JPH0450313B2 - - Google Patents
Info
- Publication number
- JPH0450313B2 JPH0450313B2 JP58197743A JP19774383A JPH0450313B2 JP H0450313 B2 JPH0450313 B2 JP H0450313B2 JP 58197743 A JP58197743 A JP 58197743A JP 19774383 A JP19774383 A JP 19774383A JP H0450313 B2 JPH0450313 B2 JP H0450313B2
- Authority
- JP
- Japan
- Prior art keywords
- cyclopropyl
- naphthyridine
- oxo
- fluoro
- 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
- 150000002148 esters Chemical class 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- 150000001875 compounds Chemical class 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000013078 crystal Substances 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- -1 aliphatic cyclic amine Chemical class 0.000 description 14
- 238000002844 melting Methods 0.000 description 14
- 230000008018 melting Effects 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 235000002639 sodium chloride Nutrition 0.000 description 8
- 238000010992 reflux Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-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
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- HDCCJUCOIKLZNM-UHFFFAOYSA-N n-pyrrolidin-3-ylacetamide Chemical compound CC(=O)NC1CCNC1 HDCCJUCOIKLZNM-UHFFFAOYSA-N 0.000 description 4
- 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
- 238000007796 conventional method Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 238000000034 method Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 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
- ZMMAJVZOYAEFNK-UHFFFAOYSA-N 4-oxo-3h-1,8-naphthyridine-3-carboxylic acid Chemical compound C1=CC=C2C(=O)C(C(=O)O)C=NC2=N1 ZMMAJVZOYAEFNK-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
- 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 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
- 239000008187 granular material Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 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
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000001953 recrystallisation 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
- 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
- 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
- RZZZOBPMYLPGBK-UHFFFAOYSA-N 4-oxo-3h-1,8-naphthyridine-3-carboxylic acid;hydrochloride Chemical compound Cl.C1=CC=C2C(=O)C(C(=O)O)C=NC2=N1 RZZZOBPMYLPGBK-UHFFFAOYSA-N 0.000 description 1
- RFOGHWGGUYDCAI-UHFFFAOYSA-N 7-(4-aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C1CC(N)CCN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1CC1 RFOGHWGGUYDCAI-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
- 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
- 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
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-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
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005907 alkyl ester 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
- 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
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- JFWURCREFDQUTD-UHFFFAOYSA-N ethyl 1,8-naphthyridine-3-carboxylate Chemical compound N1=CC=CC2=CC(C(=O)OCC)=CN=C21 JFWURCREFDQUTD-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
- PIHWQJBFCRABCQ-UHFFFAOYSA-N ethyl 2-oxo-1h-1,8-naphthyridine-3-carboxylate Chemical compound C1=CN=C2NC(=O)C(C(=O)OCC)=CC2=C1 PIHWQJBFCRABCQ-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
- PYZZLFBUPVGEBD-UHFFFAOYSA-N ethyl 6-fluoro-4-oxo-1H-1,8-naphthyridine-3-carboxylate Chemical compound C(C)OC(=O)C1=CNC2=NC=C(C=C2C1=O)F PYZZLFBUPVGEBD-UHFFFAOYSA-N 0.000 description 1
- 208000010824 fish disease Diseases 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 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
- 239000008103 glucose Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000004677 hydrates Chemical class 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
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012442 inert solvent Substances 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- BIRMYAUDHMGEME-UHFFFAOYSA-N n-(azetidin-3-yl)-2,2,2-trifluoroacetamide Chemical compound FC(F)(F)C(=O)NC1CNC1 BIRMYAUDHMGEME-UHFFFAOYSA-N 0.000 description 1
- YLWUSMHZABTZGP-UHFFFAOYSA-N n-piperidin-4-ylacetamide Chemical compound CC(=O)NC1CCNCC1 YLWUSMHZABTZGP-UHFFFAOYSA-N 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
- 239000002504 physiological saline solution Substances 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
- 238000002360 preparation method Methods 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 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
- 125000001424 substituent group Chemical group 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
- 238000005406 washing Methods 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
- Plural Heterocyclic 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およびR2は
同一または異なつて水素原子、アシル基、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１，２または３を意味する。ただし、ｍとｎ
の和が３である場合にはR1，R2の一方はアシル
基である。）
で表わされるピリドンカルボン酸誘導体は、その
エステル、あるいはその塩である。
本発明の化合物の中で好ましい化合物は、式
〔〕において、Ｘがフツ素であり、R1が水素原
子またはメチル基で、R2が水素原子であり、
（ｍ，ｎ）の組み合わせが（１，１），（１，２），
（１，３），（２，２）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、アスパラギン酸、グルタ
ミン酸等のアミノ酸との塩、或いは塩酸、リン酸
等の無機酸との塩、或いは式〔〕の化合物のナ
トリウム、カリウム、亜鉛、銀等の金属塩、或い
は有機塩基との塩である。
本発明の化合物は、また水和物としても存在し
うる。従つて、この様な形のものも当然本発明の
化合物に包含される。
本発明の化合物のうち好ましい化合物を列挙す
れば次の通りである。
・７−（３−アミノ−１−アゼチジニル）−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。
・７−（３−ジメチルアミノ−１−アゼチジニル）
−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。
・７−（３−アミノ−１−ピペリジニル）−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。
・７−（３−メチルアミノ−１−ピペリジニル）−
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。
・７−（４−アミノ−１−ピペリジニル）−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。
・７−（４−メチルアミノ−１−ピペリジニル）−
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。
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
環状アミン誘導体〔〕と置換しうる官能基を意
味する。）
で表わされるカルボン酸またはそのエステル（好
ましくは低級アルキルエステル）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誘導体を反応せし
め、エステル体が得られたときは、これをさらに
加水分解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〔〕またはそのエステル〔〕とを
５〜120分間、通常は20〜60分間混合攪拌するこ
とにより実施できる。原料化合物〔〕の原料化
合物〔〕またはそのエステルに対する使用量は
当量ないしやゝ過剰量である。原料化合物〔〕
またはそのエステルの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、その側鎖の置換基を保護した形
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−ラクタム形抗
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。
原料化合物〔〕またはそのエステルは参考例
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、水和物の形で得られるが、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。
かくして得られる化合物〔〕およびその塩は
いずれも新規化合物であり、極めて優れた抗菌活
性を示すので、抗菌剤として価値のあるものであ
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、食品の保存剤として
も使用することが可能である。
次に本発明の主要化合物の抗菌活性について、
以下にデータを挙げる。
The present invention relates to novel pyridonecarboxylic acid derivatives that exhibit extremely excellent activity. More specifically, the compound of the present invention has the following general formula: (In the formula , However, m and n
When the sum of R 1 and R 2 is 3, one of R 1 and R 2 is an acyl group. The pyridonecarboxylic acid derivative represented by ) is an ester thereof or a salt thereof. Preferred compounds among the compounds of the present invention are those in the formula [], where X is fluorine, R 1 is a hydrogen atom or a methyl group, and R 2 is a hydrogen atom,
The combinations of (m, n) are (1, 1), (1, 2),
It is a compound that is (1,3), (2,2). 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, amino acids such as aspartic acid and glutamic acid, or salts with inorganic acids such as hydrochloric acid and phosphoric acid, or metal salts such as sodium, potassium, zinc and silver of the compound of formula [], Alternatively, it is a salt with an organic base. Compounds of the invention may also exist as hydrates. Therefore, such forms are naturally included in the compounds of the present invention. Preferred compounds among the compounds of the present invention are listed below. -7-(3-amino-1-azetidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.・7-(3-dimethylamino-1-azetidinyl)
-1-cyclopropyl-6-fluoro-1,4-
Dihydro-4-oxo-1,8-naphthyridine-
3-carboxylic acid. -7-(3-amino-1-piperidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.・7-(3-methylamino-1-piperidinyl)-
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid. -7-(4-amino-1-piperidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.・7-(4-methylamino-1-piperidinyl)-
1-Cyclopropyl-6-fluoro-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 means a halogen atom, and Y means a functional group that can be substituted with the aliphatic cyclic amine derivative [ ] described below.) A carboxylic acid represented by or an ester thereof (preferably a lower alkyl ester) and the following general formula (In the formula, R 1 , R 2 , m, and n are the same as above.) When an ester is obtained by reacting the aliphatic cyclic amine derivative represented by the formula, it is produced by further hydrolysis. be able to. 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 compound [] or its ester [] for 5 to 120 minutes, usually 20 to 60 minutes. The amount of the starting compound [] to be used relative to the starting compound [] or its ester is equivalent to or slightly in excess. Raw material compound []
Or depending on the type of functional group of Y in the ester,
As a result of the reaction, acids such as organic acids and hydrochloric acid are produced as by-products, so in such cases it is common to use an acid acceptor. It may also serve as the role of In addition, the raw material compounds used in this reaction []
If possible, the substituent on the side chain may be used in a protected form, and after the reaction is completed, the protecting group may be removed by a conventional method. As protecting groups, those commonly used in the chemistry of β-lactam antibiotics, peptides or nucleic acids are used. The starting compound [] or its ester 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, a free carboxylic acid or free amine, or a hydrate, but these can be converted into the desired form depending on the purpose. Compounds of the invention are produced. The thus obtained compound [ ] and its salts are both new compounds and exhibit extremely excellent antibacterial activity, so they are valuable as antibacterial agents. These compounds can be used not only in human and veterinary medicines, but also as fish disease medicines, agricultural chemicals, and food preservatives. 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、年齢、体重、症状、投与経
路、投与回数等により異なるが、１日当たり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、散剤、シロツプ剤、注射剤が挙げられ
る。これらの製剤は常法に従つて調製される。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、グルコース溶液、輪液剤の注射剤の分野
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
の合成法を更に説明する。
実施例 １
７−（４−アミノ−１−ピペリジニル）−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
ボン酸の塩酸塩の合成
(1) ７−（ｐ−トルイルスルホニル）−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860mg、４−アセチルアミノピペ
リジン1.1g，エタノール40mlの混合物を２時間
加熱還流する。溶媒を留去し、残渣にエタノー
ルとイソプロピルエーテルの混液を加え、析出
する結晶を濾取し、７−（４−アセチルアミノ
−１−ピペリジニル）−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607mgを得る。融点226℃：再結晶溶媒、エタ
ノールとイソプロピルエーテルの混液。
(2) 前項で得たエステル470mgと20％塩酸８mlの
混合物を７時間加熱還流する。溶媒を減圧下濃
縮乾固し、残渣にエタノールを加え、析出する
結晶を濾取し、７−（４−アミノ−１−ピペリ
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−カルボン酸の塩酸塩の360mg
を得る。融点265−269℃（分解）：再結晶溶媒、
水−エーテルの混液。
実施例 ２
７−（３−アミノ−１−アゼチジニル）−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
ボン酸の合成
(1) ７−（ｐ−トルイルスルホニル）−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2g、３−トリフルオロアセチル
アミノアゼチジン1.68g，トリエチルアミン
1.2g、エタノール40mlの混合物を30分間加熱還
流する。溶媒を減圧下に留去し、得られる粗結
晶を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−トリフルオ
ロアセチルアミノ−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1.52gを得る。融
点271−273℃。
(2) 前項で得た化合物1.33g、エタノール１ml、
1N水酸化ナトリウム水溶液15mlの混合物を70
〜80℃で45分間加熱した後、2N酢酸水溶液６
mlを加え、析出する結晶を濾取し、７−（３−
アミノ−１−アゼチジニル）−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915mgを得る。融点273−274℃（分解）。
(3) 前項で得た化合物550mgと水10mlの混合物に
1N塩酸２mlを加え30分間攪拌する。析出する
結晶を濾取し、７−（３−アミノ−１−アゼチ
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−カルボン酸の塩酸塩505mgを
得る。水から再結晶し、約110℃で乾燥する。
融点281−283℃（分解）。
実施例 ３
７−（３−アセチルアミノ−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−カルボン酸の合成
７−（ｐ−トルイルスルホニル）−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
402mg、３−アセチルアミノピロリジン640mg，ア
セトニトリル５mlの混合物を30分間加熱還流す
る。溶媒を留去し、残渣に水を加え、10％塩酸で
酸性にする。析出する結晶を濾取し、結晶をクロ
ロホルム−エタノールから再結晶して、７−（３
−アセチルアミノ−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284mgを得る。融点293−294℃（分解）。
実施例 ４
７−（３−アセチルアミノ−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−カルボン酸の合成
７−（ｐ−トルイルチオ）−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200mg、
３−アセチルアミノピロリジン346mg，Ｎ，Ｎ−
ジメチルホルムアミド２mlの混合物を110〜120℃
で３時間加熱還流する。溶媒を減圧下留去し、残
渣に水を加え、塩酸水溶液で酸性にする。析出す
る結晶を濾取し、結晶をクロロホルム−エタノー
ルから再結晶して、７−（３−アセチルアミノ−
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120mgを得る。
実施例 ５
７−（３−アセチルアミノ−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−カルボン酸の合成
７−（ｐ−トルイルスルホニル）−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
804mg、３−アセチルアミノピロリジン384mg，ト
リエチルアミン202mg、アセトニトリル20mlの混
合物を30分間加熱還流する。減圧下に濃縮乾固
し、残渣に水を加え、酢酸水溶液で酸性にする。
結晶を濾取し、クロロホルム−エタノールから再
結晶して、７−（３−アセチルアミノ−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650mgを得る。融点293
−294℃（分解）。
実施例 ６
７−（３−アセチルアミノ−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−カルボン酸エチルの合成
７−（ｐ−トルイルチオ）−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
と３−アセチルアミノピロリジンを用い、実施例
４と同様に処理して、７−（３−アセチルアミノ
−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。
参考例 １
７−（ｐ−トルイルスルホニル）−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−６
−（ｐ−トルイルチオ）−５−フルオロニコチノ
ニトリル42.2g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時間加熱攪拌する。溶媒を減
圧下に留去し、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。トルエンを減圧留去し、粘稠性液体
の６−（ｐ−トルイルチオ）−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
0.32g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℃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、７−（ｐ−トルイルチオ）−１−シクロプロ
ピル−６−フルオロ−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時間加熱攪拌する。冷後、
析出する結晶を濾取し、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、７−（ｐ−トルイルチオ）−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
ナトリウムで乾燥する。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、７−（ｐ−トルイルスルホニル）−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1.55gを得る。融点216−218℃。
参考例 ２
７−（ｐ−トルイルチオ）−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
の合成
７−（ｐ−トルイルチオ）−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
1gを10N硫酸10mlに溶解し、105〜115℃で１時間
加熱攪拌する。反応混合物を氷水にあけ、析出す
る結晶を濾取し、クロロホルム−エタノールから
再結晶して、７−（ｐ−トルイルチオ）−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530mgを得る。融点224−226℃。
参考例 ３
７−（ｐ−トルイルスルホニル）−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
ボン酸の合成
７−（ｐ−トルイルスルチオ）−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
300mg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時間攪拌
する。溶媒を留去し、残渣にエタノールを加え、
冷後、析出する結晶を濾取する。得られた結晶を
クロロホルムから再結晶して、７−（ｐ−トルイ
ルスルホニル）−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, route of administration, number of administrations, etc., but the dosage is 5 mg per day.
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, glucose solution, and diaphragm. Next, the method for synthesizing the compounds of the present invention will be further explained by giving examples and reference examples. Example 1 Synthesis of hydrochloride of 7-(4-amino-1-piperidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ( 1) 7-(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-
A mixture of 860 mg of ethyl 4-oxo-1,8-naphthyridine-3-carboxylate, 1.1 g of 4-acetylaminopiperidine, and 40 ml of ethanol was heated under reflux for 2 hours. The solvent was distilled off, a mixture of ethanol and isopropyl ether was added to the residue, the precipitated crystals were collected by filtration, and 7-(4-acetylamino-1-piperidinyl)-1-cyclopropyl-
607 mg of ethyl 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are obtained. Melting point 226℃: Recrystallization solvent, a mixture of ethanol and isopropyl ether. (2) A mixture of 470 mg of the ester obtained in the previous section and 8 ml of 20% hydrochloric acid is heated under reflux for 7 hours. The solvent was concentrated to dryness under reduced pressure, ethanol was added to the residue, the precipitated crystals were collected by filtration, and 7-(4-amino-1-piperidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro- 360 mg of 4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride
get. Melting point 265-269℃ (decomposition): recrystallization solvent,
Water-ether mixture. Example 2 Synthesis of 7-(3-amino-1-azetidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1) 7 -(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-
Ethyl 4-oxo-1,8-naphthyridine-3-carboxylate 2g, 3-trifluoroacetylaminoazetidine 1.68g, triethylamine
A mixture of 1.2 g and 40 ml of ethanol is heated to reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the resulting crude crystals were recrystallized from ethanol to give 1-cyclopropyl-6-fluoro-7-(3-trifluoroacetylamino-1-azetidinyl)-1,
1.52 g of ethyl 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are obtained. Melting point 271-273℃. (2) 1.33g of the compound obtained in the previous section, 1ml of ethanol,
A mixture of 15 ml of 1N sodium hydroxide solution
After heating at ~80°C for 45 min, 2N acetic acid aqueous solution 6
ml, the precipitated crystals were collected by filtration, and 7-(3-
Amino-1-azetidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-
915 mg of oxo-1,8-naphthyridine-3-carboxylic acid are obtained. Melting point 273-274°C (decomposition). (3) Add 550 mg of the compound obtained in the previous section to a mixture of 10 ml of water.
Add 2 ml of 1N hydrochloric acid and stir for 30 minutes. The precipitated crystals were collected by filtration, and 7-(3-amino-1-azetidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was collected. Obtain 505 mg of hydrochloride. Recrystallize from water and dry at approximately 110°C.
Melting point 281-283°C (decomposition). Example 3 7-(3-acetylamino-1-pyrrolidinyl)
-1-cyclopropyl-6-fluoro-1,4-
Dihydro-4-oxo-1,8-naphthyridine-
Synthesis of 3-carboxylic acid 7-(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-
Oxo-1,8-naphthyridine-3-carboxylic acid
A mixture of 402 mg of 3-acetylaminopyrrolidine, 640 mg of 3-acetylaminopyrrolidine, and 5 ml of acetonitrile was heated under reflux for 30 minutes. The solvent is distilled off, water is added to the residue, and the mixture is made acidic with 10% hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from chloroform-ethanol to give 7-(3
284 mg of -acetylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. Melting point 293-294°C (decomposition). Example 4 7-(3-acetylamino-1-pyrrolidinyl)
-1-cyclopropyl-6-fluoro-1,4-
Dihydro-4-oxo-1,8-naphthyridine-
Synthesis of 3-carboxylic acid 200 mg of 7-(p-toluylthio)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,
3-acetylaminopyrrolidine 346mg, N,N-
A mixture of 2 ml of dimethylformamide was heated to 110-120°C.
Heat under reflux for 3 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was made acidic with an aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration and recrystallized from chloroform-ethanol to give 7-(3-acetylamino-
1-pyrrolidinyl)-1-cyclopropyl-6-
Fluoro-1,4-dihydro-4-oxo-1,
120 mg of 8-naphthyridine-3-carboxylic acid are obtained. Example 5 7-(3-acetylamino-1-pyrrolidinyl)
-1-cyclopropyl-6-fluoro-1,4-
Dihydro-4-oxo-1,8-naphthyridine-
Synthesis of 3-carboxylic acid 7-(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-
Oxo-1,8-naphthyridine-3-carboxylic acid
A mixture of 804 mg of 3-acetylaminopyrrolidine, 384 mg of triethylamine, 202 mg of triethylamine, and 20 ml of acetonitrile is heated under reflux for 30 minutes. Concentrate to dryness under reduced pressure, add water to the residue, and acidify with aqueous acetic acid.
The crystals were collected by filtration and recrystallized from chloroform-ethanol to give 7-(3-acetylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8 650 mg of -naphthyridine-3-carboxylic acid are obtained. Melting point 293
-294℃ (decomposition). Example 6 7-(3-acetylamino-1-pyrrolidinyl)
-1-cyclopropyl-6-fluoro-1,4-
Dihydro-4-oxo-1,8-naphthyridine-
Synthesis of ethyl 3-carboxylate Ethyl 7-(p-toluylthio)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 3-acetylamino 7-(3-acetylamino-1-pyrrolidinyl)-1-cyclopropyl-6
-Fluoro-1,4-dihydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylate is obtained. Reference example 1 7-(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-
Synthesis of ethyl 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-6
42.2 g of -(p-toluylthio)-5-fluoronicotinonitrile are obtained. Melting point 124-125℃ (2) 36g of this compound was dissolved in 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-toluylthio)nicotinate obtained in 400 ml of dimethylformamide, and add 25.4 g of ethyl N-cyclopropylaminopropionate and carbonate. Add 14 g of sodium hydrogen, and heat and stir at 100 to 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 a viscous liquid of ethyl 6-(p-toluylthio)-2-[N-cyclopropyl-N-(2-ethoxycarbonylethyl)amino]-5-fluoronicotinate.
Get 32g. (5) Dissolve 3.2 g of this compound in 50 ml of dry toluene and add 65% sodium hydride at room temperature.
Add 0.32g 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 7-(p-toluylthio)-1-cyclopropyl-6-fluoro-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 2.0 g of this compound in 50 ml of toluene and add 2,3-dichloro-5,6-dicyano-p
-Add 1.25g of benzoquinone and leave at room temperature for 2 hours.
Then, heat and stir at 50 to 60°C for 1 hour. After cooling,
The precipitated crystals were collected by filtration, 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 7-(p-tolylthio)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-
Obtain 1.7 g of ethyl carboxylate. 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 minutes. After cooling, add 2N sodium carbonate,
Wash sequentially with water, and dry the chloroform layer over anhydrous sodium sulfate. Chloroform was distilled off, and the resulting crude crystals were recrystallized from ethyl acetate to give 7-(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8 1.55 g of ethyl-naphthyridine-3-carboxylate are obtained. Melting point 216-218℃. Reference Example 2 Synthesis of 7-(p-toluylthio)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 7-(p-toluylthio)- Ethyl 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate
Dissolve 1 g in 10 ml of 10N sulfuric acid, and heat and stir at 105-115°C for 1 hour. The reaction mixture was poured into ice water, the precipitated crystals were collected by filtration, and recrystallized from chloroform-ethanol to give 7-(p-tolylthio)-1-cyclopropyl-6-fluoro-1,4-dihydro-
530 mg of 4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. Melting point 224-226℃. Reference example 3 7-(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-
Synthesis of 4-oxo-1,8-naphthyridine-3-carboxylic acid 7-(p-tolylsulthio)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine -3-carboxylic acid
Dissolve 300 mg in 6 ml of methylene chloride, add 350 mg of 80% m-chloroperbenzoic acid, and stir at room temperature for 2 hours. The solvent was distilled off, ethanol was added to the residue,
After cooling, precipitated crystals are collected by filtration. The obtained crystals were recrystallized from chloroform to give 7-(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-
280 mg of naphthyridine-3-carboxylic acid are obtained. Melting point 236-239℃.
Claims (1)
同一または異なつて水素原子、アシル基、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１，２または３を意味する。ただし、ｍとｎ
の和が３である場合にはR1，R2の一方はアシル
基である。） で表わされるピリドンカルボン酸誘導体、そのエ
ステル、あるいはその塩。[Claims] 1. General formula (In the formula , However, m and n
When the sum of R 1 and R 2 is 3, one of R 1 and R 2 is an acyl group. ) A pyridonecarboxylic acid derivative, its ester, or its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58197743A JPS6089480A (en) | 1983-10-21 | 1983-10-21 | Pyridonecarboxylic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58197743A JPS6089480A (en) | 1983-10-21 | 1983-10-21 | Pyridonecarboxylic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6089480A JPS6089480A (en) | 1985-05-20 |
| JPH0450313B2 true JPH0450313B2 (en) | 1992-08-13 |
Family
ID=16379601
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58197743A Granted JPS6089480A (en) | 1983-10-21 | 1983-10-21 | Pyridonecarboxylic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6089480A (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4665079A (en) * | 1984-02-17 | 1987-05-12 | Warner-Lambert Company | Antibacterial agents |
| JPS60172981A (en) * | 1984-02-17 | 1985-09-06 | Dai Ichi Seiyaku Co Ltd | 1,8-naphthyridine derivative |
| 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 |
| US5039683A (en) * | 1987-10-26 | 1991-08-13 | Pfizer Inc. | Azetidinyl quinolone carboxylic acids and esters |
| 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 |
| FR2649106A2 (en) * | 1989-06-29 | 1991-01-04 | Esteve Labor Dr | Derivatives of azetidinyl-substituted pyridonecarboxylic acids, 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 |
| FR2692577B1 (en) * | 1992-05-26 | 1996-02-02 | Bouchara Sa | NOVEL FLUORINATED QUINOLONES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| JPS57142983A (en) * | 1981-02-27 | 1982-09-03 | Dainippon Pharmaceut Co Ltd | 1-vinyl-1,8-naphthyridine derivative and its salt |
| JPS57146775A (en) * | 1981-03-06 | 1982-09-10 | Dainippon Pharmaceut Co Ltd | 1,8-naphthyridine derivative and its salt |
| JPS58138000A (en) * | 1982-02-09 | 1983-08-16 | 日新ハイボルテ−ジ株式会社 | Charged particle accelerator |
-
1983
- 1983-10-21 JP JP58197743A patent/JPS6089480A/en active Granted
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| JPS57142983A (en) * | 1981-02-27 | 1982-09-03 | Dainippon Pharmaceut Co Ltd | 1-vinyl-1,8-naphthyridine derivative and its salt |
| JPS57146775A (en) * | 1981-03-06 | 1982-09-10 | Dainippon Pharmaceut Co Ltd | 1,8-naphthyridine derivative and its salt |
| JPS58138000A (en) * | 1982-02-09 | 1983-08-16 | 日新ハイボルテ−ジ株式会社 | Charged particle accelerator |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6089480A (en) | 1985-05-20 |
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