TW201722930A - 組織蛋白去甲基酶抑制劑 - Google Patents

Info

Publication number

TW201722930A

TW201722930A TW105143541A TW105143541A TW201722930A TW 201722930 A TW201722930 A TW 201722930A TW 105143541 A TW105143541 A TW 105143541A TW 105143541 A TW105143541 A TW 105143541A TW 201722930 A TW201722930 A TW 201722930A

Authority

TW

Taiwan

Prior art keywords

compound

group

aryl

formula

methyl

Prior art date

2015-12-28

Links

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• Global Dossier
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• 102000008157 Histone Demethylases Human genes 0.000 title abstract 2
• 108010074870 Histone Demethylases Proteins 0.000 title abstract 2
• 239000003112 inhibitor Substances 0.000 title description 6
• 150000001875 compounds Chemical class 0.000 claims abstract description 411
• -1 pyridine derivative compounds Chemical class 0.000 claims abstract description 353
• 238000000034 method Methods 0.000 claims abstract description 102
• 239000000203 mixture Substances 0.000 claims abstract description 69
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 63
• 239000008194 pharmaceutical composition Chemical class 0.000 claims abstract description 55
• 201000011510 cancer Diseases 0.000 claims abstract description 46
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 28
• 201000010099 disease Diseases 0.000 claims abstract description 27
• 230000001613 neoplastic effect Effects 0.000 claims abstract description 20
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 112
• 125000000217 alkyl group Chemical group 0.000 claims description 90
• 125000000623 heterocyclic group Chemical group 0.000 claims description 90
• 229910052739 hydrogen Inorganic materials 0.000 claims description 82
• 239000001257 hydrogen Substances 0.000 claims description 82
• 125000001072 heteroaryl group Chemical group 0.000 claims description 77
• 125000003118 aryl group Chemical group 0.000 claims description 62
• 125000003944 tolyl group Chemical group 0.000 claims description 56
• 101000615488 Homo sapiens Methyl-CpG-binding domain protein 2 Proteins 0.000 claims description 55
• 102100021299 Methyl-CpG-binding domain protein 2 Human genes 0.000 claims description 55
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 54
• 125000002837 carbocyclic group Chemical group 0.000 claims description 53
• 150000003839 salts Chemical class 0.000 claims description 42
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 29
• 230000002401 inhibitory effect Effects 0.000 claims description 27
• 229910052717 sulfur Inorganic materials 0.000 claims description 26
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 25
• 239000003814 drug Substances 0.000 claims description 24
• 125000004104 aryloxy group Chemical group 0.000 claims description 23
• 229910052799 carbon Inorganic materials 0.000 claims description 21
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 19
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 19
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 18
• 125000005843 halogen group Chemical group 0.000 claims description 17
• 229910052757 nitrogen Inorganic materials 0.000 claims description 16
• 125000003107 substituted aryl group Chemical group 0.000 claims description 16
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
• 150000002431 hydrogen Chemical class 0.000 claims description 14
• 125000004452 carbocyclyl group Chemical group 0.000 claims description 13
• 125000003545 alkoxy group Chemical group 0.000 claims description 12
• 125000004470 heterocyclooxy group Chemical group 0.000 claims description 12
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 11
• 229910052736 halogen Inorganic materials 0.000 claims description 11
• 150000002367 halogens Chemical class 0.000 claims description 11
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 11
• 229910052760 oxygen Inorganic materials 0.000 claims description 11
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 10
• 125000004212 difluorophenyl group Chemical group 0.000 claims description 9
• 125000005023 xylyl group Chemical group 0.000 claims description 9
• 125000005842 heteroatom Chemical group 0.000 claims description 8
• 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 7
• 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims description 7
• RMSGQZDGSZOJMU-UHFFFAOYSA-N 1-butyl-2-phenylbenzene Chemical group CCCCC1=CC=CC=C1C1=CC=CC=C1 RMSGQZDGSZOJMU-UHFFFAOYSA-N 0.000 claims description 7
• 125000005037 alkyl phenyl group Chemical group 0.000 claims description 7
• 125000000068 chlorophenyl group Chemical group 0.000 claims description 7
• 125000006485 halo alkoxy phenyl group Chemical group 0.000 claims description 7
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
• 125000001207 fluorophenyl group Chemical group 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• DSNYFFJTZPIKFZ-UHFFFAOYSA-N propoxybenzene Chemical group CCCOC1=CC=CC=C1 DSNYFFJTZPIKFZ-UHFFFAOYSA-N 0.000 claims description 6
• GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 6
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
• 125000006005 fluoroethoxy group Chemical group 0.000 claims description 3
• 125000005059 halophenyl group Chemical group 0.000 claims description 3
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 2
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 3
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 2
• 125000003700 epoxy group Chemical group 0.000 claims 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
• 230000005764 inhibitory process Effects 0.000 abstract description 8
• 206010005003 Bladder cancer Diseases 0.000 abstract description 6
• 206010006187 Breast cancer Diseases 0.000 abstract description 6
• 208000026310 Breast neoplasm Diseases 0.000 abstract description 6
• 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 6
• 206010060862 Prostate cancer Diseases 0.000 abstract description 6
• 208000000236 Prostatic Neoplasms Diseases 0.000 abstract description 6
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 abstract description 6
• 201000005202 lung cancer Diseases 0.000 abstract description 6
• 208000020816 lung neoplasm Diseases 0.000 abstract description 6
• 201000005112 urinary bladder cancer Diseases 0.000 abstract description 6
• 201000001441 melanoma Diseases 0.000 abstract description 5
• TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 79
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 61
• 210000001519 tissue Anatomy 0.000 description 61
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 58
• 239000011541 reaction mixture Substances 0.000 description 40
• 108090000623 proteins and genes Proteins 0.000 description 38
• 235000018102 proteins Nutrition 0.000 description 32
• 102000004169 proteins and genes Human genes 0.000 description 32
• YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 32
• 235000019439 ethyl acetate Nutrition 0.000 description 31
• 239000000243 solution Substances 0.000 description 31
• OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 28
• 125000004432 carbon atom Chemical group C* 0.000 description 24
• 210000004027 cell Anatomy 0.000 description 23
• 239000002253 acid Substances 0.000 description 21
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 18
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
• 238000006243 chemical reaction Methods 0.000 description 18
• 239000011734 sodium Substances 0.000 description 18
• 101001088893 Homo sapiens Lysine-specific demethylase 4C Proteins 0.000 description 17
• 125000003342 alkenyl group Chemical group 0.000 description 17
• 239000012044 organic layer Substances 0.000 description 17
• 125000001424 substituent group Chemical group 0.000 description 17
• KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 16
• 101001025971 Homo sapiens Lysine-specific demethylase 6B Proteins 0.000 description 16
• 102100033230 Lysine-specific demethylase 4C Human genes 0.000 description 16
• 102100037461 Lysine-specific demethylase 6B Human genes 0.000 description 15
• 125000003710 aryl alkyl group Chemical group 0.000 description 15
• 239000000126 substance Substances 0.000 description 15
• 239000000651 prodrug Substances 0.000 description 14
• 229940002612 prodrug Drugs 0.000 description 14
• 125000004446 heteroarylalkyl group Chemical group 0.000 description 13
• 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 12
• 102100033246 Lysine-specific demethylase 5A Human genes 0.000 description 12
• 125000000304 alkynyl group Chemical group 0.000 description 12
• 239000002585 base Substances 0.000 description 12
• 230000000694 effects Effects 0.000 description 12
• 102100033247 Lysine-specific demethylase 5B Human genes 0.000 description 11
• 150000001412 amines Chemical class 0.000 description 11
• 238000003818 flash chromatography Methods 0.000 description 11
• 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 11
• 101001088883 Homo sapiens Lysine-specific demethylase 5B Proteins 0.000 description 10
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 10
• 239000012267 brine Substances 0.000 description 10
• RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 10
• 238000001514 detection method Methods 0.000 description 10
• 125000003709 fluoroalkyl group Chemical group 0.000 description 10
• 239000012299 nitrogen atmosphere Substances 0.000 description 10
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
• 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 9
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
• 101001088892 Homo sapiens Lysine-specific demethylase 5A Proteins 0.000 description 9
• 238000004458 analytical method Methods 0.000 description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
• 230000011987 methylation Effects 0.000 description 9
• 238000007069 methylation reaction Methods 0.000 description 9
• 238000002360 preparation method Methods 0.000 description 9
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
• 238000003786 synthesis reaction Methods 0.000 description 9
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
• 238000012360 testing method Methods 0.000 description 9
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
• 101001025967 Homo sapiens Lysine-specific demethylase 6A Proteins 0.000 description 8
• 102100037462 Lysine-specific demethylase 6A Human genes 0.000 description 8
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
• HWXBTNAVRSUOJR-UHFFFAOYSA-N alpha-hydroxyglutaric acid Natural products OC(=O)C(O)CCC(O)=O HWXBTNAVRSUOJR-UHFFFAOYSA-N 0.000 description 8
• 229940009533 alpha-ketoglutaric acid Drugs 0.000 description 8
• 239000003153 chemical reaction reagent Substances 0.000 description 8
• 125000004122 cyclic group Chemical group 0.000 description 8
• 238000010520 demethylation reaction Methods 0.000 description 8
• 125000004433 nitrogen atom Chemical group N* 0.000 description 8
• 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 8
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
• 102000004190 Enzymes Human genes 0.000 description 7
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• 238000003556 assay Methods 0.000 description 7
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• 125000001153 fluoro group Chemical group F* 0.000 description 7
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
• HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 7
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
• CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 7
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