JPH0559914B2 - - Google Patents
Info
- Publication number
- JPH0559914B2 JPH0559914B2 JP59279455A JP27945584A JPH0559914B2 JP H0559914 B2 JPH0559914 B2 JP H0559914B2 JP 59279455 A JP59279455 A JP 59279455A JP 27945584 A JP27945584 A JP 27945584A JP H0559914 B2 JPH0559914 B2 JP H0559914B2
- Authority
- JP
- Japan
- Prior art keywords
- fluoro
- naphthyridine
- dihydro
- oxo
- ethyl
- 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 20
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 56
- -1 glutamic acid Chemical class 0.000 description 41
- 238000000354 decomposition reaction Methods 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 239000013078 crystal Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 238000007796 conventional method Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 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
- XJUYGALBGGJYGF-UHFFFAOYSA-N n-(4-methylpyrrolidin-3-yl)acetamide Chemical compound CC1CNCC1NC(C)=O XJUYGALBGGJYGF-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 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
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- DKWMZBPSRSLXRC-UHFFFAOYSA-N ethyl 4-oxo-1-(1,3-thiazol-2-yl)-1,8-naphthyridine-3-carboxylate Chemical compound C12=NC=CC=C2C(=O)C(C(=O)OCC)=CN1C1=NC=CS1 DKWMZBPSRSLXRC-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- FHUVQAZMVCLIIW-UHFFFAOYSA-N n-(3-methylpyrrolidin-3-yl)acetamide Chemical compound CC(=O)NC1(C)CCNC1 FHUVQAZMVCLIIW-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SSWHTEXLCLEUBQ-UHFFFAOYSA-N 1-benzyl-3-methylpyrrolidin-3-ol Chemical compound C1C(C)(O)CCN1CC1=CC=CC=C1 SSWHTEXLCLEUBQ-UHFFFAOYSA-N 0.000 description 1
- NFZIZQCPMPUVFT-UHFFFAOYSA-N 1-benzyl-4-methylpyrrolidin-3-amine Chemical compound C1C(N)C(C)CN1CC1=CC=CC=C1 NFZIZQCPMPUVFT-UHFFFAOYSA-N 0.000 description 1
- DHGMDHQNUNRMIN-UHFFFAOYSA-N 1-benzylpyrrolidin-3-one Chemical compound C1C(=O)CCN1CC1=CC=CC=C1 DHGMDHQNUNRMIN-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
- DEDKKOOGYIMMBC-UHFFFAOYSA-N 2,6-dichloro-5-fluoropyridine-3-carbonitrile Chemical compound FC1=CC(C#N)=C(Cl)N=C1Cl DEDKKOOGYIMMBC-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- QVCSMFIUCJOJKP-UHFFFAOYSA-N 6-fluoro-4-oxo-7-piperazin-1-yl-1-(1,3-thiazol-2-yl)-1,8-naphthyridine-3-carboxylic acid Chemical compound C=1N=C(SC=1)N1C=C(C(=O)C2=CC(F)=C(N3CCNCC3)N=C12)C(=O)O QVCSMFIUCJOJKP-UHFFFAOYSA-N 0.000 description 1
- XBTHBHWFGMNSBA-UHFFFAOYSA-N 7-(3-aminopyrrolidin-1-ium-1-yl)-6-fluoro-4-oxo-1-(1,3-thiazol-2-yl)-1,8-naphthyridine-3-carboxylic acid;chloride Chemical compound Cl.C1C(N)CCN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1=NC=CS1 XBTHBHWFGMNSBA-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-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
- 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 125000005135 aryl sulfinyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 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
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- RIMYSLDPFDGCRX-UHFFFAOYSA-N diethyl 2-(2,6-dichloro-5-fluoropyridine-3-carbonyl)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)C(=O)C1=CC(F)=C(Cl)N=C1Cl RIMYSLDPFDGCRX-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- IEUHWNLWVMLHHC-UHFFFAOYSA-N ethyl 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC(F)=C(Cl)N=C1Cl IEUHWNLWVMLHHC-UHFFFAOYSA-N 0.000 description 1
- SHQOVONJQDWWRC-UHFFFAOYSA-N ethyl 4-oxo-1h-1,8-naphthyridine-3-carboxylate Chemical compound N1=CC=CC2=C(O)C(C(=O)OCC)=CN=C21 SHQOVONJQDWWRC-UHFFFAOYSA-N 0.000 description 1
- STOTYTBCQWUTQI-UHFFFAOYSA-N ethyl 4-oxo-2,3-dihydro-1h-1,8-naphthyridine-3-carboxylate Chemical compound C1=CC=C2C(=O)C(C(=O)OCC)CNC2=N1 STOTYTBCQWUTQI-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
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 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
- 238000001727 in vivo Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 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
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QAXZWHGWYSJAEI-UHFFFAOYSA-N n,n-dimethylformamide;ethanol Chemical compound CCO.CN(C)C=O QAXZWHGWYSJAEI-UHFFFAOYSA-N 0.000 description 1
- UQNMXJKZMQAZPZ-UHFFFAOYSA-N n-(1-benzyl-3-methylpyrrolidin-3-yl)acetamide Chemical compound C1C(NC(=O)C)(C)CCN1CC1=CC=CC=C1 UQNMXJKZMQAZPZ-UHFFFAOYSA-N 0.000 description 1
- HDCCJUCOIKLZNM-UHFFFAOYSA-N n-pyrrolidin-3-ylacetamide Chemical compound CC(=O)NC1CCNC1 HDCCJUCOIKLZNM-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
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 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
- GCRNGPNGNJSZCC-UHFFFAOYSA-N tert-butyl 3-amino-3a,4,6,6a-tetrahydro-1h-pyrrolo[3,4-c]pyrazole-5-carboxylate Chemical compound N1N=C(N)C2CN(C(=O)OC(C)(C)C)CC21 GCRNGPNGNJSZCC-UHFFFAOYSA-N 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
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Description
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The present invention relates to novel pyridonecarboxylic acid derivatives, esters thereof, and salts thereof, which exhibit extremely excellent antibacterial activity. More specifically, the compound of the present invention has the following general formula: (In the formula, R 1 means a thienyl, thiazolyl, isothiazolyl, isoxazolyl, or pyridyl group that may have a lower alkyl group, and R 2 is a group represented by the following formula.
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ã¯ãå¯èœãªãã°ããã®[Formula], where R 3 means a hydrogen atom or a lower alkyl group, and R 4 represents a hydrogen atom, a hydroxy group,
means an amino group, a mono- or di-lower alkylamino group, an amino-lower alkyl group, or a mono- or di-lower alkylamino lower alkyl group,
R 5 means a hydrogen atom or a lower alkyl group bonded to the 3rd or 4th position. ) Pyridonecarboxylic acid derivatives, esters thereof, and salts thereof. As used herein, a lower alkyl group means an alkyl group having 1 to 3 carbon atoms. Salts of the compounds of the present invention include acetic acid, lactic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid,
Salts with organic acids such as gluconic acid, aspartic acid,
Salts with amino acids such as glutamic acid, or hydrochloric acid,
These are salts with inorganic acids such as phosphoric acid, metal salts such as sodium, potassium, zinc, silver, etc. of the compound of formula [], or salts with organic bases. The ester of the compound of the formula [] refers to a lower alkyl ester such as methyl ester or ethyl ester of the compound [], or a compound [] that is easily eliminated by hydrolysis or in vivo.
Known esters such as pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, aminoethyl esters such as dimethylaminoethyl ester and 1-piperidinylethyl ester, 5-indanyl ester, phthalidyl ester etc. Compounds of the invention may also exist as hydrates. Therefore, compounds of this type are naturally included in the compounds of the present invention. The compounds of the present invention include those having an asymmetric carbon atom in the substituent R 2 at the 7-position, and they may exist as optically active forms. Therefore, these optically active substances are included in the compounds of the present invention. Furthermore, the compound of the present invention may have two asymmetric carbon atoms in the substituent R 2 at the 7-position,
Therefore different stereoisomers (cis, trans)
There are things that can exist as These stereoisomers are also included in the compounds of the present invention. The method for producing the compound of the present invention will be explained below. The compound of the present invention has the following general formula: (In the formula, Z means a functional group that can be substituted with the cyclic amine derivative described later, and R 1 is the same as above). A carboxylic acid or its ester (preferably a lower alkyl ester) represented by the following formula is reacted with a cyclic amine derivative represented by the following general formula R 2 -H [] (wherein R 2 is the same as above) to form a product. It can be produced by isolation using conventional methods. The reactive functional group shown by Z in formula [] is
Examples include halogen atom, arylsulfonyl, arylsulfinyl, lower alkylsulfonyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, arylsulfonyloxy, and lower alkylsulfonyloxy. In this reaction, the raw material compound [ ] or its ester and [ 120 minutes, usually
This can be carried out by mixing and stirring for 20 to 60 minutes.
The amount of starting compound [] to be used is equivalent to or slightly in excess of starting compound [] or its ester. Depending on Z of the raw material compound [ ] or its ester and the type of functional group, an acid such as hydrochloric acid may be produced as a by-product as a result of the reaction. In such cases, it is common to use an acid acceptor; ] may be used in excess to serve as an acid acceptor. In addition, the raw material compounds used in this reaction []
If possible, that
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ã«ããŒã¿ãæããã[Formula] or R 4 - may be used in a protected form with acetyl or the like, and after completion of the reaction, the protecting group may be removed by a conventional method. The starting compound [ ] or its ester can be produced by the method described in Reference Examples 1 and 2 or a method analogous thereto. The starting compound [ ] can be produced by the method described in Reference Examples 3 and 4 or a method analogous thereto. When the compound of the present invention obtained by the above method is an ester, it 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, it can be obtained in the form of a salt, a free carboxylic acid, or a free amine, but these can be mutually converted depending on the purpose to produce the compound of the present invention in the desired form. Ru. Stereoisomers (cis, trans) of the compounds of the invention can be separated from each other by conventional methods, such as fractional crystallization, chromatographic separation, and the like. In addition, by the above method using a compound [] having a cis or trans configuration,
It is also possible to produce compounds of the invention having cis and trans configurations, respectively. Optically active forms of the compounds of the present invention can be separated by applying known methods. The compound thus obtained, its ester, and its salt are all new compounds. In particular, compound [] and its salts exhibit extremely excellent antibacterial activity and are therefore valuable as antibacterial agents. The compound [ ] or its salt can be used not only as a medicine for the human body and animals, but also as a medicine for fish diseases, an agricultural chemical, a food preservative, and the like. In addition, the ester form of compound [] is of course valuable as a raw material for the synthesis of compound [], but in addition, when this compound is easily converted into compound [] in the living body, compound []
It is also a useful compound as an antibacterial agent because it can exhibit the same effect as that of antibacterial agents. Next, data regarding the antibacterial activity of the compounds of the present invention are listed below.
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å®æœäŸ 18
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å®æœäŸ 20
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å®æœäŸ 26
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å®æœäŸ 27
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解ïŒ[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, tablets, and injections. These formulations are prepared according to conventional methods. Oral preparation carriers include starch, mannitrate,
Substances commonly used in the pharmaceutical field, such as crystalline cellulose and CMC Na, and which do not react with the compound of the present invention are used. Examples of the carrier for injection include carriers commonly used in the field of injections such as water, physiological saline, glucose solution, and infusion preparations. Next, the method for producing the compound of the present invention will be explained in more detail with reference to Examples and Reference Examples. Reference example 1 7-chloro-6-fluoro-1-(2-thienyl)-1,4-dihydro-4-oxo-1,8
-Ethyl naphthyridine-3-carboxylate: (1) 60 g of 2,6-dichloro-5-fluoronicotinonitrile, a known compound, is heated in concentrated sulfuric acid at 65 to 75°C for 1 hour. Water was added and the mixture was further heated at 100-110°C for 2 hours to obtain 59.8 g of 2,6-dichloro-5-fluoronicotinic acid. mp 155-156°C (2) 45.2 g of this compound is treated with thionyl chloride to obtain 47.5 g of 2,6-dichloro-5-fluoroniconic acid chloride as an oil. (3) 47.5 g of this compound is reacted with diethyl ethoxymagnesium malonate in anhydrous ether to obtain diethyl 2,6-dichloro-5-fluoronicotinoylmalonate as an oil. Water and a catalytic amount of P-toluenesulfonic acid were added to this, heated at 140°C for 2 hours, and 46g of ethyl 2,6-dichloro-5-fluoronicotinoyl acetate was added.
get. mp69-70â (4) Treat 12g of this compound with ethyl orthoformate and acetic anhydride to obtain 2-(2,6-dichloro-5-
2-(2,6- 15 g of ethyl dichloro-5-fluoronicotinoyl)-3-(2-thienylamino)acrylate are obtained. mp114â (5) 15 g of this compound was reacted with potassium t-butoxide in anhydrous dioxane to give 7-chloro-
6-Fluoro-1-(2-thienyl)-1,4-
9.5 g of ethyl dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are obtained. mp193-195°C Reference Example 2 The following compound is produced according to the method of Reference Example 1. (1) 7-chloro-6-fluoro-1-(2-thiazolyl)-1,4-dihydro-4-oxo-1,
Ethyl 8-naphthyridine-3-carboxylate
mp182ïœ184â (2) Ethyl 7-chloro-6-fluoro-1-(3-methyl-5-isothiazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate mp179ïœ 180â (3) Ethyl 7-chloro-6-fluoro-1-(3-isoxazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate mp210-212â (4) 7 -chloro-6-fluoro-1-(5-methyl-3-isoxazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
Ethyl carboxylate mp168-169â (5) Ethyl 7-chloro-6-fluoro-1-(5-isoxazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate mp147-148 °C (6) 7-chloro-1-(3,5-dimethyl-4-
isoxazolyl)-6-fluoro-1,4-
Ethyl dihydro-4-oxo-1,8-naphthyridine-3-carboxylate mp248-250â (7) 7-chloro-6-fluoro-1-(3-pyridyl)-1,4-dihydro-4-oxo- 1,
Ethyl 8-naphthyridine-3-carboxylate
mp208ïœ209â (8) 7-chloro-6-fluoro-1-(4-pyridyl)-1,4-dihydro-4-oxo-1,
Ethyl 8-naphthyridine-3-carboxylate
mp252~253â (9) Ethyl 7-chloro-6-fluoro-1-(4-isoxazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate mp187~189â (10 ) 7-chloro-6-fluoro-1-(3-methyl-5-isoxazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
Ethyl carboxylate mp182-183â Reference example 3 3-acetylamino-4-methylpyrrolidine: 3-amino-1-benzyl-4-methylpyrrolidine (see JP-A-55-22699) is reacted with acetic anhydride to form 3-acetylamino-4-methylpyrrolidine. -acetylamino-1-benzyl-4
-Methylpyrrolidine is obtained as an oil. IR spectrum: 3300, 1650cm -1 . This compound is catalytically reduced in the presence of 5% palladium on carbon to yield 3-acetylamino-4-methylpyrrolidine as an oil. Reference example 4 3-acetylamino-3-methylpyrrolidine: 1-benzyl-3-pyrrolidone [J.Org.
Chem., 30 , 740 (1965)] with methylmagnesium bromide to give 1-benzyl-3-hydroxy-3-methylpyrrolidine as an oil. bp106â/0.5mmHg. This compound is treated with a mixed solution of acetonitrile and concentrated sulfuric acid under ice cooling to obtain 3-acetylamino-1-benzyl-3-methylpyrrolidine. mp105-106â. This was catalytically reduced in the presence of 5% palladium-carbon.
3-acetylamino-3-methylpyrrolidine is obtained as an oil. Example 1 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2-thienyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
Carboxylic acid and its hydrochloride: (1) 7-chloro-6-fluoro-1-(2-thienyl)-1,4-dihydro-4-oxo-1,
Ethyl 8-naphthyridine-3-carboxylate 500
mg, 3-acetylaminopyrrolidine 240mg, sodium bicarbonate 240mg, acetonitrile 4ml
The mixture is stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer is separated, dried, and then the chloroform is distilled off. The resulting crude crystals were recrystallized from ethanol to give 7-(3-acetylamino-1-pyrrolidinyl)-6-fluoro-1-(2-thienyl)-1,4-dihydro-4
560 mg of ethyl -oxo-1,8-naphthyridine-3-carboxylate are obtained. mp231°C (2) A mixture of 560 mg of the above ester and 4 ml of 20% hydrochloric acid is heated under reflux for 5 hours. After cooling, the crystals were collected by filtration, washed with ethanol, and dried to give 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-
400 mg of (2-thienyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride are obtained. Recrystallize from water-ethanol. mp293-295°C (decomposition) (3) Suspend 400 mg of the above hydrochloride in 10 ml of water and neutralize with 10% aqueous ammonia. The precipitated crystals are collected by filtration and dried to give 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2-thienyl).
330 mg of -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. mp288-291°C (decomposition) Compounds of Examples 2-11 were obtained in the same manner as in Example 1. Example 2 (1) 7-(3-acetylamino-3-methyl-1
-pyrrolidinyl)-6-fluoro-1-(2-thienyl)-1,4-dihydro-4-oxo-1,
Ethyl 8-naphthyridine-3-carboxylate
mp243ïœ244â (2) 7-(3-amino-3-methyl-1-pyrrolizonyl)-6-fluoro-1-(2-thienyl)
-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride mp215
~218â Example 3 (1) 7-(3-acetylamino-4-methyl-1
-pyrrolidinyl)-6-fluoro-1-(2-thienyl)-1,4-dihydro-4-oxo-1,
Ethyl 8-naphthyridine-3-carboxylate
mp236-237â (2) 7-(3-amino-4-methyl-1-pyrrolizonyl)-6-fluoro-1-(2-thienyl)
-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride mp296
~297°C (decomposition) Example 4 (1) 7-(3-acetylaminomethyl-1-pyrrolidinyl)-6-fluoro-1-(2-thienyl)-1,4-dihydro-4-oxo-1, 8
-Ethyl naphthyridine-3-carboxylate m.
p.99ã100â (2) 7-(3-aminomethyl-1-pyrrolidinyl)
-6-fluoro-1-(2-thienyl)-1,4
-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride mp237-240â Example 5 (1) 7-(3-acetylamino-1-pyrrolidinyl)-6-fluoro-1-(2 -thiazolyl)
-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl mp253~
255â (2) 7-(3-amino-1-pyrrolidinyl)-6-
Fluoro-1-(2-thiazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-
3-Carboxylic hydrochloride mp286-288â (decomposition) Example 6 (1) 7-(3-acetylamino-1-pyrrolidinyl)-6-fluoro-1-(3-isoxazolyl)-1,4-dihydro- 4-oxo-1,8
-Ethyl naphthyridine-3-carboxylate m.
p.219ã220â (2) 7-(3-amino-1-pyrrolidinyl)-6-
Fluoro-1-(3-isoxazolyl)-1,
4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride mp>300°C Example 7 (1) 7-(3-acetylamino-1-pyrrolidinyl)-6-fluoro-1-( 4-isoxazolyl)-1,4-dihydro-4-oxo-1,8
-Ethyl naphthyridine-3-carboxylate m.
p.187ã188â (2) 7-(3-amino-1-pyrrolidinyl)-6-
Fluoro-1-(4-isoxazolyl)-1,
4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride mp>300°C Example 8 (1) 7-(3-acetylaminomethyl-1-pyrrolidinyl)-6-fluoro-1- (5-isoxazolyl)-1,4-dihydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylate
mp197â (2) 7-(3-aminomethyl-1-pyrrolidinyl)
-6-Fluoro-1-(5-isoxazolyl)
-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride mp236~
239â Example 9 (1) 7-(3-acetylamino-1-pyrrolidinyl)-6-fluoro-1-(3-isoxazolyl)-1,4-dihydro-4-oxo-1,8
-Ethyl naphthyridine-3-carboxylate m.
p.230â (2) 7-(3-amino-1-pyrrolidinyl)-6-
Fluoro-1-(3-isoxazolyl)-1,
4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride mp>300°C Example 10 (1) 7-(3-acetylamino-1-pyrrolidinyl)-1-(3,5- dimethyl-4-isoxazolyl)-6-fluoro-1,4-dihydro-
Ethyl 4-oxo-1,8-naphthyridine-3-carboxylate mp243-245â (2) 7-(3-amino-1-pyrrolidinyl)-1-
(3,5-dimethyl-4-isoxazolyl)-
6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride (3) 7-(3-amino-1-pyrrolidinyl)-1-
(3,5-dimethyl-4-isoxazolyl)-
6-Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
mp264â (decomposition) Example 11 (1) 7-(3-acetylamino-1-pyrrolidinyl)-6-fluoro-1-(3-methyl-5-isoxazolyl)-1,4-dihydro-4-oxo- Ethyl 1,8-naphthyridine-3-carboxylate mp244-245â (2) 7-(3-amino-1-pyrrolidinyl)-6-
Fluoro-1-(3-methyl-5-isoxazolyl-1,4-dihydro-4-oxo-1,
8-naphthyridine-3-carboxylic hydrochloride
mp294-296â (decomposition) Example 12 6-fluoro-7-(1-piperazinyl)-1-
(2-thiazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and its hydrochloride: (1) 7-chloro-6-fluoro-1-(2-thiazolyl)- 1,4-dihydro-4-oxo-1,
Ethyl 8-naphthyridine-3-carboxylate 500
Example 1: mg and 220 mg of 4-acetylpiperazine
- 7-(4-acetyl-1-piperazinyl)-6-fluoro-1-
550 mg of ethyl (2-thiazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are obtained. Recrystallize from ethyl acetate. mp202-203°C (2) A mixture of 500 mg of the above ester and 8 ml of 10% hydrochloric acid is heated under reflux for 4 hours. After cooling, the precipitated crystals are collected by filtration and dried to give 6-fluoro-7-(1-piperazinyl)-1-(2-thiazolyl)-1,4
403 mg of -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride are obtained. (3) Suspend 380 mg of the above hydrochloride in 10 ml of water and neutralize with 1N sodium hydroxide. The precipitated crystals are collected by filtration, washed with water, and then dried. Recrystallization from dimethylformamide gave 6-fluoro-7-(1-piperazinyl)-1-(2-thiazolyl)-1,4-
284 mg of dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. mp269~271
C (Decomposition) Compounds of Examples 13 and 14 were obtained in the same manner as in Example 12. Example 13 (1) 7-(4-acetyl-1-piperazinyl)-6
-Fluoro-1-(3-pyridyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-
Ethyl 3-carboxylate mp218-219â (2) 6-fluoro-7-(1-piperazinyl)-1
-(3-pyridyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride mp296-299â (decomposition) Example 14 (1) 7-(4-acetyl-1 -piperazinyl)-6
-Fluoro-1-(5-isoxazolyl)-
Ethyl 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate mp225~
227â (2) 6-fluoro-1-(5-isoxazolyl)
-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride acid mp294-297°C (decomposition) Example 15 6-Fluoro-7-(4-methyl -1-piperazinyl)-1-(2-thienyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid: (1) 7-chloro-6-fluoro-1-(2-thienyl)-1,4-dihydro-4-oxo-1,
Ethyl 8-naphthyridine-3-carboxylate 500
Example 1-
6-Fluoro-7-
(4-methyl-1-piperazinyl)-1-(2-
thienyl)-1,4-dihydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylate
Get 500mg. Recrystallize from ethanol. m.
p.193-194°C (2) A mixture of 450 mg of the above ester and 3 ml of 0.5N sodium hydroxide is heated and stirred at 90-100°C for 30 minutes.
After cooling, neutralize with 1N acetic acid and extract with chloroform. Separate the organic layer, wash with water, and dry. Chloroform was distilled off, and the resulting crude crystals were recrystallized from chloroform-ethanol to give 6-fluoro-7-(4-methyl-1-piperazinyl)-1.
-(2-thienyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
Get 370mg. mp242-243°C Compounds of Examples 16-20 are obtained in the same manner as in Example 15. Example 16 (1) 6-fluoro-7-(4-methyl-1-piperazinyl)-1-(2-thiazolyl)-1,4-
Ethyl dihydro-4-oxo-1,8-naphthyridine-3-carboxylate mp115-116â (2) 6-fluoro-7-(4-methyl-1-piperazinyl)-1-(2-thiazolyl)-1, 4-
Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid mp274-275â (decomposition) Example 17 (1) 6-fluoro-1-(3-methyl-5-isothiazolyl)-7-(4- methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,
Ethyl 8-naphthyridine-3-carboxylate m.
p.118-119â (2) 6-fluoro-1-(3-methyl-5-isothiazolyl)-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,
8-naphthyridine-3-carboxylic acid mp275
~277°C (decomposition) Example 18 (1) 6-fluoro-1-(5-methyl-3-isoxazolyl)-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo- 1,
Ethyl 8-naphthyridine-3-carboxylate
mp154-155â (2) 6-fluoro-1-(5-methyl-3-isoxazolyl)-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,
8-naphthyridine-3-carboxylic acid mp228
~230 (Decomposition) Example 19 (1) 1-(3,5-dimethyl-4-isoxazolyl)-6-fluoro-7-(4-methyl-1-
1-(3,5-dimethyl-4-isoxazolyl)-6-fluoro-7-( 4-methyl-1-
piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
mp218-220â (decomposition) Example 20 (1) 6-fluoro-7-(4-methyl-1-piperazinyl)-1-(4-pyridyl)-1,4-dihydro-4-oxo-1,8 -Naphthyridine-
Ethyl 3-carboxylate mp203-204â (2) 6-fluoro-7-(4-methyl-1-piperazinyl)-1-(4-pyridyl)-1,4-dihydro-4-oxo-1,8- Naphthyridine
3-Carboxylic acid mp290-292â Example 21 6-fluoro-7-(1-piperazinyl)-1-
(2-thienyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid: (1) 7-chloro-6-fluoro-1-(2-thienyl)-1,4- dihydro-4-oxo-1,
Ethyl 8-naphthyridine-3-carboxylate 500
mg, anhydrous piperazine 430 mg, acetonitrile 5
ml of the mixture is stirred for 1 hour at room temperature. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer is separated, dried, and then chloroform is distilled off. The resulting crude crystals were recrystallized from ethyl acetate to give 6-fluoro-7-
(1-piperazinyl)-1-(2-thienyl)-
500 mg of ethyl 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are obtained.
mp187-188°C (2) A mixture of 402 mg of the above ester and 3 ml of 0.5N sodium hydroxide is heated and stirred at 90-100°C for 30 minutes.
Neutralize with 1N acetic acid at room temperature. After cooling, the precipitated crystals are collected by filtration, washed with water, and then dried. The crude crystals were recrystallized from chloroform-ethanol to give 6-fluoro-7-(1-piperazinyl)-1-(2-thienyl)-1,4-dihydro-4-oxo-1,
300 mg of 8-naphthyridine-3-carboxylic acid are obtained. mp222-223°C Compounds of Examples 22-23 are obtained in the same manner as in Example 21. Example 22 (1) 6-fluoro-1-(3-isoxazolyl)
-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl mp209-210â (2) 6-fluoro-1-(3-isoxazolyl)
-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid mp249-250â (decomposition) Example 23 (1) 6-fluoro-1-(5 -methyl-3-isoxazolyl)-7-(1-piperazinyl)-1,
Ethyl 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate mp170-171â (2) 6-fluoro-1-(5-methyl-3-isoxazolyl)-7-(1-piperazinyl)- 1,
4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid mp248-249°C (decomposition) Example 24 6-fluoro-7-(1-pyrrolidinyl)-1-
(2-thiazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid: (1) 7-chloro-6-fluoro-1-(2-thiazolyl)-1,4- dihydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylate
500mg, pyrrolidine 250mg, acetonitrile 5ml
The mixture is stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give 6-
Fluoro-7-(1-pyrrolidinyl)-1-(2
500 mg of ethyl (-thiazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are obtained. m.p205-206â (2) 388 mg of the above ester was treated in the same manner as in Example 21-(2), and 6-fluoro-7-(1-pyrrolidinyl)-1-(2-thiazolyl)-1,4 -dihydro-4-oxo-1,8-naphthyridine-3
- 340 mg of carboxylic acid are obtained. Recrystallize from dimethylformamide-ethanol. mpïŒ300
C. Compounds of Examples 25 to 27 are obtained in the same manner as in Example 24. Example 25 (1) 6-fluoro-1-(3-pyridyl)-7-
(1-pyrrolidinyl)-1,4-dihydro-4-
Ethyl oxo-1,8-naphthyridine-3-carboxylate mp251-252â (2) 6-fluoro-1-(3-pyridyl)-7-
(1-pyrrolidinyl)-1,4-dihydro-4-
Ethyl oxo-1,8-naphthyridine-3-carboxylate mp295-297â (decomposition) Example 26 (1) 6-fluoro-1-(4-pyridyl)-7-
(1-pyrrolidinyl)-1,4-dihydro-4-
Ethyl oxo-1,8-naphthyridine-3-carboxylate mp248-249â (2) 6-fluoro-1-(4-pyridyl)-7-
(1-pyrrolidinyl)-1,4-dihydro-4-
Ethyl oxo-1,8-naphthyridine-3-carboxylate mp>300â Example 27 (1) 6-fluoro-1-(5-methyl-3-isoxazolyl)-7-(1-pyrrolidinyl)-1,
Ethyl 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate mp200-201â (2) 6-fluoro-1-(5-methyl-3-isoxazolyl)-7-(1-pyrrolidinyl)- 1,
4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid mp266-267â (decomposition)
Claims (1)
ãããšãã«ããã¢ãŸãªã«ãã€ãœãã¢ãŸãªã«ãã€ãœ
ãªããµãŸãªã«ãŸãã¯ããªãžã«åºãæå³ããR2ã¯
äžèšåŒã§è¡šããããåº ãåŒããŸãã¯ãåŒã ãæå³ããããã«R3ã¯æ°ŽçŽ ååãŸãã¯äœçŽã¢ã«
ãã«åºãæå³ããR4ã¯æ°ŽçŽ ååãããããã·åºã
ã¢ããåºãã¢ããããã¯ãžäœçŽã¢ã«ãã«ã¢ãã
åºãã¢ããäœçŽã¢ã«ãã«åºããŸãã¯ã¢ããããã¯
ãžäœçŽã¢ã«ãã«ã¢ããäœçŽã¢ã«ãã«åºãæå³ãã
R5ã¯ïŒäœãããã¯ïŒäœã«çµåããæ°ŽçŽ ååãŸã
ã¯äœçŽã¢ã«ãã«åºãæå³ããã ã§è¡šããããããªãã³ã«ã«ãã³é žèªå°äœããã®ãš
ã¹ãã«ããã³ãã®å¡©ã[Claims] 1. General formula (In the formula, R 1 means a thienyl, thiazolyl, isothiazolyl, isoxazolyl, or pyridyl group which may have a lower alkyl group, and R 2 means a group represented by the following formula [formula] or [formula] , where R 3 means a hydrogen atom or a lower alkyl group, and R 4 means a hydrogen atom, a hydroxy group,
means an amino group, a mono- or di-lower alkylamino group, an amino-lower alkyl group, or a mono- or di-lower alkylamino lower alkyl group,
R 5 means a hydrogen atom or a lower alkyl group bonded to the 3rd or 4th position. Pyridonecarboxylic acid derivatives, esters thereof and salts thereof.
Priority Applications (1)
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JP59279455A JPS61152682A (en) | 1984-12-27 | 1984-12-27 | Pyridonecarboxylic acid derivative, its ester and salt |
Applications Claiming Priority (1)
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JP59279455A JPS61152682A (en) | 1984-12-27 | 1984-12-27 | Pyridonecarboxylic acid derivative, its ester and salt |
Publications (2)
Publication Number | Publication Date |
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JPS61152682A JPS61152682A (en) | 1986-07-11 |
JPH0559914B2 true JPH0559914B2 (en) | 1993-09-01 |
Family
ID=17611304
Family Applications (1)
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JP59279455A Granted JPS61152682A (en) | 1984-12-27 | 1984-12-27 | Pyridonecarboxylic acid derivative, its ester and salt |
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JP (1) | JPS61152682A (en) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6233176A (en) * | 1985-08-05 | 1987-02-13 | Toyama Chem Co Ltd | 1,4-dihydro-4-oxonaphthyridine derivative and salt thereof |
HU205105B (en) * | 1987-10-26 | 1992-03-30 | Pfizer | Process for producing azetidinyl quinoline carboxylic acids and pharmaceutical compositions comprising same |
TW273551B (en) * | 1993-05-24 | 1996-04-01 | Wakiei Seiyaku Kk | |
EP0713487B1 (en) * | 1993-08-13 | 2000-04-19 | Dong Wha Pharmaceutical Industrial Co. Ltd. | Novel quinolone carboxylic acid derivatives |
JP3391796B2 (en) * | 1994-06-14 | 2003-03-31 | 倧æ¥æ¬è£œè¬æ ªåŒäŒç€Ÿ | New compounds, their preparation and antitumor agents |
PT911327E (en) * | 1995-09-22 | 2002-05-31 | Wakunaga Pharma Co Ltd | NEW PYRIDONOCARBOXYLIC ACID DERIVATIVES OR ITS SALTS AND ANTIBACTERIAL AGENT UNDERSTANDING THE SAME AS THE ACTIVE INGREDIENT |
JP5079612B2 (en) * | 1995-12-13 | 2012-11-21 | 倧æ¥æ¬äœå補è¬æ ªåŒäŒç€Ÿ | Antitumor agent |
JP4364814B2 (en) | 2005-02-04 | 2009-11-18 | äžäºéå±é±æ¥æ ªåŒäŒç€Ÿ | Opening and closing device for vehicle sliding door |
US7563805B2 (en) | 2005-05-19 | 2009-07-21 | Daiichi Pharmaceutical Co., Ltd. | Tri-, tetra-substituted-3-aminopyrrolidine derivative |
DE102017218119A1 (en) * | 2017-10-11 | 2019-04-11 | Christian-Albrechts-UniversitÀt Zu Kiel | Environmentally degradable quinolone antibiotics with hemiaminal structural unit |
-
1984
- 1984-12-27 JP JP59279455A patent/JPS61152682A/en active Granted
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