KR20060121164A - 트리시클릭 인돌 히드록시에틸아민 유도체 및알쯔하이머병의 치료에서의 그의 용도 - Google Patents
트리시클릭 인돌 히드록시에틸아민 유도체 및알쯔하이머병의 치료에서의 그의 용도 Download PDFInfo
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- KR20060121164A KR20060121164A KR1020067011376A KR20067011376A KR20060121164A KR 20060121164 A KR20060121164 A KR 20060121164A KR 1020067011376 A KR1020067011376 A KR 1020067011376A KR 20067011376 A KR20067011376 A KR 20067011376A KR 20060121164 A KR20060121164 A KR 20060121164A
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- South Korea
- Prior art keywords
- alkyl
- cycloalkyl
- aryl
- heteroaryl
- methyl
- 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.)
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Links
- 238000011282 treatment Methods 0.000 title claims abstract description 21
- 208000024827 Alzheimer disease Diseases 0.000 title abstract description 11
- RUCHEPWOSATICL-UHFFFAOYSA-N 2-aminoethanol;1h-indole Chemical class NCCO.C1=CC=C2NC=CC2=C1 RUCHEPWOSATICL-UHFFFAOYSA-N 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 124
- 239000000203 mixture Substances 0.000 claims abstract description 49
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims abstract description 33
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims abstract description 33
- 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 31
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims abstract description 22
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims abstract description 20
- 208000037259 Amyloid Plaque Diseases 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 18
- 125000004367 cycloalkylaryl group Chemical group 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 14
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 11
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 103
- -1 cyano, hydroxy Chemical group 0.000 claims description 54
- 150000002431 hydrogen Chemical class 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical group 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 239000012453 solvate Substances 0.000 claims description 16
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 13
- 125000005215 cycloalkylheteroaryl group Chemical group 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 21
- 102100021257 Beta-secretase 1 Human genes 0.000 abstract description 19
- 101710150192 Beta-secretase 1 Proteins 0.000 abstract description 16
- 238000002360 preparation method Methods 0.000 abstract description 12
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 abstract description 9
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 abstract description 9
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical class NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 59
- 239000007787 solid Substances 0.000 description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 35
- 239000002904 solvent Substances 0.000 description 32
- 239000000543 intermediate Substances 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 23
- 239000002253 acid Substances 0.000 description 21
- 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
- 150000001412 amines Chemical class 0.000 description 16
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 13
- 108090000790 Enzymes Proteins 0.000 description 13
- 229940088598 enzyme Drugs 0.000 description 13
- 238000000746 purification Methods 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- 238000010992 reflux Methods 0.000 description 11
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- 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 7
- 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 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
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 7
- 238000010561 standard procedure Methods 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-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
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 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
- 150000007513 acids Chemical class 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 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 5
- VBDFCNRXYFJMPB-UHFFFAOYSA-N methyl 4-(ethenylsulfonylamino)-1h-indole-6-carboxylate Chemical compound COC(=O)C1=CC(NS(=O)(=O)C=C)=C2C=CNC2=C1 VBDFCNRXYFJMPB-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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 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
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 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
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 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
- YBIPZPBGAGTBGK-UHFFFAOYSA-N methyl 2-chlorosulfonylacetate Chemical compound COC(=O)CS(Cl)(=O)=O YBIPZPBGAGTBGK-UHFFFAOYSA-N 0.000 description 4
- 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 4
- FKUFTRVZGKCRHH-UHFFFAOYSA-N methyl 4-[(2-methoxy-2-oxoethyl)sulfonylamino]-1h-indole-6-carboxylate Chemical compound COC(=O)CS(=O)(=O)NC1=CC(C(=O)OC)=CC2=C1C=CN2 FKUFTRVZGKCRHH-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
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- GDSRKHAFTYETFA-UHFFFAOYSA-N 1-methyl-6-propyl-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=CN3CCC GDSRKHAFTYETFA-UHFFFAOYSA-N 0.000 description 3
- VGPKJZKKCPUOEF-UHFFFAOYSA-N 10,10-dioxo-10lambda6-thia-3,9-diazatricyclo[6.4.1.04,13]trideca-1(13),2,4,6,8,11-hexaene-6-carboxamide Chemical compound N=1S(C=CC=2C=NC3=CC(=CC1C23)C(=O)N)(=O)=O VGPKJZKKCPUOEF-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- CPFLTRPEVBWVPQ-UHFFFAOYSA-N 6-butyl-1-methyl-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=CN3CCCC CPFLTRPEVBWVPQ-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000004580 Aspartic Acid Proteases Human genes 0.000 description 3
- 108010017640 Aspartic Acid Proteases Proteins 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- PHFKUAXXTUZSDD-UHFFFAOYSA-N dimethyl 1-methyl-6-(1-methylethyl)-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=CN(C(C)C)C3=CC(C(=O)OC)=CC1=C32 PHFKUAXXTUZSDD-UHFFFAOYSA-N 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- IBEUSYBJTRCLQX-UHFFFAOYSA-N methyl 1,6-diethyl-1,6-dihydro[1,2]thiazepino[5,4,3-cd]indole-8-carboxylate 2,2-dioxide Chemical compound C1=CS(=O)(=O)N(CC)C2=CC(C(=O)OC)=CC3=C2C1=CN3CC IBEUSYBJTRCLQX-UHFFFAOYSA-N 0.000 description 3
- BEGRQXFBLHAUOS-UHFFFAOYSA-N methyl 1-acetyl-3-bromo-4-[ethenylsulfonyl(methyl)amino]indole-6-carboxylate Chemical compound COC(=O)C1=CC(N(C)S(=O)(=O)C=C)=C2C(Br)=CN(C(C)=O)C2=C1 BEGRQXFBLHAUOS-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- GHKGGQZHMILYEY-LEWJYISDSA-N tert-butyl n-[(2s,3r)-3-hydroxy-4-[(3-methoxyphenyl)methylamino]-1-phenylbutan-2-yl]carbamate Chemical compound COC1=CC=CC(CNC[C@@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)OC(C)(C)C)=C1 GHKGGQZHMILYEY-LEWJYISDSA-N 0.000 description 3
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- 229960001685 tacrine Drugs 0.000 description 1
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- 229960001603 tamoxifen Drugs 0.000 description 1
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- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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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
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Hospice & Palliative Care (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Psychiatry (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 (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0328900.6A GB0328900D0 (en) | 2003-12-12 | 2003-12-12 | Novel compounds |
| GB0328900.6 | 2003-12-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20060121164A true KR20060121164A (ko) | 2006-11-28 |
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| KR1020067011376A Withdrawn KR20060121164A (ko) | 2003-12-12 | 2004-12-09 | 트리시클릭 인돌 히드록시에틸아민 유도체 및알쯔하이머병의 치료에서의 그의 용도 |
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 |
|---|---|---|---|---|
| JP2007528400A (ja) | 2004-03-09 | 2007-10-11 | エラン ファーマシューティカルズ，インコーポレイテッド | 置換ヒドロキシエチルアミン系のアスパラギン酸プロテアーゼ阻害薬 |
| WO2006010095A2 (en) | 2004-07-09 | 2006-01-26 | 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 |
| 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. |
| 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. |
| PL2185561T3 (pl) * | 2007-07-27 | 2011-11-30 | Sanofi Aventis | Pochodne 1,2,3,4-tetrahydropirolo(1,2-a)pirazyno-6-karboksamidów i 2,3,4,5-tetrahydropirolo(1,2-a)-diazepino-7-karboksamidów, ich wytwarzanie i zastosowanie terapeutyczne |
| 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. |
| KR101653707B1 (ko) * | 2008-05-29 | 2016-09-02 | 알바니 몰레큘라 리써치, 인크. | 5-ｈｔ3 수용체 조절제, 이의 제조 방법, 및 그의 용도 |
| 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. |
| WO2011153359A1 (en) | 2010-06-04 | 2011-12-08 | Albany Molecular Research, Inc. | Glycine transporter-1 inhibitors, methods of making them, and uses thereof |
| MX365851B (es) * | 2012-08-24 | 2019-06-17 | Treventis Corp | Compuestos de benzofurazano anti-amiloides y metodos. |
| WO2019075358A1 (en) * | 2017-10-13 | 2019-04-18 | Ghosh Arun K | BACE1 INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE |
| US12043631B2 (en) | 2017-10-13 | 2024-07-23 | Purdue Research Foundation | BACE1 inhibitors for the treatment of Alzheimer's disease |
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| EP0958293B1 (en) * | 1997-02-04 | 2005-01-19 | 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 |
| JP2004502664A (ja) * | 2000-06-30 | 2004-01-29 | イーラン ファーマスーティカルズ、インコーポレイテッド | アルツハイマー病処置用化合物 |
| AU2002359376B2 (en) * | 2001-11-08 | 2008-01-10 | Elan Pharmaceuticals, Inc. | 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 JP JP2006543488A patent/JP2007513913A/ja not_active Withdrawn
- 2004-12-09 KR KR1020067011376A patent/KR20060121164A/ko not_active Withdrawn
- 2004-12-09 DE DE602004017777T patent/DE602004017777D1/de not_active Expired - Fee Related
- 2004-12-09 RU RU2006124863/04A patent/RU2006124863A/ru not_active Application Discontinuation
- 2004-12-09 US US10/596,296 patent/US20070073060A1/en not_active Abandoned
- 2004-12-09 AT AT04803724T patent/ATE414090T1/de not_active IP Right Cessation
- 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 AU AU2004299231A patent/AU2004299231A1/en not_active Abandoned
- 2004-12-09 CN CNA2004800416435A patent/CN1914214A/zh active Pending
- 2004-12-09 CA CA002549072A patent/CA2549072A1/en not_active Abandoned
- 2004-12-09 EP EP04803724A patent/EP1692143B1/en not_active Expired - Lifetime
-
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 |
|---|---|
| BRPI0417476A (pt) | 2007-05-08 |
| EP1692143B1 (en) | 2008-11-12 |
| CA2549072A1 (en) | 2005-06-30 |
| JP2007513913A (ja) | 2007-05-31 |
| GB0328900D0 (en) | 2004-01-14 |
| DE602004017777D1 (de) | 2008-12-24 |
| NO20063137L (no) | 2006-08-31 |
| RU2006124863A (ru) | 2008-01-20 |
| ATE414090T1 (de) | 2008-11-15 |
| MA28241A1 (fr) | 2006-10-02 |
| IL175819A0 (en) | 2006-10-05 |
| AU2004299231A1 (en) | 2005-06-30 |
| US20070073060A1 (en) | 2007-03-29 |
| WO2005058915A1 (en) | 2005-06-30 |
| IS8521A (is) | 2006-06-26 |
| CN1914214A (zh) | 2007-02-14 |
| EP1692143A1 (en) | 2006-08-23 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PA0105 | International application |
Patent event date: 20060609 Patent event code: PA01051R01D Comment text: International Patent Application |
|
| PG1501 | Laying open of application | ||
| G170 | Re-publication after modification of scope of protection [patent] | ||
| PG1701 | Publication of correction | ||
| PC1203 | Withdrawal of no request for examination | ||
| WITN | Application deemed withdrawn, e.g. because no request for examination was filed or no examination fee was paid |