EP1104421A1 - 3-(4-amino-5-ethylpyrimidin-2-yl)-1-(2-fluorbenzyl)-1h-pyrazolo 3,4-b]pyridine - Google Patents

3-(4-amino-5-ethylpyrimidin-2-yl)-1-(2-fluorbenzyl)-1h-pyrazolo 3,4-b]pyridine

Info

Publication number
EP1104421A1
EP1104421A1 EP99936550A EP99936550A EP1104421A1 EP 1104421 A1 EP1104421 A1 EP 1104421A1 EP 99936550 A EP99936550 A EP 99936550A EP 99936550 A EP99936550 A EP 99936550A EP 1104421 A1 EP1104421 A1 EP 1104421A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
compound according
medicament
manufacture
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Withdrawn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
EP99936550A
Other languages
German (de)
English (en)
Inventor
Alexander Straub
Achim Feurer
Chantal FÜRSTNER
Cristina Alonso-Alija
Johannes-Peter Stasch
Elisabeth Perzborn
Joachim Hütter
Klaus Dembowsky
Elke Stahl
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 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 AG filed Critical Bayer AG
Publication of EP1104421A1 publication Critical patent/EP1104421A1/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Withdrawn legal-status Critical Current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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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 present invention relates to the 3- (4-amino-5-ethylpyrimidin-2-yl) -l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine of the formula (I),
  • the compound can be prepared by using the amidine of formula (II)
  • the reaction takes place in a temperature range from 80 ° C to 120 ° C, preferably at 100 ° C.
  • the enamine of the formula (III) can act as solvent. But you can also work in common solvents such as toluene, dioxane and alcohols.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. 0.5 to 5 bar). Generally one works at normal pressure.
  • the compound of formula (II) is new and therefore another object of the invention. It can be prepared by using the compound of formula (IV)
  • Suitable solvents for reacting the compound of the formula (IV) -> (V) are ethers, such as diethyl ether, dioxane or tetrahydrofuran and dimethylformamide; tetrahydrofuran is preferred.
  • Triethylamine or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine can be used. Pyridine is preferred.
  • the reaction takes place in a temperature range from 0 ° C to 40 ° C, preferably at room temperature.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. 0.5 to 5 bar). Generally one works at normal pressure.
  • the amide (IV) can be carried out, for example, by saponification of a corresponding ester as the starting compound with a base to give the acid, its conversion into the acid chloride by customary methods, for example using SOCl 2 or POCl 3 and subsequent reaction with ammonia.
  • TFAA Trifluoroacetic anhydride
  • the conversion of the nitrile (V) into the imino ether (VI) can be carried out in acid, e.g. with HCl / alcohol mixtures, as well as in basic such as with methanol / sodium methoxide. It is usually carried out at 0 ° C to 40 ° C, for example at room temperature.
  • Alcohols such as methanol or ethanol. Methanol is preferred.
  • the reaction takes place in a temperature range from 0 ° C to 100 ° C, preferably at room temperature.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. 0.5 to 5 bar). Generally one works at normal pressure.
  • Alcohols such as methanol or ethanol are suitable as solvents for the reaction of the compound of the formula (VI) -> (VII). Methanol is preferred.
  • the reaction takes place in a temperature range from 0 ° C to 100 ° C, preferably at 65 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. 0.5 to 5 bar). Generally one works at normal pressure.
  • Inorganic or organic bases are suitable as bases for the reaction of the compound of the formula (VII) -> (II).
  • bases include, for example, alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate. Sodium carbonate is preferred.
  • the pyrimidine is prepared by customary methods (see, for example, MG Hoffmann et al. In: Houben-Weyl, Methods of Organic Chemistry, 4th Edition, Volume E9b, Part 1, pp. 1-249; A. Weissenberger et al ., The Chemistry of heterocyclic compounds - Pyrimidines, 1962, 16; ibid 1970, 16, Suppl. 1, ibid 1985, 16, Suppl. 2; ibid 1994, 52).
  • the imino ether (VI) can also first be converted into an amidine by means of ammonia or its salts, and this either as a free base (II) or as a salt (VII), if appropriate in the presence of one React base with enamines such as (III), acetals, enol ethers, aldehydes or enolates.
  • the enamines such as (III) can e.g. from C-H-acidic compounds such as acetonitrile derivatives by known methods by reaction with
  • Dimethylformamide derivatives such as e.g. Bis (dimethylamino) tert-butoxymethane, dialkoxy-dialkylamino-methanes can be produced.
  • the compound of formula (IV) can be prepared by the compound of formula (VIII)
  • reaction of the compound of the formula (VIII) + (IX) -> (X) can also be carried out via intermediate compounds of the formulas (A) and (B),
  • the compound of formula (III) can be prepared by the compound of formula (XIII)
  • the compound of formula (I) according to the invention shows an unforeseeable, valuable pharmacological spectrum of action.
  • the compound of the formula (I) according to the invention leads 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 compound according to the invention enhances 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 the treatment of high blood pressure and heart failure, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, of arrhythmias
  • thromboembolic diseases and ischemia such as myocardial infarction, stroke, transitory and ischemic attacks
  • peripheral circulatory disorders prevention of restenoses
  • arteriosclerosis and diseases of the genitourinary system such as prostate hypertrophy, female erectile dysfunction and erectile dysfunction.
  • the compound of formula (I) described in the present invention also represents an active ingredient for combating diseases in the central nervous system which are characterized by disorders of the NO / cGMP system.
  • diseases of the central nervous system such as anxiety, tension and depression, central nervous system-related sexual dysfunctions and sleep disorders, as well as for the regulation of pathological disorders in the intake of food, luxury foods and addictive substances.
  • the active ingredient is also suitable for regulating cerebral blood flow and is therefore an effective means of fighting migraines.
  • the compound of formula (I) according to the invention can be used to combat painful conditions.
  • the compound of the formula (I) according to the invention has anti-inflammatory activity and can therefore be used as an anti-inflammatory agent.
  • the invention comprises the combination of the compound according to the invention with organic nitrates and NO donors.
  • 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 Reif-Snyder (1990) TiPS 11 pp. 150 to 155. These inhibitors potentiate the action of the compound according to the invention and increase the desired pharmacological effect.
  • the cells were incubated in stimulation buffer with or without NO donor (sodium nitroprusside, SNP or DEA / NO 1 ⁇ M) for 10 minutes at 37 ° C./5% CO 2 .
  • NO donor sodium nitroprusside, SNP or DEA / NO 1 ⁇ M
  • the test substances final concentration 1 ⁇ M
  • the buffer solution was aspirated and 4 ° C stop buffer was added to the cells.
  • the cells were then lysed at -20 ° C for 16 hours.
  • the supernatants containing the intracellular cGMP were then removed and the cGMP concentrations were determined by the cGMP-SPA system (Amersham Buchler, Braunschweig). The results are shown in Table 1 below.
  • Rabbits are anesthetized and bled by the blow of the neck.
  • the aorta is removed, adhering tissue is removed, divided into 1.5 mm wide rings and individually pretensioned in 5 ml organ baths with carbogen at 37 ° C. fumigated Krebs-Henseleit solution with 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.
  • mM fumigated Krebs-Henseleit solution with 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 A / D converter (DAS-1802 HC, Keithley Instruments Munich) and recorded in parallel on a line recorder.
  • DAS-1802 HC A / D converter
  • phenylephrine is added cumulatively to the bath in increasing concentration.
  • the substance to be examined is examined in increasing doses in each further run and the level of the contraction is compared with the level of the contraction achieved in the last previous run. From this, the concentration is calculated which is required to reduce the level of the control value by 50% (IC 50 ).
  • the standard application volume is 5 ⁇ l, the DMSO portion in the bath solution corresponds to 0.1%.
  • Table 2 The results are shown in Table 2 below.
  • the animals were housed individually in Type III cages positioned at the individual recipient stations and were on a 12 hour light / dark
  • the blood pressure of each rat was recorded every 5 minutes for 10 seconds.
  • the measuring points were combined for a period of 15 minutes and the mean value was calculated from these values.
  • test compounds were dissolved in a mixture of Transcutol (10%), Cremophor (20%), H 2 O (70%) and administered orally using a gavage in a volume of 2 ml / kg body weight.
  • the test doses were between 0.3 and 30 mg / kg body weight. Inhibition of platelet aggregation in vitro
  • Blood from healthy volunteers of both sexes was used to determine platelet aggregation. 9 parts of blood were added to one part of 3.8% sodium citrate solution as an anticoagulant. The blood was at 900
  • the cavernous arteries and the entire erectile tissue architecture which is formed from a network of smooth muscle cells and collagenous connective tissue, have to dilate maximally so that the corpus cavernosum is completely filled with blood can (Anderson K.-E. and Wagner G., "Physiology of Penile Erection.”. Physiological Reviews 75, 191-236 (1995); Meinhardt W. Kropmann RF, Vermeig P, Lycclama a Nigelholt and Zwartendijk J. "The Influence of Medication on Erectile dysfunction. "Int. J. of Impotence Res. 9, 17-26 (1997).
  • the substances according to the invention were dissolved in a mixture of Transcutol (GATTEFOSSE GmbH) diluted with 20% Cremophor (BASF) and water in a ratio of 3/7. Sodium nitroprusside was dissolved in 0.9% NaCl. The substance was injected into the ear vein at a volume of 0.5 ml / kg injected.
  • the test substance was dissolved in a mixture of glycerin: water: polyethylene glycol 6: 10: 9.69 and applied in a volume of 1 ml / kg with the gavage.
  • guanylate cyclase stimulators The action of guanylate cyclase stimulators is enhanced by NO donors.
  • the sodium nitroprusside was injected into the ear vein at a dose of 0.2 mg / kg simultaneously with the substance according to the invention. If the substance according to the invention was given orally, these animals were given sodium nitroprusside for 30 min. injected into the ear vein after oral administration. Appropriate controls with the solvent and with sodium nitroprusside alone were carried out.
  • the rabbit penis Under resting conditions, the rabbit penis is not visible in the pubic region and completely covered by the penile skin.
  • the erection is evaluated by measuring the length of the protruding penis with a caliper. The measurement will be 5, 10, 15, 30, 45, 60min. 120 and 180 min. carried out after administration of the substance. The effect is calculated as the product of the length of the penis not covered by fur in [mmjand the time that the erection lasts in [min.].
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, include the inventive
  • Compound of the formula (I) contains and process for the preparation of these preparations.
  • the active ingredient can optionally also be present in microencapsulated form in one or more of the above-mentioned carriers.
  • the therapeutically active compound should be present in the pharmaceutical preparations listed above in a concentration of approximately 0.1 to 99.5, preferably approximately 0.5 to 95% by weight of the total mixture.
  • the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.
  • the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight per 24 hours, optionally in the form multiple doses to achieve the desired results.
  • a single dose contains the active ingredient (s) according to the invention preferably in amounts of about 1 to about 80, in particular 3 to 30 mg / kg of body weight.
  • 16 g of the compound of Example 1A are pipetted into 8 g of the compound of Example 7A in a test tube.
  • the mixture is homogenized in an ultrasonic bath, evacuated and kept in an oil bath at 100 ° C with good swiveling, the vacuum still being applied. After 30 seconds, the mixture begins to bubble up slightly, the amidine dissolving. After 1 min everything is clear and the bubbling stops. The temperature is raised to 125 ° C. for 15 minutes and the reaction is allowed to continue at 100 ° C. for about 12 hours. The mixture solidifies after cooling.
  • the mixture is stirred with a little toluene, the crystals are filtered off and washed with ether.
  • the mother liquor is spun in and chromatographed on SiO 2 with toluene / ethyl acetate 1: 1.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Diabetes (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne 3-(4-amino-5-éthylpyrimidin-2-yl)-1-(2-fluorbenzyl)-1H-pyrazolo[3,4-b]pyridine de la formule (I), son procédé de préparation et son utilisation comme médicament, notamment comme médicament pour lutter contre les maladies du système cardio-vasculaire.
EP99936550A 1998-07-29 1999-07-16 3-(4-amino-5-ethylpyrimidin-2-yl)-1-(2-fluorbenzyl)-1h-pyrazolo 3,4-b]pyridine Withdrawn EP1104421A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19834045A DE19834045A1 (de) 1998-07-29 1998-07-29 (4-Amino-5-ethylpyrimidin-2-yl)-1-(2-fluorbenzyl)-1H-pyrazolo[3,4-b]pyridin
DE19834045 1998-07-29
PCT/EP1999/005071 WO2000006567A1 (fr) 1998-07-29 1999-07-16 3-(4-amino-5-ethylpyrimidin-2-yl)-1-(2-fluorbenzyl)-1h-pyrazolo[3,4-b]pyridine

Publications (1)

Publication Number Publication Date
EP1104421A1 true EP1104421A1 (fr) 2001-06-06

Family

ID=7875638

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99936550A Withdrawn EP1104421A1 (fr) 1998-07-29 1999-07-16 3-(4-amino-5-ethylpyrimidin-2-yl)-1-(2-fluorbenzyl)-1h-pyrazolo 3,4-b]pyridine

Country Status (5)

Country Link
EP (1) EP1104421A1 (fr)
JP (1) JP2002521481A (fr)
AU (1) AU5160499A (fr)
DE (1) DE19834045A1 (fr)
WO (1) WO2000006567A1 (fr)

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DE10021069A1 (de) * 2000-04-28 2001-10-31 Bayer Ag Substituiertes Pyrazolderivat
DE10057751A1 (de) 2000-11-22 2002-05-23 Bayer Ag Neue Carbamat-substituierte Pyrazolopyridinderivate
DE10057754A1 (de) * 2000-11-22 2002-05-23 Bayer Ag Neue Sulfonamid-substituierte Pyrazolopyridinderivate
WO2002042299A1 (fr) 2000-11-22 2002-05-30 Bayer Aktiengesellschaft Nouveaux derives de pyrazolopyridine substitues par lactame
AR031176A1 (es) 2000-11-22 2003-09-10 Bayer Ag Nuevos derivados de pirazolpiridina sustituidos con piridina
DE10122894A1 (de) * 2001-05-11 2002-11-14 Bayer Ag Neue Sulfonat-substituierte Pyrazolopyridinderivate
ITMI20011308A1 (it) * 2001-06-21 2002-12-21 Nicox Sa Farmaci per il dolore cronico
DE10140421A1 (de) * 2001-08-17 2003-03-06 Bayer Ag Neue Kombination
DE10220570A1 (de) 2002-05-08 2003-11-20 Bayer Ag Carbamat-substituierte Pyrazolopyridine
DE10222550A1 (de) * 2002-05-17 2003-11-27 Bayer Ag Substituierte Benzyl-pyrazolopyridine
DE10232572A1 (de) * 2002-07-18 2004-02-05 Bayer Ag Neue 2,5-disubstituierte Pyrimidinderivate
DE10232571A1 (de) 2002-07-18 2004-02-05 Bayer Ag 4-Aminosubstituierte Pyrimidinderivate
DE10244810A1 (de) * 2002-09-26 2004-04-08 Bayer Ag Neue Morpholin-überbrückte Indazolderivate
DE102006043443A1 (de) 2006-09-15 2008-03-27 Bayer Healthcare Ag Neue aza-bicyclische Verbindungen und ihre Verwendung
DE102006054757A1 (de) 2006-11-21 2008-05-29 Bayer Healthcare Ag Neue aza-bicyclische Verbindungen und ihre Verwendung
DE102007026392A1 (de) 2007-06-06 2008-12-11 Bayer Healthcare Ag Lösungen für die Perfusion und Konservierung von Organen und Geweben
DE102007028320A1 (de) 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
DE102007028406A1 (de) 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
DE102007028407A1 (de) 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
DE102007028319A1 (de) 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
EP2138178A1 (fr) 2008-06-28 2009-12-30 Bayer Schering Pharma Aktiengesellschaft Oxazolidinones pour le traitement de maladie pulmonaire obstructive chronique (MPOC) et/ou de l'asthme
DE102008063992A1 (de) 2008-12-19 2010-09-02 Lerner, Zinoviy, Dipl.-Ing. Neue aliphatisch substituierte Pyrazolopyridine und ihre Verwendung
UY33041A (es) 2009-11-27 2011-06-30 Bayer Schering Pharma Aktienegesellschaft Procedimiento para la preparaciòn de {4,6-diamino-2-[1-(2-fluorobencil)-1h-pirazolo[3,4-b]piridin-3-il]pirimidin-5-il}carbamato de metilo y su purificaciòn para el uso como principio activo farmacèutico
PT2504334E (pt) 2009-11-27 2014-12-03 Bayer Ip Gmbh Processo para a purificação de metil-{4,6-diamino-2-[1-(2- fluorobenzil)-1h-pirazolo[3,4-b]piridin-3-il]pirimidin-5- il}metilcarbamato
DE102010021637A1 (de) 2010-05-26 2011-12-01 Bayer Schering Pharma Aktiengesellschaft Substituierte 5-Fluor-1H-Pyrazolopyridine und ihre Verwendung
RS55387B1 (sr) 2011-11-25 2017-03-31 Adverio Pharma Gmbh Postupak za dobijanje supstituisanih (z)-alfa-fluoro-beta-amino-akrilaldehida
WO2013167669A1 (fr) 2012-05-10 2013-11-14 Bayer Pharma Aktiengesellschaft Anticorps capables de lier au facteur de coagulation xi et/ou à sa forme activée, le facteur xia, et utilisations de ceux-ci
MX2015010725A (es) 2013-02-21 2016-05-31 Adverio Pharma Gmbh Formas de metil {4,6-diamino-2-[1-(2-fluorobencil)-1h-pirazolo [3,4-b] piridino-3-il] pirimidino-5-il} metil carbamato.
EA201891416A1 (ru) 2015-12-14 2018-12-28 Айронвуд Фармасьютикалз, Инк. ПРИМЕНЕНИЕ СТИМУЛЯТОРОВ sGC ДЛЯ ЛЕЧЕНИЯ ДИСФУНКЦИИ ЖЕЛУДОЧНО-КИШЕЧНОГО СФИНКТЕРА
EP3554488A2 (fr) 2016-12-13 2019-10-23 Cyclerion Therapeutics, Inc. Utilisation de stimulateurs de sgc pour le traitement de la motilité sophagienne
CN108727340B (zh) 2017-04-11 2020-12-29 广东东阳光药业有限公司 氟取代的吲唑类化合物及其用途
KR20210031931A (ko) 2018-07-11 2021-03-23 사이클리온 테라퓨틱스, 인크. 미토콘드리아 장애의 치료를 위한 sGC 자극제의 용도

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Also Published As

Publication number Publication date
WO2000006567A1 (fr) 2000-02-10
AU5160499A (en) 2000-02-21
JP2002521481A (ja) 2002-07-16
DE19834045A1 (de) 2000-02-03

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