JP2008515964A - 置換n−アルキルピリミジノン - Google Patents
置換n−アルキルピリミジノン Download PDFInfo
- Publication number
- JP2008515964A JP2008515964A JP2007536286A JP2007536286A JP2008515964A JP 2008515964 A JP2008515964 A JP 2008515964A JP 2007536286 A JP2007536286 A JP 2007536286A JP 2007536286 A JP2007536286 A JP 2007536286A JP 2008515964 A JP2008515964 A JP 2008515964A
- Authority
- JP
- Japan
- Prior art keywords
- oxy
- difluorobenzyl
- alkyl
- isopropyl
- amino
- 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.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 claims abstract description 55
- -1 carboxyal Xy Chemical group 0.000 claims description 200
- 150000001875 compounds Chemical class 0.000 claims description 190
- 125000006507 2,4-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(F)C(=C1[H])C([H])([H])* 0.000 claims description 154
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 80
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 60
- 239000001257 hydrogen Substances 0.000 claims description 56
- 229910052739 hydrogen Inorganic materials 0.000 claims description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 46
- 125000003118 aryl group Chemical group 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 38
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 28
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 28
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 26
- 208000006673 asthma Diseases 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- 150000001408 amides Chemical class 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 16
- VBNRICRDJAQAJA-UHFFFAOYSA-N n-[3-[[5-bromo-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]amino]propyl]acetamide Chemical compound O=C1N(C(C)C)C(NCCCNC(C)=O)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Br VBNRICRDJAQAJA-UHFFFAOYSA-N 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 208000027866 inflammatory disease Diseases 0.000 claims description 13
- NTKIJIDIFGRONI-UHFFFAOYSA-N 2-(2-aminoethylamino)-5-bromo-6-[(2,4-difluorophenyl)methoxy]-3-propan-2-ylpyrimidin-4-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.O=C1N(C(C)C)C(NCCN)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Br NTKIJIDIFGRONI-UHFFFAOYSA-N 0.000 claims description 11
- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
- 125000005026 carboxyaryl group Chemical group 0.000 claims description 11
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 10
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 10
- UEJKJMYZYNSSCL-UHFFFAOYSA-N n-[3-[[5-bromo-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]amino]propyl]-2-hydroxy-2-methylpropanamide Chemical compound O=C1N(C(C)C)C(NCCCNC(=O)C(C)(C)O)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Br UEJKJMYZYNSSCL-UHFFFAOYSA-N 0.000 claims description 9
- UMBNETZTFSLMMR-UHFFFAOYSA-N 3-[[5-bromo-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]amino]propylurea Chemical compound O=C1N(C(C)C)C(NCCCNC(N)=O)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Br UMBNETZTFSLMMR-UHFFFAOYSA-N 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000003106 haloaryl group Chemical group 0.000 claims description 7
- ZAJQXLOBSMVLBE-UHFFFAOYSA-N n-[2-[[5-chloro-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]amino]ethyl]acetamide Chemical compound O=C1N(C(C)C)C(NCCNC(C)=O)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Cl ZAJQXLOBSMVLBE-UHFFFAOYSA-N 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
- DISCBTTXKOZWIO-UHFFFAOYSA-N 2-[5-chloro-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]oxyethylurea Chemical compound O=C1N(C(C)C)C(OCCNC(N)=O)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Cl DISCBTTXKOZWIO-UHFFFAOYSA-N 0.000 claims description 6
- WAONXWIUTLWDCQ-UHFFFAOYSA-N 2-[[5-bromo-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]amino]ethylurea Chemical compound O=C1N(C(C)C)C(NCCNC(N)=O)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Br WAONXWIUTLWDCQ-UHFFFAOYSA-N 0.000 claims description 6
- PAFHRDGJYIXJIG-UHFFFAOYSA-N 2-[[5-chloro-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]amino]ethylurea Chemical compound O=C1N(C(C)C)C(NCCNC(N)=O)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Cl PAFHRDGJYIXJIG-UHFFFAOYSA-N 0.000 claims description 6
- QEQSKWBHCFOANW-LBPRGKRZSA-N 5-bromo-6-[(2,4-difluorophenyl)methoxy]-2-[[(2s)-2,3-dihydroxypropyl]amino]-3-propan-2-ylpyrimidin-4-one Chemical compound O=C1N(C(C)C)C(NC[C@H](O)CO)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Br QEQSKWBHCFOANW-LBPRGKRZSA-N 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 206010003246 arthritis Diseases 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- JNWNCXLSOFWTJC-UHFFFAOYSA-N n-[2-[5-bromo-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]oxyethyl]acetamide Chemical compound O=C1N(C(C)C)C(OCCNC(C)=O)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Br JNWNCXLSOFWTJC-UHFFFAOYSA-N 0.000 claims description 6
- BKSNXASLMVFGBR-UHFFFAOYSA-N n-[3-[[5-bromo-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]amino]propyl]-2-hydroxyacetamide Chemical compound O=C1N(C(C)C)C(NCCCNC(=O)CO)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Br BKSNXASLMVFGBR-UHFFFAOYSA-N 0.000 claims description 6
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
- GSTRDNSSNNCLJV-UHFFFAOYSA-N 2-(3-aminopyrrolidin-1-yl)-5-bromo-6-[(2,4-difluorophenyl)methoxy]-3-propan-2-ylpyrimidin-4-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.BrC=1C(=O)N(C(C)C)C(N2CC(N)CC2)=NC=1OCC1=CC=C(F)C=C1F GSTRDNSSNNCLJV-UHFFFAOYSA-N 0.000 claims description 5
- SSNDZPVOOJSQLK-UHFFFAOYSA-N 2-[5-bromo-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]oxyethylurea Chemical compound O=C1N(C(C)C)C(OCCNC(N)=O)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Br SSNDZPVOOJSQLK-UHFFFAOYSA-N 0.000 claims description 5
- CHSZFCSTKGLBIE-CQSZACIVSA-N 5-bromo-6-[(2,4-difluorophenyl)methoxy]-2-[(3r)-3-(methylamino)pyrrolidin-1-yl]-3-propan-2-ylpyrimidin-4-one Chemical compound C1[C@H](NC)CCN1C1=NC(OCC=2C(=CC(F)=CC=2)F)=C(Br)C(=O)N1C(C)C CHSZFCSTKGLBIE-CQSZACIVSA-N 0.000 claims description 5
- QEQSKWBHCFOANW-GFCCVEGCSA-N 5-bromo-6-[(2,4-difluorophenyl)methoxy]-2-[[(2r)-2,3-dihydroxypropyl]amino]-3-propan-2-ylpyrimidin-4-one Chemical compound O=C1N(C(C)C)C(NC[C@@H](O)CO)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Br QEQSKWBHCFOANW-GFCCVEGCSA-N 0.000 claims description 5
- JUNVPYLLMPVFJS-UHFFFAOYSA-N 5-bromo-6-[(2,4-difluorophenyl)methoxy]-2-phenyl-3-propan-2-ylpyrimidin-4-one Chemical compound BrC=1C(=O)N(C(C)C)C(C=2C=CC=CC=2)=NC=1OCC1=CC=C(F)C=C1F JUNVPYLLMPVFJS-UHFFFAOYSA-N 0.000 claims description 5
- 125000006550 alkoxycarbonyl aryl group Chemical group 0.000 claims description 5
- 125000004689 alkyl amino carbonyl alkyl group Chemical group 0.000 claims description 5
- 125000005094 alkyl carbonyl amino alkyl group Chemical group 0.000 claims description 5
- 125000005154 alkyl sulfonyl amino alkyl group Chemical group 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 125000002431 aminoalkoxy group Chemical group 0.000 claims description 5
- 125000005122 aminoalkylamino group Chemical group 0.000 claims description 5
- 125000005121 aminocarbonylalkoxy group Chemical group 0.000 claims description 5
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 5
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 5
- 125000005280 halo alkyl sulfonyloxy group Chemical group 0.000 claims description 5
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 5
- 125000005191 hydroxyalkylamino group Chemical group 0.000 claims description 5
- CBCVMZGGQYJUIF-UHFFFAOYSA-N n-[2-[[5-bromo-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]amino]ethyl]-2-hydroxy-2-methylpropanamide Chemical compound O=C1N(C(C)C)C(NCCNC(=O)C(C)(C)O)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Br CBCVMZGGQYJUIF-UHFFFAOYSA-N 0.000 claims description 5
- GTTDXZTUQIBSIS-UHFFFAOYSA-N n-[2-[[5-bromo-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]amino]ethyl]-2-hydroxyacetamide Chemical compound O=C1N(C(C)C)C(NCCNC(=O)CO)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Br GTTDXZTUQIBSIS-UHFFFAOYSA-N 0.000 claims description 5
- GTPPRMOOOHMINQ-UHFFFAOYSA-N n-[2-[[5-chloro-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]amino]ethyl]-2-hydroxyacetamide Chemical compound O=C1N(C(C)C)C(NCCNC(=O)CO)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Cl GTPPRMOOOHMINQ-UHFFFAOYSA-N 0.000 claims description 5
- IFUUCNSKRFPCLN-UHFFFAOYSA-N n-[[5-bromo-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]methyl]methanesulfonamide Chemical compound O=C1N(C(C)C)C(CNS(C)(=O)=O)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Br IFUUCNSKRFPCLN-UHFFFAOYSA-N 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- WVBPVICOMZLWIV-UHFFFAOYSA-N 2-[(1-acetylpiperidin-4-yl)amino]-5-bromo-6-[(2,4-difluorophenyl)methoxy]-3-propan-2-ylpyrimidin-4-one Chemical compound N=1C(OCC=2C(=CC(F)=CC=2)F)=C(Br)C(=O)N(C(C)C)C=1NC1CCN(C(C)=O)CC1 WVBPVICOMZLWIV-UHFFFAOYSA-N 0.000 claims description 4
- AKAFDTUDVOGBTP-OAHLLOKOSA-N 5-bromo-6-[(2,4-difluorophenyl)methoxy]-2-[(3r)-3-(ethylamino)pyrrolidin-1-yl]-3-propan-2-ylpyrimidin-4-one Chemical compound C1[C@H](NCC)CCN1C1=NC(OCC=2C(=CC(F)=CC=2)F)=C(Br)C(=O)N1C(C)C AKAFDTUDVOGBTP-OAHLLOKOSA-N 0.000 claims description 4
- SBBTWBLLBGENSR-UHFFFAOYSA-N 5-bromo-6-[(2,4-difluorophenyl)methoxy]-2-[(4-fluorophenyl)methylamino]-3-propan-2-ylpyrimidin-4-one Chemical compound N=1C(OCC=2C(=CC(F)=CC=2)F)=C(Br)C(=O)N(C(C)C)C=1NCC1=CC=C(F)C=C1 SBBTWBLLBGENSR-UHFFFAOYSA-N 0.000 claims description 4
- NCVJOLGPKBVARQ-UHFFFAOYSA-N 5-chloro-6-[(2,4-difluorophenyl)methoxy]-2-(4-hydroxybutoxy)-3-propan-2-ylpyrimidin-4-one Chemical compound O=C1N(C(C)C)C(OCCCCO)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Cl NCVJOLGPKBVARQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- CFVVRMVUSDULGG-UHFFFAOYSA-N n-[2-[5-chloro-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]oxyethyl]acetamide Chemical compound O=C1N(C(C)C)C(OCCNC(C)=O)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Cl CFVVRMVUSDULGG-UHFFFAOYSA-N 0.000 claims description 4
- 201000008482 osteoarthritis Diseases 0.000 claims description 4
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 3
- CPJJIKBDEHMSIC-UHFFFAOYSA-N 1-[[2-[(5-bromo-2-methyl-6-oxo-1-propan-2-ylpyrimidin-4-yl)oxymethyl]-5-fluorophenyl]methyl]-3-ethylurea Chemical compound CCNC(=O)NCC1=CC(F)=CC=C1COC1=C(Br)C(=O)N(C(C)C)C(C)=N1 CPJJIKBDEHMSIC-UHFFFAOYSA-N 0.000 claims description 3
- GSTRDNSSNNCLJV-BTQNPOSSSA-N 2-[(3r)-3-aminopyrrolidin-1-yl]-5-bromo-6-[(2,4-difluorophenyl)methoxy]-3-propan-2-ylpyrimidin-4-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.BrC=1C(=O)N(C(C)C)C(N2C[C@H](N)CC2)=NC=1OCC1=CC=C(F)C=C1F GSTRDNSSNNCLJV-BTQNPOSSSA-N 0.000 claims description 3
- LLTODSASWXALDV-UHFFFAOYSA-N 2-but-3-enyl-5-chloro-6-[(2,4-difluorophenyl)methoxy]-3-propan-2-ylpyrimidin-4-one Chemical compound O=C1N(C(C)C)C(CCC=C)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Cl LLTODSASWXALDV-UHFFFAOYSA-N 0.000 claims description 3
- QVSLVCNMIQIJSL-UHFFFAOYSA-N 5-bromo-6-[(2,4-difluorophenyl)methoxy]-2-(3,3-dimethylbutylamino)-3-propan-2-ylpyrimidin-4-one Chemical compound O=C1N(C(C)C)C(NCCC(C)(C)C)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Br QVSLVCNMIQIJSL-UHFFFAOYSA-N 0.000 claims description 3
- PKDJSROLEKLVEI-UQKRIMTDSA-N 5-bromo-6-[(2,4-difluorophenyl)methoxy]-2-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-3-propan-2-ylpyrimidin-4-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.BrC=1C(=O)N(C(C)C)C(N2[C@@H](CCC2)CO)=NC=1OCC1=CC=C(F)C=C1F PKDJSROLEKLVEI-UQKRIMTDSA-N 0.000 claims description 3
- MRHBQYLSGUHBKI-UHFFFAOYSA-N 5-bromo-6-[(2,4-difluorophenyl)methoxy]-3-propan-2-ylpyrimidin-4-one Chemical compound O=C1N(C(C)C)C=NC(OCC=2C(=CC(F)=CC=2)F)=C1Br MRHBQYLSGUHBKI-UHFFFAOYSA-N 0.000 claims description 3
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 3
- SLAHTTLBYXYYQH-UHFFFAOYSA-N n-[2-[[5-chloro-4-[(2,4-difluorophenyl)methoxy]-6-oxo-1-propan-2-ylpyrimidin-2-yl]amino]ethyl]-2-hydroxy-2-methylpropanamide Chemical compound O=C1N(C(C)C)C(NCCNC(=O)C(C)(C)O)=NC(OCC=2C(=CC(F)=CC=2)F)=C1Cl SLAHTTLBYXYYQH-UHFFFAOYSA-N 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 33
- 150000002431 hydrogen Chemical class 0.000 claims 18
- 125000004350 aryl cycloalkyl group Chemical group 0.000 claims 3
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims 1
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 123
- 102100040247 Tumor necrosis factor Human genes 0.000 abstract description 37
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 abstract description 29
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 abstract description 29
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 abstract description 29
- 230000000694 effects Effects 0.000 abstract description 27
- 108010037462 Cyclooxygenase 2 Proteins 0.000 abstract description 16
- 230000001575 pathological effect Effects 0.000 abstract description 15
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 abstract description 12
- 239000000126 substance Substances 0.000 abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 9
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 abstract description 4
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 abstract description 4
- 230000002265 prevention Effects 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 2
- 102000010907 Cyclooxygenase 2 Human genes 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 323
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 303
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 204
- 238000005481 NMR spectroscopy Methods 0.000 description 200
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 178
- 238000002360 preparation method Methods 0.000 description 173
- 239000007787 solid Substances 0.000 description 159
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 154
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 132
- 235000019439 ethyl acetate Nutrition 0.000 description 105
- 239000011541 reaction mixture Substances 0.000 description 102
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 78
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 74
- 239000000243 solution Substances 0.000 description 71
- 230000002829 reductive effect Effects 0.000 description 63
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 58
- 239000000843 powder Substances 0.000 description 58
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 56
- 239000000741 silica gel Substances 0.000 description 55
- 229910002027 silica gel Inorganic materials 0.000 description 55
- 238000006243 chemical reaction Methods 0.000 description 49
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 45
- 239000011734 sodium Substances 0.000 description 44
- 125000005843 halogen group Chemical group 0.000 description 43
- 235000002639 sodium chloride Nutrition 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 41
- 239000000284 extract Substances 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 38
- 125000001424 substituent group Chemical group 0.000 description 38
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 34
- 239000000047 product Substances 0.000 description 33
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 32
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 32
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 32
- 238000003818 flash chromatography Methods 0.000 description 31
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 30
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 30
- 239000003480 eluent Substances 0.000 description 30
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 30
- 239000012044 organic layer Substances 0.000 description 30
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- 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
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- 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
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61885604P | 2004-10-13 | 2004-10-13 | |
| US63794904P | 2004-12-21 | 2004-12-21 | |
| PCT/IB2005/003063 WO2006040666A1 (fr) | 2004-10-13 | 2005-10-03 | N-alkylpyrimidinones substitues |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2008515964A true JP2008515964A (ja) | 2008-05-15 |
Family
ID=35717699
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2007536286A Withdrawn JP2008515964A (ja) | 2004-10-13 | 2005-10-03 | 置換n−アルキルピリミジノン |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1802590A1 (fr) |
| JP (1) | JP2008515964A (fr) |
| BR (1) | BRPI0517555A (fr) |
| CA (1) | CA2580497A1 (fr) |
| MX (1) | MX2007004493A (fr) |
| WO (1) | WO2006040666A1 (fr) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2640665A1 (fr) * | 2006-02-10 | 2007-08-16 | Pfizer Products Inc. | Derives pyridinone-pyrazole-uree et pyrimidinone-pyrazole-uree |
| EP1992344A1 (fr) | 2007-05-18 | 2008-11-19 | Institut Curie | P38 alpha comme cible therapeutique pour les maladies associées á une mutation de FGFR3 |
| US9056110B2 (en) * | 2011-12-06 | 2015-06-16 | Confluence Life Sciences, Inc. | Substituted pyrimidinone-phenyl-pyrimidinyl compounds |
| CN108503568A (zh) * | 2017-02-27 | 2018-09-07 | 无锡杰西医药股份有限公司 | 一种适用于工业化生产的高纯度异硫氰酸酯类化合物制备方法 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63112566A (ja) * | 1986-10-28 | 1988-05-17 | Nissan Chem Ind Ltd | ピリミジノン誘導体、その製法および殺虫・殺ダニ・殺菌剤 |
| JPH01190670A (ja) * | 1988-01-22 | 1989-07-31 | Nissan Chem Ind Ltd | ピリミジノン誘導体、その製法および殺虫・殺ダニ・殺菌剤 |
| AU2003209321A1 (en) * | 2002-01-18 | 2003-07-30 | Pharmacia Corporation | Substituted pyridazinones as inhibitors of p38 |
| ATE448784T1 (de) * | 2002-02-14 | 2009-12-15 | Pharmacia Corp | Substituierte pyridinone als modulatoren für p38 map kinase |
| US7183287B2 (en) * | 2003-04-03 | 2007-02-27 | Pharmacia Corporation | Substituted pyrimidinones |
| MXPA06001002A (es) * | 2003-07-25 | 2006-04-11 | Amgen Inc | Piridonas y pirimidinonas sustituidas con propiedades antiinflamatorias. |
-
2005
- 2005-10-03 EP EP05791810A patent/EP1802590A1/fr not_active Withdrawn
- 2005-10-03 CA CA002580497A patent/CA2580497A1/fr not_active Abandoned
- 2005-10-03 BR BRPI0517555-0A patent/BRPI0517555A/pt not_active Application Discontinuation
- 2005-10-03 MX MX2007004493A patent/MX2007004493A/es unknown
- 2005-10-03 JP JP2007536286A patent/JP2008515964A/ja not_active Withdrawn
- 2005-10-03 WO PCT/IB2005/003063 patent/WO2006040666A1/fr not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| EP1802590A1 (fr) | 2007-07-04 |
| CA2580497A1 (fr) | 2006-04-20 |
| MX2007004493A (es) | 2007-05-08 |
| WO2006040666A1 (fr) | 2006-04-20 |
| BRPI0517555A (pt) | 2008-10-14 |
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