EP1546147A1 - Derives d'indazole pontes par morpholine - Google Patents

Derives d'indazole pontes par morpholine

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Publication number
EP1546147A1
EP1546147A1 EP03757849A EP03757849A EP1546147A1 EP 1546147 A1 EP1546147 A1 EP 1546147A1 EP 03757849 A EP03757849 A EP 03757849A EP 03757849 A EP03757849 A EP 03757849A EP 1546147 A1 EP1546147 A1 EP 1546147A1
Authority
EP
European Patent Office
Prior art keywords
compounds
formula
salts
solvates
treatment
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Withdrawn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
EP03757849A
Other languages
German (de)
English (en)
Inventor
Achim Feurer
Joachim Luithle
Stephan-Nicholas Wirtz
Gerhard König
Johannes-Peter Stasch
Frank Wunder
Dieter Lang
Elke Stahl
Thomas Schenke
Rudy Schreiber
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.)
Bayer AG
Original Assignee
Bayer Healthcare AG
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 Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1546147A1 publication Critical patent/EP1546147A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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 morpholine-bridged indazole derivatives which stimulate soluble guanylate cyclase, to processes for their production and to their use for the production of medicaments, in particular medicaments for the treatment of diseases of the central nervous system.
  • Cyclic guanosine monophosphate is one of the most important cellular signal transmission systems in mammalian cells. Together with nitrogen monoxide ( ⁇ O), which is released from the endothelium and transmits hormonal and mechanical signals, it forms the ⁇ O / cGMP system.
  • the guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triposphate (GTP).
  • GTP guanosine triposphate
  • the previously known representatives of this family can be divided into two groups according to structural features and the type of ligands: the particulate guanylate cyclases that can be stimulated by natriuretic peptides and the soluble guanylate cyclases that can be stimulated by ⁇ O.
  • the soluble guanylate cyclases consist of two subunits and contain at least one heme per heterodimer.
  • the heme groups are part of the regulatory center and are of central importance for the activation mechanism.
  • ⁇ O can be bound to the iron atom of the urine and thus significantly increase the activity of the enzyme.
  • Hem-free preparations cannot be stimulated by ⁇ O.
  • CO can also be bound to the iron central atom of heme, whereby the stimulation by CO is significantly less than that by ⁇ O.
  • guanylate cyclase plays a decisive role in different physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion and neuronal signal transmission as well as in diseases which are based on a disturbance of the above-mentioned processes. Under patho- the NO / cGMP system can be suppressed under physiological conditions. In Alzheimer's patients, for example, the NO-stimulated activity of soluble guanylate cyclase in the brain (cortex cerebralis) is greatly reduced.
  • a NO-independent treatment option aimed at influencing the cGMP signal pathway in organisms is a promising approach for the stimulation of soluble guanylate cyclase due to the expected high efficiency and few side effects.
  • Such compounds have a very high in vitro activity with regard to the stimulation of soluble guanylate cyclase.
  • these compounds have some in terms of their in vivo properties, such as, for example, their behavior in the liver, their pharmacokinetic behavior, their dose-response relationship and their metabolic pathway
  • the present invention relates to the compounds of the formula
  • n 1 or 2
  • R is hydrogen or NH 2
  • the compounds (I) according to the invention contain asymmetric carbon atoms, they can be present as enantiomers, diastereomers or mixtures thereof. These mixtures can be separated into the stereoisomerically uniform constituents in a known manner.
  • preferred salts are physiologically acceptable salts of the compounds according to the invention.
  • Acid addition salts of the compounds with mineral acids, carboxylic acids or sulfonic acids for example, particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or
  • Physiologically acceptable salts can also be salts with conventional bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine , Dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1-ephenamine or methylpiperidine.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example calcium or magnesium salts
  • ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine , Dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1-e
  • Solvates of the compounds according to the invention are stoichiometric compositions of the compounds or their salts with solvents, e.g. Water, ethanol.
  • Halogen stands for fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred, particularly preferably fluorine and chlorine.
  • R 2 is hydrogen or NH 2
  • R 2 is hydrogen
  • the compounds of the formula (I) according to the invention can be prepared by reacting the compound of the formula
  • R has the meanings given above and Alk is C 1 -C 4 -alkyl
  • R 1 has the meanings given above and R 3 represents halogen, and a final reaction with aqueous ammonia solution under heating and elevated pressure and by the resulting compounds of formula (I) optionally with the corresponding (i) solvents and / or (ii) bases or acids to their solvates, salts and / or solvates Salts implemented.
  • the compound of formula (II) can be prepared according to the following reaction scheme:
  • the compound of the formula (II) is in a two-stage synthesis from the literature-known 3-cyanindazole (Salkowski, H .; Chem.Ber .; 17; 1884; 506 and Chem.Ber .; 22; 1889; 2139) and 2-fluorobenzyl bromide obtainable in inert solvent and in the presence of a base and subsequent reaction of the nitrile derivative with sodium ethylate and final reaction with ammonium chloride.
  • TosCI 4-CH 3 -C 6 H 4 -S0 2 CI
  • the bicyclic system is built up, for example, by reacting the bis-hydroxymethyl tetra hydrofuran derivative (activated as bistosylate) with benzlyamine via a nucleophilic substitution reaction under conditions conventionally used for such reactions.
  • the reaction is preferably carried out in an organic solvent, for example a hydrocarbon, preferably an aromatic hydrocarbon and in particular toluene, using a 2-5-fold excess of the A ins preferably at normal pressure and stirring the reaction solution for several hours, for example 2 hours , at elevated temperature, for example 60-130 ° C, preferably 80-120 ° C, in particular 100 ° C.
  • the bicyclic system is built up, for example, by an intramolecular nucleophilic substitution reaction of the two hydroxyl groups of the piperidine-2,6-dihydroxymethyl derivative, for such
  • reactions commonly used conditions. According to the invention, it is preferred to carry out the reaction under acidic conditions, for example in the presence of concentrated sulfuric acid, preferably under normal pressure and stirring the reaction solution for several hours, for example 24 hours, at elevated temperature, for example 60-200 ° C., preferably 80-190 ° C. especially 175 ° C.
  • the piperidine-2,6-dihydroxymethyl derivative required for this can be obtained from methyl pyridine-2,6-dicarboxylic acid by hydrogenation under conditions conventionally used for such reactions, for example with hydrogen on a palladium / activated carbon catalyst, to give the corresponding piperidine-2,6-dicarbonate.
  • the bicyclic system thus obtained can in each case with elimination of the benzylic protective group under conditions conventionally used for such reactions, for example with hydrogen over a palladium / activated carbon catalyst in an organic solvent, for example an alcohol, preferably ethanol, preferably under elevated pressure of 50-200 bar, preferably 100 bar, and stirring the reaction solution for several hours, for example 5 hours, at elevated temperature, for example 60-130 ° C., preferably 80-120 ° C., in particular 100 ° C., into the corresponding bicyclic amines.
  • organic solvent for example an alcohol, preferably ethanol, preferably under elevated pressure of 50-200 bar, preferably 100 bar
  • stirring the reaction solution for several hours, for example 5 hours, at elevated temperature, for example 60-130 ° C., preferably 80-120 ° C., in particular 100 ° C., into the corresponding bicyclic amines.
  • suitable acetonitrile derivatives for example with haloacetonitriles and preferably with bromoaceton
  • Reactions of conventionally used conditions for example in an organic solvent such as N, N-dimethylformamide (DMF), using a slight excess of the acetonitrile derivative in the presence of a base, for example an amine such as N, N-diisopropylethylamine, and a halide such as sodium iodide, preferably at normal pressure and stirring the reaction solution for several hours, for example 24 hours, at elevated temperature, for example 40-130 ° C., preferably 40-100 ° C., in particular 60 ° C., to the corresponding N-methyl nitrile derivatives.
  • a base for example an amine such as N, N-diisopropylethylamine
  • a halide such as sodium iodide
  • the compounds of the formula (III) can finally be reacted with a formic acid ester such as, for example, ethyl formate under conditions conventionally used for such reactions, for example in an organic solvent.
  • a formic acid ester such as, for example, ethyl formate
  • an organic solvent for example an ether, preferably a cyclic ether such as tetrahydrofuran (THF), using a 2-5-fold excess of formic acid ester, preferably at normal pressure and stirring the reaction solution for several minutes, for example 20-60 minutes, at room temperature, and subsequent acetylation with acetic anhydride in the presence of acetic acid under for such
  • Reactions conventionally used conditions, for example using a slight excess of acetic anhydride, preferably under normal pressure and stirring the reaction solution for several minutes, for example 20-60 minutes.
  • reaction of the compounds of the formulas (II) and (III) to the compounds of the formula (I) can be carried out in an organic solvent, for example by using the reactants in equimolar amounts or using the compound of the formula (III) in a slight excess a hydrocarbon, preferably an aromatic hydrocarbon and in particular
  • Toluene preferably at normal pressure and stirring the reaction solution for several hours, for example 12 hours, at elevated temperature, for example 80-160 ° C., preferably 100-150 ° C., in particular 120 ° C.
  • the compounds of formula (IV) are commercially available (e.g. from Mercachem) or can be prepared in a manner known to those skilled in the art.
  • reaction of the compounds of the formulas (II) and (IV) to the compounds of the formula (V) can be carried out in a slight excess in an organic solvent by using the reactants in equimolar amounts or using the compound of the formula (IV) , for example a hydrocarbon, preferably an aromatic hydrocarbon and in particular toluene, preferably at normal pressure and stirring the reaction solution for several hours, for example 12 hours, at elevated temperature, for example 80-160 ° C, preferably 100-150 ° C, in particular 140 ° C , be performed.
  • a hydrocarbon preferably an aromatic hydrocarbon and in particular toluene
  • reaction of the compounds of the formula (V) to compounds of the formula (VI) can be carried out by reacting the compounds of the formula (V) with a halogenating agent, if appropriate in an organic solvent such as dimethylformamide (DMF) conventionally used for such reactions, preferably at normal pressure and stirring the reaction solution for several
  • POCl 3 can preferably be used as the halogenating agent.
  • the reaction of the compounds of the formula (VI) to the compounds of the formula (I) according to the invention can be carried out by reacting the compounds of the formula (VI) with aqueous ammonia solution, preferably at elevated pressure, for example by running the reaction in an autoclave so that the reaction takes place under the The internal pressure of the reaction mixture runs, and the reaction solution is stirred for several hours, for example 12 hours, at elevated temperature, for example
  • 80-160 ° C preferably 100-150 ° C, in particular 140 ° C, are carried out.
  • the compounds according to the invention show an unforeseeable, valuable spectrum of pharmacological activity.
  • the compounds in the invention increase the cGMP levels in neurons and thus represent active substances for combating diseases in the central nervous system which are characterized by disorders of the NO / cGMP system.
  • they are suitable for improving perception, concentration performance, learning performance, or memory performance after cognitive disorders, as they occur in particular in situations / diseases / syndromes such as "mild cognitive impairment", age-associated learning and memory disorders, age-associated memory loss, vascular dementia, Traumatic brain trauma, stroke, dementia that occurs after a stroke ("post stroke dementia"), post-traumatic skull brain trauma, general concentration disorders, concentration disorders in children with learning and memory problems, Alzheimer's disease dementia with Lewy bodies, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob Dementia, HIV dementia, schizophrenia with dementia or
  • the compounds according to the invention also lead to vascular relaxation, platelet aggregation inhibition and to a reduction in blood pressure and to an increase in the coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP.
  • the compounds according to the invention can increase the action of substances which increase the cGMP level, such as EDRF (endothelium derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
  • cardiovascular diseases such as, for example, for the treatment of high blood pressure and heart failure, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, of arrhythmias, for the treatment of thromboembolic diseases and ischemia such as myocardial infarction, stroke, transistoric and Ischemic attacks, peripheral circulatory disorders, prevention of restenosis such as after thrombolysis therapies by, for example, use in stents, percutaneously transluminal angioplasties (PTA), percutaneously transluminal coronary angioplasties (PTCA), bypass operations and for the treatment of arteriosclerosis, asthmatic glaucoma, osteoparetic diseases, osteoparesis and diseases of the genitourinary system such as incontinence, prostate hypertrophy, erectile dysfunction and female sexual dysfunction.
  • PTA percutaneously transluminal angioplasties
  • PTCA percutaneously transluminal coronary angioplasties
  • the compounds according to the invention are suitable for regulating cerebral blood flow and can be effective agents for combating
  • the compounds according to the invention are also suitable for the prophylaxis and control of the consequences of cerebral infarction (apoplexia cerebri) such as stroke, cerebral ischemia and cranial-brain trauma.
  • the compounds according to the invention can also be used to combat painful conditions.
  • the compounds according to the invention have an anti-inflammatory effect.
  • the invention comprises the combination of the compounds according to the invention with organic nitrates and NO donors.
  • Organic nitrates and NO donors in the context of the invention are generally substances which release NO or NO vaporizers.
  • Sodium nitroprusside, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.
  • the invention also includes combination with compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP).
  • cGMP cyclic guanosine monophosphate
  • These are in particular inhibitors of phosphodiesterases 1, 2 and 5; Nomenclature according to Beavo and Reifsnyder (1990) TiPS j_l p. 150 to 155. These inhibitors potentiate the activity of the compounds according to the invention and increase the desired pharmacological effect.
  • Rat embryos (embryonic day 17-19) are decapitated, the cerebrum is dissected and incubated for 30 min at 37 ° C with 5 mL papain solution and 250 ⁇ L DNAse (Papain kit from Cell-System), homogenized using a Pasteur pipette and 5 min at 1200
  • test buffer 100 ⁇ L / well test substance are dissolved in test buffer and then 100 ⁇ L / well IBMX (3-isobutyl-1-methylxanthine; dissolved in 50 mM ethanol, diluted with test buffer to a final concentration of 100 ⁇ M). After 20 min incubation at 37 ° C, the test buffer is filled with 200 ⁇ L / well lysis buffer (cGMP EIA
  • a concentration of 0.1 ⁇ M from Example 1 leads to a statistically significant increase in cGMP.
  • Rabbits are anesthetized and bled by the blow of the neck.
  • the aorta is removed, adherent tissue is removed, divided into 1.5 mm wide rings and individually pretensioned in 5 ml organ baths with carbohydrate containing 37 C brought gaster Krebs-Henseleit solution of the following composition (mM): NaCl: 119; KC1: 4.8; CaCl 2 x 2 H 2 O: 1; MgSO 4 x 7 H 2 O; 1.4; KH 2 PO 4 : 1.2; NaHCO3: 25; Glucose: 10.
  • the contraction force is recorded with Statham UC2 cells, amplified and digitized via AD converter (DAS-1802 HC, Keithley Instruments Munich) and recorded in parallel on a line recorder.
  • AD converter DAS-1802 HC, Keithley Instruments Munich
  • the substance to be examined is administered intravenously as a solution to rats via the tail vein. Blood is drawn from the rats at specified times, this is heparinized and plasma is obtained therefrom by conventional measures. The substance is bioanalytically quantified in plasma. The plasma concentration-time curves thus determined become conventional ones for this used non-compartmentalized methods calculated the pharmacokinetic parameters.
  • Trial 1 but handled without substance or vehicle application.
  • the test substances are applied directly after Trial 1.
  • the social memory is measured in Trial 2 after 24 hours.
  • Makrolon held. 4 minutes before testing, a box consisting of two aluminum side walls, an aluminum rear wall and a plexiglass front (63x41x40 cm) is placed over the cage and the lid of the cage is removed. A young animal is placed in the cage with the adult rats, and the social interaction (e.g. sniffing) is recorded over a period of 2 minutes using a stopwatch. After that the social interaction (e.g. sniffing) is recorded over a period of 2 minutes using a stopwatch. After that the social interaction (e.g. sniffing) is recorded over a period of 2 minutes using a stopwatch. After that the social interaction (e.g. sniffing) is recorded over a period of 2 minutes using a stopwatch. After that the social interaction (e.g. sniffing) is recorded over a period of 2 minutes using a stopwatch. After that the social interaction (e.g. sniffing) is recorded over a period of 2 minutes using a stopwatch. After that the social interaction (e.g. sniffing) is recorded over a period
  • Trial 2 The experiment is repeated after 24 h in the same way as in Trial 1 with the same animals. The difference between the social interaction time in Trial 1 and Trial 2 is taken as a measure of the social memory.
  • the compounds according to the invention are suitable for use as medicaments for humans and animals.
  • the present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, contain one or more compounds according to the invention, or which consist of one or more compounds according to the invention, and processes for the preparation of these preparations.
  • the compounds according to the invention should be present in these preparations in a concentration of 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight, of the total mixture.
  • the pharmaceutical preparations can also contain other active pharmaceutical ingredients.
  • the pharmaceutical preparations listed above can be prepared in a customary manner by known methods, for example using the excipient or excipients.
  • the new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should be in a concentration of about 0.5 to
  • the formulations can be prepared, for example, by diluting the active ingredients with solvents and / or carriers, optionally using emulsifiers and or dispersants, for example in the case of Using water as a diluent, organic solvents can optionally be used as auxiliary solvents.
  • the application can take place in the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously. But you can also by
  • Formulation and the time or interval at which the administration takes place In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.
  • Carrier gas helium
  • UV detection 210 nm.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne de nouveaux dérivés d'indazole pontés par morpholine, qui stimulent la guanylate cyclase soluble. L'invention concerne également des procédés pour leur production ainsi que leur utilisation pour produire des médicaments qui servent notamment au traitement de maladies du système nerveux central.
EP03757849A 2002-09-26 2003-09-16 Derives d'indazole pontes par morpholine Withdrawn EP1546147A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10244810A DE10244810A1 (de) 2002-09-26 2002-09-26 Neue Morpholin-überbrückte Indazolderivate
DE10244810 2002-09-26
PCT/EP2003/010273 WO2004031186A1 (fr) 2002-09-26 2003-09-16 Derives d'indazole pontes par morpholine

Publications (1)

Publication Number Publication Date
EP1546147A1 true EP1546147A1 (fr) 2005-06-29

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Country Status (7)

Country Link
US (2) US7427617B2 (fr)
EP (1) EP1546147A1 (fr)
JP (1) JP2006503854A (fr)
AU (1) AU2003273885A1 (fr)
CA (1) CA2500088A1 (fr)
DE (1) DE10244810A1 (fr)
WO (1) WO2004031186A1 (fr)

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US20090023717A1 (en) 2009-01-22
AU2003273885A1 (en) 2004-04-23
US7427617B2 (en) 2008-09-23
JP2006503854A (ja) 2006-02-02
CA2500088A1 (fr) 2004-04-15
US20060128700A1 (en) 2006-06-15
WO2004031186A1 (fr) 2004-04-15
DE10244810A1 (de) 2004-04-08

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