JP6276378B2 - ヒストンデメチラーゼ阻害剤 - Google Patents
ヒストンデメチラーゼ阻害剤 Download PDFInfo
- Publication number
- JP6276378B2 JP6276378B2 JP2016502219A JP2016502219A JP6276378B2 JP 6276378 B2 JP6276378 B2 JP 6276378B2 JP 2016502219 A JP2016502219 A JP 2016502219A JP 2016502219 A JP2016502219 A JP 2016502219A JP 6276378 B2 JP6276378 B2 JP 6276378B2
- Authority
- JP
- Japan
- Prior art keywords
- imidazol
- pyridine
- methyl
- preparation
- carbonitrile
- 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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- 108010074870 Histone Demethylases Proteins 0.000 title claims description 18
- 102000008157 Histone Demethylases Human genes 0.000 title claims description 18
- 229940122680 Demethylase inhibitor Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 457
- 229910052739 hydrogen Inorganic materials 0.000 claims description 276
- -1 heterocyclylalkyl compound Chemical class 0.000 claims description 148
- 125000000217 alkyl group Chemical group 0.000 claims description 142
- 239000001257 hydrogen Substances 0.000 claims description 140
- 150000002431 hydrogen Chemical class 0.000 claims description 125
- 125000001072 heteroaryl group Chemical group 0.000 claims description 69
- 125000000623 heterocyclic group Chemical group 0.000 claims description 68
- 125000003118 aryl group Chemical group 0.000 claims description 62
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 58
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 57
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 57
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 57
- 125000005884 carbocyclylalkyl group Chemical group 0.000 claims description 47
- 150000003839 salts Chemical class 0.000 claims description 43
- 239000000203 mixture Substances 0.000 claims description 40
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 23
- 125000000304 alkynyl group Chemical group 0.000 claims description 17
- 206010028980 Neoplasm Diseases 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 201000011510 cancer Diseases 0.000 claims description 8
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
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- 125000004663 dialkyl amino group Chemical group 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000002360 preparation method Methods 0.000 description 321
- 238000000034 method Methods 0.000 description 273
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 264
- 238000005481 NMR spectroscopy Methods 0.000 description 121
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 100
- REQFDBXEACLQPU-UHFFFAOYSA-N 2-(1h-imidazol-5-yl)pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC(C=2N=CNC=2)=C1 REQFDBXEACLQPU-UHFFFAOYSA-N 0.000 description 53
- 238000005160 1H NMR spectroscopy Methods 0.000 description 52
- 125000002947 alkylene group Chemical group 0.000 description 47
- 239000000243 solution Substances 0.000 description 47
- ZCJVFVODASCOHD-UHFFFAOYSA-N 2-(5-bromo-1-methylimidazol-4-yl)pyridine-4-carbonitrile Chemical compound CN1C=NC(C=2N=CC=C(C=2)C#N)=C1Br ZCJVFVODASCOHD-UHFFFAOYSA-N 0.000 description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 125000004432 carbon atom Chemical group C* 0.000 description 32
- BMTXJJVXXUHJQZ-UHFFFAOYSA-N methyl 2-[1-(2-methylsulfonyloxyethyl)imidazol-4-yl]pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(C=2N=CN(CCOS(C)(=O)=O)C=2)=C1 BMTXJJVXXUHJQZ-UHFFFAOYSA-N 0.000 description 32
- 150000003254 radicals Chemical class 0.000 description 31
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000000126 substance Substances 0.000 description 23
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
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- 125000001424 substituent group Chemical group 0.000 description 16
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- 102100021299 Methyl-CpG-binding domain protein 2 Human genes 0.000 description 15
- 238000001514 detection method Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
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- 239000000047 product Substances 0.000 description 14
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 13
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- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 12
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- 102100033247 Lysine-specific demethylase 5B Human genes 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 238000007069 methylation reaction Methods 0.000 description 12
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- 238000003756 stirring Methods 0.000 description 12
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 11
- 101001088892 Homo sapiens Lysine-specific demethylase 5A Proteins 0.000 description 11
- 101001088883 Homo sapiens Lysine-specific demethylase 5B Proteins 0.000 description 11
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 11
- 239000004472 Lysine Substances 0.000 description 11
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- 108090000765 processed proteins & peptides Proteins 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
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- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 125000004122 cyclic group Chemical group 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 10
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 10
- NZHDJNMKYDTLEC-UHFFFAOYSA-N 2-(1h-imidazol-5-yl)pyridine-4-carboxamide Chemical compound NC(=O)C1=CC=NC(C=2N=CNC=2)=C1 NZHDJNMKYDTLEC-UHFFFAOYSA-N 0.000 description 9
- 101710105678 Lysine-specific demethylase 2A Proteins 0.000 description 9
- 125000003342 alkenyl group Chemical group 0.000 description 9
- 125000004450 alkenylene group Chemical group 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 230000011987 methylation Effects 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 8
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 8
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- 230000005764 inhibitory process Effects 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 238000003016 alphascreen Methods 0.000 description 7
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 7
- MCARARBFNSEOCZ-UHFFFAOYSA-N methyl 2-(1h-imidazol-5-yl)pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(C=2N=CNC=2)=C1 MCARARBFNSEOCZ-UHFFFAOYSA-N 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 6
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- 208000026310 Breast neoplasm Diseases 0.000 description 6
- 0 C[n]1c(-c2ccc(C3(CC3)C(F)(F)F)cc2)c(-c2nccc(C(*)=O)c2)nc1 Chemical compound C[n]1c(-c2ccc(C3(CC3)C(F)(F)F)cc2)c(-c2nccc(C(*)=O)c2)nc1 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
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- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
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- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 5
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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 4
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- FFDYCLXEOFJLQL-UHFFFAOYSA-N methyl 2-(5-bromo-1-methylimidazol-4-yl)pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(C2=C(N(C)C=N2)Br)=C1 FFDYCLXEOFJLQL-UHFFFAOYSA-N 0.000 description 4
- QLURSABJFDGSCH-UHFFFAOYSA-N methyl 2-[1-[2-[benzyl(methyl)amino]ethyl]imidazol-4-yl]pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(C=2N=CN(CCN(C)CC=3C=CC=CC=3)C=2)=C1 QLURSABJFDGSCH-UHFFFAOYSA-N 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
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- 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 4
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- XGXIJKTWKKJERF-UHFFFAOYSA-N methyl 2-(1-tritylimidazol-4-yl)pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(C=2N=CN(C=2)C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 XGXIJKTWKKJERF-UHFFFAOYSA-N 0.000 description 1
- PBBNEARCAGHGCQ-UHFFFAOYSA-N methyl 2-(hydroxymethyl)pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(CO)=C1 PBBNEARCAGHGCQ-UHFFFAOYSA-N 0.000 description 1
- IEADHBCXFIHSET-UHFFFAOYSA-N methyl 2-[1-[2-(2-fluorophenyl)ethyl]imidazol-4-yl]pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(C=2N=CN(CCC=3C(=CC=CC=3)F)C=2)=C1 IEADHBCXFIHSET-UHFFFAOYSA-N 0.000 description 1
- CZNQEGMRCQUBDL-UHFFFAOYSA-N methyl 2-[5-(4-cyclopropylphenyl)-1-methylimidazol-4-yl]pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(C2=C(N(C)C=N2)C=2C=CC(=CC=2)C2CC2)=C1 CZNQEGMRCQUBDL-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 125000005322 morpholin-1-yl group Chemical group 0.000 description 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- NOUUUQMKVOUUNR-UHFFFAOYSA-N n,n'-diphenylethane-1,2-diamine Chemical compound C=1C=CC=CC=1NCCNC1=CC=CC=C1 NOUUUQMKVOUUNR-UHFFFAOYSA-N 0.000 description 1
- ARVDJBARMJFVNT-UHFFFAOYSA-N n-[(3,4-dichlorophenyl)methyl]cyclopropanamine Chemical compound C1=C(Cl)C(Cl)=CC=C1CNC1CC1 ARVDJBARMJFVNT-UHFFFAOYSA-N 0.000 description 1
- RVXJABFVIDLTSI-UHFFFAOYSA-N n-[(4-chlorophenyl)methyl]cyclopropanamine Chemical compound C1=CC(Cl)=CC=C1CNC1CC1 RVXJABFVIDLTSI-UHFFFAOYSA-N 0.000 description 1
- YKNFXOCMGURJMK-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]cyclopropanamine Chemical compound C1=CC(F)=CC=C1CNC1CC1 YKNFXOCMGURJMK-UHFFFAOYSA-N 0.000 description 1
- CURFQQZYGVCIGJ-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]ethanamine Chemical compound CCNCC1=CC=C(F)C=C1 CURFQQZYGVCIGJ-UHFFFAOYSA-N 0.000 description 1
- YLAZXWUGKKWCID-UHFFFAOYSA-N n-cyano-2-[1-[2-[cyclopropylmethyl(methyl)amino]ethyl]imidazol-4-yl]pyridine-4-carboxamide Chemical compound C1CC1CN(C)CCN(C=1)C=NC=1C1=CC(C(=O)NC#N)=CC=N1 YLAZXWUGKKWCID-UHFFFAOYSA-N 0.000 description 1
- WCTNVGNEUDTSOZ-UHFFFAOYSA-N n-methyl-1-(3-methylphenyl)methanamine Chemical compound CNCC1=CC=CC(C)=C1 WCTNVGNEUDTSOZ-UHFFFAOYSA-N 0.000 description 1
- YDFFIGRIWDSNOZ-UHFFFAOYSA-N n-methyl-1-(4-methylphenyl)methanamine Chemical compound CNCC1=CC=C(C)C=C1 YDFFIGRIWDSNOZ-UHFFFAOYSA-N 0.000 description 1
- YMSMEZAYZIYFGA-UHFFFAOYSA-N n-methyl-1-[4-(trifluoromethyl)phenyl]methanamine Chemical compound CNCC1=CC=C(C(F)(F)F)C=C1 YMSMEZAYZIYFGA-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000017095 negative regulation of cell growth Effects 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Chemical group C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 230000006548 oncogenic transformation Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 238000005895 oxidative decarboxylation reaction Methods 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 201000008129 pancreatic ductal adenocarcinoma Diseases 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 150000004841 phenylimidazoles Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000004928 piperidonyl group Chemical group 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 108700022487 rRNA Genes Proteins 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 108020004418 ribosomal RNA Proteins 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000032678 sex differentiation Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- QJTKPXFJOXKUEY-UHFFFAOYSA-N tert-butyl 3-bromopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(Br)C1 QJTKPXFJOXKUEY-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005985 thienyl[1,3]dithianyl group Chemical group 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 230000037426 transcriptional repression Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Description
XはCHであり、YはCHであり、およびZはCHであり、または、
XはCOHであり、YはCHであり、およびZはCHであり、または、
XはCHであり、YはCHであり、およびZはNであり、または、
XはNであり、YはCHであり、およびZはCHであり、または、
XはCHであり、YはNであり、およびZはCHであり、
R1は、水素、ハロゲン、−OH、−OR5、−N(R5)2、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R2は、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R3は、水素、ハロゲン、−OH、−NH2、−NH(C1−C3アルキル)、またはC1−C3アルキルであり、
R4は、−CO2H、−CO2R6、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
R5はそれぞれ独立して、水素、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、および、
R6はアルキルである。
R1は、水素、ハロゲン、−OH、−OR5、−N(R5)2、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R2は、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R3は、水素、ハロゲン、−OH、−NH2、−NH(C1−C3アルキル)、またはC1−C3アルキルであり、
R4は、−CO2H、−CO2R6、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
R5はそれぞれ独立して、水素、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、および、
R6はアルキルである。
XはCHであり、YはCHであり、およびZはCHであり、または、
XはCOHであり、YはCHであり、およびZはCHであり、または、
XはCHであり、YはCHであり、およびZはNであり、または、
XはNであり、YはCHであり、およびZはCHであり、または、
XはCHであり、YはNであり、およびZはCHであり、
R1は、水素、ハロゲン、−OH、−OR5、−N(R5)2、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R2は、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R3は、水素、ハロゲン、−OH、−NH2、−NH(C1−C3アルキル)、またはC1−C3アルキルであり、
R4は、−CO2H、−CO2R6、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
R5はそれぞれ独立して、水素、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、および、
R6はアルキルである。
XはCHであり、YはCHであり、およびZはCHであり、または、
XはCOHであり、YはCHであり、およびZはCHであり、または、
XはCHであり、YはCHであり、およびZはNであり、または、
XはNであり、YはCHであり、およびZはCHであり、または、
XはCHであり、YはNであり、およびZはCHであり、
R1は、水素、ハロゲン、−OH、−OR5、−N(R5)2、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R2は、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R3は、水素、ハロゲン、−OH、−NH2、−NH(C1−C3アルキル)、またはC1−C3アルキルであり、
R4は、−CO2H、−CO2R6、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
R5はそれぞれ独立して、水素、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、および、
R6はアルキルである。
本明細書で言及されるすべての出版物、特許、および特許出願は、あたかも個々の出版物、特許、または特許出願が参照により組み込まれるべく特別かつ個別に示されているかのような程度には、参照により本明細書に組み込まれる。
明細書と添付の請求項で使用されるように、反対のことが明記されていない限り、以下の用語は下に示す意味を有する。
ヒストンデメチラーゼ酵素を阻害する置換されたイミダゾールピリジン誘導体化合物が本明細書に記載されている。これらの化合物とこれらの化合物を含む組成物は、癌や腫瘍性疾患の処置に役立つ。したがって、本明細書に記載される化合物は、前立腺癌、乳癌、膀胱癌、肺癌、および/または黒色腫などを治療するのに役立つこともある。
XはCHであり、YはCHであり、およびZはCHであり、または、
XはCOHであり、YはCHであり、およびZはCHであり、または、
XはCHであり、YはCHであり、およびZはNであり、または、
XはNであり、YはCHであり、およびZはCHであり、または、
XはCHであり、YはNであり、およびZはCHであり、
R1は、水素、ハロゲン、−OH、−OR5、−N(R5)2、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R2は、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R3は、水素、ハロゲン、−OH、−NH2、−NH(C1−C3アルキル)、またはC1−C3アルキルであり、
R4は、−CO2H、−CO2R6、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
R5はそれぞれ独立して、水素、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、および、
R6はアルキルである。
R1は、水素、ハロゲン、−OH、−OR5、−N(R5)2、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R2は、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R3は、水素、ハロゲン、−OH、−NH2、−NH(C1−C3アルキル)、またはC1−C3アルキルであり、
R4は、−CO2H、−CO2R6、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
R5はそれぞれ独立して、水素、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、および、
R6はアルキルである。
R1は、水素、ハロゲン、−OH、−OR5、−N(R5)2、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R2は、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R3は、水素、ハロゲン、−OH、−NH2、−NH(C1−C3アルキル)、またはC1−C3アルキルであり、
R4は、メチルまたは−Rb−OC(O)−Raで置換されたテトラゾリルであり、ここで、RbはC1−C3アルキレンであり、Raはアルキルであり、および、
R5はそれぞれ独立して、水素、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルである。
R1はカルボシクリル、ヘテロシクリル、アリール、またはヘテロアリールであり、
R2は、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、ヘテロアリールアルキル、−CON(R5)2、−CO2R5、SO2N(R5)2、またはSO2R5であり、
R3は、水素、ハロゲン、−OH、−NH2、−NH(C1−C3アルキル)、またはC1−C3アルキルであり、
R4は、−CO2H、−CO2R6、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
R5はそれぞれ独立して、水素、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、および、
R6はアルキルである。
本明細書で記載された反応で使用される化合物は、市販の化学製品および/または化学文献に記載される化合物から始まって、当業者に知られている有機合成技術によって作られる。「市販の化学製品」とは、Acros Organics(ペンシルベニア州ピッツバーグ)、AldrichChemical(ウィスコンシン州ミルウォーキー。Sigma ChemicalおよびFlukaを含む)、Apin Chemicals Ltd.(英国・ミルトンパーク)、Avocado Research(英国・ランカシャー)、BDH Inc.(カナダ・トロント)、Bionet(英国・コーンウォール)、Chemservice Inc.(ペンシルベニア州ウェストチェスター)、Crescent Chemicals Co.(ニューヨーク州ホーポージ)、Eastman Organic Chemicals、Eastman Kodak Company(ニューヨーク州ロチェスター)、Fisher Scientific Co(ペンシルベニア州ピッツバーグ)、Fisons Chemicals(英国・レスターシャー)、Frontier Scientific(ユタ州ローガン)、ICN Biomedicals,Inc.(カリフォルニア州コスタメサ)、Key Organics(英国・コーンウォール)、Lancaster Synthesis(ニューハンプシャー州ウィンダム)、Maybridge Chemical Co.Ltd.(英国・コーンウォール)、Parish Chemical Co.(ユタ州オレム)、Pfaltz& Bauer,Inc.(コネチカット州ウォーターベリー)、Polyorganix(テキサス州ヒューストン)、Pierce Chemical Co.(イリノイ州ロックフォード)、Riedel de Haen AG(ドイツ・ハノーファー)、Spectrum Quality Product,Inc.(ニュージャージー州ニューブランズウィック)、TCI America(オレゴン州ポートランド)、Trans World Chemicals, Inc.(メリーランド州ロックヴィル)、およびWako Chemicals USA,Inc.(ヴァージニア州リッチモンド)を含む、標準的な商業的供給源から得られる。
特定の実施形態では、本明細書に記載されているような置換されたイミダゾールピリジン誘導体化合物は、純粋な化学薬品として投与される。他の実施形態では、本明細書に記載される置換されたイミダゾールピリジン誘導体化合物は、選択された投与経路と、例えば、Remington:The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co. , Easton,PA (2005))で記載されるような標準的な薬務に基づいて選択された薬学的に適切なまたは許容可能な担体(本明細書では薬学的に適切な(または許容可能な)賦形剤、生理学的に適切な(または許容可能な)賦形剤、あるいは生理学的に適切な(または許容可能な)担体とも呼ばれる)と組み合わされ、その文献の開示は全体として参照によって本明細書に組み込まれる。
染色質は染色体を構成するDNAとタンパク質の複合体である。ヒストンは染色質の主要なタンパク質成分であり、DNAが巻きつくスプールとして作用する。染色質構造の変化は、ヒストンタンパク質の共有結合修飾、および非ヒストン結合タンパク質による影響を受ける。様々な部位でヒストンを共有結合的に修正することができる複数のクラスの酵素が知られている。
タンパク質のJMJD2ファミリーは、トリ−メチル化されたおよびジ−メチル化されたH3−K9を非メチル化することが知られていたヒストンデメチラーゼのファミリーであり、最初に同定されたヒストン・トリ−メチル・デメチラーゼであった。とりわけ、JMJD2ファミリーメンバーの異所性発現は、トリメチル化およびジメチル化したH3−K9の値を劇的に減少させ、その一方で、異質染色質タンパク質1(HP1)を局在化して生体内の異質染色質の全般的なレベルを低下させるモノメチル化H3−K9のレベルを上昇させることが分かった。十文字タンパク質のJMJD2サブファミリーのメンバーは、JMJD2CとそのホモログJMJD2A、JMJD2B、JMJD2D、およびJMJD2Eを含んでいる。十文字タンパク質のJMJD2サブファミリーで見られる共通の構造的特徴は、JmjN、JmjC、PHD、およびTdrの配列を含む。
本明細書で使用されるように、「JARIDタンパク質」は、JARID1サブファミリー(例えば、JARID1A、JARID1B、JARID1C、およびJARID1Dタンパク質)とJARID2サブファミリー中にタンパク質とそのアナログを含んでいる。JARIDタンパク質のさらなる記載とリストは、Klose et al. (2006) Nature Reviews/Genetics 7:715−727で見られる。JARID1ファミリーは、いくつかの保存ドメイン:JmjN、ARID、JmjC、PHD、およびC5HC2ジンクフィンガー(zing finger)を含んでいる。
F−boxとロイシンリッチリピートタンパク質10(FBXL10)とF−boxとロイシンリッチリピートタンパク質11(FBXL11)は、ヒドロキシル化ベースの機構によってヒストンH3を非メチル化する多機能なF−boxファミリータンパク質である。リジン(K)−特異的な脱メチル化酵素2B(KDM2B)または十文字Cドメイン含有ヒストン脱メチル化酵素1B(JHDM1B)とも知られているFBXL10は、ヒストンH3のトリメチル化したK4とジメチル化したK36を優先的に脱メチル化するが、モノ−およびトリ−メチル化されたH3−K36に対する活性は弱く、または活性を有していない。FBXL10は、3つのドメイン、触媒JMJCドメイン、Fボックスドメイン、およびCXXC DNA結合ドメインを含んでいる。N末端JMJCドメインは、ヒドロキシル化に基づいた機構によって脱メチル反応を触媒するために鉄とα−ケトグルタル酸塩を配位結合させる。CXXC DNA結合ドメインにより、FBXL10は、リボソームRNAの転写領域に優先的に結合して、リボソームRNA遺伝子転写の抑制をもたらし、最終的には細胞の成長と増殖の阻害をもたらすことが可能になる。FBXL10は、急性骨髄白血病、膀胱癌、および膵管腺癌で過剰発現することが分かっている。最近では、FBXL10はポリコーム標的遺伝子の発現を制御し、これらのタンパク質は幹細胞分化に不可欠なエピジェネティックな制御因子であることが実証されている。この制御は、これらのポリコーム標的遺伝子の制御を介した腫瘍形成におけるFBXL10の関与を暗に示している。
本明細書では、一般にまたは1つ以上の特定の標的遺伝子に関して、細胞または被検体の脱メチル化を調整する方法が開示されている。脱メチル化は、限定されないが、分化;増殖;アポプトーシス;腫瘍形成、白血病誘発、または他の発がん性形質転換の事象;脱毛;または、性分化、を含む様々な細胞の機能を制御するために調整することができる。例えば、特定の実施形態では、本発明は、JmjCドメイン(例えば、JHDMタンパク質などのヒストンデメチラーゼ)を含むデメチラーゼ活性を調整することによって、必要としている被検体のヒストンのメチル化および/または脱メチル化によって制御される疾患を処置する方法を提供する。
特段の定めのない限り、商用源から入手した試薬と溶媒を用いた。無水の溶媒とオーブンで乾燥させたガラス器具は湿気および/または酸素に感度の高い合成形質転換に使用した。収率は最適化しなかった。反応時間は近似であり、最適化しなかった。別段の定めのない限り、カラムクロマトグラフィーと薄層クロマトグラフィー(TLC)をシリカゲル上で行なった。スペクトルはppm(δ)で与え、結合定数Jはヘルツで報告した。陽子スペクトルについては、溶媒のピークを参照ピークとして用いた。
A:2−(1−メチル−1H−イミダゾール−4−イル)ピリジン−4−カルボニトリル
実測値、204.
A:2−(5−ブロモ−1−メチル−1H−イミダゾール−4−イル)ピリジン−4−カルボニトリル
A. 2−[5−(3−ヒドロキシ−4−メチルフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[1−メチル−5−(4−メチルフェニル)−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[5−(4−エチルフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[5−(4−シクロプロピルフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A. 2−[5−(4−tert−ブチルフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A. 3−[4−(4−シアノピリジン−2−イル)−1−メチル−1H−イミダゾール−5−イル]−Nメチルベンズアミド
A. 2−{5−[3−(ヒドロキシメチル)フェニル]−1−メチル−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
A. 2−[5−(4−メトキシフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A. 2−{1−メチル−5−[4−(トリフルオロメトキシ)フェニル]−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
A.2−[5−(4−エトキシフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−{1−メチル−5−[4−(1H−ピラゾル−1−イル)フェニル]−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
A. 2−{5−[4−(シクロプロピルメトキシ)フェニル]−1−メチル−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
A.2−(5−{4−[1−(ヒドロキシメチル)シクロプロピル]フェニル}−1−メチル−1H−イミダゾール−4−イル)ピリジン−4−カルボニトリル
A.2−{1−メチル−5−[4−(ピロリジン−1−イル)フェニル]−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
A.2−[5−(4−クロロフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[5−(3−クロロフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[5−(4−エチニルフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[5−(1H−インドール−6−イル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[5−(4−フルオロフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[5−(3−フルオロフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−(5−{4−[1−(メトキシメチル)シクロプロピル]フェニル}−1−メチル−1H−イミダゾール−4−イル)ピリジン−4−カルボニトリル
A.2−[5−(4−クロロ−2−メチルフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−{5−[4−クロロ−2−(トリフルオロメチル)フェニル]−1−メチル−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
A.2−[5−(3,4−ジクロロフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A. 2−[5−(4−クロロ−3−フルオロフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル>
A.2−[5−(4−クロロ−3−メトキシフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−{5−[4−クロロ−3−(トリフルオロメチル)フェニル]−1−メチル−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
A.2−[5−(4−クロロ−2−エトキシフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[5−(2,4−ジクロロフェニル)−1−メチル−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
δ1.19(2H,m)、1.38(2H,m)、3.51(3H,s)、7.44−7.51(5H,m)、7.85(1H,s)、8.25(1H,s)、8.27(1H,s).[M+H] C20H16F3N3O2、388について算出;実測値、388。
2−(1H−イミダゾール−4−イル)ピリジン−4−カルボニトリル
工程1:2−[1−(トリフェニルメチル)−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
工程2:2−(1H−イミダゾール−4−イル)ピリジン−4−カルボニトリル
A.2−[1−(3−メトキシプロピル)−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[1−(2−メトキシエチル)−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−(5−ブロモ−1H−イミダゾール−4−イル)ピリジン−4−カルボニトリル
A.2−{1−[2−(ジメチルアミノ)エチル]−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
A.2−{1−[3−(ジメチルアミノ)プロピル]−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
A.2−{1−[2−(ピロリジン−1−イル)エチル]−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
メチル2−(1H−イミダゾール−4−イル)ピリジン−4−カルボン酸塩
A.メチル2−[1−(トリフェニルメチル)−1H−イミダゾール−4−イル]ピリジン−4−カルボン酸塩
A.2−{1−[2−(モルホリン−4−イル)エチル]−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
A.2−{1−[2−(1H−ピラゾル−1−イル)エチル]−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
A.2−[1−(ピリジン−2−イルメチル)−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−{1−[2−(2−クロロエトキシ)エチル]−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
A.2−[1−(1−メチルピぺリジン−4−イル)−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−{1−[(1−メチルピぺリジン−4−イル)メチル]−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
A.2−[1−(テトラヒドロフラン−2−イルメチル)−1H−イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.tert−ブチル3−[4−(4−シアノピリジン−2−イル)−1H−イミダゾール−1−イル]ピロリジン−1−カルボン酸塩
A.tert−ブチル2−{[4−(4−シアノピリジン−2−イル)−1H−イミダゾール−1−イル]メチル}ピロリジン−1−カルボン酸塩
A.2−{1−[(4−メチルモルホリン−2−イル)メチル]−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
A.2−{1−[(1−メチルピぺリジン−3−イル)メチル]−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
メチル2−(1−{2−[(メチルスルホニル)オキシ]エチル}−1H−イミダゾール−4−イル)ピリジン−4−カルボン酸塩>
A.5−ブロモ−1H−イミダゾール
A.2−{1−[2−(2−オキソピロリジン−1−イル)エチル]−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
A.2−{1−[2−(ピロリジン−1−イル)プロピル]−1H−イミダゾール−4−イル}ピリジン−4−カルボニトリル
1H NMR(400MHz、DMSO−d6):δ3.73(3H,s)、7.71(1H,dd,J=1.5Hzと5.1Hz)、7.74(2H,s)、8.46(1H,s)、8.51(1H,d,J=5.0Hz).[M+H] C10H9N7、228について算出;実測値、228.
A.N−ベンジル−5−[5−(4−シアノピリジン−2−イル)−3−メチルイミダゾール−4−イル]−2−フルオロベンズアミド
A.メチル2−ホルミルピリジン−4−カルボン酸塩
A.2−[1−[2−(2−クロロフェニル)エチル]イミダゾール−4−イル]ピリジン−4−カルボキサミド
A.2−[5−ブロモ−1−[(2−クロロフェニル)メチル]イミダゾール−4−イル]ピリジン−4−カルボニトリル
実測値、389.
A.2−[1−[2−(2−エトキシフェニル)エチル]イミダゾール−4−イル]ピリジン−4−カルボキサミド
A.2−[1−[(2−クロロフェニル)メチル]イミダゾール−4−イル]ピリジン−4−カルボキサミド
A.2−[1−[(3−クロロフェニル)メチル]イミダゾール−4−イル]ピリジン−4−カルボキサミド
A.2−[1−[(4−クロロフェニル)メチル]イミダゾール−4−イル]ピリジン−4−カルボキサミド
A.2−[1−(2,2,2−トリフルオロエチル)イミダゾール−4−イル]ピリジン−4−カルボキサミド
A.2−[5−(4−フルオロ−2−フェニルメトキシフェニル)−1−メチルイミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[5−(2−ブトキシ−4−フルオロフェニル)−1−メチルイミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[5−[2−(シクロプロピルメトキシ)−4−フルオロフェニル]−1−メチルイミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[1−[(2,6−ジクロロフェニル)メチル]イミダゾール−4−イル]ピリジン−4−カルボニトリル
[M+H] C16H11Cl2N7、373について算出;実測値、373.
A.2−[1−[[2−(2,2,2−トリフルオロエトキシ)フェニル]メチル]イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[1−[[2−(2−メチルプロポキシ)フェニル]メチル]イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[1−[[2−クロロ−3−(トリフルオロメチル)フェニル]メチル]イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[1−(ナフタレン−1−イルメチル)イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[1−[[2−(トリフルオロメトキシ)フェニル]メチル]イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[1−[1−(2−クロロフェニル)エチル]イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[1−[(2,3−ジクロロフェニル)メチル]イミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[5−[4−フルオロ−3−(2,2,2−トリフルオロエトキシ)フェニル]−1−メチルイミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[5−(4−フルオロ−3−フェニルメトキシフェニル)−1−メチルイミダゾール−4−イル]ピリジン−4−カルボニトリル
実測値、385.
A.2−[5−(4−クロロ−3−フェニルメトキシフェニル)−1−メチルイミダゾール−4−イル]ピリジン−4−カルボニトリル
A.2−[5−(4−フルオロ−3−ヒドロキシフェニル)−1−メチルイミダゾール−4−イル]ピリジン−4−カルボニトリル
A.5−[5−(4−シアノピリジン−2−イル)−3−メチルイミダゾール−4−イル]−2−フルオロ−N−フェニルベンズアミド
A.2−[5−(4−フルオロナフタレン−1−イル)−1−メチルイミダゾール−4−イル]ピリジン−4−カルボニトリル
例1:インビトロの酵素阻害アッセイ
このアッセイは、Jarid1A、Jarid1B、JMJD2C、およびJMJD2Aのデメチラーゼ活性を阻害する試験化合物の能力を決定するものである。バキュロウィルス発現(Baculovirus expressed)Jarid1A(GenBank Accession #NM_001042603, AA1−1090)を、BPS Bioscience (Cat#50110)から購入した。バキュロウィルス発現Jarid1B(GenBank Accession #NM_006618, AA 2−751)をBPS Bioscience (Cat # 50121)から購入し、MolecularThroughputによってカスタムメイドした。バキュロウィルス発現JMJD2C(GenBank Accession #BC143571, AA 2−372)を、BPS Bioscience (Cat#50105)から購入した。バキュロウィルス発現JMJD2A(GenBank Accession #NM_014663, AA 1−350)を、BPS Bioscience (Cat#50123)から購入した。バキュロウィルス発現FBXL10(GenBank Accession #NM_032590, AA 1−650)を、BPS Bioscience (Cat#50120)から購入した。
Jarid1A活性の酵素アッセイは、時間分解蛍光共鳴エネルギー転移(TR−FRET)の検出に基づく。Jarid1Aの活性を阻害する試験化合物の能力は、以下の反応条件下で384ウェルのプレートフォーマットで決定された:1nM Jarid1A、300nM H3K4me3ビオチン標識されたペプチド(Anaspec cat# 64357)、50mM HEPES、pH7.3、0.005%のBrij35、0.5mMのTCEP、0.2mg/mlのBSA、50μMのL−アスコルビン酸ナトリウム、および2μMの硫酸アンモニウム鉄(II)のアッセイバッファー中の2μMのα−ケトグルタル酸。反応生成物は、25nMと1nMのそれぞれの最終濃度で、LANCE検出バッファー(PerkinElmer)中の5mMのEDTAの存在下における、検出試薬Phycolink ストレプトアビジン−アロフィコシアニン(allophycocyanin)(Prozyme)とEuropiumの抗モノメチル化またはジメチル化ヒストンH3リジン4(H3K4me1−2)抗体(PerkinElmer)を追加した後に、TR−FRETによって定量的に決定された。
Jarid1Bの活性を阻害する試験化合物の能力を、以下の反応条件下において384のウェルプレートフォーマットで決定した:0.8nMのJarid1B、300nMのH3K4me3ビオチン標識したペプチド(Anaspec cat #64357)、50mM HEPESのアッセイバッファー中の2μMのα−ケトグルタル酸、pH7.3、0.005%のBrij35、0.5mMのTCEP、0.2mg/mlのBSA、50μMのL−アスコルビン酸ナトリウム、および2μMの硫酸アンモニウム鉄(II)。反応生成物は、25nMと1nMのそれぞれの最終濃度で、LANCE検出バッファー(PerkinElmer)中の5mMのEDTAの存在下における、検出試薬Phycolink ストレプトアビジン−アロフィコシアニン(allophycocyanin)(Prozyme)とEuropiumの抗モノメチル化またはジメチル化ヒストンH3リジン4(H3K4me1−2)抗体(PerkinElmer)を追加した後に、TR−FRETによって定量的に決定された。
JMJD2Cの活性を阻害する試験化合物の能力を以下の反応条件下において384ウェルプレートのフォーマットで決定した:0.3nMのJMJD2C、300nMのH3K9me3ビオチン標識したペプチド(Anaspec cat #64360)、50mMのHEPESのアッセイバッファー中の2μMのα−ケトグルタル酸、pH7.3、0.005%のBrij35、0.5mMのTCEP、0.2mg/mlのBSA、50μMのL−アスコルビン酸ナトリウム、および2μMの硫酸アンモニウム鉄(II)。反応生成物は、50nMと1nMのそれぞれの最終濃度で、LANCE検出バッファー(PerkinElmer)中の5mMのEDTAの存在下における、検出試薬Phycolink ストレプトアビジン−アロフィコシアニン(allophycocyanin)(Prozyme)とEuropiumの抗ジメチル化ヒストンH3リジン9(H3K9me2)抗体(PerkinElmer)を追加した後に、TR−FRETによって定量的に決定された。
JMJD2Aの活性を阻害する試験化合物の能力を以下の反応条件において384のウェルプレートのフォーマットで決定した:2nMのJMJD2A、300nMのH3K9me3ビオチン標識したペプチド(Anaspec cat #64360)、50mMのHEPESのアッセイバッファー中の2μMのα−ケトグルタル酸、pH7.3、0.005%のBrij35、0.5mMのTCEP、0.2mg/mlのBSA、50μMのL−アスコルビン酸ナトリウム、および2のμM硫酸アンモニウム鉄(II)。LANCE検出緩衝液(PerkinElmer)中の5mMのEDTAの存在下で、検出試薬Phycolinkストレプトアビジン−アロフィコシアニン(Prozyme)およびユウロピウム−抗−ジ−メチル化ヒストンH3リジン9(H3K9me2)抗体(PerkinElmer)を、それぞれ、50nMおよび1nMの終末濃度で加えた後に、反応生成物をTR−FRETによって定量した。
FBXL10の活性を阻害する試験化合物の能力を、以下の反応条件下において384のウェルプレートフォーマットで決定した:0.3nMのFBXL10、30nMのH3K36me2ビオチン標識したペプチド(Anaspec cat #64442)、50mMのHEPESのアッセイバッファー中の0.2μMのα−ケトグルタル酸、pH7.3、0.005%のBrij35、0.5mMのTCEP、0.2mg/mlのBSA、50μMのL−アスコルビン酸ナトリウム、および5μMの硫酸アンモニウム鉄(II)。50mMのHEPES、pH7.3、10mMのNaCl、0.005%のBrij35、5mMのEDTA、2mg/mlのBSA中に検出試薬抗H3K36me1抗体、AlphaScreen(登録商標)ストレプトアビジンでコーティングしたドナー・ビーズ、およびAlphaScreen(登録商標)タンパク質A受容体ビーズを加えて最終的な10μg/mlビーズにした後に、AlphaScreen検出によって反応生成物を定量的に決定した。
KDM5Aと5Bの細胞阻害の程度を測定するアッセイが開発された。この定量的なイムノ−ブロッティングアッセイは、ZR−75−1乳癌細胞株の抽出物からのヒストンデメチラーゼKDM5AとKDM5Bの直接的な酵素活性の特異的な基質と生成物である、アミノ酸リジン番号4におけるトリメチル化されたヒストンH3の量を測定する。
このアッセイは、試験化合物で処置された細胞から抽出したトリ−メチルH3K4を定量化するための蛍光定量イムノアッセイであり、KDM5A/Bの細胞の阻害の基準として使用される。
50,000のZR−75−1(PTENヌル、ER+)乳癌細胞(ATCC)を、96ウェルの組織培養処理されたプレートの各ウェルに播種し、その後、1250μM乃至10nMに及ぶ試験化合物の終末濃度範囲で試験化合物の11ポイント希釈物に晒した。細胞を72時間、試験化合物の存在下で残した。洗浄薬ベースの溶解と超音波処理の方法を用いて、細胞のヒストン材料をすべて含む抽出物を調製した。こうした溶解産物をその後、比色定量のビシコニン酸アッセイ(MicroBCA Pierce/Thermo Scientific)を用いて、全タンパク質含有量について標準化した。
その後、標準化した細胞抽出物をNuPage試薬(Life Technologies)を用いて典型的なイムノ−ブロッティング処置にかけた。その後、電気泳動的に分離したヒストンを移し、ポリビニリデンジフルオリド薄膜(Immobilon−FL Millipore)を用いて固定化した。トリメチル化した状態に特異的な抗体(Cell Signaling Technologies)を用いてヒストンH3のトリメチル化したリジン4の量を検出し、デンシトメトリー・ソフトウェア・パッケージ(Odyssey CLx, Image Studio, Li−Cor)を用いて赤外線イメージャー上で定量化した。このバックグラウンドを除去したデンシトメトリー値をそのサンプルのGAPDHの定量として報告し、その後、DMSO処理されたサンプルのパーセントとして計算した。
その後、ソフトウェア・パッケージXL−fit(IDBS)を用いて、以下の方程式に従って所定の試験化合物の希釈シリーズに関して相対的なIC50値を計算した:
0.72mgの17−βエストラジオールを含む持続放出型ペレット剤をn/nマウスへと皮下に移植する。5%CO2、37°Cの10%FBSを含むRPMIの中でMCF−7細胞を成長させる。細胞を、1X107細胞/mLで50%のRPMI(無血清)および50%のマトリゲルにおいて、遠心沈殿させ、再懸濁する。ペレット剤移植後2−3日に右側腹部にMCF−7細胞を皮下注射し(100μL/動物)、腫瘍の容積(長さ×幅2/2)を隔週モニターする。腫瘍が200mm3の平均容積に達すると、動物を無作為化して処置を開始する。動物を4週間にわたって毎日ビヒクルまたは化合物で処置する。腫瘍容積と体重は研究のあいだずっと隔週でモニターする。治療期間の終了時、薬物動態学的分析と薬力学的分析のために、血漿と腫瘍のサンプルをそれぞれ採取する。
<例1:経口錠剤>
錠剤は、式(I)または(III)の48重量%の化合物、あるいはその薬学的に許容可能な塩、45重量%の微結晶性セルロース、5重量%の低置換ヒドロキシプロピルセルロース、および2重量%のステアリン酸マグネシウムの重量を混合することにより調製される。錠剤は直接の圧縮によって調製される。圧縮錠剤の全重量は250−500mgで維持される。
Claims (29)
- 式(II)の構造を有する化合物またはその薬学的に許容可能な塩であって、
R1は、水素、ハロゲン、−OH、−OR5、−N(R5)2、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R2は、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、
R3は、水素、ハロゲン、−OH、−NH2、−NH(C1−C3アルキル)、またはC1−C3アルキルであり、
R4は、−CO2H、−CO2R6、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
R5はそれぞれ独立して、水素、アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、またはヘテロアリールアルキルであり、および、
R6はアルキルである、化合物またはその薬学的に許容可能な塩。 - R3は水素である、請求項1に記載の化合物。
- R4は−CO2Hである、請求項1または2に記載の化合物。
- R4は−CO2R6である、請求項1または2に記載の化合物。
- R4は−C(O)N(H)CNである、請求項1または2に記載の化合物。
- R4はテトラゾリルである、請求項1または2に記載の化合物。
- R2はアルキルである、請求項1乃至6のいずれか1つに記載の化合物。
- R2はメチルである、請求項7に記載の化合物。
- R2はアルコキシで置換されたアルキルである、請求項7に記載の化合物。
- R2はジアルキルアミノで置換されたアルキルである、請求項7に記載の化合物。
- R2は(アリール)(アルキル)アミノで置換されたアルキルである、請求項7に記載の化合物。
- R2は(カルボシクリル)(アルキル)アミノで置換されたアルキルである、請求項7に記載の化合物。
- R2は(ヘテロアリール)(アルキル)アミノで置換されたアルキルである、請求項7に記載の化合物。
- R2は(ヘテロシクリル)(アルキル)アミノで置換されたアルキルである、請求項7に記載の化合物。
- R2は(アラルキル)(アルキル)アミノで置換されたアルキルである、請求項7に記載の化合物。
- R2は(カルボシクリルアルキル)(アルキル)アミノで置換されたアルキルである、請求項7に記載の化合物。
- R2は(ヘテロアリールアルキル)(アルキル)アミノで置換されたアルキルである、請求項7に記載の化合物。
- R2は(ヘテロシクリルアルキル)(アルキル)アミノで置換されたアルキルである、請求項7に記載の化合物。
- R2はヘテロシクリルである、請求項1乃至6のいずれか1つに記載の化合物。
- R2はヘテロシクリルアルキルである、請求項1乃至6のいずれか1つに記載の化合物。
- R2はヘテロアリールである、請求項1乃至6のいずれか1つに記載の化合物。
- R2はヘテロアリールアルキルである、請求項1乃至6のいずれか1つに記載の化合物。
- R1は水素である、請求項1乃至22のいずれか1つに記載の化合物。
- R1はアリールである、請求項1乃至22のいずれか1つに記載の化合物。
- R1がハロゲン、−OH、−OR5、−N(R5)2、−CON(R5)2、アルキル、アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、カルボシクリルアルキル、ヘテロシクリルアルキル、アラルキル、およびヘテロアリールアルキルから選ばれた1つ以上の基で随意に置換されたフェニルである、請求項24に記載の化合物。
- R1がハロゲン、−OH、−OR5、アルキル、カルボシクリル、ヘテロシクリル、およびヘテロアリールから選ばれた1つ以上の基で随意に置換されたフェニルである、請求項24に記載の化合物。
- 請求項1の化合物またはその薬学的に許容可能な塩、および少なくとも1つの薬学的に許容可能な賦形剤を含む医薬組成物。
- 被験体のヒストンデメチラーゼを阻害するための製剤の製造における、請求項1の化合物またはその薬学的に許容可能な塩の使用。
- 被験体の癌を処置するための製剤の製造における、請求項1の化合物またはその薬学的に許容可能な塩を含む組成物の使用。
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