CA2549072A1 - Tricyclic indole hydroxyethylamine derivatives and their use in the treatment of alzheimer's disease - Google Patents
Tricyclic indole hydroxyethylamine derivatives and their use in the treatment of alzheimer's disease Download PDFInfo
- Publication number
- CA2549072A1 CA2549072A1 CA002549072A CA2549072A CA2549072A1 CA 2549072 A1 CA2549072 A1 CA 2549072A1 CA 002549072 A CA002549072 A CA 002549072A CA 2549072 A CA2549072 A CA 2549072A CA 2549072 A1 CA2549072 A1 CA 2549072A1
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- Canada
- Prior art keywords
- alkyl
- cycloalkyl
- amino
- methyl
- aryl
- 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
- 238000011282 treatment Methods 0.000 title claims abstract description 25
- 208000024827 Alzheimer disease Diseases 0.000 title abstract description 12
- RUCHEPWOSATICL-UHFFFAOYSA-N 2-aminoethanol;1h-indole Chemical class NCCO.C1=CC=C2NC=CC2=C1 RUCHEPWOSATICL-UHFFFAOYSA-N 0.000 title description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
- 239000001257 hydrogen Substances 0.000 claims abstract description 32
- 125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 28
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims abstract description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 18
- 208000037259 Amyloid Plaque Diseases 0.000 claims abstract description 17
- 125000004367 cycloalkylaryl group Chemical group 0.000 claims abstract description 16
- 201000010099 disease Diseases 0.000 claims abstract description 16
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 15
- 125000005215 cycloalkylheteroaryl group Chemical group 0.000 claims abstract description 14
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims abstract description 13
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 118
- 150000001875 compounds Chemical class 0.000 claims description 112
- -1 cyano, hydroxy Chemical group 0.000 claims description 76
- 125000000217 alkyl group Chemical group 0.000 claims description 67
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 150000002431 hydrogen Chemical group 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 229910052736 halogen Chemical group 0.000 claims description 18
- 150000002367 halogens Chemical group 0.000 claims description 18
- 239000012453 solvate Substances 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 1
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims 1
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 46
- 102100021257 Beta-secretase 1 Human genes 0.000 abstract description 19
- 230000008569 process Effects 0.000 abstract description 18
- 101710150192 Beta-secretase 1 Proteins 0.000 abstract description 16
- 238000002360 preparation method Methods 0.000 abstract description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical class NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 abstract description 3
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 abstract description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 138
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 92
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 69
- 235000019253 formic acid Nutrition 0.000 description 69
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 64
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 60
- 239000007787 solid Substances 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 37
- 239000000243 solution Substances 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000002904 solvent Substances 0.000 description 34
- PDBFEXRVSDJYHN-UHFFFAOYSA-N 6-ethyl-1-methyl-1,3,4,6-tetrahydro[1,2]thiazepino[5,4,3-cd]indole-8-carboxylic acid 2,2-dioxide Chemical compound C1CS(=O)(=O)N(C)C2=CC(C(O)=O)=CC3=C2C1=CN3CC PDBFEXRVSDJYHN-UHFFFAOYSA-N 0.000 description 33
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-butanol Substances CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 31
- 150000001412 amines Chemical class 0.000 description 31
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 239000002253 acid Substances 0.000 description 28
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- HDVFPYDWVICBRR-UHFFFAOYSA-N 9-methyl-10,10-dioxo-10lambda6-thia-3,9-diazatricyclo[6.4.1.04,13]trideca-1,4(13),5,7-tetraene-6-carboxamide Chemical compound C1CS(=O)(=O)N(C)C2=CC(C(N)=O)=CC3=C2C1=CN3 HDVFPYDWVICBRR-UHFFFAOYSA-N 0.000 description 13
- 102000004190 Enzymes Human genes 0.000 description 13
- 108090000790 Enzymes Proteins 0.000 description 13
- 229940088598 enzyme Drugs 0.000 description 13
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 10
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 10
- QHQHADNPZQXIEJ-UHFFFAOYSA-N 11-ethyl-9-methyl-10,10-dioxo-10lambda6-thia-3,9-diazatricyclo[6.4.1.04,13]trideca-1,4(13),5,7-tetraene-6-carboxamide Chemical compound CN1S(=O)(=O)C(CC)CC2=CNC3=CC(C(N)=O)=CC1=C23 QHQHADNPZQXIEJ-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 238000010561 standard procedure Methods 0.000 description 8
- HDMZTPBUQGSEEJ-UHFFFAOYSA-N 1,6-diethyl-1,6-dihydro[1,2]thiazepino[5,4,3-cd]indole-8-carboxylic acid 2,2-dioxide Chemical compound C1=CS(=O)(=O)N(CC)C2=CC(C(O)=O)=CC3=C2C1=CN3CC HDMZTPBUQGSEEJ-UHFFFAOYSA-N 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- WAFKOZVMQQVMSQ-UHFFFAOYSA-N methyl 1-acetyl-3-bromo-4-[ethenylsulfonyl(ethyl)amino]indole-6-carboxylate Chemical compound C=CS(=O)(=O)N(CC)C1=CC(C(=O)OC)=CC2=C1C(Br)=CN2C(C)=O WAFKOZVMQQVMSQ-UHFFFAOYSA-N 0.000 description 7
- DJZJHJRWIVNSIT-UHFFFAOYSA-N methyl 4-amino-1h-indole-6-carboxylate Chemical compound COC(=O)C1=CC(N)=C2C=CNC2=C1 DJZJHJRWIVNSIT-UHFFFAOYSA-N 0.000 description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 7
- ZSOVMLIWZNQGKL-FZMMWMHASA-N (2r,3s)-3-amino-1-(oxan-4-ylamino)-4-phenylbutan-2-ol;4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.C([C@H](N)[C@H](O)CNC1CCOCC1)C1=CC=CC=C1 ZSOVMLIWZNQGKL-FZMMWMHASA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 6
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- NGIBYUIKHXYBJM-UHFFFAOYSA-N methyl 1-methyl-1,6-dihydro[1,2]thiazepino[5,4,3-cd]indole-8-carboxylate 2,2-dioxide Chemical compound CN1S(=O)(=O)C=CC2=CNC3=CC(C(=O)OC)=CC1=C32 NGIBYUIKHXYBJM-UHFFFAOYSA-N 0.000 description 6
- OASJQPCKINNODO-UHFFFAOYSA-N methyl 3-bromo-4-[ethenylsulfonyl(methyl)amino]-1h-indole-6-carboxylate Chemical compound COC(=O)C1=CC(N(C)S(=O)(=O)C=C)=C2C(Br)=CNC2=C1 OASJQPCKINNODO-UHFFFAOYSA-N 0.000 description 6
- YSHDJOAIBGNOMM-UHFFFAOYSA-N methyl 4-[ethenylsulfonyl(methyl)amino]-1h-indole-6-carboxylate Chemical compound COC(=O)C1=CC(N(C)S(=O)(=O)C=C)=C2C=CNC2=C1 YSHDJOAIBGNOMM-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 5
- KODLUXHSIZOKTG-UHFFFAOYSA-N 1-aminobutan-2-ol Chemical compound CCC(O)CN KODLUXHSIZOKTG-UHFFFAOYSA-N 0.000 description 5
- OFACVVYZBAAKHC-UHFFFAOYSA-N 1-methyl-6-(1-methylethyl)-1,6-dihydro[1,2]thiazepino[5,4,3-cd]indole-8-carboxylic acid 2,2-dioxide Chemical compound C1=CS(=O)(=O)N(C)C2=CC(C(O)=O)=CC3=C2C1=CN3C(C)C OFACVVYZBAAKHC-UHFFFAOYSA-N 0.000 description 5
- PUFOAABKDKPTQU-UHFFFAOYSA-N 1-methyl-6-propyl-1,6-dihydro[1,2]thiazepino[5,4,3-cd]indole-3,8-dicarboxylic acid 2,2-dioxide Chemical compound C1=C(C(O)=O)S(=O)(=O)N(C)C2=CC(C(O)=O)=CC3=C2C1=CN3CCC PUFOAABKDKPTQU-UHFFFAOYSA-N 0.000 description 5
- URSFIBGZVZTDKI-UHFFFAOYSA-N 10,10-dioxo-10lambda6-thia-3,9-diazatricyclo[6.4.1.04,13]trideca-2,4,6,8(13)-tetraene-6-carboxamide Chemical compound N1S(CCC2C=NC=3C=C(C=C1C23)C(=O)N)(=O)=O URSFIBGZVZTDKI-UHFFFAOYSA-N 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 5
- HPIJDGNVPUOTHZ-UHFFFAOYSA-N 6-butyl-1-methyl-1,6-dihydro[1,2]thiazepino[5,4,3-cd]indole-3,8-dicarboxylic acid 2,2-dioxide Chemical compound C1=C(C(O)=O)S(=O)(=O)N(C)C2=CC(C(O)=O)=CC3=C2C1=CN3CCCC HPIJDGNVPUOTHZ-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- BRMBDJSDLIGTLI-UHFFFAOYSA-N dimethyl 1-methyl-1,6-dihydro[1,2]thiazepino[5,4,3-cd]indole-3,8-dicarboxylate 2,2-dioxide Chemical compound CN1S(=O)(=O)C(C(=O)OC)=CC2=CNC3=CC(C(=O)OC)=CC1=C32 BRMBDJSDLIGTLI-UHFFFAOYSA-N 0.000 description 5
- OEVAWXBIFYVXCY-UHFFFAOYSA-N dimethyl 6-butyl-1-methyl-1,6-dihydro[1,2]thiazepino[5,4,3-cd]indole-3,8-dicarboxylate 2,2-dioxide Chemical compound C1=C(C(=O)OC)S(=O)(=O)N(C)C2=CC(C(=O)OC)=CC3=C2C1=CN3CCCC OEVAWXBIFYVXCY-UHFFFAOYSA-N 0.000 description 5
- VKUMGSQLBWQBTF-UHFFFAOYSA-N dimethyl 6-ethyl-1-methyl-1,6-dihydro[1,2]thiazepino[5,4,3-cd]indole-3,8-dicarboxylate 2,2-dioxide Chemical compound C1=C(C(=O)OC)S(=O)(=O)N(C)C2=CC(C(=O)OC)=CC3=C2C1=CN3CC VKUMGSQLBWQBTF-UHFFFAOYSA-N 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- ILAYMYHCEGDLEM-UHFFFAOYSA-N methyl 4-[(2-methoxy-2-oxoethyl)sulfonyl-methylamino]-1h-indole-6-carboxylate Chemical compound COC(=O)CS(=O)(=O)N(C)C1=CC(C(=O)OC)=CC2=C1C=CN2 ILAYMYHCEGDLEM-UHFFFAOYSA-N 0.000 description 5
- XQXLEMPTISWGMH-SNAWJCMRSA-N methyl 4-[(e)-2-(dimethylamino)ethenyl]-3,5-dinitrobenzoate Chemical compound COC(=O)C1=CC([N+]([O-])=O)=C(\C=C\N(C)C)C([N+]([O-])=O)=C1 XQXLEMPTISWGMH-SNAWJCMRSA-N 0.000 description 5
- FZTGKILZHMECNQ-UHFFFAOYSA-N methyl 4-[ethenylsulfonyl(ethyl)amino]-1h-indole-6-carboxylate Chemical compound C=CS(=O)(=O)N(CC)C1=CC(C(=O)OC)=CC2=C1C=CN2 FZTGKILZHMECNQ-UHFFFAOYSA-N 0.000 description 5
- GQPWXQIRPQMEIJ-UHFFFAOYSA-N methyl 4-methyl-3,5-dinitrobenzoate Chemical compound COC(=O)C1=CC([N+]([O-])=O)=C(C)C([N+]([O-])=O)=C1 GQPWXQIRPQMEIJ-UHFFFAOYSA-N 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- QGCTWJFFUSWZHE-UHFFFAOYSA-N 1,6-diethyl-1,3,4,6-tetrahydro[1,2]thiazepino[5,4,3-cd]indole-8-carboxylic acid 2,2-dioxide Chemical compound C1CS(=O)(=O)N(CC)C2=CC(C(O)=O)=CC3=C2C1=CN3CC QGCTWJFFUSWZHE-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- 102100021277 Beta-secretase 2 Human genes 0.000 description 4
- 101710150190 Beta-secretase 2 Proteins 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 4
- 125000006242 amine protecting group Chemical group 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- YBIPZPBGAGTBGK-UHFFFAOYSA-N methyl 2-chlorosulfonylacetate Chemical compound COC(=O)CS(Cl)(=O)=O YBIPZPBGAGTBGK-UHFFFAOYSA-N 0.000 description 4
- ZINFEEDMMJJQRH-UHFFFAOYSA-N methyl 6-ethyl-1-methyl-1,3,4,6-tetrahydro[1,2]thiazepino[5,4,3-cd]indole-8-carboxylate 2,2-dioxide Chemical compound C1CS(=O)(=O)N(C)C2=CC(C(=O)OC)=CC3=C2C1=CN3CC ZINFEEDMMJJQRH-UHFFFAOYSA-N 0.000 description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/06—Peri-condensed systems
-
- 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
Landscapes
- 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)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0328900.6 | 2003-12-12 | ||
| GBGB0328900.6A GB0328900D0 (en) | 2003-12-12 | 2003-12-12 | Novel compounds |
| PCT/EP2004/014076 WO2005058915A1 (en) | 2003-12-12 | 2004-12-09 | Tricyclic indole hydroxyethylamine derivatives and their use in the treatment of alzheimer's disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2549072A1 true CA2549072A1 (en) | 2005-06-30 |
Family
ID=30130158
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002549072A Abandoned CA2549072A1 (en) | 2003-12-12 | 2004-12-09 | Tricyclic indole hydroxyethylamine derivatives and their use in the treatment of alzheimer's disease |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US20070073060A1 (https=) |
| EP (1) | EP1692143B1 (https=) |
| JP (1) | JP2007513913A (https=) |
| KR (1) | KR20060121164A (https=) |
| CN (1) | CN1914214A (https=) |
| AT (1) | ATE414090T1 (https=) |
| AU (1) | AU2004299231A1 (https=) |
| BR (1) | BRPI0417476A (https=) |
| CA (1) | CA2549072A1 (https=) |
| DE (1) | DE602004017777D1 (https=) |
| GB (1) | GB0328900D0 (https=) |
| IL (1) | IL175819A0 (https=) |
| IS (1) | IS8521A (https=) |
| MA (1) | MA28241A1 (https=) |
| NO (1) | NO20063137L (https=) |
| RU (1) | RU2006124863A (https=) |
| WO (1) | WO2005058915A1 (https=) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050239836A1 (en) | 2004-03-09 | 2005-10-27 | Varghese John | Substituted hydroxyethylamine aspartyl protease inhibitors |
| EP1773756A2 (en) | 2004-07-09 | 2007-04-18 | Elan Pharmaceuticals, Inc. | Oxime derivative substituted hydroxyethylamine aspartyl protease inhibitors |
| BRPI0515383A (pt) * | 2004-09-21 | 2008-07-22 | Pfizer Prod Inc | n-etil hidroxietilamina útil no tratamento de condições do snc |
| GB0422765D0 (en) * | 2004-10-13 | 2004-11-17 | Glaxo Group Ltd | Novel compounds |
| GB0422766D0 (en) * | 2004-10-13 | 2004-11-17 | Glaxo Group Ltd | Novel compounds |
| WO2007047305A1 (en) * | 2005-10-12 | 2007-04-26 | Elan Pharmaceuticals, Inc. | Methods of treating amyloidosis using cyclopropyl derivative aspartyl protease inhibitors |
| US7872009B2 (en) | 2005-11-21 | 2011-01-18 | Amgen Inc. | Beta-Secretase modulators and methods of use |
| US7838676B2 (en) * | 2005-11-21 | 2010-11-23 | Amgen Inc. | Beta-secretase modulators and methods of use |
| PT2185561E (pt) * | 2007-07-27 | 2011-09-07 | Sanofi Aventis | Derivados de 1,2,3,4-tetra-hidropirrolo(1,2-a)pirazina-6- carboxamidas e de 2,3,4,5-tetra-hidropirrolo(1,2-a)-diazepina-7- carboxamidas, sua preparação e sua aplicação em terapia |
| FR2919289B1 (fr) * | 2007-07-27 | 2009-09-04 | Sanofi Aventis Sa | Derives de 2,3,4,5-tetrahydropyrrolo[1,2-a][1,4]- diazepine-7-carboxamides, leur preparation et leur application en therapeutique. |
| FR2919288B1 (fr) * | 2007-07-27 | 2009-09-04 | Sanofi Aventis Sa | Derives de 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6- carboxamides, leur preparation et leur application en therapeutique. |
| FR2919286A1 (fr) | 2007-07-27 | 2009-01-30 | Sanofi Aventis Sa | Derives de derives de 1-oxo-1,2-dihydroisoquinoleine-5- carboxamides et de 4-oxo-3,4-dihydroquinazoline-8- carboxamides,leur preparation et leur application en therapeutique. |
| FR2919285B1 (fr) | 2007-07-27 | 2012-08-31 | Sanofi Aventis | Derives de 1-oxo-isoindoline-4-carboxamides et de 1-oxo- 1,2,3,4-tetrahydroisoquinoleine-5-carboxamides, leur preparation et leur application en therapeutique. |
| EP2310019A4 (en) * | 2008-05-29 | 2011-06-01 | Albany Molecular Res Inc | 5-HT3 RECEPTOR MODULATORS, MANUFACTURING METHOD AND ITS USE |
| FR2960876B1 (fr) | 2010-06-03 | 2012-07-27 | Sanofi Aventis | Derives de 3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1h)-dicarboxamide leur preparation et leur application en therapeutique. |
| AU2011261375B2 (en) | 2010-06-04 | 2016-09-22 | Albany Molecular Research, Inc. | Glycine transporter-1 inhibitors, methods of making them, and uses thereof |
| CN104768949A (zh) * | 2012-08-24 | 2015-07-08 | 特温蒂斯公司 | 苯并呋咱抗淀粉样蛋白化合物和方法 |
| US12043631B2 (en) | 2017-10-13 | 2024-07-23 | Purdue Research Foundation | BACE1 inhibitors for the treatment of Alzheimer's disease |
| WO2019075358A1 (en) * | 2017-10-13 | 2019-04-18 | Ghosh Arun K | BACE1 INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2280096A1 (en) * | 1997-02-04 | 1998-08-06 | The Regents Of The University Of California | Nanomolar, non-peptide inhibitors of cathepsin d |
| US6207664B1 (en) * | 1998-11-25 | 2001-03-27 | Pfizer Inc. | Squalene synthetase inhibitor agents |
| DE60124080T2 (de) * | 2000-03-23 | 2007-03-01 | Elan Pharmaceuticals, Inc., San Francisco | Verbindungen und verfahren zur behandlung der alzheimerschen krankheit |
| EP1299352B1 (en) * | 2000-06-30 | 2005-12-28 | Elan Pharmaceuticals, Inc. | Compounds to treat alzheimer's disease |
| NZ533107A (en) * | 2001-11-08 | 2007-04-27 | Upjohn Co | N, N'-substituted-1,3-diamino-2-hydroxypropane derivatives |
| GB0228410D0 (en) * | 2002-12-05 | 2003-01-08 | Glaxo Group Ltd | Novel Compounds |
| GB0309221D0 (en) * | 2003-04-23 | 2003-06-04 | Glaxo Group Ltd | Novel compounds |
-
2003
- 2003-12-12 GB GBGB0328900.6A patent/GB0328900D0/en not_active Ceased
-
2004
- 2004-12-09 DE DE602004017777T patent/DE602004017777D1/de not_active Expired - Fee Related
- 2004-12-09 EP EP04803724A patent/EP1692143B1/en not_active Expired - Lifetime
- 2004-12-09 AT AT04803724T patent/ATE414090T1/de not_active IP Right Cessation
- 2004-12-09 JP JP2006543488A patent/JP2007513913A/ja not_active Withdrawn
- 2004-12-09 US US10/596,296 patent/US20070073060A1/en not_active Abandoned
- 2004-12-09 CA CA002549072A patent/CA2549072A1/en not_active Abandoned
- 2004-12-09 AU AU2004299231A patent/AU2004299231A1/en not_active Abandoned
- 2004-12-09 RU RU2006124863/04A patent/RU2006124863A/ru not_active Application Discontinuation
- 2004-12-09 BR BRPI0417476-3A patent/BRPI0417476A/pt not_active IP Right Cessation
- 2004-12-09 WO PCT/EP2004/014076 patent/WO2005058915A1/en not_active Ceased
- 2004-12-09 CN CNA2004800416435A patent/CN1914214A/zh active Pending
- 2004-12-09 KR KR1020067011376A patent/KR20060121164A/ko not_active Withdrawn
-
2006
- 2006-05-22 IL IL175819A patent/IL175819A0/en unknown
- 2006-06-26 MA MA29143A patent/MA28241A1/fr unknown
- 2006-06-26 IS IS8521A patent/IS8521A/xx unknown
- 2006-07-06 NO NO20063137A patent/NO20063137L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| IL175819A0 (en) | 2006-10-05 |
| KR20060121164A (ko) | 2006-11-28 |
| BRPI0417476A (pt) | 2007-05-08 |
| AU2004299231A1 (en) | 2005-06-30 |
| EP1692143A1 (en) | 2006-08-23 |
| IS8521A (is) | 2006-06-26 |
| DE602004017777D1 (de) | 2008-12-24 |
| EP1692143B1 (en) | 2008-11-12 |
| NO20063137L (no) | 2006-08-31 |
| RU2006124863A (ru) | 2008-01-20 |
| WO2005058915A1 (en) | 2005-06-30 |
| ATE414090T1 (de) | 2008-11-15 |
| US20070073060A1 (en) | 2007-03-29 |
| CN1914214A (zh) | 2007-02-14 |
| JP2007513913A (ja) | 2007-05-31 |
| GB0328900D0 (en) | 2004-01-14 |
| MA28241A1 (fr) | 2006-10-02 |
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| Date | Code | Title | Description |
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| FZDE | Discontinued |