WO2002069944A2 - Nouvelles compositions medicamenteuses a base d'anticholinergiques et d'antagonistes de recepteurs nk1 - Google Patents

Nouvelles compositions medicamenteuses a base d'anticholinergiques et d'antagonistes de recepteurs nk1 Download PDF

Info

Publication number
WO2002069944A2
WO2002069944A2 PCT/EP2002/001987 EP0201987W WO02069944A2 WO 2002069944 A2 WO2002069944 A2 WO 2002069944A2 EP 0201987 W EP0201987 W EP 0201987W WO 02069944 A2 WO02069944 A2 WO 02069944A2
Authority
WO
WIPO (PCT)
Prior art keywords
acid
phenyl
alkyl
methyl
inhalation
Prior art date
Application number
PCT/EP2002/001987
Other languages
German (de)
English (en)
Other versions
WO2002069944A3 (fr
Inventor
Christopher John Montague Meade
Michel Pairet
Michael Paul Pieper
Original Assignee
Boehringer Ingelheim Pharma Gmbh & 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
Priority to MXPA03008051A priority Critical patent/MXPA03008051A/es
Application filed by Boehringer Ingelheim Pharma Gmbh & Co. Kg filed Critical Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority to EP02719915A priority patent/EP1370293A2/fr
Priority to JP2002569121A priority patent/JP2004519484A/ja
Priority to CA002439915A priority patent/CA2439915A1/fr
Priority to AU2002251010A priority patent/AU2002251010A1/en
Publication of WO2002069944A2 publication Critical patent/WO2002069944A2/fr
Publication of WO2002069944A3 publication Critical patent/WO2002069944A3/fr
Priority to AU2006202723A priority patent/AU2006202723B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K31/33—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • 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

Definitions

  • the present invention relates to novel pharmaceutical compositions based on anticholinergics and NK-j receptor antagonists, methods for their
  • the present invention relates to novel pharmaceutical compositions based on anticholinergics and NK-i receptor antagonists, processes for their
  • an unexpectedly advantageous therapeutic effect in particular a synergistic effect in the treatment of inflammatory and / or obstructive respiratory diseases, can be observed if one or more, preferably an anticholinergic, is used together with one or more, preferably an NK-
  • the active ingredient combinations according to the invention are surprisingly characterized both by a rapid onset of action and by a long-lasting duration of action. This is of great importance for the well-being of the patient, since on the one hand he can quickly apply the combination
  • anticholinergics 1 are understood to mean salts which are preferably selected from the group consisting of
  • Tiotropium salts, oxitropium salts and ipratropium salts with tiotropium salts being particularly preferred.
  • the cations tiotropium, oxitropium and ipratropium are the pharmacologically active constituents
  • V A reference to compounds 1_ naturally includes a reference to the constituents V (tiotropium, oxitropium or ipratropium).
  • the salts 1_ which can be used in the context of the present invention are taken to mean the compounds which, in addition to tiotropium, oxitropium or ipratropium, contain chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methyl sulfate as counterion (anion).
  • the methanesulfonate, chloride, bromide or iodide are preferred of all salts, the methanesulfonate or the bromide being of particular importance.
  • salts ⁇ which are selected from the group consisting of tiotropium bromide, oxitropium bromide and ipratropium bromide. Tiotropium bromide is particularly preferred.
  • NKi receptor antagonists are understood to be compounds which are selected from the group consisting of N- [2- (3,5-bis-trifluoromethylphenyl) ethyl] -2- ⁇ 4-cyclopropylmethyl-piperazin-1-yl ⁇ -N-methyf-2-phenyl-acetamide (BMF 1149), CP-122721, FK-888, NKP 608C, NKP 608A, CGP 60829, SR 48968 (Saredutant), SR 140333 (Noipitantium besilate / chloride), LY 303 870 (Lanepitant), MEN-11420 (Nepadutant), SB 223412, MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, SR-144190, YM- 49244, YM-44778, ZM-274773, MEN-10930
  • R 6 H -C ⁇
  • R 7 has one of the meanings (a) to (d),
  • R ⁇ 6 and R ⁇ ⁇ independently of one another H, (C «
  • R ⁇ denotes H, optionally in the form of their enantiomers and mixtures of
  • Compound 2 is preferably selected from the group consisting of BIIF 1149, CP-122721, CGP 60829, MK-869, CJ-11974, GR 205171 and the arylglycinamide derivatives of the general formula 3, in which
  • R ⁇ and R ⁇ independently of one another H, (-C-C4) alkyl, (Ca-CßJcycloalkyl, hydroxy (C2-C-4) alkyl, dihydroxy (C2-C4) alkyl, (C ⁇ -C3) alkoxy (C2-C4 ) alkyl, phenyl (C 1 -C 4) alkyl or di (C 1 -C 3) alkylamino (C2-C4) alkyl,
  • R 8 denotes H, optionally in the form of their enantiomers and mixtures of the enantiomers, and optionally in the form of their racemates.
  • the compound 2 is selected from B1IF1149 and the arylglycinamide derivatives of general formula 3 wherein R 'and R2 together with the N to which they are attached form a ring of the formula
  • R16 and R1? independently of one another are H, (C ⁇
  • Particularly preferred compounds of the formula 2 are N- [2- (3,5-bis-trifluoromethylphenyl) ethyl] -2- ⁇ 4 - [(3-hydroxypropyl) methylamino] piperidine - 1-yl ⁇ -N-methyl-2-phenyl-acetamide, N- [2- (3,5-bis-trifluoromethyl-phenyl) -ethyl] -2- [4- (2-hydroxy-1-hydroxymethyl-.
  • alkyl groups are branched and unbranched alkyl groups with 1 to 5
  • Alkenyl groups are branched and unbranched alkenyl groups with 3 to 5 carbon atoms, provided that they have at least one double bond, such as propenyl, isopropenyl, butenyl etc.
  • Cycloalkyl generally represents a saturated cyclic hydrocarbon radical having 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl etc.
  • Alkyloxy which may also be referred to as alkoxy, stands for a straight-chain or branched alkyl group bonded via an oxygen atom.
  • the methoxy group is particularly preferred.
  • a reference to the aforementioned NK-i receptor antagonists 2 includes a reference to their pharmacologically acceptable acid addition salts which may exist.
  • the physiologically compatible acid addition salts which can be formed from vii 2 are understood to be pharmaceutically compatible 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 pharmaceutical combinations according to the invention from 1_ and 2 are preferably administered by inhalation.
  • Suitable inhalable powders which are filled into suitable capsules (inhalettes) and applied by means of appropriate powder inhalers, can be used.
  • inhalative use can also be carried out by applying suitable inhalation aerosols.
  • suitable inhalation aerosols which contain, for example, HFA134a, HFA227 or their mixture as propellant.
  • the inhalation application can also be carried out using suitable solutions of the drug combination consisting of n_ and 2.
  • One aspect of the present invention accordingly relates to a medicament which contains a combination of 1_ and 2.
  • Another aspect of the present invention relates to a medicament which contains one or more salts and one or more compounds 2, optionally in the form of their solvates or hydrates.
  • the active ingredients can either be used together in a single dosage form or in two separate forms
  • Dosage forms may be included. According to the invention, preference is given to medicaments which contain the active ingredients 1 and 2 in a single dosage form.
  • the present invention further relates to the use of and 2 for the production of a therapeutically effective amount of ⁇ and 2 containing medicament for the treatment of inflammatory or obstructive respiratory diseases, in particular asthma or chronic obstructive pulmonary diseases (COPD), as well as their complications such as, for example, pulmonary hypertension also allergic and non-allergic rhinitis, provided that treatment with NKi receptor antagonists is not contraindicated from a therapeutic point of view, through simultaneous or successive application.
  • inflammatory or obstructive respiratory diseases in particular asthma or chronic obstructive pulmonary diseases (COPD)
  • COPD chronic obstructive pulmonary diseases
  • the present invention further aims at the simultaneous or successive use of therapeutically effective doses of the combination of the above drugs 1 and 2 for the treatment of inflammatory and / or obstructive respiratory diseases, in particular asthma or chronic obstructive pulmonary disease (COPD), and their complications such as pulmonary hypertension, in addition, allergic and non-allergic rhinitis, provided treatment with NK- j - receptor antagonists is not contraindicated from a therapeutic point of view, through simultaneous or successive application.
  • the constituents 1 and 2 can be present in the form of their enantiomers, mixtures of the enantiomers or in the form of the racemates.
  • the ratios in which the two active ingredients 1 and 2 can be used in the active ingredient combinations according to the invention are variable.
  • the active ingredients ⁇ and 2 may optionally be in the form of their solvates or hydrates.
  • the weight ratios which can be used in the context of the present invention vary on account of the different molecular weight of the various compounds and on account of their different potency.
  • the pharmaceutical combinations according to the invention can contain the compounds 1 and 2 in weight ratios which are in a range from 1: 300 to 50: 1, preferably from 1: 250 to 40: 1.
  • Receptor antagonists 2 contained in the following weight ratios: 1:80;
  • compositions according to the invention containing the combinations of 1 and 2 are usually used in such a way that and 2 together in doses of from 0.01 to 10000 ⁇ g, preferably from 0.1 to 2000 ⁇ g, particularly preferably from 1 to 1500 ⁇ g, further preferably from 50 to 1200 ⁇ g are included per single dose.
  • combinations of 1 and 2 according to the invention contain such an amount of tiotropium V and NK-
  • dosages that fluctuate around the above-mentioned numerical values in a range of approximately +/- 2.5 ⁇ g are also included in the values exemplified here.
  • the active ingredients V and 2 can be contained in the weight ratios described above.
  • the combinations of and 2 according to the invention can contain such an amount
  • receptor antagonist 2 contain 5 ⁇ g V and 25 ⁇ g 2, 5 ⁇ g V and 50 ⁇ g 2, 5 ⁇ g V and 100 ⁇ g 2, 5 ⁇ g V and 200 ⁇ g 2, 5 ⁇ g V and 300 ⁇ g 2, 5 ⁇ g V and 400 ⁇ g per single dose 2, 5 ⁇ g V and 500 ⁇ g 2, 5 ⁇ g V and 600 ⁇ g 2, 5 ⁇ g V and 700 ⁇ g 2, 5 ⁇ g V and 800 ⁇ g 2, 5 ⁇ g V and 900 ⁇ g 2, 5 ⁇ g V and 1000 ⁇ g 2, 10 ⁇ g V and 25 ⁇ g 2, 10 ⁇ g V and 50 ⁇ g 2, 10 ⁇ g V and 100 ⁇ g 2, 10 ⁇ g V and 200 ⁇ g 2, 10 ⁇ g V and 300 ⁇ g 2, 10 ⁇ g and 400 ⁇ g 2, 10 ⁇ g and 500 ⁇ g 2, 10 ⁇ g and 600 ⁇ g 2, 10 ⁇ g and 700 ⁇ g 2, 10 ⁇ g and 800 ⁇ g 2, 10 ⁇ g r and 900 ⁇ g 2, 10 ⁇ g V and 10OO ⁇ g 2, 18 ⁇ g V and 25 ⁇ g 2, 18 ⁇ g V and 50 ⁇ g 2, 18 ⁇ g
  • the active compound combination in which 1 is tiotropium bromide corresponds.
  • the amounts of V and 2 applied per single dose given above as examples and the following amounts of 1 and 2 applied per single dose: 6 ⁇ g 1 and 25 ⁇ g 2, 6 ⁇ g 1 and 50 ⁇ g 2, 6 ⁇ g 1 and 100 ⁇ g 2, 6 ⁇ g 1 and 200 ⁇ g 2, 6 ⁇ g 1 and 300 ⁇ g 2, 6 ⁇ g 1 and 400 ⁇ g 2, 6 ⁇ g 1 and 500 ⁇ g 2, 6 ⁇ g 1 and 600 ⁇ g 2, 6 ⁇ g 1 and 700 ⁇ g 2, 6 ⁇ g 1 and 800 ⁇ g 2, 6 ⁇ g 1 and 900 ⁇ g 2, 6 ⁇ g 1 and 1000 ⁇ g 2, 12 ⁇ g 1 and 25 ⁇ g 2 , 12 ⁇ g 1 and 50 ⁇ g 2, 12 ⁇ g 1 and 100 ⁇ g 2, 12 ⁇ g 1 and 200 ⁇ g 2, 12 ⁇ g 1 and 300 ⁇ g 2, 12 ⁇ g 1 and 400 ⁇ g 2, 12 ⁇ g 1 and 500 ⁇ g 2, 12 ⁇ g 1 and 600 ⁇ g 2, 12 ⁇ g 1 and 700 ⁇ g 2, 12 ⁇ g 1 and 700 ⁇ g 2,
  • the amounts of active ingredients of V and 2 applied per single administration given above correspond to the following amounts of 1 and 2 applied per single administration: 6.2 ⁇ g ⁇ and 25 ⁇ g 2 , 6.2 ⁇ g and 50 ⁇ g 2, 6.2 ⁇ g and 100 ⁇ g 2, 6.2 ⁇ g 1 and 200 ⁇ g 2, 6.2 ⁇ g 1 and SOO ⁇ g 2, 6.2 ⁇ g 1 and 400 ⁇ g 2, 6.2 ⁇ g 1 and 500 ⁇ g 2, 6.2 ⁇ g 1 and 600 ⁇ g 2, 6.2 ⁇ g 1 and 700 ⁇ g 2, 6.2 ⁇ g 1 and 800 ⁇ g 2, 6.2 ⁇ g 1 and 900 ⁇ g 2, 6.2 ⁇ g 1 and 1000 ⁇ g 2, 12.5 ⁇ g I and 25 ⁇ g 2, 12.5 ⁇ g 1 and 50 ⁇ g 2, 12.5 ⁇ g 1 and 100 ⁇ g 2, 12.5 ⁇ g 1 and 200 ⁇ g 2, 12.5 ⁇ g 1 and 300 ⁇ g ' 2, 12.5 ⁇ g 1 and 400 ⁇ g 2, 12.5 ⁇
  • the active compound combinations according to the invention from 1 and 2 are preferably administered by inhalation.
  • components 1 and 2 must be provided in inhalable dosage forms.
  • Inhalable dosage forms include inhalable powders, metered-dose aerosols containing propellants or propellant-free inhalation solutions.
  • Inhalation powders according to the invention containing the active ingredient combination of i and 2 can consist solely of the active ingredients mentioned or of a mixture of the active ingredients mentioned with physiologically compatible auxiliaries.
  • propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions.
  • the dosage forms according to the invention can contain the active ingredient combination of ⁇ and 2 either together in one or in two separate dosage forms. These dosage forms which can be used in the context of the present invention are described in detail in the following part of the description.
  • the inhalable powders according to the invention can contain ⁇ and 2 either alone or in a mixture with suitable physiologically acceptable auxiliaries.
  • the active ingredients ⁇ and 2 are contained in a mixture with physiologically acceptable auxiliaries
  • the following physiologically acceptable auxiliaries can be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo- and Polysaccharides (e.g. dextrans),
  • Polyalcohols eg sorbitol, mannitol, xylitol
  • salts eg sodium chloride, Ca. Lciumcarbonat
  • Mono- or disaccharides are preferably used, the use of lactose or glucose being preferred, particularly but not exclusively in the form of their hydrates. Lactose, most preferably lactose monohydrate, is used as an auxiliary as particularly preferred in the sense of the invention.
  • the auxiliaries have a maximum average particle size of up to 250 ⁇ m, preferably between 10 and 150 ⁇ m, particularly preferably between 15 and 80 ⁇ m. If appropriate, it may appear sensible to add finer excipient fractions with an average particle size of 1 to 9 ⁇ m to the excipients mentioned above. The latter finer excipients are also selected from the group of excipients that can be used.
  • micronized active ingredients i and 2 preferably having an average particle size of 0.5 to 10 ⁇ m, particularly preferably 1 to 6 ⁇ m, are admixed with the excipient mixture.
  • inhalable powders according to the invention 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 provided and applied either in the form of a single powder mixture which contains both 1 and 2 or in the form of separate inhalable powders which contain only ⁇ _ and 2.
  • the inhalable powders according to the invention can be applied using inhalers known from the prior art.
  • Inhalation powders according to the invention which in addition to and 2 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 DE 36 25 685 A are described, meter.
  • the inhalable powders according to the invention which contain, in addition to ⁇ and 2 physiologically acceptable excipients, are preferably filled into capsules (for what are known as inhalers), which are used in inhalers as described, for example, in WO 94 / 2895 ⁇ .
  • FIG. 1 A particularly preferred inhaler can be seen in FIG. 1.
  • This inhaler for inhaling 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 fastened 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 connected to the housing 1, the deck 3 and a cap 11 via an axis 10.
  • 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 either together or in each case the doses per single dose already mentioned above for V and 2.
  • Inhalation aerosols containing propellant gas according to the invention can contain 1 and 2 dissolved in the propellant gas or in dispersed form.
  • 1 and 2 can be contained in separate dosage forms or in a common dosage form, and and 2 can either be both dissolved, both dispersed or only one component dissolved and the other dispersed.
  • the propellant gases which can be used to produce the inhalation aerosols according to the invention 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 chlorinated and / or 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 propellant gases are halogenated alkane derivatives selected from the group consisting of TG11, TG12, TG134a and TG227.
  • TG 134a 1, 1, 2-tetrafluoroethane
  • TG227 1, 1,2,3,3,3-heptafluoropropane
  • the inhalation aerosols containing propellant gas according to the invention can furthermore 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 inhalation aerosols containing propellant gas according to the invention can contain up to 5% by weight of active ingredient 1 and / or 2. Aerosols 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, 0.1 to 2% by weight, 0.5 to 2% by weight or 0.5 to 1 % By weight of active ingredient 1 and / or 2.
  • 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.
  • MDIs metered dose inhalers
  • a further aspect of the present invention relates to medicaments in the form of propellant-containing aerosols as described above in connection with one or more inhalers suitable for the administration of these aerosols.
  • the present invention further relates to inhalers, characterized in that they contain propellant-containing aerosols according to the invention described above.
  • the present invention further relates to cartridges which can be used 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.
  • the active compound combination according to the invention is particularly preferably 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 volume percent, in particular up to 60 volume percent and particularly preferably up to 30 volume percent.
  • the remaining volume percentages are filled up with water.
  • Solutions and suspensions containing 2 and 2, separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. Acids selected from inorganic or organic acids can be used to adjust this pH.
  • Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
  • Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others.
  • Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active ingredients. Ascorbic acid, fumaric acid and citric acid are preferred among the organic acids.
  • mixtures of the acids mentioned can also be used, in particular in cases of acids which, in addition to their acidifying properties, also have other properties, e.g. as flavors, antioxidants or complexing agents, such as citric acid or ascorbic acid.
  • 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 in the present formulation.
  • Other embodiments include this connection (s).
  • the content based on sodium edetate is less than 100 mg / 100 ml, preferably less than 50 mg / 100 ml, particularly preferably less than 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 further auxiliaries can be added to the propellant-free inhalation solutions according to the invention.
  • 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.
  • auxiliary substances and additives are understood to mean any pharmacologically acceptable substance which is not an active substance, but which 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 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 art.
  • the additives also include pharmacologically acceptable salts such as, for example, sodium chloride as isotonic agents.
  • the preferred auxiliaries include antioxidants, such as, for example, ascorbic acid, unless already used for adjusting the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human organism.
  • Preservatives can be used to protect the formulation from contamination with germs. Suitable preservatives are those known from the prior art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
  • the above-mentioned preservatives are preferably contained in concentrations of up to 50 mg / 100 ml, particularly preferably between 5 and 20 mg / 100 ml.
  • preferred formulations only contain benzalkonium chloride and sodium edetate.
  • sodium edetate is dispensed with.
  • nebulizers are preferred in which an amount of less than 100 ⁇ L, preferably less than 50 ⁇ L, particularly preferably between 20 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 so that the inhalable portion of the aerosol already corresponds to the therapeutically effective amount.
  • Such a device for the 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 91/14463 and also in WO 97 / 126 ⁇ 7 (there in particular FIGS. 6a and 6b).
  • the nebulizers described there are also known under the name Respimat ® .
  • This nebuliser may be advantageous to produce the inhalable aerosols according to the invention containing the combination of active substances and are used. 2 Because of its cylinder-like shape and. With 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 produced.
  • the preferred atomizer consists of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a storage container, 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 nozzle arrangement carries, a hollow piston with valve body, an output flange in which the hollow piston is fastened, and which is in the
  • Upper housing part is - a locking mechanism, which is located in the upper housing part, a spring housing with the spring therein, which is rotatably mounted on the upper housing part by means of a rotary bearing, a lower housing part which is attached to the spring housing in the axial direction.
  • 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.
  • 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, i.e. made by microtechnology.
  • Microstructured nozzle bodies are disclosed, for example, in WO-94/07607; reference is hereby made to this document, in particular to FIG. 1 and its description disclosed therein.
  • 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.
  • On the nozzle outlet side there is at least one round or non-round opening 2 to 10 micrometers deep and 5 to 15 micrometers wide, the depth preferably being 4.5 to 6.5 micrometers and the length being 7 to 9 micrometers.
  • 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 with 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 particles 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 via a force-transmitting gear, e.g. a screw-type thrust gear, tensioned by an external torque which is generated when the upper housing part is turned against the spring housing in the lower housing part.
  • the upper part of the housing 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, preferably into the atomizer; the deformable ring is deformed in the ring plane. Constructive 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, for example 180 degrees.
  • the driven part in the upper part of the housing is shifted by a predetermined distance, the hollow piston is inside the cylinder in the pump housing withdrawn, whereby a portion 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 components of the atomizer are made of a material that is suitable for their function.
  • the housing of the atomizer and - as far as the function allows - other parts are preferably made of plastic, e.g. manufactured by injection molding. Physiologically harmless materials are used for medical purposes.
  • Figures 2a / b attached to this patent application which are identical to Figures 6a / b of WO 97/12687, describe the nebulizer (Respimat®) with which the aqueous aerosol preparations according to the invention can advantageously be inhaled.
  • Respimat® nebulizer
  • Figure 2a shows a longitudinal section through the atomizer with the spring under tension
  • Figure 2b shows a longitudinal section through the atomizer with the spring relaxed.
  • the upper housing part (51) contains the pump housing (52), at the ' end of which the holder (53) for the atomizing nozzle is attached.
  • the nozzle body (54) and a filter (55) are located in the holder.
  • the hollow piston (57) fastened in the output flange (56) of the locking tensioning mechanism partially protrudes into the cylinder of the pump housing.
  • the hollow piston carries the valve body (58) at its end.
  • the hollow piston is sealed by means of the seal (59).
  • Inside the upper part of the housing is the stop (60), against which the output flange rests when the spring is relaxed.
  • the stop (61) is located on the output flange, against which the output flange rests when the spring is tensioned.
  • the release button (64) is connected to the locking member.
  • the upper housing part ends in the mouthpiece (65) and is closed with the clip-on protective cap (66).
  • the spring housing (67) with compression spring (68) is rotatably mounted on the upper part of the housing by means of the snap lugs (69) and rotary bearings.
  • the lower housing part (70) is pushed over the spring housing.
  • the replaceable reservoir (71) for the fluid (72) to be atomized is located within the spring housing.
  • the storage container is closed with the stopper (73) through which the hollow piston protrudes into the storage container and with its end is immersed in the fluid (supply of active substance solution).
  • the spindle (74) for the mechanical counter is mounted in the outer surface of the spring housing.
  • the drive pinion (75) is located at the end of the spindle which faces the upper housing part.
  • the rider (76) sits on the spindle.
  • the nebuliser described above is suitable for nebulizing the aerosol preparations according to the invention into an aerosol suitable for inhalation.
  • the mass expelled in at least 97%, preferably at least 93% of all actuations of the inhaler (spray) a defined quantity with a tolerance of not more than 25%, preferably 20% of these Amount. Between 5 and 30 mg of formulation as defined are preferred per stroke. Mass applied, particularly preferably between 5 and .20 mg ..
  • formulation according to the invention can also be nebulized using inhalers other than those described above, for example jet stream inhalers.
  • a further aspect of the present invention relates to medicaments in the form of such as the above-described propellant-free - inhalable solutions or suspensions in combination with a suitable device for administering these formulations, preferably in conjunction with the Respimat ®.
  • a suitable device for administering these formulations preferably in conjunction with the Respimat ®.
  • the present invention to propellant-free inhalable solutions or suspensions characterized by the aims of the invention combination of active substances 1 and 2 in connection with the known under the name Respimat ® device.
  • the present concerns Invention above-mentioned devices for inhalation, preferably the Respimat ®, characterized in that they contain the above-described erfindu ⁇ gswashe propellant-free inhalable solutions or suspensions.
  • propellant-free inhalation solutions or suspensions according to the invention can, in addition to the solutions and suspensions intended for application in the Respimat, also be present as concentrates or sterile, ready-to-use inhalation solutions or suspensions. Ready-to-use formulations can be generated from the concentrates, for example, by adding isotonic saline solutions. Sterile ready to use
  • Formulations can be applied by means of energy-operated standing or portable nebulisers, which generate inhalable aerosols using ultrasound or compressed air according to the Venturi principle or other principles.
  • a further aspect of the present invention relates to medicaments 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 combination with a device suitable for administering these solutions, characterized in that this device is an energy-operated standing or portable nebulizer that generates inhalable aerosols using ultrasound or compressed air according to the Venturi principle or other principles.
  • Crystalline tiotropium bromide monohydrate can also be used to produce the inhalable powders according to the invention.
  • This crystalline tiotropium bromide monohydrate can be obtained according to the procedure described below. 15.0 kg of tiotropium bromide are introduced into 25.7 kg of water in a suitable reaction vessel. The mixture is heated to S0-90 ° C and stirred at a constant temperature until a clear solution is formed. Activated carbon (0, ⁇ kg), moist with water, is slurried in 4.4 kg of water, this mixture is added to the solution containing tiotropium bromide and rinsed with 4.3 kg of water. The mixture thus obtained is stirred for at least 15 min at ⁇ 0-90 ° C.
  • the crystalline tiotropium bromide monohydrate thus obtained is micronized by known methods to provide the active ingredient in the form of the average particle size which corresponds to the specifications according to the invention.
  • Toluene is mixed with a catalytic amount of p-toluenesulfonic acid and boiled under reflux on a water separator until the calculated amount of water has separated. Then the toluene is distilled off, the residue becomes
  • Formaldehyde solution are added and the mixture is stirred at about 90-100 ° C. for two hours.
  • the mixture is allowed to cool, 37 ml of formic acid and 11 ml of formaldehyde solution are added, and the mixture is stirred for another hour at about 100-110 ° C.
  • the mixture is allowed to cool, 150 ml of methanol are added, the mixture is made alkaline with about 270 ml of 32% sodium hydroxide solution while cooling, and the mixture is stirred for a further 30 minutes at 40-50 ° C. and the methanol is then distilled off.
  • the residue is shaken out twice with 100 ml of methylene chloride, the combined methylene chloride phases are dried, filtered and the solvent is removed in vacuo.
  • Methanol 8 2 are chromatographed over 150 g of silica gel. The fractions which are uniform in the TLC are combined and the solvent is removed in vacuo. 7.3 g of 1-benzyl-4- (1, 3-dihydroxyprop-2-ylamino) piperidine are obtained.
  • Triethylamine added. The mixture is boiled under reflux for 16 hours, then the solvent is removed in vacuo and the residue is taken up in 10% sodium hydrogen carbonate solution. It is extracted with ether, the combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pulmonology (AREA)
  • Otolaryngology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne de nouvelles compositions médicamenteuses à base d'anticholinergiques et d'antagonistes de récepteurs NK1, leur procédé de production et leur utilisation dans le cadre du traitement de maladies des voies respiratoires.
PCT/EP2002/001987 2001-02-23 2002-02-26 Nouvelles compositions medicamenteuses a base d'anticholinergiques et d'antagonistes de recepteurs nk1 WO2002069944A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
MXPA03008051A MXPA03008051A (es) 2001-03-08 2002-02-22 Nuevas composiciones farmaceuticas a base de anticolinergicos y/o antagonistas del receptor nk1.
EP02719915A EP1370293A2 (fr) 2001-03-08 2002-02-26 Nouvelles compositions medicamenteuses a base d'anticholinergiques et d'antagonistes de recepteurs nk1
JP2002569121A JP2004519484A (ja) 2001-03-08 2002-02-26 抗コリン作動薬およびｎｋ１−レセプタアンタゴニストに基づく新規医薬組成物
CA002439915A CA2439915A1 (fr) 2001-03-08 2002-02-26 Nouvelles compositions pharmaceutiques a base d'anticholinergiques et d'antagonistes de recepteurs nk1
AU2002251010A AU2002251010A1 (en) 2001-03-08 2002-02-26 Novel medicament compositions based on anticholinergics and on nk1 receptor antagonists
AU2006202723A AU2006202723B2 (en) 2001-02-23 2006-06-26 Novel genes encoding novel proteolytic enzymes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10111058A DE10111058A1 (de) 2001-03-08 2001-03-08 Neue Arzneimittelkompositionen auf der Basis von Anticholinergika und NK¶1¶-Rezeptor-Antagonisten
DE10111058.8 2001-03-08

Publications (2)

Publication Number Publication Date
WO2002069944A2 true WO2002069944A2 (fr) 2002-09-12
WO2002069944A3 WO2002069944A3 (fr) 2003-10-02

Family

ID=7676673

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/001987 WO2002069944A2 (fr) 2001-02-23 2002-02-26 Nouvelles compositions medicamenteuses a base d'anticholinergiques et d'antagonistes de recepteurs nk1

Country Status (7)

Country Link
EP (1) EP1370293A2 (fr)
JP (1) JP2004519484A (fr)
AU (1) AU2002251010A1 (fr)
CA (1) CA2439915A1 (fr)
DE (1) DE10111058A1 (fr)
MX (1) MXPA03008051A (fr)
WO (1) WO2002069944A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003082244A2 (fr) * 2002-03-28 2003-10-09 Boehringer Ingelheim Pharma Gmbh & Co. Kg Formulations de suspensions d'un anhydrate contenant un gaz propulseur hfa
WO2004004724A1 (fr) * 2002-07-09 2004-01-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles compositions medicamenteuses a base de nouveaux anticholinergiques et antagonistes du recepteur nk1
WO2005004875A1 (fr) * 2003-07-14 2005-01-20 Sankyo Company, Limited Composition medicinale a administration pulmonaire
JP2006160639A (ja) * 2004-12-06 2006-06-22 Sankyo Co Ltd ニューロキニン受容体拮抗剤と抗コリン剤の併用
US7244415B2 (en) 2002-03-28 2007-07-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg HFA suspension formulations of an anhydrate

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITRM20120331A1 (it) * 2012-07-12 2014-01-13 Guidotti & C Spa Labor Composizioni pediatriche orali liquide contenenti nepadutant.
WO2015111627A1 (fr) * 2014-01-21 2015-07-30 味の素株式会社 Acide aminé de sucre et application associée

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0581167A1 (fr) * 1992-07-27 1994-02-02 Kyorin Pharmaceutical Co., Ltd. Dérivés de arylglycinamide, leur procédé de préparation et leur usage pour le traitement de la dysurie
US5545617A (en) * 1993-11-12 1996-08-13 The Schepens Eye Research Institute, Inc. Therapeutic regulation of abnormal conjunctival goblet cell mucous secretion
WO1997032865A1 (fr) * 1996-03-06 1997-09-12 Boehringer Ingelheim Pharma Kg Nouveaux derives d'arylglycinamide, leur procede de fabrication et compositions pharmaceutiques contenant ces composes
WO1999064010A1 (fr) * 1998-06-11 1999-12-16 Merck Sharp & Dohme Limited Utilisation d'un antagoniste du recepteur nk-1 dans le traitement des troubles psychiatriques
US6124319A (en) * 1997-01-21 2000-09-26 Merck & Co., Inc. 3,3-disubstituted piperidines as modulators of chemokine receptor activity

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0581167A1 (fr) * 1992-07-27 1994-02-02 Kyorin Pharmaceutical Co., Ltd. Dérivés de arylglycinamide, leur procédé de préparation et leur usage pour le traitement de la dysurie
US5545617A (en) * 1993-11-12 1996-08-13 The Schepens Eye Research Institute, Inc. Therapeutic regulation of abnormal conjunctival goblet cell mucous secretion
WO1997032865A1 (fr) * 1996-03-06 1997-09-12 Boehringer Ingelheim Pharma Kg Nouveaux derives d'arylglycinamide, leur procede de fabrication et compositions pharmaceutiques contenant ces composes
US6124319A (en) * 1997-01-21 2000-09-26 Merck & Co., Inc. 3,3-disubstituted piperidines as modulators of chemokine receptor activity
WO1999064010A1 (fr) * 1998-06-11 1999-12-16 Merck Sharp & Dohme Limited Utilisation d'un antagoniste du recepteur nk-1 dans le traitement des troubles psychiatriques

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003082244A2 (fr) * 2002-03-28 2003-10-09 Boehringer Ingelheim Pharma Gmbh & Co. Kg Formulations de suspensions d'un anhydrate contenant un gaz propulseur hfa
WO2003082244A3 (fr) * 2002-03-28 2004-02-05 Boehringer Ingelheim Pharma Formulations de suspensions d'un anhydrate contenant un gaz propulseur hfa
EA008610B1 (ru) * 2002-03-28 2007-06-29 Бёрингер Ингельхайм Фарма Гмбх Унд Ко. Кг Суспензионные препараты на основе кристаллического ангидрата тиотропийбромида
US7244415B2 (en) 2002-03-28 2007-07-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg HFA suspension formulations of an anhydrate
WO2004004724A1 (fr) * 2002-07-09 2004-01-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles compositions medicamenteuses a base de nouveaux anticholinergiques et antagonistes du recepteur nk1
WO2005004875A1 (fr) * 2003-07-14 2005-01-20 Sankyo Company, Limited Composition medicinale a administration pulmonaire
JP2006160639A (ja) * 2004-12-06 2006-06-22 Sankyo Co Ltd ニューロキニン受容体拮抗剤と抗コリン剤の併用

Also Published As

Publication number Publication date
MXPA03008051A (es) 2003-12-04
DE10111058A1 (de) 2002-09-12
AU2002251010A1 (en) 2002-09-19
EP1370293A2 (fr) 2003-12-17
CA2439915A1 (fr) 2002-09-12
JP2004519484A (ja) 2004-07-02
WO2002069944A3 (fr) 2003-10-02

Similar Documents

Publication Publication Date Title
EP1372649B1 (fr) Nouvelles preparations de medicaments a base d'anticholinergiques et d'inhibiteurs pde-iv
EP2105143B1 (fr) Compositions pharmaceutiques basées sur des séls de tiotropium et ceclesonide
EP1497289B1 (fr) Medicament contenant des betamimetiques et un nouvel anticholinergique
WO2002038154A1 (fr) Nouvelles compositions de medicaments a base de sels de tiotropium et de sels de salmeterol
EP1385519A2 (fr) Composes destines au traitement de maladies inflammatoires
EP1357975A1 (fr) Compositions medicamenteuses contenant des betamimetiques et ayant des effets secondaires limites
EP1732553A1 (fr) Composes pour traiter des processus de proliferation
WO2002036106A2 (fr) Nouvelle composition medicamenteuse a base d'anticholinergiques et de corticosteroides
WO2003087049A2 (fr) Combinaisons de produits pharmaceutiques contenant des composes heterocycliques et un nouvel anticholinergique
WO2003066044A1 (fr) Nouvelles compositions de medicaments contenant, outre des anticholinergiques, des composes heterocycliques
EP1496902B1 (fr) Medicament contenant des steroides et un nouvel anticholinergique
WO2002069944A2 (fr) Nouvelles compositions medicamenteuses a base d'anticholinergiques et d'antagonistes de recepteurs nk1
EP1478398B1 (fr) Nouvelles compositions de m dicaments base d'anticholinergiques et d'inhibiteurs de kinase egfr
WO2002060533A2 (fr) Compositions medicamenteuses a faibles effets secondaires
EP1341538B1 (fr) Compositions des medicaments avec des sels du tiotropium et epinastin pour la therapie des maladies respiratoires
DE10230769A1 (de) Neue Arzneimittelkompositionen auf der Basis neuer Anticholinergika und PDE-IV-Inhibitoren
EP1379225B1 (fr) Nouvelles compositions medicamenteuses a base d'anticholinergiques et d'antagonistes de l'endotheline
EP1586574A1 (fr) Médicament contenant des betamimetiques et un nouvel anticholinergique
EP1521580A1 (fr) Nouvelles compositions medicamenteuses a base de nouveaux anticholinergiques et antagonistes du recepteur nk1
WO2004050093A1 (fr) Preparation medicamenteuse a inhaler contenant du tiotropium
EP1345626A2 (fr) Nouvelles compositions medicamenteuses a base d'anticholinergiques et d'agonistes de la dopamine

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2002719915

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2439915

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2003/008051

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2002569121

Country of ref document: JP

WWP Wipo information: published in national office

Ref document number: 2002719915

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642