JP2006524206A - 三環式インドール誘導体およびアルツハイマー病治療におけるそれらの使用法 - Google Patents
三環式インドール誘導体およびアルツハイマー病治療におけるそれらの使用法 Download PDFInfo
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- JP2006524206A JP2006524206A JP2006505223A JP2006505223A JP2006524206A JP 2006524206 A JP2006524206 A JP 2006524206A JP 2006505223 A JP2006505223 A JP 2006505223A JP 2006505223 A JP2006505223 A JP 2006505223A JP 2006524206 A JP2006524206 A JP 2006524206A
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- alkyl
- cycloalkyl
- mmol
- aryl
- heteroaryl
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- 238000011282 treatment Methods 0.000 title claims abstract description 20
- 208000024827 Alzheimer disease Diseases 0.000 title abstract description 11
- 229940054051 antipsychotic indole derivative Drugs 0.000 title 1
- 150000002475 indoles Chemical class 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 52
- 238000000034 method Methods 0.000 claims abstract description 42
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims abstract description 20
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims abstract description 20
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 18
- 230000006933 amyloid-beta aggregation Effects 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 84
- -1 cyano, hydroxy, carboxy Chemical group 0.000 claims description 84
- 150000001875 compounds Chemical class 0.000 claims description 72
- 239000001257 hydrogen Substances 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 13
- 239000012453 solvate Substances 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 10
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 208000037259 Amyloid Plaque Diseases 0.000 claims description 4
- 239000004231 Riboflavin-5-Sodium Phosphate Substances 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000004367 cycloalkylaryl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 102100021257 Beta-secretase 1 Human genes 0.000 abstract description 22
- 101710150192 Beta-secretase 1 Proteins 0.000 abstract description 19
- 238000002360 preparation method Methods 0.000 abstract description 10
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 abstract description 9
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 abstract description 9
- 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
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 94
- 230000002829 reductive effect Effects 0.000 description 80
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- 239000007787 solid Substances 0.000 description 42
- 150000001412 amines Chemical class 0.000 description 41
- 239000012074 organic phase Substances 0.000 description 40
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 38
- 238000000746 purification Methods 0.000 description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 33
- 125000005843 halogen group Chemical group 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 239000000460 chlorine Substances 0.000 description 27
- 150000002148 esters Chemical class 0.000 description 27
- 239000002253 acid Substances 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 20
- 229920006395 saturated elastomer Polymers 0.000 description 20
- 239000000741 silica gel Substances 0.000 description 20
- 229910002027 silica gel Inorganic materials 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000012299 nitrogen atmosphere Substances 0.000 description 15
- 229910000104 sodium hydride Inorganic materials 0.000 description 15
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 13
- 108090000790 Enzymes Proteins 0.000 description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 13
- 229940088598 enzyme Drugs 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000012267 brine Substances 0.000 description 11
- FLTDSRFNBLQAEJ-UHFFFAOYSA-N ethyl azulene-4-carboxylate Chemical compound CCOC(=O)C1=CC=CC=C2C=CC=C12 FLTDSRFNBLQAEJ-UHFFFAOYSA-N 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- OXERBZQPYKPVFA-UHFFFAOYSA-N methyl 7-amino-3-ethyl-1h-indole-5-carboxylate Chemical compound C1=C(C(=O)OC)C=C2C(CC)=CNC2=C1N OXERBZQPYKPVFA-UHFFFAOYSA-N 0.000 description 10
- 239000002480 mineral oil Substances 0.000 description 10
- 235000010446 mineral oil Nutrition 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 239000002243 precursor Substances 0.000 description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- ZRVDQBPIHQYYCU-UHFFFAOYSA-N ethyl 7-amino-3-ethyl-1h-indole-5-carboxylate Chemical compound CCOC(=O)C1=CC(N)=C2NC=C(CC)C2=C1 ZRVDQBPIHQYYCU-UHFFFAOYSA-N 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- PDLATMBIYFQTOJ-QWHCGFSZSA-N tert-butyl n-[(2s,3r)-4-amino-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]([C@H](O)CN)CC1=CC=CC=C1 PDLATMBIYFQTOJ-QWHCGFSZSA-N 0.000 description 7
- AJBGTOYTKPVUPX-UHFFFAOYSA-N 2-(3-methoxyphenyl)-2-methylpropanoic acid Chemical compound COC1=CC=CC(C(C)(C)C(O)=O)=C1 AJBGTOYTKPVUPX-UHFFFAOYSA-N 0.000 description 6
- RZHHKJTXXXFRFY-UHFFFAOYSA-N 3-ethyl-10-oxo-1,9-diazatricyclo[6.4.1.04,13]trideca-2,4(13),5,7-tetraene-6-carboxylic acid Chemical compound C1CC(=O)NC2=CC(C(O)=O)=CC3=C2N1C=C3CC RZHHKJTXXXFRFY-UHFFFAOYSA-N 0.000 description 6
- ZKLBPUYMTHPNOQ-UHFFFAOYSA-N 5-bromothiophene-3-carbaldehyde Chemical compound BrC1=CC(C=O)=CS1 ZKLBPUYMTHPNOQ-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 6
- LZNXSMZJMKWFQR-UHFFFAOYSA-N ethyl 2-(3-methoxyphenyl)-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)C1=CC=CC(OC)=C1 LZNXSMZJMKWFQR-UHFFFAOYSA-N 0.000 description 6
- XRGVKASNSSUQFM-UHFFFAOYSA-N ethyl 2-methyl-2-[3-(trifluoromethyl)phenyl]propanoate Chemical compound CCOC(=O)C(C)(C)C1=CC=CC(C(F)(F)F)=C1 XRGVKASNSSUQFM-UHFFFAOYSA-N 0.000 description 6
- 235000019000 fluorine Nutrition 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- HNTLUEZVPLRQEV-UHFFFAOYSA-N methyl 4-amino-3-nitrobenzoate Chemical compound COC(=O)C1=CC=C(N)C([N+]([O-])=O)=C1 HNTLUEZVPLRQEV-UHFFFAOYSA-N 0.000 description 6
- 150000002924 oxiranes Chemical class 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- OWELBZTXHNMEKC-UHFFFAOYSA-N tert-butyl n-(4,4-difluorocyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(F)(F)CC1 OWELBZTXHNMEKC-UHFFFAOYSA-N 0.000 description 6
- LYAAGWPQSQMMII-JTQLQIEISA-N tert-butyl n-[(2s)-1-(cyclohexylamino)-1-oxopropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](C)C(=O)NC1CCCCC1 LYAAGWPQSQMMII-JTQLQIEISA-N 0.000 description 6
- OITAMJBKJGSZDG-UHFFFAOYSA-N tert-butyl n-[(3-ethyl-1,2-oxazol-5-yl)methyl]carbamate Chemical compound CCC=1C=C(CNC(=O)OC(C)(C)C)ON=1 OITAMJBKJGSZDG-UHFFFAOYSA-N 0.000 description 6
- DSPYCWLYGXGJNJ-UHFFFAOYSA-N tert-butyl n-prop-2-ynylcarbamate Chemical compound CC(C)(C)OC(=O)NCC#C DSPYCWLYGXGJNJ-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- XJOFPJZWSSQZMN-UHFFFAOYSA-N 2-methyl-2-[3-(trifluoromethyl)phenyl]propanoic acid Chemical compound OC(=O)C(C)(C)C1=CC=CC(C(F)(F)F)=C1 XJOFPJZWSSQZMN-UHFFFAOYSA-N 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- YFGTZAZAUIXTBO-VQTJNVASSA-N benzyl n-[(2r,3s)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-phenylbutyl]carbamate Chemical compound C([C@H](NC(=O)OC(C)(C)C)[C@H](O)CNC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 YFGTZAZAUIXTBO-VQTJNVASSA-N 0.000 description 5
- 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 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- VDHOIZQKJIGJKD-UHFFFAOYSA-N ethyl 3-ethyl-7-(phenylmethoxycarbonylamino)-1h-indole-5-carboxylate Chemical compound C=12NC=C(CC)C2=CC(C(=O)OCC)=CC=1NC(=O)OCC1=CC=CC=C1 VDHOIZQKJIGJKD-UHFFFAOYSA-N 0.000 description 5
- LDRHMIYQHHLQFR-UHFFFAOYSA-N ethyl 3-ethyl-7-iodo-1h-indole-5-carboxylate Chemical compound CCOC(=O)C1=CC(I)=C2NC=C(CC)C2=C1 LDRHMIYQHHLQFR-UHFFFAOYSA-N 0.000 description 5
- QSVHOENZNLGNQE-UHFFFAOYSA-N ethyl 7-(3-chloropropanoylamino)-3-ethyl-1h-indole-5-carboxylate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCl)=C2NC=C(CC)C2=C1 QSVHOENZNLGNQE-UHFFFAOYSA-N 0.000 description 5
- XBAQPGKOHQKYGR-UHFFFAOYSA-N ethyl 7-(ethenylsulfonylamino)-3-ethyl-1h-indole-5-carboxylate Chemical compound CCOC(=O)C1=CC(NS(=O)(=O)C=C)=C2NC=C(CC)C2=C1 XBAQPGKOHQKYGR-UHFFFAOYSA-N 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- HEAIJOGKHVIFQN-UHFFFAOYSA-N methyl 3-bromo-5-nitro-4-[(2,2,2-trifluoroacetyl)amino]benzoate Chemical compound COC(=O)C1=CC(Br)=C(NC(=O)C(F)(F)F)C([N+]([O-])=O)=C1 HEAIJOGKHVIFQN-UHFFFAOYSA-N 0.000 description 5
- OLYZIBQKFQFKHG-UHFFFAOYSA-N methyl 7-(ethenylsulfonylamino)-3-ethyl-1h-indole-5-carboxylate Chemical compound C1=C(C(=O)OC)C=C2C(CC)=CNC2=C1NS(=O)(=O)C=C OLYZIBQKFQFKHG-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- UAMLXEOGMPDKNK-UONOGXRCSA-N tert-butyl n-[(2s,3r)-1-(3-chlorophenyl)-3-hydroxy-4-(methylamino)butan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]([C@H](O)CNC)CC1=CC=CC(Cl)=C1 UAMLXEOGMPDKNK-UONOGXRCSA-N 0.000 description 5
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 5
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 5
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 5
- LJNOFDXDKWGSTD-UHFFFAOYSA-N (3-ethyl-1,2-oxazol-5-yl)methanamine;hydrochloride Chemical compound Cl.CCC=1C=C(CN)ON=1 LJNOFDXDKWGSTD-UHFFFAOYSA-N 0.000 description 4
- XJRLZIBKKHJOHI-UHFFFAOYSA-N 2-(3-methoxyphenyl)propan-2-amine Chemical compound COC1=CC=CC(C(C)(C)N)=C1 XJRLZIBKKHJOHI-UHFFFAOYSA-N 0.000 description 4
- IJHKKRQRUUQIJU-UHFFFAOYSA-N 2-(hydroxymethylidene)propanedial Chemical compound OC=C(C=O)C=O IJHKKRQRUUQIJU-UHFFFAOYSA-N 0.000 description 4
- YEGWNHBRMASMGR-UHFFFAOYSA-N 2-[3-(trifluoromethyl)phenyl]propan-2-amine Chemical compound CC(C)(N)C1=CC=CC(C(F)(F)F)=C1 YEGWNHBRMASMGR-UHFFFAOYSA-N 0.000 description 4
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 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
- LUOVVGBKHGGZOU-LMSSTIIKSA-N 3-ethyl-N-[(2S,3R)-3-hydroxy-4-[(3-methoxyphenyl)methylamino]-1-phenylbutan-2-yl]-10-oxo-1,9-diazatricyclo[6.4.1.04,13]trideca-2,4(13),5,7-tetraene-6-carboxamide Chemical compound C([C@H](NC(=O)C=1C=C2NC(=O)CCN3C=C(C(C=1)=C32)CC)[C@H](O)CNCC=1C=C(OC)C=CC=1)C1=CC=CC=C1 LUOVVGBKHGGZOU-LMSSTIIKSA-N 0.000 description 4
- PCTLQVJGBBPFSD-UHFFFAOYSA-N 5-ethenylthiophene-3-carbaldehyde Chemical compound C=CC1=CC(C=O)=CS1 PCTLQVJGBBPFSD-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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 102000035195 Peptidases Human genes 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000006242 amine protecting group Chemical group 0.000 description 4
- XUTUMDWBNHJGCH-UHFFFAOYSA-N benzyl n-[2-(3-methoxyphenyl)propan-2-yl]carbamate Chemical compound COC1=CC=CC(C(C)(C)NC(=O)OCC=2C=CC=CC=2)=C1 XUTUMDWBNHJGCH-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 125000004639 dihydroindenyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- AGXJNGXUTBLVCQ-UHFFFAOYSA-N ethyl 3-ethyl-10-oxo-1,9-diazatricyclo[6.4.1.04,13]trideca-2,4(13),5,7-tetraene-6-carboxylate Chemical compound N1C(=O)CCN2C=C(CC)C3=CC(C(=O)OCC)=CC1=C32 AGXJNGXUTBLVCQ-UHFFFAOYSA-N 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
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- WYVFPGFWUKBXPZ-UHFFFAOYSA-N tert-butyl n-(4-oxocyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(=O)CC1 WYVFPGFWUKBXPZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
-
- 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
- C07D487/06—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
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07D487/12—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 three hetero rings
- C07D487/14—Ortho-condensed systems
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
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- Public Health (AREA)
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- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (2)
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| GBGB0309221.0A GB0309221D0 (en) | 2003-04-23 | 2003-04-23 | Novel compounds |
| PCT/EP2004/004244 WO2004094430A1 (en) | 2003-04-23 | 2004-04-21 | Tricyclic indole derivatives and their use in the treatment of alzheimer’s disease |
Publications (2)
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| JP2006524206A true JP2006524206A (ja) | 2006-10-26 |
| JP2006524206A5 JP2006524206A5 (enExample) | 2007-05-10 |
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| JP2006505223A Withdrawn JP2006524206A (ja) | 2003-04-23 | 2004-04-21 | 三環式インドール誘導体およびアルツハイマー病治療におけるそれらの使用法 |
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| US (1) | US20060229302A1 (enExample) |
| EP (1) | EP1620438A1 (enExample) |
| JP (1) | JP2006524206A (enExample) |
| KR (1) | KR20050111797A (enExample) |
| CN (1) | CN1809573A (enExample) |
| BR (1) | BRPI0409622A (enExample) |
| CA (1) | CA2523291A1 (enExample) |
| CO (1) | CO5700829A2 (enExample) |
| GB (1) | GB0309221D0 (enExample) |
| IS (1) | IS8135A (enExample) |
| MA (1) | MA27674A1 (enExample) |
| MX (1) | MXPA05011365A (enExample) |
| NO (1) | NO20055442L (enExample) |
| RU (1) | RU2005136370A (enExample) |
| WO (1) | WO2004094430A1 (enExample) |
| ZA (1) | ZA200508041B (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006508166A (ja) * | 2002-11-27 | 2006-03-09 | 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 | 置換尿素及びカルバメート |
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| GB0328900D0 (en) * | 2003-12-12 | 2004-01-14 | Glaxo Group Ltd | Novel compounds |
| US7763609B2 (en) | 2003-12-15 | 2010-07-27 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
| GB0411404D0 (en) * | 2004-05-21 | 2004-06-23 | Glaxo Group Ltd | Novel compounds |
| JP2008513433A (ja) * | 2004-09-21 | 2008-05-01 | ファイザー・プロダクツ・インク | 中枢神経系の症状の治療において有用なｎ−エチルヒドロキシエチルアミン |
| 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 |
| GB0422755D0 (en) * | 2004-10-13 | 2004-11-17 | Glaxo Group Ltd | Novel compounds |
| WO2006088705A1 (en) * | 2005-02-14 | 2006-08-24 | Wyeth | Terphenyl guanidines as [beta symbol] -secretase inhibitors |
| GB0506562D0 (en) * | 2005-03-31 | 2005-05-04 | Glaxo Group Ltd | Novel compounds |
| AU2006235344B2 (en) | 2005-04-08 | 2012-07-26 | Comentis, Inc. | Compounds which inhibit beta-secretase activity and methods of use thereof |
| WO2007019078A2 (en) * | 2005-08-03 | 2007-02-15 | Merck & Co., Inc. | Tricyclic beta-secretase inhibitors for the treatment of alzheimer's disease |
| US7745484B2 (en) | 2005-11-21 | 2010-06-29 | 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 |
| EP1971598A1 (en) * | 2005-11-21 | 2008-09-24 | Amgen Inc. | Beta-secretase modulators and methods of use |
| US7872009B2 (en) | 2005-11-21 | 2011-01-18 | Amgen Inc. | Beta-Secretase modulators and methods of use |
| JP5440984B2 (ja) | 2007-05-25 | 2014-03-12 | アムジエン・インコーポレーテツド | β−セクレターゼ修飾剤としての置換ヒドロキシエチルアミン化合物および使用方法 |
| US8163909B2 (en) | 2007-05-25 | 2012-04-24 | Amgen Inc. | Substituted hydroxyethyl amine compounds as beta-secretase modulators and methods of use |
| 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. |
| 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. |
| 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. |
| MX2010001076A (es) * | 2007-07-27 | 2010-03-09 | Sanofi Aventis | Derivados de 1,2,3,4-tetrahidropirrolo-[1,2-a]-pirazina-6-carboxam ida y 2,3,4,5-tetrahidropirrollo [1,2,a] [1,4]-diazepina-7-carboxa mida, preparacion y su uso terapeutico. |
| 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. |
| US9096541B2 (en) | 2012-03-29 | 2015-08-04 | Oklahoma Medical Research Foundation | Inhibition of memapsin 1 cleavage in the treatment of diabetes |
| IL273428B2 (en) * | 2017-09-22 | 2023-09-01 | Jubilant Epipad LLC | Heterocyclic compounds as pad inhibitors |
| 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 (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001510474A (ja) * | 1997-02-04 | 2001-07-31 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | カテプシンｄのナノモルの非ペプチド阻害剤 |
| US6207664B1 (en) * | 1998-11-25 | 2001-03-27 | Pfizer Inc. | Squalene synthetase inhibitor agents |
| ES2252257T3 (es) * | 2000-06-30 | 2006-05-16 | Elan Pharmaceuticals, Inc. | Compuestos para tratar la enfermedad de alzheimer. |
-
2003
- 2003-04-23 GB GBGB0309221.0A patent/GB0309221D0/en not_active Ceased
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2004
- 2004-04-21 CN CNA2004800175617A patent/CN1809573A/zh active Pending
- 2004-04-21 EP EP04728567A patent/EP1620438A1/en not_active Withdrawn
- 2004-04-21 MX MXPA05011365A patent/MXPA05011365A/es not_active Application Discontinuation
- 2004-04-21 BR BRPI0409622-3A patent/BRPI0409622A/pt not_active IP Right Cessation
- 2004-04-21 RU RU2005136370/04A patent/RU2005136370A/ru not_active Application Discontinuation
- 2004-04-21 KR KR1020057019979A patent/KR20050111797A/ko not_active Withdrawn
- 2004-04-21 US US10/553,878 patent/US20060229302A1/en not_active Abandoned
- 2004-04-21 CA CA002523291A patent/CA2523291A1/en not_active Abandoned
- 2004-04-21 WO PCT/EP2004/004244 patent/WO2004094430A1/en not_active Ceased
- 2004-04-21 JP JP2006505223A patent/JP2006524206A/ja not_active Withdrawn
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2005
- 2005-10-05 ZA ZA200508041A patent/ZA200508041B/en unknown
- 2005-10-19 MA MA28563A patent/MA27674A1/fr unknown
- 2005-10-21 CO CO05107375A patent/CO5700829A2/es not_active Application Discontinuation
- 2005-11-17 NO NO20055442A patent/NO20055442L/no not_active Application Discontinuation
- 2005-11-21 IS IS8135A patent/IS8135A/is unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006508166A (ja) * | 2002-11-27 | 2006-03-09 | 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 | 置換尿素及びカルバメート |
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA05011365A (es) | 2005-11-28 |
| US20060229302A1 (en) | 2006-10-12 |
| GB0309221D0 (en) | 2003-06-04 |
| NO20055442L (no) | 2005-11-17 |
| MA27674A1 (fr) | 2005-12-01 |
| ZA200508041B (en) | 2007-02-28 |
| CA2523291A1 (en) | 2004-11-04 |
| CN1809573A (zh) | 2006-07-26 |
| RU2005136370A (ru) | 2006-05-27 |
| CO5700829A2 (es) | 2006-11-30 |
| BRPI0409622A (pt) | 2006-04-18 |
| KR20050111797A (ko) | 2005-11-28 |
| WO2004094430A1 (en) | 2004-11-04 |
| IS8135A (is) | 2005-11-21 |
| EP1620438A1 (en) | 2006-02-01 |
| AU2004232475A1 (en) | 2004-11-04 |
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