JPS6256151B2 - - Google Patents
Info
- Publication number
- JPS6256151B2 JPS6256151B2 JP17127183A JP17127183A JPS6256151B2 JP S6256151 B2 JPS6256151 B2 JP S6256151B2 JP 17127183 A JP17127183 A JP 17127183A JP 17127183 A JP17127183 A JP 17127183A JP S6256151 B2 JPS6256151 B2 JP S6256151B2
- Authority
- JP
- Japan
- Prior art keywords
- oxo
- dihydroquinoline
- carboxylic acid
- mixture
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- DTYLXDLAOLOTKT-UHFFFAOYSA-N 1,4-dihydroquinoline-3-carboxylic acid Chemical class C1=CC=C2CC(C(=O)O)=CNC2=C1 DTYLXDLAOLOTKT-UHFFFAOYSA-N 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 150000001875 compounds Chemical class 0.000 description 37
- 239000000203 mixture Substances 0.000 description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 31
- 239000002904 solvent Substances 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 238000002844 melting Methods 0.000 description 25
- 230000008018 melting Effects 0.000 description 25
- 238000000921 elemental analysis Methods 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 23
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- 239000002244 precipitate Substances 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000013078 crystal Substances 0.000 description 18
- -1 phosphoric acid Chemical class 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 238000010992 reflux Methods 0.000 description 17
- 238000001914 filtration Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- ILNJBIQQAIIMEY-UHFFFAOYSA-N 4-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CN=C21 ILNJBIQQAIIMEY-UHFFFAOYSA-N 0.000 description 10
- 241000700159 Rattus Species 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 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
- 239000000463 material Substances 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- NZAUVXCUULSKDI-UHFFFAOYSA-N 2,3,4-trifluoro-n-propan-2-ylaniline Chemical compound CC(C)NC1=CC=C(F)C(F)=C1F NZAUVXCUULSKDI-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000588722 Escherichia Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 231100000111 LD50 Toxicity 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 2
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- YBEOYBKKSWUSBR-UHFFFAOYSA-N ethyl 4-oxo-1h-quinoline-3-carboxylate Chemical compound C1=CC=C2C(=O)C(C(=O)OCC)=CNC2=C1 YBEOYBKKSWUSBR-UHFFFAOYSA-N 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 230000027939 micturition Effects 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 150000004885 piperazines Chemical class 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 2
- OPELDSFLVQSDPM-UHFFFAOYSA-N 1,2,5-trifluoro-4-oxoquinoline-3-carboxylic acid Chemical compound FC1=C2C(C(=C(N(C2=CC=C1)F)F)C(=O)O)=O OPELDSFLVQSDPM-UHFFFAOYSA-N 0.000 description 1
- ARHYWWAJZDAYDJ-UHFFFAOYSA-N 1,2-dimethylpiperazine Chemical compound CC1CNCCN1C ARHYWWAJZDAYDJ-UHFFFAOYSA-N 0.000 description 1
- XJDDLMJULQGRLU-UHFFFAOYSA-N 1,3-dioxane-4,6-dione Chemical compound O=C1CC(=O)OCO1 XJDDLMJULQGRLU-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YHRXPOLYCUTZAM-UHFFFAOYSA-N 1-ethyl-6,8-difluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 YHRXPOLYCUTZAM-UHFFFAOYSA-N 0.000 description 1
- PXZDLINBBKAIPK-UHFFFAOYSA-N 1-ethyl-6-fluoro-7-(3-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 PXZDLINBBKAIPK-UHFFFAOYSA-N 0.000 description 1
- DPVAPRQGOBTQFA-UHFFFAOYSA-N 1-ethyl-7-(4-ethyl-3-methylpiperazin-1-yl)-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1C(C)N(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2CC DPVAPRQGOBTQFA-UHFFFAOYSA-N 0.000 description 1
- WRDGNXCXTDDYBZ-UHFFFAOYSA-N 2,3,4-trifluoroaniline Chemical compound NC1=CC=C(F)C(F)=C1F WRDGNXCXTDDYBZ-UHFFFAOYSA-N 0.000 description 1
- WWYFHDNQGVTJJJ-UHFFFAOYSA-N 2-cyclohexylpiperazine Chemical compound C1CCCCC1C1NCCNC1 WWYFHDNQGVTJJJ-UHFFFAOYSA-N 0.000 description 1
- DXOHZOPKNFZZAD-UHFFFAOYSA-N 2-ethylpiperazine Chemical compound CCC1CNCCN1 DXOHZOPKNFZZAD-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- JSGVZVOGOQILFM-UHFFFAOYSA-N 3-methoxy-1-butanol Chemical compound COC(C)CCO JSGVZVOGOQILFM-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- MJZVWVHWFGBYPM-UHFFFAOYSA-N 6,8-difluoro-1-methyl-7-(3-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C1CNC(C)CN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C)C2=C1F MJZVWVHWFGBYPM-UHFFFAOYSA-N 0.000 description 1
- AZDZRTMODXHCJO-UHFFFAOYSA-N 6,8-difluoro-7-(3-methylpiperazin-1-yl)-4-oxo-1-propan-2-ylquinoline-3-carboxylic acid Chemical compound FC1=C2N(C(C)C)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 AZDZRTMODXHCJO-UHFFFAOYSA-N 0.000 description 1
- KCEJQAATYWQMMQ-UHFFFAOYSA-N 6-fluoro-4-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=C(F)C=C2C(=O)C(C(=O)O)=CNC2=C1 KCEJQAATYWQMMQ-UHFFFAOYSA-N 0.000 description 1
- ZCYKSNZFXQZOLV-UHFFFAOYSA-N 7-(3,4-dimethylpiperazin-1-yl)-1-ethyl-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)C(C)C1 ZCYKSNZFXQZOLV-UHFFFAOYSA-N 0.000 description 1
- TXNIGKVRKAHETQ-UHFFFAOYSA-N 7-(3,4-dimethylpiperazin-1-yl)-1-ethyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)C(C)C1 TXNIGKVRKAHETQ-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- AUNMIRGSKUNPAQ-UHFFFAOYSA-N CCCN1C=C(C(=O)C2=CC(=C(C=C21)N3CCNC(C3)C)F)C(=O)O Chemical compound CCCN1C=C(C(=O)C2=CC(=C(C=C21)N3CCNC(C3)C)F)C(=O)O AUNMIRGSKUNPAQ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-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
- 241001465754 Metazoa Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- WVHBHPATSLQXGC-UHFFFAOYSA-N benzene;ethanol Chemical compound CCO.C1=CC=CC=C1 WVHBHPATSLQXGC-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- LNNAIKLYSCYPOG-UHFFFAOYSA-N ethyl 1-ethyl-6,8-difluoro-7-(3-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=CN(CC)C2=C(F)C=1N1CCNC(C)C1 LNNAIKLYSCYPOG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000019233 fast yellow AB Nutrition 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 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
- 239000005457 ice water Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910001389 inorganic alkali salt Inorganic materials 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 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
- 238000005259 measurement Methods 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 description 1
- 229960001732 pipemidic acid Drugs 0.000 description 1
- BRYCUMKDWMEGMK-UHFFFAOYSA-N piperazine-2-carboxamide Chemical compound NC(=O)C1CNCCN1 BRYCUMKDWMEGMK-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は新規な７−ピペラジン置換−６−フル
オロ−４−オキソ−１・４−ジヒドロキノリン−
３−カルボン酸誘導体、及びその薬理学的に許容
しうる塩に関するものである。
更に詳しく言えば、本発明は一般式（）
（式中、R1は炭素数１〜４の低級アルキル基を、
R2はアミノカルボニル基、カルボキシル基、又
は炭素数１〜４の低級アルキル基もしくは炭素数
５〜７のシクロアルキル基を、R3は水素原子又
は炭素数１〜４の低級アルキル基を、R4は水素
原子又はフツ素原子を表す。）で示される新規な
７−ピペラジン置換−６−フルオロ−４−オキソ
−１・４−ジヒドロキノリン−３−カルボン酸誘
導体、及びその薬理学的に許容しうる塩に関する
ものである。
本発明の前記一般式（）中、R1、R2及びR3
で示される低級アルキル基としては、メチル基、
エチル基、プロピル基、イソプロピル基、ブチル
基、イソブチル基、tert−ブチル基等が、又、R2
で示されるシクロアルキル基としては、シクロペ
ンチル基、シクロヘキシル基、シクロヘプチル基
が挙げられる。
前記一般式（）で示される化合物の薬理学的
に許容しうる塩としては、酸付加塩又はアルカリ
付加塩が挙げられ、酸付加塩としては、例えば、
塩酸、硫酸、硝酸、臭化水素酸、ヨウ化水素酸、
燐酸等の鉱酸塩、あるいは酢酸、マレイン酸、フ
マール酸、クエン酸、酒石酸等の有機酸塩が、ア
ルカリ付加塩としては、例えば、ナトリウム、カ
リウム、カルシウム、アンモニウム塩等の無機ア
ルカリ塩、あるいはエタノールアミン、Ｎ・Ｎ−
ジアルキルエタノールアミン等の有機塩基の塩等
が挙げられる。
本発明の前記一般式（）で示される新規な７
−ピペラジン置換−６−フルオロ−４−オキソ−
１・４−ジヒドロキノリン−３−カルボン酸誘導
体は、種々の方法により製造することができる。
本発明に係わる化合物の製造方法の第一の様式
によれば、前記一般式（）で示される化合物
は、次の一般式（）
（式中、R1及びR4は前述と同意義を表し、Ｘは塩
素原子又はフツ素原子を表す。）
で示される７−ハロゲノ−６−フルオロ−４−オ
キソ−１・４−ジヒドロキノリン−３−カルボン
酸誘導体と、次の一般式（）
（式中、R2及びR3は前述と同意義を表す。）
で示されるピペラジン誘導体とを、無溶媒下ある
いは溶媒の存在下において反応させることにより
製造することができる。
本反応において使用される溶媒としては、例え
ば、水、ブタノール、３−メトキシブタノール、
イソアミルアルコール等のアルコール類、エチレ
ングリコールジメチルエーテル（モノグライ
ム）、ジエチレングリコールジメチルエーテル
（ジグライム）、トリエチレングリコールジメチル
エーテル（トリグライム）等のエーテル類、ジメ
チルホルムアミド、ジメチルスルホキシド、ヘキ
サメチルフオスフオリツクトリアミド等の非プロ
トン性極性溶媒、ベンゼン、トルエン等の芳香族
炭化水素系溶媒、あるいは、ピリジン、ピコリ
ン、ルチジン、コリジン、トリエチルアミン等の
有機塩基が挙げられる。
また、反応は室温から200゜の範囲で行われ、
好ましくは100〜180゜の範囲で適宜選択される。
本発明の製造方法において出発原料として用い
られる前記一般式（）で示される７−ハロゲノ
−６−フルオロ−４−オキソ−１・４−ジヒドロ
キノリン−３−カルボン酸誘導体は、例えば、特
開昭53−141286号、特開昭55−47658号、特開昭
56−30964号等に既に開示されている公知の物質
である。
又、前記一般式（）で示されるピペラジン誘
導体は、一部を除き公知の物質であり、例えば、
米国特許第2780625号、南アフリカ特許6807552号
等で既に開示されている。尚、前記一般式（）
中、新規な物質については、その製造法を参考例
として記載した。
本発明に係わる化合物の製造方法の第二の様式
によれば、前記一般式（）で示される化合物
は、前記一般式（）中R3が水素原子である次
の一般式（）
（式中、R1、R2及びR4は前述と同意義を表す。）
で示される７−ピペラジン置換−６−フルオロ−
４−オキソ−１・４−ジヒドロキノリン−３−カ
ルボン酸誘導体と、次の一般式（）
（式中、R5は水素原子又は炭素数１〜３の低級ア
ルキル基を表す。）
で示されるカルボニル化合物とを、ギ酸の存在下
で反応させることにより製造することができる。
本発明の方法において使用される前記一般式
（）で示されるカルボニル化合物としては、ホ
ルムアルデヒド、アセトアルデヒド、プロピオン
アルデヒド等が挙げられ、ホルムアルデヒドはホ
ルムアルデヒド水溶液（ホルマリン）として使用
することが好ましく、又アセトアルデヒド及びプ
ロピオンアルデヒドを使用する時は、ニトロベン
ゼンを溶媒として用いることが好ましい。
又、反応は100〜200゜の温度範囲で行われる
が、好ましくは反応系の還流温度下において行わ
れる。
本発明に係わる化合物の製造方法の第三の様式
によれば、前記一般式（）で示される化合物
は、前記一般式（）で示される７−ピペラジン
置換−６−フルオロ−４−オキソ−１・４−ジヒ
ドロキノリン−３−カルボン酸誘導体と、次の一
般式（）
R3−Ａ （）
（式中、R3は前述と同意義を、Ａはハロゲン原子
を表す。）
で示されるハロゲン化アルキルとを、溶媒中、脱
酸剤としての塩基の存在下、又は非存在下で反応
させることにより製造することができる。
本発明の方法において使用される溶媒として
は、反応を阻害しない限りいかなるものでもよ
く、例えば、アセトン、エタノール、エーテル、
テトラヒドロフラン、ジメチルホルムアミド、ジ
オキサン、ベンゼン、トルエン、クロロホルム等
が挙げられる。
本発明の方法において使用される脱酸剤として
の塩基としては、例えば、トリエチルアミン、ピ
リジン、炭酸カリウム等が挙げられる。
又、反応は室温から使用される溶媒の加熱還流
温度の間の温度において行われ、好ましくは50〜
100゜の範囲で適宜選択される。
本発明に係わる化合物の製造方法の第四の様式
によれば、前記一般式（）で示される化合物
は、次の一般式（）
（式中、R1、R2、R3及びR4は前述と同意義を、R6
は低級アルキル基を表す。）
で示される７−ピペラジン置換−６−フルオロ−
４−オキソ−１・４−ジヒドロキノリン−３−カ
ルボン酸エステル誘導体を、加水分解することに
より製造される。
加水分解はそれ自体公知の方法で、酸又はアル
カリを用いて行われ、酸性加水分解には塩酸、硫
酸等の酸を用い、アルカリ性加水分解には水酸化
ナトリウム、水酸化カリウム等のアルカリを用
い、これら酸あるいはアルカリの水溶液、もしく
は、エタノール、メタノール等の溶液、あるいは
含水有機溶媒の溶液として反応に用いる。又、反
応は室温から使用される溶媒の加熱還流温度の間
の温度下において行なわれる。
尚、本発明の製造方法において出発原料に使用
される前記一般式（）で示される７−ピペラジ
ン置換−６−フルオロ−４−オキソ−１・４−ジ
ヒドロキノリン−３−カルボン酸エステル誘導体
は新規な物質であり、その製造については参考例
に記載した。
この様にして製造される前記一般式（）で示
される新規な７−ピペラジン置換−６−フルオロ
−４−オキソ−１・４−ジヒドロキノリン−３−
カルボン酸誘導体、及びその薬理学的に許容しう
る塩は、グラム陽性菌、グラム陰性菌に対し広い
抗菌作用を有し、医薬として極めて有用である。
以下、本発明を実施例によつて説明する。
実施例 １
１−エチル−６−フルオロ−７−［３−（アミノ
カルボニル−１−ピペラジニル］−４−オキソ
−１・４−ジヒドロキノリン−３−カルボン酸
１−エチル−６−フルオロ−７−クロロ−４−
オキソ−１・４−ジヒドロキノリン−３−カルボ
ン酸1.53ｇ、２−（アミノカルボニル）ピペラジ
ン2.20ｇ及びピリジン10mlの混合物を、44時間加
熱還流する。反応後溶媒を留去し、得られた残渣
を30％酢酸水溶液に溶解する。次いで20％水酸化
ナトリウム水溶液を加えて中和する。水層をクロ
ロホルムにて洗浄した後、析出物をろ取する。ろ
取物をクロロホルム及びメタノールの混液から再
結晶し、融点246〜250゜（分解）の褐色プリズム
晶として表記化合物0.34ｇを得る。
元素分析値 C17H19FN4O4
理論値 Ｃ、56.35；Ｈ、5.26；Ｎ、15.46
実測値 Ｃ、56.01；Ｈ、5.40；Ｎ、15.19
参考例 １
２−シクロヘキシルピペラジン
シクロヘキシルグリオキサール20.0ｇのメタノ
ール250ml溶液に、氷冷撹拌下、エチレンジアミ
ン9.4ｇのメタノール20ml溶液を加え、５分間撹
拌する。次いで水素化ホウ素ナトリウム13.2ｇを
加え、室温で２時間撹拌する。反応後溶媒を留去
し、残渣に水を加えて、クロロホルム抽出する。
クロロホルム層は、飽和塩化ナトリウム水溶液で
洗浄後、脱水する。溶媒を留去し、残渣をイソプ
ロパノールに溶解する。イソプロパノール溶液に
エタノール性塩酸を加え、析出物をろ取する。ろ
取物を水に溶解後、20％水酸化ナトリウム水溶液
にてアルカリ性となし、クロロホルム抽出する。
クロロホルム層は脱水後、溶媒を留去する。残渣
をアセトンから再結晶し、融点82〜82.5゜の無色
結晶として表記化合物7.1ｇを得る。
元素分析値 C10H20N2
理論値 Ｃ、71.37；Ｈ、11.98；Ｎ、16.65
実測値 Ｃ、71.21；Ｈ、11.83；Ｎ、16.43
尚、出発原料シクロヘキシルグリオキサール
は、ザ・ジヤーナル・オブ・オルガニツク・ケミ
ストリー（The Journal of Organic
Chemistry）６巻260頁（1941）により公知の化
合物である。
実施例 ２
１−エチル−６−フルオロ−７−（３−シクロ
ヘキシル−１−ピペラジニル）−４−オキソ−
１・４−ジヒドロキノリン−３−カルボン酸
１−エチル−６−フルオロ−７−クロロ−４−
オキソ−１・４−ジヒドロキノリン−３−カルボ
ン酸1.50ｇ、参考例１で得た２−シクロヘキシル
ピペラジン2.80ｇ及びピリジン10mlの混合物を、
22時間加熱還流する。反応後溶媒を留去する。残
渣に水を加え、クロロホルムにて抽出する。クロ
ロホルム層は脱水後、溶媒を留去する。残渣をベ
ンゼン及びイソプロピルエーテルの混液で洗浄
後、ベンゼンから再結晶し、融点175.5〜176.5゜
の無色結晶として表記化合物0.54ｇを得る。
元素分析値 C22H28FN3O3
理論値 Ｃ、65.82；Ｈ、7.03；Ｎ、10.47
実測値 Ｃ、65.31；Ｈ、6.90；Ｎ、10.47
実施例 ３
１−エチル−６−フルオロ−７−（３−メチル
−１−ピペラジニル）−４−オキソ−１・４−
ジヒドロキノリン−３−カルボン酸
１−エチル−６−フルオロ−７−クロロ−４−
オキソ−１・４−ジヒドロキノリン−３−カルボ
ン酸15.00ｇ、２−メチルピペラジン16.70ｇ及び
ピリジン70mlの混合物を、14時間加熱還流する。
反応後溶媒を留去する。得られた残渣を50％酢酸
水溶液にて酸性とする。水層を活性炭にて処理
後、20％水酸化ナトリウム水溶液にて中和する。
再び活性炭にて処理し、次いで濃縮する。析出物
をろ取する。ろ取物をエタノールに溶解し、エタ
ノール性塩酸を加える。溶媒を濃縮し、析出物を
ろ取する。ろ取物を水及びエタノールの混液から
再結晶し、融点300゜以上の淡黄色針状晶として
表記化合物の塩酸塩8.19ｇを得る。
元素分析値 C17H20FN3O3・HCl
理論値 Ｃ、55.21；Ｈ、5.72；Ｎ、11.36
実測値 Ｃ、55.13；Ｈ、5.72；Ｎ、11.17
実施例 ４
１−エチル−６−フルオロ−７−（３・４−ジ
メチル−１−ピペラジニル）−４−オキソ−
１・４−ジヒドロキノリン−３−カルボン酸
実施例３で得た１−エチル−６−フルオロ−７
−（３−メチル−１−ピペラジニル）−４−オキソ
−１・４−ジヒドロキノリン−３−カルボン酸・
塩酸塩2.69ｇ、90％ギ酸5.4ml、37％ホルマリン
3.5ml及び炭酸カリウム0.70ｇの混合物を５時間
加熱還流する。反応後、20％水酸化ナトリウム水
溶液を加えて中和し、析出物をろ取する。ろ取物
をクロロホルム及びメタノールの混液から再結晶
し、融点244〜246゜の無色針状晶として表記化合
物1.70ｇを得る。
元素分析値 C18H22FN3O3
理論値 Ｃ、65.24；Ｈ、6.38；Ｎ、12.10
実測値 Ｃ、62.02；Ｈ、6.37；Ｎ、12.05
実施例 ５
１−エチル−６−フルオロ−７−（４−エチル
−３−メチル−１−ピペラジニル）−４−オキ
ソ−１・４−ジヒドロキノリン−３−カルボン
酸
実施例３で得た１−エチル−６−フルオロ−７
−（３−メチル−１−ピペラジニル）−４−オキソ
−１・４−ジヒドロキノリン−３−カルボン酸・
塩酸塩1.00ｇ、ヨウ化エチル1.29ｇ、トリエチル
アミン1.09ｇのジメチルホルムアミド20ml溶液
を、70〜80゜で1.5時間加熱撹拌する。反応後溶
媒を留去し、得られた残渣を50％酢酸水溶液にて
酸性とする。水層に20％水酸化ナトリウム水溶液
を加えて中和し、析出物をろ取する。ろ取物をカ
ラムクロマトグラフイー（担体：シリカゲル、ク
ロロホルム及びメタノールの混液（９：１）によ
り溶出）にて処理し、無色結晶として表記化合物
0.47ｇを得る。クロロホルム及びメタノールの混
液から再結晶して、融点203〜205゜の無色針状晶
を得る。
元素分析値 C19H24FN3O3
理論値 Ｃ、63.14；Ｈ、6.69；Ｎ、11.63
実測値 Ｃ、62.82；Ｈ、6.78；Ｎ、11.66
実施例 ６
１−エチル−６−フルオロ−７−（３−エチル
−１−ピペラジニル）−４−オキソ−１・４−
ジヒドロキノリン−３−カルボン酸
１−エチル−６−フルオロ−７−クロロ−４−
オキソ−１・４−ジヒドロキノリン−３−カルボ
ン酸4.49ｇ、２−エチルピペラジン5.70ｇ及びピ
リジン30mlの混合物を、15時間加熱還流する。反
応後溶媒を留去する。得られた残渣を50％酢酸水
溶液に溶解し酸性となし、次いで、20％水酸化ナ
トリウム水溶液にて中和する。水層を濃縮し、析
出物をろ取する。ろ取物をクロロホルムに溶解
し、活性炭にて処理した後、エタノール性塩酸を
加える。溶媒を濃縮し、析出物をろ取する。ろ取
物を水及びアセトンの混液から再結晶し、融点
300゜以上の無色結晶として表記化合物の塩酸塩
1.81ｇを得る。
元素分析値 C18H22FN3O3・HCl
理論値 Ｃ、56.32；Ｈ、6.04；Ｎ、10.95
実測値 Ｃ、56.10；Ｈ、6.01；Ｎ、10.89
実施例 ７
１−エチル−６−フルオロ−７−（３−エチル
−４−メチル−１−ピペラジニル）−４−オキ
ソ−１・４−ジヒドロキノリン−３−カルボン
酸
実施例６で得た１−エチル−６−フルオロ−７
−（３−エチル−１−ピペラジニル）−４−オキソ
−１・４−ジヒドロキノリン−３−カルボン酸・
塩酸塩0.60ｇ、90％ギ酸1.2ml、37％ホルマリン
0.77ml及び炭酸カリウム0.17ｇの混合物を、５時
間加熱還流する。反応後20％水酸化ナトリウム水
溶液を加えて中和し、析出物をろ取する。ろ取物
をクロロホルム及びメタノールの混液から再結晶
し、融点213〜215゜の無色針状晶として表記化合
物0.33ｇを得る。
元素分析値 C19H24FN3O3
理論値 Ｃ、63.14；Ｈ、6.69；Ｎ、11.63
実測値 Ｃ、63.11；Ｈ、7.01；Ｎ、11.54
実施例 ８
１−エチル−６・８−ジフルオロ−７−（３−
メチル−１−ピペラジニル）−４−オキソ−
１・４−ジヒドロキノリン−３−カルボン酸
６・７・８−トリフルオロ−１−エチル−４−
オキソ−１・４−ジヒドロキノリン−３−カルボ
ン酸1.00ｇ、２−メチルピペラジン1.10ｇ及びピ
リシン10mlの混合物を、15分間加熱還流する。反
応後溶媒を留去する。得られた残渣にメタノール
を加え、析出物をろ取する。ろ取物をエタノール
から再結晶し、融点239〜240.5゜の無色針状晶と
して表記化合物0.36ｇを得る。
元素分析値 C17H19F2N3O3
理論値 Ｃ、58.11；Ｈ、5.45；Ｎ、11.96
実測値 Ｃ、57.98；Ｈ、5.47；Ｎ、12.18
常法に従い、表記化合物の塩酸塩とする。水か
ら再結晶して、融点290〜300゜（分解）の無色針
状晶を得る。
元素分析値 C17H19F2N3O3・HCl
理論値 Ｃ、52.65；Ｈ、5.20；Ｎ、10.84
実測値 Ｃ、52.78；Ｈ、5.32；Ｎ、10.65
実施例 ９
１−メチル−６−フルオロ−７−（３−メチル
−１−ピペラジニル）−４−オキソ−１・４−
ジヒドロキノリン−３−カルボン酸
１−メチル−６−フルオロ−７−クロロ−４−
オキソ−１・４−ジヒドロキノリン−３−カルボ
ン酸1.50ｇ、２−メチルピペラジン1.80ｇ及びピ
リシン８mlの混合物を、23時間加熱還流する。反
応後溶媒を留去する。得られた残渣にメタノール
及びエーテルの混液を加え、析出物をろ取する。
ろ取物をメタノールに溶解し、エタノール性塩酸
を加える。ろ取物を水及びエタノールの混液から
再結晶し、融点300゜以上の無色針状晶として表
記化合物の塩酸塩0.67ｇを得る。
元素分析値 C16H18FN3O3・HCl1/4H2O
理論値 Ｃ、53.34；Ｈ、5.45；Ｎ、11.66
実測値 Ｃ、53.31；Ｈ、5.75；Ｎ、11.56
参考例 ２
１−エチル−６・８−ジフルオロ−７−（３−
メチル−１−ピペラジニル）−４−オキソ−
１・４−ジヒドロキノリン−３−カルボン酸エ
チルエステル
１−エチル−６・７・８−トリフルオロ−４−
オキソ−１・４−ジヒドロキノリン−３−カルボ
ン酸エチルエステル1.50ｇ、２−メチルピペラジ
ン1.50ｇ及びピリジン５mlの混合物を、３時間加
熱還流する。反応後溶媒を留去し、得られた残渣
をクロロホルムに溶解する。クロロホルム層は水
洗後脱水し、溶媒を留去する。残渣をベンゼン及
びイソプロピルエーテルの混液から再結晶し、融
点126.5〜127.5゜の無色針状晶として表記化合物
1.00ｇを得る。
元素分析値 C19H23F2N3O3
理論値 Ｃ、60.15；Ｈ、6.11；Ｎ、11.08
実測値 Ｃ、60.30；Ｈ、6.34；Ｎ、10.84
実施例 10
１−エチル−６・８−ジフルオロ−７−（３−
メチル−１−ピペラジニル）−４−オキソ−
１・４−ジヒドロキノリン−３−カルボン酸
参考例２で得た１−エチル−６・８−ジフルオ
ロ−７−（３−メチル−１−ピペラジニル）−４−
オキソ−１・４−ジヒドロキノリン−３−カルボ
ン酸エチルエステル0.55ｇのエタノール5.5ml溶
液に、18％塩酸水溶液を加え、４時間加熱還流す
る。冷後析出物をろ取する。ろ取物をエタノー
ル、エーテルにて順次洗浄し、水から再結晶し
て、融点290〜300゜（分解）の無色針状晶として
表記化合物の塩酸塩0.43ｇを得る。
本品は実施例８で得られた化合物とNMR及び
IRスペクトルで一致した。
実施例 11
１−メチル−６・８−ジフルオロ−７−（３−
メチル−１−ピペラジニル）−４−オキソ−
１・４−ジヒドロキノリン−３−カルボン酸
１−メチル−６・７・８−トリフルオロ−４−
オキソ−１・４−ジヒドロキノリン−３−カルボ
ン酸2.00ｇ、２−メチルピペラジン2.30ｇ及びピ
リジン20mlの混合物を、30分間加熱還流する。反
応後溶媒を留去する。得られた残渣にメタノール
を加え、析出物をろ取する。ろ取物をクロロホル
ム及びエタノールの混液から再結晶して、融点
249〜250゜の黄色鱗片状晶として表記化合物1.40
ｇを得る。
元素分析値 C16H17F2N3O3
理論値 Ｃ、56.98；Ｈ、5.08；Ｎ、12.46
実測値 Ｃ、56.86；Ｈ、5.36；Ｎ、12.17
参考例 ３
１−イソプロピル−６・７・８−トリフルオロ
−４−オキソ−１・４−ジヒドロキノリン−３
−カルボン酸
２・３・４−トリフルオロアニリン3.70ｇ、酢
酸ナトリウム10.30ｇ、アセトン20ml、酢酸19.6
ml及び水39mlの混合液に、氷冷撹拌下、水素化ホ
ウ素ナトリウム7.70ｇを加え、２時間撹拌する。
反応後、混合物に炭酸カリウムを加えてアルカリ
性となし、ベンゼン抽出する。ベンゼン層は飽和
食塩水にて洗浄後、脱水。溶媒を留去し、無色液
体として２・３・４−トリフルオロ−Ｎ−イソプ
ロピルアニリン3.17ｇを得る。
IRスペクトルν（film）cm１：3450（〓NH）
２・３・４−トリフルオロ−Ｎ−イソプロピル
アニリン2.50ｇ及びエトキシメチレンマロン酸ジ
エチルエステル2.80ｇの混合物を、160〜170゜で
１時間加熱撹拌する。反応混合物にヘキサンを加
えて冷却する。析出物をろ取し、無色結晶として
ジエチル２−（２・３・４−トリフルオロ−Ｎ−
イソプロピルアニリノ）メチレンマロナート2.45
ｇを得る。ヘキサンから再結晶して、融点92.5〜
93゜の無色針状晶を得る。
元素分析値 C17H20F3NO4
理論値 Ｃ、56.82；Ｈ、5.61；Ｎ、3.90
実測値 Ｃ、56.83；Ｈ、5.67；Ｎ、3.91
ジエチル２−（２・３・４−トリフルオロ−Ｎ
−イソプロピルアニリノ）メチレンマロナート
9.00ｇ及びポリリン酸90.0ｇの混合物を、80〜85
゜で１時間加熱撹拌する。反応後、混合物を氷水
中に注ぎ、クロロホルム抽出する。クロロホルム
層は水洗後、脱水。溶媒を留去し、得られた残渣
に18％塩酸水溶液90ml及びエタノール45mlを加
え、1.5時間加熱還流する。冷後、析出物をろ取
し、エタノールにて洗浄し、褐色固体として表記
化合物1.40ｇを得る。クロロホルム及びエタノー
ルの混液から再結晶して、融点261〜262.5゜の淡
褐色針状晶を得る。
元素分析値 C13H10F3NO3
理論値 Ｃ、54.74；Ｈ、3.53；Ｎ、4.91
実測値 Ｃ、54.64；Ｈ、3.47；Ｎ、4.93
実施例 12
１−イソプロピル−６・８−ジフルオロ−７−
（３−メチル−１−ピペラジニル）−４−オキソ
−１・４−ジヒドロキノリン−３−カルボン酸
参考例３で得た１−イソプロピル−６・７・８
−トリフルオロ−４−オキソ−１・４−ジヒドロ
キノリン−３−カルボン酸0.68ｇ、２−メチルピ
ペラジン0.72ｇ及びピリジン10mlの混合物を用い
て、実施例８と同様に処理し、融点217〜218゜の
無色結晶として表記化合物0.42ｇを得る。
元素分析値 C18H21F2N3O3・1/2H2O
理論値 Ｃ、57.75；Ｈ、5.92；Ｎ、11.22
実測値 Ｃ、57.53；Ｈ、5.97；Ｎ、11.13
実施例 13
１−エチル−６・８−ジフルオロ−７−（３・
４−ジメチル−１−ピペラジニル）−４−オキ
ソ−１・４−ジヒドロキノリン−３−カルボン
酸
実施例８で得た１−エチル−６・８−ジフルオ
ロ−７−（３−メチル−１−ピペラジニル）−４−
オキソ−１・４−ジヒドロキノリン−３−カルボ
ン酸1.40ｇ、90％ギ酸2.8ml及び37％ホルマリン
2.2mlの混合物を４時間加熱還流する。冷後溶媒
を留去する。得られた残渣を水に溶解後、炭酸水
素ナトリウムにて中和し、析出物をろ取する。ろ
取物をエタノールから再結晶し、融点211.5〜212
゜の無色針状晶として表記化合物0.32ｇを得る。
元素分析値 C18H21F2N3O3
理論値 Ｃ、59.17；Ｈ、5.79；Ｎ、11.50
実測値 Ｃ、59.29；Ｈ、5.87；Ｎ、11.55
実施例 14
１−メチル−６・８−ジフルオロ−７−（３・
４−ジメチル−１−ピペラジニル）−４−オキ
ソ−１・４−ジヒドロキノリン−３−カルボン
酸
１−メチル−６・７・８−トリフルオロ−４−
オキソ−１・４−ジヒドロキノリン−３−カルボ
ン酸700mg、１・２−ジメチルピペラジン930mg及
びピリジン５mlの混合物を、20分間加熱還流す
る。反応後溶媒を留去する。得られた残渣にメタ
ノールを加え、析出物をろ取する。ろ取物をクロ
ロホルム及びメタノールの混液に溶解し、エタノ
ール性塩酸を加える。析出物をろ取し、ろ取物に
水を加え炭酸水素ナトリウムで中和する。クロロ
ホルムにて抽出し、クロロホルム層は脱水後溶媒
を留去する。残渣にメタノールを加え、析出物を
ろ取して、無色結晶として表記化合物730mgを得
る。クロロホルム及びエタノールの混液から再結
晶して、融点231〜232.5゜の無色針状晶を得る。
元素分析値 C17H19F2N3O3
理論値 Ｃ、58.11；Ｈ、5.45；Ｎ、11.96
実測値 Ｃ、58.13；Ｈ、5.54；Ｎ、11.99
以下、実施例１〜14と同様の方法により実施例
15〜20の化合物を得る。
実施例 15
１−メチル−６−フルオロ−７−（３・４−ジ
メチル−１−ピペラジニル）−４−オキソ−
１・４−ジヒドロキノリン−３−カルボン酸
無色針状晶
融点 262〜263゜（ジクロロメタン−エタノー
ル）
元素分析値 C17H20FN3O3
理論値 Ｃ、61.25；Ｈ、6.05；Ｎ、12.60
実測値 Ｃ、60.94；Ｈ、6.38；Ｎ、12.51
実施例 16
１−プロピル−６−フルオロ−７−（３−メチ
ル−１−ピペラジニル）−４−オキソ−１・４
−ジヒドロキノリン−３−カルボン酸
淡黄色結晶
融点 163〜164゜（エタノール−ベンゼン）
元素分析値 C18H22FN3O3・1/4H2O
理論値 Ｃ、61.43；Ｈ、6.44；Ｎ、11.94
実測値 Ｃ、61.20；Ｈ、6.58；Ｎ、11.73
実施例 17
１−プロピル−６−フルオロ−７−（３・４−
ジメチル−１−ピペラジニル）−４−オキソ−
１・４−ジヒドロキノリン−３−カルボン酸
淡黄色針状晶
融点 157〜158゜（ベンゼン−ヘキサン）
元素分析値 C19H24FN3O3
理論値 Ｃ、63.14；Ｈ、6.69；Ｎ、11.63
実測値 Ｃ、62.98；Ｈ、6.98；Ｎ、11.61
実施例 18
１−イソプロピル−６・８−ジフルオロ−７−
（３・４−ジメチル−１−ピペラジニル）−４−
オキソ−１・４−ジヒドロキノリン−３−カル
ボン酸
淡黄色針状晶
融点 190.5〜191.5゜（ベンゼン−ヘキサン）
元素分析値 C19H23F2N3O3
理論値 Ｃ、60.15；Ｈ、6.11；Ｎ、11.08
実測値 Ｃ、60.00；Ｈ、6.35；Ｎ、11.13
実施例 19
１−プロピル−６・８−ジフルオロ−７−（３
−メチル−１−ピペラジニル）−４−オキソ−
１・４−ジヒドロキノリン−３−カルボン酸
淡黄色針状晶
融点 211〜212゜（クロロホルム−エタノール）
元素分析値 C18H21F2N3O3
理論値 Ｃ、59.17；Ｈ、5.79；Ｎ、11.50
実測値 Ｃ、58.86；Ｈ、6.14；Ｎ、11.38
実施例 20
１−プロピル−６・８−ジフルオロ−７−
（３・４−ジメチル−１−ピペラジニル）−４−
オキソ−１・４−ジヒドロキノリン−３−カル
ボン酸黄色鱗片状晶
融点 186.5〜187.5゜（エタノール）
元素分析値 C19H23F2N3O3
理論値 Ｃ、60.15；Ｈ、6.11；Ｎ、11.08
実測値 Ｃ、59.85；Ｈ、6.31；Ｎ、10.92
本発明化合物の抗菌活性を次の試験例で示す。
その際、対照薬物としては、ピペミド酸（以下、
PPAという）、ノルフロキサシン（以下、AM−
715という）及び１−エチル−６・８−ジフルオ
ロ−１・４−ジヒドロ−４−オキソ−７−（１−
ピペラジニル）キノリン−３−カルボン酸（特開
昭55−47658号に記載の化合物（以下、公知化合
物という）を用いた。
試験例 １
抗菌試験は、日本化学療法学会指定の方法（日
本化学療法学会雑誌、29(1)、76（1981）に準じて
実施した。結果を表１に示す。
The present invention provides novel 7-piperazine-substituted-6-fluoro-4-oxo-1,4-dihydroquinoline-
This invention relates to 3-carboxylic acid derivatives and pharmacologically acceptable salts thereof. More specifically, the present invention relates to the general formula () (In the formula, R 1 is a lower alkyl group having 1 to 4 carbon atoms,
R 2 is an aminocarbonyl group, a carboxyl group, a lower alkyl group having 1 to 4 carbon atoms, or a cycloalkyl group having 5 to 7 carbon atoms, R 3 is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R 4 represents a hydrogen atom or a fluorine atom. ) and a pharmacologically acceptable salt thereof. In the general formula () of the present invention, R 1 , R 2 and R 3
As the lower alkyl group represented by, methyl group,
Ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, etc.
Examples of the cycloalkyl group represented by include a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. Examples of the pharmacologically acceptable salts of the compound represented by the general formula () include acid addition salts and alkali addition salts; examples of the acid addition salts include:
Hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid,
Mineral acid salts such as phosphoric acid, or organic acid salts such as acetic acid, maleic acid, fumaric acid, citric acid, tartaric acid, etc. are used as alkali addition salts, such as inorganic alkali salts such as sodium, potassium, calcium, ammonium salts, or Ethanolamine, N・N-
Examples include salts of organic bases such as dialkylethanolamine. Novel 7 represented by the general formula () of the present invention
-piperazine-substituted-6-fluoro-4-oxo-
The 1,4-dihydroquinoline-3-carboxylic acid derivative can be produced by various methods. According to the first mode of the method for producing a compound according to the present invention, the compound represented by the general formula () is prepared by the following general formula () (In the formula, R 1 and R 4 represent the same meanings as above, and X represents a chlorine atom or a fluorine atom.) 7-halogeno-6-fluoro-4-oxo-1,4-dihydroquinoline -3-carboxylic acid derivative and the following general formula () (In the formula, R 2 and R 3 represent the same meanings as described above.) It can be produced by reacting the piperazine derivative represented by the following in the absence of a solvent or in the presence of a solvent. Examples of the solvent used in this reaction include water, butanol, 3-methoxybutanol,
Alcohols such as isoamyl alcohol, ethers such as ethylene glycol dimethyl ether (monoglyme), diethylene glycol dimethyl ether (diglyme), triethylene glycol dimethyl ether (triglyme), aprotic properties such as dimethyl formamide, dimethyl sulfoxide, hexamethyl phosphoric triamide, etc. Examples include polar solvents, aromatic hydrocarbon solvents such as benzene and toluene, and organic bases such as pyridine, picoline, lutidine, collidine, and triethylamine. In addition, the reaction is carried out in the range of room temperature to 200°,
Preferably, the angle is appropriately selected within the range of 100 to 180°. The 7-halogeno-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative represented by the general formula () used as a starting material in the production method of the present invention is, for example, No. 53-141286, JP-A No. 55-47658, JP-A-Sho
It is a known substance already disclosed in No. 56-30964. In addition, the piperazine derivatives represented by the general formula () are known substances, with some exceptions; for example,
This has already been disclosed in US Patent No. 2780625, South African Patent No. 6807552, etc. Furthermore, the above general formula ()
For new substances, the manufacturing method is described as a reference example. According to the second mode of the method for producing a compound according to the present invention, the compound represented by the general formula () has the following general formula () in which R 3 is a hydrogen atom: (In the formula, R 1 , R 2 and R 4 have the same meanings as above.)
7-piperazine-substituted-6-fluoro-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative and the following general formula () (In the formula, R 5 represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.) It can be produced by reacting a carbonyl compound represented by the following in the presence of formic acid. Examples of the carbonyl compound represented by the general formula () used in the method of the present invention include formaldehyde, acetaldehyde, propionaldehyde, etc. Formaldehyde is preferably used as an aqueous formaldehyde solution (formalin), and acetaldehyde and propionaldehyde are preferably used. When using aldehydes, it is preferred to use nitrobenzene as a solvent. The reaction is carried out at a temperature of 100 to 200°, preferably at the reflux temperature of the reaction system. According to a third mode of the method for producing a compound according to the present invention, the compound represented by the general formula () is a 7-piperazine-substituted-6-fluoro-4-oxo-1 represented by the general formula ().・4-dihydroquinoline-3-carboxylic acid derivative and a halogen represented by the following general formula () R 3 -A () (wherein R 3 has the same meaning as above and A represents a halogen atom) It can be produced by reacting the compound with an alkyl compound in a solvent in the presence or absence of a base as a deoxidizing agent. The solvent used in the method of the present invention may be any solvent as long as it does not inhibit the reaction, such as acetone, ethanol, ether,
Examples include tetrahydrofuran, dimethylformamide, dioxane, benzene, toluene, and chloroform. Examples of the base used as a deoxidizing agent in the method of the present invention include triethylamine, pyridine, potassium carbonate, and the like. Further, the reaction is carried out at a temperature between room temperature and the heating reflux temperature of the solvent used, preferably at a temperature of 50 to
It is selected appropriately within the range of 100°. According to the fourth mode of the method for producing a compound according to the present invention, the compound represented by the general formula () has the following general formula () (In the formula, R 1 , R 2 , R 3 and R 4 have the same meanings as above, R 6
represents a lower alkyl group. ) 7-piperazine-substituted-6-fluoro-
It is produced by hydrolyzing a 4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester derivative. Hydrolysis is carried out using an acid or alkali using a method known per se. For acidic hydrolysis, an acid such as hydrochloric acid or sulfuric acid is used, and for alkaline hydrolysis, an alkali such as sodium hydroxide or potassium hydroxide is used. , used in the reaction as an aqueous solution of these acids or alkalis, a solution of ethanol, methanol, etc., or a solution of a water-containing organic solvent. Further, the reaction is carried out at a temperature between room temperature and the heating reflux temperature of the solvent used. The 7-piperazine-substituted 6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester derivative represented by the general formula () used as the starting material in the production method of the present invention is novel. Its production is described in the reference example. The novel 7-piperazine-substituted-6-fluoro-4-oxo-1,4-dihydroquinoline-3- represented by the general formula () produced in this way
Carboxylic acid derivatives and pharmacologically acceptable salts thereof have broad antibacterial activity against Gram-positive and Gram-negative bacteria and are extremely useful as medicines. Hereinafter, the present invention will be explained with reference to Examples. Example 1 1-ethyl-6-fluoro-7-[3-(aminocarbonyl-1-piperazinyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1-ethyl-6-fluoro-7- Chloro-4-
A mixture of 1.53 g of oxo-1,4-dihydroquinoline-3-carboxylic acid, 2.20 g of 2-(aminocarbonyl)piperazine and 10 ml of pyridine is heated under reflux for 44 hours. After the reaction, the solvent is distilled off, and the resulting residue is dissolved in a 30% aqueous acetic acid solution. Then, neutralize by adding 20% aqueous sodium hydroxide solution. After washing the aqueous layer with chloroform, the precipitate is collected by filtration. The filtered product is recrystallized from a mixture of chloroform and methanol to obtain 0.34 g of the title compound as brown prism crystals with a melting point of 246-250° (decomposition). Elemental analysis value C 17 H 19 FN 4 O 4 Theoretical value C, 56.35; H, 5.26; N, 15.46 Actual value C, 56.01; H, 5.40; N, 15.19 Reference example 1 2-Cyclohexylpiperazine Cyclohexylglyoxal 20.0g methanol Add a solution of 9.4 g of ethylenediamine in 20 ml of methanol to the 250 ml solution while stirring on ice, and stir for 5 minutes. Next, 13.2 g of sodium borohydride was added, and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off, water was added to the residue, and the mixture was extracted with chloroform.
The chloroform layer is washed with a saturated aqueous sodium chloride solution and then dehydrated. The solvent is evaporated and the residue is dissolved in isopropanol. Add ethanolic hydrochloric acid to the isopropanol solution and filter the precipitate. Dissolve the filtered material in water, make alkaline with 20% aqueous sodium hydroxide solution, and extract with chloroform.
After the chloroform layer is dehydrated, the solvent is distilled off. The residue is recrystallized from acetone to obtain 7.1 g of the title compound as colorless crystals with a melting point of 82-82.5°. Elemental analysis value C 10 H 20 N 2 Theoretical value C, 71.37; H, 11.98; N, 16.65 Actual value C, 71.21;・Chemistry (The Journal of Organic
Chemistry, Vol. 6, p. 260 (1941). Example 2 1-ethyl-6-fluoro-7-(3-cyclohexyl-1-piperazinyl)-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid 1-ethyl-6-fluoro-7-chloro-4-
A mixture of 1.50 g of oxo-1,4-dihydroquinoline-3-carboxylic acid, 2.80 g of 2-cyclohexylpiperazine obtained in Reference Example 1, and 10 ml of pyridine,
Heat to reflux for 22 hours. After the reaction, the solvent is distilled off. Add water to the residue and extract with chloroform. After the chloroform layer is dehydrated, the solvent is distilled off. The residue was washed with a mixture of benzene and isopropyl ether and then recrystallized from benzene to obtain 0.54 g of the title compound as colorless crystals with a melting point of 175.5-176.5°. Elemental analysis value C 22 H 28 FN 3 O 3 Theoretical value C, 65.82; H, 7.03; N, 10.47 Actual value C, 65.31; H, 6.90; N, 10.47 Example 3 1-ethyl-6-fluoro-7- (3-methyl-1-piperazinyl)-4-oxo-1,4-
Dihydroquinoline-3-carboxylic acid 1-ethyl-6-fluoro-7-chloro-4-
A mixture of 15.00 g of oxo-1,4-dihydroquinoline-3-carboxylic acid, 16.70 g of 2-methylpiperazine and 70 ml of pyridine is heated under reflux for 14 hours.
After the reaction, the solvent is distilled off. The obtained residue is acidified with 50% acetic acid aqueous solution. After treating the aqueous layer with activated carbon, neutralize it with a 20% aqueous sodium hydroxide solution.
Treat again with activated carbon and then concentrate. Filter the precipitate. Dissolve the filtered material in ethanol and add ethanolic hydrochloric acid. Concentrate the solvent and collect the precipitate by filtration. The filtered product was recrystallized from a mixture of water and ethanol to obtain 8.19 g of the hydrochloride salt of the title compound as pale yellow needle crystals with a melting point of over 300°. Elemental analysis value C 17 H 20 FN 3 O 3・HCl Theoretical value C, 55.21; H, 5.72; N, 11.36 Actual value C, 55.13; H, 5.72; N, 11.17 Example 4 1-ethyl-6-fluoro- 7-(3,4-dimethyl-1-piperazinyl)-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid 1-ethyl-6-fluoro-7 obtained in Example 3
-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
Hydrochloride 2.69g, 90% formic acid 5.4ml, 37% formalin
A mixture of 3.5 ml and 0.70 g of potassium carbonate is heated under reflux for 5 hours. After the reaction, 20% aqueous sodium hydroxide solution is added to neutralize, and the precipitate is collected by filtration. The filtered product was recrystallized from a mixture of chloroform and methanol to obtain 1.70 g of the title compound as colorless needles with a melting point of 244-246°. Elemental analysis value C 18 H 22 FN 3 O 3 Theoretical value C, 65.24; H, 6.38; N, 12.10 Actual value C, 62.02; H, 6.37; N, 12.05 Example 5 1-ethyl-6-fluoro-7- (4-ethyl-3-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1-ethyl-6-fluoro-7 obtained in Example 3
-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
A solution of 1.00 g of hydrochloride, 1.29 g of ethyl iodide, and 1.09 g of triethylamine in 20 ml of dimethylformamide is heated and stirred at 70-80° for 1.5 hours. After the reaction, the solvent is distilled off, and the resulting residue is made acidic with a 50% acetic acid aqueous solution. Add 20% aqueous sodium hydroxide solution to the aqueous layer to neutralize it, and filter the precipitate. The filtered material was treated with column chromatography (carrier: silica gel, eluted with a mixture of chloroform and methanol (9:1)) to produce the title compound as colorless crystals.
Obtain 0.47g. Recrystallization from a mixture of chloroform and methanol gives colorless needles with a melting point of 203-205°. Elemental analysis value C 19 H 24 FN 3 O 3 Theoretical value C, 63.14; H, 6.69; N, 11.63 Actual value C, 62.82; H, 6.78; N, 11.66 Example 6 1-ethyl-6-fluoro-7- (3-ethyl-1-piperazinyl)-4-oxo-1,4-
Dihydroquinoline-3-carboxylic acid 1-ethyl-6-fluoro-7-chloro-4-
A mixture of 4.49 g of oxo-1,4-dihydroquinoline-3-carboxylic acid, 5.70 g of 2-ethylpiperazine and 30 ml of pyridine is heated under reflux for 15 hours. After the reaction, the solvent is distilled off. The obtained residue is dissolved in a 50% aqueous acetic acid solution to make it acidic, and then neutralized with a 20% aqueous sodium hydroxide solution. Concentrate the aqueous layer and filter the precipitate. The filtered material is dissolved in chloroform, treated with activated carbon, and then ethanolic hydrochloric acid is added. Concentrate the solvent and collect the precipitate by filtration. The filtered material was recrystallized from a mixture of water and acetone, and the melting point
Hydrochloride of the compound described as colorless crystals of 300° or more
Obtain 1.81g. Elemental analysis value C 18 H 22 FN 3 O 3・HCl Theoretical value C, 56.32; H, 6.04; N, 10.95 Actual value C, 56.10; H, 6.01; N, 10.89 Example 7 1-ethyl-6-fluoro- 7-(3-ethyl-4-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1-ethyl-6-fluoro-7 obtained in Example 6
-(3-ethyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
Hydrochloride 0.60g, 90% formic acid 1.2ml, 37% formalin
A mixture of 0.77 ml and 0.17 g of potassium carbonate is heated to reflux for 5 hours. After the reaction, add 20% aqueous sodium hydroxide solution to neutralize, and filter the precipitate. The filtered product was recrystallized from a mixture of chloroform and methanol to obtain 0.33 g of the title compound as colorless needles with a melting point of 213-215°. Elemental analysis value C 19 H 24 FN 3 O 3 Theoretical value C, 63.14; H, 6.69; N, 11.63 Actual value C, 63.11; H, 7.01; N, 11.54 Example 8 1-Ethyl-6,8-difluoro- 7-(3-
Methyl-1-piperazinyl)-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid 6,7,8-trifluoro-1-ethyl-4-
A mixture of 1.00 g of oxo-1,4-dihydroquinoline-3-carboxylic acid, 1.10 g of 2-methylpiperazine and 10 ml of pyricine is heated under reflux for 15 minutes. After the reaction, the solvent is distilled off. Methanol is added to the obtained residue, and the precipitate is collected by filtration. The filtered product is recrystallized from ethanol to obtain 0.36 g of the title compound as colorless needle crystals with a melting point of 239-240.5°. Elemental analysis value C 17 H 19 F 2 N 3 O 3 Theoretical value C, 58.11; H, 5.45; N, 11.96 Actual value C, 57.98; . Recrystallization from water gives colorless needles with a melting point of 290-300° (decomposition). Elemental analysis value C 17 H 19 F 2 N 3 O 3・HCl Theoretical value C, 52.65; H, 5.20; N, 10.84 Actual value C, 52.78; H, 5.32; N, 10.65 Example 9 1-Methyl-6- Fluoro-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-
Dihydroquinoline-3-carboxylic acid 1-methyl-6-fluoro-7-chloro-4-
A mixture of 1.50 g of oxo-1,4-dihydroquinoline-3-carboxylic acid, 1.80 g of 2-methylpiperazine and 8 ml of pyricine is heated under reflux for 23 hours. After the reaction, the solvent is distilled off. A mixed solution of methanol and ether is added to the obtained residue, and the precipitate is collected by filtration.
Dissolve the filtered material in methanol and add ethanolic hydrochloric acid. The filtered product is recrystallized from a mixture of water and ethanol to obtain 0.67 g of the hydrochloride of the title compound as colorless needle crystals with a melting point of over 300°. Elemental analysis value C 16 H 18 FN 3 O 3・HCl1/4H 2 O Theoretical value C, 53.34; H, 5.45; N, 11.66 Actual value C, 53.31; H, 5.75; N, 11.56 Reference example 2 1-ethyl- 6,8-difluoro-7-(3-
Methyl-1-piperazinyl)-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid ethyl ester 1-ethyl-6,7,8-trifluoro-4-
A mixture of 1.50 g of oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester, 1.50 g of 2-methylpiperazine and 5 ml of pyridine is heated under reflux for 3 hours. After the reaction, the solvent is distilled off, and the resulting residue is dissolved in chloroform. The chloroform layer is washed with water, dehydrated, and the solvent is distilled off. The residue was recrystallized from a mixture of benzene and isopropyl ether to give the title compound as colorless needle-like crystals with a melting point of 126.5-127.5°.
Obtain 1.00g. Elemental analysis value C 19 H 23 F 2 N 3 O 3 Theoretical value C, 60.15; H, 6.11; N, 11.08 Actual value C, 60.30; H, 6.34; N, 10.84 Example 10 1-ethyl-6・8- difluoro-7-(3-
Methyl-1-piperazinyl)-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid 1-ethyl-6,8-difluoro-7-(3-methyl-1-piperazinyl)-4- obtained in Reference Example 2
An 18% aqueous hydrochloric acid solution is added to a solution of 0.55 g of oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester in 5.5 ml of ethanol, and the mixture is heated under reflux for 4 hours. After cooling, filter the precipitate. The filtered product was washed successively with ethanol and ether and recrystallized from water to obtain 0.43 g of the hydrochloride of the title compound as colorless needle-like crystals with a melting point of 290-300° (decomposition). This product is the compound obtained in Example 8 and the NMR and
The IR spectra matched. Example 11 1-Methyl-6,8-difluoro-7-(3-
Methyl-1-piperazinyl)-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid 1-methyl-6,7,8-trifluoro-4-
A mixture of 2.00 g of oxo-1,4-dihydroquinoline-3-carboxylic acid, 2.30 g of 2-methylpiperazine and 20 ml of pyridine is heated under reflux for 30 minutes. After the reaction, the solvent is distilled off. Methanol is added to the obtained residue, and the precipitate is collected by filtration. The filtered material was recrystallized from a mixture of chloroform and ethanol to determine the melting point.
Compound 1.40 described as yellow scaly crystals of 249-250°
get g. Elemental analysis value C 16 H 17 F 2 N 3 O 3 Theoretical value C, 56.98; H, 5.08; N, 12.46 Actual value C, 56.86; H, 5.36; N, 12.17 Reference example 3 1-isopropyl-6.7. 8-Trifluoro-4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid 2,3,4-trifluoroaniline 3.70g, sodium acetate 10.30g, acetone 20ml, acetic acid 19.6
ml and 39 ml of water, add 7.70 g of sodium borohydride under ice-cooling and stirring, and stir for 2 hours.
After the reaction, the mixture is made alkaline by adding potassium carbonate and extracted with benzene. The benzene layer was washed with saturated saline and then dehydrated. The solvent was distilled off to obtain 3.17 g of 2,3,4-trifluoro-N-isopropylaniline as a colorless liquid. IR spectrum ν (film) cm 1 : 3450 (〓NH) A mixture of 2.50 g of 2,3,4-trifluoro-N-isopropylaniline and 2.80 g of ethoxymethylenemalonic acid diethyl ester was heated at 160 to 170° for 1 hour. Stir. Add hexane to the reaction mixture and cool. The precipitate was collected by filtration, and diethyl 2-(2,3,4-trifluoro-N-
Isopropylanilino) methylene malonate 2.45
get g. Recrystallized from hexane, melting point 92.5~
Obtain colorless needle crystals of 93°. Elemental analysis value C 17 H 20 F 3 NO 4 Theoretical value C, 56.82; H, 5.61; N, 3.90 Actual value C, 56.83; H, 5.67; N, 3.91 Diethyl 2-(2,3,4-trifluoro- N
-isopropylanilino)methylene malonate
A mixture of 9.00 g and 90.0 g of polyphosphoric acid was added to 80 to 85
Heat and stir at ° for 1 hour. After the reaction, the mixture is poured into ice water and extracted with chloroform. The chloroform layer was washed with water and then dehydrated. The solvent is distilled off, 90 ml of 18% aqueous hydrochloric acid solution and 45 ml of ethanol are added to the resulting residue, and the mixture is heated under reflux for 1.5 hours. After cooling, the precipitate is collected by filtration and washed with ethanol to obtain 1.40 g of the title compound as a brown solid. Recrystallization from a mixture of chloroform and ethanol gives light brown needles with a melting point of 261-262.5°. Elemental analysis value C 13 H 10 F 3 NO 3 Theoretical value C, 54.74; H, 3.53; N, 4.91 Actual value C, 54.64; H, 3.47; N, 4.93 Example 12 1-isopropyl-6,8-difluoro- 7-
(3-Methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1-isopropyl-6,7,8 obtained in Reference Example 3
- Treated as in Example 8 using a mixture of 0.68 g of trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 0.72 g of 2-methylpiperazine and 10 ml of pyridine, melting point 217-218 0.42 g of the title compound is obtained as colorless crystals. Elemental analysis value C 18 H 21 F 2 N 3 O 3・1/2H 2 O Theoretical value C, 57.75; H, 5.92; N, 11.22 Actual value C, 57.53; H, 5.97; N, 11.13 Example 13 1- Ethyl-6,8-difluoro-7-(3,
4-dimethyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1-ethyl-6,8-difluoro-7-(3-methyl-1-piperazinyl) obtained in Example 8 )-4-
1.40 g of oxo-1,4-dihydroquinoline-3-carboxylic acid, 2.8 ml of 90% formic acid and 37% formalin
Heat 2.2 ml of the mixture to reflux for 4 hours. After cooling, the solvent is distilled off. The obtained residue is dissolved in water, neutralized with sodium hydrogen carbonate, and the precipitate is collected by filtration. The filtered material was recrystallized from ethanol, and the melting point was 211.5-212.
0.32 g of the title compound is obtained as colorless needle-like crystals. Elemental analysis value C 18 H 21 F 2 N 3 O 3 Theoretical value C, 59.17; H, 5.79; N, 11.50 Actual value C, 59.29; H, 5.87; N, 11.55 Example 14 1-Methyl-6・8- Difluoro-7-(3.
4-dimethyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1-methyl-6,7,8-trifluoro-4-
A mixture of 700 mg of oxo-1,4-dihydroquinoline-3-carboxylic acid, 930 mg of 1,2-dimethylpiperazine and 5 ml of pyridine is heated under reflux for 20 minutes. After the reaction, the solvent is distilled off. Methanol is added to the obtained residue, and the precipitate is collected by filtration. Dissolve the filtered material in a mixture of chloroform and methanol, and add ethanolic hydrochloric acid. Collect the precipitate by filtration, add water to the filtrate, and neutralize with sodium hydrogen carbonate. Extract with chloroform, and after dehydrating the chloroform layer, the solvent is distilled off. Methanol is added to the residue, and the precipitate is collected by filtration to obtain 730 mg of the title compound as colorless crystals. Recrystallization from a mixture of chloroform and ethanol gives colorless needles with a melting point of 231-232.5°. Elemental analysis value C 17 H 19 F 2 N 3 O 3 Theoretical value C, 58.11; H, 5.45; N, 11.96 Actual value C, 58.13; H, 5.54; N, 11.99 Hereinafter, the same method as Examples 1 to 14 Example by
Obtain 15-20 compounds. Example 15 1-Methyl-6-fluoro-7-(3,4-dimethyl-1-piperazinyl)-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid colorless needles Melting point 262-263° (dichloromethane-ethanol) Elemental analysis value C 17 H 20 FN 3 O 3 Theoretical value C, 61.25; H, 6.05; N, 12.60 Actual measurement Values C, 60.94; H, 6.38; N, 12.51 Example 16 1-Propyl-6-fluoro-7-(3-methyl-1-piperazinyl)-4-oxo-1.4
-Dihydroquinoline-3-carboxylic acid pale yellow crystal Melting point 163-164° (ethanol-benzene) Elemental analysis value C 18 H 22 FN 3 O 3 ・1/4H 2 O Theoretical value C, 61.43; H, 6.44; N, 11.94 Actual value C, 61.20; H, 6.58; N, 11.73 Example 17 1-propyl-6-fluoro-7-(3.4-
dimethyl-1-piperazinyl)-4-oxo-
1,4-Dihydroquinoline-3-carboxylic acid pale yellow needles Melting point 157-158° (benzene-hexane) Elemental analysis C 19 H 24 FN 3 O 3 Theoretical value C, 63.14; H, 6.69; N, 11.63 Actual value C, 62.98; H, 6.98; N, 11.61 Example 18 1-isopropyl-6,8-difluoro-7-
(3,4-dimethyl-1-piperazinyl)-4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid pale yellow needles Melting point 190.5-191.5° (benzene-hexane) Elemental analysis C 19 H 23 F 2 N 3 O 3 Theoretical value C, 60.15; H, 6.11 ;N, 11.08 Actual value C, 60.00;H, 6.35;N, 11.13 Example 19 1-propyl-6,8-difluoro-7-(3
-methyl-1-piperazinyl)-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid pale yellow needle crystals Melting point 211-212° (chloroform-ethanol) Elemental analysis C 18 H 21 F 2 N 3 O 3 Theoretical value C, 59.17; H, 5.79; N , 11.50 Actual value C, 58.86; H, 6.14; N, 11.38 Example 20 1-propyl-6,8-difluoro-7-
(3,4-dimethyl-1-piperazinyl)-4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid yellow scaly crystals Melting point 186.5-187.5° (ethanol) Elemental analysis value C 19 H 23 F 2 N 3 O 3 Theoretical value C, 60.15; H, 6.11; N, 11.08 Actual value C, 59.85; H, 6.31; N, 10.92 The antibacterial activity of the compound of the present invention is shown in the following test example.
At that time, the control drug was pipemidic acid (hereinafter referred to as
(hereinafter referred to as PPA), norfloxacin (hereinafter referred to as AM-
715) and 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-
Piperazinyl) quinoline-3-carboxylic acid (a compound described in JP-A-55-47658 (hereinafter referred to as a known compound) was used. Test Example 1 The antibacterial test was conducted using the method specified by the Japanese Society of Chemotherapy (Japanese Society of Chemotherapy). It was carried out according to Japanese Journal, 29(1), 76 (1981).The results are shown in Table 1.
【表】【table】
【表】
試験例 ２
尿路感染症に対する抗菌試験を実施した。上行
性腎感染マウスは、ICR系雌性マウス（４週令、
体重18−21ｇ、一群８匹）をペントバルビタール
麻酔下に、エシエリヒア・コリーNIHJ−JC−２
菌を5.5×107個経尿道的に膀胱内に注入して、外
尿道口をセルフインで止め、４時間後にセルフイ
ンを外して作成した。被検化合物は0.5％カルボ
キシメチルセルロース水溶液に懸濁し、菌注入４
時間後に経口投与した。48時間後に腎臓を摘出
し、カミソリ刃で半分に切り、割面を大腸菌検出
培地（デゾキシコレート培地）にスタンプし、37
゜で20時間培養し菌の発育の有無を調べ、50％有
効となる投与量（ED50）をプロビツト法により計
算した。結果を表２に示す。[Table] Test Example 2 An antibacterial test for urinary tract infections was conducted. Ascending renal infection mice were ICR female mice (4 weeks old,
Escherichia collie NIHJ-JC-2 (weight 18-21 g, 8 animals per group) were placed under pentobarbital anesthesia.
5.5×10 7 bacteria were injected into the bladder through the urethra, the external urethral meatus was closed with a self-in, and 4 hours later, the self-in was removed to create a tube. The test compound was suspended in a 0.5% carboxymethylcellulose aqueous solution and injected into bacteria 4.
It was orally administered after hours. After 48 hours, the kidney was removed, cut in half with a razor blade, and the cut surface was stamped on E. coli detection medium (desoxycholate medium).
After culturing at 20°C for 20 hours, the presence or absence of bacterial growth was examined, and the 50% effective dose (ED 50 ) was calculated using the probit method. The results are shown in Table 2.
【表】
＊：塩酸塩での値
試験例 ３
経口投与後の血中濃度を調べた。
体重120〜210ｇのSD系ラツトを一群４匹とし
て実験に供した。被検化合物を蒸留水あるいは
0.01N−NaOHに溶解後中和して、20時間絶食ラ
ツトにそれぞれ20mg／Kg経口投与した。投与後、
0.5、１、２、４、６及び８時間毎に眼静脈より
採血し、血清を分離後、化学的定量法（HPLC
法）により血中濃度を測定した。結果を表３に示
す。[Table] *: Value test example for hydrochloride 3 The blood concentration after oral administration was investigated. SD rats weighing 120 to 210 g were used in the experiment in groups of four. Test compounds were added to distilled water or
After dissolving in 0.01N-NaOH and neutralizing it, 20 mg/Kg of each was orally administered to rats fasted for 20 hours. After administration,
Blood was collected from the ophthalmic vein every 0.5, 1, 2, 4, 6, and 8 hours, and after separating the serum, it was analyzed using a chemical quantitative method (HPLC).
The blood concentration was measured using the following method. The results are shown in Table 3.
【表】
試験例 ４
体重180〜210ｇのSD系ラツトを１群８匹とし
て実験に供した。
被検化合物を0.5％カルボキシメチルセルロー
ス水溶液に懸濁し、絶食ラツトにそれぞれ20mg／
Kg経口投与して排尿ケージに入れた。被検化合物
を投与したラツトから排泄される尿を経時的に採
取し、生物学的定量法（検定菌：エシエリヒア・
コリーNIHJ−JC−２）により尿中濃度を測定
し、24時間までの排泄率を求めた。結果を表４に
示す。[Table] Test Example 4 SD rats weighing 180 to 210 g were used in experiments with 8 rats per group. The test compound was suspended in a 0.5% carboxymethylcellulose aqueous solution, and 20mg/each was administered to fasted rats.
Kg was administered orally and placed in a urination cage. Urine excreted from rats administered with the test compound was collected over time, and a biological quantitative method (test bacteria: Escherichia
Colli NIHJ-JC-2) was used to measure the urinary concentration, and the excretion rate up to 24 hours was determined. The results are shown in Table 4.
【表】
＊ 遊離塩基での値
試験例 ５
体重180〜220ｇのSD系ラツトを一群５匹とし
て実験に供した。被検化合物を蒸留水あるいは
0.01N−NaOHに溶解後中和して、20時間絶食ラ
ツトにそれぞれ20mg／Kg経口投与して排尿ケージ
に入れた。投与後、ラツトから排泄される尿を経
時的に採取した後、化学的定量法（HPLC法）に
より尿中濃度を測定し、24時間までの排泄率を求
めた。結果を表５に示す。[Table] *Value test example 5 for free base SD rats weighing 180 to 220 g were used in the experiment in groups of 5 rats. Test compounds were added to distilled water or
After dissolving in 0.01N-NaOH and neutralizing it, 20 mg/Kg of each was orally administered to rats fasted for 20 hours and placed in a urination cage. After administration, urine excreted from the rats was collected over time, and the concentration in the urine was measured using a chemical assay (HPLC method) to determine the excretion rate up to 24 hours. The results are shown in Table 5.
【表】
試験例 ６
生後４週齢のddY系雄性マウスを１群10匹とし
て実験に供した。
被検化合物は0.5％カルボキシメチルセルロー
ス水溶液に懸濁しマウスに経口投与するか、ある
いは0.1規定塩酸水溶液に溶解後、0.1規定水酸化
ナトリウム水溶液で中和しマウスに静脈内投与し
た。投与後10日間の死亡数をそれぞれ観察し、プ
ロビツト法に基づき、50％致死量（LD50）を算出
した。結果を表６に示す。[Table] Test Example 6 Four-week-old ddY male mice were used in the experiment in groups of 10 mice. The test compound was suspended in a 0.5% carboxymethyl cellulose aqueous solution and administered orally to mice, or dissolved in a 0.1N aqueous hydrochloric acid solution, neutralized with a 0.1N aqueous sodium hydroxide solution, and intravenously administered to mice. The number of deaths was observed for 10 days after administration, and the 50% lethal dose (LD 50 ) was calculated based on the probit method. The results are shown in Table 6.
Claims (1)
R2はアミノカルボニル基、カルボキシル基、又
は炭素数１〜４の低級アルキル基もしくは炭素数
５〜７のシクロアルキル基を、R3は水素原子又
は炭素数１〜４の低級アルキル基を、R4は水素
原子又はフツ素原子を表す。）で示される７−ピ
ペラジン置換−６−フルオロ−４−オキソ−１・
４−ジヒドロキノリン−３−カルボン酸誘導体、
及びその薬理学的に許容しうる塩。[Claims] 1. General formula (In the formula, R 1 is a lower alkyl group having 1 to 4 carbon atoms,
R 2 is an aminocarbonyl group, a carboxyl group, a lower alkyl group having 1 to 4 carbon atoms, or a cycloalkyl group having 5 to 7 carbon atoms, R 3 is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R 4 represents a hydrogen atom or a fluorine atom. ) 7-piperazine-substituted-6-fluoro-4-oxo-1.
4-dihydroquinoline-3-carboxylic acid derivative,
and pharmacologically acceptable salts thereof.
Priority Applications (27)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17127183A JPS6064979A (en) | 1983-09-19 | 1983-09-19 | 7-piperazine-substituted-6-fluoro-4-oxo-1,4- dihydroquinoline-3-carboxylic acid derivative |
| ZA847059A ZA847059B (en) | 1983-09-19 | 1984-09-07 | A 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxylic acid derivative and the method for preparing the same |
| AU32984/84A AU553415B2 (en) | 1983-09-19 | 1984-09-12 | 6-fluoro-1-4-dihydro-4-oxo-7-substituted piperazinyl- quinoline-3-carboxylic acids |
| DE19843433924 DE3433924A1 (en) | 1983-09-19 | 1984-09-15 | 6-FLUORO-1,4-DIHYDRO-4-OXO-7-SUBSTITUTED PIPERAZINYL-CHINOLINE-3-CARBONIC ACID DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| AT84111035T ATE34573T1 (en) | 1983-09-19 | 1984-09-15 | A 6-FLUORO-1,4-DIHYDRO-4-OXO-7 SUBSTITUTED PIPERAZINYLQUINOLINE-3-CARBONIC ACID DERIVATIVE AND PROCESS FOR ITS PREPARATION. |
| KR1019840005625A KR870001016B1 (en) | 1983-09-19 | 1984-09-15 | Process for preparing 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxylic acid derivatives |
| EP84111035A EP0140116B1 (en) | 1983-09-19 | 1984-09-15 | A 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinyl-quinoline-3-carboxylic acid derivative and the method for preparing the same |
| US06/651,423 US4528287A (en) | 1983-09-19 | 1984-09-17 | 6-Fluoro-1, 4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxylic acids and the method for preparing the same |
| FI843620A FI80033C (en) | 1983-09-19 | 1984-09-17 | Process for the preparation of pharmacologically valuable 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxyl derivative |
| YU1603/84A YU45204B (en) | 1983-09-19 | 1984-09-18 | Process for making derivatives of 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinyle-quinoline-3-carboxilic acid |
| ES536004A ES8604565A1 (en) | 1983-09-19 | 1984-09-18 | A 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinyl-quinoline-3-carboxylic acid derivative and the method for preparing the same. |
| DK445084A DK157997C (en) | 1983-09-19 | 1984-09-18 | 6-FLUOR-1,4-DIHYDRO-4-OXO-7-SUBSTITUTED PIPERAZINYLQUINOLINE-3-CARBOXYLIC ACID DERIVATIVES AND THEIR PHARMACOLOGICAL ACCEPTABLE SALTS AND PHARMACEUTICAL COMPOSITIONS FOR TREATMENT |
| HU843498A HU193226B (en) | 1983-09-19 | 1984-09-18 | Process for preparing 6-fluoro-1,4-dihydro-4-oxo-7-substituted-piperazinyl-quinoline-3-carboxylic acid derivatives |
| SI8411603A SI8411603A8 (en) | 1983-09-19 | 1984-09-18 | Process for obtaining derivatives of 6-fluoro-1,4-dihydro-4-oxo-7- substituted piperazinyl-quinoline-3-carboxylic acids |
| UA3799807A UA6324A1 (en) | 1983-09-19 | 1984-09-18 | Process for the preparation of 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinyl- quinoline-3-carboxylic acids or pharmaceutically acceptable salts thereof |
| FR8414294A FR2555584B1 (en) | 1983-09-19 | 1984-09-18 | FLUORO-6-DIHYDRO-1,4-OXO-4-PIPERAZINYL SUBSTITUE-7-QUINOLINE-CARBOXYLIC-3 ACID DERIVATIVES AND PROCESS FOR THEIR PREPARATION AND ANTI-BACTERIAL-BASED PHARMACEUTICAL COMPOSITIONS |
| SU843799807A SU1694063A3 (en) | 1983-09-19 | 1984-09-18 | Method of obtaining derivatives of 6-fluorine-1,4-dihydro-oxo-7-substituted by piperazinylquinoline |
| CA000463652A CA1238638A (en) | 1983-09-19 | 1984-09-19 | 6-fluoro-1, 4-dihydro-4-oxo-7-substituted piperazinyl- quinoline-3-carboxylic acid derivative and the method for preparing the same |
| ES545756A ES8609303A1 (en) | 1983-09-19 | 1985-07-31 | A 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinyl-quinoline-3-carboxylic acid derivative and the method for preparing the same. |
| YU195886A YU45379B (en) | 1983-09-19 | 1986-11-17 | Process for obtaining derivatives of 6-fluoro-1,4-dihydro-4-oxo-7-substituted-piperazinyl-quinolin-3-carboxilic acid |
| SI8611958A SI8611958A8 (en) | 1983-09-19 | 1986-11-17 | Process for obtaining derivatives of 6-fluoro-1,4-dihydro-4-oxo-7- substituted piperazinyl-quinoline-3-carboxylic acids |
| HK621/91A HK62191A (en) | 1983-09-19 | 1991-08-08 | A 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinyl-quinoline-3-carboxylic acid derivative and the method for preparing the same |
| HRP-1958/86A HRP930652B1 (en) | 1983-09-19 | 1993-04-01 | Process for the preparation of 6-fluoro-1,4-didydro-4-oyo-7-substituted piperazinyl-quinoline-3-carboxylic acid derivative |
| HRP-1603/84A HRP930651B1 (en) | 1983-09-19 | 1993-04-01 | Process for the preparation of 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinyl-quinoline-3-carboxylic acid derivative |
| LTRP1004A LT2516B (en) | 1983-09-19 | 1993-09-20 | ACTICALLY ACCEPTABLE SALT PREPARATION 6-FLUORO-1,4-DIHYDRO-4-OXO-7-REPLACED PIPERAZINILCHINOLIN-3-CARBONINE SACRAMINE OR FUEL |
| LV931192A LV5500A3 (en) | 1983-09-19 | 1993-11-11 | Contribution to the production of 6-fluoro-1,4-dihydro-4-osko-7- (substituted piperazino) -quinoline-3-carbonyl derivatives or their pharmaceutically acceptable islands |
| GEAP19942165A GEP19981255B (en) | 1983-09-19 | 1994-09-07 | Method of obtaining derivatives of 6-fluorine-1,4-dihydro-oxo-7-substituted by piperazinylquinoline or pharmaceutically acceptable salts thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17127183A JPS6064979A (en) | 1983-09-19 | 1983-09-19 | 7-piperazine-substituted-6-fluoro-4-oxo-1,4- dihydroquinoline-3-carboxylic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6064979A JPS6064979A (en) | 1985-04-13 |
| JPS6256151B2 true JPS6256151B2 (en) | 1987-11-24 |
Family
ID=15920228
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17127183A Granted JPS6064979A (en) | 1983-09-19 | 1983-09-19 | 7-piperazine-substituted-6-fluoro-4-oxo-1,4- dihydroquinoline-3-carboxylic acid derivative |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPS6064979A (en) |
| YU (1) | YU45379B (en) |
| ZA (1) | ZA847059B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1161956A4 (en) | 1999-03-17 | 2005-03-16 | Daiichi Seiyaku Co | Medicinal compositions |
-
1983
- 1983-09-19 JP JP17127183A patent/JPS6064979A/en active Granted
-
1984
- 1984-09-07 ZA ZA847059A patent/ZA847059B/en unknown
-
1986
- 1986-11-17 YU YU195886A patent/YU45379B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6064979A (en) | 1985-04-13 |
| YU195886A (en) | 1987-10-31 |
| ZA847059B (en) | 1985-04-24 |
| YU45379B (en) | 1992-05-28 |
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