IL102337A - Aryl-pyrrolo [A-2, 1] Pirazines, their manufacture and pharmaceutical preparations containing them - Google Patents
Aryl-pyrrolo [A-2, 1] Pirazines, their manufacture and pharmaceutical preparations containing themInfo
- Publication number
- IL102337A IL102337A IL10233792A IL10233792A IL102337A IL 102337 A IL102337 A IL 102337A IL 10233792 A IL10233792 A IL 10233792A IL 10233792 A IL10233792 A IL 10233792A IL 102337 A IL102337 A IL 102337A
- Authority
- IL
- Israel
- Prior art keywords
- solution
- formula
- methylene chloride
- treated
- mixture
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 150000003216 pyrazines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 137
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 88
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 43
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 43
- -1 trifluoro- methanesulphonyloxy Chemical group 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 230000008569 process Effects 0.000 claims description 17
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- GCZDLZHMAMLSJF-UHFFFAOYSA-N pyrazino[1,2-a]indole Chemical compound C1=CN=CC2=CC3=CC=CC=C3N21 GCZDLZHMAMLSJF-UHFFFAOYSA-N 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 230000004770 neurodegeneration Effects 0.000 claims description 6
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 5
- 208000020401 Depressive disease Diseases 0.000 claims description 5
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 5
- 208000010877 cognitive disease Diseases 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 208000018737 Parkinson disease Diseases 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 238000005661 deetherification reaction Methods 0.000 claims description 4
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 3
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- QSLLFYVBWXWUQT-UHFFFAOYSA-N 7-Azaindolizine Chemical compound C1=NC=CN2C=CC=C21 QSLLFYVBWXWUQT-UHFFFAOYSA-N 0.000 claims 2
- 239000012876 carrier material Substances 0.000 claims 2
- 230000007131 anti Alzheimer effect Effects 0.000 claims 1
- 239000000935 antidepressant agent Substances 0.000 claims 1
- 229940005513 antidepressants Drugs 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 609
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 476
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 378
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 252
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 237
- 239000000243 solution Substances 0.000 description 228
- 229940073584 methylene chloride Drugs 0.000 description 203
- 239000000203 mixture Substances 0.000 description 198
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 197
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 192
- 239000002904 solvent Substances 0.000 description 154
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 131
- 229910052786 argon Inorganic materials 0.000 description 126
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 114
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 108
- 239000003921 oil Substances 0.000 description 91
- 235000019198 oils Nutrition 0.000 description 91
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 91
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 90
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 89
- 238000003756 stirring Methods 0.000 description 89
- 239000012074 organic phase Substances 0.000 description 88
- 239000011541 reaction mixture Substances 0.000 description 79
- 239000012043 crude product Substances 0.000 description 77
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 73
- 239000001530 fumaric acid Substances 0.000 description 69
- 239000012047 saturated solution Substances 0.000 description 68
- 239000003480 eluent Substances 0.000 description 66
- 239000000741 silica gel Substances 0.000 description 64
- 229910002027 silica gel Inorganic materials 0.000 description 64
- 235000011121 sodium hydroxide Nutrition 0.000 description 64
- 229940083608 sodium hydroxide Drugs 0.000 description 64
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 62
- 238000006243 chemical reaction Methods 0.000 description 56
- 239000008346 aqueous phase Substances 0.000 description 54
- GXWNSJYVSIJRLS-UHFFFAOYSA-N 6-bromo-8-methylimidazo[1,2-a]pyrazine Chemical compound CC1=NC(Br)=CN2C=CN=C12 GXWNSJYVSIJRLS-UHFFFAOYSA-N 0.000 description 53
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 45
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 43
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 41
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 40
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 39
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 36
- 239000012071 phase Substances 0.000 description 35
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 29
- 235000011114 ammonium hydroxide Nutrition 0.000 description 29
- 239000000284 extract Substances 0.000 description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- 239000007787 solid Substances 0.000 description 27
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 26
- 238000010992 reflux Methods 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 229910000033 sodium borohydride Inorganic materials 0.000 description 24
- 239000012279 sodium borohydride Substances 0.000 description 24
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 22
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 21
- 238000000746 purification Methods 0.000 description 21
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 20
- 238000001816 cooling Methods 0.000 description 19
- 239000000725 suspension Substances 0.000 description 19
- DAKZISABEDGGSV-UHFFFAOYSA-N n-(2-aminoethyl)acetamide Chemical compound CC(=O)NCCN DAKZISABEDGGSV-UHFFFAOYSA-N 0.000 description 18
- RZPFVRFSYMUDJO-UHFFFAOYSA-N 2h-naphthalen-1-one Chemical compound C1=CC=C2C(=O)CC=CC2=C1 RZPFVRFSYMUDJO-UHFFFAOYSA-N 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 239000012442 inert solvent Substances 0.000 description 15
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 14
- 239000013078 crystal Substances 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 230000007935 neutral effect Effects 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 12
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 11
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 11
- 102000010909 Monoamine Oxidase Human genes 0.000 description 10
- 108010062431 Monoamine oxidase Proteins 0.000 description 10
- 239000005457 ice water Substances 0.000 description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000009835 boiling Methods 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
- 239000002808 molecular sieve Substances 0.000 description 9
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 9
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- HLVFKOKELQSXIQ-UHFFFAOYSA-N 1-bromo-2-methylpropane Chemical compound CC(C)CBr HLVFKOKELQSXIQ-UHFFFAOYSA-N 0.000 description 7
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 7
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 7
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 7
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 7
- 239000011777 magnesium Substances 0.000 description 7
- 229910052749 magnesium Inorganic materials 0.000 description 7
- 229910001629 magnesium chloride Inorganic materials 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 235000006408 oxalic acid Nutrition 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 6
- 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 6
- 230000000694 effects Effects 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 239000001828 Gelatine Substances 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- MKUWVMRNQOOSAT-UHFFFAOYSA-N but-3-en-2-ol Chemical compound CC(O)C=C MKUWVMRNQOOSAT-UHFFFAOYSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- BNANPEQZOWHZKY-UHFFFAOYSA-N 3-phenylfuran Chemical compound O1C=CC(C=2C=CC=CC=2)=C1 BNANPEQZOWHZKY-UHFFFAOYSA-N 0.000 description 4
- KVIOIFKWKBDGAV-UHFFFAOYSA-N 58881-41-7 Chemical compound C1=CC=C2N3C(=O)C4=CC5=CC=CC=C5N4C(=O)C3=CC2=C1 KVIOIFKWKBDGAV-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000002168 alkylating agent Substances 0.000 description 4
- 229940100198 alkylating agent Drugs 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 238000010936 aqueous wash Methods 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 4
- MPTQRFCYZCXJFQ-UHFFFAOYSA-L copper(II) chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Cu+2] MPTQRFCYZCXJFQ-UHFFFAOYSA-L 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 150000002902 organometallic compounds Chemical class 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- MHSGOABISYIYKP-UHFFFAOYSA-N (4-nitrophenyl)methyl carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(COC(Cl)=O)C=C1 MHSGOABISYIYKP-UHFFFAOYSA-N 0.000 description 3
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- 150000001241 acetals Chemical class 0.000 description 3
- 230000002152 alkylating effect Effects 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- NJAPCAIWQRPQPY-UHFFFAOYSA-N benzyl hydrogen carbonate Chemical compound OC(=O)OCC1=CC=CC=C1 NJAPCAIWQRPQPY-UHFFFAOYSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
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- 231100000053 low toxicity Toxicity 0.000 description 1
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
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- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AJVOPIPTURQEHS-UHFFFAOYSA-N pyrazine;hydroiodide Chemical compound [I-].C1=C[NH+]=CC=N1 AJVOPIPTURQEHS-UHFFFAOYSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
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- 229910052703 rhodium Inorganic materials 0.000 description 1
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- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].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 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
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- 229940076279 serotonin Drugs 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
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- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 1
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- WINYCIXPFGVTOS-UHFFFAOYSA-M sodium;dichloromethane;hydroxide Chemical compound [OH-].[Na+].ClCCl WINYCIXPFGVTOS-UHFFFAOYSA-M 0.000 description 1
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- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- 229910052723 transition metal Inorganic materials 0.000 description 1
- RUCOUXAHBYBPHL-UHFFFAOYSA-N tributyl(cyclopropyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1CC1 RUCOUXAHBYBPHL-UHFFFAOYSA-N 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/40—Radicals substituted by oxygen atoms
- C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH195091 | 1991-07-02 | ||
| CH166792 | 1992-05-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL102337A0 IL102337A0 (en) | 1993-01-14 |
| IL102337A true IL102337A (en) | 1996-01-31 |
Family
ID=25688329
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL10233792A IL102337A (en) | 1991-07-02 | 1992-06-26 | Aryl-pyrrolo [A-2, 1] Pirazines, their manufacture and pharmaceutical preparations containing them |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US5292732A (es) |
| EP (1) | EP0521368A1 (es) |
| JP (1) | JPH0774217B2 (es) |
| CN (1) | CN1030986C (es) |
| AU (1) | AU654362B2 (es) |
| CA (1) | CA2072836A1 (es) |
| CS (1) | CS202292A3 (es) |
| FI (1) | FI100242B (es) |
| HU (1) | HUT70163A (es) |
| IE (1) | IE922152A1 (es) |
| IL (1) | IL102337A (es) |
| NO (1) | NO922604L (es) |
| NZ (1) | NZ243310A (es) |
| TW (1) | TW224974B (es) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0572863A1 (de) * | 1992-06-05 | 1993-12-08 | F. Hoffmann-La Roche Ag | ZNS Pyrazinoindole |
| US5378846A (en) * | 1993-06-11 | 1995-01-03 | Russian-American Institute For New Drug Development | 1,2,3,4-tetrahydropyrrolo-[1,2-a]-pyrazine derivatives |
| US5352096A (en) * | 1993-09-27 | 1994-10-04 | Chi Wen Chen | Air compressor for automobiles |
| TW334423B (en) * | 1993-10-22 | 1998-06-21 | Hoffmann La Roche | Tricyclic 1-aminoethylpyrrole-derivatives |
| UA66370C2 (en) * | 1997-12-16 | 2004-05-17 | Lilly Co Eli | Arylpiperazines having activity to setotonin 1 receptors |
| CZ20012160A3 (cs) * | 1998-12-25 | 2001-10-17 | Shionogi & Co., Ltd. | Heteroaromatické deriváty s inhibiční aktivitou proti HIV integráze |
| EP1635641B1 (en) * | 2003-06-12 | 2009-03-25 | Merck & Co., Inc. | Mitotic kinesin inhibitors |
| EP1741709A1 (en) * | 2005-06-28 | 2007-01-10 | Sanofi-Aventis Deutschland GmbH | Heteroaryl-substituted amides comprising a saturated linker group, and their use as pharmaceuticals |
| DE102006049452A1 (de) * | 2006-10-17 | 2008-05-08 | Grünenthal GmbH | Substituierte Tetrahydropyrolopiperazin-Verbindungen und deren Verwendung in Arzneimitteln |
| BR112012031094A2 (pt) | 2010-06-09 | 2016-10-25 | Janssen Pharmaceutica Nv | derivados de 5,6-di-hidro-2h-[1,4]oxazin-3-il-maina úteis como inibidores de beta-secretase (bace) |
| JP5834091B2 (ja) | 2010-12-22 | 2015-12-16 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプＪａｎｓｓｅｎ Ｐｈａｒｍａｃｅｕｔｉｃａ Ｎａａｍｌｏｚｅ Ｖｅｎｎｏｏｔｓｃｈａｐ | ベータ−セクレターゼ（ＢＡＣＥ）の阻害剤として有用な５，６−ジヒドロ−イミダゾ［１，２−ａ］ピラジン−８−イルアミン誘導体 |
| JP5853033B2 (ja) | 2011-03-01 | 2016-02-09 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプＪａｎｓｓｅｎ Ｐｈａｒｍａｃｅｕｔｉｃａ Ｎａａｍｌｏｚｅ Ｖｅｎｎｏｏｔｓｃｈａｐ | β−セクレターゼ（ＢＡＣＥ）の阻害剤として有用な６，７−ジヒドロ−ピラゾロ［１，５−ａ］ピラジン−４−イルアミン誘導体 |
| CN103415521B (zh) | 2011-03-09 | 2016-01-06 | 詹森药业有限公司 | 用作β分泌酶（BACE）抑制剂的3,4-二氢-吡咯并[1,2-a]吡嗪-1-基胺衍生物 |
| WO2014097147A1 (en) * | 2012-12-19 | 2014-06-26 | Novartis Ag | Tricyclic compounds as cftr inhibitors |
| KR102243135B1 (ko) | 2013-06-12 | 2021-04-22 | 얀센 파마슈티카 엔.브이. | 베타-세크레타제(bace) 저해제로서의 4-아미노-6-페닐-5,6-디하이드로이미다조[1,5-a]피라진-3(2h)-온 유도체 |
| EA028775B1 (ru) | 2013-06-12 | 2017-12-29 | Янссен Фармацевтика Нв | Производные 4-амино-6-фенил-6,7-дигидро[1,2,3]триазоло[1,5-a]пиразина в качестве ингибиторов бета-секретазы (bace) |
| CN105283457B (zh) | 2013-06-12 | 2018-09-18 | 詹森药业有限公司 | 作为β-分泌酶(BACE)抑制剂的4-氨基-6-苯基-5,6-二氢咪唑并[1,5-A]吡嗪衍生物 |
| ES2768823T3 (es) | 2014-12-18 | 2020-06-23 | Janssen Pharmaceutica Nv | Derivados de 2,3,4,5-tetrahidropiridin-6-amina y 3,4-dihidro-2H-pirrol-5-amina útiles como inhibidores de beta-secretasa |
| KR102495650B1 (ko) | 2017-04-12 | 2023-02-02 | 에프. 호프만-라 로슈 아게 | 알데히드 함유 표적 분자의 라벨링 방법 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1185080A (en) * | 1967-12-07 | 1970-03-18 | Beecham Group Ltd | Pyrrolidines |
| US3906010A (en) * | 1974-06-17 | 1975-09-16 | Morton Norwich Products Inc | Series of 5-aryl-2-furamidines |
| US3931247A (en) * | 1974-12-11 | 1976-01-06 | Morton-Norwich Products, Inc. | 5-(Substituted)phenylfurfuryl alcohols |
| JPS5811878B2 (ja) * | 1974-12-19 | 1983-03-04 | 大正製薬株式会社 | フロ （ ３ ２−ｂ ） インド−ルルイノ セイホウ |
| US4188389A (en) * | 1978-11-03 | 1980-02-12 | Ayerst Mckenna & Harrison, Inc. | 1,2,3,4-Tetrahydropyrrolo(1,2-A)pyrazines |
| JPS5852995B2 (ja) * | 1981-09-28 | 1983-11-26 | 武田薬品工業株式会社 | フルフラ−ル誘導体の製造法 |
| US4882354A (en) * | 1987-12-16 | 1989-11-21 | Norwich Eaton Pharmaceuticals, Inc. | N-hydroxy-5-phenyl-2-furancarboximidamides useful as cardiotonic agents |
-
1992
- 1992-06-12 TW TW081104600A patent/TW224974B/zh active
- 1992-06-23 EP EP92110531A patent/EP0521368A1/de not_active Ceased
- 1992-06-25 NZ NZ243310A patent/NZ243310A/en unknown
- 1992-06-26 HU HU9202139A patent/HUT70163A/hu unknown
- 1992-06-26 US US07/905,584 patent/US5292732A/en not_active Expired - Fee Related
- 1992-06-26 IL IL10233792A patent/IL102337A/en not_active IP Right Cessation
- 1992-06-29 CS CS922022A patent/CS202292A3/cs unknown
- 1992-06-29 AU AU19309/92A patent/AU654362B2/en not_active Ceased
- 1992-06-30 CA CA002072836A patent/CA2072836A1/en not_active Abandoned
- 1992-07-01 NO NO92922604A patent/NO922604L/no unknown
- 1992-07-01 IE IE215292A patent/IE922152A1/en not_active Application Discontinuation
- 1992-07-02 CN CN92105314A patent/CN1030986C/zh not_active Expired - Fee Related
- 1992-07-02 FI FI923073A patent/FI100242B/fi active
- 1992-07-02 JP JP4197449A patent/JPH0774217B2/ja not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CN1068328A (zh) | 1993-01-27 |
| HUT70163A (en) | 1995-09-28 |
| CS202292A3 (en) | 1993-01-13 |
| NZ243310A (en) | 1994-11-25 |
| AU654362B2 (en) | 1994-11-03 |
| FI923073A (fi) | 1993-01-03 |
| FI100242B (fi) | 1997-10-31 |
| JPH0774217B2 (ja) | 1995-08-09 |
| CN1030986C (zh) | 1996-02-14 |
| EP0521368A1 (de) | 1993-01-07 |
| US5292732A (en) | 1994-03-08 |
| AU1930992A (en) | 1993-01-07 |
| JPH06239865A (ja) | 1994-08-30 |
| CA2072836A1 (en) | 1993-01-03 |
| HU9202139D0 (en) | 1992-10-28 |
| NO922604L (no) | 1993-01-04 |
| FI923073A0 (fi) | 1992-07-02 |
| IE922152A1 (en) | 1993-01-13 |
| TW224974B (es) | 1994-06-11 |
| NO922604D0 (no) | 1992-07-01 |
| IL102337A0 (en) | 1993-01-14 |
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Legal Events
| Date | Code | Title | Description |
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| FF | Patent granted | ||
| RH | Patent void |