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WO2001064652A9 - 5-methyldihydropyridazinones substituees et leur utilisation pour assurer la prophylaxie et/ou le traitement d'anemies - Google Patents

5-methyldihydropyridazinones substituees et leur utilisation pour assurer la prophylaxie et/ou le traitement d'anemies

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Publication number
WO2001064652A9
WO2001064652A9 PCT/EP2001/001873 EP0101873W WO0164652A9 WO 2001064652 A9 WO2001064652 A9 WO 2001064652A9 EP 0101873 W EP0101873 W EP 0101873W WO 0164652 A9 WO0164652 A9 WO 0164652A9
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WO
WIPO (PCT)
Prior art keywords
alkyl
phenyl
substituted
different
identically
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2001/001873
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German (de)
English (en)
Other versions
WO2001064652A1 (fr
Inventor
Gabriele Braeunlich
Michael Loegers
Juergen Stoltefuss
Carsten Schmeck
Ulrich Nielsch
Werner Stuermer
Christoph Gerdes
Klemens Lustig
Michael Sperzel
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Bayer AG
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Bayer AG
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Priority to EP01925339A priority Critical patent/EP1272474A1/fr
Priority to AU2001252132A priority patent/AU2001252132A1/en
Publication of WO2001064652A1 publication Critical patent/WO2001064652A1/fr
Publication of WO2001064652A9 publication Critical patent/WO2001064652A9/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of erythropoiesis.
  • the present invention relates to the use of substituted 5-methyldihydropyridazinones for the production of medicaments for the prophylaxis and / or treatment of anemias.
  • new substituted 5-methyldihydropyridazinones and their preparation are described.
  • Anemia also known as anemia, is characterized by a decrease in the number of erythrocytes, hemoglobin concentration and / or hematocrit below the age-appropriate and gender-specific reference values.
  • the anemia is characterized by the reduced oxygen transport capacity of the blood, inter alia by the disturbance of oxygen-dependent metabolic and organ functions; with acute development (e.g. due to blood loss), symptoms of shock may appear, and with chronic development there is often a slowly progressive course with decreased performance, fatigue, dyspnoea and tachycardia.
  • anemia can be classified or classified according to the morphology and hemoglobin content of the erythrocytes or according to the etiology (eg post-hemorrhagic anemia, gestational anemia, tumor anemia, infectious anemia or deficiency anemia). It is also possible to classify the various forms of anemia according to their pathogenesis, taking into account the possible causes, for example in anemia caused by over moderate blood loss (e.g. acute or chronic bleeding anemia), anemia due to reduced or ineffective erythropoiesis (e.g.
  • iron deficiency anemia iron deficiency anemia, nephrogenic anemia or myelopathic anemia
  • anemia due to excessive erythrocyte breakdown so-called hemolytic anemia
  • iron preparations are generally used, which are administered either orally or parenterally.
  • gastrointestinal disorders are observed as a side effect.
  • parenteral iron therapy which also proves to be difficult due to the low iron binding capacity of the plasma, it can lead to nausea, vomiting, heart and headache, heat sensation as well as a sharp drop in blood pressure with collapse, in addition to the deposition of iron in the overdose Reticuloendothelium (hemosiderosis) come; the walls of the vessels are damaged by the intravenous injection; thrombophlebitis and thrombosis must also be expected.
  • Dosage proves to be extremely difficult because all iron that cannot be bound physiologically with parenteral administration has a toxic effect (Gustav Kuschinsky, Heinz Lüllmann and
  • RhEPO Genetically engineered recombinant erythropoietin
  • EPO Erythropoietin
  • rh EPO is administered. These include the development and exacerbation of high blood pressure and the cause of symptoms similar to encephalopathy, to tonic-clonic convulsions and cerebral or myocardial infarction due to thrombosis. Furthermore, rh EPO is not available orally and must therefore be administered intraperitoneally (i.p.), intravenously (i.v.) or sub-cutan (s.c.), making it harder to apply to therapy
  • A, D, E and G are the same or different and represent hydrogen, (-CC 6 ) alkyl, hydroxy, halogen or (CrC 6 ) alkoxy,
  • R 1 represents hydrogen or (C 1 -C 4 ) -alkyl
  • R 2 stands for (C 3 -C 8 ) cycloalkyl, which is optionally substituted one to four times, identically or differently, by substituents which are selected from the group: (dC 6 ) alkyl, (CrC 6 ) alkoxy , (-C 6 -C) alkoxycarbonyl, hydroxyl, carboxyl and (C 6 -C ⁇ o) aryl, aryl optionally being substituted one to three times, identically or differently, by halogen,
  • R 2 for (C 6 -C ⁇ o) aryl, (C 6 -C 1 o) aryloxy, (C 6 -C ⁇ o) arylthio, dihydropyridinone or for an optionally benzo-fused 5- to 6-membered aromatic heterocycle with up to 3 Heteroatoms from the series S, N and / or O, the ring systems listed optionally being substituted one to three times, identically or differently, by substituents which are selected from the group: trifluoromethyl, nitro, hydroxyl, cyano, halogen, ( C -C 6 ) -cycloalkyl, optionally substituted by carboxyl or by mono-, di- or trihalogen-substituted phenoxy-substituted (-C-C 6 ) - Alkyl, phenoxy, (C 1 -C 6 ) alkoxy, (dC ⁇ -alkoxycarbonyl, carboxyl, (C 6 - C 1 o)
  • R 3 and R 4 are identical or different and are hydrogen, (dC 6 ) -alkyl or (-C-C ö ) -acyl,
  • R 5 , R 6 , R 7 and R 8 identical or different, have the meaning of R 3 and R 4 given above and are identical or different with these,
  • R 9 denotes hydrogen, (C 1 -C 6 ) alkyl or (C -C 6 ) alkenyl, which is optionally substituted by (C 6 -C ⁇ o) aryl,
  • (-C-C ⁇ 0 ) alkyl optionally by (C 3 -C 8 ) cycloalkyl, (C 6 -C ⁇ 0 ) aryl or by a 5- to 6-membered, aromatic or saturated, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O or a radical -NR 10 is substituted as a ring member,
  • R 10 is hydrogen, phenyl or (-C-C ö ) alkyl
  • ring systems listed above are optionally substituted one to three times, identically or differently, by substituents which are selected from the group: hydroxy, cyano, (C 3 -C 6 ) cycloalkyl, halogen, trifluoromethyl, (dC 6 ) Alkyl, (C 6 -C 10 ) aryl, phenoxy, (dC 8 ) alkoxy, (dC 6 ) alkoxycarbonyl, carboxyl and a radical of the formula -NR ⁇ R 12 ,
  • R and R identical or different, have the meaning of R and R 4 given above and are identical or different with these,
  • R represents (dC 6 ) alkoxycarbonyl or a radical of the formula -NR R,
  • R 13 and R 14 are identical or different and are hydrogen, (C ⁇ -C6) - alkoxycarbonyl, (C 6 -C ⁇ o) arylcarbonyl or represent (dC 6) acyl, or (C 6 -do) aryl, (C 3 -C 8 ) cycloalkyl or a 5- to 6-membered heterocycle with up to 3 heter atoms from the series S, N and / or O, where the ring systems listed are, if appropriate up to 2-fold, identical or different, are substituted by substituents selected from the group: hydroxy, (dC 6 ) alkyl, (dC 6 ) alkoxycarbonyl, (dC 6 ) alkoxy, halogen, nitro, trifluoromethyl and residues of the formula -CO-NR 15 R 16 and -SO 2 -NR 17 R 18 ,
  • R 15 , R 16 , R 17 and R 18 are the same or different and are hydrogen, (C 6 -C 10 ) aryl or (dC 6 ) alkyl,
  • R 13 or R 14 denotes (-C 6 ) -alkyl, which is optionally substituted by phenyl, which in turn can optionally be substituted one to three times, identically or differently, by halogen,
  • R 2 represents (dC 4 ) alkoxy or (C 2 -C 6 ) alkenyl, which is optionally substituted by (C 6 -C ⁇ o) aryl,
  • the compounds according to the invention can be in stereoisomeric forms which are either like images and mirror images
  • the invention relates both to the enantiomers or diastereomers and to their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
  • the compounds used according to the invention can optionally also be in the form of their tautomers.
  • Physiologically acceptable salts of the compounds used according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids.
  • 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 benzoic acid.
  • Salts with customary bases can also be mentioned, for example
  • Alkali metal salts e.g. sodium or potassium salts
  • alkaline earth salts e.g. calcium or magnesium salts
  • ammonium salts derived from ammonia or organic amines such as diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, or 1-ephenamine piperidine.
  • Cycloalkyl stands for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. The following may preferably be mentioned: cyclopropyl, cyclopentyl and cyclohexyl.
  • (C 6 -C ⁇ o) aryl also as a component of other substituents, represents an aromatic radical having 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • a straight-chain or branched alkyl radical having 1 to 8 carbon atoms is preferred.
  • a straight-chain or branched alkyl radical having 1 to 7 carbon atoms is particularly preferred.
  • (dC 8 ) -alkoxy stands for a straight-chain or branched alkoxy radical with 1 to 8
  • Carbon atoms examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred.
  • a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is particularly preferred.
  • (C 1 -C 6 ) - Alkoxycarbonyl stands for a straight-chain or branched alkoxycarbonyl radical with 1 to 6 carbon atoms. Examples include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl and tert-butoxycarbonyl.
  • a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred.
  • a straight-chain or branched alkoxycarbonyl radical having 1 to 3 carbon atoms is particularly preferred.
  • (dC 6 ) -acyl represents a straight-chain or branched acyl radical having 1 to 6 carbon atoms.
  • Examples include: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl.
  • a straight-chain or branched acyl radical having 1 to 4 carbon atoms is preferred. Acetyl and ethylcarbonyl are particularly preferred.
  • (C 2 -C 6 ) alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms.
  • a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms is preferred. Examples include: vinyl, allyl, isopropenyl and n-but-2-en-l-yl.
  • a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, O and / or N or a radical of the formula -NH is, for example, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Pyridyl, pyrimidyl, pyridazinyl, furyl and thienyl are preferred.
  • the compounds of the general formula (I) are preferably used for the prophylaxis and / or treatment of anemias,
  • A, D, E and G are the same or different and represent hydrogen, hydroxy, fluorine, chlorine or bromine,
  • R 1 represents hydrogen or (d -C 4 ) alkyl
  • R 2 represents cyclopropyl, cyclopentyl or cyclohexyl, which are optionally monosubstituted to trisubstituted, identically or differently, by substituents which are selected from the group: (dC 4 ) -alkyl, (dC 4 ) -alkoxy, (dC 4 ) -
  • R 2 represents phenyl, naphthyl, phenoxy, phenylthio, dihydropyridinone, pyridyl, isoxazolyl, oxazolyl, furyl or thienyl, the ring systems listed optionally being substituted one to three times, identically or differently, by substituents which are selected from the group:
  • Trifluoromethyl nitro, hydroxy, cyano, cyclopropyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, (C ⁇ -C 4 ) -alkyl, phenyl, naphthyl, phenoxy, (d- C 4 ) -alkoxy, (C ⁇ -C) - Alkoxycarbonyl, benzoyl and a radical of the formula
  • R 3 and R 4 are identical or different and are hydrogen, (-CC) -alkyl or (dC) -acyl,
  • phenyl which in turn may be substituted, once or twice, identically or differently, by fluorine, chlorine, hydroxyl, (-CC 4 ) -alkyl or (-CC) alkoxy can
  • R 5 , R 6 , R 7 and R 8 identical or different, have the meaning of R 3 and R 4 given above and are identical or different with these,
  • R 9 is hydrogen, (dC 4 ) -alkyl or (C -C 4 ) -alkenyl, which is optionally substituted by phenyl or naphthyl,
  • (-CC 8 ) alkyl optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, thienyl, furyl or by a radical -NR 10 ,
  • R, 1 ⁇ 0 ⁇ is hydrogen, phenyl or (d -C 3 ) alkyl
  • ring systems listed above are optionally substituted one to three times, identically or differently, by substituents which are selected from the group: hydroxy, cyano, cyclopropyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, trifluoromethyl, (dC) -alkyl , Phenyl, naphthyl, phenoxy, (-C-C 6 ) alkoxy, (dC 4 ) alkoxycarbonyl, carboxyl and a radical of the formula -NR n R 12 , embedded image in which
  • R 11 and R 12 identical or different, have the meaning of R 3 and R 4 given above and are identical or different with these,
  • R 13 and R 14 are the same or different and are hydrogen, (dC) -acyl,
  • (dC 4 ) -alkoxycarbonyl benzoyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl, pyridyl, thienyl or furyl, the ring systems listed optionally being substituted up to 2 times, identically or differently, by substituents which are selected from the group: hydroxy, (dC 4 ) alkyl, (-C-C 4 ) alkoxy, (dC 4 ) - alkoxycarbonyl, fluorine, chlorine, bromine, nitro, trifluoromethyl and residues of the formula -CO-NR 15 R 16 or - SO 2 -NR 17 R 18 ,
  • R 15 , R 16 , R 17 and R 18 are identical or different and are hydrogen, phenyl, naphthyl or (-CC) alkyl,
  • R 13 or R 14 denotes (dC 4 ) -alkyl, which is optionally substituted by phenyl, which in turn can be substituted once or twice, identically or differently, by fluorine or chlorine,
  • R represents (C 2 -C 6 ) alkenyl which is optionally substituted by phenyl,
  • the compounds of the general formula (I) are particularly preferably used for the prophylaxis and / or treatment of anemia
  • A, D, E and G are the same or different and represent hydrogen, hydroxy, fluorine, chlorine or bromine,
  • R 1 represents hydrogen or (C 1 -C 3 ) alkyl
  • R 2 represents cyclopropyl, cyclopentyl or cyclohexyl, which are optionally monosubstituted to trisubstituted, identically or differently, by substituents which are selected from the group: (-CC 4 ) -alkyl, (dC 4 ) -alkoxy, ( dC 4 ) - alkoxycarbonyl, hydroxyl, carboxyl, phenyl and naphthyl, where phenyl and naphthyl are optionally substituted one to three times, identically or differently, by fluorine, chlorine or bromine,
  • R 2 for phenyl, naphthyl, phenoxy, phenylthio, dihydropyridinone, pyridyl,
  • Ring systems optionally one to three times, the same or different, by
  • Substituents are substituted which are selected from the group: trifluoromethyl, nitro, hydroxy, cyano, cyclopropyl, cyclopentyl, cyclohexyl, Fluorine, chlorine, bromine, (dC 4 ) -alkyl, phenyl, naphthyl, phenoxy, (CC 4 ) - alkoxy, (-C-C 4 ) -alkoxycarbonyl and a radical of the formula -NR 3 R 4 ,
  • R 3 and R 4 are identical or different and are hydrogen, (dC) -alkyl or (dC 4 ) -acyl,
  • phenyl which in turn can be substituted one to two times, identically or differently, by fluorine, chlorine, hydroxy, (dC 3 ) alkyl or (dC 3 ) alkoxy,
  • R 5 , R 6 , R 7 and R 8 identical or different, have the meaning of R 3 and R 4 given above and are identical or different with these,
  • R 9 is hydrogen, (dC 4 ) -alkyl or (C 2 -C 4 ) -alkenyl, which is optionally substituted by phenyl or naphthyl,
  • R 10 denotes hydrogen, phenyl or (dC 3 ) alkyl
  • ring systems listed above are optionally substituted one to three times, identically or differently, by substituents which are selected from the group: hydroxy, cyano, cyclopropyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, (dC 3 ) -alkyl, Phenyl, naphthyl, phenoxy, (d-C 4 ) alkoxy, (dC) alkoxycarbonyl, carboxyl and a radical of the formula
  • R 11 and R 12 identical or different, have the meaning of R 3 and R 4 given above and are identical or different with these,
  • R 2 represents (-CC 4 ) alkoxycarbonyl or a radical of the formula -NR 13 R 14 ,
  • R 13 and R 14 are identical or different and are hydrogen, (Cj-C 3 ) -acyl or phenyl, pyridyl, thienyl or furyl, the ring systems listed optionally being substituted up to 2 times, identical or different, by substituents, which are selected from the group: hydroxy, (dC 3 ) -alkyl, (dC 3 ) -alkoxy, (CC 3 ) -alkoxycarbonyl, fluorine, chlorine, bromine, nitro, trifluoromethyl and residues of the formula -CO-NR 15 R 16 or -SO 2 -NR 17 R 18 ,
  • R 15 , R 16 , R 17 and R 18 are identical or different and are hydrogen, phenyl, naphthyl or (dC 3 ) -alkyl,
  • R 13 or R 14 denotes (-C-C) -alkyl, which is optionally substituted by phenyl, which in turn can be substituted once or twice, identically or differently, by fluorine or chlorine,
  • R represents vinyl which is optionally substituted by phenyl
  • the present invention also relates to new substances which are listed in Table A: Table A:
  • R 2 has the meaning given above
  • T is hydroxy or halogen, preferably chlorine
  • R 2 represents a radical of the formula -NR 13 R 14 ,
  • Organic solvents which are inert under the reaction conditions are suitable as solvents. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, carbon tetrachloroethane, 1,2-dichloroethylene or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, acetonitrile or Hexamethylphosphoramide. It is also possible to use mixtures of the solvents.
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, carbon tetrachloroethane, 1,2-dichloroethylene or trichlorethylene
  • hydrocarbons such as benzene
  • carboxylic acid-activating reagents for the purposes of the present invention are carbodiimides such as, for example, diisopropylcarbodiimide,
  • bases such as triethylamine or N-ethylmorpholine or N-methylpiper
  • Thionyl chloride is also suitable.
  • Preferred carboxylic acid activating reagents are carbonyldiimidazole (CDI) and thionyl chloride.
  • carboxylic acid-activating reagents are Neritatien, which can convert the carboxylic acid function into the corresponding carboxylic acid halide, e.g. Thionyl chloride.
  • the carboxylic acid-reactivating reagent is used in an amount of 1 to 5 mol, preferably 1 to 2 mol, based on 1 mol of the general compounds
  • the reaction generally takes place in a temperature range from -78 ° C to the reflux temperature, preferably in a range from -78 ° C to + 20 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. in a range from 0.5 to 5 bar). Generally one works at normal pressure.
  • the compounds of the general formula (I) according to the invention have an unforeseeable, valuable spectrum of pharmacological activity and are therefore particularly suitable for the prophylaxis and / or treatment of diseases.
  • anemia such as, for example, in prematurity anemia, in nephrogenic or renal anemia, such as anemia in chronic renal failure, in anemia after chemotherapy and in the anemia of HIV patients, ie in particular for the treatment of severe anemia.
  • anemia such as, for example, in prematurity anemia, in nephrogenic or renal anemia, such as anemia in chronic renal failure, in anemia after chemotherapy and in the anemia of HIV patients, ie in particular for the treatment of severe anemia.
  • the application is preferably oral, transdermal or perenteral. Oral application is very particularly preferred, in which there is a further advantage over the therapy of anemias with rhEPO known from the prior art.
  • the compounds according to the invention act in particular as erythropoietin
  • Erythropoietin sensitizers are compounds which are capable of influencing the effect of the EPO present in the body so efficiently that erythropoiesis is increased, in particular the oxygen supply is improved. Surprisingly, they are also orally active, which makes therapeutic use with the exclusion or reduction of known side effects significantly improved and simplified at the same time.
  • the present invention thus also relates to the use of EPO sensitizers for stimulating erythropoiesis, in particular for the prophylaxis and / or treatment of anemias, preferably severe anemias such as premature anemia, anemia in the case of chronic renal failure, anemia after
  • the Neritatien according to the invention thus enable efficient stimulation of erythropoiesis and consequently prophylaxis or therapy of anemia which intervenes before the stage in which the conventional treatment methods with EPO are used. Because the Neritatien invention allow an effective influence on the body's own EPO, whereby the direct administration of EPO with the associated disadvantages can be avoided.
  • the present invention thus furthermore relates to medicaments and pharmaceutical compositions which comprise at least one compound of the general formula (I) according to the invention together with one or more pharmacologically acceptable auxiliaries or excipients, and their use for
  • Stimulation of erythropoiesis in particular for the purposes of prophylaxis and / or treatment of anemia, such as e.g. Premature anemia, anemia with chronic renal failure, anemia after chemotherapy or anemia in HIV patients.
  • anemia such as e.g. Premature anemia, anemia with chronic renal failure, anemia after chemotherapy or anemia in HIV patients.
  • the CD34 positive cells from this cell fraction were isolated by means of a commercial purification method (CD34 multisort kit from Miyltenyi).
  • the CD34 positive cells (6000-10000 cells / ml) were in stem cell medium (0.9% methyl cellulose, 30% calf serum, 1% albumin (bovine), 100 ⁇ M 2-mercaptoethanol and 2 mM L-glutamine) from StemCell Techno- logies Inc. resuspended. 10 mU / ml human erythropoietin, 10 ng / ml human IL-3
  • the cultures were diluted with 20 ml 0.9% w / v ⁇ aCl solution for 15 min
  • mice Normal mice are treated with test substances over several days. The application takes place intraperitoneally, subcutaneously or by os.
  • Preferred solvents are Solutol / DMSO / sucrose / NaCl solution or glycofurol.
  • test substances administered according to the present invention lead to a significant increase in the hematocrit.
  • 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 approximately 0.5 to
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, for example in the case of use of water as a diluent, organic solvents can optionally be used as auxiliary solvents.
  • the application is carried out in the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously.
  • a third of the dichloromethane solution from Example 1A is diluted to 15 ml and 142.5 mg (1.05 mmol) of salicylamide are added. Solution occurs first, then colorless crystals precipitate. It is stirred overnight, suction filtered and washed with ethanol. 120 mg of crystals with a melting point of 212-213 ° C. are obtained.

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Abstract

L'invention concerne le domaine de l'érythropoïèse et plus particulièrement des 5-méthyldihydropyridazinones de formule générale (I) et leur utilisation comme médicaments, de préférence pour assurer la prophylaxie des anémies et/ou lutter contre.
PCT/EP2001/001873 2000-03-03 2001-02-20 5-methyldihydropyridazinones substituees et leur utilisation pour assurer la prophylaxie et/ou le traitement d'anemies Ceased WO2001064652A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP01925339A EP1272474A1 (fr) 2000-03-03 2001-02-20 5-methyldihydropyridazinones substituees et leur utilisation pour assurer la prophylaxie et/ou le traitement d'anemies
AU2001252132A AU2001252132A1 (en) 2000-03-03 2001-02-20 Substituted 5-methyldihydropyridazinones and their use in the prophylaxis and/ortreatment of anemias

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10010425A DE10010425A1 (de) 2000-03-03 2000-03-03 Substituierte 5-Methyldihydropyridazinone und ihre Verwendung
DE10010425.8 2000-03-03

Publications (2)

Publication Number Publication Date
WO2001064652A1 WO2001064652A1 (fr) 2001-09-07
WO2001064652A9 true WO2001064652A9 (fr) 2002-07-04

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PCT/EP2001/001873 Ceased WO2001064652A1 (fr) 2000-03-03 2001-02-20 5-methyldihydropyridazinones substituees et leur utilisation pour assurer la prophylaxie et/ou le traitement d'anemies

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EP (1) EP1272474A1 (fr)
AU (1) AU2001252132A1 (fr)
DE (1) DE10010425A1 (fr)
WO (1) WO2001064652A1 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003053997A2 (fr) * 2001-12-06 2003-07-03 Fibrogen, Inc. Methodes permettant d'augmenter l'erythropoietine endogene (epo)
DE10254336A1 (de) * 2002-11-21 2004-06-03 Merck Patent Gmbh Carbonsäureamide
US8614204B2 (en) 2003-06-06 2013-12-24 Fibrogen, Inc. Enhanced erythropoiesis and iron metabolism
JP5165586B2 (ja) 2005-12-28 2013-03-21 バーテックス ファーマシューティカルズ インコーポレイテッド 嚢胞性線維症の処置のためのＡＴＰ結合カセットトランスポーターのモジュレーターとしての、１−（ベンゾ［ｄ］［１，３］ジオキソール−５−イル）−Ｎ−（フェニル）シクロプロパン−カルボキサミド誘導体および関連化合物
US7671221B2 (en) 2005-12-28 2010-03-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
EP2502918B1 (fr) 2006-07-25 2015-03-25 Cephalon, Inc. Dérivés de pyridazinone
US8686048B2 (en) * 2010-05-06 2014-04-01 Rhizen Pharmaceuticals Sa Immunomodulator and anti-inflammatory compounds
WO2018086703A1 (fr) 2016-11-11 2018-05-17 Bayer Pharma Aktiengesellschaft Dihydropyridazinones substituées par des phénylurées
EP3746079A1 (fr) 2018-01-31 2020-12-09 Bayer Aktiengesellschaft Conjugués anticorps-médicament (adc) avec des inhibiteurs de nampt
WO2021013693A1 (fr) 2019-07-23 2021-01-28 Bayer Pharma Aktiengesellschaft Conjugués anticorps-médicament (adc) avec des inhibiteurs de nampt

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL37788A0 (en) * 1970-10-09 1971-12-29 American Cyanamid Co New pyridazinone compounds,their preparation and pharmaceutical compositions containing them
WO1983001447A1 (fr) * 1981-10-20 1983-04-28 Katakami, Tsutomu Nouveaux derives de pyridazinone
EP0728482A3 (fr) * 1995-02-10 1999-10-20 Smithkline Beecham Corporation Emploi de composés HCP spécifiques pour augmenter l'érythropoiese
JPH11292852A (ja) * 1998-04-06 1999-10-26 Mitsui Chem Inc ジヒドロピリダジノン誘導体およびそれを有効成分として含有する腫瘍壊死因子産生抑制剤
DE19929787A1 (de) * 1999-06-29 2001-01-04 Bayer Ag Neue 4-(2-Oxodihydrooxadiazinylphenyl)amide und ihre Verwendung
DE19929781A1 (de) * 1999-06-29 2001-01-04 Bayer Ag N-[4-(6-Oxotetrahydrotriazinyl)phenyl]amide und ihre Verwendung
DE19929782A1 (de) * 1999-06-29 2001-01-04 Bayer Ag 6-Carboxyphenyldihydropyridazinon-Derivate und ihre Verwendung

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Publication number Publication date
DE10010425A1 (de) 2001-09-06
EP1272474A1 (fr) 2003-01-08
WO2001064652A1 (fr) 2001-09-07
AU2001252132A1 (en) 2001-09-12

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