JP5970554B2 - Hec1活性に対する改良された調節因子およびその方法 - Google Patents
Hec1活性に対する改良された調節因子およびその方法 Download PDFInfo
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- JP5970554B2 JP5970554B2 JP2014544894A JP2014544894A JP5970554B2 JP 5970554 B2 JP5970554 B2 JP 5970554B2 JP 2014544894 A JP2014544894 A JP 2014544894A JP 2014544894 A JP2014544894 A JP 2014544894A JP 5970554 B2 JP5970554 B2 JP 5970554B2
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- Prior art keywords
- mmol
- dimethylphenyl
- thiazol
- ethanone
- solution
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 19
- 230000000694 effects Effects 0.000 title description 20
- 101001112162 Homo sapiens Kinetochore protein NDC80 homolog Proteins 0.000 title 1
- 102100023890 Kinetochore protein NDC80 homolog Human genes 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 175
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 claims description 161
- -1 C 1 -C 6 alkyl Chemical class 0.000 claims description 123
- 239000003814 drug Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 229940079593 drug Drugs 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
- 230000027455 binding Effects 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 11
- 230000003993 interaction Effects 0.000 claims description 10
- 241001465754 Metazoa Species 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- DHKNWIMBBMORIS-UHFFFAOYSA-N n-[4-[4-[5-(2-methoxyethoxy)pyrazin-2-yl]oxy-2,6-dimethylphenyl]-1,3-thiazol-2-yl]pyridine-4-carboxamide Chemical compound C1=NC(OCCOC)=CN=C1OC(C=C1C)=CC(C)=C1C1=CSC(NC(=O)C=2C=CN=CC=2)=N1 DHKNWIMBBMORIS-UHFFFAOYSA-N 0.000 claims description 6
- 230000001613 neoplastic effect Effects 0.000 claims description 6
- 102000029749 Microtubule Human genes 0.000 claims description 5
- 108091022875 Microtubule Proteins 0.000 claims description 5
- 210000004688 microtubule Anatomy 0.000 claims description 5
- 230000015556 catabolic process Effects 0.000 claims description 4
- 238000006731 degradation reaction Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 230000002452 interceptive effect Effects 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 3
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- 125000005490 tosylate group Chemical class 0.000 claims 2
- MARLAZIAHQMSOL-UHFFFAOYSA-N 2-(2-methoxyethoxy)pyrazine Chemical compound COCCOC1=CN=CC=N1 MARLAZIAHQMSOL-UHFFFAOYSA-N 0.000 claims 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims 1
- 230000000118 anti-neoplastic effect Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 455
- 239000000243 solution Substances 0.000 description 351
- 238000005481 NMR spectroscopy Methods 0.000 description 306
- 230000002829 reductive effect Effects 0.000 description 238
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 213
- 235000019439 ethyl acetate Nutrition 0.000 description 185
- 239000007787 solid Substances 0.000 description 167
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 148
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 147
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 133
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 131
- 239000000203 mixture Substances 0.000 description 127
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 120
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 118
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 91
- 239000011541 reaction mixture Substances 0.000 description 89
- 239000012044 organic layer Substances 0.000 description 87
- 229920006395 saturated elastomer Polymers 0.000 description 85
- 238000010992 reflux Methods 0.000 description 83
- 239000000741 silica gel Substances 0.000 description 76
- 229910002027 silica gel Inorganic materials 0.000 description 76
- 210000004027 cell Anatomy 0.000 description 74
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 67
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 67
- SFLXUZPXEWWQNH-UHFFFAOYSA-K tetrabutylazanium;tribromide Chemical compound [Br-].[Br-].[Br-].CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC SFLXUZPXEWWQNH-UHFFFAOYSA-K 0.000 description 67
- 239000012267 brine Substances 0.000 description 63
- 238000006243 chemical reaction Methods 0.000 description 63
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 61
- 239000002244 precipitate Substances 0.000 description 60
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
- 238000004440 column chromatography Methods 0.000 description 50
- 239000011734 sodium Substances 0.000 description 50
- 239000003921 oil Substances 0.000 description 49
- 235000019198 oils Nutrition 0.000 description 49
- 238000000746 purification Methods 0.000 description 47
- 239000003480 eluent Substances 0.000 description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- 206010028980 Neoplasm Diseases 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- QCPIZBBKBAQQSK-UHFFFAOYSA-N n-[4-[2-chloro-4-(4-methoxyphenyl)sulfanyl-6-methylphenyl]-1,3-thiazol-2-yl]pyridine-4-carboxamide Chemical compound C1=CC(OC)=CC=C1SC(C=C1Cl)=CC(C)=C1C1=CSC(NC(=O)C=2C=CN=CC=2)=N1 QCPIZBBKBAQQSK-UHFFFAOYSA-N 0.000 description 31
- 125000000217 alkyl group Chemical group 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 125000003118 aryl group Chemical group 0.000 description 24
- 238000003818 flash chromatography Methods 0.000 description 24
- 239000003112 inhibitor Substances 0.000 description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 201000011510 cancer Diseases 0.000 description 22
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- BNTRVUUJBGBGLZ-UHFFFAOYSA-N hydron;pyridine-4-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=NC=C1 BNTRVUUJBGBGLZ-UHFFFAOYSA-N 0.000 description 18
- 125000000753 cycloalkyl group Chemical group 0.000 description 17
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 16
- 229940125851 compound 27 Drugs 0.000 description 16
- IRGVMVPBEQQZEQ-UHFFFAOYSA-N 1-(4-hydroxy-2,6-dimethylphenyl)ethanone Chemical compound CC(=O)C1=C(C)C=C(O)C=C1C IRGVMVPBEQQZEQ-UHFFFAOYSA-N 0.000 description 15
- 239000005909 Kieselgur Substances 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 125000001072 heteroaryl group Chemical group 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 14
- 125000000304 alkynyl group Chemical group 0.000 description 13
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 13
- NBNNDUZYMXBCOX-UHFFFAOYSA-N n-[4-[4-(4-methoxyphenoxy)-2,6-dimethylphenyl]-1,3-thiazol-2-yl]pyridine-4-carboxamide Chemical compound C1=CC(OC)=CC=C1OC(C=C1C)=CC(C)=C1C1=CSC(NC(=O)C=2C=CN=CC=2)=N1 NBNNDUZYMXBCOX-UHFFFAOYSA-N 0.000 description 13
- 239000000651 prodrug Substances 0.000 description 13
- 229940002612 prodrug Drugs 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 13
- YTPYRGOFBLEEBD-UHFFFAOYSA-N 1-(4-chloro-2,6-dimethylphenyl)ethanone Chemical compound CC(=O)C1=C(C)C=C(Cl)C=C1C YTPYRGOFBLEEBD-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- 125000003342 alkenyl group Chemical group 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 238000011282 treatment Methods 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 10
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(i) oxide Chemical compound [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 10
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 10
- 125000000392 cycloalkenyl group Chemical group 0.000 description 10
- SACNIGZYDTUHKB-UHFFFAOYSA-N ditert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C SACNIGZYDTUHKB-UHFFFAOYSA-N 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- VYFXXRTZMRYFPX-UHFFFAOYSA-N 2-chloro-n-[4-(2,4,6-trimethylphenyl)-1,3-thiazol-2-yl]pyridine-4-carboxamide Chemical compound CC1=CC(C)=CC(C)=C1C1=CSC(NC(=O)C=2C=C(Cl)N=CC=2)=N1 VYFXXRTZMRYFPX-UHFFFAOYSA-N 0.000 description 9
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 229910005965 SO 2 Inorganic materials 0.000 description 9
- 239000010949 copper Substances 0.000 description 9
- 125000004093 cyano group Chemical group *C#N 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 239000002207 metabolite Substances 0.000 description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 9
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 description 8
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 7
- 239000012346 acetyl chloride Substances 0.000 description 7
- 229950003476 aminothiazole Drugs 0.000 description 7
- 230000022131 cell cycle Effects 0.000 description 7
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 7
- 238000003119 immunoblot Methods 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 7
- ILXXCNQLKQLLNW-UHFFFAOYSA-N n-[4-[4-[(4-methoxyphenyl)methyl]-2,6-dimethylphenyl]-1,3-thiazol-2-yl]pyridine-4-carboxamide Chemical compound C1=CC(OC)=CC=C1CC(C=C1C)=CC(C)=C1C1=CSC(NC(=O)C=2C=CN=CC=2)=N1 ILXXCNQLKQLLNW-UHFFFAOYSA-N 0.000 description 7
- 125000000335 thiazolyl group Chemical group 0.000 description 7
- CKKYIPUTRBBCIH-UHFFFAOYSA-N 1-[4-(4-methoxy-2,6-dimethylphenyl)-1,3-thiazol-2-yl]-3-pyridin-4-ylurea Chemical compound CC1=CC(OC)=CC(C)=C1C1=CSC(NC(=O)NC=2C=CN=CC=2)=N1 CKKYIPUTRBBCIH-UHFFFAOYSA-N 0.000 description 6
- MPAOOLLBWUEXOM-UHFFFAOYSA-N 1-bromo-4-propan-2-yloxybenzene Chemical compound CC(C)OC1=CC=C(Br)C=C1 MPAOOLLBWUEXOM-UHFFFAOYSA-N 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000006907 apoptotic process Effects 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- 125000002757 morpholinyl group Chemical group 0.000 description 6
- SYMUASOVWKCTEV-UHFFFAOYSA-N n-[4-[2,6-dimethyl-4-[(6-oxo-1h-pyridin-3-yl)oxy]phenyl]-1,3-thiazol-2-yl]pyridine-4-carboxamide Chemical compound C=1C(C)=C(C=2N=C(NC(=O)C=3C=CN=CC=3)SC=2)C(C)=CC=1OC1=CC=C(O)N=C1 SYMUASOVWKCTEV-UHFFFAOYSA-N 0.000 description 6
- AYTLLTLXDOJONQ-UHFFFAOYSA-N n-[4-[4-(dimethylamino)-2,6-dimethylphenyl]-1,3-thiazol-2-yl]pyridine-4-carboxamide Chemical compound CC1=CC(N(C)C)=CC(C)=C1C1=CSC(NC(=O)C=2C=CN=CC=2)=N1 AYTLLTLXDOJONQ-UHFFFAOYSA-N 0.000 description 6
- DGXVITRCLYQDRC-UHFFFAOYSA-N n-[5-bromo-4-[4-(4-methoxyphenoxy)-2,6-dimethylphenyl]-1,3-thiazol-2-yl]pyridine-4-carboxamide Chemical compound C1=CC(OC)=CC=C1OC(C=C1C)=CC(C)=C1C1=C(Br)SC(NC(=O)C=2C=CN=CC=2)=N1 DGXVITRCLYQDRC-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 125000003373 pyrazinyl group Chemical group 0.000 description 6
- 125000003107 substituted aryl group Chemical group 0.000 description 6
- QZKJDCAHBYUYPU-UHFFFAOYSA-N 2-bromo-1-(2,6-dimethyl-4-phenoxyphenyl)ethanone Chemical compound CC1=C(C(=O)CBr)C(C)=CC(OC=2C=CC=CC=2)=C1 QZKJDCAHBYUYPU-UHFFFAOYSA-N 0.000 description 5
- VLRPMRIKPZZZMT-UHFFFAOYSA-N 2-bromo-5-(2-methoxyethoxy)pyrazine Chemical compound COCCOC1=CN=C(Br)C=N1 VLRPMRIKPZZZMT-UHFFFAOYSA-N 0.000 description 5
- JZGFZITYBNEDHQ-UHFFFAOYSA-N 2-fluoro-n-[4-[4-(4-methoxyphenoxy)-2,6-dimethylphenyl]-1,3-thiazol-2-yl]pyridine-4-carboxamide Chemical compound C1=CC(OC)=CC=C1OC(C=C1C)=CC(C)=C1C1=CSC(NC(=O)C=2C=C(F)N=CC=2)=N1 JZGFZITYBNEDHQ-UHFFFAOYSA-N 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- 0 C*c1cc(*c2ccccc2)cc(*)c1C1=NC(NC(*(C)CC2=CC=CC=CC=CC=C/C=C2)=O)=S*1 Chemical compound C*c1cc(*c2ccccc2)cc(*)c1C1=NC(NC(*(C)CC2=CC=CC=CC=CC=C/C=C2)=O)=S*1 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 5
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
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- 238000005516 engineering process Methods 0.000 description 5
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 150000002440 hydroxy compounds Chemical class 0.000 description 5
- 230000006882 induction of apoptosis Effects 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
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Images
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Description
本発明者らは、化学式Iによるある特定の化合物を調製できること、および当該化合物がHec1に干渉する部分としての有利な特性を有することを見出した。特に好ましい化合物は、化学式Iによる化合物を含むであろう。
Hec1調節因子としての当該化合物の活性に基づき、本発明者らは、本発明の主題による化合物および組成物を、哺乳動物におけるHec1の機能障害および/または過剰発現に関連する様々な疾患の予防および/または治療、ならびに実際に、意図される化合物の投与に対して陽性の反応を示す全ての疾患に使用することができると意図する。本明細書において使用される場合、用語「Hec1の機能障害」は、とりわけNek2機能および紡錘体チェックポイントシグナリングとの関連に関係する場合の、Hec1におけるあらゆる異常を意味する。そのような異常は、1つ以上の変異(例えば、結合パートナーに対する親和性を増加または減少させる)、一過性もしくは永続的な過剰発現(例えば、不適切なもしくは変異したプロモーターにより活性化された)、活性化因子の非可逆的なもしくはより強い結合、非生理学的分子による不適切な活性化などに起因し得る。結果として、特に意図される疾患としては、新生物疾患、とりわけ癌性新生物疾患(例えば、乳癌、扁平上皮細胞癌、膀胱癌、胃癌、膵臓癌、頭部癌、頸部癌、食道癌、前立腺癌、結腸直腸癌、肺癌、腎臓癌、婦人科系癌、または甲状腺癌)が挙げられる。非癌性新生物疾患には、皮膚(例、乾癬)または前立腺(例えば、良性前立腺肥大(BPH))の良性過形成が含まれる。
Hec1阻害剤の例示的合成:
意図される化合物は、多数の合成経路によって調製することができ、以下は、例示的指針のためにのみ提供される。下記のスキームは、本明細書において提示した化合物の大部分を調製するために用いることができるが、他の化合物は、当業者であれば容易に明かとなるであろう、当該基本スキームに対する若干の変更を必要とする場合がある。
[例示的経路I]
[例示的経路II]
[例示的化合物および阻害活性]
上記表1の化合物27を、代謝産物同定のためにNADPHの存在下においてヒトミクロソームで処理した。当該試料をLC/MSによって分析した後、m/z値510.1、480.2、495.1、383.5の分子イオンピークおよび他のピークが観察された(ポジティブモード)。当該ピークは、化合物27の酸化、脱メチル化、酸化、脱メチル化などに対応し得る。化合物27における可能な代謝部位は、以下の構造に表される。
[選択された化合物の例示的生物活性]
Claims (17)
- 薬学的に許容される塩を形成するイオンとの組み合わせにおける、請求項1または6に記載の化合物。
- 薬学的に許容される担体と請求項1に記載の化合物とを含む医薬組成物であって、該化合物が、任意により薬学的に許容される塩として存在していてもよく、該化合物が哺乳動物に投与された場合に、該哺乳動物中においてHec1/Nek2結合を妨害するのに有効な濃度において含まれる、医薬組成物。
- さらに、微小管の形成または分解を妨げる薬物を含む、請求項8に記載の医薬組成物。
- 前記化合物が、請求項6に記載の化合物である、請求項8に記載の医薬組成物。
- 経口投与可能な薬物、注射薬、局所投与可能な薬物、または非経口投与可能な薬物として製剤化された、請求項8に記載の医薬組成物。
- 新生物性疾患を患っている哺乳動物を処置するための、請求項8に記載の医薬組成物。
- さらに、第二の抗新生物性化合物を含む、請求項8に記載の医薬組成物。
- Hec1/Nek2相互作用を妨害するための薬物の製造における、請求項1〜7のいずれか一項に記載の化合物(ただし、N−(4−(4−(5−(2−メトキシエトキシ)ピラジン−2−イルオキシ)−2,6−ジメチルフェニル)チアゾール−2−イル)イソニコチンアミド、およびN−(4−(4−(5−(2−メトキシエトキシ)ピラジン−2−イルチオ)−2,6−ジメチルフェニル)チアゾール−2−イル)イソニコチンアミドは除く。)の使用。
- 新生物性疾患を患っている哺乳動物を処置するための薬物の製造における、請求項1〜7のいずれか一項に記載の化合物(ただし、N−(4−(4−(5−(2−メトキシエトキシ)ピラジン−2−イルオキシ)−2,6−ジメチルフェニル)チアゾール−2−イル)イソニコチンアミド、およびN−(4−(4−(5−(2−メトキシエトキシ)ピラジン−2−イルチオ)−2,6−ジメチルフェニル)チアゾール−2−イル)イソニコチンアミドは除く。)の使用。
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PCT/US2012/067132 WO2013082324A1 (en) | 2011-11-29 | 2012-11-29 | Improved modulators of hec1 activity and methods therefor |
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