ES2276803T3 - Inhibidores de polimerasa viral. - Google Patents
Inhibidores de polimerasa viral. Download PDFInfo
- Publication number
- ES2276803T3 ES2276803T3 ES01951274T ES01951274T ES2276803T3 ES 2276803 T3 ES2276803 T3 ES 2276803T3 ES 01951274 T ES01951274 T ES 01951274T ES 01951274 T ES01951274 T ES 01951274T ES 2276803 T3 ES2276803 T3 ES 2276803T3
- Authority
- ES
- Spain
- Prior art keywords
- cooh
- alkyl
- alkenyl
- phenyl
- cycloalkyl
- 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.)
- Expired - Lifetime
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- 239000003112 inhibitor Substances 0.000 title claims description 16
- 230000003612 virological effect Effects 0.000 title description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 280
- 150000001875 compounds Chemical class 0.000 claims abstract description 244
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims abstract description 227
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 149
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 138
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 107
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 105
- 125000001424 substituent group Chemical group 0.000 claims abstract description 95
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 95
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 93
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 91
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 84
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 77
- 150000002367 halogens Chemical class 0.000 claims abstract description 77
- 101100294106 Caenorhabditis elegans nhr-3 gene Proteins 0.000 claims abstract description 40
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 19
- -1 -CH 2 OH Chemical group 0.000 claims description 380
- 125000003118 aryl group Chemical group 0.000 claims description 77
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 31
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 29
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 29
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 125000004076 pyridyl group Chemical group 0.000 claims description 25
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 22
- 125000005019 carboxyalkenyl group Chemical group 0.000 claims description 21
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 20
- 125000004429 atom Chemical group 0.000 claims description 19
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 19
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 19
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 17
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical group C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 16
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 16
- 125000001425 triazolyl group Chemical group 0.000 claims description 16
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 claims description 15
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 claims description 14
- 229940091173 hydantoin Drugs 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 13
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 13
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 12
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 12
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical group C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 208000015181 infectious disease Diseases 0.000 claims description 10
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 9
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical group C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 9
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Chemical group C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 8
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 8
- 125000005189 alkyl hydroxy group Chemical group 0.000 claims description 8
- 230000001419 dependent effect Effects 0.000 claims description 8
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical group C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 8
- 125000002071 phenylalkoxy group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000005356 cycloalkylalkenyl group Chemical group 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 230000010076 replication Effects 0.000 claims description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 7
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Chemical group CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 6
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Chemical group C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 6
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical group C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 6
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 5
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000006360 carbonyl amino methylene group Chemical group [H]N(C([*:1])=O)C([H])([H])[*:2] 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 230000005764 inhibitory process Effects 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 4
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 claims description 3
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 102000004190 Enzymes Human genes 0.000 claims description 2
- 108090000790 Enzymes Proteins 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
- 101100440695 Dictyostelium discoideum corB gene Proteins 0.000 abstract 1
- 239000002253 acid Substances 0.000 description 242
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 197
- 239000000243 solution Substances 0.000 description 183
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 178
- 239000000203 mixture Substances 0.000 description 178
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 135
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 126
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 124
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 122
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 108
- 229910001868 water Inorganic materials 0.000 description 104
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 98
- 235000019439 ethyl acetate Nutrition 0.000 description 98
- 239000007787 solid Substances 0.000 description 94
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 90
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 83
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 79
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 75
- 230000002829 reductive effect Effects 0.000 description 71
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 69
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 68
- 238000000034 method Methods 0.000 description 61
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 59
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 54
- 239000002904 solvent Substances 0.000 description 52
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 51
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 51
- 150000004702 methyl esters Chemical class 0.000 description 50
- 238000006243 chemical reaction Methods 0.000 description 49
- 239000011541 reaction mixture Substances 0.000 description 46
- 239000012267 brine Substances 0.000 description 45
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 45
- 235000019341 magnesium sulphate Nutrition 0.000 description 45
- 238000004007 reversed phase HPLC Methods 0.000 description 45
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 45
- JTLQUCGDQKGJMM-UHFFFAOYSA-N 1-cyclohexyl-2-(furan-3-yl)benzimidazole-5-carboxylic acid Chemical compound C1=COC=C1C1=NC2=CC(C(=O)O)=CC=C2N1C1CCCCC1 JTLQUCGDQKGJMM-UHFFFAOYSA-N 0.000 description 44
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 44
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 44
- 230000008569 process Effects 0.000 description 43
- 239000011347 resin Substances 0.000 description 43
- 229920005989 resin Polymers 0.000 description 43
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 42
- 238000003756 stirring Methods 0.000 description 42
- 238000004128 high performance liquid chromatography Methods 0.000 description 38
- 239000000047 product Substances 0.000 description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 238000003818 flash chromatography Methods 0.000 description 33
- 235000017557 sodium bicarbonate Nutrition 0.000 description 32
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 32
- 241000711549 Hepacivirus C Species 0.000 description 31
- 238000000746 purification Methods 0.000 description 31
- 239000012317 TBTU Substances 0.000 description 30
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 30
- 238000001914 filtration Methods 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
- 239000000284 extract Substances 0.000 description 25
- 150000001412 amines Chemical class 0.000 description 24
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 24
- 150000002148 esters Chemical class 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000003480 eluent Substances 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 20
- 230000008570 general process Effects 0.000 description 20
- 239000002244 precipitate Substances 0.000 description 20
- 239000000725 suspension Substances 0.000 description 20
- 239000012071 phase Substances 0.000 description 19
- 238000007127 saponification reaction Methods 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 239000003921 oil Substances 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 238000000926 separation method Methods 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- 238000005859 coupling reaction Methods 0.000 description 15
- 125000004494 ethyl ester group Chemical group 0.000 description 15
- 239000000463 material Substances 0.000 description 15
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 14
- 230000008878 coupling Effects 0.000 description 14
- 238000010168 coupling process Methods 0.000 description 14
- 238000002953 preparative HPLC Methods 0.000 description 14
- WJUFSDZVCOTFON-UHFFFAOYSA-N veratraldehyde Chemical compound COC1=CC=C(C=O)C=C1OC WJUFSDZVCOTFON-UHFFFAOYSA-N 0.000 description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 13
- 229910052786 argon Inorganic materials 0.000 description 13
- 238000001035 drying Methods 0.000 description 13
- DCMBHDKEVFGGFS-VIFPVBQESA-N (2s)-2-amino-3-(3-methoxycarbonylphenyl)propanoic acid Chemical group COC(=O)C1=CC=CC(C[C@H](N)C(O)=O)=C1 DCMBHDKEVFGGFS-VIFPVBQESA-N 0.000 description 12
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 12
- 239000006260 foam Substances 0.000 description 12
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 12
- 230000002441 reversible effect Effects 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 12
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 11
- ZYJSTSMEUKNCEV-UHFFFAOYSA-N 3-diazo-1-diazonioprop-1-en-2-olate Chemical compound [N-]=[N+]=CC(=O)C=[N+]=[N-] ZYJSTSMEUKNCEV-UHFFFAOYSA-N 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 229910052763 palladium Inorganic materials 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 11
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 10
- LQQKDSXCDXHLLF-UHFFFAOYSA-N 1,3-dibromopropan-2-one Chemical compound BrCC(=O)CBr LQQKDSXCDXHLLF-UHFFFAOYSA-N 0.000 description 10
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 10
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
- NMPVEAUIHMEAQP-UHFFFAOYSA-N alpha-bromo-acetaldehyde Natural products BrCC=O NMPVEAUIHMEAQP-UHFFFAOYSA-N 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 10
- 239000012300 argon atmosphere Substances 0.000 description 10
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 10
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
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- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- FZRNJOXQNWVMIH-UHFFFAOYSA-N lithium;hydrate Chemical compound [Li].O FZRNJOXQNWVMIH-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- DQEUYIQDSMINEY-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C=C DQEUYIQDSMINEY-UHFFFAOYSA-M 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- VXYFARNRGZWHTJ-FVGYRXGTSA-N methyl (2s)-2-amino-3-(4-hydroxyphenyl)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VXYFARNRGZWHTJ-FVGYRXGTSA-N 0.000 description 1
- IWCBTJGQEMLZIV-AWEZNQCLSA-N methyl (2s)-3-(1-acetyl-5-cyanoindol-3-yl)-2-(methoxycarbonylamino)propanoate Chemical compound C1=C(C#N)C=C2C(C[C@H](NC(=O)OC)C(=O)OC)=CN(C(C)=O)C2=C1 IWCBTJGQEMLZIV-AWEZNQCLSA-N 0.000 description 1
- KJTBTGCWOAARHD-ZDUSSCGKSA-N methyl (2s)-3-(3-acetyl-4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)OC)CC1=CC=C(O)C(C(C)=O)=C1 KJTBTGCWOAARHD-ZDUSSCGKSA-N 0.000 description 1
- XVCIWMRXULARFF-ZDUSSCGKSA-N methyl (2s)-3-(4-acetyloxy-3-iodophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)OC)CC1=CC=C(OC(C)=O)C(I)=C1 XVCIWMRXULARFF-ZDUSSCGKSA-N 0.000 description 1
- AIRPXWNLSTZXJH-AWEZNQCLSA-N methyl (2s)-3-(4-methyl-2-oxochromen-6-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound O1C(=O)C=C(C)C2=CC(C[C@@H](C(=O)OC)NC(=O)OC(C)(C)C)=CC=C21 AIRPXWNLSTZXJH-AWEZNQCLSA-N 0.000 description 1
- YKCVPDKYOBRNNT-INIZCTEOSA-N methyl (2s)-3-[4-acetyloxy-3-(3-methoxy-3-oxopropyl)phenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound COC(=O)CCC1=CC(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)=CC=C1OC(C)=O YKCVPDKYOBRNNT-INIZCTEOSA-N 0.000 description 1
- RXZBTVWWLRIUSC-DZZUKKPASA-N methyl (2s)-3-[4-acetyloxy-3-[(e)-3-methoxy-3-oxoprop-1-enyl]phenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound COC(=O)\C=C\C1=CC(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)=CC=C1OC(C)=O RXZBTVWWLRIUSC-DZZUKKPASA-N 0.000 description 1
- NTNUDYROPUKXNA-UHFFFAOYSA-N methyl 2-(triphenyl-$l^{5}-phosphanylidene)acetate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OC)C1=CC=CC=C1 NTNUDYROPUKXNA-UHFFFAOYSA-N 0.000 description 1
- QJTNAKNDPCYGKF-AWEZNQCLSA-N methyl 2-[4-[(2s)-4-bromo-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxobutyl]phenoxy]acetate Chemical compound COC(=O)COC1=CC=C(C[C@H](NC(=O)OC(C)(C)C)C(=O)CBr)C=C1 QJTNAKNDPCYGKF-AWEZNQCLSA-N 0.000 description 1
- AOXPHVNMBPFOFS-UHFFFAOYSA-N methyl 2-nitrobenzoate Chemical compound COC(=O)C1=CC=CC=C1[N+]([O-])=O AOXPHVNMBPFOFS-UHFFFAOYSA-N 0.000 description 1
- DRJSMHNYUDSRCW-UHFFFAOYSA-N methyl 4-(cyclohexylamino)-2-methyl-5-nitrobenzoate Chemical compound C1=C(C)C(C(=O)OC)=CC([N+]([O-])=O)=C1NC1CCCCC1 DRJSMHNYUDSRCW-UHFFFAOYSA-N 0.000 description 1
- RAVVJKCSZXAIQP-UHFFFAOYSA-N methyl 5-bromopentanoate Chemical compound COC(=O)CCCCBr RAVVJKCSZXAIQP-UHFFFAOYSA-N 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- NGGXACLSAZXJGM-UHFFFAOYSA-N n-(diaminomethylidene)acetamide Chemical compound CC(=O)N=C(N)N NGGXACLSAZXJGM-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- MTJYJHSLCXTBIY-NRFANRHFSA-N n-[(1s)-1-cyano-2-(4-hydroxyphenyl)ethyl]-1-cyclohexyl-2-(furan-3-yl)benzimidazole-5-carboxamide Chemical compound C1=CC(O)=CC=C1C[C@@H](C#N)NC(=O)C1=CC=C(N(C2CCCCC2)C(=N2)C3=COC=C3)C2=C1 MTJYJHSLCXTBIY-NRFANRHFSA-N 0.000 description 1
- UJUXGWDHCCTDJD-UHFFFAOYSA-N n-[4-[6-tert-butyl-8-(2,4-dioxo-1,3-diazinan-1-yl)-5-methoxyquinolin-3-yl]phenyl]methanesulfonamide Chemical compound C12=NC=C(C=3C=CC(NS(C)(=O)=O)=CC=3)C=C2C(OC)=C(C(C)(C)C)C=C1N1CCC(=O)NC1=O UJUXGWDHCCTDJD-UHFFFAOYSA-N 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- AKRYBBWYDSDZHG-UHFFFAOYSA-N nitrosobis(2-oxopropyl)amine Chemical compound CC(=O)CN(N=O)CC(C)=O AKRYBBWYDSDZHG-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 150000005331 phenylglycines Chemical class 0.000 description 1
- PEUGKEHLRUVPAN-UHFFFAOYSA-N piperidin-3-amine Chemical compound NC1CCCNC1 PEUGKEHLRUVPAN-UHFFFAOYSA-N 0.000 description 1
- 229940081310 piperonal Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- POXAIQSXNOEQGM-UHFFFAOYSA-N propan-2-ylthiourea Chemical compound CC(C)NC(N)=S POXAIQSXNOEQGM-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 1
- TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 150000004053 quinones Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000012508 resin bead Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- 239000003161 ribonuclease inhibitor Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- ZFRKQXVRDFCRJG-UHFFFAOYSA-N skatole Chemical class C1=CC=C2C(C)=CNC2=C1 ZFRKQXVRDFCRJG-UHFFFAOYSA-N 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- QPILZZVXGUNELN-UHFFFAOYSA-M sodium;4-amino-5-hydroxynaphthalene-2,7-disulfonate;hydron Chemical compound [Na+].OS(=O)(=O)C1=CC(O)=C2C(N)=CC(S([O-])(=O)=O)=CC2=C1 QPILZZVXGUNELN-UHFFFAOYSA-M 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- PWEBUXCTKOWPCW-UHFFFAOYSA-N squaric acid Chemical group OC1=C(O)C(=O)C1=O PWEBUXCTKOWPCW-UHFFFAOYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- APCBTRDHCDOPNY-SSDOTTSWSA-N tert-butyl (3r)-3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](O)C1 APCBTRDHCDOPNY-SSDOTTSWSA-N 0.000 description 1
- IVWMZGMQXHEOAR-UHFFFAOYSA-N tert-butyl 3-methyl-5-phenylmethoxyindole-1-carboxylate Chemical compound C1=C2C(C)=CN(C(=O)OC(C)(C)C)C2=CC=C1OCC1=CC=CC=C1 IVWMZGMQXHEOAR-UHFFFAOYSA-N 0.000 description 1
- QGYQKAMRDSLQRI-UHFFFAOYSA-N tert-butyl [chloro(phenyl)methyl] carbonate Chemical compound CC(C)(C)OC(=O)OC(Cl)C1=CC=CC=C1 QGYQKAMRDSLQRI-UHFFFAOYSA-N 0.000 description 1
- IOLIFIOLILZQQH-NSHDSACASA-N tert-butyl n-[(2s)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C(N)=O)CC1=CC=C(O)C=C1 IOLIFIOLILZQQH-NSHDSACASA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- KQKFNIVNRRMMHA-UHFFFAOYSA-N tributyl-[2-(phenylmethoxymethyl)tetrazol-5-yl]stannane Chemical compound N1=C([Sn](CCCC)(CCCC)CCCC)N=NN1COCC1=CC=CC=C1 KQKFNIVNRRMMHA-UHFFFAOYSA-N 0.000 description 1
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 description 1
- XYHCWLZPPYUCRZ-UHFFFAOYSA-N trifluoromethanamine;hydrobromide Chemical compound Br.NC(F)(F)F XYHCWLZPPYUCRZ-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 108010087967 type I signal peptidase Proteins 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- DJJCXFVJDGTHFX-XVFCMESISA-N uridine 5'-monophosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 DJJCXFVJDGTHFX-XVFCMESISA-N 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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Applications Claiming Priority (6)
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| US21608400P | 2000-07-06 | 2000-07-06 | |
| US216084P | 2000-07-06 | ||
| US27437401P | 2001-03-08 | 2001-03-08 | |
| US274374P | 2001-03-08 | ||
| US28134301P | 2001-04-05 | 2001-04-05 | |
| US281343P | 2001-04-05 |
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| ES2276803T3 true ES2276803T3 (es) | 2007-07-01 |
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| ES01951274T Expired - Lifetime ES2276803T3 (es) | 2000-07-06 | 2001-07-04 | Inhibidores de polimerasa viral. |
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| US (4) | US6448281B1 (https=) |
| EP (1) | EP1301487B1 (https=) |
| JP (1) | JP2004502761A (https=) |
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| AT (1) | ATE346049T1 (https=) |
| AU (1) | AU2001272258A1 (https=) |
| CA (1) | CA2412718C (https=) |
| DE (1) | DE60124718T2 (https=) |
| ES (1) | ES2276803T3 (https=) |
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-
2001
- 2001-07-03 US US09/898,297 patent/US6448281B1/en not_active Expired - Lifetime
- 2001-07-04 DE DE60124718T patent/DE60124718T2/de not_active Expired - Lifetime
- 2001-07-04 CA CA2412718A patent/CA2412718C/en not_active Expired - Fee Related
- 2001-07-04 MX MXPA02012906A patent/MXPA02012906A/es unknown
- 2001-07-04 JP JP2002509292A patent/JP2004502761A/ja active Pending
- 2001-07-04 EP EP01951274A patent/EP1301487B1/en not_active Expired - Lifetime
- 2001-07-04 AU AU2001272258A patent/AU2001272258A1/en not_active Abandoned
- 2001-07-04 WO PCT/CA2001/000989 patent/WO2002004425A2/en not_active Ceased
- 2001-07-04 ES ES01951274T patent/ES2276803T3/es not_active Expired - Lifetime
- 2001-07-04 AT AT01951274T patent/ATE346049T1/de active
- 2001-07-06 AR ARP010103219A patent/AR035038A1/es unknown
- 2001-11-27 US US09/995,099 patent/US6479508B1/en not_active Expired - Lifetime
-
2002
- 2002-09-10 US US10/238,282 patent/US6794404B2/en not_active Expired - Lifetime
-
2004
- 2004-05-21 US US10/851,710 patent/US7439258B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| US6448281B1 (en) | 2002-09-10 |
| US7439258B2 (en) | 2008-10-21 |
| US20030232816A1 (en) | 2003-12-18 |
| WO2002004425A3 (en) | 2002-04-25 |
| DE60124718T2 (de) | 2007-09-13 |
| DE60124718D1 (de) | 2007-01-04 |
| US6794404B2 (en) | 2004-09-21 |
| EP1301487A2 (en) | 2003-04-16 |
| US20040224955A1 (en) | 2004-11-11 |
| JP2004502761A (ja) | 2004-01-29 |
| US6479508B1 (en) | 2002-11-12 |
| ATE346049T1 (de) | 2006-12-15 |
| US20020065418A1 (en) | 2002-05-30 |
| CA2412718C (en) | 2010-06-22 |
| EP1301487B1 (en) | 2006-11-22 |
| AU2001272258A1 (en) | 2002-01-21 |
| AR035038A1 (es) | 2004-04-14 |
| CA2412718A1 (en) | 2002-01-17 |
| WO2002004425A2 (en) | 2002-01-17 |
| MXPA02012906A (es) | 2004-07-30 |
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