WO2007140982A1 - Benzoxazole substitué - Google Patents

Benzoxazole substitué Download PDF

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Publication number
WO2007140982A1
WO2007140982A1 PCT/EP2007/004965 EP2007004965W WO2007140982A1 WO 2007140982 A1 WO2007140982 A1 WO 2007140982A1 EP 2007004965 W EP2007004965 W EP 2007004965W WO 2007140982 A1 WO2007140982 A1 WO 2007140982A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
substituents
substituted
group
alkylcarbonyl
Prior art date
Application number
PCT/EP2007/004965
Other languages
German (de)
English (en)
Inventor
Dirk Schneider
Anja BUCHMÜLLLER
Elke Dittrich-Wengenroth
Christoph Gerdes.
Mark Jean Gnoth
Stefan Heitmeier
Martin Hendrix
Ulrich Rester
Uwe Saatmann
Stephan Siegel
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 WO2007140982A1 publication Critical patent/WO2007140982A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • 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
    • 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

Definitions

  • cycloalkyl and heterocyclyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, oxo, QC 4 alkyl, QC 4 alkoxy, QC 4 alkylthio, QC 4 alkylamino, QC 4- alkylcarbonyl and QC 4 -alkoxycarbonyl,
  • phenyl and heteroaryl having 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, C r C 4 alkyl, C, -C 4 alkoxy, C r C 4 alkylthio, C 1 -C 4 - alky lamino, C i -C 4 alkylcarbonyl and C i -C 4 alkoxycarbonyl,
  • alkyl may be substituted with a substituent, whereby the substituent is selected from the group consisting of Ci-C 4 alkoxy, Ci -C 4 - alkylcarbonylamino, R 3 is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, C r C 3 -alkyl, C r C 3 -alkoxy, C 1 -C 3 -alkyl or cyclopropyl,
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • Alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl and alkylcarbonylamino stand for a linear or branched alkyl radical having 1 to 6, preferably having 1 to 4, carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl and n-hexyl.
  • Cycloalkyl represents a mono- or bicyclic cycloalkyl group having generally 3 to 8, preferably 3, 5 or 6 carbon atoms, by way of example and preferably cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Heterocyclyl is a mono- or bicyclic, heterocyclic radical having usually 3 to 10, preferably 5 to 8 ring atoms and up to 3, preferably up to 2 heteroatoms and / or Hetero groups from the series N, O, S, SO, SO 2 , where a nitrogen atom can also form an N-oxide.
  • the heterocyclyl radicals may be saturated or partially unsaturated.
  • phenyl, 2-thienyl and 3-thienyl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, methyl, ethynyl and methoxy,
  • R 1 is C r C 6 -alkyl or C 3 -C 5 -cycloalkyl
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of trifluoromethyl, phenyl and pyridyl,
  • R 1 is C 1 -C 6 -alkyl or C 3 -C 5 -cycloalkyl
  • methyl and ethyl are substituted with a substituent, wherein the substituent is selected from the group consisting of methoxy, methylcarbonyl, 5- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl,
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, C r C 4 alkyl, C r C 4 alkoxy, Ci -C 4 alkylthio, C r C 4 - alkylamino, Ci-C4-alkylcarbonyl and CpC 4 alkoxycarbonyl,
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the
  • R 1 is C 1 -C 6 -alkyl or C 3 -C 5 -cycloalkyl
  • alkyl may be substituted with a substituent, whereby the substituent is selected from the group consisting of hydroxy, Ci-C 4 alkoxy, Ci-C 4 - alkylamino, C r C 4 alkylthio, C r C 4 alkylcarbonyl, C r C 4 alkoxycarbonyl, Ci-C 4 -
  • the reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to room temperature at atmospheric pressure.
  • the compounds of formula (HI) are known or can be synthesized by known methods from the corresponding starting compounds.
  • hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions
  • solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile or pyridine, or Mixtures of solvents, as the solvent is preferably dioxane.
  • the reaction with isothiocyanate is generally carried out in inert solvents, preferably in a temperature range from 0 ° C. to room temperature at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, such as benzene, or other solvents, such as nitromethane, dioxane, dimethylformamide, dimethyl sulfoxide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred is dimethylformamide.
  • Another object of the present invention are pharmaceutical compositions containing a compound of the invention and one or more other active ingredients.
  • the oral application is preferred.
  • Method 1 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - »2.5 min 30% A -> 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • Method 10 Device Type MS: Waters ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Onyx Monolithic C 18, 100 mm x 3 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A ⁇ 2 min 65% A - »4.5 min 5% A ⁇ 6 min 5% A; Flow: 2 ml / min; Oven: 40 ° C; UV detection: 210 nm.
  • Example 119 The following example is prepared analogously to Example 124 using the amine from Example 119:
  • Thrombogram thrombin generation assay according to Hemker
  • Octaplas® from Octapharma
  • the prothrombin time (PT, synonyms: thromboplastin time, quick test) is determined in the presence of varying concentrations of test substance or the corresponding solvent with a commercially available test kit (Neoplastin® from Boehringer Mannheim or Hemoliance® RecombiPlastin from Instrumentation Laboratory). The test compounds are incubated for 3 minutes at 37 ° C with the plasma. Subsequently, coagulation is triggered by the addition of thromboplastin and the time of coagulation is determined. The concentration of test substance is determined which causes a doubling of the prothrombin time.
  • the activated partial thromboplastin time is determined in the presence of varying concentrations of test substance or the corresponding solvent with a commercially available test kit (PTT Reagent from Roche).
  • the test compounds are incubated for 3 minutes at 37 ° C with the plasma and the PTT reagent (cephalin, kaolin). Subsequently, coagulation is triggered by addition of 25 mM CaCl 2 and the time of coagulation is determined.
  • the concentration of test substance is determined which causes a doubling of the APTT.
  • the mixture of the compound of Example 1, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un benzoxazole substitué et son procédé de fabrication, ainsi que son utilisation pour la fabrication de médicaments pour le traitement et/ou la prophylaxie de maladies, notamment de maladies cardiovasculaires, de préférence de maladies thromboemboliques.
PCT/EP2007/004965 2006-06-08 2007-06-05 Benzoxazole substitué WO2007140982A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006027163.7 2006-06-08
DE102006027163A DE102006027163A1 (de) 2006-06-08 2006-06-08 Substituierte Benzoxazole

Publications (1)

Publication Number Publication Date
WO2007140982A1 true WO2007140982A1 (fr) 2007-12-13

Family

ID=38265486

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/004965 WO2007140982A1 (fr) 2006-06-08 2007-06-05 Benzoxazole substitué

Country Status (2)

Country Link
DE (1) DE102006027163A1 (fr)
WO (1) WO2007140982A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011154460A1 (fr) 2010-06-09 2011-12-15 L'oreal Composition contenant au moins une 2‑pyrrolidone fonctionnalisée en position 4 par un acide carboxylique ou un amide et au moins un colorant ou un pigment direct pour colorer les fibres de kératine
WO2014195230A1 (fr) 2013-06-03 2014-12-11 Bayer Pharma Aktiengesellschaft Benzoxazoles substitués
WO2014195231A1 (fr) * 2013-06-03 2014-12-11 Bayer Pharma Aktiengesellschaft Benzoxazoles substitués
WO2016087322A1 (fr) * 2014-12-01 2016-06-09 Bayer Pharma Aktiengesellschaft Formes galéniques pharmaceutiques solides administrables par voie orale, à libération rapide de principe actif

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030225131A1 (en) * 2002-04-05 2003-12-04 Burgey Christopher S. Thrombin inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030225131A1 (en) * 2002-04-05 2003-12-04 Burgey Christopher S. Thrombin inhibitors

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011154460A1 (fr) 2010-06-09 2011-12-15 L'oreal Composition contenant au moins une 2‑pyrrolidone fonctionnalisée en position 4 par un acide carboxylique ou un amide et au moins un colorant ou un pigment direct pour colorer les fibres de kératine
US8585779B2 (en) 2010-06-09 2013-11-19 L'oreal Composition comprising at least one 2-pyrrolidone functionalized in the 4 position with a carboxylic acid or amide, and at least one direct dye or a pigment for dyeing keratin fibres
WO2014195230A1 (fr) 2013-06-03 2014-12-11 Bayer Pharma Aktiengesellschaft Benzoxazoles substitués
WO2014195231A1 (fr) * 2013-06-03 2014-12-11 Bayer Pharma Aktiengesellschaft Benzoxazoles substitués
CN105408327A (zh) * 2013-06-03 2016-03-16 拜耳制药股份公司 取代的苯并噁唑
CN105431428A (zh) * 2013-06-03 2016-03-23 拜耳制药股份公司 取代的苯并噁唑
JP2016520111A (ja) * 2013-06-03 2016-07-11 バイエル ファーマ アクチエンゲゼルシャフト 置換ベンゾキサゾール
US9493472B2 (en) 2013-06-03 2016-11-15 Bayer Pharma Aktiengesellschaft Substituted benzoxazoles
WO2016087322A1 (fr) * 2014-12-01 2016-06-09 Bayer Pharma Aktiengesellschaft Formes galéniques pharmaceutiques solides administrables par voie orale, à libération rapide de principe actif

Also Published As

Publication number Publication date
DE102006027163A1 (de) 2007-12-13

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