JPH0373549B2 - - Google Patents
Info
- Publication number
- JPH0373549B2 JPH0373549B2 JP58141706A JP14170683A JPH0373549B2 JP H0373549 B2 JPH0373549 B2 JP H0373549B2 JP 58141706 A JP58141706 A JP 58141706A JP 14170683 A JP14170683 A JP 14170683A JP H0373549 B2 JPH0373549 B2 JP H0373549B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- ethyl
- naphthyridine
- cyclopropyl
- ester
- 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 15
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 150000005058 1,8-naphthyridines Chemical class 0.000 claims description 2
- SKYHBWSFRMRRRT-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,8-naphthyridine-3-carboxylic acid Chemical compound C12=NC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 SKYHBWSFRMRRRT-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 56
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
- -1 pivaloyloxymethyl ester Chemical class 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000012046 mixed solvent Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000007796 conventional method Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000003197 catalytic effect Effects 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
- WLHCBQAPPJAULW-UHFFFAOYSA-N 4-methylbenzenethiol Chemical compound CC1=CC=C(S)C=C1 WLHCBQAPPJAULW-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
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- HULIOAYHEJWNGC-UHFFFAOYSA-N ethyl 2-(cyclopropylamino)propanoate Chemical compound CCOC(=O)C(C)NC1CC1 HULIOAYHEJWNGC-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- JMQOZRUNHQMKJK-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C1CN(C)CCN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1CC1 JMQOZRUNHQMKJK-UHFFFAOYSA-N 0.000 description 1
- PKDPUENCROCRCH-UHFFFAOYSA-N 1-piperazin-1-ylethanone Chemical compound CC(=O)N1CCNCC1 PKDPUENCROCRCH-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
- DNXUGBMARDFRGG-UHFFFAOYSA-N 3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile Chemical compound O=C1C=CC(=O)C(C#N)=C1C#N DNXUGBMARDFRGG-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
- LQJWCPZRNHAVJD-UHFFFAOYSA-N 5-fluoropyridine-3-carbonitrile Chemical compound FC1=CN=CC(C#N)=C1 LQJWCPZRNHAVJD-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
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-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 compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-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
- 239000002253 acid Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001298 alcohols 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
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 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
- 230000015572 biosynthetic process Effects 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
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- HUXUGTGLQIHTHX-UHFFFAOYSA-N ethyl 1-cyclopropyl-6-fluoro-7-(4-methylphenyl)sulfonyl-4-oxo-1,8-naphthyridine-3-carboxylate Chemical compound C12=NC(S(=O)(=O)C=3C=CC(C)=CC=3)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 HUXUGTGLQIHTHX-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
- 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
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 208000010824 fish disease Diseases 0.000 description 1
- 239000005452 food preservative Substances 0.000 description 1
- 235000019249 food preservative Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000005843 halogen group Chemical group 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
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 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
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 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
- 150000004702 methyl esters Chemical class 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
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 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
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- NLDYACGHTUPAQU-UHFFFAOYSA-N tetracyanoethylene Chemical group N#CC(C#N)=C(C#N)C#N NLDYACGHTUPAQU-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Description
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The present invention discloses novel 1, which exhibits extremely excellent antibacterial activity.
8-Naphthyridine derivatives. More specifically, the compound of the present invention has the following general formula: (R in the formula means a hydrogen atom or a lower alkyl group.) A 1,8-naphthyridine derivative, an ester thereof, or a salt thereof. Among the compounds of the present invention, preferred compounds are those in which R in formula [] is a hydrogen atom or a methyl group, and particularly preferred are compounds in which R is a hydrogen atom. 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 inorganic acids such as hydrochloric acid and phosphoric acid, or metal salts such as sodium, potassium, zinc and silver of the compound of formula [], or organic bases. It is salt. The ester of the compound of formula [] is a lower alkyl ester such as methyl ester or ethyl ester of the compound [], or a known ester that is easily eliminated by hydrolysis or in vivo to form the compound []. Esters such as pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, 5-indanyl ester, phthalidyl ester, etc. are meant. Compounds of the invention may also exist as hydrates. Therefore, such forms are naturally included in the compounds of the present invention. Next, the method for producing the compound of the present invention will be explained below. (1) The compound of the present invention has the following general formula: (In the formula, X means a functional group that can be substituted with the piperazine [ ] 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 is the same as above.) It can be produced by reacting piperazines represented by the following and isolating the product by a conventional method. The reactive functional group represented by X in formula [] is
Arylsulfonyl, lower alkylsulfonyl,
Examples include halogen atom, lower alkoxy, lower alkylthio, lower alkylsulfinyl, arylsulfonyloxy, and lower alkylsulfonyloxy. In this reaction, the raw material compound [] or its ester and [] are mixed in an inert solvent such as ethanol, acetonitrile, dioxane, dimethylformamide, toluene, or xylene at 20 to 180°C, preferably 50 to 150°C. 120 minutes, usually
This can be carried out by mixing and stirring for 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. Depending on the type of functional group of Compound [] may be used in excess to serve as an acid acceptor. Furthermore, when piperazine is used as a starting compound, one of its N atoms may be protected with acetyl, benzyloxycarbonyl, etc., and the protecting group may be removed by a conventional method after the reaction is completed. The raw material compound [] or its ester can be produced by the method described in Reference Example 1 or a method analogous thereto. (2) The ester form of the compound [] of the present invention can also be expressed by the following general formula: (In the formula, Y is the same or different and means a lower alkyl group, and R is the same as above.) The pyridine derivative represented by formula (In the formula, R and Y are the same as above.) It can be produced by producing a compound represented by the following and then dehydrogenating this compound []. When producing the compound [], the starting compound [] is subjected to a heating reaction in a solvent in the presence of a base catalyst such as sodium metal, sodium hydride, sodium ethylate, potassium t-butylate,
Compound [ ] is obtained by intramolecular ring closure. At this time, the reaction can be more effectively achieved by adding a catalytic amount of lower alcohols such as methanol, ethanol, and t-butanol. benzene,
Aromatic hydrocarbons such as toluene, dioxane, tetrahydrofuran, 1,2-dimethoxyethane,
Ethers such as diethylene glycol dimethyl ether are suitable as reaction solvents. The heating temperature is not particularly limited, but a temperature of 60 to 180°C is usually preferred. Note that the compound [ ] is also represented by the following general formula. (R and Y in the formula are the same as above.) To dehydrogenate compound [], compound []
2,3-dichloro-5,6-dicyano-1,4-benzoquinone ( DDQ), tetrachloro-1,4-benzoquinone (chloranil), tetracyanoethylene, palladium-on-carbon, N-bromosuccinimide (NBS), manganese dioxide or gelene dioxide at room temperature or at room temperature. The reaction may be carried out by heating for a short time near the boiling point of the solvent, or the compound [] may be directly heated above its melting point, or benzene, toluene,
Simply heating in an inert solvent such as dioxane, ethanol, n-hexane, carbon tetrachloride, dimethylformamide, or diphenyl ether is sufficient. The raw material compound [] used in this reaction is used in a form in which the N atom at position 4 of the piperazine moiety is protected with acetyl, benzyloxycarbonyl, etc., as in the case of method (1) above, and after the completion of this reaction, The protecting group may be removed by conventional methods. The raw material compound [] can be produced by the method described in Reference Example 2 or a method similar thereto. Incidentally, the compound (ester form) obtained by the above method can be converted into a compound of formula [] by hydrolyzing the ester moiety by a conventional method. Furthermore, if necessary, the compound of formula [] can be esterified by a conventional method to lead to an ester of the compound of formula []. 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 compounds of the present invention can be obtained in the form of salts, free carboxylic acids, or free amino acids, but these can be mutually converted depending on the purpose to produce the compound of the present invention in the desired form. Ru. The compound thus obtained, its ester, and its salt are all new compounds. In particular, compounds [], especially compounds in which R is a hydrogen atom, exhibit extremely excellent antibacterial activity even in living organisms and are weakly toxic, so they are valuable as antibacterial agents. The compound [] can be used not only as a medicine for humans and animals, but also as a medicine for fish diseases, an agricultural chemical, a food preservative, etc. Also,
Of course, the ester form of compound [] is valuable as a raw material for the synthesis of compound [], but in addition, this compound can easily be converted into compound [] in vivo.
When converted into , it can exhibit the same effects as compound [ ], so it is a useful compound from a pharmaceutical standpoint. Next, regarding the antibacterial activity of the main compounds of the present invention,
The following data is listed.
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ãã«4.05ïœãåŸãã[Table] When the compound of the present invention is used as an antibacterial agent in humans, the dosage varies depending on age, body weight, symptoms, administration route, number of administrations, etc.
It is recommended to administer 5g in one or several divided doses. The route of administration may be either oral or parenteral. Although the compound of the present invention may be administered as a bulk powder, it is usually administered in a prepared form together with a pharmaceutical carrier. Specific examples include tablets, capsules, granules,
Examples include fine granules, powders, syrups, and injections. These formulations are prepared according to conventional methods. Oral preparation carriers include starch, mannitrate,
Substances commonly used in the pharmaceutical field, such as crystalline cellulose and CMC Na, and which do not react with the compound of the present invention are used. Examples of the carrier for injection include carriers commonly used in the field of injections such as water, physiological saline, glycol solution, and infusion preparations. Next, the method for synthesizing the compound of the present invention will be explained in more detail by giving examples and reference examples. Example 1 1-Cyclopropyl-6-fluoro-7-(1
-Piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid synthesis method (1) 1-cyclopropyl-7-(p-tolylsulfonyl)-6-fluoro-1, A mixture of 860 mg of ethyl 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, 516 mg of anhydrous piperazine and 30 ml of acetonitrile is heated under reflux for 1 hour. The solvent was distilled off under reduced pressure to obtain an oily product of 1-cyclopropyl-6-fluoro-
7-(1-piperazinyl)-1,4-dihydro-
Ethyl 4-oxo-1,8-naphthyridine-3-carboxylate was dissolved in 10 ml of 20% hydrochloric acid and heated under reflux for 3 hours. The solvent was distilled off under reduced pressure, ethanol was added to the residue, and the resulting crude crystals were recrystallized from a mixed solvent of water and ethanol to give 1-cyclopropyl-6-fluoro-7-(1-piperazinyl)-1, 4-dihydro-4-oxo-1,8
-naphthyridine-3-carboxylic acid hydrochloride 604
Get mg. mp280-294â (decomposition) (2) Ethyl 1-cyclopropyl-7-(p-tolylsulfonyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 860 mg A mixture of 768 mg of 1-acetylpiperazine, 606 mg of triethylamine and 20 ml of dimethylformamide is heated and stirred at 120-130°C for 3 hours. The solvent was distilled off under reduced pressure, and the resulting crude crystals were recrystallized from a mixed solvent of ethanol and isopropyl ether.
683 mg of ethyl (4-acetyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are obtained. 480mg of this stuff
and 8 ml of 20% hydrochloric acid was heated under reflux for 7 hours. The solvent was distilled off under reduced pressure, ethanol was added to the residue, and after cooling, the obtained crystals were recrystallized from a mixed solvent of water and ethanol to obtain 1-cyclopropyl-6.
-fluoro-7-(1-piperazinyl)-1,4
300 mg of hydrochloride of -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. m.
p.280-294â (decomposition) Example 2 1-cyclopropyl-7-(p-tolylsulfonyl)-6-fluoro-1,4-dihydro-4
A mixture of 860 mg of ethyl -oxo-1,8-naphthyridine-3-carboxylate, 600 mg of 1-methylpiperazine, and 30 ml of acetonitrile is heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, and the resulting crude crystals were recrystallized from a mixed solvent of ethyl acetate and isopropyl ether to give 1-cyclopropyl-
7-(4-methyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-
Ethyl naphthyridine-3-carboxylate is obtained. Suspend this in 10ml of 1N sodium hydroxide,
Heat for 1.5 hours on a boiling water bath. After cooling, neutralize with 10% acetic acid solution and extract with chloroform. After drying the chloroform layer over anhydrous sodium sulfate, the chloroform was distilled off, and the resulting crystals were recrystallized from a mixed solvent of chloroform and ethanol to give 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6-fluoro- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
You get 519mg. mp246-248â Reference Example 1 7- used as the starting material in Examples 1 and 2
Synthesis method of ethyl (p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (1) Known compound 2,6-dichloro -32.5g of 5-fluoronicotinonitrile, 400ml of ethanol
In the medium, 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, mp124-125â.
2-chloro-6-(p-toluylthio)-5-
42.4 g of fluoronicotinonitrile are obtained. (2) Add 36g of this compound to dry dimethyl sulfoxide.
Dissolve in 180 ml, add 22.2 g of anhydrous potassium fluoride, and heat and stir at 130-135°C for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the resulting crude crystals were recrystallized from ethanol.
30 g of 2,5-difluoro-6-(p-tolylthio)nicotinonitrile at 121°C are obtained. (3) 4 g of this compound was reacted with dry hydrogen chloride in absolute ethanol, and 2,5-difluoro-6-
3 g of ethyl (p-toluylthio)nicotinate is obtained. (4) Repeat the above reaction, dissolve 25 g of ethyl 2,5-difluoro-6-(p-tolylthio)nicotinate obtained in 400 ml of dimethylformamide, and add 25.4 g of ethyl N-cyclopropylaminopropionate and carbonate. 14g sodium hydrogen
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 32 g of ethyl 6-(p-toluylthio)-2-[N-cyclopropyl-N-(2-ethoxycarbonylethyl)amino]-5-fluoronicotinate as a viscous liquid. . (5) Dissolve 3.2 g of this compound in 50 ml of dry toluene and add 0.32 g of 65% sodium hydride at room temperature.
g and stir the mixture for 10 minutes. Add a catalytic amount of absolute ethanol and stir for an additional 2 hours. After heating at 50 to 60°C for 1 hour, water is added and neutralized with a 10% acetic acid aqueous solution. The organic layer is separated, dried over anhydrous sodium sulfate, and then toluene is distilled off under reduced pressure. The resulting crude crystals were recrystallized from a mixed solvent of n-hexane and isopropyl ether to give 7-(p-toluylthio)-1-cyclopropyl-6-fluoro-1,
2,3,4-tetrahydro-4-oxo-1,
Ethyl 8-naphthyridine-3-carboxylate 2.5
get g. (6) Dissolve 2.0g of this compound in 50ml of toluene,
Add 1.25 g of 2,3-dichloro-5-,6-dicyano-p-benzoquinone to this, and
Then, heat and stir at 50-60°C for 1 hour.
After cooling, the precipitated crystals are collected by filtration, dissolved in chloroform, washed successively with 1N sodium hydroxide and water, and the chloroform layer is dried over anhydrous sodium sulfate. Chloroform was distilled off, and the resulting crude crystals were recrystallized from a mixed solvent of ethanol and isopropyl ether to give 7-(p
-toluylthio)-1-cyclopropyl-6-
Fluoro-1,4-dihydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylate
Obtain 1.7g. (7) Dissolve 1.59 g of this compound and 1.90 g of m-chloroperbenzoic acid (80%) in 50 ml of chloroform,
Heat at reflux for 30 minutes. After cooling, add 2N sodium carbonate,
Wash sequentially with 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 7-(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4- at mp216-218°C. 1.55 g of ethyl oxo-1,8-naphthyridine-3-carboxylate are obtained. Example 3 6-(4-acetyl-1-piperazinyl)-2-
4.5 g of ethyl [N-cyclopropyl-N-(2-ethoxycarbonylethyl)amino]-5-fluoronicotinate was dissolved in 100 ml of dry toluene, and 406 mg of 65% sodium hydroxide was added at room temperature.
Stir the mixture for 10 minutes. Add a catalytic amount of absolute ethanol and stir for an additional 2 hours. After cooling, add water and neutralize with 10% acetic acid aqueous solution. The organic layer is dispersed and dried over anhydrous sodium sulfate. 7 obtained
Isolating ethyl -(4-acetyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-1,2,3,4-tetrahydro-4-oxo-1,8-naphthyridine-3-carboxylate. 2,3-dichloro-5-,6-
Add 2.27 g of dicyano-p-benzoquinone, and heat and stir at room temperature for 2 hours, then at 50-60°C for 30 minutes. After cooling, the crystals that can be precipitated are collected by filtration, dissolved in chloroform, washed successively with 1N sodium hydroxide and water, and the chloroform layer is dried over anhydrous sodium sulfate. Chloroform was distilled off, and the resulting crude crystals were recrystallized from a mixed solvent of ethanol and isopropyl ether to give 7-(4-acetyl-1-piperazinyl)-1-cyclopropyl-
6-Fluoro-1,4-dihydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylate
Obtain 3.3g. This product was prepared in the same manner as in Example 1 (2).
% hydrochloric acid, isolated and purified to give 1-cyclopropyl-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-
Naphthyridine-3-carboxylic hydrochloride is obtained. Reference example 2 6- described in Japanese Patent Application Publication No. 1983-72981
6.6 g of ethyl (4-acetyl-1-piperazinyl)-2-chloro-5-fluoronicotinate and 18.84 g of ethyl 2-cyclopropylaminopropionate.
The mixture is heated and stirred at 130-140°C for 4 hours. Dilute with 200 ml of toluene, wash sequentially with 5% hydrochloric acid and water, and separate the organic layer. After drying the organic layer over anhydrous sodium sulfate, the toluene was distilled off and the viscous liquid
-(4-acetyl-1-piperazinyl)-2-[N
4.05 g of ethyl -cyclopropyl-N-(2-ethoxycarbonylethyl)amino]-5-fluoronicotinate is obtained.
Claims (1)
æå³ãããïŒ ã§è¡šããããïŒïŒïŒâããããªãžã³èªå°äœãŸãã¯
ãã®ãšã¹ãã«ãŸãã¯ãã®å¡©ã ïŒ ç¹èš±è«æ±ã®ç¯å²ç¬¬ïŒé èšèŒã®ïŒâïŒïŒâãã
ã©ãžãã«ïŒâïŒâã·ã¯ããããã«âïŒâãã«ãªã
âïŒïŒïŒâãžãããâïŒâãªããœâïŒïŒïŒâãã
ããªãžã³âïŒâã«ã«ãã³é žãŸãã¯ãã®å¡©ã[Claims] 1. General formula (R in the formula means a hydrogen atom or a lower alkyl group.) A 1,8-naphthyridine derivative, an ester thereof, or a salt thereof. 2 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid or a salt thereof according to claim 1 .
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP58141706A JPS6032790A (en) | 1983-08-01 | 1983-08-01 | 1,8-naphthyridines |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP58141706A JPS6032790A (en) | 1983-08-01 | 1983-08-01 | 1,8-naphthyridines |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS6032790A JPS6032790A (en) | 1985-02-19 |
JPH0373549B2 true JPH0373549B2 (en) | 1991-11-22 |
Family
ID=15298302
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP58141706A Granted JPS6032790A (en) | 1983-08-01 | 1983-08-01 | 1,8-naphthyridines |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS6032790A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3508816A1 (en) * | 1985-01-10 | 1986-07-10 | Bayer Ag, 5090 Leverkusen | 6,7-DISUBSTITUTED 1-CYCLOPROPYL-1,4-DIHYDRO-4-OXO-1,8-NAPHTYRIDINE-3-CARBONIC ACIDS |
Citations (4)
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 |
JPS5583785A (en) * | 1978-12-20 | 1980-06-24 | Dainippon Pharmaceut Co Ltd | 6-fluoro-1,8-naphthyridine 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 |
JPS57106681A (en) * | 1980-12-24 | 1982-07-02 | Dainippon Pharmaceut Co Ltd | 1,8-naphthyridine derivative and its salt |
-
1983
- 1983-08-01 JP JP58141706A patent/JPS6032790A/en active Granted
Patent Citations (4)
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 |
JPS5583785A (en) * | 1978-12-20 | 1980-06-24 | Dainippon Pharmaceut Co Ltd | 6-fluoro-1,8-naphthyridine 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 |
JPS57106681A (en) * | 1980-12-24 | 1982-07-02 | Dainippon Pharmaceut Co Ltd | 1,8-naphthyridine derivative and its salt |
Also Published As
Publication number | Publication date |
---|---|
JPS6032790A (en) | 1985-02-19 |
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