JPH0374230B2 - - Google Patents
Info
- Publication number
- JPH0374230B2 JPH0374230B2 JP58233271A JP23327183A JPH0374230B2 JP H0374230 B2 JPH0374230 B2 JP H0374230B2 JP 58233271 A JP58233271 A JP 58233271A JP 23327183 A JP23327183 A JP 23327183A JP H0374230 B2 JPH0374230 B2 JP H0374230B2
- Authority
- JP
- Japan
- Prior art keywords
- fluoro
- cyclopropyl
- naphthyridine
- oxo
- dihydro
- 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 - Lifetime
Links
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 10
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- -1 etc. Chemical class 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 238000002844 melting Methods 0.000 description 17
- 230000008018 melting Effects 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 239000013078 crystal Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 235000002639 sodium chloride Nutrition 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 5
- LHVNBNPRFRXLMD-UHFFFAOYSA-N ethyl 4-oxo-3H-1,8-naphthyridine-3-carboxylate Chemical compound C(C)OC(=O)C1C=NC2=NC=CC=C2C1=O LHVNBNPRFRXLMD-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- ZULJYVVAYGFYKU-UHFFFAOYSA-N acetonitrile;chloroform Chemical compound CC#N.ClC(Cl)Cl ZULJYVVAYGFYKU-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- WLHCBQAPPJAULW-UHFFFAOYSA-N 4-methylbenzenethiol Chemical compound CC1=CC=C(S)C=C1 WLHCBQAPPJAULW-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- OYJXTOVLKZDGFK-UHFFFAOYSA-N ethanol;2-propan-2-yloxypropane Chemical compound CCO.CC(C)OC(C)C OYJXTOVLKZDGFK-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CGXLVFZJJOXEDF-UHFFFAOYSA-N 1,8-naphthyridine-3-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CN=C21 CGXLVFZJJOXEDF-UHFFFAOYSA-N 0.000 description 1
- NNWLBMSATDGIRM-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-4-oxo-7-pyrrolidin-1-yl-1,8-naphthyridine-3-carboxylic acid Chemical compound C12=NC(N3CCCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 NNWLBMSATDGIRM-UHFFFAOYSA-N 0.000 description 1
- XBEDDDLZCIRMKE-UHFFFAOYSA-N 2,5-difluoro-6-(4-methylphenyl)sulfanylpyridine-3-carbonitrile Chemical compound C1=CC(C)=CC=C1SC1=NC(F)=C(C#N)C=C1F XBEDDDLZCIRMKE-UHFFFAOYSA-N 0.000 description 1
- DEDKKOOGYIMMBC-UHFFFAOYSA-N 2,6-dichloro-5-fluoropyridine-3-carbonitrile Chemical compound FC1=CC(C#N)=C(Cl)N=C1Cl DEDKKOOGYIMMBC-UHFFFAOYSA-N 0.000 description 1
- BFVQMOCETIVORP-UHFFFAOYSA-N 2-oxo-1h-1,8-naphthyridine-3-carboxylic acid Chemical compound C1=CN=C2NC(=O)C(C(=O)O)=CC2=C1 BFVQMOCETIVORP-UHFFFAOYSA-N 0.000 description 1
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000005135 aryl sulfinyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- GMWFCJXSQQHBPI-UHFFFAOYSA-N azetidin-3-ol Chemical compound OC1CNC1 GMWFCJXSQQHBPI-UHFFFAOYSA-N 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- FGOXNPAIQFNLCP-UHFFFAOYSA-N ethyl 2,5-difluoro-6-(4-methylphenyl)sulfanylpyridine-3-carboxylate Chemical compound N1=C(F)C(C(=O)OCC)=CC(F)=C1SC1=CC=C(C)C=C1 FGOXNPAIQFNLCP-UHFFFAOYSA-N 0.000 description 1
- HULIOAYHEJWNGC-UHFFFAOYSA-N ethyl 2-(cyclopropylamino)propanoate Chemical compound CCOC(=O)C(C)NC1CC1 HULIOAYHEJWNGC-UHFFFAOYSA-N 0.000 description 1
- FMVQKYUYTUQBTQ-UHFFFAOYSA-N ethyl 2-[cyclopropyl-(3-ethoxy-3-oxopropyl)amino]-5-fluoro-6-(4-methylphenyl)sulfanylpyridine-3-carboxylate Chemical compound N=1C(SC=2C=CC(C)=CC=2)=C(F)C=C(C(=O)OCC)C=1N(CCC(=O)OCC)C1CC1 FMVQKYUYTUQBTQ-UHFFFAOYSA-N 0.000 description 1
- 208000010824 fish disease Diseases 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000005452 food preservative Substances 0.000 description 1
- 235000019249 food preservative Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- QAXZWHGWYSJAEI-UHFFFAOYSA-N n,n-dimethylformamide;ethanol Chemical compound CCO.CN(C)C=O QAXZWHGWYSJAEI-UHFFFAOYSA-N 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は極めて優れた抗菌活性を示す新規ピリ
ドンカルボン酸誘導体に関する。
更に詳しくは、本発明の化合物は、下記一般式
（式中、Ｘはハロゲン原子を、R1は水素原子ま
たは水素基を、R2は水素原子、アミノ基、モノ
またはジ低級アルキルアミノ基を、R3は水素原
子または低級アルキル基を、ｍは整数１または２
を、ｎは整数０，１または２を意味する。但し、
R1が水素原子の場合は、R2は水素原子である。
また、R2が水素原子以外の基である場合は、ｎ
は整数１または２である。）
で表わされるピリドンカルボン酸誘導体、および
その塩である。
本発明の化合物の中で好ましい化合物は、式
〔〕において、Ｘがフツ素原子で、R1が水酸
基、R2が水素原子またはアミノ基、R3が水素原
子である化合物、およびＸがフツ素原子で、R1，
R2R3が共に水素原子である化合物である。
本発明の化合物の塩は、酢酸、乳酸、コハク
酸、メタンスルホン酸、マレイン酸、マロン酸、
グルコン酸等の有機酸との塩、アスパラギン酸、
グルタミン酸等のアミノ酸との塩、あるいは塩
酸、リン酸等の無機酸との塩、あるいは式〔〕
の化合物のナトリウム、カリウム、亜鉛、銀等の
金属塩、あるいは有機塩基との塩である。
本発明の化合物のうち、特に好ましい化合物を
列挙すれば次の通りである。
１−シクロプロピル−６−フルオロ−７−（３
−ヒドロキシ−１−アゼチジニル）−１，４−ジ
ヒドロ−４−オキソ−１，８−ナフチリジン−３
−カルボン酸。
１−シクロプロピル−６−フルオロ−７−（１
−ピロリジニル）−１，４−ジヒドロ−４−オキ
ソ−１，８−ナフチリジン−３−カルボン酸。
１−シクロプロピル−６−フルオロ−７−（３
−ヒドロキシ−１−ピロリジニル）−１，４−ジ
ヒドロ−４−オキソ−１，８−ナフチリジン−３
−カルボン酸。
７−（３−アミノ−４−ヒドロキシ−１−ピロ
リジニル）−１−シクロプロピル−６−フルオロ
−１，４−ジヒドロ−４−オキソ−１，８−ナフ
チリジン−３−カルボン酸。
１−シクロプロピル−６−フルオロ−７−（３
−ヒドロキシ−１−ピペリジニル）−１，４−ジ
ヒドロ−４−オキソ−１，８−ナフチリジン−３
−カルボン酸。
１−シクロプロピル−６−フルオロ−７−（４
−ヒドロキシ−１−ピペリジニル）−１，４−ジ
ヒドロ−４−オキソ−１，８−ナフチリジン−３
−カルボン酸。
次に本発明の化合物の製造法につき、以下に説
明する。
本発明の化合物は、下記一般式
（式中、Ｘはハロゲン原子を、Ｙは後記脂肪族環
状アミン類〔〕と置換しうる官能基を、R3は
水素原子または低級アルキル基を意味する。）
で表わされるカルボン酸類と下記一般式
（式中、R1，R2，ｍ，ｎは前掲と同じ。）
で表わされる脂肪族環状アミン類を反応せしめ、
生成物を常法により単離することにより製造する
ことができる。
式〔〕のＹで示した反応性官能基としては、
アリールスルホニル、低級アルキルスルホニル、
ハロゲン原子、低級アルコキシ、アリールチオ、
低級アルキルチオ、低級アルキルスルフイニル、
アリールスルフイニル、アリールスルホニルオキ
シ、低級アルキルスルホニルオキシ等が挙げられ
る。
本反応は、エタノール、アセトニトリル、ジオ
キサン、ジメチルホルムアミド、ジメチルスルホ
キシド、トルエン、キシレンの如き不活性溶媒
中、20〜180℃、好ましくは50〜150℃において、
原料化合物〔〕と〔〕とを５〜120分間、通
常は20〜60分間混合撹拌することにより実施でき
る。原料化合物〔〕の原料化合物〔〕に対す
る使用量は当量ないしやゝ過剰量である。原料化
合物〔〕のＹの官能基の種類により、反応の結
果、有機酸、塩酸等の酸が副生するので、かゝる
場合には酸受容体を使用するのが一般的である
が、原料化合物〔〕を過剰に用い、酸受容体と
しての役割を兼ねさせてもよい。
また本反応で使用される原料化合物〔〕は、
可能ならば、その側鎖のアミノ基またはモノ低級
アルキルアミノ基を保護した形で用い、反応完了
後常法によりその保護基を除去してもよい。保護
基としては、β−ラクタム系抗生物質、ペプチ
ド、または核酸の化学において通常用いられる保
護基が使用される。
上記の反応により、R3が低級アルキル基であ
る本発明の化合物が得られたときには、これを常
法により加水分解することによつて、R3が水素
原子である化合物に変換することができる。また
逆に、R3が水素原子および／またはR1が水酸基
である本発明の化合物が得られたときには、これ
を常法によりエステル化することによつて、R3
が低級アルキル基である化合物に導くことができ
る。
原料化合物〔〕は参考例に記載の方法或いは
これに準じた方法で製造しうる。
この様にして製造される本発明の化合物は、常
法に従い単離、精製される。単離、精製条件によ
つて、塩の形、遊離カルボン酸や遊離アミンの形
で得られるが、これらは目的に応じて相互に変換
され、目的とする形の本発明の化合物が製造され
る。
かくして得られる本発明の化合物〔〕および
その塩はいずれも新規化合物である。特にR3が
水素原子である本発明化合物が極めて優れた抗菌
活性を示し、抗菌剤として価値あるものである。
これらの化合物は、人体および動物用医薬は勿論
のこと、魚病薬、農薬、食品の保存剤等としても
使用することが可能である。
また、R3が低級アルキル基である本発明化合
物は、それ自体抗菌活性を有するが、R3が水素
原子である本発明化合物の中間原料として価値あ
るものである。
次に本発明の主要化合物の抗菌活性について、
以下にデーターを挙げる。
The present invention relates to novel pyridonecarboxylic acid derivatives that exhibit extremely excellent antibacterial activity. More specifically, the compound of the present invention has the following general formula: ( In the formula , is an integer 1 or 2
, n means an integer 0, 1 or 2. however,
When R 1 is a hydrogen atom, R 2 is a hydrogen atom.
In addition, when R 2 is a group other than a hydrogen atom, n
is an integer 1 or 2. ) and salts thereof. Preferred compounds among the compounds of the present invention are compounds in which, in the formula [], X is a fluorine atom, R 1 is a hydroxyl group, R 2 is a hydrogen atom or an amino group, R 3 is a hydrogen atom, and In elementary atoms, R 1 ,
This is a compound in which R 2 R 3 are both hydrogen atoms. Salts of the compounds of the present invention include acetic acid, lactic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid,
Salts with organic acids such as gluconic acid, aspartic acid,
Salts with amino acids such as glutamic acid, salts with inorganic acids such as hydrochloric acid and phosphoric acid, or formula []
metal salts such as sodium, potassium, zinc, silver, etc., or salts with organic bases. Among the compounds of the present invention, particularly preferred compounds are as follows. 1-Cyclopropyl-6-fluoro-7-(3
-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid. 1-Cyclopropyl-6-fluoro-7-(1
-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. 1-Cyclopropyl-6-fluoro-7-(3
-hydroxy-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid. 7-(3-Amino-4-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. 1-Cyclopropyl-6-fluoro-7-(3
-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid. 1-Cyclopropyl-6-fluoro-7-(4
-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid. Next, the method for producing the compound of the present invention will be explained below. The compound of the present invention has the following general formula: (In the formula, X is a halogen atom, Y is a functional group that can be substituted with the aliphatic cyclic amines [ ] described below, and R 3 is a hydrogen atom or a lower alkyl group.) formula (In the formula, R 1 , R 2 , m, and n are the same as above.) Reacting an aliphatic cyclic amine represented by
The product can be produced by isolating it by conventional methods. The reactive functional group represented by Y in formula [] is
Arylsulfonyl, lower alkylsulfonyl,
halogen atom, lower alkoxy, arylthio,
lower alkylthio, lower alkylsulfinyl,
Examples include arylsulfinyl, arylsulfonyloxy, lower alkylsulfonyloxy, and the like. This reaction is carried out in an inert solvent such as ethanol, acetonitrile, dioxane, dimethylformamide, dimethylsulfoxide, toluene, or xylene at 20 to 180°C, preferably 50 to 150°C.
This can be carried out by mixing and stirring the raw material compounds [] and [] for 5 to 120 minutes, usually for 20 to 60 minutes. The amount of starting compound [] to be used is equivalent to or slightly in excess of starting compound []. Depending on the type of functional group of Y in the raw material compound [], acids such as organic acids and hydrochloric acid may be produced as by-products as a result of the reaction, so in such cases it is common to use an acid acceptor. The raw material compound [] may be used in excess to serve as an acid acceptor. In addition, the raw material compound [] used in this reaction is
If possible, the side chain amino group or mono-lower alkylamino group may be used in a protected form, and after the reaction is completed, the protecting group may be removed by a conventional method. As protective groups, those commonly used in β-lactam antibiotic, peptide or nucleic acid chemistry are used. When a compound of the present invention in which R 3 is a lower alkyl group is obtained by the above reaction, it can be converted into a compound in which R 3 is a hydrogen atom by hydrolyzing it by a conventional method. . Conversely, when a compound of the present invention in which R 3 is a hydrogen atom and/or R 1 is a hydroxyl group is obtained, R 3 can be esterified by a conventional method.
is a lower alkyl group. The raw material compound [] can be produced by the method described in Reference Examples or a method analogous thereto. The compound of the present invention produced in this manner is isolated and purified according to conventional methods. Depending on the isolation and purification conditions, it can be obtained in the form of a salt, free carboxylic acid, or free amine, but these can be mutually converted depending on the purpose to produce the compound of the present invention in the desired form. . The thus obtained compound of the present invention [] and its salt are both new compounds. In particular, compounds of the present invention in which R 3 is a hydrogen atom exhibit extremely excellent antibacterial activity and are valuable as antibacterial agents.
These compounds can be used not only as medicines for humans and animals, but also as medicines for fish diseases, agricultural chemicals, food preservatives, and the like. Further, the compounds of the present invention in which R 3 is a lower alkyl group have antibacterial activity themselves, but are valuable as intermediate raw materials for the compounds of the present invention in which R 3 is a hydrogen atom. Next, regarding the antibacterial activity of the main compounds of the present invention,
The data is listed below.
【表】【table】
【表】【table】
【表】
本発明の化合物を人に抗菌剤として使用する場
合、その投与量は、年令、体重、症状、投与経
路、投与回数等により異なるが、１日当り５mg〜
５ｇを１回ないし数回に分けて投与することが推
奨される。投与経路は経口、非経口のいずれでも
よい。
本発明の化合物は原末のままでもよいが、通常
製剤用担体と共に調整された形で投与される。そ
の具体例としては、錠剤、カプセル剤、顆粒剤、
細粒剤、散剤、シロツプ剤、注射剤等が挙げられ
る。これらの製剤は常法に従つて調整される。経
口用製剤担体としては、デンプン、マンニツト、
結晶セルロース、CMC Na等の製剤分野におい
て常用され、かつ本発明の化合物と反応しない物
質が用いられる。注射用担体としては、水、生理
食塩水、グリコース溶液、輸液剤等の注射剤の分
野で常用される担体が挙げられる。
次に実施例および参考例を挙げて本発明化合物
の合成法を更に具体的に説明する。
実施例 １
１−シクロプロピル−６−フルオロ−７−（３
−ヒドロキシ−１−ピロリジニル）−１，４−
ジヒドロ−４−オキソ−１，８−ナフチリジン
−３−カルボン酸の合成
(1) １−シクロプロピル−６−フルオロ−７−
（ｐトルイルスルホニル）−１，４−ジヒドロ−
４−オキソ−１，８−ナフチリジン−３−カル
ボン酸エチル860mg、３−ヒドロキシピロリジ
ン688mg、エタノール20mlの混合物を10分間加
熱還流する。反応液を減圧下に濃縮乾固し、残
査にエタノールを加える。析出する結晶を取
し、エタノールで洗い、乾燥する。エタノール
から再結晶して、１−シクロプロピル−６−フ
ルオロ−７−（３−ヒドロキシ−１−ピロリジ
ニル）−１，４−ジヒドロ−４−オキソ−１，
８−ナフチリジン−３−カルボン酸エチル625
mgを得る。融点205−206℃。
(2) 前項で得たエステル361mg、水20ml、1N水酸
化ナトリウム水溶液７mlの混合物を沸騰水浴上
で５分間加熱する。活性炭処理後、酢酸水溶液
で中和し、析出する結晶を取する。結晶をク
ロロホルム−エタノールの混液より再結晶し
て、１−シクロプロピル−６−フルオロ−７−
（３−ヒドロキシ−１−ピロリジニル）−１，４
−ジヒドロ−４−オキソ−１，８−ナフチリジ
ン−３−カルボン酸250mgを得る。融点300℃以
上。
実施例 ２
１−シクロプロピル−６−フルオロ−７−（３
−ヒドロキシ−１−ピロリジニル）−１，４−
ジヒドロ−４−オキソ−１，８−ナフチリジン
−３−カルボン酸の合成
１−シクロプロピル−６−フルオロ−７−（ｐ
−トルイルスルホニル）−１，４−ジヒドロ−４
−オキソ−１，８−ナフチリジン−３−カルボン
酸402mg、３−ヒドロキシピロリジン258mg、トリ
エチルアミン150mg、エタノール10mlの混合物を
10分間加熱還流する。溶媒を留去し、残渣に水を
加え、1N酢酸水溶液で中和し、析出する結晶を
取する。水、エタノールで順次洗つたのち、乾
燥して、実施例１と同一の目的物である１−シク
ロプロピル−６−フルオロ−７−（３−ヒドロキ
シ−１−ピロリジニル）−１，４−ジヒドロ−４
−オキソ−１，８−ナフチリジン−３−カルボン
酸300mgを得る。
実施例 ３
１−シクロプロピル−６−フルオロ−７−（３
−ヒドロキシ−１−ピロリジニル）−１，４−
ジヒドロ−４−オキソ−１，８−ナフチリジン
−３−カルボン酸の合成
１−シクロプロピル−６−フルオロ−７−（ｐ
−トルイルチオ）−１，４−ジヒドロ−４−オキ
ソ−１，８−ナフチリジン−３−カルボン酸370
mg、３−ヒドロキシピロリジン350mg、ジメチル
ホルムアミド３mlの混合物を110〜120℃で３時間
加熱撹拌する。溶媒を減圧下留去し、残渣に水を
加え、1N酢酸水溶液で中和する。析出する結晶
を取し、クロロホルム−エタノールの混液から
再結晶して、実施例１と同一の目的物である１−
シクロプロピル−６−フルオロ−７−（３−ヒド
ロキシ−１−ピロリジニル）−１，４−ジヒドロ
−４−オキソ−１，８−ナフチリジン−３−カル
ボン酸206mgを得る。
実施例 ４
１−シクロプロピル−６−フルオロ−７−（４
−ヒドロキシ−１−ピペリジニル）−１，４−
ジヒドロ−４−オキソ−１，８−ナフチリジン
−３−カルボン酸の合成
(1) １−シクロプロピル−６−フルオロ−７−
（ｐ−トルイルスルホニル）−１，４−ジヒドロ
−４−オキソ−１，８−ナフチリジン−３−カ
ルボン酸エチルと４−ヒドロキシピペリジンを
用い、実施例１(1)と同様に処理して、１−シク
ロプロピル−６−フルオロ−７−（４−ヒドロ
キシ−１−ピペリジニル）−１，４−ジヒドロ
−４−オキソ−１，８−ナフチリジン−３−カ
ルボン酸エチルを得る。融点244−246℃：再結
晶溶媒、エタノール−イソプロピルエーテル。
(2) 上記エステルを実施例１(2)と同様に処理し
て、１−シクロプロピル−６−フルオロ−７−
（４−ヒドロキシ−１−ピペリジニル）−１，４
−ジヒドロ−４−オキソ−１，８−ナフチリジ
ン−３−カルボン酸を得る。融点255−258℃：
再結晶溶媒、クロロホルム−エタノール。
実施例 ５
１−シクロプロピル−６−フルオロ−７−（３
−ヒドロキシ−１−ピペリジニル）−１，４−
ジヒドロ−４−オキソ−１，８−ナフチリジン
−３−カルボン酸の合成
(1) １−シクロプロピル−６−フルオロ−７−
（ｐ−トルイルスルホニル）−１，４−ジヒドロ
−４−オキソ−１，８−ナフチリジン−３−カ
ルボン酸エチルと３−ヒドロキシピペリジンを
用い、実施例１(1)と同様に処理して、１−シク
ロプロピル−６−フルオロ−７−（３−ヒドロ
キシ−１−ピペリジニル）−１，４−ジヒドロ
−４−オキソ−１，８−ナフチリジン−３−カ
ルボン酸エチルを得る。融点194−196℃：再結
晶溶媒、エタノール−イソプロピルエーテル。
(2) 上記エステルを実施例１(2)と同様に処理し
て、１−シクロプロピル−６−フルオロ−７−
（３−ヒドロキシ−１−ピペリジニル）−１，４
−ジヒドロ−４−オキソ−１，８−ナフチリジ
ン−３−カルボン酸を得る。融点265−268℃：
再結晶溶媒、クロロホルム−エタノール。
実施例 ６
７−（３−アミノ−４−ヒドロキシ−１−ピロ
リジニル）−１−シクロプロピル−６−フルオ
ロ−１，４−ジヒドロ−４−オキソ−１，８−
ナフチリジン−３−カルボン酸塩酸塩の合成
(1) １−シクロプロピル−６−フルオロ−７−
（ｐ−トルイルスルホニル）−１，４−ジヒドロ
−４−オキソ−１，８−ナフチリジン−３−カ
ルボン酸エチルと３−アセチルアミノ−４−ヒ
ドロキシピロリジンを用い、実施例１(1)と同様
に処理して、７−（３−アセチルアミノ−４−
ヒドロキシ−１−ピロリジニル）−１−シクロ
プロピル−６−フルオロ−１，４−ジヒドロ−
４−オキソ−１，８−ナフチリジン−３−カル
ボン酸エチルを得る。融点258−260℃：再結晶
溶媒、クロロホルム−エタノール。
(2) 上記エステル418mgを20％塩酸10mlに溶解し、
７時間加熱還流する。溶媒を減圧下留去し、残
渣にエーテルを加え、析出する結晶を取し、
乾燥する。エタノール−エーテルから再結晶し
て、７−（３−アミノ−４−ヒドロキシ−１−
ピロリジニル）−１−シクロプロピル−６−フ
ルオロ−１，４−ジヒドロ−４−オキソ−１，
８−ナフチリジン−３−カルボン酸塩酸塩334
mgを得る。融点245−252℃（分解）。
実施例 ７
１−シクロプロピル−６−フルオロ−７−（３
−ヒドロキシ−１−アゼチジニル）−１，４−
ジヒドロ−４−オキソ−１，８−ナフチリジン
−３−カルボン酸の合成
(1) １−シクロプロピル−６−フルオロ−７−
（ｐ−トルイルスルホニル）−１，４−ジヒドロ
−４−オキソ−１，８−ナフチリジン−３−カ
ルボン酸エチルと３−ヒドロキシアゼチジンを
用い、実施例１(1)と同様に処理して、１−シク
ロプロピル−６−フルオロ−７−（３−ヒドロ
キシ−１−アゼチジニル）−１，４−ジヒドロ
−４−オキソ−１，８−ナフチリジン−３−カ
ルボン酸エチルを得る。融点221−222℃：再結
晶溶媒、アセトニトリル−クロロホルム。
(2) 上記エステルを実施例１(2)と同様に処理し
て、１−シクロプロピル−６−フルオロ−７−
（３−ヒドロキシ−１−アゼチジニル）−１，４
−ジヒドロ−４−オキソ−１，８−ナフチリジ
ン−３−カルボン酸を得る。融点280−281℃：
再結晶溶媒、エタノール−ジメチルホルムアミ
ド。
参考例 １
１−シクロプロピル−６−フルオロ−７−（ｐ
−トルイルスルホニル）−１，４−ジヒドロ−
４−オキソ−１，８−ナフチリジン−３−カル
ボン酸エチルの合成
(1) 公知化合物２，６−ジクロロ−５−フルオロ
ニコチノニトリル32.5ｇを、エタノール400ml
中、ｐ−チオクレゾール23.2ｇと水酸化カリウ
ム12.2ｇから得られるｐ−チオクレゾールのカ
リウム塩とを室温下反応させ、２−クロロ−５
−フルオロ−６−（ｐ−トルイルチオ）ニコチ
ノニトリル42.4ｇを得る。融点124−125℃。
(2) この化合物36ｇを乾燥ジメチルスルホキシド
180mlに溶解し、無水フツ化カリウム22.2ｇを
加えて130〜135℃１時間加熱撹拌する。溶媒を
減圧下留去し、残留物に水を加え、得られる粗
結晶をエタノールから再結晶して、２，５−ジ
フルオロ−６−（ｐ−トルイルチオ）ニコチノ
ニトリル30ｇを得る。融点120−121℃。
(3) この化合物４ｇに無水エタノール中乾燥塩化
水素を反応させ、２，５−ジフルオロ−６−
（ｐ−トルイルチオ）ニコチン酸エチル３ｇを
得る。
(4) 上記反応を繰り返し、得られた２，５−ジフ
ルオロ−６−（ｐ−トルイルチオ）ニコチン酸
エチル25ｇをジメチルホルムアミド400mlに溶
解し、これにＮ−シクロプロピルアミノプロピ
オン酸エチル25.4ｇと炭酸水素ナトリウム14ｇ
を加え、100〜110℃にて10時間加熱撹拌する。
溶媒を減圧下留去し、残留物に水を加え、トル
エンで抽出する。トルエン層を希塩酸、ついで
水で洗浄後、トルエン層を無水硫酸ナトリウム
で乾燥する。トルエンを減圧下留去し、粘稠性
液体の２−〔Ｎ−シクロプロピル−Ｎ−（２−エ
トキシカルボニルエチル）アミノ〕−５−フル
オロ−６−（ｐ−トルイルチオ）ニコチン酸エ
チル32ｇを得る。
(5) この化合物3.2ｇを乾燥トルエン50mlに溶解
し、これに室温にて65％水素化ナトリウム0.32
ｇを加え、混合物を10分間撹拌する。触媒量の
無水エタノールを加え、さらに２時間撹拌す
る。ついで50〜60℃にて１時間加熱後、水を加
え、10％酢酸水溶液で中和する。有機層を分取
し、無水硫酸ナトリウムで乾燥後、トルエンを
減圧下留去する。得られる粗結晶をｎ−ヘキサ
ンとイソプロピルエーテルの混液から再結晶
し、１−シクロプロピル−６−フルオロ−７−
（ｐ−トルイルチオ）−１，２，３，４−テトラ
ヒドロ−４−オキソ−１，８−ナフチリジン−
３−カルボン酸エチル2.5ｇを得る。融点124−
125℃。
(6) この化合物2.0ｇをトルエン50mlに溶解し、
これに２，３−ジクロロ−５，６−ジシアノ−
ｐ−ベンゾキノン1.25ｇを加え、室温にて２時
間、ついで50〜60℃で１時間加熱撹拌する。冷
後、析出する結晶を取、クロロホルムに溶解
し、1N水酸化ナトリウム、水にて順次洗浄し、
クロロホルム層を無水硫酸ナトリウムで乾燥す
る。クロロホルムを留去し、得られる粗結晶を
エタノールとイソプロピルエーテルの混液から
再結晶して、１−シクロプロピル−６−フルオ
ロ−７−（ｐ−トルイルチオ）−１，４−ジヒド
ロ−４−オキソ−１，８−ナフチリジン−３−
カルボン酸エチル1.7ｇを得る。融点186−187
℃。
(7) この化合物1.59ｇとｍ−クロロ過安息香酸
（80％）1.90ｇをクロロホルム50mlに溶解し、
30分間加熱還流する。冷後、2N炭酸ナトリウ
ム、水にて順次洗浄し、クロロホルム層を無水
硫酸ナトリウムにて乾燥する。クロロホルムを
留去し、得られる粗結晶を酢酸エチルから再結
晶して、１−シクロプロピル−６−フルオロ−
７−（ｐ−トルイルスルホニル）−１，４−ジヒ
ドロ−４−オキソ−１，８ナフチリジン−３−
カルボン酸エチル1.55ｇを得る。融点216−218
℃。
参考例 ２
１−シクロプロピル−６−フルオロ−７−（ｐ
−トルイルチオ）−１，４−ジヒドロ−４−オ
キソ−１，８−ナフチリジン−３−カルボン酸
の合成
１−シクロプロピル−６−フルオロ−７−（ｐ
−トルイルチオ）−１，４−ジヒドロ−４−オキ
ソ−１，８−ナフチリジン−３−カルボン酸エチ
ル１ｇを10N硫酸10mlに溶解し、105〜115℃で１
時間加熱撹拌する。反応混合物を氷水にあけ、析
出する結晶を取し、クロロホルム−エタノール
から再結晶して、１−シクロプロピル−６−フル
オロ−７−（ｐ−トルイルチオ）−１，４−ジヒド
ロ−４−オキソ−１，８−ナフチリジン−３−カ
ルボン酸530mgを得る。融点224−226℃。
参考例 ３
１−シクロプロピル−６−フルオロ−７−（ｐ
−トルイルスルホニル）−１，４−ジヒドロ−
４−オキソ−１，８−ナフチリジン−３−カル
ボン酸の合成
１−シクロプロピル−６−フルオロ−７−（ｐ
−トルイルチオ）−１，４−ジヒドロ−４−オキ
ソ−１，８−ナフチリジン−３−カルボン酸300
mgを塩化メチレン６mlに溶解し、80％ｍ−クロロ
過安息香酸350mgを加え、室温で２時間撹拌する。
溶媒を留去し、残渣にエーテルを加え、冷後析出
する結晶を取する。得られた結晶をクロロホル
ムから再結晶して、１−シクロプロピル−６−フ
ルオロ−７−（ｐ−トルイルスルホニル）−１，４
−ジヒドロ−４−オキソ−１，８−ナフチリジン
−３−カルボン酸280mgを得る。融点236−239℃。[Table] When the compound of the present invention is used as an antibacterial agent in humans, the dosage varies depending on age, body weight, symptoms, administration route, number of administrations, etc.
It is recommended to administer 5g in one or several divided doses. The route of administration may be either oral or parenteral. Although the compound of the present invention may be administered as a bulk powder, it is usually administered in a prepared form together with a pharmaceutical carrier. Specific examples include tablets, capsules, granules,
Examples include fine granules, powders, syrups, and injections. These formulations are prepared according to conventional methods. Oral preparation carriers include starch, mannitrate,
Substances commonly used in the pharmaceutical field, such as crystalline cellulose and CMC Na, and which do not react with the compound of the present invention are used. Examples of the carrier for injection include carriers commonly used in the field of injections, such as water, physiological saline, glycose solution, and infusion preparations. Next, the method for synthesizing the compound of the present invention will be explained in more detail by giving examples and reference examples. Example 1 1-Cyclopropyl-6-fluoro-7-(3
-hydroxy-1-pyrrolidinyl)-1,4-
Synthesis of dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1) 1-cyclopropyl-6-fluoro-7-
(p-tolylsulfonyl)-1,4-dihydro-
A mixture of 860 mg of ethyl 4-oxo-1,8-naphthyridine-3-carboxylate, 688 mg of 3-hydroxypyrrolidine, and 20 ml of ethanol is heated under reflux for 10 minutes. The reaction solution was concentrated to dryness under reduced pressure, and ethanol was added to the residue. Collect the precipitated crystals, wash with ethanol, and dry. Recrystallization from ethanol gave 1-cyclopropyl-6-fluoro-7-(3-hydroxy-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,
Ethyl 8-naphthyridine-3-carboxylate 625
Get mg. Melting point 205-206℃. (2) Heat a mixture of 361 mg of the ester obtained in the previous section, 20 ml of water, and 7 ml of 1N aqueous sodium hydroxide solution on a boiling water bath for 5 minutes. After treatment with activated carbon, neutralize with aqueous acetic acid solution and remove precipitated crystals. The crystals were recrystallized from a chloroform-ethanol mixture to give 1-cyclopropyl-6-fluoro-7-
(3-hydroxy-1-pyrrolidinyl)-1,4
250 mg of -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. Melting point over 300℃. Example 2 1-Cyclopropyl-6-fluoro-7-(3
-hydroxy-1-pyrrolidinyl)-1,4-
Synthesis of dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 1-cyclopropyl-6-fluoro-7-(p
-tolylsulfonyl)-1,4-dihydro-4
-A mixture of 402 mg of oxo-1,8-naphthyridine-3-carboxylic acid, 258 mg of 3-hydroxypyrrolidine, 150 mg of triethylamine, and 10 ml of ethanol.
Heat to reflux for 10 minutes. The solvent is distilled off, water is added to the residue, neutralized with 1N acetic acid aqueous solution, and the precipitated crystals are collected. After sequentially washing with water and ethanol and drying, 1-cyclopropyl-6-fluoro-7-(3-hydroxy-1-pyrrolidinyl)-1,4-dihydro- 4
300 mg of -oxo-1,8-naphthyridine-3-carboxylic acid are obtained. Example 3 1-Cyclopropyl-6-fluoro-7-(3
-hydroxy-1-pyrrolidinyl)-1,4-
Synthesis of dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 1-cyclopropyl-6-fluoro-7-(p
-Toluylthio)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 370
A mixture of 350 mg of 3-hydroxypyrrolidine and 3 ml of dimethylformamide is heated and stirred at 110 to 120°C for 3 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was neutralized with 1N acetic acid aqueous solution. The precipitated crystals were collected and recrystallized from a chloroform-ethanol mixture to obtain 1-, the same target product as in Example 1.
206 mg of cyclopropyl-6-fluoro-7-(3-hydroxy-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. Example 4 1-Cyclopropyl-6-fluoro-7-(4
-hydroxy-1-piperidinyl)-1,4-
Synthesis of dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1) 1-cyclopropyl-6-fluoro-7-
Using ethyl (p-tolylsulfonyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 4-hydroxypiperidine, the treatment was carried out in the same manner as in Example 1(1). Ethyl -cyclopropyl-6-fluoro-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is obtained. Melting point 244-246°C: Recrystallization solvent, ethanol-isopropyl ether. (2) The above ester was treated in the same manner as in Example 1(2) to obtain 1-cyclopropyl-6-fluoro-7-
(4-hydroxy-1-piperidinyl)-1,4
-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained. Melting point 255-258℃:
Recrystallization solvent, chloroform-ethanol. Example 5 1-Cyclopropyl-6-fluoro-7-(3
-hydroxy-1-piperidinyl)-1,4-
Synthesis of dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1) 1-cyclopropyl-6-fluoro-7-
Using ethyl (p-tolylsulfonyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 3-hydroxypiperidine, the treatment was carried out in the same manner as in Example 1(1). Ethyl -cyclopropyl-6-fluoro-7-(3-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is obtained. Melting point 194-196°C: Recrystallization solvent, ethanol-isopropyl ether. (2) The above ester was treated in the same manner as in Example 1(2) to obtain 1-cyclopropyl-6-fluoro-7-
(3-hydroxy-1-piperidinyl)-1,4
-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained. Melting point 265-268℃:
Recrystallization solvent, chloroform-ethanol. Example 6 7-(3-amino-4-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-
Synthesis of naphthyridine-3-carboxylic hydrochloride (1) 1-cyclopropyl-6-fluoro-7-
Using ethyl (p-tolylsulfonyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 3-acetylamino-4-hydroxypyrrolidine, the same procedure as in Example 1(1) was carried out. 7-(3-acetylamino-4-
Hydroxy-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-
Ethyl 4-oxo-1,8-naphthyridine-3-carboxylate is obtained. Melting point 258-260°C: recrystallization solvent, chloroform-ethanol. (2) Dissolve 418 mg of the above ester in 10 ml of 20% hydrochloric acid,
Heat to reflux for 7 hours. The solvent was distilled off under reduced pressure, ether was added to the residue, and the precipitated crystals were collected.
dry. Recrystallized from ethanol-ether to give 7-(3-amino-4-hydroxy-1-
pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,
8-Naphthyridine-3-carboxylic hydrochloride 334
Get mg. Melting point 245-252°C (decomposition). Example 7 1-Cyclopropyl-6-fluoro-7-(3
-hydroxy-1-azetidinyl)-1,4-
Synthesis of dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1) 1-cyclopropyl-6-fluoro-7-
Using ethyl (p-tolylsulfonyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 3-hydroxyazetidine, the same treatment as in Example 1(1) was carried out, Ethyl 1-cyclopropyl-6-fluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is obtained. Melting point 221-222°C: recrystallization solvent, acetonitrile-chloroform. (2) The above ester was treated in the same manner as in Example 1(2) to obtain 1-cyclopropyl-6-fluoro-7-
(3-hydroxy-1-azetidinyl)-1,4
-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained. Melting point 280-281℃:
Recrystallization solvent, ethanol-dimethylformamide. Reference example 1 1-cyclopropyl-6-fluoro-7-(p
-tolylsulfonyl)-1,4-dihydro-
Synthesis of ethyl 4-oxo-1,8-naphthyridine-3-carboxylate (1) 32.5 g of the known compound 2,6-dichloro-5-fluoronicotinonitrile was added to 400 ml of ethanol.
23.2 g of p-thiocresol and potassium salt of p-thiocresol obtained from 12.2 g of potassium hydroxide were reacted at room temperature to form 2-chloro-5
42.4 g of -fluoro-6-(p-tolylthio)nicotinonitrile are obtained. Melting point 124-125℃. (2) Add 36g of this compound to dry dimethyl sulfoxide.
Dissolve in 180 ml, add 22.2 g of anhydrous potassium fluoride, and heat and stir at 130-135°C for 1 hour. The solvent is distilled off under reduced pressure, water is added to the residue, and the resulting crude crystals are recrystallized from ethanol to obtain 30 g of 2,5-difluoro-6-(p-tolylthio)nicotinonitrile. Melting point 120-121℃. (3) 4 g of this compound was reacted with dry hydrogen chloride in absolute ethanol, and 2,5-difluoro-6-
3 g of ethyl (p-toluylthio)nicotinate is obtained. (4) Repeat the above reaction, dissolve 25 g of ethyl 2,5-difluoro-6-(p-tolylthio)nicotinate obtained in 400 ml of dimethylformamide, and add 25.4 g of ethyl N-cyclopropylaminopropionate and carbonate. 14g sodium hydrogen
Add and heat and stir at 100-110°C for 10 hours.
The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with toluene. After washing the toluene layer with dilute hydrochloric acid and then with water, the toluene layer is dried over anhydrous sodium sulfate. Toluene was distilled off under reduced pressure to obtain 32 g of ethyl 2-[N-cyclopropyl-N-(2-ethoxycarbonylethyl)amino]-5-fluoro-6-(p-tolylthio)nicotinate as a viscous liquid. . (5) Dissolve 3.2 g of this compound in 50 ml of dry toluene and add 0.32 g of 65% sodium hydride at room temperature.
g and stir the mixture for 10 minutes. Add a catalytic amount of absolute ethanol and stir for an additional 2 hours. After heating at 50 to 60°C for 1 hour, water is added and neutralized with a 10% acetic acid aqueous solution. The organic layer is separated, dried over anhydrous sodium sulfate, and then toluene is distilled off under reduced pressure. The resulting crude crystals were recrystallized from a mixture of n-hexane and isopropyl ether to give 1-cyclopropyl-6-fluoro-7-
(p-toluylthio)-1,2,3,4-tetrahydro-4-oxo-1,8-naphthyridine-
2.5 g of ethyl 3-carboxylate is obtained. Melting point 124−
125℃. (6) Dissolve 2.0g of this compound in 50ml of toluene,
To this, 2,3-dichloro-5,6-dicyano-
Add 1.25 g of p-benzoquinone, and heat and stir at room temperature for 2 hours, then at 50-60°C for 1 hour. After cooling, the precipitated crystals were taken, dissolved in chloroform, washed sequentially with 1N sodium hydroxide and water,
Dry the chloroform layer with anhydrous sodium sulfate. Chloroform was distilled off, and the resulting crude crystals were recrystallized from a mixture of ethanol and isopropyl ether to give 1-cyclopropyl-6-fluoro-7-(p-tolylthio)-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-
1.7 g of ethyl carboxylate is obtained. Melting point 186−187
℃. (7) Dissolve 1.59 g of this compound and 1.90 g of m-chloroperbenzoic acid (80%) in 50 ml of chloroform,
Heat to reflux for 30 minutes. After cooling, the mixture is washed successively with 2N sodium carbonate and water, and the chloroform layer is dried over anhydrous sodium sulfate. Chloroform was distilled off, and the resulting crude crystals were recrystallized from ethyl acetate to give 1-cyclopropyl-6-fluoro-
7-(p-Tolylsulfonyl)-1,4-dihydro-4-oxo-1,8 naphthyridine-3-
1.55 g of ethyl carboxylate is obtained. Melting point 216−218
℃. Reference example 2 1-cyclopropyl-6-fluoro-7-(p
-Toluylthio)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid Synthesis of 1-cyclopropyl-6-fluoro-7-(p
-Toluylthio)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1 g) was dissolved in 10 ml of 10N sulfuric acid, and heated to 105-115°C for 1 g.
Heat and stir for an hour. The reaction mixture was poured into ice water, and the precipitated crystals were collected and recrystallized from chloroform-ethanol to give 1-cyclopropyl-6-fluoro-7-(p-toluylthio)-1,4-dihydro-4-oxo- 530 mg of 1,8-naphthyridine-3-carboxylic acid are obtained. Melting point 224-226℃. Reference example 3 1-cyclopropyl-6-fluoro-7-(p
-tolylsulfonyl)-1,4-dihydro-
Synthesis of 4-oxo-1,8-naphthyridine-3-carboxylic acid 1-cyclopropyl-6-fluoro-7-(p
-Toluylthio)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 300
mg was dissolved in 6 ml of methylene chloride, 350 mg of 80% m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 2 hours.
The solvent is distilled off, ether is added to the residue, and after cooling, the precipitated crystals are collected. The obtained crystals were recrystallized from chloroform to give 1-cyclopropyl-6-fluoro-7-(p-tolylsulfonyl)-1,4
280 mg of -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. Melting point 236-239℃.
Claims (1)
たは水酸基を、R2は水素原子、アミノ基、モノ
またはジ低級アルキルアミノ基を、R3は水素原
子または低級アルキル基を、ｍは整数１または２
を、ｎは整数０，１または２を意味する。ただ
し、R1が水素原子の場合、R2は水素原子である。
また、R2が水素原子以外の基である場合は、ｎ
は整数１または２である。） で表わされるピリドンカルボン酸誘導体およびそ
の塩。[Claims] 1. General formula ( In the formula , integer 1 or 2
, n means an integer 0, 1 or 2. However, when R 1 is a hydrogen atom, R 2 is a hydrogen atom.
In addition, when R 2 is a group other than a hydrogen atom, n
is an integer 1 or 2. ) Pyridonecarboxylic acid derivatives and salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58233271A JPS60126284A (en) | 1983-12-09 | 1983-12-09 | Pyridonecarboxylic acid derivative and salt thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58233271A JPS60126284A (en) | 1983-12-09 | 1983-12-09 | Pyridonecarboxylic acid derivative and salt thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60126284A JPS60126284A (en) | 1985-07-05 |
| JPH0374230B2 true JPH0374230B2 (en) | 1991-11-26 |
Family
ID=16952469
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58233271A Granted JPS60126284A (en) | 1983-12-09 | 1983-12-09 | Pyridonecarboxylic acid derivative and salt thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60126284A (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3508816A1 (en) * | 1985-01-10 | 1986-07-10 | Bayer Ag, 5090 Leverkusen | 6,7-DISUBSTITUTED 1-CYCLOPROPYL-1,4-DIHYDRO-4-OXO-1,8-NAPHTYRIDINE-3-CARBONIC ACIDS |
| JPH08775B2 (en) * | 1986-05-22 | 1996-01-10 | 協和醗酵工業株式会社 | Drug for Pasteurella spp. Noduleosis in fish |
| HU205105B (en) * | 1987-10-26 | 1992-03-30 | Pfizer | Process for producing azetidinyl quinoline carboxylic acids and pharmaceutical compositions comprising same |
| FR2634483B2 (en) * | 1987-12-29 | 1994-03-04 | Esteve Labor Dr | DERIVATIVES OF ACIDS 7- (1-AZETIDINYL) -1,4-DIHYDRO-4-OXOQUINOLEINE-3-CARBOXYLIQUES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS |
| DE3906365A1 (en) * | 1988-07-15 | 1990-01-18 | Bayer Ag | 7- (1-PYRROLIDINYL) -3-CHINOLONE AND NAPHTHYRIDONE CARBOXYLIC ACID DERIVATIVES, METHOD AND SUBSTITUTED (OXA) DIAZABICYCLOOCTANES AND NONANESE AS INTERMEDIATE PRODUCTS, AND ANTIBACTERIAL AGENTS AND FOOD ADDITIVES CONTAINING THEM |
| FR2649106A2 (en) * | 1989-06-29 | 1991-01-04 | Esteve Labor Dr | Derivatives of azetidinyl-substituted pyridonecarboxylic acids, their preparation and their application as medicaments |
| FR2644455B1 (en) * | 1989-03-16 | 1994-09-23 | Esteve Labor Dr | SUBSTITUTED PYRIDONE CARBOXYLIC ACID AZETIDINYL ACID DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS |
| NO177302C (en) * | 1989-03-16 | 1995-08-23 | Esteve Labor Dr | Analogous Process for Preparing Therapeutically Active Substituted Azetidinyl Quinolone (Naphthyridone) Carboxylic Acid Derivatives |
| FR2690161B1 (en) * | 1992-04-16 | 1995-06-30 | Esteve Labor Dr | SUBSTITUTED PYRIDONE AZETIDINYL DERIVATIVES WITH ANTIMICROBIAL ACTIVITY. |
| WO2005026145A2 (en) * | 2003-09-12 | 2005-03-24 | Warner-Lambert Company Llc | Quinolone antibacterial agents |
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|---|---|---|---|---|
| JPS54132582A (en) * | 1978-02-24 | 1979-10-15 | Bayer Ag | Manufacture of 44pyridonee33carboxylic acid and*or its derivative |
| JPS5531042A (en) * | 1978-08-25 | 1980-03-05 | Dainippon Pharmaceut Co Ltd | 1,8-naphthylidine derivative and its salt |
| JPS5770889A (en) * | 1980-10-21 | 1982-05-01 | Dainippon Pharmaceut Co Ltd | 1-ethyl-1,8-naphthyridine derivative and salt thereof |
| JPS5777683A (en) * | 1980-09-03 | 1982-05-15 | Bayer Ag | 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro- naphthyridine-3-carboxylic acids or salts thereof, manufacture and antibacterial thereof as active ingredient |
| JPS57146775A (en) * | 1981-03-06 | 1982-09-10 | Dainippon Pharmaceut Co Ltd | 1,8-naphthyridine derivative and its salt |
| JPS6028978A (en) * | 1983-07-27 | 1985-02-14 | Dainippon Pharmaceut Co Ltd | 1,8-naphthyridine derivative |
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1983
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS54132582A (en) * | 1978-02-24 | 1979-10-15 | Bayer Ag | Manufacture of 44pyridonee33carboxylic acid and*or its derivative |
| JPS5531042A (en) * | 1978-08-25 | 1980-03-05 | Dainippon Pharmaceut Co Ltd | 1,8-naphthylidine derivative and its salt |
| JPS5777683A (en) * | 1980-09-03 | 1982-05-15 | Bayer Ag | 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro- naphthyridine-3-carboxylic acids or salts thereof, manufacture and antibacterial thereof as active ingredient |
| JPS5770889A (en) * | 1980-10-21 | 1982-05-01 | Dainippon Pharmaceut Co Ltd | 1-ethyl-1,8-naphthyridine derivative and salt thereof |
| JPS57146775A (en) * | 1981-03-06 | 1982-09-10 | Dainippon Pharmaceut Co Ltd | 1,8-naphthyridine derivative and its salt |
| JPS6028978A (en) * | 1983-07-27 | 1985-02-14 | Dainippon Pharmaceut Co Ltd | 1,8-naphthyridine derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60126284A (en) | 1985-07-05 |
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