JP2013538785A - 複素環式化合物 - Google Patents
複素環式化合物 Download PDFInfo
- Publication number
- JP2013538785A JP2013538785A JP2013515439A JP2013515439A JP2013538785A JP 2013538785 A JP2013538785 A JP 2013538785A JP 2013515439 A JP2013515439 A JP 2013515439A JP 2013515439 A JP2013515439 A JP 2013515439A JP 2013538785 A JP2013538785 A JP 2013538785A
- Authority
- JP
- Japan
- Prior art keywords
- pyridin
- phenoxy
- methylamino
- benzamide
- fluoro
- 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.)
- Granted
Links
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 130
- 125000005843 halogen group Chemical group 0.000 claims abstract description 22
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 21
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims description 26
- SWPBRQSEXVXIEB-UHFFFAOYSA-N 2,3,4-trifluoro-n-[6-[2-fluoro-4-(methylamino)phenoxy]pyridin-3-yl]benzamide Chemical compound FC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(F)C(F)=C1F SWPBRQSEXVXIEB-UHFFFAOYSA-N 0.000 claims description 8
- HPFXYIBEOIDWJN-UHFFFAOYSA-N 2,3,4-trifluoro-n-[6-[2-methoxy-4-(methylamino)phenoxy]pyridin-3-yl]benzamide Chemical compound COC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(F)C(F)=C1F HPFXYIBEOIDWJN-UHFFFAOYSA-N 0.000 claims description 8
- ULNHTIYFYMJUIV-UHFFFAOYSA-N 2,3,4-trifluoro-n-[6-[2-methyl-4-(methylamino)phenoxy]pyridin-3-yl]benzamide Chemical compound CC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(F)C(F)=C1F ULNHTIYFYMJUIV-UHFFFAOYSA-N 0.000 claims description 8
- SEGBDTCOCOTOHG-UHFFFAOYSA-N 2-fluoro-n-[6-[2-fluoro-4-(methylamino)phenoxy]pyridin-3-yl]-4-(trifluoromethyl)benzamide Chemical compound FC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(C(F)(F)F)C=C1F SEGBDTCOCOTOHG-UHFFFAOYSA-N 0.000 claims description 8
- IWTDVBYLIYMJER-UHFFFAOYSA-N 2-fluoro-n-[6-[2-methoxy-4-(methylamino)phenoxy]pyridin-3-yl]-4-(trifluoromethyl)benzamide Chemical compound COC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(C(F)(F)F)C=C1F IWTDVBYLIYMJER-UHFFFAOYSA-N 0.000 claims description 8
- ZTOUWGFPYZRDHT-UHFFFAOYSA-N 2-fluoro-n-[6-[4-(methylamino)phenoxy]pyridin-3-yl]-4-(trifluoromethyl)benzamide Chemical compound C1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(C(F)(F)F)C=C1F ZTOUWGFPYZRDHT-UHFFFAOYSA-N 0.000 claims description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
- UPZCLEPHYSLIPP-UHFFFAOYSA-N n-[6-[2-methoxy-4-(methylamino)phenoxy]pyridin-3-yl]-4-(trifluoromethyl)benzamide Chemical compound COC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(C(F)(F)F)C=C1 UPZCLEPHYSLIPP-UHFFFAOYSA-N 0.000 claims description 8
- WCVQDOZDPPGJBL-UHFFFAOYSA-N n-[6-[4-(methylamino)phenoxy]pyridin-3-yl]-4-(trifluoromethyl)benzamide Chemical compound C1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(C(F)(F)F)C=C1 WCVQDOZDPPGJBL-UHFFFAOYSA-N 0.000 claims description 8
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- JGANLFYYXIVYCU-UHFFFAOYSA-N 2-fluoro-n-[6-[2-methyl-4-(methylamino)phenoxy]pyridin-3-yl]-4-(trifluoromethyl)benzamide Chemical compound CC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(C(F)(F)F)C=C1F JGANLFYYXIVYCU-UHFFFAOYSA-N 0.000 claims description 6
- UWRFGVXMYMTBQX-UHFFFAOYSA-N n-[6-[2-fluoro-4-(methylamino)phenoxy]pyridin-3-yl]-4-(trifluoromethyl)benzamide Chemical compound FC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(C(F)(F)F)C=C1 UWRFGVXMYMTBQX-UHFFFAOYSA-N 0.000 claims description 6
- BABXEBBZRSKDTM-UHFFFAOYSA-N n-[6-[2-methoxy-4-(methylamino)phenoxy]pyridin-3-yl]-4-phenoxybenzamide Chemical compound COC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 BABXEBBZRSKDTM-UHFFFAOYSA-N 0.000 claims description 5
- LNCCCADIFAWPNE-UHFFFAOYSA-N n-[6-[2-methoxy-4-(methylamino)phenoxy]pyridin-3-yl]-4-phenylbenzamide Chemical compound COC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(C=2C=CC=CC=2)C=C1 LNCCCADIFAWPNE-UHFFFAOYSA-N 0.000 claims description 5
- KDKOZNJGKLCACK-UHFFFAOYSA-N n-[6-[2-methyl-4-(methylamino)phenoxy]pyridin-3-yl]-4-(trifluoromethyl)benzamide Chemical compound CC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(C(F)(F)F)C=C1 KDKOZNJGKLCACK-UHFFFAOYSA-N 0.000 claims description 5
- XECWHPYBKMKKLG-UHFFFAOYSA-N n-[6-[2-methyl-4-(methylamino)phenoxy]pyridin-3-yl]-4-phenoxybenzamide Chemical compound CC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 XECWHPYBKMKKLG-UHFFFAOYSA-N 0.000 claims description 5
- REYMBUXFHICWDK-UHFFFAOYSA-N n-[6-[2-methyl-4-(methylamino)phenoxy]pyridin-3-yl]-4-phenylbenzamide Chemical compound CC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(C=2C=CC=CC=2)C=C1 REYMBUXFHICWDK-UHFFFAOYSA-N 0.000 claims description 5
- USILLOAIWCXVQC-UHFFFAOYSA-N n-[6-[4-(methylamino)phenoxy]pyridin-3-yl]-4-phenoxybenzamide Chemical compound C1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 USILLOAIWCXVQC-UHFFFAOYSA-N 0.000 claims description 5
- RNHHESLIYJHPPT-UHFFFAOYSA-N n-[6-[4-(methylamino)phenoxy]pyridin-3-yl]-4-phenylbenzamide Chemical compound C1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(C=2C=CC=CC=2)C=C1 RNHHESLIYJHPPT-UHFFFAOYSA-N 0.000 claims description 5
- PERNOXACLUDDNO-UHFFFAOYSA-N n-[6-[2-fluoro-4-(methylamino)phenoxy]pyridin-3-yl]-4-phenylbenzamide Chemical compound FC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(C=2C=CC=CC=2)C=C1 PERNOXACLUDDNO-UHFFFAOYSA-N 0.000 claims description 4
- YJBBWMBYGOTRLD-UHFFFAOYSA-N 2,3,4-trifluoro-n-[6-[4-(methylamino)phenoxy]pyridin-3-yl]benzamide Chemical compound C1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(F)C(F)=C1F YJBBWMBYGOTRLD-UHFFFAOYSA-N 0.000 claims description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 3
- NBZIDJZCAMTRDO-UHFFFAOYSA-N n-[6-[2-fluoro-4-(methylamino)phenoxy]pyridin-3-yl]-4-phenoxybenzamide Chemical compound FC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 NBZIDJZCAMTRDO-UHFFFAOYSA-N 0.000 claims description 3
- AXMYOSPKHWHENM-UHFFFAOYSA-N n-[6-[2-fluoro-4-(methylamino)phenoxy]pyridin-3-yl]-4-phenoxybenzamide;hydrochloride Chemical compound Cl.FC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 AXMYOSPKHWHENM-UHFFFAOYSA-N 0.000 claims description 3
- LZSWUWPAYMWODV-UHFFFAOYSA-N n-[6-[2-methoxy-4-(methylamino)phenoxy]pyridin-3-yl]-4-phenoxybenzamide;hydrochloride Chemical compound Cl.COC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 LZSWUWPAYMWODV-UHFFFAOYSA-N 0.000 claims description 3
- WMWJRLUFJVYOIX-UHFFFAOYSA-N n-[6-[2-methyl-4-(methylamino)phenoxy]pyridin-3-yl]-4-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.CC1=CC(NC)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(C(F)(F)F)C=C1 WMWJRLUFJVYOIX-UHFFFAOYSA-N 0.000 claims description 3
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- 230000002503 metabolic effect Effects 0.000 abstract description 6
- -1 cisplatin Chemical compound 0.000 description 62
- 238000005160 1H NMR spectroscopy Methods 0.000 description 46
- 239000000203 mixture Substances 0.000 description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 32
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 28
- 239000002585 base Substances 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 230000002829 reductive effect Effects 0.000 description 22
- 238000000034 method Methods 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 18
- 238000005755 formation reaction Methods 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 239000000843 powder Substances 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000012442 inert solvent Substances 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 239000007858 starting material Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
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- 239000012044 organic layer Substances 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 10
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- 210000004027 cell Anatomy 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
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- 235000011181 potassium carbonates Nutrition 0.000 description 8
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- 108010010803 Gelatin Proteins 0.000 description 4
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- UFESVLDYFSGBGZ-UHFFFAOYSA-N tert-butyl n-(4-hydroxy-3-methylphenyl)carbamate Chemical compound CC1=CC(NC(=O)OC(C)(C)C)=CC=C1O UFESVLDYFSGBGZ-UHFFFAOYSA-N 0.000 description 1
- WVKACGRMKLGKSR-UHFFFAOYSA-N tert-butyl n-[3-fluoro-4-[5-[(4-phenoxybenzoyl)amino]pyridin-2-yl]oxyphenyl]-n-methylcarbamate Chemical compound FC1=CC(N(C(=O)OC(C)(C)C)C)=CC=C1OC(N=C1)=CC=C1NC(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WVKACGRMKLGKSR-UHFFFAOYSA-N 0.000 description 1
- HRMBDPMKTIJOHK-UHFFFAOYSA-N tert-butyl n-[3-methoxy-4-(5-nitropyridin-2-yl)oxyphenyl]carbamate Chemical compound COC1=CC(NC(=O)OC(C)(C)C)=CC=C1OC1=CC=C([N+]([O-])=O)C=N1 HRMBDPMKTIJOHK-UHFFFAOYSA-N 0.000 description 1
- RTILEUDPOWFITK-UHFFFAOYSA-N tert-butyl n-[[3-methoxy-4-(5-nitropyridin-2-yl)oxyphenyl]methyl]carbamate Chemical compound COC1=CC(CNC(=O)OC(C)(C)C)=CC=C1OC1=CC=C([N+]([O-])=O)C=N1 RTILEUDPOWFITK-UHFFFAOYSA-N 0.000 description 1
- ABTUTTDGSXQHMD-UHFFFAOYSA-N tert-butyl n-[[4-(5-aminopyridin-2-yl)oxy-3-methoxyphenyl]methyl]carbamate Chemical compound COC1=CC(CNC(=O)OC(C)(C)C)=CC=C1OC1=CC=C(N)C=N1 ABTUTTDGSXQHMD-UHFFFAOYSA-N 0.000 description 1
- SUXKOSFZDQSJLC-UHFFFAOYSA-N tert-butyl n-methyl-n-[3-methyl-4-[5-[[4-(trifluoromethyl)benzoyl]amino]pyridin-2-yl]oxyphenyl]carbamate Chemical compound CC1=CC(N(C(=O)OC(C)(C)C)C)=CC=C1OC(N=C1)=CC=C1NC(=O)C1=CC=C(C(F)(F)F)C=C1 SUXKOSFZDQSJLC-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 125000005950 trichloromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- 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
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
[式中、
R1は、ハロゲン原子、アリール基、アリールオキシ基、又は1つ若しくは複数のハロゲン原子で場合により置換されている低級アルキル基を表し、
R2は、水素原子、ハロゲン原子、低級アルキル基、又は低級アルコキシ基を表し、
mは、1から3の整数を表し、
ただし、mが2又は3を表す場合、R1は同一又は異なる]。
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2−フルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2,3,4−トリフルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド、
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド、
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2−フルオロ−N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド、
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
2−フルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2,3,4−トリフルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド、
2,3,4−トリフルオロ−N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド、
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2−フルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、及び
2,3,4−トリフルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド
からなる群から選択される、項目1に記載の化合物又はその塩。
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド、
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2−フルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2,3,4−トリフルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド、
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド、
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2−フルオロ−N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド、
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
2−フルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2,3,4−トリフルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド、
2,3,4−トリフルオロ−N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド、
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2−フルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2,3,4−トリフルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド、
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド塩酸塩、
2−フルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩、
2,3,4−トリフルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド塩酸塩、
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩、
2,3,4−トリフルオロ−N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド塩酸塩、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド塩酸塩、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩、
2−フルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩、
2,3,4−トリフルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド塩酸塩、
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩、
2−フルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩、及び
2,3,4−トリフルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド塩酸塩
からなる群から選択される、項目1に記載の化合物。
R1が、アリール基、アリールオキシ基、又は1つ若しくは複数のハロゲン原子によって場合により置換されている低級アルキル基を表し、
R2が、水素原子、ハロゲン原子、低級アルキル基、又は低級アルコキシ基を表し、
mが、整数1を表す、
一般式(1)によって表される化合物又はその塩である。
R1がハロゲン原子を表し、
R2が、水素原子、ハロゲン原子、低級アルキル基、又は低級アルコキシ基を表し、
mが、1から3の整数を表し、
ただし、mが2又は3を表す場合、R1が同一又は異なる、
一般式(1)によって表される化合物又はその塩である。
R1が、ハロゲン、又は1個若しくは複数のハロゲン原子で場合により置換されている低級アルキル基を表し、
R2が、水素原子、ハロゲン原子、低級アルキル基、又は低級アルコキシ基を表し、
mが、整数2を表し、
ただし、R1が同一又は異なる、
一般式(1)によって表される化合物又はその塩である。
化合物(6)は、化合物(5)をメチル化試薬と反応させることによって生成され得る。反応は、塩基の存在下又は非存在下、不活性な溶媒中又はいかなる溶媒なしで行われ得る。
化合物(7)は、化合物(6)を還元することによって生成され得る。還元は、触媒の水素化還元剤の存在下、不活性な溶媒中で行われ得る。
{3−メトキシ−4−[(5−ニトロピリジン−2−イル)オキシ]フェニル}カルバミン酸tert−ブチルの生成
2−メトキシ−4−ニトロフェノール(3.22g)、二炭酸ジ−tert−ブチル(4.16g)、及びパラジウム炭素(5重量%、2.03g)のEtOH(100mL)中混合液を、水素雰囲気下、40℃で5時間撹拌した。混合液をセライトのパッドを通してろ過し、ろ液を減圧下で濃縮して褐色の油状物を得た。この油状物をDMF(80mL)中に溶解した。この溶液に、2−クロロ−5−ニトロピリジン(3.02g)及び炭酸カリウム(3.95g)を加えた。室温で1時間及び50℃で3時間撹拌した後、混合液をセライトのパッドを通してろ過し、ろ液を減圧下で濃縮した。残渣をAcOEt及び水中で希釈し、AcOEtで抽出した。有機層を水、NaCl飽和水溶液で洗浄し、無水Na2SO4で乾燥し、減圧下で濃縮した。残渣にEt2O/アセトンを加え、混合液を室温で一夜撹拌した。得られた沈殿物をろ過によって回収し、ろ液をシリカゲルカラムクロマトグラフィー(n−ヘキサン/AcOEt=9/1から3/1)によって精製した。これらを合わせて、淡黄色固体の表題化合物(5.44g)を得た。
1H-NMR (CDCl3) δ: 1.53 (9H, s), 3.76 (3H, s), 6.54 (1H, s), 6.76 (1H, dd, J = 8.5, 2.4 Hz), 6.99-7.06 (2H, m), 7.43 (1H, s), 8.44 (1H, dd, J = 9.0, 2.7 Hz), 9.00-9.02 (1H, m).
{3−メチル−4−[(5−ニトロピリジン−2−イル)オキシ]フェニル}カルバミン酸tert−ブチルの生成
(4−ヒドロキシ−3−メチルフェニル)カルバミン酸tert−ブチル(5.00g)のDMF(50ml)溶液に、2−クロロ−5−ニトロピリジン(3.91g)及び炭酸カリウム(4.64g)を加えた。80℃で4時間撹拌後、混合液を減圧下で濃縮した。残渣をAcOEt及び水中で希釈し、AcOEtで抽出した。有機層を水、NaCl飽和水溶液で洗浄し、無水Na2SO4で乾燥し、減圧下で濃縮した。残渣にEt2Oを加え、混合液を室温で2時間撹拌した。得られた沈殿物をろ過によって回収して、褐色粉末状の表題化合物(6.04g)を得た。
1H-NMR (CDCl3) δ: 1.52 (9H, s), 2.12 (3H, s), 6.49 (1H, brs), 6.98 (1H, d, J = 8.6 Hz), 6.99 (1H, d, J = 9.0 Hz), 7.21 (1H, dd, J = 8.5, 2.7 Hz), 7.39 (1H, s), 8.46 (1H, dd, J = 9.0, 2.9 Hz), 9.03 (1H, d, J = 2.9 Hz).
{3−メトキシ−4−[(5−ニトロピリジン−2−イル)オキシ]フェニル}メチルカルバミン酸tert−ブチルの生成
{3−メトキシ−4−[(5−ニトロピリジン−2−イル)オキシ]フェニル}カルバミン酸tert−ブチル(4.42g)のDMF(80mL)溶液に、0℃で、NaH(油中60%、0.51g)を加えた。0℃で10分間撹拌した後、ヨードメタン(1.91g)を加え、混合液を室温で1時間撹拌した。混合液を氷水中に注ぎ、AcOEtで抽出した。有機層を水、NaCl飽和水溶液で洗浄し、無水Na2SO4で乾燥した。溶媒を減圧下で除去して、褐色油状の表題化合物(4.80g)を得た。
1H-NMR (CDCl3) δ: 1.49 (9H, s), 3.30 (3H, s), 3.74 (3H, s), 6.87 (1H, dd, J = 8.5, 2.4 Hz), 6.96-7.05 (2H, m), 7.09 (1H, d, J = 8.5 Hz), 8.45 (1H, dd, J = 9.0, 2.7 Hz), 9.02 (1H, d, J = 2.4 Hz).
以下の化合物を、好適な出発原料を用いて、参考例3におけるのと実質的に同じ方法で生成した。
{3−フルオロ−4−[(5−ニトロピリジン−2−イル)オキシ]フェニル}メチルカルバミン酸tert−ブチル
1H-NMR (CDCl3) δ: 1.49 (9H, s), 3.30 (3H, s), 7.07-7.24 (4H, m), 8.51 (1H, dd, J = 9.0, 2.7 Hz), 9.01 (1H, d, J = 2.7 Hz).
メチル{3−メチル−4−[(5−ニトロピリジン−2−イル)オキシ]フェニル}カルバミン酸tert−ブチルの生成
NaH(油中60%、640mg)のDMF(50mL)懸濁液に、0℃で、{3−メチル−4−[(5−ニトロピリジン−2−イル)オキシ]フェニル}カルバミン酸tert−ブチル(5.00g)を加えた。0℃で10分間撹拌した後、ヨードメタン(3.08g)を加え、混合液を3時間撹拌した。混合液を氷水中に注ぎ、AcOEtで抽出した。有機層を水、NaCl飽和水溶液で洗浄し、無水Na2SO4で乾燥した。溶媒を減圧下で除去した。残渣をシリカゲルカラムクロマトグラフィー(n−ヘプタン/AcOEt=6/1から1/1)によって精製して、白色固体の表題化合物(4.35g)を得た。
1H-NMR (CDCl3) δ: 1.48 (9H, s), 2.14 (3H, s), 3.28 (3H, s), 7.01 (1H, dd, J = 9.2, 0.6 Hz), 7.02 (1H, d, J = 8.5 Hz), 7.15 (1H, dd, J = 8.5, 2.4 Hz), 7.18-7.23 (1H, br m), 8.47 (1H, dd, J = 9.2, 2.8 Hz), 9.04 (1H, dd, J = 2.7, 0.5 Hz).
メチル{4−[(5−ニトロピリジン−2−イル)オキシ]フェニル}カルバミン酸tert−ブチルの生成
NaH(油中60%、1.22g)のTHF(30mL)懸濁液に、0℃で、{4−[(5−ニトロピリジン−2−イル)オキシ]フェニル}カルバミン酸tert−ブチル(7.77g)を加えた。0℃で10分間撹拌した後、ヨードメタン(4.33g)を加え、混合液を室温で3時間撹拌した。混合液を氷水中に注ぎ、AcOEtで抽出した。有機層を水、NaCl飽和水溶液で洗浄し、無水Na2SO4で乾燥した。溶媒を減圧下で除去した。残渣をシリカゲルカラムクロマトグラフィー(n−ヘキサン/AcOEt=2/1)によって精製して、淡黄色固体の表題化合物(6.30g)を得た。
1H-NMR (CDCl3) δ: 1.48 (9H, s), 3.30 (3H, s), 7.03 (1H, dd, J = 9.0, 0.5 Hz), 7.11-7.13 (2H, m), 7.31-7.34 (2H, m), 8.48 (1H, dd, J = 9.0, 2.7 Hz), 9.05 (1H, d, J = 2.7 Hz).
{4−[(5−アミノピリジン−2−イル)オキシ]−3−メトキシフェニル}メチルカルバミン酸tert−ブチルの生成
{3−メトキシ−4−[(5−ニトロピリジン−2−イル)オキシ]フェニル}メチルカルバミン酸tert−ブチル(4.80g)及びパラジウム炭素(5重量%、1.36g)のEtOH(100mL)中混合液を、水素雰囲気下40℃で2時間撹拌した。混合液をセライトのパッドを通してろ過し、ろ液を減圧下で濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n−ヘキサン/AcOEt=3/2から3/7)によって精製して、黄色油状の表題化合物(3.58g)を得た。
1H-NMR (CDCl3) δ: 1.46 (9H, s), 3.26 (3H, s), 3.46 (2H, brs), 3.77 (3H, s), 6.73-6.82 (2H, m), 6.88-6.93 (1H, m), 7.00 (1H, d, J = 8.3 Hz), 7.07 (1H, dd, J = 8.5, 2.9 Hz), 7.66 (1H, d, J = 2.9 Hz).
{4−[(5−アミノピリジン−2−イル)オキシ]−3−メチルフェニル}メチルカルバミン酸tert−ブチルの生成
メチル{3−メチル−4−[(5−ニトロピリジン−2−イル)オキシ]フェニル}メチルカルバミン酸tert−ブチル(4.35g)及びパラジウム炭素(10重量%、620mg)のAcOEt(80mL)中混合液を、水素雰囲気下45℃で3時間撹拌した。混合液をセライトのパッドを通してろ過し、ろ液を減圧下で濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n−ヘプタン/AcOEt=1/1から3/7)によって精製して、白色固体の表題化合物(3.55g)を得た。
1H-NMR (CDCl3) δ: 1.46 (9H, s), 2.19 (3H, s), 3.24 (3H, s), 3.52 (2H, brs), 6.68 (1H, d, J = 8.5 Hz), 6.90 (1H, d, J = 8.8 Hz), 7.02 (1H, dd, J = 8.5, 2.4 Hz), 7.05 (1H, dd, J = 8.5, 2.9 Hz), 7.08-7.13 (1H, br m), 7.68 (1H, d, J = 2.9 Hz).
{4−[(5−アミノピリジン−2−イル)オキシ]フェニル}メチルカルバミン酸tert−ブチルの生成
メチル{4−[(5−ニトロピリジン−2−イル)オキシ]フェニル}カルバミン酸tert−ブチル(3.28g)及びパラジウム炭素(10重量%、328mg)のEtOH(30mL)中混合液を、水素雰囲気下50℃で4時間撹拌した。混合液をセライトのパッドを通してろ過し、ろ液を減圧下で濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n−ヘキサン/AcOEt=2/1)によって精製して、淡黄色固体の表題化合物(2.79g)を得た。
1H-NMR (CDCl3) δ: 1.44 (9H, s), 3.24 (3H, s), 3.54 (2H, brs), 6.76 (1H, d, J = 8.5 Hz), 6.99-7.02 (2H, m), 7.08 (1H, dd, J = 8.5, 2.9 Hz), 7.17-7.19 (2H, m), 7.72 (1H, d, J = 2.9 Hz).
{4−[(5−アミノピリジン−2−イル)オキシ]−3−フルオロフェニル}メチルカルバミン酸tert−ブチルの生成
{3−フルオロ−4−[(5−ニトロピリジン−2−イル)オキシ]フェニル}メチルカルバミン酸tert−ブチル(2.79g)のEtOH(57mL)中溶液をアルゴンでパージし、次いで白金炭素(5重量%、担持活性炭、湿潤、DegussaタイプF101 ra/w)(0.6g)で処理した。次いで反応混合液をH2雰囲気下に配置し、40℃で2時間、激しく撹拌した。反応混合液をセライトのパッドを通してろ過し、ろ液を減圧下で濃縮して、白色粉末状の表題化合物(2.59g)を得た。
1H-NMR (CDCl3) δ: 1.45 (9H, s), 3.25 (3H, s), 3.48 (2H, brs), 6.82 (1H, d, J = 8.7 Hz), 6.98-7.03 (1H, m), 7.07-7.15 (3H, m), 7.64 (1H, dd, J = 3.1, 0.6 Hz).
[3−フルオロ−4−({5−[(4−フェノキシベンゾイル)アミノ]ピリジン−2−イル}オキシ)フェニル]メチルカルバミン酸tert−ブチルの生成
{4−[(5−アミノピリジン−2−イル)オキシ]−3−フルオロフェニル}メチルカルバミン酸tert−ブチル(0.5g)及びトリエチルアミン(0.36mL)のAcOEt(12mL)溶液に、0℃で、4−フェノキシベンゾイルクロリド(390mg)のAcOEt(5mL)溶液を加え、次いで、結果として生じた混合液を0℃で10分間撹拌した。得られた沈殿物を分離し、H2O及びEt2Oで洗浄して、白色粉末状の表題化合物(0.53g)を得た。
1H-NMR (CDCl3) δ: 1.48 (9H, s), 3.27 (3H, s), 7.01 (1H, d, J = 8.8 Hz), 7.03-7.23 (6H, m), 7.05 (2H, d, J = 8.8 Hz), 7.36-7.43 (2H, m), 7.77 (1H, s), 7.84 (2H, d, J= 8.8 Hz), 8.19 (1H, d, J = 2.2 Hz), 8.22 (1H, dd, J = 8.7, 2.8 Hz).
以下の化合物を、好適な出発原料を用いて、参考例11におけるのと実質的に同じ方法で生成した。
[4−({5−[(ビフェニル−4−イルカルボニル)アミノ]ピリジン−2−イル}オキシ)−3−フルオロフェニル]メチルカルバミン酸tert−ブチル
1H-NMR (CDCl3) δ: 1.48 (9H, s), 3.27 (3H, s), 7.03-7.08 (1H, m), 7.03 (1H, d, J = 8.8 Hz), 7.14 (1H, d, J = 11.7 Hz), 7.17 (1H, t, J = 8.7 Hz), 7.38-7.52 (3H, m), 7.61-7.65 (2H, m), 7.72 (2H, d, J= 8.5 Hz), 7.87 (1H, s), 7.95 (2H, d, J= 8.5 Hz), 8.23 (1H, d, J = 2.2 Hz), 8.27 (1H, dd, J = 8.7, 2.8 Hz).
{3−フルオロ−4−[(5−{[4−(トリフルオロメチル)ベンゾイル]アミノ}ピリジン−2−イル)オキシ]フェニル}メチルカルバミン酸tert−ブチル
1H-NMR (CDCl3) δ: 1.48 (9H, s), 3.26 (3H, s), 6.96-7.18 (4H, m), 7.73 (2H, d, J = 8.1 Hz), 7.97 (2H, d, J = 8.1 Hz), 8.15 (1H, s), 8.20 (1H, dd, J = 8.9, 2.8 Hz), 8.22 (1H, s).
{3−フルオロ−4−[(5−{[2−フルオロ−4−(トリフルオロメチル)ベンゾイル]アミノ}ピリジン−2−イル)オキシ]フェニル}メチルカルバミン酸tert−ブチル
1H-NMR (CDCl3) δ: 1.48 (9H, s), 3.28 (3H, s), 7.04 (1H, d, J = 9.0 Hz), 7.07 (1H, s), 7.14 (1H, d, J = 10.0 Hz), 7.18 (1H, t, J = 8.7 Hz), 7.49 (1H, d, J = 11.7 Hz), 7.61 (1H, d, J = 8.3 Hz), 8.21 (1H, dd, J = 8.9, 2.8 Hz), 8.27 (1H, d, J = 2.7 Hz), 8.28-8.38 (2H, m).
[3−フルオロ−4−({5−[(2,3,4−トリフルオロベンゾイル)アミノ]ピリジン−2−イル}オキシ)フェニル]メチルカルバミン酸tert−ブチル
1H-NMR (CDCl3) δ: 1.48 (9H, s), 3.28 (3H, s), 7.03-7.08 (1H, m), 7.03 (1H, d, J = 9.0 Hz), 7.12-7.21 (3H, m), 7.89-7.99 (1H, m), 8.11-8.18 (1H, m), 8.17 (1H, dd, J = 8.8, 2.7 Hz), 8.25 (1H, d, J = 2.7 Hz).
メチル[3−メチル−4−({5−[(4−フェノキシベンゾイル)アミノ]ピリジン−2−イル}オキシ)フェニル]カルバミン酸tert−ブチル
1H-NMR (CDCl3) δ: 1.47 (9H, s), 2.17 (3H, s), 3.26 (3H, s), 6.88 (1H, dd, J = 8.8, 0.8 Hz), 6.98 (1H, d, J = 8.5 Hz), 7.03-7.09 (5H, m), 7.12-7.16 (1H, br m), 7.18-7.22 (1H, m), 7.37-7.42 (2H, m), 7.84-7.86 (3H, m), 8.18-8.22 (2H, m).
[4−({5−[(ビフェニル−4−イルカルボニル)アミノ]ピリジン−2−イル}オキシ)−3−メチルフェニル]メチルカルバミン酸tert−ブチル
1H-NMR (CDCl3) δ: 1.47 (9H, s), 2.17 (3H, s), 3.26 (3H, s), 6.89 (1H, d, J = 9.0 Hz), 6.99 (1H, d, J = 8.5 Hz), 7.08 (1H, dd, J = 8.5, 2.4 Hz), 7.12-7.17 (1H, br m), 7.40-7.42 (1H, m), 7.46-7.50 (2H, m), 7.62-7.64 (2H, m), 7.70-7.72 (2H, m), 7.94-7.97 (2H, m), 7.97-8.00 (1H, br m), 8.22-8.26 (2H, m).
メチル{3−メチル−4−[(5−{[4−(トリフルオロメチル)ベンゾイル]アミノ}ピリジン−2−イル)オキシ]フェニル}カルバミン酸tert−ブチルの生成
{4−[(5−アミノピリジン−2−イル)オキシ]−3−メチルフェニル}メチルカルバミン酸tert−ブチル(0.5g)及びEt3N(0.32mL)のAcOEt(15mL)溶液に、0℃で、4−(トリフルオロメチル)ベンゾイルクロリド(237mL)をゆっくりと加え、次いで、結果として生じた混合液を室温で30分間撹拌した。この溶液にAcOEt(10mL)及び水(10mL)を加え、混合液をAcOEtで抽出した。有機層をNaHCO3飽和水溶液及びNaCl飽和水溶液で洗浄し、無水Na2SO4で乾燥し、減圧下で濃縮した。ヘキサン(20mL)を加えた後、溶液を激しく撹拌した。得られた沈殿物を回収し、白色固体の表題化合物(700mg)を得た。
1H-NMR (CDCl3) δ: 1.47 (9H, s), 2.13 (3H, s), 3.24 (3H, s), 6.86 (1H, d, J = 8.8 Hz), 6.95 (1H, d, J = 8.5 Hz), 7.01-7.08 (1H, m), 7.12 (1H, s), 7.73 (2H, d, J = 8.1 Hz), 7.98 (2H, d, J = 7.8 Hz), 8.06-8.31 (1H, br m), 8.17 (1H, d, J= 8.8 Hz), 8.26 (1H, d, J = 2.7 Hz).
以下の化合物を、好適な出発原料を用いて、参考例18におけるのと実質的に同じ方法で生成した。
{4−[(5−{[2−フルオロ−4−(トリフルオロメチル)ベンゾイル]アミノ}ピリジン−2−イル)オキシ]−3−メチルフェニル}メチルカルバミン酸tert−ブチル
1H-NMR (CDCl3) δ: 1.47 (9H, s), 2.18 (3H, s), 3.27 (3H, s), 6.91 (1H, d, J = 8.8 Hz), 7.00 (1H, d, J = 8.5 Hz), 7.10 (1H, dd, J = 8.5, 2.4 Hz), 7.13-7.19 (1H, br m), 7.49 (1H, d, J = 11.7 Hz), 7.61 (1H, d, J = 8.3 Hz), 8.18 (1H, dd, J = 8.8, 2.8 Hz), 8.29-8.36 (3H, m).
メチル[4−({5−[(4−フェノキシベンゾイル)アミノ]ピリジン−2−イル}オキシ)フェニル]カルバミン酸tert−ブチル
1H-NMR (CDCl3) δ: 1.46 (9H, s), 3.26 (3H, s), 6.94 (1H, d, J = 8.8 Hz), 7.03-7.09 (6H, m), 7.18-7.25 (3H, m), 7.37-7.43 (2H, m), 7.84-7.87 (3H, m), 8.21 (1H, dd, J = 8.8, 2.7 Hz), 8.25 (1H, d, J = 2.7 Hz).
[4−({5−[(ビフェニル−4−イルカルボニル)アミノ]ピリジン−2−イル}オキシ)フェニル]メチルカルバミン酸tert−ブチル
1H-NMR (CDCl3) δ: 1.46 (9H, s), 3.26 (3H, s), 6.96 (1H, d, J = 8.8 Hz), 7.07-7.10 (2H, m), 7.23-7.25 (2H, m), 7.40-7.42 (1H, m), 7.46-7.50 (2H, m), 7.62-7.64 (2H, m), 7.71-7.73 (2H, m), 7.95-7.97 (3H, m), 8.26 (1H, dd, J = 8.8, 2.6 Hz), 8.30 (1H, d, J = 2.6 Hz).
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミドの生成
[3−フルオロ−4−({5−[(4−フェノキシベンゾイル)アミノ]ピリジン−2−イル}オキシ)フェニル]メチルカルバミン酸tert−ブチル(0.53g)をTFA(4mL)中に溶解し、室温で5分間撹拌した。混合液を減圧下で濃縮し、残渣をAcOEt中に溶解した。氷冷した5MのNaOHを加えてpHを12に調節し、混合液をAcOEtで抽出した。有機層を水及びNaCl飽和水溶液で洗浄し、無水MgSO4で乾燥し、減圧下で濃縮した。残渣をEt2O中に溶解し、溶液を1日撹拌した。得られた沈殿物を回収し、Et2Oで洗浄して、白色粉末状の表題化合物(0.29mg)を得た。
1H-NMR (CDCl3) δ: 2.83 (3H, s), 3.78 (1H, brs), 6.35-6.44 (2H, m), 6.96 (1H, d, J = 9.3 Hz), 6.99-7.09 (5H, m), 7.17-7.22 (1H, m), 7.36-7.43 (2H, m), 7.68 (1H, s), 7.84 (2H, d, J = 8.9 Hz), 8.16-8.23 (2H, m).
以下の化合物を、好適な出発原料を用いて、実施例1におけるのと実質的に同じ方法で生成した。
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド
融点:190.0〜190.5℃(分解)
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド
1H-NMR (CDCl3) δ: 2.82 (3H, s), 6.32-6.46 (2H, m), 6.91-7.06 (2H, m), 7.74 (2H, d, J = 8.1 Hz), 7.89 (1H, s), 7.97 (2H, d, J = 8.1 Hz), 8.19 (1H, dd, J = 8.7, 2.7 Hz), 8.20 (1H, s).
2−フルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド
1H-NMR (CDCl3) δ: 2.83 (3H, d, J= 5.1 Hz), 3.80 (1H, d, J = 4.9 Hz), 6.36-6.46 (2H, m), 6.98 (1H, d, J= 8.8 Hz), 7.03 (1H, t, J = 8.7 Hz), 7.49 (1H, d, J = 11.7 Hz), 7.60 (1H, d, J = 7.3 Hz), 8.17 (1H, dd, J = 8.8, 2.7 Hz), 8.26 (1H, d, J = 2.4 Hz), 8.27-8.35 (2H, m).
2,3,4−トリフルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド
1H-NMR (CDCl3) δ: 2.83 (3H, s), 3.81 (1H, brs), 6.35-6.45 (2H, m), 6.97 (1H, d, J = 9.0 Hz), 7.03 (1H, t, J = 8.7 Hz), 7.10-7.19 (1H, m), 7.88-7.98 (1H, m), 8.12 (1H, brs), 8.13 (1H, dd, J = 8.8, 2.7 Hz), 8.24 (1H, d, J = 2.7 Hz).
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド
1H-NMR (CDCl3) δ: 2.10 (3H, s), 2.83 (3H, s), 3.63 (1H, brs), 6.47 (1H, dd, J = 8.5, 2.7 Hz), -6.50 (1H, d, J = 2.4 Hz ), 6.82 (1H, d, J = 8.8 Hz), 6.89 (1H, d, J = 8.5 Hz), 7.03-7.08 (4H, m), 7.17-7.22 (1H, m), 7.38-7.41 (2H, m), 7.79 (1H, brs), 7.83-7.85 (2H, m), 8.15 (1H, dd, J = 8.8, 2.8 Hz), 8.18 (1H, d, J = 2.4 Hz).
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド
1H-NMR (CDCl3) δ: 2.11 (3H, s), 2.83 (3H, s), 3.63 (1H, brs), 6.47 (1H, dd, J = 8.4, 2.8 Hz), 6.50 (1H, d, J = 2.8 Hz), 6.83 (1H, d, J = 8.8 Hz), 6.90 (1H, d, J = 8.4 Hz), 7.39-7.41 (1H, m), 7.46-7.49 (2H, m), 7.61-7.64 (2H, m), 7.69-7.71 (2H, m), 7.91 (1H, brs), 7.92-7.95 (2H, m), 8.19 (1H, dd, J= 8.8, 2.8 Hz), 8.22 (1H, d, J= 2.4 Hz).
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミドの生成
メチル{3−メチル−4−[(5−{[4−(トリフルオロメチル)ベンゾイル]アミノ}ピリジン−2−イル)オキシ]フェニル}カルバミン酸tert−ブチル(0.60g)のCH2Cl2(1mL)中溶液に、0℃で、TFA(3.32mL)を3回に分けて加えた。0℃で30分間撹拌後、混合液を減圧下で濃縮し、残渣をAcOEt中に溶解した。氷冷した2MのNaOH(10mL)を加え、混合液をAcOEtで抽出した。有機層を水及びNaCl飽和水溶液で洗浄し、無水Na2SO4で乾燥し、減圧下で濃縮した。Et2O(20mL)を加えた後、溶液を激しく撹拌した。得られた沈殿物を回収し、沈殿物をEt2O/AcOEt/ヘキサンから再結晶させて、白色粉末状の表題化合物(0.44g)を得た。
1H-NMR (CDCl3) δ: 2.09 (3H, s), 2.83 (3H, s), 3.64 (1H, s), 6.46 (1H, dd, J = 8.5, 2.9 Hz), 6.49 (1H, d, J = 2.9 Hz), 6.83 (1H, d, J = 9.0 Hz), 6.88 (1H, d, J = 8.5 Hz), 7.74 (2H, d, J = 8.1 Hz), 7.92-8.01 (3H, m), 8.14 (1H, dd, J = 8.9, 2.8 Hz), 8.21 (1H, d, J = 2.7 Hz).
以下の化合物を、好適な出発原料を用いて、実施例8におけるのと実質的に同じ方法で生成した。
2−フルオロ−N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド
1H-NMR (CDCl3) δ: 2.11 (3H, s), 2.84 (3H, s), 3.65 (1H, brs), 6.48 (1H, dd, J = 8.4, 2.8 Hz), 6.51 (1H, d, J = 2.4 Hz), 6.84 (1H, d, J = 8.8 Hz), 6.90 (1H, d, J = 8.4 Hz), 7.48 (1H, d, J = 11.7 Hz), 7.60 (1H, d, J = 8.1 Hz), 8.13 (1H, dd, J = 8.8, 2.8 Hz), 8.27 -8.34 (3H m).
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド
1H-NMR (CDCl3) δ: 2.84 (3H, s), 6.61-6.64 (2H, m), 6.86 (1H, d, J = 8.8 Hz), 6.96-6.99 (2H, m), 7.03-7.07 (4H, m), 7.18-7.21 (1H, m), 7.38-7.41 (2H, m), 7.80 (1H, brs), 7.83-7.85 (2H, m), 8.15 (1H, dd, J = 8.8, 2.8 Hz), 8.20 (1H, d, J = 2.8 Hz).
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド
1H-NMR (CDCl3) δ: 2.84 (3H, s), 6.62-6.64 (2H, m), 6.87 (1H, d, J = 8.8 Hz), 6.98-6.99 (2H, m), 7.40-7.41 (1H, m), 7.46-7.49 (2H, m), 7.61-7.64 (2H, m), 7.69-7.71 (2H, m), 7.90 (1H, brs), 7.93-7.95 (2H, m), 8.19 (1H, dd, J = 8.8, 2.6 Hz), 8.24 (1H, d, J = 2.6 Hz).
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミドの生成
{4−[(5−アミノピリジン−2−イル)オキシ]−3−メトキシフェニル}メチルカルバミン酸tert−ブチル(0.60g)及びトリエチルアミン(0.26g)のAcOEt(10mL)溶液に、0℃で、4−(トリフルオロメチル)ベンゾイルクロリド(0.38g)を加えた。混合液を室温で1時間撹拌した。混合液を水中に注ぎ、AcOEtで抽出した。有機層を水、NaCl飽和水溶液で洗浄し、無水Na2SO4で乾燥し、減圧下で濃縮した。残渣をカラムクロマトグラフィー(n−ヘキサン/AcOEt=9/1から7/3)によって精製して黄色非結晶粉末を得た。この粉末をCH2Cl2(10mL)中に溶解し、TFA(1mL)を加えた。混合液を室温で2時間撹拌した。減圧下で溶媒を除去した後、残渣をNaHCO3飽和水溶液中に注ぎ、AcOEtで抽出した。有機層を水、NaCl飽和水溶液で洗浄し、無水Na2SO4で乾燥し、減圧下で濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n−ヘキサン/AcOEt=7/3から3/7)によって精製して、無色油状の表題化合物(0.42g)を得た。
1H-NMR (CDCl3) δ: 2.84 (3H, s), 3.73 (3H, s), 6.20 (1H, dd, J = 8.5, 2.7 Hz), 6.25 (1H, d, J = 2.7 Hz), 6.89 (1H, d, J = 8.8 Hz), 6.95 (1H, d, J = 8.3 Hz), 7.74 (2H, d, J = 8.3 Hz), 7.94-8.02 (3H, m), 8.11-8.22 (2H, m).
以下の化合物を、好適な出発原料を用いて、実施例12におけるのと実質的に同じ方法で生成した。
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド
1H-NMR (CDCl3) δ: 2.84 (3H, s), 3.73 (3H, s), 3.74 (1H, s), 6.18-6.27 (2H, m), 6.88 (1H, d, J = 8.8 Hz), 6.94-6.98 (1H, m), 7.01-7.09 (4H, m), 7.17-7.22 (1H, m), 7.36-7.43 (2H, m), 7.72-7.87 (3H, m), 8.11-8.18 (2H, m).
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド
融点:161.4〜161.8℃
2−フルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド
1H-NMR (CDCl3) δ: 2.86 (3H, s), 3.65-3.85 (1H, brm), 3.75 (3H, s), 6.22 (1H, dd, J = 8.5, 2.7 Hz), 6.28 (1H, d, J = 2.4 Hz), 6.90 (1H, d, J = 8.8 Hz), 6.97 (1H, d, J =8.5 Hz), 7.48 (1H, d, J = 11.7 Hz), 7.60 (1H, d, J = 8.1 Hz), 8.12 (1H, dd, J = 8.8, 2.7 Hz), 8.24-8.35 (3H, m).
2,3,4−トリフルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド
1H-NMR (CDCl3) δ: 2.86 (3H, s), 3.68-3.78 (4H, m), 6.22 (1H, dd, J = 8.5, 2.7 Hz), 6.27 (1H, d, J = 2.4 Hz), 6.90 (1H, d, J = 8.8 Hz), 6.97 (1H, d, J = 8.5 Hz), 7.10-7.19 (1H, m), 7.89-7.97 (1H, m), 8.06-8.16 (2H, m), 8.24 (1H, d, J = 2.7 Hz).
2,3,4−トリフルオロ−N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド
1H-NMR (CDCl3) δ: 2.11 (3H, s), 2.83 (3H, s), 3.57-3.72 (1H, m), 6.48 (1H, dd, J = 8.5, 2.9 Hz), 6.51 (1H, d, J = 2.9 Hz), 6.83 (1H, d, J = 8.8 Hz), 6.90 (1H, d, J = 8.5 Hz), 7.10-7.19 (1H, m), 7.87-7.96 (1H, m), 8.07-8.12 (1H, m), 8.12-8.21 (1H, m), 8.23-8.28 (1H, m).
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド
1H-NMR (CDCl3) δ: 2.84 (3H, s), 6.61-6.63 (2H, m), 6.87 (1H, d, J = 8.8 Hz), 6.94-6.97 (2H, m), 7.73-7.75 (2H, m), 7.97-7.99 (2H, m), 8.04 (1H, brs), 8.14 (1H, dd, J = 8.8, 2.6 Hz), 8.23 (1H, d, J = 2.6 Hz).
2−フルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド
1H-NMR (CDCl3) δ: 2.85 (3H, s), 3.70 (1H, brs), 6.63-6.65 (2H, m), 6.88 (1H, d, J = 8.8 Hz), 6.98-7.00 (2H, m), 7.49 (1H, d, J = 12.0 Hz), 7.60 (1H, dd, J = 8.3, 1.0 Hz), 8.14 (1H, dd, J = 8.8, 2.8 Hz), 8.28-8.34 (3H, m).
2,3,4−トリフルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド
2,3,4−トリフルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミドの生成
tert−ブチル{4−[(5−アミノピリジン−2−イル)オキシ]フェニル}メチルカーバメート(0.50g)及びトリエチルアミン(0.32g)のAcOEt(10mL)溶液に、0℃で、2,3,4−トリフルオロベンゾイルクロリド(0.37g)を加えた。混合液を室温で1時間撹拌した。混合液を水中に注ぎ、AcOEtで抽出した。有機層を水、NaCl飽和水溶液で洗浄し、無水Na2SO4で乾燥し、減圧下で濃縮した。残渣をCH2Cl2(10mL)中に溶解し、TFA(3mL)を加えた。室温で2時間撹拌した後、混合液をNaHCO3飽和水溶液中に注ぎ、AcOEtで抽出した。有機層を水、NaCl飽和水溶液で洗浄し、無水Na2SO4で乾燥し、減圧下で濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n−ヘキサン/AcOEt=2/1)によって精製して、白色固体の表題化合物(0.55g)を得た。
1H-NMR (CDCl3) δ: 2.84 (3H, s), 3.71 (1H, brs), 6.62-6.65 (2H, m), 6.87 (1H, d, J = 8.8 Hz), 6.97-6.99 (2H, m), 7.11-7.18 (1H, m), 7.89-7.95 (1H, m), 8.10 (1H, dd, J = 8.8, 2.7 Hz), 8.14-8.17 (1H, br m), 8.27 (1H, d, J = 2.7 Hz).
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド塩酸塩の生成
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド(0.34g)のEtOH(7mL)溶液に、0℃で、6MのHCl(0.14mL)を加えた。結果として生じた混合液を0℃で撹拌した。得られた沈殿物をEtOH/H2Oから再結晶させて、白色粉末の表題化合物(0.28g)を得た。
1H-NMR (DMSO-d6) δ: 2.76 (3H, s), 6.60-6.69 (1H, m), 6.70-6.80 (1H, m), 7.06 (1H, d, J = 8.8 Hz), 7.08-7.17 (5H, m), 7.20-7.26 (1H, m), 7.43-7.49 (2H, m), 8.01 (2H, d, J = 9.4 Hz), 8.18 (1H, dd, J = 8.8, 2.7 Hz), 8.41 (1H, d, J = 2.2 Hz), 10.35 (1H, s).
以下の化合物を、好適な出発原料を用いて、実施例21におけるのと実質的に同じ方法で生成した。
2−フルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩
1H-NMR (DMSO-d6) δ: 2.77 (3H, s), 6.66-6.76 (1H, m), 6.77-6.88 (1H, m), 7.10 (1H, d, J = 9.0 Hz), 7.17 (1H, t, J = 8.9 Hz), 7.75 (1H, d, J = 8.3 Hz), 7.87-7.95 (2H, m), 8.17 (1H, dd, J = 9.0, 2.7 Hz), 8.38 (1H, d, J = 2.4 Hz), 10.78 (1H, s).
2,3,4−トリフルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド塩酸塩
1H-NMR (DMSO-d6) δ: 2.78 (3H, s), 6.70-6.81 (1H, m), 6.82-6.94 (1H, m), 7.10 (1H, d, J = 9.0 Hz), 7.19 (1H, t, J = 8.8 Hz), 7.44-7.54 (1H, m), 7.56-7.65 (1H, m), 8.16 (1H, dd, J = 8.8, 2.7 Hz), 8.37 (1H, d, J = 2.4 Hz), 10.70 (1H, s).
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩の生成
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド(0.30g)のEtOH(3mL)溶液に、0℃で、6MHCl水溶液(0.13mL)を加えた。結果として生じた混合液を0℃で撹拌した。得られた沈殿物をEtOH/H2Oから再結晶させて、白色粉末状の表題化合物(0.20g)を得た。
1H-NMR (DMSO-d6) δ: 2.14 (3H, s), 2.91 (3H, s), 7.11 (1H, d, J = 9.0 Hz), 7.17 (1H, d, J = 8.5 Hz), 7.32 (1H, dd, J = 8.5, 2.4 Hz), 7.36-7.43 (1H, m), 7.93 (2H, d, J = 8.3 Hz), 8.19 (2H, d, J = 8.1 Hz), 8.25 (1H, dd, J = 8.9, 2.8 Hz), 8.48 (1H, d, J = 2.4 Hz), 10.71 (1H, s).
以下の化合物を、好適な出発原料を用いて、実施例24におけるのと実質的に同じ方法で生成した。
2,3,4−トリフルオロ−N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド塩酸塩
融点:222.9〜225.4℃(分解)
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド塩酸塩
融点:202.2〜202.3℃
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩
融点:217.6〜218.2℃
2−フルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩
融点:197.0〜198.1℃
2,3,4−トリフルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド塩酸塩
融点:207.1〜209.8℃
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩
1H-NMR (DMSO-d6) δ: 2.90 (3H, s), 7.12 (1H, d, J = 8.8 Hz), 7.23-7.24 (2H, m), 7.42-7.44 (2H, m), 7.92-7.94 (2H, m), 8.18-8.20 (2H, m), 8.26 (1H, dd, J = 8.8, 2.6 Hz), 8.54 (1H, d, J = 2.6 Hz), 10.73 (1H, s).
2−フルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩
1H-NMR (DMSO-d6) δ: 2.89 (3H, s), 7.11 (1H, d, J = 8.8 Hz), 7.20-7.22 (2H, m), 7.37-7.39 (2H, m), 7.75 (1H, d, J = 8.1 Hz), 7.90-7.94 (2H, m), 8.20 (1H, dd, J = 8.8, 2.6 Hz), 8.46 (1H, d, J = 2.6 Hz), 10.83 (1H, s).
2,3,4−トリフルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド塩酸塩(1:1)の生成
2,3,4−トリフルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド(0.55g)のEtOH(10mL)溶液に、室温で、6MのHCl(0.27mL)を加えた。結果として生じた混合液を室温で撹拌した。得られた沈殿物をろ過によって回収して、白色粉末状の表題化合物(0.35g)を得た。
1H-NMR (DMSO-d6) δ: 2.89 (3H, s), 7.11 (1H, d, J = 8.8 Hz), 7.20-7.23 (2H, m), 7.38-7.40 (2H, m), 7.47-7.52 (1H, m), 7.58-7.64 (1H, m), 8.18 (1H, dd, J = 8.8, 2.7 Hz), 8.45 (1H, d, J = 2.7 Hz), 10.75 (1H, s).
以下の化合物は、好適な出発原料を用いて、実施例21におけるのと実質的に同じ方法で生成することができる。
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド塩酸塩
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド塩酸塩
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド塩酸塩
2−フルオロ−N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド塩酸塩
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド塩酸塩
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド塩酸塩
癌細胞に対する抗増殖効果(in vitro)
ヒト肝癌細胞(HuH−7)の増殖阻害を、Skehan P.ら(J Natl Cancer Inst.、1990年7月4日、82巻(13):1107〜12頁)の方法に基づき、スルホローダミンB法によって決定した。この研究では、HuH−7細胞を、96ウエルマイクロプレート中10%ウシ胎児血清を含むDMEM培地上に接種した。5%二酸化炭素の存在下、37℃で24時間インキュベートした後、試験化合物を加え、細胞をさらに5日間インキュベートした。インキュベート後、トリクロロ酢酸溶液を加えて最終濃度を10%とし、細胞を4℃で1時間放置して固定した。次いで、細胞を水で洗浄して培地及びトリクロロ酢酸を除去し、空気乾燥した。乾燥した細胞を、スルホローダミンBで染色するまで4℃で貯蔵した。各ウエルに0.4%スルホローダミンBを含む1%酢酸溶液を加え、室温で20分から30分間放置した。上清を廃棄した後、各ウエルを1%酢酸溶液で洗浄し、撹拌しながら10mMTris(tris−(ヒドロキシメチル)アミノメタン)溶液を加えて、細胞中に取り込まれた色素を溶出した。次いで、測定波長492nm及び参照波長690nmで光学密度を決定し、差を計算した。各ウエルにおける細胞増殖活性を、試験ウエルにおけるODから、細胞を含まない対照ウエルにおけるODを差し引くことによって決定した値(492nmと690nmにおける吸光度の間の差)と定義した。
この研究では、0.22mg/mLの肝ミクロソーム222.5μLを各試験管に分配し、100μMの試験化合物2.5μLをそれらに加えた。次いで、この混合液22.5μLを、0分試料としてアセトニトリルをスパイクしたIS500μLに分割し、残渣を37℃で5分間、プレインキュベートした。10mMのNADH/NADPH22.5μLを加えることによって反応を開始し、10分後及び20分後、反応混合液25μLを、アセトニトリルをスパイクしたIS500μLに分割した。試料を遠心分離し(5700rpm、4℃、10分)、上清をLC/MS/MSによって分析した。残存パーセントの対数vsインキュベーション時間の関係(−ke)からの直線回帰の傾きを計算し、固有クリアランス(CLint)を、以下の等式を用いて計算した。
長期間安定性試験を行わないで化合物の安定性を推定するために、溶解した化合物の安定性を、熱ストレス及び酸ストレスの条件下で評価した。
上記の方法によって、実施例30などのいくつかの代表的な化合物は優れた貯蔵安定性を有することが確認された。
Claims (7)
- R2が水素原子を表す、請求項1に記載の化合物又はその塩。
- R2がハロゲン原子を表す、請求項1に記載の化合物又はその塩。
- R2が低級アルキル基を表す、請求項1に記載の化合物又はその塩。
- R2が低級アルコキシ基を表す、請求項1に記載の化合物又はその塩。
- N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド、
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2−フルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2,3,4−トリフルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド、
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド、
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2−フルオロ−N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド]、
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
2−フルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2,3,4−トリフルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド、
2,3,4−トリフルオロ−N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド、
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2−フルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、及び
2,3,4−トリフルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド
からなる群から選択される、請求項1に記載の化合物又はその塩。 - N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド、
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2−フルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2,3,4−トリフルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド、
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド、
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2−フルオロ−N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド、
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ビフェニル−4−カルボキサミド、
2−フルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2,3,4−トリフルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド、
2,3,4−トリフルオロ−N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド、
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2−フルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド、
2,3,4−トリフルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド、
N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド塩酸塩、
2−フルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩、
2,3,4−トリフルオロ−N−{6−[2−フルオロ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド塩酸塩、
N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩、
2,3,4−トリフルオロ−N−{6−[2−メチル−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド塩酸塩、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−フェノキシベンズアミド塩酸塩、
N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩、
2−フルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩、
2,3,4−トリフルオロ−N−{6−[2−メトキシ−4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド塩酸塩、
N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩、
2−フルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}−4−(トリフルオロメチル)ベンズアミド塩酸塩、及び
2,3,4−トリフルオロ−N−{6−[4−(メチルアミノ)フェノキシ]ピリジン−3−イル}ベンズアミド塩酸塩
からなる群から選択される、請求項1に記載の化合物。
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JP2001522834A (ja) * | 1997-11-07 | 2001-11-20 | アムジエン・インコーポレーテツド | 抗炎症剤としての置換ピリジン化合物 |
WO2007066784A2 (en) * | 2005-12-05 | 2007-06-14 | Otsuka Pharmaceutical Co., Ltd. | Diarylether derivatives as antitumor agents |
JP2010505762A (ja) * | 2006-10-02 | 2010-02-25 | 大塚製薬株式会社 | Stat3/5活性化阻害剤 |
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