JPH0633262B2 - 1,4-Dihydro-4-oxonaphthyridine derivatives and salts thereof - Google Patents
1,4-Dihydro-4-oxonaphthyridine derivatives and salts thereofInfo
- Publication number
- JPH0633262B2 JPH0633262B2 JP62254530A JP25453087A JPH0633262B2 JP H0633262 B2 JPH0633262 B2 JP H0633262B2 JP 62254530 A JP62254530 A JP 62254530A JP 25453087 A JP25453087 A JP 25453087A JP H0633262 B2 JPH0633262 B2 JP H0633262B2
- Authority
- JP
- Japan
- Prior art keywords
- piperazinyl
- group
- fluoro
- methyl
- methoxyphenyl
- 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
- 150000003839 salts Chemical class 0.000 title claims description 52
- NQUIRWXTTAMWIU-UHFFFAOYSA-N 1h-1,8-naphthyridin-4-one Chemical class C1=CC=C2C(O)=CC=NC2=N1 NQUIRWXTTAMWIU-UHFFFAOYSA-N 0.000 title claims description 7
- -1 1-piperazinyl group Chemical group 0.000 claims description 172
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 6
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 6
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 6
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 4
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- CVAQZAKLVQJAQT-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-6-fluoro-4-oxo-7-piperazin-1-yl-1,8-naphthyridine-3-carboxylic acid Chemical compound C12=NC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1=CC=C(F)C=C1F CVAQZAKLVQJAQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims description 2
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 64
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- 239000002904 solvent Substances 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 241000894006 Bacteria Species 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-DYCDLGHISA-N trifluoroacetic acid-d1 Chemical compound [2H]OC(=O)C(F)(F)F DTQVDTLACAAQTR-DYCDLGHISA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000192125 Firmicutes Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 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 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 150000003462 sulfoxides Chemical class 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- SJKYPLMDBYUXQV-UHFFFAOYSA-N 4-oxo-7-piperazin-1-yl-1h-1,8-naphthyridine-3-carboxylic acid Chemical compound C=1C=C2C(=O)C(C(=O)O)=CNC2=NC=1N1CCNCC1 SJKYPLMDBYUXQV-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- WWLDLPOUSQVAJT-UHFFFAOYSA-N ethyl 2-(2,6-dichloro-5-fluoropyridine-3-carbonyl)-3-(2,4-difluoroanilino)prop-2-enoate Chemical compound C=1C(F)=C(Cl)N=C(Cl)C=1C(=O)C(C(=O)OCC)=CNC1=CC=C(F)C=C1F WWLDLPOUSQVAJT-UHFFFAOYSA-N 0.000 description 2
- JLSXYCZRMYCIMY-UHFFFAOYSA-N ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylate Chemical compound C12=NC(Cl)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1=CC=C(F)C=C1F JLSXYCZRMYCIMY-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000002054 inoculum Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- BWKAYBPLDRWMCJ-UHFFFAOYSA-N 1,1-diethoxy-n,n-dimethylmethanamine Chemical compound CCOC(N(C)C)OCC BWKAYBPLDRWMCJ-UHFFFAOYSA-N 0.000 description 1
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 1
- CGXLVFZJJOXEDF-UHFFFAOYSA-N 1,8-naphthyridine-3-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CN=C21 CGXLVFZJJOXEDF-UHFFFAOYSA-N 0.000 description 1
- RERHEBUXVQAXBL-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C12=NC=CC=C2C(=O)C(C(=O)O)=CN1C1=CC=C(F)C=C1F RERHEBUXVQAXBL-UHFFFAOYSA-N 0.000 description 1
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-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
- CEPCPXLLFXPZGW-UHFFFAOYSA-N 2,4-difluoroaniline Chemical compound NC1=CC=C(F)C=C1F CEPCPXLLFXPZGW-UHFFFAOYSA-N 0.000 description 1
- AATVXELAYCLVTJ-UHFFFAOYSA-N 2,6-dichloro-5-fluoropyridine-3-carbonyl chloride Chemical compound FC1=CC(C(Cl)=O)=C(Cl)N=C1Cl AATVXELAYCLVTJ-UHFFFAOYSA-N 0.000 description 1
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 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
- 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 1
- ZZLCFHIKESPLTH-UHFFFAOYSA-N 4-Methylbiphenyl Chemical compound C1=CC(C)=CC=C1C1=CC=CC=C1 ZZLCFHIKESPLTH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- XDJSDVYSHOCYIR-UHFFFAOYSA-N ClC1=C(C(=O)C(C(=O)OCC)=CNC2=C(C=C(C=C2)OC)C)C=C(C(=N1)N1CCN(CC1)C)F Chemical compound ClC1=C(C(=O)C(C(=O)OCC)=CNC2=C(C=C(C=C2)OC)C)C=C(C(=N1)N1CCN(CC1)C)F XDJSDVYSHOCYIR-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-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
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000032536 Pseudomonas Infections Diseases 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical group [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 1
- 125000004212 difluorophenyl group Chemical group 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- AJSCNDNIRMZFBQ-UHFFFAOYSA-N ethyl 1-(2,4-difluorophenyl)-4-oxo-1,8-naphthyridine-3-carboxylate Chemical compound C(C)OC(=O)C1=CN(C2=NC=CC=C2C1=O)C1=C(C=C(C=C1)F)F AJSCNDNIRMZFBQ-UHFFFAOYSA-N 0.000 description 1
- FUZDFYKEDHKZIN-UHFFFAOYSA-N ethyl 3-(2,4-difluoroanilino)prop-2-enoate Chemical compound C(C)OC(C=CNC1=C(C=C(C=C1)F)F)=O FUZDFYKEDHKZIN-UHFFFAOYSA-N 0.000 description 1
- LMJPXPMGPHJMKO-UHFFFAOYSA-N ethyl 3-[2-chloro-5-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-oxopropanoate Chemical compound ClC1=C(C(=O)CC(=O)OCC)C=C(C(=N1)N1CCN(CC1)C)F LMJPXPMGPHJMKO-UHFFFAOYSA-N 0.000 description 1
- APQGYFNHIWMRIJ-UHFFFAOYSA-N ethyl 3-oxo-3-pyridin-3-ylpropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=CN=C1 APQGYFNHIWMRIJ-UHFFFAOYSA-N 0.000 description 1
- XQHKKRWKTKRAKM-UHFFFAOYSA-N ethyl 6-fluoro-1-(4-methoxy-2-methylphenyl)-7-(4-methylpiperazin-1-yl)-4-oxo-1,8-naphthyridine-3-carboxylate Chemical compound FC=1C=C2C(C(=CN(C2=NC1N1CCN(CC1)C)C1=C(C=C(C=C1)OC)C)C(=O)OCC)=O XQHKKRWKTKRAKM-UHFFFAOYSA-N 0.000 description 1
- WHBQSCWQDOGIGB-UHFFFAOYSA-N ethyl 7-(4-acetylpiperazin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylate Chemical compound C12=NC(N3CCN(CC3)C(C)=O)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1=CC=C(F)C=C1F WHBQSCWQDOGIGB-UHFFFAOYSA-N 0.000 description 1
- RFFZPMRXTLJMPF-UHFFFAOYSA-N ethyl 7-(4-acetylpiperazin-1-yl)-6-fluoro-1-(4-fluorophenyl)-4-oxo-1,8-naphthyridine-3-carboxylate Chemical compound C(C)(=O)N1CCN(CC1)C1=C(C=C2C(C(=CN(C2=N1)C1=CC=C(C=C1)F)C(=O)OCC)=O)F RFFZPMRXTLJMPF-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 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
- 238000002955 isolation Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 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
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- 229960000210 nalidixic acid Drugs 0.000 description 1
- 150000002825 nitriles Chemical class 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
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229950009506 penicillinase Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002743 phosphorus functional group Chemical group 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
- RCIMBBZXSXFZBV-UHFFFAOYSA-N piromidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCCC1 RCIMBBZXSXFZBV-UHFFFAOYSA-N 0.000 description 1
- 229960004444 piromidic acid Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、一般式 式中、Ｒ1は水素原子またはカルボキシル保護基を；Ｒ3
が１−ピペラジニル基で、Ｒ2は、３−フルオロフェニ
ル、３，４−ジフルオロフェニル、２，４−ジフルオロ
フェニル、２，５−ジフルオロフェニル、２，６−ジフ
ルオロフェニル、４−クロロフェニル、４−ブロモフェ
ニル、４−メチルフェニル、４−シアノフェニル、４−
アミノフェニル、４−トリフルオロメチルフェニル、４
−フルオロ−２−メチルフェニル、４−フルオロ−２−
ヒドロキシフェニル、４−ヒドロキシ−２−メチルフェ
ニルあるいは２−フルオロ−４−ヒドロキシフェニル基
を；Ｒ3が４−アセチル−１−ピペラジニル基で、Ｒ
2は、３−フルオロフェニル、２，４−ジフルオロフェ
ニル、３，４−ジフルオロフェニル、２，５−ジフルオ
ロフェニル、２，６−ジフルオロフェニル、４−クロロ
フェニル、４−ブロモフェニル、４−メチルフェニル、
４−シアノフェニル、４−アセチルアミノフェニル、４
−トリフルオロメチルフェニル、４−フルオロ−２−メ
チルフェニル、４−フルオロ−２−メトキシフェニル、
２−フルオロ−４−メトキシフェニルあるいは２−メチ
ル−４−メトキシフェニル基を；Ｒ3が４−メチル−１
−ピペラジニル基で、Ｒ2は、３，４−ジフルオロフェ
ニル、４−ブロモフェニル、４−メチルフェニル、４−
メトキシフェニル、２−メトキシフェニル、４−フルオ
ロ−２−メトキシフェニル、２−フルオロ−４−メトキ
シフェニル、４−メチル−２−メトキシフェニル、４−
アセチルアミノフェニル、３−メトキシフェニル、３−
フルオロ−４−メトキシフェニル、３−メチル−４−メ
トキシフェニル、２−メチル−４−メトキシフェニル、
３−ヒドロキシフェニル、４−フルオロ−２−ヒドロキ
シフェニル、３−フルオロ−４−ヒドロキシフェニル、
２−フルオロ−４−ヒドロキシフェニル、２−ヒドロキ
シ−４−メチルフェニル、４−ヒドロキシ−３−メチル
フェニル、４−ヒドロキシ−２−メチルフェニルあるい
は４−クロロフェニル基を；Ｒ3が４−（Ｎ−アセチル
−Ｎ−メチルアミノ）ピペリジノ、４−（Ｎ−メチルア
ミノ）ピペリジノ、２，５−ジメチル−１−ピペラジニ
ル、４−（２−ヒドロキシエチル）−１−ピペラジニ
ル、３−メチルアミノ−１−ピロリジニル、３−（Ｎ−
アセチル−Ｎ−メチルアミノ）−１−ピロリジニルある
いは３−メチル−１−ピペラジニル基で、Ｒ2が４−フ
ルオロフェニル基を；Ｒ3が３−ヒドロキシ−１−ピロ
リジニル、１−ピロリジニル、ピペリジノ、４−エチル
−１−ピペラジニル、４−ｎ−プロピル−１−ピペラジ
ニル、４−イソプロピル−１−ピペラジニル、４−（２
−ヒドロキシエチル）−１−ピペラジニルあるいは４−
アリル−１−ピペラジニル基で、Ｒ2は４−メトキシフ
ェニル基を；Ｒ3が４−（Ｎ−アセチル−Ｎ−メチルア
ミノ）ピペリジノ、３−メチル−１−ピペラジニル、
３，４−ジメチル−１−ピペラジニル、２，４−ジメチ
ル−１−ピペラジニル、４−アリル−１−ピペラジニ
ル、４−エトキシカルボニル−２−メチル−１−ピペラ
ジニル、３−ジメチルアミノ−１−ピロリジニル、３−
（Ｎ−アセチル−Ｎ−メチルアミノ）−１−ピロリジニ
ル、４−（Ｎ−メチルアミノ）ピペリジノ、３−メチル
アミノ−１−ピロリジニルあるいは２−メチル−１−ピ
ペラジニル基で、Ｒ2は２，４−ジフルオロフェニル基
を；Ｒ3が３−アミノ−１−ピロリジニルあるいは３−
アセチルアミノ−１−ピロリジニル基で、Ｒ2は２，
３，４−トリフルオロフェニル基を；Ｒ3が４−エチル
−１−ピペラジニル、４−ｎ−プロピル−１−ピペラジ
ニル、４−イソプロピル−１−ピペラジニル、４−（２
−ヒドロキシエチル）−１−ピペラジニルあるいは４−
アリル−１−ピペラジニル基で、Ｒ2は４−ヒドロキシ
フェニル基を示す。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] In the formula, R 1 represents a hydrogen atom or a carboxyl protecting group; R 3
Is a 1-piperazinyl group, R 2 is 3-fluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 4-chlorophenyl, 4- Bromophenyl, 4-methylphenyl, 4-cyanophenyl, 4-
Aminophenyl, 4-trifluoromethylphenyl, 4
-Fluoro-2-methylphenyl, 4-fluoro-2-
A hydroxyphenyl, 4-hydroxy-2-methylphenyl or 2-fluoro-4-hydroxyphenyl group; R 3 is a 4-acetyl-1-piperazinyl group;
2 is 3-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl,
4-cyanophenyl, 4-acetylaminophenyl, 4
-Trifluoromethylphenyl, 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl,
2-fluoro-4-methoxyphenyl or 2-methyl-4-methoxyphenyl group; R 3 is 4-methyl-1
A -piperazinyl group, R 2 is 3,4-difluorophenyl, 4-bromophenyl, 4-methylphenyl, 4-
Methoxyphenyl, 2-methoxyphenyl, 4-fluoro-2-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 4-methyl-2-methoxyphenyl, 4-
Acetylaminophenyl, 3-methoxyphenyl, 3-
Fluoro-4-methoxyphenyl, 3-methyl-4-methoxyphenyl, 2-methyl-4-methoxyphenyl,
3-hydroxyphenyl, 4-fluoro-2-hydroxyphenyl, 3-fluoro-4-hydroxyphenyl,
2-fluoro-4-hydroxyphenyl, 2-hydroxy-4-methylphenyl, 4-hydroxy-3-methylphenyl, 4-hydroxy-2-methylphenyl or 4-chlorophenyl group; R 3 is 4- (N- Acetyl-N-methylamino) piperidino, 4- (N-methylamino) piperidino, 2,5-dimethyl-1-piperazinyl, 4- (2-hydroxyethyl) -1-piperazinyl, 3-methylamino-1-pyrrolidinyl , 3- (N-
Acetyl-N-methylamino) -1-pyrrolidinyl or 3-methyl-1-piperazinyl group, R 2 is 4-fluorophenyl group; R 3 is 3-hydroxy-1-pyrrolidinyl, 1-pyrrolidinyl, piperidino, 4 -Ethyl-1-piperazinyl, 4-n-propyl-1-piperazinyl, 4-isopropyl-1-piperazinyl, 4- (2
-Hydroxyethyl) -1-piperazinyl or 4-
An allyl-1-piperazinyl group, R 2 represents a 4-methoxyphenyl group; R 3 represents 4- (N-acetyl-N-methylamino) piperidino, 3-methyl-1-piperazinyl,
3,4-dimethyl-1-piperazinyl, 2,4-dimethyl-1-piperazinyl, 4-allyl-1-piperazinyl, 4-ethoxycarbonyl-2-methyl-1-piperazinyl, 3-dimethylamino-1-pyrrolidinyl, 3-
(N-acetyl-N-methylamino) -1-pyrrolidinyl, 4- (N-methylamino) piperidino, 3-methylamino-1-pyrrolidinyl or 2-methyl-1-piperazinyl group, R 2 is 2,4 A difluorophenyl group; R 3 is 3-amino-1-pyrrolidinyl or 3-
An acetylamino-1-pyrrolidinyl group, R 2 is 2,
A 3,4-trifluorophenyl group; R 3 is 4-ethyl-1-piperazinyl, 4-n-propyl-1-piperazinyl, 4-isopropyl-1-piperazinyl, 4- (2
-Hydroxyethyl) -1-piperazinyl or 4-
An allyl-1-piperazinyl group, R 2 represents a 4-hydroxyphenyl group.
で表わされる１，４−ジヒドロ−４−オキソナフチリジ
ン誘導体およびその塩に関するものである。The present invention relates to a 1,4-dihydro-4-oxonaphthyridine derivative represented by and a salt thereof.
本発明の目的は、グラム陽性菌およびグラム陰性菌、と
りわけ抗生物質耐性菌に対して強力な抗菌作用を示すと
ともに、経口的または非経口的投与により高い血中濃度
が得られ、かつ安全性が高いなどの優れた性質を有する
一般式〔Ｉ〕で表わされる新規な化合物およびその塩を
提供することにある。The object of the present invention is to show a strong antibacterial action against Gram-positive bacteria and Gram-negative bacteria, especially antibiotic-resistant bacteria, and obtain high blood concentration by oral or parenteral administration, and safety. It is to provide a novel compound represented by the general formula [I] and a salt thereof having excellent properties such as high properties.
従来、合成抗菌剤としてナリジクス酸、ピロミド酸また
はピペミド酸などが広く用いられているが、いずれも難
治性疾患である緑膿菌感染症やグラム陽性菌感染症の治
療に対する効果は満足すべきものではなかつた。このた
め、各種のピリドンカルボン酸系化合物、たとえば、１
−エチル−６−フルオロ−１，４−ジヒドロ−４−オキ
ソ−７−（１−ピペラジニル）−３−キノリンカルボン
酸（ノルフロキサシン）などが従来の合成抗菌剤に代わ
るものとして開発されつつあるが、これらの化合物は緑
膿菌を含む各種グラム陰性菌に対しては優れた抗菌力を
有するが、グラム陽性菌に対する抗菌力はいまだ十分と
はいえなかつた。Conventionally, nalidixic acid, pyromidic acid, pipemidic acid, etc. have been widely used as synthetic antibacterial agents, but the effects on the treatment of intractable Pseudomonas aeruginosa infection and gram-positive bacterial infection are not satisfactory. Nakatsuta. Therefore, various pyridonecarboxylic acid compounds, for example, 1
Although -ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid (norfloxacin) and the like are being developed as an alternative to conventional synthetic antibacterial agents, Although these compounds have excellent antibacterial activity against various Gram-negative bacteria including Pseudomonas aeruginosa, their antibacterial activity against Gram-positive bacteria has not been sufficient.
そこで、グラム陰性菌のみならず、グラム陽性菌に対し
ても有効な広範囲の抗菌スペクトルを有する合成抗菌剤
の開発が望まれていた。Therefore, it has been desired to develop a synthetic antibacterial agent having a wide antibacterial spectrum effective against not only Gram-negative bacteria but also Gram-positive bacteria.
このような状況下において、本発明者らは鋭意研究を行
つた結果、一般式〔Ｉ〕で表わされる１，４−ジヒドロ
−４−オキソナフチリジン誘導体およびその塩が上記の
目的を達成することを見出し、本発明を完成するに至つ
た。Under such circumstances, the inventors of the present invention have conducted extensive studies and as a result, have found that the 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula [I] and a salt thereof achieve the above object. Heading out, the present invention has been completed.
以下、本発明化合物を詳説する。Hereinafter, the compound of the present invention will be described in detail.
本発明は次の一般式〔Ｉ〕で表わされる。The present invention is represented by the following general formula [I].
〔式中、Ｒ1、Ｒ2およびＲ3は、前記と同様の意味を有
する。〕 一般式〔Ｉ〕の化合物およびその塩において、Ｒ1のカ
ルボキシル保護基としては、たとえば、接触還元、化学
的還元もしくはその他の緩和な条件で処理することによ
り脱離するエステル形成基、または生体内において容易
に脱離するエステル形成基、または水もしくはアルコー
ルで処理することにより容易に脱離する有機シリル基、
有機リン基もしくは有機スズ基など、その他の種々の公
知のエステル形成基が挙げられる。 [In the formula, R 1 , R 2 and R 3 have the same meanings as described above. In the compound of the general formula [I] and salts thereof, the carboxyl protecting group for R 1 is, for example, an ester-forming group which is eliminated by catalytic reduction, chemical reduction or treatment under other mild conditions, or An ester-forming group which is easily eliminated in the body, or an organic silyl group which is easily eliminated by treatment with water or alcohol,
Other various known ester forming groups such as an organic phosphorus group or an organic tin group can be mentioned.
これらのカルボキシル保護基のうち、好適な保護基とし
ては、たとえば、特開昭５９−８０６６５号に記載され
たカルボキシル保護基が挙げられる。Of these carboxyl protecting groups, suitable protecting groups include, for example, the carboxyl protecting groups described in JP-A-59-80665.
また、Ｒ2のフェニル基における置換基であるハロゲン
原子としては、たとえば、フッ素原子、塩素原子、臭素
原子、ヨウ素原子が；Ｃ1-10アルキル基としては、たと
えば、メチル、エチル、ｎ−プロピル、イソプロピル、
ｎ−ブチル、イソブチル、sec-ブチル、tert-ブチル、
ペンチル、ヘキシル、ヘプチル、オクチルなどの直鎖ま
たは分枝鎖Ｃ1-10アルキル基が；Ｃ1-10アルコキシ基と
しては、たとえば、メトキシ、エトキシ、ｎ−プロポキ
シ、イソプロポキシ、ｎ−ブトキシ、イソブトキシ、se
c-ブトキシ、tert-ブトキシ、ペンチルオキシ、ヘキシ
ルオキシ、ヘプチルオキシ、オクチルオキシなどの直鎖
または分枝鎖Ｃ1-10アルコキシ基が挙げられる。The halogen atom which is a substituent in the phenyl group of R 2 is, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; and the C 1-10 alkyl group is, for example, methyl, ethyl or n-propyl. , Isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl,
A straight chain or branched chain C 1-10 alkyl group such as pentyl, hexyl, heptyl, octyl; a C 1-10 alkoxy group is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy. , Se
Examples thereof include straight chain or branched chain C 1-10 alkoxy groups such as c-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy.
一般式〔Ｉ〕の化合物の塩としては、通常知られている
アミノ基などの塩基性基またはカルボキシル基などの酸
性基における塩を挙げることができる。塩基性基におけ
る塩としては、たとえば、塩酸、硫酸などの鉱酸との
塩；ギ酸、トリクロロ酢酸、トリフルオロ酢酸などの有
機カルボン酸との塩；メタンスルホン酸、ｐ−トルエン
スルホン酸、ナフタレンスルホン酸などのスルホン酸と
の塩を、酸性基における塩としては、たとえば、ナトリ
ウム、カリウムなどのアルカリ金属との塩；カルシウ
ム、マグネシウムなどのアルカリ土類金属との塩；アン
モニウム塩；プロカイン、ジベンジルアミン、Ｎ−ベン
ジル−β−フェネチルアミン、１−エフェナミン、Ｎ，
Ｎ−ジベンジルエチレンジアミン、トリエチルアミン、
トリメチルアミン、トリブチルアミン、ピリジン、Ｎ，
Ｎ−ジメチルアニリン、Ｎ−メチルピペリジン、Ｎ−メ
チルモルホリン、ジエチルアミン、ジシクロヘキシルア
ミンなどの含窒素有機塩基との塩を挙げることができ
る。Examples of the salt of the compound of the general formula [I] include salts of commonly known basic groups such as amino groups or acidic groups such as carboxyl groups. Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid and sulfuric acid; salts with organic carboxylic acids such as formic acid, trichloroacetic acid and trifluoroacetic acid; methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfone. Examples of the salt having a sulfonic acid such as an acid in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; procaine and dibenzyl. Amine, N-benzyl-β-phenethylamine, 1-ephenamine, N,
N-dibenzylethylenediamine, triethylamine,
Trimethylamine, tributylamine, pyridine, N,
Examples thereof include salts with nitrogen-containing organic bases such as N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine and dicyclohexylamine.
また、一般式〔Ｉ〕の化合物およびその塩において、異
性体（たとえば、光学異性体、幾何異性体、互変異性体
など）が存在する場合、本発明は、それらすべての異性
体を包含し、またすべての結晶形および水和物におよぶ
ものである。In addition, when isomers (for example, optical isomers, geometric isomers, tautomers, etc.) exist in the compound of the general formula [I] and salts thereof, the present invention includes all isomers thereof. , And also extends to all crystalline forms and hydrates.
つぎに、本発明化合物の製造法について説明する。Next, a method for producing the compound of the present invention will be described.
本発明化合物を製造する方法としては自体公知の方法が
挙げられるが、以下、代表的製造方法に関して詳説す
る。As a method for producing the compound of the present invention, a method known per se can be mentioned, but a typical production method will be described in detail below.
本発明化合物は、たとえば、以下の製造ルートに従つて
製造することができる。The compound of the present invention can be produced, for example, according to the following production route.
Ｒ3aにおけるハロゲン原子としては、たとえば、フッ素
原子、塩素原子、臭素原子が挙げられる。 Examples of the halogen atom in R 3a include a fluorine atom, a chlorine atom and a bromine atom.
一般式〔Ia〕、〔III〕、〔IV〕および〔Ｖ〕の化合物
の塩としては、一般式〔Ｉ〕の化合物の塩として挙げら
れたものと同様の塩が挙げられる。Examples of the salt of the compound of the general formula [Ia], [III], [IV] and [V] include the same salts as those mentioned as the salt of the compound of the general formula [I].
(i)一般式〔III〕の化合物もしくはその塩、または一般
式〔Ｖ〕の化合物もしくはその塩は、それぞれ一般式
〔II〕の化合物または一般式〔IV〕の化合物もしくはそ
の塩に、Ｎ，Ｎ−ジメチルホルムアミドジメチルアセタ
ールまたはＮ，Ｎ−ジメチルホルムアミドジエチルアセ
タールなどのアセタール類を反応させた後、式R2−NH2
（R2は前記と同様の意味を有する）で表わされるアミン
類を反応させることによつて得られる。(i) A compound of the general formula [III] or a salt thereof, or a compound of the general formula [V] or a salt thereof is a compound of the general formula [II] or a compound of the general formula [IV] or a salt thereof, and N, After reacting with acetals such as N-dimethylformamide dimethylacetal or N, N-dimethylformamide diethylacetal, the compound of the formula R 2 —NH 2
(R 2 has the same meaning as described above) and is obtained by reacting the amines.
この反応に使用される溶媒としては、反応に不活性が溶
媒であれば特に限定されないが、たとえば、ベンゼン、
トルエン、キシレンなどの芳香族炭化水素類；ジオキサ
ン、テトラヒドロフラン、アニソール、ジエチレングリ
コールジメチルエーテル、ジメチルセロソルブなどのエ
ーテル類；塩化メチレン、クロロホルム、ジクロロエタ
ンなどのハロゲン化炭化水素類；Ｎ，Ｎ−ジメチルホル
ムアミド、Ｎ，Ｎ−ジメチルアセトアミドなどのアミド
類；ジメチルスルホキシドなどのスルホキシド類などが
挙げられ、これらの溶媒を２種以上混合して使用しても
よい。アセタール類の使用量は、一般式〔II〕の化合物
または一般式〔IV〕の化合物もしくはその塩に対して等
モル以上、とりわけ約1.0〜1.3倍モルが好ましい。本反
応は通常０〜１００℃、好ましくは、５０〜８０℃で行
われ、反応時間は、通常２０分〜５０時間、好ましく
は、１〜３時間である。ついで、R2−NH2のアミン類を
反応させるには、該アミン類を一般式〔II〕の化合物ま
たは一般式〔IV〕の化合物もしくはその塩に対して等モ
ルもしくは等モル以上使用し、通常０〜１００℃、好ま
しくは、１０〜６０℃で、通常２０分〜３０時間、好ま
しくは、１〜５時間反応させる。The solvent used in this reaction is not particularly limited as long as it is a solvent inert to the reaction, for example, benzene,
Aromatic hydrocarbons such as toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether and dimethyl cellosolve; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; N, N-dimethylformamide, N, Examples thereof include amides such as N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide, and these solvents may be used as a mixture of two or more kinds. The amount of acetal used is preferably equimolar or more, particularly about 1.0 to 1.3 times the molar amount of the compound of the general formula [II] or the compound of the general formula [IV] or a salt thereof. This reaction is generally carried out at 0-100 ° C., preferably 50-80 ° C., and the reaction time is generally 20 minutes-50 hours, preferably 1-3 hours. Then, in order to react the amines of R 2 —NH 2, the amines are used in an equimolar amount or an equimolar amount or more with respect to the compound of the general formula [II] or the compound of the general formula [IV] or a salt thereof, The reaction is usually carried out at 0 to 100 ° C., preferably 10 to 60 ° C. for usually 20 minutes to 30 hours, preferably 1 to 5 hours.
また、別法として、一般式〔II〕の化合物または一般式
〔IV〕の化合物もしくはその塩に無水酢酸中、オルトギ
酸エチルまたはオルトギ酸メチルを反応させた後、R2−
NH2のアミン類を反応させて、それぞれ一般式〔III〕の
化合物もしくはその塩または一般式〔Ｖ〕の化合物もし
くはその塩へと導くことができる。As another method, the compound of the general formula [II] or the compound of the general formula [IV] or a salt thereof is reacted with ethyl orthoformate or methyl orthoformate in acetic anhydride, and then R 2-
The amines of NH 2 can be reacted to form a compound of the general formula [III] or a salt thereof or a compound of the general formula [V] or a salt thereof.
(ii)一般式〔Ｉａ〕の化合物もしくはその塩または一般
式〔Ｉ〕の化合物もしくはその塩は、それぞれ一般式
〔III〕の化合物もしくはその塩または一般式〔Ｖ〕の
化合物もしくはその塩を、塩基の存在下または不存在下
に閉環反応（好ましくは加熱下）に付すことによつて得
られる。この反応に使用される溶媒としては、反応に不
活性な溶媒であれば特に限定されないが、たとえば、
Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセ
トアミドなどのアミド類；ジオキサン、アニソール、ジ
エチレングリコールジメチルエーテル、ジメチルセロソ
ルブなどのエーテル類；ジメチルスルホキシドなどのス
ルホキシド類などが挙げられ、これらの溶媒を２種以上
混合して使用してもよい。塩基としては、たとえば、炭
酸水素ナトリウム、炭酸カリウム、tert−ブトキシカリ
ウム、水素化ナトリウムなどが挙げられ、その使用量
は、一般式〔III〕もしくは〔Ｖ〕の化合物またはそれ
らの塩に対して0.5〜５倍モルが好ましく、本反応は、
通常２０〜１６０℃、好ましくは、１００〜１５０℃で
行われ、反応時間は、通常５分〜３０分間、好ましく
は、５分〜１時間である。(ii) The compound of the general formula [Ia] or a salt thereof, the compound of the general formula [I] or a salt thereof is the compound of the general formula [III] or a salt thereof, or the compound of the general formula [V] or a salt thereof, It can be obtained by subjecting a ring closure reaction (preferably under heating) in the presence or absence of a base. The solvent used in this reaction is not particularly limited as long as it is an inert solvent in the reaction, for example,
Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; ethers such as dioxane, anisole, diethylene glycol dimethyl ether and dimethyl cellosolve; sulfoxides such as dimethyl sulfoxide; and two or more of these solvents. You may mix and use. Examples of the base include sodium hydrogen carbonate, potassium carbonate, potassium tert-butoxide, sodium hydride, etc., and the amount thereof used is 0.5 with respect to the compound of the general formula [III] or [V] or a salt thereof. ~ 5 times mol is preferable, and this reaction is
It is generally carried out at 20 to 160 ° C., preferably 100 to 150 ° C., and the reaction time is generally 5 minutes to 30 minutes, preferably 5 minutes to 1 hour.
(iii)Ｒ3が１−ピペラジニル、４−アセチル−１−ピペ
ラジニル、４−メチル−１−ピペラジニル、４−（Ｎ−
アセチル−Ｎ−メチルアミノ）ピペリジノ、４−（Ｎ−
メチルアミノ）ピペリジノ、２，５−ジメチル−１−ピ
ペラジニル、４−（２−ヒドロキシエチル）−１−ピペ
ラジニル、３−メチルアミノ−１−ピロリジニル、３−
（Ｎ−アセチル−Ｎ−メチルアミノ）−１−ピロリジニ
ル、３−メチル−１−ピペラジニル、３−ヒドロキシ−
１−ピロリジニル、１−ピロリジニル、ピペリジノ、４
−エチル−１−ピペラジニル、４−ｎ−プロピル−１−
ピペラジニル、４−イソプロピル−１−ピペラジニル、
４−アリル−１−ピペラジニル、３，４−ジメチル−１
−ピペラジニル、２，４−ジメチル−１−ピペラジニ
ル、４−エトキシカルボニル−２−メチル−１−ピペラ
ジニル、３−ジメチルアミノ−１−ピロリジニル、２−
メチル−１−ピペラジニル、３−アミノ−１−ピロリジ
ニルあるいは３−アセチルアミノ−１−ピロリジニル基
である一般式〔IV〕の化合物もしくはその塩、一般式
〔Ｖ〕の化合物もしくはその塩および一般式〔Ｉ〕の化
合物もしくはその塩は、それぞれ一般式〔II〕の化合
物、一般式〔III〕の化合物もしくはその塩または一般
式〔Ia〕の化合物もしくはその塩に、式Ｒ3−Ｈ（Ｒ
3は、前記と同様の意味を有する。）で表わされるアミ
ン類を反応させることによつて得られる。この反応に使
用される溶媒としては、反応に不活性な溶媒であれば特
に限定されないが、たとえば、ベンゼン、トルエン、キ
シレンなどの芳香族炭化水素類；ジオキサン、テトラヒ
ドロフラン、アニソール、ジエチレングリコールジエチ
ルエーテルなどのエーテル類；塩化メチレン、クロロホ
ルム、ジクロロエタンなどのハロゲン化炭化水素類；
Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセ
トアミドなどのアミド類；ジメチルスルホキシドなどの
スルホキシド類；メタノール、エタノールなどのアルコ
ール類；アセトニトリルなどのニトリル類などが挙げら
れ、これらの溶媒を２種以上混合して使用してもよい。
アミン類の使用量は、一般式〔II〕の化合物、一般式
〔III〕の化合物もしくはその塩または一般式〔Ia〕の
化合物もしくはその塩に対して過剰量、特に、２〜５倍
モルが好ましく、その使用量が約１〜1.3倍モルである
場合、一般式〔II〕の化合物、一般式〔III〕の化合物
もしくはその塩または一般式〔Ia〕の化合物もしくはそ
の塩に対して等モル量の脱酸剤を使用すればよい。脱酸
剤としては、トリエチルアミン、１，８−ジアザビシク
ロ−〔５・４・０〕−ウンデセ−７−エン（ＤＢＵ）、
tert−ブトキシカリウム、炭酸カリウム、炭酸ナトリウ
ム、水素化ナトリウムなどの無機または有機塩基が挙げ
られる。本反応は、通常０〜１５０℃、好ましくは、５
０〜１００℃で行われ、反応時間は、通常５分〜３０時
間、好ましくは、３０分〜３時間である。(iii) R 3 is 1-piperazinyl, 4-acetyl-1-piperazinyl, 4-methyl-1-piperazinyl, 4- (N-
Acetyl-N-methylamino) piperidino, 4- (N-
Methylamino) piperidino, 2,5-dimethyl-1-piperazinyl, 4- (2-hydroxyethyl) -1-piperazinyl, 3-methylamino-1-pyrrolidinyl, 3-
(N-acetyl-N-methylamino) -1-pyrrolidinyl, 3-methyl-1-piperazinyl, 3-hydroxy-
1-pyrrolidinyl, 1-pyrrolidinyl, piperidino, 4
-Ethyl-1-piperazinyl, 4-n-propyl-1-
Piperazinyl, 4-isopropyl-1-piperazinyl,
4-allyl-1-piperazinyl, 3,4-dimethyl-1
-Piperazinyl, 2,4-dimethyl-1-piperazinyl, 4-ethoxycarbonyl-2-methyl-1-piperazinyl, 3-dimethylamino-1-pyrrolidinyl, 2-
A compound of the general formula [IV] or a salt thereof, which is a methyl-1-piperazinyl group, a 3-amino-1-pyrrolidinyl group or a 3-acetylamino-1-pyrrolidinyl group, a compound of the general formula [V] or a salt thereof, and a general formula thereof. The compound of the formula [I] or a salt thereof can be obtained by adding a compound of the formula [II], a compound of the formula [III] or a salt thereof or a compound of the formula [Ia] or a salt thereof to a compound of formula R 3 -H (R
3 has the same meaning as above. ) Is obtained by reacting amines represented by The solvent used in this reaction is not particularly limited as long as it is a solvent inert to the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, etc. Ethers; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane;
Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethylsulfoxide; alcohols such as methanol and ethanol; nitriles such as acetonitrile; and two or more of these solvents. You may mix and use.
The amount of amines used is an excess amount, especially 2 to 5 times mol, relative to the compound of general formula [II], the compound of general formula [III] or a salt thereof, or the compound of general formula [Ia] or a salt thereof. Preferably, when the amount used is about 1 to 1.3 times by mole, equimolar to the compound of general formula [II], the compound of general formula [III] or a salt thereof, or the compound of general formula [Ia] or a salt thereof An amount of deoxidizer may be used. As the deoxidizing agent, triethylamine, 1,8-diazabicyclo- [5.4.0] -undec-7-ene (DBU),
Inorganic or organic bases such as potassium tert-butoxide, potassium carbonate, sodium carbonate, sodium hydride and the like can be mentioned. This reaction is generally 0 to 150 ° C., preferably 5
It is carried out at 0 to 100 ° C., and the reaction time is generally 5 minutes to 30 hours, preferably 30 minutes to 3 hours.
また、R1がカルボキシル保護基である一般式〔Ｉ〕、
〔Ia〕、〔III〕もしくは〔Ｖ〕の化合物またはそれら
の塩は、所望に応じて、加水分解反応において用いられ
る通常の酸またはアルカリの存在下に、通常０〜１００
℃、好ましくは、２０〜１００℃で５分〜５０時間、好
ましくは、５分〜４時間加水分解することにより、それ
ぞれ対応する化合物の遊離カルボン酸へ導くことができ
る。さらに一般式〔Ｉ〕、〔Ia〕、〔III〕もしくは
〔Ｖ〕の化合物またはそれらの塩は、所望に応じて、自
体公知の塩形成反応またはエステル化反応に付して、そ
れぞれ対応する化合物の塩またはエステルへ導くことが
できる。In addition, a compound of the general formula [I] in which R 1 is a carboxyl protecting group,
The compound of [Ia], [III] or [V] or a salt thereof is, if desired, usually in the presence of an ordinary acid or alkali used in the hydrolysis reaction, usually 0 to 100.
Hydrolysis at 5 ° C., preferably 20 to 100 ° C. for 5 minutes to 50 hours, preferably 5 minutes to 4 hours can lead to the free carboxylic acid of the corresponding compound. Further, the compound of the general formula [I], [Ia], [III] or [V] or a salt thereof is subjected to a salt formation reaction or an esterification reaction known per se, if desired, to give a corresponding compound. Can be converted to the salt or ester thereof.
なお、一般式〔Ia〕、〔III〕、〔IV〕もしくは〔Ｖ〕
の化合物またはそれらの塩が、反応部位以外に活性基
（たとえば、ヒドロキシル基、アミノ基など）を有する
場合、あらかじめ活性基を常法に従つて保護しておき、
反応終了後、その保護基を脱離してもよい。The general formula [Ia], [III], [IV] or [V]
When the compound or salt thereof has an active group (for example, a hydroxyl group, an amino group, etc.) at a site other than the reaction site, the active group is protected in advance by a conventional method,
After completion of the reaction, the protecting group may be removed.
以上のようにして得られた化合物は、カラムクロマトグ
ラフィー、再結晶、抽出などの通常の単離精製操作に付
してもよい。The compound obtained as described above may be subjected to usual isolation and purification operations such as column chromatography, recrystallization and extraction.
一般式［Ｉａ］の化合物は、Ｒ3が１−ピペラジニル、
４−アセチル−１−ピペラジニル、４−メチル−１−ピ
ペラジニル、４−（Ｎ−アセチル−Ｎ−メチルアミノ）
ピペリジノ、４−（Ｎ−メチルアミノ）ピペリジノ、
２，５−ジメチル−１−ピペラジニル、４−（２−ヒド
ロキシエチル）−１−ピペラジニル、３−メチルアミノ
−１−ピロリジニル、３−（Ｎ−アセチル−Ｎ−メチル
アミノ）−１−ピロリジニル、３−メチル−１−ピペラ
ジニル、３−ヒドロキシ−１−ピロリジニル、１−ピロ
リジニル、ピペリジノ、４−エチル−１−ピペラジニ
ル、４−ｎ−プロピル−１−ピペラジニル、４−イソプ
ロピル−１−ピペラジニル、４−アリル−１−ピペラジ
ニル、３，４−ジメチル−１−ピペラジニル、２，４−
ジメチル−１−ピペラジニル、４−エトキシカルボニル
−２−メチル−１−ピペラジニル、３−ジメチルアミノ
−１−ピロリジニル、２−メチル−１−ピペラジニル、
３−アミノ−１−ピロリジニルあるいは３−アセチルア
ミノ−１−ピロリジニル基である化合物を得るための中
間体として有用である。In the compound of general formula [Ia], R 3 is 1-piperazinyl,
4-Acetyl-1-piperazinyl, 4-methyl-1-piperazinyl, 4- (N-acetyl-N-methylamino)
Piperidino, 4- (N-methylamino) piperidino,
2,5-Dimethyl-1-piperazinyl, 4- (2-hydroxyethyl) -1-piperazinyl, 3-methylamino-1-pyrrolidinyl, 3- (N-acetyl-N-methylamino) -1-pyrrolidinyl, 3 -Methyl-1-piperazinyl, 3-hydroxy-1-pyrrolidinyl, 1-pyrrolidinyl, piperidino, 4-ethyl-1-piperazinyl, 4-n-propyl-1-piperazinyl, 4-isopropyl-1-piperazinyl, 4-allyl -1-piperazinyl, 3,4-dimethyl-1-piperazinyl, 2,4-
Dimethyl-1-piperazinyl, 4-ethoxycarbonyl-2-methyl-1-piperazinyl, 3-dimethylamino-1-pyrrolidinyl, 2-methyl-1-piperazinyl,
It is useful as an intermediate for obtaining a compound which is a 3-amino-1-pyrrolidinyl group or a 3-acetylamino-1-pyrrolidinyl group.
つぎに、本発明の代表的化合物についての抗菌作用およ
び急性毒性を示す。Next, the antibacterial activity and acute toxicity of the representative compounds of the present invention are shown.
1.抗菌作用 試験方法 日本化学療法学会標準法〔ケモテラピー（CHEMOTHERAP
Y）第２９巻、第１号、第７６〜７９頁（１９８１
年）〕に従いハート インフュージヨン ブロース（He
art Infusion broth）（栄研化学社製）で３７℃、２０
時間培養した菌液を薬剤を含むハート インフュージヨ
ン アガー（Heart Infusion agar）培地（栄研化学社
製）に接種し、３７℃で２０時間培養した後、菌の発育
の有無を観察し、菌の発育が阻止された最小濃度をもつ
てMIC（μｇ／ｍ）とした。ただし、接種菌量は１０4
個／プレート（１０6個／ｍ）とした。その結果を表
−１に示す。1. Antibacterial activity test method Japanese Society of Chemotherapy standard method [CHEMOTHERAP
Y) Vol. 29, No. 1, pp. 76-79 (1981)
Year)]
art infusion broth) (Eiken Chemical Co., Ltd.) at 37 ℃, 20
The bacterial solution that had been cultured for a period of time was inoculated into a Heart Infusion agar medium (manufactured by Eiken Chemical Co., Ltd.) containing a drug, and after culturing at 37 ° C for 20 hours, the presence or absence of bacterial growth was observed, The MIC (μg / m) was defined as the minimum concentration at which the growth of P. However, the inoculum is 10 4
Pieces / plate (10 6 pieces / m). The results are shown in Table-1.
なお、表−１で使用されている記号は下の意味を有す
る。The symbols used in Table 1 have the following meanings.
＊ペニシリネース産生菌 ＊＊セファロスポリネース産生菌 Ｍｅ：メチル基、Et：エチル基、 n-Pr：ｎ−プロピル基、 i-Pr：イソプロピル基 ＊１ 接種菌量が１０8個／ｍのデータ 2.急性毒性試験 前記の試験化合物５および６のマウス（ICR系，♂、体
重１８〜２４ｇ）静脈内投与におけるLD50値は２００mg
／Kg以上であつた。* Penicillinase-producing bacteria ** Cephalosporinase-producing bacteria Me: Methyl group, Et: Ethyl group, n-Pr: n-Propyl group, i-Pr: Isopropyl group * 1 Data for inoculum size of 10 8 cells / m 2. Acute toxicity test LD 50 value of the above test compounds 5 and 6 in mice (ICR strain, ♂, body weight 18 to 24 g) is 200 mg when administered intravenously.
/ It was above Kg.
本発明化合物を医薬として使用する場合、通常製剤化に
使用される担体を適宜用い、常法に従つて、錠剤、カプ
セル剤、散剤、シロツプ剤、顆粒剤、坐剤、軟こう剤、
注射剤などに調製すればよい。また、投与方法、投与量
および投与回数は患者の症状に応じて適宜選択すること
ができ、通常成人に対しては、経口または非経口（たと
えば、注射投与、点滴、直腸部位への投与など）的投与
により、0.１〜１００mg／Kg／日を１〜数回に分割して
投与すればよい。When the compound of the present invention is used as a medicine, a carrier usually used for formulation is appropriately used, and according to a conventional method, tablets, capsules, powders, syrups, granules, suppositories, ointments,
It may be prepared as an injection. In addition, the administration method, dose and frequency of administration can be appropriately selected according to the symptoms of the patient, and usually orally or parenterally for adults (eg, injection administration, infusion, administration to the rectal site, etc.) The dose may be 0.1 to 100 mg / Kg / day in 1 to several divided doses.
つぎに、本発明を参考例、実施例および製剤例を挙げて
説明する。Next, the present invention will be described with reference to Reference Examples, Examples and Formulation Examples.
なお、参考例および実施例で使用されている記号は下記
の意味を有する。The symbols used in Reference Examples and Examples have the following meanings.
Me；メチル基、Et；エチル基、n-Pr；ｎ−プロピル基、
i-Pr；イソプロピル基、Ac；アセチル基、 アリル基、 エチレン基 参考例 ２，６−ジクロロ−５−フルオロニコチン酸２１ｇをク
ロロホルム２１０ｍに溶解させ、塩化チオニル２3.８
ｇおよびＮ，Ｎ−ジメチルホルムアミド0.１ｇを加え
て、７０℃で２時間反応させる。減圧下に溶媒および過
剰の塩化チオニルを留去し、得られた残留物をテトラヒ
ドロフラン２１ｍに溶解させる。マグネシウム2.６７
ｇより調製したエトキシマグネシウムマロン酸ジエチル
２5.１ｇをテトラヒドロフラン１１０ｍに溶解させ、
−４０〜−３０℃に冷却する。この溶液に先に調製した
２，６−ジクロロ−５−フルオロニコチン酸クロリドの
テトラヒドロフラン溶液を、同温度で３０分を要して滴
下する。この混合溶液を同温度で１時間攪拌した後、徐
々に室温まで昇温させる。減圧下に溶媒を留去し、得ら
れた残渣にクロロホルム２００ｍおよび水１００ｍ
を加えて６Ｎ−塩酸でpH１に調整する。有機層を分取
し、水５０ｍ、５％炭酸水素ナトリウム水溶液５０ｍ
および飽和食塩水５０ｍで順次洗浄した後、無水硫
酸マグネシウムで乾燥する。減圧下に溶媒を留去し、得
られた油状物に水５０ｍおよびｐ−トルエンスルホン
酸0.１５ｇを加えて激しく攪拌しながら１００℃で２時
間反応させた後、クロロホルム１００ｍで抽出する。
有機層を飽和食塩水５０ｍで洗浄し、無水硫酸マグネ
シウムで乾燥させた後、減圧下に溶媒を留去し、得られ
た残渣をカラムクロマトグラフィー（和光シリカゲルＣ
−２００、溶離剤；トルエン）で精製すれば、融点６４
〜６５℃を示す２，６−ジクロロ−５−フルオロニコチ
ノイル酢酸エチルエステル２3.５ｇを得る。Me; methyl group, Et; ethyl group, n-Pr; n-propyl group,
i-Pr: isopropyl group, Ac: acetyl group, Allyl group, Ethylene Group Reference Example 21 g of 2,6-dichloro-5-fluoronicotinic acid was dissolved in 210 m of chloroform, and thionyl chloride 23.8 was added.
g and 0.1 g of N, N-dimethylformamide are added, and the mixture is reacted at 70 ° C. for 2 hours. The solvent and excess thionyl chloride are distilled off under reduced pressure, and the obtained residue is dissolved in 21 m of tetrahydrofuran. Magnesium 2.67
25.1 g of diethyl ethoxymagnesium malonate prepared from g was dissolved in 110 m of tetrahydrofuran,
Cool to -40 to -30 ° C. A tetrahydrofuran solution of 2,6-dichloro-5-fluoronicotinic acid chloride prepared above is added dropwise to this solution at the same temperature over 30 minutes. After stirring this mixed solution at the same temperature for 1 hour, the temperature is gradually raised to room temperature. The solvent was distilled off under reduced pressure, and the resulting residue was added with 200 m of chloroform and 100 m of water.
Is added and the pH is adjusted to 1 with 6N hydrochloric acid. The organic layer was separated and water 50m, 5% sodium hydrogen carbonate aqueous solution 50m
Then, it is washed successively with 50 m of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 50 m of water and 0.15 g of p-toluenesulfonic acid were added to the obtained oily substance, the mixture was reacted with vigorous stirring at 100 ° C for 2 hours, and then extracted with 100 m of chloroform.
The organic layer was washed with 50 m of saturated saline and dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (Wako Silica Gel C).
-200, eluent; toluene), melting point 64
23.5 g of 2,6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester having a temperature of ˜65 ° C. are obtained.
IR(KBr)cm-1；νｃ＝ｏ 1650，1630，1620 NMR(CDCl3)；δ値 1.25(1.29H,t,J＝7Hz）， 1.33(1.71H,t,J＝7Hz）， 4.07(1.14H,s）， 4.28(2H,q,J＝7Hz）， 5.82(0.43H,s）， 7.80(1H,d,J＝7Hz）， 12.62(0.43H,s） 実施例１ (1)２，６−ジクロロ−５−フルオロニコチノイル酢酸
エチルエステル8.８ｇをベンゼン４０ｍに溶解させ、
Ｎ，Ｎ−ジメチルホルムアミドジメチルアセタール4.５
ｇを加えて、７０℃で1.５時間反応させる。ついで、こ
の反応液に２，４−ジフルオロアニリン4.１ｇを加え
て、室温で４時間反応させた後、減圧下に溶媒を留去す
る。得られた残留物をカラムクロマトグラフイー（和光
シリカゲルＣ−２００、溶離剤；クロロホルム）で精製
すれば、融点１３８〜１３９℃を示す２−（２，６−ジ
クロロ−５−フルオロニコチノイル）−３−（２，４−
ジフルオロフェニルアミノ）アクリル酸エチルエステル
9.０ｇを得る。IR (KBr) cm −1 ; ν c = o 1650, 1630, 1620 NMR (CDCl 3 ); δ value 1.25 (1.29H, t, J = 7Hz), 1.33 (1.71H, t, J = 7Hz), 4.07 (1.14H, s), 4.28 (2H, q, J = 7Hz), 5.82 (0.43H, s), 7.80 (1H, d, J = 7Hz), 12.62 (0.43H, s) Example 1 (1) 2,6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester 8.8 g was dissolved in benzene 40 m,
N, N-dimethylformamide dimethyl acetal 4.5
g, and react at 70 ° C. for 1.5 hours. Then, 4.1 g of 2,4-difluoroaniline was added to this reaction solution, and the reaction was carried out at room temperature for 4 hours, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (Wako Silica Gel C-200, eluent: chloroform) to give 2- (2,6-dichloro-5-fluoronicotinoyl) -having a melting point of 138 to 139 ° C. 3- (2,4-
Difluorophenylamino) acrylic acid ethyl ester
Obtain 9.0 g.
IR(KBr)cm-1；νｃ＝ｏ 1690 NMR(CDCl3）；δ値 1.08(3H,t,J＝7Hz),4.10(2H,q,J＝7Hz),6.77〜7.40(4H,
m),8.50(1H,d,J＝13Hz),12.70(1H,d,J＝13Hz) 同様にして、つぎの表−２に示す化合物を得た。IR (KBr) cm −1 ; ν c = o 1690 NMR (CDCl 3 ); δ value 1.08 (3H, t, J = 7Hz), 4.10 (2H, q, J = 7Hz), 6.77 to 7.40 (4H, 4H,
m), 8.50 (1H, d, J = 13Hz), 12.70 (1H, d, J = 13Hz) In the same manner, the compounds shown in Table 2 below were obtained.
(2)２−（２，６−ジクロロ−５−フルオロニコチノイ
ル）−３−（２，４−ジフルオロフェニルアミノ）アク
リル酸エチルエステル9.０ｇをＮ，Ｎ−ジメチルホルム
アミド９０ｍに溶解させ、炭酸水素ナトリウム3.６ｇ
を加えて、１２０℃で２０分間反応させる。ついで、減
圧下に溶媒を留去し、得られた残留物をクロロホルム５
０ｍに溶解させる。この反応液を水３０ｍおよび飽
和食塩水３０ｍで順次洗浄した後、無水硫酸マグネシ
ウムで乾燥させる。減圧下に溶媒を留去し、得られた結
晶性物質をジエチルエーテル３０ｍで洗浄すれば、融
点２２０〜２２２℃を示す７−クロロ−６−フルオロ−
１−（２，４−ジフルオロフェニル）−１，４−ジヒド
ロ−４−オキソ−１，８−ナフチリジン−３−カルボン
酸エチルエステル7.０ｇを得る。 (2) 9.0 g of 2- (2,6-dichloro-5-fluoronicotinoyl) -3- (2,4-difluorophenylamino) acrylic acid ethyl ester was dissolved in 90 m of N, N-dimethylformamide to give carbonic acid. Sodium hydrogen 3.6g
Is added and reacted at 120 ° C. for 20 minutes. Then, the solvent was distilled off under reduced pressure, and the resulting residue was mixed with chloroform 5
Dissolve in 0 m. The reaction solution is washed successively with 30 m of water and 30 m of saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystalline substance was washed with 30 m of diethyl ether to give 7-chloro-6-fluoro-, which shows a melting point of 220-222 ° C.
7.0 g of 1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester are obtained.
IR(KBr)cm-1；νｃ＝ｏ 1730，1690 NMR(CDCl3)；δ値 1.36(3H,t,J＝7Hz),4.30(2H,q,J＝7Hz),6.80〜7.60(3H,
m),8.27(1H,d,J＝7Hz),8.42(1H,s) 同様にして、つぎの表−３に示す化合物を得た。IR (KBr) cm −1 ; ν c = o 1730, 1690 NMR (CDCl 3 ); δ value 1.36 (3H, t, J = 7Hz), 4.30 (2H, q, J = 7Hz), 6.80 to 7.60 (3H) ,
m), 8.27 (1H, d, J = 7Hz), 8.42 (1H, s) Similarly, the compounds shown in Table 3 below were obtained.
(3)７−クロロ−６−フルオロ−１−（２，４−ジフル
オロフェニル）−１，４−ジヒドロ−４−オキソ−１，
８−ナフチリジン−３−カルボン酸エチルエステル3.５
ｇをクロロホルム３５ｍに溶解させ、これにＮ−アセ
チルピペラジン1.５ｇおよびトリエチルアミン1.６ｇを
加えて、６０℃で１時間反応させる。ついで、減圧下に
溶媒を留去し、得られた残留物をカラムクロマトグラフ
ィー〔和光シリカゲルＣ−２００、溶離剤；クロロホル
ム：エタノール＝３０：１（容量比）〕で精製すれば、
融点２０７〜２０９℃を示す７−（４−アセチル−１−
ピペラジニル）−６−フルオロ−１−（２，４−ジフル
オロフェニル）−１，４−ジヒドロ−４−オキソ−１，
８−ナフチリジン−３−カルボン酸エチルエステル3.５
ｇを得る。 (3) 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,
8-Naphthyridine-3-carboxylic acid ethyl ester 3.5
g is dissolved in 35 m of chloroform, 1.5 g of N-acetylpiperazine and 1.6 g of triethylamine are added thereto, and the mixture is reacted at 60 ° C. for 1 hour. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography [Wako silica gel C-200, eluent; chloroform: ethanol = 30: 1 (volume ratio)].
7- (4-acetyl-1- having a melting point of 207 to 209 ° C.
Piperazinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,
8-Naphthyridine-3-carboxylic acid ethyl ester 3.5
get g.
IR(KBr)cm-1；νｃ＝ｏ 1730，1695 NMR(CDCl3)；δ値 1.38(3H,t,J＝7Hz),2.05(3H,s),3.53(8H,bs),4.30(2H,
q,J＝7Hz),6.80〜7.75(3H,m),8.0(1H,d,J＝13Hz),8.30
(1H,s) 同様にして、つぎの表−４に示す化合物を得た。IR (KBr) cm −1 ; ν c = o 1730, 1695 NMR (CDCl 3 ); δ value 1.38 (3H, t, J = 7Hz), 2.05 (3H, s), 3.53 (8H, bs), 4.30 ( 2H,
q, J = 7Hz), 6.80 to 7.75 (3H, m), 8.0 (1H, d, J = 13Hz), 8.30
(1H, s) In the same manner, the compounds shown in Table 4 below were obtained.
(4)７−（４−アセチル−１−ピペラジニル）−６−フ
ルオロ−１−（２，４−ジフルオロフェニル）−１，４
−ジヒドロ−４−オキソ−１，８−ナフチリジン−３−
カルボン酸エチルエステル2.５ｇを６Ｎ−塩酸２５ｍ
に溶解させ、還流下に２時間反応させる。ついで、反応
液を室温まで冷却し、１Ｎ−水酸化ナトリウム水溶液で
pH12に調整した後、さらに酢酸でpH6.5に調整する。析
出晶を取し、水３０ｍで洗浄した後、乾燥させ、６
−フルオロ−１−（２，４−ジフルオロフェニル）−
１，４−ジヒドロ−４−オキソ−７−（１−ピペラジニ
ル）−１，８−ナフチリジン−３−カルボン酸1.８ｇを
得る。 (4) 7- (4-Acetyl-1-piperazinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4
-Dihydro-4-oxo-1,8-naphthyridine-3-
Carboxylic acid ethyl ester 2.5 g was added with 6 N hydrochloric acid 25 m.
And dissolve under reflux for 2 hours. Then, the reaction solution was cooled to room temperature and treated with 1N-sodium hydroxide aqueous solution.
After adjusting the pH to 12, further adjust the pH to 6.5 with acetic acid. The precipitated crystals are collected, washed with 30 m of water and dried to give 6
-Fluoro-1- (2,4-difluorophenyl)-
1.8 g of 1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid are obtained.
NMR(TFA-d1）；δ値 3.30〜4.50(8H,m),7.0〜7.85(3H,m)8.33(1H,d,J＝13H
z),9.21(1H,s) 同様にして、つぎの表−５に示す化合物を得た。NMR (TFA-d 1 ); δ value 3.30 to 4.50 (8H, m), 7.0 to 7.85 (3H, m) 8.33 (1H, d, J = 13H
z), 9.21 (1H, s) In the same manner, the compounds shown in Table 5 below were obtained.
実施例２ (1)７−クロロ−６−フルオロ−１−（２，４−ジフル
オロフェニル）−１，４−ジヒドロ−４−オキソ−１，
８−ナフチリジン−３−カルボン酸エチルエステル0.５
０ｇを６Ｎ−塩酸１５ｍに懸濁させ、３時間加熱還流
する。ついで、反応液を水５０ｍで希釈し、クロロホ
ルム５０ｍずつで３回抽出し、合した抽出液を飽和食
塩水１００ｍで洗浄した後、無水硫酸マグネシウムで
乾燥させる。減圧下に溶媒に留去し、得られた結晶性物
質をジエチルエーテル１５ｍで洗浄すれば、融点２４
４〜２４８℃を示す７−クロロ−６−フルオロ−１−
（２，４−ジフルオロフェニル）−１，４−ジヒドロ−
４−オキソ−１，８−ナフチリジン−３−カルボン酸0.
４０ｇを得る。 Example 2 (1) 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,
8-Naphthyridine-3-carboxylic acid ethyl ester 0.5
0 g is suspended in 6 N-hydrochloric acid 15 m and heated under reflux for 3 hours. Then, the reaction solution is diluted with 50 m of water, extracted three times with 50 m each of chloroform, and the combined extracts are washed with 100 m of saturated saline solution and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystalline substance was washed with 15 m of diethyl ether to give a melting point of 24
7-Chloro-6-fluoro-1- showing 4 to 248 ° C
(2,4-Difluorophenyl) -1,4-dihydro-
4-oxo-1,8-naphthyridine-3-carboxylic acid 0.
40 g are obtained.
IR(KBr)cm-1；νｃ＝ｏ 1720 NMR(d6-DMSO)；δ値 7.26〜8.56(3H,m),8.86(1H,d,J＝7Hz),9.18(1H,s) (2)７−クロロ−６−フルオロ−１−（２，４−ジフル
オロフェニル）−１，４−ジヒドロ−４−オキソ−１，
８−ナフチリジン−３−カルボン酸0.３０ｇをジメチル
スルホキシド３ｍに懸濁させ、Ｎ−メチルピペラジン
0.２５ｇを加えて、６０℃で３０分間反応させる。つい
で、減圧下に溶媒を留去し、得られた残留物に水３０ｍ
を加え、１０％水酸化ナトリウム水溶液でpH１２に調
整した後、さらに酢酸でpH７に調整する。析出した結晶
性物質を取し、水５ｍで洗浄すれば、融点２０８〜
２０９℃を示す６−フルオロ−１−（２，４−ジフルオ
ロフェニル）−１，４−ジヒドロ−７−（４−メチル−
１−ピペラジニル）−４−オキソ−１，８−ナフチリジ
ン−３−カルボン酸0.２４ｇを得る。IR (KBr) cm −1 ; ν c = o 1720 NMR (d 6 -DMSO); δ value 7.26 to 8.56 (3H, m), 8.86 (1H, d, J = 7Hz), 9.18 (1H, s) ( 2) 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,
N-methylpiperazine was prepared by suspending 0.30 g of 8-naphthyridine-3-carboxylic acid in 3 m of dimethyl sulfoxide.
Add 0.25 g and react at 60 ° C. for 30 minutes. Then, the solvent was distilled off under reduced pressure, and 30 m of water was added to the obtained residue.
Is added to adjust the pH to 12 with a 10% aqueous sodium hydroxide solution, and then to pH 7 with acetic acid. If the precipitated crystalline substance is removed and washed with 5 m of water, the melting point of 208-
6-Fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-7- (4-methyl-indicating 209 ° C.
0.24 g of 1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained.
IR(KBr)cm-1；νｃ＝ｏ 1730 NMR(TFA-d1)；δ値 3.30(3H,s),(3.45〜5.25(8H,m),7.12〜8.10(3H,m),8.49
(1H,d,J＝13Hz),9.38(1H,s) 実施例３ (1)２，６−ジクロロ−５−フルオロニコチノイル酢酸
エチルエステル5.5ｇ、Ｎ−メチルピペラジン2.37ｇお
よびトリエチルアミン2.37ｇをクロロホルム５５ｍに
溶解させ、６０〜６５℃で２時間反応させる。反応液を
水３０ｍで洗浄した後、無水硫酸マグネシウムで乾燥
させる。減圧下に溶媒を留去し、得られた残渣をカラム
クロマトグラフィー（和光シリカゲルＣ−２００，溶離
剤；クロロホルム）で精製すれば、油状の２−クロロ−
５−フルオロ−６−（４−メチル−１−ピペラジニル）
ニコチノイル酢酸エチルエステル5.4ｇを得る。IR (KBr) cm −1 ; ν c = o 1730 NMR (TFA-d 1 ); δ value 3.30 (3H, s), (3.45 to 5.25 (8H, m), 7.12 to 8.10 (3H, m), 8.49
(1H, d, J = 13Hz), 9.38 (1H, s) Example 3 (1) 5.5 g of 2,6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester, 2.37 g of N-methylpiperazine and 2.37 g of triethylamine were added. It is dissolved in 55 m of chloroform and reacted at 60 to 65 ° C for 2 hours. The reaction solution is washed with 30 m of water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (Wako Silica Gel C-200, eluent: chloroform) to give oily 2-chloro-
5-fluoro-6- (4-methyl-1-piperazinyl)
5.4 g of nicotinoyl acetic acid ethyl ester are obtained.
IR（ニート）cm-1；νｃ＝ｏ 1750,1695 NMR(CDCl3)；δ値 1.25(3H,t,J＝7Hz),2.32(3H,s),2.12〜2.70(4H,m),3.55
〜3.96(4H,m),4.03(2H,s),4.20(2H,q,J＝7Hz),7.78(1H,
d,J＝13Hz) 同様にして、つぎの表−６に示す化合物を得た。IR (neat) cm −1 ; ν c = o 1750,1695 NMR (CDCl 3 ); δ value 1.25 (3H, t, J = 7Hz), 2.32 (3H, s), 2.12 to 2.70 (4H, m), 3.55
~ 3.96 (4H, m), 4.03 (2H, s), 4.20 (2H, q, J = 7Hz), 7.78 (1H,
(d, J = 13 Hz) Similarly, the compounds shown in Table 6 below were obtained.
(2)２−クロロ−５−フルオロ−６−（４−メチル−１
−ピペラジニル）ニコチノイル酢酸エチルエステル4.５
ｇをベンゼン２2.５ｍに溶解させ、Ｎ，Ｎ−ジメチル
ホルムアミドジメチルアセタール1.８７ｇを加えて、７
０℃で２時間反応させる。この反応液に４−メトキシ−
２−メチルアニリン1.８ｇを加えて、室温で４時間反応
させる。ついで、減圧下に溶媒を留去し、得られた残渣
をカラムクロマトグラフィー〔和光シリカゲルＣ−２０
０、溶離剤；クロロホルム：エタノール＝１００：１
（容量比）〕で精製し、得られた結晶性物質をジエチル
エーテル１０ｍで洗浄すれば、融点１４１〜１４２℃
を示す２−〔２−クロロ−５−フルオロ−６−（４−メ
チル−１−ピペラジニル）ニコチノイル〕−３−（４−
メトキシ−２−メチルフェニルアミノ）アクリル酸エチ
ルエステル5.０ｇを得る。 (2) 2-chloro-5-fluoro-6- (4-methyl-1
-Piperazinyl) nicotinoyl acetic acid ethyl ester 4.5
g was dissolved in 22.5 m of benzene, 1.87 g of N, N-dimethylformamide dimethyl acetal was added, and
React at 0 ° C. for 2 hours. 4-methoxy-
1.8 g of 2-methylaniline is added and reacted at room temperature for 4 hours. Then, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [Wako silica gel C-20.
0, eluent; chloroform: ethanol = 100: 1
(Volume ratio)], and the obtained crystalline substance is washed with 10 m of diethyl ether to give a melting point of 141 to 142 ° C.
2- [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] -3- (4-
5.0 g of methoxy-2-methylphenylamino) acrylic acid ethyl ester are obtained.
IR(KBr)cm-1；νｃ＝ｏ 1710(sh),1695 NMR(CDCl3)：δ値 1.08(3H,t,J＝7Hz),2.32(3H,s),2.40(3H,s),2.23〜2.68
(4H,m),3.47〜3.83(4H,m),3.75(3H,s),4.07(2H,q,J＝7H
z),6.65〜7.25(3H,m),7.20(1H,d,J＝13Hz),8.48(1H,d,J
＝13Hz),12.82(1H,d,J＝13Hz) 同様にして、つぎの表−７に示す化合物を得た。IR (KBr) cm −1 ; ν c = o 1710 (sh), 1695 NMR (CDCl 3 ): δ value 1.08 (3H, t, J = 7Hz), 2.32 (3H, s), 2.40 (3H, s) , 2.23 ~ 2.68
(4H, m), 3.47 to 3.83 (4H, m), 3.75 (3H, s), 4.07 (2H, q, J = 7H
z), 6.65-7.25 (3H, m), 7.20 (1H, d, J = 13Hz), 8.48 (1H, d, J
= 13 Hz), 12.82 (1H, d, J = 13 Hz) In the same manner, the compounds shown in Table 7 below were obtained.
(3)２−〔２−クロロ−５−フルオロ−６−（４−メチ
ル−１−ピペラジニル）ニコチノイル〕−３−（４−メ
トキシ−２−メチルフェニルアミノ）アクリル酸エチル
エステル5.０ｇをＮ，Ｎ−ジメチルホルムアミド５０ｍ
に溶解させた後、炭酸水素ナトリウム1.０３ｇを加え
て、１２０℃で３時間反応させる。ついで、減圧下に溶
媒を留去し、得られた残渣をクロロホルム５０ｍに溶
解させる。この溶液を水３０ｍおよび飽和食塩水３０
ｍで順次洗浄した後、無水硫酸マグネシウムで乾燥さ
せる。減圧下に溶媒を留去し、得られた結晶性物質をジ
エチルエーテル３０ｍで洗浄すれば、融点１４４〜１
４５℃を示す６−フルオロ−１，４−ジヒドロ−１−
（４−メトキシ−２−メチルフェニル）−７−（４−メ
チル−１−ピペラジニル）−４−オキソ−１，８−ナフ
チリジン−３−カルボン酸エチルエステル2.３８ｇを得
る。 (3) 5.0 g of 2- [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] -3- (4-methoxy-2-methylphenylamino) acrylic acid ethyl ester was added to N. , N-dimethylformamide 50m
Then, 1.03 g of sodium hydrogen carbonate is added, and the mixture is reacted at 120 ° C. for 3 hours. Then, the solvent is distilled off under reduced pressure, and the obtained residue is dissolved in 50 m of chloroform. 30 m of this solution and 30 ml of saturated saline solution
m, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystalline substance was washed with 30 m of diethyl ether to give a melting point of 144-1.
6-Fluoro-1,4-dihydro-1-indicating 45 ° C
2.38 g of (4-methoxy-2-methylphenyl) -7- (4-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester are obtained.
IR(KBr)cm-1；νｃ＝ｏ 1730,1690 NMR(CDCl3)；δ値 1.33(3H,t,J＝7Hz),1.95(3H,s),2.20(3H,s),2.05〜2.62
(4H,m),3.32〜3.63(4H,m),3.82(3H,s),4.32(2H,q,J＝7H
z),6.60〜7.15(3H,m),8.02(1H,d,J＝13Hz),8.23(1H,s) 同様にして、つぎの表−８に示す化合物を得た。IR (KBr) cm −1 ; ν c = o 1730,1690 NMR (CDCl 3 ); δ value 1.33 (3H, t, J = 7Hz), 1.95 (3H, s), 2.20 (3H, s), 2.05〜 2.62
(4H, m), 3.32-3.63 (4H, m), 3.82 (3H, s), 4.32 (2H, q, J = 7H
z), 6.60 to 7.15 (3H, m), 8.02 (1H, d, J = 13Hz), 8.23 (1H, s) Similarly, the compounds shown in the following Table-8 were obtained.
実施例４ ６−フルオロ−１，４−ジヒドロ−１−（４−メトキシ
−２−メチルフェニル）−７−（４−メチル−１−ピペ
ラジニル）−４−オキソ−１，８−ナフチリジン−３−
カルボン酸エチルエステル2.０ｇを４７％臭化水素酸５
ｍに溶解させ、１２０〜１２５℃で２時間反応させ
る。ついで、反応液に１０％水酸化ナトリウム水溶液を
加え、pH１３に調整した後、さらに、酢酸を加え、pH6.
5に調整する。析出晶を取し、水１０ｍで洗浄すれ
ば、融点２８０℃以上を示す６−フルオロ−１，４−ジ
ヒドロ−１−（４−ヒドロキシ−２−メチルフェニル）
−７−（４−メチル−１−ピペラジニル）−４−オキソ
−１，８−ナフチリジン−３−カルボン酸1.８ｇを得
る。 Example 4 6-Fluoro-1,4-dihydro-1- (4-methoxy-2-methylphenyl) -7- (4-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-
Carboxylic acid ethyl ester 2.0 g was mixed with 47% hydrobromic acid 5
It is dissolved in m and reacted at 120 to 125 ° C. for 2 hours. Then, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, and then acetic acid was further added to adjust the pH to 6.
Adjust to 5. The precipitated crystals are collected and washed with 10 m of water to give 6-fluoro-1,4-dihydro-1- (4-hydroxy-2-methylphenyl) having a melting point of 280 ° C or higher.
1.8 g of -7- (4-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained.
IR(KBr)cm-1；νｃ＝ｏ 1725,1700(sh) NMR(TFA-d1)；δ値 2.08(3H,s),3.12(3H,s),2.88〜5.12(8H,m),6.93〜7.62
(3H,m),9.43(1H,d,J＝13Hz),9.25(1H,s) 同様にして、つぎの表−９に示す化合物を得た。IR (KBr) cm −1 ; ν c = o 1725,1700 (sh) NMR (TFA-d 1 ); δ value 2.08 (3H, s), 3.12 (3H, s), 2.88 to 5.12 (8H, m) , 6.93 ~ 7.62
(3H, m), 9.43 (1H, d, J = 13Hz), 9.25 (1H, s) Similarly, the compounds shown in Table 9 below were obtained.
実施例５ ７−（４−アセチル−１−ピペラジニル）−６−フルオ
ロ−１−（４−フルオロフェニル）−１，４−ジヒドロ
−４−オキソ−１，８−ナフチリジン−３−カルボン酸
エチルエステル0.１ｇに１Ｎ−水酸化ナトリウム水溶液
２ｍおよびエタノール２ｍを加えて、４０〜５０℃
で１０分間反応させる。ついで、反応液に酢酸を加え、
pH6.5に調整した後、クロロホルム５ｍずつで２回抽
出する。合した抽出液を水５ｍおよび飽和食塩水５ｍ
で順次洗浄した後、無水硫酸マグネシウムで乾燥させ
る。減圧下に溶媒を留去し、得られた結晶性物質をジエ
チルエーテル２ｍで洗浄すれば、融点２８０℃以上を
示す７−（４−アセチル−１−ピペラジニル）−６−フ
ルオロ−１−（４−フルオロフェニル）−１，４−ジヒ
ドロ−４−オキソ−１，８−ナフチリジン−３−カルボ
ン酸0.０８ｇを得る。 Example 5 7- (4-Acetyl-1-piperazinyl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 1N-sodium hydroxide aqueous solution 2m and ethanol 2m are added to 0.1g, 40-50 degreeC.
React for 10 minutes. Then add acetic acid to the reaction mixture,
After adjusting the pH to 6.5, extract twice with 5 m each of chloroform. The combined extract was 5 m of water and 5 m of saturated saline.
After sequentially washing with, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystalline substance was washed with 2 m of diethyl ether to give 7- (4-acetyl-1-piperazinyl) -6-fluoro-1- (4 0.08 g of -fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained.
IR(KBr)cm-1；νｃ＝ｏ 1730 NMR(d6-DMSO)；δ値 2.05(3H,s),3.57(8H,bs),7.13〜7.80(4H,m),8.13(1H,d,
J＝13Hz),8.70(1H,s) 同様にして、つぎの表−１０に示す化合物を得た。IR (KBr) cm −1 ; ν c = o 1730 NMR (d 6 -DMSO); δ value 2.05 (3H, s), 3.57 (8H, bs), 7.13 to 7.80 (4H, m), 8.13 (1H, d,
(J = 13 Hz), 8.70 (1H, s) Similarly, the compounds shown in Table 10 below were obtained.
実施例６ ６−（フルオロ−１，４−ジヒドロ−１−（４−ヒドロ
キシ−２−メチルフェニル）−４−オキソ−７−（１−
ピペラジニル）−１，８−ナフチリジン−３−カルボン
酸0.25ｇを濃塩酸2.５ｍに溶解させた後、エタノール
２０ｍを室温で加えて１５分間攪拌する。析出晶を
取し、エタノール５ｍで洗浄すれば、融点２８０℃以
上を示す６−フルオロ−１，４−ジヒドロ−１−（４−
ヒドロキシ−２−メチルフェニル）−４−オキソ−７−
（１−ピペラジニル）−１，８−ナフチリジン−３−カ
ルボン酸の塩酸塩0.２ｇを得る。 Example 6 6- (Fluoro-1,4-dihydro-1- (4-hydroxy-2-methylphenyl) -4-oxo-7- (1-
After 0.25 g of piperazinyl) -1,8-naphthyridine-3-carboxylic acid is dissolved in 2.5 m of concentrated hydrochloric acid, 20 m of ethanol is added at room temperature and stirred for 15 minutes. Precipitated crystals are collected and washed with 5 m of ethanol to give 6-fluoro-1,4-dihydro-1- (4-
Hydroxy-2-methylphenyl) -4-oxo-7-
0.2 g of (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid hydrochloride is obtained.
IR(KBr)cm-1；νｃ＝ｏ 1725(sh),1705 同様にして、つぎの表−１１に示す化合物を得た。IR (KBr) cm -1 ; ν c = o 1725 (sh), 1705 In the same manner, the compounds shown in Table 11 below were obtained.
実施例７ (1)２−（２，６−ジクロロ−５−フルオロニコチノイ
ル）−３−（２，４−ジフルオロフェニルアミノ）アク
リル酸エチルエステル0.５ｇ、Ｎ−メチルピペラジン0.
１４３ｇおよびトリエチルアミン0.１４５ｇをクロロホ
ルム2.５ｍに溶解させ、3.５時間加熱還流する。つい
で、反応液を水３ｍおよび飽和食塩水３ｍで順次洗
浄した後、無水硫酸マグネシウムで乾燥させる。減圧下
に溶媒を留去し、得られた残留物をカラムクロマトグラ
フィー〔和光シリカゲルＣ−２００、溶離剤；クロロホ
ルム：エタノール＝５０：１（容量比）〕で精製すれ
ば、油状の２−〔２−クロロ−５−フルオロ−６−（４
−メチル−１−ピペラジニル）ニコチノイル〕−３−
（２，４−ジフルオロフェニルアミノ）アクリル酸エチ
ルエステル0.２９４ｇを得る。 Example 7 (1) 2- (2,6-Dichloro-5-fluoronicotinoyl) -3- (2,4-difluorophenylamino) acrylic acid ethyl ester 0.5 g, N-methylpiperazine 0.5.
143 g and 0.145 g of triethylamine are dissolved in 2.5 m of chloroform and heated under reflux for 3.5 hours. Then, the reaction solution is washed successively with 3 m of water and 3 m of saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography [Wako Silica Gel C-200, eluent; chloroform: ethanol = 50: 1 (volume ratio)] to give an oily 2- [ 2-chloro-5-fluoro-6- (4
-Methyl-1-piperazinyl) nicotinoyl] -3-
0.294 g of (2,4-difluorophenylamino) acrylic acid ethyl ester is obtained.
IR（ニート）cm-1；νｃ＝ｏ 1735,1700 NMR(CDCl3)；δ値 1.13(3H,t,J＝7Hz),2.36(3H,s),2.55(4H,t,J＝5Hz),3.7
0(4H,t,J＝5Hz),4.15(2H,q,J＝7Hz),6.77〜7.90(4H,m),
8.51(1H,d,J＝13Hz)，12.50(1H,d,J＝13Hz） (2)２−〔２−クロロ−５−フルオロ−６−（４−メチ
ル−１−ピペラジニル）ニコチノイル〕−３−（２，４
−ジフルオロフェニルアミノ）アクリル酸エチルエステ
ル0.２ｇを、実施例１−(2)と同様に反応させて処理す
れば、融点２０８〜２０９℃を示す６−フルオロ−１−
（２，４−ジフルオロフェニル）−１，４−ジヒドロ−
７−（４−メチル−１−ピペラジニル）−４−オキソ−
１，８−ナフチリジン−３−カルボン酸0.１２ｇを得
る。IR (neat) cm −1 ; ν c = o 1735,1700 NMR (CDCl 3 ); δ value 1.13 (3H, t, J = 7Hz), 2.36 (3H, s), 2.55 (4H, t, J = 5Hz ), 3.7
0 (4H, t, J = 5Hz), 4.15 (2H, q, J = 7Hz), 6.77〜7.90 (4H, m),
8.51 (1H, d, J = 13Hz), 12.50 (1H, d, J = 13Hz) (2) 2- [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] -3 -(2,4
When 0.2 g of (difluorophenylamino) acrylic acid ethyl ester was reacted and treated in the same manner as in Example 1- (2), 6-fluoro-1- having a melting point of 208 to 209 ° C was obtained.
(2,4-Difluorophenyl) -1,4-dihydro-
7- (4-methyl-1-piperazinyl) -4-oxo-
0.12 g of 1,8-naphthyridine-3-carboxylic acid is obtained.
実施例８ ７−（４−エトキシカルボニル−２−メチル−１−ピペ
ラジニル）−６−フルオロ−１−（２，４−ジフルオロ
フェニル）−１，４−ジヒドロ−４−オキソ−１，８−
ナフチリジン−３−カルボン酸エチルエステル0.３ｇに
１Ｎ−水酸化ナトリウム水溶液５ｍおよびエタノール
５ｍを加えて９０℃で２時間反応させる。ついで、反
応液に酢酸を加えpH6.5に調整する。析出晶を取し、
水洗した後、乾燥させれば、融点２３０〜２３９℃を示
す６−フルオロ−１−（２，４−ジフルオロフェニル）
−１，４−ジヒドロ−７−（２−メチル−１−ピペラジ
ニル）−４−オキソ−１，８−ナフチリジン−３−カル
ボン酸0.２ｇを得る。Example 8 7- (4-Ethoxycarbonyl-2-methyl-1-piperazinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-
To 0.3 g of naphthyridine-3-carboxylic acid ethyl ester are added 1N-sodium hydroxide aqueous solution (5 m) and ethanol (5 m), and the mixture is reacted at 90 ° C for 2 hours. Then, acetic acid is added to the reaction solution to adjust the pH to 6.5. Remove the precipitated crystals,
After washing with water and drying, 6-fluoro-1- (2,4-difluorophenyl) having a melting point of 230 to 239 ° C.
0.2 g of -1,4-dihydro-7- (2-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained.
IR(KBr)cm-1；νｃ＝ｏ 1730 NMR(TFA-d1)；δ値 1.50(3H,s),3.20〜5.15(7H,m),7.0〜7.90(3H,m),8.35(1
H,d,J＝13Hz),9.2(1H,s) 製剤例１ ６−フルオロ−１−（２，４−ジフルオロフェニル）−
１，４−ジヒドロ−４−オキソ−７−（１−ピペラジニ
ル）−１，８−ナフチリジン−３−カルボン酸５０ｇ、
結晶セルロース４９ｇ、コーンスターチ５０ｇおよびマ
グネシウムステアレート１ｇを混合し、フラット型錠剤
１０００錠に打錠して錠剤を得る。IR (KBr) cm −1 ; ν c = o 1730 NMR (TFA-d 1 ); δ value 1.50 (3H, s), 3.20-5.15 (7H, m), 7.0〜7.90 (3H, m), 8.35 ( 1
H, d, J = 13Hz), 9.2 (1H, s) Formulation Example 1 6-Fluoro-1- (2,4-difluorophenyl)-
50 g of 1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid,
49 g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate are mixed and compressed into 1000 flat tablets to give tablets.
製剤例２ ６−フルオロ−１−（２，４−ジフルオロフェニル）−
１，４−ジヒドロ−４−オキソ−７−（１−ピペラジニ
ル）−１，８−ナフチリジン−３−カルボン酸１００ｇ
およびコーンスターチ５０ｇを混合し、１０００カプセ
ルに充填してカプセル剤を得る。Formulation Example 2 6-Fluoro-1- (2,4-difluorophenyl)-
1,4-Dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid 100 g
And 50 g of corn starch are mixed and filled into 1000 capsules to obtain capsules.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 小林 順子 富山県富山市五福5242―６ (72)発明者 品川 三香子 富山県中新川郡立山町道源寺916 (72)発明者 渡辺 泰雄 富山県富山市西田地方町２―４―９ (72)発明者 四辻 彰 富山県射水郡小杉町上野30 (72)発明者 南 新三郎 富山県富山市中田167 (72)発明者 才川 勇 富山県富山市大泉中町７―52 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Junko Kobayashi 5242-6 Gofuku, Toyama City, Toyama Prefecture (72) Inventor Mikako Shinagawa 916 Dogenji, Tateyama Town, Nakashinkawa District, Toyama Prefecture (72) Inventor Yasuo Watanabe Toyama Prefecture, Toyama Prefecture 2-4-9, Nishida-cho, Nishi-shi, Japan (72) Akira Shitsuji 30 Ueno, Kosugi-cho, Imizu-gun, Toyama Prefecture (72) Inventor Shinsaburo Minami 167 Nakata, Toyama-shi, Toyama Prefecture (72) Inventor Yu Saitogawa Oizumi, Toyama-shi, Toyama Prefecture 7-52 Nakamachi
Claims (4)
を；Ｒ3が１−ピペラジニル基で、Ｒ2は、３−フルオロ
フェニル、３，４−ジフルオロフェニル、２，４−ジフ
ルオロフェニル、２，５−ジフルオロフェニル、２，６
−ジフルオロフェニル、４−クロロフェニル、４−ブロ
モフェニル、４−メチルフェニル、４−シアノフェニ
ル、４−アミノフェニル、４−トリフルオロメチルフェ
ニル、４−フルオロ−２−メチルフェニル、４−フルオ
ロ−２−ヒドロキシフェニル、４−ヒドロキシ−２−メ
チルフェニルあるいは２−フルオロ−４−ヒドロキシフ
ェニル基を；Ｒ3が４−アセチル−１−ピペラジニル基
で、Ｒ2は、３−フルオロフェニル、２，４−ジフルオ
ロフェニル、３，４−ジフルオロフェニル、２，５−ジ
フルオロフェニル、２，６−ジフルオロフェニル、４−
クロロフェニル、４−ブロモフェニル、４−メチルフェ
ニル、４−シアノフェニル、４−アセチルアミノフェニ
ル、４−トリフルオロメチルフェニル、４−フルオロ−
２−メチルフェニル、４−フルオロ−２−メトキシフェ
ニル、２−フルオロ−４−メトキシフェニルあるいは２
−メチル−４−メトキシフェニル基を；Ｒ3が４−メチ
ル−１−ピペラジニル基で、Ｒ2は、３，４−ジフルオ
ロフェニル、４−ブロモフェニル、４−メチルフェニ
ル、４−メトキシフェニル、２−メトキシフェニル、４
−フルオロ−２−メトキシフェニル、２−フルオロ−４
−メトキシフェニル、４−メチル−２−メトキシフェニ
ル、４−アセチルアミノフェニル、３−メトキシフェニ
ル、３−フルオロ−４−メトキシフェニル、３−メチル
−４−メトキシフェニル、２−メチル−４−メトキシフ
ェニル、３−ヒドロキシフェニル、４−フルオロ−２−
ヒドロキシフェニル、３−フルオロ−４−ヒドロキシフ
ェニル、２−フルオロ−４−ヒドロキシフェニル、２−
ヒドロキシ−４−メチルフェニル、４−ヒドロキシ−３
−メチルフェニル、４−ヒドロキシ−２−メチルフェニ
ルあるいは４−クロロフェニル基を；Ｒ3が４−（Ｎ−
アセチル−Ｎ−メチルアミノ）ピペリジノ、４−（Ｎ−
メチルアミノ）ピペリジノ、２，５−ジメチル−１−ピ
ペラジニル、４−（２−ヒドロキシエチル）−１−ピペ
ラジニル、３−メチルアミノ−１−ピロリジニル、３−
（Ｎ−アセチル−Ｎ−メチルアミノ）−１−ピロリジニ
ルあるいは３−メチル−１−ピペラジニル基で、Ｒ2が
４−フルオロフェニル基を；Ｒ3が３−ヒドロキシ−１
−ピロリジニル、１−ピロリジニル、ピペリジノ、４−
エチル−１−ピペラジニル、４−ｎ−プロピル−１−ピ
ペラジニル、４−イソプロピル−１−ピペラジニル、４
−（２−ヒドロキシエチル）−１−ピペラジニルあるい
は４−アリル−１−ピペラジニル基で、Ｒ2は４−メト
キシフェニル基を；Ｒ3が４−（Ｎ−アセチル−Ｎ−メ
チルアミノ）ピペリジノ、３−メチル−１−ピペラジニ
ル、３，４−ジメチル−１−ピペラジニル、２，４−ジ
メチル−１−ピペラジニル、４−アリル−１−ピペラジ
ニル、４−エトキシカルボニル−２−メチル−１−ピペ
ラジニル、３−ジメチルアミノ−１−ピロリジニル、３
−（Ｎ−アセチル−Ｎ−メチルアミノ）−１−ピロリジ
ニル、４−（Ｎ−メチルアミノ）ピペリジノ、３−メチ
ルアミノ−１−ピロリジニルあるいは２−メチル−１−
ピペラジニル基で、Ｒ2は２，４−ジフルオロフェニル
基を；Ｒ3が３−アミノ−１−ピロリジニルあるいは３
−アセチルアミノ−１−ピロリジニル基で、Ｒ2は２，
３，４−トリフルオロフェニル基を；Ｒ3が４−エチル
−１−ピペラジニル、４−ｎ−プロピル−１−ピペラジ
ニル、４−イソプロピル−１−ピペラジニル、４−（２
−ヒドロキシエチル）−１−ピペラジニルあるいは４−
アリル−１−ピペラジニル基で、Ｒ2は４−ヒドロキシ
フェニル基を示す。」 で表わされる１，４−ジヒドロ−４−オキソナフチリジ
ン誘導体およびその塩。1. A general formula "In the formula, R 1 is a hydrogen atom or a carboxyl protecting group; R 3 is a 1-piperazinyl group, and R 2 is 3-fluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 2, 5-difluorophenyl, 2,6
-Difluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-cyanophenyl, 4-aminophenyl, 4-trifluoromethylphenyl, 4-fluoro-2-methylphenyl, 4-fluoro-2- Hydroxyphenyl, 4-hydroxy-2-methylphenyl or 2-fluoro-4-hydroxyphenyl group; R 3 is 4-acetyl-1-piperazinyl group, R 2 is 3-fluorophenyl, 2,4-difluoro group Phenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 4-
Chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-cyanophenyl, 4-acetylaminophenyl, 4-trifluoromethylphenyl, 4-fluoro-
2-methylphenyl, 4-fluoro-2-methoxyphenyl, 2-fluoro-4-methoxyphenyl or 2
-Methyl-4-methoxyphenyl group; R 3 is 4-methyl-1-piperazinyl group, R 2 is 3,4-difluorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2 -Methoxyphenyl, 4
-Fluoro-2-methoxyphenyl, 2-fluoro-4
-Methoxyphenyl, 4-methyl-2-methoxyphenyl, 4-acetylaminophenyl, 3-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-methyl-4-methoxyphenyl, 2-methyl-4-methoxyphenyl , 3-hydroxyphenyl, 4-fluoro-2-
Hydroxyphenyl, 3-fluoro-4-hydroxyphenyl, 2-fluoro-4-hydroxyphenyl, 2-
Hydroxy-4-methylphenyl, 4-hydroxy-3
-Methylphenyl, 4-hydroxy-2-methylphenyl or 4-chlorophenyl group; R 3 is 4- (N-
Acetyl-N-methylamino) piperidino, 4- (N-
Methylamino) piperidino, 2,5-dimethyl-1-piperazinyl, 4- (2-hydroxyethyl) -1-piperazinyl, 3-methylamino-1-pyrrolidinyl, 3-
(N-acetyl-N-methylamino) -1-pyrrolidinyl or 3-methyl-1-piperazinyl group, R 2 is 4-fluorophenyl group; R 3 is 3-hydroxy-1
-Pyrrolidinyl, 1-pyrrolidinyl, piperidino, 4-
Ethyl-1-piperazinyl, 4-n-propyl-1-piperazinyl, 4-isopropyl-1-piperazinyl, 4
-(2-hydroxyethyl) -1-piperazinyl or 4-allyl-1-piperazinyl group, R 2 is 4-methoxyphenyl group; R 3 is 4- (N-acetyl-N-methylamino) piperidino, 3 -Methyl-1-piperazinyl, 3,4-dimethyl-1-piperazinyl, 2,4-dimethyl-1-piperazinyl, 4-allyl-1-piperazinyl, 4-ethoxycarbonyl-2-methyl-1-piperazinyl, 3- Dimethylamino-1-pyrrolidinyl, 3
-(N-acetyl-N-methylamino) -1-pyrrolidinyl, 4- (N-methylamino) piperidino, 3-methylamino-1-pyrrolidinyl or 2-methyl-1-
In the piperazinyl group, R 2 is 2,4-difluorophenyl group; R 3 is 3-amino-1-pyrrolidinyl or 3
-Acetylamino-1-pyrrolidinyl group, R 2 is 2,
A 3,4-trifluorophenyl group; R 3 is 4-ethyl-1-piperazinyl, 4-n-propyl-1-piperazinyl, 4-isopropyl-1-piperazinyl, 4- (2
-Hydroxyethyl) -1-piperazinyl or 4-
An allyl-1-piperazinyl group, R 2 represents a 4-hydroxyphenyl group. And a 1,4-dihydro-4-oxonaphthyridine derivative represented by the formula and a salt thereof.
ヒドロキシフェニル）−７−（４−メチル−１−ピペラ
ジニル）−１，４−ジヒドロ−４−オキソ−１，８−ナ
フチリジン−３−カルボン酸およびその塩である特許請
求の範囲第１項記載の１，４−ジヒドロ−４−オキソナ
フチリジン誘導体およびその塩。2. 6-Fluoro-1- (2-fluoro-4-)
A hydroxyphenyl) -7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and a salt thereof, according to claim 1. 1,4-Dihydro-4-oxonaphthyridine derivatives and salts thereof.
フェニル）−７−（１−ピペラジニル）−１，４−ジヒ
ドロ−４−オキソ−１，８−ナフチリジン−３−カルボ
ン酸およびその塩である特許請求の範囲第１項記載の
１，４−ジヒドロ−４−オキソナフチリジン誘導体およ
びその塩。3. 6-Fluoro-1- (2,4-difluorophenyl) -7- (1-piperazinyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and the same. The 1,4-dihydro-4-oxonaphthyridine derivative according to claim 1, which is a salt, and a salt thereof.
メチルフェニル）−７−（１−ピペラジニル）−１，４
−ジヒドロ−４−オキソ−１，８−ナフチリジン−３−
カルボン酸およびその塩である特許請求の範囲第１項記
載の１，４−ジヒドロ−４−オキソナフチリジン誘導体
およびその塩。4. 6-Fluoro-1- (4-fluoro-2-
Methylphenyl) -7- (1-piperazinyl) -1,4
-Dihydro-4-oxo-1,8-naphthyridine-3-
The 1,4-dihydro-4-oxonaphthyridine derivative according to claim 1, which is a carboxylic acid or a salt thereof, and a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62254530A JPH0633262B2 (en) | 1987-10-12 | 1987-10-12 | 1,4-Dihydro-4-oxonaphthyridine derivatives and salts thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62254530A JPH0633262B2 (en) | 1987-10-12 | 1987-10-12 | 1,4-Dihydro-4-oxonaphthyridine derivatives and salts thereof |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59084963A Division JPS60228479A (en) | 1984-04-26 | 1984-04-26 | 1,4-dihydro-4-oxonaphthyridine derivative and salt thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63132888A JPS63132888A (en) | 1988-06-04 |
| JPH0633262B2 true JPH0633262B2 (en) | 1994-05-02 |
Family
ID=17266323
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62254530A Expired - Lifetime JPH0633262B2 (en) | 1987-10-12 | 1987-10-12 | 1,4-Dihydro-4-oxonaphthyridine derivatives and salts thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0633262B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NO177302C (en) * | 1989-03-16 | 1995-08-23 | Esteve Labor Dr | Analogous Process for Preparing Therapeutically Active Substituted Azetidinyl Quinolone (Naphthyridone) Carboxylic Acid Derivatives |
-
1987
- 1987-10-12 JP JP62254530A patent/JPH0633262B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63132888A (en) | 1988-06-04 |
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