JPS636041B2 - - Google Patents
Info
- Publication number
- JPS636041B2 JPS636041B2 JP55032931A JP3293180A JPS636041B2 JP S636041 B2 JPS636041 B2 JP S636041B2 JP 55032931 A JP55032931 A JP 55032931A JP 3293180 A JP3293180 A JP 3293180A JP S636041 B2 JPS636041 B2 JP S636041B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- acid
- present
- antimicrobial agent
- ethyl
- 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.)
- Expired
Links
- 239000004599 antimicrobial Substances 0.000 claims description 29
- 239000004480 active ingredient Substances 0.000 claims description 11
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 description 44
- 241000894006 Bacteria Species 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 241000233866 Fungi Species 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- -1 aromatic sulfonic acids Chemical class 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 201000010099 disease Diseases 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 229920002472 Starch Polymers 0.000 description 8
- 239000000969 carrier Substances 0.000 description 8
- 235000019698 starch Nutrition 0.000 description 8
- 239000008107 starch Substances 0.000 description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 7
- 240000007594 Oryza sativa Species 0.000 description 7
- 235000007164 Oryza sativa Nutrition 0.000 description 7
- 230000000844 anti-bacterial effect Effects 0.000 description 7
- 150000007514 bases Chemical class 0.000 description 7
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 7
- 235000001727 glucose Nutrition 0.000 description 7
- 239000008103 glucose Substances 0.000 description 7
- 235000009566 rice Nutrition 0.000 description 7
- ZUVPLKVDZNDZCM-UHFFFAOYSA-N 3-chloro-2-methylaniline Chemical compound CC1=C(N)C=CC=C1Cl ZUVPLKVDZNDZCM-UHFFFAOYSA-N 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 240000003768 Solanum lycopersicum Species 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 238000007363 ring formation reaction Methods 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 239000000454 talc Substances 0.000 description 6
- 229910052623 talc Inorganic materials 0.000 description 6
- 235000012222 talc Nutrition 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 229920001817 Agar Polymers 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- 239000005995 Aluminium silicate Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 240000008067 Cucumis sativus Species 0.000 description 4
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 235000012211 aluminium silicate Nutrition 0.000 description 4
- 239000000440 bentonite Substances 0.000 description 4
- 229910000278 bentonite Inorganic materials 0.000 description 4
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 239000004927 clay Substances 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229920000137 polyphosphoric acid Polymers 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000005507 spraying Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- RPPOUWYTRJMQBO-UHFFFAOYSA-N 7-chloro-1-ethyl-8-methyl-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(Cl)C(C)=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 RPPOUWYTRJMQBO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000219112 Cucumis Species 0.000 description 3
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 244000088415 Raphanus sativus Species 0.000 description 3
- 235000006140 Raphanus sativus var sativus Nutrition 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 241000589634 Xanthomonas Species 0.000 description 3
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 235000010216 calcium carbonate Nutrition 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000019271 petrolatum Nutrition 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000001965 potato dextrose agar Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- 235000013311 vegetables Nutrition 0.000 description 3
- 239000003871 white petrolatum Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- FWYFRUJMEBBNIH-UHFFFAOYSA-N 1-ethyl-7-fluoro-8-methyl-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(F)C(C)=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 FWYFRUJMEBBNIH-UHFFFAOYSA-N 0.000 description 2
- QPUYECUOLPXSFR-UHFFFAOYSA-N 1-methylnaphthalene Chemical compound C1=CC=C2C(C)=CC=CC2=C1 QPUYECUOLPXSFR-UHFFFAOYSA-N 0.000 description 2
- VBWPVOYFHBRRDY-UHFFFAOYSA-N 3-chloro-n-ethyl-2-methylaniline Chemical compound CCNC1=CC=CC(Cl)=C1C VBWPVOYFHBRRDY-UHFFFAOYSA-N 0.000 description 2
- WNNSMMJBBOPPOT-UHFFFAOYSA-N 7-chloro-1-ethyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound FC1=C(Cl)C=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 WNNSMMJBBOPPOT-UHFFFAOYSA-N 0.000 description 2
- 244000144730 Amygdalus persica Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241000222199 Colletotrichum Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- 241001466453 Laminaria Species 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 235000006040 Prunus persica var persica Nutrition 0.000 description 2
- 241000589516 Pseudomonas Species 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241001558929 Sclerotium <basidiomycota> Species 0.000 description 2
- 244000000231 Sesamum indicum Species 0.000 description 2
- 235000003434 Sesamum indicum Nutrition 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 244000061458 Solanum melongena Species 0.000 description 2
- 235000002597 Solanum melongena Nutrition 0.000 description 2
- 241000194017 Streptococcus Species 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 244000299461 Theobroma cacao Species 0.000 description 2
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 2
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N beta-monoglyceryl stearate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 235000014121 butter Nutrition 0.000 description 2
- 235000001046 cacaotero Nutrition 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001734 carboxylic acid salts Chemical class 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000007765 cera alba Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 229940039717 lanolin Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 2
- 229960000210 nalidixic acid Drugs 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 238000003892 spreading Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
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Landscapes
- Quinoline Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
本発明は新規なキノリンカルボン酸誘導体を有
効成分とする抗微生物剤に関する。
本発明の有効成分であるキノリンカルボン酸誘
導体は文献未載の新規化合物であつて、一般式
〔式中R1及びR2はそれぞれ低級アルキル基を示
し、R3はハロゲン原子を示す。〕で表わされるキ
ノリンカルボン酸誘導体及びその塩である。
上記キノリンカルボン酸誘導体は医療用及び農
園芸用の抗微生物剤の有効成分として有用であ
る。
上記一般式(1)に於て、R1及びR2で示される低
級アルキル基の例としては炭素数1〜4の直鎖も
しくは分枝状のアルキル基を挙げることができ、
具体的にはメチル、エチル、プロピル、イソプロ
ピル、ブチル、tert−ブチル基等を例示できる。
またR3で示されるハロゲン原子としては具体的
に弗素原子、塩素原子、臭素原子、沃素原子等を
挙げることができる。
本発明の代表的な化合物を以下に挙げる。
Γ1−エチル−7−クロロ−8−メチル−4−オ
キソ−1・4−ジヒドロキノリン−3−カルボ
ン酸
Γ1・8−ジエチル−7−クロロ−4−オキソ−
1・4−ジヒドロキノリン−3−カルボン酸
Γ1−エチル−7−フルオロ−8−メチル−4−
オキソ−1・4−ジヒドロキノリン−3−カル
ボン酸
Γ1−メチル−7−クロロ−8−メチル−4−オ
キソ−1・4−ジヒドロキノリン−3−カルボ
ン酸
Γ1−エチル−7−クロロ−8−イソプロピル−
4−オキソ−1・4−ジヒドロキノリン−3−
カルボン酸
Γ1・8−ジメチル−7−ブロム−4−オキソ−
1・4−ジヒドロキノリン−3−カルボン酸
本発明で特に好ましい化合物は、1−エチル−
7−クロロ−8−メチル−4−オキソ−1・4−
ジヒドロキノリン−3−カルボン酸及び1−エチ
ル−7−フルオロ−8−メチル−4−オキソ−
1・4−ジヒドロキノリン−3−カルボン酸であ
る。
本発明の有効成分であるキノリンカルボン酸誘
導体は種々の方法により製造されるが、その代表
的な方法として下記反応式に示す方法を挙げるこ
とができる。
〔式中R1、R2及びR3は前記に同じ、R4及びR5は
低級アルキル基、Xはハロゲン原子を示す〕
一般式(2)で表わされる公知のニトロベンゼン誘
導体の還元には例えば還元剤を用いる方法、接触
還元による方法等を挙げることができる。還元剤
を用いる方法を採用する場合、用いられる還元剤
としては鉄−塩酸、亜鉛−酢酸、塩化第一鉄−塩
酸等を例示できる。還元剤の使用量としては一般
式(2)の化合物に対して通常等モル〜過剰量、好ま
しくは約3〜5倍モル量とするのがよい。該還元
反応は通常室温〜150℃、好ましくは約50〜100℃
にて行なわれ、一般に約30分〜3時間程度で反応
は終了する。斯くして一般式(3)の化合物が生成す
る。
一般式(3)の化合物と一般式(4)の化合物との反応
に於て、両者の使用割合としては通常前者に対し
て後者を等モル以上、好ましくは約2倍モル以上
とするのがよい。該反応は通常塩基性化合物の存
在下無溶媒で或いは不活性溶媒中にて行なわれ
る。塩基性化合物としては具体的には水酸化ナト
リウム、水酸化カリウム等のアルカリ金属水酸化
物、炭酸ナトリウム、炭酸カリウム、炭酸水素カ
リウム、炭酸水素ナトリウム等の無機炭酸化合物
類、ピリジン、キノリン、トリエチルアミン、ト
リブチルアミン等の第三級アミン類等を例示でき
る。斯かる塩基性化合物を一般式(3)の化合物に対
して通常等モル以上、好ましくは約1.1〜1.5倍モ
ル量用いるのがよい。用いられる不活性溶媒とし
てはメタノール、エタノール、イソプロパノール
等の低級アルコール類、ジオキサン、テトラヒド
ロフラン、ジグライム等のエーテル類、ベンゼ
ン、トルエン等の芳香族炭化水素類、ジメチルス
ルホキシド、ジメチルホルムアミド、ヘキサメチ
ルリン酸トリアミド、ピリジン等を例示できる。
この中で芳香族炭化水素類が好ましい。該反応は
通常室温〜150℃程度、好ましくは約80〜130℃に
て行なわれ、通常約0.5〜6時間程度で反応は終
了する。斯くして一般式(5)の化合物が生成する。
一般式(5)の化合物と一般式(6)の化合物との反応
は無溶媒又はメタノール、エタノール、イソプロ
パノール、アセトニトリル、ジメチルホルムアミ
ド、ジメチルスルホキシド、ヘキサメチルリン酸
アミド等の溶媒中、好ましくは無溶媒で行なわれ
る。化合物(5)に対する化合物(6)の使用割合は通常
等モル以上であればよく、無溶媒下の反応では好
ましくは等モル量、溶媒下の反応では好ましくは
約1.1〜1.5倍モル量とするのがよい。反応温度は
通常室温〜150℃程度、好ましくは約100〜130℃
であり、反応は通常約0.5〜6時間で完了し、容
易に一般式(7)で表わされる化合物を収得できる。
かくして得られる化合物(7)の環化反応は従来公
知の各種環化反応に準じて行ない得る。例えば加
熱による方法、オキシ塩化リン、五塩化リン、三
塩化リン、チオニルクロライド、濃硫酸、ポリリ
ン酸等の酸性物質を用いる環化法等を例示でき
る。加熱による環化法を採用する場合、高沸点炭
化水素類及び高沸点エーテル類例えばテトラリ
ン、ジフエニルエーテル、ジエチレングリコール
ジメチルエーテル等の溶媒を用い、通常約100〜
250℃、好ましくは約150〜200℃の加熱条件を採
用できる。又酸性物質を用いる環化法を採用する
場合これを化合物(7)に対して等モル量〜大過剰量
好ましくは約10〜20倍量用い、通常約100〜150℃
で約0.5〜6時間程度反応させればよい。斯くし
て一般式(8)の化合物が生成する。
上記環化反応により得られる化合物(8)の加水分
解反応は、常法に従い、例えば水酸化ナトリウ
ム、水酸化カリウム、水酸化バリウム等の塩基性
化合物、硫酸、塩酸、硝酸等の鉱酸、酢酸、芳香
族スルホン酸等の有機酸等の慣用の触媒の存在下
に行なわれる。該反応は一般には水、メタノー
ル、エタノール、イソプロパノール、アセトン、
メチルエチルケトン、ジオキサン、エチレングリ
コール、酢酸等の通常の溶媒中で実施される。反
応温度は通常室温〜200℃、好ましくは約50〜150
℃である。斯くして一般式(1)で表わされる本発明
の化合物が容易に収得される。
本発明においては上記で得られた一般式(1)のキ
ノリンカルボン酸の酸付加塩及びカルボン酸塩の
両方の塩を包含する。
酸付加塩の形成に用いられる酸は薬理的又は農
薬的に許容される各種の有機酸又は無機酸でよ
く、これには例えば塩酸、硫酸、硝酸、臭化水素
酸、リン酸等の無機酸及び酢酸、蓚酸、マロン
酸、コハク酸、マレイン酸、フマール酸、リンゴ
酸、マンデル酸、エタンスルホン酸、P−トシル
酸等の有機酸を例示できる。
またカルボン酸塩の形成に用いられる塩基性化
合物としては薬理的又は農薬的に許容される各種
の塩基性化合物でよく、これには例えば水酸化ナ
トリウム、水酸化カリウム、水酸化カルシウム、
水酸化アルミニウム、炭酸水素ナトリウム等の無
機の塩基性化合物等を例示できる。
斯くして生成する本発明の化合物は、上記した
反応行程の終了後に慣用の分離手段により容易に
単離精製できる。分離手段としては例えば溶媒抽
出法、希釈法、沈殿法、再結晶法、カラムクロマ
トグラフイー、プレパラテイブ薄層クロマトグラ
フイー等を例示できる。
一般式(1)で表わされる化合物を有効成分とする
本発明の抗微生物剤は低毒性であり優れた抗微生
物活性を有する。本発明の抗微生物剤は細菌、真
菌、かび等による動物及び農園芸用作物の疾病の
予防及び治療に有用である。動物としては人を含
む哺乳類、鳥類、魚類等を挙げることができる。
本発明の抗微生物剤はまた医療用器具等の殺菌及
び消毒に有用であり、更には農園芸用作物の貯蔵
や輸送等において細菌、かび等により作物被害が
予想される場合には、予めこれを作物に散布、噴
霧、塗布等により適用することによつて、その被
害を防止することができる。従つて本発明の抗微
生物剤は医療用及び農園芸用の抗微生物剤として
有用である。
本発明の抗微生物剤は各種の細菌、真菌、かび
等に対して有効である。
細菌としてはグラム陽性菌及びグラム陰性菌の
両方に対して有効であり、具体例としてはシユー
ドモナス(Pseudomonas)、キサントモナス
(Xanthomonas)等のシユードモナダケアエ
(Pseudomonadaceae)、エルビナ(Erwinia)、
エシエリヒア(Escherichia)、クレブジーラ
(Klebsiella)、セラチア(Serratia)、プロテウス
(Proteus)、サルモネラ(Salmonella)、シゲラ
(Shigella)等のエンテロバクテリアケアエ
(Enterobacteriaceae)、スタフイロコツカス
(Staphylococcus)等のミクロコツカケアエ
(Micrococcaceae)、ストレプトコツカス
(Streptococcus)等のストレプトコツカケアエ
(Streptococcaceae)等を挙げることができる。
これらのうち本発明の抗微生物剤はエルビナ、キ
サントモナス、シユードモナス及びストレプトコ
ツカスに対し優れた活性を示し、特にエルビナ及
びキサントモナスに対して極めて優れた活性を示
す。
動物の真菌症の原因となる真菌の例としては例
えばクリプトコツカス ネオホルマンス
(Cryptococcus neoformans)、コクシデイオイ
デス イミテス(Coccidioides immites)、カン
ジダアルビカンス(Candida albicans)、アスペ
ルギルス フミガタス(Aspergillus fumigatus)
等を挙げることができる。
農園芸用作物の真菌症の原因となるかびとして
は例えばイモチ病菌(Pyricularia oryzae)、稲
胡麻葉枯病菌(Helminthosporium oryzae)、稲
小球菌核病菌(Helminthosporium
sigmoideum)、キユウリ疫病菌(Phytophthora
melonis)、ジヤガイモ疫病菌(Phytophthora
infestans)、ウリ炭疽病菌(Colletotrichum
lagenarium)、ワタ炭疽病菌(Colletotrichum
indicum)、ナス菌核病菌(Sclerotinia
sclerotiorum)、メロン蔓枯病菌
(Mycosphaerella melonis)、エンドウ斑点病菌
(Mycosphaerella phaseolicola)、トマト輪紋病
菌(Alternaria solani)等を挙げることができ
る。
本発明の抗微生物剤は動物及び農園芸用作物の
細菌症及び真空症の予防及び治療に有用である。
農園芸用作物の細菌症としては例えば野菜軟腐
病、稲白葉枯病、水稲紋枯病、桃センコウ細菌
病、柑橘潰瘍病、ナス科植物青枯病、トマト青枯
病、トマト萎稠病、スイカつる割病、キユウリ斑
点細菌病等を、また真菌症の例としては稲イモチ
病、稲胡麻葉枯病、キユウリ疫病、キユウリ灰色
疫病、ウリ炭疽病、ナス菌核病、メロン蔓枯病、
トマト輪絞病等を挙げることができる。
本発明の抗微生物剤は特に野菜軟腐病に対し従
来のものに比し極めて優れた効果を発揮する。
本発明の抗微生物剤を医療用に用いた場合、例
えば後記の抗菌試験1より明らかなように、従来
この分野で用いられているナリジクス酸を含む抗
菌剤に比較して優れた効果を示す。また本発明の
抗微生物剤を農園芸用に用いた場合、例えば後記
の抗菌試験3より明らかなように従来のストレプ
トマイシンを含有した抗菌殺菌剤に比し優れた効
果を発揮する。
本発明の抗微生物剤は、之を医療用として用い
るに当り、通常医療用製剤的担体と共に製剤組成
物の形態とされる。担体としては使用形態に応じ
た薬剤を調製するのに通常使用される充填剤、増
量剤、結合剤、付湿剤、崩壊剤、表面活性剤、滑
沢剤等の希釈剤あるいは賦形剤を例示できる。
抗微生物剤の投与単位形態としては各種の形態
を治療目的に応じて選択でき、その代表的なもの
として錠剤、丸剤、散剤、液剤、懸濁剤、乳剤、
顆粒剤、カプセル剤、坐剤、注射剤(液剤、懸濁
剤等)、軟膏剤等を例示できる。錠剤の形態に成
形するに際しては、担体としてこの分野で従来公
知のものを広く使用でき、例えば乳糖、白糖、塩
化ナトリウム、ブドウ糖液、尿素、デンプン、炭
酸カルシウム、カオリン、結晶セルロース、ケイ
酸等の賦形剤、水、エタノール、プロパノール、
単シロツプ、ブドウ糖、デンプン液、ゼラチン溶
液、カルボキシメチルセルロース、セラツク、メ
チルセルロース、リン酸カリウム、ポリビニルピ
ロリドン等の結合剤、乾燥デンプン、アルギン酸
ナトリウム、カンテン末、ラミナリア末、炭酸水
素ナトリウム、炭酸カルシウム、ツウイン、ラウ
リル硫酸ナトリウム、ステアリン酸モノグリセリ
ド、デンプン、乳糖等の崩壊剤、白糖、ステアリ
ン、カカオバター、水素添加油等の崩壊抑制剤、
第四級アンモニウム塩基、ラウリル硫酸ナトリウ
ム等の吸収促進剤、グリセリン、デンプン等の保
湿剤、デンプン、乳糖、カオリン、ベントナイ
ト、コロイド状ケイ酸等の吸着剤、精製タルク、
ステアリン酸塩、ホウ酸末、ポリエチレングリコ
ール等の滑沢剤等を例示できる。丸剤の形態に成
形するに際しては、担体としてこの分野で従来公
知のものを広く使用でき、例えばブドウ糖、乳
糖、デンプン、カカオ脂、硬化植物油、カオリ
ン、タルク等の賦形剤、アラビアゴム末、トラガ
ント末、ゼラチン、エタノール等の結合剤、ラミ
ナリア、カンテン等の崩壊剤等を例示できる。更
に錠剤は必要に応じ通常の剤皮を施した錠剤例え
ば糖衣錠、ゼラチン被包錠、腸溶被錠、フイルム
コーテイング錠あるいは二重錠、多層錠とするこ
とができる。坐剤の形態に成形するに際しては、
担体として従来公知のものを広く使用でき、例え
ばポリエチレングリコール、カカオ脂、高級アル
コール、高級アルコールのエステル類、ゼラチ
ン、半合成グリセライド等を挙げることができ
る。注射剤として調製される場合には液剤及び懸
濁剤は殺菌され且つ血液と等張であるのが好まし
く、これら液剤、乳剤及び懸濁剤の形態に成形す
るのに際しては、希釈剤としてこの分野に於いて
慣用されているものをすべて使用でき、例えば
水、エチルアルコール、プロピレングリコール、
エトキシ化イソステアリルアルコール、ポリオキ
シ化イソステアリルアルコール、ポリオキシエチ
レンソルビツト、ソルビタンエステル等を挙げる
ことができる。なおこの場合等張性の溶液を調製
するに充分な量の食塩、ブドウ糖あるいはグリセ
リンを抗微生物剤中に含有せしめてもよく、また
通常の溶解補助剤、緩衝剤、無痛化剤、保存剤等
を含有せしめても良い。更に本発明の抗微生物剤
には必要に応じて着色剤、保存剤、香料、風味
剤、甘味剤等や他の医薬品を該治療剤中に含有せ
しめてもよい。ペースト、クリーム及びゲルの形
態に成形するに際しては、希釈剤としてこの分野
で従来公知のものを広く使用でき、例えば白色ワ
セリン、パラフイン、グリセリン、セルロース誘
導体、ポリエチレングリコール、シリコン、ベン
トナイト等を例示できる。本発明の医療用抗微生
物剤中に含有させるべき有効成分化合物の量は特
に限定されず広範囲に適宜選択されるが、通常全
組成物中約1〜70重量%とするのがよい。
また上記抗微生物剤は、その使用に際し特に制
限はなく各種形態に応じた方法で投与される。例
えば錠剤、丸剤、液剤、懸濁剤、乳剤、顆粒剤及
びカプセル剤の場合には経口投与され、注射剤の
場合には単独であるいはブドウ糖、アミノ酸等の
通常の補液と混合して静脈内投与され、さらに必
要に応じて単独で筋肉内、皮内、皮下若しくは腹
腔内投与され、坐剤の場合には直腸内投与され、
また軟膏剤の場合には塗布される。
本発明の医療用抗微生物剤としての投与量は使
用目的、症状等により適宜選択され、通常本発明
化合物を1日当り約10mg〜5g/body程度を3
〜4回に分けて投与すればよい。
本発明の抗微生物剤を農園芸用として用いるに
当つては、必要に応じ適当な農園芸用製剤担体、
例えば固体担体、液体担体、懸濁化剤、展着剤等
を用いて、粒剤、粉剤、分散剤、水和剤、錠剤、
油剤、噴霧剤、煙霧剤等の任意の形態に調製でき
る。用いられる担体としては、クレー、カオリ
ン、ベントナイト、タルク、酸性白土、硅藻土、
炭酸カルシウム、ニトロセルローズ、デンプン、
アラビアゴム、炭酸ガス、フレオン、水、ベンゼ
ン、ケロシン、アルコール、アセトン、キシレ
ン、メチルナフタレン、シクロヘキサノン、動植
物脂肪酸エステル等を例示できる。また懸濁化
剤、展着剤等としては、通常の界面活性剤例えば
石鹸、高級アルコールの硫酸エステル、アルキル
スルホン酸塩、第4級アンモニウム塩、ポリアル
キレンオキシド等を例示できる。
上記により調製される本発明の農園芸用抗微生
物剤中の有効成分化合物の配合量は、その使用形
態等に応じて適宜に決定できる。例えば分散剤や
水和剤等の形態とするには、約0.1〜90重量%の
範囲とするのが好ましく、また粉剤や油剤等の形
態では約0.1〜10重量%程度の範囲とするのが適
当である。
本発明の農園芸用抗微生物剤はその使用に当つ
ては公知の農園芸用抗微生物剤と同様に抗微生物
効果を必要とする箇所に散布、噴霧、塗布等によ
り適用できる。その適用量は必要とする効果に応
じて適宜に決定できる。例えば本発明の農園芸用
抗微生物剤は通常1ヘクタール当り有効成分量が
約0.1〜10Kg好ましくは約0.1〜1Kg程度となる量
を目安とすればよく、勿論これは植物やその病害
の程度に応じて適宜増減できる。またこれは例え
ば他の抗微生物剤、殺虫剤又は除草剤、肥料物
質、土壌改良剤等と併用することも可能である。
以下に本発明の有効成分化合物の製造例を参考
例として挙げ、さらに本発明抗微生物剤の製剤例
を実施例として挙げる。
参考例 1
2−メチル−3−クロロアニリンの合成
2−クロル−6−ニトロトルエン29gを塩化第
一スズ150gと濃塩酸200mlとの混合液に氷冷下加
える。次に溶液を100℃にて1時間加熱すると白
色結晶が得られる。得られた結晶を取し水400
mlと40%NaOH50mlとの混合液に溶解し500mlの
クロロホルムにて抽出する。抽出液を水400mlに
て洗浄後、クロロホルム層を無水硫酸マグネシウ
ムにて乾燥後溶媒を減圧濃縮する。残査を蒸留す
ることによつて115゜〜116℃/10mmHgの留分であ
る2−メチル−3−クロロアニリン23gを得る。
参考例 2
N−エチル−2−メチル−3−クロロアニリン
の合成
参考例1で得られる2−メチル−3−クロロア
ニリン14gをベンゼン100mlに溶解しトリエチル
アミン12g加えた後エチルブロマイド13gを加え
ベンゼン還流下3時間反応させる。反応後室温に
戻し水200ml加え振とうする。ベンゼン層を分離
し無水硫酸マグネシウムにて乾燥後濃縮する。残
査を蒸留することによつて125゜〜126℃/10mmHg
の留分であるN−エチル−2−メチル−3−クロ
ロアニリン12gを得る。
参考例 3
1−エチル−7−クロロ−8−メチル−4−オ
キソ−1・4−ジヒドロキノリン−3−カルボ
ン酸の合成
N−エチル−2−メチル−3−クロロアニリン
10gとジエチルエトキシメチレンマロネート15g
を110℃30分間加熱反応させる。次にリン酸50g
と五酸化リン50gより得られるポリリン酸
(PPA)を加え140℃にて40分間反応させる。反
応後水と氷600g中に投入すると結晶が析出する。
析出する結晶を取した後10%水酸化ナトリウム
溶液を加え1時間還流する。還流後活性炭処理し
濃塩酸にてPH2とすると淡黄色結晶が析出する。
ジメチルホルムアミドより再結晶し白色針状晶の
1−エチル−7−クロロ−8−メチル−4−オキ
ソ−1・4−ジヒドロキノリン−3−カルボン酸
11gを得る。
mp 221〜222℃
参考例 4
1−エチル−7−フルオロ−8−メチル−4−
オキソ−1・4−ジヒドロキノリン−3−カル
ボン酸の合成。
N−エチル−2−メチル−3−フルオロ−アニ
リン9gとジエチルエトキシメチレンマロネート
15gを110℃30分間加熱反応させる。次にリン酸
50gと五酸化リン50gより得られるポリリン酸
(PAA)を加え140℃にて40分間反応させる。反
応後水と氷600g中に投入すると結晶が析出する。
析出する結晶を取した後10%水酸化ナトリウム
溶液を加え1時間還流する。還流後活性炭処理し
濃塩酸にてPH2とすると淡黄色結晶が析出する。
ジメチルホルムアミドより再結晶し白色針状晶の
1−エチル−7−フルオロ−8−メチル−4−オ
キソ−1・4−ジヒドロキノリン−3−カルボン
酸10gを得る。
mp 245−246℃
実施例 1
参考例3で得られた化合物 200mg
ブドウ糖 250mg
注射用蒸留水 適量
全 量 5ml
注射用蒸留水に本発明の化合物及びブドウ糖を
溶解させた後5mlのアンプルに注入し、窒素置換
後121℃で15分間加圧滅菌を行なつて上記組成の
注射剤を得る。
実施例 2
参考例3で得られた化合物 100g
アビシエル〔商標名 旭化成(株)製〕 40g
コンスターチ 30g
ステアリン酸マグネシウム 2g
TC−5(商標名 信越化学工業(株)製、ヒドロキシ
プロピルメチルセルロース) 10g
ポリエチレングリコール−6000 3g
ヒマシ油 40gメタノール 40g
本発明化合物、アピシエル、コンスターチ及び
ステアリン酸マグネシウムを取り混合研摩後、糖
衣R10mmのキネで打錠する。得られた錠剤をTC
−5、ポリエチレングリコール−6000、ヒマシ油
及びメタノールからなるフイルムコーテイング剤
で被覆を行ない上記組成のフイルムコーテイング
錠を製造する。
実施例 3
参考例3で得られ化合物 2g
精製ラノリン 5g
サラシミツロウ 5g
白色ワセリン 88g
全 量 100g
サラシミツロウを加温して液状とし、次いで本
発明化合物、精製ラノリン及び白色ワセリンを加
え液状となるまで加温後、固化し始めるまで攪拌
して、上記組成の軟膏剤を得る。
実施例 4
参考例3で得られた化合物のナトリウム塩 20gタルク 980g
本発明化合物及びタルクを混合研摩して粉剤を
得る。
実施例 5
参考例3で得られた化合物 200g
ホワイトカーボン 20g
リグニンスルホン酸ナトリウム 20g
ポリオキシエチレンアルキルエーテル 40gクレー 720g
上記化合物を混合研摩して水和剤を得る。
実施例 6
参考例3で得られた化合物 100g
硅藻土 210g
タルク 200gアルキル硫酸ナトリウム 90g
上記化合物を混合研摩して水和剤を得る。
実施例 7
参考例3で得られた化合物 100g
タルク 380g
クレー 370g
ベントナイト 100gアルキル硫酸ナトリウム 50g
上記化合物を混合研摩し、次いで造粒機で造粒
して粒剤を得る。
<抗菌試験1>
本発明有効成分化合物、1−エチル−6−フル
オロ−7−クロロ−4−キノロン−3−カルボン
酸(特開昭54−14978号公報の特許請求の範囲第
2項に記載の化合物)及び1−エチル−1・4−
ジヒドロ−7−メチル−4−オキソ−1・8−ナ
フチリデン−3−カルボン酸(ナリジクス酸、対
照化合物)について、種々の菌に対する抗菌作用
を寒天希釈平板法により求めた。得られた菌の最
少増殖阻止濃度を下記第1表に示す。尚各種菌は
1×108菌数/ml(O.D.660mμ、0.13〜0.14)及
び1×106菌数/mlに調製した。
<供試化合物>
化合物1 1−エチル−7−(1−ピペラジニル)
−8−メチル−4−オキソ−1・4−ジヒドロ
キノリン−3−カルボン酸
化合物2 1−エチル−7−クロル−8−メチル
−4−オキソ−1・4−ジヒドロキノリン−3
−カルボン酸
化合物3 1−エチル−6−フルオロ−7−クロ
ロ−4−キノロン−3−カルボン酸
The present invention relates to an antimicrobial agent containing a novel quinoline carboxylic acid derivative as an active ingredient. The quinoline carboxylic acid derivative that is the active ingredient of the present invention is a new compound that has not been described in any literature, and has the general formula [In the formula, R 1 and R 2 each represent a lower alkyl group, and R 3 represents a halogen atom. ] These are quinoline carboxylic acid derivatives and salts thereof. The above-mentioned quinolinecarboxylic acid derivatives are useful as active ingredients of antimicrobial agents for medical and agricultural and horticultural purposes. In the above general formula (1), examples of the lower alkyl group represented by R 1 and R 2 include straight chain or branched alkyl groups having 1 to 4 carbon atoms,
Specific examples include methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl groups.
Further, specific examples of the halogen atom represented by R 3 include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like. Representative compounds of the present invention are listed below. Γ1-ethyl-7-chloro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Γ1,8-diethyl-7-chloro-4-oxo-
1-ethyl-7-fluoro-8-methyl-4-1,4-dihydroquinoline-3-carboxylate
Γ1-methyl-7-chloro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate Γ1-ethyl-7-chloro-8- Isopropyl
4-oxo-1,4-dihydroquinoline-3-
Carboxylic acid Γ1,8-dimethyl-7-bromo-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid A particularly preferred compound in the present invention is 1-ethyl-
7-chloro-8-methyl-4-oxo-1,4-
Dihydroquinoline-3-carboxylic acid and 1-ethyl-7-fluoro-8-methyl-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid. The quinoline carboxylic acid derivative, which is the active ingredient of the present invention, can be produced by various methods, and the method shown in the following reaction formula can be cited as a typical method. [In the formula, R 1 , R 2 and R 3 are the same as above, R 4 and R 5 are lower alkyl groups, and X represents a halogen atom] For the reduction of the known nitrobenzene derivative represented by the general formula (2), for example, Examples include a method using a reducing agent and a method using catalytic reduction. When a method using a reducing agent is employed, examples of the reducing agent used include iron-hydrochloric acid, zinc-acetic acid, and ferrous chloride-hydrochloric acid. The amount of the reducing agent to be used is usually equimolar to excess, preferably about 3 to 5 times the molar amount of the compound of general formula (2). The reduction reaction is usually carried out at room temperature to 150°C, preferably about 50 to 100°C.
The reaction is generally completed in about 30 minutes to 3 hours. In this way, a compound of general formula (3) is produced. In the reaction between the compound of general formula (3) and the compound of general formula (4), the ratio of the latter to the former is usually at least the same molar amount, preferably about twice the molar amount or more. good. The reaction is usually carried out in the presence of a basic compound without a solvent or in an inert solvent. Specific examples of basic compounds include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, inorganic carbonate compounds such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate, pyridine, quinoline, triethylamine, Examples include tertiary amines such as tributylamine. Such a basic compound is usually used in an amount equal to or more than the same molar amount, preferably about 1.1 to 1.5 times the molar amount of the compound of general formula (3). Inert solvents that can be used include lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane, tetrahydrofuran, and diglyme, aromatic hydrocarbons such as benzene and toluene, dimethyl sulfoxide, dimethylformamide, and hexamethylphosphoric triamide. , pyridine, etc.
Among these, aromatic hydrocarbons are preferred. The reaction is usually carried out at room temperature to about 150°C, preferably about 80 to 130°C, and is usually completed in about 0.5 to 6 hours. In this way, a compound of general formula (5) is produced. The reaction between the compound of general formula (5) and the compound of general formula (6) can be carried out without a solvent or in a solvent such as methanol, ethanol, isopropanol, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, etc., preferably without a solvent. It will be held in The ratio of compound (6) to compound (5) to be used is usually at least equimolar, preferably an equimolar amount in the reaction without a solvent, and preferably about 1.1 to 1.5 times the molar amount in the reaction in a solvent. It is better. The reaction temperature is usually about room temperature to 150℃, preferably about 100 to 130℃
The reaction is usually completed in about 0.5 to 6 hours, and the compound represented by the general formula (7) can be easily obtained. The cyclization reaction of the compound (7) thus obtained can be carried out according to various conventionally known cyclization reactions. Examples include a heating method, a cyclization method using an acidic substance such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, and polyphosphoric acid. When employing the cyclization method by heating, a solvent such as high-boiling hydrocarbons and high-boiling ethers such as tetralin, diphenyl ether, diethylene glycol dimethyl ether, etc. is used, and usually about 100 to
Heating conditions of 250°C, preferably about 150-200°C can be employed. When employing a cyclization method using an acidic substance, it is used in an equimolar amount to a large excess, preferably about 10 to 20 times the amount of compound (7), and usually at about 100 to 150°C.
The reaction time may be approximately 0.5 to 6 hours. In this way, a compound of general formula (8) is produced. The hydrolysis reaction of compound (8) obtained by the above cyclization reaction can be carried out using a basic compound such as sodium hydroxide, potassium hydroxide, or barium hydroxide, a mineral acid such as sulfuric acid, hydrochloric acid, or nitric acid, or acetic acid. , in the presence of conventional catalysts such as organic acids such as aromatic sulfonic acids. The reaction is generally carried out using water, methanol, ethanol, isopropanol, acetone,
It is carried out in common solvents such as methyl ethyl ketone, dioxane, ethylene glycol, acetic acid, etc. The reaction temperature is usually room temperature to 200℃, preferably about 50 to 150℃.
It is ℃. In this way, the compound of the present invention represented by general formula (1) can be easily obtained. The present invention includes both acid addition salts and carboxylic acid salts of the quinoline carboxylic acid of general formula (1) obtained above. The acid used to form the acid addition salt may be any pharmacologically or agrochemically acceptable organic or inorganic acid, including, for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc. and organic acids such as acetic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, mandelic acid, ethanesulfonic acid, and P-tosylic acid. The basic compound used to form the carboxylic acid salt may be any pharmacologically or agriculturally acceptable basic compound, such as sodium hydroxide, potassium hydroxide, calcium hydroxide,
Examples include inorganic basic compounds such as aluminum hydroxide and sodium hydrogen carbonate. The compound of the present invention thus produced can be easily isolated and purified by conventional separation means after the completion of the above reaction steps. Examples of the separation means include solvent extraction, dilution, precipitation, recrystallization, column chromatography, and preparative thin layer chromatography. The antimicrobial agent of the present invention containing the compound represented by general formula (1) as an active ingredient has low toxicity and excellent antimicrobial activity. The antimicrobial agent of the present invention is useful for preventing and treating diseases of animals and agricultural and horticultural crops caused by bacteria, fungi, molds, and the like. Examples of animals include mammals including humans, birds, and fish.
The antimicrobial agent of the present invention is also useful for sterilizing and disinfecting medical instruments, etc. Furthermore, when crop damage is expected due to bacteria, mold, etc. during storage or transportation of agricultural and horticultural crops, it is necessary to use antimicrobial agents in advance. The damage can be prevented by applying it to crops by spraying, spraying, coating, etc. Therefore, the antimicrobial agent of the present invention is useful as an antimicrobial agent for medical and agricultural and horticultural purposes. The antimicrobial agent of the present invention is effective against various bacteria, fungi, molds, and the like. As for bacteria, it is effective against both gram-positive and gram-negative bacteria, and specific examples include Pseudomonas, Xanthomonas, Pseudomonadaceae, Erwinia,
Enterobacteriaceae such as Escherichia, Klebsiella, Serratia, Proteus, Salmonella, and Shigella, and microscopic bacteria such as Staphylococcus. Micrococcaceae, Streptococcus, and other Streptococccaceae can be mentioned.
Among these, the antimicrobial agent of the present invention shows excellent activity against Ervina, Xanthomonas, Pseudomonas and Streptococcus, and particularly shows extremely excellent activity against Ervina and Xanthomonas. Examples of fungi that cause mycosis in animals include Cryptococcus neoformans, Coccidioides immites, Candida albicans, and Aspergillus fumigatus.
etc. can be mentioned. Examples of molds that cause fungal diseases of agricultural and horticultural crops include Pyricularia oryzae, Helminthosporium oryzae, and Helminthosporium.
sigmoideum), Phytophthora Phytophthora
melonis), Phytophthora Phytophthora
infestans), Colletotrichum anthracnose (Colletotrichum
lagenarium), cotton anthracnose fungus (Colletotrichum)
indicum), Sclerotinia
sclerotiorum), melon vine blight fungus (Mycosphaerella melonis), pea spot blight fungus (Mycosphaerella phaseolicola), and tomato ring spot fungus (Alternaria solani). The antimicrobial agent of the present invention is useful for the prevention and treatment of bacteriosis and vacuum disease in animals and agricultural and horticultural crops. Bacterial diseases of agricultural and horticultural crops include vegetable soft rot, rice leaf blight, rice sheath blight, peach leaf blight, citrus canker disease, solanaceous plant bacterial wilt, tomato bacterial wilt, tomato wilt, Watermelon vine split disease, cucumber spot bacterial disease, etc., and examples of fungal diseases include rice blast disease, rice sesame leaf blight, cucumber late blight, cucumber gray blight, cucurbit anthracnose, eggplant sclerotium, melon vine blight,
Examples include tomato round strangle disease. The antimicrobial agent of the present invention exhibits an extremely superior effect on vegetable soft rot compared to conventional agents. When the antimicrobial agent of the present invention is used for medical purposes, it exhibits superior effects compared to antibacterial agents containing nalidixic acid conventionally used in this field, as evidenced by, for example, antibacterial test 1 described later. Furthermore, when the antimicrobial agent of the present invention is used for agricultural and horticultural purposes, it exhibits superior effects compared to conventional antibacterial disinfectants containing streptomycin, as is clear from, for example, antibacterial test 3 described later. When the antimicrobial agent of the present invention is used for medical purposes, it is usually in the form of a pharmaceutical composition together with a medical pharmaceutical carrier. As carriers, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc., which are commonly used to prepare drugs according to the usage form, can be used. I can give an example. As the dosage unit form of the antimicrobial agent, various forms can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, solutions, suspensions, emulsions,
Examples include granules, capsules, suppositories, injections (solutions, suspensions, etc.), ointments, and the like. When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol,
Simple syrup, glucose, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binder such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaria powder, sodium bicarbonate, calcium carbonate, twine, Disintegrants such as sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oil;
Absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, purified talc,
Examples include lubricants such as stearate, boric acid powder, and polyethylene glycol. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, Examples include binders such as tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaria and agar. Furthermore, the tablets can be made into conventionally coated tablets, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets, if necessary. When forming into suppository form,
A wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood, and when formed into the form of solutions, emulsions and suspensions, diluents known in the art are used. All commonly used substances can be used, such as water, ethyl alcohol, propylene glycol,
Examples include ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan ester. In this case, the antimicrobial agent may contain a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution, and may also contain conventional solubilizing agents, buffers, soothing agents, preservatives, etc. may be contained. Furthermore, the antimicrobial agent of the present invention may contain coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals as necessary. When forming into a paste, cream or gel form, a wide variety of diluents conventionally known in this field can be used, such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like. The amount of the active ingredient compound to be contained in the medical antimicrobial agent of the present invention is not particularly limited and can be appropriately selected within a wide range, but it is usually about 1 to 70% by weight based on the total composition. There are no particular restrictions on the use of the above antimicrobial agents, and they can be administered in a manner appropriate for various forms. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules, and capsules, it is administered orally, and in the case of injections, it is administered intravenously alone or mixed with normal replenishing fluids such as glucose and amino acids. If necessary, it can be administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally, and in the case of suppositories, it can be administered rectally,
It is also applied as an ointment. The dosage of the medical antimicrobial agent of the present invention is appropriately selected depending on the purpose of use, symptoms, etc., and usually the compound of the present invention is administered at a dose of about 10 mg to 5 g/body per day.
It may be administered in ~4 doses. When using the antimicrobial agent of the present invention for agricultural and horticultural purposes, suitable agricultural and horticultural preparation carriers,
For example, using solid carriers, liquid carriers, suspending agents, spreading agents, etc., granules, powders, dispersants, wettable powders, tablets,
It can be prepared in any form such as oil, spray, or atomizer. The carriers used include clay, kaolin, bentonite, talc, acid clay, diatomaceous earth,
Calcium carbonate, nitrocellulose, starch,
Examples include gum arabic, carbon dioxide, freon, water, benzene, kerosene, alcohol, acetone, xylene, methylnaphthalene, cyclohexanone, and animal and plant fatty acid esters. Examples of suspending agents, spreading agents, etc. include common surfactants such as soaps, sulfuric acid esters of higher alcohols, alkyl sulfonates, quaternary ammonium salts, and polyalkylene oxides. The amount of the active ingredient compound in the agricultural and horticultural antimicrobial agent of the present invention prepared as described above can be determined as appropriate depending on its usage form. For example, in the form of dispersants and wettable powders, it is preferably in the range of about 0.1 to 90% by weight, and in the form of powders and oils, it is preferably in the range of about 0.1 to 10% by weight. Appropriate. When using the agricultural and horticultural antimicrobial agent of the present invention, it can be applied to areas requiring an antimicrobial effect by spraying, spraying, coating, etc. in the same manner as known agricultural and horticultural antimicrobial agents. The amount to be applied can be determined as appropriate depending on the desired effect. For example, the amount of the antimicrobial agent for agricultural and horticultural use of the present invention is usually about 0.1 to 10 kg, preferably about 0.1 to 1 kg per hectare, and of course this will depend on the degree of damage caused by the plants and their diseases. It can be increased or decreased as appropriate. It can also be used in combination with, for example, other antimicrobial agents, insecticides or herbicides, fertilizer substances, soil conditioners, etc. Examples of the production of the active ingredient compound of the present invention are listed below as reference examples, and further formulation examples of the antimicrobial agent of the present invention are listed as examples. Reference Example 1 Synthesis of 2-methyl-3-chloroaniline 29 g of 2-chloro-6-nitrotoluene is added to a mixture of 150 g of stannous chloride and 200 ml of concentrated hydrochloric acid under ice cooling. The solution is then heated at 100°C for 1 hour to obtain white crystals. Take the obtained crystals and add 400ml of water
ml and 50 ml of 40% NaOH and extracted with 500 ml of chloroform. After washing the extract with 400 ml of water, the chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. By distilling the residue, 23 g of 2-methyl-3-chloroaniline, a fraction of 115 DEG -116 DEG C./10 mmHg, is obtained. Reference Example 2 Synthesis of N-ethyl-2-methyl-3-chloroaniline 14 g of 2-methyl-3-chloroaniline obtained in Reference Example 1 was dissolved in 100 ml of benzene, 12 g of triethylamine was added thereto, 13 g of ethyl bromide was added, and the mixture was refluxed with benzene. Let it react for 3 hours. After the reaction, return to room temperature, add 200 ml of water, and shake. The benzene layer is separated, dried over anhydrous magnesium sulfate, and concentrated. By distilling the residue to 125°~126°C/10mmHg
12 g of N-ethyl-2-methyl-3-chloroaniline, which is a fraction of , is obtained. Reference Example 3 Synthesis of 1-ethyl-7-chloro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-2-methyl-3-chloroaniline
10g and 15g of diethyl ethoxymethylene malonate
Heat and react at 110°C for 30 minutes. Next, 50g of phosphoric acid
Add polyphosphoric acid (PPA) obtained from 50 g of phosphorus pentoxide and react at 140°C for 40 minutes. After the reaction, the mixture is poured into 600g of water and ice, and crystals precipitate out.
After removing the precipitated crystals, add 10% sodium hydroxide solution and reflux for 1 hour. After refluxing, the mixture is treated with activated carbon and adjusted to pH 2 with concentrated hydrochloric acid to precipitate pale yellow crystals.
Recrystallized from dimethylformamide to give white needle-like crystals of 1-ethyl-7-chloro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
Get 11g. mp 221-222℃ Reference example 4 1-ethyl-7-fluoro-8-methyl-4-
Synthesis of oxo-1,4-dihydroquinoline-3-carboxylic acid. 9 g of N-ethyl-2-methyl-3-fluoro-aniline and diethyl ethoxymethylene malonate
Heat and react 15g at 110°C for 30 minutes. then phosphoric acid
Add polyphosphoric acid (PAA) obtained from 50 g of phosphorus pentoxide and 50 g of phosphorus pentoxide, and react at 140°C for 40 minutes. After the reaction, the mixture is poured into 600g of water and ice, and crystals precipitate out.
After removing the precipitated crystals, add 10% sodium hydroxide solution and reflux for 1 hour. After refluxing, the mixture is treated with activated carbon and adjusted to pH 2 with concentrated hydrochloric acid to precipitate pale yellow crystals.
Recrystallization from dimethylformamide gave 10 g of 1-ethyl-7-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in the form of white needles. mp 245-246℃ Example 1 Compound obtained in Reference Example 3 200 mg Glucose 250 mg Distilled water for injection Appropriate amount Total volume 5 ml Dissolve the compound of the present invention and glucose in distilled water for injection, and then inject into a 5 ml ampoule. After purging with nitrogen, autoclaving is performed at 121°C for 15 minutes to obtain an injection having the above composition. Example 2 Compound obtained in Reference Example 3 100g Abysiel [trade name: manufactured by Asahi Kasei Corporation] 40g Cornstarch 30g Magnesium stearate 2g TC-5 (trade name: manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropyl methylcellulose) 10g Polyethylene glycol -6000 3g Castor oil 40g Methanol 40g The compound of the present invention, Apiciel, cornstarch and magnesium stearate are mixed and polished, and then tableted using a kinematic machine with a sugar coating radius of 10mm. TC the obtained tablets
-5. A film coated tablet having the above composition is produced by coating with a film coating agent consisting of polyethylene glycol-6000, castor oil and methanol. Example 3 Compound obtained in Reference Example 3 2g Purified lanolin 5g White beeswax 5g White petrolatum 88g Total amount 100g White beeswax was heated to become liquid, and then the compound of the present invention, purified lanolin and white petrolatum were added and heated until it became liquid. After warming, the mixture is stirred until it begins to solidify to obtain an ointment having the above composition. Example 4 20g of sodium salt of the compound obtained in Reference Example 3 980g of talc The compound of the present invention and talc are mixed and polished to obtain a powder. Example 5 Compound obtained in Reference Example 3 200g White carbon 20g Sodium lignin sulfonate 20g Polyoxyethylene alkyl ether 40g Clay 720g The above compounds were mixed and polished to obtain a wettable powder. Example 6 Compound obtained in Reference Example 3 100g Diatomaceous earth 210g Talc 200g Sodium alkyl sulfate 90g The above compounds are mixed and polished to obtain a wettable powder. Example 7 Compound obtained in Reference Example 3 100g Talc 380g Clay 370g Bentonite 100g Sodium alkyl sulfate 50g The above compounds were mixed and polished, and then granulated using a granulator to obtain granules. <Antibacterial Test 1> The active ingredient compound of the present invention, 1-ethyl-6-fluoro-7-chloro-4-quinolone-3-carboxylic acid (described in claim 2 of JP-A-54-14978) compound) and 1-ethyl-1.4-
The antibacterial activity of dihydro-7-methyl-4-oxo-1,8-naphthylidene-3-carboxylic acid (nalidixic acid, control compound) against various bacteria was determined by the agar dilution plate method. The obtained minimum growth-inhibiting concentrations of bacteria are shown in Table 1 below. Each type of bacteria was adjusted to 1 x 10 8 bacteria/ml (OD660mμ, 0.13-0.14) and 1 x 10 6 bacteria/ml. <Test compound> Compound 1 1-ethyl-7-(1-piperazinyl)
-8-Methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid compound 2 1-ethyl-7-chloro-8-methyl-4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid compound 3 1-ethyl-6-fluoro-7-chloro-4-quinolone-3-carboxylic acid
【表】
<抗菌試験2>
本発明の有効成分化合物をアセトンの2%溶液
とし、これを水で所定濃度に希釈後各濃度の溶液
1mlをペトリ皿にとり、9mlのポテト・デクスト
ロース寒天培地(PDA培地)と混合して、上記
各供試化合物の各種濃度の寒天平板を作成する。
PDA培地で予め培養した供試菌の菌そうの先
端部を直径10mmのコルクボーラーで打ち抜いて菌
そうのデイスクを作り、これを菌そう面を下にし
て上記で作成した各寒天平板上に静置する。
菌そうの生育の有無を2日後に肉眼で観察し、
菌そうの生育を完全に阻止する最低発育阻止濃度
(ppm)を各供試菌につき下記第2表に示す。尚
各表における供試菌は夫々次の通りである。
供試菌
A……野菜軟腐病菌
B……稲白葉枯病菌
C……桃センコウ細菌病菌
D……柑橘潰瘍病菌
E……トマト青枯病菌
F……キユウリ斑点細菌病菌
G……稲イモチ病菌
H……稲胡麻葉枯病菌
I……キユウリ疫病菌
J……キユウリ灰色疫病菌
K……ウリ炭疽病菌
L……ナス菌核病菌
M……メロン蔓枯病菌
N……トマト輪絞病菌[Table] <Antibacterial test 2> Prepare a 2% solution of the active ingredient compound of the present invention in acetone, dilute it with water to a specified concentration, place 1 ml of the solution at each concentration in a Petri dish, and place it on 9 ml of potato dextrose agar medium ( (PDA medium) to prepare agar plates containing various concentrations of each of the above test compounds. Use a cork borer with a diameter of 10 mm to punch out the tips of the bacterial cavities of the test bacteria that have been cultured in PDA medium in advance to create bacterial discs, and place them on each agar plate prepared above with the bacterial plaque side down. place The presence or absence of fungal growth was observed with the naked eye after 2 days.
The minimum inhibitory concentration (ppm) that completely inhibits the growth of fungi is shown in Table 2 below for each test fungus. The test bacteria in each table are as follows. Test bacteria A...Bacterium causing vegetable soft rot B...Bacterium causing rice white leaf blight C...Bacterium causing peach green leaf blight D...Bacterium causing citrus canker E...Bacterium causing tomato bacterial wilt F...Bacterium causing cucumber spot G...Bacterium causing rice rootworm H ...Rice and sesame leaf blight fungus I...Cucurbit late blight fungus J...Cucurbit gray blight fungus K...Cucurbit anthracnose fungus L...Eggplant sclerotium fungus M...Melon vine blight fungus N...Tomato ring strangle fungus
【表】
<抗菌試験3>
直径2cm高さ1cmのダイコンデイスクを作り、
中心部を付傷する。所定濃度に調整した薬液にダ
イコンデイスクを一時間浸漬したのち風乾する。
軟腐病菌の懸濁液(約108/ml)を10μダイコン
デイスクの付傷部に接種し28℃で湿室状態に保
つ。24時間後に発病を調査する。
発病指数は下記のように決める。
発病面積率 発病指数
0 0
0< ≦1/3 1
1/3< ≦2/3 2
>2/3 3 [Table] <Antibacterial test 3> Make a radish disc with a diameter of 2 cm and a height of 1 cm.
Injury to the center. A radish disc is immersed in a chemical solution adjusted to a predetermined concentration for one hour, and then air-dried.
A suspension of soft rot fungi (approximately 10 8 /ml) is inoculated onto the injured part of a 10 μ radish disc and kept in a moist room at 28°C. Investigate disease onset after 24 hours. The disease index is determined as follows. Disease area rate Disease index 0 0 0< ≦1/3 1 1/3< ≦2/3 2 >2/3 3
【表】
(ストレプト 〓
[Table] (Strept 〓
Claims (1)
し、R3はハロゲン原子を示す。〕 で表わされるキノリンカルボン酸誘導体又はその
塩を有効成分とする抗微生物剤。[Claims] 1. General formula [In the formula, R 1 and R 2 each represent a lower alkyl group, and R 3 represents a halogen atom. ] An antimicrobial agent containing a quinoline carboxylic acid derivative or a salt thereof as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3293180A JPS56128703A (en) | 1980-03-14 | 1980-03-14 | Antimicrobial agent |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3293180A JPS56128703A (en) | 1980-03-14 | 1980-03-14 | Antimicrobial agent |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS56128703A JPS56128703A (en) | 1981-10-08 |
JPS636041B2 true JPS636041B2 (en) | 1988-02-08 |
Family
ID=12372661
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP3293180A Granted JPS56128703A (en) | 1980-03-14 | 1980-03-14 | Antimicrobial agent |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS56128703A (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS604820B2 (en) * | 1979-02-26 | 1985-02-06 | 大塚製薬株式会社 | Quinoline carboxylic acid derivative |
DD207098A3 (en) * | 1981-12-22 | 1984-02-15 | Schmidt Hans Joerg | PROCESS FOR THE PREPARATION OF 1-ALKYL-6,7-METHYLENDIOXY-4 (1H) -OXO-CINNOLINE-3-CARBONSAEURES |
JP7282332B2 (en) * | 2017-10-25 | 2023-05-29 | 学校法人順天堂 | ryanodine receptor inhibitor |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5046673A (en) * | 1972-11-22 | 1975-04-25 | ||
JPS50108273A (en) * | 1974-02-12 | 1975-08-26 | ||
JPS50108271A (en) * | 1974-02-09 | 1975-08-26 | ||
JPS50160285A (en) * | 1974-06-17 | 1975-12-25 | ||
JPS5414978A (en) * | 1977-07-01 | 1979-02-03 | Ciba Geigy Ag | Quinolonecarboxylic acid and bactericide containing same |
-
1980
- 1980-03-14 JP JP3293180A patent/JPS56128703A/en active Granted
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5046673A (en) * | 1972-11-22 | 1975-04-25 | ||
JPS50108271A (en) * | 1974-02-09 | 1975-08-26 | ||
JPS50108273A (en) * | 1974-02-12 | 1975-08-26 | ||
JPS50160285A (en) * | 1974-06-17 | 1975-12-25 | ||
JPS5414978A (en) * | 1977-07-01 | 1979-02-03 | Ciba Geigy Ag | Quinolonecarboxylic acid and bactericide containing same |
Also Published As
Publication number | Publication date |
---|---|
JPS56128703A (en) | 1981-10-08 |
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