JP2011524356A5

JP2011524356A5 -

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Publication number: JP2011524356A5
Authority: JP; Japan
Prior art keywords: alkyl; substituted; optionally substituted; nhr; alkenyl
Prior art date: 2009-06-08
Legal status : Granted

Application number

JP2011513609A

Other languages

English (en)

Japanese (ja)

Other versions

JP5749160B2 (ja

JP2011524356A (ja

Filing date

2009-06-08

Publication date

2014-07-10

2009-06-05 Priority claimed from US12/479,075 external-priority patent/US8173621B2/en

2009-06-08 Application filed filed Critical

2011-09-01 Publication of JP2011524356A publication Critical patent/JP2011524356A/ja

2014-07-10 Publication of JP2011524356A5 publication Critical patent/JP2011524356A5/ja

2015-07-15 Application granted granted Critical

2015-07-15 Publication of JP5749160B2 publication Critical patent/JP5749160B2/ja

Status Expired - Fee Related legal-status Critical Current

2029-06-08 Anticipated expiration legal-status Critical

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229910052731 fluorine Inorganic materials 0.000 claims description 359
229910052801 chlorine Inorganic materials 0.000 claims description 341
229910052794 bromium Inorganic materials 0.000 claims description 332
125000000217 alkyl group Chemical group 0.000 claims description 299
229910052740 iodine Inorganic materials 0.000 claims description 293
125000004432 carbon atom Chemical group C* 0.000 claims description 276
229910052739 hydrogen Inorganic materials 0.000 claims description 216
-1 C 2 - C 6 -alkenyl halide Chemical class 0.000 claims description 178
125000000623 heterocyclic group Chemical group 0.000 claims description 177
125000003545 alkoxy group Chemical group 0.000 claims description 153
150000001875 compounds Chemical class 0.000 claims description 153
125000000304 alkynyl group Chemical group 0.000 claims description 119
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 113
125000001624 naphthyl group Chemical group 0.000 claims description 108
125000003118 aryl group Chemical group 0.000 claims description 101
125000003342 alkenyl group Chemical group 0.000 claims description 87
125000004183 alkoxy alkyl group Chemical group 0.000 claims description 81
125000000547 substituted alkyl group Chemical group 0.000 claims description 76
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 68
125000002252 acyl group Chemical group 0.000 claims description 66
229910002091 carbon monoxide Inorganic materials 0.000 claims description 64
125000005017 substituted alkenyl group Chemical group 0.000 claims description 62
125000004426 substituted alkynyl group Chemical group 0.000 claims description 62
125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 62
125000002877 alkyl aryl group Chemical group 0.000 claims description 59
239000000203 mixture Substances 0.000 claims description 59
125000000753 cycloalkyl group Chemical group 0.000 claims description 57
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 55
229920002554 vinyl polymer Polymers 0.000 claims description 55
241000711549 Hepacivirus C Species 0.000 claims description 47
150000001540 azides Chemical class 0.000 claims description 47
125000004093 cyano group Chemical group *C#N 0.000 claims description 44
239000002585 base Substances 0.000 claims description 42
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 34
150000003839 salts Chemical class 0.000 claims description 34
229910052757 nitrogen Inorganic materials 0.000 claims description 33
125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 31
238000000034 method Methods 0.000 claims description 28
239000000126 substance Substances 0.000 claims description 27
229910052736 halogen Inorganic materials 0.000 claims description 23
150000002367 halogens Chemical class 0.000 claims description 20
208000015181 infectious disease Diseases 0.000 claims description 17
239000003814 drug Substances 0.000 claims description 15
229910052799 carbon Inorganic materials 0.000 claims description 14
239000012453 solvate Substances 0.000 claims description 13
125000001424 substituent group Chemical group 0.000 claims description 12
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 11
208000024891 symptom Diseases 0.000 claims description 11
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 10
241000710780 Bovine viral diarrhea virus 1 Species 0.000 claims description 10
125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 10
238000004519 manufacturing process Methods 0.000 claims description 10
239000013078 crystal Substances 0.000 claims description 9
229940079593 drug Drugs 0.000 claims description 8
239000000546 pharmaceutical excipient Substances 0.000 claims description 8
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241000710772 Yellow fever virus Species 0.000 claims description 7
239000000969 carrier Substances 0.000 claims description 7
229940051021 yellow-fever virus Drugs 0.000 claims description 7
241000709661 Enterovirus Species 0.000 claims description 6
241000991587 Enterovirus C Species 0.000 claims description 6
241000709721 Hepatovirus A Species 0.000 claims description 6
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
241000710886 West Nile virus Species 0.000 claims description 6
239000003085 diluting agent Substances 0.000 claims description 6
241000725619 Dengue virus Species 0.000 claims description 5
230000008569 process Effects 0.000 claims description 5
238000006467 substitution reaction Methods 0.000 claims description 4
239000003341 Bronsted base Substances 0.000 claims description 3
150000001350 alkyl halides Chemical class 0.000 claims description 3
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
239000007800 oxidant agent Substances 0.000 claims description 3
230000001590 oxidative effect Effects 0.000 claims description 3
HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 claims 2
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 2
HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
125000005865 C2-C10alkynyl group Chemical group 0.000 claims 1
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 1
OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims 1
XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 83
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 79
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 52
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
239000000047 product Substances 0.000 description 45
230000002829 reductive effect Effects 0.000 description 42
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238000006243 chemical reaction Methods 0.000 description 36
235000019439 ethyl acetate Nutrition 0.000 description 32
125000004104 aryloxy group Chemical group 0.000 description 27
238000005481 NMR spectroscopy Methods 0.000 description 26
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 26
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 25
239000002777 nucleoside Substances 0.000 description 24
239000001257 hydrogen Substances 0.000 description 21
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
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KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 18
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
239000000706 filtrate Substances 0.000 description 18
238000005160 1H NMR spectroscopy Methods 0.000 description 17
229910052760 oxygen Inorganic materials 0.000 description 17
239000000758 substrate Substances 0.000 description 17
241000710778 Pestivirus Species 0.000 description 16
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239000002904 solvent Substances 0.000 description 16
241000700605 Viruses Species 0.000 description 14
239000003112 inhibitor Substances 0.000 description 14
229910052717 sulfur Inorganic materials 0.000 description 14
238000011282 treatment Methods 0.000 description 14
241000711557 Hepacivirus Species 0.000 description 13
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
125000005843 halogen group Chemical group 0.000 description 13
239000000725 suspension Substances 0.000 description 13
KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 12
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
239000004480 active ingredient Substances 0.000 description 12
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ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 11
150000002431 hydrogen Chemical class 0.000 description 11
238000003756 stirring Methods 0.000 description 11
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
238000001914 filtration Methods 0.000 description 10
238000009472 formulation Methods 0.000 description 10
108090000623 proteins and genes Proteins 0.000 description 10
239000011541 reaction mixture Substances 0.000 description 10
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
108091032973 (ribonucleotides)n+m Proteins 0.000 description 9
125000004122 cyclic group Chemical group 0.000 description 9
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
239000007858 starting material Substances 0.000 description 9
230000001225 therapeutic effect Effects 0.000 description 9
230000003612 virological effect Effects 0.000 description 9
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
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101800001554 RNA-directed RNA polymerase Proteins 0.000 description 8
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125000003710 aryl alkyl group Chemical group 0.000 description 8
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238000004440 column chromatography Methods 0.000 description 8
QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 8
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DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 7
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JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
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CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 6
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125000000719 pyrrolidinyl group Chemical group 0.000 description 6
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RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
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HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 4
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238000005893 bromination reaction Methods 0.000 description 3
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KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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JP2011513609A 2008-06-11 2009-06-08 ヌクレオシド環状リン酸エステル Expired - Fee Related JP5749160B2 (ja)