JP4845733B2

JP4845733B2 - Ｐ３８キナーゼ阻害剤としての３−アミノカルボニル、６−フェニル置換ピリジン−１−オキシド

Ｐ３８キナーゼ阻害剤としての３−アミノカルボニル、６−フェニル置換ピリジン−１−オキシド Download PDF

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Publication number: JP4845733B2
Authority: JP; Japan
Prior art keywords: fluoro; carbonyl; cyclopropylamino; methylphenyl; pyridinecarboxamide
Prior art date: 2003-08-11
Legal status : Expired - Lifetime

Application number

JP2006522975A

Other languages

English (en)

Japanese (ja)

Other versions

JP2007501831A5 (https=

JP2007501831A (ja

Inventor

ウォーカー，アン，ルイーズ

Original Assignee

スミスクラインビーチャムコーポレーション

Priority date

2003-08-11

Filing date

2004-08-09

Publication date

2011-12-28

2004-08-09 Application filed by スミスクラインビーチャムコーポレーション filed Critical スミスクラインビーチャムコーポレーション

2007-02-01 Publication of JP2007501831A publication Critical patent/JP2007501831A/ja

2007-09-20 Publication of JP2007501831A5 publication Critical patent/JP2007501831A5/ja

2011-12-28 Application granted granted Critical

2011-12-28 Publication of JP4845733B2 publication Critical patent/JP4845733B2/ja

2024-08-09 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

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102100022086 GRB2-related adapter protein 2 Human genes 0.000 title description 2
229940043355 kinase inhibitor Drugs 0.000 title description 2
239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims description 131
-1 3-ethyl-1-piperidinyl Chemical group 0.000 claims description 58
125000000217 alkyl group Chemical group 0.000 claims description 38
150000003839 salts Chemical class 0.000 claims description 36
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 27
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 25
238000000034 method Methods 0.000 claims description 25
229910052736 halogen Inorganic materials 0.000 claims description 23
150000002367 halogens Chemical class 0.000 claims description 23
239000001257 hydrogen Substances 0.000 claims description 22
229910052739 hydrogen Inorganic materials 0.000 claims description 22
125000003545 alkoxy group Chemical group 0.000 claims description 19
229910052757 nitrogen Inorganic materials 0.000 claims description 18
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
125000001072 heteroaryl group Chemical group 0.000 claims description 15
PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 14
150000002431 hydrogen Chemical class 0.000 claims description 13
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 12
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
125000000623 heterocyclic group Chemical group 0.000 claims description 10
125000005842 heteroatom Chemical group 0.000 claims description 9
125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
229910052731 fluorine Inorganic materials 0.000 claims description 8
239000011737 fluorine Substances 0.000 claims description 8
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
229910052760 oxygen Inorganic materials 0.000 claims description 7
239000001301 oxygen Substances 0.000 claims description 7
229910052717 sulfur Inorganic materials 0.000 claims description 7
239000011593 sulfur Chemical group 0.000 claims description 7
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 6
DFCMDCPZZZMKML-UHFFFAOYSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxido-n-pentan-3-ylpyridin-1-ium-3-carboxamide Chemical compound [O-][N+]1=CC(C(=O)NC(CC)CC)=CC=C1C1=CC(C(=O)NC2CC2)=CC(F)=C1C DFCMDCPZZZMKML-UHFFFAOYSA-N 0.000 claims description 4
WIYUGLNMUKOBJU-UHFFFAOYSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-n-(2,2-dimethylpropyl)-1-oxidopyridin-1-ium-3-carboxamide Chemical compound CC1=C(F)C=C(C(=O)NC2CC2)C=C1C1=CC=C(C(=O)NCC(C)(C)C)C=[N+]1[O-] WIYUGLNMUKOBJU-UHFFFAOYSA-N 0.000 claims description 4
FJJONJDJIDGXOS-UHFFFAOYSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-n-(2-methylbutan-2-yl)-1-oxidopyridin-1-ium-3-carboxamide Chemical compound [O-][N+]1=CC(C(=O)NC(C)(C)CC)=CC=C1C1=CC(C(=O)NC2CC2)=CC(F)=C1C FJJONJDJIDGXOS-UHFFFAOYSA-N 0.000 claims description 4
MSHRGLRYOATXIV-CQSZACIVSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-n-[(2r)-3,3-dimethylbutan-2-yl]-1-oxidopyridin-1-ium-3-carboxamide Chemical compound [O-][N+]1=CC(C(=O)N[C@H](C)C(C)(C)C)=CC=C1C1=CC(C(=O)NC2CC2)=CC(F)=C1C MSHRGLRYOATXIV-CQSZACIVSA-N 0.000 claims description 4
XDEQCYKIFPIEAL-CQSZACIVSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-n-[(2r)-3-methylbutan-2-yl]-1-oxidopyridin-1-ium-3-carboxamide Chemical compound [O-][N+]1=CC(C(=O)N[C@H](C)C(C)C)=CC=C1C1=CC(C(=O)NC2CC2)=CC(F)=C1C XDEQCYKIFPIEAL-CQSZACIVSA-N 0.000 claims description 4
MSHRGLRYOATXIV-AWEZNQCLSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-n-[(2s)-3,3-dimethylbutan-2-yl]-1-oxidopyridin-1-ium-3-carboxamide Chemical compound [O-][N+]1=CC(C(=O)N[C@@H](C)C(C)(C)C)=CC=C1C1=CC(C(=O)NC2CC2)=CC(F)=C1C MSHRGLRYOATXIV-AWEZNQCLSA-N 0.000 claims description 4
XDEQCYKIFPIEAL-AWEZNQCLSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-n-[(2s)-3-methylbutan-2-yl]-1-oxidopyridin-1-ium-3-carboxamide Chemical compound [O-][N+]1=CC(C(=O)N[C@@H](C)C(C)C)=CC=C1C1=CC(C(=O)NC2CC2)=CC(F)=C1C XDEQCYKIFPIEAL-AWEZNQCLSA-N 0.000 claims description 4
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 4
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
IGZRKBXWJWDPEO-UHFFFAOYSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-n-[(3,4-dimethylphenyl)methyl]-1-oxidopyridin-1-ium-3-carboxamide Chemical compound C1=C(C)C(C)=CC=C1CNC(=O)C(C=[N+]1[O-])=CC=C1C1=CC(C(=O)NC2CC2)=CC(F)=C1C IGZRKBXWJWDPEO-UHFFFAOYSA-N 0.000 claims description 3
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
125000001153 fluoro group Chemical group F* 0.000 claims description 3
WESCIQGEWIIPRB-UHFFFAOYSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxido-n-propylpyridin-1-ium-3-carboxamide Chemical compound [O-][N+]1=CC(C(=O)NCCC)=CC=C1C1=CC(C(=O)NC2CC2)=CC(F)=C1C WESCIQGEWIIPRB-UHFFFAOYSA-N 0.000 claims description 2
MESZBQFBSFHEEG-UHFFFAOYSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-n-(2-methylpropyl)-1-oxidopyridin-1-ium-3-carboxamide Chemical compound [O-][N+]1=CC(C(=O)NCC(C)C)=CC=C1C1=CC(C(=O)NC2CC2)=CC(F)=C1C MESZBQFBSFHEEG-UHFFFAOYSA-N 0.000 claims description 2
HJAKOLLDSZLBIM-LBPRGKRZSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-n-[(2s)-1-methoxypropan-2-yl]-1-oxidopyridin-1-ium-3-carboxamide Chemical class [O-][N+]1=CC(C(=O)N[C@@H](C)COC)=CC=C1C1=CC(C(=O)NC2CC2)=CC(F)=C1C HJAKOLLDSZLBIM-LBPRGKRZSA-N 0.000 claims description 2
150000001721 carbon Chemical group 0.000 claims description 2
229910052799 carbon Inorganic materials 0.000 claims description 2
125000001309 chloro group Chemical group Cl* 0.000 claims description 2
XWSRZGAHUYOSQY-UHFFFAOYSA-N n-tert-butyl-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxidopyridin-1-ium-3-carboxamide Chemical compound CC1=C(F)C=C(C(=O)NC2CC2)C=C1C1=CC=C(C(=O)NC(C)(C)C)C=[N+]1[O-] XWSRZGAHUYOSQY-UHFFFAOYSA-N 0.000 claims description 2
SCMUUBWYJOXVQD-UHFFFAOYSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-n-[(2,5-dimethylphenyl)methyl]-1-oxidopyridin-1-ium-3-carboxamide Chemical compound CC1=CC=C(C)C(CNC(=O)C=2C=[N+]([O-])C(C=3C(=C(F)C=C(C=3)C(=O)NC3CC3)C)=CC=2)=C1 SCMUUBWYJOXVQD-UHFFFAOYSA-N 0.000 claims 1
DQFUUKFVEQZPQQ-UHFFFAOYSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-n-[(2-ethylphenyl)methyl]-1-oxidopyridin-1-ium-3-carboxamide Chemical compound CCC1=CC=CC=C1CNC(=O)C(C=[N+]1[O-])=CC=C1C1=CC(C(=O)NC2CC2)=CC(F)=C1C DQFUUKFVEQZPQQ-UHFFFAOYSA-N 0.000 claims 1
HFIGQSSOGGAORT-UHFFFAOYSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-n-[(3,5-dimethylphenyl)methyl]-1-oxidopyridin-1-ium-3-carboxamide Chemical compound CC1=CC(C)=CC(CNC(=O)C=2C=[N+]([O-])C(C=3C(=C(F)C=C(C=3)C(=O)NC3CC3)C)=CC=2)=C1 HFIGQSSOGGAORT-UHFFFAOYSA-N 0.000 claims 1
ZWGJNQPKXGGUPF-UHFFFAOYSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-n-[[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-1-oxidopyridin-1-ium-3-carboxamide Chemical class CC1=C(F)C=C(C(=O)NC2CC2)C=C1C([N+](=C1)[O-])=CC=C1C(=O)NCC1=CC(C(F)(F)F)=CC=C1F ZWGJNQPKXGGUPF-UHFFFAOYSA-N 0.000 claims 1
PDAASRZVZWUOGC-UHFFFAOYSA-N 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-n-[[5-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-oxidopyridin-1-ium-3-carboxamide Chemical class CC1=C(F)C=C(C(=O)NC2CC2)C=C1C([N+](=C1)[O-])=CC=C1C(=O)NCC1=CC(F)=CC=C1C(F)(F)F PDAASRZVZWUOGC-UHFFFAOYSA-N 0.000 claims 1
BTWRTPSUYRKNOG-UHFFFAOYSA-N n-[1-(4-chlorophenyl)ethyl]-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxidopyridin-1-ium-3-carboxamide Chemical compound C=1C=C(Cl)C=CC=1C(C)NC(=O)C(C=[N+]1[O-])=CC=C1C(C(=C(F)C=1)C)=CC=1C(=O)NC1CC1 BTWRTPSUYRKNOG-UHFFFAOYSA-N 0.000 claims 1
IJNAYAZAIAYOHP-UHFFFAOYSA-N n-[[2,4-bis(trifluoromethyl)phenyl]methyl]-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxidopyridin-1-ium-3-carboxamide Chemical compound CC1=C(F)C=C(C(=O)NC2CC2)C=C1C([N+](=C1)[O-])=CC=C1C(=O)NCC1=CC=C(C(F)(F)F)C=C1C(F)(F)F IJNAYAZAIAYOHP-UHFFFAOYSA-N 0.000 claims 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
230000002829 reductive effect Effects 0.000 description 88
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
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238000006243 chemical reaction Methods 0.000 description 67
239000000203 mixture Substances 0.000 description 58
239000000543 intermediate Substances 0.000 description 51
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
239000000243 solution Substances 0.000 description 45
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 44
239000002904 solvent Substances 0.000 description 42
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 37
235000002639 sodium chloride Nutrition 0.000 description 37
NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 31
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 30
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239000000706 filtrate Substances 0.000 description 26
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 25
102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 24
108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 24
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230000014759 maintenance of location Effects 0.000 description 23
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239000008194 pharmaceutical composition Substances 0.000 description 20
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239000003814 drug Substances 0.000 description 18
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229940079593 drug Drugs 0.000 description 11
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
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229940002612 prodrug Drugs 0.000 description 10
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235000017557 sodium bicarbonate Nutrition 0.000 description 10
229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
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229920002472 Starch Polymers 0.000 description 9
125000004432 carbon atom Chemical group C* 0.000 description 9
229910000029 sodium carbonate Inorganic materials 0.000 description 9
235000019698 starch Nutrition 0.000 description 9
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NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 8
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239000003112 inhibitor Substances 0.000 description 8
KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 7
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239000013543 active substance Substances 0.000 description 6
150000001412 amines Chemical class 0.000 description 6
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HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
239000002674 ointment Substances 0.000 description 6
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IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 5
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