JPS60126284A - Pyridonecarboxylic acid derivative and salt thereof - Google Patents
Pyridonecarboxylic acid derivative and salt thereofInfo
- Publication number
- JPS60126284A JPS60126284A JP58233271A JP23327183A JPS60126284A JP S60126284 A JPS60126284 A JP S60126284A JP 58233271 A JP58233271 A JP 58233271A JP 23327183 A JP23327183 A JP 23327183A JP S60126284 A JPS60126284 A JP S60126284A
- Authority
- JP
- Japan
- Prior art keywords
- fluoro
- naphthyridine
- dihydro
- cyclopropyl
- oxo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000003839 salts Chemical class 0.000 title claims description 10
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 title description 2
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 abstract description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 35
- -1 aliphatic cyclic amine Chemical class 0.000 abstract description 22
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 6
- 125000004423 acyloxy group Chemical group 0.000 abstract description 5
- 125000005843 halogen group Chemical group 0.000 abstract description 5
- 125000000524 functional group Chemical group 0.000 abstract description 4
- 125000003282 alkyl amino group Chemical group 0.000 abstract description 3
- 208000010824 fish disease Diseases 0.000 abstract description 2
- 235000013305 food Nutrition 0.000 abstract description 2
- 239000012442 inert solvent Substances 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000003755 preservative agent Substances 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 239000003905 agrochemical Substances 0.000 abstract 1
- 230000000845 anti-microbial effect Effects 0.000 abstract 1
- 239000004599 antimicrobial Substances 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 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
- 239000013078 crystal Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 10
- 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
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 5
- 239000002994 raw material Substances 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
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000010410 layer Substances 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
- 125000003277 amino group Chemical group 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- WLHCBQAPPJAULW-UHFFFAOYSA-N 4-methylbenzenethiol Chemical compound CC1=CC=C(S)C=C1 WLHCBQAPPJAULW-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 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
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 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
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-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
- 239000000047 product Substances 0.000 description 2
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
- CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical compound ON1CCCC1 CWLUFVAFWWNXJZ-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
- MGICJMNPJYYFIM-UHFFFAOYSA-N 2-chloro-5-fluoro-6-(4-methylphenyl)sulfanylpyridine-3-carbonitrile Chemical compound C1=CC(C)=CC=C1SC1=NC(Cl)=C(C#N)C=C1F MGICJMNPJYYFIM-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
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-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
- PWGFUTVLNROFAK-UHFFFAOYSA-N C(C)C1=C(C(NC2=NC=CC=C12)=O)C(=O)O Chemical compound C(C)C1=C(C(NC2=NC=CC=C12)=O)C(=O)O PWGFUTVLNROFAK-UHFFFAOYSA-N 0.000 description 1
- 239000005973 Carvone Substances 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 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
- 241000588724 Escherichia coli Species 0.000 description 1
- 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 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
- 229930195725 Mannitol Natural products 0.000 description 1
- ANKWNFMCGYWNHZ-UHFFFAOYSA-N N-(3-hydroxypyrrolidin-1-yl)acetamide Chemical compound C(C)(=O)NN1CC(CC1)O ANKWNFMCGYWNHZ-UHFFFAOYSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 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 class [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical class [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical class [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- ZULJYVVAYGFYKU-UHFFFAOYSA-N acetonitrile;chloroform Chemical compound CC#N.ClC(Cl)Cl ZULJYVVAYGFYKU-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000003545 alkoxy 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
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 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 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
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- ULDHMXUKGWMISQ-UHFFFAOYSA-N carvone Natural products CC(=C)C1CC=C(C)C(=O)C1 ULDHMXUKGWMISQ-UHFFFAOYSA-N 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
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 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
- SHQOVONJQDWWRC-UHFFFAOYSA-N ethyl 4-oxo-1h-1,8-naphthyridine-3-carboxylate Chemical compound N1=CC=CC2=C(O)C(C(=O)OCC)=CN=C21 SHQOVONJQDWWRC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229940064982 ethylnicotinate Drugs 0.000 description 1
- 235000013350 formula milk 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
- 239000008103 glucose Substances 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
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 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
- 239000005457 ice water Substances 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002500 ions Chemical class 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
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 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
- QAXZWHGWYSJAEI-UHFFFAOYSA-N n,n-dimethylformamide;ethanol Chemical compound CCO.CN(C)C=O QAXZWHGWYSJAEI-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Chemical class 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
- 239000002244 precipitate Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 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 Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 230000004083 survival effect Effects 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
- 230000009885 systemic effect Effects 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
- 238000003466 welding Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Chemical class 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Abstract
Description
【発明の詳細な説明】
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。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel pyridonecarboxylic acid derivatives that exhibit extremely excellent antibacterial activity.
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、水酸基、または
アシルオキシ基を、Ｒ２は水素原子。More specifically, the compound of the present invention has the following general formula (wherein,
X is a halogen atom, R1 is a hydrogen atom, a hydroxyl group, or an acyloxy group, and R2 is a hydrogen atom.
アミン基、モノまたはジ低級ア、ルキルアミノ基を、Ｒ
３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、１
＜１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、＋１は整数ｌ
まだは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１ の塩である。amine group, mono- or di-lower alkylamino group, R
3 represents a hydrogen atom or a lower alkyl group, m represents an integer of 1 or 2, and n represents an integer of 0, 1 or 2. However, 1
When <1 is a hydrogen atom, R2 is a hydrogen atom. In addition, if R2 is a group other than a hydrogen atom, +1 is an integer l
It's still 2. ) and its salt.
本発明の化合物の中で好ましい化合物は、式〔１〕にお
いて、Ｘがフッ素原子で、 ＲＩが水酸基、Ｒ２が水素
原子またはアミン基、Ｒ３が水素原子である化合物、お
よびＸがフッ素原子で、Ｒ＋ 、 Ｒ２，Ｒ３が共に水
素原子である化合物である。Preferred compounds among the compounds of the present invention are those of formula [1] in which X is a fluorine atom, RI is a hydroxyl group, R2 is a hydrogen atom or an amine group, R3 is a hydrogen atom, and X is a fluorine atom, This is a compound in which R+, R2, and R3 are all hydrogen atoms.
本発明の化合物の塩は、酢酸、乳酸、コハク酸。Salts of the compounds of the present invention include acetic acid, lactic acid, and succinic acid.
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、グルタミン酸切の
アミノ酸とのＪｒｌＡ Ｎあるいは塩酸、リン酸１りの
無機酸との塩、あるいは式（１）の化合物のすトリウム
、カリウム、亜鉛、銀等の金属塩、あるいｖＪ有機塩基
との塩である。Salts with organic acids such as methanesulfonic acid, maleic acid, malonic acid, gluconic acid, etc., salts with inorganic acids such as JrlA N, hydrochloric acid, phosphoric acid, etc. with amino acids such as aspartic acid and glutamic acid, or formula (1) These are metal salts of compounds such as strium, potassium, zinc, silver, etc., or salts with vJ organic bases.
本発明の化合物のうち、特に好ましい化合物を夕・］挙
すれば次の通りである。Among the compounds of the present invention, particularly preferred compounds are as follows.
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−カッしボン酸。1-cyclopropyl-6-fluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-
Oxo-1,8-naphthyridine-3-katabonic acid.
１−シクロプロピルー６−フルオロー７−（１−ピロリ
ジニル）−１、４−ジヒドロ−４−オキシー１．８−ナ
フチリジン−３−カルボン酸。1-cyclopropyl-6-fluoro-7-(1-pyrrolidinyl)-1,4-dihydro-4-oxy-1,8-naphthyridine-3-carboxylic acid.
■−シクロプロピルー６−フルオロー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。■-Cyclopropyl-6-fluoro-7- (:3-hydroxy-1-pyrrolidinyl)-1,4-dihydro-4
-oxo-1,8-naphthyridine-3-carboxylic acid.
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−；３ｆ−カ
ルボン酸。7-(3-Amino-4-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1°4-dihydro-4-oxo-1,8-naphthyridine-; 3f-carboxylic acid.
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-Cyclopropyl-6-fluoro-7-(3-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.
１−シクロプロピル−６−フルオロ−７−（１−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-Cyclopropyl-6-fluoro-7-(1-hydroxy-1-piperidinyl>-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.
次に本発明の化合物の製造法につき、以下に説明する。Next, the method for producing the compound of the present invention will be explained below.
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、Ｒ＋ 、 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、生成物を常法によシ単離することにより製
造することができる。The compound of the present invention has the following general formula (wherein, X is a halogen atom, Y is a functional group that can be substituted with the aliphatic cyclic amines [■] described below), and R3 is a hydrogen atom or a lower alkyl group. ) and the following general formula (wherein R+ , R2,m ,
n is the same as above. It can be produced by reacting aliphatic cyclic amines represented by ) and isolating the product by a conventional method.
式（［１）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、
（ｌアルキルスルフィニル、アリールスルフィニル、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。The reactive functional group represented by Y in formula ([1)] includes arylsulfonyl, lower alkylsulfonyl, halogen atom, lower alkoxy, arylthio, lower alkylthio,
(I include alkylsulfinyl, arylsulfinyl, arylsulfonyloxy, lower alkylsulfonyloxy, etc.)
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”Ｃ１
好ましくは５０〜１５０°Ｃにおいて、原料化合物（Ｉ
Ｉ）と（ＩＩＩ）とを５〜１２０分間、通常は２０〜６
０分間混合攪拌することにより実施できる。原オ」化合
物（１）の原料化合物〔ＩＩ〕 に対する使用量は当Ｊ
ｊ：：ないしや＼過剰量である。原料化合物〔１１〕の
Ｙの官能基の種類により、反応の結果、有機酸、塩酸等
の酸が副生ずるので、か＼る場合には酸受容体を使用す
るのが一般的であるが、原オパ１化合物ＣＩｌｌ ）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
０
また本反応で使用される原料化合物ＣＩｌｌ ： 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、−！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。This reaction uses ethanol, acetonitrile, dioxane,
20-180"C1 in an inert solvent such as dimethylformamide, dimethylsulfoxide, toluene, xylene
Preferably at 50 to 150°C, the raw material compound (I
I) and (III) for 5 to 120 minutes, usually 20 to 6 minutes.
This can be carried out by mixing and stirring for 0 minutes. The amount of raw material compound (1) to be used for raw material compound [II] is determined by this J
j:: or \excess amount. Depending on the type of functional group of Y in the starting compound [11], 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 opa1 compound CIll) may be used in excess to serve as an acid acceptor.In addition, the raw material compound CIll 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. Protecting groups include β-lactam antibiotics, peptides, -! or protecting groups commonly used in nucleic acid chemistry.
上記の反応により、Ｒ３が低級アルキル基および／また
はＲ＋がアシルオキシ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っ
て、Ｒ３が水素原子および／−またはＲ＋が水酸基であ
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Ｒ＋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お
よび／またはアシル化することによって、Ｒ３が低級ア
ルキル基および／まだはＲ１がアシルオキシ基である化
合物に導くことができる。When a compound of the present invention in which R3 is a lower alkyl group and/or R+ is an acyloxy group is obtained by the above reaction, it can be hydrolyzed by a conventional method to form a hydrogen atom in R3 and/or an acyloxy group in R+. It can be converted into a compound that has a hydroxyl group. Conversely, when a compound of the present invention in which R3 is a hydrogen atom and/or R+ is a hydroxyl group is obtained, it can be esterified and/or acylated by a conventional method, so that R3 is a lower alkyl group and/or a hydroxyl group. can lead to a compound in which R1 is an acyloxy group.
原料化合物（ＩＩ）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。Starting compound (II) can be produced by the method described in Reference Examples or a method analogous thereto.
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、精製条件によって、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。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, the salt form,
Although it is obtained in the form of a free carboxylic acid or a free amine, these can be mutually converted depending on the purpose to produce the compound of the present invention in the desired form.
かくして得られる本発明の化合物〔１〕 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１食品の保
存剤等としても使用することが可能である。The compound [1] of the present invention thus obtained and its salt are both new compounds. In particular, compounds of the present invention in which R3 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, preservatives for pesticides and foods, and the like.
まだ、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。Although the compounds of the present invention in which R3 is a lower alkyl group have antibacterial activity themselves, they are valuable as intermediate raw materials for the compounds of the present invention in which R3 is a hydrogen atom.
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。Next, data regarding the antibacterial activity of the main compounds of the present invention are listed below.
（以下余白）
※実験条件
最小発育阻止濃度（八１１０：μｆ／ｍｅ）はＯ１＋ｅ
ｍｏもｂｏｒｎｐｙ 。(Left below) *Experimental conditions Minimum inhibitory concentration (8110: μf/me) is O1+e
mo is also bornpy.
２９巻１号７６頁（１９８１年）に記載の方法（改定案
）に晃じて行ない、その結果を上記表中に示した。The method described in Vol. 29, No. 1, p. 76 (1981) (revised version) was followed, and the results are shown in the table above.
マウス全身感染症に対する効果°゛′°゛°′実験条件
試験薬剤：実施例１の化合物
使用動物：ｄｄｙ−８系雄性マウス（平均体重２０ｙ）
大 腸 菌：９ Ｘ １０’生菌／マウス（ｉ、ｐ、）
緑 膿 菌１４Ｘ１０３生菌／マウス（ｉ・ＩＩ・）投
薬 方 法：薬剤を０２％ＯＭＯＮｕ Ｋ Ｐｇ濁さ
せ、これを感染直後および６時間後に経口投与した。Effect on mouse systemic infection °゛'°゛°' Experimental conditions Test drug: Compound of Example 1 Animal used: ddy-8 male mouse (average weight 20y)
E. coli: 9 x 10' live bacteria/mouse (i, p,)
Pseudomonas aeruginosa 14X103 live bacteria/mouse (i.II.) Medication method: The drug was suspended in 02% OMONu KPg and administered orally immediately after infection and 6 hours later.
Ｊ’ｉ！ｉ果の判定方法：感染７日後の生存率から、Ｕ
ｏｌ＋ｒｏｎｓ−に、ｕａ＋４＋ｏｒ法によりＥｉ）ｓ
ａ値を算出し、その値を表中に示した。J'i! I Judgment method: Based on the survival rate 7 days after infection, U
ol+rons-, Ei)s by ua+4+or method
The a value was calculated and the value is shown in the table.
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１体重、症状、投与経路、抄゛与回数等
により異なるが、１日当り５■〜５ｙ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。When the compound of the present invention is used as an antibacterial agent in humans, the dosage varies depending on age, body weight, symptoms, route of administration, number of administrations, etc., but the dosage is 5 to 5 years once to several times per day. It is recommended that the drug be administered in separate doses. The route of administration is oral;
Either parenteral administration is acceptable.
本発明の化合物は原末の′ｉまでもよいが、通常製剤用
担体と共に調製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。Although the compound of the present invention may be in the form of a bulk powder, it is usually administered in a prepared form together with a pharmaceutical carrier. Specific examples include tablets, capsules, granules, and fine granules.
散剤、シロップ剤、注射剤等が挙げられる。これらの製
剤は常法に従って調製される。経口用製剤担体トルてハ
、テンプン、マンニット、結晶セルロース。Examples include powders, syrups, injections, etc. These formulations are prepared according to conventional methods. Carriers for oral preparations include starch, starch, mannitol, and crystalline cellulose.
ＣＭＣＮａ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、グルコース溶液。A substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention, such as CMCNa, is used. Injectable carriers include water, saline, and glucose solutions.
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
。Examples include carriers commonly used in the field of injections such as infusion solutions.
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。Next, the method for synthesizing the compound of the present invention will be explained in more detail by giving examples and reference examples.
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／ｌ／８６
０ｍｙ ’、３−ヒドロキシピロリジン６８８巧、エタ
ノール２０ｍｅ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、残渣にエタノールを加える。Example 1 Synthesis of 1-cyclopropyl-6-fluoro-7-(3-hydroxy-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1) 1 -cyclopropyl-6-fluoro-7-(ptolylsulfonyl)-1,4-dihydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylic acid/l/86
A mixture of 0my', 3-hydroxypyrrolidine 688g and 20m 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.
析出する結晶をデ取し、エタノールで洗い、乾燥する。Collect the precipitated crystals, wash with ethanol, and dry.
エタノールから再結晶して、１−シクロプロビル−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６２５ｆｆ＋１９を得る。融
点２０５−２０６℃。Recrystallized from ethanol to give 1-cyclopropyl-6-
Fluoro-7-(3-hydroxy-1-pyrrolidinyl)
625ff+19 of ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are obtained. Melting point 205-206°C.
（２）前項で得だエステル３６１ｔｎｇ＋水２０ｍ１’
、ｌ’Ｎ水酸化ナトリウム水溶ｆｉ ７ ｎｉ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Ｐ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２５０ｍｆｌを得る
。(2) 361tng of ester obtained in the previous section + 20ml of water
, l'N sodium hydroxide aqueous fi 7 ni is heated on a boiling water bath for 5 minutes. After the activated carbon treatment, it is neutralized with an aqueous acetic acid solution and the precipitated crystals are collected. The crystals were recrystallized from a chloroform-ethanol mixture to give 1-cyclopropyl-6-fluoro-7-(3-hydroxy-1-
250 mfl of (pyrrolidinyl)-1,4-dihydro-4-oxo-1°8-naphthyridine-3-carboxylic acid are obtained.
融点３００°Ｃ以上。Melting point over 300°C.
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−シクロプロビル−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４０２〜，３−ヒド
ロキシピロリジン２５８ｍｆｌ 、 ト！Ｊエチルアミ
ン１５０ｍｆｌ 、エタノール１０ｍ１’の混合物を１
０分間加熱還流する。溶媒を留去し、残渣に水を加え、
ＩＮＮ酢酸水溶液中和し、析出する結晶をｅ取する。水
。Example 2 Synthesis of 1-cyclopropyl-6-fluoro-7-(3-hydroxy-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 1-cyclopropyl bir-6-fluoro-7-(p-tolylsulfonyl)-1,4-dihydro-4-oxo-1,
8-naphthyridine-3-carboxylic acid 402~,3-hydroxypyrrolidine 258 mfl, to! A mixture of 150 mfl of J ethylamine and 10 ml of ethanol
Heat to reflux for 0 minutes. The solvent was distilled off, water was added to the residue,
Neutralize with INN acetic acid aqueous solution and collect precipitated crystals. water.
エタノールで順次洗ったのち、乾燥して、実施例１と同
一の目的物であるｌ−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３００ｆｆｉｇを得る。After sequentially washing with ethanol and drying, l-cyclopropyl-6-fluoro-, the same target product as in Example 1, was obtained.
7-(3-hydroxy-1-pyrrolidinyl)-1,4-
300 ffig of dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained.
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−シクロプロビル−６−フルオロ−７’ −（ｐ −
トルイルチオ）−１，４−ジヒドロ−４−オキシー１．
８−ナフチリジン−３−カルボン酸３７Ｏｆｆ＋９．３
−ヒドロキシピロリジン３５０ＦＩ１ｇ、ジメチルホル
ムアミド３ｍｌ’の混合物を１１０〜１２０°Ｃで３時
間加熱撹拌する。溶媒を減圧上留去し、残ｆｆｔ、に水
を加え、ＩＮ酢酸水溶液で中和する。乍「出する結晶を
シ日取し、クロロホルム−エタノールの混液から再結晶
シて、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，＋−ジヒドロ−４−オキシーｌ、８−ナ
フチリジン−３−カルボン酸２０６ｆｆ１ｇを得る。Example 3 Synthesis of 1-cyclopropyl-6-fluoro-7-(3-hydroxy-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 1-cyclopropyl Biru-6-fluoro-7'-(p-
Toluylthio)-1,4-dihydro-4-oxy-1.
8-naphthyridine-3-carboxylic acid 37Off+9.3
-A mixture of 1 g of 350 FI of 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 remaining fft, and the mixture was neutralized with IN aqueous acetic acid solution. Collect the resulting crystals and recrystallize them from a chloroform-ethanol mixture to obtain 1-cyclopropyl-6-fluoro-7-(3-hydroxy-1- 206ff1 g of pyrrolidinyl)-1,+-dihydro-4-oxyl,8-naphthyridine-3-carboxylic acid are obtained.
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−シクロプロビル−６−フルオロ−７−（ｐ−
１−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−ピペリジニルノー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“Ｃ：再結晶溶
媒、エタノール−イソプロピルエーテル。Example 4 Synthesis of 1-cyclopropyl-6-fluoro-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1) 1 -cycloprovir-6-fluoro-7-(p-
Ethyl 1-ruylsulfonyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 4
1-cyclopropyl-6-fluoro-7-
(Obtains ethyl 4-hydroxy-1-piperidinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate. Melting point 244-246"C: Recrystallization solvent, ethanol-isopropyl ether.
（２）上記エステルを実施例１（２）と同様に処理して
、■−フシクロプロピル−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。(2) The above ester was treated in the same manner as in Example 1 (2), and ■-fucyclopropyl-6-fluoro7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-
Oxo-1,8-naphthyridine-3-carboxylic acid is obtained. Melting point 255-258°C: recrystallization solvent, chloroform
ethanol.
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。Example 5 Synthesis of 1-cyclopropyl-6-fluoro-7-(3-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1) 1 -cyclopropyl-6-fluoro-7-(p-
tolylsulfonyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 3
1-cyclopropyl-6-fluoro-7-
Ethyl (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）上記エステルを実施例１（２）と同様に処理して
、１−シクロプロビル−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−カルボン酸をイ４
Ｉる。融点２（ｉ５−２６８°Ｃ：丙結晶溶媒、クロロ
ホルム−エタノール。(2) The above ester was treated in the same manner as in Example 1 (2) to obtain 1-cycloprobyl-6-fluoro-7-(3-hydroxy-1-piperidinyl)-1,4-dihydro-4-
Oxo-1,8-naphthyridine-3-carboxylic acid
I. Melting point 2 (i5-268°C: C crystal solvent, chloroform-ethanol.
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℃：Ｆ） 結晶溶６ｒクロロ
ポルム−エタノール。Example 6 7-(3-Amino-4-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1°4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride Synthesis (1) 1-cyclopropyl-6-fluoro-7-(p-
ethyl tolylsulfonyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 3-
Using acetylamino-4-hydroxypyrrolidine, the same treatment as in Example 1 (1) was performed to obtain 7-(3-acetylamino-4-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1. Ethyl 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is obtained. Melting point 258-260°C:F) Crystalline 6r chloroporum-ethanol.
（２）上記エステル４１８巧を２０チ塩酸１ａｍｅに溶
解し、７時間加熱還流する。溶媒を減圧上留去し、残渣
にエーテルを加え、析出する結晶をお日取し、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３
３４巧を得る。融点２４５−２５２’Ｃ（分解）。(2) Dissolve the above ester 418 in 20% hydrochloric acid and heat under reflux for 7 hours. The solvent is distilled off under reduced pressure, ether is added to the residue, and the precipitated crystals are allowed to dry for a day. Recrystallization from ethanol-ether gave 7-(3-amino-4-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine- 3-carboxylic hydrochloride 3
Obtain 34 skill. Melting point 245-252'C (decomposed).
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”ｌ−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°Ｃ：再結晶溶媒
、アセトニトリル−クロロホルム０
（２）上記エステルを実施例１（２）と同様に処理して
、ｌ−シクロプロピルー６−フルオロー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°Ｃ：再結晶溶媒、エタノール−
ジメチルホルムアミド。Example 7 1-Cyclopropyl-6-fluoro-7-(3-hydroxy-1-azetidinyl"l-1,4-dihydro-4-
Synthesis of oxo-1,8-naphthyridine-3-carboxylic acid (1) 1-cyclopropyl-6-fluoro-7-(p-
ethyl tolylsulfonyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 3-
1-Cyclopropyl-6-fluoro-7-(
Ethyl 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 0 -azetidinyl)-1,4-dihydro-4-
Oxo-1,8-naphthyridine-3-carboxylic acid is obtained. Melting point 280-281°C: Recrystallization solvent, ethanol
Dimethylformamide.
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３２．５ｙを、エタノール４００ｍｅ中、
ｐ−チオクレゾール２３．２ｙと水酸化カリウム１２．
２ｙ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４２．４７を得る。Reference example 1 1-cyclopropyl-6-fluoro-7-(p-tolylsulfonyl)-1,4-dihydro-4-oxo-1,
Synthesis of ethyl 8-naphthyridine-3-carboxylate (1) 32.5 y of known compound 2,6-dichloro-5-fluoronicotinonitrile was added in 400 me of ethanol.
p-thiocresol 23.2y and potassium hydroxide 12.
The potassium salt of p-thiocresol obtained from 2y was reacted at room temperature to form 2-chloro-5-fluoro-6-(p
-Toluylthio)nicotinonitrile 42.47 are obtained.
融点１２４−１２５°Ｃ０
（２）この化合物３６ ｙを乾燥ジメチルスルホキシド
１８０ｍｅに溶解し、無水フッ化カリウム２２．２７を
加えて１３０〜１３５℃１時間加熱攪拌する。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
ノールカラ再結晶して、２，５−ジフルオロ−６−（ｐ
−１ルイルチオ）ニコチノニトリル３０ｙを得る。融点
１２０−１２１°Ｃ３
（３）この化合物４り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３ｙを得る。Melting point: 124-125°C0 (2) This compound 36y is dissolved in 180me of dry dimethyl sulfoxide, 22.27ml of anhydrous potassium fluoride is added, and the mixture is heated and stirred at 130-135°C for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the resulting crude crystals were recrystallized in ethanol to give 2,5-difluoro-6-(p
-1ruylthio)nicotinonitrile 30y is obtained. Melting point: 120-121 DEG C. (3) This compound 4 is reacted with dry hydrogen chloride in absolute ethanol to obtain ethyl 2,5-difluoro-6-(p-tolylthio)nicotinate 3y.
（４）上記反応を繰り返し、得られだ２，５−ジフルオ
ロ−Ｇ−（ｐ−）ルイルチオ）ニコチン酸エチル２５ｊ
７をジメチルホルムアミド４００ｍｅ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．
４７と炭酸水素ナトリウム１４７を加え、１００〜１１
０°Ｃにて１０時間加熱攪拌する。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。トルエンヲ減圧下留去し、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）アミン〕＝５−フルオロ−６−（ｐ
−１ルイルチオ）ニコチン酸エチル３２ｙを得る。(4) Repeat the above reaction to obtain ethyl 2,5-difluoro-G-(p-)ruylthio)nicotinate 25j
7 was dissolved in 400 me of dimethylformamide, and ethyl N-cyclopropylaminopropionate 25.
47 and sodium hydrogen carbonate 147, and add 100 to 11
Heat and stir at 0°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. The toluene was distilled off under reduced pressure to give a viscous liquid of 2-(N-cyclopropyl-N-(2-ethoxycarbonylethyl)amine)=5-fluoro-6-(p
-1ruylthio)ethyl nicotinate 32y is obtained.
（５）この化合物３．２ｙを乾燥トルエン５０ｍｅに溶
解し、これに室温にて６５チ水素化ナトリウム０．３２
ｙを加え、混合物を１０分間攪拌する。触媒量の無水エ
タノールを加え、さらに２時間攪拌する。ついで５０〜
６０°Ｃにて１時間加熱後、水を加え、１０係酢酸水溶
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。イＮＩられる粗結
晶を１１−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−）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２．５７を得る。融点１２４−１２５℃。(5) Dissolve 3.2y of this compound in 50me of dry toluene and add 0.32ml of 65 sodium thihydride at room temperature.
Add y and stir the mixture for 10 minutes. Add a catalytic amount of absolute ethanol and stir for an additional 2 hours. Then 50~
After heating at 60°C for 1 hour, water was 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 crude crystals obtained were recrystallized from a mixture of 11-hexane and isopropyl ether, and 1-cyclopropyl-6-fluoro-7-(
p-)ruylthio)-1,2,3゜4-tetrahydro-
2.57 ethyl 4-oxo-1,8-naphthyridine-3-carboxylate is obtained. Melting point 124-125°C.
（６）この化合物２．０９をトルエン５０ｍ１？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１．２５ｙを加え、室温にて２時間、つい
で５０〜６０℃で１時間加熱攪拌する。冷接、析出する
結晶をｉｌ：Ｉ取、クロロホルムに溶解し、ＩＮ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−（１）−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１．７２を得る。融点１８６−１８７℃。(6) 2.09 of this compound and 50ml of toluene? 2,3-dichloro-5,6-dicyano-p-
1.25y of benzoquinone is added, and the mixture is heated and stirred at room temperature for 2 hours, then at 50-60°C for 1 hour. After cold contact, the precipitated crystals were taken up as il:I, dissolved in chloroform, washed successively with IN sodium hydroxide and water, and the chloroform layer was dried over 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-(1)-tolylthio)-1°4-dihydro-4.
1.72 ethyl -oxo-1,8-naphthyridine-3-carboxylate is obtained. Melting point 186-187°C.
（７）この化合物１．５９７とｎ】−クロロ過安息香酸
（８０チ）１．９０ｙをクロロホルム５０ｍ１’に溶解
し、３０分間加熱還流する。冷接、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−）ルイルスルホニルＬ−１
，４−ジヒドロ−４−オキソ−１，８ナフチリジンー３
−カルボン配エチル１．５５！７をイ（Ｉる。(7) Dissolve 1.597 of this compound and 1.90 y of n]-chloroperbenzoic acid (80) in 50 ml of chloroform and heat under reflux for 30 minutes. Wash sequentially with cold welding, 2N sodium carbonate, and water, and dry the chloroform layer with 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-)ruylsulfonyl L-1.
,4-dihydro-4-oxo-1,8naphthyridine-3
- Carvone ethyl 1.55!7.
融点２１６−２１８°Ｃ０
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１りをＩＯＮ硫酸硫酸１０釦ｅ解し、１
０５〜１１５”Ｃで１時間加熱攪拌する。反応混合物を
氷水にあけ、析出する結晶を１取し、クロロホルム−エ
タノールから再結晶シて、１−シクロプロピル−６−フ
ルオロ−７−（ｐ−）ルイルチオ）−１，４−ジヒドロ
−４−オキシー１，８−ナフチリジン−３−カルボン酸
５３０ｆｆ１ｇを得る。融点２２４−２２６℃。Melting point 216-218°C0 Reference Example 2 Synthesis of 1-cyclopropyl-6-fluoro-7-(p-tolylthio)-1,4-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 ethyl ester was dissolved in ION sulfuric acid using 10 buttons.
Heat and stir at 05 to 115"C for 1 hour. Pour the reaction mixture into ice water, take one portion of the precipitated crystals, recrystallize from chloroform-ethanol, and give 1-cyclopropyl-6-fluoro-7-(p- ) 530ff1 g of (ruylthio)-1,4-dihydro-4-oxy-1,8-naphthyridine-3-carboxylic acid are obtained, melting point 224-226°C.
参考例３
１−シクロプロピルー６−フルオロー７−（ｐ−トルイ
ルスルホニル）−１，４−）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−シクロプロピルー６−フルオロー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３００ｍｆｌを塩化メチレ
ン（３ｍｅに溶解し、８０％ｍ−クロロ過安息香酸３５
０■を加え、室温で２時間攪拌する。溶媒を留去し、残
渣にエーテルを加え、今後析出する結晶を１取する。得
られた結晶をクロロポルムから再結晶して、１−シクロ
プロピル−６−フルオロ−７−（ｐ −ｔ・ルイルスル
ホニルＬ−１，４−ジヒドロ−４−オキソ−１，８−ナ
フチリジン−３−カルボン酸２８０ｎｕＩを得る。融点
２３６−２３９℃。Reference example 3 1-cyclopropyl-6-fluoro-7-(p-tolylsulfonyl)-1,4-)hydro-4-oxo-1,
Synthesis of 8-naphthyridine-3-carboxylic acid 300 mfl of 1-cyclopropyl-6-fluoro-7-(p-toluylthio)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was dissolved in methylene chloride. (Dissolved in 3me, 80% m-chloroperbenzoic acid 35
Add 0.0 kg and stir at room temperature for 2 hours. The solvent is distilled off, ether is added to the residue, and one portion of the crystals that will precipitate is collected. The obtained crystals were recrystallized from chloroporum to give 1-cyclopropyl-6-fluoro-7-(pt.ruylsulfonyl L-1,4-dihydro-4-oxo-1,8-naphthyridine-3- 280 nuI of carboxylic acid is obtained, melting point 236-239°C.
特許出願人 大日本製薬株式会社 代理人弁理士 坪 井 有 四 部Patent applicant: Dainippon Pharmaceutical Co., Ltd. Representative Patent Attorney Yu Tsuboi 4th Department
Claims (1)
、またはアシルオキシ基を、Ｒ２は水素原子１アミノ基
、モノまたはジ低級アルキルアミノ基を、１（３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、１は整数１または２であ
る。 で表わされるピリド／カルボン酸、１体、およびその塩
。[Scope of Claims] General formula (wherein, is a hydrogen atom or a lower alkyl group, m is an integer 1 or 2,
n means an integer 0, 1 or 2. However, when R1 is a hydrogen atom, R2 is a hydrogen atom. Further, when R2 is a group other than a hydrogen atom, 1 is an integer 1 or 2. Pyrido/carboxylic acid represented by 1, 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 true JPS60126284A (en) | 1985-07-05 |
| JPH0374230B2 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) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61161284A (en) * | 1985-01-10 | 1986-07-21 | バイエル・アクチエンゲゼルシヤフト | 6,7-disubstituted 1-cyclopropyl-1,4-dihydro-4-oxo-1, 8-naphthylidine-3-carboxylic acids |
| JPS62273917A (en) * | 1986-05-22 | 1987-11-28 | Kyowa Hakko Kogyo Co Ltd | Remedy for vibriosis or bacterial nodositas of genus pasteurella of fish |
| JPH01146879A (en) * | 1987-10-26 | 1989-06-08 | Pfizer Inc | Azethidinylquinolone carboxylic acid and ester thereof |
| JPH01301677A (en) * | 1987-12-29 | 1989-12-05 | Lab Del Dr Esteve Sa | 7-(1-acetidinyl)-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid derivative, its production and use thereof as drug |
| JPH0269474A (en) * | 1988-07-15 | 1990-03-08 | Bayer Ag | 7-(1-pyrrolidinyl)-3-quinolone-and-naphthylidone -carboxylic acid derivative, production thereof, antibacterial agent and feed additive |
| EP0388298A2 (en) * | 1989-03-16 | 1990-09-19 | Laboratorios Del Dr. Esteve, S.A. | Derivatives of pyridone carboxylic acids substituted by an azetidine, their preparation and their use as medicines |
| FR2644455A1 (en) * | 1989-03-16 | 1990-09-21 | Esteve Labor Dr | Azetidinyl-substituted pyridonecarboxylic acid derivatives, their preparation and their application as medicaments |
| FR2649106A2 (en) * | 1989-06-29 | 1991-01-04 | Esteve Labor Dr | Derivatives of azetidinyl-substituted pyridonecarboxylic acids, their preparation and their application as medicaments |
| ES2103218A1 (en) * | 1992-04-16 | 1997-09-01 | Esteve Labor Dr | New pyridonecarboxylic acid azitidine derivative having antimicrobial activity |
| WO2005026145A3 (en) * | 2003-09-12 | 2005-06-16 | Warner Lambert Co | Quinolone antibacterial agents |
Citations (6)
| 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 |
| 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 |
-
1983
- 1983-12-09 JP JP58233271A patent/JPS60126284A/en active Granted
Patent Citations (6)
| 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 |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4840954A (en) * | 1985-01-10 | 1989-06-20 | Bayer Aktiengesellschaft | 6,7-disubstituted 1-cycloproply-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids |
| JPS61161284A (en) * | 1985-01-10 | 1986-07-21 | バイエル・アクチエンゲゼルシヤフト | 6,7-disubstituted 1-cyclopropyl-1,4-dihydro-4-oxo-1, 8-naphthylidine-3-carboxylic acids |
| JPS62273917A (en) * | 1986-05-22 | 1987-11-28 | Kyowa Hakko Kogyo Co Ltd | Remedy for vibriosis or bacterial nodositas of genus pasteurella of fish |
| JPH01146879A (en) * | 1987-10-26 | 1989-06-08 | Pfizer Inc | Azethidinylquinolone carboxylic acid and ester thereof |
| JPH01301677A (en) * | 1987-12-29 | 1989-12-05 | Lab Del Dr Esteve Sa | 7-(1-acetidinyl)-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid derivative, its production and use thereof as drug |
| JPH0269474A (en) * | 1988-07-15 | 1990-03-08 | Bayer Ag | 7-(1-pyrrolidinyl)-3-quinolone-and-naphthylidone -carboxylic acid derivative, production thereof, antibacterial agent and feed additive |
| EP0757990A1 (en) * | 1988-07-15 | 1997-02-12 | Bayer Ag | 7-(1-Pyrrolidoinyl)-3-quinolone and naphthyridone carboxylic acid derivatives, method for their preparation and for substituted mono- and bicyclic pyrrolidine intermediates, and their antibacterial and feed additive compositions |
| US5416096A (en) * | 1988-07-15 | 1995-05-16 | Bayer Aktiengesellschaft | 7-(1-pyrrolidinyl)-3-quinolone carboxylic acid derivatives as antibacterial agents and feed additives |
| US5393758A (en) * | 1989-01-29 | 1995-02-28 | Laboratorios Del Dr. Esteve S.A. | Substituted azetidinylpyridone naphthyridine carboxylic acid derivatives and their application as medical products |
| EP0388298A2 (en) * | 1989-03-16 | 1990-09-19 | Laboratorios Del Dr. Esteve, S.A. | Derivatives of pyridone carboxylic acids substituted by an azetidine, their preparation and their use as medicines |
| JPH02279683A (en) * | 1989-03-16 | 1990-11-15 | Lab Del Dr Esteve Sa | Substituted azetidinylpyridonecarboxilic acid derivative, its production and pharmaceutical usage |
| FR2644455A1 (en) * | 1989-03-16 | 1990-09-21 | Esteve Labor Dr | Azetidinyl-substituted pyridonecarboxylic acid derivatives, their preparation and their application as medicaments |
| FR2649106A2 (en) * | 1989-06-29 | 1991-01-04 | Esteve Labor Dr | Derivatives of azetidinyl-substituted pyridonecarboxylic acids, their preparation and their application as medicaments |
| ES2103218A1 (en) * | 1992-04-16 | 1997-09-01 | Esteve Labor Dr | New pyridonecarboxylic acid azitidine derivative having antimicrobial activity |
| WO2005026145A3 (en) * | 2003-09-12 | 2005-06-16 | Warner Lambert Co | Quinolone antibacterial agents |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0374230B2 (en) | 1991-11-26 |
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