CA2657280A1 - Macrocyclic compounds useful as bace inhibitors - Google Patents
Macrocyclic compounds useful as bace inhibitors Download PDFInfo
- Publication number
- CA2657280A1 CA2657280A1 CA002657280A CA2657280A CA2657280A1 CA 2657280 A1 CA2657280 A1 CA 2657280A1 CA 002657280 A CA002657280 A CA 002657280A CA 2657280 A CA2657280 A CA 2657280A CA 2657280 A1 CA2657280 A1 CA 2657280A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- tetrahydro
- dioxo
- benzo
- cycloalkyl
- 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
- 150000002678 macrocyclic compounds Chemical class 0.000 title abstract description 4
- 239000003112 inhibitor Substances 0.000 title description 3
- 101150058765 BACE1 gene Proteins 0.000 title 1
- 239000002253 acid Substances 0.000 claims abstract description 28
- 150000003839 salts Chemical group 0.000 claims abstract description 20
- 239000012458 free base Substances 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- -1 chroman-4-yl Chemical group 0.000 claims description 101
- 125000000217 alkyl group Chemical group 0.000 claims description 80
- 150000001875 compounds Chemical class 0.000 claims description 72
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 72
- 125000001072 heteroaryl group Chemical group 0.000 claims description 57
- 125000003118 aryl group Chemical group 0.000 claims description 55
- 239000001257 hydrogen Substances 0.000 claims description 50
- 229910052739 hydrogen Inorganic materials 0.000 claims description 50
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 22
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 229910052740 iodine Inorganic materials 0.000 claims description 16
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 12
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 11
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 11
- 230000002776 aggregation Effects 0.000 claims description 11
- 238000004220 aggregation Methods 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000004043 oxo group Chemical group O=* 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- 230000000926 neurological effect Effects 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 9
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000005529 alkyleneoxy group Chemical group 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 3
- 125000005739 1,1,2,2-tetrafluoroethanediyl group Chemical group FC(F)([*:1])C(F)(F)[*:2] 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 239000002243 precursor Substances 0.000 claims description 3
- 229910052720 vanadium Inorganic materials 0.000 claims description 3
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 2
- 238000003776 cleavage reaction Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000005649 metathesis reaction Methods 0.000 claims description 2
- 229910052750 molybdenum Inorganic materials 0.000 claims description 2
- 239000011733 molybdenum Substances 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- 230000007017 scission Effects 0.000 claims description 2
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052721 tungsten Inorganic materials 0.000 claims description 2
- 239000010937 tungsten Substances 0.000 claims description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 11
- 208000012902 Nervous system disease Diseases 0.000 claims 4
- 208000025966 Neurological disease Diseases 0.000 claims 4
- 208000019553 vascular disease Diseases 0.000 claims 4
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 229940088679 drug related substance Drugs 0.000 claims 1
- 239000008024 pharmaceutical diluent Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- 239000000203 mixture Substances 0.000 description 98
- 239000000243 solution Substances 0.000 description 82
- 238000005160 1H NMR spectroscopy Methods 0.000 description 80
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 79
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- 239000000047 product Substances 0.000 description 62
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 55
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 53
- 239000011541 reaction mixture Substances 0.000 description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 48
- 229910052938 sodium sulfate Inorganic materials 0.000 description 48
- 235000011152 sodium sulphate Nutrition 0.000 description 48
- 239000012044 organic layer Substances 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- 235000019439 ethyl acetate Nutrition 0.000 description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 239000000741 silica gel Substances 0.000 description 24
- 229910002027 silica gel Inorganic materials 0.000 description 24
- 101150041968 CDC13 gene Proteins 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 238000004587 chromatography analysis Methods 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 238000007792 addition Methods 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- JPELMNSUASPHPS-UHFFFAOYSA-N 3-(methoxymethyl)-5-[pent-4-enyl(phenylmethoxycarbonyl)amino]benzoic acid Chemical compound OC(=O)C1=CC(COC)=CC(N(CCCC=C)C(=O)OCC=2C=CC=CC=2)=C1 JPELMNSUASPHPS-UHFFFAOYSA-N 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 239000012267 brine Substances 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 125000004076 pyridyl group Chemical group 0.000 description 10
- 229910052701 rubidium Inorganic materials 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 235000019270 ammonium chloride Nutrition 0.000 description 9
- 229960001040 ammonium chloride Drugs 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- CYNKCDPOIBRQLW-UHFFFAOYSA-N 1-(4-tert-butylpyridin-2-yl)cyclopropan-1-amine Chemical compound CC(C)(C)C1=CC=NC(C2(N)CC2)=C1 CYNKCDPOIBRQLW-UHFFFAOYSA-N 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000000842 isoxazolyl group Chemical group 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 235000011181 potassium carbonates Nutrition 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 230000001629 suppression Effects 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 230000002792 vascular Effects 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- 101710150190 Beta-secretase 2 Proteins 0.000 description 6
- 102100021277 Beta-secretase 2 Human genes 0.000 description 6
- 206010027476 Metastases Diseases 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 230000009401 metastasis Effects 0.000 description 6
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- CEPJQAFVPMIAJG-UHFFFAOYSA-N 1-(3-tert-butylphenyl)cyclopropan-1-amine Chemical compound CC(C)(C)C1=CC=CC(C2(N)CC2)=C1 CEPJQAFVPMIAJG-UHFFFAOYSA-N 0.000 description 5
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 5
- LPNANKDXVBMDKE-UHFFFAOYSA-N 5-bromopent-1-ene Chemical compound BrCCCC=C LPNANKDXVBMDKE-UHFFFAOYSA-N 0.000 description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 5
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 5
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 125000003107 substituted aryl group Chemical group 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- SEPPVOUBHWNCAW-FNORWQNLSA-N (E)-4-oxonon-2-enal Chemical compound CCCCCC(=O)\C=C\C=O SEPPVOUBHWNCAW-FNORWQNLSA-N 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 4
- LLBZPESJRQGYMB-UHFFFAOYSA-N 4-one Natural products O1C(C(=O)CC)CC(C)C11C2(C)CCC(C3(C)C(C(C)(CO)C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)CO5)OC5C(C(OC6C(C(O)C(O)C(CO)O6)O)C(O)C(CO)O5)OC5C(C(O)C(O)C(C)O5)O)O4)O)CC3)CC3)=C3C2(C)CC1 LLBZPESJRQGYMB-UHFFFAOYSA-N 0.000 description 4
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 4
- 102000003908 Cathepsin D Human genes 0.000 description 4
- 108090000258 Cathepsin D Proteins 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- CFGUDSWQBZVJSS-UHFFFAOYSA-N 1-[5-(2,2-dimethylpropyl)-1,2-oxazol-3-yl]cyclopropan-1-amine Chemical compound O1C(CC(C)(C)C)=CC(C2(N)CC2)=N1 CFGUDSWQBZVJSS-UHFFFAOYSA-N 0.000 description 3
- DPHOZQXFUMPVAF-UHFFFAOYSA-N 3-(1,3-oxazol-2-yl)-5-[pent-4-enyl(phenylmethoxycarbonyl)amino]benzoic acid Chemical compound C=1C(C(=O)O)=CC(N(CCCC=C)C(=O)OCC=2C=CC=CC=2)=CC=1C1=NC=CO1 DPHOZQXFUMPVAF-UHFFFAOYSA-N 0.000 description 3
- SIBYQNRJCNZUPK-UHFFFAOYSA-N 3-(1,3-oxazol-2-yl)-5-pent-4-enoxybenzoic acid Chemical compound OC(=O)C1=CC(OCCCC=C)=CC(C=2OC=CN=2)=C1 SIBYQNRJCNZUPK-UHFFFAOYSA-N 0.000 description 3
- LXZSZEGMJMPTGD-UHFFFAOYSA-N 3-methoxy-5-(pent-4-enylamino)benzoic acid Chemical compound COC1=CC(NCCCC=C)=CC(C(O)=O)=C1 LXZSZEGMJMPTGD-UHFFFAOYSA-N 0.000 description 3
- KIXANLFZKAVMTA-UHFFFAOYSA-N 3-methoxycarbonyl-5-pent-4-enoxybenzoic acid Chemical compound COC(=O)C1=CC(OCCCC=C)=CC(C(O)=O)=C1 KIXANLFZKAVMTA-UHFFFAOYSA-N 0.000 description 3
- 102100021257 Beta-secretase 1 Human genes 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 241000701447 unidentified baculovirus Species 0.000 description 3
- PHTOJBANGYSTOH-MRXNPFEDSA-N (4r)-5,5-diphenyl-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)[C@H]1NC(=O)OC1(C=1C=CC=CC=1)C1=CC=CC=C1 PHTOJBANGYSTOH-MRXNPFEDSA-N 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
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- FCDPQMAOJARMTG-UHFFFAOYSA-L benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphane Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-L 0.000 description 1
- UNOMOKBVBBHHMU-UHFFFAOYSA-N benzylidene-dicyclohexyl-(4,4-dichlorocyclohexyl)-lambda5-phosphane ruthenium Chemical compound [Ru].ClC1(Cl)CCC(CC1)P(=Cc1ccccc1)(C1CCCCC1)C1CCCCC1 UNOMOKBVBBHHMU-UHFFFAOYSA-N 0.000 description 1
- DTCCTIQRPGSLPT-UHFFFAOYSA-N beta-Aethyl-acrolein Natural products CCC=CC=O DTCCTIQRPGSLPT-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- DKDXHNMKTYUOOT-UHFFFAOYSA-N bis(4-bicyclo[2.2.1]heptanyl)phosphane Chemical compound C1CC(C2)CCC12PC1(C2)CCC2CC1 DKDXHNMKTYUOOT-UHFFFAOYSA-N 0.000 description 1
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- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
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- 229910052801 chlorine Inorganic materials 0.000 description 1
- PJGJQVRXEUVAFT-UHFFFAOYSA-N chloroiodomethane Chemical compound ClCI PJGJQVRXEUVAFT-UHFFFAOYSA-N 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
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- JMRYOSQOYJBDOI-UHFFFAOYSA-N dilithium;di(propan-2-yl)azanide Chemical compound [Li+].CC(C)[N-]C(C)C.CC(C)N([Li])C(C)C JMRYOSQOYJBDOI-UHFFFAOYSA-N 0.000 description 1
- DOSDTCPDBPRFHQ-UHFFFAOYSA-N dimethyl 5-hydroxybenzene-1,3-dicarboxylate Chemical compound COC(=O)C1=CC(O)=CC(C(=O)OC)=C1 DOSDTCPDBPRFHQ-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- LXQXGFPPYLKKSD-UHFFFAOYSA-L disodium;2,2-diethylpropanedioate Chemical compound [Na+].[Na+].CCC(CC)(C([O-])=O)C([O-])=O LXQXGFPPYLKKSD-UHFFFAOYSA-L 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Substances [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 1
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- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- NNMLFVLQJJIINL-UHFFFAOYSA-N methyl 3-(hydroxymethyl)-5-nitrobenzoate Chemical compound COC(=O)C1=CC(CO)=CC([N+]([O-])=O)=C1 NNMLFVLQJJIINL-UHFFFAOYSA-N 0.000 description 1
- FHTHCCPCKZCYLD-UHFFFAOYSA-N methyl 3-(methoxymethyl)-5-(phenylmethoxycarbonylamino)benzoate Chemical compound COC(=O)C1=CC(COC)=CC(NC(=O)OCC=2C=CC=CC=2)=C1 FHTHCCPCKZCYLD-UHFFFAOYSA-N 0.000 description 1
- XNTQPWIWNSKRJH-UHFFFAOYSA-N methyl 3-(methoxymethyl)-5-nitrobenzoate;methyl 3-(methoxymethyl)-5-(phenylmethoxycarbonylamino)benzoate Chemical compound COCC1=CC(C(=O)OC)=CC([N+]([O-])=O)=C1.COC(=O)C1=CC(COC)=CC(NC(=O)OCC=2C=CC=CC=2)=C1 XNTQPWIWNSKRJH-UHFFFAOYSA-N 0.000 description 1
- GSVQMWMNXJXPRE-UHFFFAOYSA-N methyl 3-nitro-5-(1,3-oxazol-2-yl)benzoate Chemical compound [O-][N+](=O)C1=CC(C(=O)OC)=CC(C=2OC=CN=2)=C1 GSVQMWMNXJXPRE-UHFFFAOYSA-N 0.000 description 1
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- 125000002757 morpholinyl group Chemical group 0.000 description 1
- DBNQIOANXZVWIP-UHFFFAOYSA-N n,n-dimethyl-1,1-bis[(2-methylpropan-2-yl)oxy]methanamine Chemical compound CC(C)(C)OC(N(C)C)OC(C)(C)C DBNQIOANXZVWIP-UHFFFAOYSA-N 0.000 description 1
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- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
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- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
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- 239000007974 sodium acetate buffer Substances 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- AJDAAZYPIWFUOI-UHFFFAOYSA-M sodium;1-methyl-4-sulfonatosulfonylbenzene Chemical compound [Na+].CC1=CC=C(S(=O)(=O)S([O-])(=O)=O)C=C1 AJDAAZYPIWFUOI-UHFFFAOYSA-M 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
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- QQODTRDFUWMKHF-UHFFFAOYSA-N tert-butyl 2-chloro-6-(methoxymethyl)pyridine-4-carboxylate Chemical compound COCC1=CC(C(=O)OC(C)(C)C)=CC(Cl)=N1 QQODTRDFUWMKHF-UHFFFAOYSA-N 0.000 description 1
- HSFSNZFRERNMPI-UHFFFAOYSA-N tert-butyl 2-chloro-6-(methoxymethyl)pyridine-4-carboxylate 2-chloro-6-(methoxymethyl)pyridine-4-carboxylic acid Chemical compound COCc1cc(cc(Cl)n1)C(O)=O.COCc1cc(cc(Cl)n1)C(=O)OC(C)(C)C HSFSNZFRERNMPI-UHFFFAOYSA-N 0.000 description 1
- JRYZUAWCLXNMAC-FRRDWIJNSA-N tert-butyl n-[(2s,3s,5r)-1-chloro-2-hydroxy-5-methylnon-8-en-3-yl]carbamate Chemical compound C=CCC[C@@H](C)C[C@@H]([C@H](O)CCl)NC(=O)OC(C)(C)C JRYZUAWCLXNMAC-FRRDWIJNSA-N 0.000 description 1
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
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- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
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- 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
- A61K31/5545—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having eight-membered rings not containing additional condensed or non-condensed nitrogen-containing 3-7 membered 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
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- A—HUMAN NECESSITIES
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
- C07D245/04—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D245/06—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
- C07D273/02—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and only one oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D413/12—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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06117571 | 2006-07-20 | ||
| EP06117571.7 | 2006-07-20 | ||
| PCT/EP2007/057540 WO2008009750A2 (en) | 2006-07-20 | 2007-07-20 | Macrocyclic compounds useful as bace inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2657280A1 true CA2657280A1 (en) | 2008-01-24 |
Family
ID=37467481
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002657280A Abandoned CA2657280A1 (en) | 2006-07-20 | 2007-07-20 | Macrocyclic compounds useful as bace inhibitors |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20090312370A1 (enExample) |
| EP (1) | EP2046761A2 (enExample) |
| JP (1) | JP2009544599A (enExample) |
| KR (1) | KR20090039726A (enExample) |
| CN (1) | CN101490018A (enExample) |
| AU (1) | AU2007275067A1 (enExample) |
| BR (1) | BRPI0715440A2 (enExample) |
| CA (1) | CA2657280A1 (enExample) |
| MX (1) | MX2009000710A (enExample) |
| RU (1) | RU2009105762A (enExample) |
| WO (1) | WO2008009750A2 (enExample) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0325830D0 (en) * | 2003-11-05 | 2003-12-10 | Novartis Ag | Organic compounds |
| EP1851208A1 (en) * | 2005-01-13 | 2007-11-07 | Novartis AG | Macrocyclic compounds useful as bace inhibitors |
| GB0500683D0 (en) * | 2005-01-13 | 2005-02-23 | Novartis Ag | Organic compounds |
| GB0526614D0 (en) | 2005-12-30 | 2006-02-08 | Novartis Ag | Organic compounds |
| CN101484431A (zh) * | 2006-07-20 | 2009-07-15 | 诺瓦提斯公司 | 大环内酰胺 |
| US9540366B2 (en) | 2012-07-31 | 2017-01-10 | Kyowa Hakko Kirin Co., Ltd. | Ring-fused heterocyclic compound |
| CN104995176B (zh) | 2013-02-12 | 2019-02-22 | 巴克老龄化研究所 | 调节bace所介导的app加工的乙内酰脲 |
| CN108732355B (zh) * | 2017-04-25 | 2021-06-25 | 首都医科大学附属北京安定医院 | 一种测定bace1酶切nrg1活性的检测方法及其试剂盒 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2450167A1 (en) * | 2001-06-12 | 2002-12-19 | Elan Pharmaceuticals, Inc. | Macrocycles useful in the treatment of alzheimer's disease |
| MXPA03011466A (es) * | 2001-06-12 | 2004-07-01 | Elan Pharm Inc | Macrociclos utiles en tratamiento de enfermedades de alzheimer. |
| GB0325830D0 (en) * | 2003-11-05 | 2003-12-10 | Novartis Ag | Organic compounds |
| EP1851208A1 (en) * | 2005-01-13 | 2007-11-07 | Novartis AG | Macrocyclic compounds useful as bace inhibitors |
| GB0500683D0 (en) * | 2005-01-13 | 2005-02-23 | Novartis Ag | Organic compounds |
| GB0526614D0 (en) * | 2005-12-30 | 2006-02-08 | Novartis Ag | Organic compounds |
| CN101484431A (zh) * | 2006-07-20 | 2009-07-15 | 诺瓦提斯公司 | 大环内酰胺 |
| EP2046759A1 (en) * | 2006-07-21 | 2009-04-15 | Novartis AG | 2, 4 -di (arylaminio) -pyrimidine-5-carboxamide compounds as jak kinases inhibitors |
-
2007
- 2007-07-20 MX MX2009000710A patent/MX2009000710A/es unknown
- 2007-07-20 US US12/374,467 patent/US20090312370A1/en not_active Abandoned
- 2007-07-20 KR KR1020097001065A patent/KR20090039726A/ko not_active Withdrawn
- 2007-07-20 AU AU2007275067A patent/AU2007275067A1/en not_active Abandoned
- 2007-07-20 JP JP2009519995A patent/JP2009544599A/ja not_active Withdrawn
- 2007-07-20 CN CNA2007800274885A patent/CN101490018A/zh active Pending
- 2007-07-20 RU RU2009105762/04A patent/RU2009105762A/ru not_active Application Discontinuation
- 2007-07-20 BR BRPI0715440-2A patent/BRPI0715440A2/pt not_active Application Discontinuation
- 2007-07-20 EP EP07819910A patent/EP2046761A2/en not_active Withdrawn
- 2007-07-20 WO PCT/EP2007/057540 patent/WO2008009750A2/en not_active Ceased
- 2007-07-20 CA CA002657280A patent/CA2657280A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU2007275067A1 (en) | 2008-01-24 |
| KR20090039726A (ko) | 2009-04-22 |
| BRPI0715440A2 (pt) | 2013-07-23 |
| WO2008009750A3 (en) | 2008-03-20 |
| MX2009000710A (es) | 2009-01-30 |
| WO2008009750A2 (en) | 2008-01-24 |
| EP2046761A2 (en) | 2009-04-15 |
| US20090312370A1 (en) | 2009-12-17 |
| CN101490018A (zh) | 2009-07-22 |
| RU2009105762A (ru) | 2010-08-27 |
| JP2009544599A (ja) | 2009-12-17 |
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