JP2004517090A5 - - Google Patents
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- Publication number
- JP2004517090A5 JP2004517090A5 JP2002549245A JP2002549245A JP2004517090A5 JP 2004517090 A5 JP2004517090 A5 JP 2004517090A5 JP 2002549245 A JP2002549245 A JP 2002549245A JP 2002549245 A JP2002549245 A JP 2002549245A JP 2004517090 A5 JP2004517090 A5 JP 2004517090A5
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- tetrahydro
- amino
- benzazepin
- alaninyl
- 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.)
- Granted
Links
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- 238000003786 synthesis reaction Methods 0.000 claims description 15
- 208000024827 Alzheimer disease Diseases 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- 208000031124 Dementia Alzheimer type Diseases 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 38
- 238000000034 method Methods 0.000 description 24
- 239000000203 mixture Substances 0.000 description 24
- 239000007787 solid Substances 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- 239000010410 layer Substances 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- RETLCOJLSHBJEZ-JTQLQIEISA-N (5s)-5-amino-3-methyl-2,5-dihydro-1h-3-benzazepin-4-one Chemical compound N[C@@H]1C(=O)N(C)CCC2=CC=CC=C21 RETLCOJLSHBJEZ-JTQLQIEISA-N 0.000 description 11
- RETLCOJLSHBJEZ-UHFFFAOYSA-N 5-amino-3-methyl-2,5-dihydro-1h-3-benzazepin-4-one Chemical compound NC1C(=O)N(C)CCC2=CC=CC=C21 RETLCOJLSHBJEZ-UHFFFAOYSA-N 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 239000002002 slurry Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 150000003934 aromatic aldehydes Chemical class 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- AYQMNFRCBKOMIA-UHFFFAOYSA-N 1-benzazepin-2-one Chemical compound O=C1C=CC=C2C=CC=CC2=N1 AYQMNFRCBKOMIA-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- -1 nitrogen 1-amino-3-methyl - 2,3,4,5 - tetrahydro - IH-3-benzazepin-2-one Chemical compound 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- FVMQJWDMZWHTEQ-UHFFFAOYSA-N 3-benzazepin-2-one Chemical compound C1=NC(=O)C=C2C=CC=CC2=C1 FVMQJWDMZWHTEQ-UHFFFAOYSA-N 0.000 description 4
- AGMHHPHTPYMULW-UHFFFAOYSA-N 5-hydroxyimino-3-methyl-1,2-dihydro-3-benzazepin-4-one Chemical compound ON=C1C(=O)N(C)CCC2=CC=CC=C21 AGMHHPHTPYMULW-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- ZJSQZQMVXKZAGW-UHFFFAOYSA-N 2H-benzotriazol-4-ol hydrate Chemical compound O.OC1=CC=CC2=C1N=NN2 ZJSQZQMVXKZAGW-UHFFFAOYSA-N 0.000 description 3
- NAUWUGHLFUVNQH-UHFFFAOYSA-N 3-methyl-2,5-dihydro-1h-3-benzazepin-4-one Chemical compound C1C(=O)N(C)CCC2=CC=CC=C21 NAUWUGHLFUVNQH-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229940011051 isopropyl acetate Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- PKXWXXPNHIWQHW-RCBQFDQVSA-N (2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide Chemical compound C1CN(C)C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](O)C(C)C)C2=CC=CC=C21 PKXWXXPNHIWQHW-RCBQFDQVSA-N 0.000 description 2
- CMIBUZBMZCBCAT-HZPDHXFCSA-N (2r,3r)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HZPDHXFCSA-N 0.000 description 2
- IVRQWKMFUDQDHH-LLVKDONJSA-N (5S)-3-methyl-1,2,4,5-tetrahydro-3-benzazepin-5-amine Chemical compound N[C@@H]1CN(CCC2=C1C=CC=C2)C IVRQWKMFUDQDHH-LLVKDONJSA-N 0.000 description 2
- XXZPHQDJNRNRCJ-RLJYASMLSA-N (5S)-5-amino-3-methyl-2,5-dihydro-1H-3-benzazepin-4-one (2R)-2-hydroxy-2-phenylacetic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1.N[C@@H]1C(=O)N(C)CCC2=CC=CC=C21 XXZPHQDJNRNRCJ-RLJYASMLSA-N 0.000 description 2
- FCLMPNRBYATJAR-XPTSAGLGSA-N (5s)-5-amino-5-[(2s)-2-aminopropanoyl]-3-methyl-1,2-dihydro-3-benzazepin-4-one Chemical compound C1CN(C)C(=O)[C@](C(=O)[C@@H](N)C)(N)C2=CC=CC=C21 FCLMPNRBYATJAR-XPTSAGLGSA-N 0.000 description 2
- NGEWQZIDQIYUNV-BYPYZUCNSA-N (S)-2-hydroxy-3-methylbutyric acid Chemical compound CC(C)[C@H](O)C(O)=O NGEWQZIDQIYUNV-BYPYZUCNSA-N 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- BNUHOROHUNBPAD-UHFFFAOYSA-N 1-hydroxyimino-3-methyl-3-benzazepin-2-one Chemical compound ON=C1C(=O)N(C)C=CC2=CC=CC=C21 BNUHOROHUNBPAD-UHFFFAOYSA-N 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- NTRIXPNQPWVRJU-UHFFFAOYSA-N 3-methyl-1h-3-benzazepin-2-one Chemical compound C1C(=O)N(C)C=CC2=CC=CC=C21 NTRIXPNQPWVRJU-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 150000004683 dihydrates Chemical class 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 150000003951 lactams Chemical class 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- JTVVIFFPZNRVRU-UHFFFAOYSA-N n-(2,2-dimethoxyethyl)-n-methyl-2-phenylacetamide Chemical compound COC(OC)CN(C)C(=O)CC1=CC=CC=C1 JTVVIFFPZNRVRU-UHFFFAOYSA-N 0.000 description 2
- SASNBVQSOZSTPD-UHFFFAOYSA-N n-methylphenethylamine Chemical compound CNCCC1=CC=CC=C1 SASNBVQSOZSTPD-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- VWLQIRDZHGFUQA-UHFFFAOYSA-N 1,3,4,5,5a,6-hexahydro-3-benzazepin-2-one Chemical compound C1C(NCCC2C1=CC=CC2)=O VWLQIRDZHGFUQA-UHFFFAOYSA-N 0.000 description 1
- WUYVQJOTPXVUIS-UHFFFAOYSA-N 1,3-dihydro-3-benzazepin-2-one Chemical compound C1=CNC(=O)CC2=CC=CC=C21 WUYVQJOTPXVUIS-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HUMIEJNVCICTPJ-UHFFFAOYSA-N 2,2-dimethoxy-n-methylethanamine Chemical compound CNCC(OC)OC HUMIEJNVCICTPJ-UHFFFAOYSA-N 0.000 description 1
- ZRHBGRVIKPJCDP-UHFFFAOYSA-N 2-hydroxy-5-nitrobenzaldehyde Chemical compound OC1=CC=C([N+]([O-])=O)C=C1C=O.OC1=CC=C([N+]([O-])=O)C=C1C=O ZRHBGRVIKPJCDP-UHFFFAOYSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- KLQAOIXAMBXYNI-PPHPATTJSA-N 5-amino-3-methyl-2,5-dihydro-1H-3-benzazepin-4-one (5S)-5-amino-3-methyl-2,5-dihydro-1H-3-benzazepin-4-one Chemical compound NC1C(N(CCC2=C1C=CC=C2)C)=O.N[C@@H]2C(N(CCC1=C2C=CC=C1)C)=O KLQAOIXAMBXYNI-PPHPATTJSA-N 0.000 description 1
- YFLAJACUIAQBCX-UHFFFAOYSA-N 5-methyl-1,2,3,5-tetrahydro-3-benzazepin-4-one Chemical compound C1CNC(=O)C(C)C2=CC=CC=C21 YFLAJACUIAQBCX-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001607 bioavailable molecules Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000011549 crystallization solution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24955200P | 2000-11-17 | 2000-11-17 | |
| PCT/US2001/027799 WO2002047671A2 (en) | 2000-11-17 | 2001-11-05 | Lactam compound to inhibit beta-amyloid peptide release or synthesis |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2004517090A JP2004517090A (ja) | 2004-06-10 |
| JP2004517090A5 true JP2004517090A5 (https=) | 2006-08-17 |
| JP4116437B2 JP4116437B2 (ja) | 2008-07-09 |
Family
ID=22943982
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002549245A Expired - Fee Related JP4116437B2 (ja) | 2000-11-17 | 2001-11-05 | β−アミロイドペプチドの放出および／または合成を阻害するラクタム化合物 |
Country Status (33)
| Country | Link |
|---|---|
| US (1) | US20050261495A1 (https=) |
| EP (1) | EP1341531B1 (https=) |
| JP (1) | JP4116437B2 (https=) |
| KR (1) | KR100819679B1 (https=) |
| CN (1) | CN1486184A (https=) |
| AR (1) | AR035927A1 (https=) |
| AU (2) | AU4319202A (https=) |
| BR (1) | BR0115427A (https=) |
| CA (1) | CA2427227C (https=) |
| CY (1) | CY1106366T1 (https=) |
| CZ (1) | CZ20031351A3 (https=) |
| DE (1) | DE60126132T2 (https=) |
| DK (1) | DK1341531T3 (https=) |
| DZ (1) | DZ3453A1 (https=) |
| EA (1) | EA005954B1 (https=) |
| EC (1) | ECSP034600A (https=) |
| ES (1) | ES2278804T3 (https=) |
| HR (1) | HRP20030383B1 (https=) |
| HU (1) | HU228117B1 (https=) |
| IL (2) | IL155960A0 (https=) |
| MX (1) | MXPA03004292A (https=) |
| MY (1) | MY134559A (https=) |
| NO (1) | NO324324B1 (https=) |
| NZ (1) | NZ525854A (https=) |
| PE (1) | PE20020802A1 (https=) |
| PL (1) | PL212199B1 (https=) |
| PT (1) | PT1341531E (https=) |
| SI (1) | SI1341531T1 (https=) |
| SK (1) | SK288065B6 (https=) |
| TW (1) | TWI305204B (https=) |
| UA (1) | UA74849C2 (https=) |
| WO (1) | WO2002047671A2 (https=) |
| ZA (1) | ZA200303789B (https=) |
Families Citing this family (51)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7468365B2 (en) | 2000-11-17 | 2008-12-23 | Eli Lilly And Company | Lactam compound |
| UA74849C2 (en) * | 2000-11-17 | 2006-02-15 | Lilly Co Eli | Lactam |
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| WO2012024170A2 (en) | 2010-08-17 | 2012-02-23 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF HEPATITIS B VIRUS (HBV) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
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| WO2012040444A2 (en) * | 2010-09-24 | 2012-03-29 | Bristol-Myers Squibb Company | Treatment of patients with incipient alzheimer's disease |
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| WO2014052563A2 (en) | 2012-09-28 | 2014-04-03 | Merck Sharp & Dohme Corp. | Novel compounds that are erk inhibitors |
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| JP6319912B2 (ja) | 2013-04-19 | 2018-05-09 | 国立大学法人 岡山大学 | アミロイドβ蛋白質により誘発される認知障害の治療剤およびアルツハイマー病治療薬、ならびにこれらに関連する治療方法および病態解析方法 |
| US20160194368A1 (en) | 2013-09-03 | 2016-07-07 | Moderna Therapeutics, Inc. | Circular polynucleotides |
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| EP3212773B1 (en) | 2014-10-29 | 2021-09-15 | Massachusetts Eye and Ear Infirmary | Efficient delivery of therapeutic molecules to cells of the inner ear |
| JP6840774B2 (ja) | 2016-05-16 | 2021-03-10 | ザ ジェネラル ホスピタル コーポレイション | 肺上皮エンジニアリングにおけるヒト気道幹細胞 |
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| US10947234B2 (en) | 2017-11-08 | 2021-03-16 | Merck Sharp & Dohme Corp. | PRMT5 inhibitors |
| WO2019148067A1 (en) | 2018-01-26 | 2019-08-01 | Massachusetts Eye And Ear Infirmary | Treatment of hearing loss |
| WO2020033282A1 (en) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
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| EP3833669A4 (en) | 2018-08-07 | 2022-05-11 | Merck Sharp & Dohme Corp. | PRMT5 INHIBITORS |
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| AU2020257397B2 (en) | 2019-04-19 | 2026-02-26 | Ligand Pharmaceuticals Inc. | Crystalline forms and methods of producing crystalline forms of a compound |
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| CN115003303B (zh) | 2019-12-17 | 2024-03-08 | 默沙东公司 | Prmt5抑制剂 |
| EP4076460B1 (en) | 2019-12-17 | 2026-01-21 | Merck Sharp & Dohme LLC | 1,4-dihydro-2h-spiro[isoquinoline-3,4'-piperidine derivatives as prmt5 inhibitors for the treatment of cancer |
| JP7589247B2 (ja) | 2019-12-17 | 2024-11-25 | メルク・シャープ・アンド・ドーム・エルエルシー | Ｐｒｍｔ５阻害剤 |
| JP2025511436A (ja) | 2022-09-02 | 2025-04-16 | メルク・シャープ・アンド・ドーム・エルエルシー | エキサテカン由来トポイソメラーゼ－１阻害薬医薬組成物及びその使用 |
| CN120417935A (zh) | 2022-10-25 | 2025-08-01 | 默沙东有限责任公司 | 依喜替康衍生的adc接头-载荷及其药物组合物和用途 |
| US20240207425A1 (en) | 2022-12-14 | 2024-06-27 | Merck Sharp & Dohme Llc | Auristatin linker-payloads, pharmaceutical compositions, and uses thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA002100B1 (ru) * | 1996-12-23 | 2001-12-24 | Элан Фармасьютикалз, Инк. | ЦИКЛОАЛКИЛЬНЫЕ СОЕДИНЕНИЯ, ЛАКТАМЫ, ЛАКТОНЫ И РОДСТВЕННЫЕ СОЕДИНЕНИЯ, СОДЕРЖАЩИЕ ИХ ФАРМАЦЕВТИЧЕСКИЕ КОМПОЗИЦИИ И СПОСОБЫ ИНГИБИРОВАНИЯ ВЫСВОБОЖДЕНИЯ И/ИЛИ СИНТЕЗА β-АМИЛОИДНОГО ПЕПТИДА С ПОМОЩЬЮ УКАЗАННЫХ СОЕДИНЕНИЙ |
| WO1999067219A1 (en) * | 1998-06-22 | 1999-12-29 | Elan Pharmaceuticals, Inc. | Compounds for inhibiting beta-amyloid peptide release and/or its synthesis |
| JP2003513958A (ja) * | 1999-11-09 | 2003-04-15 | イーライ・リリー・アンド・カンパニー | β−アミロイドペプチド放出および／またはその合成を阻害するために有用なβ−アミノ酸化合物 |
| UA74849C2 (en) * | 2000-11-17 | 2006-02-15 | Lilly Co Eli | Lactam |
| CA2425558C (en) * | 2000-11-17 | 2012-01-03 | Eli Lilly And Company | Lactam compound |
| UA77165C2 (en) * | 2000-11-17 | 2006-11-15 | Lilly Co Eli | (n)-((s)-2-hydroxy-3-methyl-butyryl)-1-(l-alaninyl)-(s)-1-amino-3-methyl-4,5,6,7-tetrahydro-2h-3-benzazepin-2-one dihydrate, processes for manufacturing and pharmaceutical composition |
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- 2001-11-05 CN CNA018221009A patent/CN1486184A/zh active Pending
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- 2001-11-05 DK DK01989070T patent/DK1341531T3/da active
- 2001-11-05 ES ES01989070T patent/ES2278804T3/es not_active Expired - Lifetime
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- 2001-11-05 DZ DZ013453A patent/DZ3453A1/fr active
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- 2001-11-05 EA EA200300580A patent/EA005954B1/ru not_active IP Right Cessation
- 2001-11-05 US US10/416,771 patent/US20050261495A1/en not_active Abandoned
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- 2001-11-05 KR KR1020037006721A patent/KR100819679B1/ko not_active Expired - Fee Related
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- 2001-11-14 AR ARP010105312A patent/AR035927A1/es not_active Application Discontinuation
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