JPH0586392B2 - - Google Patents
Info
- Publication number
- JPH0586392B2 JPH0586392B2 JP60123797A JP12379785A JPH0586392B2 JP H0586392 B2 JPH0586392 B2 JP H0586392B2 JP 60123797 A JP60123797 A JP 60123797A JP 12379785 A JP12379785 A JP 12379785A JP H0586392 B2 JPH0586392 B2 JP H0586392B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- fluoro
- naphthyridine
- cis
- ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- -1 phenyl-substituted 1,8-naphthyridine Chemical class 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000005907 alkyl ester group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 150000002148 esters Chemical class 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 12
- 238000002329 infrared spectrum Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 238000001819 mass spectrum Methods 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
- 238000000034 method Methods 0.000 description 8
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000007796 conventional method Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- REMBFZWYXJUGLC-BMIGLBTASA-N C1[C@H](Cl)[C@H](CN)CN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1 Chemical compound C1[C@H](Cl)[C@H](CN)CN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1 REMBFZWYXJUGLC-BMIGLBTASA-N 0.000 description 4
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- XTEULOBSYIIBTO-UHFFFAOYSA-N 1-benzyl-3-fluoropyrrolidine Chemical class C1C(F)CCN1CC1=CC=CC=C1 XTEULOBSYIIBTO-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
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MCMONGRBVLPZDE-UHFFFAOYSA-N N-[(4-fluoropyrrolidin-3-yl)methyl]acetamide Chemical compound CC(=O)NCC1CNCC1F MCMONGRBVLPZDE-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
- 239000002253 acid Substances 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
- 239000003054 catalyst Substances 0.000 description 3
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 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
- 239000000047 product Substances 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000001727 in vivo 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
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 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
- MBMBUSUISIGXCG-UHFFFAOYSA-N (1-benzyl-4-hydroxypyrrolidin-3-yl)methyl methanesulfonate Chemical compound C1C(O)C(COS(=O)(=O)C)CN1CC1=CC=CC=C1 MBMBUSUISIGXCG-UHFFFAOYSA-N 0.000 description 1
- RNWBPOAFKSKZSF-VXGBXAGGSA-N (3S,4S)-3-(azidomethyl)-1-benzyl-4-fluoropyrrolidine Chemical compound C1[C@@H](CN=[N+]=[N-])[C@H](F)CN1CC1=CC=CC=C1 RNWBPOAFKSKZSF-VXGBXAGGSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LHHGPDMZKWSDNZ-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid;hydrochloride Chemical compound Cl.C12=NC=C(F)C=C2C(=O)C(C(=O)O)=CN1C1=CC=C(F)C=C1F LHHGPDMZKWSDNZ-UHFFFAOYSA-N 0.000 description 1
- XQYUBSUGHRDQSN-UHFFFAOYSA-N 1-benzyl-4-(hydroxymethyl)pyrrolidin-3-ol Chemical compound C1C(O)C(CO)CN1CC1=CC=CC=C1 XQYUBSUGHRDQSN-UHFFFAOYSA-N 0.000 description 1
- RNSGBYUFHBXKPU-UHFFFAOYSA-N 1-chloropyrrolidine Chemical compound ClN1CCCC1 RNSGBYUFHBXKPU-UHFFFAOYSA-N 0.000 description 1
- OTWVFHZMWFGHSJ-UHFFFAOYSA-N 1-fluoropyrrolidine Chemical compound FN1CCCC1 OTWVFHZMWFGHSJ-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
- 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
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
- RNWBPOAFKSKZSF-UHFFFAOYSA-N 3-(azidomethyl)-1-benzyl-4-fluoropyrrolidine Chemical compound C1C(CN=[N+]=[N-])C(F)CN1CC1=CC=CC=C1 RNWBPOAFKSKZSF-UHFFFAOYSA-N 0.000 description 1
- WPWGDRFCVLQTBF-UHFFFAOYSA-N 4-(azidomethyl)-1-benzylpyrrolidin-3-ol Chemical compound C1C(CN=[N+]=[N-])C(O)CN1CC1=CC=CC=C1 WPWGDRFCVLQTBF-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- KBPHGYUXEIDPPV-UHFFFAOYSA-N 4-oxo-1h-1,8-naphthyridine-3-carboxylic acid Chemical compound C1=CC=C2C(=O)C(C(=O)O)=CNC2=N1 KBPHGYUXEIDPPV-UHFFFAOYSA-N 0.000 description 1
- UGFUGEXLYCNCIZ-UHFFFAOYSA-N 4-oxo-1h-1,8-naphthyridine-3-carboxylic acid;hydrochloride Chemical compound Cl.C1=CC=C2C(=O)C(C(=O)O)=CNC2=N1 UGFUGEXLYCNCIZ-UHFFFAOYSA-N 0.000 description 1
- MSHYEQPKGREGMS-UHFFFAOYSA-N 7-chloro-6-fluoro-1-(4-fluorophenyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C12=NC(Cl)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1=CC=C(F)C=C1 MSHYEQPKGREGMS-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- SHGPKKOJRMHXDW-VXGBXAGGSA-N C1[C@@H](CN=[N+]=[N-])[C@H](Cl)CN1CC1=CC=CC=C1 Chemical compound C1[C@@H](CN=[N+]=[N-])[C@H](Cl)CN1CC1=CC=CC=C1 SHGPKKOJRMHXDW-VXGBXAGGSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-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
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-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
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- MGJSUYPIWXENBZ-UHFFFAOYSA-N N-[(1-benzyl-4-fluoropyrrolidin-3-yl)methyl]acetamide Chemical compound C1C(F)C(CNC(=O)C)CN1CC1=CC=CC=C1 MGJSUYPIWXENBZ-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 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
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012043 crude product Substances 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
- JFWURCREFDQUTD-UHFFFAOYSA-N ethyl 1,8-naphthyridine-3-carboxylate Chemical compound N1=CC=CC2=CC(C(=O)OCC)=CN=C21 JFWURCREFDQUTD-UHFFFAOYSA-N 0.000 description 1
- PIHWQJBFCRABCQ-UHFFFAOYSA-N ethyl 2-oxo-1h-1,8-naphthyridine-3-carboxylate Chemical compound C1=CN=C2NC(=O)C(C(=O)OCC)=CC2=C1 PIHWQJBFCRABCQ-UHFFFAOYSA-N 0.000 description 1
- 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
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 208000010824 fish disease Diseases 0.000 description 1
- 239000011737 fluorine Substances 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
- 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
- 238000001802 infusion Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- USOGGYDQFOUYRH-UHFFFAOYSA-N n-[(4-chloropyrrolidin-3-yl)methyl]acetamide Chemical compound CC(=O)NCC1CNCC1Cl USOGGYDQFOUYRH-UHFFFAOYSA-N 0.000 description 1
- RIARYQRDUOZXEX-ZIAGYGMSSA-N n-[[(3r,4s)-1-benzyl-4-chloropyrrolidin-3-yl]methyl]acetamide Chemical compound C1[C@@H](Cl)[C@H](CNC(=O)C)CN1CC1=CC=CC=C1 RIARYQRDUOZXEX-ZIAGYGMSSA-N 0.000 description 1
- OBDFQUSHNJZDSN-UHFFFAOYSA-N n-ethylethanamine;1,1,2,3,3,3-hexafluoroprop-1-ene Chemical compound CCNCC.FC(F)=C(F)C(F)(F)F OBDFQUSHNJZDSN-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
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- 238000010898 silica gel chromatography 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
- 239000002904 solvent 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
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- 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
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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は極めて優れた抗菌活性を示す新規フエ
ニル置換１，８−ナフチリジン誘導体、そのエス
テルまたはその塩に関する。
更に詳しくは、本発明の化合物は下記一般式
The present invention relates to novel phenyl-substituted 1,8-naphthyridine derivatives, esters thereof, or salts thereof, which exhibit extremely excellent antibacterial activity. More specifically, the compound of the present invention has the following general formula:
【化】
（式中、X1，X2は同一または異なつてハロゲン
原子を意味し、R1，R2は同一または異なつて水
素原子または低級アルキル基を意味し、R3，R4
およびR5は同一または異なつて水素原子、ハロ
ゲン原子またはトリフルオロメチル基を意味し、
ｍは整数１を意味し、ｎは整数４を意味する。）
で表わされるフエニル置換１，８−ナフチリジン
誘導体、そのエステルまたはその塩である。
本明細書において、ハロゲン原子とはフツ素、
塩素、臭素またはヨウ素を意味し、低級アルキル
基とは炭素原子１ないし５個を有するアルキル基
を意味する。
本発明の化合物の塩は、酢酸、乳酸、コハク
酸、メタンスルホン酸、マレイン酸、マロン酸、
グルコン酸等の有機酸との塩、アスパラギン酸、
グルタミン酸等のアミノ酸との塩、或いは塩酸、
リン酸等の無機酸との塩、或いは式［Ｉ］の化合
物のナトリウム、カリウム、亜鉛、銀等の金属
塩、或いは有機塩基との塩である。
式［Ｉ］の化合物のエステルとは、化合物
［Ｉ］のメチルエステル、エチルエステル等の低
級アルキルエステル、或いは加水分解することに
より又は生体内で容易に脱離されて化合物［Ｉ］
になる様な公知のエステル、例えばアセトキシメ
チルエステル、ピバロイルオキシメチルエステ
ル、エトキシカルボニルオキシエチルエステル、
コリンエステル、ジメチルアミノエチルエステル
や１−ピペリジニルエチルエステル等のアミノエ
チルエステル類、５−インダニルエステル、フタ
リジルエステル等を意味する。
本発明の化合物は、また水和物としても存在し
得る。従つて、この様な形のものも当然本発明の
化合物に包含される。
本発明の化合物は、その７位の置換基に不斉炭
素原子を有するので、光学活性体として存在し得
る。従つて、これらの光学活性体は本発明の化合
物に包含される。
更にまた、本発明化合物は、その７位の置換基
に２個の不斉炭素原子を有するので、異なる立体
異性体（シス型、トランス型）として存在し得
る。これらの立体異性体およびその混合物もま
た、本発明の化合物に包含される。
本発明の化合物の製造法につき以下に説明す
る。
本発明の化合物は、下記一般式[Formula, X 1 and X 2 are the same or different and mean a halogen atom, R 1 and R 2 are the same or different and mean a hydrogen atom or a lower alkyl group, and R 3 and R 4
and R 5 are the same or different and mean a hydrogen atom, a halogen atom or a trifluoromethyl group,
m means an integer 1, and n means an integer 4. ) A phenyl-substituted 1,8-naphthyridine derivative, an ester thereof, or a salt thereof. In this specification, halogen atoms include fluorine,
It means chlorine, bromine or iodine, and lower alkyl means an alkyl group having 1 to 5 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 of the compound of formula [I] such as sodium, potassium, zinc, silver, etc., or salts with organic bases. The ester of the compound of formula [I] refers to a lower alkyl ester such as methyl ester or ethyl ester of compound [I], or a compound [I] that is easily eliminated by hydrolysis or in vivo.
Known esters such as acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester,
It means choline ester, aminoethyl esters such as dimethylaminoethyl ester and 1-piperidinylethyl ester, 5-indanyl ester, phthalidyl ester, and the like. Compounds of the invention may also exist as hydrates. Therefore, such forms are naturally included in the compounds of the present invention. Since the compound of the present invention has an asymmetric carbon atom in the substituent at the 7-position, it can exist as an optically active form. Therefore, these optically active substances are included in the compounds of the present invention. Furthermore, since the compound of the present invention has two asymmetric carbon atoms in the substituent at the 7-position, it can exist as different stereoisomers (cis type, trans type). These stereoisomers and mixtures thereof 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:
【化】
（式中、Ｚは後記環状アミン誘導体と置換し得る
官能基を意味し、X1，R3，R4およびR5は前掲と
同じ。）
で表わされるカルボン酸またはそのエステル（好
ましくは低級アルキルエステル）と下記一般式(In the formula, Z means a functional group that can be substituted with the cyclic amine derivative described below, and X 1 , R 3 , R 4 and R 5 are the same as above.) or an ester thereof (preferably is lower alkyl ester) and the following general formula
【化】
（式中、X2，R1，R2，ｍおよびｎは前掲と同
じ。）
で表わされる環状アミン誘導体を反応せしめ、生
成物を常法により単離することにより製造するこ
とができる。
式［］のＺで示した反応性官能基としては、
ハロゲン原子、アリールスルホニル、アリールス
ルフイニル、低級アルキルスルホニル、低級アル
コキシ、低級アルキルチオ、低級アルキルスルフ
イニル、アリールスルホニルオキシ、低級アルキ
ルスルホニルオキシ等が挙げられる。
本反応は、エタノール、アセトニトリル、ジオ
キサン、ジメチルホルムアミド、トルエン、キシ
レンの如き不活性溶媒中、10〜180℃、好ましく
は20〜150℃において、原料化合物［］または
そのエステルと［］とを５〜120分間、通常は
20〜60分間混合攪拌することにより実施できる。
原料化合物［］またはそのエステルに対する原
料化合物［］の使用量は当量ないしやゝ過剰量
である。原料化合物［］またはそのエステルの
Ｚの官能基の種類により、反応の結果塩酸等の酸
が副生するので、かかる場合には酸受容体を使用
するのが一般的であるが、原料化合物［］を過
剰に用い、酸受容体としての役割を兼ねさせても
よい。
また、本反応で使用される原料化合物［］
は、可能ならば、そのIt can be produced by reacting a cyclic amine derivative represented by [Chemical formula] (wherein X 2 , R 1 , R 2 , m and n are the same as above) and isolating the product by a conventional method. can. 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 the starting compound [] to be used is equivalent to or slightly in excess of the starting compound [] or its ester. Depending on the type of Z functional group in the starting compound [] or its ester, 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
【式】の部分をアセチ
ル等で保護した形で用い、反応完了後常法により
その保護基を除去してもよい。
原料化合物［］またはそのエステルは、参考
例１および２に記載の方法或いはこれに準じた方
法で製造し得る。
原料化合物［］は参考例３および４に記載の
方法或いはこれに準じた方法で製造し得る。
上記方法により得られる本発明の化合物がエス
テルである場合、そのエステル部分を常法により
加水分解することにより、式［Ｉ］の化合物に変
換することができる。更には、必要に応じ式
［Ｉ］の化合物を常法によりエステル化し、式
［Ｉ］の化合物のエステルに導くこともできる。
この様にして製造される本発明の化合物は、常
法に従い単離、精製される。単離、精製条件によ
つて、塩の形、遊離カルボン酸や遊離アミンの形
で得られるが、これらは、目的に応じて相互に変
換され、目的とする形の本発明の化合物が製造さ
れる。
本発明の化合物の立体異性体（シス型、トラン
ス型）は、通常の方法、例えば分別結晶、クロマ
トグラフイー分離等により、互いに分離すること
ができる。尚、シス型或いはトランス型の配置を
有する原料化合物［］を用い、上記方法によつ
て、それぞれシス型、トランス型の配置を有する
本発明の化合物を製造することもできる。
本発明の化合物の光学活性体は、公知の方法を
適用することによつて、分離することが可能であ
る。
かくして得られる化合物［Ｉ］、そのエステル
およびその塩はいずれも新規化合物である。特に
化合物［Ｉ］およびその塩は極めて優れた抗菌活
性を示すので、抗菌剤として価値あるものであ
る。化合物［Ｉ］またはその塩はこれを人体およ
び、動物用医薬は勿論のこと、魚病薬、農薬、食
品の保存剤等としても使用することが可能であ
る。また、化合物［Ｉ］のエステル体は化合物
［Ｉ］の合成原料として勿論価値あるものである
が、その他にこの化合物が生体内において容易に
化合物［Ｉ］に変換する場合には、化合物［Ｉ］
と同等の作用効果を発揮し得るので、抗菌剤とし
ても有用な化合物である。
次に本発明の化合物の抗菌活性について、以下
にデータを挙げる。The moiety represented by [Formula] may be used in a protected form with acetyl or the like, and after the reaction is completed, 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 to the compound of formula [I] by hydrolyzing the ester moiety by a conventional method. Furthermore, if necessary, the compound of formula [I] can be esterified by a conventional method to obtain an ester of the compound of formula [I]. 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, the compound of the present invention having a cis-type or trans-type configuration can also be produced by the above-mentioned method using a raw material compound [] having a cis-type or a trans-type configuration, respectively. Optically active forms of the compounds of the present invention can be separated by applying known methods. The compound [I] thus obtained, its ester, and its salt are all new compounds. In particular, compound [I] and its salts exhibit extremely excellent antibacterial activity and are therefore valuable as antibacterial agents. Compound [I] or a salt thereof 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 [I] is of course valuable as a raw material for the synthesis of compound [I], but if this compound is easily converted into compound [I] in vivo, the compound [I] ]
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.
【表】
本発明の化合物を人に抗菌剤として使用する場
合、その投与量は、年令、体重、症状、投与経
路、投与回数等により異なるが、１日当り５mg〜
5gを１回ないし数回に分けて投与することが推
奨される。投与経路は経口、非経口のいずれでも
よい。
本発明の化合物は原末のままでもよいが、通常
製剤用担体と共に調製された形で投与される。そ
の具体例としては、錠剤、カプセル剤、顆粒剤、
細粒剤、散剤、シロツプ剤、注射剤等が挙げられ
る。これらの製剤は常法に従つて調製される。経
口用製剤担体としては、デンプン、マンニツト、
結晶セルロース、CMC Na等の製剤分野におい
て常用され、かつ本発明の化合物と反応しない物
質が用いられる。注射用担体としては、水、生理
食塩水、グルコース溶液、輸液剤等の注射剤の分
野で常用される担体が挙げられる。
次に実施例および参考例を挙げて本発明化合物
の製造法を更に具体的に説明する。
参考例 １
７−クロロ−６−フルオロ−１−（４−フルオ
ロフエニル）−１，４−ジヒドロ−４−オキソ−
１，８−ナフチリジン−３−カルボン酸エチル：
(1) 公知化合物、２，６−ジクロロ−５−フルオ
ロニコチノニトリル60gを濃硫酸中65〜75℃で
１時間加熱する。水を加えて更に100〜110℃で
２時間加熱して、２，６−ジクロロ−５−フル
オロニコチン酸59.8gを得る。m.p.155〜156℃
(2) この化合物45.2gを塩化チオニルで処理して、
２，６−ジクロロ−５−フルオロニコチン酸ク
ロリド47.5gを油状物として得る。
(3) この化合物47.5gを無水エーテル中、エトキ
シマグネシウムマロン酸ジエチルと反応させ
て、２，６−ジクロロ−５−フルオロニコチノ
イルマロン酸ジエチルを油状物として得る。こ
れに水と触媒量のｐ−トルエンスルホン酸を加
え、140℃で２時間加熱して、２，６−ジクロ
ロ−５−フルオロニコチノイル酢酸エチル46g
を得る。m.p.69〜70℃
(4) この化合物40gをオルトギ酸エチルと無水酢
酸で処理して、２−（２，６−ジクロロ−５−
フルオロニコチノイル）−３−エトキシアクリ
ル酸エチル42gを油状物として得る。
(5) この化合物6.0gをエタノールに溶かし、室温
で４−フルオロアニリンと反応させて、２−
（２，６−ジクロロ−５−フルオロニコチノイ
ル）−３−（４−フルオロフエニルアミノ）アク
リル酸エチル7.0gを得る。m.p.111〜112℃
(6) この化合物6.0gを無水ジオキサン中でカリウ
ムｔ−ブトキシドと反応させて、７−クロロ−
６−フルオロ−１−（４−フルオロフエニル）−
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5.1gを得る。
m.p.227〜228℃
(7) この化合物3.0gを酢酸２ml、硫酸５mlおよび
水12mlの混液で加水分解して、７−クロロ−６
−フルオロ−１−（４−フルオロフエニル）−
１，４−ジヒドロ−４−オキソ−１，８−ナフ
チリジン−３−カルボン酸2.6gを得る。m.
p.273〜276℃
参考例 ２
参考例１の方法に準じて、以下の化合物を得
る。
(1) ７−クロロ−６−フルオロ−１−（２−フル
オロフエニル）−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、m.p.212〜213℃。
(2) ７−クロロ−１−（２，４−ジフルオロフエ
ニル）−６−フルオロ−１，４−ジヒドロ−４
−オキソ−１，８−ナフチリジン−３−カルボ
ン酸エチル、m.p.212〜213℃。
(3) ７−クロロ−６−フルオロ−１−（３−トリ
フルオロメチルフエニル）−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、m.p.210〜211℃。
(4) ７−クロロ−１−（４−クロロフエニル）−６
−フルオロ−１，４−ジヒドロ−４−オキソ−
１，８−ナフチリジン−３−カルボン酸エチ
ル、m.p.197〜198℃。
(5) ７−クロロ−６−フルオロ−１−フエニル−
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、m.p.221〜
222℃。
(6) ７−クロロ−６−フルオロ−１−（３−フル
オロフエニル）−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、m.p.242〜243℃。
(7) ７−クロロ−１−（３，４−ジフルオロフエ
ニル）−６−フルオロ−１，４−ジヒドロ−４
−オキソ−１，８−ナフチリジン−３−カルボ
ン酸エチル、m.p.246〜247℃。
参考例 ３
３−アセチルアミノメチル−４−フルオロピロ
リジン：
(1) 公知化合物１−ベンジル−３−ヒドロキシ−
４−ヒドロキシメチルピロリジン［J.Org.
Chem.，30，740（1965）参照］110gにクロロホ
ルム中トリエチルアミンの存在下、塩化メタン
スルホニル60.9gを反応させて、油状の１−ベ
ンジル−３−ヒドロキシ−４−メタンスルホニ
ルオキシメチルピロリジン81gを得る。IRスペ
クトル（液膜）cm-1：3370，1350，1170.マ
ス・スペクトルｍ／ｚ：285（M+），208，190，
91.
(2) この化合物50gとアジ化ナトリウム22.8gをジ
メチルホルムアミド中120〜130℃で反応させ
て、油状の３−アジドメチル−１−ベンジル−
４−ヒドロキシピロリジン30gを得る。IRスペ
クトル（液膜）cm-1：3350，2100，1450，
1265.マス・スペクトルｍ／ｚ：232（M+），
175，158，91.
(3) この化合物32gのクロロホルム溶液にヘキサ
フルオロプロペン−ジエチルアミン試薬64gを
加えて反応させ、粗生成物をシリカゲルカラム
クロマトグラフイーで分離精製して次の生成物
を得る。
初期流出分として、油状のトランス−３−ア
ジドメチル−１−ベンジル−４−フルオロピロ
リジン3.5gを得る。IRスペクトル（液膜）cm-
１：2100，1450，1270.マス・スペクトルｍ／
ｚ：234（M+），177，91.NMRスペクトル
（CDCl3）δ：3.64（2H，ｓ，CH2 Ph），4.5およ
び5.2（1H，br，Ｈ〓Ｆ），7.30（5H，ｓ，C6
H5）．
後部流出分として、油状のシス−３−アジド
メチル−１−ベンジル−４−フルオロピロリジ
ン3.0gを得る。IRスペクトル（液膜）cm-1：
2100，1450，1270.マス・スペクトルｍ／ｚ：
234（M+），177，91.NMRスペクトル（CDCl3）
δ：3.68（2H，ｓ，CH2 Ph），4.75および5.45
（1H，br，Ｈ＋Ｆ），7.30（5H，ｓ，C6H5）．
中間流出分として、３−アジドメチル−１−
ベンジル−４−フルオロピロリジンのシス体お
よびトランス体の混合物7.3gを得る。
(4) 上記化合物（トランス体）3.1gをナトリウム
ビス（２−メトキシエトキシ）アルミニウム
ヒドリドで還元したのちアセチル化して、油状
のトランス−３−アセチルアミノメチル−１−
ベンジル−４−フルオロピロリジン2.2gを得
る。IRスペクトル（液膜）cm-1：3270，1650，
1550.マス・スペクトルｍ／ｚ：250（M+），
158，91.NMRスペクトル（CDCl3）δ：1.96
（3H，ｓ，COCH3），3.61（2H，ｓ，CH2 Ph），
4.52および5.22（1H，br，Ｈ＋Ｆ），7.30（5H，
ｓ，C6H5）．
同様にして、上記化合物（シス体）から油状
のシス−３−アセチルアミノメチル−１−ベン
ジル−４−フルオロピロリジンを得る。IRス
ペクトル（液膜）cm-1：3270，1650，1550.マ
ス・スペクトルｍ／ｚ：250（M+），158，91.
NMRスペクトル（CDCl3）δ：1.98（3H，ｓ，
COCH3），3.66（2H，ｓ，CH2 Ph），4.75および
5.48（1H，br，Ｈ＋Ｆ），7.31（5H，ｓ，C6
H5）．
同様にして、３−アジドメチル−１−ベンジ
ル−４−フルオロピロリジンのシス体とトラン
ス体の混合物から、３−アセチルアミノメチル
−１−ベンジル−４−フルオロピロリジンのシ
ス体とトランス体の混合物を得る。
(5) 上記化合物（トランス体）をエタノールに溶
かし、５％パラジウム−炭素を触媒として加水
素分解する。触媒を濾去して、トランス−３−
アセチルアミノメチル−４−フルオロピロリジ
ンのエタノール溶液を得る。この溶液を次の置
換反応に使用する。
同様にして上記化合物（シス体）からシス−
３−アセチルアミノメチル−４−フルオロピロ
リジンを含む溶液を得る。
同様にして上記３−アセチルアミノメチル−
１−ベンジル−４−フルオロピロリジンのシス
体とトランス体の混合物から、３−アセチルア
ミノメチル−４−フルオロピロリジンのシス体
とトランス体の混合物を含む溶液を得る。
参考例 ４
３−アセチルアミノメチル−４−クロロピロリ
ジン：
(1) ３−アジドメチル−１−ベンジル−４−ヒド
ロキシピロリジンをクロロホルム中塩化チオニ
ルと反応させた後、カラムクロマトグラフイー
で分離精製して、次の生成物を得る。
シス−３−アジドメチル−１−ベンジル−４
−クロロピロリジン。IRスペクトル（液膜）
cm-1：2800，2100，740，700.マス・スペクト
ルｍ／ｚ：250（M+），158，91.NMRスペクト
ル（CDCl3）δ：2.6（1H，ｍ，C3−Ｈ），2.5〜
3.0（2H，ｍ，C2−Ｈ），2.8〜3.4（2H，ｍ，C5
−Ｈ），3.3〜3.7（2H，ｍ，CH2N3），3.73（2H，
ｓ，CH2 Ph），4.5（1H，ｍ，C4−Ｈ），7.34
（5H，ｓ，C6H5）．
トランス−３−アジドメチル−１−ベンジル
−４−クロロピロリジン。IRスペクトル（液
膜）cm-1：2800，2100，740，700.マス・スペ
クトルｍ／ｚ：250（M+），158，91.NMRスペ
クトル（CDCl3）δ：2.58（1H，ｍ，C3−Ｈ），
2.45〜2.8（2H，ｍ，C2−Ｈ），2.8〜3.2（2H，
ｍ，C5−Ｈ），3.44（2H，ｍ，CH2N3），3.66
（2H，br ｓ，CH2 Ph），4.05（1H，ｍ，C4−
Ｈ），7.34（5H，ｓ，C6H5）．
(2) 上記化合物（シス体）をナトリウム ビス
（２−メトキシエトキシ）アルミニウムヒドリ
ドで還元した後、無水酢酸および苛性ソーダ水
溶液で処理することにより、油状のシス−３−
アセチルアミノメチル−１−ベンジル−４−ク
ロロピロリジンを得る。IRスペクトル（液膜）
cm-1：3300，2800，1650，700.マス・スペクト
ルｍ／ｚ：266（M+），231，171，158，91.
NMRスペクトル（CDCl3）δ：1.97（3H，ｓ，
COCH3），2.5〜2.9（2H，ｍ，C2−Ｈ），2.72
（1H，ｍ，C3−Ｈ），2.8〜3.3（2H，ｍ，C5−
Ｈ），3.3〜3.7（2H，ｍ，CH2 NHCOCH3），
3.71（2H，ｓ，CH2 Ph），4.48（1H，ｍ，C4−
Ｈ），7.33（5H，ｓ，C6H5）．
同様にして上記化合物（トランス体）から、
油状のトランス−３−アセチルアミノメチル−
１−ベンジル−４−クロロピロリジンを得る。
IRスペクトル（液膜）cm-1：3300，2800，
1650，700.マス・スペクトルｍ／ｚ：266
（M+），231，158，91.NMRスペクトル
（CDCl3）δ：1.97（3H，ｓ，COCH3），2.3〜
2.8（3H，ｍ，C2−Ｈ，C3−Ｈ），3.05〜3.75
（4H，ｍ，CH2 NHCOCH3，C5−Ｈ），3.6
（2H，ｓ，CH2 Ph），4.1（1H，ｍ，C4−Ｈ），
7.3（5H，ｓ，C6H5）．
(3) 上記化合物（シス体）をエタノール中で酢酸
と５％パラジウム−炭素の存在下に加水素分解
する。触媒を濾去し、濾液を減圧下に濃縮し
て、油状のシス−３−アセチルアミノメチル−
４−クロロピロリジンを得る。
同様にして、上記化合物（トランス体）か
ら、トランス−３−アセチルアミノメチル−４
−クロロピロリジンを得る。
実施例 １
７−（３−アミノメチル−４−フルオロ−１−
ピロリジニル）−６−フルオロ−１−（４−フルオ
ロフエニル）−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
の塩酸塩：
(1) ７−クロロ−６−フルオロ−１−（４−フル
オロフエニル）−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2.21g，３−アセチルアミノメチル−４−
フルオロピロリジン1.14g、トリエチルアミン
２mlおよびアセトニトリル150mlからなる混合
物を２時間加熱攪拌する。溶媒を留去後、ガム
様残渣を水洗し、エタノールと水を加えて結晶
化させる。結晶を濾取し、酢酸エチルから再結
晶して、７−（３−アセチルアミノメチル−４
−フルオロ−１−ピロリジニル）−６−フルオ
ロ−１−（４−フルオロフエニル）−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（立体異性体の約１：１
混合物）2.0gを得る。m.p.175〜178℃
(2) 上記エステル0.95gを20％塩酸10mlと３時間
加熱攪拌する。反応液を減圧下に濃縮乾固し、
残渣にエタノールを加えて結晶化させる。エタ
ノール−水から再結晶して、７−（３−アミノ
メチル−４−フルオロ−１−ピロリジニル）−
６−フルオロ−１−（４−フルオロフエニル）−
１，４−ジヒドロ−４−オキソ−１，８−ナフ
チリジン−３−カルボン酸塩酸塩（立体異性体
の約１：１混合物）0.68gを得る。m.p.207〜
210℃
(3) 上記塩酸塩0.5gを水に溶かし、炭酸水素ナト
リウム水溶液を加えて中和する。析出結晶を濾
取し水洗して、７−（３−アミノメチル−４−
フルオロ−１−ピロリジニル）−６−フルオロ
−１−（４−フルオロフエニル）−１，４−ジヒ
ドロ−４−オキソ−１，８−ナフチリジン−３
−カルボン酸（立体異性体の約１：１混合物）
0.43gを得る。m.p.約270℃（分解）
実施例 ２
７−（シス−３−アミノメチル−４−フルオロ
−１−ピロリジニル）−１−（２，４−ジフルオロ
フエニル）−６−フルオロ−１，４−ジヒドロ−
４−オキソ−１，８−ナフチリジン−３−カルボ
ン酸およびその塩酸塩：
(1) ７−クロロ−１−（２，４−ジフルオロフエ
ニル）−６−フルオロ−１，４−ジヒドロ−４
−オキソ−１，８−ナフチリジン−３−カルボ
ン酸エチル1.94g、シス−３−アセチルアミノ
メチル−４−フルオロピロリジン1.12g、トリ
エチルアミン1.5mlおよびアセトニトリル150ml
からなる混合物を実施例１−(1)と同様にして反
応処理して、７−（シス−３−アセチルアミノ
メチル−４−フルオロ−１−ピロリジニル）−
１−（２，４−ジフルオロフエニル）−６−フル
オロ−１，４−ジヒドロ−４−オキソ−１，８
−ナフチリジン−３−カルボン酸エチル1.6gを
得る。エタノール−水から再結晶する。m.
p.239〜242℃
(2) 上記エステル1.24gを実施例１−(2)と同様に
反応処理して、７−（シス−３−アミノメチル
−４−フルオロ−１−ピロリジニル）−１−
（２，４−ジフルオロフエニル）−６−フルオロ
−１，４−ジヒドロ−４−オキソ−１，８−ナ
フチリジン−３−カルボン酸塩酸塩0.95gを得
る。エタノール−水から再結晶する。m.p.272
〜276℃（分解）
(3) 上記塩酸塩150mgを実施例１−(3)と同様に反
応処理して、７−（シス−３−アミノメチル−
４−フルオロ−１−ピロリジニル）−１−（２，
４−ジフルオロフエニル）−６−フルオロ−１，
４−ジヒドロ−４−オキソ−１，８−ナフチリ
ジン−３−カルボン酸130mgを得る。ジメチル
ホルムアミド−水から再結晶する。m.p.232〜
236℃（分解）
実施例 ３
７−（シス−３−アミノメチル−４−クロロ−
１−ピロリジニル）−６−フルオロ−１−（４−フ
ルオロフエニル）−１，４−ジヒドロ−４−オキ
ソ−１，８−ナフチリジン−３−カルボン酸：
(1) ７−クロロ−６−フルオロ−１−（４−フル
オロフエニル）−１，４−ジヒドロ−４−オキ
ソ−１，８−ナフチリジン−３−カルボン酸
1.8g、シス−３−アセチルアミノメチル−４−
クロロピロリジン1.3g、トリエチルアミン３ml
およびアセトニトリル50mlからなる混合物を室
温で１時間攪拌する。析出する結晶を濾取し、
アセトニトリルで洗つて、７−（シス−３−ア
セチルアミノメチル−４−クロロ−１−ピロリ
ジニル）−６−フルオロ−１−（４−フルオロフ
エニル）−１，４−ジヒドロ−４−オキソ−１，
８−ナフチリジン−３−カルボン酸2.0gを得
る。アセトニトリルから再結晶する。m.p.234
〜235℃
(2) 上記カルボン酸1.8gと20％塩酸18mlの混合物
を100〜115℃で５時間加熱する。減圧下に濃縮
乾固し、残渣にエタノールを加えて結晶を濾取
する。結晶を温水に溶かし活性炭処理後、アン
モニア水を加えて中和する。析出結晶を濾取し
水洗して、７−（シス−３−アミノメチル−４
−クロロ−１−ピロリジニル）−６−フルオロ
−１−（４−フルオロフエニル）−１，４−ジヒ
ドロ−４−オキソ−１，８−ナフチリジン−３
−カルボン酸1.2gを得る。m.p.220〜225℃（分
解）[Table] When the compound of the present invention is used as an antibacterial agent in humans, the dosage varies depending on age, body weight, symptoms, administration route, number of administrations, etc.
It is recommended to administer 5g in one or several divided doses. The route of administration may be either oral or parenteral. Although the compound of the present invention may be administered as a bulk powder, it is usually administered in a prepared form together with a pharmaceutical carrier. Specific examples include tablets, capsules, granules,
Examples include fine granules, powders, syrups, and injections. These formulations are prepared according to conventional methods. Oral preparation carriers include starch, mannitrate,
Substances commonly used in the pharmaceutical field, such as crystalline cellulose and CMC Na, and which do not react with the compound of the present invention are used. Examples of the carrier for injection include carriers commonly used in the field of injections such as water, physiological saline, 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-(4-fluorophenyl)-1,4-dihydro-4-oxo-
Ethyl 1,8-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. Add water and further heat at 100-110°C for 2 hours to obtain 59.8 g of 2,6-dichloro-5-fluoronicotinic acid. mp155-156℃ (2) Treat 45.2g of this compound with thionyl chloride,
47.5 g of 2,6-dichloro-5-fluoronicotinic acid chloride are obtained 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. Add water and a catalytic amount of p-toluenesulfonic acid to this and heat at 140°C for 2 hours to obtain 46 g of ethyl 2,6-dichloro-5-fluoronicotinoyl acetate.
get. mp69-70℃ (4) Treat 40g of this compound with ethyl orthoformate and acetic anhydride to obtain 2-(2,6-dichloro-5-
42 g of ethyl fluoronicotinoyl)-3-ethoxyacrylate are obtained as an oil. (5) Dissolve 6.0 g of this compound in ethanol, react with 4-fluoroaniline at room temperature, and react with 2-fluoroaniline.
7.0 g of ethyl (2,6-dichloro-5-fluoronicotinoyl)-3-(4-fluorophenylamino)acrylate is obtained. mp111-112℃ (6) 6.0g of this compound was reacted with potassium t-butoxide in anhydrous dioxane to give 7-chloro-
6-Fluoro-1-(4-fluorophenyl)-
5.1 g of ethyl 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are obtained.
mp227-228℃ (7) Hydrolyze 3.0g of this compound with a mixture of 2ml of acetic acid, 5ml of sulfuric acid and 12ml of water to obtain 7-chloro-6
-Fluoro-1-(4-fluorophenyl)-
2.6 g of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. m.
p.273-276°C Reference Example 2 According to the method of Reference Example 1, the following compound is obtained. (1) Ethyl 7-chloro-6-fluoro-1-(2-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, mp212-213°C. (2) 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4
-Ethyl oxo-1,8-naphthyridine-3-carboxylate, mp 212-213°C. (3) Ethyl 7-chloro-6-fluoro-1-(3-trifluoromethylphenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, mp210-211°C. (4) 7-chloro-1-(4-chlorophenyl)-6
-Fluoro-1,4-dihydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylate, mp 197-198°C. (5) 7-chloro-6-fluoro-1-phenyl-
Ethyl 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, mp221~
222℃. (6) Ethyl 7-chloro-6-fluoro-1-(3-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, mp242-243°C. (7) 7-chloro-1-(3,4-difluorophenyl)-6-fluoro-1,4-dihydro-4
-Ethyl oxo-1,8-naphthyridine-3-carboxylate, mp 246-247°C. Reference example 3 3-acetylaminomethyl-4-fluoropyrrolidine: (1) Known compound 1-benzyl-3-hydroxy-
4-Hydroxymethylpyrrolidine [J.Org.
Chem., 30 , 740 (1965)] was reacted with 60.9 g of methanesulfonyl chloride in the presence of triethylamine in chloroform to obtain 81 g of oily 1-benzyl-3-hydroxy-4-methanesulfonyloxymethylpyrrolidine. . IR spectrum (liquid film) cm -1 : 3370, 1350, 1170. Mass spectrum m/z: 285 (M + ), 208, 190,
91. (2) 50 g of this compound and 22.8 g of sodium azide were reacted in dimethylformamide at 120-130°C to form an oily 3-azidomethyl-1-benzyl-
30 g of 4-hydroxypyrrolidine are obtained. IR spectrum (liquid film) cm -1 : 3350, 2100, 1450,
1265.Mass spectrum m/z: 232 (M + ),
175, 158, 91. (3) 64 g of hexafluoropropene-diethylamine reagent is added to a chloroform solution of 32 g of this compound and reacted, and the crude product is separated and purified by silica gel column chromatography to obtain the following product. 3.5 g of oily trans-3-azidomethyl-1-benzyl-4-fluoropyrrolidine are obtained as initial effluent. IR spectrum (liquid film) cm -
1 :2100, 1450, 1270.Mass spectrum m/
z: 234 (M + ), 177, 91. NMR spectrum (CDCl 3 ) δ: 3.64 (2H, s, CH 2 Ph), 4.5 and 5.2 (1H, br, H〓F), 7.30 (5H, s, C 6
H5 ). 3.0 g of oily cis-3-azidomethyl-1-benzyl-4-fluoropyrrolidine are obtained as a backflow. IR spectrum (liquid film) cm -1 :
2100, 1450, 1270.Mass spectrum m/z:
234 (M + ), 177, 91.NMR spectrum (CDCl 3 )
δ: 3.68 (2H, s, CH 2 Ph), 4.75 and 5.45
(1H, br, H+F), 7.30 (5H, s, C 6 H 5 ). As the intermediate effluent, 3-azidomethyl-1-
7.3 g of a mixture of cis and trans isomers of benzyl-4-fluoropyrrolidine is obtained. (4) 3.1 g of the above compound (trans form) was reduced with sodium bis(2-methoxyethoxy)aluminum hydride and then acetylated to form an oily trans-3-acetylaminomethyl-1-
2.2 g of benzyl-4-fluoropyrrolidine are obtained. IR spectrum (liquid film) cm -1 : 3270, 1650,
1550.Mass spectrum m/z: 250 (M + ),
158, 91.NMR spectrum ( CDCl3 ) δ: 1.96
(3H, s, COCH 3 ), 3.61 (2H, s, CH 2 Ph),
4.52 and 5.22 (1H, br, H+F), 7.30 (5H,
s, C 6 H 5 ). Similarly, oily cis-3-acetylaminomethyl-1-benzyl-4-fluoropyrrolidine is obtained from the above compound (cis form). IR spectrum (liquid film) cm -1 : 3270, 1650, 1550. Mass spectrum m/z: 250 (M + ), 158, 91.
NMR spectrum (CDCl 3 ) δ: 1.98 (3H, s,
COCH 3 ), 3.66 (2H, s, CH 2 Ph), 4.75 and
5.48 (1H, br, H+F), 7.31 (5H, s, C 6
H5 ). Similarly, a mixture of the cis and trans forms of 3-acetylaminomethyl-1-benzyl-4-fluoropyrrolidine is obtained from the mixture of the cis and trans forms of 3-azidomethyl-1-benzyl-4-fluoropyrrolidine. . (5) The above compound (trans form) is dissolved in ethanol and hydrolyzed using 5% palladium-carbon as a catalyst. The catalyst was filtered off and the trans-3-
An ethanol solution of acetylaminomethyl-4-fluoropyrrolidine is obtained. This solution is used in the next substitution reaction. Similarly, from the above compound (cis form), cis-
A solution containing 3-acetylaminomethyl-4-fluoropyrrolidine is obtained. Similarly, the above 3-acetylaminomethyl-
A solution containing a mixture of the cis and trans forms of 3-acetylaminomethyl-4-fluoropyrrolidine is obtained from the mixture of the cis and trans forms of 1-benzyl-4-fluoropyrrolidine. Reference Example 4 3-acetylaminomethyl-4-chloropyrrolidine: (1) After reacting 3-azidomethyl-1-benzyl-4-hydroxypyrrolidine with thionyl chloride in chloroform, it was separated and purified by column chromatography. The following product is obtained. cis-3-azidomethyl-1-benzyl-4
-Chloropyrrolidine. IR spectrum (liquid film)
cm -1 : 2800, 2100, 740, 700. Mass spectrum m/z: 250 (M + ), 158, 91. NMR spectrum (CDCl 3 ) δ: 2.6 (1H, m, C 3 -H), 2.5 ~
3.0 (2H, m, C 2 −H), 2.8 to 3.4 (2H, m, C 5
−H), 3.3 to 3.7 (2H, m, CH 2 N 3 ), 3.73 (2H,
s, CH 2 Ph), 4.5 (1H, m, C 4 -H), 7.34
(5H, s, C 6 H 5 ). trans-3-azidomethyl-1-benzyl-4-chloropyrrolidine. IR spectrum (liquid film) cm -1 : 2800, 2100, 740, 700. Mass spectrum m/z: 250 (M + ), 158, 91. NMR spectrum (CDCl 3 ) δ: 2.58 (1H, m, C 3 -H),
2.45~2.8 (2H, m, C2 -H), 2.8~3.2 (2H,
m , C5 -H), 3.44 (2H, m, CH2N3 ), 3.66
(2H, br s, CH 2 Ph), 4.05 (1H, m, C 4 −
H), 7.34 (5H, s, C 6 H 5 ). (2) After reducing the above compound (cis form) with sodium bis(2-methoxyethoxy)aluminum hydride, the oily cis-3-
Acetylaminomethyl-1-benzyl-4-chloropyrrolidine is obtained. IR spectrum (liquid film)
cm -1 : 3300, 2800, 1650, 700. Mass spectrum m/z: 266 (M + ), 231, 171, 158, 91.
NMR spectrum (CDCl 3 ) δ: 1.97 (3H, s,
COCH 3 ), 2.5-2.9 (2H, m, C 2 -H), 2.72
(1H, m, C 3 - H), 2.8~3.3 (2H, m, C 5 -
H), 3.3-3.7 (2H, m, CH 2 NHCOCH 3 ),
3.71 (2H, s, CH 2 Ph), 4.48 (1H, m, C 4 −
H), 7.33 (5H, s, C 6 H 5 ). Similarly, from the above compound (trans form),
Oily trans-3-acetylaminomethyl-
1-Benzyl-4-chloropyrrolidine is obtained.
IR spectrum (liquid film) cm -1 : 3300, 2800,
1650, 700.Mass spectrum m/z: 266
(M + ), 231, 158, 91. NMR spectrum (CDCl 3 ) δ: 1.97 (3H, s, COCH 3 ), 2.3 ~
2.8 (3H, m, C2 -H, C3 - H), 3.05~3.75
(4H, m, CH 2 NHCOCH 3 , C 5 −H), 3.6
(2H, s, CH 2 Ph), 4.1 (1H, m, C 4 -H),
7.3 (5H, s, C 6 H 5 ). (3) The above compound (cis form) is hydrolyzed in ethanol in the presence of acetic acid and 5% palladium-carbon. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give an oily cis-3-acetylaminomethyl-
4-chloropyrrolidine is obtained. Similarly, from the above compound (trans form), trans-3-acetylaminomethyl-4
- Obtain chloropyrrolidine. Example 1 7-(3-aminomethyl-4-fluoro-1-
pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-
1,8-Naphthyridine-3-carboxylic acid and its hydrochloride: (1) 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8- Ethyl naphthyridine-3-carboxylate 2.21g, 3-acetylaminomethyl-4-
A mixture consisting of 1.14 g of fluoropyrrolidine, 2 ml of triethylamine and 150 ml of acetonitrile is heated and stirred for 2 hours. After distilling off the solvent, the gum-like residue is washed with water and crystallized by adding ethanol and water. The crystals were collected by filtration and recrystallized from ethyl acetate to give 7-(3-acetylaminomethyl-4
-fluoro-1-pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-
Ethyl 3-carboxylate (approximately 1:1 of stereoisomers)
mixture) to obtain 2.0g. mp175-178°C (2) 0.95 g of the above ester is heated and stirred with 10 ml of 20% hydrochloric acid for 3 hours. The reaction solution was concentrated to dryness under reduced pressure.
Add ethanol to the residue to crystallize it. Recrystallized from ethanol-water to give 7-(3-aminomethyl-4-fluoro-1-pyrrolidinyl)-
6-Fluoro-1-(4-fluorophenyl)-
0.68 g of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride (approximately 1:1 mixture of stereoisomers) is obtained. mp207～
210℃ (3) Dissolve 0.5g of the above hydrochloride in water and neutralize by adding aqueous sodium hydrogen carbonate solution. The precipitated crystals were collected by filtration and washed with water to give 7-(3-aminomethyl-4-
Fluoro-1-pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-carboxylic acid (approx. 1:1 mixture of stereoisomers)
Get 0.43g. mp approx. 270°C (decomposition) Example 2 7-(cis-3-aminomethyl-4-fluoro-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro −
4-Oxo-1,8-naphthyridine-3-carboxylic acid and its hydrochloride: (1) 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4
-1.94 g of ethyl oxo-1,8-naphthyridine-3-carboxylate, 1.12 g of cis-3-acetylaminomethyl-4-fluoropyrrolidine, 1.5 ml of triethylamine and 150 ml of acetonitrile.
A mixture consisting of was treated in the same manner as in Example 1-(1) to obtain 7-(cis-3-acetylaminomethyl-4-fluoro-1-pyrrolidinyl)-
1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8
1.6 g of ethyl-naphthyridine-3-carboxylate are obtained. Recrystallize from ethanol-water. m.
p.239-242℃ (2) 1.24g of the above ester was reacted in the same manner as in Example 1-(2), and 7-(cis-3-aminomethyl-4-fluoro-1-pyrrolidinyl)-1-
0.95 g of (2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride is obtained. Recrystallize from ethanol-water. mp272
~276°C (decomposition) (3) 150 mg of the above hydrochloride was reacted in the same manner as in Example 1-(3) to obtain 7-(cis-3-aminomethyl-
4-fluoro-1-pyrrolidinyl)-1-(2,
4-difluorophenyl)-6-fluoro-1,
130 mg of 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. Recrystallize from dimethylformamide-water. mp232～
236℃ (decomposition) Example 3 7-(cis-3-aminomethyl-4-chloro-
1-pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid: (1) 7-chloro-6-fluoro -1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
1.8g, cis-3-acetylaminomethyl-4-
Chloropyrrolidine 1.3g, triethylamine 3ml
and 50 ml of acetonitrile is stirred at room temperature for 1 hour. Filter the precipitated crystals,
Wash with acetonitrile to give 7-(cis-3-acetylaminomethyl-4-chloro-1-pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1. ，
2.0 g of 8-naphthyridine-3-carboxylic acid is obtained. Recrystallize from acetonitrile. mp234
-235°C (2) A mixture of 1.8 g of the above carboxylic acid and 18 ml of 20% hydrochloric acid is heated at 100-115°C for 5 hours. Concentrate to dryness under reduced pressure, add ethanol to the residue, and collect the crystals by filtration. Dissolve the crystals in warm water and treat with activated carbon, then add aqueous ammonia to neutralize. The precipitated crystals were collected by filtration and washed with water to give 7-(cis-3-aminomethyl-4
-chloro-1-pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3
- 1.2 g of carboxylic acid are obtained. mp220~225℃ (decomposition)
Claims (1)
原子を意味し、R1，R2は同一または異なつて水
素原子または低級アルキル基を意味し、R3，R4
およびR5は同一または異なつて水素原子、ハロ
ゲン原子またはトリフルオロメチル基を意味し、
ｍは整数１を意味し、ｎは整数４を意味する。） で表わされるフエニル置換１，８−ナフチリジン
誘導体、その低級アルキルエステルまたはその
塩。 ２ X1がフツ素原子である特許請求の範囲第１
項記載のフエニル置換１，８−ナフチリジン誘導
体、その低級アルキルエステルまたはその塩。[Claims] 1 General formula: (wherein, X 1 and X 2 are the same or different and mean a halogen atom, and R 1 and R 2 are the same or different and mean a hydrogen atom or a lower alkyl group , R 3 , R 4
and R 5 are the same or different and mean a hydrogen atom, a halogen atom or a trifluoromethyl group,
m means an integer 1, and n means an integer 4. ) A phenyl-substituted 1,8-naphthyridine derivative, a lower alkyl ester thereof, or a salt thereof. Claim 1 in which 2 X 1 is a fluorine atom
Phenyl-substituted 1,8-naphthyridine derivatives, lower alkyl esters thereof, or salts thereof as described in 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60123797A JPS61282382A (en) | 1985-06-06 | 1985-06-06 | Phenyl substituted 1,8-naphthyridine derivative, ester and salt thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60123797A JPS61282382A (en) | 1985-06-06 | 1985-06-06 | Phenyl substituted 1,8-naphthyridine derivative, ester and salt thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61282382A JPS61282382A (en) | 1986-12-12 |
| JPH0586392B2 true JPH0586392B2 (en) | 1993-12-10 |
Family
ID=14869546
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60123797A Granted JPS61282382A (en) | 1985-06-06 | 1985-06-06 | Phenyl substituted 1,8-naphthyridine derivative, ester and salt thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61282382A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1989003828A1 (en) * | 1987-10-26 | 1989-05-05 | Pfizer Inc. | Azetidinyl quinolone carboxylic acids and esters |
| US7563805B2 (en) | 2005-05-19 | 2009-07-21 | Daiichi Pharmaceutical Co., Ltd. | Tri-, tetra-substituted-3-aminopyrrolidine derivative |
| MY162052A (en) | 2007-01-05 | 2017-05-31 | Daiichi Sankyo Co Ltd | Fused substitute aminopyrrolidine derivative |
| SG182370A1 (en) * | 2010-01-08 | 2012-08-30 | Kyorin Seiyaku Kk | Method for producing 3,4-disubstituted pyrrolidine derivative and production intermediate thereof |
-
1985
- 1985-06-06 JP JP60123797A patent/JPS61282382A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61282382A (en) | 1986-12-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2572591B2 (en) | Novel quinolone derivatives and their salts | |
| JPH0541633B2 (en) | ||
| FR2563521A1 (en) | 1,4-DIHYDRO-4-OXONAPHTYRIDINE DERIVATIVES AND THEIR SALTS, PROCESS FOR THEIR PRODUCTION AND ANTIBACTERIAL AGENTS CONTAINING SAME | |
| JPH0676400B2 (en) | Novel pyridonecarboxylic acid derivative, its ester and its salt | |
| JPH0559914B2 (en) | ||
| JPH0516429B2 (en) | ||
| US5990106A (en) | Bicyclic amino group-substituted pyridonecarboxylic acid derivatives, esters thereof and salts thereof, and bicyclic amines useful as intermediates thereof | |
| JPH0586392B2 (en) | ||
| JPH0450313B2 (en) | ||
| JPS62469A (en) | Novel quinolone derivative and ester and salt thereof | |
| JPH0696572B2 (en) | Pyridonecarboxylic acid derivatives, their esters and their salts | |
| JPH0670032B2 (en) | Aminopyrrolidine derivative, its ester and its salt | |
| JP2991381B2 (en) | Novel quinolinecarboxylic acid derivatives, esters and salts thereof | |
| JPH0373548B2 (en) | ||
| JPH0635458B2 (en) | Pyridonecarboxylic acid derivatives, their esters and their salts | |
| JPH0561276B2 (en) | ||
| JPH0568477B2 (en) | ||
| JP2989871B2 (en) | Tricyclic compounds | |
| JP2598929B2 (en) | Novel pyridonecarboxylic acid derivatives, esters and salts thereof | |
| JPH0674260B2 (en) | Quinoline derivatives, their esters and their salts | |
| JPS63275567A (en) | Novel quinoline derivative, ester and salt thereof | |
| KR100234546B1 (en) | Pyridonecarboxylic acid derivatives and their preparation | |
| JP2951726B2 (en) | Pyridonecarboxylic acid derivatives and synthetic intermediates thereof | |
| JP2888987B2 (en) | Pyridonecarboxylic acid derivatives, esters and salts thereof, and synthetic intermediates thereof | |
| KR100359151B1 (en) | Pyridonecarboxylic acid derivatives substituted with bicyclic amino groups, esters and salts thereof, and bicyclic amines which are intermediates thereof |