JP4498745B2 - ピリミジノンウイルスポリメラーゼ阻害剤 - Google Patents
ピリミジノンウイルスポリメラーゼ阻害剤 Download PDFInfo
- Publication number
- JP4498745B2 JP4498745B2 JP2003562091A JP2003562091A JP4498745B2 JP 4498745 B2 JP4498745 B2 JP 4498745B2 JP 2003562091 A JP2003562091 A JP 2003562091A JP 2003562091 A JP2003562091 A JP 2003562091A JP 4498745 B2 JP4498745 B2 JP 4498745B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- oxo
- dihydropyrimidine
- hydroxy
- carboxylic acid
- 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 - Fee Related
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- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 title abstract description 8
- 241000700605 Viruses Species 0.000 title description 3
- YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 title description 2
- 229940123066 Polymerase inhibitor Drugs 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 205
- -1 1,1′-biphenyl-2-ylamino Chemical group 0.000 claims description 103
- 238000000034 method Methods 0.000 claims description 54
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 51
- 125000001424 substituent group Chemical group 0.000 claims description 42
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 39
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 7
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 239000005973 Carvone Substances 0.000 claims description 5
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- LRACNRDCXVPUSS-UHFFFAOYSA-N 2-(3-carboxythiophen-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C2=C(C=CS2)C(O)=O)=N1 LRACNRDCXVPUSS-UHFFFAOYSA-N 0.000 claims description 4
- SBVBCPPUBKKXFT-UHFFFAOYSA-N 2-(3-formylthiophen-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C2=C(C=CS2)C=O)=N1 SBVBCPPUBKKXFT-UHFFFAOYSA-N 0.000 claims description 4
- KKBHECRHGWXADV-UHFFFAOYSA-N 2-(furan-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C=2OC=CC=2)=N1 KKBHECRHGWXADV-UHFFFAOYSA-N 0.000 claims description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 4
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 claims description 3
- 125000006516 2-(benzyloxy)ethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 3
- YLLPUIVAWFESKJ-UHFFFAOYSA-N 5-hydroxy-1-methyl-6-oxo-2-(1,3-thiazol-2-yl)pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C=2SC=CN=2)=N1 YLLPUIVAWFESKJ-UHFFFAOYSA-N 0.000 claims description 3
- FJLKTIFYINPAQM-UHFFFAOYSA-N 5-hydroxy-1-methyl-6-oxo-2-[3-[(2-phenylphenyl)carbamoylamino]phenyl]pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C=2C=C(NC(=O)NC=3C(=CC=CC=3)C=3C=CC=CC=3)C=CC=2)=N1 FJLKTIFYINPAQM-UHFFFAOYSA-N 0.000 claims description 3
- UGYKRATUGSOVCE-BQYQJAHWSA-N 5-hydroxy-1-methyl-6-oxo-2-[3-[(e)-2-phenylethenyl]furan-2-yl]pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C2=C(C=CO2)\C=C\C=2C=CC=CC=2)=N1 UGYKRATUGSOVCE-BQYQJAHWSA-N 0.000 claims description 3
- CWHZCSASLVDDDM-UHFFFAOYSA-N 5-hydroxy-1-methyl-6-oxo-2-thiophen-2-ylpyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C=2SC=CC=2)=N1 CWHZCSASLVDDDM-UHFFFAOYSA-N 0.000 claims description 3
- DTNSUVZNLPPFGV-UHFFFAOYSA-N 5-hydroxy-2-(3-hydroxyphenyl)-1-methyl-6-oxopyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C=2C=C(O)C=CC=2)=N1 DTNSUVZNLPPFGV-UHFFFAOYSA-N 0.000 claims description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 3
- 229910052723 transition metal Inorganic materials 0.000 claims description 3
- 150000003624 transition metals Chemical class 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- SQQUQKKIPOXILA-UHFFFAOYSA-N 1-[(4-carboxyphenyl)methyl]-3-hydroxy-2-oxo-6-thiophen-2-ylpyridine-4-carboxylic acid Chemical compound C1=CC(C(=O)O)=CC=C1CN1C(=O)C(O)=C(C(O)=O)C=C1C1=CC=CS1 SQQUQKKIPOXILA-UHFFFAOYSA-N 0.000 claims description 2
- LIZCKIGWBGWSAG-UHFFFAOYSA-N 1-benzyl-5-hydroxy-6-oxo-2-thiophen-2-ylpyrimidine-4-carboxylic acid Chemical compound C=1C=CC=CC=1CN1C(=O)C(O)=C(C(=O)O)N=C1C1=CC=CS1 LIZCKIGWBGWSAG-UHFFFAOYSA-N 0.000 claims description 2
- OVKXLOYIIXNQOV-UHFFFAOYSA-N 2-(3-acetamidothiophen-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxylic acid Chemical compound C1=CSC(C=2N(C(=O)C(O)=C(C(O)=O)N=2)C)=C1NC(=O)C OVKXLOYIIXNQOV-UHFFFAOYSA-N 0.000 claims description 2
- HYUHANMPLLZQTG-UHFFFAOYSA-N 2-(3-aminothiophen-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxylic acid;hydrochloride Chemical compound Cl.OC(=O)C1=C(O)C(=O)N(C)C(C2=C(C=CS2)N)=N1 HYUHANMPLLZQTG-UHFFFAOYSA-N 0.000 claims description 2
- WFGONRCKOPFOCO-UHFFFAOYSA-N 2-(3-bromothiophen-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C2=C(C=CS2)Br)=N1 WFGONRCKOPFOCO-UHFFFAOYSA-N 0.000 claims description 2
- OOQOCWTWVMVTPD-UHFFFAOYSA-N 2-[2-[(3,4-dichlorophenyl)methoxy]phenyl]-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C=2C(=CC=CC=2)OCC=2C=C(Cl)C(Cl)=CC=2)=N1 OOQOCWTWVMVTPD-UHFFFAOYSA-N 0.000 claims description 2
- QELSZULAOQFXEU-UHFFFAOYSA-N 2-[3-[(2-chlorophenyl)sulfonylcarbamoylamino]thiophen-2-yl]-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C2=C(C=CS2)NC(=O)NS(=O)(=O)C=2C(=CC=CC=2)Cl)=N1 QELSZULAOQFXEU-UHFFFAOYSA-N 0.000 claims description 2
- WMERTXMUHUHGMZ-UHFFFAOYSA-N 2-[3-[(3-carboxyphenyl)carbamoylamino]phenyl]-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C=2C=C(NC(=O)NC=3C=C(C=CC=3)C(O)=O)C=CC=2)=N1 WMERTXMUHUHGMZ-UHFFFAOYSA-N 0.000 claims description 2
- IXPDVLWVZUWSGG-UHFFFAOYSA-N 2-[3-[3-(2-chlorophenyl)propanoylamino]thiophen-2-yl]-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C2=C(C=CS2)NC(=O)CCC=2C(=CC=CC=2)Cl)=N1 IXPDVLWVZUWSGG-UHFFFAOYSA-N 0.000 claims description 2
- GNWLTWMKATVVIQ-UHFFFAOYSA-N 2-[3-[[2-(benzylamino)-2-oxoethyl]amino]thiophen-2-yl]-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C2=C(C=CS2)NCC(=O)NCC=2C=CC=CC=2)=N1 GNWLTWMKATVVIQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- HVWIMZGMCCCTMN-UHFFFAOYSA-N 5-hydroxy-1-methyl-2-(3-nitrothiophen-2-yl)-6-oxopyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C2=C(C=CS2)[N+]([O-])=O)=N1 HVWIMZGMCCCTMN-UHFFFAOYSA-N 0.000 claims description 2
- FNGLAKHJXUWEBP-UHFFFAOYSA-N 5-hydroxy-1-methyl-2-[3-[[2-(2-methyl-1h-indol-3-yl)acetyl]amino]thiophen-2-yl]-6-oxopyrimidine-4-carboxylic acid Chemical compound CC=1NC2=CC=CC=C2C=1CC(=O)NC=1C=CSC=1C1=NC(C(O)=O)=C(O)C(=O)N1C FNGLAKHJXUWEBP-UHFFFAOYSA-N 0.000 claims description 2
- CIJZGPXGWHTJFI-UHFFFAOYSA-N 5-hydroxy-1-methyl-6-oxo-2-thiophen-3-ylpyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C2=CSC=C2)=N1 CIJZGPXGWHTJFI-UHFFFAOYSA-N 0.000 claims description 2
- YCZLZWHBYXWLGA-UHFFFAOYSA-N 5-hydroxy-2-[3-[(4-methoxyphenyl)methoxy]phenyl]-1-methyl-6-oxopyrimidine-4-carboxylic acid Chemical compound C1=CC(OC)=CC=C1COC1=CC=CC(C=2N(C(=O)C(O)=C(C(O)=O)N=2)C)=C1 YCZLZWHBYXWLGA-UHFFFAOYSA-N 0.000 claims description 2
- HHTZWNGYJPIYFE-UHFFFAOYSA-N 5-hydroxy-6-oxo-2-thiophen-2-yl-1-(2,2,2-trifluoroethyl)pyrimidine-4-carboxylic acid Chemical compound FC(F)(F)CN1C(=O)C(O)=C(C(=O)O)N=C1C1=CC=CS1 HHTZWNGYJPIYFE-UHFFFAOYSA-N 0.000 claims description 2
- ZYUZLEUJKZZXNN-UHFFFAOYSA-N C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 Chemical group C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 ZYUZLEUJKZZXNN-UHFFFAOYSA-N 0.000 claims description 2
- KAPVYZUAFYVFFI-UHFFFAOYSA-N [2-(4-carboxy-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl)thiophen-3-yl]-(3-phenylpropyl)azanium;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.OC(=O)C1=C(O)C(=O)N(C)C(C2=C(C=CS2)[NH2+]CCCC=2C=CC=CC=2)=N1 KAPVYZUAFYVFFI-UHFFFAOYSA-N 0.000 claims description 2
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 2
- 125000003705 anilinocarbonyl group Chemical group O=C([*])N([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 claims description 2
- 238000010561 standard procedure Methods 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 2
- CCNGDNIIWQFCJO-UHFFFAOYSA-N 2-(3-benzamidothiophen-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=C(O)C(=O)N(C)C(C2=C(C=CS2)NC(=O)C=2C=CC=CC=2)=N1 CCNGDNIIWQFCJO-UHFFFAOYSA-N 0.000 claims 1
- 241000711549 Hepacivirus C Species 0.000 abstract description 17
- 108090000790 Enzymes Proteins 0.000 abstract description 6
- 102000004190 Enzymes Human genes 0.000 abstract description 6
- 239000003112 inhibitor Substances 0.000 abstract description 6
- 230000003612 virological effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 188
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 94
- 239000000243 solution Substances 0.000 description 85
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
- 235000019439 ethyl acetate Nutrition 0.000 description 72
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 71
- 239000000203 mixture Substances 0.000 description 67
- 239000007787 solid Substances 0.000 description 64
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 57
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- 239000011541 reaction mixture Substances 0.000 description 43
- 239000002904 solvent Substances 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 230000002829 reductive effect Effects 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 238000000746 purification Methods 0.000 description 27
- 238000004007 reversed phase HPLC Methods 0.000 description 25
- 239000012267 brine Substances 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000012043 crude product Substances 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 229910052739 hydrogen Inorganic materials 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 238000004108 freeze drying Methods 0.000 description 13
- 239000002244 precipitate Substances 0.000 description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000003643 water by type Substances 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- 150000002825 nitriles Chemical class 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 125000001544 thienyl group Chemical group 0.000 description 8
- 238000011282 treatment Methods 0.000 description 8
- 239000008096 xylene Substances 0.000 description 8
- 239000012298 atmosphere Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 239000003039 volatile agent Substances 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 238000007363 ring formation reaction Methods 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
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- 238000013375 chromatographic separation Methods 0.000 description 1
- 229940117916 cinnamic aldehyde Drugs 0.000 description 1
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical compound O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
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- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 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 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 125000004987 dibenzofuryl group Chemical group C1(=CC=CC=2OC3=C(C21)C=CC=C3)* 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 125000006287 difluorobenzyl group Chemical group 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- IKWBUZVWSKWGFZ-UHFFFAOYSA-N ethyl 1,4-dihydropyrimidine-6-carboxylate Chemical compound C(C)OC(=O)C=1N=CNCC1 IKWBUZVWSKWGFZ-UHFFFAOYSA-N 0.000 description 1
- DEVXTNYTHYPWNR-UHFFFAOYSA-N ethyl 1-methyl-6-oxopyrimidine-4-carboxylate Chemical compound C(C)OC(=O)C=1N=CN(C(C=1)=O)C DEVXTNYTHYPWNR-UHFFFAOYSA-N 0.000 description 1
- UPXGGIRFDZENRD-UHFFFAOYSA-N ethyl 3-isocyanatobenzoate Chemical compound CCOC(=O)C1=CC=CC(N=C=O)=C1 UPXGGIRFDZENRD-UHFFFAOYSA-N 0.000 description 1
- GGFPEDDLLGJMLO-UHFFFAOYSA-N ethyl 5-ethoxy-2-(3-formylfuran-2-yl)-1-methyl-6-oxopyrimidine-4-carboxylate Chemical compound CN1C(=O)C(OCC)=C(C(=O)OCC)N=C1C1=C(C=O)C=CO1 GGFPEDDLLGJMLO-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- PZJSZBJLOWMDRG-UHFFFAOYSA-N furan-2-ylboronic acid Chemical compound OB(O)C1=CC=CO1 PZJSZBJLOWMDRG-UHFFFAOYSA-N 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- RGZRSLKIOCHTSI-UHFFFAOYSA-N hydron;n-methylhydroxylamine;chloride Chemical compound Cl.CNO RGZRSLKIOCHTSI-UHFFFAOYSA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- AMNSWIGOPDBSIE-UHFFFAOYSA-H indium(3+);tricarbonate Chemical compound [In+3].[In+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O AMNSWIGOPDBSIE-UHFFFAOYSA-H 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- AYYBSSOEBGPXHW-UHFFFAOYSA-N methyl 2-(3-aminophenyl)-5-(2,2-dimethylpropanoyloxy)-1-methyl-6-oxopyrimidine-4-carboxylate Chemical compound CN1C(=O)C(OC(=O)C(C)(C)C)=C(C(=O)OC)N=C1C1=CC=CC(N)=C1 AYYBSSOEBGPXHW-UHFFFAOYSA-N 0.000 description 1
- DUMWONKNTAWKLV-UHFFFAOYSA-N methyl 2-(3-aminothiophen-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxylate Chemical compound CN1C(=O)C(O)=C(C(=O)OC)N=C1C1=C(N)C=CS1 DUMWONKNTAWKLV-UHFFFAOYSA-N 0.000 description 1
- KMMYUYLAVIZRPC-UHFFFAOYSA-N methyl 2-(3-formylthiophen-2-yl)-1-methyl-5-[(2-methylpropan-2-yl)oxy]-6-oxopyrimidine-4-carboxylate Chemical compound CN1C(=O)C(OC(C)(C)C)=C(C(=O)OC)N=C1C1=C(C=O)C=CS1 KMMYUYLAVIZRPC-UHFFFAOYSA-N 0.000 description 1
- PVHUFBJEJTWBPB-UHFFFAOYSA-N methyl 2-(3-formylthiophen-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxylate Chemical compound CN1C(=O)C(O)=C(C(=O)OC)N=C1C1=C(C=O)C=CS1 PVHUFBJEJTWBPB-UHFFFAOYSA-N 0.000 description 1
- DDLFZCCIZTVFBQ-UHFFFAOYSA-N methyl 3-nitrothiophene-2-carboxylate Chemical compound COC(=O)C=1SC=CC=1[N+]([O-])=O DDLFZCCIZTVFBQ-UHFFFAOYSA-N 0.000 description 1
- AQBJGAUQEJFPKZ-UHFFFAOYSA-N methyl 4-(aminomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CN)C=C1 AQBJGAUQEJFPKZ-UHFFFAOYSA-N 0.000 description 1
- NRASTPGFHWCZFA-UHFFFAOYSA-N methyl 4-oxo-1h-pyrimidine-6-carboxylate Chemical compound COC(=O)C1=CC(=O)N=CN1 NRASTPGFHWCZFA-UHFFFAOYSA-N 0.000 description 1
- ZNCDYYSIXIXKDC-UHFFFAOYSA-N methyl 5-(2,2-dimethylpropanoyloxy)-1-methyl-2-(3-nitrophenyl)-6-oxopyrimidine-4-carboxylate Chemical compound CN1C(=O)C(OC(=O)C(C)(C)C)=C(C(=O)OC)N=C1C1=CC=CC([N+]([O-])=O)=C1 ZNCDYYSIXIXKDC-UHFFFAOYSA-N 0.000 description 1
- TUAFUSVZNQSJQU-UHFFFAOYSA-N methyl 5-(2,2-dimethylpropanoyloxy)-1-methyl-2-(3-nitrothiophen-2-yl)-6-oxopyrimidine-4-carboxylate Chemical compound CN1C(=O)C(OC(=O)C(C)(C)C)=C(C(=O)OC)N=C1C1=C([N+]([O-])=O)C=CS1 TUAFUSVZNQSJQU-UHFFFAOYSA-N 0.000 description 1
- ZKAKEQZDURMQHU-UHFFFAOYSA-N methyl 5-acetyloxy-2-[3-(benzylsulfonylamino)thiophen-2-yl]-1-methyl-6-oxopyrimidine-4-carboxylate Chemical compound CN1C(=O)C(OC(C)=O)=C(C(=O)OC)N=C1C1=C(NS(=O)(=O)CC=2C=CC=CC=2)C=CS1 ZKAKEQZDURMQHU-UHFFFAOYSA-N 0.000 description 1
- LMMMFENXRYLQSC-UHFFFAOYSA-N methyl 5-benzoyloxy-1-methyl-6-oxo-2-thiophen-2-ylpyrimidine-4-carboxylate Chemical compound CN1C(=O)C(OC(=O)C=2C=CC=CC=2)=C(C(=O)OC)N=C1C1=CC=CS1 LMMMFENXRYLQSC-UHFFFAOYSA-N 0.000 description 1
- UTXOSYRTLOFJAW-UHFFFAOYSA-N methyl 5-benzoyloxy-2-(3-hydroxyphenyl)-1-methyl-6-oxopyrimidine-4-carboxylate Chemical compound CN1C(=O)C(OC(=O)C=2C=CC=CC=2)=C(C(=O)OC)N=C1C1=CC=CC(O)=C1 UTXOSYRTLOFJAW-UHFFFAOYSA-N 0.000 description 1
- HHWUWRREHCWAQE-UHFFFAOYSA-N methyl 5-benzoyloxy-2-[3-[(4-methoxyphenyl)methoxy]phenyl]-1-methyl-6-oxopyrimidine-4-carboxylate Chemical compound CN1C(=O)C(OC(=O)C=2C=CC=CC=2)=C(C(=O)OC)N=C1C(C=1)=CC=CC=1OCC1=CC=C(OC)C=C1 HHWUWRREHCWAQE-UHFFFAOYSA-N 0.000 description 1
- ZPUAZENBSFZQOF-UHFFFAOYSA-N methyl 5-benzoyloxy-4-oxo-2-thiophen-2-yl-1h-pyrimidine-6-carboxylate Chemical compound COC(=O)C1=NC(C=2SC=CC=2)=NC(O)=C1OC(=O)C1=CC=CC=C1 ZPUAZENBSFZQOF-UHFFFAOYSA-N 0.000 description 1
- NMVIOAADJNUVPL-UHFFFAOYSA-N methyl 5-hydroxy-1-methyl-2-(3-nitrothiophen-2-yl)-6-oxopyrimidine-4-carboxylate Chemical compound CN1C(=O)C(O)=C(C(=O)OC)N=C1C1=C([N+]([O-])=O)C=CS1 NMVIOAADJNUVPL-UHFFFAOYSA-N 0.000 description 1
- RPMMKHGABVFVPH-UHFFFAOYSA-N methyl 5-hydroxy-2-(3-nitrothiophen-2-yl)-4-oxo-1h-pyrimidine-6-carboxylate Chemical compound O=C1C(O)=C(C(=O)OC)NC(C2=C(C=CS2)[N+]([O-])=O)=N1 RPMMKHGABVFVPH-UHFFFAOYSA-N 0.000 description 1
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- 235000010755 mineral Nutrition 0.000 description 1
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- GAKLTPUFNKNAIM-UHFFFAOYSA-N n'-hydroxy-3-nitrothiophene-2-carboximidamide Chemical compound ON=C(N)C=1SC=CC=1[N+]([O-])=O GAKLTPUFNKNAIM-UHFFFAOYSA-N 0.000 description 1
- NKMNPRXPUZINOM-UHFFFAOYSA-N n'-hydroxythiophene-2-carboximidamide Chemical compound ON=C(N)C1=CC=CS1 NKMNPRXPUZINOM-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- QGSYSJJSWZJYCB-UHFFFAOYSA-N n-hydroxy-n-methyl-3-nitrothiophene-2-carboximidamide Chemical compound CN(O)C(=N)C=1SC=CC=1[N+]([O-])=O QGSYSJJSWZJYCB-UHFFFAOYSA-N 0.000 description 1
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- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
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- 238000010422 painting Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- OAHKWDDSKCRNFE-UHFFFAOYSA-N phenylmethanesulfonyl chloride Chemical compound ClS(=O)(=O)CC1=CC=CC=C1 OAHKWDDSKCRNFE-UHFFFAOYSA-N 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- PMOIAJVKYNVHQE-UHFFFAOYSA-N phosphanium;bromide Chemical compound [PH4+].[Br-] PMOIAJVKYNVHQE-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 238000010791 quenching Methods 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
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- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
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- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
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- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
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- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical class NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
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- 150000003462 sulfoxides Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- ZCPZGKUJMOFDCC-UHFFFAOYSA-N tert-butyl n-[4-(n'-hydroxycarbamimidoyl)thiophen-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CSC=C1C(N)=NO ZCPZGKUJMOFDCC-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 description 1
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- QNMBSXGYAQZCTN-UHFFFAOYSA-N thiophen-3-ylboronic acid Chemical compound OB(O)C=1C=CSC=1 QNMBSXGYAQZCTN-UHFFFAOYSA-N 0.000 description 1
- YNVOMSDITJMNET-UHFFFAOYSA-N thiophene-3-carboxylic acid Chemical compound OC(=O)C=1C=CSC=1 YNVOMSDITJMNET-UHFFFAOYSA-N 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- RPUZOJFXAPSSJD-UHFFFAOYSA-M triphenyl(3-phenylpropyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)CCCC1=CC=CC=C1 RPUZOJFXAPSSJD-UHFFFAOYSA-M 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000007923 virulence factor Effects 0.000 description 1
- 239000000304 virulence factor Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
-
- 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
- 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
- C07D417/02—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 two hetero rings
- C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Virology (AREA)
- Public Health (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0201179.9A GB0201179D0 (en) | 2002-01-18 | 2002-01-18 | Therapeutic agents |
| PCT/GB2003/000124 WO2003062211A1 (en) | 2002-01-18 | 2003-01-15 | Pyrimidinone viral polymerase inhibitors |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2005524627A JP2005524627A (ja) | 2005-08-18 |
| JP2005524627A5 JP2005524627A5 (enExample) | 2010-02-04 |
| JP4498745B2 true JP4498745B2 (ja) | 2010-07-07 |
Family
ID=9929352
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2003562091A Expired - Fee Related JP4498745B2 (ja) | 2002-01-18 | 2003-01-15 | ピリミジノンウイルスポリメラーゼ阻害剤 |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US20050130997A1 (enExample) |
| EP (1) | EP1470113B1 (enExample) |
| JP (1) | JP4498745B2 (enExample) |
| AT (1) | ATE420078T1 (enExample) |
| CA (1) | CA2473508A1 (enExample) |
| DE (1) | DE60325692D1 (enExample) |
| GB (1) | GB0201179D0 (enExample) |
| WO (1) | WO2003062211A1 (enExample) |
Families Citing this family (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004062613A2 (en) | 2003-01-13 | 2004-07-29 | Bristol-Myers Squibb Company | Hiv integrase inhibitors |
| ATE478886T1 (de) | 2003-07-25 | 2010-09-15 | Idenix Pharmaceuticals Inc | Purin nucleoside für die behandlung von durch flavividrae verursachten krankheiten, einschliesslich hepatitis c |
| WO2005016384A1 (ja) * | 2003-08-13 | 2005-02-24 | Bf Research Institute, Inc. | アミロイド蓄積性疾患のプローブ、アミロイド染色剤、アミロイド蓄積性疾患の治療および予防薬、ならびに神経原線維変化の診断プローブおよび染色剤 |
| AR046938A1 (es) * | 2003-12-12 | 2006-01-04 | Merck & Co Inc | Procedimiento para preparar hexahidropirimido[1,2-a]azepin-2-carboxilatos y compuetos similares |
| IN2012DN04853A (enExample) | 2004-02-20 | 2015-09-25 | Boehringer Ingelheim Int | |
| AU2006242475B2 (en) | 2005-05-02 | 2011-07-07 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
| US7470664B2 (en) | 2005-07-20 | 2008-12-30 | Merck & Co., Inc. | HCV NS3 protease inhibitors |
| JP4705984B2 (ja) | 2005-08-01 | 2011-06-22 | メルク・シャープ・エンド・ドーム・コーポレイション | Ｈｃｖｎｓ３プロテアーゼ阻害剤としての大環状ペプチド |
| EP1937678B1 (en) * | 2005-10-04 | 2011-07-27 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Hiv integrase inhibitors |
| GB0609492D0 (en) | 2006-05-15 | 2006-06-21 | Angeletti P Ist Richerche Bio | Therapeutic agents |
| GB0612423D0 (en) | 2006-06-23 | 2006-08-02 | Angeletti P Ist Richerche Bio | Therapeutic agents |
| AU2007309544B2 (en) | 2006-10-24 | 2012-05-31 | Msd Italia S.R.L. | HCV NS3 protease inhibitors |
| EP2079480B1 (en) | 2006-10-24 | 2013-06-05 | Merck Sharp & Dohme Corp. | Hcv ns3 protease inhibitors |
| AU2007309546A1 (en) | 2006-10-24 | 2008-05-02 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | HCV NS3 protease inhibitors |
| AU2007318165B2 (en) | 2006-10-27 | 2011-11-17 | Msd Italia S.R.L. | HCV NS3 protease inhibitors |
| EP2083844B1 (en) | 2006-10-27 | 2013-11-27 | Merck Sharp & Dohme Corp. | Hcv ns3 protease inhibitors |
| EP2121707B1 (en) | 2006-12-20 | 2012-12-05 | Istituto di Ricerche di Biologia Molecolare P. Angeletti S.R.L. | Antiviral indoles |
| GB0625345D0 (en) | 2006-12-20 | 2007-01-31 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
| GB0625349D0 (en) | 2006-12-20 | 2007-01-31 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
| EP2494991A1 (en) | 2007-05-04 | 2012-09-05 | Vertex Pharmaceuticals Incorporated | Combination therapy for the treatment of HCV infection |
| US7763630B2 (en) | 2007-06-06 | 2010-07-27 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| CN101801982A (zh) | 2007-07-17 | 2010-08-11 | P.安杰莱蒂分子生物学研究所 | 用于治疗丙型肝炎感染的大环吲哚衍生物 |
| US8927569B2 (en) | 2007-07-19 | 2015-01-06 | Merck Sharp & Dohme Corp. | Macrocyclic compounds as antiviral agents |
| EP2188274A4 (en) * | 2007-08-03 | 2011-05-25 | Boehringer Ingelheim Int | VIRAL POLYMERASE HEMMER |
| EA201000948A1 (ru) | 2007-12-19 | 2011-02-28 | Бёрингер Ингельхайм Интернациональ Гмбх | Ингибиторы вирусной полимеразы |
| EP2271345B1 (en) | 2008-04-28 | 2015-05-20 | Merck Sharp & Dohme Corp. | Hcv ns3 protease inhibitors |
| EP2540349B1 (en) | 2008-07-22 | 2014-02-12 | Merck Sharp & Dohme Corp. | Pharmaceutical compositions comprising a macrocyclic quinoxaline compound which is an hcv ns3 protease inhibitor |
| MX2011007195A (es) | 2009-01-07 | 2013-07-12 | Scynexis Inc | Derivado de ciclosporina para el uso en el tratamiento de infección de virus de hepatitis c (vhc) y virus de inmunodeficiencia humana (vih). |
| SG173584A1 (en) | 2009-02-06 | 2011-09-29 | Elan Pharm Inc | Inhibitors of jun n-terminal kinase |
| US8143244B2 (en) | 2009-02-26 | 2012-03-27 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
| WO2010111437A1 (en) * | 2009-03-25 | 2010-09-30 | Abbott Laboratories | Antiviral compounds and uses thereof |
| US8828930B2 (en) | 2009-07-30 | 2014-09-09 | Merck Sharp & Dohme Corp. | Hepatitis C virus NS3 protease inhibitors |
| US8383639B2 (en) | 2009-10-15 | 2013-02-26 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| KR101382730B1 (ko) * | 2010-08-13 | 2014-04-08 | 에프. 호프만-라 로슈 아게 | 헤테로환형 항바이러스성 화합물 |
| WO2012151567A1 (en) * | 2011-05-05 | 2012-11-08 | St. Jude Children's Research Hospital | Pyrimidinone compounds and methods for preventing and treating influenza |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2260319B (en) * | 1991-10-07 | 1995-12-06 | Norsk Hydro As | Acyl derivatives of nucleosides and nucleoside analogues having anti-viral activity |
| DE19817265A1 (de) * | 1998-04-18 | 1999-10-21 | Bayer Ag | Verwendung von Dihydropyrimidinen als Arzneimittel und neue Stoffe |
| CN1324250A (zh) * | 1998-09-04 | 2001-11-28 | 维洛药品公司 | 治疗或预防病毒感染及其所致疾病的方法 |
| GB0017676D0 (en) * | 2000-07-19 | 2000-09-06 | Angeletti P Ist Richerche Bio | Inhibitors of viral polymerase |
-
2002
- 2002-01-18 GB GBGB0201179.9A patent/GB0201179D0/en not_active Ceased
-
2003
- 2003-01-15 DE DE60325692T patent/DE60325692D1/de not_active Expired - Lifetime
- 2003-01-15 EP EP03700366A patent/EP1470113B1/en not_active Expired - Lifetime
- 2003-01-15 AT AT03700366T patent/ATE420078T1/de not_active IP Right Cessation
- 2003-01-15 WO PCT/GB2003/000124 patent/WO2003062211A1/en not_active Ceased
- 2003-01-15 US US10/500,971 patent/US20050130997A1/en not_active Abandoned
- 2003-01-15 JP JP2003562091A patent/JP4498745B2/ja not_active Expired - Fee Related
- 2003-01-15 CA CA002473508A patent/CA2473508A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| DE60325692D1 (de) | 2009-02-26 |
| EP1470113A1 (en) | 2004-10-27 |
| JP2005524627A (ja) | 2005-08-18 |
| US20050130997A1 (en) | 2005-06-16 |
| CA2473508A1 (en) | 2003-07-31 |
| WO2003062211A1 (en) | 2003-07-31 |
| EP1470113B1 (en) | 2009-01-07 |
| GB0201179D0 (en) | 2002-03-06 |
| ATE420078T1 (de) | 2009-01-15 |
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