JP5670877B2 - ヒストン脱アセチル化酵素の選択的インヒビター - Google Patents
ヒストン脱アセチル化酵素の選択的インヒビター Download PDFInfo
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- JP5670877B2 JP5670877B2 JP2011505181A JP2011505181A JP5670877B2 JP 5670877 B2 JP5670877 B2 JP 5670877B2 JP 2011505181 A JP2011505181 A JP 2011505181A JP 2011505181 A JP2011505181 A JP 2011505181A JP 5670877 B2 JP5670877 B2 JP 5670877B2
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- hydroxy
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- 108090000353 Histone deacetylase Proteins 0.000 title description 58
- 229940124639 Selective inhibitor Drugs 0.000 title description 7
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- 150000001875 compounds Chemical class 0.000 claims description 403
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 150
- 125000003545 alkoxy group Chemical group 0.000 claims description 97
- 125000002947 alkylene group Chemical group 0.000 claims description 78
- 229910052736 halogen Inorganic materials 0.000 claims description 77
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- 150000003839 salts Chemical class 0.000 claims description 42
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- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 229910052717 sulfur Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
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- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
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- 125000001072 heteroaryl group Chemical group 0.000 description 176
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- 125000001424 substituent group Chemical group 0.000 description 116
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- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 45
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 29
- 201000010099 disease Diseases 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
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- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 22
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- 238000011282 treatment Methods 0.000 description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- 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 18
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- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
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- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 description 15
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 15
- 201000011510 cancer Diseases 0.000 description 15
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- 125000004404 heteroalkyl group Chemical group 0.000 description 15
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- 150000003573 thiols Chemical class 0.000 description 15
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 14
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- 239000002253 acid Substances 0.000 description 14
- 125000000304 alkynyl group Chemical group 0.000 description 14
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 14
- 125000001188 haloalkyl group Chemical group 0.000 description 14
- 230000028327 secretion Effects 0.000 description 14
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 14
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 13
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 12
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 12
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 12
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WWGBHDIHIVGYLZ-UHFFFAOYSA-N N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CC(C(=O)NCCCCCCC(=O)NO)=NO1 WWGBHDIHIVGYLZ-UHFFFAOYSA-N 0.000 description 12
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- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 description 12
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 12
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| WO2012027564A1 (en) | 2010-08-26 | 2012-03-01 | Millennium Pharmaceuticals, Inc. | Substituted hydroxamic acids and uses thereof |
| US8765773B2 (en) | 2010-10-18 | 2014-07-01 | Millennium Pharmaceuticals, Inc. | Substituted hydroxamic acids and uses thereof |
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| CA2721218A1 (en) | 2009-10-22 |
| EP2265590A4 (en) | 2012-04-25 |
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