JP4914355B2 - Ｃ型肝炎インヒビターペプチド類似体 - Google Patents

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Publication number

JP4914355B2

JP4914355B2 JP2007521758A JP2007521758A JP4914355B2 JP 4914355 B2 JP4914355 B2 JP 4914355B2 JP 2007521758 A JP2007521758 A JP 2007521758A JP 2007521758 A JP2007521758 A JP 2007521758A JP 4914355 B2 JP4914355 B2 JP 4914355B2

Authority

JP

Japan

Prior art keywords

alkyl

cycloalkyl

optionally

independently selected

substituents

Prior art date

2004-07-20

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.)

Expired - Fee Related

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• 108090000765 processed proteins & peptides Proteins 0.000 title claims description 12
• 239000003112 inhibitor Substances 0.000 title abstract description 48
• 208000005176 Hepatitis C Diseases 0.000 title description 9
• 150000001875 compounds Chemical class 0.000 claims abstract description 127
• 229910052727 yttrium Inorganic materials 0.000 claims abstract description 11
• 125000000217 alkyl group Chemical group 0.000 claims description 619
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 110
• 125000001424 substituent group Chemical group 0.000 claims description 99
• 229910052736 halogen Inorganic materials 0.000 claims description 87
• -1 Het Chemical group 0.000 claims description 83
• 125000003118 aryl group Chemical group 0.000 claims description 75
• 150000002367 halogens Chemical class 0.000 claims description 68
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 56
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 52
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 46
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
• 150000003839 salts Chemical class 0.000 claims description 42
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 33
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 32
• 229910052757 nitrogen Inorganic materials 0.000 claims description 30
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 29
• 229920006395 saturated elastomer Polymers 0.000 claims description 29
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 27
• 125000000623 heterocyclic group Chemical group 0.000 claims description 27
• 229910052717 sulfur Inorganic materials 0.000 claims description 26
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 25
• 229910052760 oxygen Inorganic materials 0.000 claims description 25
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 23
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 20
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 20
• 125000000304 alkynyl group Chemical group 0.000 claims description 19
• 125000005842 heteroatom Chemical group 0.000 claims description 19
• 125000004104 aryloxy group Chemical group 0.000 claims description 18
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 17
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 15
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 14
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 13
• 125000003342 alkenyl group Chemical group 0.000 claims description 11
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• 125000005843 halogen group Chemical group 0.000 claims description 11
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 11
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• 125000002950 monocyclic group Chemical group 0.000 claims description 8
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• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
• 241000711549 Hepacivirus C Species 0.000 description 55
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 50
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
• 238000000034 method Methods 0.000 description 45
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
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• 238000006243 chemical reaction Methods 0.000 description 33
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• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 29
• 238000002360 preparation method Methods 0.000 description 28
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 27
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
• 108010050904 Interferons Proteins 0.000 description 23
• 102000014150 Interferons Human genes 0.000 description 23
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
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• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
• 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 20
• 241000124008 Mammalia Species 0.000 description 19
• 239000012634 fragment Substances 0.000 description 19
• 238000011282 treatment Methods 0.000 description 19
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 18
• 238000005481 NMR spectroscopy Methods 0.000 description 17
• 239000002253 acid Substances 0.000 description 17
• 239000003443 antiviral agent Substances 0.000 description 17
• 125000004432 carbon atom Chemical group C* 0.000 description 17
• 229940079322 interferon Drugs 0.000 description 17
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 16
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
• 238000005859 coupling reaction Methods 0.000 description 16
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 15
• 239000012267 brine Substances 0.000 description 15
• 239000003814 drug Substances 0.000 description 15
• 239000008194 pharmaceutical composition Substances 0.000 description 15
• 230000010076 replication Effects 0.000 description 15
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
• 230000008878 coupling Effects 0.000 description 14
• 238000010168 coupling process Methods 0.000 description 14
• 239000000543 intermediate Substances 0.000 description 14
• 239000000463 material Substances 0.000 description 14
• KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 13
• 239000002904 solvent Substances 0.000 description 13
• 238000003756 stirring Methods 0.000 description 13
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
• 102000035195 Peptidases Human genes 0.000 description 12
• 108091005804 Peptidases Proteins 0.000 description 12
• 229940079593 drug Drugs 0.000 description 12
• 125000001624 naphthyl group Chemical group 0.000 description 12
• 125000004076 pyridyl group Chemical group 0.000 description 12
• 239000004576 sand Substances 0.000 description 12
• 241000700605 Viruses Species 0.000 description 11
• 238000003556 assay Methods 0.000 description 11
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• 229920000728 polyester Polymers 0.000 description 11
• 239000011734 sodium Substances 0.000 description 11
• 150000004331 4-hydroxyquinolines Chemical class 0.000 description 10
• 239000004365 Protease Substances 0.000 description 10
• 150000001412 amines Chemical class 0.000 description 10
• 230000003612 virological effect Effects 0.000 description 10
• 0 CC(C)(*)CC(C)(C(N**)=O)NC([C@](C=C(C1)*=C)N1C([C@](*)CC(N(*)*)=O)=O)=O Chemical compound CC(C)(*)CC(C)(C(N**)=O)NC([C@](C=C(C1)*=C)N1C([C@](*)CC(N(*)*)=O)=O)=O 0.000 description 9
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• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
• 125000001246 bromo group Chemical group Br* 0.000 description 9
• 125000001309 chloro group Chemical group Cl* 0.000 description 9
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
• 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 9
• 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 9
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• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
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• AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 8
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• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
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• 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 6
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• PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
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