EA021527B1 - Соединения для уменьшения продукции бета-амилоида - Google Patents

Info

Publication number

EA021527B1

EA021527B1 EA201270824A EA201270824A EA021527B1 EA 021527 B1 EA021527 B1 EA 021527B1 EA 201270824 A EA201270824 A EA 201270824A EA 201270824 A EA201270824 A EA 201270824A EA 021527 B1 EA021527 B1 EA 021527B1

Authority

EA

Eurasian Patent Office

Prior art keywords

aseno

methyl

metheno

cyclopenta

mmol

Prior art date

2010-07-15

Links

• Espacenet
• Global Dossier
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• 150000001875 compounds Chemical class 0.000 title claims abstract description 334
• 238000004519 manufacturing process Methods 0.000 title claims abstract description 23
• 230000009467 reduction Effects 0.000 title description 7
• 108010090849 Amyloid beta-Peptides Proteins 0.000 title description 4
• 102000013455 Amyloid beta-Peptides Human genes 0.000 title description 4
• 150000003839 salts Chemical class 0.000 claims abstract description 34
• 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 abstract description 9
• -1 halogen- C1-6 alkyl Chemical group 0.000 claims description 172
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 111
• MPJNYKXXSWCRRM-UHFFFAOYSA-N 1-oxa-2,3,4-triazacycloheptadeca-2,4,6,8,10,12,14,16-octaene Chemical compound C1=CC=CC=CC=NN=NOC=CC=CC=C1 MPJNYKXXSWCRRM-UHFFFAOYSA-N 0.000 claims description 92
• 229910052757 nitrogen Inorganic materials 0.000 claims description 86
• 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 78
• LMKPHJYTFHAGHK-UHFFFAOYSA-N cyclodrine Chemical compound C1CCCC1(O)C(C(=O)OCCN(CC)CC)C1=CC=CC=C1 LMKPHJYTFHAGHK-UHFFFAOYSA-N 0.000 claims description 39
• FVFHZKZQBYHTKR-UHFFFAOYSA-N 1-oxa-2,3,4-triazacyclohexadeca-3,5,7,9,11,13,15-heptaene Chemical compound C=1C=CC=CC=CONN=NC=CC=CC=1 FVFHZKZQBYHTKR-UHFFFAOYSA-N 0.000 claims description 26
• BBTCVLLKSAWIGB-UHFFFAOYSA-N 1-oxa-2,3-diazacycloheptadeca-2,4,6,8,10,12,14,16-octaene Chemical compound C1=CC=CC=CC=CON=NC=CC=CC=C1 BBTCVLLKSAWIGB-UHFFFAOYSA-N 0.000 claims description 22
• 125000000217 alkyl group Chemical group 0.000 claims description 21
• 239000008194 pharmaceutical composition Substances 0.000 claims description 18
• 125000001424 substituent group Chemical group 0.000 claims description 18
• 125000003545 alkoxy group Chemical group 0.000 claims description 16
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
• 125000005843 halogen group Chemical group 0.000 claims description 12
• XXVMPTJGGYAODS-UHFFFAOYSA-N 1-oxa-2,3,4,5-tetrazacyclooctadeca-3,5,7,9,11,13,15,17-octaene Chemical compound O1NN=NN=CC=CC=CC=CC=CC=CC=C1 XXVMPTJGGYAODS-UHFFFAOYSA-N 0.000 claims description 10
• 125000001072 heteroaryl group Chemical group 0.000 claims description 10
• 125000004432 carbon atom Chemical group C* 0.000 claims description 9
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
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• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
• 239000003085 diluting agent Substances 0.000 claims description 7
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• 239000003937 drug carrier Substances 0.000 claims description 6
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
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• SXLTZVXYXZVKIU-UHFFFAOYSA-N O1N=NN=CC=C(C=CC=CC=CC=CC=C1)C#N Chemical compound O1N=NN=CC=C(C=CC=CC=CC=CC=C1)C#N SXLTZVXYXZVKIU-UHFFFAOYSA-N 0.000 claims description 3
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• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
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• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
• XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 claims 1
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims 1
• 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims 1
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• 208000024827 Alzheimer disease Diseases 0.000 abstract description 18
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• 239000000243 solution Substances 0.000 description 180
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• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 157
• 230000002829 reductive effect Effects 0.000 description 155
• 239000002904 solvent Substances 0.000 description 141
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• 238000004458 analytical method Methods 0.000 description 128
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• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 111
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 107
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• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 92
• 239000000543 intermediate Substances 0.000 description 90
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 84
• 239000012044 organic layer Substances 0.000 description 75
• 238000002360 preparation method Methods 0.000 description 73
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• 238000001228 spectrum Methods 0.000 description 62
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• 239000012267 brine Substances 0.000 description 58
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 58
• 238000010992 reflux Methods 0.000 description 54
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• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 47
• 238000004440 column chromatography Methods 0.000 description 44
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