ES2549087T3 - Derivados de aminodihidrotiazina como inhibidores de BACE para el tratamiento de la enfermedad de Alzheimer - Google Patents
Derivados de aminodihidrotiazina como inhibidores de BACE para el tratamiento de la enfermedad de Alzheimer Download PDFInfo
- Publication number
- ES2549087T3 ES2549087T3 ES09739419.1T ES09739419T ES2549087T3 ES 2549087 T3 ES2549087 T3 ES 2549087T3 ES 09739419 T ES09739419 T ES 09739419T ES 2549087 T3 ES2549087 T3 ES 2549087T3
- Authority
- ES
- Spain
- Prior art keywords
- methyl
- phenyl
- dihydro
- bromo
- thiazin
- 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.)
- Active
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- 208000024827 Alzheimer disease Diseases 0.000 title 1
- 102100021257 Beta-secretase 1 Human genes 0.000 title 1
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 title 1
- 239000003112 inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 abstract description 60
- 150000003839 salts Chemical class 0.000 abstract description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract 3
- 229910052801 chlorine Inorganic materials 0.000 abstract 3
- 239000000460 chlorine Substances 0.000 abstract 3
- 229910052731 fluorine Chemical group 0.000 abstract 3
- 239000011737 fluorine Chemical group 0.000 abstract 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 2
- 239000001257 hydrogen Substances 0.000 abstract 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000001309 chloro group Chemical group Cl* 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 125000003373 pyrazinyl group Chemical group 0.000 abstract 1
- 125000004076 pyridyl group Chemical group 0.000 abstract 1
- 125000000714 pyrimidinyl group Chemical group 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 77
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 27
- -1 t-butoxycarbonyl Chemical group 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- 235000019439 ethyl acetate Nutrition 0.000 description 26
- 238000002360 preparation method Methods 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 239000002904 solvent Substances 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000000126 substance Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 150000004702 methyl esters Chemical class 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- KKJDEBKSLHYTSW-MWTRTKDXSA-N (3r)-3-(3-bromophenyl)-3-[[(s)-tert-butylsulfinyl]amino]-n-methoxy-n-methylbutanamide Chemical compound CON(C)C(=O)C[C@@](C)(N[S@@](=O)C(C)(C)C)C1=CC=CC(Br)=C1 KKJDEBKSLHYTSW-MWTRTKDXSA-N 0.000 description 3
- PFCRWJKBERQZFO-IFXJQAMLSA-N CC(C)(C)[S@@](=O)N[C@](CC(=O)O)(C)C1=CC=CC=C1 Chemical compound CC(C)(C)[S@@](=O)N[C@](CC(=O)O)(C)C1=CC=CC=C1 PFCRWJKBERQZFO-IFXJQAMLSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000012799 strong cation exchange Methods 0.000 description 3
- TYMYPXQDNHXVHF-RCDICMHDSA-N (3S)-3-(5-bromo-2,4-difluorophenyl)-3-[[(R)-tert-butylsulfinyl]amino]butanoic acid Chemical compound CC(C)(C)[S@@](=O)N[C@](CC(=O)O)(C)C1=C(C=C(C(=C1)Br)F)F TYMYPXQDNHXVHF-RCDICMHDSA-N 0.000 description 2
- JKZCGWAVLCHFCC-JTQLQIEISA-N (3s)-3-amino-3-(3-bromophenyl)butan-1-ol Chemical compound OCC[C@@](N)(C)C1=CC=CC(Br)=C1 JKZCGWAVLCHFCC-JTQLQIEISA-N 0.000 description 2
- AOEATMPDADSVRS-NSHDSACASA-N (4s)-4-(3-bromo-4-fluorophenyl)-4-methyl-5,6-dihydro-1,3-thiazin-2-amine Chemical compound C=1C=C(F)C(Br)=CC=1[C@]1(C)CCSC(N)=N1 AOEATMPDADSVRS-NSHDSACASA-N 0.000 description 2
- XYUFUGWCJIHHPR-UHFFFAOYSA-N 4-(3-bromophenyl)-4-methyl-5,6-dihydro-1,3-thiazin-2-amine Chemical compound C=1C=CC(Br)=CC=1C1(C)CCSC(N)=N1 XYUFUGWCJIHHPR-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- 239000012448 Lithium borohydride Substances 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- IFMWVBVPVXRZHE-UHFFFAOYSA-M chlorotitanium(3+);propan-2-olate Chemical compound [Cl-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-] IFMWVBVPVXRZHE-UHFFFAOYSA-M 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- DXJGNCOFSUITHI-YDALLXLXSA-N ethyl (3s)-3-amino-3-(2,4-difluorophenyl)butanoate;hydrochloride Chemical compound Cl.CCOC(=O)C[C@](C)(N)C1=CC=C(F)C=C1F DXJGNCOFSUITHI-YDALLXLXSA-N 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- VSRWDSTWWDEJFV-MERQFXBCSA-N methyl (3s)-3-amino-3-(2,4-difluorophenyl)butanoate;hydrochloride Chemical compound Cl.COC(=O)C[C@](C)(N)C1=CC=C(F)C=C1F VSRWDSTWWDEJFV-MERQFXBCSA-N 0.000 description 2
- YARKVSJAYDOCHK-MERQFXBCSA-N methyl (3s)-3-amino-3-(4-fluorophenyl)butanoate;hydrochloride Chemical compound Cl.COC(=O)C[C@](C)(N)C1=CC=C(F)C=C1 YARKVSJAYDOCHK-MERQFXBCSA-N 0.000 description 2
- OSVUNBRREMMJGT-SFHVURJKSA-N n-[(4s)-4-[3-(2-fluoropyridin-3-yl)phenyl]-4-methyl-5,6-dihydro-1,3-thiazin-2-yl]acetamide Chemical compound C1CSC(NC(=O)C)=N[C@]1(C)C1=CC=CC(C=2C(=NC=CC=2)F)=C1 OSVUNBRREMMJGT-SFHVURJKSA-N 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- APLYMLYNTZCZKB-JTQLQIEISA-N (3S)-3-amino-3-(3-bromo-4-fluorophenyl)butan-1-ol Chemical compound N[C@](CCO)(C)C1=CC(=C(C=C1)F)Br APLYMLYNTZCZKB-JTQLQIEISA-N 0.000 description 1
- IIDUHECNMVFUAV-JTQLQIEISA-N (3S)-3-amino-3-(5-bromo-2-chlorophenyl)butan-1-ol Chemical compound N[C@](CCO)(C)C1=C(C=CC(=C1)Br)Cl IIDUHECNMVFUAV-JTQLQIEISA-N 0.000 description 1
- VFWFEWXGGDLOGF-JTQLQIEISA-N (3S)-3-amino-3-(5-bromo-2-fluorophenyl)butan-1-ol Chemical compound N[C@](CCO)(C)C1=C(C=CC(=C1)Br)F VFWFEWXGGDLOGF-JTQLQIEISA-N 0.000 description 1
- RQSCZHOLHSHJQO-JTQLQIEISA-N (3s)-3-amino-3-(5-bromo-2,4-difluorophenyl)butan-1-ol Chemical compound OCC[C@@](N)(C)C1=CC(Br)=C(F)C=C1F RQSCZHOLHSHJQO-JTQLQIEISA-N 0.000 description 1
- SYDUJFUYIKVSHQ-CKUXDGONSA-N (4S)-4-(2-fluoro-5-pyrimidin-5-ylphenyl)-4-methyl-5,6-dihydro-1,3-thiazin-2-amine dihydrochloride Chemical compound Cl.Cl.C[C@]1(CCSC(N)=N1)c1cc(ccc1F)-c1cncnc1 SYDUJFUYIKVSHQ-CKUXDGONSA-N 0.000 description 1
- ZKXUGVRQEFFTSH-HNNXBMFYSA-N (4S)-4-(4-fluoro-3-pyrazin-2-ylphenyl)-4-methyl-5,6-dihydro-1,3-thiazin-2-amine Chemical compound C[C@]1(CCSC(=N1)N)C2=CC(=C(C=C2)F)C3=NC=CN=C3 ZKXUGVRQEFFTSH-HNNXBMFYSA-N 0.000 description 1
- MCFIBXYUGGXLPA-INIZCTEOSA-N (4S)-4-[2,4-difluoro-5-(2-fluoropyridin-3-yl)phenyl]-4-methyl-5,6-dihydro-1,3-thiazin-2-amine Chemical compound C[C@]1(CCSC(N)=N1)C1=C(F)C=C(F)C(=C1)C1=C(F)N=CC=C1 MCFIBXYUGGXLPA-INIZCTEOSA-N 0.000 description 1
- KVTIBSJMSLMZJK-SQKCAUCHSA-N (4S)-4-[2,4-difluoro-5-(5-fluoropyridin-3-yl)phenyl]-4-methyl-5,6-dihydro-1,3-thiazin-2-amine dihydrochloride Chemical compound Cl.Cl.C[C@]1(CCSC(N)=N1)c1cc(c(F)cc1F)-c1cncc(F)c1 KVTIBSJMSLMZJK-SQKCAUCHSA-N 0.000 description 1
- JVCHSQMVPZBOPG-INIZCTEOSA-N (4S)-4-[2-chloro-5-(5-chloro-2-fluoropyridin-3-yl)phenyl]-4-methyl-5,6-dihydro-1,3-thiazin-2-amine Chemical compound ClC1=C(C=C(C=C1)C=1C(=NC=C(C=1)Cl)F)[C@]1(N=C(SCC1)N)C JVCHSQMVPZBOPG-INIZCTEOSA-N 0.000 description 1
- RPQYFKVTZNQYQM-NSHDSACASA-N (4S)-4-amino-4-(3-bromophenyl)pentan-2-one Chemical compound CC(=O)C[C@](C)(N)C1=CC=CC(Br)=C1 RPQYFKVTZNQYQM-NSHDSACASA-N 0.000 description 1
- VYTPAOPJEUNLAQ-ABKXIKBNSA-N (4S,6R)-4-(2,4-difluoro-5-pyrimidin-5-ylphenyl)-4,6-dimethyl-5,6-dihydro-1,3-thiazin-2-amine Chemical compound C[C@@H]1C[C@@](N=C(S1)N)(C)C2=C(C=C(C(=C2)C3=CN=CN=C3)F)F VYTPAOPJEUNLAQ-ABKXIKBNSA-N 0.000 description 1
- BIFMZVVIYPSZLH-NSHDSACASA-N (4s)-4-(5-bromo-2,4-difluorophenyl)-4-methyl-5,6-dihydro-1,3-thiazin-2-amine Chemical compound C=1C(Br)=C(F)C=C(F)C=1[C@]1(C)CCSC(N)=N1 BIFMZVVIYPSZLH-NSHDSACASA-N 0.000 description 1
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- QFCZZJOMRKCYGT-UHFFFAOYSA-N 1-(3-bromo-4-fluorophenyl)ethanimine Chemical compound CC(=N)C1=CC=C(F)C(Br)=C1 QFCZZJOMRKCYGT-UHFFFAOYSA-N 0.000 description 1
- SFLKCFQSYWUGKL-UHFFFAOYSA-N 1-(3-bromophenyl)ethanimine Chemical compound CC(=N)C1=CC=CC(Br)=C1 SFLKCFQSYWUGKL-UHFFFAOYSA-N 0.000 description 1
- KXZHDRBQPYKHKS-UHFFFAOYSA-N 1-(5-bromo-2,4-difluorophenyl)ethanone Chemical compound CC(=O)C1=CC(Br)=C(F)C=C1F KXZHDRBQPYKHKS-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- DUWLIIPTRMQEAP-UHFFFAOYSA-N 2-methylpropane-2-sulfinic acid Chemical compound CC(C)(C)S(O)=O DUWLIIPTRMQEAP-UHFFFAOYSA-N 0.000 description 1
- MCPRYBIHGJROPH-UHFFFAOYSA-N 2H-1,3-thiazin-2-amine dihydrochloride Chemical compound Cl.Cl.S1C(N=CC=C1)N MCPRYBIHGJROPH-UHFFFAOYSA-N 0.000 description 1
- JOPJLJTXWMIJKO-UHFFFAOYSA-N 2h-thiazin-3-amine Chemical compound NC1=CC=CSN1 JOPJLJTXWMIJKO-UHFFFAOYSA-N 0.000 description 1
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 101150058765 BACE1 gene Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- JEMSASLKMDYHPW-UHFFFAOYSA-N CC(=N)C1=CC(Br)=CC=C1F Chemical compound CC(=N)C1=CC(Br)=CC=C1F JEMSASLKMDYHPW-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- QTHPQDYBTVANRZ-KRWDZBQOSA-N N-[(4S)-4-[2,4-difluoro-5-(3-fluoropyrazin-2-yl)phenyl]-4-methyl-5,6-dihydro-1,3-thiazin-2-yl]acetamide Chemical compound FC1=C(C=C(C(=C1)F)C1=NC=CN=C1F)[C@]1(N=C(SCC1)NC(C)=O)C QTHPQDYBTVANRZ-KRWDZBQOSA-N 0.000 description 1
- GXECLDICCSXZSP-IBGZPJMESA-N N-[(4S)-4-[3-(5-methoxypyridin-3-yl)phenyl]-4-methyl-5,6-dihydro-1,3-thiazin-2-yl]acetamide Chemical compound COC=1C=C(C=NC=1)C=1C=C(C=CC=1)[C@]1(N=C(SCC1)NC(C)=O)C GXECLDICCSXZSP-IBGZPJMESA-N 0.000 description 1
- GXECLDICCSXZSP-UHFFFAOYSA-N N-[4-[3-(5-methoxypyridin-3-yl)phenyl]-4-methyl-5,6-dihydro-1,3-thiazin-2-yl]acetamide Chemical compound COC=1C=C(C=NC=1)C=1C=C(C=CC=1)C1(N=C(SCC1)NC(C)=O)C GXECLDICCSXZSP-UHFFFAOYSA-N 0.000 description 1
- 229910020667 PBr3 Inorganic materials 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 238000006619 Stille reaction Methods 0.000 description 1
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- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- DYDOITXRFFQQKH-MERQFXBCSA-N methyl (3S)-3-amino-3-(3-bromo-4-fluorophenyl)butanoate hydrochloride Chemical compound Cl.COC(=O)C[C@](C)(N)c1ccc(F)c(Br)c1 DYDOITXRFFQQKH-MERQFXBCSA-N 0.000 description 1
- KQBDWDOQBQWJDG-MERQFXBCSA-N methyl (3S)-3-amino-3-(5-bromo-2-fluorophenyl)butanoate hydrochloride Chemical compound Cl.COC(=O)C[C@](C)(N)c1cc(Br)ccc1F KQBDWDOQBQWJDG-MERQFXBCSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 1
- ZYGGDAIQRNBGHM-ZDUSSCGKSA-N n-[(4s)-4-(3-bromo-4-fluorophenyl)-4-methyl-5,6-dihydro-1,3-thiazin-2-yl]acetamide Chemical compound C1CSC(NC(=O)C)=N[C@]1(C)C1=CC=C(F)C(Br)=C1 ZYGGDAIQRNBGHM-ZDUSSCGKSA-N 0.000 description 1
- VJIUYRLAAHCVIS-ZDUSSCGKSA-N n-[(4s)-4-(3-bromophenyl)-4-methyl-5,6-dihydro-1,3-thiazin-2-yl]acetamide Chemical compound C1CSC(NC(=O)C)=N[C@]1(C)C1=CC=CC(Br)=C1 VJIUYRLAAHCVIS-ZDUSSCGKSA-N 0.000 description 1
- XNXNVFVQLXRZIS-SFHVURJKSA-N n-[(4s)-4-[3-(5-chloro-2-fluoropyridin-3-yl)phenyl]-4-methyl-5,6-dihydro-1,3-thiazin-2-yl]acetamide Chemical compound C1CSC(NC(=O)C)=N[C@]1(C)C1=CC=CC(C=2C(=NC=C(Cl)C=2)F)=C1 XNXNVFVQLXRZIS-SFHVURJKSA-N 0.000 description 1
- LICUJTDRZXSSOT-KRWDZBQOSA-N n-[(4s)-4-[4-fluoro-3-(3-fluoropyrazin-2-yl)phenyl]-4-methyl-5,6-dihydro-1,3-thiazin-2-yl]acetamide Chemical compound C1CSC(NC(=O)C)=N[C@]1(C)C1=CC=C(F)C(C=2C(=NC=CN=2)F)=C1 LICUJTDRZXSSOT-KRWDZBQOSA-N 0.000 description 1
- FDWTWBRRSKCTAA-KRWDZBQOSA-N n-[(4s)-4-methyl-4-(3-pyrimidin-5-ylphenyl)-5,6-dihydro-1,3-thiazin-2-yl]acetamide Chemical compound C1CSC(NC(=O)C)=N[C@]1(C)C1=CC=CC(C=2C=NC=NC=2)=C1 FDWTWBRRSKCTAA-KRWDZBQOSA-N 0.000 description 1
- LJYVHAAXTPZBPB-MRXNPFEDSA-N n-[1-(3-bromophenyl)ethylidene]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N=C(C)C1=CC=CC(Br)=C1 LJYVHAAXTPZBPB-MRXNPFEDSA-N 0.000 description 1
- PMFCPCOIHBIRHC-GOSISDBHSA-N n-[1-(5-bromo-2,4-difluorophenyl)ethylidene]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N=C(C)C1=CC(Br)=C(F)C=C1F PMFCPCOIHBIRHC-GOSISDBHSA-N 0.000 description 1
- VJIUYRLAAHCVIS-UHFFFAOYSA-N n-[4-(3-bromophenyl)-4-methyl-5,6-dihydro-1,3-thiazin-2-yl]acetamide Chemical compound C1CSC(NC(=O)C)=NC1(C)C1=CC=CC(Br)=C1 VJIUYRLAAHCVIS-UHFFFAOYSA-N 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- HZFPPBMKGYINDF-UHFFFAOYSA-N pyrimidin-5-ylboronic acid Chemical compound OB(O)C1=CN=CN=C1 HZFPPBMKGYINDF-UHFFFAOYSA-N 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- CESUXLKAADQNTB-UHFFFAOYSA-N tert-butanesulfinamide Chemical compound CC(C)(C)S(N)=O CESUXLKAADQNTB-UHFFFAOYSA-N 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- JUDXOKKZTISQDJ-UHFFFAOYSA-N triphenylphosphane;hydrochloride Chemical compound Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 JUDXOKKZTISQDJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
- C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other 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
- A61P25/28—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
Landscapes
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US49881P | 1997-06-17 | ||
| US4988108P | 2008-05-02 | 2008-05-02 | |
| PCT/US2009/040589 WO2009134617A1 (en) | 2008-05-02 | 2009-04-15 | Aminodihydrothiazine derivatives as bace inhibitors for the treatment of alzheimer's disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2549087T3 true ES2549087T3 (es) | 2015-10-22 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES09739419.1T Active ES2549087T3 (es) | 2008-05-02 | 2009-04-15 | Derivados de aminodihidrotiazina como inhibidores de BACE para el tratamiento de la enfermedad de Alzheimer |
Country Status (32)
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US7700603B2 (en) | 2003-12-15 | 2010-04-20 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
| US7763609B2 (en) | 2003-12-15 | 2010-07-27 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
| SG162790A1 (en) | 2005-06-14 | 2010-07-29 | Schering Corp | Aspartyl protease inhibitors |
| CN101394852A (zh) | 2005-06-14 | 2009-03-25 | 先灵公司 | 作为蛋白酶抑制剂的化合物的制备和用途 |
| AU2006307314C1 (en) | 2005-10-25 | 2011-08-25 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivative |
| PE20080155A1 (es) | 2006-06-12 | 2008-03-10 | Schering Corp | Compuestos heterociclicos como inhibidores de aspartil-proteasa |
| ES2476605T3 (es) | 2007-04-24 | 2014-07-15 | Shionogi & Co., Ltd. | Derivados de aminohidrotiazina sustituidos con grupos cíclicos |
| JP5383483B2 (ja) | 2007-04-24 | 2014-01-08 | 塩野義製薬株式会社 | アルツハイマー症治療用医薬組成物 |
| ES2548774T3 (es) * | 2008-01-18 | 2015-10-20 | Eisai R&D Management Co., Ltd. | Derivado de aminodihidrotiazina condensado |
| US8541427B2 (en) | 2008-04-22 | 2013-09-24 | Merck, Sharp & Dohme, Corp. | Phenyl-substituted 2-imino-3-methyl pyrrolo pyrimidinone compounds as BACE-1 inhibitors, compositions, and their use |
| TWI431004B (zh) * | 2008-05-02 | 2014-03-21 | Lilly Co Eli | Ｂａｃｅ抑制劑 |
| AU2009258496B8 (en) | 2008-06-13 | 2014-06-26 | Shionogi & Co., Ltd. | Sulfur-containing heterocyclic derivative having beta-secretase-inhibiting activity |
| WO2010013794A1 (en) * | 2008-07-28 | 2010-02-04 | Eisai R&D Management Co., Ltd. | Spiroaminodihydrothiazine derivatives |
| EP2324032B1 (en) | 2008-08-19 | 2014-10-01 | Vitae Pharmaceuticals, Inc. | Inhibitors of beta-secretase |
| CN102209721A (zh) | 2008-09-11 | 2011-10-05 | 安姆根有限公司 | 作为β-分泌酶调节剂的螺四环化合物及其使用方法 |
| KR20110076965A (ko) * | 2008-09-30 | 2011-07-06 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 신규한 축합 아미노 디하이드로티아진 유도체 |
| WO2010047372A1 (ja) | 2008-10-22 | 2010-04-29 | 塩野義製薬株式会社 | Ｂａｃｅ１阻害活性を有する２－アミノピリミジン－４－オンおよび２－アミノピリジン誘導体 |
| CN102348698B (zh) | 2009-03-13 | 2015-06-03 | 生命医药公司 | β-分泌酶的抑制剂 |
| GB0912778D0 (en) | 2009-07-22 | 2009-08-26 | Eisai London Res Lab Ltd | Fused aminodihydro-oxazine derivatives |
| GB0912777D0 (en) | 2009-07-22 | 2009-08-26 | Eisai London Res Lab Ltd | Fused aminodihydropyrimidone derivatives |
| UA108363C2 (uk) | 2009-10-08 | 2015-04-27 | Похідні імінотіадіазиндіоксиду як інгібітори bace, композиція на їх основі і їх застосування | |
| AU2013234424B9 (en) * | 2009-10-08 | 2014-07-03 | Merck Sharp & Dohme Llc | Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use |
| US8563543B2 (en) | 2009-10-08 | 2013-10-22 | Merck Sharp & Dohme Corp. | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
| US8569310B2 (en) | 2009-10-08 | 2013-10-29 | Merck Sharp & Dohme Corp. | Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions and their use |
| EP2485590B1 (en) | 2009-10-08 | 2015-01-07 | Merck Sharp & Dohme Corp. | Pentafluorosulfur imino heterocyclic compounds as bace-1 inhibitors, compositions, and their use |
| EP2514747A4 (en) | 2009-12-09 | 2013-05-08 | Shionogi & Co | SUBSTITUTED AMINOTHIAZINE DERIVATIVE |
| JP5554346B2 (ja) * | 2009-12-09 | 2014-07-23 | 塩野義製薬株式会社 | 含硫黄複素環誘導体を含有するアルツハイマー症の治療用または予防用医薬組成物 |
| UA110467C2 (uk) | 2009-12-11 | 2016-01-12 | Шионогі Енд Ко., Лтд. | Похідні оксазину |
| WO2011077726A1 (ja) | 2009-12-24 | 2011-06-30 | 塩野義製薬株式会社 | ４－アミノ－１，３－チアジンまたはオキサジン誘導体 |
| EP2539322B1 (en) | 2010-02-24 | 2014-01-01 | Vitae Pharmaceuticals, Inc. | Inhibitors of beta-secretase |
| JP5584352B2 (ja) | 2010-03-15 | 2014-09-03 | アムジエン・インコーポレーテツド | β−セクレターゼ調節剤としてのアミノ−ジヒドロオキサジン系およびアミノ−ジヒドロチアジン系スピロ化合物ならびにそれらの医学的用途 |
| JP2013522305A (ja) | 2010-03-15 | 2013-06-13 | アムジエン・インコーポレーテツド | β−セクレターゼ調節剤としてのスピロ−四環式環化合物 |
| PH12012502377A1 (en) | 2010-06-09 | 2014-10-14 | Janssen Pharmaceutica Nv | 5,6-dihydro-2h-[1,4]oxazin-3-yl-amine derivatives useful as inhibitors of beta-secretase (bace) |
| US20130079349A1 (en) * | 2010-06-09 | 2013-03-28 | Janssen Pharmaceutica Nv | 5-amino-3,6-dihydro-1h-pyrazin-2-one derivatives useful as inhibitors of beta-secretase (bace) |
| EP2601197B1 (en) | 2010-08-05 | 2014-06-25 | Amgen Inc. | Amino-iso-indole, amino-aza-iso-indole, amino-dihydroisoquinoline and amino-benzoxazine compounds as beta-secretase modulators and methods of use |
| JP5766198B2 (ja) | 2010-10-29 | 2015-08-19 | 塩野義製薬株式会社 | 縮合アミノジヒドロピリミジン誘導体 |
| CN103261199A (zh) | 2010-10-29 | 2013-08-21 | 盐野义制药株式会社 | 萘啶衍生物 |
| WO2012071279A1 (en) | 2010-11-23 | 2012-05-31 | Amgen Inc. | Spiro-amino-imidazolone and spiro-amino-dihydro-pyrimidinone compounds as beta-secretase modulators and methods of use |
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