JPH02138261A - Quinolone carboxylic acid derivative - Google Patents
Quinolone carboxylic acid derivativeInfo
- Publication number
- JPH02138261A JPH02138261A JP1189214A JP18921489A JPH02138261A JP H02138261 A JPH02138261 A JP H02138261A JP 1189214 A JP1189214 A JP 1189214A JP 18921489 A JP18921489 A JP 18921489A JP H02138261 A JPH02138261 A JP H02138261A
- Authority
- JP
- Japan
- Prior art keywords
- carboxylic acid
- formula
- lower alkyl
- dihydro
- oxoquinoline
- 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.)
- Granted
Links
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 125000005843 halogen group Chemical group 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 19
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 229910052736 halogen Inorganic materials 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 150000002367 halogens Chemical class 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000007795 chemical reaction product Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- -1 L-butyl group Chemical group 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- QSJCIPBBQKEQJF-UHFFFAOYSA-N ethyl 6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1-prop-1-en-2-ylquinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=CN(C(C)=C)C2=CC=1N1CCN(C)CC1 QSJCIPBBQKEQJF-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- QZRPEIZVZYDQDS-UHFFFAOYSA-N 2-(2-methylsulfonylpropoxy)oxane Chemical compound CS(=O)(=O)C(C)COC1CCCCO1 QZRPEIZVZYDQDS-UHFFFAOYSA-N 0.000 description 1
- RFYOAPQLOIWVPK-UHFFFAOYSA-N 6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1-prop-1-en-2-ylquinoline-3-carboxylic acid Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C(C)=C RFYOAPQLOIWVPK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000032536 Pseudomonas Infections Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 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
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- WEALJLJOARVSPK-UHFFFAOYSA-N ethyl 1-(1-chloropropan-2-yl)-6,7,8-trifluoro-4-oxoquinoline-3-carboxylate Chemical compound FC1=C(F)C=C2C(=O)C(C(=O)OCC)=CN(C(C)CCl)C2=C1F WEALJLJOARVSPK-UHFFFAOYSA-N 0.000 description 1
- MAUXMFWFQFTOJI-UHFFFAOYSA-N ethyl 7-(3-aminopyrrolidin-1-yl)-1-(1-chloropropan-2-yl)-6,8-difluoro-4-oxoquinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=CN(C(C)CCl)C2=C(F)C=1N1CCC(N)C1 MAUXMFWFQFTOJI-UHFFFAOYSA-N 0.000 description 1
- HIYPUORWLJANPY-UHFFFAOYSA-N ethyl 7-chloro-1-(1-chloropropan-2-yl)-6-fluoro-4-oxoquinoline-3-carboxylate Chemical compound ClC1=C(F)C=C2C(=O)C(C(=O)OCC)=CN(C(C)CCl)C2=C1 HIYPUORWLJANPY-UHFFFAOYSA-N 0.000 description 1
- QQDPCLSVWWTVLK-UHFFFAOYSA-N ethyl 7-chloro-6-fluoro-1-(1-hydroxypropan-2-yl)-4-oxoquinoline-3-carboxylate Chemical compound ClC1=C(F)C=C2C(=O)C(C(=O)OCC)=CN(C(C)CO)C2=C1 QQDPCLSVWWTVLK-UHFFFAOYSA-N 0.000 description 1
- VLOYRWBXBBOLJW-UHFFFAOYSA-N ethyl 7-chloro-6-fluoro-4-oxo-1h-quinoline-3-carboxylate Chemical compound ClC1=C(F)C=C2C(=O)C(C(=O)OCC)=CNC2=C1 VLOYRWBXBBOLJW-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 229940049920 malate Drugs 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- 229960000210 nalidixic acid Drugs 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- RCIMBBZXSXFZBV-UHFFFAOYSA-N piromidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCCC1 RCIMBBZXSXFZBV-UHFFFAOYSA-N 0.000 description 1
- 229960004444 piromidic acid Drugs 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- YLLIGHVCTUPGEH-UHFFFAOYSA-M potassium;ethanol;hydroxide Chemical compound [OH-].[K+].CCO YLLIGHVCTUPGEH-UHFFFAOYSA-M 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は優れた抗菌作用を有する新規なキノロンカルボ
ン酸誘導体及びのそ塩並びにその中間体に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel quinolone carboxylic acid derivatives and their salts having excellent antibacterial activity, and intermediates thereof.
従来、ダラム陰性菌による感染症の治療薬としては、ナ
リジクス酸、ピロミド酸等の合成抗菌剤が知られている
。しかし、これらは緑膿菌感染等の難治性疾患に対して
効果が低いという欠点があった。また一方、ノルフロキ
サシン、シプロフロキサシン等の抗菌活性の強い抗菌剤
が開発され、臨床において使用されている。Conventionally, synthetic antibacterial agents such as nalidixic acid and pyromidic acid have been known as therapeutic agents for infections caused by Durham-negative bacteria. However, these have the drawback of being less effective against intractable diseases such as Pseudomonas aeruginosa infection. On the other hand, antibacterial agents with strong antibacterial activity, such as norfloxacin and ciprofloxacin, have been developed and are in clinical use.
合成抗菌剤が生体で有効に作用するには、抗菌活性が強
いことと、利用率がよいことが必要であるが、上記の従
来の合成抗菌剤は、吸収が悪く、生体利用率が低いとい
う欠点があった。In order for synthetic antibacterial agents to act effectively in living organisms, they must have strong antibacterial activity and good utilization rate, but the conventional synthetic antibacterial agents mentioned above have poor absorption and low bioavailability. There were drawbacks.
斯かる実情において、本発明者は、数多くのキノリン誘
導体を合成し、その抗菌活性及び生体への吸収を検討し
たところ、後記一般式（Ｉ）で表わされるキノロンカル
ボン酸誘導体及びその塩が優れた抗菌活性と吸収性を有
することを見出し、本発明を完成した。Under these circumstances, the present inventor synthesized a number of quinoline derivatives and examined their antibacterial activity and absorption into living organisms, and found that the quinolone carboxylic acid derivative represented by the general formula (I) below and its salts were superior. They discovered that it has antibacterial activity and absorbability, and completed the present invention.
すなわち、本発明は、次の一般式（Ｉ）、（式中、Ｒ＋
は低級アルキル基、Ｒｚは水素原子又は低級アルキル
基、Ｒ３は水素原子又はハロゲン原子、Ｒ１及びＲ２は
一緒になって他の異種原子を含んでもよく、また置換基
を有していてもよい５〜６員環を形成する。だたし、Ｒ
１がメチルがピペラジニル基である場合を除く）
で表わされるキノロンカルボン酸誘導体及びその塩並び
にその中間体である後記式（Ｖ）で表わされるキノロン
カルボン酸誘導体を提供するものである。That is, the present invention provides the following general formula (I), (wherein R+
is a lower alkyl group, Rz is a hydrogen atom or a lower alkyl group, R3 is a hydrogen atom or a halogen atom, R1 and R2 together may contain other heteroatoms, and may have a substituent. ~ forms a 6-membered ring. Dada, R
The present invention provides quinolone carboxylic acid derivatives represented by the following formulas (except when methyl is a piperazinyl group in 1), salts thereof, and intermediates thereof, quinolone carboxylic acid derivatives represented by the following formula (V).
される基としては、例えばピペラジニル基、ピロリジニ
ル基、モルホリノ基等が挙げられ、その置換基としては
、例えば低級アルキル基、ヒドロキシ基、アミノ基、ア
ミノ低級アルキル基等が挙げられる。Examples of the group include a piperazinyl group, a pyrrolidinyl group, a morpholino group, etc., and examples of the substituent thereof include a lower alkyl group, a hydroxy group, an amino group, an amino lower alkyl group, etc.
なお、本発明において低級アルキル基は通常炭素数１〜
６の直鎖又は分岐鎖のアルキル基を意味するが、具体例
としてはメチル基、エチル基、ｎ−プロビル基、イソプ
ロピル基、イソブチル基、Ｌ−ブチル基、ｎ−ペンチル
基、ｎ−ヘキシル基などが挙げられる。またハロゲン原
子としては塩素、フッ素、臭素、ヨウ素原子が挙げられ
る。In addition, in the present invention, the lower alkyl group usually has 1 to 1 carbon atoms.
6 means a straight chain or branched alkyl group, specific examples include methyl group, ethyl group, n-propyl group, isopropyl group, isobutyl group, L-butyl group, n-pentyl group, n-hexyl group. Examples include. Furthermore, examples of the halogen atom include chlorine, fluorine, bromine, and iodine atoms.
本発明化合物（Ｉ）は、例えば次の方法によって製造さ
れる。Compound (I) of the present invention can be produced, for example, by the following method.
製法１：
以下余白
（式中、Ｒ２−３は低級アルキル基、Ｘはハロゲン原子
を示し、Ｒ＋ 、Ｒ：Ｉ 、Ｒ４及びＲ３は前記と同じ
）
原料化合物（ｎ）は、例えば西独特許
ＤＥ３．５２２．４０６号に記載の方法によって製造さ
れる。Production method 1: The blank below (in the formula, R2-3 is a lower alkyl group, X is a halogen atom, and R+, R:I, R4 and R3 are the same as above) The raw material compound (n) is, for example, as described in West German patent DE3. No. 522.406.
化合物（ＩＩ）から（Ｉ［）を製造するには、（ＩＩ）
１モルに対しハロゲン他剤１〜５モルを使用し、溶媒中
、室温ないし還流下、１〜２０時間反応させる。ここで
ハロゲン化剤としては、塩化チオニル、臭化チオニル、
オキシ塩化リン、三塩化リン、三臭化リン、五塩化リン
等が使用され、また溶媒としては、塩化メチレン、クロ
ロホルム、四塩化炭素、１．２−ジクロルエタン、トリ
クロルエタン等が使用される。反応終了後、反応物を濃
縮し、残渣をシリカゲルカラムクロマトグラフィー等で
精製すれば、（ＩＩＩ）が得られる。To produce (I[) from compound (II), (II)
Using 1 to 5 moles of halogen and other agents per mole, the reaction is carried out in a solvent at room temperature to reflux for 1 to 20 hours. Here, the halogenating agent includes thionyl chloride, thionyl bromide,
Phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, etc. are used, and as a solvent, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, etc. are used. After the reaction is completed, the reaction product is concentrated and the residue is purified by silica gel column chromatography or the like to obtain (III).
化合物（ＩＩＩ）から（Ｖ）を製造するには、（ＩＩＩ
）１モルに対して（ＩＶ）を１〜５モル使用し、ジメチ
ルスルホキシド、アセトニトリル等の溶媒中、室温ない
し１００ ’Ｃで、１〜１５時間加温して反応させる。To produce (V) from compound (III), (III)
) Use 1 to 5 moles of (IV) per mole, and react in a solvent such as dimethyl sulfoxide or acetonitrile by heating at room temperature to 100'C for 1 to 15 hours.
反応終了後、反応物を冷水に注加し、酸で中和した後ク
ロロホルム等の溶媒で抽出し、次いで溶媒を留去するか
、あるいは反応物を濃縮し、残渣を水洗して粗生成物を
得、更にこれをシリカゲルカラムクロマトグラフィー又
は再結晶等で精製して（Ｖ）を得る。After the reaction is complete, the reaction product is poured into cold water, neutralized with acid, extracted with a solvent such as chloroform, and then the solvent is distilled off, or the reaction product is concentrated, and the residue is washed with water to obtain the crude product. This is further purified by silica gel column chromatography or recrystallization to obtain (V).
化合物（Ｖ）から（Ｉ−１）を製造するには、（Ｖ）１
モルに対しアルカリを２〜４モル使用し、エタノール等
の溶媒中５〜６０時間加熱反応させ、次いで水を加え１
〜２０時間加熱して反応させる。To produce (I-1) from compound (V), (V)1
Using 2 to 4 moles of alkali per mole, heat the reaction in a solvent such as ethanol for 5 to 60 hours, then add water and give 1
Heat and react for ~20 hours.
ここでアルカリとしては水酸化ナトリウム、水酸化カリ
ウムが好ましい０反応終了後、反応物を冷水に注加し、
酸で中和後、クロロホルム等の溶媒で抽出し、溶媒を留
去後、残渣を適当な溶媒で再結晶すれば（Ｉ−１）の純
品が得られる。Here, the alkali is preferably sodium hydroxide or potassium hydroxide. After the reaction is completed, the reactant is poured into cold water,
After neutralization with an acid, extraction is performed with a solvent such as chloroform, the solvent is distilled off, and the residue is recrystallized with an appropriate solvent to obtain a pure product (I-1).
製法２：
以下余白
（式中、Ｐは保護基、Ｌは脱離基を示し、Ｒ１、Ｒｚ−
＋ 、Ｒａ 、Ｒｓ及びＸは前記と同じ）原料化合物（
Ｖｌ）は公知の化合物であり、例えばジャーナル・オブ
・メディシナル・ケミストリー、１３−．１３５Ｂ （
Ｉ９８０）に記載の方法によって製造される。Manufacturing method 2: The following margins (in the formula, P represents a protecting group, L represents a leaving group, R1, Rz-
+ , Ra , Rs and X are the same as above) raw material compound (
Vl) is a known compound, for example, Journal of Medicinal Chemistry, 13-. 135B (
I980).
化合物（Ｖｌ）から（■）を製造するには、（Ｖｌ）１
モルと炭酸アルカリ２〜４モルをジメチルホルムアミド
等の溶媒に溶かし、これに室温ないし還流下、（■）を
２〜４モル添加し、１〜２０時間反応させる。反応終了
後、反応物を濃縮し、酢酸等で酸性とした後、４０〜８
０°Ｃで１〜５時間加温し、濃縮後、クロロホルム等の
溶媒で抽出し、シリカゲルカラムクロマトグラフィー等
で精製し、更に必要ならば、再結晶を行えば（■）が得
られる。To produce (■) from compound (Vl), (Vl)1
mol and 2 to 4 mol of alkali carbonate are dissolved in a solvent such as dimethylformamide, and 2 to 4 mol of (■) is added thereto at room temperature or under reflux, and the mixture is allowed to react for 1 to 20 hours. After the reaction is completed, the reaction product is concentrated and made acidic with acetic acid etc., and then
After heating at 0°C for 1 to 5 hours, concentrating, extraction with a solvent such as chloroform, purification by silica gel column chromatography, etc., and recrystallization if necessary, yields (■).
化合物（■）から（ＩＸ）を得る反応は、製法ｌの（■
）から（ＩＩ）を得る反応と同様にして行われる。The reaction to obtain (IX) from compound (■) is (■
) to obtain (II).
化合物（ＩＸ）から（Ｉ−２）を製造するには、（■）
１モルに対して（ＩＶ）を１〜５モル使用し、ジメチル
スルホキシド、アセトニトリル等の溶媒中、室温ないし
１００°Ｃで、１〜６０時間反応させる。反応終了後、
反応物を冷水に江刺し、クロロホルム等の溶媒で抽出し
、更にクロロホルム層を酸で逆抽出し、水層をアルカリ
性とし、再度クロロホルム等で抽出し、溶媒を留去後、
残渣をシリカゲルカラムクロマトグラフィー等で精製す
ればＮ−２）が得られる。To produce (I-2) from compound (IX), (■)
1 to 5 mol of (IV) is used per 1 mol, and the reaction is carried out at room temperature to 100°C for 1 to 60 hours in a solvent such as dimethyl sulfoxide or acetonitrile. After the reaction is complete,
The reaction product is poured into cold water, extracted with a solvent such as chloroform, the chloroform layer is back-extracted with an acid, the aqueous layer is made alkaline, extracted again with chloroform, etc., and the solvent is distilled off.
If the residue is purified by silica gel column chromatography or the like, N-2) can be obtained.
化合物（Ｉ−２）から（Ｉ−３）を製造する反応は、（
Ｉ−２）を水酸化ナトリウム、水酸化カリウム等のアル
カリの存在下、含水アルコール中、１〜５時間加熱する
ことにより行われる。反応終了後、反応物を酸で中和し
、濃縮後、アルコール等で抽出し、溶媒を留去し、残渣
を再結晶等で精製すれば（Ｉ−３）が得られる。The reaction for producing (I-3) from compound (I-2) is (
This is carried out by heating I-2) in a hydrous alcohol for 1 to 5 hours in the presence of an alkali such as sodium hydroxide or potassium hydroxide. After the reaction is completed, the reaction product is neutralized with an acid, concentrated, extracted with alcohol, etc., the solvent is distilled off, and the residue is purified by recrystallization or the like to obtain (I-3).
斯くして得られた本発明化合物（Ｉ）は、更に必要に応
じて、常法により、アルカリ金属、無機酸、有機酸等の
塩とすることができる。例えば、アルカリ金属塩として
は、リチウム塩、ナトリウム塩、カリウム塩等；無機酸
塩としては、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、
リン酸塩等；有機酸塩としては、酢酸塩、フマル酸塩、
マレイン酸塩、乳酸塩、酒石酸塩、クエン酸塩、リンゴ
酸塩、シュウ酸塩、メタンスルホン酸塩、ベンゼンスル
ホン酸塩等が挙げられる。The compound (I) of the present invention thus obtained can be further converted into a salt of an alkali metal, an inorganic acid, an organic acid, etc. by a conventional method, if necessary. For example, alkali metal salts include lithium salt, sodium salt, potassium salt, etc.; inorganic acid salts include hydrochloride, sulfate, nitrate, hydrobromide,
Phosphate, etc.; organic acid salts include acetate, fumarate,
Examples include maleate, lactate, tartrate, citrate, malate, oxalate, methanesulfonate, benzenesulfonate, and the like.
本発明化合物（Ｉ）は優れた抗菌活性及び吸収性を示す
、生体利用率の高い抗菌剤である。Compound (I) of the present invention is an antibacterial agent with high bioavailability and exhibits excellent antibacterial activity and absorbability.
次に参考例及び実施例を挙げて説明する。 Next, reference examples and examples will be given and explained.
参考例１
ｌ−（Ｉ−クロロプロプ−２−イル） −６，７，８−
トリフルオロ−１，４−ジヒドロ−４−オキソキノリン
−３−カルボン酸エチルエステル：
６．７．８− ）リフルオロ−１，４−ジヒドロ−１−
（Ｉ−ヒドロキシプロプ−２−イル）−４−オキソキノ
リン−３−カルボン酸エチルエステル０．９８８ｇ （
３，０ＩＩＩｎｏｔｅ）をクロロホルム５０１ＩＩｌに
溶解し、塩化チオニル０．７１４ ｇ （６，０ｍｍｏ
ｌｅ）を加え、加熱還流下１０時間反応させる。反応混
合物を減圧濃縮し、残留物をシリカゲルカラムクロマト
グラフィー（クロロホルム：メタノール＝１００：１）
により精製し、無色針状晶の１−（Ｉ−クロロプロプ−
２−イル’） −６，７，８−トリフルオロ−１，４−
ジヒドロ−４−オキソキノリン−３−カルボン酸エチル
エステル１．００１ｇを得る。融点１９０〜１９１’Ｃ
。Reference example 1 l-(I-chloroprop-2-yl) -6,7,8-
Trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester: 6.7.8- ) Trifluoro-1,4-dihydro-1-
(I-Hydroxyprop-2-yl)-4-oxoquinoline-3-carboxylic acid ethyl ester 0.988 g (
3,0IIInote) was dissolved in 501IIIl of chloroform, and 0.714 g of thionyl chloride (6,0mmol
le) and reacted under heating and reflux for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform:methanol = 100:1).
1-(I-chloroprop-
2-yl') -6,7,8-trifluoro-1,4-
1.001 g of dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester is obtained. Melting point 190-191'C
.
ＩＲ（ＫＢｒ）： １７３０，１６１８ｃｍ−’’ＨＮ
ＭＲ（ＣＤＣｊ！ｚ ） ＰｐＩＩＩ ：１．４０（
３１１，ｔ、 Ｊ＝７．２１１ｚ） 、 １．７７（３
１１，ｄ、 ｄ、 Ｊ＝６．５゜１．８１１ｚ）、３．
８９（２１１，ｄ、ｄ、Ｊ＝５．５．１．８１１ｚ）、
４．３１（２）１．ｑ、Ｊ＝７．２Ｈｚ）、５．２−５
．７（ｉｌｌ、ｍ）、７．９−８．３（ｉｌｌ、ｍ）、
８．５８（Ｉ１１，ｓ）実施例１
７−（３−アミノ−１−ピロリジニル）−１−（Ｉ−ク
ロロプロプ−２−イル） −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−（Ｉ−クロロプロプ−２−イル） −６，７，８ト
リフルオロ−１，４−ジヒドロ−４−オキソキノリン−
３−カルボン酸エチルエステル１７４ｍｇ（０，５ｎ＋
ｍｏｌｅ）をアセトニトリル２０ｍｆｆ１に溶解し、３
−アミノピロリジン２１５ ｍｇ （２，５ｍｍｏｌｅ
）を加え、加熱還流下７時間反応させる。反応混合物を
減圧濃縮し、残留物をシリカゲルカラムクロマトグラフ
ィー（クロロホルム：メタノール＝１００： １＝２０
： １）により精製し、淡黄色結晶の７−（３−アミ
ノ−１−ピロリジニル）＝ｌ−（Ｉ−クロロプロプ−２
−イル） −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（
化合物１）１７２ｍｇを得る。IR (KBr): 1730, 1618cm-''HN
MR (CDCj!z) PpIII: 1.40 (
311,t, J=7.211z), 1.77(3
11, d, d, J=6.5°1.811z), 3.
89 (211, d, d, J=5.5.1.811z),
4.31(2)1. q, J=7.2Hz), 5.2-5
．． 7 (ill, m), 7.9-8.3 (ill, m),
8.58(I11,s) Example 1 7-(3-amino-1-pyrrolidinyl)-1-(I-chloroprop-2-yl)-6,8-difluoro-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester: 1-(I-chloroprop-2-yl)-6,7,8 trifluoro-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid ethyl ester 174 mg (0,5n+
mole) in 20 mff1 of acetonitrile, and
-Aminopyrrolidine 215 mg (2,5 mmole
) and react under heating under reflux for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: methanol = 100: 1 = 20
: 1) to give pale yellow crystals of 7-(3-amino-1-pyrrolidinyl)=l-(I-chloroprop-2).
-yl) -6,8-difluoro-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid ethyl ester (
172 mg of compound 1) is obtained.
本実施例と同様にして第１表の化合物２〜１８を得た。Compounds 2 to 18 in Table 1 were obtained in the same manner as in this example.
以下余白
実施例２
７−（３−アミノ−１−ピロリジニル） −６，８ジフ
ルオロ−１，４−ジヒドロ−４−オキソ−１−（プロブ
−１−エン−２−イル）−キノリン−３−カルボン酸：
実施例１で得られた７−（３−アミノ−１−ピロリジニ
ル）−１−（Ｉ−クロロプロア”−２−イル）−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（化合物１ ） １５
９ｍｇ （０，３８ｍｍｏｌｅ）をエタノール２０ｍｆ
に溶解し、粉砕した水酸化カリウム６５ｏ＋ｇ （Ｉ，
１５＋ｎ＋ｗｏｌｅ）を加え、加熱還流下１４時間反応
させ、更に水３ ｔｓｉを添加し、３時間加熱還流する
。冷後反応物を減圧濃縮し、残渣を水洗後、乾燥し、粗
生成物を得、更にシリカゲルカラムクロマトグラフィー
（クロロホルム：メタノール＝５：ｌ）で精製し、淡黄
色結晶の７−（３−アミノ−１−ピロリジニル） −６
，８−ジフルオロ−１，４−ジヒドロ−４−オキソ−１
−（プロブ−１−エン−２−イル）−キノリン−３−カ
ルボン酸（化合物１９）５２ｍｇを得る。Margin below Example 2 7-(3-amino-1-pyrrolidinyl)-6,8difluoro-1,4-dihydro-4-oxo-1-(prob-1-en-2-yl)-quinoline-3- Carboxylic acid: 7-(3-amino-1-pyrrolidinyl)-1-(I-chloroproa"-2-yl)-6,8 obtained in Example 1
-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (compound 1) 15
9mg (0.38mmole) in 20mf ethanol
Potassium hydroxide 65o+g (I,
15+n+wole) was added, and the mixture was allowed to react under heating and reflux for 14 hours, and then 3 tsi of water was added, and the mixture was heated and refluxed for 3 hours. After cooling, the reaction product was concentrated under reduced pressure, and the residue was washed with water and dried to obtain a crude product, which was further purified by silica gel column chromatography (chloroform:methanol = 5:l) to give pale yellow crystals of 7-(3- amino-1-pyrrolidinyl) -6
,8-difluoro-1,4-dihydro-4-oxo-1
52 mg of -(prob-1-en-2-yl)-quinoline-3-carboxylic acid (compound 19) is obtained.
本実施例と同様にして第２表の化合物２０〜３６を得た
。Compounds 20 to 36 in Table 2 were obtained in the same manner as in this example.
以下余白
参考例２
７−クロロ−６−フルオロ−１，４−ジヒドロ−１−（
Ｉ−ヒドロキシプロプ−２−イル）−４−オキソキノリ
ン−３−カルボン酸エチルエステル：７−クロロ−６−
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４．１１ ｇ （Ｉ５，３ｍ
ｍｏｌｅ）と無水炭酸カリウム６、３２ ｇ （４５，
７ｍｍｏｌｅ）をＮ、Ｎ−ジメチルホルムアミドＢＯｔ
ｍｌに懸濁させ、１２０°Ｃに加熱しなから１−（テト
ラヒドロ−２−ピラニルオキシ）２−メタンスルホニル
プロパン１０．９０ ｇ （４５，７ｍＩ１ｍｏ ｌｅ
）のＮ、Ｎ−ジメチルホルムアミド２０Ｉ２溶液を滴下
し、１０時間１２０°Ｃにて激しく攪拌する。The following margin reference example 2 7-chloro-6-fluoro-1,4-dihydro-1-(
I-hydroxyprop-2-yl)-4-oxoquinoline-3-carboxylic acid ethyl ester: 7-chloro-6-
Fluoro-1,4-dihydro-4oxoquinoline-3-
Carboxylic acid ethyl ester 4.11 g (I5,3m
mole) and anhydrous potassium carbonate 6.32 g (45,
7 mmole) in N,N-dimethylformamide BOt
10.90 g of 1-(tetrahydro-2-pyranyloxy)2-methanesulfonylpropane (45.7 ml of
) was added dropwise to the mixture, and the mixture was stirred vigorously at 120° C. for 10 hours.
反応物を濾過し、濾液を減圧濃縮した後、残渣に酢酸５
０ｍ２と水１０ｍ１を加え、６０°Ｃにて２時間加水分
解する。反応物を濾過し、濾液を減圧濃縮し、残渣をク
ロロホルムにて抽出し、クロロホルムを留去し残渣を得
る。得られた残渣をシリカゲルカラムクロマトグラフィ
ー（クロロホルム：メタノール＝２０７１）により精製
し、更に少鼠のクロロホルムから再結晶し、無色針状結
晶の７−クロロ−６−フルオロ−１，４−ジヒドロ−１
（Ｉ−ヒドロキシプロプ−２−イル）−４−オキソキノ
リン−３−カルボン酸エチルエステルを得る。融点２３
８〜２３９“Ｃ
ＩＲ（ＫＢｒ）：３３８０，１７２３゜１６１２ｃｍ−
’
’ＨＮＭＲ（ＣＤＣｊ２ｘ ） ｐｐｍ ：１．３６
（３１１，ｔ、Ｊ＝７．１１１ｚ） 、 １．６５（３
１１，ｄ、Ｊ＝６．８１１ｚ） 。After filtering the reaction product and concentrating the filtrate under reduced pressure, 5% acetic acid was added to the residue.
Add 0 m2 and 10 ml of water and hydrolyze at 60°C for 2 hours. The reaction product is filtered, the filtrate is concentrated under reduced pressure, the residue is extracted with chloroform, and the chloroform is distilled off to obtain a residue. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 2071) and further recrystallized from a small amount of chloroform to give colorless needle-like crystals of 7-chloro-6-fluoro-1,4-dihydro-1.
(I-Hydroxyprop-2-yl)-4-oxoquinoline-3-carboxylic acid ethyl ester is obtained. Melting point 23
8~239"C IR (KBr): 3380, 1723° 1612cm-
''HNMR (CDCj2x) ppm: 1.36
(311,t, J=7.111z), 1.65(3
11, d, J=6.811z).
２．４−２．８（ｉｌｌ、ｂｒ） 、３．８−４．２（
４１１，ｍ） 、４．６−５．０（Ｉ１１，ｎ＋）、７
．５１（ｌ１１．ｄ、Ｊ・９．２１１ｚ） 、７．７６
（ＩＩＩ、ｄ。2.4-2.8 (ill, br), 3.8-4.2 (
411,m), 4.6-5.0(I11,n+), 7
．． 51 (l11.d, J・9.211z), 7.76
(III, d.
Ｊ＝５．９ｔｌｚ）、８．５７（ＩＩＩ、ｓ）参考例３
７−クロロ−１−（Ｉ−クロロプロプ−２−イル）−６
−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：参考例２で得られた７
−クロロ−６−フルオロ−１，４−ジヒドロ−１−（Ｉ
−ヒドロキシプロプ−２−イル）−４−オキソキノリン
−３−カルボン酸エチルエステルを参考例１と同様に処
理して、無色プリズム品の７−クロロ−１−（Ｉ−りｏ
。J = 5.9tlz), 8.57 (III, s) Reference Example 3 7-chloro-1-(I-chloroprop-2-yl)-6
-Fluoro-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid ethyl ester: 7 obtained in Reference Example 2
-chloro-6-fluoro-1,4-dihydro-1-(I
-Hydroxyprop-2-yl)-4-oxoquinoline-3-carboxylic acid ethyl ester was treated in the same manner as in Reference Example 1 to obtain a colorless prism product of 7-chloro-1-(I-Rio
.
プロプ−２−イル）−６−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。融点１５１〜１５３°ＣＩＲ（ＫＢｒ）： １
７２５，１６１２ｃ＋ｎ−’ＩＨＮＭＲ（ＣＤＣ」（！
、 ） ｐｐｍ ：１．４２（３１１，ｔ、Ｊ＝７
．１ｌｌｚ） 、 １．７８（３１１，ｄ、Ｊ＝６．８
１１ｚ） 。Prop-2-yl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester is obtained. Melting point 151-153° CIR (KBr): 1
725,1612c+n-'IHNMR(CDC'(!
, ) ppm: 1.42 (311,t, J=7
．． 1llz), 1.78(311,d, J=6.8
11z).
３．８８（２１１，ｄ、Ｊ＝５．７１１ｚ）、４．４１
（２１１，ｑ、Ｊ＝７．１＋１２）、４．８−５．２（
Ｉ１！、Ｑ、 １ｉｋｅ）、７．６４（ＩＩＩ、ｄ、Ｊ
＝５．５Ｈｚ） 、８．２７（ＩＨ，ｄ、Ｊ＝９．０Ｉ
Ｉｚ） 、８．５６（ｆｉｌ、ｓ）実施例３
６−フルオロ−７−（４−メチル−１−ピペラジニル）
−１−（プロプ−１−エン−２−イル）−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：
参考例３で得られた７−クロロ−１−（Ｉ−クロロプロ
プ−２−イル）−６−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１と同様に処理して淡黄色結晶の６−フルオロ−７
−（４−メチル−１−ピペラジニル）−１−（プロプ−
１−エン−２−イル） −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（化合物３
７）を得る。3.88 (211, d, J=5.711z), 4.41
(211, q, J=7.1+12), 4.8-5.2(
I1! , Q, 1ike), 7.64 (III, d, J
=5.5Hz) ,8.27(IH,d,J=9.0I
Iz) , 8.56 (fil, s) Example 3 6-fluoro-7-(4-methyl-1-piperazinyl)
-1-(Prop-1-en-2-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester: 7-chloro-1-(I-chloropropyl) obtained in Reference Example 3 -2-yl)-6-fluoro-1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid ethyl ester was treated in the same manner as in Example 1 to obtain pale yellow crystals of 6-fluoro-7.
-(4-methyl-1-piperazinyl)-1-(prop-
1-en-2-yl) -1,4-dihydro-4-oxoquinoline-3=carboxylic acid ethyl ester (compound 3
7) is obtained.
本実施例と同様にして第３表の化合物３８〜４２を得た
。Compounds 38 to 42 in Table 3 were obtained in the same manner as in this example.
以下余白
実施例４
６−フルオロ−７−（４−メチル−１−ピペラジニル）
−１−（プロプ−１−エン−２−イル）−１，４−ジヒ
ドロ−４−オキソキノリン−３−カルボン酸：
実施例３で得られた６−フルオロ−７−（４メチル−１
−ピペラジニル）−１−（プロプ−ｌ−エン−２−イル
） −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（化合物３７ ） ２８ｍｇ
（０，０７８ｍｍｏｌｅ）を含水エタノール（エタノー
ル：水＝５：１）６ｍｊ！に溶解し、２Ｎ水酸化ナトリ
ウム水溶液０．１２ｎ／！を滴下し、加熱還流下３時間
加水分解する。反応物にＩＮ塩酸０．２＋／！を加え中
和した後、減圧濃縮し残渣を得、更に、残渣からメタノ
ールにて抽出し、メタノールを留去することにより淡黄
褐色の６−フルオロ−７−（４−メチル−１−ピペラジ
ニル）−１−（プロプ−１−エン−２−イル） −１，
４−ジヒドロ−４−オキソキノリン−３−カルボン酸（
化合物２９）を２４ｍｇ得る。Below is the blank space Example 4 6-fluoro-7-(4-methyl-1-piperazinyl)
-1-(Prop-1-en-2-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: 6-fluoro-7-(4methyl-1
-piperazinyl)-1-(prop-l-en-2-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (compound 37) 28 mg
(0,078 mmole) in 6 mj of hydrated ethanol (ethanol:water = 5:1)! Dissolved in 2N sodium hydroxide aqueous solution 0.12n/! was added dropwise and hydrolyzed under heating under reflux for 3 hours. IN hydrochloric acid 0.2+/! to the reactant! After neutralization, it was concentrated under reduced pressure to obtain a residue, which was further extracted with methanol, and the methanol was distilled off to obtain light yellowish brown 6-fluoro-7-(4-methyl-1-piperazinyl). -1-(prop-1-en-2-yl) -1,
4-dihydro-4-oxoquinoline-3-carboxylic acid (
24 mg of compound 29) is obtained.
Claims (1)
は低級アルキル基、Ｒ＿３は水素原子又はハロゲン原子
、Ｒ＿４及びＲ＿５は一緒になって他の異種原子を含ん
でもよく、また置換基を有していてもよい５〜６員環を
形成する。だたし、Ｒ＿１がメチル基、Ｒ＿２及びＲ＿
３が水素原子で、かつ▲数式、化学式、表等があります
▼がピペラジニル基である場合を除く） で表わされるキノロンカルボン酸誘導体及びその塩。 ２、次の一般式（Ｖ） ▲数式、化学式、表等があります▼（Ｖ） （式中、Ｒ＿１は低級アルキル基、Ｒ＿２＿−＿１は低
級アルキル基、Ｒ＿３は水素原子又はハロゲン原子、Ｘ
はハロゲン原子を示し、Ｒ＿４及びＲ＿５は一緒になっ
て他の異種原子を含んでもよく、また置換基を有してい
てもよい５〜６員環を形成する） で表わされるキノロンカルボン酸誘導体。[Claims] 1. The following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ (I) (In the formula, R_1 is a lower alkyl group, R_2 is a hydrogen atom or a lower alkyl group, R_3 is hydrogen Atom or halogen atom, R_4 and R_5 together form a 5- to 6-membered ring which may contain other heteroatoms and may have a substituent.However, R_1 is a methyl group, R_2 and R_
Quinolone carboxylic acid derivatives and their salts, where 3 is a hydrogen atom and ▲a numerical formula, chemical formula, table, etc. is included, except when ▼ is a piperazinyl group). 2. The following general formula (V) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) (In the formula, R_1 is a lower alkyl group, R_2_-_1 is a lower alkyl group, R_3 is a hydrogen atom or a halogen atom,
represents a halogen atom, and R_4 and R_5 together form a 5- to 6-membered ring which may contain other heteroatoms and may have a substituent.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019910701725A KR920701163A (en) | 1988-08-08 | 1990-03-29 | Quinolone Carboxylic Acid Derivatives |
| US07/807,856 US5324735A (en) | 1989-07-21 | 1990-03-29 | Quinoline carboxylic acid derivatives |
| PCT/JP1990/000425 WO1991001308A1 (en) | 1989-07-21 | 1990-03-29 | Quinolonecarboxylic acid derivatives |
| CA002058424A CA2058424A1 (en) | 1989-07-21 | 1990-03-29 | Quinoline carboxylic acid derivatives |
| EP19900905660 EP0486687A4 (en) | 1989-07-21 | 1990-03-29 | Quinolonecarboxylic acid derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19773588 | 1988-08-08 | ||
| JP63-197735 | 1988-08-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02138261A true JPH02138261A (en) | 1990-05-28 |
| JP2526128B2 JP2526128B2 (en) | 1996-08-21 |
Family
ID=16379470
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1189214A Expired - Fee Related JP2526128B2 (en) | 1988-08-08 | 1989-07-21 | Quinolonecarboxylic acid derivative |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JP2526128B2 (en) |
| KR (1) | KR920701163A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5630964A (en) * | 1979-08-22 | 1981-03-28 | Kyorin Pharmaceut Co Ltd | Novel substituted quinolinecarboxylic acid and its preparation |
| JPS6230776A (en) * | 1985-08-01 | 1987-02-09 | Dainippon Pharmaceut Co Ltd | Quinoline derivative, ester and salt thereof |
| JPS62207258A (en) * | 1986-03-06 | 1987-09-11 | Toyama Chem Co Ltd | Novel quinoline derivative and salt thereof |
-
1989
- 1989-07-21 JP JP1189214A patent/JP2526128B2/en not_active Expired - Fee Related
-
1990
- 1990-03-29 KR KR1019910701725A patent/KR920701163A/en not_active Application Discontinuation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5630964A (en) * | 1979-08-22 | 1981-03-28 | Kyorin Pharmaceut Co Ltd | Novel substituted quinolinecarboxylic acid and its preparation |
| JPS6230776A (en) * | 1985-08-01 | 1987-02-09 | Dainippon Pharmaceut Co Ltd | Quinoline derivative, ester and salt thereof |
| JPS62207258A (en) * | 1986-03-06 | 1987-09-11 | Toyama Chem Co Ltd | Novel quinoline derivative and salt thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR920701163A (en) | 1992-08-11 |
| JP2526128B2 (en) | 1996-08-21 |
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