JPS63166876A - Pyridonecarboxylic acid derivative - Google Patents
Pyridonecarboxylic acid derivativeInfo
- Publication number
- JPS63166876A JPS63166876A JP61311992A JP31199286A JPS63166876A JP S63166876 A JPS63166876 A JP S63166876A JP 61311992 A JP61311992 A JP 61311992A JP 31199286 A JP31199286 A JP 31199286A JP S63166876 A JPS63166876 A JP S63166876A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- ethyl
- formula
- distilled
- water
- 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
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 7
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract description 6
- 229910052701 rubidium Inorganic materials 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 229910052705 radium Inorganic materials 0.000 claims abstract description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 3
- 229920002554 vinyl polymer Chemical group 0.000 claims abstract description 3
- -1 monofluorophenyl Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 2
- 125000004212 difluorophenyl group Chemical group 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 2
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 claims 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- 208000035473 Communicable disease Diseases 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 24
- 239000002904 solvent Substances 0.000 abstract description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 abstract description 7
- 125000001424 substituent group Chemical group 0.000 abstract description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 5
- FKCMADOPPWWGNZ-YUMQZZPRSA-N [(2r)-1-[(2s)-2-amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O FKCMADOPPWWGNZ-YUMQZZPRSA-N 0.000 abstract description 4
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 abstract description 2
- 125000006414 CCl Chemical group ClC* 0.000 abstract description 2
- 150000001412 amines Chemical class 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract description 2
- 150000002367 halogens Chemical class 0.000 abstract description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 abstract description 2
- 125000001207 fluorophenyl group Chemical group 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 239000013078 crystal Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 230000000844 anti-bacterial effect Effects 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000010446 mirabilite Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- AWRBCMYGSHMVHB-UHFFFAOYSA-N 4-acetyl-1-benzylpyrrolidin-2-one Chemical compound O=C1CC(C(=O)C)CN1CC1=CC=CC=C1 AWRBCMYGSHMVHB-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 5
- QQWYQAQQADNEIC-RVDMUPIBSA-N tert-butyl [(z)-[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)O\N=C(/C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-RVDMUPIBSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102100034741 Cyclin-dependent kinase 20 Human genes 0.000 description 3
- 101500014379 Lymnaea stagnalis Ovulation hormone Proteins 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- HJUZGKGDCUOVML-UHFFFAOYSA-N tert-butyl n-(1-pyrrolidin-3-ylethyl)carbamate Chemical compound CC(C)(C)OC(=O)NC(C)C1CCNC1 HJUZGKGDCUOVML-UHFFFAOYSA-N 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- ZXVOCOLRQJZVBW-UHFFFAOYSA-N azane;ethanol Chemical compound N.CCO ZXVOCOLRQJZVBW-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000031891 intestinal absorption Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NDCFBPDNHOZORS-UHFFFAOYSA-N 1,2-dihydroquinoline-3-carboxylic acid Chemical compound C1=CC=C2NCC(C(=O)O)=CC2=C1 NDCFBPDNHOZORS-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CGPHGPCHVUSFFA-UHFFFAOYSA-N 1-(4-methylphenyl)sulfonylpyrrolidine-2-carboxylic acid Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C(C(O)=O)CCC1 CGPHGPCHVUSFFA-UHFFFAOYSA-N 0.000 description 1
- VYKQDWPBYULGPF-UHFFFAOYSA-N 1-benzyl-5-oxopyrrolidine-3-carboxylic acid Chemical compound O=C1CC(C(=O)O)CN1CC1=CC=CC=C1 VYKQDWPBYULGPF-UHFFFAOYSA-N 0.000 description 1
- FKKUVCHFRDLBHN-UHFFFAOYSA-N 1-ethyl-6,7,8-trifluoro-4-oxoquinoline-3-carboxylic acid Chemical compound FC1=C(F)C(F)=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 FKKUVCHFRDLBHN-UHFFFAOYSA-N 0.000 description 1
- VUFNLQXQSDUXKB-DOFZRALJSA-N 2-[4-[4-[bis(2-chloroethyl)amino]phenyl]butanoyloxy]ethyl (5z,8z,11z,14z)-icosa-5,8,11,14-tetraenoate Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)OCCOC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 VUFNLQXQSDUXKB-DOFZRALJSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- RVDLHGSZWAELAU-UHFFFAOYSA-N 5-tert-butylthiophene-2-carbonyl chloride Chemical compound CC(C)(C)C1=CC=C(C(Cl)=O)S1 RVDLHGSZWAELAU-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 206010024971 Lower respiratory tract infections Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000287531 Psittacidae Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 241001148470 aerobic bacillus Species 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- WHQLQYRFIHPMNA-UHFFFAOYSA-N ethyl acetate;oxolane Chemical compound C1CCOC1.CCOC(C)=O WHQLQYRFIHPMNA-UHFFFAOYSA-N 0.000 description 1
- UKFXDFUAPNAMPJ-UHFFFAOYSA-N ethylmalonic acid Chemical compound CCC(C(O)=O)C(O)=O UKFXDFUAPNAMPJ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002576 ketones Chemical group 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000010865 sewage Substances 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000829 suppository Substances 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
- QQWYQAQQADNEIC-UHFFFAOYSA-N tert-butyl [[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)ON=C(C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 208000000143 urethritis Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
[産業上の利用分野]
本発明は極めて強い抗菌力と優れた体内動態を有する化
合物に関するものである。[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a compound having extremely strong antibacterial activity and excellent pharmacokinetics.
[従来の技術]
これまでに抗菌性を有する化合物については種々の検討
が行われており、特開昭59−67269号公報および
特開昭60−214773号公報には、抗菌性を有する
物質としてピリドンカルボン酸誘導体に属する広範な化
合物群が特許請求の範囲に記載されている。そして、好
ましい化合物として、式:においてXがN、 CHまた
はCFであり、Yがフッ素、R1がエチル、2−フルオ
ロエチル、シクロプロピルである化合物が記載されてい
る。[Prior Art] Various studies have been conducted on compounds having antibacterial properties, and Japanese Patent Application Laid-Open Nos. 59-67269 and 60-214773 disclose compounds having antibacterial properties. A wide group of compounds belonging to the pyridone carboxylic acid derivatives are claimed. As preferred compounds, compounds in which X is N, CH, or CF, Y is fluorine, and R1 is ethyl, 2-fluoroethyl, or cyclopropyl are described as preferred compounds.
しかし、抗菌力および物理化学的性質に大きく影響する
塩基性置換基2のうち、最も好ましいものとしてピロリ
ジン基を有するものとしては、特開昭59−67279
号の実施例11(化合物のコード名Cl−934)およ
び特開昭60−214773号の実施例43〜47(実
施例44の化合物hjP+)−111558、第26回
I CAAC抄録参照)に、
(式中R2およびB、は水素または低級アルキル)で表
わされる基を有する化合物を示しである。しかし、Cl
−934はダラム陰性菌に対する抗菌力が、PD−11
7558は緑膿菌に対する抗菌力が不充分であり、未だ
満足とは言い難い。However, among the basic substituents 2 that greatly influence antibacterial activity and physicochemical properties, those having a pyrrolidine group as the most preferable one are disclosed in JP-A No. 59-67279.
No. 11 (compound code name Cl-934) and Examples 43 to 47 (compound hjP+ of Example 44)-111558 of JP-A-60-214773 (see the 26th I CAAC abstract). In the formula, R2 and B represent a compound having a group represented by hydrogen or lower alkyl. However, Cl
-934 has antibacterial activity against Durham-negative bacteria compared to PD-11.
7558 has insufficient antibacterial activity against Pseudomonas aeruginosa and is still far from satisfactory.
[発明の目的]
本発明は、好気性菌はもとより、嫌気性菌に対しても優
れた抗菌力を有するとともに水に対する溶解性が高く、
腸管吸収性および代謝的安定性に優れた化合物を提供す
ることを目的とする。[Object of the invention] The present invention has excellent antibacterial activity against aerobic bacteria as well as anaerobic bacteria, and has high solubility in water.
The purpose of the present invention is to provide a compound with excellent intestinal absorption and metabolic stability.
[目的を達成するための手段]
本発明者は、ピリドンカルボン酸誘導体において、一般
式:
で示される基を有し、この式中少なくともRbまたはR
cのいずれか一方が低級アルキル基である化合物、特に
この置換基と1位置換基の種類および8位の原子の種類
の組合せにより、ざらに左旋性の光学活性体が、強力な
抗菌作用と良好な水溶性を兼ねそなえた化合物であるこ
とを見出し、本発明の目的を達成することができた。[Means for achieving the object] The present inventor has discovered that a pyridonecarboxylic acid derivative has a group represented by the general formula: In this formula, at least Rb or R
Compounds in which either one of c is a lower alkyl group, especially the combination of this substituent, the type of substituent at the 1-position, and the type of the atom at the 8-position, give a roughly levorotatory optically active substance with strong antibacterial activity. It was discovered that the compound has good water solubility, and the object of the present invention was achieved.
[発明の構成]
本発明は、一般式
(式中、RaおよびRbはそれぞれ水素または低級アル
キルを、Rcは低級アルキルを意味する。またRbはR
aまたはRcと(CH2)llで表わされるメチレン鎖
(nは2〜5)を形成してもよい、 Rdはエチル、2
−フルオロエチル、ビニル、イソプロピル、イソプロペ
ニル、シクロプロピル、モノフルオロフェニルまたはジ
フルオロフェニルを意味する。qはCHlC−F、 C
−ClまたはNである)で表わされる化合物およびその
塩に関する。[Structure of the Invention] The present invention is based on the general formula (wherein Ra and Rb each represent hydrogen or lower alkyl, Rc represents lower alkyl, and Rb represents R
a or Rc may form a methylene chain (n is 2 to 5) represented by (CH2)ll, Rd is ethyl, 2
- means fluoroethyl, vinyl, isopropyl, isopropenyl, cyclopropyl, monofluorophenyl or difluorophenyl. q is CHlC-F, C
-Cl or N) and salts thereof.
ここで、低級アルキル基としては炭素数1〜6のもの、
特にメチルおよびエチルが適当である。Here, the lower alkyl group has 1 to 6 carbon atoms,
Particularly suitable are methyl and ethyl.
また、RbとRcとで炭素数2〜5のメチレン鎖を形成
するものおよびRaとRbとで炭素数2〜4のメチレン
鎖を形成するものも好ましい、 Rdとしてはエチル、
シクロプロピル、2.4−ジフルオロフェニルが好まし
く、qとしてはC−H%C−F、 C−ClまたはNが
好ましい。Also preferred are those in which Rb and Rc form a methylene chain having 2 to 5 carbon atoms, and those in which Ra and Rb form a methylene chain having 2 to 4 carbon atoms; Rd is ethyl;
Cyclopropyl and 2,4-difluorophenyl are preferred, and q is preferably C-H%C-F, C-Cl or N.
本発明の化合物の塩としては、塩酸、硫酸、メタンスル
ホン酸の如き無機酸もしく有機酸との塩あるいはカルボ
ン酸のナトリウム塩やカルシウム塩の如きアルカリ金属
塩もしくはアルカリ土類金属塩等が例示される。さらに
本発明化合物は水和物としても存在し得る。Examples of the salts of the compounds of the present invention include salts with inorganic or organic acids such as hydrochloric acid, sulfuric acid, and methanesulfonic acid, and alkali metal salts or alkaline earth metal salts such as sodium salts and calcium salts of carboxylic acids. be done. Furthermore, the compounds of the present invention may also exist as hydrates.
本発明の化合物は、次に例示する方法により合成可能で
ある。すなわち、一般式[11]:(式中、Rdおよび
Qは前記に同じ、Xsはアミンと求核置換され得る置換
基、たとえばハロゲン、メタンスルホニル基等を意味す
る)
で表わされる化合物に、一般式[HI3:(式中、Ra
%Rb及びRcは前記に同じ)で表わせれるピロリジン
誘導体を反応させて製造することがで籾る。The compound of the present invention can be synthesized by the method exemplified below. That is, a compound represented by the general formula [11]: (wherein Rd and Q are the same as above, and Xs means a substituent that can be nucleophilically substituted with an amine, such as a halogen, methanesulfonyl group, etc.) Formula [HI3: (wherein, Ra
%Rb and Rc are the same as above).
この反応は、アセトニトリル、テトラヒドロフラン (
T)IF)、エタノール、クロロホルム、ジメチルスル
ホキシド (DMSO)、ジメチルホルムアミド(DM
F) 、ピリジン、ピコリン、水などの非反応性溶媒の
存在下において約20°〜約150℃の温度で行うのが
よい。This reaction consists of acetonitrile, tetrahydrofuran (
T)IF), ethanol, chloroform, dimethyl sulfoxide (DMSO), dimethylformamide (DM
F) is preferably carried out at a temperature of about 20 DEG to about 150 DEG C. in the presence of a non-reactive solvent such as pyridine, picoline, water, etc.
一般式[III ]で表わされるピロリジン誘導体は例
えば次の方法により合成される。The pyrrolidine derivative represented by the general formula [III] can be synthesized, for example, by the following method.
すなわち、公知化合物の1−ベンジル−4−カルボキシ
−2−ピロリドンを塩化チオニルと処理して酸クロリド
とし、さらにメルドラム酸と反応させ、次いで脱炭酸し
て4−アセチル体に誘導する。そのアセチル基のケトン
部分をヒドロキシルアミンでオキシムとした後、ラネー
ニッケルで接触還元して4−(l−アミノエチルit−
ベンジルー2−ピロリドンを得る。これを2−[第三級
ブトキシカルボニルオキシイミノ]−2−フェニルアセ
トニトリル (以下Boc−ONと略示する)で第三級
ブトキシカルボニル化(Boc化)し、この化合物を、
高速液体クロマトグラフィー(HPLC)または分別再
結晶で二種の立体異性体に分離する。その一方をトリフ
ルオロ酢酸(TF^)で処理して脱Boc化する。得ら
れる第一級アミノ体に、N−バラトルエンスルホニルプ
ロリンの酸クロライドを作用させた後カラムクロマトグ
ラフィーで光学分割する。得られる光学活性体を塩基で
処理してトシルプロリンをはずした後、水素化アルミニ
ウムリチウムでピロリジン環のアミドを還元し、さらに
第一級アミン部分をBoc化して保護後、パラジウム−
炭素等で脱ベンジル化して、光学活性の3−(1−第三
級ブトキシカルボニルアミノ)エチルピロリジンを得る
。That is, the known compound 1-benzyl-4-carboxy-2-pyrrolidone is treated with thionyl chloride to form an acid chloride, which is further reacted with Meldrum's acid, and then decarboxylated to derive a 4-acetyl form. The ketone moiety of the acetyl group was made into an oxime with hydroxylamine, and then catalytically reduced with Raney nickel to 4-(l-aminoethyl it-
Benzyl-2-pyrrolidone is obtained. This was tertiary-butoxycarbonylated (Boc-formed) with 2-[tert-butoxycarbonyloxyimino]-2-phenylacetonitrile (hereinafter abbreviated as Boc-ON), and this compound was
It is separated into two stereoisomers by high performance liquid chromatography (HPLC) or fractional recrystallization. One of them is treated with trifluoroacetic acid (TF^) to remove Boc. The obtained primary amino compound is treated with acid chloride of N-balatoluenesulfonylproline, and then optically resolved by column chromatography. After treating the obtained optically active substance with a base to remove tosylproline, the amide of the pyrrolidine ring was reduced with lithium aluminum hydride, the primary amine moiety was protected by Boc conversion, and palladium-
Debenzylation with carbon or the like yields optically active 3-(1-tert-butoxycarbonylamino)ethylpyrrolidine.
なお、上記の本発明の製造方法において、一般式[II
I ]で表わされるピロリジン誘導体のアミノ基を、反
応に対して実質的に不活性なように保護してもよい。こ
のような保護基としては、ホルミル、アセチル、トリフ
ルオロアセチルなどのアシル基;エトキシカルボニル、
第三級ブトキシカルボニル(Boc)などの炭素数2〜
6のアルコキシカルボニル基:ベンジルオキシカルボニ
ル、p−メトキシベンジルオキシカルボニル、フェノキ
シカルボニルなどのアリールオキシカルボニル:トリメ
チルシリルなとのシリル基ニトリチル、テトラヒドロピ
ラニル、ビニルオキシカルボニル、0−ニトロフェニル
スルフェニル、ジフェニルホスフィニル、p−トルエン
スルホニル及びベンジルなどの基が例示される。これら
の保護基は、反応後所望により酸または塩基加水分解な
どの公知の方法により除去できる。In addition, in the manufacturing method of the present invention described above, general formula [II
The amino group of the pyrrolidine derivative represented by I] may be protected so as to be substantially inert to the reaction. Such protecting groups include acyl groups such as formyl, acetyl, trifluoroacetyl; ethoxycarbonyl,
2 or more carbon atoms such as tertiary butoxycarbonyl (Boc)
Alkoxycarbonyl group of 6: Aryloxycarbonyl such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, phenoxycarbonyl: Silyl group such as trimethylsilyl, nitrityl, tetrahydropyranyl, vinyloxycarbonyl, 0-nitrophenylsulfenyl, diphenylphos Examples include groups such as finyl, p-toluenesulfonyl and benzyl. These protecting groups can be removed by known methods such as acid or base hydrolysis after the reaction, if desired.
次に参考例および実施例により説明するが、これにより
本発明は限定されるものではない。Next, the present invention will be explained using reference examples and examples, but the present invention is not limited thereto.
考仔1:4−アセチルー1−ベンジル−2−ピロリドン
(1)
l−ベンジル−4−カルボキシ−2−ピロリドン4.4
gに塩化チオニル10m1.ジオキサン30m1を加え
、90〜100℃で30分加熱攪拌した後、溶媒および
過剰の塩化チオニルを減圧留去すると酸クロリドの残漬
が得られる。1: 4-acetyl-1-benzyl-2-pyrrolidone (1) l-benzyl-4-carboxy-2-pyrrolidone 4.4
g and 10 ml of thionyl chloride. After adding 30 ml of dioxane and heating and stirring at 90 to 100°C for 30 minutes, the solvent and excess thionyl chloride are distilled off under reduced pressure to obtain a residue of acid chloride.
無水エーテル40+alに、マグネシウムエトキシド2
.5gおよびマロン酸エチル3.5gを加え、1時間半
還流し、得た溶液を水冷下で攪拌しつつ、上記酸クロリ
ドのエーテル溶液を滴下する。滴下後1時間還流し、水
冷下、過剰の希硫酸を加え弱酸性とし、エーテル抽出し
乾燥する。Magnesium ethoxide 2 in 40+ al of anhydrous ether
.. 5 g and 3.5 g of ethyl malonate were added, and the mixture was refluxed for 1.5 hours. While stirring the resulting solution under water cooling, the above ether solution of acid chloride was added dropwise. After dropping, the mixture is refluxed for 1 hour, and while cooling with water, an excess of dilute sulfuric acid is added to make it weakly acidic, followed by extraction with ether and drying.
溶媒留去後、残渣に酢酸10a+1、水45m1、濃硫
酸1mlを加え、5時間速流した後、溶媒を減圧留去す
る。残漬をクロロホルムに溶解し、10*塩酸、飽和炭
酸水素ナトリウムで順次洗浄後乾燥し、溶媒を留去する
と、上記化合物(1)3.3gが油状物として得られた
。After evaporating the solvent, 10a+1 acetic acid, 45 ml of water, and 1 ml of concentrated sulfuric acid were added to the residue, and after 5 hours of rapid flow, the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform, washed successively with 10* hydrochloric acid and saturated sodium bicarbonate, dried, and the solvent was distilled off to obtain 3.3 g of the above compound (1) as an oil.
NMR(CDC13)δppm : 2.2(3H,
s)2.66 (2H,d、J−7,2Hz)、3.0
〜3.6 (3H,n)4.32,4.52(各々IH
,d、J=14Hx、AB−q) 、 7.29 (5
H,s)化合物(1) 3.3gおよび塩酸ヒドロキシ
ルアミン2.5gにピリジン15o+1を加え、90℃
で5時間加熱する。水を加え、塩酸酸性とした後、ジク
ロルメタンで抽出する。ジクロルメタンを留去し、得た
残漬をシリカゲル30gのカラムクロマトグラフィーに
付し、メタノール−クロロホルム(1:20)で溶出し
、上記化合物(2) 2.6gを粉末として得た。NMR (CDC13) δppm: 2.2 (3H,
s) 2.66 (2H, d, J-7, 2Hz), 3.0
~3.6 (3H, n) 4.32, 4.52 (IH
, d, J=14Hx, AB-q), 7.29 (5
H,s) Pyridine 15o+1 was added to 3.3 g of compound (1) and 2.5 g of hydroxylamine hydrochloride, and the mixture was heated at 90°C.
Heat for 5 hours. Add water and acidify with hydrochloric acid, then extract with dichloromethane. Dichloromethane was distilled off, and the resulting residue was subjected to column chromatography using 30 g of silica gel and eluted with methanol-chloroform (1:20) to obtain 2.6 g of the above compound (2) as a powder.
NMR(CDC13)δppm : 1.8(3H,s
)2.62 (2)1.d、J−7,2H1)、2.9
〜3.6 (3)1.m)4.44(2H,S)、7.
28(5H,s)オキシム体(2) 69.3g、ラネ
ーニッケル20m1およびメタノール700m1を混合
し水素気流下8時間娠盪する。触媒を濾去しメタノール
を減圧留去し淡黄色油状物(3)84gを得た。NMR (CDC13) δppm: 1.8 (3H, s
)2.62 (2)1. d, J-7, 2H1), 2.9
~3.6 (3)1. m) 4.44 (2H, S), 7.
69.3 g of 28(5H,s) oxime (2), 20 ml of Raney nickel and 700 ml of methanol were mixed and stirred for 8 hours under a hydrogen stream. The catalyst was filtered off and methanol was distilled off under reduced pressure to obtain 84 g of pale yellow oil (3).
JINMR(CDCH3) δppm : 0.09
(3H,d、J−7Hz)、1.08 (3H,d、J
−7Hz)、1.96 (3H,s)、2.0〜2.6
(3)1.m) 、2.6〜3.5 (3H,m)、
4.42 (2H,s)、7.28(5)1.S)アミ
ノ体(3) 84.0gをテトラヒドロフラン600m
1に溶解し、Boc−ON 72.2gを加え70分攪
拌する。溶媒を留去し、残漬を酢酸エチル1λに溶解す
る。JINMR (CDCH3) δppm: 0.09
(3H, d, J-7Hz), 1.08 (3H, d, J
-7Hz), 1.96 (3H, s), 2.0 to 2.6
(3)1. m), 2.6 to 3.5 (3H, m),
4.42 (2H, s), 7.28 (5) 1. S) Amino body (3) 84.0g in tetrahydrofuran 600m
1, add 72.2 g of Boc-ON, and stir for 70 minutes. The solvent was distilled off, and the residue was dissolved in 1λ of ethyl acetate.
0.2N水酸化ナトリウム液、飽和食塩水で洗浄後有機
層を芒硝にて乾燥する。溶媒を留去し残漬にn−ヘキサ
ンを加えると固化する。濾取後石油エーテルで洗い67
.0gの粉末を得た。After washing with 0.2N sodium hydroxide solution and saturated brine, the organic layer was dried with sodium sulfate. When the solvent is distilled off and n-hexane is added to the residue, it solidifies. After filtering, wash with petroleum ether67
.. 0 g of powder was obtained.
エーテルより再結晶すると23.7gの異性体4Aを融
点138℃の無色針状晶として得た。母液をエーテルで
再結晶をくり返し12.9gの異性体4Bを融点139
〜141 t:の無色プリズム晶として得た。4Aおよ
び4BはHPLCにて阜−のピークを示す。Recrystallization from ether gave 23.7 g of isomer 4A as colorless needles with a melting point of 138°C. Repeated recrystallization of the mother liquor with ether yielded 12.9 g of isomer 4B with a melting point of 139.
~141t: Obtained as colorless prism crystals. 4A and 4B show black peaks in HPLC.
カラム:ヌクレオシル50−5 20X 250mm溶
媒:酢酸エチル−THF(95:5)、流速: 5a+
l/分
保持時間: 4A 4B、5分 4B 52.5分’H
−NMR(CDC1a) δppm :4A 1.
06(3H,d、J−7H2)、1.42(9H,S)
2.2〜2.7(2H,l11) 、2.9〜3.5
(2Lm)、3.5〜3.9(IH,IB) 、 4.
3〜4.5 (1)1.m)、4.46(2H,八〇−
q、 J−16)1z)、7.35 (58,m)4B
1.09(3H,d、J−7H2)、1.42(9
H,s)2.1〜2.6(2H,m) 、2.8〜3.
4 (2H,m)、3.4〜3.8(LH,l) 、4
.L 〜4.4 (18,l)、4.48(2B、AB
−q、J−16Hz)、7.37(5H,m)Boc体
(4B)8.0gを水冷下トリフロロ酢酸50m1に加
えた後、室温で1時間攪拌する。トリフロロ酢酸を減圧
留去する。残漬に水50m1を加えNaHCO,で中和
する。クロロホルム抽出し、Na、SO,乾燥後溶媒を
留去し5.5gの無色油状物(5B)を得た。Column: Nucleosil 50-5 20X 250mm Solvent: Ethyl acetate-THF (95:5), Flow rate: 5a+
l/min holding time: 4A 4B, 5 min 4B 52.5 min'H
-NMR (CDC1a) δppm: 4A 1.
06 (3H, d, J-7H2), 1.42 (9H, S)
2.2-2.7 (2H, l11), 2.9-3.5
(2Lm), 3.5-3.9 (IH, IB), 4.
3-4.5 (1)1. m), 4.46 (2H, 80-
q, J-16) 1z), 7.35 (58, m) 4B
1.09 (3H, d, J-7H2), 1.42 (9
H, s) 2.1-2.6 (2H, m), 2.8-3.
4 (2H, m), 3.4-3.8 (LH, l), 4
.. L ~4.4 (18, l), 4.48 (2B, AB
-q, J-16Hz), 7.37 (5H, m) Boc form (4B) 8.0 g was added to 50 ml of trifluoroacetic acid under water cooling, and then stirred at room temperature for 1 hour. Trifluoroacetic acid is distilled off under reduced pressure. Add 50ml of water to the residue and neutralize with NaHCO. After extraction with chloroform, Na, SO, and drying, the solvent was distilled off to obtain 5.5 g of colorless oil (5B).
’11−NMR(CDCH、) δppm : 1.
05(3H,d、J−7)1z)、1.24(2H,S
)、2.0〜2.5 (3H,m) 、2.6〜3.
0 (IH,m)、3.0〜3.5 (2H,m)
、4.45 (2H,s)、7.211(5H,5)
(S) −?1−p−トルエンスルホニルプロリン2.
5g、塩化チオニル2.1ff11およびベンゼン20
m1を混合し5時間加熱還流する。ベンゼンを留去し残
渣にベンゼンを加え留去をくり返しく3回)酸クロリド
を油状物として得る。'11-NMR (CDCH,) δppm: 1.
05 (3H, d, J-7) 1z), 1.24 (2H, S
), 2.0-2.5 (3H, m), 2.6-3.
0 (IH, m), 3.0-3.5 (2H, m)
, 4.45 (2H, s), 7.211 (5H, 5)
(S) -? 1-p-toluenesulfonylproline2.
5g, thionyl chloride 2.1ff11 and benzene 20
Mix m1 and heat under reflux for 5 hours. Benzene is distilled off, benzene is added to the residue, and the distillation is repeated three times) to obtain acid chloride as an oil.
4−アミノエチル体(5B) 3.55gとピリジン1
.1mlをジクロルメタン15m1に溶解し、これに室
温攪拌下、上記酸クロリドをジクロルメタン15ffl
!に溶解し滴下する。24時間後反応液を2N塩酸、水
、2N水酸化ナトリウム、水の順で洗浄し芒硝乾燥後溶
媒留去し黄色油状物を得た。このものはシリカゲルTL
C(酢酸エチル−メタノール95:5)で1:1の混合
物(Rf O,29およびRf O,26)であること
が認められたのでシリカゲル100gのカラムに付し、
酢酸工チル−メタノール(95:5)で溶出して得られ
る各異性体を酢酸エチル−〇−ヘキサンにて再結晶した
。4-aminoethyl compound (5B) 3.55g and pyridine 1
.. Dissolve 1 ml in 15 ml of dichloromethane, and add the above acid chloride to 15 ffl of dichloromethane while stirring at room temperature.
! Dissolve and drip. After 24 hours, the reaction solution was washed with 2N hydrochloric acid, water, 2N sodium hydroxide, and water in this order, dried over sodium sulfate, and the solvent was distilled off to obtain a yellow oil. This one is silica gel TL
Since it was found to be a 1:1 mixture (Rf O, 29 and Rf O, 26) with C (ethyl acetate-methanol 95:5), it was applied to a column of 100 g of silica gel.
Each isomer obtained by elution with ethyl acetate-methanol (95:5) was recrystallized from ethyl acetate-〇-hexane.
異性体6a 870mg、融点96〜98℃ TLC
Rf−0,29、[α] D−91,3°(c−0,5
15、クロロホルム)異性体6b 820mg、融点1
26〜132℃TLCRf−0,26[α] D −
136,0” (c−0,350,クロロホルム)’
H−NMR(CDCh)δppIIl:6a 1.1
9(3H,d、J=7Hz)、1.4〜1.8(3H,
m)1.8〜2.2(2H,m) 、2.44(3H,
m)、2.28〜2.8(2H,a+) 、3.0〜3
.4 (3H,m)、3.4〜3.7(ill、m)
、3.9〜4.2(2H,m)、4.50(2H,八B
−q、J=16Hz)、6.88 (IH,d、 J−
8)1z)7.28(5H,s)、7.44 (2H,
d、J−7Hz)、7.70(2H,d、J=7Hz)
6b 1.15(3H,d、J−782)、1.4〜
1.9(41(、m)2.0〜2.8(3H,m) 、
2.45(3H,s)、3.0〜3.4(2H,m)
、3.4〜3.8 (2H,m)、4.45(2H,^
B−q、J−16Hx)、6.138 (IH、d 、
J−8)IZ)7.39 (5)1.s)、7.44
(2H,d、J−7Hz)、7.89 (2H,d、J
−78x)
参考例7 : (−)−4−(1−アミノエチル)−1
−ベンジ異性体(6b) 1.08g、 15に水酸化
ナトリウム10m1゜エタノール30111を混合し3
日間加熱速流する。Isomer 6a 870 mg, melting point 96-98°C TLC
Rf-0,29, [α] D-91,3° (c-0,5
15, chloroform) isomer 6b 820 mg, melting point 1
26-132°C TLCRf-0,26[α]D-
136,0" (c-0,350, chloroform)'
H-NMR (CDCh) δppIIl:6a 1.1
9 (3H, d, J=7Hz), 1.4-1.8 (3H,
m) 1.8-2.2 (2H, m), 2.44 (3H,
m), 2.28-2.8 (2H, a+), 3.0-3
.. 4 (3H, m), 3.4-3.7 (ill, m)
, 3.9-4.2 (2H, m), 4.50 (2H, 8B
-q, J=16Hz), 6.88 (IH, d, J-
8) 1z) 7.28 (5H, s), 7.44 (2H,
d, J-7Hz), 7.70 (2H, d, J=7Hz) 6b 1.15 (3H, d, J-782), 1.4~
1.9 (41 (, m) 2.0 to 2.8 (3H, m),
2.45 (3H, s), 3.0-3.4 (2H, m)
, 3.4-3.8 (2H, m), 4.45 (2H, ^
B-q, J-16Hx), 6.138 (IH, d,
J-8) IZ) 7.39 (5)1. s), 7.44
(2H, d, J-7Hz), 7.89 (2H, d, J
-78x) Reference example 7: (-)-4-(1-aminoethyl)-1
-benziisomer (6b) 1.08g, 15 mixed with 10ml of sodium hydroxide and 30111 ethanol 3
Heat fast for days.
エタノールを濃縮しクロロホルム抽出後芒硝乾燥し溶媒
を留去し480mgの無色油状物(7b)を得た。Ethanol was concentrated, extracted with chloroform, dried over Glauber's salt, and the solvent was distilled off to obtain 480 mg of a colorless oil (7b).
[α] 、 −4,6″″(c−2,0、クロロホルム
)異性体(8a) t、og、8水酸化ナトリウム10
m1、エタノール30m1を混合し上記と同様に反応し
無色油状物(7a) 430Bを得た。[α], -4,6″″ (c-2,0, chloroform) isomer (8a) t, og, 8 sodium hydroxide 10
ml and 30 ml of ethanol were mixed and reacted in the same manner as above to obtain colorless oil (7a) 430B.
[al o + 4.4” (c−2,o、クロロホル
ム)’H−NMR(CDCHs) δppm ニアa
、7b 1.05(3H,d、J−7)1z)、1.2
4(2H,S)2.0〜2.6(3H,a+) 、 2
.6〜3.0(IH,m)3.0〜3.5(2H,m)
、4.45(2H,s)、7.28(5H,s)
(+)アミノ体(7a) 345mgをTHF 30m
1に溶解しこれにBoc−ON 389mgを加え3日
間放置する。溶媒を減圧留去し、残漬を酢酸エチル50
m1に溶解する。[al o + 4.4” (c-2, o, chloroform)'H-NMR (CDCHs) δppm Near a
, 7b 1.05 (3H, d, J-7) 1z), 1.2
4 (2H, S) 2.0 to 2.6 (3H, a+), 2
.. 6-3.0 (IH, m) 3.0-3.5 (2H, m)
, 4.45 (2H, s), 7.28 (5H, s) (+) 345 mg of amino body (7a) in THF 30 m
1 and 389 mg of Boc-ON was added thereto and left for 3 days. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (50%).
Dissolve in m1.
0.5N水酸化ナトリウム、水で洗浄し芒硝乾燥後溶媒
を留去する。シリカゲル30gのカラムに付しクロロホ
ルム−メタノール(98:2)にて溶出し340mgの
無色結晶(8a)を得た。融点129−130℃[αコ
ロ+31.9° (C−0,295、クロロホルム)(
−)アミノ体(7b) 406mgをTHF 20a+
1に溶解しこれにBoc−ON 530mgを加え24
時間攪拌する。THFを留去後上記と同様に処理し融点
129−131℃の無色結晶(8b)410mgを得た
。After washing with 0.5N sodium hydroxide and water and drying with sodium sulfate, the solvent was distilled off. It was applied to a column of 30 g of silica gel and eluted with chloroform-methanol (98:2) to obtain 340 mg of colorless crystals (8a). Melting point 129-130℃ [α coro + 31.9° (C-0,295, chloroform) (
-) Amino compound (7b) 406mg in THF 20a+
Dissolve in 1 and add 530mg of Boc-ON to it and add 24
Stir for an hour. After THF was distilled off, the residue was treated in the same manner as above to obtain 410 mg of colorless crystals (8b) with a melting point of 129-131°C.
[α] D−32,5@(C−0,30、クロロホルム
)’ H−NMRは4Bに一致した。[α] D-32,5@(C-0,30, chloroform)' H-NMR was consistent with 4B.
(−) アミノ体(7b) 480111gをTHF
30m1に溶解し、これにLiAlH4500mgを加
えた後2時間加熱還流する。水冷下水2mlを滴下し不
溶物を濾去する。濾液にBoc−ON 540n+gを
加え12時間攪拌する。溶媒を留去し残渣を酢酸エチル
50m1に溶解し0.5N水酸化ナトリウムおよび水で
洗浄し芒硝乾燥する。シリカゲル30gのカラムクロマ
トに付し酢酸エチル−ベンゼン(2:1)で溶出し48
0mgの無色油状物(9b)を得た。(-) Amino form (7b) 480111g in THF
The mixture was dissolved in 30 ml of water, 4500 mg of LiAlH was added thereto, and the mixture was heated under reflux for 2 hours. Add 2 ml of water-cooled sewage dropwise and remove insoluble matter by filtration. Boc-ON 540n+g was added to the filtrate and stirred for 12 hours. The solvent was distilled off, and the residue was dissolved in 50 ml of ethyl acetate, washed with 0.5N sodium hydroxide and water, and dried over Glauber's salt. Column chromatography using 30 g of silica gel and elution with ethyl acetate-benzene (2:1)
0 mg of colorless oil (9b) was obtained.
IQ]D−9,80” (c−2,0、クロロホルム)
’H−NMR(CDCHs) δ11p■ :
1.10(3H,d、J−7Hz)1.44 (9)
1.S)、1.6〜3.0(鵡、2H)3.60 (2
H,AB−q 、J−16Hz) 、 7.30 (5
)1 、5)1−ベンジル体(9b)460mgを5X
Pd−C(水分52 、5!k)800I1gを触媒と
しエタノール20m1中4気圧水素気流下タングステン
ランプ照射し4時間振盪する。IQ] D-9,80" (c-2,0, chloroform)
'H-NMR (CDCHs) δ11p■:
1.10 (3H, d, J-7Hz) 1.44 (9)
1. S), 1.6-3.0 (Parrot, 2H) 3.60 (2
H, AB-q, J-16Hz), 7.30 (5
)1,5) 460 mg of 1-benzyl compound (9b) 5X
Using 800I1g of Pd-C (moisture 52,5!k) as a catalyst, 20ml of ethanol was irradiated with a tungsten lamp under a 4-atmosphere hydrogen stream and shaken for 4 hours.
触媒を濾去し濾液を濃縮乾固し320mgの無色油状物
(10b)を得た。放置すると一部固化する。The catalyst was removed by filtration and the filtrate was concentrated to dryness to obtain 320 mg of colorless oil (10b). If you leave it for a while, it will partially solidify.
ヒドロ−4−オキソキノリン−3−カルボン光ベンジル
体(9bH,04gを接触還元して得られる(−) −
3−(1−第三級ブトキシカルボニルアミノエチル)ピ
ロリジン(10b)および1−エチル−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800Bをトリエチルアミン2ml と
共にアセトニトリル20m1中2時間加熱還流する。Hydro-4-oxoquinoline-3-carboxylic photobenzylic compound (obtained by catalytic reduction of 04 g of 9bH (-) -
3-(1-tert-butoxycarbonylaminoethyl)pyrrolidine (10b) and 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-
3-Carboxylic acid 800B is heated under reflux with 2 ml of triethylamine in 20 ml of acetonitrile for 2 hours.
濃縮して析出する結晶を濾取しエーテルで洗う。The crystals precipitated by concentration are collected by filtration and washed with ether.
これをTF八へ0m1 に加え20分攪拌する。TFA
を留去し水150m1を加えると結晶が析出する。これ
に濃塩酸を加えて溶液とし、クロロホルムで抽出する。Add this to 0ml of TF8 and stir for 20 minutes. T.F.A.
is distilled off and 150 ml of water is added to precipitate crystals. Add concentrated hydrochloric acid to this to make a solution, and extract with chloroform.
水層を100m1に濃縮し水冷下1繋水酸化ナトリウム
液でpH12とし塩酸にてpH7,20とする。クロロ
ホルム抽出し、芒硝乾燥後溶媒を留去する。残漬をエタ
ノールより再結晶し、融点218℃の無色結晶608m
gを得た。The aqueous layer was concentrated to 100 ml, and the mixture was cooled with water and adjusted to pH 12 with sodium hydroxide solution and adjusted to pH 7.20 with hydrochloric acid. After extraction with chloroform and drying with Glauber's salt, the solvent was distilled off. The residue was recrystallized from ethanol to give 608m colorless crystals with a melting point of 218°C.
I got g.
[αlo −221,0@(C−0,428,0,I
N塩酸)元素分析値 C+ah+hNsOs・%H20
として計算値 C57,7515,92N 11.22
分析値 C58,13H5,90N 11.14’)I
−NMR(NaOD) : 1.12(3)1. d、
J−7)1z)、1.44(3H,t、J−7H1)
1.4〜1.7(kl(、m)1.9〜2.2 (
2H,m)、2.7〜2.9 (IH,m)3.4〜4
.0(4Lm)、4.3〜4.6 (2H,m)7.7
2 (IHdd、J−2Hz、15Hz)、 8.
32 (IH,S)ベンジル体(9b)1.10gを
接触還元して得られるピロリジン誘導体(10b)およ
び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
750mgをトリエチルアミン2mlと共にアセトニト
リル20m1中4時間加熱還流すると結晶が析出する。[αlo -221,0@(C-0,428,0,I
N-hydrochloric acid) elemental analysis value C+ah+hNsOs・%H20
Calculated value as C57,7515,92N 11.22
Analysis value C58,13H5,90N 11.14')I
-NMR (NaOD): 1.12 (3) 1. d,
J-7) 1z), 1.44 (3H, t, J-7H1)
1.4-1.7 (kl (, m) 1.9-2.2 (
2H, m), 2.7-2.9 (IH, m) 3.4-4
.. 0 (4Lm), 4.3-4.6 (2H, m) 7.7
2 (IHdd, J-2Hz, 15Hz), 8.
32 (IH,S) Pyrrolidine derivative (10b) obtained by catalytic reduction of 1.10 g of benzylic compound (9b) and 1-cyclopropyl-6,7,8-trifluoro-1
, 750 mg of 4-dihydro-4-oxoquinoline-3-carboxylic acid and 2 ml of triethylamine were heated under reflux in 20 ml of acetonitrile for 4 hours to precipitate crystals.
6後結晶を濾取し、融点233−236℃の黄色針状晶
1.07gを得た。この1.04gをTFA20mlに
加え20分攪拌する。 TFAを留去し水150m1
を加えた後、水冷下2N水酸化ナトリウム液でpH12
とする。塩酸にてpH7,20としクロロホルム抽出す
る。有機層を芒硝乾燥後溶媒を留去する。残渣をエタノ
ール−アンモニア水より再結晶し融点217−229℃
の無色針状晶86Oa+gを得た。After 6 days, the crystals were collected by filtration to obtain 1.07 g of yellow needle-like crystals with a melting point of 233-236°C. Add 1.04 g of this to 20 ml of TFA and stir for 20 minutes. 150ml of water after distilling off TFA
After adding, adjust the pH to 12 with 2N sodium hydroxide solution under water cooling.
shall be. Adjust the pH to 7.20 with hydrochloric acid and extract with chloroform. After drying the organic layer with Glauber's salt, the solvent was distilled off. The residue was recrystallized from ethanol-ammonia water to give a melting point of 217-229°C.
86 Oa+g of colorless needle crystals were obtained.
[α]、−250,Q@ (C−〇、49K、 Q、
IN塩酸)元素分析値C+eHz+FJ30sとして計
算値 C60,47H5,61N 11.13分析値
C60,37H5,69N 11.11’H−NMR(
NaOD): 1.12(3H,d 、y−yox
)、1.0〜1.3(41(、m)、 1.4〜1.7
(1)1劃)、1.9〜2.2 (2H,m)、 2.
7〜2.9 (IH,m)、3.4〜3.9 (2)1
.l11)、3.9〜4.0 (IH,m)、7.65
(IH,dd J−ISHz、2Hz)、 8.4
7(IH,5)7−クロロ−1−(2,4−ジフルオロ
フェニル)−1,4−ジヒドロ−6−フルオロ−4−オ
キソ−1,8−ナフチリジン−3−カルボン酸200m
gにアセトニトリル50m1と3−[1−第三級ブトキ
シカルボニルアミノエチルコピロワジン250mgを加
え、1,5時間速流する。6後、溶媒を減圧留去し、残
漬にエタノール5mlを加えて結晶化させ、濾取し、エ
ーテル洗浄する。[α], -250, Q@ (C-〇, 49K, Q,
IN Hydrochloric acid) Elemental analysis value Calculated value as C+eHz+FJ30s C60,47H5,61N 11.13 Analysis value
C60,37H5,69N 11.11'H-NMR (
NaOD): 1.12 (3H,d,y-yox
), 1.0-1.3 (41 (, m), 1.4-1.7
(1) 1st part), 1.9-2.2 (2H, m), 2.
7-2.9 (IH, m), 3.4-3.9 (2)1
.. l11), 3.9-4.0 (IH, m), 7.65
(IH, dd J-ISHHz, 2Hz), 8.4
7(IH,5)7-chloro-1-(2,4-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid 200m
50 ml of acetonitrile and 250 mg of 3-[1-tert-butoxycarbonylaminoethylcopyrowazine were added to the solution, and the mixture was allowed to flow rapidly for 1.5 hours. After 6 days, the solvent was distilled off under reduced pressure, and 5 ml of ethanol was added to the residue to crystallize it, collected by filtration, and washed with ether.
得られた粗結晶にトリフルオロ酢酸5mlを加え、室温
で10分攪拌して脱Boc化し、溶媒を減圧留去し、残
渣にIN水酸化ナトリウム10m1を加えて溶解後0.
05N塩酸で中和し、析出晶を濾取する。粗結晶を濃ア
ンモニア−エタノールから再結晶し融点213〜214
℃の標記化合物70mgを得た。5 ml of trifluoroacetic acid was added to the obtained crude crystals, stirred at room temperature for 10 minutes to remove Boc, the solvent was distilled off under reduced pressure, 10 ml of IN sodium hydroxide was added to the residue, and after dissolution, 0.0 ml of trifluoroacetic acid was added and stirred at room temperature for 10 minutes to remove Boc.
Neutralize with 05N hydrochloric acid and collect the precipitated crystals by filtration. The crude crystals were recrystallized from concentrated ammonia-ethanol to give a melting point of 213-214.
70 mg of the title compound was obtained at .
元素分析値C□HsJsNa03・%1(20として計
算値: C60,86H6,32N 10.14分析値
: C60,65H5,99N to。07’)I−N
MR(NaOD) : 1.04(3)1.d J−7
)IZ)、1.35〜1.6(1)1.m)、1.8〜
2.1(IH,m)、1.70.(IH,m)、3.0
〜4.0 (4H,m)、7.25 (2H,m)7.
45(IH,m)、7.90(IH,d、J=12)1
z)、8.34 (IH,s)層側4ニア−3−(1−
アミノエチル)−1−ピロサジ1−ベンジル−3−(1
−第三級ブトキシカルボニルアミノエチル)−ピロリジ
ン270mgを54kPd−C500mgを触媒としエ
タノール40m1中還元して得られる脱ベンジル体と8
−クロロ−1−シクロプロピル−6,7−ジフルオロ−
1,4−ジヒドロキノリン−3−カルボン酸150mg
%トリエチルアミン1ml、アセトニトリル20m1と
を混合し12時間加熱還流する。Elemental analysis value C□HsJsNa03・%1 (calculated value as 20: C60,86H6,32N 10.14 analysis value: C60,65H5,99N to.07') I-N
MR (NaOD): 1.04 (3) 1. d J-7
) IZ), 1.35-1.6 (1) 1. m), 1.8~
2.1 (IH, m), 1.70. (IH, m), 3.0
~4.0 (4H, m), 7.25 (2H, m)7.
45 (IH, m), 7.90 (IH, d, J = 12) 1
z), 8.34 (IH, s) layer side 4 near-3-(1-
aminoethyl)-1-pyrosadi-1-benzyl-3-(1
-Tertiary butoxycarbonylaminoethyl)-pyrrolidine (270 mg) is reduced in 40 ml of ethanol using 54 kPd-C (500 mg) as a catalyst.
-chloro-1-cyclopropyl-6,7-difluoro-
1,4-dihydroquinoline-3-carboxylic acid 150mg
% triethylamine and 20 ml of acetonitrile were mixed and heated under reflux for 12 hours.
6後アセトニトリルを減圧?UIiして析出する結晶を
濾取しTF^10m1に溶解する。30分攪拌後減圧濃
縮する。残漬に水20m1を加え2N水酸化ナトリウム
液でpH12とし塩酸でpH7,2とする。クロロホル
ム抽出し、芒硝乾燥後溶媒を留去し、残留物をエタノ−
アンモニア水より再結晶し融点131’eの淡黄結晶5
5IIIgを得た。After 6, reduce the pressure of acetonitrile? The crystals precipitated by UIi are collected by filtration and dissolved in 10 ml of TF. After stirring for 30 minutes, concentrate under reduced pressure. Add 20 ml of water to the residue, adjust the pH to 12 with 2N sodium hydroxide solution, and adjust the pH to 7.2 with hydrochloric acid. After extraction with chloroform and drying of Glauber's salt, the solvent was distilled off and the residue was evaporated with ethanol.
Pale yellow crystals with a melting point of 131'e recrystallized from aqueous ammonia 5
5IIIg was obtained.
元素分析値C+gHztFCHNs03・%H20とし
て計算値: C56,02H5,77N l0J2分析
値: C56,19)15.18 N 10.35
’ H−NMRδ(DMSO−d、) : 1.Q9
(3H,d J−7Hz)、0.8〜1.3(411
,m)、 1.4〜1.8 (IH,m)、1.13〜
2.2(2H,m)、2.8〜2.9 (IH,m)、
3.2〜4.0(4H,m)、4.1〜4.5(IH,
m)、7.118(IH,d J−15Hz)、8.8
7 (LH,s)ヱヱ韮
!−ベンジルー3−(1−第三級ブトキシカルボニルア
ミノエチル)ピロリジン(9b) 410mgを596
Pd−C1,0gを触媒としエタノール50m1中通元
して得られる脱ベンジル体と、8−クロル−1−シクロ
プロピル−6,7−ジフルオロ−4−オキソ−1,4−
ジヒドロキノリン−3−カルボン酸150mg、 トリ
エチルアミン1ml。Elemental analysis value C + gHztFCHNs03・%H20 Calculated value: C56,02H5,77N l0J2 analysis value: C56,19) 15.18 N 10.35
'H-NMRδ (DMSO-d,): 1. Q9
(3H, d J-7Hz), 0.8-1.3 (411
, m), 1.4~1.8 (IH, m), 1.13~
2.2 (2H, m), 2.8-2.9 (IH, m),
3.2-4.0 (4H, m), 4.1-4.5 (IH,
m), 7.118 (IH, d J-15Hz), 8.8
7 (LH,s) ヱヱ韮! -benzy-3-(1-tert-butoxycarbonylaminoethyl)pyrrolidine (9b) 410 mg to 596
The debenzylated product obtained by passing through 50 ml of ethanol using 1.0 g of Pd-C as a catalyst and 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-
150 mg of dihydroquinoline-3-carboxylic acid, 1 ml of triethylamine.
アセトニトリル30m1とを混合し12時間加熱還流す
る。アセトニトリルを減圧留去して残漬をクロロホルム
に溶解する。l鴎りエン酸、水で洗浄し有機層を芒硝乾
燥後、溶媒を留去する。残漬に水20m1を加えIN水
酸化ナトリウムでpH11にした後、塩酸でIH7,2
5とする。クロロホルム抽出しNa25O,乾燥後溶媒
を留去する。エタノールより再結晶し、融点198−2
00℃の無色結晶性粉末118mgを得た。The mixture was mixed with 30 ml of acetonitrile and heated under reflux for 12 hours. Acetonitrile is distilled off under reduced pressure and the residue is dissolved in chloroform. The organic layer was washed with mirabilite acid and water, dried with sodium chloride, and the solvent was distilled off. Add 20ml of water to the residue, adjust the pH to 11 with IN sodium hydroxide, and then adjust to pH 7.2 with hydrochloric acid.
5. After extraction with chloroform, Na25O, and drying, the solvent was distilled off. Recrystallized from ethanol, melting point 198-2
118 mg of colorless crystalline powder at 00°C was obtained.
[α]D−163,7° (c−0,430,0,IN
塩酸)元素分析値 C1eH*+CHFN30s・局8
20として計算値 C56,65H5,50N 10.
43分析値 C56,58H5,59N 10.41’
H−NMR(NaOD) : o、oa 〜1.10(
28,m)、1.16 (3H,d、J−7Hz)、1
.1〜1.35(2H,m)1.5〜1.9(IH,m
) 、2.0〜2.3(2H,m)、2.8〜3.0(
01,m) 、3.4〜3.7(4)1.m)3.7〜
4.0(IH,m) 、4.2〜4.4(II(、[
0)7.82 (1)1.d、J−15H2) 、
8.61 (IH,s)[発明の効果]
本発明によれば、化合物[I]において、置換基Rbま
たはRcの少なくとも一つに低級アルキル基を導入する
ことにより、強力な抗菌活性を維持しながら水溶性を向
上させることができ、腸管吸収性および代謝安定性に優
れた化合物が得られる。[α]D-163,7° (c-0,430,0,IN
Hydrochloric acid) elemental analysis value C1eH*+CHFN30s/station 8
Calculated value as 20 C56, 65H5, 50N 10.
43 analysis value C56, 58H5, 59N 10.41'
H-NMR (NaOD): o, oa ~1.10 (
28, m), 1.16 (3H, d, J-7Hz), 1
.. 1-1.35 (2H, m) 1.5-1.9 (IH, m
), 2.0-2.3 (2H, m), 2.8-3.0 (
01,m), 3.4-3.7(4)1. m) 3.7~
4.0(IH,m), 4.2-4.4(II(,[
0)7.82 (1)1. d, J-15H2),
8.61 (IH,s) [Effects of the Invention] According to the present invention, strong antibacterial activity is maintained by introducing a lower alkyl group into at least one of the substituents Rb or Rc in the compound [I]. At the same time, water solubility can be improved, and a compound with excellent intestinal absorption and metabolic stability can be obtained.
つまり、本発明の化合物は、良好な体内動態を示すこと
が予想され、また毒性も弱く、医薬品として高い有用性
を期待できる。In other words, the compounds of the present invention are expected to exhibit good pharmacokinetics, have low toxicity, and can be expected to be highly useful as pharmaceuticals.
従って、本発明の化合物は、抗菌剤として、例えば人間
およびその他の哺乳動物への、経口、非経口および局所
投与の形態で幅広く使用可能である。すなわち、呼吸器
系、協尿器系、腸管等の各種感染症の治療に適しており
、気管支炎、腎炎、膀胱炎、前立腺炎、尿道炎等のほか
、肺炎の如き下気道感染症に対しては特に優れた効果h
≧期待できる。Accordingly, the compounds of the present invention can be widely used as antibacterial agents, for example in the form of oral, parenteral and topical administration to humans and other mammals. In other words, it is suitable for treating various infections of the respiratory system, urinary system, intestinal tract, etc., and is effective against lower respiratory tract infections such as pneumonia, as well as bronchitis, nephritis, cystitis, prostatitis, urethritis, etc. It has a particularly good effect
≧You can expect it.
投与量としては、成人−日当り50mg〜2g、通常は
100〜800mgを1回乃至3回に分けて経口投与す
ればよい。また、非経口投与することもでき、例えば成
人−回当り50〜150mgを点滴静注する方法、ある
いは坐剤、軟膏、クリーム剤、点眼剤等として外用する
こともできる。The dosage for adults is 50 mg to 2 g per day, usually 100 to 800 mg, administered orally in 1 to 3 divided doses. It can also be administered parenterally, for example, by intravenous infusion of 50 to 150 mg per dose for adults, or externally as suppositories, ointments, creams, eye drops, etc.
製剤としては、賦形剤、崩壊剤、溶解補助剤、安定化剤
等を適宜用いて、錠剤、カプセル剤、散剤、顆粒剤、シ
ロップ剤のばか注射剤等を製造することがで担る0例え
ば、本発明化合物100mgに対し、コーンスターチ2
3mg、CMC−Na 22.5mg、ヒドロキシプロ
ピルセルロース3B、ステアリン酸マグネシウム1.5
mgとなるように混合してカプセル剤とすることができ
る。As for formulations, it is possible to manufacture tablets, capsules, powders, granules, syrups, and other injections by appropriately using excipients, disintegrants, solubilizing agents, stabilizers, etc. For example, for 100 mg of the compound of the present invention, 2
3mg, CMC-Na 22.5mg, hydroxypropyl cellulose 3B, magnesium stearate 1.5
It can be mixed to make a capsule.
本発明の化合物の毒性は弱く、例えば実施例1の化合物
200mgを5匹のマウスに静注したところ死亡するも
のはなく、1.0.0は2QQl1g以上と考えられる
。The toxicity of the compound of the present invention is weak; for example, when 200 mg of the compound of Example 1 was intravenously injected into 5 mice, none of them died, and 1.0.0 is considered to be more than 1 g of 2QQl.
次に本発明化合物の代表例について、抗菌活性(MIC
μg/ml)を記す。Next, we will discuss the antibacterial activity (MIC) of representative examples of the compounds of the present invention.
μg/ml).
Claims (1)
キルを、Rcは低級アルキルを意味する。またRbはR
aまたはRcと(CH_2)_nで表わされるメチレン
鎖(nは2〜5)を形成してもよい。Rdはエチル、2
−フルオロエチル、ビニル、イソプロピル、イソプロペ
ニル、シクロプロピル、モノフルオロフェニルまたはジ
フルオロフェニルを意味する。QはCH、C−F、C−
Cl又はNである)で表わされる化合物およびその塩 (2)一般式[ I ]において、Raが水素またはメチ
ル、Rbが水素またはメチル、Rcがメチルまたはエチ
ル、Rdがエチルまたはシクロプロピル、4−フルオロ
フェニル、2,4−ジフルオロフェニル、QがCHまた
はNである特許請求の範囲第1項記載の化合物 (3)一般式[ I ]において、RaおよびRbが水素
、Rcがメチルまたはエチル、Rdがエチルまたはシク
ロプロピル、QがC−Fである特許請求の範囲第1項記
載の化合物 (4)一般式[ I ]で表わされる化合物が、光学活性
体である特許請求の範囲第1項記載の化合物(5)光学
活性体が左旋性である特許請求の範囲第4項記載の化合
物 (6)特許請求の範囲第1項記載の化合物を有効成分と
する感染症治療剤[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ I (In the formula, Ra and Rb each mean hydrogen or lower alkyl, Rc means lower alkyl, and Rb means R
a or Rc may form a methylene chain represented by (CH_2)_n (n is 2 to 5). Rd is ethyl, 2
- means fluoroethyl, vinyl, isopropyl, isopropenyl, cyclopropyl, monofluorophenyl or difluorophenyl. Q is CH, C-F, C-
Cl or N) and its salts (2) In the general formula [I], Ra is hydrogen or methyl, Rb is hydrogen or methyl, Rc is methyl or ethyl, Rd is ethyl or cyclopropyl, 4- Fluorophenyl, 2,4-difluorophenyl, the compound (3) according to claim 1, wherein Q is CH or N. In the general formula [I], Ra and Rb are hydrogen, Rc is methyl or ethyl, Rd Compound (4) according to claim 1, wherein is ethyl or cyclopropyl, and Q is C-F Claim 1, wherein the compound represented by general formula [I] is an optically active compound Compound (5) Compound (6) according to Claim 4, in which the optically active form is levorotatory A therapeutic agent for infectious diseases containing the compound according to Claim 1 as an active ingredient
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP61311992A JPH0723369B2 (en) | 1986-12-27 | 1986-12-27 | Pyridonecarboxylic acid derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP61311992A JPH0723369B2 (en) | 1986-12-27 | 1986-12-27 | Pyridonecarboxylic acid derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS63166876A true JPS63166876A (en) | 1988-07-11 |
JPH0723369B2 JPH0723369B2 (en) | 1995-03-15 |
Family
ID=18023898
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP61311992A Expired - Lifetime JPH0723369B2 (en) | 1986-12-27 | 1986-12-27 | Pyridonecarboxylic acid derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0723369B2 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0550019A2 (en) * | 1991-12-31 | 1993-07-07 | Korea Research Institute Of Chemical Technology | Novel quinolone carboxylic acid derivatives and processes for preparing same |
US5278317A (en) * | 1990-11-30 | 1994-01-11 | Warner-Lambert Company | Optically pure R-enantiomer of alpha,alpha-dilower alkyl-pyrrolidine-3-methane amines |
US5364861A (en) * | 1990-11-30 | 1994-11-15 | Warner-Lambert Company | Optical isomers of 7-[3-(1,1-dialkylmethyl-1-amino-1-pyrrolidinyl]-quinolones and naphthyridones as antibacterial agents |
US5461165A (en) * | 1990-11-30 | 1995-10-24 | Warner-Lambert Company | Individual stereoisomers of intermediates of 7-[3-(1-aminoalkyl)-1-pyrrolidinyl]-quinolones and naphthyridones as antibacterial agents |
WO2000053594A1 (en) * | 1999-03-10 | 2000-09-14 | Daiichi Pharmaceutical Co., Ltd. | Aminomethylpyrrolidine derivatives having aromatic substituents |
US7514451B2 (en) | 2003-09-10 | 2009-04-07 | Kyorin Pharmaceutical Co., Ltd. | 7-(4-Substituted-3-cyclopropylaminomethyl-1 pyrrolidinyl) quinolonecarboxylic acid derivative |
-
1986
- 1986-12-27 JP JP61311992A patent/JPH0723369B2/en not_active Expired - Lifetime
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5278317A (en) * | 1990-11-30 | 1994-01-11 | Warner-Lambert Company | Optically pure R-enantiomer of alpha,alpha-dilower alkyl-pyrrolidine-3-methane amines |
US5364861A (en) * | 1990-11-30 | 1994-11-15 | Warner-Lambert Company | Optical isomers of 7-[3-(1,1-dialkylmethyl-1-amino-1-pyrrolidinyl]-quinolones and naphthyridones as antibacterial agents |
US5461165A (en) * | 1990-11-30 | 1995-10-24 | Warner-Lambert Company | Individual stereoisomers of intermediates of 7-[3-(1-aminoalkyl)-1-pyrrolidinyl]-quinolones and naphthyridones as antibacterial agents |
US5563155A (en) * | 1990-11-30 | 1996-10-08 | Warner-Lambert Company | Individual stereosiomers of 7-[3-(aminoalkyl)-1-pyrrolidinyl]-quinolones and naphthyridones as antibacterial agents |
US5633264A (en) * | 1990-11-30 | 1997-05-27 | Warner-Lambert Company | Individual stereoisomers of 7-[3-(1-aminoalkyl)-1-pyrrolidinyl]-Quinolones and naphthyridones as antibacterial agents |
EP0550019A2 (en) * | 1991-12-31 | 1993-07-07 | Korea Research Institute Of Chemical Technology | Novel quinolone carboxylic acid derivatives and processes for preparing same |
EP0550019A3 (en) * | 1991-12-31 | 1993-09-01 | Korea Research Institute Of Chemical Technology | Novel quinolone carboxylic acid derivatives and processes for preparing same |
WO2000053594A1 (en) * | 1999-03-10 | 2000-09-14 | Daiichi Pharmaceutical Co., Ltd. | Aminomethylpyrrolidine derivatives having aromatic substituents |
US6762181B1 (en) | 1999-03-10 | 2004-07-13 | Daiichi Pharmaceutical Co., Ltd. | Aminomethylpyrrolidine derivatives having aromatic substituents |
US7186843B2 (en) | 1999-03-10 | 2007-03-06 | Daiichi Pharmaceutical Co. Ltd. | Aminomethylpyrrolidine derivatives having aromatic substituents |
US7514451B2 (en) | 2003-09-10 | 2009-04-07 | Kyorin Pharmaceutical Co., Ltd. | 7-(4-Substituted-3-cyclopropylaminomethyl-1 pyrrolidinyl) quinolonecarboxylic acid derivative |
Also Published As
Publication number | Publication date |
---|---|
JPH0723369B2 (en) | 1995-03-15 |
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