JPS62249974A - 1-hydroxy-2-pyridones - Google Patents
1-hydroxy-2-pyridonesInfo
- Publication number
- JPS62249974A JPS62249974A JP62093445A JP9344587A JPS62249974A JP S62249974 A JPS62249974 A JP S62249974A JP 62093445 A JP62093445 A JP 62093445A JP 9344587 A JP9344587 A JP 9344587A JP S62249974 A JPS62249974 A JP S62249974A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- methyl
- pyridone
- atoms
- 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
- SNUSZUYTMHKCPM-UHFFFAOYSA-N 1-hydroxypyridin-2-one Chemical class ON1C=CC=CC1=O SNUSZUYTMHKCPM-UHFFFAOYSA-N 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 52
- 239000000203 mixture Substances 0.000 claims description 28
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 150000007529 inorganic bases Chemical class 0.000 claims description 12
- 150000007530 organic bases Chemical class 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- 125000004434 sulfur atom Chemical group 0.000 claims description 11
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 10
- GGOZGYRTNQBSSA-UHFFFAOYSA-N pyridine-2,3-diol Chemical compound OC1=CC=CN=C1O GGOZGYRTNQBSSA-UHFFFAOYSA-N 0.000 claims description 10
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 150000001204 N-oxides Chemical class 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 241000233866 Fungi Species 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- UDYUIWXQUBNDHC-UHFFFAOYSA-N 6-[[4-(4-chlorophenoxy)phenoxy]methyl]-1-hydroxy-4-methylpyridin-2-one Chemical compound ON1C(=O)C=C(C)C=C1COC(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 UDYUIWXQUBNDHC-UHFFFAOYSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 3
- VGYYSIDKAKXZEE-UHFFFAOYSA-L hydroxylammonium sulfate Chemical compound O[NH3+].O[NH3+].[O-]S([O-])(=O)=O VGYYSIDKAKXZEE-UHFFFAOYSA-L 0.000 claims description 3
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 229940121375 antifungal agent Drugs 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 3
- 239000000654 additive Substances 0.000 claims 2
- ZTXCCUXGZQMUFW-UHFFFAOYSA-N 1-hydroxy-4-methyl-6-[(4-phenylphenoxy)methyl]pyridin-2-one Chemical compound ON1C(=O)C=C(C)C=C1COC1=CC=C(C=2C=CC=CC=2)C=C1 ZTXCCUXGZQMUFW-UHFFFAOYSA-N 0.000 claims 1
- CMJRXUFGEJJSCZ-UHFFFAOYSA-N 1-hydroxy-4-methyl-6-[[4-[4-(trifluoromethyl)phenoxy]phenoxy]methyl]pyridin-2-one Chemical compound ON1C(=O)C=C(C)C=C1COC(C=C1)=CC=C1OC1=CC=C(C(F)(F)F)C=C1 CMJRXUFGEJJSCZ-UHFFFAOYSA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 239000003429 antifungal agent Substances 0.000 claims 1
- 125000002619 bicyclic group Chemical group 0.000 claims 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims 1
- 230000001717 pathogenic effect Effects 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- 238000002844 melting Methods 0.000 description 57
- 230000008018 melting Effects 0.000 description 57
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
- 239000002904 solvent Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 14
- 235000011181 potassium carbonates Nutrition 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 238000004821 distillation Methods 0.000 description 12
- -1 phenyloxymethyl Chemical group 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- WTDHULULXKLSOZ-UHFFFAOYSA-N hydroxylamine hydrochloride Substances Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 238000005292 vacuum distillation Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 244000005700 microbiome Species 0.000 description 5
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 4
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 4
- LUIDLGSVCGOJGK-UHFFFAOYSA-N 6-(chloromethyl)-4-methylpyran-2-one Chemical compound CC=1C=C(CCl)OC(=O)C=1 LUIDLGSVCGOJGK-UHFFFAOYSA-N 0.000 description 4
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
- YXVFYQXJAXKLAK-UHFFFAOYSA-N biphenyl-4-ol Chemical compound C1=CC(O)=CC=C1C1=CC=CC=C1 YXVFYQXJAXKLAK-UHFFFAOYSA-N 0.000 description 4
- 230000000855 fungicidal effect Effects 0.000 description 4
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- JQZAEUFPPSRDOP-UHFFFAOYSA-N 1-chloro-4-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C=C1 JQZAEUFPPSRDOP-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 206010017533 Fungal infection Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000000843 anti-fungal effect Effects 0.000 description 3
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 3
- 229960004022 clotrimazole Drugs 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 244000144972 livestock Species 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- XMWGTKZEDLCVIG-UHFFFAOYSA-N 1-(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1 XMWGTKZEDLCVIG-UHFFFAOYSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- QCOBRTWWFHKJFN-UHFFFAOYSA-N 1-hydroxy-4-methyl-6-[[3-(naphthalen-1-ylmethoxy)phenyl]sulfanylmethyl]pyridin-2-one Chemical compound ON1C(=O)C=C(C)C=C1CSC1=CC=CC(OCC=2C3=CC=CC=C3C=CC=2)=C1 QCOBRTWWFHKJFN-UHFFFAOYSA-N 0.000 description 2
- QXRPZAARCBAZKD-UHFFFAOYSA-N 3-(naphthalen-1-ylmethylsulfanyl)phenol Chemical compound OC1=CC=CC(SCC=2C3=CC=CC=C3C=CC=2)=C1 QXRPZAARCBAZKD-UHFFFAOYSA-N 0.000 description 2
- XQMRZWSYBUCVAX-UHFFFAOYSA-N 4-(4-chlorophenoxy)phenol Chemical compound C1=CC(O)=CC=C1OC1=CC=C(Cl)C=C1 XQMRZWSYBUCVAX-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 241001045770 Trichophyton mentagrophytes Species 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- MXZNUGFCDVAXLG-CHWSQXEVSA-N [(2S)-1-[(2R)-3-methyl-2-(pyridine-4-carbonylamino)butanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@@H](NC(=O)c1ccncc1)C(=O)N1CCC[C@@H]1B(O)O MXZNUGFCDVAXLG-CHWSQXEVSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
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- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- IWTYTFSSTWXZFU-QPJJXVBHSA-N [(e)-3-chloroprop-1-enyl]benzene Chemical compound ClC\C=C\C1=CC=CC=C1 IWTYTFSSTWXZFU-QPJJXVBHSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 239000003809 bile pigment Substances 0.000 description 1
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000037304 dermatophytes Effects 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- LTYMSROWYAPPGB-UHFFFAOYSA-N diphenyl sulfide Chemical class C=1C=CC=CC=1SC1=CC=CC=C1 LTYMSROWYAPPGB-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 208000024386 fungal infectious disease Diseases 0.000 description 1
- 244000053095 fungal pathogen Species 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- RBLWMQWAHONKNC-UHFFFAOYSA-N hydroxyazanium Chemical compound O[NH3+] RBLWMQWAHONKNC-UHFFFAOYSA-N 0.000 description 1
- 150000002443 hydroxylamines Chemical class 0.000 description 1
- WCYJQVALWQMJGE-UHFFFAOYSA-M hydroxylammonium chloride Chemical compound [Cl-].O[NH3+] WCYJQVALWQMJGE-UHFFFAOYSA-M 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- SVEUVITYHIHZQE-UHFFFAOYSA-N n-methylpyridin-2-amine Chemical compound CNC1=CC=CC=N1 SVEUVITYHIHZQE-UHFFFAOYSA-N 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229960005323 phenoxyethanol Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000011182 sodium carbonates Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 239000000003 vaginal tablet Substances 0.000 description 1
- 229940044977 vaginal tablet Drugs 0.000 description 1
- 238000005303 weighing Methods 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
- C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Pyridine Compounds (AREA)
- Pyrane Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
(57)【要約】本公報は電子出願前の出願データであるた
め要約のデータは記録されません。(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】
本発明は後記式■で表わされる新規な１−ヒドロキシ−
２−ピリドン類、主として真菌および酵母菌による感染
症を抑制するためのそれらの用途およびこれらの化合物
を含有する医薬に関し、さらにまた新規１−ヒドロキシ
−２−ピリドン類の製造において生成される特定の中間
体に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 1-hydroxy-
Concerning 2-pyridones, their use primarily for inhibiting fungal and yeast infections and medicaments containing these compounds, and also regarding certain compounds produced in the production of novel 1-hydroxy-2-pyridones. Regarding intermediates.
***特許第２，２３４，００９号明細書には式■−１７
＝
（式中Ｒ１はとりわけ１〜４個の炭素原子のアルキルを
有するアリールオキシアルキルまたはアリールメルカプ
トアルキルを表ゎｆ−）で示される化合物が開示されて
いる。これらの基の唯一の具体的説明はフェニルオキシ
メチルまたはフェニルメルカプトメチルだけである。西
独特許第２，２３４，００９号明細書によれば、アリー
ルオキシアルキルまたはアリールメルカプトアルキルの
外にＲ１はまた種々のその他の基例えばアリール、１〜
４個の炭素原子のアルキルを有スるアルアルキル、２〜
４個の炭素原子のアルケニルを有するアリールアルケニ
ル、ベンズヒドリルおよび１〜４個の炭素原子のアルキ
ルを有するフェニルスルホニルアルキルをも表ワスこと
ができる。前記特許にはこれらの基について具体例が示
されている場合、それらは常に、−アリール基それ自体
（且つまたナフチルとしても述べられているが）を除い
て一場合により１〜４個の炭素原子を有するアルキル基
、１〜４個の炭素原子を有するアルコキシ基、ニトロ基
、シアノ基またはハロゲンによって置換されているフェ
ニル基だけである。これに対して１本発明は６−位の置
換基（式ｎ中のＲ１）が少なくとも２個の離れていて且
つ場合により置換された芳香環を含有し且つオキシメチ
ル基またはチオメチル基を介してピリドン残基に結合し
ている芳香族系を有する１−ヒドロキシ−２−ピリドン
誘導体に関するもので、その誘導体は一般式Ｉによって
表わされる。In West German Patent No. 2,234,009, the formula ■-17
Compounds of the formula = (f-) in which R1 represents, inter alia, aryloxyalkyl or arylmercaptoalkyl having alkyl of 1 to 4 carbon atoms are disclosed. The only specific illustrations of these groups are phenyloxymethyl or phenylmercaptomethyl. According to DE 2,234,009, in addition to aryloxyalkyl or arylmercaptoalkyl, R1 can also contain various other groups, such as aryl, 1-
aralkyl having alkyl of 4 carbon atoms, 2-
Arylalkenyl with alkenyl of 4 carbon atoms, benzhydryl and phenylsulfonylalkyl with alkyl of 1 to 4 carbon atoms can also be used. Where specific examples are given for these groups in said patents, they always include groups of 1 to 4 carbon atoms, with the exception of the -aryl group itself (and also mentioned as naphthyl). Only alkyl groups having atoms, alkoxy groups having 1 to 4 carbon atoms, nitro groups, cyano groups or phenyl groups substituted by halogens. In contrast, the present invention provides a method in which the substituent at the 6-position (R1 in formula n) contains at least two separate and optionally substituted aromatic rings and is linked via an oxymethyl group or a thiomethyl group. It concerns 1-hydroxy-2-pyridone derivatives having an aromatic system attached to the pyridone residue, which derivatives are represented by the general formula I.
すなわち１本発明は一般式Ｉ 〔式中。That is, 1 the present invention is based on the general formula I [During the ceremony.
Ｒ１，Ｒ２およびＲ５は同一で５あるかまたは相異なっ
ていて、水素または１〜４個の炭素原子を有する低級ア
ルキルを表わすが Ｒ１およびＲ２け好ましくは水素で
あり Ｒ２は好ましくはメチルであり。R1, R2 and R5 are the same 5 or different and represent hydrogen or lower alkyl having 1 to 4 carbon atoms, R1 and R2 are preferably hydrogen and R2 is preferably methyl.
ＸはＳまたは好ましくは０を表わし、
Ｙは水素または２個までのハロゲン原子、すなわち塩素
および／または臭素を表わし。X represents S or preferably 0; Y represents hydrogen or up to two halogen atoms, ie chlorine and/or bromine.
２は単結合または２価の基のＯ，Ｓ、 −ＣＲ２−（Ｒ
＝Ｈもしくは０１〜ｃ４−アルキル）または２〜１０個
の炭素並びに場合により、飴を形昨するのに結合された
酸素および（！、たけ）硫黄原子を有するその他の２価
基を表わし、その際該第が２個またはそれ以上の酸素お
よび（または）硫黄原子を含有する場合には、これらの
原子は少なくとも２個の炭素原子によって隔てられるこ
とを必須としそして２個の隣接炭素原子はまた二重結合
によって結合され且つ該炭素原子の自由原子１曲はＨお
よび／または０１〜ｃ４−アルキル基により飽和されて
いることが可能であり、Ａｒけ２個までの環を有し且つ
弗素、塩素、臭素、メトキシ、０１〜Ｃ４−アルキル、
トリフルオロメチルおよびトリフルオロメトキシからな
る群より選択される６個までの基によって置換されうる
芳香族環系を表わす〕で示される１−ヒドロキシ−２−
ピリドンに関する。2 is a single bond or a divalent group O, S, -CR2-(R
=H or 01-c4-alkyl) or other divalent radicals having 2 to 10 carbons and optionally oxygen and (!) sulfur atoms attached to form the candy; When said number contains two or more oxygen and/or sulfur atoms, these atoms must be separated by at least two carbon atoms and two adjacent carbon atoms must also be separated. bonded by a double bond and one free atom of said carbon atom can be saturated by H and/or 01-c4-alkyl groups, having up to two rings and fluorine, Chlorine, bromine, methoxy, 01-C4-alkyl,
1-hydroxy-2- represents an aromatic ring system which can be substituted by up to 6 groups selected from the group consisting of trifluoromethyl and trifluoromethoxy
Regarding pyridone.
２基における炭素鎖はＯＨ２基が好ましい。該ＣＨ２基
が０１〜Ｃ４−アルキル基により置換されている場合、
好ましい置換基はＯＨ３および０２Ｈ５である。２基の
例としては以下のものを挙げるととができる。The carbon chain in the two groups is preferably an OH2 group. When the CH2 group is substituted by an 01-C4-alkyl group,
Preferred substituents are OH3 and 02H5. Two examples are listed below.
−Ｏ−、−８−、−０Ｈ２−，−（ＣＨ２）ｍ−（ｍ＝
２〜１０）、−ｃ（ａＨｇ）２−＋−ＣＨ２０−、０Ｃ
Ｈ２−、−０Ｈ２Ｓ−、−８ＯＨ２−、−８ＯＨ（０２
Ｈ５）−。-O-, -8-, -0H2-, -(CH2)m- (m=
2-10), -c(aHg)2-+-CH20-, 0C
H2-, -0H2S-, -8OH2-, -8OH(02
H5)-.
２ｌ−
−ｏＨ−ｃ＋ｎ−ｏｎ２ｏ−、−０−ＯＨ２−ＯＨ＝Ｏ
Ｈ−ＯＨ２０−１−ｏｃＨ２ａａ２ｏ−。2l- -oH-c+n-on2o-, -0-OH2-OH=O
H-OH20-1-ocH2aa2o-.
−０ＯＨ２０Ｈ２０Ｈ２０−、−５ａＨ２ｃｕ２ｃｎ２
ｓ−、−５ａｎ２ｃｕ２ａＨ２ｃａ２ｏ−。-0OH20H20H20-, -5aH2cu2cn2
s-, -5an2cu2aH2ca2o-.
−８ＯＨ２０Ｈ２００Ｈ２０Ｈ２０−、−８ＯＨ２０Ｈ
２００Ｈ２０Ｈ２０−ＯＨ２０Ｈ２Ｓ−。-8OH20H200H20H20-, -8OH20H
200H20H20-OH20H2S-.
−８−ＯＨ２−０（ＯＨ５）２−ＯＨ２−８−１等「芳
香族環系」の用語は、フェニル系並びに縮合系例えばナ
フチル、テトラヒドロナフチルおよびインデニル、並び
に隔離された系例えばビフェニル、ジフェニルアルカン
類、ジフェニルエーテル類およびジフェニルチオエーテ
ル類から誘導されるものを包含する。The term "aromatic ring system" such as -8-OH2-0(OH5)2-OH2-8-1 refers to phenyl systems as well as fused systems such as naphthyl, tetrahydronaphthyl and indenyl, and isolated systems such as biphenyl, diphenylalkanes. , diphenyl ethers and diphenylthioethers.
式■によって定義される化合物の重要な代表例としては
以下のものを挙げることができる。Important representative examples of compounds defined by formula (1) include the following:
６−Ｃ４−（４−”ロロフエノキシ）フェノキシメチル
〕−１−ヒドロキシ−４−メチル−２−ピリドン、融点
１６７℃（１）。6-C4-(4-''lolophenoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 167°C (1).
６− ［４−（２，４−ジクロロフェノキン）フェノキ
シメチル〕−１−ヒドロキシ−４ノブルー２−ピリドン
、融点１６２℃（２）。6-[4-(2,4-Dichlorophenoquine)phenoxymethyl]-1-hydroxy-4-noble 2-pyridone, melting point 162°C (2).
６−＜ビフェニリル−４−オキシメチル）−１−ヒドロ
キシ−４−メチル−２−ピリドン。6-<biphenylyl-4-oxymethyl)-1-hydroxy-4-methyl-2-pyridone.
融点１８４°Ｃ（３）、
６−（４−ベンジルフェノキシメチル）−１−ヒドロキ
シ−４−メチル−２−Ｌ’ ＩＪトン、融点１４９℃（
４）。Melting point 184°C (3), 6-(4-benzylphenoxymethyl)-1-hydroxy-4-methyl-2-L' IJton, melting point 149°C (
4).
６− Ｃ４−（２，４−ジクロロばンジルオキシ）フェ
ノキシメチル〕−１−ヒドロキシ−４−メチル−２−ピ
リドン、融点１７２℃（５）。6-C4-(2,4-dichlorobandyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 172°C (5).
６−Ｃ４−Ｃ４−クロロフェノキシ）フェノキシメチル
〕−１−ヒドロキシ−３，４−ジメチル−２−ピリドン
、融点１５５°Ｃ（６）。6-C4-C4-chlorophenoxy)phenoxymethyl]-1-hydroxy-3,4-dimethyl-2-pyridone, melting point 155°C (6).
６− Ｃ４−（２，４−ジクロロベンジル）フェノキシ
メチル〕−１−ヒドロキシ−６，４−ジメチル−２−ピ
リドン、融点１６９℃（ハ、６−（４−（シンナミルオ
キシ）フェノキシメチル〕−１−ヒドロキシ−４−メチ
ル−２−ピリドン、融点１７９℃（８）。6-C4-(2,4-dichlorobenzyl)phenoxymethyl]-1-hydroxy-6,4-dimethyl-2-pyridone, melting point 169°C (c, 6-(4-(cinnamyloxy)phenoxymethyl)- 1-Hydroxy-4-methyl-2-pyridone, melting point 179°C (8).
１−ヒドロキシ−４−メチル−６−（４−（４−トリフ
ルオロメチルフェノキシ）フェノキシメチルツー２−ピ
リドン、融点１４９℃（９）。1-Hydroxy-4-methyl-6-(4-(4-trifluoromethylphenoxy)phenoxymethyl-2-pyridone, mp 149°C (9).
１−ヒドロキシ−４−メチル−６−［４−（１−ナフチ
ルメトキシ）フェノキシメチルツー２−ピリドン、融点
１７９℃（１０） 。1-Hydroxy-4-methyl-6-[4-(1-naphthylmethoxy)phenoxymethyl-2-pyridone, melting point 179°C (10).
６−（４−（４−クロロフェノキシ）フェノキシメチル
〕−１−ヒドロキシ−４，５−ジメチル−２−ピリドン
（１１） 。6-(4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-4,5-dimethyl-2-pyridone (11).
６−Ｃ４−＜４−＜４−クロロフェノキシ）フェノキシ
メチル）フェノキシメチル、］−］１−ヒドロキシー４
−メチルー２ピリドン、融点１５８℃（１２）、
６− （２，６−：）クロロ−４−（２−ナフチルチオ
メチル）フェノキシメチル〕−１−ヒドロキシ−４−メ
チル−２−ピリドン、吊虫点１６８”Ｃ（１３）。6-C4-<4-<4-chlorophenoxy)phenoxymethyl)phenoxymethyl,]-]1-hydroxy-4
-Methyl-2-pyridone, melting point 158°C (12), 6-(2,6-:)chloro-4-(2-naphthylthiomethyl)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, H. Point 168”C (13).
６− （２，６−ジクロロ−４−（４−フェニルフェノ
キシメチル）フェノキシメチル：）−１−ヒドロキシ−
４−メチル−２−ピリドン、融点１９０℃（１４）。6-(2,6-dichloro-4-(4-phenylphenoxymethyl)phenoxymethyl:)-1-hydroxy-
4-Methyl-2-pyridone, melting point 190°C (14).
６−Ｃ４−Ｃ４−クロロベンジルオキシ）フェノキシメ
チル〕−１−ヒドロキシ−４−メチル−２−ピリドン、
融点１７３℃（１５）。6-C4-C4-chlorobenzyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone,
Melting point 173°C (15).
１−ヒドロキシ−４−メチル−６−（４−（４−トリフ
ルオロメトキシ×ンジルオキシ）フェノキシメチルツー
２−ピリドン、融点１４３℃（１６）、
６−Ｃ４−＜４−第三ブチルベンジルオキシ）フェノキ
シメチル〕−１−ヒドロキシ−４−メチル−２−ピリド
ン、融点１８１℃（１７）＆６−［２−（４−クロロベ
ンジルオキシ）フエノキシメチル〕−１−ヒドロキシ−
４−メチル−２−ピリドン、融点１６１℃（１８）。1-Hydroxy-4-methyl-6-(4-(4-trifluoromethoxyxndyloxy)phenoxymethyl-2-pyridone, melting point 143°C (16), 6-C4-<4-tert-butylbenzyloxy)phenoxy Methyl]-1-hydroxy-4-methyl-2-pyridone, melting point 181°C (17) & 6-[2-(4-chlorobenzyloxy)phenoxymethyl]-1-hydroxy-
4-Methyl-2-pyridone, melting point 161°C (18).
１−ヒドロキシ−４−メチル−６−（２−（ナフト−１
−イル−メトキシ）フェノキシメチルツー２−ピリドン
、融点１５０℃Ｃ１ｑ）。1-hydroxy-4-methyl-6-(2-(naphtho-1
-yl-methoxy)phenoxymethyl-2-pyridone, melting point 150°C C1q).
１−ヒドロキシ−４−メチル−６−〔ろ−Ｃ１−ナフチ
ルメトキシ）フエ、ノキシタチＡ］−２−ピリＶン、融
点１５５℃（２０）。1-Hydroxy-4-methyl-6-[ro-C1-naphthylmethoxy)]-2-pyrylene, melting point 155°C (20).
６−［３−（４−クロロベンジルオキシ）フェノキシメ
チル〕−１−ヒドロキシ−４−メチル−２−ピリドン、
融点１４９℃（２１）。6-[3-(4-chlorobenzyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone,
Melting point 149°C (21).
６−Ｃ４−Ｃ４−クロロフェノキシ）フェノキシメチル
〕−１−ヒドロキシ−２−ピリドン、融点１８０℃（２
２）。6-C4-C4-chlorophenoxy)phenoxymethyl]-1-hydroxy-2-pyridone, melting point 180°C (2
2).
６−（２，６−ジクロロ−４−（４−クロロフェノキシ
）フェノキシメチル〕−１−ヒドロキシ−４−メチル−
２−ピリドン、融点１５０℃（２３）。6-(2,6-dichloro-4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-4-methyl-
2-Pyridone, melting point 150°C (23).
６−（４−ベンジルオキシ−２，６−ジクロロフエノキ
シメチル）−１−ヒドロキシ−４−メチル−２−ピリド
ン、融点１６１℃（２４）。6-(4-benzyloxy-2,6-dichlorophenoxymethyl)-1-hydroxy-4-methyl-2-pyridone, m.p. 161°C (24).
６− （２，６−’）クロロ−４−フェニルフェノキシ
メチル）−１−ヒドロキシ−４−メチル−２−ピリドン
、融点１９５℃（２５）。6-(2,6-')chloro-4-phenylphenoxymethyl)-1-hydroxy-4-methyl-2-pyridone, m.p. 195°C (25).
６−（４−（４−プロモー２−クロロフェノキシ）フェ
ノキシメチル〕−１−ヒドロキシ−４−メチル−２−ピ
リドン、融点１７４℃（２６）。6-(4-(4-promo-2-chlorophenoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, mp 174°C (26).
１−ヒドロキシ−４−メチル−６−Ｃ４−（３，４，５
−トリメトキシベンジルオキシ）フェノキシメチル〕−
２−ピリドン、融点１５４℃（２７）。1-hydroxy-4-methyl-6-C4-(3,4,5
-Trimethoxybenzyloxy)phenoxymethyl]-
2-Pyridone, melting point 154°C (27).
６− （４−（２，４−ジクロロベンジル）フェノキシ
メチル〕−１−ヒドロキシ−４−メチル−２−ピリドン
、融点１７３℃（２８）。6-(4-(2,4-dichlorobenzyl)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, m.p. 173°C (28).
６− （２，６−ジプロモー４−（４−クロロフェノキ
シ）フェノキシメチル〕−１−ヒドロキシ−４−メチル
−２−ピリドン（２９）、６− （２，６−ジブロモ−
４−フェニルフェノキシメチル）−１−ヒドロキシ−４
−メチル−２−ピリドン（３０）。6-(2,6-dibromo4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone (29), 6-(2,6-dibromo-
4-phenylphenoxymethyl)-1-hydroxy-4
-Methyl-2-pyridone (30).
６−＜２−プロモー４−フェニルフェノキシメチル）−
１−ヒドロキシ−４−メチル−２−ピリドン、融点２４
５℃（３１）、
６−（２−プロモー６−クロロ−４−フェニルフェノキ
シメチル）−１−ヒドロキシ−４−メチル−２−ピリド
ン（３２）。6-<2-promo 4-phenylphenoxymethyl)-
1-Hydroxy-4-methyl-2-pyridone, melting point 24
5°C (31), 6-(2-promo-6-chloro-4-phenylphenoxymethyl)-1-hydroxy-4-methyl-2-pyridone (32).
６−Ｃ４−＜４−フルオロフェノキら）ブＪツキジメチ
ル〕−１−ヒドロキシ−４−メブ九−２−ピリドン、融
点１５１℃（３３）。6-C4-<4-Fluorophenoki et al.)butydimethyl]-1-hydroxy-4-mebu-9-2-pyridone, melting point 151°C (33).
６−Ｃ３−＜４−クロロフェニルチオ）フェノキシメチ
ル〕−１−ヒドロキシ−４１４−１゜−２−ピリドン（
３４）。6-C3-<4-chlorophenylthio)phenoxymethyl]-1-hydroxy-414-1°-2-pyridone (
34).
１−ヒドロキシ−４−メチル−６−（３−（１−ナフチ
ルメチルチオ）フェノキシメチル〕−２−ピリドン、融
点１４４℃＜５５）。1-Hydroxy-4-methyl-6-(3-(1-naphthylmethylthio)phenoxymethyl]-2-pyridone, melting point 144°C<55).
１−ヒドロキシ−４−メチル−６−（３−（１−ナフチ
ルメトキシ）フェニルチオメチル〕−２−ピリドン、融
点１６５℃（３６）。1-Hydroxy-4-methyl-6-(3-(1-naphthylmethoxy)phenylthiomethyl]-2-pyridone, mp 165°C (36).
１−ヒドロキシ−４−メチル−６−（２−フェニルフェ
ノキシメチル＞ −２−ピリドン、融点１７９℃（３７
）。1-Hydroxy-4-methyl-6-(2-phenylphenoxymethyl>-2-pyridone, melting point 179°C (37
).
６−Ｃ２−ばンジルフエノキシメチル）−１−ヒトロキ
シー４−メチル−２−ピリドン、融点１５５℃（３８）
。6-C2-vanzylphenoxymethyl)-1-hydroxy4-methyl-2-pyridone, melting point 155°C (38)
.
１−ヒドロキシ−５，４−’）メチル−６−〔３−（１
−ナフチルメチルチオ）フェノキシメチル〕−２−ピリ
ドン、融点１４３℃（３９）。1-hydroxy-5,4-')methyl-6-[3-(1
-naphthylmethylthio)phenoxymethyl]-2-pyridone, melting point 143°C (39).
６− （２，４−）フロモー６−フェニルフェノキシメ
チル）−１−ヒドロキシ−４−メチル−２−ピリドン、
融点１３０℃（４０）。6-(2,4-)furomor6-phenylphenoxymethyl)-1-hydroxy-4-methyl-2-pyridone,
Melting point 130°C (40).
６−（４−（４−（４−クロロフェノキシ）フェノキシ
）フェノキシメチル〕−１−ヒドロキシ−４−メチル−
２−ピリドン、融点１００”Ｃ（４１）％
６−［３−（４−クロロベンジルオキシ）フェニルチオ
メチル］−１−ヒドロキシ−４−メチル−２−ピリドン
、融点９４℃（４２）。6-(4-(4-(4-chlorophenoxy)phenoxy)phenoxymethyl]-1-hydroxy-4-methyl-
2-Pyridone, mp 100"C (41)% 6-[3-(4-chlorobenzyloxy)phenylthiomethyl]-1-hydroxy-4-methyl-2-pyridone, mp 94C (42).
６−Ｃ４−（４−クロロフェニルチオ）フェノキシメチ
ル〕−１−ヒドロキシ−４−メチル−２−ピリドン、融
点１５８℃（４３）。6-C4-(4-chlorophenylthio)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, mp 158°C (43).
１−ヒＶロキシー６−（４−（４−メトキシフェニルチ
オ）フェノキシメチル〕−４−メチル−２−ピリドン、
融点１６２℃（４４）、１−ヒト１０キシ−４−メチル
−６−（３−（２＝フエノキシエトキシ）フェノキシメ
チル〕＝２−ビリＶン、融点１４８℃（４５）。1-HyVroxy6-(4-(4-methoxyphenylthio)phenoxymethyl]-4-methyl-2-pyridone,
Melting point 162°C (44), 1-human 10xy-4-methyl-6-(3-(2=phenoxyethoxy)phenoxymethyl)=2-bilin, melting point 148°C (45).
６−Ｃ４−＜４−クロロフェノキシプロポキシ）フェノ
キシメチル〕−１−ヒドロキシ−４−メチル−２−ピリ
ドン、融点１６２℃（４６） ＊６−［３−（４−クロ
ロフェニルチオプロピルチオ）フェノキシメチル］−１
−ヒドロキシ−４−メチル−２−ピリドン、融点１０２
℃（４７）。6-C4-<4-chlorophenoxypropoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 162°C (46) *6-[3-(4-chlorophenylthiopropylthio)phenoxymethyl] -1
-Hydroxy-4-methyl-2-pyridone, melting point 102
°C (47).
６−Ｃ３−（４−クロロフェニルチオフトキシ）フェノ
キシメチル〕−１−ヒドロキシ−４−メチル−２−ピリ
ドン、融点１０４℃（４８）、６−Ｃ３−＜４−クロロ
フェニルチオエトキシエトキシ）フェノキシメチル〕−
１−ヒドロキシ−４−メチル−２−ピリドン、融点９８
℃（４９）。6-C3-(4-chlorophenylthiophthoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 104°C (48), 6-C3-<4-chlorophenylthioethoxyethoxy)phenoxymethyl] −
1-Hydroxy-4-methyl-2-pyridone, melting point 98
°C (49).
６−（４−（α、α−ジメチルー４−メトキシばンジル
）フェノキシメチル〕−１−ヒドロキシ−４−メチル−
２−ピリドン、融点１５６℃（５０）。6-(4-(α,α-dimethyl-4-methoxyvanzyl)phenoxymethyl]-1-hydroxy-4-methyl-
2-Pyridone, melting point 156°C (50).
６−（３−［１−（４−クロロフェニルチオ）−２，２
−ジメチルプロプ−６−イルチオ〕フェノキシメチル〉
−１−ヒドロキシ−４−メチル−２−ピリドン、融点１
３４°Ｃ（５１） 。6-(3-[1-(4-chlorophenylthio)-2,2
-dimethylprop-6-ylthio]phenoxymethyl>
-1-hydroxy-4-methyl-2-pyridone, melting point 1
34°C (51).
６−＜４−［１−（４−クロロフェニル）ブドー２−エ
ン−４−イルオキシ〕フェノキシメチル〉−１−ヒドロ
キシ−４−メチル−２−ピリＦン、融点１６７℃（５２
）。6-<4-[1-(4-chlorophenyl)boudo-2-en-4-yloxy]phenoxymethyl>-1-hydroxy-4-methyl-2-pyrifone, melting point 167°C (52
).
６−（３−（４−クロロフェニルチオエトキシエトキシ
ヱチルチオ）フェノキシメチル〕−１−ヒｖロキシー４
−メチル−２−ピリドン、融点９５℃（５３）。6-(3-(4-chlorophenylthioethoxyethoxyethylthio)phenoxymethyl]-1-hydroxy4
-Methyl-2-pyridone, melting point 95°C (53).
６−（４−（１−（４−クロロフェニル）−５−はンチ
ル〕フェノキシメチル〉−１−ヒドロキシ−４−メチル
−２−ピリドン、融点１５９”Ｃ（５４）。6-(4-(1-(4-chlorophenyl)-5-ethylphenoxymethyl)-1-hydroxy-4-methyl-2-pyridone, mp 159"C (54).
本発明化合物はそれ自体知られた種々の方法によって製
造でき１例えば式■
（式中Ｒ１，Ｒ２およびＲ５は前述の定義をＮＬ、ｓＨ
ａｌはハロゲン原子特に塩素または臭素原子を示す）の
６−ハロゲノメチル−２−ピロンを場合により適尚に置
換されている式■
（式中、Ｘ、Ｙ、ＺおよびＡｒは前述の定義を有するン
のフェノールまたはチオフェノールト反応させ、得られ
た式Ｖ
アリールオキシメチルピロンまたはアリールチオメチル
ピロンをヒドロキシルアミンの作用によりヒドロキシピ
リドンに変換することによって製造できる。アルキル化
は好都合にはプロトン性または非プロトン性溶媒例えば
メタノール。The compounds of the present invention can be produced by various methods known per se. For example, the compounds of the formula
6-halogenomethyl-2-pyrone of the formula (wherein X, Y, Z and Ar have the above definition The alkylation is conveniently carried out by reacting a phenol or thiophenol with a phenol or thiophenol and converting the resulting formula V aryloxymethylpyrone or arylthiomethylpyrone into a hydroxypyridone by the action of hydroxylamine. Protic solvents such as methanol.
エタノール、インプロパツール、アセトン、アセトニ）
ＩＪル、エチレングリコールジメチルエーテル、ジエ
チレングリコールジメチルエーテル、ジメチルホルムア
ミドもしくはジメチルスルホキシド中で行われるが、非
プロトン性溶媒の方が好ましい。遊離されているハロゲ
ン化水素を結合させるには無機または有機塩基例えば水
酸化ナトリウムもしくは水酸化カリウム、炭酸ナトリウ
ム、炭酸カリウムもしくは炭酸カルシウム、トリエチル
アばン、トリブチルアミン、ピリジン、４−ジメチルア
ミノピリジン、：５アザビシクロノナン、Ｎ−メチルビ
ぼりジンがとりわけ少なくとも当量で用いられる。反応
温度は一般に室温〜約８０℃であるが、しかしながら特
別の場合には明らかにより高いかまたはより低い温度例
えば１１０℃または０℃が有利でありうる。ethanol, impropatul, acetone, acetoni)
The reaction is carried out in IJ, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, dimethyl formamide or dimethyl sulfoxide, but aprotic solvents are preferred. To bind the liberated hydrogen halides, inorganic or organic bases are used, such as sodium or potassium hydroxide, sodium carbonate, potassium carbonate or calcium carbonate, triethylabane, tributylamine, pyridine, 4-dimethylaminopyridine: The 5-azabicyclononane, N-methyl biboridine, is especially used in at least an equivalent amount. The reaction temperature is generally between room temperature and about 80°C, but clearly higher or lower temperatures, such as 110°C or 0°C, may, however, be advantageous in special cases.
２−ピロンを１−ヒドロキシ−２−ピリドンに変換する
には、一般にはヒドロキシルアミンを無機せたけ有機酸
好適には塩酸、硫酸もしくは酢酸との塩の形態において
該ヒドロキシルアンモニウム塩に対して少なくとも約１
当量の塩基の存在下で反応させる。ヒドロキシルアミン
塩の量は用いるピロンに対して少なくとも約１モルであ
るが、しかしながら反応速度および収率を増加させるに
は過剰量例えば１モルに対して２〜１０モルを使用する
ことが好ましいし、さらにはこの量を反応時間中いくつ
かの部分に分けて加えるのが好ましい。この反応のだめ
の適当な塩基は有機と無機の両塩基である。好ましい有
機塩基はアミノピリジン（誘導体）並びにイミダゾール
（誘導体）例えば２−アミノピリジン、２−アミノピコ
リン、２−メチルアミノピリジン、イミダゾールおよび
２−メチルイミダゾールであり、好オしい無機塩基はア
ルカリ金属の炭酸塩および（または）炭酸水素塩（Ｌｔ
２ｃｏ３゜Ｎａ２００５． Ｋ２Ｏ０５，ＮａＨＯＪ、
ＫＨＯＪ、Ｒｂ２００５． ＣＢＨＯＯｘ。For the conversion of 2-pyrone to 1-hydroxy-2-pyridone, hydroxylamine is generally added in the form of a salt with an inorganic or organic acid, preferably hydrochloric acid, sulfuric acid or acetic acid, to the hydroxylammonium salt. 1
The reaction is carried out in the presence of an equivalent amount of base. The amount of hydroxylamine salt is at least about 1 mole based on the pyrone used; however, to increase the reaction rate and yield it is preferred to use an excess amount, e.g. 2 to 10 moles to 1 mole; Furthermore, it is preferable to add this amount in several portions during the reaction time. Suitable bases for this reaction are both organic and inorganic bases. Preferred organic bases are aminopyridine (derivatives) and imidazoles (derivatives) such as 2-aminopyridine, 2-aminopicoline, 2-methylaminopyridine, imidazole and 2-methylimidazole, and preferred inorganic bases are alkali metal carbonates. salt and/or bicarbonate (Lt
2co3°Na2005. K2O05, NaHOJ,
KHOJ, Rb2005. CBHOOx.
等）である。上記無機塩基のうちナトリウムおよびカリ
ウムの炭酸塩および炭酸水素塩１％にＮａ２００５が最
も適当である。etc.). Among the above inorganic bases, Na2005 is most suitable for 1% of sodium and potassium carbonates and hydrogen carbonates.
有機塩基は一般に、１吏用するピロンのモル当たり約１
〜２０モル好適には約３〜１０モルの量で用いられ、そ
れらは同時に溶媒として作用することができ、これはま
た通常、使用するヒドロキシルアンモニウム塩に関して
少なくともＰ１１当量の塩基が存在する条件を満たす。The organic base is generally about 1 mole of pyrone used.
~20 mol Preferably used in amounts of about 3 to 10 mol, which can act at the same time as a solvent, which also usually satisfies the condition that there are at least P11 equivalents of base with respect to the hydroxylammonium salt used. .
勿論１例えば本操作が低温で実施されうる場合にはその
系の融解範囲を減少させるのにこれら塩基の混合物を使
用することもできる。一般に、このための反応温度は約
２０℃〜１５０℃、好適には約５０℃〜１００℃である
。Of course, mixtures of these bases can also be used to reduce the melting range of the system, for example if the operation can be carried out at low temperatures. Generally, the reaction temperature for this is about 20<0>C to 150<0>C, preferably about 50<0>C to 100<0>C.
ノ、α機塩基を用いる場合には、有機塩基の場合と同様
に使用するヒドロキシルアンモニウム塩の蹟に対して少
なくともほぼ等量の量を加えるのが好都合である。例え
ばヒドロキシルアンモニウムクロライドのモル当たり少
なくとも１７２モルのＮａ ２００３または１モルのＮ
ａＨＣＯ２を使用すべきである。さらにまた、該無機塩
基を単釉および任意の所望混合物の両方で用いることも
できる。When using alpha bases, it is advantageous to add at least approximately the same amount to the hydroxylammonium salt used as in the case of organic bases. For example at least 172 mol Na 2003 or 1 mol N per mole of hydroxylammonium chloride
aHCO2 should be used. Furthermore, the inorganic bases can be used both in single glazes and in any desired mixtures.
無機塩基を用いてその変法を行うには２−ピロンをヒド
ロキシルアンモニウム塩この場合には好ｔＬ＜Ｒヒドロ
キシルアンモニウムスルフ−３フ−
エート、並びにアルカリ金属の炭酸塩および（または）
炭酸水素塩とともに混合し且つ生成する結晶物を、ピロ
ンができるだけ多く変換される筐で加熱するのが有利で
あり、無機塩の除去後に生成する２−ピリドンは直接単
離されうるかまたはより好ましくは有機塩基の塩例えば
エタノールアミン塩として単離されうる。A variant thereof using an inorganic base is to convert the 2-pyrone into a hydroxylammonium salt, in this case preferably tL<R hydroxylammonium sulf-3 phosphate, as well as an alkali metal carbonate and/or
It is advantageous to mix with the bicarbonate and to heat the resulting crystalline product in a housing in which as much pyrone is converted as possible, and the 2-pyridone formed after removal of the inorganic salt can be isolated directly or more preferably It can be isolated as a salt of an organic base, such as an ethanolamine salt.
この変法を行う際の温度は、決して約１２０℃を越える
べきではない。それは好都合には約５０°Ｃ以上、好適
には約６Ｄ〜１０５°Ｃである。The temperature when carrying out this variant should never exceed about 120°C. It is conveniently above about 50°C, preferably about 6D to 105°C.
さらにまた、有機塩基を用いる場合と無機塩基を用いる
場合の両変法では不活性溶媒または希釈剤を加えること
も可能である。これは一般には必要ではないけれども１
個々の場合には利点を有することができる。溶媒または
希釈剤が添加される場合これは一般に少量でのみ、通常
は全反応混合物の約５０重ｉ％まででなされる。Furthermore, it is also possible to add inert solvents or diluents in both the variants with organic and inorganic bases. Although this is generally not necessary, 1
There may be advantages in individual cases. If a solvent or diluent is added, this is generally done only in small amounts, usually up to about 50% by weight of the total reaction mixture.
好ましい量は約３〜１５重量係である。Preferred amounts are about 3 to 15 parts by weight.
該溶媒または希釈剤は、憾性もしくは非極性でありセし
て水ど混和性もしくは非混合性でありうる。使用できる
物質の例としては以下のもの、すなわち水、低分子量ア
ルコール例えばメタノール、エタノール、イソプロパツ
ール、エチレングリコール、エチレングリコールモノメ
チルエーテルおよびプロピレングリコール、アミド類例
えばジメチルホルムアミドおよびジエチルホルムアミド
、エーテル類例えばジイソプロピルエーテル、塩素化灰
化水素例えばクロロベンゼン、ニトリル類例えばアセト
ニトリルまたは脂肪族、指環式もしくは芳香族性の炭化
水素を挙げることができる。The solvent or diluent may be astringent or non-polar and water-miscible or immiscible. Examples of substances that can be used are: water, low molecular weight alcohols such as methanol, ethanol, isopropanol, ethylene glycol, ethylene glycol monomethyl ether and propylene glycol, amides such as dimethylformamide and diethylformamide, ethers such as diisopropyl. Mention may be made of ethers, chlorinated hydrogen ash such as chlorobenzene, nitriles such as acetonitrile or aliphatic, cyclic or aromatic hydrocarbons.
６−ハロゲノメチル−２−ピロン類、特にその塩素化合
物は、例えば（−０ｈｅｍｉｓｃｈｅ Ｂｅｒｉｃｈｔ
ｅ ｊす０（１９６７）、 ６５８は−ジに記載の方法
で製造することができる。6-halogenomethyl-2-pyrones, especially their chlorine compounds, can be used, for example (-0hemische Bericht
e jsu 0 (1967), 658 can be produced by the method described in -.
ヒドロキシピリドンを合成するだめの別の可能性は、２
−ハロゲノ−６−ピコリンの側Ｍハロゲン化を行って式
■
（式中Ｒ１，Ｒ２、Ｒ３およびＲａｎは前述の定義を有
する）を有する２−ハロゲノ−６−ハロゲノメチルピリ
ジンを得、そのハロゲノメチル基を場合により適当に置
換されているフェノールと反応させ、得られた化合物を
酸化してＮ−オキシドを得ついでその核上のハロゲンを
直接または間接的手段によって加水分解することからな
る。Another possibility for synthesizing hydroxypyridone is 2
- Halogeno-6-picoline is subjected to side M halogenation to obtain 2-halogeno-6-halogenomethylpyridine having the formula It consists of reacting the group with an optionally suitably substituted phenol, oxidizing the resulting compound to give the N-oxide and hydrolyzing the halogen on the nucleus by direct or indirect means.
前記のハロゲノメチル基とフェノールとの反応ハ、ハロ
ゲノメチルビロンとフェノールとの反応について前述し
たような条件下で行うのが好ましい。該ピリジンをそれ
らのＮ−オキシドに変換するのに用いる酸化剤は、無機
または有機例えば過酸化水素、過ギ酸、過酢酸、過安息
香酸、６−クロロ過安息香酸および第三ブチルヒドロは
ルオキシドであり、その変換は適切ならば例えば硫酸、
過塩素酸、トルエンスルホン酸、トリフルオロ酢酸およ
びトリフルオロメタンスルホン酸のような強酸による触
媒作用を用いて。The reaction between the halogenomethyl group and phenol is preferably carried out under the same conditions as described above for the reaction between halogenomethylviron and phenol. The oxidizing agents used to convert the pyridines to their N-oxides can be inorganic or organic, such as hydrogen peroxide, performic acid, peracetic acid, perbenzoic acid, 6-chloroperbenzoic acid and tert-butylhydroxide. , for example sulfuric acid, if the transformation is appropriate
With catalysis by strong acids such as perchloric acid, toluenesulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid.
好ましくは室温〜約１００“Ｃで実施される。前記の核
上ハロゲンの加水分解け１例えば水酸化ナトリウム、水
酸化カリウムもしくは水酸化バリウムのような塩基との
反応により直接的に行うことができるし、または次の番
には再び容易に除去されうるアルコール例えば第三ブタ
ノールもしくは２−メトキシエタノールとのエーテル化
により間接的に行うこともできる。Preferably carried out at room temperature to about 100"C. Hydrolysis of the supranuclear halogens 1 can be carried out directly by reaction with a base such as sodium hydroxide, potassium hydroxide or barium hydroxide. Alternatively, it can also be carried out indirectly by etherification with an alcohol, such as tert-butanol or 2-methoxyethanol, which can be easily removed again in the next turn.
本発明による一般式１の化合物の代表的な製遣方法を以
下の実施例により説明する。A typical method for preparing compounds of general formula 1 according to the present invention is illustrated by the following examples.
前記方法のうちの一方が、 Ａｒまだはピロン環中に依
然として反応性置換基を含廟する中間体を生成する場合
には、これらの置換基を介してＲ１−Ｒ３の定義および
Ａｒで指摘した置換基に相当するさらに別の基を導入す
ることが口」能である。If one of the above methods produces an intermediate that still contains reactive substituents in the pyrone ring, then the definitions of R1-R3 and the It is possible to introduce further groups corresponding to the substituents.
例えば、後に遊離のヒドロキシル基もしくはメルカプト
基をエーテル化することが可能であり。For example, it is possible to subsequently etherify free hydroxyl or mercapto groups.
または例えばアルデヒド基の還元により生成されたヒド
ロキシメチル基をハロゲノメチル基に変換することつい
でそのハロゲンをフェノールもしくはチオフェノールで
再び求核的に交換すＡことが可能である。また同様に、
式■のジハロゲノピコリンとフェノールとの反応から得
られるピリジン誘導体またはそれの酸化で得られるＮ−
オキシドが依然として反応性置換基を含有している場合
にはそれらを他の型の置換生成物に変換することも可能
である。Alternatively, it is possible, for example, to convert the hydroxymethyl group produced by reduction of an aldehyde group into a halogenomethyl group and then exchange the halogen nucleophilically again with phenol or thiophenol. Similarly,
Pyridine derivatives obtained from the reaction of dihalogenopicoline of formula ■ with phenol or N- obtained by oxidation thereof
If the oxides still contain reactive substituents, it is also possible to convert them into other types of substitution products.
本発明はまた。中間体として適当な式Ｖ（式中ＲζＲ２
、Ｒ３，Ｘ％ＹおよびＡｒは前述の定義を有する）を有
する化合物に関する。The present invention also includes: Formula V (where RζR2
, R3, X% Y and Ar have the above definitions).
本発明によれば式■の化合物は、病原性真菌例えば皮膚
糸状菌（繊維状真菌）および皮膚ないしは粘膜の両方に
作用する真菌例えば酵母菌（例えばカンジダ種）並びに
カビ（例えばアスはルギルスニガー）に対して広汎スは
クトルの作用を伴う優れた局所抗真菌性を有する。従っ
てそれらは例えば犬、猫および鳥のような家庭内家畜並
びに例えば反物動物、馬および豚のような商業家畜の動
物医薬、およびヒトの医薬においてこれら病原体によっ
て惹起される感染症を抑制するのに使用されうる。該ヒ
ドロキシピリドン類は、真菌抑制用の常套製剤例えば溶
液。According to the invention, compounds of the formula (III) are used against pathogenic fungi, such as dermatophytes (filamentous fungi) and fungi that act on both the skin and the mucous membranes, such as yeasts (e.g. Candida sp.) and molds (e.g. Asus niger). On the other hand, the broad spectrum has excellent topical antifungal properties with the action of a cuttle. They are therefore useful in veterinary medicine for domestic livestock such as dogs, cats and birds as well as commercial livestock such as livestock animals, horses and pigs, and in human medicine to control infections caused by these pathogens. can be used. The hydroxypyridones are used in conventional formulations for fungal control, such as solutions.
懸濁−ｔＬ、クリーム、軟膏、粉剤または坐剤（膣錠剤
）として遊前形態でまたは無機もしくは有機塩基（例え
ばＮａＯＨ，ＫＯＨ，０ａ（ＯＨ）２． ＮＨ５゜Ｈ２
ＮＯＨ２０Ｈ２０Ｈ等）とのそれらの生理学的に許容し
うる塩の形態で使用されうる。新規製剤は特にそれらの
高い殺真菌活性および感染部位における長い保持時間に
よって特徴づけられ、且つこの点において後記の比較試
験に示されるように標準の商業製剤よりも優れている。Suspension-tL, as a cream, ointment, powder or suppository (vaginal tablet) in pre-absorbent form or with an inorganic or organic base (e.g. NaOH, KOH, 0a(OH)2.NH5°H2
NOH20H20H etc.) may be used in the form of their physiologically acceptable salts. The new formulations are particularly characterized by their high fungicidal activity and long retention time at the site of infection and are superior in this respect to standard commercial formulations, as shown in the comparative tests below.
さらにこれらの化合物は抗菌活性を有し且つ例えばヘル
はスウイルスに対して抗ウィルス活性も有する。Furthermore, these compounds have antibacterial activity and also antiviral activity, for example against viruses.
実施例
１： ６−Ｃ４−（２，４−ジクロロベンジル）フェ
ノキシメチル〕−１−ヒドロキシ−３，４−ジメチル−
２−ピリドン（化合物１９．８５ｊｌの６−クロロメチ
ル−３，４−ジメチル−２−ピロン（化合物Ａ）および
２５．３９の４− （２，４−ジクロロベンジル）フェ
ノールヲ７０１ｒｌＱのジメチルホルムアミドに溶解し
、２０９の微砕炭酸カリウムを加えそして混合物を室温
で４８時間攪拌した。ついで２ＱＱｍＱのメチレンクロ
ライドおよび５ＤＤｍＱの水を加え、各層を分離しそし
て有機相をそれぞれ１ｏｏｍｅの水で２回洗浄し、乾燥
させついでウォータポンプ真空下で蒸発させた。４２．
７９の残留物は薄層クロヤトグラフイーによりほとんど
純粋であり、これを２００Ｆの２−アミノピリジンとと
もに７５℃で５６時間加熱したが、その際最初の４１時
間中Ｋ ＶＢ ｔｔ ４ ｔ ７９のヒドロキシルアミ
ン塩酸塩を５回に分けて加えた。ついで２５０峨のメチ
レンクロライドを加え、その有機相を希塩酸で１回そし
て水で２回洗浄し、溶媒な波圧蒸留で除去した。３９．
７９の残留物をエチレングリコールモノメチルエーテル
から再結晶させて３２．５Ｆの純粋なヒドロキシピリド
ンを得た。融点１６９℃。Example 1: 6-C4-(2,4-dichlorobenzyl)phenoxymethyl]-1-hydroxy-3,4-dimethyl-
2-pyridone (compound 19.85jl of 6-chloromethyl-3,4-dimethyl-2-pyrone (compound A) and 25.39g of 4-(2,4-dichlorobenzyl)phenol dissolved in 701rlQ of dimethylformamide 209 ml of finely ground potassium carbonate was added and the mixture was stirred at room temperature for 48 hours. Then 2QQmQ of methylene chloride and 5DDmQ of water were added, the layers were separated and the organic phase was washed twice with 1oome of water each, Dry and evaporate under water pump vacuum.42.
The residue of 79 was nearly pure by thin layer chromatography and was heated with 200F 2-aminopyridine at 75°C for 56 hours, during the first 41 hours the hydroxyl of K VB tt 4 t 79 Amine hydrochloride was added in 5 portions. Then 250 μm of methylene chloride was added and the organic phase was washed once with dilute hydrochloric acid and twice with water, and the solvent was removed by wave pressure distillation. 39.
The residue of 79 was recrystallized from ethylene glycol monomethyl ether to give 32.5F pure hydroxypyridone. Melting point: 169°C.
２〜１９： 実施例１と同じ方法で、４−（４−クロロ
フェノキシ）フェノールおよびＡから出発して化合物６
を得、３−（１−ナフチルメチルチオ）フェノールおよ
びＡから化合物３９を得、４−（４−１０ロフエノキシ
）フェノールおよび６−クロロメチル−４−メチル−２
−ピロン（化合物Ｂ）から化合物１を得、 ４−（２，
４−ジクロロフェノキシ）フェノールおよびＢから化合
物２を得、４−（４−トリフルオロメチルフェノキシ）
フェノールおよびＢから化合物９を得、２，６−ジクロ
ロ−４−（４−クロロフェノキシ）フェノールおよびＢ
から化合物２３４６一
１４Ｌ ２．６−：）クロロ−４−フェニルフェノー
ルおよびＢから化合物２５を得、４−（４−フルオロフ
ェノキシ）フェノールおよびＢかう化合物３６を得、！
＋−（４−クロロフェニルチオ）フェノールおよびＢか
ら化合物３４を得、３−（１−ナフチルメチルチオ）フ
ェノールおよびＢから化合物３５を得、２．４−ジブロ
モ−６−フェニルフェノールおよびＢから化合物４０を
得、４−Ｃ４−（４−クロロフェノキシ）フェノキシ〕
フェノールおよびＢから化合物４１を得、４−Ｃ４−ク
ロロフェニルチオ）フェノールおよびＢから化合物４３
を得、４−ベンジルフェノールおよびＢから化合物４を
得、２−ベンジルフェノールおよびＢから化合物３８を
得。2-19: In the same manner as Example 1, starting from 4-(4-chlorophenoxy)phenol and A, compound 6
Compound 39 was obtained from 3-(1-naphthylmethylthio)phenol and A, 4-(4-10lophenoxy)phenol and 6-chloromethyl-4-methyl-2
Compound 1 is obtained from -pyrone (compound B), and 4-(2,
Compound 2 was obtained from 4-dichlorophenoxy)phenol and B, and 4-(4-trifluoromethylphenoxy)
Compound 9 was obtained from phenol and B, 2,6-dichloro-4-(4-chlorophenoxy)phenol and B
From compound 2346-14L 2.6-:) chloro-4-phenylphenol and from B, compound 25 was obtained, from 4-(4-fluorophenoxy)phenol and from B, compound 36 was obtained, and!
Compound 34 was obtained from +-(4-chlorophenylthio)phenol and B, compound 35 was obtained from 3-(1-naphthylmethylthio)phenol and B, and compound 40 was obtained from 2,4-dibromo-6-phenylphenol and B. obtained, 4-C4-(4-chlorophenoxy)phenoxy]
Compound 41 was obtained from phenol and B, and compound 43 was obtained from 4-C4-chlorophenylthio)phenol and B.
Compound 4 was obtained from 4-benzylphenol and B, and compound 38 was obtained from 2-benzylphenol and B.
４−フェニルフェノールおよびＢから化合物３を得、４
−（４−７’ロモー２−クロロフェノキシ）フェノール
およびＢから化合物２６を得そして４−［１−（４−ク
ロロフェニル）−５−はンチル〕フェノールおよびＢか
ら化合物５４を得た。Compound 3 was obtained from 4-phenylphenol and B, and 4
-(4-7' lomo-2-chlorophenoxy)phenol and B gave compound 26 and 4-[1-(4-chlorophenyl)-5-ethyl]phenol and B gave compound 54.
２０： １−ヒドロキシ−４−メチル−６−「４−（１
−ナフチルメトキシ）フェノキシメチル〕−２−ピリド
ン（化合物１０）１００Ｐの６−クロロメチル−４−メ
チル−２−ピロン、 ２１０ｊｌのヒドロキノン、
１３２ｊｌの炭酸カリウムおよび４００ｍＱのジメチ
ルホルムアミドの混合物を室温で７２時間攪拌し、水を
加え。20: 1-hydroxy-4-methyl-6-'4-(1
-naphthylmethoxy)phenoxymethyl]-2-pyridone (compound 10) 100P of 6-chloromethyl-4-methyl-2-pyrone, 210jl of hydroquinone,
A mixture of 132 jl of potassium carbonate and 400 mQ of dimethylformamide was stirred at room temperature for 72 hours and water was added.
その混合物を塩酸で中和しそして沈殿を吸引炉去し、水
洗しついで乾燥させた。メチレンクロライドで処理し、
続いてアセトニトリルから再結晶させて６８９の実質的
に純粋な６−（４−ヒドロキシフェノキシメチル）−４
−メチル−２−ピロンを得た。融点１７９℃。この化合
物４８９ ヲ４９の１−クロロメチルナフタレン。The mixture was neutralized with hydrochloric acid and the precipitate was removed with suction, washed with water and dried. treated with methylene chloride,
Subsequent recrystallization from acetonitrile yielded 689, substantially pure 6-(4-hydroxyphenoxymethyl)-4.
-Methyl-2-pyrone was obtained. Melting point: 179°C. This compound 489 1-chloromethylnaphthalene of 49.
２０ｍＱのジメチルホルムアミドおよび８９の炭酸カリ
ウムとともに室温で７２１４間攪拌しついで希水酸化す
） ＩＪウム溶液を加え、その混合物をメチレンクロラ
イドとともに振盪し、有機相を水洗しついで乾燥させ、
溶媒を蒸留により除去した。７．０９の残留物をシリカ
ゲル含有カラムでメチレンクロライド中においてクロマ
トグラフィーにかけそして４．６９の純粋な４−メチル
−６−［４−（１−ナフチルメトキシ）フェノキシメチ
ル〕−２−ピロンを得た。融点１３２℃。この生成物を
１５９の２−アミノピリジンとともに７５℃で加熱し、
３２時間の攪拌中に７Ｆのヒドロキシルアミン塩酸塩を
４回に分けて加えた。反応を総計４２時間続けた後に、
残留物をメチレンクロライド中に取り入れ、その溶液を
希塩酸および水で洗浄しついで乾燥させ。Stirred with 20 mQ of dimethylformamide and 89 m of potassium carbonate at room temperature for 7214 h and diluted with hydroxide), the IJ solution was added, the mixture was shaken with methylene chloride, the organic phase was washed with water and dried,
The solvent was removed by distillation. The residue of 7.09 was chromatographed in methylene chloride on a column containing silica gel to yield 4.69 of pure 4-methyl-6-[4-(1-naphthylmethoxy)phenoxymethyl]-2-pyrone. . Melting point: 132°C. This product was heated at 75°C with 159 2-aminopyridine,
During stirring for 32 hours, 7F hydroxylamine hydrochloride was added in four portions. After continuing the reaction for a total of 42 hours,
The residue was taken up in methylene chloride and the solution was washed with dilute hydrochloric acid and water and dried.
溶媒を蒸留により除去しそして残留物をアセトニトリル
から再結晶させた。１．９９のＫ１１ｌ枠な化合物１０
が単離された。融点１７９℃。The solvent was removed by distillation and the residue was recrystallized from acetonitrile. Compound 10 in the K11l frame of 1.99
was isolated. Melting point: 179°C.
２１〜３０： 実施例２０と同じ方法で、化合物５、８
．１５，１６．１７．２７．４６および５２は中間体６
−（４−ヒドロキシフェノキシメチル）−４−メチル−
２−ピロンをクロライドすなわち２，４−ジクロロズン
ジルクロライド、シンナミルクロライド、４−クロロベ
ンジルクロライド、４−トリフルオロメトキシベンジル
クロライド。21-30: Compounds 5, 8 in the same manner as Example 20
．． 15,16.17.27.46 and 52 are intermediate 6
-(4-hydroxyphenoxymethyl)-4-methyl-
2-pyrone chlorides, i.e. 2,4-dichloronzyl chloride, cinnamyl chloride, 4-chlorobenzyl chloride, 4-trifluoromethoxybenzyl chloride.
４−第三プチルベンジルク口ジイド、 ３，４．５−
トリメトキシベンジルクロライド、１−クロロ−３−（
４−クロロフェノキシ）フロパンおよび１−クロロ−４
−（４−１０ロフゴノ千シ）−２−ブテンでアルキル化
し、得らｈ ７こヒ１１ンをヒドロキシピリドンに変換
することにより得られた。ヒドロキノンの代りにカテコ
ールを使用しそして１−ナソチルメチルクロライドでア
ルキル化すると化曾物１９が得られ、レゾルシノールお
よび４−クロロベンジルクロライドでは化合物２１が得
られた。4-Tertiary butylbenzyl chloride, 3,4.5-
Trimethoxybenzyl chloride, 1-chloro-3-(
4-chlorophenoxy)furopane and 1-chloro-4
It was obtained by alkylating with -(4-10)-2-butene and converting the obtained h7-11-ene into hydroxypyridone. Using catechol in place of hydroquinone and alkylation with 1-nasothylmethyl chloride gave compound 19, and resorcinol and 4-chlorobenzyl chloride gave compound 21.
５１： ６−（２，Ｓ−ジクロロ−４−（２−ナフチ
ルチオメチル）ノエノキシタチル〕−１−ヒドロキシ−
４−メチル−２−
ピリドン（化合物１３）
４．８２のナトリウムおよび４２９の３．５−：）クロ
ロ−４−ヒドロキシベンズアルデヒドヲ２５０ｍｆｆ１
のメタノールに溶解し、溶媒を減圧蒸留で除去し、残留
物を２００ｍＱのジメチルホルムアミド中に卓り入れ、
６２Ｆの６−クロロメチル−４−メチル−２−ピロンを
ガロえそして混合物を室ｉＭＫ３日間放置して反応させ
た。ついでジメチルホルムアミドを減圧蒸留により実質
的に除去し、メタノールを加えそして総計４４５１の６
− （２，６−ジクロロ−４−ホルミルフェノキシメチ
ル）−４−メチル−２−ピロンを母液の冷却および濃縮
により数フラクションで単離させた。この化合物６４．
５９を２５０ｍ１！のナト２ヒドロフランおよび１００
ｍｆｆ１のメタノールの混合物中においてｔ５Ｐの水素
化硼素ナトリウムを用いて室温で還元し、混合物をその
後５０℃に加熱しついで１０ｍＱの濃硫酸を加え、溶媒
の大部分を蒸留により除去し、残留物を水とともに振盪
しそして固形物を吸引沖去し、水洗しついで乾燥させた
。この生成物（３３，１ｊｌ、融点１５４℃）を２００
蛾のメチレンクロライドに懸濁し、０１ ｍＱのジメチ
ルホルムアミドを加えついで室温で１１峨のチオニルク
ロライドを少しずつ加えた。２４時間後溶媒を蒸留によ
り除去し、残留物を２００−のメタノールとともに煮沸
し、混合物を０℃に冷却しそして生成物を吸引沖去し、
洗浄しついで乾燥させた。３［Ｌｌｊｌの純粋な６−
（２，６−ジクロロ−４−クロロメチルフェノキシメチ
ル）＝４−メチル−２−ピロンを得た。融点１３６℃０
７、５９の得られた化合物を４２の２−チオナフトール
、３０ｍｅのジメチルホルムアミドおよび７Ｐの炭酸カ
リウムとともに室温で２４時間攪拌しついで水を加え、
その混合物をメチレンクロライドとともに振樹し、その
溶液を水洗し。51: 6-(2,S-dichloro-4-(2-naphthylthiomethyl)noenoxytatyl]-1-hydroxy-
4-Methyl-2-pyridone (compound 13) 250 mff1 of 4.82 sodium and 429 3.5-:)chloro-4-hydroxybenzaldehyde
of methanol, the solvent was removed by vacuum distillation, and the residue was taken up in 200 mQ of dimethylformamide.
62F 6-chloromethyl-4-methyl-2-pyrone was added to the mixture and the mixture was left to react indoors for 3 days. The dimethylformamide was then substantially removed by vacuum distillation, methanol was added and a total of 4451 6
- (2,6-dichloro-4-formylphenoxymethyl)-4-methyl-2-pyrone was isolated in several fractions by cooling and concentrating the mother liquor. This compound 64.
59 for 250m1! of nato2hydrofuran and 100
mff1 was reduced with sodium borohydride in a mixture of methanol at room temperature, the mixture was then heated to 50°C and 10 mQ of concentrated sulfuric acid was added, most of the solvent was removed by distillation and the residue was It was shaken with water and the solids were suctioned off, washed with water and dried. This product (33.1jl, melting point 154°C) was heated to 200
The moth was suspended in methylene chloride, 01 mQ of dimethylformamide was added, and 11 mQ of thionyl chloride was added portionwise at room temperature. After 24 hours the solvent was removed by distillation, the residue was boiled with 200 methanol, the mixture was cooled to 0° C. and the product was suctioned off.
Washed and dried. 3[Lljl pure 6-
(2,6-dichloro-4-chloromethylphenoxymethyl)=4-methyl-2-pyrone was obtained. Melting point 136℃0
The resulting compound of 7,59 was stirred with 2-thionaphthol of 42, dimethylformamide of 30me and potassium carbonate of 7P for 24 hours at room temperature, then water was added,
Shake the mixture with methylene chloride and wash the solution with water.
乾燥させついでシリカゲル含有カラム上でクロマトグラ
フィーにかけた。ａ５Ｐの６−１” ２．６−ジクロロ
−４−（２−ナフチルチオメチル）フェノキシメチル〕
−４−メチル−２−ピロンを得た。融点１２５℃。この
生成物を２５９の２−アミノピリジンとともに７５℃で
加熱し、３７時間以内に総計８９のヒドロキシルアミン
塩酸塩を４回に分けて加えた。反応を４８時間続けた後
に、残留物をメチレンクロライド中に取り入れ、有機相
を希塩酸および水で洗浄しついで乾燥させ、溶媒を蒸留
により除去した。残留物をアセトニトリルから１回およ
び酢酸エチルから１回再結晶させて２．１９の純粋な化
合物１３を得た。融点１３８℃。It was dried and chromatographed on a column containing silica gel. a5P 6-1” 2,6-dichloro-4-(2-naphthylthiomethyl)phenoxymethyl]
-4-methyl-2-pyrone was obtained. Melting point: 125°C. This product was heated at 75° C. with 259 portions of 2-aminopyridine and a total of 89 portions of hydroxylamine hydrochloride were added in four portions within 37 hours. After the reaction had continued for 48 hours, the residue was taken up in methylene chloride, the organic phase was washed with dilute hydrochloric acid and water and dried, and the solvent was removed by distillation. The residue was recrystallized once from acetonitrile and once from ethyl acetate to give 2.19 of pure compound 13. Melting point: 138°C.
３２および３３： 実施例３１の操作と同様にして。32 and 33: Same procedure as in Example 31.
化合物１４は中間体６− （２，６−ジクロロ−４−ク
ロロメチルフェノキシメチル）−４−メチル−２−ピロ
ンを４−フェニルフェノールト反応させ、得られたピロ
ンをヒドロキシピリドンに変換することによって得られ
た。３，５−ジクロロ−４−ヒドロキシベンズアルデヒ
ドの代りに４−ヒドロキシベンズアルデヒドを用い、同
様の還元を行い、チオニルクロ２イドと反応させ、４−
（４−クロロフェノキシ）フェノールと縮合させついで
ヒドロキシルアミンと反応させて化合物１２を得た。Compound 14 can be obtained by subjecting the intermediate 6-(2,6-dichloro-4-chloromethylphenoxymethyl)-4-methyl-2-pyrone to 4-phenylphenol reaction and converting the resulting pyrone to hydroxypyridone. Obtained. Similar reduction was carried out using 4-hydroxybenzaldehyde instead of 3,5-dichloro-4-hydroxybenzaldehyde, and reaction with thionylchloride resulted in 4-hydroxybenzaldehyde.
Condensation with (4-chlorophenoxy)phenol followed by reaction with hydroxylamine gave compound 12.
３４： ６−Ｃ４−＜４−クロロフェノキン）フェノ
キシメチル〕−１−ヒドロギシ
−２−ピリドン（化合物２２）
３０９の２−ブロモ−６−ピコリンを６ｔ６９のＮ−ブ
ロモスクシンイミド、０．０１５ｊｌのジベンゾイルペ
ルオキシドおよび１５０ｍｅの四塩化炭素とともにＵＶ
照射下で５０時間還流加熱し、混合物を沖過し、Ｐ液を
炭酸ナトリウム水溶液で１回および水で３回洗浄しつい
で乾燥させ、溶媒を減圧蒸留で除去した。残留物（４０
，１９）を１５０ｍ＋！のヘキサンとともに振盪しつい
で吸引沖過を行って、主に所望のモノブロモメチル化合
物からなるが少量のジブロモメチル化合物の加わった混
合物２７．３９を得た。この混合物を２１．４２の４−
（４−クロロフェノキシ）フェノール。34: 6-C4-<4-chlorophenoquine)phenoxymethyl]-1-hydroxy-2-pyridone (compound 22) UV with benzoyl peroxide and 150me carbon tetrachloride
After heating at reflux under irradiation for 50 hours, the mixture was filtered, the P solution was washed once with aqueous sodium carbonate and three times with water, then dried and the solvent was removed by vacuum distillation. Residue (40
,19) 150m+! Shaking with 100 ml of hexane followed by suction filtration yielded 27.39 of a mixture consisting primarily of the desired monobromomethyl compound, but with a small amount of dibromomethyl compound. Add this mixture to 21.42 4-
(4-chlorophenoxy)phenol.
２α７Ｐの炭酸カリウムおよび５０峨のジメチルホルム
アミドと一緒に室温で４８時間攪拌しついで２００ｍｆ
ｆ１のメチレンクロライドを加えそして有機溶液を３回
水洗し、濃縮しついでシリカゲル上でのクロマトグラフ
ィーおよびジイソプロピルエーテルからの再結晶により
１６．３ｊ１の２−ブロモー６−Ｃ４−Ｃ４−クロロフ
ェノキシ）フェノキシメチルコピリジンを単離した。Stir at room temperature for 48 hours with 2α7P potassium carbonate and 50 μm dimethylformamide, then 200 mf
Methylene chloride of f1 was added and the organic solution was washed three times with water, concentrated and chromatographed on silica gel and recrystallized from diisopropyl ether to give 2-bromo 6-C4-C4-chlorophenoxy)phenoxymethyl of 16.3j1. Copyridine was isolated.
得られた化合物ｉｓ、ａｐを５（１ｍｌｊの氷酢酸に溶
解したＦ３，５９の過酢酸の溶液とともに５０℃で３０
時間加熱しついで溶媒を４０℃での減圧蒸留により一部
分除去し、残留物をそれぞれ２００ｍ１ｌの水で３回そ
して炭酸水素ナトリウム水溶液で１回振盪し、それぞれ
に傾瀉除去を行い、最後ｖｃ１ｏｏｍｐのジイソプロピ
ルエーテルで処理し。The resulting compound is,ap was incubated with a solution of 5 (F3,59 peracetic acid dissolved in 1 mlj of glacial acetic acid at 50 °C for 30 min.
After heating for an hour, the solvent was partially removed by vacuum distillation at 40° C., the residue was shaken three times with 200 ml of water and once with aqueous sodium bicarbonate solution, decanted each time, and finally dissolved in vcl. Process it with.
生成物を吸引沖去しついで乾燥させた。こうして１α２
９のほぼ純粋なＮ−オキシドを得た。融点１００℃。こ
のＮ−オキシド５Ｐを、９ｍ？の水およ（ｊ ２［１ｍ
Ｑのエチレングリコールモノメチルエーテルの混合物に
溶解した１、２９の水酸化ナトリウムの溶液とともに７
０℃で加熱した。この間にアルコールとの反応で、１２
５℃で融解するＮ−オキシドのメトキシエチルエーテル
が急速に生成されついでそのエーテルを徐々に加水分解
させた。６０時間後、溶媒を減圧蒸留で除去し、残留物
を２００蛾のメチレンクロライドおよび５０ ｍｌ！の
希硫酸とともに振盪し、その有機相を分離し、乾燥させ
ついで蒸発させた。残留物をアセトニトリルから再結晶
させて２．５９の純粋化合物２２を得た。融点１８０℃
。The product was removed with suction and dried. Thus 1α2
Almost pure N-oxide of 9 was obtained. Melting point: 100°C. This N-oxide 5P is 9m? of water (j 2[1m
7 with a solution of sodium hydroxide of 1,29 dissolved in a mixture of ethylene glycol monomethyl ether of Q.
Heated at 0°C. During this time, 12
The methoxyethyl ether of the N-oxide, which melts at 5°C, was rapidly formed and the ether was slowly hydrolyzed. After 60 hours, the solvent was removed by vacuum distillation and the residue was diluted with 200 g of methylene chloride and 50 ml! of dilute sulfuric acid, the organic phase was separated, dried and evaporated. The residue was recrystallized from acetonitrile to yield 2.59 pure compound 22. Melting point 180℃
.
３５： １−ヒドロキシ−４−メチル−６−〔３−（１
−ナフチルメトキシ）フェニル
チオメチル〕−２−ピリドン
２６９のモノチオレゾルシノールおよび３１．８９の６
−１０ロメチル−４−メチル−２−ピロンを１００ＩＩ
ＩＱのジメチルホルムアミドに溶解し。35: 1-hydroxy-4-methyl-6-[3-(1
-naphthylmethoxy)phenylthiomethyl]-2-pyridone 269 monothioresorcinol and 31.89 6
-10lomethyl-4-methyl-2-pyrone 100II
Dissolve IQ in dimethylformamide.
水中で攪拌および冷却しながら３０分以内に３８ｐの粉
末状炭酸カリウムを加えついで混合物を０℃で４時間お
よび室温で１６時間攪拌し、これに５００峨のメチレン
クロライドを加え２Ｍ機相を水で３回振盪することによ
り抽出し１分離しついで乾燥させ、溶媒を蒸留により除
去した。38p of powdered potassium carbonate was added within 30 minutes while stirring and cooling in water and the mixture was stirred for 4 hours at 0°C and 16 hours at room temperature, to which 500g of methylene chloride was added and the 2M organic phase was dissolved in water. It was extracted by shaking three times, separated for one minute and then dried, and the solvent was removed by distillation.
残留物をメタノールから再結晶させて４４９の６−（３
−ヒドロキシフェニルチオメチル）−４−メチル−２−
ピロン、化合物（Ｃ）を得た。融点１２９℃。２００＋
＋＋ｆｔのアセトンに溶解した８９の沃化ナトリウムの
溶液にＦ！、９９の１−クロロメチルナフタレンを加え
、混合物を室温で１６時間攪拌しついで１２．４９の化
合物Ｃをこの混合物中に溶解し、それを０℃に冷却しそ
して６．９９の粉末状炭酸カリウムを５時間以内に少し
ずつ加えた。０℃での全反応時間の７９時間が経堝後に
溶媒をウォータポンプ真空中での蒸留により除去し、残
留物をメチレンクロライド中に取＝５８−
り入れそして溶液を水洗し１分離し、乾燥させついで濃
縮し、生成物を移動相としてメチレンクロライＦを用い
て、シリカゲル含有カラム上でクロマトグラフィーにか
けそして主要フラクションをメタノールカ為ら再結晶さ
せた。９Ｆの純粋な４−メチル−６−（３−（１−ナフ
チルメトキシ）フェニルチオメチル〕−２−ピロンを得
た。融点１３９℃。The residue was recrystallized from methanol to give 449 6-(3
-hydroxyphenylthiomethyl)-4-methyl-2-
Pyrone, compound (C) was obtained. Melting point: 129°C. 200+
F! to a solution of 89 sodium iodide dissolved in ++ft acetone! , 99 of 1-chloromethylnaphthalene was added, the mixture was stirred at room temperature for 16 hours and 12.49 of compound C was dissolved in this mixture, it was cooled to 0° C. and 6.99 of powdered potassium carbonate was added. was added little by little within 5 hours. After a total reaction time of 79 hours at 0° C., the solvent was removed by distillation in a water pump vacuum, the residue was taken up in methylene chloride and the solution was washed with water, separated and dried. After concentration, the product was chromatographed on a column containing silica gel using methylene chloride F as the mobile phase and the main fraction was recrystallized from methanol. 9F pure 4-methyl-6-(3-(1-naphthylmethoxy)phenylthiomethyl]-2-pyrone was obtained. Melting point 139°C.
この化合物ａ５９を５０９の２−アミノピリジンととも
に７５℃で加熱し、４０時間以内に８９Ｆのヒドロキシ
ルアミン塩酸塩を少しずつ加えた。６０時間の反応時間
の後に、混合物を室温に冷却し、メチレンクロライドを
加えそして有機相を希塩酸で１回および水で６回洗浄し
ついで乾燥させ、溶媒を蒸留により除去した。This compound a59 was heated at 75° C. with 2-aminopyridine of 509, and 89F hydroxylamine hydrochloride was added portionwise within 40 hours. After a reaction time of 60 hours, the mixture was cooled to room temperature, methylene chloride was added and the organic phase was washed once with dilute hydrochloric acid and six times with water and dried, and the solvent was removed by distillation.
残留物を酢酸エチルから再結晶させて４９のヒドロキシ
ピリドンを得た。融点１６３℃。The residue was recrystallized from ethyl acetate to give 49 hydroxypyridone. Melting point: 163°C.
５６： ピロンＣ（実施例３５を参照）を４−クロロベ
ンジルクロライドと反応させそして残りの過程を実施例
６５のようにして行うと、化合物４２が得られた。56: Reaction of pyrone C (see Example 35) with 4-chlorobenzyl chloride and remaining steps as in Example 65 gave compound 42.
３７： １−ヒドロキシ−４−メチル−６−〔４−（
４−クロロフェノキシ）フェノキ
シメチル〕−２−ピリドン
５０ｍＱのトルエン中における１７１．４９（０，５モ
ル）の４−メチル−６−Ｃ４−＜４−クロロフェノキシ
）フェノキシメチル〕−２−ピロンを８０”ＣＫ加熱シ
タ。ついで５９．９ｊｌ （［１，３６モル）のヒドロ
キシルアンモニウムスルフェートおよび３ａ３ｊｌ（［
Ｌ３６モル）の炭酸ナトリウムを加えた。１０分後さら
Ｋ 別（７） ５９．９９ （０，３６モル）のヒドロ
キシルアンモニウムスルフェートおよび３ａ３９（０，
３６モル）の炭酸ナトリウムを加えた。約４時間後加熱
を外しついで約４０℃において５００ｍｆｆ１のメチレ
ンクロライドを加えた。ついで溶解した反応生成物を不
溶性塩から炉去した。次にＰ液を硫酸ナトリウムで乾燥
させ、メチレンクロライドを蒸発させた。残留物を５ｏ
ｏｔＩ１１！の酢酸エチルとともに攪拌し１反応生成物
を晶出させた。最終精製のタメに、１−ヒドロキシ−４
−メチル−６−［４−（４−クロロフェノキシ）フェノ
キシメチル〕−２−ピリドンをジメチルホルムアミドか
ら再結晶させた。37: 1-hydroxy-4-methyl-6-[4-(
4-chlorophenoxy)phenoxymethyl]-2-pyridone 171.49 (0.5 mol) of 4-methyl-6-C4-<4-chlorophenoxy)phenoxymethyl]-2-pyridone in 50 mQ of toluene to 80 "CK heating. Then 59.9jl ([1,36 mol) of hydroxylammonium sulfate and 3a3jl ([
36 mol) of sodium carbonate was added. After 10 minutes, K separated (7) 59.99 (0.36 mol) of hydroxylammonium sulfate and 3a39 (0.36 mol).
36 mol) of sodium carbonate was added. After about 4 hours, the heat was removed and 500 mff1 of methylene chloride was added at about 40°C. The dissolved reaction product was then removed from the insoluble salts. Next, the P solution was dried with sodium sulfate, and the methylene chloride was evaporated. 5o of residue
otI11! The mixture was stirred with ethyl acetate to crystallize a reaction product. For final purification, 1-hydroxy-4
-Methyl-6-[4-(4-chlorophenoxy)phenoxymethyl]-2-pyridone was recrystallized from dimethylformamide.
収量８１５Ｆ（４５チ）；融点１６８〜１７０”Ｃ６３
８： １−ヒドロキシ−４−メチル−６−［３−（２−
フェノキシエトキシ）フ
ェノキシメチル〕−２−ピリドン（化
合物４５）
８０９の６−クロロメチル−４−メチル−２−ピロン、
２２０９のレゾルシノール、４００ｍｆｆ１のジメチル
ホルムアミドおよび１ｏ５ｊＩの微粉化炭酸カリウムの
混合物を室温で７２時間攪拌し。Yield 815F (45 inches); Melting point 168-170"C63
8: 1-hydroxy-4-methyl-6-[3-(2-
phenoxyethoxy) phenoxymethyl]-2-pyridone (compound 45) 6-chloromethyl-4-methyl-2-pyrone of 809,
A mixture of 2209 resorcinol, 400 mff1 dimethylformamide and 105j1 micronized potassium carbonate was stirred at room temperature for 72 hours.
ついでメチレンクロライドを加え、その有機相を水で数
回振盪させることにより抽出しついで乾燥させ、溶媒を
減圧蒸留で除去した。粘稠性残留物Ｃ２２３ｐ）を水で
摩砕しついでメタノールから再結晶させそして５３９の
６−（３−ヒドロキシフェノキシメチル）−４−メチル
−２−ピロン（化合物Ｄ）を単離させた。融点１４５℃
。Methylene chloride was then added, the organic phase was extracted by shaking several times with water and dried, and the solvent was removed by vacuum distillation. The viscous residue C223p) was triturated with water and recrystallized from methanol and 539 6-(3-hydroxyphenoxymethyl)-4-methyl-2-pyrone (compound D) was isolated. Melting point 145℃
.
１０ｊ＋の化合物りを１ ｔ２ｊｌの１−ヨード−２−
フェノキシエタン（２−フェノキシエタノールをＳＯＯ
β２と反応させついでアセトン中の沃化ナトリウムを用
いて塩素を沃素で置き換えることによって製造される）
、６．９９の炭酸カリウムおよび５０ｍｅのジメチルホ
ルムアミドとともに５０℃で３５時間攪拌し、メチレン
クロライドを加え、その溶液を数回水洗し、乾燥させっ
いでシリカゲル上でクロマトグラフィーにかけた。単離
された主生成物は１［Ｌ４９の４−メチル−６−［３−
（２−フェノキシエトキシ）フェノキシメチル〕−２−
ピロンであった。融点９５℃。このピロン１０９を５０
２の２−アミノピリジンとともに７５℃で６３時間加熱
し、その間にａ５Ｆのヒドロキシルアミン塩酸塩を少し
ずつ加えついで残留物をメチレンクロライド中に取り入
れ、その溶液を希塩酸（水溶液相の−。The compound of 10j+ is 1 t2jl of 1-iodo-2-
Phenoxyethane (SOO 2-phenoxyethanol)
(produced by reacting with β2 and replacing chlorine with iodine using sodium iodide in acetone)
, 6.99 m potassium carbonate and 50 me dimethylformamide at 50°C for 35 h, methylene chloride was added, the solution was washed several times with water, dried and chromatographed on silica gel. The main product isolated was 4-methyl-6-[3-
(2-phenoxyethoxy)phenoxymethyl]-2-
It was Piron. Melting point: 95°C. 50 of this piron 109
2 with the 2-aminopyridine at 75° C. for 63 hours, during which time the hydroxylamine hydrochloride of a5F was added in portions, the residue was taken up in methylene chloride, and the solution was dissolved in dilute hydrochloric acid (in the aqueous phase).
３〜４）との振盪によって抽出しついで乾燥させ、溶媒
を蒸留により除去しそして残留物をアセトニトリルから
結晶化させた。４．３９の純粋なヒドロキシピリドンが
得られた。融点１４８℃。3-4) and drying, the solvent was removed by distillation and the residue was crystallized from acetonitrile. 4.39 of pure hydroxypyridone was obtained. Melting point: 148°C.
３９および４０： 実施例３８と同じ方法で、化合物４
８は中間体りおよび１−（４−り四ロフェニルチオ）−
４−ヨードブタンから出発して得られ、化合物４９はＤ
および２−（４−クロロフェニルチオ）エチル２′−ヨ
ードエチルエーテルから得られた。39 and 40: Compound 4 in the same manner as Example 38
8 is an intermediate and 1-(4-di-tetraphenylthio)-
obtained starting from 4-iodobutane, compound 49 is D
and 2-(4-chlorophenylthio)ethyl 2'-iodoethyl ether.
４１： ６−〔３−（４−クロロフェニルチオプロピ
ルチオ）フェノキシメチル〕−
１−ヒドロキシ−４−メチル−２−ピ
リドン（化合物４７）
１２．６Ｆのモノチオレゾルシノール、３１．３Ｆの１
−（４−１０ロフエニルチオ）−３−ヨードプロパン（
４−クロロチオフェノールと１−ブロモ−３−クロロプ
ロノ々ンを反応させついでアセトン中の沃化ナトリウム
を用いて塩素を沃素で置き換えることにより製造された
）、１６．６９の炭酸カリウムおよび６０ｍＱのアセト
ンからなる混合物を室温で２４時間攪拌しついで溶媒を
減圧蒸留で除去し、メチレンクロライドを加え。41: 6-[3-(4-chlorophenylthiopropylthio)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone (compound 47) 12.6F monothioresorcinol, 31.3F 1
-(4-10lophenylthio)-3-iodopropane (
prepared by reacting 4-chlorothiophenol with 1-bromo-3-chloropronophenol and replacing chlorine with iodine using sodium iodide in acetone), 16.69 mQ of potassium carbonate and 60 mQ of acetone. The mixture was stirred at room temperature for 24 hours, the solvent was removed by vacuum distillation, and methylene chloride was added.
その溶液を数回水洗し、乾燥させついで移動相としてメ
チレンクロライドを用いるシリカゲル上でのクロマトグ
ラフィーによって１．５ｊの３− （４−クロロフェニ
ルチオプロピルチオ）フェノールを単離させた。この生
成物を９５９の６−クロロメチル−４−メチル−２−ピ
ロン。The solution was washed several times with water, dried and 1.5j of 3-(4-chlorophenylthiopropylthio)phenol was isolated by chromatography on silica gel using methylene chloride as the mobile phase. This product was converted into 959 6-chloromethyl-4-methyl-2-pyrone.
１ａ４２の炭酸カリウムおよび６０ｍ（Ｌのアセトンと
一緒に５０℃で３１時間攪拌しついで溶媒を減圧蒸留で
除去し、残留物をメチレンクロライド中に取り入れそし
てその溶液を数回水洗し。After stirring for 31 hours at 50° C. with 1a42 of potassium carbonate and 60 m(L) of acetone, the solvent was removed by distillation under reduced pressure, the residue was taken up in methylene chloride and the solution was washed several times with water.
乾燥させついでシリカゲル上でクロマトグラフィーにか
けた。１ｔ２９の主フラクションを５０夕の２−アミノ
ピリジンとともに７５℃で６５時間加熱し、総計１２９
のヒドロキシルアミン塩酸塩をいくつかの部分に分けて
加えた。次に残留物をメチレンクロライド中に取り入れ
、有機相を希塩酸とともに振盪しそして水とともに数回
振盪することにより抽出し、乾燥させ、溶媒を蒸留によ
り除去した。残留物は９．９夕であつた。これをメタノ
ールで処理して２．７９の純粋なヒドロキシピリドンを
得た。融点１０２℃。It was dried and chromatographed on silica gel. The main fraction of 1t29 was heated with 50g of 2-aminopyridine at 75°C for 65 hours to give a total of 129
of hydroxylamine hydrochloride was added in several portions. The residue was then taken up in methylene chloride, the organic phase was extracted by shaking with dilute hydrochloric acid and several times with water, dried and the solvent was removed by distillation. The residue remained at 9.9 pm. This was treated with methanol to give 2.79 pure hydroxypyridone. Melting point: 102°C.
４２および４５： 前記と同一の反応順序および同一の
条件で、化合物５１はモノチオレゾルシノールおよび１
−（４−クロロフェニルチオ）−２，２−ジメチル−３
−ヨードブタンぞンから出発して得られ、化合物５３は
モノチオレゾルシノールおよび（４−クロロフェニルチ
オ）エトキシエトキシエチルヨーダイドから得られた。42 and 45: In the same reaction sequence and under the same conditions as above, compound 51 was reacted with monothioresorcinol and 1
-(4-chlorophenylthio)-2,2-dimethyl-3
Compound 53 was obtained starting from monothioresorcinol and (4-chlorophenylthio)ethoxyethoxyethyl iodide.
活性の調査
抗真菌性物質の生体外調査では、増殖している微生物に
対する作用（制菌作用）と静止している微生物に対する
作用（殺真菌活性）とを区別することが必要である。Investigation of activity In in vitro investigations of antifungal substances, it is necessary to distinguish between action on proliferating microorganisms (bacteriostatic action) and action on stationary microorganisms (fungicidal activity).
生長していない真菌で試験する殺真菌活性は比較的信頼
性のあるモデルとして類別される。Fungicidal activity tested on non-growing fungi classifies as a relatively reliable model.
これにはマイクロタイタープレート中で調製される試験
すべき生成物の希釈系（３１，２５〜Ｄ、２５１ｔ９／
ｍＱ ； ８段階）が必要である。プレート上の各Ｕ型
ウェルに１０４個のコロニー形成単位（ＯＦＵ）の皮膚
真薗、トリコフィトンメンタグロフィテス（Ｔｒｉｃｋ
ｏｐｈｙｔｏｎ ｍｅｎｔａｇｒｏｐｈｙｔｅｓ）を接
種する（媒体：生理学的ＮａＯβ溶液）。３０ ”Ｃで
１８時間培養後、微生物を５０係ポリエチレングリコー
ル４００およびＮａＣＡ溶液で洗浄しく２回の遠心分離
）そして微生物の数を測定するために自動装置を用いて
麦芽寒天プレート上に縞状にする。６０℃で３日間培養
後コロニーを数えそしてそのＯＦＵ／ｍｆｆ１を計算す
る。未処置対照との比較により、微生物の数の減少係を
測定する（対照−０％）。作用強度は、標準製剤例えば
以下の式を有する化合物の一般名であるクロ） ＩＪマ
ゾールによって測定される。This includes a dilution series of the product to be tested prepared in microtiter plates (31, 25-D, 251t9/
mQ; 8 stages) is required. Each U-shaped well on the plate contains 104 colony forming units (OFU) of the skin mana, Trichophyton mentagrophytes (Trick).
(vehicle: physiological NaOβ solution). After incubation for 18 hours at 30"C, the microorganisms were washed with 50% polyethylene glycol 400 and NaCA solution, centrifuged twice) and streaked onto malt agar plates using an automated device to determine the number of microorganisms. After 3 days of incubation at 60°C, colonies are counted and their OFU/mff1 is calculated. The reduction factor in the number of microorganisms is determined by comparison with the untreated control (control - 0%). The formulation is measured by IJ Mazole, which is a common name for a compound having the following formula:
後記衣１から明らかなように５本発明化合物は標準製剤
クロトリマゾールに対して住めて小さい数のＯＦＵを示
した。すなわち本発明による化合物の殺真菌または致死
効果は標準剤のそれよりも明らかＫ ｔｍ著である。As is clear from Figure 1 below, the compound of the present invention showed a significantly lower number of OFU than the standard preparation clotrimazole. Thus, the fungicidal or lethal effect of the compounds according to the invention is significantly greater than that of the standard agents.
表 １
１５ １ ９９．３２
１７ １５ ９８．９８
クロトリマゾール ６３，６ ５７
未処置
対照 １４７．９ ０
ｎ−測定数
ｉ−平均値
６８一
本発明による化合物の局所用の生体内における高活性の
例として、実験的にトリコフィトンメンタグロフィテス
を感染させた実験室動物を処置した結果を詳述する。こ
れは体重がそれぞれ４５０〜５００９のモルモット（ピ
ルブライドホワイト種）２匹または４匹必要とし、各場
合。Table 1 15 1 99.32 17 15 98.98 Clotrimazole 63,6 57
Untreated control 147.9 0 n - Number of measurements i - Mean value 68 - As an example of the high in vivo activity of topical compounds according to the invention, laboratory animals experimentally infected with Trichophyton mentagrophytes were Detail the results of the treatment. This requires 2 or 4 guinea pigs (Pilbride White breed) each weighing 450-5009 kg, in each case.
各々の表皮に６個所の感染点に分配した１、５×１０４
個分生胞子／動物を感染させた。これらの動物を前記感
染の３日および４日前に、各場合において背中の右側の
３個所の感染部位上にαδチ濃度の生成物溶液を適用す
ることにより処置した。各場合３個所の感染部位を有す
る背中の左側を同じように生成物を全く含有していない
ビヒクル（ビヒクル対照）で処置した。1,5 x 104 cells distributed to 6 infection points on each epidermis.
Individualispores/animals were infected. The animals were treated 3 and 4 days before the infection by applying a solution of the product at a concentration of αδ on the three infection sites on the right side of the back in each case. The left side of the back, with three infection sites in each case, was treated in the same way with vehicle without any product (vehicle control).
本発明による物質で処置した動物の外に、２匹の動物を
参考物質クロトリマゾールで処置しそして２匹の感染動
物を未処置のままにした＝６９−
（感染対照）。Besides the animals treated with the substance according to the invention, two animals were treated with the reference substance clotrimazole and two infected animals were left untreated = 69- (infected control).
表２から明らかなように１本発明による化合物は標準製
剤クロトリマゾールよりも明瞭に大きな真菌症の直径（
日）の差を示した。すなわち本発明による化合物の抗真
菌効果はクロ） ＩＪマゾールの場合よりも疑いもなく
優れていた。As is clear from Table 2, the compound according to the invention has a significantly larger mycosis diameter (
(days). The antifungal effect of the compounds according to the invention was thus undoubtedly superior to that of Clo) IJ mazole.
Claims (1)
なっていて、水素または１〜４個の炭素原子を有する低
級アルキルを表わすが、Ｒ＾１およびＲ＾２は好ましく
は水素であり、Ｒ＾２は好ましくはメチルであり、 ＸはＳまたは好ましくはＯを表わし、 Ｙは水素または２個までのハロゲン原子、 すなわち塩素および／または臭素を表わし、Ｚは単結合
または２価の基のＯ、Ｓ、−ＣＲ＿２−（Ｒ−Ｈもしく
はＣ＿１〜Ｃ＿４−アルキル）または２〜１０個の炭素
並びに場合により、鎖を形成するのに結合された酸素お
よび（または）硫黄原子を有するその他の２価基を表わ
し、その際該基が２個またはそれ以上の酸素および（ま
たは）硫黄原子を含有する場合には、これらの原子は少
なくとも２個の炭素原子によって隔てられることを必須
としそして２個の隣接炭素原子はまた二重結合によって
結合され且つ該炭素原子の自由原子価はＨおよび／また
はＣ＿１〜Ｃ＿４−アルキル基により飽和されているこ
とが可能であり、 Ａｒは２個までの環を有し且つ弗素、塩素、臭素、メト
キシ、Ｃ＿１〜Ｃ＿４−アルキル、トリフルオロメチル
およびトリフルオロメトキシからなる群より選択される
３個までの基によって置換されうる芳香族環系を表わす
〕で示される１−ヒドロキシ−２−ピリドン。 ２）Ａｒが場合により置換されているフェニル環を表わ
す特許請求の範囲第１項記載の化合物。 ３）Ａｒが好ましくはビフェニル、ジフェニルアルカン
またはジフェニルエーテルから誘導され且つ場合により
置換されている隔てられた二環式系を表わす特許請求の
範囲第１項記載の化合物。 ４）Ｚが単結合である特許請求の範囲第１〜３項のうち
の１つまたはそれ以上の項に記載の化合物。 ５）Ｚが酸素を表わすかまたは酸素を含むものである特
許請求の範囲第１〜３項のうちの１つまたはそれ以上の
項に記載の化合物。 ６）６−〔４−（４−クロロフェノキシ）フェノキシメ
チル〕−１−ヒドロキシ−４−メチル−２−ピリドンす
なわち式 I においてＲ＾１、Ｒ＾３およびＹがＨであ
り、Ｒ＾２がＣＨ＿３であり、ＸがＯであり、ＺがＸＣ
Ｈ＿２基に対して４−位にあるＯでありそしてＡｒが▲
数式、化学式、表等があります▼である特許請求の範囲
第１項記載の化合物。 ７）６−（４−ビフェニルオキシメチル）−１−ヒドロ
キシ−４−メチル−２−ピリドンすなわち式 I におい
てＲ＾１、Ｒ＾３およびＹがＨであり、Ｒ＾２がＣＨ＿
３であり、ＸがＯであり、Ｚが単結合でありそしてＡｒ
がＸＣＨ＿２基に対して４−位にあるＣ＿６Ｈ＿５であ
る特許請求の範囲第１項記載の化合物。 ８）１−ヒドロキシ−４−メチル−６−〔４−（４−ト
リフルオロメチルフェノキシ）フェノキシメチル〕−２
−ピリドンすなわち式 I においてＲ＾１、Ｒ＾３およ
びＹがＨであり、Ｒ＾２がＣＨ＿３であり、ＸがＯであ
り、ＺがＸＣＨ＿２基に対して４−位にあるＯでありそ
してＡｒが▲数式、化学式、表等があります▼である特
許請求の範囲第１項記載の化合物。 ９）式 I ▲数式、化学式、表等があります▼ I 〔式中、 Ｒ＾１、Ｒ＾２およびＲ＾３は同一であるかまたは相異
なっていて、水素または１〜４個の炭素原子を有する低
級アルキルを表わすが、Ｒ＾１およびＲ＾２は好ましく
は水素であり、Ｒ＾２は好ましくはメチルであり、 ＸはＳまたは好ましくはＯを表わし、 Ｙは水素または２個までのハロゲン原子、 すなわち塩素および／または臭素を表わし、Ｚは、単結
合または２価の基のＯ、Ｓ、−ＣＲ＿２−（Ｒ＝Ｈもし
くはＣ＿１〜Ｃ＿４−アルキル）または２〜１０個の炭
素並びに場合により、鎖を形成するのに結合された酸素
および（または）硫黄原子を有するその他の２価基を表
わし、その際該基が２個またはそれ以上の酸素および（
または）硫黄原子を含有する場合には、これらの原子は
少なくとも２個の炭素原子によって隔てられることを必
須とし、そして２個の隣接炭素原子はまた二重結合によ
って結合され且つ該炭素原子の自由原子価はＨおよび／
またはＣ＿１〜Ｃ＿４−アルキル基により飽和されてい
ることが可能であり、 Ａｒには２個までの環を有し且つ弗素、塩素、臭素、メ
トキシ、Ｃ＿１〜Ｃ＿４−アルキル、トリフルオロメチ
ルおよびトリフルオロメトキシからなる群より選択され
る３個までの基によって置換されうる芳香族環系を表わ
す〕 で示される１−ヒドロキシ−２−ピリドンを製造する方
法において、 ａ）式III ▲数式、化学式、表等があります▼III （式中Ｒ＾１、Ｒ＾２およびＲ＾３は前述の定義を有し
、Ｈａｌはハロゲン原子殊に塩素又は臭素を表わす）の
６−ハロゲノメチル−２−ピロンを式IV ▲数式、化学式、表等があります▼IV （式中、Ｘ、Ｙ、ＺおよびＡｒは前述の定義を有する）
のフェノールまたはチオフェノールと反応させ、得られ
た式Ｖ ▲数式、化学式、表等があります▼Ｖ のアリールオキシメチルピロンまたはアリールチオメチ
ルピロンをヒドロキシルアミンの作用により式 I のヒ
ドロキシピリドンに変換するかまたは ｂ）式IV ▲数式、化学式、表等があります▼IV （式中、Ｒ＾１、Ｒ＾２、Ｒ＾３および Ｈａｌは前述
の定義を有する）のジハロゲノピコリンを式IVのフェノ
ールと反応させ、得られた化合物を酸化してＮ−オキシ
ドを得ついでその化合物をその核上のハロゲンの加水分
解により式 I の化合物に変換する ことからなるかまたは基Ｒ＾１、Ｒ＾２、Ｒ＾３および
Ａｒの置換基の定義に従うその他の置換基をａ）もしく
はｂ）の操作によって得られた化合物中に、またはＡｒ
もしくはピリドン環中に依然として反応性基を含有して
いる中間体中に該反応性基の置換により導入することか
らなる前記式 I の化合物の製法。 １０）ａ）の別法として、式Ｖを有するアリールオキシ
メチルピロンまたはアリールチオメチルピロンの式 I
を有するヒドロキシピリドンへの変換を、式Ｖの化合物
１モル当たり少なくとも約１モルのヒドロキシアンモニ
ウム塩と、該塩に対して少なくとも約１当量の少なくと
も１種の有機または無機塩基の存在下での反応により行
う特許請求の範囲第９項記載の方法。 １１）使用する塩基がアルカリ金属好ましくはナトリウ
ムおよび／またはカリウムの炭酸塩および／または重炭
酸塩、特にＮａ＿２ＣＯ＿３である特許請求の範囲第１
０項記載の方法。 １２）使用するヒドロキシルアンモニウム塩が、硫酸ヒ
ドロキシルアンモニウムである特許請求の範囲第１１項
記載の方法。 １３）医薬用としての特許請求の範囲第１項〜第８項の
１つまたはそれ以上に記載の化合物または特許請求の範
囲第９項〜第１２項の１つまたはそれ以上で得られた化
合物および／または無機もしくは有機塩基によるこの型
の化合物の少なくとも１種の生理学的に許容しうる塩。 １４）特許請求の範囲第１項〜第８項の１つまたはそれ
以上に記載の化合物、または特許請求の範囲第９項〜第
１２項の１つまたはそれ以上で得られた少なくとも１種
の式 I ▲数式、化学式、表等があります▼ I 〔式中、 Ｒ＾１、Ｒ＾２およびＲ＾３は同一であるかまたは相異
なっていて、水素または１〜４個の炭素原子を有する低
級アルキルを表わすが、Ｒ＾１およびＲ＾２は好ましく
は水素であり、Ｒ＾２は好ましくはメチルであり、 ＸはＳまたは好ましくは０を表わし、 Ｙは水素または２個までのハロゲン原子、 すなわち塩素および／または臭素を表わし、Ｚは単結合
または２価の基のＯ、Ｓ、−ＣＲ＿２個（Ｒ＝Ｈもしく
はＣ＿１〜Ｃ＿４−アルキル）または２〜１０個の炭素
並びに場合により、鎖を形成するのに結合された酸素お
よび（または）硫黄原子を有するその他の２価基を表わ
し、その際該基が２個またはそれ以上の酸素および（ま
たは）硫黄原子を含有する場合には、これらの原子は少
なくとも２個の炭素原子によって隔てられることを必須
としそして２個の隣接炭素原子はまた二重結合によって
結合され且つ該炭素原子の自由原子価はＨおよび／また
はＣ＿１〜Ｃ＿４−アルキル基により飽和されているこ
とが可能であり、 Ａｒは２個までの環を有し且つ弗素、塩素、臭素、メト
キシ、Ｃ＿１〜Ｃ＿４−アルキル、トリフルオロメチル
およびトリフルオロメトキシからなる群より選択される
３個までの基によって置換されうる芳香族環系を表わす
〕で示される１−ヒドロキシ−２個ピリドンおよび／ま
たは無機もしくは有機塩基による上記型の化合物の少な
くとも１種の生理学的に許容しうる塩の有効量を生理学
的に許容しうるビヒクルおよび適切ならばさらに別の添
加剤および（または）補助剤に加えて含有する医薬。 １５）特に病原性皮腐真菌および粘膜真菌に対する抗真
菌剤として使用するための特許請求の範囲第１４項記載
の医薬。 １６）特許請求の範囲第１項〜第８項の１つまたはそれ
以上に記載の化合物または特許請求の範囲第９項〜第１
２項の１つまたはそれ以上で得られた少なくとも１種の
式 I ▲数式、化学式、表等があります▼ I 〔式中、 Ｒ＾１、Ｒ＾２およびＲ＾３は同一であるかまたは相異
なっていて、水素または１〜４個の炭素原子を有する低
級アルキルを表わすか、Ｒ＾１およびＲ＾２は好ましく
は水素であり、Ｒ＾２は好ましくはメチルであり。 ＸはＳまたは好ましくはＯを表わし、 Ｙは水素または２個までのハロゲン原子、 すなわち塩素および／または臭素を表わし、Ｚは単結合
または２価の基のＯ、Ｓ、−ＯＲ＿２−（Ｒ＝Ｈもしく
はＣ＿１〜Ｃ＿４−アルキル）または２〜１０個の炭素
並びに場合により、鎖を形成するのに結合された酸素お
よび（または）硫黄原子を有するその他の２価基を表わ
し、その際該基が２個またはそれ以上の酸素および（ま
たは）硫黄原子を含有する場合には、これらの原子は少
なくとも２個の炭素原子によって隔てられることを必須
としそして２個の隣接炭素原子はまた二重結合によって
結合され且つ該炭素原子の自由原子価はＨおよび／また
はＣ＿１〜Ｃ＿４−アルキル基により飽和されているこ
とが可能であり、 Ａｒは２個までの環を有し且つ弗素、塩素、臭素、メト
キシ、Ｃ＿１〜Ｃ＿４−アルキル、トリフルオロメチル
およびトリフルオロメトキシからなる群より選択される
３個までの基によって置換されうる芳香族環系を表わす
〕で示される１−ヒドロキシ−２−ピリドンおよび／ま
たは無機もしくは有機塩基による上記型の化合物の少な
くとも１種の生理学的に許容しうる塩を生理学的に許容
しうるビヒクルおよび適切ならばさらに別の添加剤およ
び／または補助剤で適当な製剤に変換することからなる
特許請求の範囲第１４項または第１５項記載の医薬の製
法。 １７）式Ｖ ▲数式、化学式、表等があります▼Ｖ （式中、Ｒ＾１、Ｒ＾２、Ｒ＾３、Ｘ、ＹおよびＡｒは
特許請求の範囲第１項記載の定義を有する）で表わされ
る化合物。 １８）式III ▲数式、化学式、表等があります▼III （式中、Ｒ＾１、Ｒ＾２およびＲ＾３は特許請求の範囲
第１項記載の定義を有しそしてＨａｌはハロゲン原子殊
に塩素または臭素を表わす）の６−ハロゲノメチル−２
−ピロンを式IV ▲数式、化学式、表等があります▼IV （式中、Ｘ、Ｙ、ＺおよびＡｒは特許請求の範囲第１項
記載の定義を有する）のフェノールまたはチオフェノー
ルと反応させることからなる式Ｖ ▲数式、化学式、表等があります▼Ｖ で表わされる化合物の製法。[Claims] 1) Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I [In the formula, R^1, R^2 and R^3 are the same or different, and hydrogen or 1 represents lower alkyl having ~4 carbon atoms, R^1 and R^2 are preferably hydrogen, R^2 is preferably methyl, X represents S or preferably O, and Y is represents hydrogen or up to two halogen atoms, i.e. chlorine and/or bromine, Z is a single bond or a divalent group O, S, -CR_2-(R-H or C_1-C_4-alkyl) or 2-10 represents two or more carbon atoms and optionally other divalent radicals with oxygen and/or sulfur atoms bonded to form a chain, in which case the radical represents two or more oxygen and/or sulfur atoms. When containing atoms, these atoms must be separated by at least two carbon atoms and two adjacent carbon atoms are also connected by a double bond and the free valence of the carbon atom is H and/or C_1-C_4-alkyl groups, Ar having up to two rings and containing fluorine, chlorine, bromine, methoxy, C_1-C_4-alkyl, trifluoromethyl and trifluorocarbons. 1-Hydroxy-2-pyridone represents an aromatic ring system which can be substituted by up to three groups selected from the group consisting of fluoromethoxy. 2) The compound according to claim 1, wherein Ar represents an optionally substituted phenyl ring. 3) Compounds according to claim 1, wherein Ar represents an isolated bicyclic system, preferably derived from biphenyl, diphenylalkane or diphenyl ether and optionally substituted. 4) The compound according to one or more of claims 1 to 3, wherein Z is a single bond. 5) Compounds according to one or more of claims 1 to 3, wherein Z represents or contains oxygen. 6) 6-[4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, i.e. in formula I, R^1, R^3 and Y are H and R^2 is CH_3, X is O, and Z is XC
O in the 4-position relative to the H_2 group and Ar is ▲
The compound according to claim 1, which has a mathematical formula, a chemical formula, a table, etc. 7) 6-(4-biphenyloxymethyl)-1-hydroxy-4-methyl-2-pyridone, i.e. in formula I, R^1, R^3 and Y are H and R^2 is CH_
3, X is O, Z is a single bond, and Ar
2. A compound according to claim 1, wherein is C_6H_5 in the 4-position relative to the XCH_2 group. 8) 1-hydroxy-4-methyl-6-[4-(4-trifluoromethylphenoxy)phenoxymethyl]-2
- pyridone, i.e., in formula I, R^1, R^3 and Y are H, R^2 is CH_3, X is O, Z is O in the 4-position relative to the XCH_2 group, and The compound according to claim 1, wherein Ar is ▲a mathematical formula, a chemical formula, a table, etc.▼. 9) Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I [In the formula, R^1, R^2 and R^3 are the same or different, and hydrogen or 1 to 4 carbon atoms R^1 and R^2 are preferably hydrogen, R^2 is preferably methyl, X represents S or preferably O, and Y represents hydrogen or up to 2 represents a halogen atom, i.e. chlorine and/or bromine, Z represents a single bond or a divalent group O, S, -CR_2- (R=H or C_1-C_4-alkyl) or 2 to 10 carbons and stands for other divalent radicals having oxygen and/or sulfur atoms linked to form a chain, in which case the radical contains two or more oxygen and/or sulfur atoms;
or) if it contains sulfur atoms, these atoms must be separated by at least two carbon atoms, and two adjacent carbon atoms are also bound by a double bond and the free The valence is H and/
or C_1-C_4-alkyl groups, Ar having up to two rings and fluorine, chlorine, bromine, methoxy, C_1-C_4-alkyl, trifluoromethyl and trifluoro represents an aromatic ring system which may be substituted by up to three groups selected from the group consisting of methoxy. a) Formula III ▲ Numerical formula, chemical formula, table etc. ▼III (wherein R^1, R^2 and R^3 have the above definitions and Hal represents a halogen atom, especially chlorine or bromine), by the formula IV ▲Mathematical formulas, chemical formulas, tables, etc.▼IV (In the formula, X, Y, Z and Ar have the above definitions)
React with phenol or thiophenol of formula V to obtain formula V ▲Mathematical formulas, chemical formulas, tables, etc.▼Is aryloxymethylpyrone or arylthiomethylpyrone of V converted to hydroxypyridone of formula I by the action of hydroxylamine? or b) Formula IV ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Dihalogenopicoline of formula IV (wherein R^1, R^2, R^3 and Hal have the above definitions) with phenol of formula IV reacting, oxidizing the compound obtained to obtain the N-oxide and converting the compound into a compound of formula I by hydrolysis of the halogen on its nucleus or with the radicals R^1, R^2, R^3 and other substituents according to the definition of substituents for Ar in the compound obtained by operation a) or b), or
or a process for the preparation of compounds of formula I, which comprises introducing the reactive group into an intermediate which still contains the reactive group in the pyridone ring by substitution. 10) As an alternative to a), aryloxymethylpyrones or arylthiomethylpyrones of formula V have the formula I
with at least about 1 mole of hydroxyammonium salt per mole of compound of formula V in the presence of at least about 1 equivalent of at least one organic or inorganic base relative to the salt. The method according to claim 9, which is carried out by. 11) Claim 1, wherein the base used is a carbonate and/or bicarbonate of an alkali metal, preferably sodium and/or potassium, in particular Na_2CO_3
The method described in item 0. 12) The method according to claim 11, wherein the hydroxylammonium salt used is hydroxylammonium sulfate. 13) Compounds according to one or more of claims 1 to 8 or compounds obtained according to one or more of claims 9 to 12 for pharmaceutical use and/or a physiologically acceptable salt of at least one compound of this type with an inorganic or organic base. 14) At least one compound according to one or more of claims 1 to 8 or obtained from one or more of claims 9 to 12 Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I [In the formula, R^1, R^2 and R^3 are the same or different and have hydrogen or 1 to 4 carbon atoms represents lower alkyl, R^1 and R^2 are preferably hydrogen, R^2 is preferably methyl, X represents S or preferably 0, Y represents hydrogen or up to 2 halogen atoms , i.e. chlorine and/or bromine, Z is a single bond or a divalent group O, S, -CR_2 (R=H or C_1-C_4-alkyl) or 2 to 10 carbons and optionally a chain represents other divalent radicals having oxygen and/or sulfur atoms combined to form, if the radical contains two or more oxygen and/or sulfur atoms; These atoms must be separated by at least two carbon atoms and two adjacent carbon atoms are also connected by a double bond and the free valence of the carbon atom is H and/or C_1-C_4-alkyl. Ar can have up to two rings and be selected from the group consisting of fluorine, chlorine, bromine, methoxy, C_1-C_4-alkyl, trifluoromethyl and trifluoromethoxy. 1-hydroxy-2 pyridone and/or an inorganic or organic base representing an aromatic ring system which can be substituted by up to 3 groups A medicament containing an effective amount of a salt in addition to a physiologically acceptable vehicle and if appropriate further additives and/or auxiliaries. 15) The medicament according to claim 14 for use as an antifungal agent, particularly against pathogenic skin rot fungi and mucosal fungi. 16) Compounds according to one or more of claims 1 to 8 or claims 9 to 1
At least one formula obtained by one or more of the following two terms I ▲ May be a mathematical formula, chemical formula, table, etc. ▼ I [In the formula, R^1, R^2 and R^3 are the same or R^1 and R^2, which are different and represent hydrogen or lower alkyl having 1 to 4 carbon atoms, are preferably hydrogen and R^2 is preferably methyl. X represents S or preferably O, Y represents hydrogen or up to two halogen atoms, i.e. chlorine and/or bromine, Z represents a single bond or a divalent group O, S, -OR_2-(R= H or C_1-C_4-alkyl) or other divalent radicals having 2 to 10 carbons and optionally oxygen and/or sulfur atoms bonded to form a chain, in which case the radicals When containing two or more oxygen and/or sulfur atoms, these atoms must be separated by at least two carbon atoms and two adjacent carbon atoms must also be separated by a double bond. bonded and the free valency of the carbon atom can be saturated by H and/or C_1-C_4-alkyl groups, Ar having up to 2 rings and containing fluorine, chlorine, bromine, methoxy , C_1-C_4-alkyl, trifluoromethyl and trifluoromethoxy. converting the physiologically acceptable salts of at least one of the above-mentioned compounds with an inorganic or organic base into a suitable formulation with a physiologically acceptable vehicle and, if appropriate, further additives and/or auxiliaries; A method for producing a medicament according to claim 14 or 15, comprising: 17) Formula V ▲There are mathematical formulas, chemical formulas, tables, etc.▼V (In the formula, R^1, R^2, R^3, X, Y, and Ar have the definitions described in claim 1) A compound represented by 18) Formula III ▲There are mathematical formulas, chemical formulas, tables, etc.▼III (In the formula, R^1, R^2 and R^3 have the definitions in claim 1 and Hal is a halogen atom, especially 6-halogenomethyl-2 (representing chlorine or bromine)
- Reacting pyrone with phenol or thiophenol of formula IV ▲ Numerical formula, chemical formula, table, etc. ▼ IV (wherein X, Y, Z and Ar have the definitions in claim 1) Formula V consisting of ▲There are mathematical formulas, chemical formulas, tables, etc.▼V Method for producing the compound represented by.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3613061.3 | 1986-04-18 | ||
| DE19863613061 DE3613061A1 (en) | 1986-04-18 | 1986-04-18 | 1-Hydroxy-2-pyridones, process for their preparation and medicaments which contain them |
| DE3626211.0 | 1986-08-02 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62249974A true JPS62249974A (en) | 1987-10-30 |
| JPH03864B2 JPH03864B2 (en) | 1991-01-09 |
Family
ID=6298947
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62093445A Granted JPS62249974A (en) | 1986-04-18 | 1987-04-17 | 1-hydroxy-2-pyridones |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS62249974A (en) |
| DE (1) | DE3613061A1 (en) |
| MX (1) | MX6093A (en) |
| ZA (1) | ZA872745B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2540218A (en) * | 1947-08-25 | 1951-02-06 | Squibb & Sons Inc | 2-hydroxy-pyridine-n-oxide and process for preparing same |
| FR3691M (en) * | 1963-05-06 | 1965-11-15 | Olin Mathieson | New pharmaceutical composition useful as a fungicide. |
| NL156397B (en) * | 1968-08-31 | 1978-04-17 | Hoechst Ag | PROCESS FOR THE PREPARATION OF PREPARATIONS AGAINST FUNGAL DISEASES, MOLDED PREPARATIONS AND PROCEDURE FOR THE PREPARATION OF SUITABLE ACTIVE SUBSTANCES. |
-
1986
- 1986-04-18 DE DE19863613061 patent/DE3613061A1/en not_active Withdrawn
-
1987
- 1987-04-15 MX MX609387A patent/MX6093A/en unknown
- 1987-04-16 ZA ZA872745A patent/ZA872745B/en unknown
- 1987-04-17 JP JP62093445A patent/JPS62249974A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| ZA872745B (en) | 1987-12-30 |
| JPH03864B2 (en) | 1991-01-09 |
| DE3613061A1 (en) | 1987-10-22 |
| MX6093A (en) | 1994-02-28 |
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