Patent NZ-603427-A (NZ)
Title: 5,6-dihydro-2h-[1,4]oxazin-3-yl-amine derivatives useful as inhibitors of beta-secretase (bace)
Inventor: TRESADERN GARY JOHN
IPC: A61K31/5377
Filed: 2011-06-08
Abstract: Abstract - 603427 Disclosed are 5-(3-(aryl / heteroaryl)-phenyl)-5,6-dihydro-2H-1,4-oxazin-3-amine derivatives as represented by the general Formula (I) or a tautomer or a stereoisomeric form thereof, wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, fluoro, cyano, alkyl, mono- and polyhalo-alkyl, and cycloalkyl; R4 is fluoro or trifluoromethyl; or R1 and R2, or R3 and R4 taken together with the carbon atom to which they are attached may form a cycloalkanediyl ring; R5 is selected from the group consisting of hydrogen, alkyl, cyclopropyl, mono- and polyhalo-alkyl, homoaryl and heteroaryl; X1, X2, X3, X4 are independently C(R6) or N, provided that no more than two thereof represent N; each R6 is selected from the group consisting of hydrogen, halo, alkyl, mono- and polyhalo-alkyl, cyano, alkyloxy, mono- and polyhalo-alkyloxy; L is a bond or -N(R7)CO-, wherein R7 is hydrogen or alkyl; Ar is homoaryl or heteroaryl; homoaryl is phenyl or phenyl substituted with one, two or three substituents selected from the group consisting of halo, cyano, alkyl, alkyloxy, mono and polyhalo-alkyl, mono- and polyhalo-alkyloxy; heteroaryl is selected from the group consisting of pyridyl, pyrimidyl, pyrazyl, pyridazyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl and oxadiazolyl, each optionally substituted with one, two or three substituents selected from the group consisting of halo, cyano, alkyl, alkynyl, alkyloxy, mono- and polyhalo-alkyl, mono- and polyhalo-alkyloxy, and alkyloxy-alkyloxy; or an addition salt or a solvate thereof. Also disclosed are compounds such as 5-biphenyl-3-yl-5-methyl-5,6-dihydro-2H-1,4-oxazin-3-amine trifluoroacetate salt, 5-(3',5'-dichlorobiphenyl-3-yl)-5-methyl-5,6-dihydro-2H-1,4-oxazin-3-amine, 5-methyl-5-(3-pyrimidin-5-ylphenyl)-5,6-dihydro-2H-1,4-oxazin-3-amine trifluoroacetate salt, 5-[3-(5-methoxypyridin-3-yl)phenyl]-5-methyl-5,6-dihydro-2H-1,4-oxazin-3-amine, 5-[3-(5-methoxypyridin-3-yl)phenyl]-5-methyl-5,6-dihydro-2H-1,4-oxazin-3-amine, N-[3-(5-amino-3-methyl-3,6-dihydro-2H-1,4-oxazin-3 -yl)phenyl]-5-chloropyridine-2-carboxamide, 6-[3-(5-methoxypyridin-3-yl)phenyl]-6-methyl-4-oxa-7-azaspiro[2.5]oct-7-en-8-amine, N-{ 3-[5-amino-6-fluoro-3-methyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl]phenyl} -5-chloropyridine-2-carboxamide, 5-(2,4-difluoro-5-pyrimidin-5-ylphenyl)-6-fluoro-5-methyl-5,6-dihydro-2H-1,4-oxazin-3-amine and N-[3-(5-amino-2-fluoro-3-methyl-3,6-dihydro-2H-1,4-oxazin-3-yl)phenyl]-5-chloropyridine-2-carboxamide. Further disclosed is a pharmaceutical composition which comprises a therapeutically effective amount of a compound as defined above and a pharmaceutically acceptable carrier for the treatment of Alzheimer's disease, mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease and dementia associated with beta-amyloid.