CA2819158A1 - 1,4 oxazines as bace1 and/or bace2 inhibitors - Google Patents
1,4 oxazines as bace1 and/or bace2 inhibitors Download PDFInfo
- Publication number
- CA2819158A1 CA2819158A1 CA2819158A CA2819158A CA2819158A1 CA 2819158 A1 CA2819158 A1 CA 2819158A1 CA 2819158 A CA2819158 A CA 2819158A CA 2819158 A CA2819158 A CA 2819158A CA 2819158 A1 CA2819158 A1 CA 2819158A1
- Authority
- CA
- Canada
- Prior art keywords
- dihydro
- methyl
- oxazin
- alkyl
- fluoro
- 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.)
- Abandoned
Links
- 239000003112 inhibitor Substances 0.000 title claims description 18
- 150000004896 1,4-oxazines Chemical class 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 238
- 102100021277 Beta-secretase 2 Human genes 0.000 claims abstract description 37
- 101000894883 Homo sapiens Beta-secretase 2 Proteins 0.000 claims abstract description 36
- 102100021257 Beta-secretase 1 Human genes 0.000 claims abstract description 34
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 claims abstract description 33
- 238000004519 manufacturing process Methods 0.000 claims abstract description 27
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 26
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 26
- 238000011321 prophylaxis Methods 0.000 claims abstract description 23
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 23
- 239000013543 active substance Substances 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- -1 difluoromethoxy, 2-fluoro-ethoxy, 2,2-difluoro-ethoxy Chemical group 0.000 claims description 116
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 75
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 66
- 229910052736 halogen Inorganic materials 0.000 claims description 66
- 150000002367 halogens Chemical class 0.000 claims description 65
- 125000001424 substituent group Chemical group 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 43
- 230000005764 inhibitory process Effects 0.000 claims description 30
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 230000000694 effects Effects 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 25
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 208000037259 Amyloid Plaque Diseases 0.000 claims description 14
- 206010012601 diabetes mellitus Diseases 0.000 claims description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 12
- 208000037765 diseases and disorders Diseases 0.000 claims description 11
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 9
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 claims description 8
- 201000008319 inclusion body myositis Diseases 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 7
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 201000010374 Down Syndrome Diseases 0.000 claims description 6
- 206010044688 Trisomy 21 Diseases 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 125000003368 amide group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 5
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 206010003178 Arterial thrombosis Diseases 0.000 claims description 4
- 102000007368 Ataxin-7 Human genes 0.000 claims description 4
- 108010032953 Ataxin-7 Proteins 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 4
- 201000010915 Glioblastoma multiforme Diseases 0.000 claims description 4
- 208000003807 Graves Disease Diseases 0.000 claims description 4
- 208000015023 Graves' disease Diseases 0.000 claims description 4
- 208000002972 Hepatolenticular Degeneration Diseases 0.000 claims description 4
- 208000023105 Huntington disease Diseases 0.000 claims description 4
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 208000003456 Juvenile Arthritis Diseases 0.000 claims description 4
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims description 4
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 4
- 208000002447 Macrophagic myofasciitis Diseases 0.000 claims description 4
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 4
- 208000006011 Stroke Diseases 0.000 claims description 4
- 208000018839 Wilson disease Diseases 0.000 claims description 4
- 206010003246 arthritis Diseases 0.000 claims description 4
- 230000001363 autoimmune Effects 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 201000001981 dermatomyositis Diseases 0.000 claims description 4
- 208000005017 glioblastoma Diseases 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 claims description 4
- 206010025135 lupus erythematosus Diseases 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- QRXTWNWAFMAMIP-AWEZNQCLSA-N (5r)-5-[2-fluoro-5-(1,2-oxazol-3-ylamino)phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC2=NOC=C2)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 QRXTWNWAFMAMIP-AWEZNQCLSA-N 0.000 claims description 3
- DSRMJUAEYUDBRT-ZDUSSCGKSA-N (5r)-5-[5-(2,2-difluoroethylamino)-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NCC(F)F)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 DSRMJUAEYUDBRT-ZDUSSCGKSA-N 0.000 claims description 3
- 125000005955 1H-indazolyl group Chemical group 0.000 claims description 3
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 3
- BIQLWJAOBRCFDO-UHFFFAOYSA-N 5-[3-[(5-chloro-2,3-dihydro-1h-inden-1-yl)amino]phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C=CC(NC2C3=CC=C(Cl)C=C3CC2)=CC=1C1(C)COCC(N)=N1 BIQLWJAOBRCFDO-UHFFFAOYSA-N 0.000 claims description 3
- 208000025212 Constitutional neutropenia Diseases 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- 208000027207 Whipple disease Diseases 0.000 claims description 3
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 208000027390 severe congenital neutropenia 3 Diseases 0.000 claims description 3
- IUECETKEUARTFS-MHTVFEQDSA-N (5r)-5-[2-fluoro-5-(oxolan-3-ylamino)phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC2COCC2)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 IUECETKEUARTFS-MHTVFEQDSA-N 0.000 claims description 2
- IVCFPJIINVIDFL-ROPPNANJSA-N (5s)-5-[5-[(5-chloro-2,3-dihydro-1h-inden-1-yl)amino]-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC2C3=CC=C(Cl)C=C3CC2)=CC=C(F)C=1[C@@]1(C)COCC(N)=N1 IVCFPJIINVIDFL-ROPPNANJSA-N 0.000 claims description 2
- JXUFFJSEYVIGAA-MLVYHOMMSA-N (5s)-5-[5-[(5-chloro-2,3-dihydro-1h-inden-1-yl)amino]-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine;hydrochloride Chemical compound Cl.C=1C(NC2C3=CC=C(Cl)C=C3CC2)=CC=C(F)C=1[C@@]1(C)COCC(N)=N1 JXUFFJSEYVIGAA-MLVYHOMMSA-N 0.000 claims description 2
- MNPQSOIYEJRNIW-UHFFFAOYSA-N 5-[3-[(3-chlorophenyl)methylamino]phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C=CC(NCC=2C=C(Cl)C=CC=2)=CC=1C1(C)COCC(N)=N1 MNPQSOIYEJRNIW-UHFFFAOYSA-N 0.000 claims description 2
- IIOABHPKSLIUSW-UHFFFAOYSA-N 5-[3-[2-(difluoromethoxy)anilino]phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C=CC(NC=2C(=CC=CC=2)OC(F)F)=CC=1C1(C)COCC(N)=N1 IIOABHPKSLIUSW-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 4
- SNBVGRNXFMZUNZ-INIZCTEOSA-N (5r)-5-[5-(cyclopentylamino)-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC2CCCC2)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 SNBVGRNXFMZUNZ-INIZCTEOSA-N 0.000 claims 2
- RWCZTUDBYGQJTK-LZWOXQAQSA-N (1r,2s)-2-[3-[(3r)-5-amino-3-methyl-2,6-dihydro-1,4-oxazin-3-yl]-4-fluoroanilino]cyclopentan-1-ol Chemical compound C=1C(N[C@@H]2[C@@H](CCC2)O)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 RWCZTUDBYGQJTK-LZWOXQAQSA-N 0.000 claims 1
- RWCZTUDBYGQJTK-DZKIICNBSA-N (1s,2s)-2-[3-[(3r)-5-amino-3-methyl-2,6-dihydro-1,4-oxazin-3-yl]-4-fluoroanilino]cyclopentan-1-ol Chemical compound C=1C(N[C@@H]2[C@H](CCC2)O)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 RWCZTUDBYGQJTK-DZKIICNBSA-N 0.000 claims 1
- FOMKAUKZKZNSRI-LBPRGKRZSA-N (5r)-5-[2-fluoro-5-(2,2,2-trifluoroethylamino)phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NCC(F)(F)F)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 FOMKAUKZKZNSRI-LBPRGKRZSA-N 0.000 claims 1
- IDIJEPWZHXCJCL-LBPRGKRZSA-N (5r)-5-[2-fluoro-5-(2,2,3,3,3-pentafluoropropylamino)phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NCC(F)(F)C(F)(F)F)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 IDIJEPWZHXCJCL-LBPRGKRZSA-N 0.000 claims 1
- YHBCCGYRJHZRIT-ZDUSSCGKSA-N (5r)-5-[2-fluoro-5-(3,3,3-trifluoropropylamino)phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NCCC(F)(F)F)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 YHBCCGYRJHZRIT-ZDUSSCGKSA-N 0.000 claims 1
- VEBDOPAMPGWBDV-NBFOKTCDSA-N (5r)-5-[2-fluoro-5-(3-methylbutan-2-ylamino)phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound CC(C)C(C)NC1=CC=C(F)C([C@@]2(C)N=C(N)COC2)=C1 VEBDOPAMPGWBDV-NBFOKTCDSA-N 0.000 claims 1
- VGSIYGKAKNKCHH-INIZCTEOSA-N (5r)-5-[2-fluoro-5-(3-methylbutylamino)phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound CC(C)CCNC1=CC=C(F)C([C@@]2(C)N=C(N)COC2)=C1 VGSIYGKAKNKCHH-INIZCTEOSA-N 0.000 claims 1
- HCGNKVLPKJMANG-HNNXBMFYSA-N (5r)-5-[2-fluoro-5-(3-methylsulfanylpropylamino)phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound CSCCCNC1=CC=C(F)C([C@@]2(C)N=C(N)COC2)=C1 HCGNKVLPKJMANG-HNNXBMFYSA-N 0.000 claims 1
- FZNGSQOVFGNTTD-INIZCTEOSA-N (5r)-5-[2-fluoro-5-(pentan-3-ylamino)phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound CCC(CC)NC1=CC=C(F)C([C@@]2(C)N=C(N)COC2)=C1 FZNGSQOVFGNTTD-INIZCTEOSA-N 0.000 claims 1
- AZHQHJIUMFMAEH-SFHVURJKSA-N (5r)-5-[2-fluoro-5-[2-(2,2,2-trifluoroethoxy)anilino]phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC=2C(=CC=CC=2)OCC(F)(F)F)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 AZHQHJIUMFMAEH-SFHVURJKSA-N 0.000 claims 1
- CGDLCHMMXOYPSB-IBGZPJMESA-N (5r)-5-[2-fluoro-5-[2-(2-fluoroethoxy)anilino]phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC=2C(=CC=CC=2)OCCF)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 CGDLCHMMXOYPSB-IBGZPJMESA-N 0.000 claims 1
- FSAJCWVALVMAKW-WBMJQRKESA-N (5r)-5-[2-fluoro-5-[[(2r)-oxolan-2-yl]methylamino]phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC[C@@H]2OCCC2)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 FSAJCWVALVMAKW-WBMJQRKESA-N 0.000 claims 1
- PEKTURXUQVGPEG-NRFANRHFSA-N (5r)-5-[2-fluoro-5-[[3-(2,2,2-trifluoroethoxy)quinolin-8-yl]amino]phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC=2C3=NC=C(OCC(F)(F)F)C=C3C=CC=2)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 PEKTURXUQVGPEG-NRFANRHFSA-N 0.000 claims 1
- BAKRUGCZKCVDEM-QFIPXVFZSA-N (5r)-5-[2-fluoro-5-[[3-(2-fluoroethoxy)quinolin-8-yl]amino]phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC=2C3=NC=C(OCCF)C=C3C=CC=2)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 BAKRUGCZKCVDEM-QFIPXVFZSA-N 0.000 claims 1
- FMVKCRWWNAQUEF-HNNXBMFYSA-N (5r)-5-[5-(butylamino)-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound CCCCNC1=CC=C(F)C([C@@]2(C)N=C(N)COC2)=C1 FMVKCRWWNAQUEF-HNNXBMFYSA-N 0.000 claims 1
- KKLMFSIUUFHDAW-HNNXBMFYSA-N (5r)-5-[5-(cyclobutylamino)-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC2CCC2)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 KKLMFSIUUFHDAW-HNNXBMFYSA-N 0.000 claims 1
- MFIGRCBCTKHMRZ-KRWDZBQOSA-N (5r)-5-[5-(cyclohexylamino)-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC2CCCCC2)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 MFIGRCBCTKHMRZ-KRWDZBQOSA-N 0.000 claims 1
- ORNNHNZPHILLPY-HNNXBMFYSA-N (5r)-5-[5-(cyclopropylmethylamino)-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NCC2CC2)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 ORNNHNZPHILLPY-HNNXBMFYSA-N 0.000 claims 1
- JQWLQZLXFFDJIN-CVMIBEPCSA-N (5r)-5-[5-[(3-chloro-6,7-dihydro-5h-cyclopenta[b]pyridin-7-yl)amino]-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC2C3=NC=C(Cl)C=C3CC2)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 JQWLQZLXFFDJIN-CVMIBEPCSA-N 0.000 claims 1
- QMXOUBXMBUQGFI-FQEVSTJZSA-N (5r)-5-[5-[(3-chloro-6-fluoroquinolin-8-yl)amino]-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC=2C3=NC=C(Cl)C=C3C=C(F)C=2)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 QMXOUBXMBUQGFI-FQEVSTJZSA-N 0.000 claims 1
- UCGIYSHWKADWCV-BDQAORGHSA-N (5r)-5-[5-[(3-chloro-6-fluoroquinolin-8-yl)amino]-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine;hydrochloride Chemical compound Cl.C=1C(NC=2C3=NC=C(Cl)C=C3C=C(F)C=2)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 UCGIYSHWKADWCV-BDQAORGHSA-N 0.000 claims 1
- OSRJQZXSYLZQHL-BDQAORGHSA-N (5r)-5-[5-[(3-chloroquinolin-8-yl)amino]-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine;hydrochloride Chemical compound Cl.C=1C(NC=2C3=NC=C(Cl)C=C3C=CC=2)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 OSRJQZXSYLZQHL-BDQAORGHSA-N 0.000 claims 1
- QNHDYGNNUMCCRR-IBGZPJMESA-N (5r)-5-[5-[2-(2,2-difluoroethoxy)anilino]-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC=2C(=CC=CC=2)OCC(F)F)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 QNHDYGNNUMCCRR-IBGZPJMESA-N 0.000 claims 1
- XUDAQSPLHDYMTP-ANYOKISRSA-N (5r)-5-[5-[[1-(5-chloropyridin-2-yl)-2-methylpropyl]amino]-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C=C(Cl)C=NC=1C(C(C)C)NC(C=1)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 XUDAQSPLHDYMTP-ANYOKISRSA-N 0.000 claims 1
- HLTYVBBHDLMJQB-DEOSSOPVSA-N (5r)-5-[5-[[3-(cyclopropylmethoxy)-6-fluoroquinolin-8-yl]amino]-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC=2C3=NC=C(OCC4CC4)C=C3C=C(F)C=2)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 HLTYVBBHDLMJQB-DEOSSOPVSA-N 0.000 claims 1
- CHPYWNCYTLASBD-NRFANRHFSA-N (5r)-5-[5-[[3-(difluoromethoxy)quinolin-8-yl]amino]-2-fluorophenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine Chemical compound C=1C(NC=2C3=NC=C(OC(F)F)C=C3C=CC=2)=CC=C(F)C=1[C@]1(C)COCC(N)=N1 CHPYWNCYTLASBD-NRFANRHFSA-N 0.000 claims 1
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Classifications
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- 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
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- 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
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- 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
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- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
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- Engineering & Computer Science (AREA)
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- Physical Education & Sports Medicine (AREA)
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- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Psychology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (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)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP11151294 | 2011-01-18 | ||
| EP11151294.3 | 2011-01-18 | ||
| PCT/EP2012/050537 WO2012098064A1 (en) | 2011-01-18 | 2012-01-16 | 1,4 oxazines as bace1 and/or bace2 inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2819158A1 true CA2819158A1 (en) | 2012-07-26 |
Family
ID=45491607
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2819158A Abandoned CA2819158A1 (en) | 2011-01-18 | 2012-01-16 | 1,4 oxazines as bace1 and/or bace2 inhibitors |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US9242943B2 (enExample) |
| EP (1) | EP2665713A1 (enExample) |
| JP (1) | JP2014502982A (enExample) |
| KR (1) | KR20140014133A (enExample) |
| CN (1) | CN103328454A (enExample) |
| BR (1) | BR112013016360A2 (enExample) |
| CA (1) | CA2819158A1 (enExample) |
| MX (1) | MX2013007558A (enExample) |
| RU (1) | RU2013135678A (enExample) |
| WO (1) | WO2012098064A1 (enExample) |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936690B (zh) | 2005-10-25 | 2016-06-08 | 盐野义制药株式会社 | 氨基二氢噻嗪衍生物 |
| RU2476430C2 (ru) | 2007-04-24 | 2013-02-27 | Сионоги Энд Ко., Лтд. | Производные аминодигидротиазина, замещенные циклической группой |
| WO2008133273A1 (ja) | 2007-04-24 | 2008-11-06 | Shionogi & Co., Ltd. | アルツハイマー症治療用医薬組成物 |
| ES2738123T3 (es) | 2008-06-13 | 2020-01-20 | Shionogi & Co | Derivado heterocíclico que contiene azufre que tiene actividad inhibitoria de ß-secretasa |
| 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 |
| UA108363C2 (uk) | 2009-10-08 | 2015-04-27 | Похідні імінотіадіазиндіоксиду як інгібітори bace, композиція на їх основі і їх застосування | |
| EP2485920B1 (en) | 2009-10-08 | 2016-04-27 | 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 |
| WO2011044187A1 (en) | 2009-10-08 | 2011-04-14 | Schering Corporation | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
| WO2011071135A1 (ja) | 2009-12-11 | 2011-06-16 | 塩野義製薬株式会社 | オキサジン誘導体 |
| 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) |
| US8927721B2 (en) | 2010-10-29 | 2015-01-06 | Shionogi & Co., Ltd. | Naphthyridine derivative |
| WO2012057247A1 (ja) | 2010-10-29 | 2012-05-03 | 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 |
| EP2655376B1 (en) | 2010-12-22 | 2017-08-23 | Janssen Pharmaceutica NV | 5,6-DIHYDRO-IMIDAZO[1,2-a]PYRAZIN-8-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE) |
| MY161407A (en) | 2011-03-01 | 2017-04-14 | Janssen Pharmaceutica Nv | 6,7-DIHYDRO-PYRAZOLO[1,5-a]PYRAZIN-4-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE) |
| SG193342A1 (en) | 2011-03-09 | 2013-10-30 | Janssen Pharmaceutica Nv | 3,4-DIHYDRO-PYRROLO[1,2-a]PYRAZIN-1-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE) |
| EP2694521B1 (en) | 2011-04-07 | 2015-11-25 | Merck Sharp & Dohme Corp. | Pyrrolidine-fused thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
| EP2694489B1 (en) | 2011-04-07 | 2017-09-06 | Merck Sharp & Dohme Corp. | C5-c6 oxacyclic-fused thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
| JPWO2012147763A1 (ja) | 2011-04-26 | 2014-07-28 | 塩野義製薬株式会社 | オキサジン誘導体およびそれを含有するｂａｃｅ１阻害剤 |
| KR20140054295A (ko) | 2011-08-22 | 2014-05-08 | 머크 샤프 앤드 돔 코포레이션 | Bace 억제제로서의 2-스피로-치환된 이미노티아진 및 그의 모노- 및 디옥시드, 조성물 및 그의 용도 |
| WO2013054291A1 (en) * | 2011-10-13 | 2013-04-18 | Novartis Ag | Novel oxazine derivatives and their use in the treatment of disease |
| WO2013083556A1 (en) * | 2011-12-06 | 2013-06-13 | Janssen Pharmaceutica Nv | 5-(3-aminophenyl)-5-alkyl-5,6-dihydro-2h-[1,4]oxazin-3-amine derivatives |
| US9556135B2 (en) * | 2012-10-12 | 2017-01-31 | Amgen, Inc. | Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use |
| EP2912035A4 (en) | 2012-10-24 | 2016-06-15 | Shionogi & Co | DERIVATIVES OF DIHYDROOXAZINE OR OXAZEPINE HAVING BACE1 INHIBITING ACTIVITY |
| AU2014280124B2 (en) | 2013-06-12 | 2018-11-01 | Janssen Pharmaceutica Nv | 4-amino-6-phenyl-5,6-dihydroimidazo[1,5-a]pyrazine derivatives as inhibitors of beta-secretase (BACE) |
| JP6387402B2 (ja) | 2013-06-12 | 2018-09-05 | ヤンセン ファーマシューティカ エヌ．ベー． | β−セクレターゼ（ＢＡＣＥ）の阻害剤としての４−アミノ−６−フェニル−５，６−ジヒドロイミダゾ［１，５−Ａ］ピラジン−３（２Ｈ）−オン誘導体 |
| BR112015030597A2 (pt) | 2013-06-12 | 2017-07-25 | Janssen Pharmaceutica Nv | derivados 4-amino-6-fenil-6,7-di-hidro[1,2,3]triazolo[1,5-a]pirazina como inibidores de beta-secretase (bace) |
| CN107108582B (zh) | 2014-12-18 | 2019-10-18 | 詹森药业有限公司 | β-分泌酶的2，3，4，5-四氢吡啶-6-胺化合物抑制剂 |
| EP3271355B1 (en) | 2015-03-20 | 2020-07-29 | H. Hoffnabb-La Roche Ag | Bace1 inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PE20060692A1 (es) | 2004-09-21 | 2006-07-19 | Lilly Co Eli | Inhibidores bace |
| WO2009024615A1 (en) * | 2007-08-23 | 2009-02-26 | Novartis Ag | Aminobenzyl-substituted cyclic sulfones useful as bace inhibitors |
| ES2738123T3 (es) | 2008-06-13 | 2020-01-20 | Shionogi & Co | Derivado heterocíclico que contiene azufre que tiene actividad inhibitoria de ß-secretasa |
| US8461160B2 (en) | 2009-05-08 | 2013-06-11 | Hoffmann-La Roche, Inc. | Dihydropyrimidinones |
| AR077328A1 (es) * | 2009-07-24 | 2011-08-17 | Novartis Ag | Derivados de oxazina y su uso en el tratamiento de trastornos neurologicos |
| US8188079B2 (en) | 2009-08-19 | 2012-05-29 | Hoffman-La Roche Inc. | 3-amino-5-phenyl-5,6-dihydro-2H-[1,4]oxazines |
| US8673894B2 (en) * | 2010-05-07 | 2014-03-18 | Hoffmann-La Roche Inc. | 2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine or 2,3,6,7-tetrahydro-[1,4]oxazepin-5-ylamine compounds |
| US8748418B2 (en) * | 2011-03-18 | 2014-06-10 | Hoffmann-La Roche Inc. | 1,4-oxazepines as BACE1 and/or BACE2 inhibitors |
| US8785436B2 (en) * | 2011-05-16 | 2014-07-22 | Hoffmann-La Roche Inc. | 1,3-oxazines as BACE 1 and/or BACE2 inhibitors |
-
2012
- 2012-01-12 US US13/348,675 patent/US9242943B2/en not_active Expired - Fee Related
- 2012-01-16 WO PCT/EP2012/050537 patent/WO2012098064A1/en not_active Ceased
- 2012-01-16 RU RU2013135678/04A patent/RU2013135678A/ru not_active Application Discontinuation
- 2012-01-16 JP JP2013549780A patent/JP2014502982A/ja active Pending
- 2012-01-16 KR KR1020137021420A patent/KR20140014133A/ko not_active Withdrawn
- 2012-01-16 BR BR112013016360A patent/BR112013016360A2/pt not_active IP Right Cessation
- 2012-01-16 CA CA2819158A patent/CA2819158A1/en not_active Abandoned
- 2012-01-16 EP EP12700341.6A patent/EP2665713A1/en not_active Withdrawn
- 2012-01-16 CN CN201280005579XA patent/CN103328454A/zh active Pending
- 2012-01-16 MX MX2013007558A patent/MX2013007558A/es active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| EP2665713A1 (en) | 2013-11-27 |
| US9242943B2 (en) | 2016-01-26 |
| CN103328454A (zh) | 2013-09-25 |
| MX2013007558A (es) | 2013-08-21 |
| WO2012098064A1 (en) | 2012-07-26 |
| US20120184540A1 (en) | 2012-07-19 |
| KR20140014133A (ko) | 2014-02-05 |
| BR112013016360A2 (pt) | 2018-06-26 |
| JP2014502982A (ja) | 2014-02-06 |
| RU2013135678A (ru) | 2015-02-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |
Effective date: 20170118 |