JP2004521084A5

JP2004521084A5 -

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Publication number: JP2004521084A5
Authority: JP; Japan
Prior art keywords: methyl; formula; amino; acid; tetrahydro
Prior art date: 2001-11-02
Legal status : Granted

Application number

JP2002542779A

Other languages

English (en)

Japanese (ja)

Other versions

JP2004521084A (ja

JP4116431B2 (ja

Filing date

2001-11-02

Publication date

2005-12-22

2001-11-02 Application filed filed Critical

2001-11-02 Priority claimed from PCT/US2001/027795 external-priority patent/WO2002040451A2/en

2004-07-15 Publication of JP2004521084A publication Critical patent/JP2004521084A/ja

2005-12-22 Publication of JP2004521084A5 publication Critical patent/JP2004521084A5/ja

2008-07-09 Application granted granted Critical

2008-07-09 Publication of JP4116431B2 publication Critical patent/JP4116431B2/ja

2021-11-02 Anticipated expiration legal-status Critical

Status Expired - Fee Related legal-status Critical Current

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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
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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
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WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
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LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
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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
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239000002585 base Substances 0.000 description 13
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210000004027 cell Anatomy 0.000 description 11
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235000011121 sodium hydroxide Nutrition 0.000 description 8
150000003573 thiols Chemical class 0.000 description 8
238000001665 trituration Methods 0.000 description 8
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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
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229910052736 halogen Inorganic materials 0.000 description 7
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239000008194 pharmaceutical composition Substances 0.000 description 7
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YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
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ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 6
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125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
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HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
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JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
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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
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JP2002542779A 2000-11-17 2001-11-02 ラクタム化合物 Expired - Fee Related JP4116431B2 (ja)