JP2004521084A5 - - Google Patents
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- JP2004521084A5 JP2004521084A5 JP2002542779A JP2002542779A JP2004521084A5 JP 2004521084 A5 JP2004521084 A5 JP 2004521084A5 JP 2002542779 A JP2002542779 A JP 2002542779A JP 2002542779 A JP2002542779 A JP 2002542779A JP 2004521084 A5 JP2004521084 A5 JP 2004521084A5
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- formula
- amino
- acid
- tetrahydro
- 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
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- 150000001875 compounds Chemical class 0.000 claims description 147
- 238000000034 method Methods 0.000 claims description 72
- 238000006243 chemical reaction Methods 0.000 claims description 69
- 239000002253 acid Substances 0.000 claims description 52
- 125000003118 aryl group Chemical group 0.000 claims description 49
- -1 (S) -1-amino-3-methyl- 2,3,4,5 -tetrahydro- 1H -3-benzazepin-2-one dihydrate Chemical compound 0.000 claims description 48
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- 125000001072 heteroaryl group Chemical group 0.000 claims description 45
- 238000004519 manufacturing process Methods 0.000 claims description 40
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 40
- 125000000623 heterocyclic group Chemical group 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 125000005309 thioalkoxy group Chemical group 0.000 claims description 32
- 239000013078 crystal Substances 0.000 claims description 31
- 239000007787 solid Substances 0.000 claims description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- 238000003786 synthesis reaction Methods 0.000 claims description 24
- 230000015572 biosynthetic process Effects 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 238000002425 crystallisation Methods 0.000 claims description 22
- 230000008025 crystallization Effects 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 21
- 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 20
- 239000003814 drug Substances 0.000 claims description 20
- 235000001014 amino acid Nutrition 0.000 claims description 19
- 208000024827 Alzheimer disease Diseases 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000000304 alkynyl group Chemical group 0.000 claims description 18
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 15
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 15
- 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 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 14
- 125000004423 acyloxy group Chemical group 0.000 claims description 14
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 14
- 125000001246 bromo group Chemical group Br* 0.000 claims description 14
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 14
- 238000005859 coupling reaction Methods 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 150000001299 aldehydes Chemical class 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 13
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 claims description 12
- 125000004104 aryloxy group Chemical group 0.000 claims description 12
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 12
- 239000003085 diluting agent Substances 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical group OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 claims description 12
- 230000003213 activating effect Effects 0.000 claims description 11
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 11
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 10
- 150000003951 lactams Chemical class 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 239000003125 aqueous solvent Substances 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 150000002923 oximes Chemical class 0.000 claims description 6
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 6
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 6
- 208000031124 Dementia Alzheimer type Diseases 0.000 claims description 5
- 238000005481 NMR spectroscopy Methods 0.000 claims description 4
- 125000006242 amine protecting group Chemical group 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- FABVMBDCVAJXMB-UHFFFAOYSA-N 3,5-dichloro-2-hydroxybenzaldehyde Chemical compound OC1=C(Cl)C=C(Cl)C=C1C=O FABVMBDCVAJXMB-UHFFFAOYSA-N 0.000 claims description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 3
- 238000001640 fractional crystallisation Methods 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 2
- NSFIAKFOCAEBER-ROUUACIJSA-N (2r,3r)-2,3-dihydroxy-2,3-bis(4-methylphenyl)butanedioic acid Chemical compound C1=CC(C)=CC=C1[C@](O)(C(O)=O)[C@@](O)(C(O)=O)C1=CC=C(C)C=C1 NSFIAKFOCAEBER-ROUUACIJSA-N 0.000 claims 9
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 8
- 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 claims 3
- 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 claims 2
- INHREOICJVEPGN-UHFFFAOYSA-N 1-benzazepin-2-one dihydrate Chemical compound O.O.O=C1C=CC=C2C=CC=CC2=N1 INHREOICJVEPGN-UHFFFAOYSA-N 0.000 claims 2
- NGEWQZIDQIYUNV-UHFFFAOYSA-N 2-hydroxy-3-methylbutyric acid Chemical compound CC(C)C(O)C(O)=O NGEWQZIDQIYUNV-UHFFFAOYSA-N 0.000 claims 2
- 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 claims 2
- 208000012186 Alzheimer disease 3 Diseases 0.000 claims 2
- 125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 claims 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 claims 1
- IHFRMUGEILMHNU-UHFFFAOYSA-N 2-hydroxy-5-nitrobenzaldehyde Chemical compound OC1=CC=C([N+]([O-])=O)C=C1C=O IHFRMUGEILMHNU-UHFFFAOYSA-N 0.000 claims 1
- 150000007513 acids Chemical class 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 58
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 239000002904 solvent Substances 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000004480 active ingredient Substances 0.000 description 24
- 125000001424 substituent group Chemical group 0.000 description 22
- 125000004432 carbon atom Chemical group C* 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 18
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 18
- 238000009472 formulation Methods 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 229940024606 amino acid Drugs 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
- 238000001914 filtration Methods 0.000 description 15
- 239000004615 ingredient Substances 0.000 description 15
- 239000000523 sample Substances 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 150000001413 amino acids Chemical class 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 238000000605 extraction Methods 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- 125000002947 alkylene group Chemical group 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 150000004683 dihydrates Chemical class 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- 239000003826 tablet Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 229920002472 Starch Polymers 0.000 description 10
- 239000002775 capsule Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 239000008107 starch Substances 0.000 description 10
- 235000019698 starch Nutrition 0.000 description 10
- AVNSYQHGYITKAM-UHFFFAOYSA-N 5-amino-3-methyl-2,5,8,9-tetrahydro-1h-3-benzazepin-4-one Chemical compound NC1C(=O)N(C)CCC2=C1C=CCC2 AVNSYQHGYITKAM-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 238000007796 conventional method Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 238000001556 precipitation Methods 0.000 description 9
- 239000002002 slurry Substances 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
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000007795 chemical reaction product Substances 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- 150000003573 thiols Chemical class 0.000 description 8
- 238000001665 trituration Methods 0.000 description 8
- 229930194542 Keto Natural products 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 125000004442 acylamino group Chemical group 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 239000005018 casein Substances 0.000 description 7
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 7
- 235000021240 caseins Nutrition 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 125000000468 ketone group Chemical group 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 125000005323 thioketone group Chemical group 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000002965 ELISA Methods 0.000 description 6
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001540 azides Chemical class 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- FVMQJWDMZWHTEQ-UHFFFAOYSA-N 3-benzazepin-2-one Chemical compound C1=NC(=O)C=C2C=CC=CC2=C1 FVMQJWDMZWHTEQ-UHFFFAOYSA-N 0.000 description 5
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 5
- 239000008108 microcrystalline cellulose Substances 0.000 description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- AVNSYQHGYITKAM-JTQLQIEISA-N (5s)-5-amino-3-methyl-2,5,8,9-tetrahydro-1h-3-benzazepin-4-one Chemical compound N[C@@H]1C(=O)N(C)CCC2=C1C=CCC2 AVNSYQHGYITKAM-JTQLQIEISA-N 0.000 description 4
- XLQHMRZFENOWLG-UHFFFAOYSA-N 1,2,3,5,8,9-hexahydro-3-benzazepin-4-one Chemical compound C1CNC(=O)CC2=C1CCC=C2 XLQHMRZFENOWLG-UHFFFAOYSA-N 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 4
- LCRVSUZIDWQHIN-UHFFFAOYSA-N 3-methyl-2,5,8,9-tetrahydro-1h-3-benzazepin-4-one Chemical compound C1C(=O)N(C)CCC2=C1C=CCC2 LCRVSUZIDWQHIN-UHFFFAOYSA-N 0.000 description 4
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 4
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 4
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- OKLGOCQOWMJCQQ-UHFFFAOYSA-N O.O.C=1C(N=CC=C2C1C=CC=C2)=O Chemical compound O.O.C=1C(N=CC=C2C1C=CC=C2)=O OKLGOCQOWMJCQQ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 125000004450 alkenylene group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000002285 corn oil Substances 0.000 description 4
- 235000005687 corn oil Nutrition 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
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| UA74849C2 (en) * | 2000-11-17 | 2006-02-15 | Lilly Co Eli | Lactam |
| TWI323256B (en) | 2002-12-20 | 2010-04-11 | Glaxo Group Ltd | Novel benzazepine derivatives and pharmaceutical compositions comprising said compounds |
| CN102558155A (zh) | 2003-01-14 | 2012-07-11 | 阿伦纳药品公司 | 作为代谢调节剂的芳基和杂芳基衍生物及其所涉及的疾病如糖尿病和高血糖症的预防和治疗 |
| AR045047A1 (es) | 2003-07-11 | 2005-10-12 | Arena Pharm Inc | Derivados arilo y heteroarilo trisustituidos como moduladores del metabolismo y de la profilaxis y tratamiento de desordenes relacionados con los mismos |
| RU2404968C2 (ru) | 2005-04-08 | 2010-11-27 | Дайити Санкио Компани, Лимитед | Пиридилдиметилсульфоновое производное |
| US8258302B2 (en) | 2006-01-31 | 2012-09-04 | Api Corporation | Method for producing benzazepinone |
| TW200920362A (en) | 2007-09-11 | 2009-05-16 | Daiichi Sankyo Co Ltd | Alkylsulfone derivatives |
| FR2932800B1 (fr) * | 2008-06-20 | 2015-02-20 | Servier Lab | Nouveau procede de synthese de la 7,8-dimethoxy-1,3-dihydro- 2h-3-benzazepin-2-one, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| BR112013008100A2 (pt) | 2010-09-22 | 2016-08-09 | Arena Pharm Inc | "moduladores do receptor de gpr19 e o tratamento de distúrbios relacionados a eles." |
| KR101899014B1 (ko) | 2012-01-06 | 2018-09-17 | 삼성전자주식회사 | 비엘디씨 모터의 제어 장치 및 그 방법 |
| CN102690231B (zh) * | 2012-04-11 | 2014-07-09 | 南京友杰医药科技有限公司 | 治疗阿尔茨海默病潜在药物司马西特的合成方法 |
| EP2987496B1 (en) | 2013-04-19 | 2018-08-08 | National University Corporation Okayama University | Treatment agent for cognitive disorders, induced by amyloid -protein, therapeutic agent for alzheimer's disease, and treatment method and pathological analysis method related to these |
| EP3242666B9 (en) | 2015-01-06 | 2024-12-25 | Arena Pharmaceuticals, Inc. | Compound for use in treating conditions related to the s1p1 receptor |
| IL285890B (en) | 2015-06-22 | 2022-07-01 | Arena Pharm Inc | Slate-free crystal of the arginine salt of (Ar)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-4,3,2,1-tetrahydro-cyclopent[b]indole-3-yl ) acetic acid |
| MX2019009841A (es) | 2017-02-16 | 2020-01-30 | Arena Pharm Inc | Compuestos y metodos para el tratamiento de la colangitis biliar primaria. |
| KR102859841B1 (ko) | 2018-06-06 | 2025-09-12 | 아레나 파마슈티칼스, 인크. | S1p1 수용체와 관련된 병태의 치료 방법 |
| KR20230005163A (ko) | 2020-03-26 | 2023-01-09 | 씨젠 인크. | 다발성 골수종 치료 방법 |
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| JP2002518481A (ja) * | 1998-06-22 | 2002-06-25 | 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 | β−アミロイドペプチドの放出および／またはその合成を阻害するための化合物 |
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- 2001-11-02 PL PL360991A patent/PL211018B1/pl unknown
- 2001-11-02 JP JP2002542779A patent/JP4116431B2/ja not_active Expired - Fee Related
- 2001-11-02 EA EA200300579A patent/EA006919B1/ru unknown
- 2001-11-02 CN CN200910203885A patent/CN101624372A/zh active Pending
- 2001-11-02 AU AU2002224321A patent/AU2002224321B2/en not_active Ceased
- 2001-11-02 KR KR10-2003-7006660A patent/KR20030045194A/ko not_active Ceased
- 2001-11-02 CA CA2425497A patent/CA2425497C/en not_active Expired - Fee Related
- 2001-11-02 MX MXPA03004250A patent/MXPA03004250A/es active IP Right Grant
- 2001-11-02 EP EP01996530A patent/EP1353910B1/en not_active Expired - Lifetime
- 2001-11-02 SK SK543-2003A patent/SK287794B6/sk not_active IP Right Cessation
- 2001-11-02 IL IL15527501A patent/IL155275A0/xx unknown
- 2001-11-02 CN CNB018189962A patent/CN100516047C/zh not_active Expired - Fee Related
- 2001-11-02 DZ DZ013454A patent/DZ3454A1/fr active
- 2001-11-02 DK DK01996530T patent/DK1353910T3/da active
- 2001-11-02 PT PT01996530T patent/PT1353910E/pt unknown
- 2001-11-02 AT AT01996530T patent/ATE362919T1/de active
- 2001-11-02 WO PCT/US2001/027795 patent/WO2002040451A2/en not_active Ceased
- 2001-11-15 TW TW090128351A patent/TWI235151B/zh not_active IP Right Cessation
- 2001-11-15 AR ARP010105339A patent/AR031356A1/es not_active Application Discontinuation
- 2001-11-15 MY MYPI20015251A patent/MY141607A/en unknown
- 2001-11-16 SV SV2001000741A patent/SV2003000741A/es unknown
- 2001-11-16 PE PE2001001143A patent/PE20020798A1/es not_active Application Discontinuation
-
2003
- 2003-05-02 ZA ZA200303411A patent/ZA200303411B/en unknown
- 2003-05-13 EC EC2003004598A patent/ECSP034598A/es unknown
- 2003-05-15 NO NO20032215A patent/NO325217B1/no unknown
-
2007
- 2007-06-28 CY CY20071100848T patent/CY1106682T1/el unknown
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