JPH0977739A - 5-alkylthio-4-aryloxynitroaniline compound - Google Patents
5-alkylthio-4-aryloxynitroaniline compoundInfo
- Publication number
- JPH0977739A JPH0977739A JP7233543A JP23354395A JPH0977739A JP H0977739 A JPH0977739 A JP H0977739A JP 7233543 A JP7233543 A JP 7233543A JP 23354395 A JP23354395 A JP 23354395A JP H0977739 A JPH0977739 A JP H0977739A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- group
- production example
- fluoro
- hexane
- 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
- 150000001875 compounds Chemical class 0.000 title abstract description 64
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 8
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- 125000001424 substituent group Chemical group 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 239000003814 drug Substances 0.000 abstract description 19
- 229940124597 therapeutic agent Drugs 0.000 abstract description 17
- 238000006722 reduction reaction Methods 0.000 abstract description 10
- 208000001132 Osteoporosis Diseases 0.000 abstract description 8
- 230000009467 reduction Effects 0.000 abstract description 8
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 7
- 239000002260 anti-inflammatory agent Substances 0.000 abstract description 7
- 238000005732 thioetherification reaction Methods 0.000 abstract description 7
- 208000020084 Bone disease Diseases 0.000 abstract description 6
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract description 6
- 230000021736 acetylation Effects 0.000 abstract description 4
- 238000006640 acetylation reaction Methods 0.000 abstract description 4
- TZRGWZGGYLXQMN-UHFFFAOYSA-N 5-methylsulfanyl-2-nitro-4-phenoxyaniline Chemical compound CSC1=CC(N)=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 TZRGWZGGYLXQMN-UHFFFAOYSA-N 0.000 abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 3
- 238000006396 nitration reaction Methods 0.000 abstract description 3
- 230000001684 chronic effect Effects 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 72
- -1 n-octyl group Chemical group 0.000 description 54
- 238000000034 method Methods 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 239000013078 crystal Substances 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 230000007062 hydrolysis Effects 0.000 description 9
- 238000006460 hydrolysis reaction Methods 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-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
- 238000001953 recrystallisation Methods 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- 108010002352 Interleukin-1 Proteins 0.000 description 6
- 102000000589 Interleukin-1 Human genes 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000008096 xylene Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 230000017306 interleukin-6 production Effects 0.000 description 5
- 230000000802 nitrating effect Effects 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 150000003568 thioethers Chemical class 0.000 description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 4
- PMBXCGGQNSVESQ-UHFFFAOYSA-N 1-Hexanethiol Chemical compound CCCCCCS PMBXCGGQNSVESQ-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 108090001005 Interleukin-6 Proteins 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 4
- 229910052802 copper Inorganic materials 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- RUBQQRMAWLSCCJ-UHFFFAOYSA-N 1,2-difluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1 RUBQQRMAWLSCCJ-UHFFFAOYSA-N 0.000 description 3
- XGLVDUUYFKXKPL-UHFFFAOYSA-N 2-(2-methoxyethoxy)-n,n-bis[2-(2-methoxyethoxy)ethyl]ethanamine Chemical compound COCCOCCN(CCOCCOC)CCOCCOC XGLVDUUYFKXKPL-UHFFFAOYSA-N 0.000 description 3
- MCYJINKNZSJACB-UHFFFAOYSA-N 2-fluoro-4-nitro-1-phenoxybenzene Chemical compound FC1=CC([N+](=O)[O-])=CC=C1OC1=CC=CC=C1 MCYJINKNZSJACB-UHFFFAOYSA-N 0.000 description 3
- JFPJVTNYCURRAB-UHFFFAOYSA-N 2-nitro-n-phenylacetamide Chemical compound [O-][N+](=O)CC(=O)NC1=CC=CC=C1 JFPJVTNYCURRAB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- 229960001413 acetanilide Drugs 0.000 description 3
- 230000000397 acetylating effect Effects 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- 238000006266 etherification reaction Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 150000002828 nitro derivatives Chemical class 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- CRBJBYGJVIBWIY-UHFFFAOYSA-N 2-isopropylphenol Chemical compound CC(C)C1=CC=CC=C1O CRBJBYGJVIBWIY-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- YQUQWHNMBPIWGK-UHFFFAOYSA-N 4-isopropylphenol Chemical compound CC(C)C1=CC=C(O)C=C1 YQUQWHNMBPIWGK-UHFFFAOYSA-N 0.000 description 2
- ZSBDGXGICLIJGD-UHFFFAOYSA-N 4-phenoxyphenol Chemical compound C1=CC(O)=CC=C1OC1=CC=CC=C1 ZSBDGXGICLIJGD-UHFFFAOYSA-N 0.000 description 2
- 102000055006 Calcitonin Human genes 0.000 description 2
- 108060001064 Calcitonin Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 2
- 239000005751 Copper oxide Substances 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- CEKILAKGGFRTKU-UHFFFAOYSA-N [2-(4-amino-2-methylsulfanyl-5-nitrophenoxy)phenyl]-phenylmethanone Chemical compound CSC1=CC(N)=C([N+]([O-])=O)C=C1OC1=CC=CC=C1C(=O)C1=CC=CC=C1 CEKILAKGGFRTKU-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- LLEMOWNGBBNAJR-UHFFFAOYSA-N biphenyl-2-ol Chemical compound OC1=CC=CC=C1C1=CC=CC=C1 LLEMOWNGBBNAJR-UHFFFAOYSA-N 0.000 description 2
- YXVFYQXJAXKLAK-UHFFFAOYSA-N biphenyl-4-ol Chemical compound C1=CC(O)=CC=C1C1=CC=CC=C1 YXVFYQXJAXKLAK-UHFFFAOYSA-N 0.000 description 2
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 2
- 229960004015 calcitonin Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229910000431 copper oxide Inorganic materials 0.000 description 2
- 150000003983 crown ethers Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- JYVHOGDBFNJNMR-UHFFFAOYSA-N hexane;hydrate Chemical compound O.CCCCCC JYVHOGDBFNJNMR-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 230000019189 interleukin-1 beta production Effects 0.000 description 2
- 230000018276 interleukin-1 production Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
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- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、サイトカイン類のイン
ターロイキン−１（ＩＬ−１）及びインターロイキン−
６（ＩＬ−６）産生阻害作用を有し、これらサイトカイ
ンに起因する疾患の治療剤、例えば、抗炎症剤、慢性関
節リウマチなどに対する自己免疫疾患治療剤及び骨粗鬆
症などに対する骨疾患治療剤として有用な５−アルキル
チオ−４−アリールオキシニトロアニリン化合物に関す
る。TECHNICAL FIELD The present invention relates to cytokines of interleukin-1 (IL-1) and interleukin-.
It is useful as a therapeutic agent for diseases caused by these cytokines, such as an anti-inflammatory agent, an autoimmune disease therapeutic agent for rheumatoid arthritis, etc., and a bone disease therapeutic agent for osteoporosis etc. It relates to 5-alkylthio-4-aryloxynitroaniline compounds.
【０００２】[0002]
【従来の技術】従来、非ステロイド性抗炎症剤（ＮＳＡ
ＩＤ）はシクロオキシゲナーゼ阻害作用によるプロスタ
グランジン（ＰＧ）生合成阻害作用を作用機序とするも
のであり、解熱・鎮痛・抗炎症作用を主たる薬理作用と
して各種の炎症性・疼痛性疾患に繁用されてきた。2. Description of the Related Art Conventionally, non-steroidal anti-inflammatory drugs (NSA)
ID) has a prostaglandin (PG) biosynthesis inhibitory action by a cyclooxygenase inhibitory action as a mechanism of action, and is widely used for various inflammatory / painful diseases as a pharmacological action mainly having antipyretic / analgesic / anti-inflammatory action. It has been.
【０００３】また、慢性関節リウマチなどに対しては対
症療法的な目的でＮＳＡＩＤ、原因療法的な目的で免疫
調節剤（ＤＭＡＲＤ）が使用されている。NSAIDs are used for symptomatic treatment of rheumatoid arthritis and the like, and immunomodulators (DMARDs) are used for causal therapy.
【０００４】さらに、骨粗鬆症は閉経後骨粗鬆症と老人
性骨粗鬆症に分類されるが、閉経後骨粗鬆症の原因は、
閉経後のエストロジェン喪失が骨吸収を過度に促進する
ことにあることから、閉経後骨粗鬆症に対する第一選択
治療剤としてはカルシトニンやエストロジェンなどの骨
吸収抑制剤が使用されている。Further, although osteoporosis is classified into postmenopausal osteoporosis and senile osteoporosis, the causes of postmenopausal osteoporosis are:
Since postmenopausal loss of estrogen promotes excessive bone resorption, bone resorption inhibitors such as calcitonin and estrogen are used as the first-line therapeutic agent for postmenopausal osteoporosis.
【０００５】[0005]
【発明が解決しようとする課題】従来のＮＳＡＩＤはそ
の作用機序から胃潰瘍などの消化管障害を惹起し、長期
の連続使用において問題点を有している。また、ＤＭＡ
ＲＤは未だ薬効と副作用の分離が十分ではない。さら
に、カルシトニンは筋肉注射による投与に限られること
や耐性化しやすいという問題が上げられ、エストロジェ
ンは乳ガン、子宮内膜ガンの発生率が増加するという問
題がある。このように、現在まで満足できる薬剤は開発
されていない。Conventional NSAIDs cause gastrointestinal disorders such as gastric ulcers due to their mechanism of action, and have problems in long-term continuous use. Also, DMA
RD still has insufficient separation of drug efficacy and side effects. Further, calcitonin has problems that it is limited to administration by intramuscular injection and that it tends to be resistant, and estrogen has a problem that the incidence of breast cancer and endometrial cancer increases. Thus, no satisfactory drug has been developed to date.
【０００６】近年、免疫担当細胞が産生するサイトカイ
ンと総称される活性物質が見い出されてきている。その
中でＩＬ−１、ＩＬ−６、腫瘍壊死因子などは炎症性サ
イトカインと呼ばれ、ＰＧの代謝産生系であるアラキド
ン酸代謝系の活性化、白血球の遊走、急性期蛋白の誘導
など炎症メディエーターとしての多彩な働きが解明され
てきおり、これら炎症性サイトカインの産生阻害剤は従
来とは異なった作用機序による新世代の抗炎症剤、慢性
関節リウマチなどに対する自己免疫疾患治療剤として期
待されている。更にＩＬ−１やＩＬ−６は、破骨細胞形
成促進因子としても知られており、その産生抑制剤は閉
経後骨粗鬆症治療剤として期待されている。しかしなが
ら、ＩＬ−１及びＩＬ−６産生阻害作用を有する、有用
な抗炎症剤、慢性関節リウマチなどに対する自己免疫疾
患治療剤及び骨粗鬆症などに対する骨疾患治療剤は見い
だされていない。In recent years, active substances generally called cytokines produced by immunocompetent cells have been found. Among them, IL-1, IL-6, tumor necrosis factor, etc. are called inflammatory cytokines, and are inflammatory mediators such as activation of arachidonic acid metabolism system, which is a metabolic production system of PG, migration of leukocytes, induction of acute phase proteins. These inflammatory cytokine production inhibitors are expected to be used as a new-generation anti-inflammatory drug with a different mechanism of action and as a therapeutic agent for autoimmune diseases against rheumatoid arthritis, etc. I have. Further, IL-1 and IL-6 are also known as osteoclast formation promoting factors, and their production inhibitors are expected as therapeutic agents for postmenopausal osteoporosis. However, a useful anti-inflammatory agent, an autoimmune disease therapeutic agent for rheumatoid arthritis and the like and a bone disease therapeutic agent for osteoporosis and the like, which have IL-1 and IL-6 production inhibitory effects, have not been found.
【０００７】[0007]
【課題を解決するための手段】本発明者らは、ＩＬ−１
及びＩＬ−６産生阻害作用を有する、有用な抗炎症剤、
慢性関節リウマチなどに対する自己免疫疾患治療剤及び
骨粗鬆症などに対する骨疾患治療剤を提供することを目
的に鋭意検討した結果、下記の５−アルキルチオ−４−
アリールオキシニトロアニリン化合物がその目的を達成
できることを見いだし、本発明を完成した。The present inventors have found that IL-1
And a useful anti-inflammatory agent having an IL-6 production inhibitory effect,
As a result of extensive studies aimed at providing a therapeutic agent for autoimmune diseases such as rheumatoid arthritis and a therapeutic agent for bone diseases such as osteoporosis, the following 5-alkylthio-4-
The inventors have found that an aryloxynitroaniline compound can achieve the object, and completed the present invention.
【０００８】すなわち、本発明は、式（Ｉ）That is, the present invention relates to a compound of the formula (I)
【０００９】[0009]
【化２】 Embedded image
【００１０】［式中、Ｒ1は未置換もしくはハロゲン原
子、炭素原子数１〜８個のアルキル基、フェニル基、フ
ェノキシ基、ベンジル基、ベンゾイル基、炭素原子数２
〜６個のアルコキシカルボニル基またはカルボキシル基
から選ばれる置換基により１箇所または２箇所を置換さ
れた、フェニル基またはテトラヒドロナフチル基であ
る。Ｒ2は炭素原子数１〜８個のアルキル基または炭素
原子数５〜８個のシクロアルキル基である。Ｘは−Ｓ
−、−ＳＯ−または−ＳＯ2−で示される基である。］
で表される５−アルキルチオ−４−アリールオキシニト
ロアニリン化合物またはその塩である。[In the formula, R 1 is an unsubstituted or halogen atom, an alkyl group having 1 to 8 carbon atoms, a phenyl group, a phenoxy group, a benzyl group, a benzoyl group, or a carbon atom having 2 carbon atoms.
Is a phenyl group or a tetrahydronaphthyl group substituted at one or two positions with a substituent selected from 6 alkoxycarbonyl groups or carboxyl groups. R 2 is an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 5 to 8 carbon atoms. X is -S
-, - SO- or -SO 2 - is a group represented by the. ]
Is a 5-alkylthio-4-aryloxynitroaniline compound or a salt thereof.
【００１１】本発明においてハロゲン原子とはフッ素原
子、塩素原子、臭素原子またはヨウ素原子である。炭素
原子数１〜８個のアルキル基とは、直鎖状または分岐鎖
状のアルキル基であり、例えば、メチル基、エチル基、
ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソ
ブチル基、ｔ−ブチル基、ｎ−ペンチル基、ｔ−ペンチ
ル基、ｎ−ヘキシル基、ｎ−ヘプチル基、ｎ−オクチル
基などである。炭素原子数２〜６個のアルコキシカルボ
ニル基とは、直鎖状または分岐鎖状のアルコキシカルボ
ニル基であり、例えば、メトキシカルボニル基、エトキ
シカルボニル基、ｎ−プロポキシカルボニル基、イソプ
ロポキシカルボニル基、ｎ−ブトキシカルボニル基、ｔ
−ブトキシカルボニル基、ｎ−ペンチルオキシカルボニ
ル基などである。テトラヒドロナフチル基とは、１−テ
トラヒドロナフチル基または２−テトラヒドロナフチル
基である。炭素原子数５〜８個のシクロアルキル基と
は、シクロペンチル基、シクロヘキシル基、シクロヘプ
チル基またはシクロオクチル基である。In the present invention, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The alkyl group having 1 to 8 carbon atoms is a linear or branched alkyl group, for example, a methyl group, an ethyl group,
Examples thereof include n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, t-pentyl group, n-hexyl group, n-heptyl group and n-octyl group. The alkoxycarbonyl group having 2 to 6 carbon atoms is a linear or branched alkoxycarbonyl group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, and n. -Butoxycarbonyl group, t
-Butoxycarbonyl group, n-pentyloxycarbonyl group and the like. The tetrahydronaphthyl group is a 1-tetrahydronaphthyl group or a 2-tetrahydronaphthyl group. The cycloalkyl group having 5 to 8 carbon atoms is a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group.
【００１２】また、本発明において塩とは生体内で無害
の無機酸または有機酸との塩である。In the present invention, the salt is a salt with an inorganic acid or an organic acid, which is harmless in vivo.
【００１３】本発明の化合物（Ｉ）は、以下に示す方法
によって製造することができる。The compound (I) of the present invention can be produced by the method shown below.
【００１４】（１）本発明の化合物（Ｉ）において、Ｒ
1が無置換またはハロゲン原子、炭素原子数１〜８個の
アルキル基、フェニル基、フェノキシ基、ベンジル基、
ベンゾイル基または炭素原子数２〜６個のアルコキシカ
ルボニル基により、１箇所または２箇所置換されたフェ
ニル基またはテトラヒドロナフチル基であり、Ｘが−Ｓ
−で示される基である化合物（Ｉａ）は、例えば、下記
の反応式で示す方法によって得ることができる。(1) In the compound (I) of the present invention, R
1 is an unsubstituted or halogen atom, an alkyl group having 1 to 8 carbon atoms, a phenyl group, a phenoxy group, a benzyl group,
A phenyl group or a tetrahydronaphthyl group substituted at one or two positions with a benzoyl group or an alkoxycarbonyl group having 2 to 6 carbon atoms, and X is -S
The compound (Ia), which is a group represented by-, can be obtained, for example, by the method represented by the following reaction formula.
【００１５】［反応式］[Reaction formula]
【００１６】[0016]
【化３】 Embedded image
【００１７】［反応式中、Ｒ2は前記と同意義であり、
Ｒ3は無置換またはハロゲン原子、炭素原子数１〜８個
のアルキル基、フェニル基、フェノキシ基、ベンジル
基、ベンゾイル基または炭素原子数２〜６個のアルコキ
シカルボニル基から選ばれる置換基により１箇所または
２箇所置換されたフェニル基またはテトラヒドロナフチ
ル基であり、Ｚはハロゲン原子である。］ 以下に前記反応式の詳細な説明を反応順に示す。[In the reaction formula, R 2 has the same meaning as described above,
R 3 is 1 or less by a substituent selected from a halogen atom, an alkyl group having 1 to 8 carbon atoms, a phenyl group, a phenoxy group, a benzyl group, a benzoyl group, or an alkoxycarbonyl group having 2 to 6 carbon atoms. A phenyl group or a tetrahydronaphthyl group substituted at two or two positions, and Z is a halogen atom. ] The following is a detailed description of the above reaction formula in the order of reactions.
【００１８】（ａ）３，４−ジハロニトロベンゼン（Ｉ
Ｉ）を出発原料として塩基存在下アルコール化合物（Ｉ
ＩＩ）を反応させることにより、４−ニトロフェニルエ
ーテル化合物（ＩＶ）を得ることができる。(A) 3,4-dihalonitrobenzene (I
Alcohol compound (I
By reacting II), 4-nitrophenyl ether compound (IV) can be obtained.
【００１９】本反応に使用する塩基としては、水酸化リ
チウム、水酸化ナトリウム、水酸化カリウムなどのアル
カリ金属水酸化物、炭酸リチウム、炭酸ナトリウム、炭
酸カリウムなどのアルカリ金属炭酸塩、炭酸水素ナトリ
ウム、炭酸水素カリウムなどのアルカリ金属炭酸水素
塩、水素化ナトリウム、水素化カリウムなどのアルカリ
金属水素化物、金属ナトリウム、金属カリウム、ナトリ
ウムアミドなどの無機塩基、トリエチルアミン、ジイソ
プロピルエチルアミン、トリ−ｎ−ブチルアミン、１，
５−ジアザビシクロ［４．３．０］−５−ノネン、１，
８−ジアザビシクロ［５．４．０］−７−ウンデセン、
ピリジン、Ｎ，Ｎ−ジメチルアミノピリジンなどの有機
塩基などがあげられる。As the base used in this reaction, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, sodium hydrogen carbonate, Alkali metal hydrogen carbonates such as potassium hydrogen carbonate, sodium hydride, alkali metal hydrides such as potassium hydride, inorganic bases such as sodium metal, potassium metal, sodium amide, triethylamine, diisopropylethylamine, tri-n-butylamine, 1 ，
5-diazabicyclo [4.3.0] -5-nonene, 1,
8-diazabicyclo [5.4.0] -7-undecene,
Examples thereof include organic bases such as pyridine and N, N-dimethylaminopyridine.
【００２０】本反応は、適当な溶媒中で行うことができ
る。使用する溶媒としては、メタノール、エタノール、
ｎ−プロパノール、イソプロパノール、ｎ−ブタノー
ル、ｔ−ブタノール、ジオキサン、テトラヒドロフラ
ン、エチルエーテル、石油エーテル、ｎ−ヘキサン、シ
クロヘキサン、ベンゼン、トルエン、キシレン、クロロ
ベンゼン、ピリジン、酢酸エチル、Ｎ，Ｎ−ジメチルホ
ルムアミド、ジメチルスルホキシド、ジクロロエタン、
クロロホルム、四塩化炭素、水などがあげられる。This reaction can be carried out in a suitable solvent. Solvents used include methanol, ethanol,
n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, ethyl acetate, N, N-dimethylformamide, Dimethyl sulfoxide, dichloroethane,
Examples include chloroform, carbon tetrachloride and water.
【００２１】本反応においては、銅、酸化銅、ハロゲン
化銅、ヨウ化カリウム、トリス［２−（２−メトキシエ
トキシ）エチル］アミン、テトラ−ｎ−ブチルアンモニ
ウムクロリド、テトラ−ｎ−ブチルアンモニウムブロミ
ド、ベンジルトリエチルアンモニウムクロリド、ベンジ
ルトリエチルアンモニウムブロミド、トリカプチルメチ
ルアンモニウムクロリドなどの４級アンモニウム塩、１
８−クラウン−６ エーテルなどのクラウンエーテルな
どを任意に加えることにより反応を加速することもでき
る。In this reaction, copper, copper oxide, copper halide, potassium iodide, tris [2- (2-methoxyethoxy) ethyl] amine, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide. , Benzyltriethylammonium chloride, benzyltriethylammonium bromide, tricaptylmethylammonium chloride and other quaternary ammonium salts, 1
The reaction can also be accelerated by optionally adding a crown ether such as 8-crown-6 ether.
【００２２】（ｂ）４−ニトロフェニルエーテル化合物
（ＩＶ）のニトロ基を還元してアミノ基とすることによ
り、４−アミノフェニルエーテル化合物（Ｖ）を得るこ
とができる。引続き、化合物（Ｖ）は単離精製すること
なくアミノ基をアセチル化することにより、アセトアニ
リド化合物（ＶＩ）を得ることができる。(B) The 4-aminophenyl ether compound (V) can be obtained by reducing the nitro group of the 4-nitrophenyl ether compound (IV) to an amino group. Subsequently, the acetoanilide compound (VI) can be obtained by acetylating the amino group of the compound (V) without isolation and purification.
【００２３】還元はニトロ基を還元してアミノ基とする
通常の還元方法でよく、例えば、パラジウム−炭素、ラ
ネーニッケル、白金などを触媒として使用する接触還
元、鉄や錫を使用する還元、硫化ナトリウム−塩化アン
モニウムを使用する還元、水素化ホウ素ナトリウム、水
素化リチウムアルミニウムなどを使用する還元などがあ
げられる。The reduction may be carried out by a conventional reduction method in which a nitro group is reduced to an amino group, for example, catalytic reduction using palladium-carbon, Raney nickel, platinum, etc. as a catalyst, reduction using iron or tin, sodium sulfide. -Reduction using ammonium chloride, reduction using sodium borohydride, lithium aluminum hydride and the like.
【００２４】本反応に使用する溶媒としては、還元方法
により任意に選択すればよく、一般的にはメタノール、
エタノール、ｎ−プロパノール、イソプロパノール、ｎ
−ブタノール、ｔ−ブタノールなどのアルコール、水、
酢酸、酢酸エチル、ジオキサン、テトラヒドロフラン、
アセトニトリルなどがあげられる。The solvent used in this reaction may be arbitrarily selected according to the reduction method, and generally, methanol,
Ethanol, n-propanol, isopropanol, n
Alcohols such as butanol, t-butanol, water,
Acetic acid, ethyl acetate, dioxane, tetrahydrofuran,
Acetonitrile and the like.
【００２５】アセチル化はアニリンをアセチル化する通
常の方法でよく、アセチル化剤としては酢酸、アセチル
クロリド、アセチルブロミド、無水酢酸などがあげられ
る。Acetylation may be carried out by a conventional method for acetylating aniline, and examples of the acetylating agent include acetic acid, acetyl chloride, acetyl bromide, acetic anhydride and the like.
【００２６】本反応に使用する溶媒としては、還元反応
に使用した溶媒またはエチルエーテル、石油エーテル、
ｎ−ヘキサン、シクロヘキサン、ベンゼン、トルエン、
キシレン、クロロベンゼン、ピリジン、Ｎ，Ｎ−ジメチ
ルホルムアミド、ジメチルスルホキシド、ジクロロエタ
ン、クロロホルム、四塩化炭素、水、酢酸、硫酸などが
あげられる。As the solvent used in this reaction, the solvent used in the reduction reaction or ethyl ether, petroleum ether,
n-hexane, cyclohexane, benzene, toluene,
Xylene, chlorobenzene, pyridine, N, N-dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform, carbon tetrachloride, water, acetic acid, sulfuric acid and the like.
【００２７】（ｃ）アセトアニリド化合物（ＶＩ）をニ
トロ化することにより、２−ニトロアセトアニリド化合
物（ＶＩＩ）を得ることができる。(C) The 2-nitroacetanilide compound (VII) can be obtained by nitrating the acetanilide compound (VI).
【００２８】本反応に使用するニトロ化剤としては、硝
酸、発煙硝酸、硝酸ナトリウム、硝酸カリウム、硝酸
鉄、硝酸ウレアなどがあげられる。Examples of the nitrating agent used in this reaction include nitric acid, fuming nitric acid, sodium nitrate, potassium nitrate, iron nitrate and urea nitrate.
【００２９】使用する溶媒は、ニトロ化剤に応じて任意
に選択するが、好ましくは酢酸、無水酢酸、トリフルオ
ロ酢酸、硫酸、ジクロロエタン、クロロホルム、四塩化
炭素、ベンゼン、トルエン、ジオキサン、エタノール、
ｎ−プロパノール、イソプロパノールなどがあげられ
る。The solvent used is arbitrarily selected according to the nitrating agent, but preferably acetic acid, acetic anhydride, trifluoroacetic acid, sulfuric acid, dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, dioxane, ethanol,
Examples include n-propanol and isopropanol.
【００３０】（ｄ）２−ニトロアセトアニリド化合物
（ＶＩＩ）に塩基存在下チオール化合物（ＶＩＩＩ）を
反応させることにより、化合物（ＩＸ）を得ることがで
きる。化合物（ＩＸ）は、反応系内で引続き、もしくは
単離後加水分解することにより、本発明の化合物（Ｉ
ａ）を得ることができる。(D) The compound (IX) can be obtained by reacting the 2-nitroacetanilide compound (VII) with the thiol compound (VIII) in the presence of a base. The compound (IX) can be produced by subjecting the compound (I) of the present invention to hydrolysis in the reaction system, or by hydrolysis after isolation.
a) can be obtained.
【００３１】本反応に使用する塩基としては、水酸化リ
チウム、水酸化ナトリウム、水酸化カリウムなどのアル
カリ金属水酸化物、炭酸リチウム、炭酸ナトリウム、炭
酸カリウムなどのアルカリ金属炭酸塩、炭酸水素ナトリ
ウム、炭酸水素カリウムなどのアルカリ金属炭酸水素
塩、水素化ナトリウム、水素化カリウムなどのアルカリ
金属水素化物、金属ナトリウム、金属カリウム、ナトリ
ウムアミドなどの無機塩基またはトリエチルアミン、ジ
イソプロピルエチルアミン、トリ−ｎ−ブチルアミン、
１，５−ジアザビシクロ［４．３．０］−５−ノネン、
１，８−ジアザビシクロ［５．４．０］−７−ウンデセ
ン、ピリジン、Ｎ，Ｎ−ジメチルアミノピリジンなどの
有機塩基などがあげられる。Examples of the base used in this reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, sodium hydrogen carbonate, Alkali metal hydrogencarbonates such as potassium hydrogen carbonate, sodium hydride, alkali metal hydrides such as potassium hydride, inorganic bases such as sodium metal, potassium metal, sodium amide or triethylamine, diisopropylethylamine, tri-n-butylamine,
1,5-diazabicyclo [4.3.0] -5-nonene,
Examples include organic bases such as 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine, and N, N-dimethylaminopyridine.
【００３２】本反応は、適当な溶媒中で行うことができ
る。使用する溶媒としては、メタノール、エタノール、
ｎ−プロパノール、イソプロパノール、ｎ−ブタノー
ル、ｔ−ブタノール、ジオキサン、テトラヒドロフラ
ン、エチルエーテル、石油エーテル、ｎ−ヘキサン、シ
クロヘキサン、ベンゼン、トルエン、キシレン、クロロ
ベンゼン、ピリジン、酢酸エチル、Ｎ，Ｎ−ジメチルホ
ルムアミド、ジメチルスルホキシド、ジクロロエタン、
クロロホルム、四塩化炭素、水などがあげられる。This reaction can be carried out in a suitable solvent. Solvents used include methanol, ethanol,
n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, ethyl acetate, N, N-dimethylformamide, Dimethyl sulfoxide, dichloroethane,
Examples include chloroform, carbon tetrachloride and water.
【００３３】本反応においては、銅、酸化銅、ハロゲン
化銅、ヨウ化カリウム、トリス［２−（２−メトキシエ
トキシ）エチル］アミン、テトラ−ｎ−ブチルアンモニ
ウムクロリド、テトラ−ｎ−ブチルアンモニウムブロミ
ド、ベンジルトリエチルアンモニウムクロリド、ベンジ
ルトリエチルアンモニウムブロミド、トリカプチルメチ
ルアンモニウムクロリドなどの４級アンモニウム塩、１
８−クラウン−６ エーテルなどのクラウンエーテルな
どを任意に加えることにより反応を加速することもでき
る。In this reaction, copper, copper oxide, copper halide, potassium iodide, tris [2- (2-methoxyethoxy) ethyl] amine, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide. , Benzyltriethylammonium chloride, benzyltriethylammonium bromide, tricaptylmethylammonium chloride and other quaternary ammonium salts, 1
The reaction can also be accelerated by optionally adding a crown ether such as 8-crown-6 ether.
【００３４】また、加水分解は塩基性条件または酸性条
件における通常のアミドの加水分解方法であり、反応系
内で引続き加水分解する場合は、塩基性条件が好まし
く、塩基としては、水酸化リチウム、水酸化ナトリウ
ム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、
ナトリウムメトキシド、ナトリウムエトキシド、ｔ−ブ
トキシカリウムなどがあげられる。また、酸性条件の場
合は、塩酸、臭化水素酸、硫酸などの酸を使用する方法
があげられる。Further, the hydrolysis is a usual amide hydrolysis method under basic or acidic conditions. When the hydrolysis is continued in the reaction system, the basic conditions are preferable, and the base is lithium hydroxide, Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
Examples thereof include sodium methoxide, sodium ethoxide, potassium t-butoxide and the like. In the case of acidic conditions, a method of using an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or the like can be mentioned.
【００３５】本反応で使用する溶媒は、加水分解条件に
より任意に選択すればよく、水、メタノール、エタノー
ル、プロパノール、ｔ−ブタノール、テトラヒドロフラ
ン、ジオキサン、ベンゼン、トルエン、キシレン、クロ
ロベンゼン、Ｎ，Ｎ−ジメチルホルムアミド、ジメチル
スルホキシド、蟻酸、酢酸などが好ましい。The solvent used in this reaction may be arbitrarily selected depending on the hydrolysis conditions, such as water, methanol, ethanol, propanol, t-butanol, tetrahydrofuran, dioxane, benzene, toluene, xylene, chlorobenzene, N, N-. Dimethylformamide, dimethylsulfoxide, formic acid, acetic acid and the like are preferable.
【００３６】（２）化合物（Ｉ）において、Ｒ1がカル
ボキシル基の置換したフェニル基であり、Ｘが−Ｓ−で
示される基である化合物（Ｉｂ）は、化合物（Ｉａ）の
Ｒ1が炭素原子数２〜６個のアルコキシカルボニル基に
より１箇所または２箇所置換されたフェニル基である本
発明の化合物を加水分解して得ることができる。[0036] In (2) Compound (I), a phenyl group R 1 is substituted carboxyl group, compounds wherein X is a group represented by -S- (Ib) is, by R 1 of the compound (Ia) It can be obtained by hydrolyzing the compound of the present invention, which is a phenyl group substituted at one or two positions with an alkoxycarbonyl group having 2 to 6 carbon atoms.
【００３７】加水分解は、塩基性条件あるいは酸性条件
における通常のアミドの加水分解方法であり、反応系内
で引続き加水分解する場合は、塩基性条件が好ましく、
塩基としては水酸化リチウム、水酸化ナトリウム、水酸
化カリウム、炭酸ナトリウム、炭酸カリウム、ナトリウ
ムメトキシド、ナトリウムエトキシド、ｔ−ブトキシカ
リウムなどがあげられる。また、酸性条件の場合は、塩
酸、臭化水素酸、硫酸などの酸を使用する方法があげら
れる。Hydrolysis is a usual method for hydrolyzing an amide under basic conditions or acidic conditions, and in the case of continuing hydrolysis in the reaction system, basic conditions are preferable,
Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium t-butoxide and the like. In the case of acidic conditions, a method of using an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or the like can be mentioned.
【００３８】本反応で使用する溶媒は、加水分解条件に
より任意に選択すればよく、水、メタノール、エタノー
ル、プロパノール、ｔ−ブタノール、テトラヒドロフラ
ン、ジオキサン、ベンゼン、トルエン、キシレン、クロ
ロベンゼン、Ｎ，Ｎ−ジメチルホルムアミド、ジメチル
スルホキシド、蟻酸、酢酸などの溶媒があげられる。The solvent used in this reaction may be arbitrarily selected depending on the hydrolysis conditions, and is water, methanol, ethanol, propanol, t-butanol, tetrahydrofuran, dioxane, benzene, toluene, xylene, chlorobenzene, N, N-. Solvents such as dimethylformamide, dimethylsulfoxide, formic acid, acetic acid, etc.
【００３９】（３）本発明の化合物（Ｉ）において、Ｘ
が−ＳＯ−または−ＳＯ2−で示される基である化合物
は、例えば、前記（１）または（２）の方法で得ること
ができる化合物（１ａ）または（Ｉｂ）を酸化すること
により得ることができる。(3) In the compound (I) of the present invention, X
The compound wherein is a group represented by —SO— or —SO 2 — is obtained by, for example, oxidizing the compound (1a) or (Ib) obtainable by the above method (1) or (2). You can
【００４０】酸化は、スルフィドを酸化してスルホキシ
ドまたはスルホンとする通常の酸化反応もしくはスルホ
キシドを酸化してスルホンとする通常の酸化反応であ
り、例えば、過酸化水素、ｔ−ブチルハイドロパーオキ
シド、メタクロロ過安息香酸、過酢酸、メタ過ヨウ素酸
ナトリウム、亜臭素酸ナトリウム、次亜塩素酸ナトリウ
ム、過ヨードベンゼンなどを使用する方法などがあげら
れる。Oxidation is a usual oxidation reaction that oxidizes a sulfide to a sulfoxide or sulfone or a normal oxidation reaction that oxidizes a sulfoxide to a sulfone, such as hydrogen peroxide, t-butyl hydroperoxide, and metachloro. Examples thereof include a method using perbenzoic acid, peracetic acid, sodium metaperiodate, sodium bromate, sodium hypochlorite, periodobenzene and the like.
【００４１】本反応で使用する溶媒は、メタノール、エ
タノール、ｎ−プロパノール、イソプロパノール、ジク
ロロメタン、クロロホルム、四塩化炭素、ジオキサン、
テトラヒドロフラン、アセトン、アセトニトリル、酢酸
エチル、エチルエーテル、石油エーテル、ｎ−ヘキサ
ン、シクロヘキサン、ベンゼン、トルエン、キシレン、
クロロベンゼン、ピリジン、Ｎ，Ｎ−ジメチルホルムア
ミド、水などがあげられる。The solvent used in this reaction is methanol, ethanol, n-propanol, isopropanol, dichloromethane, chloroform, carbon tetrachloride, dioxane,
Tetrahydrofuran, acetone, acetonitrile, ethyl acetate, ethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene,
Chlorobenzene, pyridine, N, N-dimethylformamide, water and the like can be mentioned.
【００４２】本発明の化合物は、経口または非経口的に
慣用の投与剤型で投与することができる。これらは、例
えば、錠剤、顆粒剤、散剤、カプセル剤、液剤、乳剤、
懸濁剤、注射剤などであり、いずれも通常の方法により
製造することができる。人に対して抗炎症剤、慢性関節
リウマチなどに対する自己免疫疾患治療剤及び骨粗鬆症
などに対する骨疾患治療剤として使用する場合、その投
与量は、年齢、体重、症状、投与経路、投与回数などに
よって異なるが、通常１日当り１〜１０００ｍｇであ
る。The compounds of the present invention can be administered orally or parenterally in conventional dosage forms. These include, for example, tablets, granules, powders, capsules, solutions, emulsions,
Suspensions, injections, etc., all of which can be produced by ordinary methods. When used as an anti-inflammatory agent for humans, an autoimmune disease therapeutic agent for rheumatoid arthritis etc. and a bone disease therapeutic agent for osteoporosis etc., the dose varies depending on age, weight, symptoms, administration route, number of administrations, etc. Is usually 1-1000 mg per day.
【００４３】[0043]
【発明の効果】本発明の化合物は、後述の試験例から明
らかなようにＩＬ−１、ＩＬ−６産生阻害作用を有する
ので、ＩＬ−１、ＩＬ−６に起因する疾患の治療剤、例
えば、抗炎症剤、慢性関節リウマチなどに対する自己免
疫疾患治療剤及び骨粗鬆症などに対する骨疾患治療剤と
して有用である。EFFECTS OF THE INVENTION The compound of the present invention has an inhibitory effect on IL-1 and IL-6 production, as will be apparent from the test examples described below. Therefore, it is a therapeutic agent for diseases caused by IL-1 and IL-6, for example, , An anti-inflammatory agent, a therapeutic agent for autoimmune diseases such as rheumatoid arthritis, and a therapeutic agent for bone diseases such as osteoporosis.
【００４４】試験例ＩＬ−１β及びＩＬ−６産生阻害作用 ［試験方法］ヘパリン処理した正常人末梢血を無菌条件
下でリンホプレップ（商品名、第一製薬）に重層して赤
血球を除去後、細胞を牛胎児血清１０％、ペニシリン１
００Ｕ／ｍｌ、ストレプトマイシン１００Ｕ／ｍｌ、ヘ
ペス緩衝液１０ｍＭ及びＬ−グルタミン２ｍＭを加えた
ＲＰＭＩ−１６４０培地（商品名、ギブコ社）に浮遊さ
せて細胞数を２×１０6ｃｅｌｌｓ／ｍｌに調製した。Test Example IL-1β and IL-6 production inhibitory action [Test method] Heparin-treated normal peripheral blood was layered on lymphoprep (trade name, Daiichi Pharmaceutical Co., Ltd.) under sterile conditions to remove red blood cells, and then cells Fetal bovine serum 10%, penicillin 1
The number of cells was adjusted to 2 × 10 6 cells / ml by suspending the cells in RPMI-1640 medium (trade name, Gibco) supplemented with 00 U / ml, streptomycin 100 U / ml, hepes buffer 10 mM and L-glutamine 2 mM.
【００４５】調製した細胞浮遊液５００μｌ、ＣｏｎＡ
（シグマ社）２．０μｇ及び被験化合物（本発明化合
物）の上記培地溶液２５０μｌをマイクロプレート（平
底２４穴、イワキガラス社製）に添加し、５％ＣＯ2イ
ンキュベーターで４８時間培養した。検体の培地溶液は
検体をエタノールで溶解後、エタノールの最終濃度が
０．０５％になるように上記培地溶液で希釈することに
より調製した。培養後、細胞上清液中でＩＬ−１β及び
ＩＬ−６量（ｐｇ／ｍｌ）をＥＬＩＳＡキット（アマシ
ャム社）で測定し、その産生阻害率（％）を求めた。な
お、被験化合物の濃度は１あるいは３μｇ／ｍｌの濃度
とし、被験化合物の濃度を０に調製したものをコントロ
ールとした［阻害率（％）＝（１−Ｔ／Ｃ）×１００：
Ｔは被験化合物の各濃度におけるＩＬ−１βあるいは６
産生量、ＣはコントロールのＩＬ−１βあるいはＩＬ−
６産生量］。500 μl of the prepared cell suspension, ConA
2.0 μg (Sigma) and 250 μl of the above-mentioned medium solution of the test compound (compound of the present invention) were added to a microplate (flat bottom 24 holes, manufactured by Iwaki Glass Co., Ltd.) and cultured in a 5% CO 2 incubator for 48 hours. The medium solution of the sample was prepared by dissolving the sample with ethanol and then diluting with the above-mentioned medium solution so that the final concentration of ethanol became 0.05%. After the culture, the amount of IL-1β and IL-6 (pg / ml) was measured in the cell supernatant with an ELISA kit (Amersham) to determine the production inhibition rate (%). The concentration of the test compound was 1 or 3 μg / ml, and the concentration of the test compound adjusted to 0 was used as a control [inhibition rate (%) = (1-T / C) × 100:
T is IL-1β or 6 at each concentration of the test compound
Production amount, C is control IL-1β or IL-
6 production].
【００４６】［結果］試験結果を表１に示す。[Results] Table 1 shows the test results.
【００４７】[0047]
【表１】 [Table 1]
【００４８】[0048]
【実施例】以下に製造例を示して本発明をより具体的に
説明する。EXAMPLES The present invention will be described more specifically by showing production examples below.
【００４９】製造例１５−メチルチオ−２−ニトロ−４−フェノキシアニリン ａ）３−フルオロ−４−フェノキシニトロベンゼン フェノール１１０．６ｇに水酸化ナトリウム４５ｇを含
む水４２５ｍｌ溶液、次いで３、４−ジフルオロニトロ
ベンゼン８５ｇを順に加え、１．５時間加熱還流した。
反応液を室温に戻し、３規定塩酸を加え中和後トルエン
で抽出した。有機層を洗浄（水、５％水酸化ナトリウム
水溶液、水、飽和食塩水の順）、乾燥（無水硫酸マグネ
シウム）後、有機層を減圧下濃縮し、黄色結晶の３−フ
ルオロ−４−フェノキシニトロベンゼン１１８．８ｇ
（９５％）を得た。 ｍ．ｐ．６７．５〜６８．５℃。Production Example 1 5-Methylthio-2-nitro-4-phenoxyaniline a) 3-Fluoro-4- phenoxynitrobenzene 110.6 g of phenol and 45 g of sodium hydroxide in 425 ml of water, and then 3,4-difluoronitrobenzene. 85 g was sequentially added, and the mixture was heated under reflux for 1.5 hours.
The reaction solution was returned to room temperature, 3N hydrochloric acid was added thereto, and the mixture was neutralized and extracted with toluene. The organic layer was washed (water, 5% aqueous sodium hydroxide solution, water, saturated brine in this order), dried (anhydrous magnesium sulfate), and the organic layer was concentrated under reduced pressure to give yellow crystals of 3-fluoro-4-phenoxynitrobenzene. 118.8g
(95%) was obtained. m. p. 67.5-68.5 ° C.
【００５０】ｂ）３−フルオロ−４−フェノキシアセト
アニリド ３−フルオロ−４−フェノキシニトロベンゼン１１８．
７ｇ、鉄粉１７９．９ｇおよび塩化アンモニウム８．２
ｇを含む水溶液１５０ｍｌの混合物を８５℃で３時間加
熱撹拌した。反応液を室温に戻した後、イソプロパノー
ル５００ｍｌを加え、不溶物をセライト濾去した。濾液
に無水酢酸６２．５ｇを徐々に加えた後、室温で１０分
間撹拌した。反応液に水５００ｍｌを加え、析出物を濾
取、洗浄（水、ｎ−ヘキサンの順）し、無色結晶の３−
フルオロ−４−フェノキシアセトアニリド１０７．８ｇ
（８６％）を得た。 ｍ．ｐ．１１０〜１１１℃（一部をジエチルエーテル−
ｎ−ヘキサンから再結晶）。 B) 3-Fluoro-4-phenoxyacetate
Anilide 3-fluoro-4-phenoxynitrobenzene 118.
7 g, iron powder 179.9 g and ammonium chloride 8.2
The mixture of 150 ml of an aqueous solution containing g was heated and stirred at 85 ° C. for 3 hours. After the temperature of the reaction solution was returned to room temperature, 500 ml of isopropanol was added, and the insoluble matter was removed by filtration through celite. After gradually adding 62.5 g of acetic anhydride to the filtrate, the mixture was stirred at room temperature for 10 minutes. 500 ml of water was added to the reaction solution, and the precipitate was collected by filtration, washed (in the order of water and n-hexane) to give 3-colorless crystals.
107.8 g of fluoro-4-phenoxyacetanilide
(86%). m. p. 110-111 ° C (partially diethyl ether-
Recrystallized from n-hexane).
【００５１】ｃ）５−フルオロ−２−ニトロ−４−フェ
ノキシアセトアニリド ３−フルオロ−４−フェノキシアセトアニリド８７．２
ｇを含む酢酸３６０ｍｌ溶液に６０℃で加熱撹拌下発煙
硝酸２３．６ｇを徐々に加え、１時間撹拌した。反応液
を室温に戻し、水７５０ｍｌを加え、析出物を濾取、水
洗した。得られた結晶を酢酸エチル−ｎ−ヘキサンから
再結晶することにより、黄色結晶の５−フルオロ−２−
ニトロ−４−フェノキシアセトアニリド８９．３ｇ（８
６％）を得た。 ｍ．ｐ．１１６．５ 〜１１７．５℃。 C) 5-Fluoro-2-nitro-4-phen
Nonoxyacetanilide 3-fluoro-4-phenoxyacetanilide 87.2
23.6 g of fuming nitric acid was gradually added to a 360 ml acetic acid solution containing g under heating and stirring at 60 ° C., and the mixture was stirred for 1 hour. The reaction solution was returned to room temperature, 750 ml of water was added, and the precipitate was collected by filtration and washed with water. The resulting crystals were recrystallized from ethyl acetate-n-hexane to give 5-fluoro-2-yellow crystals.
89.3 g of nitro-4-phenoxyacetanilide (8
6%) was obtained. m. p. 116.5-117.5 ° C.
【００５２】ｄ）５−メチルチオ−２−ニトロ−４−フ
ェノキシアニリン（本発明の化合物） ５−フルオロ−２−ニトロ−４−フェニキシアセトアニ
リド３．０ｇを含むイソプロピルアルコール３０ｍｌ懸
濁液に１５％メチルメルカプタンナトリウム水溶液６．
８ｍｌを加え、６０℃で３時間加熱撹拌した。反応液を
室温に戻し、水を加え析出物を濾取した。得られた結晶
をイソプロパノールで再結晶することにより、橙色結晶
の５−メチルチオ−２−ニトロ−４−フェノキシアニリ
ン２．７ｇ（９６％）を得た。 ｍ．ｐ．１６０．５〜１６１℃。 D) 5-methylthio-2-nitro-4-ph
6. Enoxyaniline (compound of the present invention) A 15% aqueous solution of methylmercaptan sodium in a 30 ml suspension of isopropyl alcohol containing 3.0 g of 5-fluoro-2-nitro-4- phenoxyacetanilide .
8 ml was added, and the mixture was heated with stirring at 60 ° C. for 3 hours. The reaction solution was returned to room temperature, water was added, and the precipitate was collected by filtration. The obtained crystals were recrystallized from isopropanol to obtain 2.7 g (96%) of orange crystals of 5-methylthio-2-nitro-4-phenoxyaniline. m. p. 160.5-161 ° C.
【００５３】製造例２〜１６ａ）エーテル化合物 製造例１−ａ）で用いたフェノールの代わりに２−フル
オロフェノール、４−フルオロフェノール、４−クロロ
フェノール、４−ブロモフェノール、４−メチルフェノ
ール、２−イソプロピルフェノール、４−イソプロピル
フェノール、２−ベンジルフェノール、２−フェニルフ
ェノール、３−フェニルフェノール、４−フェニルフェ
ノール、４−フェノキシフェノール、２，４−ジフルオ
ロフェノール、５，６，７，８−テトラヒドロ−１−ナ
フトールあるいは５，６，７，８−テトラヒドロ−２−
ナフトールを用い、製造例１−ａ）の方法に準拠してエ
ーテル化することにより、表２に示したエーテル化合物
［製造例２−ａ）〜１６−ａ）の化合物］を得た。Production Examples 2 to 16 a) Ether Compound Instead of the phenol used in Production Example 1-a), 2-fluorophenol, 4-fluorophenol, 4-chlorophenol, 4-bromophenol, 4-methylphenol, 2-isopropylphenol, 4-isopropylphenol, 2-benzylphenol, 2-phenylphenol, 3-phenylphenol, 4-phenylphenol, 4-phenoxyphenol, 2,4-difluorophenol, 5,6,7,8- Tetrahydro-1-naphthol or 5,6,7,8-tetrahydro-2-
By etherification using naphthol according to the method of Production Example 1-a), the ether compounds shown in Table 2 [Compounds of Production Examples 2-a) to 16-a] were obtained.
【００５４】[0054]
【表２】 [Table 2]
【００５５】（注）表２中のＮＭＲ1)〜ＮＭＲ6)を以下
に示した。(Note) NMR 1) to NMR 6) in Table 2 are shown below.
【００５６】NMR1)(200MHz,CDCl3)δ:6.87(1H,m),7.10
〜7.40(4H,m),7.97(1H,m),8.08(1H,dd,J=2,10Hz)。NMR 1) (200MHz, CDCl 3 ) δ: 6.87 (1H, m), 7.10
~ 7.40 (4H, m), 7.97 (1H, m), 8.08 (1H, dd, J = 2,10Hz).
【００５７】NMR2)(200MHz,CDCl3)δ:2.37(3H,s),6.93
(1H,dd,J=8,8Hz),6.98(2H,m),7.23(2H,m),7.95(1H,m),
8.07(1H,dd,J=2,10Hz)。NMR 2) (200MHz, CDCl 3 ) δ: 2.37 (3H, s), 6.93
(1H, dd, J = 8,8Hz), 6.98 (2H, m), 7.23 (2H, m), 7.95 (1H, m),
8.07 (1H, dd, J = 2,10Hz).
【００５８】NMR3)(200MHz,CDCl3)δ:1.21(6H,d,J=6H
z),3.15(1H,m),6.83(1H,dd,J=10,10Hz),6.90〜7.00(1H,
m),7.18〜7.30(2H,m),7.40(1H,m),7.94(1H,m),8.10(1H,
dd,J=2,10Hz)。NMR 3) (200 MHz, CDCl 3 ) δ: 1.21 (6H, d, J = 6H
z), 3.15 (1H, m), 6.83 (1H, dd, J = 10,10Hz), 6.90 ~ 7.00 (1H,
m), 7.18 to 7.30 (2H, m), 7.40 (1H, m), 7.94 (1H, m), 8.10 (1H,
dd, J = 2,10Hz).
【００５９】NMR4)(200MHz,CDCl3)δ:1.26(6H,d,J=6H
z),2.95(1H,m),6.94(1H,t,J=10Hz),7.00(2H,m),7.28(2
H,m),7.95(1H,m),8.08(1H,dd,J=2,10Hz)。NMR 4) (200MHz, CDCl 3 ) δ: 1.26 (6H, d, J = 6H
z), 2.95 (1H, m), 6.94 (1H, t, J = 10Hz), 7.00 (2H, m), 7.28 (2
H, m), 7.95 (1H, m), 8.08 (1H, dd, J = 2,10Hz).
【００６０】NMR5)(200MHz,CDCl3)δ:3.95(2H,s),6.60
(1H,dd,J=8,10Hz),6.96(1H,dd,J=2,8Hz),7.07〜7.40(8
H,m),7.80(1H,m),8.04(1H,dd,J=2,10Hz)。NMR 5) (200MHz, CDCl 3 ) δ: 3.95 (2H, s), 6.60
(1H, dd, J = 8,10Hz), 6.96 (1H, dd, J = 2,8Hz), 7.07 ~ 7.40 (8
H, m), 7.80 (1H, m), 8.04 (1H, dd, J = 2,10Hz).
【００６１】NMR6)(200MHz,CDCl3)δ:7.00〜7.70(10H,
m),8.00(1H,m),8.11(1H,dd,J=2,8Hz)。NMR 6) (200 MHz, CDCl 3 ) δ: 7.00 to 7.70 (10H,
m), 8.00 (1H, m), 8.11 (1H, dd, J = 2,8Hz).
【００６２】ｂ）アセトアニリド化合物 エーテル化合物［製造例２−ａ）〜１６−ａ）の化合
物］を製造例１−ｂ）の方法に準拠して還元、アセチル
化することにより、表３に示したアセトアニリド化合物
［製造例２−ｂ）〜１６−ｂ）の化合物］を得た。 B) Acetanilide compounds Ether compounds [Compounds of Production Examples 2-a) to 16-a)] are reduced and acetylated according to the method of Production Example 1-b), and shown in Table 3. An acetanilide compound [compounds of Production Examples 2-b) to 16-b) was obtained.
【００６３】[0063]
【表３】 [Table 3]
【００６４】ｃ）ニトロ化合物 アセトアニリド化合物［製造例２−ｂ）〜１６−ｂ）の
化合物］を製造例１−ｃ）の方法に準拠してニトロ化す
ることにより、表４に示したニトロ化合物［製造例２−
ｃ）〜１６−ｃ）の化合物］を得た。 C) Nitro Compounds The nitro compounds shown in Table 4 are obtained by nitrating the acetanilide compounds [Compounds of Production Examples 2-b) to 16-b) according to the method of Production Example 1-c). [Production Example 2-
Compounds of c) to 16-c)] were obtained.
【００６５】[0065]
【表４】 [Table 4]
【００６６】（注）表４中のＮＭＲ7)を以下に示した。 NMR7)(200MHz,CDCl3)δ:1.25(6H,d,J=6Hz),2.30(3H,s),
3.26(1H,m),6.81(1H,m),7.19(2H,m),7.38(1H,m),7.74(1
H,d,J=6Hz),8.77(1H,d,J=12Hz)。(Note) NMR 7) in Table 4 is shown below. NMR 7) (200MHz, CDCl 3 ) δ: 1.25 (6H, d, J = 6Hz), 2.30 (3H, s),
3.26 (1H, m), 6.81 (1H, m), 7.19 (2H, m), 7.38 (1H, m), 7.74 (1
H, d, J = 6Hz), 8.77 (1H, d, J = 12Hz).
【００６７】ｄ）チオーテル化合物（本発明の化合物） ニトロ化合物［製造例２−ｃ）〜１６−ｃ）の化合物］
を製造例１−ｄ）の方法に準拠してチオエーテル化する
ことにより、表５に示した本発明のチオエーテル化合物
［製造例２）〜１６）の化合物］を得た。 D) Thiotel compound (compound of the present invention) nitro compound [Compounds of Production Examples 2-c) to 16-c]]
Was thioetherified in accordance with the method of Production Example 1-d) to obtain the thioether compounds of the present invention shown in Table 5 [Compounds of Production Examples 2) to 16)].
【００６８】[0068]
【表５】 [Table 5]
【００６９】製造例１７４−（２，４−ジ−ｔ−アミルフェノキシ）−５−メチ
ルチオ−２−ニトロアニリン ａ）４−（２，４−ジ−ｔ−アミルフェノキシ）−３−
フルオロニトロベンゼン ６０％水素化ナトリウム４．３ｇを含むテトラヒドロフ
ラン１６０ｍｌ懸濁液に２，４−ジ−ｔ−アミルフェノ
ール２５ｇを加え、３０分間撹拌後、３，４−ジフルオ
ロニトロベンゼン１１．３ｇを加え、３時間撹拌した。
反応液を室温に戻し、水を加えトルエンで抽出した。有
機層を洗浄（５％水酸化ナトリウム水溶液、水、飽和食
塩水の順）、乾燥（無水硫酸マグネシウム）後、有機層
を減圧下濃縮し、シリカゲルカラムクロマトグラフィー
（展開溶媒：ｎ−ヘキサン／酢酸エチル＝３０：１）で
精製することにより、黄色油状の４−（２，４−ジ−ｔ
−アミルフェノキシ）−３−フルオロニトロベンゼン２
１．７ｇ（８２％）を得た。Production Example 17 4- (2,4-di-t-amylphenoxy) -5-methyi
Luthio-2-nitroaniline a) 4- (2,4-di-t-amylphenoxy) -3-
25 g of 2,4-di-t-amylphenol was added to 160 ml of a tetrahydrofuran suspension containing 4.3 g of fluoronitrobenzene 60% sodium hydride, and after stirring for 30 minutes, 11.3 g of 3,4-difluoronitrobenzene was added, and Stir for hours.
The reaction solution was returned to room temperature, water was added, and the mixture was extracted with toluene. The organic layer was washed (5% aqueous sodium hydroxide solution, water, saturated saline solution in this order), dried (anhydrous magnesium sulfate), and the organic layer was concentrated under reduced pressure and subjected to silica gel column chromatography (developing solvent: n-hexane / acetic acid). Purification with ethyl = 30: 1) gave 4- (2,4-di-t as a yellow oil.
-Amylphenoxy) -3-fluoronitrobenzene 2
1.7 g (82%) were obtained.
【００７０】NMR(200MHz,CDCl3)δ:0.68(6H,dd,J=8,15H
z),1.30(6H,s),1.33(6H,s),1.55〜1.80(4H,m),6.79(1H,
d,J=8Hz),6.91(1H,dd,J=8,10Hz),7.17(1H,dd,J=2,8Hz),
7.35(1H,d,J=2Hz),7.97(1H,m),8.09(1H,dd,J=2,10Hz)。NMR (200 MHz, CDCl 3 ) δ: 0.68 (6H, dd, J = 8,15H
z), 1.30 (6H, s), 1.33 (6H, s), 1.55 ~ 1.80 (4H, m), 6.79 (1H,
d, J = 8Hz), 6.91 (1H, dd, J = 8,10Hz), 7.17 (1H, dd, J = 2,8Hz),
7.35 (1H, d, J = 2Hz), 7.97 (1H, m), 8.09 (1H, dd, J = 2,10Hz).
【００７１】ｂ）４−（２，４−ジ−ｔ−アミルフェノ
キシ）−３−フルオロアセトアニリド ４−（２，４−ジ−ｔ−アミルフェノキシ）−３−フル
オロニトロベンゼン２１．３ｇ、鉄粉２９．９ｇ及び塩
化アンモニウム０．９ｇを含む水溶液１７ｍｌの混合物
を８５℃２０分間加熱撹拌した。反応液を室温に戻した
後、イソプロパノール９０ｍｌを加え、不溶物をセライ
ト濾去した。濾液に無水酢酸６．４ｇを徐々に加えた
後、室温で１０分間撹拌した。反応液に水２００ｍｌを
加え、イソプロパノールを減圧濃縮し、シリカゲルカラ
ムクロマトグラフィー（展開溶媒：ｎ−ヘキサン／酢酸
エチル＝４：１〜１：２）で精製することにより、黄色
油状の４−（２，４−ジ−ｔ−アミルフェノキシ）−３
−フルオロアセトアニリド２０．９ｇ（９５％）を得
た。 B) 4- (2,4-di-t-amylpheno
Xy) -3-fluoroacetanilide 4- (2,4-di-t-amylphenoxy) -3-fluoronitrobenzene 21.3 g, iron powder 29.9 g, and a mixture of 17 ml of an aqueous solution containing 0.9 g of ammonium chloride at 85 ° C. The mixture was heated and stirred for 20 minutes. After returning the reaction solution to room temperature, 90 ml of isopropanol was added, and the insoluble matter was filtered off through Celite. After 6.4 g of acetic anhydride was gradually added to the filtrate, the mixture was stirred at room temperature for 10 minutes. 200 ml of water was added to the reaction solution, isopropanol was concentrated under reduced pressure, and purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 4: 1 to 1: 2) to give 4- (2) as a yellow oil. , 4-di-t-amylphenoxy) -3
20.9 g (95%) of -fluoroacetanilide was obtained.
【００７２】NMR(200MHz,CDCl3)δ:0.68(6H,dt,J=1,6H
z),1.26(6H,s),1.39(6H,s),1.60(2H,q,J=1,6Hz),1.85(2
H,q,J=6Hz),2.17(3H,s),6.60(1H,d,J=10Hz),6.88(1H,d
d,J=10,10Hz),7.03(1H,dd,J=2,10Hz),7.08(1H,m),7.26
(1H,d,J=2Hz),7.55(1H,dd,J=2,12Hz),7.60(1H,broad)。NMR (200 MHz, CDCl 3 ) δ: 0.68 (6H, dt, J = 1,6H
z), 1.26 (6H, s), 1.39 (6H, s), 1.60 (2H, q, J = 1,6Hz), 1.85 (2
H, q, J = 6Hz), 2.17 (3H, s), 6.60 (1H, d, J = 10Hz), 6.88 (1H, d
d, J = 10,10Hz), 7.03 (1H, dd, J = 2,10Hz), 7.08 (1H, m), 7.26
(1H, d, J = 2Hz), 7.55 (1H, dd, J = 2,12Hz), 7.60 (1H, broad).
【００７３】ｃ）４−（２，４−ジ−ｔ−アミルフェノ
キシ）−５−フルオロ−２−ニトロアセトアニリド ４−（２，４−ジ−ｔ−アミルフェノキシ）−３−フル
オロアセトアニリド１９．２ｇを用い、製造例１−ｃ）
の方法に準拠してニトロ化することにより、黄色油状の
４−（２，４−ジ−ｔ−アミルフェノキシ）−５−フル
オロ−２−ニトロアセトアニリド１５．４ｇ（７２％）
を得た［シリカゲルカラムクロマトグラフィー（展開溶
媒：ｎ−ヘキサン／酢酸エチル＝１５：１）で精製］。 C) 4- (2,4-di-t-amylpheno
Xy) -5-Fluoro-2-nitroacetanilide 4- (2,4-di-t-amylphenoxy) -3-fluoroacetanilide (19.2 g), Production Example 1-c).
By nitration according to the method described in 1., 15.4 g (72%) of yellow oily 4- (2,4-di-t-amylphenoxy) -5-fluoro-2-nitroacetanilide.
[Purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 15: 1)].
【００７４】NMR(200MHz,CDCl3)δ:0.68(3H,t,J=6Hz),
0.69(3H,t,J=6Hz),1.29(6H,s),1.35(6H,s),1.63(2H,q,J
=6Hz),1.80(2H,q,J=6Hz),2.30(3H,s),6.67(1H,d,J=8H
z),7.10(1H,dd,J=2,8Hz),7.32(1H,d,J=2Hz),7.80(1H,m,
J=8Hz),8.75(1H,d,J=12Hz),10.38(1H,broad)。NMR (200MHz, CDCl 3 ) δ: 0.68 (3H, t, J = 6Hz),
0.69 (3H, t, J = 6Hz), 1.29 (6H, s), 1.35 (6H, s), 1.63 (2H, q, J
= 6Hz), 1.80 (2H, q, J = 6Hz), 2.30 (3H, s), 6.67 (1H, d, J = 8H
z), 7.10 (1H, dd, J = 2,8Hz), 7.32 (1H, d, J = 2Hz), 7.80 (1H, m,
J = 8Hz), 8.75 (1H, d, J = 12Hz), 10.38 (1H, broad).
【００７５】ｄ）４−（２，４−ジ−ｔ−アミルフェノ
キシ）−５−メチルチオ−２−ニトロアニリン（本発明
の化合物） ４−（２，４−ジ−ｔ−アミルフェノキシ）−５−フル
オロ−２−ニトロアセトアニリド３．０ｇを用い、製造
例１−ｄ）の方法に準拠してチオエーテル化することに
より、橙色結晶の４−（２，４−ジ−ｔ−アミルフェノ
キシ）−５−メチルチオ−２−ニトロアニリン２．１ｇ
（７２．５％）を得た。 ｍ．ｐ．１４６〜１４７．５℃（再結晶溶媒：ジエチル
エーテル−ｎ−ヘキサン）。 D) 4- (2,4-di-t-amylpheno
Xy) -5-methylthio-2-nitroaniline (the present invention
Compound of 4- (2,4-di-t-amylphenoxy) -5-fluoro-2-nitroacetanilide by using 3.0 g of thioetherification according to the method of Production Example 1-d). 2.1 g of orange crystalline 4- (2,4-di-t-amylphenoxy) -5-methylthio-2-nitroaniline
(72.5%) was obtained. m. p. 146 to 147.5 ° C. (recrystallization solvent: diethyl ether-n-hexane).
【００７６】製造例１８４−（２−ベンゾイルフェノキシ）−５−メチルチオ−
２−ニトロアニリン ａ）４−（２−ベンゾイルフェノキシ）−３−フルオロ
ニトロベンゼン ６０％水素化ナトリウム５．０ｇを含むテトラヒドロフ
ラン１３０ｍｌ懸濁液に２−ベンゾイルフェノール２５
ｇを加え、２０分間撹拌後、３，４−ジフルオロニトロ
ベンゼン１３．４ｇを加えた後、減圧下濃縮した。得ら
れた残渣にトリス［２−（２−メトキシエトキシ）エチ
ル］アミン１．３ｇを加え、１１０℃で１．５時間加熱
撹拌した。反応液を室温に戻し、３規定塩酸３５ｍｌを
加えトルエンで抽出した。有機層を洗浄（水、飽和食塩
水の順）、乾燥（無水硫酸マグネシウム）後、有機層を
減圧下濃縮し、シリカゲルカラムクロマトグラフィー
（展開溶媒：ｎ−ヘキサン）で精製することにより、黄
色油状の４−（２−ベンゾイルフェノキシ）−３−フル
オロニトロベンゼン２６．２ｇ（９２．５％）を得た。Production Example 18 4- (2-benzoylphenoxy) -5-methylthio-
2-Nitroaniline a) 4- (2-benzoylphenoxy) -3-fluoro
2-Benzoylphenol 25 was added to a suspension of 130 ml of tetrahydrofuran containing 5.0 g of 60% sodium hydride in nitrobenzene.
g, and after stirring for 20 minutes, 13.4 g of 3,4-difluoronitrobenzene was added, followed by concentration under reduced pressure. To the obtained residue, tris [2- (2-methoxyethoxy) ethyl] amine (1.3 g) was added, and the mixture was heated with stirring at 110 ° C for 1.5 hours. The reaction solution was returned to room temperature, 3N hydrochloric acid (35 ml) was added, and the mixture was extracted with toluene. The organic layer is washed (water, saturated brine in this order), dried (anhydrous magnesium sulfate), concentrated under reduced pressure, and purified by silica gel column chromatography (developing solvent: n-hexane) to give a yellow oil. 2-4 g (92.5%) of 4- (2-benzoylphenoxy) -3-fluoronitrobenzene was obtained.
【００７７】NMR(200MHz,CDCl3)δ:6.92(1H,dd,J=8,10H
z),7.12(1H,dd,J=1,8Hz),7.35〜7.50(3H,m),7.51〜7.67
(3H,m),7.72〜7.82(2H,m),7.88〜8.00(2H,m)。NMR (200 MHz, CDCl 3 ) δ: 6.92 (1H, dd, J = 8,10H
z), 7.12 (1H, dd, J = 1,8Hz), 7.35 ~ 7.50 (3H, m), 7.51 ~ 7.67
(3H, m), 7.72 to 7.82 (2H, m), 7.88 to 8.00 (2H, m).
【００７８】ｂ）４−（２−ベンゾイルフェノキシ）−
３−フルオロアセトアニリド ４−（２−ベンゾイルフェノキシ）−３−フルオロニト
ロベンゼン２０．６ｇを用い、製造例１−ｂ）の方法に
準拠して還元、アセチル化することにより、無色結晶の
４−（２−ベンゾイルフェノキシ）−３−フルオロアセ
トアニリド２６．２ｇ（９２．５％）を得た。 ｍ．ｐ．１１１〜１１２．５℃（一部を酢酸エチル−ｎ
−ヘキサンで再結晶）。 B) 4- (2-benzoylphenoxy)-
2 -Fluoroacetanilide 4- (2-benzoylphenoxy) -3-fluoronitrobenzene 20.6 g was used for reduction and acetylation according to the method of Production Example 1-b) to give 4- (2) as colorless crystals. 26.2 g (92.5%) of -benzoylphenoxy) -3-fluoroacetanilide were obtained. m. p. 111-112.5 ° C (part of ethyl acetate-n
Recrystallized with hexane).
【００７９】ｃ）４−（２−ベンゾイルフェノキシ）−
５−フルオロ−２−ニトロアセトアニリド ４−（２−ベンゾイルフェノキシ）−３−フルオロアセ
トアニリド１９．１ｇを用い、製造例１−ｃ）の方法に
準拠してニトロ化することにより、４−（２−ベンゾイ
ルフェノキシ）−５−フルオロ−２−ニトロアセトアニ
リド１１．５ｇ（５３％）を得た。 ｍ．ｐ．１００〜１０１．５℃（再結晶溶媒：イソプロ
パノール−ｎ−ヘキサン）。 C) 4- (2-benzoylphenoxy)-
4 -Fluoro-2-nitroacetanilide 4- (2-benzoylphenoxy) -3-fluoroacetanilide 19.1 g was nitrated according to the method of Production Example 1-c) to give 4- (2- 11.5 g (53%) of benzoylphenoxy) -5-fluoro-2-nitroacetanilide was obtained. m. p. 100 to 101.5 ° C. (recrystallization solvent: isopropanol-n-hexane).
【００８０】ｄ）４−（２−ベンゾイルフェノキシ）−
５−メチルチオ−２−ニトロアニリン （本発明の化合物） ４−（２−ベンゾイルフェノキシ）
−５−フルオロ−２−ニトロアセトアニリド２．５ｇを
用い、製造例１−ｄ）の方法に準拠してチオエーテル化
することにより、橙色結晶の４−（２−ベンゾイルフェ
ノキシ）−５−メチルチオ−２−ニトロアニリン２．４
ｇ（９８％）を得た。 ｍ．ｐ．１９３．５〜１９４．５℃（再結晶溶媒：イソ
プロパノール−ｎ−ヘキサン）。 D) 4- (2-benzoylphenoxy)-
5-Methylthio-2-nitroaniline (the compound of the present invention) 4- (2-benzoylphenoxy)
Using 2.5 g of -5-fluoro-2-nitroacetanilide, thioetherification was carried out according to the method of Production Example 1-d) to give 4- (2-benzoylphenoxy) -5-methylthio-2 as orange crystals. -Nitroaniline 2.4
g (98%) were obtained. m. p. 193.5-194.5 ° C (recrystallization solvent: isopropanol-n-hexane).
【００８１】製造例１９５−（ｎ−ヘキシルチオ）−２−ニトロ−４−フェノキ
シアニリン 製造例１−ａ）〜ｃ）の方法で得た５−フルオロ−２−
ニトロ−４−フェノキシアセトアニリド３．０ｇを含む
イソプロパノール３０ｍｌ懸濁液に２０％水酸化ナトリ
ウム水溶液４．６ｍｌ及びｎ−ヘキサンチオール１．４
ｇを加え、６０℃で２時間加熱撹拌した。反応液を室温
に戻し、水を加え析出物を濾取、洗浄（水、ｎ−ヘキサ
ンの順）した。得られた粗結晶をシリカゲルカラムクロ
マトグラフィー（展開溶媒：ｎ−ヘキサン／酢酸エチル
＝６：１）で精製、ジエチルエーテル−ｎ−ヘキサンで
再結晶することにより、赤橙色結晶の５−（ｎ−ヘキシ
ルチオ）−２−ニトロ−４−フェノキシアニリン１．１
ｇ（３１％）を得た。 ｍ．ｐ．１０８．５〜１１０℃。Production Example 19 5- (n-hexylthio) -2-nitro-4-phenoxy
5-Fluoro-2-obtained by the method of Cyaniline Production Example 1-a) to c)
A suspension of 30 ml of isopropanol containing 3.0 g of nitro-4-phenoxyacetanilide was added to 4.6 ml of 20% aqueous sodium hydroxide solution and 1.4 ml of n-hexanethiol.
g was added, and the mixture was heated with stirring at 60 ° C. for 2 hours. The reaction solution was returned to room temperature, water was added, and the precipitate was collected by filtration and washed (water and n-hexane in this order). The obtained crude crystals were purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 6: 1) and recrystallized from diethyl ether-n-hexane to give 5- (n-) of reddish orange crystals. Hexylthio) -2-nitro-4-phenoxyaniline 1.1
g (31%) were obtained. m. p. 108.5-110 ° C.
【００８２】製造例２０〜２２ 製造例１９で用いた製造例１−ｃ）の化合物の代わりに
製造例７−ｃ）、１０−ｃ）あるいは１４−ｃ）の化合
物を用い、製造例１９の方法に準拠してチオエーテル化
することにより、表６に示した本発明の化合物（製造例
２０〜２２の化合物）を得た。Production Examples 20 to 22 Instead of the compound of Production Example 1-c) used in Production Example 19, the compound of Production Example 7-c), 10-c) or 14-c) was used. The compound of the present invention shown in Table 6 (Compounds of Production Examples 20 to 22) was obtained by thioetherification according to the method.
【００８３】[0083]
【表６】 [Table 6]
【００８４】製造例２３５−シクロヘキシルチオ−２−ニトロ−４−フェノキシ
アニリン 製造例１９で用いたｎ−ヘキサンチオールの代わりにシ
クロヘキサンチオールを用い、製造例１９の方法に準拠
してチオエーテル化することにより、５−シクロヘキシ
ルチオ−２−ニトロ−４−フェノキシアニリン（本発明
の化合物）を得た。 ｍ．ｐ．１４８．５〜１４９．５℃（再結晶溶媒：エタ
ノール）。Production Example 23 5-Cyclohexylthio-2-nitro-4-phenoxy
Cycloline thiol was used in place of n-hexane thiol used in Production Example 19 of aniline, and thioetherification was carried out according to the method of Production Example 19 to give 5-cyclohexylthio-2-nitro-4-phenoxyaniline (the present invention. Compound) was obtained. m. p. 148.5-149.5 ° C (recrystallization solvent: ethanol).
【００８５】製造例２４５−シクロヘキシルチオ−４−（２−フルオロフェノキ
シ）−４−ニトロアニリン 製造例２３で用いた製造例１−ｃ）の化合物の代わりに
製造例２−ｃ）の化合物を用いて製造例２３の方法に準
拠してチオエーテル化することにより、表７に示した５
−シクロヘキシルチオ−４−（２−フルオロフェノキ
シ）−４−ニトロアニリン（製造例２４の化合物）を得
た。Production Example 24 5-Cyclohexylthio-4- (2-fluorophenoxy)
Si) -4-Nitroaniline By substituting the compound of Production Example 2-c) for the compound of Production Example 1-c) used in Production Example 23, and performing thioetherification according to the method of Production Example 23, 5 shown in Table 7
-Cyclohexylthio-4- (2-fluorophenoxy) -4-nitroaniline (Compound of Production Example 24) was obtained.
【００８６】製造例２５４−（２−クロロフェノキシ）−５−シクロヘキシルチ
オ−２−ニトロアニリンａ）４−（２−クロロフェノキ
シ）−３−フルオロニトロベンゼン 製造例１−ａ）で用いたフェノールの代わりに２−クロ
ロフェノールを用い、製造例１−ａ）の方法に準拠して
エーテル化することにより、黄色油状のクロロフェノキ
シ）−３−フルオロニトロベンゼンを得た。Production Example 25 4- (2-chlorophenoxy) -5-cyclohexylthio
O-2-nitroaniline a) 4- (2-chlorophenoki
Si) -3-Fluoronitrobenzene By using 2-chlorophenol in place of the phenol used in Production Example 1-a) and etherification according to the method of Production Example 1-a), yellow oily chlorophenoxy is obtained. ) -3-Fluoronitrobenzene was obtained.
【００８７】NMR(200MHz,CDCl3)δ:6.80(1H,dd,J=8,10H
z),7.16(1H,dd,J=2,8Hz),7.25(3H,m),7.35(3H,m),7.53
(1H,dd,J=2,8Hz),7.98(1H,m),8.10(1H,m)。NMR (200 MHz, CDCl 3 ) δ: 6.80 (1H, dd, J = 8,10H
z), 7.16 (1H, dd, J = 2,8Hz), 7.25 (3H, m), 7.35 (3H, m), 7.53
(1H, dd, J = 2,8Hz), 7.98 (1H, m), 8.10 (1H, m).
【００８８】ｂ）４−（２−クロロフェノキシ）−５−
フルオロアセトアニリド ４−（２−クロロフェノキシ）−３−フルオロニトロベ
ンゼンを製造例１−ｂ）の方法に準拠して還元、アセチ
ル化することにより、４−（２−クロロフェノキシ）−
５−フルオロ−２−アセトアニリドを得た。 ｍ．ｐ．１３５〜１３６℃（再結晶溶媒：酢酸エチル−
ｎ−ヘキサン）。 B) 4- (2-chlorophenoxy) -5-
By reducing and acetylating fluoroacetanilide 4- (2-chlorophenoxy) -3-fluoronitrobenzene according to the method of Production Example 1-b), 4- (2-chlorophenoxy)-
5-Fluoro-2-acetanilide was obtained. m. p. 135-136 ° C (recrystallization solvent: ethyl acetate-
n-hexane).
【００８９】ｃ）４−（２−クロロフェノキシ）−５−
フルオロ−２−ニトロアセトアニリド ４−（２−クロロフェノキシ）−３−フルオアセトアニ
リドを製造例１−ｃ）の方法に準拠してニトロ化するこ
とにより、４−（２−クロロフェノキシ）−５−フルオ
ロ−２−ニトロアセトアニリドを得た。 ｍ．ｐ．１２１〜１２２．５℃（再結晶溶媒：ジクロロ
メタン−ｎ−ヘキサン）。C ) 4- (2-chlorophenoxy) -5-
4- (2-chlorophenoxy) -5-fluoro was obtained by nitrating fluoro-2-nitroacetanilide 4- (2-chlorophenoxy) -3-fluoracetanilide according to the method of Production Example 1-c). 2-Nitroacetanilide was obtained. m. p. 121-122.5 ° C (recrystallization solvent: dichloromethane-n-hexane).
【００９０】ｄ）４−（２−クロロフェノキシ）−５−
シクロヘキシルチオ−２−ニトロアニリン ４−（２−クロロフェノキシ）−５−フルオロ−２−ニ
トロアセトアニリドを製造例２３の方法に準拠してチオ
エーテル化することにより、表７に示した４−（２−ク
ロロフェノキシ）−５−シクロヘキシルチオ−２−ニト
ロアニリン（製造例２５の化合物）を得た。D ) 4- (2-chlorophenoxy) -5-
By cyclohexylthio-2-nitroaniline 4- (2-chlorophenoxy) -5-fluoro-2-nitroacetanilide being thioetherified according to the method of Production Example 23, 4- (2- Chlorophenoxy) -5-cyclohexylthio-2-nitroaniline (Compound of Production Example 25) was obtained.
【００９１】製造例２６〜３２ 製造例２３で用いた製造例１−ｃ）の化合物の代わりに
製造例７−ｃ）、９−ｃ）、１０−ｃ）、１４−ｃ）、
１６−ｃ）１７−ｃ）あるいは１８−ｃ）の化合物を用
いて製造例２３の方法に準拠してチオエーテル化するこ
とにより、表７に示した本発明の化合物（製造例２６〜
３２の化合物）を得た。Production Examples 26 to 32 Instead of the compound of Production Example 1-c) used in Production Example 23, Production Examples 7-c), 9-c), 10-c), 14-c),
16-c) The compound of 17-c) or 18-c) was used for thioetherification according to the method of Production Example 23 to give the compound of the present invention shown in Table 7 (Production Example 26-
32 compounds) were obtained.
【００９２】[0092]
【表７】 [Table 7]
【００９３】製造例３３５−シクロヘキシルチオ−４−（２−イソプロポキシカ
ルボニルフェノキシ）−２−ニトロアニリン ａ）３−フルオロ−４−（２−イソプロポキシカルボニ
ルフェノキシ）ニトロベンゼン 製造例１８−ａ）で用いた２−ベンゾイルフェノールの
代わりにサリチル酸イソプロピル２７．３ｇを用い、製
造例１８−ａ）の方法に準拠してエーテル化することに
より、黄色油状の３−フルオロ−４−（２−イソプロポ
キシカルボニルフェノキシ）ニトロベンゼン３０．４ｇ
（９４％）を得た［シリカゲルカラムクロマトグラフィ
ー（展開溶媒：ｎ−ヘキサン）で精製］。Production Example 33 5-Cyclohexylthio-4- (2-isopropoxyca)
Rubonylphenoxy) -2-nitroaniline a) 3-fluoro-4- (2-isopropoxycarboni)
Ruphenoxy ) nitrobenzene 27.3 g of isopropyl salicylate was used in place of 2-benzoylphenol used in Production Example 18-a), and etherification was performed according to the method of Production Example 18-a) to give a yellow oily product. -Fluoro-4- (2-isopropoxycarbonylphenoxy) nitrobenzene 30.4 g
(94%) was obtained [purified by silica gel column chromatography (developing solvent: n-hexane)].
【００９４】NMR(200MHz,CDCl3)δ:1.15(6H,d,J=6Hz),
5.12(1H,m),6.69(1H,dd,J=8,10Hz),7.16(1H,dd,J=2,8H
z),7.40(1H,dt,J=2,8Hz),7.63(1H,dt,J=2,8Hz),7.93(1
H,m),8.05(1H,dd,J=2,8Hz),8.10(1H,dd,J=2,10Hz)。NMR (200MHz, CDCl 3 ) δ: 1.15 (6H, d, J = 6Hz),
5.12 (1H, m), 6.69 (1H, dd, J = 8,10Hz), 7.16 (1H, dd, J = 2,8H
z), 7.40 (1H, dt, J = 2,8Hz), 7.63 (1H, dt, J = 2,8Hz), 7.93 (1
H, m), 8.05 (1H, dd, J = 2,8Hz), 8.10 (1H, dd, J = 2,10Hz).
【００９５】ｂ）３−フルオロ−４−（２−イソプロポ
キシカルボニルフェノキシ）アセトアニリド ３−フルオロ−４−（２−イソプロポキシカルボニルフ
ェノキシ）ニトロベンゼン２７．８ｇを用い、製造例１
８−ｂ）の方法に準拠して還元、アセチル化することに
より、無色結晶の３−フルオロ−４−（２−イソプロポ
キシカルボニルフェノキシ）アセトアニリド２８．４ｇ
（９８％）を得た。 ｍ．ｐ．６３〜６４℃（一部をイソプロパノール−ｎ−
ヘキサンで再結晶）。 B) 3-Fluoro-4- (2-isopropo)
Production Example 1 using 27.8 g of xycarbonylphenoxy ) acetanilide 3-fluoro-4- (2-isopropoxycarbonylphenoxy) nitrobenzene.
2-fluoro-4- (2-isopropoxycarbonylphenoxy) acetanilide 28.4 g as colorless crystals by reduction and acetylation according to the method of 8-b).
(98%) was obtained. m. p. 63-64 ° C (Part of isopropanol-n-
Recrystallized with hexane).
【００９６】ｃ）５−フルオロ−４−（２−イソプロポ
キシカルボニルフェノキシ）−２−ニトロアセトアニリ
ド ３−フルオロ−４−（２−イソプロポキシカルボニルフ
ェノキシ）アセトアニリド２７．７ｇを用い、製造例１
−ｃ）の方法に準拠してニトロ化することにより、５−
フルオロ−４−（２−イソプロポキシカルボニルフェノ
キシ）−２−ニトロアセトアニリド２０．９ｇ（６６
％）を得た。 ｍ．ｐ．１０１〜１０２℃（再結晶溶媒：酢酸エチル−
ｎ−ヘキサン）。 C) 5-Fluoro-4- (2-isopropo)
Xycarbonylphenoxy) -2-nitroacetanil
Using 2-7.7 g of de 3-fluoro-4- (2-isopropoxycarbonylphenoxy) acetanilide, Production Example 1
-By nitration according to the method of c), 5-
Fluoro-4- (2-isopropoxycarbonylphenoxy) -2-nitroacetanilide 20.9 g (66
%) Was obtained. m. p. 101 to 102 ° C (recrystallization solvent: ethyl acetate-
n-hexane).
【００９７】ｄ）５−シクロヘキシルチオ−４−（２−
イソプロポキシカルボニルフェノキシ）−２−ニトロア
セトアニリド ６０％水素化ナトリウム０．６ｇを含むテトラヒドロフ
ラン１３．５ｍｌ懸濁液に氷冷下シクロヘキサンチオー
ル１．７ｇを加え、２０分間撹拌後、５−フルオロ−４
−（２−イソプロポキシカルボニルフェノキシ）−２−
ニトロアセトアニリド５．０ｇを含むテトラヒドロフラ
ン１３．５ｍｌ懸濁液を加え、室温で１２時間撹拌し
た。反応液に３規定塩酸１４．６ｍｌを加え酢酸エチル
で抽出した。有機層を洗浄（水、飽和食塩水の順）、乾
燥（無水硫酸マグネシウム）後、有機層を減圧下濃縮
し、シリカゲルカラムクロマトグラフィー（展開溶媒：
ｎ−ヘキサン／酢酸エチル＝５：１）で精製、イソプロ
パノール−ｎ−ヘキサンで再結晶することにより、黄色
結晶の５−シクロヘキシルチオ−４−（２−イソプロポ
キシカルボニルフェノキシ）−２−ニトロアセトアニリ
ド５．４ｇ（８６％）を得た。 ｍ．ｐ．１１８．５〜１１９．５℃。 D) 5-Cyclohexylthio-4- (2-
Isopropoxycarbonylphenoxy ) -2-nitroa
1.7 g of cyclohexanethiol was added to a suspension of 13.5 ml of tetrahydrofuran containing 0.6 g of sodium hydride 60% in cetoanilide under ice cooling, and after stirring for 20 minutes, 5-fluoro-4
-(2-isopropoxycarbonylphenoxy) -2-
A suspension of 13.5 ml of tetrahydrofuran containing 5.0 g of nitroacetanilide was added, and the mixture was stirred at room temperature for 12 hours. To the reaction solution was added 14.6 ml of 3N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed (water, saturated saline solution in that order), dried (anhydrous magnesium sulfate), concentrated under reduced pressure, and subjected to silica gel column chromatography (developing solvent:
Purification with n-hexane / ethyl acetate = 5: 1) and recrystallization from isopropanol-n-hexane gave yellow crystals of 5-cyclohexylthio-4- (2-isopropoxycarbonylphenoxy) -2-nitroacetanilide 5. Yield 0.4 g (86%). m. p. 118.5-119.5 ° C.
【００９８】ｅ）５−シクロヘキシルチオ−４−（２−
イソプロポキシカルボニルフェノキシ）−２−ニトロア
ニリン（本発明の化合物） ５−シクロヘキシルチオ−４−（２−イソプロポキシカ
ルボニルフェノキシ）−２−ニトロアセトアニリド２．
０ｇを含むイソプロパノール３２ｍｌ懸濁液に２％水酸
化ナトリウム水溶液１２ｍｌを加え、６０℃で２時間加
熱撹拌した。反応液を室温に戻し、３規定塩酸を加え中
和した後、酢酸エチルで抽出した。有機層を洗浄（水、
飽和食塩水の順）、乾燥（無水硫酸マグネシウム）後、
有機層を減圧下濃縮し、シリカゲルカラムクロマトグラ
フィー（展開溶媒：ｎ−ヘキサン／酢酸エチル＝５：
１）で精製、イソプロパノール−ｎ−ヘキサンで再結晶
することにより、橙色結晶の５−シクロヘキシルチオ−
４−（２−イソプロポキシカルボニルフェノキシ）−２
−ニトロアニリン１．１ｇ（６１．５％）を得た。 ｍ．ｐ．１２３．５〜１２５℃。 E) 5-Cyclohexylthio-4- (2-
Isopropoxycarbonylphenoxy ) -2-nitroa
Niline (a compound of the present invention) 5-cyclohexylthio-4- (2-isopropoxycarbonylphenoxy) -2-nitroacetanilide 2.
12 ml of 2% aqueous sodium hydroxide solution was added to a 32 ml suspension of isopropanol containing 0 g, and the mixture was heated with stirring at 60 ° C. for 2 hours. The reaction solution was returned to room temperature, neutralized with 3N hydrochloric acid, and extracted with ethyl acetate. Wash the organic layer (water,
After saturated saline solution) and dried (anhydrous magnesium sulfate),
The organic layer was concentrated under reduced pressure and subjected to silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 5:
Purified in 1) and recrystallized from isopropanol-n-hexane to give orange-colored 5-cyclohexylthio-
4- (2-isopropoxycarbonylphenoxy) -2
-1.1 g (61.5%) of nitroaniline was obtained. m. p. 123.5-125 ° C.
【００９９】製造例３４４−（２−カルボキシフェノキシ）−５−シクロヘキシ
ルチオ−２−ニトロアニリン 製造例３４−ａ）〜ｄ）の方法で得た５−シクロヘキシ
ルチオ−４−（２−イソプロポキシカルボニルフェノキ
シ）−２−ニトロアセトアニリド１．５ｇを含むテトラ
ヒドロフラン６ｍｌ及びメタノール６ｍＬ懸濁液に２０
％水酸化ナトリウム水溶液１．４ｍｌを加え、６０℃で
加熱撹拌した。反応液を室温に戻し、３規定塩酸を加え
中和した後、酢酸エチルで抽出し、有機層を洗浄（水、
飽和食塩水の順）、乾燥（無水硫酸マグネシウム）し
た。有機層を減圧下濃縮し、残渣を酢酸エチル−ｎ−ヘ
キサンで再結晶することにより、橙色結晶の４−（２−
カルボキシフェノキシ）−５−シクロヘキシルチオ−２
−ニトロアニリン１．２ｇ（９７％）を得た。 ｍ．ｐ．１８４．５〜１８５．５℃。Production Example 34 4- (2-Carboxyphenoxy) -5-cyclohexyl
Lucio-2-nitroaniline Preparation 34-a) method 5- cyclohexylthio-4 obtained in (2-isopropoxycarbonyl phenoxy in to d)) -2-tetrahydrofuran containing nitro acetanilide 1.5 g 6 ml and methanol 6mL 20 in suspension
% Aqueous sodium hydroxide solution (1.4 ml) was added, and the mixture was heated with stirring at 60 ° C. The reaction solution is returned to room temperature, neutralized with 3N hydrochloric acid, extracted with ethyl acetate, and the organic layer is washed (water,
Saturated saline (in that order) and dried (anhydrous magnesium sulfate). The organic layer was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-n-hexane to give orange crystals of 4- (2-
Carboxyphenoxy) -5-cyclohexylthio-2
-1.2 g (97%) of nitroaniline was obtained. m. p. 184.5-185.5 ° C.
【０１００】製造例３５５−メチルスルフィニル−２−ニトロ−４−フェノキシ
アニリン 製造例１の方法で得た５−メチルチオ−２−ニトロ−４
−フェノキシアニリン１．７ｇを含む５０ｍｌ溶液に氷
冷下ｍ−クロロ過安息香酸０．５ｇを加え、２時間撹拌
した。反応液に水を加え、クロロホルムで抽出後、有機
層を洗浄（飽和炭酸水素ナトリウム水溶液、水、飽和食
塩水の順）、乾燥（無水硫酸マグネシウム）した。有機
層を減圧下濃縮し、残渣をアセトンで再結晶することに
より、５−メチルスルフィニル−２−ニトロ−４−フェ
ノキシアニリン０．９５ｇ（５３％）を得た。 ｍ．ｐ．２２２．５〜２２３℃。Production Example 35 5-Methylsulfinyl-2-nitro-4-phenoxy
5-Methylthio-2-nitro-4 obtained by the method of Aniline Production Example 1
-0.5 g of m-chloroperbenzoic acid was added to a 50 ml solution containing 1.7 g of phenoxyaniline under ice cooling, and the mixture was stirred for 2 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed (saturated sodium hydrogen carbonate aqueous solution, water, saturated saline solution in this order) and dried (anhydrous magnesium sulfate). The organic layer was concentrated under reduced pressure, and the residue was recrystallized from acetone to obtain 0.95 g (53%) of 5-methylsulfinyl-2-nitro-4-phenoxyaniline. m. p. 222.5-223 ° C.
【０１０１】製造例３６〜５９ 製造例３６で用いたチオエーテル（製造例１の方法で得
た本発明の化合物）の代わりに製造例２〜２３、２８あ
るいは２９の方法で得た本反応のチオエーテル化合物を
用い、製造例３５と同様に酸化することにより、表８−
１及び８−２に示した本発明の化合物（製造例３６〜５
９の化合物）を得た。Production Examples 36 to 59 Instead of the thioether used in Production Example 36 (the compound of the present invention obtained by the method of Production Example 1), the thioether of this reaction obtained by the method of Production Examples 2 to 23, 28 or 29. By using the compound and oxidizing in the same manner as in Production Example 35, Table 8-
The compounds of the present invention shown in 1 and 8-2 (Production Examples 36 to 5)
9 compound) was obtained.
【０１０２】[0102]
【表８】 [Table 8]
【０１０３】[0103]
【表９】 [Table 9]
【０１０４】製造例６０５−メチルスルホニル−２−ニトロ−４−フェノキシア
ニリン 製造例１の方法で得た５−メチルチオ−２−ニトロ−４
−フェノキシアニリン１．７ｇを含む５０ｍｌ溶液に室
温でｍ−クロロ過安息香酸１．０ｇを加え、２時間撹拌
した。反応液に水を加え、クロロホルムで抽出後、有機
層を洗浄（飽和炭酸水素ナトリウム、水、飽和食塩水の
順）、乾燥（無水硫酸マグネシウム）した。有機層を減
圧下濃縮し、残渣を酢酸エチル−ｎ−ヘキサンで再結晶
することにより、５−メチルスルホニル−２−ニトロ−
４−フェノキシアニリン１．７ｇ（８９％）を得た。 ｍ．ｐ．１５２．５〜１５３．５℃。Production Example 60 5-Methylsulfonyl-2-nitro-4-phenoxya
5-methylthio-2-nitro-4 obtained by the method of Niline Preparation Example 1
-To a 50 ml solution containing 1.7 g of phenoxyaniline, 1.0 g of m-chloroperbenzoic acid was added at room temperature and stirred for 2 hours. Water was added to the reaction solution, the mixture was extracted with chloroform, the organic layer was washed (saturated sodium hydrogen carbonate, water, and saturated saline in this order) and dried (anhydrous magnesium sulfate). The organic layer was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-n-hexane to give 5-methylsulfonyl-2-nitro-
1.7 g (89%) of 4-phenoxyaniline was obtained. m. p. 152.5-153.5 ° C.
【０１０５】製造例６１〜７１ 製造例６０で用いたチオエーテル（製造例１の方法で得
た本発明の化合物）の代わりに製造例３〜６、８、１０
〜１４または２１の方法で得たチオエーテル化合物を用
い、製造例６０の方法に準拠して酸化することにより、
表９に示した本発明の化合物（製造例６１〜７１の化合
物）を得た。Preparation Examples 61 to 71 Instead of the thioether used in Preparation Example 60 (the compound of the present invention obtained by the method of Preparation Example 1), Preparation Examples 3 to 6, 8, and 10.
~ 14 or by using the thioether compound obtained by the method of 21 by oxidizing according to the method of Production Example 60,
The compounds of the present invention shown in Table 9 (Compounds of Production Examples 61 to 71) were obtained.
【０１０６】[0106]
【表１０】 [Table 10]
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 31/135 ＡＥＤ Ａ６１Ｋ 31/135 ＡＥＤ (72)発明者 吉川 賢成 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 畑山 勝男 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 6 Identification number Reference number within the agency FI Technical indication location A61K 31/135 AED A61K 31/135 AED (72) Inventor Kensei Yoshikawa 3 Takada, Toshima-ku, Tokyo No. 24-1 Taisho Pharmaceutical Co., Ltd. (72) Inventor Katsuo Hatayama 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd.
Claims (1)
数１〜８個のアルキル基、フェニル基、フェノキシ基、
ベンジル基、ベンゾイル基、炭素原子数２〜６個のアル
コキシカルボニル基またはカルボキシル基から選ばれる
置換基により１箇所または２箇所を置換されたフェニル
基またはテトラヒドロナフチル基である。Ｒ2は炭素原
子数１〜８個のアルキル基または炭素原子数５〜８個の
シクロアルキル基である。Ｘは−Ｓ−、−ＳＯ−または
−ＳＯ2−で示される基である。］で表される５−アル
キルチオ−４−アリールオキシニトロアニリン化合物ま
たはその塩。(1) Formula (1) [In the formula, R 1 is an unsubstituted or halogen atom, an alkyl group having 1 to 8 carbon atoms, a phenyl group, a phenoxy group,
A phenyl group or a tetrahydronaphthyl group substituted at one or two positions with a substituent selected from a benzyl group, a benzoyl group, an alkoxycarbonyl group having 2 to 6 carbon atoms or a carboxyl group. R 2 is an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 5 to 8 carbon atoms. X is -S -, - SO- or -SO 2 - is a group represented by the. ] The 5-alkylthio-4-aryloxy nitro aniline compound represented by these, or its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23354395A JP3740719B2 (en) | 1995-09-12 | 1995-09-12 | 5-alkylthio-4-aryloxynitroaniline compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23354395A JP3740719B2 (en) | 1995-09-12 | 1995-09-12 | 5-alkylthio-4-aryloxynitroaniline compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0977739A true JPH0977739A (en) | 1997-03-25 |
| JP3740719B2 JP3740719B2 (en) | 2006-02-01 |
Family
ID=16956711
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP23354395A Expired - Fee Related JP3740719B2 (en) | 1995-09-12 | 1995-09-12 | 5-alkylthio-4-aryloxynitroaniline compounds |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3740719B2 (en) |
-
1995
- 1995-09-12 JP JP23354395A patent/JP3740719B2/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| JP3740719B2 (en) | 2006-02-01 |
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