DK2580200T3 - 5,6-dihydro-2h-[1,4]oxazin-3-ylaminderivater, der kan anvendes som inhibitorer af beta-secretase (bace) - Google Patents

5,6-dihydro-2h-[1,4]oxazin-3-ylaminderivater, der kan anvendes som inhibitorer af beta-secretase (bace) Download PDF

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DK2580200T3
DK2580200T3 DK11723974.9T DK11723974T DK2580200T3 DK 2580200 T3 DK2580200 T3 DK 2580200T3 DK 11723974 T DK11723974 T DK 11723974T DK 2580200 T3 DK2580200 T3 DK 2580200T3
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mmol
mixture
yield
compound
hydrogen
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DK11723974.9T
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Frederik Jan Rita Rombouts
Gary John Tresadern
Gool Michiel Luc Maria Van
Gregor James Macdonald
Lamenca Carolina Martinez
Henricus Jacobus Maria Gijsen
Andrés Avelino Trabanco-Suã�Rez
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Janssen Pharmaceutica Nv
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/10—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 carbon chain containing aromatic rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Claims (17)

1. Forbindelse med formel (I)
eller en tautomer eller en stereoisomer form deraf, hvor R1, R2 og R3 er udvalgt uafhængigt fra gruppen, der består af hydrogen, fluor, cyano, Ci-3alkyl, mono- og polyhalogen-Ci-3alkyl og C3_6cycloalkyl; R4 er fluor eller trifluormethyl; eller R1 og R2 eller R3 og R4 sammen med carbonatomet, hvortil de er bundet, kan danne en C3_6cycloalkandiylring; R5 er udvalgt fra gruppen, der består af hydrogen, Ci_3alkyl, cyclopropyl, mono- og polyhalogen-Ci_3alkyl, homoaryl og heteroaryl; X1, X2, X3, X4 uafhængigt er C (R6) eller N, forudsat at ikke mere end to af disse er N; hver R6 er udvalgt fra gruppen, der består af hydrogen, halogen, Ci_3alkyl, mono- og polyhalogen-Ci_ 3alkyl, cyano, Ci_3alkyloxy, mono- og polyhalogen-Ci_3alkyloxy; L er en binding eller -N(R7)CO-, hvor R7 er hydrogen eller Ci-3alkyl; Ar er homoaryl eller heteroaryl; homoaryl er phenyl eller phenyl substitueret med en, to eller tre substituenter udvalgt fra gruppen, der består af halogen, cyano, Ci-3alkyl, Ci_3alkyloxy, mono- og polyhalogen-Ci-3alkyl, mono- og polyhalogen-Ci-3alkyloxy; heteroaryl er udvalgt fra gruppen, der består af pyridyl, pyrimidyl, pyrazyl, pyridazyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl og oxadiazolyl, der hver eventuelt er substitueret med en, to eller tre substituenter udvalgt fra gruppen, der består af halogen, cyano, Ci_3alkyl, C2-3alkynyl, Ci_3alkyloxy, mono- og polyhalogen-Ci_3alkyl, mono- og polyhalogen-Ci_3alkyloxy og Ci_ 3alkyloxy-Ci-3alkyloxy; eller et additionssalt eller et solvat deraf.
2. Forbindelse ifølge krav 1, hvor R1, R2 og R3 er hydrogen, R4 er fluor, og L er -N(R7)CO-, hvor R7 er hydrogen.
3. Forbindelse ifølge krav 2, hvor R1, R2 og R3 er hydrogen, R4 er fluor, L er -N(R7)CO-, hvor R7 er hydrogen, og R5 er methyl, ethyl eller cyclopropyl.
4. Forbindelse ifølge krav 2, hvor R1, R2 og R3 er hydrogen, R4 er fluor, L er -N(R7)CO-, hvor R7 er hydrogen, og R5 er methyl, ethyl eller cyclopropyl, X2, X3 og X4 er CH, og X1 er CH, CF eller N.
5. Forbindelse ifølge krav 2, hvor R1, R2 og R3 er hydrogen, R4 er fluor, L er -N(R7)CO-, hvor R7 er hydrogen, og R5 er methyl, ethyl eller cyclopropyl, og Ar er pyridyl eller pyrazyl, der hver eventuelt er substitueret med en eller to substituenter udvalgt blandt halogen, cyano, methoxy, trifluorethoxy og difluormethyl.
6. Forbindelse ifølge krav 1, hvor R1, R2 og R3 er hydrogen, R4 er trif luormethyl, og L er -N(R7)CO-, hvor R7 er hydrogen.
7. Forbindelse ifølge krav 6, hvor R1, R2 og R3 er hydrogen, R4 er trif luormethyl, L er -N(R7)CO-, hvor R7 er hydrogen, og R5 er methyl, ethyl eller cyclopropyl.
8. Forbindelse ifølge krav 6, hvor R1, R2 og R3 er hydrogen, R4 er trif luormethyl, L er -N(R7)CO-, hvor R7 er hydrogen, R5 er methyl, ethyl eller cyclopropyl, X2, X3 og X4 er CH, og X1 er CH, CF eller N.
9. Forbindelse ifølge krav 6, hvor R1, R2 og R3 er hydrogen, R4 er trif luormethyl, L er -N(R7)CO-, hvor R7 er hydrogen, R5 er methyl, ethyl eller cyclopropyl, og Ar er pyridyl eller pyrazyl, der hver eventuelt er substitueret med en eller to substituenter udvalgt blandt halogen, cyano, methoxy, trifluorethoxy og difluormethyl.
10. Forbindelse ifølge krav 1, hvor R1 og R2 er hydrogen, R3 er fluor, R4 er trifluormethyl, og L er -N(R7)CO-, hvor R7 er hydrogen.
11. Farmaceutisk sammensætning, der omfatter en terapeutisk effektiv mængde af en forbindelse ifølge et hvilket som helst af kravene 1 til 10 og et farmaceutisk acceptabelt bæremateriale.
12. Fremgangsmåde til fremstilling af en farmaceutisk sammensætning ifølge krav 11, der er kendetegnet ved, at et farmaceutisk acceptabelt bæremateriale blandes omhyggeligt med en terapeutisk effektiv mængde af en forbindelse ifølge et hvilket som helst af kravene 1 til 10.
13. Forbindelse ifølge et hvilket som helst af kravene 1 til 10 til anvendelse til behandling, forebyggelse eller profylakse af Alzheimers sygdom (AD), let nedsat kognitiv funktion, senilitet, demens, demens med Lewy-legemer, Downs syndrom, demens i forbindelse med apopleksi, demens i forbindelse med Parkinsons sygdom eller demens i forbindelse med beta-amyloid.
14. Forbindelse ifølge krav 1, hvor forbindelsen er • (5R,6S)-N-[3-[5-amino-2-fluor-3,6-dihydro-3-methyl-2-(trifluormethyl)-2H-1,4-oxazin-3-yi]-4-fluorphenyl]-5-cyano-2-pyridincarboxamid; • (5R,6R)-N-[3-(5-amino-3-cyclopropyl-2-fluor-3, 6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorphenyl]-5-methoxy-2-pyrazincarboxamid; • (5R,6R)-N-[3-[5-amino-3,6-dihydro-3-methyl-2- (trifluormethyl)-2H-1,4-oxazin-3-yl]-4-fluorphenyl]-3,5-dichlor-2-pyridincarboxamid; • (5R,6R)-N-[3-(5-amino-2-fluor-3,6-dihydro-3-methyl-2H-l,4-oxazin-3-yl)-4-fluorphenyl]-5-cyano-2-pyridincarboxamid; • (5R,6R)-N-[3-(5-amino-2-fluor-3,6-dihydro-3-methyl-2H-l,4-oxazin-3-yl)-4-fluorphenyl]-5-methoxy-2-pyrazincarboxamid; • (5R, 6R)-N-[3-(5-amino-2-fluor-3,6-dihydro-3-methyl-2H-l,4-oxazin-3-yl)-4-fluorphenyl]-3,5-dichlor-2-pyridincarboxamid; • (5R,6R)-N-[3-[5-amino-3,6-dihydro-3-methyl-2- (trifluormethyl)-2H-1,4-oxazin-3-yl]-4-fluorphenyl]-5-methoxy-2-pyrazincarboxamid; eller • (5R,6R)-N-[3-[5-amino-3,6-dihydro-3-methyl-2- (trifluormethyl)-2H-1,4-oxazin-3-yl]-4-fluorphenyl]-5-cyano-2-pyridincarboxamid.
15. Forbindelse ifølge krav, 1, hvor forbindelsen er (5R,6R)-N-[3-(5-amino-2-fluor-3,6-dihydro-3-methyl-2H-l,4-oxazin-3- yl)-4-fluorphenyl]-5-cyano-2-pyridincarboxamid.
16. Forbindelse ifølge krav 1, hvor forbindelsen er (5R,6R)-N-[3-[5-amino-3,6-dihydro-3-methyl-2-(trifluormethyl)-2H-1,4-oxazin-3-yl]-4-fluorphenyl]-5-methoxy-2-pyrazincarboxamid.
17. Forbindelse ifølge krav 1, hvor forbindelsen er (5R,6R)-N-[3-[5-amino-3,6-dihydro-3-methyl-2-(trifluormethyl)-2H-1,4-oxazin-3-yl]-4-fluorphenyl]-5-cyano-2-pyridincarboxamid.
DK11723974.9T 2010-06-09 2011-06-08 5,6-dihydro-2h-[1,4]oxazin-3-ylaminderivater, der kan anvendes som inhibitorer af beta-secretase (bace) DK2580200T3 (da)

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Application Number Priority Date Filing Date Title
EP10165335 2010-06-09
EP11152314 2011-01-27
EP11157765 2011-03-10
EP11164999 2011-05-05
PCT/EP2011/059441 WO2011154431A1 (en) 2010-06-09 2011-06-08 5,6-dihydro-2h-[1,4]oxazin-3-yl-amine derivatives useful as inhibitors of beta-secretase (bace)

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US (2) US20130109683A1 (da)
EP (1) EP2580200B1 (da)
JP (1) JP5711813B2 (da)
KR (1) KR101730937B1 (da)
CN (1) CN102933564B (da)
AR (1) AR081587A1 (da)
AU (1) AU2011263797B2 (da)
BR (1) BR112012031094A2 (da)
CA (1) CA2799640C (da)
CL (1) CL2012003428A1 (da)
CO (1) CO6602112A2 (da)
DK (1) DK2580200T3 (da)
EA (1) EA021240B1 (da)
ES (1) ES2607083T3 (da)
HK (1) HK1182098A1 (da)
IL (1) IL223423A (da)
MX (1) MX339640B (da)
NZ (1) NZ603427A (da)
SG (1) SG185651A1 (da)
TW (1) TWI537263B (da)
WO (1) WO2011154431A1 (da)
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