JP5718332B2 - 新規な二環式尿素化合物 - Google Patents

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Publication number

JP5718332B2

JP5718332B2 JP2012523650A JP2012523650A JP5718332B2 JP 5718332 B2 JP5718332 B2 JP 5718332B2 JP 2012523650 A JP2012523650 A JP 2012523650A JP 2012523650 A JP2012523650 A JP 2012523650A JP 5718332 B2 JP5718332 B2 JP 5718332B2

Authority

JP

Japan

Prior art keywords

fluoro

phenyl

oxo

pyrimidin

tetrahydropyrido

Prior art date

2009-08-06

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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• -1 bicyclic urea compounds Chemical class 0.000 title claims description 176
• 150000001875 compounds Chemical class 0.000 claims description 371
• 150000003839 salts Chemical class 0.000 claims description 59
• 239000012453 solvate Substances 0.000 claims description 41
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 29
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
• 201000010099 disease Diseases 0.000 claims description 28
• 206010028980 Neoplasm Diseases 0.000 claims description 26
• 229910052731 fluorine Inorganic materials 0.000 claims description 24
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
• 238000011282 treatment Methods 0.000 claims description 18
• 201000011510 cancer Diseases 0.000 claims description 17
• 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 16
• 229910052739 hydrogen Inorganic materials 0.000 claims description 16
• 239000008194 pharmaceutical composition Substances 0.000 claims description 15
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
• 239000004480 active ingredient Substances 0.000 claims description 13
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 13
• 125000004434 sulfur atom Chemical group 0.000 claims description 13
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
• 229910052760 oxygen Inorganic materials 0.000 claims description 11
• 230000033115 angiogenesis Effects 0.000 claims description 10
• 229910052794 bromium Inorganic materials 0.000 claims description 10
• 125000004432 carbon atom Chemical group C* 0.000 claims description 10
• 230000003463 hyperproliferative effect Effects 0.000 claims description 10
• CSZLHAZTZZCCEL-UHFFFAOYSA-N n-[4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)amino]phenyl]benzamide Chemical compound C=1C=C(NC=2C=3CNC(=O)NC=3N=CC=2)C=CC=1NC(=O)C1=CC=CC=C1 CSZLHAZTZZCCEL-UHFFFAOYSA-N 0.000 claims description 10
• 125000001424 substituent group Chemical group 0.000 claims description 10
• 229910052757 nitrogen Inorganic materials 0.000 claims description 9
• 229910052801 chlorine Inorganic materials 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 8
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 7
• 125000000217 alkyl group Chemical group 0.000 claims description 7
• 239000003814 drug Substances 0.000 claims description 7
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 6
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• 125000004429 atom Chemical group 0.000 claims description 6
• 125000000623 heterocyclic group Chemical group 0.000 claims description 6
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• 125000002950 monocyclic group Chemical group 0.000 claims description 6
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• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
• 230000005747 tumor angiogenesis Effects 0.000 claims description 5
• YOWGCQRWOILZBA-UHFFFAOYSA-N 1-(3-chlorophenyl)-3-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]urea Chemical compound C=1C=C(OC=2C=3CNC(=O)NC=3N=CC=2)C(F)=CC=1NC(=O)NC1=CC=CC(Cl)=C1 YOWGCQRWOILZBA-UHFFFAOYSA-N 0.000 claims description 4
• NLRJBIXXRDJCAU-UHFFFAOYSA-N 1-[4-fluoro-2-(trifluoromethyl)phenyl]-3-[4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)amino]phenyl]urea Chemical compound FC(F)(F)C1=CC(F)=CC=C1NC(=O)NC(C=C1)=CC=C1NC1=CC=NC2=C1CNC(=O)N2 NLRJBIXXRDJCAU-UHFFFAOYSA-N 0.000 claims description 4
• SPNNXEKFUAFBSG-UHFFFAOYSA-N 2,5-dichloro-n-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]pyridine-3-carboxamide Chemical compound C=1C=C(OC=2C=3CNC(=O)NC=3N=CC=2)C(F)=CC=1NC(=O)C1=CC(Cl)=CN=C1Cl SPNNXEKFUAFBSG-UHFFFAOYSA-N 0.000 claims description 4
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• XCMVCFHQUUNMEG-UHFFFAOYSA-N n-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1N1C(=O)C(C(=O)NC=2C=C(F)C(OC=3C=4CNC(=O)NC=4N=CC=3)=CC=2)=CC=C1 XCMVCFHQUUNMEG-UHFFFAOYSA-N 0.000 claims description 4
• BZNMSNRKROOLNQ-UHFFFAOYSA-N n-[3-fluoro-4-[[2-oxo-3-(2,2,2-trifluoroethyl)-1,4-dihydropyrido[2,3-d]pyrimidin-5-yl]oxy]phenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1N1C(=O)C(C(=O)NC=2C=C(F)C(OC=3C=4CN(CC(F)(F)F)C(=O)NC=4N=CC=3)=CC=2)=CC=C1 BZNMSNRKROOLNQ-UHFFFAOYSA-N 0.000 claims description 4
• XTXULARVLBAOQE-UHFFFAOYSA-N n-[4-[(3-ethyl-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidin-5-yl)amino]phenyl]benzamide Chemical compound C1=CN=C2NC(=O)N(CC)CC2=C1NC(C=C1)=CC=C1NC(=O)C1=CC=CC=C1 XTXULARVLBAOQE-UHFFFAOYSA-N 0.000 claims description 4
• OPZMCVRYMSWKMH-UHFFFAOYSA-N n-[4-[(3-ethyl-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidin-5-yl)oxy]-3-fluorophenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound C1=CN=C2NC(=O)N(CC)CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=CC=CN1C1=CC=C(F)C=C1 OPZMCVRYMSWKMH-UHFFFAOYSA-N 0.000 claims description 4
• LJKYTSCKMNOCHV-UHFFFAOYSA-N n-[4-[(3-methyl-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidin-5-yl)amino]phenyl]benzamide Chemical compound C1=CN=C2NC(=O)N(C)CC2=C1NC(C=C1)=CC=C1NC(=O)C1=CC=CC=C1 LJKYTSCKMNOCHV-UHFFFAOYSA-N 0.000 claims description 4
• JHNPANQOHNYANI-UHFFFAOYSA-N n-[4-[[2-oxo-3-(2,2,2-trifluoroethyl)-1,4-dihydropyrido[2,3-d]pyrimidin-5-yl]amino]phenyl]benzamide Chemical compound C1=CN=C2NC(=O)N(CC(F)(F)F)CC2=C1NC(C=C1)=CC=C1NC(=O)C1=CC=CC=C1 JHNPANQOHNYANI-UHFFFAOYSA-N 0.000 claims description 4
• 208000037803 restenosis Diseases 0.000 claims description 4
• KOEIPWCNSYGSKR-UHFFFAOYSA-N 3-bromo-n-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]benzamide Chemical compound C=1C=C(OC=2C=3CNC(=O)NC=3N=CC=2)C(F)=CC=1NC(=O)C1=CC=CC(Br)=C1 KOEIPWCNSYGSKR-UHFFFAOYSA-N 0.000 claims description 3
• UGLWODDRRMZTFH-UHFFFAOYSA-N 3-fluoro-n-[3-fluoro-4-[(3-methyl-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidin-5-yl)amino]phenyl]benzamide Chemical compound C1=CN=C2NC(=O)N(C)CC2=C1NC(C(=C1)F)=CC=C1NC(=O)C1=CC=CC(F)=C1 UGLWODDRRMZTFH-UHFFFAOYSA-N 0.000 claims description 3
• QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 3
• 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
• 229910052799 carbon Inorganic materials 0.000 claims description 3
• 229910052740 iodine Inorganic materials 0.000 claims description 3
• AVKARBOPQCYVOP-UHFFFAOYSA-N n-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NC=2C=C(F)C(OC=3C=4CNC(=O)NC=4N=CC=3)=CC=2)=C1 AVKARBOPQCYVOP-UHFFFAOYSA-N 0.000 claims description 3
• JUWMAKCBIVNAFD-UHFFFAOYSA-N n-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]-3-methylbenzamide Chemical compound CC1=CC=CC(C(=O)NC=2C=C(F)C(OC=3C=4CNC(=O)NC=4N=CC=3)=CC=2)=C1 JUWMAKCBIVNAFD-UHFFFAOYSA-N 0.000 claims description 3
• 125000004076 pyridyl group Chemical group 0.000 claims description 3
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
• 229910052717 sulfur Inorganic materials 0.000 claims description 3
• DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 3
• 208000017520 skin disease Diseases 0.000 claims description 2
• OTEOVRYFHLUAOE-GKLJAUDBSA-N 3-[(2r,3r,4r,5r)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]-5-morpholin-4-yl-1,4-dihydropyrido[2,3-d]pyrimidin-2-one Chemical compound C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(N=CC=C2N3CCOCC3)=C2C1 OTEOVRYFHLUAOE-GKLJAUDBSA-N 0.000 claims 1
• HTEGQKNWROCYAS-GKLJAUDBSA-N 3-[(2r,3r,4r,5r)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]-5-piperazin-1-yl-1,4-dihydropyrido[2,3-d]pyrimidin-2-one Chemical compound C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(N=CC=C2N3CCNCC3)=C2C1 HTEGQKNWROCYAS-GKLJAUDBSA-N 0.000 claims 1
• ULPQSWKMSCISSV-GZOSKZMVSA-N 3-[(2r,3r,4r,5r)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]-5-piperidin-1-yl-1,4-dihydropyrido[2,3-d]pyrimidin-2-one Chemical compound C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(N=CC=C2N3CCCCC3)=C2C1 ULPQSWKMSCISSV-GZOSKZMVSA-N 0.000 claims 1
• GXLFDRZBAMFXTI-GKLJAUDBSA-N 3-[(2r,3r,4r,5r)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]-5-pyrrolidin-1-yl-1,4-dihydropyrido[2,3-d]pyrimidin-2-one Chemical compound C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(N=CC=C2N3CCCC3)=C2C1 GXLFDRZBAMFXTI-GKLJAUDBSA-N 0.000 claims 1
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
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• 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 62
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