JPH0784459B2 - Novel pyridonecarboxylic acid derivative, its ester and its salt - Google Patents
Novel pyridonecarboxylic acid derivative, its ester and its saltInfo
- Publication number
- JPH0784459B2 JPH0784459B2 JP62221681A JP22168187A JPH0784459B2 JP H0784459 B2 JPH0784459 B2 JP H0784459B2 JP 62221681 A JP62221681 A JP 62221681A JP 22168187 A JP22168187 A JP 22168187A JP H0784459 B2 JPH0784459 B2 JP H0784459B2
- Authority
- JP
- Japan
- Prior art keywords
- dihydro
- cyclopropyl
- carboxylic acid
- pyrrolyl
- group
- 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 15
- 150000002148 esters Chemical class 0.000 title claims description 12
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 title claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- -1 2,5-dihydropyrrolyl group Chemical group 0.000 description 97
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 60
- 150000001875 compounds Chemical class 0.000 description 57
- 239000013078 crystal Substances 0.000 description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 238000001914 filtration Methods 0.000 description 14
- 239000007858 starting material Substances 0.000 description 13
- 238000007796 conventional method Methods 0.000 description 12
- 238000000354 decomposition reaction Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical class C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 125000000168 pyrrolyl group Chemical group 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- 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 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- RFZHFIFSQNIHAI-UHFFFAOYSA-N 1-cyclopropyl-5,6,7,8-tetrafluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(F)C(F)=C(F)C(F)=C2C(=O)C(C(=O)O)=CN1C1CC1 RFZHFIFSQNIHAI-UHFFFAOYSA-N 0.000 description 2
- NMASXYCNDJMMFR-UHFFFAOYSA-N 1-cyclopropyl-6,7,8-trifluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(F)C(F)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 NMASXYCNDJMMFR-UHFFFAOYSA-N 0.000 description 2
- BSHJNDAASYLRNA-UHFFFAOYSA-N 4-oxo-1h-quinoline-3-carboxylic acid;hydrochloride Chemical compound Cl.C1=CC=C2C(=O)C(C(=O)O)=CNC2=C1 BSHJNDAASYLRNA-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- SCZNXLWKYFICFV-UHFFFAOYSA-N 1,2,3,4,5,7,8,9-octahydropyrido[1,2-b]diazepine Chemical compound C1CCCNN2CCCC=C21 SCZNXLWKYFICFV-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RNSGBYUFHBXKPU-UHFFFAOYSA-N 1-chloropyrrolidine Chemical compound ClN1CCCC1 RNSGBYUFHBXKPU-UHFFFAOYSA-N 0.000 description 1
- CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical compound ON1CCCC1 CWLUFVAFWWNXJZ-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- BFVQMOCETIVORP-UHFFFAOYSA-N 2-oxo-1h-1,8-naphthyridine-3-carboxylic acid Chemical compound C1=CN=C2NC(=O)C(C(=O)O)=CC2=C1 BFVQMOCETIVORP-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- DTPFSSOXQXWKEV-UHFFFAOYSA-N 3-methyl-2,5-dihydro-1h-pyrrole Chemical compound CC1=CCNC1 DTPFSSOXQXWKEV-UHFFFAOYSA-N 0.000 description 1
- CQPUZLMNORVQPG-UHFFFAOYSA-N 5-amino-1-cyclopropyl-6,7,8-trifluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C(O)=O)C(=O)C=2C(N)=C(F)C(F)=C(F)C=2N1C1CC1 CQPUZLMNORVQPG-UHFFFAOYSA-N 0.000 description 1
- WRAHFEWSPIEFTP-UHFFFAOYSA-N 6-benzyl-1-oxa-6-azaspiro[2.4]heptane Chemical compound C=1C=CC=CC=1CN(C1)CCC21CO2 WRAHFEWSPIEFTP-UHFFFAOYSA-N 0.000 description 1
- JPWMVLHABXIWCF-PELKAZGASA-N 7-[(3R,4R)-3-(aminomethyl)-4-chloropyrrolidin-1-yl]-1-cyclopropyl-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1CC1N2C=C(C(=O)C3=CC(=C(C(=C32)F)N4C[C@H]([C@H](C4)Cl)CN)F)C(=O)O JPWMVLHABXIWCF-PELKAZGASA-N 0.000 description 1
- OXNZWNNMJBOZQO-UHFFFAOYSA-N 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C12=NC(Cl)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 OXNZWNNMJBOZQO-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000005973 Carvone Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa 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
- 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
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 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
- WGPAQYSVWYWZKT-UHFFFAOYSA-N [C].[Ra] Chemical compound [C].[Ra] WGPAQYSVWYWZKT-UHFFFAOYSA-N 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 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
- JJXYNZBZMVYOJV-UHFFFAOYSA-N ethyl 1-fluoro-4-oxo-1,8-naphthyridine-3-carboxylate Chemical compound C(C)OC(=O)C1=CN(C2=NC=CC=C2C1=O)F JJXYNZBZMVYOJV-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
- 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
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229940097043 glucuronic acid Drugs 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
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 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
- 150000004679 hydroxides Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 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
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 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
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000002798 polar solvent Substances 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
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003233 pyrroles Chemical class 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
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Description
【発明の詳細な説明】 産業上の利用分野 本発明は極めて優れた抗菌活性を示す新規ピリドンカル
ボン酸誘導体、そのエステルおよびその塩に関する。TECHNICAL FIELD The present invention relates to a novel pyridonecarboxylic acid derivative, an ester thereof and a salt thereof which exhibit extremely excellent antibacterial activity.
従来の技術 ピリドンカルボン酸の７位にピロリル基あるいは2,5−
ジヒドロピロリル基を有する化合物は、例えば特開昭61
-277669号公報あるいは特開昭57-88182号公報等に記載
されているが、これら化合物の７位は無置換ピロリル基
または無置換2,5−ジヒドロピロリル基であり、その抗
菌作用は満足すべきものではない。Prior art Pyridonecarboxylic acid has a pyrrolyl group or 2,5-
The compound having a dihydropyrrolyl group is described in, for example, JP-A-61 / 1986.
-277669 or JP-A-57-88182, the 7-position of these compounds is an unsubstituted pyrrolyl group or an unsubstituted 2,5-dihydropyrrolyl group, and its antibacterial action is satisfactory. It shouldn't be.
発明の目的 本発明は優れた抗菌作用を有する新規ピリドンカルボン
酸誘導体を提供するものである。OBJECT OF THE INVENTION The present invention provides a novel pyridonecarboxylic acid derivative having an excellent antibacterial action.
発明の構成 本発明の化合物は、下記一般式 （式中、Ｘは窒素原子またはＣ−Ｙを意味し、ここにＹ
は水素原子またはハロゲン原子を意味し、 Y1は水素原子またはハロゲン原子を意味し、Y2は水素原
子、フッ素原子、水酸基または−NR′Ｒ″を意味し、こ
こにＲ′およびＲ″は同一または異なって水素原子、低
級アルキル基、ベンジル基またはハロゲン原子で置換さ
れていてもよいアシル基を意味し、 R1は低級アルキル基、ハロゲノ低級アルキル基、低級ア
ルケニル基、シクロアルキル基または置換基を有してい
てもよいフェニル基を意味し、 Ａは下記式で表わされる基 を意味し、ここにR2は水素原子または低級アルキル基を
意味し、R3は水素原子、低級アルキル基またはハロゲン
で置換されていてもよいアシル基を意味し、 R4は水素原子または低級アルキル基を意味する。） で表わされるピリドンカルボン酸誘導体、そのエステル
およびその塩である。The compound of the present invention has the following general formula: (In the formula, X means a nitrogen atom or C—Y, where Y
Means a hydrogen atom or a halogen atom, Y 1 means a hydrogen atom or a halogen atom, Y 2 means a hydrogen atom, a fluorine atom, a hydroxyl group or —NR′R ″, wherein R ′ and R ″ are The same or different, means a hydrogen atom, a lower alkyl group, a benzyl group or an acyl group which may be substituted with a halogen atom, R 1 is a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a cycloalkyl group or a substituted group. Means a phenyl group which may have a group, and A is a group represented by the following formula: Wherein R 2 represents a hydrogen atom or a lower alkyl group, R 3 represents a hydrogen atom, a lower alkyl group or an acyl group optionally substituted with halogen, and R 4 represents a hydrogen atom or a lower atom. Means an alkyl group. ) Is a pyridonecarboxylic acid derivative, its ester and its salt.
本明細書において、ハロゲン原子とはフッ素，塩素また
は臭素を意味し、低級アルキル基としては、例えばメチ
ル，エチル，プロピル，ブチル，イソブチル,t−ブチ
ル，ペンチル，ネオペンチル等が挙げられる。低級アル
ケニル基としては、例えばビニル，アリル,1−プロペニ
ル，イソプロペニル等が挙げられる。シクロアルキル基
としては、例えばシクロプロピル，シクロブチル，シク
ロペンチル，シクロヘキシル等が挙げられる。また置換
基を有していてもよいフェニル基における置換基として
は、例えばハロゲン，低級アルキル，低級アルキルオキ
シ，アミノ，ニトロ等が挙げられる。アシル基として
は、例えばホルミル，アセチル，プロピオニル，ブチリ
ル，イソブチリル，ビバロイル等が挙げられる。In the present specification, the halogen atom means fluorine, chlorine or bromine, and examples of the lower alkyl group include methyl, ethyl, propyl, butyl, isobutyl, t-butyl, pentyl, neopentyl and the like. Examples of the lower alkenyl group include vinyl, allyl, 1-propenyl, isopropenyl and the like. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Further, examples of the substituent in the phenyl group which may have a substituent include halogen, lower alkyl, lower alkyloxy, amino, nitro and the like. Examples of the acyl group include formyl, acetyl, propionyl, butyryl, isobutyryl, vivaloyl and the like.
本発明の化合物の塩は、塩酸，リン酸等の無機酸との
塩：酢酸，シュウ酸、コハク酸、メタンスルホン酸，マ
レイン酸，マロン酸，グルクロン酸等の有機酸との塩；
アスパラギン酸，グルタミン酸等の酸性アミノ酸との
塩；あるいは式（Ｉ）の化合物のナトリウム，カリウ
ム，カルシウム，マグネシウム，亜鉛，銀等の金属塩；
ジメチルアミン，トリエチルアミン，ジシクロヘキシル
アミン，ベンジルアミン等の有機塩基との塩；リジン，
アルギニン等の塩基性アミノ酸との塩である。The salt of the compound of the present invention is a salt with an inorganic acid such as hydrochloric acid or phosphoric acid: a salt with an organic acid such as acetic acid, oxalic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid or glucuronic acid;
A salt with an acidic amino acid such as aspartic acid or glutamic acid; or a metal salt of the compound of the formula (I) such as sodium, potassium, calcium, magnesium, zinc or silver;
Salts with organic bases such as dimethylamine, triethylamine, dicyclohexylamine, benzylamine; lysine,
It is a salt with a basic amino acid such as arginine.
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、あるいは加水分解することによりまたは生体内で容
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，ビバロイルオキ
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。The ester of the compound of the formula (I) means a lower alkyl ester such as a methyl ester or an ethyl ester of the compound (I), or a compound (I) which can be easily eliminated by hydrolysis or in vivo. Known esters such as acetoxymethyl ester, bivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, choline ester, aminoethyl esters such as dimethylaminoethyl ester and 1-piperidinylethyl ester, 5-indanyl ester, Means phthalidyl ester and the like.
本発明の化合物はまた、水和物としても存在し得る。従
って、この様な形のものも当然本発明の化合物に包含さ
れる。The compounds of the present invention may also exist as hydrates. Therefore, such forms are naturally included in the compound of the present invention.
以下、本発明化合物の製造法について説明する。Hereinafter, the method for producing the compound of the present invention will be described.
（１） Ａが2,5−ジヒドロピロール誘導体である本発
明化合物は、下記一般式（II） （式中、X1はハロゲン原子を意味し、R5は水素原子ある
いは低級アルキル基を意味し、X,Y1，Y2およびR1は前掲
と同じ。） で表わされる化合物と下記一般式（III） （式中、R2，R3およびR4は前掲と同じ。）で表わされる
2,5−ジヒドロピロール類を反応させ、生成物を常法に
より単離することによって製造することができる。(1) The compound of the present invention in which A is a 2,5-dihydropyrrole derivative has the following general formula (II): (In the formula, X 1 represents a halogen atom, R 5 represents a hydrogen atom or a lower alkyl group, and X, Y 1 , Y 2 and R 1 are the same as the above.) And a compound represented by the following general formula: (III) (In the formula, R 2 , R 3 and R 4 are the same as the above.)
It can be produced by reacting 2,5-dihydropyrroles and isolating the product by a conventional method.
本反応は不活性溶媒中、０℃〜150℃，好ましくは50℃
〜100℃において、原料化合物（II）と（III）とを１〜
24時間、好ましくは１〜３時間撹拌することにより実施
できる。This reaction is carried out in an inert solvent at 0 ° C to 150 ° C, preferably 50 ° C.
The raw material compounds (II) and (III) at 1 to 100 ° C
It can be carried out by stirring for 24 hours, preferably 1 to 3 hours.
溶媒としては、例えばメタノール，エタノール，アセト
ニトリル，ジメチルホルムアミド，水，クロロホルム等
が挙げられる。これらの溶媒は、単独あるいは混合して
使用してもよい。Examples of the solvent include methanol, ethanol, acetonitrile, dimethylformamide, water, chloroform and the like. You may use these solvents individually or in mixture.
本反応は酸受容体の存在下に原料化合物（III）を原料
化合物（II）に対して当量ないしやや過剰量使用して行
うのが一般的であるが、原料化合物（III）を過剰に用
いて酸受容体としての役割を兼ねさせてもよい。酸受容
体としては、例えばトリエチルアミン等の有機塩基また
は炭酸カリウム等の無機塩基が挙げられる。This reaction is generally carried out in the presence of an acid acceptor, using the starting compound (III) in an equivalent or slightly excess amount relative to the starting compound (II), but using the starting compound (III) in excess. It may also serve as an acid acceptor. Examples of the acid acceptor include organic bases such as triethylamine and inorganic bases such as potassium carbonate.
本反応で使用される原料化合物（III）は、可能なら
ば、反応に関与しないアミノ基を保護した形で用い、反
応完了常法により保護基を除去してもよい。If possible, the starting compound (III) used in this reaction may be used in a form in which an amino group not involved in the reaction is protected, and the protecting group may be removed by a conventional method of completion of the reaction.
原料化合物（III）は新規化合物であり、参考例３で示
した方法あるいはこれに準じた方法によって製造するこ
とができる。The starting compound (III) is a novel compound and can be produced by the method shown in Reference Example 3 or a method analogous thereto.
原料化合物（II）は公知化合物であり、例えば以下の文
献記載の方法あるいはこれに準じた方法で製造し得る。The starting compound (II) is a known compound, and can be produced, for example, by the method described in the following literature or a method analogous thereto.
（２） Ａが2,5−ジヒドロピロール誘導体である本発
明の化合物はまた、下記一般式 （X2はハロゲン原子を意味し、X,Y1，Y2，R1，R2，R3，
R4およびR5は前掲と同じ。）で表わされる化合物（IV）
を塩基で処理し、生成物を常法により単離することによ
って製造することができる。 (2) The compound of the present invention in which A is a 2,5-dihydropyrrole derivative also has the following general formula: (X 2 means a halogen atom, and X, Y 1 , Y 2 , R 1 , R 2 , R 3 ,
R 4 and R 5 are the same as above. ) Compound (IV)
Is treated with a base and the product is isolated by a conventional method.
本反応は極性溶媒中、50〜150℃において原料化合物（I
V）を塩基の存在下に10分〜３時間、好ましくは20分〜
１時間撹拌することにより実施できる。This reaction is carried out in a polar solvent at 50 to 150 ° C with the starting compound (I
V) in the presence of a base for 10 minutes to 3 hours, preferably 20 minutes to
It can be carried out by stirring for 1 hour.
溶媒としては、例えば水，アセトニトリル，エタノー
ル，メタノール，ジメチルホルムアミド等が挙げられ
る。これらの溶媒は単独あるいは混合して使用してもよ
い。Examples of the solvent include water, acetonitrile, ethanol, methanol, dimethylformamide and the like. You may use these solvent individually or in mixture.
塩基としては、例えば水酸化ナトリウムや水酸化カリウ
ム等の水酸化物、炭酸ナトリウム等の炭酸塩、重炭酸ナ
トリウム等の重炭酸塩、トリエチルアミン，ジメチルア
ニリン,N,N−ジイソプロピルエチルアミン,1,8−ジアザ
ビシクロ〔5,4,0〕−７−ウンデセン（DBU）等の有機塩
基が挙げられる。Examples of the base include hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate, triethylamine, dimethylaniline, N, N-diisopropylethylamine, 1,8- Examples thereof include organic bases such as diazabicyclo [5,4,0] -7-undecene (DBU).
本反応で使用される原料化合物（IV）は、可能ならば、
反応に関与しないアミノ基を保護した形で用い、反応完
了後常法により保護基を除去してもよい。The starting compound (IV) used in this reaction is, if possible,
The amino group which does not participate in the reaction may be used in a protected form, and the protecting group may be removed by a conventional method after completion of the reaction.
原料化合物（IV）は参考例７〜９で示した方法あるいは
これに準じた方法で製造することができる。The starting compound (IV) can be produced by the method shown in Reference Examples 7 to 9 or a method analogous thereto.
（３） Ａが2,5−ジヒドロピロール誘導体である本発
明の化合物はまた、下記一般式 （R6は水素原子、低級アルキル基またはハロゲンで置換
されててもよいアシル基を意味し、X,Y1，Y2，R1，R2，
R3，R4およびR5は前掲と同じ。） で表わされる化合物（Ｖ）を酸で処理し、生成物を常法
により単離することによって製造することができる。(3) The compound of the present invention in which A is a 2,5-dihydropyrrole derivative also has the following general formula: (R 6 represents a hydrogen atom, a lower alkyl group or an acyl group which may be substituted with a halogen, and X, Y 1 , Y 2 , R 1 , R 2 ,
R 3 , R 4 and R 5 are the same as above. ) Is treated with an acid, and the product can be isolated by a conventional method.
本反応は溶媒中あるいは無溶液で50〜150℃において原
料化合物（Ｖ）を酸の存在下に２〜10時間好ましくは３
〜５時間撹拌することによって実施できる。In this reaction, the starting compound (V) is preferably used in the presence of an acid for 2 to 10 hours at 50 to 150 ° C. in a solvent or without solution, preferably 3
It can be carried out by stirring for ~ 5 hours.
酸としては、例えば濃硫酸，ポリリン酸等の無機酸，塩
化亜鉛等のルイス酸が挙げられる。Examples of the acid include inorganic acids such as concentrated sulfuric acid and polyphosphoric acid, and Lewis acids such as zinc chloride.
溶媒としては、例えば酢酸等の不活性溶媒が使用される
が、濃硫酸やポリリン酸等を過剰に用い溶媒としての役
割を兼ねさせるのが好都合である。As the solvent, for example, an inert solvent such as acetic acid is used, but it is convenient to use concentrated sulfuric acid, polyphosphoric acid or the like in excess to serve also as a solvent.
本反応で使用される原料化合物（Ｖ）は、可能ならば、
反応に関与しないアミノ基を保護した形で用い、反応完
了後常法により保護基を除去してもよい。The starting compound (V) used in this reaction is, if possible,
The amino group which does not participate in the reaction may be used in a protected form, and the protecting group may be removed by a conventional method after completion of the reaction.
原料化合物（Ｖ）は参考例４〜６で示した方法あるいは
これに準じた方法で製造することができる。The starting compound (V) can be produced by the method shown in Reference Examples 4 to 6 or a method analogous thereto.
（４） Ａがピロール誘導体である本発明の化合物はＡ
が2,5−ジヒドロピロール誘導体である本発明の化合物
を酸化し、生成物を常法により単離することによって製
造することができる。(4) The compound of the present invention in which A is a pyrrole derivative is A
It can be produced by oxidizing a compound of the present invention in which is a 2,5-dihydropyrrole derivative and isolating the product by a conventional method.
本反応は不活性溶媒中、50〜150℃において酸化剤の存
在下に８〜36時間、好ましくは15〜24時間撹拌すること
によって製造することができる。This reaction can be carried out by stirring in an inert solvent at 50 to 150 ° C. for 8 to 36 hours, preferably 15 to 24 hours in the presence of an oxidizing agent.
溶媒としては、酢酸，トルエン，ジオキサン,t−ブタノ
ール等が挙げられる。これらの溶媒は単独あるいは混合
して使用してもよい。酸化剤としては、例えばクロラニ
ル、2,3−ジクロロ−5,6−ジシアノベンゾキノン（DD
Q）等が挙げられる。Examples of the solvent include acetic acid, toluene, dioxane, t-butanol and the like. You may use these solvent individually or in mixture. Examples of the oxidant include chloranil, 2,3-dichloro-5,6-dicyanobenzoquinone (DD
Q) etc.
本反応で使用される原料化合物は、可能ならば、反応に
関与しないアミノ基を保護した形で用い、反応完了後常
法により保護基を除去してもよい。If possible, the starting compound used in this reaction may be used in a form in which an amino group not participating in the reaction is protected, and the protecting group may be removed by a conventional method after completion of the reaction.
上記の各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
ることによって、式（Ｉ）の化合物に変換することがで
きる。更には必要に応じて式（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。When the compound of the present invention obtained by each of the above methods is an ester, it can be converted to the compound of formula (I) by hydrolyzing the ester portion by a conventional method. Further, if necessary, the compound of formula (I) can be esterified by a conventional method to give an ester of the compound of formula (I).
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、精製条件によって、塩の形や
遊離の形で得られるが、これらは、目的に応じて相互に
変換され、目的とする本発明の化合物が製造される。The compound of the present invention produced in this manner is isolated and purified by a conventional method. Depending on the isolation and purification conditions, it can be obtained in the form of a salt or a free form, which are mutually converted depending on the purpose to produce the desired compound of the present invention.
発明の効果 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、ヒト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。EFFECTS OF THE INVENTION The compound (I) thus obtained, its ester and its salt are all novel compounds. In particular, compound (I) and its salt exhibit extremely excellent antibacterial activity and are therefore valuable as antibacterial agents. The compound (I) or a salt thereof can be used not only as a drug for humans and animals but also as a fish disease drug, an agricultural chemical, a preservative for foods, and the like. The ester of the compound (I) is of course valuable as a raw material for synthesizing the compound (I). In addition, when the compound is easily converted into the compound (I) in vivo, the compound (I) It is a compound useful as an antibacterial agent because it can exhibit the same action and effect as.
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。Next, data will be given below on the antibacterial activity of the compounds of the present invention.
本発明の化合物をヒトに抗菌剤として使用する場合、そ
の投与量は、年齢，体重，症状，投与経路等により異な
るが、１日当たり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。 When the compound of the present invention is used as an antibacterial agent in humans, its dosage may vary depending on age, body weight, symptoms, administration route, etc., but 5 mg to 5 g per day may be administered once or in several divided doses. Recommended. The route of administration may be oral or parenteral.
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，液剤，カプセル剤，果粒剤，細粒剤，散剤，
シロップ剤，注射剤，軟膏剤等が挙げられる。これらの
製剤は常法に従って調製される。経口用製剤担体として
は、デンプン，マンニット，結晶セルロース,CMC Na,
水，エタノール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，グリコール溶液，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。Although the compound of the present invention may be used as a bulk, it is usually administered in a form prepared with a carrier for formulation. Specific examples thereof include tablets, liquids, capsules, fruit granules, fine granules, powders,
Examples include syrups, injections and ointments. These preparations are prepared according to a conventional method. Oral pharmaceutical carriers include starch, mannitol, crystalline cellulose, CMC Na,
Substances which are commonly used in the field of pharmaceuticals such as water and ethanol and which do not react with the compound of the present invention are used. Examples of carriers for injection include carriers commonly used in the field of injectables such as water, physiological saline, glycol solutions, and infusions.
上記液剤および軟膏剤はまた、耳鼻咽喉科や眼科におけ
る治療においても使用され得る。The solutions and ointments may also be used in otolaryngology and ophthalmology treatments.
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。Next, the production method of the compound of the present invention will be described more specifically with reference to Examples and Reference Examples.
参考例１ ３−アセチルアミノメチル−１−ベンジル−３−ヒドロ
キシピロリジン： （１） ５−ベンジル−５−アザ−１−オキサスピロ
〔2.4〕ヘプタン（特開昭62-19583参照）15gと12％アン
モニア性エタノール500mlの混合物を、室温で38時間密
封下に撹拌する。反応液を減圧乾固し、残渣をクロロホ
ルム20mlで溶解し、これに無水酢酸15.3mlを加える。室
温で６日間撹拌後、水を加える。10％水酸化ナトリウム
でアルカリ性とし、クロロホルム層を分取し、水洗後乾
燥する。溶媒を減圧で留去し、残渣をシリカゲルクロマ
トグラフィーで分離精製し、油状の３−アセトキシ−３
−アセチルアミノメチル−１−ベンジルピロリジン10.2
gを得る。Reference Example 1 3-Acetylaminomethyl-1-benzyl-3-hydroxypyrrolidine: (1) 5-benzyl-5-aza-1-oxaspiro [2.4] heptane (see JP-A-62-19583) 15 g and 12% ammonia A mixture of 500 ml of ethanol in ethanol is stirred at room temperature for 38 hours in a sealed manner. The reaction solution is evaporated to dryness under reduced pressure, the residue is dissolved in 20 ml of chloroform, and 15.3 ml of acetic anhydride is added thereto. After stirring for 6 days at room temperature, water is added. Make alkaline with 10% sodium hydroxide, separate the chloroform layer, wash with water and dry. The solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel chromatography to give oily 3-acetoxy-3.
-Acetylaminomethyl-1-benzylpyrrolidine 10.2
get g.
（２） 上記化合物10g,2N炭酸カリウム水溶液70mlおよ
びエタノール150mlの混合物を3.5時間加熱還流する。エ
タノールを減圧で留去し、水およびクロロホルムを加
え、クロロホルム層を分ける。(2) A mixture of 10 g of the above compound, 70 ml of 2N potassium carbonate aqueous solution and 150 ml of ethanol is heated under reflux for 3.5 hours. Ethanol is distilled off under reduced pressure, water and chloroform are added, and the chloroform layer is separated.
クロロホルム層を乾燥後、溶媒を留去する。残渣をアセ
トニトリルから再結晶し、無色針状晶の３−アセチルア
ミノメチル−１−ベンジル−３−ヒドロキシピロリジン
7.4gを得る。After the chloroform layer is dried, the solvent is distilled off. The residue was recrystallized from acetonitrile to give colorless needle crystals of 3-acetylaminomethyl-1-benzyl-3-hydroxypyrrolidine.
Get 7.4 g.
m.p.133-135℃． 参考例２ ３−アセチルアミノメチル−１−ベンジル−３−ヒドロ
キシ−４−メチルピロリジン： （１） ５−ベンジル−５−アザ−７−メチル−１−オ
キサスピロ〔2.4〕ヘプタンを参考例１（１）と同様に
処理して、３−アセトキシ−３−アセチルアミノメチル
−１−ベンジル−４−メチルピロリジンを油状物として
得る。mp133-135 ° C. Reference Example 2 3-acetylaminomethyl-1-benzyl-3-hydroxy-4-methylpyrrolidine: (1) 5-benzyl-5-aza-7-methyl-1-oxaspiro [2.4] heptane was used in Reference Example 1 (1 ) And 3-acetoxy-3-acetylaminomethyl-1-benzyl-4-methylpyrrolidine as an oil.
（２） 上記化合物を参考例１（２）と同様に処理し
て、３−アセチルアミノメチル−１−ベンジル−３−ヒ
ドロキシ−４−メチルピロリジンを得る。(2) The above compound is treated in the same manner as in Reference Example 1 (2) to obtain 3-acetylaminomethyl-1-benzyl-3-hydroxy-4-methylpyrrolidine.
m.p.129-130℃． 参考例３ ３−アセチルアミノメチル−４−メチル−2,5−ジヒド
ロピロール： （１） ３−アセチルアミノメチル−１−ベンジル−３
−ヒドロキシ−４−メチルピロリジン4.0gと濃硫酸10ml
の混合物を50〜60℃で６時間撹拌し、氷水を加え希釈す
る。この溶液に40％水酸化ナトリウム水溶液を加え、強
アルカリ性とした後、酢酸エチルで抽出する。乾燥後溶
媒を留去し、残渣をジイソプロピルエーテルから再結晶
して、残渣をジイソプロピルエーテルから再結晶して、
３−アセチルアミノメチル−１−ベンジル−４−メチル
−2,5−ジヒドロピロール2.8gを得る。mp129-130 ° C. Reference Example 3 3-Acetylaminomethyl-4-methyl-2,5-dihydropyrrole: (1) 3-Acetylaminomethyl-1-benzyl-3
-Hydroxy-4-methylpyrrolidine 4.0g and concentrated sulfuric acid 10ml
The mixture is stirred at 50-60 ° C for 6 hours, and ice water is added to dilute it. A 40% aqueous sodium hydroxide solution is added to this solution to make it strong alkaline and then extracted with ethyl acetate. After drying, the solvent was distilled off, the residue was recrystallized from diisopropyl ether, and the residue was recrystallized from diisopropyl ether.
2.8 g of 3-acetylaminomethyl-1-benzyl-4-methyl-2,5-dihydropyrrole are obtained.
m.p.82-83℃． （２） 上記化合物2.4gを酢酸1mlおよびエタノール30m
lに溶解し、５％ラジウム炭素0.3gを加えて50〜60℃で
接触還元し、淡黄色油状の３−アセチルアミノメチル−
４−メチル−2,5−ジヒドロピロール1.5gを得る。mp82-83 ° C. (2) 2.4 g of the above compound was added to 1 ml of acetic acid and 30 m of ethanol.
It was dissolved in 1 l, 0.3 g of 5% radium carbon was added, and catalytic reduction was carried out at 50-60 ° C to give 3-acetylaminomethyl-
1.5 g of 4-methyl-2,5-dihydropyrrole are obtained.
参考例４ ７−（３−アセチルアミノメチル−３−ヒドロキシ−１
−ピロリジニル）−１−シクロプロピル−６−フルオロ
−1,4−ジヒドロ−４−オキソ−1,8−ナフチリジン−３
−カルボン酸エチルエステル： （１） ３−アセチルアミノメチル−１−ベンジル−３
−ヒドロキシピロリジン5.0gをエタノール60mlに溶解
し、これに５％パラジウム炭素0.5gを加え、50℃で接触
還元する。理論量の水素を吸収させた後触媒を除去す
る。溶媒を留去して油状の３−アセチルアミノメチル−
３−ヒドロキシピロリジン3.1gを得る。Reference Example 4 7- (3-Acetylaminomethyl-3-hydroxy-1)
-Pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid ethyl ester: (1) 3-acetylaminomethyl-1-benzyl-3
-5.0 g of hydroxypyrrolidine is dissolved in 60 ml of ethanol, 0.5 g of 5% palladium carbon is added thereto, and catalytic reduction is carried out at 50 ° C. After absorbing the theoretical amount of hydrogen, the catalyst is removed. The solvent was distilled off to give oily 3-acetylaminomethyl-
3.1 g of 3-hydroxypyrrolidine are obtained.
（２） 上記化合物3.1g,7−クロロ−１−シクロプロピ
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−カルボン酸エチルエステル5.0g,ト
リエチルアミン5.6mlおよびアセトニトリル50mlの混合
物を30分加熱還流する。反応液を氷冷後析出結晶を濾取
する。結晶を水洗後、エタノールから再結晶して無色針
状晶の７−（３−アセチルアミノメチル−３−ヒドロキ
シ−１−ピロリジニル）−１−シクロプロピル−６−フ
ルオロ−1,4−ジヒドロ−４−オキソ−1,8−ナフチリジ
ン−３−カルボン酸エチルエステル5.8gを得る。m.p.12
3-125℃． 参考例５ ７−（３−アセチルアミノメチル−３−ヒドロキシ−４
−メチル−１−ピロリジニル）−１−シクロプロピル−
６−フルオロ−1,4−ジヒドロ−４−オキソ−1,8−ナフ
チリジン−３−カルボン酸エチルエステル： （１） ３−アセチルアミノメチル−１−ベンジル−３
−ヒドロキシ−４−メチルピロリジンを参考例４（１）
と同様に処理して、３−アエチルアミノメチル−３−ヒ
ドロキシ−４−メチルピロリジンを得る。(2) 3.1 g of the above compound, 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-
A mixture of 5.0 g of naphthyridine-3-carboxylic acid ethyl ester, 5.6 ml of triethylamine and 50 ml of acetonitrile is heated under reflux for 30 minutes. After cooling the reaction solution with ice, the precipitated crystals are collected by filtration. The crystals were washed with water and recrystallized from ethanol to give colorless needle crystals of 7- (3-acetylaminomethyl-3-hydroxy-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4. 5.8 g of -oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester are obtained. mp12
3-125 ° C. Reference Example 5 7- (3-Acetylaminomethyl-3-hydroxy-4
-Methyl-1-pyrrolidinyl) -1-cyclopropyl-
6-Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester: (1) 3-acetylaminomethyl-1-benzyl-3
-Hydroxy-4-methylpyrrolidine is used in Reference Example 4 (1).
Treatment in the same manner as above gives 3-aethylaminomethyl-3-hydroxy-4-methylpyrrolidine.
（２） 上記化合物を参考例４（２）と同様に処理し
て、７−（３−アセチルアミノメチル−３−ヒドロキシ
−４−メチル−１−ピロリジニル）−１−シクロプロピ
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−カルボン酸エチルエステルを得る。
m.p.215-216℃． ５考例６ ７−（３−トリフルオロアセチルアミノメチル−３−ト
リフルオロアセトキシ−４−メチル−１−ピロリジニ
ル）−１−シクロプロピル−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： （１） ７−（３−アセチルアミノメチル−３−ヒドロ
キシ−４−メチル−１−ピロリジニル）−１−シクロプ
ロピル−６−フルオロ−1,4−ジヒドロ−４−オキソ−
1,8−ナフチリジン−３−カルボン酸エチルエステル5.0
gと10％塩酸50mlの混合物を３時間加熱還流後、反応液
を減圧で濃縮乾固する。残渣にエタノールを加え結晶を
濾取する。結晶を1N水酸化ナトリウム水溶液に加熱溶解
し、活性炭処理後、10％塩酸で中和し析出結晶を濾取す
る。結晶を水洗後乾燥して、無色状晶の７−（３−アミ
ノメチル−３−ヒドロキシ−４−メチル−１−ピロリジ
ニル）−１−シクロプロピル−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3.11gを得る。m.p.237-239℃（分解）． （２） 上記化合物を氷冷下無水トリフルオロ酢酸で処
理して、７−（３−トリフルオロアセチルアミノメチル
−３−トリフルオロアセトキシ−４−メチル−１−ピロ
リジニル）−１−シクロプロピル−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
ルボン酸を得る。(2) The above compound was treated in the same manner as in Reference Example 4 (2) to give 7- (3-acetylaminomethyl-3-hydroxy-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-. 1,4-dihydro-4-oxo-1,8-
Naphthyridine-3-carboxylic acid ethyl ester is obtained.
mp215-216 ° C. 5 Consideration 6 7- (3-trifluoroacetylaminomethyl-3-trifluoroacetoxy-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1 , 8-Naphthyridine-3-carboxylic acid: (1) 7- (3-acetylaminomethyl-3-hydroxy-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-
1,8-Naphthyridine-3-carboxylic acid ethyl ester 5.0
A mixture of g and 50 ml of 10% hydrochloric acid is heated under reflux for 3 hours, and the reaction solution is concentrated under reduced pressure to dryness. Ethanol is added to the residue and the crystals are collected by filtration. The crystals are dissolved by heating in a 1N sodium hydroxide aqueous solution, treated with activated carbon, neutralized with 10% hydrochloric acid, and the precipitated crystals are collected by filtration. The crystals were washed with water and dried to give colorless crystals of 7- (3-aminomethyl-3-hydroxy-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-. 3.11 g of oxo-1,8-naphthyridine-3-carboxylic acid are obtained. mp237-239 ° C (decomposition). (2) The above compound was treated with trifluoroacetic anhydride under ice cooling to give 7- (3-trifluoroacetylaminomethyl-3-trifluoroacetoxy-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6. -Fluoro-1,4
-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained.
参考例７ ７−（シス−３−アミノメチル−４−クロロ−１−ピロ
リジニル）−１−シクロプロピル−5,6,8−トリフルオ
ロ−1,4−ジヒドロ−４−オキソキノリン−３−カルボ
ン酸塩酸塩： （１） １−シクロプロピル−5,6,7,8−テトラフルオ
ロ−1,4−ジヒドロ−４−オキソキノリン−３−カルボ
ン酸2g、シス−３−アセチルアミノメチル−４−クロロ
ピロリジン2.3g,トリエチルアミン2.8mlおよびアセトニ
トリル40mlの混合物を50℃で１時間撹拌後、氷冷する。
析出結晶を濾取し、水，エタノールで順次洗浄して、淡
黄色針状晶の７−（シス−３−アエチルアミノメチル−
４−クロロ−１−ピロリジニル）−１−シクロプロピル
−5,6,8−トリフルオロ−1,4−ジヒドロ−４−オキソキ
ノリン−３−カルボン酸2.3gを得る。m.p.234-235℃ （２） 上記化合物2.1gに20％塩酸21mlを加え３時間加
熱還流後、溶媒を減圧で留去する。残渣を水に溶解し、
活性炭処理後エタノールを加え、析出する結晶を濾取す
る。結晶をエタノールで洗浄して、無色針状晶の７−
（シス−３−アミノメチル−４−クロロ−１−ピロリジ
ニル）−１−シクロプロピル−5,6,8−トリフルオロ−
1,4−ジヒドロ−４−オキソキノリン−３−カルボン酸
塩酸塩1.2gを得る。m.p.214-217℃（分解）． 参考例８ ７−（シス−３−アミノメチル−４−クロロ−１−ピロ
リジニル）−１−シクロプロピル−6,8−ジフルオロ−
1,4−ジヒドロ−４−オキソキノリン−３−カルボン酸
塩酸塩： （１） １−シクロプロピル−6,7,8−トリフルオロ−
1,4−ジヒドロ−４−オキソキノリン−３−カルボン酸
とシス−３−アセチルアミノメチル−４−クロロピロリ
ジンとを参考例７（１）と同様に処理して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）−１−シクロプロピル−6,8−ジフルオロ−1,4−
ジヒドロ−４−オキソキノリン−３−カルボン酸を得
る。Reference Example 7 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic Hydrochloride: (1) 1-Cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2 g, cis-3-acetylaminomethyl-4- A mixture of 2.3 g of chloropyrrolidine, 2.8 ml of triethylamine and 40 ml of acetonitrile is stirred at 50 ° C for 1 hour and then cooled with ice.
The precipitated crystals were collected by filtration, washed successively with water and ethanol to give pale yellow needle crystals of 7- (cis-3-aethylaminomethyl-
2.3 g of 4-chloro-1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained. mp234-235 ° C (2) 21 ml of 20% hydrochloric acid is added to 2.1 g of the above compound, and the mixture is heated under reflux for 3 hours, and then the solvent is distilled off under reduced pressure. Dissolve the residue in water,
After treatment with activated carbon, ethanol is added and the precipitated crystals are collected by filtration. The crystals were washed with ethanol to give 7-colorless needle crystals.
(Cis-3-Aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-
1.2 g of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride are obtained. mp214-217 ° C (decomposition). Reference Example 8 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride: (1) 1-cyclopropyl-6,7,8-trifluoro-
1,4-Dihydro-4-oxoquinoline-3-carboxylic acid and cis-3-acetylaminomethyl-4-chloropyrrolidine were treated in the same manner as in Reference Example 7 (1) to give 7- (cis-
3-Acetylaminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid is obtained.
（２） 上記化合物を参考例７（２）と同様に処理して
７−（シス−３−アミノメチル−４−クロロ−１−ピロ
リジニル）−１−シクロプロピル−6,8−ジフルオロ−
1,4−ジヒドロ−４−オキソキノリン−３−カルボン酸
塩酸塩を得る。(2) The above compound was treated in the same manner as in Reference Example 7 (2) to give 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-.
1,4-Dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride is obtained.
参考例９ ５−アミノ−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）−１−シクロプロピル
−6,8−ジフルオロ−1,4−ジヒドロ−４−オキソキノリ
ン−３−カルボン酸： ５−アミノ−１−シクロプロピル−6,7,8−トリフルオ
ロ−1,4−ジヒドロ−４−オキソキノリン−３−カルボ
ン酸とシス−３−アセチルアミノメチル−４−クロロピ
ロリジンとを参考例７（１）と同様に処理して５−アミ
ノ−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）−１−シクロプロピル−6,8−
ジフルオロ−1,4−ジヒドロ−４−オキソキノリン−３
−カルボン酸を得る。m.p.233-234℃ 実施例１ ７−（３−アミノメチル−４−メチル−2,5−ジヒドロ
−１−ピロリル）−１−シクロプロピル−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： （１） ７−クロロ−１−シクロプロピル−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1.8g,3−アセチルアミノメチル−４−メ
チル−2,5−ジヒドロピロール1.95g,トリエチルアミノ
4.38mlおよびアセトニトリル30mlの混合物を45分間加熱
還流する。冷後、析出結晶を濾取し、水洗した後アセト
ニトリルから再結晶して、無色針状晶の７−（３−アエ
チルアミノメチル−４−メチル−2,5−ジヒドロ−１−
ピロリル）−１−シクロプロピル−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2.0gを得る。m.p.230-231℃． （２） 上記化合物1.8gと20％塩酸18mlの混合物を４時
間加熱還流後、活性炭で処理し、溶媒を減圧で留去す
る。残渣を水に溶解し、20％水酸化ナトリウム水溶液で
中和して、析出する結晶を濾取する。結晶を水洗後乾燥
して、無色針状晶の７−（３−アミノメチル−４−メチ
ル−2,5−ジヒドロ−１−ピロリル）−１−シクロプロ
ピル−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1.2gを得る。Reference Example 9 5-amino-7- (cis-3-acetylaminomethyl-
4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: 5-amino-1-cyclopropyl-6,7,8 -Trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and cis-3-acetylaminomethyl-4-chloropyrrolidine were treated in the same manner as in Reference Example 7 (1) to give 5-amino-. 7- (cis-3-acetylaminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6,8-
Difluoro-1,4-dihydro-4-oxoquinoline-3
-Obtaining a carboxylic acid. mp233-234 ° C Example 1 7- (3-Aminomethyl-4-methyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1 , 8-naphthyridine-3
-Carboxylic acid: (1) 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-
3-carboxylic acid 1.8 g, 3-acetylaminomethyl-4-methyl-2,5-dihydropyrrole 1.95 g, triethylamino
A mixture of 4.38 ml and 30 ml of acetonitrile is heated to reflux for 45 minutes. After cooling, the precipitated crystals were collected by filtration, washed with water, and recrystallized from acetonitrile to give colorless needle crystals of 7- (3-aethylaminomethyl-4-methyl-2,5-dihydro-1-).
Pyrrolyl) -1-cyclopropyl-6-fluoro-1,4
2.0 g of dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. mp230-231 ° C. (2) A mixture of 1.8 g of the above compound and 18 ml of 20% hydrochloric acid is heated under reflux for 4 hours, treated with activated carbon, and the solvent is distilled off under reduced pressure. The residue is dissolved in water, neutralized with 20% aqueous sodium hydroxide solution, and the precipitated crystals are collected by filtration. The crystals were washed with water and dried to give colorless needle crystals of 7- (3-aminomethyl-4-methyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-6-fluoro-1,4-dihydro. -4-oxo-1,8
1.2 g of naphthyridine-3-carboxylic acid are obtained.
m.p.234-238℃（分解）． 実施例２ ７−（３−アミノメチル−４−メチル−2,5−ジヒドロ
−１−ピロリル）−１−シクロプロピル−6,8−ジフル
オロ−1,4−ジヒドロ−４−オキソキノリン−３−カル
ボン酸： （１） １−シクロプロピル−6,7,8−トリフルオロ−
1,4−ジヒドロ−４−オキソキノリン−３−カルボン酸
を実施例１（１）と同様に反応処理して、７−（３−ア
セチルアミノメチル−４−メチル−2,5−ジヒドロ−１
−ピロリル）−１−シクロプロピル−6,8−ジフルオロ
−1,4−ジヒドロ−４−オキソキノリン−３−カルボン
酸を得る。m.p.238-239℃． （２） 上記化合物を実施例１（２）と同様に処理し
て、７−（３−アミノメチル−４−メチル−2,5−ジヒ
ドロ−１−ピロリル）−１−シクロプロピル−6,8−ジ
フルオロ−1,4−ジヒドロ−４−オキソキノリン−３−
カルボン酸を得る。m.p.249-254℃（分解）． 実施例３ ７−（３−アミノメチル−４−メチル−2,5−ジヒドロ
−１−ピロリル）−１−シクロプロピル−5,6,8−トリ
フルオロ−1,4−ジヒドロ−４−オキソキノリン−３−
カルボン酸： （１） １−シクロプロピル−5,6,7,8−テトラフルオ
ロ−1,4−ジヒドロ−４−オキソキノリン−３−カルボ
ン酸を実施例１（１）と同様に反応処理して、７−（３
−アセチルアミノメチル−４−メチル−2,5−ジヒドロ
−１−ピロリル）−１−シクロプロピル−5,6,8−トリ
フルオロ−1,4−ジヒドロ−４−オキソキノリン−３−
カルボン酸を得る。m.p.255-257℃． （２） 上記化合物を実施例１（２）と同様に処理し
て、７−（３−アミノメチル−４−メチル−2,5−ジヒ
ドロ−１−ピロリル）−１−シクロプロピル−5,6,8−
トリフルオロ−1,4−ジヒドロ−４−オキソキノリン−
３−カルボン酸を得る。m.p.175-178℃（分解）． 実施例４ ５−アミノ−７−（３−アミノメチル−４−メチル−2,
5−ジヒドロ−１−ピロリル）−１−シクロプロピル−
6,8−ジフルオロ−1,4−ジヒドロ−４−オキソキノリン
−３−カルボン酸： （１） ５−アミノ−１−シクロプロピル−6,7,8−ト
リフルオロ−1,4−ジヒドロ−４−オキソキノリン−３
−カルボン酸を実施例１（１）と同様に反応処理して、
５−アミノ−７−（３−アセチルアミノメチル−４−メ
チル−2,5−ジヒドロ−１−ピロリル）−１−シクロプ
ロピル−6,8−ジフルオロ−1,4−ジヒドロ−４−オキソ
キノリン−３−カルボン酸を得る。mp234-238 ℃ (decomposition). Example 2 7- (3-Aminomethyl-4-methyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3- Carboxylic acid: (1) 1-cyclopropyl-6,7,8-trifluoro-
1,4-Dihydro-4-oxoquinoline-3-carboxylic acid was treated in the same manner as in Example 1 (1) to give 7- (3-acetylaminomethyl-4-methyl-2,5-dihydro-1).
-Pyrrolyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained. mp238-239 ° C. (2) The above compound was treated as in Example 1 (2) to give 7- (3-aminomethyl-4-methyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-6,8. -Difluoro-1,4-dihydro-4-oxoquinoline-3-
Obtain the carboxylic acid. mp249-254 ℃ (decomposition). Example 3 7- (3-Aminomethyl-4-methyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline -3-
Carboxylic acid: (1) 1-Cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was treated in the same manner as in Example 1 (1). 7- (3
-Acetylaminomethyl-4-methyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-
Obtain the carboxylic acid. mp255-257 ℃. (2) The above compound was treated as in Example 1 (2) to give 7- (3-aminomethyl-4-methyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-5,6. , 8−
Trifluoro-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid is obtained. mp175-178 ℃ (decomposition). Example 4 5-amino-7- (3-aminomethyl-4-methyl-2,
5-dihydro-1-pyrrolyl) -1-cyclopropyl-
6,8-Difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: (1) 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4 -Oxoquinoline-3
-The carboxylic acid is treated in the same manner as in Example 1 (1),
5-amino-7- (3-acetylaminomethyl-4-methyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid is obtained.
m.p.280-283℃（分解）． （２） 上記化合物を実施例１（２）と同様に処理し
て、５−アミノ−７−（３−アミノメチル−４−メチル
−2,5−ジヒドロ−１−ピロリル）−１−シクロプロピ
ル−6,8−ジフルオロ−1,4−ジヒドロ−４−オキソキノ
リン−３−カルボン酸を得る。m.p.264-269℃（分
解）． 実施例５ ７−（３−アミノメチル−2,5−ジヒドロ−１−ピロリ
ル）−１−シクロプロピル−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： ７−（シス−３−アミノメチル−４−クロロ−１−ピロ
リジニル）−１−シクロプロピル−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（特開昭61-243081参照）1.0gを10％水酸化ナ
トリウム水溶液30mlの混合物を90-100℃で20分間加熱す
る。放冷後10％酢酸水で中和し、析出結晶を濾取する。
結晶を10％酢酸水に溶解し、活性炭処理後、28％アンモ
ニア水を加えアルカリ性とする。析出結晶を濾取し、水
洗した後乾燥して、淡黄色結晶の７−（３−アミノメチ
ル−2,5−ジヒドロ−１−ピロリル）−１−シクロプロ
ピル−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0.86gを得る。mp280-283 ℃ (decomposition). (2) The above compound was treated as in Example 1 (2) to give 5-amino-7- (3-aminomethyl-4-methyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl. -6,8-Difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained. mp264-269 ℃ (decomposition). Example 5 7- (3-Aminomethyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carvone Acid: 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4
A mixture of 1.0 g of dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (see JP-A-61-243081) in 30 ml of 10% aqueous sodium hydroxide solution is heated at 90-100 ° C. for 20 minutes. After allowing to cool, it is neutralized with 10% aqueous acetic acid, and the precipitated crystals are collected by filtration.
The crystals are dissolved in 10% acetic acid water, treated with activated carbon, and made alkaline with 28% ammonia water. The precipitated crystals were collected by filtration, washed with water and dried to give pale-yellow crystals of 7- (3-aminomethyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-6-fluoro-1,4- Dihydro-4-oxo-1,8
0.86 g of naphthyridine-3-carboxylic acid are obtained.
m.p.205-215℃（分解）． 実施例６ ７−（３−アミノメチル−2,5−ジヒドロ−１−ピロリ
ル）−１−シクロプロピル−6,8−ジフルオロ−1,4−ジ
ヒドロ−４−オキソキノリン−３−カルボン酸： ７−（シス−３−アミノメチル−４−クロロ−１−ピロ
リジニル）−１−シクロプロピル−6,8−ジフルオロ−
1,4−ジヒドロ−４−オキソ−キノリン−３−カルボン
酸を実施例５と同様に処理して、７−（３−アミノメチ
ル−2,5−ジヒドロ−１−ピロリル）−１−シクロプロ
ピル−6,8−ジフルオロ−1,4−ジヒドロ−４−オキソキ
ノリン−３−カルボン酸を得る。mp205-215 ° C (decomposition). Example 6 7- (3-Aminomethyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: 7 -(Cis-3-Aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-
1,4-Dihydro-4-oxo-quinoline-3-carboxylic acid was treated as in Example 5 to give 7- (3-aminomethyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl. -6,8-Difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.
m.p.208-209℃（分解）． 実施例７ ７−（３−アミノメチル−2,5−ジヒドロ−１−ピロリ
ル）−１−シクロプロピル−5,6,8−トリフルオロ−1,4
−ジヒドロ−４−オキソキノリン−３−カルボン酸： ７−（シス−３−アミノメチル−４−クロロ−１−ピロ
リジニル）−１−シクロプロピル−5,6,8−トリフルオ
ロ−1,4−ジヒドロ−４−オキソキノリン−３−カルボ
ン酸を実施例５と同様に処理して、７−（３−アミノメ
チル−2,5−ジヒドロ−１−ピロリル）−１−シクロプ
ロピル−5,6,8−トリフルオロ−1,4−ジヒドロ−４−オ
キソキノリン−３−カルボン酸を得る。mp 208-209 ° C (decomposition). Example 7 7- (3-Aminomethyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-5,6,8-trifluoro-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid: 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4- Dihydro-4-oxoquinoline-3-carboxylic acid was treated as in Example 5 to give 7- (3-aminomethyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-5,6, 8-Trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.
m.p.231-235℃（分解）． 実施例８ ５−アミノ−７−（３−アミノメチル−2,5−ジヒドロ
−１−ピロリル）−１−シクロプロピル−6,8−ジフル
オロ−1,4−ジヒドロ−４−オキソキノリン−３−カル
ボン酸： ５−アミノ−７−（シス−３−アミノメチル−４−クロ
ロ−１−ピロリジニル）−１−シクロプロピル−6,8−
トリフルオロ−1,4−ジヒドロ−４−オキソキノリン−
３−カルボン酸を実施例５と同様に処理して、５−アミ
ノ−７−（３−アミノメチル−2,5−ジヒドロ−１−ピ
ロリル）−１−シクロプロピル−6,8−ジフルオロ−1,4
−ジヒドロ−４−オキソキノリン−３−カルボン酸を得
る。m.p.218-223℃（分解）． 実施例９ ７−（３−アセチルアミノメチル−2,5−ジヒドロ−１
−ピロリル）−１−シクロプロピル−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
ルボン酸エチルエステル： ７−（３−アセチルアミノメチル−３−ヒドロキシ−１
−ピロリジニル）−１−シクロプロピル−６−フルオロ
−1,4−ジヒドロ−４−オキソ−1,8−ナフチリジン−３
−カルボン酸エチルエステル4.32gと濃硫酸20mlの混合
物を80℃で４時間加熱後、氷冷し、氷水100ml中に注
ぐ。析出結晶を濾取し水洗後、エタノールから再結晶し
て、淡黄色針状晶の７−（３−アセチルアミノメチル−
2,5,−ジヒドロ−１−ピロリル）−１−シクロプロピル
−６−フルオロ−1,4−ジヒドロ−４−オキソ−1,8−ナ
フチリジン−３−カルボン酸エチルエステル2.98gを得
る。mp231-235 ° C (decomposition). Example 8 5-Amino-7- (3-aminomethyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3- Carboxylic acid: 5-amino-7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6,8-
Trifluoro-1,4-dihydro-4-oxoquinoline-
The 3-carboxylic acid was treated as in Example 5 to give 5-amino-7- (3-aminomethyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-6,8-difluoro-1. ,Four
-Dihydro-4-oxoquinoline-3-carboxylic acid is obtained. mp218-223 ° C (decomposition). Example 9 7- (3-Acetylaminomethyl-2,5-dihydro-1
-Pyrrolyl) -1-cyclopropyl-6-fluoro-1,
4-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester: 7- (3-acetylaminomethyl-3-hydroxy-1
-Pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-A mixture of 4.32 g of carboxylic acid ethyl ester and 20 ml of concentrated sulfuric acid is heated at 80 ° C for 4 hours, cooled with ice and poured into 100 ml of ice water. The precipitated crystals were collected by filtration, washed with water, and recrystallized from ethanol to give pale yellow needle crystals of 7- (3-acetylaminomethyl-
There are obtained 2.98 g of 2,5, -dihydro-1-pyrrolyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester.
m.p.216-217℃． 実施例10 ７−（３−トリフルオロアセチルアミノメチル−４−メ
チル−2,5,−ジヒドロ−１−ピロリル）−１−シクロプ
ロピル−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： ７−（３−トリフルオロアセチルアミノメチル−３−ト
リフルオロアセトキシ−４−メチル−１−ピロリジニ
ル）−１−シクロプロピル−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
酸を実施例９と同様に処理して、７−（３−トリフルオ
ロアセチルアミノメチル−４−メチル−2,5−ジヒドロ
−１−ピロリル）−１−シクロプロピル−６−フルオロ
−1,4−ジヒドロ−４−オキソ−1,8−ナフチリジン−３
−カルボン酸を得る。mp216-217 ° C. Example 10 7- (3-Trifluoroacetylaminomethyl-4-methyl-2,5, -dihydro-1-pyrrolyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-
1,8-Naphthyridine-3-carboxylic acid: 7- (3-trifluoroacetylaminomethyl-3-trifluoroacetoxy-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4- Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was treated as in Example 9 to give 7- (3-trifluoroacetylaminomethyl-4-methyl-2,5-dihydro-1- Pyrrolyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-Obtaining a carboxylic acid.
実施例11 ７−（３−トリフルオロアセチルアミノメチル−2,5−
ジヒドロ−１−ピロリル）−１−シクロプロピル−６−
フルオロ−1,4−ジヒドロ−４−オキソ−1,8−ナフチリ
ジン−３−カルボン酸エチルエステル： （１） ７−（３−アミノメチル−2,5−ジヒドロ−１
−ピロリル）−１−シクロプロピル−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7.0gを氷冷した無水トリフルオロ酢酸50mlに加
え、室温で20分間撹拌する。反応溶液を氷水200ml中に
注ぎ析出結晶を濾取し、水，エタノール，アセトンで順
次洗浄し、７−（３−トリフルオロアセチルアミノメチ
ル−2,5−ジヒドロ−１−ピロリル）−１−シクロプロ
ピル−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6.8gを得る。Example 11 7- (3-trifluoroacetylaminomethyl-2,5-
Dihydro-1-pyrrolyl) -1-cyclopropyl-6-
Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester: (1) 7- (3-aminomethyl-2,5-dihydro-1
-Pyrrolyl) -1-cyclopropyl-6-fluoro-1,
7.0 g of 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is added to 50 ml of ice-cooled trifluoroacetic anhydride, and the mixture is stirred at room temperature for 20 minutes. The reaction solution was poured into 200 ml of ice water, and the precipitated crystals were collected by filtration, washed successively with water, ethanol and acetone, and then 7- (3-trifluoroacetylaminomethyl-2,5-dihydro-1-pyrrolyl) -1-cyclo. Propyl-6-fluoro-1,4-dihydro-4-oxo-1,8
6.8 g of naphthyridine-3-carboxylic acid are obtained.
（２） 上記化合物6.8gをクロロホルム100mlに溶解
し、氷冷下トリエチルアミン10ml、クロル炭酸エチル6m
lを加え室温で30分間撹拌後、エタノール20ml加え、室
温で１時間撹拌する。溶媒を減圧で留去し、残渣に水を
加え析出結晶を濾取する。結晶をエタノールから再結晶
して、淡黄色針状晶の７−（３−トリフルオロアセチル
アミノメチル−2,5−ジヒドロ−１−ピロリル）−１−
シクロプロピル−６−フルオロ−1,4−ジヒドロ−４−
オキソ−1,8−ナフチリジン−３−カルボン酸エチルエ
ステル5.8gを得る。m.p.242-244℃． 実施例12 ７−（３−トリフルオロアセチルアミノメチル−2,5,−
ジヒドロ−１−ピロリル）−１−シクロプロピル−6,8
−ジフルオロ−1,4−ジヒドロ−４−オキソキノリン−
３−カルボン酸エチルエステル： （１） ７−（３−アミノメチル−2,5−ジヒドロ−１
−ピロリル）−１−シクロプロピル−6,8−ジフルオロ
−1,4−ジヒドロ−４−オキソキノリン−３−カルボン
酸を実施例11（１）と同様に処理して、７−（３−トリ
フルオロアセチルアミノメチル−2,5−ジヒドロ−１−
ピロリル）−１−シクロプロピル−6,8−ジフルオロ−
1,4−ジヒドロ−４−オキソキノリン−３−カルボン酸
を得る。(2) Dissolve 6.8 g of the above compound in 100 ml of chloroform, and under ice cooling, 10 ml of triethylamine, 6 m of ethyl chlorocarbonate.
Add l and stir at room temperature for 30 minutes, then add 20 ml of ethanol and stir at room temperature for 1 hour. The solvent is distilled off under reduced pressure, water is added to the residue, and the precipitated crystals are collected by filtration. The crystals were recrystallized from ethanol to give pale yellow needle crystals of 7- (3-trifluoroacetylaminomethyl-2,5-dihydro-1-pyrrolyl) -1-.
Cyclopropyl-6-fluoro-1,4-dihydro-4-
5.8 g of oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester are obtained. mp242-244 ℃. Example 12 7- (3-trifluoroacetylaminomethyl-2,5,-
Dihydro-1-pyrrolyl) -1-cyclopropyl-6,8
-Difluoro-1,4-dihydro-4-oxoquinoline-
3-Carboxylic acid ethyl ester: (1) 7- (3-aminomethyl-2,5-dihydro-1
-Pyrrolyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was treated as in Example 11 (1) to give 7- (3-tri Fluoroacetylaminomethyl-2,5-dihydro-1-
Pyrrolyl) -1-cyclopropyl-6,8-difluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.
： （２） 上記化合物を実施例11（２）と同様に処理し
て、７−（３−トリフルオロアセチルアミノメチル−2,
5−ジヒドロ−１−ピロリル）−１−シクロプロピル−
6,8−ジフルオロ−1,4−ジヒドロ−４−オキソキノリン
−３−カルボン酸エチルエステルを得る。m.p.217-218
℃． 実施例13 ７−（３−アセチルアミノメチル−2,5−ジヒドロ−１
−ピロリル）−１−シクロプロピル−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
ルボン酸エチルエステル： （１） ７−（３−アミノメチル−2,5−ジヒドロ−１
−ピロリル）−１−シクロプロピル−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
ルボン酸を無水酢酸を用い実施例11（１）と同様に処理
して７−（３−アセチルアミノメチル−2,5−ジヒドロ
−１−ピロリル）−１−シクロプロピル−６−フルオロ
−1,4−ジヒドロ−４−オキソ−1,8−ナフチリジン−３
−カルボン酸を得る。(2) The above compound was treated in the same manner as in Example 11 (2) to give 7- (3-trifluoroacetylaminomethyl-2,
5-dihydro-1-pyrrolyl) -1-cyclopropyl-
6,8-Difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester is obtained. mp217-218
° C. Example 13 7- (3-Acetylaminomethyl-2,5-dihydro-1
-Pyrrolyl) -1-cyclopropyl-6-fluoro-1,
4-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester: (1) 7- (3-aminomethyl-2,5-dihydro-1
-Pyrrolyl) -1-cyclopropyl-6-fluoro-1,
4-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was treated with acetic anhydride in the same manner as in Example 11 (1) to give 7- (3-acetylaminomethyl-2,5-dihydro- 1-pyrrolyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-Obtaining a carboxylic acid.
m.p.236-239℃ （２） 上記化合物を実施例11（２）と同様に処理し
て、７−（３−アセチルアミノメチル−2,5−ジヒドロ
−１−ピロリル）−１−シクロプロピル−６−フルオロ
−1,4−ジヒドロ−４−オキソ−1,8−ナフチリジン−３
−カルボン酸エチルエステルを得る。m.p.216-217℃． 実施例14 ７−（３−トリフルオロアセチルアミノメチル−１−ピ
ロリル）−１−シクロプロピル−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
ボン酸エチルエステル： ７−（３−トリフルオロアセチルアミノメチル−2,5−
ジヒドロ−１−ピロリル）−１−シクロプロピル−６−
フルオロ−1,4−ジヒドロ−４−オキソ−1,8−ナフチリ
ジン−３−カルボン酸エチルエステル1.7g、クロラニー
ル1.03g、酢酸30mlおよびトルエン30mlの混合物を100℃
で17時間加熱撹拌後、溶媒を減圧で留去する。残渣にク
ロロホルムを加え、不溶物を濾去し、濾液に４％水酸化
ナトリウム水溶液10mlを加える。クロロホルム層を分け
て乾燥後、溶媒を減圧で留去し、残渣を酢酸とエタノー
ルの混合溶媒から再結晶して、７−（３−トリフルオロ
アセチルアミノメチル−１−ピロリル）−１−シクロプ
ロピル−６−フルオロ−1,4−ジヒドロ−４−オキソ−
1,8−ナフチリジン−３−カルボン酸エチルエステル3g
を得る。m.p.235-254℃． 実施例15 ７−（３−アセチルアミノメチル−１−ピロリル）−１
−シクロプロピル−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
エステル： ７−（３−アセチルアミノメチル−2.5−ジヒドロ−１
−ピロリル）−１−シクロプロピル−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
ルボン酸エチルエステルを実施例14と同様にして処理し
て、７−（３−アセチルアミノメチル−１−ピロリル）
−１−シクロプロピル−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
チルエステルを得る。mp236-239 ° C (2) The above compound was treated as in Example 11 (2) to give 7- (3-acetylaminomethyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-6-. Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-Obtain carboxylic acid ethyl ester. mp216-217 ° C. Example 14 7- (3-Trifluoroacetylaminomethyl-1-pyrrolyl) -1-cyclopropyl-6-fluoro-1,4-
Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester: 7- (3-trifluoroacetylaminomethyl-2,5-
Dihydro-1-pyrrolyl) -1-cyclopropyl-6-
A mixture of fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 1.7 g, chloranil 1.03 g, acetic acid 30 ml and toluene 30 ml was added at 100 ° C.
After heating and stirring for 17 hours, the solvent is distilled off under reduced pressure. Chloroform was added to the residue, the insoluble matter was filtered off, and 10 ml of a 4% aqueous sodium hydroxide solution was added to the filtrate. After the chloroform layer was separated and dried, the solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of acetic acid and ethanol to give 7- (3-trifluoroacetylaminomethyl-1-pyrrolyl) -1-cyclopropyl. -6-Fluoro-1,4-dihydro-4-oxo-
1,8-Naphthyridine-3-carboxylic acid ethyl ester 3 g
To get mp235-254 ° C. Example 15 7- (3-Acetylaminomethyl-1-pyrrolyl) -1
-Cyclopropyl-6-fluoro-1,4-dihydro-4
-Oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester: 7- (3-acetylaminomethyl-2.5-dihydro-1
-Pyrrolyl) -1-cyclopropyl-6-fluoro-1,
4-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was treated as in Example 14 to give 7- (3-acetylaminomethyl-1-pyrrolyl).
-1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester is obtained.
m.p.219-220℃． 実施例16 ７−（３−トリフルオロアセチルアミノメチル−４−メ
チル−１−ピロリル）−１−シクロプロピル−６−フル
オロ−1,4−ジヒドロ−４−オキソ−1,8−ナフチリジン
−３−カルボン酸エチルエステル： ７−（３−トリフルオロアセチルアミノメチル−４−メ
チル−2,5−ジヒドロ−１−ピロリル）−１−シクロプ
ロピル−６−フルオロ−1,4−ジヒドロ−４−オキソ−
1,8−ナフチリジン−３−カルボン酸エチルエステルを
実施例14と同様に処理して、７−（３−トリフルオロア
セチルアミノメチル−４−メチル−１−ピロリル）−１
−シクロプロピル−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
エステルを得る。m.p.234-235℃． 実施例17 ７−（３−トリフルオロアセチルアミノメチル−１−ピ
ロリル）−１−シクロプロピル−6,8−ジフルオロ−1,4
−ジヒドロ−４−オキソキノリン−３−カルボン酸エチ
ルエステル： ７−（３−トリフルオロアセチルアミノメチル−2,5−
ジヒドロ−１−ピロリル）−１−シクロプロピル−6,8
−ジフルオロ−1,4−ジヒドロ−４−オキソキノリン−
３−カルボン酸エチルエステルを実施例14と同様に処理
して、７−（３−トリフルオロアセチルアミノメチル−
１−ピロリル）−１−シクロプロピル−6,8−ジフルオ
ロ−1,4−ジヒドロ−４−オキソキノリン−３−カルボ
ン酸エチルエステルを得る。mp219-220 ° C. Example 16 7- (3-Trifluoroacetylaminomethyl-4-methyl-1-pyrrolyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3- Carboxylic acid ethyl ester: 7- (3-trifluoroacetylaminomethyl-4-methyl-2,5-dihydro-1-pyrrolyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-
The 1,8-naphthyridine-3-carboxylic acid ethyl ester was treated as in Example 14 to give 7- (3-trifluoroacetylaminomethyl-4-methyl-1-pyrrolyl) -1.
-Cyclopropyl-6-fluoro-1,4-dihydro-4
-Oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester is obtained. mp234-235 ° C. Example 17 7- (3-Trifluoroacetylaminomethyl-1-pyrrolyl) -1-cyclopropyl-6,8-difluoro-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester: 7- (3-trifluoroacetylaminomethyl-2,5-
Dihydro-1-pyrrolyl) -1-cyclopropyl-6,8
-Difluoro-1,4-dihydro-4-oxoquinoline-
The 3-carboxylic acid ethyl ester was treated as in Example 14 to give 7- (3-trifluoroacetylaminomethyl-
1-Pyrrolyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester is obtained.
m.p.173-174℃． 実施例18 ７−（３−アミノメチル−１−ピロリル）−１−シクロ
プロピル−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： ７−（３−トリフルオロアセチルアミノメチル−１−ピ
ロリル）−１−シクロプロピル−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
ボン酸エチルエステル1.0g、1N炭酸ナトリウム10mlおよ
びエタノール10mlの混合物を水浴上30分間加熱する。冷
後、10％酢酸で中和し、析出結晶を濾取する。結晶を５
％酢酸に溶解し、活性炭処理後、28％アンモニア水を加
えて、アルカリ性とする。析出結晶を濾取し、水洗後乾
燥して、淡黄色針状晶の７−（３−アミノメチル−１−
ピロリル）−１−シクロプロピル−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0.64gを得る。m.p.254-256℃（分解）． 実施例18 ７−（３−アミノメチル−１−ピロリル）−１−シクロ
プロピル−6,8−ジフルオロ−1,4−ジヒドロ−４−オキ
ソキノリン−３−カルボン酸： ７−（３−トリフルオロアセチルアミノメチル−１−ピ
ロリル）−１−シクロプロピル−6,8−ジフルオロ−1,4
−ジヒドロ−４−オキソキノリン−３−カルボン酸エチ
ルエステルを実施例18と同様に処理して、７−（３−ア
ミノメチル−１−ピロリル）−１−シクロプロピル−6,
8−ジフルオロ−1,4−ジヒドロ−４−オキソキノリン−
３−カルボン酸を得る。m.p.235-236℃． 実施例20 ７−（３−アミノメチル−４−メチル−１−ピロリル）
−１−シクロプロピル−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： ７−（３−トリフルオロアセチルアミノメチル−４−メ
チル−１−ピロリル）−１−シクロプロピル−６−フル
オロ−1,4−ジヒドロ−４−オキソ−1,8−ナフチリジン
−３−カルボン酸エチルエステル実施例18と同様に処理
して、７−（３−アミノメチル−４−メチル−１−ピロ
リル）−１−シクロプロピル−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
ン酸を得る。m.p.261-264℃．mp173-174 ° C. Example 18 7- (3-Aminomethyl-1-pyrrolyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid: 7- (3 -Trifluoroacetylaminomethyl-1-pyrrolyl) -1-cyclopropyl-6-fluoro-1,4-
A mixture of 1.0 g of dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 10 ml of 1N sodium carbonate and 10 ml of ethanol is heated on a water bath for 30 minutes. After cooling, it is neutralized with 10% acetic acid and the precipitated crystals are collected by filtration. Crystal 5
% Dissolve in acetic acid, treat with activated carbon, and add 28% aqueous ammonia to make it alkaline. The precipitated crystals were collected by filtration, washed with water and dried to give pale yellow needle crystals of 7- (3-aminomethyl-1-).
Pyrrolyl) -1-cyclopropyl-6-fluoro-1,4
0.64 g of -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. mp254-256 ℃ (decomposition). Example 18 7- (3-Aminomethyl-1-pyrrolyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: 7- (3-trifluoro Acetylaminomethyl-1-pyrrolyl) -1-cyclopropyl-6,8-difluoro-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester was treated as in Example 18 to give 7- (3-aminomethyl-1-pyrrolyl) -1-cyclopropyl-6,
8-difluoro-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid is obtained. mp235-236 ° C. Example 20 7- (3-Aminomethyl-4-methyl-1-pyrrolyl)
-1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid: 7- (3-trifluoroacetylaminomethyl-4-methyl-1-pyrrolyl) -1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester Treated as in Example 18 to give 7- (3-aminomethyl- 4-Methyl-1-pyrrolyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained. mp261-264 ° C.
Claims (1)
は水素原子またはハロゲン原子を意味し、 Y1は水素原子またはハロゲン原子を意味し、Y2は水素原
子、フッ素原子、水酸基または−NR′Ｒ″を意味し、こ
こにＲ′およびＲ″は同一または異なって水素原子、低
級アルキル基、ベンジル基またはハロゲン原子で置換さ
れていてもよいアシル基を意味し、 R1は低級アルキル基、ハロゲノ低級アルキル基、低級ア
ルケニル基、シクロアルキル基または置換基を有してい
てもよいフェニル基を意味し、 Ａは下記式で表わされる基 を意味し、ここにR2は水素原子または低級アルキル基を
意味し、R3は水素原子、低級アルキル基またはハロゲン
で置換されていてもよいアシル基を意味し、 R4は水素原子または低級アルキル基を意味する。） で表わされるピリドンカルボン酸誘導体、そのエステル
およびその塩。1. A general formula (In the formula, X means a nitrogen atom or C—Y, where Y
Means a hydrogen atom or a halogen atom, Y 1 means a hydrogen atom or a halogen atom, Y 2 means a hydrogen atom, a fluorine atom, a hydroxyl group or —NR′R ″, wherein R ′ and R ″ are The same or different, means a hydrogen atom, a lower alkyl group, a benzyl group or an acyl group which may be substituted with a halogen atom, R 1 is a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a cycloalkyl group or a substituted group. Means a phenyl group which may have a group, and A is a group represented by the following formula: Wherein R 2 represents a hydrogen atom or a lower alkyl group, R 3 represents a hydrogen atom, a lower alkyl group or an acyl group optionally substituted with halogen, and R 4 represents a hydrogen atom or a lower atom. Means an alkyl group. ) A pyridonecarboxylic acid derivative represented by :, its ester and its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62221681A JPH0784459B2 (en) | 1987-09-03 | 1987-09-03 | Novel pyridonecarboxylic acid derivative, its ester and its salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62221681A JPH0784459B2 (en) | 1987-09-03 | 1987-09-03 | Novel pyridonecarboxylic acid derivative, its ester and its salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6463579A JPS6463579A (en) | 1989-03-09 |
| JPH0784459B2 true JPH0784459B2 (en) | 1995-09-13 |
Family
ID=16770609
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62221681A Expired - Lifetime JPH0784459B2 (en) | 1987-09-03 | 1987-09-03 | Novel pyridonecarboxylic acid derivative, its ester and its salt |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0784459B2 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01128978A (en) * | 1987-11-13 | 1989-05-22 | Shionogi & Co Ltd | Pyridonecarboxylic acid antibacterial |
| JPH01233270A (en) * | 1988-03-14 | 1989-09-19 | Shionogi & Co Ltd | Pyrroline and tetrahydropyridine derivative |
| DE4037353C1 (en) * | 1990-11-20 | 1992-03-12 | Mannesmann Ag, 4000 Duesseldorf, De | |
| JP2001278857A (en) * | 2000-01-28 | 2001-10-10 | Toray Ind Inc | High-purity pyrroline derivative and method for storing the same |
| CN109280047A (en) * | 2017-12-12 | 2019-01-29 | 中国药科大学 | A kind of moxifloxacin hydrochloride Photodegradation Products and preparation method thereof and detection method |
-
1987
- 1987-09-03 JP JP62221681A patent/JPH0784459B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6463579A (en) | 1989-03-09 |
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