ⁇ -.
  • R, R, R and R the same or different, hydrogen, -CF3 or fluorine, preferably hydrogen;
  • R x and R x are the same or different, hydrogen, -CF3 or fluorine, preferably hydrogen, or
  • R x and R x together represent a single bond or -O-.
  • Particularly preferred compounds of the formula L12 are also those in which
  • R 16 is hydrogen, hydroxy or methyl; R 1 " and R 2" methyl; 17 IS 1 '1 R'
  • R, R, R and R are hydrogen or fluorine, preferably hydrogen;
  • R and R x ' are the same or different, hydrogen or fluorine, preferably hydrogen, or
  • cyclopropyltropine benzilate methobromide (1.12.1); - 2,2-Diphenylpropionic acid cyclopropyltropine ester methobromide (1.12.2); 9-Hvdroxv-xanthene-9-carboxylic acid cyclopropyltropine ester methobromide (1.12.3); 9-methylene fluorene-9-carboxylic acid cyclopropyltropinester methobromide (1.12.4); Cyclopropyltropine 9-methyl-xanthene-9-carboxylic acid methobromide (1.12.5); 9-hydroxyfluorene-9-carboxylic acid cyclopropyltropinester methobromide (1.12.6); - 4,4'-difluorobenzic acid methyl ester cyclopropyltropinester methobromide (1.12.7).
  • the compounds of the formula 1.12 selected from the group consisting of: cyclopropyltrop
  • R 19 is hydroxy, methyl, hydroxymethyl, ethyl, -CF3, CHF 2 or fluorine;
  • R 1 and R ⁇ are identical or different, Cj-C5-alkyl, which may optionally be substituted by C3-Cö-cycloalkyl, hydroxy or halogen, or R 1 and R 2 together form a -C3-C5-alkylene bridge;
  • R 20 , R 21 , R 20 ' and R 21' are hydrogen, -Ci-C4-alkyl, -C-C4-alkyloxy, hydroxy, -CF3, -CHF 2 , CN, NO 2 or halogen ,
  • Preferred compounds of the formula 1.13 are those in which A 'is a divalent group selected from " Chloride, bromide or methanesulfonate, preferably bromide;
  • R 19 is hydroxy or methyl
  • R 1 and R 2 are the same or different, methyl or ethyl, preferably methyl;
  • R 20 , R 21 , R 20 ' and R 21' are hydrogen, -CF3, -CHF 2 or fluorine, preferably hydrogen or fluorine.
  • Particularly preferred compounds of the formula 1.13 are those in which A 'is a divalent group selected from
  • R 19 is hydroxy or methyl, preferably methyl
  • R and R are the same or different, methyl or ethyl, preferably methyl;
  • compounds of the formula 1.13 which are selected from the group consisting of: 9-hydroxy-xanthene-9-carboxylic acid tropenol ester methobromide (1.13.1); 9-hydroxy-xanthene-9-carboxylic acid copinate methobromide (1.13.2); - 9-methyl-xanthene-9-carboxylic acid tropenol ester methobromide (1.13.3); 9-methyl-xanthene-9-carboxylic acid copinate methobromide (1.13.4); 9-ethyl-xanthene-9-carboxylic acid tropenol ester methobromide (1.13.5); 9-difluoromethyl-xanthene-9-carboxylic acid tropenol ester methobromide (1.13.6); 9-hydroxymethyl-xanthene-9-carboxylic acid copinate methobromide (1.13.7).
  • the compounds of formula 1.13 can optionally be present in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or solvates.
  • the alkyl groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl or butyl. To designate the groups methyl, ethyl, propyl or butyl, the abbreviations Me, Et, Prop or Bu may also be used. 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.
  • cycloalkyl groups are understood to be alicyclic groups having 3 to 6 carbon atoms. These are the groups cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Of particular importance according to the invention is cyclopropyl in the context of the present invention.
  • 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 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. For example, propyloxy includes n-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy, sec. Butyloxy and tert. -Butyloxy etc. Where appropriate, the term alkoxy is used in the context of the present invention instead of the term alkyloxy.
  • the terms methoxy, ethoxy, propoxy or butoxy are also used to designate the groups methyloxy, ethyloxy, propyloxy or butyloxy.
  • the alkylene-alkyloxy groups are 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 have one
  • 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.
  • a reference to anticholinergics V_ is to be understood as a reference to the pharmacologically active cations of the respective salts. These cations are tiotropium (Ll '), oxitropium (1.2'), flutropium (1.3 '), ipratropium (1.4'), glycopyrronium (1.5 '), trospium (1.6') and the following cations
  • the present invention preferably relates to the use of the abovementioned anticholinergics 1 for the production of a medicament for the prevention or treatment, preferably for the treatment of proliferative processes in cell types selected from the group consisting of fibroblasts, myofibroblasts, epithelial cells, endothelial cells, serous and mucous cells in submucosal glands, clara cells, pneumocytes type I + II and goblet cells.
  • the present invention preferably relates to the abovementioned use of the abovementioned anticholinergics 1 for the production of a medicament for the prevention or treatment, preferably for the treatment of proliferative processes which occur in diseases of the upper and lower respiratory organs, including the lungs.
  • the present invention preferably relates to the abovementioned use of the abovementioned anticholinergics 1 for the production of a medicament for the prevention or treatment, preferably for the treatment of proliferative processes which occur in diseases selected from the group consisting of pneumonia, pulmonary hypertension, pulmonary emphysema, pulmonary fibrosis, pulmonary edema, bronchiectasis, Adult Respiratory Distress Syndrome (ARDS), Boeck's disease, fibrotic alveolitis, pulmonary embolism, pneumoconiosis (e.g. asbestosis, silicosis), lung cancer and tuberculosis.
  • diseases selected from the group consisting of pneumonia, pulmonary hypertension, pulmonary emphysema, pulmonary fibrosis, pulmonary edema, bronchiectasis, Adult Respiratory Distress Syndrome (ARDS), Boeck's disease, fibrotic alveolitis, pulmonary embolism, pneumoconi
  • the present invention preferably relates to the abovementioned use of the abovementioned anticholinergics 1 for the production of a medicament for
  • the present invention preferably relates to the use of the aforementioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of proliferative processes which occur in pneumonia. Furthermore, the present invention relates to the use of the above-mentioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of pneumonia. The present invention preferably relates to the abovementioned use of the abovementioned anticholinergics 1 for the preparation of a medicament for the prevention or treatment, preferably for the treatment of proliferative processes which occur in the case of pulmonary hypertension. Furthermore, the present invention relates to the use of the aforementioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of pulmonary hypertension.
  • the present invention preferably relates to the use of the aforementioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of proliferative processes which occur in pulmonary emphysema.
  • the present invention further relates to the use of the above-mentioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of emphysema of the lungs.
  • the present invention preferably relates to the use of the aforementioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of proliferative processes which occur in pulmonary edema.
  • the present invention further relates to the use of the abovementioned anticholinergics 1 for the production of a medicament for the prevention or treatment, preferably for the treatment of pulmonary edema.
  • the present invention preferably relates to the use of the aforementioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of proliferative processes which occur in ARDS. Furthermore, the present invention relates to the use of the above-mentioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of ARDS.
  • the present invention preferably relates to the use of the aforementioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of proliferative processes which occur in Boeck's disease.
  • the present invention further relates to the use the aforementioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of Boeck's disease.
  • the present invention preferably relates to the use of the aforementioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of proliferative processes which occur in pulmonary fibrosis. Furthermore, the present invention relates to the use of the above-mentioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of pulmonary fibrosis.
  • the present invention preferably relates to the use of the aforementioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of proliferative processes which occur in pulmonary embolism. Furthermore, the present invention relates to the use of the aforementioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of pulmonary embolism.
  • the present invention preferably relates to the abovementioned use of the abovementioned anticholinergics 1 for the production of a medicament for the prevention or treatment, preferably for the treatment of proliferative processes which occur in pneumoconiosis (e.g. asbestosis, silicosis). Furthermore, the present invention relates to the use of the above-mentioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of pneumoconiosis (e.g. asbestosis, silicosis).
  • pneumoconiosis e.g. asbestosis, silicosis
  • the present invention preferably relates to the use of the aforementioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of proliferative processes which occur in lung cancer.
  • the present invention further relates to the use of the aforementioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of lung cancer.
  • the present invention preferably relates to the abovementioned use of the abovementioned anticholinergics 1 for the production of a medicament for the prevention or treatment, preferably for the treatment of proliferative processes occur in tuberculosis. Furthermore, the present invention relates to the use of the aforementioned anticholinergics 1 for the manufacture of a medicament for the prevention or treatment, preferably for the treatment of tuberculosis.
  • Another aspect of the present invention relates to pharmaceutical formulations containing anticholinergic 1 for the treatment of the abovementioned diseases.
  • the present invention further relates to the use of formulations containing an anticholinergic 1 for the production of a medicament for the prevention or treatment, preferably for the treatment of the abovementioned diseases.
  • tiotropium 1.1 ' pharmaceutical formulations, without restricting the scope of the invention thereto, can contain such amounts of anticholinergic (1.1') that 0.1-180 ⁇ g, preferably 0.5-60 ⁇ g, particularly preferably approximately 1, per single dose - 50 ⁇ g are included.
  • anticholinergic 1.1'
  • 2.5 ⁇ g, 5 ⁇ g, 10 ⁇ g, 18 ⁇ g, 20 ⁇ g, 36 ⁇ g or 40 ⁇ g 1.1 ′ can be applied per single dose.
  • the person skilled in the art can easily calculate the corresponding amount of the salt L1 used or, if appropriate, the hydrates or solvates used.
  • the amounts of active ingredient of 1.1 'applied per single dose above correspond to the following amounts of LI applied per single dose: 3 ⁇ g, 6 ⁇ g, 12 ⁇ g, 21.7 ⁇ g, 24, l ⁇ g, 43.3 ⁇ g and 48 , l ⁇ g LL
  • the above-mentioned dosages are preferably applied once or twice a day, with the once-daily application being particularly preferred according to the invention.
  • compositions without restricting the scope of the invention thereto, in the case of the cation 1.2 'contain such amounts of anticholinergic (1.2') that 1-500 ⁇ g, preferably 5-300 ⁇ g, particularly preferably 15-200 ⁇ g are contained per single dose ,
  • the person skilled in the art can easily calculate the corresponding amount of the salt L2 used or, if appropriate, the hydrates or solvates used.
  • the above-mentioned dosages are preferably applied one to four times a day, with two to three times a day being particularly preferred according to the invention.
  • compositions can contain, in the case of the cation 1.3 ', such amounts of anticholinergic (1.3'), without restricting the scope of the invention, that 1-500 ⁇ g, preferably 5-300 ⁇ g, particularly preferably 15-200 ⁇ g are contained per single dose ,
  • 1-500 ⁇ g, preferably 5-300 ⁇ g, particularly preferably 15-200 ⁇ g are contained per single dose ,
  • the person skilled in the art can easily calculate the corresponding amount of the salt L3 used or, where appropriate, the hydrates or solvates used.
  • the above-mentioned dosages are preferably applied one to four times a day, with two to three times a day being particularly preferred according to the invention.
  • pharmaceutical formulations can contain, without restricting the scope of the invention thereto, such amounts of anticholinergic (1.4 ') that 1-500 ⁇ g, preferably 5-300 ⁇ g, particularly preferably 20-200 ⁇ g, are contained per single dose ,
  • the person skilled in the art can easily calculate the corresponding amount of the salt L4 used or, if appropriate, the hydrates or solvates used.
  • the person skilled in the art can easily calculate the corresponding amount of the salt L4 used or, if appropriate, the hydrates or solvates used.
  • the above-mentioned dosages preferably one to four times a day, with the two to three times, particularly preferably the three times daily application being particularly preferred according to the invention.
  • compositions can contain, in the case of the cation 1.5 ', amounts of anticholinergic (1.5') in the case of the cation 1.5 'in such a way that 1-500 ⁇ g, preferably 5-300 ⁇ g, particularly preferably 15-200 ⁇ g are contained per single dose ,
  • the above-mentioned dosages are preferably applied one to four times a day, with two to three times a day being particularly preferred according to the invention.
  • pharmaceutical formulations can contain, in the case of the cation 1.6', such amounts of anticholinergic (1.6 ') that 1000-6500 ⁇ g, preferably 2000-6000 ⁇ g, particularly preferably 3000-5500 ⁇ g, particularly preferably 4000, per single dose - 5000 ⁇ g are included.
  • 3500 ⁇ g, 3750 ⁇ g, 4000 ⁇ g, 4250 ⁇ g, 4500 ⁇ g, 4750 ⁇ g, or 5000 ⁇ g 1.6 ' can be applied per single dose.
  • the person skilled in the art can easily calculate the corresponding amount of the salt L6 used or, where appropriate, the hydrates or solvates used.
  • the doses mentioned above are preferably applied one to four times a day, with the two to three times a day being particularly preferred according to the invention.
  • compositions can contain, in the case of the cation LT, such amounts of anticholinergic (1.7 '), without restricting the scope of the invention, that 50-10000 ⁇ g, preferably 100-800 ⁇ g, particularly preferably per single administration 200-700 ⁇ g, particularly preferably 300-600 ⁇ g are contained.
  • 50-10000 ⁇ g, preferably 100-800 ⁇ g, particularly preferably per single administration 200-700 ⁇ g, particularly preferably 300-600 ⁇ g are contained.
  • 300 ⁇ g, 350 ⁇ g, 400 ⁇ g, 450 ⁇ g, 500 ⁇ g, 550 ⁇ g, or 600 / g 1.7 ' can be applied per single dose.
  • the person skilled in the art can easily calculate the corresponding amount of the salt L7 used or, if appropriate, the hydrates or solvates used.
  • the dosages mentioned above are preferably applied once to three times a day, with the once or twice, particularly preferably the once daily application being particularly preferred according to the invention.
  • the respective corresponding amount of the salt 1.9 'or 1.10' used or, if appropriate, the hydrates or solvates used can be easily calculated by the person skilled in the art, depending on the choice of the anion.
  • the above-mentioned dosages are preferably applied one to three times a day, with once or twice, particularly preferably once daily application being particularly preferred according to the invention.
  • compositions can contain, in the case of cations 1.11 'to 1.13', amounts of anticholinergic (1.11 ', 1.12' or 1.13 ') in the case of cations 1.11' to 1.13 'in such a way that 1 - 500 ⁇ g, preferably 5 - 300 ⁇ g, per single dose , particularly preferably 10-200 ⁇ g are contained.
  • the respective corresponding amount of used arriving salt 1.11, 1.12 or 1.13 or possibly used hydrates or solvates can easily be calculated by the person skilled in the art depending on the choice of the anion.
  • the above-mentioned dosages are preferably applied one to three times a day, with once or twice, particularly preferably once daily application being particularly preferred according to the invention.
  • the anticholinergics 1 are preferably administered by inhalation.
  • the anticholinergics 1 must be provided in inhalable dosage forms.
  • Dosage forms are inhalation powder, propellant aerosols or propellant-free inhalation solutions.
  • Inhalation powder according to the invention containing the anticholinergics. optionally in a mixture with physiologically compatible auxiliaries.
  • propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions.
  • the inhalable powders which can be used in the context of the use according to the invention can contain 1 either alone or in a mixture with suitable physiologically acceptable auxiliaries.
  • physiologically acceptable auxiliary substances can be used to prepare these inhalable powders according to the invention: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligosaccharides and polysaccharides (eg dextrans), Polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g.
  • 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.
  • micronized active ingredient 1 preferably with an average particle size of 0.5 to 10 ⁇ m, particularly preferably 1 to 6 ⁇ 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.
  • Inhalation powders according to the invention which in addition to 1 also contain a physiologically acceptable auxiliary, can be applied, for example, by means of inhalers, which take a single dose from a supply by means of a measuring chamber, as described in US 4570630A, or via other apparatus as described in US Pat DE 36 25 685 A are described, dose.
  • the inhalable powders according to the invention which contain 1 optionally in conjunction with a physiologically acceptable excipient, for example, by means of the known by the name Turbuhaler ® inhaler or using inhalers as are disclosed, for example 237507 A in the EP, are applied.
  • the inhalable powders according to the invention which contain not only 1 physiologically acceptable excipient, are preferably filled into capsules (for what are known as inhalers), which are used in inhalers as described, for example, in WO 94/28958.
  • FIG. 1 An inhaler which is particularly preferred for use of the pharmaceutical combination according to the invention in inhalettes can be seen in FIG. 1.
  • This inhaler for the inhalation of powdered pharmaceuticals from capsules is characterized by a housing 1, containing two windows 2, a deck 3, in which there are air inlet openings and which is provided with a sieve 5 attached via a sieve housing 4, one with a deck 3 connected inhalation chamber 6, on which a pusher 9 provided with two ground needles 7 and movable against a spring 8 is provided, as well as a mouthpiece 12 which can be folded via an axis 10 and is connected to the housing 1, the deck 3 and a cap 11, as well as air passage holes 13 for adjusting the flow resistance.
  • a housing 1 containing two windows 2, a deck 3, in which there are air inlet openings and which is provided with a sieve 5 attached via a sieve housing 4, one with a deck 3 connected inhalation chamber 6, on which a pusher 9 provided with two ground needles 7 and movable against a spring 8 is provided, as well as a mouthpiece 12 which can be folded via an axis 10 and is connected to the housing 1, the deck
  • inhalable powders according to the invention are to be filled into capsules (inhalettes) in the sense of the preferred use mentioned above, fill quantities of 1 to 30 mg, preferably 3 to 20 mg, preferably 5 to 10 mg inhalable powder per capsule are appropriate. According to the invention, these contain the dosages per single dose already mentioned above for the cations V_.
  • the inhalable aerosols containing propellant gas which can be used in the context of the use according to the invention can contain 1 dissolved in the propellant gas or in dispersed form.
  • 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 preferably 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 fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof.
  • Inhalation aerosols can also contain other components such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and agents for adjusting the pH. All of these components are known in the art.
  • the inhalable aerosols containing propellant gas which can be used in the context of the use according to the invention can contain up to 5% by weight of active ingredient 1.
  • the propellant gases which can be used in the context of the use according to the invention contain, for example, 0.002 to 5% by weight, 0.01 to 3% by weight, 0.015 to 2% by weight of active ingredient 1.
  • the active ingredient particles preferably have an average particle size of up to 10 ⁇ m, preferably from 0.1 to 5 ⁇ m, particularly preferably from 1 to 5 ⁇ m.
  • the present invention further relates to the use according to the invention of 1 for the production of cartridges which can be used equipped with a suitable valve in a suitable inhaler and which contain one of the above-mentioned inhalation aerosols containing propellant gas according to the invention.
  • Suitable cartridges and methods for filling these cartridges with the inhalation aerosols containing propellant gas according to the invention are known from the prior art.
  • tiotropium salts 1 is preferably carried out for the preparation 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.
  • 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 above Acids are used, in particular in cases 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 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 can be added with co-solvents and other auxiliary substances.
  • 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 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 additives known in the prior art.
  • 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 in the concentration known from the prior art.
  • the preservatives mentioned above are preferably contained in concentrations of up to 50 mg 100 ml, particularly preferably between 5 and 20 mg 100 ml.
  • the preferred propellant-free inhalation solutions which can be used in the context of the use according to the invention only contain benzalkonium chloride and sodium edetate.
  • sodium edetate is dispensed with.
  • those inhalers are particularly suitable which can nebulize a small amount of a liquid formulation in the therapeutically necessary dosage into an aerosol suitable for therapeutic inhalation within a few seconds.
  • those nebulizers are preferred in which an amount of less than 100 ⁇ L, preferably less than 50 ⁇ L, particularly preferably between 10 and 30 ⁇ L of active ingredient solution, preferably with a stroke to an aerosol with an average particle size of less than 20 ⁇ m, preferably less than 10 ⁇ m, can be atomized in such a way that the inhalable portion of the aerosol already corresponds to the therapeutically effective amount.
  • Such a device for propellant-free administration of a metered amount of a liquid medicament for inhalation use is described in detail, for example, in international patent application WO 91/14468 and also in WO 97/12687 (there in particular FIGS. 6a and 6b).
  • the nebulizers described there are also known under the name Respimat ® .
  • This nebuliser (Respimat ®), the tiotropium salts 1 are advantageously used to produce the inhalable aerosols according to the invention containing. Due to its cylinder-like shape and a handy size of less than 9 to 15 cm in length and 2 to 4 cm in width, this device can be carried by the patient at any time.
  • the nebulizer sprays a defined volume of the drug formulation using high pressures through small nozzles, so that inhalable aerosols are formed.
  • the preferred atomizer consists of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a reservoir, characterized by a pump housing which is fastened in the upper housing part and which has a nozzle body with the nozzle at one end or carries the nozzle arrangement, - a hollow piston with valve body,
  • the hollow piston with valve body corresponds to a device disclosed in WO 97/12687. It projects partially into the cylinder of the pump housing and is arranged axially displaceably in the cylinder. In particular, reference is made to FIGS. 1-4 - in particular FIG. 3 - and the associated parts of the description.
  • the hollow piston with valve body exerts a pressure of 5 to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa (about 100 to 600 bar) on the fluid, the measured active ingredient solution on its high pressure side at the time the spring is triggered. Volumes of 10 to 50 microliters are preferred, volumes of 10 to 20 microliters are particularly preferred, and a volume of 15 microliters per stroke is very particularly preferred.
  • the valve body is preferably attached to the end of the hollow piston which faces the nozzle body.
  • the nozzle in the nozzle body is preferably microstructured, that is to say produced by micro technology. Microstructured nozzle bodies are disclosed, for example, in WO-94/07607; reference is hereby made to this document, in particular to FIG. 1 disclosed there and its description.
  • the nozzle body is e.g. from two firmly connected plates made of glass and / or silicon, of which at least one plate has one or more microstructured channels which connect the nozzle inlet side to the nozzle outlet side.
  • the jet directions of the nozzles in the nozzle body can run parallel to one another or they are inclined towards one another in the direction of the nozzle opening.
  • the jet directions can be inclined at an angle of 20 degrees to 160 degrees, an angle of 60 to 150 degrees is preferred, particularly preferably 80 to 100 °.
  • the nozzle openings are preferably arranged at a distance of 10 to 200 micrometers, more preferably at a distance of 10 to 100 micrometers, particularly preferably 30 to 70 micrometers. Most preferred are 50 microns.
  • the jet directions meet in the vicinity of the nozzle openings.
  • the liquid pharmaceutical preparation hits the nozzle body at an inlet pressure of up to 600 bar, preferably 200 to 300 bar, and is atomized into an inhalable aerosol via the nozzle openings.
  • the preferred particle or droplet sizes of the aerosol are up to 20 micrometers, preferably 3 to 10 micrometers.
  • the locking mechanism contains a spring, preferably a cylindrical helical compression spring, as a store for the mechanical energy.
  • the spring acts on the output flange as a jumping piece, the movement of which is determined by the position of a locking element.
  • the path of the output flange is precisely limited by an upper and a lower stop.
  • the spring is preferably tensioned via a force-transmitting gear, for example a screw-push gear, by an external torque which is generated when the upper housing part is rotated against the spring housing in the lower housing part.
  • the upper housing part and the output flange contain a single or multi-speed wedge gear.
  • the locking member with engaging locking surfaces is arranged in a ring around the output flange.
  • the ring is arranged in a plane perpendicular to the atomizer axis. After tensioning the spring, the locking surfaces of the locking member slide into the path of the output flange and prevent the spring from relaxing.
  • the locking element is triggered by a button.
  • the trigger button is connected or coupled to the locking member.
  • the release button is moved parallel to the ring plane, and preferably into the atomizer; the deformable ring is deformed in the plane of the ring. Structural details of the locking mechanism are described in WO 97/20590.
  • the lower part of the housing is pushed in the axial direction over the spring housing and covers the bearing, the drive of the spindle and the reservoir for the fluid.
  • the upper housing part When the atomizer is actuated, the upper housing part is rotated against the lower housing part, the lower housing part taking the spring housing with it.
  • the spring is compressed and tensioned via the screw-type thrust gear, and the locking mechanism engages automatically.
  • the angle of rotation is preferably an integer fraction of 360 degrees, e.g. 180 degrees.
  • the driven part in the upper part of the housing is shifted by a predetermined distance, the hollow piston is withdrawn within the cylinder in the pump housing, whereby a part of the fluid is sucked from the reservoir into the high-pressure space in front of the nozzle.
  • the storage container contains the aqueous aerosol preparation according to the invention.
  • the atomization process is initiated by gently pressing the trigger button.
  • the barrage clears the way for the stripping section.
  • the tensioned spring pushes the piston into the cylinder of the pump housing.
  • the fluid exits the atomizer nozzle in atomized form.
  • nebulizer described above is suitable for nebulizing the aerosol preparations which can be used in the context of the use according to the invention to give an aerosol suitable for inhalation.
  • propellant-free inhalable solutions used within the scope of the inventive use nebulised using the method described above (Respimat ®), the mass expelled, in at least 97%, preferably at least 98% of all
  • Actuations of the inhaler (hub) correspond to a defined amount with a tolerance range of at most 25%, preferably 20% of this amount. Between 5 and 30 mg of formulation are preferably applied as a defined mass per stroke, particularly preferably between 5 and 20 mg.
  • propellant-free inhalation solutions that can be used in the context of the use according to the invention can also be nebulized using inhalers other than those described above, for example jet stream inhalers or other stationary nebulizers.
  • a further aspect of the present invention relates to the use of anticholinergicsJ according to the invention.
  • a suitable device for administering these formulations preferably in conjunction with the Respimat ®.
  • the present invention aims at in the framework of the inventive use of 1 for the production of propellant-free inhalable solutions or suspensions by a content of 1 in connection with the known under the name Respimat ® device.
  • the present invention relates to the use according to the invention of the aforementioned devices for inhalation, preferably the
  • Respimat ® characterized in that they contain propellant-free inhalable solutions or suspensions according to the invention described above.
  • a further aspect of the present invention relates to the use according to the invention of 1 in the form of propellant-free inhalable solutions or suspensions as described above, which are present as concentrates or sterile, ready-to-use formulations, in conjunction with a device suitable for the administration of these solutions, characterized in that it is this device is an energy-operated standing or transportable nebuliser that generates inhalable aerosols by means of ultrasound or compressed air according to the Venturi principle or other principles.

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Abstract

La présente invention concerne l'utilisation d'anticholinergiques pour produire un agent pharmaceutique qui sert à prévenir et à traiter des processus de prolifération.
EP05716229A 2004-03-30 2005-03-19 Composes pour traiter des processus de proliferation Withdrawn EP1732553A1 (fr)

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DE102004016179A DE102004016179A1 (de) 2004-03-30 2004-03-30 Verbindungen zur Behandlung von proliferativen Prozessen
PCT/EP2005/002946 WO2005097126A1 (fr) 2004-03-30 2005-03-19 Composes pour traiter des processus de proliferation

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CA2560131A1 (fr) 2005-10-20
US20060030579A1 (en) 2006-02-09

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