CN101137623A - N-磺酰基吡咯及其作为组蛋白脱乙酰酶抑制剂的用途 - Google Patents
N-磺酰基吡咯及其作为组蛋白脱乙酰酶抑制剂的用途 Download PDFInfo
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- CN101137623A CN101137623A CNA2006800073504A CN200680007350A CN101137623A CN 101137623 A CN101137623 A CN 101137623A CN A2006800073504 A CNA2006800073504 A CN A2006800073504A CN 200680007350 A CN200680007350 A CN 200680007350A CN 101137623 A CN101137623 A CN 101137623A
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- Prior art keywords
- phenyl
- base
- methyl
- biphenyl
- pyrroles
- 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.)
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- 239000003276 histone deacetylase inhibitor Substances 0.000 title claims abstract description 15
- 229940121372 histone deacetylase inhibitor Drugs 0.000 title claims description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 557
- -1 1-4C-alkyl Inorganic materials 0.000 claims description 642
- 239000001257 hydrogen Substances 0.000 claims description 357
- 229910052739 hydrogen Inorganic materials 0.000 claims description 357
- 125000001072 heteroaryl group Chemical group 0.000 claims description 324
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 170
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 168
- 229910052760 oxygen Inorganic materials 0.000 claims description 165
- 239000001301 oxygen Substances 0.000 claims description 165
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 158
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 135
- 238000000034 method Methods 0.000 claims description 126
- 125000003118 aryl group Chemical group 0.000 claims description 108
- 150000002431 hydrogen Chemical group 0.000 claims description 108
- 229910052757 nitrogen Inorganic materials 0.000 claims description 97
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 91
- 150000003839 salts Chemical class 0.000 claims description 87
- 125000005842 heteroatom Chemical group 0.000 claims description 84
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 83
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 82
- 125000002757 morpholinyl group Chemical group 0.000 claims description 81
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 79
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 70
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- GXGJIOMUZAGVEH-UHFFFAOYSA-N Chamazulene Chemical group CCC1=CC=C(C)C2=CC=C(C)C2=C1 GXGJIOMUZAGVEH-UHFFFAOYSA-N 0.000 claims description 60
- 229910052736 halogen Inorganic materials 0.000 claims description 53
- 150000002367 halogens Chemical class 0.000 claims description 53
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 39
- 125000001624 naphthyl group Chemical group 0.000 claims description 39
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims description 38
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 29
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 25
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- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 24
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 23
- BUYUFJZVMVFQLQ-UHFFFAOYSA-N 4-[2-(5,5,8,8-tetramethyl-6,7-dihydroquinoxalin-2-yl)ethynyl]benzoic acid Chemical compound CC1(C=2N=CC(=NC=2C(CC1)(C)C)C#CC1=CC=C(C(=O)O)C=C1)C BUYUFJZVMVFQLQ-UHFFFAOYSA-N 0.000 claims description 22
- 210000004027 cell Anatomy 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 125000004076 pyridyl group Chemical group 0.000 claims description 21
- 125000002619 bicyclic group Chemical group 0.000 claims description 20
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- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 20
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
- 125000001544 thienyl group Chemical group 0.000 claims description 18
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- 238000011282 treatment Methods 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 12
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 238000011275 oncology therapy Methods 0.000 claims description 9
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 claims description 7
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 7
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
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- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
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- 230000001939 inductive effect Effects 0.000 claims description 5
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 5
- 125000001425 triazolyl group Chemical group 0.000 claims description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
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- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 4
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- 125000005605 benzo group Chemical group 0.000 claims description 4
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- 150000002148 esters Chemical class 0.000 claims description 4
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 claims description 4
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- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 claims description 3
- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical compound C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 claims description 3
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 3
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 3
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- OBISXEJSEGNNKL-UHFFFAOYSA-N dinitrogen-n-sulfide Chemical compound [N-]=[N+]=S OBISXEJSEGNNKL-UHFFFAOYSA-N 0.000 claims description 3
- INVTYAOGFAGBOE-UHFFFAOYSA-N entinostat Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)OCC1=CC=CN=C1 INVTYAOGFAGBOE-UHFFFAOYSA-N 0.000 claims description 3
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- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 claims description 3
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- BWDQBBCUWLSASG-MDZDMXLPSA-N (e)-n-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1h-indol-3-yl)ethyl]amino]methyl]phenyl]prop-2-enamide Chemical compound C=1NC2=CC=CC=C2C=1CCN(CCO)CC1=CC=C(\C=C\C(=O)NO)C=C1 BWDQBBCUWLSASG-MDZDMXLPSA-N 0.000 claims description 2
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Classifications
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Abstract
Description
化合物 | IC50 |
1-7 | 所列化合物IC50值的范围为0.75nM-7.5μM |
8,9,10,11,12,14,16-34,35,36-38,40-48,50-52,53,54-59,60,61,62和63 | 所列化合物IC50值的范围为0.32nM-10uM |
64-68,70-85,89-108 | 所列化合物IC50值的范围为1.7nM-32μM |
化合物 | IC50 |
1-12,14,16-68,70-85,89-108 | 所列化合物IC50值的范围为1nM-0.94μM |
化合物 | EC50(μM) |
1-7 | 所列化合物EC50值的范围为0.28-5.3 |
8,9,10,12,16,17,18,20-31,33,34,36-38,42,43,45-47,54,56-59,62和63 | 所列化合物EC50值的范围为0.027-4.4 |
64-68,70-72,74-78,81,90,96-99,102,104,106-108, | 所列化合物EC50值的范围为0.0052-5.8 |
化合物 | IC50(μM) |
1-7 | 所列化合物IC50值的范围为0.078-2.3 |
8,9,10,11,12,14,16-34,36-52,54-59,60,61,62和63 | 所列化合物IC50值的范围为0.006-20 |
64-68,70-85,89-108 | 所列化合物IC50值的范围为0.014-6.7 |
化合物 | cpu@10μM |
1-10,12,16,26和46 | 所列化合物的cpu值范围为15.3-349.3 |
Claims (25)
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EP05102019.6 | 2005-03-15 | ||
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PCT/EP2006/060712 WO2006097474A1 (en) | 2005-03-15 | 2006-03-14 | N-sulphonylpyrroles and their use as histone deacetylase inhibitors |
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EP (1) | EP1861365B1 (zh) |
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PT (1) | PT1861365E (zh) |
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