WO2016012384A1 - Amidines de trifluormethyloxazine utilisées comme inhibiteurs de bace1 - Google Patents

Amidines de trifluormethyloxazine utilisées comme inhibiteurs de bace1 Download PDF

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Publication number
WO2016012384A1
WO2016012384A1 PCT/EP2015/066505 EP2015066505W WO2016012384A1 WO 2016012384 A1 WO2016012384 A1 WO 2016012384A1 EP 2015066505 W EP2015066505 W EP 2015066505W WO 2016012384 A1 WO2016012384 A1 WO 2016012384A1
Authority
WO
WIPO (PCT)
Prior art keywords
oxazin
dihydro
trifluoromethyl
fluoro
dihydroquinazolin
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
Application number
PCT/EP2015/066505
Other languages
English (en)
Inventor
Cosimo Dolente
Bjoern Bartels
Wolfgang Guba
Wolfgang Haap
Ulrike Obst Sander
Jens-Uwe Peters
Mark Rogers-Evans
Thomas Woltering
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.)
F Hoffmann La Roche AG
Siena Biotech SpA
Hoffmann La Roche Inc
Original Assignee
F Hoffmann La Roche AG
Siena Biotech SpA
Hoffmann La Roche Inc
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 F Hoffmann La Roche AG, Siena Biotech SpA, Hoffmann La Roche Inc filed Critical F Hoffmann La Roche AG
Publication of WO2016012384A1 publication Critical patent/WO2016012384A1/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
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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

Definitions

  • Ci_6-alkyl stands for a hydrocarbon radical which may be linear or branched, with single or multiple branching, wherein the alkyl group in general comprises 1 to 6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl (ie/t-butyl), isopentyl,
  • halogen denotes chloro (CI), iodo (I), fluoro (F) and bromo (Br). Particular "halogen” is CI and F.
  • a specific group is F.
  • heteroaryl alone or in combination with other groups, refers to an aromatic carbocyclic group of having a single 4 to 8 membered ring, in particular 5 to 8, or multiple condensed rings comprising 6 to 14, in particular 6 to 10 ring atoms and containing 1, 2 or 3 heteroatoms individually selected from N, O and S, in particular IN or 2N, in which group at least one heterocyclic ring is aromatic.
  • Ci_6-alkoxy as defined herein, which is substituted by one or multiple C 2 -6-alkynyl as defined herein, in particular 1 C 2 -6-alkynyl. Specific is but-2-ynyloxy.
  • leaving group denotes the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions.
  • leaving groups include halogen, in particular bromo, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, and acyloxy.
  • R 1 is selected from the group consisting of
  • R 5 is selected from the group consisting of
  • R 4 is hydrogen
  • a certain embodiment relates to a compound of formula la as described herein,
  • a certain embodiment relates to a compound of formula I as described herein, wherein R 1 is 2-methyloxazol-4-yl, 3,5-dichloropyridin-2-yl, 5-(2,2,2-trifluoroethoxy)pyridin-2-yl, 5- (2,2,3,3, 3-pentafluoropropoxy)pyrazin-2-yl, 5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl, 5-(2,2- difluoroethoxy)pyridin-2-yl, 5-(but-2-ynyloxy)pyrazin-2-yl, 5-(but-2-ynyloxy)pyridin-2-yl, 5- (cyclopropylmethoxy)pyrazin-2-yl, 5-(cyclopropylmethoxy)pyridin-2-yl, 5-(difluoromethoxy)-2- pyridyl, 5-(difluoromethoxy)pyrazin-2-yl, 5-(diflu
  • a certain embodiment relates to a compound of formula I as described herein, wherein R is methyl.
  • a certain embodiment relates to a compound of formula I as described herein, wherein R is -CH 2 F.
  • the compounds of formula I may contain one or more asymmetric centers and can therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within this invention.
  • the present invention is meant to encompass all such isomeric forms of these compounds.
  • the independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein.
  • the compounds of formula I and the pharmaceutically acceptable salts can be used as therapeutically active substances, e.g. in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions.
  • the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
  • the compounds of formula I and the pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
  • the suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45°C. Thereupon, the finely powdered compound of formula I is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool; the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Psychiatry (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

La présente invention concerne des composés de formule (I) ayant une activité inhibitrice de BACE1, leur fabrication, des compositions pharmaceutiques les contenant et leur utilisation en tant que substances thérapeutiquement actives. Les composés actifs de la présente invention sont utiles pour le traitement thérapeutique et/ou prophylactique de la maladie d'Alzheimer, par exemple.
PCT/EP2015/066505 2014-07-22 2015-07-20 Amidines de trifluormethyloxazine utilisées comme inhibiteurs de bace1 Ceased WO2016012384A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP14178088 2014-07-22
EP14178088.2 2014-07-22

Publications (1)

Publication Number Publication Date
WO2016012384A1 true WO2016012384A1 (fr) 2016-01-28

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Application Number Title Priority Date Filing Date
PCT/EP2015/066505 Ceased WO2016012384A1 (fr) 2014-07-22 2015-07-20 Amidines de trifluormethyloxazine utilisées comme inhibiteurs de bace1

Country Status (1)

Country Link
WO (1) WO2016012384A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2511268B2 (fr) † 2009-12-11 2021-02-17 Shionogi & Co., Ltd. Dérivé d'oxazine
WO2021113917A1 (fr) * 2019-12-11 2021-06-17 Ambetex Pty Ltd Compositions thérapeutiques et procédés de prévention et de traitement d'un dysfonctionnement diastolique

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011058763A1 (fr) 2009-11-13 2011-05-19 塩野義製薬株式会社 Dérivé d'aminothiazine ou d'aminooxazine contenant un lieur amino
WO2011071135A1 (fr) 2009-12-11 2011-06-16 塩野義製薬株式会社 Dérivé d'oxazine
WO2012000001A2 (fr) 2010-07-01 2012-01-05 Psw Systems Ag Réservoir
WO2012156284A1 (fr) 2011-05-16 2012-11-22 F. Hoffmann-La Roche Ag 1,3-oxazines en tant qu'inhibiteurs de bace1 et/ou de bace2

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011058763A1 (fr) 2009-11-13 2011-05-19 塩野義製薬株式会社 Dérivé d'aminothiazine ou d'aminooxazine contenant un lieur amino
WO2011071135A1 (fr) 2009-12-11 2011-06-16 塩野義製薬株式会社 Dérivé d'oxazine
EP2511268A1 (fr) * 2009-12-11 2012-10-17 Shionogi & Co., Ltd. Dérivé d'oxazine
WO2012000001A2 (fr) 2010-07-01 2012-01-05 Psw Systems Ag Réservoir
WO2012156284A1 (fr) 2011-05-16 2012-11-22 F. Hoffmann-La Roche Ag 1,3-oxazines en tant qu'inhibiteurs de bace1 et/ou de bace2

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2511268B2 (fr) † 2009-12-11 2021-02-17 Shionogi & Co., Ltd. Dérivé d'oxazine
WO2021113917A1 (fr) * 2019-12-11 2021-06-17 Ambetex Pty Ltd Compositions thérapeutiques et procédés de prévention et de traitement d'un dysfonctionnement diastolique

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